**2. Sleep in PTSD patients**

PTSD is unique among mental disorders in that a disturbance of sleep is included twice among the diagnostic criteria in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) [1]—as recurrent nightmares, a re-experiencing symptom, and also as insomnia, a symptom of hyperarousal. By self-report, 52–96% of individuals with PTSD have endorsed experiencing frequent nightmares [2, 3] while insomnia is reported by up to 70% of individuals with PTSD [4]. Unmentioned in the DSM-5, but well recognized by clinicians and PTSD patients alike, is excessive, disruptive movement during sleep [5].

In recent years, much has been learned about the clinical phenomenology and pathophysiology of PTSD, including the sleep disturbances. However, there have been remarkably few studies of the optimal approaches to treating the recurrent nightmares and insomnia that are so prevalent in the disorder and represent two of its major morbidities. We proceed to provide a description of the sleep disturbances experienced by individuals with PTSD, the brain mechanisms implicated by clinical studies, and the treatments, both psychotherapeutic and pharmacological, that have been proposed.

Largely because nightmares occur during rapid eye movement sleep (REMS) and are a distinguishing symptom of only PTSD, among all mental disorders, we (RJR; [5]) originally proposed that REMS mechanisms are essential to the pathophysiology of disturbed sleep in PTSD. At the same time dreams, albeit less vivid and more thought-like than nightmares, also emerge from non-REMS (NREMS) and as such a role of NREMS mechanisms must also be considered. The extant polysomnographic (PSG) literature provides no firm consensus regarding defining sleep abnormalities in PTSD. Enhanced, fragmented, and preserved REMS all have been reported [6–9]. Mellman et al. [10] have emphasized the likely importance of the duration of time following the trauma as an explanation of the diverse PSG findings in PTSD. In a non-clinical community sample of young adults assessed retrospectively by patient interview, both REMS percentage (amount of time spent in REMS/total sleep time) and average REMS segment duration were positively correlated with PTSD chronicity [10]. In addition, REMS latency (time from sleep onset to the start of the first REMS episode of the sleep period) was negatively correlated [10]. These findings point to a view of PTSD pathogenesis in which REMS plays a prominent role, as a biomarker or perhaps as a central etiologic element.

estimated 20% of those who experience significant trauma will go on to develop PTSD. Sleep complaints and disturbances in arousal are continuing and distressing symptoms in PTSD and stress-induced alterations in sleep have been linked to the development of PTSD. However, the exact role sleep plays in PTSD is unknown. This chapter will describe our current understanding of disturbed sleep in PTSD patients, how sleep is altered in animal models employed to study PTSD, linkages between the neurobiology of PTSD and sleep regulation, and current therapies for treating sleep disturbances in PTSD. Our review will discuss the complex effects of stress on sleep, stress parameters that appear to be important in determining post-stress sleep, and the neuroanatomical substrates important in regulating the relationship between stress and sleep. Lastly, we will discuss some of the limitations that need to be addressed in

PTSD is unique among mental disorders in that a disturbance of sleep is included twice among the diagnostic criteria in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) [1]—as recurrent nightmares, a re-experiencing symptom, and also as insomnia, a symptom of hyperarousal. By self-report, 52–96% of individuals with PTSD have endorsed experiencing frequent nightmares [2, 3] while insomnia is reported by up to 70% of individuals with PTSD [4]. Unmentioned in the DSM-5, but well recognized by clinicians and PTSD patients alike, is

In recent years, much has been learned about the clinical phenomenology and pathophysiology of PTSD, including the sleep disturbances. However, there have been remarkably few studies of the optimal approaches to treating the recurrent nightmares and insomnia that are so prevalent in the disorder and represent two of its major morbidities. We proceed to provide a description of the sleep disturbances experienced by individuals with PTSD, the brain mechanisms implicated by clinical studies, and the treatments, both psychotherapeutic and

Largely because nightmares occur during rapid eye movement sleep (REMS) and are a distinguishing symptom of only PTSD, among all mental disorders, we (RJR; [5]) originally proposed that REMS mechanisms are essential to the pathophysiology of disturbed sleep in PTSD. At the same time dreams, albeit less vivid and more thought-like than nightmares, also emerge from non-REMS (NREMS) and as such a role of NREMS mechanisms must also be considered. The extant polysomnographic (PSG) literature provides no firm consensus regarding defining sleep abnormalities in PTSD. Enhanced, fragmented, and preserved REMS all have been reported [6–9]. Mellman et al. [10] have emphasized the likely importance of the duration of time following the trauma as an explanation of the diverse PSG findings in PTSD. In a non-clinical community sample of young adults assessed retrospectively by patient interview, both REMS percentage (amount of time spent in REMS/total sleep time) and average REMS segment duration were positively correlated with PTSD chronicity [10]. In addition, REMS latency (time from sleep onset to the start of the first REMS episode of the sleep period)

order to advance our understanding of the role that sleep may play in PTSD.

