WELCOME TO DAY 2 OF UNDERSTANDING TBI IN WOMEN CONFERENCE. AND IT'S MY PLEASURE TODAY TO START US OFF WITH DR. JANINE CLAYTON, WHO'S THE DIRECTOR OF THE NIH OFFICE OF RESEARCH ON WOMEN'S HEALTH, AND THE NIH ASSOCIATE DIRECTOR FOR RESEARCH ON WOMEN'S HEALTH. DR. CLAYTON EARNED HER UNDERGRADUATE DEGREE AT JOHNS HOPKINS AND MEDICAL DEGREE AT HOWARD UNIVERSITY COLLEGE OF MEDICINE. SHE COMPLETED A RESIDENCY IN OPHTHALMOLOGY AT THE MEDICAL COLLEGE OF VIRGINIA AND FELLOWSHIP AT THE EYE INSTITUTE AT JOHNS HOPKINS HOSPITAL AND NATIONAL EYE INSTITUTE. HER RESEARCH INTERESTS INCLUDE AUTOIMMUNE OCULAR DISEASES, THE ROLE OF SEX IN GENDER, HEALTH AND DISEASE AND SHE'S THE ARCHITECT OF THE POLICY THAT REQUIRES SCIENTISTS TO CONSIDER SEX AS A BIOLOGICAL VARIABLE, WHICH WE HEARD ABOUT YESTERDAY, IN THE RESEARCH AND THE NIH EFFORT TO ADVANCE WOMEN IN SCIENTIFIC CAREERS. PLEASE WELCOME DR. CLAYTON. [APPLAUSE] >> GOOD MORNING, EVERYONE. ALL RIGHT, ALL RIGHT, AWESOME, AWESOME! CONGRATS TO ALL OF US BEING HERE AT 8:00 A.M., AND WELCOME TO THE SECOND DAY OF "UNDERSTANDING TRAUMATIC BRAIN INJURY IN WOMEN." AS YOU HEARD, I'M JANINE CLAYTON, DIRECTOR OF THE OFFICE OF RESEARCH ON WOMEN'S HEALTH, DELIGHTED TO BE HERE TODAY. I'M ALSO VERY GRATEFUL NOT FOR ONLY PARTICIPATING IN THIS CONFERENCE BUT THAT SUCH AN IMPORTANT CONFERENCE IS TAKING PLACE, AND THAT IT IS SO COMPREHENSIVE. NOT ONLY IN THE RANGE OF TOPICS THAT ARE BEING DISCUSSED TODAY, BUT ALSO FOR INCLUDING SO MANY WOMEN SPEAKERS PRESENTING ON OUR AGENDA TODAY. 15 OF OUR 25 PRESENTERS. COULD YOU IMAGINE THAT? WE'RE STILL HAVING PROBLEM WITH THAT TODAY. SO CONGRATS TO THE ORGANIZERS FOR HAVING SUCH A GREAT PANEL OF SPEAKERS. YES. [APPLAUSE] I AGREE. AS YOU MAY KNOW, THE OFFICE OF RESEARCH ON WOMEN'S HEALTH'S MISSION IS NOT JUST TO PROMOTE RESEARCH ABOUT HOW SEX AND GENDER CAN IMPROVE THE HEALTH OF WOMEN, BUT ALSO TO ADVANCE THE CAREERS OF WOMEN IN SCIENCE, AND I'M SO GLAD TO SEE THAT HAPPENING HERE. THIS WORKSHOP BRINGS TOGETHER MANY DIFFERENT STAKEHOLDERS TO LEARN ABOUT GAPS IN THE KNOWLEDGE BASE OF TBI. ONCE WE CAN IDENTIFY WHAT WE KNOW WE DON'T KNOW, WE CAN WORK ON FILLING THOSE GAPS. THAT IS WHAT THE AFTERNOON WILL BE ABOUT TODAY. AFTER LUNCH IS THE MOST IMPORTANT PART OF THE MEETING. WE GET TO HEAR BACK FROM YOU. PLEASE DON'T SKIP OUT ON THAT PART BECAUSE AFTER HEARING PRESENTERS TALK FOR A DAY AND A HALF, THIS IS YOUR CHANCE TO SPEAK OUT AND BE HEARD. IN THE BREAKOUT SESSION, LET US KNOW WHAT YOU THINK ARE THE KEY AREAS OF TBI RESEARCH TO FOCUS ON IN THE FUTURE. ARE THERE UNDERSERVED POPULATIONS OR GROUPS THAT YOU KNOW ABOUT, ARE THERE BETTER MODELS TO BE DEVELOPED, ARE THERE NOVEL TREATMENTS THAT SHOULD BE PURSUED? THEN PRIORITIZE THEM AMONG YOUR SMALL GROUPS AND THEN WE'LL RECONVENE AND EACH GROUP WILL REPORT OUT ON THEIR DISCUSSIONS. YESTERDAY WE GOT A GOOD LOOK AT THE LANDSCAPE OF TRAUMATIC BRAIN INJURY AND RESEARCH ACROSS THE LIFE COURSE AND ACROSS THE BIOMEDICAL RESEARCH SPECTRUM FROM PRE-CLINICAL TO CLINICAL STUDIES. WE LOOKED IN DEPTH AT TWO SPECIAL TYPES OF TBI THAT ARE CAUSED BY INTIMATE PARTNER VIOLENCE AND ALSO BY SPORTS INJURY. FOR THOSE WHO MISSED YESTERDAY, LET ME GIVE YOU A QUICK RECAP. FIRST I'D LIKE TO COMMEND ALL THE SPEAKERS, PERIOD, THAT ARE SO COMMITTED TO THIS IMPORTANT TOPIC, BUT ESPECIALLY THOSE THAT WERE AFFECTED BY THE BLACKOUT IN ATLANTA'S AIRPORT AND GAVE THEIR PRESENTATIONS VIA WEBEX. THANK YOU TO EVERYONE WHO HELPED MAKE THAT HAPPEN. DR. MARGARET MCCARTHY, JUMP STARTED MEETING, LAYING OUT A COMPREHENSIVE FRAMEWORK ON THE PURPOSE AND OBJECTIVES OF THIS CONFERENCE. SHE EXPLAINED ALL SEX DIFFERENCES ARE NOT CREATED EQUAL BUT IF YOU LOOK FOR A DIFFERENCE, YOU PROBABLY WILL FIND ONE. THE FIRST SESSION, SEX DIFFERENCES IN TBI ACROSS THE LIFESPAN, STARTED WITH AN OVERVIEW OF THE SEX DIFFERENCES IN THE INCIDENCE OF SEVERAL DIFFERENT CAUSES OF TBI DISAGGREGATED BY AGE BASED ON DATA FROM THE CDC. THIS SESSION LOOKED AT HOW TBI DIFFERS BETWEEN BOYS AND GIRLS WHO GET INJURED. SURPRISINGLY SHOWING THAT GIRLS PLAYING SOCCER ARE AT THE HIGHEST RISK FOR TBI, EVEN BEING AT HIGHER RISK THAN BOYS PLAYING FOOTBALL. THE LEADING CAUSE OF TBI IN FEMALES IN AGGREGATE IS FALLS, ESPECIALLY IN OLDER ADULTS. IN GENERAL, OVERALL FEMALES REPORT MORE NEURAL BEHAVIORAL SYMPTOMS AND DISABILITY. FOR EXAMPLE, AGE AND FEMALE SEX PREDICT PTSD6 MONTHS AFTER TBI. I'D ALSO LIKE TO GIVE SPECIAL THANKS TO DR. COLANTONIA FOR HIGHLIGHTING INFORMATION PROVIDED BY OUR OFFICE. IN SESSION 2, TBI AS A CONSEQUENCE OF INTIMATE PARTNER VIOLENCE, WE TOOK A GOOD LOOK AT A TOPIC THAT DESERVES MUCH MORE PUBLIC AWARENESS, AS WELL AS FURTHER RESEARCH. TBI IS NOT A BRUISE NESES NECESSARILY YOU CAN SEE ON THE OUTSIDE AND UNFORTUNATELY CLINICIANS DO NOT ALWAYS CONDUCT A WORKUP TO LOOK FOR WHETHER A TBI HAS OCCURRED, MISSING THE INTERNAL INJURY AND ONLY TREATING THE BLACK EYE THAT MIGHT BE VISIBLE ON THE OUTSIDE. WE LEARNED THAT IPV OR INTIMATE PARTNER VIOLENCE CAN HAVE LIFELONG CONSEQUENCES, INCLUDING DELETERIOUS EFFECTS ON BOTH LEARNING AND MEMORY. I SHOULD NOTE HERE THAT IPV IS AN IMPORTANT TOPIC FOR NIH. IN FACT, IN 2013, THE DEPARTMENT OF HEALTH AND HUMAN SERVICES CONVENED THE INTIMATE PARTNER VIOLENCE SCREENING AND COUNSELING RESEARCH SYMPOSIUM HERE AT NIH. THE REPORT OF THAT SYMPOSIUM IS AVAILABLE ONLINE ON OUR WEBSITE AND IS STILL VERY TIMELY. IT WAS PUBLISHED IN 2015 AS A SPECIAL SUPPLEMENT IN THE JOURNAL OF WOMEN'S HEALTH, AND SINCE 2015, NIH HAS SPENT APPROXIMATELY $31 MILLION PER YEAR TO FUND RESEARCH ON VIOLENCE AGAINST WOMEN. AND YESTERDAY WE HEARD THE RESULTS OF SOME OF THAT IMPORTANT WORK. IN THE THIRD SESSION, ""LOST IN TRANSLATION": SEX DIFFERENCES IN PRE-CLINICAL AND CLINICAL RESEARCH," WE SAW THAT HORMONES CAN BE INVOLVED IN BOTH RESPONSE TO TBI TRAUMA AND THAT PROGESTERONE IN FACT MIGHT EVEN AB TREATMENT FOR IT. WE LEARNED THAT UNFORTUNATELY MANY PHASE III CLINICAL TRIALS IN THE TBI SPACE HAVE NOT BEEN SUCCESSFUL. IN ORDER TO TRANSLATE SEX DIFFERENCES, THERE ARE CERTAINLY SEVERAL OBSTACLES TO BE OVERCOME INCLUDING BUT NOT LIMITED TO MORE RIGOROUS STUDIES THAT ADDRESS HETEROGENEITY OF MECHANISMS OF RESILIENCE, OF SEVERITY OF PATHOLOGY AND SO ON. INDEED ANIMAL MODELS SPECIFICALLY PORE SEEN MODELS CAN BE USEFUL AS A BRIDGE BETWEEN RODENTS AND HUMANS, BECAUSE THEY HAVE A HIGH DEGREE OF BIOLOGIC COMPLEXITY OF VARIABLES THAT ARE IMPORTANT IN THE STUDY OF TBI AND THEY PROVIDE AN OPPORTUNITY TO EVALUATE AND REFINE SURGICAL PROCEDURES PRIOR TO USE IN HUMANS. NEVERTHELESS, THERE ARE UNIQUE CHAL CHALLENGES TO TRANSLATING PRE-CLINICAL RESEARCH TO CLINICAL STUDIES FOR TBI IN PARTICULAR, INCLUDING CONSIDERING THE ROLE OF SEX HORMONES, ESPECIALLY IN SOME RODENT MODELS. SEX HORMONE LEVELS AT THE TIME OF TBI MAY BE A RISK FACTOR FOR OUTCOMES. FOR EXAMPLE, WOMEN WHO HAVE HIGH LEVELS OF PROGESTERONE AT THE TIME OF THE INJURY HAVE BETTER OUTCOMES THAN THOSE WHO HAVE HIGH LEVELS OF ESTROGEN AT THAT TIME, AND REPEATED CONCUSSIONS, WE KNOW, CAN CAUSE PITUITARY DYSFUNCTION. THE SILVER LINING IS THAT SOME RESEARCHERS ARE DEFINING WAYS TO IMPROVE ANIMAL RESEARCH ON TBI BY MODIFYING THE TYPICAL STRUCTURE OF A TRIAL USING MULTICENER ANIMAL TRIALS AND LARGER ANIMAL MODELS THAT CAN OVERCOME SOME OF THE CHALLENGES INHERENT TO RODENT MODELS. IN THE FINAL SESSION YESTERDAY, PERTAINING TO SEX DIFFERENCES IN SPORTS-RELATED CONCUSSION, PRIMARILY IN SCHOOL-AGED CHILDREN, WE SAW THE CONCUSSION RATES ARE HIGHER IN GIRLS IN ALL GENDER-COMPARABLE SPORTS SUCH AS SOCCER AND BASKETBALL. IN YOUNGER CHILDREN, BOYS DO REPORT MORE SYMPTOMS AFTER TBI-RELATED CONCUSSION WHEREAS IN TEENS, FEMALES REPORT MORE SYMPTOMS. PERHAPS BECAUSE WE ARE PUSHING OUR CHILDREN TO EXCEL AT YOUNGER AND YOUNGER AGES, THEY ARE EXPOSED TO POTENTIAL TBI-RELATED INJURIES IF ADEQUATE PRECAUTIONS ARE NOT TAKEN. TODAY WE HAVE ANOTHER EXCITING DAY PLANNED FOR YOU. ONE WITH FEWER TALKS BR MORE TIME FOR YOUR IMPORTANT PARTICIPATION IN PRIORITIZING THE NEEDS OF THE FIELD IN THE FUTURE. FIRST WE'LL LEARN MORE ABOUT SEX DIFFERENCES AMONG SERVICE MEMBERS, NOT ONLY ARE THOSE IN THE MILITARY EXPOSED TO WEAPONS AND SHRAPNEL AND VEHICLE ACCIDENTS, BUT ALSO TO BLAST INJURY AND HIGH DECIBEL LEVELS OF NOISE. HOW DO WOMEN AND MEN FAIR AFTER SUCH EXPOSURES? ARE COMORBIDITIES SAME IN THE MILITARY IN MEN AND WOMEN? WE'LL FIND OUT. IN THE NEXT SESSION, WE'LL HEAR MORE ABOUT SEX DIFFERENCES IN THE DIAGNOSIS, PROGNOSIS AND MANAGEMENT OF TRAUMATIC INJURY. AN OVERVIEW PERSPECTIVE WILL BE PROVIDED THAT IS RELEVANT TO ALL TYPES OF TBI TO HELP UNDERSTAND HOW SEX DIFFERENCES SHOW UP IN PROGNOSTIC MARKERS, INFLAMMATION AND IMAGING, AND IN OUTCOMES AND REHABILITATION RESULTS. AFTER LUNCH AGAIN, I URGE YOU TO PARTICIPATE IN THE BREAKOUT SESSIONS WE GET TO HEAR FROM YOU, THE SCIENTIFIC COMMUNITY. PLEASE LET US KNOW WHAT WE CAN DO TO BETTER INVESTIGATE AND UNDERSTAND TRAUMATIC BRAIN INJURY. BASED ON YOUR CONTRIBUTIONS, THE NIH WILL PREPARE A WHITE PAPER THAT DESCRIBES THE CONFERENCE, OUTLINES THE STATE OF THE SCIENCE AND IDENTIFIES FUTURE DIRECTIONS FOR RESEARCH. SO NOW HERE IS KATHRYN HELMICK, WHO WILL INTRODUCE OUR FIRST PANEL FOR TODAY. THANK YOU FOR YOUR ATTENTION. [APPLAUSE] MY NAME IS CATHY HELMICK, ACTING DIVISION HEAD FOR THE DEFENSE AND VETERANS BRAIN INJURY CENTER. WE'VEWE STARTED TALKING ABOUT PLANNING THIS MEETING BACK IN MARCH. VERY EXCITING TO HAVE THE FOCI ON UNDERSTANDING WOMEN IN TRAUMATIC BRAIN INJURY. SO THIS SECTION WE'RE TALKING ABOUT TODAY, THIS MORNING, IS GOING TO BE ON MILITARY PERSPECTIVE, SEX DIFFERENCES IN TBI AMONG SERVICE MEMBERS AND VETS RANS, AND VETERANS. IT'S MY PLEASURE TO INTRODUCE DR. SARA LIPPA, UNDERGRADUATE DEGREE AT UNIVERSITY OF VIRGINIA, GRADUATE DEGREE AT THE UNIVERSITY OF HOUSTON, SERVING AS NEUROPSYCHOLOGIST AT WALTER REID NATIONAL MILITARY MEDICAL CENTER. THERE SHE WORKS ON THE 15 YEAR CONGRESSIONALLY MANDATED STUDY EXPLORING THE NATURAL HISTORY OF TRAUMATIC BRAIN INJURY. DR. LIPPA? >> THANK YOU, CATHY. [APPLAUSE] SO THANK YOU SO MUCH FOR INVITING ME HERE TO TALK TODAY. I'M REALLY HONORED TO BE AMONG SUCH WONDERFUL SPEAKERS. TODAY I'M GOING TO START BY PROVIDING A BRIEF OUTLINE OF SOME OF THE DIFFERENCES BETWEEN MILITARY AND CIVILIAN TBI, TALK BRIEFLY ABOUT SOME OF THE DIFORTS IN STUDYING TBI IN FEMALE SERVICE MEMBERS AND VETERANS, BRIEFLY DISCUSS POST CONCUSSION SYMPTOMS AND WHY THEY MAY NOT BE THE BEST MEASURE OF OUTCOME, AND THEN SPEND MOST OF THE TIME TALKING ABOUT FOUR SPECIFIC STUDIES THAT HAVE LOOKED AT SEX DIFFERENCES IN POST CONCUSSION SYMPTOM REPORTING IN SERVICE MEMBERS AND VETERANS. ONE OF THE BIGGEST DIFFERENCES BETWEEN MILITARY TBI AND CIVILIAN TBI IS MANY MILITARY TBIs ARE THE RESULT OF BLAST INJURY. BLAST INJURY HAS BEEN DUBBED THE SIGNATURE INJURY OF RECENT WARS, LARGELY DUE TO THE INCREASED USE OF IMPROVISED EXPLOSIVE DEVICES. AND SOME HAVE POSITED THAT THIS UNIQUE MECHANISM OF INJURY MAY AFFECT THE BRAIN DIFFERENTLY THAN BLUNT FORCE TBI. HOWEVER, THERE HAVE BEEN NO CLEAR DIFFERENCES IN HUMAN STUDIES THAT SUGGEST NEUROIMAGING, COGNITIVE PERFORMANCE OR POST-CONCUSSIVE SYMPTOMS ARE DIFFERENT WHEN YOU LOOK AT THE PREPONDERANCE OF THE EVIDENCE. IMPORTANT TO NOTE, HOWEVER, BLASTS OFTEN OCCUR IN PSYCHOLOGICALLY TRAUMATIC SITUATIONS, SO PATIENTS WITH TBI SECONDARY TO BLAST INJURY LIKELY HAVE HIGHER LEVELS OF PTSD SYMPTOMS THAN PATIENT WHO SUSTAIN TBI SECONDARY TO NON-BLAST INJURIES. ADDITIONALLY, SERVICE MEMBERS ARE MORE LIKELY TO SUSTAIN THEIR INJURIES WHILE THEY'RE IN A FRAGILE PREMORBID STATE, SUCH AS BEING SLEEP-DEPRIVED OR DEHYDRATED, AND THEY'RE MORE LIKELY TO SUSTAIN THESE INJURIES IN CHAOTIC SITUATIONS WITH FEWER OPPORTUNITIES FOR DIAGNOSIS, TREATMENT OR REST. SO FOR EXAMPLE, IF YOU HAVE A SERVICE MEMBER WHO'S ENGAGED IN A FIREFIGHT, IT'S POSSIBLE THAT THEY'LL SUSTAIN A MILD TBI AND NO ONE WILL NOTICE. IT'S ALSO POSSIBLE THAT SOMEONE WILL NOTICE BUT THEY'RE UNABLE TO DO ANYTHING ABOUT IT BECAUSE THEY'RE LITERALLY MATTERS OF LIFE AND DEATH AT STAKE. ALSO IMPORTANT TO NOTE, THERE HAVE BEEN IMPROVEMENTS IN PROTECTIVE GEAR AND MEDICAL PROCEDURES IN RECENT YEARS. WHICH MEANS THAT MORE PEOPLE ARE SURVIVING MORE SEVERE INJURIES. THIS MEANS THAT THEY'RE MORE LIKELY TO HAVE OTHER SEVERE BODILY YOU THINK RES INJURIES AND MENTAL HEALTH ISSUES. MORE WOMEN THAN EVER ARE SERVING IN THE MILITARY. ABOUT 18% OF OFFICERS AND 16% OF ENLISTED PERSONNEL ARE WOMEN. AND WOMEN HAVE RECENTLY BEEN ALLOWED TO SERVE IN COMBAT ROLE, INCREASING THEIR RISK OF TBI. DESPITE THESE FACTS, VERY FEW STUDIES HAVE FOCUSED ON GENDER EFFECTS. MANY STUDIES EITHER EXCLUDE WOMEN OR INCLUDE ONLY A VERY SMALL PROPORTION OF WOMEN, 1 TO 2% OR LESS USUALLY. NOW WE'RE GOING TO SWITCH GEARS A LITTLE BIT AND TALK ABOUT POST CONCUSSION SYMPTOMS. WE TALKED ABOUT THIS A BIT YESTERDAY. BUT THESE ARE SELF-REPORTED SYMPTOMS LIKE SLEEP DIFFICULTY, HEADACHES, ANXIETY, MEMORY ISSUES, CHANGED APPETITE, POOR SLEEP, AND THEY CAN BE SEPARATED INTO FOUR CLUSTERS THAT WE'LL BE TALKING ABOUT IN THE STUDYS THAT WE DISCUSS LATER TODAY: COGNITIVE, AFFECTIVE, SOMATOSENSORY AND VESTIBULAR. SO LIKE I MENTIONED, POST CONCUSSION SYMPTOMS ARE SELF-REPORTED SYMPTOMS, WHICH MEANS THEY'RE SUBJECTIVE. SOME PEOPLE WILL TEND TO TELL YOU EVERYTHING THAT'S BOTHERING THEM, OTHER PEOPLE WILL TEND TO REALLY NOT REPORT MUCH AT ALL. AND INTENTIONAL OVER AND UNDERREPORTING IS AN ISSUE. SO SERVICE MEMBERS AND VETERANS SPECIFICALLY, OVERREPORTING CAN BE AN ISSUE IF PATIENTS WANT TO GET OUT OF THE MILITARY OR IF THEY WANT TO RECEIVE MORE COMPENSATION FOR THEIR INJURYIES, AND UNDERREPORTING CAN BE AN ISSUE IF PATIENTS WANT TO STAY IN THE MILITARY, THEY WANT TO STAY ON THE MISSION, STAY ON DEPLOYMENT OR GET PROMOTED. SO IT'S VERY IMPORTANT TO ASSESS BOTH OF THESE ISSUES. AND WE HAVE MANY MEASURES THAT CAN ASSESS SYMPTOM VALIDITY. ONE OF THESE WAS RECENTLY DEVELOPED THAT'S ACTUALLY EMBEDDED WITHIN A MEASURE OF POST CONCUSSION SYMPTOMS, THE NEUROBEHAVIORAL SYMPTOM INVENTORY. THIS IS CALLED THE VALID 10 SCALE. IT CONSISTS OF 10 ITEMS THAT ARE ALREADY GIVEN WITH THE POST CONCUSSION INVENTORY, AND YOU BASICALLY SUM UP THOSE SCORES ON THE 10 ITEMS AND WHETHER THAT TOTAL SCORE IS ABOVE OR BELOW THE CUTOFF TELLS YOU WHETHER YOU NEED TO BE CONCERNED ABOUT OVERREPORTING. IN ADDITION TO BEING SELF-REPORTED, POST CONCUSSION SYMPTOMS ARE ALSO SHOWN TO BE NONSPECIFIC, WHICH MANY SPEAKERS HINTED AT YESTERDAY. SO THEY'RE FREQUENTLY REPORTED IN PATIENTS WHO DO NOT HAVE TBI, BUT WHO DO HAVE BODILY INJURIES, CHRONIC PAIN, DEPRESSION. THEY'RE FREQUENTLY REPORTED IN HEALTHY COLLEGE STUDENTS, FINDING THAT 45% OF HEALTHY COLLEGE STUDENTS REPORTED FIVE OR MORE POST CONCUSSION SYMPTOMS. DEPENDING WHICH SYMPTOMS THOSE ARE, THAT COULD DEFINITELY BE ENOUGH TO MEET OFFICIAL CRITERIA FOR POST CONCUSSION SYNDROME. THEY'VE ALSO BEEN SHOWN TO BE UNRELATED OR WEAKLEY RELATED TO TBI SEVERITY AND NUMBER OF MILD TBIs, THINGS THAT WE MIGHT EXPECT TO AFFECT OUTCOME, AND THEY'VE ALSO BEEN SHOWN TO BE WEAKLEY OR ONLY MILDLY RELATED TO OTHER MEASURES OF OUTCOME, LIKE NEUROCOGNITIVE PERFORMANCE AND NEUROIMAGING. SO THIS IS A PIE CHART THAT KIND OF JUST DEMONSTRATES THE PERCENT VARIANCE EXPLAINED IN POST CONCUSSION SYMPTOMS. WE KNOW IN SERVICE MEMBERS AND VETERANS, POST CONCUSSION SYMPTOMS ARE MOST STRONGLY RELATED TO PTSD AND DEPRESSION, AND THIS STUDY FOUND THAT 45% OF THE VARIANTS IN POST CONCUSSION SYMPTOMS WAS EXPLAINED BY PTSD SYMPTOMS. MORE THAN 10 TIMES THE VARIANCE WAS EXPLAINED BY PTSD SYMPTOMS COMPARED TO INJURY VARIABLES. ANOTHER GRAPHIC THAT JUST SHOWS HOW MUCH PTSD AND POST CONCUSSION SYMPTOMS OVERLAP. THE MAJORITY OF THESE SYMPTOMS CAN BE EXPLAINED BY PTSD, NOT THAT THEY ARE, BUT IT IS SOMETHING THAT WE NEED TO CONSIDER. AND THE FIRST STUDY WAS PUBLISHED IN 2011 BY KATHRYN IVERSON AND COLLEAGUES, AND WE HEARD FROM KATHRYN YESTERDAY. THEY LOOKED AT THE MEDICAL RECORDS OF OVER 12,000 VETERANS WITH A HISTORY OF TBI, AND AFTER CONTROLLING FOR BLAST EXPOSURE, MECHANISM OF INJURY, AND DEMOGRAPHICS, FOUND THAT WOMEN WERE MORE LIKELY TO REPORT SEVERE OR VERY SEVERE POST CONCUSSION SYMPTOMS ACROSS ALL CLUSTERS, COGNITIVE, AFFECTIVE, SOMATOSENSORY AND VESTIBULAR. THEY WERE ALSO MORE LIKELY TO BE DIAGNOSED WITH DEPRESSION, CO-MORBID DEPRESSION IN PTSD, OR ALCOHOL-RELATED DISORDERS. SO OVERALL, THIS STUDY SHOWED THAT WOMEN WERE MORE LIKELY THAN MEN TO REPORT ALL POST CONCUSSION SYMPTOMS AND HAVE PSYCHOLOGICAL DIAGNOSES. IN 2013, KATHRYN IVERSON AND COLLEAGUES DID ANOTHER STUDY WHERE THEY MAILED SURVEYS OUT TO 6,000 VETERANS, HEARD BACK FROM OVER 2,000 VETERANS ABOUT HALF OF WHOM WERE FEMALE, AND SOME OF THESE PARTICIPANTS HAD A HISTORY OF TBI, SOME DID NOT. SO THEY EXAMINED SELF-REPORTED PSYCHOLOGICAL AND PHYSICAL HEALTH EVIDENCE, AND HOW MUCH TBI WAS ASSOCIATED WITH THESE OUTCOMES. SO IN THIS TABLE, THE ODDS RATIOS THAT THEY FOUND SHOWING THE ROW LAITION SHIP BETWEEN TBI AND THE SELF-REPORTED ANXIETY, PHYSICAL HEALTH, DEPRESSION AND ALCOHOL USE IN THE TOP ROW, IN FOUR DIFFERENT GROUPS WHICH ARE LISTED IN THE FIRST COLUMN. WOMEN AND MEN WITH AND WITHOUT PTSD. SO WHAT WE NOTICE WHEN WE LOOK AT THIS TABLE IS THAT TBI SIGNIFICANTLY PREDICTED CLINICALLY SIGNIFICANT ANXIETY AND PHYSICAL HEALTH SYMPTOMS IN ALL GROUP, IN WOMEN AND MEN WITH AND WITHOUT PTSD. IN WOMEN WITHOUT PTSD -- -- DEPRESSION AND ALCOHOL USE. IF WE LOOK AT THE STRENGTH OF THESE RELATIONSHIPS, WE SEE THAT IN WOMEN WITHOUT PTSD, TBI INCREASED THE ODDS OF ANXIETY BY ABOUT SIX TIMES COMPARED TO PATIENTS WITH -- COMPARED TO WOMEN WITHOUT PTSD WHO DID NOT HAVE TBI, BUT IN MEN WITHOUT PTSD, TBI ONLY INCREASED THE ODDS OF ANXIETY BY ABOUT TWO. IN WOMEN WITHOUT PTSD, TBI INCREASED THE ODDS OF DEPRESSION AND ALCOHOL USE BY ABOUT 2, BUT TBI HAD NO EFFECT ON DEPRESSION AND ALCOHOL USE IN MEN WITHOUT PTSD. AND FINALLY, IN WOMEN WITH PTSD, IT INCREASED THE ODDS OF ANXIETY AND PHYSICAL HEALTH ISSUES BY ABOUT FOUR OR FIVE TIMES COMPARED TO IN MEN WITH PTSD, WHERE TBI ONLY INCREASED THE ODDS BY ABOUT TWO OR THREE TIMES. SO WE SEE A GREATER IMPACT OF TBI ON SELF-REPORTED SYMPTOMS IN WOMEN COMPARED TO MEN. MORE RECENTLY IN 2017, OUR GROUP PUBLISHED A MANUSCRIPT LOOKING AT 86 WOMEN WHO WERE MATCHED TO 86 MALE SERVICE MEMBERS WITH A HISTORY OF MILD TBI DIAGNOSIS. SO WE BASICALLY TOOK ALL OF THE WOMEN IN OUR SAMPLE WHO MET INCLUSION CRITERIA SO THEY HAD MILD TBI WITHIN 10 YEARS POST INJURY, AND WE MATCHED THEM TO 86 OUT OF 3,000 MALES, SO WE WERE VERY CRITICAL OF HOW WE MATCHED OUR PARTICIPANTS. AND WE MATCHED THEM ON NINE VARIABLES CONSISTING OF DEMOGRAPHIC, INJURY-RELATED VARIABLES AND MILITARY-RELATED VARIABLES. WE FOUND THAT WOMEN REPORTED SIGNIFICANTLY MORE POST CONCUSSION SYMPTOMS AND MORE PTSD SYMPTOMS THAN MEN. WOMEN REPORTED -- HAD A HIGHER POST CONCUSSION SYMPTOM TOTAL SCORE, AS WELL AS HIGHER SCORES ACROSS ALL OF THE CLUSTERS. COGNITIVE, AFFECTIVE, SOMATOSENSORY AND VESTIBULAR. WOMEN HAD HIGHER SCORES ON 14 OUT OF 22 INDIVIDUAL POST CONCUSSION SYMPTOMS WITH THE LARGEST DIFFERENCES BEING IN NAUSEA, SENSITIVITY TO LIGHT, CHANGE IN TASTE AND SMELL, CHANGE IN APPETITE, FATIGUE