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Circadian rhythms in conditioned threat extinction emerge from a tissue-level circadian timekeeper, or local clock, in the ventromedial prefrontal cortex (vmPFC). Yet it remains unclear how this local clock contributes to extinction-dependent adaptations. Here we used single-unit and local field potential analyses to interrogate neural activity in the male rat vmPFC during repeated extinction sessions at different times of day. In association with superior recall of a remote extinction memory during the circadian active phase, vmPFC putative principal neurons exhibited phasic firing that was amplified for cue presentations and diminished at transitions in freezing behavior. Coupling of vmPFC gamma amplitude to the phase of low-frequency oscillations was greater during freezing than mobility, and this difference was augmented during the active phase, highlighting a time-of-day dependence in the organization of freezing- versus mobility-associated cell assemblies. Additionally, a greater proportion of vmPFC neurons were phase-locked to low-frequency oscillations during the active phase, consistent with heightened neural excitability at this time of day. Our results suggest that daily fluctuations in vmPFC excitability precipitate enhanced neural recruitment into extinction-based cell assemblies during the active phase, providing a potential mechanism by which the vmPFC local clock modulates circuit and behavioral plasticity during conditioned threat extinction. [ABSTRACT FROM AUTHOR]

While self-construal and posttraumatic stress disorder (PTSD) are independently associated with altered self-referential processes and underlying default mode network (DMN) functioning, no study has examined how self-construal affects DMN connectivity in PTSD. A final sample of 93 refugee participants (48 with DSM-5 PTSD or sub-syndromal PTSD and 45 matched trauma-exposed controls) completed a 5-minute resting state fMRI scan to enable the observation of connectivity in the DMN and other core networks. A self-construal index was calculated by substracting scores on the collectivistic and individualistic sub-scales of the Self Construal Scale. Independent components analysis identified 9 active networks-of-interest, and functional network connectivity was determined. A significant interaction effect between PTSD and self-construal index was observed in the anterior ventromedial DMN, with spatial maps localizing this to the left ventromedial prefrontal cortex (vmPFC), extending to the ventral anterior cingulate cortex. This effect revealed that connectivity in the vMPFC showed greater reductions in those with PTSD with higher levels of collectivistic self-construal. This is an observational study and causality cannot be assumed. The specialized sample of refugees means that the findings may not generalize to other trauma-exposed populations. Such a finding indicates that self-construal may shape the core neural architecture of PTSD, given that functional disruptions to the vmPFC underpin the core mechanisms of extinction learning, emotion dysregulation and self-referential processing in PTSD. Results have important implications for understanding the universality of neural disturbances in PTSD, and suggest that self-construal could be an important consideration in the assessment and treatment of post-traumatic stress reactions. • Studies that consider cultural influences on PTSD brain mechanisms are rare. • PTSD interacted with self-construal to affect default mode network connectivity. • The ventromedial prefrontal cortex was the site of interaction. • Findings suggest cultural variables shape the neural substrates of PTSD. [ABSTRACT FROM AUTHOR]

The regulation of emotions is a crucial facet of well‐being and social adaptability, with explicit strategies receiving primary attention in prior research. Recent studies, however, emphasize the role of implicit emotion regulation, particularly implicating the ventromedial prefrontal cortex (VMPFC) in association with its implementation. This study delves into the nuanced role of the VMPFC through focality‐optimized multichannel transcranial direct current stimulation (tDCS), shedding light on its causal involvement in implicit reappraisal. The primary goal was to evaluate the effectiveness of VMFPC‐targeted tDCS and elucidate its role in individuals with high trait anxiety. Participants engaged in implicit and explicit emotion regulation tasks during multichannel tDCS targeting the VMPFC. The outcome measures encompassed negative emotion ratings, pupillary diameter, and saccade count, providing a comprehensive evaluation of emotion regulation efficiency. The intervention exhibited a notable impact, resulting in significant reductions in negative emotion ratings and pupillary reactions during implicit reappraisal, highlighting the indispensable role of the VMPFC in modulating emotional responses. Notably, these effects demonstrated sustained efficacy up to 1 day postintervention. This study underscores the potency of VMPFC‐targeted multichannel tDCS in augmenting implicit emotion regulation. This not only contributes insights into the neural mechanisms of emotion regulation but also suggests innovative therapeutic avenues for anxiety disorders. The findings present a promising trajectory for future mood disorder interventions, bridging the gap between implicit emotion regulation and neural stimulation techniques. [ABSTRACT FROM AUTHOR]

Naturalistic observations show that animals pre-empt danger by moving to locations that increase their success in avoiding future threats. To test this in humans, we created a spatial margin of safety (MOS) decision task that quantifies pre-emptive avoidance by measuring the distance subjects place themselves to safety when facing different threats whose attack locations vary in predictability. Behavioral results show that human participants place themselves closer to safe locations when facing threats that attack in spatial locations with more outliers. Using both univariate and multivariate pattern analysis (MVPA) on fMRI data collected during a 2 h session on participants of both sexes, we demonstrate a dissociable role for the vmPFC in MOS-related decision-making. MVPA results revealed that the posterior vmPFC encoded for more unpredictable threats with univariate analyses showing a functional coupling with the amygdala and hippocampus. Conversely, the anterior vmPFC was more active for the more predictable attacks and showed coupling with the striatum. Our findings converge in showing that during pre-emptive danger, the anterior vmPFC may provide a safety signal, possibly via foreseeable outcomes, while the posterior vmPFC drives unpredictable danger signals. [ABSTRACT FROM AUTHOR]

