Age-related changes in amygdala-frontal connectivity during emotional face processing from childhood into young adulthood.

The ability to process and respond to emotional facial expressions is a critical skill for healthy social and emotional development. There has been growing interest in understanding the neural circuitry underlying development of emotional processing, with previous research implicating functional connectivity between amygdala and frontal regions. However, existing work has focused on threatening emotional faces, raising questions regarding the extent to which these developmental patterns are specific to threat or to emotional face processing more broadly. In the current study, we examined age-related changes in brain activity and amygdala functional connectivity during an fMRI emotional face matching task (including angry, fearful, and happy faces) in 61 healthy subjects aged 7-25 years. We found age-related decreases in ventral medial prefrontal cortex activity in response to happy faces but not to angry or fearful faces, and an age-related change (shifting from positive to negative correlation) in amygdala-anterior cingulate cortex/medial prefrontal cortex (ACC/mPFC) functional connectivity to all emotional faces. Specifically, positive correlations between amygdala and ACC/mPFC in children changed to negative correlations in adults, which may suggest early emergence of bottom-up amygdala excitatory signaling to ACC/mPFC in children and later development of top-down inhibitory control of ACC/mPFC over amygdala in adults. Age-related changes in amygdala-ACC/mPFC connectivity did not vary for processing of different facial emotions, suggesting changes in amygdala-ACC/mPFC connectivity may underlie development of broad emotional processing, rather than threat-specific processing. Hum Brain Mapp 37:1684-1695, 2016. © 2016 Wiley Periodicals, Inc.

Reduced default mode network connectivity following combat trauma.

Recent studies show decreased functional connectivity in the default mode network (DMN) in PTSD; however, few have directly examined combat trauma specifically. There is limited understanding of how combat itself may affect the DMN. Some literature suggests that trauma exposure, rather than PTSD, can disrupt the DMN. To further elucidate the effect of trauma and PTSD on the DMN, we investigated DMN functional connectivity during the resting-state in veterans with PTSD, combat-exposed controls, and never-traumatized healthy controls. Results revealed that DMN connectivity was reduced in veterans exposed to combat trauma with and without PTSD compared to healthy civilian controls. Specifically, both groups of veterans demonstrated weaker connectivity within a network involving the precuneus, medial prefrontal cortex (mPFC) and right superior parietal lobule regardless of whether the mPFC or precuneus was chosen as a seed region. Findings suggest that the experience of trauma, rather than the pathology of PTSD, may be related to DMN changes.

Prefrontal control and predictors of cognitive behavioral therapy response in social anxiety disorder.

Generalized social anxiety disorder (gSAD) is associated with aberrant anterior cingulate cortex (ACC) response to threat distractors. Perceptual load has been shown to modulate ACC activity such that under high load, when demands on processing capacity is restricted, individuals with gSAD exhibit compensatory activation to threat distractors yet under low load, there is evidence of reduced activation. It is not known if neural predictors of response to cognitive behavioral therapy (CBT), based on such emotional conflict resolution, interact with demands on controlled processes. Prior to CBT, 32 patients with gSAD completed an fMRI task involving a target letter in a string of identical targets (low perceptual load) or a target letter in a mixed letter string (high perceptual load) superimposed on fearful, angry and neutral face distractors. Whole-brain voxel-wise analyses revealed better CBT outcome was predicted by more frontopartial activity that included dorsal ACC (dACC) and insula to threat (vs neutral) distractors during high, but not low, perceptual load. Psychophysiological interaction analysis with dACC as the seed region revealed less connectivity with dorsolateral prefrontal cortex to threat distractors during high load. Results indicate patients with less regulatory capability when demands on higher-order control are great may benefit more from CBT.

Emotion Regulatory Brain Function and SSRI Treatment in PTSD: Neural Correlates and Predictors of Change.

