1. Is this the same for stroke?
2. What is the intervention that will cure this?
https://www.nature.com/articles/s41598-017-08846-6
- Scientific Reports 7, Article number: 8973 (2017)
- doi:10.1038/s41598-017-08846-6
- Received:
- Accepted:
- Published online:
Abstract
We
investigated differences in brain activation associated with cognitive
fatigue between persons with traumatic brain injury (TBI) and healthy
controls (HCs). Twenty-two participants with moderate-severe TBI and 20
HCs performed four blocks of a difficult working memory task and four
blocks of a control task during fMRI imaging. Cognitive fatigue,
assessed before and after each block, was used as a covariate to assess
fatigue-related brain activation. The TBI group reported more fatigue
than the HCs, though their performance was comparable. Regarding brain
activation, the TBI group showed a Task X Fatigue interaction in the
caudate tail resulting from a positive correlation between fatigue and
brain activation for the difficult task and a negative relationship for
the control task. The HC group showed the same Task X Fatigue
interaction in the caudate head. Because we had prior hypotheses about
the caudate, we performed a confirmatory analysis of a separate dataset
in which the same subjects performed a processing speed task. A
relationship between Fatigue and brain activation was evident in the
caudate for this task as well. These results underscore the importance
of the caudate nucleus in relation to cognitive fatigue.
Introduction
Traumatic
Brain Injury (TBI) is one of the most prevalent causes of neurological
insult in the US, with over 1.7 million cases reported annually1, and it is a growing problem in other countries2.
The effects of TBI on cognition are profound and diverse: TBI has been
shown to affect working memory (the ability to hold information ‘in
mind’ for short periods of time, and also to manipulate that
information) e.g., refs 3,4,5, processing speed e.g. refs 6 and 7, neural efficiency4, 5 and cognitive fatigue e.g. refs 8,9,10,11. In the work presented here, we focused on cognitive fatigue, or the fatigue that results from performing cognitive tasks.
Cognitive fatigue can be defined as a subjective lack of mental energy that is perceived by the individual (or caregiver) to interfere with usual and desired activities12. It has been known for over a century that individuals who have sustained neurological damage frequently report cognitive fatigue13, yet a comprehensive and accurate model for studying fatigue remains elusive. This difficulty stems, at least in part, from the lack of consistent correlation between objective measures of fatigue such as response time (RT), error rate (ER) or even brain lesions14 and subjective reports of fatigue13. That is, although subjects’ experience of fatigue may increase as a cognitive task is repeatedly performed, performance is not usually affected.
The inability to relate behavioral decrements to self-reported cognitive fatigue led us to investigate other dependent measures that may correlate better with fatigue: specifically, the BOLD signal associated with changes in neural activation8. While others have investigated the relationship between fatigue and white matter integrity15, we chose fMRI on the hypothesis that increased BOLD activation represented an increase in the cognitive work that individuals with TBI must expend in order to perform a given task16. In that work8, we showed that individuals with TBI recruit the fronto-striatal network more during performance of a demanding cognitive task compared to healthy participants, including ventromedial prefrontal cortex (VMPFC), parietal areas, and the basal ganglia. This network has been previously shown to be involved in cognitive fatigue16,17,18,19.
Additionally, cognitive fatigue research has been limited due to the fact that historically, investigators have assessed subjective fatigue using scales which assess “trait” fatigue, rather than “state” fatigue. For example, one frequently used fatigue questionnaire is the Fatigue Severity Scale (FSS), which asks participants to rate their fatigue over the past week. Thus, the FSS is a measure of trait fatigue, or the extent to which subjects are prone to experiencing fatigue over an extended period of time. Recently, the literature on fatigue has begun to distinguish between state and trait fatigue19,20,21. The assessment of state fatigue, or the extent to which subjects are experiencing fatigue at the instant of assessment, may more consistently correlate with behavior inasmuch as it is measured at the same time the behavior is measured. Thus, in the current study, we used the Visual Analog Scale of Fatigue (VAS-F), which asks subjects to rate the amount of fatigue they experience at the time of behavioral performance.
In previous work, we have shown that the caudate nucleus of the basal ganglia shows a different pattern of activation over time in individuals with TBI relative to HCs8. This result accorded well with a model of fatigue proposed by Chauduri & Behan17 in which the basal ganglia played a key role in the experience of fatigue; however, Kohl et al.8 did not assess subjects’ instantaneous (state) experience of fatigue, but rather inferred the presence of fatigue based on the pattern of brain activation over time. The current study therefore represents the first investigation of state fatigue in individuals with moderate-severe TBI. Furthermore, we specifically investigated the role of the caudate nucleus in fatigue by investigating whether the caudate modulates its activity in direct proportion to subjects’ instantaneous (state) experience of fatigue19. Indeed, while the caudate nucleus, and the striatum as a whole, have been previously considered to be responsible purely for the control of motor behavior22, recent evidence from animal and human research demonstrates that this region plays a significant role in a variety of cognitive behaviors, such as learning23,24,25, outcome processing26, 27, and working memory28, 29. More recent evidence suggests that the fatigue resulting from such cognitive processes may also be reflected in caudate nucleus activation30. This is particularly likely in the TBI population given the nature of brain injury sustained by most individuals with TBI: damage to the prefrontal cortex that sends afferent connections to the basal ganglia and interruption of dopamine transmission in the basal ganglia after TBI31. Indeed, cognitive fatigue has been associated with a network of areas in the striatum and PFC including vmPFC, nucleus accumbens and anterior cingulate cortex (ACC) in children who have sustained a TBI32.
