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

Webinar Training: an acceptable, feasible and effective approach for multi-site medical record abstraction: the BOWII experience

<p>Abstract</p> <p>Background</p> <p>Abstractor training is a key element in creating valid and reliable data collection procedures. The choice between in-person vs. remote or simultaneous vs. sequential abstractor training has considerable consequences for time and resource utilization. We conducted a web-based (webinar) abstractor training session to standardize training across six individual Cancer Research Network (CRN) sites for a study of breast cancer treatment effects in older women (BOWII). The goals of this manuscript are to describe the training session, its participants and participants' evaluation of webinar technology for abstraction training.</p> <p>Findings</p> <p>A webinar was held for all six sites with the primary purpose of simultaneously training staff and ensuring consistent abstraction across sites. The training session involved sequential review of over 600 data elements outlined in the coding manual in conjunction with the display of data entry fields in the study's electronic data collection system. Post-training evaluation was conducted via Survey Monkey^©. Inter-rater reliability measures for abstractors within each site were conducted three months after the commencement of data collection.</p> <p>Ten of the 16 people who participated in the training completed the online survey. Almost all (90%) of the 10 trainees had previous medical record abstraction experience and nearly two-thirds reported over 10 years of experience. Half of the respondents had previously participated in a webinar, among which three had participated in a webinar for training purposes. All rated the knowledge and information delivered through the webinar as useful and reported it adequately prepared them for data collection. Moreover, all participants would recommend this platform for multi-site abstraction training. Consistent with participant-reported training effectiveness, results of data collection inter-rater agreement within sites ranged from 89 to 98%, with a weighted average of 95% agreement across sites.</p> <p>Conclusions</p> <p>Conducting training via web-based technology was an acceptable and effective approach to standardizing medical record review across multiple sites for this group of experienced abstractors. Given the substantial time and cost savings achieved with the webinar, coupled with participants' positive evaluation of the training session, researchers should consider this instructional method as part of training efforts to ensure high quality data collection in multi-site studies.</p

The utility of ocular motor assessment in patients with a clinically isolated syndrome suggestive of multiple sclerosis

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system characterised pathologically by areas of demyelination, t-cell predominant perivascular inflammation, and axonal degeneration. Approximately 85% of patients with MS initially present with a clinically isolated syndrome (CIS), which manifests as an acute or subacute episode consistent with white-matter lesion(s) in eloquent areas of the central nervous system. At present there is little understanding of either the pathological processes or the consequential functional capacity occurring at CIS. Preliminary evidence suggests that cognitive changes are present at CIS, potentially predate overt clinical symptoms, and represent an early marker of disease processes in MS. However, these deficits are often subtle and largely subclinical, with widely used measures lacking sufficient precision to elucidate changes informatively. As such, there is a clinical and research imperative to identify alternate measures that can sensitively characterise deficit. Ocular motor (OM) assessment provides an opportunity to measure a range of cognitive processes within the context of a system with a stereotyped output. This system is highly ramified and sensitive to the detection of subtle and diffuse pathological changes to the functionality of cognitive networks, and which are consequential of discrete isolated pathology (lesions) and/or (micro)structural changes, all of which occur in CIS. Previous work in patients with a confirmed diagnosis of MS has demonstrated the utility of OM assessment in these individuals, by characterising a range of deficits not demonstrable using standard clinical assessments. This thesis therefore aimed to determine the utility of OM assessment in measuring cognitive deficit in patients with CIS, both at presentation (visit 1) and over time (one year post visit 1). Given the subtlety of deficit at CIS, a range of cognitively challenging tasks were created, which place increased demands on specific cognitive domains demonstrated to be implicated in clinically definite MS (CDMS); specifically, inhibition, working memory, executive control. For all tasks, CIS patients performed significantly more poorly than neurologically healthy individuals, with deficits reflecting disruption to inhibitory control (Chapter 3) working memory (maintenance: Chapter 4), and executive control processes (cognitive flexibility and top down control: Chapter 5). Further, results suggested that inhibitory control deficits might be consequential of deficits in working memory, affecting the efficiency of top down control mechanisms (Chapter 6). Lastly, longitudinal assessment of inhibitory control demonstrated functional change both within and between patients, with a cluster of deficits appearing to predict the likelihood of conversion to CDMS. Significantly, standard neuropsychological assessment failed to demonstrate similar sensitivity both as an assessment of functional change over time, as well as a discrete measure at visit 1. Overall, results highlight the utility of OM assessment in CIS, affording the sensitive and informative characterisation of cognitive deficits in these patients. Due to the simple and quick nature of assessment, and the robust results found herein, it is proposed that OM assessment might be a clinically viable means of measuring deficit and of monitoring progression from CIS to CDMS

