Ekaterina Dobryakova

The Dopamine Imbalance Hypothesis of Fatigue in Multiple Sclerosis and Other Neurological Disorders

Fatigue is one of the most pervasive symptoms of multiple sclerosis (MS), and has engendered hundreds of investigations on the topic. While there is a growing literature using various methods to study fatigue, a unified theory of fatigue in MS is yet to emerge. In the current review, we synthesize findings from neuroimaging, pharmacological, neuropsychological, and immunological studies of fatigue in MS, which point to a specific hypothesis of fatigue in MS: the dopamine imbalance hypothesis. The communication between the striatum and prefrontal cortex is reliant on dopamine, a modulatory neurotransmitter. Neuroimaging findings suggest that fatigue results from the disruption of communication between these regions. Supporting the dopamine imbalance hypothesis, structural and functional neuroimaging studies show abnormalities in the frontal and striatal regions that are heavily innervated by dopamine neurons. Further, dopaminergic psychostimulant medication has been shown to alleviate fatigue in individuals with traumatic brain injury, chronic fatigue syndrome, and in cancer patients, also indicating that dopamine might play an important role in fatigue perception. This paper reviews the structural and functional neuroimaging evidence as well as pharmacological studies that suggest that dopamine plays a critical role in the phenomenon of fatigue. We conclude with how specific aspects of the dopamine imbalance hypothesis can be tested in future research.

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.

Investigation of Information Flow During a Novel Working Memory Task in Individuals with Traumatic Brain Injury

Working memory (WM) is often compromised after traumatic brain injury (TBI). A number of functional and effective connectivity studies investigated the interaction between brain regions during WM task performance. However, previously used WM tasks did not allow differentiation of WM subprocesses such as capacity and manipulation. We used a novel WM paradigm, CapMan, to investigate effective connectivity associated with the capacity and manipulation subprocesses of WM in individuals with TBI relative to healthy controls (HCs). CapMan allows independent investigation of brain regions associated with capacity and manipulation, while minimizing the influence of other WM-related subprocesses. Areas of the fronto-parietal WM network, previously identified in healthy individuals as engaged in capacity and manipulation during CapMan, were analyzed with the Independent Multiple-sample Greedy Equivalence Search (IMaGES) method to investigate the differences in information flow between healthy individuals and individuals with TBI. We predicted that diffuse axonal injury that often occurs after TBI might lead to changes in task-based effective connectivity and result in hyperconnectivity between the regions engaged in task performance. In accordance with this hypothesis, TBI participants showed greater inter-hemispheric connectivity and less coherent information flow from posterior to anterior brain regions compared with HC participants. Thus, this study provides much needed evidence about the potential mechanism of neurocognitive impairments in individuals affected by TBI.

The relationship between outcome prediction and cognitive fatigue: A convergence of paradigms

Cognitive fatigue is common after strenuous cognitive effort. A large body of literature has implicated a network of brain areas in fatigue, including the basal ganglia and cortical areas including ventro-medal prefrontal cortex and anterior cingulate cortex (ACC). Furthermore, the ACC has been shown to be involved in processes such as error and conflict monitoring, outcome prediction, and effort processing. Thus, the ACC appears to be one common denominator between clinical work on fatigue and research on outcome prediction and effort. In the present study, we examined whether the same region of the ACC is activated during the processing of errors and fatigue. Cognitive fatigue was induced by having subjects perform a difficult working memory task, during which they rated on-task fatigue. Activation associated with error processing was determined by using error trials on the working memory task. After localizing the region engaged in error processing, we evaluated whether there was a relationship between BOLD activation of that region and on-task fatigue scores. The results showed that as subjects became more fatigued, they responded with longer latencies and increased accuracy for the more difficult task. Moreover, the ACC areas that were activated by error processing were also associated with fatigue. These results suggest that cognitive fatigue may be related to changes in effort and reward. We speculate that as the brain detects these changes, cognitive fatigue is generated as a way for the brain to signal itself that the effort required for the task no longer merits the rewards received for performing it.

