Ventromedial Prefrontal Cortex

IntroductionCortical thickness (CT) and surface area (SA) are established biomarkers of brain pathology in posttraumatic stress disorder (PTSD). Structural covariance networks (SCN) constructed from CT and SA may represent developmental associations, or unique interactions between brain regions, possibly influenced by a common causal antecedent. The ENIGMA-PGC PTSD Working Group aggregated PTSD and control subjects’ data from 29 cohorts in five countries (n=3439).MethodsUsing Destrieux Atlas, we built SCNs and compared centrality measures between PTSD subjects and controls. Centrality is a graph theory measure derived using SCN.ResultsNotable nodes with higher CT-based centrality in PTSD compared to controls were left fusiform gyrus, left superior temporal gyrus, and right inferior temporal gyrus. We found sex-based centrality differences in bilateral frontal lobe regions, left anterior cingulate, left superior occipital cortex and right ventromedial prefrontal cortex (vmPFC). Comor...

Changed reward functions have been proposed as a core feature of stimulant addiction, typically observed as reduced neural responses to non-drug-related rewards. However, it was unclear yet how specific this deficit is for different types of non-drug rewards arising from social and non-social reinforcements. We used functional neuroimaging in cocaine users to investigate explicit social reward as modeled by agreement of music preferences with music experts. In addition, we investigated non-social reward as modeled by winning desired music pieces. The study included 17 chronic cocaine users and 17 matched stimulantnaive healthy controls. Cocaine users, compared with controls, showed blunted neural responses to both social and non-social reward. Activation differences were located in the ventromedial prefrontal cortex overlapping for both reward types and, thus, suggesting a non-specific deficit in the processing of non-drug rewards. Interestingly, in the posterior lateral orbitofrontal cortex, social reward responses of cocaine users decreased with the degree to which they were influenced by social feedback from the experts, a response pattern that was opposite to that observed in healthy controls. The present results suggest that cocaine users likely suffer from a generalized impairment in value representation as well as from an aberrant processing of social feedback.

Stress exposures and dysregulated responses to stress are implicated in psychiatric disorders of mood, anxiety, and cognition. Perceived stress, an individual's appraisal of experienced stress and ability for coping, relates to dysregulated functioning in resting state brain networks. Alterations in GABAergic function may underlie perceived stress-related functional dysregulation in resting state networks but this has not yet been explored. Therefore, the current study examined the association of perceived stress, via the Perceived Stress Scale (PSS), with prefrontal GABA levels and corresponding resting state functional connectivity (RSFC) alterations. Twelve women and five men, ages 35–61, participated. MR spectroscopy was used to measure brain GABA levels in the anterior cingulate cortex (ACC), left dorsolateral prefrontal cortex (DLPFC), and ventromedial prefrontal cortex (VMPFC). Resting state functional scans acquired at 3 Tesla were used to measure RSFC within and between...

Traditionally, lust and pride have been considered pleasurable, yet sinful in the West. Conversely, guilt is often considered aversive, yet valuable. These emotions illustrate how evaluations about specific emotions and beliefs about their hedonic properties may often diverge. Evaluations about specific emotions may shape important aspects of emotional life (e.g. in emotion regulation, emotion experience and acquisition of emotion concepts). Yet these evaluations are often understudied in affective neuroscience. Prior work in emotion regulation, affective experience, evaluation/attitudes and decision-making point to anterior prefrontal areas as candidates for supporting evaluative emotion knowledge. Thus, we examined the brain areas associated with evaluative and hedonic emotion knowledge, with a focus on the anterior prefrontal cortex. Participants (N = 25) made evaluative and hedonic ratings about emotion knowledge during functional magnetic resonance imaging (fMRI). We found that greater activity in the medial prefrontal cortex (mPFC), ventromedial PFC (vmPFC) and precuneus was associated with an evaluative (vs hedonic) focus on emotion knowledge. Our results suggest that the mPFC and vmPFC, in particular, may play a role in evaluating discrete emotions.

We examined whether anterior and posterior hippocampal subregions in humans show distinct relationships to state and trait anxiety. In rodents, the ventral (but not dorsal) hippocampus is critically involved in contextual anxiety, whereas dorsal hippocampus is affected by chronic stress and genetically bred trait anxiety. These studies suggest that state forms of anxiety may be more associated with anterior (ventral in rodents) hippocampus, whereas trait forms of anxiety maybe more associated with posterior (dorsal in rodents) hippocampus. Participants were placed under alternating blocks of threat of shock and safety conditions while performing a secondary task, and state and trait anxiety measures were obtained. Using subject-specific anatomically defined masks, we found that state anxiety was related to activity in anterior but not posterior hippocampus, whereas trait anxiety showed the opposite pattern. Additionally, a psychophysiological connectivity analysis showed that activity in anterior hippocampus was more strongly related to activity in ventromedial prefrontal cortex under threat than under safety conditions, significantly more so than activity in posterior hippocampus was. Hence, anterior hippocampus shows a distinct moment-to-moment connectivity profile with other neural regions during threat relative to posterior hippocampus. The findings provide several lines of evidence for functional differentiation of anterior and posterior hippocampal involvement across state and trait components of anxiety in humans.