AND POOR SLEEP. WOMEN ALSO HAD SIGNIFICANTLY HIGHER PCL SCORES THAN MEN, AND HAD HIGHER SCORES ON REEXPERIENCING AND HYPERAROUSAL DOMAINS, AND WOMEN HAD HIGHER SCORES ON SIX OUT OF 17 INDIVIDUAL PTSD SYMPTOMS WITH THE LARGEST DIFFERENCES BEING IN POOR CONCENTRATION, TROUBLE REMEMBERING A STRESSFUL EVENT AND DISTURBING MEMORIES, THOUGHTS OR IMAGES. AND JUST THIS YEAR, OR VERY RECENTLY, WE GOT THIS PAPER ACCEPTED THAT WAS VERY SIMILAR TO THE PRIOR STUDY. IN THIS STUDY, WE USED A HEAVILY OVERLAPPING SAMPLE OF FEMALES, WE MATCHED THEM ON NEW CRITERIA TO MALE SERVICE MEMBERS, ALL OF WHOM HAD A HISTORY OF MILD TBI. WE MATCHED ON FIVE VARIABLES: AGE, TBI SEVERITY, SO WHETHER THE PATIENT SUSTAINED ALTERATION OF CONSCIOUSNESS ONLY VERSUS POST-TRAUMATIC AMNESIA OR LOSS OF CONSCIOUSNESS, DAYS POST INJURY, BODILY INJURY SEVERITY, SO WHETHER THEY HAD NO OTHER BODILY INJURY OR MILD BODILY INJURY COMPARED TO THOSE WITH MODERATE OR SEVERE BODILY INJURIES, AND PTSD SYMPTOM SEVERITY AND CLASSIFICATION. SO NOT ONLY DID THEY VL PTSD HAVE PTSD OR NOT, BUT ALSO DID THEY HAVE PTSD OR NOT AND ALSO WHAT WAS THEIR TOTAL SCORE ON THE PCL. WE TRIED TO GET THAT WITHIN THREE POINTS OF EACH OTHER. ADDITIONALLY, ALL OF THE PARTICIPANTS PASSED THAT VALIDITY 10 MEASURE THAT I TALKED ABOUT EARLIER, SO THE BIGGEST DIFFERENCES BETWEEN THIS STUDY AND THE PREVIOUS STUDY WERE THAT WE RIGOROUSLY CONTROLLED FOR SYMPTOM VALIDITY AND PTSD SEVERITY. WE FOUND THAT PTSD EXPLAINED A SIGNIFICANT PROPORTION OF THE VARIANCE OF POST CONCUSSION SYMPTOMS WHICH WE WOULD EXPECT BASED ON THE LITERATURE. TBI SEVERITY AND BODILY INJURY WERE NOT SIGNIFICANTLY RELATED TO OVERALL POST CONCUSSION SYMPTOM REPORT WHICH WE WOULD ALSO -- I MEAN IT'S NOT TERRIBLY SURPRISING, BUT WHAT WAS SURPRISING WAS THAT GENDER WAS NOT SIGNIFICANTLY RELATED TO OVERALL POST CONCUSSION SYMPTOM REPORT. THIS HAS BASICALLY GONE AGAINST EVERYTHING WE KNOW IN THE MILITARY LITERATURE AND MOST OF WHAT WE SEE IN THE CIVILIAN LITERATURE AS WELL. WE DID FIND THAT WOMEN IN SOME GROUPS REPORTED MORE SOMATOSENSORY AND VESTIBULAR SYMPTOMS THAN MEN, SO WOMEN WHO DID -- SO IN PEOPLE WHO HAD PTSD, MORE MILD TBIs AND MORE SEVERE BODILY I THINK RES, WOMEN WERE REPORTING MORE SOMATOSENSORY SYMPTOMS THAN MEN. AND WHEN WE LOOKED ONLY AT PEOPLE WITH AOC ONLY, AND MINOR BODILY INJURIES, WOMEN IN THOSE GROUPS REPORTED MORE VESTIBULAR SYMPTOMS THAN MEN. WOMEN WERE NEVER MORE LIKELY THAN MEN TO REPORT COGNITIVE OR AFFECTIVE SYMPTOMS. SO WHAT WE CONCLUDED WAS THAT CONTROLLING FOR PTSD AND SYMPTOM VALIDITY RESULTED IN FEWER GENDER BASED DIFFERENCES IN POST CONCUSSION SYMPTOMS THAN PREVIOUSLY DEMONSTRATED IN THE LITERATURE. SO THIS IS JUST A SLIDE THAT SUMMARIZES THESE THREE STUDIES -- FOUR STUDIES, EXCUSE ME. BASICALLY WHEN PEOPLE LOOKED AT COGNITIVE, AFFECTIVE, SOMATOSENSORY AND VESTIBULAR SYMPTOMS, THEY ALWAYS FOUND THAT WOMEN WERE REPORTING MORE SYMPTOMS THAN MEN. HOWEVER, WHEN WE STRICTLY CONTROL FOR PTSD AND SYMPTOM VALIDITY, WE SEE THESE RELATIONSHIPS ARE AT10 WAITED. ATTENUATED. SO THE TAKE HOME POINTS AND RECOMMENDATIONS FROM THIS PRESENTATION, NUMBER ONE, DESPITE INCREASING INVOLVEMENT OF WOMEN IN THE MILITARY AND IN COMBAT ROLES, MANY MILITARY STUDIES EXCLUDE OR INCLUDE ONLY A VERY SMALL PROPORTION OF FEMALES. WE NEED MORE STUDIES TO FOCUS ON FEMALE SERVICE MEMBERS AND VETERANS IF WE WANT TO UNDERSTAND FEMALE SERVICE MEMBERS AND VETERANS INVOLVING TBI. NUMBER TWO, POST CONCUSSION SYMPTOMS ARE SUBJECTIVE AND NONSPECIFIC. IF WE'RE GOING TO SPEND ALL THIS TIME AND ENERGY STUDYING OUTCOME FOLLOWING TBI, WE SHOULD PROBABLY BE FOCUSING ON OBJECTIVE MEASURES OF OUTCOME THAT ARE SPECIFIC TO TBI. IT'S IMPORTANT TO NOTE THAT THE FIRST THREE STUDIES IN THIS AREA DO SUGGEST THAT WOMEN REPORT MORE COGNITIVE, AISKTIVE, SOMATOSENSORY SYMPTOMS THAN MEN WHICH SL CONSISTENT WITH THE LITERATURE, HOWEVER, WHEN WE CONTROL -- WITH ONLY SOME WOMEN REPORTING MORE SOMATOSENSORY AND VESTIBULAR SYMPTOMS THAN MEN, AND WOMEN NOT REPORTING MORE COGNITIVE OR AFFECTIVE SYMPTOM THAN MEN. SO WHEN WE DO ASSESS POST CONCUSSION SYMPTOMS AND OTHER SELF-REPORTED OUTCOMES, IT'S REALLY IMPORTANT THAT WE CONTROL FOR PTSD AND SYMPTOM VALIDITY. THAT'S ALL VI. THANK YOU SO MUCH. [APPLAUSE] >> NEXT WE HAVE DR. ODETTE HARRIS FROM STANFORD UNIVERSITY. DR. HARRIS IS CURRENTLY AN ASSOCIATE PROFESSOR OF NEUROSURGERY AT STANFORD UNIVERSITY SCHOOL OF MEDICINE AND DIRECTOR OF BRAIN INJURY FOR STANFORD MEDICAL CENTER. SHE MANAGES AND COORDINATES THE MEDICAL AND SURGICAL CARE OF ALL PATIENTS SUFFERING FROM TRAUMATIC BRAIN INJURY AS THEY ARE ADMITTED TO THE STANFORD SYSTEM. SHE'S ALSO THE ASSOCIATE CHIEF OF STAFF, REHABILITATION AT THE VETERANS AFFAIRS PALO ALTO HEALTHCARE SYSTEM AND THE SITE DIRECTOR AND PRINCIPAL INVESTIGATOR FOR THE DEFENSE AND VETERANS BRAIN INJURY CENTER. IT'S MY PLEASURE TO INTRODUCE DR. HARRIS. [APPLAUSE] >> HI. GOOD MORNING. AND THANK YOU FOR HAVING US. THIS IS A WONDERFUL FORUM AND SO EXCITED TO BE PART OF IT. ONE OF THE BEST THINGS ABOUT GOING ON THE SECOND DAY IS THAT MUCH OF WHAT I HAVE TO SAY HAS BEEN SAID AND PROBABLY MORE ELOQUENTLY, SO IT WILL BE FUN, SO I'LL SKIP THROUGH SLIDES THAT DON'T REALLY SEEM AS RELEVANT AS THEY MIGHT HAVE WHEN I WAS PREPARING MY SLIDES, BUT ANYWAY, THANK YOU SO MUCH. I'M GOING TO TALK TO YOU TODAY ABOUT GENDER AND THE EFFECTS OF POLYTRAUMA, BRIEFLY INTRODUCING THE POLYTRAUMA SYSTEM OF CARE WHICH SOME MIGHT NOT BE FAMILIAR WITH, THEN GO RIGHT INTO GENDER AND THE EFFECTS IN MULTI-TELL DIFFERENT REALMS AND HOPEFULLY CONCLUDE WITH JUST A TOUCH OF DISCUSSION OF BRAIN AND BEHAVIOR RELATIONSHIP. I HAVE NO RELEVANT DISCLOSURES, ACTUALLY NO DISCLOSURES AT ALL. SO IN THE BEGINNING, I LIKE TO SHOW THIS SLIDE TO SAY THAT WHEN WE ENTERED INTO THE CONFLICT, OUR UNDERSTANDING OF BRAIN INJURY IN THE CONTEXT OF BLAST REALLY DIDN'T EXIST, AND SO IT'S NOT UNUSUAL THAT A CONFERENCE LIKE THIS, WHEN WE'RE TALKING ABOUT WOMEN OR EVEN MEN, WOULD NOT REALLY HAVE EVEN OCCURRED. THERE WAS REALLY LITTLE THAT WE UNDERSTOOD. OUR GENERAL REHABILITATION UNIT LOOKED MUCH LIKE THIS VERY ISOLATED, AND BRAIN INJURY WAS VERY ISOLATED IN HOW WE APPROACHED THE MANAGEMENT. THEN, OF COURSE, THE CONFLICTS OCCURRED AND AS SOMEONE -- THE PREVIOUS SPEAKER NOTED TOO, WE BECAME -- TBI BECAME THE SIGNATURE INJURY OR WOUND OF THE CONFLICTS, AND IT WAS EVERYWHERE. EVERYONE WAS NOW CONCERNED ABOUT IT. THIS LED TO, I THINK, A VERY COMPREHENSIVE RESPONSE BY OUR GOVERNMENT IN TRYINGS TO PROVIDE TRYING TO PROVIDE THE BEST POSSIBLE CARE. IF WE CENTRALIZED FOR CARE AND ALLOWED EXPERTISE TO DEVELOP, THIS WOULD PROBABLY BE THE BEST APPROACH SO IT EVOLVED UNDER THIS CONSTRUCT. INTERESTINGLY WHEN I INTRODUCE THE TERM, PEOPLE LOOK AT ME LIKE I'M FROM MARS AND I HAVE TO REALLY SORT OF EXPLAIN. THE TERM WAS COOPTED -- WELL, SINCE WE'RE AT A GOVERNMENT INSTITUTE, WE'LL SAY THE TERM WAS REAPPROPRIATED, BORROWED? [LAUGHTER] BUT IN ANY CASE, THE TERM AS MANY PEOPLE REFER TO IT IN THE GENERAL NEUROSURGICAL LITERATURE AND THE GENERAL LITERATURE IS THAT REPRESENTS MULTIPLE INJURIES, RIGHT? BUT IN THE CONTEXT OF THE MILITARY, THE DOD AND THE V.A., THE TERM POLYTRAUMA SPECIFICALLY REFERS TO A BRAIN INJURY OR THE PRESENCE OR ASSUMPTION OF A BRAIN INJURY IN THAT THE RECOVERY WILL BE DRIVEN LARGELY BY THE PRESENCE OF THAT OR AGAIN THE ASSUMPTION OF THAT. SO THE CENTERS WERE DEVELOPED AND EXPANDED TO FOCUS ON THAT, SO YOU HAD THE COMPREHENSIVE REHABILITATION CENTER, TRANSITIONAL UNIT, EMERGING CONSCIOUSNESS PROGRAMS AND CONSTELLATION OF OUTPATIENT NETWORKS FOCUSED ALL ON THE MANAGEMENT OF TRAUMATIC BRAIN INJURY. AGAIN, THE MISSION WAS DRIVEN SPECIFICALLY ON PROVIDING SERVICES, COMPREHENSIVE LIFELONG SERVICES AGAIN FOCUSING BY -- FOCUSED ON THE TRAUMATIC BRAIN INJURY ITSELF. SO WE EVOLVED INTO SOMETHING THAT LOOKED MUCH LIKE THIS, WHICH WAS A WHOLE NETWORK OF CLINICS AND CENTER, ET CETERA, ALL FOCUSED ON DELIVERING CARE AROUND TRAUMATIC BRAIN INJURY. PALO ALTO WAS ONE OF THOSE SITES THROUGH GEOMAPPING, ET CETERA, THAT WAS DESIGNATED, SO THAT'S HOW WE HAVE BOTH THE DVBIC CENTER, POLYTRAUMA CENTER AND A LOT OF OUR WORK ON TRAUMATIC BRAIN INJURY. OUR REHAB UNITS CHANGED DRAMATICALLY AS A RESULT OF THIS AS WELL AND BECAME SORT OF WAY MORE COMPREHENSIVE IN HOW WE APPROACHED AND I THINK OBVIOUSLY WAY BETTER. WE NOW TREAT THE PATIENT AS A WHOLE. WE'VE COME TO RECOGNIZE THAT TRAUMATIC BRAIN INJURY CANNOT BE ADDRESSED JUST IN SILO AND MULTIPLE DIFFERENT AREAS HAVE TO BE ADDRESSED IN ORDER TO FULLY TAKE CARE OF THESE PATIENTS. SO TRAUMATIC BRAIN INJURY RIGHT AROUND THE TIME I ACTUALLY MOVED TO PALO ALTO BECAME SORT OF THE "IT" THING TO STUDY, ESPECIALLY IN THE CONTEXT OF CONFLICTS. SO A GAZILLION AMOUNT OF PAPERS RESULTED AND EVERYONE WANTED TO STUDY THIS, IT WAS SORT OF A VERY FASCINATING, VERY INTERESTING, ET CETERA. MUCH OF WHAT WE WERE DOING AT OUR INSTITUTIONS WAS BUILT ON A LOT OF THIS LITERATURE. RIGHT? HOW WE MANAGED THESE PATIENTS, HOW WE THOUGHT ABOUT THESE PATIENTS. AS YOU KNOW, RESEARCH BEGETS RESEARCH. SO THESE STUDIES LED TO MORE STUDIES THAT SORT OF PILED OP EACH OTHER. THE QUESTION THAT I HAD, YOU KNOW, IN LOOKING AT THIS FROM THE OUTSIDE WAS, WHAT ARE WE LEARNING ABOUT THESE PATIENTS? SO WE WERE LEARNING THAT THE MAJORITY WERE MILD, MOST OF THE PUBLISHED RESEARCH, HOWEVER, WAS FOCUSED ON MALE, AND IF YOU LOOK AT ALL OF THIS DATA IN AGGREGATE, THE META-ANALYSIS THAT WAS DONE, YOU WILL FIND THAT IT WAS REALLY LARGELY DESCRIPTIVE AND, AGAIN, MOST OF THE STUDIES HAD 80 TO 100% OF WOMEN, SO SOME EVENTUALLY EXCLUDED WOMEN IN ITS ENTIRED. WE LEARNED THE PREVALENCE, WE LEARNED OTHER THINGS IN TERMS OF THE POST-CONCUSSIVE SYMPTOMS, A LOT OF WHAT WAS ALREADY STATED, WE LEARNED A LOT ABOUT WHAT THE UNEMPLOYMENT RATES WERE, ET CETERA, AND THESE STU DUS STUDIES ENDED UP PROVIDING A BROAD DESCRIPTION OF THE NEEDS OF THE COHORT AS A WHOLE, AND WE WERE SUPPOSED TO USE THIS TO DRIVE OUR TREATMENT AND OUR SERVICES. THEN IT OCCURRED TO US THROUGH A SERIES OF QUESTIONS, SOME OF WHICH WE'LL GET TO, BUT ARE THESE CONCLUSIONS APPLICABLE TO EVERYBODY? AND MORE SPECIFICALLY, ARE THESE CONCLUSIONS APPLICABLE TO WOMEN? SO WE'RE TAKING THE PLETHORA OF INFORMATION, WE'RE SYNTHESIZING IT AND WE'RE SAYING, THIS IS HOW WE SHOULD MANAGE THE POLYTRAUMA COHORT. AGAIN, THESE STUDIES, THOUGH, EXCLUDED WOMEN, RIGHT? SO A LOT OF THEM HAD VERY LITTLE WOMEN OR NO WOMEN AT ALL, AND SO THE QUESTION WAS, IS IT CONCEIVABLE, IS IT POSSIBLE, IS IT ACTUALLY ACCURATE TO THEN GENERALIZE THE TREATMENT TO WOMEN AND OTHER SUBGROUPS? SO IS THIS QUESTION EVEN VALID? SO WE TAKE YOU TO A HISTORICAL PERSPECTIVE, THIS IS NOT NEW IN SCIENCE. THE FRAMINGHAM HEART STUDY, MANY CLINICIANS IN THIS ROOM ARE VERY FAMILIAR WITH THIS. THIS IS A HALLMARK LONGITUDINAL STUDY STARTED IN THE 1940s, IT IS THE STUDY BY WHICH EPIDEMIOLOGY AND THE TERM OF RISK FACTOR BECAME COMMON TERM IN MEDICINE. TODAY IT'S IN ITS THIRD GENERATION, OVER 1,000 PUBLICATIONS HAVE COME FROM THIS, AND ANYONE WHO'S A CLINICIAN HAS PROBABLY USED SOME OF THE RESULTS OF FRAMINGHAM STUDY TO INFUSE THE MANAGEMENT OF THEIR PATIENTS. BUT THE FRAMINGHAM STUDY WAS INTERESTINGLY ENOUGH COMPLETELY UNREPRESENTATIVE OF THE AMERICA WE TREAT TODAY, JUST LIKE PERHAPS THESE STUDIES ARE EXREETLY ARE COMPLETELY UNREPRESENTATIVE OF THE MILITARY TODAY. FRAMINGHAM CONSISTS OF WHITE EURO AMERICANS, THERE WERE NO BLACKS, LATINOS OR ASIANS IN THIS STUDY, YET WE THEN TRANSLATED A LOT OF THE RECOMMENDATIONS FROM THE STUDY INTO THESE POPULATIONS, SOME OF WHICH, BY THE WAY, WERE DELETERIOUS. FOR INSTANCE, IF YOU LOOK AT ANTIHYPERTENSIVE MANAGEMENT THAT CAME OUT OF FRAMINGHAM, WHEN APPLIED TO THE AFRICAN-AMERICAN COMMUNITY, IT WAS ACTUALLY DELETERIOUS TO THAT POPULATION, BUT PEOPLE WERE LIKE, WELL, THIS IS THE LANDMARK STUDY, THIS IS THE STUDY. LIKE, THE FACT THAT YOUR BODY IS NOT RESPONDING TO THIS THERAPY, MAYBE SOMETHING'S WRONG WITH YOU. WELL, NO, ACTUALLY SOMETHING IS WRONG WITH THE STUDIES AND HOW WE'RE APPLYING THAT, AND THE FACT THAT NOBODY ACTUALLY STOPPED TO ACTUALLY SAY, WAIT A SECOND, IS THIS REPRESENTATIVE OF OUR COHORTS? AND SO WE TRIED TO WRITE THAT -- RIGHT THA T HISTORICAL WRONG WITH THE NEW FRAMINGHAM STUDY, BUT AS YOU KNOW SOMETHING THAT IS ON THE FRONT PAWJ AND CORRECTED ON PAGE 6, VERY F EW PEOPLE KNOW ABOUT THAT, SO NOW THERE WERE STUDIES LOOKING AT SUBCOHORTS NOT CAPTURED IN THE FRAMINGHAM STUDY TRYING TO SAY HEY, WE DIDN'T DO IT CORRECTLY THE FIRST TIME, SHOULD WE DO IT DIFFERENTLY. SO I ACTUALLY DIDN'T WANT US AS A POLYTRAUMA SYSTEM OF CARE TO GO DOWN THAT SAME RABBIT HOLE WHERE WE'RE MAKING RECOMMENDATIONS, MAKING ALL OF THESE TREATMENT DECISIONS, ET CETERA, BASED ON STUDIES THAT MIGHT NOT, IN FACT, BE REPRESENTATIVE OF THE COHORT IN GENERAL. SO OUR QUESTION WAS, HOW VALID ARE THE TREATMENT RECOMMENDATIONS THAT WE'RE MAKING? AND IS THERE BIAS? WE KNOW AS THE PREVIOUS SPEAKER TALKED ABOUT, SO I'LL SKIP THROUGH MUCH OF THE SLIDES, THAT WOMEN ARE MUCH MORE PREVALENT IN THE MILITARY NOW AND THAT THEY DO HAVE UNIQUE STRESSORS, WE SEE THE TRENDS GOING FORWARD MORE AND MORE, AND AT PALO ALTO, WE ACTUALLY HAVE A LARGER PERCENTAGE THAN THE NATIONAL NUMBERS, ABOUT 6% OF OUR SERVICE MEMBERS ARE WOMEN. WE DECIDED TO ASK THE QUESTION THROUGH GENEROUS FUNDING, THROUGH THE DEFENSE AND VETERANS BRAIN INJURY CENTER, THREUM THROUGH OUR POLYTRAUMA CENTERS, AND THE LARGEST GENDER BASED INSTITUTE OR THE OLDEST, RATHER, AT STANFORD. WE HAD A VERY, VERY, VERY SIMPLE HYPOTHESIS: DO THE DATA REPRESENT WOMEN? THAT'S IT. LIKE, THE DATA THAT EVERYONE IS USING, EVERYONE IS TALKING ABOUT, EVERYONE IS MANAGING PATIENTS ACCORDINGLY, DO THOSE DATA ACTUALLY REPRESENT WOMEN, AND ARE WOMEN'S EXPERIENCE DIFFERENT THAN WHAT IS PRESENTED IN THIS DATA. AND SO WHAT WE DECIDED TO DO WAS TO TAKE ALL OF THIS INFORMATION THAT WAS OUT THERE, AND THEN TO TAKE THE WOMEN COHORT IN PALO ALTO, AND TO JUST DO A VERY SIMPLE COMPARISON. AND OF COURSE AS YOU KNOW, WE HAVE LIFELONG DATA, THE V.A. IS AMAZING IN TERMS OF INFORMATION, SO WE COLLECTED THIS INFORMATION AND WE WANTED TO EVALUATE APPLES TO APPLES SO WE LOOKED IT AT ALL THE SAME DOMAINS IN THE LITERATURE SO WE COULD COMPARE OUR COHORT TO THAT. SO THIS WAS THE GENERAL COHORT IN THE LITERATURE AS REPRESENTED AND THIS IS THE V.A. WOMEN COHORT THAT WE THEN COMPARED, AND AGAIN, WE'RE ONE OF THE -- AT THE TIME, ONE OF FOUR, NOW ONE OF FIVE POLYTRAUMA SITES. AND WHAT WE FOUND WAS THAT WOMEN IN OUR COHORT, IN GREEN YOU'LL SEE, TEND TO BE BETTER EDUCATED THAN THE MEN THAT WERE REPRESENTED IN THE GENERAL COHORT IN THE LITERATURE, BUT THEY WERE MORE LIKELY TO BE UNEMPLOYED, MORE LIKELY TO BE HOMELESS, RIGHT, AND INTERESTINGLY ENOUGH, PERCENTAGE-WISE, 50%, THEY WERE LESS LIKE TO HAVE SUFFERED BLAST INJURY, SINCE THEY WERE NOT AT THAT TIME IN COMBAT-RELATED POSITIONS. AND SO THIS IS SORT OF WHAT WE FOUND, WHICH WAS INTERESTING, AND THEN WE LOOKED AT THE PSYCHIATRIC DIAGNOSES AND WHAT WE FOUND AGAIN WAS THAT WOMEN ACTUALLY DID WORSE ON ALL OF THE DOMAINS REPRESENTED THERE IN COMPARISON TO THE GENERAL COHORT WHICH WAS IN THE PUBLISHED LITERATURE. EVERYONE WAS VERY EXCITED ABOUT PTSD IN THE LITERATURE WITH THE GENERAL COHORT REPORTING ABOUT 67.8 IF YOU TAKE EVERYTHING IN AGGREGATE, ALL THE LITERATURE OUT THERE. BUT WOMEN, 92.3% WERE SUFFERING FROM DEPESSION IN THIS COHORT. AND YET WE WEREN'T SEEING THE SAME KIND OF PRESS AND EXCITEMENT ABOUT TREATING DEPRESSION IN OUR MILITARY SERVICE PEOPLE, BUT WE WERE SEEING, OH, MY GOSH, PTSD. AND NOT TO PUT DOWN PTSD IN ANY WAY, BUT IT WAS JUST INTERESTING THAT WHEN IT HAPPENED IN A FEMALE COHORT, IT REALLY WASN'T AS EXCITING OR AS -- CAUSED THE SAME SORT OF RESPONSE. WHEN WE LOOKED AT OTHER SUPPOSED CONCUSSIVE SYMPTOMS, WHAT WE FOUND WAS THAT WOMEN WERE, AGAIN, MORE LIKELY TO SUFFER FROM CHRONIC PAIN, CHRONIC HEADACHES, NEUROLOGIC -- WHEN WE LOOKED AT SELF-REPORTED SEVERITY SYMPTOMS, AGAIN THIS HAS BEEN COVERED, OUR DATA WAS NOT DIFFERENT, WE FOUND MORE SOMATOSENSORY, MORE VESTIBULAR COMPLAINTS. WHAT WAS INTERESTING WAS THAT WOMEN WERE HAVING A HARDER TIME IN REINTEGRATION, AGAIN, BUT THEY WERE LOWER PERCENTAGE WORKING, MORE HOMELESS, AND THAT IS THE OPPOSITE OF WHAT YOU WOULD EXPECT IN A HIGHLY EDUCATED COHORT. SO USUALLY WHEN YOU THINK ABOUT HOW DO YOU GET PEOPLE OUT OF HOMELESSNESS, BACK TO WORK, YOU THINK, LET'S APPLY EDUCATION, RIGHT? BUT IN THIS COHORT, WOMEN WERE ACTUALLY WAY MORE EDUCATED THAN THEIR MALE COUNTERPART. SO THAT ACTUALLY CAUSED US TO PAUSE IN TERMS OF, OKAY, CLEARLY SOME OF OUR REHABILITATION, OUR TRANSITIONAL PROGRAMS NEEDED TO BE RETHOUGHT, RIGHT? BECAUSE HERE WE WERE APPLYING EDUCATION AS THE PANACEA WHEN, IN FACT, THAT MIGHT NOT BE THE CASE. WOMEN, AS WE SAID, WERE MORE OFTEN TO BE DIAGNOSED WITH THIS IN OUR COHORT AND MORE LIKELY TO REPORT THE SOMATOSENSORY AND VESTIBULAR SYMPTOMS, SO VERY CONSISTENT WITH WHAT WAS PREVIOUSLY STATED. SO HERE'S ALL THE DATA OUT THERE, AND OUR DATA IS IN MANY WAYS SAYING WAIT A SECOND, A LITTLE BIT DIFFERENT FOR THE FEMALE COHORT. SO WE DECIDED TO LOOK AT BOTH CROSS-SECTIONAL AND LONGITUDINAL, WE DECIDED TO HONE IN ON OUR OWN INFORMATION, OWN IN ON OUR OWN COHORTS BECAUSE WE WERE COMPARING OUR COHORT TO THE GENERAL PUBLISHED LITERATURE. NOW WE WANTED TO COMPARE OUR COHORT TO OUR COHORT, DATA THAT WE CAN CONTROL, DATA THAT WE'RE AWARE OF. AND SO WE DID THAT, WE DID A CROSS-SECTIONAL ANALYSIS, WE MATCHED OUR TBI PATIENT, MALE TO FEMALE, LOOKED AT THE SAME OUTCOME DOMAINS BECAUSE WE WANTED TO COMPARE, AGAIN, APPLES TO APPLES, AND WHAT WE FOUND WAS VERY SIMILAR TO THE LAST SPEAKER THAT, YES, WOMEN REPORTED SIGNIFICANTLY INCREASED SOMATOSENSORY AND VESTIBULAR SYMPTOMS. AND AGAIN, THIS WAS CONSISTENT WITH OUR OWN RESULTS WHEN WE COMPARED THE COHORT TO THE GENERAL LITERATURE. SO ALL RIGHT, CONSISTENCY THERE. SO THEN WE WANTED TO SEE, DO THE SYMPTOMS THAT WOMEN ARE ESPOUSING OVER TIME PERSIST, AND THAT DISCREPANCY OR THAT DIFFERENCE, DOES THAT PERSIST OVER TIME. WE DECIDED TO APPROACH IT TWO WAYS, ONE, LONGITUDINALLY -- SORRY, ONE, MATCHING AND ONE, OVERALL COHORT ANALYSIS. WHEN WE LOOKED AT OVERALL COHORT ANALYSIS, SAME COMPARISON METRICS, WHAT WE DID FIND WAS THAT THE MALE PATIENTS ACTUALLY ENDORSED MORE SYMPTOMS WHEN COMPARED TORE TO THEIR FEMALE COHORTS, AND ALL THE IMPROVEMENTS WE SAW IN FEMALE OR DIFFERENCES WERE NOT STATISTICALLY SIGNIFICANT. WHEN WE DID THE CROSS-SECTIONAL ANALYSIS OF THIS SAME COHORT AGAIN COMPARING APPLES TO APPLES, WHAT WE DID FIND WAS THERE WAS NO SIGNIFICANT DIFFERENCES IN NSI BETWEEN THE TWO. THERE WERE SOME DIFFERENCES WITH THE MALE COHORT SHOWING SOME IMPROVEMENT FROM BASELINE TO YEAR TWO AND NO IMPROVEMENT IN FEMALES, BUT OVERALL, THERE WERE NO DIFFERENCES. SO IN SUMMARY, WE FOUND THAT WOMEN, AGAIN, THE CROSS-SECTIONAL DATA WAS CONSISTENT WITH THE GENERAL STUDIES, NO SIGNIFICANT -- SORRY -- WOMEN REPORTED SIGNIFICANTLY INCREASED SYMPTOMS, AND THEN THE LONGITUDINAL SYMPTOMS WERE KIND OF ALL OVER THE PLACE, WITH MEN HAVING MORE BEHAVIORAL SYMPTOMS FROM BASELINE TO YEAR TWO, THE FEMALE SHOWING SOME MARGINAL BUT NOT STATISTICAL