BENNETT, MAXWELL Virginia Woolf and Neuropsychiatry PDF

Virginia Woolf and Neuropsychiatry
Maxwell Bennett
Virginia Woolf
and Neuropsychiatry
Maxwell Bennett
Brain and Mind Research Institute
Camperdown, NSW, Australia
ISBN 978-94-007-5747-9 ISBN 978-94-007-5748-6 (eBook)

DOI 10.1007/978-94-007-5748-6
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For
Peter Hacker
Also by M.R. Bennett
Autonomic Neuromuscular Transmission
Optimizing Research and Development
Idea of Consciousness
History of the Synapse
Philosophical Foundations of Neuroscience
(with P.M.S. Hacker)
Neuroscience and Philosophy
(with D. Dennett, P.M.S. Hacker & J. Searle)
History of Cognitive Neuroscience
(with P.M.S. Hacker)
Cover image: Adeline Virginia Stephen, known from birth as Virginia, Ginny or Ginia to her family.
An undated photograph from the album of her half-sister, Stella Duckworth. Copyright with Henry W. and
Albert A. Berg Collection of English and American Literature, The New York Public Library, Astor, Lenox and Tilden Foundations.
Preface
Virginia Woolf, perhaps the greatest narrative writer in English of the twentieth
century, had a tragic life. Her suicide at 59, in 1941 during the Second World War,
was the final act in a series of earlier attempts against a background of sexual abuse
and the loss of members of her loving family. This final act had its additional stress
engendered by the extraordinary circumstances that Britain faced in the years just
prior to her death, with the bombing of her home in London and of the flights of
German raider aircraft close to her country residence near the coast. Because of her
literary genius, we find in her novels, plays, critical reviews, autobiographical
sketches and diaries an unparalleled insight into the mind of someone destined to
end their life. These offer those concerned with mitigating the incidence of suicide a
unique opportunity to consider the circumstances and familial burdens that promote
severe depression and so design programs that will ameliorate them.
The essays brought together in this work are an attempt to begin this process of
understanding and are grouped into three parts. The first of these is concerned with
those aspects of Virginia Woolf’s life that are pertinent to her depression, and how
this was treated by the leading psychiatrists in Britain in the first half of the twenti-
eth century, including King Edward’s psychiatrist Sir Maurice Craig as well as
Sigmund Freud. These lead to the major essay in Part I that outlines how we now
view the significant factors leading to depression and suicide from a contemporary
neuropsychiatric perspective, particularly in the circumstances of early childhood
abuse. This also provides an introduction to the following neuropsychiatric presen-
tations in Part II. All four essays in the first part should be of interest to the general
reader. They have been written in a style which I hope will promote understanding
of the issues involved, and what needs to be done to gain further insights into the
maladies of concern.
Part II provides a neuropsychiatric analysis of the state of present knowledge
concerning what goes awry in the functioning of the brain in depression, particularly
that leading to suicide. The five essays here are meant for the cognoscenti in neuro-
psychiatry, but I hope that the general reader, by dipping into them, might gain some
appreciation of how far we have probed brain functions related to major psychiatric
problems. The first two essays are on identifying networks coupling different parts
ix
x Preface
of the brain that have now been shown to have abnormal function in depression.
Particular emphasis is placed on how this might arise as a consequence of childhood
abuse and of later-life stress and anxiety. The next two essays are concerned with
the action of drugs that might help restore normal function in the brain networks,
such as the anti-depressant Prozac, and a new class of drugs that hold out hope of
militating against the circuit changes that are very likely to occur following child-
hood abuse. Virginia Woolf suffered from psychosis, with auditory hallucinations,
throughout her life. The final essay in this Part II considers these and the likely brain
networks involved as well as what might be done to correct their functioning.
This emphasis on brain networks and their constituent neurons and connections,
the subject matter of neuropsychiatry, might lead the general reader to think that
patients are to be considered as complicated machines, as automotons. Such an
attitude obviously debases what it means to be human, a particularly unfortunate
attitude towards those suffering from depression so severe that suicide is contem-
plated or acted on. The essay in the final Part III shows that the mechanistic study of
brain function in relation to mental illness does not logically lead to this perspective.
The concept of ‘mind’, that which goes awry in mental illness, has undergone many
transformations since it was first used by Plato. Virginia Woolf, famous together
with William James, for emphasizing the ‘stream of consciousness’ in her work,
had a particular view of the mind and of consciousness that harks back to Descartes.
This final essay shows that the views of both Plato and Descartes on mind and
consciousness lead to an illogical and degenerate view of what it means to be human.
It is to Aristotle that we must turn if we are to restore dignity to what it means to be
human while pursuing neuropsychiatry.
It might surprise the reader that these essays were inspired by Sigmund Freud.
I asked myself, if Freud were alive today what would he do with his life? Unequivocally,
my answer was that he would be a neuropsychiatrist. Freud began his creative life as
a neurophysiologist, during which time he showed prodigious powers of experimen-
tal observation and technical ability. He was one of the first to recognise neurons as
individual cells as well as to study the actions of cocaine, subsequently shown to be
a local anaesthetic. He was unable to find suitable stable employment as an academic
in the new field of neurophysiology, following these great discoveries, and so became
a general practitioner, during which time he began to see patients suffering from
hysteria. So began the development of psychoanalysis for which he is known today,
and which is briefly described in Part I. Of considerable surprise here is that Freud’s
early Seduction Theory rested on a frequency of childhood sexual abuse that was
unacceptable and regarded by his contemporaries as scandalous, leading to his aban-
doning it. We now know, as indicated at the end of this part, that the occasions of
childhood sexual abuse are indeed high, and that they have terrible consequences for
the future life of the child, as Freud would have probably predicted.
Nevertheless, Freud never left the attempt to relate the maladies of mental life
that he observed in his patients to changes in the neurons and the networks they
form in the brain. He realized that this attempt was virtually hopeless, given the
state of ignorance of the neural networks of the brain during his lifetime, but never-
theless he felt driven to make an attempt. Contemporary neuropsychiatry embodies
Preface xi
this attitude, but now, as the essays in this work show in Part II, we have the tools to
make significant contributions in defining what has gone awry in brain networks
that give rise to the mental conditions which Freud identified in his patients and for
which he strove unsuccessfully to find a neural basis. I like to think that the neural
networks underling major mood disorders provided in Part II bring Freud’s sketches
up to date.
Finally, Freud has been something of an inspiration in relation to the last Part,
given over to consideration of spirit, soul and mind in the work of Virginia Woolf.
There are many photographs of Freud’s famous studies and consulting rooms where
he met his patients, including Virginia Woolf in London. These photographs show
Egyptian artefacts dating back to the third millennium BCE on his desk and on
display shelves. At this time the Egyptians were the first to envisage the concept of
a ‘soul’, one they elaborated on in sophisticated detail that laid the foundations for all
further considerations of the spiritual. It was then natural that Freud, given his pre-
occupation with the mind, should surround himself with such sculptures. I have made
an attempt in the last chapter to consider ‘spirit’, ‘soul’ and ‘mind’ in an historical
and philosophical context, including that of Virginia Woolf’s work as representative
of contemporary views on this subject. For without clarity as to what we mean by
‘mind’ how can neuropsychiatry contribute in significant ways to the amelioration
of ‘mental illness’?
Brain and Mind Research Institute M.R. Bennett

University of Sydney
Note to the Reader
These essays are divided into three Parts as mentioned in the Preface, of which the
first and last should be immediately accessible to the general reader. The middle Part
is largely for the neuropsychiatric cognoscenti. I have therefore provided extensive
notes at the ends of the essays in the first and last Parts so as to allow the general
reader the opportunity of delving deeper into the subject matter if they should be so
inclined. These notes also give references to the material that supports the various
claims made. The collection of essays in the middle Part are presented in a more
formal academic style, with references provided to all the claims made as to the
function of brain networks. This is the case, except for essay 8 in which I have
retained the note style of the earlier essays. This has been done in order to promote an
understanding amongst the general readers of the great promise that the approaches
outlined there have for ameliorating the suffering of those, like Virginia Woolf, that
have experienced childhood abuse.
xiii
Contents
Part I Introduction
1 Sexual Abuse, Literary Genius and a Mind Gone Awry ..................... 3

References ................................................................................................. 8
2 The Development of Early 20th Century
Psychiatry and Its Failure ...................................................................... 9
Introduction ............................................................................................... 9
Notes ......................................................................................................... 16
References ................................................................................................. 17
3 Freud, the Subconscious and Virginia Woolf ....................................... 19
Notes ......................................................................................................... 29
References ................................................................................................. 29
4 Virginia Woolf’s Suicide ......................................................................... 31
Stress ......................................................................................................... 35
Anxiety...................................................................................................... 39
Depression................................................................................................. 39
Childhood Abuse: Stress, Depression and Suicide in Later in Life .......... 41
Notes ......................................................................................................... 45
References ................................................................................................. 59
Part II Neuropsychiatry and Suicide
5 Brain Networks, Hormones and Genes

Implicated in Depression ........................................................................ 67
Introduction: The Prefrontal–Limbic Network
(PLN) in Depression ................................................................................. 67
Hypothalamic-Pituitary–Adrenal (HPA) Axis
Modulation of PLN in Depression ....................................................... 69
xv
xvi Contents
Basal Ganglia Modulation of PLN....................................................... 69

Midbrain Modulation of PLN .............................................................. 70
Modulation of the PLN by the Hypothalamus in Depression ................... 70
Glucocorticoid Modulation of the PLN ............................................... 70
Epigenetics and Depression ................................................................. 73
Conclusion............................................................................................ 80
Modulation of the PLN by the Basal Ganglia in Depression.................... 81
The PLN–Basal Ganglia Loop ............................................................. 81
The Habit-Learning Basal Ganglia Networks ...................................... 85
Conclusion............................................................................................ 86
Modulation of the PLN by the Midbrain in Depression ........................... 87
The PLN-Midbrain Loop ..................................................................... 88
The PLN–Ventral Tegmentum Loop .................................................... 91
The PLN–Raphe Nucleus Loop ........................................................... 93
Conclusion............................................................................................ 95
The PLN and Depression .......................................................................... 96
References ................................................................................................. 96
6 The Pathology of Synapses in Brain Networks
Implicated in Depression ........................................................................ 107
Introduction ............................................................................................... 107
The Volume Fraction of Human Cortical Grey Matter
Occupied by Different Cellular Constituents ............................................ 108
The Core Pathology of Synapse Regression
in the Cortical Grey Matter of Stressed Animals ...................................... 115
Anterior Cingulate Cortex .................................................................... 116
Orbitofrontal Cortex ............................................................................. 117
Prefrontal Cortex .................................................................................. 117
Hippocampus........................................................................................ 117
The Effects of Synapse Regression on the Cellular
Constituents of Cortical Grey Matter in Animals ..................................... 119
Changes in Grey Matter and Its Cellular Constituents
in Major Depressive Disorder ................................................................... 120
Anterior Cingulate Cortex .................................................................... 120
Orbitofrontal Cortex ............................................................................. 121
Hippocampus........................................................................................ 121
Prefrontal Cortex .................................................................................. 122
Conclusion ................................................................................................ 122
The Cellular Constituents of Human Cortical Grey Matter ................. 122
The Cellular Basis for the Loss of Grey Matter
in Major Depressive Disorder (MDD) ................................................. 124
References ................................................................................................. 124
7 On the Mechanism of Action of an Anti-depressant............................ 133
Synaptic Connections of the Anterior Cingulate
Cortex and the Amygdala ......................................................................... 133
Contents xvii
Changes in Synaptic Connections of the Anterior Cingulate

Cortex and the Amygdala in Depression .................................................. 135
Cortex and the Amygdala of Depressed Patients Following
Serotonergic Uptake Blockers .................................................................. 137
The Mechanism by Which Changes in Serotonin Transporters
Bring About Changes in Synaptic Activity in Anterior Cingulate
Cortex and Amygdala 5-HT Receptor Distributions on Neurons
and Their Interaction with NMDA Receptors........................................... 137
The Mechanism by Which Changes in Serotonin Transporter
Genes Alter the Level of Excitability in Anterior Cingulate
Cortex and Amygdala ............................................................................... 138
The Mechanism by Which Serotonin Transporter Antagonists
Alter the Level of Excitability in Anterior Cingulate
Cortex and Amygdala ............................................................................... 139
Conclusion ................................................................................................ 141
References ................................................................................................. 141
8 On the Identification of Drugs Modulating Epigenetic
Mechanisms in Depression ..................................................................... 145
Introduction: A Proposal for the Most Efficacious
Course to Lower Rates of Suicide............................................................. 145
Childhood Abuse: Stress, Depression
and Suicide in Later in Life ...................................................................... 146
Interventions Preventing Suicide Arising from Childhood....................... 147
Gray Matter Changes in the Cortex Following
Child Sexual and Physical Abuse ............................................................. 147
Behavioural Therapies for Sexually Abused Children.............................. 148
Cognitive Behavioural Therapy (CBT) ................................................ 148
Trauma-Focused Cognitive Behavioural Therapy (TF-CBT) .............. 148
Child Centred Therapy (CCT) ............................................................. 149
Childhood Abuse, Depression, Suicide and Epigenetic Drugs ................. 149
Identification of Epigenetic Drugs for Mood Disorders:
The HDAC Inhibitors ................................................................................ 150
Epigenetic Drugs and Suicide Prevention ................................................. 151
What Remains to be Done ........................................................................ 151
Notes ......................................................................................................... 152
References ................................................................................................. 160
9 Brain Networks in Psychosis .................................................................. 165
Introduction ............................................................................................... 165
Consciousness ........................................................................................... 166
Perceptual Consciousness ......................................................................... 167
Awareness and Perception .................................................................... 167
Attention and Perception ...................................................................... 168
xviii Contents
Visual and Auditory Illusions ................................................................... 169

Visual Illusions.......................................................................................... 169
Kanisza Illusions .................................................................................. 170
McCullough Illusions ........................................................................... 170
Movement Illusions .............................................................................. 170
Synaesthesia ......................................................................................... 171
Binocular Rivalry ................................................................................. 172
Auditory Illusions ..................................................................................... 172
Continuity Illusion ............................................................................... 174
Auditory Illusions and Mismatch Negativity ....................................... 174
Summary .............................................................................................. 175
Visual Hallucinations ................................................................................ 175
Claude Bonnet Hallucinations.............................................................. 175
Auditory Hallucinations ............................................................................ 176
Types of Auditory Hallucinations ........................................................ 176
Auditory Hallucinations in Psychosis .................................................. 177
Summary .............................................................................................. 177
Deafferentation Hypothesis for Visual
and Auditory Hallucinations ..................................................................... 177
Deafferentation of Visual Centres ........................................................ 178
Deafferentation of Auditory Centres .................................................... 178
Summary .............................................................................................. 179
Determination of the Brain Areas Involved in ‘Attention’........................ 179
Visual Attention ................................................................................... 179
Auditory Attention ............................................................................... 180
Summary .............................................................................................. 182
Determination of Brain Areas Involved in Awareness .............................. 182
Visual Awareness ................................................................................. 182
Auditory Awareness ............................................................................. 184
Summary .............................................................................................. 186
Conclusion: Attention and Awareness in a Psychosis............................... 186
References ................................................................................................. 187
Part III On Mental Illness
10 The Mind, Mental Illness and the Stream of Consciousness .............. 193
Notes ......................................................................................................... 201
References ................................................................................................. 209
Index ................................................................................................................. 211

Part I
Introduction
This Part I first includes a description of Virginia Woolf’s life from the point of view
of psychiatry (Chap. 1), and then goes on to describe how the leading psychiatrists
of the day in early twentieth century England treated her malaises (Chap. 2). As
Sigmund Freud was first introduced to England through publication of his works by
the Hogarth Press that Virginia and her husband Leonard Woolf founded, and as she
consulted him towards the end of her life, special emphasis is given to Freud in
Chap. 3. This Part I concludes with an introduction to how twenty-first century
neuropsychiatry considers depression, especially that arising largely from child-
hood abuse, as a disease of the brain.
Chapter 1
Sexual Abuse, Literary Genius
and a Mind Gone Awry
Virginia Woolf: The Interleaving of Literary
Precociousness and Major Depression
Nowhere do we have a more detailed and powerfully moving record of repeated

episodes of decline into and recovery from mental illness than that in the life of
Virginia Woolf, perhaps the finest narrative writer in English in the twentieth century
(Fig. 1.1). Her diaries and letters provide an unparalleled insight into experiences
spanning nearly 50 years, if the cottage industry of interpretations of her novels in
terms of events and experiences in her own life are set aside. A short account of that
life is given here as a prelude to considering which of the various opposed revolu-
tions in psychiatry at the beginning of the twentieth century had anything to offer to
militate against her suffering.
Virginia Woolf was sexually abused by her half-brothers as a child and adoles-
cent. When she was 38 in 1920 she gave a talk to the Memoir Club, which had been
established by Freudians, with the title ‘22 Hyde Park Gate’, the address of the
house she resided in as a child. In this disturbing talk she described how George
Duckworth, her half-brother, came to her bedroom at night and committed various
‘malefactions’ over a period lasting from childhood to late adolescence. These expe-
riences ‘had spoilt her life for her before it had fairly begun’ (DeSalvo 1989, pp. 3,
5, 100, 121). Virginia had her first bout of major depressive illness during this
period of sexual abuse, precipitated by the stress brought on by her mother Julia
Stephen’s death when Virginia was 13 in 1895 (Fig. 1.2). Two years later, when she
was 15 and the sexual abuse came to an end, her half sister died after running the
Stephen’s household since Julia’s death. This engendered another period of severe
stress, which surprisingly she managed to survive without a breakdown. But that
was only deferred for at 22, after her father’s death from stomach cancer in 1904,
she tried to commit suicide by jumping out of a window and was briefly institution-
alized (Fig. 1.3a).
Some 6 years later, in 1910, Virginia broke down again following the death of her
brother Thoby Stephen from typhoid. He was only 26. The sense of the loss of
Thoby was heightened by the fact that both of them had contracted typhoid after
visiting Greece but she alone recovered and bore the guilt of survival. After the
death of her father and brother she worked intensely on her first novel, The Voyage
Out, in a concentrated effort to put behind her the loss of these loved ones. But this
M. Bennett, Virginia Woolf and Neuropsychiatry, DOI 10.1007/978-94-007-5748-6_1, 3

4 1 Sexual Abuse, Literary Genius and a Mind Gone Awry
Fig. 1.1 Portrait of Virginia

Woolf by George Charles
Beresford, 1902, © Hulton-Deutsch
Collection/CORBIS
did not succeed in relieving the stress that precipitated her third breakdown. This
necessitated her rest in the Twickenham asylum in the summer of 1910, during
which time she seemed to have made a complete recovery. Her sister Vanessa’s
husband, Clive Bell, commented on visiting Virginia that his formerly suicidal
sister-in-law seemed ‘transformed .. suddenly life, which she had found drab and
dreary, had become thrilling and precious .. everything seemed exciting or amusing ..
and all the trivial things that made up that existence had significance too. The magi-
cian had cast her spell’ (Woolf and Bell 1977, vol 1, p. 164).
That spell was not to last for Virginia suffered a fourth breakdown 3 years later when
she was 31, shortly after her marriage to Leonard Woolf and the completion of her
novel The Voyage Out. Her convalescence back to health, now with the loving sup-
port of Leonard, took an extended period, from 1913 to 1915. It might be anticipated
that her marriage to Leonard Woolf precipitated, at least in part, her fourth breakdown,
but that is very unlikely. Leonard played a principal role in maintaining her stability
during the years of her greatest creativity, helping her to ward off deep depression, and
so allowing her full expression of her extraordinary narrative gifts (Fig. 1.3b).
Nevertheless, periods of depression that did not lead to breakdowns were still
experienced, although frequently analysed and used to support her literary work.
She comments in 1924 at 42, writing critically about the Stephens, their ‘cold
fingers, so fastidious, so critical, such taste’, she adds: ‘My madness has saved me’
1 Sexual Abuse, Literary Genius and a Mind Gone Awry 5
Fig. 1.2 Portrait of Julia

Jackson, Virginia Woolf’s
mother, by Julia Margaret
Cameron, 1867. © SSPL/National
Media Museum/Getty Images
(Nicolson and Banks 1975, vol. 3, p. 92). In 1930 she wrote in her Diary ‘I believe
these illnesses are in my case--how shall I express it?--partly mystical’ (Woolf and
Bell 1977, Diary 3, p. 287). Her essay, ‘On Being Ill’ described the ‘astonishing’
spiritual changes she experienced. ‘Undiscovered countries’ are revealed ‘when the
lights of health go down’. Only a ‘lion tamer’ would have the strength ‘to look these
things squarely in the face’. ‘There is a virgin forest in each’ (Woolf 1947, p. 10).
She describes two mildly depressed episodes in her diary as follows:
‘Here is a whole nervous breakdown in miniature. We came on Tuesday. Sank into a chair,
could scarcely rise; everything insipid; tasteless, colourless. Enormous desire to rest …
avoided speech; could not read. Thought of my own power of writing with veneration, as of
something incredible, belonging to someone else; never again to be enjoyed by me. Mind a
blank. Slept in my chair. Thursday. No pleasure in life whatsoever; but it felt perhaps more
attuned to existence. Character and idiosyncrasy as Virginia Woolf completely sunk out.
Humble and modest. Difficulty in thinking what to say.’
Virginia writes further:

‘Considering how common illness is, how tremendous the spiritual change that it brings,
how astonishing, when the lights of health go down, the undiscovered countries that are
then disclosed, what wastes and deserts of the soul a slight attack of influenza brings to
light…it becomes strange indeed that illness has not taken its place with love, battle, and
jealousy among the prime themes of literature. Novels, one would have thought, would
have been devoted to influenza; epic poems to typhoid; odes to pneumonia, lyrics to tooth-
ache. But no; … literature does its best to maintain that its concern is with the mind; that the
Fig. 1.3 (a) Virginia Woolf with her father, Sir Leslie Stephen, circa 1900, © Hulton-Deutsch Collection/
CORBIS. (b) Virginia and Leonard Woolf. © English School/The Bridgeman Art Library/Getty Images
1 Sexual Abuse, Literary Genius and a Mind Gone Awry 7
body is a sheet of plain glass through which the soul looks straight and clear’ (Woolf and
Bell 1977, Diary 3, p. 103).
She sometimes pictures herself as the neurotic writer:

‘And I haven’t said anything very much, or given you any notion of the terrific high waves,
and the infernal deep gulfs, on which I mount and toss in a few days ….and I’m half
ashamed, now I try to write it, to see what pigmy egotisms are at the root of it, with me
anyhow’ (Nicolson and Banks 1975, 3, p. 174).
When mildly manic, she felt energized and creative, and invention came easily to
her:
‘my body was flooded with rapture and my brain with ideas. I wrote rapidly till 12’; ‘I’ve
had some very curious visions in this room too, lying in bed, mad, and seeing the sunlight
quivering like gold water, on the wall. I’ve heard the voices of the dead here. And felt,
through it all, exquisitely happy’ (Woolf and Bell 1977, Diary 1, p. 310).
And in a diary entry in 1928 she comments:

‘ …such an exaggerated tiredness; such anguishes and despairs; and heavenly relief and
rest; and then misery again. Never was anyone so tossed up and down by the body as I am,
I think’ (Woolf and Bell 1977, Diary 2, p. 1310).
In late middle age (45–59) Virginia published her three great novels, ‘The
Waves’ (at 49), ‘Flesh’ (at 41), ‘The Years’ (at 55), as well as a biography of Roger
Fry (at 58) and a play ‘Between the Acts’ (at 59). Although these years had moments
of exhilaration the deepening signs of a sustained descent into major depression are
apparent, leading to her suicide. The occasional euphoric state is indicated when she
associates illness with her artistic capabilities:
‘and these curious intervals in life – I’ve had many … are the most fruitful artistically – one
becomes fertilized – think of my madness at Hogarth – and all the little illnesses, that before
I wrote the Lighthouse’. ‘Six weeks in bed now would make a masterpiece of Moths’
(Woolf and Bell 1977, Diary 3, p. 254).
However thoughts about suicide were frequent in the last decade of her life. On the
30th October 1930 she wrote, in correspondence with the composer Ethel Smyth:
‘By the way, what are the arguments against suicide? You know what a flibberti-gibbet I
am: well there suddenly comes in a thunder-clap a sense of the complete uselessness of my
life. It’s like suddenly running one’s head against a wall at the end of a blind alley. Now
what are the arguments against that sense – “Oh it would be better to end it”? I need not say
that I have no sort of intention of taking any steps: I simply want to know.....what are the
arguments against it?’ (Nicolson and Banks 1975, p. 143).
Six months later, on the 29th March 1931, she returns to the subject:
‘Why did I feel violent after the party? It would be amusing to see how far you can make
out, with your insight, the various states of mind which led me, on coming home, to say to
L: – “If you weren’t here, I should kill myself – so much do I suffer.”’
She wrote to Beatrice Webb on the 8th April, after hearing her commenting on
suicide:
‘I wanted to tell you but was too shy, how much I was pleased by your views upon the
possible justification of suicide. Having made the attempt myself, from the best of motives
as I thought – not to be a burden on my husband – the conventional accusation of cowardice

and sin has always rather rankled’ (Woolf and Strachey 1956, 4, p. 63).
She goes on in relation to thoughts on suicide that:

‘[It’s] a physical feeling as if I were drumming slightly in the veins: very cold; impotent:
and terrified. As if I were exposed on a high ledge in full light….And I am powerless to
ward it off; I have no protection. And this anxiety and nothingness surround me with a
vacuum’ (Woolf and Strachey 1956, 4, p. 63).
Signs of ‘serious mental disturbances’ were identified by Leonard Woolf at

least a year before she committed suicide. This might have been precipitated by her
autobiographical writing in 1939, for in ‘A Sketch of the Past’, she went deeper and
further back. She then attempted to ‘autoanalyse’ herself, as she called it. This
involved a form of searching for the underlying causes of her condition through the
act of intense concentration on writing. Revising a draft of ‘Between the Acts’ on
the 25th January 1940, her birthday, the first of which had been completed during
the previous November, she commented on how much she had enjoyed writing the
book, ‘I am a little triumphant about the book…I’ve enjoyed writing almost every
page.’ As the last episode of depression grew she became convinced that her book
was worthless. Dr Wilberforce, her local doctor, recounts that on considering what
were to be her last short stories she recounted being ‘desperate – depressed to the
lowest depths.’ A year later she was dead.
References
Desalvo LA (1989) Virginia Woolf: the impact of childhood sexual abuse on her life and work.
Beacon, Boston
Nicolson N, Banks JT (eds) (1975) The letters of Virginia Woolf. Hogarth Press, London
Woolf V (1947) The moment: and other essays. Hogarth, London
Woolf L, Strachey L (eds) (1956) Virginia Woolf and Lytton Strachey: letters. Hogarth Press &
Chatto and Windus, London
Woolf V, Bell AO (eds) (1977) The diary of Virginia Woolf. Hogarth Press, London
Chapter 2
The Development of Early 20th Century
Psychiatry and Its Failure
The Incapacity of Psychiatry to Alleviate Virginia
Woolf’s Suffering
Introduction
Leonard Woolf (1964) has recorded the names of all the doctors whom Virginia
consulted during her several breakdowns, including the lengthy episode of
1913−1915 (Woolf 1964, p. 160). These were George Savage, Maurice Craig, T. B.
Hyslop, Henry Head and Maurice Wright. The first three were Harley Street
(London) specialists and successive superintendents of London’s Bethlehem
Hospital (‘Bedlam’). They all concurred that she had ‘neurasthenia’. What is neur-
asthenia and how did these leading psychiatrists treat it?
Sir Maurice Craig (1866−1935) was the psychiatrist to Virginia and to King
Edward VIII at the time of his abdication (Fig. 2.1a). He was assistant medical
officer at Bethlem Royal Hospital (previously called Bedlam, hence the name for a
noisy and confused place), then Physician in Psychological Medicine at Guy’s
Hospital in London. He was responsible, with T. Beaton, for the major book of
reference during this period, ‘Psychological Medicine’. Craig’s highlighting neur-
asthenia as the condition that afflicted Virginia Woolf can be traced to the 1916
edition of his book, first published in 1905. She was attended to by Craig following
her Veronal overdose in 1913, with the subsequent collapse in her condition lasting
until 1916. Craig was consulted frequently thereafter until his death in 1935 when
she was 53, so providing her with psychiatric support for 22 years. As Leonard
Woolf puts it ‘for the rest of Virginia’s life the mental specialist to whom we went
for advice when we wanted it’ was Craig (Woolf 1964, p. 160). During this period
her masterworks were written and published, namely The Lighthouse, Mrs Dalloway,
Orlando and The Waves. Furthermore there were no breakdowns on the scale of
those that had occurred between the ages of 13 and 33. Craig’s book Nerve
Exhaustion (Craig 1922) stresses that the earliest departure from normal health and
conduct, both in childhood and adult life, which indicates the beginning of nervous
exhaustion, if taken in hand at once, prevents occurrence of functional nervous
disease which is commonly the precursor of the psychoses. As to whether these
treatment scenarios were the basis of Virginia’s relative stability and therefore

10 2 The Development of Early 20th Century Psychiatry and Its Failure
Fig. 2.1 (a) Sir Maurice Craig (1866–1935) Reproduced from “Sir Maurice Craig, C.B.E., M.D., F.R.C.P.”, Authors
unknown, British Medical Journal, 1, 87–88. (Copyright (1935) with permission from BMJ Publishing Group Ltd). (b) George
Beard (1839–1883), circa 1870. (c) Jean-Martin Charcot (1825–1893), © Hulton-Deutsch Collection/
CORBIS. (d) Emil Kraepelin (1856–1926), Copyright (1926), Wellcome Library, London
creativity during these years is a question that needs consideration. It is clear that
Virginia thought this was the case as evidenced by the readiness with which she
submitted herself to the treatment prescribed for those suffering from so-called
‘neurasthenia’ or nervous exhaustion. This evidence can be found, for example, in
her letters to Lytton Strachey. In the fall of 1915 (at 33), when her long illness,
beginning in 1913, seemed to be finally over, and whilst under the guidance of Craig
she says that:
‘I really am all right and weigh 12 stone!—three more than Ive ever had, and the conse-
quence is I can hardly toil uphill, but it’s evidently good for the health. I look forward to
being rid of the nurse soon’ (Woolf 1956, p. 70).
And again in 1921 the process is repeated:

‘All sorts of plagues descended on me. I’m now recovered, gained 6 lbs’ (Woolf 1956,
p. 133).
Henry Head was one of the most famous neurologists of his day and the editor of
the journal Brain. Maurice Wright, who had once treated Leonard Woolf for a ner-
vous tremor of the hands, utilized the technique of suggestion (Woolf 1960, p. 113).
Although Wright was a more forward-looking mental specialist than the others, his
advice to Virginia in 1913–1915 was identical with theirs: that she go to a nursing
home for a few weeks and stay in bed, resting and eating. This was the standard
treatment for neurasthenia (Woolf 1964, p. 148), the catchall diagnosis of fashion among
the genteel classes of Europe and America since the 1870s (Bromberg 1954, p. 152).
The family doctor, George Savage, also reinforced this diagnosis of neurasthenia, the
same label he had earlier given to the complaints of her father, Leslie. Head treated
Virginia as a disturbed person. He said that ‘Diagnosis of the psycho-neuroses is an
individual investigation; they are not diseases, but morbid activities of a personality
which demand to be understood.’
The treatment prescribed for her was the standard one for neurasthenics – the Weir
Mitchell treatment, or rest cure as it was popularly called. The name is misleading
Introduction 11
because rest was only ancillary in Mitchell’s conception of the cure. The cardinal
element was nutrition – excess eating which was supposed to ‘stabilize’ the neurons
in her brain and so alleviate the neurasthenic condition (Jones 1963, pp. 24–25).
Though the popularity of the Weir Mitchell treatment declined sharply with the
coming of suggestive therapies and psychoanalysis (Bromberg 1954, p. 155),
Virginia stuck with it till the end. For some 30 years she relied upon bed rest and
dietary supplements to get through her periods of mental distress. It was during
most of this period that her treatment was guided by Sir Maurice Craig. He was
amply and most effectively assisted by Leonard Woolf who always took immediate
action when he saw a crisis looming.
‘For years I had been accustomed to watch for signs of danger in V’s mind; and the warning
symptoms had come on slowly and unmistakably; the headache, the sleeplessness, the
inability to concentrate. We had learnt that a breakdown could always be avoided, if she
immediately retired into a cocoon of quiescence when the symptoms showed themselves.’
This was then in accordance with the standard treatment for neurasthenia.
In order to assess whether the diagnosis of neurasthenia makes any sense and
indeed whether the syndrome makes any sense, it is necessary to place it in the
contemporary context of psychiatry at the beginning of the twentieth century.
George Miller Beard made the pseudo-discovery in 1869 of the loss of nervous
energy in the cortex as the cause of fatigue, anxiety, headache, neuralgia and
depressed mood (Fig. 2.1b; Beard 1869). This idea was forcefully argued for by
Beard, who called the deficiency in nervous energy ‘Neurasthenia’, a condition
responsible for excessive muscle weakness and mental fatigue as manifest in the
symptoms of depression, fear, insomnia, lack of concentration and irritability. There
is a lag of some 17 years from Beard’s first introduction of the term in 1869 to the
first appearance of the diagnosis in discharges from London’s Queen Square
National Hospital for the Relief and Cure of the Paralyzed and Epileptic. This is
probably because it took some 20 years for the diagnosis to reach Europe where it
was not considered to be a major disease until the 1890s (Wessely 1996, pp. 509–
532). Unfortunately neurasthesia remained stubbornly a ‘functional’ disorder for
which no structural pathology could be found (Gowers 1893). The senior neurolo-
gists in the UK at the time of the First World War, such as Buzzard, Ferrier, Gowers,
Holmes and Kinnier-Wilson, no longer considered neurasthenia to have an organic
basis leaving its treatment to the psychiatrists (Wessely 1996; Bynum 1985, pp.
89–102).
Nevertheless this diagnosis was common during the First World War and only
really declined in the following decade. This is shown by the statistics of the National
Hospital in Queens Square London for the years 1870–1932 (Taylor 2001) which
show a decline in those diagnosed with neurasthenia from 107 a few years after the
War to 29 in 1932, with a transfer of those diagnosed with neurasthenia to a diagno-
sis of depression, or anxiety, or obsessive compulsive disorder. The popularity of
neurasthenia as a diagnosis collapsed at the time of introduction of the concept of
‘neurosis’ that originally had four subcategories. By 1932 these subcategories has
grown to 11, and the word ‘psychoneuroses’ came to replace that of ‘neuroses’, with
neurasthenia belonging to just one of these sub-categories. In this way neurasthenia
came to be considered a not prominent form of psychoneuroses. So neurasthenia,

that had been a separate category in the statistical returns since 1886, became merely
a subcategory of the psychoneuroses 46 years later as a consequence of the evolu-
tion of medical nosology. Now the symptoms of fatigue and poor concentration
form part of the criteria for both depression and neurasthenia and only if other
criteria for depression are not fulfilled are these symptoms attributed to a diagnosis
of neurasthenia (Farmer et al. 1995).
The failure to find a pathological change in the brains of those that had been diag-
nosed with neurasthenia and subsequently died in the early part of the twentieth
century had profound implications for how the source of the disease was to be judged.
At the time of Beard’s first description of the condition and its popular diagnosis in
Europe, between 1869 and 1986, the discipline of neurology was evolving, in which
pathological changes in the brain were identified with changes in psychological
capacities of a patient as judged in the clinic. Failure to identify such pathological
changes in neurasthenia meant that it was abandoned as a fit study for neurology and
became regarded as a so-called ‘functional’ disease of the mind, unrelated to pathol-
ogy, and hence relegated to psychiatry. What were the historical forces at play that
forced this distinction, accompanied as they were by the stigma associated with those
suffering such ‘mental’ conditions requiring psychiatric support?
Cruveilhier in his two volume work Anatomie Pathologique du corps humain ou
descriptions avec figures lithographies morbides don’t le corps humain est suscep-
tible (1829) pioneered what came to be known as the clinico-pathological approach
for correlating brain diseases to clinical symptoms. This involves correlating
changes in behaviour, that is changes in one or more of our psychological capacities
such as remembering, perceiving, feeling, thinking, with pathological changes in
the cellular constituents of the brain and spinal cord. In this work Cruveilhier
emphasized both the living patient and his symptoms along with their pathological
anatomy. He gave the first case of multiple sclerosis that has been documented using
the clinico-pathological approach, depicting the lesions of multiple sclerosis in the
brain of the patient Josephine Paget.
There were several observations in the second half of the nineteenth century that
related changes in behaviour to major endogenous lesions of the brain. In 1863
Virchow discovered amyloid (starchy) degeneration and devoted a great deal of work
to the pathology of brain tumors, which he erroneously attributed to conversion of
connective tissue. However it is to Charcot that one must turn for the first compre-
hensive description of disseminated sclerosis (Fig. 2.1c). Charcot, the father of clini-
cal neurology, emphasized the importance of collecting detailed clinical information
as well as detailed pathological information on the same patient. He gives numerous
examples of this in his Lectures on the diseases of the nervous system (1877). One of
these shows lesions in the upper lumbar region of the spinal cord of a patient who had
suffered from multiple sclerosis, indicating clearly the posterior columns of the
spinal cord invaded throughout with lesions consisting of axons, some of very small
diameter, all deprived of their medullary sheaths. Although Paul Broca had shown,
before these lectures of Charcot in 1861, an association between aphasia and damage
to the frontal cortex in his patient M. Leborgne, otherwise known as Tan (Broca
Introduction 13
1861), it is Charcot that established the clinico-pathological approach as a powerful

tool for teasing out the biological basis of neurological symptoms.
One must, however, turn to Alzheimer in order to find a correlation between fine
cellular changes in the cortex of a patient and changes in their behaviour. By the
time of Alzheimer’s work, Santiago Ramon y Cajal had discovered the individual
cellular constituents of the cortex and identified these as neurons and glial cells,
opening up the study of pathological changes in these cellular constituents of the
brain and their correlation with changes in psychological capacities, that is in behav-
iour (Cajal 1909). The seminal thesis by Alzheimer on the histopathology of general
paralysis of the insane was published in 1896. This is a late stage of syphilis, with
about 10% of all hospitalized psychiatric patients suffering from this disease at the
time of Alzheimer. He showed that there were histological changes in the brain that
accompanied the diseased state. In 1901 Alzheimer identified a patient in the
Frankfurt Asylum with a loss of short-term memory and other psychological capac-
ities whom he called Mrs Auguste D. This patient died in 1906 at the age of 56 and
Alzheimer had access to her brain for histological purposes. Using the newly
invented technique for silver-staining neurons, perfected by Max Bielschowsky,
Alzheimer showed in 1907 that the cortex of the brain of Mrs Auguste D. contained
neurofibrillary tangles in the neurons as well as amyloid plaques (Alzheimer 1907).
Subsequent postmortem examination of the brain of a 56-year-old demented patient
(Johann F.), after silver staining, showed the widespread presence of amyloid
plaques without any indication of neurofibrillary tangles (Alzheimer 1911). These
cases provided evidence that this psychiatric condition, namely loss of memory
accompanied by the loss of other psychological powers, was associated with mor-
phological changes in the cellular constituents of the cortex.
Curiously, the claim of an association between cortical degeneration and dementia
was not resisted, even though loss of capacities that clearly fall into the psychological
such as memory and rational thought are involved in addition to changes in motor
performance, that is in a neurological condition that since Descartes had been attrib-
uted to abnormalities in the ‘machinery’ of the body. Contemporary textbooks of
neurological illness highlight this ‘machinery’, emphasizing that neurological patients
are those that present with symptoms of a disease of the nervous system. A typical list
concerns diseases of cranial nerves (involving tests on smell, face sensations, reaction
to light and auditory phenomena), of motor function (maintaining limb posture), of
reflex function (reflex activity of the spinal cord viz. biceps, triceps etc.), of sensory
function (skin of face, legs and neck), of gait (standing and walking) and most inter-
esting for the present purposes diseases of higher cortical function (memory, aphasia).
Loss of memory is certainly loss of a psychological capacity, yet this has been taken
as falling in the purview of neurology, that is to be considered in terms of something
that has gone awry with the ‘machinery’ of the body. On the other hand, contemporary
manuals of psychiatry, such as the Diagnostic and Statistical Manual of Mental
Disorder (4th Edition; American Psychiatric Association 2000), provide a startlingly
unhelpful and incoherent definition for the diagnosis of a mental illness as:
‘a clinically significant behavioural or psychological syndrome or pattern that occurs in an
individual and that is associated with present distress (e.g. a painful symptom) or disability
(i.e. impairment in one or more important areas of functioning) or with a significantly

increased risk of suffering death, pain, disability, or an important loss of freedom. Whatever
it’s original cause, it must currently be considered a manifestation of a behavioural, psycho-
logical or biological dysfunction in the individual (p.xxi).’ (American Psychiatric
Association 2000).
So the psychological powers of memory, thinking, perceiving, feeling etc., which

if they go awry inevitably show up in behavioural changes, are separated out from
such changes, and biological dysfunction is not credited with always being an
accompaniment of a mental illness. A fault in the biological ‘machinery’ is not then
a necessary concomitant of such an illness whereas it is for a neurological illness
(putting memory aside). The association of the foundations of neurology with the
Cartesian machinery of the corporeal body has often left psychiatry, still working in
the shadow of Descartes, with treating the incorporeal Cartesian soul, taken as the
mind and equivalent to consciousness, as discussed in the last chapter.
The discovery of correlations between the loss of cells in the cortex and both
classical neurological diseases such as multiple sclerosis together with the neuro-
logical and psychiatric changes accompanying dementia, as well as the discovery of
localized brain areas for different psychological capacities such as language,
unleashed a wide ranging research program in clinico-pathology. Such programs
were not accompanied by concerns about the soul, identified now with conscious-
ness as defined by Descartes, and its relation with the brain. This was because the
clinico-pathological approach was taken, as noted above, to be consistent with the
now accepted Cartesian view that mechanistic biology was responsible for those
functions which neurology now covered, so that questions concerning the relation-
ship between the brain and mind were not considered relevant. This was of course
not the case when considering problems concerned with mental illness. Here the
Cartesian paradigm determined that these involved the mind, identified with con-
sciousness, which had gone awry, not the biological mechanisms of the body.
The idea that mental illness did not involve an organic change in the brain was
challenged by Emil Kraepelin (Fig. 2.1d). He made the revolutionary suggestion that
mental illness is caused by biological changes conditional on genetic and environmen-
tal factors (Kraepelin 1974). He argued in 1904 that each psychiatric disorder has
some specific underlying biological cause and to discover one or more of these he
focused on the psychoses. Such gross mental disturbances, he hoped, would be
distinctly paralleled by physiological abnormalities in the brain. This he thought likely
as some other severe afflictions such as syphilitic paralytic dementia, cretinism, as
well as various tumors had specific identifiable causes or etiologies. His observations
on the differences in the weight of different regions of the brain of subjects with
psychosis as compared with normal subjects did not elicit any reliable result. Also
his attempts to identify toxins in the blood of psychotic patients were also unsuccess-
ful. This forced Kraepelin to abandon the biological approach to the subject and to
then take on the arduous task of nosology, of careful classification of symptoms that
might lead to a reliable classification of different psychiatric disorders.
Phillippe Pinel in France in the late eighteenth century had made valiant attempts
to classify different psychiatric diseases but his manner of going about this was
Introduction 15
flawed. On the other hand Kraepelin’s genius was manifest in the meticulous way
in which he kept records of thousands of patients he examined, many over exten-
sive periods of time, while occupying posts at Universities in Dorpat, Heidelberg
and Munich. He was able to identify symptoms in some forms of psychosis that
indicated that the patient was likely to follow a path of continual deterioration.
This cluster of symptoms he called dementia praecox, later to be named schizo-
phrenia. Another cluster involved manic-depressive behavior, which Kraepelin
was also able to subcategorize into subtypes in which the emphasis was on depres-
sion or on manic stupor.
Kraepelin claimed that what distinguishes each disease symptomatically is
not any particular symptom or symptoms, but a specific pattern of symptoms.
He reached the conclusion that the symptom – picture of a mental disorder is cor-
related with the course and outcome. His major work Compendium der Psychiatrie
(1883) is where he proselytized on behalf of the idea that psychiatric illness has an
organic basis. The psychiatrist then should be engaged in scientific observations
and experiments as in any other scientific discipline. In the 1896 edition of
Compendium der Psychiatrie he claimed that ‘The terms of a tradition of over
2000 years are overthrown … Mental symptoms are dethroned unless they are
characteristic of etiology, course and outcome’.
The first edition of Robert Burton’s encyclopedic treatise The Anatomy of
Melancholy appeared in 1621 and its popularity ensured some 40 subsequent
editions (Burton 1832). It combines contemporary medical knowledge with erudi-
tion, wit, poetry, and fantasy. Towards the end of the nineteenth century the use of
the term ‘melancholia’ gave way to that of ‘depression’ and much of this transition
was due to Kraepelin, who used depression as a synonym for a range of melancholic
conditions (Davidson 2006). By the beginning of the twentieth century he had
unified all types of affective disorder into ‘manic-depressive disorder’, a concept
that overshadowed the first half of the twentieth century. Kraepelin then went on to
show that not only did these conditions have particular characteristic time courses
of expression but also that they were delineated by particular genetic patterns. Thus
the relatives of manic-depressive patients showed a higher frequency of the condi-
tion than that found in the population in general (Whybrow 1997, p. 180). He
described manic-depressive illness not as a neurosis that could reveal a patient’s
psychodynamics, but as a familial disorder resistant to psychoanalysis. The evi-
dence for genetic transmission is now quite strong. If one identical twin has manic-
depressive illness, the other runs a 70% chance of having it too, whereas a fraternal
twin risks only a 20% chance. Studies of adopted manic-depressive children show
that more than 30% of their biological parents display clear signs of the disorder, but
only 2% of the adoptive parents do.
In summary, the mighty contribution of Kraepelin was to distinguish manic –
depressive disorders from schizophrenia (Kraepelin 1883). Although he failed in
the task he had set himself of placing psychiatry on an organic footing, identifying
different psychiatric diseases with different pathologies of the brain, his attempts to
do so together with his nosology distinguishing the major forms of mental illness,
set the foundations to this day for much of psychiatry and indeed neuropsychiatry.
He is therefore recognized today as the originator of pharmacogenomics, of both

pharmacological and the genetic considerations of mental diseases. But this was not
always the case, for much of the twentieth century practice of psychiatry came to be
dominated by the ideas of Freud. Now the clock has turned full circle, as biological
psychiatry as conceived by Kraepelin is once more the dominant influence in
attempts to ameliorate diseases of the mind.
Sir Maurice Craig was not enlightened by the revolution that Kraepelin had
effected before the First World War. The diagnosis of Virginia Woolf as suffering
from neurasthenia lasted for 22 years until Craig died in 1935 when Virginia was
53 and as noted in Chap. 1, had created her greatest works. It is clear in retrospect
that she suffered from mood disorders, probably of the bipolar variety as do a dis-
proportionate number of great literary figures, and certainly not from schizophre-
nia. Whether such a correct diagnosis would have helped her is a moot point, for
there was no effective cognitive therapy or pharmaceutical intervention available
until 1948. In that year the great Melbourne psychiatrist John Cade discovered
lithium for the treatment of bipolar disorder, the dominant form of effective treat-
ment to this day.
Notes
Kraepelin’s emphasis on searching for what has gone awry in brain function that
leads to a loss of normal psychological capacities raises insurmountable difficulties
for the concepts of mind adopted by either Plato or Descartes, for according to
them, mind is a incorporeal substance. Such difficulties are not removed by iden-
tifying the mind with the brain rather than with an incorporeal substance. This has
been termed the ‘mereological fallacy’, namely of attributing to a part (in this case
the brain, which does not possess psychological capacities) powers that can only
be logically attributed to the whole (in this case the person whose brain it is, and
who does possess psychological capacities; see Bennett and Hacker 2003, 2008).
The ‘insurmountable difficulties’ facing Kraepelin in the shadow of Plato and
Descartes were not present during the 1500 year period in which Aristotelian
thought was considered highly significant. For Aristotle the mind is but a manner
of speaking about our psychological powers in thinking, feeling, perceiving,
remembering etcetera. Contrary ideas of the concept of mind which are held by
contemporary philosophers and psychiatrists cannot be maintained in the face of
Aristotle’s criticisms and ideas (see Bennett et al. 2007). The continuing resis-
tance to Kraepelin’s proselytizing efforts on behalf of the search for biological
changes that underlie what has gone awry in our psychological abilities, which
have been traditionally treated as belonging to the domain of psychiatry, cannot
be sustained in the light that Aristotle casts on the relation between the biological
and the psychological.
References 17
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Chapter 3
Freud, the Subconscious and Virginia Woolf
Freud’s Failure to Support Virginia Woolf
Sigmund Freud, a founding father of twentieth century psychiatry, was born in

1856 in Freiberg, situated in the Austrian Empire (Fig. 3.1). He was a brilliant
student at school and during his medical degree at university, showing precocious
intellectual and observational powers. These were such that by the time he was 22
he had discovered, through extraordinary technical skill and perseverance in dis-
secting out neurons in lamprey and crayfish, that neurons are individual cells and
not parts of a continuous syncytium of cells (Fig. 3.2a, b). This work places him
with Ramon y Cajal as co-discoverer of the neuron. Freud then went on to make
seminal contributions concerning the identity of groups of neurons in the medulla
oblongata of the vertebrate nervous system and the arrangement of the nerve tracts
in this part of the brain, applying his technical skills to early developing fetal brains
for ease of dissection and identification. By the early 1890s Freud was making con-
tributions to neurology such as in his On Aphasia (1891), which emphasizes the
distinction between an organic aphasia and the condition of hysterical speech, as
well as in his A Psychology for Neurologists in which he attempted to distinguish
between normal and pathological activities of the mind on neurological grounds.
In his 1893 work, Diagnostisches Lexikon für praktische Ärzte, he identified four
areas of the brain in which lesions give rise to disorders of speech (Fig. 3.3), and
made the very important distinction that although such lesions can be localized
anatomically, functions cannot. This marks the departure of Freud from clinical
neurology to psychiatry, for he then realized that the functional changes in the cortex
giving rise to neuroses that he observed in his patients could not be localized to
distinct areas that have by one means or another been lesioned. No pathological
anatomy could be identified as underlying clinical observations on mood disorders
and neuroses. In this case only careful clinical observations could be made to infer
hypothetical relations between, for example, pathological mood conditions and
sexual activity, as illustrated in the sketches he drew for his friend Wilhelm Fleiss in
1894 (Fig. 3.4a). However Freud still attempted from time to time to give a neuronal
network account of his psychiatric observations, as in a description of how repressed
memories might arise in the 1895 manuscript, Entwurf einer Psychologie (Project
for a Scientific Psychology). Here he provided a neuronal model illustrating how

