THEORETICAL Review
Sleep-specific mechanisms underlying posttraumatic stress disorder: Integrative review and neurobiological hypotheses

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Summary

Posttraumatic stress disorder (PTSD) is a prevalent disorder that is associated with poor clinical and health outcomes, and considerable health care utilization and costs. Recent estimates suggest that 5–20% of military personnel who serve in current conflicts in Iraq and Afghanistan meet diagnostic criteria for PTSD. Clinically, sleep disturbances are core features of PTSD that are often resistant to first-line treatments, independently contribute to poor daytime functioning, and often require sleep-focused treatments. Physiologically, these observations suggest that PTSD is partially mediated by sleep disruption and its neurobiological correlates that are not adequately addressed by first-line treatments. However, polysomnographic studies have provided limited insights into the neurobiological underpinnings of PTSD during sleep. There is an urgent need to apply state-of-the-science sleep measurement methods to bridge the apparent gap between the clinical significance of sleep disturbances in PTSD and the limited understanding of their neurobiological underpinnings. Here, we propose an integrative review of findings derived from neurobiological models of fear conditioning and fear extinction, PTSD, and sleep–wake regulation, suggesting that the amygdala and medial prefrontal cortex can directly contribute to sleep disturbances in PTSD. Testable hypotheses regarding the neurobiological underpinnings of PTSD across the sleep–wake cycle are offered.

Introduction

Posttraumatic stress disorder (PTSD) is a clinical syndrome characterized by re-experiencing, avoidance, and hyperarousal reactions that persist for more than 1 month after exposure to a traumatic event. Violent crimes, including rape and physical assaults, combat exposure, and natural disasters constitute examples of traumatic events that can involve threat to integrity of the self or others and can be accompanied by intense fear, helplessness, or horror.1 Trauma exposure is not a rare event: more than two-thirds of the general population is exposed to at least one traumatic event over their lifetime.2 Epidemiological studies indicate that community prevalence estimates of PTSD range from 1% to 10%,2, 3 with higher estimates reported in victims of interpersonal violence (20–30%)2, 3, 4 and combat veterans (15–30%).5 In veterans of the current Operation Iraqi Freedom (OIF) and Operation Enduring Freedom (OEF), Hoge et al.6 found that 31% of OEF service members and 71–86% of OIF service members reported multiple combat experiences, and as many as one out of nine troops returning from Afghanistan, and one out of six troops returning from Iraq endorse clinically significant PTSD symptoms.6 These estimates are likely to rise over time, based on a recent report that indicates that 33.4% of OIF/OEF returnees evaluated at VA Healthcare facilities between 2002 and 2006 met diagnostic criteria for mental disorders, including PTSD.7 PTSD is often a chronic condition, and is associated with enormous health care costs in both military and civilian samples.8 Recommended first-line treatments for PTSD include selective serotonin reuptake inhibitors (SSRIs), and cognitive–behavioral approaches such as exposure-based and cognitive therapy.9, 10

