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Structural vs. Psychiatric Predictors of Sleep Disturbance in Veterans With Mild Trsaumatic Brain Injury

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Structural vs. Psychiatric Predictors of Sleep Disturbance in Veterans With Mild Trsaumatic Brain Injury
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Goldstein, Jared
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Gray matter ( jstor )
Imaging ( jstor )
Locus coeruleus ( jstor )
Post traumatic stress disorder ( jstor )
Quality of life ( jstor )
Respiratory mechanics ( jstor )
Sleep ( jstor )
Symptomatology ( jstor )
Traumatic brain injury ( jstor )
Veterans ( jstor )

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Background: In Veterans, post-traumatic stress disorder (PTSD) and mild traumatic brain injury (mTBI) are each related to persistent sleep disturbances that are detrimental to overall health and quality of life. Although symptoms of sleep disturbance are similar in PTSD and mTBI, neurobiological mechanisms producing disordered sleep may differ. One key neurobiological substrate of sleep is the ascending noradrenergic system originating in the locus coeruleus (LC). Methods: An MRI imaging protocol (T1-weighted; Fast Gray Matter Acquisition Tl Inversion Recovery [FGATIR]; and diffusion-weighted) was used to locate and segment the locus coeruleus (LC) in a sample of 12 veterans with mTBl. LC volume was calculated for each participant using a protocol developed in collaboration with the Mareci neuroimaging laboratory at UF. Relationships among LC volume, PTSD severity and subjective sleep quality were analyzed. Results: PTSD Checklist - Military Version (PCL-M) total score was positively correlated with inability to breathe comfortably during sleep (r=.594, p=.041), having bad dreams (r=.691, p=.013), delayed sleep latency (r-.655, p=.021), sleep disturbances (r-.849, p= <.00 I), and poor sleep efficiency (r-.576, p=.050) on the Pittsburgh Sleep Quality Index (PSQn. LC volume was negatively correlated with poor sleep efficiency (r=-.596, p=.041) and discomfort with breathing during sleep (r--.619, r-.032) on the PSQI. Conclusion: Sleep disturbances after mTBI and PTSD may involve different neural mechanisms. We hypothesize that mTBI is related to damage within neurobiological systems involved in sleep regulation (LC and its projections). Understanding the mechanism whereby comorbid PTSD relates to an exacerbation of sleep problems is important in designing effective treatment programs for symptomatic mTBI patients. ( en )

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Running head: PREDICTORS OF SLEEP IN MTBI 1 Structural v s. Psychiatric Predictors of Sleep Disturbance in Veterans With Mild Traumatic Brain Injury Jared Goldstein University of Florida A thesis presented to the College of Public Health and Health Professions of the University of Florida in fulfillment of the Bachelor of Health Science Honors Program requirement.

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PREDICTORS OF SLEEP IN MTBI ! " Abstract Background In Veterans, post traumatic stress disorder (PTSD) and mild traumatic brain injury (mTBI) are each related to persistent sleep disturbanc es that are detrimental to overall health and quality of life. Although symptoms of sleep disturbance are similar in PTSD and mTBI, neurobiological mechanisms producing disordered sleep may differ. One key neurobiological substrate of sleep is the ascendi ng noradrenergic system originating in the locus coeruleus (LC). Methods An MRI imaging protocol (T1 weighted; Fast Gray Matter Acquisition T1 Inversion Recovery [FGATIR]; and diffusion weighted) was used to locate and segment the locus coeruleus (LC) i n a sample of 12 veterans with mTBI. LC volume was calculated for each participant using a protocol developed in collaboration with the Mareci neuroimaging laboratory at UF. Relationships among LC volume, PTSD severity and subjective sleep quality were ana lyzed. Results PTSD Checklist Ð Military Version (PCL M) total score was positively correlated with in ability to breathe comfortably during sleep (r=.594, p=.041), having bad dreams (r=.691, p=.013), delayed sle ep latency (r=.655, p=.021), sleep disturban ces (r=.849, p= <.001 ) , and poor sleep efficiency (r=.576, p=.050) on the Pittsburgh Sleep Quality Index (PSQI). LC volume was negatively correlated with poor sleep efficiency (r= .596, p=.041) and discomfort with breathing during sleep (r= .619, r=.032) o n the PSQI. Conclusion S leep disturbances after mTBI and PTSD may involve different neural mechanisms. We hypothesize that mTBI is related to damage within neurobiological systems involved in sleep regula tion (LC and its projections). Understanding the mec hanism whereby comorbid PTSD relates to an exacerbation of sleep problems is important in designing effective treatment programs for symptomatic mTBI patients.