LEAST SIGNIFICANT IMPROVEMENT, AND WHEN WE MATCHED THEM, NO SIGNIFICANT DIFFERENCES WERE OBSERVED. SO WHAT WE CAME AWAY WITH WAS THAT, YOU KNOW WHAT, WE STILL NEED MORE DATA, WE REALLY DON'T UNDERSTAND WHAT'S HAPPENING HERE, AND I THINK THAT'S SORT OF THE RECURRENT THEME HERE. SO WE DECIDED, OKAY, WE UNDERSTAND THAT FUNCTION IS IMPORTANT THAT OUTCOMES ARE NOW DIFFERENT, BUT WE NEED TO UNDERSTAND WHAT WE SEE FUNCTIONALLY, IS THERE A CORRELATE ANATOMICALLY OR VICE VERSA, WHAT WE SEE ANATOMICALLY, IS THERE A CORRELATE FUNCTIONALLY. SO WE DECIDED TO TAKE ANOTHER PLUNGE AT THIS, AND WE'VE ADDED THIS COMPONENT TO OUR LABS. SO FUNCTIONAL DIFFERENCES REPORTED BY MEN AND WOMEN IS CHARACTERIZED BY NEUROPSYCHOLOGICAL TESTS OF VERBAL MEMORY AND EXECUTIVE FUNCTION. DO THEY CORRELATE WITH BRAIN FUNCTION? AND USING IMAGING ANALYSIS, AND I'M GOING TO, AGAIN, GO THROUGH THIS WAY TOO QUICKLY BUT HAPPY TO ANSWER QUESTIONS, WE WANTED TO UNDERSTAND THE RELATIONSHIP BETWEEN ANATOMY AND FUNCTIONAL OUTCOMES. SO WE LOOKED AT CORTICAL THICKNESS AS A SURROGATE FOR THAT, AND JUST VERY SORT OF BRIEFLY, WHAT WE WERE ABLE TO FIND WAS THAT THERE WERE SOME DIFFERENCES, THE AREAS IN RED ARE HIGHLIGHTED DIFFERENCES GREATER FOR WOMEN, IN BLUE, NOT TO BE VERY STEREOTYPICAL, RED AND BLUE, BUT AREAS OF DIFFERENCE WERE GREATER FOR MEN ARE DEPICTED IN BLUE. WHAT WE DID FIND FROM THAT WAS THAT THOSE WERE CORRELATED WITH SELF-REPORT DATA, SO WE WANTED TO -- WE TRIED TO ANALYZE THAT IN THE CONTEXT OF SELF-REPORT DATA. AND WE ACTUALLY FOUND NO STATISTICAL SIGNIFICANCE WHEN WE LOOKED AT THAT ANATOMY COMPARED TO -- CORRELATED WITH SELF-REPORT DATA. SO THEN WE DECIDED TO LOOK AT MORE EXECUTIVE FUNCTION, SO NEUROPSYCHOLOGICAL TESTS FOCUSED ON VERBAL MEMORY AND PSYCH LODGE PSYCHOLOGICAL FUNCTION AND SEE IF THAT CORRELATED. WHAT WE WERE ABLE TO FIND WAS DEFINITE CORRELATION IN THE FEMALE COHORT AND THE MAIL THE MALE COHORT. SPECIFICALLY WHAT WE WERE ABLE TO FIND WAS THAT THE WOMEN'S BRAINS WERE, IN FACT, IMPACTED MOSTLY BY SEVERITY, SO THE MORE SEVERE THE INJURY, THE MORE SEVERE THE ATROPHY. AND IN THE MALE COHORT, THE INCREASED ATROPHY ACTUALLY EXHIBITED OR CORRELATED WITH POORER PERFORMANCES ON THOSE TESTS, THE EXECUTIVE FUNCTION TESTS IN THE NEUROPSYCHOLOGICAL VERBAL MEMORY TEST. SO THAT WAS AN INTERESTING DIFFERENCE THAT WE WERE ABLE TO FIND. AND WHERE DID THAT LEAD US? BASICALLY WHAT THAT SAYS TO US IS THAT WE REALLY NEED A BETTER UNDERSTANDING OF THE BRAIN BIOLOGY INTERFACE. WE ALL AGREE, AND I THINK WHAT I'VE HEARD A LOT IN THIS CONFERENCE IS THAT, YES, ANATOMY IS DIFFERENT, YES, FUNCTIONAL OUTCOMES ARE DIFFERENT, YES, WE NEED MORE STUDIES, AND SORT OF PUTTING THIS ALL TOGETHER, YOU KNOW, WHAT WE'VE LEARNED IS THAT TRULY, TRULY MORE BIOLOGICAL UNDERSTANDING IS NECESSARY, AND HUMAN BIOLOGY. WE'VE TALK AID LOT ABOUT HUMAN MODELS, ET CETERA, AND WE ALL AGREE THOSE ARE IMPORTANT PRECURSORS TO UNDERSTANDING HUMAN BIOLOGY, BUT WHEN WE MOVE INTO TRANSLATING THAT INTO HUMAN BIOLOGY, SOMEHOW WE ARE FALLING SHORT IN THAT UNDERSTANDING. SO OUR CONCERN IS THAT, NUMBER ONE, USING THE TERMINOLOGY OF PRECISION MEDICINE, THAT WE NEED TO MORE PRECISELY UNDERSTAND THE DETERMINE DETERMINANTS OF WHAT IS CORRELATING ANATOMY AND FUNCTION FUNCTION. SO WE BELIEVE WE NEED TO PRECISELY HONE OUR TOOLS IN A DATA ACQUISITION AND DATA ANALYTICS. THE FIRST HALF OF THE TALK WHICH TALKED ABOUT HOW WE LOOKED AT OUR FEMALE COHORT COMPARED TO THE GENERAL COHORT, I THINK UNDERSCORES THAT PRETTY CLEARLY. WHICH IS THAT THE INFORMATION THAT IS OUT THERE IS NOT ACQUIRED IN A WAY THAT'S SPECIFIC TO THE FEMALE COHORT, AND THEN IT'S NOT ANALYZED IN A WAY THAT'S NUANCED TO BE ABLE TO ACCOUNT FOR THE FACT THAT WOMEN REPRESENT SUCH SMALL PROPORTION IN THIS DATASET, LARGELY THEY'RE NOISE IN THE DATASET, RIGHT, AND THEY HAVE TO BE ANALYZED IN A VERY NUANCED WAY IN ORDER TO TRULY UNDERSTAND THE COHORT. SO I THINK WE NEED MORE PRECISE ANALYTICAL AND ACQUISITION TOOLS, AND THEN I THINK ALSO WHEN WE LOOK AT CHRONIC SYMPTOMS, THAT'S CLEAR, BECAUSE WE DID FIND SOME CORRELATION, BUT THE SAME GAPS THAT EXISTED WHEN WE LOOKED AT OUR CROSS-SECTIONAL DAY TALL IS IMPORTANT TO -- ALSO HAVE AT PLAY HERE AS WELL. SO WE NEED -- IN ORDER TO MORE PRECISELY TARGET INTERVENTIONS AND TREATMENT MANAGEMENT STRATEGIES, WE REALLY HAVE TO MORE PRECISELY ACQUIRE THE DATA THAT'S OUT THERE. THINK THAT'S REALLY SORT OF THE ONLY HOPE IN GETTING TO A SOLUTION HERE. MANY PEOPLE HAVE ASKED, WHEN WILL WE GET THERE, HOW SOON, HOW OFTEN, WHAT IS HAPPENING WITH THE RESEARCH? I THINK I JOIN MANY IN THE COLLEAGUES IN THE AUDIENCE IN SAYING, I THINK WE'VE COME A LONG WAY IN MAYBE JUST EVEN THE LAST FOUR OR FIVE YEARS, THE FACT THAT WE'RE EVEN HAVING THIS CONFERENCE, THERE'S A LOT OF HOPE AMONGST US THAT WE'LL GET THERE. BUT I THINK WITHOUT ACCURATE ANALYTICAL TOOLS, WITHOUT ACCURATE FOCUS ON DATA ACQUISITION, THERE'S NO WAY THAT WE'RE GOING TO BE ABLE TO PRECISELY TARGET THE INTERVENTIONS THAT ARE NECESSARY FOR THIS COHORT. SO THAT WOULD BE OUR ASK TO THE NIH AT THIS FORUM. THANK YOU VERY MUCH FOR YOUR TIME AND YOUR ATTENTION. [APPLAUSE] THANK YOU SO MUCH, DR. HARRIS. THANK YOU, DR. LIPPA TOO. NEXT, OUR THIRD SPEAKER IS DR. MARY JO PUGH. MARY JO IS PROFESSOR EVER EPIDEMIOLOGY AND A CAREER RESEARCH SCIENTIST AT THE VA SALT LAKE CITY HEALTHCARE SYSTEM. HER WORK USES LONGITUDINAL DOD AND VA DATA DATASETS TO EXAMINE LONG TERM OUTCOMES OF MILITARY EXPERIENCES WITH A FOCUS ON TBI AND TBI SEQUELAE. DR. MARY JO PUGH. [APPLAUSE] >> SO I'VE BEEN PRIMED FOR THIS TALK BY AN AMAZING DESCRIPTION OF THE THINGS THAT WE DO KNOW AND THE IMPACT OF TBI ON WOMEN, AND IT MAKES IT CLEAR, AS DR. HARRIS JUST SAID, WE KNOW A BUNCH BUT THERE'S A LOT WE NEED TO KNOW. WE NEED TO LEARN -- AND HONESTLY THAT WE NEED TO DO. SO TODAY I'M GOING TO TALK ABOUT WHY IT'S -- I'M GOING TO GET MY CLICKER -- WHY IT IS IMPORTANT TO LOOK AT LONGITUDINAL TRAJECTORIES TO REALLY UNDERSTAND TBI IN WOMEN, AND WHAT WE KNOW, WHAT WE DON'T KNOW AND WHAT WE NEED TO LEARN AND WHAT WE NEED TO DO. SO WHAT WE DO KNOW IS THERE ARE SIMILARITIES AND SOME DIFFERENCES IN POST-CONCUSSIVE SYMPTOM DESCRIPTIONS AND REPORTING AND THAT THERE ARE SOME SIMILARITIES AND DIFFERENCES IN THE TYPES OF DIAGNOSED CONDITIONS THAT OCCUR OVER TIME. BUT LITTLE IS KNOWN REALLY ABOUT THE LONGITUDINAL IMPACT AND THE LONGITUDINAL PICTURE AND THE LONGITUDINAL PHENOTYPES OF COMORBIDITIES AMONG WOMEN WITH TBI IN THE MILITARY AND IN THE VA POPULATION. AND WHAT I WOULD ARGUE, AND I'M GOING TO TALK ABOUT MORE, IS THAT WE WOULD LIKE TO -- WE NEED TO IDENTIFY RESOURCES TO PROVIDE OPTIMAL CARE, AND TO DO THAT, WE NEED THE LONGITUDINAL DATA, AND WITH LONGITUDINAL DATA AND RICH LONGITUDINAL DATASETS, WE CAN DEVELOP PROGNOSTIC MODELS. THE CHALLENGE, THOUGH, IS -- IN TBI AND UNDERSTANDING TBI LONGITUDINAL IMPACTS IS THAT AS WE HAVE SEEN IN TALK AFTER TALK AFTER TALK, THAT THERE'S MULTI-MORBIDITY, NOT JUST IN POST-CONCUSSIVE SYMPTOMS, BUT IN DIAGNOSED CONDITIONS AS WELL. SO HOW DO WE UNDERSTAND THESE PATTERNS? WE NEED BIG DATA TO DO THAT. HONESTLY, IF WE WANT TO REALLY UNDERSTAND THE PATTERNS, WE HAVE TO LOOK AT PATTERNS, NOT CROSS-SECTIONAL SCHWARZENEGGER SWATHS OF D ATA. SO THESE ARE THE CHALLENGES THAT WE FACE, AND THESE -- WHAT I WILL DESCRIBE NOW WILL BE SOME EXAMPLES IN THE LITERATURE THAT HAVE ATTEMPTED TO DESCRIBE MULTI-MORBIDITY IN TBI OR THESE CO-MORBIDITY PHENOTYPES OR TRAJECTORIES. SO THE THREE BASIC TYPES ARE THE BRUTE FORCE TYPE, KIND OF BASED ON WHAT WE OBSERVE IN CLINICAL CARE, ANOTHER GROUP USED FACTOR ANALYSIS AND ANOTHER GROUP HAS USED LATENT CLASS ANALYSIS, AND WE DO SEE WITH THESE THREE APPROACHES SOMEWHAT SIMILAR BUT SOMEWHAT DIFFERENT RESULTS, AND I'LL DESCRIBE THOSE NOW. SO THE EARLIEST APPROACH WAS THE BRUTE FORCE APPROACH. THAT WAS BASED ON WHAT CLINICIANS SAW IN THE TBI CLINIC, AND REMEMBER THE TBI CLINIC IS AS DR. HARRIS DESCRIBED IS A CLINIC POPULATED BY PATIENTS WHO HAVE HAD A TBI AND TEND TO HAVE PERSISTENT PROBLEMS. SO THEY NOTED THERE WAS ENORMOUS CO-MORBIDITY BETWEEN TBI, PTSD AND PAIN IN THEIR CLINICAL POPULATION, AND THE EVALUATION OF THE OVERLAP, HE EVALUATED THE OVERLAB OF THE TBI AND HE FOUND THAT IT RARELY OCCURRED IN ISOLATION. IN FACT, IN HIS CLINICAL POPULATION, ABOUT 42% OF THE SAMPLE HAD PERSISTENT POST-CONCUSSIVE SYMPTOMS FROM TBI, IN ADDITION TO PTSD AND PAIN. THAT'S AN ENORMOUS IMPACT. SO THEY EXAMINED THIS PHENOMENON IN A POPULATION OF VETERANS WHO RECEIVED CARE IN 2009, SO THIS IS KIND OF -- GOES FROM A VERY SMALL CLINICAL SAMPLE TO A POPULATION-BASED APPROACH, AND THEY FOUND NOT QUITE THE SAME NUMBERS BECAUSE WE HAVE A LARGE -- IT'S A POPULATION, BUT THAT ABOUT 6% OF THE VETERANS THAT RECEIVE CARE, VETERANS DEPLOYED IN 2009, HAD WHAT WE CALL THE POLYTRAUMA CLINICAL TRIAD, TBI, PTSD AND PAIN. ONLY LESS THAN 1% ACTUALLY HAD ISOLATED TBI. THEY FURTHER FOUND THAT THE POLYTRAUMA CLINICAL TRIAL ASSOCIATED WITH IMPORTANT CLINICAL OUTCOMES, IN FACT, TAYLOR ET AL., EXAMINING THESE DATA, FOUND THAT AMONG VETERANS WITH TBI, THE MEDIAN ANNUAL COST FOR CARE IN 2009 WAS ABOUT -- ALMOST $6,000. VETERANS WITHOUT TBI, THE MEDIAN ANNUAL COST WAS ABOUT $1,500. AND AMONG THOSE WITH TBI, THE MOST COSTLY PATIENTS TO PROVIDE CARE FOR WERE THOSE WITH THE POLYTRAUMA CLINICAL TRIAD. SO THESE COMBINATIONS OF COMORE BUDDITIES HAVE IMPACTS. THERE ARE ALSO STUDIES THAT SUGGEST THE TRIAD IS MORE COMMONLY ASSOCIATED WITH HEADACHE AND SUICIDE-RELATED BEHAVIOR WEASSMENTS SO TURNING TO THE FACTOR ANALYSIS TYPES, THE STUDY WA S ACTUALLY CONDUCTED BY DR. LIPPA WHO AS IN THE AUDIENCE AND HER TEAM IN THE BOSTON AREA WHO RECRUITED TBI PATIENTS WITHIN THE COMMUNE IT, SO NOT NECESSARILY A CLINICAL SAMPLE, ALTHOUGH SOME PATIENTS DID COME FROM THEIR CLINIC, WHETHER IT WAS DEPLOYMENT-RELATED OR NOT, AND THEN THEY USED VALIDATED MEASURES TO UNDERSTAND THE IMPACT OR THE BURDEN OF A COUPLE OF -- A NUMBER OF DIFFERENT CONDITIONS INCLUDING PTSD, ANXIETY, DEPRESSION, SUBSTANCE USE DISORDER, PAIN AND SLEEP DISTURBANCE. THEN AS A PRELIMINARY -- AS KIND OF A PRELIMINARY DATA PIECE OF THAT STUDY, THEY USED DICHOTOMOUS VARIABLES OF HAVING THESE CONDITIONS OR NOT AND THEN USED AN EXPLORATORY FACTOR ANALYSIS APPROACH, AND THEY FOUND FOUR FACTORS. INTERESTINGLY, THE DEPLOYMENT TRAUMA FACTOR WAS A LITTLE BIT DIFFERENT THAN THE POLYTRAUMA CLINICAL TRIAD, WHICH INCLUDES DEPRESSION, PTSD AND MILITARY-RELATED TBI. THEN THERE WAS A SOMATIC FACTOR, WHICH INCLUDED SLEEP AND PAIN, AND ANXIETY FACTOR THAT INCLUDED NON-PTSD ANXIETY DISORDERS, AND AGAIN THEY FOUND THIS DEPLOYMENT TRAUMA FACTOR WAS SIGNIFICANTLY ASSOCIATED WITH WORSE GENERAL FUNCTIONING BASED ON THE TOTAL SCORE AND SUBSCORES, COMPARED TO THOSE PEOPLE WHO HAD NON-DEPLOYMENT FACTORS WITH THREE DIFFERENT COMORBIDITIES, SO THEY KIND OF TRIED TO CONTROL FOR DISEASE BURDEN OR PILE-ON BURDEN OF DIFFERENT CONDITIONS BY HAVING THREE DIFFERENT KINDS OF CO-MORBIDITIES THAT WERE NOT THESE -- WERE NOT TBI, PTSD AND DEPRESSION. IN A STENT SCWENT STUDY, THEY LOOKED AT PATIENTS WHO RECEIVED A COMPREHENSIVE TBI EVALUATION AND EXAMINED THE SAME DEPLOYMENT TRAUMA FACTOR AND FOUND THAT A VERY FUNCTIONAL OUTCOME OF EMPLOYMENT OR UNEMPLOYMENT, THAT INDIVIDUALS WHO HAD THE COMBINATION OF TBI, PTSD AND DEPRESSION HAD MUCH HIGHER RATES OF UNEMPLOYMENT THAN PEOPLE WITH MILD TBI ALONE, BUT THIS WASN'T REALLY SIGNIFICANTLY HIGHER THAN THOSE WERE PTSD AND DEPRESSION. SO SIGNIFICANT OUTCOMES BASED ON THESE KINDS OF COMPILATIONS OF CO-MORBIDITY PATTERNS. STUDY WITH LATENT CLASS ANALYSIS HAVE BEEN PREDOMINANTLY DONE BY MY TEAM, AND WE'VE DONE A NUMBER OF DIFFERENT APPROACHES, WE'VE LATENT CLASS ANALYSIS OF PCS SYMPTOM PATTERNS AND WE'VE USED DIFFERENT KINDS OF CO-MORBIDITY COMBINATIONS AND WHAT WE DO KNOW IS WHAT YOU PUT IN A MODEL WILL INFLUENCE WHAT WE SEE COME OUT. TODAY I'M GOING TO SHOW YOU SOME RESULTS THAT ARE BASED ON ONLY THE RESULTS THAT I'LL DESCRIBE ARE BASED ON STRATIFIED BY SEX AND LONGITUDINAL ASSESSMENTS, BECAUSE WE DO FIND THAT CROSS-SECTIONAL ANALYSES USING THE SAME METHOD GIVES YOU DIFFERENT KINDS OF PERCEPTIONS AND IT'S BECAUSE IT'S FILTERED BY PEOPLE WHO HAVE BEEN IN THE SYSTEM LONGER, WHO MAY HAVE HAD SIGNIFICANT DETERIORATION OVER TIME, SO THAT REALLY GIVES US A VERY HETEROGENEOUS GROUP OF INDIVIDUALS, AND IT'S VERY DIFFICULT TO SEE KIND OF THE PROGRESSION OF CO-MORBIDITY OR KIND OF THE PROGRESSION OF CO-MORBIDITY OVER TIME IF WE HAVE EVERYBODY LUMPED IN AS SINGLE CROSS-SECTIONAL ANALYSIS. SO THE FIRST STUDY WE DID THAT USEED STRATIFIED ANALYSIS, LIKE THE DEPLOYMENT TRAUMA FACTOR, WE FOUND THAT DEPRESSION SEEMED TO HAVE A BIGGER IMPACT ON THE PTSD/TBI COMBINATION, SO WE DECIDED TO PUT A VARIETY OF DIFFERENT TYPES OF COMORBIDITIES THAT ARE THEORETICALLY RELEVANT TO TBI AND TBI CO-MORBIDITY PROGRESSION. SO WE USED VA, INPATIENT AND OUTPATIENT PHARMACY DATA TO IDENTIFY PEOPLE WHO HAD CARE DURING ANY PARTICULAR YEAR, AND WE SPECIFIED A COHORT WHO ENTERED VA CARE BETWEEN FISCAL YEAR 2007 AND 2009. NOW WE DID THAT BECAUSE IN FISCAL YEAR 2007, V.A. STARTED TBI SCREENING FOR DEPLOYED AFGHANISTAN RAC WAR VETERANS, AND WE KNOW PRIOR TO THAT TIME, THE TBI THAZ WEREs THAT WERE DIAGNOSED TENDED TO BE MORE MODERATE AND SEVERE -- SO WE WANTED TO GIVE EVERYONE THE SAME OPPORTUNITY TO HAVE A TBI DIAGNOSED IF ONE EXISTED. WE THEN REQUIRED THAT THEY HAVE AT LEAST THREE YEARS OF CARE SO THAT WE COULD ACTUALLY SEE SOME LONGITUDINAL PATTERNS. THIS REALLY LONNESTLY IS NOT A VERY LONG PERIOD OF TIME. SO WHEN WE COMPLETED THOSE CRITERIA, WE HAD ABOUT 145,000 MEN AND ABOUT 20,000 WOMEN WHO MET THE INCLUSION CRITERIA. THEN WE USED DIAGNOSIS CODES AND INPATIENT AND OUTPATIENT FILES TO IDENTIFY TBI-BE RELATED CONDITIONS LIKE HEADACHE AND SENSORY ISSUE, NEUROSENSORY ISSUES, PAIN INCLUDING BACK PAIN, OTHER PAIN, AND HEADACHE. ACTUALLY HEADACHE WAS TBI, AND MENTAL HEALTH CONDITIONS AND CHRONIC DISEASE. BECAUSE BASED ON SOME OF THE BASIC INFORMATION, THE BASE UK SCIENCE INFORMATION, WE HEARD ABOUT YESTERDAY, THERE IS SOME THOUGHT THAT DEVELOPMENT OF CHRONIC DISEASE, THESE PHYSICAL CHRONIC DISEASES, MAY EMERGE OVER TIME FOR PATIENTS WHO HAVE TBI. AND OTHER TYPES OF COMORBIDITIES AND MENTAL HEALTH COMORBIDITIES. SO WE DID STRATIFY BY SEX, AND WE FOUND THAT THERE WERE FIVE CONSISTENT PATTERNS FOR MEN AND WOMEN. THERE WERE TWO ADDITIONAL PATTERNS FOR MEN AND WE BELIEVE HONESTLY THAT THOSE PATTERNS EMERGED BECAUSE THERE WERE 145,000 MEN AND 20,000 WOMEN AND YOU COULDN'T SEE AS FINE A GRANULAR DETAIL FOR THE WOMEN. BUT IN GENERAL, THIS IS NOT WHAT YOU SEE ON THE EVENING NEWS, ABOUT 40% OF THIS COHORT LOOKED BASED ON THESE DIAGNOSES TO BE RELATIVELY -- TO BE PRETTY HEALTHY WITH ALMOST NO CONDITIONS DIAGNOSED OVER A THREE-YEAR PERIOD OF TIME. THERE WERE A GROUP THAT HAD CHRONIC DISEASE, AND ABOUT 10% FOR MEN AND WOMEN, AND THE HEALTHY WERE ABOUT 40% FOR MEN AND WOMEN. THE MENTAL HEALTH GROUP FOCUSED ON DEPRESSION, PTSD, SUBSTANCE USE DISORDER AND REALLY VERY LITTLE OTHER THINGS DIAGNOSED, ABOUT 21% OF THE MEN AND WOMEN IN EACH OF THE MEN AND WOMEN COHORT. THEN THERE WAS A GROUP THAT HAD JUST REALLY BACK PAIN AND OTHER PAIN WHICH IS PREDOMINANTLY ARTHRITIS. NO MENTAL HEALTH COMPONENT TO THAT. THEN WE HAD THIS POLYTRAUMA CLINICAL TRIAD, THE TBI, PTSD, DEPRESSION, BUT ALSO PAIN. AND ABOUT 12% OF WOMEN AND 10% OF MEN WERE IN THAT COHORT, OR IN THAT GROUP. FOR MEN, THERE WAS ALSO THIS MINOR CHRONIC THAT LOOKED LIKE IT MIGHT BE KIND OF INCHING IN FROM THE HEALTHY TO THE CHRONIC DISEASE WHERE YOU SAW LITTLE BLIPS OF HYPERTENSION, LITTLE BLIEPS IN OBESITY, LITTLE BLIPS IN CHRONIC LUNG DISEASE AND LITTLE BLIPS IN DIABETES. IN MEN THERE WAS ALSO A GROUP THAT HAD A CHRONIC DISEASE COMPONENT AND THAT WAS ASSOCIATED WITH GENERALLY HAVING A HIGHER AGE. GIVEN THAT THESE -- THAT WE HAD ONLY A THREE-YEAR PERIOD OF OBSERVATION, WE BELIEVE THAT THESE ARE JUST OLDER VETERANS WHO CAME IN TO CARE AND HAD PRE-EXISTING CHRONIC DISEASE. WE DID SEE SIGNIFICANT INCREASES IN SOME OF THESE CONDITIONS OVER TIME, BUT THERE WEREN'T DRAMATIC SHIFTS. SO WE LOOKED AT THE POLYTRAUMA CLINICAL TRIAD BECAUSE THAT WAS THE ONLY GROUP THAT HAD A SIGNIFICANT IMPLICATION FOR TBI. THE QUESTION THEN BECOMES, CAN WE DISAGGREGATE THIS GRUP AND CAN GROUP AND CAN WE FIND OTHER PATTERNS IN AMONG VETERAN MEN AND WOMEN WITH TBI? THESE DATA ARE VERY FRESH AND ACTUALLY HAVEN'T DONE A TON OF COMPILATION ON THEM, BUT WHAT WE DID IS THERE WERE SIX TRAJECTORIES, FIVE FOR MEN, FIVE FOR WOMEN, TWO THAT DID NOT OVERLAP, ONE FOR MEN AND ONE FOR WOMEN. IN BOTH SETS, WE'RE NOT GOING TO CALL THEM HEALTHY ANYMORE, WE'RE GOING TO CALL THEM RELATIVELY HEALTHY, AND YOU SEE SOME PAIN AND YOU SEE SOME MENTAL HEALTH COMPONENT AND I'LL SHOW YOU SOME PICTURES THAT WILL HELP EXPLAIN THIS IN A LITTLE MORE DETAIL. WE SEE ONE WHERE WE START HEALTHY AND WE TURN -- THAT'S AN EXTREMELY IMPORTANT AND INTERESTING GROUP. WE SEE A MENTAL HEALTH AND PAIN GROUP, WE SEE THE POLYTRAUMA CLINICAL TRIAD GROUP, THEN WE SEE FOR WOMEN, A GROUP THAT'S VERY MOOD-FOCUSED WITH PRETTY HIGH PAIN, AND MEN ONLY WHERE THEY START OUT WITH THIS POLYTRAUMA CLINICAL TRIAD PATTERN BUT SEE IMPROVEMENT OVER TIME. AND WHAT WE DID WITH THIS GROUP IS WE ACTUALLY USED A FIVE YEAR OBSERVATION PERIOD SO WE HAVE A TINY BIT LONGER OBSERVATION PERIOD FOR THESE INDIVIDUALS AS WELL. SO JUST TO ORIENT YOU TO THIS -- THE GRAPHS THAT I'M GOING TO SHOW YOU, THE BOTTOM WILL DESCRIBE THE SPECIFIC TYPES OF COMORBIDITIES THAT WERE DIAGNOSED. THE GRAY LINE IS YEAR ONE, AND THE RED OR BLUE LINE WILL BE -- THE PROBABILITY OF HAVING EACH OF THESE CONDITIONS IN YEAR FIVE. WE COULD SHOW YOU ALL FIVE LINES, BUT YEAR 1 AND YEAR 5 ARE REALLY THE MOST GENERALIZED -- IT'S TOO MUCH INFORMATION IF YOU HAVE THEM ALL. SO THIS RELATIVELY HEALTHY GROUP AS I INFERRED EARLIER TENDS TO HAVE A BIT OF PAIN AND A BIT OF MENTAL HEALTH. FOR WOMEN -- A BIT OF PTSD, AND WOMEN HAVE A TINY BIT MORE DEPRESSION, MEN HAVE A BIT HIGHER PRESIDENT PTSD, SO IT'S KIND AFTER LOW DISTRESS BUT NOT EXACTLY HEALTHY GROUP EITHER. ABOUT 35% OF WOMEN AND ABOUT 31% OF MEN FIT THIS PROFILE. THERE WERE ABOUT 5500 WOMEN INCLUDED IN THE OVERALL ANALYSIS AND ABOUT 8 # THOUSAND -- 85,000 MEN. THE NEXT GROUP STARTED HEALTHY BUT TURNED TO POLYCLINICAL TRIAD, THE SAME GENERAL PATTERN, SO FOR WOMEN, DEPRESSION WAS HIGHER, FOR MEN, PTSD AND SUBSTANCE USE, ACTUALLY FOR MEN -- ACTUALLY FOR MEN, JUST THE SUBSTANCE USE WAS HIGHER. SO YOU SEE ESSENTIALLY VERY SIMILAR PATTERNS JUST SLIGHTLY DIFFERENT PROFILES WITHIN THE PATTERN. WHICH ARE CONSISTENT WITH WHAT YOU SEE IN THE LITERATURE. SO THE MENTAL HEALTH AND PAIN GROUP, IT'S HEAVIER ON THE MENTAL HEALTH, LOWER ON THE PAIN, BUT THERE IS A PAIN BLIP TO THAT. WE SEE FOR MEN TREMENDOUS LEVELS OF SUBSTANCE USE DISORDER. THIS IS, I BELIEVE, A PARTICULARLY VULNERABLE GROUP. WE SEE ABOUT 21% OF WOMEN THAT MEET -- THAT ARE IN THIS PROFILE AND ABOUT 20% OF MEN. THEN OUR POLYCLINICAL TRIAD GROUP, AGAIN PRETTY SIMILAR FOR MEN AND WOMEN EXCEPT FOR THE SUBSTANCE USE DISORDER. THEN FOR THE WOMEN, WE SEE THIS MOOD IN PAWN GROUP, WHICH HAS A MUCH HIGHER