Cognitive Fatigue In Multiple Sclerosis Research Articles

Subjective valuation of performance feedback is robust to trait cognitive fatigue in multiple sclerosis.

Performance feedback is vital to rehabilitation interventions that treat cognitive impairments from multiple sclerosis (MS). Optimal treatment relies on participants' motivation to learn from feedback throughout these interventions. Cognitive fatigue, a prevalent symptom of MS, is associated with aberrant reward processing, which necessitates research into how fatigue affects perceived reward value of feedback in these individuals. The current study investigated how trait fatigue influences subjective valuation of feedback and subsequent feedback-seeking behavior in people with MS. 33 MS and 32 neurotypical (NT) participants completed a willingness-to-pay associative memory paradigm that assessed feedback valuation via trial-by-trial decisions to either purchase or forego feedback in service of maximizing a performance-contingent monetary reward. Participant ratings of trait fatigue were also collected. Generalized logistic mixed modeling was used to analyze factors that influenced trial-wise feedback purchase decisions and task performance. Despite reporting greater trait fatigue, MS participants purchased comparable amounts of feedback as NT participants. Like NT participants, MS participants were more likely to purchase feedback when they were less confident about response accuracy. MS participants also performed comparably to NT participants, who both particularly benefited from purchase decisions that yielded negative feedback (i.e., indicating a response error). Trait cognitive fatigue may not impact performance feedback valuation in people with MS. Nonetheless, confidence in performance may drive their feedback-seeking behavior and may serve as a target for improving learning throughout cognitive rehabilitation and maximizing treatment success.

Dysfunction of basal ganglia functional connectivity associated with subjective and cognitive fatigue in multiple sclerosis.

Central fatigue is one of the most common symptoms in multiple sclerosis (MS). It has a profound impact on quality of life and a negative effect on cognition. Despite its widespread impact, fatigue is poorly understood and very difficult to measure. Whilst the basal ganglia has been implicated in fatigue the nature of its role and involvement with fatigue is still unclear. The aim of the present study was to establish the role of the basal ganglia in MS fatigue using functional connectivity measures. The present study examined the functional connectivity (FC) of the basal ganglia in a functional MRI study with 40 female participants with MS (mean age = 49.98 (SD = 9.65) years) and 40 female age-matched (mean age = 49.95 (SD = 9.59) years) healthy controls (HC). To measure fatigue the study employed the subjective self-report Fatigue Severity Scale and a performance measure of cognitive fatigue using an alertness-motor paradigm. To distinguish physical and central fatigue force measurements were also recorded. The results suggest that decreased local FC within the basal ganglia plays a key role in cognitive fatigue in MS. Increased global FC between the basal ganglia and the cortex may sub serve a compensatory mechanism to reduce the impact of fatigue in MS. The current study is the first to show that basal ganglia functional connectivity is associated with both subjective and objective fatigue in MS. In addition, the local FC of the basal ganglia during fatigue inducing tasks could provide a neurophysiological biomarker of fatigue.

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.

Cognitive fatigue in multiple sclerosis is associated with alterations in the functional connectivity of monoamine circuits.

Fatigue is a highly prevalent and debilitating symptom in multiple sclerosis, but currently the available treatment options have limited efficacy. The development of innovative and efficacious targeted treatments for fatigue in multiple sclerosis has been marred by the limited knowledge of the underlying mechanisms. One of the hypotheses postulates that multiple sclerosis pathology might cause reduced monoaminergic release in the central nervous system with consequences on motivation, mood and attention. Here, we applied the recently developed Receptor-Enriched Analysis of Functional Connectivity by Targets method to investigate whether patients with high and low fatigue differ in the functional connectivity (FC) of the monoamine circuits in the brain. We recruited 55 patients with multiple sclerosis, which were then classified as highly fatigued or mildly fatigued based on their scores on the cognitive sub-scale of the Modified Fatigue Impact scale. We acquired resting-state functional MRI scans and derived individual maps of connectivity associated with the distribution of the dopamine, noradrenaline and serotonin transporters as measured by positron emission tomography. We found that patients with high fatigue present decreased noradrenaline transporter (NAT)-enriched connectivity in several frontal and prefrontal areas when compared to those with lower fatigue. The NAT-enriched FC predicted negatively individual cognitive fatigue scores. Our findings support the idea that alterations in the catecholaminergic functional circuits underlie fatigue in multiple sclerosis and identify the NAT as a putative therapeutic target directed to pathophysiology.

