Cingulate Response Research Articles

Identification of a Composite Latent Dimension of Reward and Impulsivity Across Clinical, Behavioral, and Neurobiological Domains Among Youth

BackgroundIndividual differences in reward processing are central to heightened risk-taking behaviors during adolescence, but there is inconsistent evidence for the relationship between risk-taking phenotypes and the neural substrates of these behaviors. MethodsHere, we identify latent features of reward in an attempt to provide a unifying framework linking together aspects of the brain and behavior during early adolescence using a multivariate pattern learning approach. Data (N = 8295; n male = 4190; n female = 4105) were acquired as part of the Adolescent Brain Cognitive Development (ABCD) Study and included neuroimaging (regional neural activity responses during reward anticipation) and behavioral (e.g., impulsivity measures, delay discounting) variables. ResultsWe revealed a single latent dimension of reward driven by shared covariation between striatal, thalamic, and anterior cingulate responses during reward anticipation, negative urgency, and delay discounting behaviors. Expression of these latent features differed among adolescents with attention-deficit/hyperactivity disorder and disruptive behavior disorder, compared with those without, and higher expression of these latent features was negatively associated with multiple dimensions of executive function and cognition. ConclusionsThese results suggest that cross-domain patterns of anticipatory reward processing linked to negative features of impulsivity exist in both the brain and in behavior during early adolescence and that these are representative of 2 commonly diagnosed reward-related psychiatric disorders, attention-deficit/hyperactivity disorder and disruptive behavior disorder. Furthermore, they provide an explicit baseline from which multivariate developmental trajectories of reward processes may be tracked in later waves of the ABCD Study and other developmental cohorts.

Neural activation to peer acceptance and rejection in relation to concurrent and prospective depression risk in adolescent and pre-adolescent girls

Neurobiological sensitivity to peer interactions is a proposed marker of risk for adolescent depression. We investigated neural response to peer rejection and acceptance in relation to concurrent and prospective depression risk in adolescent and pre-adolescent girls. Participants were 76 girls (Mage=13, 45% racial/ethnic minorities) varying in depression risk: 22 with current major depressive disorder (MDD), 30 at High Risk for MDD based on parental history, and 24 at Low Risk with no psychiatric history. Girls participated in the Chatroom-Interact task—involving rejection and acceptance feedback from fictitious peers—while undergoing functional magnetic resonance neuroimaging. Activation in response to peer rejection and acceptance was extracted from regions of interest. Depressive symptoms were assessed at 6- and 12-month follow-up. Girls with MDD showed blunted left subgenual anterior cingulate response to acceptance versus girls in High and Low Risk groups. Girls in the High Risk group showed greater right temporo-parietal junction (rTPJ) and right anterior insula (AI) activation to both acceptance and rejection versus girls in the MDD (rTPJ) and Low Risk (rTPJ, AI) groups. Greater rTPJ response to rejection was associated with fewer depressive symptoms at 12-months and mediated the association between High Risk group status and 12-month depressive symptoms; greater rTPJ response to acceptance mediated the association between High Risk and increased 12-month depressive symptoms. Our finding of associations between altered neural response to peer interactions and concurrent and prospective depression risk/resilience highlights the importance of neural underpinnings of social cognition as risk and compensatory adaptations along the pathway to depression.

Relation of Overweight/Obesity to Reward Region Response to Food Reward and the Moderating Effects of Parental History of Eating Pathology in Adolescent Females.

