pathways to effective treatments for traumatic brain injuries...referred to as concussion) can lead...

CohenVeteransBioscience:ProceedingsoftheSecondAnnualBrainTraumaBlueprintStateoftheScienceSummit:PathwaystoEffectiveTreatmentsforTraumaticBrainInjuries

©CohenVeteransBioscienceBrainTraumaBlueprintSummit2019 2

AbstractOverview:TheBrainTraumaBlueprint(BTB)isaroadmaptoadvanceprecisiontherapeuticsforsurvivorsofbraintraumabyoutliningresearchendeavorsandfosteringcollaborationacrossthebroaderstakeholdercommunity.OnepivotalcomponentoftheBlueprintProcessistoconvenekeystakeholdersataStateoftheScienceSummit(SoSS)tosurveythecurrentscientificknowledge,identifyknowledgegaps,andconsidernewscientificandclinicalmodelstofillthesegaps.ThethemeofthesecondSoSS,heldinJune2019,wasPathwaystoEffectiveTreatmentsfor TraumaticBrain Injuries (TBIs).This summit focusedon the chronic sequelaeof TBI andaimed to identifycurrentknowledgegapsintheetiologyandmechanismsofpersistentsymptoms.Theresultingprioritizedlistofspecific recommendations that address the identified knowledge gaps were then used to create actionableresearch priorities that will inform funding efforts and accelerate the development of a new generation ofprecisiondiagnosticsandtargetedtherapeutics.Outcomes:TheBTBimplementationteamwascomprisedofaScientificPlanningCommitteeoftenkeythoughtleaders with deep expertise in TBI and an additional 14 domain experts in TBI epidemiology, preclinical andtranslational science, patient phenotypes and biotypes, biomarker development, clinical trial design, andimplementationsciencetoengagewithCohenVeteranBioscience’sBTBexecutiveteamtoenvision,plan,andexecute the summit. The SoSS was designed as a two-day retreat that convened over 100 stakeholdersrepresenting a variety of prominent academic institutions, government agencies including the VeteransAdministration,DepartmentofDefense,andtheNationalInstitutesofHealth,patientadvocacygroupsandnot-for-profitfundingorganizations.Attendeesdiscussedthecurrentstateofthefield,includingtheheterogenousmechanismsof injury,methodsofdiagnosis, and failures in clinical trials. Theyalsoaddressedhowsubtypingpatientstobetterselectpotentialtreatmentsforspecificdiseasepatternscouldassistcliniciansinsuccessfullyadvancingpotentialtreatmentsthroughclinicaltrials.Throughbreakoutandgroupdiscussions,attendeesworkedtobuildconsensusaroundknowledgegaps,discussstrategiestoleveragethecombinedintellectualresourcesofthescientificandclinicalcommunitiesinorderovercomethosegaps,andgeneratedresearchprioritiestohastenthedevelopmentofprecision-therapeuticoptionsforindividualslivingwithTBIs.Conclusion: The SoSS strengthened the cohesion of the TBI scientific, clinical and patient communities andenhancedopportunitiesforfuturecollaborationbyprovidingacohesivestrategytogenerateresearchprioritiesthatwilladdresslong-termTBIsequelae.ThesummitresultedinasynthesisofthecurrentstateofthescienceinsixspecificdomainsofTBIandastrategiclistofnextstepsinthesespecificareasthatthecommunitycanleveragetoconductorfundfutureresearch.Thesedocumentswillbeupdatedandreleasedtothebroadercommunityaspeer-reviewedscientificpublications.As thecommunity fundsandconducts researchefforts thataddress theidentifiedknowledgegaps,theBTBimplementationteamwillcontinueworkingwithkeystakeholderstoensurethat these documents are updated and move towards precision diagnostics and treatments for patientsrecoveringfromTBIs.



BackgroundTraumaticbraininjuries(TBIs)affectatleast2.87millionAmericanseachyear,including288,000hospitalizationsandmorethan56,000deaths(1).Ofthesurvivors,approximately80,000willsufferfromlong-termdisabilities(1). Tragically, these numbers are likely underestimates as they are based only on cases identified in theemergencyroomandexcludeindividualswhodonotseekorhaveaccesstocare,acommonoccurrenceamongpatientswithmildTBI.Traditionally,TBIhasbeenclassifiedatthetimeof injuryasmild,moderate,orsevere,basedontheGlasgowComaScale(GSC)score(2),theprimarydiagnosticcriteriaforassessingtheseverityofTBI.However,thisbroadclassificationschemadoesnottakeintoaccountthelargeheterogeneityofthepathophysiologythatunderliesthese injuries incurred through multiple causes. Additionally, clinicians and researchers alike recognize thatdiagnosis of the condition at the time of injurymay not accurately predict patient outcomes; other factors,includingsubjectivemeasures,fluctuatingpresentations,thepresenceofadditionaldisorders,andthepatient’senvironmentall influence long-termoutcomes.Hence, theabilityof theseclassifications toaccuratelypredictpatientoutcomesisgenerallypoor.ThemanagementofpatientsimmediatelyfollowingTBIofallseveritieshasimprovedinrecentyears.However,despite initial hospitalization and inpatient rehabilitation services, a substantial proportion of people withmoderateorsevereTBIexperiencelastingcognitiveandpsychologicaleffects,unemployment,lowerattainmentofeducation,challengesintheirsocialenvironment,andfurtherdeclineintheirdailylives(3).EvenmildTBI(oftenreferredtoasconcussion)can leadtopersistentsymptomsandfunctional impairments,with10-30%ofcasestreatedinanemergencydepartmentcontinuingtohavesymptomsthreemonthsfollowingtheinitialtrauma(4).PatientspresentingtotheclinicmonthsaftertheirTBIareoftenprescribedtreatmentplansbasedontheirself-reportedsymptomburdenandfamilyreports.Complicatingtreatmentfurther,guidelinesarebasedonsparseevidenceand,therefore,drivingtheiradoptionhasbeenlimited.WithnoFoodandDrugAdministration(FDA)-approvedtreatmentsforTBI,thedevelopmentoftargetedtherapeuticsforthechronicstagesofTBIswillrequireaclearerunderstandingoftheirbiologicalunderpinnings.Identifyinggapsinourunderstandingofthelong-termeffectsofTBIacrosstheinjuryspectrumisanimportantstep indevelopingbetter treatmentsand implementingthemeffectively in theclinic.Toaccomplishthis task,CohenVeteransBioscience(CVB)isleadingthedevelopment,advocacyandimplementationofaBrainTraumaBlueprint(BTB)thatwillacceleratetheprogressiontowardanewgenerationofprecisiondiagnosticsandtargetedtherapeutics for trauma-related brain disorders. The BTB was initiated to advance precision therapeutics bymappingandtrackingtheimpactofresearchendeavorsandisfacilitatedthroughaseriesofStateoftheScienceSummits(SoSS’s)tofostercollaborationacrossamultidisciplinarystakeholdercommunity(researchers,clinicians,policymakers,patientsandfunders) toadvancetranslational research.TheBTB isoperationalizedthroughtheestablishmentofaScientificPlanningCommitteetoguidethedevelopmentofStateoftheSciencesummaries.Thesesummariesincludeanin-depthexplorationofmajorgapsintheunderstandingofTBIsasidentifiedbykeystakeholdersandareaugmentedbyanSoSS.Eachsummitbringsinbroaderexpertisetofurtherdevelopapathforwardbyassessingthecurrentscientificknowledge,identifyingknowledgegaps,andconsideringnewscientificandclinicalmodels to fill thesegaps.Thegoalof the summaries is tobuildaprioritized roadmap focusedonacceleratingTBI therapies frompreclinical researchanddevelopmentstages topatientshavingaccess tonew



therapies as well as to highlight for the research community, government leaders, legislators and privatefoundationsthespecificneedsofthispopulation.

Building on a successful, inaugural BTB SoSS, Diagnosis of Trauma-Related Disorders with a Focus on Post-TraumaticStressDisorder(PTSD),heldin2018,CVBleveragedthesamemethodstoplanforandcarryoutthe2019SoSSwithafocusonTBI.

MethodsEstablishmentofaScientificPlanningCommitteeThesecondannualSoSSwaslaunchedinJanuary2019withtheestablishmentofacharteredScientificPlanningCommittee(SPC)consistingofinterdisciplinarythoughtleadersfromdiverseperspectivesanddeepexpertiseinTBI.Employingvariousresearchtoolstoenvision,planandexecutethestepsneededtosynthesizethestateofthescience inTBIclinicaldevelopment,theSPCfocusedonthefollowingkeydomainsofresearchthatreflectimportant factors in advancing precision solutions in TBI: epidemiology, preclinical and translational science,patientphenotypesandbiotypes,biomarkerdevelopment,clinicaltrialdesign,andimplementationscience.Theroleof theSPCwastoguidethedevelopmentof theSoSSasanengaginganddynamicworkingmeetingwithdefineddeliverables thatwouldhelpmove the field forward.TheSPChelped todevelop theagenda, identifyspeakersandinviteabroadarrayofexpertstakeholderstojoininthemeetingpreparationandactivities.TheSPCaimedtoleverageandengagethebroaderecosystemtogainconsensusontheworkinprogressandtheareasthatarenotyetfullyaddressed,ifatall.