An Integrative Review of Causes, Manifestations and Evaluation of Cognitive Fatigue among Persons with Multiple Sclerosis

Background: Fatigue is the most distinguishing symptom for patients with Multiple Sclerosis (MS) and for some of these patients it can be quite disabling. Studies exploring MS-related fatigue have differentiated this into various dimensions: motor, cognitive, physical, psychosocial, performance, and subjective. It is the cognitive dimension that can have serious consequences such as loss of vocation, independence, and possibly, more relapses or worsening of the disease. Objective: The aims of this integrative review were to explore the advances in understanding cognitive fatigue in MS, as well as its causes and manifestations, and to identify the objective methodologies that best measure cognitive fatigue in MS. Methodology: An integrative review of the scientific literature was performed using methods and criteria following the PRISMA-P2015 guidelines for data extraction. The studies were critically appraised using the Rapid Critical Appraisal and the qualitative study method of Constant Comparison. Results: Twenty-three studies (2010-2019) were identified from the United States and other countries. The majority of articles were published within the last three years. Evaluation of outcomes from these studies was conducted through self-reporting. Cognitive fatigue may result in more relapses among those with relapsing and remitting MS and from those with secondary progressive MS. Cognitive fatigue and physical fatigue should be considered distinct domains. Conclusion and Recommendations: An increasing number of studies focused on cognitive fatigue, however, there is no standard definition or conceptual framework available to understand this phenomenon. Various methodologies were identified to evaluate cognitive fatigue. Additionally, there should be a valid, reliable, and readily available instrument for use in the clinical setting. Keywords: Multiple Sclerosis, Cognitive Fatigue, Fatigue, Integrative Review

Cognitive Fatigue in Multiple Sclerosis: An Objective Approach to Diagnosis and Treatment by Transcranial Electrical Stimulation.

Cognitive fatigue is one of the most frequent symptoms in multiple sclerosis (MS), associated with significant impairment in daily functioning and quality of life. Despite its clinical significance, progress in understanding and treating fatigue is still limited. This limitation is already caused by an inconsistent and heterogeneous terminology and assessment of fatigue. In this review, we integrate previous literature on fatigue and propose a unified schema aiming to clarify the fatigue taxonomy. With special focus on cognitive fatigue, we survey the significance of objective behavioral and electrophysiological fatigue parameters and discuss the controversial literature on the relationship between subjective and objective fatigue assessment. As MS-related cognitive fatigue drastically affects quality of life, the development of efficient therapeutic approaches for overcoming cognitive fatigue is of high clinical relevance. In this regard, the reliable and valid assessment of the individual fatigue level by objective parameters is essential for systematic treatment evaluation and optimization. Transcranial electrical stimulation (tES) may offer a unique opportunity to manipulate maladaptive neural activity underlying MS fatigue. Therefore, we discuss evidence for the therapeutic potential of tES on cognitive fatigue in people with MS.

Electrophysiological and behavioral effects of frontal transcranial direct current stimulation on cognitive fatigue in multiple sclerosis.