Posttraumatic stress disorder (PTSD)-a chronic, debilitating condition, broadly characterized by emotion dysregulation-is prevalent among US military personnel who have returned from Operations Enduring Freedom (OEF) and Iraqi Freedom (OIF). Selective serotonin reuptake inhibitors (SSRIs) are a first-line treatment for PTSD, but treatment mechanisms are unknown and patient response varies. SSRIs may exert their effects by remediating emotion regulatory brain activity and individual differences in patient response might be explained, in part, by pre-treatment differences in neural systems supporting the downregulation of negative affect. Thirty-four OEF/OIF veterans, 17 with PTSD and 17 without PTSD underwent 2 functional magnetic resonance imaging scans 12 weeks apart. At each scan, they performed an emotion regulation task; in the interim, veterans with PTSD were treated with the SSRI, paroxetine. SSRI treatment increased activation in both the left dorsolateral prefrontal cortex (PFC) and supplementary motor area (SMA) during emotion regulation, although only change in the SMA over time occurred in veterans with PTSD and not those without PTSD. Less activation of the right ventrolateral PFC/inferior frontal gyrus during pre-treatment emotion regulation was associated with greater reduction in PTSD symptoms with SSRI treatment, irrespective of pre-treatment severity. Patients with the least recruitment of prefrontal emotion regulatory brain regions may benefit most from treatment with SSRIs, which appear to augment activity in these regions.

Frontolimbic Morphometric Abnormalities in Intermittent Explosive Disorder and Aggression.

BACKGROUND: Converging evidence from neuroimaging studies suggests that impulsive aggression, the core behavior in the DSM-5 diagnosis intermittent explosive disorder (IED), is regulated by frontolimbic brain structures, particularly orbitofrontal cortex, ventral medial prefrontal cortex, anterior cingulate cortex, amygdala, insula, and uncus. Despite this evidence, no brain volumetric studies of IED have been reported as yet. This study was conducted to test the hypothesis that gray matter volume in frontolimbic brain structures of subjects with IED is lower than in healthy subjects and subjects with other psychiatric conditions. METHODS: High-resolution magnetic resonance imaging scans using a three-dimensional magnetization-prepared rapid acquisition gradient-echo sequence were performed in 168 subjects (n = 53 healthy control subjects, n = 58 psychiatric controls, n = 57 subjects with IED). Imaging data were analyzed by voxel-based morphometry methods employing Statistical Parametric Mapping (SPM8) software. RESULTS: Gray matter volume was found to be significantly lower in subjects with IED compared with healthy control subjects and psychiatric controls in orbitofrontal cortex, ventral medial prefrontal cortex, anterior cingulate cortex, amygdala, insula, and uncus. These differences were not due to various confounding factors or to comorbidity with other disorders previously reported to have reduced gray matter volume. Gray matter volume in these areas was significantly and inversely correlated with measures of aggression. CONCLUSIONS: Reductions in the gray matter volume of frontolimbic structures may be a neuronal characteristic of impulsively aggressive individuals with DSM-5 IED. These data suggest an anatomic correlate accounting for functional deficits in social-emotional information processing in these individuals.

Neurostructural abnormalities in pediatric anxiety disorders.

Functional neuroimaging studies have consistently demonstrated abnormalities in fear and threat processing systems in youth with anxiety disorders; however, the structural neuroanatomy of these systems in children and adolescents remains largely unknown. Using voxel-based morphometry (VBM), gray matter volumes were compared between 38 medication-free patients with anxiety disorders (generalized anxiety disorder; social phobia; separation anxiety disorder, mean age: 14.4±3 years) and 27 comparison subjects (mean age: 14.8±4 years). Compared to healthy subjects, youth with anxiety disorders had larger gray matter volumes in the dorsal anterior cingulate and had decreased gray matter volumes in the inferior frontal gyrus (ventrolateral prefrontal cortex), postcentral gyrus, and cuneus/precuneus. These data suggest the presence of structural differences in regions previously implicated in the processing and regulation of fear in pediatric patients with anxiety disorders.

Neural correlates of individual differences in fear learning.

Variability in fear conditionability is common, and clarity regarding the neural regions responsible for individual differences in fear conditionability could uncover brain-based biomarkers of resilience or vulnerability to trauma-based psychopathologies (e.g., post-traumatic stress disorder). In recent years, neuroimaging work has yielded a detailed understanding of the neural mechanisms underlying fear conditioning common across participants, however only a minority of studies have investigated the brain basis of inter-individual variation in fear learning. Moreover, the majority of these studies have employed small sample sizes (mean n=17; range n=5-27) and all have failed to meet the minimum recommended sample size for functional magnetic resonance imaging (fMRI) studies of individual differences. Here, using fMRI, we analyzed blood-oxygenation level dependent (BOLD) response recorded simultaneously with skin conductance response (SCR) and ratings of unconditioned stimulus (US) expectancy in 49 participants undergoing Pavlovian fear conditioning. On average, participants became conditioned to the conditioned stimulus (CS+; higher US expectancy ratings and SCR for the CS+ compared to the unpaired conditioned stimulus, CS-); the CS+ also robustly increased activation in the bilateral insula. Amygdala activation was revealed from a regression analysis that incorporated individual differences in fear conditionability (i.e., a between-subjects regressor of mean CS+>CS- SCR). By replicating results observed using much smaller sample sizes, the results confirm that variation in amygdala reactivity covaries with individual differences in fear conditionability. The link between behavior (SCR) and brain (amygdala reactivity) may be a putative endophenotype for the acquisition of fear memories.

