Avoidant symptoms in PTSD predict fear circuit activation during multimodal fear extinction

Convergent evidence suggests that individuals with posttraumatic stress disorder (PTSD) exhibit exaggerated avoidance behaviors as well as abnormalities in Pavlonian fear conditioning. However, the link between the two features of this disorder is not well understood. In order to probe the brain basis of aberrant extinction learning in PTSD, we administered a multimodal classical fear conditioning/extinction paradigm that incorporated affectively relevant information from two sensory channels (visual and tactile) while participants underwent fMRI scanning. The sample consisted of fifteen OEF/OIF veterans with PTSD. In response to conditioned cues and contextual information, greater avoidance symptomatology was associated with greater activation in amygdala, hippocampus, vmPFC, dmPFC, and insula, during both fear acquisition and fear extinction. Heightened responses to previously conditioned stimuli in individuals with more severe PTSD could indicate a deficiency in safety learning, consistent with PTSD symptomatology. The close link between avoidance symptoms and fear circuit activation suggests that this symptom cluster may be a key component of fear extinction deficits in PTSD and/or may be particularly amenable to change through extinction-based therapie

Cannabinoidok szerepe a traumák által előidézett viselkedési zavarok kialakulásában = The role of cannabinoids in the development of trauma-induced behavioral deficits

A projekt fontos felismerése, hogy a traumák által előidézett poszt-traumás stressz zavar-szerű viselkedési zavarok neuronális háttere erősen függ a traumatikus élmény jellegétől, és attól a kihívástól, amelyet a kísérleti szituáció jelent. Sőt, a trauma által előidézett idegrendszeri változásoknak van egy olyan időbeli fejlődése, amely a viselkedés szintjén nem ismerhető fel. Ez a komplexitás tükörképe a humán zavar komplexitásának, és magyarázatul szolgálhat a zavar kezelésének nehézségeire. Eredményeink arra is rámutatnak, hogy a zavar laboratóriumi tanulmányozása komplex megközelítést igényel; a szokványosan alkalmazott kétnapos kondicionált félelem teszt nem alkalmas a traumák által előidézett viselkedési zavarok mechanizmusainak megértésére. Eredményeink szerint a cannabinoidok szerepét a viselkedés szabályozásában a ""coping"" stratégiákkal összefüggésben érthetjük meg. A fokozott anandamid és esetleg 2-AG jelátvitel az aktív coping stratégiákat erősíti. Azok az alapvető viselkedési stratégiák, amelyek alapján az egyed megválaszolja a környezeti kihívásokat (vagyis a coping), fontos szerepet játszanak a pszichiátriai zavarok kialakulásában, és az aktív coping stratégiák erősítését konkrét terápiás célként jelölték meg több pszichiátriai zavar esetében. Így az endocannabinoid jelátvitel fokozása terápiás opcióként jelenik meg olyan pszichiátriai zavaroknál, amelyeknél a coping stratégiák fontos szerepet játszanak, többek között a poszt-traumás stressz zavar esetében is. | Our studies revealed that neural changes underlying trauma-induced post-traumatic stress disorder-like behavioral deficits depend on the nature of the traumatic experience and the challenge subjects are exposed to during behavioral testing. Moreover, neural changes have a temporal evolution that is not reflected at behavioral level. This complexity mirrors the complexity of the human disorder and may explain why the treatment of this disorder is so difficult. Our findings also show that this field needs a complex, multidimensional approach; the frequently used 2-day long conditioned fear test is insufficient to understand the mechanisms of trauma-induced behavioral deficits. As it regards the role of cannabinoid signaling in trauma-induced behavioral deficits, we suggest that this role can be best described in terms of coping styles. Enhanced anandamide (and possibly 2-AG) signaling increases the predilection of animals to adopt an active coping style. Basic alternative strategies by which individuals respond to environmental challenges (i.e. coping styles) have wide-ranging health implications from immunity to psychopathology, and active coping has been indicated as a therapeutic goal for psychological interventions in various disorders. As such, the enhancement of endocannabinoid signaling may become a therapeutic option in emotional disorders that are characterized changes in coping strategies e.g. in post-traumatic stress disorder

Traces of a trauma - pharmacological interventions of PTSD

Posttraumatic stress disorder (PTSD) is characterized by exaggerated trauma-related memories (contextual fear), increased avoidance of trauma-related cues, and hyperarousal. Pharmacotherapy of PTSD is still unsatisfactory, with SSRIs being the first choice drugs. However, as known for depressed patients, PTSD patients are prone for relapse of symptoms upon discontinuation of treatment. This urges for a refinement of therapeutic interventions and the identification of markers of treatment success. These issues were addressed in our mouse model of PTSD. In this model, mice are exposed to a brief, inescapable electric foot shock. Within 1 month after the trauma, they developed PTSD-like symptoms such as generalized contextual fear, generalized avoidance, and increased hyperarousal symptomatology. This time frame allows for pharmacological interventions during maturation of PTSD-like symptoms (i.e. preventive treatment) or at time points when the symptoms have fully developed (i.e. therapeutic treatment). The work presented in this thesis revealed the following key findings: (1) Fear incubation (i.e. simply the passage of time after trauma) was accompanied by highly selective changes in neuronal activity, as assessed by cytochrome c oxidase (CO) activity >1 month after trauma. (2) Chronic treatment with fluoxetine via drinking water starting either right after the trauma (preventive treatment) or 28 days later (therapeutic treatment) completely reversed the PTSD-like symptoms assessed during ongoing treatment 1 (preventive treatment) or 2 months (therapeutic treatment) after trauma. (3) Despite the similarities to PTSD-like symptoms, preventive treatment with fluoxetine abolished most of the trauma-related changes in CO activity, whereas those changes were maintained after therapeutic intervention. (4) If fluoxetine was washed out after 1 month of treatment, PTSD-like symptoms remained absent following preventive treatment, but re-occurred after therapeutic treatment. In conclusion, these data suggest preventive treatment with fluoxetine starting in the early aftermath of a trauma as a successful intervention strategy for preventing the development of PTSD-like symptoms. In contrast, therapeutic treatment abolishes the expression of symptoms, without curative effects. Chronic changes in CO activity reflect traces of a trauma. They might serve as an indicator of PTSD relapse

