Brain Advance Access published online on November 26, 2008
Brain, doi:10.1093/brain/awn306
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Vergence deficits in patients with cerebellar lesions
1Department of Neurology, University Hospitals Schleswig-Holstein, Campus Lübeck, Ratzeburger Allee 160 and 2Institute of Neuroradiology, University Lübeck, D-23538 Lübeck, Germany
Correspondence to:
Thurid Sander, MD, Department of Neurology, University Hospitals Schleswig-Holstein, Campus Lübeck, Ratzeburger Allee 160, D-23538 Lübeck, Germany. E-mail: thurid.sander{at}neuro.uni-luebeck.de
 |
Summary |
|---|
 Top Summary IntroductionMethodsResultsDiscussionReferences |
|---|
The cerebellum is part of the cortico–ponto–cerebellar circuit for conjugate eye movements. Recent animal data suggest an additional role of the cerebellum for the control of binocular alignment and disconjugate, i.e. vergence eye movements. The latter is separated into two different components: fast vergence (to step targets) and slow vergence (to ramp and sinusoidal targets). The aim of this study was to investigate whether circumscribed cerebellar lesions affect these dynamic vergence eye movements. Disconjugate fast and slow vergence, conjugate smooth pursuit and saccades were binocularly recorded by a scleral search coil system in 20 patients with acute cerebellar lesions (all ischemic strokes except for one) and 20 age-matched healthy controls. Patients showed impairment of slow vergence while fast vergence was unaffected. Slow vergence gain to sinusoidal targets was significantly reduced, both in convergence and divergence direction. Divergence but not convergence velocity to ramp targets was reduced. Conjugate smooth pursuit eye movements to sinusoidal and to step-ramp targets were impaired. Patients had saccadic hypometria. All defects were particularly expressed in patients with vermis lesions. In contrast to recent animal data fast vergence was not impaired in any of our patient subgroups. We conclude that (i) the human cerebellum, in particular the vermis, is involved in the processing of dynamic vergence eye movements and (ii) cerebellar lesions elicit dissociable effects on fast and slow vergence.
Key Words: fast vergence; slow vergence; divergence; vermis
Abbreviations: FEF, frontal eye field; FOR, fastigial oculomotor region; IP, posterior interposed nucleus; MST, medial superior temporal area; NRTP, nucleus reticularis tegmenti pontis; SEF, supplementary eye field; SE, standard error; SPEM, smooth pursuit eye movements
Received June 30, 2008. Revised September 22, 2008. Accepted October 21, 2008.
|
Introduction |
|---|
|
TopSummaryIntroductionMethodsResultsDiscussionReferences |
|---|
Neurologists usually use eye movements at the bedside as a sensitive parameter for topodiagnostic localization and pathophysiological understanding of involuntary eye movements (Leigh and Zee, 2006
; Ramat et al., 2007). Clinical textbook knowledge is usually related to conjugate eye movements, i.e. movements that rotate the eyes simultaneously in the same direction by about the same amount in frontoparallel planes. Unlike those conjugate movements, vergence eye movements refer to eye movements that rotate the eyes simultaneously in the opposite direction (disconjugate eye movements). Frontal-eyed human and non-human primates use the vergence system to track a moving target in sagittal planes or to change the gaze point in depth. To track a target in 3D space both systems have to be coordinated. Under natural viewing conditions, shifts of the point of fixation usually combine vergence and saccade movements.
Neurons in the medial superior temporal visual area (MST), the supplementary eye field (SEF) and the frontal eye field (FEF) are active during either smooth pursuit or vergence eye movements or their combination (Fukushima et al., 2004; Akao et al., 2005a, b). MST and the caudal FEF neurons are likely to be involved in the initiation of vergence eye movements. There is some evidence that smooth pursuit and vergence eye movements are processed separately in the brainstem (Mays et al., 1986), and neurons discharging during divergence and convergence are also anatomically separated (Gamlin, 2002). One downstream pathway from the caudal FEF reaches the nucleus reticularis tegementi pontis (NRTP) (Suzuki et al., 1999). NRTP also receives input from superior colliculi and pretectal midbrain areas and projects to the deep cerebellar nuclei. There is some evidence from animal experiments that NRTP is involved in the cortico-ponto-cerebellar circuits for disconjugate eye movements (vergence) (Gamlin and Clarke, 1995; Gamlin et al., 1996; Gamlin, 2002).
Like conjugate smooth pursuit and saccadic eye movements, vergence can be distinguished in vergence responses to ramp (slow vergence) and to step (fast vergence) targets. We have recently identified impairment of slow vergence in patients with caudal pontine infarctions involving the NRTP while fast vergence responses to step targets remained unaffected (Rambold et al., 2004). In contrast, upper pontine lesions, which spare NRTP, elicit an additional deficit of fast vergence (Rambold et al., 2005a). These data provide some evidence that (i) pontine nuclei are involved in vergence processing and (ii) fast and slow vergence may be under separate neural control. This is in contrast to the cortical vergence control which does not seem to show dissociable activity to slow and fast vergence (Gamlin and Yoon, 2000; Akao et al., 2005b).
For conjugate eye movements (e.g. smooth pursuit) the pontine nuclei, particularly NRTP, are known to be a crucial precerebellar relay to the cerebellum, particularly the dorsal vermis (Thielert and Thier, 1993). Purkinje cells in the vermis discharge during smooth pursuit and saccadic eye movements in one depth plane (Suzuki and Keller, 1988; Helmchen and Buttner, 1995; Krauzlis and Miles, 1998; Barash et al., 1999; Takagi et al., 2000). There is accumulating evidence that the cerebellum is also involved in the processing of vergence: (i) cerebellar ablation elicits transient paralysis of convergence (Westheimer and Blair, 1973); (ii) patients with degenerative cerebellar disease have impaired binocular alignment (esotropia during binocular viewing) and disconjugate saccadic dysmetria (Versino et al., 1996); (iii) anatomical projections of brainstem areas carry vergence signals to the dorsal vermis and deep cerebellar nuclei (May et al., 1992; Gamlin et al., 1996) and (iv) vermis is activated in humans during the near response (Richter et al., 2004). Recently, vergence related neurons have been recorded in the posterior vermis of monkeys (Nitta et al., 2008a,b). Accordingly, vermis lesions elicited impairment of vergence, static alignment (Takagi et al., 2003), and conjugate smooth pursuit impairment (Nitta et al., 2008a,b). There is some additional evidence that the deep cerebellar nuclei, i.e. posterior interposed (IP) (Gamlin et al., 1996; Zhang and Gamlin, 1998; Gamlin, 1999, 2002) and fastigial nucleus (FOR) (Gamlin and Zhang, 1996; Zhang and Gamlin, 1996; Gamlin, 1999, 2002) are involved in vergence.
