Saccade Related Gamma Potentials Recorded in Human … · 2013-10-18 · Nucleus, Globus Pallidus...
Transcript of Saccade Related Gamma Potentials Recorded in Human … · 2013-10-18 · Nucleus, Globus Pallidus...
Saccade Related Gamma Potentials Recorded in
Human Subthalamic Nucleus, Globus Pallidus Interna
and Ventrointermediate Nucleus of the Thalamus
by
Arun N.E. Sundaram
A thesis submitted in conformity with the requirements
for the degree of Master of Science
School of Graduate Studies
Institute of Medical Sciences
University of Toronto
© Copyright by Arun Sundaram (2010)
Master of Science 2009, Arun N.E. Sundaram, Institute of Medical Science, University of
Toronto
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Saccade Related Gamma Potentials Recorded in Human Subthalamic
Nucleus, Globus Pallidus Interna and Ventrointermediate Nucleus of the
Thalamus Master of Science 2010, Arun Sundaram, Institute of Medical Science, University of
Toronto
Abstract
Gamma oscillations of local field potentials (LFP) in the basal ganglia and thalamus had
not been studied during saccades.
Eleven patients were studied during deep brain stimulation (DBS); 6 were in the
subthalamic nucleus (STN); 3 in the globus pallidus interna (GPi); and 2 in the thalamic
ventralis intermedius nucleus (Vim). Patients performed horizontal saccades to visual
targets while LFPs from DBS electrodes, scalp electroencephalogram (EEG), and
electrooculogram (EOG) were recorded. Wavelet spectrograms were generated and
saccade onset and event-related gamma synchronizations (ERS) were compared to
baseline without eye motion.
ERS were recorded at and after saccade onset in the STN, GPi and Vim, EEGs and
EOGs; but were absent during target light illumination without saccades. ERS were
symmetric in all DBS contacts and appeared identical in DBS LFPs, frontal EEGs and
EOGs. These findings indicate their origin from extraocular muscle spike potentials
rather than brain neural activity.
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Table of Contents
1 INTRODUCTION ...................................................................................................... 1
1.1 Parkinson’s Disease.............................................................................................. 1 1.1.1 Etiology and Pathogenesis of Parkinson’s Disease ...................................... 2 1.1.2 Clinical features of Parkinson’s Disease....................................................... 4 1.1.3 Other Motor Abnormalities in Parkinson’s disease ...................................... 7 1.1.4 Other Non-motor Abnormalities in Parkinson’s Disease ............................. 7
1.1.5 Neuro-Ophthalmic Manifestations of PD ..................................................... 8 1.1.6 Treatment of PD ............................................................................................ 9
1.2 DEEP BRAIN STIMULATION ........................................................................ 12 1.2.1 Stereotactic neurosurgery in kinesiology and evolution of DBS ................ 12
1.2.2 Thalamic DBS ............................................................................................. 12 1.2.3 Pallidal DBS................................................................................................ 13 1.2.4 Subthalamic DBS ........................................................................................ 14
1.2.5 Mechanisms of Action of DBS ................................................................... 15 1.3 DYSTONIA ....................................................................................................... 18
1.4 ESSENTIAL TREMOR ..................................................................................... 20 1.5 ANATOMY AND PHYSIOLOGY OF EYE MOVEMENTS .......................... 22
1.5.1 Introduction ................................................................................................. 22
1.5.2 The Extraocular Muscles ............................................................................ 22 1.5.3 Extraocular Muscle Fiber Types ................................................................. 24
1.5.4 Uniocular and Binocular Eye Movements .................................................. 25 1.5.5 Six Eye Movement Systems ....................................................................... 26
1.5.6 Laws Governing Eye Movements ............................................................... 28 1.6 SACCADIC SYSTEM ....................................................................................... 29
1.6.1 Classification and Definition of Saccades .................................................. 29 1.6.2 Pulse-Step Innervation of Saccades ............................................................ 30 1.6.3 Saccadic Peak Velocity and Duration ......................................................... 31
1.6.4 Latency of Saccades (Saccadic Reaction Time) ......................................... 32 1.6.5 Gap and Overlap Stimuli ............................................................................ 33 1.6.6 Antisaccades ............................................................................................... 34
1.6.7 Saccadic Accuracy ...................................................................................... 35 1.6.8 Visual Stability during Saccades ................................................................ 37
1.7 NEUROANATOMY AND NEUROPHYSIOLOGY OF SACCADES ............ 38 1.7.1 Overview ..................................................................................................... 38 1.7.2 Frontal Eye Fields ....................................................................................... 39
1.7.3 Parietal Eye Fields ...................................................................................... 41 1.7.4 Dorsolateral Prefrontal Cortex .................................................................... 41
1.7.5 Supplimentary Eye Fields ........................................................................... 42 1.7.6 Superior Colliculus ..................................................................................... 44 1.7.7 Brain Stem Generation of Horizontal Saccades .......................................... 45
1.8 BASAL GANGLIA CONTROL OF SACCADES ............................................ 48 1.8.1 Basal Ganglia Circuitry and Mechanisms of Oculomotor Disinhibition .... 50 1.8.2 Caudate Nucleus ......................................................................................... 51 1.8.3 Substantia Nigra Pars Reticulata ................................................................. 54
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1.8.4 The Disinhibition Theory ............................................................................ 57
1.8.5 Subthalamic Nucleus .................................................................................. 59 1.8.6 Globus Pallidus Internal Segment ............................................................... 60 1.8.7 Globus Pallidus External Segment.............................................................. 62
1.9 Saccadic Dysfunctions of Basal Ganglia Disorders ........................................... 63 1.10 Thalamus and its Role in the Control of Saccades ......................................... 66 1.11 Local Field Potential Oscillations ................................................................... 71
2 Objectives and Hypotheses ....................................................................................... 75 2.1 Hypotheses ......................................................................................................... 77
3 Methods..................................................................................................................... 78 3.1 Preface ................................................................................................................ 78 3.2 Introduction ........................................................................................................ 78 3.3 Patients ............................................................................................................... 79
3.4 Surgery ............................................................................................................... 81 3.5 Tasks................................................................................................................... 83
3.5.1 Four blocks of visually-cued saccades ........................................................ 83 3.5.2 Gap and Overlap Paradigms with Short and Long Sequences ................... 85
3.5.3 Vestibulo-ocular Reflex .............................................................................. 88 3.6 Local Field Potential Recording ......................................................................... 89 3.7 DATA ANALYSIS ............................................................................................ 91
3.7.1 SPIKE 2 SOFTWARE ANALYSIS ........................................................... 91 3.7.2 MATLAB ANALYSIS ............................................................................... 94
4 RESULTS ................................................................................................................. 97 4.1 Spike 2 Results ................................................................................................... 97
4.1.1 Comparison of Gamma Activity ............................................................... 106
4.2 Matlab Analysis................................................................................................ 108
4.2.1 Duration of Saccade Related Gamma Synchronization ............................ 112 4.2.2 Bipolar Derivations of DBS LFPs ............................................................ 112 4.2.3 LFPs during Vestibulo-Ocular Reflex ...................................................... 115
4.3 Saccade Metrics................................................................................................ 118 4.3.1 Prosaccades versus Antisaccades .............................................................. 118
4.3.2 Gap Effect ................................................................................................. 118 4.4 Beta Desynchronization in Bipolar Derivations............................................... 122
5 DISCUSSION ......................................................................................................... 127 5.1 Non-lateralized Gamma Synchronizations....................................................... 128 5.2 Quadripolar Symmetry of ERS ........................................................................ 129 5.3 What is the origin of Gamma ERS? ................................................................. 129
5.4 SPIKE POTENTIALS...................................................................................... 132 5.4.1 Source of Spike Potentials ........................................................................ 133 5.4.2 Intracranial volume conduction of Spike Potentials ................................. 134
5.4.3 Duration of Saccade Related Gamma Synchronizations .......................... 136 5.4.4 High versus Low Gamma Synchronizations............................................. 137 5.4.5 Relationship between Spike Potentials and Magnitude of Saccades ........ 139
5.5 Surface EEG Gamma Oscillations caused by Nuchal Musculature ................. 139 5.6 Gamma Oscillations – Facts versus Artifacts .................................................. 140 5.7 Saccade Metrics................................................................................................ 142
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5.8 Saccade Related Beta Desynchronizations ...................................................... 142
6 Study limitations ..................................................................................................... 145 7 Conclusions ............................................................................................................. 146 8 Synopsis .................................................................................................................. 148
9 Acknowledgments................................................................................................... 151
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ABBREVIATIONS
Antisaccade AS
Basal ganglia BG
Corneo-retinal dipole CRD
Deep brain stimulation DBS
Electromyography EMG
Electrooculography EOG
Electroencephalography EEG
Event related desynchronization ERD
Event related synchronization ERS
Intracerebral EEG iEEG
Globus pallidus externa GPe
Globus pallidus interna GPi
Local field potentials LFP
Levodopa induced dyskinesia LID
Parkinson’s disease PD
Spike potentials SP
Substantia nigra pars compacta SNc
Substantia nigra pars reticulata SNr
Subthalamic nucleus STN
Superior colliculus SC
Ventrointermediate nucleus of the Thalamus Vim
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine MPTP
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LIST OF FIGURES
Fig. 1 Pathways for horizontal saccades in human
Fig. 2 Cortical, subcortical and brainstem areas in human brain involved in saccades
Fig. 3 Saccadic premotor neurons in human brainstem shown through sagittal view
Fig. 4 Coronal section of human brain through the mid thalamus
Fig. 5 Direct and indirect saccadic pathways through the basal ganglia
Fig. 6 Sagittal section of macaque monkey brain showing the saccade-related areas
Fig. 7 Disinhibition theory - the key mechanism of basal ganglia control of saccades
Fig. 8 Oblique dorsolateral view of the thalami and its major nuclear groups
Fig. 9 Brown’s model of changes in basal ganglia oscillatory power during motor tasks
Fig. 10 Saccadic tasks – Prosaccades and Antisaccades
Fig. 11 Illustration of gap and overlap paradigms
Fig. 12 Trajectory of STN quadripolar DBS contacts in the sagittal plane
Fig. 13 Analysis of dynamic brain oscillations
Fig. 14 Saccade related gamma oscillations from STN # 5 (Spike 2 analysis)
Fig. 15 Incidence of gamma oscillations for rightward saccades (all STN subjects
averaged)
Fig. 16 Incidence of gamma oscillations for leftward saccades (all STN subjects
averaged)
Fig. 17 Incidence of gamma oscillations for all saccades (all GPi subjects averaged)
Fig. 18 Incidence of gamma oscillations for all saccades (all Vim subjects averaged)
Fig. 19 Normalized percentage of gamma peak for all saccades in STN and GPi regions
Fig. 20 Wavelet spectrograms (Matlab analysis) of DBS and scalp EEG potentials (STN
# 5)
Fig. 21 Attenuation of gamma peak in central EEG contacts
Fig. 22 Wavelet spectrograms of DBS LFPs and scalp EEG aligned to target light
illumination
Fig. 23 Duration of saccade related gamma activity
Fig. 24 Bipolar derivations (wavelet spectrograms) of saccade related DBS LFPs from
STN # 5
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Fig. 25 Gamma oscillations in DBS LFPs during smooth eye motion of vestibulo-ocular
reflex
Fig. 26 Gamma oscillations in scalp EEG during smooth eye motion of vestibulo-ocular
reflex
Fig. 27 Saccade reaction times of prosaccades and antisaccades
Fig. 28 Saccade reaction time showing the ‘Gap effect’ in prosaccades
Fig. 29 Saccade reaction times in antisaccades with and without gap
Fig. 30 Saccade related beta desynchronization in Vim # 1
LIST OF TABLES
Table 1 Characteristics for 11 DBS patients studied
Table 2 Incidence of saccade related gamma synchronization in STN patients (all blocks)
Table 3 Incidence of saccade related gamma synchronization in GPi and Vim patients
(all blocks)
Table 4 Incidence of saccade related beta desynchronization in STN patients (all blocks)
Table 5 Incidence of saccade related beta desynchronization in GPi and Vim patients (all
blocks)
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1 INTRODUCTION
1.1 Parkinson’s Disease
Parkinson’s disease (PD) is a progressive neurodegenerative disorder caused by
degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc)
resulting in rigidity, tremor and bradykinesia (poverty of spontaneous movements and
reduction in speed and amplitude during repetitive actions) or akinesia (absence or failure
of movements). PD was first described by James Parkinson in the 19th
century as
‘shaking palsy’, which still remains an accurate description of the entity (Parkinson,
1817). Next to Alzheimer’s disease, it is the most common neurodegenerative disorder
(Lew, 2007), affecting 3% of people over the age of 65 and 0.3% of world population
(Zhang and Roman, 1993). Over 1 million North Americans suffer from this movement
disorder (Lang and Lozano, 1998a).
PD is an age-related disorder with a higher prevalence in older age (Bennett et al., 1996)
and mean age of onset of symptoms is around 60 years (Hughes et al., 1993). 90-95% of
patients get the first symptom after 40 years of age. Patients with PD have 2-5 times
higher risk of mortality compared to age-matched population (Louis et al., 1997).
Clinical diagnosis of PD is based on the criteria, asymmetry of the motor signs and
improvement of symptoms with Levodopa (Lang and Lozano, 1998a). There are several
neurodegenerative disorders with Parkinsonian features like multisystem atrophy (MSA)
and progressive supranuclear palsy (PSP), as well disorders with asymmetric
involvement such as corticobasal ganglionic degeneration (CBGD) and misdiagnosis is
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common. Hence, the neuropathological examination still remains the gold standard for
confirmation of PD (Lang and Lozano, 1998a).
1.1.1 Etiology and Pathogenesis of Parkinson’s Disease
Although the exact etiopathogenesis of PD is unclear, genetic, epidemiologic,
environmental and pathological evidence suggest several etiological factors. Motor
symptoms in PD are primarily caused by basal ganglia (BG) disorder, and decreased
concentration of dopamine in the BG is the central mechanism for the physiological
dysfunction. Progressive degeneration of the dopaminergic pigmented neurons in the
substantia nigra pars compacta (SNc) is the pathological hallmark of PD (Hornykiewicz,
1966). There are several dopaminergic neuronal cell groups in the central nervous
system (Moore and Bloom, 1978), of which mesotelencephalic group is the most
prominent one. Nigrostriatal system is a part of the mesetelencephalic group, which
projects from the SNc to the caudate (CD) and putamen (collectively referred to as the
striatum). There is selective loss of dopaminergic neurons in the lateral ventral tier of the
substantia nigra in PD, a pattern which is strikingly different from pigmented neuron loss
seen in normal aging where lateral ventral tier is relatively spared (Fearnley and Lees,
1991). Apart from dopaminergic neurons, loss of cathecholaminergic, serotoninergic and
cholinergic neurons is also characteristic of PD (Lang and Lozano, 1998a).
Lewy bodies, which are eosinophilic hyaline inclusions, are seen in the affected neurons
in PD. Although this is a consistent finding in patients with PD, Lewy bodies are not
specific for PD. Lewy bodies are primarily composed of structurally altered
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neurofilament and can be seen in several degenerative diseases where there is excessive
neuronal loss. Also the prevalence of Lewy bodies in normal aging increases from 3.8%
to 12.8% between the 6th
and the 9th
decades (Gibb and Lees, 1988). Mitochondrial
dysfunction of the genetically susceptible dopaminergic neurons is a proposed etiology
for PD. Defective electron transport chain in the mitochondria results in reduced energy
production, apotosis and cell death (Lang and Lozano, 1998b). This theory is supported
by 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) models. MPTP, a neurotoxin,
inhibits complex 1 of the electron transport chain and selectively kills the dopaminergic
neurons (Beal, 2003). Other studies have also reported decreased complex 1 activity in
substantia nigra of PD patients (Mann et al., 1992). Activation of N-methyl-d-aspartate
(NMDA) receptor can trigger neurotoxicity as result of mitochondrial damage. NMDA
excitotoxicity is mediated by a cascade of events including production of nitric oxide,
activation of caspase-3, mitochondrial DNA fragmentation and nuclear shrinkage,
ultimately resulting in neuronal cell death (Dawson and Dawson, 2004).
Mutations of certain genes can result in PD. Examples are α-synuclein, parkin, DJ-1 and
PINK. Aggregation of α-synuclein proteins, a precursor of Lewy body is caused by
mutation in α-synuclein gene. Point mutations in α-synuclein causes neuronal
dysfunction and eventually cell death by both apoptotic and non-apoptotic mechanisms
(Cookson and Van Der, 2008). Mutations in parkin gene causes defective hydrolysis of
misfolded or damaged proteins and thus accumulation of neurotoxic proteins and cell
death. DJ-1 and PINK mutations lead to mitochondrial damage of dopaminergic neurons.
There are environmental factors that might possibly cause PD which include living in a
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rural area, drinking well water, farming, and exposure to neurotoxins such as pesticides
(Priyadarshi et al., 2001).
1.1.2 Clinical features of Parkinson’s Disease
1.1.2.a Akinesia/Bradikinesia
The cardinal signs in PD are akinesia/bradyknesia, rigidity and tremors. The former sign
is a result of decreased or absent spontaneous movements. Reaction times are increased
in PD (Kutukcu et al., 1999;Evarts et al., 1981). When the complexity of the task is
increased, the reaction time is further prolonged for motor tasks, cognitive tasks and
combined cognitive and motor tasks (Brown and Marsden, 1991;Oliveira et al., 1998).
During sequential tasks, PD patients showed slowness in movement velocity and
increased pauses between the elements of sequential tasks when the complexity of the
tasks was increased (Benecke et al., 1986;Benecke et al., 1987).
Bradykinesia is improved when tasks are externally cued (Fernandez and Cudeiro, 2003),
which implies a central mechanism for bradykinesia. EEG studies of Bereitschaft
potentials (BP) implicate a central mechanism for bradykinesia in PD. BP reflect motor
preparatory activity in the motor and premotor areas (Hallett, 1994). NS1 component of
the BP which reflect the motor preparatory activity of the supplementary motor area
(SMA) is reduced in PD compared to age-matched normal subjects (Dick et al., 1989).
Velocity of movements are also reduced in PD and muscle weakness has been
hypothesized for reduction in the movement velocities in PD (Berardelli et al., 2001).
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Muscle weakness and relaxation improved in PD with Levodopa treatment (Corcos et al.,
1996).
1.1.2.b Rigidity
Rigidity in PD is caused by increased tone in the antagonistic muscles during active
movements. Both peripheral and central mechanisms are thought to play a role in rigidity
in PD. Muscle spindles in PD show increased sensitivity (Lee, 1989), which results in
exaggerated spinal-stretch reflex leading to increased resistance to passive stretch.
Improvement of rigidity in PD following Deep Brain Stimulation (DBS) surgery in
Globus pallidus interna (GPi) and Subthalamic nucleus (STN) support a central
mechanism to play a role in rigidity in PD (Fine et al., 2000;Baron et al., 2000;Krack et
al., 2003). Normally during active contraction of a muscle, the antagonistic muscles must
be reciprocally inhibited. Reciprocal inhibition is impaired in PD, which could result in
rigidity (Tsai et al., 1997).
1.1.2.c Tremor
Tremor occurs in 75% of patients with PD (Hughes et al., 1993). PD tremors typically
occur during rest at 4-6 Hz frequency, which are more pronounced during periods of
mental stress and are diminished during active movements (Deuschl et al., 1998). Both
peripheral (Rack and Ross, 1986) and central mechanisms (Levy et al., 2000) are
implicated in the pathogenesis of tremor in PD. Loss of dopamine causes tremor in PD
(Hirsch et al., 1992), and treatment with Levodopa and dopamine agonists improve this
symptom (Elble, 2002).
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1.1.2.d Type of Motor Movements affected in Parkinson’s Disease
Movements can be broadly divided into ‘internally generated’ and ‘externally cued’.
Patients with PD show significant deficits in internally generated movements compared
to externally cued motor tasks. Deiber et al. reported activation in human SMA and
dorsolateral prefrontal cortex (DLPF) in motor preparation and selection of new
movements (Deiber et al., 1991;Deiber et al., 1996). Cunnington et al. suggested deficits
in the SMA, which in turn are due to Basal Ganglia (BG) dysfunction, to be the cause
(Cunnington et al., 1999). This is also supported by a study where lesion in the SMA
caused in impaired sequential movements without visual cues in monkeys (Chen et al.,
1995). This suggests that the SMA is essential in internally generated movements.
Positron emission tomography (PET) and Electroencephalogram (EEG) studies in PD
have shown decreased activity in the SMA (Playford et al., 1992;Dick et al., 1989). But,
the DLPF function is relatively preserved in PD and this may compensate for certain
deficient internally generated movements caused by dysfunctional SMA (Cunnington et
al., 1999). Apomorphine, a dopamine receptor agonist, improves akinesia/bradykinesia
in PD. PET scan following administration of apomorphine has shown improvement in
the SMA activity in PD (Jenkins et al., 1992;Rascol et al., 1992).
1.1.2.e Postural Instability
Postural instability is a well recognized feature seen in late stages of PD (Jankovic,
2008). It is associated with frequent falls and thus is a major cause of other co-
morbidities such as hip fracture (Williams et al., 2006). Orthostatic hypotension and age-
related sensory changes have cumulative influence in falls in PD patients (Bloem, 1992).
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Abnormal modulation of postural reflexes in the lower extremities is postulated to be the
cause of the impairment in the balance (Beckley et al., 1991). Other factors that can
contribute to postural instability in PD are increased motor tone and tremor in the lower
extremities (Burleigh et al., 1995).
1.1.3 Other Motor Abnormalities in Parkinson’s disease
PD is associated with a number of other motor abnormalities. Re-emergence of primitive
reflexes is a notable one, especially the snout reflex (Vreeling et al., 1993). Persistent
eye blinking to repeated forehead tapping, called Myerson’s sign or sustained glabellar
reflex is a feature of PD. Disruption of the frontal lobe inhibitory control is the cause of
recurrence of primitive reflexes (Thomas, 1994;Vreeling et al., 1993). Various speech
disorders have been described in PD (Critchley, 1981). Other motor symptoms include
dysphagia, sialorrhoea, festination (involuntary tendency to take short accelerating steps
while walking), micrographia, shuffling gait, freezing, and dystonia (Jankovic, 2008).
1.1.4 Other Non-motor Abnormalities in Parkinson’s Disease
PD patients have several non motor features like autonomic dysfunction, cognitive
abnormalities, sleep disorders as well as sensory abnormalities (Jankovic, 2008).
Dysautonomia can manifest as orthostatic hypotension, gastrointestinal dysmotility,
thermoregulatory and urogenital dysfunction. Cognitive decline is seen in majority of
patients with PD 15 years after initial assessment (Hely et al., 2005). Apart from
dementia, PD patients suffer from a number of neurobehavioral and neuropsychiatric
disorders including depression, apathy, anxiety or hallucinations (Aarsland et al., 2007).
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Depression is seen in 60% of patients with dementia and is caused by fronto-cortical
dysfunction (Ziemssen and Reichmann, 2007). Sensory abnormalities in PD include
paresthesias, pain and anosmia (Jankovic, 2008).
Several sleep disorders are common in PD including sleep fragmentation, rapid eye
movement (REM) behaviour disorder, and nocturnal sleep disturbances secondary to
concomitant medical problems in PD such as nocturia, depression, anxiety, sleep apnea,
and periodic limb movements of sleep. Excessive day time sleepiness can result from
nocturnal sleep disturbances, medications or disruption of central sleep mechanisms in
PD (Comella, 2003). Vicious dreams are common in REM sleep behaviour disorder
which is characterized by violent motor activities during sleep such as kicking, jumping,
grabbing, punching, yelling and swearing (Gagnon et al., 2006).
1.1.5 Neuro-Ophthalmic Manifestations of PD
PD causes a variety of neuro-ophthalmic disorders. Causes of impaired visual functions
include decreased color discrimination, decreased contrast sensitivity, retinal dopamine
deficiency, altered tear film, visuospatial deficits, and visual hallucinations. Eyelid
abnormalities in PD are reduced blink rate, blepharospasm (uncontrolled spasm of the
eyelid muscle and involuntary closing of the eyes), apraxia of eye lid opening and
sustained glabellar response or Myerson’s sing (Biousse et al., 2004).
Ocular motor manifestations include convergence insufficiency, smooth pursuit
impairment and saccadic dysfunction like increased saccadic latencies, hypometric
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saccades with corrective-step saccades, preferentially affected memory-guided saccades
and inability to voluntarily suppress visually guided saccades during antisaccade tasks.
