Asthma and posttraumatic stress disorder (PTSD): Emerging links,potential models and mechanisms

Posttraumatic stress disorder (PTSD) is a highly prevalent, debilitating mental health condition. A better understanding of contributory neurobiological mechanisms will lead to effective treatments, improving quality of life for patients. Given that not all trauma-exposed individuals develop PTSD, identification of pre-trauma susceptibility factors that can modulate posttraumatic outcomes is important. Recent clinical evidence supports a strong link between inflammatory conditions and PTSD. A particularly strong association has been reported between asthma and PTSD prevalence and severity. Unlike many other PTSD-comorbid inflammatory conditions, asthma often develops in children, sensitizing them to subsequent posttraumatic pathology throughout their lifetime. Currently, there is a significant need to understand the neurobiology, shared mechanisms, and inflammatory mediators that may contribute to comorbid asthma and PTSD. Here, we provide a translational perspective of asthma and PTSD risk and comorbidity, focusing on clinical associations, relevant rodent paradigms and potential mechanisms that may translate asthma-associated inflammation to PTSD development.     

Traumatic Brain Injury and Disturbed Sleep and Wakefulness

Traumatic brain injury is a frequent condition worldwide, and sleep-wake disturbances often complicate the course after the injuring event. Current evidence suggests that the most common sleep-wake disturbances following traumatic brain injury include excessive daytime sleepiness and posttraumatic hypersomnia, that is, increased sleep need per 24?h. The neuromolecular basis of posttraumatic sleep pressure enhancement is not entirely clear. First neuropathological and clinical studies suggest that impaired hypocretin (orexin) signalling might contribute to sleepiness, but direct or indirect traumatic injury also to other sleep-wake modulating systems in the brainstem and the mesencephalon is likely. Posttraumatic insomnia may be less common than posttraumatic sleepiness, but studies on its frequency revealed conflicting results. Furthermore, insomnia is often associated with psychiatric comorbidities, and some patients with posttraumatic disruption of their circadian rhythm may be misdiagnosed as insomnia patients. The pathophysiology of posttraumatic circadian sleep disorders remains elusive; however, there is some evidence that reduced evening melatonin production due to traumatic brain damage may cause disruption of circadian regulation of sleep and wakefulness.     

Sleep in Posttraumatic Stress Disorder

Posttraumatic stress disorder (PTSD) is often associated with sleep disturbances. In this review, we focus on the published literature on subjective and objective findings of sleep in patients with PTSD. Insomnia and nightmares are most commonly reported subjective sleep disturbances. Polysomnographic investigations have frequently reported rapid eye movement (REM) sleep abnormalities in PTSD. However, studies have not been consistent about the type of REM sleep dysfunction in PTSD patients. Antidepressants such as nefazodone, trazodone, fluvoxamine, and imagery rehearsal therapy are found to be beneficial in the treatment of PTSD associated sleep disturbances as well as core symptoms of this anxiety disorder. We propose use of such modalities of treatment in PTSD patients with predominant sleep disturbances. Further studies are required to clarify polysomnographic sleep changes especially role of REM sleep dysregulation and treatment of sleep disturbances in PTSD.     

Disturbed sleep in post-traumatic stress disorder: secondary symptom or core feature?

Sleep disturbances are often viewed as a secondary symptom of post-traumatic stress disorder (PTSD), thought to resolve once PTSD has been treated. Specific screening, diagnosis and treatment of sleep disturbances is therefore not commonly conducted in trauma centres. However, recent evidence shows that this view and consequent practices are as much unhelpful as incorrect. Several sleep disorders-nightmares, insomnia, sleep apnoea and periodic limb movements-are highly prevalent in PTSD, and several studies found disturbed sleep to be a risk factor for the subsequent development of PTSD. Moreover, sleep disturbances are a frequent residual complaint after successful PTSD treatment: a finding that applies both to psychological and pharmacological treatment. In contrast, treatment focusing on sleep does alleviate both sleep disturbances and PTSD symptom severity. A growing body of evidence shows that disturbed sleep is more than a secondary symptom of PTSD-it seems to be a core feature. Sleep-focused treatment can be incorporated into any standard PTSD treatment, and PTSD research needs to start including validated sleep measurements in longitudinal epidemiologic and treatment outcome studies. Further clinical and research implications are discussed, and possible mechanisms for the role of disturbed (REM) sleep in PTSD are described.     

