Activity In Ventromedial Prefrontal Cortex Research Articles

Altered frontolimbic activity during virtual reality-based contextual fear learning in patients with posttraumatic stress disorder.

Deficiency in contextual and enhanced responding in cued fear learning may contribute to the development of posttraumatic stress disorder (PTSD). We examined the responses to aversive Pavlovian conditioning with an unpredictable spatial context as conditioned stimulus compared to a predictable context. We hypothesized that the PTSD group would demonstrate less hippocampal and ventromedial prefrontal cortex (vmPFC) activation during acquisition and extinction of unpredictable contexts and an over-reactive amygdala response in the predictable contexts compared to controls. A novel combined differential cue-context conditioning paradigm was applied using virtual reality with spatial contexts that required configural and cue processing. We assessed 20 patients with PTSD, 21 healthy trauma-exposed (TC) and 22 non-trauma-exposed (HC) participants using functional magnetic resonance imaging, skin conductance responses, and self-report measures. During fear acquisition, patients with PTSD compared to TC showed lower activity in the hippocampi in the unpredictable and higher activity in the amygdalae in the predictable context. During fear extinction, TC compared to patients and HC showed higher brain activity in the vmPFC in the predictable context. There were no significant differences in self-report or skin conductance responses. Our results suggest that patients with PTSD differ in brain activation from controls in regions such as the hippocampus, the amygdala, and the vmPFC in the processing of unpredictable and predictable contexts. Deficient encoding of more complex configurations might lead to a preponderance of cue-based predictions in PTSD. Exposure-based treatments need to focus on improving predictability of contextual processing and reducing enhanced cue reactivity.

The neural correlates of value representation: From single items to bundles.

One of the core questions in Neuro-economics is to determine where value is represented. To date, most studies have focused on simple options and identified the ventromedial prefrontal cortex (VMPFC) as the common value region. We report the findings of an fMRI study in which we asked participants to make pairwise comparisons involving options of varying complexity: single items (Control condition), bundles made of the same two single items (Scaling condition) and bundles made of two different single items (Bundling condition). We construct a measure of choice consistency to capture how coherent the choices of a participant are with one another. We also record brain activity while participants make these choices. We find that a common core of regions involving the left VMPFC, the left dorsolateral prefrontal cortex (DLPFC), regions associated with complex visual processing and the left cerebellum track value across all conditions. Also, regions in the DLPFC, the ventrolateral prefrontal cortex (VLPFC) and the cerebellum are differentially recruited across conditions. Last, variations in activity in VMPFC and DLPFC value-tracking regions are associated with variations in choice consistency. This suggests that value based decision-making recruits a core set of regions as well as specific regions based on task demands. Further, correlations between consistency and the magnitude of signal change with lateral portions of the PFC suggest the possibility that activity in these regions may play a causal role in decision quality.

Disrupted network switching in euthymic bipolar disorder: Working memory and self-referential paradigms

BackgroundPatients with bipolar disorder (BD) frequently suffer from neurocognitive deficits that can persist during periods of clinical stability. Specifically, impairments in executive functioning such as working memory and in self-processing have been identified as the main components of the neurocognitive profile observed in euthymic BD patients. The study of the neurobiological correlates of these state-independent alterations may be a prerequisite to develop reliable biomarkers in BD. MethodsA sample of 27 euthymic BD patients and 25 healthy participants (HC) completed working memory and self-referential functional Magnetic Resonance Imaging (fMRI) tasks. Activation maps obtained for each group and contrast images (i.e., 2-back > 1-back/self > control) were used for comparisons between patients and HC. ResultsEuthymic BD patients, in comparison to HC, showed a higher ventromedial prefrontal cortex activation during working memory, a result driven by the lack of deactivation in BD patients. In addition, euthymic BD patients displayed a greater dorsomedial and dorsolateral prefrontal cortex activation during self-reference processing. LimitationsPharmacotherapy was described but not included as a confounder in our models. Sample size was modest. ConclusionOur findings revealed a lack of deactivation in the anterior default mode network (aDMN) during a working memory task, a finding consistent with prior research in BD patients, but also a higher activation in frontal regions within the central executive network (CEN) during self-processing. These results suggest that an imbalance of neural network dynamics underlying external/internal oriented cognition (the CEN and the aDMN, respectively) may be one of the first reliable biomarkers in euthymic bipolar patients.