20 3 Freud, the Subconscious and Virginia Woolf
Fig. 3.1 Portrait of Sigmund

Freud in 1891. Freud Museum,
London
Fig. 3.2 (a) Spinal ganglion of lamprey larvae (stained with gold). Although several neurons
appear to have only one process, close investigation showed that they had two processes, with the
exception of the cell labelled ‘dpy’. Magnification x305 Abbreviations: gf blood vessel, sa sympa-
thetic axon, dz group of axons passing through the ganglion, hw posterior root of the ganglion, ang
so called ‘anaclitic fibres’. (b) Gastric ganglions of the river crayfish. Two neurons are shown, one
with a T-shaped axon partitioning. Abbreviations: s thick, concentrically organised cell-sheath, ks
nuclei, hm margin of the neuron, f axon rom another neuron (By permission of The Marsh Agency Ltd on behalf
of Sigmund Freud Copyrights)
3 Freud, the Subconscious and Virginia Woolf 21
Fig. 3.3 Figure showing areas of the brain that if lesioned give rise to major language disorders.
The black areas indicate language centres and the hatched areas to so called language fields. The
following regions are delineated: 1 lesions here give rise to agraphia, 2 lesions here give rise to
aphasia (this is Broca’s area), 3 lesions here give rise to word-deafness, 4 lesions here give rise to
alexia (this is Wernicke’s area) (By permission of The Marsh Agency Ltd on behalf of Sigmund Freud Copyrights)
repression might work, reproduced in Fig. 3.4b. A particular perception or sensation,

represented by impulse firing of neuron ‘a’, normally activates the lower neuron
representing a hostile memory giving rise to feelings of ‘unpleasure’, a neuron
which Freud called the psi (mnemic or mnemonic) neuron. This is prevented by a
process that he referred to as ‘side cathexis’ which diverts the impulses away from
the mnemonic neuron via the upper pathway (alpha, beta, gamma, delta pathway),
through a series of what we would now call synapses (each indicated by short parallel
lines), so the hostile memory is repressed. The use of a hypothetical neural network to
elucidate possible functions that are at play in the cortex in mood disorders such as
depression has become a hallmark of twenty first century neuropsychiatry, as we
shall see in Chap. 5. Freud may be regarded then not only as a founder of the neuron
doctrine, but also of the use of neural networks to unravel what has gone awry with
cortical functions implicated in psychiatric disorders.
The other founding father of twentieth century psychiatry, as has been
noted, is Emil Kraepelin, born the same year as Freud and only 300 miles apart in
Neustrelitz, Prussia, on the Baltic coast. Kraepelin carried out exhaustive studies on
large numbers of patients and arrived at the conclusion that they could be divided
into two major cohorts, dementia praecox (schizophrenia) and manic-depression,
with no transitions occurring between these. He also claimed that transitions could
not be observed between patients with dementia praecox (schizophrenia) and hyste-
ria (involving emotional outbursts, paralysis and susceptibility to autosuggestion).
On the other hand Freud developed the idea that there was no discontinuity between
the underlying mechanisms giving rise to the neuroses (characterized by anxiety,
hysteria and obsessive compulsive disorder), a relatively less serious disorder than
Fig. 3.4 (a) A drawing of Freud’s in which he attempts to understand the neural network mechanisms
that underpin mental states. In this schematic diagram he attempts to depict the relationship
between sexual physiology and pathological moods in a hypothetical framework. (b) Letter to
Wilhelm Fleiss, December 17, 1894. Freud made this, now famous, drawing in order to consider a
neural network that might underpin the way in which the consequences of ‘excessive stimulation’
might be dealt with by ‘side cathexis’, a mechanism by which energy is diverted away from memory
(mnemonic) neurons. For a further explanation, see text (By permission of The Marsh Agency Ltd on behalf of
Sigmund Freud Copyrights)
schizophrenia, and the normal functioning of these mechanisms in the general

population. There was no necessary conflict then between Kraepelin’s claim that the
very serious conditions of schizophrenia and manic-depression disorder did not
exist along a continuum of psychiatric illness and Freud’s claim that in the case of
the less serious condition of the neuroses there was a continuum, at least between
neurotic patients and those that are normal. But there is a contradiction between the
claims of Freud and Kraepelin, when it comes to the suggestion that the milder
condition of hysteria, compared with schizophrenia, is not continuous with the latter
or with normal subjects.
In Mourning and Melancholia (Freud 1917), Freud expressed the opinion in
1917 that major depression was akin to mourning. He argued that a major trauma,
such as that due to the loss of a loved partner or a member of the family through
death, can have severe emotional consequences resulting from the individual iden-
tifying with the loved one through an unconscious, narcissistic process. A major
loss can then lead to melancholic symptoms that are much more severe than those
normally occasioned in mourning. Not only does the patient view their surround-
ings negatively, but such feelings also arise as a consequence of identification with
the lost loved one. The patient’s decline in normal regard for themselves is replaced
by blame, inferiority, and unworthiness. This decline is greatly emphasized by early
life experiences that become in themselves a predisposing factor (Radden 2003).
Freud then came to adopt a more psychological approach than Kraepelin, with his
emphasis on the organic, for Freud realized as we have seen that the then contem-
porary knowledge of the brain was far too shallow to reveal the underlying cortical
defects that give rise to such complex psychiatric conditions.
Freud came to the conclusion after very careful clinical observations of his
patients that depression is primarily due to past experiences affecting the current
life of the sufferer, resulting in aggression towards a lost loved one with which the
patient has identified. If the patient can be made aware of the origins of their symp-
toms, for example through hypnosis, so they reveal their unexpressed emotions,
then these no longer express themselves as symptoms. A main source of these past
experiences impacting on adult mood disorders was sexual, and involves Freud’s
‘seduction theory’. In the mid 1890s Freud believed that the origins of hysteria and
obsessional neurosis in his patients was to be found in repressed memories of early
childhood sexual abuse or other forms of physical molestation, for which he pro-
posed the neuronal network theory already described (Fig. 3.4b). This abuse was
generally due to a close family member such as a father or stepfather, although in
Virginia Woolf’s case by her half-brothers.
Later on, however, as many were unwilling to believe so many perverted acts had
been committed by respectable family members (Rush 1980), Freud abandoned the
seduction theory and replaced it with the drive theory. This was the idea that the
child’s own unconscious desire for the parent led to the delusion that seduction had
occurred. In Virginia Woolf’s time the latter view had been accepted, including by
her own sister-in-law Karin Stephen. Now we know that the incidence of these per-
verted acts is very much higher than Freud had anticipated, as described in Chaps.
4 and 8. The original framing of his theory is therefore more likely to be correct than
his later theory that such seduction was a delusion that led to repressed memories.
It is a great pity that Freud had abandoned his earlier theory by the time he saw
Virginia as a patient in London towards the end of her life, for otherwise he might
have been some help to her rather than most likely undermining her confidence in
identifying the sexual abuse of her childhood as the foundation of her depression.
Freud suggested that our motivations, whether to satisfy the vegetative functions
for food and sex, or to carry out creative acts or to satisfy neurotic compulsions, were
driven by the ‘unconscious’ which he called the id. The id is closely associated with
our personalities, our instincts and with what Freud called ‘psychic energy’. This id
operates on the basis of the pleasure principle and is completely separate from our
experiences, such as those gained through perceptions and sensations. The id is pow-
ered by the libido, of which sex is the most important part, together with aggression.
Consciousness of perceptions and sensations as well as some components of precon-
sciousness, are due to the ego, which relates a person to reality as it searches for
objects to satisfy the wishes that the id creates in order to meet a person’s needs. The
ego is then the interface between the person and the world. Freud’s concept of what he
called the superego is that it mediates between the id and the ego, the former driving
the subject through desires and the latter having to meet the practical problem of deal-
ing with the real world as it is. The superego then develops strategies to reach what is
often a compromise solution, circumscribed by the sense of morality arising from the
practical necessity of being involved in the world of other individuals.
In 1933 Freud drew a sketch (Fig. 3.5 from Figure 45 in The psychical apparatus;
Freud 1933) to explain the relationship between the ego, superego and the id which
he explains as follows:
‘I should like to portray the structural relations of the mental personality, as I have described
it to you, in the unassuming sketch which I now present you with. As you see here, the
superego merges into the id; indeed, as heir to the Oedipus complex it has intimate relations
with the id; it is more remote than the ego from the perceptual system. The id has inter-
course with the external world only through the ego – at least according to the diagram.
It is certainly hard to say today how far the drawing is correct. In one respect it is undoubt-
edly not. The space occupied by the unconscious id ought to have been incomparably
greater than that of the ego or the preconscious. I must ask you to correct this in your
thoughts.’
The question now arises as to how the id is satisfied during the different stages of
child and adolescent development through driving different motivations of the ego.
In order to satisfy the id the ego is said by Freud to participate in five different
psycho-sexual stages of development as follows:
The first of these is the oral stage, in the first year or so after birth, in which the
id attempts to find pleasure through the oral erogenous zones through sucking and
eating. The second is the anal stage, during the next 2 years, when the id seeks its
main pleasures through use of the anus in excretion. It is during this time that the id
is restrained by the superego as a consequence of the ego being constrained through
societal pressures to carry out anal functions in an appropriately acceptable manner.
Indeed it is these requirements that mature the superego in discriminating between
right and wrong. Freud’s famous Oedipus Complex emerges during the Phallic
Fig. 3.5 A diagram by Freud showing his conception of the relationship between the ego and the
id. With regards to the ego he comments that: “The ego is first and foremost a bodily ego; it is not
merely a surface entity, but is itself the projection of a surface. If we wish to find an anatomical
analogy for it we may best identify it with the ‘cortical homunculus’ of the anatomists, which
stands on its head in the cortex, sticks up its heels, faces backwards and, as we know, has its speech
area on the left-hand side” (By permission of The Marsh Agency Ltd on behalf of Sigmund Freud Copyrights)
fourth stage at about 4–5 years of age. At this stage female children, for example,
become envious of brothers and fathers that possess a penis, and resent this to such
an extent that they reject their mothers and wish to have a child by their fathers.
These unconscious drives of the id are repressed by the superego, so that the child
comes to identify with the mother and so in this way reconciles the desire for pos-
session of the father. In this context some commentators believe that when Virginia
Woolf met Freud in 1939, just over a year before her suicide, he denied that she had
been sexually abused when a child by the Duckworths, but rather her despair arose
from repression of her need to have a child by her father. This, it is argued, brought
down the entire edifice that she had built to partly protect her from going irrevers-
ibly insane, namely that it was the abuse by her half-brothers that had led to her
malaise. The fourth, Latency stage, occurs at about 6 years and it has this name as
during this stage the child has entered a sexually latent period before full sexuality
emerges. It was at this age that Virginia was first sexually molested by Gerald
Duckworth. According to Freud this was a period when she would have been effec-
tively neutral concerning sexual molestation, if it had occurred. In the fifth stage, the
Genital, sexuality emerges in its final form that lasts throughout the individual’s life.
Now the sexual drive of the id is satisfied by the ego negotiating an acceptable soci-
etal setting involving the taking of a partner. We do not know what Freud said to
Virginia, if anything, about her bisexual life with both her husband Leonard and her
sexual partner of about 10 years, Vita Sackville-West.
The ego has to contend with the current demands of the circumstances in
which the individual finds itself, adhere to the norms of society as represented by the
superego and finally deal with the pressures of the vegetative functions represented
by the id. Anxiety arises when these contending demands cannot be reconciled.
Freud suggests that three different forms of this anxiety exist, depending on their
origins: first there is realistic anxiety that arises from a perceived threat; second there
is moral anxiety, arising from the failure to meet the norms set by the superego,
giving rise to guilt and shame; and finally there is neurotic anxiety, arising from the
vegetative demands of the id that are not being met and so give rise to the feeling that
one is about to completely loose restraint and control.
The ego has three different ways to defend itself when overwhelmed with the
anxieties considered above. According to Freud these are through isolation from
society, or by repressing the contending forces, or by turning against oneself. The
first of these involves removing consideration of the immediate circumstances that
constitute the threat, or of a memory that contains a disturbing threat, by convincing
oneself that the anxiety arises from an abusive event some time ago, during child-
hood. The second involves the ego repressing the ugly impulses generated by the
vegetative functions of the id such as the refusal to remember sexual abuse as a child
when an adult. The third form of defence of the ego, involves turning against oneself;
this begins with hatred and anger at another person which overtime becomes redi-
rected to oneself as a substitute, leading to feelings of guilt and depression. It seems
clear from Virginia’s letters, diary entries and lectures that she was not able or will-
ing to strip the emotions away from her sexual abuse by the Duckworths.
Furthermore, she remained aware throughout her life of what she had gone
through as a child and adolescent. But it is possible, according to Freud, that she
suffered from self-hatred as a consequence of a substitution, of directing the anger
and hatred of the Duckworth brothers towards herself. It was this that led to her deep
depression and breakdowns.
Virginia Woolf’s life and suicide have been a rich field for psychoanalytic
speculation. Some authors such as Betty Kushen, while tremendously impressed
with Woolf’s abilities, do not think she advanced much beyond the pre-oedipal stage
of attachment to her mother. The death of her mother then had such devastating
effects, heightened by the death of her brother, that the only way she could achieve
some form of stability was to concentrate on her writing to the exclusion of every-
thing else, leading to periods of great productivity which could not be indefinitely
sustained, collapsing into periods of great depression. Roger Poole agrees with this
assessment that periods of feverish writing acted as a means of putting away feel-
ings of anger, hatred, guilt and debasement. Mark Spilka speculates:
‘Did she want her mother to die, as some Freudians might conjecture, and was she then
secretly pleased (and later overcome by guilt) when life granted her wish? Or was she angry
with her mother for dying, for depriving her of love, and … was she then unable to grieve
(and later overcome by guilt), as still other Freudians .. might argue.’ (Spilka 1980, p. 16)
Louise De Salvo attempts to trace the major depressive episodes in her life back
to the sexual abuse she was subjected to from six into her teenage years by her step-
brothers, Gerald and George Duckworth. This was the case according to Virginia,
for she states quite explicitly in A Sketch of the Past that she came to connect her
appalling moments of depression, the sense which she had earlier described as being
‘exposed on a high ledge in full light’ with her childhood experiences of incest.
These began at age six when, recovering from a bad bout of flu, “her step-brother
Gerald Duckworth lifted her up on a ledge usually used for stacking dishes and
explored her body, down to her private parts” (Woolf 1939, p. 69).
Did Virginia possess a deep knowledge of Freud’s ideas, and if so did she
regard them with hostility? If she found them interesting or even profound, did she
apply them to interpret the origins of her own major depression? Her first implicit
mention of Freud’s ideas occurs in 1920 in a brief anonymous review of J.D.
Beresford’s novel, An Imperfect Mother (Woolf 1920, pp. 152–154).
‘This [plot] is strictly in accordance with the new psychology which in the sphere of medi-
cine claims to have achieved positive results of great beneficence. A patient who has never
heard a canary sing without falling down in a fit can now walk through an avenue of cages
without a twinge of emotion since he has faced the fact that his mother kissed him in the
cradle. The triumphs of science are beautifully positive.’
The Hogarth Press, at which she was responsible for the typesetting, took over the
responsibility for publication in English of the International Psycho-Analytical
Institute papers in 1924, when Virginia was 42. Freud’s work on psychoanalytic
theory was then made available in England through these publications. Twenty-seven
volumes of papers were then released through the Hogarth Press over the years
1924–1946, under the general editorship of Dr Ernest Jones. Twenty-two of the vol-
umes were made available in special named collections constituting the Collected
Papers of Freud (1924), Freud’s The Ego and the Id (1927) as well as his daughter’s
work, Anna Freud’s The Ego and the Mechanisms of Defence (1937). All of these
were published while Virginia took an active role in the Hogarth Press in which her
interest was not sold until 1938. Her press was then the main source of Freud’s ideas
in England for 13 years. Did the deep knowledge of his thought gained through the
Hogarth enterprise meet with hostility from her? This seems very unlikely for she
would sometimes amuse herself with amateurish analysis as, at 47 she writes that:
‘Drawing a picture was an idle way of finishing an unprofitable morning’s work. Yet it is in
our idleness, in our dreams, that the submerged truth sometimes comes to the top. A very
elementary exercise in psychology, not to be dignified by the name of psychoanalysis,
showed me, on looking at my notebook, that the sketch of the angry professor had been
made in anger. Anger had seized my pencil while I dreamt. But what was anger doing there?
Interest, confusion, amusement, boredom—all these emotions I could trace and name as
they succeeded each other throughout the morning. Had anger, the black snake, been lurking
among them? Yes, said the sketch, anger had.’ (Woolf 1929, p. 31)
Her most important comments regarding analysis occur after she visited Freud
on 28 January, 1939, at the beginning of the second World War. She writes that the
meeting stimulated her to read him more carefully and in December of that year
comments that:
‘Began reading Freud last night; to enlarge the circumference: to give my brain a wider
scope: to make it objective; to get outside. Thus defeat the shrinkage of age. Always take on
new things.’ (Woolf 1953, p. 309)
Much has been made of the comment in her diary that Freud reduced her ‘to a
whirlpool’. This has been interpreted as resulting from Freud denying that she had
experienced repeated acts of incest as a child, and that her claims were a result of
oedipal repressions. But this interpretation is not supported by Virginia’s comments

after seeing him in January that:
‘Consider how difficult it is to tell the truth about oneself—the unpleasant truth… The
nineteenth-century writers never told that kind of truth, and that is why so much nineteenth-
century writing is worthless; why for all their genius, Dickens and Thackeray seem so often
to write about dolls and puppets, not about full-grown men and women; why they are forced
to evade the main themes and make do with diversions instead. If you do not know the truth
about yourself, you cannot tell it about other people. The leaning-tower writer has had the
courage at any rate … to tell the truth, the unpleasant truth, about himself… By analysing
themselves honestly, with help from Dr. Freud, these writers have done a great deal to free
us from nineteenth-century suppressions. The writers of the next generation may inherit
from them … that unconsciousness which … is necessary to writers… For that great gift of
unconsciousness the next generation will have to thank the creative and honest egotism of
the leaning tower group’ (Woolf 1940, pp. 148–9).
So Freudian analysis is seen here as having a liberating effect on the literary

imagination.
Was then Virginias meeting with Freud in the penultimate year of her life a pre-
cipitating factor in her suicide? This seems very unlikely. She was one of the first in
England to know his work through the Hogarth Press over some 17 years before she
met him. There is no indication in her diaries, letters or lectures that this knowledge,
which all of us attempt to apply to ourselves on first reading Freud, had destabilized
her. It is far-fetched to suggest that meeting Freud was the first time she had come
to know and understand his ideas on repressions arising from childhood, and that
this was the possible basis for her psychiatric illness.
Why then, knowing Freud’s ideas when they first came to be understood in
England, did Virginia not consult a professional psychoanalyst? According to Alex
Strachey it was feared that psychoanalysis might endanger Virginia’s creativity, at
least so Leonard Woolf thought. A far more likely reason is that the diagnosis of
neurasthenia had been confirmed by all the leading psychiatrists of the time in
London. Chief amongst these was, as has been noted, Sir Maurice Craig who treated
her for over 20 years until his death when Virginia was 53. A more cogent argument
is that Virginia regarded psychoanalysis as an interesting way of looking at and
interpreting behaviour, in much the same way as one might regard her own literary
works. Freudian analysis might then give a view of the origins of the literary process
and so further the creativity that it can display, for:
‘We all have experience of the work done by unconsciousness in our own daily lives. You
have a crowded day, let us suppose, sightseeing in London. Could you say what you had
seen and done when you came back? Was it not all a blur, a confusion? But after a rest …
the sights and sounds and sayings that had been of most interest to you swam to the surface,
apparently of their own accord; … what was unimportant sank into forgetfulness. So it is
with the writer. After a hard day’s work, trudging round, seeing all he can, feeling all he can,
… the writer becomes—if he can—unconscious. In fact, his undermind works at top speed
while his upper-mind drowses. Then after a pause, the veil lifts; and there is the thing—the
thing he wants to write about—simplified, composed’ (Woolf 1940, p. 134).
In retrospect it seems highly likely that Virginia Woolf was prone to a familial
mental illness in addition to the mental instability that arose from being sexually
References 29
abused as a child. The interaction between these two is considered in Chap. 8.

Virginia’s father, Leslie Stephen, had a daughter by his first marriage, Laura, who
was institutionalized for a life-long psychosis, which was probably childhood
schizophrenia (Love 1977, p. 162). Virginia’s cousin, James Kenneth Stephens, had a
seemingly insignificant head injury in 1886 and was institutionalized for intense mania
until his death by self-starvation in 1892 (Woolf and Bell 1977, Diary 1, pp. 35–6).
Leslie Stephen’s brother, Fitzjames, suffered from severe mental illness, probably
schizophrenia, and died in 1894 (Marcus 1983, pp. 30, 48). Freud’s original thoughts
on schizophrenia described it as due to the flight of libidinal or emotional energy,
generally sexual in origin and emanating from the id, away from a loved person onto
one’s self, a form of repression. This concentration of libidinal energy onto one’s
self, amounting to a pathological narcissism, finds expression in the grandiosity and
ego-centrism of the schizophrenic patient (Freud 1911).
Leslie Stephen’s father, the gloomy Sir James Stephens, was given to acts of self-
mortification and suffered from chronic depression (Woolf and Bell 1977, Diary 1, p. 5).
Leslie suffered from sudden changes in mood between excitement and depression,
which probably amounted to a mild form of manic-depressive psychosis. It
seems likely then that Virginia was predisposed to manic-depressive disorder
because of a familial inheritance from her father besides carrying the added psycho-
logical burdens arising from childhood sexual abuse. Of Leslie’s three daughters,
Vanessa was the only normal one (Morizot 1978, p. 77).
Notes
(p. 19) ‘A Psychology for Neurologists’.

To illustrate this Freud produced clinical neurological (or neuropathological)
drawings. One of these identifies the four areas of the brain in which damage pro-
duces major language disorders. These anatomical areas can be mapped onto the
functional zones and elements that Freud had previously identified. The distinction
between those (functional) images and this (anatomical) one coincides with an
important theoretical distinction that Freud drew in his neurophysiological studies
from this period: lesions can be localized anatomically but functions cannot.
References
Freud S (1911) Psychoanalytic notes on an autobiographical account of a case of paranoia. Hogarth

Press, London
Freud S (1917) Mourning and melancholia. In: Richards A (ed) On metapsychology: the theory of
psycholoanalysis. Pelican, Aylesbury, Bucks
Freud S (1933) Neue Folge der Vorlesungen zur Einfuhrung in die Psychoanalyse. International
Psychoanalytic University, Berlin
Freud A (1937) The ego and the mechanisms of defence. Hogarth Press and the Institute of
Psycho-analysis, London
Freud S, Riviere J, Strachey J (1924) Collected papers. Hogarth Press and the Institute of Psycho-
Analysis, London
Freud S, Riviere J, Strachey J (1927) The ego and the id. Hogarth Press and the Institute of Psycho-
Analysis, London
Love J (1977) Virginia Woolf’s source of madness and art. California Press, Berkeley
Marcus J (1983) Virginia Woolf and her violin: mothering, madness and music. In: Ginsberg EK,
Gottlieb LM (eds) Virginia Woolf: centennial essays. Whitston Pub. Co, Troy
Morizot CA (1978) Just this side of madness: creativity and the drive to create. Yale University
Press, New Haven
Radden J (2003) Is this dame melancholy?: equating today’s depression and past melancholia.
Philos, Psychiatry & Psychol 10:37–52
Rush F (1980) The best kept secret: sexual abuse of children. Prentice-Hall, Englewood Cliffs
Spilka M (1980) Virginia Woolf’s quarrel with grieving. University of Nebraska Press, Lincoln
Woolf V (1920) “Freudian Fiction.” Review of an imperfect mother by J.D. Beresford (25 March
1920). In: Guiguet J (ed) Contemporary writers: essays on twentieth century books and authors.
Harcourt Brace Jovanovich, New York
Woolf V (1929) A room of one’s own. Hogarth Press, London
Woolf V (1939) A sketch of the past. In: Schulkind J (ed) Moments of being. Triad/Granada,
London
Woolf V (1940) The leaning tower. In: Leaska MA (ed) The collected essays of Virginia Woolf.
Harcourt, Brace, and World, New York
Woolf V (1953) A writer’s diary: being extracts from the diary of Virginia Woolf. Hogarth Press,
London
Chapter 4
Virginia Woolf’s Suicide
An Introduction to the Neuropsychiatry of Depression
in the 21st Century: The Central Role of the Synapse
In the last two chapters we have considered the prevailing opinions of psychiatry in
the twentieth century as they impacted on Virginia Woolf. An introduction is now
given as to how twenty first century neuropsychiatry understands her condition and
to what extent it holds out the prospects of ameliorating the suffering of those who
have similar conditions.
Virginia Woolf committed suicide in early 1941. Why did the greatest narrative
writer in English of the twentieth century end her life at 59? There are two strands
to this tragedy. One relates to the very stressful events that occurred at the beginning
of the Second World War, just before her death, together with recurring episodes of
depression throughout most of her life prior to this time. The other involves her
childhood experiences of sexual abuse by her 12-year older half-brother Gerald
Duckworth, which began when she was 6 and continued until she was 15. She was
also sexually abused by her other half-brother George Duckworth. As we will see,
twenty first century neuropsychiatry now provides considerable insight into the
biological changes that such abuses effect in the normal functioning of the brain of
a child. These changes are of a type which make it very difficult for the maturing
individual to restrain themselves from fits of anxiety and deep depression, particu-
larly when they are confronted by very stressful events. So a violent act of self-
harm, such as when Virginia at 22 threw herself out of a window at the time of the
death of her father and her half-sister, cannot be considered in isolation from the
abusive experiences of her childhood. She was admitted to a sanatorium on frequent
occasions between 28 and 31 years with the worst hysterical conditions reaching a
climax at 33 years, near the beginning of the first world war in 1915. These can all
be traced in biological terms to the precipitation of an un-restrained tendency to
melancholy by stressful experiences played out against a background of changes to
her brain due to the behaviour of George and Gerald Duckworth. What are these
changes that will place the future life of a child in such jeopardy? And what are the
biological changes in the brain that occur when not only Virginia but anyone goes
down the path of major depression?
There is a fear held by many that discussions concerning the functioning of the
brain in the detail provided by twenty first century psychiatry, although clearly relevant

32 4 Virginia Woolf’s Suicide
to understanding depression, will be far too esoteric for the non-professional to grasp.
Others, on the other hand, regard such discussions as a form of ‘medicalization’,
that is an attempt to reduce our humanity to that of an android, and bring aspects of it
under the control of professionals whose explanations as to our condition are opaque.
Neither of these worries is justified. We all suffer depression from time to time for it is
part of our humanity to have such experiences, indeed ‘depression’ is the ‘common
cold’ of the brain. What we rarely experience, thank heavens, is clinical debilitating
depression. An image that gives feeling to this malady is one of Goya’s etchings from
the Caprichos series, in which the despairing figure is bent over, face covered with both
hands in an attempt at protection from the dark figures of encompassing sharp-beaked
birds of prey and hound- like cats (Fig. 4.1). There is a need to consider some of the
major types of cells and their properties in the brain in order to understand how changes
in our brains can make it very difficult for some to reject the thoughts and feelings
epitomized by Goya’s visual metaphor.
The idea that a normal working brain is necessary for our being able to think,
remember, perceive, feel and have emotions, that is to have psychological capacities,
is relatively recent (Fig. 4.2a). The thought that the heart is the organ required to
have sensations and emotions goes back to Egypt in the 3rd millennium BC and was
still being proposed by Aristotle in the fourth century BC. It was not until Galen in
the first century AD that it was finally understood that it is something in the head
that must function in order for us to possess psychological abilities, but even then
Galen thought that it was the fluid-filled hollow chambers of the brain, the ventri-
cles, that must be intact for these abilities to be expressed. Over 1500 years later, in
the seventeenth century, Thomas Willis working with Christopher Wren showed
that it was likely to be the cortex of the brain rather than its ventricles that must
function for us to be able to possess psychological capacities. None of these
researchers, responsible for such ground-breaking discoveries, claimed that what-
ever part of the body seemed to be necessary for a human to have a capacity was
identical to that capacity. They were simply endeavoring to discover by experiment
what organ or parts of an organ must function for a human being to possess these
capacities, as described in more detail in Chap. 10. Very unfortunately there is an
arrogance amongst many contemporary neuropsychiatrists that leads them to make
the claim that a part of the cortex is identical to the capacity that fails if that part is
lesioned. But evidence for such a claim is not possible. All we neuropsychiatrists do
is study the workings of the cortex that accompany the expression of a psychological
capacity such as perceiving and feeling. What then is being examined in the brain
when a subject is expressing such capacities?
The principal cells of interest in the brain are neurons, discovered as individual
cells in the second half of the nineteenth century by the famous neuroanatomist
Ramón y Cajal and also, as we have seen in Chap. 3, by Sigmund Freud when he
was a young man. Freud wanted to peruse his first-rate research at the cellular level
into the workings of the brain but failed to find a salary-paying position and so went
off in other directions as a consultant doctor in brain disorders which are so well
known as not to need elaboration here. Freud’s work, summarized in From Neurology
to Psychoanalysis, provides much information about different kinds of neurons.
4 Virginia Woolf’s Suicide 33
Fig. 4.1 “El sueño de la razón produce monstruos” (“The dream of reason brings forth monsters”)
by Franciso Goya, 1799
Both Cajal and Freud discovered that neurons were generally small, in the cortex
about one fiftieth of a millimeter in diameter, and possess about nine thin processes.
Eight of these processes are relatively short, about one tenth of a millimeter, and are
called dendrites. The ninth is generally much longer, is called an axon, and proceeds
from the cell body for distances that range from a few thousandths of a millimeter
to metres. An axon in the cortex makes between hundreds and thousands of connec-
a
Axon
terminal
2 4
Synaptic
cleft 3
Dendritic spine
Fig. 4.2 (a) The human cortex. Regions indicated are: A precentral gyrus and primary motor cortex,
B superior frontal gyrus, posterior end near central sulcus, C inferior frontal gyrus, posterior end,
D inferior frontal sulcus, anterior end in the ventrolateral prefrontal cortex, E inferior frontal sulcus
in the dorsolateral prefrontal cortex, F anterior limit of superior frontal sulcus, G frontal pole, H pri-
mary sensory cortex in postcentral gyrus, I supramarginal gyrus (area 40), J angular gyrus (area 39),
K occipital pole, L–N anterior, middle, and posterior portions of STG, O–Q anterior, middle, and
posterior points along the inferior temporal gyrus anterior end. All quadratic, cubic, or linear terms
were significant with P < 0.05. Copyright (2004) National Academy of Sciences, USA (Gogtay et al. 2004). (b) Synaptic
transmissions between neurons. Action potential conduction along axons end at the axon terminal
that contains synaptic vesicles of neurotransmitters (1). The electrical depolarisation of the mem-
brane causes the voltage gated calcium channels (2) to open. The influx of calcium induces the vesi-
cles to dock to the membrane wall and release the neurotransmitter into the synaptic cleft. These
molecules bind to the post-synaptic neurotransmitter receptors (3) to invoke an action potential in the
dendritic spine, propagating the signal forward. The neurotransmitter is then metabolised or taken up
by re-uptake pumps (4) to be repackaged into new vesicles
Stress 35
tions onto the dendrites of other neurons. These connections, called synapses, are
only about 1,000 of a millimeter in diameter. Neuropsychiatry has shown that what
goes awry in depression, and indeed other psychiatric diseases such as schizophre-
nia, is principally the functioning of particular synapses.
Cajal showed that the cortex of the brain is partitioned into gray matter and white
matter. This distinction arises because axons passing from one part of the cortex to
make synapses in a distant cortical area are grouped together and as each axon is
covered by a white fatty-sheath this area appears white. The area that appears gray
in comparison lies above the white matter and contains principally the cell bodies of
neurons as well as the dendritic processes of the neurons on which synapses are
located. It is useful to specify the number of neuron cell bodies and the synapses
they form in order to obtain some idea of the exceptionally high degree of connec-
tivity provided by these synapses. The gray matter contains about 100,000 million
neurons, each with an axon forming connections with many other neurons so that on
average each neuron possesses more than 20,000 synaptic connections (Fig. 4.2b).
This means that the number of synaptic connections in the brain is immense, about
100,000 million multiplied by 20,000, and these are served by about 100,000 km
(62,000 miles) of axons in the white matter. This level of connectivity reflects the
very large number of specialized networks of neurons that must function in order for
us to be able to exercise such psychological capacities as thinking, remembering,
perceiving, sensing and feeling.
What changes occur in the cortex that makes it so difficult for some individuals
to restrain themselves from entering into melancholia? In general this malaise is
preceded by stress that subsequently develops into a sustained sense of anxiety that
then unfolds into deep depression. It is best to consider each of these in that sequence.
The tragic example we will follow is that of Virginia Woolf in the year leading up
to her eventual suicide.
Stress
We know from our own experience what very stressful circumstances are. They
might take the form of observing a violent act towards someone, including ones self,
of being threatened by such an act, of the death of a loved one, of losing one’s job
or of suddenly being displaced from one’s accommodation. The response to these
experiences is generally one of intense fear and of helplessness or even horror. Fear
that the events will be repeated in some form. This often leads to the blunting of
one’s usual emotional responses to normal events, to a kind of numbness, to a
decline in the quality of one’s memory as well as awareness of one’s immediate
environment.
It is abundantly clear in Virginia Woolf’s diaries that the beginning of the Second-
World War led to a series of events in her life that resulted in severe stress with the
consequences just spelt out. She was married to a well-known literary Jew, Leonard
Woolf, and therefore feared that she would be on the Nazi list of those to be
‘removed’ in the United Kingdom after the successful invasion of Britain by the
Germans. This was anticipated in 1939 to be a near certainty. As it turned out there
was one such list and she and Leonard were on it. Then on the 19th June, 1940,
France suddenly capitulated, bringing the implementation of the Nazi program with
respect to Britain very close indeed. Virginia notes in here diaries (Woolf 1939,
p. 124) that by the 18th August in that year German raider aircraft were flying to
their targets so close to her country house on the east coast, the so-called Monks
House, that while she was there ‘they brushed the trees at the gate’. Then on the 18th
of September her London house in Mecklenburgh Square was bombed, with all the
windows smashed as was much of the interior. Virginia was stricken by this as all
24 volumes of her diaries were kept at Mecklenburgh (entries, 23rd Nov.; 18th Sept.;
22nd Oct., 1940; Woolf and Bell 1977). On rushing down from Monks House to
London she was able to save most of these but the shock had been great. Virginia
had in 1940 experienced many such events. She comments that she couldn’t ‘plan
anymore long books’ and writes in September that ‘all writers are unhappy’ (entries,
15th May, 1940; Woolf and Bell 1977). The picture of the world in books is thus too
‘dark’ (entry, 26th July, 1940; Woolf and Bell 1977).
What is happening in the gray matter of the cortex under conditions of such
severe stress? We know from animal studies that even mild stress, such as induced
by gently handling a mouse on a regular basis each day, will give rise to loss of
synapses and the dendrites on which they connect in particular parts of the frontal
cortex. This leads to a loss of gray matter and the failure of synaptic neural networks.
For example, mild stress of animals for 20 min during 7 consecutive days results in
a decrease in the number of synapses along dendrites of neurons in the prefrontal
and anterior cingulate cortex (Fig. 4.3a). Stressing animals by restraining them for
about 3 h each day for over 3 weeks leads to a loss of about 30% of all synapses on
neurons in some prefrontal cortical regions and this is accompanied by a loss of
dendritic branches. This loss of synapses and dendrites is largely reversed if a period
of rest from stress is allowed or in some cases if the agent lithium is administered.
Thus a 3-week recovery period following a 3-week regime of daily stress results in
the return of most of the dendrites and their synapses lost during the stress period.
There is a loss of gray matter from the cortex in people who are stressed through
fears of the kind that Virginia experienced often during 1940 (Fig. 4.3b). These are
the same areas of cortex affected in stressed animals. Such cortical changes are very
likely due to the loss of synaptic connections and dendrites like those observed in
fearful and stressed animals. On the other hand the amygdala of the cortex becomes
highly excitable in both animals and humans that are stressed through fear (Fig. 4.3a).
This very likely occurs as a consequence of the abnormal prefrontal and anterior
cingulate cortical regions in stressed patients failing to inhibit the activity in the
amygdala, which as a consequence becomes abnormally excitable (Fig. 4.3a).
The decreased activity in the gray matter of some prefrontal cortical regions and
enhanced activity in the amygdala due to stress is accompanied by enhanced release
of the steroid hormone cortisol from the adrenal glands into the blood (Fig. 4.4a).
This is of great interest as cortisol can enter the cortex where, if in high enough con-
centration, it acts to strip out synapses in certain gray matter regions and enhance
synaptic activity in others. In particular, cortisol-like compounds enhance excitation in
the amygdala but lead to the loss of synapses and dendrites in the prefrontal cortical
Stress 37
Fig. 4.3 (a) Functional

pathways between the rostral
anterior cingulate cortex and
the amygdala, in which the
former exerts inhibitory
control on the latter. Image
from Carter and Krug (2009)
(Reprinted with permission from the
American Journal of Psychiatry
(Copyright ©2009). American Psychiatric
(b) Outlines of the
Association).
anterior and posterior
subregions of the cingulate
cortex (Reprinted from Caetano et al.
2004. Copyright (2004), with permission
from Elsevier)
Fig. 4.4 (a) The circuits for ‘psychological’ stress (upper box) and ‘physiological stress’ (lower
box). ‘Psychological’ stress (large open arrow) engages the hippocampus whereas ‘physiological’
stress engages the hypothalamic periventricular nucleus (PVN) that then releases corticotropin-
releasing hormone (CRH) into the hypothalamo-pituitary portal system. CRH stimulates the
release of adrenocorticotropic hormone (ACTH) from the pituitary which is then responsible for
the adrenal glands releasing glucocorticoids (GC). The vertical arrow leading from the vicinity of
the adrenals show GCs crossing the blood–brain barrier to act on the type-2 corticoid receptors
(GR, not labeled) in the amygdala increasing stress, and leading to an increase in CRH release
from the PVN. In addition, GCs act on the hippocampus, PVN and pituitary to ‘shut-off’ the
release of GCs (blunt-ended lines) (Reprinted from Fenoglio et al. 2006. Copyright (2006), with permission from Elsevier).
(b) Observations for control subjects, suicide victims with a history of childhood abuse and suicide
victims with no history of childhood abuse of the frequency of methylation of each CpG site in the
NR3C1 promoter region. Abused suicides versus controls (*P < 0.05,**P < 0.001). Non-abused sui-
cides versus controls (&P < 0.05,&&P < 0.001). Abused suicides versus non-abused suicides
(#P < 0.05, ##P < 0.001) (Reprinted by permission from Macmillan Publishers Ltd: Nature Neuroscience, McGowan et al. 2009.
Copyright (2009))
regions that normally dampen down activity in the amygdala. Thus the precipitating
factor in the loss of prefrontal cortical synapses leading to enhanced amygdala activ-
ity is probably the excess release of cortisol from the adrenal glands into the blood
stream, as described in greater detail in Chap. 5. Virginia Woolf would have had such
elevated levels of cortisol hormone following the German raider craft passing over
Monks House, and the bombing of her Mecklenburgh Square house in London, with
the anticipated loss of the 24 volumes of her diaries (Woolf 1939, p. 124).
Depression 39
Anxiety
Stress is often followed by anxiety, by excessive worry about an apprehensive

expectation, anticipating that stressful events will recur even though that is extremely
unlikely. Such anxiety is generally accompanied by irritability, tiredness, fatigue
and sleepless nights. Anxiety precedes the development of a first experience of
major depressive disorder in about 30% of cases with anxiety preceding recurrent
cases of such depression in about 75% of cases. About 75% of patients with major
depression, also suffer anxiety. This was the case with Virginia Woolf. After the
stressful events of the mid 1940s she lived in expectation of an imminent German
invasion occurring near Monk’s House, perhaps starting at Newhaven, three miles
away (entry 26th Jan., 1941; Woolf and Bell 1977). She felt that writing was now
carried out under the threat of imminent death, that there was not long to live before
being carted off to the death camps. She wanted the invasion to start and that ‘It’s this
standing about in a dentist’s waiting room that I hate’ (Woolf et al. 1975, p. 3710).
Her anxiety was now overlapping into major depression. The changes in her cortex
accompanying the development of these symptoms were probably the same as those
who suffer from generalized anxiety disorders. These changes can now be examined
with non-invasive imaging techniques, that is with magnetic resonance imaging in
which both the extent of gray matter and its activity in particular parts of the brain
can be ascertained without significantly disturbing the patient. These imaging stud-
ies show that there is even greater activity in the amygdala than that found under
conditions of stress alone and it is accompanied by subdued prefrontal gray matter
activity.
Depression
Major depression, precipitated by anxiety, is characterized by excessive guilt, deep

sadness, feelings of worthlessness and thoughts of suicide. Virginia Woolf makes
explicit in her diaries, at the end of 1940 and the beginning of 1941, that she suf-
fered from all these symptoms. In November she writes that her autobiography was
worthless, ‘too circuitous and unrelated: too many splutters; as it stands’ and that
indeed her entire life’s work was worthless (entry, 1st Nov., 1940; Woolf and Bell
1977). By January she is trying to fend off overwhelming feelings of ‘rejection’.
She feels being engulfed by a ‘trough of despair’ (entry, 15th Jan., 1941; Woolf and
Bell 1977) and prepares for suicide by carrying around a lethal dose of morphine
(entry, 20th June, 1940; Woolf and Bell 1977). In addition, she arranges for Leonard
to keep gasoline in the garage so that they can gas themselves with car exhaust
fumes. Finally Virginia loads her coat up with heavy stones so as to facilitate drown-
ing herself in the creek nearby Monks House. On the 28th of March she commits
suicide. The power of the disease of major depression in distorting one’s grasp on
reality is no more clearly delineated than here, with the author of Mrs Delaway, The
Waves, Orlando and To the Lighthouse thinking that her life’s work is ‘worthless’.
What then are the cortical gray matter changes that made it so difficult for Virginia
Woolf to restrain herself from entertaining such ridiculous notions of worthlessness
and so descending into deep depression?
The incapacity to restrain oneself from thoughts that epitomize major depression
almost certainly occurs as a consequence of the substantial loss of gray matter that
can be detected in the cortex. Magnetic resonance imaging of prefrontal and ante-
rior cingulate cortex regions shows that there is a gray matter loss of about 12%
(Fig. 4.3b). Although 12% may not seem very much, it probably indicates that there
has been a 40% loss of dendrites in these areas of the brain, as shown in Chap. 6.
This amounts to the disconnection of an enormous number of synapses, normally
found on the lost dendrites, and so of the neural networks they support. Such failure
leads to an exceptional increase in activity of the amygdala as it is no longer inhib-
ited by these prefrontal gray matter areas (Fig. 4.3a), with the consequences that
Virginia Woolf experienced. Indeed the depth of depression is greater the larger the
loss of gray matter in these particular prefrontal areas.
So the development of depression through periods of stress and anxiety is char-
acterized by gradually increasing activity in the amygdala. It is this increase that has
been the subject of a very large number of recent studies both at the level of resolu-
tion provided by the imaging of gray matter as well as at the level of single neurons
and the networks they serve, as described in detail in Chap. 5. We now have insights
into how our incapacity to restrain fear is supported by these networks in the
amygdala and although we do not know how an incapacity to restrain ourselves
from depression is related to certain networks in the amygdala becoming exces-
sively active, we will in the near future.
What is the trigger for the loss of synapses and dendrites in the prefrontal regions
of the brain in major depression? Again this seems to be due to very high levels of
cortisol stripping out synapses in the prefrontal brain regions and directly exciting
activity in the amygdala, but now this high concentration is maintained independent
of chronically experienced stress. How does this happen? The amount of cortisol
released from the adrenal glands is under tight control. Once cortisol is released it
can act back on the pathway that leads to its own release and dampen down this
release (Fig. 4.4a). A process whereby the initial release feeds back to decrease
further release is called negative feedback. The site that cortisol acts on is given the
technical name of ‘glutocorticoid receptor II’ abbreviated ‘GRII’. If something goes
wrong in the functioning of GRII then the negative feedback ceases to function and
so there is no break on the release of cortisol from the adrenals (Holsboer 2000).
Cortisol then rises to high concentrations, penetrates the brain and causes damage
to synapses and the dendrites on which they connect in the cortical prefrontal gray
matter. The consequences are that amygdala activity rises in an unrestrained manner
with all the ramifications for melancholia that Virginia Woolf details in her diary
towards the end of her life.
The creativity of Virginia Woolf no doubt had its origins in the brilliance of her
father and the talent of her mother, together with the exceptional literary milieu in
which she grew up, supported by a great private library of the kind one might expect
to find in the home of the editor of a major literary journal, the Cornhill Magazine.
Childhood Abuse: Stress, Depression and Suicide in Later in Life 41
But to seek out the tragedy of her life, recurring major depression, we must search
into the events of her childhood and the changes these brought about in her cortex
that predisposed her to this terrible condition.
Childhood Abuse: Stress, Depression and Suicide

in Later in Life
The major risk factor for suicide is sexual or physical abuse in childhood. Indeed
those that have been sexually or physically abused when children amount to about
65% of all those who attempt suicide. This was shown in a study of adolescents in a
State comparable to that of an Australian State (namely, Seattle, State of Washington).
In this study suicide rates in which the victim succeeds in injuring themselves were
five times higher if the victim had been sexually abused as a child than if they have
not been abused. Early life abuse increases significantly the risk of life-time major
depressive disorder. Even children who experience mild adversities are likely to be
more reactive to later major difficulties in life (Seguin et al. 2007).
Besides sexual or physical abuse another major risk factor is a family history of
suicide. Family, twin and adoption studies indicate that suicidal behavior has an
underlying genetic predisposition that, although distinct from a genetic predisposi-
tion to mental illness, is nevertheless perhaps dependent on it, so that these genetic
predispositions are not independent when considering suicide. For example a large
group amongst those that commit suicide or attempt to do so consists of patients
with borderline personality disorder and impulsive-aggressive behavior. Levels of
impulsive-aggressive behavior are correlated with the history of suicidal behavior in
patients such that suicide behavior is at least partly explained by familial transmis-
sion of impulsive-aggressive behavior. Adolescent male suicide attempters are
nearly six times more likely to suffer from post-traumatic stress syndrome and over
three times more likely to suffer from borderline personality disorder if they have
been sexually abused as children.
Virginia Woolf, as we have noted, was first sexually abused as a child of 6 by
her 18-year old half brother, George Duckworth, and this continued until she was
15. As is to be expected, it had a profound effect on the course of her life that can
be clearly traced in her diaries up to the time of her suicide at 59. It is highly
probable that it is the abuse in her childhood that led to suicide, for suicide had
not occurred in her family and she did not suffer from borderline personality
disorder or impulsive-aggressive behavior. Virginia gives a detailed account of
the first of these encounters in which George lifted her onto a ledge outside the
dining room door. The ledge was usually used for stacking dishes. But George
lifted her onto it and:
‘as I sat there he began to explore my body. I can remember the feel of his hand going under
my clothes; going firmly and steadily lower. I remember how I hoped that he would stop;
how I stiffened and wriggled as his hand approached my private parts. But it did not stop.
His hand explored my private parts too.’ (Woolf 1939, p. 69).
This abuse was punctuated by her being briefly institutionalized at 13. A few
years after it ceased, at 22, she threw herself out of a window. At 26 she unburdens
herself, writing of George’s ‘violent gusts of passion’ of how he behaved ‘little better
than a brute’ (Woolf 1939, pp. 45, 58). This was followed by her being returned to
the institution on frequent occasions between the ages of 28 and 30. Such treatment
did not prevent her condition deteriorating into a severe hysterical state at 33. During
these periods of incarceration her diary is silent, sometimes up to a year at a time.
Much later, at 54, she wrote that she had seen Gerald Duckworth for the first time in
20 years and that visiting him was
‘like visiting an alligator in a tank an obese and obsolete alligator, lying … half in water and
half out of water.’
(entry, 1st April, 1936; Woolf and Bell 1977).
And at the end of her life she still found telling the truth about these sexual events
very disturbing
‘like breaking the hymen – if that’s the membrane’s name – a painful operation … I still
shiver with shame at the memory of my half brother, standing me on a ledge, aged about six,
and so exploring my private parts. Why should I have felt shame then?’
(Nicolson and Banks 1975, p. 3678).
Indeed why was Virginia unable to lead a normal life for 44 years after the sexual
abuse ceased? Are there changes in the gray matter of the developing brain follow-
ing abuse as a child that made it extremely difficult for her to exert the restraint
necessary to prevent collapsing into severe anxiety and deep depression following
even minor stressful experiences?
It is very likely that Virginia, as an abused child, often had major elevation of her
cortisol hormone levels for even young children in an insecure relationship with their
parents have such excess elevations following mildly stressful events, whereas those
in secure relationships do not. Such elevations are known to lead to both emotional
and behavioural problems as the child matures. The maturing abused child carries an
additional burden due to failure of the negative feedback pathway that dampens down
the extent of cortisol release. This leads to high elevation of the hormone in the blood
on experiencing mildly stressful events. It does not happen to those that experience
occasions of clinical depression who have not been abused as children.
Some mention should be made of another hormone that is secreted under stress-
ful conditions, namely ‘corticotropin releasing hormone’ abbreviated CRH in the
scientific literature. This hormone is secreted by the hypothalamus in the brain, and
is integral to triggering the release of cortisol from the adrenals (Fig. 4.4a). The
sensitivity of the gene for this hormone is set early during development to a level
that is determined by maternal care: if this decreases, the hormone is found in high
levels in the brain at maturity, with consequent higher levels of cortisol in the blood
and this is accompanied by fearful behaviour; on the other hand, sustaining mater-
nal care leads in maturity to decreased levels of the hormone and so decreased
amounts of cortisol in the blood and reduction in fearful behaviour when faced with
a stressful experience.
Childhood Abuse: Stress, Depression and Suicide in Later in Life 43
Virginia was 13 when her mother suddenly died and then her half-sister 2 years
later, at which time Virginia had the first of what was then called a ‘serious nervous
breakdown’. A teenager is especially vulnerable to stressful events, particularly one
that is carrying the burden of an uncontrolled cortisol response to stress as Virginia
did following abuse by the Duckworth’s. What is it about the teenage years that
makes us vulnerable in a way that most of us do not experience later in life, even if
we do have a loving, caring and protective relationship with our parents in child-
hood? In late childhood and throughout adolescence the gray matter of the cortex
declines, some areas more than others, with each area possessing a characteristic
time course of decline. By the time youth is over there has been on average a 30%
loss of dendrites and synaptic connections compared with that in the gray matter
towards the end of childhood. It is likely that this loss of synapses is due to the matu-
ration of neural networks using synaptic connections that are found to be ‘useful’.
Their use is determined by our adolescent experiences, with the pruning of those
networks and their synapses that prove not to be useful. The cortex requires a very
large amount of energy to sustain its activities, about 20% of the entire energy expen-
diture of the body, so that this sculpting out of neural networks has the effect of
reducing the energy demand by a significant amount. But it leaves an adolescent
especially vulnerable to the possibility of excessive loss of cortical networks. This
readily occurs following substance abuse such as taking cocaine or metamphet-
amines. Sexual or physical abuse as a child introduces a major factor for stripping out
excess numbers of synapses during adolescence when mature and stable neural net-
works are being established, for mildly stressful events leading to elevated levels of
cortisol hormone will strip out synapses and the networks they serve. If the number
of synaptic connections serving a network falls below about 60% then the network
will fail, with all the consequences this has for a normal life both during adolescence
and through one’s mature years, a life that was denied to Virginia Woolf. This was
denied because the abuse she experienced, like all those so abused, brought about
synaptic changes in her cortex due to excess levels of cortisol following failure of the
negative-feedback control normally mediated by the glucocorticoid molecule GRII.
Abused girls more often think of committing suicide and actually attempt to do
so, than those not abused and this is accompanied by failure of the negative feed-
back that dampens down cortisol release (De Bellis et al. 1994). Indeed measures of
the extent of this failure provide a good prediction of subsequent suicide behaviour,
which has been traced to a decline in the normal function of GRII. In contrast, a
loving, caring and protective family environment militates against this decline in
function of GRII. The increase in cortisol hormone in the blood that occurs as a
consequence of the failure of GRII is almost certainly responsible for the reduced
gray matter in prefrontal cortex that follows major depressive disorder in those that
have been sexually abused as children, most likely reflecting a loss of synapses and
dendrites in these parts of the brain (see Chap. 6). It is interesting to note that this is
accompanied by an increase in size of the amygdala, reflecting the increased excit-
ability of this part of the brain in such depression. The question that now needs an
answer is how does childhood abuse bring about a change in GRII? The answer to
this question lies in the recently described phenomenon of epigenetics of the GRII.
Epigenetics refers to alterations in the function of genes that can be inherited, but
are not due to any changes in the sequence of nucleotides that make up DNA, the
normal basis for changes in the function of genes. It is now known that children who
have been sexually or physically abused and are victims of suicide possess epigenetic
changes in the gene for GRII that lead to its down-regulation. Genes possess promot-
ers that are regions which when activated, for example by proteins delivered to the cell
nucleus, can regulate expression of the gene. If these promoters are blocked such
expression ceases. Such a block is affected by a process called methylation which is
instigated in children through a cascade of chemical events triggered by abuse.
Examination of the gene promoter for GRII in suicide victims who have suffered from
childhood abuse shows extensive methylation compared with suicide victims with no
history of such abuse or of subjects that have not committed suicide (Fig. 4.4b).
Virginia Woolf’s failure to be able to restrain herself from suicidal thoughts
throughout her life can be traced to the disease state arising from a loss of gray mat-
ter in the prefrontal and anterior cingulate cortex due to the abuse she received from
George and Gerald Duckworth. Underlying this loss are the pathological changes in
synaptic connections with the subsequent failure of neural networks, described in
Chap. 5. The core pathology involves excess levels of the hormone cortisol, released
under stressful conditions from the adrenals, entering the brain and acting to disturb
synapses in the prefrontal cortex. The resulting failure of normal prefrontal cortex
releases the amygdala from inhibitory control so that it becomes hyperexcitable, a
signature for severe depression. The traumatic effect that the Duckworth’s behav-
iour had on Virginia led to decreases in the expression of GRII genes so removing
the normal regulatory mechanisms that control cortisol reaching excessive levels. If
Virginia were alive today what could be done to protect her from the consequences
of the Duckworth’s abuse? Clearly the paramount requirement is reconstitution of
the GRII gene to its normal function. This will have the effect of once more placing
cortisol under regulatory control so ensuring that it does not reach concentrations at
which it exerts deleterious effects. Since it is methylation of the GRII gene promoter
that is at the heart of the problem the search is on to try and produce demethylation
agents. Such agents have to be tailored to rehabilitate the GRII gene to normal func-
tion without reactivating genes whose methylation state needs to be retained for
other cellular processes to proceed normally. Agents such as zebularine have been
found that can reverse the methylation state providing the first proof of the concept
that changes in the extent of gene methylation can be induced by a drug. This is
spelt out in detail in Chap. 8.
Virginia saw Freud, who had migrated to London to escape the Nazis, just before
she committed suicide. She did not need knowledge of modern neuropsychiatry to
know that her episodes of major depression were due to her childhood experiences
of incest. What Freud had to offer was that her memories of the occasions of this
incest were distorted, and probably not even true. Rather her memories were
invented in order to fulfill the desire of what she wished to have happened rather
Notes 45
than what actually happened. So the various incidences involving the Duckworths
were actually fantasies. There seems very little chance of significant rehabilitating
of an abused child to a normal adult life, free of debilitating depression, by means
of psychoanalysis or for that matter modern cognitive behavioural therapy. What we
do have is clear evidence for the deleterious biological changes that occur consequent
on child abuse and a way forward to ameliorate them. The appalling consequences
for reasonable happiness following childhood abuse could not be more vividly spelt
out than in the diaries and other writings of one with such great narrative gifts as
Virginia Woolf. If we cannot protect most children from abuse then we can at least
work to understand the neuropsychiatric basis of their life-long suffering and by that
means effect practical interventions to ameliorate it.
Notes
These notes are of two kinds. First, there are scholarly references to the studies on
which the various claims in this essay are based (see References). Second, the mate-
rial in these references are elaborated on more fully than in the text with consider-
ation given to interesting details as well as to the assumptions on which hypotheses
are based. All these notes are preceded by the page number and a phrase or sentence
from the essay to which they refer.
(p. 35) These connections, called synapses.
The eight or so long dendritic processes of the dominant class of neurons of the
cortex, the pyramidal cells, are cumulatively about one millimetre in length. Each
dendrite possesses thousands of small protrubences or spines about one thousandth
of a millimetre in length on which the terminals of the axons of other neurons about
forming the synapse. Of great interest is that during normal late childhood and ado-
lescence the number of these spines declines dramatically and this decline is precipi-
tous in some psychiatric diseases such as schizophrenia (Glantz and Lewis 2000).
(p. 35) develops into a sustained sense of anxiety that unfolds into deep
depression.
Although this is the established progression into major depression, the reverse
is possible, that is major depression may precede anxiety. The evidence points to
progression of these mental illnesses in about 30% of cases in either direction with
high levels of comorbidity (Moffitt et al. 2007).
In one of the most famous and important studies every carried out in neuropsy-
chiatry, Caspi and his colleagues followed the lives of over 1,000 children in New
Zealand during a period from 5 years to over 20 years in order to record the influence
of stressful events on their development of major depression. They found that certain
individuals exhibited depressive symptoms, diagnosable depression and suicidality
on the experiencing of the stressful vicissitudes of life. Other individuals did not
develop these illnesses when experiencing the stressful events. Caspi and colleagues
went on to show that those in the former category possessed one or two copies of the
short allele of the serotonin synaptic transmitter pump promoter polymorphism