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PREDICTORS OF SLEEP IN MTBI # " Introduction M ild traumatic brain i njury (mTBI) and p ost trauma tic Stress Disorder (PTSD) have become important issues among veterans, especially those returning from Operations Enduring Freedom (OEF) and Iraqi Freedom (OIF). Department of Defense (2014) records indicate that from 2000 2013 , approximately 294,000 servicemen received diagnose s of TB I. Out of these , 82.5% of them were categorized as mild based on clinical criteria . More specifically, research has found that 15 23% of service members returning from OIF/OEF sustained an mTBI ( Farrel Carnahan, Franke, Graham, & McNamee, 2013 ) . A recent s tudy by Wisco et al. (2014) found the overall lifetime prevalence of PTSD in veterans to be 8.0%. A review of studies by Ramchand et al. (2010) showed that the prevalence of clinically significant Post traumatic stress disorder symptoms among veterans who served in Iraq and Afghanistan ( OEF/OIF) are between 1 60% for those not seeking treatment and between 4.2 50% for those who do seek treatment . Since mTBI s sustained in theater are often in the course of life threatening events, hi gh levels of comorbid mTB I and PTSD in OEF/OIF veterans are expected (Schneiderman, Braver, & Kang, 2008). Sleep disturbances are commonly seen in the aftermath of both mTBI and PTSD. As a result of the high prevalence of sleep disturbances , their poorly understood nature and cau ses , and their potential to significant ly harm the health of the patient, they have been gaining importance in the related research. Research has shown that sleep is vital in ensuring metabolic homeostasis and in the clearance of neurodegenerative metaboli c waste such as b eta amyloid from the brain (Xie et al., 2012). Additional studies have indicated that large amounts of beta amyloid are linked to neurodegenerative diseases such as Alzheimer's disease (Cirrito et al., 2005). Sleep is understood to be a re storative function and chronic sleep disruptions are highly associated with the presence of other symptoms that further negatively impact quality of life , such as depression . ( Farrel Carnahan et al., 2013; Hou et al., 2013). Sleep disturbances are a core symptom of PTSD and are found in two of the symptom clusters in the DSM V diagnostic criteria (American Psychiatric Association, 2013). Furthermore, studies have consistently found subjective sleep quality to be the primary concer n of veterans with PTSD ( B elleville,

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PREDICTORS OF SLEEP IN MTBI $ " Guay, & Marchand, 2009 ; Ohayon & Shapiro, 2000). A review of PTSD and sleep by Germain (2013) indicates that clinical observations of PTSD patients have been inconsist ent but suggest dysregulation in both rapid eye movement (REM) and non REM (NR EM) sleep . These disturbances include insomnia, nightmares, and sleep disordered breathing (SDB) such as sleep apnea . The relationship of sleep disturbances to PTSD have not yet been established , but it has been suggested that altered f unctioning in neurob iological mechanisms of arousal and fear conditioning in the amygdala and medial prefrontal cortex may provide a common substrate ( Cartwright, 1991; Germain, 2013; Goodenough, Witkin, Koulack, & Cohen, 1975; Milad, Rauch, Pitman, & Quirk, 2006; Van Liempt, 2012). Sleep disturbances have been reported in up to 80% of patients with mTBI (Orff et al., 2009). Even when PTSD is not present, s leep disturbances have been well documented following injury (Orff, Ayalon, & Drummond, 2009; Ouellet, Beaulieu Bonneau, & Morin, 2006; Parcell, Ponsford, Rajaratnam, & Redman, 2006; Ponsford et al., 2012). The nature of post mTBI sleep disturbances vary and often include poor sleep efficiency, insomnia, reduced time spent in REM , daytime sleepiness, and sleep disordered bre athing (e.g., sleep apnea ) (Castriotta et al., 20 07). The frequency of reported sleep disturbances by mTBI patients suggests a primary neurobiological mechanism. Howev er, the etiology of these sleep disturbances ha s yet to be determined. Advances in techno logy such as diffusion weighted i maging (DWI) have suggested the involvement of microscopic structural damage to neural connectivity known as diffuse axonal inj ury (DAI) ( Bazarian et al., 2007; Gardner et al., 2012; Shenton et al., 2012). However , Rosen bau m and Lipton (2012) indicate that these structural changes have been difficult to locate in the post TBI brain due to the amount of inter subject variability . More recent research has proposed that sleep disturbances are related more specifically to damage to the locus coeruleus (LC) (Sullan et. al, 2014). The LC, a small structure located within the brainstem, is vital to the sleep wake cycle (Chamberlain & Robbins, 2013; Samuels & Szabadi, 2008a). The LC is the primary source of ascending noradrenergic (NA) innervation in the brain and projects to other regions that play a key role in sleep wake cycles, including the vent rolateral preoptic area (VLPO) and medial preoptic nucl eus (MnPN)

