pii: jc- 00085 -15http://dx.doi.org/10.5664/jcsm.5392

S CI E NT IF IC IN VES TIGATIONS

Effects of Blast Exposure on Subjective and Objective Sleep Measures in Combat Veterans with and without PTSD Ryan P.J. Stocker, PsyD1,2; Benjamin T.E. Paul, MSW1; Oommen Mammen1,2; Hassen Khan, BS1; Marissa A. Cieply, BS1; Anne Germain, PhD2 University of Pittsburgh Medical Center, Pittsburgh, PA; 2University of Pittsburgh School of Medicine, Department of Psychiatry, Pittsburgh, PA

1

Study Objectives: This study examined the extent to which self-reported exposure to blast during deployment to Iraq and Afghanistan affects subjective and objective sleep measures in service members and veterans with and without posttraumatic stress disorder (PTSD). Methods: Seventy-one medication-free service members and veterans (mean age = 29.47 ± 5.76 years old; 85% men) completed self-report sleep measures and overnight polysomnographic studies. Four multivariate analyses of variance (MANOVAs) were conducted to examine the impact of blast exposure and PTSD on subjective sleep measures, measures of sleep continuity, non-rapid eye movement (NREM) sleep parameters, and rapid eye movement (REM) sleep parameters. Results: There was no significant Blast × PTSD interaction on subjective sleep measures. Rather, PTSD had a main effect on insomnia severity, sleep quality, and disruptive nocturnal behaviors. There was no significant Blast × PTSD interaction, nor were there main effects of PTSD or Blast on measures of sleep continuity and NREM sleep. A significant PTSD × Blast interaction effect was found for REM fragmentation. Conclusions: The results suggest that, although persistent concussive symptoms following blast exposure are associated with sleep disturbances, selfreported blast exposure without concurrent symptoms does not appear to contribute to poor sleep quality, insomnia, and disruptive nocturnal disturbances beyond the effects of PTSD. Reduced REM sleep fragmentation may be a sensitive index of the synergetic effects of both psychological and physical insults. Keywords: veterans, sleep, blast exposure, mild traumatic brain injury (mTBI), PTSD, REM sleep Citation: Stocker RP, Paul BT, Mammen O, Khan H, Cieply MA, Germain A. Effects of blast exposure on subjective and objective sleep measures in combat veterans with and without PTSD. J Clin Sleep Med 2016;12(1):49–56.

I N T RO D U C T I O N

BRIEF SUMMARY

Current Knowledge/Study Rationale: The potential pervasive effects of blast exposure on subjective and objective sleep measures continue to be a phenomenon that has not been fully investigated. The aim of the present study was to explore the relationships between blast exposure and/or prior mild traumatic brain injury and subjective sleep measures, as well as objective measures of sleep continuity, and non-rapid eye movement (NREM) and rapid eye movements (REM) sleep parameters in a sample of combat-exposed military service members and veterans with and without posttraumatic stress disorder (PTSD), and with no current post-concussive symptoms. Study Impact: Results of the present study suggests that prior blast exposure or TBI alone, in the absence of current chronic concussive symptoms, does not adversely affect sleep quality, insomnia, disruptive nocturnal behaviors, or objective sleep measures beyond the effects of PTSD. Preliminary observations suggest that attenuation of REM sleep may be an especially sensitive index of central changes resulting from psychological or physical insults. Further investigation is needed to elucidate the of REM sleep mechanisms that may be affected by either or both blast exposure and PTSD.

Mild traumatic brain injury (mTBI) is one of the signature injuries of the Global War on Terror, and is among the leading factors contributing to disability and death among military service members of Operations Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF).1–4 mTBI is defined as a loss of consciousness lasting up to 30 minutes, alteration of consciousness/mental state from a moment up to 24 hours, and posttraumatic amnesia lasting 1 day or less, in the absence of detectable abnormal structural imaging findings.5 Between 30% and 40% of combat infantry and other military personnel who have served in OEF/OIF have been exposed to blast forces resulting from explosives, particularly improvised explosive devices (IEDs).6,7 While mTBI sustained from blast injuries are not the only means of sustaining mTBI (i.e., blunt trauma), blast injuries represent the most common type of mTBI reported in returning military personnel.3,8 Of those exposed to blasts, the reported prevalence rates of subsequent mTBI in warfighters vary between 4.9% to 22%.6,7,9,10 The projected 2-year costs associated with chronic mTBI, which refers to symptoms and impairments that last more than three months post-injury, could average as much as $591 billion.10 Sleep disturbances are prevalent among both warfighters and civilians with subacute (i.e., < 3 months in duration) and chronic mild traumatic brain injury (cmTBI), and can impede recovery.11,12 As many as 50% of traumatic brain injury (TBI)

patients report sleep/wake disturbances, and 25% to 30% meet diagnostic criteria for sleep disorders.13,14 Obstructive sleep apnea, hypersomnia, and periodic limb movement disorders are prevalent among patients with cmTBI.15 In military personnel, Collen and colleagues reported that 97% of warfighters with cmTBI reported sleep complaints.16 These sleep complaints were corroborated by polysomnographic sleep/wake studies, and included hypersomnia (85%), insomnia (55%), sleep 49

