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.

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.

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.

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.

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.

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.

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.

Effects of walking exercise training on learning and memory and hippocampal neuroimaging outcomes in MS: A targeted, pilot randomized controlled trial.

PURPOSE: The current pilot study involved a single-blind, randomized controlled trial (RCT) on the effects of treadmill walking exercise training compared with an active control condition on learning and memory (L/M) and hippocampal neuroimaging outcomes in 11 fully-ambulatory persons with multiple sclerosis (MS) who demonstrated impairments in new learning. METHODS: The study protocol is registered at clinicaltrials.gov: NCT03319771 (February 2018). Eleven fully-ambulatory persons with MS-related impairments in new learning were randomly assigned into either 12-weeks of supervised, treadmill walking exercise training or 12-weeks of low-intensity resistive exercise (active control condition). Participants underwent neuropsychological tests of L/M and hippocampal neuroimaging before and after the 12-week study period; outcomes were administered by treatment-blinded assessors. RESULTS: There were moderate-to-large intervention effects on measures of verbal L/M (ηp2 = 0.11, d = 0.63, 95% CI: -0.61, 1.83), whereby those in the intervention condition demonstrated improvement in California Verbal Learning Test-II (CVLT-II) scores compared with the control condition. There were smaller effects on a composite L/M measure (ηp2 = 0.02, d = 0.28, 95% CI: -0.93, 1.46). There were large intervention effects on normalized hippocampal volume (ηp2 = 0.36, d = 1.13, 95% CI: 0.09, 2.82), whereby hippocampal volume was preserved in the intervention condition, compared with hippocampal atrophy in the control condition. By comparison, there were no intervention effects on hippocampal resting-state functional connectivity. CONCLUSIONS: Collectively, this study provides initial proof-of-concept data for further examining treadmill walking exercise training as a possible behavioral approach for managing L/M impairment and preserving hippocampal volume as common and debilitating manifestations of MS.

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.

Predicting post-exertional malaise in Gulf War Illness based on acute exercise responses.

AIMS: Post-exertional malaise (PEM) is poorly understood in Gulf War Illness (GWI). Exercise challenges have emerged as stimuli to study PEM; however, little attention has been paid to unique cardiorespiratory and perceptual responses during exercise. This study tested whether select exercise parameters explained variability in PEM responses. MAIN METHODS: Visual analog scale (0-100) versions of the Kansas questionnaire were used for daily symptom measurements one week before and one week after 30-min of cycling at 70% heart rate reserve in 43 Veterans with GWI and 31 Veteran controls (CON). Cardiopulmonary exercise testing (CPET) methods were used to measure oxygen (VO2), carbon dioxide (VCO2), ventilation (VE), heart rate, work rate, and leg muscle pain. Symptom changes and CPET parameters were compared between groups with independent samples t-tests. Linear regression (GLM) with VE/VCO2, cumulative work, leg muscle pain, and self-reported physical function treated as independent variables and peak symptom response as the dependent variable tested whether exercise responses predicted PEM. KEY FINDINGS: Compared to CON, Veterans with GWI had greater ventilatory equivalent for oxygen (VE/VO2), peak leg muscle pain, fatigue, and lower VCO2, VO2, power, and cumulative work during exercise (p < 0.05), and greater peak symptom responses (GWI = 38.90 ± 29.06, CON = 17.84 ± 28.26, g = 0.70, p < 0.01). The final GLM did not explain significant variance in PEM (Pooled R2 = 0.15, Adjusted R2 = 0.03, p = 0.34). SIGNIFICANCE: The PEM response was not related to the selected combination of cardiorespiratory and perceptual responses to exercise.

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.

Cognitive Fatigue Is Associated with Altered Functional Connectivity in Interoceptive and Reward Pathways in Multiple Sclerosis.

Cognitive fatigue is common and debilitating among persons with multiple sclerosis (pwMS). Neural mechanisms underlying fatigue are not well understood, which results in lack of adequate treatment. The current study examined cognitive fatigue-related functional connectivity among 26 pwMS and 14 demographically matched healthy controls (HCs). Participants underwent functional magnetic resonance imaging (fMRI) scanning while performing a working memory task (n-back), with two conditions: one with higher cognitive load (2-back) to induce fatigue and one with lower cognitive load (0-back) as a control condition. Task-independent residual functional connectivity was assessed, with seeds in brain regions previously implicated in cognitive fatigue (dorsolateral prefrontal cortex (DLPFC), ventromedial prefrontal cortex (vmPFC), dorsal anterior cingulate cortex (dACC), insula, and striatum). Cognitive fatigue was measured using the Visual Analogue Scale of Fatigue (VAS-F). Results indicated that as VAS-F scores increased, HCs showed increased residual functional connectivity between the striatum and the vmPFC (crucial in reward processing) during the 2-back condition compared to the 0-back condition. In contrast, pwMS displayed increased residual functional connectivity from interoceptive hubs-the insula and the dACC-to the striatum. In conclusion, pwMS showed a hyperconnectivity within the interoceptive network and disconnection within the reward circuitry when experiencing cognitive fatigue.

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.

Neural mechanisms underlying state mental fatigue in multiple sclerosis: a pilot study.