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PREDICTORS OF SLEEP IN MTBI % " (Chamberlain & Robbins, 2013; Samuels & Szabadi, 2008b; Schwartz & Roth, 2008). Bigler (2013) identified the brainstem to be prone to injury in TBI. Therefore, in accordance with research by Sullan et al. (2014), evaluating possible trauma ind uced abnormalities within the LC may provide further understanding of the nature of sleep disturbances in symptomatic TBI patients . The prevalence of comorbidity between mTBI and PTSD, especially in OEF / OIF veterans, and the ov erlap of their symptoms has been debated. According to Bryant (2011), debate exists because PTSD and mTBI "É B oth independently and additively, are regarded as being responsible for much impairment following deployments [in OEF/OIF veterans]" (p. 251) . This statement can be applied di rectly to sleep disturbances after PTSD and mTBI. Some studies have found mTBI to be minimally responsible for impairment after controlling for the effects of PTSD and other psychological comorbidities (Hoge et al., 2008; Schneiderman et al. 2008) , suggest ing that PTSD and associated psychological symptoms are more strongly associated wit h sleep disturbances after mTBI than the injury itself . However, other studies have contradicted this notion by showing that many mTBI patients with sleep disorders do not suffer from PTSD or other psychological disorders (Bauman n , Werth, Stocker, Ludwig, & Bassetti, 2007). To the knowledge of the authors, no stud y has yet tried to contrast the presentation and etiologies of sleep disturbances among co occuring PTSD and mTBI . Aims and Hypotheses The following study aims to determine if correl ations exist among LC volume, measures of PTSD on the PCL M , and subjective measures of sleep on the PSQI . Based on the notion that mTBI wi ll lead to DAI and contribute to decrease d LC v olume, w e hypothesize d that traumatically induced loss of LC volume would be associated with subjective sleep disturbances (SSD) indicative of insomnia and less comfortable breathing (sleep apnea) on the PSQI . We also hypothesize d that the PCL M w ould be a ssociated with various categories of subjective sleep disturbances suggestive of n ightmares , sleep apnea , and insomnia on the PSQI . Thus we predict ed that there w ould be both similarities and differences between mTBI induced and PTSD related subjective sle ep disturbances (PSQI items) . This is in

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PREDICTORS OF SLEEP IN MTBI & " concurre nce with our hypothesis that the neuro biological mechanisms responsible for sleep disturbances after mTBI (more struc tural) and PTSD (more psychological ) are at least partially separate in nature. Method Pa rticipants Our participants were recruited from the North Florida/South Georgia Malcom Randall Veteran's Affairs Medical Center. In order to be included in the study, patients had to have been deployed in OIF/OEF campaigns and had to have sustained an mTB I at least 6 months prior to evaluation. For the purposes of our study, the ACRM definition of mTBI was used (ACRM, 1993 ). Accordingly, all participants had loss of consciousness (LOC) lasting less than 30 minutes, posttraumatic amnesia (PTA) lasting less than 24 hours, and lack of abnormalities on a standard clinical magnetic resonance (MR) scan as determined by a physician. Recruitment resulted in a study sample of 18 veterans . However, incomplete sleep questionnaires for 5 participants and one significan t outlier on LOC/AOC events (>3 SD from the mean ) resulted in a final study population of 12 veterans. Our study participants were male only due to the fact that no female participants met the study criteria. Additional participant demographic information can be found in T able 1 . Instrument s As found in Sullan et al. (2014), t he scanner in our study was a Philips Achieva 3T scanner (Best, Netherlands) with a 32 channel SENSE head coil. For additional details regarding T1 acquisition parameters, see Ford et al. ( 2013 ) . For this study, high resolution struct ural T1 weighted (1 x 1 x 1mm) and FGATIR (1 x 1 x 1mm) were analyzed for each participant . FGATIR images were acquired with 160, 1.0 mm axial slices (no gap), FOV = 256 mm ! 192 mm, matrix = 320 ! 256, TR = 3000ms, TE = 4.39ms, voxel size = 1.0 ! 1.0 ! 1.0 mm, and time of acquisition = 11 min 14 s. Further details of FG ATIR acquisition parameters can be found in Sudhyadhom et al., 2009. S egmentation and volumetric analysis of the LC was conducted using the previously published FGATIR Locus Coeruleus Segmentation (FLoCS ) protocol developed within the Bauer and Mareci lab oratories at UF. For further details regarding LC segmentation and the image processing protocol, see Sullan et al., 2014 .