To test whether overweight/obesity is associated with an elevated reward region response to milkshake cues and a low reward region response to milkshake receipt. To test whether the risk for eating pathology moderates the effects of weight status on the neural response to milkshake cues and milkshake receipt. The current study used functional magnetic resonance imaging (fMRI) to examine the neuronal responses of female adolescents (n = 80; M age = 14.6 ± 0.9; M BMI = 21.9 ± 3.6; 41% with a biological parental history of eating pathology) during a food receipt paradigm. Females with overweight/obesity showed a greater ventromedial prefrontal cortex (vmPFC), and ventral anterior cingulate (ACC) response to milkshake cues and a greater ventral striatum, subgenual ACC, and dorsomedial prefrontal cortex response to milkshake receipt than those with a healthy weight. Females with overweight/obesity plus a parental history of eating pathology showed a greater vmPFC/medial orbitofrontal cortex response to milkshake cues than those without a parental history of eating pathology and those with a healthy weight. Females with overweight/obesity and without a parental history of eating pathology showed a greater thalamus and striatum response to milkshake receipt. Overweight/obesity is associated with an elevated reward region response to palatable food cues and food receipt. A risk for eating pathology enhances the reward region response to food cues in those with excess weight.

Eliciting Implicit Awareness in Alzheimer’s Disease and Mild Cognitive Impairment: A Task-Based Functional MRI Study

BackgroundRecent models of anosognosia in dementia have suggested the existence of an implicit component of self-awareness about one’s cognitive impairment that may remain preserved and continue to regulate behavioral, affective, and cognitive responses even in people who do not show an explicit awareness of their difficulties. Behavioral studies have used different strategies to demonstrate implicit awareness in patients with anosognosia, but no neuroimaging studies have yet investigated its neural bases.MethodsPatients with amnestic mild cognitive impairment and dementia due to Alzheimer’s disease underwent functional magnetic resonance imaging (fMRI) during the execution of a color-naming task in which they were presented with neutral, negative, and dementia-related words (Dementia-Related Emotional Stroop).ResultsTwenty-one patients were recruited: 12 were classified as aware and 9 as unaware according to anosognosia scales (based on clinical judgment and patient-caregiver discrepancy). Behavioral results showed that aware patients took the longest time to process dementia-related words, although differences between word types were not significant, limiting interpretation of behavioral results. Imaging results showed that patients with preserved explicit awareness had a small positive differential activation of the posterior cingulate cortex (PCC) for the dementia-related words condition compared to the negative words, suggesting attribution of emotional valence to both conditions. PCC differential activation was instead negative in unaware patients, i.e., lower for dementia-related words relative to negative-words. In addition, the more negative the differential activation, the lower was the Stroop effect measuring implicit awareness.ConclusionPosterior cingulate cortex preserved response to dementia-related stimuli may be a marker of preserved implicit self-awareness.

Processing of pain by the developing brain: evidence of differences between adolescent and adult females.

Adolescence is a sensitive period for both brain development and the emergence of chronic pain particularly in females. However, the brain mechanisms supporting pain perception during adolescence remain unclear. This study compares perceptual and brain responses to pain in female adolescents and adults to characterize pain processing in the developing brain. Thirty adolescent (ages 13-17 years) and 30 adult (ages 35-55 years) females underwent a functional magnetic resonance imaging scan involving acute pain. Participants received 12 ten-second noxious pressure stimuli that were applied to the left thumbnail at 2.5 and 4 kg/cm 2 , and rated pain intensity and unpleasantness on a visual analogue scale. We found a significant group-by-stimulus intensity interaction on pain ratings. Compared with adults, adolescents reported greater pain intensity and unpleasantness in response to 2.5 kg/cm 2 but not 4 kg/cm 2 . Adolescents showed greater medial-lateral prefrontal cortex and supramarginal gyrus activation in response to 2.5 kg/cm 2 and greater medial prefrontal cortex and rostral anterior cingulate responses to 4 kg/cm 2 . Adolescents showed greater pain-evoked responses in the neurologic pain signature and greater activation in the default mode and ventral attention networks. Also, the amygdala and associated regions played a stronger role in predicting pain intensity in adolescents, and activity in default mode and ventral attention regions more strongly mediated the relationship between stimulus intensity and pain ratings. This study provides first evidence of greater low-pain sensitivity and pain-evoked brain responses in female adolescents (vs adult women) in regions important for nociceptive, affective, and cognitive processing, which may be associated with differences in peripheral nociception.

