The Neural Mechanisms Underlying Processing Speed Deficits in Individuals Who Have Sustained a Spinal Cord Injury: A Pilot Study.

Our objective was to determine differences in brain activation during a processing-speed task in individuals with SCI compared to a group of age-matched healthy controls and to a group of older healthy controls. Ten individuals with cervical SCI (C3-C5), 10 age-matched healthy controls and 10 older healthy controls participated in a cross-sectional study in which performance on neuropsychological tests of processing speed and brain activation were the main outcome measures. The brain areas used by the individuals with SCI during the processing-speed task differed significantly from the age-matched healthy controls, but were similar to the older control cohort, and included activation in frontal, parietal and hippocampal areas. This suggests that individuals with SCI may compensate for processing-speed deficits by relying on brain regions that classically support control cognitive processes such as executive control and memory.

Progressive resistance exercise training and changes in resting-state functional connectivity of the caudate in persons with multiple sclerosis and severe fatigue: A proof-of-concept study.

Fatigue is one of the most disabling symptoms of multiple sclerosis (MS). While progressive resistance training (PRT) has been shown to reduce fatigue in persons with MS, it is not clear why these reductions occur. One hypothesis is that PRT may induce functional changes to the caudate, a region highly implicated in MS fatigue. The aim of the current study was to study the effects of PRT on overall fatigue impact and resting-state functional connectivity of the caudate in persons with MS reporting severe fatigue. Participants were semi-randomly assigned to either a 16-week home-based PRT (n = 5) or stretching control (n = 5) condition. Both groups demonstrated reductions in overall fatigue impact (main effect of time: F = .84, d = .65). Significant group × time interactions were found, with the PRT group demonstrating post-training increases in functional connectivity between the caudate and left inferior parietal (F = 66.0, p < .001), bilateral frontal (both p < .001), and right insula (F = 21.8, p = .002) regions compared to the stretching group. Furthermore, greater post-training increases in functional connectivity between the caudate and left inferior parietal region were associated with greater decreases in cognitive fatigue (r = -.52) specifically. This study provides initial evidence for the caudate as a potential neural substrate for the beneficial effects of PRT on fatigue in persons with MS.

Fronto-striatal network activation leads to less fatigue in multiple sclerosis.

BACKGROUND: The fronto-striatal network has been implicated in both fatigue, a common multiple sclerosis (MS) symptom, and goal attainment, which has been shown to reduce fatigue in healthy individuals. OBJECTIVES: To investigate whether stimulation of the fronto-striatal network through goal attainment (potential monetary gain) leads to fatigue reduction in MS and healthy control (HC) participants. METHODS: In all, 14 healthy and 19 MS participants performed a gambling task during functional magnetic resonance imaging (fMRI). Participants were presented with an opportunity to receive monetary reward during the outcome condition of the task but not during the no outcome condition. Self-reported fatigue measures were obtained after each condition and outside of the scanner. Structural alterations were also examined. RESULTS: A significant decrease in fatigue was observed after the outcome condition compared to the no outcome condition in both groups. Significantly greater activation was observed in the ventral striatum in association with the outcome condition compared to the no outcome condition in both groups. Ventromedial prefrontal cortex showed significantly greater activation during the no outcome condition compared to the outcome condition with greater difference between conditions in the HC group. CONCLUSION: This is the first functional neuroimaging study showing that stimulation of the fronto-striatal network through goal attainment leads to decreased on-task fatigue in MS and healthy participants.

Awareness of Subjective Fatigue After Moderate to Severe Traumatic Brain Injury.

OBJECTIVE: As measurements of subjective fatigue after traumatic brain injury (TBI) rely on self-assessment, deficits in self-awareness after TBI may distort subjective fatigue reports. This study investigates awareness of subjective fatigue after TBI using self- and informant reports. PARTICIPANTS: Fourteen adults with moderate to severe TBI and 7 healthy controls (HCs). MEASURES: Modified Fatigue Impact Scale (MFIS) and battery of cognitive and emotional tests. Informants completed an "other-report," rating their perception of participant's fatigue. Subjective fatigue awareness was defined as discrepancy between self- and other-MFIS scores. RESULTS: Adults with TBI showed greater discrepancies between self- and other-MFIS scores than did HCs. Negative relations were found between fatigue awareness and symptoms of depression, but there were no relationships between fatigue awareness and cognitive performance. CONCLUSIONS: Results indicate that adults with TBI have poorer awareness of subjective fatigue than HCs. Correlations between subjective fatigue awareness and depression support existing literature implicating strong emotional components in the experience of subjective fatigue postinjury. Findings suggest cautious interpretation of subjective fatigue, as responses may not reflect fatigue symptoms exclusively.