whereas those in the latter cohort generally were homozygous for the long allele.
This monumental study provided a major insight into how genes and the environ-
ment interact, how an individual’s response to environmental insults is moderated by
their genetic make-up in the development of mental illnesses (Caspi et al. 2003).
The classical research by Caspi and colleagues in 2003 was confirmed in 2007
by a study in which threatening life events that occurred to 737 participants were
followed over a 6-month period. The extent of development of major depression by
these participants in relation to their possessing the short allele of the serotonin
pump promoter polymorphism was then ascertained. It was found that the short
allele genotype required minimal exposure to threatening life events in order to
acquire a level of risk for depression. Those that had just the long alleles or a mix-
ture of short and long alleles required higher exposure to these events before being
at risk of depression (Cervilla et al. 2007).
(p. 36) even mild stress, such as induced by gently handling a mouse on a
regular basis each day, will give rise to loss of synapses and the dendrites...
Repeated stress of rodents by restraining them for a few hours each day over
3 weeks leads to a loss of relatively large synaptic spines and an increase of small
spines on dendrites of neurons in the prefrontal cortex. This suggests that stress has
led not only to a remodeling of the dendrites, mentioned above, but has also resulted
in the failure of synaptic spines to mature, so leading to immature synapses (Radley
et al. 2008). Although restraint stress leads to dendritic atrophy and therefore syn-
apse loss this need not be irreversible. If the state of the dendrites is reexamined
after 10 days of restraint then the dendrites gradually return to their normal size and
shape (Conrad et al. 1999). Glucocorticoid hormones such as cortisol, released from
adrenals under stressful conditions, reorganize the dendrites on neurons in the pre-
frontal cortex, such that the more distal parts of the dendrites atrophy and so loose
the synapses that normally abut on them (Wellman 2001).
There is little evidence that neurons are lost in stress, anxiety or major depression
although there is evidence for loss of glial cells in major depression and in stressed
rodents. A principal class of these glial cells is the oligodendrocyte, which has pro-
cesses that wrap around the axon, providing insulation. A significant percentage
of these oligodendrocytes are lost in depression and stress (Banasr et al. 2007).
A review of the effects of stress on the atrophy of dendrites and on other cellular
structures is provided by McEwen and Magarinos (2001).
(p. 36) leading to a loss of gray matter and the failure of synaptic neural
networks.
Theoretical simulation of the functioning of neural networks shows the extent to
which the pruning of synapses, as occurs following stressful events, may have significant
effects on the capacity of the brain to store memories (Miyoshi and Okada 2004).
(p. 36) Stressing animals … leads to a loss of … synapses on neurons
in some prefrontal cortical regions … accompanied by a loss of dendritic
branches.
There is selective atrophy of the distal (apical) dendrites of pyramidal neurons in
the medial prefrontal cortex (such as the rostral anterior cingulated cortex; rACC)
Notes 47
following mild restraint stress of rodents, such that many dendrites are lost and
those that remain are significantly shorter than normal. Such loss of the principal
dendrites of pyramidal neurons means that a large proportion of the excitatory
synapses on these neurons regress (Liu and Aghajanian 2008). Even very mild
restraint stress of rodents, amounting to no more than 10 min of restraint each day
for a week, results in the atrophy of about 35% of the distal branches of dendrites in
the medial prefrontal cortex including rACC (Cook and Wellman 2004). Mild
restraint stress of rodents removes about 30% of all dendritic spines on which syn-
apses form as a consequence of the atrophy of dendrites and also a decrease in the
density of remaining spines (Radley et al. 2006).
The functional consequences of the loss of many of the synaptic connections to
these regions of the dendrites is that the release of the transmitter serotonin fails. The
loss of these synapses and the dendrites on which they abut is likely to be mediated
by actions of the stress hormone corticosterone, the main steroid glucocorticoid
released from the adrenals of rodents (Brown et al. 2005). Chronic treatment with
lithium, still the main agent to treat patients suffering from bipolar depression since
its discovery by John Cade in Melbourne over 60 years ago, prevents the atrophy of
dendrites in mildly stressed rodents (Wood et al. 2004).
(p. 36) a three-week recovery period following … stress results in the return
of most of the dendrites.
Not only can lithium treatment reverse the loss of distal (apical) dendrites and
their synaptic connections in the medial prefrontal cortex due to mild stress but so
can periods of rest from the stress that are comparable to the length of the stress
period (Radley et al. 2005).
(p. 36) the amygdala of the cortex becomes highly excitable … stressed
through fear … as a consequence of the now abnormal prefrontal cortical
regions in stressed patients.
If patients with post-traumatic stress disorder are asked to view photographs of
fearful faces they showed an increase in amygdala activity coupled with a marked
reduction in the activity of medial prefrontal cortex (particularly in the anterior
cingulated cortex, rACC) in comparison with normal subjects, determined using
functional magnetic resonance imaging. This implicates a loss of inhibitory control
of the amygdala by the rACC in the stressed patients compared with healthy con-
trols (Shin et al. 2005). Further evidence for an exaggerated amygdala activity,
diminished medial prefrontal activity, and a reciprocal relationship between the
two is shown in similar experiments to those of Shin and his colleagues (Williams
et al. 2006).
A seminal contribution to determining correlations between fear, stress, anxiety
and major depression on the one hand and cortical activity on the other was made
by introducing non-invasive brain imaging to determine the spatial extent of
changes in cortical activity while subjects viewed photographs of fearful or happy
faces, varying systematically in emotional intensity. Significant correlations were
found between activity in the amygdala and fearful as opposed to happy expres-
sions. Importantly amygdala activity increased with the intensity of the emotion
which increased with the extent of fearfulness (Morris et al. 1996).
If subjects were asked to intentionally mimic an emotional expression, such as

one of happiness, instead of passively viewing photographs then non-invasive imag-
ing showed that activity in the amygdala was again involved. This and the results of
other facial mimicry, such as anger and sadness, are given in Lee et al. (2006).
The use of the non-invasive technique of functional magnetic resonance imag-
ing has recently been utilized to measure cortical activity of patients with major
depression when they view photographs of faces with sad facial expressions,
both before and after receiving therapy. During acute depressive episodes patients
showed elevated amygdala activity when viewing sad faces compared with
healthy patients and in addition showed decreased activity in the anterior cingu-
late cortex. This reciprocal relationship suggests that anterior cingulate activity
might normally inhibit amygdala activity, and this fails in major depression, as
indicated in Fu et al. (2008)
(p. 36) On the other hand the amygdala of the cortex becomes highly
excitable…
The amygdala is a relatively small group of neurons that lies below the cortex,
towards the front of the brain and close to the hippocampus that is required for the
exercise of our ability to remember things for more than about 30 s. LeDoux has
carried out very extensive research on the role of the amygdala in the behavioural
manifestations of fear, including the connections between the neurons that mediate
this fear conditioning. With the advent of functional magnetic resonance imaging it
has been possible to show that there is heightened activity in the amygdala of people
that are experiencing fear. A further discovery which has been of great interest is
that such increased activity also occurs during feelings of anxiety and with occur-
rences of depression. This activity of the amygdala can be suppressed by input from
a region of the cortex called the anterior cingulate, which lies above the amygdala
in the midline of the cortex, just above the millions of axons that connect the two
halves of the cortex or hemispheres called the corpus callosum. In particular, the
part of the anterior cingulate that is closest to the front of the brain, and dips just
below the corpus callosum, called the subgenual, has a key role in modulating
amygdala activity and hence our capacity to experience fear, anxiety and depres-
sion. If the subgenual is damaged or looses synaptic connections with the amygdala
then neurons here become particularly active and we are unable to suppress feelings
of anxiety and even depression.
The rostral anterior cingulate cortex is a prefrontal cortical region that indirectly
modulates the amygdala through its connections with the contiguous subgenual
anterior cingulate cortex that plays a key role in modulating fear extinction in the
amygdala. Magnetic resonance imaging determination of the size of the anterior
cingulate cortex show that its volume is smaller in patients with major depression
as compared with normal subjects. Furthermore, the volume of the anterior cingu-
late in patients with major depression decreases with an increase in symptom
severity.
Non-invasive brain imaging shows that subjects suffering from post-traumatic
stress syndrome, common in soldiers returning from active duty, have heightened
activity in their right amygdala when viewing photographs of fearful faces com-
pared with normal subjects that are not suffering from the syndrome.
Notes 49
(p. 35) feared that she would be on the Nazi list of those to be ‘removed’
in the United Kingdom.
‘In 1939 she was living her life under the threat of imminent death. She believed
that she did not have long to live. She knew that if the invasion of England by the
Nazis ever materialized, she and Leonard, a Jew, would be seized and carted off to
the death camps; indeed their names were on a list of people to be taken immedi-
ately following the invasion’ (Zwerdling 1986, p. 289).
(p. 36) There is a loss of gray matter from the cortex in people who
are stressed through fears …
In order to identify those parts of the cortex that are implicated in our experiencing
fear and stress, cortical activity is assessed using non-invasive brain imaging (such as
that provided by functional magnetic resonance imaging; fMRI) whilst a subject views
separate photographs of faces that express the emotions of steadily increasing fear and
horror. When the activity in the amygdala is assessed with non-invasive brain imaging
during the viewing of progressively more fearful faces, there is a progressively
enhanced activity as the faces express greater fear and horror. If faces are viewed in a
series of photographs that express progressively increased happiness then non-
invasive brain imaging shows that activity in the amygdala becomes progressively
more subdued. During acute depression the right amygdala of patients shows
increased activity (using non-invasive brain imaging) when they are presented with
photographs of subjects expressing increased sadness compared with normal subjects.
After 16 weeks of Cognitive Behavioural Therapy there is no difference. Non-invasive
brain imaging (fMRI) shows that subjects suffering from post-traumatic stress syn-
drome have heightened activity in their right amygdala when viewing photographs of
fearful faces compared with normal subjects that are not suffering from the syndrome.
The amygdala of depressed patients taking the antidepressant fluoxetine (Prozac)
show reduced capacity for activation when viewing photographs of sad faces as com-
pared with viewing the same photographs before taking the anti-depressant.
(p. 36) cortisol-like compounds … lead to the loss of synapses and dendrites
in the prefrontal cortical regions.
Molecules at synapses that bind glucocorticoids released from the adrenals, such
as cortisol in humans and corticosterone in rodents, are called ‘glucocorticoid recep-
tors’ or GRII. Meaney and Aitken discovered that medial prefrontal cortex in rats
possesses such receptors and that these grow in number during the equivalent of the
adolescent period in rat (Meaney and Aitken 1985).
Injections of corticosterone into rats in order to activate their glucocorticoid recep-
tors has the effect of decreasing the (apical) dendritic length of pyramidal neurons,
for instance in the archicortex (hippocampus). So the injected glucocorticoids target
the same components of the gray matter, namely the (apical) dendrites of pyramidal
neurons, as does the experience of stress which is known itself to release glucocorti-
coids from the adrenals. This suggests that this steroid mediates the stress induced
loss of dendrites and their synapses (Woolley et al. 1990; Watanabe et al. 1992).
(p. 39) imaging studies show … greater activity in the amygdala …accompa-
nied by subdued prefrontal gray matter activity.
Patients with generalized anxiety disorder were presented with aversive pictures
preceded by a warning cue and this repeated using neutral pictures. During these
presentations the patients underwent functional magnetic resonance imaging to

determine the activity in the amygdala and the prefrontal anterior cingulate cortex.
The patients showed heightened activity in the amygdala during the anticipatory
period compared with healthy subjects. Consistent with the important role of the
rACC was the observation that less hypoactivity here was associated with a more
efficacious outcome of pharmaceutical intervention (Nitschke et al. 2009). A very
interesting commentary and elucidation of the implications of the Nitschke et al.,
observations can be found in Carter and Krug (2009).
(p. 40) major depression … consequence of the substantial loss of gray mat-
ter … in the cortex.
Measurements have been made of the volume of the rostral anterior cingulate
cortex (rACC) in patients with bipolar depression as compared with lithium-treated
patients and healthy subjects using magnetic resonance imaging. The volume is
reduced by about 15% in the bipolar-depressed patients compared with healthy
subjects. Furthermore, the cingulate volume in the lithium-treated patients was not
significantly different to that in the healthy patients, indicating that lithium had
restored a constituent of the gray matter that is lost in bipolar depression (Sassi
et al. 2004).
In a comprehensive summary and analysis of the results of magnetic resonance
imaging determinations of gray matter loss in patients suffering from major depres-
sion, not only were significant volume decreases noted in the rACC but also
significant but smaller decreases in frontal cortical regions such as the orbitofrontal
cortex and the prefrontal cortex, the latter also thought to normally inhibit activity
in the amygdala. These affected cortical regions show changes in activity during
emotional and stressful events (Koolschijn et al. 2009). The decreases in rACC
volume occur in both unipolar and bipolar depression (Caetano et al. 2004).
There is not only better outcome predictions for medication of patients with
major depression that have less volume diminution of their rACC, that is their rACC
is closer in volume to that of normal subjects, but also if the volume of their prefron-
tal cortex is closer to that of normal subjects. This result is to be expected if both the
normal rACC and the prefrontal cortex exert inhibition over excessive amygdala
activity associated with major depression. If the volume of rACC and prefrontal
regions are closer to normal so will be the inhibitory control exerted over the
amygdala (Chen et al. 2007).
The idea that it is normal activity in the rACC which is especially important in
restraining activity in the amygdala is emphasized by observations on male children
which are showing just subclinical depressive symptoms. They have smaller
rACCs, especially if they come from families with a history of major depression,
compared with children that do not have such subclinical signs. As anticipated,
there is no change in amygdala volume in children with subclinical depression
signs (Boes et al. 2008). Decreases in activity of prefrontal cortex (subgenual) in
both bipolar and unipolar depressed patients determined by imaging glucose
metabolism and cerebral blood flow using positron emission tomography (PET)
shows that these regions are depressed in proportion to decreases in prefrontal gray
matter (Drevets et al. 1997).
Notes 51
The gray matter volume of the rACC is reduced in patients with major depressive
disorder as well as in bipolar disorder. Although this reduction is accompanied by a
loss of glial cells in the rACC, there is no change in the number of neurons. However
the loss of glial cells is insufficient to account for the decrease in volume of rACC
whereas a loss of dendrites consequent on loss of their synapses is (Kassem et al.
2012). Of considerable interest is that stimulation of the (subgenual) rACC with
electrodes in patients with treatment-resistant major depression ameliorates their
condition (Drevets et al. 1997). Gray matter volume in the prefrontal cortex is
increased towards normal in patients with bipolar depression after 4 weeks treatment
with lithium (Moore et al. 2009).
The ventro-medial prefrontal cortex is defined here as a broad area in the lower (ven-
tral) central (medial) region of the prefrontal cortex, of which the medial orbitofrontal
cortex constitutes the lower-most part. Both of these papers show, using magnetic reso-
nance imaging, that the gray matter in this part of the cortex decreases by about 32%
in major depressive disorder (Bremner et al. 2002; Lacerda et al. 2004). The anterior
cingulate cortex, another medial prefrontal cortical region, also shows a decrease in
volume in patients with depression amounting to about 33% (Kaur et al. 2005).
(p. 40) loss of synapses and dendrites in the prefrontal regions … in major
depression.
There is direct evidence for a loss of dendrites and synaptic spines in patients with
mood disorders through labeling these structures with a protein unique to them, namely
microtubule-associated proteins 2 (Rosoklija et al. 2000). Specific labeling of protein
expression and messenger RNA for proteins located at synapses (complexin I and II)
show that this is decreased in some areas of cortex (e.g. hippocampus) in bipolar
depression patients, consistent with a loss of synapses (Eastwood and Harrison 2000).
(p. 40) The site that cortisol acts on is given the technical name of ‘glutocor-
ticoid receptor II’ abbreviated ‘GRII’.
Another molecule besides GRII is of considerable interest in relation to the loss of
synapses and their dendrites in prefrontal cortex (rostral anterior cingulate cortex)
that normally inhibits the amygdala, and that is brain-derived neurotrophic factor
(BDNF), synthesized by neurons in the cortex. This factor is required for the devel-
opment of dendrites and their synapses, particularly inhibitory synapses. It might be
then anticipated that the failure of synthesis of normal BDNF would lead to changes
in the rostral anterior cingulate cortex and the amygdala, the two regions of cortex of
particular interest in relation to major depression and suicidality; this seems to be the
case. The following three papers give particulars of how BDNF controls the growth
of synaptic spines and their dendrites (An et al. 2008; Rauskolb et al. 2010; Hong
et al. 2008). Changes in the volume of gray matter in the rostral anterior cingulate
cortex consequent on changes in BDNF are described in Pezawas et al. (2005).
There is a decrease in the expression of BDNF in the prefrontal cortex of
depressed patients and of suicide victims. Maternal separation of animals leads to a
decrease in adulthood of BDNF expression in different cortical areas including the
prefrontal cortex. These decreases are due to increased methylation of the BDNF
gene. It seems likely that part of the excitability of the amygdala, the cortical region
so important in relations to suicidality, is determined by suitable levels of BDNF
gene expression and that this is under methylation control as is GRII. The decrease
in expression of BDNF in cortical regions associated with depression and suicidality
is given in several reports (Perroud et al. 2008; Calabrese et al. 2009; Cirulli et al.
2003; Fumagalli et al. 2004; Lippmann et al. 2007). The key paper showing methy-
lation repression of the BDNF gene is Roth et al. (2009).
(p. 41) sexually or physically abused … 65% of all those that attempt
suicide…
This American study is the best carried out on the extent to which those that
attempt to commit suicide have experienced sexual abuse. It would be of great
interest to know if these statistics can be extrapolated to countries with a not to
dissimilar culture, such as Australia. The details of the methodology used and the
results obtained in the American study are to be found in Bensley et al. (1999). An
interesting review of the entire literature on this subject, which covers other nations
than just America, is by Evans et al. (2005).
(p. 41) Early life abuse increases … risk of life-time major depressive
disorder.
A 20-year study of 600 American children that had been sexually or physically
abused showed that they had a markedly increased risk of suffering major depres-
sion over their lifetimes. A separate study of 1,000 New Zealand children, from
birth to 18 years, established significantly higher rates of major depression, anxiety
disorders, conduct disorders, substance use disorders and suicidal behaviour. Those
in the highest risk category had been abused through sexual intercourse as children
(Widom et al. 2007; Fergusson et al. 1996).
(p. 41) suicidal behavior … underlying genetic predisposition… distinct
from a genetic predisposition to mental illness… perhaps dependent on it.
By studying monozygotic and dizygotic twins the extent of genetic inheritance of
a predisposition to suicide was established 20 years ago (Roy et al. 1991, 1995). More
recent research has shown that youth suicide attempts are familial and have managed
to establish this is the case even though problems such as alcohol dependence, social
phobias and conduct disorders had to be controlled for when interpreting the results
(Glowinski et al. 2001). The complex interplay between psychiatric history and
genetic vulnerability specific to suicidal behaviour is given in Statham et al. (1998).
Also consult the monograph by Schulsinger et al. (1979).
A very interesting study has been made of the frequency of psychiatric disor-
ders and suicide behaviour in the biological and adoptive relatives of adoptees with
these disorders. It was found that both showed family-associated transmission of
the genesis of the disorders (Wender et al. 1986).
(p. 41) that commit suicide … consists of patients with borderline personal-
ity disorder and impulsive-aggressive behavior.
This is a well-researched subject establishing that clear associations exist between
a subjects tendency to participate in impulsive violence and their committing suicide
(Brent et al. 1994).
The natural history of over 1,500 Canadian students has been followed over a
period of 15 years, from age 6 until 21. Surprisingly 33% of these experienced a
high level of suicidal thoughts and 9% actually made at least one serious attempt at
Notes 53
committing suicide. The capacity for disruptive disorders amongst the 33% was
quite marked. This work emphasizes the need for collecting statistics on individuals
through their early lives, rather than just collecting data on collections of students at
different ages (Brezo et al. 2007). Of 104 Canadian males that committed suicide,
and who died during an episode of major depression, both impulsive and aggressive
behaviors were shown to be major risk factors (Dumais et al. 2005). Those that
commit suicide and suffered from borderline personality disorder differ from those
that suffer from this disorder in acute psychiatric settings in as much the former
show a comorbid interaction between impulsive behaviour on the one hand and
violent-aggressive tendencies on the other (McGirr et al. 2007).
(p. 41) suicide behavior … partly explained by familial transmission
of impulsive-aggressive behavior.
Early American studies of the extent of suicide in families with a history of suicide
attempts suggested that suicidal behavior is a genetic trait that is transmitted together
with aggressive behavior (Brent et al. 1996).
This early work has been confirmed in three separate Canadian studies. One
involving 500 psychiatric patients found that those with a personal history of sui-
cidality had a three times more frequent history of suicidal behavior in the family,
and their behavior was associated with higher impulsivity and aggressive tendencies
than the non-suicidal patients (Diaconu and Turecki 2009). This research is sup-
ported in the following Canadian report (Kim et al. 2005).
The interaction between the genetics of impulsivity and childhood abuse, leading
to epigenetic changes, is described in Figure 1 in Mann (2003). Interestingly, the
extent of impulsivity amongst female suicide victims is less than amongst male
victims, although still a risk factor, as reported in McGirr et al. (2006).
The interaction between parental mood disorders and impulsivity and their abu-
sive behaviour on the one hand and the effects of such disorders inherited from the
parents together with abuse of the children is described in the figure in Brent and
Mann (2006). These interactions are spelt out in some detail by Braquehais et al.
(2010) as well as Currier and Mann (2008).
(p. 41) borderline personality disorder … sexually abused as children.
Men who have been subjected to childhood sexual abuse and have recently
attempted suicide not only have a higher level of suicidal thoughts but also of feel-
ings of hopelessness. They are much more likely to have made several suicide
attempts compared with those men who attempt to commit suicide but have not been
subjected to childhood sexual abuse (Spokas et al. 2009).
(p. 42) elevation of …cortisol hormone levels for …young children
in an insecure relationship with their parents.
Toddlers are inhibited in their approach to novel objects or in their participation
in novel events if they have a poor attachment relationship with their mothers. The
inhibited toddlers have elevated levels of the stress hormone cortisol indicating
activation of the stress system (namely the hypothalamic – pituitary – adrenal axis
system; Nachmias et al. 1996). It is likely that disturbance of the mother-child
relationship leads to both loss of synapses in the developing cortex through
enhancement of the stress system (mediated by glucocorticoids) as well as in the
availability of neurotrophic factors that also impact on the integrity of synapses

(Cirulli et al. 2003). Exposure to stress in childhood leads to early and long-lived
hyperactivity of the stress system, resulting in increased stress responsiveness that
probably underlies the tendency to anxiety and mood disorders in adulthood (Heim
and Nemeroff 2001).
(p. 42) The maturing abused child carries an additional burden due to failure
… that dampens down the extent of cortisol release.
Changes in the adrenal cortisol levels in the blood of children between birth and
5 years in relation to variations in their care quality have been determined. Less than
optimal care leads to elevation of cortisol in infants, especially those with negative
emotional temperaments (Hertsgaard et al. 1995; Gunnar and Donzella 2002).
This review establishes the extent to which different degrees of disorganized
attachment between a child and its carer leads to behavioral and emotional problems
later in life (Van Ijzendoorn et al. 1999).
(p. 42) It does not happen to those that experience occasions of clinical
depression who have not been abused as children.
This major work establishes that a history of childhood abuse of a female leads to
their reacting to a stressful event when they reach maturity, and are suffering from
depression, with a significant elevation of cortisol compared with those not so abused.
There is then increased responsiveness of their hypothalamic-pituitary-adrenal stress
system. Furthermore the elevation in cortisol in maturity is greater the more frequent
the abusive events when they were children (Heim et al. 2002).
(p. 42) another hormone that is secreted under stressful conditions, namely
‘corticotropin releasing hormone’
Corticotropin releasing hormone (CRH), secreted by cells in the hyptothala-
mus, possesses receptor molecules that it activates located in the cortex and in the
hypothalamus. The most important influence on the expression of these CRH
receptor molecules is determined by the extent of stress during childhood, primar-
ily determined by the quality of maternal care (Korosi and Baram 2008). Primates
exposed as infants to adverse early rearing conditions possess elevated levels of
corticotropin releasing hormone when they reach maturity (Coplan et al. 1996).
Cortisol, released from the adrenals following the action of corticotropin-releasing
hormone from the hypothalamus, is elevated in the blood of those with unipolar
depression. Interestingly, in the case of those with ultra-high risk of developing
psychoses, the elevation of cortisol is best correlated with these patients experi-
encing ‘hassles’ (like trying to find lost keys) rather than major stressful events
(Thompson et al. 2007).
(p. 42) The sensitivity of the gene for this hormone is set early during devel-
opment to a level that is determined by maternal care.
When mothers are confronted with an unpredictable environment they are less
able to maintain a stable attachment relationship with their child. This then exposes
the child to stressful circumstances leading the infant to manifest depressive symp-
toms. It leads to the young adult experiencing reduced sociability and enhanced
timidity. These young adults are also different in their behavioral responses to anx-
iety-altering pharmaceutical interventions compared with young adults that have
Notes 55
not experienced stressful circumstances as children (Rosenblum and Andrews 1994;

Rosenblum et al. 1994).
(p. 42) sustaining maternal care leads in maturity to decreased levels of the
hormone.
In these classic papers Meaney and his colleagues show that female rodents that
provide increased licking and grooming of their pups during the first 10 days after
birth show reduced glucocorticoid (corticosterone) hormonal responses to acute
stress and substantially reduced behavioral fearfulness in response to novelties. As
there was also evidence for increased glucocortiocoid receptor molecules the reduc-
tion in the hormone was probably due to an increased capacity for corticosterone to
feedback and inhibit its own release by acting on these molecules. The conclusion
is that enhanced maternal care has led to an increase in the expression of the gluco-
corticoid receptor (GRII) throughout the rest of the life of the animal, with all the
benefits that confers in relation to responses to stress. The chief amongst these is
less excitability of the amygdala in stressful situations, which is correlated with a
decrease in the development of depression (Liu et al. 1997; Caldji et al. 1998).
(p. 43) the time youth is over there has been on average a 30% loss of den-
drites and synaptic connections.
It was shown for the first time in this classical paper of Huttenlocher, using the
electronmicroscope, that there is a very significant decrease in the number of syn-
apses in the cortex of adolescents compared with early childhood and that after ado-
lescence the number stabilizes, with only a slight decrease after age 74 (Huttenlocher
1979). The observations of Huttenlocher have been largely confirmed using modern
techniques of immunology and tracing the changes in proteins that are unique to
synapses (Glantz et al. 2007; Petanjek et al. 2011).
(p. 43) If the number of synaptic connections serving a network falls below
60% then the network will fail.
The following four papers largely provide a review of the literature up to
2007 concerning evidence for synapse loss in the cortex and archicortex (hip-
pocampus) in patients suffering from either bipolar or unipolar depression. The
two papers by Eastwood and Harrison also provide additional evidence, using
immunological methods, that there are changes in the extent of synaptic pro-
teins in the cortex of patients suffering from these diseases. Collectively, the
reviews support a synaptic pathology as the core problem that leads to these
diseases. Given this is the case, then such diseases during the teenage years
make an adolescent particularly vulnerable to multiple co-morbid difficulties as
the normal loss of synapses in the cortex during this period, amounting to about
30% is now compounded by the additional loss due to synaptic pathology of the
order of 30% (Eastwood and Harrison 2000, 2001; Czeh and Lucassen 2007;
Insel 2007; Gupta et al. 2004).
(p. 43) excess levels of cortisol following failure of the negative-feedback
control normally mediated by the glucocorticoid molecule GRII.
Meaney and his colleagues, having established that there is an enhanced expres-
sion of glucocorticoid receptors (GRIIs) in new-borns following high levels of mater-
nal care and that this is due to increases in GRII gene activity. In this landmark paper
they subsequently investigated the mechanisms that increase GRII gene activity in
the hippocampus. This region of the brain involved in depressing activity of the
hypothalamus (specifically the paraventricular nucleus (PVN) group of neurons) that
initiates the cascade of events ending with the release of cortisol. So cortisol entering
the brain can act to increase the activity of the hippocampus in depressing the PVN
as a consequence of an increase of GRII in the hippocampus. This in turn leads to a
decrease in the cascade of events that results in the release of the glucocorticoid cor-
tisol. As high levels of cortisol lead to excitation in the amygdala then a decrease of
the hormone restricts amygdala excitability associated with depression. Epigenetic
programming referred to in this paper is a mechanism that can prevent the expression
of a gene, in this case the GR gene, by means of chemically masking the gene, either
through methylation of the DNA of the gene itself or by deacetylation of the histones
which package the DNA. Of great interest is the discovery by Meaney and his col-
leagues that the processes of demethylation and of acetylation are under control of
cellular processes that are initiated by maternal behavior towards the infant, involv-
ing the release of the synaptic transmitter serotonin in the hippocampus (Weaver
et al. 2004).
(p. 43) Indeed measures of the extent of this failure provide a good predic-
tion of subsequent suicide behaviour.
There is a negative feedback repression of cortisol release effected by the gluco-
corticoid cortisol itself acting on GR receptors in the hypothalamic-pituitary-adre-
nal system, referred to repeatedly above. A test for the efficiency of this feedback
system has been designed in which a synthetic glucocorticoid, dexamethasone, is
introduced into patients and their cortisol level then measured to ascertain the extent
of its suppression. High levels of suppression indicate an efficient negative feedback
system, probably due to normal expression and activation of the receptor molecules
that mediate this repression, namely the GR molecules. Coryell and Schlesser have
used the dexamethasone test to determine if inpatients at a clinic in Iowa that had
elevated cortisol levels following dexamethasone treatment were at high risk of sui-
cide. They showed that 27% of those with high cortisol release went on to suicide
whereas only 3% did so that had a normal level of cortisol release in the dexametha-
sone test. In a subsequent study by Jokinen and Nordstrom about 39% of young
adult suicide attempters and 25% of those suffering from major mood disorders had
high levels of cortisol in the dexamethasone test (Coryell and Schlesser 2001;
Jokinen and Nordstrom 2009).
This review considers the relevance of changes in genes for the glucocorti-
coid receptor in suicidal behaviour with that for other genes such as those
involved in the serotonergic, noradrenergic and dopaminergic systems (Currier
and Mann 2008).
(p. 43) In contrast, a loving, caring and protective family environment
militates against this decline in function of GRII.
Oberlander and colleagues have recently made a very important observation that
the extent to which the glucocorticoid receptor (GR) is masked by methylation in
new born babies is very sensitive to prenatal maternal depressed/anxious mood fol-
lowing on the early review by Meaney suggesting the importance of variations in
Notes 57
maternal care on the expression of genes that regulate behavioral responses to stress.
Such new-born babies are then at risk of developing depressive symptoms as a con-
sequence of a faulty GRII-mediated repression of cortisol release. Elevated levels of
the hormone, particularly in response to mild stress, have consequences for enhanced
amygloid activity and major depression as already noted (Meaney 2001; Oberlander
et al. 2008).
(p. 43) reduced gray matter in prefrontal cortex that follows major depres-
sive disorder.
The decrease in volume and activity of medial prefrontal cortex (rACC) in major
depression disorder has been noted. The following two papers give reviews of this
claim and extend consideration of such losses to the archicortex (the hippocampus)
(Sheline et al. 2002; Campbell and MacQueen 2006).
(p. 43) reduced gray matter … follows major depressive disorder in … sexu-
ally abused as children.
This very important study, noted below, establishes that women suffering from
major depressive disorder that have been sexually abused as children have an 18%
smaller archicortex (hippocampus) than women that suffer from the same disorder
but have not been sexually abused as children (Vythilingam et al. 2002).
(p. 43) reflecting a loss of synapses and dendrites in these parts of the brain.
It has now been shown in a series of animal studies that paternal deprivation dur-
ing development leads to decreases in the number of synapses and neuronal den-
drites in ventro-medial prefrontal cortex (orbitofrontal cortex). This will almost
certainly be reflected in a decrease in gray matter and therefore volume of the orb-
itofrontal cortex (Helmeke et al. 2009).
(p. 43) increase in size of the amygdala … of the brain in such depression.
Female suicidal patients with major depressive disorder possess a smaller ven-
tro-medial prefrontal cortex (orbitofrontal cortex) than do normal healthy females.
Of considerable interest is that the amygdala actually increases in size in these
patients (Monkul et al. 2007).
(p. 44) Epigenetics refers to alterations in the function of genes that can be
inherited, but are not due to any changes in the sequence of nucleotides that
make up DNA.
Here we begin the inquiry into what the process of epigenetics is and to what
extent it is implicated in ‘masking’ the glucocorticoid receptor (GRII). Two main
processes that underpin epigenetics are sketched in the two papers below. One
involves methylation of DNA, a process that does not alter the DNA sequence but
acts to attract what are called ‘transcriptional repressors’ that prevent the binding of
agents that normally activate the gene (in the region of the gene called the ‘promo-
tor’). The other involves modifications of the histones that are concerned with
‘packaging’ the DNA into a relatively small volume; at least parts of this package
has to be unwrapped in order, again, for agents that normally activate the gene to
have access to it; histone modification occurs most frequently through the process
of acetylation. Functions that are under epigenetic control are wide ranging, and
some of these are described in these two papers (Graff and Mansuy 2008; Jaenisch
and Bird 2003).
(p. 44) gene promoter for GRII in suicide victims who have suffered
from childhood abuse shows extensive methylation compared with suicide vic-
tims with no history of such abuse.
The relevance of research on epigenetic changes in GR gene expression in
young animals as a consequence of the kind of maternal rearing they receive bore
fruit in this classical paper from Meaney and his colleagues. They show increased
methylation of the promotor of the GR gene that is specific to neurons in victims
of suicide that had been physically or sexually abused as children compared with
suicide victims that had not been abused. This resulted in decreased production of
the mRNA for the GRII necessary for synthesis of the GRII protein. Methylation
of GRII is therefore likely to be caused by abuse in childhood, with all the conse-
quences for cortisol overproduction, amygdala hyperactivity and major depressive
disorders (McGowan et al. 2009).
(p. 44) The core pathology involves excess .. cortisol, released under stressful
conditions … acting to disturb synapses in the prefrontal cortex.
It is proposed that the increase in cortisol, as a consequence of disregulation of
the GRII gene, acts at synapses to induce their regression and loss. This leads to
subsequent retraction and atrophy of the dendrites. There is then a decrease in gray
matter volume. The mechanisms by which cortisol acts on synapses to induce their
regression are reviewed in (Bennett 2008, 2010).
(p. 44) it is methylation of the GRII gene promoter that is at the heart
of the problem.
The pathway linking, for example, the effects of increased maternal care on
an increase in GRII expression, and therefore on improved repression of excess
cortisol levels, has been identified. Weaver describes how, for instance, tactile
stimulation of an infant by the mother leads to the release of serotonin in the
hippocampus of the infant’s brain with subsequent binding of serotonin to recep-
tor molecules on the surface of neurons. This activates a chemical pathway in
the neurons that produces a substance called ‘nerve growth factor-inducible A’
(NGF1A), which in turn acts on the promotor region of the GR gene. This
chemical pathway also produces cyclic AMP response element-binding protein
(CBP). As CBP is an acetylation transferase of histones it has the effect of open-
ing up the histone packaging of the DNA making it available for NGF1A to act
on the promotor and activate gene expression. Not only is NGF1A an activator
of the GR gene but it also a demethylation agent, so releasing the promotor,
when it becomes available following histone acetylation, to be demethylated
further increasing the access of NGF1A to the promotor and so GR gene expres-
sion (Weaver 2009).
(p. 44) zebularine … can reverse the methylation state.
These two papers consider the progress made in introducing compounds that
modify the state of methylation of DNA and of acetylation of histones. The aim is to
reverse these states and so, for instance, make the promoter of the GRII gene acces-
sible for activation (Roth et al. 2009; Grayson et al. 2010; Schroeder et al. 2010).
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Part II
Neuropsychiatry and Suicide
Part II begins with two chapters that offer details of what contemporary neuropsychiatry
provides in the way of understanding what goes awry in the brain in depression and
following childhood abuse (Chaps. 5 and 6). These are followed by two chapters
concerned with first, how pharmaceutical interventions act in the brain to alleviate
depression (Chap. 7), and second, what class of pharmaceutical interventions are
available or might be possible to ameliorate the psychiatric effects of childhood
abuse (Chap. 8). This Part II concludes with a consideration of the neural basis of one
of the hall-marks of psychosis, namely hallucinations, from which Virginia Woolf
suffered from time to time. All of the chapters in this Part II might be considered to be
so specialized and detailed as to have a restricted audience, namely that of the cogno-
scenti in neuropsychiatry. I hope this is not entirely the case and that the previous four
chapters have enticed the general reader to at least dip into the more specialist chapters
that constitute this Part. In particular Chap. 8, concerned with the identification of
pharmaceutical interventions, has a set of notes at the end which attempt to ease the
reader into the more technical issues given in the body of the text.
Chapter 5
Brain Networks, Hormones and Genes
Implicated in Depression
The Pre-frontal Limbic Network: Modulation
of Synapses by Hormones and Epigenetic Mechanisms
Introduction: The Prefrontal–Limbic Network (PLN)

in Depression
The anterior cingulate cortex, amygdala and hippocampus form part of an interconnected
prefrontal neocortical and limbic archicortical network, as shown in Fig. 5.1, which
is dysregulated in major depressive disorders (MDD; for a review see Bennett 2010b).
This dysregulation is manifested in decreased activity, according to functional
magnetic imaging (fMRI) studies, in dorsal prefrontal areas such as dorsolateral
prefrontal cortex (dlPFC), dorsomedial prefrontal cortex (dmPFC) and both dorsal
and rostral anterior cingulate cortices (dACC and rACC) (Fig. 1; summarized in
Table 1 of Taylor and Liberzon 2007). Such dysregulation is accompanied by increased
activity in ventral prefrontal areas, namely in the ventrolateral prefrontal cortex
(vlPFC), in the subgenual anterior cingulate cortex (sgACC) and in the amygdala
(Fig. 1; Taylor and Liberzon 2007). These differences in activity during MDD have
led to the concept that dorsal areas, associated with cognitive capacities, normally
exert an inhibitory influence over more ventral areas, associated with affective
capacities, but that this influence fails in those suffering from MDD (see Taylor and
Liberzon 2007 for a critical review of this idea). Special emphasis is placed on the
increased activity in the amygdala, as this has been correlated with a range of mood
disorders (Bennett 2010b, 2011). This review canvases the mechanisms of interac-
tion, relevant to MDD, between the PLN and three systems, namely those provided
by the hypothalamic pituitary– adrenal axis, the basal ganglia and the midbrain.
Reprinted from Progress in Neurobiology, Bennett MR, The prefrontal-limbic network in depression: modulation by hypothalamus, basal
ganglia and midbrain. Vol 93: 468-487. Copyright (2010), with permission from Elsevier.

68 5 Brain Networks, Hormones and Genes Implicated in Depression
Fig. 5.1 The PLN–hypothalamic loop. Here the hypothalamus is added to the PLN, receiving
anatomical connections from the rACC, the amygdala and the hippocampus. Dotted lines indicate
hormonal pathways from hypothalamus to pituitary, mediated by corticotropin releasing factor
(CRF), from pituitary to adrenal cortex mediated by adrenocorticotropic hormone (ACTH) and
glucocorticoids (cortisol in humans) released from the adrenal cortex. The broken vertical arrows
adjacent to some boxes indicate whether there is an increase in activity (arrow up) or a decrease in
activity (arrow down) in that part of the brain during depression (from Taylor and Liberzon 2007).
The glucocorticoids act on the prefrontal–limbic neural network as well as providing a negative
feedback pathway, as indicated by the negative signs on the hypothalamic release of CRF and the
release of ACTH by the pituitary. The continuous vertical arrows adjacent to some boxes indicates
whether there is an increase in activity (arrow up) or a decrease in activity (arrow down) in
that part of the brain when high glucocorticoid acts on GRII in that part (after Dedovic et al. 2009).
The negative sign on the projection from rACC to the amygdala indicates that it normally has an
inhibitory influence. The negative sign on the projection from rACC to the hypothalamus indicates
that inhibition derives from the fact that anterior cingulate/prelimbic cortices have excitatory con-
nections to peri-hypothalamic paraventricular neurons (periPVN) which in turn exert an inhibitory
influence on the release of CRF, so producing a net inhibitory influence of rACC on hypothalamic
secretion of CRF (see Herman et al. 2005). The hippocampus also exerts an inhibitory influence on
hypothalamic secretion of CRF, as the ventral subiculum of the hippocampus projects an excitatory
connection to the periPVN, the BST ventral region of the medial preoptic area (vlPOA) and the
ventrolateral region of the dorsomedial hypothalamic nucleus (vlDMH); these in turn inhibit
secretion of CRF from the hypothalamus so the net effect of hippocampus on hypothalamus is to
inhibit secretion. The amygdala however exerts an excitatory influence over hypothalamic secre-
tion of CRF as the medial amygdaloid nucleus has inhibitory connections to inhibitory neurons in
the medial parvocellular paraventricular nucleus, which exerts an inhibitory influence on release of
CRH. The amygdala also has inhibitory connections to the bed nucleus of the stria terminalis
(BST) neurons, which in turn exert an inhibitory influence on the periPVN; the net effect of these
connections is then excitatory from amygdala for CRH release (see Herman et al. 2005) (Reprinted
from Bennett 2010a. Copyright (2010), with permission from Elsevier)
Introduction: The Prefrontal–Limbic Network (PLN) in Depression 69
Hypothalamic-Pituitary–Adrenal (HPA) Axis Modulation

of PLN in Depression
Childhood abuse is a significant factor in depression and suicidal diathesis. The inabil-
ity of the synthetic glucocorticoid dexamethasone to suppress serum levels of cortisol
in suicidal patients points to failure in the normal function of the low affinity gluco-
corticoid receptor (GRII) that mediates inhibition of secretion of corticotropin releas-
ing factor and adrenocorticotropic hormone (ACTH) in the HPA axis through the
action of cortisol. Knocking out GRII in the hippocampus, amygdala and cortex indi-
cates that the PLN control of the HPA axis is subsidiary to direct cortisol control of the
axis. However partial down-regulation of GRII throughout the brain and the HPA axis
in animal models gives results very similar to those observed in suicidal youths: these
are normal basal levels of glucocorticoids, failure to suppress the release of these with
dexamethasone and increased depressive behavior when stressed, as well as substan-
tial increases in cortisol release when stressed. There is now good evidence that epi-
genetic effects are responsible for a decrease in GRII following childhood neglect and
abuse leading to suicidal diathesis. It is now known that suicide victims with a history
of childhood abuse possess increased cytosine methylation in the exon 1F promoter of
the GRII gene (NR3C1), with consequent decreased binding of transcription factor
NGFI-A (nerve growth factor-inducible protein-A) to the promoter, and so down-
regulation of GRII (McGowan et al. 2009).
In suicidal patients with depression, there is a large decrease in the volume of
gray matter in the anterior cingulate cortex with a concomitant increase in gray mat-
ter in the amygdala (Drevets 2007; Drevets et al. 1997), which animal studies indi-
cate is due to a loss or gain of neuropil, reflecting the regression and formation of
synaptic spines, respectively (Bennett 2008a). There is now a plausible model link-
ing epigenetic changes in GRII brought about by childhood abuse, subsequent fail-
ure of the intrinsic regulation of the HPA axis, increased cortisol release under
stress, followed by increased amygdala as well as decreased anterior cingulate cor-
tex activity in the PLN and suicidal diathesis. This hypothesis is developed below.
Basal Ganglia Modulation of PLN
Older persons with depression have significantly higher hyperintensities, due to cere-
brovascular disease, primarily in the basal ganglia with smaller caudate nuclei vol-
umes. In humans, the caudate of the striatum is involved in networks concerned with
goal-oriented behavior, whereas the putamen participates in networks that subserve
habit learning. Hyperintensities in the caudate in late-life interrupt two distinct PLN–
basal ganglia loops as do decreases in 5-HT receptors and transporters. The first of
these, comprising the dorsolateral prefrontal cortex of the PLN and its subcortical
projections, is involved in goal-directed behavior that includes the capacity to exclude
negative thoughts (Balleine and O’Doherty 2010). The second, comprising the
orbitofrontal cortex, the subgenual anterior cingulate cortex, the ventromedial

striatum and the amygdala of the PLN, is involved in goal-directed behavior con-
cerned with the attainment of rewards and the avoidance of punishments (Balleine
and O’Doherty 2010). In severe mood disorders there is hypoactivity in the first PLN–
basal ganglia loop whereas there is hyperactivity in the second loop. The thesis is
developed in subsequent sections that hyperintensities in the caudate are responsible
for these changes in activity that lead to late-life depression.
Midbrain Modulation of PLN
Depression is one of the five different symptoms that characterize schizophrenia. Each
of these symptoms has distinctive times of onset during the prodromal period: depres-
sive, negative (social impairment), unspecific, dystrophic (anxiety) and finally posi-
tive, with about 3 years separating the beginning of depressive symptoms from that of
the positive symptoms (Hafner et al. 2008). The now classical dopaminergic hypoth-
esis for schizophrenia posits that there are low dopamine levels (hypodopaminergic)
in prefrontal cortex of the PLN together with high levels (hyperdopaminergic) in the
striatum of the basal ganglia, the negative symptoms being associated with the former
and the positive symptoms with the latter (Davis et al. 1991). There is good evidence
for increased dopamine in the striatum of patients with schizophrenia (McGowan
et al. 2004; Abi-Dargham et al. 1998, 2000; Howes et al. 2007). The depressive symp-
toms are characterized in the PLN by relatively high levels of activity in the amygdala
and low levels of activity in dorsal cortical areas (Bennett 2009). Mechanisms are
proposed by which pharmaceutical interventions can be identified that exert effects to
partly restore normal function in the PLN and basal ganglia (Leucht et al. 2009).
Modulation of the PLN by the Hypothalamus in Depression
Glucocorticoid Modulation of the PLN
The rostral anterior cingulate (rACC) and prelimbic cortices (plC) have excitatory
connections in the peri-hypothalamic paraventricular nucleus (periPVN) that exert
an inhibitory influence on the release of corticotropin releasing factor (CRF). The
net effect of rACC and plC is then to inhibit CRF release from the hypothalamus
(Fig. 5.1; Herman et al. 2005). The ventral subiculum of the hippocampus (upsilon-
SUB) projects excitatory connections to inhibitory neurons in the periPVN, the bed
nucleus of the stria terminalis (BST), the ventral region of the medial preoptic area
(POA) and the ventrolateral region of the dorsal hypothalamic nucleus (DMH).
These inhibit release of CRF, so that the net effect of the hippocampus on the hypo-
thalamus is to inhibit CRF release (Fig. 5.1; Herman et al. 2005). The medial nucleus
of the amygdala has inhibitory connections with inhibitory neurons in the medial
Modulation of the PLN by the Hypothalamus in Depression 71
parvocellular paraventricular nucleus (mpPVN) that exert an inhibitory influence on

the release of CRF. The amygdala also has inhibitory connections to the BST neurons,
which in turn exert an inhibitory influence on the periPVN. The net effect of these
connections is, then, that the amygdala exerts an excitatory influence on CRF release
by the hypothalamus (see Fig. 5.1; Herman et al. 2005).
Interaction Between the PLN and Glucocorticoids
The question arises, given the PLN in Fig. 5.1 and its neural control of the hypotha-
lamic secretion of CRF, as to the normal interaction between the neuronal and hor-
monal components of this system. Exogenous application of high concentrations of
glucocorticoids (cortisone in humans and corticosterones in rodents), that engage the
low affinity type II GRs (GRII), rather than just the high affinity type 1 (mineralocor-
ticoid) GRs (GRI) in the anterior cingulate cortex, hippocampus and amygdala, has
diverse effects on excitability (summarized in the review by Dedovic et al. 2009; see
especially their Fig. 1). In the case of the hippocampus, engagement of GRII leads to
depression of excitatory synaptic transmission and of long-term potentiation (LTP:
Pavlides et al. 1993; McEwen and Sapolsky 1995; Joels and de Kloet 1991; Zou et al.
2001; Korz and Frey 2003). Engagement of GRI increases LTP and hippocampal
excitability. Thus stress, accompanied by high glucocorticoid levels, leads to deficits
in LTP at synapses between Schaffer collaterals on CA1 pyramidal neurons as well
as between perforant path axon terminals and neurons in the dentate gyrus (Pavlides
et al. 1993; Kim and Haller 2007; Garcia 2001; Yamada et al. 2003).
As GRII are gradually engaged with rising cortisol levels during stress there is
a decrease in activity of the rACC indicating that high levels of cortisol during
stress decrease rACC activity (Kern et al. 2008). Implanting crystalline corticoster-
one into the cingulate gyrus of rodents decreases corticosteroid and ACTH plasma
levels (Diorio et al. 1993). This is consistent with the interpretation of the human
results if the crystalline corticosterone acts on GRI in the rACC. Taken together,
the observations suggest that increasing cortisol levels decrease rACC excitability
and transmission.
Finally, the effect of stress levels of glucocorticoids on the amygdala is to increase
excitability (due to an after-hyperpolarization block) and decrease inhibitory post-
synaptic potentials (ipsp’s due to gamma-amino-butyric acid; GABA) in principal
basolateral neurons by acting on GRII (Duvarci and Pare 2007). Lower concentra-
tions of glucocorticoids that engage GRI still increase excitability due to a depolar-
izing effect on the neurons (Duvarci and Pare 2007; Karst et al. 2002). Thus the
effect of glucocorticoids at all concentrations is excitatory on amygdala activity.
Figure 5.1 summarizes the effects of stress levels of glucocorticoids on the pre-
frontal–limbic control of the hypothalamus. As indicated by the continuous vertical
arrows next to the boxes, the effect of these glucocorticoids is to decrease the
normal inhibitory influence on CRF secretion by the rACC and the hippocampus,
whilst at the same time increasing the normal excitatory influence on CRF secretion
by the amygdala. The net effect of this glucocorticoid influence on the prefrontal–
limbic network is then to increase its own circulation through enhanced CRF release
in a positive feedback cycle, linking the HPA axis and the PLN. High levels of
glucocorticoid will contribute in important ways to the high level of excitability of
the amygdala, through a direct effect as well as indirectly through decreasing excit-
ability in the dorsal prefrontal regions that normally exert an inhibitory influence on
the amygdala (Fig. 5.1). This hypermetabolism and activity in the amygdala are the
main inductive correlates of MDD following childhood abuse.
The Role of Glucocorticoid Receptors in Determining the Basal Level

of Glucocorticoids and Hence of PLN Activity
Besides the action of glucocorticoids on the PLN control of the hypothalamus

described above, mediated by GR, there is also the classical role of GRII in the
hypothalamus and pituitary in mediating inhibition of secretion of CRF and ACTH,
respectively (Fink 1997). What then is the effect of down-regulation of GRII, dis-
tributed throughout the HPA and the PLN, on the level of glucocorticoids that have
such considerable effects on amygdala excitability (for a review, see Kolber et al.
2008)? Investigation of the basis for dysregulation of the HPA axis in suicidal
victims, using rodent models, shows that the locus of this dysregulation is likely to
reside in a decreased expression of the GRII gene, designated NR3CI in humans. For
example, following knockout of this receptor gene in the nervous system of rodents,
including the hypothalamus but not the pituitary or adrenal cortex, the baseline cor-
ticosterone level doubles and the mice are easily stressed (Reichardt et al. 2000).
If there is a 50% gene dose reduction of the GRII levels throughout the brain and
HPA axis, then the mice exhibit normal baseline levels of corticosterone but poor
suppression of corticosterone release in response to dexamethasone and increased
helplessness when stressed, as well as a 30% increase in corticosterone levels when
stressed (Ridder et al. 2005). Specific time-dependent deficits in the expression of
GRII in the forebrain (excluding the hypothalamus and the pituitary) lead to slightly
elevated baseline levels of corticosterone, failure of dexamethasone to inhibit corti-
costerone release, and increased depression-like behavior, as well as a 20% increase
in corticosterone levels when stressed (Boyle et al. 2005, 2006). These last two sets
of observations on the effect of partial down-regulation of GRII or of incomplete
downregulation of GRII throughout the brain and HPA axis in animal models give
results very similar to those observed in suicidal youths: these are normal basal
levels of glucocorticoids, failure to suppress the release of these with dexametha-
sone and increased depressive behavior when stressed, as well as substantial
increases in cortisol release when stressed (De Bellis et al. 1994; Heim et al. 2000;
Jokinen and Nordstrom 2009).
Disturbing GRII using either a GRII exon 2 knockout (Kretz et al. 1999) or a
GRII DNA binding (Reichardt et al. 1998 see below) enhances CRF, ACTH and
corticosterone secretion. Mice deficient in GRII have more than fivefold increases
in CRF and several fold increases in corticosterone. This must reflect the failure of
the negative feedback of glucocorticoids on the hypothalamus and pituitary as the
PLN can, under these circumstances, exert its normal inhibitory (hippocampal and
rACC) and excitatory (amygdala) influences on hypothalamic CRF secretion.

