(SpringerBriefs in Space Life Sciences) Clarke, Andrew H-Vestibulo-oculomotor Research in Space-Springer (2017)

SPRINGERBRIEFS IN SPACE LIFE SCIENCES
Andrew H. Clarke
Vestibulo-
Oculomotor
Research in Space
123
SpringerBriefs in Space Life Sciences
Series Editors
Prof. Dr. Günter Ruyters
Dr. Markus Braun
Space Administration, German Aerospace Center (DLR), Bonn, Germany
The extraordinary conditions of space, especially microgravity, are utilized for
research in various disciplines of space life sciences. This research that should
unravel – above all – the role of gravity for the origin, evolution, and future of life
as well as for the development and orientation of organisms up to humans, has only
become possible with the advent of (human) spaceflight some 50 years ago. Today,
the focus in space life sciences is 1) on the acquisition of knowledge that leads to
answers to fundamental scientific questions in gravitational and astrobiology,
human physiology and operational medicine as well as 2) on generating applications
based upon the results of space experiments and new developments e.g. in non-
invasive medical diagnostics for the benefit of humans on Earth. The idea behind
this series is to reach not only space experts, but also and above all scientists from
various biological, biotechnological and medical fields, who can make use of the
results found in space for their own research. SpringerBriefs in Space Life Sciences
addresses professors, students and undergraduates in biology, biotechnology and
human physiology, medical doctors, and laymen interested in space research. The
Series is initiated and supervised by Dr. Günter Ruyters and Dr. Markus Braun from
the German Aerospace Center (DLR). Since the German Space Life Sciences
Program celebrated its 40th anniversary in 2012, it seemed an appropriate time to
start summarizing – with the help of scientific experts from the various areas – the
achievements of the program from the point of view of the German Aerospace
Center (DLR) especially in its role as German Space Administration that defines
and implements the space activities on behalf of the German government.
More information about this series at http://www.springer.com/series/11849

Andrew H. Clarke
Vestibulo-Oculomotor
Research in Space
Andrew H. Clarke
Charité Medical School
Berlin, Germany
ISSN 2196-5560 ISSN 2196-5579 (electronic)

SpringerBriefs in Space Life Sciences
ISBN 978-3-319-59932-8 ISBN 978-3-319-59933-5 (eBook)
DOI 10.1007/978-3-319-59933-5
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© The Author(s) 2017

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Preface to the Series
The extraordinary conditions in space, especially microgravity, are utilised today

not only for research in the physical and materials sciences—they especially pro-
vide a unique tool for research in various areas of the life sciences. The major goal
of this research is to uncover the role of gravity with regard to the origin, evolution
and future of life and to the development and orientation of organisms from single
cells and protists up to humans. This research only became possible with the
advent of manned spaceflight some 50 years ago. With the first experiment having
been conducted onboard Apollo 16, the German Space Life Sciences Program cel-
ebrated its 40th anniversary in 2012—a fitting occasion for Springer and the DLR
(German Aerospace Center) to take stock of the space life sciences achievements
made so far.
The DLR is the Federal Republic of Germany’s National Aeronautics and
Space Research Center. Its extensive research and development activities in aero-
nautics, space, energy, transport, and security are integrated into national and
international cooperative ventures. In addition to its own research, as Germany’s
space agency, the DLR has been charged by the federal government with the task
of planning and implementing the German space program. Within the current
space program, approved by the German government in November 2010, the
overall goal for the life sciences section is to gain scientific knowledge and to
reveal new application potentials by means of research under space conditions,
especially by utilising the microgravity environment of the International Space
Station (ISS).
With regard to the program’s implementation, the DLR Space Administration
provides the infrastructure and flight opportunities required, contracts the German
space industry for the development of innovative research facilities, and provides
the necessary research funding for the scientific teams at universities and other
research institutes. While so-called small flight opportunities like the drop tower in
Bremen, sounding rockets, and parabolic airplane flights are made available within
the national program, research on the International Space Station (ISS) is imple-
mented in the framework of Germany’s participation in the ESA Microgravity
Program or through bilateral cooperations with other space agencies. Free flyers
v
vi Preface to the Series
such as BION or FOTON satellites are used in cooperation with Russia. The recently
started utilisation of Chinese spacecrafts like Shenzhou has further expanded
Germany’s spectrum of flight opportunities, and discussions about future coopera-
tion on the planned Chinese Space Station are currently under way.
From the very beginning in the 1970s, Germany has been the driving force for
human spaceflight as well as for related research in the life and physical sciences in
Europe. It was Germany that initiated the development of Spacelab as the European
contribution to the American Space Shuttle System, complemented by setting up a
sound national program. And today Germany continues to be the major European
contributor to the ESA programs for the ISS and its scientific utilisation.
For our series, we have approached leading scientists first and foremost in
Germany, but also—since science and research are international and cooperative
endeavours—in other countries to provide us with their views and their summaries
of the accomplishments in the various fields of space life sciences research. By
presenting the current SpringerBriefs on muscle and bone physiology, we start the
series with an area that is currently attracting much attention—due in no small part
to health problems such as muscle atrophy and osteoporosis in our modern aging
society. Overall, it is interesting to note that the psychophysiological changes that
astronauts experience during their spaceflights closely resemble those of aging peo-
ple on Earth but progress at a much faster rate. Circulatory and vestibular disorders
set in immediately, muscles and bones degenerate within weeks or months, and even
the immune system is impaired. Thus, the aging process as well as certain diseases
can be studied at an accelerated pace, yielding valuable insights for the benefit of
people on Earth as well. Luckily for the astronauts: these problems slowly disappear
after their return to Earth, so that their recovery processes can also be investigated,
yielding additional valuable information.
Booklets on nutrition and metabolism, on the immune system, on vestibular and
neuroscience, on the cardiovascular and respiratory system, and on psychophysio-
logical human performance will follow. This separation of human physiology and
space medicine into the various research areas follows a classical division. It will
certainly become evident, however, that space medicine research pursues a highly
integrative approach, offering an example that should also be followed in terrestrial
research. The series will eventually be rounded out by booklets on gravitational and
radiation biology.
We are convinced that this series, starting with its first booklet on muscle and
bone physiology in space, will find interested readers and will contribute to the goal
of convincing the general public that research in space, especially in the life sci-
ences, has been and will continue to be of concrete benefit to people on Earth.
Bonn, Germany Prof. Dr. Günter Ruyters

Bonn, Germany Dr. Markus Braun
July 2014
Preface to the Series vii
DLR Space Administration in Bonn-Oberkassel (DLR)
The International Space Station (ISS); photo taken by an astronaut from the space shuttle
Discovery, March 7, 2011 (NASA)
viii Preface to the Series
Extravehicular activity (EVA) of the German ESA astronaut Hans Schlegel working on the
European Columbus lab of ISS, February 13, 2008 (NASA)
Foreword
The extraordinary conditions of space, especially microgravity, lead to significant

changes in the physiology and psychology of astronauts and cosmonauts. In this
booklet, the author discusses findings of a series of spaceflight experiments under-
lining the crucial role of gravity in such processes and, more specifically, as a refer-
ence in the central nervous system for the efficient functioning of the sensorimotor
complex.
On Earth, the vestibular system senses the position and movement of the head in
the three-dimensional world and facilitates—through integration of visual, vestibu-
lar and proprioceptive information—spatial orientation and coordinated movement.
The graviceptive otolith organs in the vestibular labyrinth sense the direction of
gravity and thus provide a spatial reference for the central nervous system.
During spaceflight, this gravity reference is no longer present; this is why the
majority of astronauts suffer—in addition to other health issues—some degree of
malaise or nausea after transitioning to microgravity. During the necessary adapta-
tion, the associated symptoms prevail for the first few days in space. Such space
motion sickness can be likened to sea sickness, albeit in which case the gravity
reference is still present but becomes unstable due to the ship’s motion.
Since it is mandatory to ensure the health and well-being of astronauts in space,
much of life sciences research in space focused on changes to human physiology
from the beginning of human spaceflight in the early 60s of the last century. In this
context, understanding the vestibular system and how it adapts to microgravity to
ensure its proper functioning is of critical importance. As the booklet will demon-
strate, many of the findings from such research have also proved important for the
improvement of clinical diagnosis and generally for life on Earth, especially in the
ageing societies of the Western industrial countries.
In the introduction, the author gives a summary description of the vestibular
system and its development and discusses briefly the beginnings of the European
life sciences space research programme. In the following chapters, he focuses on a
series of experimental studies of the adaptation of the vestibular system during
spaceflight. These were designed to examine comprehensively the three-dimensional
aspects of the vestibuloocular responses and the role of the graviceptive otolith
ix
x Foreword
organs. Thus, in Chap. 2, the role of the graviceptive otolith organs on Earth and in
space is described. This investigation led to the surprising finding of a dominant
labyrinth in most humans—similar to the right- or left-handedness of humans. In
Chap. 3, the adaptation of the three-dimensional vestibulo-oculomotor reflex (VOR)
in microgravity is demonstrated. In Chap. 4, results from parabolic and spaceflight
experiments are presented that demonstrate that the oculomotor system, governed
by the so-called Listing’s Law, is modified in the absence of the gravity reference.
Altogether, the findings underline the role of gravity as a reference in the central
nervous system—not only for spatial orientation and coordination of movement but
also for a number of autonomic functions including control of blood pressure and
bone-muscle synergy.
Essential to the research presented here has been the development of adequate
eye movement recording technologies. In Chap. 5, the author, therefore, describes a
suite of measurement devices, which since the early 1980s have been developed
within the framework of the German space life sciences programme for spaceflight
studies and which have gone on to find application in the fields of clinical research
and diagnostics.
In the final chapter, the author outlines a number of clinical research studies
made possible with the measurement technology designed originally for spaceflight
deployment. In particular, the most recently developed 3D eye tracking device has
proved of considerable value for applications in laser eye surgery, neurology, and
neurosurgery as well as for clinical diagnostic testing.
All in all, it becomes convincingly clear that space research in vestibular physiol-
ogy together with the accompanying technology developments is of great benefit
not only for the health and well-being of astronauts and cosmonauts during their
space missions but also for humans on Earth.
Bonn, Germany Günter Ruyters

February 2017
Acknowledgements
When writing this manuscript, I find myself indebted to many colleagues and friends
who have assisted, taught and encouraged me in the process of the research described
here. First and foremost, I thank Professor Hans Scherer who introduced me to the
field of vestibular research and clinical diagnosis. He supported me enthusiastically
throughout the various science and technology projects discussed here.
I owe much to my colleagues from the Vestibular Research Lab at the
Universitätsklinikum Benjamin Franklin of the Charité Medical School in Berlin; to
my personal assistant Gabi Minarek; to Dr. Uwe Schönfeld who also assisted in
preparing the manuscript; to my engineers and technicians Waldemar Krzok,
Wolfgang Bierhals and Heinz Rösler; and to my clinical colleagues Dr. Katrin
Waltmann and Dr. Kai Helling. Thanks also to Dr. Kai Just and Dr. Jörg Grigull who
took part in the performance of the space-related experiments and development of
the necessary mathematical tools.
My admiration and gratitude goes to the astronauts and cosmonauts who per-
formed the experiments on the MIR and International Space Station (ISS). Special
thanks to Dr. Sigmund Jähn who ensured that the operations in the Gagarin
Cosmonaut Training Centre in Star City and the interface to our Russian colleagues
from RSC Energia functioned efficiently, to the astronaut Ulf Merbold for his con-
tinuous support and to Thomas Reiter who worked diligently with us on the 3D
VOR and LP experiments onboard the MIR and the ISS, to astronaut Andre Kuipers
whose initiative enabled the deployment of the Eye Tracking Device on the ISS and
to the Russian cosmonauts, especially Gennadij Padalka and Sergei Krikaliev, who
provided invaluable information and suggestions for the performance of the ISS
experiments.
I am also indebted to the ESA/DLR mission support teams, in particular Patrik
Sundblad, Marin Le Gouic, Simone Thomas, Jennifer Ngo-Anh, Benny Elmann-
Larsen and Crew Surgeon Uli Straube, to name but a few, and their Russian coun-
terparts from RSC Energia in Star City, and to the Russian colleagues at the Institute
for Biomedical Problems (IBMP) under the leadership of Professor Inessa
Kozlovskaya and Dr. Ludmilla Kornilova.
xi
xii Acknowledgements
The research with the Shuttle astronauts on the unilateral otolith responses was
conducted in cooperation with Scott Wood and his colleagues of Johnson Space
Center, Houston. Many thanks to Mimi Shao and her team at Kennedy Space Center
for the excellent support during the postflight sessions.
Throughout my space-related research, the company Kayser-Threde has been
involved in the development and spaceflight qualification of the necessary equip-
ment. For the many years of close cooperation, I acknowledge the team led by Peter
Hofmann, with Andreas Kellig, Jürgen Vergin, Jürgen Schmolke and the previous
CEO and founder Reiner Klett. For his creative and innovative input to the design
and development of the eye tracking hardware and software and the many fruitful
discussions, I thank Caspar Steineke of Mtronix GmbH, Berlin. I thank my col-
leagues Fritz Baartz, Marion Schoele, Wolfgang Pogade and all of the company
staff at Chronos Vision GmbH for the successful ETD development and the subse-
quent commercial success of the eye tracking technologies in the field of laser eye
surgery.
The clinical application of the eye tracking equipment would not have been pos-
sible without the cooperation of the neurological team of Profs. Thomas Lempert
and Michael von Brevern from the Dept of Neurology and Georg Schlosser from the
Dept of Neurosurgery at the Charité Medical School, Berlin.
The research work and the engineering of the various eye movement measure-
ment systems were supported throughout by the German Space Agency (DLR).
Here I thank Günter Ruyters, who encouraged me to put this manuscript together,
and his colleagues Ulrich Hoffmann, Peter Graf, Markus Braun, Horst Binnenbruck
and last but not least Helmut Bauer, for their continued support and confidence in
my research projects.
Contents
1 Introduction�� 1
1.1 A Brief Introduction to the Vestibular System�� 2
1.2 Visual-Vestibular Interactions �� 6
1.3 Adaptation�� 6
1.4 Motion Sickness�� 7
1.5 Historical Perspective �� 8
2 The Role of the Otoliths�� 13
2.1 Which Functions Do the Otoliths Fulfil?�� 13
2.2 Early Spaceflight-Related Studies of Otolith Responses�� 16
2.3 Recent Postflight Testing of Otolith Function�� 17
2.3.1 Utricle Function Tests �� 18
2.3.2 Saccule Function Test �� 19
2.4 Related Experimental Findings�� 19
2.4.1 Subjective Vertical�� 19
2.4.2 Utriculo-Ocular Reflex�� 21
2.4.3 Saccule Function Test �� 21
2.4.4 Discussion of the Findings�� 22
2.5 Summary �� 23
Appendix�� 23
Unilateral Centrifugation�� 23
Subjective Visual Vertical�� 24
Utriculo-Ocular Response �� 25
Cervical Evoked Myogenic Potentials (cVEMPs)�� 27
3 The Three-Dimensional Vestibulo-Ocular Reflex During Prolonged
Microgravity �� 29
3.1 Introduction�� 29
3.1.1 Test Procedure�� 31
xiii
xiv Contents
3.2 Spaceflight Findings�� 32

3.2.1 Horizontal VOR�� 33
3.2.2 Vertical VOR �� 33
3.2.3 Torsional VOR�� 34
4 Listing’s Plane and the 3D-VOR in Microgravity�� 37
4.1 Introduction�� 37
4.2 Parabolic Flight Study�� 39
4.3 Spaceflight Study�� 40
Appendix�� 47
Determination of Listing’s Plane Coordinates�� 47
Determination of Minimal Gain Vector Coordinates�� 49
5 Technology Developments and Transfer�� 51
5.1 Eye Movement Measurement Technology�� 51
5.2 The DLR Eye Tracking Device�� 52
5.2.1 Front-End Image Processing�� 54
5.2.2 Online Acquisition and Measurement�� 55
5.2.3 Offline Image Evaluation�� 55
5.2.4 Convention for Describing 3D Eye Position�� 56
5.2.5 Offline 3D Tracking�� 56
5.2.6 Determination of 3D Eye Position�� 57
5.3 Laser Eye Surgery�� 57
5.4 Clinical Diagnostic Testing�� 58
6 Clinical Applications and Related Projects �� 59
6.1 Unilateral Otolith Dysfunction �� 60
6.2 Subjective Visual Vertical as a Clinical Test �� 60
6.3 Testing Utricular Function by Means of On-Axis Rotation�� 61
6.4 Head Pitch Affects Eye Torsion�� 61
6.5 Migrainous Vertigo�� 62
6.6 Benign Paroxysmal Positioning Nystagmus (BPPN) �� 63
6.7 Galvanic Stimulation of the Vestibular Labyrinth�� 64
6.8 Vestibulo-Ocular Monitoring of Comatose Patients as Predictor
of Outcome After Severe Brain Injury�� 64
6.9 Vestibulo-Autonomic Regulation of Muscle Structure�� 65
References�� 67
Chapter 1
Introduction
Since the onset of human spaceflight, it has been obvious that the absence of the Earth’s
gravity would have repercussions for many aspects of physiology. This is clearly the
case for the vestibular system and more specifically for the function of the otolith
organs, which normally would perceive the orientation of the head relative to gravity.
Generally, the vestibular system provides information on the position and movement of
the head in the three-dimensional world. Of critical importance to this task and for the
coordination of head and body movement is the veridical perception of gravity.
This is manifest in various high-performance sports where despite extreme body
positions, the head is maintained in an upright position, i.e. parallel to the gravity
vector. In this head position, the direction of gravity is optimally perceived. In turn
visual perception and motor coordination are optimised. A few examples are shown
in Fig. 1.1. While movements of the environment and objects are largely perceived
by the visual system, self-motion is sensed by the integration of visual, vestibular
and proprioceptive information.
What’s so important about gravity?
Head on Body . . .
Eye in Head . . .
Fig. 1.1 Examples of

sport activities where the
control of upright head
position is essential to
maintaining high
performance
© The Author(s) 2017 1