Background: Coordination of activity between the amygdala and ventromedial prefrontal cortex (vmPFC) is important for fear-extinction learning. Aberrant recruitment of this circuitry is associated with anxiety disorders. Here, we sought to determine if individual differences in future threat uncertainty sensitivity, a potential risk factor for anxiety disorders, underly compromised recruitment of fear extinction circuitry. Twenty-two healthy subjects completed a cued fear conditioning task with acquisition and extinction phases. During the task, pupil dilation, skin conductance response, and functional magnetic resonance imaging were acquired. We assessed the temporality of fear extinction learning by splitting the extinction phase into early and late extinction. Threat uncertainty sensitivity was measured using self-reported intolerance of uncertainty (IU). Results: During early extinction learning, we found low IU scores to be associated with larger skin conductance responses and right amygdala activity to learned threat vs. safety cues, whereas high IU scores were associated with no skin conductance discrimination and greater activity within the right amygdala to previously learned safety cues. In late extinction learning, low IU scores were associated with successful inhibition of previously learned threat, reflected in comparable skin conductance response and right amgydala activity to learned threat vs. safety cues, whilst high IU scores were associated with continued fear expression to learned threat, indexed by larger skin conductance and amygdala activity to threat vs. safety cues. In addition, high IU scores were associated with greater vmPFC activity to threat vs. safety cues in late extinction. Similar patterns of IU and extinction learning were found for pupil dilation. The results were specific for IU and did not generalize to self-reported trait anxiety. Conclusions: Overall, the neural and psychophysiological patterns observed here suggest high IU individuals to disproportionately generalize threat during times of uncertainty, which subsequently compromises fear extinction learning. More broadly, these findings highlight the potential of intolerance of uncertainty-based mechanisms to help understand pathological fear in anxiety disorders and inform potential treatment targets.

Background Despite the critical role of choice processes in substance use disorders, the neurobehavioral mechanisms guiding human decisions about drugs remain poorly understood. We adapted a neuroeconomic framework to characterize the neural encoding of subjective value (SV) for cannabis versus non-drug rewards (snacks) in near-daily cannabis users. We also assessed the impact of cannabis and snack stimuli ('cues') on SV encoding. Methods Twenty-one non-treatment-seeking cannabis users (≥4 days/week; 1 female) participated in an inpatient, crossover experiment with four counterbalanced conditions: 1. neutral cues/cannabis choices; 2. cannabis cues/cannabis choices; 3. neutral cues/snack choices; and 4. snack cues/snack choices. In each condition, participants were exposed to cues before an fMRI scan during which they repeatedly chose between 0-6 cannabis puffs/snacks and a set monetary amount, with randomly-selected choices implemented. The SV signal was operationalized as the neural correlates of the strength of preference for cannabis/snack choices. fMRI data were analyzed for twenty participants. Results Despite equivalent choice behavior, SV signals for cannabis, but not snacks, were observed in regions known to encode SV for various rewards (ventromedial prefrontal cortex, vmPFC; ventral striatum; dorsal posterior cingulate cortex, dPCC). SV encoding in vmPFC was stronger for cannabis than snacks. In the dPCC, the impact of cues on SV signals was moderated by the reward type. Conclusions Near-daily cannabis users had expected neural value encoding for cannabis but disrupted non-drug SV encoding, despite equivalent choice behavior. Results provide support for models identifying dysregulated neural valuation of non-drug rewards as a hallmark of problematic substance use.

Own-age bias is a well-known bias reflecting the effects of age, and its role has been demonstrated, particularly, in face recognition. However, it remains unclear whether an own-age bias exists in facial impression formation. In the present study, we used three datasets from two published and one unpublished functional magnetic resonance imaging (fMRI) study that employed the same pleasantness rating task with fMRI scanning and preferential choice task after the fMRI to investigate whether healthy young and older participants showed own-age effects in face preference. Specifically, we employed a drift-diffusion model to elaborate the existence of own-age bias in the processes of preferential choice. The behavioral results showed higher rating scores and higher drift rate for young faces than for older faces, regardless of the ages of participants. We identified a young-age effect, but not an own-age effect. Neuroimaging results from aggregation analysis of the three datasets sugges...

Previous neuroimaging studies demonstrated that ventromedial prefrontal cortex (vmPFC) activity reflects how much an individual positively views each person (impression). Here, we investigated whether the degree to which individuals think others positively view them (reflected impression) is similarly tracked by activity in the vmPFC by using fMRI and speed-dating events. We also examined whether activity of the vmPFC in response to the faces of others would predict the impression formed through direct interactions with them. The task consisted of three sessions: pre-speed-dating fMRI, speed-dating events, and post-speed-dating fMRI (not reported here). During the pre-speed-dating fMRI, each participant passively viewed the faces of others whom they would meet in the subsequent speed-dating events. After the fMRI, they rated the impression and reflected impression of each face. During the speed-dating events, the participants had 3-min conversations with partners whose faces were presented during the fMRI task, and they were asked to choose the partners whom they preferred at the end of the events. The results revealed that the value of both the impression and reflected impression were automatically represented in the vmPFC. However, the impression fully mediated the link between the reflected impression and vmPFC activity. These results highlight a close link between reflected appraisal and impression formation and provide important insights into neural and psychological models of how the reflected impression is formed in the human brain.

Previous findings have revealed abnormal visual attention or processing of faces among individuals with autism spectrum condition (ASC). However, little attention has been paid to the relationship between autistic traits and neural mechanisms associated with representing facial values. Using fMRI, we investigated the patterns of brain activity in the vmPFC and VS in response to faces of elderly males, elderly females, young males, and young females. During fMRI, subjects with a relatively high autism quotient (high group) and those with a relatively low autism quotient (low group) were presented with a face and asked to rate its pleasantness. After fMRI, the subjects were presented with pairs of faces and asked to select the face that they preferred. Our results indicate a dissociable modulatory effect of autistic traits on the vmPFC and VS: The vmPFC activity in the low group was more sensitive to age differences in female faces compared to that in the high group, whereas VS activi...