Prefrontal engagement by cognitive reappraisal of negative faces.

Cognitive reappraisal has been associated with increased activation in prefrontal cortex (PFC) and cingulate regions implicated in cognitive control and affect regulation. To date, neuroimaging studies of reappraisal have primarily used emotionally evocative scenes, and it remains unclear whether the same cognitive strategy applied to emotional facial expressions would involve similar or different neural underpinnings. The present study used fMRI to examine brain activation during cognitive reappraisal of negatively valenced facial expressions relative to passive viewing of negative and neutral facial expressions. Twenty-two healthy adults completed a cognitive reappraisal task comprised of three different conditions (Look-Neutral, Maintain-Negative, Reappraise-Negative). Results indicated that reappraisal was associated with a decrease in negative affect and engagement of PFC brain regions implicated in cognitive control and affect regulation (DLPFC, mPFC, and VLPFC). Furthermore, individual differences in habitual reappraisal use were associated with greater DLPFC and mPFC activation, while suppression use was associated with greater amygdala activation. The present study provides preliminary evidence that facial expressions are effective alternative 'targets' of prefrontal engagement during cognitive reappraisal. These findings are particularly relevant for future research probing the neural bases of emotion regulation in populations for whom aversive scenes may be less appropriate (e.g., children) and illnesses in which aberrant responses to social signals of threat and negative feedback are cardinal phenotypes.

Oxytocin modulation of amygdala functional connectivity to fearful faces in generalized social anxiety disorder.

The neuropeptide oxytocin (OXT) is thought to attenuate anxiety by dampening amygdala reactivity to threat in individuals with generalized social anxiety disorder (GSAD). Because the brain is organized into networks of interconnected areas, it is likely that OXT impacts functional coupling between the amygdala and other socio-emotional areas of the brain. Therefore, the aim of the current study was to examine the effects of OXT on amygdala functional connectivity during the processing of fearful faces in GSAD subjects and healthy controls (HCs). In a randomized, double-blind, placebo (PBO)-controlled, within-subjects design, 18 HCs and 17 GSAD subjects performed a functional magnetic resonance imaging task designed to probe amygdala response to fearful faces following acute intranasal administration of PBO or OXT. Functional connectivity between the amygdala and the rest of the brain was compared between OXT and PBO sessions using generalized psychophysiological interaction analyses. Results indicated that within individuals with GSAD, but not HCs, OXT enhanced functional connectivity between the amygdala and the bilateral insula and middle cingulate/dorsal anterior cingulate gyrus during the processing of fearful faces. These findings suggest that OXT may have broad pro-social implications such as enhancing the integration and modulation of social responses.

Aberrant amygdala functional connectivity at rest in pediatric anxiety disorders.

BACKGROUND: Childhood onset of anxiety disorders is associated with greater functional impairment and burden across the lifespan. Recent work suggests that generalized anxiety disorder (GAD) is characterized by dysfunctional connectivity in amygdala-based circuits at rest in adolescents, consistent with adults. However, neural mechanisms underlying a broad spectrum of often-comorbid anxiety disorders in children remains unclear and understudied. The current study examines amygdala functional connectivity at rest in children and adolescents across comorbid anxiety disorders (ADs) including youth with primary diagnoses of GAD and social phobia (SP). RESULTS: Compared with healthy controls (HCs), AD youth exhibited hyperconnectivity between the right amygdala and the insula and hypoconnectivity between the left amygdala and the ventromedial prefrontal cortex (vmPFC) and posterior cingulate cortex (PCC). Within the AD group, connectivity was not correlated with anxiety severity and only the amygdala-PCC connectivity was positively correlated with age. CONCLUSIONS: Our findings indicate that youth with comorbid ADs demonstrate aberrant connectivity in the anterior limbic network (ALN) as well as the PCC at rest. This extends upon previous work suggesting alterations in amygdala circuits underlying fear learning, emotion regulation, and the processing of interoceptive states. Presence of these findings within this young, comorbid sample points to underlying common mechanisms across ADs and illuminates future targets for prevention and intervention in childhood.