A.H. Clarke, Vestibulo-Oculomotor Research in Space, SpringerBriefs in Space
Life Sciences, DOI 10.1007/978-3-319-59933-5_1
2 1 Introduction
1.1 A Brief Introduction to the Vestibular System
Throughout life, the vestibular system is essential for maintaining spatial orientation
and coordinated movement. To this end, a major task of its brainstem circuitry is to
integrate the afferent information from the vestibular end organs in the inner ear with
that from the visual, proprioceptive, somatosensory and tactile systems. The main
components of the vestibular system are illustrated schematically in Fig. 1.2.
The inner ear houses both the auditory and vestibular sensory organs. The ves-
tibular organ (Fig. 1.3) contains the three near-orthogonal semicircular canals
Fig. 1.2 This outline of the various Oculomotor

components of the nervous system nuclei
involved in the vestibular system
illustrates the complex neural pathways
connecting the vestibular organs in the
inner ear via the brainstem to the
oculomotor muscles controlling eye Med. long. fasc.
movements and the cortical areas
responsible for spatial orientation as well
as to the vestibulospinal pathways Reticular
formaiton
necessary for posture and locomotor
coordination. The neural pathways of the S S
central vestibular system include areas of
the vestibular nuclei in the brainstem, L
thalamus, hippocampus and vestibular M M

D
cortex (From Brodal 1981) Utricle
a Med. long. fasc.
Sacculus
endolymphaticus
Canalis
semicircularis anterior
N. vestibularis
Ampulla
Canalis
semicircularis
lateralis
Utriculus
N. cochlearis
ulus
Sacc
Cochlea
Canalis
semicircularis posterior
Fig. 1.3 The vestibular
organ (and cochlea) in
the inner ear
1.1 A Brief Introduction to the Vestibular System 3
(SCC)—for transduction of rotation—and the otolith organs, responsible for

transducing omnidirectional linear acceleration of the head and most critically
perceiving the direction of gravity. The inclusion of this apparatus in both ears
enhances the performance and sensitivity of the system.
Via the vestibulo-oculomotor reflex (VOR) pathways in the brainstem, the semi-
circular canal and otolith afferents are used synergistically in a number of systems,
including stabilisation of eye movement via the vestibulo-ocular reflex pathways;
coordination of posture, via vestibulo-spinal pathways; vestibulo-autonomic regula-
tion of blood pressure; and in the central nervous system providing a general refer-
ence for spatial orientation, namely, the gravity vector.
The relationship between eye and head movements is illustrated schematically
in Fig. 1.4. For the investigation and diagnosis of vestibular function, the examina-
tion of systematic reflex eye movements, i.e. the vestibulo-ocular response, has
played a major role. This is illustrated in Fig. 1.5. During head yaw (rotation about
the Z-axis), there is no change with respect to gravity, and a predominant horizontal
eye movement occurs (Fig. 1.5: traces 1 and 4). In contrast, a head pitch movement
(rotation about the Y-axis) stimulates the vertical semicircular canals, by angular
acceleration, and the otolith organs by the concomitant modulation of the gravity
component. In this case the combined stimulation of canal and otolith organs elicits
predominantly a vertical eye movement (Fig. 1.5: traces 2 and 5). During head roll
(rotation about the X-axis), the combined canal and otolith stimulation elicits a
more complex eye movement pattern with a dominant torsional component
(Fig. 1.5: traces 3 and 6).
The inner ear apparatus, as exists in all higher vertebrates, has been traced back
to species which existed more than 150 million years ago (Gray 1955),
as documented, for example, by fossil remains of the Brachiosaurus brancai held in
the Natural History Museum in Berlin (Fig. 1.6).
The orthogonal arrangement of SCCs demonstrates the remarkable consis-
tency in the morphology and presumably the physiology of the vestibular appara-
tus over this period. Generally, there is evidence across many species showing
that labyrinth dimensions are closely related to the dynamics of the natural move-
+Az
Rotation +Translation of the head
Fig. 1.4 Idealisation of the = 6 degrees of freedom
degrees of freedom of head +az
and eye movement. Head
+ax
movement can be described Right
as a combination of eye
rotation (ax, ay, az) about +Ax +Ay
and translation (Ax, Ay, Az) Left +ay
along the three orthogonal X eye
axes. Similarly movement Y
of the eye can be described
as rotation about the three X
Rotation of each eye
cardinal axes by the three Y = 3 degrees of freedom
sets of extraocular muscles
4 1 Introduction
Roll Pitch Yaw
40 horizontal
0
–40
Eye position (°)
40 vertical
0
–40
20 torsional
0
–20
Z-rotation
100
0
Head velocity (°/s)
–100
100 Y-rotation
0
–100
100 X-rotation
0
–100
0 2 4 t(s) 0 2 4 t(s) 0 2 4 t(s)
Fig. 1.5 Demonstration of the three-dimensional vestibulo-ocular reflex (3D–VOR) elicited by

yaw, pitch and roll oscillations of the head while fixating an imaginary target at 1 m. From top to
bottom: eye angular velocity about the z-, y- and x-axes of the eye (Fick convention) and the cor-
responding head angular velocity about the z (yaw)-, y (pitch)- and x (roll)-axes
ment repertoire unique to each species. It is argued that by necessity each species,
through its phylogeny, has developed a vestibular sensory system that is optimally
adapted to its natural behavioural pattern and its immediate natural environment.
In a similar vein, Sandeman (1983) comments that “there are few other sensory-
motor systems where quite such remarkable parallels exists across several phyla,
as in the compensatory eye movements produced by the organs of balance and
vision”.
Further, in the higher vertebrates, commensurate information is delivered to the
cerebral cortex for cognitive processing and subjective perception associated with
orientation and movement in space. Taken collectively, these individual sensory
processes and their neurophysiological integration are the stuff of vestibular
physiology.
1.1 A Brief Introduction to the Vestibular System 5
50 mm
12 m
30
10
Fig. 1.6 Comparison of body dimensions and labyrinths of Brachiosaurus brancai and
humans. Note also that the body mass of B. brancai is approx. 1000-fold that of humans (From
Clarke 2005)
Nevertheless, the existence of a specific sensory organ for spatial orientation was
first reasoned by Goltz in 1870, followed by Breuer (1874), Crum Brown (1874)
and Mach (1875), who simultaneously described the function of the semicircular
canals. This resulted in what is now referred to as the Breuer-Crum Brown-Mach
model.
From his studies of the otolith organs in various fish and birds, Breuer (1891)
was first to conclude that linear accelerations of the head caused the otolith mem-
brane to shear across the sensory hair cells. In principle this description of the oto-
lith function remains valid to the present day.
The research described here underlines the crucial role of the gravity vector
in providing a reference in the central nervous system for the efficient function-
ing of the entire sensorimotor complex. An interesting speculation is that the
perception of gravity permits an internal representation of verticality to be
established in the brain (e.g. Bles et al. 1998), thus providing a reference vector
for the entire central nervous system (CNS). Further, it has been postulated that
a model of Newton’s laws of motion actually exists in the brain (McIntyre et al.
2001).
6 1 Introduction
Fig. 1.7 Representation of the neural

pathways between the vestibular organ in
the inner ear and the extraocular muscles
(From Nieuwenhuys et al. 1988)
Musc.
lateralis
Nucl.
oculomotorius
Nucl.
abducens
Ganglion
Scarpa Nucl.
vestibularis
medialis
1.2 Visual-Vestibular Interactions
The orientation of the labyrinthine canals in the head is intrinsically related to that
of the extraocular muscles. This appears as a uniform configuration of the extraocu-
lar muscles (Fig. 1.7); thus, it has been determined that the rotation axis of each
agonist-antagonist muscle pair is functionally parallel to the axis of that canal from
which it receives its primary excitatory input (reviewed by Simpson and Graf 1981).
These authors outline the relationships between the natural reference frames intrin-
sic to the canal and extraocular muscle configurations and argue the case for a com-
mon vertebrate “Bauplan” for the sensorimotor integration underlying compensatory
eye movements.
1.3 Adaptation
As is the case for many aspects of the central nervous system, the phylogeny of the
vestibular system has established neural pathways as necessity has demanded. Thus,
it appears that the morphology and neurophysiology in each species are optimally
attuned to the requirements of its particular behavioural environment. Other exam-
ples of this evolutionary process are described by Dawkins (1986) who outlines the
optimisation process for the vertebrate eye and Lorenz (1973) who describes the
general facility of the nervous system for adaptation.
An essential feature of this teleonomic process is the integration of sensory infor-
mation from the vestibular receptors with the concomitant afferents from the vari-
ous other sensory systems. As Horn (1983) comments, in ethological terms, such
convergence of sensory information is important for increasing the property of
adaptivity.
1.4 Motion Sickness 7
In his treatment of the brainstem, Hobson and Scheibel (1977) has defined sen-
sorimotor integration as the “neuronal process(es) through which spatiotemporal
specificity of inputs from a variety of sensory sources is compared and unified to
produce an organised motor output”. In his words, “… the coordination of eye, head
and body position inputs from eye muscle, visual afferent channels, labyrinth and
joint receptors represents such an integrative process performed by the neurons of
the reticular formation”.
1.4 Motion Sickness
The facility for adaptation to changes is a critically important property of the ner-
vous system, whether these result from aging, injury or disease where loss or injury
to the neuronal circuits may occur. Similarly, adaptive processes are triggered by
alterations in gravitoinertial conditions, i.e. loss of the gravity vector as reference,
as is the case during the initial days of spaceflight, after transferring from constant
one-g conditions on the Earth to the microgravity of orbital flight. See Clément and
Ngo-Anh (2013) for a recent review of related spaceflight studies.
The occurrence of space motion sickness was first reported after the Vostok 2
mission in 1961 by the cosmonaut Titov, who was second to fly in space. Subsequently
it was reported by American astronauts on the Apollo 8 mission in 1968. In the
meantime, it is known that the majority of space travellers (60–80%) experience
some degree of malaise during the first few days of spaceflight. The symptoms are
similar to those in other forms of motion sickness, including pallor, increased body
warmth, cold sweating, malaise, loss of appetite, nausea, fatigue, vomiting and
anorexia. These are important because they may affect the operational performance
of astronauts. Space motion sickness is usually treated using pharmaceuticals, most
of which have undesirable side effects. This has been reviewed by Heer and Paloski
(2006). They discuss the two main hypotheses that have been proposed to explain
space motion sickness: the fluid shift hypothesis and the sensory conflict hypothesis.
According to the fluid shift hypothesis, space motion sickness results from the cra-
nial shifting of body fluids resulting from the loss of hydrostatic pressure gradients
in the lower body when entering microgravity, leading to an increase in intracranial
pressure. The sensory conflict hypothesis suggests that loss of tilt-related otolith
signals upon entry into microgravity causes a conflict between actual and antici-
pated signals from sense organs subserving spatial orientation. A variation of the
sensory conflict hypothesis is the otolith asymmetry hypothesis which was proposed
earlier by Yegorov and Samarin (1970) and von Baumgarten and Thumler (1979).
This maintains that the mass difference between the otoconial crystals in the two
inner ear labyrinths is compensated for under Earthbound, one-g conditions, but is
no longer correct under zero-g conditions. The findings of the experiments described
in Chap. 2 support the more adequate idea of a unilateral dominance in the utriculo-
ocular neural circuitry as the primary factor rather than a morphological asymmetry
as contributing to inflight and postflight disorientation.
Here, rather than neuronal damage as occurs in disease, the loss of the gravity
reference initiates a re-programming of the sensory integrative processes in the
8 1 Introduction
Labyrinth
Neck Proprioceptors
Nucleus Vestibular nuclei Respiration

Locus Coeruleus
Vomiting Centre Cardiovascular
Fig. 1.8 Illustration of the brainstem interconnections from the vestibular labyrinth. In particular,
demonstrating the influence of vestibular information on autonomic functions, including those
areas responsible for emesis, namely, the vomiting centre and the chemoreceptive trigger zone in
the medulla oblongata
brain. A further example can be observed during the initial hours and days aboard a
sea-going vessel, where the perceived gravity reference is no longer stable, but fluc-
tuates with the motion of the sea.
The malaise and nausea experience by space or sea travellers is above all due to the
sensory conflict which arises in the first case from the absence of the gravity reference
and in the second case to the instability of the gravity reference caused by the ship’s
motion, hence the characterisation as motion sickness, respectively, space sickness
and seasickness. Lackner and Dizio (2006) conclude that space motion sickness does
represent a form of motion sickness and that it does not represent a unique diagnostic
entity. Motion sickness arises when movements are made during exposure to unusual
force backgrounds both higher and lower in magnitude than 1 g earth gravity.
Whether through disease, injury or changes in g-conditions, it is generally held
that the resultant discrepancy amongst the signals from the vestibular and visual
senses and that which is expected—the so-called sensory conflict—is responsible
for the vegetative symptoms (Bles et al. 1998). The neural pathways are illustrated
schematically in Fig. 1.8. For the specific case of space motion sickness, the otolith
asymmetry hypothesis was proposed by von Baumgarten (von Baumgarten and
Thumler 1979). This has been examined in animal and human experiments, but with
inconclusive results (Scherer et al. 1997, 2001; Diamond and Markham 1998). The
current understanding of motion sickness and, more generally, nausea is presented
in a recent review by Balaban and Yates (2017).
The sensory discrepancy caused by transitions between one-g and zero-g condi-
tions is instrumental to the occurrence of altered perception and malaise, as experi-
enced by the majority of spaceflight travellers. Fortunately, vestibular adaptation to the
microgravity environment alleviates these complaints. Following their return to one-g,
Earthbound conditions after spaceflight, the process is reversed (Paloski et al. 1993).
1.5 Historical Perspective
After the initial success of manned spaceflight, effort increased into the monitor-
ing of physiological functions influenced by microgravity in order to maintain
the health and wellbeing of the astronauts and cosmonauts. The development of
1.5 Historical Perspective 9
manned orbital stations, albeit originally for military purposes, began in the
early 1960s. The Soviets launched the first in a series of “Saljut” space stations
in 1971 to coincide with the tenth anniversary of Yuri Gagarin’s flight on “Vostok
1” rocket. Further stations followed in the Saljut programme including Saljut 6
with the German cosmonaut Sigmund Jähn and Saljut 7 missions in 1977 and
1982. These missions included a limited number of physiology experiments.
The technology developed during the Saljut programme was subsequently
refined for the modular design of the MIR space station launched in 1986 and the
International Space Station (ISS), the first components of which were launched
in 1998.
When NASA’s Apollo project with six successful moon landings was termi-
nated in 1972, the manned orbital station, known as Skylab, was launched. This
provided facilities for the first astronomy and life science experiments in micro-
gravity. Originally the Space Shuttle was intended to support and refurbish Skylab,
but due to delays with the development of the Shuttle, Skylab was abandoned.
NASA’s research programme then continued with the use of the Shuttle as orbital
platform.
In the mid-1970s, preparations were started by the European Space Agency to
perform human physiology experiments onboard the Space Shuttle. The first experi-
ments were performed during the Spacelab 1 mission flown in 1983. An artist’s
impression of the various tests is shown in Fig. 1.9.
Fig. 1.9 Graphic impression of the