The aim of our study was to elucidate the role of the cerebellum in dynamic vergence in patients with acute circumscribed cerebellar lesions. Static misalignments and disconjugate dysmetria have been studied in cerebellar patients (Versino et al., 1996). However, no patient study has examined dynamic vergence yet. We specifically hypothesized that the vermis is implicated in vergence processing and that vermis lesions impair tracking in depth. We examined divergence and convergence as well as slow and fast vergence separately since animal studies and our previous studies in patients with pontine lesions showed selective impairment. As fast and slow vergence are age related (Rambold et al., 2006) we compared patients with age-matched healthy control subjects.
|
Methods |
|---|
|
TopSummaryIntroductionMethodsResultsDiscussionReferences |
|---|
Subjects
Twenty patients (mean age: 54 years, range: 26–81 years) participated in the study. All had an acute cerebellar infarction (<3 weeks after stroke) except for one patient (#13) who had a cavernoma. All subjects gave written informed consent for participation in the study which was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of the University of Luebeck. All patients were clinically examined at the day of recording by two experienced neuro-ophthalmologists (CH, TS). Symptoms and clinical signs of patients are listed in Table 1. Patients had no other history of previous neurological disease affecting the central nervous system. Most of the patients complained about acute gait unsteadiness and dizziness. Ataxia of gait and stance was the leading clinical sign. Neuro-ophthalmological examination revealed cogwheel pursuit in most of the patients. All of them were able to perform vergence eye movements to targets slowly moving towards or away from the patient's nose. None of them had visible cogwheel slow vergence eye movements. Fast vergence responses appeared largely unimpaired in most of the patients. Vision and stereovision (Stereo Optical Co., Inc., Chicago, OH, USA) were examined in all patients as well as the subjective visual vertical. All patients had a visual acuity above 20/25. At the time of eye movement recordings none of the patients had nystagmus or blurred vision any more; there was no clinical evidence for static misalignment, particularly skew deviation. Binocular fusion (Bagolini Test) and stereovision were normal (<100''). All patients had a high resolution MRI scan of the brain (see below).
|
Twenty healthy control subjects (mean age: 54 years, range: 26–81 years) without any previous history of neurological symptoms or diseases participated in the study as controls and were normal on neurological examination. Neither patients nor healthy subjects were on medications known to have side-effects on the central nervous system.
Eye movement recording and stimuli
Binocular eye movements were recorded by a scleral search coil system (Remmel Labs), which has three orthogonal magnetic fields and a frame size of 180 cm. The two eyes were calibrated using a combined off-line in vitro and in vivo calibration based on previous studies (Rambold et al., 2002b, 2004). Using the inter-ocular distance (5.8–7.2 cm) the vergence angles of the stimuli were calculated for each subject individually. The subject's head was comfortably stabilized in a natural upright position with a chin rest and the forehead was kept stationary by a firm head support.
Conjugate eye movements were elicited by a laser stimulus projected on a flat white tangent screen that was 145 cm from the subject's eyes in dark surroundings while vergence stimuli were produced by a laser stimulus projected onto a horizontal plane 3 cm below the level of the eyes and aligned in the patient's midsagittal plane (Rambold et al., 2002b). Due to the slightly lowered stimulus platform eye movements were accompanied by small (vertical) saccades. The laser target (spot diameter: 0.1°, 635 nm) was moved by mirror galvanometers, precise timing was controlled by a PC.
Experimental paradigms
As it was our aim to study the effect of cerebellar lesions on vergence but not saccade–vergence interaction we designed the stimulus to move either in the midsagittal plane or in the frontoparallel plane in order to investigate the subsystems separately. All subjects were examined using the following paradigms: slow and fast vergence, conjugate smooth pursuit eye movements and horizontal saccades. Due to the non-linear relation between target distance and target vergence, we included this non-linearity in the stimulus control in order to elicit constant vergence angle motion. To prevent anticipatory effects the duration of fixation before each trial was varied from 1500 to 2500 ms.
Vergence
(i) Slow sinusoidal vergence was elicited by a sinusoidal moving laser target at 0.12 Hz and 3.6° amplitude (range 4.7–8.3°, peak velocity 1.35°/s). (ii) Slow vergence responses to ramp stimuli of 1.5°/s velocity were elicited in divergence and convergence directions (20 repetitions, pseudorandomized); convergence started at 2.8° vergence angle, divergence at 10.0° vergence angle. (iii) Laser stimuli for divergence and convergence steps were presented with a vergence angle amplitude of 7° moving between 3.0° vergence angle at distance and 10.0° vergence angle at nearness.
Conjugate smooth pursuit
Conjugate smooth pursuit eye movements were elicited by a sinusoidal slowly moving target (0.2 Hz, ± 25°amplitude). Smooth pursuit initiation was tested by a step ramp smooth pursuit paradigm (Carl and Gellman, 1987; Helmchen et al., 2003). Each sequence consisted of 10 foveopetal pursuit step-ramps (3° step, opposite to ramp direction, 20°/s ramp velocity) to either side, presented in a random order.
Conjugate saccades
Conjugate horizontal saccades of 10° and 20° amplitude were performed to either side in a pseudorandomized order (four repetitions per direction and each amplitude), starting from gaze straight ahead, i.e. 10 centrifugally and 10 centripetally.
Data analysis
Eye movements were recorded unfiltered by a 16-bit AD converter (NI PCI 6033E) at a sampling rate of 600 Hz. After calibration all position data were filtered by using a 100 Hz (3-dB value) Gaussian filter (Matlab, The Math-Works, Natick MA, USA). Horizontal disparity vergence was calculated as left minus right horizontal eye position, horizontal version eye position was calculated as cyclopean eye (average of left and right eye position). Positive values indicate rightward, upward, or convergence movement direction and negative values indicate leftward, downward, or divergence movement direction of the eyes. Slow eye movements (sinusoidal vergence and version, ramp stimuli) were analysed using de-saccaded and linearly interpolated eye velocity signals.
Analysis of sinusoidal vergence was performed after applying a 20 sample median filter and a 30 Hz Gaussian filter. Vergence gain was calculated as the ratio of best fitted vergence velocity to target velocity.
