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Award Number: W81XWH-11-2-0061 TITLE: Investigation of Chronic Pain Following Traumatic Brain Injury PRINCIPAL INVESTIGATOR: Dr. Wendy Chao CONTRACTING ORGANIZATION: The Geneva Foundation Tacoma, WA 98402 REPORT DATE: January 2013 TYPE OF REPORT: Annual Report PREPARED FOR: U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 DISTRIBUTION STATEMENT: Approved for Public Release; Distribution Unlimited The views, opinions and/or findings contained in this report are those of the author(s) and should not be construed as an official Department of the Army position, policy or decision unless so designated by other documentation.

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Investigation of Chronic Pain Following Traumatic Brain Injury 5b. GRANT NUMBER W81XWH-11-2-0061

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14. ABSTRACT- A better understanding of the nature of chronic pain after combat related to TBI is of central importance in the treatment of warfighters who suffer from this condition. The broad objective of this work is to characterize the neural networks involved in post-traumatic pain using functional MRI both in the resting state and during activation with a moderately painful stimulus. The hypothesis is that the patterns of activation under both conditions are abnormal and similar to those in other chronic pain states such as migraine and fibroyalgia when controlled for co-morbid insomnia, depression and PTSD. The study groups to be compared for this work include patients with chronic migraine, fibromyalgia, post-traumatic pain post mTBI, asymptomatic individuals post mTBI, and normal controls. Resting state network characteristics will be determined by MRI at rest and contrasted to the pattern of activation during a visual attention task. Next, a calibrated degree of moderate pressure will be applied to the left thumb. Resting state fMRI data will be compared between groups and a general linear model including the scores on the depression, insomnia and PTSD inventories will be tested. The impact of this research will be a better characterization of the disturbances within the central nervous system that cause and propagate pain after mild TBI to lead to improved strategies to treat this. 15. SUBJECT TERMS- mild TBI, functional MRI, resting state, neural works

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Table of Contents

Page

Introduction ... ........ .. ...... ... .. ..... .. ........................... ...... ...................... 1

Body......... .... ....................................................................... ... ... ..... 1

Key Research Accomplishments. ........... .... ........... .. ..... . ...... ............ .... 3

Reportable Outcomes... ...... ............. .......... ................................. ...... . 3

Conclusion............... .. ................................. ....................... ...... ........ 4

References.......... ..... ...... ...... ... ... .. ......................................... ...... .. .. .. 4

Appendices........................................ ...... ...... .... ..... ....... .... ..... .......... 5

INTRODUCTION: This is a prospective study designed to characterize pain pathway activation in the brains of mild traumatic brain injury patients with chronic pain , and to compare with other demographically-matched individuals with and without chronic pain disorders. The specific study groups to be compared for this work include patients with chronic migraine, fibromyalgia , post-traumatic pain post mTBI , asymptomatic individuals post mTBI, and normal controls The understanding of the neurobiology of chronic pain and mTBI uses magnetic resonance imaging (MRI) methods to quantify the structural changes and functional activation patterns at rest and during task performance associated with chronic pain in TBI. A major emphasis of our study is to understand the connectivity of regions associated with chronic pain.

Structural imaging metrics involve high resolution MRI for grey matter analyses and DTI to assess white matter connectivity. Resting state fMRI is used to develop a neural network model of functional connectivity within regions of interest (those known to be part of the classic pain matrix and the so cal led "default" mode, a network that regulated higher cortical processing). The broad objective of this work is to gain a better understanding of the pattern of resting state connectivity in chron ic pain and use these data to differentiate chronic pain in TBI from normal and other pain states. We will also use task fMRI to assess the regions activated during pain stimulation in each subject group and to then conduct effective connectivity analysis that will allow us to probe which connections are modulating others in the pain pathway of individuals who suffer from chronic headache and somatic pain after mTBI using non-invasive brain imaging methods. Imaging data will be correlated with behavioral data and be used to understand the neural networks involved in chronic pain in the experimental group when controlling for comorbid PTSD, life stress, depression and insomnia. The intent is to more fully characterize the nature of pain pathway abnormalities and use this information to develop measures that assist in differential diagnosis of pain syndromes, provide a metric of treatment responsiveness, and be used to predict treatment outcomes.