experiments performed during the
European Spacelab mission in 1983.
These were intended to explore changes
in vestibular function and visual-
vestibular interactions, posture, tactile
function and venous pressure on exposure
to microgravity. The compact helmet
structure was specially developed for this
mission
10 1 Introduction
These included examination of the vestibular organs by the so-called caloric test.
This involves thermal stimulation to the inner ear by irrigation of each ear by hot or
cold water (Scherer 1984; Scherer et al. 1986), which by way of the vestibulo-ocular
reflex elicits eye movement patterns.
Since its development in the early twentieth century (Bárány 1907) as a clinical
test of vestibular function the caloric test had been generally understood that the
thermal stimulus induced some sort of thermoconvection in the liquid-filled semi-
circular canals. The working hypothesis for the Spacelab experiment was therefore
that in the weightlessness of spaceflight, no thermoconvection would take place and
consequently no such eye movements would result. However, a systematic response
was recorded (Fig. 1.10), which led to reconsideration of the mechanisms respon-
sible for the response to caloric stimulation.
This did not turn out to be the case. Repeatedly, a clear nystagmus response was
recorded. The findings were confirmed during the subsequent D1 Shuttle mission.
In the clinical situation, it was generally assumed that only the horizontal semi-
circular canal was stimulated. This understanding was revised after technology for
recording three-dimensional eye movements such as scleral search coils (SSC) and
video-oculography (VOG) became available. It became clear that caloric irrigation
caused stimulation to the entire vestibular apparatus and consequently induced a
complex three-dimensional eye movement response. Interestingly the early, purely
visual observations reported by Bárány (1907) describe such complex movements.
Subsequently, interest in the three-dimensional vestibular and oculomotor
responses, both in the research lab and in microgravity, flourished with the
availability of adequate measurement equipment. The VOG technology devel-
oped for the experimental studies described in the following chapters and their
results have contributed to these advances in basic research and clinical diagno-
sis. Over time this has contributed to approaches for the differential testing, and
diagnosis, of the individual semicircular canals and the two otolith organs in
each ear.
Is 10º
Is 10º
d
Fig. 1.10 Right: Scientists H. Scherer and R.V. Baumgartner observing the caloric nystagmus
during online downlink from the experiment onboard the Spacelab mission in 1983. Left: Examples
of the caloric nystagmus response recorded in microgravity
1.5 Historical Perspective 11
In the following chapters, experimental studies involving investigation of the

vestibular system during and after spaceflight are described. These were performed
onboard the Mir, the ISS and the Space Shuttle in cooperation with Russian, US
American and European colleagues under the auspices of the Russian, US American,
European and German Space Agencies.
The first series examines the influence of microgravity on the function of the
otolith system and the validity of the otolith asymmetry hypothesis. The second
series investigates into the three-dimensional nature of the vestibulo-oculomotor
responses to active head movement. Following on from these findings, the subse-
quent study is focussed on the relationship between the CNS representation of the
vestibular system and that of the oculomotor system, as described by Listing’s
Plane. Accordingly, the coordination, or congruency, of the two systems was exam-
ined prior to, during and after spaceflight.
Chapter 2
The Role of the Otoliths
2.1 Which Functions Do the Otoliths Fulfil?
It has gradually been recognised that the gravitational vector, primarily mediated by
the otolith organs in the inner ear, is utilised as a reference by diverse systems.
Besides its obvious role in the vestibulo-ocular and vestibule-spinal responses (e.g.
Yates et al. 2014), it also subserves a number of systems ranging from those cogni-
tive processes involved in spatial orientation and navigation (Wraga et al. 2000;
McIntyre et al. 2001; Indovina et al. 2005; Besnard et al. 2015) to the regulation of
autonomic mechanisms (e.g. Watenpaugh et al. 2002; Salanova et al. 2016).
The importance of maintaining correct spatial orientation becomes apparent in a
variety of extreme sporting activities such as surfing, motorcycle racing or ice skat-
ing where it is notable that well-trained participants maintain their head in an upright
position while performing their various activities (see Fig. 1.1).
With the head axis parallel to gravity, the visual surround is optimally aligned
with the vertical and horizontal meridia of the retina and is thus beneficial to visual
acuity and cognitive processing. This phenomenon is also reflected in the recent
findings of Mast and Meissner (2004), who demonstrate that retinal images of the
environment are processed optimally, i.e. with a minimum of processing time with
the head in an upright position. In the absence of the otolith-mediated gravity refer-
ence, the astronaut must rely largely on the visual field for orientation (cf. Fig. 2.1).
Fig. 2.1 In the prolonged absence of the gravitational

reference during spaceflight, it is necessary for the
spaceflight traveller to take reference from visual
(exotropic) cues or from some internal or idiotropic
vector (Glasauer and Mittelstaedt 1998)
14 2 The Role of the Otoliths
In the meantime, an increasing body evidence demonstrates the role of the otolith
afferent information in the regulation of other body functions, e.g. blood pressure
(Yates et al. 1999). This effect was demonstrated by the work of Denise and co-
workers (Etard et al. 2004) who demonstrated that arterial blood pressure is modu-
lated by changes in the gravitoinertial force during parabolic flight. This work
contributes to the increasing evidence of the role of otolith afferences in the regula-
tory mechanisms of the sympathetic nervous system, contributing to the control of
vascular resistance and blood pressure. In this sense, it has been demonstrated that
the afferent information from the otolith system plays a role in the maintenance of
bone-muscle synergy (Luxa et al. 2013; Salanova et al. 2016; Vignaux et al. 2015).
A number of experiments have been performed that demonstrate altered spatial
perception during prolonged microgravity and the nature of adaptation to the altered
conditions. In one example reported by Clément et al. (2001), subjects were required
to indicate their perception of tilt during centrifugation (Fig. 2.2).
Fig. 2.2 The short-arm centrifuge employed for

the tilt-translation experiment onboard the Shuttle
seen here in the training mock-up (from Clément
et al. 2001)
Under one-g conditions, the tilt of the gravitoinertial vector—resulting from the
additional centripetal acceleration generated by the short-arm centrifuge—was by
and large correctly perceived. When performed onboard the Space Shuttle, the sub-
jects’ perception was initially very similar to that under one-g test conditions,
despite the fact that the bias of the otolith-mediated gravity vector was absent.
However, over the course of the 16-day mission, a gradual adaptation was observed,
during which the subjective perception became aligned with the direction of the
predominant centripetal acceleration vector.
Together with the subjective reports from space travellers, this demonstrates that
transitions to and from microgravity radically alter the demands on sensorimotor
coordination. This is reflected in the interaction between the vestibular and oculo-
motor systems as manifested during those head movements involving changes in
orientation to the gravity vector. This is illustrated by measuring eye and head move-
ment while tilting the head to the shoulder. Under Earthbound, one-g conditions, the
otolith organs continuously signal head orientation relative to the gravity vector.
When the head is tilted, e.g. to the left, this reorientation with respect to gravity is
perceived by the otolith organs, and via reflex pathways to the extraocular muscles, a
2.1 Which Functions Do the Otoliths Fulfil? 15
One-g One-g
Ocular Head
5° torsion tilt 60°
0.5G
1G
1G
30 s
30°
Zero-g Ocular Zero-g Head

5° torsion tilt 60°
0G
0G
0G
30 s
30°
Fig. 2.3 Upper panels: Under one-g Earthbound conditions, a head tilt to the left directly elicits a
rapid counterclockwise eye movement to the left, followed by a transient burst of nystagmus beats
and a static ocular torsion to the right. Lower panels: In microgravity a similar counterclockwise
head tilt elicits a similar burst of counterclockwise nystagmus beats but no change in static ocular
torsion occurs (from Clarke and Kornilova 2007)
compensatory rotation, or counterroll, of the eye is elicited. In contrast, when performed

during spaceflight, in the absence of the gravity bias to the otolith organs, the same
manoeuvre elicits no counterroll. Comparative recordings of eye and head position for
a head tilt to the left, under one-g and zero-g conditions, are shown in Fig. 2.3.
Under one-g test conditions, active head-to-shoulder tilt, or rotation, stimulates
not only the semicircular canals but also the otolith organs due to the reorientation
to gravity. The combined canal- and otolith-mediated oculomotor response mani-
fests as a volley of torsional nystagmus beats combined with a tonic ocular
counterroll (OCR) (Fig. 2.3 upper panel). In microgravity (Fig. 2.3 lower panel), in
the absence of gravity, only the transitory canal-mediated torsional nystagmus
response remains.1
1
Under both one-g and zero-g conditions, the volley of nystagmus beats commences consistently
with an anticompensatory saccade. This has been observed in previous ground-based studies
(Pansell et al. 2003) and can be likened to the case of the horizontal anticompensatory saccade
found to initiate the eye movement response to active and passive yaw rotation of the head (Melvill
Jones 1964; Henriksson et al. 1974; Barnes 1979). This is understood to be related to the intention
of directing visual attention, and a neuronal substrate has recently been proposed (Roy and Cullen
2002). Whether a similar perhaps more rudimentary mechanism exists for the control of torsional
eye position remains to be determined.
2.2 Early Spaceflight-Related Studies of Otolith Responses
The effects of exposure to microgravity on the otolith-mediated oculomotor

responses have been investigated in a number of ways in previous studies (Yakovleva
et al. 1982; Vogel and Kass 1986; Reschke and Parker 1987; Diamond and Markham
1988; Wetzig et al. 1990; Merfeld 1996; Clarke and Kornilova 2007). In this con-
text, the so-called tilt-translation hypothesis was proposed after the observation was
made that immediately postflight pure roll stimulation in the dark was perceived by
the astronauts as translatory self-motion with only a small angular component
(Reschke and Parker 1987); i.e. the CNS adapts to prolonged microgravity by rein-
terpreting all otolith signals to be an indication of linear translation. With regard to
the functioning of the otolith organs, the asymmetry hypothesis (Yegorov and
Samarin 1970; von Baumgarten and Thumler 1979) proposed that differences in
weight between the right and left otolith apparatus of the inner ear are appropriately
compensated on Earth, but when exposed to novel gravitational states, these com-
pensatory stratagems become ineffective, leading to unstable vestibular responses.
Testing this hypothesis, Diamond and Markham (1998) measured examined
increases in OCR disconjugacy, which they interpreted as an indicator for such oto-
lith asymmetry. This increased fluctuation of torsional eye position in their zero-g
recordings could also be an indication of a stabilising, or inhibitive, role of the
otolith information.
All of these previous studies lacked the methodology for unilateral stimulation to
each of the otolith organs, the utricle and saccule. A unique approach to applying
linear acceleration independently to the left or the right otolith organ was introduced
a number of years ago (Wetzig et al. 1990). Rather than accelerate the whole body
with simultaneous stimulation of both vestibular labyrinths, this approach employs
unilateral centrifugation (UC) (see Fig. 2.4 and Appendix for details).
In principle this stimulus technique provides for linear acceleration along the
interaural axis, i.e. predominantly across the planes of the utricles. That the right
and left labyrinths are separated by approximately 7 cm permits the generation of
centripetal acceleration when one labyrinth is positioned on axis on a rotator. Thus
left labyrinth right labyrinth

on-axis on-axis
Fig. 2.4 Basic principle

of unilateral
centrifugation for the
exclusive stimulation of
the right respectively left
otolith organs in the right utricle left utricle
stimulated stimulated
inner ear
2.3 Recent Postflight Testing of Otolith Function 17
the eccentric labyrinth is exposed to a centripetal acceleration along the interaural

axis, while the on-axis labyrinth remains unaffected. See Appendix for details.
The refinement of this procedure as a means of evaluating the unilateral utricle
function has resulted in a useful test in the clinical diagnosis of vestibular disorders
(Clarke et al. 1996, 2001; Schönfeld et al. 2010; Schönfeld and Clarke 2011; Wuyts
et al. 2003; Buytaert et al. 2010).
2.3 Recent Postflight Testing of Otolith Function
The availability of unilateral utricle and saccule testing facilitates investigation of

how and to what extent the individual otolith subsystems adapt to microgravity. To
this end unilateral utricle and saccule tests were performed during the preflight and
postflight phases of spaceflight missions.
The study described here represents the first approach to comprehensive unilat-
eral examination of otolith function with respect to the effects of spaceflight and the
associated adaptation of vestibular function (Clarke et al. 2010; Clarke and
Schönfeld 2015). It must also be noted that while this approach has proven useful in
research and clinical settings, the influence of additional graviceptive receptors in
the estimation of the vertical cannot be excluded. The existence and influence of
such truncal graviceptors have been documented, above all by Mittelstaedt (e.g.
1997). The extent to which they may influence eye position or movement remains
to be examined. In the past, it has often been tacitly assumed that the utricles and
saccules are arranged orthogonally in the temporal bone. However, current anatomi-
cal knowledge demonstrates quite clearly the non-orthogonality of the otolith macu-
lae (e.g. Curthoys et al. 2009). Accordingly, it is perhaps more correct to refer to
horizontally polarised cells of the otolith maculae rather than the utricle and verti-
cally polarised cells rather than the saccule. With this in mind, the shorthand terms
utricle and saccule will be employed. Furthermore, the otolith system in its entirety
(i.e. otoconia, peripheral neural network, central neurons plus commissures) will
have over the course of adaptation to microgravity re-established symmetrical
responses to those translational accelerations of the head that still occur in micro-g.
Rather than a simplistic addition of left and right responses, the complex circuitry
in the central vestibular system, involving excitatory and inhibitory commissure
fibres, must be considered here (Markham 1989; Uchino and Kushiro 2011). It is
pointed out that under these circumstances, it would be incorrect to liken the post-
flight condition of healthy subjects with that of pathological loss of function. The
use of cervical vestibular evoked myogenic potentials (VEMPs) as an indicator of
unilateral saccule function has found widespread use in both research and clinical
diagnoses (Colebatch and Halmagyi 1992; Welgampola and Colebatch 2005).
Despite the recent reports that the stimuli employed induce responses not only in the
otolith organs but also in the semicircular canals, the measurement of cervical
VEMPs is at present the only practical approach to testing the unilateral saccule
function.
2.3.1 Utricle Function Tests
During a comprehensive postflight examination of unilateral otolith function, two

approaches to testing utricle function were made, both employing unilateral stimu-
lation (see Appendix for details).
Subjective visual vertical (SVV) requires the test subject to rotate a luminous line
in otherwise complete darkness so that it is aligned with his/her perception of
gravity (Fig. 2.5). This test encompasses not only brainstem processing of utricle
signals but also those cortical brain areas required for spatial perception.
Fig. 2.5 Left: Test Subject

in rotating chair. The insert CW 15
shows the subject’s view of
10
the luminous line in the
SVV Estimate (°)

SVV dome. Right: Graph 5
showing the normal 0

response range for unilateral
-5
stimulation of the right and
left labyrinths. The test data –10 Range for normal subjects
25–75 %
from one patient with CCW –15

5–95 %
dysfunction related to the Right ear

eccentric
Centre
rotation
Left ear
eccentric
right labyrinth are shown
for comparison
Utriculo-ocular reflex (UOR) test involves the measurement of ocular counterroll,

induced by stimulation of the right or the left utricle and mediated directly via
brainstem pathways without any involvement of higher brain functions. An example
of the torsional eye movement elicited by such stimulation is shown in Fig. 2.6.

on-axis on-axis
left utricle
right utricle stimulated
stimulated
Ocular torsion Radius

2.0 (º right) 4 cm
left
1.0
Fig. 2.6 During unilateral

centrifugation of the right, period
= 17.12 s
respectively, the left
1.0 left eye
labyrinth elicits a right eye
radius
conjugate ocular torsion or

counterroll of the eyes 2.0 (º left)
2.4 Related Experimental Findings 19
2.3.2 Saccule Function Test
To evaluate the postflight response of the right and left saccule, cervical vestibular
evoked myogenic potentials (cVEMPs) were measured. This procedure is widely
regarded and used as a clinical test of unilateral saccule function.
The VEMP provides a measure of saccular function indirectly through a
vestibulo-collic reflex (Fig. 2.7). Short auditory clicks gave rise to a short-latency
inhibition of activity in the contracted neck (sternocleidomastoid) muscle. The
activity of this muscle is recorded with surface electrodes (see Appendix for more
details). As with the UOR test of the utricles, the cVEMP is mediated directly via
brainstem pathways and does not involve higher brain activity.
Fig. 2.7 Acoustic clicks elicit a Normalised VEMP response

characteristic response in the neck 1.0
n23 Right ear
muscles, recorded with surface electrodes n34
0.0
on the sternocleidomastoid neck muscle.
The test subject lies supine with head 1.0 p13 p44
lifted to contract the neck muscle. The
p13-n23 potential is taken as measure of 1.0 Left ear
response (for details see Appendix to this 0.0
chapter) 1.0
0 20 40 60 80 100
Time (ms)
2.4 Related Experimental Findings
The results of the pre- to postflight tests, derived from the right-left ear symmetry
ratios for subjective visual vertical, utriculo-ocular reflex and VEMPs, are
summarised in Fig. 2.8.
2.4.1 Subjective Vertical
The significant shift in asymmetry on landing day (Fig. 2.8 top panel) results from
an increase in those SVV estimations made during unilateral stimulation to one ear
and a corresponding decrease with stimulation to the other. This relationship is
inverted during day 2/3 testing where the dominant labyrinth responses approach
preflight reference, while the responses from the contralateral labyrinth are clearly
increased. This fluctuation dampens over the course of the 10-day postflight phase.
This prolonged return to preflight values appears to take the form of a damped
oscillation.
Fig. 2.8 Longitudinal SVV UC–Asymmetry Ratio of Eccentric Values

in relation to individual median of preflight data
course of the asymmetry 1.0
ratios for SVV, UOR and 0.8
CVEMP testing over the
0.6
postflight period.
Asymmetry Ratio
0.4
Distributions of the ratios
for each postflight 0.2
measurement session are 0.0

shown relative to the –0.2
preflight values (shown left) –0.4
∇ –0.6
–0.8 n = 10
–1.0
-- 0 2–3 4–5 8–9 10
Preflight Postflight Period (days)
OOR Asymmetry Ratio in relation to individual