Neurobiological mechanisms underlying delayed expression of posttraumatic stress disorder: A scoping review

BACKGROUNDThe capacity of posttraumatic stress disorder (PTSD) to occur with delayed onset has been documented in several systematic reviews and meta-analyses. Neurobiological models of PTSD may provide insight into the mechanisms underlying the progressive increase in PTSD symptoms over time as well as into occasional occurrences of long-delayed PTSD with few prodromal symptoms. AIMTo obtain an overview of key concepts explaining and types of evidence supporting neurobiological underpinnings of delayed PTSD.METHODSA scoping review of studies reporting neurobiological findings relevant to delayed PTSD was performed, which included 38 studies in the qualitative synthesis. RESULTSNeurobiological mechanisms underlying PTSD symptoms, onset, and course involve several interconnected systems. Neural mechanisms involve the neurocircuitry of fear, comprising several structures, such as the hippocampus, amygdala, and prefrontal cortex, that are amenable to time-dependent increases in activity through sensitization and kindling. Neural network models explain generalization of the fear response. Neuroendocrine mechanisms consist of autonomic nervous system and hypothalamic-pituitary-adrenocortical axis responses, both of which may be involved in sensitization to stress. Neuroinflammatory mechanisms are characterized by immune activation, which is sometimes due to the effects of traumatic brain injury. Finally, neurobehavioral/contextual mechanisms involve the effects of intervening stressors and mental and physical disorder comorbidities, and these may be particularly relevant in cases of long-delayed PTSD. CONCLUSIONThus, delayed PTSD may result from multiple underlying neurobiological mechanisms that may influence the likelihood of developing prodromal symptoms preceding the onset of full-blown PTSD.     

The centrality of fear extinction in linking risk factors to PTSD: A narrative review

Recent prospective studies in emergency services have identified impaired fear extinction learning and memory to be a significant predictor of Posttraumatic Stress Disorder (PTSD), complementing a wealth of cross-sectional evidence of extinction deficits associated with the disorder. Additional fields of research show specific risk factors and biomarkers of the disorder, including candidate genotypes, stress and sex hormones, cognitive factors, and sleep disturbances. Studies in mostly nonclinical populations also reveal that the aforementioned factors are involved in fear extinction learning and memory. Here, we provide a comprehensive narrative review of the literature linking PTSD to these risk factors, and linking these risk factors to impaired fear extinction. On balance, the evidence suggests that fear extinction may play a role in the relationship between risk factors and PTSD. Should this notion hold true, this review carries important implications for the improvement of exposure-based treatments, as well as strategies for the implementation of treatment.     

Sleep in post-traumatic stress disorder and panic: convergence and divergence

Disturbed sleep is a common clinical problem in anxiety disorders, particularly in patients with post-traumatic stress disorder (PTSD) and panic disorder (PD). Several studies have attempted to validate the subjective sleep complaints of these disorders using laboratory polysomnography. These attempts, typically focusing on PTSD or PD independently, have demonstrated inconsistent results. To our knowledge, no such studies have attempted to directly compare and contrast sleep disturbances in PTSD and PD together. Our review of the studies of subjective sleep disturbances, sleep architecture, and sleep-related biologic phenomena suggests that a comparative characterization of sleep disturbances in these two disorders is timely. Such an inference is based on our identification of several areas of convergence and divergence between PTSD and PD found in the published literature, as well as our own preliminary investigations. Specifically, PTSD and PD seem to converge on several sleep-related parameters, namely, sleep quality, presence of episodic parasomnias, and movement time. They also appear to diverge in other important sleep-related areas such as respiratory disturbances and the particular phenomenological nature of episodic parasomnias, namely nightmares or nocturnal panic attacks. Investigations focusing on such overlapping phenomena may provide groundwork for further elucidation of central fear systems underlying these two disorders. Additionally, such sleep studies have the potential to provide important insights into ongoing efforts to develop a cohesive conceptual framework into the patho-physiologies of these disorders.     