Competition between Associations in Memory.

If two associations share an item, one may be remembered at the expense of the other (BC recalled but not AB). Here, we identify the neural processes by which this competition materializes and is resolved. We analyzed fMRI signal while participants studied sets of pairs that reliably induced pair-to-pair associative interference, but which participants could not fully resolve. Precuneus activity tracked retrieval of previous pairs during study of later overlapping pairs. This retrieval apparently produced interference by diverting study resources from the currently displayed pair. However, when activity in ventromedial prefrontal cortex, as well as anterior subregions of the hippocampus, was present while the earlier pair had been studied, interference was reversed, and both pairs were likely to be recalled. Angular gyrus and mid-frontal activity were related to interference resolution once the participant had seen both pairs. Taken together, associations compete via precuneus-mediated competitive retrieval, but ventromedial prefrontal cortex may neutralize this by ensuring that when the earlier association is remembered while studying the later pair, memories of the two pairs can overcome interference likely via activity in mid-frontal cortex and angular gyrus.

Persistent Dissociation and Its Neural Correlates in Predicting Outcomes After Trauma Exposure.

Dissociation, a disruption or discontinuity in psychological functioning, is often linked with worse psychiatric symptoms; however, the prognostic value of dissociation after trauma is inconsistent. Determining whether trauma-related dissociation is uniquely predictive of later outcomes would enable early identification of at-risk trauma populations. The authors conducted the largest prospective longitudinal biomarker study of persistent dissociation to date to determine its predictive capacity for adverse psychiatric outcomes following acute trauma. All data were part of the Freeze 2 data release from the Advancing Understanding of Recovery After Trauma (AURORA) study. Study participants provided self-report data about persistent derealization (N=1,464), a severe type of dissociation, and completed a functional MRI emotion reactivity task and resting-state scan 2 weeks posttrauma (N=145). Three-month follow-up reports were collected of posttraumatic stress, depression, pain, anxiety symptoms, and functional impairment. Derealization was associated with increased ventromedial prefrontal cortex (vmPFC) activation in the emotion reactivity task and decreased resting-state vmPFC connectivity with the cerebellum and orbitofrontal cortex. In separate analyses, brain-based and self-report measures of persistent derealization at 2 weeks predicted worse 3-month posttraumatic stress symptoms, distinct from the effects of childhood maltreatment history and current posttraumatic stress symptoms. The findings suggest that persistent derealization is both an early psychological and biological marker of worse later psychiatric outcomes. The neural correlates of trauma-related dissociation may serve as potential targets for treatment engagement to prevent posttraumatic stress disorder. These results underscore dissociation assessment as crucial following trauma exposure to identify at-risk individuals, and they highlight an unmet clinical need for tailored early interventions.

Right inferior frontal gyrus and ventromedial prefrontal activation during response inhibition is implicated in the development of PTSD symptoms

ABSTRACT Background Inhibition is a critical executive control process and an established neurobiological phenotype of PTSD, yet to our knowledge, no prospective studies have examined this using a contextual cue task that enables measurement of behavioural response and neural activation patterns across proactive and reactive inhibition. Objective The current longitudinal study utilised functional magnetic resonance imaging (fMRI) to examine whether deficits in proactive and reactive inhibition predicted PTSD symptoms six months after trauma. Method Twenty-three (65% males) medical patients receiving emergency medical care from a level 1 trauma centre were enrolled in the study and invited for an MRI scan 1-2-months post-trauma. PTSD symptoms were measured using self-report at scan and 6-months post-trauma. A stop-signal anticipation task (SSAT) during an fMRI scan was used to test whether impaired behavioural proactive and reactive inhibition, and reduced activation in right inferior frontal gyrus (rIFG), ventromedial prefrontal cortex (vmPFC), and bilateral hippocampus, were related to PTSD symptoms. We predicted that lower activation levels of vmPFC and rIFG during reactive inhibition and lower activation of hippocampus and rIFG during proactive inhibition would relate to higher 6-month PTSD symptoms. Results No significant associations were found between behavioural measures and 6-month PTSD. Separate linear regression analyses showed that reduced rIFG activation (F1,21 = 9.97, R2 = .32, p = .005) and reduced vmPFC activation (F1,21 = 5.19, R2 = .20, p = .03) significantly predicted greater 6-month PTSD symptoms; this result held for rIFG activation controlling for demographic variables and baseline PTSD symptoms (β = −.45, p = .04) and Bonferroni correction. Conclusion Our findings suggest that impaired rIFG and, to a lesser extent, vmPFC activation during response inhibition may predict the development of PTSD symptoms following acute trauma exposure. Given the small sample size, future replication studies are needed. HIGHLIGHTS Impaired inhibition may be an important risk factor for the development of PTSD following trauma, with less right inferior frontal gyrus and ventromedial prefrontal cortex activation during response inhibition predicting PTSD development.