IMPACT OF PROPHYLACTIC INTRANASAL OXYTOCIN ADMINISTRATION ON SYMPTOMS OF POST-TRAUMATIC STRESS

Post-traumatic stress disorder (PTSD) is a mental health condition that affects people after instances of severe emotional trauma. Research suggests that oxytocin treatment decreases PTSD symptoms. This study served to evaluate the efficacy of intranasal oxytocin pre-treatment on symptoms related to PTSD. The hypotheses are that oxytocin will decrease fear and anxiety, and increase reward-seeking behaviors. Sprague Dawley rats were assigned to three groups (Control, Stress, Oxytocin, and Oxytocin+Stress; n=6 per group) to conduct this experiment. Prior to foot shock treatment, rats were trained to expect a food reward (Kellogg’s Froot Loops) in an open field enclosure. Subsequently, the Oxytocin and the Oxytocin+Stress groups were pre-treated with intranasal oxytocin and then the Stress and Oxytocin+Stress groups were exposed to an inescapable foot shock (a model PTSD inducing stressor). After oxytocin and shock treatments, rats underwent various behavioral tests: re-exposure to the shock chamber to assess fear, elevated O-maze to assess anxiety, and food reward trials in the open field enclosure to assess reward-seeking behavior. The oxytocin treatment decreased fear related symptoms upon re-exposure to the fear conditioning chamber; both colonic motility and freezing time were lower in the Oxytocin+Stress group compared to the Stress group. The foot shock model failed to produce significant behavioral changes related to anxiety and reward-seeking behavior between the Control and Stress groups

An fMRI study of unconditioned responses in post-traumatic stress disorder

BACKGROUND: Both fear and pain processing are altered in post-traumatic stress disorder (PTSD), as evidenced by functional neuroimaging studies showing increased amygdala responses to threats, and increased insula, putamen and caudate activity in response to heat pain. Using psychophysiology and functional magnetic resonance imaging, we studied conditioned and unconditioned autonomic and neuronal responses in subjects with PTSD versus trauma-exposed non-PTSD control (TENC) subjects. A design using an electric shock selected by subjects to be 'highly annoying but not painful' as an unconditioned stimulus (US) with partially reinforced cues allowed us to partly disentangle the expectancy- and prediction-error components from sensory components of the unconditioned response. RESULTS: Whereas responses to the conditioned stimulus (CS) were similar in PTSD and TENC, the former displayed higher putamen, insula, caudate and amygdala responses to the US. Reactivity to the US in the anterior insula correlated with PTSD symptom severity. Functional connectivity analyses using the putamen as a seed region indicated that TENC subjects had increased amygdala-putamen connectivity during US delivery; this connection was disengaged in PTSD. CONCLUSIONS: Our results indicate that although neural processing of fear learning in people with PTSD seems to be comparable with controls, neural responses to unconditioned aversive stimuli in PTSD seem to be increased

A HOLISTIC APPROACH TO POST-TRAUMATIC STRESS DISORDER: ALPHA-2 ADRENERGIC RECEPTOR-SINOPHILIN COFILIN AXIS BIOLOGIC ANTIBODY TREATMENT PROPOSAL

PTSD affects about 5% of adults in the United States every year.1 This thesis investigates the common biologic therapies for PTSD and the specificity factor of the catecholamine binding to related norepinephrine alpha-2A adrenergic receptors. The binding of these catecholamines to adrenaline receptors in the spinophilin cofilin axis of the dorsal hippocampus causes fear-memory modulation and storage by altering dendritic morphology and thus manipulating neuronal plasticity. Targeting the inhibition of these respective receptors and increasing the activity of cofilin, a protein responsible for breaking down actin utilized for dendrite reaction to stimulus appears promising. By preventing the binding of catecholamines in this axis which would depress cofilin, dendritic changes of elongation would be small rather than dramatized and prolonged as seen in PTSD, eliminating a change in plasticity and future responsiveness to recurring stimuli. The use of a polyclonal antibody rather than an SSRI or beta blocker – which only treats symptoms without changing the modulation of fear itself– was proposed due to the more bodily ‘holistic’ approach to PTSD rather than using an artificially synthesized pharmaceutical. Coupling the proposed antibody treatment with cognitive behavioral therapy can aid in making long term PTSD symptoms a thing of the past

Long-term effects of traumatic stress on subsequent contextual fear conditioning in rats

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