The utility of ocular motor assessment in patients with a clinically isolated syndrome suggestive of multiple sclerosis

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system characterised pathologically by areas of demyelination, t-cell predominant perivascular inflammation, and axonal degeneration. Approximately 85% of patients with MS initially present with a clinically isolated syndrome (CIS), which manifests as an acute or subacute episode consistent with white-matter lesion(s) in eloquent areas of the central nervous system. At present there is little understanding of either the pathological processes or the consequential functional capacity occurring at CIS. Preliminary evidence suggests that cognitive changes are present at CIS, potentially predate overt clinical symptoms, and represent an early marker of disease processes in MS. However, these deficits are often subtle and largely subclinical, with widely used measures lacking sufficient precision to elucidate changes informatively. As such, there is a clinical and research imperative to identify alternate measures that can sensitively characterise deficit. Ocular motor (OM) assessment provides an opportunity to measure a range of cognitive processes within the context of a system with a stereotyped output. This system is highly ramified and sensitive to the detection of subtle and diffuse pathological changes to the functionality of cognitive networks, and which are consequential of discrete isolated pathology (lesions) and/or (micro)structural changes, all of which occur in CIS. Previous work in patients with a confirmed diagnosis of MS has demonstrated the utility of OM assessment in these individuals, by characterising a range of deficits not demonstrable using standard clinical assessments. This thesis therefore aimed to determine the utility of OM assessment in measuring cognitive deficit in patients with CIS, both at presentation (visit 1) and over time (one year post visit 1). Given the subtlety of deficit at CIS, a range of cognitively challenging tasks were created, which place increased demands on specific cognitive domains demonstrated to be implicated in clinically definite MS (CDMS); specifically, inhibition, working memory, executive control. For all tasks, CIS patients performed significantly more poorly than neurologically healthy individuals, with deficits reflecting disruption to inhibitory control (Chapter 3) working memory (maintenance: Chapter 4), and executive control processes (cognitive flexibility and top down control: Chapter 5). Further, results suggested that inhibitory control deficits might be consequential of deficits in working memory, affecting the efficiency of top down control mechanisms (Chapter 6). Lastly, longitudinal assessment of inhibitory control demonstrated functional change both within and between patients, with a cluster of deficits appearing to predict the likelihood of conversion to CDMS. Significantly, standard neuropsychological assessment failed to demonstrate similar sensitivity both as an assessment of functional change over time, as well as a discrete measure at visit 1. Overall, results highlight the utility of OM assessment in CIS, affording the sensitive and informative characterisation of cognitive deficits in these patients. Due to the simple and quick nature of assessment, and the robust results found herein, it is proposed that OM assessment might be a clinically viable means of measuring deficit and of monitoring progression from CIS to CDMS

Towards a Greater Understanding of Visual Snow

Visual Snow (VS) is a persistent, visual disturbance that affects the entire visual field, often described as similar to the static of a poorly tuned analogue television. Despite recent reports of neuronal changes within visual processing areas of cortex, little is known about the underlying causes of VS or the functional impact of these changes. As the first in a series of studies integrating behavioural, neuroimaging and electrophysiological techniques we report results from a suite of ocular motor assessments, designed to provide insight into how impairments in the way visual signals are propagated, organised, processed and transformed, manifest in this often debilitating phenomena

