Reduced resting-state functional connectivity between amygdala and orbitofrontal cortex in social anxiety disorder
Research highlights
►Resting state functional connectivity of amygdala in social anxiety disorder. ►Reduced amygdala connectivity with orbitofrontal and posterior cingulate cortices. ►Decreased coupling between orbitofrontal and anterior cingulate cortices.
Introduction
Social anxiety disorder (SAD), classified as “social phobia” in DSM-IV, is characterized by an excessive physiological and emotional arousal (Milad and Rauch, 2007) in response to social interaction, unfamiliar faces and performance situations like public speaking (Milad and Rauch, 2007, Tillfors et al., 2001). The repeated experience of anxiety in relatively harmless situations (Rauch et al., 2003) leads to pronounced avoidance behavior and consecutively interferes with daily life, occupational performance and relationships of SAD patients.
The subcortical brain region most often associated with the neural processing of anxiety and threat is the amygdala. It is essential for initial processing of emotional memory and arousal (Cahill et al., 1996), fast evaluation of novel stimuli (Larson et al., 2006) and threat perception (Cannistraro and Rauch, 2003). Electrical stimulation of the amygdala has been shown to elicit fear, anxiety and social withdrawal and to increase the stress response via cortisol release (Drevets et al., 2008, Lanteaume et al., 2007). Lesions within the amygdala compromise face processing (Young et al., 1995) and judgment of trustworthiness in social context (Adolphs et al., 1998), impair the recognition of fear (Broks et al., 1998) and increase social anxiety (Prather et al., 2001). Accordingly, functional amygdala hyperactivation in response to aversive and potentially threatening social stimuli (Etkin and Wager, 2007, Phelps et al., 2001, Rauch et al., 2003, Tillfors et al., 2001) and during face perception (Hariri et al., 2002, Phan et al., 2006, Stein et al., 2002) is consistently observed in SAD patients.
Less known, however, is the way how this important relay station of social performance and emotion perception interacts with other regions of the anxiety network (Cannistraro and Rauch, 2003). Receiving input from higher-order sensory cortices, the amygdala appears to have a centre or gate function in a hub of connections associated with the perception, evaluation and response to threatening and socially relevant stimuli (Ghashghaei and Barbas, 2002, Stein et al., 2007a). With respect to the amygdala hyperreactivity, inverse activation patterns have been identified in several other areas of the anxiety network in functional magnetic resonance imaging (fMRI) studies examining the reaction to and suppression of negative affect (Phan et al., 2005). This suggests a disturbed interplay between these regions in anxiety-prone subjects (Stein et al., 2007b) and challenged SAD patients (Lorberbaum et al., 2004, Phan et al., 2006, Stein et al., 2002, Tillfors et al., 2001).
Resting-state functional connectivity MRI (rs-fMRI) has become a valuable tool for the investigation of network function, allowing for a paradigm-free analysis of connectivity in functional MRI without a priori assumptions about neural activation (Biswal et al., 1995, Greicius et al., 2003). Investigating the spatial distribution of correlations in the spontaneous activity of the brain not only resembles the activation patterns found within task-specific fMRI, but also reflects structural connections between these regions (Fox et al., 2005, Greicius et al., 2008). Alterations of resting-state connectivity were shown in attention deficit hyperactivity disorder (Castellanos et al., 2008), Alzheimer's disease (Greicius et al., 2004), obsessive compulsive disorder (Harrison et al., 2009), depression (Anand et al., 2005), bipolar disorder (Wang et al., 2009) and schizophrenia (Salvador et al., 2010). Functional connectivity analysis furthermore revealed a discoordination of task-related networks in patients with generalized anxiety disorder (Etkin et al., 2009, Monk et al., 2008), social anxiety disorder in adolescents (Guyer et al., 2008) and adults (Zhao et al., 2007) as well as specific phobia (Ahs et al., 2009), pointing to a dysregulation of the fronto-amygdalar interplay.