Belief, defined by William James as the mental state or function of cognizing reality, is a core psychological function with strong influence on emotion and behavior. Furthermore, strong and aberrant beliefs about the world and oneself play important roles in mental disorders. The underlying processes of belief have been the matter of a long debate in philosophy and psychology, and modern neuroimaging techniques can provide insight into the underlying neural processes. Here, we conducted a functional magnetic resonance imaging study with N = 30 healthy participants in which we presented statements about facts, politics, religion, conspiracy theories, and superstition. Participants judged whether they considered them as true (belief) or not (disbelief) and reported their certainty in the decision. We found belief‐associated activations in bilateral dorsolateral prefrontal cortex, left superior parietal cortex, and left lateral frontopolar cortex. Disbelief‐associated activations were found in an anterior temporal cluster extending into the amygdala. We found a larger deactivation for disbelief than belief in the ventromedial prefrontal cortex that was most pronounced during decisions, suggesting a role of the vmPFC in belief‐related decision‐making. As a category‐specific effect, we found disbelief‐associated activation in retrosplenial cortex and parahippocampal gyrus for conspiracy theory statements. Exploratory analyses identified networks centered at anterior cingulate cortex for certainty, and dorsomedial prefrontal cortex for uncertainty. The uncertainty effect identifies a neural substrate for Alexander Bain's notion from 1859 of uncertainty as the real opposite of belief. Taken together, our results suggest a two‐factor neural process model of belief with falsehood/veracity and uncertainty/certainty factors. Belief is a core psychological function with strong influence on emotion and behavior. We provide neuroimaging evidence of a two‐factor neural process model with falsehood/veracity and uncertainty/certainty factors. Specifically, the identified uncertainty processes can be understood as a neural marker of the subjective epistemic risk of statements. [ABSTRACT FROM AUTHOR]

With age, parasympathetic activity decreases, while sympathetic activity increases. Thus, the typical older adult has low heart rate variability (HRV) and high noradrenaline levels. Younger adults with this physiological profile tend to be unhappy and stressed. Yet, with age, emotional experience tends to improve. Why does older adults' emotional well‐being not suffer as their HRV decreases? To address this apparent paradox, I present the autonomic compensation model. In this model, failing organs, the initial phases of Alzheimer's pathology, and other age‐related diseases trigger noradrenergic hyperactivity. To compensate, older brains increase autonomic regulatory activity in the pregenual prefrontal cortex (PFC). Age‐related declines in nerve conduction reduce the ability of the pregenual PFC to reduce hyperactive noradrenergic activity and increase peripheral HRV. But these pregenual PFC autonomic compensation efforts have a significant impact in the brain, where they bias processing in favor of stimuli that tend to increase parasympathetic activity (e.g., stimuli that increase feelings of safety) and against stimuli that tend to increase sympathetic activity (e.g., threatening stimuli). In summary, the autonomic compensation model posits that age‐related chronic sympathetic/noradrenergic hyperactivity stimulates regulatory attempts that have the side effect of enhancing emotional well‐being. [ABSTRACT FROM AUTHOR]

Objectives Generativity, the desire and action to improve the well-being of younger generations, is associated with purpose in life among older adults. However, the neurobehavioral factors supporting the relationship between generativity and purpose in life remain unknown. This study aims to identify the functional neuroanatomy of generativity and mechanisms linking generativity with purpose in life in at-risk older adults. Methods Fifty-eight older adults (mean age = 70.8, SD =  5.03, 45 females) with a family history of Alzheimer's disease (AD) were recruited from the PREVENT-AD cohort. Participants underwent brain imaging and completed questionnaires assessing generativity, social support, and purpose in life. Mediation models examined whether social support mediated the association between generativity and purpose in life. Seed-to-voxel analyses investigated the association between generativity and resting-state functional connectivity (rsFC) to the ventromedial prefrontal cortex (vmPFC) and ventral striatum (VS), and whether this rsFC moderated the relationship between generativity and purpose in life. Results Affectionate social support mediated the association between generative desire and purpose in life. Generative desire was associated with rsFC between VS and precuneus, and, vmPFC and right dorsolateral prefrontal cortex (rdlPFC). The vmPFC–rdlPFC rsFC moderated the association between generative desire and purpose in life. Discussion These findings provide insight into how the brain supports complex social behavior and, separately, purpose in life in at-risk aging. Affectionate social support may be a putative target process to enhance purpose in life in older adults. This knowledge contributes to future developments of personalized interventions that promote healthy aging. [ABSTRACT FROM AUTHOR]

Deep transcranial magnetic stimulation has been effectively used as a therapy for refractory obsessive compulsive disorder (OCD). Number of sessions approved by FDA is 20. Here, we report the case of 59 year old female with treatment refractory obsessive compulsive disorder (OCD) whose symptoms markedly improved only after 10 sessions of deep TMS over Dorso Medial Prefrontal Cortex. Our case report shows that, even with fewer sessions than indicated, significant symptoms remission can be achieved with deeper penetration of magnetic field with marked reduction in distress of patient and significant improvement in socio-occupational domain. Her Y-BOCS score reduced by 66% at the end of 10 completed sessions.

Background and Aims Increasing data suggest that stress-related neural activity (SNA) is associated with subsequent major adverse cardiovascular events (MACE) and may represent a therapeutic target. Current evidence is exclusively based on populations from the U.S. and Asia where limited information about cardiovascular disease risk was available. This study sought to investigate whether SNA imaging has clinical value in a well-characterized cohort of cardiovascular patients in Europe. Methods In this single-centre study, a total of 963 patients (mean age 58.4 ± 16.1 years, 40.7% female) with known cardiovascular status, ranging from 'at-risk' to manifest disease, and without active cancer underwent 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography between 1 January 2005 and 31 August 2019. Stress-related neural activity was assessed with validated methods and relations between SNA and MACE (non-fatal stroke, non-fatal myocardial infarction, coronary revascularization, and cardiovascular death) or all-cause mortality by time-to-event analysis. Results Over a maximum follow-up of 17 years, 118 individuals (12.3%) experienced MACE, and 270 (28.0%) died. In univariate analyses, SNA significantly correlated with an increased risk of MACE (sub-distribution hazard ratio 1.52, 95% CI 1.05–2.19; P =.026) or death (hazard ratio 2.49, 95% CI 1.96–3.17; P <.001). In multivariable analyses, the association between SNA imaging and MACE was lost when details of the cardiovascular status were added to the models. Conversely, the relationship between SNA imaging and all-cause mortality persisted after multivariable adjustments. Conclusions In a European patient cohort where cardiovascular status is known, SNA imaging is a robust and independent predictor of all-cause mortality, but its prognostic value for MACE is less evident. Further studies should define specific patient populations that might profit from SNA imaging. [ABSTRACT FROM AUTHOR]