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fragmentation (54%), and obstructive sleep apnea syndrome (OSAS) (35%). Those with comorbid mTBI and posttraumatic stress (PTS) or anxiety endorsed more severe sleep complaints.16 Other studies have found similarly high rates of sleep complaints in military and civilian samples, which were also corroborated by objective measures.17–19 There is preliminary evidence that blast- vs. blunt-related TBI may be accompanied by distinct profiles of sleep disturbances. For instance, blast injuries are associated with insomnia and elevated anxiety symptoms, whereas blunt injuries are more commonly associated with OSAS.16 Over 60% of patients with cmTBI continue to endorse clinically significant sleep disturbances 3 years post-injury,18 and there is evidence that sleep disturbances impede recovery and rehabilitation. Although aspects of the nature and impact of subacute and chronic mTBI have been studied, the potential pervasive effects of blast exposure on subjective and objective sleep measures, even in the absence of chronic post-concussive symptoms, have not been investigated. We have recently reported that blast exposure and/or prior mTBI is associated with hypometabolic cerebral profiles during wakefulness and REM sleep, but not during NREM sleep in a small sample of OEF/OIF service members and veterans.20 Alterations in regional cerebral metabolism are viewed as a hallmark of mTBI and seen across a number of populations at various post-injury time points with vastly diverse outcomes.21–27 Altered cerebral metabolic profiles documented in blast exposure and/or prior mTBI may affect sleep-related processes during REM sleep and NREM sleep that can be captured with polysomnography (PSG). Thus, the goal of the present study was to explore the relationships between blast exposure and/or prior mTBI and subjective sleep measures, as well as objective measures of sleep continuity, NREM sleep parameters, and REM sleep parameters in a sample of 71 combat-exposed service members and veterans with and without PTSD, and with no current post-concussive symptoms. While exploratory, we nevertheless hypothesized that blast exposure would be associated with increased severity of self-reported sleep disturbances, reduced sleep continuity (e.g., increased sleep latency and wake time after sleep onset, decreased total sleep time and sleep efficiency), regardless of the presence of current PTSD. Based on our prior sleep neuroimaging findings, we also hypothesized that objective indices of REM sleep disruption, but not of NREM sleep disruption, would be detectable.

measures, and overnight PSG studies. All were medicationfree for ≥ 2 weeks prior to study entry (6 weeks for fluoxetine); individuals who were taking medications allowed as part of the parent studies were not included in the present analyses. Among the 71 participants, 37 reported being directly exposed to a blast during deployment (26 with PTSD), and 34 reported that they did not experience blast exposure while on deployment (21 with PTSD). None of the participants reported experiencing current post-concussive symptoms at study entry during the medical review. After providing written, informed consent, participants enrolled in studies completed a series of screening procedures to ascertain eligibility. All completed a through medical evaluation, during which prior history of blast exposure, TBI, and concussive symptoms was evaluated. To guide the medical review, participants first completed the 3-item Defense and Veterans Brain Injury Center (DVBIC) TBI Screening Tool10 to determine the cause of brain injuries sustained during deployment, resulting alterations or loss of consciousness, and current concussive symptoms (e.g., headaches, dizziness, tinnitus, vestibular problems). Next, the study physician or nurse practitioner reviewed sections I through VIII of the Military Acute Concussion Evaluation (MACE)28 questionnaire with participants. During the initial interview, participants were asked to describe whether or not they experienced loss of consciousness (LOC); altered state of consciousness; or if amnesia occurred after the injury. The nature and duration of symptoms following the injury was then evaluated. As previously mentioned, none of the participants enrolled in parent studies endorsed current post-concussive symptoms related to blast exposure or TBI. To estimate blast exposure and/or prior TBI, data gathered from the DVBIC,10 the Clinician-Administered PTSD Scale for DSM-IV (CAPS),30 sections I through VIII of the MACE,28 and during the medical review were cumulated. The blast exposure/ TBI group included veterans who reported that they had been exposed to an explosive blast while deployed on at least one of these assessments. Veterans in the no blast exposure group did not report any exposure to blast before, during, or after deployment on any of the assessments. Certified master’s or doctoral level assessors administered the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID)29 in order to assess the presence and severity of mood, anxiety, or alcohol/substance use disorders. The presence and severity of PTSD was determined using the CAPS,30 the gold standard for PTSD assessment using the 1F-2I scoring rule. The Structured Clinical Interview for DSM-IV Sleep Disorders (SLD), a clinician-administered tool developed locally, was used to evaluate current and past symptoms of insomnia, sleep disordered breathing, restless legs syndrome and other sleep-related movement disorders, and parasomnias. This instrument, like the SCID, assesses the presence of core symptoms of these sleep disorders as defined by the International Classification of Sleep Disorders31 and DSM-IV.32 All participants also completed a battery of self-report measures to assess sleep quality and sleep disturbances, as well as combat exposure, symptoms of PTSD, depression, and anxiety. Sleep measures included the Insomnia Severity Index (ISI)33; the Pittsburgh Sleep Quality Index (PSQI)34; the Pittsburgh