1.0 median of preflight data
0.8
0.6
Asymmetry Ratio
0.4
0.2
0.0
–0.2
–0.4
∇
–0.6
–0.8 n=8
–1.0
-- 0 2–3 4–5 8–9 10
VEMP–Asymmetry Ratio of p13–n23 Amplitude @ 135dB (SPL)

in relation to individual median of preflight data
1.0
0.8
0.6
Asymmetry Ratio
0.4
0.2
0.0
–0.2
–0.4
∇
–0.6
–0.8 n = 10
–1.0
-- 0 2–3 4–5 8–9 10
2.4.1.1 Single-Case Responses
Figure 2.9 illustrates the variety of response types amongst the individuals. In the
three cases shown, the postflight responses obtained approximately 3 h after landing
demonstrate a clear unilateral SVV deficit, i.e. with one labyrinth testing within
normal range, while the contralateral shows a clear deficit.
2.4 Related Experimental Findings 21
cw 25 cw 25 cw 25
20 x 20 x 20
x
x x
x
15 xx 15 x 15
x x
10 xx 10 10 x
x
x
SVV Estimate (º)
SVV Estimate (º)
SVV Estimate (º)

x
5 x 5 x 5
x x x
x xx x
0 x 0 0 x
x
x x
x
–5 –5 –5 x
x
x
x x x
–10 –10 x –10 x
x
x
–15 –15 –15
x
–20 x –20 –20
x
ccw –25 ccw –25 ccw –25
right ear centre left ear right ear centre left ear right ear centre left ear
eccentric rotation eccentric eccentric rotation eccentric eccentric rotation eccentric
cw 25 cw 25 cw 25
20 20 20
x
15 15 15
x
10 10 x x 10
x x x
SVV Estimate (º)
SVV Estimate (º)

x x
SVV Estimate (º)
5 x 5 x
x 5 x
x x
x
0 0 0 x
x x
–5 –5 –5
x
x
–10 –10 –10 x
x
–15 –15 –15
–20 –20 –20
ccw –25 ccw –25 ccw –25

right ear centre left ear right ear centre left ear right ear centre left ear
eccentric rotation eccentric eccentric rotation eccentric eccentric rotation eccentric
range for normal subjects

25–75 %
5–95 %
Fig. 2.9 Three individual cases illustrating postflight asymmetries. Top row: Preflight responses,
symmetrical within the normal range (shaded area). Lower row: Responses from L + 3 h, demon-
strating clear asymmetries
2.4.2 Utriculo-Ocular Reflex
As with the SVV responses, the first postflight tests performed 3 h after landing
yielded a significant asymmetry change (Fig. 2.8 centre panel). In general, testing
early after landing demonstrated a significant gain increase for the right labyrinth
together with a reduced UOR gain for the right labyrinth. Over the course of the
10-day postflight period, the asymmetry gradually approached preflight reference
with a pattern resembling a damped oscillation.
2.4.3 Saccule Function Test
The course of alteration of the asymmetry ratios is shown in Fig. 2.8 (lower panel)
for a 10 dB suprathreshold stimulus. On landing day, the asymmetry ratio differs
significantly from the preflight reference values. During the subsequent readapta-
tion period, the asymmetry ratio of the cVEMP responses fluctuates in a similar
fashion to the UOR and SVV responses. No consistent changes in response thresh-
old were observed.
2.4.4 Discussion of the Findings
The results of the utricular functional tests (UOR and SVV) indicated a consistent
course of adaptation over the 10-day postflight period, characterised by a prompt
increase in asymmetry between labyrinths on landing day and a subsequent rever-
sal, tailing off to preflight baseline values after 5–8 days. The prompt increase in
asymmetry observed in the early hours after re-entry demonstrates clearly the influ-
ence of the renewed exposure to Earth’s gravity and supports the idea that the gain
of the otolith responses is up-regulated during a stay in microgravity.
Neurophysiological evidence of such up-regulation during spaceflight was reported
in the toadfish (Boyle et al. 2001) on the basis of the responses of vestibular nerve
afferents supplying the utricular otolith organ.
Comparison of the courses of the UOR and SVV responses clearly demon-
strates the correlation between these two measures. With regard to the more pro-
nounced response asymmetry in the SVV findings, it is noted that the UOR and
cVEMP tests are based on short interneuron reflex pathways, whereas the SVV, as
a subjective perceptual task, obviously involves a cognitive component that may
well enhance the basic physiological signal. Comparing the time course of post-
flight adaptation, the results indicate a longer time constant for SVV than for either
UOR or cVEMP measures. This could be explained by the more complex neural
circuitry involved in SVV estimation. All told, it appears that the brainstem func-
tions involved adapt more quickly than the associated higher -order cognitive pro-
cesses. Since it has been demonstrated that vestibular neurons are influenced by
tilt-sensitive truncal receptors (Yates et al. 2000), this effect could also play a role.
The increased responses measured early after landing would support the idea that
otolith sensitivity, or response gain, is increased during prolonged microgravity.
The findings show that after the Shuttle flight durations of on average 10 days, the
return to preflight values proceeds over a period of 8–10 days. It is likely that this
recovery interval would be extended after longer flights, as was observed previ-
ously in the findings on the canal-based vestibulo-oculomotor responses during
and after spaceflights of 180 days in the monkey (Dai et al. 1994) and in humans
(Clarke et al. 2000). With regard to the estimation of the SVV, it is argued here that
the horizontally polarised cells, predominantly on the utricular maculae, play a
dominant role in detecting changes of head angle relative to the gravity vector.
Accordingly, in a head-upright position, any head tilt will increase their afferent
discharge rate according to a sine function, i.e. most sensitive to small changes in
tilt angle. In contrast, the discharge rate from the vertically polarised cell, pre-
dominantly on the saccular maculae, will change according to a cosine function,
i.e. least sensitive for small changes in head tilt. The findings from SVV testing,
that the response during stimulation of one utricle recovers more rapidly than the
contralateral, refute the previously proposed otolith asymmetry hypothesis as the
sole factor, in favour of a dominance in the CNS otolith pathways as being respon-
sible for adaptively modifying the perception of the otolith information. The oto-
lith asymmetry hypothesis, based on mass differences between the otoconia of the
Appendix 23
right and left organs, cannot accommodate such a difference in adaptation. These
results thus support the idea of a unilateral dominance in the utriculo-ocular neural
circuitry as the primary factor rather than a morphological asymmetry as contrib-
uting to inflight and postflight disorientation.
2.5 Summary
The aim of the study was to resolve the issue of spaceflight-induced, adaptive modi-
fication of the otolith system by measuring unilateral otolith responses in a pre- ver-
sus postflight design. The study represents the first comprehensive approach to
examining unilateral otolith function following space flight. Ten astronauts partici-
pated in unilateral otolith function tests, three times preflight and up to four times
after Shuttle flights from landing day through the subsequent 10 days. During uni-
lateral centrifugation, utricular function was examined by the perceptual changes
reflected by the subjective visual vertical (SVV) and the otolith-mediated ocular
counterroll, designated as utriculo-ocular response (UOR). Unilateral saccular
reflexes were recorded by measurement of cervical vestibular evoked myogenic
potentials (cVEMPs).
The findings demonstrate a general increase in interlabyrinth asymmetry of
otolith responses on landing day relative to preflight baseline, with subsequent
reversal in asymmetry within 2–3 days. Recovery to baseline levels was achieved
within 10 days. This fluctuation in asymmetry was consistent for the utricle tests
(SVV and UOR) while apparently stronger for SVV. A similar asymmetry was
observed during cVEMP testing. In addition, the results provide initial evidence
of a dominant labyrinth. The findings require reconsideration of the otolith asym-
metry hypothesis; in general, on landing day, the response from one labyrinth
was equivalent to preflight values, while the other showed considerable discrep-
ancy. The finding that one otolith response can return to one-g level within hours
after re-entry while the other takes considerably longer demonstrates the
importance.
Appendix
Unilateral Centrifugation
Unilateral centrifugation is performed on a rotating chair with the additional facility

of shifting the test subject to the left or to the right. The UC stimulus profile consists
of a spin-up with angular acceleration of 3°/s2 around the earth-vertical Z-axis up to
an angular rate of 400°/s. Details of this equipment and stimulus technique have
been published previously (Clarke et al. 1996, 2001, 2013).
top view

co-axis co-axis
FR FR
right utricle left utricle

stimulated stimulated
rear view
Stimulus cycle
GIA tilt
12º
FR To left
FL labyrinth
period
= 17.12 g
Feff Fef Fer Feff

Fg Fg
To right
labyrinth
Eccentric left Centric rotation Eccentric right 12º
Fig. 2.10 Left: During constant angular rate rotation this stimulus technique provides for linear
acceleration along the interaural axis, i.e. predominantly across the planes of the utricles. During
centric, on-axis rotation, the centrifugal forces to the right and left utricles are equal and opposite.
However, the right and left labyrinths are separated by approximately 7 cm, so that when one laby-
rinth is positioned on axis on the rotator, the eccentric labyrinth is exposed to a centrifugal force
along the interaural axis, and the gravitoinertial force profile is tilted; the opposite labyrinth
remains unaffected. Right: Unilateral centrifugation thus provides for exclusive stimulation of the
right or left labyrinth. Note: the semicircular canals respond only to changes in angular velocity
(i.e. acceleration). During rotation at constant angular velocity they remain silent
Unilateral testing is commenced after at least 2 min of constant angular rate

rotation to ensure extinction of any perrotatory nystagmus or canal-induced ocu-
lar torsion (Smith et al. 1995; Buytaert et al. 2010). Translating the subject chair
laterally by ±3.5 cm from the vertical rotation axis during constant-velocity rota-
tion then generates a centripetal acceleration to the off axis, or eccentric laby-
rinth of typically 0.35 g. The resulting stimulus profile is shown in Fig. 2.10
(right panel).
Subjective Visual Vertical
SVV testing is carried out in complete darkness with only a luminous line visible to
the test subject, i.e. without any visual cues, and thus dependent on the information
from the otolith organs for the estimation of the direction of gravity.
The SVV trials commence after the rotating chair has been accelerated (as
described above), and the subject is rotating at constant velocity. Testing is usually
performed with the subject in the on-centre position, where equal and opposite cen-
trifugal forces act on the left and right utricles. Unilateral trials are then performed
in the positions, left ear eccentric and right ear eccentric. The stimulus profile is
illustrated in Fig. 2.11.
During the test the subject views a dimly lit red luminous line of 20 cm in length,
mounted at the centre of a dome with a 60 cm diameter. The test subjects use a
Appendix 25
cw 25
20
15
SVV Estimate (º)

10
5
0
–5
–10
–15
range for normal subjects
–20 25 - 75 %
5 - 95 %
ccw –25
right ear centre left ear
eccentric rotation eccentric
UC – plateau profile
Chair position
right 60 s. 60 s. 60 s.
left
Chair rate [ º/s]
400
Time
Fig. 2.11 Left: Subject in eccentric rotator in the Vestibular Lab. The insert shows the interior of
the SVV dome with the luminous line. Top right: Normal SVV response range (95%). Lower
Right: Schema of rotation and chair position profile during SVV testing
joystick to rotate the motor-driven luminous line to be parallel with the perceived
gravitational vertical. Between trials, the line was extinguished and rotated to a
random position under programme control and then switched on and the procedure
repeated. SVV estimation was performed in each position (on-centre, left ear eccen-
tric, right ear eccentric). The SVV asymmetry ratio was calculated from the median
values of the set of trials performed in the eccentric positions.
The SVV asymmetry ratio (AR) was calculated as follows:
SVVright - SVVleft
SVVAsymmetry Ratio = ´100
SVVright + SVVleft

Utriculo-Ocular Response
During UOR testing the subject chair was oscillated from left to right. An exam-
ple of one complete cycle is shown in Fig. 2.6, together with the torsional com-
ponent of the eye movement response. Throughout testing, video images of the
eyes were monitored, and the coordinates of each eye were recorded for offline
analysis. See Appendix for details. All measurement and evaluation of eye
movements were performed with the DLR Eye tracking Device (ETD),
Chair position
17.2s
left
Chair rate
400º/s
0º/s
Time
Vertical
2.5º
horizontal
2.5º
torsional
2.5º
Lateral g-force
0.4g
Fig. 2.12 Left: Rotating chair, insert showing astronaut wearing the ETD for recording eye move-
ments. Top right: Schema illustrating the UOR stimulus profile. Lower right: Resultant three-
dimensional eye movement response with clear modulation of the torsional component, as elicited
b the stimulus to the utricle. The two full lines represent the torsional movement of the subject’s
right and left. The lower trace shows the acceleration level as measured at the subject’s head
providing high-resolution and sampling-rate measurement of 3D eye movement

(see Chap. 5 for details). The stimulus profile for UOR testing is illustrated in
Fig. 2.12.
The measure of change in the UOR was determined by calculating the ratio of the
OCR magnitude (in degrees) to the effective tilt of the gravitoinertial vector (in degrees)
at the eccentric ear. The left-right asymmetry of the UOR was calculated as:
OCR right - OCR left

OORAsymmetry Ratio = ´100
OCR right + OCR left

Appendix 27
Cervical Evoked Myogenic Potentials (cVEMPs)
The VEMP provides a measure of saccular function indirectly through a vestibulo-

collic reflex (Fig. 2.13). Short auditory clicks gave rise to a short-latency inhibition
of activity in the contracted neck (sternocleidomastoid) muscle. The activity of this
muscle is recorded with surface electrodes. Left-right asymmetry values are based
on the amplitude of the response from the p13-n23 segment.
The left-right asymmetry ratio was based on the amplitude of the response from
the p13-n23 segment. The normalised p13-n23 amplitudes and the symmetries of
the subjects’ responses are analysed using the following formula:
p13 n 23 Amp right - p13 n 23 Amp left

VEMP Asymmetry Ratio = ´ 100
p13 n 23 Amp right + p13 n 23 Amp left

During the preflight sessions, the reference data were determined for each indi-
vidual: VEMP threshold—125 dB (SPL) in one subject, 130 dB (SPL) in six s ubjects
and 135 dB (SPL) in two subjects. The asymmetry ratios all remained within the
30% range employed clinically for normal subjects.
VEMP Electrode Derivation

Forehead
Ground
SCM right SCM left

Ch 1 Ch 2
Sternum right Sternum left

Ch 1 Ch 2
Fig. 2.13 Muscle activity in the neck is recorded with surface electrodes as subjects lay supine
and lifted their heads to contract the neck muscle. Responses are averaged across sets of 150 audi-
tory clicks (five clicks per second) presented during tonic contraction
Chapter 3
The Three-Dimensional Vestibulo-Ocular
Reflex During Prolonged Microgravity
3.1 Introduction
Given the influence of gravity as a reference for spatial orientation, the following
questions arise for the microgravity scenario:
How does the vestibular system adapt to the absence in space, and to the reintroduc-
tion after landing, of the gravity vector?
Is the vestibule-oculomotor response simply modified by an amount equivalent to
the otolith-mediated contribution?
Or does it adapt with a systematic latency or time constant to some other level?
To this end a series of experiments was designed to examine the three-dimensional
nature of the vestibulo-oculomotor responses in microgravity. The three-dimensional
axes for eye movement and head movement are illustrated in Fig. 3.1.
Right
+A z
eye
Left +αz
X eye
Y +αx
X
+A x +A y
Y
+α y
Eye movements are described by Head movements can be described by

rotations around the 3 orthogonal axes rotation about, and translation along
= 3 degrees of freedom (+ vergence). each of the 3 orthogonal axes
= 6 degrees of freedom
Governed primarily by visual attention,
but also by vestibular input.
Fig. 3.1 Head and eye movements—two closely coupled systems. Illustration of the degrees of
freedom of eye and head movement. The eyes can be rotated about the three orthogonal axes cor-
responding to the orthogonal axes of the head. Adopting the aeronautical terminology, these rota-
tions are known as yaw, pitch and roll

