Faculty Bibliography

BACKGROUND: Neuroendocrine studies have shown profound alterations in HPA-axis regulation in posttraumatic stress disorder (PTSD). Based on baseline assessments and the response to dexamethasone, a hypothalamic overdrive with enhanced glucocorticoid feedback inhibition has been suggested. The dexamethasone-corticotrophin releasing hormone (DEX-CRH) test has shown to be a more sensitive test to assess HPA-axis dysregulation in major depression and therefore may provide a useful test tool to probe HPA-axis regulation in PTSD. METHODS: To evaluate the effect of PTSD on HPA-axis regulation, we compared the response to a DEX-CRH test between male veterans with PTSD (n=26) and male veterans, who had been exposed to similar traumatic events during their deployment, without PTSD (n=23). Patients and controls were matched on age, year and region of deployment. Additionally, we compared the response of PTSD patients with (n=13) and without co-morbid major depressive disorder (MDD) (n=13). RESULTS: No significant differences were observed in ACTH and cortisol response to the DEX-CRH test between patients and controls. PTSD patients with co-morbid MDD showed a significantly lower ACTH response compared to patients without co-morbid MDD. The response to the DEX-CRH test did not correlate with PTSD or depressive symptoms. CONCLUSION: The DEX-CRH test did not reveal HPA-axis abnormalities in PTSD patients as compared to trauma controls. PTSD patients with a co-morbid MDD showed an attenuated ACTH response compared to PTSD patients without co-morbid MDD, suggesting the presence of subgroups with different HPA-axis regulation within the PTSD group. Altered sensitivity of the CRH receptors at the pituitary or differences in AVP secretion might explain these differences in response.

BACKGROUND: Posttraumatic stress disorder (PTSD) is associated with altered hypothalamic-pituitary-adrenal (HPA) axis functioning. Arginine vasopressin (AVP), in conjunction with corticotrophin releasing hormone, has shown to be an important modulator of the HPA axis. In order to evaluate the effect of trauma and PTSD on central AVP secretion we assessed plasma AVP levels in equally trauma exposed veterans with and without PTSD and a non-traumatized healthy control group. METHODS: Assessment of plasma AVP in 29 male veterans with PTSD, 29 traumatized veterans without PTSD, matched for age, gender, year and region of deployment (trauma controls), and 26 age matched healthy controls. RESULTS: Plasma AVP levels were higher in PTSD patients compared to both healthy controls (p = 0.004) and trauma controls (p < 0.001). In PTSD patients without a comorbid MDD a significant correlation was observed between plasma AVP levels and symptoms of avoidance measured with the Clinician Administered PTSD Scale (CAPS). CONCLUSION: Elevated plasma AVP levels are specifically related to PTSD and not to exposure to traumatic stress during deployment. Our results indicate that AVP may play a role as an anxiogenic factor, but they do not support a role for AVP in the altered response to dexamethasone in PTSD.

Gamma-aminobutyric acid (GABA(A)) receptors are thought to play an important role in modulating the central nervous system in response to stress. Animal data have shown alterations in the GABA(A) receptor complex by uncontrollable stressors. SPECT imaging with benzodiazepine ligands showed lower distribution volumes of the benzodiazepine-GABA(A) receptor in the prefrontal cortex of patients with post-traumatic stress disorder (PTSD) in one, but not in another study. The objective of the present study was to assess differences in the benzodiazepine-GABA(A) receptor complex in veterans with and without PTSD using [(11)C]flumazenil and positron emission tomography (PET). Nine drug naive male Dutch veterans with deployment related PTSD and seven male Dutch veterans without PTSD were recruited, and matched for age, region and year of deployment. Each subject received a [(11)C]flumazenil PET scan and a structural magnetic resonance imaging scan. Dynamic 3D PET scans with a total duration of 60 min were acquired, and binding in template based and manually defined regions of interest (ROI) was quantified using validated plasma input and reference tissue models. In addition, parametric binding potential images were compared on a voxel-by-voxel basis using statistical parametric mapping (SPM2). ROI analyses using both template based and manual ROIs showed significantly reduced [(11)C]flumazenil binding in PTSD subjects throughout the cortex, hippocampus and thalamus. SPM analysis confirmed these results. The observed global reduction of [(11)C]flumazenil binding in patients with PTSD provides circumstantial evidence for the role of the benzodiazepine-GABA(A) receptor in the pathophysiology of PTSD and is consistent with previous animal research and clinical psychopharmacological studies.