Slow vergence to ramp stimuli were analysed by using mean eye velocity values (filtered by 30 sample median filter and 20 Hz Gaussian filter) for each direction; in order to detect peak acceleration multiple linear regressions were calculated consecutively for 600 ms beginning at ramp onset. The slope of the regression with the highest slope and lowest Euclidian distance was defined as peak acceleration. The intersection of the regression line with zero was defined as latency. The analysis was controlled and adjusted interactively if required. Mean vergence velocity was quantified over the period of 600–4000 ms. For the ramp stimuli means of individual responses were derived from averaged data (control: 13 trials, median, range 10–20; patients: 14 trials, median, range 9–20).
Fast vergence to step target trials were analysed by using filtered vergence velocity (four sample median filter, 70 Hz Gaussian filter) on a trial by trial basis similar to the saccade analysis (see below).
Conjugate smooth pursuit eye movements were analysed offline using an interactive program. Eye position data were low pass filtered by a 50 Hz Gaussian filter. Pursuit eye velocity was calculated by differentiating the mean eye position of the eight data points (equivalent 13.3 ms) before and the eight data points (equivalent 13.3 ms) after that given data point. Sinusoidal smooth pursuit velocity gain was calculated similar to sinusoidal vergence velocity. Step-ramp latency, initial acceleration and steady state velocity (interval 400–800 ms) were analysed as reported previously (Carl and Gellman, 1987; Helmchen et al., 2003). The gain was calculated by the ratio of eye velocity to target velocity.
Saccades were filtered by a 100 Hz Gaussian filter (–3 dB) and pre-detected automatically using velocity threshold of 30°/s and subsequently searching for peak velocity in a time window of 50 ms. Begin and end of saccade were detected at the level of 20°/s. All computerized saccade detections were controlled and adjusted manually if required.
Mean data are given with standard error unless otherwise stated. Dependent variables were analysed by analysis of variance (ANOVA), including a within-subject factor direction (convergence, divergence) and a between-subject factor group (patient, control). For post-hoc comparison of two groups or conditions Student's t test was performed. Statistics was applied using SPSS package (SPSS 15.0.1, SPSS Inc., Chicago, IL, USA), statistical significance was considered at P-values <0.05.
Subjects
We compared mean data of oculomotor parameters between cerebellar patients and controls. Based on our specific a priori hypothesis we also analysed patients with (n = 11) versus those without (n = 9) vermis lesions. Due to the low number of patients with floccular lesions (n = 3) statistical comparison was not possible. There was a large overlap of patients with vermis and deep cerebellar nuclei lesions (n = 9). However, seven patients had vermis sparing lesions of the deep cerebellar nuclei, which were compared to controls.
MRI scanning and anatomical reconstruction
High-resolution MRI was performed with an MRI unit (1.5-T Siemens Magnetom Symphony; Siemens, Erlangen, Germany) using a contrast-enhanced T1-weighted spin-echo and a T2-weighted turbospin-echo sequence with a slice thickness of 3 mm.
Vascular supply assignment was conducted according to previously validated MR anatomic templates (Tatu et al., 1996). Lesions were systematically analysed by one experienced neuroradiologist irrespective of and blinded for the clinical data. They were reconstructed according to the appropriate axial and sagittal sections of the MRI atlas of the human cerebellum (Schmahmann et al., 2000) (Fig. 1). Analysis was focused on specific regions (e.g. flocculus, uvula/nodulus, deep cerebellar nuclei and posterior vermis, see Table 2) with respect to regions potentially involved in the control of vergence.
|
|
|
Results |
|---|
|
TopSummaryIntroductionMethodsResultsDiscussionReferences |
|---|
Lesion data
Ischemic strokes were confined to the cerebellum. Sixteen out of 20 patients had an infarction in the territory of the posterior inferior cerebellar artery (PICA; 11 left-sided, 5 right-sided lesions), five patients suffered from an infarction in the territory of the superior cerebellar artery (SCA, four right-sided, one left-sided); one (#5) of these patients had a combined unilateral SCA and PICA infarction, another patient bilateral infarctions (PICA, SCA, #4, Table 2). Affected regions of interest with respect to the control of smooth pursuit and vergence eye movements are listed in Table 2. Eleven patients had lesions involving the vermis while nine patients had vermis sparing lesions. Sixteen patients showed lesions of the deep cerebellar nuclei, nine of them combined with vermis lesions and seven with vermis sparing lesion of the deep cerebellar nuclei.
Eye movements
Eye movement data will be presented in the sequence of the following comparisons: (i) patients versus healthy control subjects, (ii) subgroup analysis of patients with vermis versus vermis sparing cerebellar lesions, (iii) patients with vermis sparing lesions of the deep cerebellar nuclei versus healthy controls.
Comparison of patients versus healthy control subjects
Disconjugate eye movements
Slow vergence
In sinusoidal vergence tasks patients showed significantly smaller slow vergence gain (0.76 ± 0.03, T(27) = 3.33, P < 0.01) than age-matched control subjects (0.89 ± 0.03) (Fig. 2, Table 3). There was no difference between the phase shift of patients and controls (controls = 5.97 ± 0.94, patients = 8.77 ± 2.00, T(27) = –1.12, P = 0.273) during sinusoidal vergence responses. Slow vergence gain was calculated for each direction separately. Analysis of variance with between-subject factor GROUP and within-subject factor DIRECTION revealed a main effect of DIRECTION [F(1,27) = 5.19, P = 0.031] but no interaction of GROUP x DIRECTION. A post-hoc t test showed no directional gain asymmetry in patients (gain convergence: 0.77 ± 0.03, gain divergence: 0.75 ± 0.03, P = 0.49). For illustration, Fig. 2 shows original recordings of sinusoidal slow vergence eye movements of one patient (A, #17) and a control subject (B).
|
|
In the ramp paradigm analysis of variance (ANOVA) on mean vergence velocity revealed no effect of DIRECTION but a significant interaction of DIRECTION x GROUP [F(1,26) = 4.39, P < 0.05]. Post-hoc t tests showed a reduced mean vergence velocity in divergence (1.33 ± 0.05°/s, T(27) = 2.90, P < 0.01) but not in convergence direction (1.51 ± 0.06°/s), when compared with the control subjects (divergence: 1.55 ± 0.06°/s, convergence: 1.55 ± 0.05°/s) (Fig. 3). There was some variability of vergence velocities (even in healthy controls) but most individual patients had reduced divergence (but not convergence) velocity compared to the control subjects. Even when comparing individual velocities for convergence and divergence there was a consistent reduction of divergence in most patients.
|
Analysis of variance for slow vergence latency and acceleration of DIRECTION (convergence, divergence) and between subject factor GROUP (patient, control) showed a significant main effect for DIRECTION (P always < 0.001) but no interaction. Acceleration of divergence (div.) responses to ramp stimuli were smaller compared to convergence (conv.), both in controls (div.: 10.42 ± 0.87°/s2; conv.: 13.38 ± 0.91°/s2) and patients (div.: 9.47 ± 0.81°/s2; conv.: 14.23 ± 1.34°/s2). However, there was no difference between controls and patients in any direction. There was also no latency difference between controls and patients, neither in convergence nor in divergence (Table 3).