Sleep-wake states in transgenic mouse models overexpressing the human beta-amyloid precursor protein

Studies testing the amyloid hypothesis and recent advances in mouse molecular genetic technologies have played a critical role in improving our understanding of Alzheimer's disease (AD). Mouse models of AD currently available show only some of the characteristic neuropathology in human AD. Studies have demonstrated, however, that these models are excellent tools for characterizing different aspects of the molecular pathology of AD and the neurobiological basis for the clinical heterogeneity in AD. The present discussion focuses on behavioral and physiological data obtained in transgenic (Tg) mice overexpressing the mutant human beta-amyloid precursor protein (hbetaAPP). This mouse model exhibits memory and neurophysiological deficits at ages preceding amyloid-beta-peptide (Abeta) plaque formation that worsened with age and Abeta plaque formation. In spite of these findings, very little emphasis has been placed on characterizing the neurobiological basis of the diverse neuropsychiatric symptoms that are also observed in AD, including sleep disturbances. Taking into consideration the relationship between memory processes and sleep, the use of animal models of AD as a preclinical bioassay has the potential to characterize the neural substrates mediating clinical manifestations of AD, such as sleep-wake states, and contribute to the development of treatments for early stages of AD.     

Chronic Sleep Disruption and the Reexperiencing Cluster of Posttraumatic Stress Disorder Symptoms Are Improved by Olanzapine: Brief Review of the Literature and a Case-Based Series

BACKGROUND: Posttraumatic stress disorder (PTSD) is one of the most prevalent psychiatric disorders in young adults. Early diagnosis and treatment of PTSD are essential to avoid possible long-term neuropsychiatric changes in brain physiology and function. A cardinal symptom of PTSD is chronic sleep disruption, often with recurring nightmares. If untreated, PTSD symptoms often contribute to substance abuse and the development of other comorbid psychiatric disorders. Once PTSD is diagnosed, drug treatment should begin with antidepressant therapy. If antidepressants do not correct the sleep disruption, adjunctive treatment with the atypical antipsychotic olanzapine or other agents should be considered. METHOD: This case series reviews 7 cases of patients with PTSD (DSM-IV criteria) seen in primary care clinics who were successfully treated with olanzapine. In most cases, olanzapine therapy was adjunctive and followed failed treatment with antidepressant monotherapy for sleep disturbances. RESULTS: All patients reported improved sleep with decreased or absent nightmares, as well as improvements in other PTSD symptom clusters. CONCLUSION: Further controlled studies are needed to better characterize and validate this therapeutic indication.     

Sleep and Dreaming in Posttraumatic Stress Disorder

Purpose of Review

Sleep disturbances are core features of posttraumatic stress disorder (PTSD). This review aims to characterize sleep disturbances, summarize the knowledge regarding the relationships between trauma exposure and sleep difficulties, and highlight empirically supported and/or utilized treatments for trauma-related nightmares and insomnia.

Recent Findings

Trauma-related nightmares and insomnia, and other sleep disorders, are frequently reported among trauma survivors. The roles of fear of sleep, REM density, and decreased parasympathetic activity are beginning to inform the relationship between trauma exposure and sleep difficulties. Additionally, the potential adaptive role of sleep loss immediately following a traumatic experience is being recognized. Interventions targeting these sleep disturbances show promise in reducing symptoms.

Summary

Research in understanding the role of sleep on the development, course, and treatment of PTSD is expanding. Longitudinal investigations are needed to further elucidate these relationships and identify treatments most effective in ameliorating symptoms.

     

Understanding posttraumatic stress disorder through fear conditioning,extinction and reconsolidation

Careaga MBL, Girardi CEN, Suchecki D. Understanding posttraumatic stress disorder through fear conditioning, extinction and reconsolidation. NEUROSCI BIOBEHAV REV −Posttraumatic stress disorder (PTSD) is a psychopathology characterized by exacerbation of fear response. A dysregulated fear response may be explained by dysfunctional learning and memory, a hypothesis that was proposed decades ago. A key component of PTSD is fear conditioning and the study of this phenomenon in laboratory has expanded the understanding of the underlying neurobiological changes in PTSD. Furthermore, traumatic memories are strongly present even years after the trauma and maintenance of this memory is usually related to behavioral and physiological maladaptive responses. Persistence of traumatic memory may be explained by a dysregulation of two memory processes: extinction and reconsolidation. The former may explain the over-expression of fear responses as an imbalance between traumatic and extinction memory. The latter, in turn, explains the maintenance of fear responses as a result of enhancing trauma-related memories. Thus, this review will discuss the importance of fear conditioning for the establishment of PTSD and how failure in extinction or abnormal reconsolidation may contribute to the maintenance of fear response overtime.     