2019TBIScientificPlanningCommitteeMembers

StephenAhlers,PhD DavidXCifu,MDDirector,OperationalandUndersea AssociateDeanforInnovationandSystemIntegrationMedicineDirectorateatNavalMedical VirginiaCommonwealthUniversity,SeniorTBISpecialistResearchCenter U.S.DepartmentofVeteransAffairsFionaCrawford,PhD JamGhajar,MD,PhD,FACSPresidentandCEO,RoskampInstitute President,BrainTraumaFoundation,ClinicalProfessorof

NeurosurgeryatStanfordUniversitySchoolofMedicineJessicaGill,PhD,RN,FAAN GrantIverson,PhDDeputyScientificDirectorofthe Director,SportsConcussionProgram,DivisionofIntramuralResearchatthe MassGeneralHospitalforChildren;NationalInstituteofNursingResearch Director,NeuropsychologyOutcome

AssessmentLaboratory,DepartmentofPhysicalMedicineandRehabilitation,HarvardMedicalSchool,andSpauldingRehabilitationNetwork;AssociateDirector,TraumaticBrainInjuryProgram,HomeBase,ARedSoxFoundationandMassachusettsGeneralHospitalProgram

MichaelMcCrea,PhD,ABPP JamesStone,MD,PhDProfessor,NeurosurgeryandNeurology; ViceChairmanofClinicalResearch,Director,BrainInjuryResearchProgram, AssociateProfessorofRadiologyandMedicalImaging,MedicalCollegeofWisconsin UniversityofVirginiaElisabethAWilde,PhD KristineYaffe,MDAssociateProfessor,Departmentof ProfessorofPsychiatry,NeurologyandEpidemiology,Neurology,UniversityofUtahand RoyandMarieScolaEndowedChair,GeorgeEWahlenVASaltLakeCity ViceChairofResearchinPsychiatry,UCSFHealthcaresystem,DepartmentofPhysicalMedicineandRehabilitationBaylorCollegeofMedicine



ScientificPlanningCommitteeCharterEachsummitisledbyanSPCcomprisedofseniorcontentexpertsinspecificresearchdomains.SPCmembersareselectedbasedonthefollowingcharacteristics:(1)auniquevantagepointtocontributetothecurationoftheevent(e.g.,diversityinbackground,domain,ortechniques);(2)consideredthoughtleadersintheirfields;and(3)proven flexibility and freedom to think outside of the box, bringing original, creative ideas and processes tounderstandwhatisfundamentallyneededtoidentifyresearchgapsandassessnewresearchopportunitiestofillthesegaps.A common goal of each SoSS is to complete a survey of the current scientific knowledge (i.e., a landscapesummary),positknowledgegaps,andconsidernewmodelstofillthesegaps.TheSPCcollaborativelydevelopssubdomainsummarydocumentsthatrelatetothetopicasidentifiedbydiscussionsamongtheSPCandtheBTBexecutiveteam.Additionally,theSPCcuratedvariousstakeholdergroups:(1)anextendedsciencecommitteeofscientiststohelpdeveloptheaforementionedsummaries;(2)summitspeakersandmoderatorswhoengagedthemeetingparticipantsonthemajorthemes;and(3)summitattendeeswhocontributedtoboththe interactivemeetingandthestateofthesciencesummaries,whichwereaugmentedbythediscussionsheldthroughoutthesummit.Workinggroupsdevelopedduringthesummitcriticallyinvestigatedresearchgapareasinadata-drivenmannerandmapped theopportunities needed to fill them. Importantly, the SPCwas also chargedwithdeveloping ameeting format to promote cross-functional and cross-organizational discussion of the major themes andquestions posed. The goal was collaboration on defining shared research priorities. Finally, the SPC guides aprocesstoensurethatallfindingsarebroadlydisseminatedacrosstherelevantecosysteminrealtimewiththesupportofthemeetingattendees,theBTBteam,andourstrategicpartners.SpecificdeliverablesofeachSPCincludes:

1. Designinganinnovativeandeffectiveagendathroughregularparticipationingroupand/orindividualcalls2. Identifyingprominent speakersandkey stakeholders thatwoulddrive the selectedagenda toward its

objectives3. Identifyingandcritiquinginformationforthelandscapingeffort4. Co-leadingdomainspecificworkgroupstoengageleadersanddrivediscussionandconsensus5. ProvidingtimelyfeedbackonthelandscapingdocumentspreparedbytheBTBteam

Questionstobeaddressedinthesummaries:

1) WhatisourcurrentunderstandingofthepathogenicmechanismsoretiologyofTBI?2) Howdopreclinicalandclinicalworkinformthetranslationalresearchgaps?3) WhateffortsareunderwaytoadvanceourknowledgeofTBImechanismsandtheirrelationshiptothe

variedlong-termconsequencesofTBI?4) WhatarethelessonslearnedfromfailedTBIclinicaltrials?5) Whatistheevidencebehindthecurrentdiagnosisandtreatmentselectioncriteria?6) Whatarereal-worldapproachestothediagnosisandeffectivetreatmentofthechronicneuropsychiatric

sequelaeofTBI?7) Whatisthestrengthoftheevidenceforcurrentinterventionsandclinicalpractice?



Tofurtheradvanceourunderstanding,sessionsandsubdomainbreakoutsalsoconsidered:

1) Frameworks for a new mechanism-based taxonomy, specifically bridging symptoms and biotypes orconstructsandaddressingcausality

2) Toolstoadvancemajorresearcheffortssuchasdatasciencetools,imaging,biomics,wearables,andotheradvancetechnologies

3) Infrastructureandsystemstosupportresearchanddevelopmentacrossthetranslationalsciencepipeline4) Evidencetooptimizeanddesignbetterclinicaltrials

TheSummitTheSoSS,PathstoEffectiveTreatmentsforTraumaticBrainInjuries,washeldinJune2019attheKelloggCenterinWashington,DC and focusedon the chronic sequelaeof TBIs. The summit’s goalswere to (1) establish anunderstanding of the root cause issues andobstacles in advancing TBI diagnosis and treatment solutions, (2)landscapeexistingresearcheffortsthataddressthesechallenges,(3)identifyknowledgegapsandbrainstormnewopportunities, (4)generateaprioritized listofspecific recommendationsthataddress identified issues&gapsacross the field, and (5) share this blueprint broadlywith researchers, legislators, public and private fundingorganizations,andthepublictoinformtranslationalresearch,nowandinthefuture.

Morethan100stakeholders,representingavarietyofprominentacademicinstitutionsandgovernmentagencies,includingtheFDA,VeteransAdministration (VA),DepartmentofDefense (DoD),andtheNational InstitutesofHealth(NIH),VeteranServiceOrganizations,patientadvocacygroups,andnot-for-profitfundingorganizations,gatheredtoadvancetheBTBsummariesduringassemblysessionsandbreakoutworkingsessionsbycontributingtheir unique expertise using a collaborative approach to create an effective translational research activityblueprint.Thesummaries,whichwereprovidedtoattendeesbeforehandtooptimizeproductivity,servedasthelaunchingpointforthesessions.

TheSPCdesignedthemeetingsuchthatitwasnotredundantwithothereffortsinthefieldandthatallattendeeshadaclearunderstandingofthecurrentstateofthefieldbeforethestartofthemeeting.Tothatend,theSPCidentified key areas of research that reflect important factors in advancing precision medicine in TBI:epidemiology,preclinicalandtranslationalscience,patientphenotypesandbiotypes,biomarkerdevelopment,clinicaltrialdesign,andimplementationscience.AlongsideCVBteammembers,theSPCandtheexpandedsciencecommitteesynthesizedthestateof thesciencerelatedtopathways foreffectivetreatmentofTBI foreachofthesetopics.Thesesummariesservedasthe launchingpoint fortheworkingsessionsduringthemeetingandoptimizedproductivity. AssemblySessionsTwoassemblysessions,whichincludedallsummitparticipantsandconsistedoflecturesanddebates,wereheldtoadddepthandbreadthtotheconversationsandgenerateconsensusfromtheaudienceonselecttopicsthatspannedthesixdomains.



Day1:Summitleadershipreiteratedthemissionoftheinitiative,thecalltoactionforthegroup,andcliniciansandapatientofferedperspectivesonthechallengesofdevelopingtreatmentstomitigatethelong-termsequelaeofTBI.Beforedividing intobreakoutsessions, leaders inTBIresearchacrossseveralgovernmental institutionspresentedalandscapeofcurrentresearchpriorities.TheSPChighlightedthesummaries’keyconcepts,providingdomainoverviewsthatwouldserveasthefocusareasofthebreakoutgroupdiscussions.

Day2:Participantsreceivedadditionalcontextofthepolicyandregulatoryrealmswithinwhichtheywouldneedto conceptualize opportunities and challenges. Presentations and panels provided multiple approaches indiscussing a path forward to provide a framework for how participants collectively might approach thedevelopment of future precision medicine in TBI. Finally, each group leveraged the combined intellectualresourcesofthefullcommunitytodeliveraprioritizedrecommendationlist.