DEPRESSION AND ANXIETY PROFILE WITH QUITE HIGH PAIN. IT SEEMS TO BE A MIX BETWEEN THE POLYTRAUMA CLINICAL TRIAD AND THE MENTAL HEALTH AND PAIN GROUP, BUT WITH THE MUCH HIGHER FOCUS ON PAIN AND REALLY NOT MUCH PTSD, SO IT'S REALLY VERY MOOD-FOCUSED. THEN FOR MEN, WE HAVE A GROUP THAT'S EXTREMELY INTERESTING. IN YEAR ONE, WE HAVE A PATTERN THAT LOOKS LIKE IT'S THE POLYTRIAD WITH LOWER LEVEL OF SUBSTANCE USE DISORDER, AND INTERESTINGLY ENOUGH, BY YEAR FIVE, THINGS ARE BEGINNING TO -- THEY APPEAR TO BE GETTING TO IMPROVE. SO THE PROBABILITY OF HAVING EVEN PTSD SUBSTANCE USE DISORDER, HEADACHE, BACK PAIN, OTHER PAIN AND INSOMNIA, AND THE COGNITIVE COMPLAINTS, IS SIGNIFICANTLY DIMINISHED OVER TIME. SO WHAT WE SEE, AND HONESTLY, I'VE RUN THE ANALYSIS, I DON'T HAVE TIME TO DESCRIBE THEM, BUT THIS PCT TO IMPROVE GROUP ACTUALLY HAS A LOWER RISK FOR SUICIDALITY, OVERDOSE AND MORTALITY AND HOMELESSNESS THAN THE RELATIVELY HEALTHY GROUP. SO WHAT THESE DATA SUGGEST IS THAT THERE ARE -- WE HAVE DESCRIPTIVE INFORMATION THAT CAN BE USED TO ACTUALLY CONDUCT MORE FOCUSED RESEARCH WITH TARGETED POPULATIONS. WE CAN COLLECT SURVEY DATA, WE COULD CONCEIVABLY DO IMAGING, BUT WHAT LIMITATION THAT WE DO HAVE IS THAT THIS IS JUST VA DATA. WE HAVE THE D OCHT D-DAYO D-DAY TA AND WE'RE RUNNING THE LONGITUDINAL ANALYSIS FROM THE TIME THEY WERE IN D OSM D ONWARD BUT THEY ARE FORTHCOMING. BUT IF WE WANT TO DO THIS RIGHT, THAT'S WHAT WE HAVE TO DO, BECAUSE WE DON'T KNOW WHAT'S COMING IN TO VA CARE, BUT FOR BOUNDARY -- TO NOT HAVE THAT INFORMATION IS A MISSED OPPORTUNITY BECAUSE WE COULD FAR BETTER PREDICT WHO'S COMING IN TO V.A. CARE, WHAT KIND OF SERVICES THEY NEED, AND HOW WE NEED TO APPROACH SPECIFIC PATIENTS. WE COULD CONCEIVABLY DEVELOP PROGNOSTIC MODELS USING VA DATA FOR PEOPLE WHO WE SHOULD PREFERENTIALLY FUNNEL INTO V.A. USING DO D-DAY TA THAT WE CAN PREFERENTIALLY FUNNEL INTO V.A. CARE SO THAT WE COULD MITIGATE SOME OF THE RISK FACTORS FOR SUBSTANCE USE DISORDER, SUICIDALITY AND HOMELESSNESS AND A VARIETY OF OTHER POTENTIAL ADVERSE EVENTS. SO BASICALLY FROM OUR FINDINGS, WE SEE THERE ARE SOME SIMILARITIES, THERE ARE SOME GENDER-SPECIFIC OR SEX-SPECIFIC PATTERNS WITHIN THOSE PHENOTYPES PHENOTYPES, AND THESE ARE WHAT I THINK IS A GOOD START AND WE CERTAINLY CAN USE THIS TO MOVE FORWARD, BUT THESE ARE DEFINITELY NOT THE END ALL AND BE ALL AND THEY'RE NOT DEFINITIVE DATA. BUT WE DO NEED TO, HOW WE TREAT PEOPLE MAY AFFECT THESE TRAJECTORIES AND MAY BE THE GROUP WHO IMPROVED OVER TIME, WE'RE IN POLYTRAUMA SYSTEM OF CARE, IT MAY BE THAT THEY RECEIVED CARE IN DIFFERENT SETTINGS. AND SOME OF THE MEDICATIONS THAT WE PRESCRIBE MAY GIVE ADVERSE SIDE EFFECTS THAT MAY START DOWN A RABBIT HOLE OF DIFFERENT SYMPTOMS. SO WE NEED TO USE BROADER DATA AND IF WE WANT TO UNDERSTAND THESE MILITARY CHARACTERISTICS, WE NEED TO HAVE EVEN MORE LONGITUDINAL DATA AND THAT'S HOW WE EXAMINE WOMEN, IN POPULATIONS, THAT'S ONE WAY TO EXAMINE WOMEN, IS IN POPULATIONS. THAT'S ALL. [APPLAUSE] >> I LOOK FORWARD TO OUR TIME WHEN WE HAVE PANEL DISCUSSION AND 20 MINUTES TO TALK ABOUT SOME OF THE PHENOTYPING IN SOME OF THE PROGNOSTIC MODELS THAT MARY JO JUST DISCUSSED WITH US. OUR LAST SPEAKER IS DR. DEBORAH YURGELUN-TODD FROM UNIVERSITY OF UTAH SCHOOL OF MEDICINE. SHE'S ALSO THE ASSOCIATE DIRECTOR OF THE MENTAL ILLNESS RESEARCH EDUCATION AND CLINICAL CENTERS AT THE SALT LAKE CITY VA HEALTHCARE SYSTEM. SHE ALSO -- HER RESEARCH ALSO APPLIES MR IMAGING TECHNIQUES TO IDENTIFY BRAIN CHANGES IN MOOD PROCESSING AND NEUROCOGNITIVE FUNCTIONS AND TO EXAMINE IRREGULARITIES IN THE BRAINS OF PEOPLE AT RISK FOR DEVELOPING SEVERAL PSYCHIATRIC DISORDERS. >> THANK YOU. >> THANK YOU VERY MUCH TO THE ORGANIZERS FOR INVITING ME TO PARTICIPATE. THIS IS A REAL HONOR, AND I'M A LITTLE BIT OF AN OUTSIDER IN THE FACT THAT I CAME IN TO WORKING WITH THE MILITARY POPULATION ONLY IN THE LAST DECADE, AND THE WORK THAT WE HAD DONE PREVIOUS TO THAT WAS REALLY LOOKING AT BRAIN BEHAVIOR CORRELATES, FOR RISK FOR PSYCHIATRIC DISORDER. NONE OF THE INFORMATION THAT I'M GOING TO PRESENT OR COMMENTS ARE THE -- CAN BE ATTRIBUTED TO THE V.A. ON BEHALF OF THE FUNDING THEY HAVE PROVIDED. SO WHAT MY TALK WILL DO TODAY IS GIVE YOU A LITTLE BIT OF AN OAF VIEW ON NEUROPHYSIOLOGICAL CHANGES IN TRAUMATIC BRAIN INJURY. I'M GOING TO TALK A LITTLE BIT ABOUT MAGNETIC RESONANCE IMAGING METHODS, AND THEN THE EVIDENCE FOR SEXUAL DIFFERENTIATION BASED ON IMAGING, SOME NEUROPHYSIOLOGICAL CORRELATES OF TBI AND THEN SOME STUDIES WE'VE DONE ON ORBITAL FRONTAL CONNECTIVITY IN MALE AND FEMALE VETERANS, AND FINALLY OUR GAPS IN KNOWLEDGE. SO ONE OF THE THINGS WE'VE HEARD A LOT ABOUT AT THIS MEETING IS THE POTENTIAL COMPOUNDS THAT EXIST IN TRYING TO UNDERSTAND OUR DATABASES, AND THAT'S TRUE FOR ANYBODY WHO'S TRYING TO UNDERSTAND THE NEUROPHYSIOLOGICAL CORRELATES OF TRAUMATIC BRAIN INJURY. SEX OBVIOUSLY IS THE ONE WE'RE MOST INTERESTED IN LOOKING AT AND WE'RE NOT CONSIDERING THAT A COMPOUND, BUT I THINK MANY TIMES WHEN WE LOOK AT AN IMAGE OR LOOK AT BIOLOGICAL DATA, WE DON'T TAKE INTO ACCOUNT THE FACT THAT WE HAVE A NUMBER OF OTHER THINGS THAT CONTRIBUTE TO THE INTEGRITY OF THE BRAIN TISSUE REAR WE'RE LOOKING AT. THESE HAVE BEEN REALLY NICELY HIGHLIGHTED YESTERDAY AND THIS MORNING BUT I JUST WANT TO MENTION AGAIN THAT MEDICAL HISTORY IS A CONFOUND OR IS A POTENTIAL CONCERN WHEN YOU'RE LOOKING AT A BRAIN OF AN INDIVIDUAL EVEN IF THEY DON'T HAVE TBI, BECAUSE IF THEY HAD DIABETES OR IF THEY HAVE CORONARY PROBLEMS, THAT WILL IMPACT THE TISSUE. OBVIOUSLY PSYCHIATRIC HISTORY. DRUG AND ALCOHOL ABUSE WHICH WE HAVE MENTIONED, IN PASSING, WE HAVE NOT TAKEN VERY SERIOUSLY TO THE EXTENT TO WHICH THEY COULD CONTRIBUTE TO OUTCOME DATA THAT WE'RE LOOKING AT IN OUR TRAUMATIC BRAIN INJURY POPULATION, AND WHEN I SAY OUTCOME, I MEAN FROM THE POINT OF VIEW OF NEUROBIOLOGY, BECAUSE THESE POTENTIALLY TOXIC SUBSTANCES REALLY DO IMPACT THE BRAIN AND THEN THE CIRCUITRY THAT IS AFFECTED IN THE LIMBIC REGIONS IN PARTICULAR. WE TALKED PREVIOUSLY YESTERDAY ABOUT THE DIAGNOSIS AND FEET TOURS IN TBI, SO LOCATION SEVERITY, CAUSE, ALL IMPORTANT CONSIDERATIONS, AND FINALLY, WHAT YOU'RE DOING OR HOW YOU'RE EVALUATING YOUR BRAIN TISSUE, AND ARE THESE METHODS THE BEST METHODS, HOW RIGOROUS ARE THEY, HOW CONSISTENT ARE THEY, AND HOW WELL CAN THEY BE INTERPRETED. SO MY FOCUS WAS, I MENTIONED BEING ON NEUROIMAGING DATA AND WE'D LIKE TO ARGUE THAT NEUROIMAGING DOES PROVIDE IMPORTANT CONTRIBUTION TO UNDERSTANDING TRAUMATIC BRAIN INJURY IN VETERANS AND ANY POPULATION BECAUSE IT HAS A FAMILY OF TECHNIQUES, IT'S NOT A SINGLE TECHNIQUE, AND IF YOU CAN UNDERSTAND HOW TO APPLY THESE TECHNIQUES, I THINK YOU THEY'RE FAIRLY INFORMATIVE OF THE NEUROBIOLOGY. SO OUR ABILITY TO CHARACTERIZE THESE BRAIN CHAINGS AND RELATE THEM TO BEHAVIOR IS AN IMPORTANT HUMAN COMPONENT IN UNDERSTANDING TRAUMATIC BRAIN INJURY. LOOKING AT BASELINE PREDICTERS FROM NEUROIMAGING TO LOOK AT WHO MIGHT IMPROVE IN TERMS OF OUTCOME, WE JUST HEARD THERE ARE MULTIPLE EXTRA TRAJECTORIES IN TERMS OF OUTCOMES, IT WOULD BE NICE IF WE HAVE A MODEL OR SIGNATURE THAT WOULD ALLOW US TO UNDERSTAND WHAT KIND OF TREATMENTS TO PROVIDE AND HOW THIS INDIVIDUAL MIGHT MAXIMALLY USE INTERVENTIONS. WE CAN ALSO LOOK AT CORE MORBID SYMPTOMS AND COURSE OF RECOVERY, SO THAT IF WE REPEAT IMAGING, AND MR IMAGING IS A VERY NON-TOXIC KIND OF APPLICATION, YOU CAN LOOK OVER TIME AND SEE WHETHER OR NOT INDIVIDUALS LOOK TO BE IMPROVING IN AREAS THAT YOU WOULD LIKE TO SEE IMPROVED. IMAGING AS IT HELPS US UNDERSTAND DRUG DEVELOPMENT OR TREATMENT INTERVENTION, BUT THERE ARE IN ALL THE MAJOR DRUG COMPANIES FAIRLY LARGE IMAGING INITIATIVES THAT LOOK AT DIFFERENT TECHNIQUES FOR DEVELOPING POTENTIAL BIOCHEMICAL OR PHARMACOLOGICAL INTERVENTIONS. SO MAGNETIC RESONANCE IMAGING MODALITIES, I'M SURE ALL OF YOU KNOW STRUCTURAL MRI, WHERE THERE WAS THE ELUSION TO DIFFUSION TENSOR IMAGING YESTERDAY, WE CAN LOOK AT IN VIVO BIOCHEMISTRY, THEN FUNCTIONAL MAGNETIC RESONANCE IMAGING, WHICH HAS MANY MODALITIES AS WELL, IT HAS A RESTING STATE COMPONENT WHERE WE CAN LOOK AT CONNECTIVITY OR WE CAN LOOK AT REGIONAL ACTIVATION DEPENDING ON TASKS. AND MY TAKE HOME MESSAGE HERE IS NOT ONLY -- IS THERE THIS GROUP OF MODALITIES THAT WE CAN APPLY, BUT HOW WE UNDERSTAND WHAT'S GOING ON IN THE BRAIN WILL BE TOTALLY DEPENDENT ON THE TECHNIQUES WE USE WHEN WE ARE APPLYING THEM AND THE TECHNIQUES WE USE FOR ANALYZING THE DATA. NOW THIS IS A SCHEMATIC THAT KIND OF SHOWS YOU ON THE TOP ROW THAT THESE ARE DIFFERENT WAYS OF LOOKING AT STRUCTURAL DATA, BOTTOM ROW IS DIFFERENT WAYS TO LOOK AT WHITE MATTER AND STRUCTURAL DTI DATA, MIDDLE ROW IS A MORE CONVENTIONAL STRUCTURAL -- I'M SORRY -- THE TOP ROW IS THE RESTING STATE FMRI. HERE I'M JUST TRYING TO HIGHLIGHT THAT YOU CAN GENERATE DIFFERENT OUTPUT BY UNDERSTANDING THE QUESTION YOU WANT TO ASK. AND THIS IS AN IMPORTANT THING IN CONSIDERING HOW WE WANT TO UNDERSTAND TRAUMATIC BRAIN INJURY. WHEN IT COMES TO SEX DIFFERENCES IN THE BRAIN, WE DISCUSSED YESTERDAY THAT THERE ARE SEX DIFFERENCES IN THE BRAIN AND THIS HAS BEEN SHOWN EARLY IN ANIMAL MODELS, BUT IT HAS BEEN A REALLY, REALLY DIFFICULT TOPIC TO ADDRESS WITH HUMAN MAGNETIC RESONANCE IMAGING, AND THERE HAVE BEEN FOR THE LAST, I WOULD SAY, 30 YEARS MULTIPLE STUDIES WHICH HAVE FAILED TO REPLICATE, BECAUSE THERE'S A REAL INCONSISTENCY IN FINDINGS. THERE ARE SO MANY SEX DIFFERENCES HAS BEEN A TOPIC THAT SOME INVESTIGATORS AT THE NIH HAVE TAKEN ON, AND THEY HAVE SUGGESTED, PARTICULARLY ONE GROUP, THAT CROSS-SECTIONAL ANALYSIS IS NOT A WAY TO EXPLORE SEX DIFFERENCES, YOU REALLY HAVE TO LOOK OVER A LIFESPAN. OTHER INDIVIDUALS HAVE SAID IT DEPENDS WHEN DURING THE DEVELOPMENTAL PHASE YOU'RE EVALUATING THE BRAIN. OTHERS HAVE SUGGESTED BOTH THE METHODS AND THE ANALYSIS OR THE PROBLEM AND THE INCONSISTENCIES. THIS DATA I'M SHOWING YOU BECAUSE I THINK IT'S FAIRLY ROBUST AND REALLY HIGHLIGHTS THAT IF YOU LOOK AT INDIVIDUALS FROM AGE 5 TO ALMOST 30, THE TOP ROW ON THE LEFT-HAND SIDE IN BLUE IS MALES AND RED IS FEMALES, YOU CAN SEE THERE'S A FAIRLY CONSISTENT PATTERN WHEN YOU LOOK AT THE WHOLE BRAIN OF THERE BEING LARGER BRAIN VOLUME IN MALES THAN FEMALES. THAT DOESN'T SEEM LIKE NEWS. WHEN YOU LOOK ON THE RIGHT-HAND SIDE, YOU CAN SEE THAT IF WE THEN TAKE THAT WHOLE BRAIN VOLUME AND LOOK AT IT AS TOTAL WHITE MATTER, GRAY MATTER, OR VENTRICULAR VOLUME, THAT STILL HOLDS TRUE THAT THERE ARE LARGER AREAS OR MORE VOLUME ASSOCIATED WITH BEING A MALE. AND, THEREFORE, THESE INVESTIGATORS HAVE CONCLUDED THAT WHILE YOU MIGHT ACCIDENTALLY HAVE A SNAPSHOT IN ONE -- AND YOU CAN SEE IN THE LEFT-HAND SIDE, THERE ARE RED DOTS UP IN THE BLUE REGION DEPENDING ON WHO YOUR SAMPLE IS, HAVE AN OPPORTUNITY TO HAVE EITHER NO VOLUME DIFFERENCES OR FEMALES LOOKING LARGER THAN MALES. OVERALL, IT APPEARS THAT OVER THE LIFE COURSE, BRAIN VOLUME IS JUST LARGER IN MALES. HOWEVER, A RECENT META-ANALYSIS -- ACTUALLY THIS IS 2014, THERE'S ANOTHER ONE ABOUT TO BE PUBLISHED WHICH IS VERY SIMILAR TO THIS -- LOOKED AT REGIONAL DIFFERENCES IN THE BRAIN, AND THIS IS A METHOD WHERE INSTEAD OF JUST TAKING WHOLE BRAIN ANALYSES, A STANDARDIZED TEMPLATE WAS APPLIED TO MALE AND FEMALE BRAINS, AND IT SHOWED THAT -- AND I TOOK THE LIBERTY OF SORT OF OVERSIMPLIFYING HERE, THAT THERE ARE REGIONS LARGE NER VOLUME FOR FEMALES, THOSE ARE THE ONES IN RED, AND THERE ARE REGIONS OF THE BRAIN THAT ARE LARGER IN MALES, AND THOSE ARE THE ONES IN BLUE. AND PARTICULARLY NOTEWORTHY THAT THE RIGHT INTERIOR SINK LAT IS SING LAT IS LACIALGER IN FEMALES AND THE LARGER -- AND THESE MEASUREMENTS ARE CONTROLLED FOR WHOLE BRAIN VOLUME. SO MY POWNT IN SHOWING YOU THESE IS THAT WHILE WE UNDERSTAND THERE ARE SEX DIFFERENCES, JUST TRYING TO USE IMAGING TO LOOK AT WHAT THESE SEX DIFFERENCES ARE IN TBI ISN'T THAT STRAIGHTFORWARD, AND WE HAVE TO BE CAUTIOUS IN HOW WE'RE LOOKING AT THE DATA. SO WE'VE ALREADY HEARD A LOT ABOUT THE FACT THAT THE MOST IMPORTANT -- I MEAN THE MOST PREVALENT TYPE OF TBI IN THE MILITARY IS MILD TBI, AND THE BLAST AND ENERGY PULSE IS THE ONE THAT TENDS TO BE THE ONE WE SEE MOST FREQUENTLY. HOWEVER, MANY OF OUR VETERANS ALSO HAVE MULTIPLE FORMS OF TBI, BOTH BECAUSE AT THE TIME OF GETTING THE TBI, THEY WERE EXPOSED TO SHRAPNEL AS WELL AS BLAST, OR BECAUSE THEY'VE HAD MULTIPLE TBI. SO THESE TYPES OF INJURYS HAVE TRICKY, AGAIN, BECAUSE SOME OF THE EARLIER METHODS, BOTH IN TERMS OF ASSESSMENT AND FROM A CLINICAL PERSPECTIVE ALSO FROM AN IMAGING PERSPECTIVE HAVEN'T REALLY SHOWN CLEAR DIAGNOSTIC INDICATORS. SO IN IMAGING, WE HAVE MADE PROGRESS IN LOOKING AT THAT. WE'VE ALREADY REVIEWED FAIRLY FREQUENTLY THE SYMPTOMS SO I WON'T GO OVER THOSE HERE. SO WHEN WE'RE LOOKING FOR BRAIN CHANGES ASSOCIATED WITH TRAUMATIC BRAIN INJURY, WE LIKE TO THINK WE COULD FIND THE DIFFERENCE BETWEEN THE DIFFERENT BRAIN REGIONS THAT RIM PACTED ARE IMPACTED AND THE TYPE OF MECHANISM MAKING THAT CHANGE IN THE BRAIN. YOU CAN SEE THE TOP OF THE HEAD OR THE SUPERIOR REGION IS IMPACTED FREQUENTLY, SO IS THE ANTERIOR AND POST TIER POSTERIOR REGIONS AND THE SUBCORTICAL REGIONS, WE SEE MORE OF A HEMORRHAGIC EVENT. SO WE DO EXPECT WHEN WE'RE GOING TO DEVELOP OUR PROTOCOLS THAT WE WANT TO DEVELOP PROTOCOLS THAT ARE SENSITIVE TO THE TYPES OF INJURY WE WOULD EXPECT TO SEE AND IN THE LOCATION WE WOULD EXPECT TO SEE THEM. AND AS I'VE ALREADY POINTED OUT, MANY VETERANS WILL HAVE MULTIPLE TYPES OF INJURIES, MAKING IT VERY DIFFICULT TO ALLOCATE ANY PATHOPHYSIOLOGY TO ANY SINGLE TBI. THIS IS AN EXAMPLE OF -- YOU CAN SEE ON THE TOP ROW -- IMPACT INJURY AND THE BOTTOM ROW BLAST INJURY OF TWO PATIENTS WHO SHOWED NORMAL SCANS IN A TRADITIONAL CLINICAL SCAN, HOWEVER, USING SUSCEPTIBILITY WEIGHTED IMAGING, THIS TECHNIQUE HIGHLIGHTS, AS YOU CAN SEE WHERE THOSE RED ARROWS ARE, DIFFERENT SPOTS IN THE BRAIN WHICH ARE INDICATIVE OF WHITE MATTER CHANGES. AND SO PEOPLE BEGAN TO REALIZE THAT WE NEEDED TO PAY MORE ATTENTION TO THE TECHNIQUES WE WERE USING TO LOOK AT THE TYPES OF INJURIES WE WANTED TO SEE. ANOTHER IMPORTANT THING ABOUT THESE KIND OF WHITE MATTER HYPERINTENSITIES IS THESE ARE VERY TYPICAL OF INDIVIDUALS WITH DEPRESSION AND WITH BIPOLAR DISORDER AND SUBSTANCE ABUSE. ZIPS I COME FROM THEWE HAVE STUDIED THOSE FOR THE LAST FEW DECADES. IT'S INTERESTING TO ME THAT I DON'T THINK WE'RE PAYING ATTENTION TO THE POTENTIAL IMPACT THAT MAY HAVE ON THE IMAGING IN OUR TBI POPULATION. I'M GOING TO REVIEW NOW SOME JUST REALLY BRIEFLY SELECT LITERATURE IN THE DIFFERENT IMAGING DOMAINS TO GIVE YOU A FLAVOR THERE ARE SO MANY REALLY GOOD PAPERS OUT THERE SO I APOLOGIZE TO ANYONE WHO ISN'T INCLUDED. MORPHOMETRIC MEASURES, BASED ON STRUCTURAL IMAGING DATA. WE ALREADY HEARD EARLIER TODAY ABOUT SOME OF THE CORTICAL THICKNESS DATA THAT WAS EVALUATED AND CORRELATED WITH COGNITIVE FUNCTIONING. IT IS NOT UNUSUAL TO SEE CORTICAL THINNESS OR REDUCTION IN CORTICAL TISSUE IN THE FRONT OR THE BACK OF THE BRAIN ASSOCIATED WITH TBI. WE ALSO HAVE SEEN SOME DIFFERENCES IN OVERALL VOLUMES AND IN SHAPE, AND WHAT I THINK YOU CAN SEE VERY CLEARLY HERE IS THE NUMBER OF FEMALES IS VERY FEW ON THAT FIRST STUDY, 47 MALES, 8 FEMALES. SECOND STUDY, 54 MALES, 1 FEMALE. AND THIRD STUDY, 71 MALES, FIVE FEMALES. SO IT IS VERY DIFFICULT TO SAY ANYTHING ABOUT FEMALES BEING DIFFERENT THAN MALES WITH THIS SMALL SAMPLE SIZE. ONE OF THE INTERESTING THINGS ABOUT THE CORTICAL THINNESS CHANGES IN THE BRAIN IS THEY COULD BE DUE TO LOSS OF TISSUE OR CELL DEATH. WE DON'T KNOW THAT FOR SURE BECAUSE IT ALSO COULD BE DUE TO SHRINKING OF NEURONS, BUT PART OF WHAT'S INTERESTING ABOUT THESE IMAGING MODALITIES IS THEY COULD POINT US TOWARD MECHANISMS. WOULD ALSO POINT OUT THAT IN MANY OF THE MORPHOMETRIC STUDIES, WHEN THERE'S BEEN AN EXAMINATION OF THE PRESENCE OF PTSD, IT LOOKS AS IF IT EXACERBATES TISSUE LOSS, SO THAT IS INDIVIDUALS WITH TBI ALONE HAVE LESS TSH EU TISSUE LOSS THAN INDIVIDUALS WHO HAVE TBI AND PTSD. IN DIFFUSION TENSOR IMAGING, THIS IS THE TECHNIQUE THAT LOOKS AT MYELIN AND WHITE MATTER PROJECTIONS, THERE ARE A NUMBER OF DIFFERENT TECHNIQUES. MOST OF THE TECHNIQUES HAVE FOCUSED ON FRACTIONAL -- A MEASURE OF LIKE WHITE MATTER INTEGRITY, AND THE IDEA WITH THE FA MEASURES IS TO EX-PLORM BOTH THROUGHOUT THE PLAIN AND IN LOCAL REGIONS TO SEE WHETHER OR NOT THE WHITE MATTER INTEGRITY LOOKS INTACT, BECAUSE WE THINK THERE IS A SHARING AND TEARING OF THOSE LONG WHITE MATTER TRACTS WHEN THERE IS A BLAST AND IN OTHER TYPES OF CONCUSSION AND TBI AS WELL, BUT PARTICULARLY IN THAT. SO YES, HERE WE SEE A NUMBER OF STUDIES YET AGAIN SHOWING THAT THERE IS THIS REDUCTION IN FA IN INDIVIDUALS WHO HAVE HAD A TBI, AGAIN VERY, VERY FEW FEMALES ARE INCLUDED, IN FACT, THAT LAST STUDY IS 72 MALES ONLY. SECOND STUDY IS 24 MALES AND 1 FEMALE. THE OTHER THING TO NOTE IS THAT TRAUMATIC BRAIN INJURY HAS ALSO BEEN SHOWN TO HAVE FRONTAL CEREBELLAR AND SUBCORTICAL REION INJURY, AND WE SEE A DIFFUSE PATTERN OF THOSE HYPERINTENSITIES, THAT FIRST SLIDE THAT I SHOWED YOU. SO THESE ARE NOT FOCAL CHANGES WHEN WE'RE LOOKING AT THE T2 HYPERINTENSITIES. THROWS GENERALLY DISTRIBUTED THROUGHOUT THE BRAIN. THE CORTICAL THINNESS TENDS TO BE MORE FRONTAL AND THEN POSTERIOR. FUNCTIONAL STUDIES ALLOW US TO LOOK AT CONNECTIVITY IN DIFFERENT BRAIN REGIONS, SO SOME OF THE NEWER STUDIES HAVE LOOKED AT WHETHER OR NOT THERE APPEARS TO BE LIKE A DISCONNECTION SYNDROME MEASURED ON THE BASIS OF BOLD ACTIVATION, SO AS OPPOSED TO USING STRUCTURAL APPROACHES THAT LOOKS AT ACTUAL TISSUE, THESE ARE TECHNIQUES THAT LOOK AT A REGIONAL ACTIVATION OR BLOOD FLOW OR SIGNAL CHANGES THAT ARE MORE PHYSIOLOGIC. IT IS INTERESTING TO LOOK AT HOW CONSISTENT THESE FINDINGS ARE AND, IN FACT, THEY ARE CONSISTENT, THAT THERE IS EVIDENCE THAT CONNECTIVITY IS ALTERED BETWEEN FOCAL BRAIN REGIONS IN VETERANS WHO HAVE TRAUMA TUCK BRAUN INJURY. THE FUNCTIONAL IMAGING STUDYS THAT USE TASK, THERE ARE VERY FEW OF THEM THAT HAVE BEEN PUBLISHED IN TBI POPULATIONS BUT ONE OF THEM THAT WAS HIGHLIGHTED HERE SHOWS THE REGIONS THAT ARE ACTIVATED IN RESPONSE TO COMPLETING THE TASK IN INDIVIDUALS WITH TBI SHOW AREAS THAT ARE BOTH HIGHER AND AREAS THAT ARE LOWER, SO YOU CAN'T JUST CONCLUDE THAT THERE IS A REDUCTION IN ACTIVITY IN THE BRAIN AND YOU HAVE TO HAVE MORE INSIGHT AND MORE AWARENESS AS TO WHAT THESE POTENTIAL REGIONAL DIFFERENCES MIGHT MEAN. THERE'S BEEN TWO STU DID YOUS IN CIVILIAN TBI I WANTED TO HIGHLIGHT BECAUSE I THOUGHT THEY WERE QUITE INFORMATIVE. THE FIRST IT 47 MALES AND 22 FEMALES AND LOOKED AGAIN AT THE WHITE MATTER TRACTS AND IT WAS LOOKING AT ONE OF THE LONG WHITE MATTER -- IT FOUND THE FA IN THAT REGION WAS A BIT LOWER THAN IN THE FEMALES WITH TBI AND COMPARED TO CONTROLS, SO THERE WAS A DIFFERENCE BOTH BETWEEN MALE TBI AND FEMALE TBI AND BOTH CONTROLS. A SECOND STUDY SHOWED THAT FEMALE PATIENTS WITH M TBI BOTH HAD LOWER DIGIT SPAN SCORES BUT ALSO HAD DECREASED ACTIVATION SHOWING A COUPLING. NOW QUICKLY I'M GOING TO TALK ABOUT THE OSH THE OR -- HERE WE HAVE 17 FE MALES WITH TBI, 24 MALES WITH TBI, AND I THINK IN TERMS OF THEIR EDUCATION, APPROXIMATELY THE SAME EDUCATION, YOU CAN SEE THE DISTRIBUTION