Square-wave jerks are common in PD. Compared to skeletal motor symptoms in PD,
saccadic functions are relatively preserved in PD (White et al., 1983b;Briand et al.,
1999). Ocular motor dysfunction in PD and other disorders of basal ganglia will be
discussed in detail later under the topic ‘Saccadic system’.
1.1.6 Treatment of PD
Loss of dopaminergic neurons in the SNc is the known pathology in PD and medical
treatment consists of replacing dopamine. Dopamine therapy is the gold standard for
treatment of PD (Lang and Lozano, 1998b). As dopamine cannot cross the blood brain
barrier, its metabolic precursor levodopa is given orally. Cotzias was the first to study
the role of high-dose oral levodopa in the treatment of PD in the 1960s (Cotzias et al.,
1967;Cotzias et al., 1969), following which levodopa was approved for use in PD by U.S.
food and drug administration department in 1970. Levodopa is absorbed in the
duodenum and proximal bowel, and converted to dopamine in the brain at the
dopaminergic neurons in striatal terminals by the enzyme aromatic L-amino-acid
decarboxylase. Dopamine is metabolized peripherally by two enzymes: dopamine
decarboxylase and cathechol-O-methyltransferase (COMT). So, levodopa is
administered in combination with carbidopa, a dopamine decarboxylase inhibitor, to
improve the bioavailability of dopamine in the nigrostriatal neurons. In the brain,
dopamine is broken down by monoamine oxidase (MAO).
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Levodopa improves several PD symptoms, especially bradykinesia and akinesia. Other
symptoms that are effectively treated by levodopa are tremor (Yuill, 1976), rigidity,
increased movement amplitudes in hypometria (reduced movement amplitude) and
improved postural instability (Beckley et al., 1995). Burleigh et al. reported
improvement in the abnormally increased motor tone and tremor in the lower extremities
in PD following levodopa treatment (Burleigh et al., 1995). Levodopa also improves gait
initiation deficits in PD, which implies its influence on internally generated movements
in PD (Burleigh-Jacobs et al., 1997).
Despite the well-documented benefits from levodopa, its use is constrained because of
the most troublesome complication seen in chronic levodopa therapy called ‘levodopa
induced dyskinesia’ (LID). LID is more common in patients treated with levodopa for
long duration (Schrag and Quinn, 2000;Miyawaki et al., 1997). An alternate for
levodopa is dopamine agonists like bromocriptine, cabergoline, pergolide, pramipexole or
ropinirole. These drugs act independently on the dopamine terminal, thus significantly
reducing the risk of motor complications seen in levodopa. But these drugs have other
side effects such as nausea, dizziness, hypotension, hallucinations and edema (Junghanns
et al., 2004). Other categories of PD medications are MAO inhibitors (eg. Selegiline),
which reduces the breakdown of levodopa. But, it potentiates the side effects of
levodopa like nausea, orthostatic hypotension, dyskinesia and psychosis (Tetrud and
Koller, 2004). Amantadine, an antiviral drug, has been used in PD. It probably works by
dopaminergic or anticholinergic mechanisms by promoting release of endogenous
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dopamine (Farnebo et al., 1971), and by blocking glutamate activity through its NMDA
receptor antagonistic properties (Greenamyre and O'Brien, 1991).
With LID as an annoying adverse effect of dopamine replacement therapy, and other
groups of anti-Parkinson medications not preferred either because of inefficaciousness in
LID or due to their adverse effects, deep brain stimulation surgery (DBS) is considered
the new strategy for treatment of PD.
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1.2 DEEP BRAIN STIMULATION
1.2.1 Stereotactic neurosurgery in kinesiology and evolution of
DBS
Stereotactic neurosurgery has been successfully used in treating several movement
disorders including PD, essential tremor (ET), and dystonia. The surgical targets in use
are the subthalamic nucleus (STN) and the globus pallidus internus (GPi) for PD, GPi for
dystonia, and ventralis intermedius (Vim) nucleus of the thalamus for ET. Lesion
surgery for PD was first described in 1954 following injection of procaine in the globus
pallidus (COOPER, 1954). Following this, lesion surgeries of the thalamus
(thalamotomy) and globus pallidus (pallidotomy) were done in 1950s for movement
disorders such as Parkinsonism and dyskinesias (KRAYENBUHL and YASARGIL,
1960;SVENNILSON et al., 1960;VELASCO SUAREZ, 1960). Although stereotactic
lesion surgeries effectively controlled symptoms of PD, the discovery of levodopa and its
efficacy in the medical management of the disease in late 1960s (Cotzias et al.,
1967;Cotzias et al., 1969) gradually reduced these invasive procedures. After a few years
LID, the disabling iatrogenic side-effect of chronic levodopa therapy was a major
limitation for the use of this drug, and eventually lead to the reconsideration of surgical
options in the management of PD (Siegfried, 1980).
1.2.2 Thalamic DBS
Benabid et al. reported the improvement in PD tremor following thalamotomy and high-
frequency (< 100 Hz) stimulation of Vim (Benabid et al., 1987;Benabid et al., 1991) and
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since then DBS surgeries have become an important aspect in the treatment of many
movement disorders. Thalamic DBS improved PD symptoms such as tremors and
rigidity, but was ineffective for bradykinesia/akinesia. It currently remains as an option
for treatment of ET in many institutions. Vim DBS improved tremors caused by PD and
ET, but is not as effective in cerebellar tremors (Lozano, 2000). Thalamic DBS gained
preference over lesion surgery as the procedure is reversible, programmable and can
implanted bilaterally (Benabid et al., 1991;Benabid et al., 1996). As thalamic DBS does
not significantly alleviate the major symptoms of PD except tremor, it is rarely indicated
in PD (Lozano, 2000) and it is done for treating ET in many institutions.
1.2.3 Pallidal DBS
Following Vim DBS, GPi DBS (Siegfried and Lippitz, 1994;Iacono et al., 1995) were
introduced in the treatment of PD, especially as the Vim is not effective in other
symptoms of PD like bradykinesia/akinesia and postural instability. The reason for DBS
in GPi was based on the favourable result of the thalamic DBS surgery that resolved
tremors. Thalamotomy gave symptomatic relief to tremor and so did thalamic DBS.
Similarly, stereotactic pallidotomy was found to be beneficial for akinesia/bradykinesia,
tremor and rigidity in PD (SVENNILSON et al., 1960) and pallidal DBS was expected
give the same effects. Laitinen et el. observed global improvement in PD symptoms in
81 patients, including LID following stereotactic pallidotomy of the ventroposterolateral
part of the GPi, possibly by interruption of some striatopallidal or subthalamopallidal
pathways (Laitinen et al., 1992). This prompted DBS surgery of the ventroposterolateral
part of GPi and similar results were observed as anticipated (Siegfried and Lippitz, 1994).
14
This observation was later confirmed by others (Kumar et al., 2000;Ghika et al., 1998).
Once again, the major advantage of GPi DBS versus pallidotomy is that DBS is non-
destructive and reversible. DBS electrodes can be removed with minimal damage
(Lozano and Mahant, 2004).
1.2.4 Subthalamic DBS
STN DBS has also been successful in treating PD (Limousin et al., 1995a;Limousin et al.,
1995b;Benabid et al., 1994). STN and GPi hyperactivity is thought to cause the motor
symptoms in PD and subthalamotomy (ablation of STN) in MPTP model (MPTP induced
experimental PD in monkey) alleviated rigidity, akinesia and tremor (Bergman et al.,
1990). This seeded the thought for stereotactic subthalmotomy in humans for treating PD
(Guridi et al., 1993). Benazzouz et al. reported improvement in motor symptoms in
MPTP monkeys following high frequency stimulation of STN (Benazzouz et al., 1993).
Subsequently, STN DBS in humans were shown to improve symptoms of PD (Limousin
et al., 1995b;Limousin et al., 1995a;Benabid et al., 1994). Although both STN and GPi
DBS have shown improvement in most of the PD symptoms (Burchiel et al.,
1999;Anderson et al., 2005;Rodriguez-Oroz et al., 2005), some authors favour STN
rather than GPi stimulation because of the better motor outcome in PD (Krack et al.,
1998;Krause et al., 2001;Pollak et al., 2002;Peppe et al., 2004;Lozano and Mahant,
2004). DBS in both targets are effective in dyskinesias. DBS of GPi has a direct effect
on suppressing LID (Follett, 2004), and DBS of STN decreases LID by postoperative
reduction of levodopa use (Moro et al., 1999;Krack et al., 1998). However, pallidal DBS
is very effective in dystonia and is considered to be the preferred site for DBS in treating
15
patients with dystonia (Valldeoriola et al., 2009;Vidailhet et al., 2007;Mueller et al.,
2008;Skogseid, 2008).
DBS electrode target positioning and implantation is done based on stereotactic brain
mapping and microelectrode exploration (Lemaire et al., 2007;Hutchison et al., 1998).
The electrode wires are then connected to a programmable pulse generator that is
implanted in the subclavicular region. After internalization of the leads, stimulation of
the electrodes is done through non-invasive radio-telemetry.
1.2.5 Mechanisms of Action of DBS
Although DBS is done for a wide range of neurological as well as psychiatric disorders,
the exact mechanisms of action of DBS is not clearly understood and remains elusive.
High-frequency deep brain stimulation produces clinical effects similar to lesion
surgeries such as thalamotomy, subthalamotomy and pallidotomy. The proposed
mechanisms of action of DBS are: 1. Depolarization blockade, 2. Synaptic inhibition, 3.
Synaptic depression, 4. Stimulation-induced modulation of pathological network activity
(McIntyre et al., 2004) and 5. Neurotransmitter release (Meissner et al., 2003).
High-frequency stimulation of the STN resulted in decreased spontaneous neuronal
activity which is thought secondary to strong depression of intrinsic voltage-gated
currents (Beurrier et al., 2001). Magarinos-Ascone et al. proposed that sustained high-
frequency (> 100 Hz) electrical stimulation (also called tetanic stimulation) of the STN in
rats silenced the STN neurons probably due to gradual inactivation of Na+-mediated
16
action potentials (Magarinos-Ascone et al., 2002). High-frequency stimulation of the
STN decreased the firing rate of large number of neurons in the STN and also in the SNr,
which receives excitatory projections from STN. Another finding in STN DBS is an
increased activity in the neurons of the ventrolateral thalamic nucleus, which receives
inhibitory projections from SNr. These findings suggest synaptic inhibition of the STN
during high-frequency stimulation (Benazzouz et al., 2000). Microstimulation of human
GPi during stereotactic exploration of DBS surgery decreases spontaneous neuronal
activity in the GPi, probably by releasing GABA from the axon terminals of external
pallidal and/or striatal neurons (Dostrovsky et al., 2000). These studies imply that high-
frequency stimulation results in inhibition of the DBS target area and the outcome is
similar to ablation of that area. STN high-frequency stimulation is proposed to release
dopamine from the striatal neurons in rats (Meissner et al., 2003). However, a human
study using PET imaging does not support this finding as there was no difference in the
dopamine level during high-frequency DBS of STN (Hilker et al., 2003).
Apart from the above-proposed mechanisms, an interesting hypothesis is modulation of
pathological oscillatory activity in the basal ganglia network with high-frequency
stimulation. Brown et al. described the synchronized discharges in the basal ganglia
during movement (Brown, 2003). There are two principal modes of synchronised
activity within the human subthalamo-pallidal-thalamo-cortical circuit at <30 Hz and >60
Hz. These two frequency modes have opposing actions and are inversely affected by
movement. PD patients have abnormally high ‘akinetic’ beta oscillations. High-
frequency (>70 Hz) DBS of the STN in PD patients inhibit the pathological
17
synchronization of basal ganglia at around 20 Hz, which reversed the symptoms of PD.
Also, low-frequency DBS of the STN in the same PD patients, worsened the PD
symptoms (Brown, 2003;Brown et al., 2004). Thus, modulation of the pathological, beta
oscillations in the basal ganglia of PD patients is one of the hypotheses for mechanism of
action of DBS.
18
1.3 DYSTONIA
Dystonia, once believed to be a psychiatric condition, is a well recognized movement
disorder. It is characterized by sustained, involuntary contractions of opposing muscles
resulting in twisting movements, abnormal postures and spasms. Dystonic muscle
spasms may be focal involving a particular part of the body or generalized affecting the
whole body. Dystonia can be primary due to an abnormal gene or secondary due to
structural cerebral lesions or lesions caused by neurodegenerative disorders. The
pathophysiology of dystonia is thought to involve decreased excitability of the inhibitory
connections in the motor cortex (Ridding et al., 1995) and the spinal cord (Panizza et al.,
1990). Also, patients with dystonia have an abnormally increased excitability in the
motor cortex when compared to age matched normal controls (Ikoma et al., 1996).
Microelectrode recordings from GPi in a dystonic patient case study who underwent DBS
surgery were initially said to have decreased firing rates when compared to the GPi of PD
patients (Lozano et al., 1997). But Hutchison et al. studied a larger sample of patients
with various types of dystonia and PD and determined that there were no significant
difference in the firing rates between the two groups (Hutchison et al., 2003). However,
local field potentials recorded from GPi DBS macroelectrodes have shown abnormally
high oscillations in a low frequency range (2 – 10 Hz) in patients with dystonia (Starr et
al., 2005). This suggests that oscillations in the GPi may play an important role in the
pathogenesis of dystonia. This finding is also consistent with the model of dystonia, in
which abnormalities in the BG output result in defective thalamo-cortical inhibition,
which in turn adversely affect the cortical motor function.
19
Dystonia, especially the generalized and severe forms, are difficult to manage medically.
This therapeutic challenge has eventually led to the consideration of various
neurosurgical options. Since pallidotomy was found effective against dyskinesia in PD
patients, it was considered to have potential therapeutic efficacy for the hyperkinetic
symptoms of dystonia. DBS of the GPi has been found to be effective in the
management of primary generalized dystonia (Diamond et al., 2006;Kumar et al.,
1999;Lozano and Abosch, 2004). Unlike the effect of DBS in PD which is immediate,
the beneficial effects of GPi DBS in dystonia are sometimes progressive and may take
several weeks.
20
1.4 ESSENTIAL TREMOR
Tremor is an involuntary, rhythmic, oscillatory movement of body parts. Tremors are
broadly classified as rest and action tremors. Rest tremors appear when the affected body
part is supported against gravity. Rest tremors tend to worsen during mental stress and
diminish with target directed limb movement. Action tremors are provoked by voluntary
movement of the affected limb and are further divided into postural, isometric and kinetic
tremors (Zesiewicz and Hauser, 2001).
Essential tremor (ET), a postural tremor affecting the hands and forearm, is the most
common movement disorder (Louis et al., 1998). The prevalence of ET increases
steadily with age, occurring in about 5% of patients over 60 years of age; affecting men
more than women. ET may present initially with involvement of a single limb, but
eventually becomes bilateral in the later stages of the diesease. ET affects the wrists most
often with rhythmic flexion-extension movements at a frequency of 4 – 12 Hz. Head
involvement can result in ‘yes - yes’ or ‘no - no’ tremors. Occasionally, tremor may
affect the face, trunk and voice. The amplitude of ET increases during mental stress,
fatigue and with medications that stimulate the central nervous system. ET is alleviated
by rest. A striking improvement in the tremors is observed following ingestion of small
amount of alcohol. Beta adrenergic blockers and primidone are the pharmacological
agents commonly used to treat ET (Evidente, 2000;Lou and Jankovic, 1991).
In 1962, Guiot et al. described neurons in the ventral lateral thalamus that fired
synchronously during tremors (GUIOT et al., 1962). These neurons are thought to be
21
tremorigenic, which led to thalamotomies as a surgical option for treating tremors. Even
though Vim thalamotomy effectively controlled ET, these procedures are associated with
sensory, motor, cerebellar, memory and speech complications. Memory and speech
disturbances are more pronounced in bilateral thalamotomies (Ojemann G and Ward A.,
1990). Currently Vim DBS remains to be the most effective surgical option for ET
(Lozano, 2000). The mechanism of action of Vim DBS in ET is not clear. Neuronal
jamming and blocking (Benabid et al., 1996), and activation of inhibitory mechanisms
(Ashby et al., 1995;Strafella et al., 1997) are hypothesized. One PET study has shown
decreased blood flow to the human cerebellum during Vim DBS, which suggest that
tremor suppression with Vim DBS may be because of decreased synaptic activity in the
cerebellum (Deiber et al., 1993).
22
1.5 ANATOMY AND PHYSIOLOGY OF EYE MOVEMENTS
1.5.1 Introduction
Eyes are suspended in the orbit in a matrix of fascia and extraocular muscles. The orbital
fascia extends from the apex of the orbit to the orbital rim. There are six extra-ocular
muscles around each eye that control the eye movements – four rectus muscles (lateral,
medial, superior and inferior rectus) and two oblique muscles (superior and inferior
oblique muscles). Ocular movements take place in X (Horizontal axis), Y (Antero-
posterior axis) and Z (vertical axis) axes, termed as Fick’s axes. Fick’s axes pass through
the centre of rotation of the globe, which is located on the line of sight about 13.5 mm
behind the corneal apex. Horizontal, vertical and torsional eye movements take place
around the Z, X and Y axes respectively.
1.5.2 The Extraocular Muscles
All the extraocular muscles, except the inferior oblique, take origin from the ‘annulus of
Zinn’ – a fibro-tendinous ring that is located in the apex of the orbit. This fibro-
tendinous ring has a central opening called oculomotor foramen. Many important
structures pass through the oculomotor foramen including the optic nerve, ophthalmic
artery, superior and inferior divisions of the oculomotor nerve, nasociliary branch of
trigeminal nerve and abducens nerve (Burde R.M and Feldon S.E, 1992). All the four
rectus muscles run anteriorly from the origin at the tendinous ring adjacent to their
respective walls in the orbit. These muscles insert by tendinous expansions in the sclera
near the corneal limbus. The distance from the insertion of the rectus muscles to the
23
corneal limbus gradually increases and an imaginary line drawn joining the insertions of
the medial, inferior, lateral and superior rectus appears like a spiral termed ‘spiral of
Tillaux’. The superior oblique muscle takes origin at the annulus of Zinn, runs anteriorly
and is anchored through the trochlea – a fibrous cartilaginous structure that is attached to
the orbital bone close to the supero-medial part of the orbital rim. From the trochlea, the
muscle belly runs backwards and laterally in an oblique direction and inserts to the upper
part of the globe, posterior to the insertion of the superior rectus. The inferior oblique
muscle takes origin from the orbial rim at the inferior nasal aspect and runs in an oblique
postero-lateral direction and inserts to the lower sclera behind the equator of the globe.
The actions of the extraocular muscles depend on the origin and insertion of the muscle,
the direction of the muscle belly and the axis of rotation of the eye. The lateral and
medial rectus muscles move the eyes in the horizontal plane. The superior and the
inferior rectus muscles elevate and depress the eyes in abducted position. The inferior
and superior oblique muscles also move the eyes in the vertical plane (elevation and
depression respectively), but when the eyes are adducted. The superiors (rectus and
oblique) are responsible for incyclotorsion and the inferiors (rectus and oblique) are
excyclotortors. The oculomotor nerve (3rd
cranial nerve) innervates the medial rectus,
superior rectus, inferior rectus and the inferior oblique muscles. Trochlear nerve (4th
cranial nerve) supplies the superior oblique muscle and the abducens (6th) nerve
innervates the lateral rectus muscle.
24
1.5.3 Extraocular Muscle Fiber Types
The extraocular muscles contain muscle fibers measuring 9-30 µm in diameter and are
different from skeletal muscles (Porter and Baker, 1996;Porter et al., 1995). The
extraocular muscles have two layers, an outer layer adjacent to the orbit and periorbita
called orbital layer and an inner layer adjacent to the ocular globe called global layer.
80% of the fibers in the orbital layer are singly innervated and are rich in mitochondria
and oxidative enzymes. These fibers also possess the most fatigue-resistant property.
The rest 20% of the orbital fibers are multiply innervated. Among the global layer, 33%
are composed of red singly innervated fibers, another 33% are pale singly innervated
fibers, 23% are intermediate singly innervated fibers and the rest 10% are multiply
innervated fibers. The red fibers are highly fatigue resistant, and the intermediate and
pale type fibers exhibit intermediate and low fatigue-resistance respectively.
The singly innervated fibers of the orbital and global layers have fast-twitch capacity.
The multiply innervated fibers of the orbital layer have twitch capacity only near the
center of the fiber (Jacoby et al., 1989) and those of the global layer are nontwitch. The
twitch and nontwitch extraocular muscle fibers receive different types of innervation.
Twitch fibers are innervated by large motoneurons within the 3rd
, 4th
and 6th
cranial
nerves and the nontwitch fibers by the smaller motoneurons around the periphery of these
nuclei (Buttner-Ennever et al., 2001). It was once beleived that the fast-twitch fibers are
responsible for rapid eye movements and the slower, vestibular induced eye movements
are attributed to the tonic, nontwitch fibers (ALPERN and WOLTER, 1956;Jampel,
1967). But later on, it was demonstrated that all types of muscle fibers are involved in
25
different classes of ocular motility including the fast and the slow eye movements (Scott
and Collins, 1973).
1.5.4 Uniocular and Binocular Eye Movements
In order to obtain single binocular vision, both the eyes must move simultaneously. So
extraocular muscles in each eye are paired to place the object of interest in fovea of each
eye. These paired extraocular muscles are called as yoke muscles. Yoke muscles are
synergistic muscles that move the eyes in a given direction. E.g. the right lateral rectus
and the left medial rectus are yoked muscles that synergistically contract to move the
eyes to the right. Agonist is a primary muscle that moves the eye in a given direction e.g
medial rectus is the agonist muscle responsible for adduction of that eye. During an eye
movement, more than one muscle in that eye can bring about the movement, termed
‘ipsilateral synergists’. An example for this is the superior rectus and inferior oblique
muscles, which cause elevation in that eye. Similarly, muscles in the eye with opposing
actions are termed ‘ipsilateral antagonists’. An example of ipsilateral antagonists is the
lateral and medial rectus muscles.
Conjugate eye movement in which both the eyes are moving in the same direction is
called as version, whereas disconjugate eye movement in which eyes are moving in
opposite directions is termed vergence. There are six cardinal positions of gaze. These
are dextroversion (eyes to the right), laevoversion (eyes to the left), dextroelevation (eyes
up and to the right), laevoelevation (eyes up and to the left), dextrodepression (eyes down
and to the right) and laevodepression (eyes down and to the left). There are different
26
paired muscles that are activated in each types of version like dextroversion (right lateral
rectus and left medial rectus), laevoversion (left lateral rectus and right medial rectus),
dextroelevation (right superior rectus and left inferior oblique), laevoelevation (left
superior rectus and right inferior oblique), dextrodepression (right inferior rectus and left
superior oblique) and laevodepression (left inferior rectus and right superior oblique).
1.5.5 Six Eye Movement Systems
Ocular movements are broadly divided into six types, which are called as systems. These
are 1) Saccadic eye movements, 2) Smooth pursuit, 3) Vergence, 4) Fixation, 5)
Vestibulo-ocular (VOR) and 6) Optikinetic movements. Saccades, smooth pursuit, VOR
and optokinetic eye movements are conjugate eye movements (versions), whereas
vergence is a disconjugate eye movement. Saccades are fast eye movements, but the
other systems are slower eye movements that are generated to maintain fixation at an
object and/or prevent retinal slip. Saccades are rapid eye movements that place the object
of interest in the center of gaze. Smooth pursuit is slow ocular movements that maintain
fixation on a slow moving target or during slow movement of the body. Vergence is a
disjunctive movement (eyes moving in horizontal opposite directions). Vergence is
essential to maintain foveal fixation and attain stereopsis (binocular single vision) when
the object of interest is approaching or receding from the eyes. There are two types of
vergence: convergence, which is movement of both the eyes nasally (adduction) and
divergence, which is movement of both eyes temporally (abduction).
27
During visual fixation three distinctive miniature eye movements are seen namely
microsaccades, microtremor and microdrift, which occur in horizontal, vertical and
torsional directions (Ferman et al., 1987;Steinman et al., 1973). Microsaccades have
amplitude < 26 minutes of arc and occur at a mean frequency of 120 / minute. There are
no known visual functions for microsaccades (Kowler and Steinman, 1980).
