Disrupted Effective Connectivity Between the Amygdala and Orbitofrontal Cortex in Social Anxiety Disorder During Emotion Discrimination Revealed by Dynamic Causal Modeling for fMRI

Abstract

Social anxiety disorder (SAD) is characterized by over-reactivity of fear-related circuits in social or performance situations and associated with marked social impairment. We used dynamic causal modeling (DCM), a method to evaluate effective connectivity, to test our hypothesis that SAD patients would exhibit dysfunctions in the amygdala–prefrontal emotion regulation network. Thirteen unmedicated SAD patients and 13 matched healthy controls performed a series of facial emotion and object discrimination tasks while undergoing fMRI. The emotion-processing network was identified by a task-related contrast and motivated the selection of the right amygdala, OFC, and DLPFC for DCM analysis. Bayesian model averaging for DCM revealed abnormal connectivity between the OFC and the amygdala in SAD patients. In healthy controls, this network represents a negative feedback loop. In patients, however, positive connectivity from OFC to amygdala was observed, indicating an excitatory connection. As we did not observe a group difference of the modulatory influence of the FACE condition on the OFC to amygdala connection, we assume a context-independent reduction of prefrontal control over amygdalar activation in SAD patients. Using DCM, it was possible to highlight not only the neuronal dysfunction of isolated brain regions, but also the dysbalance of a distributed functional network.

Three distinct fiber pathways of the bed nucleus of the stria terminalis to the amygdala and prefrontal cortex

“…In all examined patients, these lesions contained the areas targeted by the anterior pathway, while neither amygdala nor CN showed altered blood flow during resting state. Functional coupling of OFC and amygdala in processes that are likely to involve the BNST (e.g., threat-induced anxiety), however, has been observed both in non-human primates (e.g., Rygula et al, 2014) and in humans (e.g., Gold, Morey, & , 2015); this concurs with clinical observations in patients with social anxiety disorder including increased amygdalar activity during emotional face perception (Hahn et al, 2011) and a disrupted connectivity between amygdala and OFC (Sladky et al,2015). In summary, the available data is in agreement with our finding of a pathway reaching the OFC and not already terminating in more caudally located parts of the mPFC, as it appears to be the case in non-primates.…”

Basolateral Amygdala to Orbitofrontal Cortex Projections Enable Cue-Triggered Reward Expectations

“…Indeed, deficits in the cognitive consideration of potential rewarding events have been detected in patients diagnosed with addiction (Hogarth et al, 2013), schizophrenia (Morris et al, 2015, depression (Seymour and Dolan, 2008), and social anxiety disorder (Alvares et al, 2014). Disrupted amygdala and OFC activity and connectivity have also been associated with these diseases (Ressler and Mayberg, 2007;Price and Drevets, 2010;Goldstein and Volkow, 2011;Passamonti et al, 2012;Sladky et al, 2015). These data therefore have important implications for the understanding and treatment of these psychiatric conditions, and suggest that they might arise, in part, from disrupted transmission of reward information from the BLA to the OFC.…”

GABA content within the ventromedial prefrontal cortex is related to trait anxiety

“…Specifically, Simpson et al (2001) have observed a positive correlation between the activity within vmPFC and both self-reported anxiety ratings and increase in heart rate. Sladky et al (2015) have recently suggested that the amygdala hyperactivation in patients with social anxiety disorder could be a consequence of reduced inhibitory top-down neuronal control from the vmPFC. Particularly, the reduced glutamatergic stimulation of the ITC cells and of the GABAergic neurons could reduce the GABA-mediated inhibition on the BLA and the CeA (Lewis et al 2005;Bishop, 2007;Calhoon and Tye, 2015;Nuss, 2015).…”

“…Abnormal functional activity within the vmPFC has been reported in patients with social anxiety disorder (McClure et al, 2007;Monk et al, 2008;Price et al, 2011;Labuschagne et al, 2012;Sladky et al, 2015) and in healthy volunteers with elevated anxiety traits (Etkin et al, 2004;Stein et al, 2007). Histological studies in rodents and primates have documented direct and reciprocal projections between the vmPFC and the amygdala, highlighting the presence of a viable anatomic substrate for the functional interaction (McDonald et al, 1996;Ghashghaei and Barbas, 2002;Kim et al, 2011).…”