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PREDICTORS OF SLEEP IN MTBI ' " The measures use d for sleep quality and PTSD were the Pitts burgh Sleep Quality Index (PSQI) and the PTSD Checklist Ð Military Versi on (PCL M ) . Both the PSQI and PCL M are commonly used metrics of sleep disturbances and PTSD symptom severity (Buysse, Reynolds, Monk, Berman , & Kupfer, 1989; Weathers et al., 1993 ; Weathers et al., 1994 ) . The data were analyzed using the SPSS statistical package , v ersion 22 . Procedure MRI scans for each participant were acquired during their clinical visit . Each participant then received a fu ll neuropsychological battery and self report questionnaires a dministered by a trained psychom etrist. This battery included the PSQI and P CL M. MR images were processed using eddy current correction and skull stripping to enhance brain visualization . T he L C was then segmented based on associated anatomical landmarks using the FLoCS protocol , which yields inter rater reliabilities >.90 for image localization and segmentation ( Sullan et al. , 2014). E ach item on the PSQI was separately analyzed using SPSS in o rder to examine relationships between our independent variables (LC volume, PCL M) and our dependent variables (specific qualitative types of sleep disturbances). Results Due to the nature of the PSQI items (ordinal ranking for frequency and severity measu res), we used a Spearman rank order c orre lation to analyze our data. The S leep E fficiency component score was determined by comparing hours spent asleep with hours spent a wake while in bed, with higher scores indicative of poorer sleep efficiency (more hou rs awake, less hours asleep). Higher score s on the "cannot breathe comfortably" item indicated a greater frequency of uncomfortable breathing during sleep . Higher scores on the S leep L atency component score, S leep D isturbances component score , and PSQI Glo bal S core were indicative of greater time taken to fall asleep, greater frequency of sleep disturbances per week, and worse overall sleep quality , respectively. The PTSD Checklist Ð Military Version (PCL M) total score was positively and significantly cor related with the following items on the PSQI : cannot breathe comfortably during sleep (r=.594, p < .05 ), having bad dreams (r=.691 , p <.05 ), S leep L atency component score (r=.655, p <.05 ) , Sleep

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PREDICTORS OF SLEEP IN MTBI ( " Disturbances component score (r=.849, p <.001) , Sleep Efficienc y component score (r .576, p < .05 ), and Global S core (r=.761, p <.01 ) . LC volume was n egatively and significantly correlated with the Sleep E fficiency component score (r= .596, p <.05 ) and inability to breath comfortably during sleep (r= .619, p<.05 ) on the PSQI. Additional relationships included a positive correlation between PCL M and the S leep E fficiency component score (r=.576) and a negative correlation between LC volume and Global score (r= .550). Although not significant, both of these relationships a pproached significance. Discussion Data Interpretation As anticipated, we found a significant amount of overlap and some differences in relationships between measures of PTSD, LC volume, and subjective sleep problems. P revious research has indicated that s leep apnea (suggested by inability to breathe comfortably) and insomnia (suggested by poor sleep efficiency) have both been separately associated with mTBI a nd PTSD ( Castriotta et al., 2007; Germain et al., 2013; Hoge et al., 2008; Schneiderman et al., 2 008) . Howev er, to our knowledge, no prior study had examined them side by side in the same population . O ur study results agreed with these previously es tablished findings. Our results also agreed with literature in the field linking PTSD and nightmares (ha ving bad dreams). We found differences in types of SSD associated with LC volume and PCL M as predicted . For instance, h aving bad dreams, delayed sleep latenc y, and a higher frequency of overall sleep disturbances were associated only with heightened score s on the PCL M , suggestive of PTSD and not with reduced LC volume. Although the PSQI sleep efficiency score was related to both PCL M scores and LC vol umes with equal strength (both correlations |.576|), the correlation involving LC likely failed to reach significance because of restricted range within the LC variable. Despite this result, o ur data showed moderate negative correlation trends for LC volume with sleep latency (reduced LC volume, more time to fall asleep) and overall sleep disturbances (reduc ed LC volume, greater frequency of sleep disturbances ) . Once again, this was also in the hypothesized direction. Thus , a similar study with greater power may be able to more accurately represent these relationships.