Thefollowingrecapsprovidesessionsummariesandkeytakeaways:

1) SessionTheme:PerspectivesontheChronicSequelaeofTBISpeakers:NicoleHarmon,PhD,ExecutiveDirector,ExternalAffairs,CohenVeteransBioscience;Lt.JohnnyCebak,MD,PhDSessionGoal:TointroducetheSoSSandthegoalsofthemeetingandtoprovideapatientperspectiveonthechronicsequelaeofTBI

NicoleHarmon, PhD, CVB, introduced the summit by discussing theoverall goals of themeeting. By bringingtogetheradiversegroupofparticipants, includingscientists fromacademia, life sciences,government,healthproviders,technology,patients,andcaregivers,thegoaloftheSoSSwastoconvenethebestmindstobuildabraintraumablueprintforthefuture.Lt.JohnnyCebak,PhD,providedapatientperspectiveonthechroniceffectsofTBI.HewasamedicintheMarinesin Iraq, saw improvised explosive device blasts on a daily basis, andwitnessed around 400 casualties. In oneinstanceduringhistimeinthemilitaryaspartofanarmoredinfantryunit,Lt.Cebakwasthrownfromavehicleandsubmergedinaravinethatledtoseriousinjury.However,becausetheunitdidnothaveadequatemanpower,Lt.Cebakwasrequiredtoreturntohisjobonedayaftertheinjury.Heimmediatelyrecalledhavingnightmares,wasunabletofocus,and,ashedescribed,was“adifferentperson”.Twoweeksafterreturninghome,Lt.Cebakdescribedhissymptomsas“livinginafog”,whichincludedproblemswithattention,balance,andsequelaeofPTSD.Afterreturninghomefromduty,hestartedtofailinschool,struggleinhisrelationshipsandturntoself-medicationwithdrugsandalcohol.Withfamilysupport,Lt.CebakbecameaggressivewithhistreatmentwiththeVA, targetingvarioussymptomswithstimulants,beta-blockers, therapy,andanti-depressants.Hewasable topersevere enough to complete two bachelor’s degrees and a PhD focused on TBI and subsequently enteredmedicalschool.However,thisisnotthecaseformanyindividualswhosufferfromthelong-termeffectsofTBI.Lt.Cebakemphasizedthatmanyofhis friendshavesuccumbedtoorarestill fightingthesequelaeofcombatexposure.



KeyTake-Aways:TreatmentsforthechronicsymptomsofTBIareneeded.Creativethinking,bringingtogetherkeyminds,andworkingtogetherwillhelpmovethefieldforward.2) SessionTheme:WelcomebyCohenVeteransBioscience

Speakers:MagaliHaas,MD,PhD;CEOandPresident,CohenVeteransBioscience

SessionGoal:Topreviewthegoalsandprocessesofthemeeting,considertheoverallmission,anddeliverthecalltoaction.

ThesecondsessionincludedawelcomingaddressbyCVB’sChiefExecutiveOfficerandPresident,Dr.MagaliHaas.Dr. Haas thanked veteran and Dr. Cebak for sharing his serious and inspirational story and sought to raiseawarenessthatevendiagnosisofmildTBIisarealconcernandthattherearemanycasesinwhichindividualsarenotdiagnosedandmightcontinuetohavelong-lastingeffects.Shesharedthatsomeimportantprogresshasbeenmadeinrecentyears,onthediagnosticsideofTBI,withapprovalsbytheFDAofthreenewaides-in-diagnosticsforTBI.However,shenotedthatfutureprogressrequiresthatthefieldundertakestorevisetheframeworkofdiagnostic criteria are based on –which informs the gold-standard reference for developing diagnostic tests.Currentdiagnosticcriteriaarebasedonclinicalsymptomsandpresentationattimeoftrauma,notthespecificbiologicalprocessthatresultsfromthetraumaoritssubsequenttrajectoryandseverity.Shesuggestedthatamore holistic approach be adopted thatmeasures disease processes throughmulti-modal platforms such asgenetics, imaging,wearables and track disease processes over time to understand the systemic changes anddiseaseprocessforanewmechanistic-baseddiagnosticapproach.The goal for the treatment of TBI and related comorbidities is personalized and precision therapeutics, buteffectivetreatmentrequiresaparadigmshiftinhowresearchersapproachtheprobleminitially.Dr.Haassharedhow CVB is building platformswith strategic partners to incentivize a team-science approach toward findingsolutions for trauma-related diseases efficiently. Instead of defining conditions syndromically based onobservation,wemustlookatthemolecular,circuit-basedreasonstheseconditionsaredeveloping.Thisstartsbycombiningmulti-modaldatatypesusingadvancedcomputationalapproachesforthesedisorders.Forexample,theRAPID-DxframeworkisaninfrastructuretobringtogetherdatathroughtheBRAINCommons–aresourceforthe research community to share, store, and analyzedata – and increase thepower formeaningful researchoutcomes. This approach has already enabled success in the field of PTSD genetics by integrating 56 studiesworldwide and generating the first genome-wide significant findings for PTSD. The study identified six single-nucleotidepolymorphisms,showingthatthisknowledge-sharingapproachcanworkandcouldbeappliedtothefieldofTBI.CVBhasleveragedthismethodologyforotherworkinneuroimagingbiomarkersforPTSD.Inthespaceofneuroimaging,CVBhelpedlaunchthedevelopmentofanormativeneuroimaginglibraryofover3,000subjectstoinformcurrentlyavailableFDA-approvedtoolsforinterrogatingadvancedimaging.Thesearejusttwoexampleswherecollaborativeapproaches,marriedtoaroadmappedeffortforPTSD,isyieldingprogress.Dr.Haascalledonthoseassembled,tohelpbuildablueprinttofurthereffortstoobjectivelydiagnosisandtreatTBIasaproductofthisSummit.



KeyTake-Aways:ThismeetingandtheresultingrecommendationsdocumentaimtoaddvaluetotheeffortsthatarealreadyunderwayforTBI.Thismeetingintendedtounderstandthestateofthescience,determinenecessarynextstepsandunderstandhoweachstakeholdercancontributetowardsthateffort.3) Keynote:OneBiteataTime:ClinicalTrials–SpecificAspectsofTBI

Speaker:DavidBrody,MD,PhD;DirectorattheCenterforNeuroscienceandRegenerativeMedicine,theUSU/NIHTraumaticBrainInjuryResearchGroup

Sessiongoal:TohighlightsomeofthereasonspromisingTBItherapeuticsfailtotranslateandintroducepotentialpathwaystowardbringingeffectivetreatmentstotheclinic.

DavidBrody,MD,PhD,gaveacalltoactionforTBI.Over30late-phaseclinicaltrialshavefailedtotranslatetoatherapeutic;thiscouldbeduetoanumberofreasons,includinginsufficientsamplesize,heterogeneity,ordesign,patientoroutcomeissues.AsDr.Brodynoted,wehavebeenmakingthesamemistakewithincreasingconfidence.Apotentialpathforwardistoperformclinicaltrialsthatarefocusedononesubdomainatatime,orasGeneralCreightonAdamssaid,“wheneatingandelephant,takeonebiteatatime.”Thisstrategywouldincludeidentifyingspecific subdomains, symptoms, and candidate treatments, and then designing rigorous, multicenter,randomized, blinded, controlled clinical trials. To this end, the field needsa clinical trial infrastructure, smartclinicaldesigns,selectivepatientsubsetsthatarelikelytobenefitfromspecifictreatments,anddomain-specificprimaryandsecondaryoutcomemeasures.Thisplatformapproachcould reduce the time,cost,and logisticalbarriersassociatedwithindividualtrials(5).Dr.BrodydescribedaninitiativeoftheCenterforNeuroscienceandRegenerativeMedicinetoperform30clinicaltrialsforcandidatetreatmentsintenyearsatthecostoftentrials.HisworkconsidersseveralTBIsubdomainssuchasmooddisorders,sleepdisorders,post-traumaticheadaches,andcognitivedisorders,aswellasseveraltreatmentapproaches, includingpharmacology,cognitivebehavioraltherapy(CBT), lifestyle interventions,andneuromodulationtherapiessuchasrepetitivetranscranialmagneticsimulation(rTMS).TherapieslikeCBTmighthelp with mood disorders; behavioral therapy could help relieve fatigue; and computer-based brain fitnesstrainingmayimproveworkingmemory.Forpharmacology,onedirectionincludesdevelopinganevidencebasefor FDA-approved drugs that are being used “off-label” in the clinic for TBI patients, such as anti-epileptictreatmentsformood labilityorstimulants forcognitiveendurance.For lifestyle interventions,mooddisorderscouldbetreatedwith intensedailycardiovascularexercise, sleepand fatiguemaybeamelioratedwithgentlecardiovascularexercise,headachesmightberelievedbyremovingspecificfoodtriggers,andcognitivedisorderscouldpotentiallybeaddressedbyprescribingadietthatislowinrefinedsugar.Forneuromodulationtherapies,rTMS has potential to amelioratemood disorders. In addition, hybrid and combination therapies could be asuccessfulwaytotreatsubdomains.Thereisalsoanurgentneedtoestablishanetworkofpartnerclinicaltrialsitesthatcanoperateundertheapprovalofasingleinstitutionalreviewboard(IRB).Dr.Brodythendiscussedanexemplar:individualconnectomemapping-basedTMSfordepressivesymptomsandTBI patients (6). TMS is an FDA-approved therapeutic that induces electrical currents, which cause actionpotentialstofireandstimulatethecortexdirectlyunderamagneticstimulator.Thegoalofthisstudywastomakea reliablemapof thedorsolateralprefrontal cortexwith the resting-state functionalconnectivityof individual



subjects. The researchers mapped the dorsal attention and default-mode network, which are strongly anti-correlated;thehypothesisisthatstimulatingthedorsalattentionnetworkwilldownregulatethedefault-modenetworkincludingthesubgenualanteriorcingulate,whichcanbeoveractive indepression.Deepbraintargetsoftenhaveacorrelateoranti-correlateinmoreaccessiblecorticalregions,soifonewantstoinhibitadeepbrainregion,onecouldtargetacorticalcorrelate.Thetrialincluded15enrolledpatientsandperformed20sessionsofbilateralrTMSonthistargetedarea.Whiletheshamplacebogroupshowedareductionindepressivesymptoms,therewasalsoasubstantialeffectofrTMS,withdramaticreductionsindepressionreadouts,specificallylassitude,aspatientsshowedincreasedenergy.Neuroimagingfurtherrevealedchangesinthefunctionalconnectivityofthebrain (i.e., remappingof thenetworkarchitecture),but itwasnotobviouswhichportionsof theresting-statenetworkarchitecturearemostcorrelatedwithchangesinsymptoms.Notably,thepatientsweremorelikelytoseekothertherapiesandmakelifestylechangesafterthetherapy.Alargemulticentertrialisunderwaytotestthisapproachcomparedtothestandard,FDA-approvedTMSprotocolusingaBayesianadaptivedesign.Thetrialwillalsoinvestigateunilateralversusbilateralmethods.KeyTake-Aways:Numerous late-stage trialshavenotbeen successful and the “onebiteat a time”approachaddressessomeshortcomingoftrialswhilemaintainingrigorousscientificdesigns.Thecostsandtimeinvestmentofindividualtrialscanbereducedusinganetworkofpartnerclinicaltrialsites. 4) PanelDiscussion:ImplementationScience:TheClinicalPerspective

