Meaghan Clough

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.

Brain structure and intragenic DNA methylation are correlated and predict executive dysfunction in fragile X premutation females

DNA methylation of the Fragile X mental retardation 1 (FMR1) exon 1/intron 1 boundary has been associated with executive dysfunction in female carriers of a FMR1 premutation (PM: 55–199 CGG repeats), whereas neuroanatomical changes have been associated with executive dysfunction in PM males. To our knowledge, this study for the first time examined the inter-relationships between executive function, neuroanatomical structure and molecular measures (DNA methylation and FMR1 mRNA levels in blood) in PM and control (<44 CGG repeats) females. In the PM group, FMR1 intron 1 methylation was positively associated with executive function and cortical thickness in middle and superior frontal gyri, and left inferior parietal gyrus. By contrast, in the control group, FMR1 intron 1 methylation was negatively associated with cortical thickness of the left middle frontal gyrus and superior frontal gyri. No significant associations were revealed for either group between FMR1 mRNA and neuroanatomical structure or executive function. In the PM group, the lack of any significant association between FMR1 mRNA levels and phenotypic measures found in this study suggests that either FMR1 expression is not well conserved between tissues, or that FMR1 intron 1 methylation is linked to neuroanatomical and cognitive phenotype in PM females via a different mechanism.

Behavioral and Neural Plasticity of Ocular Motor Control: Changes in Performance and fMRI Activity Following Antisaccade Training.

The antisaccade task provides a model paradigm that sets the inhibition of a reflexively driven behavior against the volitional control of a goal-directed behavior. The stability and adaptability of antisaccade performance was investigated in 23 neurologically healthy individuals. Behavior and brain function were measured using functional magnetic resonance imaging (fMRI) prior to and immediately following 2 weeks of daily antisaccade training. Participants performed antisaccade trials faster with no change in directional error rate following 2 weeks of training; however this increased speed came at the cost of the spatial accuracy of the saccade (gain) which became more hypometric following training. Training on the antisaccade task resulted in increases in fMRI activity in the fronto-basal ganglia-parietal-cerebellar ocular motor network. Following training, antisaccade latency was positively associated with fMRI activity in the frontal and supplementary eye fields, anterior cingulate and intraparietal sulcus; antisaccade gain was negatively associated with fMRI activity in supplementary eye fields, anterior cingulate, intraparietal sulcus, and cerebellar vermis. In sum, the results suggest that following training, larger antisaccade latency is associated with larger activity in fronto-parietal-cerebellar ocular motor regions, and smaller antisaccade gain is associated with larger activity in fronto-parietal ocular motor regions.

Ocular motor signatures of cognitive dysfunction in multiple sclerosis

The anatomical and functional overlap between ocular motor command circuitry and the higher-order networks that form the scaffolding for cognition makes for a compelling hypothesis that measures of ocular motility could provide a means to sensitively interrogate cognitive dysfunction in people with multiple sclerosis (MS). Such an approach may ultimately provide objective and reproducible measures of cognitive dysfunction that offer an innovative capability to refine diagnosis, improve prognostication, and more accurately codify disease burden. A further dividend may be the validation and application of biomarkers that can be used in studies aimed at identifying and monitoring preventative, protective and even restorative properties of novel neurotherapeutics in MS. This Review discusses the utility of ocular motor measures in patients with MS to characterize disruption to wide-ranging networks that support cognitive function.

Disassociation between brain activation and executive function in fragile X premutation females

Executive dysfunction has been demonstrated among premutation (PM) carriers (55–199 CGG repeats) of the Fragile X mental retardation 1 (FMR1) gene. Further, alterations to neural activation patterns have been reported during memory and comparison based functional magnetic resonance imaging (fMRI) tasks in these carriers. For the first time, the relationships between fMRI neural activation during an interleaved ocular motor prosaccade/antisaccade paradigm, and concurrent task performance (saccade measures of latency, accuracy and error rate) in PM females were examined. Although no differences were found in whole brain activation patterns, regions of interest (ROI) analyses revealed reduced activation in the right ventrolateral prefrontal cortex (VLPFC) during antisaccade trials for PM females. Further, a series of divergent and group specific relationships were found between ROI activation and saccade measures. Specifically, for control females, activation within the right VLPFC and supramarginal gyrus correlated negatively with antisaccade latencies, while for PM females, activation within these regions was found to negatively correlate with antisaccade accuracy and error rate (right VLPFC only). For control females, activation within frontal and supplementary eye fields and bilateral intraparietal sulci correlated with prosaccade latency and accuracy; however, no significant prosaccade correlations were found for PM females. This exploratory study extends previous reports of altered prefrontal neural engagement in PM carriers, and clearly demonstrates dissociation between control and PM females in the transformation of neural activation into overt measures of executive dysfunction. Hum Brain Mapp 38:1056–1067, 2017.