Indeed if anything these influences will be enhanced by the increased corticosterone
levels acting on GRI in these structures to increase their excitation (Fig. 5.1).
If GRII are only knocked out in the brain, then GRII are lost in the hypothalamus
but not in the pituitary or adrenal glands (Tronche et al. 1999). Under these circum-
stances there is a more than tenfold increase in corticosterone, necessarily due to
the glucocorticoid acting on GRII outside of the nervous system. CRF is elevated
eightfold in the hypothalamus, indicating failure of negative control in this organ
in the absence of GRII. There is also a moderate increase in ACTH (1.6-fold) in the
pituitary, indicating that although GRII are intact in the pituitary the negative feed-
back through the elevated corticosterone is insufficient to fully antagonize the
stimulation of the pituitary by the very high levels of CRF. The relatively high
elevation in corticosterone compared with ACTH probably reflects the known fact
that ACTH levels evoke higher secretion of glucocorticoids in mutant animals
compared with controls (Tronche et al. 1999). These observations together indicate
that feedback pathways in the HPA axis regulating glucocorticoid levels are more
powerful than the inhibitory effects of the hippocampus/rACC mechanism for regu-
lating these levels.
When GRII are knocked out in discrete limbic areas such as the hippocampus,
the basolateral and basomedial amygdala as well as parts of cortex but not the hypo-
thalamus or the pituitary or the central nucleus of the amygdala, there is no increase
in corticosterone levels, either before or after stimulation with injected ACTH
(see Fig. 6e in Boyle et al. 2006). This indicates that circulating corticosterone acting
on intrinsic GRII in the hippocampus, basolateral–basomedial amygdala or cortex
does not have a major role in setting prefrontal–limbic control on hypothalamic
secretion of CRF. It is surprising in this regard that recent experiments in which GRI
is overexpressed in the basolateral amygdala showed a reduction in corticosterone
secretion (Mitra et al. 2009), even though it is known that glucocorticoids acting on
GRI increase excitability in the amygdala (Duvarci and Pare 2007).
In summary, the above observations indicate that downregulation of GRII
throughout the brain and HPA axis significantly elevates glucocorticoids under
stress and greatly increases basal levels of glucocorticoids if the GRII are com-
pletely knocked out. Down-regulation of GRII will have the effect of elevating
excitability in the amygdala through the remaining GRII and perhaps GRI, predis-
posing an individual to anxiety and depression. There is very good evidence that
epigenetic effects leading to a decrease in GRII occur following childhood neglect
and abuse. These are now considered.
Epigenetics and Depression
Epigenetics is the ensemble of alterations in gene functions that are heritable through
both mitosis and meiosis, but that cannot be explained by changes in the DNA
sequence itself (Graff and Mansuy 2008; Jaenisch and Bird 2003). Biochemical
Fig. 5.2 Epigenetic marks on histone tails and on DNA. (a) Schematic representation of the
four-nucleosome core histones, H2A, H2B, H3 and H4. (b) Schematic representation of the N- and
C-termini of the core histone H3 and its residue-specific epigenetic modifications. C C-terminus,
N N-terminus tail, A acetylation, M methylation, P phosphorylation. Residues K, R, S and T are
also indicated. From Fig. 1 in Graff and Mansuy (2008) (Reprinted from Bennett 2010a. Copyright (2010), with
permission from Elsevier)
changes in the major constituents of chromatin, namely DNA and histone proteins
(Fig. 5.2a), drive epigenetics through post-translational modifications of histone
proteins and methylation of DNA at cytosine–guanine dinucleotides (CpGs; for a
review see Graff and Mansuy 2008). Histones undergo changes which modify the
condensation of chromatin through acetylation, methylation and phosphorylation
on their N-terminal tails (Fig. 5.2b), and so change the access of transcriptional
mechanisms to the DNA (Fig. 5.3). DNA methylation often occurs in CpG-rich
regions or islands, frequently in the promoter regions, where it can block the binding
of transcription factors through attachment of methyl groups to the C5 carbon in
cytosine in the CpG (Fig. 5.3b). In the case of histone acetylation, there is neutral-
ization of the positive charge on lysine residues in the histone tail (Fig. 5.2b) that
decreases the affinity between DNA and the protein tail so that the chromatin struc-
ture relaxes, allowing co-activators and the transcriptional mechanisms to operate
(Fig. 5.3c). On the other hand, methylation at specific lysine residues (Fig. 5.2b)
leads to condensation of the chromatin (heterochromatin), so that the transcriptional
machinery gains less access to the chromatin (Fig. 5.3a). This, together with the
binding of transcriptional repressors to the methylated DNA ensures transcriptional
silencing (Fig. 5.3b).
Effect of Epigenetic Methylation of the Type II Glucocorticoid Receptor

Gene in the Hippocampus on PLN-Hypothalamic Function
Meaney and co-workers first showed that maternal care exhibited by rats, as indi-
cated by more licking and grooming of pups during the early post-natal period,
Fig. 5.3 Epigenetic regulation in depression. The transcriptional potential of genes involving
responses to stress can be regulated through chromatin modelling events catalyzed by the specific
enzymes shown in this figure. (a) The methylation (Me) histones on specific lysine residues is
associated with condensed chromatin (heterochromatin; this occurs in the repression of brain-
derived neurotrophic factor in the hippocampus of mature animals, following stress through activa-
tion of histone methyl transferase; (Tsankova et al. 2006)). (b) In contrast to this, repression of
other histones can occur through the methylation of cytosine within CpG islands in promoter
regions, attracting proteins involved in transcriptional repression, as shown (this occurs in the case
of DNA methylation, through activation of DNA methyltransferase of the promoter of the gluco-
corticoid receptor gene in rat pups born to mothers with inherently low levels of maternal behavior)
(Weaver et al. 2004). (c) Histone acetylation (Ac) catalyzed by histone acetyltransferase is associ-
ated with decondensed chromatin (euchromatin), increasing the activity of transcriptional com-
plexes (diagrams after Fig. 3 in Krishnan and Nestler (2008) and Fig. 2 in Graff and Mansuy
(2008)) (Reprinted from Bennett 2010a. Copyright (2010), with permission from Elsevier)
leads to increased hippocampal glucocorticoid receptor mRNA expression with

consequent reduction in plasma ACTH and corticosterone responses to acute stress
(Liu et al. 1997). This was later shown to be due to alterations in the pup’s epigenome,
Fig. 5.4 Model of epigenetic reprogramming of hippocampal glucocorticoid receptor (GR) gene
expression and stress responses by maternal behavior. Maternal licking/grooming and arched-back
nursing (LG-ABN) of the offspring increase hippocampal serotonin (5-HT) turnover and activa-
tion of a 5-HT7 receptor, which is positively coupled to cyclic adenosine-30, 50-monophosphate
(cAMP). Increased cAMP activity results in activation of protein kinase-A (PKA) and cAMP
response element-binding protein (CREB). Subsequent phosphorylated-CREB (p-CREB) activity
drives expression of the transcription factor nerve growth factor-inducible protein-A (NGFI-A),
which targets its cognate binding site on the GR exon I7 promoter. NGFI A recruits a histone acetyl
transferase called CREB-binding protein (CBP) that increases acetylation and accessibility to the
DNA demethylase MBD2 and stable glucocorticoid receptor (GR) promoter activation (compare
with Fig. 5.3C; after Fig. 1 in Weaver et al. (2004), and Fig. 2A in Graff and Mansuy (2008))
(Reprinted from Bennett 2010a. Copyright (2010), with permission from Elsevier)
composed of chromatin and a covalent modification of DNA by methylation, at the

GRII (NR3C1) gene promoter (Szyf et al. 2007). In the hippocampus this involves
changes in DNA methylation and altered histone acetylation with transcription fac-
tor NGFI-A (nerve growth factor-inducible protein-A) binding to the GRII promoter
in exon 1.7 (Weaver et al. 2004). This is due to increased histone acetyl-transferase
activity and DNA demethylation consequent on the release of serotonin (5-HT) in
the hippocampus onto 5-HT7 receptors (Fig. 5.4; Weaver 2009). These are posi-
tively coupled to cyclic adenosine-30, 50-mono-phosphate (cAMP) activity, result-
ing in increased protein kinase A (PKA) and cAMP response element-binding
protein (CREB). Phosphorylation of CREB (pCREB), which drives the expression
of NGFI-A transcription factor, is followed by it targeting its binding site on the exon
17 promoter (Fig. 5.4). This factor recruits a histone acetyl transferase CREB-binding
protein (CBP) that increases acetylation and accessibility to the DNA methylase
MBD2 so stabilizing GRII promoter activation.
NR3CI is located on chromosome 5q31 and contains 10 exons that code for a
777 amino-acid protein, with two isoforms GRalpha (functional) and GRbeta (no
hormone-binding ability; Bray and Cotton 2003). There are 11 splice variants of
the human NR3CI exon 1 at the 50 untranslated region, based on seven exon 1’s
(1-D,1-E, 1-B, 1-F, 1-G, 1-C and 1-H; Turner et al. 2006). Exon 1-D is only
found in the hippocampus, and all exon variants possess a proximal promotor
region, unique splice donor sites and share a common exon 2 splice acceptor site
(Turner and Muller 2005).
The multiple first exons upstream of exon 2, each with its own promotor region,
possess CpG rich regions, with exon 2 containing an in-frame stop codon immediately
upstream of the ATG start codon to ensure that 50 heterogeneity is not translated so
determining that the sequence and structure of the GRII is unaffected (Alt et al. 2010).
GRII levels are transcriptionally controlled by these multiple untranslated alterna-
tive first exons, each with its own promoter, so giving tissue-specific fine-tuning of
GRII levels (Alt et al. 2010). There is differential usage of exon 1’s in the brain of
humans, with alternative first exons each under the control of specific transcription
factors. Among the alternative first exons, 1B and 1C are the most active in the
amygdala, hippocampus, cingulate gyrus, nucleus accumbens and inferior frontal
gyrus (Alt et al. 2010). Exons 1E and 1J show the lowest expression and 1F
intermediate levels of expression.
In MDD, the transcription factor of exon 1F, NGFI-A, is down-regulated in the
hippocampus, so reducing exon 1F expression, whereas 1F is uniformly unmethy-
lated indicating that promoter methylation does not contribute to the decreased
exon 1F transcript levels (Alt et al. 2010). On the other hand, the methylation status
of CpG-rich regions in exon 1F of newborns is sensitive to prenatal maternal mood
(Oberlander et al. 2008; Meaney et al. 2007). In particular, suicide victims with a
history of childhood abuse possess increased cytosine methylation in the exon 1F
promoter with consequent decreased NGFI-A transcription factor binding and so
NGFI-A inducible gene transcription of NR3C1 (Fig. 5.4; McGowan et al. 2009).
This does not occur in suicide victims that have no history of childhood abuse,
consistent with the lack of evidence for such methylation of the promoter in exon
1F of patients with major depressive illness that is most likely to be a concomitant
of suicide victims that did not suffer childhood abuse.
Epigenetics of Brain-Derived Neurotrophic Factor (BDNF) in Suicide Victims
There are alterations in epigenetic markers for BDNF and its receptor TrkB in the
brains of suicide victims (for a brief summary, see Autry et al. 2009). It has been
known for some years that BDNF levels are significantly lower in the serum of
patients suffering from MDD (Karege et al. 2002). More recently, reduced expres-
sion of BDNF and TrkB has been observed in the postmortem hippocampus and
prefrontal cortex of suicide victims (Dwivedi et al. 2003). In the case of suicide
victims who had suffered neglect/abuse from early childhood, this decrease might
be due to the observed hypermethylated promoter and 50 regulatory region of genes
(McGowan et al. 2008), especially at CpG dinucleotides on TrkB which leads to
reduced TrkB expression in the prefrontal cortex (Brodmann Areas 8 and 9; Ernst
et al. 2009). There is then epigenetic control of both BDNF and TrkB genes.
The observations of possible epigenetic regulation of BDNF in the human brain of
those subjected to abuse are supported by animal studies. Defeat stress gives rise to
long-lasting decreases in BDNF transcripts III and IV and increases in repressive
histone methylation at their corresponding promoters (Tsankova et al. 2006). Like-
wise, early maltreatment gives changes in BDNF DNA methylation in the adult pre-
frontal cortex, resulting in altered BDNF gene expression (Roth et al. 2009). Histone
acetylation levels of histone H3 are decreased at the promoters of exons I, IV, and VI
following immobilization stress, with reduction in exons I and IV mRNA, giving rise
to significantly reduced levels of BDNF protein (Fuchikami et al. 2009).
Changes in Gray Matter in PLN of Suicidal Patients: Synapse Regression

Due to Changes in Glucocorticoids and Brain-Derived Neurotrophic Factors
In MDD the orbital cortex has a reduced volume (Bremner et al. 2002) due to a
decrease in gray matter (Lacerda et al. 2004), as does the hippocampus (Caetano
et al. 2004). This is particularly the case following sexual abuse as a child
(Vythilingam et al. 2002). A reduced volume also occurs in the anterior cingulate
cortex (Kaur et al. 2005), but not the subgenual prefrontal cortex (Brambilla et al.
2002) nor the amygdala that increases in size in MDD (van Elst et al. 2000). In sui-
cidal patients with depression, there is a large decrease in the volume of gray matter
in the orbitofrontal cortex with a concomitant increase in gray matter in the amygdala
(Monkul et al. 2007). It is interesting to note that an increase in hyperintensities has
been observed in the gray matter of suicidal and depressed patients, particularly in
subcortical gray matter, but not in depressed patients at mid-life (Ahearn et al. 2001;
Pompili et al. 2007, 2008; Ehrlich et al. 2005).
There is a paucity of evidence at present for synaptic changes involving a loss of
neuropil gray matter in those areas of the brain in which volume changes in gray matter
have been detected in MDD patients and those that are suicidal. The synaptic marker
synaptophysin does not change in the prefrontal cortex of MDD patients although there
is a loss of glia (Ongur et al. 1998). However in animal studies, in which direct staining
and counting of synaptic spines have been made, there is about a 30% decrease in
spines of layer II/III pyramidal neuron apical dendrites in 3-month old rodents that
have been subjected to a lack of paternal/maternal care in the first 3 weeks (Helmeke
et al. 2009). Furthermore, low maternal licking and grooming gives rise in the adult
offspring to shorter dendritic branches and lower synaptic-spine density of pyramidal
neurons in CA1 field of the hippocampus (Champagne et al. 2008).
Chronic elevation of glucocorticoids such as corticosterone in rodents leads to
a decrease in volume of the hippocampus and prefrontal cortex, due to a loss of
neuropil as a consequence of a loss of synapses and, in some cases, whole dendrites
(Tata et al. 2006; Tata and Anderson 2010; Zhu et al. 2007; McEwen 2005). The
opposite occurs in the amygdala (McEwen 2005). In the case of the rostral anterior
cingulate cortex (rACC) of humans, increases in cortisol levels that accompany
MDD and stress are associated with a decrease in gray matter volume of rACC
(Treadway et al. 2009). Repeated stress has similar effects, as it is accompanied
by a loss of synapses and dendrites in the prefrontal cortex and hippocampus, with
the opposite occurring in the amygdala, in which there is dendritic hypertrophy
(Fuchs et al. 2006). The details of how activation of the GRs on synaptic spines
modulates N-methyl-D-aspartate (NMDA) receptors and hence spine regression
are outlined in Bennett (2009). What is of great interest here is that there is evidence
in both human and animal studies of a loss of gray matter in those areas of the
brain that normally have an inhibitory influence on the amygdala, such as the rACC
(Fig. 5.1), with a concomitant increase in gray matter in the amygdala accompanying
stress, depression and elevated glucocorticoids. In animals it can be shown that
these changes are almost certainly due to regression of synapses where there is a
loss of gray matter such as in the rACC and formation of synapses where there is
increase of gray matter such as in the amygdala.
BDNF is released at glutametergic synapses onto postsynaptic TrkB receptors
to initiate phosphorylation of glutamate receptor subunits, thereby changing their
sensitivity to transmitter (Carvalho et al. 2008). Activation of the TrkB receptor also
induces immediate early gene activity-regulated cytoskeleton-associated protein
(Arc), essential for consolidation of the F-action network in synaptic spines, neces-
sary for stabilization of LTP (Bramham 2007). On release of BDNF onto the TrkB
of synaptic spines there is rapid activation and translocation of the translational
machinery in the spines and transcription in cell bodies. Activated spines capture
and translate local mRNA pools, with this followed by sustained translation of
newly synthesized and dendritically transported Arc mRNA. Arc-dependent con-
solidation of the spine and stable LTP requires sustained translation of Arc for cofo-
lin phosphorolation and local F-action expansion. Stress suppresses BDNF synthesis
through modification of chromatin structure, resulting in a failure of synaptic-spine
stabilization and LTP (Castren et al. 2007).
Epigenetic Regulation of the Glucocorticoid Receptor in Suicide Victims
The hypothesis suggested here is that childhood neglect and abuse lead to changes
in the release of serotonin that determine the epigenetic status of GRII expression
through histone acetyltransferase and DNA demethylation. This down-regulation of
GRII, without total removal of the receptor, adjusts the set point of the HPA axis
such that the basal level of plasma cortisone is not much changed from normal, but
there is much greater release of cortisone associated with anxiety and stress. Such
elevated glucocorticoids act on synaptic-spine receptors to desensitize the NMDA
receptors on the spines, leading to their regression (previously reviewed in Bennett
2008b) in areas of the brain that normally exert an inhibitory influence on the
amygdala, such as the rACC. Interestingly, the opposite happens in the amygdala,
where spine density increases. The net effect is hyperexcitability of the amygdala, a
necessary condition for depression and suicidal diathesis.
The critical question that arises for this model is: does it lead to the identification
of appropriate pharmaceutical interventions that will arrest the biological mecha-
nisms that support suicidal diathesis? Injection of trichostatin A (TSA) into the
hippocampus of adult offspring from less licking and grooming mothers increases
histone acetylation, facilitates demethylation and increases activation of the GR
exon 17 promoter to levels the same as that of adult offspring of high licking and
grooming mothers (Weaver et al. 2004). Most importantly it reduces stress respon-
sivity to the levels found in the adult offspring of high licking and grooming moth-
ers. On the other hand, L –methionine (MET) inhibits DNA demethylation and
increases DNA methylation, so inhibiting NGFI-A binding and reducing GRII exon
17 promoter activity in the offspring of high licking and grooming mothers so that
they revert to a condition of increased stress responsiveness (Fig. 4; Weaver 2009).
Dietary factors can also provide a means of changing the state of methylation in the
epigenome. For instance DNA methyltransferase catalyzes the transfer of a methyl
group from the methyl donor s-adenoslymethionine (SAM) onto the 50 position of
the dinucleotide sequence CG. Synthesis of SAM is dependent on the availability of
dietary foliates, vitamin B12 and choline, so opening up another approach to alter-
ing the expression of the GRII exon 17 promoter and so the cascade of events lead-
ing to changes in amygdala activity, depression and suicidal diathesis.
Conclusion
Epidemiology shows that the major risk factors for suicide are sexual and/or physical
abuse in childhood and a family history of suicide, together with mental health
problems such as borderline personality disorder and post-traumatic stress syndrome.
These risk factors are not independent as adolescent male suicide attempters are 5.6
times more likely to suffer from post-traumatic stress syndrome and 3.1 times more
likely to suffer from borderline personality disorder if they have been sexually
abused as children (Spokas et al. 2009). Indeed those that have been sexually and/or
physically abused when children amount to about 65% of all those who attempt
suicide in a study of adolescents in Seattle (Bensley et al. 1999, for a review see
Evans et al. 2005). In this study suicide rates in which the victims injure themselves
are five times higher if they have been sexually abused as children than if they have
not been abused (Bensley et al. 1999).
Besides sexual and/or physical abuse the other major risk factor is a family
history of suicide. Family, twin and adoption studies indicate that suicidal behavior
has an underlying genetic predisposition which, although distinct from a genetic
predisposition to mental illness, is nevertheless perhaps contingent on it (Roy
et al. 1991, 1995; Glowinski et al. 2001; Statham et al. 1998; Wender et al. 1986;
Schulsinger et al. 1979), so that these genetic predispositions are not independent
when considering suicide. For example a large cohort among those that commit
Modulation of the PLN by the Basal Ganglia in Depression 81
suicide or attempt to do so consists of patients with borderline personality disorder

and impulsive–aggressive behavior (Brent et al. 1994; Brezo et al. 2007; Dumais
et al. 2005; McGirr et al. 2007). Levels of impulsive–aggressive behavior are
correlated with the history of suicidal behavior in patients (Diaconu and Turecki
2009) such that suicide behavior is at least partly explained by familial transmis-
sion of impulsive–aggressive behavior (Brent et al. 1996; Kim et al. 2005; McGirr
et al. 2006).
Early life abuse increases significantly the risk of life-time major depressive dis-
order (MDD; Widom et al. 2007; Fergusson et al. 1996). Even children who experi-
ence mild adversities are likely to be more reactive to later major difficulties in life
(Seguin et al. 2007). MDD is accompanied by changes in the ‘set-point’ of the hypo-
thalamic-pituitary–adrenal (HPA) cortex axis, with increased corticotropin releasing
factor (CRF), adrenocorticotropic hormone (ACTH) and cortisol secretory activity
occurring which is contingent on impairment in the expression of the glucocorticoid
receptor (GR; Holsboer 2000). Abused girls have a greater incidence of suicidal
ideation and suicide attempts than those not abused, and this is accompanied by
lower CRF stimulated levels of plasma ACTH and cortisol, without much difference
in the basal levels of these, indicating dysregulation of the HPA axis (De Bellis et al.
1994). The inability of the synthetic glucocorticoid dexamethasone to suppress serum
levels of cortisol in these suicidal patients points to failure in the normal function of
the GR (Jokinen and Nordstrom 2009). Maternal care has effects that militate against
this impairment of the GR (Meaney 2001). This involves epigenetic changes in the
expression of the GR gene in new-borns, determined in part by both prenatal mood
and postnatal care (Oberlander et al. 2008).
Modulation of the PLN by the Basal Ganglia in Depression
The PLN–Basal Ganglia Loop
The Goal-Directed PLN–Basal Ganglia Loop
These goal-directed networks are principally of four types. The first type is a limbic
loop, the B-loop in Fig. 5.5, that consists of the rostral anterior cingulate cortex
(Brodman Area (BA) 24) and the pregenual (BA 32) and subgenual (BA 25) cingu-
late cortices of the PLN. These project to the nucleus accumbens (NAc) shell in the
basal ganglia and from there the projection goes through the ventral pallidium (GPi)
and dorsal substantia nigra pars reticulare (SNr)/ventral tegmental area (VTA) to the
dorso-medial thalamic nucleus magnocellular portion (DMmc) which projects back
to the cortex (Fig. 5.5). In this B-loop the subgenual cingulate (BA 25) cortex in
particular, as well as the pregenual cingulate (BA 32) cortex, provides a powerful
projection to the NAc shell (Fig. 5.5) and may play a major role in influencing goals
associated with regulatory and consummatory activities (Haber et al. 1995; Freedman
et al. 2000).
Fig. 5.5 PLN–basal ganglia loops in humans. Four separate network loops are delineated, designated
A, B, C and D. Reading from left to right is the PLN, followed by the caudate– putamen/nucleus
accumbens, the globus pallidus/substantia nigra/ventral tegmentum, and finally the thalamus.
Abbreviations in the PLN are (from top to bottom of the networks): dlPFC dorsolateral prefrontal
cortex, rACC rostral anterior cingulate cortex, sgACC subgenual anterior cingulate cortex, hipp
hippocampus, vmPFC ventromedial prefrontal cortex, OFC orbitofrontal cortex. Abbreviations in
the basal ganglia are: NAc nucleus accumbens, GPi globus pallidus (interior), vlGPi ventrolateral
globus pallidus (interior), SNr substantia nigra pars reticulata, VTA ventral tegmentum area, clSNr
caudolateral substantia nigra pars reticulata. Abbreviations in the thalamus are: VLo ventrolateral
nucleus of thalamus pars oralis, VLm ventrolateral nucleus of thalamus pars medialis, DMmc
medial dorsal nucleus, pars magnocellularis, VApc ventral anterior nucleus, pars parvocellularis,
VAmc ventral anterior nucleus of thalamus magnocellularis, DMpc medial dorsal nucleus, pars
parvocellularis. Continuous lines with arrowheads indicate major connections. Broken lines with
arrowheads indicate separate projections (Reprinted from Bennett 2010a. Copyright (2010), with permission from
Elsevier)
The second network type is the associative loop, the D-loop in Fig. 5.5, that
involves projections from ventromedial prefrontal cortex (vmPFC; BA medial 10)
and the medial orbitofrontal cortex (BA medial 11, 12, 13) of the PLN (Hampton
et al. 2006; Daw et al. 2006; Kim et al. 2006; Tanaka et al. 2004; Valentin et al.
2007). These project to the ventromedial caudate and nucleus accumbens core of
the basal ganglia (Haber et al. 2006; Ongur and Price 2000), and from there the
projection goes through the ventromedial pallidum (GPi) and dorsal substantia nigra
pars reticulare (SNr) to DMmc (Fig. 5.5). In the D-loop, the orbitofrontal cortex
(OFC; BA 11) is very important in relation to goal-directed behavior, in which
rewards and punishments on the performance of goal-directed actions play a role
(Kringelbach and Rolls 2004).
The third network is the dorsolateral prefrontal associative C-loop in Fig. 5.5 that
involves primarily the dorsolateral prefrontal cortex (dlPFC; BA 9, 46) and aspects of
the lateral orbitofrontal cortex (lateral BA 10 and 47; not shown in Fig. 5.5) of the PLN.
Fig. 5.6 PLN–basal ganglia loops in the rat. Three separate network loops are delineated, designated
A, C and D (to be compared with the network loops in humans labeled with the same letters in
Fig. 5.5). These networks are laid out in an analogous fashion to those in Fig. 5.5. Abbreviations
for the cortical networks are the same as in Fig. 5.5. Abbreviations in the basal ganglia are the same
as for Fig. 5.5, with DM dorsal medium striatum. Abbreviations in the thalamus are MD mediodor-
sal thalamus, PO posterior thalamus, continuous lines with arrowheads indicate major connec-
tions. Broken lines with arrowheads indicate separate projections (Reprinted from Bennett 2010a. Copyright
(2010), with permission from Elsevier)
These project via the head of the caudate and the central/rostral portions of the
putamen of the basal ganglia, and from there to the dorsomedial GPi and the rostro-
lateral SNr; the projection from there is then to the thalamic nuclei VApc (ventral
anterior thalamic nucleus parvocellular portion), DMpc (dorsomedial thalamic
nucleus parvocellular position) as well as VAmc (ventral anterior thalamic nucleus
magnocellular portion; see Fig. 5.5, C-loop). This loop is involved in goal-directed
activity involving working memory, spatial memory and executive function, insight
into one’s well being, including the capacity to exclude negative feelings so that
failure of this loop may involve severe mood disorders (Haber et al. 2000; Alexander
and Crutcher 1990; Tanaka and Naquet 1976; Levesque et al. 2003; Daffner et al.
2000). Research on goal-directed learning in animals shows that a C-loop network,
analogous to that of the human C-loop network, is engaged (compare Fig. 5.6 with
Fig. 5.5). In rats this comprises the prelimbic region of the prefrontal cortex (MPC)
and the area of the dorsal striatum to which this region of cortex projects, namely
the dorsomedial striatum (DM: see also Corbit and Balleine 2003). Lesions of either
of these regions prevent the acquisition of goal-directed learning rendering the per-
formance of otherwise deliberate actions reflexive or habitual (Yin et al. 2005a, b).
In summary, circuits related to goal-directed behavior involve the limbic PLN–
basal ganglia loop, with the medial orbitofrontal cortex (Fig. 5.5, D-loop and Fig. 5.7a,
Fig. 5.7 (a) Diagrammatic presentation of the spatial distribution of PLN and related basal ganglia
loops of Fig. 5.5. From top to bottom, abbreviations are: SMA supplementary motor areas, ACC
anterior cingulate cortex, MOFC medial orbitofrontal cortex, PMC pre-motor cortex, SEF supple-
mentary eye field, DLPC dorsolateral prefrontal cortex, LOFC lateral orbitofrontal cortex, MC
motor cortex. (b) Diagrammatic representation in the outer shell of the PLN in (a), and inside the
shell of the basal ganglia, shown in transverse section. The PLN–basal ganglia loops identified in
Fig. 5.5 as the A to D loops are indicated here as the SMA-loop (dots); the limbic B- and D-loops
(horizontal lines) and the associative C-loop (small open circles). This figure then shows the
projection from the cortex to specific areas in the basal ganglia associated with each network loop.
This figure is drawn after Fig. 3 in Haber (2003) (Reprinted from Bennett 2010a. Copyright (2010), with permission
from Elsevier)
upper) and anterior/subgenual anterior cingulate cortex (Fig. 5.5, B-loop and
Fig. 5.7a, upper), requiring the ventromedial caudate/nucleus accumbens core
(Fig. 5.7b) in the first circuit and the nucleus accumbens shell in the second circuit
(Fig. 5.7b). The other pathway related to goal-directed behavior is that of the asso-
ciative PLN–basal ganglia loop, with dorsolateral prefrontal cortex and lateral
orbitofrontal cortex (Fig. 5.5, C-loop and Fig. 5.7a, lower), requiring the central
striatum (head of the caudate and rostral putamen; Fig. 5.7b).
The Goal-Directed PLN–Basal Ganglia Loop in Depression
The interaction between loops is critical to normal function and any short-term
changes or longer term pathology in these interactions are likely to have significant
effects. For instance hypoactivity in the dorsolateral prefrontal cortex C-loop is
coupled with hyperactivity in the ventral OFC (BA 11) and the subgenual ACC
(BA 25) D-loop in severe mood disorders, implying a failure of inhibitory control
of the former over the latter (Goldapple et al. 2004; Bennett 2010b, 2011; Kopell
and Greenberg 2008). As noted above the D-loop in Fig. 5.5, involving the orbitof-
rontal cortex, is important for goal-directed behavior concerned with rewards and
punishments and highlights the role of the subgenual ACC (BA 25; see Fig. 5.5).
Kopell and Greenberg (Kopell and Greenberg 2008) commented that in severe mood
disorders, there appears to be a relative increase in activity in a ventral compart-
ment, involving regions such as OFC, area 25 and the ventromedial striatum, that is
in the D-loop in Fig. 5.5, and hypoactivity in a dorsal compartment, exemplified by
the dlPFC in the C-loop in Fig. 5.5, and in subcortical projections. Reciprocal inhib-
itory connections between the dorsal and ventral compartments, combined with
amygdala hyperactivity and abnormal hippocampal activity, could generate their
overall relationship leading to depression symptoms’ (p. 415; Fig. 5.5; Kopell and
Greenberg 2008; see also, Bennett 2010b, 2011).
Older persons with depression have significantly higher hyperintensities, due to
cerebrovascular disease, primarily in the basal ganglia (Thomas et al. 2002;
Greenwald et al. 1996; Steffens et al. 1999; Krishnan 1993; Rogers et al. 1998) with
smaller caudate nuclei volumes (Krishnan 1993; Naismith et al. 2002; Strakowski
et al. 2002; Soares and Mann 1997; Bonelli et al. 2006; Goodwin 1997). The hypo-
activity observed in the dlPFC very likely arises as a consequence of hyperintensi-
ties in the head of the caudate and the putamen (see Figs. 5.5 and 5.7), as such
hyperintensities are observed in the caudate and putamen in latelife depression
(Tupler et al. 2002).
It has been hypothesized that one source of basal ganglia dysfunction leading to
depression in the aged involves decreased 5-HT release and 5-HT receptors in the
caudate of the basal ganglia, involving the C- and D-loops (Fig. 5.5; Gareri et al.
2002; Robinson and Kolb 1999). Indeed changes in caudate nuclei volumes are
found in subjects with the short allele of the 5-HT transporter (Hickie et al. 2007).
It is likely that as a result of this allele and its associated decrease in the inhibitory
5-HT receptor, 5-HT1AR (see Bennett 2010b, 2011), a concomitant increase occurs
in neuronal excitability and N-methyl-D-aspartate receptor (NMDAR) activation.
These change the neuropil through alterations in the number of synaptic spines and
hence the neuropil and volume of the caudate nucleus (see Compan et al. 1998;
Mijnster et al. 1997; Di Matteo et al. 2008).
The Habit-Learning Basal Ganglia Networks
Habit-learning reflects a loss of executive control over an action; essentially, the

term is used to characterize an action that is impulsive or reflexive, less controlled
or deliberated. There is thus a gradual loss of cognitive and motivational control as
the action becomes more impulsive. Habit-learning in humans involves a network in
which the supplementary motor area projects to the posteriolateral putamen (Fig. 5.5,
A-loop). The emergence of habitual behavior is related to increased activity in the
posteriolateral putamen (Jueptner et al. 1997; Lehericy et al. 2005; Fig. 5.7a,
upper). It is interesting that increased basal ganglia hyperintensities are significantly
associated with reduced orbitofrontal cortex volumes (Lee et al. 2003; Ballmaier
et al. 2004; Brody et al. 2001) suggesting that there is failure of the orbitofrontal
cortex-ventral striatum D-loop (Fig. 5.5) is involved in goal directed behavior
(Balleine et al. 2009; Balleine and O’Doherty 2010), perhaps leading to an empha-
sis on the habit supplementary motor area-putamen A-loop (Fig. 5.5) and to obses-
sive compulsive disorder (Saint-Cyr et al. 1995). Habit-learning in rats involves the
A-loop network shown in Fig. 5.6, analogous to the A-loop network in humans
(compare Fig. 5.6 with Fig. 5.5), that includes sensorimotor cortex and its efferents
to dorsolateral striatum (Fig. 5.6, A-loop; Graybiel 2008). Lesions in this region
leave the rats capable still of goal-directed behavior (Yin et al. 2005b). These and
other studies indicate that the dorsolateral striatum in rodents is involved in the
habitual control of behavior. Thus inactivation of dorsomedial striatum immediately
places actions under habitual control (Yin et al. 2005a), whereas inactivation of the
dorsolateral striatum immediately renders actions goal-directed (Yin et al. 2006).
Conclusion
Subcortical hyperintensities identified with magnetic resonance imaging (MRI) are

common in severely depressed elderly patients (Coffey et al. 1990; Nebes et al.
2002; Hickie et al. 1995; Kumar et al. 2000; Lesser et al. 1996). Quantitative MRI
shows that these can be divided into periventricular hyperintensities and deep white-
matter hyperintensities, and are found particularly in subcortical regions, giving rise
to the concept that late-life-onset depression is essentially a subcortical vascular
disease (Salloway et al. 1996; Alexopoulos et al. 1997; Krishnan et al. 1997). This
hypothesis has been examined here with special attention to lesions in various
fronto-subcortical networks that might mediate mood disorders (Lafer et al. 1997;
Shah et al. 2002; Hoptman et al. 2006).
In humans, the caudate of the striatum is involved in networks concerned with
goal-oriented behavior, whereas the putamen participates in networks that sub-
serve habit learning [(Grahn et al. 2008); see especially Fig. 1 after Fig. 3 in Grahn
et al. (2008); and Fig. 1 in Alexander and Crutcher (1990)]. Hyperintensities in the
caudate in late-life interrupt two distinct PLN–basal ganglia loops as do decreases
in 5-HT receptors and transporters in the caudate. One of these is the C-loop
(Fig. 5.5), involved in goal directed behavior that includes the capacity to exclude
negative thoughts. The other is the D-loop (Fig. 5.5) involved in goal-directed
behavior concerned with the attainment of rewards and the avoidance of punishments.
As noted above, in severe mood disorders there is hypoactivity in the C-loop’s dlPFC
and its subcortical projections whereas there is hyperactivity in the D loop’s OFC,
area 25, the ventromedial striatum and especially the amygdala. It is suggested that
hyperintensities in the caudate are responsible for these changes in activity that lead
to late-life depression.
Modulation of the PLN by the Midbrain in Depression 87
Fig. 5.8 The PLN–basal ganglia–brain stem loop in humans. This network is the same as that of
the PLN–basal ganglia loop D in Fig. 5.5 except that the midbrain Raphe nucleus is included
together with the VTA. In addition, direct reciprocal connections exist between both the Raphe and
VTA on the one hand and PLN (vmPFC and OFC) on the other. VTA also projects to the NAC
(Reprinted from Bennett 2010a. Copyright (2010), with permission from Elsevier)
Modulation of the PLN by the Midbrain in Depression
Carlsson (1990) has put forward the hypothesis that striatal hyperdopaminergic
activity and prefrontal hypodopaminergic activity arise as a consequence of hypo-
function of the N-methyl- D-aspartate receptor (NMDAR). What evidence is there
for a causal relationship between striatal hyperdopaminergic and prefrontal hypodo-
paminergic activity? Animal experiments involving lesions in the medial prefrontal
cortex in the neonatal period first show increases in dopamine D2 receptor in the
striatum at the postpubertal period, suggesting that failure of prefrontal activity had
effects on D2 in the striatum dependent on the development of the animal (Flores
et al. 1996). On the other hand if transgenic mice are manipulated to produce excess
D2 receptor in the striatum then this leads, after subsequent development, to over
activation of dopamine D1 receptors in the prefrontal cortex. An effect that cannot
be reversed by subsequent restoration of normal D2 receptor complements to the
striatum (Kellendonk et al. 2006). These observations indicate that there are recip-
rocal causal relations between the prefrontal cortex and the striatum.
The hypothesis that hypofunction of the NMDAR is responsible for striatal
hyperdopaminergic activity and prefrontal hypodopaminergic activity is attractive
as it integrates failure of loops involving the prefrontal cortex of the PLN, the ven-
tral tegmental area (VTA) of the midbrain, the nucleus accumbens (NAc) of the
basal ganglia and the thalamus (see Fig. 5.8) with the positive and negative symp-
toms in schizophrenia, as well as with changes in dopamine and serotonin in these
structures. However this hypothesis does not make clear whether something has
gone awry in the functioning of the NMDA receptor itself or whether changes in
this receptor occur as a consequence of failure in the major modulatory influences

on the receptor, such as those mediated by dopamine and serotonin (Stephan et al.
2009), or whether all these factors are independently involved. The functioning of
NMDA receptors is the major determinant of synaptic-spine growth and regres-
sion, and hence in the stability of synapses (for a review see Bennett 2009). It
follows that the integrity of the pathways that control NMDA receptors is impor-
tant for the pattern of synapses that constitute neural networks. Attention is given
here to the principal transmitter receptors that determine NMDA receptor efficacy,
namely dopamine D1- and D2-type receptors and serotonin 5-HT1A and 5- HT2A
type receptors. It is suggested that the changes in PLN function consequent on
failure of these modulatory receptor systems and hence NMDA receptor function
and synaptic spine loss underlay the positive, negative and depressive symptoms of
schizophrenia.
The PLN-Midbrain Loop
The Mesolimbic Network
Figure 5.9a shows the glutamatergic prefrontal projection to inhibitory gamma-

amino-butyric-acid (GABA) containing spiny neurons in the VTA that in turn
synapse on dopaminergic mesolimbic projecting neurons to the nucleus accum-
bens of the striatum (NAc; Laruelle et al. 2003; Stahl 2007a, b). The Carlsson
(1990) hypothesis suggests that hypofunctioning NMDA receptor-mediated
transmission in the VTA is responsible for failure of the neurons projecting from
cortex to stimulate the GABAergic neurons in the VTA leading to increased dop-
amine release from the disinhibited dopamine neurons projecting from the VTA
to the NAc (Fig. 5.9a). This dopamine acts on D2 receptors located on the excitatory
glutamateric terminals from the prefrontal cortex that terminate on GABAergic
projecting neurons in the NAc to inhibit the release of glutamate onto them and
therefore to down-regulate their excitation (Fig. 5.9a, b; Laruelle et al. 2003;
Gerfen et al. 1990). As a consequence these GABAergic neurons in the NAc have
smaller inhibitory effects on the GABAergic projection neurons in the pallidum
resulting in their being able to inhibit GABAergic neurons in the reticular nucleus
of the thalamus (Fig. 5.9a; Carlsson et al. 1999; Carlsson and Carlsson 1990,
2006; Carlsson 2006). This releases the principal projecting pyramidal neurons
in the thalamus to the sensory cortex from inhibition (Fig. 5.9a). It is argued that
a subject’s sensory awareness is no longer ‘gated’ to just a few items but now
covers a very wide range of sensory stimuli because of the disinhibition of the
thalamic-cortical neurons. The subject then confabulates a story to fit all this
information into a coherent pattern, which is called a delusion. In this way, it is
suggested, NMDA hypofunctioning can lead to the positive symptoms in
schizophrenia.
Fig. 5.9 (a) The neural (mesolimbic) circuit and its transmitter receptors subserving the positive
symptoms of schizophrenia. For description see the text. Gray neurons, GABAergic. Vertical
striped neurons, dopaminergic. Unfilled neurons, glutamatergic. NAc nucleus accumbens, GABA
gamma-amino-butyric-acid, VTA ventral tegmental area. The dotted circular outline is shown
enlarged in b. Predominant receptor types are indicated by arrows (Reprinted from Bennett 2010a. Copyright
(2010), with permission from Elsevier) (b) An excitatory (glutamatergic) synapse from a prefrontal cortical
pyramidal neuron synapses on a synaptic spine of an inhibitory (GABAergic, gray) neuron in the
NAc; a dopaminergic terminal (vertical hatching) from a ventral tegmentum area neuron synapses
in close proximity to the spine, forming a triadic unit. Dopamine is released onto the dominant
presynaptic D2 receptors to decrease the release of glutamate and onto postsynaptic D1 receptors
located on the spine and adjacent parent dendrite that enhances the excitatory glutamatergic trans-
mission. (c) An excitatory (glutamatergic) synapse from an intracortical pyramidal neuron syn-
apses on a spine of another pyramidal neuron in prefrontal cortex together with a dopaminergic
terminal somewhat removed from the spine, on the parent dendrite (vertical hatching); dopamine
D1 receptors (excitatory) are shown on the spine and proximal dendrite rather than uniquely adja-
cent to the dopaminergic terminal (Reprinted from Bennett 2010a. Copyright (2010), with permission from Elsevier)
Distribution of Dopamine Receptors in the Striatum
Given these observations it is then of considerable interest to inquire into the spatial
relationships between dopamine nerve terminals and those of glutamatergic syn-
apses. D2 receptors in the NAc are preferentially expressed on the GABAergic
spiny neurons projecting to the pallidum that they disinhibit (Fig. 5.9a; Laruelle
et al. 2003; Gerfen et al. 1990). On the other hand the relatively sparse D1 receptors
in the NAc are found postsynaptically on spiny inhibitory neurons where they act to
enhance glutamatergic input arriving from the prefrontal cortex (Fig. 5.9a, b;
Carlsson and Carlsson 2006; Carlsson 2006). A triadic spatial relationship exists
between dopamine and glutamate afferents targeting dendritic spines of spiny inhib-
itory neurons in the NAc as shown in Fig. 5.9b (Sesack et al. 2003). The dopamin-
ergic synapse occurs at the neck of the spine and the glutamatergic synapse on the
spine head. Given that the principal dopamine receptor in the NAc is of the D2 type,
and this is found on the presynaptic membrane of glutamate synapses on the spine
heads (Fig. 5.9b; Goto and Grace 2008), then dopamine must diffuse from the spine
neck to the spine head in order to be effective.
Interaction Between Dopamine and Glutamate Receptors in the Striatum
In the striatum, the timing between the excitatory postsynaptic potential (epsp) gen-
erated by corticostriatal synapses and that of back-propagating action potentials in
the spiny projection neurons determines whether the epsp will undergo long-term
potentiation (LTP) or long-term depression (LTD), with activation of the presynap-
tic D2 receptors accelerating the spike-timing-dependent synaptic plasticity and D1
postsynaptic receptors critical for the expression of this plasticity (Pawlak and Kerr
2008). The NMDA-induced activation of extracellular-signal-regulated kinase
(ERK) is regulated in opposite ways by D1 and D2 receptors in the caudate puta-
men, as is the NMDA-receptor subunit NR1 via calcium/calmodulin-dependent
protein kinase II and the cAMP-response element binding protein (CREB; Jiao
et al. 2007). There are two kinds of dopamine release, phasic and tonic. Phasic dop-
amine release selectively excites D1-like receptors whilst tonic release the D2-like
receptors (Goto and Grace 2008).
The formation of the very dense set of synaptic spines on striatal inhibitory neu-
rons (Shen et al. 2008) is likely to be under the control of excitatory afferents, as
co-culture of these spinous neurons with cortical neurons increases the number of
these spines over tenfold more than that found when the cultures do not contain
cortical neurons (Fig. 5.9a; Segal et al. 2003). All stimulants increase spine density
on striatal neurons, including amphetamine (Diaz Heijtz et al. 2003) and cocaine
(Robinson and Kolb 1999), but this increase in density is not restricted to the stria-
tum as it also occurs on neurons in the medial prefrontal cortex. In relation to the
effects of amphetamine increasing spine density it is very interesting to note that
dopamine depletion increases calcium entry into dendrites of striato-pallidal neu-
rons due to back-propagating action potentials, with very high concentrations of
Fig. 5.10 The neural (mesocortical) circuit and its transmitter receptors subserving the negative
symptoms of schizophrenia. For description see the text. Gray neurons, GABAergic. Vertical
striped neurons, dopaminergic. Horizontal striped neurons, serotonergic. VTA ventral tegmental
area. The dotted circular outline is shown enlarged in Fig. 5.9C. Predominant receptor types are
indicated by arrows (Reprinted from Bennett 2010a. Copyright (2010), with permission from Elsevier)
calcium in the spines leading to disassembly of the spine cytoskeleton and collapse
of the spines (Fig. 5.9a; Day et al. 2008). Dopamine depletion leads to loss of
glutamatergic synapses on the spines and it might be that this leads to spine loss
rather than a direct effect of dopamine on the spine loss.
The PLN–Ventral Tegmentum Loop
The Mesocortical Network
Figure 5.10 shows prefrontal cortex control by glutamate of dopamine neuron

firing in the VTA that projects back to the prefrontal cortex (see also Fig. 5.8;
Laruelle et al. 2003; Stahl 2007a, b). Down-regulation of NMDA receptors on pre-
frontal cortical neurons and those on dopaminergic neurons in the VTA should lead
to a decrease in the activity of these neurons and so failure in the mesocortical
dopaminergic innervation of the prefrontal cortex. This leads to decrease in excitation
of the pyramidal neurons in the cortex through the normal excitatory action of
dopamine on D1 receptors and a concomitant decrease in GABA interneurons due
to the action of dopamine on their D1, D2 and D4 receptors which is normally
responsible for maintaining a generalized inhibitory tone in the cortex resulting in
an increased signal to noise ratio (Fig. 5.10; Laruelle et al. 2003). Such a drop in
dopamine in the prefrontal regions leads, according to the present hypothesis, to
cognitive (prefrontal cortex) symptoms. It is claimed that this might be responsible
for the negative symptoms in schizophrenia, that is decreases in normal cognitive
and affective abilities.
The extent of dopamine in prefrontal cortex determines the efficacy of cognition
(Gray and Roth 2007): increasing levels of dopamine, acting on D1 receptors,
increase the excitability of glutamatergic neurons but as the dopamine levels rise
further this enhanced excitability is gradually lost as the D1 receptors on GABAergic
neurons are engaged, so decreasing excitability (Fig. 5.10; Laruelle et al. 2003). D1
agonists, such as dihydrexidine, are therefore potential drugs for cognitive enhance-
ment in schizophrenia and at present are in positive proof-of-concept trials (Gray
and Roth 2007).
Distribution of Dopamine Receptors in Prefrontal Cortex
In medial prefrontal cortex, D1 receptors predominate and are preferentially found

on glutamatergic neurons that they excite and to some extent on GABAergic neu-
rons, together with D2 and D4 receptors (Fig. 5.10). D1 receptors are located at the
base of dendritic spine heads and on the adjacent dendrite, with the dopaminergic
terminal well-removed from there (Fig. 5.9b).
Interaction Between Dopamine and Glutamate Receptors

in Prefrontal Cortex
Dopamine acts on the postsynaptic D1 receptor in the prefrontal cortex to enhance

the epsp due to activation of NMDAR and facilitates LTP after a tetanus whereas
most studies show that activation of this receptor blocks the epsp due to glutamate
acting on AMPA receptors (see Tables 2 in Seamans and Yang 2004). On the other
hand dopamine acting on postsynaptic D2 receptors suppresses the NMDA medi-
ated epsp as well as ipsp due to GABA (Table 2 in Seamans and Yang 2004).
D1 receptor activation stimulates IP3 second messenger pathways which pro-
mote protein kinases A and C (PKA, PKC), phosphorylation of the dopamine recep-
tor phosphoprotein 32 kDa (DARPP32) and inhibition of protein phosphatase-1
(PP1); this leads to activation of calcium calmodulin kinase II and upregulation of
the NMDAR subunit NR1 and activation of nuclear transcription factor cAMP
dependent response element binding protein (CREB; Tseng and O’Donnell 2004).
The IP3 second messenger pathway also leads to activation of immediate early
genes (IEG) and late response genes (LRG) that encode particular membrane proteins
and enzymes necessary to mediate long-term changes in NMDAR. D1 receptor

activation also co-ordinates regulation of NMDAR trafficking to the membrane and
D1 receptors participate in a heteromeric receptor complex with NMDAR (Missale
et al. 2006). In contrast to this, D2 receptors suppress cAMP synthesis and trans-
activate platelet-derived growth factor (PDGF) to stimulate the release of intracellular
calcium so stimulating calcium-calmodulin (CaM) to inactivate NMDAR. D2-like
receptors can also suppress PKA and so PP1 to decrease CaMKII upregulation of
the NR1 subunit of NMDAR (see Fig. 11 in Seamans and Yang 2004; Neve et al.
2004).
Because D1-receptors enhance NMDAR activation and depress AMPAR activa-
tion, slow trains of impulses mediated by AMPA are suppressed whereas fast trains
are enhanced. On the other hand the action of D2-receptors in suppressing NMDAR
results in the opposite effect (Seamans and Yang 2004). Changes in the ambient
level of dopamine can therefore change the entire physiology of neural networks.
The PLN–Raphe Nucleus Loop
Serotonin has a neuromodulatory influence on neurotransmission in the brain, acting

on a wide variety of at least 15 different serotonin (5-HT) receptor subtypes (Barnes
and Sharp 1999). Raphe neurons release serotonin onto excitatory 5-HT2A recep-
tors present on glutamatergic neurons in the medial prefrontal cortex which project
to the mesocortical dopaminergic neurons in the VTA leading to elevation of dop-
amine in the prefrontal cortex (Figs. 5.8 and 5.10; Alex and Pehek 2007). Such a
direct projection from the Raphe nucleus to the prefrontal cortex is also responsible
for exciting 5-HT2A receptors on GABA neurons there that inhibit the activity of
glutamatergic neurons that project to the VTA as well as those that project to GABA
neurons in the NAc (Fig. 5.10; Alex and Pehek 2007; Carlsson and Carlsson 2006).
Raphe neurons also release serotonin onto 5-HT2A receptors located on dopamin-
ergic neurons in the VTA to excite their release of dopamine from mesocortical
projections to the medial prefrontal cortex, an effect that is curtailed by the release
of serotonin onto 5-HT2C receptors located on GABAeric neurons in the VTA
(Fig. 5.10; see also Fig. 2 in Alex and Pehek 2007). It is argued that these antago-
nistic effects of the Raphe nucleus on the VTA dopamine neurons promotes ‘stabi-
lization’ of the mesocortical dopamine release in the medial prefrontal cortex (Alex
and Pehek 2007) providing an optimal balance of dopaminergic tone which is nec-
essary for normal cognitive function (Williams and Goldman-Rakic 1995; Brozoski
et al. 1979).
Interaction Between Serotonin and Glutamate Receptors in Prefrontal Cortex
Activation of 5-HT1AR inhibits the NMDA receptor-mediated ionic and synaptic

currents in prefrontal cortex pyramidal neurons whilst activation of 5-HT2AR
enhances them (Yuen et al. 2005; Zhong et al. 2008). The mechanism by which
5-HTR modulates NMDAR involves control of the expression of the NR2B subunit
of NMDAR at the membrane, guided by microtubule-based transport of these
subunits from the dendrite that is under the regulatory influence of ERK (extracel-
lular signal regulated kinase) and calcium calmodulin kinase II (Yuen et al. 2005).
These are modulated by 5-HT1AR inhibiting protein kinase A (PKA) and 5- HT2AR
exciting protein kinase C, which are upstream of ERK/CaMKII (Zhong et al. 2008).
Thus 5-HT2AR, by activating ERK, opposes the 5-HT1AR disruption of microtu-
bule transport of the NMDA subunit NR2B and its clustering in the membrane
(Yuen et al. 2005). As synaptic spine stability is dependent on functioning NMDAR
(Bennett 2009), 5-HT2AR should enhance and 5-HT1AR destabilize synaptic
spines.
The PLN–Midbrain Loop: Pharmaceutical Interventions Targeting

Serotonin and Dopamine Receptors
Clozapine acts as an antagonist at D2 receptors, thereby decreasing the effects of

excess dopamine in the hyper-dopaminergic striatum associated with schizophrenia
so allowing the spiny inhibitory neurons to once more exert an inhibitory influence
over the inhibitory neurons in the pallidum with the resultant return towards normal-
ity of the capacity of the inhibitory neurons in the reticular nucleus of the thalamus
to gate sensory activity through the thalamus to cortex (Figs. 5.9a and 5.10; Carlsson
and Carlsson 1990).
Clozapine acts as an agonist at D1 receptors (Ahlenius 1999) so that it can act at
D1 receptors in prefrontal cortex to increase activity mediated by this receptor so
partially compensating for the hypodopaminergic condition in schizophrenia.
Clozapine, when administered systemically, increases extracellular dopamine
levels in the medial prefrontal cortex by a 5-HT1AR dependent mechanism
(Rollema et al. 1997, 2000; Kuroki et al. 1999; Ichikawa et al. 2001; Li et al. 2004;
Kapur and Remington 1996), as indicated by the fact that this does not occur in 5
HT1AR knockout mice (Diaz-Mataix et al. 2005). Clozapine acts as an agonist
when applied locally to neurons in the mPFC, giving hyperpolarization and there-
fore reduction of neuronal activity (Puig et al. 2005). Given that there is reduced
excitability it does not seem possible that clozapine could increase activity of dop-
aminergic neurons in the VTA to which mPFC neurons project (see Fig. 5.10), as
such activity is dependent on excitation in the mPFC pyramidal neurons (Murase
et al. 1993; Bortolozzi et al. 2003). However it is now known that systemic admin-
istration of 5-HT1AR agonists, such as BAY, increases the activation of mPFC
pyramidal neurons (Borsini et al. 1995), as well as in the VTA (Diaz-Mataix et al.
2006), rather than decreasing activation as occurs on local application. It has been
suggested then that 5- HT1AR agonists such as clozapine act predominantly on
5-HT1AR located on inhibitory GABAergic interneurons in the mPFC to disinhibit
the pyramidal neurons there and so enhance excitation in the mPFC–VTA–
mPFC loop, a possibility supported by the observation that the effects of clozapine
are blocked by bicuculline (Bortolozzi et al. 2005). It seems likely then that the
enhancement of dopamine in the hypodopaminergic mPFC in schizophrenia by the

most effective neuroleptic in relation to the suppression of negative symptoms,
namely clozapine, arises from its action on 5-HT1AR in the mPFC.
In schizophrenia, 5-HT1AR is low in the amygdala, a condition that would facili-
tate excitation there associated with depression (see (Bennett 2010b, 2011; Yasuno
et al. 2004). It is know that the atypical antipsychotic aropiprazole increases
5-HT1AR in the amygdala (Yasuno et al. 2004) and if this is also the case for clo-
zapine then it would help explain its outstanding antidepressant properties in schizo-
phrenia (see Fig. 3 in Leucht et al. 2009). In addition, clozapine’s agonist effects at
5-HT1AR and antagonist effects at 5-HT2AR will significantly depress activity in
the amygdala. Furthermore, if clozapine reduces 5-HT1AR in the anterior cingulate
cortex, as does olanzapine, then the abnormally high levels found there in schizo-
phrenia will be lowered (Gurevich and Joyce 1997), thus restoring the excitability
of these dorsal regions of cortex necessary for them to inhibit the hyperexcitability
of the amygdala associated with depression (Bennett 2010b, 2011).
Conclusion
There are two main difficulties in claiming that hypo-dopaminergic prefrontal and
hyper-dopaminergic striatum activities are causally linked. The first is that many of
the symptoms that participate in the characterization of schizophrenia are separable,
including the positive and negative symptoms that, it is claimed, arise from a hypo-
dopaminergic medial prefrontal cortex and a hyper-dopaminergic striatum, respectively
(Dutta et al. 2007). At least eight major dimensions characterize schizophrenia:
psychoses, negative affect, depression, disorganization, mania, excitement, catatonia
and lack of insight (Peralta and Cuesta 2001). One of these, psychoses, is experienced
by about 10% of the population world-wide, with these experienced transiently unless
the subject is exposed to abnormal stress (van Os et al. 2009). Since these psychotic
episodes are not necessarily coupled with, for example, negative affect, it follows that
one tenant of the dopamine model is not sustainable or that these psychotic episodes
have a different aetiology to those that occur in schizophrenia. Furthermore, first
degree relatives of patients with schizophrenia show increased dopamine release in
the cortex without psychotic symptoms, although they do have a higher risk of psy-
choses (Huttunen et al. 2008). In addition, there is good evidence that negative
symptoms are evident some 2 years before psychotic symptoms are revealed during
the prodromal period of schizophrenia (summarized in Hafner et al. 2008).
It is suggested that the main effect of a drug like clozapine in normalizing activity
in the cortex and striatum is through its action on D2 receptors in the striatum and
5-HT1AR in the cortex. In the striatum, clozapine potentiates glutamate release
from cortico-limbic terminals onto the spiny inhibitory neurons there through blocking
D2 receptors on the terminals, so helping to reestablish the inhibitory gating of the
thalamic-cortical activity. In the medial prefrontal cortex, chronic clozapine acts as
an agonist on 5-HT1AR of GABAergic inhibitory interneurons, blocking these and
so disinhibiting normal excitability in the cortex. In addition, clozapine acts to

antagonize 5-HT2AR and excite 5-HT1AR in the amygdala, thus decreasing excit-
ability there, a normal concomitant of depression. It is suggested that clozapine
possesses its unique properties as a neuroleptic as a consequence of restoring
normal levels of excitability in the PLN and the basal ganglia.
The PLN and Depression
The PLN is now recognized as a key regulatory system involved in MDD. Here
three modulatory systems that act on the PLN have been considered. Namely that
through the hypothalamic-pituitary– adrenal axis; that through the basal ganglia and
finally a modulatory influence through the midbrain ventral tegmentum/Raphe
nucleus. Failure of the normal modulatory effects of each of these systems has been
identified as giving rise to depression in adolescence leading to suicidal diathesis, to
late-life depression and to the depressive symptoms in schizophrenia. In each of
these cases it may be hypothesized that failure of synapses in the anterior cingulate,
the caudate and the midbrain, respectively are implicated. In the following Chap. 6
it is shown that the failure of synapses through their regression gives rise to decreases
in gray matter in different components of the PLN itself and that this decrease can
be measured using magnetic resonance imaging (Bennett 2010b, 2011).
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Chapter 6
The Pathology of Synapses in Brain Networks
Implicated in Depression
Brain Imaging of Prefrontal-Limbic Networks Point
to a Loss of Synapses in Depression
Introduction
Non-invasive brain imaging has identified changes in the prefrontal–limbic network

(Fig. 6.1) in patients suffering from major depression disease (MDD), principally in
prefrontal cortex, anterior cingulate cortex, orbitofrontal cortex, hippocampus and
the amygdala. For example, different regions in the medial prefrontal cortex and
orbitofrontal cortex normally exert an inhibitory influence over activity in the
amygdala, but fail to do so in depression according to functional magnetic reso-
nance imaging (fMRI) studies (Drevets 2007; Savitz and Drevets 2009). Furthermore
the evidence suggests there is a lack of functional connection in depressed patients
between the subgenual anterior cingulate cortex (ACC) on the one hand and the
rostral (pregenual) ACC and hippocampus on the other, as well as between the
rostral ACC and the amygdala (Anand et al. 2009; Savitz and Drevets 2009).
In depressed patients there is increased activity in the subgenual ACC accompanied
by decreased activity in the dorsolateral prefrontal cortex (Drevets et al. 2008;
Mayberg et al. 1999) leading to the conjecture that it is failure of inhibitory control
from the dorsal areas over the ventral areas that leads to increased activity in the
ventral areas (Taylor and Liberzon 2007). Use of multivariate techniques combined
with structural equation modeling, applied to resting-state positron emission tomog-
raphy (PET) scans of acutely depressed patients, show differences in known ana-
tomical and physiological pathways. An estimate has been made of the strength and
direction of ‘effective connections’ between these areas (James et al. 2009). Changes
are observed between subgenual ACC, pregenual ACC, orbitofrontal cortex, hip-
pocampus/amygdala, and the prefrontal cortex (Fig. 6.1).
Are there pathological changes in the areas of the brain that show abnormal activity
and functional connections according to fMRI and PET brain imaging (Tan et al.
Reprinted from Progress in Neurobiology, Bennett MR, The prefrontal-limbic network in depression: A core pathology of synapse regression.
Vol 93: 457-467. Copyright (2011), with permission from Elsevier.