30 3 The Three-Dimensional Vestibulo-Ocular Reflex During Prolonged Microgravity
Fig. 3.2 Testing on the

MIR station with the
monocular VOG system
Horizontal, vertical and torsional components of eye movements were measured

during active yaw, pitch and roll oscillation of the head. An example of the eye and
head movements is shown in Fig. 1.5.
Measurements were performed under Earthbound, one-g conditions to obtain
baseline reference values. Initial spaceflight tests were performed during the 10-day
Mir92 mission (Clarke et al. 1993a, b) and during the 30-day EuroMIR 94 mission
using the monocular VOG system. Figure 3.2 shows the German astronaut during
the performance of the so-called VOG experiment. Subsequently, more comprehen-
sive measurements were made during the EuroMIR 95 mission using the binocular
VOG system (Clarke et al. 1996, 2000). Over the course of this 180-day space mis-
sion, the spaceflight subjects performed the test procedure at regular intervals.
Finally, postflight testing was performed over the 10-day period after return to one-g
conditions. Figure 3.3 depicts the inflight experiment in progress. The prolonged
duration of the mission permitted repeated testing of the VOR under stable
Fig. 3.3 3D-VOR
experiment performance
during the EuroMIR 95
mission on the MIR space
station
3.1 Introduction 31
microgravity conditions, beyond the initial phase of spaceflight during which vari-
ous adaptation processes are to be expected. As further reference, comparative
measurements were carried out with a group of 12 control subjects under one-g
conditions in the laboratory.
3.1.1 Test Procedure
Initially, all subjects were trained to perform smooth head oscillations in synchrony
with a metronome cue and with peak amplitude of approximately 15°–20° (cf.
Fig. 1.5, lower traces of head movement). During each experiment session, a pre-
recorded soundtrack provided verbal instructions and metronome cues to ensure
uniform performance of the head movements. Identical test procedures were
performed with all control and spaceflight subjects.
The spaceflight subjects were familiarised with the scientific background and
trained thoroughly in the experimental procedure during the 6-month period prior to
the spaceflight. See Clarke et al. (2000) for details.
During each measurement session, the subject wore a head-mounted assembly
incorporating (a) two infrared-sensitive video cameras for high-resolution image
recording of right and left eyes, (b) three-dimensional angular rate sensors and linear
accelerometers for recording head movement and (c) headphones for acoustic cues.
Eye-to-head velocity gain and phase shifts were calculated for each of the hori-
zontal, vertical and torsional VOR components during yaw, pitch and roll move-
ments of the head, respectively. VOR gain was calculated as the ratio of the eye/
head peak velocities and the phase shift as the difference (eye-head) between their
phase angles. Up/down gain asymmetry was calculated for the v-VOR for each trial
as the difference between v-VOR gain for head downward and head upward veloc-
ity. A typical 3 × 3 gain matrix is shown in Fig. 3.4.
Head & eye coordination

is supported by the 3D
vestibulo-ocular reflex.
Z
Hx Hy Hz
Fig. 3.4 From the Ex -0.39 0.07 0.06
three-dimensional
measurement of head and X Ey 0.02 -0.92 0.02
eye movements, as
illustrated in Fig. 1.5, a Y
Ez 0.15 -0.18 -0.93
3 × 3 gain matrix can be
calculated (see text) The 3x3 ‘gain’ matrix is a useful quantitative description.
3.2 Spaceflight Findings
The modification of the 3D-VOR in the absence of gravity is reflected by the reduc-
tion of the torsional component, which is largely driven by the information from the
otolith organs (see Fig. 3.5).
Yaw Rotation
1.2 1.2
1.0 1.0
0.8 0.8
0.6 0.6
0.4 0.4
0.2 0.2
0.0 0.0
5 10 15 20 25 140 160 0 5 10 15
Pitch Rotation
1.2 1.2
1.0 1.0
0.8 0.8
0.6 0.6
0.4 0.4
0.2 0.2
0.0 0.0
5 10 15 20 25 140 160 0 5 10 15
Ss1
Preflight baseline
Ss2
Preflight baseline
Roll Rotation
1.2 1.2
1.0 1.0
0.8 0.8
0.6 0.6
0.4 0.4
0.2 0.2
0.0 0.0
5 10 15 20 25 140 160 0 5 10 15
Preflight Days inflight Days after landing
Fig. 3.5 Examples of VOR gain ratios for yaw, pitch and roll rotations. Each member of the con-
trol group was tested (a) in the upright position for yaw rotation and (b) for head pitch rotation in
the upright and in the g-neutral position (lying onside) and for roll rotation in the upright and
g-neutral position (lying supine). The left panels show the average gain (±1 SD) for the control
group (n = 13). The right panels show the single-case, longitudinal data across the preflight,
inflight and postflight test periods with the two spaceflight subjects (Ss1, Ss2). The time axis over
the 180-day mission is scaled to accommodate the different sampling schedules during the early
inflight, late inflight and postflight phases of the mission
3.2 Spaceflight Findings 33
The study constituted the first comprehensive examination of the three-

dimensional VOR in humans over the course of long-term spaceflight. The results
of the control study provide the necessary reference data for the two single-case,
longitudinal studies conducted with the spaceflight subjects.
3.2.1 Horizontal VOR
The h-VOR results from the control group proved compatible with those of previous
studies of eye/head coordination during voluntary head movements (e.g. Tomlinson
and Schwarz 1980; Wall and Black 1984). The spaceflight findings confirm that the
h-VOR elicited by active yaw oscillation of the head, while fixating a visible target,
is not altered during prolonged spaceflight. This concurs with the findings from the
majority of reported human and monkey studies (humans: Benson and Viéville
1986; Thornton et al. 1989; Clarke et al. 1993a, b; monkeys, Correia et al. 1992;
Cohen et al. 1992; Dai et al. 1994).
There have been reports of h-VOR modification during spaceflight (Viéville
et al. 1986; Kornilova et al. 1987); however the present findings suggest that any
such changes lie within the individual’s range of variation, e.g. mediated by a modi-
fication in the subjects’ mental set (e.g. Barr et al. 1976; Skipper and Barnes 1989).
3.2.2 Vertical VOR
Under one-g conditions, pitch movements of the head involve dynamic stimulation
to the vertical semicircular canals and the otolith organs. In microgravity and in the
on-side, gravity-neutral position on Earth, head pitch stimulates only the canals so
that a decrease in v-VOR gain might be expected. This was not the case. The space-
flight findings show no difference to one-g, baseline testing. Likewise, the results
from the control study demonstrate that v-VOR gain is equivalent in the upright and
onside positions. These findings suggest that the visually driven fixation overrides
any change in gain due to the absence of a matching otolith contribution. These find-
ings agree with those of Baloh and Demer (1991) and Clément et al. (1999) who
concluded that body orientation had no significant effect on the gain and phase of
the vertical vestibulo-ocular or visual-vestibular reflex.
Discussing their laboratory findings, Baloh and Demer (1991) pointed out that,
in addition to visual drive, neck sensory input can compensate for deficiencies in the
v-VOR during active pitch movements. While this may be doubtful in the laboratory
situation—as Morrow and Sharpe (1993) concluded from their comparative study
of active and passive head roll—it may well be the case over a stay of 6 months in
microgravity. This is analogous to the adaptive modification observed in patients
after bilateral loss of labyrinth function and attributed to the re-weighting of neck
proprioceptive information, which appeared to proceed over many months (Kasai
and Zee 1978; Bles and de Graaf 1991). It might also be speculated that during
0.3 0.3
Preflight Inflight Postflight

0.2 0.2
VOR Asymmetry
VOR Asymmetry
0.1 0.1
-54 -26 1 25 140 170 1 5 9 13 days
–0.1 –0.1
–0.2 –0.2
Controls Spaceflight Subject S1

–0.3 –0.3
Fig. 3.6 Up/down asymmetry of slow-phase velocity, as measured over the course of the space-
flight mission. For reference the control group’s results in the upright (i.e. gravity-dependent) and
onside (i.e. gravity-neutral) positions are shown on the left
earth-based positional studies, the presence and direction of the g-vector is continu-
ously processed by central vestibular networks and that this information facilitates
a correction to the efferent drive to the oculomotor plant, despite the lack of a direct
modulation of the dynamic otolith-ocular response (OOR) component.
3.2.2.1 Up/Down Asymmetry
Of particular interest is the occurrence of an inversion in the up/down asymmetry of

the v-VOR during prolonged microgravity. This finding indicates that the VOR—
after adaptation to prolonged microgravity—cannot simply be equated to the
response obtained by positioning an otherwise “one-g-adapted” test subject in the
g-neutral orientation. Such inversion does not occur under one-g conditions regard-
less of body orientation (cf. left panel in Fig. 3.6). On the other hand, the absence of
inversion during real-target fixation again demonstrates that attention to a visual
target is sufficient to override the vestibular effect.
Related to these results are the response inversions observed during testing in
microgravity during optokinetic (Clément et al. 1986) and smooth pursuit testing in
man (André-Deshays et al. 1993; Glasauer et al. 1993) and the earlier observations
of vertical eye movements after macular ablation (Igarashi et al. 1978).
3.2.3 Torsional VOR
The t-VOR results from the control group concur with those reported from earlier
studies (Collewijn et al. 1985; Morrow and Sharpe 1993). The high interindividual
variability in t-VOR gain as reported in those studies was also confirmed with
3.3 Summary 35
values ranging between 0.32 and 0.70. This confirms the interpretation of Morrow
and Sharpe (1993), who attributed this enhancement to torsional optokinetic
stimulation.
In contrast to the v-VOR during head pitch, the t-VOR gain during head roll was
found to be significantly lower in the gravity-neutral, supine position than in the
upright position. Thus, during testing in the upright position, the canal-mediated
torsional VOR is supplemented by the dynamic OOR, primarily mediated by stimu-
lation to the utricles (Jauregui-Renaud et al. 1996; Groen et al. 1996).
In the spaceflight subjects, notable modification of t-VOR gain was observed
over the course of the inflight and postflight periods. After entry into microgravity,
this was characterised by a consistent decrease over all tested conditions for the
initial 26 days of spaceflight. This reduction lies within the range measured in the
control group in the gravity-neutral position and corresponds to existing measures
of OOR gain during linear acceleration testing, i.e. approx. 0.2 (Lichtenberg et al.
1993; Paige and Seidman 1999; Clarke et al. 1999); it can therefore be directly
attributed to the elimination of the OOR contribution in microgravity. However, in
the later inflight session (days 139–171), there is clear indication of a gain
enhancement towards preflight level. This finding supports the idea of adaptive
modification proceeding over several months. As suggested above, it is likely that
this modification is associated with a re-weighting of the neck-proprioceptive affer-
ents in the vestibular nuclei.
The postflight t-VOR gain from the first session on R + 0 is, in almost all condi-
tions, comparable to that measured in the last inflight session. The subsequent dis-
tinct drop in t-VOR gain, between the first (12 h) and second sessions (30 h) after
landing, indicates that during the postflight phase adaptation involves an initial
decrease in t-VOR gain (approx.) over the first 24 h. As postflight testing continues,
the t-VOR gain remains low and unstable over the first 7 days and then increases to
levels equivalent to or greater than preflight baseline values.
3.3 Summary
The findings confirm that the dynamic t-VOR, in contrast to the h-VOR and v-VOR,
is clearly modified by alterations in gravitational loading. Whereas the initial
decrease in t-VOR gain corresponds to the reduction of concomitant otolith stimula-
tion, v-VOR gain is only minimally influenced. This is attributed to the two comple-
mentary factors—the dominance of visual drive over vertical eye movements, which
masks the influence of altered vestibular input, and to the fact that torsional eye
movements, being largely involuntary, provide better indication of changes in the
vestibular system.
On the other hand, the reversal of up/down gain asymmetry in the v-VOR in
microgravity complements earlier evidence of the role of the otolith organs in the
control of vertical eye movements (Clément et al. 1986, Clément and Lathan 1991;
Igarashi et al. 1978).
The gradual increase in t-VOR from the first to the sixth month in microgravity
demonstrates the existence of longer-term adaptive processes than has previously
been considered. Likely factors are the adaptive re-weighting of neck-proprioceptive
afferents and/or enhancement of efference copy. Taken together with the findings
from parallel studies of visuomotor testing (Manzey 1998), the long-term adaptive
modification of the 3D-VOR over the 6-month spaceflight indicates that adaptation
of the sensory-motor systems to microgravity proceeds over a considerably longer
time course than the interval of a few days, as has often been assumed and subjec-
tively reported by most astronauts and cosmonauts.
Chapter 4
Listing’s Plane and the 3D-VOR
in Microgravity
4.1 Introduction
Eye movements are generally described by terms such as looking left, right up or
down, i.e. described as movement in two dimensions. However, as described in
previous chapters, direction of gaze is defined by rotations of the eyeball in the
orbit, controlled by the three pairs of extraocular muscles (Fig. 4.1). Accordingly,
eye movement is more correctly described by rotations around the horizontal, verti-
cal and torsional axes.1
While horizontal and vertical eye rotations are voluntarily controlled by the indi-
vidual, this is not the case for torsional rotations. Since the late nineteenth century (e.g.
Helmholtz 1867), it has been known that under normal circumstances the torsional
orientation of the eye is minimised by neural control. This restriction implies a reduc-
tion from three to two degrees of freedom for the eyeball and is known as Listing’s
Law. Numerous investigations have verified the validity of Listing’s Law during those
Fig. 4.1 Eye movements are described by Z

rotations around the three orthogonal axes
and are controlled by the actions of the
three extraocular muscles
1
While the convention of three orthogonal axes is convenient for measurement and analysis, in
reality the situation is more complex. The eye has no fixed centre of rotation, and the extraocular
muscles do not operate orthogonally.

38 4 Listing’s Plane and the 3D-VOR in Microgravity
eye movements related to gaze direction, i.e. fixations, saccades and smooth pursuit
(e.g. Straumann et al. 1996). In consequence all axes about which the eye is voluntarily
rotated lie in one plane, called Listing’s Plane (LP). However, as described in the pre-
vious chapters, this is not the case for vestibulo-ocular reflex responses, where a con-
siderable torsional component can be elicited, contrary to Listing’s Law.
Initially it was held that LP is head-fixed and independent of head orientation to
gravity, i.e. unchanged in different head positions relative to the Earth’s gravity vec-
tor. One exception to this is related to the occurrence of OCR, which leads to a
translation of Listing’s Plane along the x-axis (see Fig.2.3 for an example). More
recently a number of LP studies in humans indicated that its orientation is slightly
tilted (1°–2°) in different head pitch positions. (Bockisch and Haslwanter 2001;
Furman and Schor 2003). This effect appears to be stronger in the monkey
(Haslwanter et al. 1992). A further study in the monkey (Crawford and Vilis 1991)
showed that LP tends to be collinear with the coordinate frame of reference of the
3D-VOR. These authors introduced the concept of the minimal gain vector (MGV)
as an indicator for the orientation of the 3D-VOR as it is represented in the CNS. The
MGV is defined as that vector parallel to the head axis around which the VOR has
minimal gain, i.e. representing the effective axis for torsional rotation of the eye.
Fig. 4.2 Depiction of brain areas Vestibular cortex

involved with vestibular and
oculomotor control. The internal
coordinate representations for the
Oculomotor control
vestibular and oculomotor control
systems are illustrated as 3D
vectors
Eye
Central vestibular
system
Vestibular labyrinth
It was described in Chap. 3 how during prolonged microgravity the three-

