Tristin Baxter

Sleep Disorders in US Military Personnel: A High Rate of Comorbid Insomnia and Obstructive Sleep Apnea

BACKGROUND Sleep disturbances are among the most common symptoms of military personnel who return from deployment. The objective of our study was to determine the presence of sleep disorders in US military personnel referred for evaluation of sleep disturbances after deployment and examine associations between sleep disorders and service-related diagnoses of depression, mild traumatic brain injury, pain, and posttraumatic stress disorder (PTSD). METHODS This was a cross-sectional study of military personnel with sleep disturbances who returned from combat within 18 months of deployment. Sleep disorders were assessed by clinical evaluation and polysomnogram with validated instruments to diagnose service-related illnesses. RESULTS Of 110 military personnel included in our analysis, 97.3% were men (mean age, 33.6 ± 8.0 years; mean BMI, 30.0 ± 4.3 kg/m2), and 70.9% returned from combat within 12 months. Nearly one-half (47.3%) met diagnostic criteria for two or more service-related diagnoses. Sleep disorders were diagnosed in 88.2% of subjects; 11.8% had a normal sleep evaluation and served as control subjects. Overall, 62.7% met diagnostic criteria for obstructive sleep apnea (OSA) and 63.6% for insomnia. The exclusive diagnoses of insomnia and OSA were present in 25.5% and 24.5% of subjects, respectively; 38.2% had comorbid insomnia and OSA. Military personnel with comorbid insomnia and OSA were significantly more likely to meet criteria for depression (P < .01) and PTSD (P < .01) compared with control subjects and those with OSA only. CONCLUSIONS Comorbid insomnia and OSA is a frequent diagnosis in military personnel referred for evaluation of sleep disturbances after deployment. This diagnosis, which is difficult to treat, may explain the refractory nature of many service-related diagnoses.

Lower health related quality of life in U.S. military personnel is associated with service-related disorders and inflammation

Military personnel who have combat exposures are at increased risk for the service-related disorders of post-traumatic stress disorder (PTSD), depression, sleep disturbances and decreased health related quality of life (HRQOL). Those with a traumatic brain injury (TBI) are at even greater risk. Inflammation is associated with these disorders and may underlie the risk for health declines. We evaluated 110 recently deployed, military personnel presenting with sleep disturbances for service-related disorders (TBI, PTSD, and depression) as well as HRQOL. ANOVA models were used to examine differences among military personnel with two or more service-related disorders (high comorbid group), or one or no disorders (low comorbid group). Logistic regression models were used to determine associations among interleukin-6 (IL-6) to HRQOL and service-related disorders. Approximately one-third of the sample had two or more service-related disorders. HRQOL was lower and IL-6 concentrations were higher in military personnel with PTSD or depression, with the most profound differences in those with more service-related disorders, regardless of sleep disorder. Having symptoms of depression and PTSD resulted in a 3.5-fold risk to be in the lower quartile of HRQOL and the highest quartile of IL-6. In a linear regression model, 41% of the relationship between HRQOL and IL-6 concentrations was mediated by PTSD and depression. Military personnel with PTSD and depression are at high risk for lower HRQOL, and higher IL-6 concentrations. Comprehensive treatment is required to address co-occurring service-related disorders in military personnel to promote health and well-being.

Improved Sleep Quality is Associated with Reductions in Depression and PTSD Arousal Symptoms and Increases in IGF-1 Concentrations.

STUDY OBJECTIVES One-third of deployed military personnel will be diagnosed with insomnia, placing them at high risk for comorbid depression, posttraumatic stress disorder (PTSD), and medical conditions. The disruption of trophic factors has been implicated in these comorbid conditions, which can impede postdeployment recovery. This study determined if improved sleep quality is associated with (1) reductions in depression and posttraumatic symptoms, as well as enrichments in health-related quality of life (HRQOL), and (2) changes in plasma concentrations of brain derived neurotrophic factor (BDNF) and insulin-like growth factor-1 (IGF-1). METHODS Forty-four military personnel diagnosed with insomnia underwent clinical evaluations and blood draws at pretreatment and at posttreatment following cognitive behavioral therapy for insomnia and automatic positive airway pressure treatment. Participants were classified as sleep improved (n = 28) or sleep declined (n = 16) based on their change in pretreatment to posttreatment Pittsburgh Sleep Quality Index (PSQI) score. Both groups were compared on outcomes of depression, PTSD, HRQOL, BDNF, and IGF-1. RESULTS Paired t-tests of the sleep improved group revealed significant declines in depression (p = 0.005) and posttraumatic arousal (p = 0.006) symptoms, and a significant increase in concentrations of IGF-1 (p = 0.009). The sleep declined group had no relevant change in psychiatric symptoms or trophic factors, and had further declines on five of eight dimensions of HRQOL. Between-group change score differences were significant at p < 0.05. CONCLUSIONS These findings suggest that interventions, which successfully improve sleep quality, are an effective means to reduce the depression and posttraumatic arousal symptoms common to military personnel, as well as increase protective trophic factors implicated in these conditions.