18 A Multidimensional Approach to Post-Traumatic Stress Disorder - from Theory to Practice

**2. Sleep in PTSD patients**

excessive, disruptive movement during sleep [5].

pharmacological, that have been proposed.

Mellman et al. [10] suggested that increases in REMS percentage and continuity that occur over time post-trauma could indicate a role of REMS in promoting adaptation to, and recovery from, trauma. While acknowledging that this hypothesis fits well with independent evidence that REMS processes help in the processing of emotional memories, we (RJR; [11]) have suggested that the reconstituted REMS observed long after traumatization may be pathological and, in fact, a sign of poor adaptation to a severe stressor. In a psychoanalytic framework, the repeating traumatic dream would be an indication of the failure of the normal dream mechanism.

An increase in REMS continuity with the passage of time following trauma warrants consideration in the context of the extant PTSD treatment literature. The alpha-adrenoceptor antagonist prazosin is arguably the most effective pharmacotherapy for recurrent posttraumatic nightmares. Although PSG has not been carried out in most prazosin trials, Taylor et al. [12] reported that the drug increased total REMS time and average REMS episode duration in a civilian group with PTSD. This suggests that prazosin's therapeutic effect may depend on a normalization of REMS continuity. Pharmacotherapy for PTSD will be reviewed at greater length below.

Understanding the dynamics of REMS changes after exposure to a traumatic stressor must account for phasic as well as tonic REMS processes. REM density (number of rapid eye movements/REMS time) is the phasic REMS measure most often reported in clinical investigations. In a meta-analysis of 20 PSG studies of PTSD, an increased REM density was the strongest finding [13]. An emphasis on heightened REM density in PTSD is consistent with the early observation of a direct relation between rapid eye movement activity and the intensity of dream mentation in healthy subjects [14].

A greater frequency of phasic leg muscle twitches (calculated as the percentage of REMS epochs with at least one prolonged tibialis anterior twitch; REMS phasic leg activity (RPLA) index) also has been described in PTSD [15]. Although no clear association between RPLA and rapid eye movement activity was seen overall, a single recorded nightmare occurred out of a REMS episode with a particularly high REM density. This observation led to the hypothesis that, as a nightmare unfolds, diverse REMS phasic processes, which can otherwise be uncoupled, may be recruited en masse [15].

Largely because investigations in animals have implicated REMS phasic activity in the processing of fearful stimuli [16, 17], it is important to consider the possibility that severe psychological stress initiates processes in REMS phasic event generators that promote adaptation to trauma, or, alternatively, maladaptation in the form of PTSD. Studying fear conditioning in rats, DaSilva et al. [18] proposed that failure to mount a strong phasic REMS response in the early aftermath of a stressful experience could predispose individuals to the increase in REMS phasic activity that has been observed in humans with chronic PTSD.

PTSD is very often comorbid with other mental disorders, most commonly depression [19]. In addition, new to the criteria for diagnosing PTSD is a set of symptoms, including low selfworth and anhedonia, classed as "negative alterations in cognition and mood" [1]. This raises the question whether REMS abnormalities that have been described in PTSD are in fact a function of depression, for which heightened "REMS pressure" (analogous to increased REMS continuity in evolving PTSD), is the best characterized PSG finding [20].

In order to clarify the distinct roles of PTSD and depression in the REMS changes observed after psychological traumatization, Ross et al. [9] analyzed PSG data by thirds of the night and found increases in REMS percentage and REM density throughout the sleep period in a group of military veterans with chronic combat-related PTSD. These distributions were distinguished from shifts in REMS amount and REM number to earlier in the night, which characterize major depressive disorder [20]. Supporting the importance of brain mechanisms fundamental to PTSD in mediating REMS changes following traumatization, Mellman et al. [10] found that a positive correlation between REMS percentage and time elapsed following traumatization remained significant after excluding subjects with comorbid major depression. Nonetheless, the current emphasis by the National Institutes of Health on Research Domain Criteria (RDoC) in neurobehavioral research provides an alternative perspective, in which both PTSD and depression can be conceptualized as disorders of "dysphoric hyperarousal," sharing in elements of a common REMS pathophysiology.
