Striatal Response Research Articles

Intelligence mindset shapes neural learning signals and memory

Intelligence mindset, which denotes individual beliefs about whether intelligence is fixed versus malleable, shapes academic success, but the neural mechanisms underlying mindset-related differences in learning are unknown. Here, we probe the effects of individual differences in mindset on neural responses to negative feedback after a competence threat manipulation. We hypothesized that when their competence was threatened, participants with fixed mindsets would interpret further negative feedback as punishing. After receiving either no score or a competence-threatening IQ score, participants performed a learning task with feedback that emphasized either the evaluative or informational weight of negative feedback. Participants who experienced the competence threat had the strongest predictive relationships between mindset, performance, and caudate activation. The competence threat may have compounded the subjective punishment of negative feedback for fixed mindsets relative to growth mindsets, causing poorer learning from negative feedback in the evaluative context and inflexible striatal responses to negative feedback across feedback contexts.

State-Dependent Effects of Ventromedial Prefrontal Cortex Continuous Thetaburst Stimulation on Cocaine Cue Reactivity in Chronic Cocaine Users.

Cue-induced craving is a significant barrier to obtaining abstinence from cocaine. Neuroimaging research has shown that cocaine cue exposure evokes elevated activity in a network of frontal-striatal brain regions involved in drug craving and drug seeking. Prior research from our laboratory has demonstrated that when targeted at the medial prefrontal cortex (mPFC), continuous theta burst stimulation (cTBS), an inhibitory form of non-invasive brain stimulation, can decrease drug cue-related activity in the striatum in cocaine users and alcohol users. However, it is known that there are individual differences in response to repetitive transcranial magnetic stimulation (rTMS), with some individuals being responders and others non-responders. There is some evidence that state-dependent effects influence response to rTMS, with baseline neural state predicting rTMS treatment outcomes. In this single-blind, active sham-controlled crossover study, we assess the striatum as a biomarker of treatment response by determining if baseline drug cue reactivity in the striatum influences striatal response to mPFC cTBS. The brain response to cocaine cues was measured in 19 cocaine-dependent individuals immediately before and after real and sham cTBS (110% resting motor threshold, 3600 total pulses). Group independent component analysis (ICA) revealed a prominent striatum network comprised of bilateral caudate, putamen, and nucleus accumbens, which was modulated by the cocaine cue reactivity task. Baseline drug cue reactivity in this striatal network was inversely related to change in striatum reactivity after real (vs. sham) cTBS treatment (ρ = -.79; p < .001; R 2 Adj = .58). Specifically, individuals with a high striatal response to cocaine cues at baseline had significantly attenuated striatal activity after real but not sham cTBS (t 9 = -3.76; p ≤ .005). These data demonstrate that the effects of mPFC cTBS on the neural circuitry of craving are not uniform and may depend on an individual’s baseline frontal-striatal reactivity to cues. This underscores the importance of assessing individual variability as we develop brain stimulation treatments for addiction.

T92. Reduction in Anhedonia Mediates the Relationship Between Left Ventral Striatal Reward Response and 6-Month Improvement in Life Satisfaction in Young Adults

T92. Reduction in Anhedonia Mediates the Relationship Between Left Ventral Striatal Reward Response and 6-Month Improvement in Life Satisfaction in Young Adults

175. Targeting the Gut-Brain Axis to Regulate Preference and Striatal Response to Fat

High fat diet (HFD) leads to disrupted striatal dopamine function and alterations in fat preference. One mechanism by which this occurs is depletion of gut lipid messengers, including oleoylethanolamine (OEA), which when replenished rescues dopamine response and increases preference for low fat emulsions via the generation of vagal afferent signals (Tellez et al., 2013). Using a supplement containing the OEA precurser N-oleyl-phosphatidylethanolamine and epigallocatechin-3-gallate (NOPE+EGCG), we tested whether this effect translates to humans and whether supplementation improves outcomes on a behavioral weight loss trial.