Moderator:NoelGunther,ExecutiveDirector,BrainLineSpeakers:DavidCifu,MD,SeniorTBISpecialist,USDepartmentofVeteransAffairs;UzmaSamadani,MD,PhD, Associate Professor, Department of Bioinformatics and Computational Biology, University ofMinnesota,Neurosurgeon,MinneapolisVAMedicalCenter;ChristopherTWhitlow,MD,PhD,MHA,ChairofAmericanCollegeofRadiologyHeadInjuryInstitute,DiagnosticRadiologistResearcheratWakeForestBaptist Health Hospital; Thomas DeGraba, MD, Chief Innovations Officer, National Intrepid Center ofExcellence

Sessiongoal:Todiscusscurrentpracticemodelsforacutecare,radiologicdiagnosis,rehabilitationmedicine,andmanagementguidelines.Thispaneldiscussedaclinicianperspectivetoimplementevidence-basedguidelinesinanefforttounderstandthebraininjurypopulation,includingchangesinpersonality,behavioralhealthandcomorbidities.Dr.DavidCifudiscussedtheneedforimplementationtosuccessfullybringtherapiestotheclinic.Despitemanyclinicalpracticeguidelines,thefieldhasnotyetreachedaconsensusonwhatrecommendationsareevidencebasedandshouldbefollowed.Thislackofconsensusorplantoeducatecliniciansandget“buyin”frompatientsoftenresultsinpoorprognosticsand long-lastingsequelae.Manystrategies for implementationanddisseminationhavebeenused in other fields; TBI guidelines could borrow these techniques and develop a better decision tree andinfrastructuretoimprovecare.Dr.UzmaSamadaninotedacommonmisconceptionamongVeteransisthatnon-life-threateningbraininjuryisnottreatableandhencethereisnoneedforTBIpatientstogototheemergencyroom.Thismisconceptionis



reinforcedbythecurrentmedicalsystem,whichdoesnotfocusontheclassificationofthepathophysiologyoftheproblemandresultsinalargepopulationofpatientswhoneverseekcareandspiralintodownstreamproblemslikeself-medicatingandfallingbehindinjobs,schools,andrelationships.Thereisaneednotonlyforsolutionsintheacutesettingbutalsoforsolutionsthataretranslatabletothecommunityandthedirect-consumersetting.Dr. Christopher T.Whitlow discussed the standard triage approach for TBI care using existing guidelines. Dr.Whitlownotedthatpatientsarecurrentlyimagedindiscriminately,butthismightnotbethemostcost-effectiveorappropriateapproach.Alternativewayssuchasgenetictesting,physicalexams,andbiomarkerscanreducethecost anddirect thepatients towardsmore effective treatments. For patientswithmild TBI, there is a lackofinfrastructuretomanagetheirsymptomsorevenconsidertherapeutics.Stratificationcouldhelpidentifypatientswhowillnotachieveoptimalrecoverywithtime.Preventionandmitigationofexposurearealsoimportantaspectsofcarethatshouldnotbeignored.Fromthemilitaryserviceperspective,Dr.ThomasDeGrabadiscussedtheneedtobetterunderstandthemildTBIpopulation. A more comprehensive, holistic approach to these patients is required to address their manyoverlapping symptoms. For severe trauma, there areprocesses inplace tomonitor compliance to guidelines;however,thefieldcurrentlylackstheabilitytomonitortheuseofguidelinesformildtraumaandforcommunityclinicians. By harnessing multiple disciplines, a treatment paradigm should combat multiple symptoms,consideringhoweachonemightimpactanother.Moreover,familymembersshouldbepartoftheprocessforapatient’streatmentandmanagement.AbigchallengeforVeteransisthattheyhavetwopersonas—oneinbattleandoneathome.InDr.DeGraba’sexperience,irritabilityisthenumberonesymptomthatVeteranssaytheywanttoaddress.KeyTake-Aways:TheconceptofimplementationneedstobeincludedineverydiscussiononTBItreatment.Thepanel discussed developing a composite understanding of all of the symptoms at the same time to create atreatmentparadigmthatputsintoplayatreatmentthatwillaffectthesymptomsasawhole,butthisinvolvesintegrativemedicineandacommonsetofstandardsandguidelinesthatmustbeimplementedacrossthemedicalspectrum.5) SessionTheme:NationalPriorities:GovernmentInvestment

Speakers: Stuart Hoffman, PhD, Scientific Program Manager for Brain Health and Injury at the USDepartmentofVeteransAffairs;PatrickBellgowan,PhD,ProgramDirector,RepairandPlasticity,NationalInstituteforNeurologicalDiseasesandStroke;CarlosPeña,Director,OfficeofNeurologicalandPhysicalmedicineDevices,OfficeofProductEvaluationandQuality,Center forDevicesandRadiologicalHealth,FDA;SaafanMalik,MD,DirectorofResearchandActingDeputyDivisionChief,DefenseandVeteransBrainInjuryCenterJ9-Research,DevelopmentDirectorate,DefenseHealthAgency

Sessiongoal:Toexploreportfolioinvestmentstodateandprioritiesbyinstitutions.Dr.StuartHoffmandiscussedgovernmenteffortsthathavefocusedonbraininjurymonthstoyearsafterthelastrecordedinsult.InresponsetoanExecutiveOrderin2011thatsetouttoprevent,diagnose,andtreatTBI,PTSD,andmental health conditions, the DoD, VA, Department of Health and Human Services, and Department of



EducationworkedtogethertodevelopaNationalResearchActionPlan(NRAP),whichformedanofficialcross-departmental relationship and announced larger projects in TBI, including longitudinal studies. Efforts by theChronic Effects of Neurotrauma Consortium, headed by Dr. Cifu and formed in response to the NRAP, haveincluded(1)alongitudinalstudyfocusedon1,800VeteransandServicememberswithcombat-relatedmTBI,(2)aretrospectivedatabaseoftwomillionVeteransusingelectronicmedicalrecordsfromtheDoDandVA,(3)sixadditionalprospectiveclinicalstudiesreviewedandapprovedbytheconsortium,(4)a long-termbasicsciencestudyofhumantau-producingmiceexposedtorepetitiveconcussions,and(5)thedevelopmentofadiffusion-tensorimagingphantomtostandardizeimagingplatformsforTBI.TheworkhasrevealedthatTBI,atanylevel,increases the risk of dementia, which is dose-dependent based on the intensity of injury. Dr. Hoffman alsodescribed correlations between chronic pain and TBI severity, among other examples. Finally, Dr. Hoffmandescribedotherfundinginitiativesincluding:(1)aVApreclinicalopen-fieldblastexposuresitethatfocusesonthechroniceffectsofblastinjury;(2)aBiomedicalLaboratoryResearchandDevelopmentcollaborativemeritreviewawardforTBItobringtogethernewideasandproposejointfundingtodevelopinnovativeresearch;(3)VA/Officeof Research and Development/Rehabilitation Research and Development special-emphasis areas, includingexoskeletonresearchforTBIandtheeffectofprolongedexposuretoopioidsonlong-termoutcomesfollowingTBI;and(4)clinicalstudiesongrowth-hormonereplacementinVeteranswithahistoryofmildTBI.Dr.PatrickBellgowangaveabroadoverviewonhowtheNIHfundsTBIresearchandprovidedexamplesofthreeinitiatives theyaremoving forward. TheNational InstituteofNeurologicalDisorder andStroke (NINDS) fundsbasic,translational,andclinicalresearchandtheNIHasawholehasmorethandoubleditsexpendituresonTBIinthelast10years,withincreasedfundingformildTBIandthechroniceffectsofheadtrauma.Asaninvestigator-driven institute, the science is driven by researchers. While there is still a majority of preclinical research,development of the Common Data Elements (CDEs), which align and standardize outcomes by allowingresearcherstousethesamedatameasuresandcomparedataacrossclinicalstudies,hasledtoanincreaseinclinical research opportunities; preclinical CDEs are also underway, aiming to improve communication,transparency, and rigor. One goal is to develop novel preclinical outcome measures for TBI that arepathophysiologicallyspecificandclinicallyrelevant,throughtheTranslationalOutcomesProjectinNeurotraumaConsortium.Biomarker studies are alsoabig focusofNINDS, including those in thediscovery, validationandclinicalutilityphase.Dr.CarlosPeñagavearegulatoryprimeronmedicaldevices.TheFDAaimstofindhigh-quality,safeandeffectivemedicaldevicesforpatients.TherehavebeenadvancesindiagnosticmedicaldevicesforheadinjurythathavegonethroughtheFDAprocess.Importantly,theFDAoffersguidancetohelpsponsorsthroughtheprocess.Pre-submission guidelines give anopportunity, at no cost, to obtain FDA feedback prior to InvestigationalDeviceExemptionormarketingsubmissions.MappingoutexpectationswiththeFDAearlycanhelpinvestigatorsmakemoreinformedandoptimaldecisionsalongtheway.Dr.SaafanMalikgaveanoverviewaboutprogramsandprioritiesforTBIattheDefenseHealthAgencyandDoD.Rather thanbeing investigator driven, theDoDuses a requirement-driven approach for funding. TheMilitaryHealthSystemisacomplexorganizationthataimsforacomprehensiveapproachtofindingsolutionsforTBI.TheDoDaimstobridgeresearchandclinicalgapsbyinvestinginfoundationalandclinicalresearchstudiesaswellasinproductandpolicyrecommendations.Theresearchinvestmentstrategyaddressesthehighest-priorityneeds,



