Cerebellum, Psychiatry & Routine Disorders

Dr Khalid Mansour Locum Consultant Psychiatrist Northgate Hospital

Cerebellum and Psychiatric Disorders: Introduction

Traditionally: cerebellum > posture, balance,

motor control (Flourens, 1824). Recently: cerebellum > perceptions, emotions, cognition, speech & personality
(Chung et al, 2010; Konarski et al, 2005; Roskies et al, 2001; Schmahmann, 1991; schmahmann and Sherman, 1989; Papez, 1937)

Cerebellar abnormalities have been found of

most of the major psychiatric disorders

(Hoppenbrouwers et al, 2008)

Cerebellum > automation of brain

performances like a computer (Eccles, 1973): software programmer of the brain. Some clinical implications

Contents:
1. Cerebellar Anatomy, Histology &

Physiology 2. Cerebellar Abnormalities in Psychiatric Disorders. 3. Psychiatric Aspects of Cerebellar Disorders. 4. Clinical applications > Routines
Disorders

Cerebellar Anatomy, histology & Physiology

Cerebellar Anatomy

Structural Anatomy Functional Anatomy Deep Cerebellar Nuclei

Cerebellar Histology and Physiology

Cerebellar Cortex Mossy Fibers & Granule Cells Climbing Fibers & Purkinje Cells Compartmentalization

Cerebellum Anatomy

Cerebellar Anatomy
Structural anatomy: Cortex and White matter Cortex (Gross Anatomy):

Anterior lobe (3 lobules), Posterior lobe (6 lobules) & Flocculonodular lobe (2 lobules).

White matter: Nerve fibre tracts Deep nuclei Dentate, Interposed (Globose & Emboliform) Fastigial nuclei.

Cerebellar Anatomy
Functional Anatomy: Vestibulocerebellum (flocculonodular lobe). Spinocerebellum (vermis & paravermis). Cerebrocerebellum (lateral cerebellar
hemispheres).

Deep Cerebellar Nuclei

They receive inhibitory final output from the

cerebellar cortex (Purkinje calls).

They also receive afferent projections from

excitatory inputs from

Mossy fibers
Climbing fibers

provide feedback control of the cerebellar

cortex.

Deep Nuclei

Cerebellum Anatomy

Cerebellar Cortex:
Three layers:

Bottom thick granular layer, densely packed with Granule cells and Golgi cells. Middle Purkinje layer Top molecular layer, Dendrite trees of Purkinje cells, Parallel Fibers Stellate cells and Basket cells

Micrograph of the cerebellar cortex showing its three layers (molecular layer, Purkinje cells layer and granule cell layer) and its meningeal coverings (pia mater and arachnoid mater). H&E stain.

Mossy Fibers & Granule Cells

Mossy Fibers arise from brainstem

spinal cord and cerebrum (about 200 million in humans) > A single mossy fiber makes contact with an estimated 400600 granule cells. Granule cells> Parallel Fiber. A Parallel fiber > 80100 synaptic connections with Purkinje cell dendritic spines.

Climbing Fibers
Spinal cord, brainstem, and cerebral cortex >

Inferior Olivary nucleus > Climbing fibers > deep cerebellar nuclei and Purkinje cell. A single climbing fibre > 3000 contacts with 10 different Purkinje cell > Axons travel into deep cerebellar nuclei (1000 contacts each).

Purkinje Cells (Plasticity)

(Mial et al, 1998; Ohtsuki et al, 2009 )

Purkinje cells normally emit action potentials at a

high rate even in the absence of synaptic input:

Simple spike > single action potential followed by a refractory period of about 10 msec Complex spike > stereotyped sequence of action potentials with very short inter-spike intervals and declining amplitudes Parallel fiber-Purkinje cell synapse can undergo longterm depression (LTD) in response to the coincident firing of both parallel and climbing fibers1. Repetitive firing of parallel fibers alone can induce long-term potentiation (LTP) at the same synapses. in controlling this balance.

Compartmentalization
Each body part maps to specific points in

the cerebellum. Cerebellar cortex is compartmentalized into zones and microzones. A Microzones were found to contain on the order of 1000 Purkinje cells. Cellular interactions within a microzone are much stronger than interactions between different microzones.