Cue Reactivity in the Ventral Striatum Characterizes Heavy Cannabis Use, Whereas Reactivity in the Dorsal Striatum Mediates Dependent Use

BackgroundAnimal models of addiction suggest that the transition from incentive-driven drug use to habitual and ultimately compulsive drug use is mediated by a shift from ventral to dorsal striatal cue control over drug seeking. Previous studies in human cannabis users reported elevated trait impulsivity and neural cue reactivity in striatal circuits; however, these studies were not able to separate addiction-related from exposure-related adaptations. MethodsTo differentiate the adaptive changes, the current functional magnetic resonance imaging study examined behavioral and neural cue reactivity in dependent (n = 18) and nondependent (n = 20) heavy cannabis users and a nonusing reference group (n = 44). ResultsIrrespective of dependence status, cannabis users demonstrated elevated trait impulsivity as well as increased ventral striatal reactivity and striatal frontal coupling in response to drug cues. Dependent users selectively exhibited dorsal striatal reactivity and decreased striatal limbic coupling during cue exposure. An exploratory analysis revealed that higher ventral caudate neural cue reactivity was associated with stronger cue-induced arousal and craving in dependent users, whereas this pattern was reversed in nondependent users. ConclusionsTaken together, the current findings suggest that exaggerated responses of the ventral striatal reward system may promote excessive drug use in humans, whereas adaptations in dorsal striatal systems engaged in habit formation may promote the transition to addictive use.

Reward Processing in Adolescent Depression Across Neuroimaging Modalities.

Depressive symptoms have long been associated with abnormalities in neural processing of reward. However, no review has yet consolidated evidence of such deficits in adolescent depression, integrating findings across neuroimaging modalities, such as functional magnetic resonance imaging (fMRI) and electroencephalography (EEG). The current review found consistent evidence of reduced striatal responses in anticipation and upon receipt of rewards, and blunted feedback-related negativity (FRN) potentials associated with depression in adolescence, consistent with the adult literature. Furthermore, while these occurred in currently depressed adolescents, they were also found to be predictive of the onset of depressive symptoms in longitudinal studies with community-based adolescent samples. This paper makes recommendations for future work to continue to elucidate this relationship, a greater understanding of which may lead to more targeted and efficacious treatments for depression in adolescence.

Neurobiological responses in the adolescent striatum to being 'tested'.

While emerging research implicates the striatum in adolescents' ability to learn from feedback, little is known about how motivational contexts, such as emphasizing the evaluative nature of learning tasks, modulate adolescents' striatal learning. We used functional magnetic resonance imaging during a feedback-based learning task, in conjunction with a within-subject evaluative threat manipulation, to determine whether evaluation threat influences behavioral and neural responses to feedback in adolescents. On average, adolescents were less sensitive than adults to the evaluation threat. In the adolescents, the effect of evaluation threat on performance was tracked with the striatal response to performance feedback during the evaluation threat condition, such that greater striatal sensitivity correlated with greater gains in learning performance. Our findings suggest that variability in how adolescents respond to a contextual threat of evaluation and associated striatal sensitivity can facilitate enhanced learning.

Ventral Striatal Reactivity in Compulsive Sexual Behaviors.

Compulsive Sexual Behaviors (CSB) are a reason to seek treatment. Given this reality, the number of studies on CSB has increased substantially in the last decade and the World Health Organization (WHO) included CSB in its proposal for the upcoming ICD-11. Sixty percent of the neuroimaging studies on CSB published since 2014 aimed to examine similarities and differences between brain mechanisms underlying CSB, gambling disorder, and substance use disorders. One of the crucial brain circuits involved in addiction is the reward system involving the ventral striatum (including nucleus accumbens). There are two distinct theories describing ventral striatal activity in addictions: Incentive Salience Theory (IST) and Reward Deficiency Syndrome (RDS). IST describes increased ventral striatal activations during the anticipation of addiction-related reward, while RDS describes decreased ventral striatal reactivity both during the anticipation of the reward and during the reward processing. Here, we aim to investigate how the findings on ventral striatal reactivity in CSB support each of these two addiction frameworks. For this purpose, we conducted a systematic review of neuroimaging studies on CSB available in Pubmed, EBSCO, and Google Scholar between 2005 and 2018. We found nine relevant research papers. Only four of these studies directly investigated processing of erotic cues and/or rewards and reported findings related to ventral striatum activations. Three of these studies indicate increased ventral striatal reactivity for erotic stimuli, which is consistent with IST and does not support predictions based on RDS. Therefore, the current state of this data suggest that CSB is related to increased ventral striatal reactivity during the anticipation of erotic stimuli.

Age-related differences in the activation of the mentalizing- and reward-related brain regions during the learning of others' true trustworthiness.

