Is PTSD an Evolutionary Survival Adaptation Initiated by Unrestrained Cytokine Signaling and Maintained by Epigenetic Change?

INTRODUCTION: Treatment outcomes for PTSD with current psychological therapies are poor, with very few patients achieving sustained symptom remission. A number of authors have identified physiological and immune disturbances in Post Traumatic Stress Disorder (PTSD) patients, but there is no unifying hypothesis that explains the myriad features of the disorder. MATERIALS AND METHODS: The medical literature was reviewed over a 6-year period primarily using the medical database PUBMED. RESULTS: The literature contains numerous papers that have identified a range of physiological and immune dysfunction in association with PTSD. This paper proposes that unrestrained cytokine signaling induces epigenetic changes that promote an evolutionary survival adaptation, which maintains a defensive PTSD phenotype. The brain can associate immune signaling with past threat and initiate a defensive behavioral response. The sympathetic nervous system is pro-inflammatory, while the parasympathetic nervous system is anti-inflammatory. Prolonged cholinergic withdrawal will promote a chronic inflammatory state. The innate immune cytokine IL-1ß has pleiotropic properties and can regulate autonomic, glucocorticoid, and glutamate receptor functions, sleep, memory, and epigenetic enzymes. Changes in epigenetic enzyme activity can potentially alter phenotype and induce an adaptation. Levels of IL-1ß correlate with severity and duration of PTSD and PTSD can be prevented by bolus administration of hydrocortisone in acute sepsis, consistent with unrestrained inflammation being a risk factor for PTSD. The nervous and immune systems engage in crosstalk, governed by common receptors. The benefits of currently used psychiatric medication may arise from immune, as well as synaptic, modulation. The psychedelic drugs (3,4-Methylenedioxymethamphetamine (MDMA), psilocybin, and ketamine) have potent immunosuppressive and anti-inflammatory effects on the adaptive immune system, which may contribute to their reported benefit in PTSD. There may be distinct PTSD phenotypes induced by innate and adaptive cytokine signaling. CONCLUSION: In order for an organism to survive, it must adapt to its environment. Cytokines signal danger to the brain and can induce epigenetic changes that result in a persistent defensive phenotype. PTSD may be the price individuals pay for the genomic flexibility that promotes adaptation and survival.

Five-Year PTSD Symptom Remission in Two Patients Following Treatment With Rivastigmine.

INTRODUCTION: The beneficial effect of rivastigmine, an acetylcholinesterase inhibitor (AChEi), which increases levels of acetylcholine (ACh), was first reported in 2013. This paper replicates those findings and reports sustained symptom remission. METHODS AND MATERIALS: The high-frequency (HF) component of heart rate variability (HRV) is a measure of cholinergic withdrawal and was measured using a Zephyr Bioharness HR monitor, pre- and post-commencement of treatment. Data analysis was performed using Kubios HRV software. PTSD symptom severity was assessed using the Post-Traumatic Checklist-Civilian (PCL-C). RESULTS: Low HF HRV was observed in both patients before rivastigmine treatment and reductions in PCL-C scores paralleled increases in HF HRV values. Follow-up revealed low HF HRV values in both patients despite PCL-C scores indicating remission. Sympathetic nervous system hyperactivity was observed in one patient, just before a suicide attempt. Following rivastigmine treatment, the patient had no further suicidal ideation or attempts. Another patient reported worsening of her PTSD symptoms in the peri-menstrual period, which was abolished by rivastigmine. She also experienced symptom relapse following prolonged infections. CONCLUSION: Low HF HRV has been reported in PTSD patients, but findings have been inconsistent. Cholinergic withdrawal could explain the disturbances in sleep, learning, and memory seen in PTSD patients. The relapse of symptoms following prolonged infection implicates the immune system as a possible initiator of the disorder. ACh and estrogen have anti-inflammatory properties, supporting a possible role of inflammation in initiating PTSD. The effect of rivastigmine treatment should be tested in properly controlled clinical trials.

Influence of postexercise cooling techniques on heart rate variability in men.

The reduction of core body temperature (T(C)) is vitally important in the treatment of hyperthermia; however, little is known regarding the impact of cooling treatments on the autonomic control of heart rate (HR). The aim of the present study was to examine the influence of three field-based hyperthermia treatments on the neural control of HR via heart rate variability (HRV). Following exercise-induced hyperthermia (T(C) approximately 40.0 degrees C) in a warm environment (34.2 +/- 0.5 degrees C), nine healthy, active men were treated during recovery, in a randomized order, with intravenous cold saline infusion (IV) or ice packs (ICE) or fan cooling with intermittent water spray (FAN) for 40 min. During each treatment, HR dynamics via power spectral (VLF, LF, HF), Poincare plot (SD1, SD2), approximate entropy (ApEn) and short- (alpha(1)) and long-term (alpha(2)) fractal scaling analyses were determined every 10 min. At recovery onset, HR and T(C) were similar between treatments and were significantly reduced over the 40 min recovery period. During recovery, HR and alpha(2) were significantly reduced from initial levels but were significantly greater for IV compared with ICE and FAN. In contrast, VLF, LF, HF, SD1, SD2 and ApEn increased during recovery, with all being significantly lower for IV compared with ICE and/or FAN. The present results demonstrated that IV, compared with ICE and FAN, resulted in significantly greater HR, reduced spectral and geometrical HRV, lower HR complexity and reduced long-term HR control, indicative of reduced vagal and/or increased sympathetic modulation. Specific treatments for exercise-induced hyperthermia may result in an altered sympathovagal balance that requires further examination.

Efficacy of field treatments to reduce body core temperature in hyperthermic subjects.

PURPOSE: To contrast the effects of three postcooling techniques in reducing body core temperature (Tc) in exercise-induced hyperthermic participants on the cessation of exercise. METHODS: Eleven healthy active male volunteers were cooled during a 40-min period using three different methods: ice packs to the neck, axillae, and groin (ICE); water spray and fan (FAN); and 2 L of chilled (20 degrees C) intravenous saline administered during a 20-min period (IV). Rate of decrease in Tc, cardiovascular responses, and any incidence of reported adverse effects were investigated. Trials were presented in a counterbalanced order with the volunteers' body core temperature being elevated to 40.0 degrees C on three occasions via an intermittent walk-run (2 min at 6 km x h and 4 min at 10 km x h) protocol conducted within a climate-controlled chamber (34.2 +/- 0.5 degrees C and 62.3 +/- 3.1% relative humidity). RESULTS: Rate of Tc reduction during the first 20 min of cooling was greater for FAN compared with ICE (0.09 +/- 0.02 degrees C.min vs 0.07 +/- 0.02 degrees C.min, P < 0.05), whereas IV did not differ with the other trials (0.08 +/- 0.01 degrees C.min, P > 0.05). Three participants complained of numbness or paresthesia in their arm or hand during administration of the chilled saline, although these symptoms resolved within 5 min of ceasing the infusion. CONCLUSIONS: All three cooling techniques reduced Tc and would be suitable for first aid application in a field setting during transportation to adequate medical facilities. Chilled IV saline did not produce any contraindications, providing a suitable alternative for Tc cooling.