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PREDICTORS OF SLEEP IN MTBI ) " Our overall results indicated a pattern of negative relationships between LC volume and subjective sleep disturbance on the PSQI. Jointly taken with the results of Sullan et al. (2014), these findings suggest tha t structural damage to the LC may be a viable predictor of the sleep problems docume nted in mTBI patients. This provides preliminary support for the hypothesis that the etiology of sleep disturbances following mTBI is the result of disruption to a primary neurobiological mechanism. While these mechanisms were not examined for neural syste ms related to PTSD, future studies may work to examine the differences in PTSD related networks as they relate to increased disturbances to sleep. Also, because our results demonstrated a pattern of significant positive correlations between the PCL M and a ll analyzed PSQI items, we are unable to infer specific information about the etiology of sleep disturbances after PTSD. Limitations and Future Directions Our small sample size (N=12 ) was a n obvious limitation in our ability to fully examine PCL M and LC volume relationships with PSQI items. Smaller sample sizes decrease the power of results and limit the ability to use more comprehensive statistical analyses . Also, w e lacked a control group for comparison, which wou ld have been useful in examining differ ences in LC volume between mTBI patients and healthy controls . O ur sample was all male , limiting the generalizability of the study. Using our research as a first step, future research should work to furth er examine the LC with respect to sleep disturbance s following mTBI. Our study focused solely on LC volume, whereas future research may extend to the LC NA related n etworks and projections. This could potentially lead to better understanding of the neurobiological mechanism s underlying sleep disturbances f rom mTBI. Understanding the ways which comorbid PTSD further exacerbate s sleep proble ms is important in designing more targeted therapeutic interventions for the large number of injured veterans. A more highly powered study that evaluates LC and PSQI sleep data in a matched group of veterans with and without TBI and PTSD (TBI/PTSD; TBI/no PTSD; no TBI/PTSD, noTBI/noPTSD) is needed to better understand the multifactorial etiology of sleep problems in this population.

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PREDICTORS OF SLEEP IN MTBI *+ " References American Congress of Rehabi lition Medicine (1993). Definition of mild traumatic brain injury. Journal of Head Trauma Rehabilitation, 83(3) , 86 87. Baumann CR, Werth E, Stocker R, Ludwig S, Bassetti CL. Sleep wake disturbances 6 months after traumatic brain injury: a prospective study. Brain. 2007; 130: 1873 1883. Bazarian, J. J., Zhong, J., Blyth, B., Zhu, T., Kavcic, V., & Peterson, D. (2007). Diffusion tensor imaging detects clinically important axonal damage after mild traumatic brain injury: a pilot study. J Neurotrauma, 24 ( 9), 1447 1459. doi: 10.1089/neu.2007.0241 Belleville, G., Guay, S., & Marchand, A. (2009). Impact of sleep disturbances on PTSD symptoms and perceived health. The Journal of nervous and mental disease , 197 (2), 126 132. Bigler, E. D. (2013). Neuroimaging bi omarkers in mild traumatic brain injury (mTBI). Neuropsychol Rev, 23 (3), 169 209. doi: 10.1007/s11065 013 9237 2 Bryant R. Post traumatic stress disorder vs traumatic brain injury. Dialogues Clin Neurosci . 2011;13:251 Ð 262. Buysse DJ, Reynolds CF 3rd, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res . 1989; 28: 193 213. Cartwright, R. 1991. Dreams that work: The relation of dream incorporation to adaptation to stressful events. Dreaming , 1:3 10. Castriotta, R. J., Wilde, M. C., Lai, J. M., Atanasov, S., Masel, B. E., & Kuna, S. T. (2007). Prevalence and consequences of sleep disorders in traumatic brain injury. J Clin Sleep Med, 3 (4), 349 356. Chamberlain, S. R., & Rob bins, T. W. (2013). Noradrenergic modulation of cognition: therapeutic implications. J Psychopharmacol, 27 (8), 694 718. doi: 10.1177/0269881113480988 Cirrito, J. R., Deane, R., Fagan, A. M., Spinner, M. L., Parsadanian, M., Finn, M. B., . . . Holtzman, D. M. (2005). P glycoprotein deficiency at the blood brain barrier increases amyloid beta deposition in an Alzheimer disease mouse model. J Clin Invest, 115 (11), 3285 3290. doi: 10.1172/JCI25247 DoD TBI Worldwide Numbers since 2000: Defense and Veterans Brain Injury Center (DVBIC); 2013.

