Functional MRI of the amygdala and bed nucleus of the stria terminalis during conditions of uncertainty in generalized anxiety disorder

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Abstract

Generalized anxiety disorder (GAD) is a common psychiatric disorder characterized by constant worry or anxiety over every day life activities and events. The neurobiology of the disorder is thought to involve a wide cortical and subcortical network that includes but is not limited to the amygdala and the bed nucleus of the stria terminalis (BNST). These two regions have been hypothesized to play different roles in stress and anxiety; the amygdala is thought to regulate responses to brief emotional stimuli while the BNST is thought to be involved in more chronic regulation of sustained anxiety. In this study, we exposed medication-free GAD patients as well as non-anxious controls to a gambling game where one of the conditions involved non-contingent monetary loss. This condition of high uncertainty was intended to elicit a stressful response and sustained anxiety. Functional MRI scans were collected simultaneously to investigate BOLD activity in the amygdala and BNST during performance of this task. Compared to controls, we found that GAD patients demonstrated decreased activity in the amygdala and increased activity in the BNST. Skin conductance measures showed a consistent early versus late effect within block where GAD patients demonstrated higher arousal than controls late in the task blocks. Based on these results, we hypothesize that GAD patients disengage the amygdala and its response to acute stress earlier than non-anxious controls making way for the BNST to maintain a more sustained response. Future studies are needed to investigate the temporal dynamics of activation and deactivation in these regions.

Introduction

Generalized anxiety disorder is characterized by chronic worry, possibly due to abnormalities in regulating emotional processing (Mennin et al., 2005; McLaughlin et al., 2007). This regulation involves a wide network of brain regions, which encompasses the extended amygdala (including the bed nucleus of the stria terminalis, BNST) and the prefrontal cortex. The role of the amygdala in processing emotional stimuli is relatively well established in animal (Davis, 2006) and human studies (Kent and Rauch, 2004; Costafreda et al., 2008; Sergerie et al., 2008). However, its role in modulating fear and anxiety in generalized anxiety disorder (GAD) is less well understood.

Although one might predict that GAD involves a heightened amygdala response to fearful or anxiety-provoking stimuli (Etkin and Wager, 2007), studies in GAD patients have often provided conflicting results. Several studies have noted greater amygdala activation to noxious stimuli in pediatric and adolescent GAD samples (McClure et al., 2007; Monk et al., 2008). However, studies in adults have been less consistent. Some have reported in GAD patients a heightened amygdala response to all stimuli, including non-aversive ones (Hoehn-Saric et al., 2004a; Nitschke et al., 2009), while others have found no group differences in levels of amygdala fMRI BOLD activation between GAD patients and controls during processing of emotional stimuli (Whalen et al., 2008; Etkin et al., 2010). One study also reported a reduced amygdala response to fearful faces in GAD patients (Blair et al., 2008).

Davis and colleagues (Davis, 1998, 2006; Walker et al., 2003; Walker and Davis, 2008; Walker et al., 2009; Davis et al., 2010) have suggested that fear and anxiety may be expressed through two separate but complementary systems, a rapid response system that mediates short-term responses to threatening stimuli and includes the central nucleus of the amygdala (phasic fear) and a second system that includes the BNST, which while sluggish in response, continues to influence behavior long after the initiating stimulus has been terminated (sustained fear or “anxiety”).

The BNST is a region of the extended amygdala complex that consists of a heterogeneous group of nuclei (Walker and Davis, 2008). The pattern of connectivity in the BNST suggests that this region acts as a relay center coordinating the activity of autonomic, neuroendocrine, and somatic motor systems into fully organized physiological functions and behavior (Dumont, 2009), possibly under the control of the medial prefrontal cortex (Spencer et al., 2005). The BNST may also receive emotional and learning-associated information and possibly plays a role in integrating these inputs with reward/motivational circuits (Jalabert et al., 2009). The BNST is thought to maintain sustained anxiety-like responses in animals (Walker et al., 2003), such as the gradual elevation in baseline startle seen in animals over the course of training (Gewirtz et al., 1998). Stress-induced “hyperanxiety” in rats is correlated with increased volumes of the BNST but not the amygdala; this appears to be driven by dendritic remodeling in anteromedial areas, which are implicated in emotional and neuroendocrine control of stress responses (Pego et al., 2008). Thus, the BNST appears to be highly plastic and is in a key position to regulate stress and anxiety responses.