Improved Sleep in Military Personnel is Associated with Changes in the Expression of Inflammatory Genes and Improvement in Depression Symptoms

Study objectives Sleep disturbances are common in military personnel and are associated with increased risk for psychiatric morbidity, including posttraumatic stress disorder (PTSD) and depression, as well as inflammation. Improved sleep quality is linked to reductions in inflammatory bio-markers; however, the underlying mechanisms remain elusive. Methods In this study, we examine whole genome expression changes related to improved sleep in 68 military personnel diagnosed with insomnia. Subjects were classified into the following groups and then compared: improved sleep (n = 46), or non-improved sleep (n = 22) following three months of standard of care treatment for insomnia. Within subject differential expression was determined from microarray data using the Partek Genomics Suite analysis program and the ingenuity pathway analysis (IPA) was used to determine key regulators of observed expression changes. Changes in symptoms of depression and PTSD were also compared. Results At baseline, both groups were similar in demographics, clinical characteristics, and gene-expression profiles. The microarray data revealed that 217 coding genes were differentially expressed at the follow-up-period compared to baseline in the participants with improved sleep. Expression of inflammatory cytokines were reduced including IL-1β, IL-6, IL-8, and IL-13, with fold changes ranging from −3.19 to −2.1, and there were increases in the expression of inflammatory regulatory genes including toll-like receptors 1, 4, 7, and 8 in the improved sleep group. IPA revealed six gene networks, including ubiquitin, which was a major regulator in these gene-expression changes. The improved sleep group also had a significant reduction in the severity of depressive symptoms. Conclusion Interventions that restore sleep likely reduce the expression of inflammatory genes, which relate to ubiquitin genes and relate to reductions in depressive symptoms.

Sleep restoration is associated with reduced plasma C-reactive protein and depression symptoms in military personnel with sleep disturbance after deployment.

BACKGROUND Deployed military personnel are vulnerable to chronic sleep disturbance, which is highly comorbid with post-traumatic stress disorder (PTSD) and depression, as well as declines in health-related quality of life (HRQOL). Inflammation is associated with HRQOL declines and sleep-related comorbidities; however, the impact of sleep changes on comorbid symptoms and inflammation in this population is unknown. METHODS In this observational study, we examined the relationship between reported sleep changes and concentrations of inflammatory biomarkers, interleukin 6 (IL-6), and C-reactive protein (CRP) in peripheral blood. The sample was dichotomized into two groups: (1) decrease in Pittsburgh Sleep Quality Index (PSQI; restorative sleep) and (2) no change or increase in PSQI (no change). Mixed between-within subjects analysis of variance tests were used to determine group differences on changes of inflammation and comorbid symptoms. RESULTS In our sample of 66 recently deployed military personnel with insomnia, 34 participants reported restorative sleep whereas 32 reported no sleep changes. The two groups did not differ in demographic or clinical characteristics, with the exception of PTSD diagnosis at baseline. The restorative sleep group had significant reductions in CRP concentrations and depression symptoms, as well as reduced fatigue and improvements in emotional well-being, social functioning, and physical functioning at follow-up. CONCLUSIONS Military personnel who report sleep restoration after deployment have reduced CRP concentrations, decreased severity of depression, and improved HRQOL. These findings suggest that treatment for sleep disturbances may be associated with improvements in mental and physical health, thereby supporting continued study in this line of research.

