Fear Processing, Psychophysiology, and PTSD :

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). Sixteen individuals diagnosed with PTSD and 15 trauma-exposed non-PTSD control subjects underwent a 2-day fear conditioning and extinction protocol in a 3-T functional magnetic resonance imaging 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. The 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 functional magnetic resonance imaging 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 were 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. 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.

Pituitary adenylate cyclase-activating polypeptide (PACAP) is known to broadly regulate the cellular stress response. In contrast, it is unclear if the PACAP/PAC1 receptor pathway has a role in human psychological stress responses, such as posttraumatic stress disorder (PTSD). In heavily traumatized subjects, we find a sex-specific association of PACAP blood levels with fear physiology, PTSD diagnosis and symptoms in females (N=64, replication N=74, p<0.005). Using a tag-SNP genetic approach (44 single nucleotide polymorphisms, SNPs) spanning the PACAP (ADCYAP1) and PAC1 (ADCYAP1R1) genes, we find a sex-specific association with PTSD. rs2267735, a SNP in a putative estrogen response element within ADCYAP1R1, predicts PTSD diagnosis and symptoms in females only (combined initial and replication samples: N=1237; p<2x10 − 5). This SNP also associates with fear discrimination and with ADCYAP1R1 mRNA expression. Methylation of ADCYAP1R1 is also associated with PTSD (p < 0.001). Complementing these human data, ADCYAP1R1 mRNA is induced with fear conditioning or estrogen replacement in rodent models. These data suggest that perturbations in the PACAP/PAC1 pathway are involved in abnormal stress responses underlying PTSD. These sex-specific effects may occur via estrogen regulation of ADCYAP1R1. PACAP levels and ADCYAP1R1 SNPs may serve as useful biomarkers to further our mechanistic understanding of PTSD.

In an attempt to capture the variety of symptoms that emerge following traumatic stress, the revision of posttraumatic stress disorder (PTSD) criteria in the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) has expanded to include additional symptom presentations. One consequence of this expansion is that it increases the amorphous nature of the classification. Using a binomial equation to elucidate possible symptom combinations, we demonstrate that the DSM-IV criteria listed for PTSD have a high level of symptom profile heterogeneity (79,794 combinations); the changes result in an eightfold expansion in the DSM-5, to 636,120 combinations. In this article, we use the example of PTSD to discuss the limitations of DSM-based diagnostic entities for classification in research by elucidating inherent flaws that are either specific artifacts from the history of the DSM or intrinsic to the underlying logic of the DSM's method of classification. We discuss new directions in research that can provide better information regarding both clinical and nonclinical behavioral heterogeneity in response to potentially traumatic and common stressful life events. These empirical alternatives to an a priori classification system hold promise for answering questions about why diversity occurs in response to stressors.