Behavioral studies suggest that older adults may be less adept than younger adults at remembering information contradicting their first impressions about others' trustworthiness. To identify the neural bases associated with such age-related differences, we measured the brain activity of older and younger participants using functional magnetic resonance imaging while they processed feedback on whether their initial trustworthiness impressions of stimulus persons, whose true trustworthiness had been predetermined, were right or wrong. Of special interest was the activation in mentalizing- (e.g., medial prefrontal cortex) and reward-related brain regions (e.g., striatum), which are known to be involved in impression formation and feedback learning, respectively. The reduction in the striatal responses to impression-contradicting versus impression-confirming feedback was greater in older than in younger participants. The activation of some mentalizing-related regions (medial prefrontal cortex and precuneus) was lower in older than younger participants; however, it was not modulated by impression-feedback congruency. The results suggest that age-related differences in the striatum engagement may underlie older adults' inefficiency in learning impression-incongruent information about others' trustworthiness.

Relation of neural response to palatable food tastes and images to future weight gain: Using bootstrap sampling to examine replicability of neuroimaging findings

Because understanding neural vulnerability factors that predict future weight gain may guide the design of more effective obesity prevention programs and treatments, we tested whether neural response to palatable food tastes and images predicted future weight gain. We recruited 135 initially healthy weight adolescents, to reduce the possibility that a history of overeating affected neural responsivity, had them complete fMRI paradigms examining neural response to tastes of milkshakes that varied in fat and sugar content and images of palatable foods, and assessed BMI annually over a 3-year follow-up. We used a novel bootstrapping analytic approach to investigate the replicability of the fMRI findings. Whole-brain analyses indicated that lower response in the pre-supplemental motor area to high-fat/low-sugar milkshake taste predicted future BMI gain in the full sample and in 5 out of the 10 bootstrap samples. Elevated response in the precentral gyrus/Rolandic operculum to images of appetizing foods predicted future BMI gain in the full sample and in 4 out of the 10 bootstrap samples. Other peaks that emerged in the full sample did not replicate in most of the bootstrap samples, suggesting they were not reliable. Region of interest analyses did not replicate the predictive effects of peaks reported in past papers that used similar paradigms, including the evidence that TaqIA polymorphism moderated the relation of striatal response to palatable food tastes to future weight gain. Results suggest that lower responsivity of a region implicated in motor processing in response to palatable taste was associated with greater BMI gain over time, and further that bootstrap sampling may be useful for estimating the replicability of findings that emerge from whole brain analyses or regions of interest analyses with the full sample.

Ventral Striatal Function Interacts With Positive and Negative Life Events to Predict Concurrent Youth Depressive Symptoms

BackgroundLife events and reward-system functioning contribute to resilience and risk for depression. However, interactions between life events and neural responses to reward and loss have not been previously investigated in relation to depression symptoms in child and adolescent populations. MethodsAn unselected sample (N = 130) of 8- to 14-year-old girls (mean = 12.6 years) completed the Child Depression Inventory and a functional magnetic resonance imaging guessing task in which they won or lost money on each trial. Parents completed a measure of life events experienced by the child. Life events were separated by positive versus negative and whether they were likely related or unrelated to the daughter’s behavior (i.e., dependent vs. independent, respectively). Multiple regressions tested whether the interaction between ventral striatal (VS) response to wins or losses and recent life events were associated with child-reported depressive symptoms. ResultsA greater number of dependent positive life events related to decreased total depression symptoms when VS response to wins was robust. Conversely, a greater number of independent negative life events related to increased negative mood depression symptoms when VS response to losses was robust; this relationship was in the opposite direction when VS response to loss was low. ConclusionsVS response to reward and loss were independent moderators of the relationship between recent life events (positive and negative, respectively) and depressive symptoms. Findings suggest that targeting neural responses (i.e., increasing responses to winning or decreasing responses to losing) may be important for both improving resilience and reducing risk in different environmental contexts.

Acupuncture Alleviates Levodopa-Induced Dyskinesia via Melanin-Concentrating Hormone in Pitx3-Deficient aphakia and 6-Hydroxydopamine-Lesioned Mice.