dimensional vestibulo-ocular reflex (3D-VOR) is altered, primarily due to the radi-
cal loss of stimulation to the otolith organs during head movement.
This chapter describes the influence of prolonged microgravity, i.e. the effective
absence of the gravity reference, on the orientation of LP and the 3D-VOR coordi-
nate frames, and their behaviour after return to Earthbound, one-g conditions
(Fig. 4.2). Examination of the collinearity between the Listing and VOR coordinate
systems is of interest in order to determine whether a uniform representation of
three-dimensional space exists in those CNS areas related to spatial orientation.
Spatial aspects of the 3D-VOR can be evaluated by calculating the orientation vec-
tors associated with slow-phase eye velocity generated by the VOR. The requirements
for the modelling of the 3D aspects of this response are fulfilled by employing rotation
vector and quaternion representations of eye position and velocity as cited above.
4.2 Parabolic Flight Study 39
4.2 Parabolic Flight Study
In a preliminary study, the orientation of Listing’s Plane was measured in ten healthy
subjects during parabolic flight (Clarke and Haslwanter 2007).
The parabolic flight manoeuvre provides for short-term changes in the gravitoin-
ertial vector between one and zero gravity (Fig. 4.3). It was found that in the zero-g
condition, LP orientation was consistently altered (Fig. 4.4). LP elevation was tilted
backwards on average by approx. 10°.
34 000
32 000
ALTITUDE, FEET
45º NOSE HIGH 45º NOSE LOW
30 000
28 000
350 KIAS
26 000
350 KIAS
24 000
1.8g ZERO-g 1.8g
0 20 45 65
MANEUVER TIME, SECONDS
Fig. 4.3 Left: The European parabolic flight aircraft. Right: Illustration of classic zero-g flight
profile with zero-g during free-fall interval. See Karmali and Shelhamer (2008) for a detailed
description of the dynamics of parabolic flight
0.89x + 0.11y + 0.04z = 0 0.12x + 0.01y + 0.01z = 0 1.26x + 0.10y + 0.02z = 0 0.63x + 0.16y + 0.06z = 0
hz hz hz hz
1g 1g 1g 1g
10 10 10 10
0 0 0 0
-10 -10 -10 -10
5 0 5 hx 5 0 5 hx 5 0 5 hx 5 0 5 hx
3.59x + 0.27y + 0.49z = 0 3.68x + 0.52y + 0.59z = 0 3.30x + 0.19y + 0.35z = 0 3.47x + 0.12y + 0.37z = 0
hz hz hz hz
0g 0g 0g 0g
10 10 10 10
0 0 0 0
-10 -10 -10 -10
5 0 5 hx 5 0 5 hx 5 0 5 hx 5 0 5 hx
Parabola: 1 2 3 4
Fig. 4.4 X–Z projection of the calculated displacement planes as recorded during the one-g and
zero-g phases of four consecutive parabolae, illustrating the consistent change in elevation in zero
g. The equation for the fitted plane is included for each trial. The laser diode projection of calibra-
tion points is indicated in the cartoon depicting straight and level flight (upper panel)
Fig. 4.5 3D vector Right Eye

representation of the
Left Eye
orientation of Listing’s z
Plane (LP) of the left and
right eye during one-g and
zero-g conditions during
0,25
parabolic flight. Each
0G
vector depicts the median 0G
value calculated from the
data of five subjects. The
tilt in LP elevation and the
1G
divergence of azimuth in 0,00 1G
zero-g conditions as
quantified in the results
chapter are clearly
visualised y
x
0,50
0,00
–0,25 1,00
The azimuth angles of the left and right eyes also diverged in zero g, with a ver-
gence angle varying between 6.1° and 11.8° (p = 0.04). Dissociation in torsional eye
position between 1g and 0g was also observed (p = 0.03) (Fig. 4.5). Concurring
changes in LP orientation have also been reported from centrifuge experiments
(Nooij et al. 2008) involving increased gravitoinertial conditions.
4.3 Spaceflight Study
This next section describes a series of five single-case longitudinally studies, per-
formed during spaceflight missions of 6-month duration. These were conducted
onboard the International Space Station (ISS). Measurement carried out prior to
spaceflight provided baseline reference values and subsequent postflight measure-
ments conducted over a period of up to 60 days after landing provided a measure of
readaptation to Earthbound conditions (Clarke 2008; Clarke et al. 2013). As in the
parabolic flight study, binocular eye images and head movement sensor signals
were recorded throughout the experiment protocol using the DLR Eye Tracking
Device. This equipment is described in detail in Chap. 5 on Technology.
During the preflight sessions, the spaceflight subjects were also trained thor-
oughly to operate the measurement equipment and to perform the test procedure, in
order that they could carry out the experiment protocol autonomously onboard the
space station (Fig. 4.6).
To evaluate the 3D-VOR coordinate frame of reference, recordings of eye and
head movement were made during active head movements around the yaw, pitch
and roll axes, as described in the previous section.
During spaceflight each of the spaceflight subjects performed the experimental
procedure at 3-week intervals over the course of their 6-month stay onboard the ISS.
4.3 Spaceflight Study 41
The inflight measurements were performed in a one-man subject/operator

scenario with online monitoring and recording of eye and head movements on the
ETD system unit (see Fig. 4.7). After completion of each spaceflight, the hard disk
with the experiment recordings was returned to the investigators, and all measurement
sequences were subsequently analysed offline in the laboratory.
Fig. 4.6 Astronaut
training session with the
ETD equipment in the
Gagarin Cosmonaut
Training Centre
Fig. 4.7 Inflight testing on the ISS. The crew member uses the ETD eye and head tracker to per-
form the experiment autonomously. The individually moulded facemask provides a comfortable
interface and prevents device slippage. The inset shows the ETD software GUI with eye images
and online traces of horizontal and vertical eye positions
Preflight Inflight
20 20
Horiz
Horiz
0 0
–20 –20
20 20
Vert
0 0
Vert
–20 –20
20 20
Tors
Tors
0 0
–20 –20
0 10 20 30 s 0 10 20 30 s
20 20
Elevation
Elevation
0
0
–20 –20
–20 0 20 –20 0 20 –20 0 20 –20 0 20
20
20
Azimuth
Azimuth
0
0
–20
–20
–20 0 20 –20 0 20 –20 0 20 –20 0 20
Left Right Left Right
Fig. 4.8 Upper panels: Examples of three-dimensional recordings of saccade sequences from pre-
flight (one-g) and inflight (zero-g) sessions. Lower panels: Corresponding LP elevation (X–Z) and
azimuth (Y–Z) projections for right and left eyes. Ordinate units are degrees for all plots
The examples shown in Fig. 4.8 illustrate the increased torsional component
(upper panels) and the resultant backward tilt of LP under zero-g conditions.
Furthermore, the inflight data show changes in the azimuth projections, resulting
from a divergence in eye position compared to preflight one-g results, demonstrat-
ing the influence of the otolith input in regulating torsional eye position.
The LP thickness for each of the eyes of the five tested long-term subjects
amounted on average to preflight 0.59° ± 0.13° inflight 0.61° ± 0.13° and postflight
=0.62° ± 0.14°, respectively, demonstrating that LP thickness does not change in
microgravity. No statistical difference within and across the five tested subjects
could be determined.
During preflight testing the coordinate frames of LP and MGV were near col-
linear (see boxplots on the left in Fig. 4.9). The subsequent dissociation between LP
and the MGV, which occurred after transition to zero-g conditions, was maintained
throughout the 180-day mission. This dissociation was consistently observed in all
tested subjects. The vector representations shown in Fig. 4.10 demonstrate clearly
how both the MGV and LP are altered in zero g, i.e. in opposite directions. LP tilts
backwards while MGV tilts forwards under zero-g conditions. The data in Fig. 4.9
also show the distinct readaptation to preflight values after return to Earthbound,
one-g conditions.
This readaptation pattern to one-g conditions fluctuated diversely amongst sub-
jects, but consistently with a time constant of several days. Testing after 60 days
30
20
Angle of Elevation (º)
10
–10
–20
–30
0 100 180 R+0 +12 +60 days
Fig. 4.9 Longitudinal course of the elevation component of LP and MGV as measured in one
subject over the course of the 6-month period on the International Space Station (ISS). Preflight
averages are shown on the left
L/1g R/1g
0.5 R/1g L/1g 0.5
L/0g R/0g
L/1g
0.0 R/0g
L/0g 0.0
R/0g R/1g
L/0g
–0.5 0.0 –0.5 0.0

0.0 0.5 0.0 0.5
0.5 1.0 0.5 1.0
Fig. 4.10 Vectors representing the orientation in the CNS of the 3D-VOR (MGV) (left) and orien-
tation of Listing’s Plane (LP) (right) during one-g Earthbound (1g) and zero-g conditions (0g), for
the right and left eyes. The vectors represent the averages across five tested subjects
indicates comparable values to preflight, i.e. with the two coordinate frames (LP and
MGV) again effectively collinear.
The results can be understood as reflecting the absence of the gravity-induced,
otolith-mediated component of the VOR during head movements around the roll axis
in microgravity, where only the canal-induced component persists, i.e. the torsional
component is significantly reduced as compared to normal Earth-gravity conditions.
This confirms the findings of the previous study (in Chap. 3) where the 3D-VOR was
examined during an equivalent length of stay on the MIR space station.
In contrast to the VOR, the LP recordings from the spaceflight experiments
reveal a consistent backward tilt of the LP frame of reference compared to
Earthbound values (Fig. 4.10, right panel). Under zero-g conditions, the corre-
sponding LP projections demonstrate the backwards tilt in elevation and divergence
in azimuth observed. These findings result from the increased torsional component
during inflight microgravity conditions.
This proves consistent with the results of the LP measurements performed dur-
ing the short durations of microgravity available in parabolic flight (Clarke and
Haslwanter 2007). After onset of microgravity during the parabolic manoeuvre, a
backward tilt of approx. 10° and a divergence in the azimuth angles of LP of
greater than 6° were observed. This finding is clearly in contrast to the results of
earlier Earthbound studies where only a slight change in LP orientation (<2°) was
observed with changes of head pitch position (Bockisch and Haslwanter 2001;
Furman and Schor 2003; Hess and Angelaki 2003). This is presumably due to the
fact that under Earthbound conditions the gravity vector persists and will continue
to be perceived and processed by the otolith circuitry, regardless of head position.
On the other hand, the complete absence of the otolith-mediated gravity vector in
space represents a radical loss for the otolith apparatus and the entire sensorimotor
complex. It is proposed that the gravity vector provides a basic reference for the
CNS and effectively stabilises the various mechanisms of the sensorimotor
complex.
The backward tilt of LP observed in microgravity results from an increase in the
torsional component during horizontal and vertical saccades and fixations. This may
be interpreted as a disinhibition in the control of torsional eye position by the otolith
afferent signals. Thus it appears that the otolith-mediated gravity vector has a stabi-
lising, or inhibitory, influence on torsional eye position in the human. It is worthy of
note that the changes in orientation of LP and the 3D-VOR occur directly within
seconds after removal of the gravity vector and as such cannot be regarded as an
adaptive response. Further, the reorientation of both coordinate frames of reference
(LP and 3D-VOR) remains throughout the inflight period in microgravity, indicat-
ing that no substitute for the gravity vector is made. In contrast, however, after
returning to one-g conditions, a readaptation to preflight values was observed in
each individual. The readaptation observed here proceeded over the postflight,
2-week test period and beyond. This observation demonstrates that during pro-
longed microgravity, adaptation in the CNS takes place due to the chronic loss of
the otolith-mediated gravity reference.
The concept of a stabilising, or inhibitory, function of the otolith afferences is in
line with various findings of gravity specific adaptation of the canal-mediated VOR
(Cohen et al. 2002; Wearne et al. 1998) and earlier reports of a modulation of veloc-
ity storage parameters by the otolith afferences (Vilis 1993; Raphan and Cohen
1988; Bos and Bles 2002). It has been determined that this otolith-canal interaction
most likely occurs in the nodulus and uvula (Angelaki and Hess 1995).
This is also supported by clinical evidence from patients with cerebellar lesions
in this area and in whom a gravity-dependent drift component in downbeat nystag-
mus was determined. It was concluded that lesions in the nodulus and uvula lead to
a dysfunction of the otolith-ocular pathways (Marti and Straumann 2002). In a pre-
vious report, the author proposed the concept of an inhibitory function of the otolith
afferences on the SCC-driven torsional VOR (Clarke and Kornilova 2007). The
present findings provide evidence that such an inhibitory function assists in the
maintenance of LP. Further evidence of such a coupling between the gravity refer-
ence and the oculomotor control circuitry is the gravity-dependent bias component
on neural signals described by Frens et al. (1998) who found that the oculocentric
coordinate system is biased in the direction of gravity.
The thickness of LP did not alter significantly between one-g and zero-g condi-
tions. On first glance this seems to contradict the findings of Diamond and Markham
(1998) from a previous microgravity study where they reported an increase in the
torsional component of eye movement under microgravity conditions. However
their analysis yielded eye position relative to head, rather than in LP coordinates. A
backward tilt of LP elevation when projected onto a head coordinate frame of refer-
ence would mimic an increased thickness.
It appears that given the lack of voluntary control of ocular torsion, the tonic otolith
afferences and the resultant generation of an internal gravity reference stabilise tor-
sional eye position during normal oculomotor tasks. In this sense, the otolith-mediated
gravity vector provides for a coupling of the frames of reference of LP and the 3D-VOR.
Consideration of the OCR gain per se is warranted here. In an earlier report,
Leigh et al. (1989) demonstrated that those factors that influence horizontal and
vertical VOR gain—visual fixation, the smooth pursuit and optokinetic systems
and mental set—have little or no effect on torsional VOR gain. Similar to reorien-
tations of the head (and eye) around the horizontal and vertical axes, it can be
presumed that under natural circumstances the head is actively tilted in order to
direct attention to some visual scene. In the case of horizontal or vertical rotation,
visual fixation would override the VOR, and the eyes would be aligned to the
intended target.
On the other hand, since the torsional VOR is not normally cancelled by visual
fixation, it would make sense to keep the OCR gain as low as possible so that the
meridians of the retina remain aligned as well as possible with the main axes of the
intended visual target. In the case of sports and artistic performers, for example,
who intuitively keep their head upright, the visual surround would thus be near
optimally aligned with the orientation-specific organisation of the visual system so
that visual acuity and processing would function most efficiently.
The findings of an experimental study (Mast and Meissner 2004) demonstrate
such an effect during mental rotation tasks. Accuracy proves to be highest when
the direction of mental and physical body rotation are congruent. A separate study
(Wraga et al. 2000) where subjects were required to update computer displays
reported an improved performance when subjects mentally rotated themselves
compared to when they mentally rotated the display. It is postulated that such
behaviour results from the so-called oblique effect, i.e. the fact that visual acuity
is highest along the vertical and horizontal meridians of the retina. This “oblique
effect” and its neural substrate are well documented in the literature on the visual
system (see Li et al. 2003 for review). Of particular interest is the narrow tuning
width (±17°) of those cells in the primary visual cortex sensitive to horizontal and
vertical orientations, which matches well with the range of ocular counterroll that
occurs during natural head tilting. It follows that a low torsional gain effectively
restricts torsional eye position to correspond to this tuning width.
More generally, it appears that the absence of the otolith-mediated gravity vector
represents a radical change for the sensorimotor complex. A number of micrograv-
ity studies (Casellato et al. 2007; Indovina et al. 2005) have indicated that the entire
sensorimotor complex is reliant on the gravity reference and, as such, undergoes
adaptive modification during prolonged microgravity in spaceflight. Given the
omnipresence of Earth’s gravity, some authors have postulated that Newton’s laws
are internalised in the CNS.
In many natural situations, e.g. during locomotion, the torsional VOR component
is useful in correcting for fluctuations of the roll position of the head. All told, this
synergy can be regarded as complementing the trade-off between the restrictions to
torsional eye position as dictated by Listing’s Law and VOR-elicited compensation
for head rotations. This idea of “cognitive control “ of brainstem function (as first
suggested by Melvill-Jones (1986) is supported by the recent study by Roy and
Cullen (2002) who present neurophysiological evidence that in the case of the hori-
zontal VOR, gain is altered to be maximal for gaze stabilisation and reduced when
the behavioural goal is to redirect visual attention.
Contrary to speculations that the torsional VOR in humans be considered as
some evolutionary relic, it is more likely to have resulted from an adaptive process,
optimised to accommodate the various sensorimotor requirements of eye and head
movement coordination in frontal-eyed species.
4.4 Summary
The study addresses the question as to what extent the otolith-mediated gravity vec-
tor maintains the stability of the coordinate frames of the vestibulo-ocular reflex and
the oculomotor system, described by Listing’s Plane. Under normal 1g conditions, it
has been demonstrated in the monkey that Listing’s Plane (LP) and the 3D vestibulo-
ocular response (3D-VOR) are close to collinear (Crawford and Vilis 1991).
In the present study, the coordinate frames of the oculomotor system and the
three-dimensional vestibulo-ocular reflex (3D-VOR) system were measured under
one-g gravity conditions and during a period of prolonged microgravity, onboard
the International Space Station (ISS). To this end, the coordinate frame of the ocu-
lomotor system is described in Listing’s coordinates and that of the 3D-VOR system
by the minimal gain vector.
Appendix 47
The findings demonstrate that under Earthbound, one-g conditions, the two
coordinate frames diverge by approximately 20° in the human. In the absence of
the gravity vector, the radical loss in the otolith-mediated contribution to the
dynamic VOR leads to a reduction of the torsional VOR component and in turn to
a forward tilt of the oculomotor coordinate frame, described by the minimal gain
vector. In contrast, the torsional component of LP during horizontal and vertical
saccades was found to increase, resulting in a backward tilt of LP. Together with
the backward tilt of LP, a small but consistent change in LP vergence was
observed.
The thickness of LP did not appear to change in the absence of gravity. The
changes in coordinate frame orientation persisted over the 6-month periods spent in
zero gravity. The postflight measurements demonstrate that readaptation to preflight
values proceeds over several days to weeks.
The findings demonstrate that the gravity vector represents a common reference
for vestibular and oculomotor responses. They also support the idea that the gravity
vector provides a central reference for the entire sensorimotor complex—as reflected
in perception and motor control in addition to the basic vestibulo-ocular, vestibulo-
spinal and vestibulo-autonomic mechanisms.
Appendix
Determination of Listing’s Plane Coordinates
For the determination of the orientation of Listing’s Plane, 3D eye movement