METHODS The present study was a secondary analysis of data collected from sleep studies in post-9/11 servicemembers and veterans with and without PTSD (MH083035, MH080696, PR073961) that were approved by the Institutional Review Board at the University of Pittsburgh and Human Research Protection Office of the Department of Defense (ClinicalTrials.gov # NCT01637584 and # NCT00871650). Seventy-one service members and veterans (59 males, 12 females) between the ages of 20 and 45 (Mean age = 29.47 ± 5.76 years old) had all completed clinical assessments, self-report Journal of Clinical Sleep Medicine, Vol. 12, No. 1, 2016

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Table 1—Demographic, military, and clinical measures for blast exposed and non-blast exposed combat veterans with and without PTSD.

% men (n)

Blast Exposure (n = 37) No PTSD (n = 11) PTSD (n = 26) % (n) % (n) 21.1 (15) 16.9 (12)

% Army (n)

21.1 (15)

11.3 (8)

18.3 (13)

12.7 (9)

% Caucasian (n)

33.8 (24)

14.1 (10)

25.4 (18)

Mean ± SD 28.55 ± 5.73

Mean ± SD 31.73 ± 6.50

Mean ± SD 29.13 ± 5.50

Age Apnea-hypopnea index Epworth Sleepiness Scale

a

No Blast Exposure (n = 34) No PTSD (n = 13) PTSD (n = 21) % (n) % (n) 31.0 (22) 14.1 (10)

2.14 ± 2.61 1.63 ± 2.04 (Range: 0.0–7.65) (Range: 0.0–8.00)

Group Difference χ2 (df) χ (3) = 3.34 2

p 0.34

χ2(9) = 9.94

0.36

16.9 (12)

2

χ (12) = 13.96

0.30

Mean ± SD 29.94 ± 5.71

F(df) F3, 67 = 0.83

p 0.48

F3, 66 = 4.63

0.73

1.04 ± 1.59 1.84 ± 2.92 (Range: 0.0–5.23) (Range: 0.0–13.94)

6.55 ± 3.45 (n = 11)

8.24 ± 4.12

6.20 ± 3.82

5.88 ± 3.46

F3, 64 = 1.66

0.18

Combat exposure scale

13.38 ± 10.24

12.76 ± 9.42

18.09 ± 9.43

22.12 ± 9.66

F3, 67 = 4.42

0.007

CAPS total

13.62 ± 10.53

52.52 ± 15.64

18.09 ± 11.10

53.58 ± 15.29

F3, 67 = 37.60

< 0.001

PTSD checklist a

1.29 ± 0.067

1.52 ± 0.11 (n = 20)

1.32 ± 0.088

1.53 ± 0.12

F3, 66 = 23.20

< 0.001

Beck Depression Inventory b

1.52 ± 0.55 (n = 10)

2.68 ± 1.02 (n = 16)

1.79 ± 0.83 (n = 10)

2.77 ± 0.61 (n = 22)

F3, 54 = 8.72

< 0.001

Beck Anxiety Inventory b

0.24 ± 0.35 (n = 11)

0.58 ± 0.47 (n = 16)

0.17 ± 0.40 (n = 9)

0.65 ± 0.30 (n = 23)

F3, 55 = 5.45

0.002

Log10-transformed. b Log10+1-tranformed.

