Zeev Kaplan

Blunted HPA axis response to stress influences susceptibility to posttraumatic stress response in rats.

BACKGROUND Posttraumatic stress disorder (PTSD) is associated with low levels of circulating cortisol, and recent studies suggest that cortisol administration may reduce PTSD symptoms. This study investigated the role of cortisol in the manifestation of anxiety- and fear-like symptoms in an animal model of PTSD. METHOD Magnitude of changes in prevalence of anxiety-like behaviors on the elevated plus-maze and nonhabituated exaggerated startle reaction were compared in three strains of rats exposed to predator stress, with and without prior corticosterone treatment. Extreme behavioral changes in both paradigms implied an extreme behavioral response (EBR), representing PTSD-like symptoms. RESULTS Lewis rats exhibited greater baseline anxiety-like behaviors and greater stress-induced increases in anxiety-like behaviors than Fischer F344 or Sprague-Dawley rats, with only minor corticosterone increases following stress. Prevalence of EBR was 50% among Lewis rats compared with 10% of Fischer F344 and 25% of Sprague-Dawley rats. Administering corticosterone 1 hour before stress exposure reduced the prevalence of EBR from 50% to 8% in the Lewis rats. CONCLUSIONS These results suggest that a blunted HPA response to stress may play a causal role in this model of PTSD and that this susceptibility may be prevented by administration of cortisol before stress exposure.

POSTTRAUMATIC STRESS DISORDER, TENDERNESS AND FIBROMYALGIA

The aims of the present study were to inquire into the prevalence of fibromyalgia syndrome, to assess nonarticular tenderness, to measure fibromyalgia syndrome-related symptoms, quality of life, and functional impairment among posttraumatic stress disorder (PTSD) patients as compared with control subjects. Furthermore, the differences between the PTSD patients with and without fibromyalgia syndrome were studied. Twenty-nine PTSD patients and 37 control subjects were assessed as to the diagnosis of fibromyalgia syndrome according to the American College of Rheumatology. Tenderness was assessed manually and with a dolorimeter. Fibromyalgia syndrome-related symptoms, quality of life, physical functioning, PTSD symptomatology, and psychiatric features were assessed by valid and reliable self-report inventories. Results showed that the prevalence of fibromyalgia syndrome in the PTSD group was 21% vs. 0% in the control group. Furthermore, the PTSD group was more tender than the control group. PTSD subjects suffering from fibromyalgia syndrome were more tender, reported more pain, lower quality of life, higher functional impairment and suffered more psychological distress than the PTSD patients not having fibromyalgia syndrome. It is suggested that previous reports on diffuse pain in PTSD in fact described undiagnosed fibromyalgia syndrome. The link between psychological stress and pain syndromes is emphasized.

The Neuropeptide Y (NPY)-ergic System is Associated with Behavioral Resilience to Stress Exposure in an Animal Model of Post-Traumatic Stress Disorder

Converging evidence implicates the regulatory neuropeptide Y (NPY) in anxiety- and depression-related behaviors. The present study sought to assess whether there is an association between the magnitude of behavioral responses to stress and patterns of NPY in selected brain areas, and subsequently, whether pharmacological manipulations of NPY levels affect behavior in an animal model of PTSD. Animals were exposed to predator-scent stress for 15 min. Behaviors were assessed with the elevated plus maze and acoustic startle response tests 7 days later. Preset cutoff criteria classified exposed animals according to their individual behavioral responses. NPY protein levels were assessed in specific brain regions 8 days after the exposure. The behavioral effects of NPY agonist, NPY-Y1-receptor antagonist, or placebo administered centrally 1 h post-exposure were evaluated in the same manner. Immunohistochemical technique was used to detect the expression of the NPY, NPY-Y1 receptor, brain-derived neurotrophic factor, and GR 1 day after the behavioral tests. Animals whose behavior was extremely disrupted (EBR) selectively displayed significant downregulation of NPY in the hippocampus, periaqueductal gray, and amygdala, compared with animals whose behavior was minimally (MBR) or partially (PBR) disrupted, and with unexposed controls. One-hour post-exposure treatment with NPY significantly reduced prevalence rates of EBR and reduced trauma-cue freezing responses, compared with vehicle controls. The distinctive pattern of NPY downregulation that correlated with EBR as well as the resounding behavioral effects of pharmacological manipulation of NPY indicates an intimate association between NPY and behavioral responses to stress, and potentially between molecular and psychopathological processes, which underlie the observed changes in behavior. The protective qualities attributed to NPY are supported by the extreme reduction of its expression in animals severely affected by the stressor and imply a role in promoting resilience and/or recovery.