Working Memory Phenotypes in Early Multiple Sclerosis: Appraisal of Phenotype Frequency, Progression and Test Sensitivity

Working memory (WM) impairments are common and debilitating symptoms of multiple sclerosis (MS), often emerging early in the disease. Predominantly, WM impairments are considered in a binary manner, with patients considered either impaired or not based on a single test. However, WM is comprised of different activated subcomponents depending upon the type of information (auditory, visual) and integration requirements. As such, unique WM impairment phenotypes occur. We aimed to determine the most frequent WM phenotypes in early MS, how they progress and which WM test(s) provide the best measure of WM impairment. A total of 88 participants (63 early relapsing–remitting MS: RRMS, 25 healthy controls) completed five WM tests (visual–spatial, auditory, episodic, executive) as well as the symbol digit modalities test as a measure of processing speed. RRMS patients were followed-up for two years. Factors affecting WM (age/gender/intelligence/mood) and MS factors (disease duration/disability) were also evaluated. Some 61.9% of RRMS patients were impaired on at least one WM subcomponent. The most subcomponents impaired were visual,–spatial and auditory WM. The most common WM phenotypes were; (1) visual–spatial sketchpad + episodic buffer + phonological loop + central executive, (2) visual–spatial sketchpad + central executive. The test of visual–spatial WM provided the best diagnostic accuracy for detecting WM impairment and progression. The SDMT did not achieve diagnostic accuracy greater than chance. Although this may be unsurprising, given that the SDMT is a measure of cognitive processing speed in MS, this does highlight the limitation of the SDMT as a general screening tool for cognitive impairment in early MS

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

Functional correlates of cognitive dysfunction in clinically isolated syndromes

Cognitive dysfunction can be identified in patients with clinically isolated syndromes suggestive of multiple sclerosis using ocular motor testing. This study aimed to identify the functional neural correlates of cognitive dysfunction in patients with clinically isolated syndrome using MRI. Eighteen patients with clinically isolated syndrome and 17 healthy controls were recruited. Subjects underwent standard neurological and neuropsychological testing. Subjects also underwent functional MRI (fMRI) during a cognitive ocular motor task, involving pro-saccade (direct gaze towards target) and anti-saccade (direct gaze away from target) trials. Ocular motor performance variables (averaged response time and error rate) were calculated for each subject. Patients showed a trend towards a greater rate of anti-saccade errors (p = 0.09) compared to controls. Compared to controls, patients exhibited increased activation in the right postcentral, right supramarginal gyrus, and the right parietal operculum during the anti-saccade>pro-saccade contrast. This study demonstrated that changes in functional organisation of cognitive brain networks is associated with subtle cognitive changes in patients with clinically isolated syndrome

Differential Impact of Sleep Deprivation and Circadian Timing on Reflexive Versus Inhibitory Control of Attention

In a visually stimulating environment with competing stimuli, we continually choose where to allocate attention, and what to ignore. Wake and circadian-dependent modulation of attentional control and resolution of conflict is poorly understood. Twenty-two participants (17males; 25.6 ± 5.6 years) completed ocular motor tasks throughout 40 hours of sleep deprivation under constant routine conditions. A prosaccade task required a reflexive saccade toward a stimulus (no conflict), while an antisaccade task required inhibiting a reflexive saccade to the peripheral stimulus, and looking in the mirror opposite instead (conflict resolution). Antisaccade inhibitory errors showed circadian modulation, being highest in the morning, progressively decreasing until melatonin onset, before returning to the prior morning's peak throughout the biological night. This diurnal rhythm was blunted by sleep loss (>24 hours), with inhibitory control remaining impaired across the second biological day. For prosaccade, responses slowed down during the biological night. Taken together, we provide evidence for a circadian modulation of attentional bias: the morning being biased toward reflexive responding, and the evening toward higher inhibitory control. Our data show that sleep loss and circadian timing differentially impact attention, depending on whether a response conflict is present (antisaccade) or absent (prosaccade)