Brain activity patterns underlying memory confidence.

The primary aim of this review is to examine the brain activity patterns that are related to subjectively perceived memory confidence. We focus on the main brain regions involved in episodic memory: the medial temporal lobe (MTL), prefrontal cortex (PFC), and posterior parietal cortex (PPC), and relate activity in their subregions to memory confidence. How this brain activity in both the encoding and retrieval phase is related to (subsequent) memory confidence ratings will be discussed. Specifically, encoding related activity in MTL regions and ventrolateral PFC mainly shows a positive linear increase with subsequent memory confidence, while dorsolateral and ventromedial PFC activity show mixed patterns. In addition, encoding‐related PPC activity seems to only have indirect effects on memory confidence ratings. Activity during retrieval in both the hippocampus and parahippocampal cortex increases with memory confidence, especially during high‐confident recognition. Retrieval‐related activity in the PFC and PPC show mixed relationships with memory confidence, likely related to post‐retrieval monitoring and attentional processes, respectively. In this review, these MTL, PFC, and PPC activity patterns are examined in detail and related to their functional roles in memory processes. This insight into brain activity that underlies memory confidence is important for our understanding of brain–behaviour relations and memory‐guided decision making.

Neural Processing of Health Information and Hypertension Self-Management in African Americans.

Uncontrolled blood pressure (BP) rates are persistently high among African Americans with hypertension. Although self-management is critical to controlling BP, little is known about the brain-behavior connections underlying the processing of health information and the performance of self-management activities. In this pilot study, we explored the associations among neural processing of two types of health information and a set of self-management cognitive processes (self-efficacy, activation, decision-making, and hypertension knowledge) and behaviors (physical activity, dietary intake, and medication taking) and health status indicators (BP, health-related quality of life, anxiety, and depression). Using a descriptive cross-sectional design, 16 African Americans with uncontrolled hypertension (mean age = 57.5 years, 68.8% women) underwent functional magnetic resonance imaging to assess activation of two neural networks, the task-positive network and the default mode network, and a region in the ventromedial prefrontal cortex associated with emotion-focused and analytic-focused health information. Participants completed self-reports and clinical assessments of self-management processes, behaviors, and health status indicators. Our hypothesis that neural processing associated with different types of health information would correlate with self-management cognitive processes and behaviors and health status indicators was only partially supported. Home diastolic BP was positively associated with ventromedial prefrontal cortex activation ( r = .536, p = .09); no other associations were found among the neural markers and self-management or health status variables. Expected relationships were found among the self-management processes and behaviors and health status indicators. To advance our understanding of the neural processes underlying health information processing and chronic illness self-management, future studies are needed that use larger samples with more heterogeneous populations and additional neuroimaging techniques.

Altered prefrontal activation during the inhibition of eating responses in women with bulimia nervosa.