OF THEIR RANK AND SERVICE IS ABOUT SIMILAR, AND THE BIGGEST DIFFERENCE WAS WITH REGARD TO MARITAL STATUS WHERE FEMALES WERE NOT MAUER HE'D NOT MARRIED AN D MALES WERE MARRIED. THIS IS A FUNCTIONAL CONNECTIVITY, AND WHAT WE LOOKED AT HERE IS THE EXTENT TO WHICH THE OSH TOE OSH WE FIGURED THIS WOULD BE A PLACE WE'D LIKELY SEE DIFFERENCES. IN FACT WE DO SEE DIFFERENCES IN COULD NECK FIFTH BETWEEN MALES AND FEMALES SUCH THAT MALES HAVE INCREASED CONNECTIVITY BETWEEN SPECIFIC BRAIN REGIONS AND THEY DIFFER FROM FEMALES. THE TIME IS SO LIMITED I WON'T GO INTO TOO MUCH DETAIL HERE. AN IMPORTANT COMPONENT TO THIS WAS THAT WE LOOKED AT THIS IN THE CONTEXT OF SYMPTOMS AND SYNDROMES AND FOUND VERY STRONGLY FOR MALES BUT DID NOT CORRELATE FOR FEMALES, AND AS YOU CAN SEE WHEN YOU LOOK AT THE DISTRIBUTION HERE, THE CONNECTIVITY FOR FEMALE WAS MORE UNILATERAL AND FOCAL, WHERE THE CONNECTIONS FOR MALES WERE MORE DISTRIBUTED. SO WHAT DOES THIS MEAN? WELL, WE BELIEVE IT GIVES US INSIGHT INTO UNDERSTANDING AGGRESSION AND TERMS OF POTENTIAL RELATIONSHIP TO SUICIDE AND POTENTIAL RELATIONSHIP TO ACTING OUT AND OTHER PROBLEMS. QUICKLY HERE, THIS IS A PICTURE OF DATA COLLECTED ON 64 TRAUMATIC BRAIN INJURY VETERANS WHO UNDERWENT SPECTROSCOPY TO LOOK AT BIOCHEMICAL CHANGES. -- HAS BEEN ASSOCIATED WITH INFLAMMATION AND NEURODEGENERATION AND HERE WE SEE THIS TRAUMATIC BRAIN INJURY POPULATION IN OUR GROUP DOES SHOW THIS INCREASE IN MYELINOSITOL. THIS IS AN ANALYSIS OF THE LEFT AND RIGHT HIPPOCAMPUS LOOKING AT SHAPE, IMPORTANCE HERE WAS IF YOU DO STRAIGHT VOLUME ANALYSIS, YOU SEE NO DIFFERENCES BETWEEN ANY OF THESE POPULATIONS. THIS IS 57 INDIVIDUALS WITH TBI, AND IF YOU DIVIDE THEM INTO TBI WITH PTSD AND TBI WITHOUT PTSD, YOU SEE THAT YOU DO -- THOSE CHANGES EMERGED IF YOU LOOK AT THE LEFT-HAND SIDE, ON THE RIGHT, YOU DO SEE CORRELATIONS. THESE CORRELATIONS ARE WITH DEPRESSION SYMPTOMS, SO EVEN THOUGH THIS IS PTSD, WE CAN SEE THAT THE CA1 REGION OF THE HIPPOCAMPUS CORRELATES SIGNIFICANTLY WITH DEPRESSION, IF WE LOOK AT OUR SHAPE ANALYSIS. SO IN SUMMARY, AND WE'RE AGAIN LATE SO I WON'T GO ON TOO MUCH HERE, I THINK THE CONCLUSION SR. THAT WE DOOZIE DO SEE DIFFERENCES IN TRAUMATIC PRAIN INJURY RELATED TO WHITE MATTER, VOLUMES, FUNCTIONAL ACTIVITY, THE STRENGTH OF THE MODALITY WILL BE WHEN WE USE MULTIMODAL APPROACHES TO TRY TO GET AT MECHANISMS AS WELL AS STRUCTURE. WE NEED TO HAVE A BETTER UNDERSTANDING OF SEX DIFFERENCES IN BRAIN AND ORGANIZATION. I THINK THAT'S PARTICULARLY TRUE IN A PREMORBID OR PRE-INJURY CONDITION BECAUSE I THINK THERE ARE GOING TO BE CHANGES IN BRAIN THAT OCCUR THAT ARE NOT RELATED TO TBI, INDIVIDUALS WHO ENROLL AND ARE IN THE MILITARY ARE A SELECT GROUP WHO HAVE SELF SELECTED IN PART, AND WE NEED TO UNDERSTAND HOW REPRESENTATIVE EVEN PRIOR TO THE BLAST THEIR BRAINS ARE. WE NEED TO CONSIDER HORMONE LEVELS. WE HEARD ABOUT THAT YESTERDAY, I DON'T WANT TO GIVE THAT SHORT SHRIFT, I THINK WE CAN COMBINE THAT IN OUR IMAGING STUDIES. WE HAVE TO HAVE MORE OBJECTIVE EVALUATION OF OUR TBI SYMPTOMS RATHER THAN SELF-REPORT, IMPACT OF CO-MORBIDITY HAS TO BE FRONT AND CENTER BECAUSE I THINK MANY OF OUR TRAUMATIC BRAIN INJURY NEUROPATHOLOGY CHANGES RELATED TO NON-TBI-RELATED INJURY, AND MAY ALSO INTERACT WITH THEM. SEX DIFFERENCES IN MEDICATION RESPONSE ARE INCREDIBLY IMPORTANT IN DOCUMENTING CHANGES IN THE BRAIN, AND STANDARDIZED ASSESSMENT METHODS FOR ANALYSIS AND IMAGING WOULD HELPFUL BECAUSE RIGHT NOW WE HAVE MANY GROUPS USING MANY DIFFERENT FORMS AND IT'S VERY HARD TO MAKE CONCLUSIONS BASED ON THE DATA. SO I THINK I'VE COVERED MOST OF THIS ALREADY. DIFFERENTIATING ACUTE AND CHRONIC EFFECTS OF TBI. MOST OF THESE IMAGING STUDIES ARE DONE ANYWHERE FROM THREE TO FIVE TO 10 YEARS AFTER INJURY, SO WE'RE REALLY NOT LOOKING AT ACUTE EFFECTS OF THE INJURY. SO WE REALLY WANT TO INCREASE OUR ABILITY TO TRY TO UNDERSTAND BRAIN CHANGES RELATED TO THE ACUTE INJURY. THANK YOU VERY MUCH. SPECIAL THANKS TO AARON WHO DRIVES ALL THE VETERAN DATA IMAGING AND ANALYSIS IN OUR LAB. [APPLAUSE] >> I THINK WE HAVE ABOUT 18 MINUTES UNTIL WE HIT OUR 10:00 BREAK TIME TO TAKE SOME QUESTIONS TO OUR PANELISTS. LET'S MAKE SURE THEY'RE ALL SET. RIGHT HERE ON THE LEFT. >> HI, LYN FROM McMASTER UNIVERSITY. I HAVE A QUESTION ABOUT EDUCATION DIFFERENCES BETWEEN MEN AND WOMEN, SO IT CAME UP ACTUALLY WHEN DR. MCCRAY WAS TALKING ABOUT IT YESTERDAY, I WAS THINKING ABOUT IT BECAUSE I HAVE THE SENSE THAT FEMALE COLLEGIATE ATHLETES ALSO MIGHT BE A LITTLE MORE EDUCATED THAN MALE COLLEGIATE ATHLETES AND BECAUSE THERE ARE SOME DATA THAT WOMEN WHO ENLIST MIGHT HAVE HIGHER EDUCATION LEVELS THAN MEN, I WONDER IF ANY OF YOU HAVE THOUGHT OF HOW THAT MIGHT INTERACT WITH OUTCOME. THERE ARE SOME OLD, OLD TBI DATA SHOWING A LOSS OF IQ OF THE SAME NUMBER OF POINTS HAS DIFFERENTIAL EFFECTS AT DIFFERENT TAILS OF THE DISTRIBUTION, SO I WONDERED IF SOME OF THE REASONS WOMEN MIGHT REPORT MORE SYMPTOMS IS BECAUSE THEY'RE IN HIGHER DEMAND -- HIGHER COGNITIVELY DEMANDING POSITIONS. >> I'LL COMMENT A LITTLE BIT BECAUSE I'M STUDYING MALE AND FEMALE BASKETBALL PLAYERS AT THE UNIVERSITY OF UTAH. WHAT I WOULD SAY IS THAT ABSOLUTELY AT THE TAIL, WE DO SEE IT IMPACTED A FEWER IQ POINTS WOULD HAVE A BIGGER IMPACT. I DON'T THINK, AT LEAST IN THE DATA THAT WE'VE BEEN -- I'VE BEEN LOOKING AT WITH IMAGING, THEIR ESTIMATED IQ -- AND THE EDUCATION IS APPROXIMATELY THE SAME. SO IT IS A FACTOR, AND WE SHOULD PAY ATTENTION BOTH TO OVERALL CAPACITY, HOWEVER YOU WANT TO DEFINE THAT, AND TO EDUCATION, BUT I DON'T THINK IT HAS BEEN A PROBLEM FOR OUR IMAGES. >> ONE THING I KNOW AND IT'S NOT REALLY GETTING AT YOUR QUESTION, IN THE MILITARY AND VETERAN POPULATION, THE WOMEN -- A HIGHER PROPORTION OF WOMEN ARE OFFICERS COMPARED TO MEN, WHICH IS HIGHLY CORRELATED WITH EDUCATION, AND THOSE POSITIONS MAY HAVE DIFFERENT ROLES SO THAT MIGHT BE WHERE IT IS IMPACT SOME OF THE THINGS THAT WE SEE. IN ADDITION TO JUST THE EDUCATION. >> I WOULD ALSO ADD THAT IN MOST OF THE STUDIES OF NEUROPSYCHOLOGICAL DATA WE'VE LOOKED AT, THERE HAVEN'T BEEN STRONG DIFFERENCES IN EDUCATION BETWEEN MEN AND WOMEN, SO CERTAINLY A FACTOR THAT SHOULD BE CONSIDERED AND INVESTIGATED BUT I'M NOT AWARE OF ANY EVIDENCE. YET. >> IN OUR COHORT, WE DID FIND THAT DIFFERENT AND I THINK THE KEY THING WE WANTED TO FOCUS ON IN THAT INFORMATION WAS THAT, IN FACT, NOT ALL STRATEGIES ARE APPLICABLE TO ALL COHORTS. SO IF YOU'RE DEALING WITH A HIGHLY EDUCATED COHORT, YOUR GO-TO STRATEGY OF VOCATIONAL REHAB AND EDUCATION, ET CETERA, MIGHT NOT, IN FACT, BE APPROPRIATE UNTIL WE NEED TO THINK OUTSIDE THE BOX. >> DR. HOFFMAN? >> STU HOFFMAN, OFFICE OF RESEARCH AND DEVELOPMENT AT THE V.A. MY QUESTIN IS FOR DEBRA. I WAS REALLY INTRIGUED BY YOUR IMAGE ANALYSIS OF THE SHAPE OF THE HIPPOCAMPPI. DO YOU THINK THAT'S THE INTERACTION THAT'S CAUSING THE SHAPE CHANGE OR DO YOU THINK THE DETERIORATION OF THAT STRUCTURE OR CHANGE IN THAT STRUCTURE'S SHAPE IS INDICATIVE OF ADDED PSYCHIATRIC INVOLVEMENT IN THE DISABILITY? AND TWO, WAS THERE ANY DIFFERENCES WITH SEX IN THE SHAPE? >> SECOND ONE FIRST BECAUSE THAT'S EASY. THE SAMPLE HAD SUCH A SMALL NUMBER OF WOMEN, WE DIDN'T DO A SEX DIFFERENCE COMPARISON. I THINK IT WAS EIGHT WOMEN, SO IF YOU'RE INTERESTED, I COULD PULL IT OUT AND SEND IT, BUT WHAT WE THINK IT MEANS IS THAT THERE IS POTENTIAL RISK FOR PTSD AND THAT HIPPOCAMPPI HAD THAT SHAPE PRIOR TO THE TBI. WE DON'T KNOW THAT, THAT'S CROSS-SECTIONAL DATA, BUT THAT'S OUR WORKING HYPOTHESIS AT THE MOMENT. BECAUSE A TBI DID NOT SHOW THAT CORRELATION, TBI ALONE. >> DON MARAN. MY QUESTION IS FOR ODETTE. I WAS FOLLOWING WITH YOUR CROSS-SECTIONAL DATA AND THOUGHT I UNDERSTOOD A FEW THINGS AND THEN YOU TALKED ABOUT LONGITUDINAL DATA AND SAID IT DIDN'T CONFIRM. LET ME JUST ASK YOU, IS PTSD AND DEPRESSION, ARE PTSD AND DEPRESSION MORE COMMON IN ACTIVE DUTY WOMEN OR VETERAN WOMEN, AND IF SO OR IF NOT, HOW DO YOU FACTOR IN SEXUAL ASSAULT AND THE EFFECT OF THAT ON PTSD? >> I ACTUALLY DON'T THINK I'M PROBABLY THE BEST PERSON ON THE PANEL TO ANSWER THAT, MAYBE EVEN DR. LIPPA AND HER WORK. OUR WORK REALLY DIDN'T GO INTO ANY SORT OF CAUSATIVE OR PREDICTIVE ANALYSIS OF THAT INFORMATION. AND WE DIDN'T LOOK AT MILITARY SEXUAL TRAUMA AT ALL IN OUR DATASET. SO I REALLY COULDN'T ANSWER THAT UNFORTUNATELY. WE COULD SORT OF HYPOTHESIZE IF WE THINK THERE IS A LINK, BUT I DON'T HAVE THE DATA TO BACK THAT ASSUMPTION. >> UNFORTUNATELY IN OUR STUDIES, WE TOOK OUR FEMALES WITH PTSD, MATCHED THEM TO MALES WHO ALSO HAD PTSD AND MATCHED WOMEN WHO DID NOT HAVE PTSD TO MALES WHO DID NOT AND WE DIDN'T REALLY LOOK AT THE DIFFERENCE IN PREVALENCE RATES. WE ALSO DIDN'T LOOK AT MST, SO I CAN'T REALLY SPEAK TO THAT. >> I THINK ARMY STARS DATA SUGGEST THAT PTSD IS PERHAPS A FACTOR AT LEAST IN SOME CASES OF SEXUAL ASSAULT AND CERTAINLY SUICIDE IS GREATER AND WOMEN OFFICERS HAVE A HIGHER RISK OF PTSD, ACCORDING TO -- >> YEAH, I THINK EVERYONE SORT OF AGROWS TO THAT. I THINK THE IOM REPORT WAS PRETTY CLEAR IN STATING THAT WE SHOULD ACTUALLY BE LOOKING AT THAT AND ASKING THOSE QUESTIONS AS WE FRAME FUTURE WORK. UNFORTUNATELY BECAUSE WE WERE LOOKING IN RETROSPECTIVE ANALYSIS IN A LOT OF THE DATA THAT WE REVIEWED FOR THE FIRST PART OF THE STUDY THAT I TALKED ABOUT, WE COULDN'T GO BACK AND ASK THOSE QUESTIONS, SO THAT'S WHAT I WAS ALSO HINTING AT WHEN I SAID THAT WE NEED MORE PRECISE TATA ACQUISITION AND BETTER METHODOLOGIES, AND I THINK WE SHOULD INCORPORATE THAT FOR SURE. >> DEBRA, DID YOU HAVE ANYTHING TO ADD ON THAT? >> I WAS JUST GOING TO SAY, WE HAVE A SMALL PILOT DATASET OF ABOUT 90 PEOPLE THAT WE INTERVIEWED AND WE SAW AGAIN THE NUMBER OF WOMEN WAS VERY SMALL, 10, I THICK, THINK, IN THAT POPULATION, BUT MILITARY SEXUAL TRAUMA OCCURRED IN MALES AND FEMALES AND WAS ASSOCIATED WITH PTSD IN BOTH OF THOSE GROUPS. >> DR. RASMUSSEN? >> HI, ANNE RASMUSSEN, THE NATIONAL CENTER FOR PTSD, WOMEN'S HEALTH SCIENCE DIVISION UP IN BOSTON, AND ACTUALLY IN JUST A FOLLOW-UP TO THE QUESTION ABOUT THE DEPRESSION, I NOTICE PEOPLE OFTEN LOOK AT PTSD AND DEPRESSION AS SEPARATE AND INDEPENDENT FACTORS IN ANALYSES, AND SO I HAVE A COMMENT FIRST ABOUT THAT AND A QUESTION, AND THE COMMENT IS THAT VIRTUALLY ALL EPIDEMIOLOGIC STUDIES SHOW THAT DEPRESSION ALONE IS PRESENT IN ABOUT 5% OF THE POPULATION BEFORE TRAUMA. AFTER TRAUMA, DEPRESSION ALONE IS PRESENT IN ABOUT 6%, BUT DEPRESSION GOES WAY UP AFTER TRAUMA IN ABOUT 95% OF THE CASES, IT'S IN THE CONTEXT OF PTSD SO I THINK WE NEED TO KEEP IN MIND THERE'S A VERY BIG OVERLAP OF SYMPTOMS, BUT PTSD WITH DEPRESSION MAY BE SORT OF ITS OWN ENTITY WHICH IS HIGHLY INFLUENCED BY EXPOSURE TO STRESS, IF WE LOOK AT DEPRESSION ALONE AND SAY DEPRESSION IS HIGH IN WOMEN, THEN IT IGNORES THE FACT THAT IT'S IN THE CONTEXT OF PTSD IN THE LEVEL OF STRESS EXPOSURE, WHICH WOULD BE IMPORTANT TO QUANTIFY, AND ALSO OUR NEUROBIOLOGICAL DATA SUGGESTS THAT THE ENDOPHENOTYPE WHERE YOU HAVE, FOR EXAMPLE, WITHIN PTSD THE DEPRESSIVE SYMPTOMS WHICH ARE BEST CAPTURED NOT BY THE COMMITTEE DERIVED AVOIDANCE STUFF, BUT RATHER BY THE CONFIRMATORY FACTOR ANALYSIS THAT ARE -- EUPHORIA FACTOR, FOR EXAMPLE, LINES UP BETTER WITH THE NEUROBIOLOGY, SO IT WOULD MAKE SENSE AGAIN NOT NECESSARILY ALWAYS TO LOOK AT TOTAL PTSD WHICH IS MORE IMPORTANT, BUT ALSO THESE FACTOR ANALYZED COMPONENTS IF WE WANT TO MAP IT BACK TO THE BIOLOGY. SO I DIDN'T SEE THAT HAPPEN SO ONE QUESTION IS DID YOU CONSIDER THAT. THE SECOND QUESTION I HAVE IS ABOUT NICOTINE, AND I NOTICE THAT EVERYBODY IS LOOKING AT SUBSTANCE ABUSE, BUT OFTEN WHEN I GO BACK TO LOOK, IT LOOKS LIKE FOLKS HAVEN'T ACTUALLY INCLUDED NICOTINE OR DEPENDENCE, AND WE ACTUALLY RECENTLY LOOKED AGAIN, SARAH, AT THE TRACKS DATASET AND FOUND AMONG THE SMOKERS, THE CLUSTERING OF PTSD, DEPRESSION AND PAIN HAD AN ODDS RATIO OF 3.5 COMPARED TO ANY OTHER COMBINATION, DIAGNOSIS OR DIAGNOSIS ALONE SO IT CONFERRED CO-MORBIDITY AND THE ALCOHOL DIDN'T DO THE SAME THING, BUT I THINK WE OFTEN LEAVE THAT OUT AND IT MAY BE A FACTOR THAT CAN EXPLAIN SOME OF THE BIOLOGY AND THE COMORBIDITIES THAT WE'RE GRAPPLING WITH. SO THE QUESTION IS IN YOUR STUDIES, DID YOU CONSIDER THE NICOTINE DEPENDENCE AS WELL? >> SO THANK YOU VERY MUCH FOR YOUR COMMENTS AND QUESTIONS. WE CERTAINLY DO LACK AT NICOTINE. I DIDN'T PRESENT THAT DATA. AND WE ARE USING ALSO AN RDOC APPROACH LOOKING AT INDIVIDUAL SYMPTOMS AS WELL AS SYNDROMES, SO WE HAVE BROKEN THAT OUT. IN THE AMOUNT OF TIME WE HAD TODAY AND THE AMOUNT THAT HAD TO BE COVERED, I TRIED TO GIVE A SNAPSHOT. SO I WOULD SAY FOR OUR POPULATION, NICOTINE WAS NOT A SIGNIFICANT FACTOR RELATIVE TO THE DEPRESSIVE SYMPTOMATOLOGY OR THE ANXIETY OR THE ALCOHOL. ALCOHOL WAS OUR BIGGEST PROBLEM. UTAH TENDS TO HAVE A NON-SMOKING KIND OF ENVIRONMENT. WE DO HAVE SMOKERS FOR SURE, BUT IT'S NOT LIKE WHEN I COME BACK TO CAN BOSTON, IT'S BOSTON, IT'S REALLY DIFFERENT. SO I DON'T KNOW IF THAT HAD A CONTRIBUTING FACTOR OR NOT. >> I THINK AGAIN IF IT'S CLUSTERED WITH IT. >> I UNDERSTAND. THANK YOU. >> I HAVE NOT INCLUDED THAT BECAUSE WE HAVE A LIMITED NUMBER OF THINGS WE CAN PUT IN A MODEL THAT ALLOW IT TO CONVERGE, BUT I WILL RE-EVALUATE THAT BECAUSE I THINK IT'S A GREAT IDEA. >> THANKS. >> DR. LAVIN? >> HI, THANK YOU FOR A REALLY INFORMATIVE AND CLEARLY PRESENTED TALKS. I HAVE A QUESTION FOR DEBORAH, ACTUALLY TWO QUESTIONS, BUT THE SECOND ONE, PERHAPS OTHER PANELISTS MIGHT WANT TO COMMENT. FIRST IS, IN THE FUNCTIONAL CONNECTIVITY OF ORBITOFRONTAL INDEX AMIG DID YOU LA, I WAS WONDERING, IF, IN FACT, THE LEVEL OF AGRESSIVITY WAS HIGHER IN THE MALES AND IT WAS LOW IN THE FEMALES, COULD THAT HAVE ATTENUATEED THE POTENTIAL FOR FINDING A CORRELATION IN THE FEMALES? THAT'S MY FIRST QUESTION. SECOND QUESTION, YOU'VE PROBABLY SEEN IN THE LITERATURE, I DON'T RECALL THE SOURCE OFFHAND, BUT THAT IN TERMS OF STRUCTURAL CONNECTION, MAYBE IT'S ALSO FUNCTIONAL, BUT THERE ARE MORE THAT ARE ANTERIOR POSTERIOR CONNECTIVITY IN MALES AS COMPARED TO LATERAL INTERHEMISPHERIC CONNECTIVITY IN FEMALES. I WAS WONDERING IF YOU'VE LOOKED AT THAT AND THERE THAT MIGHT -- WHETHER ALTERATIONS FOLLOWING TBI MIGHT BE INFORMATIVE TO STUDY. >> THANK YOU FOR YOUR QUESTION. WE HAVE NOT LOOKED AT WHETHER INTERHEMISPHERIC CONNECTIVITY IS STRONGER OR DIFFERENT IN MALES AND FEMALES, BUT THAT CERTAINLY WOULD BE A GOOD IDEA. THE ANALYSIS I SHOWED WAS JUST A DIRECT COMPARISON OF MALE MALE VETERANS AND FEMALE VETERANS SO IT DIDN'T TAKE INTO ACCOUNT A PARTICULAR HYPOTHESIS REGARDING DIRECTION OR LATERALITY. REGARDING THE AGGRESSION CORRELATION WITH THE OVER THE FRONTAL CONNECTIVITY, THERE WAS GREATER AGGRESSION IN MALES AND THAT FEMALES SO THERE IS CERTAINLY THE POTENTIAL THAT WE'VE MISSED A POTENTIAL CORRELATION SHOULD IT EXIST IN THE FEMALES. AND I THINK WE NEED TO GET A LARGER SAMPLE SIZE BUT IT WAS INTERESTING THAT WE SAW IT IN THE MALES. BUT IT SHOULD DEFINITELY BE REPLICATED. I FEEL LAKE ALL THE IMAGING DATA IS PROBLEMATIC BECAUSE OF THE SMALL SAMPLE SIZE AND THE HETEROGENEITY THAT WE TALKED ABOUT BOTH CLINICALLY AND IN TERMS OF INJURY. BUT IMAGING AS YOU KNOW IS VERY EXPENSIVE SO WE HAVE TO CONVINCE SOMEBODY TO PAY US TO DO THOSE STUDIES. BUT IT'S AN INTERESTING PILOT PRELIMINARY FINDING. >> HI. I'M HARMONY ALLEN. SO I'M A PATIENT, AND I WANTED TO FIRST JUST STATE THAT I DO LOVE THE TAMPA POLYTRAUMA, THEY'VE BEEN WONDERFUL TO ME. BUT WHEN I WAS FIRST INJURED, I WENT TO MINNEAPOLIS V.A. WHO ALL AGREED I SHOULD BE ACCEPTED INTO P -- BUT BECAUSE I WOULD TAKE UP TWO ROOMS BECAUSE THERE'S CONJOINING BATHROOM, I WAS REFUSED TO THE POLYTRAUMA PROGRAM. SO I THINK IF YOU GUYS LOOK AT THE HEADS OF THESE POLYTRAUMA PROGRAMS, I BET YOU'RE GOING TO HAVE A LOT MORE FEMALES THAT ARE BRAIN-DAMAGED THAT YOU COULD DO STUDIES ON, BUT WE ARE BEING REFUSED. AND THAT IS A SERIOUS PROBLEM THROUGHOUT THE V.A., AND SO I WAS SENT BACK TO ACTIVE DUTY WHERE I WAS PUT ON MENTAL HEALTH DRUGS TO GET ME THROUGH UNTIL I WAS MEDICALLY DISCHARGED, BUT THAT WASN'T THE CASE. IT WAS TBI. THEY DID FOLLOW UP MRI, THEY PROVED THAT, HEY, SHE'S GOT FRONTAL BRAIN DAMAGE, BUT THAT WAS A TRUE CASE WHERE MINNEAPOLIS SAID, HEY, WE GOT TOO MANY GUY TBIs, WE JUST CAN'T TAKE YOU. AND SECOND, BECAUSE MY ACCIDENT WAS PARACHUTING, I WANTED -- MY HOPES, WHICH I WAS EXCITED ABOUT THE V.A. PANEL, IS THAT WHEN YOU'RE SKY-DIVING, YOU'RE FALLING AT 120 MILES PER HOUR. UNDERNEATH YOUR PARACHUTE, YOU'RE GLIDING AT 35 MILES PER HOUR DOWN. YOU KNOW, YOUR HELMET DOESN'T PROTECT YOU. A HUMMINGBIRD'S TONGUE WRAPS AROUND THEIR BRAIN, WHICH IS HOW THEY'RE ABLE TO PET, SO WE HAVE ALL THESE MULTIPLE OPENINGS WITH OUR HEADS BEING FLUNG BACK, GETTING COUP-CONTRECOUP. I'VE HAD A COUPLE DOCTORS STATE, YES, WITH ALL THOSE OPENINGS, YOU'RE GETTING MINI CONCUSSIONS. BUT WITH ALL THESE STUDIES AND ALL THESE SPORTS, NOBODY ADDS SKY-DIVING TO IT. YOU KNOW, THEY SAY BASKETBALL. YOU'RE NOT EVEN GETTING HIT IN THE HEAD. MAYBE EXCEPT IF YOU MISS THE PASS, YOU KNOW, THE HOCKEY, THE SOCCER. BUT THE REALITY IS,ER EVERY SINGLE OPENING, YOU'RE BEING SLAMMED AT BASICALLY 90 MILES PER HOUR, AND SO THERE'S A LOT OF VETERAS WHO END UP HOMELESS, THERE'S A LOT OF VETERANS WHO AREN'T GETTING THE RIGHT TREATMENT BECAUSE NOBODY LOOKED NOBODY LOOKED AT THEIR ACTUAL OCCUPATION. AND SKY-DIVING IS SOMETHING THAT IS IMPORTANT TO ME AND MY HOPES ARE THAT YOU GUYS CAN EXPAND YOUR RESEARCH BECAUSE THERE'S A LOT OF VETERANS NOT GETTING THAT RIGHT TREATMENT BECAUSE NOBODY EVER STOPPED AND SAID, HEY, THEY'RE SKY DIVERS. HOW MANY OPENINGS DID THEY GO THROUGH? AND THE HELMET DOESN'T DO ANYTHING FOR IT EXCEPT PROTECT THE OUTSIDE OF THE CRANE, SO THEY'RE ALL SUFFERING FROM COUP-CONTRECOUP. I JUST WANTED TO MAKE THOSE COMMENTS IN ORDER TO HELP WOMEN AND TO HELP PROFESSIONAL SKY DIVERS. SO THANK YOU GUYS. >> THANK YOU VERY MUCH FOR LETTING US KNOW. I'M REALLY TROUBLED TO HEAR THAT YOU WERE DENIED SERVICES JUST BECAUSE YOU WOULD HAVE HAD TO SHARE A BATHROOM AND THEY COULDN'T WASTE THE RESOURCES ON THAT. I DO THINK THE POINT ABOUT THE SKY-DIVING AND THE MULTIPLE HITS IS GETTING AT SOMETHING THAT WE ALSO NEED TO FOCUS ON, WHICH IS SUBCONCUSSIVE HITS, SO IT MIGHT NOT BE THAT IF YOU'VE DONE 200 JUMPS, EVERY TIME YOU HIT THE GROUND, YOU SUSTAINED A CONCUSSION. BUT WE SHOULD DEFINITELY BE ASKING ABOUT THOSE HITS AND GETTING MORE INFORMATION AND EVALUATING THEM. >> YES, IT'S MORE THE OPENINGS. >> AND THE OPENINGS. >> AND YOU'RE BEING THROWN BACK, IS HOW I GOT A C2 FRCT. >> SO2 FRACTURE. I ACTUALLY BROKE MY NECK. >> SO THE OPENINGS AS WELL. >> YES. >> I KNOW THERE'S A LOT OF RESEARCH STARTING TO LOOK AT SUBCONCUSSIVE HITS, BUT WE'RE JUST REALLY IN THE INFANCY IN THAT AREA AS WELL, BUT CERTAINLY THE OPENINGS WILL BE IMPORTANT TO LOOK AT. >> THANK YOU. >> THANK YOU, HARMONY. WE'LL TAKE THESE LAST TWO QUESTIONS TOO. >> WE ARE ACTUALLY LOOKING AT JOB KIND OF MILITARY OCCUPATIONAL SPECIALTIES AND WE ARE LOOKING AT PARATROOPERS SPECIFICALLY. >> THANK YOU SO MUCH. >> HOPEFULLY WE'LL HAVE SOME GOOD DATA FOR YOU SOON. >> THANK YOU SO MUCH. >> HI. COLE FROM WEST VIRGINIA UNIVERSITY. I'LL TROOB TO BE TRI-TO BE BRIEF. ONE OF THE THINGS I'VE