Sleep Quality Index Addendum for PTSD Study (PSQI-A)35 and the Epworth Sleepiness Scale (ESS). The Combat Exposure Scale (CES)36 was used to assess whether veterans experienced combat exposure and whether those entailed 7 stressful criteria for the event(s). Scoring for the CES consisted of Light Combat (0–8); Light-Moderate (9–16); Moderate Combat (17–24); Moderate-Heavy Combat (25–32); and Heavy Combat (33–41). Other tools which were used to measure symptoms included the PTSD Checklist (PCL),37 the Beck Depression Inventory (BDI),38 and the Beck Anxiety Inventory (BAI).39 Participants then underwent three nights of PSG in the Neuroscience Clinical and Translational Research Center (NCTRC; RR024153). The first night was a screening study to rule out the presence of sleep disordered breathing or periodic leg movement disorder. Two more consecutive nights were collected in participants who did not have an apnea-hypopnea index > 15 on the screening night. For all nights in the laboratory, bedtime and rise times were individually determined to closely match participant’s habitual schedule. PSG was conducted using Grass Telefactor M15 bipolar Neurodata amplifiers and using Stellate-Harmonie collection software. The recording montage consisted of bilateral frontal, central, and occipital (F3, F4, C3, C4, O1, O2) electroencephalography (EEG) leads referenced to A1+A2; right and left electro-oculogram referenced to A1+A2; and bipolar submentalis electromyogram (EMG). On the screening night, additional channels were used to monitor sleep related breathing (nasal-oral thermistors, inductance plethysmography, fingertip oximetry, V2 electrocardiography (EKG)) and periodic limb movements (bilateral anterior tibialis EMG). EEG recordings used a high-frequency filter of

100 Hz, a low-frequency filter of 0.3 Hz, and a 60-Hz notch filter. Sleep stages were scored in 20-sec epochs according to the Rechtschaffen and Kales criteria. REM density was calculated using an automated algorithm as previously described.40 Data from the last PSG night was used for the present study. Measures of interest for sleep continuity included sleep latency, wake time after sleep onset, total sleep time, and sleep efficiency. NREM sleep parameters of interested included % NREM sleep, % stage 1 sleep, % stage 2 sleep, % delta sleep, and delta sleep ratio. REM sleep parameters of interested included REM latency, REM density, % REM sleep, and REM sleep fragmentation. A χ2 test was first conducted to evaluate whether the rate of PTSD differed in blast exposed or non-blast exposed veterans. Four (MANOVAs were then conducted using the Statistical Package for the Social Sciences, version 21 (SPSS, version 21) in order to determine the effects of current PTSD status (yes/no) and blast exposure (yes/no) across (1) self-report sleep measures, (2) objective measures of sleep continuity, (3) NREM sleep parameters, and (4) REM sleep parameters. The statistical significance was set at p < 0.05. Distributions were verified for normality, and variables with non-normal distributions were transformed prior to statistical analyses as needed. R ES U LT S

Sample Characteristics

Demographic, military, clinical measures for blast exposed and non-blast exposed combat veterans with and without PTSD is 51

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Table 2—Mean scores (and standard deviations) and univariate effects of self-report sleep measures, PSG, NREM, and REM sleep parameters on blast exposed and non-blast exposed combat veterans with and without PTSD. No Blast Exposure (n = 34)

Blast Exposure (n = 37)

No PTSD (n = 13) Mean ± SD

PTSD (n = 21) Mean ± SD

No PTSD (n = 11) Mean ± SD

PTSD (n = 26) Mean ± SD

5.64 ± 5.45 (n = 11)

14.95 ± 3.95 (n = 20)

4.82 ± 5.60

PSQI

3.82 ± 1.10 (n = 11)

8.85 ± 2.66 (n = 20)

PSQIAa

0.64 ± 0.67 (n = 11)

1.78 ± 0.82 (n = 20)

Sleep questionnaires ISI

PSG measures Sleep latency a WASO a Total sleep rime Sleep efficiency b

2.50 ± 1.16 2.88 ± 0.77 2.89 ± 0.60 3.16 ± 0.67 420.15 ± 31.62 441.71 ± 55.20 2.10 ± 0.59 2.26 ± 0.56

Main Effect

Interaction Blast × PTSD

Blast

PTSD

F(df)

p

13.64 ± 4.64 (n = 25)

F1, 63 = 0.039

0.84

F1, 63 = 0.74

0.39

F1, 63 = 53.50 < 0.001

4.55 ± 2.58

7.60 ± 2.60 (n = 25)

F1, 63 = 2.42

0.13

F1, 63 = 0.17

0.68

F1, 63 = 40.42 < 0.001

0.29 ± 0.64

1.56 ± 0.71 (n = 25)