Neuroimaging underpinnings of state (in the moment, transient) mental fatigue in multiple sclerosis (MS) are not well understood. The current pilot study examined the effect of state mental fatigue on brain activation (measured using functional magnetic resonance imaging [fMRI]) during conditions of varying cognitive loads of rapid information processing in persons with MS relative to healthy controls. Nineteen persons with MS and 17 healthy controls underwent fMRI scanning while performing a modified version of the Symbol Digit Modalities Test, which consisted of high and low cognitive load conditions with comparable visual stimulation. State mental fatigue was assessed using the Visual Analog Scale of Fatigue before and after each run of the behavioral task. Results indicated that the healthy control group recruited significantly more anterior brain regions (superior and middle frontal gyri, insula, and superior temporal gyrus) to meet increased task demands during the high cognitive load condition as fatigue level increased (p < 0.05), which was accompanied by shorter response time. In contrast, the MS group did not recruit anterior areas to the same extent as the healthy control group as task demands and fatigue increased. Indeed, the MS group continued to activate more posterior brain regions (precuneus, lingual gyrus, and middle occipital gyrus) for the high cognitive load condition (p < 0.05) with no improvement in speed. In conclusion, persons with MS may allocate neural resources less efficiently than healthy controls when faced with increased task demands, which may result in increased mental fatigue. Results of the current pilot investigation warrant replication with a larger sample size.

Walking and cognitive performance in adults with multiple sclerosis: Do age and fatigability matter?

BACKGROUND: Co-occurring walking and cognitive performance deficits are debilitating consequences of multiple sclerosis (MS) that worsen with age. However, it is unknown if fatigability influences such age-related worsening of walking and cognitive performance. OBJECTIVE: This cross-sectional study examined possible age-related differences in walking-related motor fatigability (incremental six-minute-walk (6MW) performance) and cognitive fatigability (incremental Symbol Digit Modalities Test (SDMT) performance) in adults with MS. METHODS: 196 adults with MS were categorized into age-groups: younger (20-39 years; n = 53), middle-aged (40-59 years; n = 89), and older (60-79 years; n = 54), and completed the 6MW and SDMT. Age-group differences in incremental 6MW and SDMT performance, controlling for disability status, were examined using separate, mixed-factor ANCOVAs. RESULTS: There were no statistically significant age-group-by-time interactions on walking-related motor or cognitive fatigability when controlling for disability. However, there were significant main effects of time on incremental 6MW (p = 0.01) and SDMT (p < 0.01) performance indicating the presence of walking-related motor and cognitive fatigability, respectively, collapsed across age-groups. CONCLUSION: Fatigability does not exert a primary influence on age-related worsening of walking and cognitive neuroperformance outcomes among adults with MS. This suggests that walking-related motor fatigability and cognitive fatigability may not be optimal targets for mitigating age-related declines in ambulation and cognition among adults with MS.

Reward presentation reduces on-task fatigue in traumatic brain injury.

While cognitive fatigue is experienced by up to 80% of individuals with traumatic brain injury (TBI), little is known about its neural underpinnings. We previously hypothesized that presentation of rewarding outcomes leads to cognitive fatigue reduction and activation of the striatum, a brain region shown to be associated with cognitive fatigue in clinical populations and processing of rewarding outcomes. We have demonstrated this in individuals with multiple sclerosis. Here, we tested this hypothesis in individuals with TBI. Twenty-one individuals with TBI and 24 healthy participants underwent functional magnetic resonance imaging. Participants performed a task during which they were presented with 1) the Outcome condition where they were exposed to monetary rewards, and 2) the No Outcome condition that served as the control condition and was not associated with monetary rewards. In accordance with our hypothesis, results showed that attainment of rewarding outcomes leads to cognitive fatigue reduction in individuals with TBI, as well as activation of the striatum. Specifically, we observed a significant group by condition interaction on fatigue scores driven by the TBI group reporting lower levels of fatigue after the Outcome condition. fMRI data revealed a significant main-effect of condition in regions previously implicated in outcome processing, while a significant group by condition interaction was observed in the left ventral striatum as revealed by a priori region of interest analysis. Results suggest that a salient motivator can significantly reduce fatigue and that outcome presentation leads to increased activation of the ventral striatum in TBI. These findings can inform the development of future non-pharmacological cognitive fatigue treatment methods and contribute to the growing body of evidence showing the association between cognitive fatigue and the striatum.

Using Signal Detection Theory to Better Understand Cognitive Fatigue.

When we are fatigued, we feel that our performance is worse than when we are fresh. Yet, for over 100 years, researchers have been unable to identify an objective, behavioral measure that covaries with the subjective experience of fatigue. Previous work suggests that the metrics of signal detection theory (SDT)-response bias (criterion) and perceptual certainty (d')-may change as a function of fatigue, but no work has yet been done to examine whether these metrics covary with fatigue. Here, we investigated cognitive fatigue using SDT. We induced fatigue through repetitive performance of the n-back working memory task, while functional magnetic resonance imaging (fMRI) data was acquired. We also assessed cognitive fatigue at intervals throughout. This enabled us to assess not only whether criterion and d' covary with cognitive fatigue but also whether similar patterns of brain activation underlie cognitive fatigue and SDT measures. Our results show that both criterion and d' were correlated with changes in cognitive fatigue: as fatigue increased, subjects became more conservative in their response bias and their perceptual certainty declined. Furthermore, activation in the striatum of the basal ganglia was also related to cognitive fatigue, criterion, and d'. These results suggest that SDT measures represent an objective measure of cognitive fatigue. Additionally, the overlap and difference in the fMRI results between cognitive fatigue and SDT measures indicate that these measures are related while also separate. In sum, we show the relevance of SDT measures in the understanding of fatigue, thus providing researchers with a new set of tools with which to better understand the nature and consequences of cognitive fatigue.

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.