Although L-3,4-dihydroxyphenylalanine (L-DOPA) is currently the most effective medication for treating Parkinson's disease (PD) motor symptoms, its prolonged administration causes several adverse effects, including dyskinesia. To identify the mechanisms underlying the effects of acupuncture on L-DOPA-induced dyskinesia (LID), antidyskinetic effects of acupuncture were investigated in two mouse models of PD. Acupuncture stimulation at GB34 alleviated abnormal involuntary movements (AIMs) in Pitx3-deficient aphakia mice (ak/ak) following L-DOPA administration and these effects were reproduced in 6-hydroxydopamine (6-OHDA)-lesioned mice with LID. A transcriptome analysis of the hypothalamus revealed pro-melanin-concentrating hormone (Pmch) gene was highly expressed in acupuncture-treated mouse from ak/ak model of LID as well as 6-OHDA model of LID. Acupuncture combined with the administration of MCH receptor antagonist did not have any beneficial effects on dyskinesia in L-DOPA-injected ak/ak mice, but the intranasal administration of MCH attenuated LID to the same degree as acupuncture in both ak/ak and 6-OHDA mice with LID. A gene expression profile with a hierarchical clustering analysis of the dyskinesia-induced ak/ak mouse brain revealed an association between the mechanisms underlying acupuncture and MCH. Additionally, altered striatal responses to L-DOPA injection were observed after prolonged acupuncture and MCH treatments, which suggests that these treatment modalities influenced the compensatory mechanisms of LID. In summary, present study demonstrated that acupuncture decreased LID via hypothalamic MCH using L-DOPA-administered ak/ak and 6-OHDA mouse models and that MCH administration resulted in novel antidyskinetic effects in these models. Thus, acupuncture and MCH might be valuable therapeutic candidates for PD patients suffering from LID.

Appetite changes reveal depression subgroups with distinct endocrine, metabolic, and immune states.

There exists little human neuroscience research to explain why some individuals lose their appetite when they become depressed, while others eat more. Answering this question may reveal much about the various pathophysiologies underlying depression. The present study combined neuroimaging, salivary cortisol, and blood markers of inflammation and metabolism collected prior to scanning. We compared the relationships between peripheral endocrine, metabolic, and immune signaling and brain activity to food cues between depressed participants experiencing increased (N=23) or decreased (N=31) appetite and weight in their current depressive episode and healthy control participants (N=42). The two depression subgroups were unmedicated and did not differ in depression severity, anxiety, anhedonia, or body mass index. Depressed participants experiencing decreased appetite had higher cortisol levels than subjects in the other two groups, and their cortisol values correlated inversely with the ventral striatal response to food cues. In contrast, depressed participants experiencing increased appetite exhibited marked immunometabolic dysregulation, with higher insulin, insulin resistance, leptin, CRP, IL-1RA, and IL-6, and lower ghrelin than subjects in other groups, and the magnitude of their insulin resistance correlated positively with the insula response to food cues. These findings provide novel evidence linking aberrations in homeostatic signaling pathways within depression subtypes to the activity of neural systems that respond to food cues and select when, what, and how much to eat. In conjunction with prior work, the present findings strongly support the existence of pathophysiologically distinct depression subtypes for which the direction of appetite change may be an easily measured behavioral marker.

Adolescents at high risk of obesity show greater striatal response to increased sugar content in milkshakes

Children of overweight or obese parents are at a high risk of developing obesity. This study sought to examine the underlying neural factors related to parental obesity risk and the relative impact of sugar and fat when consuming a palatable food, as well as the impact of obesity risk status on brain response to appetizing food images. With the use of functional MRI, the responses of 108 healthy-weight adolescents [mean ± SD body mass index (kg/m2): 20.9±1.9; n=53 who were at high risk by virtue of parental obesity status, n=55 who were low risk] to food stimuli were examined. Stimuli included 4 milkshakes, which systematically varied in sugar and fat content, a calorie-free tasteless solution, and images of appetizing foods and glasses of water. High-risk compared with low-risk adolescents showed greater blood oxygen-dependent response to milkshakes (all variants collapsed) compared with the tasteless solution in the primary gustatory and oral somatosensory cortices (P-family-wise error rate <0.05), replicating a previous report. Notably, high-risk adolescents showed greater caudate, gustatory, and oral somatosensory responses to the high-sugar milkshake than to the tasteless solution; however, no effect of risk status was observed in the high-fat milkshake condition. Responses to food images were not related to obesity risk status. Collectively, the data presented here suggest that parental weight status is associated with greater striatal, gustatory, and somatosensory responses to palatable foods-in particular, high-sugar foods-in their adolescent offspring, which theoretically contributes to an increased risk of future overeating. This trial was registered at www.clinicaltrials.gov as NCT01949636.