Effect of transcranial magnetic stimulation in posttraumatic stress disorder: a preliminary study

BACKGROUND Transcranial magnetic stimulation (TMS) has become, over the last few years, a promising avenue for new research in affective disorders. In this study we have evaluated the clinical effect of slow TMS on posttraumatic stress disorder (PTSD) symptoms. METHODS Ten PTSD patients were given one session of slow TMS with 30 pulses of 1 m/sec each, 15 to each side of the motor cortex. RESULTS Symptoms of PTSD were assessed by using three psychological assessment scales, at four different time points. In this first, pilot, open study, TMS was found to be effective in lowering the core symptoms of PTSD: avoidance (as measured by the Impact of Event Scale), anxiety, and somatization (as measured by the Symptom Check List-90). A general clinical improvement was found (as measured by the Clinical Global Impression scale); however, the effect was rather short and transient. CONCLUSIONS The present study showed TMS to be a safe and tolerable intervention with possibly indications of therapeutic efficacy for PTSD patients.

Long-term down-regulation of BDNF mRNA in rat hippocampal CA1 subregion correlates with PTSD-like behavioural stress response

Brain-derived neurotrophic factor (BDNF) and its intracellular kinase-activating receptor TrkB, have been implicated in the neurobiological mechanisms underlying the clinical manifestations of PTSD, especially those related to synaptic efficacy and neural plasticity. BDNF interacts with components of the stress response such as corticosterone, and plays an important role in growth, maintenance and functioning of several neuronal systems. This study employed an animal model of PTSD to investigate the relationship between prevalence rates of distinct patterns of behavioural responses to predator stress, circulating levels of corticosterone and local levels of mRNA for BDNF, TrkB and two other neurotrophic factors in selected brain areas. Animals whose behaviour was extremely disrupted by exposure selectively displayed significant down-regulation of mRNA for BDNF and up-regulation of TrkB mRNA in the CA1 subregion of the hippocampus, compared to animals whose behaviour was minimally or partially affected and to unexposed controls. The response was consistent throughout the entire study only in CA1. The consistent long-term the BDNF down-regulation and TrkB up-regulation associated with extreme behavioural compromise may be associated with chronic stress-induced psychopathological processes, especially in the hippocampus. The corresponding changes in neural plasticity and synaptic functioning may mediate clinical manifestations of PTSD.

Power spectral analysis of heart rate variability in psychiatry.

Power spectrum analysis of heart rate variability (PSA of HRV) is a promising method, which can be used as an index of cardiac autonomic balance. PSA of HRV is a noninvasive technique, based on ECG sampling of RR interval variation, thus providing a dynamic assessment of sympathetic and parasympathetic tone, reflecting the interactions between the two. It has been shown to have potential value in various laboratory and clinical conditions. It is influenced by many factors such as age, sex, position, breathing, smoking, hour of the day and medications. Different methods of data processing by various authors have often elicited conflicting results. Standard values are not yet available to be used or compared in different settings. From the interest it has raised, it may be expected that this method will be in widespread use in clinical practice in the future, providing a useful tool, both for diagnostic and prognostic purposes, as well as serving as a further aid towards monitoring therapeutic interventions. This review highlights techniques of dynamic assessment of HRV and studies of its clinical applications in psychiatry in particular. It raises the potentially important prognostic implications of protracted autonomic dysfunction in psychiatric patient populations, especially for cardiovascular morbidity and mortality.

Anisomycin, a protein synthesis inhibitor, disrupts traumatic memory consolidation and attenuates posttraumatic stress response in rats.

BACKGROUND Paradoxical changes in memory represent a troublesome characteristic of posttraumatic stress disorder (PTSD). Exceptionally vivid intrusive memories of some aspects of the trauma are mingled with patchy amnesia regarding other important aspects. Molecular studies of the memory process suggest that the conversion from labile short-term memory into long-term fixed traces involves protein synthesis. This study assessed the effects of administration of anisomycin, a protein synthesis inhibitor, after initial exposure, after exposure to a cue associated with triggering experience, and after reexposure to the triggering trauma in an animal model of PTSD. METHOD Magnitude of changes in prevalence of anxiety-like behaviors on the elevated plus-maze and nonhabituated exaggerated startle reaction were compared in rats that were exposed to predator stress, with and without microinjection of anisomycin. RESULTS Microinjection of anisomycin before and after stress exposure reduced anxiety-like and avoidant behavior, reduced the mean startle amplitude, and reversed the stress-induced habituation deficit 7 days later. The persistent anxiety-like behaviors that were seen after stress exposure do not appear to be sensitive to anisomycin after reexposure to a cue associated with the event or after reexposure to the index experience. CONCLUSIONS Disruption of the process of traumatic memory consolidation may be useful for mitigating PTSD symptoms.