Gabapentin in PTSD: A Retrospective, Clinical Series of Adjunctive Therapy

Posttraumatic stress disorder (PTSD) symptoms may improve significantly with antidepressant medications, however some phenomena often remain refractory to the most commonly used treatments. Frequently, sleep disturbances, such as insomnia and nightmares, are symptoms of PTSD that are refractory to antidepressant treatment. Gabapentin, a novel anticonvulsant agent, has been of interest as a potential anxiolytic agent, but has not been evaluated in PTSD. We reviewed records of 30 consecutive patients who had been diagnosed with PTSD according to structured interviews and had received gabapentin as an adjunctive medication. For each patient, the target symptoms that led to the initiation of gabapentin treatment were identified. Using the most recent clinical data available, the change in target symptom severity following treatment was rated as unimproved, mildly improved, moderately improved, or markedly improved. The gabapentin was often first prescribed to facilitate sleep. The majority (77%) of patients showed moderate or greater improvement in duration of sleep, and most noted a decrease in the frequency of nightmares. The dose range was 300–3600 mg/day. Sedation and mild dizziness were the most commonly reported side effects. This retrospective study suggests that gabapentin may improve in particular sleep difficulties and also other symptoms associated with chronic PTSD. Prospective, controlled studies are needed to further investigate the effects of gabapentin on insomnia, nightmares, and other core PTSD symptoms.     

Interaction of sleep disturbances and anxiety in later life: perspectives and recommendations for future research

Both sleep disturbances and anxiety are quite common in older adults. Although increasing research efforts have investigated sleep disturbances and anxiety in older adults, little has been written concerning the relation between sleep disturbances and anxiety in this population. This article reviews the epidemiological and clinical literature concerning the overall prevalence of sleep disturbances and relations between sleep and anxiety in later life. The article begins with a discussion of the prevalence of sleep and anxiety problems in older individuals, continues with a clinical review of the complex interrelationship between sleep and anxiety in older adults, and briefly considers possible neurobiological underpinnings of this interrelationship. This is followed by a brief discussion of the impact of medical illness on both anxiety and sleep disturbances. The article ends with a summary of findings from this review and provides recommendations for future research.     

The role of circadian clock genes in mental disorders

The study of molecular clock mechanisms in psychiatric disorders is gaining significant interest due to data suggesting that a misalignment between the endogenous circadian system and the sleep-wake cycle might contribute to the clinical status of patients suffering from a variety of psychiatric disorders. Sleep disturbances in major depressive disorder (MDD) are characterized by increased sleep latency, poorer sleep efficiency reduced latency to the first rapid eye movement (REM) sleep episode, and early-morning awakening, but there is little data to indicate a role of circadian clock genes in MDD. There is also relatively little information regarding the role of clock genes in anxiety. In contrast, a significant amount of evidence gathered in bipolar disorder (BPD) patients suggests a circadian rhythm disorder, namely an advanced circadian rhythm and state-dependent alterations of REM sleep latency. Most research on the role of clock genes in BPD has focused on polymorphisms of CLOCK, but the lithium target GSK3 may also play a significant role. A circadian phase shift is also theorized to contribute to the pathophysiology of winter seasonal affective disorder (SAD). Certain allelic combinations of NPAS2, PER3, and BMAL1 appear to contribute to the risk of SAD. In chronic schizophrenia, disturbances of sleep including insomnia and reduced sleep efficiency have been observed. Genetic studies have found associations with CLOCK, PER1, PER3, and TIMELESS. Sleep and circadian changes associated with dementia due to Alzheimer's disease suggest a functional change in the circadian master clock, which is supported by postmortem studies of clock gene expression in the brain.     