BODY: The approved statement of work outlined the tasks to be completed:

Task 1 (months 1-6): Characterize resting state and mild pain stimu lated neural networks in previously identified individuals with chronic pain . Two subtasks were identified, that included:

1) Enrollment of 150 participants from five experimental groups: chronic pain following mild traumatic brain injury (mTBI), those with fibromyalgia, chronic migraine without aura, asymptomatic individuals after mTBI, and in normal controls, and

2) MRI scanning and completion of the behavioral measures on all enrolled participants

Task 2 (months 18-21 ): Data analysis to include DTI, resting state network and fMRI analysis, and functional/structural imaging correlation.

Task 3 (months 21-24): Generate final report and publish results.

To complete subtasks two and three, following approvals and MRI sequence refinement, a phased recruitment strategy was implemented in September 2011 . To date, five control

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participants, five fibromyalgia patients, one migraine with aura, and one mild TBI patient have completed the study. One control patient scan is incomplete, and another control patient withdrew from the study after consenting. Two additional patients, one migraine without aura, and one control patient, are awaiting scanning.

Figure 2. MRI scanner used for this study

Preliminary fMRI results from the first 10 patients show consistent activations in response to the moderately painful stimulus in all of the regions of the pain network (i.e. primary and secondary somatosensory regions, insula , cingulate, primary motor regions, thalamus and cerebellum). In the same subjects, fMRI during mental tasking has also shown consistent activation. Analysis of the DTI and resting state data for these subjects will be completed next, for quality assurance purposes.

Figure 3. BOLD response for a single subject (migraine with aura patient). Activations shown are a result of the pain condition versus rest contrast and identify regions of the pain network. Transverse slices are shown on the left and a 30 rendered image is shown on the right.

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Recruitment continues to be the major obstacle in the study for various reasons. First, the overall population of mTBI patients available to be enrolled in the clinic remains low; most are still being recruited primarily into the SCORE! (Study of Cognitive Rehabilitation Effectiveness for mild traumatic brain injury) and its associated MRI intensive counterpart iSCORE study. Fortunately recruitment for these studies will be completed soon, and recruitment efforts will be renewed with the TBI Service at SAMMC (San Antonio Military Medical Center, formerly BAMC-Brooke Army Medical Center) and the DVBIC Service (Defense Veterans Brain Injury Consortium) also at SAMMC. Second, though additional subjects have been included by expanding the Als on this study and through increased awareness/publicity, the logistics of scanning subjects at a separate nonmilitary institution is daunting to some subjects. Third, the research coordinator hired at the time of the last report was quickly let go and the study lacks a suitable research coordinator able to spearhead recruitment as well as facilitate operations between SAMMC and the Research Imaging Center at UTHSCSA (University of Texas Health Science Center at San Antonio). The study has been extended for another 6 months and recruitment goals are now incorporated into the study.

Task 2 and 3. These will be completed upon enrollment of additional participants

KEY RESEARCH ACCOMPLISHMENTS: • Successful development of an experimental paradigm to support this study, and future

studies of chronic pain in active duty service members, veterans, and civilians. • Analysis strategy for fully developed and we are getting excellent brain data (e.g. ,

Figure above fMRI results).

REPORTABLE OUTCOMES:

Publications: Lewis, JD, Wassermann EM, Chao W, Ramage AE, Robin DA, Clauw OJ , Central Sensitization as a Component of Post-Deployment Syndrome. NeuroRehabilitation 31 (2012)": 367-372.

Presentations: Robin DA, Lewis JD "Understanding the Mechanisms of Action of Chronic Pain in Warfighters with Mild Traumatic Brain Injury: Non-invasive Imaging Approaches", Presented at 3rd Federal Interagency TBI Meeting, June 2011.

Robin, DA, Parkinson, A, Manes J. Using quantitative meta-analytic techniques to understand the neural substrates of pain and chronic pain syndromes with VBM and fMRI data. Presented at University of Michigan Center for Chronic Pain and Fatigue. July 2011.

Robin, DA Using brain imaging to understand chronic pain and fatigue. Presented to Neuroscience Grand Rounds, UTHSCSA, September 2011.