Pro-social lying, which serves to benefit listeners, is considered more socially and morally acceptable than anti-social lying, which serves to harm listeners. However, it is still unclear whether the neural mechanisms underlying the moral judgment of pro-social lying differ from those underlying the moral judgment of anti-social lying. We used functional magnetic resonance imaging (fMRI) to examine the neural activities associated with moral judgment in anti-and pro-social lying. During fMRI scanning, subjects were provided with scenarios describing a protagonist's anti-and pro-social lying and were then asked to judge whether the protagonist's act was morally appropriate. The behavioral data showed that anti-social lying was mostly judged to be morally inappropriate and that prosocial lying was mainly judged to be morally appropriate. The functional imaging data revealed dissociable neural systems for moral judgment in anti-and pro-social lying. The anti-social lying, which was judged to be morally inappropriate, was associated with increased activity in the right ventromedial prefrontal cortex, right middle frontal gyrus, right precuneus/posterior cingulate gyrus, left posterior cingulate gyrus, and bilateral temporoparietal junction when compared with the control condition. The pro-social lying, which was judged to be morally appropriate, was associated with increased activity in the right middle temporal gyrus, right supramarginal gyrus, and the left middle cingulate gyrus when compared with the control condition. No overlapping activity was observed during the moral judgment of anti-and pro-social lying. Our data suggest that cognitive and neural processes for the moral judgment of lying are modulated by whether the lie serves to harm or benefit listeners.

Whether maximizing rewards and minimizing punishments rely on distinct brain systems remains debated, given inconsistent results coming from human neuroimaging and animal electrophysiology studies. Bridging the gap across techniques, we recorded intracerebral activity from twenty participants while they performed an instrumental learning task. We found that both reward and punishment prediction errors (PE), estimated from computational modeling of choice behavior, correlate positively with broadband gamma activity (BGA) in several brain regions. In all cases, BGA scaled positively with the outcome (reward or punishment versus nothing) and negatively with the expectation (predictability of reward or punishment). However, reward PE were better signaled in some regions (such as the ventromedial prefrontal and lateral orbitofrontal cortex), and punishment PE in other regions (such as the anterior insula and dorsolateral prefrontal cortex). These regions might therefore belong to brain s...

SummaryWhether maximizing rewards and minimizing punishments rely on distinct brain systems remains debated, inconsistent results coming from human neuroimaging and animal electrophysiology studies. Bridging the gap across species and techniques, we recorded intracerebral activity from twenty patients with epilepsy while they performed an instrumental learning task. We found that both reward and punishment prediction errors (PE), estimated from computational modeling of choice behavior, correlated positively with broadband gamma activity (BGA) in several brain regions. In all cases, BGA increased with both outcome (reward or punishment versus nothing) and surprise (how unexpected the outcome is). However, some regions (such as the ventromedial prefrontal and lateral orbitofrontal cortex) were more sensitive to reward PE, whereas others (such as the anterior insula and dorsolateral prefrontal cortex) were more sensitive to punishment PE. Thus, opponent systems in the human brain migh...

Despite ample support for enhanced affective well-being and emotional stability in healthy aging, the role of potentially important dimensions, such as the emotional arousal, has not been systematically investigated in neuroimaging studies. In addition, the few behavioral studies that examined effects of arousal have produced inconsistent findings. The present study manipulated the arousal of pictorial stimuli to test the hypothesis that preserved emotional functioning in aging is modulated by the level of arousal, and to identify the associated neural correlates. Young and older healthy participants were presented with negative and neutral pictures, which they rated for emotional content, while fMRI data were recorded. There were three main novel findings regarding the neural mechanisms underlying the processing of negative pictures with different levels of arousal in young and older adults. First, the common engagement of the right amygdala in young and older adults was driven by high arousing negative stimuli. Second, complementing an age-related reduction in the subjective ratings for low arousing negative pictures, there were opposing patterns of activity in the rostral/ventral anterior cingulate cortex (ACC) and the amygdala, which showed increased vs. decreased responses, respectively, to low arousing negative pictures. Third, increased spontaneous activity in the ventral ACC/ventromedial prefrontal cortex (vmPFC) in older adults was linked to reduced ratings for low arousing negative pictures. Overall, these findings advance our understanding of the neural correlates underlying processing of negative emotions with different levels of arousal in the context of enhanced emotional functioning in healthy aging. Notably, the results support the idea that older adults have emotion regulation networks chronically activated, in the absence of explicit induction of the goal to regulate emotions, and that this effect is specific to low arousing negative emotions.

Despite ample support for enhanced affective well-being and emotional stability in healthy aging, the role of potentially important dimensions, such as the emotional arousal, has not been systematically investigated in neuroimaging studies. In addition, the few behavioral studies that examined effects of arousal have produced inconsistent findings. The present study manipulated the arousal of pictorial stimuli to test the hypothesis that preserved emotional functioning in aging is modulated by the level of arousal, and to identify the associated neural correlates. Young and older healthy participants were presented with negative and neutral pictures, which they rated for emotional content, while fMRI data were recorded. There were three main novel findings regarding the neural mechanisms underlying the processing of negative pictures with different levels of arousal in young and older adults. First, the common engagement of the right amygdala in young and older adults was driven by ...

Remembering emotional autobiographical memories (AMs) is important for emotional well-being, and investigation of the role of emotion regulation (ER) during AM recollection has relevance for understanding mental health issues. Although significant progress has been made in understanding the brain mechanisms underlying ER and AM, less is known about the role of ER during AM recollection. The present study investigated how focusing away (or distracting) from the emotional content during AM recollection influences the subjective re-experiencing of emotions and the associated neural correlates, by manipulating the retrieval focus of participants who remembered emotional AMs while fMRI data were recorded. First, focusing away from emotion led to decreased self-reported emotional responses, along with increased engagement of ER-related regions (ventro-medial prefrontal cortex, vmPFC), and reduced activity in emotion-related regions (amygdala, AMY). Second, increased vmPFC activity was linked to reduced emotional ratings, during the non-emotional focus. Third, mediation analysis identified vmPFC as a functional hub integrating affective signals from AMY and mediating their impact on the subjective re-experiencing of emotion, according to the current retrieval focus. Collectively, these findings shed light on the neural mechanisms underlying the ability to effectively switch attentional focus away from emotions during AM recollections and have direct relevance for understanding, preventing and treating affective disorders, characterised by reduced ability to regulate emotions.