Comorbid Insomnia and Obstructive Sleep Apnea in Military Personnel: Correlation With Polysomnographic Variables

OBJECTIVES Military personnel undergoing polysomnography are typically diagnosed only with obstructive sleep apnea (OSA). Comorbid insomnia with OSA is a well-established, underappreciated diagnosis. We sought to determine if military personnel with mild OSA met clinical criteria for insomnia and if there was a pattern of polysomnogram (PSG) variables that identified insomnia in these patients. METHODS Retrospective chart review of military personnel with mild OSA; cluster analysis to describe PSG variables. RESULTS 206 personnel assessed, predominately male (96.6%), mean age 36.5 ± 8.14 years, body mass index 30.2 ± 3.66 kg/m(2) and apnea hypopnea index of 8.44 ± 2.92 per hour; 167 (81.1%) met criteria for insomnia. Cluster analysis identified a group of patients (N = 52) with PSG variables of increased wakefulness after sleep onset 77.3 minutes (27.7) (p < 0.001) and decreased sleep efficiency 82.6% (5.82) (p < 0.001) consistent with insomnia. Patients in this group were more likely to meet criteria for insomnia with an odds ratio 5.27 (1.20, 23.1), (p = 0.009). CONCLUSIONS The majority of military personnel with mild OSA meet criteria for insomnia. Roughly one-third of these patients can be identified by a pattern of PSG variables. Recognizing and treating both comorbid insomnia and OSA could improve clinical outcomes.

Military Personnel with Chronic Symptoms Following Blast Traumatic Brain Injury Have Differential Expression of Neuronal Recovery and Epidermal Growth Factor Receptor Genes

Objective: Approximately one-quarter of military personnel who deployed to combat stations sustained one or more blast-related, closed-head injuries. Blast injuries result from the detonation of an explosive device. The mechanisms associated with blast exposure that give rise to traumatic brain injury (TBI), and place military personnel at high risk for chronic symptoms of post-concussive disorder (PCD), post-traumatic stress disorder (PTSD), and depression are not elucidated. Methods: To investigate the mechanisms of persistent blast-related symptoms, we examined expression profiles of transcripts across the genome to determine the role of gene activity in chronic symptoms following blast-TBI. Active duty military personnel with (1) a medical record of a blast-TBI that occurred during deployment (n = 19) were compared to control participants without TBI (n = 17). Controls were matched to cases on demographic factors including age, gender, and race, and also in diagnoses of sleep disturbance, and symptoms of PTSD and depression. Due to the high number of PCD symptoms in the TBI+ group, we did not match on this variable. Using expression profiles of transcripts in microarray platform in peripheral samples of whole blood, significantly differentially expressed gene lists were generated. Statistical threshold is based on criteria of 1.5 magnitude fold-change (up or down) and p-values with multiple test correction (false discovery rate <0.05). Results: There were 34 transcripts in 29 genes that were differentially regulated in blast-TBI participants compared to controls. Up-regulated genes included epithelial cell transforming sequence and zinc finger proteins, which are necessary for astrocyte differentiation following injury. Tensin-1, which has been implicated in neuronal recovery in pre-clinical TBI models, was down-regulated in blast-TBI participants. Protein ubiquitination genes, such as epidermal growth factor receptor, were also down-regulated and identified as the central regulators in the gene network determined by interaction pathway analysis. Conclusion: In this study, we identified a gene-expression pathway of delayed neuronal recovery in military personnel a blast-TBI and chronic symptoms. Future work is needed to determine if therapeutic agents that regulate these pathways may provide novel treatments for chronic blast-TBI-related symptoms.

Chapter 8 Military Personnel With Traumatic Brain Injuries and Insomnia Have Reductions in PTSD and Improved Perceived Health Following Sleep Restoration: A Relationship Moderated by Inflammation.

BACKGROUND Up to one-third of deployed military personnel sustain a traumatic brain injury (TBI). TBIs and the stress of deployment contribute to the vulnerability for chronic sleep disturbance, resulting in high rates of insomnia diagnoses as well as symptoms of posttraumatic stress disorder (PTSD), depression, and declines in health-related quality of life (HRQOL). Inflammation is associated with insomnia; however, the impact of sleep changes on comorbid symptoms and inflammation in this population is unknown. METHODS In this study, we examined the relationship between reported sleep changes and the provision of the standard of care, which could include one or more of the following: cognitive behavioral therapy (CBT), medications, and continuous positive airway pressure (CPAP). We compared the following: (a) the group with a decrease in the Pittsburgh Sleep Quality Index (PSQI; restorative sleep) and (b) the group with no change or increase in PSQI (no change). Independent t tests and chi-square tests were used to compare the groups on demographic and clinical characteristics, and mixed between-within subjects analysis of variance tests were used to determine the effect of group differences on changes in comorbid symptoms. Linear regression models were used to examine the role of inflammation in changes in symptoms and HRQOL. RESULTS The sample included 70 recently deployed military personnel with TBI, seeking care for sleep disturbances. Thirty-seven participants reported restorative sleep and 33 reported no sleep changes or worse sleep. The two groups did not differ in demographic characteristics or clinical symptoms at baseline. The TBI+restored sleep group had significant reductions in PTSD and depression over the 3-month period, whereas the TBI+no change group had a slight increase in both PTSD and depression. The TBI+restored sleep group also had significant changes in HRQOL, including the following HRQOL subcomponents: physical functioning, role limitations in physical health, social functioning, emotional well-being, energy/fatigue, and general health perceptions. In a linear regression model using a forced entry method, the dependent variable of change in C-reactive protein (CRP) concentrations was significantly related to changes in PTSD symptoms and HRQOL in the TBI+restored sleep group, with R2=0.43, F33,3=8.31, p<.01. CONCLUSIONS Military personnel with TBIs who have a reduction in insomnia symptoms following a standard-of-care treatment report less severe symptoms of depression and PTSD and improved HRQOL, which relate to decreased plasma concentrations of CRP. These findings suggest that treatment for sleep disturbances in this TBI+military population is associated with improvements in health and decreases in inflammation. The contributions of inflammation-induced changes in PTSD and depression in sleep disturbances in TBI + military personnel require further study.