The human posterior cingulate and the stress-response benefits of viewing green urban landscapes

The mechanistic and neural bases of why green environments drive positive mental health outcomes remain poorly understood. We show that viewing green urban landscapes that vary in terms of green-space density elicits corresponding changes in the activity of the human ventral posterior cingulate cortex that is correlated to behavioural stress-related responses. We further show that cingulate responses are engaged early in the processing cascade, influencing attentional and executive regions in a predominantly feedforward manner. Our data suggest a key role for this region in regulating (nature) dose-dependent changes in stress responses, potentially through its extensive connections to the prefrontal and hippocampal regions which in turn project towards the neuroendocrine system. As the posterior cingulate cortex is implicated in a variety of neurological diseases and disorders, these findings raise a therapeutic potential for natural environmental exposure, highlighting green-cover as a modifiable element that links to changes in limbic responses, and has health consequences for practitioners and city-planners alike.

Short-Term Consumption of Sucralose with, but Not without, Carbohydrate Impairs Neural and Metabolic Sensitivity to Sugar in Humans

There is a general consensus that overconsumption of sugar-sweetened beverages contributes to the prevalence of obesity and related comorbidities such as type 2 diabetes (T2D). Whether a similar relationship exists for no- or low-calorie "diet" drinks is a subject of intensive debate and controversy. Here, we demonstrate that consuming seven sucralose-sweetened beverages with, but not without, a carbohydrate over 10days decreases insulin sensitivity in healthy human participants, an effect that correlates with reductions in midbrain, insular, and cingulate responses to sweet, but not sour, salty, or savory, taste as assessed with fMRI. Taste perception was unaltered and consuming the carbohydrate alone had no effect. These findings indicate that consumption of sucralose in the presence of a carbohydrate rapidly impairs glucose metabolism and results in longer-term decreases in brain, but not perceptual sensitivity to sweet taste, suggesting dysregulation of gut-brain control of glucose metabolism.

Thoughts of death affect reward learning by modulating salience network activity

Thoughts of death substantially influence human behavior and psychological well-being. A large number of behavioral studies have shown evidence that asking individuals to think about death or mortality salience leads to significant changes of their behaviors. These findings support the well-known terror management theory to account for the psychological mechanisms of existential anxiety. However, despite increasing findings of mortality salience effects on human behavior, how the brain responds to reminders of mortality and changes the activity underlying subsequent behavior remains poorly understood. By scanning healthy adults (N = 80) of both sexes using functional magnetic resonance imaging, we showed that, relative to reading emotionally neutral sentences, reading sentences that evoke death-related thoughts decreased the salience network activity, reduced the connectivity between the cingulate cortex and other brain regions during a subsequent resting state, and dampened the speed of learning reward-related objects and cingulate responses to loss feedback during a subsequent reward learning task. In addition, the decreased resting-state cingulate connectivity mediated the association between salience network deactivations in response to reminders of mortality and suppressed cingulate responses to loss feedback. Finally, the suppressed cingulate responses to loss feedback further predicted the dampened speed of reward learning. Our findings demonstrate sequential modulations of the salience network activity by mortality salience, which provide a neural basis for understanding human behavior under mortality threat.