Cannabinoid modulation of amygdala subregion functional connectivity to social signals of threat.

BACKGROUND: Δ(9)-Tetrahydrocannabinol has been shown to modulate anxiety and facilitate the extinction of fear by inhibiting amygdala reactivity. Since functional coupling between the amygdala and prefrontal cortex is implicated in affective processes, it is possible that Δ(9)-tetrahydrocannabinol affects amygdala-prefrontal cortex functional connectivity in ways that differ across amygdala subregions: basolateral, centromedial, and superficial. METHODS: The aim of the study was to examine the effects of Δ(9)-tetrahydrocannabinol on functional connectivity between amygdala subregions and the prefrontal cortex during socio-emotional threat in healthy adults using a double-blind, placebo-controlled, within-subjects design. Sixteen subjects completed a functional magnetic resonance imaging task designed to probe amygdala responses to social threat. Amygdala subregion-prefrontal cortex functional connectivity was compared between Δ(9)-tetrahydrocannabinol and placebo using generalized psychophysiological interaction analyses. RESULTS: Findings indicated that Δ(9)-tetrahydrocannabinol enhanced basolateral and superficial amygdala connectivity to the rostral anterior cingulate/medial prefrontal cortex. CONCLUSION: These effects, including Δ(9)-tetrahydrocannabinol's potential ability to reduce threat perception or enhance socio-emotional regulation, may help understand the neurocircuitry of affect.

Resting state amygdala-prefrontal connectivity predicts symptom change after cognitive behavioral therapy in generalized social anxiety disorder.

BACKGROUND: Aberrant amygdala-prefrontal interactions at rest and during emotion processing are implicated in the pathophysiology of generalized social anxiety disorder (gSAD), a common disorder characterized by fears of potential scrutiny. Cognitive behavioral therapy (CBT) is first-line psychotherapy for gSAD and other anxiety disorders. While CBT is generally effective, there is a great deal of heterogeneity in treatment response. To date, predictors of success in CBT for gSAD include reduced amygdala reactivity and increased activity in prefrontal regulatory regions (e.g., anterior cingulate cortex, "ACC") during emotion processing. However, studies have not examined whether tonic (i.e., at rest) coupling of amygdala and these prefrontal regions also predict response to CBT. RESULTS: Twenty-one patients with gSAD participated in resting-state functional magnetic resonance imaging (fMRI) before 12 weeks of CBT. Overall, symptom severity was significantly reduced after completing CBT; however, the patients varied considerably in degree of symptom change. Whole-brain voxel-wise findings showed symptom improvement after CBT was predicted by greater right amygdala-pregenual ACC ("pgACC") connectivity and greater left amygdala-pgACC coupling encompassing medial prefrontal cortex. In support of their predictive value, area under receiver operating characteristic curve was significant for the left and right amygdala-pgACC in relation to treatment responders. CONCLUSIONS: Improvement after CBT was predicted by enhanced resting-state bilateral amygdala-prefrontal coupling in gSAD. Preliminary results suggest baseline individual differences in a fundamental circuitry that may underlie emotion regulation contributed to variation in symptom change after CBT. Findings offer a new approach towards using a biological measure to foretell who will most likely benefit from CBT. In particular, the departure from neural predictors based on illness-relevant stimuli (e.g., socio-emotional stimuli in gSAD) permits the development of biomarkers that reflect commonalities in the neurobiology of anxiety and mood disorders.

Opioid modulation of resting-state anterior cingulate cortex functional connectivity.

Individuals misuse oxycodone, a widely prescribed opioid analgesic, in part to self-medicate physical and emotional pain. Physical and emotional pain is thought to be represented in the brain by a 'pain matrix,' consisting of the insula, thalamus, and somatosensory cortices, with processing of the affective dimension of pain in the dorsal and rostral anterior cingulate cortex (ACC). The current study examined oxycodone's effects on resting-state functional connectivity between the dorsal ACC, rostral ACC, and other regions of the pain matrix using functional magnetic resonance imaging (fMRI). In a within-subjects, randomized, double-blind, placebo-controlled, dose-response design, 14 healthy subjects completed a resting-state scan following ingestion of placebo, 10 mg, or 20 mg of oxycodone. Functional correlations between the dorsal and rostral ACC seed regions and the pain matrix were examined and compared across sessions. Both doses of oxycodone reduced functional coupling between the dorsal ACC and bilateral anterior insula/putamen and the rostral ACC and right insula relative to placebo (no differences between doses). The findings do not withstand correction for multiple comparisons, and thus should be considered preliminary. However, they are consistent with the idea that oxycodone may produce its physical and emotional 'analgesic' effects through disruption of ACC-insula and ACC-putamen connectivity.