Fatigue is one of the most common and debilitating symptoms affecting patients with multiple sclerosis (MS). Sustained cognitive effort induces cognitive fatigue, operationalized as subjective exhaustion and fatigue-related objective alertness decrements with time-on-task. During prolonged cognitive testing, MS patients show increased simple reaction times (RT) accompanied by lower amplitudes and prolonged latencies of the P300 event-related potential. Previous studies suggested a major role of structural and functional abnormalities in the frontal cortex including a frontal hypo-activation in fatigue pathogenesis. In the present study we investigated the neuromodulatory effect of transcranial direct current stimulation (tDCS) over the left dorsolateral prefrontal cortex (DLPFC) on objective measures of fatigue-related decrements in cognitive performance in MS patients. P300 during an auditory oddball task and simple reaction times in an alertness test were recorded at baseline, during and after stimulation. Compared to sham, anodal tDCS caused an increase in P300 amplitude that persisted after the end of stimulation and eliminated the fatigue-related increase in RT over the course of a testing session. Our findings demonstrate that anodal tDCS over the left DLPFC can counteract performance decrements associated with fatigue thereby leading to an improvement in the patient's ability to cope with sustained cognitive demands. This provides causal evidence for the functional relevance of the left DLPFC in fatigue pathophysiology. The results indicate that tDCS-induced modulations of frontal activity can be an effective therapeutic option for the treatment of fatigue-related declines in cognitive performance in MS patients.

P316 Influence of transcranial direct current stimulation on electrophysiological and behavioral correlates of cognitive fatigue in multiple sclerosis

Introduction Cognitive fatigue is one of the most common and difficult to treat symptoms affecting patients with Multiple Sclerosis (MS). Previous studies suggested structural and functional abnormalities in the frontal cortex, especially a frontal hypo-activation, as a possible substrate for fatigue. Fatigue severity can be quantified by prolonged reaction times (RT) in alertness tests accompanied by lower amplitudes of the P300 event-related potential. Objectives In the present study we investigated whether neuromodulation of the left dorsolateral prefrontal cortex (DLPFC) by means of transcranial direct current stimulation (tDCS) has influence on electrophysiological and behavioral correlates of cognitive fatigue in MS. Materials and Methods: 15 MS patients with cognitive fatigue symptoms were enrolled in the study. In two sessions they were either stimulated with anodal tDCS (1.5 mA, 25 min) or sham stimulation over the left DLPFC. To assess fatigue severity, P300 during an auditory oddball task and performance on a simple reaction time test were recorded at baseline, during and after stimulation. Results Analysis revealed a significant stimulation effect on the P300 component. Compared to baseline, anodal but not sham tDCS caused an increase in P300 amplitude that persisted after the end of stimulation. In addition, anodal tDCS significantly attenuated the fatigue-related increase in RT over the course of a testing session. Conclusion Our findings demonstrate that a single dose of anodal tDCS over the left DLPFC has positive effects on electrophysiological and behavioral correlates of cognitive fatigue. In accordance with previous studies that showed a subjective fatigue relief by repeated stimulation sessions, our findings give important insight into the potential underlying mode of action of tDCS. The results provide causal evidence for a functional relevance of the left DLPFC in the pathogenesis of cognitive fatigue and show that tDCS-induced modulations of frontal activity can be a promising therapeutic option for the treatment of MS-related fatigue.

A study of cognitive fatigue in Multiple Sclerosis with novel clinical and electrophysiological parameters utilizing the event related potential P300