Microsaccades can stop during fine visuomotor tasks like threading a needle or sighting a
rifle and can be voluntarily suppressed by normal individuals (Winterson and Collewijn,
1976). Ocular microtremor is a continuous high-frequency, low amplitude physiological
tremor that is coherent between the eyes. The origin of ocular microtremor is
controversial and is suggested to be of central/neurogenic origin (Spauschus et al.,
1999;Bolger et al., 1999b;Bolger et al., 1999a). Microdrift occurs at amplitude between 2
and 5 minutes of arc and at rates less than 20 minutes of arc per second. The rates of
microdrift increase in the absence of a visual target, suggesting its relationship in fixation
mechanism when an object is viewed. Microdrift is believed to prevent fading of images
(Steinman et al., 1973).
The VOR, the most primitive form of eye movement, is essential for visual perception by
compensating for head movements. The VOR prevents retinal slip by holding images
steadily on the retina during head motion. During head movement, VOR eye movement
generated results in an eye movement in the orbit that is equal in amplitude and opposite
the direction of the head movement. Thus the position of the eyes remains unchanged in
space during the VOR. The translational VOR is activated by heave (side-to-side), surge
(fore-and-aft) and bob (up-and –down) head movements. The angular VOR is activated
28
by rotational head movements in its pitch (interaural), yaw (earth-vertical) or roll (naso-
occipital) axes. Translational head movements are detected by the otolith receptors in the
maculae of the utricle and saccule, whereas angular head movements are detected by the
cupulae in the semicircular canals. Optokinetic smooth eye movements are essential to
hold images on the retina during head rotations at very low frequencies or, after the VOR
fades away. The angular VOR normally responds to transient, high-frequency head
motion, but fades away when the head rotation is sustained. The optokinetic system is
considered to be the helpmate of angular VOR during low-frequency head rotations.
1.5.6 Laws Governing Eye Movements
Hering’s law of equal innervation: Hering’s law states that during conjugate eye
movements, equal and simultaneous innervations flow to the yoked (synergistic) muscles.
For example, during a rightward eye movement the right lateral rectus and the left medial
rectus receive equal innervations. It is also called the law of motor correspondence.
Sherrington’s law of reciprocal innervation: Sherrington’s law states that, whenever an
agonist muscle receives an excitatory signal to contract, an equivalent inhibitory signal is
sent to its antagonist muscle of the same eye. An example is relaxation of the left lateral
rectus and contraction of the left medial rectus during left adduction.
29
1.6 SACCADIC SYSTEM
Saccades are quick eye movements that redirect the eyes to place the object of interest on
the fovea. Quick phases of VOR and optokinetic nystagmus are also considered to be
saccades because of their amplitude-velocity relationships which are similar to saccades
(Sharpe et al., 1975;Garbutt et al., 2003).
1.6.1 Classification and Definition of Saccades
Volitional saccades: Volitional (voluntary) saccades direct the gaze towards a
remembered location or to a point where the target will most likely appear. These are
elective saccades that are made as part of purposeful behaviour. Volitional saccades can
be further categorized into four types: Saccades on command, anticipatory saccades,
memory-guided saccades and antisaccades.
Saccades on command: These are saccades generated on cue.
Anticipatory saccades: These are also called as predictive saccades. Anticipatory
saccades are generated in anticipation of or in search of the appearance of a target at a
particular location.
Memory-guided saccades: These are saccades that are generated to a location in which a
target was previously present.
Antisaccades: Antisaccades are saccades that are generated in the opposite direction to a
suddenly appearing target. Subjects in advance are instructed to do so. Antisaccades
require voluntary effort and attention in order to suppress the reflexive saccades towards
the visual target.
30
Reflexive saccades: These are saccades that are generated to unexpectedly appearing
novel stimuli. The stimuli can be visual, auditory or tactile. A new target that appears in
the retina can provoke a visually guided reflexive saccade.
Express saccades: Very short latency saccades that are seen when fixation target is
extinguished before the presentation of the novel stimulus (gap paradigm).
Spontaneous saccades: Random saccades that occur when the subject is not required to
perform any particular visual task.
Quick phases: These are quick phases of nystagmus of VOR and/or optokinetic
nystagmus (OKN), as well as automatic resetting ocular movements following
spontaneous drift of the eyes.
1.6.2 Pulse-Step Innervation of Saccades
There are two components of saccadic innervation, a pulse and a step. The pulse of
innervation is a high-frequency burst of the agonist motoneurons. This phasic activity
results in the contraction of the agonist extraocular muscles and moves the eye rapidly
from one point to another against the viscous drag of the orbit. After the saccadic eye
movement, a tonic innervation of the agonist motoneurons holds the globe in the new
orbital position, resisting the orbital elastic force that tends to rotate the eye back to the
orbital mid position. This tonic component constitutes the step of saccadic innervation.
During saccades, a neural network mathematically integrates the pulse (eye velocity)
command into the step (eye position) command. This neural network is called as
‘velocity-to-position neural integrator’. The medial vestibular nucleus and nucleus
31
prepositus hypoglossi located in the medulla are the neural integrators for horizontal eye
movements. Neural integrators for vertical and torsional eye movements are in the
interstitial nucleus of Cajal in the midbrain in concert with the vestibular nuclei. Lesions
in the neural integrators cause gaze-evoked nystagmus. The pulse and step of innervation
applies for all types of eye movements: saccades, smooth pursuit, slow phases of the
VOR and optikinetic movements, and vergence. But, for low-velocity ocular movements
like smooth pursuit, slow phases of optokinetic and VOR and vergence, the phasic
increase (pulse) of innervation is small when compared to saccades.
Saccadic dysfunction can result from an abnormal pulse, abnormal step or a pulse-step
mismatch. A decrease in saccadic pulse height (firing rate for an eye velocity command)
results in ‘slow saccades’, whereas a decrease in saccadic pulse amplitude (firing rate
[height] X duration of firing [width]) causes saccades of small amplitude (hypometric
saccades). On the other hand, an increase in pulse amplitude causes hypermetric
saccades. If there is an abnormality in the step (tonic) innervation, the new eye position
cannot be maintained and thus the eye slowly drifts towards the mid-orbital position
(Bahill et al., 1978). This ocular drift causes a gaze-evoked nystagmus, with the
corrective quick phase towards the direction of the original saccade.
1.6.3 Saccadic Peak Velocity and Duration
The stimulus for a saccadic eye movement is usually an image of an object of interest in
the periphery of vision. Saccadic peak velocity varies between 30 and 700 deg/sec and
these values fall within a limited range among normal individuals (Sharpe et al., 1975).
32
For a saccadic amplitude of 0.5° - 40°, the duration of saccades varies from 30 to 100 ms
(Smeets and Hooge, 2003;Smit et al., 1987). The saccadic peak velocity saturates for
large-amplitude eye movement. Saccadic velocities are decreased during times of mental
fatigue and inattention (Sharpe et al., 1975;Smit et al., 1987;Fletcher and Sharpe, 1986),
but are not reduced by neuromuscular fatigue (Barton and Sharpe, 1994;Fuchs and
Binder, 1983). Saccades of rapid eye movement (REM) sleep have lower velocity and
are generally not conjugate. REMs are sometimes monocular in vertical or horizontal
directions, and this disjunctive ocular movements suggest separate saccadic pathways for
each eye, which is not consistent with Herring’s law of equal innervation (Zhou and
King, 1997). Peak velocity is attained between 1/3 and ½ distance of the saccadic eye
movement and the velocity decelerates before the abrupt termination of the saccade (Smit
et al., 1987).
1.6.4 Latency of Saccades (Saccadic Reaction Time)
Saccadic latency is the duration between the appearance of the target / object of interest
and the onset of the eye movement. Normally it is 150-250 ms. Saccadic latencies are
prolonged with advancing age (Sharpe and Zackon, 1987;Warabi et al., 1984). Attentive
and motivational state of the subject has a major influence on saccadic initiation time
(Groner and Groner, 1989). Other factors that influence saccadic latencies are
predictability of the target of interest, target size, luminance, contrast and complexity
(Doma and Hallett, 1988;Ottes et al., 1984); and whether the target is visual or auditory
(Zambarbieri, 2002).
33
1.6.5 Gap and Overlap Stimuli
As mentioned above, the stimulus for a saccadic eye movement is the presentation or
appearance of an object of interest or a novel visual stimulus away from the fovea. This
can be done in the laboratory setting in a dark room by illuminating a ‘target light’ in the
visual periphery and extinguishing the central ‘fixation light’, which the subject is
viewing. Saccadic latency is influenced by the temporal relationship between the time
when the fixation light is turned off and the illumination of the peripherally located target
light. During experimental tasks, saccadic latency reduces to 100 ms when a brief
temporal ‘gap’ (~ 100 – 400 ms) is introduced between the disappearance of the fixation
light and the appearance of the target light. This is called ‘gap stimulation’. Saccades
with this decreased reaction time in gap paradigms are called express saccades (Fischer
and Ramsperger, 1986;Fischer and Ramsperger, 1984). Conversely, the saccadic latency
increases when the fixation light remains illuminated even after the appearance of the
target light. This is called ‘overlap stimulation’.
When compared to adults, children can perform express saccades easily (Klein and
Foerster, 2001). Express saccades improve with practice and when performed with the
same target positions used during training (Pare and Munoz, 1996;Fischer and
Ramsperger, 1986). This probably implies a predictive mechanism in express saccades.
In natural viewing conditions with several simultaneous visual stimuli, express saccades
are unlikely to happen and thus, express saccades are mostly observed with experimental
paradigms in the laboratory (Schiller et al., 2004). The rostral pole of the superior
colliculus (SC) plays an important role in express saccades. Express saccades are
34
completely eliminated in monkeys with lesions of the SC, whereas lesions of the frontal
lobe did not abolish the express saccades (Schiller et al., 1987). The gap and overlap
conditions reveal the influence of fixation and attention on the saccadic reaction time to a
new target.
1.6.6 Antisaccades
Antisaccade paradigms are developed to study the control of voluntary saccades (Munoz
and Everling, 2004). Antisaccade task is execution of an eye movement away from the
target by voluntary suppression of the visual stimulus. Thus, there are two components
of an antisaccade task: 1) suppression of a saccade towards a visual stimulus (prosaccade)
and 2) generation of an equal sized saccadic eye movement towards the opposite
direction (i.e. the mirror location). To measure the accuracy of an antisaccade task, the
target light is illuminated at the correct location shortly after the time given for the
antisaccade to happen. Errors are frequent in normal subjects initially. Following brief
period of practice the error rate decreases, typically to 25%. Error rates are higher for
antisaccade tasks with shorter fixation period (Smyrnis et al., 2002). Antisaccades have
longer latency and can be less accurate than prosaccades (ie. saccades toward a visual
target). Also, antisaccade velocities are slower than prosaccades (Edelman et al., 2006).
The ability to suppress reflexive saccades and perform antisaccades is defective in
children but develops during adolescence (Fukushima et al., 2000). The saccade
direction accuracy during antisaccade tasks worsens with increasing age, suggesting the
decline of the inhibitory control to suppress reflexive saccade in older age (Butler et al.,
1999). Human dorsolateral prefrontal cortex (DLFP), frontal eye fields (FEF) and
35
supplementary eye fields (SEF) are preferentially activated during antisaccade tasks on
PET study (Sweeney et al., 1996).
Introduction of a gap condition for antisaccade task reduces saccade reaction time to 175
ms (Fischer and Weber, 1997). Several cerebral lesions, especially involving the frontal
lobes, are known to cause antisaccade abnormalities. Patients with such lesions have
significant difficulties suppressing reflexive saccades towards the target light and make
frequent prosaccade errors during antisaccade tasks.
1.6.7 Saccadic Accuracy
Saccadic inaccuracies can result from abnormalities in the pulse innervation (called
saccadic pulse dysmetria) and / or pulse-step mismatch resulting in a post-saccadic drift.
If the pulse and step are inaccurate, saccades overshoot or undershoot their target, a
condition called saccadic dysmetria. Slight overshooting (saccadic hypermetria) can
happen with normal small-amplitude saccades and similarly undershooting (termed
saccadic hypometria) is seen during normal large-amplitude saccades (Weber and Daroff,
1971). Hypometria is more pronounced in centrifugally directed saccades (directed
towards the periphery) and hypermetria in centripetally directed saccades (directed
towards the center). This minor degree of saccadic dysmetria is usually less than 10% of
the amplitude of the original saccade (Becker and Fuchs, 1969) and is considered to be
physiologic. However, this can be more prominent in old age (Sharpe and Zackon,
1987;Huaman and Sharpe, 1993;Warabi et al., 1984) and during mental fatigue and
inattention (Bahill and Stark, 1975). Infants take several small saccades to view an
36
eccentric target (Shupert and Fuchs, 1988). The range and accuracy of vertical saccades
decreases with advancing age (Huaman and Sharpe, 1993).
Following a saccadic undershoot (during a large-amplitude saccade), a corrective saccade
happens towards the original saccadic target. The latency of these corrective saccades is
100 – 130 ms, much shorter than normal saccadic latency (about 200 ms). This saccadic
correction happens even when the target is extinguished before the completion of the
initial saccade, strongly suggesting a non-visual process that is responsible for this. This
is mediated by maintaining an efference copy of the ocular motor commands, termed
‘corollary discharge’ (Grusser, 1995;Bridgeman, 1995). Similarly, after completion of a
saccade the eye can make a small saccade of 0.25 - 0.5 in the opposite direction, called
‘dynamic overshoot’ (Bahill et al., 1975). Dynamic overshoot might be caused by
elasticity of the extraocular muscles or due to brief reversal of the higher saccadic
command (Kapoula et al., 1989;Enderle, 2002).
At the end of a saccade the eye can drift for a few hundred milliseconds in the direction
of the saccade called ‘glissade’ or ‘post-saccadic drift’ (Weber and Daroff, 1972;Bahill et
al., 1978). Glissades are caused by mismatch of pulse (phasic) and step (tonic)
innervation of saccade and are seen during times of fatigue (Bahill and Stark, 1975;Bahill
et al., 1978). Post-saccadic drifts can be conjugate or disjunctive and eye movement
recordings are essential to determine this.
37
1.6.8 Visual Stability during Saccades
During saccadic eye movements, despite the rapidly sweeping visual background across
the retina, there is absence of blurring of images. Essentially, it appears we do not see
during saccades. This absence of blurred images during saccades is called ‘saccadic
omission’. There are two reasons for this: saccadic suppression and visual masking.
Saccadic suppression is elevation of the visual threshold for detecting light during the
rapid eye movement (MacKay, 1970;Diamond et al., 2000;Matin, 1974). Visual masking
is a process by which the blurred visual perception of the sweeping world during the
saccade is eliminated by the highly contoured, stationary visual background before and
after the saccade. During saccadic omission, there is reduced sensitivity in the
magnocellular visual pathway (Burr et al., 1994). During image motion induced by
saccades, many neurons in the middle temporal (MT), middle superior temporal cortical
(MST) and lateral intraparietal (LIP) areas of monkeys are selectively silenced (Kusunoki
and Goldberg, 2003). But, these neurons respond well during external image motion
without saccades. This suggests that these neurons are not merely silenced by motion
blur.
38
1.7 NEUROANATOMY AND NEUROPHYSIOLOGY OF
SACCADES
1.7.1 Overview
The frontal eye fields (FEF) and SC are both important in the generation of saccades.
FEF initiate volitional and reflexive saccades, whereas the parietal eye fields (PEF)
mediate the visually guided saccades of both volitional and reflexive types. However,
because of the strong interconnections between the two areas, FEF and PEF influence
each other during initiation of saccades. The saccadic pathway from the FEF projects to
the contralateral paramedian pontine reticular formation (PPRF) located in pons. The
impulse streams from the PEF synapse with ipsilateral SC, before projecting to the
contralateral PPRF. Another important pathway through the BG modulates saccadic eye
movements by their excitatory or inhibitory influence on the SC. FEF, PEF and
dorsolateral prefrontal cortex (DLPF) project to the caudate. From the caudate two
parallel saccadic pathways, with opposing effects, project to the SC. This will be
discussed later in depth.
For horizontal saccades, short-lead burst cells in the PPRF send signals to the abducens
nucleus, which activates the abducens motoneurons as well as the interneurons.
Motoneurons supply the lateral rectus muscle on the same side and the interneurons cross
the midline then ascend, through the medial longitudinal fasciculus (MLF), to reach the
contralateral oculomotor nucleus in the midbrain and innervate the medial rectus muscle
on the opposite side (Fig. 1). The pathway for vertical saccades is from the PPRF too,
but there is an additional relay in the rostral interstitial nucleus (riMLF) and the
39
interstitial nucleus of Cajal, located in the tegmentum of rostral midbrain. These nuclei,
through their connections to the oculomotor and trochlear nuclei, regulate vertical and
torsional eye movements. As my research project is on changes in the oscillatory
potentials in the BG and thalamus during horizontal saccades, neuroanatomy and
neurophysiology of horizontal saccades is primarily focussed here.
1.7.2 Frontal Eye Fields
In humans the FEF is located in the posterior part of the middle frontal gyrus and
precentral sulcus and gyrus (Fig. 2), based on positron emission tomography (PET) and
functional MRI (fMRI) studies (Fox et al., 1985;Sweeney et al., 1996;Cornelissen et al.,
2002). The FEF receives projections from lateral intraparietal area (LIP) also known as
parietal eye fields (PEF); supplementary eye fields (SEF): dorsolateral prefrontal cortex
(DLPF), cingulate gyrus and superior temporal cortex; and intralaminar and pulvinar
areas of the thalamus. Neurons of the FEF project to internal capsule and through four
pathways these neurons reach the premotor structures of the brainstem: 1) striatal fibers
to the caudate and putamen, 2) dorsal transthalamic pathway to the thalamus, 3) ventral
pedunculo-tegmental pathway to contralateral PPRF and 4) intermediate pathway.
Through these pathways, FEF projects ipsilaterally to SC, omnipause neurons in nucleus
raphe interpositus (rip), nucleus reticularis tegmenti pontis (NRTP) and rostral interstitial
MLF (riMLF); and to the PPRF on both sides.
40
Figure 1: Pathways for horizontal saccades in human. The left hemisphere directs the
eyes to the right (opposite) side. LGB = Lateral geniculate body, SC = Superior
colliculus, SNr = Substantia nigra pars reticulata, PPRF = Paramedian pontine reticular
formation, MLF = Medial longitudinal fasciculus. (Redrawn from Manter and Gatz.
Clinical Neuroanatomy and Neurophysiology. 10th
edition. Philadelphia, USA: F. A.
Davis company, 2003)
Frontal eye field Parietal eye field
Caudate and Putamen
LGB
SC
MLF
Right lateral rectus
Left medial rectus
Oculomotor nucleus
PPRF Abducens nucleus
Area 19
Area 18
Area 17 Left hemisphere
SNr
Rightward saccade
41
1.7.3 Parietal Eye Fields
The LIP area in the intraparietal sulcus of the inferior parietal lobule of the monkey is the
PEF. This area is involved in reflexive shifts of visual attention. PEF neurons project to
FEF and SC and receive projections from FEF. Stimulation of this area elicits saccades
and lesions here cause delay in visually guided reflexive saccades (Lynch and McLaren,
1989). The human PEF (homolog of LIP area of monkey) is probably Brodmann areas
39 and 40 located in the angular gyrus and supramarginal gyrus (Fig. 2). Lesions in these
areas located in the human posterior parietal cortex result in delayed visually-guided
saccades in both gap and overlap paradigms, but overlap paradigms are more affected
(Pierrot-Deseilligny et al., 1991). Human posterior parietal cortex is activated during
visually-guided reflexive saccades and memory-guided saccades on PET study
(Anderson et al., 1994). The simian middle temporal area (MT) and medial superior
temporal visual area (MST) are homologues to areas V5 and V5a in human respectively,
and are responsible for generation of smooth pursuit eye movements. Striate cortex (area
V1) has projections to V5 and LIP and this partly constitute the dorsal magnocellular
pathway, responsible for perception of moving targets (Fig. 2). Lesions in these areas
result in retinotopic defects and saccades to moving targets in the contralateral visual
field are impaired (Morrow and Sharpe, 1993;Thurston et al., 1988).
1.7.4 Dorsolateral Prefrontal Cortex
DLPF is located anterior to the FEF and corresponds to Brodmann areas 9 and 46 (Fig.
2). DLPF receives input from the posterior parietal cortex and projects to FEF, SC and
supplementary eye fields (SEF). DLPF plays an important role in visuospatial memory,
42
and antisaccade tasks. Human PET studies show activation of DLPF during antisaccade
tasks and memory-guided saccades to a single target (Sweeney et al., 1996;Anderson et
al., 1994). Lesions in the human DLPF result in inability to suppress reflexive saccades
to visual targets and thus impaired antisaccade tasks and defects in memory-guided
saccades (Pierrot-Deseilligny et al., 1991;Pierrot-Deseilligny et al., 1993).
1.7.5 Supplimentary Eye Fields
SEF is located in the dorsomedial aspect of the frontal cortex in the upper part of the
paracentral sulcus (Fig. 2). Primate SEF is connected to LIP area (PEF), SC and the FEF
(Shook et al., 1990). Human SEF is active during volitional saccades (memory-guided
saccades, antisaccades and self-paced saccades) on PET studies (Sweeney et al.,
1996;Anderson et al., 1994). Stimulation of SEF in rhesus monkeys result in a saccadic
eye movement in craniotopic space i.e. towards a specific region in the orbit (Tehovnik
and Lee, 1993), whereas saccades elicited by FEF and SC are in the retinotopic space.
Study of human SEF lesion suggest its participation in learning and planning of memory-
guided saccades (Pierrot-Deseilligny et al., 1993).
43
Figure 2: Cortical, subcortical and brainstem areas in human brain involved in control of
saccadic eye movements. SC = Superior colliculus, SNr = Substantia nigra pars
reticulata, MT = Middle temporal visual area, MST = Medial superior temporal visual
area. (Redrawn from Leigh RJ, Zee DS. The Neurology of eye Movements. Oxford,
UK: Oxford University Press, 1999)
Supplimentary eye field
Dorsolateral Prefrontal cortex
Frontal eye field
Superior parietal lobule
Angular gyrus
Parietal eye field
Supramarginal gyrus
MST
MT
Striate cortex
Caudate SNr
SC Thalamus
44
1.7.6 Superior Colliculus
The superior colliculi are a pair of eminences that are located at the roof of the midbrain
– the tectum. Cerebral cortical and BG inputs converge onto the SC. SC is composed of
7 alternating layers of fibers. The superficial layer primarily participates in visual
sensory function and the intermediate layer, beneath the visual superficial layer is
involved in ocular motor function (Sparks, 1986). Visual (sensory) information reaches
the SC directly from the optic tract and also indirectly from striate cortex. All sensory
signals including visual, auditory and tactile information converge onto the superficial
layer in a topographic pattern to form a spatial map (Wallace et al., 1996). Retinal visual
inputs project directly to the SC in a two-dimensional retinotopic manner (Schiller and
Stryker, 1972). FEF projects to the SC directly and also indirectly through the caudate
and substantia nigra pars reticulata (SNr) (Helminski and Segraves, 2003;Hikosaka and
Wurtz, 1983a;Hikosaka and Wurtz, 1983c). Through antidromic and orthodromic
stimulation studies, it is evident that SNr projects to SC on the same side and to the
opposite side – uncrossed and crossed nigrocollicular pathways, and it is hypothesized
that these two pathways have opposing effects on the SC (Jiang et al., 2003). SC also
receives projections from the LIP area (PEF) (Gaymard et al., 2003).
SC has three types of cells that are responsible for saccadic eye movements: 1) Burst T
neurons, 2) Fixation neurons and 3) Build-up neurons. T cells are located in the
intermediate layers and discharge in relation to contraversive saccades in both horizontal
and vertical directions. Fixation neurons maintain the eyes still and silence the build-up
neurons until the appearance of a new target. Fixation cells in the SC are inhibited by the
45
build-up neurons, thus saccades are triggered. Ablation of the unilateral SC in rhesus
monkeys resulted in elimination of express saccades contralateral to the side of the lesion
(Schiller et al., 1987). Removal of primate SC bilaterally caused a slight increase in
saccadic latency, decrease in saccadic amplitude, enhanced fixation and decreased
distractibility (Albano et al., 1982). Horizontal voluntary saccades were preserved on
both directions following transient inactivation of a cerebral hemisphere by injecting
amobarbital via the internal carotid artery in humans (Lesser et al., 1985). Similarly,
patients with chronic hemidecortication had preserved voluntary bi-directional horizontal
saccades suggesting that there are structures in the brain other than FEF, like the SC, that
can generate saccadic eye movements (Sharpe et al., 1979).
