Cerebellar Excitability Regulates Physical Fatigue Perception.

Fatigue is the subjective sensation of weariness, increased sense of effort, or exhaustion and is pervasive in neurologic illnesses. Despite its prevalence, we have a limited understanding of the neurophysiological mechanisms underlying fatigue. The cerebellum, known for its role in motor control and learning, is also involved in perceptual processes. However, the role of the cerebellum in fatigue remains largely unexplored. We performed two experiments to examine whether cerebellar excitability is affected after a fatiguing task and its association with fatigue. Using a crossover design, we assessed cerebellar inhibition (CBI) and perception of fatigue in humans before and after "fatigue" and "control" tasks. Thirty-three participants (16 males, 17 females) performed five isometric pinch trials with their thumb and index finger at 80% maximum voluntary capacity (MVC) until failure (force <40% MVC; fatigue) or at 5% MVC for 30 s (control). We found that reduced CBI after the fatigue task correlated with a milder perception of fatigue. In a follow-up experiment, we investigated the behavioral consequences of reduced CBI after fatigue. We measured CBI, perception of fatigue, and performance during a ballistic goal-directed task before and after the same fatigue and control tasks. We replicated the observation that reduced CBI after the fatigue task correlated with a milder perception of fatigue and found that greater endpoint variability after the fatigue task correlated with reduced CBI. The proportional relation between cerebellar excitability and fatigue indicates a role of the cerebellum in the perception of fatigue, which might come at the expense of motor control.SIGNIFICANCE STATEMENT Fatigue is one of the most common and debilitating symptoms in neurologic, neuropsychiatric, and chronic illnesses. Despite its epidemiological importance, there is a limited understanding of the neurophysiological mechanisms underlying fatigue. In a series of experiments, we demonstrate that decreased cerebellar excitability relates to lesser physical fatigue perception and worse motor control. These results showcase the role of the cerebellum in fatigue regulation and suggest that fatigue- and performance-related processes might compete for cerebellar resources.

Sensorimotor Cortex GABA Moderates the Relationship between Physical Exertion and Assessments of Effort.

Experiences of physical exertion guide our assessments of effort. While these assessments critically influence our decisions to engage in daily activities, little is known about how they are generated. We had female and male human participants exert grip force and assess how effortful these exertions felt; and used magnetic resonance spectroscopy to measure their brain GABA concentration. We found that variability in exertion (i.e., the coefficient of variation in their force exertion profile) was associated with increases in assessments of effort, making participants judge efforts as more costly. GABA levels in the sensorimotor cortex (SM1) moderated the influence of exertion variability on overassessments of effort. In individuals with higher sensorimotor GABA, exertion variability had a diminished influence on overassessments of effort. Essentially, sensorimotor GABA had a protective effect on the influence of exertion variability on inflations of effort assessment. Our findings provide a neurobiological account of how the brain's GABAergic system integrates features of physical exertion into judgments of effort, and how basic sensorimotor properties may influence higher-order judgments of effort.SIGNIFICANCE STATEMENT Feelings of effort critically shape our decisions to partake in activities of daily living. It remains unclear how the brain translates physical activity into judgments about effort (i.e., "How effortful did that activity feel?"). Using modeling of behavior and neuroimaging, we show how the nervous system uses information about physical exertion to generate assessments of effort. We found that higher variability in exertion was associated with increases in assessments of effort, making participants judge efforts as more costly. GABA, the brain's main inhibitory neurotransmitter, moderated the influence of exertion variability on overassessments of effort. These findings illustrate how low-level features of motor performance and sensorimotor neurochemistry influence higher-order cognitive processes related to feelings of effort.

Motor Cortex Excitability Reflects the Subjective Value of Reward and Mediates Its Effects on Incentive-Motivated Performance.