Objective: Alcohol use disorders (AUDs) are associated with neuroadaptations in brain stress and reward circuits. It is not known whether such neuroadaptations are affected by alcohol abstinence days and also influence heavy drinking during the early treatment phase. A novel Functional Magnetic Resonance Imaging (fMRI) approach was utilized to assess brain responses during sustained exposure to standardized visual stimuli of stressful, alcohol cue and control, neutral images combined with prospective assessment of drinking outcomes during early outpatient treatment. In study 1, 44 treatment entering AUD patients and 43 demographically matched healthy controls (HC) participated in the fMRI experiment to identify dysfunctional responses associated with chronic alcohol abuse. In study 2, 69 AUD patients entering treatment assessed for whether fMRI responses at treatment initiation were influenced by alcohol abstinence and were prospectively predictive of early heavy drinking outcomes. Results: AUD patients, relative to HC showed hyperreactivity in the Ventro-medial Prefrontal Cortex (VmPFC) to neutral images, but VmPFC and ventral striatum hypoactivation to stress, and to alcohol cues relative to response to neutral images (whole brain, voxel based, p<.001, cluster corrected alpha=.05). In study 2, this specific prefrontal-ventral striatal dysfunction was associated with shorter days of alcohol abstinence (corr p<0.05), and also predicted greater number heavy drinking days during subsequent 2 weeks of treatment engagement (corr p<0.05). Alcohol abstinence days at treatment initiation significantly affects functional disruption of the prefrontal-striatal responses to stress and alcohol cues in AUD patients, and severity of this disruption, in turn, predicts greater heavy drinking during early treatment.

Please cite this article as: Madden JT, Reyna NC, Pentkowski NS, Antagonizing serotonin 2A (5-HT 2A ) receptors attenuates methamphetamine-induced reward and blocks methamphetamine-induced anxiety-like behaviors in adult male rats, Drug and Alcohol Dependence (2020),

Glutamate (Glu) and gamma-aminobutyric acid (GABA) are implicated in the pathophysiology of major depressive disorder (MDD). GABA levels or GABAergic interneuron numbers are generally low in MDD, potentially disinhibiting Glu release. It is unclear whether Glu release or turnover is increased in depression. Conversely, a meta-analysis of prefrontal proton magnetic resonance spectroscopy (1H MRS) studies in MDD finds low Glx (combination of glutamate and glutamine) in medicated MDD. We hypothesize that elevated Glx or Glu may be a marker of more severe, untreated MDD. We examined ventromedial prefrontal cortex/anterior cingulate cortex (vmPFC/ACC) Glx and glutamate levels using1H MRS in 34 medication-free, symptomatic, chronically ill MDD patients and 32 healthy volunteers, and GABA levels in a subsample. Elevated Glx and Glu were observed in MDD compared with healthy volunteers, with the highest levels seen in males with MDD. vmPFC/ACC GABA was low in MDD. Higher Glx levels correlat...

Craving elicited by drug-associated cues intensifies across protracted drug abstinence -a phenomenon termed "incubation of craving" -and drug-craving in human addicts correlates with frontal cortical hyperactivity. Herein, we employed a rat model of cue-elicited cocaine-craving to test the hypothesis that the time-dependent incubation of cue-elicited cocaine-craving is associated with adaptations in dopamine and glutamate neurotransmission within the ventromedial prefrontal cortex (vmPFC). Rats were trained to self-administer intravenous cocaine (6h/day × 10 days) and underwent in vivo microdialysis procedures during 2h-tests for cue-elicited cocaine-craving at either 3 or 30 days withdrawal. Controls rats were trained to either self-administer sucrose pellets or received no primary reinforcer. Cocaine-seeking rats exhibited a withdrawal-dependent increase and decrease, respectively, in cue-elicited glutamate and dopamine release. These patterns of neurochemical change were not observed in either control condition. Thus, cue-hypersensitivity of vmPFC glutamate terminals is a biochemical correlate of incubated cocaine-craving that may stem from dopamine dysregulation in this region.

Anomalies in prefrontal cortex (PFC) function are posited to underpin difficulties in learning to suppress drug-seeking behavior during abstinence. Because group 1 metabotropic glutamate receptors (mGluRs) regulate drug-related learning, we assayed the consequences of extended access to intravenous cocaine (6 h/d; 0.25 mg/infusion for 10 d) on the PFC expression of group 1 mGluRs and the relevance of observed changes for cocaine seeking. After protracted withdrawal, cocaine-experienced animals exhibited a time-dependent intensification of cue-induced cocaine-seeking behavior and an impaired extinction of this behavior. These behavioral phenomena were associated with a time-dependent reduction in mGluR1/5 expression within ventromedial PFC (vmPFC) of cocaine-experienced animals exposed to extinction testing but not in untested ones. Interestingly, pharmacological manipulations of vmPFC mGluR1/5 produced no immediate effects on cue-induced cocaine-seeking behavior but produced residual effects on a subsequent test for cocaine seeking. At 3 d withdrawal, cocaine-experienced rats infused intra-vmPFC with mGluR1/5 antagonists, either before or after an initial test for cocaine seeking, persisted in their cocaine seeking akin to cocaine-experienced rats in protracted withdrawal. Conversely, cocaine-experienced rats infused with an mGluR1/5 agonist before the initial test for cocaine-seeking at 30 d withdrawal exhibited a facilitation of extinction learning. These data indicate that cue-elicited deficits in vmPFC group 1 mGluR function mediate resistance to extinction during protracted withdrawal from a history of extensive cocaine self-administration and pose pharmacological stimulation of these receptors as a potential approach to facilitate learned suppression of drug-seeking behavior that may aid drug abstinence.