Administration of high-dose ketoconazole, an inhibitor of steroid synthesis, prevents posttraumatic anxiety in an animal model

Acute psychological stress is the presumed immediate cause of post-traumatic stress disorder (PTSD), and may also contribute to other anxiety disorders. Abnormal activity of the hypothalamic-pituitary-adrenal (HPA) axis has been tentatively implicated in some of the features of these disorders. Ketoconazole (KTCZ), an imidazole derivative, is a potent inhibitor of gonadal and adrenal steroidogenesis. The aim of this study was to explore the effects of KTCZ blockade of adrenal steroidogenesis, and consequent elevation of adreno-corticotropic hormone (ACTH), on a model of chronic post-traumatic anxiety in rats. Amelioration of anxious behaviors after reduction of corticosterone would suggest that corticosterone (and by implication cortisol in humans) is an important mediator of anxious symptoms: exacerbation of such behaviors would suggest that corticosterone elevations are only secondary, and possibly implicate corticotropin releasing hormone (CRH) and/or ACTH in the pathogenesis of anxious symptoms. We exposed rats for 10 min to cat scent, a prima facie valid model for acute psychological stress, with and without high dose KTCZ for 14 days. Treatment with KTCZ abolished the chronic behavioral effects of acute exposure to a cat scent. Lower levels of anxious behavior in KTCZ-treated and exposed rats were accompanied by lower plasma corticosterone, ACTH and prolactin (PRL) levels compared to untreated exposed rats. Results in this model implicate corticosterone, but not ACTH, in the pathogenesis of chronic anxiety following acute psychological stress.

Unsupervised Fuzzy Clustering Analysis Supports Behavioral Cutoff Criteria in an Animal Model of Posttraumatic Stress Disorder

BACKGROUND Unsupervised fuzzy clustering (UFC) analysis is a mathematical technique that groups together objects in the multidimensional feature space according to a specified similarity measurement, thereby yielding clusters of similar data points that can be represented by a set of prototypes or centroids. METHODS Since clinical studies of mental disorders distinguish between affected and unaffected individuals, we designed an inclusion/exclusion criteria (cutoff behavioral criteria [CBC]) approach for animal behavioral studies. The effect of classifying the study population into clearly affected versus clearly unaffected individuals according to behaviors on two behavioral paradigms was statistically significant. RESULTS Here the raw data from previous studies were subjected to UFC algorithms as a means of objectively testing the validity of the concept of the CBC for our experimental model. The first UFC algorithm yielded two clearly discrete clusters, found to consist almost exclusively of the exposed animals in the one and unexposed animals in the other. The second algorithm yielded three clusters corresponding to animals designated as clearly affected, partially affected, and clearly unaffected. The algorithm for physiological data in addition to behavioral data failed to elicit discrete clusters. CONCLUSIONS The UFC analysis yielded data that support the conceptual contention of the CBC and lends additional validity to our previous behavioral studies.

Sexual Dysfunction in Male Posttraumatic Stress Disorder Patients

Background: Previous studies have suggested that sexual dysfunction may be associated with posttraumatic stress disorder (PTSD). Yet such studies have not examined a full range of sexual functioning and have not accounted for the possibility that medication used to treat PTSD may contribute to sexual dysfunction. Objective: The current study compares the various components of sexual functioning among three groups of males: (1) untreated PTSD patients (n = 15), (2) PTSD patients currently treated with selective serotonin reuptake inhibitor (SSRI) agents (n = 27) and (3) a group of normal controls (n = 49). Methods: All participants completed an 18-item questionnaire for assessment of sexual functioning. Those with PTSD also completed the Impact of Events Scale and the Symptom Check List-90 (SCL-90). Results: Untreated and treated PTSD patients had significantly poorer sexual functioning in all domains (desire, arousal, orgasm, activity and satisfaction) as compared to normal controls. Those treated with SSRI had greater impairment in desire, arousal and frequency of sexual activity with a partner. There was a high correlation between sexual dysfunction among the PTSD group and the anger-hostility subscale of the SCL-90. Conclusions: PTSD appears to be associated with pervasive sexual dysfunction that is exacerbated by treatment with SSRIs. PTSD may represent a heterogeneous syndrome. Patients with PTSD have a high rate of comorbid panic disorder, major depression and anxiety, and it could thus be argued that these comorbid disorders, rather than PTSD, accounted for the observed result. Future research aimed at understanding comorbidity and heterogeneity should help to illuminate the psychobiology of PTSD and eventually guide both medication and psychosocial treatments.