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CONCLUSION: There continues to be an increased recognition of the problem of chronic pain following mTBI and deployment in active duty service members and veterans [2]. This study, despite its limitations, remains well-poised to contribute to an understanding of the changes in the brain that perpetuate pain in this population and other chronic pain conditions. In addition, it offers a platform for which to build clinical trials with an objective endpoint measure (fMRI activation to a painful stimulus), relevant to post-concussive symptoms.

REFERENCES: 1. Gracely, R.H ., et al., Functional magnetic resonance imaging evidence of augmented pain

processing in fibromyalgia. Arthritis Rheum, 2002. 46(5): p. 1333-43. 2. Lew, H.L. , et al. , Prevalence of chronic pain, posttraumatic stress disorder, and persistent

postconcussive symptoms in OIF! OEF veterans: polytrauma clinical triad. J Rehabil Res Dev, 2009. 46(6): p. 697-702.

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:\euroRrhabiln"llon 31 <2012) 367- 372 DOl IO.:l233/:\RE·20 12-00805 lOS Pres;

APPENDIX A

367

Central sensitization as a component of post-deployment syndrome

Jeffrey D . Lewisa.h . Eric M. Wassermanna·*. Wendy Chaoc. Amy E. Ramage" . Donald A. Robinc and Daniel J. C lauwf "Nmionallnwitllle of Neurological Disorders and Stroke. Behm·ioral Neurology Unit. Bethesda. MD. USA h Uniformed Sen•ices Uni1·ersin· of the Health SciPnces. IJethPsda. MD. USA •· Depart111e11t of Neurolog_1; Brooke Armr Medical Cente1; Ft Sam Houston. TX. USA d Departn/£'111 of Pnchiatrr. Uni1•ersitr ofTe.ras Health Science Center m San A111onio, San Antonio, TX. USA ''Research Imaging lnstitllle. Unil'l' rsin· ofTe.ras Health Science Ce/1/er a t San Awonio, San Antonio. TX. USA r Cluv nic l'ain and Fatigue Cente1; Uni1•ersitr of Michigan. Ann Arbo1; MI. USA

Abstnlct. tvl any service members and "eterans report chronic unexplained symptoms such as pain. fati gue and memory complaints. which have most recently been characteriLed as post-deployrnelll syndrome (PDS). Chronic widespread pain is a cornponelll of this syndrome. producing significant disability and considerable health care costs. The simila1ity between the nalllre of these complaints and other medically unexplained illnesses such as fibromyalgia. initable bowel syndrome. and chronic fat igue syndrome suggest that they may share a common mechanism. Here. we provide suppon for PDS as a consequence of pain and sensory ampli fication secondary to neuroplastic changes within the cemralnervous system. a phenomenon often termed cemral sensi ti zation. \Ve also discuss how factors such as stress and genetics may promote chronic wide,pread pain in veterans and service members who develop I'DS.

Key\\ords: Chronic widespread pain. post-deployment. mi ld traumatic brain injury

I. Introduction

After mi I itary deployment. many service members and veterans experience unexplained symptoms. in­cluding pain. irritability. headaches. tinnitus. extremity numbness. fatigue. dizziness. and memory difficulty with long-term or permanent disabil ity 11 11. This syn­drome was called "shell shock .. during World War I and "postconcussional syndrome .. during and after World War II. where it was attributed completely to combat and nearby explosions [38.39]. After the fi rst Persian Gulf War [ 19.4 1.64]. many veterans reported simi lar chronic symptoms. i.e .. Gulf War Illness or chronic multisymptom illness. Citing personal accounts of ill ­ness after deployment. Cifu and Blake [II ] used the

· Corresponding aUJhor: Eric ~ l. Wasscnnann. ':nional l nslilul~

of Neurological Disorders and Stroke. lkha-·ior.tl N~urolog~ Unin' r­sil~ . 10 Crmcr Dri\ C. !IISC 1-l-10. Bldg. 10. Room 7D~3. 13ethesda. ~ID 20892. USA. Tel. : +I JOI ~96 0220: F:l\: +I JOI ~SO 2909: E-mail: \Vassennanne@' ninds.nih.go \.

term post-deployment syndrome (PDS) for the core set of symptoms in veterans of the curren t connicts in Iraq nnd Afghanistan (OIF/OEF). While th is aggregation of symptoms has traditionall~· been att ributed to com­bat exposure. it is al so true that in each war. troops who were not in the vicinity of fighting have developed the same syndrome 120]. Although the symploms arc varied. chronic widespread pain (CWP). involving the limbs. lower back and neck. has been increasingly rec­ognized as a common symptom l l llthat has no clear ··cause·- in more than 50'/f of reported cases [25].