Objectives-Individuals with bipolar disorder (BD) have trait-like deficits in attention and working memory (WM). A fundamental dissociation for most verbal WM theories involves the separation of sensory-perceptual encoding, reliant upon attention, from the maintenance of this information in WM proper. The present paper examined if patients with BD demonstrate differential neural changes in encoding and maintenance WM processes that underlie cognitive impairment. Methods-Event-related functional magnetic resonance imaging during a delayed match-tosample WM paradigm was employed with 23 inter-episode medicated patients with BD and 23 demographically similar healthy comparison participants. We examined brain regions during encoding and maintenance task intervals to identify regions that demonstrated differential effects between groups. Medication effects and functional connectivity between prefrontal cortex and basal ganglia/thalamus were examined during the encoding interval due to the importance of these regions and the connection among them for encoding into WM. Results-Patients with BD exhibited deficits in task accuracy and attenuated brain response during the encoding interval in areas of the prefrontal cortex, caudate, thalamus, and posterior visual regions. In contrast, patients with BD exhibited hyperactivation in posterior sensory regions during the maintenance interval. Among the BD group, those with greater medication load exhibited the greatest brain response within the prefrontal cortex. Conclusions-Reduction in activation during the encoding interval suggests that attentional deficits underlie WM deficits in patients with BD. These deficits appear to be trait-like in so far as they were observed during periods of euthymia in patients with BD. Medication effects remain to be further explored as there was evidence of prefrontal changes dependent on medication load.

The ventromedial prefrontal cortex (vmPFC) is a major focus of investigation in human neuroscience, particularly in studies of emotion, social cognition, and decision making. Although the term vmPFC is widely used, the zone is not precisely defined, and for varied reasons has proven a complicated region to study. A difficulty identifying precise boundaries for the vmPFC comes partly from varied use of the term, sometimes including and sometimes excluding ventral parts of anterior cingulate cortex and medial parts of orbitofrontal cortex. These discrepancies can arise both from the need to refer to distinct sub-regions within a larger area of prefrontal cortex, and from the spatially imprecise nature of research methods such as human neuroimaging and natural lesions. The inexactness of the term is not necessarily an impediment, although the heterogeneity of the region can impact functional interpretation. Here we briefly address research that has helped delineate sub-regions of the h...

The authors investigated whether cocaine use disorder is associated with abnormalities in the neural underpinnings of aversive conditioning and extinction learning, as these processes may play an important role in the development and persistence of drug abuse.

People tend to intervene in others' injustices by either punishing the transgressor or helping the victim. Injustice events often occur under stressful circumstances. However, how acute stress affects a third party's intervention in injustice events remains open. Here, we show a stress-induced shift in third parties' willingness to engage in help instead of punishment by acting on emotional salience and central-executive and theory-of-mind networks. Acute stress decreased the third party's willingness to punish the violator and the severity of the punishment and increased their willingness to help the victim. Computational modeling revealed a shift in intervention severity bias from punishment toward help under stress. This finding is consistent with the increased dorsolateral prefrontal engagement observed with higher amygdala activity and greater connectivity with the ventromedial prefrontal cortex. A brain connectivity theory-of-mind network predicted stress-induced severity bias in punishment. Our findings suggest a neurocomputational mechanism of how acute stress reshapes third parties' decisions by reallocating neural resources in emotional, executive and mentalizing networks to inhibit punishment bias and decrease punishment severity.

The human brain undergoes protracted development, with dramatic changes in expression and regulation of emotion from childhood to adulthood. The amygdala is a brain structure that plays a pivotal role in emotion-related functions. Investigating developmental characteristics of the amygdala and associated functional circuits in children is important for understanding how emotion processing matures in the developing brain. The basolateral amygdala (BLA) and centromedial amygdala (CMA) are two major amygdalar nuclei that contribute to distinct functions via their unique pattern of interactions with cortical and subcortical regions. Almost nothing is currently known about the maturation of functional circuits associated with these amygdala nuclei in the developing brain. Using intrinsic connectivity analysis of functional magnetic resonance imaging data, we investigated developmental changes in functional connectivity of the BLA and CMA in twenty-four 7- to 9-y-old typically developing ...

Several lines of evidence indicate verbal abuse (VA) critically impacts the developing brain; however, whether VA results in changes in brain neurochemistry has not been established in humans. Here, we hypothesized that exposure to recurrent parental VA elicits heightened glutamate (Glu) responses during the presentation of swear words, which can be measured with functional magnetic resonance spectroscopy (fMRS). During an emotional Stroop task consisting of blocks of color and swear words, metabolite concentration changes were measured in the ventromedial prefrontal cortex (vmPFC) and the left amygdalohippocampal region (AMHC) of healthy adults (14 F/27 M, 23±4 years old) using fMRS. The dynamic changes in Glu and their associations with the emotional state of the participants were finally evaluated based on 36 datasets from the vmPFC and 30 from the AMHC.A repeated-measures analysis of covariance revealed a modest effect of parental VA severity on Glu changes in the vmPFC. Further...

Birds are extremely interesting animals for studying the neurobiological basis of cognition and its evolution. They include species that are highly social and show high cognitive capabilities. Moreover, birds rely more on visual and auditory cues than on olfaction for social behavior and cognition, just like primates. In primates, there are two major brain networks associated to sociality: (1) one related to perception and decision-making, involving the pallial amygdala (with the basolateral complex as a major component), the temporal and temporoparietal neocortex, and the orbitofrontal cortex; (2) another one related to affiliation, including the medial extended amygdala, the ventromedial prefrontal and anterior cingulate cortices, the ventromedial striatum (largely nucleus accumbens), and the ventromedial hypothalamus. In this account, we used an evolutionary developmental neurobiology approach, in combination with published comparative connectivity and functional data, to identify areas and functional networks in the sauropsidian brain comparable to those of mammals that are related to decision-making and affiliation. Both in mammals and sauropsids, there is an important interaction between these networks by way of cross projections between areas of both systems.

