Trauma modulates amygdala and medial prefrontal responses to consciously attended fear☆
Introduction
Evidence from lesion and neuroimaging studies suggests that key components of the neural system for fear processing include the amygdala and medial prefrontal cortex (MPFC). The role of the amygdala in the appraisal, generation and maintenance of fear has been demonstrated in a wealth of human and non-human animal studies (e.g., Adolphs et al., 1994, LeDoux, 1998, Morris et al., 1996; for a review, see Adolphs, 2002, Phan et al., 2002, Zald, 2003). Facial expressions of fear are the most salient of our basic facial emotions and provide a universal signal of fear for use in human neuroimaging, including comparison across different experimental groups (Ekman, 1992). Fearful face stimuli have been found to be a robust and reliable probe for amygdala activity (Hariri et al., 2002, Phan et al., 2002).
It is proposed that the MPFC is involved in the formation of explicit cognitive–emotional associations between amygdala-mediated emotional responses and knowledge of the fear stimulus (innate or previously acquired) (Damasio, 1994). Anatomically, the ventral portion of the primate MPFC is strongly interconnected with the amygdala (Carmichael and Price, 1995, Barbas, 1995). The ventral MPFC has been associated with particular sensitivity to the emotional content of stimuli and the dorsal MPFC with cognitive activity (Bechara et al., 1999, Lane et al., 1997). Although this distinction is unlikely to be straightforward, it has also been demonstrated in the anterior cingulate cortex (Bush et al., 2000, Drevets and Raichle, 1998, Yamasaki et al., 2002), which is typically defined as part of the MPFC.
Other lines of research have focused on the role of the MPFC in providing top–down regulation of the amygdala and reciprocal modulation of MPFC activity by the amygdala. Animal fear conditioning studies have shown that the MPFC may be involved in reducing fear responses, whereas the amygdala is required for fear expression and has the effect of reducing MPFC activity (Garcia et al., 1999). Similarly, evidence from neuroimaging studies suggests a reciprocal relationship between the amygdala and MPFC, such that emotion-related activity in the amygdala is reduced during higher cognitive processing which engages the MPFC, as well as the reverse (Taylor et al., 1999).
From such findings, it has been suggested that pathological fear and anxiety may be the manifestation of abnormal modulations in amygdala and MPFC activity and their interaction. PTSD is defined by symptoms of reexperiencing the trauma, avoidance of associated stimuli and hyperarousal symptoms, suggesting a heightened fear response (APA, 1994). Drawing on evidence from animal fear-conditioning studies (Davis et al., 1997, Morgan and LeDoux, 1995), it has been proposed that PTSD symptoms reflect amygdala hyperresponsivity to fear-related stimuli, with a concomitant lack of ‘top–down’ prefrontal inhibition.
Consistent with this proposal, neuroimaging studies of PTSD have to date observed abnormal reductions in MPFC activity (Bremner et al., 1999, Shin et al., 1999, Shin et al., 2004), as well as enhanced and distinctive amygdala engagement (Liberzon et al., 1999, Rauch et al., 2000), particularly for combat veterans (Shin et al., 2004). Yet, a PET study of civilian trauma subjects with and without PTSD has reported a positive amygdala and MPFC association in PTSD and a lack of association in the non-PTSD group (Gilboa et al., 2004). We used a higher temporal resolution technique, functional MRI, to further elucidate the changes in amygdala and MPFC activity following trauma.
In this study, we examined responses to fearful face stimuli, as a standardized probe for amygdala–MPFC activity, which allows generalization to other studies and populations. To date, most PTSD neuroimaging studies have been undertaken using script-driven imagery, which may recruit state-based responses specific to the task, rather than more trait-like systems for fear processing. In the one previous study to use fearful face stimuli to study PTSD, stimuli were presented briefly and masked, to maximize automatic ‘bottom up’ aspects of processing involving the amygdala and to minimize ‘top–down’ MPFC regulation (Rauch et al., 2000). The study revealed exaggerated amygdala responses to masked (nonconscious) fear in combat PTSD compared to control subjects, while MPFC activity was absent in both groups. Changes in MPFC activity, associated with ‘top–down’ processing, have not been examined in the context of trauma using consciously attended facial signals of fear. In this study, we examined whether post-trauma reactions are characterized by reduced MPFC activity, with concomitant amygdala enhancement, in response to overtly presented signals of fear.
Section snippets
Subjects
Thirteen patients with PTSD (mean age = 36.5 years, SD = 9.7; 7 males, 6 females) were recruited from the Westmead PTSD Unit, and 13 matched non-traumatized comparison subjects (mean age = 34.8 years, SD = 8.5; 7 males, 6 females) were recruited from equivalent geographical regions, in collaboration with the Brain Resource International Database (http://www.brainresource.com; Gordon, 2003).
Diagnoses of PTSD were made by clinicians independent of the study using the Clinician Administered PTSD
ROI analysis
For non-traumatized control subjects, significant responses (P < 0.05SVC) to fear (versus neutral) were observed in the left amygdala and bilateral MPFC, encompassing the anterior cingulate cortex (ACC) and dorsomedial prefrontal gyrus (Table 1; Fig. 1). PTSD patients showed activity in the right amygdala and MPFC/ACC, extending more ventrally (Table 1; Fig. 1).
Between-group analyses showed that PTSD subjects had significantly less activity than comparison subjects in the bilateral MPFC
Discussion
The present results provide evidence that traumatic emotional reactions have a primary impact on the medial prefrontal systems engaged by the conscious processing of fear signals. Moreover, the findings indicate that there is a breakdown in laterality of anterior cingulate responses over the experimental time course, with a greater impact of trauma during the later phase of processing. There was a corresponding disturbance in the lateralized time course of amygdala activity, with right amygdala
Acknowledgments
This study was supported by Australian Research Council (ARC) Discovery (DP0452237) and ARC Linkage (LP02120481) funding, with the support of the Brain Resource Company and Castlereagh Radiology, and by NHMRC Program (300304) funding. LW is supported by a Pfizer senior research fellowship. We acknowledge the support of the International Brain Database, http://www.brainresource.com) in data acquisition.
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The study was conducted at The Brain Dynamics Centre, Westmead Hospital and University of Sydney, NSW, 2006, Australia.