Dopaminergic drug treatment remediates exaggerated cingulate prediction error responses in obsessive-compulsive disorder

RationalePatients with obsessive-compulsive disorder (OCD) have been found to show exaggerated error responses and prediction error learning signals in a variety of EEG and fMRI tasks, with data converging on the anterior cingulate cortex as a key locus of dysfunction. Considerable evidence has linked prediction error processing to dopaminergic function.ObjectiveIn this study, we investigate potential dopaminergic dysfunction during reward processing in the context of OCD.MethodsWe studied OCD patients (n = 18) and controls (n = 18) whilst they learned probabilistic associations between abstract stimuli and monetary rewards in the fMRI scanner involving administration (on separate visits) of a dopamine receptor agonist, pramipexole 0.5 mg; a dopamine receptor antagonist, amisulpride 400 mg; and placebo. We fitted a Q-learning computational model to fMRI prediction error responses; group differences were examined in anterior cingulate and nucleus accumbens regions of interest.ResultsThere were no significant group, drug, or interaction effects in the number of correct choices; computational modeling suggested a marginally significant difference in learning rates between groups (p = 0.089, partial ƞ2 = 0.1). In the imaging results, there was a significant interaction of group by drug (p = 0.013, partial ƞ2 = 0.13). OCD patients showed abnormally strong cingulate signaling of prediction errors during omission of an expected reward, with unexpected reduction by both pramipexole and amisulpride (p = 0.014, partial ƞ2 = 0.26, 1-β error probability = 0.94). Exaggerated cingulate prediction error signaling to omitted reward in placebo was related to trait subjective difficulty in self-regulating behavior in OCD.ConclusionsOur data support cingulate dysfunction during reward processing in OCD, and bidirectional remediation by dopaminergic modulation, suggesting that exaggerated cingulate error signals in OCD may be of dopaminergic origin. The results help to illuminate the mechanisms through which dopamine receptor antagonists achieve therapeutic benefit in OCD. Further research is needed to disentangle the different functions of dopamine receptor agonists and antagonists during bidirectional modulation of cingulate activation.

Improving therapy outcome prediction in major depression using multimodal functional neuroimaging: A pilot study

Mounting evidence emphasizes the usefulness of imaging biomarkers for predicting therapy outcome in major depressive disorder (MDD), in particular building on functional imaging studies of task-based responses to emotional face stimuli and resting state-related connectivity patterns. To explore the possibility that prediction accuracy even in small patient samples would significantly gain from integrating data from different imaging modalities, we acquired functional neuroimaging data both at-rest and during exposure to emotional faces from 21 MDD patients before and 7 weeks after treatment-as-usual, as well as from 20 age- and gender-matched control participants assessed at similar intervals. As expected, MDD patients showed disturbed pre-treatment responses to emotional faces, including left amygdala hyperactivation. Therapeutic outcome correlated with pre-treatment activation, with subgenual cingulate response to emotional faces yielding best results (r values ranging from 0.4 to 0.66). A support vector machine classifier trained on task-based or resting-state data predicted responder status, with the right dorsolateral prefrontal cortex connectivity pattern yielding best accuracy (88.9%). Crucially, combining task-based with resting-state data increased prediction accuracy by 6.5–7.7 percentage points on average. From this pilot study, we conclude that multimodal functional imaging has the potential of improving therapy outcome prediction even in small MDD sample sizes, resulting in about one additional correct classification every 15 patients. The present results inform future studies which are needed to consolidate imaging approaches as a means of establishing precision medicine in psychiatry.

11.4 Greater Dorsal Anterior Cingulate Response to Conflict, Lower Anxiety: An Adaptive Brain Response in Pediatric Anxiety Disorders?

Cognitive control enables the flexible adjustment of behavior by constraining attention to task-relevant stimuli and may be critically impaired by anxiety. Frontoparietal and cingulo-opercular regions mediate cognitive control, as shown by activation of these regions during a range of cognitive tasks, including conflict between competing cognitive stimuli. In youth with anxiety disorders, compared with healthy control subjects, hypoactivation of these networks during errors, induced by conflict, suggests impaired ability to engage cognitive control. It is unknown whether the capacity to engage task-control networks associates with anxiety across the spectrum of severity. In theory, if greater engagement of task-control regions associates with lower anxiety, then treatment-induced increases in activation should associate with anxiety reduction.