Neuroimaging studies demonstrate alterations in fronto-striatal neurocircuitry in gambling disorder (GD) during anticipatory processing, which may influence decision-making impairments. However, to date little is known about fronto-striatal anticipatory processing and emotion-based decision-making. While undergoing neuroimaging, 28 GD and 28 healthy control (HC) participants performed the Monetary Incentive Delay Task (MIDT). Pearson correlation coefficients assessed out-of-scanner Iowa Gambling Task (IGT) performance with the neural activity during prospect (A1) processing on the MIDT across combined GD and HC groups. The HC and GD groups showed no significant difference in out-of-scanner IGT performance, although there was a trend for higher IGT scores in the HC group on the last two IGT trial blocks.

Previous studies have shown that people who develop psychopathology such as posttraumatic stress disorder (PTSD) following stress exposure are characterized by reduced hippocampal (HC) volume and impaired HC functional connectivity with the ventromedial prefrontal cortex (vmPFC). Nevertheless, the exact interrelationship between reduced HC volume and HC‐vmPFC connectivity deficits in the context of stress has yet to be established. Furthermore, it is still not clear whether such neural abnormalities are stress induced or precursors for vulnerability. In this study, we combined measurements of MRI, functional MRI (fMRI), and diffusion tensor imaging (DTI) to prospectively study 33 a priori healthy Israeli soldiers both pre‐ and post‐exposure to stress during their military service. Thus, we were able to assess the contributions of structural and functional features of the HC and its connectivity to the onset and progression of maladaptive response to stress (i.e., increased PTSD symp...

The present interdisciplinary study explored whether perceived loneliness is associated with ventromedial prefrontal cortex (vMPFC) activation during self-and social judgments (friends and teachers) in adolescents. Moreover, we examined how vMPFC activity is related to the academic self-concept (ASC). Results of manifest path analysis indicated that high perceived loneliness was related to lower neural response to self-judgments. In turn, high neural response to selfjudgments was positively associated with the ASC, whereas there was a trendwise negative association between high neural response to teacher-related judgments and ASC. This study reveals associations between perceived loneliness and neural processing of the self, underlining the idea that feeling isolated from others may hinder self-insight and, by extension, the formation of a stable academic self-concept.

A fundamental challenge in social cognition is how humans learn another person's values to predict their decision-making behavior. This form of learning is often assumed to require simulation of the other by direct recruitment of one's own valuation process to model the other's process. However, the cognitive and neural mechanism of simulation learning is not known. Using behavior, modeling, and fMRI, we show that simulation involves two learning signals in a hierarchical arrangement. A simulated-other's reward prediction error processed in ventromedial prefrontal cortex mediated simulation by direct recruitment, being identical for valuation of the self and simulated-other. However, direct recruitment was insufficient for learning, and also required observation of the other's choices to generate a simulated-other's action prediction error encoded in dorsomedial/dorsolateral prefrontal cortex. These findings show that simulation uses a core prefrontal circuit for modeling the other's valuation to generate prediction and an adjunct circuit for tracking behavioral variation to refine prediction. Neuron

A principle of brain organization is that networks serving higher cognitive functions are widely distributed across the brain. One exception has been the parietal memory network (PMN), which plays a role in recognition memory but is often defined as being restricted to posteromedial association cortex. We hypothesized that high-resolution estimates of the PMN would reveal small regions that had been missed by prior approaches. High-field 7T functional magnetic resonance imaging (fMRI) data from extensively sampled participants was used to define the PMN within individuals. The PMN consistently extended beyond the core posteromedial set to include regions in the inferior parietal lobule; rostral, dorsal, medial, and ventromedial prefrontal cortex; the anterior insula; and ramus marginalis of the cingulate sulcus. The results suggest that, when fine-scale anatomy is considered, the PMN matches the expected distributed architecture of other association networks, reinforcing that parall...

Investigate the effects of CACNA1C rs1006737 on cortical and subcortical neurostructural phenotypes in Caucasian bipolar disorder (BD) and healthy control (HC) adolescents. Methods: Seventy-one adolescents (14-20 years; 38BD, 33HC) underwent 3-Tesla Magnetic Resonance Imaging (MRI). Region of interest (ROI) and vertex-wise analyses examined cortical volume, surface area (SA), and thickness, as well as subcortical volume. ROIs included the ventromedial prefrontal cortex (vmPFC), ventrolateral prefrontal cortex (vlPFC), anterior cingulate cortex (ACC), putamen, and amygdala. General linear models included main effects of diagnosis and rs1006737, and an interaction term, controlling for age, sex, and total intracranial volume. Results: Vertex-wise analysis found significant BD-by-rs1006737 interactions for prefrontal and occipital regions such that BD A-carriers were found to have greater SA relative to BD non-carriers, while HC A-carriers had reduced SA relative to HC non-carriers. ROI analysis found an interaction in the ACC such that BD A-carriers were found to have greater SA relative to BD non-carriers, while no significant difference was found in HCs. Main effects of rs1006737 were also found on ACC SA from ROI analysis, and occipital SA from vertex-wise analysis, such that A-carriers had larger SA relative to non-carriers in both of these regions. Conclusions: The current study identified neurostructural intermediate phenotypes relevant to the impact of CACNA1C rs1006737 on adolescent BD. Further investigation is warranted into the neurofunctional and neurocognitive relevance of rs1006737 associations with BD-specific elevations in regional SA.