The prevnlence of post-deployment CWP in mili­tary veterans is high. In a survey-based. cross-sec tional study of 12.000 United Kingdom (U K) veterans of the Persian Gulf War. Stimpson et al. [62] found that more than 16'/f of indi,·iduals deployed to the Gul r expressed symptoms of CWP. This prevnlence equated to an ad­justed odds ratio of 1.82 for those deployed Yersus those who served concurrently. but were not deployed. A high prevalence or CWP wns al so obsen ·ed in a survey of

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368 J.D. U•tt'il <'tal. I Central .\etuiti:atitm in polt-tleployml'llf ·'.\'lulrmm!

more than 3.500 US veterans who served in the Persian Gulf War du ring the same time period 11 8 1.

Interesti ngly. the prevalence of CWP is conOict­specific. For instance. in the previously described UK study [62]. tho e deployed to Bosnia instead of the Persian Gulf reported CWP no more often than non­deployed veterans. and those deployed to both regions had a prevalence equal to the Persian Gulf War group. A simi lar di iTcrcncc in unexplained symptoms. such as chronic fatigue syndrome. has also been noted between these cohort s [34.59]. and has contributed to persistent speculation about an environmental exposure such as pesticide or depleted uranium as the cause of Gulf War Illness 11 3].

Large-scale stud ies of CWP in OIF/OEF veterans have not been completed. but preliminary data suggest the prevalence of CWP in veterans of 0 1 F/OEF is sim­ilar. if not higher. than those of the Persian Gulf War. Within the VA system. 53'K of those seeking medi­cal care are classi tied as having ''di seases of muscu­loskeletal system/connect ive system·· that typically in­clude chronic pain 1661. In a review of the records of 429 OIF/OEF veterans seen in a post-deployment clinic, 29'11 had pain in all four limbs 130].

The similarity between PDS and other medically unexplained conditions such as fibromyalgia 126.761. chronic fatigue syndrome [3.33.37]. irritable bow­el syndrome [74]. post-concussion disorder [4.36]. chronic headache 1571. and post-traumatic stress disor­der 1431 has been previously noted 1341. In all these condit ions. CWP occurs together with memory difficul­ties. fatigue. sleep diswrbances and. often. depressed mood 1751. These syndromes arc frequently seem in the same individuals: for example. the associat ion be­tween fibromyalgia and other conditions such as in·ita­blc bowel syndrome and migraine headaches was first reponed near! ~· thirty years ago 17-1] . In an extensive review. Yunus 1751 describes the common clinical fea­tures of several of these conditions and discusses how they share a hypersensitivi ty to cutaneous and visceral stimulation. In both ani mal models and humans. this hypersensitivity manifests as increased sensitivity to

normally painful stimu li (hyperalgesia) and/or pain in response to normally non-painful stimuli (allodynia) 12. 69 1. In addition. patients demonstrate hypersensitivity to non-somatosensory stimuli. such as lights. noises. and odors 123.24.32]. The terms ··central sensitization·· or ··cent ral augmentation·· are increasingly used to de­scribe these phenomena of increased pain and senso­ry transmission that produce the common set or symp­toms in the pre\'iously listed disorders [2.68.69.7 1.72].

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Specificall y. individuals who have ··centrali zed'' their pain al so complain of fatigue. insomnia. memory diffi­culties. and mood disturbances. perhaps because many of the same neurotransmitter systems that control pain and sensory sensitivity also control level of alertness. sleep. memory. and mood 169].

2. Cent ral sensitization as a component of PDS symptoms

The term. central sensitization. was first used by Woolf (re\' icwcd in [7 l j)to describe a spinal cord mechan ism in animals and humans [45.50.5 11 sec­ondary to peripheral nerve injury characterized by pain amplificat ion. hyperalgesia. and allodynia. Recently. thi s term was used by Woolf and others to more brondly denote sensitization hcyond the spinal cord to include the ent ire nervous system and panicularly the brain. In functional ncuroin1aging studies. induced pain has demonstrated augmented neuronal activation in pai n­processing regions in pat ien ts with CWP and other chronic pain states. panicularl y hyperactivity or the in­sular cortex 11 5.271 as compared to healthy controls. The uniqueness of this brain area to central sensitization is supported in nn imnl models of chronic pain. where surgical lesions in the caudal granular insular cortex reduce allodynia without affecti ng normal mechanical stimu lus thresholds [61.