Examining the Efficacy of the Modified Story Memory Technique (mSMT) in Persons With TBI Using Functional Magnetic Resonance Imaging (fMRI): The TBI-MEM Trial.

BACKGROUND: New learning and memory deficits are common following traumatic brain injury (TBI). Yet few studies have examined the efficacy of memory retraining in TBI through the most methodologically vigorous randomized clinical trial. Our previous research has demonstrated that the modified Story Memory Technique (mSMT) significantly improves new learning and memory in multiple sclerosis. METHODOLOGY: The present double-blind, placebo-controlled, randomized clinical trial examined changes in cerebral activation on functional magnetic resonance imaging following mSMT treatment in persons with TBI. Eighteen individuals with TBI were randomly assigned to treatment (n = 9) or placebo (n = 9) groups. RESULTS: Baseline and follow-up functional magnetic resonance imaging was collected during a list-learning task. Significant differences in cerebral activation from before to after treatment were noted in regions belonging to the default mode network and executive control network in the treatment group only. Results are interpreted in light of these networks. CONCLUSIONS: Activation differences between the groups likely reflect increased use of strategies taught during treatment. This study demonstrates a significant change in cerebral activation resulting from the mSMT in a TBI sample. Findings are consistent with previous work in multiple sclerosis. Behavioral interventions can show significant changes in the brain, validating clinical utility.

Functional magnetic resonance imaging movers and shakers: does subject-movement cause sampling bias?

Head movement during functional magnetic resonance imaging (fMRI) degrades data quality. The effects of small movements can be ameliorated during data postprocessing, but data associated with severe movement is frequently discarded. In discarding these data, it is often assumed that head-movement is a source of random error, and that data can be discarded from subjects with severe movement without biasing the sample. We tested this assumption by examining whether head movement was related to task difficulty and cognitive status among persons with multiple sclerosis (MS). Thirty-four persons with MS were scanned while performing a working memory task with three levels of difficulty (the N-back task). Maximum movement (angle, shift) was estimated for each difficulty level. Cognitive status was assessed by combining performance on a working memory and processing speed task. An interaction was found between task difficulty and cognitive status (high vs. low cognitive ability): there was a linear increase in movement as task difficulty increased that was larger among subjects with lower cognitive ability. Analyses of the signal-to-noise ratio (SNR) confirmed that increases in movement degraded data quality. Similar, though far smaller, effects were found in a cohort of healthy control (HC) subjects. Therefore, discarding data with severe movement artifact may bias MS samples such that only those with less-severe cognitive impairment are included in the analyses. However, even if such data are not discarded outright, subjects who move more (MS and HC) will contribute less to the group-level results because of degraded SNR.

Default network activity is a sensitive and specific biomarker of memory in multiple sclerosis.

BACKGROUND: Patients with multiple sclerosis (MS) suffer memory impairment but the link between MS-related neuroanatomical changes (brain atrophy) and memory is relatively weak. OBJECTIVE: The purpose of this study was to use functional magnetic resonance imaging (fMRI) to investigate task-induced default network (DN) deactivation as a neurophysiologic biomarker of memory functioning in MS. METHODS: Twenty-eight MS patients underwent high-resolution MRIs to measure brain atrophy (third ventricle width, cerebral gray matter, cerebral white matter, parenchymal fraction, and thalamic, caudate, hippocampal, and amygdala volumes), and fMRI blood oxygen level dependent (BOLD) signal to measure DN deactivation during sustained attention relative to rest. Neuropsychological assessment of episodic memory was performed on a separate day. We used hierarchical regression to predict memory, with age, education, and depression in step one, brain atrophy within step two, DN activity within step three, and the interaction between brain atrophy and DN activity in step four. RESULTS: Brain atrophy predicted worse memory but DN activity independently predicted memory over-and-above measurements of brain atrophy (R (2)=0.108), with greater DN activity (lesser deactivation) linked to better memory. A significant brain atrophy by DN activity interaction indicated a stronger relationship between memory and DN activity among patients with more advanced disease, at which point higher DN activity protects patients from disease/atrophy-related memory impairment. To establish specificity, we showed no relationship between DN activity and non-memory cognition, and no relationship between non-DN brain activity and memory. CONCLUSION: Maintenance of DN activity during sustained attention was supported as a sensitive and specific neurophysiologic biomarker of episodic memory functioning in MS, even when controlling for neuroanatomical changes (brain atrophy).