Costly punishment of social norms transgressors by third-parties has been considered as a decisive stage in the evolution of human cooperation. An important facet of social relationship knowledge concerns the strength of the social ties between individuals, as measured by social distance. Yet, it is unclear how the enforcement of social norms is in uenced by the social distance between a third-party and a norm violator at the behavioral and the brain system levels. Here, we investigated how social distance between punishers and norm-violators in uences third-party punishment. Participants as third-party punished norm violators more severely as social distance between them increased. Using model-based fMRI, we disentangled key computations contributing to third-party punishment: inequity aversion, social distance with the norm violator and integration of the cost to punish with these signals. Inequity aversion increased activity in the anterior cingulate cortex and bilateral insula, and processing social distance engaged a bilateral fronto-parietal cortex brain network. These two brain signals and the cost to punish were integrated in a subjective value signal of sanctions that modulated activity in the ventromedial prefrontal cortex. Taken together, our results reveal the neurocomputational underpinnings of third-party punishment and how social distance modulates enforcement of social norms in humans.

Costly punishment of social norm transgressors by third-parties has been considered as a decisive stage in the evolution of human cooperation. An important facet of social relationship knowledge concerns the strength of the social ties between individuals, as measured by social distance. Yet, it is unclear how the enforcement of social norms is influenced by the social distance between a thirdparty and a norm violator at the behavioral and the brain system levels. Here, we investigated how social distance between punishers and norm-violators influences third-party punishment. Participants as third-party punished norm violators more severely as social distance between them increased. Using model-based fMRI, we disentangled key computations contributing to third-party punishment: inequity aversion, social distance between participant and norm violator and integration of the cost to punish with these signals. Inequity aversion increased activity in the anterior cingulate cortex and bilateral insula, and processing social distance engaged a bilateral fronto-parietal cortex brain network. These two brain signals and the cost to punish were integrated in a subjective value signal of sanctions that modulated activity in the ventromedial prefrontal cortex. Together, our results reveal the neurocomputational underpinnings of third-party punishment and how social distance modulates enforcement of social norms in humans. Cooperation among strangers is a major evolutionary puzzle 1,2 . One key mechanism for maintaining cooperation in large groups is that some individuals enforce social norms by applying punishment to defectors . In a modified Dictator Game, called the Third-Party Dictator Game (TP-DG) 3,5 , participants as observers may pay to punish greedy dictators that share money unfairly with recipients. Such third-party punishment (TPP) may be costly to the third-party who themselves receive no material benefit . Little is known about the brain representations of TPP despite the crucial role it plays in norm enforcement. In contrast, "second-party" punishment (SPP), in which victims retaliate directly against their aggressors, and its underlying brain systems have been thoroughly investigated . TPP may be an evolutionary elaboration of this more ancient mechanism 8 . A classical model of SPP defined "egocentric inequity" as the absolute payoff difference between self and others . This inequity aversion model has been extended to a third-party perspective deciding sanctions based on the inequity between the dictator and the recipient, as perceived by the third-party 11 . However, it is unclear how the strength of the social ties (social distance, SD) between the third-party and the dictator affects the sanctions to the dictator. As SD in a social network determines how much one collaborates with others 12 and decreases generosity , a third-party might be more likely to turn a blind eye when close others violate social norms. Here we ask how does the strength of social ties alter our tolerance of norm violation? What are the neurocomputational mechanisms engaged in making TPP decisions? To disentangle the role of fairness preferences and SD to the norm violator in punishment, we developed a new TPP computational model and a modified TPP task to investigate how SD affects TPP at both the behavioral and neural level. Participants, as third-party observers, were presented monetary splits advocated by a dictator to a recipient. Crucially, the SD between the third-party (participants) and the dictator varied systematically, but the recipient was always a stranger. Participants were

Although severe early life stress has been shown to accelerate the development of frontolimbic resting-state functional connectivity (RSFC), less is known about the effects of socioeconomic disadvantage, a prolonged and multifaceted stressor. In a cross-sectional study of 127 participants aged 5–25, we examined whether lower neighborhood socioeconomic status (SES; measured by Area Deprivation Index and neighborhood poverty and educational attainment) was associated with prematurely reduced amygdala-ventromedial prefrontal cortex (vmPFC) RSFC. We further tested whether neighborhood SES was more predictive than household SES and whether SES effects on connectivity were associated with anxiety symptoms. We found reduced basolateral amygdala-vmPFC RSFC at earlier ages in participants from more disadvantaged neighborhoods; this effect was unique to neighborhood SES and absent for household SES. Furthermore, this reduced connectivity in more disadvantaged youth and increased connectivity ...

Transcranial direct current stimulation (tDCS) is a potential treatment strategy for mood and anxiety disorders, but how this application may influence emotional processes, and whether this is related to individual characteristics, is not well understood. It has been proposed that perceived criticism (PC) may represent a vulnerability factor for the development of such mental illnesses. To decipher whether neural mechanisms of action of tDCS potentially differ depending on PC status (low vs. high), we evaluated mood and brain perfusion before and after applying MRI-compatible tDCS, and after participants were exposed to verbal criticism in the scanner. Experimental design 30 healthy nondepressed females were included in a sham-controlled crossover MRI-compatible tDCS study. Brain perfusion was measured by means of arterial spin labeling (ASL) before and after tDCS applied to the left dorsolateral prefrontal cortex (DLPFC), and after hearing criticism. Before the experiment, all part...

Activity within the ventral medial prefrontal cortex (VMPFC) during encoding of persuasive messages has been shown to predict message-consistent behaviors both within scanner samples and at the population level. This suggests that neuroimaging can aid in the development of better persuasive messages, but little is known about how the brain responds to different message features. Building on past findings, the current study found that gain-framed persuasive messages elicited more VMPFC activation than loss-framed messages, but only when messages addressed outcomes that would be experienced by participants directly. Participants also perceived gain-framed messages as more effective than loss-framed messages, and self-reported perceptions of message effectiveness were positively correlated with VMPFC activation. These results support theories that VMPFC activity during message encoding indexes perceptions of value and self-relevance and demonstrate that established theories of persuasi...

