Mike Angstadt

Amygdala–frontal connectivity during emotion regulation

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.

Beyond threat: amygdala reactivity across multiple expressions of facial affect.

The amygdala has been consistently isolated as a key neural substrate for processing facial displays of affect. Recent evidence from human lesion and functional neuroimaging studies have begun to challenge the notion that the amygdala is reserved for signals of threat (fear/anger). We performed a 4 T fMRI study in which 20 subjects viewed a contemporary set of photographs displaying 6 different facial expressions (fearful, disgusted, angry, sad, neutral, happy) while performing a task with minimal cognitive demand. Across subjects, the left amygdala was activated by each face condition separately, and its response was not selective for any particular emotion category. These results challenge the notion that the amygdala has a specialized role in processing certain emotions and suggest that the amygdala may have a more general-purpose function in processing salient information from faces.

Oxytocin Attenuates Amygdala Reactivity to Fear in Generalized Social Anxiety Disorder

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.

Cannabinoid Modulation of Amygdala Reactivity to Social Signals of Threat in Humans

The cannabinoid (CB) system is a key neurochemical mediator of anxiety and fear learning in both animals and humans. The anxiolytic effects of Δ9-tetrahydrocannabinol (THC), the primary psychoactive ingredient in cannabis, are believed to be mediated through direct and selective agonism of CB1 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.

Preliminary evidence of white matter abnormality in the uncinate fasciculus in generalized social anxiety disorder.

BACKGROUND Individuals with generalized social anxiety disorder (GSAD) exhibit exaggerated amygdala reactivity to aversive social stimuli. These findings could be explained by microstructural abnormalities in white matter (WM) tracts that connect the amygdala and prefrontal cortex, which is known to modulate the amygdalas response to threat. The goal of this study was to investigate brain frontal WM abnormalities using diffusion tensor imaging (DTI) in patients with social anxiety disorder. METHODS A Turboprop DTI sequence was used to acquire diffusion tensor images in 30 patients with GSAD and 30 matched healthy control subjects. Fractional anisotropy, an index of axonal organization, within WM was quantified in individual subjects, and an automated voxel-based, whole-brain method was used to analyze group differences. RESULTS Compared with healthy control subjects, patients had significantly lower fractional anisotropy localized to the right uncinate fasciculus WM near the orbitofrontal cortex. There were no areas of higher fractional anisotropy in patients than controls. CONCLUSIONS These findings point to an abnormality in the uncinate fasciculus, the major WM tract connecting the frontal cortex to the amygdala and other limbic temporal regions, in GSAD, which could underlie the aberrant amygdala-prefrontal interactions resulting in dysfunctional social threat processing in this illness.

Altered amygdala resting-state functional connectivity in post-traumatic stress disorder.

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.

Altered function and connectivity of the medial frontal cortex in pediatric obsessive compulsive disorder

BACKGROUND Exaggerated concern for correct performance has been linked to hyperactivity of the medial frontal cortex (MFC) in adult obsessive-compulsive disorder (OCD), but the role of the MFC during the early course of illness remains poorly understood. We tested whether hyperactive MFC-based performance monitoring function relates to altered MFC connectivity within task control and default mode networks in pediatric patients. METHODS Eighteen pairs of OCD and matched healthy youth underwent functional magnetic resonance imaging during performance monitoring and at rest. Task-related hyperactivations in the posterior and ventral MFC were used as seeds for connectivity analyses during task and resting state. RESULTS In posterior MFC, patients showed greater activation of dorsal anterior cingulate cortex (dACC) than control subjects, with greater activation predicting worse performance. In ventral MFC, control subjects exhibited deactivation, whereas patients activated this region. Compared with control subjects, patients showed increased dACC-ventral MFC connectivity during task and decreased dACC-right anterior operculum and ventral MFC-posterior cingulate connectivity during rest. CONCLUSIONS Excessive activation and increased interactions of posterior and ventral MFC during performance monitoring may combine with reduced resting state connectivity of these regions within networks for task control and default mode to reflect early markers of OCD. Alteration of reciprocal interactions between these networks could potentiate the intrusion of ventral MFC-based affectively laden, self-referential thoughts, while disrupting posterior MFC-based performance-monitoring function in young patients.