Neural correlates of cognitive fatigue: cortico-striatal circuitry and effort-reward imbalance.

Recently, there has been renewed interest in the study of cognitive fatigue. It is known that fatigue is one of the most disabling symptoms in numerous neurological populations, including stroke, multiple sclerosis, Parkinson's disease, and traumatic brain injury. Behavioral studies of cognitive fatigue are hampered by lack of correlation of self-report measures with objective performance. Neuroimaging studies provide new insight about cognitive fatigue and its neural correlates.Impairment within the cortico-striatal network, involved in effort­reward calculation, has been suggested to be critically related to fatigue. The current review surveys the recent neuroimaging literature, and suggests promising avenues for future research.

Autonomic Cardiovascular Control, Psychological Well-Being, and Cognitive Performance in People With Spinal Cord Injury.

PURPOSE: To examine associations between parameters of psychological well-being, injury characteristics, cardiovascular autonomic nervous system (ANS) control, and cognitive performance in persons with spinal cord injury (SCI) compared with age-matched uninjured controls. This is an observational, cross-sectional study including a total of 94 participants (52 with SCI and 42 uninjured controls: UIC). Cardiovascular ANS responses were continuously monitored at rest and during administration of the Paced Auditory Serial Addition Test (PASAT). Self-report scores on the SCI-Quality of Life questionnaires are reported for depression, anxiety, fatigue, resilience, and positive affect. Participants with SCI performed significantly more poorly on the PASAT compared with the uninjured controls. Although not statistically significant, participants with SCI tended to report more psychological distress and less well-being than the uninjured controls. In addition, when compared with uninjured controls, the cardiovascular ANS responses to testing were significantly altered in participants with SCI; however, these responses to testing did not predict PASAT performance. Self-reported levels of anxiety were significantly related to PASAT score in the SCI group, but there was no significant relationship between PASAT and the other indices of SCI-Quality of Life. Future investigations should more closely examine the relationship among cardiovascular ANS impairments, psychological disorders, and cognitive dysfunction to better elucidate the underpinnings of these deficits and to guide interventions aimed at improving physiological, psychological, and cognitive health after SCI. Tetraplegia, paraplegia, blood pressure variability, cognitive, mood.

Evaluating the effects of brain injury, disease and tasks on cognitive fatigue.

Because cognitive fatigue (CF) is common and debilitating following brain injury or disease we investigated the relationships among CF, behavioral performance, and cerebral activation within and across populations by combining the data from two cross-sectional studies. Individuals with multiple sclerosis (MS) were included to model CF resulting from neurological disease; individuals who had sustained a traumatic brain injury (TBI) were included to model CF resulting from neurological insult; both groups were compared with a control group (Controls). CF was induced while neuroimaging data was acquired using two different tasks. CF significantly differed between the groups, with the clinical groups reporting more CF than Controls-a difference that was statistically significant for the TBI group and trended towards significance for the MS group. The accrual of CF did not differ across the three groups; and CF ratings were consistent across tasks. Increasing CF was associated with longer response time for all groups. The brain activation in the caudate nucleus and the thalamus was consistently correlated with CF in all three groups, while more dorsally in the caudate, activation differed across the groups. These results suggest the caudate and thalamus to be central to CF while more dorsal aspects of the caudate may be sensitive to damage associated with particular types of insult.

Exercise-induced changes in gene expression do not mediate post exertional malaise in Gulf War illness.