1.7.7 Brain Stem Generation of Horizontal Saccades
There are two types of cells in the brain stem responsible for saccades: 1) Burst neurons
and 2) Omnipause neurons. Burst neurons are further divided into excitatory and
inhibitory burst neurons. Excitatory short-lead burst neurons are in the nucleus reticularis
pontis caudalis (NRPC) located in the PPRF (Fig. 3) and deliver high frequency (1000
Hz) discharges 8-15 ms before, and during saccades. These neurons excite the lateral
rectus motoneurons and the internuclear neurons that reside in the abducens nucleus.
Long-lead burst neurons are located in the rostral PPRF and discharge irregularly for ~
100 ms before the onset of saccades. Inhibitory burst neurons are located in the nucleus
paragiganto cellularis dorsalis (PGD) in the PPRF (Fig. 3), which cross the midline and
inhibit the contralateral abducens motoneurons. Omnipause neurons are in the nucleus
raphe interpositus (RIP) in the PPRF (Fig. 3), and show a reverse pattern of firing to
46
short-lead burst neurons. Omnipause neurons inhibit the short-lead burst neurons during
smooth eye movements and fixation and are characterized by tonic, high frequency (>
100 Hz) discharge pattern, which pause for 10-15 ms before and during saccades.
Long-lead burst neurons and SC inhibit omnipause neurons during saccades, which
results in phasic disinhibition of the short-lead burst neurons, which in turn activates the
motoneurons to dispatch a saccade (Moschovakis and Highstein, 1994). The PPRF
receives projections from bilateral FEF, contralateral SC, fastigial nucleus of the
cerebellum and certain ipsilateral brain stem structures like nucleus prepositus
hypoglosus, vestibular nucleus and nucleus of the posterior commisure. Stimulation of
the PPRF results in an ipsiversive saccade (Cohen and Komatsuzaki, 1972). Lesions in
the PPRF excitatory short-lead burst neurons cause decreased peak velocity and increased
duration of saccades towards the side of the lesion (Barton et al., 2003).
Cerebellar control of eye movements is vast and beyond the scope of my research area
and hence is not included in this discussion.
47
Figure 3: Saccadic premotor neurons in human brainstem shown through sagittal view.
NRPC = Nucleus reticularis pontis caudalis, RIP = Nucleus raphe interpositus, PGD =
Nucleus paragiganto cellularis dorsalis, INC = Interstitial nucleus of Cajal, riMLF =
Rostral interstitial medial longitudinal fasciculus. (Redrawn from Horn AKE, Buttner U.
Saccadic premotor neurons in brainstem: functional neuroanatomy and clinical
implications. Neuroophthalmology 1996;16: 229-240.)
Thalamus
INC Superior colliculus
Cerebellum
Oculomotor nuclei
Trochlear nuclei
Oculomotor nerve
riMLF
Abducens nuclei
Excitatory short-lead burst neurons (NRPC)
Omnipause neuron (RIP)
Hypoglossal nuclei
Inhibitory short-lead burst neurons (PGD)
Inferior colliculus
48
1.8 BASAL GANGLIA CONTROL OF SACCADES
The BG constitute several subcortical nuclei at the base of the cerebrum, which includes
the caudate nucleus, putamen, globus pallidus, substantia nigra and subthalamic nucleus
(STN). The caudate and putamen are collectively called as the striatum, because they
arise from the same embryonic structures and have common cell types. The globus
pallidus is divided into two segments – globus pallidus externa (GPe) and globus pallidus
interna (GPi). The lentiform nucleus consists of the putamen and globus pallidus. The
lentiform nucleus and caudate are collectively termed the corpus striatum. The substantia
nigra consists of two parts: substantia nigra pars compacta (SNc), which contains the
dopaminergic neurons, and substantia nigra pars reticularis (SNr), which contains
gamma-aminobutyric acid releasing (GABA-ergic) neurons. The subthalamic nucleus is
a small lens shaped aggregate of neurons overlying the substantia nigra (Fig. 4). It
receives projections directly from the cerebral cortex. The striatum (caudate and
putamen) is considered to be the major input station in the BG that receives signals from
cerebral cortical areas and the thalamus, whereas GPi and SNr are the two major output
areas sending neuronal signals to the thalamus and the brainstem including the SC. GPi
and SNr are structurally and functionally homologous. SNc, STN and GPe, through their
connections with other nuclei in the BG, act as modulators (Hikosaka et al., 2000).
49
Figure 4: Coronal section of human brain through the mid thalamus at the level of the
mamillary bodies. All the important structures of the basal ganglia including caudate
nucleus, putamen, globus pallidus externa and interna, subthalamic nucleus and
substantia nigra pars reticulata are prominent through this section. VA = Ventral anterior
nucleus, VL = Ventral lateral nucleus, and CM = Centromedian nucleus of the thalamus.
(Adapted from Fix JD: Neuroanatomy, 4th
edition. Philadelphia, USA: Lippincott
Williams & Wilkins, 2008.)
Caudate
Fornix
Lateral ventricle
Corpus callosum
Putamen
Globus pallidus externa and interna
Insula
Subthalamic nucleus
Lateral ventricle
Hippocampus
Mamillary body Amygdala
Substantia nigra
Optic tract
Third ventricle
Claustrum
Internal Capsule
Thalamus
50
The basal ganglia exert an inhibitory effect on the thalamocortical and brainstem
networks and are proposed to have two major functions: 1) control of learned movements
through the thalamocortical network, and 2) control over initiation of various movements
(including eye-head, locomotion, mastication and vocalization) through the projections to
the brainstem motor area (Hikosaka et al., 2000). The striatal motor system, also called
as the extrapyramidal system, participates in initiation and execution of voluntary as well
as automated stereotyped motor activities. Diseases affecting the BG result in a wide
range of motor symptoms from difficulty with suppressing involuntary movements to
inability in initiating voluntary movements, and thus either excessive or poverty of
movements in the limbs or trunk. Oculomotor deficits, if present, can be missed on
clinical exam, perhaps due to the substantial skeletal motor involvement.
1.8.1 Basal Ganglia Circuitry and Mechanisms of Oculomotor
Disinhibition
The basal ganglia play a crucial role in the modulation of saccadic eye movements.
Unlike the cortical structures such as FEF, PEF and SEF, the basal ganglia do not provide
the drive for saccades. But, the basal ganglia select the most appropriate saccadic eye
movement through the strong tonic inhibitory effect on the SC. The caudate, SNr and SC
have been studied during saccades and the conclusion is that SNr inhibits the SC, and the
SNr in turn is inhibited by the caudate (Hikosaka et al., 1993;Hikosaka, 1989). SNr, one
of the major output stations of the BG, projects to the intermediate layer of the SC
(Graybiel, 1978;Karabelas and Moschovakis, 1985). SNr exerts a tonic inhibition over
the SC burst neurons. The caudate nucleus sends inhibitory projections to the SNr.
51
Based on the cortical inputs, the caudate suppresses the tonic nigro-collicular inhibition
through its GABAergic influence on the SNr. Thus the nigro-collicular inhibition is
tonically active and the caudo-nigral inhibition is phasically active. There are three
saccadic pathways through the basal ganglia. 1) Direct pathway: cortico-striato-nigral, 2)
Indirect pathway: cortico-striato-external pallido-subthalamo-nigral, and 3) Hyperdirect
pathway bypassing the striatum: cortico-subthalamo-nigral pathways (Fig. 5) (Hikosaka
et al., 2000).
1.8.2 Caudate Nucleus
The caudate (and a few parts in the putamen), the major input station of the BG, receives
saccade-related signals from the FEF, SEF, DLPC and the intramedullary laminar portion
of the thalamus (Hikosaka et al., 2000) and also dopaminergic projection from SNc
which convey reward-related signals (Fig. 5). The caudate lies along the lateral verntricle
and has three parts: head, body and tail. There are two groups of neurons in the caudate,
called projection neurons and interneurons. The majority of the neurons (especially the
projection neurons) in the striatum are GABAergic, although a small portion (< 2%) of
the interneurons in the caudate are cholinergic. Saccade-related neurons in the caudate
are thought to be projection neurons, which have a low firing rate and discharge prior to
saccades. These presaccadic neurons are clustered in the central longitudinal zone at the
junction of the head and body of the caudate nucleus, posterior to the anterior
commissure (Hikosaka et al., 1989a;Hikosaka et al., 1989b). Caudate neurons
discharging in relation to saccades show a strong dependency for expectation, reward,
attention and memory rather than direction or size of the saccade (Hikosaka et al.,
52
1989c). Some neurons in the caudate change discharge rate even before the appearance
of a visual target in the contralateral visual field (anticipatory activity associated with
reward) (Lauwereyns et al., 2002).
PET study in human shows extensive activation of the putamen and SNr during memory-
guided saccades (O'Sullivan et al., 1995). Dopamine depletion (by experimental MPTP
infusion) of the primate caudate nucleus on one side results in decreased amplitude and
velocity of spontaneous saccades (Kato et al., 1995), and hypometric, slow and delayed
memory-guided saccades (Kori et al., 1995) in the contralateral direction; as well as
contralateral visual hemi-neglect (Miyashita et al., 1995). Humans with bilateral caudate
infarction show impaired memory-guided saccades and preserved memory-guided finger-
pointing, implying the specific role of caudate in spatial short term memory network
devoted to eye movements (Vermersch et al., 1999).
53
Figure 5: Direct (cortex-caudate-SNr-SC), indirect (cortex-caudate-GPe-STN-SNr-SC)
and hyperdirect (cortex-STN-SNr-SC) saccadic pathways through the basal ganglia.
Open and closed circles are excitatory and inhibitory neurons respectively. The two
parallel pathways have opposing effects on the SC. Dopaminergic neurons from the SNc
modulate the output neurons of the caudate via D1 receptors on the neurons projecting to
SNr and via D2 receptors on neuronal streams to the GPe. Cerebral cortical areas (FEF,
PEF and LIP) project to the caudate and also directly to the STN, bypassing the striatum.
FEF = Frontal eye field, DLPF = Dorsolateral prefrontal cortex, LIP = Lateral
intraparietal area, STN = Subthalamic nucleus, SNr = Subtantia nigra pars reticulata, SC
= Superior colliculus, SNc = Substantia nigra pars compacta, GPe = Globus pallidus
externa. (Adapted from Hikosaka et al. Role of the Basal Ganglia in the control of
Purposive Saccadic Eye Movements. Physiological reviews 80: 953-978, 2000.)
54
Caudate neurons project to the SNr through the direct and indirect pathways (Fig. 5 and
6). Caudate and SNr have a mirror image like relationship during saccades. During
visuo-oculomotor tasks, caudate discharge increases while SNr spike activity decreases;
suggesting the pause in the tonic SNr activity is caused by phasic activity in the caudate.
Stimulation of the caudate nucleus with trains of current pulses results in generation of
saccades and head movement in the contralateral direction in cats (Kitama et al., 1991),
supporting the hypothetical connections between the caudate-SNr-SC. However,
experimental stimulation of caudate in monkeys has shown a significant increase in the
SNr activity which suppresses eye movements (Hikosaka et al., 1993). The indirect
pathway from caudate-GPe-STN-SNr probably mediates this nigral excitation observed
with caudate stimulation (Fig. 5).
1.8.3 Substantia Nigra Pars Reticulata
Saccade-related neurons lie in the laterodorsal aspect of the SNr closer to the cerebral
peduncles. These neurons project to the intermediate layer of the SC and are
spontaneously active, discharging at 50-100 Hz. They are characterized by their high
tonic discharge rates, which reduce prior to memory-guided as well as prior to visually-
guided saccades (Hikosaka and Wurtz, 1983a;Hikosaka and Wurtz, 1983b). The pause of
SNr activity recorded from monkeys is observed only during saccadic tasks, with no
change in the SNr activity during spontaneous saccades. Saccade-related neurons in
monkey SNr show a change in activity during target selection and saccade initiation
(Basso and Wurtz, 2002). Modulation of the SNr saccade neurons that disinhibit SC
neurons promote saccades oriented to reward (Sato and Hikosaka, 2002).
55
Figure 6: Sagittal section of macaque monkey brain showing the saccade-related areas
of the basal ganglia and the brainstem. The caudate nucleus projects to the superior
colliculus directly through the substantia nigra pars reticulata, and indirectly through the
globus pallidus externa and the subthalamic nucleus. Superior colliculus projects to the
contralateral brainstem saccade generator located in the pons. (Redrawn from Hikosaka
et al. Role of the Basal Ganglia in the control of Purposive Saccadic Eye Movements.
Physiological reviews 80: 953-978, 2000.)
Superior colliculus Caudate
Brain stem saccade generators
Substantia nigra pars reticulata
56
SNr receives inhibitory projections from the caudate through the direct pathway (caudate-
SNr-SC) and excitatory projections from the STN through the indirect pathway (caudate-
GPe-STN-SNr). Stimulation of the caudate nucleus can thus cause suppression or
inhibition of the SNr neurons (Hikosaka et al., 1993). SNr neurons that respond to
memory-guided saccades were inhibited during caudate stimulation. SNr exerts strong
tonic inhibition over the SC burst neurons, through GABAergic projections. Injecting
mucimol (a GABA agonist) into the SNr or bicuculline (a GABA antagonist) into the SC
causes similar general effects – repetitive, irrepressible saccades in the contralateral
direction (Hikosaka and Wurtz, 1985). The reason for this is the loss of the normal tonic
suppression of the SC neurons by the SNr neurons, which results in a state of sustained
disinhibition. These studies suggest that the tonic nigral inhibition of the SC is crucial in
preventing unwanted eye movements. Projection from the SNr to the SC has also been
demonstrated electrophysiologically by antidromic stimulation of primate SC (Hikosaka
and Wurtz, 1983c). Due to its small size and being surrounded by important brainstem
structures including cerebral peduncles, lesion experiments on the SNr are difficult.
Apart from the two (direct and indirect) pathways discussed above, nigral inhibition of
the SC is also influenced by two other mechanisms: 1) Direct cerebral cortical
connections to the STN (Kitai and Deniau, 1981) i.e. cortex-STN-SNr, and 2) Direct
connection from GPe (Smith and Bolam, 1991) i.e. caudate-GPe-SNr. GPe sends
inhibitory signals to the SNr, and thus this is also a double inhibitory pathway like the
indirect pathway (Fig. 5). The hyperdirect pathway from the cerebral cortical areas to the
57
STN bypasses the striatum and hence it is faster in conveying the cortical information to
the SNr.
1.8.4 The Disinhibition Theory
Based on the studies mentioned above, ‘disinhibition’ is the key mechanism by which the
BG modulate saccadic eye movements. The SNr discharges in a tonic fashion to
suppress the SC burst neurons constantly. Caudate neurons, which have an inhibitory
effect on the SNr, remain relatively silent and discharge prior to saccadic eye movements.
The phasic inhibitory activity of the caudate pauses the tonic high frequency discharge in
the SNr which yields a powerful facilitatory effect on the SC. Interruption of the tonic
SNr-SC inhibition, also called disinhibition, causes transient firing of the SC burst cells
and an eye movement in the contralateral direction (Fig. 7). BG disinhibiton is a crucial
mechanism in the control of saccades because of several excitatory inputs that project to
the SC. Without the SNr-SC constant inhibition, the SC will be in a chaotic state with the
various excitatory inputs, each suggesting a saccade in a different context. Thus the BG
play an important role in suppressing unnecessary eye movements and open the gate for
saccades by removing the tonic inhibition. BG control of skeletal movements operates in
a similar mechanism - the putamen removes the tonic inhibition of the GPi on the
ventromedial nucleus of the thalamus (Deniau and Chevalier, 1985).
58
Figure 7: The disinhibition theory. This is the key mechanism of basal ganglia control of
saccades. Substantia nigra pars reticulata exerts tonic inhibitory effect on the superior
colliculus, which normally suppresses unwanted saccades. Caudate projects GABAergic
neurons to the substantia nigra pars reticulata. Prior to a saccade, there is phasic activity
in the caudate nucleus, which interrupts the tonic inhibition of the superiror colliculus by
the substantia nigra pars reticulata. The allows the superior colliculus to dispatch a
saccade. (Redrawn from Hikosaka et al. Role of the Basal Ganglia in the control of
Purposive Saccadic Eye Movements. Physiological reviews 80: 953-978, 2000.)
59
1.8.5 Subthalamic Nucleus
STN is a small lens-shaped structure overlying the SNr. It is another important basal
ganglion that participates in saccadic eye movements. STN is unique because, unlike
other BG nuclei, it uses glutamate – an excitatory neurotransmitter. STN receives input
from the GPe (Shink et al., 1996) and frontal cortical areas (Kitai and Deniau, 1981), and
projects to the SNr and GPi (Kanazawa et al., 1976;Kita and Kitai, 1987). Cortical areas
projecting to the STN includes the FEF (Huerta et al., 1986), SEF (Huerta and Kaas,
1990) and prefrontal association cortex (Monakow et al., 1978) (Fig. 5). Visual
responses in the STN are phasic, and have shorter latencies (70-120 ms) when compared
with those in the caudate nucleus (100-250 ms) because of the direct cortical inputs to the
STN. Neurons responding to saccades are located in the ventral part of the STN based on
stereotactic microelectrode recordings from human subjects undergoing DBS surgery
(Fawcett et al., 2005a).
Caudate projects to the STN via the GPe (Fig. 5) (Nambu et al., 2002). This is a double
inhibitory pathway – caudate inhibits the GPe, which has an inhibitory effect over the
subthalamic nucleus. STN sends excitatory signals to the SNr. The overall effect of
caudate stimulation is excitation of the STN due to the double inhibitory indirect pathway
and is the opposite of the caudate-SNr-SC (direct) pathway. Local field potentials
recorded from STN DBS contacts during self-paced and visually cued saccades show
‘pre-movement readiness potentials’ prior to saccade onset, similar to Bereitschafts
potentials and contingent negative variations seen before limb movements. This study
60
signifies STN’s ocular motor role in preparation of saccadic eye movements (Fawcett et
al., 2007).
1.8.6 Globus Pallidus Internal Segment
As mentioned earlier, GPi and SNr are the two major output stations in the basal ganglia
sending neuronal signals to the thalamus and the brainstem including the SC. Even
though GPi and SNr are considered structurally and functionally homologous, the GPi is
generally thought to control somatic rather than ocular movements. SNr on the other
hand, is known for its role in the control of the saccadic system.
Straube et al. studied PD patients who underwent GPi DBS and observed that electrical
stimulation of the posteroventral part of GPi not only improved motor symptoms of PD
such as bradykinesia and rigidity, but also influenced saccades by shortening the latency
of antisaccades and increasing the gain of memory-guided saccades (Straube et al., 1998).
The skeletal motor control of GPi is primarily thought to be because of the Basal
Ganglia-thalamocortical circuits. The motor cortex and the supplementary motor areas
are connected to the putamen, which in turn projects to the ventrolateral pallidum and
caudolateral SNr, which again project back to the cortex via the thalamus (Alexander et
al., 1986;Alexander et al., 1990). The ocular motor control of the GPi on the other hand
is believed to be because of the projections through the caudate (and not the putamen).
This ocular motor pathway through the GPi is anatomically distinct from the skeletal
motor pathway, where the FEF and DLPF project to the head-body junction of the
caudate and from there to the caudal dorsomedial GPi and the ventrolateral SNr (Kato et
61
al., 1995;Kori et al., 1995). This pathway explains why depletion of dopamine in the
head-body junction of the caudate result in ocular motor deficits, but spare the skeletal
motor system (Kato et al., 1995;Kori et al., 1995).
Pallidotomy in patients with PD disrupts ocular fixation by increasing the number and
amplitude of square wave jerks (O'Sullivan et al., 2003), and decreases peak velocity of
internally-generated saccades (Blekher et al., 2000). Fawcett at al. assessed prosaccades,
antisaccades and memory-guided saccades in Huntington’s disease patients with pallidal
DBS (Fawcett et al., 2005b). Pallidal stimulation influenced prosaccades and memory-
guided saccades. Following GPi DBS, an improvement was observed during prosaccade
tasks with a decrease in saccadic latencies and an increase in the saccadic gain. But
pallidal stimulation negatively affected memory-guided saccades with prolonged saccadic
latencies, decrease in saccadic gain and worsening of the patient’s ability to suppress
unwanted saccades. That study strongly supported the ocular motor role of GPi and
demonstrated a task-specific improvement of ocular motor deficits in Huntington’s
disease patients with stimulation of the GPi (Fawcett et al., 2005b).
Functional imaging has shown significant activation of the lentiform nuclei (putamen and
globus pallidus) during antisaccade tasks (Matsuda et al., 2004;Tu et al., 2006). Yoshida
and Tanaka studied neurons in the primate globus pallidus that responded to saccadic eye
movement (Yoshida and Tanaka, 2009). In that study, the activity modulation of globus
pallidus neurons was found to be more enhanced during the preparation and execution of
antisaccades, when compared to prosaccades. A recent primate study compared ocular
62
motor activities of the GPe and GPi, and concluded that GPe neurons showed visual-
related activity, whereas GPi neurons respond more to reward-related activity (Shin and
Sommer, 2010). This observation is consistent with the findings of Hong and Hikosaka,
which showed GPi to be the source of reward-related signals to lateral habenula during
reward-predicting ocular motor tasks (Hong and Hikosaka, 2008).
1.8.7 Globus Pallidus External Segment
When compared to the other structures in the BG, ocular motor functions of the external
segment of the globus pallidus is less clearly understood (Hikosaka et al., 2000). GPe
receives input from the striatum (Gimenez-Amaya and Graybiel, 1990) and projects
GABAergic signals to SNr (Parent and De Bellefeuille, 1983), GPi (Kincaid et al., 1991)
and STN (Carpenter et al., 1968). It is an integral part of the indirect pathway – caudate-
GPe-STN-SNr-SC. Visuo-oculomotor neurons are segregated in the dorsal aspect of GPe
and the inputs to this region are predominantly from the caudate nucleus in monkeys
(Hazrati and Parent, 1992). Some of these neurons are selective during saccades to
remembered locations, whereas others are active during visually guided saccades. A few
neurons in the GPe demonstrate a sustained increase or decrease in activity when
monkeys were fixating. In general, neurons in the GPe are active during a few visual-
saccadic behaviors, but this activity is non-selective.
63
1.9 Saccadic Dysfunctions of Basal Ganglia Disorders
Involuntary limb movements characterize diseases affecting the BG. Eye movement
abnormalities can be obscured in BG disorders because of the more apparent robust,
involuntary limb movements. Involuntary eye movements observed following drug-
induced reversible inactivation of the SNr might also be based on the same mechanism as
limb movement abnormalities (Hikosaka and Wurtz, 1985). Saccadic functions of
MPTP-induced Parkinson’s disease in human subjects studied during OFF state period
(off Levodopa during drug holidays) revealed preferential involvement of memory-
guided saccades, which were hypometric with prolonged latencies (Hotson et al., 1986).
Similar findings were reported in experimental PD monkeys following intravenous
infusion of MPTP (Brooks et al., 1986). Kato et al. caused dopamine depletion in
primate caudate nucleus unilaterally by locally infusing MPTP using an osmotic mini
pump and the following three types of saccadic dysfunctions were observed: 1)
Spontaneous saccades: Paucity and restriction of spontaneous saccades with decreased
amplitudes and velocities, and the areas scanned by saccades in the contralateral field
became narrower and shifted to the hemifield on the side of dopamine depletion (Kato et
al., 1995), 2) Memory-guided saccades: Memory-guided saccades were preferentially
involved in the contralateral side with consistently prolonged latencies and were
occasionally misdirected towards the side of MPTP infusion (Kori et al., 1995), 3) Visual
hemineglect: Monkeys showed saccadic and attention hemineglect contralateral to the
side of MPTP infusion (Miyashita et al., 1995).
64
Humans with PD have several ocular motor disturbances. Steady fixation can be
disrupted by square-wave jerks (White et al., 1983b). Patients with Parkinsonian
syndromes also have impaired smooth pursuit eye movements (White et al., 1983b) and
convergence insufficiency (Rottach et al., 1996). Saccades are hypometric (White et al.,
1983b). Memory-guided saccades and anticipatory saccades also are hypometric (Lueck
et al., 1992). In contrast to this, reflexive saccades are of normal amplitudes in PD, until
the disease is more advanced when both voluntary and visually guided unpredictable
saccades become delayed and hypometric (White et al., 1983b). PD patients have
difficulties in the generation of memory-guided saccades and have ‘fragmented multistep
responses’ during these tasks. Error rates are also higher in PD patients during saccadic
tasks to remembered target locations. Interestingly, prolonging the memory period from
3 to 30 seconds resulted in an improvement in the saccadic performance in PD patients
(Le Heron et al., 2005). This finding suggests that the DLPF, responsible for
intermediate spatial memory, is impaired in PD; and there is relative preservation of the
medial temporal lobe and parahippocampal cortex, which mediate longer-term spatial
memory. PD patients have significant trouble with internally generated saccades.