The sense of 'loss of control' (LOC), or a feeling of being unable to stop eating or control what or how much one is eating, is the most salient aspect of binge eating. However, the neural alterations that may contribute to this experience and eating behavior remain poorly understood. We used functional near-infrared spectroscopy (fNIRS) to measure activation in the prefrontal cortices of 23 women with bulimia nervosa (BN) and 23 healthy controls (HC) during two tasks: a novel go/no-go task requiring inhibition of eating responses, and a standard go/no-go task requiring inhibition of button-pressing responses. Women with BN made more commission errors on both tasks. BN subgroups with the most severe LOC eating (n = 12) and those who felt most strongly that they binge ate during the task (n = 12) showed abnormally reduced bilateral ventromedial prefrontal cortex (vmPFC) and right ventrolateral prefrontal cortex (vlPFC) activation associated with eating-response inhibition. In the entire BN sample, lower eating-task activation in right vlPFC was related to more frequent and severe LOC eating, but no group differences in activation were detected on either task when this full sample was compared with HC. BN severity was unrelated to standard-task activation. Results provide initial evidence that diminished PFC activation may directly contribute to more severe eating-specific control deficits in BN. Our findings support vmPFC and vlPFC dysfunction as promising treatment targets, and indicate that eating-specific tasks and fNIRS may be useful tools for identifying neural mechanisms underlying dysregulated eating.

Abnormal dynamic functional connectivity during fear extinction learning in PTSD and anxiety disorders

Examining the neural circuits of fear/threat extinction advanced our mechanistic understanding of several psychiatric disorders, including anxiety disorders (AX) and posttraumatic stress disorder (PTSD). More is needed to understand the interplay of large-scale neural networks during fear extinction in these disorders. We used dynamic functional connectivity (FC) to study how FC might be perturbed during conditioned fear extinction in individuals with AX or PTSD. We analyzed neuroimaging data from 338 individuals that underwent a two-day fear conditioning and extinction paradigm. The sample included healthy controls (HC), trauma-exposed non-PTSD controls, and patients diagnosed with AX or PTSD. Dynamic FC during extinction learning gradually increased in the HC group but not in patient groups. The lack of FC change in patients was predominantly observed within and between the default mode, frontoparietal control, and somatomotor networks. The AX and PTSD groups showed impairments in different, yet partially overlapping connections especially involving the dorsolateral prefrontal cortex. Extinction-induced FC predicted ventromedial prefrontal cortex activation and FC during extinction memory recall only in the HC group. FC impairments during extinction learning correlated with fear- and anxiety-related clinical measures. These findings suggest that relative to controls, individuals with AX or PTSD exhibited widespread abnormal FC in higher-order cognitive and attention networks during extinction learning and failed to establish a link between neural signatures during extinction learning and memory retrieval. This failure might underlie abnormal processes related to the conscious awareness, attention allocation, and sensory processes during extinction learning and retrieval in fear- and anxiety-related disorders.

Association of Generalized Anxiety Disorder With Autonomic Hypersensitivity and Blunted Ventromedial Prefrontal Cortex Activity During Peripheral Adrenergic Stimulation

β-Adrenergic stimulation elicits heart palpitations and dyspnea, key features of acute anxiety and sympathetic arousal, yet no neuroimaging studies have examined how the pharmacologic modulation of interoceptive signals is associated with fear-related neurocircuitry in individuals with generalized anxiety disorder (GAD). To examine the neural circuitry underlying autonomic arousal induced via isoproterenol, a rapidly acting, peripheral β-adrenergic agonist akin to adrenaline. This crossover randomized clinical trial of 58 women with artifact-free data was conducted from January 1, 2017, to November 31, 2019, at the Laureate Institute for Brain Research in Tulsa, Oklahoma. Functional magnetic resonance imaging was used to assess neural responses during randomized intravenous bolus infusions of isoproterenol (0.5 and 2.0 μg) and saline, each administered twice in a double-blind fashion. Blood oxygen level-dependent responses across the whole brain during isoproterenol administration in patients with GAD vs healthy comparators. Cardiac and respiratory responses, as well as interoceptive awareness and anxiety, were also measured during the infusion protocol. Of the 58 female study participants, 29 had GAD (mean [SD] age, 26.9 [6.8] years) and 29 were matched healthy comparators (mean [SD] age, 24.4 [5.0] years). During the 0.5-μg dose of isoproterenol, the GAD group exhibited higher heart rate responses (b = 5.34; 95% CI, 2.06-8.61; P = .002), higher intensity ratings of cardiorespiratory sensations (b = 8.38; 95% CI, 2.05-14.71; P = .01), higher levels of self-reported anxiety (b = 1.04; 95% CI, 0.33-1.76; P = .005), and significant hypoactivation in the ventromedial prefrontal cortex (vmPFC) that was evident throughout peak response (Cohen d = 1.55; P < .001) and early recovery (Cohen d = 1.52; P < .001) periods. Correlational analysis of physiological and subjective indexes and percentage of signal change extracted during the 0.5-μg dose revealed that vmPFC hypoactivation was inversely correlated with heart rate (r56 = -0.51, adjusted P = .001) and retrospective intensity of both heartbeat (r56 = -0.50, adjusted P = .002) and breathing (r56 = -0.44, adjusted P = .01) sensations. Ventromedial prefrontal cortex hypoactivation correlated inversely with continuous dial ratings at a trend level (r56 = -0.38, adjusted P = .051), whereas anxiety (r56 = -0.28, adjusted P = .27) and chronotropic dose 25 (r56 = -0.14, adjusted P = .72) showed no such association. In this crossover randomized clinical trial, women with GAD exhibited autonomic hypersensitivity during low levels of adrenergic stimulation characterized by elevated heart rate, heightened interoceptive awareness, increased anxiety, and a blunted neural response localized to the vmPFC. These findings support the notion that autonomic hyperarousal may be associated with regulatory dysfunctions in the vmPFC, which could serve as a treatment target to help patients with GAD more appropriately appraise and regulate signals of sympathetic arousal. ClinicalTrials.gov Identifier: NCT02615119.