BackgroundAlthough cognitive fatigue plays a significant part in Multiple Sclerosis (MS) related impairment, knowledge regarding it is largely lacking. Until now, not many tools are available to a clinician to detect cognitive fatigue. The subjective tools of fatigue have never been reliable.tabl ObjectivesTo assess the prevalence and clinical/ demographic profile of cognitive fatigue in MS using novel clinical and electrophysiological measures and to find their accuracy. We also aimed to test the three leading hypotheses - the temporal fatigue, cognitive load and cognitive domain hypotheses of cognitive fatigue in MS. Methods50 consecutive MS patients attending the Neurology OPD in Madras Medical College, Chennai from May 2015 to February 2016 satisfying the 2010 revised McDonald criteria for MS with an equal number of matched controls were recruited. Modified versions (a shorter version, and longer and more demanding versions) of the Stroop test, symbol digit modalities test, and serial addition tests were used in addition to modified tests of P300 latency and amplitude each specifically tailored to reveal cognitive fatigue. ResultsOut of the seven measures of cognitive fatigue used, 46% (n=23) of MS patients had impairment in two or more of the scores compared to that of 8% (n=4) in the healthy control group. The Expanded disability status scale (EDSS) scores were significantly higher for MS patients with cognitive fatigue compared to those without. All the clinical and electrophysiological measures used in this study had a relatively high sensitivity and specificity. In addition, all the clinical measures correlated with the electrophysiological measures of cognitive fatigue in this study. Our data also supported all three hypotheses implying that cognitive fatigue in MS may be a multifaceted entity. ConclusionCognitive fatigue is widely prevalent in MS and can be detected with specific tools. The tools developed and described in this study may be used as an effective means of detecting cognitive fatigue in MS patients and thus allowing patients to realise their limitations. Institution of appropriate remedial measures like advising such patients to break up a more cognitively demanding task into smaller subtasks may help to improve their quality of life.

Diagnosis and quantification of cognitive fatigue in multiple sclerosis.

To standardize a method to measure cognitive fatigue in patients with multiple sclerosis (MS). Many patients with MS complain of cognitive fatigue, defined as a decline in cognitive performance during a task requiring sustained activity. Until now there has not been a standardized way to detect cognitive fatigue or determine its severity. We administered the Paced Auditory Serial Addition Test (PASAT) to 130 normal controls and 100 randomly selected patients with MS, and compared the number of correct responses between the first third and last third of the test. The controls averaged 2 more correct responses in the last third of the PASAT than in the first third. The patients with MS averaged 2 to 3 fewer correct responses in the last third than the first third. Our study showed that comparing responses between the first and last thirds of the PASAT is a reliable method to measure cognitive fatigue in patients with MS. We also present normative data to be used to determine whether patients with MS have cognitive fatigue.

Integrity of hypothalamic fibers and cognitive fatigue in multiple sclerosis

Cognitive fatigue is a common and disabling symptom of multiple sclerosis (MS), but little is known about its pathophysiology. The present study investigated whether the posterior hypothalamus, which is considered as the waking center, is associated with MS-related cognitive fatigue. We analyzed the integrity of posterior hypothalamic fibers in 49 patients with relapsing-remitting MS and 14 healthy controls. Diffusion tensor imaging (DTI) parameters were calculated for fibers between the posterior hypothalamus and, respectively, the mesencephalon, pons and prefrontal cortex. In addition, DTI parameters were computed for fibers between the anterior hypothalamus and these regions and for the corpus callosum. Cognitive fatigue was assessed using the Fatigue Scale for Motor and Cognitive Functions. Analyses of variance with repeated measures were performed to investigate the impact of cognitive fatigue on diffusion parameters. Cognitively fatigued patients (75.5%) showed a significantly lower mean axial and radial diffusivity for fibers between the posterior hypothalamus and the mesencephalon than cognitively non-fatigued patients (Group⁎Target area⁎Diffusion orientation: F=4.047; p=0.023). For fibers of the corpus callosum, MS patients presented significantly higher axial and radial diffusivity than healthy controls (Group⁎Diffusion orientation: F=9.904; p<0.001). Depressive mood, used as covariate, revealed significant interaction effects for anterior hypothalamic fibers (Target area⁎Diffusion orientation⁎Depression: F=5.882; p=0.021; Hemisphere⁎Diffusion orientation⁎ Depression: F=8.744; p=0.008). Changes in integrity of fibers between the posterior hypothalamus and the mesencephalon appear to be associated with MS-related cognitive fatigue. These changes might cause an altered modulation of hypothalamic centers responsible for wakefulness. Furthermore, integrity of anterior hypothalamic fibers might be related to depression in MS.