Background: Post-exertional malaise (PEM) is considered a characteristic feature of chronic multi-symptom illnesses (CMI) like Gulf War illness (GWI); however, its pathophysiology remains understudied. Previous investigations in other CMI populations (i.e., Myalgic Encephalomyelitis/Chronic Fatigue Syndrome) have reported associations between PEM and expression of genes coding for adrenergic, metabolic, and immune function. Objectives: To investigate whether PEM is meditated by gene expression in Veterans with GWI. Methods: Veterans with GWI (n = 37) and healthy control Gulf War Veterans (n = 25) provided blood samples before and after 30-min of cycling at 70% of age-predicted heart rate reserve. Relative quantification of gene expression, symptom measurements, and select cardiopulmonary parameters were compared between groups at pre-, 30 minpost-, and 24 hpost-exercise using a doubly multivariate repeated measures analysis of variance (RM-MANOVA). Mediation analyses were used to test indirect effects of changes in gene expression on symptom responses (i.e., PEM) to the standardized exercise challenge. Results: Veterans with GWI experienced large symptom exacerbations following exercise compared to controls (Cohen's d: 1.65; p < 0.05). Expression of ß -actin (ACTB), catechol-O-methyltransferase (COMT), and toll-like receptor 4 (TLR4) decreased in Veterans with GWI at 30 min (p < 0.05) and 24 h post-exercise (p < 0.05). Changes in gene expression did not mediate post-exercise symptom exacerbation in GWI (Indirect Effect Slope Coefficient: 0.06 - 0.02; 95% CI: 0.19, 0.12). Conclusion: An acute bout of moderate intensity cycling reduced the expression of select structural, adrenergic, and immune genes in Veterans with GWI, but the pathophysiological relevance to PEM is unclear.

The effects of cognitive rehabilitation combined with aerobic exercise or stretching-and-toning on new learning and memory in persons with moderate-to-severe TBI: Protocol for a randomized controlled trial.

This paper describes the protocol for a Phase I/II, parallel-group, blinded randomized controlled trial that compares the effects of 12-weeks of combined learning and memory rehabilitation with either aerobic cycling exercise or stretching on cognitive, neuroimaging, and everyday life outcomes in 60 persons with moderate-to-severe traumatic brain injury (TBI) who demonstrate impairments in new learning. Briefly, participants will undergo baseline testing consisting of neuropsychological testing, neuroimaging, daily life measures, and cardiorespiratory fitness. Following baseline testing, participants will be randomized to one of 2 conditions (30 participants per condition) using concealed allocation. Participants will be masked as to the intent of the conditions. The conditions will both involve supervised administration of an enhanced, 8-week version of the Kessler Foundation modified Story Memory Technique, embedded within either 12-weeks of supervised and progressive aerobic cycling exercise training (experimental condition) or 12-weeks of supervised stretching-and-toning (active control condition). Following the 12-week intervention period, participants will complete the same measures as at baseline that will be administered by treatment-blinded assessors. The primary study outcome is new learning and memory impairment based on California Verbal Learning Test (CVLT)-III slope, the secondary outcomes include neuroimaging measures of hippocampal volume, activation, and connectivity, and the tertiary outcomes involve measures of daily living along with other cognitive outcomes. We further will collect baseline sociodemographic data for examining predictors of response heterogeneity. If successful, this trial will provide the first Class I evidence supporting combined memory rehabilitation and aerobic cycling exercise training for treating TBI-related new learning and memory impairment.

Associations of White Matter and Basal Ganglia Microstructure to Cognitive Fatigue Rate in Multiple Sclerosis.

Fatigue, including cognitive fatigue, is one of the most debilitating symptoms reported by persons with multiple sclerosis (pwMS). Cognitive fatigue has been associated with disruptions in striato-thalamo-cortical and frontal networks, but what remains unknown is how the rate at which pwMS become fatigued over time relates to microstructural properties within the brain. The current study aims to fill this gap in knowledge by investigating how cognitive fatigue rate relates to white matter and basal ganglia microstructure in a sample of 62 persons with relapsing-remitting MS. Participants rated their level of cognitive fatigue at baseline and after each block (x7) of a within-scanner cognitive fatigue inducing task. The slope of the regression line of all eight fatigue ratings was designated as "cognitive fatigue rate." Diffusional kurtosis imaging maps were processed using tract-based spatial statistics and regional analyses (i.e., basal ganglia) and associated with cognitive fatigue rate. Results showed cognitive fatigue rate to be related to several white matter tracts, with many having been associated with basal ganglia connectivity or the previously proposed "fatigue network." In addition, cognitive fatigue rate was associated with the microstructure within the putamen, though this did not survive multiple comparisons correction. Our approach of using cognitive fatigue rate, rather than trait fatigue, brings us closer to understanding how brain pathology may be impacting the experience of fatigue in the moment, which is crucial for developing interventions. These results hold promise for continuing to unpack the complex construct that is cognitive fatigue.