Ventromedial prefrontal cortex activity differentiates sick from healthy faces: Associations with inflammatory responses and disease avoidance motivation

BackgroundHumans are able to discern the health status of others using olfactory and visual cues, and subsequently shift behavior to make infection less likely. However, little is known about how this process occurs. The present study examined the neural regions involved in differentiating healthy from sick individuals using visual cues. MethodsWhile undergoing a functional magnetic resonance imaging scan, participants (N = 42) viewed facial photos of 30 individuals (targets) who had been injected with an inflammatory challenge--low-dose endotoxin (i.e., sick) or placebo (i.e., healthy), and rated how much they liked each face. We examined regions implicated in processing either threat (amygdala, anterior insula) or cues that signal safety (ventromedial prefrontal cortex [VMPFC]), and how this activity related to their liking of targets and cytokine levels (interleukin-6, tumor necrosis factor-α) exhibited by the targets. ResultsPhotos of sick faces were rated as less likeable compared to healthy faces, and the least liked faces were those individuals with the greatest inflammatory response. While threat-related regions were not significantly active in response to viewing sick faces, the VMPFC was more active in response to viewing healthy (vs. sick) faces. Follow-up analyses revealed that participants tended to have lower VMPFC activity when viewing the least liked faces and the faces of those with the greatest inflammatory response. ConclusionsThis work builds on prior work implicating the VMPFC in signaling the presence of safe, non-threatening visual stimuli, and suggests the VMPFC may be sensitive to cues signaling relative safety in the context of pathogen threats.

Abstract 13714: Stress-Related Neural Pathways Mediate the Link Between Depression/Anxiety Disorders and Cardiovascular Disease

Background: Depression and anxiety disorders are linked with a greater risk of major adverse cardiac events (MACE) via unclear mechanisms. Since heightened stress-related neural activity (SNA) associates with a greater risk of MACE, we hypothesized that the link between depression/anxiety disorders and MACE is in part mediated by increased SNA. Methods: Data were obtained from subjects in the Mass General Brigham Biobank (N=118 871). A subset (N=1520) underwent clinical 18 F-fluorodeoxyglucose positron emission tomography imaging. Stress-related neural activity (SNA) was determined as the ratio of amygdalar to regulatory (ventromedial prefrontal cortex) activity. MACE (i.e., myocardial infarction, stroke, and heart failure), depression, and anxiety disorders were defined by the International Classification of Disease codes. Results: The median age was 59 years [interquartile range (IQR) 28]; 56.2% were female. MACE occurred in 4149 subjects (4.3%) over a median follow up of 3.3 years (IQR 2.9). Depression and anxiety independently predicted incident MACE (HR [95% CI]: 1.415 [1.323-1.513], p=5.696 x 10 -24 and 1.515 [1.418-1.618], p=4.548 x 10 -35 , respectively, adjusted for cardiovascular risk factors). In the 1520 subjects with brain imaging, depression and anxiety associated with higher SNA (standardized ß [95% CI]: 0.151 [0.048-0.254], p=0.004 and 0.123 [0.022-0.225], p=0.01, respectively, adjusted for age and sex). Further, SNA associated with MACE (OR [95% CI]: 1.295 [1.163-1.443], p=3 x 10 -6 ). Using path analysis, increased SNA mediated the effect of both depression and anxiety on MACE (log OR [95% CI]: 0.036 [0.009-0.072], p&lt;0.05 and 0.030 [0.005-0.063], p&lt;0.05, respectively). Conclusion: Depression and anxiety disorders associate with greater MACE risk via a mechanism that includes heightened stress-related neural activity. Future studies should evaluate the impact of therapies on this neural pathway and downstream MACE.