NOTICED, THINGS LIKE SUBSTANCE USE DISORDER, ORBITOFRONTAL CONNECTION PROBLEMS, RELATED AGGRESSION POTENTIALLY. ARE ANY OF YOU IN YOUR STUDIES DIRECTLY MEASURING IMPULSIVITY OR IMPULSE CONTROL? IT SEEMS LIKE SOMETHING THAT COULD POTENTIALLY BE RELATED TO A LOT OF THESE SPECIFIC DIFFERENT DISORDERS THAT ARE BEING LOOKED AT AND POTENTIALLY EVEN SERVE AS SOMEWHAT OF AN INTERMEDIARY PHENOTYPE,& POTENTIALLY EVEN LINKING TO SOME OF THE PTSD THINGS WITH IMPAIRED EMOTIONAL REGULATION AS WELL, SO ARE YOU MEASURING THAT IN ANY WAY? >> YEAH, WE ARE. WE HAVE ABOUT AN EIGHT-HOUR CLINICAL BATTERY THAT WE GIVE ALONG WITH OUR IMAGING PROTOCOL, SO IT HAS FULL NEUROCOGNITIVE ASSESSMENT AS WELL AS A NUMBER OF IMPULSIVITY MEASURE, BOTH OBJECTIVE ONES LIKE BLEUL NAN LOG TEST AND SELF-REPORT MEASURES. THANK YOU. >> LAST QUESTION BEFORE A 10-MINUTE BREAK. >> THANK YOU ALL SO MUCH FOR YOUR IMPORTANT WORK. MY QUESTION, MAYBE IT'S MORE OF A COMMENT AS WE HEARD ABOUT WE ALSO NEED TO BE STUDYING THE EFFECTS OF SEXUAL ASSAULT, BUT IT HAD ME THINKING FOR THIS PANEL IN PARTICULAR AMONG MILITARY POPULATIONS, WE HAVE TO LET ALL OUR POPULATIONS REALLY UNDERSTAND THE CONTEXT OF WOMEN'S LIVES AND THE FACTS THAT WOMEN EXPERIENCE MORE INTERPERSONAL VIOLENCE OVER THE COURSE OF THEIR LIFE THAT UNFORTUNATELY OFTEN STARTS AT A VERY YOUNG AGE. BOTH MEN AND WOMEN GO INTO THE MILITARY AND ARE LIKELY TO HAVE CHILD FOOD HIZ CHILDHOOD PHYSICAL AND SEXUAL ABUSE, AND I'M WONDERING AS A WHOLE HOW WE CAN DO A BETTER JOB OF INCORPORATING LIFE HISTORY, INTO OUR STUDIES WITH MILITARY POPULATIONS BUT ALSO AMONG -- WHEN WE STUDY THE EFFECTS OF TBI IN SPORTS AND AMONG SPORTS MEMBER, WE KNOW THAT CERTAINLY THE WOMEN AND MEN ARE NOT IMMUNE TO VIOLENCE OVER THE COURSE OF THEIR LIFETIME INCLUDING INTERPERSONAL VIOLENCE. SO MORE OF A PLEA I GUESS FOR ALL OF US TO INCORPORATE MORE OF THAT INTO OUR WORK MOVING FORWARD. >> THANK YOU FOR THAT. I THINK THAT'S SORT OF WHAT DON IS GETTING AT AS WELL, I THINK ALL OF US RECOGNIZE THAT THAT IS IMPORTANT, AND I THINK YOUR COMMENT, THAT'S DEFINITELY ONE OF THE TAKEAWAYS FROM THESE TWO DAYS, IS THAT WE SHOULD BE VIEWING THESE PATIENTS AS A WHOLE AND NOT JUST IN SILO OF THEIR EXPERIENCE AROUND THE TBI ITSELF BUT THAT MUCH IS PROBABLY INFLUENCING THEIR OUTCOMES IN HOW THEY EVENTUALLY DO. >> OKAY, THAT WILL CONCLUDE. THANK YOU TO OUR FOUR SPEAKERS AND THANK YOU FOR YOUR ATTENTION. WE'LL BE BACK AT 10:15 TO START THE NEXT SESSION. [APPLAUSE] WE WANTED TO REMIND EVERYONE OF TWO THINGS. ONE IS THAT IN JUNE, ON JUNE 11TH THROUGH THE 13TH, THE FEDERAL INTERAGENCY TBI CONFERENCE IS HAPPENING. I THINK -- IT HASN'T HAPPENED IN FOUR YEARS OR SOMETHING? FOUR YEARS. SO THIS IS A BIG CONFERENCE, A LOT OF PEOPLE, AND THEY'RE STILL ACCEPTING ABSTRACTS, SO IF YOU -- THE DATA THAT YOU'VE PRESENTED HERE, IF YOU WANT TO PRESENT AT THAT MEETING, PLEASE FEEL FREE TO SUBMIT, AND THE OTHER THING IS, THE OFFICE OF RESEARCH IN WOMEN'S HEALTH HAS AVAILABLE FOR THOSE OF YOU THAT HAVE NIH GRANTS HAS ADMINISTRATIVE SUPPLEMENTS THAT YOU CAN APPLY FOR, SO PLEASE LOOK AT THAT ONLINE. THAT'S A REALLY GREAT PROGRAM THAT CAN HELP YOU EXPAND YOUR RESEARCH SCOPE TO INCLUDE DIFFERENCES IN SEX AND GENDER. OUR NEXT MODERATOR IS THE DIRECTOR OF NCMRR, ALISON CERNICH, SO PLEASE WELCOME HER. >> WELCOME BACK TO THE SECOND PART OF THE MORNING, FOLKS. THIS WOULD BE A PANEL ON SEX DIFFERENCES IN DIAGNOSIS, PROGNOSIS AND MANAGEMENT OF TBI, AND NCMRR FOR THOSE NOT FAMILIAR STANDS FOR THE NATIONAL CENTER FOR MEDICAL REHABILITATION RESEARCH AT NIH. WE'RE LOCATED IN THE EUNICE KENNEDY SHRIVER INSTITUTE FOR CHILD HEALTH AND HUMAN DEVELOPMENT. IF YOU CAN SAY THAT THREE TIMES FAST, YOU CAN ALSO COME AND CHECK OUR OUR OPPORTUNITIES FOR FUNDING REHABILITATION RESEARCH AND ALSO WE JUST WANT TO PROMOTE THE FACT THAT NIH DOES FUND A GREAT DEAL OF REHABILITATION RESEARCH, ESPECIALLY IN TBI. SO FOR THOSE REALLY MORE INTERESTED IN THE POST INJURY MANAGEMENT AND REHABL TAI WE REHABILITATIO N, WE DO WELCOME THOSE APPLICATIONS. WE'LL START WITH DR. REBEKAH MANNIX FROM BOSTON CHILDREN'S HOSPITAL. HER CLINICAL RESEARCH INTEREST IS IN THE IDENTIFICATION OF NEW SERUM IMAGING BIOMARKERS FOR DIAGNOSING AND MANAGING MILD TRAUMATIC BRAIN INJURY AND SHE ALSO DEVELOPS NEW TARGETED INTERVENTIONS FOR PEDIATRIC TRAUMATIC BRAIN INJURY. SHE'S GOING TO TALK ABOUT SEX DIFFERENCES IN PROGNOSTIC MARKERS. DR. MANNIX. >> THANK YOU FOR INVITING ME TO SPEAK TODAY. I'M GOING TO TALK ABOUT SEX DIFFERENCES IN PROGRESS NOISE TICK AND DIAGNOSTIC MARKERS IN TBI. I HAVE NO RELEVANT FINANCIAL DISCLOSURES OR CONFLICTS OF INTERESTS TO REPORT FOR WHICH I BLAME DR. GOWAN. [LAUGHTER] SO WHEN I WAS FIRST ASKED TO GIVE THIS TALK, I IMMEDIATELY, OF COURSE, THOUGHT ABOUT SEINFELD. AS YOU ALL PROBABLY REMEMBER, SEINFELD IS A SHOW ABOUT NOTHING. WHICH IS ACTUALLY WHAT THIS TALK IS GOING TO BE ABOUT BECAUSE AS YOU'VE LEARNED IN THE PAST DAY, WE REALLY HAVE VERY FEW DIAGNOSTIC OR PROGNOSTIC MARKERS OF TRAUMATIC BRAIN INJURY. SO TODAY I'M GOING TO TALK A LITTLE ABOUT THE EPIDEMIOLOGY, NOT ABOUT THE WAY WE'VE ALREADY HEARD WITH IN DEPTH DETAILS BUT SOME META CONCEPTS ABOUT EPIDEMIOLOGY IN MILD TRAUMATIC BRAIN INJURY AND TRAUMATIC BRAIN INJURY. I'M GOING TO TALK ABOUT SOME LESSONS FROM ALZHEIMER'S AND STROKE, WHICH IS ALSO SLIGHTLY IRONIC SINCE I'M A PEDIATRIC EMERGENCY MEDICINE PHYSICIAN SO I REALLY KNOW NOTHING ABOUT ALZHEIMER'S OR STROKE, THEN I'M GOING TO TALK ABOUT THE STATE OF THE STATE IN TERMS OF BIOMARKERS OF TBI. A CAVEAT WE HEARD YESTERDAY THAT WHEN EAR TALKING ABOUT TBI, WE SHOULD BE PRETTY SPECIFIC ABOUT WHAT SORT OF FORM OF TBI ARE WE TALKING ABOUT, MILD, MODERATE/SEVERE, THE UNDERLYING PATHOLOGY, DIFFUSE AXONAL INJURY, HEMORRHAGIC. I'M GOING TO SPEND MOST TIME TALKING ABOUT MILD TRAUMATIC BRAIN INJURY BUT YESTERDAY MY OWN FAMILY WAS SORT OF BROUGHT INTO THE WORLD OF SEVERE TRAUMATIC BRAIN INJURY. I GOT A PANICKED CALL FROM MY HUSBAND BECAUSE THE ELF ON THE SHELF WAS EATEN BY OUR DOG. IT LOOKS LIKE A CAP TERRY LESION. I THINK THE PROGNOSIS WAS BAD, BUT LUCKILY THE ELF WAS ENROLLED IN THE ADAPT TRIAL. I'M HAPPY TO REPORT THAT AFTER INTRACRANIAL PRESSURE MONITORING AND HYPERTONIC SALINE, THE ELF IS NOW SITTING ON A SHELF IN OUR HOUSE. SO THE FIRST CONCEPT IS EPIDEMIOLOGY 101. I HAVE FOUR QUESTIONS THAT I WANT THE GROUP TO CONSIDER. IS SEX ASSOCIATED WITH OUTCOMES AFTER TBI? THE NEXT QUESTION IS, IS SEX ASSOCIATED WITH A GIVEN PROGNOSTIC BIOMARKER BUT DOES NOT LIE -- THAT MARKER DOES NOT LIE IN THE CAUSATIVE PATHWAY. AND THIS IS THE CLASSIC CONFOUNDER, RIGHT? THIS IS WHAT WE TALK ABOUT CONFOUNDING. SO THERE'S AN ASSOCIATION WITH THE MARKER, THERE'S AN ASSOCIATION WITH THE OUTCOME, BUT IT'S SORT OF A NUISANCE VARIABLE. AND FOR THAT, IN TERMS OF STATISTICAL MODELING, WHAT WE REALLY DO IS JUST THROW OUT THE MODEL, RIGHT? THIS IS WHAT YOU DO WHEN YOU'RE JUST THROWN SOMETHING IN THE MODEL. I THINK IT'S RELATED, I'M NOT SURE WHAT TO DO, I'M JUST GOING TO THROW IT IN THAT STATISTICAL MODEL. BUT THERE'S ANOTHER QUESTION WHICH WE'VE TALKED ABOUT PRETTY MUCH THIS WHOLE CONFERENCE, AND IS THAT -- IS SEX IN THE CAUSATIVE PATHWAY, SO THERE'S A BIOLOGICAL EFFECT OF SEX. AND FOR THAT QUESTION, WE ACTUALLY HAVE TO THINK ABOUT OUR ANALYSES A LITTLE BIT DIFFERENTLY. SO THIS IS THE CLASSIC EFFECT MODIFICATION BY SEX, AND THIS ISN'T A THROW IT IN THE MODEL KIND OF ANALYSIS, THIS IS KIND OF ANALYZED SEPARATELY. THAT IS A HUGE STATISTICAL DIFFERENCE THAT I WANT YOU ALL TO THINK ABOUT. FINALLY, AS I BROUGHT UP THIS CONCEPT WITH A STATISTICIAN WHO IS A VERY SALTY PERSON, MANY OF YOU KNOW THIS PERSON, I WON'T NAME HIS NAME, SO I POSED THESE QUESTIONS TO HIM AND HE SAID: DOES IT MATTER? AND THAT ACTUALLY THREW ME OFF BECAUSE I'D ALREADY WRITTEN THIS THOUGHT, I THOUGHT IT MATTERED, THEN I THOUGHT MAYBE IT DOESN'T MATTER, BUT I ACTUALLY THINK IT MATTERS. THE REASON I THINK IT MATTERS IS BASED ON OTHER DISEASE PROCESSES THAT I THINK ARE DOING A MUCH BETTER JOB OF THINKING ABOUT SEX-RELATED DIFFERENCES. SO THIS IS WHY IT MATTERS. I'M GOING TO BRING UP THE CONCEPT OF HIGH CONCEPT TRA TROPONIN, THIS IS SOMETHING THAT PLAGUES ER DOCTORS WHICH IS THE CONCEPT OF RULE OUT MYOCARDIAL INFARCTION, AND RULING OUT MYOCARDIAL INFARCTION IS BASED ON TROPONIN ASSAYS, WHICH IS A BIOMARKER OF CARDIAC INJURY. SO THE REASON THIS IS HARD IN EMERGENCY MEDICINE IS WHEN YOU'RE RULING OUT MYOCARDIAL INFARCTION, YOU USE THE TROPONIN AS SORT OF YOUR RISK STRATIFICATION, YES, I'M WORRIED ABOUT IT, NO, I'M NOT, BUT IT'S NOT A ONE-TIME MEASUREMENT. IT'S A MEASUREMENT YOU DO SERIALLY OVER SIX HOURS. NOW FOR ANY OF YOU WHO HAVE FRIENDS IN EMERGENCY MEDICINE, YOU KNOW SIX HOURS TO US IS LIKE FIVE YEARS, RIGHT? WE ALL HAVE ADHD, SIX HOURS IS AN INCREDIBLY LONG TIME, SO THE SEARCH FOR BIOMARKERS THAT COULD MORE QUICKLY RULE OUT MYOCARDIAL INFARCTION WAS ON. AND SO FOLKS CAME UP WITH THIS THING CALLED A HIGH SENSITIVITY TROPONIN AND COULD WE WITH BUN ONE BIOMARKER ASSESSMENT RULE OUT MYOCARDIAL INFARCTION. SO WHEN HIGH SENSITIVITY TRA TOE NIN WAS SORT OF INTRODUCED TO THE WORLD, ALL THE OBLIGATORY ANALYSES CAME OUT AND THE FIRST THING THAT HAPPENED IN THE NEW ENGLAND JOURNAL OF MEDICINE WAS A LARGE PAPER WAS SORT OF PUBLISHED ABOUT THE SENSITIVITY AND PREDICTIVE VALUE OF HIGH SENSITIVITY TROPONIN. WHAT I WANTED TO SHOW YOU IS THAT IN THESE ORIGINAL ANALYSES, WHAT CAN YOU SEE? YOU CAN SEE THAT SEX WAS TREATED AS WHAT? A CONFOUNDER, RIGHT? IT'S THROWN IN THE MODEL. WE'RE ADJUSTING FOR AGE AND GENDER, WE'RE SAYING SEX IS A CONFOUNDER POTENTIALLY OF HIGH SENSITIVITY OF TROPONIN, IT PERFORMS VERY WELL ACUTELY AND AT CERTAIN TIME POINTS, SO THE HOLY GRAIL OF QUICK ER RULEOUT OF MYOCARDIAL INFARCTION. SO OVER TIME, PEOPLE SAID THIS IS IT, WE'RE GOING TO GO TO QUICK RULEOUTS, WE'RE GOING TO USE THIS HIGH SENSITIVITY TROPONIN, THEN PEOPLE STARTED REALIZING WE WERE MISSING PEOPLE, WHO DO YOU GUYS THINK WE WERE MISSING? I'LL GIVE YOU A GUESS. WE WERE MISSING WOMEN. AND SO THIS IS A STUDY LOOKING AT THE COMPARISON OF THE CLASSIC TROPONIN ASSAY ON THE LEFT SIDE HERE, AND WHAT DO YOU SEE? WITH THE CLASSIC TROPONIN, YOU SEE THAT A LARGER PROPORTION OF MEN ARE DIAGNOSED THAN A PROPORTION OF WOMEN WITH MYOCARDIAL INFARCTION. WHEN WE MOVED TO THE HIGH SENSITIVITY TROPONIN, SO WE'RE ABLE TO RULE PEOPLE OUT QUICKER BUT WHO ARE WE STILL MISSING? WE'RE MISSING WOMEN. THEN THE OBSERVATION WAS THAT IF WE ACTUALLY USE SEX-SPECIFIC CUTOFFS, SO INSTEAD OF SAYING ONE CUTOFF FOR MEN AND WOMEN, WE ACTUALLY USE SEX-SPECIFIC CUTOFFS, THAT'S VERY HARD TO SAY, YOU CAN SEE THAT THE DIAGNOSIS OF MYOCARDIAL INFARCTION DRASTICALLY INCREASED IN WOMEN. THERE ARE PLENTY OF OTHER CLINICAL EXAMPLES IN THE CARDIOVASCULAR WORLD, AND YOU CAN'T READ THIS AND I DON'T EXPECT YOU TO READ THIS, BUT YOU CAN SEE THAT THE COLORS HIGHLIGHT THAT THERE ARE VAST BIOLOGICAL DIFFERENCES IN THESE BIOCHEMICAL ASSAYS IN TERMS OF DIAGNOSING METABOLIC SYNDROME AND CARDIAC INJURY. SO THE FIELD OF CARDIOLOGY IS PRETTY ADVANCED AT THINKING ABOUT SEX-SPECIFIC DIFFERENCES IN BIOMARKERS. SO DOES IT MATTER? WELL, I WOULD PUT TO YOU IT DOES MATTER. IT MATTERS A LOT WHEN YOU'RE MAKING DECISIONS ABOUT TREATMENTS, RIGHT? SO THE DIFFERENCE BETWEEN A POSITIVE CARDIAC TROPONIN AND A NEGATIVE ONE IS YOU GET WHISKED TO THE CATH LAB OR NOT. RIGHT? BIG DURCHES. THE DIFFERENCE BETWEEN A POSITIVE CARDIAC TROPONIN AND A NEGATIVE ONE IS THE DIFFERENCE BETWEEN IMMEDIATE TREATMENT, WHICH WE KNOW IMPROVES OUTCOMES IN PEOPLE WITH M.I., AND DELAYED TREATMENT. SO IT DOES MAKE A DIFFERENCE. AND EVEN MORE IMPORTANT, AS WE START TO THINK ABOUT INTERVENTIONS, TO UNDERSTAND THE EFFECTS OF TREATMENTS, WE REALLY HAVE TO UNDERSTAND THE MARKERS WE'RE USING TO STUDY THOSE EFFECTS. SO I WANT TO GO BACK TO OUR FOUR QUESTIONS, IS SEX ASSOCIATED WITH OUTCOMES AFTER TBI? THIS SEEMS LIKE A VERY SIMPLE QUESTION, WE SHOULD KNOW THIS, AND IS YOUR IMPRESSION THAT WE KNOW THIS AFTER THIS CONFERENCE? I THINK IT'S HARD. THIS WAS A REVIEW BY GRANT IVERSON. AND HE LOOKED AT THE STUDIES SHOWING WHETHER THERE'S AN ASSOCIATION WITH FEMALE SEX AND OUTCOMES AFTER TBI. AND IF YOU LOOK AT WHAT I'VE HIGHLIGHTED, FEMALE SEX YES, ASSOCIATED WITH OUTCOMES, FEMALE SEX NO, NOT ASSOCIATED WITH OUTCOMES, YOU CAN SEE THAT THE JURY IS STILL OUT ABOUT WHETHE SEX ITSELF IS ASSOCIATED WITH OUTCOMES AFTER TBI. NOW, IF I'VE LEARNED ONE THING FROM THIS CONFERENCE, I'VE LEARNED A TON OF THINGS BUT IF I'VE LEARNED ONE THING, IT REMINDS ME OF IT DEPENDS ON WHAT THE DEFINITION OF "IS" IS, SO IT DEPENDS ON WHAT THE DEFINITION -- I KNOW, THAT WAS BOTH APPROPRIATE AND AN INAPPROPRIATE REFERENCE AT THE SAME TIME GIVEN THIS CONFERENCE, BUT IT DEPENDS ON WHAT THE DEFINITION OF OUTCOME IS, RIGHT? SO WE KNOW THAT NOT ALL OUTCOMES ARE CREATED EQUALLY IN TERMS OF UNDERSTANDING SEX-SPECIFIC DIFFERENCES IN TBI. SO WHAT I'D LIKE TO DO IS SWITCH GEARS AND TALK ABOUT LESSONS LEARNED FROM NEUROLOGIC DISEASES THAT HAVE GIVEN A LOT MORE THOUGHT TO SEX-SPECIFIC DIFFERENCES. WE HEARD SOME OF THIS YESTERDAY. SO ALZHEIMER'S AND STROKE. SO IN TERMS OF THESE FOUR QUESTIONS, IS SEX ASSOCIATED WITH OUTCOMES, ONE THING THAT I SORT OF HAVE NOTICED IN BOTH THE STROKE AND THE ALZHEIMER'S LITERATURE IS THAT THEY ARE FAR ALONG THE PATH OF LOOKING SPECIFICALLY AT SEX-RELATED MALL SEES. THEY ACTUALLY DO SEX-SPECIFIC ANALYSES. ALL RIGHT OF THE HERE'S ONE. SEX EFFECTS. CLINICAL PREDICTERS. SO NOW WE'RE TALKING ABOUT DOING STRATIFIED ANALYSIS ON OTHER CLINICAL PREDICTERS, RIGHT? AND THAT'S A LITTLE BIT WHAT I'M TRYING TO CALL FOR HERE. THINGS LIKE AING, IF AGE. YOU CAN SEE ODDS RATIO, THE ODDS RATIO OF WOMEN HAVING A WORST FUNCTIONAL OUT COME. AND YOU CAN SEE THAT IN YOUNGER WOMEN, THE EFFECT OF SEX IS SIGNIFICANT. WE SEE INCREASED ODDS OF WORSE OUT COME. STROKE SUBTYPE, SO NON-CARDIOEMBOLIC TYPES OF STROKE, WORSE OUT COME IN WOMEN. DEPENDING ON THE CIRCULATION INVOLVED, WORSE OUT COME IN WOMEN. NON-SEVERE BASELINE STROKE SEVERITY, WORSE OUT COME IN WOMEN. SO THE ONLY WAY THAT YOU CAN FIND THESE OUTCOMES IS IF YOU ACTUALLY LOOK FOR THEM AND THAT'S ANOTHER THEME I THINK FROM TODAY. YOU CAN ONLY FIND THINGS THAT YOU LOOK FOR. IN ALZHEIMER'S DISEASE, THERE'S BEEN A LOT OF EMPHASIS ON LOOKING AT DIFFERENCES IN GENE EXPRESSION BASED ON SEX, SO THESE ARE SOME OF THE SORT OF CLASSIC GENES AND ULTIMATELY PROTEINS IMPLICATED IN THE PATHOGENESIS OF ALZHEIMER'S DISEASE, AND WHAT YOU CAN SEE, THE DETAILS OF THIS ARE NOT TOO IMPORTANT, THAT BOTH IN HEALTHY PEOPLE, CONTROLS, AND THOSE WITH ALZHEIMER'S DISEASE, A.D., THERE ARE SEX-SPECIFIC DIFFERENCES IN GENE EXPRESSION. CAN'T KNOW UNLESS YOU LOOK FOR IT. SIMILARLY, THIS SHOULD BE A GENE THAT'S VERY FAMILIAR TO ALL OF US IN THIS ROOM, ALL OF US WHO STUDY TBI. HOW MANY OF YOU FEEL LIKE YOU HAVE A GOOD HANDLE ON THE EFFECTS OF APOE E4 AND EFFECTS AFTER TBI. THE TRUTH IS WE DON'T KNOW. AND IN ALZHEIMER'S DISEASE, THIS MOST RECENT META-ANALYSIS LOOKING AT SEX RELATED DIFFERENCES IN OUTCOMES BASED ON APOE4, THERE MAY BE A SMALL AGE-SPECIFIC DIFFERENCE AT CERTAIN AGE POINTS BUT OVERALL, THE CURVES LOOK PRETTY SIMILAR. AND SO STUDYING THAT EFFECT OF APOE4 ACROSS MULTIPLE STUDIES FINDING NO CONSISTENT SEX-RELATED DIFFERENCES IN OUT COME. SO I'M GOING TO CONTRAST SOME OF THIS TO THE STATE OF THE STATE CURRENTLY IN TBI. WE'VE HEARD A LOT OVER THE COURSE OF THIS CONFERENCE ABOUT VARIOUS POTENTIAL BIOMARKERS. WE'VE NOT TALKED AT ALL ABOUT SERUM BIOMARKERS, WE'RE NOT GOING TO TALK TOO MUCH ABOUT IT TODAY. NEUROPHYSIOLOGIC IMAGING, WE JUST HAD A BUNCH OF GREAT IMAGING TALKS, THINKING ABOUT SEX-RELATED DIFFERENCES IN IMAGING OUTCOMES, A LOT OF THE PHYSIOLOGIC WORK, I THINK IS THE NEXT FRONTIER, LOOKING AT DIFFERENCE IN VARIOUS PHYSIOLOGIC OUTCOMES, THEN I THINK SOMETHING THAT WE DON'T TALK A LOT ABOUT IS ACTUALLY SYMPTOMS. SYMPTOMS IS A PROGNOSTIC OR DIAGNOSTIC MARKER. WE'VE TALKED A LOT ABOUT SYMPTOMS, WE'VE TALKED A LOT ABOUT HOW SYMPTOMS MEN VERSUS WOMEN ARE DIFFERENT. BUT SYMPTOMS ARE ACTUALLY ONE OF THE MOST SIGNIFICANT DIAGNOSTIC AND PROGNOSTIC MARKERS OF INJURY AND RECOVERY. AND YET THERE ARE SIGNIFICANT SEX-RELATED DIFFERENCES THAT HAVE NOT BEEN EXPLORED. THIS IS GOING TO BE A BRIEF DIGRESSION BUT I THINK IT'S REALLY IMPORTANT IN THE FIELD OF TBI TO UNDERSTAND WHY THIS IS SO HARD FOR US, RIGHT? A LOT OF OUR BIOMARKERS ARE ALSO OUR OUTCOMES. THAT MAKES THINGS REALLY CONFUSING. SO SYMPTOMS CURRENTLY ARE THE WAY WE DIAGNOSE ESPECIALLY MILD DRAW MATIC BRAIN INJURY. THEY'RE ALSO OUR MAIN PREDICTER OF WORSE OUT COME. SO WHEN YOUR BIOMARKER IS ACTUALLY YOUR OUT COME, THINGS GET TO BE A LITTLE BIT OF A HOT MESS, AND I THINK THAT'S WHY OUR FIELD IS ACTUALLY HAVING BIOMARKERS. ALL RIGHT. THE GOOD NEWS IS, WE HAVE A LOT OF OPPORTUNITIES IN THIS GROUP TO START MAKING A DENT IN UNDERSTANDING SEX-SPECIFIC DIFFERENCES IN PROGNOSTIC AND DIAGNOSTIC MARKERS OF INJURY. SO THIS IS SOME OF THE PILOT DATA FROM THE TRACT TBI STUDY, AND YOU CAN SEE THAT WE HAVE SOME PROMISING MARKERS IN THE PERFORMANCE WHICH HAS BEEN STUDIED PREVIOUSLY, WHEN YOU ACTUALLY LOOK AT PHOSPHORYLATED TAU, IT ACTUALLY HAS INCREDIBLE TEST PERFORMANCE IN TERMS OF DIAGNOSING AND PROGNOSTICATING MILD TRAUMATIC BRAIN INJURY. BUT HERE'S THE PROBLEM. AT LEAST IN THE PRELIMINARY DATA. SO THIS HAS COME UP AGAIN, THIS IS ANOTHER THEME FROM THE LAST FEW DAYS. LOOK AT THE NUMBER OF FEMALES THAT ARE REPRESENTED IN THE ACUTE TBI COHORT. SO IT'S 51. AND IN TERMS OF THE CHRONIC, 5. THIS STUDY IS UNDERPOWERED, WE'RE GOING TO GET MUCH MORE DATA AS THE TRACT TBI DATA KEEP COMING OUT, BUT I JUST WANT YOU TO KNOW AGAIN THAT THE ONLY WAY WE CAN ACTUALLY STUDY SEX-SPECIFIC DIFFERENCES IS IF WE ACTUALLY ENROLL WOMEN IN OUR STU DID STUDIES, AND THEY HAVE TO BE EMPOWERED TO UNDERSTAND THESE SEX-SPECIFIC DIFFERENCES. SUMSIMILARLY, LOOKING AT THE RISK OF WORSE OUTCOME, I LOVE THIS STUDY BECAUSE AS A PEDIATRICIAN, IT ACTUALLY STRATIFIES BY AGE, THAT'S RELU IMPORTANT, BUT WHAT WAS NOT DONE IN THIS STUDY, STRATIFYING BY SEX. SO IF WE'VE LEARNED ANYTHING FROM THE ALZHEIMER'S COMMUNITY, ONCE AGAIN, THEY HAD THIS QUESTION, THERE WAS BIOLOGIC PLAUSIBILITY THAT APOE 4 MIGHT BE MODIFIED BY SEX AND THEY LOOKED OVER AND OVER AND OVER AGAIN TO TRY TO UNDERSTAND THAT INTERACTION. CAN'T KNOW UNLESS YOU LOOK. THIS IS A VERY BUSY SLIDE. THIS GETS AT THE CONCEPT OF BIOLOGIC PLAUSIBILITY. SO THIS IS A STUDY BASICALLY LOOKING AT BIOMARKERS FROM A LARGE COHORT STUDY IN THE NETHERLANDS, SO I THINK IT WAS ABOUT 1600 PEOPLE, MEN AND WOMEN. AND THEY LOOKED AT PROTEIN EXPRESSION ACROSS A BUNCH OF CANDIDATE BIOMARKERS FOR VARIOUS PSYCHIATRIC DISEASES, AND THEY LOOKED AT DIFFERENCES IN EXPRESSION BASED ON BIOLOGIC SEX BUT THEY ALSO LOOKED AT DIFFERENCES BASED ON HORMONE STATUS, SO WHERE YOU WERE IN THE MENSTRUAL CYCLE OR WHETHER YOU'RE TAKING EXOGENOUS HORMONES. ON THE LEFT PANEL, YOU CAN ACTUALLY SEE AN ODDS RATIO OF THE DIFFERENCE BETWEEN WOMEN VERSUS MEN, SAME THING ON THE RIGHT, THE LEFT PANEL IS PROTEINS OVEREXPRESSED IN WOMEN, THE RIGHT PANEL IS PROTEINS THAT ARE OVEREXPRESSED IN MEN. AS YOU CAN SEE, THERE ARE