Saccadic latencies during non-predictable saccadic tasks can be normal or mildly
increased in PD compared to age matched controls (White et al., 1983a). Saccadic
velocities are typically normal in PD, but can be mildly slowed in advanced cases (White
et al., 1983b). During gap paradigms, PD patients are able to perform express saccades
with short-latencies (Vidailhet et al., 1994). Ability to perform antisacacdes tasks are
normal in early stages of PD. However, in advanced stages, PD patients show more
65
directional errors due to trouble inhibiting reflexive saccades towards a novel stimuli
(Briand et al., 1999).
Levodopa treatment does not improve oculomotor deficits of PD significantly. However,
patients on levodopa have shown some improvement in saccadic accuracy, and
occasional improvement of convergence insufficiency (Racette et al., 1999;Gibson et al.,
1987). High-frequency stimulation of bilateral STN improves the accuracy of memory-
guided saccades, but no noticeable changes during antisaccade or visually-guided
saccadic tasks (Rivaud-Pechoux et al., 2000). Conversely, DBS of the GPi has shown
improvements in memory-guided as well as antisaccade tasks (Straube et al., 1998).
Pallidotomy causes square-wave jerks and disrupts ocular fixation (Averbuch-Heller et
al., 1999;O'Sullivan et al., 2003).
Patients with Huntington’s disease (HD) show several saccadic dysfunctions including
impairment in the initiation of saccades, prolonged saccadic reaction times, decreased
velocity of saccades and quick phases of nystagmus, inability to suppress reflexive
saccades and difficulties in performing saccades without an accompanying head
movement (Leigh et al., 1983). Other disorders of the BG considered in the differential
diagnosis of HD are dentatorubro-pallidoluysian atrophy, which causes slow saccades;
and neuroacanthocytosis, which causes square-wave jerks, multistep hypometric saccades
and occasional slow saccades (Nielsen et al., 1996;Gradstein et al., 2005). Humans with
bilateral lentiform nucleus (globus pallidus and putamen) lesions have impaired memory-
guided saccades with preservation of visually-guided saccades and antisaccades
66
(Vermersch et al., 1996). Patients with Tourette’s syndrome have normal visually-guided
saccades, but impaired antisaccades and memory-guided saccades (Straube et al., 1997).
1.10 Thalamus and its Role in the Control of Saccades
The thalamus is the largest division of the diencephalon and plays an important role in
the integration of motor and sensory system. The right and left thalami are seperated by
the third ventricle. Each thalamus has several nuclear groups and can be anatomically
categorized into: anterior nucleus, mediodorsal nucleus, intralaminar nuclei, dorsal tier
nuclei, ventral tier nuclei and metathalamus (Fig. 8). The internal medullary lamina
(IML) subdivides each thalamic hemisphere into three unequal nuclear groups called
medial, lateral and ventral nuclei (Fig. 8). IML encloses the intralaminar nuclei, which
includes the centromedian and the parafascicular nuclei. The pulvinar is the largest
thalamic nucleus and lies in the dorsal tier group. The metathalamus consists of the
lateral and medial geniculate bodies which are visual and auditory relay nuclei
respectively. A thin layer of cells that form the lateral wall of the thalamus is called the
reticular nucleus (Fig. 8). The thalamus receives cortical inputs from various motor as
well as sensory areas and projects primarily to the cerebral cortex and to a lesser extent to
the BG. The medial dorsal and ventral anterior thalamic nuclei are connected with the
frontal cortex and BG via the cortico-basal ganglia-thalamic loop (Alexander et al.,
1986). The ventral intermediate (Vim) nucleus and ventraloralis nuclei within the
ventrolateral thalamic nucleus receive input from the GPi and cerebellum and project to
frontal cortical areas.
67
Figure 8: Left: Schematic representation of oblique dorsolateral view of the thalami and
its major nuclear groups after removal of the reticular nuclei and the external medullary
lamina. The 3rd
ventricle divides the thalami into right and left halves. Right: Schematic
section of the right thalamus through the broken line shown in figure in the left. MGB
and LGB = Medial and lateral geniculate bodies, VA = Ventral anterior nucleus, VL =
Ventral lateral nucleus, VI = Ventral intermedial nucleus, VP = Ventral posterior nucleus,
VPL = Ventral posterolateral nucleus, VPM = Ventral posteromedial nucleus, LP =
Lateral posterior nucleus, LD = Lateral dorsal nucleus, CM = Centro median nucleus, M
= Medial nucleus, MD = Medial dorsal nucleus (Adapted from Netter FH. Atlas of
Human Anatomy, 3rd edition. New Jersey, USA: Icon learning systems, 2003.)
Lateral group
Medial group
Anterior group
Intrathalamic adhesion
3rd ventricle
3rd ventricle
Pulvinar
LGB
MGB
Pulvinar
Intralaminar nuclei
Reticular nuclei
Internal medullary lamina
Median nuclei
External medullary lamina
68
PET study in human shows activation of the thalamus during self-paced voluntary
saccades (Petit et al., 1993). Several thalamic nuclei participate in the programming of
saccades, especially the central (centromedian) nuclei of the IML, pulvinar, mediodorsal
nuclei and the ventrolateral nuclei. Neurons scattered throughout the IML demonstrate
saccade-related activity. The neurons in the IML receive inputs from many cortical and
brainstem areas including the SC and project to the cortex and the BG. These neuronal
networks through the IML nuclei may be relaying an efference copy of the ocular motor
commands (corollary discharge) from the brainstem to higher cortical centres (Wyder et
al., 2003;Schlag-Rey and Schlag, 1989).
Humans with small central thalamic lesions are reported to have normal memory-guided
saccades, but marked impairment of saccadic accuracy in paradigms that involved
displacement of the eyes from the target prior to memory-guided saccades (Gaymard et
al., 1994). This infers the impairment in the relay of the efference copy to the cortical
saccadic centres because of the central thalamic lesion. IML neurons discharge during
visually-guided and spontaneous saccades. Electrical stimulation of the neurons in the
IML provoke saccades contralateral to the side of stimulation. Some neurons in the IML
show an increase in activity in postsaccadic period or during periods of fixation. Lesions
affecting the IML may contribute to thalamic neglect syndrome (Schlag-Rey and Schlag,
1984).
The mediodorsal nuclei is another important thalamic centre that relays information about
the brainstem ocular motor signals to the frontal cortex (Sommer and Wurtz, 2004a).
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When primate mediodosal nucleus is temporarily inactivated by injecting muscimol,
monkeys had inaccuracies with the second saccade during double-step task (Sommer and
Wurtz, 2004b). That study further suggests that the thalamic nuclei including the
mediodorsal nucleus relay information regarding efference copy of the ocular motor
commands from the SC to the frontal cortex.
Neurons in the pulvinar, especially the inferior-lateral and dorsomedial pulvinar are
related to saccades. The dorsomedial pulvinar seems to participate in shifting of attention
towards salient features in the environment (Robinson, 1993). Injecting a GABA agonist
into the primate dorsomedial nucleus suppresses the attention shift towards the
contralateral visual field and injection of a GABA antagonist caused a reverse effect i.e.
facilitation of attention shift in the visual field contralateral to the side of the injection
(Robinson and Petersen, 1992). This finding is supported by a human PET study which
shows increased activity in the pulvinar during attention tasks and its role in directing
visual attention (LaBerge and Buchsbaum, 1990).
Inactivation of the paralaminar part of the ventrolateral thalamus in monkeys resulted in
delayed initiation of contraversive memory-guided saccades (Tanaka, 2006).
Microelectrode recordings from primate ventrolateral and ventroanterior nucleus showed
a strong build-up of activity preceding self-initiated saccades (Tanaka, 2007). Neurons in
the ventral posterior lateral nucleus in monkeys, corresponding to Vim in human, show
saccade-related activity (Tanibuchi and Goldman-Rakic, 2005;Macchi and Jones, 1997).
Patients with hemorrhagic and / or ischemic thalamic lesions show hypometric saccades
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contralateral to the side of the lesion (Brigell et al., 1984;Rousseaux et al., 1985). Single
unit potential recordings from patients who underwent DBS surgery for essential tremor
showed neurons responding to saccades in the Vim region (unpublished data).
Postoperative high frequency DBS of this area resuled in hypometric saccades towards
the contralateral direction (Kronenbuerger et al. unpublished data).
Kunimatsu and Tanaka studied the neuronal activities of primate ventral anterior (VA),
ventral lateral (VL) and medial dorsal (MD) nuclei during pro and antisaccades. VA and
VL showed greater firing rates during antisaccades than prosaccades. Inactivation of VA
and VL resulted in increased error rates during antisaccades, suggesting the role of
primate motor thalamus in the generation of antisaccades (Kunimatsu and Tanaka, 2010).
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1.11 Local Field Potential Oscillations
Electrical potentials from cortical and subcortical structures can be recorded as local field
potentials (LFP) using extracellular macro-electrodes. Oscillatory LFPs are thought to be
generated by synchronized rhythmic synaptic or neuronal activities from a large
population of neurons. Despite the origin from local neuronal elements, these potentials
are said to reflect the overall oscillations of the basal ganglia-cortical loop (Brown and
Williams, 2005;Hammond et al., 2007). DBS surgery provides the opportunity to record
and understand the electrophysiology of the basal ganglia. Single unit potentials can be
recorded intra-operatively through micorelectrodes and LFPs in the inter-operative
interval from the DBS macroelectrodes. LFPs are influenced by changes in the firing rate
of neurones and the pattern of synchronisation of discharges between neurones. There are
two principal modes of synchronised LFP oscillations in the human subthalamo-pallidal-
thalamo-cortical circuit: at < 30 Hz and > 60 Hz (Brown, 2003). Based on the frequency
and the location, these oscillations can be further categorized as theta (2-7 Hz), alpha (7-
13 Hz), beta (14-30 Hz) and gamma (> 31 Hz) (Hutchison et al., 2004). Oscillatory
changes in the local field potentials are believed to reflect synchronized oscillatory
synaptic or neuronal activity generated by large populations of local neural elements
(Galvan and Wichmann, 2008).
Recent animal and human studies have proven the existence of several types of LFP
oscillations, although their exact functions are not clearly determined. These oscillatory
changes are believed to be the reason for symptoms in PD patients. PD patients who
underwent DBS in the STN and GPi showed prominent oscillations in the 10-30 Hz
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range. These oscillations in the beta range of frequency are considered to be pathological
and are more pronounced when patients are withdrawn from levodopa (OFF state)
(Brown et al., 2001). This pathological oscillatory activity in the beta frequency is
abnormally high in patients with PD and is probably the cause of bradikinesia
(Dostrovsky and Bergman, 2004). Oscillations in the beta range are suppressed during
voluntary limb movement and with exogenous dopaminergic therapy (Fig. 9) (Brown et
al., 2001;Levy et al., 2002). Several cortical areas associated with BG also show
abnormal beta oscillations in patients with PD (Williams et al., 2002). High-frequency
DBS of human STN suppresses the beta oscillations in PD and as hypothesized, DBS
probably works by desynchronizing the pathological oscillations, and thus reversing
parkinsonism. Conversely, low frequency stimulation (~ 20 Hz) of the STN resulted in
exacerbation of synchronization at a similar frequency in the GPi (Brown et al., 2004).
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Figure 9: Brown’s model (redrawn with permission from Brown 2003) of changes in
basal ganglia oscillatory power during motor tasks. Local field potential oscillations in
the basal ganglia can influence motor output. Pathological increase in the power of beta
activity may be responsible for akinesia and bradykinesia in Parkinson’s disease, which is
more prominent in OFF state (Off levodopa). High frequency (> 60Hz) oscillations
within basal ganglia circuits facilitate voluntary movements (pro-kinetic), while increased
power in the beta frequency range prevent or slow movement generation (anti-kinetic).
There is an increase in the gamma-synchronization when Parkinson’s disease patients
were treated with levodopa (ON state).
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During voluntary self-paced and externally-paced limb movements, desynchronization in
the beta frequency band was observed in STN and GPi regions of PD patients in the pre-
movement and movement periods (Kuhn et al., 2004;Cassidy et al., 2002). The degree of
suppression in this pathological beta synchronization clinically correlates with the
improvement in the parkinsonian motor symptoms on the contralateral hemibody (Kuhn
et al., 2006).
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2 OBJECTIVES AND HYPOTHESES
Summarizing all the pertinent studies mentioned above, it is evident that the basal ganglia
are crucial structures in the modulation of saccades. The tonic inhibition of the SNr on
the SC and the phasic activation of the caudate before saccades that inhibit the SNr is a
unique mechanism called ‘disinhibition’. The BG, thus serve as a latch to release
saccades that are essential and inhibit unwanted eye movements. Similarly, disinhibition
is also the key mechanism in skeletomotor control, where the putamen (instead of caudate
for oculomotor control) transiently removes the tonic inhibition of GPi on the thalamus.
Diseases affecting the BG cause several saccadic dysfunctions as described above.
Importantly, memory-guided saccades and antisaccades are affected in disorders of the
BG, implying the specific role of the BG during these tasks. Patients with PD show
significant deficits in internally generated movements compared to externally-cued motor
tasks. Similarly, PD patients have a paucity of spontaneous saccades with decreased
amplitudes, which improves when the saccades are visually cued.
LFP oscillations in cortical and subcortical structures have been studied in many
functional domains. Sychronized oscillations of the BG have been of special interest,
especially in understanding the pathogenesis of PD. Gamma (> 31 Hz) synchronizations
of the LFPs are thought to enhance motor movements and are more pronounced in PD
patients in ON state. LFPs recorded from STN and GPi show transient event-related
gamma synchronization (ERS) before and during limb movements on the contralateral
side (Androulidakis et al., 2007;Brucke et al., 2008). There is also event related
desychronization (ERD) in the beta frequency during voluntary limb movements, but this
76
is seen bilaterally. This phasic ERS in the gamma frequencies and ERD in the beta range
support the oscillatory model of PD by Brown et al. and generally oscillations above 30
Hz are considered ‘prokinetic’ and oscillations below above 30 Hz are considered
‘antikinetic’ (Brown, 2003).
Given the fact that the ocular motor and skeletal motor systems are controlled by similar
mechanism in the BG, it is expected that BG and thalamic LFP oscillations observed
during limb movements have similar influence on saccadic eye movements. There are
several primate studies showing the activity of various subcortical structures including
STN, GPi and different thalamic subnuclei during saccades. Single-unit potentials
recorded from human STN (Fawcett et al., 2005a), GPi and Vim (unpublished data)
during DBS implantation have identified neurons in these regions that responded to
saccadic eye movements. Based on these studies, we hypothesize that the LFP activity in
the STN, GPi and Vim should show event-related gamma synchronization with saccade
onset that are similar to those predicted by Brown’s model for limb movements.
Antisaccade task requires voluntary suppression of the visual stimulus and generation of
an eye movement in the opposite mirror location. Hence, during an antisaccade task the
location of the novel stimulus and saccadic goal (direction) are decoupled. Through the
serial tonic inhibitory connections between the DLPF and SC, the BG suppress unwanted
saccades. If BG activity should increase more during antisaccade tasks compared to
prosaccades, then it may be expected that the gamma oscillations are greater during
antisaccades than prosaccades. Introducing a brief temporal gap decreases saccade
77
reaction time (express saccades). If the gap effect modifies saccadic latency, then gamma
activity should also be altered in STN, GPi and Vim during gap paradigms compared to
overlap paradigms.
2.1 Hypotheses
1. Local Field Potentials in STN, GPi and Vim show gamma oscillations related to
saccadic activity
2. The basal ganglia nuclei are more activated by antisaccades away from a target
than prosaccades toward a target
3. If the gap effect modifies saccadic timing, then gamma activity should also be
altered in STN, GPi and Vim
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3 METHODS
3.1 Preface
Inter-operative DBS macroelectrode LFP recordings (data collection) were done in Dr.
Robert Chen’s lab at Toronto Western Hospital with the assistance of Dr. W. Hutchison,
E. Tsang and U. Saha. Dr. W. Hutchison, L Srejic and K. Udupa provided assistance
with statistical analysis of the data. The majority of work regarding data analysis, writing
and presentation was done by A. Sundaram.
3.2 Introduction
Stereotactic, microelectrode-guided DBS implantation for PD is becoming a more
acceptable option for surgical management of PD because of its remarkable clinical
benefits for various disorders of kinesiology including PD, dystonia and essential tremor.
DBS electrodes can be implanted in one of two BG structures for PD – GPi and STN.
DBS of the STN region has become the predominant choice for surgical treatment of PD
in most centers. Intra-operative microelectrode single unit recordings are used to help
identify the STN based on its electrophysiology and localize the target for DBS electrode
implantation (Hutchison et al., 1998).
DBS is a reversible neurosurgical procedure that has been beneficial for other movement
disorders that are refractory to medical therapy, including essential tremor and dystonia.
DBS surgery is a two day procedure. In the inter-operative interval between the insertion
79
of DBS electrodes and before the internalization of the leads to the subdermal pulse
generator, it is possible to record the deep brain potentials from DBS electrode contacts.
3.3 Patients
We studied 11 patients; 6 patients had bilateral STN DBS, 3 GPi DBS (one unilateral and
two bilateral) and two unilateral Vim DBS. STN DBS was performed to treat PD
patients who had cardinal symptoms including bradykinesia, tremor and rigidity. PD
patients were able to understand and perform saccadic tasks despite the motor symptoms
from the underlying neurological problem. All PD patients were on dopamine
medication during LFP recording and were in the clinically defined ‘on’ state without
dyskinesia (except STN # 6, who was tested in the ‘off’ state). GPi DBS surgeries were
performed for patients with dystonia. Vim DBS patients had the procedure for essential
tremor. Patient characteristics are shown in Table 1. The group, consisting of eight men
and three women, had a mean age 61.63 ± 8.07 of years. The experiments were approved
by the University Health Network and University of Toronto Research Ethics Boards.
Patients provided written informed consent prior to the procedure.
80
Patient Age Sex Diagnosis DBS side and site
STN # 1
STN # 2
STN # 3
STN # 4
STN # 5
STN # 6
GPi # 1
GPi # 2
GPi # 3
Vim # 1
Vim # 2
55
65
55
64
56
60
51
55
72
75
70
M
F
M
M
M
M
F
F
M
M
M
PD
PD
PD
PD
PD
PD
Dystonia
Dystonia
Dystonia
ET
ET
Bilateral STN
Bilateral STN
Bilateral STN
Bilateral STN
Bilateral STN
Bilateral STN
Bilateral GPi
Bilateral GPi
Left GPi
Right Vim
Right Vim
Table 1: Characteristics for 11 DBS patients studied. Eight men and three women
(mean age 61.63 ± 8.07, range 51 to 75 years) were studied. STN = subthalamic nucleus,
GPi = globus pallidus interna, Vim = ventrointermediate thalamic nucleus, PD =
Parkinson’s disease, ET = essential tremor.
81
3.4 Surgery
The surgical procedure for stereotactic, microelectrode-guided target localization and
placement of DBS electrodes (Medtronic Model 3387, Minneapolis, MN) has been
described in detail (Hutchison et al., 1998). Briefly, a stereotactic frame is affixed to the
patient’s head after local anesthetic is applied. Pre-operative MR images are obtained
and axial images are used to determine the x, y and z coordinates of the anterior and
posterior commissures with respect to the stereotactic frame. The pre-operative target
(STN, GPi or Vim) was chosen.
Patients lie in a supine position on the operating room table. Burr holes are then drilled at
the coronal suture and the underlying dura mater is opened to allow the microelectrodes
access to the brain. Surgical fibrin glue (Tisseel, Baxter) is used to cover the dural
opening and prevent cerebrospinal fluid loss during the surgery. A Leksell arc is attached
to the head frame and set to the coordinates of the target. A cannula is inserted into the
brain to a depth of 10 mm above target and the inner stylet is removed. Two
microelectrodes, enclosed in individual steel guide tubes and spaced 600 to 800 μm apart,
are then inserted into the cannula and driven by sub-millimeter increments into the brain
by independent manual hydraulic microdrives. Single and multi unit neuronal discharges
were band pass filtered (300-5000 Hz), amplified (10, 000x), fed into an audio monitor
and displayed on an oscilloscope. DBS target region is identified based on frequency and
amplitude of the neuronal activity.
82
DBS surgery is a two-day procedure. On the first day of the operation, DBS electrodes
are implanted under microelectrode guidance as mentioned above. 3 - 5 days later, the
DBS leads are internalized and connected to a subclavicular pulse generator. During the
interval between the two surgeries, we are able to record LFPs of deep subcortical
structures from the unhooked DBS contacts. The advantages of inter-operative DBS
macroelectrode LFP recordings compared to intra-operative microelectrode recordings
include less time constraint and the ability to record from cooperative patients who may
be on or off medications. All patients have a post-operative MRI to confirm the location
of the DBS contacts.
83
3.5 Tasks
In the inter-operative interval between the insertion of DBS electrodes and before the
internalization of the leads to the subdermal pulse generator, patients performed saccadic
tasks. During the saccadic tasks subjects were seated 0.9 m in front of a flat black panel
with three light emitting diodes (LEDs) at right, left and middle positions. The panel was
set-up so that the middle LED was aligned to the patient’s binocular centre of vision at
the level of the subject’s eyes and so that right and left targets were 20° from middle
position (Figure 10).
3.5.1 Four blocks of visually-cued saccades
Patients performed four blocks of visually-guided saccades; two blocks of Prosaccades
and Antisaccades in Gap and NoGap (overlap) paradigms. In the Prosaccade blocks,
patients were instructed to focus on the fixation light and then make a saccade to the
target light following its illumination. Antisaccade task is execution of an eye movement
away from the target, and voluntary suppression of saccades to the cue light (Figure 10).
Each block consisted of 50 randomly cued trials of left and right saccades (~ 25 left, 25
right).
84
Fixation lightCue light
Cue light
Fixation light
Prosaccade Antisaccade
20
Amplitude
Distance
90 cm
Figure 10: Saccadic tasks. Patients were seated 90 cm from a panel containing three
LEDs which consist of a central fixation light and two horizontal target lights calibrated
at 20° eccentricity. Before each block patients were instructed to look at (prosaccade
blocks) or in the opposite mirror-image location (antisaccade blocks) during the target
light illumination.
85
3.5.2 Gap and Overlap Paradigms with Short and Long
Sequences
In the ‘overlap’ (nogap) paradigm, each trial consisted of fixation light illumination for
900 ms followed by target light illumination for 1000 ms. The fixation light remained
illuminated for the entire duration of the trial even after the appearance of the target light
(1900 ms). In the ‘gap’ paradigm the fixation light was illuminated for only 900 ms. A
brief temporal gap of 200 ms was introduced after the disappearance of the fixation light,
which was followed by illumination of the target light for 1000 ms. Inter-trial intervals
for gap and overlap paradigms were 2000 ms and 3000 ms respectively (Figure 11).
Each block lasted for about 4 minutes. 6 patients (STN patients # 1, 2, 3 and GPi patients
# 1, 2 & 3) were tested with the above paradigms of short fixation period (900 ms) and
inter-trial intervals (2000 – 3000 ms). Due to the short fixation period, STN patients # 1,
2 and GPi patients # 1 & 2 performed poorly, especially during antisaccade tasks. With
closer supervision and verbal guidance through each block, performance of STN patient #
3 and GPi patient # 3 improved somewhat, but still was not satisfactory. This poor
performance of the patients studied initially, particularly during the antisaccade blocks,
was probably because of short fixation periods. Trials preceded by shorter fixation
intervals during antisaccade tasks in normal subjects increased the error rates and
prolonged saccadic latencies (Smyrnis et al., 2002).
To improve the saccadic performance, fixation period and inter-trial intervals were
increased for both gap and overlap paradigms, which we termed ‘Gap and Overlap
86
paradigms with long sequences’ (Figure 11). In the modified paradigms, fixation period
was increased to 1300 ms, followed by a gap of 200 ms and target light illumination for
1000 ms (gap paradigm). In the overlap paradigms, fixation light is illuminated for 1500
ms, and then the target light is turned on (simultaneously) for 1000 ms (Figure 11). Inter-
trial interval was increased to 6000 ms for both gap and overlap paradigms. Patients
investigated after the modification of the saccadic parameters showed better performance.