Location-dependent threat and associated neural abnormalities in clinical anxiety

Anxiety disorders are characterized by maladaptive defensive responses to distal or uncertain threats. Elucidating neural mechanisms of anxiety is essential to understand the development and maintenance of anxiety disorders. In fMRI, patients with pathological anxiety (ANX, n = 23) and healthy controls (HC, n = 28) completed a contextual threat learning paradigm in which they picked flowers in a virtual environment comprising a danger zone in which flowers were paired with shock and a safe zone (no shock). ANX compared with HC showed 1) decreased ventromedial prefrontal cortex and anterior hippocampus activation during the task, particularly in the safe zone, 2) increased insula and dorsomedial prefrontal cortex activation during the task, particularly in the danger zone, and 3) increased amygdala and midbrain/periaqueductal gray activation in the danger zone prior to potential shock delivery. Findings suggest that ANX engage brain areas differently to modulate context-appropriate emotional responses when learning to discriminate cues within an environment.

Moderate alcohol intake associates with a decreased risk of venous thrombosis: mediation through decreased stress-associated brain activity

Abstract Background Prior studies suggest that moderate alcohol intake may associate with a lower incidence of deep venous thrombosis (DVT). However, it is unclear if this association persists after robust adjustment for confounders. Moreover, the mechanisms mediating this potential benefit are unclear. Prior studies show that chronic stress promotes stress-related neural activity (amygdalar activity: AmygA), which in turn triggers inflammation and elevates thrombosis risk. Since moderate alcohol intake decreases AmygA, we hypothesize that this neural effect of alcohol may partially mediate its beneficial impact on DVT risk. Purpose To evaluate whether the association between moderate alcohol intake and decreased DVT risk: A) persists after robustly accounting for potential confounders and B) is mediated by reductions in stress-related neural activity. Methods Data were obtained from the Mass General Brigham Biobank, which included detailed health, lifestyle, and follow-up outcomes information on 53 059 adult participants. Alcohol intake was classified as low (&amp;lt;1 drink/week), moderate (1–14 drinks/week), or high (&amp;gt;14 drinks/week). A subset of 656 study subjects underwent clinical 18F-fluorodeoxyglucose positron emission tomography imaging from which AmygA was measured as the ratio of amygdalar to regulatory (ventromedial pre-frontal cortex) activity. Individuals on anticoagulant therapies for atrial fibrillation prior to enrolment and/or imaging were excluded. Cox analysis were performed wherein patients who developed DVT prior to Biobank enrolment (1064 subjects) were excluded. Mediation analysis was used to examine the role of AmygA in mediating the link between alcohol intake and DVT. Results The median age of the study population was 59 years [interquartile range (IQR) 26] and 51.9% were female. DVT occurred in 573 participants (1.2%) over a median follow up period of 3.4 years (IQR 2.9). Cox regression analysis showed that moderate alcohol intake was associated with lower incident DVT rates after controlling for confounders (hazard ratio [95% confidence intervals (CI)] 0.773 [0.644,0.929], p=0.006, Table 1). In the subset of participants who underwent brain imaging, moderate alcohol intake associated with decreased AmygA activity (standardized β [95% CI]: −0.218 [−0.370, −0.065], p=0.005). Further, AmygA associated with DVT (odds ratio (OR) [95% CI]: 1.374 [1.089, 1.734], p=0.007). Path analysis demonstrated that decreased AmgyA mediated the salutary effect of moderate alcohol on DVT (log OR [95% CI]: −0.0635 [−0.1383, −0.0078], p&amp;lt;0.05, Figure 1). Conclusion Moderate alcohol intake is associated with a decreased risk of DVT via a mechanism that may involve a reduction in stress-related neurobiological activity. Alternative therapies targeting this neural pathway should be identified with the goal of reducing the burden of DVT. Funding Acknowledgement Type of funding sources: None.

