Ann M. Rasmusson

Biological studies of post-traumatic stress disorder

Post-traumatic stress disorder (PTSD) is the only major mental disorder for which a cause is considered to be known: that is, 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. This Review attempts to present the current state of this understanding on the basis of psychophysiological, structural and functional neuroimaging, and endocrinological, genetic and molecular biological studies in humans and in animal models.

Downregulation of BDNF mRNA in the Hippocampal Dentate Gyrus after Re-exposure to Cues Previously Associated with Footshock ☆ ☆☆

This study examined the effects of footshock stress and re-exposure to cues previously associated with footshock on expression of brain-derived neurotrophic factor (BDNF) mRNA in the hippocampus of male rats. Exposure to twenty 0.5-s 0.4-mA footshocks co-terminating with 70 dB, 5-s long pure tones over 60 min decreased dentate gyrus BDNF mRNA by 21.5%. Baseline BDNF mRNA levels returned to normal by two days after footshock exposure. Re-exposure for 60 min to the chamber and tones previously paired with 0.4 mA footshock decreased BDNF mRNA by 12%. Re-exposure to the conditioning chamber and tones previously paired with 0.6 mA footshock over 60 min decreased BDNF mRNA by 20.8%. The data suggest that psychological, as well as unconditioned physical stress, can decrease hippocampal BDNF mRNA. Possible implications for stress-related and other neuropsychiatric disorders associated with deficits in hippocampal function and volume, such as depression, post-traumatic stress disorder, and Alzheimers Disease, are discussed.

The role of mesoprefrontal dopamine neurons in the acquisition and expression of conditioned fear in the rat

The mesoprefrontal dopamine neurons are sensitive to physical, pharmacological and psychological stressors. In this report, the role of these neurons in the response to classical fear conditioning was investigated. 6-Hydroxydopamine lesions to the medial prefrontal cortex reduced dopamine levels to about 13% of controls but did not alter behavior during the acquisition of fear conditioning. As expected, conditioned fear increased dopamine metabolism (3,4-dihydroxyphenylacetic acid/dopamine ratio) in the nucleus accumbens in sham-lesion rats. The medial prefrontal 6-hydroxydopamine lesions did not alter this effect. During the expression, however, lesioned rats demonstrated a delayed extinction of the conditioned response without an overall increase in the initial conditioned response. This effect was consistent in rats receiving 6-hydroxydopamine lesions before or after the acquisition period. The calculated rates of extinction showed that the 6-hydroxydopamine lesioned rats had a reduced rate of extinction, but not acquisition, of fear conditioning. The results presented in this manuscript indicate that the mesoprefrontal dopamine neurons are involved in co-ordinating the normal extinction of a fear response but do not alter the acquisition of fearful behaviors. These data are consistent with the conclusion that the mesoprefrontal dopamine neurons are involved in maintaining the animals response adaptability with regards to stress-related changes in the external environment.

Neuropeptide-Y, cortisol, and subjective distress in humans exposed to acute stress: replication and extension of previous report

BACKGROUND We previously reported that stress-related release of cortisol and neuropeptide-Y (NPY) were significantly and positively associated in U.S. Army soldiers participating in survival training. Furthermore, greater levels of NPY were observed in individuals exhibiting fewer psychologic symptoms of dissociation during stress. This study tested whether these findings would be replicated in a sample of U.S. Navy personnel participating in survival school training. METHODS Psychologic as well as salivary and plasma hormone indices were assessed in 25 active duty personnel before, during, and 24 hours after exposure to U.S. Navy survival school stress. RESULTS Cortisol and NPY were significantly and positively associated during stress and 24 hours after stress; NPY and norepinephrine (NE) were significantly and positively related during and 24 hours after stress. There was a significant, negative relationship between psychologic distress and NPY release during stress. Finally, psychologic symptoms of dissociation reported at baseline predicted significantly less NPY release during stress. CONCLUSIONS These data replicate our previous studies demonstrating that acute stress elicits NPY release and that this release is positively associated with cortisol and NE release. These data also replicate our previous finding that greater levels of NPY release are associated with less psychologic distress suggesting that NPY confers anxiolytic activity.