Subjective cognitive fatigue in multiple sclerosis depends on task length.

Objective: The objective of this paper is to investigate the interrelationship between subjective and objective cognitive fatigue, information processing domain [processing speed (PS) vs. working memory (WM)], cognitive load (high vs. low), and time on task in Multiple Sclerosis (MS).Methods: Thirty-two MS participants and 24 healthy controls completed experimental tasks in both the PS and WM domains with different levels of cognitive load. Subjective cognitive fatigue was measured using a visual analog scale at baseline and at multiple time points throughout the experiment.Results: A mixed model ANOVA revealed that subjective cognitive fatigue was higher for the PS task, increased across time, and was higher in the MS group. These findings were qualified by an interaction demonstrating that the MS group showed a steeper increase in subjective cognitive fatigue over time than the healthy control group. Subjective and objective (i.e., performance) cognitive fatigue were not correlated.Conclusion: In this study, subjective and objective cognitive fatigue appears to be independent and cognitive fatigue does not depend on cognitive load. Subjective cognitive fatigue increased with time on task and subjective cognitive fatigue increased more steeply for the MS group. These data suggest that cognitive fatigue in MS is a function of time, that is, the longer participants were engaged in a cognitive task, the more likely it was for them to report increases in cognitive fatigue.

Examination of Cognitive Fatigue in Multiple Sclerosis using Functional Magnetic Resonance Imaging and Diffusion Tensor Imaging

The present study investigated the neural correlates of cognitive fatigue in Multiple Sclerosis (MS), looking specifically at the relationship between self-reported fatigue and objective measures of cognitive fatigue. In Experiment 1, functional magnetic resonance imaging (fMRI) was used to examine where in the brain BOLD activity covaried with “state” fatigue, assessed during performance of a task designed to induce cognitive fatigue while in the scanner. In Experiment 2, diffusion tensor imaging (DTI) was used to examine where in the brain white matter damage correlated with increased “trait” fatigue in individuals with MS, assessed by the Fatigue Severity Scale (FSS) completed outside the scanning session. During the cognitively fatiguing task, the MS group had increased brain activity associated with fatigue in the caudate as compared with HCs. DTI findings revealed that reduced fractional anisotropy in the anterior internal capsule was associated with increased self-reported fatigue on the FSS. Results are discussed in terms of identifying a “fatigue-network” in MS.

Response variability is associated with self-reported cognitive fatigue in multiple sclerosis.

Cognitive fatigue is a common, often debilitating symptom of multiple sclerosis (MS). Although MS patients frequently report that fatigue negatively affects cognitive functioning, most studies have found little evidence for a direct relationship between self-reported cognitive fatigue and traditional measures of neuropsychological functioning. The purpose of the present study was to examine the association between self-reported cognitive fatigue and a measure of response time variability (RTV). MS patients demonstrated significantly higher RTV than controls, and RTV was highly correlated with self-reported cognitive fatigue among relapsing-remitting and secondary progressive MS patients. Results highlight the need to implement newer methods to further elucidate the relationship between cognitive fatigue and neuropsychological functioning in MS.

Neural correlates of cognitive fatigue in multiple sclerosis using functional MRI

Although fatigue is one of the major symptoms of persons with multiple sclerosis (MS), the behavioral and neural correlates are poorly understood. The present study utilized a novel approach to cognitive fatigue examining objective behavioral performance while simultaneously monitoring brain activity using fMRI. Fifteen persons with MS and 15 healthy controls were given 4 trials of a behavioral task assessing processing speed (mSDMT) during fMRI acquisition. It was hypothesized that individuals with MS would show an abnormal pattern of activity across time in specific brain areas previously hypothesized to subserve fatigue [Chaudhuri A, Behan PO. Fatigue and basal ganglia. J Neurol Sci 2000;179:34-42]. Specifically, it was hypothesized that persons with MS would show a greater increase in cerebral activation across time during behavioral performance than that seen in healthy controls, which was interpreted as fatigue. No difference in performance accuracy on the mSDMT was observed, although the MS group was significantly slower than controls. Behavioral alterations indicative of fatigue in the MS group were associated with increased activation in the basal ganglia, frontal areas including superior, medial, middle and inferior regions, parietal regions (precuneus and cuneus), thalamus and the occipital lobes. These data provide direct support for the Chaudhuri and Behan model of "central" fatigue which hypothesizes a specific role of the "non-motor" functions of the basal ganglia.