MULTIPLE PROTEINS THAT HAVE SIGNIFICANTLY DIFFERENT EXPRESSION IN MEN VERSUS WOMEN. IF YOU LOOK AT THE DIFFERENT COLORS, DO THESE PROTEINS VARY BASED ON HORMONAL STATUS, BLUE BEING NO, RED EQUALS YES. YOU CAN SEE A GOOD CHUNK OF THESE PRO TEEPS ACTUALLY VARY BASED ON HORMONAL STATUS. SO THESE ARE THE KINDS OF ANALYSES, SOME OF THESE ACTUALLY ARE TBI-RELATED PROTEINS, SOME AREN'T, BUT YOU CAN SEE THAT THESE ARE -- THIS IS THE COMPLEXITY OF WHAT WE'RE DEALING WITH WHEN WE'RE DEALING WITH BIOMARKER STUDIES IN TBI. SPECIFICALLY SEX-RELATED DIFFERENCES. SO IS THERE A BIOLOGIC BASIS TO STUDY SEX DIFFERENCES IN PROGNOSTIC/DIAGNOSTIC MARKERS. I HOPE THAT PROTEIN STUDY STARTS TO GET AT IT. WE'VE TALKED A LOT ABOUT HOW HUMAN STUDIES NEED TO GET ON BOARD IN STU EING THIS BUT I WOULD ALSO ARGUE OUR PRE-CLINICAL STUDIES ARE THE FIRST PASS AT UNDERSTANDING WHETHER THERE IS A BASIS TO LOOK AT BIOLOGICAL SEX. I KNOW A TON OF YOU HAVE BEEN DOING WORK IN THIS REALM SO PLEASE FORGIVE ME BUT DUE TO THE LIMITS OF TIME, I WAS THREATENED BEFORE I STARTED THAT I BETTER BE ON TIME, I'M ONLY GOING TO TALK ABOUTONE STUDY, BUT I THINK IT'S IMPORTANT. SO THIS IS A STUDY LOOKING AT THE EFFECTS OF REPETITIVE MILD TRAUMATIC BRAIN INJURY IN MICE. IN GENERAL WE KNOW THERE'S ALMOST NO EFFECTS ON REPETITIVE TRAUMATIC BRAIN INJURY ON WOMEN IN GENERAL AND THAT PAUCITY IS MAGNIFIED IN THE PRE-CLINICAL SETTING AS WE HEARD YESTERDAY. MOST OF THESE PRE-CLINICAL STUDIES DO NOT INCLUDE FEMALE ANIMALS. SO THIS WAS A STUDY THAT ACTUALLY LOOKED AT THE DIFFERENCE IN REPETITIVE MILD TRAUMATIC BRAIN INJURY IN FEMALE VERSUS MALE MICE, AND I JUST BRING UP THIS ONE EXAMPLE OF HOW THERE'S A DIFFERENCE, AND I USE THIS SLIDE PURPOSELY BECAUSE IT'S GFAP, RIGHT? AND GFAP IS PROBABLY ONE OF OUR BEST STUDIED, BEST KNOWN BIOMARKERS IN THE TRAUMATIC BRAIN INJURY REALM, AND I THINK WE KNOW VERY LITTLE IF ANYTHING ABOUT SEX-RELATED DIFFERENCES IN GFAP, AND SO JUST EVEN LOOKING AT THIS MOUSE MODEL, YOU CAN SEE JUST EYEBALLING THAT THERE ARE SIGNIFICANT DIFFERENCES IN EXPRESSION, REGIONAL DIFFERENCES IN EXPRESSION IN GFAP, BASED ON BIOLOGIC SEX. WHETHER THIS TRANSLATES INTO DIFFERENCES IN GFAP IN THE SERUM, I DON'T KNOW. ALL BETTS ARE OFF. BUT IT DOES SUGGEST THERE'S JUST LIKE WE'VE HEARD IN ALL THE IMAGING STUFF, THERE IS A BIOLOGICAL BASIS OF DIFFERENCES BOTH IN GLIAL RESPONSE AND A WHOLE BUNCH OF OTHER THINGS BASED ON SEX. THEY FOUND A LOT OF OTHER DIFFERENCES IN THIS STUDY. THEY FOUND THAT MALES VERSUS FEMALES HAD DIFFERENCES IN SHORT TERM WORKING MEMORY, FEMALES LIKE WE'VE HEARD A LOT IN THE PAST FEW DAYS IN THE HUMAN STUDIES HAVE DIFFERENCE IN DEPRESSIVE-LIKE BEHAVIOR, THERE WERE DIFFERENCES IN BALANCE AND LOCOMOTION, DIFFERENCES ACTUALLY IN ATROPHY, AND DIFFERENCES IN ALL THE BIOMARKERS THAT WE WERE JUST TALKING ABOUT. GFAP, MYELIN-BASED PROTEIN, NFL, AND TAU, BASED ON THE SEX AND THE NUMBER OF INJURIES. THIS IS REALLY, REALLY IMPORTANT IN OUR STUDIES. THESE ARE ALL THE BIOMARKERS WE'RE ACTUALLY TALKING ABOUT USING IN SERUM STUDIES IN TERMS OF PROGNOSTICATING OUTCOME, AND THE FACT THAT WE STILL DON'T KNOW HOW SEX BASED DIFFERENCES MIGHT HELP OUR PROGNOSIS LIKE WE'VE ACTUALLY LEARNED IN ALL THE TROPONIN WORK LIKE OUR FRIENDS IN ONCOLOGY DO ALL THE TIME IN TERMS OF RISK STRATIFICATION, THIS IS WHAT I THINK THE FIELD NEEDS. TAKEAWAY POINTS. BASIC EPIDEMIOLOGIC QUESTIONS IN SEX SPECIFIC OUTCOMES IN TBI NEED ANSWERING. WE'VE HEARD THAT TIME AND TIME AGAIN TODAY. LESSONS FROM OUR ALZHEIMER'S AND STROKE COLLEAGUES, YOU ACTUALLY HAVE TO LOOK FOR THE SEX-SPECIFIC DIFFERENCES TO ACTUALLY FIND THEM. AND THAT HAS TO START WITH PRE-CLINICAL MODELS. AND I AM, I WILL SAY RIGHT NOW, MORE GUILTY THAN MOST OF YOU PROBABLY IN THE ROOM AT ACTUALLY NOT LOOKING AT SEX-SPECIFIC DIFFERENTS IN MY PRE-CLINICAL MODELS. STATE OF THE STATE. THERE'S GOOD REASON, WE ALREADY HAVE A LOT OF DATA TO SUGGEST THAT THE BIOLOGY OF TBI MAY BE SUBJECT TO SEX-SPECIFIC DIFFERENCES. WE HAVE TO UNDERSTAND THE TEST CHARACTERISTICS OF PUTATIVE MARKERS AND WE JUST -- THAT IS FIRST LINE OF WHAT WE HAVE TO DO. I'M GOING TO GO BACK ONCE AGAIN TO THE HEAR BAW I THINK THEY'RE LEADING THE WAY IN SORT OF SEX DIFFERENCES IN OUTCOMES AND ANALYSES, AND THIS IS A STATEMENT FROM THE AMERICAN HEART ASSOCIATION WHICH I THINK FITS US PERFECTLY. THE FIRST STEP TO PERSONALIZED MEDICINE, WHICH IS THE HOLY GRAIL OF MEDICINE RIGHT NOW, IS ATTENTION TO SEX-SPECIFIC CHARACTERISTICS, AND ATTENTION TO SEX DISPARITIES LIKELY WILL IMPROVE THE AWARENESS, PREVENTION, RECOGNITION, TREATMENT, AND OUTCOMES. THANK YOU. [APPLAUSE] >> I GUESS JUST A NOTE FOR THE RECORD SHE WAS A MINUTE EARLY, SO IF THERE WAS ANY THREAT FROM THE DOCTOR, HE NOW HAS TO GO TO 13 MINUTES. JUST JOKING. I WILL NOW CALL DR. JEFFREY BAZARIAN FROM THE UNIVERSITY OF ROCHESTER MEDICAL CENTER, AN EMERGENCY PHYSICIAN WHO TODAY WILL PROVIDE AN OVERVIEW OF THE ON OUT COME FROM MILD TRAUMATIC BRAIN INJURIES. >> THANK YOU, PLEASURE TO BE HERE. REBEKAH, I OWE YOU A MINUTE. I'LL FIGURE OUT SOME WAY TO MAKE IT UP TO YOU, I'M NOT SURE HOW YOU WANT TO WORK THAT OUT. CASH? OKAY. I DO WANT TO SAY I REALLY ENJOYED YOUR TALK, IT'S KIND OF A TOUGH ACT TO FOLLOW. I'D LIKE TO TALK ABOUT IMPACT OF MENSTRUAL PHASE ON OUTCOME. ONE OF THE THINGS THAT WORKS EASIEST FOR ME IS TO TELL YOU RIGHT UP FRONT WHAT THE NEXT FEW SLIDES ARE GOING TO SAY. I WOULD LIKE TO BILTD BILD THE ARGUMENT THAT FEMALES HAVE POORER OUTCOMES AFTER MALES WITH TBI, I THINK THERE'S CERTAINLY A LOT OF GOOD EVIDENCE TO PUSH IT IN THAT DIRECTION, AND I WANTED TO SHOW YOU AND MAYBE ECHO WHAT REBEKAH JUST SAID, THAT THERE'S THIS INTERACTION BETWEEN SEX AND AGE AND THIS DIFFERENCE IN OUTCOME LOOKS TO BE MOST PRONOUNCED DURING CHILD BEARING YEARS. THE OUTCOME MIGHT BE RELATED TO MENSTRUAL PHASE AT THE TIME OF INJURY. ONE OF THE THINGS WE FOUND WAS THAT THE OUTCOME WAS WORST DURING THE LUTEAL PHASE, THE LAST TWO WEEKS OF THE CYCLE, THE MENSTRUAL CYCLE, COMPARED TO INJURY INCURRED DURING THE FOLLICULAR PHASE, WHICH IS THE FIRST TWO WEEKS OF THE CYCLE. THERE HAVE BEEN STUDIES THAT HAVE SHOWN WOMEN DO WORSE AFTER TBI, THERE HAVE BEEN A COUPLE OF STUDIES THAT SHOWED MORTALITY IS HIGHER, AFTER MODERATE TO SEVERE TBI AND WOMEN HAVE POORER FUNCTIONAL OUTCOMES AFTER MODERATE TO SEVERE TBI, AND THEY TEND TO HAVE MORE SYMPTOMS AFTER MODERATE TO SEVERE TBI THAN THEIR MALE COUNTERPARTS. IN THE MILD TBI WORLD, THERE ALSO ARE SEVERAL STUDIES THAT SHOW THAT WOMEN TEND TO DO WORSE, POORER COGNITIVE PERFORMANCE. YOU CAN SEE, THOUGH, THAT THE AGES KIND OF VARY AMONG THESE STUDY, WHICH MAY BE WHY SOME STUDIES SHOW THAT WOMEN DO WORSE AND SOME DON'T. THEY'RE NOT EXACTLY KIND OF BREAKING THIS DOWN IN THE WAY DR. MANNIX SUGGESTED. SOME STUDIES KIND OF OVERLAP THE PEDIATRIC AND ADULT AGE RANGES AND OTHERS DON'T. OTHER STUDIES SHOW WOMEN HAVE MORE POST-CONCUSSIVE SYMPTOMS AFTER MILD TBI, AND THEN YESTERDAY WE HEARD ABOUT AT LEAST TWO STUDIES THAT SHOWED THAT AFTER SPORT-RELATED CONCUSSION, WOMEN TAKE LONGER IN GENERAL TO RECOVER THAN THEIR MALE COUNTERPARTS. SO WHY WOULD THIS BE? TO TRY TO ANSWER THIS, WE LOOKED AT A GROUP OF PEOPLE COMING IN TO OUR EMERGENCY DEPARTMENT ACROSS THE LIFESPAN, ZERO TO 99, COMING IN TO RED WITH MILD TBI. WE GOT ABOUT 1425 SUBJECTS, AND WE LOOKED AT THEIR POST-CONCUSSIVE SYMPTOM SCORE THREE MONTHS AFTER INJURY, AND THEN WE COMPAREED MALES TO FEMALES. AND WHAT WE FOUND WAS THAT WOMEN TENDED TO HAVE MORE POST-CONCUSSIVE SYMPTOMS AT THREE MONTHS OR ACTUALLY A HIGHER PROBABILITY OF PCS AT THREE MONTHS, BUT THAT WAS PREDOMINANTLY CONFINED TO LIKE THIS CHILD BEARING AGE GROUP, SO BEFORE THE AGE OF ABOUT 12 OR SO, AND AFTER THE AGE OF ABOUT 60, MEN AND WOMEN LOOKED PRETTY MUCH THE SAME IN TERMS OF THIS PARTICULAR OUTCOME. AFTER MILD TBI. BUT IN BETWEEN, WOMEN CLEARLY ARE REPORTING MORE POST-CONCUSSIVE SYMPTOMS, WHICH IS KIND OF A CURIOUS PHENOMENON. SO WE THOUGHT, WELL, WHY WOULD THAT BE, WHAT KIND OF OTHER THINGS KIND OF VARY LIKE THAT ACROSS THE LIFESPAN, THAT KIND OF ARE DIFFERENT, AND THERE ARE A LOT OF THINGS WE'VE LEARNED ABOUT OVER THE LAST FEW DAYS. THINGS THAT CAME TO OUR MIND WERE SEX HORMONES, IN PARTICULAR, ESTROGEN AND PROGESTERONE. AND VERY SIMILAR TO THE KIND OF THE PATTERN OF OUTCOME DIFFERENCES WE JUST SHOWED, WOMEN TEND TO HAVE HIGHER LEVELS OF ESTROGEN/PROGESTERONE DURING THOSE CHILD BEARING YEARS AND THAT'S IN THE BLUE LINE, AND MEN DON'T HAVE MUCH OF THAT, YOU KNOW, ACROSS THE LIFESPAN. THOSE HORMONES KIND OF DIFFER -- WE'RE SEEING DIFFERENCE IN OUTCOME. THE ONLY PROBLEM IS, PROGESTERONE IS SUPPOSED TO BE GOOD FOB YOUR GOOD FOR YOUR BRAIN, NOT BAD. PROGESTERONE DOES A LOT OF GOOD THINGS FOR ENHANCING MOOD AND COGNITION. SO IF THAT'S THE CASE, IF WOMEN HAVE MORE ESTROGEN OR PROGESTERONE DURING THIS PERIOD OF TIME WHERE IF THEY GET INJURED, THEY LOOK LIKE THEY DO WORSE, HOW DOES THAT WORK? IT DOESN'T SEEM TO MAKE SENSE. SO WE TRIED TO KIND OF PULL THAT APART. IN THE STUDY THAT WE ENDED UP DOING. ONE OF THE THINGS THAT WE HAD TO KEEP IN MIND WAS THAT ESTROGEN AND PROGESTERONE ARE NOT CONSTANT ACROSS THE MENSTRUAL CYCLE, AND IT MAY MAKE A DIFFERENCE AT WHAT POINT SOMEONE GETS INJURED. SO AT THE VERY -- THE FIRST PHASE OF THE MENSTRUAL CYCLE, THE FOLLICULAR PHASE, PROGESTERONE, PRETTY LOW, THE LUTE YAL PHASE, IT'S PRETTY HIGH HIGH. ONE OF THE INTERESTING THINGS IS AT THE END OF THE LUTEAL PHASE, RIGHT BEFORE MENSTRUATION, WOMEN CAN GET PREMENSTRUAL SYMPTOMS THAT ARE VERY SIMILAR TO POST-CONCUSSIVE SYMPTOMS. SO THE SYMPTOMS THAT OCCUR DURING THIS -- THE VERY END OF THIS PHASE, NOT HEAD INJURY-RELATED, PREMENSTRUAL SYMPTOMS THAT OCCUR AT THE END OF THE LUTEAL PHASE HAVE A LOT OF OVERLAP WITH POST CONCUSSION SYMPTOMS. I MEAN, THERE'S HEADACHE, FATIGUE, NAUSEA, SLEEP DISTURBANCE, TROUBLE CONCENTRATING, TAKING LONGER TO THINK, A LOT OF EMOTIONAL SYMPTOMS. AND THAT'S VERY SIMILAR TO POST-CONCUSSIVE SYMPTOMS. SO THAT WAS INTRIGUING TO US AS WELL. WE THOUGHT IS THERE SOMETHING ABOUT GETTING INJURED DURING THIS PHASE THAT MAY SOMEHOW MIMIC PREMENSTRUAL SYMPTOMS? SO WE DECIDED TO TRY TO LOOK AT INJURY OCCURRING IN THE LUTEAL PHASE, COMPARE THAT TO INJURY OCCURRING IN THE FOLLICULAR PHASE, TO SEE WHETHER THERE WAS A DIFFERENCE IN OUTCOME. WE TOOK A GROUP OF WOMEN, CHILD BEARING AGE, COMING IN TO EMERGENCY, THAT WE WERE ABLE TO GET BLOOD WITHIN SIX HOURS, OTHER INJURY, AND WE HAD ABOUT 189 OF THOSE FOLKS, CONVENIENT SAMPLE, AND WE EXCLUDED WOMEN WHO WE THOUGHT THEIR AXIS WAS PROBABLY NOT WORKING EITHER BECAUSE THEY SAID THEY HAD HYSTERECTOMY OR WERE POST-MENOPAUSAL, AND WE CONFIRMED THAT BY CHECKING THEIR FSH LEVEL AND IF IT WAS HIGH, WE SAID OKAY, YOU'RE RIGHT, AND WE ALSO LOOKED AT FSH IN ALL WOMEN WHO WERE OVER 45, JUST TO CONFIRM THAT THEY WERE NOT POST-MENOPAUSAL. SO WE ENDED UP GETTING RID OF 45 FOLKS WHO DIDN'T HAVE AN INTACT HB GONADAL ACCESS IN 144 WOMEN. SO SOME OF THOSE WOMEN WERE ALREADY TAKING SYNTHETIC PROGESTINS LIKE BIRTH CONTROL PILLS, SO WE PUT THEM IN A SEPARATE GROUP. THEY CONTAINED PROGESTERONE AND ESTROGEN, SO WE KIND OF GOT TO PUT THEM OFF IN A SEPARATE GROUP, AND THE REST OF THE WOMEN, WE MEASURED THEIR PROGESTERONE IN THEIR BLOOD TO DETERMINE WHETHER THEY WERE IN THE LOU -- WE ENDED UP WITH A GROUP OF WOMEN TAKING SYNTHETIC PROGESTINS, A GROUP IN THE LOU TEAL AND -- WE LOOKED AT MOSTLY STUFF WE COULD GET OVER THE PHONE BECAUSE THIS IS NOT THE KIND OF GROUP THAT YOU USUALLY CAN GET BACK, SO THE POST-CONCUSSIVE QUESTIONNAIRE KIND OF GRADES SYMPTOMS AND THEN WE LOOKED AT QUALITY OF LIFE USING AN INDEX SCORE AND WE DID ANOTHER QUALITY OF LIFE MEASURE LOOKING AT GENERAL HEALTH RATING, JUST TELL US HOW GOOD YOU FEEL ON A SCALE OF ZERO TO 100. SO THOSE ARE OUR THREE OUTCOMES THAT WE TRIED TO COMPARE IN OUR THREE ESTRUS CYCLE GROUPS. GSC, PRIOR HISTORY OF CONCUSSION, OTHER INJURIES. THE MAIN -- THE GROUP ON BIRTH CONTROL PILLS TENDED TO BE LIGHTER THAN THE OTHER TWO GROUPS. SO HERE'S WHAT WE FOUND. SO HERE'S OUR THREE GROUPS. FOLLICULAR PHASE, THE PHASE WHERE THE PROGESTERONE IS LOW, LUTEAL PHASE, THE PHASE WHERE PROGESTERONE IS HIGH, AND HERE'S YOUR SYNTHETIC PROGESTIN GROUP. THE GROUP THAT GOD INJURED IN THE LUTEAL PHASE TENDED TO HAVE MORE POST-CONCUSSIVE SYMPTOMS AT A MONTH AFTER INJURY. THE OTHER TWO GROUPS ARE PRETTY SIMILAR. FOLLICULAR AND BIRTH CONTROL, THEY LOOK PRETTY SIMILAR. SO WHETHER YOUR PROGESTERONE WAS LOW AT THE TIME OF INJURY OR WHETHER YOU WERE TAKING SYNTHETIC PROGESTIN, PRETTY SIMILAR OUTCOME. WOMEN INJURED DURING THE LUTEAL PHASE HAD LOWER QUALITY OF LIFE, AND WOMEN IN FOLLICULAR AND THE BIRTH CONTROL GROUP LOOKED ABOUT THE SAME. SO AGAIN, THIS PERIOD OF TIME OF THE ESTRUS CYCLE WHERE PRO GENERAL TROAN IS HIGH, WOMEN DID WORSE. SAME THING WITH OUR OTHER WAY OF LOOKING AT QUALITY OF LIFE USING THIS GENERAL HEALTH RATING, HOW DO YOU FEEL ON A SCALE OF ZERO TO 100, WOMEN FELT WORSE IF THEY WERE INJURED DURING THE LUTEAL PHASE THAN IF THEY WERE INJURED DURING THE FOLLICULAR PHASE, AND THE FOLLICULAR PHASE WAS VERY SIMILAR TO WOMEN WHO WERE TAKING SYNTHETIC PROGESTINS, BIRTH CONTROL PILLS. WE DID A MULTIVARIATE MODEL WHERE WE STUCK THE ESTRUS CYCLE PHASE IN WITH THE OTHER THINGS THAT I SHOWED YOU IN THE SUBJECT CHARACTERISTIC SLIDE, AGE, GSC, OTHER INJURY, TRIED TO CONTROL FOR OTHER THINGS THAT MIGHT AFFECT OUTCOME, AND WE FOUND PRETTY MUCH THE SAME PATTERN, AGAIN THAT WOMEN INJURED DURING THIS LUTEAL PHASE WHERE PROGESTERONE WAS HIGH, HAD MUCH HIGHER ODDS RATIO OF POOR OUT COME BY THE SOMATIC SUBSCORE, THAT'S HEADACHE, DIZZY, NAUSEA, ALSO HAD LOWER QUALITY OF LIFE, SO HIGHER OUTCOME OF POOR QUALITY OF LIFE AT A MONTH. THIS OVERALL KIND OF POST CON COW SIEVE SYMPTOM SCORE WAS CLOSE BUT JUST MISSED BUT THE PATTERN IS THE SAME, THAT THAT MIDDLE GROUP, WOMEN INJURED DURING THAT PART OF THEIR CYCLE WHERE PROGESTERONE IS HIGH, TENDED TO DO WORSE, AN THE OTHER TWO GROUPS WERE KIND OF EQUIVALENT AND DID BETTER. SO THE QUESTION IS, WHY IS THIS HAPPENING? KIND OF LIKE THE SEINFELD EPISODE ABOUT NOTHING, WE REALLY DON'T KNOW. WHICH HAVE SOME POTENTIAL EXPLANATIONS. THE PITUITARY SITS IN A VERY PRECARIOUS SPOT IN THE SKULL AND IT'S KIND OF TRAPPED INSIDE THIS BONY STRUCTURE, SO IF THE HEAD ROTATES, THE PITUITARY ISN'T MOVING AND IT'S POSSIBLE THAT THE BLOOD VESSELS THAT SUPPLY THE PITUITARY ARE KIND OF STRETCHED AND MAYBE SO YOU THAT DAMAGES SOMEHOW THAT DOOJS THE PITUITARY, SO MAYBE SOMETHING ABOUT HEAD INJURY DAMAGES THE -- DAMAGED BY THE IMMUNE RESPONSE THAT GETS SET UP AFTER THE INJURY, EITHER AN AUTOIMMUNE RESPONSE, THERE HAVE BEEN GROUPS THAT HAVE FOUND ANTIBODIES AGAINST THE PITUITARY AFTER MILD TBI, OR BY SOME OTHER COMPONENT OF THE INFLAMMATORY PROCESS. THAT SOMEHOW INVOLVES THE HYPOTHALAMUS OR THE PITUITARY. WE'RE KIND OF TALKING ABOUT DISRUPTION OF THIS AXIS HERE, STIMULATING THE OVARIES TO PRODUCE ESTROGEN AND PROGESTERONE, SO WE'RE TRYING TO FIGURE OUT HOW THIS WOULD BE ALTERED BY A BLOW TO THE HEAD. WE ALREADY KNOW THAT TBI AFFECTS GROWTH HORMONE, THYROID FUNCTION, SO OTHERS HAVE SHOWN THAT MILD TBI AND EVEN MORE SEVERE TBI DISRUPTING OTHER FUNCTIONS OF THE PITUITARY, SO THE QUESTION IS, IS THIS AXIS ALSO DISRUPTED. SO SUPPORT FOR THIS IDEA THAT THE PITUITARY IS SOMEHOW DISTURB DISTURBED AND THAT GONADAL FUNCTION IS DISRUPTED BY CONCUSSION WAS RECENTLY PROVIDED BY ANTHONY CONTOS'S GROUP AT PITTSBURGH, DID A REALLY NICE STUDY THAT SHOWED THAT WOMEN WHO UNDERWENT -- WERE MORE LIKELY THAN UNINJURED CONTROLS TO HAVE MENSTRUAL IRREGULARITIES AND EVEN MISSED PERIODS ALL TOGETHER. SO THERE IS SOME EVIDENCE THAT THAT AXIS IS DISRUPTED BASED ON THE REPORTING OF MENSTRUAL IRREGULARITIES AND THAT BEING -- AMONG WOMEN WHO HAVE BEEN -- COMPARED TO THOSE WHO DIDN'T. ANOTHER LINE OF EVIDENCE THAT SUPPORTS THIS IDEA IS WORK THAT WE DID WHERE WE LOOKED AT THE CHANGES IN MRNA EXPRESSION AFTER SPORT CONCUSSION AND WE FOUND THAT EXPRESSION RELATED TO FSH AND LH REGULATION WERE IDENTIFIED BY PATHWAY ANALYSIS IS KEY FUNCTIONAL NETWORKS AMONG THOSE WHO HAD GOOD RECOVERY SEVEN DAYS AFTER CONCUSSION, SO REGULATING FSH AND LH IN THIS SMALL STUDY APPEARED TO BE IMPORTANT FOR WOMEN TO RECOVER AFTER CONCUSSION. OKAY. SO THIS IS LIKE AN INTERESTING OBSERVATION, RIGHT, BUT REALLY WE'VE GOT A LOT OF WORK TO DO. WHAT ARE THE QUESTIONS AND GAPS, WE NEED TO HAVE SOME IDEA OF WHAT THE PUTATIVE MECHANISM OF THIS IS. DOES MILD TBI REALLY ALTER MENSTRUAL CYCLE CHANGES IN THESE HORMONES, PROGESTERONE, FSH, LH, MAYBE SOME OF THE MORE KNEW OWE ACTIVE -- DO THEY AFFECT OTHER NEUROACTIVE STEROIDS? ARE THESE CHANGES RELATED TO THE MENSTRUAL CYCLE PHASE AT THE TIME OF INJURY OR IS IT REALLY IRRESPECTIVE TO THE TIMING OF YOU THINK REACROSS THAT INJURY ACROSS THAT MONTH, AND ARE THESE CHANGES RELATED TO RECOVERY, MENSTRUAL FUNCTION, THOSE ARE IMPORTANT THINGS TO ANSWER. I WOULD ALSO ARGUE IF WE'RE GOING TO DO PRE-CLINICAL WORK IN THIS AREA, IF WE THINK THAT THIS IS A LEGITIMATE -- WE HEARD YESTERDAY HOW RODENTS HAVE A MENSTRUAL CYCLE THAT IS NOT SIMILAR TO HUMANS AND PRIMATES AND RODENTS DON'T MEN STRAIGHT, THEY HAVE AN ESTRUS CYCLE, IT'S LIKE A FOUR-DAY CYCLE. IT MIGHT NOT BE THE BEST MODEL FOR TRYING TO UNLOCK THIS PROBLEM, SO THE PRIMATES, WE HEARD ABOUT PIGS AND OTHERS THAT MIGHT BE MORE APPROPRIATE MODELS TO THINK ABOUT. AND THEN ARE SYNTHETIC PROGESTINS POTENTIAL THERAPY FOR MILD TBI. SO THERE'S A LOT OF WORK TO DO, I AM NOT A PITUITARY EXPERT, I KNOW DR. RASMUSSEN WHO IS HERE IS, I ENCOURAGE OTHERS LIKE HER TO HELP OUT WITH THIS PROBLEM. DR. GILL, WHO'S HERE AT THE NIH, HAD A BRILLIANT IDEA TO HELP US MAYBE UNDERSTAND WHAT'S HAPPEN HAPPENING TO THE PITUITARY AFTER MILD TBI, THIS IDEA OF USING SWEAT COLLECTED ON A PATCH AS A WITH WAY TO MEASURE PROTEINS IN THE BLOOD. MANY PROTEINS IN THE BLOOD ARE SECRETED IN SWEAT AND CAN BE COLLECTED, AND WHAT'S NICE ABOUT THAT IS, SOME OF THESE HORMONES VARY ACROSS THE COURSE OF THE DAY, SO IF YOU TAKE A BLOOD SAMPLE OR A SPIT SAMPLE AT EIGHT TYPE IN THE MORNING, IT MIGHT NOT REPRESENT WHAT'S HAPPENING AT 8:00 AT NIGHT. SO SWEAT IS NICE BECAUSE YOU KIND OF GET LIKE AN AVERAGE SIGNAL ACROSS THE TIME YOU'RE MEASURING IT. WE DID THIS ON A GROUP OF ATHLETES, WE PUT THE PATCH ON EVERY DAY FOR EIGHT WEEKS. SO FAR WE HAVE EIGHT CON CUSSEDS AND EIGHT CONTROLS. IF DR. GILL ISN'T NOW, IT'S PROBABLY BECAUSE -- OH, SHE IS HERE NOW? I WAS GOING TO SAY SHE'S PROBABLY IN THE LAB MEASURING. WE'RE VERY EXCITED TO BE ABLE TO SEE -- CAN WE SEE SOME OF THESE HORMONES CHANGE FROM THE POINT OF INJURY EVERY THREE DAYS FOR EIGHT WEEKS TO TRY TO UNDERSTAND ARE THEY GOING UP, ARE THEY GOING DOWN, WHAT EXACTLY IS HAPPENING TO THEM. SO I THOUGHT THAT WAS A BRILLIANT IDEA, AND I THINK THIS IS A PRETTY FLATTERING PICTURE OF YOU, JESSICA, JUST -- YOU KNOW, UNLIKE THE ONE YOU SHOWED ME YESTERDAY. [LAUGHTER] TAKE HOME POINTS. WOMEN WHO EXPERIENCE MILD TBI DURING THE LUTEAL PHASE WHERE PROGESTERONE IS HIGH HAVE WORSE OUTCOME THAN WOMEN INJURED DURING THE FOLLICULAR PHASE. THIS IS BY SYMPTOMS. AND WOMEN TAKING SYNTHETIC PROGESTINS HAD OUT COME SIMILAR TO THOSE FROM WOMEN IN THE FOLLICULAR PHASE