108 6 The Pathology of Synapses in Brain Networks Implicated in Depression
Fig. 6.1 The prefrontal–

limbic network (PLN). This
consists of connections in
humans of the rostral anterior
cingulate cortex (rACC),
subgenual anterior cingulate
cortex (sgACC), the
amygdala, the dorsolateral
(dlPFC) and dorsomedial
(dmPFC) prefrontal cortex,
the ventromedial prefrontal
cortex (vmPFC), the
orbitofrontal cortex (OFC)
and the hippocampus. The
continuous lines ending in
arrowheads indicate the
connections based on
anatomical criteria (Reprinted
from Bennett 2011. Copyright (2011),
with permission from Elsevier)
2007)? Observations using MRI show a decrease in the grey matter of certain parts
of the prefrontal cortex of those suffering from MDD. A meta-analysis of 64 studies
of over 2,418 MDD patients reveals large decreases in the volume of grey matter.
This occurs in the anterior cingulate cortex (11.5%), the orbitofrontal cortex (9%),
the prefrontal cortex (5%) and the hippocampus (1.8%; see Koolschijn et al. 2009).
There are therefore pathological changes in just those areas of the cortex for which
non-invasive imaging has shown both abnormal activity and functional connectivity.
This meta-analysis of MRI studies may be compared with occasional histological
measurements on the cortex of deceased MDD patients, such as the reported 15%
decrease in grey matter in orbitofrontal cortex of such patients (Rajkowska et al.
1999). This chapter is concerned with the question as to whether these reported
losses of grey matter are compatible with the reported pathological changes of cells
and their processes in the brain that accompany development of MDD?
The Volume Fraction of Human Cortical Grey Matter

Occupied by Different Cellular Constituents
The thickness of grey matter in the primate neocortex is about 2.5 mm (Cragg 1967)
and is conventionally divided into six layers (Cotter et al. 2002b). Certain classes of
neurons predominate in each of these layers, such as granule cells neurons in layer
IV of what is called granular cortex, pyramidal neurons in layer V and stellate
neurons in layer III with glial cells distributed throughout these layers at approxi-
mately the same density as the neurons (Cotter et al. 2002b). The cell bodies of
The Volume Fraction of Human Cortical Grey Matter Occupied… 109
these neurons and glial cells occupy a relatively small volume of the grey matter,
compared with that taken up by their processes. These processes are the dendrites
and axons of neurons in the grey matter, together with synapses and capillaries,
collectively referred to as the neuropil (DeFelipe et al. 1999). The two principal
classes of glial cell are astrocytes, whose processes come into intimate apposition
with synapses and neurons, and satellite oligodendrocytes which, as the name
implies, possess cell bodies in close apposition to the cell bodies of neurons
(Vostrikov 2007). In Nissl silver stains the neuron cell body is easily distinguished
by its relatively large nucleus possessing a nucleolus. The satellite oligodendrocytes
are identified by a small nucleus with very little surrounding cytoplasm, and the
astrocytes by an intermediate size nucleus with some surrounding cytoplasm (Pelvig
et al. 2008).
There are now a large number of studies providing quantitative detail on the size
and density of neurons, astrocytes and satellite oligodendrocytes in the human
cortex, summarized in Table 6.1. The density of these varies somewhat from layer
to layer of grey matter, as well as from one area of cortex to another (Table 6.2,
columns 1 and 2), although their relative numbers do not. Averaging over different
cortical areas as well as cortical layers, and not differentiating between different
neuronal types, gives a mean grey matter density of neuron cell bodies of 7.8 ± 7 × 104/
mm3 of grey matter (Table 6.2, column 1). In the case of glial cells, the density is
8.5 ± 3.3 × 104/mm3 of grey matter (Table 6.2, column 2). Distinguishing between
classes of glial cells gives an astrocyte density of 1.5 × 104/mm3 of grey matter and
a satellite oligodendrocyte density of 7.0 × 104/mm3 of grey matter, based on the
measured ratio of oligodendrocytes to astrocytes of 4.6 (Pelvig et al. 2008; Azevedo
et al. 2009; Pennington et al. 2008). The average size of the cell somas is 1,008 mm3
for neurons (Table 6.2, column 3), 359 mm3 for astrocytes (Oberheim et al. 2009)
and 120 mm3 for satellite oligodendrocytes (Vostrikov et al. 2007, 2008; Vostrikov
2007). Given this density and volume of neuron somas, they occupy 0.078 mm3/
mm3 of grey matter (Table 6.1). In the case of astrocyte cell bodies (Oberheim et al.
2009), they occupy 0.005 mm3/mm3 of grey matter and the satellite oligodendrocyte
cell bodies 0.008 mm3/mm3 of grey matter (see Table 6.1).
As noted above, the neuropil is dominated by the processes of neurons, namely
collateral axons and dendrites upon which the great majority of synapses are located.
The extent of the apical and basal dendrites of a neuron in the human neocortex can
be ascertained by silver stain using the Golgi method, with the furthest extent of the
long apical dendrite giving lengths of 400 mm or so (Jacobs and Scheibel 1993;
Jacobs et al. 1993a, b). The Golgi technique clearly delineates the high density of
spines on the dendrites (e.g. 0.26 spines per mm length of dendrite; (Jacobs et al.
2001)). The total length of dendrite of a neuron in human cortex is about
5,200 ± 544 mm (see note 3 in Table 6.1) and this is about equally distributed between
apical and basal dendrites (Becker et al. 1984; Jacobs and Scheibel 1993; Jacobs
et al. 1993a, b). This may be compared with the total length of dendrites of rat
hippocampal CA1 pyramidal neurons of 6,689 ± 3,511 mm and of non-primate cortical
pyramidal and stellate neurons of 2,827 ± 303 mm (Table 6.3, column 3). The aver-
age dendrite diameter is 1.08 ± 0.31 mm (see note 3’ in Tables 6.1 and 6.3, column
4), the volume of grey matter occupied by the dendrites of a pyramidal neuron is
Table 6.1 Volumes of cells and their processes in 1 mm3 of human cortical grey matter (superscript
numbers on parentheses refer to items in ‘References and notes for Table 6.1 below)
A Neuron Vol: (soma volume)1 × (neuron
density)2 = (1008 × 10−9) × (7.8 × 104) = 0.078 mm3
B Dendritic Vol: (dendritic vol of single neuron)3, 4 × (neuron density)2 = (length of
dendrite/neuron (l) × cross sectional area of dendrite) × neuron density
2
= (l × p d ) × (neuron density) = (5,200 × p1 ) × (7.8 × 104) = 0.31 mm3
4 4
3 5
C Dendritic Vol: (total dendritic length per mm ) × (cross sectional area of
dendrite)4 = (0.39 × 106) × ( p d
2
× 10−6) = 0.30 mm3
4
D Axon collateral Vol: (collateral length per mm3)6 × (collateral cross sectional
p
area)7 = (4.1 × 106) × ( (0.3)2 × 10−6) = 0.29 mm3
4
E Astrocyte cell body: (astrocyte soma volume)8 × (astrocyte
density)9 = (359 × 10−9) × (1.5 × 104) = 0.005 mm3
F Astrocyte Process: (astrocyte process volume)10 × (astrocyte
density)11 = (3,990 × 10−9) × (1.5 × 104) = 0.059 mm3
G Oligodendrocyte Cell Body: (oligodendrocyte soma volume)12
× (oligodendrocyte density)13 = (120 × 10−9) × (7.0 × 104) = 0.0084 mm3
H Oligodendrocyte Process: (oligodendrocyte process volume)14
× (oligodendrocyte density)15 = (624 × 10−9) × (7.0 × 104) = 0.044 mm3
I Volume Fraction of Extracellular Space 16 = 0.18 mm3
J Capillaries Vol = (average length per mm3)17 × (average cross
sectional area)17 = (251) × ( p d
2
× 10−6) = 0.005 mm3
4
K Microglial Vol = (microglial soma process volume)18 × (microglial
density)19 = (2 × 10−6) × (6.5 × 103) = 0.013 mm3
L Synaptic (presynaptic bouton) Vol = (single synapse volume)20
× (synapse density)21 = (0.13 mm3) × (3.6 × 108) = 0.047 mm3
M Synaptic spine end-bulb Vol = (single end-bulb volume)22
× (end-blub density)23 = (0.055) × (2.4 × 108) = 0.013 mm3
Total = 1.048 mm3
References and Notes for Table 6.1
1. Table 6.2, Column 3
3. Value of l – Table 6.3, Column 2 [compare with 6,689 ± 3,511 mm hippocampus of rat (n = 4);
2,827 ± 303 mm cortex of cat and mouse (n = 3)]
4. Value of d – Table 6.3, Column 3
5. Dendritic length/mm3 from Stepanyants et al. (2004) of 0.39 km/mm3
6. Collateral length/mm3 from Stepanyants et al. (2004) of 4.1 km/mm3 ; see also Foh et al. (1973)
7. Collateral diameter 0.3 mm (from Brainenberg and Schuz (1998) for mouse; see also Bolstad et al.
(2007) for rat 0.4 mm ± 0.02; see also Rockland and Virga (1990) for macaque 0.7 to 1.6 mm)
8. Oberheim et al. (2009)
9. Table 6.2, Column 2: total glial density = 8.5 ± 3.3 × 104/mm3 so astrocytes 1.5 × 104/mm3 as
ratio of oligodendrocytes to astrocytes = 14:3 (Pelvig et al. 2008)
(continued)
Table 6.1 (continued)

10. Oberheim et al. (2009)
11. Table 6.2, Column 2 (as for point 7) 1.5 × 104/mm3
12. DeFelipe et al. (2002; Vostrikov et al. 2007, 2008; Vostrikov 2007)
13. Table 6.2, Column 2 gives total glial density = 8.5 ± 3.3 × 104/mm3 so oligodendrocyte density is
7.0 × 104/mm3 as ratio of oligos to astrocytes is 14:3 (Pelvig et al. 2008)
14. D’Ambrosio et al. (1998)
15. Same as 13
16. 0.18 ± 0.02 (Lehmenkuhler et al. 1993; Nicholson and Phillips 1981; Sykova et al. 2005a, b;
Yao et al. 2008)
17. Average length of capillary = 251 mm/mm3; diameter = 5 × 10−3 mm; Table 1 in Bell and Ball
(1985)
18. Fig. 2B in Bolmont et al. (2008)
19. Nimmerjahn et al. (2005)
20. Cragg (1967); diameter of bouton, d = 0.64 mm
22. Spacek and Hartmann (1983): 0.055 mm3; see Figure 5 and Table 2 herein. It may be argued the
whole synaptic spine and not just the end-blub should be included in this calculation. That being
the case then the average volume is 0.16 ± 0.10 mm3 (Spacek and Hartmann 1983). This would
give a synaptic spine contribution of (0.16) × (2.4 × 108) = 0.038 mm3/mm3 of grey matter
23. Stepanyants et al. (2009). Average number of spines over all cortical layers = 0.24/mm3
= 2.4 × 108/mm3
NB: Pilgrim et al. (1982) show for rat supraoptic nucleus a volume ratio of neuronal elements: glial
elements = 9:1. Table 6.1 shows a ratio of 7.6:1
4,030 mm3. This figure, together with the density of neurons (Table 6.2, column 1)
gives the volume of dendritic processes in the grey matter as 0.31 mm3/mm3 of grey
matter (Table 6.1; compare with 0.3 mm3 or 30% of grey matter in the cat; Broman
et al. 1987). This estimate may be compared with that arrived at on the basis of
determinations of the extent of the average total length of dendrites in a mm3 of grey
matter of 0.39 km (Stepanyants et al. 2009) which gives a dendritic volume of
0.30 mm3/mm3 of grey matter (Table 6.1), confirming the previous estimate.
The entire extent of the branches of astrocytes has been determined for rats by
injecting procion yellow into their cell bodies, revealing the enormous extent of fine
processes emanating from relatively large diameter branches (Bushong et al. 2002).
These fine processes evidently provide the intimate contact with which astrocytes
are known to almost entirely envelop synaptic boutons. It is estimated that the pro-
cesses of a single astrocyte in the rat are of sufficient number to envelop more than
10,000 synapses (Bushong et al. 2002). The envelope of an astrocyte and its pro-
cesses is not invaded by the processes of adjoining astrocytes, so that each astrocyte
has a unique ‘sphere of influence’ over the set of synapses that it envelops (Bushong
et al. 2002). Recently it has been shown that human astrocytes, stained by the procion
yellow method, are substantially larger than those of the rat, at least three times, with
astrocytes possessing about 38 main processes each on average 140 mm long (occu-
pying a net volume of about 3,635 mm3; Oberheim et al. 2009). The only determinations
of the dimensions of the very large number of small astrocyte processes has been
Table 6.2 Neuronal and glial cell densities in human cortex

1. Neuronal 2. Glial
density density 3. Neuron soma
Cortex Author Level (#/mm3 × 10−4) (#/mm3 × 10−4) volume (mm3)
Neocortex Pakkenberg 864
and Gundersen (1997)
BA24 Ongur et al. (1998) 2.5 4.6
BA9 Rajkowska et al. (1998) L5 5.4 9.1
BA9 Rajkowska et al. (1998) L3 9.3 5.3
OFC Rajkowska et al. (1999) L1 2.4 9.7
OFC Rajkowska et al. (1999) L2 12.0 11.0
ACC Cotter et al. (2002a, b) L1 5.8 11.3
ACC Cotter et al. (2002a, b) L2 18.0 6.5
Neocortx Rabinowicz et al. (2002) 828
Neocortx Rabinowicz et al. (2002) 871
Temporal DeFelipe et al. (2002) L1 0.8
Cortex
Temporal DeFelipe et al. (2002) L2 4.5
Cortex
Motor Toft et al. (2005) 3.2 6.1
Cortex
Neocortex Pelvig et al. (2008) 6.5
Neocortex Pennington et al. (2008) L2 27.0 10.9 518
Neocortex Pennington et al. (2008) L3 9.2 12.9 1,414
Neocortex Azevedo et al. (2009) 1.2 1.8
Neocortex Fabricius et al. (2007) 1,545
Neocortex Dwork et al. (2009) 10.0
Mean ± SD 7.8 ± 7 × 104 8.5 ± 3.3 × 104 1,008 ± 391
provided for astrocytes in the molecular layer of the rat dentate gyrus, using
computer electron tomography and stereo-photogrammetry, and these take up a
volume of about 355 mm3 (Hama et al. 2004). The volume occupied by an astrocyte
is then 3,635 ± 355 mm3 equal to 3,990 mm3. The density of astrocytes can be deter-
mined from the density of glial cells of 8.5 × 104/mm3 of grey matter (Table 6.2,
column 2) and the fact that the ratio of satellite oligodendrocytes to astrocytes is 4.6
(Pelvig et al. 2008). This gives an astrocyte density of 1.5 × 104/mm3 so that their
processes occupy 0.059 mm3/mm3 of grey matter (Table 6.1).
Satellite oligodendrocytes in rats possess a relatively short branching tree of
processes, in total extending for about 0.60 mm, and lack the fine processes of astro-
cytes, as can be observed when they are filled with biocytin (D’Ambrosio et al.
1998). The branching of the processes is clearly delineated if the oligodendrocytes
are stained for their tubulin content (Richter-Landsberg 2008). It is estimated that an
oligodendrocyte possesses collectively about 52 branches with an average length of
15 mm and diameter of 1 mm, giving a total volume occupied by the branches of
Table 6.3 Dimensions of neuronal dendrites

2. Total
1. Dendrite dendritic l 3. Dendrite
length ength diameter
Cortex Author Dendrite Neuron (mm) (mm) (mm)
Human Becker Basalar Pyramidal 1,700 3,400
cortex et al. (1984)
Human Becker Apical Pyramidal 1,700
Human Jacobs Basalar Pyramidal 2,672 5,344
cortex et al. (1993a)
cortex et al. (1993b)
Human Anderson Basalar Pyramidal 2,239 4,478
cortex and Rutledge
(1996)
Cat visual Sholl (1953) Total Pyramidal 2,882 2,882 1.3
cortex and
Stellate
Mouse Braitenberg and Total Pyramidal 3,100 3,100
neocortex Schuz (1998)
Mouse frontal Lloyd Total Pyramidal 2,500 2,500
Rat hippocampus Englisch Total Pyramidal 4,359 4,359
CA1 et al. (1974)
Rat hippocampus Minkwitz and Total Pyramidal 5,613 5,613
CA1 Holz (1975)
Rat hippocampus Pokorny and Basalar Pyramidal 2,621 4,886
CA1 Yamamoto
(1981a, b)
Rat hippocampus Braitenberg and 0.9
CA1 Schuz (1998)
Rat hippocampus Trommald Basalar Pyramidal 4,524 11,900 0.73
CA1 et al. (1995)
Mean ± SD Human cortex 5,200 ±
1,544
Mean ± SD Animal cortex 2,827 ±
303
Mean ± SD Animal 6,689 ±
hippocampus 3,511
Mean ± SD Dendrite 1.08 ± 0.31
diameter
624 mm3 (Chvatal et al. 2001; D’Ambrosio et al. 1998; Rajasekharan et al. 2009; Song
et al. 2001; Vostrikov et al. 2007, 2008; Vostrikov 2007). Given that the density of
satellite oligodendrocytes is 7.0 × 104 cells/mm3 of grey matter (determined from
Table 6.2 column 2 and the ratio of oligodendrocytes to astrocytes of 4.6) then the
volume of their processes is 0.0044 mm3/mm3 of grey matter (see Table 6.1).
Table 6.4 Synapse density in human cortex

1. Synapse density
Cortex Author Level (#/mm3 × 10−9)
BA9 Scheff et al. (1990) L3 0.4
BA9 Scheff et al. (1990) L5 0.3
BA9 DeKosky and Scheff (1990) 0.4
Frontal Paula-Barbosa et al. (1986) 0.14
BA9 Scheff and Price (2001) L3 0.5
BA9 Scheff and Price (2001) L5 0.3
BA9, 21–24, 28 Scheff and Price (2003) L3 0.4
BA9, 21–24, 28 Scheff and Price (2003) L5 0.3
Prefrontal Scheff and Price (2006) L3 0.4
Prefrontal Scheff and Price (2006) L5 0.5
Cortex Huttenlocher (1990) 0.4
Mean ± SD 0.367 ± 0.102 × 109
The volume of grey matter taken up by collateral axons has not been determined
for the human cortex, although it was determined for the cat and the mouse cortex
(Foh et al. 1973; Stepanyants et al. 2009), where it was estimated as 4.1 km/mm3 of
grey matter with the average axon diameter of 0.3 mm (Braitenberg and Schuz 1998;
p. 42). This gives a volume of axon of 0.29 mm3/mm3 of grey matter (see Table 6.1)
which can be compared with 0.30 mm3 (26%) estimated from measurements on the
cat lateral cervical nucleus (Broman et al. 1987). Although Stepanyants et al. (2009)
confirm the much earlier estimate by Foh et al. (1973) for collateral axon length in
grey matter, the diameter estimate by Braitenberg and Schuz (1998) may be an
underestimate. An estimate for this diameter in rat cortex is 0.40 ± 0.02 mm (Bolstad
et al. 2007) and in the macaque cortex ranges between 0.7 and 1.6 mm (Rockland
and Virga 1990). So the acceptance of 0.3 mm for the axon collateral diameter in
these calculations is quite provisional.
Microglia are at a relatively low density in grey matter (6.5 × 103/mm3;
Nimmerjahn et al. 2005), less than 10% of the satellite oligodendrocyte density,
and have a volume that is less than half of that of astrocytes. This results in a relatively
small volume contribution of 0.013 mm3/mm3 of grey matter. On the other hand
the very large number of synapses in the grey matter of the human cortex of
3.6 ± 1.0 × 108/mm3 (Table 6.4, column 1) ensures they make a significant contribution
to the grey matter volume, even given that the bouton/varicosity size is only 0.13 mm3
(Cragg 1967) and the synaptic spine bulbs on which many boutons/varicosities
terminate is 0.055 mm3 (Spacek and Hartmann 1983). According to these consid-
erations, pre- and post-synaptic elements of the synapse contribute 0.06 mm3/mm3
of grey matter (Table 6.1). Capillaries make only a small contribution to grey matter
volume of 0.005 mm3/mm3 of grey matter (Table 6.1 and note 15; (Bell and Ball
1985); Table 6.2). However the volume of extracellular space is considerable, at
0.18 ± 0.02 mm3/mm3 of grey matter (Table 6.1 and note 14). Considering all 12
contributions of cell bodies, their processes as well as the vascular and extracellular
The Core Pathology of Synapse Regression in the Cortical… 115
Fig. 6.2 Cellular

composition of the grey
matter in the human
neocortex. Shown is a pie
diagram summarizing the
percentage cellular
composition of human
cortical grey matter given by
the calculations in Table 6.1
(Reprinted from Bennett 2011. Copyright
(2011), with permission from Elsevier)
space of the grey matter gives a total volume contribution of 1.048 mm3. Thus there
is at least a 4.8% inaccuracy in these determinations.
According to the calculations, summarized in Table 6.1 and illustrated by the pie
diagram given in Fig. 6.2, most of the grey matter (59%) is taken up by the dendritic
(30%) and axonal (29%) processes of neurons, with those of astrocytes taking up
5.9% and of satellite oligodendrocytes accounting for 4.4%. The cell bodies of neu-
rons, astrocytes and oligodendrocytes only take up 7.8, 0.5 and 0.8%, respectively.
The Core Pathology of Synapse Regression in the Cortical

Grey Matter of Stressed Animals
About one in six individuals in a Western country (e.g. United States) will experi-
ence MDD during their lifetime (Kessler et al. 2005). There is a causal relation-
ship between stressful life events and MDD (Hammen 2005). Less than 30% of
the association between stressful life events and the onset of depression is non-
causal in as much as individuals predisposed to MDD select themselves into high-
risk environments (Kendler et al. 1999). The causal relationship between the
effects of stressful life events on first episode MDD and of acute or chronic stress-
ful events on the recurrence of MDD is a subject of intense research (reviewed in
(Kessler et al. 1997). The famous paper by Caspi and colleagues (Caspi et al.
2003) highlighted the extent to which polymorphisms in the promotor region of
the serotonin transporter (5-HTT) gene moderated the effects of stressful life
events on MDD occurrence, indicating for the first time in specific terms the
possible nature–nurture relationship between genetic endowment modulating the
response to stressful life events and MDD. The biological mechanisms involved
in this causal relationship are a matter of ongoing study (see, for example, (Burke
et al. 2005)). Stressed animals are therefore likely to provide good models for
examining the biological changes that accompany the pathway to MDD in humans
(for a review, see Czeh et al. 2008). With the application of MRI to rodents
(Cerqueira et al. 2005) direct comparison can be made between changes in grey
matter of different brain regions of stressed animals and those of stressed patients
and those with MDD. This could provide insights into the extent to which changes
in cells and their processes in grey matter of stressed animals are likely also to
occur in stressed and MDD humans (see Kassem et al. 2012). For example, the
increased corticoid levels in humans recovering from a stressful event (Burke
et al. 2005), and the large decrease in the amount of grey matter in the anterior
cingulate nucleus of 11.5% in patients with MDD suggests a causal relationship
between corticosteroids and the extent of grey matter loss. MRI studies of the
anterior cingulate nucleus in rats show that it is indeed reduced by corticosteroids
by about 8% (Cerqueira et al. 2005). As there are extensive studies on the effects
of stress on the cellular constituents and their processes in the grey matter of rat
brain, in particular of those regions that have been shown in MDD patients to lose
grey matter, such as the anterior cingulate cortex, the prefrontal cortex and the
hippocampus, these are now considered.
Anterior Cingulate Cortex
Rats subjected to different forms of stress, such as daily or chronic restraint for a
month (Perez-Cruz et al. 2007; Radley et al. 2006) show about a 20% decrease in
length of apical dendrites of neurons in the anterior cingulate cortex (layers II and
III), and a comparable percentage loss of synaptic spines. A similar percentage loss
also occurs of synaptic spines in the cortical area in rats that have been stressed
through maternal separation as neonates (Bock et al. 2005; Gos et al. 2008) and a
large decrease of about 30% of dendrites also occurs (Murmu et al. 2006). There has
been no reported loss of neurons in the anterior cingulate cortex of stressed rats,
although various and sometimes contradictory claims have been made concerning a
decrease in GFAP-labeled processes (Braun et al. 2009; Leventopoulos et al. 2007)
or no change in these processes (Musholt et al. 2009). Some of these authors report
a small drop in astrocyte density (Leventopoulos et al. 2007) whilst others report an
increase in density (Braun et al. 2009). Taken together, the evidence is clear for a
loss of synapses and their dendrites of about 20% in anterior cingulate cortex grey
matter following restraint stress or that due to neonatal separation. Such a loss of
synapses and dendrites would be expected to lead to a 7% change in volume of the
anterior cingulate cortex following stress (based on a dendritic volume of
0.30 mm3/mm3 of grey matter and synapse volume of 0.06 mm3/mm3 of grey matter
determined for the human cortex).
The Core Pathology of Synapse Regression in the Cortical… 117
Orbitofrontal Cortex
Chronic restraint stress leads to a decrease of about 20% in apical dendrites belonging
to neurons in the orbitofrontal cortex (Liston et al. 2006) with a comparable loss of
synaptic spines following paternal separation for 3 weeks (Murmu et al. 2006;
Helmeke et al. 2009). It was also suggested by Liston et al. (2006) that there is a
gain of synapses in orbitofrontal cortex following restraint stress. There have been
no reports of loss of neurons or changes in glia in this cortex due to stress. If there
is a concomitant percentage loss of dendrites with the 20% loss of synapses then the
volume change of grey matter in orbitofrontal cortex is estimated at 7% (based on
the above volume densities of dendrites and synapses in the human cortex).
Prefrontal Cortex
A large number of studies of the prefrontal cortex of stressed rats indicate both
decreases in the number of synaptic spines (Liston et al. 2006; Liu and Aghajanian
2008; Michelsen et al. 2007; Radley et al. 2008; Silva-Gomez et al. 2003) as well as
in the length and number of dendrites of neurons (e.g. Radley et al. 2005; Czeh et al.
2008; Garrett and Wellman 2009; Goldwater et al. 2009; Shansky and Morrison
2009). Quantitative measurements show that daily restraint leads to about 20%
decrease in the number of dendrites of neurons in the prefrontal cortex (Brown et al.
2005; Cook and Wellman 2004; Liston et al. 2006; Radley et al. 2004). Following
such stress about 5% of all cells become apoptopic in the cortex (Bachis et al. 2008).
These may be glial cells rather than neurons, as there is a decrease in the number of
oligodendrocytes following chronic stress (Banasr et al. 2007), possibly due to
apoptosis and a decrease in the proliferation rate of these glial cells (Czeh et al.
2007). However a 5% loss of oligodendrocytes would only contribute a 0.25%
decrease in grey matter volume of prefrontal cortex (based on an oligodendrocyte
volume (including processes) of 0.05 mm3/mm3 of grey matter in human cortex)
whereas a 20% decrease in the amount of dendrites in this cortex would lead to a 7%
change in grey matter volume (based on the above volume density of dendrites and
synapses). It would appear then that any decrease in volume of prefrontal grey
matter following stress in rats is most likely due to a loss of synapses and their
dendrites.
Hippocampus
A large number of reports provide observations on the decrease of synaptic spines

and synapses of up to 32% in the hippocampus following stress of different forms
in rats (Afadlal et al. 2010; Aisa et al. 2009; Dalla et al. 2009; Hayashi et al. 1998;
Rosenbrock et al. 2005; Wood et al. 2004). Following restraint stress there is a
decrease in length of apical dendrites of CA3 pyramidal neurons (Conrad et al.
1999; McLaughlin et al. 2007; Watanabe et al. 1992) and synaptic spines (Sandi
et al. 2003; Stewart et al. 2005). Following maternal separation stress or stress due
to overcrowding of neonates there is a decrease of synapses of about 35% on CA3
pyramidal neurons (Andersen and Teicher 2004; Huot et al. 2002). Chronic restraint
stress, prenatal stress and learned helplessness stress (due to inescapable shock
treatment) all lead to loss of synapses on pyramidal neurons in the CA1 region of
the hippocampus (Donohue et al. 2006; Hajszan et al. 2009; Martinez-Tellez et al.
2009). Interestingly 30% of the 300 genes that are under-expressed following stress
are genes concerned uniquely with synaptic function (Bogoch et al. 2007).
No neuronal loss has been reported in the CA3/CA1 fields of the rat hippocam-
pus following restraint stress (Fujioka et al. 2006; Mizoguchi et al. 1992) but there
is following extremely stressful conditions, such as those when the animals are
exposed to a predator (Hosseini-Sharifabad and Nyengaard 2007; McEwen 2000;
Swaab et al. 2005; Zhao et al. 2007). There are two reports that following either
maternal deprivation or stress due to environmental pressures (such as decreased
food and wheel turning) which report an increase in GFAP-labeling of as much as
30% (Lambert et al. 2000; Llorente et al. 2008), perhaps indicating an increase in
astrocytes or their processes. Overall these observations on the effects of stress on
the CA3/CA1 grey matter fields indicate that about a 30% decreases in synapses
(Andersen and Teicher 2004; Hayashi et al. 1998) with a concomitant decrease in
dendrites (McLaughlin et al. 2007; Watanabe et al. 1992; Wood et al. 2004) is the
likely major change in the CA3/CA1 grey matter field following stress.
The grey matter of the dentate gyrus (DG) of the hippocampus, which occupies
53% of the total grey matter of the hippocampus (Sabbatini et al. 2000), requires
special consideration in the context of the effects of stress on changes in the con-
stituents of grey matter. This is because of the generation of new granule cell neu-
rons in this area of the mature brain. There are no observations on the effects of
stress on synapses or on their dendrites in DG, but a large number on cell loss in
the DG following stress, using BrdU labeling. A large range of different stressful
conditions (ranging through prenatal stress, restraint stress, social stress and forced
swimming) all give rise to substantial decrease in cells in the DG (Borcel et al.
2008; Chen et al. 2006; Czeh et al. 2001, 2007; Dupret et al. 2007; Fujimoto et al.
2007; Jayatissa et al. 2008; Namestkova et al. 2005; Oomen et al. 2009; Thomas
et al. 2007; Veena et al. 2009b; Westenbroek et al. 2004), with reported loss of cells
ranging from 22% (Jayatissa et al. 2008) to 70% (Veena et al. 2009a, b). What
proportion of this large cell loss is due to neurons versus glia is not clear. If this
loss is completely due to loss of granule cell neurons and the volume ratio of neu-
ronal elements to glial elements is 8:1 (see note in Table 6.1), then such a loss
could substantially impact on the volume of the hippocampus. Loss of synapses
and their dendrites in the CA3/CA1 could also produce the observed changes in
hippocampal grey matter of stressed rats. The 30% estimate for loss of synapses in
CA3/CA1, if accompanied by a similar percentage loss of dendrites, would give
rise to about 8% decrease in volume of grey matter in the hippocampus (based on
The Effects of Synapse Regression on the Cellular Constituents… 119
volume density of synapses and dendrites in CA3/CA1 subfields of 0.48 mm3/mm3

of grey matter and that CA3/CA1 grey matter volume is about the same as that of
the DG grey matter volume).
The Effects of Synapse Regression on the Cellular Constituents

of Cortical Grey Matter in Animals
Given the good evidence for a substantial loss of boutons in the cortical areas
implicated in MDD, the questions arise as to whether, as claimed above, such syn-
apse loss is accompanied by a similar percentage loss of dendrites, and if so whether
such loss of boutons and dendrites is likely to give rise to a decrease in grey matter
volume. Such a decrease implies that the grey matter compacts on the loss of these
constituents. An alternative is the occupation of any additional extracellular space
within the grey matter by the growth of other cellular processes such as those of
astrocytes.
Deafferentation of the cat’s lateral cervical nucleus leads to similar percentage
decreases in boutons, and dendrites (Benes et al. 1977; Griph and Westman 1977),
as noted above. These authors comment that ‘the similarity in reduction of boutons
and dendritic fractional volume is striking (67 and 64%, respectively (p. 740))’.
Deafferentation of specific dendrites on neurons in the avian nucleus laminaris
leads to selective shortening of these dendrites, due to their reabsorption into the
cell body (Deitch and Rubel 1989b) a process that does not involve astrocytes
(Deitch and Rubel 1989a). Such deafferentation leaves normally innervated den-
drites on the same neuron unaffected (Sorensen and Rubel 2006). Similar results
have been obtained for the deafferented cat lateral geniculate nucleus (Somogyi
et al. 1987) and in gerbil superior olivary nucleus (Russell and Moore 1999). Very
interestingly, pharmacological block of transmission of boutons on specific den-
drites leads to a decrease in their length (Sorensen and Rubel 2006). Griph and
Westman (1977) note that following deafferentation there is ‘a considerable shrinkage
of the whole nucleus from day 9 to 14. Such a shrinkage might be caused by a
disappearance of boutons and dendrites (p. 739; Griph and Westman 1977)’. This
shrinkage is accompanied by very little change in the extent of extracellular space
or oedma so that it may be attributed to the loss of the cellular constituents and/or
their processes in the grey matter as there is little evidence for substantial changes
in the size of the cell somas (Griph and Westman 1977). It has been known for
some time that the vacant synaptic sites on deafferented neurons in the hippocampus
may be reinnervated by sprouting axon terminals of other axons (Frotscher et al.
1981; Hoff 1986; Matthews et al. 1976a, b). However this has not been shown to
be the case in other brain regions such as the cerebellar cortex and the lateral
geniculate nucleus, where deafferentation is followed by dendritic reduction
(Hamori 1990). The conditions that lead to reinnervation of vacant sites by sprouting
axons versus those in which the dendrites possessing these vacant sites are
reabsorbed by the neurons are not known. Deafferentation of some nuclei leads to
a substantial increase in glia, presumably due to an increase in the primary pro-
cesses of astrocytes (Griph and Westman 1977) as reactive astrocytes are known to
increase the diameter of their primary processes without changes in the length of
processes or in the extent of the large number of small processes (Wilhelmsson
et al. 2006). To what extent this might require modification of the quantitative
considerations in this work is not clear.
Changes in Grey Matter and Its Cellular Constituents

in Major Depressive Disorder
Anterior Cingulate Cortex
Magnetic resonance imaging shows that the largest decrease in grey matter is found
in anterior cingulate cortex of patients with MDD (−11.5%; Koolschijn et al. 2009).
Two post-mortem studies of this region of the brain (BA24) in MDD patients show
no changes in the density of neurons and either no change in the size of their somas
(Ongur et al. 1998) or a small change in layer VI (Cotter et al. 2001a, b). On the
other hand, both these researchers observed a decrease of between 12 and 20% in
the density of glial cells, which are probably satellite oligodendrocytes (Cotter et al.
2001a; Ongur et al. 1998; Rajkowska et al. 1999). Given that these cells and their
process occupy about 5% of the grey matter (see Table 6.1), a decrease of 20% in
their numbers will contribute only 1.0% to the observed 11.2% decrease in grey
matter observed in MDD patients. If the density of both oligodendrocytes and astro-
cytes is considered, that is, all the glial cells except the low-density microglia, then
they amount to 11.2% of grey matter (see Table 6.1), of which a 20% loss will still
only provide a decrease of about 2.2% in grey matter. The highest levels of glia
density (astrocytes and oligodendrocytes) observed in cortex of other species, is that
in the cat of about 23% (Griph and Westman 1977). This still only contributes little
over 4% to the loss of grey matter for a 20% loss of these glial cells, insufficient to
account for the observed 11.5% decrease in grey matter.
On the other hand, a 38% loss of synapses has been observed in anterior cingu-
late cortex of patients with MDD (see Table 4 in Eastwood and Harrison 2001).
Given that synapses occupy 0.06 mm3/mm3 of grey matter (Table 6.1), this would
amount to a loss of 2.2% of grey matter, at least comparable to the estimate of grey
matter decrease due to the loss of glial cells of 2.3% noted above. Furthermore, a
concomitant of the deafferentation of neuronal dendrites by such a large loss of
synapses is the loss of dendritic branches. In cats, deafferentation of the lateral cer-
vical nucleus to the extent that the grey matter volume occupied by the boutons
declines by 67% gives rise to a 64% decrease in the volume of the nucleus occupied
by dendrites (Griph and Westman 1977). It is interesting in this regard that the loss
of synapses between 16 and 29% in the anterior cingulate cortex of stressed rats is
Changes in Grey Matter and Its Cellular Constituents… 121
accompanied by similar percentage decreases in the length of apical dendrites

(Radley et al. 2006). If the 38% decline in synapses in the rostral ACC of patients
with MDD is accompanied by a similar percentage decline in the length of den-
drites, then the volume of grey matter they occupy of 0.30 mm3/mm3 of grey matter
(Table 6.1) will decline by 0.11 mm3/mm3 of grey matter that is by 11% of the grey
matter volume. Such a cumulative loss of synapses and dendrites amounts to a loss
of grey matter of 2.2% plus 11 or 13.2%. If the loss of these structures is not com-
pensated for by the growth of other components of the grey matter, then a 13%
shrinkage of the grey matter is to be expected, comparable to the 11.5% decrease
observed in MDD patients with MRI.
Orbitofrontal Cortex
Magnetic resonance imaging shows a 9% decline in the grey matter of the orbitof-
rontal cortex of patients with MDD (Koolschijn et al. 2009). No change in the
density of neurons accompanies this decrease, although decreases in the diameter of
neurons of between 6 and 10% have been reported in layers II, V and VI (Rajkowska
et al. 1999). A uniform change of 10% diameter of neurons throughout the orbito-
frontal cortex would be expected to decrease the volume of cortex at most
0.27 ± 0.078 mm3/mm3 of grey matter (see Table 6.1) that is by less than 2%. A 12%
decrease in the diameter of glia has been reported in layers III and IV without a
change in glia density (Rajkowska et al. 1999) and in another report from this group
a 10% decrease in density without changes in size (Rajkowska 2000). A uniform
12% decrease in diameter of astrocytes and oligodendrocytes would only provide at
most a change of 0.32 ± 0.013 mm3 of grey matter (Table 6.1) or less than 0.4%,
whereas a 10% decrease in density would amount to a decrease of 1.3% (Table 6.1).
It seems then that these relatively small changes in neurons and glia are not primarily
responsible for the 9% loss of grey matter according to MRI. This leaves a loss of
synapses and concomitantly their dendrites on which they synapse as the most likely
source of loss leading to shrinkage of grey matter in the orbitofrontal cortex of
MDD patients.
Hippocampus
The meta-analysis of MRI studies of patients with MDD indicates a 5% loss of

grey matter in the hippocampus (Koolschijn et al. 2009). This change may be
accommodated by the reported loss of synapses in the hippocampus, which is 11%
in the subiculum, 17% in parahippocampal gyrus, 17% in CA3 and 20% in CA4,
with an average of 16% (Eastwood and Harrison 2000). This 16% decrease of
synapses will provide 16% of 0.06 mm3 loss of grey matter or less than 1% (see
Table 6.1). If there is a concomitant loss of dendrites, then this will add a volume
loss of 16% of 0.30 mm3 (see Table 6.1) or 4.8%. So the total percentage loss of
grey matter is 5.8%, which is similar to the 5% loss determined by MRI. It should
be noted that these figures are conditional on similarities in the distribution of cells
and their processes in the grey matter of the cortex and hippocampus. This is not
the case as the length of pyramidal cell dendrites in the hippocampus is greater
than that on average in the cortex (see note 3 in Table 6.1). Unfortunately there are
no observations on possible neuronal or glial loss in the hippocampus in MDD
to confirm this suggestion.
Prefrontal Cortex
A 1.8% decrease in prefrontal cortical grey matter has been observed in MDD
patients with MRI (Koolschijn et al. 2009). No changes in neuron dimensions or
densities have been reported for prefrontal cortex in MDD with no changes in glial
fibrillary acid protein (GFAP)-labeled astrocytes (Miguel-Hidalgo et al. 2000) in
Brodman Area 9 (BA9) and some variations in different isoforms of GFAP reported
in BA10 using proteomics (Johnston-Wilson et al. 2000). However an up to 40%
decrease in a marker for oligodendrocytes (myelin basic protein) in the grey matter
of anterior frontal cortex of MDD patents has been reported (Honer et al. 1999). If
this is taken to indicate a 40% loss of satellite oligodendrocytes, it would amount to
a volume change in the anterior frontal cortex of about 0.05 × 0.40 or 2.0% (see
Table 6.1). This would accommodate the observed 1.8% decrease in grey matter
detected by MRI if the grey matter decreased with this loss of satellite oligodendro-
cytes. No changes in markers for synaptic boutons, such as synaptophysin, have
been noted in the anterior frontal cortex of patients with MDD (Honer et al. 1999).
Conclusion
The Cellular Constituents of Human Cortical Grey Matter
The fraction volume of neuropil occupied by the processes of neurons amounts to

60% so these dominate the grey matter. This is the case even though the density of
glial cells is much greater than that of neurons (see Table 6.1). However the volume
fraction occupied by dendrites and collateral axons is extremely sensitive to esti-
mates of the dimensions of dendritic and axonal processes. These vary widely, for
example, in the case of dendrites from 0.73 to 1.3 mm in different species (see
Table 6.3, column 3). This is likely to give rise to the greatest inaccuracies in deter-
mination of the volume fractions given in Fig. 6.2. The dendritic diameter of 1.08 mm,
derived from animal studies (Table 6.3, column 3), has been used in the present
calculations. For collateral axons the diameter for human cortex given in the book by
Braitenberg and Schuz (1998) of 0.3 mm has been used. This, as noted above, is small
Conclusion 123
compared with that in most animal studies and the details of how it is arrived at are
not clear. It is likely to give rise to the greatest error in the estimates. Of course, when
considering these diameters no allowance is given for diameter variation between
primary, secondary and tertiary processes, another source of error not only for neu-
ronal processes but also for those of astrocytes and oligodendrocytes.
It is interesting to compare the percentage of cortical grey matter occupied by
axons and dendrites determined here (Fig. 6.2) with that for other structures such as
the rat olfactory glomerulus (Nawroth et al. 2007). The volume fraction for axon
collaterals estimated for the glomerulus is 0.30 (compared with the present estimate
for cortex of 0.29) and for dendrites is 0.45 (compared with 0.30). The volume
fraction for astroglia is 0.08 for the glomerulus (compared with 0.06). A large dif-
ference is found for the volume fraction of the vasculature which is 0.06 compared
with 0.005 in the cortex. No estimate is given for the extracellular space in the glom-
erulus, although the volume fraction not accounted for suggests it is about 0.10
(compared with 0.18). It is conceivable that the difference of 0.08 is accounted for
by inaccuracies in the estimations for the vasculature. It should be noted that the
extracellular space determination in cortex is likely to be accurate as it is based on
reliable quantitative methods developed by Nicholson and Phillips (1981). Of course
these comparisons are between different neuropils.
Lennie (2003), in his determinations of energy consumption of the human cortex,
summarizes some basic statistics concerning volume fractions found in the literature
(see his Table 6.1). Some of these are more likely to be for the rodent cortex than the
human cortex as they come from the book by Braitenberg and Schuz (1998). It is
interesting, nevertheless, to compare them with the values arrived at here which have
been primarily obtained from the literature on human cortex, as the tables and Fig. 6.2
show. Lennie (2003) gives the following values that may be compared with those
arrived at in the present tables: for axon collateral length, 4 × 106 mm/mm3 (compared
with the present estimate for human cortex of 4.1 × 106); for dendritic length,
0.4 × 106 mm/mm3 (compared with 0.4 × 106); for dendritic diameter, 0.9 mm (com-
pared with 1.0 mm); and for number of synapses, 7 × 108/mm3 (compared with
3.6 × 108). So the estimates for the human cortex derived from the publications consid-
ered in the tables for neurons and glia is about twice that given by Lennie (2003)
whereas the number of synapses is about half. However, since the volume fraction of
cortex is by far the greatest for the dendritic and axonal processes of neurons (75% in
the glomerulus and 60% in human cortical grey matter) it is satisfying to see general
agreement between the dimensions given for these structures in Lennie (2003) with
those presented here based on averages from tabulations of human cortical data.
The conclusion from this study of volume fractions is that reductions in grey
matter of the order of 10% as determined by MRI are unlikely to be achieved by
degeneration of significant proportions (i.e. >30%) of astrocytes or satellite oligo-
dendrocytes. Nor would they be achieved by the regression of synapses per se.
However these changes could be achieved by a substantial decrease in the predomi-
nant volume fraction occupied by dendrites or by a smaller decrease in this volume
fraction together with significant decreases in the volume fraction of astrocytes and
oligodendrocytes.
The Cellular Basis for the Loss of Grey Matter in Major

Depressive Disorder (MDD)
There is very little evidence for a loss of neurons in the prefrontal–limbic network
but there is for glial cells in the anterior cingulate cortex, orbitofrontal cortex and
prefrontal cortex in MDD. Present evidence suggests that these are primarily satel-
lite oligodendrocytes that occupy about 6% of grey matter (Fig. 6.2). The highest
loss of these cells reported for the prefrontal–limbic network is between 20 and
40%, a loss that would contribute at most a 2.4% volume decrease. This is less than
30% of the grey matter loss reported for the anterior cingulate cortex (11.5%) and
orbitofrontal cortex (9%) in MDD and 50% of that for the hippocampus (5%) but it
does accommodate the 1.8% loss of grey matter in prefrontal cortex.
The present quantitative considerations of the cellular composition of cortical
grey matter emphasize the dominant contributions of neuronal dendrites and axon
collaterals (Fig. 6.2). As already noted, there is evidence for a quantitatively simi-
lar retraction of deafferented dendrites following the loss of synapses in the pre-
frontal–limbic network in MDD of between 16 and 38%. This accounts for the
reported grey matter losses, at least in anterior cingulate cortex, orbitofrontal cortex
and hippocampus. A most important assumption in arriving at these conclusions
concerns the extent to which regressing synapses and their dendrites are replaced
by glial cell processes, especially those of the enveloping astrocytes.
This chapter and the preceding one argue for the hypothesis that the core pathol-
ogy responsible for the loss of function in the prefrontal–limbic network is the
regression of synapses. It is clear that what is now urgently required is further
quantitative studies on the cellular composition of grey matter in the prefrontal–
limbic networks of MDD patients. If the hypothesis survives such investigations
then the vital task of identifying the means for restoring these synapses will have a
firm basis.
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Chapter 7
On the Mechanism of Action
of an Anti-depressant
The Role of Fluoxetine (Prozac®) in Modulating
Synapses in the Prefrontal-Limbic Network
Mood disorders such as depression are accompanied by changes in the structure and
function of the prefrontal cortex, cingulate cortex and amygdala (Drevets et al.
2008). In particular, specific connections between these areas are lost (Mayberg
2003) and animal studies suggest that this probably occurs as a consequence of the
disappearance of spines on neuronal dendrites leading to the regression of synapses
(Bennett 2008). Selective serotonin reuptake inhibitors (SSRIs) are known to at
least partly reverse this loss of synapses but no consistent account of how this might
occur has been given (Norrholm and Ouimet 2001). N-methyl-D-aspartate receptor
(NMDAR) activation is a principal means of ensuring the integrity of synaptic
spines (Bennett 2009). The present work considers a means by which changes in
SSRIs modulate NMDA receptors and so determine the formation and regression of
synaptic spines and hence the viability of synaptic connections between cortical
regions and the amygdala that accompany depression.
Synaptic Connections of the Anterior Cingulate Cortex

and the Amygdala
The anterior cingulate cortex (ACC) consists of four regions, delineated in Fig. 7.1a, b:
dorsal ACC (BA 24b’, 24c’ and 32’; compare Fig. 7.1b with Fig. 7.1c); rostral ACC
(BA 24a, 24b and 24c; compare Fig. 7.1b with Fig. 7.1c), and a subgenual ACC
which can be subdivided into anterior (continuation of rostral BA 24a and 24b;
compare Fig. 7.1b with Fig. 7.1c) and a posterior component (BA25; compare
Fig. 7.1b with Fig. 7.1c). The rostral ACC is anatomically connected with the dorsal
The final, definitive version of this paper has been published in Australian New Zealand Journal of Psychiatry 44:301–308 April 2010 by SAGE
Publications Let, All rights reserved. Copyright (2010). Online version available from http://apn.sagepub.com/content/44/4/301

134 7 On the Mechanism of Action of an Anti-depressant
Fig. 7.1 Anatomy of the anterior cingulate cortex, dorsal and ventral prefrontal cortex and the
amygdala in humans. (a) The delineations of anterior insula (a INS); CN caudate nucleus, dACC
dorsal anterior cingulate cortex, dlPFC dorso-lateral prefrontal cortex, dmPFC dorsomedial pre-
frontal cortex, vmPFC ventro-medial prefrontal cortex (includes the medial aspect of orbito-frontal
cortex), pMFC posterior medial cortex, rACC rostral anterior cingulate cortex, sgACC subgenual
anterior cingulated cortex, vmPFC ventromedial prefrontal cortex (after Figure 1 in Taylor and
Liberzon 2007). (b) Parcellation scheme for subregions of the anterior cingulate cortex (ACC).
The green region indicates the dorsal ACC (consisting of BA 24b’, 24c’ and 32’ (see Fig. 7.1c));
the red region indicates rostral ACC (BA 24a, 24b and 24c; sometimes referred to as pregenual
ACC, anterior to the genu of the corpus callosum); the yellow region indicates anterior subgenual
ACC (continuation of the rostral cingulate gyrus (BA 24a and 24b), which wrap around the corpus
callosum and generally corresponds to the subgenual region (originally identified by Drevets et al.
(2002) as ACC ventral to the genu of the corpus callosum). The blue region indicates posterior
subgenual ACC (BA 25; sometimes referred to as the subclossal gyrus; after Figure 1 in Gunning
et al. 2009). (c) Detailed anatomy of the anterior cingulate cortex in humans. The cortical surface
has been partially inflated to allow simultaneous viewing of gyri and sulci, with a single cingulate
gyrus lying between the cingulate sulcus and the corpus callosum. The numbered cytoarchitectural
areas of the ACC delineate what are taken to be the cognitive division (areas 24’, 24b’, 24c’and 32’)
and the affective division (24a, 24b, 24c, 25, 32 and 33) (after Figure 1 in Bush et al. 2000).
(d) Relative proportion of input and output connections in prefrontal cortex with projections
involving the amygdala in the monkey. Shown is the medial surface of the prefrontal cortex.
Prefrontal areas with input from the amygdala greater than output to the amygdala are shown
(after Figure 8a in Ghashghaei et al. 2007). The densest connections of the monkey prefrontal
cortex with the amygdala are similar to those in the human, and involve the posterior medial cortex
(M25 and D24 and MPA11) and the posterior orbitofrontal cortex (OPA11, OPro). Of these
cortices, cingulate areas D24 and M25 project more heavily to the amygdala than they receive
projections from the amygdala, in contrast to the caudal orbital areas that receive more projections
than they send (Figure 7.1a, c, d has been reproduced with permission from Elsevier. Figure 7.1b has been reproduced with permission
from John Wiley & Sons, Inc)
Changes in Synaptic Connections of the Anterior Cingulate Cortex… 135
prefrontal cortex (BA9, 10, 46), while the subgenual ACC is primarily connected to
the orbitofrontal cortex (BA11) as well as the hippocampus and amygdala (Vogt and
Pandya 1987; Pezawas et al. 2005; Schlösser et al. 2008). Anatomical connectivity
determinations indicate that these regions can be compartmentalized into the dorsal
ACC (comprising BA24a’, 24b’, 24c’ and 32’), with dense connections to the
subgenual ACC, the medial prefrontal (BA10), the orbitofrontal cortex (BA11) and
the amygdala; and a rostral and subgenual region (comprising areas BA24a, 24b,
24c and 25), with dense connections to the amygdala and the orbitofrontal cortex
(Bush et al. 2000; Johansen-Berg et al. 2008). It has been suggested that dorsal areas
are concerned with cognition and exert control over ventral areas such as the subgenual
ACC that are concerned with the affections (Fig. 7.1a; described and criticized in
Taylor and Liberzon 2007). This claim may be reflected in the fact that in healthy
subjects the ventral ACC shows partial deactivation during tasks that demand cognitive
capacities whereas the dorsal ACC is partially deactivated during tasks that involve
emotional responses (Schlösser et al. 2008).