recordings of sequences of saccades were recorded over a period of 40 s while the
test subject was required to fixate at random a number of target points spaced over
a 20° × 20° field of view at 2 m distance. An example of the eye movement sequence
together with the X–Z projection of Listing’s Plane is shown in Fig. 4.11 (top panel).
LP is calculated using appropriate three-dimensional mathematics. This approach
using quaternions was introduced by Tweed and Vilis (1987). Thus, the horizontal,
vertical and torsional eye position sequences as measured by the eye tracking equip-
ment2 are transformed into quaternions. Haslwanter (1995) provides a comprehen-
sive review of the mathematical background as applied to eye rotations.
A principal components analysis is then employed to calculate the best-fit plane
for each data set. This provides the elevation, azimuth and thickness of the Listing’s
Plane. Further details of the methods are described in Clarke and Haslwanter
(2007).
2
The measurement data are originally provided in Euler coordinates, which are transformed to so-
called Fick coordinates and then to quaternion coordinates. The Fick convention describes each
eye position as a rotation sequence about the Z-axis, then the Y axis and finally the X axis.
20
horizontal (Z )
–20
20
vertical (Y )
0
–20
20
torsional (X )
0
–20
5 10 15 20 s
Z-axis Z-axis hz
hz
hx
20 hy
sition
0 Primary po
–20
Y-axis X-axis
–20 0 20 –10 0 10
Fig. 4.11 Measurement of Listing’s Plane. Top panel: example of data recording of vertical, hori-
zontal and torsional eye positions during a sequence of fixations and saccades. Lower panel: on the
left the Z–Y projection of the resultant LP and on the right the corresponding Z–X projection of
Listing’s Plane. The tilt (or elevation) of the resultant primary position is taken as a measure of the
torsional component
A typical set of spontaneous fixations is presented in Fig. 4.11 (top panel) illus-

trating the minimised torsional component. In the lower-left panel, each point of
fixation in the frontal field is plotted, while the right panel shows the side projection
of this set of fixations. According to Listing’s Law, the fixation points are distributed
closely in one so-called Listing’s Plane. The tilt, or elevation, of this plane is caused
by the small torsional component of eye position. In the example of Fig. 4.8, both
the X–Z and Y–Z projections of LP are shown, illustrating the role of the torsional
component in generating eye vergence.
Appendix 49
Determination of Minimal Gain Vector Coordinates
The orthogonal components of head velocity were obtained from the head tracking
rate sensor data. The 3 × 3 gain matrices relating head velocity and eye velocity
were computed by stepwise least square regression, starting from the main diagonal
components.
w e = Gw h ,
where w e = (w xe ,,w ye ,,w ze ) and w h = (w xh ,,w yh ,,w zh ) represent the angular velocity
of the eye and head, respectively. The resultant minimal gain vector is defined as the
head angular velocity unity vector ωh such that Gωh is minimal in the Euclidean
norm (Fig. 4.12).
Hx Hy Hz
Ex –0.15 –0.06 0.04
Ey –0.12 –0.89 0.11
Ez 0.19 0.02 –0.87
Fig. 4.12 Example of a 3 × 3 gain matrix for the VOR under 1g conditions and the resultant mini-
mal gain vector (MGV) representing the internal orientation of the 3D-VOR coordinate
framework
Chapter 5
Technology Developments and Transfer
5.1 Eye Movement Measurement Technology
The measurement of eye and head movement remains central to the investigation of
the vestibular and oculomotor systems. This applies equally to clinical investigation
and experimental studies. Around 80 years ago, the first reports of the employment
of image-based techniques for oculometric measurement were published. These
involved photographic and cinematographic recording of the eye for pupillometric
analysis (Machemer 1933; Lowenstein and Friedman 1942). Some 25 years later,
Lowenstein and Lowenfeld (1958) reported the use of mechano-optical image scan-
ning, as adapted from classic television camera principles. This seminal report was
succeeded by a number of refinements. For example, Stark and Sandberg (1961)
employed electronic techniques based on the television image-scanning principle.
Subsequent developments by Green and Maaseidvaag (1967) and O’Neill and Stark
(1968) employed more sophisticated exploitation of vidicon imaging tubes. In the
meantime a wide range of image-based video eye trackers have been developed.
In this context a number of eye tracking systems have been developed over the
course of European participation in life science experiments during spaceflight.
Figure 5.1 shows a summary of the earlier equipment developed under the auspices
of the German Space Agency (DLR).
A considerable drawback with these, and numerous commercially available
devices, is their use of standard video frame rates of 50 or 60 Hz, which ultimately
proves inadequate for the correct acquisition of eye movements, such as saccades
with angular velocities of up to 500°/s (Clarke 1994).
The concept for the 3D eye tracker utilises CMOS imaging technology to pro-
vide accurate high-frame-rate, three-dimensional measurement of eye position.
As a multiple-purpose eye movement monitoring device, the system provides the
user with online measurement of 2D eye position, binocular digital image recording
and offline evaluation of 3D binocular eye position. These features permit reviewing
of the eye image sequences and repeated evaluation, if desired with different

52 5 Technology Developments and Transfer
Fig. 5.1 Early eye tracking equipment used in space life science. Top to bottom, the DLR vestibu-
lar helmet developed for the European Spacelab experiments (1983–1986), the video-oculography
device (VOG) and the binocular VOG device used during the MIR experiments (1992–1996)
algorithms. Furthermore, the straightforward setup procedure and the noninvasive

nature of the device is particularly attractive for use in the clinic, where due consid-
eration must be given to patient comfort, and in many other experimental situations
where operating conditions preclude the more invasive scleral search coil
technique.
5.2 The DLR Eye Tracking Device
For this reason the Eye Tracking Device (ETD) was designed to provide two- and
three-dimensional eye position measurement at sampling rates of up to 400/s,
together with high measurement resolution (<0.05° for all three components of eye
5.2 The DLR Eye Tracking Device 53
Fig. 5.2 The eye tracker head unit, originally flown to the ISS in 2004, was used to test several
astronauts and cosmonauts. The cameras are mounted laterally to optimise the free field-of-view
for the test subject. The image of the eye is reflected by the dichroic mirror to the optical lens and
projected onto the image sensor. Triaxial angular and linear movement sensors are also mounted
on the visor (cubes on top left and right of visor) to record the six degrees of freedom of head
movement. On the left, the inset shows the online tracking display with video images of the eyes
together with traces for the horizontal and vertical eye movement
position). This instrument was developed in the first instance for integration in the
Human Research Facility on the International Space Station (Clarke 1998).
The head unit was designed to permit binocular, free field-of-view recordings
(see Fig. 5.2). Adjustors are provided for fitting to individual head form and align-
ment of the cameras to the right and left eyes (e.g. to encompass interocular dis-
tance, right-left asymmetries, etc.). Miniature triaxial angular rate sensors and linear
accelerometers are also integrated into the head unit to permit measurement of rota-
tion around and translation along the three orthogonal axes in space.
As with all head-mounted systems, the problem of device-to-head slippage must
be addressed. In the present system, the thermoplastic facemould (see Fig. 5.2) is
designed both to minimise head-to-device slippage and improve wearer comfort.1
Since, ultimately, no device can be perfectly fixed to the human head under normal
experimental circumstances, means must be found to measure and compensate for
any device slippage.
The image cameras and head movement sensors are mounted orthogonally on
the visor plate to ensure a consistent frame of reference. The visor as such can be
inclined to be parallel with a user-defined anatomical reference plane (e.g. Frankfort
horizontal). The eyes are illuminated by infrared-emitting diodes invisible to the
human eye (940 nm wavelength). This facilitates measurements “in the dark”, as is
often required in vestibular and visual research and testing. The IR image of each
eye is reflected by the dichroic mirror to the optical lens and projected onto the
image sensor. These optical elements and the cameras are arranged on the head unit
The use of a thermoplastic mask against slippage was first suggested by Dr. Ian Curthoys.
1
to facilitate maximal field-of-view for the test subject. In practice, a field-of-view of

the order of 75° to the right and to the left and 25° upwards and 40° downwards is
attained.
5.2.1 Front-End Image Processing
Significant progress in image processing devices is evident in the most recent

CMOS image sensors. Amongst the most important features are the configurable
acquisition of pixel-defined areas of interest and on-chip parallel processing of
pixel data.
The digital cameras, which have been specially designed around state-of-the-art
CMOS image sensors, include 10 bit analogue-to-digital converters and are inter-
faced to a dedicated processor board in the system unit via bidirectional high-speed
digital transmission links (192 Mb/s). This incorporates a field-programmable gate
array (FPGA) for each image sensor and a digital signal processor (DSP) with asso-
ciated storage arrays. These components are firmware-programmed to perform the
online, pixel-oriented acquisition and two-dimensional measurement of pupil
coordinates (Fig. 5.3).
Online pupil detection and tracking runs automatically and requires only that the
operator aligns the head unit and adjusts camera focus.
This concept eliminates the bottleneck in classical framegrabber systems and
facilitates image sample-and-process rates of up to 400/s. Additionally, the binocu-
lar image sequences can be stored digitally using standard PC components,
providing all advantages of offline evaluation. Synchronous audio recording via a
standard sound card is also implemented.
Windows GUI
Dedicated
CMOS FPGA DSP
Vision- Hardware
Sensor
PCI
Bus
LVDS Transmission Line
Storage
Fig. 5.3 Outline of the system architecture and the principal system components of the 3D Eye
Tracking Device. The camera and processor board were developed in cooperation between the
Berlin-based companies Chronos Vision GmbH and Berlin Mtronix GmbH
5.2 The DLR Eye Tracking Device 55
Fig. 5.4 Screenshot of GUI for online measurement and monitoring of eye movements and measured
coordinates (superimposed as crosshairs on the video inlays and displayed on data scrollers). This
GUI also provides for selection of acquisition parameters (sampling rate, mono-/binocular, audio)
5.2.2 Online Acquisition and Measurement
The online acquisition and measurement software utilises a set of front-end firm-
ware modules for the dedicated FPGA and DSP elements (Fig. 5.4).
The online algorithm, providing output of pupil coordinates with a uniform
latency time of 2 ms, is supervised by a scheduler.
5.2.3 Offline Image Evaluation
In many applications it is expedient to videorecord the eye movement behaviour of

interest, as opposed to making a one-off measurement of eye position. On the one
hand, a thorough offline evaluation can be performed and if necessary repeated for
verification, while on the other, critical experiment time is not expended with setting
up online evaluation parameters. This is particularly true in the clinic and in the space-
flight situation where time is always at a premium. Furthermore, the digital recording
facility enables the user to archive image sequences of interest for subsequent use, e.g.
for considerably more convincing demonstration or teaching purposes.
5.2.4 Convention for Describing 3D Eye Position
As the eyeball is limited to three degrees of rotational freedom, only three indepen-
dent parameters are required to specify the orientation of the eye in 3D space. The
most common description used in oculomotor research involves Euler angles. This
parameterisation can be derived from the 3 × 3 direction cosine matrix, which, in
turn, is derived from the projections of unit normal vectors aligned with the three eye-
fixed axes onto the space-fixed coordinate frame (for details, see Haslwanter 1995).
5.2.5 Offline 3D Tracking
The majority of algorithms for calculation of eye position are based on determina-
tion of centre-of-pupil. While the simpler approaches (e.g. pupil centroid) can be
rejected for their artefact susceptibility, a number of more robust and more accurate
“circle approximation” techniques for the pupil perimeter have been developed (e.g.
Barbur et al. 1987; Groen et al. 1996; Sung and Reschke 1997; Zhu et al. 1999).
Ellipse-fitting (e.g. Pilu et al. 1996) to the pupil form allows for compensation of
any geometric distortion during eye rotation (Moore et al. 1996) (Fig. 5.5).
Fig. 5.5 Screenshot of GUI of the offline software, with user control elements, interactive win-
dows and 3D data scrollers
5.3 Laser Eye Surgery 57
The main offline algorithm is based on the Hough transform technique. It per-
mits the user to adjust image contrast, edge detection threshold and circle/ellipse
detection.
5.2.6 Determination of 3D Eye Position
For evaluation of three-dimensional eye position, the polar correlation algorithm

first described by Hatamian and Anderson (1983) can be employed. The approach
exploits the fact that the relevant information for determining ocular torsion is
contained in the natural landmarks of the iris. This requires the extraction of a natu-
ral luminance profile derived from circular sampling around the iris. The selected
segment is then used for polar correlation to yield the torsional eye coordinate.
Calculation of ocular torsional position is then performed by one-dimensional
cross-correlation of the current iris signature against the predetermined reference
signature. During the frame-by-frame evaluation, the nonlinear distortion of the
iris segment (due to the projection of the spherical eyeball onto the image plane) is
corrected on the basis of the calibration model (Moore et al. 1996; Peterka and
Merfeld 1996).
Alternatively, the more complex technique described by Bos and de Graaf (1994)
can be performed. Groen et al. (1996) demonstrated that an iterative weighted
sinusoidal fit of torsion estimates about the full 360 degrees yields a more accurate
measure of torsion.
5.3 Laser Eye Surgery
The development of various techniques for laser surgery of the eye has required
accurate monitoring of eye position during the operations. Thus, the eye tracker is
of critical importance for measurement of eye position relative to the laser device
and for guidance of the laser beam. The camera and processor technology devel-
oped for the ETD is currently employed in such systems for laser surgery of the
eye. The high frame rate and more importantly the short latency (<2 ms) enable
real-time tracking and control of the laser as it sculpts the cornea to correct for
short- or long-sightedness. The modification of the ETD components for this
application was carried out by the industrial partner Chronos Vision GmbH
(Fig. 5.6).
The successful transfer of the ETD technology to such terrestrial applications led
to the induction of Chronos Vision GmbH into the US Space Technology Hall of
Fame in 2016.
Fig. 5.6 Left: illustration of excimer laser surgical procedure. Right: a typical operation suite
5.4 Clinical Diagnostic Testing
The investigation of otolith function after spaceflight as described in Sect. 5.2 was
largely made possible by the development and refinement of vestibular testing pro-
cedures in the clinical laboratory (Fig. 5.7).
The tests described for utricle function were established as clinical tests, primar-
ily in the Vestibular Lab at the Benjamin Franklin Campus of the Charité Medical
School in Berlin. Subsequent to the spaceflight experiments, commercially avail-
able versions of the eccentric rotating chair and the device for testing SVV were
developed in the laboratory and in cooperation with industrial partners (Chronos
Vision GmbH).
Fig. 5.7 Left: testing SVV on the eccentric rotating chair in the Vestibular Lab of the HNO Clinic
at the Benjamin Franklin Campus of the Charité Medical School in Berlin. Right: the GUI of the
SVV test and assessment software
Chapter 6
Clinical Applications and Related Projects
Considerable progress in the differential diagnosis of vestibular disease and related

neurological disorders has been made over recent years. It hardly needs to be men-
tioned that the case history is of extreme importance in the diagnosis of disorders
involving any symptoms of dizziness, imbalance and/or spatial disorientation. In
consequence, the selection of laboratory tests to be performed on any single patient
must derive from the indications observed during preliminary screening or bedside
examination. Thus, in many cases, laboratory testing serves the confirmation and
refinement of the findings of a well-conducted physical or bedside examination.
Given the cost in time and effort involved in the laboratory tests, judicious selection
is recommended. Fortunately, the facilities in the laboratory provide for objective
assessment of the related brain functions and for quantifying asymmetry, hypofunc-
tion or hyperfunction of the vestibular labyrinth.
In addition to the diagnostic process, laboratory testing is important in monitor-
ing the effect of medication or operation over the course of recovery and
rehabilitation.
In parallel to the spaceflight experiment programmes described in the previous
chapters, a number of clinical studies were performed in the Vestibular Research
Lab, Charité Campus Benjamin Franklin. These were directed at the improvement
of clinical diagnosis procedures for suspected disorders of the vestibular function.
Besides the case history and bedside examination, objective measurement of the
vestibulo-ocular reflex in all of its facets remains the cornerstone in the diagnostic
process. Accordingly, the development of the noninvasive eye tracking device for
the comprehensive measurement of eye movement in the clinical lab provides the
ENT or neurology specialist with an important instrument. Examples of clinical
studies employing this technology in neurology and neurosurgery are included
below.
Examination and diagnosis of otolith function have eluded the clinician for many
years. The combination of unilateral centrifugation, as described in Chap. 2, and
measurement of the subjective visual vertical (SVV) provides a viable basis for
routine testing.