With the longer sequences, each block lasted for about 7 minutes. A rest period of 5
minutes was given in between blocks.
Before each block, patients were instructed about the saccadic tasks (prosaccade or
antisaccade). During the saccadic tasks, patients were instructed to avoid unnecessary
eye movements and fixate on the centre LED in the inter-trial interval in order to have a
baseline without eye movements. Patients who were drowsy (post-operative patients
treated with analgesics and sedatives the previous night) were verbally instructed to
follow the tasks.
87
Gap paradigm
short sequences
Gap paradigm
long sequences
Overlap paradigm
short sequences
Overlap paradigm
long sequences
Fixation light
Target light
Eye movement
Eye movement
Eye movement
Fixation light
Eye movement
Target light
Fixation light
Target light
Target light
Fixation light
2000 ms
6000 ms
Inter-trial interval
Inter-trial interval
200 ms
(Gap)
(Gap)
200 ms
900 ms
1300 ms
1000 ms
1900 ms
1000 ms
1000 ms
1000 ms
2500 ms
3000 ms
Inter-trial interval
Inter-trial interval
6000 ms
Figure 11: Illustration of gap and overlap paradigms (one trial). STN patients # 1, 2, 3
and GPi patients # 1, 2, & 3 performed saccadic tasks with short sequences (top two
sequences). To improve the saccadic performance, fixation period and inter-trial
intervals were increased for both gap and overlap paradigms in patients (STN patients #
4, 5, 6 and Vim patients # 1 and 2) investigated later in the study (bottom two sequences).
During the inter-trial interval, patients were advised to avoid unnecessary eye or limb
movements and remain fixated at the central fixation light. Each block consist of 50 such
trials (25 random saccades in right or left directions).
88
3.5.3 Vestibulo-ocular Reflex
One STN patient (STN # 6) performed the visually enhanced vestibulo-ocular reflex.
The subject was seated at 90 cms in front of the black panel, similar to the visually-
guided saccadic tasks, fixating at the central LED in the panel. He was instructed to turn
his face to rightward or leftward direction, activating the reflex in the yaw axis, following
verbal cue by the examiner, while maintaining the fixation at the central LED. 15
random verbal cues for rightward or leftward face-turns were instructed. Eye movements
were monitored by the examiner. During rightward or leftward face turns, there was an
eye movement in the opposite direction in order to manintain ocular fixation. The subject
was instructed to avoid unnecessary eye movements during the task. DBS LFPs, scalp
EEGs and electrooculogram were recorded similar to the visually-guided saccadic tasks.
STN # 6 was the last subject studied in our project, and hence the VOR task was recorded
in one patient only.
89
3.6 Local Field Potential Recording
When the patients performed saccadic tasks, LFP from DBS electrodes (STN, GPi or
Vim), electrooculogram (EOG) and scalp EEG (Fp1, Fz, Cz, C3 and C4) were
simultaneously recorded using SynAmp amplifiers (NeuroScan Laboratories, El Paso,
TX). Sampling rate for all the potentials were 2.5 kHz. DBS contacts (Medtronic model
3387, Minneapolis, MN) are quadripolar with platinum/iridium electrodes numbered 0
(most ventral) to 3 (most dorsal). Electrodes are 1.27 mm in diameter, 1.5 mm in length
and are separated from the next closest electrode by 1.5 mm. An illustration of STN DBS
trajectory and location of SNr is Figure 12.
Monopolar recordings from DBS contacts are amplified by a SynAmps amplifier,
sampled at 10,000 Hz, recorded and then band passed from 0.5 to 500 Hz by Neuroscan
4.3 software (Compumedics, El Paso, TX, USA). DBS LFP signals were referenced to
linked ear lobe electrodes. Scalp EEG silver-silver chloride electrodes were arranged
according to the International 10-20 System. The impedance was < 5 kΩ for all
electrodes. EOG electrodes were placed at the outer canthi to detect binocular horizontal
movements. EOG signals were amplified, digitized at 500 Hz and recorded by the same
method as above. Offline data analysis was done using Spike 2 and Matlab software.
90
Figure 12: Trajectory of STN quadripolar DBS contacts in the sagittal plane +12.5 mm
lateral to the midline. The contacts are arbitrarily numbered from 0 to 3 (from ventral to
dorsal location). It is possible to record from 8 DBS contacts in patients who have
bilateral DBS surgery. Inset from Fawcett et al. 2006.
91
3.7 DATA ANALYSIS
3.7.1 SPIKE 2 SOFTWARE ANALYSIS
3.7.1.a Electrooculogram processing
Offline analysis of the signals recorded from DBS contacts, EEG and EOG were done
using Spike 2 software version 6 (CED, Cambridge, UK). The primary aim of this study
is to investigate the oscillations in the STN, GPi and Vim during the pre-saccadic,
saccadic and post-saccadic time periods. Saccade onsets were manually selected from
the EOG traces and edited for errors. Only saccades made in the cued direction (for
prosaccades) and / or opposite direction (for antisaccades) were considered to be correct.
EOG electrodes were placed at the outer canthi to detect the horizontal eye movements.
EOG signals were smoothed and down sampled. EOG channels and the cue-light trigger
channels were aligned and correct right and left saccades for each trial were manually
selected.
Epochs of the EOG signal data were constructed around saccade onset, starting 1.5 s
before and 0.5 s after the onset of the eye movements. Epochs of correct rightward and
leftward eye movements were then averaged for each block. To analyze baseline of 1.5
seconds without eye movements and compare it with the changes in the potentials during
the pre-saccadic, saccadic and post-saccadic periods, all saccades preceded by an
unwanted eye movement in the baseline period were discarded. Random saccades, which
do not correspond to the cue-light illumination, were also discarded. Saccades that
started within 100 ms after the target light illumination are considered to be anticipatory
92
saccades and discarded (normal saccade reaction time for prosaccades is between 150-
250 ms and little longer for antisaccades). Reflexive saccades, saccades erroneously
directed towards the target light during antisaccade tasks were also disposed. Patients
with BG disorders such as PD have trouble suppressing reflexive saccades, as mentioned
above.
3.7.1.b DBS Local Field Potential Processing
The aim of this study is to determine the presence of gamma synchronization in the STN,
GPi and Vim during saccadic eye movements. LFPs of all the four DBS contacts from
both sides (for bilateral DBS patients) were analyzed as explained by Le Van and Bragin
(Le Van and Bragin, 2007). DBS signals were smoothed and down sampled. Then the
smoothed LFP signals were gamma band-pass filtered, which will filter the gamma
oscillations from the wide-band raw potentials. Filters were set at 31 – 200 Hz
frequency. Following this, the gamma band-pass filtered signals were converted in to an
amplitude wave by a method called root mean square (RMS) amplitude (Figure 13).
Epochs of the gamma band-pass filtered LFPs were constructed, by aligning with each
previously determined correct rightward and leftward saccade onset, and averaged across
each block similar to the averaged EOG epochs (1.5 s before and 1 s after each correct
saccade onset).
93
Figure 13: Analysis of dynamic brain oscillations. Raw wide band (top) and high-
frequency gamma band-pass filtered (middle) local field potentials. Root mean square
(RMS) amplitude converts the neuronal oscillations in to an amplitude wave (bottom).
Adapted with permission from LeVan and Bragin 2007.
94
3.7.1.c Electroencephalogram Processing
Event-related potentials recorded from scalp EEG are thought to reflect cortical neuronal
processing. Scalp EEG data was recorded from sites FP1, Fz, Cz, C3 and C4. Extensive
scalp EEG recordings were limited because of the post-operative swelling of the scalp
wound and the need to maintain sterility. EEG data were smoothed, down sampled, and
averaged Epochs of gamma band-pass filtered EEG signals were built around saccade
onset, similar to the DBS LFPs. EOG signals were direct current removed and also
processed similarly to construct averaged Epochs, aligned to saccade onset.
3.7.2 MATLAB ANALYSIS
The frequency content of DBS LFPs and EEG signals can be investigated by several
techniques, including the fast Fourier transform (FFT), event-related potential (ERP)
analysis and the continuous wavelet transform (CWT). The FFT is a powerful analysis
technique that determines the frequency power for stationary signals that do not change
their frequency content over time. Thus, the FFT has limitations when analyzing non-
stationary signals. The CWT is a superior technique, when compared to FFT in spectral
analysis of EEG signals because of its increased temporal resolution (Muthuswamy and
Thakor, 1998). The CWT can use windows of varying size to maximize time-frequency
representation of the signal. Thus, the CWT can use different window sizes for different
frequency ranges to maximize time-frequency resolution, while this cannot be done using
FFT.
95
We used custom MATLAB 7.0 software (The MathWorks, Natick, MA) to perform
CWT of the DBS LFPs, scalp EEGs and EOG potentials in time-frequency relationship,
in order to corroborate the frequency type and timing of responses to eye movements.
Coherence between DBS LFPs, scalp EEGs and EOG signals can be examined by the
wavelet spectrograms. Scalp electrodes remained referenced to the ears. Epochs of data
around each saccade onset were constructed starting 1.5 s before and lasting 0.5 s
afterwards. A Morlet wavelet was used in all CWTs. The Morlet is a complex function
with sinusoidal oscillation. The Morlet parameter determines the time-frequency
resolution of the CWT. As the Morlet parameter increases time resolution decreases,
while frequency resolution increases. The Morlet parameter used in our study was 4.
Time (tind) and frequency (ω) resolution are a function of the Morlet parameter as shown.
2
22 2MMtind
212
2
21
MM
CWTs determined the time-frequency power of the DBS LFPs, EEG and EOG signals for
epochs around each saccade. Epoch signal power data were averaged and mean signal
time-frequency power for all correct saccadic tasks in rightward and leftward directions
were generated for each block. For each frequency, mean power was determined for a
baseline period of 0.5 s, in which the eyes were not moving. The ratio of time-frequency
power during saccades to baseline period for each task and direction was then
determined, as follows:
96
Sx,t = log ( Px,t / Px )
Where Sx,t ≡ the saccade to baseline ratio for frequency ‘x’ at time ‘t’, Px,t ≡ mean
saccade power of frequency ‘x’ at time ‘t’, Px ≡ baseline power of frequency ‘x’
Saccade-onset was manually determined by inspecting the horizontal EOG signals and
triggers placed at all correct rightward and leftward saccades for each block using Spike 2
software as described above. Consequently, each epoch was constructed around 1.5 s
before to 0.5 s after saccade onset. Changes in oscillatory power in DBS LFP, EEG and
EOG signals were defined to be significant if they lasted for more than 100 ms and had a
p value < 0.05 as determined by a random field theory method.
Far field potentials such as focal cortical interictal spikes and sleep potentials like K-
complexes and sleep spindles have been recorded in the DBS electrodes located in human
STN; central median nucleus, anterior nucleus and dorsal medial nucleus of the thalamus.
These far field potentials were synchronous with scalp EEG signals (Wennberg and
Lozano, 2003). This indicates that LFPs recorded from DBS macroelectrodes can be
contaminated by far field activity that is originating several centimeters away from the
site of DBS. Such far field conduction potentials were eliminated by subtracting
potentials from each of the four monopolar channels (3, 2, 1, 0) from the next closest
ventral contact to make three bipolar channels (3-2, 2-1, 1-0). The average frequency
power across all event-triggered windows was calculated for all the bipolar derivations,
similar to the monopolar wavelet spectrograms as described above.
97
4 RESULTS
The objective of this project is to study the gamma oscillations in the STN, GPi and Vim
during saccades. We studied 11 patients who underwent DBS surgery (6 STN, 3 GPi and
2 Vim). DBS LFPs and scalp EEG were analyzed by two methods, using Spike 2
software and Matlab programs. STN # 1, 2, 3 and GPi # 1, 2 and 3 performed the
saccadic tasks with short inter-trial intervals and the rest of the subjects were studied with
longer sequences (See Fig. 11). As the overall performance of the former was not
satisfactory, we selected all rightward and leftward fast eye movements for STN # 1, 2, 3
and GPi 1, 2 and 3.
4.1 Spike 2 Results
Spike 2 analysis of DBS LFPs showed oscillations in gamma frequency (> 31 Hz) during
perisaccadic periods. Event (saccade) related gamma synchronization (ERS) was
observed in LFPs recorded from STN, GPi and Vim regions. ERS usually began about
50 ms prior to saccade onset saccade onset and lasted for about 100 – 150 ms. When
present, saccade related gamma oscillations were present in all the DBS contacts (dorsal
to ventral location). Also, ERS were consistently symmetric in all DBS contacts
bilaterally (in bilateral DBS patients). This implies the similarity of LFP gamma
oscillations during ipsiversive and contraversive saccades. Figure 14 demonstrates the
gamma peak in all the DBS contacts during leftward saccades, which clearly begins a few
milliseconds before the onset of the eye movements (saccade onset marked by the
vertical line). Gamma oscillations were observed in anterior surface contacts such as
EOG and FP1 compared to the more posterior contacts (See Fig. 21).
98
Figure 14: Leftward saccades recorded from STN # 5 (n=21) during Prosaccade task,
analyzed with Spike 2 software. Vertical lines mark the onset of saccades in each epoch,
which consist of 1.5 s pre-saccadic baseline and 0.5 s post-saccadic periods. Averaged
EOG aligned with gamma (31-200 Hz) band-pass filtered DBS LFPs from Right (R3, R2,
R1 and R0) and Left (L3, L2, L1 and L0) DBS contacts. The Y axis calibration is in µ
volts, with a gain of 5000. Error bars are standard error of mean.
99
Patients / tasks R 3 R 2 R 1 R 0 L 3 L 2 L 1 L 0 EOG FP1 F z C z C 3 C 4
STN # 1 All Right saccades
PG (n=11) + + + + + + + + + + + 0 0 0 PO (n=10) + + + + + + + + + + 0 0 0 0 AG (n=8) + + + + + + + + + + 0 0 0 0 AO (n=11) + + + + + + + + + + + + + +
STN # 1 All Left saccades
PG (n=13) + + + + + + + + + + 0 0 0 0 PO (n=15) + + + + + + + + + + 0 0 0 0 AG (n=9) + + + + + + + + + + 0 0 0 0 AO (n=13) + + + + + + + + + + 0 0 0 0
STN # 2 All Right saccades
PG (n=8) + + + + + + + + 0 0 0 0 0 0 PO (n=11) 0 0 0 0 0 0 0 0 0 0 0 0 0 0 AG (n=8) 0 0 0 0 0 0 0 0 0 0 0 0 0 0 AO (n=8) 0 0 0 0 0 0 0 0 0 0 0 0 0 0
STN # 2 All Left saccades
PG (n=15) + + + + + + + + 0 0 0 0 0 0 PO (n=9) 0 0 0 0 0 0 0 0 0 0 0 0 0 0 AG (n=17) + + + + + + + + 0 0 0 0 0 0 AO (n=10) 0 0 0 0 0 0 0 0 0 0 0 0 0 0
STN # 3 All Right saccades
PG (n=15) + + + + + + + + 0 0 0 0 0 0 PO (n=16) 0 0 0 0 0 0 0 0 0 0 0 0 0 0 AG (n=10) 0 0 0 0 0 0 0 0 0 0 0 0 0 0 AO (n=19) 0 0 0 0 0 0 0 0 0 0 0 0 0 0
STN # 3 All Left saccades
PG (n=17) + + + + + + + + 0 0 0 0 0 0 PO (n=27) 0 + + + 0 + + + 0 0 0 0 0 0 AG (n=14) 0 0 0 0 0 0 0 0 0 0 0 0 0 0 AO (n=22) + + + + + + + + 0 0 0 0 0 0
STN # 4 Right saccades
PG (n=20) 0 0 0 0 + + + + + 0 0 + 0 0 PO (n=14) 0 0 0 0 + + + + + 0 0 + 0 0 AG (n=16) 0 0 0 0 0 + 0 0 + 0 0 0 0 0 AO (n=19) + + + + + + + + + 0 + + 0 0
STN # 4 Left saccades
PG (n=12) + + + + + + + + + 0 0 0 0 0 PO (n=21) + + + + 0 + + + + 0 0 0 0 + AG (n=20) + + + + + + + + + + 0 + 0 0 AO (n=18) 0 0 0 0 + + + 0 + + 0 + 0 0
STN # 5 Right saccades
PG (n=11) 0 + + + 0 + + + 0 0 0 0 0 0 PO (n=11) 0 0 + 0 0 0 0 0 0 0 0 0 0 0 AG (n=16) 0 0 0 0 0 + 0 + 0 0 0 0 0 0 AO (n=9) 0 0 0 0 0 0 0 0 + 0 0 0 0 0
STN # 5 Left saccades
PG (n=16) + + + + + + + + + + 0 0 0 0 PO (n=14) 0 0 0 0 0 0 0 0 0 0 0 0 0 0 AG (n=20) + + + + + + + + + + 0 + 0 0 AO (n=11) 0 0 + + + + 0 + 0 0 0 0 0 0
STN # 6 Right saccades
PG (n=27) + + + + + + + + + + 0 0 0 0 PO (n=19) + + + + + + + + + + 0 0 0 0 AG (n=10) 0 0 0 0 0 0 0 0 0 0 0 0 0 0 AO (n=14) + + + + + + + + + + 0 0 0 0
STN # 6 Left saccades
PG (n=12) + + + + + + + + + 0 0 0 0 0 PO (n=20) + + + + + + + + + + 0 0 + 0 AG (n=9) + + + + + + + + 0 0 0 0 0 0 AO (n=9) 0 0 + + 0 + + 0 0 0 0 0 0 0
100
Table 2 (in page 99): Shows the presence or absence of gamma synchronization in Spike
2 and/or Matlab analysis during rightward and leftward saccades for each of the four
blocks tested in STN patients. R3 to R0 and L3 to L0 represent the Right and Left DBS
LFPs recorded from dorsal to ventral contacts respectively. FP1, Fz, Cz, C3, C4 and
EOG are surface potentials recorded from scalp EEG and electrooculogram contacts
(which were analyzed similar to the DBS LFPs). ‘+’ and ‘0’ marks symbolize the
presence or absence of saccade related gamma synchronizations. PG = Prosaccades with
gap paradigm, PO = Prosaccades with overlap paradigm, AG = Antisaccades with gap
paradigm and AO = Antisaccades with overlap paradigm. ‘n’ represents number of
correct rightward or leftward saccades in every block. Each block consisted of 50 trials
(25 random saccades in right or left directions). Due to short fixation period and inter-
trial intervals, STN patients # 1, 2 and 3 performed poorly and hence triggers were placed
at onset of all rightward and leftward saccades. STN patients # 2 and 3 had hypomertric
saccades, from the underlying PD, which probably is the cause of the fewer ERS. It is
evident from Table 2 that ERS, when present in surface EEG contacts, is mostly observed
in EOG, FP1 and Fz (frontal) contacts and tends to disappear in Cz, C3 and C4 contacts
which are further away from the ocular globes.
101
Figure 15: Incidence of saccade related gamma synchronizations in Spike 2 and/or
Matlab analysis during rightward pro- and anti-saccades among STN patients. R3 to R0
and L3 to L0 represent the Right and Left DBS LFPs recorded from dorsal to ventral
contacts respectively. EOG = Electrooculogram, FP1, Fz, Cz, C3 and C4 = Scalp EEG,
PG = Prosaccades with gap, PO = Prosaccades overlap (without gap), AG = Antisaccades
with gap, and AO = Antisaccades overlap (without gap). Number of correct saccades is
displayed in Y-axis.
102
Figure 16: Incidence of saccade related gamma synchronizations in Spike 2 and/or
Matlab analysis during leftward pro- and anti-saccades among STN patients. R3 to R0
and L3 to L0 represent the Right and Left DBS LFPs recorded from dorsal to ventral
contacts respectively. EOG = Electrooculogram, FP1, Fz, Cz, C3 and C4 = Scalp EEG,
PG = Prosaccades with gap, PO = Prosaccades overlap (without gap), AG = Antisaccades
with gap, and AO = Antisaccades overlap (without gap). Number of correct saccades is
displayed in Y-axis.
103
Table 3: ERS in GPi and Vim patients. N/A = Unilateral DBS patients. ‘+’ and ‘0’
represent the presence or absence of saccade related gamma synchronization.
Patients / tasks R 3 R 2 R 1 R 0 L 3 L 2 L 1 L 0 EOG FP1 F z C z C 3 C 4
GPi # 1 All Right saccades
PG (n=11) +
+
+
+
+
+
+
+
+
+
+
+
+
+ PO (n=11) +
+
+
+
+
+
+
+
0 0 0 0 0 0 AG (n=15) +
+
+
+
+
+
+
+
0 0
0 +
+
0 0 AO (n=16) 0 0 +
+
0 0 +
+
0 0 0 0 0 0 GPi # 1 All Left saccades
PG (n=10) 0 +
+
+
0 +
+
+
0 0 0 0 0 0 PO (n=9) 0 0 0 0 0 0 0 0 0 0 0 0 0 0 AG (n=12) 0 +
+
0 +
0 +
+
+
0 0 0 0 0 0 AO (n=11) 0 +
+
+
+
+
+
+
0 0 0 +
0 0 GPi # 2 All Right saccades
PG (n=13) 0 0 0 0 0 0 0 0 0 0 0 0 0 0 PO (n=19) 0 0 0 0 0 0 0 0 0 0 0 0 0 0 AG (n=13) +
+
+
+
+
+
+
+
0 0 0 0 0 0 AO (n=12) 0 0 0 0 0 0 0 0 0 0 0 0 0 0
GPi # 2 All Left saccades
PG (n=15) + 0
+
+
+
+
+
0 +
0 +
+
+
+
+ PO (n=13) 0 0 0 0 0 0 0 0 0 0 0 0 0 0
AG (n=15) 0 +
+
+
0 0 0 0 0 0 0 0 0 0 AO (n=11) +
+
+
+
0 0 0 0 0 0 0 0 0 0 GPi # 3 All Right saccades
PG (n=23) N/A N/A N/A N/A +
+
+
+
0 0 0 +
0 + PO (n=18) N/A N/A N/A N/A +
+
+
+
0 0 +
+
+
+ AG (n=17) N/A N/A N/A N/A +
+
0 0 0 0 +
0 0 + AO (n=21) N/A N/A N/A N/A +
+
+
+
0 0 0 +
0 + GPi # 3
All Left saccades
PG (n=19) N/A N/A N/A N/A +
+
+
+
+
0 +
+
+
0 PO (n=19) N/A N/A N/A N/A +
+
+
+
0 +
+
+
+
+ AG (n=11) N/A N/A N/A N/A 0 0 0 0 0 0 0 0 0 0
AO (n=18) N/A N/A N/A N/A +
0 0 0 0 0 0 +
0 0 Vim # 1 Right saccades
PG (n=14) +
+
+
+
N/A
N/A N/A N/A 0 0 +
+
+
+ PO (n=16) +
+
+
+
N/A N/A N/A N/A 0 +
+
+
+
+ AG (n=8) +
+
+
+
N/A N/A N/A N/A 0 0 0 0 0 0 AO (n=11) 0 0 0 0 N/A N/A N/A N/A 0 0 0 0 0 0
Vim # 1 Left saccades
PG (n=14) 0 0 0 0 N/A N/A N/A N/A 0 0 0 0 0 0 PO (n=14) +
+
+
+
N/A N/A N/A N/A 0 +
+
+
+
+ AG (n=11) +
+
+
+
N/A N/A N/A N/A 0 +
+
+
0 + AO (n=14) 0 +
0 +
0 N/A N/A N/A N/A 0 0 0 0 0 0 Vim # 2 Right saccades
PG (n=18) +
0 0 0 N/A N/A N/A N/A 0 0 0 0 0 0 PO (n=14) +
+
+
+
N/A N/A N/A N/A 0 0 0 0 0 0 AG (n=12) +
0 0 0 N/A N/A N/A N/A 0 0 0 0 0 0
AO (n=16) +
0 0 0 N/A N/A N/A N/A 0 0 0 0 0 0 Vim # 2 Left saccades
PG (n=13) +
0 0 0 N/A N/A N/A N/A 0 0 0 0 0 0 PO (n=17) +
+
+
+
N/A N/A N/A N/A 0 0 0 0 0 0 AG (n=14) 0 +
+
+
N/A N/A N/A N/A 0 0 0 0 0 0 AO (n=12) +
0 0 0 N/A N/A N/A N/A 0 0 0 0 0 0
104
Figure 17: Incidence of saccade related gamma synchronizations in Spike 2 and/or
Matlab analysis during rightward and leftward saccades (Pro- and anti-saccades) among
GPi patients. R3 to R0 and L3 to L0 represent the Right and Left DBS LFPs recorded
from dorsal to ventral contacts respectively. EOG = Electrooculogram, FP1, Fz, Cz, C3
and C4 = Scalp EEG, PG = Prosaccades with gap, PO = Prosaccades overlap (without
gap), AG = Antisaccades with gap, and AO = Antisaccades overlap (without gap).
