Joanne Fielding

Quantitative meta-analysis of fMRI and PET studies reveals consistent activation in fronto-striatal-parietal regions and cerebellum during antisaccades and prosaccades.

The antisaccade task is a classic task of oculomotor control that requires participants to inhibit a saccade to a target and instead make a voluntary saccade to the mirror opposite location. By comparison, the prosaccade task requires participants to make a visually-guided saccade to the target. These tasks have been studied extensively using behavioral oculomotor, electrophysiological, and neuroimaging in both non-human primates and humans. In humans, the antisaccade task is under active investigation as a potential endophenotype or biomarker for multiple psychiatric and neurological disorders. A large and growing body of literature has used functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) to study the neural correlates of the antisaccade and prosaccade tasks. We present a quantitative meta-analysis of all published voxel-wise fMRI and PET studies (18) of the antisaccade task and show that consistent activation for antisaccades and prosaccades is obtained in a fronto-subcortical-parietal network encompassing frontal and supplementary eye fields (SEFs), thalamus, striatum, and intraparietal cortex. This network is strongly linked to oculomotor control and was activated to a greater extent for antisaccade than prosaccade trials. Antisaccade but not prosaccade trials additionally activated dorsolateral and ventrolateral prefrontal cortices. We also found that a number of additional regions not classically linked to oculomotor control were activated to a greater extent for antisaccade vs. prosaccade trials; these regions are often reported in antisaccade studies but rarely commented upon. While the number of studies eligible to be included in this meta-analysis was small, the results of this systematic review reveal that antisaccade and prosaccade trials consistently activate a distributed network of regions both within and outside the classic definition of the oculomotor network.

Neurobehavioural evidence for the involvement of the FMR1 gene in female carriers of fragile X syndrome

For years, premutation-carriers of fragile X-syndrome (FXS) were assumed free from any deleterious phenotype. In this review, we discuss the current literature on neurocognitive, emotional and neuromotor profiles emerging in females with the fragile-X premutation, and discuss phenotypic profiles in male premutation-carriers to gain insights into possible underlying mechanisms associated with FMR1 gene expression. We contend that this emerging phenotypic profile in females with the fragile-X premutation needs further investigation using experimentally-driven tasks sensitive to neural networks especially vulnerable to FMR1 gene expression. Further investigation of developmental aspects of the female carrier profile is needed to determine the extent to which emotional, cognitive and neurobehavioural challenges indicate at-risk profiles for later degenerative decline, or rather a stable developmental phenotype. These future research avenues will provide critical new information which will enable identification of women at greatest risk for subtle age-dependent neurobehavioural changes well before the onset of more serious clinical consequences alongside the identification of biomarkers which may be useful in establishing the efficacy of future therapeutic interventions.

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.

Impaired response inhibition is associated with self-reported symptoms of depression, anxiety, and ADHD in female FMR1 premutation carriers

Fragile X Mental Retardation 1 (FMR1) premutation carriers (PM‐carriers) have a defective trinucleotide expansion on the FMR1 gene that is associated with continuum of neuropsychological and mental disorders. Currently, little is known about the distinct subcomponents of executive function potentially impaired in female PM‐carriers, and there have been no investigations into associations between executive function and incidences of mental disorders. A total of 35 female PM‐carriers confirmed by Asuragen triple primed PCR DNA testing and 35 age‐ and intelligence‐matched controls completed tests of executive function (i.e., response inhibition and working memory) and self‐reported on social anxiety, depression, and ADHD predominantly inattentive (ADHD‐PI) symptoms. Compared to controls, PM‐carriers were significantly elevated on self‐reported social anxiety and ADHD‐PI symptoms. Irrespective of mental symptoms, female PM‐carries performed significantly worse than controls on a response inhibition test, and further investigations revealed significant correlations between executive function performance and self‐reported symptoms of anxiety, depression and ADHD‐PI. Critically, among PM‐carriers with good executive function performance, no women exceeded threshold markers for probable caseness of mental disorder. However, rates of probable caseness were elevated in those with average performance (response inhibition: social anxiety: 41.7%; depression: 20%; ADHD: 44.4%; working memory: social anxiety: 27.3%; depression: 9.1%; ADHD: 18.2%) and highly elevated for those with poor executive function performance (response inhibition: social anxiety: 58.3%; depression: 80%; ADHD: 55.6%; working memory: social anxiety: 100%; depression: 50%; ADHD: 83.3%). These data suggest that subtle executive dysfunction may be a useful neuropsychological indicator for a range of mental disorders previously reported in female PM‐carriers.