60 6 Clinical Applications and Related Projects
6.1 Unilateral Otolith Dysfunction
In order to examine the incidence of unilateral utricular dysfunction, a retrospective

clinical study was conducted with a group of 110 vestibular patients.
Utricular function was evaluated by estimation of SVV during unilateral cen-
trifugation. Bithermal caloric testing was performed to assess unilateral semicircu-
lar canal function. Saccular function was tested by measurement of VEMPs.
Preconditions for classification as isolated, unilateral utricular hypofunction were
the presence of asymmetric SVV estimates together with symmetric caloric
responses, indicating normal SCC function, and symmetric VEMP responses indi-
cating normal saccular function.
A total of 46 patients were found with asymmetric SVV findings but symmetric
caloric responses and VEMPs. Statistical testing also verified that their SVV asym-
metry factors were significantly higher than those calculated for caloric responses
and VEMPs.
The findings demonstrate that an enduring unilateral utricular dysfunction,
possibly together with canal hypofunction, can occur after labyrinthine disease
or injury. They also suggest that unilateral, isolated utricular dysfunction—or
utricle paresis—can occur, representing a novel entity in the differential diag-
nosis of peripheral vestibular function. The occurrence of subjective visual ver-
tical (SVV) asymmetry in the presence of symmetric vestibular evoked
myogenic potentials (VEMPs) also confirms that the information from the utri-
cles, rather than the saccules, dominates SVV estimation (Schoenfeld et al.
2010).
6.2 Subjective Visual Vertical as a Clinical Test
A further study demonstrates that various response patterns of subjective visual

vertical (SVV) can be identified during unilateral centrifugation (UC). It is pro-
posed that these response types correspond to different degrees of compensation
after disease. This is advantageous for monitoring the effect of rehabilitative mea-
sures and is useful in medico-legal issues. It also emerges that diagnosis of unilat-
eral utricle function requires the determination not only of asymmetry ratio but also
offset of SVV estimates.
SVV measurements were made in 473 patients recruited from the dizziness
clinic. A control group of healthy subjects (n = 43) was tested with the same proto-
col. Testing with bilateral stimulation (stationary upright, 15°, 30° tilt) and UC was
performed. During UC testing, 61% of the patients showed an asymmetric response
indicating a unilateral utricular hypofunction/dysfunction. These results could be
classified into three subgroups, indicating different degrees of compensation. The
model parameters can be adapted to reflect this classification (Schoenfeld and
Clarke 2011).
6.4 Head Pitch Affects Eye Torsion 61
6.3 T
esting Utricular Function by Means
of On-Axis Rotation
While the advantages of unilateral testing of labyrinth function are indisputable,

only a few clinics have the necessary rotating chair with eccentric positioning. For
this reason, a study was carried out to determine whether testing on a standard rotat-
ing chair could detect unilateral dysfunction and thus provide a useful screening
procedure. This was based on the idea that during on-centre rotation, the right and
left labyrinths are subject to equal and opposite centrifugal forces, and accordingly
a right/left symmetry would result in a balanced response to testing, i.e. no deviation
of the SVV from vertical. In the presence of a unilateral dysfunction, a SVV devia-
tion would be enhanced by the centrifugation.
SVV was estimated (a) while held stationary and (b) during constant angular
velocity (240°/s), with the head centred on axis. In all, 230 patients were recruited
from the dizziness clinic. For each patient, the bithermal caloric testing was also
performed in 201 of the patients.
Of those patients with normal SVV results during stationary testing, 18.3% were
pathological during rotation testing. In those cases with pathological SVV during
stationary testing, a significantly greater deviation from the norm was observed dur-
ing rotation. Of those patients with normal caloric responses, 44.4% showed patho-
logical SVV estimates; this increased to 54.3% for cases with unilateral weakness
and 56.5% for unilateral loss.
The results indicate that subjective visual vertical (SVV) estimation during on-
axis rotation provides an efficient screening test of utricle function. The survey fur-
ther demonstrates that isolated disorders of peripheral utricular function can occur
while SCC function appears normal (Helling et al. 2006).
6.4 Head Pitch Affects Eye Torsion
Related to the study described in Chap. 4, the question arose as to whether system-
atic changes in eye torsion occur when subjects are rotated in forward and backward
pitch, i.e. oriented in different positions relative to gravity.
Normal, healthy subjects were seated in a dual axis human rotator, positioned so
that the interaural axis was aligned with the axis of pitch rotation. Each subject was
tilted, once from upright to 90° backwards and then 45° forward.
Testing was carried out in total darkness apart from a fixation LED. Eye move-
ments were recorded with the ETD.
Changes in eye torsional position in response to pitch amounted to approxi-
mately 2° for 90° backward and 1° for 45° forward tilt, although the direction of
torsion varied between subjects. Opposite responses may be the result of individual
variation in anatomical or physiological vector orientations of hair cells of the utri-
cle (Diamond et al. 2006).
6.5 Migrainous Vertigo
Migrainous vertigo (MV) is an increasingly recognised cause of episodic vertigo.

However, the pathophysiology of MV is still a matter of speculation, and it is not
known to what extent the dysfunction is located in the central or peripheral ves-
tibular system. The aim of this prospective study was to describe the clinical spec-
trum of acute MV and to clarify which structures of the vestibular system are
involved.
Testing of 20 patients with acute MV included neuro-otological examination,
recording of spontaneous and positional nystagmus with 3D video-oculography
(ETD) and audiometry (Fig. 6.1). The findings indicate that MV should be consid-
ered in the differential diagnosis of vertigo with spontaneous and positional nystag-
mus and can present both as a central and a peripheral vestibular disorders (von
Brevern et al. 2001, 2004a, b).
15° UP 15° UP
–15° DN –15° DN
15° R 15° R
–15° L –15° L
15° CW 15° CW
–15° CCW –15° CCW

0 5 10 15s 0 5 10s 0 5 10 15s 0 5 10s
Upright Supine
15° UP 15° UP
–15° DN –15° DN
15° R 15° R
–15° L –15° L
15° CW 15° CW
–15° CCW –15° CCW

0 5 10 15s 0 5 10s 0 5 10 15s 0 5 10s
Right Side Down Left Side Down
Fig. 6.1 Recording of spontaneous and persistent positional nystagmus in a patient with acute
migrainous vertigo and during the symptom-free interval (grey shading). Vertical (V), horizontal
(H) and torsional (T) eye movement components are shown. Note the downbeating nystagmus in
the upright position, which ceases in the supine position. In the lateral positions, a predominantly
horizontal, geotropic nystagmus appears
6.6 Benign Paroxysmal Positioning Nystagmus (BPPN) 63
6.6 Benign Paroxysmal Positioning Nystagmus (BPPN)
Benign paroxysmal positional vertigo (BPPV) is a frequent vestibular disorder that

causes brief attacks of vertigo precipitated by changes of head position.
The objective of this study was to test the hypothesis that utricular function is
impaired in patients with idiopathic benign paroxysmal positional vertigo. Otolith
function was assessed with estimation of the subjective visual vertical and analysis
of the torsional otolith-ocular reflex. Unilateral stimulation of the utricle was per-
formed on the eccentric rotating chair and the otolith-ocular reflex recorded by the
ETD equipment.
There was no difference in the estimation of the subjective visual vertical between
patients and controls. The peak-to-peak amplitude of the otolith-ocular reflex tor-
sional eye position was smaller in patients than in the control group. The unilateral
otolith-ocular reflex was reduced in patients on both sides on first testing. After
several weeks, only the affected labyrinth showed a reduced otolith-ocular reflex
gain (Fig. 6.2).
The findings document otolith dysfunction in patients with idiopathic benign
paroxysmal positional vertigo possibly secondary to degeneration of the utricular
macula. This finding may account for the transient mild imbalance and dizziness
that some patients with benign paroxysmal positional vertigo experience even after
resolution of positional vertigo. The study was conducted in cooperation with the
Neurology Department of the Charité Medical School in Berlin (von Brevern et al.
2006).
OOR (°) GIA tilt (°)

2 a 12
0 0
–2 –12
2 b 12
0 0
–2 –12
0 2 4 6 8 10 12 14 16 time (s)
Fig. 6.2 Torsional component of the otolith-ocular response in a normal subject (a) and in a
patient with BPPV (b). The dashed line represents the stimulus cycle. The OOR waveform of both
eyes is depicted
6.7 Galvanic Stimulation of the Vestibular Labyrinth
After it had been demonstrated (Breuer 1889; Ewald 1892) that the galvanic stimu-
lus acts on peripheral vestibular structures and not on the brain itself, the value of
the galvanic vestibulo-ocular reflex in the diagnosis of vestibular disorders was
repeatedly investigated (Bárány 1906; Pfaltz 1965). However, due to the lack of
appropriate eye movement recording techniques, these clinical applications relied
chiefly on horizontal components of the galvanic VOR, although the dominance
of the torsional components was frequently emphasised (Romberg et al. 1951;
Watson et al. 1998).
In the present study, the torsional eye movements elicited by sinusoidal gal-
vanic vestibular stimulation (GVS) were examined in healthy humans. GVS con-
sistently induced sinusoidal modulation of the torsional slow-phase velocity
(SPV), which was linearly related to stimulus intensity. At low frequencies
(0.1 Hz), nystagmic responses could be discriminated from an underlying “tonic”
modulation of eye position, which was prominent in some, but negligible in other
subjects, and was not correlated with the SPV modulation. The actual SPV modu-
lation consistently exceeded the (hypothetical) velocity modulation derived from
the tonic positional components, albeit variably by almost 20-fold across subjects.
This indicates that the contribution of possibly otolith-related response compo-
nents to the galvanic vestibulo-ocular reflex may vary considerably in normal
individuals (Kleine et al. 1999).
6.8 V
estibulo-Ocular Monitoring of Comatose Patients
as Predictor of Outcome After Severe Brain Injury
Reliable determination of brain death remains a subject of debate. Based on the

knowledge that traumatic brainstem damage often leads to alteration in brainstem
functions, including the vestibulo-ocular reflex (VOR), a study involving vestibulo-
ocular monitoring of comatose patients was carried out with a modified ETD camera
setup. The objective being to determine whether prediction of outcome in the early
phase after severe traumatic brain injury is possible by means of such monitoring
(Fig. 6.3).
Thus, the integrity of the vestibulo-ocular reflex in the brainstem is determined
from the eye movement response during galvanic stimulation to the labyrinth.
The results indicate that such monitoring performed during the first days after
TBI helps to predict favourable or unfavourable outcome. As an indicator of brain-
stem function, vestibulo-ocular monitoring appears to be useful as a complementary
approach to the identification of brainstem lesions in comatose patients. This study
was carried out in cooperation between the Vestibular Lab and the Neurosurgery
Department at the Benjamin Franklin Campus of the Charité Medical School in
Berlin (Schlosser et al. 2005, 2009).
6.9 Vestibulo-Autonomic Regulation of Muscle Structure 65
Fig. 6.3 Cartoon illustrating the direct galvanic galvanic galvanic

galvanic stimulation to the brainstem right Σ left
and the eye tracker for measurement of

oculomotor response
6.9 Vestibulo-Autonomic Regulation of Muscle Structure
During spaceflight, microgravity-induced muscle atrophy is a well-documented

occurrence. However, the possibility of vestibulo-autonomic regulatory mecha-
nisms affecting skeletal muscle structure and function had not yet been addressed.
It was hypothesised that the vestibular system affects anti-gravitational skeletal
muscle phenotype composition, size and the transcriptional factor called nuclear
factor of activated T cells (NFATc1).
In a laboratory study, the authors examined the morphological and histochemical
properties including intramyocellular NFATc1 changes in slow-type soleus muscle
of chemically labyrinthectomised rats (n = 8) compared to a control group (n = 6)
after a period of 1 month.
Neurochemical vestibular deafferentation resulted in smaller myofibre sizes,
altered myofibre phenotype composition, high yields of hybrid fibre formation and
reduced myonuclear NFATc1 accumulation as signs of slow-type myofibre atrophy,
myofibre type remodelling and altered nuclear transcriptional activity in the pos-
tural soleus muscle of rats.
The findings support the idea that vestibulo-autonomic modification of skeletal
muscles occurs during prolonged microgravity (Luxa et al. 2013).
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SPRINGERBRIEFS IN SPACE LIFE SCIENCES

More information about this series at http://www.springer.com/series/11849

ISSN 2196-5560 ISSN 2196-5579 (electronic)

Library of Congress Control Number: 2017943105

© The Author(s) 2017

Printed on acid-free paper

This Springer imprint is published by Springer Nature

The extraordinary conditions in space, especially microgravity, are utilised today

Bonn, Germany Prof. Dr. Günter Ruyters

DLR Space Administration in Bonn-Oberkassel (DLR)

The extraordinary conditions of space, especially microgravity, lead to significant

Bonn, Germany Günter Ruyters

3.2 Spaceflight Findings����������������������������������������������������������������������������� 32

What’s so important about gravity?

Fig. 1.1 Examples of

© The Author(s) 2017 1

1.1 A Brief Introduction to the Vestibular System

Fig. 1.2 This outline of the various Oculomotor

thalamus, hippocampus and vestibular M M

a Med. long. fasc.

(SCC)—for transduction of rotation—and the otolith organs, responsible for

Roll Pitch Yaw

Fig. 1.5 Demonstration of the three-dimensional vestibulo-ocular reflex (3D–VOR) elicited by

Fig. 1.7 Representation of the neural

1.2 Visual-Vestibular Interactions

1.4 Motion Sickness

Nucleus Vestibular nuclei Respiration

Vomiting Centre Cardiovascular

1.5 Historical Perspective

Fig. 1.9 Graphic impression of the

In the following chapters, experimental studies involving investigation of the

2.1 Which Functions Do the Otoliths Fulfil?

Fig. 2.1 In the prolonged absence of the gravitational

Fig. 2.2 The short-arm centrifuge employed for

Zero-g Ocular Zero-g Head

compensatory rotation, or counterroll, of the eye is elicited. In contrast, when performed

2.2 Early Spaceflight-Related Studies of Otolith Responses

The effects of exposure to microgravity on the otolith-mediated oculomotor

left labyrinth right labyrinth

Fig. 2.4 Basic principle

the eccentric labyrinth is exposed to a centripetal acceleration along the interaural

2.3 Recent Postflight Testing of Otolith Function

The availability of unilateral utricle and saccule testing facilitates investigation of

2.3.1 Utricle Function Tests

During a comprehensive postflight examination of unilateral otolith function, two

Fig. 2.5 Left: Test Subject

SVV Estimate (°)

showing the normal 0

from one patient with CCW –15

dysfunction related to the Right ear

Utriculo-ocular reflex (UOR) test involves the measurement of ocular counterroll,

left labyrinth right labyrinth

Ocular torsion Radius

Fig. 2.6 During unilateral

conjugate ocular torsion or

2.3.2 Saccule Function Test

Fig. 2.7 Acoustic clicks elicit a Normalised VEMP response

2.4 Related Experimental Findings

2.4.1 Subjective Vertical

Fig. 2.8 Longitudinal SVV UC–Asymmetry Ratio of Eccentric Values

measurement session are 0.0

OOR Asymmetry Ratio in relation to individual

VEMP–Asymmetry Ratio of p13–n23 Amplitude @ 135dB (SPL)

2.4.1.1 Single-Case Responses

Bonn, Germany Prof. Dr. Günter Ruyters

Bonn, Germany Günter Ruyters

3.2 Spaceflight Findings�� 32

1.1 A Brief Introduction to the Vestibular System

1.2 Visual-Vestibular Interactions

1.4 Motion Sickness

1.5 Historical Perspective

2.1 Which Functions Do the Otoliths Fulfil?

2.2 Early Spaceflight-Related Studies of Otolith Responses

2.3 Recent Postflight Testing of Otolith Function

2.3.1 Utricle Function Tests

2.3.2 Saccule Function Test

2.4 Related Experimental Findings

2.4.1 Subjective Vertical

2.4.1.1 Single-Case Responses

2.4.2 Utriculo-Ocular Reflex

2.4.3 Saccule Function Test

2.4.4 Discussion of the Findings

Subjective Visual Vertical

Cervical Evoked Myogenic Potentials (cVEMPs)

The VEMP provides a measure of saccular function indirectly through a vestibulo-

3.1.1 Test Procedure

3.2 Spaceflight Findings

The study constituted the first comprehensive examination of the three-

3.2.1 Horizontal VOR

3.2.2 Vertical VOR

3.2.2.1 Up/Down Asymmetry

3.2.3 Torsional VOR

It was described in Chap. 3 how during prolonged microgravity the three-

4.2 Parabolic Flight Study

4.3 Spaceflight Study

Determination of Listing’s Plane Coordinates

Determination of Minimal Gain Vector Coordinates

5.1 Eye Movement Measurement Technology

5.2 The DLR Eye Tracking Device

5.2.1 Front-End Image Processing