Developmental cascades linking stress inoculation, arousal regulation, and resilience.

Stressful experiences that are challenging but not overwhelming appear to promote the development of arousal regulation and resilience. Variously described in studies of humans as inoculating, steeling, or toughening, the notion that coping with early life stress enhances arousal regulation and resilience is further supported by longitudinal studies of squirrel monkey development. Exposure to early life stress inoculation diminishes subsequent indications of anxiety, increases exploration of novel situations, and decreases stress-levels of cortisol compared to age-matched monkeys raised in undisturbed social groups. Stress inoculation also enhances prefrontal-dependent cognitive control of behavior and increases ventromedial prefrontal cortical volumes. Larger volumes do not reflect increased cortical thickness but instead represent surface area expansion of ventromedial prefrontal cortex. Expansion of ventromedial prefrontal cortex coincides with increased white matter myelination inferred from diffusion tensor magnetic resonance imaging. These findings suggest that early life stress inoculation triggers developmental cascades across multiple domains of adaptive functioning. Prefrontal myelination and cortical expansion induced by the process of coping with stress support broad and enduring trait-like transformations in cognitive, motivational, and emotional aspects of behavior. Implications for programs designed to promote resilience in humans are discussed.

Prefrontal plasticity and stress inoculation-induced resilience.

Coping with mild early life stress tends to make subsequent coping efforts more effective and therefore more likely to be used as a means of arousal regulation and resilience. Here we show that this developmental learning-like process of stress inoculation increases ventromedial prefrontal cortical volumes in peripubertal monkeys. Larger volumes do not reflect increased cortical thickness but instead represent surface area expansion of ventromedial prefrontal cortex. Expansion of ventromedial prefrontal cortex coincides with increased white matter myelination inferred from diffusion tensor magnetic resonance imaging. These findings suggest that the process of coping with early life stress increases prefrontal myelination and expands a region of cortex that broadly controls arousal regulation and resilience.

Stress-induced changes in corticosteroid receptor expression in primate hippocampus and prefrontal cortex.

Neurobiological studies of stress often focus on the hippocampus where cortisol binds with different affinities to two types of corticosteroid receptors, i.e., mineralocorticoid receptor (MR) and glucocorticoid receptor (GR). The hippocampus is involved in learning and memory, and regulates the neuroendocrine stress response, but other brain regions also play a role, especially prefrontal cortex. Here, we examine MR and GR expression in adult squirrel monkey prefrontal cortex and hippocampus after exposure to social stress in infancy or adulthood. In situ hybridization histochemistry with (35)S-labeled squirrel monkey riboprobes and quantitative film autoradiography were used to measure the relative distributions of MR and GR mRNA. Distinct cortical cell layer-specific patterns of MR expression differed from GR expression in three prefrontal regions. The relative distributions of MR and GR also differed in hippocampal Cornu Ammonis (CA) regions. In monkeys exposed to adult social stress compared to the no-stress control, GR expression was diminished in hippocampal CA1 (P=0.021), whereas MR was diminished in cell layer III of ventrolateral prefrontal cortex (P=0.049). In contrast, exposure to early life stress diminished GR but not MR expression in cell layers I and II of dorsolateral prefrontal cortex (P's<0.048). Similar reductions likewise occurred in ventrolateral prefrontal cortex, but the effects of early life stress on GR expression in this region were marginally not significant (P=0.053). These results provide new information on regional differences and the long-term effects of stress on MR and GR distributions in corticolimbic regions that control cognitive and neuroendocrine functions.

Cerebral blood flow in chronic symptomatic mild traumatic brain injury.

Patients with mild traumatic brain injury (MTBI) challenge physicians' skills and test their patience. Their manifold symptomatology is often not supported by objective neurological findings. We sought to compare regional cerebral blood flow (rCBF) between symptomatic subjects with longstanding MTBI and healthy controls, and to examine the correspondence between neuropsychological deficit and rCBF compromise. Twenty-eight clinically symptomatic male subjects with MTBI and twenty matched controls underwent neuropsychological testing and Tc-99m-HMPAO brain SPECT imaging. Neuropsychological test data were used to categorize subjects into sub-groups according to the presumed location of lesions based on their neurobehavioral deficits. Image subtraction comparisons were made between controls, all MTBI subjects and sub-groups. MTBI patients demonstrated regions of hypoperfusion in frontal, pre-frontal and temporal cortices, and sub-cortical structures. Hypoperfusion in 'frontal', 'left posterior' and to a lesser extent 'sub-cortical' sub-groups was concordant with neuropsychological localization. This was not the case for the 'right posterior' group, where no concordance was found. The rCBF is reduced in symptomatic patients with longstanding MTBI and unremarkable structural brain imaging. Although group analysis is appropriate for the generation of statistically significant differences, the clinical application of brain SPECT imaging in MTBI calls for a capability to associate clinical examination, neuropsychological assessment and cerebral perfusion at the individual subject level. Such competence is still to be attained.