The insular cortex is involved in many processes including sensory integrat ion 116], working memo­ry 161]. and awareness of the physiological condi tion of the body. Neuroplastic changes in this region resulting from chronic pain (discussed in 146]) and other psy­chological or physiological strcssors 160 I arc ;~ssoci­

atcd with several symptoms. e.g .. memory difficulties. fatigue 165]. sleep ;~nd mood disturbances 18].

Gulf War veterans have complained common! y of so­matic and visceral hypcralgcsialallodynia 114. 171. nnd the multitude or PDS symptoms close ly match those previously associated with neuroplastic changes in the insular con ex that can occur with chronic pain. Togeth­er. these complaints suggest central sensi ti zation as a potential mechanism for PDS.

3. Relationship hetween stress, mili tary deployment and central sensitization

Stress appears to play an imponant role in develop­ing chronic pain and its accompanying symptoms [49].

J.D. l.t'H'i.\ et a/. I Ct'mra/ Jl'IBiti~mion in po.\t-dtwloym£'111 ,_,·m/rome 369

Table I Selected phannacologic treatmems for m nditions in \\ hich cemral sensitizat ion has been dcmonstra1ed

Condition Phannacologic tre<uments References

Fibrom~ algia Irritable bowel s~ ndrome Chronic fat igues~ ndrome Chronic headache

Duloxetine ·. milnacipran ·. pregabaliu ". ami1rypt il ine. paroxctinc. c iwloprJm lmipr.unine. a mill) p1i line. gabapemin. pregabaliu

(8 ( (~ 1.54)

(53)

P~ l (44 (

A mit~ ptiline. doxcpin. c italopr.un. cscitalopr.un

Complex regioual pain syndrome Amit~·p1 yliuc . nonrip1yline. di, a lproex . propr.onolol. gabapcmin. topirimatc Am~ tal. ke tamine

· Food and Dmg Adminis trJtion appro,·ed.

This is supported in animal models. where fear learn ­ing and unpredictable sound stress produce increased pai n sensitivity 128.56]. 1n humans. infections. acciden­tal trauma. surgery. and other major life strcssors can trigger regional or widespread chronic pai n. fa tigue. memory problems. and sleep disturbances 19.29.3 1 .40. .Q]. For instance, chronic threat of monalit y from mis­sile attack was associated with increased prevalence of CWP and somatic symptoms in Israeli civilians [ 1). Coping style and cognition appear to mediate between chronic stress and pain development. with the possibili ­ty of pain-related fear. irrational belief that the situation is worse than it nctually is. and avoidance amplify ing peripheral sensations and increasing chronic pain [48. 60[.

However. C\VP is not n un ivcrsnl consequence of stressfu l life experiences. For instance. brief or indi­rect threat docs not appear to be suffic ient lll produce CW P. As an example. after the terrorist attacks of 911 I. studies in Washington. DC and ew York Ci ty reg ions showed no significant increase in pain or· other somatic symptoms in individuals with fihromyalgia. or in the general population H 7 .55.68[. There is evidence for a genetic predisposition to CW P after a stressfu l life experience 158 1. and this likely extends to PDS in gen­eral.

It should not be surprising that some individuals de­ployed to war develop C\V P accompanied by other so­matic symptoms such as fat igue and memory problems. since this same phenomenon occurs after ex posure to a broad vari ety of "strcssors ... For example. the 1958 British Birt h Cohon Study led to many publications showing that individuals who early in life arc inl'o lvcd in a motor traffi c accident. the death of a parent. severe financial hardship. or a prolonged hospitalization. arc 50- I OO'k more likely to ha\'c CW P later in life than those that do not hal'e these same exposures. Other known triggers of CWP include infections (e.g .. Lyme disease. Q fever. Epstein-Barr virus). trauma (especial­ly motor \'chicle coll isions). and "peripheral .. muscu­loskeletal conditions such as anhritis that cause con­stant ongoing peripheral nocicepti,·e input. Since in-

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di1·iduals deployed to war may experience many of these triggers. the association between combat-related deployment and CWP is unsurprising.