Trends in moral psychology largely support the role that emotion plays in moral cognition with human lesion studies offering the most compelling evidence to date. Specifically, data from ventromedial prefrontal cortex (vmPFC) patients on moral judgment tasks has suggested the necessity of having intact emotion to behave in morally appropriate ways. However, patients with vmPFC damage also have deficits in a variety of complex judgment and decision-making tasks, regardless of whether emotion is involved. This paper argues that a basic information processing perspective of vmPFC functionality is a better interpretation of vmPFC patient deficits, specifically with the vmPFC being necessary for value assessment rather than being specific to emotion. [ABSTRACT FROM AUTHOR]

The ventromedial prefrontal cortex (vmPFC) and the ventral striatum are brain regions that are critical for the reward circuit and the maintenance of pleasure. The relationship between these regions and alcohol use disorder has been investigated in the literature in a variety of ways. In this context, it is aimed to determine whether there are structural changes in the vmPFC and ventral striatum regions in patients with alcohol use disorder (AUD) compared to healthy control subjects. Fifteen patients with AUD according to the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM 5) diagnostic criteria and seventeen healthy controls participated in our study. The volumes of the vmPFC and ventral striatum were measured in subjects. The mean volumes of both sides of the vmPFC were significantly smaller in patients with AUD than those in the healthy control group whereas both sides of ventral striatum volumes were larger. This study is one of the few to examine structural changes in the vmPFC and ventral striatum together in patients with ACD. Although the contribution of the positive findings to the literature is important, more comprehensive studies are needed to strengthen the existing findings. [ABSTRACT FROM AUTHOR]

Chronic pain is a source of substantial physical and psychological suffering, yet a clear understanding of the pathogenesis of chronic pain is lacking. Repeated studies have reported an altered behaviour of the salience network (SN) and default mode network (DMN) in people with chronic pain, and a majority of these studies report an altered behaviour of the dorsal ventromedial prefrontal cortex (vmPFC) within the anterior DMN. In this topical review, we therefore focus specifically on the role of the dorsal vmPFC in chronic pain to provide an updated perspective on the cortical mechanisms of chronic pain. We suggest that increased activity in the dorsal vmPFC may reflect maladaptive overthinking about the meaning of pain for oneself and one's actions. We also suggest that such overthinking, if negative, may increase the personal "threat" of a given context, as possibly reflected by increased activity in, and functional connectivity to, the anterior insular cortex within the SN. [ABSTRACT FROM AUTHOR]

Sex differences in human brain structure and function are important, partly because they are likely to be relevant to the male–female differences in behavior and in mental health. To analyse sex differences in cortical function, functional connectivity was measured in 36,531 participants (53% female) in the UK Biobank (mean age 69) using the Human Connectome Project multimodal parcellation atlas with 360 well-specified cortical regions. Most of the functional connectivities were lower in females (Bonferroni corrected), with the mean Cohen's d = − 0.18. Removing these as covariates reduced the difference of functional connectivities for females—males from d = − 0.18 to − 0.06. The lower functional connectivities in females were especially of somatosensory/premotor regions including the insula, opercular cortex, paracentral lobule and mid-cingulate cortex, and were correlated with lower maximum workload (r = 0.17), and with higher whole body fat mass (r = − 0.17). But some functional connectivities were higher in females, involving especially the ventromedial prefrontal cortex and posterior cingulate cortex, and these were correlated with higher liking for some rewards such as sweet foods, higher happiness/subjective well-being, and with better memory-related functions. The main findings were replicated in 1000 individuals (532 females, mean age 29) from the Human Connectome Project. This investigation shows the cortical systems with different functional connectivity between females and males, and also provides for the first time a foundation for understanding the implications for behavior of these differences between females and males. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to explore decision‐making impulsivity and its neural mechanisms in patients with episodic migraine without aura (EMoA). Background: Previous evidence indicates increased impulsivity and altered reward processing in patients with chronic migraine and medication overuse; however, whether the same holds true for those with EMoA is unclear. Methods: Patients newly diagnosed with EMoA (n = 51) and healthy controls (HC, n = 45) were recruited. All participants completed delay discounting task, cognitive assessments, a questionnaire for headache profile, and resting‐state function magnetic resonance imaging scans. Resting‐state functional connectivity (RSFC) between the regions of interest and the entire brain was explored. Results: Patients with EMoA showed a steeper subjective discount rate than HCs (F = 4.74, p =.032), which was positively related to a history of migraines (r =.742, p <.001). RSFC among the ventral striatum (vSTR), ventromedial prefrontal cortex, and occipital cortex was lower in patients with EMoA than in control groups, which was correlated with history (r′ =.294, p =.036) and subjective discount rate (r′ =.380, p =.006). Additionally, discounting rates and RSFC between the vSTR and occipital regions were significantly abnormal in the triptan group than the non‐triptan group. Mediating effect analysis indicated a significant mediating effect in the change in RSFC between the vSTR and occipital status, history of triptan use, and subjective discount rate. Conclusion: This study further elucidated that an increase in delayed discounting rate exists in patients with EMoA and is related to the abnormality of the value processing network. [ABSTRACT FROM AUTHOR]

One of the most prevalent nonverbal, social phenomena known to automatically elicit self- and other-referential processes is eye contact. By its negative effects on the perception of social safety and views about the self and others, childhood emotional maltreatment (CEM) may fundamentally affect these processes. To investigate whether the socioaffective consequences of CEM may become visible in response to (prolonged) eye gaze, 79 adult participants (mean [M]age = 49.87, standard deviation [SD]age = 4.62) viewed videos with direct and averted gaze of an unfamiliar other and themselves while we recorded self-reported mood, eye movements using eye-tracking, and markers of neural activity using fMRI. Participants who reported higher levels of CEM exhibited increased activity in ventromedial prefrontal cortex to one's own, but not to others', direct gaze. Furthermore, in contrast to those who reported fewer of such experiences, they did not report a better mood in response to a direct gaze of self and others, despite equivalent amounts of time spent looking into their own and other peoples' eyes. The fact that CEM is associated with enhanced neural activation in a brain area that is crucially involved in self-referential processing (i.e., vmPFC) in response to one's own direct gaze is in line with the chronic negative impact of CEM on a person's self-views. Interventions that directly focus on targeting maladaptive self-views elicited during eye gaze to self may be clinically useful. [ABSTRACT FROM AUTHOR]