Cortex and the Amygdala in Depression
During psychological tests with fearful stimuli, functional magnetic resonance

imaging (fMRI) shows that there is tight functional coupling of a feedback pathway
involving synaptic connections formed by amygdala axons projecting to the sub-
genual ACC and synaptic connections formed by the subgenual axons projecting
to the rostral (pregenual) ACC, which has synaptic connections formed by axons
projecting to the caudal amygdala that lead to its inhibition (Fig. 7.2a; Pezawas
et al. 2005). Thus when the rostral (pregenual) ACC is stimulated it causes inhibi-
tion in the amygdala (Maren and Quirk 2004; Stefanacci and Amaral 2002). Of
great interest is the fact that synaptic connections are partially lost in depression,
primarily those subserving the projection from the amygdala to subgenual ACC and
less along the synaptic pathway from the rostral (pregenual) ACC that causes inhibi-
tion in the amygdala (Fig. 7.2b). There is a decrease in the rostral (pregenual)
ACC synaptic connectivity to the amygdala in both unipolar and bipolar depressed
patients (Anand et al. 2009; Savitz et al. 2009). Reduced synaptic projections
between subgenual ACC and the amygdala have been observed during a post
mortem in a patient with bipolar disorder (McNab et al. 2009). Different regions
in the medial prefrontal cortex and orbitofrontal cortex exert an inhibitory
influence over activity in the amygdala, and fail to do so in mood disorders (com-
pare Fig. 7.2a, b; Drevets et al. 2008; Drevets 2007; Savitz and Drevets 2009).
Mayberg and her colleagues have used structural equation modeling to investi-
gate the synaptic connectivity, determined by fMRI, of the cortical dorsal (cogni-
tive) area with the limbic ventral (affective) area of normal subjects compared
with those suffering from depression (James et al. 2009). First they confirmed in
Fig. 7.2 Connection of the anterior cingulate cortex, dorsal and ventral prefrontal cortex and the
amygdala in humans. (a) Control connections based on anatomical determinations. (b) Connections
determined for depressed patients. Definitions of the acronyms are given in the legend to Fig. 7.1a
(After Figure 2 in Seminowicz et al. 2004)
normal subjects the synaptic projection from the rostral (pregenual) ACC to the
subgenual ACC, as well as that of the subgenual ACC with the orbitofrontal cor-
tex and the dorsolateral prefrontal cortex (Fig. 7.2a). In addition, they showed
strong synaptic input from the hippocampus-amygdala to the subgenual ACC
(Fig. 7.2). Of further interest was the finding that in depressed patients there is a
lack of functional synaptic connections between the subgenual ACC and the rostral
(pregenual) ACC, as well as of the hippocampal input to the subgenual ACC and all
functional synapses with the dorsolateral prefrontal cortex (Fig. 7.2b). This amounts
to failure of most of the regulatory synaptic inputs to the subgenual ACC. Such
observations may help explain the enhanced metabolic and fMRI activity in the
subgenual ACC of depressed patients (Mayberg 2003). Use of multivariate techniques
combined with structural equation modeling, applied to resting-state positron emis-
sion tomography scans of acutely depressed patients, show differences in known
anatomical and physiological pathways. An estimate has been made of the strength
and direction of ‘effective synaptic connections’ between these areas (McIntosh
1999; McIntosh et al. 1996; McIntosh and Gonzalez-Lima 1994). Changes are
observed between the subgenual ACC, the pregenual ACC, the orbitofrontal cortex,
the hippocampus (amygdala), the medial pre-frontal cortex, the dorsolateral pre-
frontal cortex and the thalamus (Fig. 7.2b). The decrease in rostral (pregenual)
ACC to amygdala functional synaptic connectivity in bipolar disorder, even
detected in patients in different mood states, could reflect a decrease in the inhibi-
tory effects exerted by the ACC’s perigenual region over the amygdala (Wang
et al. 2009) which might occur as a consequence of loss of integrity of white
matter bundles between the subgenual and the amygdala (Wang et al. 2009).
The Mechanism by Which Changes in Serotonin Transporters… 137

Cortex and the Amygdala of Depressed Patients
Following Serotonergic Uptake Blockers
In major depressive disorder there is increased blood flow and metabolism in the
subgenual ACC (Drevets et al. 2008; Savitz and Drevets 2009; Liotti et al. 2002;
Mayberg et al. 1999). There is a decrease in metabolic and fMRI measured activity
in the dorsolateral prefrontal cortex (BA9, 46) concomitant with the increased
metabolic activity and fMRI signal in the subgenual ACC (BA25) in patients with
depression, leading to the conjecture that it is failure of control from the dorsal areas
to the ventral areas that leads to increased activity in the ventral areas (Fig. 7.1;
Taylor and Liberzon 2007). In general, SSRI medication-responding patients show
normalization of dorsal hypometabolism and ventral hypermetabolism (Brody et al.
2001; Nitschke et al. 2009; Kennedy et al. 2001) so that effective anti-depressant
action is associated with reduced subgenual ACC activity (Drevets et al. 2002, 2008;
Savitz and Drevets 2009). The question arises as to how SSRIs bring about such
normalization of metabolism.
The Mechanism by Which Changes in Serotonin Transporters

Bring About Changes in Synaptic Activity in Anterior Cingulate
Cortex and Amygdala 5-HT Receptor Distributions on Neurons
and Their Interaction with NMDA Receptors
Serotonergic 1A receptors (5-HT IA R) are localized at relatively high density on the

axon hillock of pyramidal neurons in the cerebral cortex, and more diffusely over
dendrites, synaptic spines and the perikaryon (Fig. 7.3; Azmitia et al. 1996; Moreau
et al. 2010; Holmes 2008). In contrast to this distribution the 5-HT 2A/C receptors
are found localized to the proximal dendritic shafts, and more diffusely on synaptic
spines of pyramidal neurons, in association with the NR1 subunit of NMDA receptors,
as well as on the perikaryon of inhibitory interneurons (Fig. 7.3; Holmes 2008;
Moreau et al. 2010; Peddie et al. 2008a, b). The Raphe nucleus serotonergic neurons
are likely to make synaptic connections on 5-HT 1A R found on the axon hillocks of
excitatory neurons whereas the 5-HT 2A R are found on the proximal dendritic
regions of excitatory neurons as well as on inhibitory neurons (Holmes 2008).
5-HT IA R activation decreases NMDA receptor-mediated currents through
inhibition of protein kinase A, which leads to a decrease in microtubules involved in
clustering the NR2B subunit of NMDAR (Yuen et al. 2008; Zhong et al. 2008). In
contrast to this, 5HT 2A R activation increases NMDAR-mediated currents by
increasing protein kinase C and activating ERK via the beta-arrestin-dependant
pathway, thus counteracting the effects of 5HT IA R activation in decreasing
NMDAR-mediated currents (see above and Yuen et al. 2008; Zhong et al. 2008).
In summary, the inhibitory 5-HT 1A R both decrease excitability at the axon hillock
Fig. 7.3 Synaptic connections of serotonin (5-HT) containing neurons in the Raphe nucleus
(hatched) with neurons in the amygdala, pyramidal neurons in the cortex and inhibitory GABA-
containing neurons (filled) in both. Shown are the 5-HT synapses formed on the axon hillock of
neurons, with localized 5-HTIA receptors, and on dendrites, with localized 5-HT2A receptors
(After 5-HT receptor distributions given in Figure 9 of Moreau et al. 2010, Figure 3 in Holmes 2008)
of pyramidal neurons and also indirectly reduce excitability through down-regulation

of NMDA receptors. In contrast, the opposite is the case for the 5-HT 2A R.
The Mechanism by Which Changes in Serotonin Transporter

Genes Alter the Level of Excitability in Anterior Cingulate
Cortex and Amygdala
Transgenic mice knockouts for the 5-HT transporter (5-HTT) show a marked
decrease in 5HT IA R in the amygdala (Li 2006; Li et al. 2000, 2003; Mathews et al.
2004). It would then be expected, following consideration of the serotonergic circuit
The Mechanism by Which Serotonin Transporter Antagonists… 139
in Fig. 7.3, that the 5HT 1A R-mediated inhibition of pyramidal neurons at their
axon hillock would be lost. This should lead to a net loss of inhibition of these
neurons, an enhancement of NMDAR currents and therefore an increase in synaptic
spines. Such an increase is observed in the amygdala, a site of normally high 5HT
1A R density (Wellman et al. 2007). Increases in excitability of pyramidal neurons
are also expected to occur in humans with functional polymorphisms in their 5-HTT
genes (specifically 5-HTTLPR short genotype), as this results in lower 5-HT IA R
(David et al. 2005). Given that 5HT IA R are at highest density in the limbic areas
of the brain, it might be that the enhanced activity and hypermetabolism in the
amygdala observed in depressed patients arises in part as a consequence of down-
regulation of 5-HT 1A R there. It is interesting to note that such down-regulation
also occurs following release of corticotrophin releasing factor during stress
(Leonard 2005). The subgenual ACC is the major region of gray matter volume loss
in carriers of the short allele of the serotonin transporter gene 5-HTTLPR that have
increased amygdala activity and elevated risks of depression (Pezawas et al. 2005).
Decreases in gray matter in the subgenual ACC have been observed in patients with
mood disorders (Drevets et al. 2008), including bipolar disorder (Lyoo et al. 2006)
and major depressive disorder (Savitz and Drevets 2009). If these changes in gray
matter are primarily due to a decrease in the neuropil, consisting of the processes
of synapses and astrocytes, then the increase in NMDAR contingent on the loss of
5-HT 1A R would be anticipated to give an increase in synapses, the opposite of
what is observed. On the other hand, the use of 5-HT 2A R antagonists as antide-
pressants leads to a down-regulation of the receptor and so an expected increase in
NMDAR activity is accompanied by synaptic-spine growth (Leonard 2005; Van
Oekelen et al. 2003). However another observation that cannot be easily accommo-
dated with the idea that it is ultimately the activity of the NMDAR that determines
the growth and stability of synaptic spines is that in some cases the NMDAR antag-
onist ketamine is an effective anti-depressant, unless is it claimed that this antagonist
is principally acting on NMDAR in the amygdala (Skolnick et al. 2009).
The Mechanism by Which Serotonin Transporter

Antagonists Alter the Level of Excitability in Anterior
Cingulate Cortex and Amygdala
Depletion of 5-HT in neonatal and adult mice leads to a 20 % decrease in density of

spines and the size of dendrites in the dorsomedial prefrontal cortex (Perez-Vega
et al. 2000) as well as of both dentate granule cells and CA1 pyramidal cells in the
hippocampus (Fig. 7.4; Yan et al. 1997a, b; Alves et al. 2002). In contrast to this,
blocking the 5-HTT in developing mammals with antagonists such as fluoxetene
increases the ambient level of 5-HT (Koch et al. 2004) and synaptic spine density
(Norrholm and Ouimet 2001). Fluoxetine also restores the density of synaptic spines
on hippocampal pyramidal cells of ovariectomized female rats (Hajszan et al. 2005)
and increases synaptophysin-labeled synapses in normal rats (Varea et al. 2007).
These are the results to be expected if a decrease in 5-HT leads to an enhancement
Fig. 7.4 Abnormal synaptic-spine density on the dendrites of pyramidal neurons in the amygdala
of 5-HTT knockout mice. The left panel shows a sketch of dendritic synaptic-spines on a fourth-
order branch of a Golgi-stained pyramidal neuron in a wild-type mouse. Right panel shows the
distribution of synaptic-spines on such branches in a 5-HTT knockout mouse (After Figure 7a in Wellman
et al. 2007)
of inhibitory over excitatory modulation of excitability of these neurons through

5HT 1A R and 5HT 2A R (see Fig. 7.3), giving rise to a decrease in NMDA receptor
activity and hence spine loss, with an increase in 5-HT leading to an enhancement
of excitatory over inhibitory modulation and hence resulting in a gain of spines.
SSRIs such as fluoxetine have been reported to change the sensitivity of 5HT 1A R,
at least in the Raphe nucleus where they can act as autoreceptors, but the matter is
controversial (for a review see Savitz et al. 2009). The means by which blocking the
5-HTT leads to the return of dorsal hypometabolism and of ventral hypermetabolism
towards normal levels might then be as follows. Increases in 5-HT following the
block of 5-HTT enhances excitability through 5-HT 2A R over that through inhibi-
tory 5-HT 1A R, giving rise to increases in NMDA receptor activity at afferent
synapses in the dorsal areas which is further enhanced by an increase in spines
contingent on this increase in NMDA activity (Fig. 7.3; Bennett 2009). As a conse-
quence dorsal areas are excited and able to exert enhanced inhibitory control over
the subgenual anterior cingulate cortex and the amygdala (see Fig. 7.2a), giving a
normalization of levels of metabolism in these structures. It might be argued that
increasing 5-HT after blocking 5-HTT should also increase excitability in the ventral
References 141
regions as it is claimed to do in the dorsal regions. However, there is a relative

paucity of 5-HT 2A R receptors on principal neurons in the amygdala compared
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operate in bipolar disorder is unknown, but it should be noted that the transporter
might undergo a conformational change in patients with this disorder (Dean et al.
2001, 2003; Naylor et al. 1996), although no changes in the density of either 5-HT
2A R or 5HT 1A R have been detected in either the frontal cortex (Dean et al. 2001)
or hippocampus (Dean et al. 2003).
Conclusion
During development, decreased 5-HTT activity in humans as a consequence of

functional polymorphisms or a complete loss of 5-HTT activity in knockout ani-
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regions such as the amygdala that have few 5-HT 2A R, allowing dorsal regions to
once more exert their inhibitory influence over ventral regions. It is suggested that it
is in this way that SSRIs exert their effect in reversing dorsal hypometabolism and
ventral hypermetabolism in those suffering from depression.
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Chapter 8
On the Identification of Drugs Modulating
Epigenetic Mechanisms in Depression
Pathways to Restoring Synapses After Childhood
Abuse Leading to Depression
Introduction: A Proposal for the Most Efficacious

Course to Lower Rates of Suicide
Two important facts about suicide rates need to be highlighted. First, the rates of
suicide in the United States and Australia are about the same, and considerably
greater than that in the United Kingdom. It is clearly of the first importance to deter-
mine why there are such differences in English-speaking countries with such
common heritage and values. Claims made along the lines that countries like the
United States and Australia ‘developed from pioneering European origins (Cantor
et al. 1996) where toughness, independence and industriousness were central to the
male-dominated cultures’ leading to ‘hard working, violence and firearms’ of a kind
not associated with the United Kingdom seem wholly inadequate. Clearly deep
epidemiological and sociological studies are called for to assess how these very
different suicide rates arise and so identify what can possibly be done to bring
down the rates to those comparable in the United Kingdom.
Recent considerations of the best way to prevent suicide have emphasized
restricting access to lethal methods, such as guns (Mann et al. 2005). However
Australia has very strict gun laws compared with the United States but still has
about the same suicide rate. The second important fact is that a decline and subse-
quent stabilization in the rate of suicide occurred between 1990 and 2006. Each
country has taken pride in claiming that suicide rates decline because of suicide
prevention policies that country put in place, even though these are different. A well-
substantiated suggestion is that the decline was primarily related to the correlation
between rates of suicide and the economic cycle, obviously implicating the social
stress brought on by major economic down-turns, a stress that would of course fall
most heavily on those with a familial genetic predisposition to mood disorders and
impulsivity. Indeed suicide prevention strategies, based on solid evidence, place
emphasis on the training of physicians to recognize and adequately treat those with
major depressive disorders (Mann et al. 2005).

146 8 On the Identification of Drugs Modulating Epigenetic Mechanisms in Depression
In this chapter it is argued that the core problem in preventing suicide in a large
proportion of cases involves overcoming not only familial genetic predispositions to
mood disorders and impulsivity but also epigenetic mechanisms set in train by
childhood abuse, and introduced in Chap. 5. One might argue that a major effort
should be made to prevent childhood abuse in the first place. This is extremely
difficult, given the complex relationship between the genetic and epigenetic compo-
nents of the problem that sets the main acts of abuse in the family itself, acts which
increase in frequency during economic down-turns. This chapter then sets out the
case for concentrating on ameliorating the mood disorders set in train by these
epigenetic mechanisms through development and research on agents that will
reverse the epigenetic changes leading to major depression and suicide.
At the beginning of the twenty-first century what can be done do restore abused
children to the possibilities of a normal life? This chapter begins with a consideration
of statistics that show the high level of child sexual and physical abuse in the
community and how such abuse is accompanied by clearly identifiable changes in
the gray matter of the brain as well as the epigenetic changes noted in Chap. 5.
Consideration is then given to the extent to which traumatized children might be
rescued from major depressive disorders with different kinds of behavioural therapies.
Given that these are attempting to correct an epigenetic change that will lead to
rehabilitation, it is shown that they are not all that successful, although useful. Major
emphasis is then given to the development of epigenetic drugs that can reconstitute
the normal genetic make up that has been distorted by the epigenetic processes of
methylation and deacetylation (see Chap. 5). There is considerable promise that
such drugs will soon become available, given the success of clinical trials for their
use in the inhibition of tumorgenesis.
Childhood Abuse: Stress, Depression and Suicide

in Later in Life
The major risk factor for suicide is sexual or physical abuse in childhood. Indeed
those that have been sexually or physically abused when children amount to about
65% of all those who attempt suicide. This was shown in a study of adolescents in
Seattle, State of Washington. In this study suicide rates in which the victim succeeds
in injuring themselves were five times higher if the victim had been sexually abused
as a child than if they have not been abused. Early life abuse significantly increases
the risk of life-time major depressive disorder. Even children who experience mild
adversities are likely to be more reactive to later major difficulties in life (Seguin
et al. 2007).
Besides sexual or physical abuse, another major risk factor is a family history of
suicide. Family, twin and adoption studies indicate that suicidal behavior has an
underlying genetic predisposition that, although distinct from a genetic predisposition
to mental illness, is nevertheless perhaps dependent on it, so that these genetic
predispositions are not independent when considering suicide. For example a large
group amongst those that commit suicide or attempt to do so consists of patients
Gray Matter Changes in the Cortex Following Child Sexual and Physical Abuse 147
Table 8.1 Prevalence rates for child sexual abuse

Prevalence rate (%)
Location Women Men Age
1
Greenland 8 3 Child
Melbourne, Australia2 36 Child to adult
Europe3 10–20 3–10 <18 years
Europe4 6–36 1–15 <16 years
San Francisco, USA5 54 <18 years
North Carolina, USA6 11 (women and men) <16 years
with borderline personality disorder and impulsive-aggressive behavior. Levels of

impulsive-aggressive behavior are correlated with the history of suicidal behavior in
patients such that suicide behavior is at least partly explained by familial transmis-
sion of impulsive-aggressive behavior. Adolescent male suicide attempters are
nearly six times more likely to suffer from post-traumatic stress syndrome and over
three times more likely to suffer from borderline personality disorder if they have
been sexually abused as children.
Interventions Preventing Suicide Arising from Childhood
The annual rate of severe sexual abuse of children (kicked, punched, beaten-up,
assaulted with a weapon) is similar in USA (annual rate of 3.6%) and in Sweden
(4.1%). The prevalence rates for child sexual abuse are set out in the following table
(prevalence rates = (number sexually abused up to the time of assessment/all assessed)
in %). The numbered references are given in the Notes and References at the end of
this chapter (Table 8.1).
Of traumatic events unique to the individual child, 40% are sexual and 60% are
physical in the childhood range of 12–17 years, with post-traumatic stress occurring
at a prevalence rate of 6.3% in females and 3.7% in males as a direct consequence
of such abuse. After a major natural disaster like the Japan tsunami of 2011 the risk
of a child suffering post-traumatic stress is greater than 40%.
Gray Matter Changes in the Cortex Following Child Sexual

and Physical Abuse
Magnetic resonance imaging scans taken of children (age 11–12 years) after being
abused, most of whom have been sexually abused (>67%), and therefore very likely
to be suffering from post traumatic stress, show an increase in volume of the pre-
frontal cortex, of the superior temporal gyrus and of the hippocampus, which at
least in the case of the prefrontal and temporal regions is due to an increase in
gray matter. An increase in gray matter at this age in the prefrontal cortex is also
prominent in autism spectrum disorders. In contrast to these observations, if the

magnetic resonance imaging scans are taken at the end of adolescence after sexual
abuse as a child, then a decrease in gray matter of the prefrontal cortex is observed,
as well as in most of the visual cortex, together with a decrease in volume of the
hippocampus.
It will be of great interest to see if these changes in gray matter reflect at first an
excessive increase in the number of synapses normally formed in the childhood
period followed by an excessive loss over and above the normal loss of synapses
that occurs during adolescence.
Behavioural Therapies for Sexually Abused Children
Four different kinds of therapies have been assessed for sexually abused children;
three of them forms of cognitive behavioural therapy and the fourth of pharmaco-
therapy. The cognitive therapies are defined as follows:
Cognitive Behavioural Therapy (CBT)
1. Focuses particularly on the meaning of events for children and non-offending

parents.
2. Endeavours to identify and address maladaptive conditions (e.g. being permanently
soiled); misattributions (feelings of blame and responsibility) and low self-
esteem.
3. Addresses overtly behavioural problems: externalism behaviour (aggressive);
internalized behaviour (anxiety, self-blame and deprecation).
Trauma-Focused Cognitive Behavioural Therapy (TF-CBT)
Reviewed in Deblinger and Heflin (1996).

1. Develop skills in the child for expressing feelings.
2. Training in the development of coping skills.
3. Recognize relationships between thoughts, feelings and behaviour.
4. Carry out joint child–parent sessions for parent management skills; and for
education about child sexual abuse and body safety.
5. Children encouraged to create a narrative (both written and illustrated) of their
sexual abuse experiences; sharing this with parent so the narrative is developed
together.
Childhood Abuse, Depression, Suicide and Epigenetic Drugs 149
Child Centred Therapy (CCT)
This offers a supportive, client-centred approach that focuses on establishing a trusting

therapeutic relationship that is self-affirming and empowering for both child and
caregiver (a standard text on this therapy is Cohen and Mannarino 1996).
TF-CBT is superior to CCT at 6–12 months after therapy sessions with fewer
symptoms of post-traumatic stress, feelings of shame and of stress of non-offend-
ing parents. Although CBT probably does assist in ameliorating the trauma of sex-
ual abuse this is not really well established.
Pharmacotherapy, using serotonin reuptake inhibitors (such as Prozac, see Chap. 7),
reduces trauma in adults but the evidence is unclear for sexually abused children.
Nor is it clear that a combination of reuptake inhibitors and CBT is better in adults
suffering post-traumatic stress than CBT alone. So the use of psychopharmacology
to assist sexually abused children requires much more study and there is no empirical
study of early intervention with children that have suffered traumas as a conse-
quence of a mass disaster such as the recent tsunami in Japan.
All-in-all TF-CBT seems to be the most favorable therapy although many clinical
trials need to be carried out still, especially in the field of psychopharmacology
and in early intervention of both children traumatized by sexual abuse and those
traumatized by a catastrophe.
Childhood Abuse, Depression, Suicide and Epigenetic Drugs
Psychiatric diseases such as major depressive disorders and bipolar (manic/

depressive) disorders are associated with failure of normal gene expression as a
consequence of abuse and neglect in childhood leading to epigenetic changes in the
genome. Many of these genes are concerned with the functioning of synapses. There
is then enormous potential for the use of epigenetic drugs to restore gene function
and therefore return synapses to their normal activity. The consideration of such
epigenetic drugs requires knowledge concerning epigenetic mechanisms that are
spelt out in Chap. 5. Without this knowledge the reader will find much of what
follows difficult to understand. But given the main thesis of this work, that the
childhood abuse of Virginia Woolf led, through epigenetic mechanisms, to her
major mood disorders and suicide, it is necessary to understand these mechanisms
and importantly what can be done to put aright what has gone awry with them
following abuse.
The recent observation of significant epigenetic changes in the prefrontal cortex
of suicide victims raises the question of how these come about and to what extent
they can be reversed using epigenetic drugs? In animal experiments it has been
shown that stress during early life can lead to epigenetic changes involving
modifications of histone/chromatin determining the expression of genes that act at
synapses such as those for gamma-amino-butyric-acid, glucocorticoid receptors and
brain-derived neurotrophic factor. Such changes are accompanied by depressive

behaviour in the animals that can be reversed by inhibitors of histone deacetylation
(HDAC). This restores expression of the down-regulated messenger ribonucleic
acids. Such observations suggest that drugs should be used to ameliorate these
epigenetic changes in children that lead to depression and suicide.
DNA methylation changes are observed in the prefrontal cortex in genes for the
transmitters glutamate and gamma-amino-butyric-acid as well as for brain-derived
neurotrophic factor, leading to down-regulation of their messenger ribonucleic
acids. The potential to reverse these changes, often brought about through early
childhood abuse, is evident using DNA methyltransferase inhibitors.
Identification of Epigenetic Drugs for Mood Disorders:

The HDAC Inhibitors
Inhibition of HDACs is currently being used in cancer therapy to support affected

tumor suppressors by tipping the acetylation/deacetylation activity toward acetyla-
tion using the epigenetic drug Vorinostat, which is currently in clinical trials. HDAC
inhibitors are also known to reverse the histone acetylation found in rodents subjected
to early life stress that leads to hypothalamic-pituitary-adrenal responses associated
with depression. The early success of inhibitors of HDAC in cancer therapy holds
out hope that mood disorders associated with stress experienced in early life can
also be treated with epigenetic drugs (such success is described in Schroeder et al.
2010; Grayson et al. 2010; Machado-Vieira et al. 2011).
Valproic acid (2-propyl pentanoic acid; Divalproex) is an epigenetic drug that
acts as a class I and IIa HDAC inhibitor, as do other derivatives of aliphatic acid
such as sodium butyrate and sodium phenylbutyrate, although with different poten-
cies. These are all mood stabilizers for treatment of acute mania and bipolar (manic/
depressive) disorders but are not effective in schizophrenia. Other very effective
inhibitors of class I and II HDACs exist, such as suberoylanilide hydroxamic acid
(Vorinostat and Scriptaid), which are yet to be tested thoroughly for antidepressant
effectiveness (some of these are considered in Grayson et al. 2010; Machado-Vieira
et al. 2011).
The HDAC inhibitor MS-275 is an epigenetic drug that increases histone
acetylation about 100 times more effectively than Valproic acid, and possesses high
selectivity for HDAC1. There is no doubt that the epigenetic drug MS-275 is far
more powerful than Valproate as a brain region selective HDAC inhibitor (Simonini
et al. 2006). This drug has similar effects to the anti-depressant Prozac (fluoxetine).
There are high hopes that MS-275 will be effective in both cancer treatment and in
major mood disorders.
The tricyclic antidepressant imipramine is an inhibitor of HDACs, particularly of
HDAC5, and leads to the recovery of brain-derived neurotrophic factor messenger
ribonucleic acid transcripts III and IV in the hippocampus (a comprehensive review
of epigenetic drugs, of which imipramine is one, can be found in Hamm and Costa
What Remains to Be Done 151
2011). In animal experiments this leads to alleviation of depression behaviour

following stress arising from long-term social defeat, suggesting its use to support
those with major mood disorders following childhood abuse.
The HDAC inhibitor M344 is a benzamide with as yet unknown therapeutic
actions.
Epigenetic Drugs and Suicide Prevention
Major epigenetic changes to the functioning of synapses have been identified in the
brains of suicide victims. These include hypermethylation in the promoter of the glu-
cocorticoid receptor, of the gamma-amino-butyric-acid receptor, and of the
brain-derived neurotrophic receptor.
The epigenome or pattern of methylation at single neucleotide resolution throughout
the genome can now be determined. Methylation of regions of DNA at which a
cytosine nucleotide occurs next to a guanine nucleotide, CpG sites, has been deter-
mined for dentate granule neurons in the hippocampus. Three thousand of the
approximately one quarter of a million CpGs in the genome of these neurons show
changes in the extent of their methylation following impulse activity (Keller et al.
2010). Of particular interest is that many of these are associated with genes involved
in synaptic plasticity. Such epigenetic control of activity-dependent plasticity is not
confined to the hippocampus as the transcription of arginine vasopressin in the
hypothalamus is under the control of methyl CpGs that in turn are regulated by
membrane depolarization of hypothalamic neurons that produce a site-specific
phosphorylation via calcium calmodulin kinase II of methyl CpGs.
Early-life stress (in mice) leads to life-long hypersecretion of corticosterone
consequent on an increase in arginine vasopressin release from neurons of the hypo-
thalamic paraventricular nucleus. This leads to failure of memory and the capacity
to cope normally with stress. It is likely that the increased hypothalamic neuronal
activity accompanying early life stress utilizes activity-dependent epigenetic mech-
anisms to set this sustained increase in arginine vasopressin secretion (Murgatroyd
et al. 2009). It appears that early-life stress leads to hypomethylation by reducing
methylated CpG binding by phosphorylating it and so leading to arginine vasopressin
overexpression and severe long-lasting behavioural changes such as maintained
major depressive disorder leading to suicide.
What Remains to Be Done
Although it is known that epigenetic effects are orchestrated using methylated CpG
as a platform to produce gene silencing through the interaction of DNA methylation
and of histone deacetylation, details of how this occurs are missing (Murgatroyd
et al. 2009).
Currently available inhibitors block all the classic HDACs, so that they antagonize
a wide range of mechanisms at the cellular level, such as different intracellular
signaling pathways, cell cycle regulation and cyto-toxicity (Machado-Vieira et al.
2011). These in turn impact on the expression of multiple genes amounting to as
much as 2–2.5% of the genome (Schroeder et al. 2010). The result is that inhibitors
of HDAC such as Valproic acid can produce severe side effects such as teratogenicity,
tumor growth and invasion, greatly limiting the range of their applications. A major
effort is now underway to increase specificity of HDAC inhibitors. This involves
determining the changes in messenger ribonucleic acids in different regions of the
brain and peripheral organs following introduction of a variety of HDAC inhibitors
in order to determine their potency, specificity and so ensure that all side-effects are
benign.
Some epigenetic drugs cross the blood–brain barrier such as Valproic acid,
Vorinostat, MS-275, sodium butyrate and phenyl butyrate although many do not.
A formidable challenge in the design of epigenetic drugs is to ensure that they do
cross the barrier. The attempt to obtain inhibitors of HDAC with minimum side-effects
rests in part on a knowledge of the distribution of HDAC enzymes in different brain
regions and peripheral organs. This needs to be determined for each individual
before treatment.
Biological markers of major mood disorders, using for example the changes in
gray matter in different brain regions as determined with magnetic resonance imaging,
need to be refined. They can then be used to track prodromal changes for the purposes
of intervention with epigenetic drugs as well as to test the efficacy of different
concentrations of these drugs.
Notes
(p. 145) … suicide in the United States and Australia are about the same…
In the period around 2007 these were 11 per 100,000 per year in the United
States, 10.3 per 100,000 per year in Australia and a lower figure of 7.0 per 100,000
per year in the United Kingdom (OECD 2009; La Vecchia et al. 1994; Thomas et al.
2011). The changes in suicide rates between 1960 and 1989 vary by age group
and sex across ‘New World’ countries such as the United States, Australia and
Canada as well as ‘Old World’ countries such as England, Wales and Scotland.
However as Fig. 1 shows in Cantor et al. 1996; see also Milner et al. 2011),
the Old World countries have very substantially lower suicide rates than the
New World countries.
(p. 145) …a decline and subsequent stabilization in the rate of suicide
between 1990 and 2006.
Figure 1a in the following reference shows how the suicide rate declined in the
United States over the period from1992 to 2000 and then rose very slightly. In the
prior period from 1964 to 1992 the suicide rate did not change markedly. However
during both periods the rates were very different over time for different age groups
Notes 153
and sex. It is very interesting to compare these figures for different age groups and
sex in Australia over the period 1974–1990 with those in the United States, as they
tend to show similar fluctuations in particular age groups in the two countries (Luo
et al. 2011; Cantor et al. 1996).
(p. 145) …suicide rates declined because of suicide prevention policies that
they put in place.
Table 1 in the following reference gives a comprehensive overview of the diver-
sity of suicide prevention strategies in different countries (Mann et al. 2005). In
addition the following paper lays out the diversity of mental health care initiatives
in different countries (Spaeth-Rublee et al. 2010).
(p. 145) … correlation between rates of suicide and the economic cycle…
The overall suicide rate generally rose during recessions and fell during expan-
sions. Specifically the suicide rates of the groups aged 25–34 years, 35–44 years,
45–54 years, and 55–64 years rose during contractions and fell during expansions
(Luo et al. 2011).
(p. 146) …sexually or physically abused … 65% of all those that attempt
suicide…
This American study is the best carried out on the extent to which those that
attempt to commit suicide have experienced sexual abuse. It would be of great interest
to know if these statistics can be extrapolated to countries with a not too dissimilar
culture, such as Australia. The details of the methodology used and the results
obtained in the American study are to be found in Bensley et al. (1999). An interesting
review of the entire literature on this subject, which covers other nations than just
America, is by Evans et al. (2005).
(p. 146) Early life abuse significantly increases … risk of life-time major
depressive disorder.
A 20 year study of 600 American children that had been sexually or physically
abused showed that they had a markedly increased risk of suffering major depres-
sion over their lifetimes. A separate study of 1,000 New Zealand children, from
birth to 18 years, established significantly higher rates of major depression, anxiety
disorders, conduct disorders, substance use disorders and suicidal behaviour. Those
in the highest risk category had been abused with intercourse as children (Widom
et al. 2007; Fergusson et al. 1996).
(p. 146) …suicidal behaviour … underlying genetic predisposition…
distinct from a genetic predisposition to mental illness… perhaps dependent
on it.
By studying monozygotic and dizygotic twins the extent of genetic inheritance
of a predisposition to suicide was established 20 years ago (Roy et al. 1991, 1995).
More recent research has shown that youth suicide attempts are familial and
have managed to establish this is the case even though problems such as alcohol
dependence, social phobias and conduct disorders had to be controlled for when
interpreting the results (Glowinski et al. 2001). The complex interplay between
psychiatric history and genetic vulnerability specific to suicidal behaviour is given
by Statham et al. (1998). Also consult the monograph by Schulsinger et al. (1979).
A very interesting study has been made of the frequency of psychiatric disorders
and suicide behaviour in the biological and adoptive relatives of adoptees with these
disorders. It was found that both showed family-associated transmission of the
genesis of the disorders (Wender et al. 1986).
(p. 146 and 147) …that commit suicide … consists of patients with borderline
personality disorder and impulsive-aggressive behaviour.
This is a well-researched subject establishing that clear associations exist between
a subjects tendency to participate in impulsive violence and their committing sui-
cide (Brent et al. 1994). The natural history of over 1,500 Canadian students has
been followed over a period of 15 years, from age 6 until 21. Surprisingly 33% of
these experienced a high level of suicidal thoughts and 9% actually made at least
one serious attempt at committing suicide. The capacity for disruptive disorders
amongst the 33% was quite marked. This work emphasizes the need for collecting
statistics on individuals through their early lives, rather than just collecting data on
collections of students at different ages (Brezo et al. 2007). Of 104 Canadian males
that committed suicide, and who died during an episode of major depression, both
impulsive and aggressive behaviours were shown to be major risk factors (Dumais
et al. 2005). Those that commit suicide and suffer from borderline personality dis-
order differ from those that suffer from this disorder in acute psychiatric settings in
as much the former show a comorbid interaction between impulsive behaviour on
the one hand and violent-aggressive tendencies on the other (McGirr et al. 2007).
(p. 147) The prevalence rates of child sexual abuse… (numbered references
in the Table are given here).
1. A study of 1,393 members of the Inuit population of Greenland in 1993–1994
provides prevalence figures for violence against children and shows a strong
correlation between such violence and mental health problems in later life
(Curtis et al. 2002).
2. Over a period of 6 years, 362 women were followed for incidences of abuse during
that period as well as prior to the 6 years. All-together 9% had experienced phys-
ical abuse and a very large number (36%) sexual abuse as children and 6% had
experienced physical abuse by their partners in the last year (Mazza et al. 2001).
3. Family dysfunction, with deviant behaviour, secrecy and isolation have been
shown in a European survey to be correlated with high levels of sexual abuse of
about 10% before the age of 18, with the level for women about twice that for
girls (Svedin et al. 2002).
4. The incidence of traumatic events over a period of about 6 years affecting North
American children in the age group from 9 to 13 and the extent to which such
events lead to the development of posttraumatic stress disorder have been deter-
mined. The results showed a surprisingly high frequency of traumatic life events
of about 60% with 13% of these children going on to develop posttraumatic
stress symptoms. Sexual and violent traumas gave rise to the highest levels of
stress symptoms (Russell 1983).
5. Epidemiological research in North America shows a high correlation between
childhood traumatic experiences and subsequent mental health deterioration
(Copeland et al. 2007).
Notes 155
Fig. 8.1 Suicidal behaviour in relation to impulsivity and mood disorders, effected by childhood
abuse, genetics and head injury. Suicide behaviour is increased if impulsivity occurs in combination
with post-traumatic stress disorder (PTSD) or with a mood disorder. CRF corticotrophin releasing
factor, CRFR CRF receptor, HPA hypothalamic pituitary adrenal, MDE major depressive episode,
PFC prefrontal cortex (Reprinted by permission from Macmillan Publishers Ltd: Nature Reviews in Neuroscience. Mann (2003)
Copyright (2003))
Fig. 8.2 Early-onset suicidal behaviour. Familial pathways are shown from this behaviour. From
Brent and Mann (2006). (Copyright (2006), Massachusetts Medical Society (Reprinted with permission from Massachusetts
Medical Society))
6. Epidemiological research shows that the incidence of traumatic events in childhood

is higher than previously thought and that multiple incidences of stress events
have cumulative effects on the rates of mental and physical health deterioration
(Fairbank and Fairbank 2009).
(p. 147) …suicide behaviour … partly explained by familial transmission of
impulsive-aggressive behaviour.
Early American studies of the extent of suicide in families with a history of
suicide attempts suggested that suicidal behaviour is a genetic trait that is transmitted
together with aggressive behaviour (Brent et al. 1996). This early work has been
confirmed in three separate Canadian studies. One involving 500 psychiatric patients
found that those with a personal history of suicidality had a three times more frequent
history of suicidal behavior in the family, and their behaviour was associated with
higher impulsivity and aggressive tendencies than the non-suicidal patients
(Diaconu and Turecki 2009). This research is supported in the following Canadian
report in Kim et al. (2005). The interaction between the genetics of impulsivity and
childhood abuse, leading to epigenetic changes, is described in Fig. 8.1 (see also
Mann 2003).
Interestingly, the extent of impulsivity amongst female suicide victims is less
than amongst male victims, although still a risk factor, as reported in McGirr et al.
(2006). The interaction between parental mood disorders and impulsivity and their
abusive behaviour on the one hand and the effects of such disorders inherited from
the parents together with abuse of the children is described in the following figure
from Brent and Mann (2006). These interactions are spelt out in some detail in
Fig. 8.2 (see also Braquehais et al. 2010; Currier and Mann 2008).
(p. 147) …borderline personality disorder … sexually abused as children.
Men who have been subjected to childhood sexual abuse and have recently
attempted suicide not only have a higher level of suicidal thoughts but also of feelings
of hopelessness. They are much more likely to have made several suicide attempts
compared with those men who attempt to commit suicide but have not been
subjected to childhood sexual abuse (Spokas et al. 2009).
(p. 147) The annual rates of severe sexual abuse…
It was only in the 1980s that the extent of abuse within the family in America
was properly documented and found to be much higher than anticipated (Straus
et al. 1980).
(p. 147) Of traumatic events unique to the individual child…
Physical assault, sexual assault, or witnessed violence by adolescents are high
risk factors for posttraumatic stress disorder with high levels of comorbidity involving
major depression and substance abuse (Kilpatrick et al. 2003).
(p. 148) Cognitive behavioural therapy (CBT)…
The use of such therapy for children (ages 9–13) suffering from anxiety disorders
is of considerable value in bringing the children back to normal limits of anxiety
(Kendall 1994). Children with severe antisocial difficulties that are provided with a
range of cognitive behavioural therapies, including problem-solving skills training
and client-centered relationship therapy, show significant reductions in antisocial
behaviour. This is particularly the case for children receiving problem-solving skills
Notes 157
training therapy with improvement in behaviour lasted for at least 1 year. However,
even given this improvement, such children still remain outside the normal range
of social behavior (Kazdin et al. 1989). Sexually abused children suffering from
posttraumatic stress disorder have been provided with three different cognitive
behavioural therapy conditions and followed for up to 2 years. All three kinds of
therapy, involving either treating the child alone, the non-offending mother alone, or
both together, provide significant improvement in both scores for depression and
for posttraumatic stress in the children (Deblinger et al. 1999).
(p. 148) TF-CBT is superior to CCT…
Sexually abused children from 8 to 14 have been provided with either trauma-
focused therapy, child-centred therapy or cognitive-behavioural therapy and the
efficacy of these different treatments ascertained 12 months later. Child-centred ther-
apy is at least as effective in ameliorating feelings of shame and posttraumatic stress
compared with the other two therapies (Deblinger et al. 2006). Trauma based cogni-
tive behavioural therapy is definitely favored over other therapies for the treatment
of traumatized children, aged 8–14, as it significantly alleviates depression, shame and
posttraumatic stress symptoms (Cohen et al. 2004). A note of caution should be made
concerning the efficacy of cognitive behavioural therapy for the treatment of sexually
abused children suffering from anxiety, fear and posttraumatic stress symptoms. It
has been argued that whilst such therapy is efficacious it is not clear to what extent
it provides very significant improvement (Macdonald et al. 2006).
(p. 149) Pharmacotherapy, using serotonin reuptake inhibitors…
The use of pharmacological interventions in place of or in addition to behav-
ioural therapies for posttraumatic stress disorders suffered by abused children have
been assessed, especially the use of serotonin reuptake antagonists like Prozac
(Davidson 2000; Hetrick et al. 2010).
(p. 149) … no empirical study of early intervention with children…
Although there is evidence for the efficacy of trauma-focused cognitive behav-
ioural therapy for the alleviation of depression and posttraumatic stress symptoms
in sexually abused children, there are a number of promising pharmacological inter-
ventions that are available, although not yet subjected to appropriate randomized,
placebo-controlled trials (Cohen 2005).
(p. 147) Magnetic resonance imaging (MRI) scans taken of children …
The increases in gray matter of the cortex indicated here in the ventral prefrontal
area are accompanied by abnormal frontal lobe morphology changes (Carrion et al.
2009; De Bellis et al. 2002). There are significant increases in the gray matter of the
hippocampus of children with posttraumatic stress disorder (Tupler and De Bellis
2006).
(p. 148) … MRI scans are taken at the end of adolescence…
Although the hippocampus gray matter, and therefore volume, is increased in
children after sexual abuse this is not the case if they are followed up into adulthood
(ages 18–22 years), as the volume of the hippocampus is then reduced. What these
changes mean in terms of the changes in the synapses and dendrites that compose a
major part by volume of the gray matter is not know (Andersen et al. 2008).
Childhood sexual abuse not only changes gray matter volume of prefrontal cortex
but also leads in females when they reach maturity to a very significant (13–18%)
loss of gray matter in the visual cortex (Tomoda et al. 2009).
(p. 149) There is then enormous potential for the use of epigenetic drugs…
Epigenetic changes alter the expression of genes as a consequence of abuse
during early childhood. Particular emphasis is often placed on the glucocorticoid
receptors (GRII) in this regard because of the changes these can bring about in
synaptic action in those parts of the brain involved in major depressive disorders
that lead to suicide. The principal epigenetic mechanisms that come into play
following childhood sexual or physical abuse involve DNA methylation, and histone
deacetylases (HDACs). These processes modulate a number of genes, including that
for GRII, so altering a large range of intracellular pathways impacting on synaptic
transmission, the cell cycle and the apoptotic death of cells. The identification of
compounds that can reverse DNA methylation or histone deacetylation, compounds
called here ‘epigenetic drugs’, are then of great interest in trying to rectify the
biological concomitants of early childhood abuse (Grayson et al. 2010). In regard to
the usefulness of inhibitors of DNA methylation and of HDACs in the context of
epigenetic determinants of major depression it is encouraging that they have already
been shown in preclinical models to alter cognition and behaviour. Indeed Valporate,
a prescribed drug for major depression and bipolar disorder, is an HDAC inhibitor
(Machado-Vieira et al. 2011). The prospect of HDAC inhibitors being used in the
pharmacotherapy of depression and other psychiatric disorders are considered in the
following review (Abel and Zukin 2008).
(p. 150) Such observations suggest that drugs should be used…
The fact that animal experiments show HDAC inhibitors can reverse some epige-
netic changes brought on by early life stress emphasizes the opportunity for using
epigenetic drugs to ameliorate the effects of such stress on late-life major depression
(Schroeder et al. 2010).
(p. 150) The potential to reverse these changes…
Such changes have now been spelt out as a consequence of the great advances in
genome-wide epigenomics using microarray techniques. These have been used to
determine the pattern of DNA-methylation changes in the prefrontal cortex of
patients with schizophrenia. Of particular interest is that these tend to be concen-
trated in genetic regions associated with brain development and synaptic transmission
involving the transmitter substances glutamate and gamma aminobutyric acid.
The identification of these genome-wide epigenetic changes provides a firm basis
for designing and using epigenetic drugs that target those regions of DNA-
methylation changes associated with major mood disorders leading to suicide
(Mill et al. 2008).
(p. 150) … derivatives of aliphatic acid such as sodium butyrate and sodium
phenylbutyrate.
Although derivatives of aliphatic acid are effective HDAC inhibitors they lack
specificity for particular HDAC isoforms and so can potentially produce serious
side effects (Machado-Vieira et al. 2011). When the HDAC inhibitor sodium
butyrate is given to mice it produces anti-depressant effects and this is enhanced
Notes 159
with addition of the serotonin reuptake inhibitor (Prozac) fluoxetine (Schroeder

et al. 2007).
(p. 150) … mood stabilizers for treatment of acute mania…
The HDAC inhibitor Valproate is as effective as lithium in the treatment of bipolar
disorder and the combination of Valproate with an antipsychotic drug such as
olanzapine is more effective still. The side effects of Valproate include tremor, seda-
tion, weight gain and gastrointestinal symptoms, none of which are life-threatening.
However Valproate can, on rare occasions, lead to serious hepatic toxicity and is
tetratogenic, leading to neural tube defects (Haddad et al. 2009). The key issue then
relates to the specificity of epigenetic drugs and their potency, given they cross
the blood–brain barrier and so can enter the brain from the circulation (Grayson
et al. 2010).
(p. 150) … MS-275 will be effective in both cancer treatment…
We now know that epigenetic changes are involved in tumorigenesis so a con-
centrated search has occurred for HDAC inhibitors that might be used in cancer
therapy, amongst which MS-275 is prominent (Hess-Stumpp et al. 2007; Kazantsev
and Thompson 2008).
(p. 151) … alleviation of depression behaviour following stress.
Stress increases histone methylation in the genes for brain derived neurotrophic
factor leading to down-regulation of its transcripts and depression behaviour. This
is reversed by the tricyclic anti-depressant imipramine (Tsankova et al. 2006).
(p. 151) M344 is a benzamide with novel HDACi effects…
Although therapeutic actions of M344 are not yet fully established it is of great
interest that this epigenetic drug promises to offer a causal therapy for spinal
muscular atrophy as it corrects the splicing errors of the gene for survival motor
neuron 2 (SMN2) which are restored by inhibition of HDAC (Riessland et al. 2006).
The progression of spinal muscular atrophy is affected by SMN2, which is under the
control of DNA methylation. Inhibition of HDACs with Vorinostat or Romidepsin
promises to be effective in alleviating the seriousness of this atrophy (Hauke
et al. 2009).
(p. 151) Major epigenetic changes to the functioning of synapses…
This discovery is of the first importance and establishes that epigenetic mecha-
nisms play a major role in the biology of suicide victims. The methylation pattern
of ribosomal ribonucleic acid (rRNA) genes is changed throughout the cortex of
such victims who have been subjected to childhood neglect/abuse (McGowan et al.
2008). Suicide victims with a history of major depression show changes in the DNA
methylation pattern for important molecules at synapses in the brain, such as the
receptor molecules for the inhibitory synaptic transmitter gamma-aminobutyric acid
(GABA) (Poulter et al. 2008). This paper provides a recent review of the range of
genes showing altered expression in the brains of suicide victims (Fiori and Turecki
2010). Brain derived neurotrophic factor is decreased in the brain of suicide victims.
DNA methylation is increased for the brain derived neurotrophic factor gene in
the brains of such victims and it is this that leads to down-regulation of the factor
(Keller et al. 2010).
(p. 151) … produce a site-specific phosphorylation via calcium calmodulin

kinaseII of methyl CpGs.
In animal studies, early-life stressful events modulate the extent of DNA methy-
lation that lead to an increase in the hypothalamic transmitter arginine vasopressin,
associated with depression, through an impulse dependent mechanism (Murgatroyd
et al. 2009).
(p. 152) Currently available inhibitors block all the classic HDAC
isoforms…
Although a range of inhibitory agents for HDACs is now available they lack
specificity and so can lead to unwanted side effects, including tumourigenesis
(Machado-Vieira et al. 2011).
(p. 152) … increase specificity of HDAC inhibitors…
The possibility of obtaining inhibitors of HDACs that are potent, specific for
major depressive conditions initiated by childhood abuse and do not produce
dangerous side effects have been greatly enhanced with the discovery of their use in
the inhibition of tumor cells (Johnstone 2002). The specificity and relative toxicity
of a number of HDAC inhibitors have now been determined enhancing identification
of isoform specific inhibitors for clinical use (Balasubramanian et al. 2009).
(p. 152) … the design of epigenetic drugs…
Beside designing and identifying HDAC inhibitors that are potent and specific
there is the added major problem of ensuring that they can penetrate the blood–brain
barrier due to the endothelial cells of the cortical blood vessels (Kazantsev and
Thompson 2008).
(p. 152) … distribution of HDAC enzymes in different brain regions…
There is a growing knowledge of the tissue distribution of HDAC2 in both
peripheral organs as well as in different cortical areas. This is necessary if the
specificity of HDAC inhibitors is to be improved (de Ruijter et al. 2003).
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Chapter 9
Brain Networks in Psychosis
Identifying Synaptic Changes in Networks
Responsible for Hallucinations
Introduction
Virginia Woolf wrote in her suicide note that: ‘I feel certain that I am going mad
again: I feel we can’t go through another of those terrible times. And I shan’t
recover this time. I begin to hear voices, and can’t concentrate. So I am doing
what seems the best thing to do’ (Virginia Woolf to Leonard Woolf, 18 March
1941, quoted in Bell 1972). Her depression was accompanied by such psychotic
features as auditory hallucinations at many different periods of her life. As far
back as 1921 she was writing in her memoir Old Bloomsbury that: ‘I had lain in
bed at the Dickinsons’ house at Welwyn thinking that the birds were singing choruses
and that King Edward was using the foulest possible language among the Ozzie
Dickinson’s azaleas’ (Woolf 1921). Her husband Leonard Woolf writes that: ‘She
spoke somewhere about ‘the voices that fly ahead’, and she followed them …
when she was at her worst and her mind was completely breaking down again the
voices flew ahead of her thoughts: and she actually heard voices which were not
her voice; for instance, she thought she heard the sparrows outside the window
talking in Greek. When that happened to her, in one of her attacks, she became
incoherent because what she was hearing and the thoughts flying ahead of her
became completely disconnected’ (Woolf 1995; Bell 1972). There is also evidence
that on rare occasions she suffered from visual hallucinations. For instance, she
says on becoming less obsessed with her deceased mother, that ‘I no longer hear
her voice; I do not see her’ (Woolf 1939). This chapter presents what we now
know of the failure of brain function leading to the distortions of consciousness as
occurs in auditory and visual hallucinations.
The final, definitive version of this paper has been published in Australian New Zealand Journal of Psychiatry 42:915–931 Nov 2008 by
SAGE Publications, All rights reserved. Copyright (2008). Online version available from http://anp.sagepub.com/content/42/11/915