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PREDICTORS OF SLEEP IN MTBI ** " Farrell Carnahan, L., Franke, L., Graham, C., & McNamee, S. (2013). Subjective sleep disturbance in veterans receiving care in the Veterans Affairs Polytrauma System following blast related mild traumatic brain injury. Mil Med , 178 (9), 951 956. doi: 10.7205/MILMED D 13 00037 Ford AA, Triplett W, Sudhyadhom A, Gullett J, McGregor K, Fitzgerald DB, Mareci T. Broca's area and its striatal and thalamic connections: a diffusion MRI tractography study. Front Neuroanat. 2013; 7: 8. Ga rdner, A., Kay Lambkin, F., Stanwell, P., Donnelly, J., Williams, W. H., Hiles, A., . . . Jones, D. K. (2012). A systematic review of diffusion tensor imaging findings in sports related concussion. J Neurotrauma, 29 (16), 2521 2538. doi: 10.1089/neu.2012.26 28 Germain A. Sleep disturbances as the hallmark of PTSD: where are we now?American Journal of Psychiatry. 2013;170(4):372 Ð 382. doi: 10.1176/appi.ajp.2012.12040432. Goodenough, D. R., Witkin, H. A., Koulack, D. and Cohen, H. (1975), The Effects of Stress Films on Dream Affect and on Respiration and Eye Movement Activity During Rapid Eye Movement Sleep. Psychophysiology, 12: 313 Ð 320. doi: 10.1111/j.1469 8986.1975.tb01298.x Hoge, C., McGurk, D., Thomas, J., Cox, A., Engel, C., & Castro, C. (2008). Mild Traum atic Brain Injury In U.S. Soldiers Returning From Iraq. New England Journal of Medicine, 358 , 453 463. Hou, L., Han, X., Sheng, P., Tong, W., Li, Z., Xu, D., . . . Dong, Y. (2013). Risk factors associated with sleep disturbance following traumatic brain in jury: clinical findings and questionnaire based study. PLoS One, 8 (10), e76087. doi: 10.1371/journal.pone.0076087 Milad MR, Rauch SL, Pitman RK, Quirk GJ (2006) Fear extinction in rats: implications for human brain imaging and anxiety disorders. Biol Psych ol 73: 61 Ð 71. Ohayon MM, Shapiro CM. Sleep disturbances and psychiatric disorders associated with posttraumatic stress disorder in the general population. Compr Psychiatry.2000;41:469 Ð 78. Orff, H. J., Ayalon, L., & Drummond, S. P. (2009). Traumatic brain i njury and sleep disturbance: a review of current research. J Head Trauma Rehabil, 24 (3), 155 165. doi: 10.1097/HTR.0b013e3181a0b281 Ouellet, M. C., & Morin, C. M. (2006). Subjective and objective measures of insomnia in the context of traumatic

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PREDICTORS OF SLEEP IN MTBI *! " brain injur y: a preliminary study. Sleep Med, 7 (6), 486 497. doi: 10.1016/j.sleep.2006.03.017 Parcell, D. L., Ponsford, J. L., Rajaratnam, S. M., & Redman, J. R. (2006). Self reported changes to nighttime sleep after traumatic brain injury. Arch Phys Med Rehabil, 87 ( 2), 278 285. doi: 10.1016/j.apmr.2005.10.024 Ponsford, J., Cameron, P., Fitzgerald, M., Grant, M., Mikocka Walus, A., & Schšnberger, M. (2012). Predictors of postconcussive symptoms 3 months after mild traumatic brain injury. Neuropsychology, 26 (3), 304 31 3. doi: 10.1037/a0027888 Ponsford JL, Ziino C, Parcell DL, Shekleton JA, Roper M et al. (2012) Fatigue and sleep disturbance following traumatic brain injury -their nature, causes, and potential treatments. J Head Trauma Rehabil 27: 224 233. doi:10.1097/HT R.0b013e31824ee1a8. Ramchand, R., Schell, T. L., Karney, B. R., Osilla, K. C., Burns, R. M., & Caldarone, L. B. (2010). Disparate prevalence estimates of PTSD among service members who served in Iraq and Afghanistan: Possible explanations. Journal of trauma tic stress , 23 (1), 59 68. Rosenbaum, S. B., & Lipton, M. L. (2012). Embracing chaos: the scope and importance of clinical and pathological heterogeneity in mTBI. Brain Imaging Behav, 6 (2), 255 282. doi: 10.1007/s11682 012 9162 7 Samuels, E. R., & Szabadi, E. (2008a). Functional neuroanatomy of the noradrenergic locus coeruleus: its roles in the regulation of arousal and autonomic function part I: principles of functional organisation. Curr Neuropharmacol, 6 (3), 235 253. doi: 10.2174/157015908785777229 Samue ls, E. R., & Szabadi, E. (2008b). Functional neuroanatomy of the noradrenergic locus coeruleus: its roles in the regulation of arousal and autonomic function part II: physiological and pharmacological manipulations and pathological alterations of locus coe ruleus activity in humans. Curr Neuropharmacol, 6 (3), 254 285. doi: 10.2174/157015908785777193 Schwartz, J. R., & Roth, T. (2008). Neurophysiology of sleep and wakefulness: basic science and clinical implications. Curr Neuropharmacol, 6 (4), 367 378. doi: 1 0.2174/157015908787386050

