Disrupted amygdala-prefrontal functional connectivity in civilian women with posttraumatic stress disorder

Abstract

Many features of posttraumatic stress disorder (PTSD) can be linked to exaggerated and dysregulated emotional responses. Central to the neurocircuitry regulating emotion are functional interactions between the amygdala and the ventromedial prefrontal cortex (vmPFC). Findings from human and animal studies suggest that disruption of this circuit predicts individual differences in emotion regulation. However, only a few studies have examined amygdala-vmPFC connectivity in the context of emotional processing in PTSD. The aim of the present research was to investigate the hypothesis that PTSD is associated with disrupted functional connectivity of the amygdala and vmPFC in response to emotional stimuli, extending previous findings by demonstrating such links in an understudied, highly traumatized, civilian population. 40 African-American women with civilian trauma (20 with PTSD and 20 non-PTSD controls) were recruited from a large urban hospital. Participants viewed fearful and neutral face stimuli during functional magnetic resonance imaging (fMRI). Relative to controls, participants with PTSD showed an increased right amygdala response to fearful stimuli (p_corr < .05). Right amygdala activation correlated positively with the severity of hyperarousal symptoms in the PTSD group. Participants with PTSD showed decreased functional connectivity between the right amygdala and left vmPFC (p_corr < .05). The findings are consistent with previous findings showing PTSD is associated with an exaggerated response of amygdala-mediated emotional arousal systems. This is the first study to show that the amygdala response may be accompanied by disruption of an amygdala-vmPFC functional circuit that is hypothesized to be involved in prefrontal cortical regulation of amygdala responsivity.

Introduction

PTSD is a highly debilitating anxiety disorder that develops in some individuals after exposure to trauma. Among the general population, PTSD is estimated to affect approximately 7% (Kessler et al., 2005), and a critical question for the field is why this disorder develops in some, but not others, following severe trauma exposure. An increasing body of evidence shows that in addition to combat veterans, the risk for traumatic life experiences and PTSD is especially high among impoverished individuals living in urban settings with high violence exposure, with trauma rates at nearly 88% and PTSD prevalence at 46% (Alim et al., 2006, Gillespie et al., 2009, Liebschutz et al., 2007, Schwartz et al., 2005).

After a traumatic event, symptoms may develop that interfere with everyday function, including increased emotional arousal and hypervigilance, reexperiencing the traumatic event, and avoidance of trauma reminders. Because these symptoms only persist in a subset of people who experience trauma, one important goal of PTSD research is to identify characteristics that confer resilience or vulnerability for the disorder. Current neurobiological models of PTSD posit that neural circuits typically involved in healthy emotion regulation are disrupted in PTSD (Liberzon and Sripada, 2007, Shin et al., 2006). The goal of the current research was to examine the neural circuits involved in emotion processing in a high-risk urban civilian sample of traumatized African American women.

A wealth of functional neuroimaging evidence has shown that PTSD symptoms are associated with increased activation of the amygdala and insula, brain regions that are involved in initiating and coordinating emotional arousal responses (e.g., Fonzo et al., 2010, Rauch et al., 2000, Shin et al., 2005, Simmons et al., 2011). In addition, PTSD has been associated with decreased activation of prefrontal regions involved in emotion regulation such as the ventromedial prefrontal cortex (vmPFC) and rostral anterior cingulate cortex (ACC; Jovanovic et al., 2012, Milad et al., 2009, Rougemont-Bucking et al., 2011, Shin et al., 2001, Shin et al., 2005, Williams et al., 2006). A meta-analysis of neuroimaging studies of anxiety disorders found that reduced vmPFC activation is specific to PTSD, and is not consistently observed in studies of other anxiety disorders (Etkin and Wager, 2007). Evidence from studies of overt emotion regulation and fear extinction in healthy participants suggests that the vmPFC and rostral ACC are involved in decreasing arousal responses to negative emotional stimuli (Etkin et al., 2011, Kim and Hamann, 2007, Milad et al., 2007b, Ochsner et al., 2002).

Examining connectivity between the amygdala and vmPFC can provide a more direct test of the hypothesis that PTSD involves a disruption of medial prefrontal regulation of amygdala responses to emotional stimuli. Recent diffusion tensor imaging (DTI) evidence suggests that white matter integrity is compromised in the cingulum bundle, a major pathway between the amygdala and vmPFC/ACC (Fani et al., 2012b). Similarly, examination of resting state functional connectivity, which often parallels structural connectivity, has shown decreased functional coupling between the amygdala and vmPFC in PTSD (Sripada et al., 2012).

Only a small number of studies have examined amygdala functional connectivity in response to emotionally arousing stimuli in PTSD, with mixed findings relating to the strength of connectivity between the amygdala and vmPFC. In response to angry face stimuli, PTSD participants showed decreased connectivity in a circuit involving the amygdala, insula, and dorsal ACC (Fonzo et al., 2010). In contrast, PTSD participants recalling traumatic or emotionally negative autobiographical memories showed increased amygdala functional connectivity with the vmPFC relative to controls (Gilboa et al., 2004, Jacques et al., 2011). The variability in findings may relate to differences in the experimental tasks used, or in the populations examined. Previous studies examined PTSD related to recent intimate-partner violence, accidental injury, and among a general civilian population, respectively. In addition, these studies did not include traumatized controls and thus did not differentiate the effects of trauma versus PTSD on amygdala connectivity (Fonzo et al., 2010, Jacques et al., 2011), or included participants who were taking psychotropic medications at the time of the scan (Gilboa et al., 2004).

In the present study, we investigated the effects of PTSD on amygdala responses to threat cues (fearful facial expressions) and on the functional coupling of the amygdala with other brain areas, in a highly traumatized sample of African-American women. The primary comparison was between unmedicated participants with or without current PTSD, matched for degree of trauma exposure. Little previous work has examined the neural processing of emotional stimuli in an urban civilian population with very high levels of trauma. We hypothesized that PTSD would be associated with an increased amygdala response, and with decreased functional connectivity between the amygdala and vmPFC/ACC, in response to fearful stimuli.