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).

7

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.

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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).

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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.)

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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

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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

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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

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(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

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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

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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

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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.

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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

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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

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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.

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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.

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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.

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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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