Polysomnography in patients with post‐traumatic stress disorder

Aims: The purpose of the present study was to investigate sleep structure in post‐traumatic stress disorder (PTSD) patients with and without any psychiatric comorbidities. The relationship between sleep variables and measurements of clinical symptom severity were also investigated. Methods: Sleep patterns of 24 non‐medicated male PTSD patients and 16 age‐ and sex‐matched normal controls were investigated on polysomnography on two consecutive nights. Six PTSD‐only patients and 15 PTSD patients with major depressive disorder (MDD) were also compared to normal controls. Sleep variables were correlated with PTSD symptoms. Results: Compared to the normal controls, the PTSD patients with MDD had difficulty initiating sleep, poor sleep efficiency, decreased total sleep time, decreased slow wave sleep (SWS), and a reduced rapid eye movement (REM) sleep latency. The PTSD patients without any comorbid psychiatric disorders had moderately significant disturbances of sleep continuity, and decreased SWS, but no abnormalities of REM sleep. REM sleep latency was inversely proportional to the severity of startle response. SWS was found to be inversely correlated with the severity of psychogenic amnesia. Conclusions: PTSD patients have disturbance of sleep continuity, and SWS deficit, without the impact of comorbid depression on sleep. The relationship between SWS and the inability to recall an important aspect of trauma may indicate the role of sleep in the consolidation of traumatic memories. The relationship between the severity of the startle response and REM latency may suggest that REM sleep physiology shares common substrates with the symptoms of PTSD.     

Actigraphic sleep monitoring in posttraumatic stress disorder (PTSD) patients

Posttraumatic stress disorder (PTSD) patients frequently complain that they suffer from sleep disturbances. To date, the polysomnographic studies that have attempted to study PTSD patients' subjective complaints of sleep difficulties have produced conflicting results. The objective of the present study was to compare PTSD patients' subjective complaints of poor sleep and objective actigraphic recordings of their sleep over a period of several consecutive nights. The results indicate that PTSD patients do not suffer from poorer sleep than a control group, based on actigraphic measures, and that their subjective sleep evaluation is inconsistent with objective sleep measures. These patients fail to correctly estimate their sleep.     

Psychopharmacological treatment in PTSD: a critical review

Introduction: Posttraumatic stress disorder (PTSD) is a prevalent psychiatric disorder that is heterogeneous in its nature, and often presents with other psychiatric comorbidities. As a result, empirical research on effective pharmacotherapy for PTSD has produced complex findings. This article reviews the existing research literature on pharmacological treatments for PTSD, identifies the most effective treatments, and where possible examines their mechanism of action with respect to the neurobiology of PTSD. Methods: We examined reports of clinical trials of psychotropic agents carried out with PTSD patients and published in peer-reviewed journals, as well as reports from presentations at scientific meetings between 1966 and 2001. Results: Numerous medications are effective in treating PTSD. These include tricyclic antidepressants, monoamine oxidase inhibitors, and serotonin reuptake inhibitors. Considering reported overall efficacy and side effects profiles, selective serotonin reuptake inhibitors emerge as the preferred first line treatment for PTSD. Mood stabilizers, atypical neuroleptics, adrenergic agents, and newer antidepressants also show promise, but require further controlled trials to clarify their place in the pharmacopoeia for PTSD. Discussion: There is clear evidence for effective pharmacotherapy of PTSD. Future improvements in the treatment of this disorder await further clinical trials and neurobiological research.     

Aerobic exercise in the treatment of PTSD: An examination of preclinical and clinical laboratory findings,potential mechanisms,clinical implications,and future directions

Posttraumatic stress disorder (PTSD) is associated with heightened emotional responding, avoidance of trauma related stimuli, and physical health concerns (e.g., metabolic syndrome, type 2 diabetes, cardiovascular disease). Existing treatments such as exposure-based therapies (e.g., prolonged exposure) aim to reduce anxiety symptoms triggered by trauma reminders, and are hypothesized to work via mechanisms of extinction learning. However, these conventional gold standard psychotherapies do not address physical health concerns frequently presented in PTSD. In addition to widely documented physical and mental health benefits of exercise, emerging preclinical and clinical evidence supports the hypothesis that precisely timed administration of aerobic exercise can enhance the consolidation and subsequent recall of fear extinction learning. These findings suggest that aerobic exercise may be a promising adjunctive strategy for simultaneously improving physical health while enhancing the effects of exposure therapies, which is desirable given the suboptimal efficacy and remission rates. Accordingly, this review 1) encompasses an overview of preclinical and clinical exercise and fear conditioning studies which form the basis for this claim; 2) discusses several plausible mechanisms for enhanced consolidation of fear extinction memories following exercise, and 3) provides suggestions for future research that could advance the understanding of the potential importance of incorporating exercise into the treatment of PTSD.