Successful control of affect partly depends on the capacity to modulate negative emotional responses through the use of cognitive strategies (i.e., reappraisal). Recent studies suggest the involvement of frontal cortical regions in the modulation of amygdala reactivity and the mediation of effective emotion regulation. However, within-subject inter-regional connectivity between amygdala and prefrontal cortex in the context of affect regulation is unknown. Here, using psychophysiological interaction analyses of functional magnetic resonance imaging data, we show that activity in specific areas of the frontal cortex (dorsolateral, dorsal medial, anterior cingulate, orbital) covaries with amygdala activity and that this functional connectivity is dependent on the reappraisal task. Moreover, strength of amygdala coupling with orbitofrontal cortex and dorsal medial prefrontal cortex predicts the extent of attenuation of negative affect following reappraisal. These findings highlight the importance of functional connectivity within limbic-frontal circuitry during emotion regulation.

Significance Childhood poverty has been linked to emotion dysregulation, which is further associated with negative physical and psychological health in adulthood. The current study provides evidence of prospective associations between childhood poverty and adult neural activity during effortful attempts to regulate negative emotion. Adults with lower family income at age 9 exhibited reduced ventrolateral and dorsolateral prefrontal cortex activity and failure to suppress amygdala activation at age 24. Chronic stressor exposure across childhood mediated the relations between family income at age 9 and prefrontal cortex activity. The concurrent adult income, on the other hand, was not associated with neural activity. The information on the developmental timing of poverty effects and neural mechanisms may inform early interventions aimed at reducing health disparities.

Patients with generalized social anxiety disorder (GSAD) exhibit heightened activation of the amygdala in response to social cues conveying threat (eg, fearful/angry faces). The neuropeptide oxytocin (OXT) decreases anxiety and stress, facilitates social encounters, and attenuates amygdala reactivity to threatening faces in healthy subjects. The goal of this study was to examine the effects of OXT on fear-related amygdala reactivity in GSAD and matched healthy control (CON) subjects. In a functional magnetic resonance imaging study utilizing a double-blind placebo-controlled within-subjects design, we measured amygdala activation to an emotional face matching task of fearful, angry, and happy faces following acute intranasal administration of OXT (24 IU or 40.32 μg) and placebo in 18 GSAD and 18 CON subjects. Both the CON and GSAD groups activated bilateral amygdala to all emotional faces during placebo, with the GSAD group exhibiting hyperactivity specifically to fearful faces in bilateral amygdala compared with the CON group. OXT had no effect on amygdala activity to emotional faces in the CON group, but attenuated the heightened amygdala reactivity to fearful faces in the GSAD group, such that the hyperactivity observed during the placebo session was no longer evident following OXT (ie, normalization). These findings suggest that OXT has a specific effect on fear-related amygdala activity, particularly when the amygdala is hyperactive, such as in GSAD, thereby providing a brain-based mechanism of the impact of OXT in modulating the exaggerated processing of social signals of threat in patients with pathological anxiety.

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The cannabinoid (CB) system is a key neurochemical mediator of anxiety and fear learning in both animals and humans. The anxiolytic effects of ⌬ 9 -tetrahydrocannabinol (THC), the primary psychoactive ingredient in cannabis, are believed to be mediated through direct and selective agonism of CB 1 receptors localized within the basolateral amygdala, a critical brain region for threat perception. However, little is known about the effects of THC on amygdala reactivity in humans. We used functional magnetic resonance imaging and a well validated task to probe amygdala responses to threat signals in 16 healthy, recreational cannabis users after a double-blind crossover administration of THC or placebo. We found that THC significantly reduced amygdala reactivity to social signals of threat but did not affect activity in primary visual and motor cortex. The current findings fit well with the notion that THC and other cannabinoids may have an anxiolytic role in central mechanisms of fear behaviors and provide a rationale for exploring novel therapeutic strategies that target the cannabinoid system for disorders of anxiety and social fear.

Post-traumatic stress disorder (PTSD) is often characterized by aberrant amygdala activation and functional abnormalities in corticolimbic circuitry, as elucidated by functional neuroimaging. These “activation” studies have primarily relied on tasks designed to induce region-specific, and task-dependent brain responses in limbic (e.g., amygdala) and paralimbic brain areas through the use of aversive evocative probes. It remains unknown if these corticolimbic circuit abnormalities exist at baseline or “at rest,” in the absence of fear/anxiety-related provocation and outside the context of task demands. Therefore the primary aim of the present experiment was to investigate aberrant amygdala functional connectivity patterns in combat-related PTSD patients during resting-state. Seventeen Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) veterans with combat-related PTSD (PTSD group) and 17 combat-exposed OEF/OIF veterans without PTSD [combat-exposed control (CEC) group] underwent an 8-min resting-state functional magnetic resonance imaging scan. Using an anatomically derived amygdala “seed” region we observed stronger functional coupling between the amygdala and insula in the PTSD group compared to the CEC group, but did not find group differences in amygdala–prefrontal connectivity. These findings suggest that the aberrant amygdala and insula activation to fear-evocative probes previously characterized in PTSD may be driven by an underlying enhanced connectivity between the amygdala, a region known for perceiving threat and generating fear responses, and the insula, a region known for processing the meaning and prediction of aversive bodily states. This enhanced amygdala–insula connectivity may reflect an exaggerated, pervasive state of arousal that exists outside the presence of an overt actual threat/danger. Studying amygdala functional connectivity “at rest” extends our understanding of the pathophysiology of PTSD.

