Reduced sensory gating of the P1 potential in rape victims and combat veterans with posttraumatic stress disorder

Anxiety disorders are a group of mental disorders that include generalized anxiety disorder (GAD), panic disorder, phobic disorders (e.g., specific phobias, agoraphobia, social phobia) and posttraumatic stress disorder (PTSD). Anxiety disorders are among the most common of all mental disorders and, when coupled with an awareness of the disability and reduced quality of life they convey, they must be recognized as a serious public health problem. Over 20 years of preclinical studies point to a role for the CRF system in anxiety and stress responses. Clinical studies have supported a model of CRF dysfunction in depression and more recently a potential contribution to specific anxiety disorders (i.e., panic disorder and PTSD). Much work remains in both the clinical and preclinical fields to inform models of CRF function and its contribution to anxiety. First, we will review the current findings of CRF and HPA axis abnormalities in anxiety disorders. Second, we will discuss startle reflex measures as a tool for translational research to determine the role of the CRF system in development and maintenance of clinical anxiety. KeywordsCRH; CRF; Posttraumatic stress disorder; Anxiety; Panic disorder; Startle Overview of CRF neuroendocrine effects and its effects on G-protein-coupled receptorsCorticotropin releasing factor (CRF; also termed "CRH" for corticotropin releasing hormone) was first described in Science by Vale et al. (1981). They reported the discovery of a hypothesized hypothalamic factor, CRF, a 41 amino acid peptide which selectively and potently activated pituitary corticotropin (or adrenal corticotropin releasing hormone, ACTH) secretion. They predicted that this peptide could be "a key signal in mediating and integrating an organism's endocrine, visceral and behavioral response to stress" (Vale et al., 1981(Vale et al., p. 1397). More than 20 years of subsequent animal research and clinical studies have confirmed this hypothesis, supporting a role for CRF, and its more recently discovered ligand family Urocortin 1, 2 and 3, in anxiety and stress responses Reyes et al., 2001;Spina et al., 1996). In this review, we will focus on the current state of knowledge of CRF system dysregulation in clinical anxiety and discuss future avenues of translational research on the role of CRF in startle phenotypes observed in some anxiety disorders. CRF mediation of the neuroendocrine response to stressIn response to stress, CRF is released from the median eminence of the hypothalamus, where it subsequently binds to receptors at the anterior pituitary and increases ACTH release into the * Corresponding author. 8950 Villa La Jolla Drive, Suite B-218, La Jolla, CA 92037, USA. E-mail address: mstein@ucsd.edu (M.B. Stein). bloodstream. ACTH consequently acts at the adrenal cortex to facilitate release of glucocorticoids such as cortisol. This system, known as the hypothalamic-pituitary-adrenal axis (HPA), is an important component of the response to stress and has been shown to be dysregulated in both anxiety and de...

Prenatal exposure to cigarette smoke is known to produce lasting arousal, attentional and cognitive deficits in humans. The pedunculopontine nucleus (PPN), as the cholinergic arm of the reticular activating system (RAS), is known to modulate arousal, waking and REM sleep. Rapid eye movement (REM) sleep decreases between 10 and 30 days postnatally in the rat, with the greatest decrease occurring at 12-21 days. Pregnant dams were exposed to 150 ml of cigarette smoke for 15 min, 3 times per day, from day E14 until parturition, and the pups allowed to mature. We analyzed a) intrinsic membrane properties of PPN neurons in slices from pups aged 12-21 days, and b) the sleep state-dependent P13 auditory evoked potential, which is generated by PPN outputs, in animals allowed to age to adolescence. We found significant changes in the intrinsic membrane properties of PPN cells in prenatally exposed animals compared to intact ones, rendering these cells more excitable. In addition, we found disturbances in the habituation to repetitive stimulation in adolescent, freely moving animals, suggestive of a deficit in the process of sensory gating. These findings could explain some of the differences seen in individuals whose parents smoked during pregnancy, especially in terms of their hypervigilance and increased propensity for attentional deficits and cognitive/behavioral disorders.

Objective-Quantitative measures of pre-attentional, attentional and frontal lobe processes were compared to evaluate quantitative measures of these deficits in Ex-Preterm vs. Ex-Term adolescents.Methods-We compared 43 Ex-Preterm with 26 Ex-Term adolescents using the P50 auditory potential, the Psychomotor Vigilance Task (PVT), a reaction time (RT) test, and Near Infrared Spectroscopy (NIRS).Results-The mean amplitude (±SE) of the P50 amplitude was similar in the Ex-Preterm (1.8 ±1.4µv) vs. Ex-Term adolescents (1.8±0.6µv, df=68, F=0.05, p=0.8), but the Ex-Preterm group showed a trimodal distribution in amplitude (High, 3.3±0.4 µv,df=42.25, F=19.2, p<0.01; Medium, 1.7±0.1 µv, df=39, F=0.41, p=0.53; Low, 0.7±0.1 µv, df=40, F=49.5, p<0.01) suggested by statistically significant variance between populations (Kolmogorov-Kuiper test, df=42.25, F=5.4, p<0.01). Mean RT was longer in Ex-Preterm (250±8 msec) vs. Ex-Term subjects (200±5 ms, df=68, F=18.8, p<0.001). PVT lapses were increased in Ex-Preterm subjects, and varied inversely with P50 amplitude (Overall Mean 17±5 lapses, df=67, F=5.34, p<0.05; Low P50 amplitude, 25±10, df=40, F=8.8, p<0.01; Medium, 21±11, df=38, F=5.37, p<0.05; High, 6±2, df=39, F=6.78, p<0.01) vs. ExTerm subjects (2±0.4 lapses, p<0.01). NIRS levels did not differ statistically, but tended to correlate with P50 amplitude in the Ex-Preterm group.Conclusions-These findings suggest differential pre-attentional, attentional and frontal lobe dysfunction in ex-preterm adolescents.Significance-These measures could provide a means to objectively assess differential dysregulation of arousal and attention in Ex-Preterm adolescents, allowing optimization of therapeutic designs.