Performance-based incentives tend to increase an individual's motivation, resulting in enhancements in behavioral output. While much work has focused on understanding how the brain's reward circuitry influences incentive-motivated performance, fewer studies have investigated how such reward representations act on the motor system. Here we measured motor cortical excitability with transcranial magnetic stimulation while female and male human participants performed a motoric incentive motivation task for prospective monetary gains and losses. We found that individuals' performance increased for increasing prospective gains and losses. While motor cortical excitability appeared insensitive to prospective loss, temporal features of motor cortical excitability for prospective gains were modulated by an independent measure of an individual's subjective preferences for incentive (i.e., loss aversion). Those individuals that were more loss averse had a greater motor cortical sensitivity to prospective gain, closer to movement onset. Critically, behavioral sensitivity to incentive and motor cortical sensitivity to prospective gains were both predicted by loss aversion. Furthermore, causal modeling indicated that motor cortical sensitivity to incentive mediated the relationship between subjective preferences for incentive and behavioral sensitivity to incentive. Together, our findings suggest that motor cortical activity integrates information about the subjective value of reward to invigorate incentive-motivated performance.SIGNIFICANCE STATEMENT Increasing incentives tend to increase motivation and effort. Using a motoric incentive motivation task and transcranial magnetic stimulation, we studied the motor cortical mechanisms responsible for incentive-motivated motor performance. We provide experimental evidence that motor cortical sensitivity to incentive mediates the relationship between subjective preferences for incentive and incentive-motivated performance. These results indicate that, rather than simply being a reflection of motor output, motor cortical physiology integrates information about reward value to motivate performance.

Motor cortical thickness is related to effort-based decision-making in humans.

Although motor cortex is integral in driving physical exertion, how its inherent properties influence decisions to exert is unknown. In this study, we examined how anatomical properties of motor cortex are related to participants' subjective valuations of effort and their decisions to exert effort. We used computational modeling to characterize participants' subjective valuation of physical effort during an effort-based decision-making task in which they made choices about exerting different levels of hand-grip exertion. We also acquired structural MRI data from these participants and extracted anatomical measures of each individual's hand knob, the region of motor cortex recruited during hand-grip exertion. We found that individual participants' cortical thickness of hand knob was associated with their effort-based decisions regarding hand exertion. These data provide evidence that the anatomy of an individual's motor cortex is an important factor in decisions to engage in physical activity.NEW & NOTEWORTHY How effortful a task feels is an integral aspect of human decision-making that influences choices to engage in physical activity. We show that properties of motor cortex (the brain region responsible for physical exertion) are related to assessments of effort and decisions to exert. These findings provide a link between the anatomical properties of motor cortex and the cognitive function of effort-based choice.

Roles of Ventromedial Prefrontal Cortex and Anterior Cingulate in Subjective Valuation of Prospective Effort.

The perceived effort level of an action shapes everyday decisions. Despite the importance of these perceptions for decision-making, the behavioral and neural representations of the subjective cost of effort are not well understood. While a number of studies have implicated anterior cingulate cortex (ACC) in decisions about effort/reward trade-offs, none have experimentally isolated effort valuation from reward and choice difficulty, a function that is commonly ascribed to this region. We used functional magnetic resonance imaging to monitor brain activity while human participants engaged in uncertain choices for prospective physical effort. Our task was designed to examine effort-based decision-making in the absence of reward and separated from choice difficulty-allowing us to investigate the brain's role in effort valuation, independent of these other factors. Participants exhibited subjectivity in their decision-making, displaying increased sensitivity to changes in subjective effort as objective effort levels increased. Analysis of blood-oxygenation-level dependent activity revealed that the ventromedial prefrontal cortex (vmPFC) encoded the subjective valuation of prospective effort, and ACC activity was best described by choice difficulty. These results provide insight into the processes responsible for decision-making regarding effort, partly dissociating the roles of vmPFC and ACC in prospective valuation of effort and choice difficulty.

The effects of incentive framing on performance decrements for large monetary outcomes: behavioral and neural mechanisms.