Fast vergence
Group comparison of vergence responses to step targets (fast vergence) did not show significant differences between patients and control subjects with respect to latency, gain, peak velocity, neither for convergence nor for divergence (Fig. 4, Table 3). Accompanying small vertical saccades during vergence steps showed vertical and horizontal disjunctive components. The part of the vertical disjunctive component on the vertical amplitude was 3.49 ± 1.57% and of the horizontal disjunctive component 6.53 ± 2.17% (Versino et al., 1996).
|
Conjugate eye movements
Smooth pursuit
Patients showed significantly lower smooth pursuit velocity gain (0.78 ± 0.04) than control subjects (0.94 ± 0.01, T(17) = 3.62, P < 0.01) (Fig. 5A) and a significant increased phase shift during sinusoidal smooth pursuit (patients = 4.05 ± 0.70, controls = 1.67 ± 0.46, T(18) = –2.70, P = 0.015). Initial acceleration of smooth pursuit in the step-ramp paradigm was decreased in all patients (39.79 ± 4.03°/s2, T(18) = 4.94, P < 0.001) when compared with control subjects (79.15 ± 7.33°/s2) (Fig. 5B). Latency of smooth pursuit in the step-ramp paradigm was significantly prolonged in patients (231.95 ± 12.33 ms) versus controls (165.77 ± 4.80 ms, T(18) = –4.61, P < 0.001) (Fig. 5C). Steady state velocity pursuit gain was significantly smaller in patients (0.68 ± 0.06) than in control subjects [0.86 ± 0.35, T(18) = 2.35, P = 0.03].
|
Saccades
Since amplitude gain did not differ between 10° and 20° target amplitudes data were pooled. Patients showed hypometria with a significantly lower saccade gain (0.81 ± 0.02) than control subjects [0.91 ± 0.01, T(2,25) = 4.01, P = 0.001] (Fig. 5D).
Comparison of patients with versus patients without vermis lesion
Slow vergence
In sinusoidal vergence tasks there were significant differences between patients with and without vermis lesions, when compared with controls [F(2,28) = 6.25 P < 0.01]. In post-hoc tests, patients with vermis lesions (0.73 ± 0.05) but not patients without vermis lesions (0.79 ± 0.03) had significantly lower slow vergence gain when compared to controls (P < 0.01). Patients without vermis lesions did not significantly differ from controls (Fig. 6A). In a subgroup ANOVA of mean vergence velocity in the ramp task, mean divergence velocity was different between the three groups [F(2,28) = 6.07, P < 0.01]. Post-hoc analysis showed significant differences between patients with vermis lesions (1.23 ± 0.09°/s) compared to controls (P < 0.01) while those without vermis lesions (1.40 ± 0.04°/s) did not differ from controls (Fig. 6B). In contrast, there was no difference for mean convergence velocity between these subgroups. Unlike the group of all patients, latency of divergence response to ramp stimuli was significantly longer in patients with vermis lesions (205.23 ± 22.3 ms) than in controls [147.36 ± 9.95 ms, T(17) = –2.72, P = 0.01] (Fig. 6C). Patients with vermis sparing cerebellar lesions (152.59 ± 15.40 ms) did not differ from controls.
|
Fast vergence
Group comparison of vergence responses to step targets (fast vergence) did not show significant differences between patients with and without vermis lesions (Table 3).
Conjugate smooth pursuit
Subgroup ANOVA showed a significant difference in sinusoidal conjugate smooth pursuit gain between the groups [F(2,18) = 7.37, P < 0.01]. Patients with vermis lesions (0.74 ± 0.06) had significantly lower smooth pursuit velocity gain than controls (P < 0.01) while patients without vermis lesions (0.81 ± 0.05) did not differ from controls (0.94 ± 0.01).
Subgroup analysis (ANOVA) of smooth pursuit in the step-ramp paradigm revealed that the initial acceleration of both, patients with vermis [37.42 ± 3.90°/s2, F(2,19) = 11.92, P = 0.001] and those with vermis sparing cerebellar lesions (43.95 ± 9.32°/s2, P = 0.01) was significantly reduced compared to healthy controls (79.15 ± 7.33°/s2). Subgroup ANOVA of smooth pursuit latency showed a significant difference when both patient subgroups [F(2,19) = 10.66, P = 0.001] were compared with controls. Patients with (226.31 ± 15.6 ms, P < 0.01) and without (241 ± 22.20 ms, P < 0.01) vermis lesions did not differ in latency.
Conjugate saccades
Saccadic hypometria was found in both patients with vermis lesions and patients with vermis sparing cerebellar lesions. The subgroup analysis revealed a difference between controls and both subgroups of cerebellar patients [F(2,26) = 8.36, P < 0.01]. Both patient subgroups had a lower saccadic gain than control subjects [patients with vermis lesion (0.82 ± 0.02, P = 0.01); patients with vermis sparing cerebellar lesions (0.81 ± 0.04, P < 0.01)].
Comparison of healthy control subjects and patients with vermis sparing lesions of the deep cerebellar nuclei
Slow vergence
In sinusoidal vergence tasks mean vergence gain did not differ between healthy controls and patients with vermis sparing lesions of the deep cerebellar nuclei [T(17) = 1.72, P = 0.10; controls 0.90 ± 0.03, patients 0.82 ± 0.03].
There were no significant differences in the mean vergence velocity in the ramp task between healthy controls and patients with vermis sparing lesions of the deep cerebellar nuclei (n = 7), neither for convergence [T(17) = 0.12, P = 0.86; controls 1.55 ± 0.05°/s, patients 1.53 ± 0.07°/s] nor for divergence [T(17) = 1.61, P = 0.13; controls 1.55 ± 0.06°/s, patients 1.42 ± 0.04°/s].