Effect of maternal rumination and disengagement during childhood on offspring neural response to reward in late adolescence

Maternal rumination is a cognitive-affective trait that could influence offspring's ability to respond flexibly to positive and negative events, depending on the quality of maternal problem-solving behaviors with which rumination co-occurs. As reward circuitry is sensitive to stressors and related to risk for depression, reward circuitry is an appropriate candidate mechanism for how maternal characteristics influence offspring. We evaluated the independent and combined effect of maternal rumination and disengagement on adolescent neural response to reward win and loss. Participants were 122 boys and their mothers from low-income, urban backgrounds followed prospectively in a longitudinal study. The combination of high maternal rumination at child age 6 and high maternal disengagement during problem-solving at child age 10–12 was associated with lower anterior cingulate response to winning reward at age 20, but unrelated to neural response to losing reward. Lower anterior cingulate response to winning reward was associated with fewer anxiety symptoms during late adulthood. Findings suggest that maternal rumination occurring within the context of maternal disengagement during challenging experiences may be related to offspring blunted engagement during positive events. Helping highly ruminative mothers to restructure repetitive negative thoughts and to develop context-appropriate problem-solving behaviors may be important for promoting offspring affective development.

Unlike adults, children and adolescents show predominantly increased neural activation to social exclusion by members of the opposite gender

ABSTRACTThe effects of group membership on brain responses to social exclusion have been investigated in adults, revealing greater anterior cingulate responses to exclusion by members of one’s in-group (e.g., same-gender). However, social exclusion is a critical aspect of peer relations in youth and reaches heightened salience during adolescence, a time when social anxiety disorders are also emergent. While the behavioral and neural correlates of social exclusion in adolescence have been extensively explored, the effects of group membership on peer rejection are less clear. The current study used functional magnetic resonance imaging (fMRI) to investigate the differential neural correlates of being excluded by peers of one’s same- versus opposite-gender during an online ball-toss game. Participants were a group of typically developing children and adolescents (7–17 years). As predicted, anterior cingulate cortex showed a main effect of social exclusion versus fair play. However, unlike a previous adult study, this region did not show increased activation to same-gender exclusion. Instead, several regions differentiating same- versus opposite-gender exclusion were exclusively more sensitive to exclusion by one’s opposite gender. These results are discussed in the context of adolescent socio-emotional development.

Voluntary modulation of anterior cingulate response to negative feedback.

Anterior cingulate and medial frontal cortex (dACC/mFC) response to negative feedback represents the actions of a generalized error-monitoring system critical for the management of goal-directed behavior. Magnitude of dACC/mFC response to negative feedback correlates with levels of post-feedback behavioral change, and with proficiency of operant learning processes. With this in mind, it follows that an ability to alter dACC/mFC response to negative feedback may lead to representative changes in operant learning proficiency. To this end, the present study investigated the extent to which healthy individuals would show modulation of their dACC/mFC response when instructed to try to either maximize or minimize their neural response to the presentation of contingent negative feedback. Participants performed multiple runs of a standard time-estimation task, during which they received feedback regarding their ability to accurately estimate a one-second duration. On Watch runs, participants were simply instructed to try to estimate as closely as possible the one second duration. On Increase and Decrease runs, participants performed the same task, but were instructed to “try to increase [decrease] their brain's response every time they received negative feedback”. Results indicated that participants showed changes in dACC/mFC response under these differing instructional conditions: dACC/mFC activity following negative feedback was higher in the Increase condition, and dACC activity trended lower in the Decrease condition, compared to the Watch condition. Moreover, dACC activity correlated with post-feedback performance adjustments, and these adjustments were highest in the Increase condition. Potential implications for neuromodulation and facilitated learning are discussed.

Alexithymia is associated with blunted anterior cingulate response to social rejection: implications for daily rejection.