Number of correct saccades is displayed in Y-axis.
105
Figure 18: Incidence of saccade related gamma synchronizations in Spike 2 and/or
Matlab analysis during rightward and leftward saccades (Pro- and antisaccades) among
Vim patients. R3 to R0 represent the Right DBS LFPs recorded from dorsal to ventral
contacts respectively.Both the essential tremor subjects had right Vim DBS. EOG =
Electrooculogram, FP1, Fz, Cz, C3 and C4 = Scalp EEG, PG = Prosaccades with gap, PO
= Prosaccades overlap (without gap), AG = Antisaccades with gap, and AO =
Antisaccades overlap (without gap). Number of correct saccades is displayed in Y-axis.
106
4.1.1 Comparison of Gamma Activity
Pairwise multiple comparison procedures (ANOVA) and Bonferroni corrected t-tests
were done to compare lateralization of saccade related gamma activity and difference
between gamma peak amplitudes in the regions of STN (# 1, 2 and 3) and GPi (# 1, 2 and
3). There was no difference between saccade related gamma synchronization for
ipsiversive and contraversive saccades (p = 0.926). Gamma peak amplitude is
significantly higher in the STN, compared to GPi (p < 0.001). Figure 19 shows the
normalized percentage of baseline to gamma peak for Ipsiversive and Contraversive DBS
LFPs in STN and GPi regions.
107
Figure 19: Normalized percentage of baseline to gamma peak for ipsiversive and
contraversive LFPs in STN and GPi regions (grand average of all blocks in STN patients
# 1, 2, 3 and GPi patients # 1, 2 and 3). There was no significant difference between
ipsiversive and contraversive ERS in STN and GPi regions ((p = 0.926). Gamma
synchronization during saccades had higher amplitude in the STN region than the GPi (p
< 0.001). Error bars are standard error of mean.
108
4.2 Matlab Analysis
Wavelet spectrograms of DBS LFPs showed gamma synchronization just prior to saccade
onset in all the STN, GPi and Vim patients. DBS LFPs showed ERS which was
symmetric in all the DBS contacts (3, 2, 1 and 0) and were symmetric bilaterally (See
Figure 20). Also, the perisaccadic gamma oscillations of the DBS LFPs, frontal EEGs
and EOG appeared identical (See Figure 20). Consistent with this, Spike 2 analysis of
DC removed EOG contacts and anterior scalp EEGs showed ERS, which appeared
similar to DBS LFP gamma synchronization. But this ERS was not as apparent in EEG
contacts further away from the frontal channel such as C3 and C4 (See Figure 21).
Morlet wavelets of DBS LFPs aligned to target light illumination did not show any
gamma synchronization. 200 ms after the presentation of target light, gamma
synchronization was recorded. This correlates to the onset of the eye movements (Figure
22).
109
Figure 20: Wavelet spectrograms of scalp EEG (Fz and Cz), EOG, DBS LFPs (R3, R2,
R1, R0, L3, L2, L1 and L0) recorded during rightward saccades from STN # 5, generated
with time (X-axis) and frequency (Y-axis) relationship, aligned to saccade onset (Spike-2
EOG trace on top for reference). Spectral content of the LFPs in the period prior to,
during and post ipsiversive or contraversive saccades were analyzed for event-related
gamma synchronization and significant regions (p < 0.05) identified as outlined above.
Warmer color represents synchronization. Note the saccade related gamma
synchronization starting about 50 ms before the saccade onset and extending for 75 ms
after. ERS appears similar in all the DBS LFPs, frontal scalp EEG contacts and EOG.
110
Figure 21: Spike 2 analysis of leftward saccades recorded from STN # 5 (n=21) during
prosaccade task. Vertical lines mark the onset of saccades in each epoch. Averaged
EOG aligned with gamma (31-200 Hz) band-pass filtered LFPs dorsal right (R3) and left
(L3) DBS contacts, DC removed EOG contact, frontal scalp EEG (FP1), and central left
(C3) and right (C4) scalp EEG contacts. Note the ERS in DBS contacts (R3 and L3), DC
removed EOG and FP1 contacts. ERS is not as prominent in the central contacts C3 and
C4. DC removed EOG and surface EEG contacts were band pass filtered and analyzed
similar to the DBS LFPs. The Y axis calibration is in µ volts, with a gain of 5000. Error
bars are standard error of mean. Gamma band-pass filtered LFPs (Spike 2 analysis) of all
the DBS contacts from this same patient and the same block is shown in Figure 14.
111
Figure 22: Wavelet spectrograms of Left DBS LFPs and surface EEG contacts (Fp1 and
C3) recorded from STN # 3, aligned to right target light illumination (n=24). Vertical
line on the EOG trace (top) corresponds to the onset of target light illumination. There
was no obvious change in the baseline LFPs during the target light illumination. 200 ms
after the averaged target light illumination, gamma synchronization is observed in L2
channel, which corresponds to onset of saccades. Red arrow in channel L1 shows a trend
towards gamma synchronization.
112
4.2.1 Duration of Saccade Related Gamma Synchronization
As shown in tables 2 and 3, ERS was present in all the STN, GPi and Vim patients, but
this was not noticed in all the blocks. The presence of gamma synchronization was
mostly proportional to the number of correct saccades (n), which varied with each block,
depending on the effort and concentration of the (post-operative) patients. When present,
ERS started about 50 ms before saccade onset and lasted for about 100 ms after, which
may roughly correspond to the time taken for the completion (duration) of the saccade.
Figure 23 shows the grand average of the duration of saccade related gamma activity
recorded from all the STN, GPi and Vim patients.
4.2.2 Bipolar Derivations of DBS LFPs
DBS LFPs recorded from DBS macroelectrodes can include or be dominated by far field
activity that is originating several centimeters away from the site of DBS. In order to
eliminate such far field conduction potentials, bipolar derivations of DBS LFPs were
generated by subtracting potentials from each of the four monopolar channels (3, 2, 1, 0)
from the next closest ventral contact to make three bipolar channels (3-2, 2-1, 1-0).
The ERS recorded from STN, GPi and Vim patients during the perisaccadic period
disappeared in bipolar derivations, suggesting the ERS origin to be a far field conduction
potential (See Figure 24).
113
Figure 23: Duration of saccade related gamma activity. This is a grand average of all
rightward and leftward saccades, recorded from the STN, GPi and Vim patients. X-axis
shows the time in ms, with saccade onset at ‘0’. Y-axis shows the channel for which the
average duration of the gamma activity was calculated. Note the gamma activity
begining ~ 50 ms prior to the onset of the eye movement and lasting for ~ 100 ms after
the saccade onset.
114
Figure 24: Wavelet spectrograms of EOG channel, R3 and L3 (unipolar DBS) and
bipolar derivation of DBS contacts (R3-R2, R2-R1, R1-R0, L3-L2, L2-L1, L1-L0)
aligned with rightward saccades (n = 19) from STN # 5. Note the gamma
synchronization in the perisaccadic period, which dispersed in the bipolar channels. Red
arrow in channel R2-R1 points to desynchronization in beta frequency. Gamma band-
pass filtered LFPs from all the DBS contacts from the same patient (same block) is
shown in Figure 14.
115
4.2.3 LFPs during Vestibulo-Ocular Reflex
To identify the source of origin of the gamma synchronization, DBS LFPs and surface
EEG were recorded during VOR in one patient (STN # 6, Table 1), with triggers placed
at the onset of the slow (vestibular) eye movement. ERS was seen in all the DBS
contacts (dorsal to ventral), which once again, was similar in ipsiversive and
contraversive LFPs. In contrast to ERS observed during saccades, gamma
synchronization recorded during vestibular smooth eye movement of the VOR began ~
100 ms before the eye movement and lasted longer, for ~ 500 ms (Figure 25). These
gamma synchronizations were also prominent in all the scalp EEG contacts, including the
electrodes further away from the eyes (C3 and C4) (Figure 26).
116
Figure 25: Wavelet spectrogram of the DBS LFPs recorded during smooth eye motion of
left vestibulo-ocular reflex (n=9) in STN # 6 showing symmetric gamma
synchronizations in all the DBS electrodes. Note the gamma synchronization starting at
(–) 100 ms and lasting to longer (500 ms) than average saccade related gamma
oscillations.
117
Figure 26: Wavelet spectrograms of surface EEG contacts recorded during left VOR in
STN # 6. DBS LFPs of the same is task shown in Figure 25. Note longer duration of the
ERS in the scalp EEGs (similar to DBS LFPs during VOR). ERS is also prominent in the
central contact on the righ side (C4). This may represent the origin of this gamma from
the sternocleidomastoid muscle on the right side.
118
4.3 Saccade Metrics
Saccade reaction times (SRT) were calculated from interval between the illumination of
the target lights and the onset of the eye movements. As mentioned above, STN # 4, 5
and 6 performed better in the saccadic tasks with longer sequences. Hence SRT of these
patients were pooled and analyzed for statistical difference between the two tasks
(prosaccades and antisaccades) and the two paradigms (Gap and Overlap paradigms).
4.3.1 Prosaccades versus Antisaccades
Saccadic latencies were longer for antisaccades, compared to prosaccdes (Figure 27). 2-
tailed student t-test comparing this difference was statistically significant (p < 0.001)
4.3.2 Gap Effect
Saccade reaction times were reduced significantly in prosaccade blocks with gap
paradigms (~ 80 ms), when compared to prosaccades with overlap paradigms (~ 180 ms)
as shown in Figure 28. 2-tailed student t-test comparing the gap effect in prosaccades
was also statistically significant (p < 0.001)
Gap effect was not obvious in the antisaccade tasks (Figure 29). Student t-test shows no
statistical significance (p = 0.101).
119
Figure 27: Saccade reaction times of prosaccades and antisaccades from STN # 4, 5 and 6.
Student t-test shows statistically significant difference (p < 0.001).
120
Figure 28: Saccade reaction time showing the ‘Gap effect’ in prosaccades. Prosaccade
blocks with and without gap of STN # 4, 5 and 6 were compared using 2-tailed student t-test
which was statistically significant (p < 0.001).
121
Figure 29: Saccade reaction times in antisaccades with and without gap. There was no
significant difference between gap and overlap paradigms in antisaccade tasks (p = 0.101).
122
4.4 Beta Desynchronization in Bipolar Derivations
Occasionally saccade related beta desynchronization was observed in the STN, GPi and
Vim DBS LFPs on bipolar derivations, which strongly localizes the source of these
potentials to the DBS contacts (STN, GPi or Vim). However, this is not a consistent
finding like ERS. Figure 30 shows an example of event relaed beta desynchronization
(ERD). Unlike ERS, the time interval of ERD was highly variable between (-) 400 ms to
500 ms (before and after onset of saccades). Tables 4 and 5 shows the presence or
absence of ERD in STN and GPi/Vim subjects respectively. Occasionally ERD was
observed in all the three bipolar channels (eg R3-R2, R2-R1 and R1-R0).
123
Figure 30: Wavelet spectrogram of bipolar derivations from Vim # 1 during leftward
antisaccades (n=14). Note the beta desynchronization in bipolar channels R3-R2 and R1-
R0.
124
Patients / tasks R 3 - R 2 R 2 – R 1 R 1 – R 0 L 3 – L 2 L 2 – L 1 L 1 – L 0 STN # 1 Right saccades
PG (n=11) 0 0 0 0 0 0 PO (n=10) 0 0 0 0 0 0 AG (n=8) 0 0 0 0 0 0 AO (n=11) 0 0 0 0 0 0
STN # 1 Left saccades
PG (n=13) 0 0 0 0 0 0 PO (n=15) 0 0 0 0 0 + AG (n=9) 0 0 0 + 0 0 AO (n=13) 0 0 0 0 0 0
STN # 2 Right saccades
PG (n=8) 0 0 0 0 0 0 PO (n=11) + 0 0 0 0 0 AG (n=8) 0 0 0 0 0 0 AO (n=8) 0 0 0 0 0 0
STN # 2 Left saccades
PG (n=15) 0 0 0 0 0 0 PO (n=9) 0 0 0 0 0 0 AG (n=17) 0 0 0 0 0 0 AO (n=10) 0 0 0 0 0 0
STN # 3 Right saccades
PG (n=15) 0 0 0 0 0 0 PO (n=16) + + 0 0 0 0 AG (n=10) 0 0 0 + 0 0 AO (n=19) + 0 0 + 0 0
STN # 3 Left saccades
PG (n=17) + + 0 0 0 0 PO (n=27) 0 0 0 0 + 0 AG (n=14) 0 0 0 0 0 0 AO (n=22) 0 + 0 0 0 0
STN # 4 Right saccades
PG (n=20) 0 0 + 0 0 0 PO (n=14) 0 0 0 0 0 0 AG (n=16) 0 0 0 + 0 0 AO (n=19) 0 + 0 0 0 0
STN # 4 Left saccades
PG (n=12) 0 0 0 0 0 0 PO (n=21) 0 0 0 + 0 0 AG (n=20) 0 0 0 + 0 0 AO (n=18) 0 0 0 0 0 0
STN # 5 Right saccades
PG (n=11) 0 0 0 0 0 0 PO (n=11) 0 0 0 0 0 0 AG (n=16) 0 0 0 0 0 0 AO (n=9) 0 0 0 0 0 0
STN # 5 Left saccades
PG (n=16) 0 0 0 0 0 0 PO (n=14) 0 0 0 0 0 0 AG (n=20) 0 0 0 0 0 0 AO (n=11) 0 0 0 0 0 0
STN # 6 Right saccades
PG (n=27) + + 0 0 0 0 PO (n=19) 0 + 0 0 + 0 AG (n=10) 0 0 0 0 0 0 AO (n=14) 0 + 0 0 + 0
STN 6 Left saccades
PG (n=12) 0 0 0 0 + 0 PO (n=20) 0 0 0 0 0 0 AG (n=9) 0 0 0 0 0 0 AO (n=9) 0 0 0 0 0 0
125
Table 4 (page 124): Saccade related beta desynchronization in bipolar derivations for all
STN patients. ‘+’ and ‘0’ marks represent the presence or absence of saccade related beta
desynchronization. Occurrence of the saccade related beta desynchronization is not a
consistent finding like gamma synchronization.
126
Table 5: Saccade related beta desynchronization in bipolar derivations for all GPi and
Vim patients. N/A = Unilateral DBS patients. ‘+’ and ‘0’ marks indicate the presence or
absence of saccade related beta desynchronization.
Patients / tasks R 3 - R 2 R 2 – R 1 R 1 – R 0 L 3 – L 2 L 2 – L 1
L 1 – L0
GPi # 1 Right saccades
PG (n=11) 0 0 0 0 0 0 PO (n=11) 0 0 0 0 0 0 AG (n=15) 0 0 0 0 0 0 AO (n=16) 0 0 + 0 0 0
GPi # 1 Left saccades
PG (n=10) 0 0 0 0 0 0 PO (n=9) 0 0 0 0 0 0 AG (n=12) 0 0 0 0 0 0 AO (n=11) 0 0 0 0 0 0
GPi # 2 Right saccades
PG (n=13) 0 0 0 0 0 0 PO (n=19) 0 0 0 0 0 0 AG (n=13) 0 0 0 0 0 0 AO (n=12) 0 0 0 0 0 0
GPi # 2 Left saccades
PG (n=15) 0 0 0 0 0 0 PO (n=13) 0 0 0 + 0 0 AG (n=15) 0 0 0 0 0 0 AO (n=11) 0 0 0 0 0 0
GPi # 3 Right saccades
PG (n=23) N/A N/A N/A 0 0 0 PO (n=18) N/A N/A N/A 0 0 0 AG (n=17) N/A N/A N/A 0 0 0 AO (n=21) N/A N/A N/A 0 0 0
GPi # 3 Left saccades
PG (n=19) N/A N/A N/A 0 0 0 PO (n=19) N/A N/A N/A 0 0 0 AG (n=11) N/A N/A N/A 0 0 0 AO (n=18) N/A N/A N/A 0 0 0
Vim # 1 Right saccades
PG (n=14) + 0 + N/A N/A N/A PO (n=16) 0 0 0 N/A N/A N/A AG (n=8) 0 0 0 N/A N/A N/A AO (n=11) 0 0 + N/A N/A N/A
Vim # 1 Left saccades
PG (n=14) 0 + 0 N/A N/A N/A PO (n=14) 0 0 0 N/A N/A N/A AG (n=11) 0 0 0 N/A N/A N/A AO (n=14) 0 0 + N/A N/A N/A
Vim # 2 Right saccades
PG (n=18) 0 0 0 N/A N/A N/A PO (n=14) 0 0 0 N/A N/A N/A AG (n=12) 0 0 0 N/A N/A N/A AO (n=16) 0 0 0 N/A N/A N/A
Vim # 2 Left saccades
PG (n=13) 0 0 0 N/A N/A N/A PO (n=17) 0 0 0 N/A N/A N/A AG (n=14) 0 0 0 N/A N/A N/A AO (n=12) 0 0 0 N/A N/A N/A
127
5 DISCUSSION
LFPs are said to reflect the extracellular voltage fluctuations in the brain. LFPs and their
extracranial counterpart – scalp EEG, have been studied widely to understand the neural
mechanisms involved in various functional domains. Neural oscillations in the gamma
band (> 31 Hz) have been of growing interest in the past few years. High frequency
oscillations in the gamma range have been studied during various tasks and there is
substantial evidence supporting their role in cortical activation as well multi-regional and
multi-modal integration of cortical processing.
Crone et al. studied neural oscillations in human subjects using subdural
electrocorticogram (ECoG) and observed low and high frequency gamma ERS over
contralateral sensorimotor cortex during unilateral limb movements, which is consistent
with traditional maps of sensorimotor functional anatomy (Crone et al., 1998). Following
this several studies, using depth electrodes, have shown gamma ERS during various tasks
such as visual perception in the occipital, parietal and temporal areas (Lachaux et al.,
2005), auditory tone and phoneme discrimination tasks in human auditory cortex (Crone
et al., 2001a), attention in the lateral occipital cortex and fusiform gyrus (Tallon-Baudry
et al., 2005), and language tasks such as word production and naming in parietal regions
and basal temporal-occipital cortex respectively (Crone et al., 2001b). While this
evidence supports a role of gamma oscillations in cortex, relatively less is known of
gamma oscillations in the BG.
128
Brown’s model is a prototype in understanding the oscillatory changes in the BG during
limb movements. LFPs recorded from STN, GPi and Vim showed event related gamma
synchronization during limb movements (Androulidakis et al., 2007;Brucke et al.,
2008;Kempf et al., 2009). As the skeletal motor and ocular motor control of the BG are
probably through similar mechanisms, we anticipated that the LFPs in the STN, GPi and
Vim regions might show gamma ERS during saccadic eye movements.
5.1 Non-lateralized Gamma Synchronizations
Spike 2 and Malab analysis of the DBS LFPs showed saccade related gamma
synchronizations in all the STN, GPi and Vim subjects. But, in contrast to the limb
movement-related gamma oscillations in the STN, GPi and Vim which were lateralized
in the previous studies (ie. gamma synchronizations contralateral to the limb
movements), gamma ERS that we recorded during saccades were consistently bilateral
and symmetric. This was also evident from the fact that data analysis showed no
difference between ERS for ipsiversive and contraversive saccades. Figure 19 compares
the normalized percentage of baseline to gamma peak between ipsiversive and
contraversive saccades. One possible explanation for this bilateral oscillatory activity,
which we initially assumed to be the reason, was the crossed and uncrossed nigro-
collicular pathways described by Jiang et al. (Jiang et al., 2003).
129
5.2 Quadripolar Symmetry of ERS
Saccade related gamma synchronizations, when present, appeared symmetric in all the
four DBS contacts in the STN, GPi and Vim regions (see Figure 20). From figure 12,
which shows the trajectory of STN DBS, it is apparent that it is not possible for all the
four DBS contacts to reside within the STN. This strongly suggests the origin of these
potentials to be not limited to the DBS target sites and thus raised the possibility of an
origin as a far field potential. ERS disappeared in the bipolar derivations (Figure 24),
which proved this possibility to indeed be the case. Wennberg et al. observed interictal
epileptiform activity and sleep potentials in centromedian nucleus, anterior nucleus and
dorsal medial nucleus of thalamus, as well as STN DBS contacts in patients who were
treated with DBS for epilepsy and PD (Wennberg and Lozano, 2003). In that study, focal
interictal cortical spikes and subcortical sleep potentials (K-complexes and sleep
spindles) were found to occur synchronously in scalp EEG and DBS LFPs. That study
has demonstrated that the DBS LFPs, despite their placement in deeper subcortical
regions, are still vulnerable to intracranial volume conduction from neocortical
discharges.
5.3 What is the origin of Gamma ERS?
If the DBS LFPs cancel-out on bipolar derivations and if these are far field potentials,
then where do these potentials originate? As mentioned above, gamma oscillations have
been observed during presentation of visual stimuli, attention, as well as visual perception
130
(Lachaux et al., 2005;Tallon-Baudry et al., 2005). Those studies raised the possibility
that the ERS could represent gamma oscillations in the parieto-occipital regions, induced
by target light illumination during the visually-cued saccades. To address this question,
we generated wavelet spectrograms of DBS contacts (unipolar derivations) with triggers
placed at the target light illumination (Figure 22). There was no change in the LFPs at
the time of target light illumination when compared to the baseline. Also, 200 ms after
the averaged taget light illumination there was gamma synchronization. This duration
(200 ms) is roughly equivalent to normal saccade reaction time and thus suggested that
the gamma ERS, probably originated somewhere in the cerebral cortex and played a
motor-execution role during saccade initiation.
Lachaux et al. used intracerebral EEG (iEEG) in epilepsy surgery patients to study the
activity in FEF and SEF during prosaccades and antisaccades respectively (Lachaux et
al., 2006). There were focal and transient increases in iEEG power in the gamma
frequency (over 60 Hz) during the generation of prosaccades and antisaccades, which
spatio-temporally correlated to preparation and execution of saccades. In order to rule-
out volume conduction from FEF and SEF, we performed VOR task in one STN patient,
and triggers for averaging were placed at the onset of slow phases of the VOR. The
function of VOR is to stabilize the image on the retina during head rotations. When head
rotates in a direction, the eyes move in the opposite direction. During horizontal VOR,
when the head rotates to the right side, the hair cells in the right horizontal semicircular
canals are depolarized. This results in the activation of the right vestibular nucleus, and
in-turn the left abducens nucleus is also activated. This causes an eye movement to the
131
left side. Thus, the slow phase of VOR is induced by vestibular system and is not a
saccadic eye movement. Our results showed the presence of gamma oscillations during
the slow phase of VOR, which provides evidence against the origin of these potentials
from cortical saccadic centers such as FEF or SEF. The presence of the gamma ERS
with different types of eye movement thus raised the suspicion of their origin in the
extraocular muscles.
132
5.4 SPIKE POTENTIALS
In 2009, Yuval-Greenberg first reported that the high frequency gamma oscillations in
scalp EEG during execution of saccades are caused by strong electrical potentials due to
contraction of extraocular muscles, called saccadic spike potentials (SP) (Yuval-
Greenberg and Deouell, 2009). Saccadic eye movements cause two types of electrical
potentials that originate in the orbit: 1. Rotation of corneo-retinal dipole (CRD) and 2.
Saccadic spike potentials produced by extraocular muscles. The ocular globes have a
dipolar electrical field with the positively charged cornea anteriorly and the more
negative retina posteriorly. Rotation of the eye changes the orientation of the dipole,
which results in a change in the CRD potentials recorded at various scalp EEG electrodes
relative to the distance and position from the eyes. CRD is a slow potential, when
compared to the sharp SP (Thickbroom and Mastaglia, 1985).
Spike Potentials are of myogenic origin and are said to represent summated electrical
activity from the near synchronous recruitment of the motor units in the extra-ocular
muscles (Thickbroom and Mastaglia, 1985). In human, three types of presaccadic
potentials have been observed using scalp EEG during visually-cued and/or self-paced
saccades: 1. A slow negative shift with largest amplitude in the frontal region, 650 ms
preceeding self-initiated saccades; 2. A ramp-like positivity occuring 100-250 ms before
self-initiated and visually-cued saccades, with maximal amplitude over the parietal
regions; 3. A sharp positive potential 10-40 ms before the onset of self-paced as well as
triggered saccades (Kurtzberg and Vaughan, Jr., 1982). The first two potentials are of
133
cerebral origin. The negative potentials that preceed self-initiated saccades are similar to
readiness or Bereitschafts potential (BP) that are recorded from scalp EEG electrodes
prior to self-paced limb movement (Becker et al., 1972).