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PREDICTORS OF SLEEP IN MTBI *# " Schneiderman, A. I., Braver, E. R., & Kang, H. K. (2008). Understanding sequelae of injury mechanisms and mild traumatic brain injury incurred during the conflicts in Iraq and Afghanistan: persistent postconcussive symptoms and po sttraumatic stress disorder. American journal of epidemiology , 167 (12), 1446 1452. Shenton, M. E., Hamoda, H. M., Schneiderman, J. S., Bouix, S., Pasternak, O., Rathi, Y., . . . Zafonte, R. (2012). A review of magnetic resonance imaging and diffusion tenso r imaging findings in mild traumatic brain injury. Brain Imaging Behav, 6 (2), 137 192. doi: 10.1007/s11682 012 9156 5 Sudhyadhom A, Haq IU, Foote KD, Okun MS, Bova FJ. A high resolution and high contrast MRI for differentiation of subcortical structures fo r DBS targeting: the Fast Gray Matter Acquisition T1 Inversion Recovery (FGATIR). Neuroimage. 2009;47 Suppl 2:44 52. Sullan, M., Bohsali, A., Gullet, J., Goldstein, J., Bauer, R., Mareci, T., & Fitzgerald, D. (2014). The Locus Coeruleus and SleepWake Distu rbances in Veterans with mTBI. Journal of Sleep Medicine and Disorders,1 (1), 1004 1004. Trauma and Stress Related Disorders. (2013). In Diagnostic and statistical manual of mental disorders: DSM 5. (5th ed.). Washington, D.C.: American Psychiatric Associat ion. Van Liempt S. (2012). Sleep disturbances and PTSD: a perpetual circle? Eur. J. Psychotraumatol. 3, 1 Ð 9 10.3402/ejpt.v3i0.19142 Veteran Population Washington, D.C.: United States Department of Veterans Affairs; 2014 . Weathers F, Litz B, Herman D, Hus ka J, Keane T. The PTSD Checklist: Reliability, validity, & diagnositic utility. Annual Meeting of the Internation Society of Traumatic Stress Studies; San Antonio, TX. 1993. Weathers F, Litz B, Huska J, Keane T. PTSD Checklist Military version. In: PTSD N Cf, editor. Behavioral Sciences Division. Boston: 1994. Wisco, B., Marx, B., Wolf, E., Miller, M., Southwick, S., & Pietrzak, R. (2014). Posttraumatic Stress Disorder in the US Veteran Population: Results From the National Health and Resilience in

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PREDICTORS OF SLEEP IN MTBI *$ " Veteran s Study. The Journal of Clinical Psychiatry , 75(12), 138 1346. doi: 10.4088/JCP.14m09328. Xie, L., Kang, H., Xu, Q., Chen, M. J., Liao, Y., Thiyagarajan, M., . . . Nedergaard, M. (2013). Sleep drives metabolite clearance from the adult brain. Science, 342 (6156), 373 377. doi: 10.1126/science.1241224

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PREDICTORS OF SLEEP IN MTBI *% " Tables and Figures Table 1 Demographic table. a. Abbreviations: (LOC) is Loss of Consciousness, (AOC) is Alteration of Consciousness b. Depression in table acquired through neuropsychological ba t tery . Age: Mean Range 30.7 24 37 Education Mean Range 14 years (12 18 years) Gender: Male Female 100% 0% Ethnicity: Caucasian African American 73.3% 26.7% Mean Time Since Inquiry 4.3 years LOC Events Mean Range 1.2 (1 10) AOC Events Mean Range 3.9 (0 6) Combined AOC/LOC Events Mean Range 5.07 (1 14) Sleep Disturbance (>5 P SQI) Mean Range 83% 10.92 (5 19) Psychological Disturbances: PTSD Depression 92% 4 2%