F1, 63 = 0.13

0.72

F1, 63 = 2.23

0.14

F1, 63 = 40.70 < 0.001

F1, 67 = 0.12 F1, 67 = 0.074 F1, 67 = 1.61 F1, 67 = 0.12

0.73 0.79 0.21 0.73

F1, 67 = 0.21 F1, 67 = 0.004 F1, 67 = 0.32 F1, 67 = 0.028

0.65 0.95 0.58 0.87

F1, 67 = 1.52 F1, 67 = 1.90 F1, 67 = 0.061 F1, 67 = 1.93

0.22 0.17 0.81 0.17

2.69 ± 0.69 2.90 ± 1.03 2.92 ± 0.47 3.10 ± 0.72 430.18 ± 34.06 415.65 ± 71.88 2.07 ± 0.43 2.35 ± 0.76

F(df)

p

F(df)

p

NREM measures % NREM % stage 1 sleep c % stage 2 sleep d % delta sleep e Delta sleep ratio f

77.37 ± 4.17 0.52 ± 0.25 3.48 ± 1.64 3.00 ± 1.09 1.28 ± 0.22

75.31 ± 5.85 0.56 ± 0.23 3.77 ± 1.06 2.95 ± 1.34 1.30 ± 0.32

74.03 ± 4.17 0.65 ± 0.22 3.94 ± 0.52 2.76 ± 1.14 1.38 ± 0.24

74.91 ± 6.90 0.65 ± 0.26 4.14 ± 0.99 3.19 ± 1.21 1.35 ± 0.30

F1, 67 = 1.01 F1, 67 = 0.16 F1, 67 = 0.037 F1, 67 = 0.59 F1, 67 = 0.072

0.32 0.69 0.85 0.44 0.79

F1, 67 = 1.64 F1, 67 = 3.21 F1, 67 = 3.38 F1, 67 = 0.001 F1, 67 = 1.13

0.21 0.08 0.07 0.99 0.29

F1, 67 = 0.16 F1, 67 = 0.093 F1, 67 = 1.13 F1, 67 = 0.37 F1, 67 = 0.012

0.69 0.76 0.29 0.55 0.92

REM measures REM latency c REM fragmentation c % REM REM density c

1.92 ± 0.20 0.63 ± 0.32 22.62 ± 4.11 0.86 ± 0.24

1.83 ± 0.33 0.85 ± 0.31 24.57 ± 5.74 0.91 ± 0.27

1.77 ± 0.23 0.91 ± 0.21 25.82 ± 4.09 0.89 ± 0.26

1.90 ± 0.17 0.58 ± 0.40 25.08 ± 6.97 0.97 ± 0.23

F1, 67 = 3.37 F1, 67 = 10.93 F1, 67 = 0.86 F1, 67 = 0.059

0.07 0.002 0.36 0.81

F1, 67 = 0.39 F1, 67 = 0.010 F1, 67 = 1.62 F1, 67 = 0.46

0.53 0.92 0.21 0.50

F1, 67 = 0.13 F1, 67 = 0.49 F1, 67 = 0.17 F1, 67 = 1.11

0.72 0.49 0.68 0.30

Ln-transformed, b Reverse scored and Ln-transformed, c Log10-transformed, d Reverse scored and Sqrt-transformed, e Sqrt-transformed, f Arcsine and Sqrt-transformed. a

provided in Table 1. The mean ESS scores and apnea-hypopnea index (AHI) for each group is also included in Table 1. Among the 71 veterans, 34 reported they did not report experiencing blast exposure while on deployment (13 without PTSD diagnosis; 29.94 ± 5.71 years) compared to 21 with PTSD diagnosis (29.13 ± 5.50 years). Thirty-seven veterans reported being exposed to a blast while on deployment (11 without PTSD diagnosis; 31.73 ± 6.50 years) compared to 26 with PTSD diagnosis (28.55 ± 5.73 years). The proportion of service members and veterans with PTSD did not differ between those with and without prior blast exposure, χ2(1, n = 71) = 0.57, p = 0.45. Regarding combat exposure as measured by the CES, the group with no blast exposure and no PTSD and the group of veterans not exposed to blast exposure with a diagnosis of PTSD both reported statistically significant lower levels of combat exposure compared to veterans with both blast exposure and with a diagnosis of PTSD. The mean CAPS scores were similar for veterans without PTSD diagnosis, regardless of presence or absence of blast exposure. Additionally, participants with PTSD, regardless of blast exposure, had similar CAPS scores. CAPS scores were significantly lower for both groups of veterans with no blast exposure and no PTSD diagnosis and veterans with blast exposure and no PTSD diagnosis compared to veterans with no blast exposure and PTSD diagnosis and both blast exposure and PTSD diagnosis. While there were significant interactions between blast exposure and PTSD on PCL, BDI, and BAI scores, the Journal of Clinical Sleep Medicine, Vol. 12, No. 1, 2016

assumption of homogeneity of variances were violated for the measures. Thus the statistical significance of the results should be viewed with caution. The mean PCL scores, mean BDI scores, and mean BAI scores were similar for the 2 groups of veterans without PTSD, regardless of blast exposure, as well as for veterans with PTSD diagnosis, regardless of presence or absence of blast exposure.