Objective This study aimed to explore decision‐making impulsivity and its neural mechanisms in patients with episodic migraine without aura (EMoA). Background Previous evidence indicates increased impulsivity and altered reward processing in patients with chronic migraine and medication overuse; however, whether the same holds true for those with EMoA is unclear. Methods Patients newly diagnosed with EMoA (n = 51) and healthy controls (HC, n = 45) were recruited. All participants completed delay discounting task, cognitive assessments, a questionnaire for headache profile, and resting‐state function magnetic resonance imaging scans. Resting‐state functional connectivity (RSFC) between the regions of interest and the entire brain was explored. Results Patients with EMoA showed a steeper subjective discount rate than HCs (F = 4.74, p = .032), which was positively related to a history of migraines (r = .742, p

Making good economic and social decisions is essential for individual and social welfare. Decades of research have provided compelling evidence that damage to the ventromedial prefrontal cortex (vmPFC) is associated with dramatic personality changes and impairments in economic and social decision-making. However, whether the vmPFC subserves a unified mechanism in the social and non-social domains remains unclear. When choosing between economic options, the vmPFC is thought to guide decision by encoding value signals that reflect the motivational relevance of the options on a common scale. A recent framework, the "extended common neural currency" hypothesis, suggests that the vmPFC may also assign values to social factors and principles, thereby guiding social decision-making. Although neural value signals have been observed in the vmPFC in both social and non-social studies, it is yet to be determined whether they have a causal influence on behavior or merely correlate with decision-making. In this review, we assess whether lesion studies of patients with vmPFC damage offer evidence for such a causal role of the vmPFC in shaping economic and social behavior. [ABSTRACT FROM AUTHOR]

The hippocampus has long been considered a pivotal region implicated in both stress susceptibility and resilience. A wealth of evidence from animal and human studies underscores the significance of hippocampal functional connectivity with the ventromedial prefrontal cortex (vmPFC) in these stress-related processes. However, there remains a scarcity of research that explores and contrasts the roles of hippocampus-vmPFC connectivity in stress susceptibility and resilience when facing a real-life traumatic event from a prospective standpoint. In the present study, we investigated the contributions of undirected and directed connectivity between the hippocampus and vmPFC to stress susceptibility and resilience within the context of the COVID-19 pandemic. Our findings revealed that the left hippocampus-left vmPFC connectivity prior to the pandemic exhibited a negative correlation with both stress susceptibility and resilience. Specifically, individuals with stronger left hippocampus-left vmPFC connectivity reported experiencing fewer stress-related feelings during the outbreak period of the epidemic but displayed lower levels of stress resilience five months later. Our application of spectral dynamic causal modeling unveiled an additional inhibitory connectivity pathway from the left hippocampus to the left vmPFC in the context of stress susceptibility, which was notably absent in stress resilience. Furthermore, we observed a noteworthy positive association between self-inhibition of the vmPFC and stress susceptibility, with this effect proving substantial enough to predict an individual's susceptibility to stress; conversely, these patterns did not manifest in the realm of stress resilience. These findings enrich our comprehension of stress susceptibility and stress resilience and might have implications for innovative approaches to managing stress-related disorders.

Making good economic and social decisions is essential for individual and social welfare. Decades of research have provided compelling evidence that damage to the ventromedial prefrontal cortex (vmPFC) is associated with dramatic personality changes and impairments in economic and social decision-making. However, whether the vmPFC subserves a unified mechanism in the social and non-social domains remains unclear. When choosing between economic options, the vmPFC is thought to guide decision by encoding value signals that reflect the motivational relevance of the options on a common scale. A recent framework, the “extended common neural currency” hypothesis, suggests that the vmPFC may also assign values to social factors and principles, thereby guiding social decision-making. Although neural value signals have been observed in the vmPFC in both social and non-social studies, it is yet to be determined whether they have a causal influence on behavior or merely correlate with decision-making. In this review, we assess whether lesion studies of patients with vmPFC damage offer evidence for such a causal role of the vmPFC in shaping economic and social behavior.

Introduction: Studies suggest an involvement of the ventromedial prefrontal cortex (vmPFC) in reward prediction and processing, with reward-based learning relying on neural activity in response to unpredicted rewards or non-rewards (reward prediction error, RPE). Here, we investigated the causal role of the vmPFC in reward prediction, processing, and RPE signaling by transiently modulating vmPFC excitability using transcranial Direct Current Stimulation (tDCS). Methods: Participants received excitatory or inhibitory tDCS of the vmPFC before completing a gambling task, in which cues signaled varying reward probabilities and symbols provided feedback on monetary gain or loss. We collected self-reported and evaluative data on reward prediction and processing. In addition, cue-locked and feedback-locked neural activity via magnetoencephalography (MEG) and pupil diameter using eye-tracking were recorded. Results: Regarding reward prediction (cue-locked analysis), vmPFC excitation (versus inhibition) resulted in increased prefrontal activation preceding loss predictions, increased pupil dilations, and tentatively more optimistic reward predictions. Regarding reward processing (feedback-locked analysis), vmPFC excitation (versus inhibition) resulted in increased pleasantness, increased vmPFC activation, especially for unpredicted gains (i.e., gain RPEs), decreased perseveration in choice behavior after negative feedback, and increased pupil dilations. Discussion: Our results support the pivotal role of the vmPFC in reward prediction and processing. Furthermore, they suggest that transient vmPFC excitation via tDCS induces a positive bias into the reward system that leads to enhanced anticipation and appraisal of positive outcomes and improves reward-based learning, as indicated by greater behavioral flexibility after losses and unpredicted outcomes, which can be seen as an improved reaction to the received feedback. [ABSTRACT FROM AUTHOR]