and the aim is to see projects all the way through to the clinic, including training clinicians to adopt newapproaches.OneissuediscussedinthissessionwasthelackofconsensusondefinitionsforTBI.Currenteffortsinthefieldareworkingtowardsstandardizingdefinitions,allowingthemtobemoreprecise.TerminologyfromtheFDAcomesfromcommunicationwithresearchersandfindingconsensusinthefield;forindicationsforuse,theFDAbasesdefinitionsonhowtheywerestudiedinclinicalstudies.Collaborations between government groups has been successful, but industry investment is lagging for TBI.Initiativeswheregroupsarecomingtogethertoadvanceresearcharemakingprogress,suchastheNIHHelpingtoEndAddictionLong-Terminitiativesinthepainfield. Key Take-Away: Mild TBIs and their chronic outcomes have received increased attention from governmentfundingagencies.Onegoalistoincreasepartnershipswithotherfederalcolleaguesandmodernizethemanagingof the infrastructure. Becauseof the complexity, theremust be synergybetween thedifferentorganizations;bettercoordinationwillallowforimprovementsinresearchoutputandforumssuchastheSoSS.6) BreakoutWorkingSessionAll attendees participated in one of four working group breakout sessions, each led by SPCmembers and afacilitator.EachbreakoutsessioncenteredaroundoneoffourdomainsofTBI.Priortothemeeting,strawmansummariesofthestateofthescienceweredraftedforeachofthefourareasasatooltofacilitatetheworkinggroupdiscussions.Thegoalof theworking sessionswas to review, reviseandaugment these summariesandidentify any open questions. The SPC defined the agenda and questions to address throughout the workingsessions.Thesesmallbreakoutgroupsweretaskedwithsynthesizingthekeyconceptswithinthedomain,themaingapsinourknowledge,andthetoolsthatmightbeneededtoachievethisknowledge.ThediscussionsaresummarizedbelowandwereincorporatedintothemoreextensiveSoSSsummaries.

PreclinicalandTranslationalSciencegroup:LedbySPCmembersFionaCrawford,PhD,(RoskampInstitute)andStephenAhlers,PhD,(NavalMedicalResearchCenter)andextendedSPCmembersPatrickKochanek,MD,MCCM,(UniversityofPittsburgh),SusannaRosi,PhD,(UniversityofCalifornia,SanFrancisco),andDouglasSmith,MD,(University of Pennsylvania), and facilitated by Chantelle Ferland-Beckham, PhD, (CVB), the Preclinical andTranslationalSciencegroupdiscussedhowtousedatafrompreclinicalmodelstobetterinformappliedclinicalresearchinTBI,howtoassessthesemodelsandhowtostandardizepreclinicalmodelstostudymildinjury.Thegroupemphasizedthatbi-directionalcommunicationbetweenpreclinicalresearchersandtheclinicisimportant,asmodelsneedtorecapitulatehumanpatientphenotypes.Theyalsodiscussedharmonizingoutcomemeasuresbetweenanimalsandhumanstobetterunderstandwhatmightbeclinicallyrelevantandunderstandhowmodelscanbebetterusedtoinformclinicalresearchandviceversa.ThegroupalsohighlightedthatthechroniceffectsofmildTBIareunderstudied,especiallyinthepreclinicalfield.Comorbiditiesandpreexistingconditionsarenotyetmodeledinanimals.Thesestudiestaketimeandareabiginvestment.Overall,participantsfeltthatthemajorprioritiesinthefieldinclude:



1. Developingandaugmentingpreclinicalmodelsbasedonclinicalrelevance2. FocusingonchronicstudiesofmildTBI3. Focusingonmakingnegativedataavailableeitheraspublicationsorsearchableinadatabase4. Performingcross-speciesvalidationofphenotypes/models.5. Consideringunderstudiedvariableslikelossofconsciousness,age,sex,andcomorbidities

Biomarkersgroup:LedbySPCmembers JessicaGill, PhD,RN,FAAN, (National InstituteofNursingResearch),JamesStone,MD,PhD,(UniversityofVirginia),andElisabethWilde,PhD,(UniversityofUtah/GeorgeE.WahlenVASalt lakeCityHealthcareSystem),andextendedSPCmembersKimbraKenney,MD, (WalterReedNationalMilitaryMedicalCenter)andInaWanner,PhD,(UniversityofCalifornia,LosAngeles),andfacilitatedbyRajeevRamchand,PhD,(CohenVeteransNetwork),theBiomarkersgroupexaminedhowfluidbiomarkersmightadvancetreatmentdevelopmentandwhatstepsareneededtofacilitatedevelopmentofmorerobustbiomarkers.Idealbiomarkersshouldbesensitive,specificandselectivefororlinkedtobraininjury.Biomarkersshouldalsobesafe,characterized in biofluid dynamics, reproducible and relatively operational. Combining modalities will helpoptimizeand improve the careprovided topatientswithTBI. This group’s goalwas toparseoutbiomarkers,understand their dynamics and determine the best ways to use them for clinical development and care.Participantsfeltthatthemajorprioritiesinthefieldinclude:

1. Consideringthetimingofdataacquisitionandtimingoverthecourseofthepostinjurytrajectoryforbiomarkers

2. Harmonizingandstandardizingdataacrossdifferentplatformstoensurereproducibilityandqualitycontrol

3. Integratingmodalitieswithinthesamepatientsandatthesametimepoints4. Identifyingandintegratingconstellationsofrelateddatafromdifferentmodalitiestotargetspecific

patientpopulationsPatientPhenotypesandBiotypesgroup:LedbySPCmember JamshidGhajar,MD,PhD,FACS, (BrainTraumaFoundation; Stanford University School of Medicine) and extended SPC members Anthony Kontos, PhD,(UniversityofPittsburghMedicalCenter)andAdamFerguson,PhD,(UCSF)andfacilitatedbyLeeLancashire,PhD,(CVB), the Patient Phenotypes and Biotypes group evaluated the extent towhichmethods to enrich patientsubtypes(i.e.,cognitive,ocular-motor,headache/migraine,vestibular,andanxiety/mood)couldinformtreatmentdevelopmentandhowtobestcharacterizethesesubtypes.Thediscussionfocusedonpost-concussion,clinicallyprevalent impairments and symptoms, called clinical phenotypes. Setting, mechanism, age, gender and pre-concussionconditionscanallaffectoutcomesofTBI.Thegoalofthegroupwastoproposeaframeworkforanewclassification, bridging clinical phenotypes and biotypes and ultimately having more objective measures todevelopbiotypestoreplacephenotypes.Participantsfeltthatthemajorprioritiesinthefieldinclude:

1. Gatheringclinicallyrichpatientdatatocharacterizepatients,fromacutetochronic2. Understandingthenatureofcurrenttreatmentdelivery(educationandimplementation)3. Gainingevidenceforclinicalmeasuresthatrelatetoassessmentforspecificphenotypesforclinicaltrials

Clinical Trial Design group: Led by SPC members Grant Iverson, PhD, (Harvard Medical School; SpauldingRehabilitationNetwork)andDr.CifuandextendedSPCmembersLisaBrenner,PhD,ABPP,(VARockyMountainMentalIllnessResearchEducationandClinicalCenter),DavidWright,MD,(EmoryUniversitySchoolofMedicine),



MikeBell,MD,(Children’sNationalHealthSystem),RamonDiaz-Arrastia,MD,PhD,(UniversityofPennsylvania),Dr.Brody,andDonStein,PhD,(EmoryUniversitySchoolofMedicine),andfacilitatedbyTerryFrangiosa,(CVB),theClinicalTrialDesigngroupconsideredthecurrentbestpracticesofclinicaltrialdesignandrecommendationsforstrategiesforfutureimplementations.RatherthanviewingTBIasaunidimensionaldisorder,thefieldshouldfocusontreatmentsthathaveevidencetosupportefficacyforaparticularsymptomintendedforaspecificgroupofpatients.Thefieldshouldfocusontreatmentapproachesbeyondpharmaceuticals,suchasdevicesandlifestylechanges.Networktheorycouldinformclinicaltrialsbyclarifyingthearchitectureofthesymptomsandproblems.ClinicaltrialsshouldutilizebetteroutcomemeasuresforTBIthatfocusonspecificsymptoms.Participantsfeltthatthemajorprioritiesinthefieldinclude:

1. Establishinganinfrastructureforaclinicaltrialnetwork2. ImprovingknowledgegainedfromPhase2research3. Rather than treatingTBIasahomogenousdisease,developingspecificoutcomemeasures for specific

domainsinprecision-medicinetrials4. Improvingpost-hocanalysisofclinicaltrials5. Usingpatient-centeredoutcomesthatsolvetheneedofthepatients