Comparison between slow conjugate and disconjugate eye movements
Patients showed a reduced vergence and conjugate smooth pursuit gain with sinusoidal stimulation, particularly patients with vermis lesions. However, there was no significant correlation between both parameters (controls: R = 0.07, P > 0.05, R2 = 0.00; patients: R = 0.60, P > 0.05, R2 = 0.36). There was no significant correlation between the phase shift of sinusoidal vergence and smooth pursuit (controls: R = 0.15, P = 0.70, R2 = 0.02, patients: R = 0.56, P = 0.09, R2 = 0.31). Furthermore, there was no significant correlation between conjugate smooth pursuit steady state velocity in the step-ramp paradigm and vergence mean velocity in the ramp paradigm (controls: convergence: R = 0.49, P > 0.05, R2 = 0.24; divergence: R = 0.25, P > 0.05, R2 = 0.06; patients: convergence: R = 0.49, P > 0.05, R2 = 0.24; divergence: R = 0.42, P > 0.05, R2 = 0.17).
|
Discussion |
|---|
|
TopSummaryIntroductionMethodsResultsDiscussionReferences |
|---|
Based on several lines of evidence we tested the hypothesis that vergence eye movements are impaired in patients with circumscribed cerebellar lesions. This assumption is derived from anatomical (May et al., 1992
; Gamlin et al., 1996), single unit recording (Nitta et al., 2008a,b) and lesion studies in animal experiments (Takagi et al., 2003). Here we show that disparity-induced vergence to slowly moving targets is impaired in cerebellar patients, particularly in patients with vermis lesions. In contrast, fast vergence to step targets remained unimpaired. Concomitantly, patients showed reduced acceleration in the initiation of conjugate smooth pursuit, diminished smooth pursuit gain and saccadic hypometria. The main implications of our study are 2-fold: (i) the human cerebellum is involved in vergence processing and (ii) the cerebellum, noticeably the vermis, controls slow vergence. After a brief consideration of methodological aspects of vergence eye movements, we will focus on the implications of identified vergence abnormalities for the role of the cerebellum in the control of slow and fast vergence eye movements.
Methodological considerations
The slighty lowered position of the stimulus platform caused accompanying small vertical saccades during vergence eye movements particularly during vergence steps. Since (vertical) saccades enhance horizontal vergence step responses (Enright, 1984; Zee et al., 1992; Busettini and Mays, 2005), one portion of the vergence step movement is affected by saccadic enhancement. However, the influence of saccades should be the same for patients and controls due to the same laboratory setup. The disjunctive portion of these accompanying saccades was negligibly small and has probably no impact on the vergence responses.
Vergence eye movements can be distinguished in vergence to step (fast or transient vergence) and to ramp targets (slow or sustained vergence) (Jones, 1980; Schor, 1980; Hung et al., 1983; Semmlow et al., 1986, 2007; Erkelens et al., 1989b; Semmlow and Yuan, 2002a,b; Gayed and Alvarez, 2006; Leigh and Zee, 2006; Straumann, 2007). Both subsystems have different properties: the fast vergence system is best elicited by stimuli with large retinal disparity errors; the slow vergence by small disparity errors and disparity velocities of less than 3°/s (Erkelens et al., 1989a). Semmlow and co-workers (1986) suggested stimulus velocities up to 2°/s to elicit slow vergence, velocities larger than 4°/s to evoke fast vergence. Accordingly, for slow vergence we have chosen 1.5°/s and 7°/s disparity angle for fast vergence. Furthermore these stimulus properties are comparable to our previous studies in healthy human subjects and patients (Rambold et al., 2004, 2005a, 2006).
As the timing of stimulus onset was not predictable it is unlikely that predictive components influenced our vergence ramp responses (Kumar et al., 2002).
Recent clinical evidence for selective deficits of vergence tracking of a slowly moving target in depth but preserved fast vergence responses (Rambold et al., 2004) suggested that both types of vergence have distinctly different neural control and hence different anatomical representations. Based on the evidence for pontine projections to the cerebellum (introduction) we hypothesized that vergence eye movements to either fast or slowly moving targets or both may be impaired in cerebellar lesions.
Cerebellum and eye movements
We specifically examined patients with focal and acute cerebellar lesions. Unlike previous studies on smooth pursuit in spinocerebellar ataxia or other cerebellar degenerations, lesions of cerebellar stroke patients can be identified to be confined to the cerebellum. We focussed our analysis on structures which are known to be involved in vergence in animal studies and in the cerebellar control of smooth pursuit eye movements (SPEM), i.e. vermis (Nitta et al., 2008a), the underlying deep nuclei (Gamlin et al., 1996) and the flocculus (Tsubuku et al., 2004).
Conjugate eye movements
There are two pathways conveying SPEM signals to the cerebellum: one involves the posterior vermis (lobule VI and VII) and the underlying deep cerebellar nuclei and the other the flocculus/paraflocculus (Leigh and Zee, 2006). In our study–except for three patients–the flocculus was usually not involved. Our cerebellar patients showed impaired SPEM, not only in the closed loop but also in the open loop phase which is in accord with previous studies on cerebellar degeneration (Moschner et al., 1999) or infarctions (Straube et al., 1997; Moschner et al., 1999). Accordingly, latency was prolonged and the initial acceleration was reduced in the step-ramp paradigm. Smooth pursuit gain to sinusoidal stimulation was particularly reduced in our patients with vermis lesions as has been shown elsewhere (Vahedi et al., 1995). In a non-human animal study (Takagi et al., 2000), vermis ablation with sparing of the deep cerebellar nuclei in monkeys caused a decrease in SPEM gain, a decrease in peak acceleration and a decrease in pursuit velocity, which is in accord with our patients with vermis lesions. In contrast, vermis was spared in cerebellar patients examined by Straube and coworkers who found reduced smooth pursuit initiation using the step-ramp paradigm (Straube et al., 1997).
Patients also had conjugate saccadic dysmetria with decreased saccadic gain. As it is well known that experimental and clinical lesions of the deep cerebellar nuclei cause saccadic hypermetria (Selhorst et al., 1976; Robinson et al., 1993) the saccadic hypometria in our patients is consistent with vermis impairment (Takagi et al., 1998). In contrast, saccadic dysmetria is not found in flocculus lesions (Rambold et al., 2002a). Therefore both SPEM and saccade deficits are compatible with lesions of the posterior vermis.
Vergence
Vergence to slowly moving targets
Vergence to slowly moving targets was impaired in our cerebellar patients. Gain of slow vergence to sinusoidal moving targets and slow vergence velocity in the ramp paradigm was significantly reduced in patients. Therefore our data provide some evidence for an important role of the cerebellum in the processing of slow vergence eye movements in humans. This is in accord with previous animal (Donaldson and Hawthorne, 1979; Gamlin et al., 1996; Zhang and Gamlin, 1998; Takagi et al., 2003; Nitta et al., 2008a), human PET (Richter et al., 2000, 2004) and human lesion studies (Ohtsuka et al., 1993). A functional imaging study in humans showed activation of the cerebellar hemispheres and the vermis during the near response and disparity vergence (Gulyas and Roland, 1994). The slow vergence deficits of our patients are probably not caused by an impairment of the pursuit system in 3D space since there was no correlation between both slow vergence and conjugate smooth pursuit responses.