There is growing evidence that sleep disruption that occurs following trauma exposure may constitute a specific mechanism involved in the pathophysiology of chronic PTSD and poor clinical outcomes. Subjective and objective sleep disturbances occurring early after trauma exposure, as well as heightened sympathovagal tone during REM sleep, are associated with an increased risk of meeting criteria for PTSD at subsequent assessments conducted up to 1 year later.11, 12, 13 Sleep disturbances are a core feature of PTSD. Nightmares and insomnia are diagnostic symptoms of PTSD,1 and other sleep disturbances such as sleep avoidance, sleep terrors, nocturnal anxiety attacks, simple and complex motor behaviors and vocalizations, acting out dreams, sleep apnea, and periodic leg movement disorders are also frequently reported and observed by PTSD patients.14, 15 Additionally, sleep disturbances independently exacerbate daytime symptoms, and contribute to poor clinical outcomes in PTSD, such as increased severity of depression,16 suicidality,16 and general psychiatric distress,17 poorer quality of life and functioning,17 and poorer perceived physical health,18 and increased alcohol and drug use.19, 20 While these associations between sleep disturbances and poor clinical outcomes are derived from a posteriori observations, they stress the need for prospectively monitoring the possible development of sleep disturbances in trauma-exposed individuals, and the role of sleep disturbances as mediators of the relationship between PTSD and clinical outcomes. Finally, sleep disturbances are often resistant to recommended first-line interventions.21, 22 Adjunctive sleep-focused pharmacological or behavioral interventions are commonly used to alleviate PTSD-related nightmares and insomnia. Of note, the use of benzodiazepines remains highly common in PTSD, possibly for alleviating daytime anxiety symptoms and sleep disturbances, despite the absence of evidence supporting their efficacy.25, 26 Effective treatments of nightmares and insomnia also associated with improvements in daytime PTSD symptoms, depression, quality of life, and perceived physical health (e.g.,23, 24, 27 see also Ref.4 for review). Together, these observations raise the possibilities that (1) trauma exposure directly alters sleep–wake regulation mechanisms, (2) PTSD is partially mediated by sleep-specific mechanisms, and (3) normalization of altered neurobiological mechanisms underlying sleep disturbances in PTSD requires targeted treatments.

The overarching goal of this paper is to integrate convergent lines of evidence derived from sleep neuroimaging studies in related disorders, from waking neuroimaging studies conducted on PTSD patients, and from animal models of fear conditioning to provide a preliminary model and testable hypotheses of the neurobiological underpinnings of PTSD during rapid-eye movement (REM) and non-REM (NREM) sleep. Prior sleep findings in PTSD samples are only briefly reviewed here. Extensive critical review of prior qualitative and polysomnographic studies of sleep in PTSD samples and review of pharmacological and behavioral treatments that target PTSD-related sleep disturbances are available elsewhere.28, 29, 30 Findings derived from sleep neuroimaging studies in healthy human subjects are then briefly reviewed. Because the hyperactivity of the amygdala and impaired function of the medial frontal cortex are neurobiological correlates of PTSD, animal and human studies suggesting that the amygdala and medial prefrontal cortex directly influence the regulation and/or expression of REM and NREM sleep are highlighted. The neurobiology of fear conditioning and fear extinction, complementary animal models of PTSD in humans, their effects on sleep, as well as neuroimaging findings observed in PTSD samples are also presented. Findings from these areas of research evidence potentially significant dual roles of the amygdala and medial prefrontal cortex as both critical structures involved in the fear response and PTSD, and important modulator of NREM and REM sleep. Based on these observations, preliminary models and hypotheses regarding potential neurobiological correlates of PTSD during NREM and REM sleep are described.

An in-depth understanding of the sleep-specific underpinnings of PTSD, acquired with state-of-the-science measurement methods, is essential to guide for development, refinement, and testing of innovative prevention and interventions strategies across the sleep–wake cycle. More broadly, better empirically derived models of PTSD during sleep may generate novel insights into the pathophysiology, prevention, and treatment of other adjustment and stress-related disorders, such as those affecting cohorts of combat-exposed military veterans, as well as of victims of violent crimes and terrorist attacks, and survivors of natural disasters. Finally, elucidating the neurobiological underpinnings of PTSD during sleep can inform efforts to identify the mechanisms subserving resistance of sleep disturbances to first-line treatments of PTSD, as well as the distinct mechanisms underlying treatment response to sleep treatments in PTSD, and other stress-related disorders.