Subjective Sleep Measures

To assess group differences on self-report sleep measures (ISI, PSQI, and PSQI-A), a MANOVA was conducted. Of the 71 total participants found to have the in-lab PSG studies necessary for this analysis, 4 were had missing or incomplete data on these measures. Therefore, these analyses were conducted on the remaining 67 participants (Table 2). As the assumptions of independence of observations and homogeneity of variance and covariance were checked and not violated, Wilks’ Λ was utilized to examine the multivariate statistics. The Blast × PTSD interaction was not statistically significant (Wilks’ Λ = 0.94, F3, 61 = 1.20, p = 0.32, multivariate η2 = 0.056). Rather, a main effect of PTSD was found (Wilks’ Λ = 0.46, F3, 61 = 24.00, p < 0.001, multivariate η2 = 0.54). This indicates that the linear composite of ISI, PSQI, and PSQIA scores differed for participants with and without PTSD. No main effect of Blast exposure was found. Univariate analysis of variance (ANOVAs) revealed that the effect of PTSD diagnosis was statistically significant for all 3 self-report sleep measures. 52

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Specifically, those with PTSD endorsed higher scores on all three measures compared to those without PTSD diagnosis (Table 2). Means and standard deviations, as well as univariate effects of Blast Exposure and PTSD diagnosis on ISI, PSQI, and PSQIA are provided in Table 2.

distinguishing any of the other interactions. A follow-up univariate ANOVA revealed that REM fragmentation was statistically different between groups (F1, 67 = 10.93, p = 0.002). Tukey post hoc tests revealed no significant differences between the group of veterans’ with neither blast exposure nor PTSD with the other groups. In contrast, a statistically significant difference was found between the group of veterans with both blast exposure and PTSD and the group with no blast exposure and PTSD (p = 0.037). Additionally, a statistically significant difference was found between the group of veterans with both blast exposure and PTSD and the group with blast exposure and no diagnosis of PTSD (p = 0.033). Means and standard deviations, as well as univariate effects of Blast Exposure and PTSD on REM parameters are provided in Table 2. Including AHI as a covariate did not change these results.

Polysomnographic Measures of Sleep Continuity

The ESS scores and AHI did not significantly differ across groups (Table 1). None of the participants were found to have AHI > 15. Six had an AHI ≥ 5: three with a history of blast exposure and PTSD; one with a history of blast exposure without PTSD; one without a history of blast exposure with PTSD; and one with neither a history of blast exposure or PTSD. A second MANOVA was conducted to assess group differences on objective measures of sleep continuity, including sleep latency, wake time after sleep onset (WASO), total sleep time, and sleep efficiency. As the assumptions of independence of observations and homogeneity of variance and covariance were violated, Pillai’s Trace was utilized to examine the multivariate statistics. The Blast × PTSD interaction was not statistically significant, Pillai’s Trace = 0.064, F4, 64 = 1.10, p = 0.36, multivariate η2 = 0.33, and no main effects of Blast or PTSD were detected. Means and standard deviations, as well as univariate effects of Blast Exposure and PTSD on sleep latency, WASO, total sleep time, and sleep efficiency are provided in Table 2 for completeness.

