Lynette Millist

Inhibitory control and spatial working memory in Parkinson's disease.

Patients with Parkinsons disease (PD) have difficulty performing tasks relying on inhibitory control and working memory, functions of the prefrontal cortex. Eye movement paradigms can be used to investigate basic sensorimotor functions and higher order cognitive aspects of motor control. This study investigated inhibitory control and spatial working memory in the saccadic system of 13 individuals with mild‐moderate PD and 13 age‐matched controls. Tasks explored suppression of reflexive saccades during qualitatively different tasks, generation of express and anticipatory saccades, and the ability to respond to occasional, unpredictable (“oddball”) targets that occurred during a sequence of well‐learned, reciprocating saccades between horizontal targets. Spatial working memory was assessed using single and two‐step (involving a visually guided saccade during the delay period) memory‐guided tasks. Results for the PD group indicated an increased percentage of response selection errors during an oddball task, reduced suppression of inappropriate reflexive saccades during memory‐guided tasks (but not during fixation or saccade‐engagement tasks), and an increased percentage of express and anticipatory saccades. Spatial working memory was preserved in the PD group during single and two‐step memory‐guided tasks. These findings are consistent with dysfunction within fronto‐striatal and prefrontal‐collicular pathways influencing suppression and selection of eye movements.

A closer look at visually guided saccades in autism and Asperger’s disorder

Motor impairments have been found to be a significant clinical feature associated with autism and Asperger’s disorder (AD) in addition to core symptoms of communication and social cognition deficits. Motor deficits in high-functioning autism (HFA) and AD may differentiate these disorders, particularly with respect to the role of the cerebellum in motor functioning. Current neuroimaging and behavioral evidence suggests greater disruption of the cerebellum in HFA than AD. Investigations of ocular motor functioning have previously been used in clinical populations to assess the integrity of the cerebellar networks, through examination of saccade accuracy and the integrity of saccade dynamics. Previous investigations of visually guided saccades in HFA and AD have only assessed basic saccade metrics, such as latency, amplitude, and gain, as well as peak velocity. We used a simple visually guided saccade paradigm to further characterize the profile of visually guided saccade metrics and dynamics in HFA and AD. It was found that children with HFA, but not AD, were more inaccurate across both small (5°) and large (10°) target amplitudes, and final eye position was hypometric at 10°. These findings suggest greater functional disturbance of the cerebellum in HFA than AD, and suggest fundamental difficulties with visual error monitoring in HFA.

Disruption to higher order processes in Friedreich ataxia.

Friedreich ataxia (FRDA), the most common of the genetically inherited ataxias, is characterised by ocular motor deficits largely reflecting disruption to brainstem-cerebellar circuitry. These deficits include fixation instability, saccadic dysmetria, disrupted pursuit, and vestibular abnormalities. Whether higher order or cognitive control processes involved the generation of more volitional eye movements are similarly impaired, has not been explored previously. This research examined antisaccade and memory-guided saccade characteristics in 13 individuals with genetically confirmed FRDA, and contrasted performance with neurologically healthy individuals. We demonstrate, for the first time, a broad range of deficits in FDRA consistent with disruption to higher order processes involved in the control of saccadic eye movement. Significant differences between FDRA and control participants were revealed across all movement parameters (latency, gain, velocity, position error), and across all saccade types, including alterations to velocity profiles. FDRA participants also generated significantly more erroneous responses to non-target stimuli in both saccade paradigms. Finally, a number of correlations between ocular motor and clinical measures were revealed including those between contrast acuity and saccadic latency (all saccade types), disease duration and measures of response inhibition (errors and relative latencies for antisaccades), and neurological scores and error latencies, arguably a reflection of difficulty resolving response conflict. These results suggest a role for the cerebellum in higher order cognitive control processes, and further support the proposal that eye movement markers, which can be measured with accuracy and reliability, may be a useful biomarker in FDRA.