A clear understanding of the neural circuit underlying emotion regulation (ER) is important for both basic and translational research. However, a lack of evidence based on combined neuroimaging and neuromodulation techniques calls into question (1) whether the change of prefrontal-subcortical activity intrinsically and causally contributes to the ER effect; and (2) whether the prefrontal control system directly modulates the subcortical affective system. Accordingly, we combined fMRI recordings with transcranial magnetic stimulation (TMS) to map the causal connections between the PFC and subcortical affective structures (amygdala and insula). A total of 117 human adult participants (57 males and 60 females) were included in the study. The results revealed that TMS-induced ventrolateral PFC (VLPFC) facilitation led to enhanced activity in the VLPFC and ventromedial PFC (VMPFC) as well as attenuated activity in the amygdala and insula during reappraisal but not during nonreappraisal (i.e., baseline). Moreover, the activated VLPFC intensified the prefrontal-subcortical couplings via the VMPFC during reappraisal only. This study provides combined TMS-fMRI evidence that downregulating negative emotion involves the prefrontal control system suppressing the subcortical affective system, with the VMPFC serving as a crucial hub within the VLPFC-subcortical network, suggesting an indirect pathway model of the ER circuit. Our findings outline potential protocols for improving ER ability by intensifying the VLPFC-VMPFC coupling in patients with mood and anxiety disorders. [ABSTRACT FROM AUTHOR]

An important open question in neuroeconomics is how the brain represents the value of offers in a way that is both abstract (allowing for comparison) and concrete (preserving the details of the factors that influence value). Here, we examine neuronal responses to risky and safe options in five brain regions that putatively encode value in male macaques. Surprisingly, we find no detectable overlap in the neural codes used for risky and safe options, even when the options have identical subjective val)ues (as revealed by preference) in any of the regions. Indeed, responses are weakly correlated and occupy distinct (semi-or)thogonal) encoding subspaces. Notably, however, these subspaces are linked through a linear transform of their constituent encodings, a property that allows for comparison of dissimilar option types. This encoding scheme allows these regions to multiplex decision related processes: they can encode the detailed factors that influence offer value (here, risky and safety) but also directly compare dissimilar offer types. Together these results suggest a neuronal basis for the qualitatively different psychological properties of risky and safe options and highlight the power of population geometry to resolve outstanding problems in neural coding. [ABSTRACT FROM AUTHOR]

Early exposure to family material hardship is an essential risk for problematic mobile phone use (PMPU). However, less is known about the reason for the association between early material hardship and PMPU. One possibility is that early hardship is a stressor that negatively affects brain structure, increasing the risk for PMPU. In testing this model, we also took into account the possible mitigating effect of strong parent-child attachment in this risk process. Participants were 45 young adults aged 18 to 23 years old who completed questionnaires to assess early material hardship, PMPU, and parental attachment. Deficits in brain structure were measured by estimating grey matter volume (GMV) using a voxel-based morphometry method via structural magnetic resonance imaging. Results revealed a significant association between early exposure to family material hardship and decreased GMV in right ventromedial prefrontal cortex (vmPFC), left orbital inferior frontal cortex (orbIFC) and left middle cingulate cortex (MCC). Importantly, subsequent structural equation modeling showed that decreased GMV within vmPFC fully mediated the association between high family material hardship and PMPU. Furthermore, stronger parental attachment mitigated the risk of decreases in vmPFC volume on PMPU following early exposure to family material hardship. [ABSTRACT FROM AUTHOR]

The orbitofrontal cortex and amygdala are involved in emotion and in motivation, but the relationship between these functions performed by these brain structures is not clear. To address this, a unified theory of emotion and motivation is described in which motivational states are states in which instrumental goal-directed actions are performed to obtain rewards or avoid punishers, and emotional states are states that are elicited when the reward or punisher is or is not received. This greatly simplifies our understanding of emotion and motivation, for the same set of genes and associated brain systems can define the primary or unlearned rewards and punishers such as sweet taste or pain. Recent evidence on the connectivity of human brain systems involved in emotion and motivation indicates that the orbitofrontal cortex is involved in reward value and experienced emotion with outputs to cortical regions including those involved in language, and is a key brain region involved in depression and the associated changes in motivation. The amygdala has weak effective connectivity back to the cortex in humans, and is implicated in brainstem-mediated responses to stimuli such as freezing and autonomic activity, rather than in declarative emotion. The anterior cingulate cortex is involved in learning actions to obtain rewards, and with the orbitofrontal cortex and ventromedial prefrontal cortex in providing the goals for navigation and in reward-related effects on memory consolidation mediated partly via the cholinergic system. [ABSTRACT FROM AUTHOR]

The parent-child relationship and family context influence the development of emotion regulation (ER) brain circuitry and related skills in children and adolescents. Although both parents' and children's ER neurocircuitry simultaneously affect how they interact with one another, neuroimaging studies of parent-child relationships typically include only one member of the dyad in brain imaging procedures. The current study examined brain activation related to parenting and ER in parent-adolescent dyads during concurrent fMRI scanning with a novel task - the Testing Emotional Attunement and Mutuality (TEAM) task. The TEAM task includes feedback trials indicating the other dyad member made an error, resulting in a monetary loss for both participants. Results indicate that positive parenting practices as reported by the adolescent were positively correlated with parents' hemodynamic activation of the ventromedial prefrontal cortex, a region related to empathy, during these error trials. Additionally, during feedback conditions both parents and adolescents exhibited fMRI activation in ER-related regions, including the dorsolateral prefrontal cortex, anterior insula, fusiform gyrus, thalamus, caudate, precuneus, and superior parietal lobule. Adolescents had higher left amygdala activation than parents during the feedback condition. These findings demonstrate the utility of dyadic fMRI scanning for investigating relational processes, particularly in the parent-child relationship.