Schematic Illustration of The Structure of Zones and Microzones in The

Cerebellar Cortex (Apps & Garwicz, 2005).

Cerebellar Learning
1. Marr & Albus model

2. Modern Views

Cerebellar Functional Organisation

Cerebellum functional structures are largely

suitable for regulating brain processes (Katz & Steinmetz, 2002; Ito, 2008)

10% of the weight of the brain 4 times number of neurones in the cerebral cortex. 50% of brain neurones Fewer types of neurones Different systems of interconnections

Marr & Albus Model for Cerebellar learning

Most theories that assign learning to the

circuitry of the cerebellum are derived from early ideas of David Marr (1969) and James Albus (1971). Albus (1971) formulated his model as a software algorithm he called a CMAC (Cerebellar Model Articulation Controller), which has been tested in a number of applications.

Marr & Albus model for Cerebellar learning

Eccles, Ito & Szentagothai (1967);

Feedforward processing: signals move

unidirectionally through the system from input to output, with very little recurrent internal transmission > a quick and clear response. Divergence and convergence: In the human cerebellum, information from 200 million Mossy fibers inputs is expanded to 40 billion granule cells, whose parallel fibers outputs then converge onto 15 million Purkinji cells. Modularity: The cerebellar system is functionally divided into more or less independent modules. Plasticity: The synapses between parallel fibers and Purkinje cells, and the synapses between mossy fibers and deep nuclear cells, are both susceptible to modification of strength LTP and LTD.

Model of Cerebellar Perceptron, James Albus 1971

Model of Cerebellar functioning; James Albus, 1971

Cerebellar Learning:
? Software programmer
Cerebellar dysfunction > continue to be able

to generate motor activity, but uncoordinated. Boydon (2004): Cerebellum is involved in motor learning to make fine adjustments to the way an action is performed. Kenji Doya (2000): function of the cerebellum is best understood as neural computation. Ito (2005): A modulator role of motor and non-motor functions: matches intentions with actual performance.

(3) Cerebellar Abnormalities in Psychiatric Disorders (Hoppenbrouwers et al, 2008)

A- Psychological Studies of Normal Individuals with Reduced Cerebellar Volume B- Cerebellar Abnormalities in Schizophrenia: C- Cerebellar Abnormalities in Autism: D- Cerebellar Abnormalities in other psychiatric disorders:

Cerebellar Studies in Psychiatric Disorders: General Observations

The most common studies but not the most

evident. Significant number of studies have positive findings. Findings are not always consistent and conclusions are debatable. Cerebellar abnormalities can also be secondary / compensatory pathology e.g. increased dopamine in schizophrenia cause both psychosis and cerebellar pathology. Best studied; autism and schizophrenia.

A - Psychological Studies of Normal Individuals with Reduced Cerebellar Volume

Normal individuals with reduced cerebellar

volume > higher scores on scales of anxiety, type A personality, phobia, tenderness and hostility (Chung et al, 2010):

B- Cerebellar Abnormalities in Schizophrenia: General

Large part of imaging studies

(Varnas et al, 2007)

support

cerebellar malformation in schiz.

Smaller cerebellar volume (Bottmer et al, 2005) Reduced blood flow on PET scan (Andreasen et al, 1996). Reduced level of N-acetylaspartate (marker of neurone density and viability) in vermis and cerebellar cortex in Magnetic Resonance Spectroscopy Imaging (MRSI) studies (Ende et al, 2005). Volume reduction in the cerebello-thalamic-cortical network (Rusch et al, 2007). Neuronal disorganisation in the superior peduncle on Diffusion Tensor Imaging (DTI) studies (Okugawa et al,
2006).

B- Cerebellar Abnormalities in Schizophrenia: Specific Symptoms

(Picard et al, 2008) Hallucinations

Shergill et al, 2003; Neckelman et al, 2006 Formal Thought Disorder Kircher et al, 2001; Levitt et al, 1999 Affect disorder in schiz Stip et al, 2005; Paradiso et al, 2003; Abel et al, 2003 Cognitive function in schiz Szesko et al 2003; Toulopoulou et al 2004 Attention Eyler et al, 2004; Honey et al, 2005; Aasen et al, 2005 Language Shergill et al, 2003; Boksman et al 2005; Kircher et al 2005 Memory (all types) Mendrek et al, 2005; Whyte et al 2006

B- Cerebellar Abnormalities in Schizophrenia: Clinical Studies

Increased prevalence of motor impairment in

schizophrenic patients even drug nave ones, could suggest possible cerebellar abnormalities (Hoppenbrouwers et al, 2008; Varambally et al,
2006).

