A signature injury of service members deployed during the conflicts in Iraq and Afghanistan is traumatic brain injury (TBI). Of the approximately 360,000 service members who suffer from TBI, 70% are classified as mild injuries (mTBI; DVBIC Quarterly Reports). At least 19% of the service members with mTBI have persistent symptoms that contribute to difficulty engaging in social and work activities. The consequences of persistent fatigue in mTBI pose a real challenge to rehabilitation (1). High levels of mental fatigue commonly persist and relate to failure to return to work and loss of productivity (2, 3). In fact, presence of fatigue is the strongest predictive factor of poor outcomes following TBI (1). Despite the prevalence of fatigue in TBI, our understanding of its behavioral and neural underpinnings is lacking.
Mental fatigue is a complex process that is operationally defined by time on task and increased mental effort. When performance suffers (reaction time, accuracy, etc.) over time, presumably from fatigue, there tends to be fairly diffusely increased brain activity (4). Simultaneously, there may also be decreased motivation under high effort (5). According to Kahneman’s “resource capacity theory,” the amount of effort needed to perform a task is related to the complexity of the task and an individual’s limited general capacity to perform mental work [i.e., resource capacity, (6, 7)]. When a task is difficult, the demand for resources is high, and performance suffers when resources near depletion. When a person recognizes that performance is suffering, tasks are perceived as more difficult, and require greater effort, which Kahneman equates with the experience of mental fatigue.
Brain imaging in mTBI indicates an increase in brain activity with increased time on task regardless of the type or demand requirements of the task (8). In contrast, healthy individuals have decreased activation over time without a serious decrement in performance, and without reporting significant fatigue. This brain response in TBI may suggest a perception of higher levels of effort when the task is long, or that individuals with TBI inefficiently regulate cognitive control and exert more mental effort to maintain a high-level of performance, resulting in fatigue.
While there is a plethora of literature reporting that task demand causes degradation of performance in mTBI, few have investigated whether task demand results in fatigue more so than in healthy controls, or how this fatigue manifests in behavior or in neural function. The few available studies have small sample sizes [e.g., (9)] limiting their generalizability. The brain networks implicated in effort and fatigue include frontostriatal circuitry, or the ventromedial prefrontal cortex more specifically. Damage to these brain regions is thought to diminish resource capacity and impair allocation of resources, resulting in an increased perception of expended effort (10–12). Additionally, fatigue related to lack of motivation to engage and maintain performance on a task, or to predict and manage change in performance based on feedback about performance, is associated with the integrity of the ventromedial prefrontal cortical. That is, individuals with larger lesions of this brain region report more fatigue and apathy (13, 14). The frontostriatal network is involved in coding the incentive value for an expected outcome (15), and is mediated by dopaminergic frontostriatal networks (13, 16–19). Breakdowns in ventromedial prefrontal cortex-related network connectivity may disrupt the ability to appropriately detect, monitor, and self-correct errors or to adequately motivate behavior (20, 21). For example, the anterior cingulate cortex is associated with monitoring and detecting errors, the pre-supplementary motor area with engaging in task, and the connectivity amongst these two regions is related to fatigue (22).
One gap in the existing literature on fatigue is that paradigms infer “probable” fatigue [exception is Wylie et al. (22)], rather than directly measuring it. In the present study, we investigate brain activity and network connectivity in mTBI participants while they perform a task explicitly designed to study the relationship between task-related effort and fatigue. We assess fatigue with a questionnaire about fatigue over the week prior to scanning (trait) as well as with task manipulation during brain imaging [state, Constant Effort Task [CE]]. For Constant Effort, subjects are asked to squeeze a bulb to a prescribed effort level and hold it constant for a discrete period of time. The task is considered a general index of central fatigue as it is not specific to motor system engagement (23, 24). Varying effort levels result in predictable changes in the ability to maintain pressure on the bulb such that the time it takes to fatigue is slower at low effort levels than at higher effort levels. Performance on the CE task during functional fMRI allowed for identification of the neural systems underlying effort and fatigue as well as the differences in these systems in mTBI relative to control. We hypothesize that fatigue in mTBI arises when there is an altered perception of the amount of effort needed to perform the task, either because there is a failure to:
a) update the amount of effort given to the task based on internal feedback about performance, which is assessed by contrasting performance across effort levels,
b) sustain a given effort level, which is assessed via time on task, or
Because estimating and maintaining effort are likely a result of a complex network of interacting brain regions, we examined not only brain activation during task performance, but also functional connectivity (FC) amongst the regions active during the task. We predict that mTBI participants will demonstrate increased pre-frontal and anterior cingulate cortex activation, as well as increased connectivity of these regions to ventral-striatal regions relative to Control participants.[…]