Parent-daughter discrepancies in perception of family function in bulimia nervosa.

Eating disorders have traditionally been associated with disturbed family function. Most empirical data regarding this issue, however, were gathered from eating disorders patients. Attitudes, function, and inter-personal relationships were examined within 16 families with a member suffering from bulimia nervosa (BN) and compared to 16 matched healthy families. Perception of family function was significantly more derogatory in bulimic subjects than in their parents, while in control subjects and parents, perception was largely congruent. Subjects suffering from BN perceived their families as less cohesive, adaptable, and supportive than did healthy subjects. No such difference in perception of family function was observed between parents of respective groups. This preliminary study shows that parent-daughter discrepancy in perception of family function may prove more characteristic of eating disorder families than any particular deficit. Future research should aim to replicate these findings, incorporate them into treatment paradigms, and employ them to monitor treatment outcome.

[Emotional distress in Israeli medical students].

INTRODUCTION: Increased distress in medical students has been previously documented. However, causal relationship between putative, nh stress factors and emotional state has not yet been determined. Moreover, most data concerning mental health of medical students has been acquired in the USA. METHODS: A list of conceivable stress factors and the Brief Symptom Inventory were used to identify specific loci of stress and examine levels of distress among first, third and fifth year Israeli medical students. RESULTS: Levels of mental distress in all subjects were higher than population norms, with the highest levels in the third (of six) year of Medical Faculty. Predefined stress factors were capable of accounting for most of the variance in medical student distress, although specific factors differed between year and gender. CONCLUSIONS: Considering medical students' reluctance to utilize mental health services, the attempt to modify stress-eliciting elements inherent to the Medical Faculty environment is particularly warranted.

Does short-term diet restriction in mice precipitate the development of anorexia?

Anorexia nervosa (AN) inevitably begins with dieting. Yet, it is unknown whether anyone who will ultimately suffer from anorexia is already ill upon "going on a diet", or whether disease begins during, and is perhaps triggered by, dieting. The objective of the following study was to precipitate anorexia by imposing diet restriction on animals, as a model for generating AN in humans. Three hundred young female Sabra mice were diet restricted to 40% of daily nutrient requirements for 12 days, lost 17% of body weight and were then re-fed ad-lib. All mice regained appetite and weight. Our conclusions are that diet restriction does not precipitate anorexia in mice. Our findings do not support a role for diet restriction per se in triggering AN.

A randomized, double-blind, placebo-controlled study of classical homeopathy in generalized anxiety disorder.

BACKGROUND: Homeopathy is commonly used for the treatment of medical and psychological conditions. Such prevalent use, however, is not supported by robust, methodologically sound research. This study evaluates the effect of homeopathic treatment in generalized anxiety disorder, a prevalent mental disorder characterized by an enduring pattern of excessive apprehension and distress and by mental and bodily complaints. METHOD: Forty-four patients with DSM-IV generalized anxiety disorder participated in a randomized, double-blind, placebo-controlled 10-week trial of individually tailored homeopathic remedy. Homeopathic therapy was administered by an expert who followed the traditional routines of homeopathic diagnosis and prescription. Thirty-nine subjects completed the study (20 in the active treatment group and 19 in the placebo group). Subjects' symptoms were rated before treatment and after 5 and 10 weeks of treatment, with the Hamilton Rating Scale for Anxiety (HAM-A) as main outcome measure. Additional measures of outcome included the Brief Symptom Inventory, the Psychological General Well-Being Index, the Hamilton Rating Scale for Depression, the Beck Depression Inventory, Spielberger's State-Trait Anxiety Inventory, and a Visual Analogue Scale of subjective distress. RESULTS: Significant (p <.05) improvement in most measures, including the HAM-A, was observed in both the active treatment and placebo groups, yet no group effect was observed. CONCLUSION: The effect of homeopathic treatment on mental symptoms of patients with generalized anxiety disorder did not differ from that of placebo. The improvement in both conditions was substantial. Improvement of such magnitude may account for the current belief in the efficacy of homeopathy and the current increase in the use of this practice.