However, these motor abnormalities could be

secondary to schizophrenia e.g. increased dopaminergic activities affect the cerebellar functioning or morphology (Mittleman et al, 2008).

B- Cerebellar Abnormalities in Schizophrenia: Cognitive Dysmetria Theory: (Andreasen et al, 1998)

A dysfunctional Cortico-cerebellar-thalamo-

cortical circuit > poor mental coordination (cognitive dysmetria) > Schizophrenia. Some disagreed e.g. Kaprinis et al, 2002: split between positive & negative symptoms > different psychopathologies. Others support the theory e.g. Schmahman, 2004 & Honey et al, 2005: Dysmetria also affect affective and motivational aspects of brain functioning.

C- Cerebellar Abnormalities in Autism

One of the most consistent abnormalities

found in ASD are cerebellar degenerative changes, especially Reduced Purkinji cells, especially in vermal lobules I & II (DiCicco-Bloom
et al, 2006).

Theory: cerebellar malfunction > loss of modulatory control of frontal cortex > ASD,
(catani et al, 2008).

D- Cerebellar Abnormalities in Psychiatric Disorders: Others

Bipolar Affective Disorder: e.g. reduced Cerebellar /

Vermis volume (Glaser et al, 2006) Anxiety: e.g. cerebellar-vestibular dysfunction (Levinson,
1989)

Depression: e.g. reduced posterior cerebellar

activities (Fitzgerald et al, 2009) ADHD: e.g. reduced Cerebellar volume (Glaser et al, 2006) Post Traumatic Stress Disorder: e.g. altered function of the vermis (Anderson et al, 2002) Alcohol abuse: e.g. induced reduction in Cerebellar / Vermis volume (Glaser et al, 2006) Gender differences: (Dean & McCarthy, 2008) Antisocial Personality Disorder: e.g. reduced Cerebellar volume (Barkataki et al, 2006). Alzheimer Dementia: e.g. cerebellar atrophy (Wegiel et al,
1999)

(4) Psychiatric Aspects of Cerebellar Disorders

(1) Cerebellar Cognitive Affective Syndrome (2) Anatomically Specific Psychiatric Aspects of

Cerebellar Disorders (3) Other Psychiatric Aspects of Cerebellar Disorders

(1) Cerebellar Cognitive Affective Syndrome (Schmahman & Shermen, 1998).

Cerebellar lesions in general e.g. acquired lesions, congenital

cerebellar malformations, cerebellar tumour resection, etc can cause motor impairments plus the following (Schmahman et
al, 2007; Tavano et al, 2007; Levisohn et al, 2000)

Cognitive impairments:

Executive dysfunctions e.g. in working memory and planning Visuo-spatial abnormalities e.g. in visual memory and visuospatial organisation Linguistic dysfunction e.g. dysprosodia, agrammatism and anomia anxiety, lethargy, depression, lack of empathy, ruminativeness, perseveration, anhedonia and aggression

Affective impairments:

(2) Anatomically Specific Psychiatric Aspects of Cerebellar Disorders

Vermal Agenesis > severe LD, Autism &

abnormal motor development (Tavano et al, 2007). Vermal lesions > affective and relational disorders (Schmahman et al, 2007). Spinocerebellar Ataxia > impairment in attention, memory, executive functions and theory of mind (Garard et al, 2008).

(3) Other Psychiatric Aspects of Cerebellar Disorders:(Wolf

et al, 2007)

Clinical Implications

Clinical Implications:

Assessment: (1) Motor disorders in psychiatric disorders as signs of cerebellar dysfunctioning (2) Non-motor symptoms equivalent to motor symptoms related to cerebellum Treatments: (3) Cerebellar exercises (4) Transcranial Magnetic Stimulation (TMS) (5) Routine disorders

(1) Motor disorders in psychiatric patients: signs of cerebellar dysfunctioning

E.g. Poor saccadic eye movement, Motor

clumsiness, Gait abnormalities, Stuttering, cluttering, stammering, etc Used mainly in research as markers and/or associations Not highly specific to cerebellum but to the motor brain circuits which include the cerebellum ? Clinical significance

(2) Non-motor symptoms equivalent to motor symptoms related to cerebellum

Usage of Non-motor Dysmetria
1998) as
(Andreasen et al,

clinical concepts in assessment and treatment of psychiatric disorders (Schmahmann, 2010): e.g.