Low baseline and yohimbine-stimulated plasma neuropeptide Y (NPY) levels in combat-related PTSD

BACKGROUND Consistent with many studies demonstrating enhanced reactivity of the sympathetic nervous system in posttraumatic stress disorder (PTSD), the administration of yohimbine, a noradrenergic alpha(2)-antagonist, has been shown to increase core symptoms of PTSD and to induce greater increases in plasma 3-methyl-4-hydroxy-phenyl-glycol (MHPG) in subjects with PTSD compared with healthy control subjects. In turn, neuropeptide Y (NPY) has been shown to inhibit the release of norepinephrine from sympathetic noradrenergic neurons. METHODS In the following study, plasma NPY responses to yohimbine and placebo were measured in a subgroup of 18 subjects with PTSD and 8 healthy control subjects who participated in the previous study of the effect of yohimbine on plasma MHPG. RESULTS The PTSD subjects had lower baseline plasma NPY and blunted yohimbine-stimulated increases in plasma NPY compared with the healthy control subjects. Within the PTSD group, baseline plasma NPY levels correlated negatively with combat exposure scale scores, baseline PTSD and panic symptoms, and yohimbine-stimulated increases in MHPG and systolic blood pressure. CONCLUSIONS This study suggests that combat stress-induced decreases in plasma NPY may mediate, in part, the noradrenergic system hyperreactivity observed in combat-related PTSD. The persistence of this decrease in plasma NPY may contribute to symptoms of hyperarousal and the expression of exaggerated alarm reactions, anxiety reactions, or both in combat veterans with PTSD long after war.

Increased pituitary and adrenal reactivity in premenopausal women with posttraumatic stress disorder.

BACKGROUND Limited studies of hypothalamic-pituitary-adrenal axis regulation in posttraumatic stress disorder have been performed in premenopausal women. We therefore undertook a study of hypothalamic-pituitary-adrenal axis regulation in this population. METHODS Outpatient posttraumatic stress disorder subjects were compared with healthy, age- and weight-matched nontraumatized subjects. Subjects were free from psychotropic medications, alcohol and other illicit substances for at least 4 weeks before study. Menstrual cycle phase was determined by monitoring the LH surge and plasma progesterone levels. Corticotropin releasing factor and adrenocorticotropin stimulation tests, as well as 24-hour urinary-free cortisol measurements were performed. RESULTS Corticotropin releasing factor test: Baseline adrenocorticotropic hormone and cortisol levels did not differ between the 12 PTSD and 11 comparison subjects, but the posttraumatic stress disorder group had greater adrenocorticotropic hormone and cortisol responses to corticotropin releasing factor, as well as a later cortisol peak. Adrenocorticotropic hormone test: Baseline cortisol levels did not differ between the 10 posttraumatic stress disorder subjects and seven controls, but the posttraumatic stress disorder group showed greater cortisol responses to adrenocorticotropic hormone. Peak cortisol responses to corticotropin releasing factor and adrenocorticotropic hormone were correlated with each other and with 24-hour urinary-free cortisol excretion. CONCLUSIONS Pituitary and adrenal hyperreactivity to exogenous corticotropin releasing factor and adrenocorticotropic hormone is demonstrated in premenopausal women with chronic posttraumatic stress disorder. Cortisol hyperreactivity thus may play a role in the pathophysiology of posttraumatic stress disorder in women.

Relationship among plasma cortisol, catecholamines, neuropeptide Y, and human performance during exposure to uncontrollable stress.

Objective Although many people are exposed to trauma, only some individuals develop posttraumatic stress disorder; most do not. It is possible that humans differ in the degree to which stress induces neurobiological perturbations of their threat response systems, which may result in a differential capacity to cope with aversive experiences. This study explored the idea that differences in the neurobiological responses of individuals exposed to threat are significantly related to psychological and behavioral indices. Methods Individual differences in neurohormonal, psychological, and performance indices among 44 healthy subjects enrolled in US Army survival school were investigated. Subjects were examined before, during, and after exposure to uncontrollable stress. Results Stress-induced release of cortisol, neuropeptide Y, and norepinephrine were positively correlated; cortisol release during stress accounted for 42% of the variance in neuropeptide Y release during stress. Cortisol also accounted for 22% of the variance in psychological symptoms of dissociation and 31% of the variance in military performance during stress. Conclusions Because dissociation, abnormalities in the hypothalamic-pituitary-adrenocortical axis, and catecholamine functioning have all been implicated in the development of stress disorders such as posttraumatic stress disorder, these data suggest that some biological differences may exist before index trauma exposure and before the development of stress-related illness. The data also imply a relationship among specific neurobiological factors and psychological dissociation. In addition, the data provide clues about the way in which individuals’ psychobiological responses to threat differ from one another.