Section snippets

Sleep neuroimaging findings in healthy human subjects

Consistent with animal models of sleep regulation, sleep neuroimaging studies in healthy humans indicate that specific patterns of neuronal activation and deactivation characterize NREM and REM sleep relative to wakefulness. Specifically, whole-brain glucose metabolism and blood flow are reduced by 30–40% during NREM sleep in healthy subjects relative to wakefulness.31 NREM sleep is also associated with relative reduced metabolic activity and blood flow in the wake-promoting areas including the

The amygdala and medial prefrontal cortex as modulators of REM sleep and NREM sleep

It is clear from animal studies that limbic and paralimbic regions are not among the primary regulators of NREM and REM sleep.35, 36, 37, 38 However, sleep neuroimaging studies in humans have shown that neuronal activity in amygdala and anterior paralimbic cortices including the medial prefrontal cortex varies across the sleep wake cycle. Although the amygdala and medial prefrontal cortex are not primary brain sites involved in the regulation of sleep per se, growing evidence suggests that both

Neurobiological correlates of fear conditioning, fear extinction, and PTSD

Pavlovian fear conditioning and fear extinction paradigms have been proposed as animal models of PTSD.45 Fear conditioning arises when a neutral stimulus (e.g., light, tone) closely precedes in time the occurrence of an aversive, emotionally significant event (e.g., shock) that will elicit a fear response (e.g., freezing). The neutral stimulus is termed the conditioned stimulus (CS), and the aversive event is termed the unconditioned stimulus (UCS). With repetition of the association, the

Effects of fear conditioning and PTSD on sleep

Animal studies have investigated the acute effects of fear conditioning on sleep as a model of the physiological underpinnings of sleep in PTSD. While this model does not closely reflect the persistence of sleep disturbances long after exposure to the original trauma seen in human PTSD, it nevertheless provides insights into the effects of fear conditioning on sleep and their physiological substrates. In rats and mice, fear conditioning increases REM sleep latency, decreases REM sleep duration63

Neurobiological hypotheses of PTSD during sleep

The study of the neurobiological correlates of PTSD during NREM and REM sleep offers a unique paradigm to observe natural activation and deactivation patterns in endogenous states of attenuated central arousal and heightened limbic activity, respectively.

To further the prior hypothesis that sleep mechanisms contribute to the pathophysiology of PTSD, we propose that REM sleep amplifies altered function of the amygdala and medial frontal cortex in PTSD patients; amplification of abnormal amygdala

Discussion

PTSD is a prevalent disorder that is often resistant to recommended treatments, and is associated with enormous health care costs. Sleep disturbances are a core feature of PTSD that are often resistant to recommended first-line treatments, and independently contribute to poor clinical outcomes. The contribution of sleep disturbances to long-term health outcomes and costs in PTSD is not currently known, but is likely to be substantial. Emerging evidence suggests that sleep-specific mechanisms

Acknowledgments

This manuscript was supported by the Department of Defense Peer Reviewed Medical Research Program (PR054093), and the National Institutes of Health (MH60473; MH24652; MH061566; MH066227).

References (82)

  • T. Deboer et al.

    Effects of electrical stimulation in the amygdala on ponto-geniculo-occipital waves in rats

    Brain Res

    (1998)
  • L.D. Sanford et al.

    Effects of tetrodotoxin (TTX) inactivation of the central nucleus of the amygdala (CNA) on dark period sleep and activity

    Brain Res

    (2006)
  • R.M. Benca et al.

    Effects of amygdala lesions on sleep in rhesus monkeys

    Brain Res

    (2000)
  • J.J. Kim et al.

    Neural circuits and mechanisms involved in Pavlovian fear conditioning: a critical review

    Neurosci Biobehav Rev

    (2006)
  • K.S. LaBar et al.

    Human amygdala activation during conditioned fear acquisition and extinction: a mixed-trial fMRI study

    Neuron

    (1998)
  • E.A. Phelps et al.

    Extinction learning in humans: role of the amygdala and vmPFC

    Neuron

    (2004)
  • R.A. Lanius et al.

    Brain activation during script-driven imagery induced dissociative responses in PTSD: a functional magnetic resonance imaging investigation

    Biol Psychiatry

    (2002)
  • R.A. Lanius et al.

