Top-down and bottom-up control of stress-coping.

In this 30th anniversary issue review, we focus on the glucocorticoid modulation of limbic-prefrontocortical circuitry during stress-coping. This action of the stress hormone is mediated by mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) that are co-expressed abundantly in these higher brain regions. Via both receptor types, the glucocorticoids demonstrate, in various contexts, rapid nongenomic and slower genomic actions that coordinate consecutive stages of information processing. MR-mediated action optimises stress-coping, whereas, in a complementary fashion, the memory storage of the selected coping strategy is promoted via GR. We highlight the involvement of adipose tissue in the allocation of energy resources to central regulation of stress reactions, point to still poorly understood neuronal ensembles in the prefrontal cortex that underlie cognitive flexibility critical for effective coping, and evaluate the role of cortisol as a pleiotropic regulator in vulnerability to, and treatment of, trauma-related psychiatric disorders.

Neuroendocrine and immune responses to a cognitive stress challenge in veterans with and without PTSD.

BACKGROUND: PTSD has been associated with altered hypothalamus-pituitary-adrenal-axis (HPA-axis), immune and sympathetic nervous system (SNS) regulation. The purpose of this study was to evaluate the effect of cognitive stress on these systems in PTSD patients and controls. METHODS: The subjective units of distress score (SUDS), NK-cell response, plasma levels of noradrenalin and ACTH in response to cognitive stress were assessed in male veterans with PTSD (n=15) and age, region and year of deployment matched veterans without psychopathology (n=15). RESULTS: The challenge induced an increase in SUDS, noradrenalin, ACTH and NK-cell response in both groups. Baseline levels of ACTH were lower in PTSD patients. The test was experienced as more stressful by PTSD patients and resulted in an augmented ACTH response in patients. The noradrenalin and NK-cell responses showed no group differences. The ACTH response correlated with the severity of symptoms in patients, and the noradrenalin response correlated with the ACTH and NK-cell response in controls, but not in patients. DISCUSSION: PTSD patients experience more distress and present with an exaggerated pituitary response to this stressor. In addition, our results suggest an altered interaction between the HPA-axis, SNS and immune system in PTSD.

Neuropsychological performance is related to current social and occupational functioning in veterans with posttraumatic stress disorder.

BACKGROUND: Several studies have reported deficits in both immediate and delayed recall of verbal memory in patients with posttraumatic stress disorder (PTSD). However, most of these studies had several methodological disadvantages. None of these studies assessed parameters related to social or occupational functioning. METHODS: Fifty Dutch veterans of UN peacekeeping missions (25 with PTSD and 25 without PTSD) were assessed with a comprehensive neuropsychological test battery consisting of four subtests of the Wechsler Adult Intelligence Scale-III, California Verbal-Learning Test, and the Rey Auditory Verbal-Learning Test. Veterans with PTSD were free of medication and substance abuse. RESULTS: Veterans with PTSD had similar total intelligence quotient scores compared to controls, but displayed deficits of figural and logical memory. Veterans with PTSD also performed significantly lower on measures of learning and immediate and delayed verbal memory. Memory performance accurately predicted current social and occupational functioning. CONCLUSIONS: Deficits of memory performance were displayed in a sample of medication- and substance abuse-free veterans with PTSD. Deficits in memory performance were not related to intelligence quotient, length of trauma exposure, or time since trauma exposure. This study showed that cognitive performance accurately predicted current social and occupational functioning in veterans with PTSD.

Thinner prefrontal cortex in veterans with posttraumatic stress disorder.