D I SCUS S I O N The purpose of this study was to explore the potential of selfreported blast exposure on subjective and objective sleep measures in combat-exposed service members and veterans with and without PTSD. Approximately 70% of blast exposed participants met diagnostic criteria for current PTSD compared to 61.8% of those who were not exposed to blast or denied a prior history of concussive injuries. This nonsignificant difference is consistent with the observations that a multitude of deployment-related stressors can contribute to chronic PTSD.41 In this sample of convenience, PTSD was a stronger determinant of subjective sleep complaints than self-reported blast exposure. This finding is consistent with previous studies that have shown that sleep disturbances are highly prevalent and strongly correlated with PTSD in combat deployment military veterans.42–51 Although sleep difficulties often follow TBI or blast exposure,52 the present study suggests that prior blast exposure or TBI alone, in the absence of current chronic concussive symptoms, does not adversely affect sleep quality, insomnia, disruptive sleep disturbances, or objective sleep measures beyond the effects of PTSD. Indeed, post hoc analyses revealed that service members and veterans with PTSD endorsed higher scores on the ISI, PSQI, and PSQIA than those without PTSD diagnosis, regardless of presence or absence of blast exposure. These observations also raise the possibility that sleep complaints in the context of active concussive symptomatology may be an indicator of concurrent PTSD. Further investigation of the relationship between sleep, PTSD, and mTBI in larger patient samples with active chronic postconcussive symptoms is required to examine this possibility. Neither blast exposure nor PTSD was associated with detectable changes in objective measures of sleep continuity and NREM sleep. These observations are consistent with a previous meta-analysis and recent studies in new cohorts of combat-exposed veterans showing modest objective changes in objective sleep parameters with PTSD.53,54 However, we and others55–59 have shown that the absence of objective sleep disturbances in PTSD may not capture functionally meaningful and detectable neural changes during sleep. For instance, despite similar PSG characteristics, there have been differences in brain glucose

NREM Sleep Measures

A third MANOVA was conducted to assess group differences on NREM sleep parameters, including percent of time spent in NREM sleep, percent of time spent in stage 1 sleep, percent of time spent in stage 2 sleep, percent of time spent in delta sleep, and delta sleep ratio. As the assumptions of independence of observations and homogeneity of variance and covariance were not violated, Wilks’ Λ was utilized to examine the multivariate statistics. The Blast × PTSD interaction was not statistically significant (Wilks’ Λ = 0.97, F5, 63 = 0.40, p = 0.85, multivariate η2 = 0.15), and no main effects of Blast or PTSD were detected. Means and standard deviations, as well as univariate effects of Blast Exposure and PTSD on these NREM variables are provided in Table 2 for completeness. Including AHI as a covariate did not change these results.

REM Sleep Measures

Finally, a fourth MANOVA was conducted to assess group differences on REM sleep parameters, which included REM latency, REM fragmentation, percent of time spent in REM, and REM density. The assumptions of independence of observations and homogeneity of variance and covariance were met. The interaction effect was statistically significant (Wilks’ Λ = 0.85, F4, 64 = 3.13, p = 0.021, multivariate η2 = 0.79). Examination of the coefficients for the linear combinations distinguishing the interaction between blast exposure and PTSD groups indicated that REM fragmentation contributed most to distinguishing the groups. In particular, REM fragmentation (β = 0.14, p = 0.002, multivariate η2 = 0.90) contributed significantly toward discriminating the effect of the interaction, but no other variables statistically significantly contributed to 53

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RP Stocker, BT Paul, O Mammen et al. Sleep in Blast-Exposed Combat Veterans

metabolism during NREM sleep observed in adults with depression or insomnia when compared to healthy sleepers.55–60 Similarly, we have recently reported that blast exposure and/or prior mild TBI was associated with detectable reductions in cerebral glucose metabolism during both wakefulness and REM sleep, despite similar findings on objective measures of sleep continuity and NREM sleep.20 Probing the functional neuroanatomical correlates of TBI and PTSD separately or when comorbid using sleep neuroimaging methods may reveal group differences during NREM sleep in cerebral perfusion or glucose metabolism relative that are not captured by PSG. REM fragmentation was the only REM sleep parameter that differed across the four groups of veterans. Specifically, veterans with both blast exposure and PTSD showed the lowest amount of REM fragmentation compared to the other three groups. In a recent study, we have found that blast exposure (beyond the effects of PTSD) was associated with reduced cerebral metabolic activity in brainstem, limbic and paralimbic regions, the basal ganglia, and thalamus during REM sleep in veterans with a blast and mTBI exposure compared to those without blast and mTBI exposure.20 Together, these preliminary observations suggest that attenuation of REM sleep may be an especially sensitive index of central changes resulting from psychological or physical insults. Given the overlap in symptoms of PTSD and TBI, further investigation of REM sleep mechanisms are needed to elucidate the reasons as to why the presence of both blast exposure and PTSD significantly decreased the amount of REM fragmentation when compared to the group in which only blast exposure or PTSD was present. Regardless, it appears as though REM sleep mechanisms may provide novel indicators to aid the diagnosis and treatment of these conditions. The study comprises a number of limitations that should be acknowledged. First, we cannot verify the accuracy of the retrospective, self-reports of blast exposure. Similarly, the evaluation of the nature and severity of immediate and subsequent concussive symptoms in the present study was limited, and retrieved from a number of self-report and clinical assessments. Since each blast exposure and/or blunt force TBI was self-reported, and since there is no infallible measure to ascertain the reliability of self-reports, we selected measures that were deemed reliable by combining information from the DVBIC TBI rating tool, the first section of the MACE, medical review, and CAPS. Collection of objective assessments given more proximally to blast exposure is necessary to ascertain the exactitude of self-reports of previous blast or TBI. Given the role of sleep in neuroplasticity,61–63 changes in objective sleep parameters may be detectable in the immediate aftermath of blast exposure, which may normalize over time and/or with the remission of concussive symptoms. Sleep assessments more proximal to the time of injury are necessary to provide insights into the impact of sleep preservation, or of sleep disturbance, on the trajectory of TBI recovery and of PTSD. In a related manner, obtaining more proximal and reliable measures of severity and proximity to blast exposure and/ or TBI severity and duration of subsequent symptoms would also provide more fine-grained understanding on the impact of brain insults on sleep measures. In this sample of convenience, the mean AHI were well below the clinical cutoff of 5 events Journal of Clinical Sleep Medicine, Vol. 12, No. 1, 2016