Age-related differences in striatal, medial temporal, and frontal involvement during value-based decision processing

Appropriate neural representation of value and application of decision strategies are necessary to make optimal investment choices in real life. Normative human aging alters neural selectivity and control processing in brain regions implicated in value-based decision processing including striatal, medial temporal, and frontal areas. However, the specific neural mechanisms of how these age-related functional brain changes modulate value processing in older adults remain unclear. Here, young and older adults performed a lottery-choice functional magnetic resonance imaging experiment in which probabilities of winning different magnitudes of points constituted expected values of stakes. Increasing probability of winning modulated striatal responses in young adults, but modulated medial temporal and ventromedial prefrontal areas instead in older adults. Older adults additionally engaged higher responses in dorso-medio-lateral prefrontal cortices to more unfavorable stakes. Such extrastriatal involvement mediated age-related increase in risk-taking decisions. Furthermore, lower resting-state functional connectivity between lateral prefrontal and striatal areas also predicted lottery-choice task risk-taking that was mediated by higher functional connectivity between prefrontal and medial temporal areas during the task, with this mediation relationship being stronger in older than younger adults. Overall, we report evidence of a systemic neural mechanistic change in processing of probability in mixed-lottery values with age that increases risk-taking of unfavorable stakes in older adults. Moreover, individual differences in age-related effects on baseline frontostriatal communication may be a central determinant of such subsequent age differences in value-based decision neural processing and resulting behaviors.

Ventral striatal response during decision making involving risk and reward is associated with future binge drinking in adolescents.

Beginning to engage in heavy alcohol use during adolescence, as opposed to later in life, is associated with elevated risk for a variety of negative consequences, including the development of an alcohol use disorder. Behavioral studies suggest that poor decision making predicts alcohol use during adolescence; however, more research is needed to determine the neurobiological risk factors that underlie this association. Using functional magnetic resonance imaging, brain activation during decision making involving risk and reward was assessed in 47 adolescents (14-15 years old) with no significant history or alcohol or drug use. After baseline assessment, participants completed follow-up interviews every 3 months to assess the duration to onset of binge drinking. Adolescents who made a greater number of risky selections and had greater activation in the nucleus accumbens, precuneus, and occipital cortex during decision making involving greater potential for risk and reward began binge drinking sooner. Findings suggest that heightened activation of reward circuitry during decision making under risk is a neurobiological risk factor for earlier onset of binge drinking. Furthermore, brain activation was a significant predictor of onset to binge drinking, even after controlling for decision-making behavior, suggesting that neurobiological markers may provide additional predictive validity over behavioral assessments. Interventions designed to modify these behavioral and neurobiological risk factors may be useful for curbing heavy alcohol use during adolescence.

Dopamine modulates striatal response to reward and punishment in patients with Parkinson's disease: a pharmacological challenge fMRI study.

It is well established that Parkinson's disease leads to impaired learning from reward and enhanced learning from punishment. The administration of dopaminergic medications reverses this learning pattern. However, few studies have investigated the neural underpinnings of these cognitive processes. In this study, using fMRI, we tested a group of Parkinson's disease patients on and off dopaminergic medications and matched healthy individuals. All individuals completed an fMRI cognitive task that dissociates feedback learning from reward versus punishment. The administration of dopaminergic medications attenuated blood oxygen level dependent (BOLD) responses to punishment in the bilateral putamen, in bilateral dorsolateral prefrontal cortex and the left premotor cortex. Further, the administration of dopaminergic medications resulted in a higher ratio of BOLD activity between reward and punishment trials in these brain areas. BOLD activity in these brain areas was significantly correlated with learning from punishment, but not from reward trials. Furthermore, the administration of dopaminergic medications altered BOLD activity in the right insula and ventromedial prefrontal cortex when Parkinson's disease patients were anticipating feedback. These findings are in agreement with a large body of literature indicating that Parkinson's disease is associated with enhanced learning from punishment. However, it was surprising that dopaminergic medications modulated punishment learning as opposed to reward learning, although reward learning has been directly linked to dopaminergic function. We argue that these results might be attributed to both a change in the balance between direct and indirect pathway activation in the basal ganglia as well as the differential activity of D1 versus D2 dopamine receptors.

Brief exposure to obesogenic diet disrupts brain dopamine networks.