Structural neuroimaging studies in posttraumatic stress disorder (PTSD) have focused primarily on structural alterations in the medial temporal lobe, and only a few have examined grey matter reductions in the cortex. Recent advances in computational analysis provide new opportunities to use semi-automatic techniques to determine cortical thickness, but these techniques have not yet been applied in PTSD. Twenty-five male veterans with PTSD and twenty-five male veterans without PTSD matched for age, year and region of deployment were recruited. All the subjects were scanned using MRI. Subjects' brains were aligned using cortex-based alignment in a region of interest based approach. Individual cortical thickness maps were calculated from the MR images. Regions of interest examined included the bilateral superior frontal gyri, bilateral middle frontal gyri, bilateral inferior frontal gyri, bilateral superior temporal gyri, and bilateral middle temporal gyri. In a large number of patients and controls, IQ scores and memory scores were also obtained. Individual cortical thickness maps were calculated from the MR images. Veterans with PTSD revealed reduced cortical thickness in the bilateral superior and middle frontal gyri, the left inferior frontal gyrus, and the left superior temporal gyrus. Veterans with PTSD performed significantly worse on memory measures compared to control veterans. Cortical thickness correlated with memory measures in the veterans without PTSD, but not in the veterans with PTSD. Cortical thinning in these regions may thus correspond to functional abnormalities observed in patients with PTSD.

Neural correlates of associative learning and memory in veterans with posttraumatic stress disorder.

Impaired attention and memory are symptoms frequently associated with posttraumatic stress disorder (PTSD). Although patients with PTSD frequently report memory difficulties and empirical research provides support for a memory deficit in PTSD, as of yet, no fMRI study has adequately investigated the neural correlates of learning and memory of neutral (i.e. not trauma related) material in patients with PTSD compared to controls. Twelve male veterans with PTSD, and twelve male veterans without PTSD, were recruited, and matched for age, region and year of deployment. Encoding and retrieval of 12 word-pair associates was assessed during fMRI in both experimental groups. Compared to controls veterans with PTSD revealed underactivation of the frontal cortex, and overactivation of the temporal cortex during the encoding phase. Retrieval of the paired associates resulted in underactivation of right frontal cortex, bilateral middle temporal gyri, and the left posterior hippocampus/parahippocampal gyrus in patients with PTSD. Deficits in memory performance in PTSD appear to be related to altered activity in fronto-temporal areas during both the encoding and retrieval phase of memory processing.

Precuneal activity during encoding in veterans with posttraumatic stress disorder.

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.

Altered pain processing in veterans with posttraumatic stress disorder.

CONTEXT: Posttraumatic stress disorder (PTSD) is a chronic and debilitating anxiety disorder. Several brain areas related to pain processing are implicated in PTSD. To our knowledge, no functional imaging study has discussed whether patients with PTSD experience and process pain in a different way than control subjects. OBJECTIVE: To examine neural correlates of pain processing in patients with PTSD. DESIGN: The experimental procedure consisted of psychophysical assessment and neuroimaging with functional magnetic resonance imaging. Two conditions were assessed during functional magnetic resonance imaging in both experimental groups, one condition with administration of a fixed temperature of 43 degrees C (fixed-temperature condition) and the other condition with an individual temperature for each subject but with a similar affective label equaling 40% of the subjective pain intensity (individual temperature condition). SETTING: Academic outpatient unit in a department of military psychiatry in collaboration with an imaging center at a psychiatric hospital. PARTICIPANTS: Twelve male veterans with PTSD and 12 male veterans without PTSD were recruited and matched for age, region of deployment, and year of deployment. MAIN OUTCOME MEASURES: Changes in functional magnetic resonance imaging blood oxygenation level-dependent response to heat stimuli, reflecting increased and decreased activity of brain areas involved in pain processing. RESULTS: Patients with PTSD rated temperatures in the fixed-temperature assessment as less painful compared with controls. In the fixed-temperature condition, patients with PTSD revealed increased activation in the left hippocampus and decreased activation in the bilateral ventrolateral prefrontal cortex and the right amygdala. In the individual temperature condition, patients with PTSD showed increased activation in the right putamen and bilateral insula, as well as decreased activity in the right precentral gyrus and the right amygdala. CONCLUSIONS: These data provide evidence for reduced pain sensitivity in PTSD. The witnessed neural activation pattern is proposed to be related to altered pain processing in patients with PTSD.