The role of the BNST in anxiety disorders has not been systematically examined, with two notable exceptions. A human fMRI study of spider phobics (Straube et al., 2007), found that the anticipation of adverse visual stimuli activated the BNST but not the amygdala. Another study of healthy participants with varying degrees of trait anxiety (Somerville et al., 2010) found that during observation of a fluctuating line, which provided information relevant to subsequent risk of electric shocks, participants showed increased activity in the BNST but not in the amygdala. This response was pronounced in more anxious individuals. Thus, sustained anxiety led to an increased engagement of the BNST but not the amygdala.

In this study, we used a non-contingent monetary loss task which involves high uncertainty on a trial-by-trial basis to attempt to induce a state of sustained anxiety while we explored the nature of BOLD fMRI responses in the amygdala and the BNST in individuals with and without GAD. Based on previous work by Straube et al. (2007) and Somerville et al. (2010) as well as the Davis model discussed above, we predicted that we would find a potentiated BNST response in GAD patients compared to controls and that there would be no group differences in amygdala activity. Consistent with our first prediction, we observed enhanced activity in the BNST in GAD patients in the “high-uncertainty” condition. Somewhat surprisingly, however, we found decreased amygdala activation in GAD patients in the same condition. This suggests that these two brain regions might be operating in different and possibly opposite ways, supporting observations from animal studies.

Section snippets

Participants

Fifteen right-handed medication-free patients diagnosed with GAD according to DSM-IV criteria and no other pathology and fifteen right-handed controls underwent a psychiatric and medical examination that included the Structured Clinical Interview for DSM-IV (SCID-IV) and a urine toxicology screen. See Table 1 for clinical and demographic data. Participants were recruited on the Johns Hopkins medical campus through advertisement, screened by telephone and subsequently evaluated by a psychiatrist

Behavioral results

Average accuracy and latency values are shown in Table 2. We used a repeated measures ANOVA with group as a between-subject variable and condition as a within-subject variable. For accuracy, we found a significant main effect of condition (F1,28 = 346.7, P < .05) but no significant effect of group (F1,28 = .05, P > .05) nor a group by condition interaction (F1,28 = 1.39, P > .05). For latency, we found similar results; a significant main effect of condition (F1,28 = 4.95, P < .05) but not for

Discussion

The present study compared fMRI brain activation patterns in medication-free generalized anxiety disorder patients and healthy controls during a non-contingent monetary loss task intended to use uncertainty to elicit sustained anxiety. Based on animal models of phasic and sustained fear (i.e. anxiety), we predicted that the BNST would be engaged in this task. Further, we predicted that its activity levels would be increased in patients compared to controls. We found evidence for our prediction

Funding source

The study was supported by the Johns Hopkins University School of Medicine General Clinical Research Center Grant #MO1-RR00052 from the National Center for Research Resources (NCRR). The NCRR had no further role in study design, in the collection, analysis and interpretation of data, in the writing of the report, and in the decision to submit the paper for publication.

Contributors

M.Y., C.S., R.H-S. designed the study, M.Y., R.H., C.S., R.H-S. collected the data, M.Y., R.H., R.H-S. analyzed the data, M.Y. and R.H-S. wrote the paper with input from all authors.

Conflict of interest

All the authors declare no conflicts of interest.

Acknowledgment

We would like to thank, posthumously, Professor Lennart Heimer for his generous advice how to accurately delineate the BNST on MRI scans.

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