ObjectiveWe have previously demonstrated that insulin signaling, through the downstream signaling kinase Akt, is a potent modulator of dopamine transporter (DAT) activity, which fine-tunes dopamine (DA) signaling at the synapse. This suggests a mechanism by which impaired neuronal insulin receptor signaling, a hallmark of diet-induced obesity, may contribute to impaired DA transmission. We tested whether a short-term (two-week) obesogenic high-fat (HF) diet could reduce striatal Akt activity, a marker of central insulin, receptor signaling and blunt striatal and dopaminergic network responsiveness to amphetamine (AMPH).MethodsWe examined the effects of a two-week HF diet on striatal DAT activity in rats, using AMPH as a probe in a functional magnetic resonance imaging (fMRI) assay, and mapped the disruption in AMPH-evoked functional connectivity between key dopaminergic targets and their projection areas using correlation and permutation analyses. We used phosphorylation of the Akt substrate GSK3α in striatal extracts as a measure of insulin receptor signaling. Finally, we confirmed the impact of HF diet on striatal DA D2 receptor (D2R) availability using [18F]fallypride positron emission tomography (PET).ResultsWe found that rats fed a HF diet for only two weeks have reductions in striatal Akt activity, a marker of decreased striatal insulin receptor signaling and blunted striatal responsiveness to AMPH. HF feeding also reduced interactions between elements of the mesolimbic (nucleus accumbens–anterior cingulate) and sensorimotor circuits (caudate/putamen–thalamus–sensorimotor cortex) implicated in hedonic feeding. D2R availability was reduced in HF-fed animals.ConclusionThese studies support the hypothesis that central insulin signaling and dopaminergic neurotransmission are already altered after short-term HF feeding. Because AMPH induces DA efflux and brain activation, in large part via DAT, these findings suggest that blunted central nervous system insulin receptor signaling through a HF diet can impair DA homeostasis, thereby disrupting cognitive and reward circuitry involved in the regulation of hedonic feeding.

Transdiagnostic Effects of Ventromedial Prefrontal Cortex Transcranial Magnetic Stimulation on Cue Reactivity

BackgroundElevated frontal and striatal reactivity to drug cues is a transdiagnostic hallmark of substance use disorders. The goal of these experiments was to determine if it is possible to decrease frontal and striatal reactivity to drug cues in both cocaine users and heavy alcohol users through continuous theta burst stimulation (cTBS) to the left ventromedial prefrontal cortex (VMPFC). MethodsTwo single-blinded, within-subject, active sham–controlled experiments were performed wherein neural reactivity to drug/alcohol cues versus neutral cues was evaluated immediately before and after receiving real or sham cTBS (110% resting motor threshold, 3600 pulses, Fp1 location; N = 49: 25 cocaine users [experiment 1], 24 alcohol users [experiment 2]; 196 total functional magnetic resonance imaging scans). Generalized psychophysiological interaction and three-way repeated-measures analysis of variance were used to evaluate cTBS-induced changes in drug cue-associated functional connectivity between the left VMPFC and eight regions of interest: ventral striatum, left and right caudate, left and right putamen, left and right insula, and anterior cingulate cortex. ResultsIn both experiments, there was a significant interaction between treatment (real/sham) and time (pre/post). In both experiments, cue-related functional connectivity was significantly attenuated following real cTBS versus sham cTBS. There was no significant interaction with region of interest for either experiment. ConclusionsThis is the first sham-controlled investigation to demonstrate, in two populations, that VMPFC cTBS can attenuate neural reactivity to drug and alcohol cues in frontostriatal circuits. These results provide an empirical foundation for future clinical trials that may evaluate the efficacy, durability, and clinical implications of VMPFC cTBS to treat addictions.

Neural mechanisms of the rejection-aggression link.

Social rejection is a painful event that often increases aggression. However, the neural mechanisms of this rejection–aggression link remain unclear. A potential clue may be that rejected people often recruit the ventrolateral prefrontal cortex’s (VLPFC) self-regulatory processes to manage the pain of rejection. Using functional MRI, we replicated previous links between rejection and activity in the brain’s mentalizing network, social pain network and VLPFC. VLPFC recruitment during rejection was associated with greater activity in the brain’s reward network (i.e. the ventral striatum) when individuals were given an opportunity to retaliate. This retaliation-related striatal response was associated with greater levels of retaliatory aggression. Dispositionally aggressive individuals exhibited less functional connectivity between the ventral striatum and the right VLPFC during aggression. This connectivity exerted a suppressing effect on dispositionally aggressive individuals’ greater aggressive responses to rejection. These results help explain how the pain of rejection and reward of revenge motivate rejected people to behave aggressively.