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.

CapMan: independent investigation of capacity and manipulation with a new working memory paradigm

In a new working memory paradigm, CapMan, we independently investigated brain activity associated with capacity and manipulation of information. The investigation of Capacity, resulted in activation of the fronto-parietal network of regions that overlapped with areas usually found to be active in working memory tasks. The investigation of Manipulation revealed a more dorsal network of areas that also overlapped with areas usually found to be active in working memory tasks, but that did not overlap with the areas associated with Capacity. The CapMan paradigm thus appears to be able to separate the processes associated with capacity and manipulation increases and promises to be a valuable addition to the tools available for the study of working memory.

Modulation of ventral striatal activity by cognitive effort

ABSTRACT Effort discounting theory suggests that the value of a reward should be lower if it was effortful to obtain, whereas contrast theory suggests that the contrast between the costly effort and the reward makes the reward seem more valuable. To test these alternative hypotheses, we used functional magnetic resonance imaging (fMRI) as participants engaged in feedback‐based learning that required low or high cognitive effort to obtain positive feedback, while the objective amount of information provided by feedback remained constant. In the low effort condition, a single image was presented with four response options. In the high effort condition, two images were presented, each with two response options, and correct feedback was presented only when participants responded correctly to both of the images. Accuracy was significantly lower for the high effort condition, and all participants reported that the high effort condition was more difficult. A region of the ventral striatum selected for sensitivity to feedback value also showed increased activation to feedback presentation associated with the high effort condition relative to the low effort condition, when controlling for activation from corresponding control conditions where feedback was random. These results suggest that increased cognitive effort produces corresponding increases in positive feedback‐related ventral striatum activity, in line with the predictions made by contrast theory. The accomplishment of obtaining a hard‐earned intrinsic reward, such as positive feedback, may be particularly likely to promote reward‐related brain activity. HIGHLIGHTSWe examined performance on feedback learning task with low/high cognitive effort.The ventral striatum showed sensitivity to high vs. low effort feedback.High cognitive effort leads to positive feedback‐related ventral striatum activity.

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.

A pilot study of changes in functional brain activity during a working memory task after mSMT treatment: The MEMREHAB trial

BACKGROUND Working memory deficits are common in multiple sclerosis (MS). The modified Story Memory Technique (mSMT) has been shown to improve new learning and memory in MS, but its effects on working memory (WM) are currently unknown. OBJECTIVE The present study presents a secondary analysis of data from a larger double-blind, placebo-controlled, randomized clinical trial and examines changes in cerebral activation on a WM task following mSMT treatment. METHODS Sixteen participants with clinically definite MS were randomly assigned to treatment (n=7) or placebo-control groups (n=9) matched for gender, age and education. Baseline and immediate follow-up functional Magnetic Resonance Imaging (fMRI) was obtained for all subjects. During fMRI participants completed an N-back task, consisting of 0-, 1-and 2-back conditions. RESULTS Significant increases in cerebral activation were noted in the dorsolateral prefrontal cortex, supplementary motor area and inferior parietal lobule at follow-up in the treatment group. No significant changes were noted in the placebo control group. CONCLUSION Due to the small sample size, results of the current study should be interpreted as preliminary. However, the observed pattern of activation of the frontoparietal network involved in WM found in the treatment group, suggests that mSMT training increases recruitment of attention- and WM-related neural networks. We conclude that mSMT treatment leads to changes in WM-related cerebral activation.

Reward circuitry activation reflects social preferences in the face of cognitive effort

&NA; Research at the intersection of social neuroscience and cognitive effort is an interesting new area for exploration. There is great potential to broaden our understanding of how social context and cognitive effort processes, currently addressed in disparate literatures, interact with one another. In this paper, we briefly review the literature on cognitive effort, focusing on effort‐linked valuation and the gap in the literature regarding cognitive effort in the social domain. Next, we present a study designed to explore valuation processes linked to cognitive effort within the social context of an inequality manipulation. More specifically, we created monetary inequality among the participant (SELF, endowed with