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.

Diffusion Tensor Imaging Correlates of Visual Impairment in Multiple Sclerosis and Chronic Optic Neuritis

PURPOSE To compare white matter (WM) injuries associated with vision loss in multiple sclerosis (MS) and optic neuritis (ON). METHODS Twenty-three patients with clinically definite relapsing-remitting MS and chronic unilateral ON and 14 neurologically healthy volunteers were monocularly tested with Sloan 100%, 2.5%, and 1.25% contrast visual acuity charts. Primary visual pathway and whole-brain WM injury were assessed with optical coherence tomography (OCT) and diffusion tensor imaging (DTI). OCT and DTI correlates of high- and low-contrast visual impairment were identified using correlation analyses. RESULTS The MS patients displayed significantly reduced retinal nerve fiber layer (RNFL) thickness and altered optic nerve and radiation DTI measures compared with the controls. In the patients, 2.5% and 1.25% contrast letter acuity in the unaffected eye correlated significantly and independently with optic nerve and optic radiation DTI measures. Visual acuity in affected eyes did not correlate with optic nerve or optic radiation DTI measures, but did correlate with DTI measures in prefrontal and temporal brain regions that were shown to connect structurally to visual cortices. CONCLUSIONS In unaffected eyes, visual impairment was associated with WM injury in the visual pathway. In contrast, irrecoverable visual impairment after ON was associated with injury to frontal WM, which potentially impairs the capacity for remapping visual processing.

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.

Cognition and eye movements: assessment of cerebral dysfunction.

Background: Many neurological disorders show deficits in ocular motor function. In the past, evaluation has been limited to assessing abnormalities largely generated by pathology of the brainstem andcerebellum. In disorders that primarily or substantially, affect the cerebral hemispheres, disruption of cognitive processes occur, often early in the clinical course. While neuropsychological testing traditionally is used to measure cognitive performance, the cerebral influences on the ocular motor system provides another quantitative paradigm. This review explores the relationship between cognitive sensory processing and execution of planned ocular motor tests in Parkinsons disease, Huntington\x{2019}s disease and multiple sclerosis and explores areas of clinical utility. Methods: Review of the literature regarding cognitive and ocular motor abnormalities in neurological disease. Results: The literature indicates that in systems degeneration there are abnormalities of cognitive processing, defined both by conventional behavioural testing and by assessment of cognitive function utilizing ocular motor studies, which characterise those processes. Moreover, in diffuse disease, in processes such as multiple sclerosis, the assessment of cognitive processes involved in ocular motor function may well provide an added level of sensitivity indicating more widespread pathology than would be apparent with conventional clinical assessment. Conclusions: Assessment of cognitive function in the ocular motor system may provide insight into cerebral function, in health and disease, and may provide both diagnostic information and permit quantification of deficit in future.

The role of the basal ganglia in the control of automatic visuospatial attention

Cognitive impairments in patients with basal ganglia dysfunction are primarily revealed where performance relies on internal, voluntary control processes. Evidence suggests that this also extends to impaired control of more automatic processes, including visuospatial attention. The present study used a non-predictive peripheral cueing paradigm to compare and contrast visuospatial deficits in patients with Parkinsons disease (PD) with those previously revealed in patients with Huntingtons disease (HD) (Fielding et al., 2006a). Compared to age-matched controls, both PD and HD patients exhibited increased distractibility or poor fixation, however only PD patients responded erroneously to cue stimuli more frequently than control subjects. All subjects demonstrated initial facilitation for valid versus invalid cues following the shorter stimulus-onset asynchronies (SOAs) and a performance decrement at the longer SOAs (inhibition of return), although there was a clear differentiation between these groups for immediate SOAs. Unlike both control and PD subjects, where IOR manifested between 350 and 1000 msec, IOR was evident as early as 150 msec for HD patients. Further, for PD patients, spatially valid cues resulted in hyper-reflexivity following 150 msec SOAs, with saccadic latencies shorter than those generated in response to un-cued targets. Thus contrasting deficits were revealed in PD and HD, emphasizing the important contribution of the basal ganglia in the control of more automatic behaviors