A Comparative Analysis of Sleep Disordered Breathing in Active Duty Service Members with and without Combat-Related Posttraumatic Stress Disorder.

STUDY OBJECTIVES Posttraumatic stress disorder (PTSD) and obstructive sleep apnea (OSA) are frequently co-occurring illnesses. The purpose of this study was to determine whether comorbid PTSD/OSA is associated with increased PTSD symptoms or decreased OSA severity compared to PTSD or OSA alone in recently deployed Active Duty Service Members (ADSM). METHODS Cross-sectional observational study of ADSM who returned from combat within 24 months. Participants underwent an attended diagnostic polysomnogram and were assessed for PTSD, depression, combat exposure severity, sleepiness, and sleep quality with validated clinical instruments. RESULTS Our study included 109 military personnel who returned from a combat deployment within 24 months with a mean age of 34.3 ± 8.23 and BMI of 30.8 ± 3.99. Twenty-four participants had PTSD/OSA, 68 had OSA, and 17 had PTSD. Mean PTSD Checklist- Military Version (PCL-M) scores were 62.0 ± 8.95, 60.5 ± 4.73, and 32.5 ± 8.95 in PTSD/OSA, PTSD, and OSA, respectively. The mean AHI was 16.9 ± 15.0, 18.9 ± 17.0, and 1.73 ± 1.3 for those with PTSD/OSA, OSA, and PTSD. PTSD symptoms and OSA severity in military personnel with comorbid PTSD/OSA were not significantly different from those with PTSD or OSA alone. On multivariate analysis, BMI was a significant predictor of OSA (OR, 1.21; 95% CI, 1.04-1.44) and age trended towards significance. Depression, but not OSA severity, was associated with PTSD symptoms. CONCLUSIONS Following recent combat exposure, comorbid PTSD/OSA is not associated with increased PTSD symptoms or decreased severity of OSA. Early evaluation after traumatic exposure for comorbid OSA is indicated in PTSD patients with sleep complaints given the high co-occurrence and adverse clinical implications.

A Diagnosis of Insomnia Is Associated With Differential Expression of Sleep-Regulating Genes in Military Personnel

Sleep disturbance is a common and disturbing symptom in military personnel, with many individuals progressing to the development of insomnia, which is characterized by increased arousals, wakefulness after sleep onset, and distorted sleep architecture. The molecular mechanisms underlying insomnia remain elusive, limiting future therapeutic development to address this critical issue. We examined whole gene expression profiles associated with insomnia. We compared subjects with insomnia (n = 25) to controls (n = 13) without insomnia using microarray gene expression profiles obtained from peripheral samples of whole blood obtained from military personnel. Compared to controls, participants with insomnia had differential expression of 44 transcripts from 43 identified genes. Among the identified genes, urotensin 2 was downregulated by more than 6 times in insomnia participants, and the fold-change remained significant after controlling for depression, posttraumatic stress disorder, and medication use. Urotensin 2 is involved in regulation of orexin A and B activity and rapid eye movement during sleep. These findings suggest that differential expression of these sleep-regulating genes contributes to symptoms of insomnia and, specifically, that switching between rapid eye movement and nonrapid eye movement sleep stages underlies insomnia symptoms. Future work to identify therapeutic agents that are able to regulate these pathways may provide novel treatments for insomnia.