    Recall of emotional states in posttraumatic stress disorder: an fMRI investigation

    Biol Psychiatry

    (2003)
  • S.L. Rauch et al.

    Exaggerated amygdala response to masked facial stimuli in posttraumatic stress disorder: a functional MRI study

    Biol Psychiatry

    (2000)
  • J.D. Bremner et al.

    Neural correlates of exposure to traumatic pictures and sound in Vietnam combat veterans with and without posttraumatic stress disorder: a positron emission tomography study

    Biol Psychiatry

    (1999)
  • L.M. Shin et al.

    An fMRI study of anterior cingulate function in posttraumatic stress disorder

    Biol Psychiatry

    (2001)
  • S.H. Woodward et al.

    Decreased anterior cingulate volume in combat-related PTSD

    Biol Psychiatry

    (2006)
  • N. Kitayama et al.

    Smaller volume of anterior cingulate cortex in abuse-related posttraumatic stress disorder

    J Affect Disord

    (2006)
  • A.C. Pawlyk et al.

    A rodent model of sleep disturbances in posttraumatic stress disorder: the role of context after fear conditioning

    Biol Psychiatry

    (2005)
  • X. Liu et al.

    Fear-conditioned suppression of REM sleep: relationship to Fos expression patterns in limbic and brainstem regions in BALB/cJ mice

    Brain Res

    (2003)
  • A.J. Silvestri

    REM sleep deprivation affects extinction of cued but not contextual fear conditioning

    Physiol Behav

    (2005)
  • D. Riemann et al.

    Advanced vs. normal sleep timing: effects on depressed mood after response to sleep deprivation in patients with a major depressive disorder

    J Affect Disord

    (1996)
  • T.A. Mellman et al.

    Nocturnal/daytime urine noradrenergic measures and sleep in combat-related PTSD

    Biol Psychiatry

    (1995)
  • B.E. Engdahl et al.

    Sleep in a community sample of elderly war veterans with and without posttraumatic stress disorder

    Biol Psychiatry

    (2000)
  • T.D. Hurwitz et al.

    Polysomnographic sleep is not clinically impaired in Vietnam combat veterans with chronic posttraumatic stress disorder

    Biol Psychiatry

    (1998)
  • P. Lavie et al.

    Elevated awaking thresholds during sleep: characteristics of chronic war-related posttraumatic stress disorder patients

    Biol Psychiatry

    (1998)
  • Diagnostic and statistical manual of mental disorders (DSM-IV)

    (1994)
  • N. Breslau et al.

    Trauma and posttraumatic stress disorder in the community: the 1996 Detroit Area Survey of Trauma

    Arch Gen Psychiatry

    (1998)
  • R.C. Kessler et al.

    Posttraumatic stress disorder in the National Comorbidity Survey

    Arch Gen Psychiatry

    (1995)
  • H.S. Resnick et al.

    Prevalence of civilian trauma and posttraumatic stress disorder in a representative national sample of women

    J Consult Clin Psychol

    (1993)
  • D.S. Weiss et al.

    The prevalence of lifetime and partial post-traumatic stress disorder in Vietnam theater veterans

    J Trauma Stress

    (1992)
  • C.W. Hoge et al.

    Combat duty in Iraq and Afghanistan, mental health problems, and barriers to care

    N Engl J Med

    (2004)
  • Kang HK. VA health care utilization among Operation Iraqi Freedom /Operation Endurieng Freedom veterans. 〈www.iom.edu〉;...
  • E.A. Walker et al.

    Health care costs associated with posttraumatic stress disorder symptoms in women

    Arch Gen Psychiatry

    (2003)
  • J.C. Ballenger et al.

    Consensus statement on posttraumatic stress disorder from the International Consensus Group on Depression and Anxiety

    J Clin Psychiatry

    (2000)
  • Treatment of posttraumatic stress disorder. The Expert Consensus Panels for PTSD

    J Clin Psychiatry

    (1999)
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    The most important references are denoted by an asterisk.

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