The amygdala, hippocampus, and subgenual cortex area 25 (A25) are engaged in complex cognitive-emotional processes. Yet pathway interactions from hippocampus and A25 with postsynaptic sites in amygdala remain largely unknown. In rhesus monkeys of both sexes, we studied with neural tracers how pathways from A25 and hippocampus interface with excitatory and inhibitory microcircuits in amygdala at multiple scales. We found that both hippocampus and A25 innervate distinct as well as overlapping sites of the basolateral (BL) amygdalar nucleus. Unique hippocampal pathways heavily innervated the intrinsic paralaminar basolateral nucleus, which is associated with plasticity. In contrast, orbital A25 preferentially innervated another intrinsic network, the intercalated masses, an inhibitory reticulum that gates amygdalar autonomic output and inhibits fear-related behaviors. Finally, using high-resolution confocal and electron microscopy (EM), we found that among inhibitory postsynaptic targets in BL, both hippocampal and A25 pathways preferentially formed synapses with calretinin (CR) neurons, which are known for disinhibition and may enhance excitatory drive in the amygdala. Among other inhibitory postsynaptic sites, A25 pathways innervated the powerful parvalbumin (PV) neurons which may flexibly regulate the gain of neuronal assemblies in the BL that affect the internal state. In contrast, hippocampal pathways innervated calbindin (CB) inhibitory neurons, which modulate specific excitatory inputs for processing context and learning correct associations. Common and unique patterns of innervation in amygdala by hippocampus and A25 have implications for how complex cognitive and emotional processes may be selectively disrupted in psychiatric disorders. [ABSTRACT FROM AUTHOR]

Background: Medication overuse headache shares several characteristics with substance use disorders. However, key features of substance use disorders such as increased impulsivity and alterations in reward processing remain little explored in medication overuse headache. Methods: Temporal discounting and impulsive decision making behavior and the associated brain mechanisms were assessed in 26 chronic migraine patients with medication overuse headache and in 28 healthy controls. Regions-of-interest analyses were first performed for task-related regions, namely the ventral striatum and the ventromedial and dorsomedial prefrontal cortices. Resting-state functional connectivity between these regions were then explored. An additional 27 chronic migraine patients without medication overuse headache were included for comparison in the latter analysis. Results: Patients with medication overuse headache showed steeper temporal discounting behavior than healthy controls. They also showed weaker subjective value representations in the dorsomedial prefrontal cortex, when accepting larger delayed rewards, and in ventral striatum and ventromedial prefrontal cortex, when accepting the smaller immediate reward. Resting-state functional connectivity was reduced among the valuation regions when comparing patients with medication overuse headache to the other two control groups. Conclusions: Patients with medication overuse headache were characterized by altered processing and dysconnectivity in the reward system during intertemporal choices and in the resting-state. [ABSTRACT FROM AUTHOR]

Contexts associated with prior reinforcement can renew extinguished conditioned responding. The prelimbic (PL) and infralimbic (IL) cortices are thought to mediate the expression and suppression of conditioned responding, respectively. Evidence suggests that PL inputs to the paraventricular nucleus of the thalamus (PVT) drive the expression of cue‐induced reinstatement of drug seeking and that IL inputs to the PVT mediate fear extinction retrieval. However, the role of these projections in renewal of appetitive Pavlovian conditioned responding is unknown. We trained male and female Long‐Evans rats to associate a conditioned stimulus (CS; 10 s white noise) with delivery of a 10% sucrose unconditioned stimulus (US;.2 ml/CS) to a fluid port in a distinct context (Context A). We then extinguished responding by presenting the CS without the US in a different context (Context B). At test, rats were returned to Context A, and optogenetic stimulation was delivered to either the IL‐to‐PVT or PL‐to‐PVT pathway during CS presentations. Optically stimulating the IL‐to‐PVT, but not the PL‐to‐PVT pathway, attenuated ABA renewal of CS port entries, and this effect was similar in males and females. Further, rats self‐administered optical stimulation of the IL‐to‐PVT but not the PL‐to‐PVT pathway suggesting that activation of the IL‐to‐PVT pathway is reinforcing. The effectiveness of optical stimulation parameters to activate neurons in the IL, PL and PVT was confirmed using Fos immunohistochemistry. These findings provide evidence for novel neural mechanisms in renewal of responding to a sucrose‐predictive CS, as well as more generally in contextual processing and appetitive associative learning. [ABSTRACT FROM AUTHOR]

Background and Hypotheses Auditory verbal hallucinations (AVHs) is not only a common symptom in schizophrenia but also observed in individuals in the general population. Despite extensive research, AVHs are poorly understood, especially their underlying neuronal architecture. Neuroimaging methods have been used to identify brain areas and networks that are activated during hallucinations. A characteristic feature of AVHs is, however, that they fluctuate over time, with varying frequencies of starts and stops. An unanswered question is, therefore, what neuronal events co-occur with the initiation and inhibition of an AVH episode. Study Design We investigated brain activation with fMRI in 66 individuals who experienced multiple AVH-episodes while in the scanner. We extracted time-series fMRI-data and monitored changes second-by-second from 10 s before to 15 s after participants indicated the start and stop of an episode, respectively, by pressing a hand-held response-button. Study Results We found a region in the ventromedial prefrontal cortex (VMPFC) which showed a significant increase in activation initiated a few seconds before participants indicated the start of an episode, and a corresponding decrease in activation initiated a few seconds before the end of an episode. Conclusions The consistent increase and decrease in activation in this area in advance of the consciously experienced presence or absence of the "voice" imply that this region may act as a switch in turning episodes on and off. The activation is unlikely to be confounded by motor responses. The findings could have clinical implications for brain stimulation treatments, like transcranial magnetic stimulation. [ABSTRACT FROM AUTHOR]

IntroductionStudies suggest an involvement of the ventromedial prefrontal cortex (vmPFC) in reward prediction and processing, with reward-based learning relying on neural activity in response to unpredicted rewards or non-rewards (reward prediction error, RPE). Here, we investigated the causal role of the vmPFC in reward prediction, processing, and RPE signaling by transiently modulating vmPFC excitability using transcranial Direct Current Stimulation (tDCS).MethodsParticipants received excitatory or inhibitory tDCS of the vmPFC before completing a gambling task, in which cues signaled varying reward probabilities and symbols provided feedback on monetary gain or loss. We collected self-reported and evaluative data on reward prediction and processing. In addition, cue-locked and feedback-locked neural activity via magnetoencephalography (MEG) and pupil diameter using eye-tracking were recorded.ResultsRegarding reward prediction (cue-locked analysis), vmPFC excitation (versus inhibition) resulted in increased prefrontal activation preceding loss predictions, increased pupil dilations, and tentatively more optimistic reward predictions. Regarding reward processing (feedback-locked analysis), vmPFC excitation (versus inhibition) resulted in increased pleasantness, increased vmPFC activation, especially for unpredicted gains (i.e., gain RPEs), decreased perseveration in choice behavior after negative feedback, and increased pupil dilations.DiscussionOur results support the pivotal role of the vmPFC in reward prediction and processing. Furthermore, they suggest that transient vmPFC excitation via tDCS induces a positive bias into the reward system that leads to enhanced anticipation and appraisal of positive outcomes and improves reward-based learning, as indicated by greater behavioral flexibility after losses and unpredicted outcomes, which can be seen as an improved reaction to the received feedback.