Interestingly, divergence but not convergence eye movement responses to ramp targets were impaired. This is in line with an animal study which showed reduced divergence acceleration, divergence velocity and delayed divergence responses after ablation of the dorsal vermis with sparing of the deep cerebellar nuclei (Takagi et al., 2003). In contrast, in a more recent animal study convergence (ramp velocity 10°/s) were impaired after circumscribed vermis inactivation (muscimol) of regions containing largely convergence-modulated neurons: a reduction of convergence eye velocity by 20% in the ramp paradigm (Nitta et al., 2008a). Divergence was less affected (Nitta et al., 2008b). Several reasons might account for the differential lesion effects on divergence and convergence ramp responses. First, while ablation affects both cell soma and fibres of passage, muscimol inactivates neurons only. Secondly, stimulus velocities were different in both studies. While Takagi and colleagues stimulated small vergence step targets of 0.5° and 1° (Takagi et al., 2003), Nitta and colleagues used step targets of 10° amplitude and ramp target velocities of 10°/s (Nitta et al., 2008a). Finally, convergence- and divergence-related neurons are anatomically separated in the cerebellum, not only in the fastigial oculomotor region (FOR) and posterior interposed nucleus (IP) (Mays et al., 1986; Gamlin et al., 1996, 2002; Zhang and Gamlin, 1998; Nitta et al., 2008a) but also in the posterior vermis (Nitta et al., 2008a). Our selective divergence impairment in the ramp paradigm indicates separate organization of both, convergence and divergence eye movements. Divergence-related neurons in the IP (Zhang and Gamlin, 1998) receive projections from the ventral paraflocculus (Nagao et al., 1997) and vermis (Leigh and Zee, 2006). Since the paraflocculus contains divergence-related cells (Tsubuku et al., 2004) the parafloccular-IP pathway has been suspected to be involved in the control of divergence eye movements while the dorsal vermis/FOR pathway may be rather related to convergence (Nitta et al., 2008a). As divergence-related cells were found sparsely in the vermis when compared to convergence-related neurons (Nitta et al., 2008a), divergence-related control mechanisms may be more susceptible to vermis lesions and may show a greater vulnerability while convergence may be better compensated in cerebellar lesions. Although these arguments may explain the divergence deficit they do not account for the additional convergence impairment during sinusoidal vergence.
Esodeviation was found after vermis ablation (Takagi et al., 2003) but not with vermis inactivation (Nitta et al., 2008a). Esodeviation was also found in patients with cerebellar degeneration reflecting an increase in convergence tone (Versino et al., 1996). This might be related to sparing of the fastigial oculomotor region (FOR) since inactivation of these deep cerebellar nuclei also cause convergence deficits with exodeviation (Scheurer et al., 2001). Binocular static misalignment was neither reported in vermis inactivation (Nitta et al., 2008a) nor found in our study.
Vergence to fast moving targets
Step tasks elicit fast vergence eye movements which are coded by the fast vergence system, in contrast to slow vergence eye movements which underlie visual feedback. Fast vergence responses to step targets were unaffected in our patients. This contradicts animal data with impairment of convergence step responses after vermis inactivation (Nitta et al., 2008a). After cerebellar lesions the monkeys showed much slower convergence velocities (15–20°/s) than prior inactivation (48–87°/s) and had a prolonged latency of convergence in the vergence step task. However, divergence responses could not be analysed due to concomitant saccades. Interestingly, while vermis lesions elicit impairment of both conjugate eye movement systems, smooth pursuit and saccades, fast vergence seemed to remain unaffected in our patients. This is some additional evidence that fast and slow vergence are under separate neural control. It remains to be investigated in future studies whether the normal fast vergence responses in our patients are related to (i) extracerebellar control mechanisms of fast vergence, (ii) the fact that we missed critical cerebellar lesion sites in our patient study group, or (iii) more rapidly adaptive recovery mechanisms in fast vergence.
Eye movements in patients with vermis lesions
Based on animal data we pursued the hypothesis that the cerebellar vermis is involved in the processing of vergence eye movements. Fortunately, a large number of our patients showed vermis involvement which allowed statistical comparison with patients with vermis sparing cerebellar lesions. This is of interest since significant vergence tracking impairment to slowly moving targets was particularly found in our patients with lesions involving the vermis. It supports the concept of a crucial role of the cerebellar vermis in controlling slow vergence eye movements in humans as assumed by recent animal data (Donaldson and Hawthorne, 1979; Takagi et al., 2003) and imaging studies (Richter et al., 2000, 2004; Nitta et al., 2008a). While animal lesion studies of the cerebellum up to now only investigated vergence eye movements in vermis lesions (Takagi et al., 2003; Nitta et al., 2008a) our patients’ lesions were larger and not confined to the vermis. Accordingly, we cannot infer from our data how far only vermis lesions or other defined cerebellar structures cause slow vergence deficits. At least two results argue against the deep cerebellar nuclei to cause the vergence deficits. First, patients with vermis sparing lesions of the deep cerebellar nuclei did not show any significant difference in slow vergence compared to healthy controls. Second, there was no saccadic hypermetria which is usually found in lesions of the fastigial oculomotor region (Robinson et al., 1993). Therefore, the deep cerebellar nuclei alone can probably not account for the slow vergence deficit in our patients.
In conclusion, this is the first study on a comparative investigation of fast and slow dynamic vergence in patients with cerebellar lesions. Our a priori hypothesis of a critical cerebellar role in vergence was derived from animal lesion and single unit recording data as well as anatomical ponto-cerebellar projections of vergence modulated neurons. Our patient data implicate the cerebellum, noticeably the vermis, in the control of slow but not fast vergence. We cannot exclude that lesions of other cerebellar structures not involved in our patients might evoke fast vergence deficits. However, we provide additional evidence for a separate neural control of fast and slow vergence, not only in the pons (Rambold et al., 2004, 2005b) but also in the cerebellum.
|
References |
|---|
|
TopSummaryIntroductionMethodsResultsDiscussionReferences |
|---|
Akao T, Kurkin SA, Fukushima J, Fukushima K. Visual and vergence eye movement-related responses of pursuit neurons in the caudal frontal eye fields to motion-in-depth stimuli. Exp Brain Res (2005a) 164:92–108.[CrossRef][Web of Science][Medline]
Akao T, Mustari MJ, Fukushima J, Kurkin S, Fukushima K. Discharge characteristics of pursuit neurons in MST during vergence eye movements. J Neurophysiol (2005b) 93:2415–34.