Day27) SessionTitle:ReviewofDayOneDiscussions

Moderator:RetsinaMeyer,PhD,ScientificProgramManager,CVBSpeakers:LisaBrenner,PhD,ABPP,Director,VARockyMountainMentalIllnessResearchEducationandClinicalCenter;DouglasSmith,MD,RobertA.GroffProfessorOfTeachingAndResearchInNeurosurgeryPerelmanSchoolofMedicine,UniversityofPennsylvania;ElizabethWilde,PhD,AssociateProfessor,UniversityofUtahandGeorgeE.WahlenVASaltLakeCityHealthcareSystem;andMaryJoPugh,PhD,RN,ProfessorEpidemiology,UniversityofUtahandGeorgeE.WahlenVASaltLakeCityHealthcareSystem

Sessiongoal:TodiscusstheoverallconclusionsfromtheworkinggroupsonDay1. OnDay2oftheSoSS,aconversationalpaneldiscussionsummarizedthethemesfromtheworkinggroups.Thepanel includedonememberfromeachworkinggroup:Drs.Smith(PreclinicalandTranslationalScience),Pugh(PatientPhenotypesandBiotypes),Wilde(Biomarkers),andBrenner(ClinicalTrialDesign).Inadditiontolistingtheoverallconclusionsdescribedfromdiscussionsintheworkinggroups,thepanelistsdelveddeeperintogapsinthefieldandpossiblesolutionstofillthem.Respondingtoaquestionfromtheaudience,Dr.Smithdiscussedpossiblecriteriaforestablishingtranslationalvalidity.Hehighlightedthatimagingandbloodbiomarkerscouldprovideinformationinanon-invasiveway.Inaddition, he described developing the same type of outcome measures in animals and humans, such aselectroencephalography(EEG)orimaging.Thiswouldallowforimprovedharmonizationwithresearchersbeingabletomorereliablycompareanimalstohumans. Inresponsetoaquestionabout individualswholooksmildinitiallyandmayhaveadisablingconditioninthreemonths,Dr.Smithdiscussedwhyhavingamorefocusedtargetterm,suchasaxonalinjury,inflammation,focalcontusion,andvascularinjury,ismoreusefulinprognosticsratherthanusingscalessuchasmild,moderateorsevere.Hearguedthatweshouldtargettheunderlyingpathologyand



notthesymptomconditionoropinion.Dr.Smithalsonotedthatnosingleanimalmodelcanrecapitulatethelevelof complexity as observed in humans with TBI. Rather, models must emphasize different aspects of thepathophysiologyofTBI,whichwillsteerresearchersandcliniciansawayfrombroadterminologylike“concussion”and“TBI”.Finally,Dr.Smithfocusedonwaystoassessanimalmodelsmoredeeply,suchas(1)developingthesameoutcomemeasuresinhumansandanimalsand(2)improvingthegranularitywhendefiningphenotypes.Muchofthediscussionaroundbiomarkers,ledbyDr.Wilde,focusedonthetimingofthemarkersevaluatedandthedifferencesinthepatternandmagnitudeoverthecourseofrecovery.Inaddition,Dr.Wildediscusseddataharmonizationandstandardization.Thereisaneedtointegratemodalitiesinpatientpopulationsandtimepoints.Dr.Wildediscussedhowdatafromonemodalityisusuallydifficulttointegratewithotherdatasincetheymaynotcomefromthesamepointintime.Intheclinic,determiningprecisetimingcanbedifficultduetoimperfectpatientrecalloftheinjury,especiallyincaseswithlossofconsciousnessorinmilitarysettingswhetherthereisa“fogofwar”.Thesecircumstancescanalteranindividual’sperceptionofthepassageoftime.However,itmaynotalwaysbepossibletohavedatacollectedatthesametimepoint.Usingmathematicalalgorithms,itispossibletointegratethetimeandcontrolforittoperformthesamecorrelations.Thiscouldleadtobetterpredictionsoftheoutcomes.Inresponsetoquestionsaboutbarrierstopatientconsentingettingparticipantssoonafteraninjuryoccurs,Dr.Wildenotedthatcollectingdatafrompeopleverysoonafteraninjurycanbechallengingandexpensive,althoughit is possible. Recruiting patients in the emergency room, for example, is difficult because patientsmight beuncomfortableand/orwaitingforprocedures,orrecruitmentmaybedifficultduetothespecificlocationinwhichthepatientwassent.Nonetheless,researchershaverecruitedpatientswithin24hoursofaninjuryforbiomarkerandimagingstudies.Dr.Wildealsoemphasizedthattheriskhistoryofanindividual(e.g.,socioeconomicstatus,current/past residences, participation in sports) is important for biomarker development—some biomarkersmightbesensitivetoinjuriesonlyatacertaintimepointwhileotherbiomarkersmaydetectpasttraumaload.After listing the key points from the Patient Phenotypes and Biotypes group, Dr. Pugh discussed the lack ofconsensusaroundusingtwodifferentapproachestophenotyping:(1)usingadata-drivenapproachor(2)startingfromhumansymptomssuchasoculomotororcognitive.Dr.Pughalsonotedthatthereisalargegapinhowtobestphenotype;itisn’tmerelytheinjurythatisphenotyped,butalsothebackgroundofthepatient,includingexposuresandhistory,amongotherfactors.Thisargumentsuggestedthatmoredataarenecessarytophenotypepatients.Dr.Pughandtheworkinggroupemphasizedthatthereisaneedforclinicallyrichdatatocharacterizepatientsfromacutetochronic.Thiscouldbeaccomplishedbyusingdatafromelectronichealthrecordstoprovidea minimal dataset. Big data could also be leveraged to develop patient clusters; longitudinal analyses couldevaluatehowtheseclusterschangeover time.Dr.Pughnoted thatwith theclinical trials thatdidnotdeliverpositiveeffects,itwasunknownwhetherthiswasduetotreatmenteffectsorwhethertheeffectswereduetoenormoushomogeneouspopulationonwhichasmallportionofthesetrialsareeffective,butthesignalwastooweaktoemerge.Sheindicatedthatknowingwhattypeofcareishappeningbroadly,wecanphenotypeandbetterunderstandwhetherspecifickindsofcareleadtobetteroutcomesforspecificindividuals. Dr.Brenneremphasizedtheneedforaclinicaltrial infrastructure,similarto theNIHStrokenet(7), topreventresearchersfromhavingto“reinventthewheel”everytimetheyinitiateatrial.Thiswouldinvolvesupporting



anythingfromdesigntorecruitmenttodatacollectionandharmonizationacrosssites.AsecondareaofdiscussionwashowtoimprovetheknowledgegapgainedduringPhase2research,soitismoreapplicabletoPhase3trialsand how to have these trials runmore than one at a time. A third discussion areawas developing outcomemeasures for specific domains, aprecisionmedicine focus.Anaspectof this infrastructure couldalso includephenotypingofthepatientbase,whichwouldprovidearichreservoirofdatathatisaccessibletoclinicaltrials.Discussion centered on getting the field and funders to value replication asmuch as innovation and provideimportant clues from failed clinical trials. To increase efficiency, trials could run in tandem to test multipleinterventionsatatime.Afinalrecommendationwastoimprovethepost-hocanalysisofclinicaltrials.Perhapsmostimportantly,thefieldshouldusepatient-centeredoutcomestosolvethepressingneedsofthepatients.

SynthesisofWorkingGroups

Groupleadersconvenedafterthebreakoutsessionstosynthesizetheidentifiedgapsandprioritiesatahighlevel.Thegoalwastodetermineiftherewereanysimilarthemesacrossthegroupsorareasthatstoodoutasprioritiesforreviewwithallattendees.Fivemajorthemesemerged:

1. Timinga. Ageofinjuryb. Ageofsamplingc. Repeatinjuryd. Lifetime/cumulativeinjurye. Variableinjurytypef. Continualorfrequentdatacollection

2. Rigora. ImprovingknowledgegaininPhase2(e.g.,Bayesianmethods)b. Outcomes:Objectivequantifiablemeasures

3. DataStandardization,aggregation,harmonization/comparabilitya. Definition/metricsb. Objective/variablemeasuresc. Resurrectpriortrialdatad. Negativedatapublication/searchability

4. Patient/Subjecta. Disorderofinterestb. Phase2knowledgegainc. Outcomes–objectived. Endophenotypes/domainoffunctione. Phenotypicenrichmentinclinicaltrialsf. Patient-focuseddrugdevelopmentg. Precisionmedicine:preclinical,clinicaltrialdesign,biomarkers

5. Infrastructurea. Aclinicaltrialnetworkthatincludes:

i. Subtypesofpatientsii. Multipleoutcomesiii. Accessiblepatientpool



iv. Clearpipelines/pointsofengagementKeyTake-Away:Thefourworkinggroupsidentifiedseveral importantgapsintheTBIfieldthatarehamperingclinical development. The afternoonworking session’s goalwas to build on these gaps and begin to developprioritizedsolutions.8) SessionTitle:TBIPolicyUpdate