Fatigue Across the Lifespan in Men and Women: State vs. Trait.

Objective: Fatigue is commonly thought to worsen with age, but the literature is mixed: some studies show that older individuals experience more fatigue, others report the reverse. Some inconsistencies in the literature may be related to gender differences in fatigue while others may be due to differences in the instruments used to study fatigue, since the correlation between state (in the moment) and trait (over an extended period of time) measures of fatigue has been shown to be weak. The purpose of the current study was to examine both state and trait fatigue across age and gender using neuroimaging and self-report data. Methods: We investigated the effects of age and gender in 43 healthy individuals on self-reported fatigue using the Modified Fatigue Impact Scale (MFIS), a measure of trait fatigue. We also conducted fMRI scans on these individuals and collected self-reported measures of state fatigue using the visual analog scale of fatigue (VAS-F) during a fatiguing task. Results: There was no correlation between age and total MFIS score (trait fatigue) (r = -0.029, p = 0.873), nor was there an effect of gender [F (1,31) < 1]. However, for state fatigue, increasing age was associated with less fatigue [F (1,35) = 9.19, p < 0.01, coefficient = -0.4]. In the neuroimaging data, age interacted with VAS-F in the middle frontal gyrus. In younger individuals (20-32), more activation was associated with less fatigue, for individuals aged 33-48 there was no relationship, and for older individuals (55+) more activation was associated with more fatigue. Gender also interacted with VAS-F in several areas including the orbital, middle, and inferior frontal gyri. For women, more activation was associated with less fatigue while for men, more activation was associated with more fatigue. Conclusion: Older individuals reported less fatigue during task performance (state measures). The neuroimaging data indicate that the role of middle frontal areas change across age: younger individuals may use these areas to combat fatigue, but this is not the case with older individuals. Moreover, these results may suggest greater resilience in females than males when faced with a fatiguing task.

Signal Detection Theory as a Novel Tool to Understand Cognitive Fatigue in Individuals With Multiple Sclerosis.

Multiple Sclerosis (MS) affects 2.8 million persons worldwide. One of the most persistent, pervasive, and debilitating symptoms of MS is cognitive fatigue. While this has been known for over a century, cognitive fatigue has been difficult to study because patients' subjective (self-reported) cognitive fatigue has consistently failed to correlate with more objective measures, such as reaction time (RT) and accuracy. Here, we investigated whether more nuanced metrics of performance, specifically the metrics of Signal Detection Theory (SDT), would show a relationship to cognitive fatigue even if RT and accuracy did not. We also measured brain activation to see whether SDT metrics were related to activation in brain areas that have been shown to be sensitive to cognitive fatigue. Fifty participants (30 MS, 20 controls) took part in this study and cognitive fatigue was induced using four blocks of a demanding working memory paradigm. Participants reported their fatigue before and after each block, and their performance was used to calculate SDT metrics (Perceptual Certainty and Criterion) and RT and accuracy. The results showed that the SDT metric of Criterion (i.e., response bias) was positively correlated with subjective cognitive fatigue. Moreover, the activation in brain areas previously shown to be related to cognitive fatigue, such as the striatum, was also related to Criterion. These results suggest that the metrics of SDT may represent a novel tool with which to study cognitive fatigue in MS and other neurological populations. These results hold promise for characterizing cognitive fatigue in MS and developing effective interventions in the future.

Thalamic atrophy moderates associations among aerobic fitness, cognitive processing speed, and walking endurance in persons with multiple sclerosis.