There is a nuanced interplay between the provision of monetary incentives and behavioral performance. Individuals' performance typically increases with increasing incentives only up to a point, after which larger incentives may result in decreases in performance, a phenomenon known as "choking." We investigated the influence of incentive framing on choking effects in humans: in one condition, participants performed a skilled motor task to obtain potential monetary gains; in another, participants performed the same task to avoid losing a monetary amount. In both the gain and loss frame, the degree of participants' behavioral loss aversion was correlated with their susceptibility to choking effects. However, the effects were markedly different in the gain and loss frames: individuals with higher loss aversion were susceptible to choking for large prospective gains and not susceptible to choking for large prospective losses, whereas individuals with low loss aversion choked for large prospective losses but not for large prospective gains. Activity in the ventral striatum was predictive of performance decrements in both the gain and loss frames. Moreover, a mediation analysis revealed that behavioral loss aversion hindered performance via the influence of ventral striatal activity on motor performance. Our findings indicate that the framing of an incentive has a profound effect on an individual's susceptibility to choking effects, which is contingent on their loss aversion. Furthermore, we demonstrate that the ventral striatum serves as an interface between incentive-driven motivation and instrumental action, regardless of whether incentives are framed in terms of potential losses or gains.

The Neurobiology of Cognitive Fatigue and Its Influence on Effort-Based Choice.

Feelings of cognitive fatigue emerge through repeated mental exertion and are ubiquitous in our daily lives. However, there is a limited understanding of the neurobiological mechanisms underlying the influence of cognitive fatigue on decisions to exert. We use functional magnetic resonance imaging to examine brain activity while participants make choices to exert effort for reward, before and after bouts of fatiguing cognitive exertion. We found that when participants became cognitively fatigued, they were more likely to choose to forgo higher levels of reward that required more effort. We describe a mechanism by which signals related to cognitive exertion in dlPFC influence effort value computations, instantiated by the insula, thereby influencing an individual's decisions to exert while fatigued. Our results suggest that cognitive fatigue plays a critical role in decisions to exert effort and provides a mechanistic link through which information about cognitive state shapes effort-based choice.

Increased Sensitivity to Effort and Perception of Effort in People with Schizophrenia.

OBJECTIVE: Motivational deficits in schizophrenia are proposed to be attributable in part to abnormal effort-cost computations, calculations weighing the costs vs. the benefits of actions. Several reports have shown that people with schizophrenia display a reduced willingness to exert effort for monetary rewards when compared to controls. The primary goal of the current study was to further characterize reduced willingness to exert effort in schizophrenia by determining whether reduced willingness reflects (1) reduced sensitivity to reward, (2) increased sensitivity to effort, or (3) a combination of both. DESIGN: We assessed effort-cost decision-making in 30 controls and 30 people with schizophrenia, using 2 separate experimental tasks. Critically, one paradigm allowed for independent estimation of effects of reward and effort sensitivity on choice behavior. The other task isolated effort sensitivity by measuring effort in the absence of reward. Clinical interviews and self-report questionnaires were administered to people with schizophrenia to determine negative symptom severity. RESULTS: Across both tasks, we found evidence for reduced willingness to exert effort in people with schizophrenia compared to controls. Further, in both paradigms reduced willingness to exert effort was driven by increased sensitivity to effort in people with schizophrenia compared to controls. In contrast, measures of reward sensitivity did not significantly differ between groups. Surprisingly, we did not find correlations between task variables and measures of negative symptom severity. CONCLUSIONS AND RELEVANCE: These findings further specify prior work by identifying a specific contributory role for increased effort sensitivity in effort-cost decision-making deficits in schizophrenia.

Dopamine facilitates the translation of physical exertion into assessments of effort.

Our assessments of effort are critically shaped by experiences of exertion. However, it is unclear how the nervous system transforms physical exertion into assessments of effort. Availability of the neuromodulator dopamine influences features of motor performance and effort-based decision-making. To test dopamine's role in the translation of effortful exertion into assessments of effort, we had participants with Parkinson's disease, in dopamine depleted (OFF dopaminergic medication) and elevated (ON dopaminergic medication) states, exert levels of physical exertion and retrospectively assess how much effort they exerted. In a dopamine-depleted state, participants exhibited increased exertion variability and over-reported their levels of exertion, compared to the dopamine-supplemented state. Increased exertion variability was associated with less accurate effort assessment and dopamine had a protective influence on this effect, reducing the extent to which exertion variability corrupted assessments of effort. Our findings provide an account of dopamine's role in the translation of features of motor performance into judgments of effort, and a potential therapeutic target for the increased sense of effort observed across a range of neurologic and psychiatric conditions.