Speakers:RogerMurry,ExecutiveDirector,CoalitiontoHealInvisibleWounds

SessionGoal:TodiscusshowpolicycanaddressthenationalmentalhealthpriorityoffindingeffectivetreatmentsforPTSDandTBI.Founded in 2017, the Coalition to Heal InvisibleWounds (CHIW) aims to bridge Congresswith the Veterans’researchandtheclinicalcommunity.TheCoalition’sExecutiveDirector,RogerMurry,highlightedsomeof therolesoftheorganization, includingconsultingand lobbyingwithCongress.CHIW’smission istosecurefederalpolicyreformsthathelptodevelopnewtherapiesanddiagnosticsforVeteransdiagnosedwithPTSDandTBI.Theorganization’scurrentfocusistoboosttheVA’scapacitybyleveragingindustrypartnersandmakingtheprocessforclinicaltrialstartupattheVA100daysfaster.ThisinvolvesallowingtheuseofcommercialIRBs,speedingupthe information security review process and reforming the Research andDevelopment Committee. AlthoughCongresshasprovidedaccesstocareandboostedbasicresearchonTBIandPTSD,thereisanurgentneedtopivottothedevelopmentofnewtreatments.CongresshopestopreventVeteransuicidesandsolvethebrain-healthcrisis.AsfewinCongresshaveclinicalresearchexperience,organizationslikeCHIWcanbringforwardcompellingideas; once Congress receives a funding or statutory request, the Coalition sees this process through tocompletion.Mr.MurryprovidedanupdateonCongress’soutlookforTBI.In2018,CongresstookthreeactionsrelatedtoTBI:(1) passing the VAMISSIONAct,which requires the VA to set standards for provision of TBI care by non-VAproviders;(2)authorizingaone-yearVApilotprogramthroughtheNoHeroLeftUntreatedAct,whichprovidesaccesstomagneticEEG/electrocardiogram-guidedresonancetherapytotreatVeteranswithPTSDorTBI;and(3)passingtheTBIProgramReauthorizationActof2018,afive-year,$23MreauthorizationofCentersforDiseaseControlandPreventionprogramsfocusedondatacollectionandaccesstocare.For2019,twoprovisionsoftheCommanderJohnScottHannonVeteransMentalHealthCareImprovementActarebeingconsidered,includingdevelopingclinicalpracticeguidelines.Someof the issueson theCoalition’swatch list includedevelopingTBIresearchnetworks,pushingforacongressionalmandateforTBIresearch,updatingtheNationalResearchActionPlan,andenhancingdatasharingforTBI.KeyTake-Away:WorkingwithCongresstosecurefederalpolicyreformsisanimportantaspectofspurringthedevelopmentofnewtherapiesanddiagnosticsforVeteransdiagnosedwithPTSDandTBI.9) Session Theme: Advancing BrainHealth for TBI:QuantitativeNeuroimaging for PrecisionMedicine and

ClinicalTranslationintheLearningHealthcareSystem



Speaker:Dr.ChristopherTWhitlow,MD,PhD,MHA,ChairofAmericanCollegeofRadiologyHeadInjuryInstitute,DiagnosticRadiologistResearcheratWakeForestBaptistHealthHospital

Sessiongoal:TodiscussthecurrentstatusandfuturedirectionsoftheneuroimagingfieldwithrespecttoTBI.Dr.ChristopherT.WhitlowdiscussedtheroleofimaginginTBI.Histalkcenteredaroundthreemaintopics:(1)thecurrentstateofthescienceinimaging;(2)movingimagingforwardbyusingitasaquantitativetool;and(3)newandemergingtoolsforimagingthebrainandanalyzingandcomparingthesedatawithotherbiomarkers.Imaging is a large part of clinical practice,with non-contrast computed tomography (CT) being a first line ofimagingthatcanpredictmortalityandunfavorableoutcomesinthesepatients.Magneticresonanceimaging(MRI)maybeindicatedincaseswithnormalCTbutunexplainedneurologicfindings.Unfortunately,theseconventionalneuroimagingtechniquesoftenfailtodetectissuesforpatientswithsymptoms,especiallywhenpatientspresentwithmildinjuries;thisleadstothenecessityformoreadvancedmethodsthatmightidentifyabnormalitiesnotbeenseenonCT.Forinstance,MRIdiffusiontensorimaging,BOLDfunctionalMRI,MRspectroscopy,perfusionimaging,positronemissionstomography(PET)/SPECT,andmagnetoencephalography(MEG)canidentifychangesinthebraincomparedtoacontrolgroup.Thenextstepforthefield istodeterminewhat informationcanbeextractedfromthesedatathatmighthelpinclinicalpractice.Clinicianscouldtakeadvantageofthesedatasetstousequantitativeratherthanqualitativeapproachestopractice,whichallowclinicianstoextractandunderstandthesignals.Forexample,aqualitativeassessmentofaT1-weightedimagemayobserveamilddegreeofdiffusecerebralloss.Aquantitativereview,bycontrast,wouldinvolvebrainsegmentationtoquantifytheamountofgrayandwhitematterloss.Dr.Whitlow’sgroupisexploringquantitativeapproachestoMRI,suchascerebralbloodflowimagingandbrainfunctionalconnectivityandisdevelopinganormativepatientdataset.Forlongitudinaldata,thisapproachwouldonlyworkusingthesamescannereachtime.Downtheroad,phantomscannerset-upscouldhelpdecreasetheerrorbetweenscanners.Otherquantitativeapproachestargetendophenotypes;forexample,forcerebrovascularreactivity,researcherscanuseMEGtomeasureelectricalactivitytopulloutdefaultmodeactivity,assessdeltawaveswhichincreaseafterTBI,orchangesinsub-concussiveexposureinathleteswhoexperiencerepetitivehitstotheheadthatdonotreachthethresholdofconcussion.Toassessmolecularimaging,DrWhitlow’sgroupcanuse PET/CT and extract quantitative metrics from brain using specific ligands in an attempt to get at themechanism. Another way to improve the use of neuroimaging in the field of TBI – where patients areheterogeneous,havecomorbidities,andoftenshowsimilar symptomsas individualswithoutTBI– is toapplymethods like machine learning and artificial neural networks. Researchers can leverage advanced statisticaltechniques to separate groups that are similar. This could facilitate a big-data approach to identifying andstratifying subtypes for clinical trials. Finally, Dr. Whitlow discussed tools that should be validated againstbiomechanicalexposure,theimpactitself.Whiledifficulttomeasureexposure,therearedevicesthatcanbeusedtoassistcliniciansinthesetrials.Thiswillallowresearcherstoregressthebiomechanicaldataouttoshowthatasexposureincreases,thebrainchanges.Bylookingatanindividualparticipant,researcherscouldusethesetoolstoidentifytheregionofthebrainthathasthemostshearandstress.Thiscouldhelpstratifypatientsbasedonthelocationandmagnitudeofexposure.



KeyTake-Away: Theneuroimaging field is seeingmajor advances that couldprovidedeeper insights into TBIpatients.10) PanelDiscussion:R&DandRegulatoryChallengesPanel

Moderator:Dr.MagaliHaasSpeakers: Ronald L Hayes, PhD, Founder and Chief Science Officer, Banyan Biomarkers, Inc; StephenXenakis,MD,BrigadierGeneral(Ret.),USArmy,FisherWallaceLaboratories;WilliamSKorinek,PhD,CEO,Astrocyte Pharmaceuticals, Inc.; Rosina Samadani, PhD CEO, Oculogica; Michael E Singer, PhD, CEO,BrainScope Company, Inc.; Michael Hoffman, Deputy Director, Division of Neurological and PsychicalMedicineDevices,FDA

Sessiongoal:Toprovidereal-worldexperience fromregulatoryagenciesandentrepreneursontheregulatoryapprovalprocess.To begin the session,Michael Hoffman (FDA) offered important points for designing clinical tests ofmedicalproducts that are seeking FDA approval. The FDA primarily considers benefits and risks, looking for clinicallymeaningfulresults,durationoftreatment,andpreclusionofadditionaltherapies.ItisimportanttoworkwiththeFDAatanearlystagetoensurethatthestudydesigniswellthoughtout,includinginclusionandexclusioncriteria,interventionsandcomparators,endpoints,andapre-specifiedstatisticalanalysisplan.Studiesshouldhaveacleardefinition of the study population and co-morbid conditions. Mr. Hoffman noted that clinically meaningfuloutcomes require a diagnostic gold standard,which is lacking, but there also needs to be gold standards foroutcomemeasures. Mr. Hoffman also discussed that somemedical devices have been marketed directly toconsumersforconcussiondiagnosis,treatment,ormanagementwithoutFDAevaluation.Toprovidethepublicwiththebestandsafestadvice,theFDAhasputtogetheralistofcleareddevicesontheirwebsite.Several industry professionals discussed their experiences with the regulatory approval process for medicaldevices forTBI.RonaldL.Hayes,PhD, is the founderofBanyanBiomarkers, Inc.,which received the firstFDAclearanceforablood-basedbiomarkerthatcandistinguishbetweenmildandmoderateTBIattheacutephase.Dr.HayesnotedthatBanyanstarteditsprocessin2002;thus,thisprocesswasslowandexpensive.BanyanreliedonsupportfromtheDoD.StephenXenakis,MD,BrigadierGeneral(Ret.),U.S.Army,(FisherWallaceLaboratories)emphasizedthat2.8millionindividualshavebeensenttowar.Manyhavereturnedsufferingfrominjuriesthatwefailtotreat.Whileheknowsthescientistsareworkinghard,heemphasizedthatwearefailingourVeterans.Evenwithnewbiomarkers, there arenonewdiagnostic platformsor treatmentson thehorizons.He furtheremphasizedthatwecontinuetodebatethesameissuesabouttheclinicalchallenges.Dr.Xenakisarguedthatthemostimportantthingistothinkaboutthepatientsandfindwaystomaketheirlivesbetterinadditiontoworkingtounderstandingtheetiologyandtreatmentoptions.Dr.William S. Korinek emphasized that the fieldmust show progress and success in clinical trials to reduceskepticismandmakethefieldappealingagaintoindustryandventureinvestors.Dr.RosinaSamadaninotedthatdevelopingasoundbusinessmodeliskeytoconvincingfunderstosupportaproduct.Dr.MichaelE.SingeralsoemphasizedthatthebiggesthurdleforcompaniestoachieveFDAclearanceisfunding.Thecompanyhasseven



FDAclearancesfortheirEEGproduct,whichwasalongprocessthatrequiredrigorousclinicalstudiesandfunding.Furthermore,gettingFDAclearancewasonlythebeginningoftheroad.ManystepsarerequiredtoreachsuccessfollowingFDAapproval.Dr.Hayespointedoutsomeshort-termopportunitiestochangethemedicalpractice,suchascross-validatingexistingFDA-clearedtechnologiesasaquickpathtosecuringtheconfidenceneededtogettreatmentsintopracticetohelpTBIpatientslivetheirlives.ThepanelistsnotedthatTBIisthatfundingisamajorissueforTBI.TheynotedthatTBIhasareputationofbeingadeathmarchandthatitisverydifficulttoraiseventurecapital.Thesedifficultiesmakeitchallengingtoraisepublicfunds.However,pathstomovetherapeuticinnovationintotheclinicalspaceexist,butthereneedstobeprogressandapprovals.Collectively,thegrouphighlightedthebenefitofdevelopingagameplantoaddresstheproblemgiventhecurrentinformationandevaluatehowwecanusethatinformationtodevelopareasonablesetoftreatmentsandinterventions.Thepanelistshopedthattheircompanies’successesinprogressingthroughtheFDAregulatoryapprovalprocesswouldpavethewayforshorterandsimplerprocessesforothers.