In the current study, we investigated the role of the caudate nucleus in fatigue by asking subjects to perform a working memory task (the N-Back task), since working memory is known to be compromised in TBI. Secondly, we included both a difficult task (the 2-back condition) and a less difficult task (the 0-back condition). We hypothesized that the TBI group would show more fatigue-related activation for both the 0-back task and for the 2-back task than the healthy control (HC) group, and that this would be associated with basal ganglia activation17. We then performed a second experiment using a processing speed task to confirm that the activation in the caudate was related to fatigue rather than to the task.
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Cognitive fatigue can be defined as a subjective lack of mental energy that is perceived by the individual (or caregiver) to interfere with usual and desired activities12. It has been known for over a century that individuals who have sustained neurological damage frequently report cognitive fatigue13, yet a comprehensive and accurate model for studying fatigue remains elusive. This difficulty stems, at least in part, from the lack of consistent correlation between objective measures of fatigue such as response time (RT), error rate (ER) or even brain lesions14 and subjective reports of fatigue13. That is, although subjects’ experience of fatigue may increase as a cognitive task is repeatedly performed, performance is not usually affected.
The inability to relate behavioral decrements to self-reported cognitive fatigue led us to investigate other dependent measures that may correlate better with fatigue: specifically, the BOLD signal associated with changes in neural activation8. While others have investigated the relationship between fatigue and white matter integrity15, we chose fMRI on the hypothesis that increased BOLD activation represented an increase in the cognitive work that individuals with TBI must expend in order to perform a given task16. In that work8, we showed that individuals with TBI recruit the fronto-striatal network more during performance of a demanding cognitive task compared to healthy participants, including ventromedial prefrontal cortex (VMPFC), parietal areas, and the basal ganglia. This network has been previously shown to be involved in cognitive fatigue16,17,18,19.
Additionally, cognitive fatigue research has been limited due to the fact that historically, investigators have assessed subjective fatigue using scales which assess “trait” fatigue, rather than “state” fatigue. For example, one frequently used fatigue questionnaire is the Fatigue Severity Scale (FSS), which asks participants to rate their fatigue over the past week. Thus, the FSS is a measure of trait fatigue, or the extent to which subjects are prone to experiencing fatigue over an extended period of time. Recently, the literature on fatigue has begun to distinguish between state and trait fatigue19,20,21. The assessment of state fatigue, or the extent to which subjects are experiencing fatigue at the instant of assessment, may more consistently correlate with behavior inasmuch as it is measured at the same time the behavior is measured. Thus, in the current study, we used the Visual Analog Scale of Fatigue (VAS-F), which asks subjects to rate the amount of fatigue they experience at the time of behavioral performance.
In previous work, we have shown that the caudate nucleus of the basal ganglia shows a different pattern of activation over time in individuals with TBI relative to HCs8. This result accorded well with a model of fatigue proposed by Chauduri & Behan17 in which the basal ganglia played a key role in the experience of fatigue; however, Kohl et al.8 did not assess subjects’ instantaneous (state) experience of fatigue, but rather inferred the presence of fatigue based on the pattern of brain activation over time. The current study therefore represents the first investigation of state fatigue in individuals with moderate-severe TBI. Furthermore, we specifically investigated the role of the caudate nucleus in fatigue by investigating whether the caudate modulates its activity in direct proportion to subjects’ instantaneous (state) experience of fatigue19. Indeed, while the caudate nucleus, and the striatum as a whole, have been previously considered to be responsible purely for the control of motor behavior22, recent evidence from animal and human research demonstrates that this region plays a significant role in a variety of cognitive behaviors, such as learning23,24,25, outcome processing26, 27, and working memory28, 29. More recent evidence suggests that the fatigue resulting from such cognitive processes may also be reflected in caudate nucleus activation30. This is particularly likely in the TBI population given the nature of brain injury sustained by most individuals with TBI: damage to the prefrontal cortex that sends afferent connections to the basal ganglia and interruption of dopamine transmission in the basal ganglia after TBI31. Indeed, cognitive fatigue has been associated with a network of areas in the striatum and PFC including vmPFC, nucleus accumbens and anterior cingulate cortex (ACC) in children who have sustained a TBI32.
In the current study, we investigated the role of the caudate nucleus in fatigue by asking subjects to perform a working memory task (the N-Back task), since working memory is known to be compromised in TBI. Secondly, we included both a difficult task (the 2-back condition) and a less difficult task (the 0-back condition). We hypothesized that the TBI group would show more fatigue-related activation for both the 0-back task and for the 2-back task than the healthy control (HC) group, and that this would be associated with basal ganglia activation17. We then performed a second experiment using a processing speed task to confirm that the activation in the caudate was related to fatigue rather than to the task.
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