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PREDICTORS OF SLEEP IN MTBI *& " Table 2 Significant Correlations. a. Asterisk indicates significant relationship (p " .05) b. Higher scores in Sleep Efficiency Component Score, Global Score, Sleep Disturbances Component Score, Cannot breathe comfortably, Sleep Latency Component Score, and Had bad dreams, are indicative of worse sleep. PSQI Items LC Volume PCL M Sleep Latency Component Score: Pearson Correlation Sig. (2 tailed) .426 .167 .655 .021* Cannot breathe comfortably: Pearson Correlation Sig. (2 tailed) .619 .032* .594 .041* Had bad dreams: Pearson Correlation Sig. (2 tailed) .381 .221 .691 .013* Sleep Disturbances Component Score: Pearson Correlation Sig. (2 tailed) .424 .169 .849 .000* Global Score: Pearson Correlation Sig. (2 tailed) .550 .064 .761 .004* Sleep Efficiency Component Score: Pearson Correlation Si g. (2 tailed) .596 .041* .576 .050*

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PREDICTORS OF SLEEP IN MTBI *' " Appendix Acknowledgements I would like to acknowledge the expertise and assistance of Molly J. Sullan, without whom this thesis could not have been completed. Research was supported in part by Department of Veterans Affairs RR&D CDA 2 # B6698W; State of Florida Brain and Spinal Cord Injury Research Trust Fund; USAMRMC/TATRC Contract #W81XH 11 1 0454 (D. FitzGerald, PI). Mark Eckert and Noam Keren generously provided standardized LC masks for use in developing the FLoCs protocol.





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(For Office Use Only) Honors Thesis Submission Form Major: _____ _ Designation: ___ _ Graduation Term: Name: Jared Goldstein UFID:99916167 Additional Authors: Molly Sullan, Russell Bauer Email: jaredgol@ufl.edu Major: Health Science Advisor Name: Russell Bauer Advisor Email: rbauer@PHHP.ufl.edu Advisor Department:Clinical and Health Psychology Thesis Title:Structural vs. Psychiatric Predictors of Sleep Disturbance in Veterans With Mild Trsaumatic Brain Injury Abstract (200 words max): Background: In Veterans, post-traumatic stress disorder (PTSD) and mild traumatic brain injury (mTBI) are each related to persistent sleep disturbances that are detrimental to overall health and quality of life. Although symptoms of sleep disturbance are similar in PTSD and mTBI, neurobiological mechanisms producing disordered sleep may differ. One key neurobiological substrate of sleep is the ascending noradrenergic system originating in the locus coeruleus (LC). Methods: An MRI imaging protocol (T1-weighted; Fast Gray Matter Acquisition Tl Inversion Recovery [FGATIR]; and diffusion-weighted) was used to locate and segment the locus coeruleus (LC) in a sample of 12 veterans with mTBl. LC volume was calculated for each participant using a protocol developed in collaboration with the Mareci neuroimaging laboratory at UFo Relationships among LC volume, PTSD severity and subjective sleep quality were analyzed. Results: PTSD Checklist Military Version (PCL-M) total score was positively correlated with inability to breathe comfortably during sleep (r=.594, p= .041), having bad dreams (r=.691, p=.013),

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delayed sleep latency (r-.655, p=.021), sleep disturbances (r-.849, p= <.00 I), and poor sleep efficiency (r-.576, p=.050) on the Pittsburgh Sleep Quality Index (PSQn. LC volume was negatively correlated with poor sleep efficiency (r=-.596, p = .041) and discomfort with breathing during sleep (r--.619, r-.032) on the PSQI. Conclusion: Sleep disturbances after mTBI and PTSD may involve different neural mechanisms. We hypothesize that mTBI is related to damage within neurobiological systems involved in sleep regulation (LC and its projections). Understanding the mechanism whereby comorbid PTSD relates to an exacerbation of sleep problems is important in designing effective treatment programs for symptomatic mTBI patients. Student SignaturelDate Thesis Advisor SignaturelDate Departmental Honors Coordinator Please indicate your preference for public access to your the y initialing the appropriate statement below: X 1 grant pennission to the University oj Florida to list the title and abstract oJthis thesis in a publicly accessible database. _ _ I do not grant pennission to the University oj Florida to list the title and abstract oJthis tilesis publicly. If you wish to make the entire thesis publicly available, you must also complete the Internet Distribution Permissions Form, available at http://digital.uflib.ufl.edu!procedures!copyright!GrantofPermissions.doc If you do not include this form, your thesis win be archived but will not be viewable online.


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