KeyTake-Aways:Majorchallengescontinuetoimpederegulatorysuccess,includingthelackofgoldstandardsfordiagnostics,outcomesandfunding.Sciencediscoveryisjustoneaspectofensuringthatapatientreceivesanewtreatment;thespectrumofgettingaproductthroughregulatoryapproval,buildingasustainablebusinessmodel,marketingandeducatingclinicians,aswellasthepracticalityofthatprocess,areallbarrierstosuccess.11) WORKINGLUNCHBREAKOUTSAttendees broke out into four groups to reevaluate the state of the science and prioritize solutions for gapsidentified in Day 1. Several priorities emerged for the field of trauma-related research, including datastandardization,aggregation,harmonization/comparability,andrigor.Attendeesalsoaddressedtheneedforaninfrastructure fora clinical trialnetwork, the importanceofmakingpreclinical researchclinically relevantandimprovingthephenotyping/biotypingofpatients.Conclusionsofthebreakouts:

• Datastandardization,aggregation,harmonization/comparability,andrigoro AsectionofNIHgrantreportingcouldincludeashortversionofnegativedatao TheNIH couldmandate publishing ormaking available negative data, such as throughNIH E-

journalsfornegativefindings,BioArchive,orF1000o Standard operating procedures should be in place for preclinical research to ensure

reproducibilityinprotocols;thesecouldbepublishedinplacessuchasBioProtocolo Forneuroimaging,effortsshouldfocusondecreasingmeasurementerrorandvariabilityacross

devicestostandardizedatacollectiono Fundingshouldbeincreasedfordataanalysis/dataminingofexisting/soon-to-be-acquireddata,

as this couldbeanefficientway tomakeprogress.Forexample,CT images frompatientsareaccessible(aswellasmany legacybloodsamples)andcouldbeusedto identifysubcohortsofpatients

o Thereshouldbemorefocusongeneratingdatathatiscomparableacrossgroups,asitisdifficulttopooldatawhenithasbeenmeasuredindifferentwaysoratdifferenttimes



o Genetic approaches (e.g., genome-wide association studies) could help establish symptomclustersandprovideinformationaboutmechanisms

• Aninfrastructureforaclinicaltrialnetworko Thenetwork should apply principles fromother successful efforts, such as StrokeNet and the

NationalCancerInstituteo Thenetworkshouldincludeimaging,biostatisticsandbiomarkercoreso Aprimary focus shouldbequality assuranceonhow thedata ishandledand controlled,with

oversightbyagovernmentsteeringcommitteeo Thenetworkshouldincludeapatientandfamilycoreandrequireaplanforstakeholderso Implementationanddisseminationshouldbepartoftheclinicaltrialnetwork.Forinstance,the

networkshouldupdateclinicalpracticeguidelinesonayearlybasis,orasneededo Thenetworkshouldbeaccessibletojuniorinvestigatorsandincludeadiverseportfolioofhigh-

andlow-risktrialso The network could incorporate patient recruitment, where patients receive a battery for all

studiesaswellasstudy-specifictesting,helpingtogatherdata• Makepreclinicalresearchclinicallyrelevant

o A consensus statement should be developed on clinical correlates via an NINDS-sponsoredsymposiumonclinicalrelevancewithkeyopinionleaders;thiseffortwouldleadtoawhitepaperthatoutlinestheneedforaculturechangeandasetofrecommendationsfordeterminingtheclinicalrelevanceofagivenTBImodel

o Fundingagencies’grantapplicationscouldaddarequirementforinvestigatorstoclearlyoutlinetheclinicalrelevanceofamodelanddemonstraterigor/reproducibility

o Clinicians could consult on preclinical experimental design, and innovations in diagnostics inhumanscouldbebroughtbacktothepreclinicalspace

• Improvephenotyping/biotypingofpatientso Researchers should perform algorithmic assessment and clustering of patients based on this

clinicalassessmento Bigdatashouldbeleveragedtodescribetheseclustersbiologically;theseclusterscouldformthe

basisofpatientstratificationforselectioninclinicaltrialso ResearchersshouldconsiderlifetimeTBIandpharmaceuticalhistory(15%ofpeopleinVAsystem

areonfiveormoremedications)o Aretrospectivedata-analysisworkinggroupandaclinicalassessmentworkinggroupwouldbe

beneficial

12) SessionTheme:ClosingSessionCalltoAction

Speaker:RachelRamoni,DMD,ScD,ChiefResearchandDevelopmentOfficer,USDepartmentofVeteransAffairs

Sessiongoal:TodiscussthestrategicprioritiesoftheVAtohelpVeteransDr.RachelRamonidiscussedhowtheTBIfieldcouldworktogethertofillknowledgegaps.ShehighlightedtheimportanceofusingthemoneyinTBIresearchwisely.Thiscanbeaccomplishedbyimprovingtransparencyinthe



designandexecutionoftheresearch,avoidingsiloedwork,inwhichunderpoweredstudiesandredundancyarethenormandensuringthatnegativeandpositiveresultsofallwell-conductedstudiesaremadeavailableandreadilydiscoverable.Researchersneedtosetobjectivesandrelentlesslycoordinateandcollaboratetoaccomplishtheseobjectives, sharing informationandcreating thenecessary structures todo this. Finally, individualsandorganizationsshouldfocusontheareasinwhichtheycanbemostuseful.TheVAaimstoincreaseVeterans’accesstohigh-qualitytrials,increasethereal-worldimpactofVAresearch,andputVAdatatoworkforVeterans.Oneefforthasbeentodevelopanopen-blastcoreviatheTrumanVAtostudythechroniceffectsofblastinjury,whichincludes a world-class preclinical bioimaging center and a preclinical neurobehavioral center. Three strategicprioritiesmight include: (1) increasing Veterans’ access to high-quality trials; (2) putting VA data towork forVeterans;and(3)increasingthereal-worldimpactoftheresearch.Key Take-Aways: A coordinated effort among multiple TBI-focused public and private organizations will benecessarytoaddresstheprioritizedgapsdiscussedduringthesummit.TheVA iswillingtosupportpreclinicalknowledgegapsforTBIresearchandwillspearheadthecoordinationacrossorganizations.OVERALLCONCLUSIONSThesecondannualSoSSleveragedthebrainpowerofleadersacrossthebrainhealthspectrumandstrengthenedthecohesionofthescientific,clinical,andpatientcommunitieswithinTBIbybringingawarenessofglobalresearcheffortsandremovingsiloedapproachestoresearchthroughprovocativediscussionsdrivingtowardinnovation.Thesummit resulted inadocument that reviewedthestateof thesciencewithinspecificdomainsofTBIandproduced a strategic list of next steps for these areas.Working groupswillmeet to refine and further thesesummariesintoaspecialissueofapeer-reviewedjournal.Fromthiseffort,thebrainhealthcommunitywillhavea roadmap to guide and accelerate future translational research. Theseprioritieswill be sharedbroadlywithstakeholders to encourage adoption to inform TBI research, treatment, and funding initiatives and will bereassessedonaregularbasis.Theeffortwillbereviewedataregulatorcadenceasnewinnovationandtreatmentsariseaswellasbroadeningtheeffortacrossbrainhealth.

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Visits,Hospitalizations,andDeaths—UnitedStates,2014.CentersforDiseaseControlandPrevention,U.S.DepartmentofHealthandHumanServices,(2019).

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3. J.D.Corriganetal.,USpopulationestimatesofhealthandsocialoutcomes5yearsafterrehabilitationfortraumaticbraininjury.JHeadTraumaRehabil29,E1-9(2014).

4. L.D.Nelsonetal.,ValidatingMultidimensionalOutcomeAssessmentUsingtheTBICommonData

Elements:AnAnalysisoftheTRACK-TBIPilotSample.JNeurotrauma,(2017).5. D.L.Brody,L.Chan,G.Cizza,Howdoyoutreattraumaticbraininjury?Onesymptomatatime.Ann

Neurol86,329-331(2019).6. S.H.Siddiqietal.,RepetitiveTranscranialMagneticStimulationwithResting-StateNetworkTargeting

forTreatment-ResistantDepressioninTraumaticBrainInjury:ARandomized,Controlled,Double-BlindedPilotStudy.JNeurotrauma36,1361-1374(2019).

7. J.P.Broderick,Y.Y.Palesch,L.S.Janis,I.NationalInstitutesofHealthStrokeNet,TheNationalInstitutes

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