Although alterations of some resting-state networks in social anxiety disorder patients were suggested (Liao et al.), the role of primary emotional processing structures such as the amygdala in resting-state networks is still unknown. We hypothesized that dysfunctions in the fronto-amygdalar network of SAD patients are reflected by an altered functional connectivity of the amygdala as assessed with rs-fMRI. Hence, this study investigated spontaneous blood oxygen level dependent (BOLD) activity patterns in patients with social anxiety and/or panic disorder compared to healthy controls. Primary data analysis focused on the amygdala due to its crucial role in threat assessment. In addition, an exploratory connectivity analysis was performed targeting alterations in indirect modulatory pathways by using areas with disrupted amygdalar connectivity as secondary seed regions. Finally, borders between functionally distinct regions were evaluated based on the variability of individual connectivity maps (Biswal et al., 2010), since putative functional boundaries between areas were suggested to provide supplementary insight into the functional organization of brain networks (Cohen et al., 2008).
Section snippets
Participants
Fifteen unmedicated patients with anxiety disorders and 30 healthy controls were recruited from the local community via media advertisements. Patients had to fulfill criteria for social anxiety disorder and/or panic disorder (SAD/PD) according to the Structured Clinical Interview for DSM-IV Diagnoses (SCID) and no other DSM-IV diagnosis except for agoraphobia. Healthy controls were required to have no history of or current psychiatric DSM-IV diagnosis. Five patients and 3 healthy volunteers had
Facial expression discrimination task
The comparison of patients to healthy controls revealed a hyperactivation of the left amygdala in response to faces showing emotional expressions (t = 4.91, p < 0.0001, Table 1, Fig. 1b). At lower thresholds, this was also found for the right amygdala (t = 3.34, p < 0.005), and the hyperreactivity was still present when comparing only male SAD patients with male healthy subjects (t = 3.33 and t = 3.07, p < 0.005 for left and right amygdalae, respectively). No differences in amygdala reactivity were found
Discussion
We observed a reduced resting-state functional connectivity between left amygdala and medial orbitofrontal cortex as well as posterior cingulate cortex/precuneus in patients with social anxiety disorder as compared to healthy controls. The patient sample exhibited the typical amygdala hyperactivation to emotionally-laden facial expressions. Our findings therefore substantiate the proposed fronto-amygdalar network disruption in anxiety disorders (Etkin and Wager, 2007, Phelps et al., 2004).
Conclusions
Our data suggest a severe disorganization between major parts of the functional amygdala network already in resting state in patients with social anxiety, extending orbitofrontal deficiencies to the posterior and anterior cingulate cortices. Considering the strong correlation between anatomical and functional connectivity (Greicius et al., 2008), these results add important complementary information to task-related neuronal processing (Phan et al., 2005, Stein et al., 2007b) and provide a
Conflict of interest statement
Without any relevance to this work, S. Kasper declares that he has received grant/research support from Eli Lilly, H. Lundbeck A/S, Bristol-Myers Squibb, Servier, Sepracor, GlaxoSmithKline, Organon, and has served as a consultant or on advisory boards for AstraZeneca, Austrian Sick Found, Bristol-Myers Squibb, GlaxoSmithKline, Eli Lilly, H. Lundbeck A/S, Pfizer, Organon, Sepracor, Janssen, and Novartis, and has served on speakers' bureaus for AstraZeneca, Eli Lilly, H. Lundbeck A/S, Servier,
Acknowledgments
This research was funded by grants from the Austrian National Bank OeNB P11468 to R. Lanzenberger and OeNB P12982 to C. Windischberger. We are grateful to the technical team of the MR Centre of Excellence and the medical team of the Department of Psychiatry, MUV.
The sponsor was not involved in the design and conduct of the study, the collection, management, analysis and interpretation of the data, the preparation, review or approval of the manuscript.
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These authors contributed equally.