Social rejection elicits distress through the brain's alarm system, the dorsal anterior cingulate cortex (dACC). The distress of rejection facilitates subsequent inclusion. As a result, traits that blunt this dACC response to social rejection might then threaten group membership, leading to further subsequent rejection. Alexithymia, the inability to identify and describe affective states, is associated with social impairment and reduced dACC activity under conditions of negative affect. Thus, we expected that alexithymia would relate to less dACC activation during rejection and that this blunted response would explain an association between alexithymia and greater rejection in everyday life. Using functional magnetic resonance imaging and daily diaries, we found that subclinical individual differences in the core feature of alexithymia, difficulty identifying affect, was associated with a blunted dACC response to social rejection. Deficits in affect identification were also associated with greater daily rejection and that this effect was mediated and suppressed by dACC activation to rejection. Our findings emphasize the crucial role of the dACC in response to social rejection and extend the literature on alexithymia's ability to dampen neural responses and contribute to poor social functioning. The suppressing role of the dACC suggests future directions for clinical interventions on those with affective disorders.

Enhanced subgenual cingulate response to altruistic decisions in remitted major depressive disorder.

BackgroundMajor depressive disorder (MDD) is associated with functional abnormalities in fronto-meso-limbic networks contributing to decision-making, affective and reward processing impairments. Such functional disturbances may underlie a tendency for enhanced altruism driven by empathy-based guilt observed in some patients. However, despite the relevance of altruistic decisions to understanding vulnerability, as well as everyday psychosocial functioning, in MDD, their functional neuroanatomy is unknown.MethodsUsing a charitable donations experiment with fMRI, we compared 14 medication-free participants with fully remitted MDD and 15 demographically-matched control participants without MDD.ResultsCompared with the control group, the remitted MDD group exhibited enhanced BOLD response in a septal/subgenual cingulate cortex (sgACC) region for charitable donation relative to receiving simple rewards and higher striatum activation for both charitable donation and simple reward relative to a low level baseline. The groups did not differ in demographics, frequency of donations or response times, demonstrating only a difference in neural architecture.ConclusionsWe showed that altruistic decisions probe residual sgACC hypersensitivity in MDD even after symptoms are fully remitted. The sgACC has previously been shown to be associated with guilt which promotes altruistic decisions. In contrast, the striatum showed common activation to both simple and altruistic rewards and could be involved in the so-called “warm glow” of donation. Enhanced neural response in the depression group, in areas previously linked to altruistic decisions, supports the hypothesis of a possible association between hyper-altruism and depression vulnerability, as shown by recent epidemiological studies.

Affective neural response to restricted interests in autism spectrum disorders.

Restricted interests are a class of repetitive behavior in autism spectrum disorders (ASD) whose intensity and narrow focus often contribute to significant interference with daily functioning. While numerous neuroimaging studies have investigated executive circuits as putative neural substrates of repetitive behavior, recent work implicates affective neural circuits in restricted interests. We sought to explore the role of affective neural circuits and determine how restricted interests are distinguished from hobbies or interests in typical development. We compared a group of children with ASD to a typically developing (TD) group of children with strong interests or hobbies, employing parent report, an operant behavioral task, and functional imaging with personalized stimuli based on individual interests. While performance on the operant task was similar between the two groups, parent report of intensity and interference of interests was significantly higher in the ASD group. Both the ASD and TD groups showed increased BOLD response in widespread affective neural regions to the pictures of their own interest. When viewing pictures of other children's interests, the TD group showed a similar pattern, whereas BOLD response in the ASD group was much more limited. Increased BOLD response in the insula and anterior cingulate cortex distinguished the ASD from the TD group, and parent report of the intensity and interference with daily life of the child's restricted interest predicted insula response. While affective neural network response and operant behavior are comparable in typical and restricted interests, the narrowness of focus that clinically distinguishes restricted interests in ASD is reflected in more interference in daily life and aberrantly enhanced insula and anterior cingulate response to individuals' own interests in the ASD group. These results further support the involvement of affective neural networks in repetitive behaviors in ASD.