The Cost of Gait Slowness: Can Persons with Parkinson's Disease Save Energy by Walking Faster?

BACKGROUND: Gait slowing is a common feature of Parkinson's disease (PD). Many therapies aim to improve gait speed in persons with PD, but goals are often imprecise. How fast should each patient walk? And how do persons with PD benefit from walking faster? There is an important need to understand how walking speed affects fundamental aspects of gait-including energy cost and stability-that could guide individualized therapy decisions in persons with PD. OBJECTIVE: We investigated how changes in walking speed affected energy cost and spatiotemporal gait parameters in persons with PD. We compared these effects between dopaminergic medication states and to those observed in age-matched control participants. METHODS: Twelve persons with PD and twelve control participants performed treadmill walking trials spanning at least five different speeds (seven speeds were desired, but not all participants could walk at the fastest speeds). Persons with PD participated in two walking sessions on separate days (once while optimally medicated, once after 12-hour withdrawal from dopaminergic medication). We measured kinematic and metabolic data across all trials. RESULTS: Persons with PD significantly reduced energy cost by walking faster than their preferred speeds. This held true across medication conditions and was not observed in control participants. The patient-specific walking speeds that reduced energy cost did not significantly affect gait variability metrics (used as proxies for gait stability). CONCLUSION: The gait slowing that occurs with PD results in energetically suboptimal walking. Rehabilitation strategies that target patient-specific increases in walking speed could result in a less effortful gait.

Neural correlates of doubt in decision-making.

The experience of doubt, the lack of confidence in one's perceptions, internal states, memory and attention, can be due to the variability in occurrence of a phenomenon or can be driven by the internal experience of uncertainty based on subjective evaluation of the environment. Although the experience of some doubt is adaptive in normal cognitive functioning, excessive doubt can significantly impair decision-making and in extreme cases give rise to psychopathology. Although neuroimaging studies have provided some insight into the network of brain areas that is engaged when decision-making involves uncertainty, it remains unclear if dysfunction in these areas also gives rise to the experience and pathological expression of doubt. This study examined the neural correlates of doubt using neuroimaging during the performance of a forced-choice perceptual decision-making task under varying levels of uncertainty in participants who reported either low or high doubt. Participants reporting high doubt exhibited increased activation in the bilateral inferior parietal lobule (IPL) during perceptual decision-making which was not observed in participants who reported low doubt. Furthermore, activity in the IPL in high doubt participants was associated with clinical measures of doubt and showed functional connectivity differences between the high and low doubt groups. The findings of the current study suggest a key role of the IPL and provide a network of brain regions that may play a role in the experience and expression of doubt.

Evidence for a common representation of decision values for dissimilar goods in human ventromedial prefrontal cortex.

To make economic choices between goods, the brain needs to compute representations of their values. A great deal of research has been performed to determine the neural correlates of value representations in the human brain. However, it is still unknown whether there exists a region of the brain that commonly encodes decision values for different types of goods, or if, in contrast, the values of different types of goods are represented in distinct brain regions. We addressed this question by scanning subjects with functional magnetic resonance imaging while they made real purchasing decisions among different categories of goods (food, nonfood consumables, and monetary gambles). We found activity in a key brain region previously implicated in encoding goal-values: the ventromedial prefrontal cortex (vmPFC) was correlated with the subjects' value for each category of good. Moreover, we found a single area in vmPFC to be correlated with the subjects' valuations for all categories of goods. Our results provide evidence that the brain encodes a "common currency" that allows for a shared valuation for different categories of goods.

The separate neural control of hand movements and contact forces.