Chronic pain is among the most common reasons adults in the U.S. seek medical care. Despite chronic pain's substantial impact on individuals' physical, emotional, and financial wellness, the biologic underpinnings of chronic pain remain incompletely understood. Such deleterious impact on an individuals' wellness is also manifested in the substantial co-occurrence of chronic stress with chronic pain. However, whether chronic stress and adversity and related alcohol and substance misuse increases risk of developing chronic pain, and, if so, what the overlapping psychobiological processes are, is not well understood. Individuals suffering with chronic pain find alleviation through prescription opioids as well as non-prescribed cannabis, alcohol, and other drugs to control pain, and use of these substances have grown significantly. Substance misuse also increases experience of chronic stress. Thus, given the evidence showing a strong correlation between chronic stress and chronic pain, we aim to review and identify overlapping factors and processes. We first explore the predisposing factors and psychologic features common to both conditions. This is followed by examining the overlapping neural circuitry of pain and stress in order to trace a common pathophysiologic processes for the development of chronic pain and its link to substance use. Based on the previous literature and our own findings, we propose a critical role for ventromedial prefrontal cortex dysfunction, an overlapping brain area associated with the regulation of both pain and stress that is also affected by substance use, as key in the risk of developing chronic pain. Finally, we identify the need for future research in exploring the role of medial prefrontal circuits in chronic pain pathology. Critically, in order to alleviate the enormous burden of chronic pain without exacerbating the co-occurring substance misuse crisis, we emphasize the need to find better approaches to treat and prevent chronic pain.

BackgroundHuman beings find social stimuli rewarding, which is thought to facilitate efficient social functioning. Although reward processing has been extensively studied in schizophrenia, a few studies have examined neural processes specifically involved in social reward processing. This study examined neural sensitivity to social and nonsocial rewards in schizophrenia.MethodsTwenty-seven patients with schizophrenia and 25 community controls completed a One-Armed Bandit Task, an implicit reinforcement learning task, in the scanner. There were 2 conditions with an identical trial structure, one with social rewards and the other with nonsocial rewards. The data were analyzed using a region of interest (ROI) approach, focusing on the ventral striatum, ventromedial prefrontal cortex, and anterior cingulate cortex.ResultsAcross all 3 ROIs, patients showed reduced activation for social rewards compared to controls. However, the 2 groups showed comparable levels of activation for nonsocial rewards. Within the patient group, levels of neural activation in these ROIs during the social reward condition were associated with better performance.ConclusionsThis study found reduced neural sensitivity in patients with schizophrenia in key reward-processing regions for social but not for nonsocial rewards. These findings suggest a relatively specific social reward-processing deficit in schizophrenia during an implicit reinforcement learning task.

Human thought is prone to biases. Some biases serve as beneficial heuristics to free up limited cognitive resources or improve well-being, but their neurocognitive basis is unclear. One such bias is a tendency to construe events in the distant future in abstract, general terms and events in the near future in concrete, detailed terms. Temporal construal may rely on our capacity to orient toward and/or imagine context-rich future events. We tested 21 individuals with impaired episodic future thinking resulting from lesions to the hippocampus or ventromedial prefrontal cortex (vmPFC) and 57 control participants (aged 45–76 years) from Canada and Italy on measures sensitive to temporal construal. We found that temporal construal persisted in most patients, even those with impaired episodic future thinking, but was abolished in some vmPFC cases, possibly in relation to difficulties forming and maintaining future intentions. The results confirm the fractionation of future thinking and that parts of vmPFC might critically support our ability to flexibly conceive and orient ourselves toward future events. [ABSTRACT FROM AUTHOR]

Recent work on the cognitive regulation of dietary decision-making suggests that regulation can alter both the choices that people make in the moment and longer-lasting preferences. However, it is unclear what mechanisms lead to temporary or lingering changes. To address this question, we used fMRI during a task employing the cognitive regulation of food choice and assessed changes in food preference from baseline to post-regulation. We found evidence that regulation may result in a temporary reconfiguration of the neural drivers of choice, de-emphasizing goal-inconsistent value-related computations in the ventromedial prefrontal cortex and resulting in more goal-consistent changes in value-related computations in the dorsolateral prefrontal cortex (dlPFC). Moreover, we find that the extent to which the dlPFC was recruited to represent different regulatory goals during the moment of choice negatively predicted the extent to which those regulatory goals produced lingering changes in preference. Our results suggest that the recruitment of the dlPFC in the service of regulation may have a downside: it is effective at changing behavior in the moment, but its effects on preferences are transient. [ABSTRACT FROM AUTHOR]

Recent work using multivariate-pattern analysis (MVPA) on functional magnetic resonance imaging (fMRI) data has found that distinct affective states produce correspondingly distinct patterns of neural activity in the cerebral cortex. However, it is unclear whether individual differences in the distinctiveness of neural patterns evoked by affective stimuli underlie empathic abilities such as perspective-taking (PT). Accordingly, we examined whether we could predict PT tendency from the classification of blood-oxygen-level-dependent (BOLD) fMRI activation patterns while participants (n  = 57) imagined themselves in affectively charged scenarios. We used an MVPA searchlight analysis to map where in the brain activity patterns permitted the classification of four affective states: happiness, sadness, fear and disgust. Classification accuracy was significantly above chance levels in most of the prefrontal cortex and in the posterior medial cortices. Furthermore, participants' self-reported PT was positively associated with classification accuracy in the ventromedial prefrontal cortex and insula. This finding has implications for understanding affective processing in the prefrontal cortex and for interpreting the cognitive significance of classifiable affective brain states. Our multivariate approach suggests that PT ability may rely on the grain of internally simulated affective representations rather than simply the global strength. [ABSTRACT FROM AUTHOR]