The political (and physiological) divide: Political orientation, performance monitoring, and the anterior cingulate response

Our goal was to test a model of sociopolitical attitudes that posits a relationship between individual differences in liberal versus conservative political orientation and differential levels of anterior cingulate cortex (ACC) responsivity. We recorded event-related potentials (ERPs) while participants who varied along a unidimensional liberal-conservative continuum engaged in a standard Go/NoGo task. We also measured component attitudes of political orientation in the form of traditionalism (degree of openness to social change) and egalitarianism (a preference for social equality). Generally, participants who reported a more liberal political orientation made fewer errors and produced larger ACC-generated ERPs (the error-related negativity, or ERN and the NoGo N2). This ACC activation, especially as indicated by a larger NoGo N2, was most strongly associated with greater preference for social equality. Performance accuracy, however, was most strongly associated with greater openness to social change. These data are consistent with a social neuroscience view that sociopolitical attitudes are related to aspects of neurophysiological responsivity. They also indicate that a bidimensional model of political orientation can enhance our interpretation of the nature of these associations.

Neural responses during emotional processing before and after cognitive trauma therapy for battered women

Therapy for combat and accident-related posttraumatic stress disorder (PTSD) has been reported to influence amygdala and anterior cingulate cortex (ACC) response during emotional processing. It is not yet understood how therapy influences different phases of emotional processing, and whether previous findings generalize to other PTSD populations. We hypothesized that cognitive trauma therapy for battered women (CTT-BW) would alter insula, amygdala, and cingulate responses during anticipation and presentation of emotional images. Fourteen female patients with PTSD related to domestic violence completed the Clinician Administered PTSD Scale (CAPS) and functional magnetic resonance imaging (fMRI) before and after CTT-BW. The fMRI task involved cued anticipation followed by presentation of positive versus negative affective images. CTT-BW was associated with decreases in CAPS score, enhanced ACC and decreased anterior insula activation during anticipation, and decreased dorsolateral prefrontal cortex and amygdala response during image presentation (negative–positive). Pre-treatment ACC activation during anticipation and image presentation exhibited positive and negative relationships to treatment response, respectively. Results suggest that CTT-BW enhanced efficiency of neural responses during preparation for upcoming emotional events in a way that reduced the need to recruit prefrontal-amygdala responses during the occurrence of the event. Results also suggest that enhancing ACC function during anticipation may be beneficial for PTSD treatment.

Dopaminergic involvement during mental fatigue in health and cocaine addiction

Dopamine modulates executive function, including sustaining cognitive control during mental fatigue. Using event-related functional magnetic resonance imaging (fMRI) during the color-word Stroop task, we aimed to model mental fatigue with repeated task exposures in 33 cocaine abusers and 20 healthy controls. During such mental fatigue (indicated by increased errors, and decreased post-error slowing and dorsal anterior cingulate response to error as a function of time-on-task), healthy individuals showed increased activity in the dopaminergic midbrain to error. Cocaine abusers, characterized by disrupted dopamine neurotransmission, showed an opposite pattern of response. This midbrain fMRI activity with repetition was further correlated with objective indices of endogenous motivation in all subjects: a state measure (task reaction time) and a trait measure (dopamine D2 receptor availability in caudate, as revealed by positron emission tomography data collected in a subset of this sample, which directly points to a contribution of dopamine to these results). In a second sample of 14 cocaine abusers and 15 controls, administration of an indirect dopamine agonist, methylphenidate, reversed these midbrain responses in both groups, possibly indicating normalization of response in cocaine abusers because of restoration of dopamine signaling but degradation of response in healthy controls owing to excessive dopamine signaling. Together, these multimodal imaging findings suggest a novel involvement of the dopaminergic midbrain in sustaining motivation during fatigue. This region might provide a useful target for strengthening self-control and/or endogenous motivation in addiction.