Anxiety and depression associate with heightened risk of deep venous thrombosis: mediation through neural pathways

Abstract Background Anxiety disorders and depression associate with an increased risk of deep venous thrombosis (DVT). However, it is unclear if this association persists after robust adjustment for confounders. Further, the mechanism mediating this potential link remains unknown. Prior studies show that anxiety and depression associate with heightened stress-associated neural activity (notably in the amygdala: AmygA), which in turn promotes chronic inflammation, a driver of thrombosis syndromes. Purpose To evaluate whether the association between anxiety/depression and DVT risk: A) persists after robustly accounting for potential confounders, and B) is mediated by upregulated stress-associated neural activity (namely AmygA). Methods Data were obtained from the Mass General Brigham Biobank, which included detailed health information on 118 871 adult participants. A subset of 1520 study subjects underwent clinical 18F-fluorodeoxyglucose positron emission tomography imaging during the follow up period, from which AmygA was measured as the ratio of amygdalar to regulatory (ventromedial pre-frontal cortex) activity. International Classification of Disease (ICD) codes in the medical record were used to define anxiety disorders, depression, and lower extremity DVT. Individuals on anticoagulant therapies for atrial fibrillation prior to enrolment and/or imaging were excluded. Cox analysis were performed wherein patients who developed DVT prior to Biobank enrolment (2599 subjects) were excluded. Mediation analysis was used to examine the role of AmygA in mediating the link between anxiety/depression and DVT. Results The median age of the study population was 57 years [interquartile range (IQR) 28] and 58.4% were female. DVT occurred in 1231 participants (1.2%) over a median follow up period of 3.3 years (IQR 3.0). Cox regression analysis showed that anxiety disorders and depression were independent predictors of incident DVT after controlling for confounders (Table 1; p&amp;lt;0.0001 for all analyses). In the subset of 1383 participants who underwent brain imaging, anxiety disorders and depression associated with increased AmygA activity after controlling for risk factors including age, sex, Charlson index, hormone use and cancer history (standardized β [95% CI]: 0.124 [0.017–0.232], p=0.023 and 0.151 [0.041–0.260], p=0.007 respectively). Further, AmygA associated with DVT (odds ratio (OR) [95% CI]: 1.248 [1.064–1.465], p=0.007). Path analysis demonstrated that increased AmgyA mediated the effect of both anxiety and depression on DVT (log OR [95% CI]: 0.0256 (0.0009–0.0592), p&amp;lt;0.05 and 0.0314 (0.0033 to 0.0718), p&amp;lt;0.05 respectively, Figure 1). Conclusion Anxiety disorders and depression associate with an increased risk of DVT via a mechanism that includes heightened stress-related neurobiological activity. Future studies should evaluate whether modulating this neural pathway could reduce the incidence of DVT. Funding Acknowledgement Type of funding sources: None.

Increased Ventromedial Prefrontal Cortex Activity in Adolescence Benefits Prosocial Reinforcement Learning

Learning which of our behaviors benefit others contributes to forming social relationships. An important period for the development of (pro)social behavior is adolescence, which is characterized by transitions in social connections. It is, however, unknown how learning to benefit others develops across adolescence and what the underlying cognitive and neural mechanisms are. In this functional neuroimaging study, we assessed learning for self and others (i.e., prosocial learning) and the concurring neural tracking of prediction errors across adolescence (ages 9–21, N = 74). Participants performed a two-choice probabilistic reinforcement learning task in which outcomes resulted in monetary consequences for themselves, an unknown other, or no one. Participants from all ages were able to learn for themselves and others, but learning for others showed a more protracted developmental trajectory. Prediction errors for self were observed in the ventral striatum and showed no age-related differences. However, prediction error coding for others showed an age-related increase in the ventromedial prefrontal cortex. These results reveal insights into the computational mechanisms of learning for others across adolescence, and highlight that learning for self and others show different age-related patterns.