Williams Syndrome (WS) is a neurodevelopmental disorder caused by a deletion of 25⁻28 genes on chromosome 7 and characterized by a specific behavioral phenotype, which includes hypersociability and anxiety. Here, we examined the density of neurons and glia in fourteen human brains in Brodmann area 25 (BA 25), in the ventromedial prefrontal cortex (vmPFC), using a postmortem sample of five adult and two infant WS brains and seven age-, sex- and hemisphere-matched typically developing control (TD) brains. We found decreased neuron density, which reached statistical significance in the supragranular layers, and increased glia density and glia to neuron ratio, which reached statistical significance in both supra- and infragranular layers. Combined with our previous findings in the amygdala, caudate nucleus and frontal pole (BA 10), these results in the vmPFC suggest that abnormalities in frontostriatal and frontoamygdala circuitry may contribute to the anxiety and atypical social behavior observed in WS.

Background: Acquired brain injury (ABI) is accompanied by impairments in social, emotional, cognitive and behavioural skills and highly prevalent in the population. Social and emotional skills are crucial for moral cognition, but the extent to which moral cognition contributes to social competence deficits in people with ABI is largely unclear. Method: To provide more insight on this topic, we conducted a scoping review according to the PRISMA guidelines. After screening 1269 articles that we obtained via PubMed and Scopus, we found 27 articles on moral cognition in ABI. Results: We encountered four important topics across these studies which include traumatic brain injury (TBI) versus non-TBI, the influence of the different approaches used to measure moral cognition in ABI, the role of age of onset and the role of location of the injury. Overall, evidence suggests that the earlier the brain damage occurred, the more this leads to impairments in moral cognitive functioning. The location of the injury furthermore seems to differentially affect the way impairments are manifested. Finally, we found that the use of different measurement approaches can heavily influence the interpretation of the impairment. Conclusion: We conclude that impairments in moral cognition in people with ABI are derived from a complex interplay between the age of onset, the location and the approach used to index moral cognition. [ABSTRACT FROM AUTHOR]

Aims: To identify the impact of ventromedial prefrontal cortex injury (vmpFC) on social cognition (SC) processes in a stroke patient in relation to a control group matched by age, gender, and schooling. Possible associations between post-injury behavior and impacted neuropsychological attributes of emotion recognition, Theory of Mind (tom), and empathy are discussed. Method: One male patient (n = 1) (58 years old) with stroke in right vmpFC and 10 healthy participants completed different screening, neuropsychological assessment, and SC tests as: Addenbrooke's Cognitive Examination-Revised; The Trail Making Test; Raven's Matrices; Faux Pas Test; Reading Mind in the Eyes Test, among others. Results: Due single cases are reported, p< .05 values of a tail were considered statistically significant in all comparisons. Correlations were found between damage in vmpFC and alterations in affective tom, working and retrograde memory, mood and relational alterations in the patient. Discrepancies were found with respect to other studies in relation to the laterality of the injury and the impact of cognitive and affective empathy that seems to be relatively intact. Conclusions: There is a need to clarify the role of affective tom after acquired brain injury (aBi) in vmpFC. A protocol is needed to assess and intervene in aspects of tom that would involve documenting strengths and deficits of tom: inter and intrapersonal after an aBi. Similarly, there is a need to address the lateralization of different domains of function in vmpFC and their relationship to affective tom. [ABSTRACT FROM AUTHOR]

Childhood maladaptive aggression is associated with disrupted functional connectivity within amygdala-prefrontal circuitry. In this study, neural correlates of childhood aggression were probed using the intrinsic connectivity distribution, a voxel-wise metric of global resting-state brain connectivity. This sample included 38 children with aggressive behavior (26 boys, 12 girls) ages 8–16 years and 21 healthy controls (14 boys, 6 girls) matched for age and IQ. Functional MRI data were acquired during resting state, and differential patterns of intrinsic functional connectivity were tested in a priori regions of interest implicated in the pathophysiology of aggressive behavior. Next, correlational analyses tested for associations between functional connectivity and severity of aggression measured by the Reactive-Proactive Aggression Questionnaire in children with aggression. Children with aggressive behavior showed increased global connectivity in the bilateral amygdala relative to controls. Greater severity of aggressive behavior was associated with decreasing global connectivity in the dorsal anterior cingulate and ventromedial prefrontal cortex. Follow-up seed analysis revealed that aggression was also positively correlated with left amygdala connectivity with the dorsal anterior cingulate, ventromedial and dorsolateral prefrontal cortical regions. These results highlight the potential role of connectivity of the amygdala and medial prefrontal and anterior cingulate cortices in modulating the severity of aggressive behavior in treatment-seeking children. [ABSTRACT FROM AUTHOR]

Behavioral flexibility depends on our capacity to build and leverage abstract knowledge about tasks. Recently, two separate lines of research have implicated distinct brain networks in representing abstract task information: a frontoparietal cortical network, and a network involving the medial temporal lobe (MTL), medial prefrontal, and orbitofrontal cortex (OMPFC). These observations have mostly been made in parallel, with little attempt to understand their relationship. Here, we hypothesize that abstract task representations in these networks differ primarily in format, not content. Namely, that the MTL–OMPFC network maintains task knowledge in a flexible cognitive map, while the frontoparietal network formats this knowledge as productions that facilitate action selection. We discuss novel implications and predictions for behavioral flexibility arising from this hypothesis. Recent research has identified two distinct cortical networks representing abstract task knowledge: a frontoparietal network, and a network involving the MTL and OMPFC. Here, we suggest that these networks differ in format but not content, with the MTL–OMPFC network maintaining abstract task knowledge in a cognitive map, while frontoparietal cortex uses this knowledge to build rules for action selection. This format distinction would allow the MTL–OMPFC network to form novel inferences and plan trajectories in an abstract state space, and for the frontoparietal network to rapidly apply abstract rules without referencing a more elaborate internal task model. This hypothesis makes novel predictions about the function of these networks in learning and promoting flexible behavior. [ABSTRACT FROM AUTHOR]