Perceptual load modulates anterior cingulate cortex response to threat distractors in generalized social anxiety disorder.

Generalized social anxiety disorder (gSAD) is associated with impoverished anterior cingulate cortex (ACC) engagement during attentional control. Attentional Control Theory proposes such deficiencies may be offset when demands on resources are increased to execute goals. To test the hypothesis attentional demands affect ACC response 23 patients with gSAD and 24 matched controls performed an fMRI task involving a target letter in a string of identical targets (low load) or a target letter in a mixed letter string (high load) superimposed on fearful, angry, and neutral face distractors. Regardless of load condition, groups were similar in accuracy and reaction time. Under low load gSAD patients showed deficient rostral ACC recruitment to fearful (vs. neutral) distractors. For high load, increased activation to fearful (vs. neutral) distractors was observed in gSAD suggesting a compensatory function. Results remained after controlling for group differences in depression level. Findings indicate perceptual demand modulates ACC in gSAD.

Serotonin transporter gene alters insula activity to threat in social anxiety disorder.

Amygdala and insula hyper-reactivity to threat is implicated in social anxiety disorder (SAD) yet inconsistencies in activation have been reported. One source of variance are individual differences in 5-HTTLPR genotype where the short (S), relative to long (L) allele, corresponds with greater amygdala activation. However, the impact of genotype on insula to threat in SAD is not known. During functional MRI, 34 SAD patients and 28 healthy controls completed a perceptual assessment task comprising angry, fear, and happy faces. Results showed no diagnostic group differences in limbic/paralimbic regions but within SAD, greater insula, but not amygdala, activation to fearful faces was observed in patients with SS genotype compared with LaLa genotype. Findings indicate genotype influenced insula activation to threat in SAD.

Neural response to reward anticipation in those with depression with and without panic disorder.

BACKGROUND: One of the hallmark features of major depressive disorder (MDD) is reduced reward anticipation. There have been mixed findings in the literature as to whether reward anticipation deficits in MDD are related to diminished mesolimbic activation and/or enhanced dorsal anterior cingulate activation (dACC). One of the reasons for these mixed findings is that these studies have typically not addressed the role of comorbid anxiety, a class of disorders which frequently co-occur with depression and have a common neurobiology. METHODS: The aim of the current study was to examine group differences in neural responses to reward anticipation in 40 adults with either: (1) current MDD with no lifetime diagnosis of an anxiety disorder (MDD-only), (2) current MDD with comorbid panic disorder (MDD-PD), or (3) no lifetime diagnosis of psychopathology. All participants completed a passive slot machine task during a functional magnetic resonance imaging (fMRI) scan. RESULTS: Analyses indicated that there were no group differences in activation of mesolimbic reward regions; however, the MDD-only group exhibited greater dACC activation during the anticipation of rewards compared with the healthy controls and the comorbid MDD-PD group (who did not differ from each other). LIMITATIONS: The sample size was small which limits generalizability. CONCLUSIONS: These findings provide preliminary support for the role of hyperactive dACC functioning in reduced reward anticipation in MDD. They also indicate that comorbid anxiety may alter the association between MDD and neural responding to reward anticipation.

Effects of oxycodone on brain responses to emotional images.

RATIONALE: Evidence from animal and human studies suggests that opiate drugs decrease emotional responses to negative stimuli and increase responses to positive stimuli. Such emotional effects may motivate misuse of oxycodone (OXY), a widely abused opiate. Yet, we know little about how OXY affects neural circuits underlying emotional processing in humans. OBJECTIVE: We examined effects of OXY on brain activity during presentation of positive and negative visual emotional stimuli. We predicted that OXY would decrease amygdala activity to negative stimuli and increase ventral striatum (VS) activity to positive stimuli. Secondarily, we examined the effects of OXY on other emotional network regions on an exploratory basis. METHODS: In a three-session study, healthy adults (N = 17) received placebo, 10 and 20 mg OXY under counterbalanced, double-blind conditions. At each session, participants completed subjective and cardiovascular measures and underwent functional MRI (fMRI) scanning while completing two emotional response tasks. RESULTS: Our emotional tasks reliably activated emotional network areas. OXY produced subjective effects but did not alter either behavioral responses to emotional stimuli or activity in our primary areas of interest. OXY did decrease right medial orbitofrontal cortex (MOFC) responses to happy faces. CONCLUSIONS: Contrary to our expectations, OXY did not affect behavioral or neural responses to emotional stimuli in our primary areas of interest. Further, the effects of OXY in the MOFC would be more consistent with a decrease in value for happy faces. This may indicate that healthy adults do not receive emotional benefits from opiates, or the pharmacological actions of OXY differ from other opiates.