BACKGROUND AND OBJECTIVES: Thalamic atrophy (TA) represents a biomarker of neurodegeneration and associated dysfunction/decline in physical and cognitive functioning among persons with multiple sclerosis (MS). Aerobic fitness, as an end point of exercise training, represents a promising target for restoring function in MS, but it is unknown if such effects differ by TA. This cross-sectional study examined whether aerobic fitness was differentially associated with cognitive processing speed and walking endurance in persons with MS who present with and without TA. METHODS: 44 fully ambulatory persons with MS completed a graded exercise test for measuring aerobic fitness (VO2peak) and underwent 3T MRI for measuring TA, the Symbol Digit Modalities Test (SDMT), and the 6-min walk (6MW). We performed Spearman correlations (rs) among VO2peak, SDMT, and 6MW scores overall, and in persons with and without TA. We applied Fisher's z-test for comparing correlations based on TA status. RESULTS: When controlling for age, EDSS score, and global MRI measures of atrophy, VO2peak was strongly associated with SDMT scores (prs = 0.74, p < 0.01) and 6MW performance (prs = 0.77, p < 0.01) in persons with TA, whereas VO2peak was not associated with SDMT scores (prs = - 0.01, p = 0.99) or 6MW performance (prs = 0.25, p = 0.38) in those without TA. The correlations between VO2peak and SDMT (z = 2.86, p < 0.01) and VO2peak and 6MW (z = 2.33, p = 0.02) were significantly stronger in the TA group. DISCUSSION: This study provides initial evidence of strong, selective associations among aerobic fitness, cognitive processing speed, and walking endurance in persons with TA as a biomarker for MS-related neurodegeneration. Such data support TA as a moderator of the association among aerobic fitness, cognitive processing speed, and walking endurance in persons with MS. Future research should carefully consider the role of TA when designing trials of aerobic exercise, cognition, and mobility in MS.

Intellectual enrichment is linked to cerebral efficiency in multiple sclerosis: functional magnetic resonance imaging evidence for cognitive reserve.

The cognitive reserve hypothesis helps to explain the incomplete relationship between brain disease and cognitive status in people with neurologic diseases, including Alzheimer's; disease and multiple sclerosis. Lifetime intellectual enrichment (estimated with education or vocabulary knowledge) lessens the negative impact of brain disease on cognition, such that people with greater enrichment are able to withstand more severe neuropathology before suffering cognitive impairment or dementia. The current research is the first to investigate directly the relationship between intellectual enrichment and an index of cerebral activity (the blood oxygen level dependent signal) in a neurologic sample. Multiple sclerosis patients completed a vocabulary-based estimate of lifetime intellectual enrichment. Disease severity was estimated with brain atrophy. Cognitive status was measured with the Symbol Digit Modalities Test. Cerebral activity (functional magnetic resonance imaging blood oxygen level dependent signal) and behavioural performance (accuracy, reaction time) were recorded during the visual N-Back working memory task (three levels of demand: 0-, 1-, 2-Back). All patients produced perfect/nearly perfect accuracy during lower demands (0- and 1-Back), and reaction time was unrelated to intellectual enrichment; however, voxelwise partial correlations controlling for brain atrophy revealed strong positive correlations between intellectual enrichment and cerebral activity within the brain's; default network (e.g. anterior and posterior cingulate corticies), indicating that patients with greater enrichment were able to maintain resting state activity during cognitive processing better. In turn, intellectual enrichment was negatively associated with prefrontal recruitment, suggesting that patients with lesser enrichment required more cerebral resources to perform the same cognitive task as patients with greater enrichment. This same pattern of enrichment-related cerebral activity was observed when cognitive demands increased (2-Back), and intellectual enrichment was negatively associated with reaction time. Principle components analysis revealed a single cognitive reserve network across tasks (greater default network, lesser prefrontal recruitment). Expression of this network almost fully mediated the positive relationship between intellectual enrichment and cognitive status (Symbol Digit Modalities Test). Also, expression of this network was positively associated with brain atrophy when controlling for cognitive status, indicating that patients with greater expression of this network can withstand more severe brain disease before exhibiting cognition similar to patients with lesser network expression. Of note, similar functional magnetic resonance imaging research with healthy adults has not found an association between intelligence and cerebral efficiency. The unique relationship between intellectual enrichment and cerebral efficiency in neurologic patients is consistent with the cognitive reserve hypothesis, which does not posit that enrichment leads to gains in neurocognitive functioning per se; rather, enrichment protects against neurocognitive decline secondarily to disease.

Are there control processes, and (if so) can they be studied?