Decreased Cerebrospinal Fluid Allopregnanolone Levels in Women with Posttraumatic Stress Disorder

BACKGROUND Alterations in the gamma-amino-butyric acid (GABA) neurotransmitter system have been identified in some populations with posttraumatic stress disorder (PTSD). METHODS To further investigate factors of relevance to GABAergic neurotransmission in PTSD, we measured cerebrospinal fluid (CSF) levels of allopregnanolone and pregnanolone combined (ALLO: congeners that potently and positively modulate effects of GABA at the GABA(A) receptor), 5alpha-dihydroprogesterone (5alpha-DHP: the immediate precursor for allopregnanolone), dehydroepiandrosterone (DHEA: a negative modulator of GABA(A) receptor function), and progesterone with gas chromatography, mass spectrometry in premenopausal women with (n = 9) and without (n = 10) PTSD. Subjects were free of psychotropic medications, alcohol, and illicit drugs; all were in the follicular phase of the menstrual cycle except three healthy and four PTSD subjects receiving oral contraceptives. RESULTS There were no group differences in progesterone, 5alpha-DHP, or DHEA levels. The PTSD group ALLO levels were < 39% of healthy group levels. The ALLO/DHEA ratio correlated negatively with PTSD re-experiencing symptoms (n = -.82, p < 008; trend) and with Profile of Mood State depression/dejection scores (n = -0.70, p < 0008). CONCLUSION Low CSF ALLO levels in premenopausal women with PTSD might contribute to an imbalance in inhibitory versus excitatory neurotransmission, resulting in increased PTSD re-experiencing and depressive symptoms.

The neuroendocrinology of posttraumatic stress disorder: new directions.

Studies of the hypothalamic-pituitary-adrenal (HPA) axis in persons with posttraumatic stress disorder (PTSD) have produced variable findings. This review focuses on the factors likely to have affected the outcome of these studies, including population characteristics and experimental design. Also discussed is a possible role for the adrenal neurosteroid dehydroepiandrosterone (DHEA) as a mediator of HPA axis adaptation to extreme stress and the psychiatric symptoms associated with PTSD. The antiglucocorticoid properties of DHEA may contribute to an upregulation of HPA axis responses as well as mitigate possible deleterious effects of high cortisol levels on the brain in some PTSD subpopulations. The neuromodulatory effects of DHEA and its metabolite DHEAS at gamma-aminobutyric acid and N-methyl-D-aspartate receptors in the brain may contribute to psychiatric symptoms associated with PTSD. The possible importance of other neurohormone systems in modulating HPA axis and symptom responses to traumatic stress is also discussed. Understanding the complex interactions of these stress-responsive neurosteroid and peptide systems may help explain the variability in patterns of HPA axis adaptation, brain changes, and psychiatric symptoms observed in PTSD and lead to better targeting of preventive and therapeutic interventions.

Clinical and Functional Correlates of Posttraumatic Stress Disorder in Urban Adolescent Girls at a Primary Care Clinic

OBJECTIVE To identify clinical and functional correlates of posttraumatic stress disorder (PTSD) in trauma-exposed urban adolescent girls. METHOD Ninety female adolescents aged 12 to 21 years (mean 17.3 years) who presented for routine medical care at an adolescent primary care clinic were assessed with self-report questionnaires and interviews for trauma exposure, posttraumatic stress symptoms, other psychopathology, and psychosocial, family, and school function. RESULTS Ninety-two percent (n = 83) endorsed at least one trauma. Witnessing community violence (85.6%) and hearing about a homicide (67.8%) were the most common traumatic events endorsed. Twelve (14.4%) and 10 (11.6%) traumatized girls met DSM-IV symptom criteria for full and partial PTSD, respectively. Compared with traumatized girls without PTSD, girls with PTSD were significantly more depressed, used more cigarettes and marijuana, and were more likely to have failed a school grade, been suspended from school, or been arrested. CONCLUSIONS Urban adolescent girls are exposed to multiple types of trauma. Whereas most develop at least one posttraumatic stress symptom, girls who meet full symptom criteria for PTSD show evidence of other psychopathology, increased cigarette and marijuana use, and poorer school performance. Further research is needed to identify and treat inner-city girls with PTSD.