166 9 Brain Networks in Psychosis
Consciousness
There are two forms of consciousness, transitive and intransitive (Bennett and
Hacker 2003). Transitive consciousness is a matter of being conscious of something
or other, or of being conscious that something or other is thus or otherwise.
Intransitive consciousness, by contrast, has no object. It is a matter of being con-
scious or awake, as opposed to being unconscious or asleep. To say, on awakening
after an operation, ‘I am conscious’ does not impress as an occasion during which
something mysterious has occurred. There is nothing intrinsically private to one
when turning to the nurse and saying ‘I am now conscious, can I have a cup of tea?
If a veterinarian anaesthetizes a cat, we say it is now unconscious, and after the
operation, that it has gained consciousness. Only a sentient animal can be ‘unconscious’.
This particular form of consciousness we may refer to as intransitive, that is, it is
something that a person or animal may lose (as when being anaesthetized) and then
subsequently recover (as when regaining consciousness as the anesthetic wears off).
To be unconscious is to be incapable of perceiving the environment and to be insen-
sible to stimuli. Being unconscious and being asleep are clearly different because in
the latter we can easily be awakened. During the waking hours we experience, are
conscious of, different things at different times, for a period. Such consciousness,
when our attention is caught by something and held, so we become aware of it, is
clearly different from intransitive consciousness, for it has an object and so is called
‘transitive consciousness’. There are many forms of transitive consciousness, such
as perceptual consciousness, where one becomes conscious of what one perceives,
as becoming conscious of the ticking clock, which is not the same as perceiving the
ticking clock; somatic consciousness, to become conscious of a sensation such as
the pain of a toothache capturing our attention; kinaesthetic consciousness of one’s
cramped limb; affective consciousness, as becoming conscious of one’s current
emotions, for example anger or annoyance; reflective consciousness, to become
conscious of something that is not present, such as an honour due to one; conscious
of one’s actions, as in cracking a joke; conscious of one’s motives, to become
conscious of feeling jealous of Daniel for the honours he has received; self-
consciousness, as in becoming aware of being the centre of attraction and on
introspective reflection on one’s motives, successes and failures. Clearly all these
forms of transitive consciousness are dependent on intransitive consciousness.
The concept of transitive consciousness is clearly allied to that of becoming
aware, of noticing, that is, of having one’s attention caught. Paying attention often
involves taking an interest in something, thinking about it. Lack of attention is
linked to unawareness, failure to notice, absent mindedness. That which makes what
we do a case of attending in one or other of the forms already enumerated is that
when we do it, something is made the centre, object or topic of whatever it is we are
doing. Cognitive neuroscientists attribute consciousness to humans and other animals
on the grounds of their behaviour in the context of their lives. They investigate the
neural networks in the brain that make it possible for an animal to have and exhibit
forms of feeling, perceiving and purposiveness. Neuroscientists would regard it as
Perceptual Consciousness 167
unintelligible to claim that an animal that manifests powers of perception, memory

and emotions is unconscious. By establishing inductive correlations between such
facts of consciousness as seeing features of different kinds in the visual field and the
firing of certain neurons, neuroscientist infer that when these neurons are observed
to fire, the animal, possessing normal visual capacities, sees. The question does not
arise as to whether the animal is conscious because it is clear that it enjoys perceptual
and affective experiences. The challenge to cognitive neuroscience is to first establish
the neural correlates of various forms of perception, sensation, affective feeling and
mood. Then unravel the neural activity accompanying, attending to, and becoming
aware of something within these psychological categories. Here the focus is then to
determine the neural activity associated with attention and awareness. In cognitive
neuroscience the experimental paradigm defines what the experimenter means when
he uses the terms ‘attention’ and ‘awareness’. It is then important to consider the
relationship between such words and phrases used in the laboratory and those in
general parlance in order to ensure that incoherences do not arise when in general
discussion it is claimed that the neuroscientists have discovered the neural concomi-
tants of ‘attention’ and ‘awareness’.
Perceptual Consciousness
Of the different forms of transient consciousness, cognitive neuroscientists have

mostly sought the neural concomitants of perceptual consciousness. Perception per
se is not a form of consciousness, but becoming aware and retaining an awareness
is. Whatever one is perceptually conscious of, one is also aware of. It should be
noted in passing, however, that one may be aware of things of which one is not
conscious, for example the things that one has been informed of, but in this case we are
not talking of perceptual awareness or consciousness that is the subject of the present
considerations. The phrase ‘to become conscious of’ belongs to a small family of
cognitive verbs, that includes ‘to become aware of’, ‘to realize’, and ‘to notice’.
Awareness and Perception
To be successful in a perceptual activity such as looking, scenting, tasting, listening

or sniffing amounts to seeing, smelling, tasting, hearing or smelling; that is, recog-
nizing, detecting, discerning or distinguishing percepts. To become and to be con-
scious of such things as colours, smells, and sounds, is not an alternative to perceiving
them. Furthermore, what one is perceptually conscious of is not something over and
above some of the things one perceives. It is only those things that we perceive and
realize we perceive that are things of which we are conscious. It is obvious that
whatever one is perceptually conscious of, it is something perceived, although not
everything one perceives is something of which one is conscious. For example while
reading the above sentence I am not conscious of reading, which is undoubtedly

a process that involves perception of the written word. That is, much of what is
perceived is not even noticed, let alone attended to, so we are not conscious of it.
The act of perception is accompanied by activity in specific sensory areas of the
cortex, each associated with a specific sensory modality. The establishment of this
fact was a major triumph of twentieth century neuroscience (Kandel et al. 1991).
Such cortical activity is a necessary condition for us to be able to act, while being
unaware or conscious of the action, most of the time, as when driving a car. Certain
specific sensory areas must of course be active if we are to be aware or conscious of
driving the car, as would occur if a car in front of us suddenly stopped and we had
to avoid a collision. Cognitive neuroscientists have shown that conditions of visual
awareness are accompanied by enhanced activity in fronto-parietal areas of the cortex,
distinct from those involving attention. The question arises here as to whether,
besides the parts of the nervous system supporting the perceptual faculties engaged
in whatever one is perceptually conscious of, there could be said to be a single part
of the cortex that supports our capacity to be aware or conscious of that which is
perceived. This is probably not the case. When seeing Daisy in the corner of the
room, without becoming aware of her, and therefore walking towards her, activation
of visual cortical areas 17, 18 and extending down into the temporal cortex are
active but not the fronto-parietal area of the cortex. If, in contrast, on entering the
room we see Daisy and walk towards her, that is, we are aware and conscious of her,
the fronto-parietal area of the cortex is active. Binocular rivalry experiments are
ones in which we do not concentrate our attention on an object, and so become
conscious of it, but rather the object imposes itself upon our attention. Seeing Daisy
on entering the room is not necessarily to become aware of Daisy, but it is a condition
of being aware of her. Seeing the change in perceptibilia during binocular rivalry
experiments is what catches our attention and therefore awareness and so, as experi-
ments indicate, is accompanied by activity in the fronto-parietal area of the cortex.
Attention and Perception
We cannot remain conscious of something that no longer holds our attention or

occupies our thoughts. So we are perceptually conscious of that which catches and
holds our attention. The emphasis here is on that which ‘captures and holds our
attention’ because if we are looking at a painting or talking to somebody we are not
conscious of the painting or of the person unless our attention is focused or riveted
on the painting or the person. So what we become and are conscious of is not that
which we intentionally attend to but rather that which catches and holds our attention.
While looking at the texture of the paint on the surface of a wall in search of signs
of decay one may become conscious of the poor rendering of a small section of
mortar but not of the surface of the wall being scanned. In other words we do not
become conscious of the particular attribute of an object to which we are intentionally
Visual Illusions 169
attentive but we do become conscious of those features of the object that have
brought about a shift in our attention and which then holds our attention. It is that
which intrudes and impresses itself on us, and with which we are not purposefully
occupied at all, such as a distracting feature that catches and holds our attention, like
the creaking of a door or the smell of a coffee aroma. It is this that we become
conscious of. The phrase ‘conscious of [the name or description of a material object
or person]’ specifies what object or person has caught and held our attention. When
cognitive neuroscientists attempt to measure the neuronal concomitants of ‘attention’,
involving visual or auditory perception, they use experimental designs that aim to
distinguish between attending to the object or person and being aware of the object
or person that is being conscious of them. In this case, when a subject is asked to
attend to the left-hand lower quadrant of a blank screen occupying the visual field,
an intentional act to so attend is carried out that requires us to rivet our attention on
that particular quadrant. When this is performed, as we will see in the following
section, fronto-parietal areas of the cortex are excited, and these areas overlap for
attending either in the visual or auditory modalities.
Visual and Auditory Illusions
The question asked here is whether areas of cortex that subsume specialized sensory
modalities must be active in order to experience, be aware of, an illusion in that
modality. The answer to this question is necessary before an enquiry is made into
the neural concomitants of hallucinations.
Visual Illusions
Visual illusions are distortions or misconceptions of a visual scene currently being

viewed. Psychologists use several different methods to achieve such illusions. Chief
among these are the awareness of illusory objects as in the Kanizsa illusion, in
which one seems to perceive a non-existent rectangle emerging from four corner
discs; the McCulloch after-effect in which one perceives, while viewing achromatic
oriented contours, illusory colours; the motion after-effect in which, after prolonged
viewing of the motion of an object in one direction, a stationary object subsequently
viewed appears to be moving in the opposite direction; and synaesthesia, such as
seeing colours when viewing achromatic letters. All of these conditions produce
awareness of an illusory visual phenomenon without any changes in the objects
being viewed. Here evidence is presented that shows that there is a very good
correlation between the type of reported awareness of an illusion and activity in
the appropriate specialized area of visual cortex that is normally activated when
actually viewing the substance of the illusion.
Kanisza Illusions
The Kanisza figure consists of four corner discs and some lines, lying on a ground
of even light intensity. One is aware, however, of an illusory bright square, which
seems to lie over the other patterned elements. At the time of becoming aware of the
illusory contours in a newly presented Kanisza figure, records of primate cortical
electrical activity show that it begins in neurons in the primary visual cortex (V1) as
well as in the surrounding (extrastriate) cortex (V2), but with different delays. In V1
superficial cortical layers the delay is 100 ms and in the deep layers the delay is
120–190 ms, whereas in V2 superficial layers the delay is much shorter than in V1,
namely 70 ms, and in deep layers, 95 ms (Lee and Nguyen 2001). As these neurons
fire when the primate signals it is aware of real contours, as well as illusory contours,
then awareness of illusory contours is accompanied by appropriate activity in those
parts of the visual cortex that are active during normal vision of the objects
projected onto the retina. The earlier firing of neurons in higher visual areas such as
V2 (i.e. further along the visual pathway from the retina), compared with lower
ones such as V1, suggests a top-down effect; that is, the illusion is accompanied by
interaction between higher and lower areas of the visual pathway.
McCullough Illusions
These arise when looking at a test stimulus consisting, for example, of a pattern of
black and white lines, some vertical and some horizontal. Before doing so the visual
system is adapted by looking for 10 s at a pattern of red vertical lines and then for
10 s at a pattern of green horizontal lines (each against a black background), with
this procedure repeated by alternating between the two for approximately 5 min.
On then looking at an achromatic test stimulus one is aware that the vertical
lines are faintly greenish and the horizontal lines faintly reddish (i.e. the white areas
surrounding the vertical lines are tinged green and the white areas surrounding the
horizontal lines are tinged red). The coloured illusions have then become ‘tied’ to
the opposite orientations of the coloured lines used in the conditioning period.
Awareness of these illusory effects correlates with increased activity in extrastriate
(outside V1) visual areas involved in colour vision, namely the lingual and fusiform
gyri (V4) in humans, as has been determined using functional magnetic resonance
imaging (fMRI) (Humphrey et al. 1999; Morita et al. 2004).
Movement Illusions
After watching movement in a single direction for a long time and then subse-
quently looking at a stationary scene it seems to move in the opposite direction.
This is often referred to as the ‘waterfall effect’ because on staring at a waterfall for
Visual Illusions 171
a prolonged period of time and then looking at a stationary image, such as the trees
at the base of the waterfall, one is aware of them moving upwards for a few seconds.
In humans the visual cortical area V5 is activated during motion in the visual field
of a subject. Using fMRI shows that such motion in one direction leads to a gradual
decrease in the activity of V5, whereas following such decreased activity, if a motion
in the opposite direction is presented a vigorous response is elicited from V5 over
and above that obtained during the initial motion (Huk et al. 2001). It is this imbalance
in the neuronal population level responses that favors the excitability of the non-
adapted neurons during the test period, which underlies the movement after-effect.
Synaesthesia
Subjects with synaesthesia have the illusory experience of a perception or a sensa-

tion in a modality different from the one being stimulated as a consequence of
attending to something. For example, grapheme-colour synaesthetes experience
particular colours associated with specific achromatically presented numbers or letter
characters. In colour-hearing synaesthesia subjects have colour experiences when
hearing spoken words. During speech the cortical colour centre in such subjects,
V4, is active according to fMRI, but it is not active when imagining colours (Nunn
et al. 2002). These fMRI studies also show that V4 is active when graphemes of
words or numbers are presented to grapheme-colour synaesthetes (Hubbard et al.
2005). Of interest in this case is that the area of cortex activated during perception
of word forms is adjacent to the colour area in V4 (so-called hV4; Wade et al. 2002).
It has been proposed that during normal development these two areas are connected
and only later removed by the process of synapse regression (Bennett 2008b). Young
infants confuse the inputs from different senses, suggesting that at an early age we
are all synaesthetic (reviewed in Maurer 1997). For example, at 12 months of age an
infant will look longer at a novel object rather than one they had explored with their
mouths earlier, whereas preterm 12-month-olds do not (Gottfried et al. 1978). It is
probable that the baby is just developing separate schemas for listening and seeing
and manipulating, suggesting that during this period each sensory modality does not
involve sensory receptors uniquely projecting to particular sensory cortices. This is
supported by observations made during early infancy that show that electrically
recorded evoked responses to spoken words can be recorded from the occipital
(visual) cortex as well as over temporal (auditory) cortex (Neville 1993). Visual
stimuli give rise to evoked responses recorded over other areas of cortex than those
devoted to vision (Hoffman and McGlashan 1997). This suggests that a newborn
does not have distinct sensory modalities; rather, these are intermingled in a synaes-
thetic confusion. If this is the case then a normal newborn perceives a jumble of
sensations in the context of a particular perception. Mature synaesthetic subjects
may fail to have such connections between primary visual cortex and auditory
cortex removed, so that they experience colours when viewing numbers or letters
(Maurer 1997; Baron-Cohen et al. 1993, for a recent review, see Hubbard and
Ramachandran 2005). There is anatomical evidence that transient synaptic connec-

tions exist in the monkey’s brain at birth (Kennedy and Dehay 1993; de Boysson-
Bardies et al. 1993), although there is as yet no evidence for such connections between
the primary visual cortex and the auditory cortex (Dehay et al. 1986). Evidence exists
for the regression of most of the synaptic projections from higher areas to V4 during
development (Kennedy et al. 1997), although it is not known to what extent failure of
synapse regression occurs in synaesthetes, with the potential to leave different regions
of the brain that subserve different modalities directly connected (for a review of
these considerations, see articles in Baron-Cohen et al. 1996). In summary, although
there is at present both behavioural and electrophysiological evidence for synaesthesia
in the newborn, there is as yet no anatomical evidence to suggest transient direct
connections between different parts of cortex subserving different sensory modalities,
which are permanent rather than transient in synaesthetes.
Binocular Rivalry
Although not an illusory phenomenon, binocular rivalry is of interest in enforcing

the argument that perceptual experiences involve activity in the appropriate part of
the brain that supports that kind of experience. If two different images are presented
stereoscopically, then the view presented to one eye will dominate that of the other
for a period of time before it alternates. In such binocular rivalry, if a stimulus con-
sisting of dissimilar images is presented separately to each eye, then one is aware of
perceptual alterations between each monocular view every few seconds (Rees
et al. 2002b). Of interest is that if the rival stimuli are those of a face and a house, the
switch in awareness of these occurs at the same time as the fMRI signal increases
in either the fusiform face area or the parahippocampal place area, whichever is
appropriate for the experienced image (Rees et al. 2002b).
Auditory Illusions
The auditory cortex is composed of Heschl’s nucleus, the planum temporale, the
lateral superior temporal gyrus, the dorsal bank of the superior temporal sulcus, the
ventral bank of the superior temporal sulcus and the lateral middle temporal gyrus
(Fig. 9.1b; Desai et al. 2005; Gueguin et al. 2007). Speech perception studies using
fMRI suggest that the part of the auditory cortex activated by unmodulated broad
spectrum noise is to be found in Heschl’s gyrus, whereas planum temporale as well
as the dorsolateral superior temporal gyrus, areas surrounding Heschl’s gyrus, are
activated by frequency-modulated tones rather than noise (Fig. 9.1b; Binder et al.
2000). The part of the auditory cortex activated by speech (i.e. containing phonetic
information), rather than by frequency-modulated tones is found in the superior
temporal gyrus that extends into the superior temporal sulcus, with only the anterior
part of this sulcus active if the phonetics are intelligible (Scott et al. 2000).
Auditory Illusions 173
Fig. 9.1 Attention and awareness of auditory percepts. In the absence of attention, (a) activity in
auditory cortex is low and (b) confined to the early auditory pathway, namely Heschl’s gyri (areas
3, 4). (c) Excitation of auditory cortex on hearing an auditory percept may be accompanied by
activity increases in the inferior parietal and the dorsolateral prefrontal cortex if the percept is
attended to, with the possibility that salience of the percept activates inferior parietal cortex
whereas the intention to attend to the percept involves activation of the dorsolateral prefrontal
cortex. Such attention leads to enhanced excitation in Heschl’s gyrus (areas 3, 4 in d) and to some
extent in the planum temporale (area 2). If attention is caught and held, as in (d), it is possible that
activity in the superior temporal and prefrontal cortex is enhanced (e). Whether there is a threshold
at which activity in these areas increases explosively, like that in the brain areas subserving aware-
ness in the visual cortex (Fig. 9.2c), is not known. (f) What is known is that the growth of activation
in superior temporal and prefrontal cortex leads to the enhancement of activity in auditory cortex,
spreading from Heschl’s gyrus (areas 3, 4), into all of planum temporale (area 2), lateral superior
temporal gyrus (area 5), as well as perhaps into the dorsal and ventral banks of the superior temporal
sulcus (areas 6, 7) and the anterior supramarginal gyrus (area 1). The increase in the extent of
recruitment of extra-Heschl’s gyrus and planum temporale as well as of activity in the prefrontal
and superior temporal cortex is associated with being conscious of the auditory percept; that is, the
subject reports being aware
Interestingly this sulcus also shows sustained activation during silent rehearsal of
speech (Hickok et al. 2003). There is then a hierarchy of auditory activity, starting
in medial and intermediate parts of Heschl’s gyrus, sometimes called the primary
auditory cortex, to regions that support advanced phoneme auditory activity in the
superior temporal gyrus, including the superior temporal sulcus (Hickok and
Poeppel 2004).
Continuity Illusion
If a sound being listened to is interrupted by silence then it is perceived as discon-

tinuous. What perhaps is not realized is that if noise replaces the silent period then
the sound being listened to is often heard as being uninterrupted, depending on the
frequency characteristics of the noise with respect to the sound. So when parts of a
speech are deleted comprehension declines, whereas if the deleted parts are filled in
with appropriate loud noise speech comprehension is restored. This phenomenon in
the auditory modality is similar to that of visual illusory contours. Studies using
fMRI have been made of activity in the cortex of subjects during trials in which they
perceive this illusory tone. The perception of the illusion correlates with changes in
neural activity in early auditory cortical regions in Heschl’s gyrus (Riecke et al.
2007). Experiments that show the importance of primary auditory cortex during
experience of auditory illusions were designed in which a target tone, varying in
frequency between 500 and 3,223 Hz, is interrupted for 600 ms by a noise burst that
contains a notch or band-stop filter, parameterized across zero, 0.25, 1.25, and 2.0
octaves. The noise and the notch are centred on the target frequency. At the highest
masking level, when there is no notch, the interrupted targets are perceived as
continuity illusions, which are accompanied by changes in Heschl’s gyrus. It is very
likely that these fMRI responses reflect changes in neuronal activity because neurons
in monkey primary auditory cortex (A1) fire impulses during continuous presentation
of the tone interrupted by intense noise, as if they were responding to presentation
of the tone without any interruptions (Petkov et al. 2007).
Auditory Illusions and Mismatch Negativity
The event-related potential that occurs when a continuous regular auditory stimulus
is interrupted by an unrelated auditory stimulus sequence is referred to as ‘mismatch
negativity’. This potential is very likely generated pre-attentively, without any
associated awareness, in auditory cortex (Kasai et al. 1999). Mismatch negativity
can reflect the neural concomitants of an auditory illusion, as is shown in the following
(Micheyl et al. 2003). Consider experimental conditions in which a tone stimulus is
interrupted both in the prior standard and later deviant intervals, and one in which
the tone is continuous in the standard interval but interrupted in the deviant interval.
Visual Hallucinations 175
Noise bursts are introduced that are filtered in some cases in the same frequency
range as the tones, and in other cases in a higher frequency region that does not
spectrally overlap with the tones. The mismatch negativity in the case of a continu-
ous tone in the standard interval, interrupted in the deviant interval by a noise burst
in a different frequency region from the tone, gives the largest mismatch negativity
(here the percept changes from a continuous tone to an interrupted tone). This mis-
match negativity is larger than that in the case of a continuous tone in the standard
interval followed by a discontinuous tone filled in by a noise burst in the deviant
interval (here the percept does not change from a continuous tone). For the
cases involving discontinuous tones in the standard intervals, when the gap is filled
by a noise burst for which the frequency is centred about that of the tone in the deviant
interval (here the percept is one that changes from that of an interrupted tone to one
in which the tone is continuous), the mismatch negativity is greater than that for
the case in which the noise burst is not centred on the tone frequency (in this case
the percept is one of a discontinuous tone followed by a discontinuous tone). These
results support the idea that mismatch negativity gives a measure of the continuity
illusion. The mismatch negativity response then gives a measure of the deviance in
the auditory modality between the memory of a standard sound and that of a subse-
quent deviant sound. The ventral superior temporal gyrus that is involved in shifts
of attention to irrelevant auditory stimuli (Sabri et al. 2006) is not activated under
these conditions but the dorsal superior temporal gyrus is.
Summary
The question posed at the beginning of this section on auditory illusions can be
answered in the affirmative, given the observations outlined in the previous sections.
The area of the cortex that subserves a specialized sensory modality must minimally
be active in order for one to experience, be aware of, an illusion in that modality.
Note that this establishes only the cortical activity that is necessary to be aware of
an illusion but does not claim that such activity is sufficient to be aware of an illusion.
The sufficient cortical activity for supporting awareness is considered in a following
section. This enquiry into some of the neuronal concomitants of illusions provides
the necessary foundation for consideration of the neuronal systems supporting
hallucinations that are now described.
Visual Hallucinations
Claude Bonnet Hallucinations
Visual hallucinations are dependent on the electrical activity of neurons that are
unrelated to the visual environment of the subject at the time of the hallucination
whereas visual illusions are so related and indeed are distortions of the visual scene.
Claude Bonnet syndrome involves visual hallucinations that cover the range from
simple flashes to the appearance of scenes, animals and people. These generally
occur in subjects that have a deteriorating visual pathway, such as occurs in macular
degeneration, optic neuritis and retinitis pigmentosa. The pathological visual expe-
riences of these subjects are associated in such a way that they can be grouped into
categories: hallucinations of disembodied heads with leering and grotesque gri-
maces; of objects that remain in the visual field when the patient turns away from
viewing them or which suddenly return to the visual field sometime after the patient
has looked away from them (so-called perseveration and delayed palinopsia;
Santhouse et al. 2000); and hallucinations of small dancing figures wearing strange
hats and of extensive landscapes. It was established in the section on visual illusions
that there are correlations between particular kinds of visual illusions and activity in
the appropriate visual centres that normally subserve non-illusory phenomena of the
same kind. It is anticipated then that visual hallucinations involve something going
awry in these centres. This is the case because the different categories of hallucina-
tions have been correlated with spontaneous activity in the particular parts of cortex
known to support capacities for identifying faces, landscapes/figures, and those uti-
lizing eye-centred reference frames. These are the superior temporal sulcus, ventral
occipito-temporal lobe and the visual parietal lobe (Santhouse et al. 2000). For
example fMRI studies of subjects experiencing hallucinations involving faces show
heightened activity in the fusiform face area (Ffytche et al. 1998).
Auditory Hallucinations
Types of Auditory Hallucinations
Auditory hallucinations, generated by spontaneous endogenous electrical activity,

cover the range from the less often experienced simple clicking and humming
sounds to the more frequently experienced hallucinations of haunting voices, of
voices telling one where to go and what to do as well as the voices of children crying
(Table 7 in Braun et al. 2003). These hallucinations generally occur in subjects with
an identifiable lesion somewhere in the auditory pathway, typically due to haemor-
rhaging or to a glioma in sites such as the superior temporal gyrus. Such auditory
post-lesion hallucinations are very similar to those first reported for patients conse-
quent on direct electrical stimulation of their exposed temporal cortex during opera-
tions, often for intractable epilepsy. It is interesting in this regard that the superior
temporal gyrus is established as involved in speech perception (for a review see
Hickok and Poeppel 2004). Auditory hallucinations also occur in approximately
10% of the normal population for whom no lesion has been identified. Half of these
have hallucinatory experiences each day, at a rate higher in adolescence than in later
life (Barrett and Etheridge 1992; Glicksohn and Barrett 2003).
Deafferentation Hypothesis for Visual and Auditory Hallucinations 177
Auditory Hallucinations in Psychosis
The most common and positive symptom in schizophrenia, involving approximately

70% of all patients, is auditory hallucinations of speech (Ditman and Kuperberg
2005). Non-invasive imaging studies show that speech hallucinations experienced
by schizophrenia subjects are accompanied by excitation in the auditory cortex
(Copolov et al. 2003). Studies with fMRI show that in schizophrenia not only is the
primary auditory cortex in Heschl’s gyrus active, as it is in auditory illusions, but
also the auditory cortical areas in the superior temporal gyrus (Lennox et al. 2000,
for a review see Allen et al. 2008). Confirmation of the importance of this gyrus in
auditory hallucinations is provided by observations using trans-cranial magnetic
stimulation in which the magnetic coils are arranged in such a way as to direct the
field into the left superior temporal gyrus. Such fields suppress auditory hallucina-
tions for periods of up to 3 months, bringing great relief to patients (Merabet
et al. 2003). It is interesting to note that the part of the secondary auditory cortex in
planum temporale, next to Heschl’s gyrus (Fig. 9.1b), is activated according
to fMRI, on the perception of real voices located in external space in normal
subjects (Hunter 2004; Hoffman et al. 2003) but not in schizophrenia subjects
(Kircher et al. 2004).
Summary
Both visual and auditory illusions involve activity triggered by percepts in centres
of visual and auditory cortex that subserve normal visual and auditory percepts. The
observations reported here support the hypothesis that hallucinatory visual and
auditory experiences arise from spontaneous endogenous activity in these centres,
unrelated to percepts. Of great interest is that identifiable lesions in specific centres
within the visual or auditory pathways give rise to hallucinations of a type found in
subjects with schizophrenia, such as of grotesque, disembodied and distorted faces,
as well as of voices telling one where to go and what to do. This suggests the
hypothesis that lesions in specific centres, be they molecular or cellular, are respon-
sible for different experiences during hallucinations in schizophrenia.
Deafferentation Hypothesis for Visual and Auditory

Hallucinations
It is most likely that auditory hallucinations involve experiences that arise as a con-
sequence of spontaneous activity in these regions of the cortex that subserve the
normal experience of percepts. Consideration is now given to the mechanisms that
might give rise to this spontaneous activity, especially in the context of deafferenta-
tion of neural networks in schizophrenia (Selemon and Goldman-Rakic 1999).
Deafferentation of Visual Centres
Burke has put forward a deafferentation hypothesis for Claude Bonnet hallucina-
tions in order to explain why certain parts of visual cortex are spontaneously active
during these hallucinations; that is, engage cortical networks in bursts of activity
without an input (Burke 2002). He points out the similarities between hallucinations
and local seizures caused by bursts of activity originating in a group of neurons that
have been isolated either by deafferentation or by trauma or tumours. It is known
that almost any region of cortex can be made hyperexcitable by partial or complete
isolation (Echlin et al. 1952). Burke’s hypothesis, which is akin to that suggested
some time ago by Konorski (1967), postulates that hallucinations can be regarded as
local paroxysms in the sensory systems arising from deafferentation. Such deaffer-
entation may occur as a consequence of age-related degeneration, direct injury to
the cerebral cortex or more peripheral visual structures or, in the case of hallucina-
tions in a disease such as schizophrenia, to failure of synapse formation during
childhood and excess regression of synapses during adolescence (Bennett 2008b).
Deafferentation of Auditory Centres
Studies with fMRI show a 20% reduction of grey matter in the planum temporale of
patients with schizophrenia (Hirayasu et al. 2000), probably due to a loss of syn-
apses as indicated by the decrease in synaptic proteins (Eastwood 2004, for review
see Bennett 2008b). This loss in planum temporale is likely to have implications for
the generation of auditory hallucinations, because it is known from fMRI studies
that the planum temporale is critically involved in the perception of real voices
located in external space. It is therefore of considerable interest that there are cor-
relations between the reduced size of planum temporale in schizophrenia subjects
and the extent of auditory mismatch negativity (Yamasue et al. 2004), as well as
between the extent of grey matter loss in Heschl’s gyri and mismatch negativity
(Salisbury et al. 2007). Deafferentation of planum temporale in schizophrenia sub-
jects, due to excess loss of synapses during adolescence, or indeed failure to form
adequate numbers of synapses during childhood, may lead to spontaneous activity
in the planum temporale, giving rise to auditory hallucinations (for a model of this
process see Hoffman and McGlashan 1997, 2006). If the loss of synapses is taken
as a measure of the onset and development of the frequency of auditory hallucina-
tions then the number of synapses may be used to give a measure of the develop-
ment of schizophrenia. As the extent of synapse loss increases, primarily during
adolescence, a subject either enters the prodromal period without a later full onset
of schizophrenia, or enters this period and proceeds into a mild onset, or passes
through the prodromal period to onset and maximal expression of the illness. These
suggestions may be compared with those in which the rate of synapse loss in schizo-
phrenia is the same as that of normals during the adolescent period, but in the case
of schizophrenia it follows a failure of initial synapse formation during early child-
hood (McGlashan and Hoffman 2000, for review see Bennett 2008b). In this case
Determination of the Brain Areas Involved in ‘Attention’ 179
mild, moderate and severe schizophrenia still arises, but at later times during devel-
opment. It is important to determine whether the fewer synapses found in the pla-
num temporale of subjects with schizophrenia occurs because of a failure of synapse
formation or excess synapse regression.
Summary
Consideration of auditory illusions as well as hallucinations in the previous sections

led to the hypothesis that hallucinations in schizophrenia arise because of a lesion
in specific cortical regions that give rise to the components of the hallucination. It is
suggested in this section that the lesion is one that constitutes deafferentation of
specific regions. Whether this takes the form of loss of the different afferent connec-
tions to the regions or to a general loss of synaptic connections within the regions,
or both, remains to be determined.
Determination of the Brain Areas Involved in ‘Attention’
Visual Attention
To be conscious, that is, to be aware, is to have one’s attention caught and held. But
one can be attentive without being aware. Indeed separate neural networks subserve
visual attention, and these networks are found in the fronto-parietal region of the
brain, centred in the lateral and medial sub-regions. This is shown by experiments
in which brain activity is recorded with fMRI from subjects performing a cued spa-
tial attention task. In this task single letter cues (L, R, P) are given at central fixation
that instruct the subject to either covertly attend to a location in the left (L) or right
(R) lower visual field or to detect a possible (P) faint dot target there or to interpret
the cue but then not attend to the target (Woldorff et al. 2004). In some trials there
is no target, so that any brain response is only due to the cue. At the end of the trial
the letters ‘REP’ are presented in the mid-line lower visual field, at which point the
subject presses a button to indicate target detection on that trial. The following
named procedures were used in these experiments: ‘interpret-cue’, the letter ‘p’ is
presented instructing the subject not to attend to a target on that trial; ‘attention-cue-
plus-target trials’, target presented at randomized times (900–1,900 ms) after the
onset of the cue; ‘attend cue only trials’ and ‘interpret cue only trials’, no target
presented so the brain response is due to the cue only; ‘no stimulation trials’, peri-
ods of fixation only. The images obtained with fMRI in these different trials after
being subtracted from each other, show that medial frontal and parietal regions are
involved in attention (Fig. 9.2b). All of the interpret cues and other interpret-cue
only trials activate the parietal and frontal areas (Fig. 9.2b). Frontal and parietal
regions that are activated by the interpret-cues are lateral, whereas more medial
regions are activated by the attend-cues relative to the interpret-cues. Thus specific
attentional orienting is accompanied by activity in medial frontal and parietal

regions (Fig. 9.2b). This functional specialization for the different aspects of cue
processing in the lateral and medial subregions of the superior frontal and parietal
cortex is shown by the fMRI signal time courses in the superior frontal and parietal
cortex during these trials. The amplitude of these changes is much larger in medial
areas for the attend-cue trials compared with the interpret cue trials. In contrast, the
responses to the interpret-cue trials were nearly as large as those for the attend-cue-
only and the attend-cue-plus-target trials in the lateral areas, whereas the interpret-
cue responses were smaller than for the attend-cue trials in the medial areas. The
conclusion of these studies attempting to identify the regions of the brain concerned
with visual spatial attention, summarized in Fig. 9.2b, is that these are to be found
as medial subregions of the medial frontal (including frontal eyefields) and parietal
cortex (Bisley and Goldberg 2003; Schall et al. 1995; Reynolds and Chelazzi 2004,
for a review see Corbetta and Shulman 2002). Within this parieto-frontal network it is
likely that visual target selection involving attention to a salient target is associated
first with firing of neurons in the lateral intraparietal area (Fig. 9.2b; Bisley and
Goldberg 2003; Constantinidis and Steinmetz 2005; Itti and Koch 2001). In contrast to
this, top-down selection, involving volitional acts of attention, is associated first with
firing of neurons in the frontal eye fields (Fig. 9.2b; Buschman and Miller 2007).
Auditory Attention
It is known that patients with parietal lobe damage may neglect auditory or visual
modalities or both (Behrmann et al. 2004). Early fMRI studies indicated that the
regions of the brain that must be active for one to attend to an auditory spatial stimulus
are similar to those involved in attending to a visual spatial stimulus (Figs. 9.1c,
9.2b; Mayer et al. 2006). Recently Woldorff and colleagues used an attend-cue
experimental paradigm for subjects exposed to acoustic stimuli like that which they
used in their experiments on visual stimuli (Wu et al. 2007). The fMRI responses
throughout the brain for the different cue conditions indicated that activation of
frontal and parietal areas as well as of left and right auditory cortices occurs both
in interpret-cue-only trials as well as in attend-cue-only trials (although the
interpret-cue-only trials did not activate as many areas as the attend-cue-only trials).
Attend-cue-only trials were looked at in relation to interpret-cue-only trials in order
to determine which parts of the brain must be active in auditory spatial attention.
The results showed that auditory spatial attention involves activation bilaterally of
the frontal and superior parietal gyri, which is similar to the same areas activated in
visual spatial attention (Salmi et al. 2007; Sabri et al. 2008). In general, activation
for visual spatial attention in the fronto-parietal cortex is not as superior and medial
as that for auditory spatial attention (Figs. 9.1c, 9.2b). Note should also be made of
activation in other areas during auditory attention such as the anterior cingulate
cortex, the middle cingulate cortex, the anterior insula and at the putamen/caudate
nuclei. Of particular interest is the fact that cue-triggered orienting of auditory
spatial attention leads to enhancement of activity in the auditory cortex, and this
Determination of the Brain Areas Involved in ‘Attention’ 181
Fig. 9.2 Attention and awareness of visual percepts. (a) In the absence of attention, percepts
evoke only slight activity in the visual extrastriate (outside primary visual cortex, V1) pathways,
subserving, for example, the detection of motion or colour. (b) If the visual percepts are salient,
networks in lateral intraparietal cortex are activated that most likely increase the extent of the
extrastriate visual pathway activity; slightly later the frontal eyefield attentional area of the brain is
active that also contributes to activity in the extrastriate pathway. (c) If attention is caught and held
as in (b) it is possible that activity in the superior parietal and dorsolateral prefrontal cortex is
enhanced, as is shown in (d) for the dorsolateral prefrontal cortex. This is graded with an increase
in extrastriate visual cortex activity (e, first peak near 200 ms; signals 1, 2), until a threshold is
reached (d, signal 3), at which time there is a sudden non-graded large increase in activity in
dorsolateral prefrontal cortex (signal 4, d, e) as well as in superior parietal cortex, which drives a
very large late increase in extrastriate visual cortex (e; approx. 350 ms; signal 4). The increase in
the extent of recruitment of extrastriate visual cortex and of activity in the dorsolateral prefrontal
and superior parietal cortex is associated with being conscious of the percepts; that is, the subject
reports awareness of these
also occurs on those occasions in which no targets are present (Fig. 9.1c, d). Thus
the fronto-parietal cortices involved in auditory spatial attention are likely to enhance
activity in the auditory cortex. Attention to auditory phenomena is supported by
activity in the inferior parietal and inferior prefrontal cortices (Pugh et al. 1996;
Salmi et al. 2007). These cortical areas enhance activation by auditory stimuli in the
superior temporal gyrus (area 5, Fig. 9.1b) and left inferior frontal cortex, and in the
case of the phonetics of speech in the precentral gyrus as well as supramarginal
gyrus (area 1, Fig. 9.1b), with lexicality (words over pseudo-words) in the left lateral
prefrontal cortex (Sabri et al. 2008). In the absence of attention, activity in relation
to auditory phenomena remains in the early auditory areas around Heschl’s gyrus
(Fig. 9.1b). So, as in vision, without attention engaged, the activity enhancement
to a sensory experience is confined to early perceptual-mediating neural systems.
An exception arises, however, if novel sounds are presented, such as rotated speech
and to some extent pseudo-words, in which case attention is caught and focused on
the auditory task even though attention has been directed to a task in a different
sensory modality (Sabri et al. 2008; see Fig. 9.1c, d for a possible saliency of the
auditory percept activity in the inferior parietal cortex supporting attention and
feeding back to excite further the auditory cortex).
Summary
Visual attention is supported by activity in lateral intraparietal and frontal (eyefield)

cortical areas and that for auditory attention supported by activity in inferior parietal
and dorsolateral prefrontal cortex.
Determination of Brain Areas Involved in Awareness
Visual Awareness
What are the neural correlates in the cortex of being aware of an object in its spatial
extent? Recently, high-density (128 electrode) sets of electroencephalographic
recordings have been made from subjects carrying out particular psychophysical
tests designed to identify the temporal and spatial evolution of electrical signals
(sampled at 250 Hz) in the cortex that accompany the subject’s awareness of an
object when the subject attends to part of the visual field; that is, their being
conscious of the object (Del Cul et al. 2007). These experiments of Del Cul and
colleagues are of such importance as to warrant direct quotation of their methods
and observations.
“Recordings are made when there is an object in the part of the visual field attended to,
when there is no object in the attended field and when an object in the attended visual field does
not enter awareness, because it is masked. In this latter case the subject is asked to fixate on
a point on a screen, and after a variable delay a target object (a numeral) is presented for
Determination of Brain Areas Involved in Awareness 183
16 ms in one of the screen’s quadrants, followed by a letter mask for 250 ms. The letter
mask consists of four alphabetical letters crowding the numeral. Six conditions of delay
between the presentation of the target and the mask are used (the stimulus-onset asynchrony
or SOA), namely 16 ms, 33 ms, 50 ms, 66 ms, 83 ms or 100 ms and one mask only condition
(without the target numeral). Following each such stimulus, subjects are asked to perform
two consecutive tasks: (i) a forced-choice comparison of the target numeral with the numeral
5; and (ii) evaluation of subjective target visibility using a continuous scale labeled ‘not
seen’ at the left and ‘maximal visibility’ at the right. The results of such experiments for the
condition when the subject reported maximal visibility of the numeral (which occurred at
SOA of 100 ms) indicated two phases of cortical activation: a first phase, before 300 ms,
when activation progresses from the occipital pole towards both parietal and ventral sites
(Fig. 9.2c, e; signals 1–3); and a second phase, after 300 ms, when there is a sudden onset
of high-amplitude activity, which is very prominent in ventral prefrontal cortex, and is
accompanied by a concomitant reactivation of all previous posterior sites (Fig. 9.2c, e;
signal 4).
Masked stimuli that are insufficient for the subject to be aware of the target evoke
activation in extrastriate visual cortex, but their intensity is attenuated in higher visual areas
(Fig. 9.2c–e; signals 1, 2), whereas stimuli insufficient for the subject to be aware of the
target numeral generate a sudden increase in activation in the superior parietal and dorsolateral
prefrontal areas (Fig. 9.2c, d; signal 4), followed by a large increase in activation in extras-
triate visual areas (areas 19, 20, 21; Fig. 9.2c, e; signal 4 at 300 ms).
Studies with fMRI confirm that activation of superior parietal and dorsolateral
prefrontal cortex are necessary for visual awareness, together with, of course, activation
of a distributed set of regions for the different components of the visual scene in
primary visual cortex and ventral visual areas (for a review see Rees 2007).
These observations and their interpretation are supported by a further electroen-
cephalographic study (20 electrodes) using a similar experimental masking paradigm
to relate awareness of a target object to cortical excitation (Koivisto et al. 2008;
Koivisto and Revonsuo 2007). Electrodes were used to record event-related
potentials over the occipital, posterior temporal and parietal cortex. Left-hemisphere
waveforms were obtained when the target was in the right visual field, and right-
hemisphere waveforms when the target was in the left field. These waveforms consist
of a small early positive component at 80–120 ms (P1), followed by, in general, a
larger negative component at 130–200 ms (N1), with this followed by a very large
positive waveform at 290–700 ms (P3).
Attending to a target in space (spatial attention), without any object presented
or any masking, increased the amplitude of P1 and N1 amplitudes over occipital
and posterior temporal regions so that the effect of spatial attention is to amplify
activity in these regions. Selection negativity (SN), defined as the negativity between
160 and 300 ms (i.e. nearly all of the N1 waveform component) did not differ
between masked and unmasked stimuli, so it is related to attention rather than
awareness. SN, however, did differ in latency between the unattended and the
attended field, this being longer in the unattended field, as expected, if it is related to
attention. In contrast to this, the visual awareness negativity, defined as the negativity
between 120 and 290 ms (i.e. taking in nearly all of the N1 waveform component
and occurring at times that include those for the SN waveform component) increases
significantly for masked versus unmasked conditions, particularly over the occipital
cortex, as does the very large late positivity. These observations indicate that
electrophysiological correlates of attention (SN) are elicited independently of
awareness of a target, whereas the electrophysiological correlates of awareness of
the target occur independently of manipulations of spatial and non-spatial attention
(Koivisto and Revonsuo 2007). Electrical correlates related to reflection on the
aware target, are associated with working memory in the prefrontal cortex, and occur
as a late positive potential. A technical issue here is that if the frequency range of
electrophysiological recordings in the EEG reflects that of local field potentials
due to synaptic currents, then the psychophysical experiments relating attention
and awareness to specific brain regions are approximately consistent with those
using fMRI, whereas if high-frequency components that take in action potential
firing are used, this is not the case (Wilke et al. 2006). Such a difference might be
expected because the fMRI haemodynamic signal is very likely to be causally
driven by excitatory glutamatergic synaptic transmission, not by action potentials
(Bennett 2008b; Bennett et al. 2008). Magneto-encephalographic recordings of
activity during psychophysical experiments attempting to identify the brain regions
involved in attention and awareness give rise to similar conclusions to those
arrived at using electroencephalographic and fMRI recording methods (Wyart and
Tallon-Baudry 2008), supporting the idea that the activity of interest is due to synaptic
currents. The fact that different types of illusions are accompanied by activation of
areas of the brain that are also active when actually perceiving or experiencing the
subject matter of the illusion does not mean that awareness of these is just depen-
dent on such activation. The phenomenon of extinction shows this. For example,
patients with right parietal cortex damage are often not aware of presentations to
areas of their left visual field when the same image is presented simultaneously to the
right visual field; that is, there is often left visual field extinction. fMRI, however,
shows that there is elevated activity in the right fusiform face area of these patients,
whether they report awareness of a face presented to their left visual field or not
(Rees et al. 2002b). Interestingly, when the patient is aware of the left visual stimu-
lus in bilateral trials, greater activity is detected by fMRI in the right ventral visual
cortex but now elevated activity is also recorded in the left frontal and parietal areas
(Rees et al. 2002b). Two points emerge from such studies. First, category-specific
areas of visual cortex are still activated by extinguished stimuli (one that the subject
is unaware of), so that such activation is not sufficient for awareness. Second, parietal
and pre-frontal areas are, in addition, activated when the patients are aware, sug-
gesting that these areas form a network that must be engaged to support awareness
(Rees et al. 2002a).
Auditory Awareness
Auditory awareness requires activation in the dorsolateral prefrontal cortex and

the superior temporal cortex whereas visual awareness, as we have seen, requires
Determination of Brain Areas Involved in Awareness 185
activation in the dorsolateral prefrontal cortex and the superior parietal cortex
(Figs. 9.1e, 9.2c; Eriksson et al. 2007). Whether this auditory awareness involves
the triggering of a late surge of activity in the prefrontal and superior temporal
cortex is not known, although it is very likely to be responsible for an increase in
the intensity and spread of activity in the auditory cortex (Fig. 9.1e). Why should
subjects with schizophrenia be aware of hallucinatory voices as alien? The audi-
tory cortex in planum temporale allows one to locate voices in external space and
this cortex does not function properly in schizophrenia. One argument is that there
is failure of corollary discharges involving the planum temporale in subjects with
schizophrenia (Feinberg and Guazzelli 1999). Corollary discharges are thought to
be normally required in order to be able to distinguish between percepts arising
from one’s own activities and those arising independently in one’s environment.
The concept of corollary discharge is that it is an efferent copy of a motor command
sent to the related sensory system in order for one to be alerted to the motor act
carried out, such as when lifting a weight. Without the collateral discharge it would
appear as if the motor act is imposed on one rather than being voluntary. Corollary
discharge is taken to be the reason you cannot tickle yourself; sensory perception
of the tickle is damped out by the corollary discharge accompanying intention to
carry out the motor act of tickling. If a stroke interferes with the production of a
corollary discharge then even lifting one’s arm appears to involve lifting a very
heavy weight, as if someone was resisting you lifting your arm. In the case of the
auditory system a corollary discharge might exist whereby signals that arise when
one is about to speak are sent to the auditory cortex, where they are compared with
the signals relating to hearing the speech (Heinks-Maldonado et al. 2007). In this
model of auditory corollary discharges, a motor command to the sensorimotor system
accompanying speech generates an efference copy that, through a corollary dis-
charge, is compared with the auditory feedback of the heard speech. Self-produced
speech sounds are correctly predicted by the efference copy, with this lack of
discrepancy detected by the comparator giving rise to suppression of auditory cortex
activity to the self-produced sound. These ideas are supported by experiments in
which the N1 event-related potential due to a 1,000 Hz tone probe (baseline), in the
absence of speech, is decreased in normal subjects when they talk aloud, but it is
not decreased in patients with schizophrenia. During normal speech the corollary
discharge to auditory cortex dampens its activity (indicated by the N1 potential)
and this supports the interpretation that the speech emanates from oneself and not
from outside. If, however, the corollary discharge mechanism fails, as indicated by
the failure to suppress the N1 potential, then this supports the misinterpretation
that the self-initiated speech can be attributed to an outside source that does not
exist. The failure of mismatch negativity in patients with schizophrenia also points
to abnormalities in auditory cortical mechanisms (Catts et al. 1995). There appears
then to be a problem in the corollary discharge mechanism in patients with schizo-
phrenia whereby the feedback from the neural pathway that underpins the effort or
intention to use a word is faulty, so the words do not appear to be self-generated;
that is, they appear alien.
Summary
Visual awareness requires activity in the dorsolateral prefrontal and superior parietal
cortex. Auditory awareness requires activity in the prefrontal and superior temporal
cortex.
Conclusion: Attention and Awareness in a Psychosis
When attention is caught and held activation in cortical regions subserving a percept
is greatly amplified, leading to a burst of activity in the networks subserving
awareness, that is consciousness. The hypothesis proposed here is that in a psychosis
endogenous spontaneous activity occurs in a cortical region associated with a
particular percept as a consequence of that region being deafferented. For example,
if this deafferentation occurs in the anterior temporal cortex, hallucinations involving
grimacing faces may occur. In contrast, if deafferentation occurs in the planum
temporale then hallucinations of declamatory voices may occur. The salience of
these hallucinations can activate the lateral intraparietal cortex in the case of vision
(Fig. 9.2b) or perhaps the dorsolateral prefrontal cortex in the case of audition
(Fig. 9.1c), leading to amplification of the endogenous activity in the visual or
auditory areas. This can in turn activate the prefrontal/superior parietal regions that
support visual awareness (Fig. 9.2c) or the prefrontal/superior temporal areas that
support auditory awareness (Fig. 9.1e) of the hallucinations.
On completing her great work The Waves, Virginia Woolf commented in her
diary (Woolf and Bell 1977):
I wrote the words O’Death fifteen minutes ago, having reeled across the last ten pages with
some moments of such intensity and intoxication that I seemed only to stumble after my
own voice, or almost, after some sort of speaker (as when I was mad). I was almost afraid,
remembering the voices that used to fly ahead.
The neuropsychiatry of these auditory hallucinations, as set out above, requires

answers to the following questions: (i) do the different categories of auditory
hallucinations (e.g. voices of children crying) pertain to different regions of auditory
cortex as do different categories of visual hallucinations to different regions of
visual cortex; (ii) to what extent is there synapse loss in such regions or in the main
afferent projections to these regions; (iii) can the site of mismatch negativity be
better spatially resolved so as to assist in identifying the region(s) of the auditory
cortex that have gone awry in schizophrenia; is this region deafferented; and (iv)
finally, is the activity in the fronto-parietal cortex devoted to auditory attention, and in
the frontal and superior temporal cortex supporting awareness, normal in subjects
suffering from psychosis? Until these questions are met we will not have the appro-
priate insights into the mechanisms that go awry in the cortex that subjected Virginia
Woolf to her terrifying experiences.
References 187
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Part III
On Mental Illness
Human beings are not automatons, yet much of the previous Part II considered them
as Cartesian machines, for which interventions are sought that will reconstitute normal
synaptic wiring. In this final Part that perspective is corrected. This is achieved by
tracing the history of what philosopher/scientists have thought is the relation
between the corporeal body and the mind. What has become known as ‘the stream
of consciousness’ figures largely in the works of Virginia Woolf. How did this word
‘consciousness’ arise in relation to the mind, and in particular what is meant by the
term ‘mind’? We cannot place the work of neuropsychiatry in proper perspective
unless the meaning of these concepts is clarified, and this is attempted in the
present Part.
Chapter 10
The Mind, Mental Illness and the Stream
of Consciousness
Virginia Woolf’s Concept of the Mind. Origin
of the Term and its Relation with Consciousness
and Cortical Mechanisms
Virginia Woolf, along with James Joyce, is credited with introducing into
narrative writing the ‘stream of consciousness’. This term was first used by the
great American psychologist William James at the end of the nineteenth century.
James provides a phenomenological description of consciousness as follows:
‘Consciousness, then, does not appear to itself chopped up in bits. Such words as “chain” or
“train” do not describe it fitly as it presents itself in the first instance. It is nothing jointed; it
flows. A “river” or a “stream” are the metaphors by which it is most naturally described. In talk-
ing of it hereafter let us call it the stream of thought, of consciousness, or of subjective life.’
During Virginia’s life it was thought that description of the emotional and
psychological processes taking place in the minds of one or more characters consti-
tutes their stream of consciousness. In this kind of literature the important traits of
characters are revealed through a description of what is going on in their minds. The
stream of consciousness forms the interior monologue of characters in the narrative
and by this means we come to know their perceptions or impressions, as well as
both thoughts initiated by sensory stimuli as well as fragments of random, discon-
nected thoughts unrelated to the senses.
Virginia talks little of ‘consciousness’ but much of the spirit and the soul on
the one hand and mind on the other. It is clear from her work that she identified
consciousness with the mind. Her way of looking at spirit, soul, mind and con-
sciousness, was much the same as it has been since the seventeenth century. But no
scientific discovery or logical form of argument led to this highlighting of con-
sciousness in our discussions of literature or science or philosophy. In order to grasp
what Virginia Woolf might have meant when using the terms spirit, soul and mind,
indeed what James could have meant by the stream of consciousness, we have to
trace the steps by which these terms arose historically. Without understanding their
evolution it is not possible to grasp whether Virginia’s ideas about spirit and soul
make sense. What might the stream-of-consciousness, the workings of the mind,
mean in her work and in the claims in her diaries about the malaises she felt beset
her mind? Furthermore, unless we have a clear idea of what we mean by soul, mind
and consciousness it will not be possible to arrive at a coherent description of