per hour in all four study groups, and AHI was not found to affect the main findings when included as a covariate. Recent studies, however, have highlighted the high prevalence of sleep disordered breathing and high rates of comorbidity with PTSD in military samples.16,54,59 Thus, different patterns of findings may emerge from studies including samples with more severe sleep disordered breathing, and/or with concurrent concussive symptoms. Furthermore, the absence of neurocognitive assessments in the parent studies does not allow us to completely rule out the presence of mild cognitive deficits in the sample. Administration of the full MACE would have provided additional information regarding potential residential cognitive deficits across the four study groups. It would be especially important to include more comprehensive sensitive neurocognitive measures to further evaluate the relationship between prior blast exposure/TBI, PTSD, sleep, and neurocognitive performance. Finally, the small sample and relative homogeneity of the sample did not allow for the exploration the potential moderating effects of gender, racial, or ethnic characteristics on subjective and objective sleep measures. Larger samples are required to fully evaluate potential moderators of blast exposure and PTSD on subjective and objective sleep measures in combatexposed servicemembers and veterans. Despite these limitations, results from this exploratory study suggest that blast exposure alone does not adversely affect subjective measures of sleep quality beyond the effects of PTSD, although blast and PTSD may both affect REM-related processes. Blast exposure alone did not have detectable effects on global measures of sleep continuity or of NREM sleep. Reevaluating the relationship between blast exposure or other traumatic brain injuries, PTSD, and sleep in service members, veterans, and civilians with active concussive symptoms is necessary to fully understand the brain mechanisms that contribute to this common triad of complaints. A B B R E V I AT I O N S AHI, apnea-hypopnea index ANOVA, analysis of variance BAI, Beck Anxiety Inventory BDI, Beck Depression Inventory CAPS, Clinician-Administered PTSD Scale for DSM-IV CES, Combat Exposure Scale cmTBI, chronic mild traumatic brain injury DVBIC, Defense and Veterans Brain Injury Center EEG, electroencephalography EKG, electrocardiography EMG, electromyogram ESS, Epworth Sleepiness Scale IED, improvised explosive device ISI, Insomnia Severity Index LOC, loss of consciousness MACE, Military Acute Concussion Evaluation MANOVA, multivariate analyses of variance mTBI, mild traumatic brain injury N-CTRC, Neuroscience Clinical and Translational Research Center 54

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ACK N O W L E D G M E N T S The authors acknowledge the service and sacrifice of the members of the United States Armed Services. Additionally, the authors would like to recognize the hard work and dedication of Robin Richardson, Rachel Good, Tyler Conrad, Noelle Rode, and others who have contributed to the operations of the Military Sleep Tactics and Resilience Research Team.

SUBM I SSI O N & CO R R ESPO NDENCE I NFO R M ATI O N Submitted for publication February, 2015 Submitted in final revised form July, 2015 Accepted for publication July, 2015 Address correspondence to: Anne Germain, PhD, Associate Professor of Psychiatry and Psychology, University of Pittsburgh School of Medicine, 3811 O’Hara Street, Pittsburgh PA 15213. Tel: (412) 383-2150. Fax: (412) 383-5412. Email: germax@ upmc.edu

D I SCLO S U R E S TAT E M E N T This study was supported by the Department of Defense Congressionally Directed Medical Research Program (PR0504093 and PT07396; PI: Germain) and the National Institutes of Health (MH083035 and MH080696, PI: Germain; N-CTRC # RR024153; PI: Reis). The views expressed in this article are those of the authors and do not reflect the official policy or position of the DOD. The authors have indicated no financial conflicts of interest.

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