Cognitive dysmetria, Emotional dysmetria, Social dysmetria, Speech/Communication dysmetria,

? No available publications

(3) Cerebellar Training

(Schmahmann, 2010)

Physical exercises that combine movement

and balance, designed to improve the slow information processing with dyslexia and ADHD; claimed to speed up information processing and improve cerebellar functioning > Controversial treatments for which there is no known published scientific literature.

Cerebellar Trancranial Magnetic Stimulation (TMS) (Schmahmann, 2010)

Demirtas-Tatlidede et al (2010): stimulation of

the vermis in 8 schizophrenic patients > improvements in mood, alertness, memory, attention, visual-spatial skills and energy. Very early stages No RCT

Routine Disorders
Follow the established neurological models

for Motor Behavioural Routines Function of brain circuits involving cerebrum, striatum, cerebellum and thalamus.

The cortico-cereller-thalamo-cortical circuit The cortico-striato-thalamo-cortical circuit

Motor Learning Models:

(Doya, 2000)
The cerebellum, is best understood as a

device for supervised learning (also Imamizu et al, 2000)

in contrast to the basal ganglia, which

perform reinforcement learning

and the cerebral cortex, which performs

unsupervised learning

Differences Between Routines, Habits and Compulsions

When brain wants to learn a behaviour for a frequent

use: > Cerebellum then provides the software programme >

Gradually learn the most efficient way to do the task with least effort > a successful Routine (functional Routine) if the process fails > Routine Disorder

Differences between Routines, Habits and Compulsions

When brain wants to learn a behaviour for a frequent use: > Basal Ganglia > Checking / Feedback System:

Checks that the learnt behaviour is consistent with the data from the Reward System (via Nucleus

Accumbens + Dopamine) (thermostat) > if reward System is dysfunctional > Habits Disorder e.g. addiction, gambling > (dysfunctional routines) Avoid anxiety provoking errors (via lateral amygdala + serotonin) (alarm) > if gives faulty checking > OCD and/or compulsive disorder > (functional routine unnecessarily repeated)

Routine Disorders
Problems with clinical uses: Multiple systems involved: striatum, frontal lobe, limbic system as well as environmental factors Complex system of assessment Advantages: Following a system which is a product of a brain circuit is more neurologically meaningful that monitoring symptoms related to a singlebrain-centre. More clinically relevant

Examples of Routine, Habit and Compulsion Disorders

Want to learn how to drive the car from home to

work:

Cerebellum > software for smooth and quick drive, if still struggling to drive smoothly or efficiently > Routine disorder Basal ganglia: checks your routine if achieving the target > if you develop the habit of drive fast to attract attention > Habit Disorder Basal ganglia: checks your routine if no errors committed > if it keeps giving you unjustified signal that tyres and you have to stop to check time after time > Compulsion.

Seven Stages of a successful Behavioural Routines

1. Identifying the data relevant to the routine

2. Process (analyse) these data

3. Developing a partial routine 4. Learn from ones mistakes as well as from

others 5. Develop an efficient routine 6. Routine works well even in unfamiliar circumstances 7. Routine works well even under pressure

Routine Disorders
Can not detect the relevant data to the routine

Can not understand them properly

Can not formulate a routine Can not learn from others how to improve or develop

the routine Can only formulate partially functional (mechanical) routines Can not use the routine under pressure Can not use the routine in unfamiliar situations

Applying the Seven Stages of Social Routines in Autism

Can not detect the relevant social data: severe Autism Can do the above but can not understand them well: severe Autism Can do the above but can not formulate a even partially functional routines: e.g. High Functioning Autism Can do the above but can not imitate routines of other people: High Functioning Autism. Can do the above but can not use the routine in an unfamiliar situations: Asperger Syndrome Can do the above but can not use the routine under pressure: Asperger Syndrome

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