Barash S, Melikyan A, Sivakov A, Zhang M, Glickstein M, Thier P. Saccadic dysmetria and adaptation after lesions of the cerebellar cortex. J Neurosci (1999) 19:10931–9.
Busettini C, Mays LE. Saccade-vergence interaction in macaques. II. Vergence eenhancement as the product of a local feedback vergence motor error and a weighted saccadic burst. J Neurophysiol (2005) 94:2312–30.
Carl JR, Gellman RS. Human smooth pursuit: stimulus-dependent responses. J Neurophysiol (1987) 57:1446–63.
Donaldson IM, Hawthorne ME. Coding of visual information by units in the cat cerebellar vermis. Exp Brain Res (1979) 34:27–48.[Web of Science][Medline]
Enright JT. Changes in vergence mediated by saccades. J Physiol (1984) 350:9–31.
Erkelens CJ, Steinman RM, Collewijn H. Ocular vergence under natural conditions. II. Gaze shifts between real targets differing in distance and direction. Proc R Soc Lond B Biol Sci (1989a) 236:441–65.[Medline]
Erkelens CJ, Van der Steen J, Steinman RM, Collewijn H. Ocular vergence under natural conditions. I. Continuous changes of target distance along the median plane. Proc R Soc Lond B Biol Sci (1989b) 236:417–40.[Medline]
Fukushima K, Yamanobe T, Shinmei Y, Fukushima J, Kurkin S. Role of the frontal eye fields in smooth-gaze tracking. Prog Brain Res (2004) 143:391–401.[Web of Science][Medline]
Gamlin PD, Clarke RJ. Single-unit activity in the primate nucleus reticularis tegmenti pontis related to vergence and ocular accommodation. J Neurophysiol (1995) 73:2115–9.
Gamlin PD, Yoon K, Zhang H. The role of cerebro-ponto-cerebellar pathways in the control of vergence eye movements. Eye (1996) 10:167–71.[Web of Science][Medline]
Gamlin PD, Yoon K. An area for vergence eye movement in primate frontal cortex. Nature (2000) 407:1003–7.
Gamlin PD, Zhang HY. Effects of muscimol blockade of the posterior fastigial nucleus on vergence and ocular accomodation in the primate. Soc Neurosci Abstr (1996) 22:1034.
Gamlin PD. Neural mechanisms for the control of vergence eye movements. Ann NY Acad Sci (2002) 956:264–72.[Web of Science][Medline]
Gamlin PD. Subcortical neural circuits for ocular accommodation and vergence in primates. Ophthalmic Physiol Opt (1999) 19:81–9.[CrossRef][Web of Science][Medline]
Gayed BA, Alvarez TL. Quantitative assessment of divergence eye movements to ramp stimuli. Conf Proc IEEE Eng Med Biol Soc (2006) 1:3954–7.[Medline]
Gulyas B, Roland PE. Binocular disparity discrimination in human cerebral cortex: functional anatomy by positron emission tomography. Proc Natl Acad Sci USA (1994) 91:1239–43.
Helmchen C, Buttner U. Saccade-related Purkinje cell activity in the oculomotor vermis during spontaneous eye movements in light and darkness. Exp Brain Res (1995) 103:198–208.[Web of Science][Medline]
Helmchen C, Hagenow A, Miesner J, Sprenger A, Rambold H, Wenzelburger R, et al. Eye movement abnormalities in essential tremor may indicate cerebellar dysfunction. Brain (2003) 126:1319–32.
Hung GK, Semmlow JL, Ciuffreda KJ. Identification of accommodative vergence contribution to the near response using response variance. Invest Ophthalmol Vis Sci (1983) 24:772–7.
Jones R. Fusional vergence: sustained and transient components. Am J Optom Physiol Opt (1980) 57:640–4.[Web of Science][Medline]
Krauzlis RJ, Miles FA. Role of the oculomotor vermis in generating pursuit and saccades: effects of microstimulation. J Neurophysiol (1998) 80:2046–62.
Kumar AN, Han Y, Garbutt S, Leigh RJ. Properties of anticipatory vergence responses. Invest Ophthalmol Vis Sci (2002) 43:2626–32.
Leigh RJ, Zee DS. The Neurology of Eye Movements, (2006) 55. New York: Oxford University Press.
May PJ, Porter JD, Gamlin PD. Interconnections between the primate cerebellum and midbrain near-response regions. J Comp Neurol (1992) 315:98–116.[CrossRef][Web of Science][Medline]
Mays LE, Porter JD, Gamlin PD, Tello CA. Neural control of vergence eye movements: neurons encoding vergence velocity. J Neurophysiol (1986) 56:1007–21.
Moschner C, Crawford TJ, Heide W, Trillenberg P, Kompf D, Kennard C. Deficits of smooth pursuit initiation in patients with degenerative cerebellar lesions. Brain (1999) 122:2147–58.
Nagao S, Kitamura T, Nakamura N, Hiramatsu T, Yamada J. Location of efferent terminals of the primate flocculus and ventral paraflocculus revealed by anterograde axonal transport methods. Neurosci Res (1997) 27:257–69.[CrossRef][Web of Science][Medline]
Nitta T, Akao T, Kurkin S, Fukushima K. Involvement of the cerebellar dorsal vermis in vergence eye movements in monkeys. Cereb Cortex (2008a) 18:1042–57.
Nitta T, Akao T, Kurkin S, Fukushima K. Vergence eye movement signals in the cerebellar dorsal vermis. Prog Brain Res (2008b) 171:173–6.[CrossRef][Medline]
Ohtsuka K, Maekawa H, Sawa M. Convergence paralysis after lesions of the cerebellar peduncles. Ophthalmologica (1993) 206:143–8.[Web of Science][Medline]
Ramat S, Leigh RJ, Zee DS, Optican LM. What clinical disorders tell us about the neural control of saccadic eye movements. Brain (2007) 130:10–35.
Rambold H, Churchland A, Selig Y, Jasmin L, Lisberger SG. Partial ablations of the flocculus and ventral paraflocculus in monkeys cause linked deficits in smooth pursuit eye movements and adaptive modification of the VOR. J Neurophysiol (2002a) 87:912–24.