To manipulate an object, we must simultaneously control the contact forces exerted on the object and the movements of our hand. Two alternative views for manipulation have been proposed: one in which motions and contact forces are represented and controlled by separate neural processes, and one in which motions and forces are controlled jointly, by a single process. To evaluate these alternatives, we designed three tasks in which subjects maintained a specified contact force while their hand was moved by a robotic manipulandum. The prescribed contact force and hand motions were selected in each task to induce the subject to attain one of three goals: (1) exerting a regulated contact force, (2) tracking the motion of the manipulandum, and (3) attaining both force and motion goals concurrently. By comparing subjects' performances in these three tasks, we found that behavior was captured by the summed actions of two independent control systems: one applying the desired force, and the other guiding the hand along the predicted path of the manipulandum. Furthermore, the application of transcranial magnetic stimulation impulses to the posterior parietal cortex selectively disrupted the control of motion but did not affect the regulation of static contact force. Together, these findings are consistent with the view that manipulation of objects is performed by independent brain control of hand motions and interaction forces.

Neural mechanisms underlying the effects of physical fatigue on effort-based choice.

Physical fatigue crucially influences our decisions to partake in effortful action. However, there is a limited understanding of how fatigue impacts effort-based decision-making at the level of brain and behavior. We use functional magnetic resonance imaging to record markers of brain activity while human participants engage in uncertain choices for prospective physical effort, before and after bouts of exertion. Using computational modeling of choice behavior we find that fatiguing exertions cause participants to increase their subjective cost of effort, compared to a baseline/rested state. We describe a mechanism by which signals related to motor cortical state in premotor cortex influence effort value computations, instantiated by insula, thereby increasing an individual's subjective valuation of prospective physical effort while fatigued. Our findings provide a neurobiological account of how information about bodily state modulates decisions to engage in physical activity.

Reappraisal of incentives ameliorates choking under pressure and is correlated with changes in the neural representations of incentives.

It has been observed that the performing for high stakes can, paradoxically, lead to uncharacteristically poor performance. Here we investigate a novel approach to attenuating such 'choking under pressure' by instructing participants performing a demanding motor task that rewards successful performance with a monetary gain, to reappraise this incentive as a monetary loss for unsuccessful performance. We show that when participants applied this simple strategy, choking was significantly reduced. This strategy also influenced participants' neural and physiological activity. When participants reappraised the incentive as a potential monetary loss, the representation of the magnitude of the incentive in the ventral striatum Blood Oxygenation Level Dependent (BOLD) signal was attenuated. In addition, individual differences in the degree of attenuation of the neural response to incentive predicted the effectiveness of the reappraisal strategy in reducing choking. Furthermore, participants' skin conductance changed in proportion to the magnitude of the incentive being played for, and was exaggerated on high incentive trials on which participants failed. Reappraisal of the incentive abolished this exaggerated skin conductance response. This represents the first experimental association of sympathetic arousal with choking. Taken together, these results suggest that reappraisal of the incentive is indeed a promising intervention for attenuating choking under pressure.

Validating a dimension of doubt in decision-making: A proposed endophenotype for obsessive-compulsive disorder.

Doubt is subjective uncertainty about one's perceptions and recall. It can impair decision-making and is a prominent feature of obsessive-compulsive disorder (OCD). We propose that evaluation of doubt during decision-making provides a useful endophenotype with which to study the underlying pathophysiology of OCD and potentially other psychopathologies. For the current study, we developed a new instrument, the Doubt Questionnaire, to clinically assess doubt. The random dot motion task was used to measure reaction time and subjective certainty, at varying levels of perceptual difficulty, in individuals who scored high and low on doubt, and in individuals with and without OCD. We found that doubt scores were significantly higher in OCD cases than controls. Drift diffusion modeling revealed that high doubt scores predicted slower evidence accumulation than did low doubt scores; and OCD diagnosis lower than controls. At higher levels of dot coherence, OCD participants exhibited significantly slower drift rates than did controls (q<0.05 for 30%, and 45% coherence; q<0.01 for 70% coherence). In addition, at higher levels of coherence, high doubt subjects exhibited even slower drift rates and reaction times than low doubt subjects (q<0.01 for 70% coherence). Moreover, under high coherence conditions, individuals with high doubt scores reported lower certainty in their decisions than did those with low doubt scores. We conclude that the Doubt Questionnaire is a useful instrument for measuring doubt. Compared to those with low doubt, those with high doubt accumulate evidence more slowly and report lower certainty when making decisions under conditions of low uncertainty. High doubt may affect the decision-making process in individuals with OCD. The dimensional doubt measure is a useful endophenotype for OCD research and could enable computationally rigorous and neurally valid understanding of decision-making and its pathological expression in OCD and other disorders.