194 10 The Mind, Mental Illness and the Stream of Consciousness
Fig. 10.1 Photograph

of Virginia Woolf by Gisèle
Freund, 1939, two years
before her suicide.
(Copyright Centre Pompidou,
MNAM-CCI, Dist.
RMN-Grand Palais/Gisèle Freund,
reproduction by Georges Meguerditchian)
Virginia’s own mental condition, fragile as it was (Fig. 10.1). Without that, no
progress can be hoped for in putting aright what has gone awry with the mind of
those suffering from mental illness.
When Virginia speaks of the spirit and soul as in
‘But when the self speaks to the self, who is speaking? The entombed soul, the spirit driven
in, in, in to the central catacomb; the self that took the veil and left the world.’
she is subscribing to a traditional way of talking about ‘spirits’ and the ‘soul’ that
goes back over 6,000 years. This idea of ‘the spirit driven in, in, in to the central cata-
comb’ reflects metaphorically the concept of spirits that arose in Neolithic times.
Experiences involving dreams and shadows seem to have been particularly impor-
tant in establishing the notion of spirits. In dreams both dead and alive persons
could be encountered in places visited during the waking hours. These had the
substance of shadows which in themselves were important, following and uniquely
associated with the individual. But they did not have the psychological characteris-
tics of the individual, what we would say distinguishes their personality, although
they did take on their appearance. There seemed no other explanation for such
entities than that something ‘shadow-like’ left the body during sleep and visited
another place, returning on awakening. Furthermore, such shadows or shades must
10 The Mind, Mental Illness and the Stream of Consciousness 195
be immortal for they included shades of those that were dead. These shades were
called spirits and Shamanism formalized and codified the world they inhabited.
Most importantly, this concept of the spirit was taken up by the Ancient Egyptians,
and almost certainly conveyed from there to the Archaic Greeks and through Homer
to Plato and hence into Western culture. Aristotle wrote three treatises on sleep and
dreaming: De Somno et Vigilia (On Sleep and Dreams), De Insomnis (On Sleeping)
and De Divinatione Per Somnum (On Divination through Sleep). Over 2,000 years
later, in 1900, Freud was to provide major theoretical insights into his psychiatry
through The Interpretation of Dreams.
Virginia refers to the ‘The entombed soul, the spirit driven in, in, in to the central
catacomb.’ This reflects the idea that spirits of the living joined the shades of the
dead in an underground abyss at night,
‘where there is not work, nor knowledge nor wisdom but endless topor.’
Her further reference to

‘the self that took the veil and left the world.’
is also akin to the idea in Mesopotamia that at exhalation of the last breath the spirit
leaves the body. Given the importance of the psychological in Woolf’s writings, it is
interesting to note here that Homer called the spirit, located in the head, the psyche.
This is the first time the word, that has played such an important role in Western
culture, is used.
Virginia sometimes speaks of the soul as synonymous with the spirit, as in ‘The
entombed soul, the spirit driven in, in, in to the central catacomb’. At other times she
talks of the soul as taking in the entire experiences of life as in
‘Every secret of a writer’s soul, every experience of his life, every quality of his mind is
written large in his works.’
Here the soul is made synonymous with the mind. And on other occasions she
speaks of the soul as involved in thinking as in:
‘We all indulge in the strange, pleasant process called thinking, but when it comes to say-
ing, even to someone opposite, what we think, then how little we are able to convey! The
phantom is through the mind and out of the window before we can lay salt on.’
And that ‘This soul, or life within us, by no means agrees with the life outside us.
If one has the courage to ask her what she thinks, she is always saying the very
opposite to what other people say’. What is meant here by the mind, and why
should it be associated intimately with the soul and with thinking?
Talk of the soul in the context of the spirit follows then the ancient tradition of
humans regarding themselves possessing an immortal shade, which while being
recognized as belonging to the individual whose shade it is, does not have their
psychological attributes and personality. But what is meant here by the soul taking in
all the experiences of life, of being associated with or identical to the mind, and with
thinking? To unravel this complex set of associations and to clarify what is meant by
the terms necessitates consideration of the historical development of the concept
of the soul and of its evolving relationships with the mind and with thinking.
The most profound development in the long history of spirit and soul, from
Neolithic times to the present day, is due to the Ancient Egyptians 5,000 years ago.
For although they believed in immortal shadow spirits, devoid of personality and
psychological traits, and belonging to a corporeal body, they also believed in another
immortal entity belonging to the body, which they called the soul. Their revolutionary
idea was that this soul carried a person’s individuality and was not just a spirit like
that of the shades. Furthermore, the soul was taken as having three parts, a concept
that sounds strange to us but which was to dominate the thinking of philosophers for
thousands of years and in one form or another colors our thinking to the present day,
including that of Virginia Woolf.
These three parts were concerned with, first, a person’s individuality and intel-
lectual gifts; second, with their intentions, will and emotions; and finally, with their
sustaining life-force, rather akin to the ‘life force’ in the Star Wars trilogy. A person
dies when the life force leaves the body at which time a measure is made by the
Gods of the extent to which their intentions were just and right during their life
times. If this proved to be the case then they retained their individuality and the
capacity for having intentions and a fine emotional life for eternity. If on the other
hand they were found unworthy then their capacities for having emotions and
intentions were stripped away, and although retaining some individuality they were
effectively reduced to a comatose condition. Sigmund Freud was fascinated with
these Egyptian concepts, and kept on his desk, wherever he traveled, a bronze statue
of Osiris, the God that presided over the trial of the recent dead and of also of Thoth,
who recorded the results of the trial (Fig. 10.2).
The Ancient Egyptians had then evolved an idea of the immortal soul that laid
the foundations for all future considerations of this subject. First, and most
importantly, a person’s soul retained their individuality, their personality. Second
their soul was subject to a judgment based on the life led by the individual, the
results of this judgment leading to either a happy existence taken up amongst one’s
living loved ones, without work or sorrow, or condemned forever to a comatose
condition. Finally, the soul was conceived of in three parts, one associated with
individuality and rationality, thinking; another with the energy required to sustain
the former, and therefore a life-force requiring nutritional support; finally, an
emotional and intentional aspect of the individual, considered as identifying an
individual’s worthiness.
These ideas went through many modifications over the next several thousand
years, in which they were recombined and synthesized in different ways up to the
time of Descartes, who was, as we shall see, responsible for a fundamental break
with the Egyptian concept of the soul.
As in contemporary times we have accepted the notion that the Archaic and
Ancient Greeks are the foundation of our Western Civilization. However it is
important to understand what they took from the Egyptian notion of the soul,
modified, and then passed onto Christianity. Homer, at the time of the Archaic
period around the ninth century BC, in addition to attributing an immortal spirit or
psyche akin to a shade to the individual, he also borrowed from the Egyptian notion
of the soul. In Homer’s case the soul also possessed parts. One of these was
Fig. 10.2 Photograph of Sigmund Freud in his study by Edmund Engelman, 1938, the year before
he died. Freud Museum, London
identified with the individual’s rationality and another with their emotional and
intentional characteristics. These were then similar to those of two of the Egyptian
parts of the soul with the very significant difference that in Homer’s considerations
they were not immortal. Furthermore, we have for the first time an emphasis on
rationality and on the reasoning functions of one part of the soul. Thinking and the
soul now become intertwined, an intimacy that is retained to the present day,
including in the work of Virginia Woolf, when she says
‘This soul, or life within us, by no means agrees with the life outside us. If one has the courage
to ask her what she thinks, she is always saying the very opposite to what other people say.’
The two figures who have had the most profound influence on contemporary
views of what constitutes the soul are Plato and Descartes. The Ancient Greek concept
of the soul underwent a profound transition at the end of the Archiac period, just
before Plato at the beginning of the fourth century BC. No longer is there an immortal
psyche or spirit, and a mortal soul associated with the individual’s intentions and
emotions. Now the shade composing the psyche is displaced by the soul, carrying
the individual’s intentions and emotional capacities. The Greek soul, the one we
have inherited, becomes immortal. This shift has been attributed to the lyric poets at
the end of the Archiac period, who presumably borrowed it from the Egyptians, as
they never relinquished the idea of an immortal soul carrying the individuality of a
person together with intentions, will and emotions as well as the life-force to sustain
these, both in life and for eternity following death.
Virginia regards the soul as synonymous with the mind. She says that
‘Every secret of a writer’s soul, every experience of his life, every quality of his mind is
written large in his works.’
It is to Plato that one must first turn for an understanding of the idea of a mind
and how this is related to the soul. Plato, following the notion of the soul attrib-
uted to the lyric poets, considered it to be composed of parts. These parts are will and
the emotions, closely associated with a person’s individuality, as subscribed to by the
Egyptians and Homer; the appetites, akin to the life force of the Egyptians; and
reasoning, as suggested by Homer. But unlike Homer, all parts of the soul make up
the immortal psyche. Plato gives the first fully realized psychological description of
the soul in his dialogues. The psychological, cognitive and emotional activities that
have been attributed to a particular person were now attributed to their soul.
In Plato’s dialogues the reasoning part of the soul, involving thinking, is called
the mind. Plato institutes a train of reasoning in which the soul is taken to be some-
thing that can engage in activities like thinking and planning. By the beginning of
the fourth century BC Plato had consolidated a view in which one attributes to the
psyche or soul a wide variety of cognitive and emotional activities and responses as
well as it being the bearer of such attributes as courage and justice. This dualistic
philosophy of Plato, of a corporeal body and an incorporeal immortal soul, had a
major effect on the Neoplatonists and via St Augustine came to dominate all
Christian thought. Platonic dualism became the most natural conception for popular
Christianity and it was this dualism that was to become a characteristic of the
Renaissance form of Neoplatonism. Although not a Christian, Virginia Woolf’s idea
of the soul is thoroughly Neoplatonic.
Virginia belonged to the Bloomsbury group of creative and intellectual genius
in which the dominant figure was the economist John Maynard Keynes. Keynes was
instrumental in bringing Ludwig Wittgenstein back from Austria after the first-
world war. Wittgenstein, the greatest philosopher since Kant, is not know to have
met Virginia Woolf, although it seems highly likely that they did meet. If she had
inquired as to his ideas on the relationship between the soul and the mind she
would have come across a radically different concept to that of the Neoplatonists.
This concept followed in the tradition of Plato’s pupil, Aristotle.
For Aristotle the word ‘mind’ is a manner of speaking, a façon de parler, about
the capacities for intellect, thought, and reasoning. So we say ‘keep that in mind’,
remember it; ‘to have something in one’s mind’, is to be thinking about something.
If one has a powerful mind then the reference is generally to one’s powers of thinking.
To ‘lose one’s mind’ is usually reserved for those occasions when one’s rational
abilities are not correctly used, as in the severe depression suffered by Virginia
Woolf. This does not of course mean that one has lost all psychological abilities.
Each use of the word ‘mind’ is paraphrasable into a phrase that does not include the
word ‘mind’ but does include a psychological predicate that is predictable of a
human being. In such phrases ‘mind’ has been eliminated without the sentence
failing to convey it’s information. Use of the word ‘mind’ is then a convenient way
of talking about certain human faculties and their use.
It then makes no sense to ascribe psychological abilities to the mind, such as
thinking as Plato would have it, or indeed seeing, remembering, feeling and believing.
As the word ‘mind’ is a manner of speaking it does not stand in relation to anything.
The ‘mind’ is not then an entity made of a substance, be that the corporeal brain
(as claimed by many neuropsychiatrists and cognitive neuroscientists), or an incor-
poreal soul.
We have traced the origins of the Neoplatonist heritage concerning soul and mind
that Virginia Woolf adopted like most in the Western world. It is a heritage that
needs explication in order to both understand what soul and mind mean as well as
to indicate that there is no logical or factual necessity to adopt this heritage. This has
been emphasized by considering a very different heritage that Virginia could have
adopted through Ludwig Wittgenstein, namely that of Aristotle. Indeed although
Neoplatoism is now dominant this was not the case for over 1,500 years when
Aristotle’s concepts of the soul and mind held sway.
Virginia thought about how the mind deals with all that it sees, hears, feels,
tastes and remembers,
‘The mind receives a myriad of impressions, … From all sides they come, an incessant
shower of innumerable atoms.’
She thought that novelists should

‘record the atoms as they fall upon the mind in the order in which they fall, let us trace the
pattern, however disconnected and incoherent ….’
Here the mind is no longer that part of the soul given over to rationality and
thinking. It is now something that allows us to be aware of all that we experience, of
all our thoughts and desires. This is to treat the mind as identical to what William
James called the ‘stream of consciousness’:
‘Consciousness, then, does not appear to itself chopped up in bits. Such words as “chain” or
“train” do not describe it fitly as it presents itself in the first instance. It is nothing jointed; it
flows. A “river” or “stream” are the metaphors by which it is most naturally described. In talk-
ing of it hereafter let us call it the stream of thought, of consciousness, or of subjective life.’
Virginia is celebrated, together with James Joyce, as pioneering the literary

technique of ‘stream of consciousness’. It is characterized by a flow of thoughts
and images, which may not always appear to have a coherent structure or cohe-
sion. Writers who create stream-of-consciousness works of literature focus on
the emotional and psychological thoughts of their characters. The stream of

consciousness generally involves fragments of unspoken monologues that might
be associated with the experience of images and sensations.
What can be made of this idea of a ‘stream of consciousness’ and how is it
related to the soul and mind? Platonic dualism, an immortal soul consisting of parts
concerned with the emotions, will, the appetites and reasoning, interacting with
our bodies, came via St Augustine to dominate Christian thought to the time of
Descartes in the seventeenth century. He initiated the most radical, one might say
revolutionary change in the concept of the soul and mind in the last 2,000 years.
Drawing on Neoplatonism, this concept has become the dominant view of what it
means to have a soul and mind in the Western world to the present day. Descartes
did this by introducing the concept of ‘consciousness’. He held that perception as
well as emotion, nutrition, growth and reproduction are neither parts of the soul as
Plato would have it, nor functions which constitute the soul as Aristotle suggested,
but essentially physiological functions of the body. They are then essential features
of animal life, including human life, of the material substance of which we are
composed, and therefore open to physiological study of the mechanisms involved
in perception and nutrition. In the Neoplatonist’s scheme this left the mind, reason-
ing, as identical to the immortal soul. Descartes then, having discarded most of the
Platonic soul to physiological function, greatly expanded the notion of the concept
of mind, now identical to the soul.
Mind, which Plato had posited as concerned with reasoning, was now elaborated
on by Descartes so that it included ‘everything which we are aware of as happening
within us, in so far as we have awareness of it’. This new concept of the mind was
given the name ‘consciousness’. Thought was identified with consciousness, so that
it was no longer just concerned with understanding but also with sensations and
even will power. Consciousness entailed that one could not think and have experi-
ences such as feeling, perceiving, willing or imagining, without knowing or being
aware that one does. In this way Descartes assimilated the mind into his notion of
consciousness that now became the immortal soul.
In Descartes scheme, which Virginia inherited, we experience colours, tastes,
smells etc. as a consequence of these being produced in the mind, which is in
consciousness, in the form of ideas. These ideas are generated by physiological
mechanisms involved in these sensations impacting the mind. In this scheme,
movements of the body are affected by an act of will by the mind, which then
acts on the physiological mechanisms that move the body. What Descartes did
then was to assimilate thought and reasoning, defined by Plato as properties of
the mind, into the concept of consciousness and then expand this to include sen-
sations and will-power as immediately experienced. Consciousness was now
immortal, identified with the person, and this consciousness received sensations
or acted on the world through a body that was an elaborate physiological mecha-
nism. It is this Cartesian scheme, developed out of the dualism of Plato, which
now dominates not only Christianity but all thought about soul, mind and
consciousness to this time.
Notes 201
When Virginia says that

‘The mind receives a myriad of impressions, … From all sides they come, an incessant
shower of innumerable atoms’,
she is conceiving of the mind in the Cartesian tradition of being identical with con-
sciousness, that is of all that we experience at any one time, including our thoughts
and desires. The mind is no longer, as Plato first defined it, just that part of the
immortal soul given over to rationality and thinking. When Virginia suggests that
novelists should
‘record the atoms as they fall upon the mind in the order in which they fall, let us trace the
pattern, however disconnected and incoherent …’,
then the description by William James that such activity constitutes a ‘stream of
consciousness’ is most apt. For Descartes’ introduction of consciousness as ‘every-
thing which we are aware of as happening within us, in so far as we have awareness
of it’ at any particular time means that successive episodes of such consciousness,
described by Woolf as ‘atoms as they fall upon the mind in the order in which they
fall’ constitutes a stream of such episodes, a stream of consciousness.
Notes
These notes are of two kinds. First, there are scholarly references to the studies
on which the various claims in this chapter are based (see References). Second,
the material in these references are elaborated on more fully than in the text with
consideration given to interesting details as well as to the assumptions on which
hypotheses are based.
All these notes are preceded by the page number and a phrase or sentence in the
chapter, placed in bold, to which they refer.
(p. 195) These shades were called spirits and the world they inhabited was
formalized and codified in Shamanism.
This is shown in (Frazer 1890). People in southwest Asia during the Neolithic
period believed that it was very important to shrink the head of their enemies as soon
as they were killed in battle. This was apparently from fear that once the enemy’s
spirit had left the body at death it could then act out revenge on the living. Perhaps
during sleep when the spirits of the living met those of the dead. The only way to
prevent this was to seal up the spirit of the dead enemy in the head by shrinking it.
So over 6,000 years ago the spirit was already associated with the head.
(p. 195) Most importantly, this concept of the spirit was taken up by the
Ancient Egyptians, and almost certainly conveyed from there to the Archaic
Greeks and through Homer to Plato and hence into Western literature.
Homer took much of the conceptual framework of the spirit devised by the
Ancient Egyptians, with a scheme much the same as that of the spirit of early
Animism and the etêmmu of early Mesopotamia, namely with the psyche identified
with the shadow spirit called eidolon (Snell 1953; p. 8).
(p. 195) …where there is not work, nor knowledge nor wisdom but endless
topor’.
Where did the spirit of the dead and of the sleeping meet up? In Mesopotamia, at
about 2000 BC, the spirit, or etêmmu as it was called, joined other shadows in an
underground abyss, ‘where there is not work, nor knowledge nor wisdom but endless
topor’ (Bottéro 2001; p. 204).
(p. 195) …in Mesopotamia that at exhalation of the last breath the spirit
leaves the body.
The moment of death of a person, or awîlu, was recognized in much the same
way as we do now: it was when exhalation of the last breath occurred. So even in
ancient times individuals, persons, possessed a spirit, called the etêmmu in
Mesopotamia, that was immortal, did not have any particular attributes or capaci-
ties unique to the individual whose spirit it was, and located in the head. The spirit
only left the body at night or at death, when the last breath was exhaled (Bremmer
1983; p. 25).
(p. 195) This is the first time the word, that has played such an important
role in Western culture, is used.
Only the psyche, the spirit associated with the head and possessing no particular
psychological attributes unique to the individual, survives death. According to
Homer this shadow spirit, the eidolon, then goes to reside in Hades, a dark place
unlit by the sun beneath the level of the oceans. The eidolon then wanders through-
out Hades without senses, incapable of speech, indeed in a comatose state (Bremmer
1983; p. 73).
(p. 196) Their revolutionary idea was that this soul carried a person’s
individuality and was not just a spirit like that of the shades.
The Ancient Egyptians believed in shadow spirits, devoid of personality and
psychological traits (called sheut) and that a living person had a physical body
(called ha). But then they conceived of the revolutionary idea of an immortal entity
(called soul) that did carry a person’s individuality and was not just a spirit like that
of a shadow (Allen 2010; pp. 81–83).
(p. 196) Furthermore, the soul was taken as having three parts.
One part of the soul, called the ba, confers a person’s individuality and intellec-
tual gifts. The ba, like the spirit of Neolithic times, was immortal and almost
certainly associated with the human head. It was thought to be able to come and go
at will from the vicinity of the mummified body after death. Given these two attributes
of the ba it was represented in hieroglyphs as a bird with a human head. Another
part of the soul, called the ka, was a ‘life force’, somewhat akin to the notion of ‘life
force’ in the Star Wars trilogy. The life force of the living required nutriment in the
form of food and water. Even after death the immortal ka was offered food and
water by relatives of the deceased that were taken as sustaining the ka, but now in a
more subtle way than just through ingestion by the living. A person dies when the
ka leaves their body, synonymous with the ka being exhaled in the last breath. The
immortal ba must then be joined by the ka if it is to be sustained throughout eternity,
living now as the immortal akh. Interestingly, the third part of the soul is the seat of
Notes 203
intentions and emotions in the Egyptian scheme. Called the jb, it was thought to
reside in the heart and to be mortal. Nevertheless the mortality of the jb belied it’s
importance, for it was critical in judgement of the individual as to whether they would
be regarded as worthy of retaining their individuality and lead the good after-life
for eternity. This judgement took place before the leader of the underworld,
Osiris, and involved weighing the heart to measure if its jb indicated that good
intentions and behaviour had been followed throughout life. If they were not then
the heart was devoured, the jb destroyed, and so the capacity for emotion and for
having any intentions lost. As this left the ba, the individuality of the soul, intact
the loss of the jb effectively reduced the individual in the after-life comatose
forever. On the other hand, if on measuring the heart before Osiris it was found
that the individual had led a noble life, full of good intentions, then the akh was
allowed to take up its non-physical existence amongst the people of Egypt with-
out suffering any of the discomforts of the living. But the akh had to replenish its
life force component (the ka) each night, which it did so by means of the ba
returning to the vicinity of the mummified body where, as already mentioned,
food was placed for ‘replenishment’ of the ka, so that in the morning the akh
could once more take up its very pleasant existence amongst the living and work-
ing Egyptian people (Allen 2010).
(p. 196) As in contemporary times we have accepted the notion that the
Archaic Greeks are the foundation of our Western Civilization.
In recent times this has been severely challenged by Martin Bernal who
suggests that scholarship took a turn in the period between 1785 and 1850
towards mythologizing the importance of ancient Greek civilization at the
expense of the much earlier Egyptian civilization some 2,000 years earlier
(Bernal 1987).
(p. 196) In Homer’s case the soul also possessed parts.
This soul has three parts: first there is the nous, which is akin to the ba in Ancient
Egypt in as much as it is related to one’s particular rational abilities that play such a
large part in one’s distinctive individuality and personality although Homer does not
give any particular location of the nous in the body. Perhaps he does not locate it in
the head as the Egyptians apparently do with the ba, as he has already allocated the
psyche to the head.
A second part of the Homeric soul of the living is called the thymos, which is
concerned with one’s intentions and emotions as in anger, courage and zeal, and so
is quite personal to the individual, indeed it is often called the ego soul. It is there-
fore similar to the Egyptian jb and like it resides in the organs of the chest, probably
the heart and also the lungs (Allen 2010; pp. 81–83).
However the thymos is not immortal like the jb, but is closely associated with
breath, departing the body at the time of the last exhalation from the lungs at death.
Thus although the thymos is not immortal it does escape the body at death, carrying
away the personal psychological powers of a particular individual, but only outlasting
separation from the body for a short unspecified time.
Homer then restrained himself from following the Ancient Egyptians with their
immortal ba and ka, Nevertheless there is still a striking similarity between the
Ancient Egyptian notion of the soul and that of Homer (Bernal 1987).
A third part of the living soul in Homer is the menos, which is related to martial
rage but not to any particular organ of the body and is also lost at death (Bremmer
1983; p. 54).
(p. 198) Now the shade composing the psyche is displaced by the soul,
carrying the individuals intentions and emotional capacities.
The first writer to feature this new concept of the soul, that is of the psyche
bearing personal psychological activities, their intentions and emotional capacities,
into the afterlife, is Heraclitus (540 BC to 475 BC), although it is possible that
Anaximines (about 525 BC) also wrote in this way at about this time. It is Heraclitus
who first calls the soul of living man the psyche and suggests that man consists of
body and soul and that the psyche is a “ thinking thing” (Snell 1953; p. 16).
Heraclitus says that “the human will and the ethical disposition of man are signs
of the state of the soul that animates him”. He claims that ‘you could not find
the ends of the soul that you travelled every way, so deep is its logos’ (Claus 1981;
p. 126).
With Heraclitus the psyche takes on a highly personalized form that leads him to
discuss the psychological value of the psyche. Intelligence and the emotional life
now depend on the psyche (Claus 1981; p. 138).
This reference to the profundity of the soul, involving a dimension that cannot be
applied to a physical organ or its function, indicates a link to the Archaic lyric poets
before Heraclitus (Snell 1953; p. 17).
The lyric poets were the first to suggest that intellectual and spiritual matters
could have ‘depth’, for they refer to ‘deep pondering’ and to ‘deep pain’ and to
‘deep thinking’. The thymos takes on quite personal traits, for example the lyric poet
Archilochus says that his thymos ‘ is stirred after suffering’.
It is then to the lyric poets of the Archaic period that one must turn to find the
transition of the personal psychological properties of the thymos to the immortal
psyche. But of course the lyric poets could draw on elements of Egyptian thought in
which the living and immortal soul certainly had personal psychological attributes,
being composed of the ba (being everything that makes a person an individual,
including their personality). Scholars believe that Plato’s claim that Pythagoras is
responsible for this conceptual shift of the psychological identity of a human from
the thymos to an immortal psyche or soul is simply a device that Plato uses for the
purpose of his own dialogues and is not based on historical fact. Plato’s description
in his Georgias of the Pythagorean psyche as possessing personal psychological
attributes is given without any documentary evidence (Claus 1981).
Pythagoras seems to have been a Shaman who believed in the form of what
is called metapsychosis or reincarnation in which psyche, devoid of any per-
sonal attributes, wanders aimlessly through the bodies of animals and humans.
Although on some occasions Pythagoras attributed a somewhat richer existence to
Notes 205
the psyche after death this was simply to allow that psyche to punish a living person
who had committed a grave offence. Scholars suggest that the transition of the con-
cept of the psyche or shade that survives death in Hades to that of the psyche
spoken of as possessing the psychological capacities previously associated with the
thymos in the chest, might be attributed to Alcmaeon of Croton (450 BC to 500 BC).
Alcmaeon in his “Concerning Nature” identifies the ‘passages’ leading from the
eyes to the brain, that is the optic nerve. This probably led Alcmaeon to the idea that
the brain is the organ required for perception as in sight, sound and smell, and there-
fore that the brain is the seat of thought (Onians 1954; p. 115).
In this way, it is surmised, there is a shift away from the conceptual scheme
in which the immortal psyche or soul is located in the head and does not possess
psychological powers although it persists after death in Hades as a visible but
impalpable semblance of a once living being, that is a shade, like in a dream. In
this scheme the psyche and thymos, with its rich emotional and other psycho-
logical attributes, leave the body at death with the thymos then being destroyed.
The new post-Archaic scheme is one in which these attributes reside with the
psyche and hence with a soul that can be identified with the individual and sur-
vives death.
(p. 198) Plato, following the notion of the soul attributed to the lyric
poets, considered it to be composed of parts.
Plato gives the first psychological description of the soul in his dialogues named
the Charmides and the Gorgias as well as touching on related issues in the Phaedrus,
Republic and the Timaeus (Claus 1981; p. 183).
For Plato the soul comprised three parts, in much the same way as that envisaged
during the late Archaic period: the thymos (the ego soul concerned with the emo-
tions and the will; associated with the organs of the chest, including the heart);
the nous or logos (concerned with reason; associated with the head) and the id or
pathos (concerned with the appetites; associated with the liver).
Clearly there are close parallels between Plato’s ideas of the thymos, nous and id
on the one hand and the Egyptian notions of the jb, ba and ka on the other, as set out
in Table 10.1.
(p. 198) …‘all parts of the soul make up the immortal psyche’.
Plato in his dialogues puts into the mouth of Pythagoras his ideas concerning
the continued existence of a person after death. Here the term ‘psyche’ or ‘soul’
is used to denote the person that continues to exist after death (Claus 1981 ;
pp. 111–120).
(p. 198) The psychological, cognitive and emotional activities that have been
attributed to a particular person had now to be attributed to their soul.
By the end of the fifth century BC Antiphon has a defendant say that he is sure
of his innocence ‘for though his body may surrender, his soul saves him by its
willingness to struggle, through knowledge of its innocence’. Souls become the
bearers of moral qualities. Euripides now has Ajax saying, before he commits
suicide that ‘nothing binds the soul of man more than dishonour’.
Table 10.1 Comparison of conceptual schemes concerning spirit, soul and mind
206
Siberia Ancient Egypt Mesopotamia Greece, Homer Greece, Plato Greece, Aristotle Europe, Descartes
(4000–2400 BC) (2650–1700 BC) (1650 BC) (800–400 BC) (428–348 BC) (384–322 BC) (1596–1650)
spirita (head) I sheut b I etemmua,c I psychea (head) I psyched I
{shadows, {shadows} {shadows in {shadows in {name of thymos, nous
dreams} the Hades} or logos and id
Abyss} collectively}
jbe (heart) M thymos (heart) M thymos (heart) I sensitivef (heart) NA
[intentions, [emotions, [emotions, will] [desires, movement,
will & emotions] intentions] sensory perception]
bae (head) I nous g M nous (head) rational f NA mind h (head) I
[individuality] [reasoning] I = mind [reasoning] [reasoning]; consciousness
[reasoning] [aware of everything
within e.g. sensations,
willing]
kae,i I id (liver) I nutritivef NA
[life force requiring [appetites] [nutrition, growth
nutriment] & reproduction]
Notes Key
The parenthesize ( ) indicate the organ in which the particular component of spirit, soul or mind resides. The parenthesize [ ] indicate the functions of that
component
I immortal, M mortal, NA not applicable
a
While these are all spirits related to the person who has died they do not carry any psychological attributes particular to the deceased
b
The sheut or shadow, was taken by the Ancient Egyptian’s to depend on the person whose shadow it is, and that a person could not exist without a shadow. The
sheut may not be immortal
c
The theology of the Mesopotamians at this time, according to the great Atrahasîs poem of 1646 BC in Akkadian, is as follows: a human being, a awîlu, is
formed out of clay which is imbued with the spirit têmu of a minor deity, We. At death the spirit, named etemmu, leaves the body and joins the shadows of the
dead in the underground abyss
d
Plato gave the psyche of Homer psychological attributes that are particular to a person as it now includes the immortal thymos, logos and id. Plato’s scheme is
similar to that of the Ancient Egyptians
10 The Mind, Mental Illness and the Stream of Consciousness
e
At death the heart (jb) is measured to see if one has acted with good intentions and if so the ba is presented to the god Osiris so that the ba may go through the
cycle of rejoining the ka each evening and so recover the power of new life on awakening the next day as akh, able to join the living. This is symbolized by a
Notes
bird with a human head that can move about the community and return each evening to the mummified body at which place during the evening the ba can once
more receive the life force of the ka )
f
Most importantly, the three different kinds of soul here are not incorporeal substances but powers or capacities. Here Aristotle departs from all the other con-
ceptual schemes given in this Table and provides, amongst other things, a solution to the problem of how an incorporeal substance can interact with the corpo-
real body
g
Homer also specifies that the living soul possesses a menos, responsible for martial rage
h
Descartes scheme is based on that of Plato, and in turn that of Homer and the Ancient Egyptians. First he places the nutritive functions (id) with the body only,
as he does most of the thymos (emotions) but retains the immortal nous (mind) in the head. This he elevates to not only being responsible for reasoning, as it
has been for thousands of years, but for an awareness of everything within us. The mind does not then just include rationality, intellect, but also
consciousness
i
The Ancient Egyptian scheme also included ren, which is the name of an individual or object considered to be an essential part of them
207
(p. 198) Plato institutes a train of reasoning in which the soul is taken to be
something that can engage in activities like thinking and planning.
The central problem with this conception, as Aristotle was first to point out, is
how could interaction occur between these two very different kinds of substances,
that of an incorporeal soul and that of a corporeal body?
(p. 198) This concept followed in the tradition of Plato’s pupil, Aristotle.
Unlike Plato, who considered that the soul was composed of three parts, Aristotle
distinguished three different kinds of soul.
First, a rational soul which conferred powers of thought (reasoning) and is unique
to humans, a distinction like that of the Ancient Egyptian ba and of the nous in the
Archaic period and accepted by Plato as one of his three parts of the soul (see
Table 10.1); now however this component of the soul is a power or capacity and not
a thinking incorporeal substance.
Second, a sensitive soul which confers powers of perception, locomotion and
desires, possessed by all animals; like that of the Egyptian jb and of the thymos of
the Archaic period and one of the three parts of the Platonic soul but claimed by
Aristotle to be associated with the heart as is the jb (see Table 10.1); again a power
or capacity and not an incorporeal perceiving and desiring substance.
Finally, a nutritive soul conferring powers of growth, nutrition and reproduction,
possessed by all living things, that is both flora and fauna like the Egyptian ka and
like the id component in Plato’s conception of the soul except that again Aristotle
considers this is a power or capacity and not an incorporeal substance (see Table 10.1;
Hicks 1907; pp. 23–26).
The Aristotelian soul was then an array of powers and capacities and therefore
not a substance at all, be it a shade or other ghost-like substance. Hence the problem
did not arise as to the form of interaction between two very different kinds of
substances, namely that of the incorporeal soul and that of the corporeal body
(Hicks 1907; pp. 6–7, see also Bennett and Hacker 2002; pp. 1–4).
(p. 198) For Aristotle the word ‘mind’ is a manner of speaking, a façon de
parler, about the capacities for intellect, thought, and reasoning.
Mind is then related to the powers of perception, memory and emotion, which
may or may not be exercised by human beings and, depending on the power concerned,
by other animals (Bennett and Hacker 2003; pp. 12–6).
(p. 199) This is to treat the mind as identical to what William James called
the ‘stream of consciousness’: (James 1890; Chapter IX).
(p. 200) Consciousness was now immortal, identified with the person, and
received sensations or acted on the world through a body that was an elaborate
physiological mechanism.
This left Descartes, and those dominated by his way of thinking, which is to say
most of humanity, with the criticism first made of Plato by Aristotle. Plato had an
immortal soul (with the three parts related to reason, emotion and the appetites)
interacting with a material body, Descartes now shifted the problem to that of an
immortal soul, identified with the mind or consciousness, in fact with feeling,
perceiving, imagining, cogitating and willing, interacting with a material body.
But of course all of this is open to Aristotle’s criticism: how can an immaterial
substance, here the mind or consciousness, act on the material body?
References 209
References
Allen JP (2010) Middle Egyptian: an introduction to the language and culture of hieroglyphs.
Cambridge University Press, Cambridge
Bennett MR, Hacker PMS (2002) The motor system in neuroscience: a history and analysis of
conceptual developments. Prog Neurobiol 67:1–52
Bennett MR, Hacker PMS (2003) Philosophical foundations of neuroscience. Blackwell, Oxford
Bernal M (1987) Black Athena: the Afroasiatic roots of classical civilization. Rutgers University
Press, New Brunswick
Bottéro J (2001) Religion in ancient Mesopotamia. University of Chicago Press, Chicago
Bremmer J (1983) The early Greek concept of the soul. Princeton University Press, Princeton
Claus DB (1981) Toward the soul: an inquiry into the meaning of psyche before Plato. Yale
University Press, New Haven
Frazer JG (1890) The golden bough: a study in comparative religion. Macmillan, London
Hicks RD (ed) (1907) De anima/Aristotle. Cambridge University Press, Cambridge
James W (1890) The principles of psychology. Macmillan, London
Onians RB (1954) The origins of European thought. Cambridge University Press, Cambridge
Snell B (1953) The discovery of the mind. Harper & Row, New York
Index
A Attention, 86, 88, 166–169, 173, 175,

Abuse 179–184, 186
childhood, ix, x, 38, 41–45, 53, 54, 58, 69, Auditory cortex, 171–174, 177, 180, 182,
72, 77, 145–147, 149, 150, 152, 156, 185, 186
158, 159 Awareness, 35, 88, 167–170, 172–175,
physical, 41, 43, 80, 146, 147, 155, 157 181–186, 201, 207
sexual, ix, x, 3–8, 23, 24, 26, 29, 31, 42, Axons, 12, 20, 34, 35, 45, 48, 109, 114, 120,
52, 53, 78, 147–149, 153, 155–157 123, 135
Adrenal cortex, 54, 68, 72
Adrenocorticotropic hormone (ACTH), 38,
69, 81 B
Aggressive behaviour, 148, 156 Beard, George, 10–12
Alcohol dependence, 52, 154 Bipolar disorder
Alzheimer, Alois, 13 mania, 150, 177
Alzheimer’s disease, 13 manic-depression, 21, 23
Amphetamine, effect of, 90 Borderline personality disorder, 41, 52, 53, 80,
Amygdala, 36, 67, 107, 133 81, 147, 154, 155
Amyloid, 12, 13 Brain-derived neurotrophic factor (BDNF), 51,
Anterior cingulate cortex (ACC) 75, 149, 150
rostral anterior cingulate cortex (rACC), receptor, TrkB, 77–79
37, 48, 51, 79, 81, 108, 134, 141 Broca, Paul, 12, 21
subgenual anterior cingulate cortex (sgACC),
48, 67, 70, 82, 84, 108, 140, 141
Anxiety C
abuse leads to, 153, 156 Cade, John, 16, 47
cognitive behavioral therapy for, 148, 157 Capillaries, 109, 110, 114
cortical imaging in, 49 Caudate, 69, 70, 82–86, 90, 96, 134, 180
epigenetic contribution to, 79 Charcot, Jean-Martin, 10, 12, 13
Freud’s understanding of, 26 Child centred therapy (CCT), 148–149, 156
glucocorticoid receptors involved in, 73 Clinico-pathological approach, 12–14
neuroses related to, 21 Clozapine, 94–96
depression following, 35, 40 Cocaine, effect of, 43, 90
stress induced, 54 Cognitive behavioural therapy (CBT), 44, 49,
Virginia Woolf’s experience of, 39, 42, 45 148, 156, 157
Aripiprazole, 95 Conduct disorder, 52, 153, 154
Aristotle, x, 16, 32, 195, 198, 199, 206–208 Consciousness, stream of consciousness,
Astrocytes, 109–115, 118–124, 139 x, 193–208
M. Bennett, Virginia Woolf and Neuropsychiatry, DOI 10.1007/978-94-007-5748-6, 211

212 Index
Corollary discharge, 185 F

Corpus callosum, 48, 134 Fear, 11, 31, 35, 36, 40, 47–49, 157, 201
Corticotropin releasing factor (CRF), 68–73, behavioral therapy in, 157
81, 152 early conditioning of, 55
Corticotropin releasing hormone (CRH), 38, gray matter loss in, 36, 49
42, 54, 68 neural networks involved, 40, 47, 135
Cortisol, 55–58, 68, 69, 71, 72, 79, 81 neurasthenia associated with, 11
Cortisosterone, 47, 49, 55, 71–73, 75, stress associated with, 35
78, 151 Fluoxetine, Prozac, 49, 133, 150
Craig, Maurice, ix, 9–11, 16, 28 Freud, Sigmund, ix–xi
Cruveilhier, Jean, 12 childhood sexual abuse frequency in, 23
Cyclic AMP response element-binding protein depression interpretations in, 23
(CBP), 58, 76, 77 co-discovery of the neuron by 19, 20
Egyptian religion and the soul interest of,
195–196
D id, ego and superego concepts of, 24–26
Dendrites, 33, 78, 109, 137, 157 Kraepelin’s concepts in contrast to those
Dentate gyrus (DG), 71, 112, 118 of, 21–23
Depression neural networks of the brain developed by,
abuse involved in, 9, 52–55, 69, 153 21–22
cortical function in, 40, 43–44, 48, neurology to psychiatry transition by, 19
67–68 Virginia Woolf consults, 25, 28, 44
cortical imaging in, 47–48, 50, Virginia Woolf publishes the work of, 1, 27
78–79 Frontal lobe, 157
epigenetics in, 75, 150–151, 158 Functional magnetic resonance imaging,
Freud’s conception of, 23, 26 fMRI, 47–50, 67, 107, 135–137,
glucocorticoid action in, 44, 56–57, 170–172, 174, 176–180, 183, 184
71, 73
Kraepelin’s conception of, 15, 23
Neurasthenia and, 11–12 G
older person’s experience of, 85 Galen of Pergamon, 32
Virginia Woolf’s experience of, 4, 7–8, 26, Gamma-amino-butyric acid (GABA), 71, 88,
29, 31, 39, 42 89, 92, 93, 138, 149, 150, 159
Descartes, René, x, 13, 14, 16, 197, 200, 201, Glia, 78, 117, 118, 120–121, 123
206, 207 Glucocorticoids (GC)
Dexamethasone, 56, 69, 72, 81 receptor type I, GRI, 71, 73
Dopamine receptor type II, GRII, 55, 57, 69,
D1-type dopamine receptor, D1, 87, 89, 74–77
90, 92–94 Glutamate, 88–92, 95, 149, 158
D2-type dopamine receptor, D2, 87–90, Glutamate receptor, 79, 90–93
92–95 Goal-directed
D4-type dopamine receptor, D4, 92 behaviour, 69, 82–86
Duckworth, George, 3, 26, 31, 41, 44 networks, 81
Duckworth, Gerald, 25–27, 31, 42–44
H
E Habit-learning, 69, 85–86
Ego, 24–29, 203, 205 Hallucinations
Egyptian spirituality, ancient, 195, 196, auditory, 176–177
201–208 Claude-Bonnet type, 175–176
Epigenetics, 43, 57, 73–74, 77–78 deafferentation origins of, 178
Extracellular-signal-regulated kinase (ERK), Virginia Woolf’s experiencing, 165
90, 94, 137 visual, 165, 175–176
Index 213
Head, Henry, 9, 10 Mismatch negativity (MMN), 174–175, 178,

Heraclitus, 204 185, 186
Heschl’s nucleus, 172 Multiple sclerosis, 12, 14
Hippocampus, 38, 48, 49, 51, 55–58,
68–71, 73–80, 82, 107, 108, 110,
113, 116, 117–119, 121–122, 124, N
135, 136, 139, 141, 147, 150, Nerve growth factor-inducible A (NGF1A),
151, 157 58, 69, 76
Histones, 56–58, 74, 75 Neurasthenia
Hypothalamic–pituitary–adrenal (HPA) axis, definition of, 9–10
67, 68, 72, 73, 79, 81 nosology of, 12
Hypothalamus, 42, 54, 56, 68, 70–80, 151 Virginia Woolf’s diagnosis, 10–11, 16, 28
Hyslop, T.B., 9 Neurofibrillary tangles, 13
Neuron
doctrine, 21
I pyramidal, 46, 47, 49, 71, 78, 88, 89,
Id, 24–27, 29, 205, 206 92–94, 108, 109, 118, 137–140
Illusions soma, 109, 112
auditory, 172–174 Neuropil, 69, 78, 85, 109, 122, 139
visual, 169, 176 N-methyl-D-aspartate (NMDA) receptor,
Impulsive behaviour, 53, 154 79, 85, 87, 88, 90, 91, 93, 133,
137–138, 140
J
Jackson, Julia, 5 O
James, William, x, 29, 107, 135, 193, 199, Obsessive compulsive disorder, 11, 21, 86
200, 206 Olanzapine, 95, 158
Oligodendrocyte, 46, 109–115, 117, 120–124
Orbitofrontal cortex (OFC), 50, 51, 57, 70, 78,
K 82–87, 107, 108, 112, 117, 118, 121,
Kraeplin, Emil, 10, 14–16, 21–23 124, 134–136
L P
Lithium, 16, 36, 47, 50, 51, 158 Pallidum, 82, 88, 90, 94
Long-term depression (LTD), 90 Parietal lobe, 176, 180
Long-term potentiation (LTP), 71, 90 Perception, 21, 24, 167–169, 171, 172, 174,
176–178, 185, 193, 200, 205, 206
Pinel, Phillippe, 14
M Pituitary cortex, 68, 72
Magnetic resonance imaging (MRI), 39, 40, Plato, x, 16, 195, 197–201, 204–208
47–51, 86, 96, 107, 108, 116, 121–123, Positron emission tomography (PET), 47, 50,
135, 147, 152, 157, 170 107, 136, 177
Maternal care, childhood neglect, 69, 73, Post-traumatic stress disorder (PTSD), 152
79, 159 Prefrontal cortex (PFC)
Microglia, 114, 120 dorsolateral, dlPFC, 34, 67, 69, 82, 84–86,
Mind, 206 107, 108, 134, 136, 137, 173, 181–186
and mental illness, 3, 12, 16, 193 dorsomedial, dmPFC, 67, 108, 134, 139
Aristotle’s conception of, 16, 208 medial, 46, 47, 49, 51, 57, 87, 90, 92–95,
Cartesian conception of, 14, 200, 208 107, 135, 136
Plato’s conception of, 199 ventrolateral, vlPFC, 34, 67
Virginia Woolf’s conception of, 193, ventromedial, vmPFC, 51, 57, 82, 87,
195,198–199, 201 108, 134
214 Index
Prefrontal-limbic network (PLN), 67–96, 107, prevention, 149

108, 124, 133 psychiatric disorders leading to, 155–156
Putamen, 69, 82–86, 90, 180 rates of, 145, 152–153
Pythagoras, 204, 205 Virginia Woolf and Freud’s interpretations
of, 26, 28
Virginia Woolf’s thoughts on, 7–8, 39
R Superego, 24–26
Ramon y Cajal, Santiago, 13, 19 Supplementary motor area (SMA), 84–86
Raphe nucleus, 87, 93–96, 137, 138, 140 Synapses
regression, 78–79, 115–116, 119–120, 133,
171, 172
S synaptic bulbs, 110, 114
Savage, George, 9, 10 synaptic spines, 46, 51, 69, 78, 79, 85,
Schizophrenia 88–90, 94, 110, 111, 114, 116, 117,
dementia praecox, 21 118, 137, 139–141
depressive symptoms, 70, 88, 96 synaptic transmissions, 34
negative symptoms, 87, 91, 92
positive symptoms, 70, 88, 89
Selective serotonin reuptake inhibitors T
(SSRIs), 137, 140, 141 Temporal cortex
Serotonin (5-HT), 76, 93, 138 superior temporal gyrus (STG), 147,
receptors, 69, 85, 86, 133 172–177, 182
Shamanism, 195, 201 superior temporal sulcus, 172–174, 176
Soul, 5, 14, 193 Thalamus, 70, 73, 82, 83, 87, 88, 94, 136
Spirit, xi, 193–196, 198, 201, 202, 204 Trauma
Stephens, James, 29 cognitive behavioural therapy treatments
Stephens, Julia, 3 of, 148–149, 156–157
Stephens, Leslie, 6, 29 epidemiology in relation to, 80
Stephens, Thoby, 3 Freud’s interpretations of the consequences
Stress, 3, 9, 35, 69, 115–116, 139, 145 of, 23
children experiencing, 53–54, 156–157 post-traumatic stress disorders and, 47–48,
child-centred therapy for, 149 155–157
cortisol involved in 53, 58, 69 suicide following, 41, 147
epigenetics of, 75–76, 78–79, 150–151, Virginia Woolf’s experience of, 44
158, 160
glucocorticoids involved in, 38, 57, 71–73
gray matter changes related to, 36, 46, V
49–50, 116, 147 Valpronic acid, Divalproex, 150
post-traumatic stress disorders and, 147, Vasopressin, 151, 159
155–156 Virchow, Rudolf, 12
depression related to, 45 Voyage Out, 3, 4
synapse loss (regression) and, 46–47,
115–118
Virginia Woolf’s experience of, 3–4, 9, 31, W
35, 39, 42–43 Weir Mitchell treatment, 10, 11
Substance abuse disorder, 156 Willis, Thomas, 32
Suicide Wittgenstein, Ludwig, 198, 199
abuse leading to, 41, 43, 52, 69, 81, 153 Woolf, Leonard, 4, 6, 8–11, 28,
brain derived neurotrophic factor changes 35, 165
in, 51 Woolf, Virginia, 3–10, 16, 23, 25–29, 35, 36,
epigenetic changes related to, 38, 44, 69, 39–40, 165, 186, 198–199
77, 79, 146, 151, 158–159 Wren, Christopher, 32
familial transmission involved in, 53, 146 Wright, Maurice, 9, 10

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Virginia Woolf and Neuropsychiatry

ISBN 978-94-007-5747-9 ISBN 978-94-007-5748-6 (eBook)

Library of Congress Control Number: 2012954281

© Springer Science+Business Media Dordrecht 2013

Printed on acid-free paper

Springer is part of Springer Science+Business Media (www.springer.com)

Brain and Mind Research Institute M.R. Bennett

1 Sexual Abuse, Literary Genius and a Mind Gone Awry ..................... 3

Part II Neuropsychiatry and Suicide

5 Brain Networks, Hormones and Genes

Basal Ganglia Modulation of PLN....................................................... 69

Changes in Synaptic Connections of the Anterior Cingulate

Visual and Auditory Illusions ................................................................... 169

Part III On Mental Illness

Index ................................................................................................................. 211

Nowhere do we have a more detailed and powerfully moving record of repeated

M. Bennett, Virginia Woolf and Neuropsychiatry, DOI 10.1007/978-94-007-5748-6_1, 3

Fig. 1.1 Portrait of Virginia

Fig. 1.2 Portrait of Julia

Virginia writes further:

She sometimes pictures herself as the neurotic writer:

And in a diary entry in 1928 she comments:

as I thought – not to be a burden on my husband – the conventional accusation of cowardice

She goes on in relation to thoughts on suicide that:

Signs of ‘serious mental disturbances’ were identified by Leonard Woolf at

M. Bennett, Virginia Woolf and Neuropsychiatry, DOI 10.1007/978-94-007-5748-6_2, 9

And again in 1921 the process is repeated:

came to be considered a not prominent form of psychoneuroses. So neurasthenia,

1861), it is Charcot that established the clinico-pathological approach as a powerful

(i.e. impairment in one or more important areas of functioning) or with a significantly

So the psychological powers of memory, thinking, perceiving, feeling etc., which

He is therefore recognized today as the originator of pharmacogenomics, of both

Sigmund Freud, a founding father of twentieth century psychiatry, was born in

M. Bennett, Virginia Woolf and Neuropsychiatry, DOI 10.1007/978-94-007-5748-6_3, 19

Fig. 3.1 Portrait of Sigmund

repression might work, reproduced in Fig. 3.4b. A particular perception or sensation,

schizophrenia, and the normal functioning of these mechanisms in the general

oedipal repressions. But this interpretation is not supported by Virginia’s comments

So Freudian analysis is seen here as having a liberating effect on the literary

abused as a child. The interaction between these two is considered in Chap. 8.

(p. 19) ‘A Psychology for Neurologists’.

Freud S (1911) Psychoanalytic notes on an autobiographical account of a case of paranoia. Hogarth

M. Bennett, Virginia Woolf and Neuropsychiatry, DOI 10.1007/978-94-007-5748-6_4, 31

Fig. 4.3 (a) Functional

Stress is often followed by anxiety, by excessive worry about an apprehensive

Major depression, precipitated by anxiety, is characterized by excessive guilt, deep

Childhood Abuse: Stress, Depression and Suicide

short allele of the serotonin synaptic transmitter pump promoter polymorphism

If subjects were asked to intentionally mimic an emotional expression, such as

presentations the patients underwent functional magnetic resonance imaging to

availability of neurotrophic factors that also impact on the integrity of synapses

not experienced stressful circumstances as children (Rosenblum and Andrews 1994;

Introduction: The Prefrontal–Limbic Network (PLN)

M. Bennett, Virginia Woolf and Neuropsychiatry, DOI 10.1007/978-94-007-5748-6_5, 67

Hypothalamic-Pituitary–Adrenal (HPA) Axis Modulation

Basal Ganglia Modulation of PLN

orbitofrontal cortex, the subgenual anterior cingulate cortex, the ventromedial

Midbrain Modulation of PLN

Modulation of the PLN by the Hypothalamus in Depression

Glucocorticoid Modulation of the PLN

parvocellular paraventricular nucleus (mpPVN) that exert an inhibitory influence on

Interaction Between the PLN and Glucocorticoids

The Role of Glucocorticoid Receptors in Determining the Basal Level