Cognitive fatigue in multiple sclerosis: Findings from a two-wave screening project

Background Multiple sclerosis (MS) patients commonly suffer from fatigue and define it as one of their most disabling symptom profoundly disrupting their lives. However, the relationship of fatigue to cognitive functions and its impact on quality of life have not been widely studied. Aim To define (1) “cognitive fatigue”, (2) survey its frequency and (3) characterize severity and impact on quality of life in MS patients in the first 10 years of the disease. Methods A two-wave design was utilized to enrich the studied population in subjects whose fatigue is significant. In the first wave, fatigue was measured by the self-reported fatigue severity scale (FSS) in randomly selected MS patients from our computerized database. Patients responding to the 9th item of the FSS i.e., “Fatigue interferes with my work, family, or social life” by a grade of 3 or higher (of 7) were further assessed (wave two) by the fatigue impact scale (FIS) and the RAYS quality of life questionnaire. Results Of the 259 patients that completed the first-wave screening, 158 patients (61%, 118 females, mean age 41.1 ± 9.2 years, mean disease duration 6.2 ± 5.5 years) satisfied the additional criterion and were defined to suffer from significant fatigue. The great majority of these patients–91.7%–had a relapsing–remitting disease course, mean FIS score was 77 ± 25.9 and their mean EDSS was 2.9 ± 2.6. Fatigue was reported to occur most of the day in 30.9% of patients, persist in 69% for more than 1 year, and in 59.8%, it was reported not to be associated with effort. No correlations were found between age, gender, disease duration or neurological disability and FIS cognitive subscale score. Significant correlations were found between the FIS cognitive subscale score and the three domains (physical, psychological and social-familial) of the RAYS quality of life questionnaire ( p < 0.001). Conclusions Cognitive fatigue was found in more than half of MS patients in the first decade from onset that were particularly selected for significant fatigue in their lives. This aspect of fatigue correlated with all quality of life domains and especially with psychological everyday tasks.

Changes in Neuropsychological Test Performance Over the Workday in Multiple Sclerosis

Fatigue, a common symptom of multiple sclerosis (MS), is associated with impairment in performing daily activities, poor quality of life and premature retirement from the workforce. There is little doubt that patients with MS can exhibit marked weakness and other objective signs of physical fatigue, but whether cognitive performance by patients declines more rapidly than that by controls as a function of time engaged in mental activity remains controversial. Krupp and Elkins (2000) reported more rapid deterioration of performance by MS patients on two of five cognitive measures when subjects performed 3 hr of continuously effortful tasks between baseline and posttest. Others, using shorter and less taxing interpolated tasks found similar changes in performance over time for patients and controls. In the present study participants completed a timed walk, fatigue ratings and four cognitive tests that emphasized processing novel information before they went to work and again after completing a normal workday. Patients with MS walked somewhat more slowly and performed more poorly on two of the cognitive tests, but they did not show more decline from baseline to posttest on any of these objective measures of cognitive fatigue. By contrast, subjective ratings of fatigue showed a greater increase over the day for patients than for controls. These results confirm other reports that patients’ subjective ratings of their fatigue are not valid indicators of their actual performance on cognitive tests. Furthermore, laboratory studies that report “objective” cognitive fatigue in MS may utilize conditions that model the cognitive fatigue associated with the jobs patients actually perform rather poorly.