Generally, so-called control processes are thought to be necessary when we must perform one out of several competing actions. Some examples include performance of a less well-practiced action instead of a well-practiced one (prepotency); learning a new action (novelty); and rapidly switching from one action to another (task-switching). While it certainly is difficult to perform the desired action in these circumstances, it is less clear that a separate set of processes (e.g., control processes) are necessary to explain the observed behavior. Another way to approach the study of control processes is to investigate physiological dependent measures (e.g., electrophysiological or neuroimaging measures). Although these offer another avenue of inquiry into control processes, they have yet to furnish unambiguous evidence that control processes exist. While this might suggest that there are no control processes, it is also possible that our methods are insufficiently sensitive to measure control processes. We have investigated this latter possibility using tasks that are neuroanatomically distinct, though within the same modality (vision). This approach did not yield evidence for a separable set of control processes. However, recent works using a task-switching paradigm in which subjects switch between a visual and an auditory task suggest that switching both task and modality may be importantly different than switching task within a given modality. This may represent a way forward in the study of control processes.

An internet-based survey of synesthesia in multiple sclerosis: Incidence, characteristics and implications.

Objective Prior work raises the interesting possibility that both multiple sclerosis and synesthesia share a common etiology, that being immune system dysfunction, as well as neuroanatomical and neurochemical abnormalities, including those involving white matter and serotonergic pathways, respectively. Given these links between these two syndromes, we examined the possibility that prevalence of synesthesia would be elevated in a population of individuals with MS, relative to what is thought to be the prevalence in the neurotypical population. It was not known whether synesthesia might be a marker for subsequent development of MS, or if synesthesia might reflect neurological damage resulting from MS disease progression. Method Individuals with self- reported clinically definite MS were recruited online via the internet and social media using sites specifically relevant to the MS community. Data from 147 individuals who completed several questionnaires related to synesthesia were analyzed. Results Depending on criteria, between approximately 7 and 16% of individuals with MS reported synesthesia here. This is an estimated 1.57 to 3.55 times increased incidence of synesthesia here relative to previous findings in neurotypical samples. Limitations of the study include that this was an internet survey, and that synesthesia was not directly assessed in this sample. Conclusions Results suggest a link between the syndromes, primarily indicating that synesthesia may be a marker for subsequent MS development, and the implications and directions for future study are discussed.

A pilot randomized controlled trial of robotic exoskeleton-assisted exercise rehabilitation in multiple sclerosis.

BACKGROUND: Co-occurring mobility and cognitive impairments are common, debilitating, and poorly-managed with pharmacological therapies in persons with multiple sclerosis (MS). Exercise rehabilitation (ER), particularly walking ER, has been suggested as one of the best approaches for managing these manifestations of MS. However, there is a focal lack of efficacy of ER on mobility and cognitive outcomes in persons with MS who present with substantial neurological disability. Such severe neurological disability oftentimes precludes the ability for participation in highly-intensive and repetitive ER that is necessary for eliciting adaptations in mobility and cognition. To address such a concern, robotic exoskeleton-assisted ER (REAER) might represent a promising intervention approach for managing co-occurring mobility and cognitive impairments in those with substantial MS disability who might not benefit from traditional ER. METHODS: The current pilot single-blind, randomized controlled trial (RCT) compared the effects of 4-weeks of REAER with 4-weeks of conventional gait training (CGT) as a standard-of-care control condition on functional mobility (timed up-and-go; TUG), walking endurance (six-minute walk test; 6MWT), cognitive processing speed (CPS; Symbol Digit Modalities Test; SDMT), and brain connectivity (thalamocortical resting-state functional connectivity (RSFC) based on fMRI) outcomes in 10 persons with substantial MS-related neurological disability. RESULTS: Overall, compared with CGT, 4-weeks of REAER was associated with large improvements in functional mobility (ηp2=.38), CPS (ηp2=.53), and RSFC between the thalamus and ventromedial prefrontal cortex (ηp2=.72), but not walking endurance (ηp2=.01). Further, changes in RSFC were moderately associated with changes in TUG, 6MWT, and SDMT performance, respectively, whereby increased thalamocortical RSFC was associated with improved functional mobility, walking endurance, and CPS (|ρ|>.36). CONCLUSION: The current pilot RCT provides initial support for REAER as an approach for improving functional mobility and CPS, perhaps based on adaptive and integrative central nervous system plasticity, namely increases in RSFC between the thalamus and ventromedial prefrontal cortex, in a small sample of persons with substantial MS disability. Such a pilot trial provides proof-of-concept data for the design and implementation of an appropriately-powered RCT of REAER in a larger sample of persons with MS who present with co-occurring impairments in both mobility and cognitive functioning.