Preface Posttraumatic stress disorder (PTSD) is the only major mental disorder for which a cause is considered to be known, viz., an event that involves threat to the physical integrity of oneself or others and induces a response of intense fear, helplessness, or horror. Although PTSD is still largely regarded as a psychological phenomenon, over the past three decades the growth of the biological PTSD literature has been explosive, and thousands of references now exist. Ultimately, the impact of an environmental event, such as a psychological trauma, must be understood at organic, cellular, and molecular levels. The present review attempts to present the current state of this understanding, based upon psychophysiological, structural and functional neuroimaging, endocrinological, genetic, and molecular biological studies in humans and in animal models.

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Background: A clinical characteristic of posttraumatic stress disorder (PTSD) is persistently elevated fear responses to stimuli associated with the traumatic event. The objective herein is to determine whether extinction of fear responses is impaired in PTSD and whether such impairment is related to dysfunctional activation of brain regions known to be involved in fear extinction, viz., amygdala, hippocampus, ventromedial prefrontal cortex (vmPFC), and dorsal anterior cingulate cortex (dACC). Methods: Sixteen individuals diagnosed with PTSD and 15 trauma-exposed non-PTSD controls (TENCs) underwent a two-day fear conditioning and extinction protocol in a 3T fMRI scanner. Conditioning and extinction training were conducted on day 1. Extinction recall (or extinction memory) test was conducted on day 2 (extinguished conditioned stimuli presented in the absence of shock). Skin conductance response (SCR) was scored throughout the experiment as an index of the conditioned response. Results: SCR data revealed no significant differences between groups during acquisition and extinction of conditioned fear on day 1. On day 2, however, PTSD subjects showed impaired recall of extinction memory. Analysis of fMRI data showed greater amygdala activation in the PTSD group during day 1 extinction learning. During extinction recall, lesser activation in hippocampus and vmPFC, and greater activation in dACC, was observed in the PTSD group. The magnitude of extinction memory across all subjects was correlated with activation of hippocampus and vmPFC during extinction recall testing. Conclusions: These findings support the hypothesis that fear extinction is impaired in PTSD. They further suggest that dysfunctional activation in brain structures that mediate fear extinction learning, and especially its recall, underlie this impairment.

Anxiety disorders are a significant problem in the community, and recent neuroimaging research has focused on determining the brain circuits that underlie them. Research on the neurocircuitry of anxiety disorders has its roots in the study of fear circuits in animal models and the study of brain responses to emotional stimuli in healthy humans. We review this research, as well as neuroimaging studies of anxiety disorders. In general, these studies have reported relatively heightened amygdala activation in response to disorder-relevant stimuli in post-traumatic stress disorder, social phobia, and specific phobia. Activation in the insular cortex appears to be heightened in many of the anxiety disorders. Unlike other anxiety disorders, post-traumatic stress disorder is associated with diminished responsivity in the rostral anterior cingulate cortex and adjacent ventral medial prefrontal cortex. Additional research will be needed to (1) clarify the exact role of each component of the fear circuitry in the anxiety disorders, (2) determine whether functional abnormalities identified in the anxiety disorders represent acquired signs of the disorders or vulnerability factors that increase the risk of developing them, (3) link the findings of functional neuroimaging studies with those of neurochemistry studies, and (4) use functional neuroimaging to predict treatment response and assess treatment-related changes in brain function.

The last decade of neuroimaging research has yielded important information concerning the structure, neurochemistry, and function of the amygdala, medial prefrontal cortex, and hippocampus in posttraumatic stress disorder (PTSD). Neuroimaging research reviewed in this article reveals heightened amygdala responsivity in PTSD during symptomatic states and during the processing of trauma-unrelated affective information. Importantly, amygdala responsivity is positively associated with symptom severity in PTSD. In contrast, medial prefrontal cortex appears to be volumetrically smaller and is hyporesponsive during symptomatic states and the performance of emotional cognitive tasks in PTSD. Medial prefrontal cortex responsivity is inversely associated with PTSD symptom severity. Lastly, the reviewed research suggests diminished volumes, neuronal integrity, and functional integrity of the hippocampus in PTSD. Remaining research questions and related future directions are presented.

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These results provide evidence for exaggerated amygdala responsivity, diminished medial prefrontal cortex responsivity, and a reciprocal relationship between these 2 regions during passive viewing of overtly presented affective stimuli unrelated to trauma in PTSD.

These results suggest a reciprocal relationship between medial prefrontal cortex and amygdala function in PTSD and opposing associations between activity in these regions and symptom severity consistent with current functional neuroanatomic models of this disorder.