Neural substrates of social facilitation effects on incentive-based performance.

Throughout our lives we must perform tasks while being observed by others. Previous studies have shown that the presence of an audience can cause increases in an individual's performance as compared to when they are not being observed-a phenomenon called 'social facilitation'. However, the neural mechanisms underlying this effect, in the context of skilled-task performance for monetary incentives, are not well understood. We used functional magnetic resonance imaging to monitor brain activity while healthy human participants performed a skilled-task during conditions in which they were paid based on their performance and observed and not observed by an audience. We found that during social facilitation, social signals represented in the dorsomedial prefrontal cortex (dmPFC) enhanced reward value computations in ventromedial prefrontal cortex (vmPFC). We also found that functional connectivity between dmPFC and ventral striatum was enhanced when participants exhibited social facilitation effects, indicative of a means by which social signals serve to modulate brain regions involved in regulating behavioral motivation. These findings illustrate how neural processing of social judgments gives rise to the enhanced motivational state that results in social facilitation of incentive-based performance.

Optical merger of direct vision with virtual images for scaled teleoperation.

Scaled teleoperation is increasingly prevalent in medicine, as well as in other applications of robotics. Visual feedback in such systems is essential and should make maximal use of natural hand-eye coordination. This paper describes a new method of visual feedback for scaled teleoperation in which the operator manipulates the handle of a remote tool in the presence of a registered virtual image of the target in real time. The method adapts a concept already used successfully in a new medical device called the Sonic Flashlight, which permits direct in situ visualization of ultrasound during invasive procedures. The Sonic Flashlight uses a flat-panel monitor and a half-silvered mirror to merge the visual outer surface of a patient with a simultaneous ultrasound scan of the patient's interior. Adapting the concept to scaled teleoperation involves removing the imaging device and the target to a remote location and adding a master-slave control device. This permits the operator to see his hands, along with what appears to be the tool, and the target, merged in a workspace that preserves natural hand-eye coordination. Three functioning prototypes are described, one based on ultrasound and two on light microscopy. The limitations and potential of the new approach are discussed.

Lucky Rhythms in Orbitofrontal Cortex Bias Gambling Decisions in Humans.

It is well established that emotions influence our decisions, yet the neural basis of this biasing effect is not well understood. Here we directly recorded local field potentials from the OrbitoFrontal Cortex (OFC) in five human subjects performing a financial decision-making task. We observed a striking increase in gamma-band (36-50 Hz) oscillatory activity that reflected subjects' decisions to make riskier choices. Additionally, these gamma rhythms were linked back to mismatched expectations or "luck" occurring in past trials. Specifically, when a subject expected to win but lost, the trial was defined as "unlucky" and when the subject expected to lose but won, the trial was defined as "lucky". Finally, a fading memory model of luck correlated to an objective measure of emotion, heart rate variability. Our findings suggest OFC may play a pivotal role in processing a subject's internal (emotional) state during financial decision-making, a particularly interesting result in light of the more recent "cognitive map" theory of OFC function.

Neural mechanisms underlying paradoxical performance for monetary incentives are driven by loss aversion.

Employers often make payment contingent on performance in order to motivate workers. We used fMRI with a novel incentivized skill task to examine the neural processes underlying behavioral responses to performance-based pay. We found that individuals' performance increased with increasing incentives; however, very high incentive levels led to the paradoxical consequence of worse performance. Between initial incentive presentation and task execution, striatal activity rapidly switched between activation and deactivation in response to increasing incentives. Critically, decrements in performance and striatal deactivations were directly predicted by an independent measure of behavioral loss aversion. These results suggest that incentives associated with successful task performance are initially encoded as a potential gain; however, when actually performing a task, individuals encode the potential loss that would arise from failure.