Crack cocaine use impairs anterior cingulate and prefrontal cortex function in women with HIV infection.

Crack cocaine use is associated with impaired verbal memory in HIV-infected women more than uninfected women. To understand the neural basis for this impairment, this study examined the effects of crack cocaine use on activation of the prefrontal cortex (PFC) and strategic encoding during a verbal memory task in HIV-infected women. Three groups of HIV-infected women from the Chicago Consortium of the Women's Interagency HIV Study were compared: current users of crack cocaine (n = 10), former users of cocaine (n = 11), and women who had never used cocaine (n = 9). Participants underwent functional magnetic resonance imaging during a verbal memory task and completed a neuropsychological test of verbal memory. On the neuropsychological test, current crack users performed significantly worse than other groups on semantic clustering, a measure of strategic encoding, p < 0.05. During encoding, activation in left anterior cingulate cortex (ACC) was lower in current and former cocaine users compared to never users. During recognition, activation in bilateral PFC, specifically left dorsal medial PFC and bilateral dorsolateral PFC, was lower in current and former users compared to women who had never used cocaine. Lower activation in left dorsolateral PFC was correlated with worse performance on the recognition task, p < 0.05. The verbal learning and memory deficits associated with cocaine use in women with HIV may be partially accounted for by alterations in ACC and PFC function.

Anterior insula responds to temporally unpredictable aversiveness: an fMRI study.

A heightened sensitivity to unpredictable aversiveness is a key component of several anxiety disorders. Neuroimaging studies of unpredictable aversiveness have shown that the anterior region of the insula cortex (AIC) plays a central role in the anticipation of unpredictable aversiveness. The present study extended these findings by examining the role of the AIC in temporal unpredictability (i.e. not knowing when the stimulus will occur), a particularly critical aspect of unpredictability as it increases contextual anxiety and vigilance, given that the danger could happen 'at any time'. Nineteen healthy participants underwent functional MRI while anticipating either temporally unpredictable or predictable aversive (or neutral) images. Participants showed greater right AIC activation while anticipating unpredictable relative to predictable aversive images. In addition, activation in this region was correlated positively with self-reported individual differences in a key facet of intolerance of uncertainty (inhibitory behavior). Taken together, the present study suggests that the AIC plays an important role in the anticipation of temporally unpredictable aversiveness and may mediate key deficits in anxiety disorders.

Modulation of resting-state amygdala-frontal functional connectivity by oxytocin in generalized social anxiety disorder.

Generalized social anxiety disorder (GSAD) is characterized by aberrant patterns of amygdala-frontal connectivity to social signals of threat and at rest. The neuropeptide oxytocin (OXT) modulates anxiety, stress, and social behaviors. Recent functional neuroimaging studies suggest that these effects are mediated through OXT's effects on amygdala reactivity and/or amygdala-frontal connectivity. The aim of the current study was to examine OXT's effects on amygdala-frontal resting-state functional connectivity (rsFC) in GSAD patients and healthy controls (HCs). In a randomized, double-blind, cross-over design, 18 GSAD and 18 HC participants received intranasal OXT (24 IU or 40.32 µg) or placebo (PBO) before resting-state functional magnetic resonance imaging. In individuals with GSAD, OXT enhanced rsFC of the left and right amygdala with rostral anterior cingulate cortex (ACC)/medial prefrontal cortex (mPFC), and in doing so, reversed (ie, 'normalized') the reduced amygdala-frontal connectivity observed relative to HCs evident on PBO. Higher social anxiety severity in GSAD subjects correlated with lower amygdala-ACC/mPFC connectivity on PBO and higher social anxiety also correlated with greater enhancement in amygdala-frontal connectivity induced by OXT. These findings show that OXT modulates a neural circuit known for social threat processing and emotion regulation, suggesting a neural mechanism by which OXT may have a role in the pathophysiology and treatment of social anxiety disorder.