SACCADE ADAPTATION IN AUTISM AND ASPERGER'S DISORDER

Autism and Aspergers disorder (AD) are neurodevelopmental disorders primarily characterized by deficits in social interaction and communication, however motor coordination deficits are increasingly recognized as a prevalent feature of these conditions. Although it has been proposed that children with autism and AD may have difficulty utilizing visual feedback during motor learning tasks, this has not been directly examined. Significantly, changes within the cerebellum, which is implicated in motor learning, are known to be more pronounced in autism compared to AD. We used the classic double-step saccade adaptation paradigm, known to depend on cerebellar integrity, to investigate differences in motor learning and the use of visual feedback in children aged 9-14 years with high-functioning autism (HFA; IQ>80; n=10) and AD (n=13). Performance was compared to age and IQ matched typically developing children (n=12). Both HFA and AD groups successfully adapted the gain of their saccades in response to perceived visual error, however the time course for adaptation was prolonged in the HFA group. While a shift in saccade dynamics typically occurs during adaptation, we revealed aberrant changes in both HFA and AD groups. This study contributes to a growing body of evidence centrally implicating the cerebellum in ocular motor dysfunction in autism. Specifically, these findings collectively imply functional impairment of the cerebellar network and its inflow and outflow tracts that underpin saccade adaptation, with greater disturbance in HFA compared to AD.

Antisaccade performance in patients with multiple sclerosis.

Commonly used measures of disability in patients with Multiple sclerosis (MS) inadequately reflect disease severity and progression. Further, cognitive deficits experienced by up to 70% of patients, are poorly represented by these measures. Saccadic eye movements may provide a powerful tool for the analysis of cognitive changes in MS, providing a surrogate measure of performance that extends more conventional measures. The cognitive control of eye movements has not previously been investigated in patients with MS. We studied antisaccade (AS) performance in 25 patients with MS and compared the results with 25 age matched healthy controls, to evaluate the resolution of response conflict between volitional and automatic processes. Experimental measures were also correlated with a battery of neuropsychological tests evaluating attention, working memory and executive processes, the most commonly reported cognitive deficits in MS. Compared to controls, patients with MS generated significantly more prosaccade errors, and AS latencies were prolonged and more variable. Error rates correlated significantly with scores on the commonly used PASAT. MS patients also exhibited poor spatial accuracy, with mean absolute error significantly larger and more variable than control subjects. The sensitivity of this task in dissociating function in MS, as well as clear correlation with a key measure of cognition, suggests that eye movements, may provide a surrogate measure of cognitive function in MS, with the potential to sensitively assess disease severity and progression.

Hypometric primary saccades and increased variability in visually-guided saccades in Huntington's disease

Eye movement abnormalities can be distinctive and suggestive of a specific pathophysiology. To further investigate the deficits in the control of saccades in patients with Huntingtons disease (HD), we investigated the ability of 11 HD patients and 11 matched controls to perform visually-guided saccades. We adopted reflexive saccade tasks involving predictable and unpredictable sequences, at different amplitudes of target step (10 degrees, 20 degrees, 30 degrees, 40 degrees ), as well as voluntary self-paced saccades. Prolongation of initiation was observed in the HD group as the target amplitude of predictable saccades increased. During the self-paced saccade task, the HD patients had increased intersaccadic intervals, performed fewer saccades in the allocated time and displayed an increased temporal variability in comparison to the controls. Furthermore, hypometric primary saccades, and an increased number of corrective saccades, were observed during both reflexive and voluntary saccades in the HD group. The delayed initiation of large saccades, deficits in voluntary, self-paced saccades, impaired saccadic accuracy and increased corrective saccades in HD, were interpreted in light of other ocular motor and limb studies, and appear to be due to damage to the fronto-striatal loop, including the supplementary eye fields, as well as possible brainstem and cerebellar involvement.

Multiple sclerosis: Cognition and saccadic eye movements

Ocular motor abnormalities are frequently reported in Multiple Sclerosis (MS), the most salient of which are well represented by the commonly used clinical measure, the EDSS. However, cognitive function, which is poorly represented by this scale, may also be ascertained from ocular motor measures, suggesting that an analysis of eye movements has the potential to extend and complement this more conventional measure. The generation of single and triple-step memory-guided saccades was investigated in 25 individuals with MS and a comparable number of neurologically healthy individuals matched for age and IQ. Experimental measures were correlated with a battery of neuropsychological tests evaluating attentional, working memory and executive processes, the cognitive domains most commonly compromised in MS. For single memory-guided saccades, MS patients were less accurate and generated more erroneous responses to non-target stimuli. Saccadic latencies were also prolonged. For triple-step memory-guided saccades, MS patients were less accurate and more variable. A number of significant correlations were revealed between measures of each of these characteristics and scores on the range of neuropsychological assessments. These ocular motor measures demonstrate considerable sensitivity with respect to evaluating cognitive function in MS, particularly working memory and inhibitory control processes. This suggests that they could represent the foundation of a user-friendly surrogate marker of disease severity and progression in MS.