Glutamate (Glu) and gamma-aminobutyric acid (GABA) are implicated in the pathophysiology of major depressive disorder (MDD). GABA levels or GABAergic interneuron numbers are generally low in MDD, potentially disinhibiting Glu release. It is unclear whether Glu release or turnover is increased in depression. Conversely, a meta-analysis of prefrontal proton magnetic resonance spectroscopy (1H MRS) studies in MDD finds low Glx (combination of glutamate and glutamine) in medicated MDD. We hypothesize that elevated Glx or Glu may be a marker of more severe, untreated MDD. We examined ventromedial prefrontal cortex/anterior cingulate cortex (vmPFC/ACC) Glx and glutamate levels using1H MRS in 34 medication-free, symptomatic, chronically ill MDD patients and 32 healthy volunteers, and GABA levels in a subsample. Elevated Glx and Glu were observed in MDD compared with healthy volunteers, with the highest levels seen in males with MDD. vmPFC/ACC GABA was low in MDD. Higher Glx levels correlat...

Temporal discounting (TD), the preference for earlier, smaller rewards over delayed, larger rewards, is a pervasive phenomenon that covaries with Big Five personality traits and Intelligence (IQ). This study provides novel insight by identifying correlates for IQ and Extraversion in the neural representation of TD preferences. An intertemporal choice task was employed, where offers were sequentially presented, distinguishing between one evaluation phase (first offer is presented) and one comparison phase (second offer is presented and values are compared). IQ correlated with responses of caudate nucleus to the subjective values of the offers, suggesting a role of cognitive abilities in modulating reward responses. Extraversion correlated with the strength of functional connectivity of a reward evaluation network centered on ventromedial prefrontal cortex.

Acute pain serves to warn an organism of potential damage. When nociceptive stimulation persists, two possible responses emerge: If no risk of harm is anticipated, habituation may occur. If harm is considered possible, pain sensitization is likely. An individual’s adaptation to prolonged pain may provide insight into their ability to manage resources, and possibly their likelihood of developing chronic pain. Yet, little is known about the stability of these individual differences or their underlying neural mechanisms. Eighty-five participants undertook a repetitive noxious stimulation task and a resting-state scan in an MRI scanner, in a first session. They then completed the same task outside the scanner on three separate days. Pain adaptation was operationalized as the slope of change in pain ratings within session. Intraclass correlations were calculated between slopes across the four sessions, which demonstrated high stability and association with emotional disposition. Individu...

Background: The literature frequently notes inconsistent findings in Black-White mental health comparisons in the U.S.: a lower prevalence of psychiatric disorder, particularly major depression, in Blacks compared with Whites, coupled with higher psychological distress. From the vantage point of social stress theory, these findings represent a double paradox. Social stress theory, the dominant framework for interpreting associations between social location and mental health, predicts worse mental health in disadvantaged versus advantaged groups by virtue of their greater stressor exposure and fewer coping resources. Given the stark social, economic, and political divides between Blacks and Whites in the U.S., Black-White mental health comparisons are a strong test of the theory. Blacks' lower prevalence of psychiatric disorder in general and depression in particular represents the first paradox. The divergence of depression-distress findings in Black-White comparisons is a second paradox, given that depression and distress are correlated. These paradoxes have emerged only from limited reviews of the findings, however, indicating the need for a systematic literature review. Systematic mapping of Black-White depression and distress findings could provide the empirical foundation for developing methodological and substantive hypotheses to explain both paradoxes, ultimately reinforcing or diminishing our confidence in social stress theory. This study is the first systematic review of the literature documenting Black-White comparisons of major depression prevalence and distress in nationally representative household samples of the adult U.S. population. Methods: Following Cochrane guidelines, a search of PubMed and PsycInfo databases yielded 17,892 unique articles for potential inclusion in the review. Title and abstract reviews resulted in 87 articles for full review, 26 of which satisfied inclusion criteria. A secondary literature review will be conducted of these 26 articles' reference lists. Results from included papers will be reported by outcome (major depression or distress), and then subdivided by measure used and outcome timeframe. Results to date: In the preliminary 26 articles, Blacks had a lower prevalence of major depression than Whites in 8 of 9 comparisons, 7 of which were statistically significant and Blacks had higher distress levels than Whites in 17 of 19 comparisons, 7 of which were statistically significant. Conclusions: Preliminary results from this systematic review support observations in the literature that Blacks generally have a lower prevalence of major depression but higher levels of distress than Whites. This systematically documented discordant pattern could provide the basis for novel hypotheses to explain the double paradox.

Background: Fear generalization is thought to contribute to the development and maintenance of anxiety symptoms and accordingly has been the focus of recent research. Previously, we reported that in healthy individuals (N = 25) neural reactivity in the insula, anterior cingulate cortex (ACC), supplementary motor area (SMA), and caudate follow a generalization gradient with a peak response to a conditioned stimulus (CS) that declines with greater perceptual dissimilarity of generalization stimuli (GS) to the CS. In contrast, reactivity in the ventromedial prefrontal cortex (vmPFC), a region linked to fear inhibition, showed an opposite response pattern. The aim of the current study was to examine whether neural responses to fear generalization differ in generalized anxiety disorder (GAD). A second aim was to examine connectivity of primary regions engaged by the generalization task in the GAD group versus healthy group, using psychophysiological interaction analysis. Methods: Thirty-two women diagnosed with GAD were scanned using the same generalization task as our healthy group. Results: Individuals with GAD exhibited a less discriminant vmPFC response pattern suggestive of deficient recruitment of vmPFC during fear inhibition. Across participants, there was enhanced anterior insula (aINS) coupling with the posterior insula, ACC, SMA, and amygdala during presentation of the CS, consistent with a modulatory role for the aINS in the execution of fear responses. Conclusions: These findings suggest that deficits in fear regulation, rather than in the excitatory response itself, are more critical to the pathophysiology of GAD in the context of fear generalization. Depression and Anxiety 00:1-9, 2012.