Developmental Alterations of Frontal-Striatal-Thalamic Connectivity in Obsessive-Compulsive Disorder

OBJECTIVE Pediatric obsessive-compulsive disorder is characterized by abnormalities of frontal-striatal-thalamic circuitry that appear near illness onset and persist over its course. Distinct frontal-striatal-thalamic loops through cortical centers for cognitive control (anterior cingulate cortex) and emotion processing (ventral medial frontal cortex) follow unique maturational trajectories, and altered connectivity within distinct loops may be differentially associated with OCD at specific stages of development. METHOD Altered development of striatal and thalamic connectivity to medial frontal cortex was tested in 60 OCD patients compared with 61 healthy control subjects at child, adolescent, and adult stages of development, using resting-state functional connectivity MRI. RESULTS OCD in the youngest patients was associated with reduced connectivity of dorsal striatum and medial dorsal thalamus to rostral and dorsal anterior cingulate cortex, respectively. Increased connectivity of dorsal striatum to ventral medial frontal cortex was observed in patients at all developmental stages. In child patients, reduced connectivity between dorsal striatum and rostral anterior cingulate cortex correlated with OCD severity. CONCLUSIONS Frontal-striatal-thalamic loops involved in cognitive control are hypoconnected in young patients near illness onset, whereas loops implicated in emotion processing are hyperconnected throughout the illness.

Medial frontal hyperactivity to sad faces in generalized social anxiety disorder and modulation by oxytocin

Generalized social anxiety disorder (GSAD) is associated with heightened limbic and prefrontal activation to negative social cues conveying threat (e.g. fearful faces), but less is known about brain response to negative non-threatening social stimuli. The neuropeptide oxytocin (Oxt) has been shown to attenuate (and normalize) fear-related brain activation and reactivity to emotionally negative cues. Here, we examined the effects of intranasal Oxt on cortical activation to non-threatening sad faces in patients with GSAD and matched controls (Con). In a double-blind placebo-controlled within-subjects design, the cortical activation to sad and happy (vs. neutral) faces was examined using functional magnetic resonance imaging following acute intranasal administration of 24 IU Oxt and placebo. Relative to the Con group, GSAD patients exhibited heightened activity to sad faces in the medial prefrontal cortex (mPFC/BA 10) extending into anterior cingulate cortex (ACC/BA 32). Oxt significantly reduced this heightened activation in the mPFC/ACC regions to levels similar to that of controls. These findings suggest that GSAD is associated with cortical hyperactivity to non-threatening negative but not positive social cues and that Oxt attenuates this exaggerated cortical activity. The modulation of cortical activity by Oxt highlights a broader mechanistic role of this neuropeptide in modulating socially negative cues in GSAD.

Corticolimbic brain reactivity to social signals of threat before and after sertraline treatment in generalized social phobia

BACKGROUND Generalized social phobia (gSP), also known as generalized social anxiety disorder, is characterized by excessive fear of scrutiny by others and pervasive avoidance of social interactions. Pathophysiologic models of gSP implicate exaggerated reactivity of the amygdala and insula in response to social evaluative threat, making them plausible targets for treatment. Although selective serotonin reuptake inhibitor (SSRI) treatment is known to be an effective treatment, little is known about the mechanism through which these agents exert their anxiolytic effects at a brain level in gSP. METHODS We acquired functional magnetic resonance imaging data of brain response to social signals of threat (fearful/angry faces) in 21 gSP patients before and after they completed 12 weeks of open-label treatment with the SSRI sertraline. For comparison, 19 healthy control (HC) subjects also underwent two functional magnetic resonance imaging scans, 12 weeks apart. RESULTS Whole-brain voxelwise analysis of variance revealed significant Group×Time interactions in the amygdala and the ventral medial prefrontal cortex. Follow-up analyses showed that treatment in gSP subjects reduced amygdala reactivity to fearful faces (which was exaggerated relative to HCs before treatment) and enhanced ventral medial prefrontal cortex activation to angry faces (which was attenuated relative to HCs before treatment). However, these brain changes were not significantly related to social anxiety symptom improvement. CONCLUSIONS SSRI treatment response in gSP is associated with changes in a discrete limbic-paralimbic brain network, representing a neural mechanism through which SSRIs may exert their actions.