Rambold H, Neumann G, Helmchen C. Vergence deficits in pontine lesions. Neurology (2004) 62:1850–3.
Rambold H, Neumann G, Sander T, Helmchen C. Age–related changes of vergence under natural viewing conditions. Neurobiol Aging (2006) 27:163–72.[CrossRef][Web of Science][Medline]
Rambold H, Neumann G, Sander T, Helmchen C. Pontine lesions may cause selective deficits of ‘slow’ vergence eye movements. Ann NY Acad Sci (2005a) 1039:567–70.[CrossRef][Web of Science][Medline]
Rambold H, Sander T, Neumann G, Helmchen C. Palsy of ‘fast’ and ‘slow’ vergence by pontine lesions. Neurology (2005b) 64:338–40.
Rambold H, Sprenger A, Helmchen C. Effects of voluntary blinks on saccades, vergence eye movements, and saccade-vergence interactions in humans. J Neurophysiol (2002b) 88:1220–33.
Richter HO, Costello P, Sponheim SR, Lee JT, Pardo JV. Functional neuroanatomy of the human near/far response to blur cues: eye-lens accommodation/vergence to point targets varying in depth. Eur J Neurosci (2004) 20:2722–32.[CrossRef][Web of Science][Medline]
Richter HO, Lee JT, Pardo JV. Neuroanatomical correlates of the near response: voluntary modulation of accommodation/vergence in the human visual system. Eur J Neurosci (2000) 12:311–21.[CrossRef][Web of Science][Medline]
Robinson FR, Straube A, Fuchs AF. Role of the caudal fastigial nucleus in saccade generation. II. Effects of muscimol inactivation. J Neurophysiol (1993) 70:1741–58.
Scheurer W, Petz T, Eggert T, Straube A. Static alignment after unilateral and bilateral pharmacological inactivation of the caudal fastigial nucleus in the monkey. Soc Neurosci Abstr (2001) 27.
Schmahmann JD, Doyon J, Toga A, Petrides M, Evans A. MRI Atlas of the Human Cerebellum (2000) New York: Academic Press.
Schor C. Fixation of disparity: a steady state error of disparity-induced vergence. Am J Optom Physiol Opt (1980) 57:618–31.[Web of Science][Medline]
Selhorst JB, Stark L, Ochs AL, Hoyt WF. Disorders in cerebellar ocular motor control. I. Saccadic overshoot dysmetria. An oculographic, control system and clinico-anatomical analysis. Brain (1976) 99:497–508.
Semmlow JL, Alvarez TL, Pedrono C. Dry dissection of disparity divergence eye movements using independent component analysis. Comput Biol Med (2007) 37:910–8.[CrossRef][Web of Science][Medline]
Semmlow JL, Hung GK, Ciuffreda KJ. Quantitative assessment of disparity vergence components. Invest Ophthalmol Vis Sci (1986) 27:558–64.
Semmlow JL, Yuan W. Adaptive modification of disparity vergence components: an independent component analysis study. Invest Ophthalmol Vis Sci (2002a) 43:2189–95.
Semmlow JL, Yuan W. Components of disparity vergence eye movements: application of independent component analysis. IEEE Trans Biomed Eng (2002b) 49:805–11.[CrossRef][Web of Science][Medline]
Straube A, Scheuerer W, Eggert T. Unilateral cerebellar lesions affect initiation of ipsilateral smooth pursuit eye movements in humans. Ann Neurol (1997) 42:891–8.[CrossRef][Web of Science][Medline]
Straumann D. Disconjugate eye movements. Dev Ophthalmol (2007) 40:90–109.[CrossRef][Medline]
Suzuki DA, Keller EL. The role of the posterior vermis of monkey cerebellum in smooth-pursuit eye movement control. II. Target velocity-related Purkinje cell activity. J Neurophysiol (1988) 59:19–40.
Suzuki DA, Yamada T, Hoedema R, Yee RD. Smooth-pursuit eye-movement deficits with chemical lesions in macaque nucleus reticularis tegmenti pontis. J Neurophysiol (1999) 82:1178–86.
Takagi M, Tamargo R, Zee DS. Effects of lesions of the cerebellar oculomotor vermis on eye movements in primate: binocular control. Prog Brain Res (2003) 142:19–33.[Web of Science][Medline]
Takagi M, Zee DS, Tamargo RJ. Effects of lesions of the oculomotor vermis on eye movements in primate: saccades. J Neurophysiol (1998) 80:1911–31.
Takagi M, Zee DS, Tamargo RJ. Effects of lesions of the oculomotor cerebellar vermis on eye movements in primate: smooth pursuit. J Neurophysiol (2000) 83:2047–62.
Tatu L, Moulin T, Bogousslavsky J, Duvernoy H. Arterial territories of human brain: brainstem and cerebellum. Neurology (1996) 47:1125–35.
Thielert CD, Thier P. Patterns of projections from the pontine nuclei and the nucleus reticularis tegmenti pontis to the posterior vermis in the rhesus monkey: a study using retrograde tracers. J Comp Neurol (1993) 337:113–26.[CrossRef][Web of Science][Medline]
Tsubuku T, Akao T, McCrea R, Kurkin S, Fukushima J, Fukushima K. Purkinje cell activity in the cerebellar floccular region during vergence eye movements. Soc Neurosci Abstr (2004) 30.
Vahedi K, Rivaud S, Amarenco P, Pierrot-Deseilligny C. Horizontal eye movement disorders after posterior vermis infarctions. J Neurol Neurosurg Psychiatry (1995) 58:91–4.
Versino M, Hurko O, Zee DS. Disorders of binocular control of eye movements in patients with cerebellar dysfunction. Brain (1996) 119:1933–50.
Westheimer G, Blair SM. Oculomotor defects in cerebellectomized monkeys. Invest Ophthalmol (1973) 12:618–21.
Zee DS, Fitzgibbon EJ, Optican LM. Saccade-vergence interactions in humans. J Neurophysiol (1992) 68:1624–41.
Zhang H, Gamlin PD. Neurons in the posterior interposed nucleus of the cerebellum related to vergence and accommodation. I. Steady-state characteristics. J Neurophysiol (1998) 79:1255–69.
Zhang HY, Gamlin PD. Single-unit activity within the posterior fastigial nucleus during vergence and accommodation in the alert primate. Soc Neurosci Abstr (1996) 22:2034.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  B. Baier, P. Stoeter, and M. Dieterich Anatomical correlates of ocular motor deficits in cerebellar lesions Brain, August 1, 2009; 132(8): 2114 - 2124. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||