The third ‘sharp’ potential that occurs immediately (10-40 ms) before initiation of self-
paced or visually-cued saccades is SP, which originates in the extraocular muscles
(Thickbroom and Mastaglia, 1985). SP starts starts simultaneously with saccade onset as
a sharp potential around the eyes, with maximal negativity in the anterior region of the
head. SP reverses polarity along a line that approximately extends from nasion to the
temporal region (Thickbroom and Mastaglia, 1985). Computing the short and fast
variations in the SP power spectrum typically results in energy almost exclusive in
gamma frequency (Jerbi et al., 2009).
5.4.1 Source of Spike Potentials
Thickbroom and Mastaglia were the first to extensively investigate saccadic SP using
multichannel scalp EEG recordings and spatio-temporal mapping. They used dipole
modelling and source derivation techniques, which localized the origin of the SP to the
extraocular muscles. Patients with abducens palsy, showed markedly attenuated SP for
saccades in the direction of the lateral rectus paresis. SP recorded from a
hemispherectomy patient showed normal bilateral topographic distribution, which makes
cortical origin of these potentials unlikely (Thickbroom and Mastaglia, 1985). The
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following facts exclude CRD as a source of SP: 1. Polarity of the SP is the same around
the eye, compared to the vector of CRD potentials which changes during rotation of the
ocular globes (Yuval-Greenberg and Deouell, 2009), and 2. SP are obtainable in subjects
with an ocular prosthesis who had residual functioning extra-ocular muscles, which rules-
out retinal source (Thickbroom and Mastaglia, 1985). Furthermore, one patient who had
orbital exenteration (removal of the eye, extra-ocular muscles and complete orbital
contents) for an infiltrating tumor showed no saccadic SP. Presence of SP in patients
with an ocular prosthesis (and still preserved extraocular muscle action), and its absence
in orbital exenteration, provides concrete evidence that these potentials originate in the
extraocular muscles and not the retina (Thickbroom and Mastaglia, 1985).
5.4.2 Intracranial volume conduction of Spike Potentials
Modulations of gamma activity can be recorded with high spatial and temporal resolution
using iEEG acquired from electrodes implanted in the brain of epilepsy patients. IEEGs,
in contrast to surface EEG recordings, had been assumed to be immune to contamination
by extracranial volume conduction such as SP. Jerbi and colleagues first reported that
potentials recorded from the temporal lobe using iEEG electrodes in epilepsy patients
showed power increase in gamma frequency which coincides with the execution of
saccades (Jerbi et al., 2009). Analysis of multiple depth electrodes in this study have
shown that the gamma-band SP were confined to the temporal pole, the electrode site
closest to the orbit. Also, saccade induced gamma power increase was strongest in the
contacts that were closer to the lateral rectus muscle. Consistent with this finding, our
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study showed stronger gamma ERS in the scalp EEG contacts closer to the ocular globes
in contacts Fp1, Fz and Cz. These potentials were either not present or weaker in the
contacts further away from the ocular globes such as C3 and C4 (See Figure 21).
The conductive properties of the intracranial tissue appear to differ from those in the
scalp and the cranium. Saccade induced gamma oscillations in the scalp EEG reported
by Yuval-Greenberg was a low gamma burst (~31-90 Hz), whereas the invasive iEEG
recording of Jerbi et al. was higher gamma synchronization (~65-135 Hz). The reason
for this frequency difference is attenuation of higher gamma frequency in scalp EEG
recordings, described as a ‘low-pass filtering effect’ in the scalp (Jerbi et al., 2009).
Saccadic spike potentials are contributed by the yoke muscles. That is, during horizontal
saccades, both abducting lateral rectus and adducting medial rectus muscles contribute to
the SP. Previously it was thought that the lateral rectus muscle is the entire source of the
spike potentials (BLINN, 1955). But Thickbroom and Mastaglia recorded SP from both
outer and inner canthi and have concluded that both the lateral and medial recti contribute
to the SP. However, the contribution from the lateral rectus is said to be greater than the
medial rectus (Thickbroom and Mastaglia, 1985). If SP are caused by recruitment of the
motor units in the extrocular muscles, then it can be expected that there is equal
innervation of agonist muscles, as per Hering’s law.
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5.4.3 Duration of Saccade Related Gamma Synchronizations
Averaged gamma synchronization of the DBS and scalp EEGs began ~ 50-60 ms prior to
saccade onset and lasted ~ 80-120 ms after initiation of the eye movement (See Figure
23). The average duration of post-saccadic gamma synchronization is slightly longer than
the time taken to complete the saccade. This finding is different from what was observed
in the past. Thickbroom and Mastaglia reported that SP begin 14-30 ms before eye
movement onset, with duration of 18-32 ms. Peak amplitude was reached ~ 7.5 ms
before the saccade onset, which was followed by rapid decline in the amplitude
(Thickbroom and Mastaglia, 1985).
The reason why this potential did not last for the entire duration of saccade in that study
was not clearly explained. However, it was postulated that the SP represent compound
action potential of highly synchronized motor neurone volley of the extraocular muscles
and hence it is a discrete potential that last for only a short duration (Thickbroom and
Mastaglia, 1985). Contrary to this, we noticed that the gamma ERS began a few ms
earlier (~ 50-60 ms) and lasted for the entire duration of the saccade in our study. The
reason for this may be because we a used different method (Matlab) to analyze the
saccade related scalp EEG and DBS LFPs. The rapid decline in the SP following saccade
onset observed by Thickbroom and Mastaglia is thought to be due to progressive
desynchronization of the motor unit discharge.
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Both our study and the one by Thickbroom and Mastaglia, there was a definite time
interval between SP and saccade onset. SP consistently began earlier that the averaged
eye movement onset. This delay has been explained because of the generation of
maximal tension in the ocular muscles which is required to overcome the visco-elastic
forces in the orbit (Thickbroom and Mastaglia, 1985).
5.4.4 High versus Low Gamma Synchronizations
The spectral frequency of the SP was found to vary in relationship to the eye movement.
As described above, the SP began clearly a few ms before the saccade onset. At the time
of the eye movement, there was a transient synchronization at high gamma frequency (up
to 210 Hz) lasting for less than half the duration of the saccade, which is followed by low
gamma activity (< 50 Hz) (see Figure 20). This short duration high gamma ERS, and the
subsequent low gamma ERS could represent the step (phasic) and pulse (tonic)
innervations of the agonist extraocular muscles. As explained previously in the
introduction under the neurophysiology of saccades, a pulse of innervation is a high-
frequency burst of the agonist motoneurons, which moves the eye rapidly from one point
to another against the viscous drag of the orbit. The tonic innervation of the agonist
motoneurons holds the globe in the new orbital position, resisting the orbital elastic force
that tends to rotate the eye back to the orbital mid position. During saccades, a neural
network mathematically integrates the pulse (eye velocity command) into the step (eye
position command).
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The saccadic pulse height corresponds to the firing rate, and is an eye velocity command.
Thus, a decrease in saccadic pulse height results in ‘slow saccades’ and if there is an
abnormality in the step (tonic) innervation, the new eye position cannot be maintained
and the eye slowly drifts towards the mid-orbital position (Bahill et al., 1978). The
saccade related high gamma synchronization observed in the DBS and scalp EEG
contacts may correspond to the saccadic pulse innervations (rapid firing rate) during
execution of the saccade. Interestingy, this high gamma oscillation is short lasting with
duration of about 30 ms. This is consistent with the saccadic peak velocity, which is
attained between 1/3 and ½ distance of the saccadic eye movement (Smit et al., 1987).
The low gamma activity that follows this is probably caused by the step (tonic)
innervation of the extraocular muscle motoneurons, which is responsible for holding the
eyes in the new position after the completion of the saccades. This also explains why the
average duration of gamma ERS is longer than the duration required to complete the
saccade. Typically it takes 30 to 100 ms to complete saccades of 0.5° to 40° amplitude
(Smeets and Hooge, 2003). From Figure 23 showing the grand average of all subjects, it
is evident that the gamma ERS began ~ 50-60 ms prior to saccade onset and lasted ~ 80-
120 ms after initiation of the eye movement. This time is longer than the time taken to
complete saccades of 20° amplitude.
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5.4.5 Relationship between Spike Potentials and Magnitude of
Saccades
The incidence of gamma ERS was less in STN subjects with hypometric saccades,
especially STN # 2 and 3. This is obvious from the raw data displayed in Table # 2. The
reason for this may be the small amplitude of the saccade which influences SP amplitude.
In the earlier study by Thickbroom and Mastaglia, the onset to peak of the SP amplitude
was unaffected by saccades of varying sizes between 10° and 40° (Thickbroom and
Mastaglia, 1985). Following this, Doig and Boylan studied the SP amplitudes in normal
subjects for a range of horizontal saccades (5°, 10°, 20° and 40°). In contrast to the
earlier observation, this study has shown there is an increase in the SP amplitude between
10° and 40° saccades (Doig and Boylan, 1989).
5.5 Surface EEG Gamma Oscillations caused by Nuchal
Musculature
Gamma oscillations in the scalp EEG are not contaminated by extraocular muscle spike
potentials alone. Recently, Pope et al. studied scalp EEG gamma activity in healthy
volunteers before and after complete neuro-muscular paralysis using cisatracurium. This
study has concluded that the noise in the circumferential scalp EEG electrodes seen
before administration of the paralysant was abolished after. This noise arises from the
neck muscles and the corresponding spectral power is in the gamma range (Pope et al.,
2009).
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The scalp EEG recorded during slow-phase of left VOR in our subject shows gamma
oscillations in the central-right channel (C4) more than central-left channel (C3) (Figure
26). This gamma activity is probably caused by the contraction of the right
sternocleidomastoid muscle which turns the face to the left and hence is more prominent
in the right side (C4) than the left (C3). Of note, saccadic spike potentials recorded from
the scalp in our study generally had the tendency to vanish in the contacts C3 and C4,
which are further away from the ocular globes and extraocular muscles.
5.6 Gamma Oscillations – Facts versus Artifacts
We believe that the existence of real gamma oscillations in the cortical and subcortical
structures described in the past is undisputable. As mentioned above, gamma
synchronizations have been described during several functional domains using depth
electrode recordings. Gamma oscillations have been documented from various cerebral
regions during cognitive tasks (Tallon-Baudry et al., 2005) without skeletal motor or
ocular motor activity.
With our study, we are able to conclude that during saccadic tasks the DBS LFPs and
surface EEG signals are dominated by spike potentials that originate from the extraocular
muscles. Apart from SP, scalp EEG and DBS LFPs can also be masked by
electromyographic artifacts arising from neck as well as facial muscles. The challenge is
to remove the myogenic artifacts when analyzing EEG or LFP signals. As the EMG
activity has spectral properties similar to gamma oscillations, this becomes more
important in studies that analyze gamma synchronizations during any specific tasks, more
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so if the task involves saccadic eye movements or any skeletal motor movement closer to
the recording site (eg. movement in the facial or neck muscles). Bardouille et al. studied
eyeblink related activity using magnetic encephalography and noticed that there were
oscillations in the gamma range 150 ms after the onset of the blink and lasting for about
400 ms (Bardouille et al., 2006). This gamma activity corresponded to period of eye
closure and hence thought to originate from the contraction of orbicularis oculi muscles.
We were unable to subtract the EOG channel potentials from the DBS LFPs and surface
EEG channels to determine the presence of true central neural gamma activity during
saccades. Hence, this became a major limitation of our study. But from our study and
other studies reported in the past (Yuval-Greenberg and Deouell, 2009;Jerbi et al., 2009),
it is clear that the gamma oscillations recorded from surface EEG, iEEG and DBS LFPs
can be dominated by extraocular muscle spike potentials and EMG potentials and the
data need to be analyzed carefully. For studies other than saccades, such as visual,
cognitive or limb movement tasks, these studies warrant the need to instruct the subjects
to avoid unnecessary eye or other facial/neck movements, and for investigators to
monitor them.
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5.7 Saccade Metrics
Saccade reaction time depends on various factors such as the age, attention, and
motivation of the subject as well as size, luminance, contrast, complexity and
predictability of the target. Figure 27 shows the saccadic latencies for prosaccades and
antisaccades (average of STN # 4, 5 and 6). Saccadic latencies are longer in antisaccades
compared to prosaccades. The reason for this longer latency is because of the time taken
to voluntarily suppress a prosaccade towards the target and execution of an eye
movement in the opposite direction.
Figure 28 compares the saccadic latencies in gap and overlap (no gap) paradigms during
prosaccades. When compared to the overlap paradigms SRTs are roughly 100 ms lesser
in the gap paradigms, beginning around 100 ms after the illumination of the target light.
This decreased saccadic reaction time in gap paradigms (termed express saccades) is
consistent with the past finding (Fischer and Ramsperger, 1984;Fischer and Ramsperger,
1986). Figure 29 shows no difference between the saccadic latencies between gap and
overlap paradigms in antisaccade tasks. This is also consistent with past observation
(Fischer and Weber, 1997).
5.8 Saccade Related Beta Desynchronizations
Wavelet spectrograms of the DBS LFPs showed event (saccade) related desychronization
(ERD) in the alpha and beta frequency (8 – 30 Hz). Alpha-beta ERD was observed in
STN, GPi and Vim regions during saccadic eye movements, although this finding was
not observed as frequently as the gamma ERS. Even though the beta ERD is an
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inconsistent finding, ERD was observed in the bipolar derivations of the wavelet
spectrograms of the DBS LFPs, which strongly suggest the origin of these potentials to
be the DBS contacts (and thus not a far-field potential). So, unlike the gamma ERS
caused by extroaocular SP, beta ERD are true potentials recorded from the target site
(STN, GPi or Vim). The incidence of beta ERD is displayed in Tables 4 and 5.
When compared to saccade related gamma synchronizations, the duration of the beta
ERD was longer. Figure 30 shows an example of beta ERD in Vim patient # 1, during an
antisaccade block. When present beta ERD, began 500 – 300 ms before the onset of
saccades and lasted for around 500 ms after the initiation of saccades. Average of the
beta ERD across patients was not performed as this was not a frequent finding when
compared to the synchronizations in gamma frequency.
In patients with bilateral DBS such as STN # 3 and 6, beta ERD was bilateral. This
finding is consistent with the past observations of limb movement related beta
desynchronizations recorded from STN (Androulidakis et al., 2007), GPi (Brucke et al.,
2008) and Vim (Kempf et al., 2009). Brown’s model described beta oscillations to be
pathologic and hence are considered to be ‘antikinetic’ (Brown, 2003). LFPs from STN
and GPi studied during self-paced limb movements, showed the magnitude of the beta
ERD to be greater in an ON state (experiments done when patients were on Levodopa).
If beta synchronization is pathological and inhibits movements, then beta
desychronization is considered a physiological pattern of motor processing which
144
enhances limb movement. Thus, presence of beta desynchronization during a saccade,
may imply a similar physiological process that promotes eye movements.
In one Vim subject (Vim # 1), beta ERD began earlier for antisaccades when compared to
prosaccades. This early onset of the beta ERD in the Vim during antisaccades, may
suggest more activation of the motor thalamus during antisaccades, which was recently
observed by Kunimatsu and Tanaka (Kunimatsu and Tanaka, 2010). But this is not a
consistent finding, as beta ERD was not always larger during antisaccade tasks. Despite
the clear presence of the beta ERD during the perisaccadic interval, there are a few
confounding factors which warrant further investigation in this interesting finding. Most
importantly, occurrence of beta ERD was infrequent. Also, beta ERD appeared similar in
the STN, GPi and Vim. One possible explanation for this is the coherence of the LFP
oscillations in these regions. Kempf et al. studied LFPs from Vim and GPi regions
simultaneously and observed strong thalamo-pallidal coherence during self-paced limb
movements (Kempf et al., 2009). This being said, the coherence between LFPs in the
STN and thalamus needs to be explored.
One more interesting finding is the presence of beta desynchronizations in more than one
bipolar channel. Figure 30 is a good example for this, which shows saccade related beta
desychronizations in R3-R2 and R1-R0 channels and absent in the middle bipolar channel
(R2-R1). The reason for this is unclear. Also, beta ERD was seen in more than one
bipolar derivation during different blocks in the same patient, which suggested that
stronger desynchronization is localizing to more than one contact in the same patient on
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the same side. Sometimes, saccade related desychronization is not limited to beta
frequency but also extends to the gamma frequency (> 30Hz). There is no physiological
explanation for this finding, as beta and gamma oscillations are thought to have opposite
effects on somatomotor control. To determine the significance of the beta
desynchronization, more detailed analysis (Spike and Matlab) is required through
recruitment of more patients and increasing the number of saccadic trials in each block.
6 STUDY LIMITATIONS
Our study had several advantages: 1. We analyzed our data using two different
techniques (Spike 2 and Matlab) and had similar results, 2. We were able to recruit good
number subjects (with STN, GPi and Vim DBS) as the research work was conducted in a
large center that is renowned for DBS surgeries, 3. Compared to previous studies (Jerbi et
al., 2009;Yuval-Greenberg and Deouell, 2009) where subjects performed sentence
reading paradigms or eye tracking while visualizing a target, to our knowledge our study
is the first one to analyze visually-cued saccadic tasks using different paradigms. But
there were a few limitations to our study. The major one was the inability to subtract the
extraocular muscle spike potentials as well as EMG from the DBS LFPs and scalp EEG.
Saccadic tasks were performed a day or two after the DBS insertion (in the inter-
operative interval) and some of the patients were sleepy from lack of sleep on the night of
the surgery.
Pain and drowsiness from pain medications were also confounding factors in some
patients, especially during antisaccade tasks which require voluntary suppression of the
146
prosaccade and looking away from the target cue in the opposite direction. As evident
from the data tables (Table 2 and 3) the number of correct antisaccades was less than
correct prosaccades. Our recordings were done in the immediate post-operative period
and LFPs recorded from the DBS contacts can be affected by the edema surrounding the
electrodes.
7 CONCLUSIONS
Saccade related potentials recorded in the STN, GPi and Vim regions are spike potentials.
Spike potentials are of myogenic origin, which are hypothesised to be summated
electrical activity from the near synchronous recruitment of the motor units in the extra-
ocular muscles. The short and fast variations in the spike potential power spectrum
results in energy in the gamma frequency range. Intracerebral depth electrode recordings
and local field potentials recorded from DBS contacts had been assumed to be immune to
far field potentials. Our study is the first one to prove that spike potentials from the
extraocular muscles can generate and account for the local field potentials recorded from
DBS contacts far away from the ocular globes.
Apart from spike potentials, remote electromygraphic potentials from neck or facial
movements can generate the DBS LFPs. This warrants careful analysis of LFP data,
especially if gamma oscillations are studied. Magnetic encephalographic study has
shown contraction of orbicularis oculi (eyeblink) to cause gamma oscillations. It will be
interesting to study eyeblink artifacts by recording DBS LFPs with triggers placed to
voluntary eyeblinks.
147
Bilateral beta desynchronizaton during saccadic eye movements is an interesting finding
in our study. The presence of beta desynchronization in bipolar derivations suggests that
these are not far field potentials. The duration of the beta ERD is longer than the duration
of the saccade, the reason for this being unclear. In one Vim patient, saccade related beta
desynchronization occurred earlier during antisaccades than prosaccades. This may
suggest more activation of the motor thalamus during antisaccades than prosaccades.
Unfortunately, saccade related beta desynchronizations are not observed frequently in our
study and hence require recruitment of more subjects.
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8 SYNOPSIS
Saccades are quick eye movements that place the object of interest in the centre of gaze.
Gamma (31–200 Hz) oscillations of local field potentials occur in the basal ganglia and
thalamus during limb movements, but had not been studied during saccades. ‘Spike
potentials’ from extraocular muscles have been recorded from surface
electroencephalogram potentials, especially in the gamma frequency. But local field
potentials recorded from intracranial depth electrodes had been assumed to be not
affected by such remote conduction potentials from extraocular muscle activity. Deep
brain stimulation surgery provides an opportunity to record local field potentials in the
basal ganglia and thalamus during saccades.
We recorded local field potentials during deep brain stimulation in eleven patients while
they made saccades: 6 recordings were in the subthalamic nucleus of patients with
Parkinson’s disease; 3 in the globus pallidus interna of patients with dystonia; and 2 in
the ventralis intermedius nucleus of the thalamus of patients with essential tremor.
Subjects performed visually-cued horizontal saccades while local field potentials from
quadripolar deep brain stimulation electrodes, scalp electroencephalograms, and
electrooculograms were recorded. Saccade onsets were selected and averaged from
electrooculograms, and aligned to gamma band-pass filtered local field potentials.
Averaged wavelet spectrograms of local field potentials, scalp electroencephalograms
and electrooculograms were generated, showing the time-frequency relationship during
target light illumination and eye-movement onset; event-related gamma synchronizations
were compared to baseline without eye motion.
149
Event-related gamma synchronizations were recorded at and after saccade onset in the
subthalamic nucleus, globus pallidus interna and ventrointermediate nucleus of the
thalamus, and in scalp electroencephalograms; but were absent during target light
illumination without saccades. Gamma waves were consistently bilaterally symmetric in
all deep brain stimulation contacts, during both rightward and leftward saccades.
Wavelet spectrograms from deep brain stimulation local field potentials, frontal
electroencephalograms and electrooculograms appeared identical. Eye-movements
recorded during vestibulo-ocular reflex smooth eye motion in one patient undergoing
subthalamic nucleus recording reproduced similar event-related gamma synchronizations,
suggesting that it originated from extraocular muscle spike potentials.
Bilaterally symmetric event-related gamma synchronizations recorded during eye
movements in both horizontal directions from all deep brain stimulation contacts,
similarity of event-related gamma synchronizations between the deep brain stimulation
local field potentials and frontal electroencephalogram, and event-related gamma
synchronizations during vestibular smooth eye motion provide evidence for their origin
from extraocular muscle spike potentials rather than central neural activity. Event-related
gamma synchronizations recorded from electrooculogram channels also confirm this as a
‘gamma imposter’ arising from ocular muscles.
This study is the first to demonstrate that spike potentials from the extraocular muscles
can generate and account for the local field potentials recorded from deep brain
150
stimulation contacts far away from the ocular globes. This warrants careful analysis of
local field potential data, especially if gamma oscillations are studied.
Apart from saccade-related gamma synchronizations, we also observed
desynchronizations in the beta frequency on bipolar derivations. Even though they are an
inconsistent finding, their presence in the bipolar derivations suggest the origin of these
potentials to be the deep brain stimulation contacts and thus not a far field potentials. But
the occurrence of the event-related beta desynchronization was infrequent and hence
more detailed analysis through recruitment of more patients and increasing the number of
saccadic trials in each block are required to determine the significance of this interesting
additional finding.
151
9 ACKNOWLEDGMENTS
I extend my sincere gratitude to Dr. James Sharpe, who has been an extremely supportive
supervisor for my Master’s programme and clinical Neuro-Ophthalmology fellowship;
and my co-supervisor Dr. William Hutchison for his tremendous mentorship and
guidance during the Master’s degree programme. I am grateful to Dr. Robert Chen, my
MSc program advisory committee member, for his valuable feedbacks and academic
advice. Patient data were collected in Dr. Robert Chen’s laboratory.
I thank Mr. Utpal Saha, Mr. Eric Tsang, and Dr. William Hutchison who helped with data
collection, and Dr. Kaviraj Udupa and Mr. Luka Srejic for their help with statistical
analysis. I also thank my lab mates Mr. Luka Srejic and Mr. Ian Prescott for their
collegial help and guidance in thesis preparation.
I acknowledge the financial support of the Vision Science Research Program (VSRP) at
University of Toronto and Fight for Sight. I am thankful to Dr. William Hutchison who
provided an additional financial assistance to support the completion my project.
I thank my wife and my daughters for their enormous moral support and my parents for
all their difficulties in supporting my medical school and post-graduation education.
Last, but not the least, I extend my sincere thanks to my brother Mr. Ashok Sundaram,
who has made many sacrifices for my career.
152
This work was supported by Vision Science Research Program Award (University of
Toronto, Toronto, Canada) and a Fight For Sight Fellowship Award, USA.
153
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