Impaired attention and memory are symptoms frequently associated with posttraumatic stress disorder (PTSD). Previous studies have identified fronto-temporal alterations during encoding in patients with PTSD. We examine the role of the precuneus (located in the posteromedial parietal lobe) that is known to play a role in memory, but has largely been neglected in PTSD research. Male veterans with and without PTSD (n=12 per group) were subjected to fMRI during encoding of 12 neutral, non-trauma related word pairs. The precuneus was less activated in veterans with PTSD, which correlated significantly with the severity of PTSD. Like fronto-temporal regions the precuneus is differentially activated during memory formation in veterans with PTSD.

Posttraumatic stress disorder (PTSD) is associated with alterations in corticotrophin-releasing hormone (CRH) secretion. Plasma CRH levels, which are easily acquired, might serve as a predictor of hypothalamic CRH levels. Assessment of plasma CRH, adrenocorticotrophin hormone (ACTH), and cortisol levels in 31 veterans with PTSD, 30 traumatized veterans without PTSD matched on age, year, and region of deployment (traumacontrols), and 28 age-matched healthy controls (HCs) was carried out. Plasma CRH levels were higher in PTSD patients compared to both HCs (p=0.005) and traumacontrols (p=0.007). This led to our conclusion, that elevated plasma CRH levels are specifically related to PTSD and not to exposure to traumatic stress during deployment.

Posttraumatic stress disorder (PTSD) is associated with long-term changes in neurobiology. Brain areas involved in the stress response include the medial prefrontal cortex, hippocampus, and amygdala. Neurohormonal systems that act on the brain areas to modulate PTSD symptoms and memory include glucocorticoids and norepinephrine. Dysfunction of these brain areas is responsible for the symptoms of PTSD. Brain imaging studies show that PTSD patients have increased amygdala reactivity during fear acquisition. Other studies show smaller hippocampal volume. A failure of medial prefrontal/anterior cingulate activation with re-experiencing of the trauma is hypothesized to represent a neural correlate of the failure of extinction seen in PTSD. The brain has the capacity for plasticity in the aftermath of traumatic stress. Antidepressant treatments and changes in environment can reverse the effects of stress on hippocampal neurogenesis, and humans with PTSD showed increased hippocampal volume with both paroxetine and phenytoin.

Preclinical studies have shown long-term alterations in several hormonal systems including cortisol, dehydroepiandrosterone (DHEA) and DHEA-Sulfate, and estradiol. The purpose of this study was to assess cortisol, DHEA, and estradiol over a 24-hour period in women with early childhood sexual abuse and posttraumatic stress disorder (PTSD); with early abuse and without PTSD; and women without early abuse or PTSD. Forty-three women with early childhood sexual abuse and PTSD, early abuse without PTSD, and without abuse or PTSD, underwent a comprehensive assessment of hormones in plasma at multiple time points over a 24-hour period. Abused women with PTSD had lower concentrations of cortisol during the afternoon hours (12-8 p.m.) compared with women with abuse without PTSD and women without abuse or PTSD. DHEA-Sulfate was elevated throughout the 24-hour period in PTSD women, although this was of marginal statistical significance. There were no differences between groups in DHEA or estradiol. PTSD women also had increased cortisol pulsatility compared with the other groups. These findings suggest that a resting hypocortisolemia in the afternoon hours with increased cortisol pulsatility is associated with childhood abuse-related PTSD in women.