Control of visually guided saccades in multiple sclerosis: Disruption to higher-order processes

Ocular motor abnormalities are a common feature of multiple sclerosis (MS), with more salient deficits reflecting tissue damage within brainstem and cerebellar circuits. However, MS may also result in disruption to higher level or cognitive control processes governing eye movement, including attentional processes that enhance the neural processing of behaviourally relevant information. The attentional control of eye movement was investigated in 25 individuals with MS and a comparable number of neurologically healthy individuals matched for age and IQ. This entailed an evaluation of distractor-related effects on the generation of both unpredictable and predictable visually guided saccades, as well as an evaluation of the effects of presenting endogenous cues prior to target onset. For unpredictable saccades, we revealed an exaggerated distractor effect in MS, with saccade latencies prolonged and endpoints less accurate in the presence of a visual distractor. Predictable saccades tended to be hypometric for MS patients, although we found no significant distractor effects. For endogenously cued saccades, we found no group differences in latency following a valid cue, but an exaggerated increase in latency following invalid cues for MS patients. MS patients also generated a significantly greater proportion of erroneous responses to cue stimuli. These ocular motor characteristics demonstrate considerable sensitivity with respect to evaluating attentional deficits in MS, evident even in the absence of clinical signs of disease.

Longitudinal Assessment of Antisaccades in Patients with Multiple Sclerosis

We have previously demonstrated that assessment of antisaccades (AS) provides not only measures of motor function in multiple sclerosis (MS), but measures of cognitive control processes in particular, attention and working memory. This study sought to demonstrate the potential for AS measures to sensitively reflect change in functional status in MS. Twenty-four patients with relapsing-remitting MS and 12 age-matched controls were evaluated longitudinally using an AS saccade task. Compared to control subjects, a number of saccade parameters changed significantly over a two year period for MS patients. These included saccade error rates, latencies, and accuracy measures. Further, for MS patients, correlations were retained between OM measures and scores on the PASAT, which is considered the reference task for the cognitive evaluation of MS patients. Notably, EDSS scores for these patients did not change significantly over this period. These results demonstrate that OM measures may reflect disease evolution in MS, in the absence of clinically evident changes as measured using conventional techniques. With replication, these markers could ultimately be developed into a cost-effective, non-invasive, and well tolerated assessment tool to assist in confirming progression early in the disease process, and in measuring and predicting response to therapy.

Inhibitory control during smooth pursuit in Parkinson's disease and Huntington's disease.

The basal ganglia are involved in the preferential selection and suppression of competing responses. Parkinsons disease and Huntingtons disease are 2 prototypical basal ganglia disorders that feature impaired inhibitory control, a function of poor conflict resolution. Previous saccadic studies showed that individuals with Parkinsons disease experience difficulty suppressing unwanted ocular motor responses, whereas evidence for a similar difficulty in Huntingtons disease is more equivocal. Relative to saccades, few research studies have examined inhibitory control processes in the context of an ongoing smooth pursuit task. In this study, we examined the ability of 16 patients with Parkinsons disease and 12 patients with Huntingtons disease to suppress automatic responses to irrelevant distracters that transiently appeared during the tracking of a moving visual stimulus. Compared with an equivalent number of age‐matched controls, patients with Parkinsons disease generated proportionately more saccades to distracter stimuli. This was particularly evident for distracters appearing far away from the target. Conversely, whereas individuals with early‐stage Huntingtons disease and healthy controls made a comparable number of errors toward distracter stimuli, those in a more advanced clinical stage demonstrated significantly poorer inhibitory control. The current findings in parkinsonian patients replicate those previously reported in the saccadic and manual response literature, demonstrating difficulty inhibiting a competing motor response. However, in Huntingtons disease we demonstrate for the first time that inhibitory control declines in more advanced‐disease stages. This suggests that ocular motility may provide a sensitive marker of clinical disease progression in Huntingtons disease.