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

Cognitive behavioral therapy (CBT) is empirically supported psychotherapy for generalized social anxiety disorder (gSAD), a common, debilitating illness marked by excessive fears of negative evaluation by others [1]. CBT primarily attempts to reduce symptoms via cognitive restructuring, an emotion regulation strategy aimed at decreasing thought-related negative affect, in conjunction with exposure exercises (e.g., facing anxiety-evoking situations). While generally effective, treatment response is varied with approximately 30%–40% of patients with gSAD not fully responding to CBT [2],[3]. Findings from neuroimaging studies indicate heterogeneity in treatment outcome may relate in part to brain regions implicated in the pathophysiology of gSAD that are utilized by CBT.

Accumulating data indicate the amygdala, a key emotion processing region that mediates fear [4], plays a prominent role in gSAD. The amygdala has interconnections to prefrontal regions that down-regulate emotional reactivity (e.g., medial prefrontal cortex (mPFC); [5]). In gSAD, amygdala hyper-reactivity to salient signals has been demonstrated in addition to disturbances in regulatory regions (e.g., exaggerated or attenuated mPFC activation; [6]). Moreover, in the absence of stimuli presentation or task engagement (i.e., during rest), aberrant amygdala connectivity with prefrontal regulatory areas (e.g., anterior cingulate cortex (ACC), medial orbitofrontal cortex (mOFC)) has been observed [7]-[9]. Findings suggest phasic hyper-reactive amygdala responses to external information involve tonic disturbances in core amygdala-prefrontal circuitry [8] and that individual differences in such circuitry may factor into the likelihood of benefiting from CBT.

To date, studies of amygdala as a brain-based marker in predicting CBT response in gSAD appear to be limited to emotion perception tasks, and results have been mixed. For example, we recently showed less pre-CBT amygdala activity to emotional faces predicted CBT success [10]; however, other emotion processing studies of gSAD have not revealed amygdala effects [11],[12]. Regarding prefrontal regions as predictors, we have observed a positive link between dorsal ACC and mOFC activity in gSAD during emotion processing and symptom improvement in CBT [10],[12] even in the absence of amygdala findings [12]. However, it is not clear whether amygdala response contributed to symptom change as regions were examined in isolation as opposed to nodes in a network.

A means of increasing our understanding of amygdala-based circuitry as a biomarker in predicting who will likely respond to CBT is with resting-state functional MRI (rs-fMRI). An advantage of rs-fMRI is that it examines fundamental networks that are task independent but may underlie emotion and regulatory processes in the unprovoked state [13]. Therefore, the objective of this study was to use pre-CBT rs-fMRI to investigate the relationship between amygdala-prefrontal coupling and CBT success in gSAD. Based on the literature [10],[12], we hypothesized greater rs-fMRI amygdala-ACC or amygdala-mOFC connectivity would correspond with CBT response.

As hypothesized, clinical improvement following CBT in the patients with gSAD was predicted by greater pre-treatment amygdala connectivity with prefrontal regions implicated in controlling emotion. Specifically, greater symptom reduction was foretold by increased pre-CBT right amygdala-pgACC and left amygdala-pgACC/mPFC coupling, a circuit involved in emotion processing and regulation [25],[26]. In support of its predictive capacity, ROC results pertaining to CBT responder based on a CGI-I cutoff were also significant. Pointing to the potential relevance of the circuit as a brain predictor and/or target for treatment is a resting-state study showing lower amygdala-ACC/mPFC connectivity in gSAD correlated with social anxiety severity and that deficient coupling was enhanced by an acute challenge of the neuropeptide oxytocin [9]. Together, findings indicate intrinsic amygdala-medial prefrontal interactions may play a role in predicting the likelihood of responding to an intervention in gSAD. Findings expand on emotion activation paradigms that have demonstrated associations between increases in ACC or mOFC activity before treatment and improvement after CBT in gSAD [10],[12]. Further study is needed to examine whether phasic (e.g., task/emotion-based) in combination with tonic (i.e., “at rest”) biomarkers can be used to predict response to CBT.

Beyond prefrontal regions of interest, symptom change was foretold by more and less connectivity in an extensive network indicative of the regions interconnected with the amygdala (e.g., insula, occipital lobe, middle temporal gyrus, superior frontal gyrus, parahippocampal gyrus; [27]) in addition to wide-scale coupling within and between networks exhibited at rest [13]. We did not have a priori hypotheses for these regions and, therefore, hesitate to interpret these preliminary, exploratory findings. Nevertheless, it is interesting to note symptom improvement also positively corresponded with the right amygdala-insula (i.e., rolandic operculum) coupling and, based on ROC findings, served as a good estimate of treatment response. The insula is proposed to play a role in anxiety disorders [28],[29], which is supported by observations of exaggerated insula reactivity to emotional stimuli in gSAD relative to healthy controls [6]. In the context of treatment for gSAD, we observed insula hyper-reactivity to threat relevant stimuli decreased after CBT [12]; however, task-based pre-CBT insula activity to threat has not yet been shown to predict symptom change in gSAD [10]-[12]. Our findings suggest that in the absence of external stimuli, baseline emotion processing circuitry appears to function as a predictor. More study is needed to understand how the intrinsic amygdala-insula and other resting-state networks beyond a priori regions might be utilized by CBT.

First, our study is not without important limitations. These include a relatively small sample size which increases risk for type II errors. Second, 2 of the 21 participants with gSAD were taking bupropion. Even though the medication was stable before the study and remained unchanged during the study, and these participants did not serve as outliers in a priori findings as indicated by scatterplots, any influence it may have had on other outcomes cannot be ruled out. Third, the lack of a waitlist group to serve as a control for changes in symptoms unrelated to treatment reduces our ability to draw firm conclusions about neural predictors of CBT response. Fourth, replication in an independent sample is necessary before conclusions can be made as to the clinical relevance of our findings. Fifth, connectivity results were limited to the bilateral amygdala. Future studies may want to “seed” prefrontal regions implicated in emotion regulation (e.g., dorsolateral, dorsomedial prefrontal cortex; orbitofrontal cortex; anterior cingulate cortex; [5]) to examine their relationship with the amygdala and ability to predict CBT success. Sixth, the lack of independent evaluators of treatment fidelity and symptom change warrants replication and further investigation. Despite limitations, findings suggest individual differences in intrinsic amygdala-prefrontal connectivity can help explain the heterogeneity in response to CBT in gSAD. Findings also indicate resting-state fMRI may be a useful approach in identifying brain-based biomarkers in treatment response. Among the advantages of resting-state biomarkers is the ease of application across other internalizing psychopathologies that may have common pathophysiology and for which CBT is an empirically validated treatment option (e.g., post-traumatic stress disorder, major depressive disorder).