Behavioral measures of cortical hyperexcitability assessed in people who experience visual snow

Objective: To determine whether visual perceptual measures in people who experience visual snow are consistent with an imbalance between inhibition and excitation in visual cortex. Methods: Sixteen patients with visual snow and 18 controls participated. Four visual tasks were included: center-surround contrast matching, luminance increment detection in noise, and global form and global motion coherence thresholds. Neuronal architecture capable of encoding the luminance and contrast stimuli is present within primary visual cortex, whereas the extraction of global motion and form signals requires extrastriate processing. All these tasks have been used previously to investigate the balance between inhibition and excitation within the visual system in both healthy and diseased states. Results: The visual snow group demonstrated reduced center-surround contrast suppression (p = 0.03) and elevated luminance increment thresholds in noise (p = 0.02). Groups did not differ on the global form or global motion task. Conclusion: Our study demonstrates that visual perceptual measures involving the suprathreshold processing of contrast and luminance are abnormal in a group of individuals with visual snow. Our data are consistent with elevated excitability in primary visual cortex; however, further research is required to provide more direct evidence for this proposed mechanism. The ability to measure perceptual differences in visual snow reveals promise for the future development of clinical tests to assist in visual snow diagnosis and possibly a method for quantitatively assaying any benefits of treatments.

Multiple sclerosis: Executive dysfunction, task switching and the role of attention

Background It has been suggested that switching ability might not be affected in multiple sclerosis (MS) as previously thought; however, whether this is true under more ‘real-world’ conditions when asymmetry in task difficulty is present has not been ascertained. Objective The objective of this paper is to examine the impact of task difficulty asymmetry on task switching ability in MS. Method An ocular motor (OM) paradigm that interleaves the simple task of looking towards a target (prosaccade, PS) with the cognitively more difficult task of looking away from a target (antisaccade, PS) was used. Two switching conditions: (1) PS switch cost, switching to a simple task from a difficult task (PS switch), relative to performing two simple tasks concurrently (PS repeat); (2) AS switch cost, switching to a difficult task from a simple task (AS switch) relative to performing two difficult tasks concurrently (AS repeat). Forty-five relapsing–remitting MS patients and 30 control individuals were compared. Results Controls and patients produced a similar magnitude PS switch cost, suggesting that task difficulty asymmetry does not detrimentally impact MS patients when transitioning from a more difficult task to a simpler task. However, MS patients alone found switching from the simpler PS trial to the more difficult AS trial easier (shorter latency and reduced error) than performing two AS trials consecutively (AS switch benefit). Further, MS patients performed significantly more errors than controls when required to repeat the same trial consecutively. Conclusion MS patients appear to find the maintenance of task-relevant processes difficult not switching per se, with deficits exacerbated under increased attentional demands.

Impairment of Smooth Pursuit as a Marker of Early Multiple Sclerosis

Background Multiple sclerosis (MS) is a diffuse disease that disrupts wide-ranging cerebral networks. The control of saccades and smooth pursuit are similarly dependent upon widespread networks, with the assessment of pursuit offering an opportunity to examine feedback regulation. We sought to characterize pursuit deficits in MS and to examine their relationship with disease duration. Methods Twenty healthy controls, 20 patients with a clinically isolated syndrome (CIS), and 40 patients with clinically definite MS (CDMS) participated. Thirty-six trials of Rashbass’ step–ramp paradigm of smooth pursuit, evenly split by velocity (8.65°, 17.1°, and 25.9°/s) and ramp direction (left/right), were performed. Four parameters were measured: latency of pursuit onset, closed-loop pursuit gain, number of saccades, and summed saccade amplitudes during pursuit. For CDMS patients, these were correlated with disease duration and Expanded Disability Status Scale (EDSS) score. Results Closed-loop pursuit gain was significantly lower in CIS than controls at all speeds. CDMS gain was lower than controls at medium pursuit velocity. CDMS patients also displayed longer pursuit latency than controls at all velocities. All patients accumulated increased summed saccade amplitudes at slow and medium pursuit speeds, and infrequent high-amplitude saccades at the fast speed. No pursuit variable significantly correlated with EDSS or disease duration in CDMS patients. Conclusion Smooth pursuit is significantly compromised in MS from onset. Low pursuit gain and increased saccadic amplitudes may be robust markers of disseminated pathology in CIS and in more advanced MS. Pursuit may be useful in measuring early disease.