Attention-deficit/hyperactivity disorder (ADHD) is among the most common psychiatric disorders of childhood, and there is great interest in understanding its neurobiological basis. A prominent neurodevelopmental hypothesis proposes that ADHD involves a lag in brain maturation. Previous work has found support for this hypothesis, but examinations have been limited to structural features of the brain (e.g., gray matter volume or cortical thickness). More recently, a growing body of work demonstrates that the brain is functionally organized into a number of large-scale networks, and the connections within and between these networks exhibit characteristic patterns of maturation. In this study, we investigated whether individuals with ADHD (age 7.2-21.8 y) exhibit a lag in maturation of the brain's developing functional architecture. Using connectomic methods applied to a large, multisite dataset of resting state scans, we quantified the effect of maturation and the effect of ADHD at more than 400,000 connections throughout the cortex. We found significant and specific maturational lag in connections within default mode network (DMN) and in DMN interconnections with two task positive networks (TPNs): frontoparietal network and ventral attention network. In particular, lag was observed within the midline core of the DMN, as well as in DMN connections with right lateralized prefrontal regions (in frontoparietal network) and anterior insula (in ventral attention network). Current models of the pathophysiology of attention dysfunction in ADHD emphasize altered DMN-TPN interactions. Our finding of maturational lag specifically in connections within and between these networks suggests a developmental etiology for the deficits proposed in these models.resting state | connectomics | default network A ttention-deficit/hyperactivity disorder (ADHD) is a serious neuropsychiatric disorder characterized by inattention, hyperactivity, and impulsivity. One influential neurodevelopmental model of the disorder posits a lag in the maturational trajectories of key features of the brain (1-4). This model has mostly been investigated by examining developmental pathways of structural features of the brain (3,(5)(6)(7)(8). In recent years, however, theorists have increasingly used resting state functional MRI (fMRI)-scanning participants in a task-free resting state-to explore the brain's functional architecture. This work has led to the recognition that the human brain is organized into several large-scale intrinsic connectivity networks (ICNs), each associated with specific neurocognitive functions (9, 10). ICNs have been shown to undergo significant maturation from childhood to early adulthood, with individual ICNs exhibiting spatially specific reliable patterns of integration (increased connectivity with age) and segregation (decreased connectivity with age) with other ICNs (11-17). These advances raise possibilities for investigating maturational lag in ADHD in the developing ICN architecture of the brain (18).Independent lines of res...

RATIONALE ±3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy’) reportedly produces unique subjective effects, including increased sociability, feelings of closeness with others, and reduced interpersonal defensiveness. Despite their apparent importance in recreational and potential psychotherapeutic use of MDMA, the defining characteristics and neurobiological mechanisms of these interpersonal effects are poorly understood. MATERIALS AND METHODS We investigated acute effects of MDMA on self-reported sociability, and neuronal activation in response to socially threatening (angry and fearful faces) and socially rewarding (happy faces) stimuli. Assessment of social threat response focused on amygdala activation, whereas assessment of social reward focused on ventral striatum activation. Healthy volunteers (N=9) reporting past ecstasy use completed three experimental sessions, receiving MDMA (0.75mg/kg, and 1.5mg/kg), and placebo (PBO) under double-blind conditions. During peak drug effects, participants underwent functional magnetic resonance imaging while viewing standardized images depicting emotional facial expressions including angry, fearful, happy and neutral expressions. They also completed standardized self-report measures of sociability. RESULTS MDMA (1.5mg/kg) increased self-reported sociability compared to MDMA (0.75mg/kg) and PBO. MDMA (1.5mg/kg) attenuated left amygdala response to angry facial expressions compared to PBO, but MDMA did not affect amygdala reactivity to fearful expressions. MDMA (0.75mg/kg) enhanced ventral striatum response to happy expressions relative to PBO. CONCLUSIONS These data present the first evidence that MDMA may increase sociability in humans both by diminishing responses to threatening stimuli and enhancing responses to rewarding social signals.