~- The potential role of concussion in promoting central sensitization

Wh ile the somat ic and behavioral complaints of Per­sian Gulf War and OJ F/OEF veterans arc similar. one imponam di fference is the greater prevalence of con­cussion as a result of explosives. producing mild trau­matic brain injury (mT BI) in OIF/OEF retumees. Af­ter concussion. approximately 5(k or fewer of individ­uals have persistent complaints. including headache. tinnitus. fatigue. sleep disturbance and irritability 135 l­In those paticms with continued complaints. changes appear to occur in the brain over time. For instance. changes in gray matter volume. similar to those seen in fib romyalgia. have been previously noted in civil­ian patients with chronic posttraumatic headache 152]. Whether TBI itse lf causes these changes directl y. or if they arc a consequence of the accompan~' ing chronic pain. stress. or other "non-kineti c .. factors. is unclear and further research is needed to clarify this re lation­ship.

5. Treatment approaches lor conditions in which central sensitization is a component

Several treatments. both pharmacologic and non­pharmacologic. have been effecti ve in treati ng condi­tions in which central sensitizat ion has been demon­strated (see Table I). Most medicat ions for these con­ditions target pain processing in some fashion. and their use is supported by several randomized. comrolled trials. Classes of compounds wi th the greatest effica­cy across the various conditions include tricyc lic an­tidcprc sams. dual action serotonin-norepinephrine in­hibitors. and alpha 2 delta receptor ligands. such as pregabal in and gabapent in.

.\70 J. D. l...i.'lri., eta/. I Ct~mral !1l'n~iti:ation in po~t-d£•ploymC'III ~yndrmne

Intravenous amytal. a medi um acting barbilllratc, has been used to treat complex regional pain syndrome (CRPS) 14-1]. More rcccmly. imravcnous kctamine has shown promise in treating CRPS. as wel l 15 1. Of the central sensit ivity syndromes. this condit ion is unique in the usc of these two medicat ions.

In addit ion to medications. behavioral imervcntions have shown efficacy. For example. several randomized controlled trials of cogniti ve behavioral therapy strate­gies have have found clinically significalll effects on pain and associated symptoms. such as. fatigue. and demonstrated increased function after treatment 167. 73]. The utility of these medical and behavioral intcr­vcmions for treat ing PDS has yet to be determined.

6. Implications for rehabilitation and need for future research

Post-dcploymelll CWP. as a component of PDS. has significant implications for public health. With 257< of 697.000 Persian Gulf War veterans reponing CWP [ 17] and almost 2 mi llion troop-years deployed in support of OIF/OEF as of December 2008171. the health care -related costs of PDS arc likely to be considerable: Av­erage annual health care costs estimates for chronic pain treatment alone range from $ 13.000 10 $ 19.000 per individual ( 1988- 1997 dollars) [63]. CWP is as­sociated wi th worse post-dcplovmcnt health outcomes. independent of co-morbid health conditions. such as post-traumatic stress disorder and depression. and may represent the most debilitat ing featu re of PDS 118.30].

'early I 00 years after the ··shell shock·· epidemic of World War I. advances in understanding the neurobiol­ogy of chronic pain and cognit ion. coupled with sensi­tive structural and functional imaging techn iques. final­ly oil er the promise of dramat ically improved aware­ness and rehabi litat ion of these symptoms associated with war. To date. the neurobiological basis for these symptoms has not been establi shed. but there is suffi­cient overlap with condi tions such as chronic fat igue syndrome and fi bromyalgia to suggest central sensiti ­zation as a signi ficanl comributor. More research is clearly needed to confi rm this association and would inform future treatment trials for C\VP in veterans.

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(101 Cho~ . E .. MarshalL D .. Gabriel. z. L 1\li tche ll. S. A .. G~lce . E .. & Dakin. H. A. (2011). A s~stematic re• ic" and mixed treatment comparison of the efficacy of phannacological treat­ments for fibrom•·algia. Smri11 Anlu·iri' Rile11m. -1/(3). 335-3-!5 c336.

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10