Neural mechanisms of intimate partner aggression

People sometimes hurt those they profess to love; yet our understanding of intimate partner aggression (IPA) and its causes remains incomplete. We examined brain activity using functional magnetic resonance imaging (fMRI) in an ethnically and racially diverse sample of 50 female-male, monogamous romantic couples as they completed an aggression task against their intimate partner, a close friend, and a different-sex stranger. Laboratory and real-world IPA were uniquely associated with altered activity within and connectivity between cortical midline structures that subserve social cognition and the computation of value. Men’s IPA most corresponded to lower posterior cingulate reactivity during provocation and women’s IPA most corresponded to lower ventromedial prefrontal cortex activity during IPA itself. Actor-partner independence modeling suggested women’s IPA may correspond to their male partner’s neural reactivity to provocation. Broadly, these findings highlight the importance of self-regulatory functions of the medial cortex and away from effortful inhibition subserved by dorsolateral cortices.

A Neurocomputational Model for Intrinsic Reward.

Standard economic indicators provide an incomplete picture of what we value both as individuals and as a society. Furthermore, canonical macroeconomic measures, such as GDP, do not account for non-market activities (e.g., cooking, childcare) that nevertheless impact well-being. Here, we introduce a computational tool that measures the affective value of experiences (e.g., playing a musical instrument without errors). We go on to validate this tool with neural data, using fMRI to measure neural activity in male and female human subjects performing a reinforcement learning task that incorporated periodic ratings of subjective affective state. Learning performance determined level of payment (i.e., extrinsic reward). Crucially, the task also incorporated a skilled performance component (i.e., intrinsic reward) which did not influence payment. Both extrinsic and intrinsic rewards influenced affective dynamics, and their relative influence could be captured in our computational model. Individuals for whom intrinsic rewards had a greater influence on affective state than extrinsic rewards had greater ventromedial prefrontal cortex (vmPFC) activity for intrinsic than extrinsic rewards. Thus, we show that computational modeling of affective dynamics can index the subjective value of intrinsic relative to extrinsic rewards, a “computational hedonometer” that reflects both behavior and neural activity that quantifies the affective value of experience.SIGNIFICANCE STATEMENT Traditional economic indicators are increasingly recognized to provide an incomplete picture of what we value as a society. Standard economic approaches struggle to accurately assign values to non-market activities that nevertheless may be intrinsically rewarding, prompting a need for new tools to measure what really matters to individuals. Using a combination of neuroimaging and computational modeling, we show that despite their lack of instrumental value, intrinsic rewards influence subjective affective state and ventromedial prefrontal cortex (vmPFC) activity. The relative degree to which extrinsic and intrinsic rewards influence affective state is predictive of their relative impacts on neural activity, confirming the utility of our approach for measuring the affective value of experiences and other non-market activities in individuals.

Impact of exogenous estradiol on task-based and resting-state neural signature during and after fear extinction in healthy women.

Fluctuations of endogenous estrogen modulates fear extinction, but the influence of exogenous estradiol is less studied. Moreover, little focus has been placed on the impact of estradiol on broad network connectivity beyond the fear extinction circuit. Here, we examined the effect of acute exogenous estradiol administration on fear extinction-induced brain activation, whole-brain functional connectivity (FC) during the fear extinction task and post-extinction resting-state. Ninety healthy women (57 using oral contraceptives [OC], 33 naturally cycling [NC]) were fear conditioned on day 1. They ingested an estradiol or placebo pill prior to extinction learning on day 2 (double-blind design). Extinction memory was assessed on day 3. Task-based functional MRI data were ascertained on days 2 and 3 and resting-state data were collected post-extinction on day 2 and pre-recall on day 3. Estradiol administration significantly modulated the neural signature associated with fear extinction learning and memory, consistent with prior studies. Importantly, estradiol administration induced significant changes in FC within multiple networks, including the default mode and somatomotor networks during extinction learning, post-extinction, and during extinction memory recall. Exploratory analyses revealed that estradiol impacted ventromedial prefrontal cortex (vmPFC) activation and FC differently in the NC and OC women. The data implicate a more diffused and significant effect of acute estradiol administration on multiple networks. Such an effect might be beneficial to modulating attention and conscious processes in addition to engaging neural processes associated with emotional learning and memory consolidation.