WHERE PROGESTERONE IS LOW. THESE FINDINGS, BY THE WAY, REALLY NEED TO BE CONFIRMED AS WELL. I THINK PROB BLIL ONE OF THE MOST IMPORTANT TAKE HOME POINTS IN ADDITION TO TRYING TO CONFIRM THIS IS THAT IF WE'RE THINKING ABOUT DOING CLINICAL TRIALS OF MILD TBI, IT MIGHT BE NICE TO CONSIDER DETERMINING THE MENSTRUAL PHASE DURING WHICH THE INJURY OCCURS, AND TRYING TO CONTROL FOR THIS WHEN YOU'RE LOOKING AT THE EFFECT OF TREATMENT ON OUTCOME. SINCE IT MIGHT MAKE A DIFFERENCE. AND SO THAT'S A PRETTY SIMPLE THING TO DO. I THINK IT'S VERY DOABLE. AND THANK YOU FOR YOUR ATTENTION. [APPLAUSE] >> TAB TAS TICK. ALSO IT BEGS THE QUESTION OF WHO DO WE NEED TO COLLABORATE WITH IN THOSE AREAS TO REALLY STRENGTHEN THE SCIENCE, SO THANK YOU SO MUCH, DR. BAZARIAN. SO NOW I'D LIKE TO INTRODUCE DR. CHRISTINE TURTZO, INTRAMURAL INVESTIGATOR WITH NINDS AND THE STROKE RESEARCH PROGRAM AND IS ACTIVE IN RESEARCH EXAMINING THE ROLE OF WHITE MATTER AND CEREBRAL VASCULATURE IN CLOSED HEAD INJURY AND ANIMAL MODELING. SHE WILL DISCUSS SEX DIFFERENCES IN INFLAMMATION AND IMAGING. DR. TURTZO. >> THANK YOU. MY THANKS TO THE ORGANIZATIONERS ORGANIZER S. I AM THE STAFF CLINICIAN WITH NINDS TBI PROGRAM WHERE WE'RE FOCUSING MOSTLY ON YOU A CUTE 'NOTHER OWE IMAGING, BUT WHAT I'M GOING TO TALK TO YOU TODAY IS GOING TO BE AN OVERVIEW OF NEUROINFLAMMATION AND HOW WE MIGHT BE ABLE TO USE SOME IMAGING TOOLS TO INVESTIGATE IT RANGING FROM PRE-CLINICAL TO SOME CLINICAL WORK, AND THIS ACTUALLY IS DRAWN FROM SOME WORK I DID AS A PRE-CLINICAL FELLOWSHIP BEFORE I GOT INTO MY CURRENT POSITION. SO I HAVE NO FINANCIAL DISCLOSURES. FIRST I'D LIKE TO SAY AS YOU'VE HEARD OVER AND OVER THE PAST TWO DAYS IS THAT THE VAST MAJORITY OF TBI STUDIES IN THIS AREA OF NEUROINFLAMMATION HAVE NOT BEEN DESIGNED SPECIFICALLY TO LOOK AT SEX DIFFERENCES AND THEY FOCUSED PREDOMINANTLY ON MALES, IN ARE SOME THAT FOCUSED ON FEMALES. SPEAKING OF NEUROINFLAMMATION, I'M A NEUROLOGIST, I FOCUS ON THE BRAIN PREDOMINANTLY ALTHOUGH I RECOGNIZE THE REST OF THE BODY IS IMPORTANT, AND WHEN WE'RE TALKING ABOUT THE BRAIN PARENCHYMA AS MANY OF YOU ARE AWARE, THE KEY CELLS WITH RESPECT TO INFLAMMATION ARE THE RESIDENT MY ROW GLIA BUT YOU ALSO HAVE MICROPHAGES THAT COME IN AFTER INJURY AS WELL AS NEUTROPHILS THAT MIGRATE IN FROM THE BLOOZ VESSELS. WITH RESPECT TO WHAT WE KNOW ABOUT VARIOUS CELLS OF THE IMMUNE SYSTEM AND SEX DIFFERENCES, THIS IS SUMMARIZED VERY NICELY IN A REVIEW ACTUALLY FROM THE STROKE LITERATURE FROM SPICHELLA AND MICULEK. THE CELLS I MENTIONED, OF THE THREE OF THEM THAT WE KNOW FROM GENERAL STUDIES OF TBI AND NEUROINFLAMMATION, OTHER RESEARCHERS HAVE FOUND THAT TO DATE, NEUTROPHIL, WE DON'T KNOW THAT MUCH ABOUT SEX DIFFERENCES, BUT WE KNOW THAT MICROGLIA AND MACROPHAGES BOTH DISPLAY SEX DIFFERENTIAL RESPONSES DEPENDING ON WHAT YOU'RE LOOKING AT, AND THESE ARE LIKELY ALSO IMPORTANT IN TBI. NOW WHEN WE'RE TALKING ABOUT INFLAMMATION AFTER TBI, WE'RE ALL VERY FOCUSED ON THE BRAIN INJURY AND THE EFFECTS ON THE BRAIN AND LOOKING AT THE RESIDENT MICROGLIA AND MACROPHAGES, BUT THE BRAIN ITSELF ALSO SENDS SIGNALS TO THE REST OF THE BODY, AND WE DON'T PAY ATTENTION TO THAT AS MUCH AS WE SHOULD. WE ARE AWARE FROM SOME CLINICAL WORK THAT AFTER A TBI, PARTICULARLY SEVERE TBI, THERE ARE IMMUNOSUPPRESSIVE EFFECTS ON THE REST OF THE BODY, PUTTING PATIENTS WHO ARE IN THE ICU AT HIGHER RISK OF INFECTION THAN THEY MIGHT OTHERWISE BE. WHY THAT HAPPEN, WE DON'T ENTIRELY KNOW. LIKEWISE, THE PERIPHERAL IMMUNE SYSTEM IS DOING FEEDBACK BACK, AND WE ALSO KNOW THAT THIS OCCURS IN SEVERE STROKE PATIENTS AS WELL, AND AS WE'VE HEARD THROUGHOUT THE PRESENTATION SO FAR OVER THE PAST TWO DAYS, THERE ARE A LOT OF DIFFERENT COVARIABLES THAT ARE AFFECTING THESE RESPONSES AND THIS IS EVEN MORE SO WHEN YOU'RE TALKING ABOUT INFLAMMATION AFTER TBI. SO I JUST WANT EVERYONE TO KEEP THAT IN MIND, AND AS WELL, THE INFLAMMATORY RESPONSE DOES VARY DEPENDING ON WHETHER YOU'RE TALKING ABOUT RIGHT AT THE TIME OF INJURY IN AN ACUTE PHASE, OUT TO SUBACUTE TO CHRONIC, AND I'LL GIVE A LITTLE BIT OF EVIDENCE TO THAT AS WE GO ALONG. NOW, I WANT TO TAKE A STEP BACK RIGHT NOW, WE'RE FOCUSED VERY MUCH ON ACUTE TRAUMATIC BRAIN INJURY HERE, WHICH HAS A VARIETY OF DIFFERENT MECHANISMS THAT CAN LEAD TO THESE TYPES OF PARENCHYMAL AND EXTRA AXIAL INJURY. IN STROKE, IT'S A LOT SIMPLER. MOST OF IT IS ISCHEMIC, SOME OF IT'S HEMORRHAGIC, SOME HAS COMPONENTS OF BOTH. BUT I'D LIKE TO POINT OUT THAT THERE ARE SIMILARITIES BETWEEN HOW THE BRAIN RESPONDS TO TRAUMA AND STROKE WHEN IT COMES TO SECONDARY INJURY MECHANISMS, AND THERE'S A LOT THAT'S BEEN DONE IN THE STROKE WORLD BOTH CLINICALLY AND PRECLINICALLY THAT HELPS US UNDERSTAND THE RESPONSE OF THE BRAIN TO INJURY AFTER YOU GET THROUGH THAT INITIAL INSULT. AND WITH RESPECT TO THE STROKE LITERATURE, YOU CAN HAVE SECONDARY CEREBRAL ISCHEMIA THAT HAPPENS AS A RESULT OF TBI, EITHER AT THE MICRO VASCULAR LEVEL OR A LARGER LEVEL IF YOU HAVE ENOUGH EDEMA. SO I'M GOING TO USE THAT TO SEGUE INTO A VERY BRIEF OVERVIEW OF SOME HIGHLIGHTS FROM THE STROKE WORLD. ONE OF WHICH IS THAT DIFFERENT PHARMACOLOGICAL AGENTS CAN DIFFERENTIAL EFFECTS WHETHER YOU GIVE THEM IN MEN AND WOMEN, AND ONE OF THE KEY EARLY STUDIES ON THIS IS JUST LOOKING AT ASPIRIN IN THE PRIMARY PREVENTION OF STROKE VERSUS MYOCARDIAL INFARCTION, AND IT TURNS OUT THAT ASPIRIN IS GOOD AT REDUCING THE RELATIVE RISK OF MYOCARDIAL INFARCTION IN MEN. IT'S NOT AS GOOD IN WOMEN. BUT IT'S BETTER AT REDUCING THE RELATIVE RISK OF STROKE IN WOMEN THAN IN MEN WHEN YOU'RE TALKING ABOUT POST-MENOPAUSAL WOMEN. AND THIS IS IMPORTANT TO RECOGNIZE THAT WE HAVE AGENTS THAT WE'VE BEEN USING CLINICALLY FOR A LONG TIME, AND THEY CAN ACT DIFFERENTLY IN MEN AND WOMEN. IN THIS CASE, AN EXAMPLE OF ASPIRIN, THIS ACTUALLY A GOOD THING BECAUSE YOU MIGHT WANT TO REDUCE THE RISK OF MYOCARDINAL INFARCTION IN GENERAL AND STROKE IN AN OLDER POPULATION. BUT THERE ARE -- WHERE IT MIGHT NOT WORK OR HAVE DETRIMENTAL EFFECTS IN ONE SEX VERSUS ANOTHER AND WE NEED TO KEEP THAT IN MIND. ANOTHER THING WE'VE LEARNED FROM THE STROKE LITERATURE IS WHEN YOU LOOK AT ESTROGEN, FOR INSTANCE, IT CAN BE BOTH ANTI-INFLAMMATORY OR PRO INFLAMMATORY, DEPENDING NOT ONLY ON THE TYPE OF INSULT AND WHERE YOU'RE LOOKING AT IN THE BODY, BUT ALSO WHEN YOU'RE LOOKING AT BLOOD VESSELS, IT DEPENDS ON HOW DAMAGED THE BLOOD VESSEL IS, HOW INFLAMED THE VESSEL IS TO BEGIN WITH. IT'S NOT NECESSARILY A SIMPLE THING TO SAY ALL INFLAMMATION IS BAD AND ALL AGENTS SHOULD BE GIVEN AT A CERTAIN TIME. YOU HAVE TO LOOK AT TIMING, YOU HAVE TO UNDERSTAND THE OVERALL DISEASE CONDITION OF THE ORGANISM AND PRE-CLINICAL STU DID YOUS OR HUMANS. AND ONE OTHER POINT I'D LIKE TO DRAW FROM A LOT OF WORK THAT'S BEEN DONE IN THE STROKE LITERATURE IS THAT THERE ARE TWO PREFERENTIAL PATHWAYS OF PROGRAMMED CELL DEATH IN BODY, DEPENDING ON WHETHER YOU'RE MALE OR FEMALE. ALL OF US HAVE BOTH OF THESE, BUT IF GIVEN A CHOICE AND NOT DRIVEN TO ANOTHER PATHWAY, FEMALE CELLS TEND TO DIE VIA THIS DEPENDENT PATHWAY WHEREAS MALE CELLS VIA THIS PATHWAY. THERE ARE AGENTS OUT THERE THAT HAVE SHOWN INITIALLY THEY WERE GIVEN EXCLUSIVELY TO MALE ANIMALS, THEY WORKED WONDERFULLY. THEN THEY DID THEM IN A BROADER POPULATION, DID THEM IN FEMALE ANIMALS, AND THEY FOUND IT DIDN'T WORK AS WELL, AND THIS IS BECAUSE OF WHERE THAT AGENT ACTUALLY WORKS. IT ACTUALLY TARGETS A -- INDEPENDENT PATHWAY NOT THE FEMALE PATHWAY. AND THERE WILL BE OTHER EXAMPLES OF THIS AS WE GO ALONG. NOW WHY IS THIS RELEVANT TO TBI? I SUSPECT THE SAME TYPE OF THINGS ARE GOING ON IN TBI BECAUSE THERE'S A LOT OF OVERLAP IN HOW THE BODY MANAGING THOSE SECONDARY INJURY PATHWAYS. SO ALSO WITH RESPECT TO INFLAMMATION AND TBI TO KEEP IN MIND IS THAT IN A HEALTHY BRAIN, EVERYTHING IS BALANCED, BUT IN THE INJURED BRAIN, WHAT HAPPENS WITH SEVERITY OF INJURY OR OTHER FACTORS PUSHING IN THIS DIRECTION, YOU'RE GOING TO HAVE PREDOMINENCE OF PRO INFLAMMATION VERSUS ANTIINFLAMMATION, AND WHAT WE WANT TO DO AFTER INJURY HAS OCCURRED IS WE WANT TO TRY TO BALANCE THIS SO WE GET MINIMAL INJURY AND MAXIMAL RECOVERY, BUT INFLAMMATION ITSELF, YOU NEED TO HAVE SOME INFLAMMATION TO BE ABLE TO CLEAR OUT THE DEBRIS AND THEN HAVE REPAIR, SO IT'S A DUAL EDGED SWORD IN THAT YES IT PLAYS A ROLE IN SECONDARY INJURY BUT YOU ALSO NEED TO GET RID OF THE DEAD CELLS AND THE RESIDUAL BLOOD THAT'S THERE BEFORE YOU CAN REBUILD WHAT YOU CAN. SO THE IDEA THAT PEOPLE HAD INITIALLY OF THROWING CORTICOSTEROIDS ON AFTER TBI, I AM NOT SURPRISED AT ALL THAT IT FAILED, BECAUSE YOU'RE TAKING A SLEDGE HAMMER AND DOING SOMETHING THAT SHOULD BE A DELICATE BALANCING ACT. WE NEED TO DO A BETTER JOB OF BALANCING ACT JUST IN GENERAL AS WELL AS WITH RESPECT TO THE EFFECT OF SEX. SO THIS IS AN OVERVIEW OF WHAT WE KNOW FROM THE PRE-CLINICAL LITERATURE ABOUT WHAT HAPPENS AFTER YOU HAVE ACUTE BRAIN INJURY. YOU HAVE A SPIKE OF INFLAMMATORY CYTOKINES, YOU HAVE MACROPHAGES THAT INFILTRATE RESIDENT MICROGLIA, GET ACTIVATED, AND ANTI-INFLAMMATORY CYTOKINES THAT COME IN. MOST OF THIS WORK WAS DONE IN MALE ANIMAL, SOME STUDIES WERE DONE ON FEMALE, AND THIS IS WHAT HAPPENS WHEN YOU'RE IN THAT FIRST WEEK AFTER INJURY. WHETHER OR NOT YOU TAKE A LOOK AT THESE MICROGLIA AND FROM WHAT YOU CAN DISTINGUISH OF THE DISTINCT MACROPHAGES, WHETHER THEY'RE MORE PRO OR ANTI-INFLAMMATORY AT A PARTICULAR TIME DEPENDS A LOT ON THE ENVIRONMENT THAT THEY'RE IN AND THE STATUS OF THE BRAIN AT THAT TIME. THERE'S BEEN A LOT OF WORK AS I MENTIONED IN GROUPS LOOKING AT ONE SEX OR ANOTHER, LOOKING AT INFLAMMATION, BUT THERE'S A STUDY THAT JUST CAME OUT FROM MARK BERNS' LAB THAT LOOKS AT BOTH. I THOUGHT THIS STUDY WAS PRETTY WELL DESIGNED, THEY LOOKED AT BOTH MALES AND FEMALES NOT JUST AGE MATCHED BUT WEIGHT MATCHED. WHAT THEY FIND IN THIS STUDY IS THAT EARLY ON, WITHIN THE FIRST SEVERAL DAYS AFTER INJURY, THERE'S INCREASED MYOGREE A IN MALES VERSUS FEMALES, THEY ALSO LEARNED THERE'S EARLY ASTROCYTOSIS MORE SO IN MALES VERSUS FEMALES AND ALSO FOUND INCREASED INNOVATION OF PERIPHERAL MACROPHAGES IN MALES VERSUS FEMALES. INTERESTINGLY, THOUGH, WHEN THEY LOOKED AT LESION VOLUME, LESION VOLUME IN THESE ANIMALS SHOWED THAT WHEN YOU LOOKED EARLY ON, YOU ACTUALLY HAD -- MALES HAD HIGHER LESION VOLUME THAN THEE MAILS AT 3 DAYS AND 7 DAYS, THEN WHEN YOU GOT TO 30 DAYS, THE LESION VOLUMES WERE EQUIVALENT. SO THAT'S TELLING US THAT THERE MAY BE A TEMPORAL EFFECT IN SOME OF THE THINGS THAT WE'RE LOOKING AT FOR OUTCOMES IN OUR PRE-CLINICAL STUDIES, AND WE DON'T HAVE A GOOD HANDLE RIGHT NOW IN TERMS OF WHAT THAT IS. THE LAB FROM THE BERNS PAPER ALSO DOES A LOT OF INVESTIGATION OF SOME GENE EXPRESSION AND CYTOKINES BUT I'M NOT GOING TO HAVE TIME TO TALK ABOUT THAT TODAY. SO ONE OTHER CAVEAT FROM THE PRE-CLINICAL LITERATURE I'D LIKE TO LEAVE YOU WITH ON THIS POINT IS THE MODEL YOU'RE INVESTIGATING CAN HAVE VERY DIFFERENT NEESKTS TERMS OF INFLAMMATION, AND THESE ARE STUDIES THAT I PARTICIPATED IN IN JOE FRANK'S LAB WHERE THIS ONE IS THE CCI MODEL IN FEMALE RAT, WHICH THE MAIN REASON WE ACTUALLY WERE STUDYING FEMALE RAT BECAUSE BECAUSE WE WERE DOING FROM MRI STUDIES AND THE BORE OPENING DIDN'T FIT THE LARGER MALE RATS, AND THIS DIFFUSIONARY MODEL WAS THE WEIGHT DROP MODEL. YOU CAN JUST SEE LOOKING AT THE STRUCTURAL MRI PATTERNS THAT THE INJURY LOOKS VERY DIFFERENT. IN THIS ONE, IF I DIDN'T TELL YOU THIS WAS AN INJURED RAT, YOU WOULDN'T KNOW. IN THIS ONE, YOU CAN CLEARLY SEE THIS IS WHERE THE CONTUSION IS. WHAT'S INTERESTING ABOUT THESE TWO DIFFERENT MODELS IN SAME AGE RATS DONE IN THE SAME LABORATORY, SAME METHODS, IS THE MICROGLIAL ACTIVATION IN THE FOCAL CONTUSION MODEL WAS MAXIMAL WITHIN THE FIRST WEEK, WHEREAS WE HAD A LATE ACTIVATION IN THE DIFFUSE MODEL. SO THAT'S SOMETHING ELSE THAT WE NEED TO CONSIDER THESE STUDIES RIGHT HERE SINCE AS I CONFESSED THIS WAS JUST DONE IN ONE SEX, I CAN'T TELL YOU THE SAME PATTERN HOLDS IN THE MALE, BUT WE NEED TO BE AWARE OF THAT, WHEN WE'RE LOOKING AT NEUROINFLAMMATION, WE HAVE TO BE AWARE OF OUR MODELS WE'RE LOOKING AT, THE SEXES OF OUR MODELS, AND PARALLEL FROM THE STROKE LITERATURE AS WELL AS SOME STUDIES THAT DAVID LONES' LAB HAS DONE, WHETHER YOU'RE LOOKING AT YOUNG MICE OR OLD MICE AND FROM THE STROKE LIT TEU WE KNOW THAT THAT ALSO VARIES DEPENDONICS WHEN YOU'RE TALKING ABOUT OLD MALE MICE OR OLD FEMALE MICE VERSUS YOUNG MALES AND FEMALES. SO THIS IS JUST AN OVERALL SUMMARY OF THE FIRST PART OF MY TALK. IN ORDER TO GET A HANDLE ON WHAT'S GOING ON WITH SEX DIFFERENCES IN INFLAMMATION, WE NEED TO HAVE A MULTIFACETED APPROACH. PRE-CLINICAL STUDIES CAN BE GREAT WHEN WE HAVE THE RIGHT HYPOTHESIS AND WE SET UP OUR STUDIES PROPERLY TO GET A HANDLE ON THE MECHANISM, BUT IT'S GOING TO BE REALLY HARD TO HAVE ANY ONE PRE-CLINICAL MODEL THAT'S GOING TO ENCOMPASS THE HETEROGENEITY WE SEE IN TBI IN PEOPLE. IF WE'RE REALLY GOING TO UNDERSTAND SYMPTOMS AND RELATIONSHIP OF THE BIOMARKERS, WE HAVE TO LOOK AT THE HUMANS. THAT'S A TRANSITION OF WHY I AM IN THE POSITION I'M IN RIGHT NOW WHERE WE ARE LOOKING AT ACUTE NEUROIMAGING MARKERS AND TRYING TO GET A HANDLE ON WHAT IT MEANS FOR THE TBI PATIENTS LONG TERM. I'M NOT GOING TO FOCUS ON THE DETAILS OF MY WORK THAT LARRY'S GROUP IS DOING WITH MY WORK RIGHT NOW BUT I WANT TO GIVE UL AN IDEA OF WHAT WE DO CLINICALLY, RESEARCH WISE WHAT PEOPLE ARE TRYING AND SOME THINGS I THINK WE NEED TO PAY ATTENTION TO IN THE FUTURE WITH RESPECT TO LOOKING AT NEUROINFLAMMATION VIA NEUROIMAGING. SO FIRST FROM A CLINICAL PERSPECTIVE, IF SOMEONE COMES IN AND THERE ARE INDICATIONS THAT THEY'VE HAD A HEAD INJURY AND THEY NEED A HEAD CT, THIS IS WHAT MOST OF OUR TBI PATIENTS SHORT OF THE VERY MILDEST OF THE MILD RECEIVE. THIS IS NOT WHAT YOU WANT THEIR HEAD CT TO LOOK LIKE, THIS IS SOMEONE WHO ACTUALLY HAS AN ACUTE SUBDURAL HEMATOMA AND A LOT OF MASS EFFECT. BUT THIS IS WHAT'S GOOD ABOUT DOING A HEAD CT. IT WILL TELL YOU IF THERE'S ENOUGH EDEMA AND MIDLINE SHIFT THAT YOU NEED TO GO TO NEUROSURGICAL INTERVENTION, AND IT'S BEEN SHOWN TO BE PREDICTIVE OF MORTALITY. WITH RESPECT TO INFLAMMATION, IT'S VERY INSENSITIVE ASIDE FROM GIVING US THIS IDEA THAT THERE'S THE DEGREE OF EDEMA AND THAT WE MIGHT HAVE TO LOOK AT SOMETHING FURTHER. BUT THIS IS WHAT MOST PATIENTS WHO HAVE COME IN TO AN EMERGENCY DEPARTMENT UNLESS, AGAIN, THEY ARE THE MILDEST OF THE MILD, WILL HAVE DONE AND IT TELLS YOU THE WORST-CASE SCENARIO BUT IT DOESN'T TELL YOU ABOUT A WHOLE LOT OF INJURY BENEATH THE SURFACE. NOW WITH RESPECT TO MRI AFTER TBI, I'M LUCKY THAT I GET TO SEE A LOT OF ACUTE, HYPERACUTE MRIs. THIS ONE HAD FALLEN OFF THE BACK OF A TRUCK, HAS A BIG FRONTAL CONTUSION. I USE THIS SO I CAN SHOW YOU THAT FLARE IMAGING, THE FAIR SEQUENCE IS GOOD AT SHOWING YOU INFLAMMATION WHERE IT WILL BE VERY HYPERINTENSE AND THEN THIS AREA IN HERE, IF I HAD THE GRE OR SWI, YOU WOULD SEE THIS IS ACTUALLY WHERE THE BLOOD IS WITHIN THE AREA OF HE DEMA AND EDEMA AND INFLAMMATION, BUT THE PART ABOUT THE STRUCTURAL MRI THAT'S DIFFICULT IS THIS DOESN'T TELL YOU IF THIS IS NEW OR OLD, YOU HAVE TO KNOW THE HISTORY OF THE PATIENT TO KNOW WHETHER THIS TH IS NEW OR OLD. SO MRI, IT CAN HELP TELL YOU AT A GIVEN TIME POINT THE OVERALL DEGREE OF INJURY TO THE BRAIN, BUT UNLESS YOU'RE DOING LONGITUDINAL STUDIES AND YOU CAN WATCH THINGS CHANGE OVER TIME, IT CAN BE HARD FOR YOU TO TIME HOW THE INFLAMMATION IS CHANGING JUST BY STANDARD MRI ALONE. WITH RESPECT TO SOME OF THE DTI SEQUENCES THAT ARE BEING DONE AND FMRI, LOOKING AT BOTH THE STRUCTURAL AND FUNCTIONAL CONNECTIVITY, THEY'RE GREAT AT SHOWING YOU CONNECTIONS BUT I CAN'T YET RELATE HOW WE'RE GOING TO LOOK AT INFLAMMATION JUST LOOKING AT THE CONNECTIONS WITHOUT GOING TO THE STEP OF FIGURING OUT WHAT UNDERLYING TISSUE LOOKS LIKE. SO THEY'RE GOOD BUT I'M NOT CERTAIN THOSE TECHNIQUES ALONE ARE GOING TO TELL US INFLAMMATION. NOW WHAT HAS BEEN DONE FROM AN INFLAMMATION STANDPOINT IS THERE'S A LOT OF WORK THAT'S BEEN DONE IN PET, POSITIVE EMISSION TOM TBRA TOMOGRAPHY, SPECIFICALLY LOOKING AT TRANSLOCATER PROTEIN. THERE'S ALSO RESEARCH WORK BEING DONE IN MAGNETIC RESONANCE SPECTROSCOPY AND A COUPLE DIFFERENT MRI TECHNIQUE, ALL OF WHICH HAVE THEIR BENEFITS BUT ARE STILL VERY PRELIMINARY IN TERMS OF BEING ABLE FOR US TO FIGURE OUT EXACTLY WHAT CELLS ARE LOOKING AT. ONE CAVEAT THAT I'LL MAKE USING THESE IRON LABELED PARTICLES THAT ARE TAKEN UP BY PERIPHERAL MACROPHAGES AND WATCHING THEM GET INTO THE BRAIN IS THEY CAN BE REALLY GOOD IF YOU CAN HAVE ANOTHER MARKER, YOU ACTUALLY KNOW WHAT YOU'RE SEEING IS THE PERIPHERAL MACROPHAGE, BUT A LOT OF TBI HAS SOME BLOOD ASSOCIATED WITH IT, EVEN IF IT'S NOT AT THE LEVEL YOU'RE PICKING IT UP ON YOUR HEAD CT OR EVEN YOUR HIGH RESOLUTION MRI, AND IF YOU DO HISTOLOGY, IT CAN BE HARD TO DISTINGUISH THE STAINING THAT'S FROM RESIDUAL BLOOD THAT'S BEEN TAKEN UP BY MACROPHAGES THAT ARE ALREADY PRESENT VERSUS ONES THAT CAME FROM THE PERIPHERY. THAT WAS A CAVEAT WE LEARNED FROM SOME OF THE STUDIES I WAS DOG IN JOE FRANK'S LAB. SO COUPLE EXAMPLES FROM THE RESEARCH. THIS IS A STUDY FROM THE NATIONAL INSTITUTES OF MENTAL HEALTH THAT OUR GROUP HELPED WITH, WHERE HE LOOKED AT TRANSLOCATER PROTEIN IN A COHORT OF PATIENTS WHO HAD TBI IN THE CHRONIC PHASE. WHAT YOU HAVE HERE IS IMAGES AT ONE YEAR POST INJURY THIS, IS THE FLARE MRI SEQUENCE IN TWO PATIENTS, SIMILAR MECHANISM, SIMILAR AGE, HEALTHY CONTROL, AND THIS IS THEIR TRANSLOCATER PROTEIN PET IMAGING AND WHAT YOU CAN SEE IS THAT THIS ONE PATIENT HAS AN INCREASE IN UPTAKE OF THE LIGAND VERSUS THIS ONE DOESN'T, WHEREAS LOOKING AT JUST THE STRUCTURAL MRI, WE CAN'T TELL WHICH IS WHICH. AND THIS IS ONE OF THE BIG BURNING QUESTIONS THAT WE HAVE IN -- BOTH LOOKING IN TERMS OF MRI, IF YOU'RE LOOKING PAST THE ACUTE PHASE, AS WELL AS JUST TBI IN GENERAL, WHY IS IT THAT SOME PATIENTS WILL HAVE A BIGGER INFLAMMATORY RESPONSE OR DON'T RECOVER AS WELL AND OTHERS DON'T. I DON'T HAVE AN ANSWER FOR YOU YET, BUT I'M HOPING THIS FROM THIS CONFERENCE, PEOPLE WILL HAVE BETTER IDEAS TOWARDS THAT IN THE FUTURE. I'LL ALSO SAY THAT THE VAST MAJORITY OF PET STUDIES THAT HAVE BEEN DONE THAT ARE AT ALL TBI-RELATED HAVE HAD, LIKE IN EVERY OTHER ASPECT OF THIS RESEARCH, A PREDOMINENCE OF MALES. MAGNETIC RESONANCE SPECTROSCOPY IS ALSO IN THE EARLY STAGES OF BEING USED TO LOOK FOR SPECIFIC BIOMARKERS AND CHANGES AFTERWARDS, AND ONE THING THAT I'D JUST LIKE TO MENTION IN GENERAL THAT I ALLUDED TO EARLIER IS THAT I THINK IT IS IMPORTANT FOR US TO HAVE A BETTER HANDLE IN TERMS OF WHAT WE'RE SEEING ON MRI AND WHAT THE UNDERLYING HISTOLOGY IS FOR A VARIETY OF REASONS. THIS IS A STUDY DRIVEN BY MATT BUDDY NOW AT MEDICAL COLLEGE OF WISCONSIN WHERE IN THE CCI MODEL, WHAT HE DID IS HE DID NOT JUST HIGH RESOLUTION DTI IMAGING AND -- LONGITUDINALLY, BUT HE THEN ALSO, WHEN THE RATS WERE EUTHANIZED, LOOKED TO SEE WHAT WAS EXACTLY GOING ON AT THE LEVEL OF HISTOLOGY UNDERPINNING THE CHANGES HE WAS SEEING UP HERE. AND THIS IS THE TYPE OF STUDY THAT WE NEED MORE OF SO WE'RE CONFIDENT THAT WHEN WE'RE SEEING THESE DIFFERENT CHANGES IN CONNECTIVITY, WHAT'S GOING ON UNDERPINNING IT. I'M NOT SAYING THAT EVERY SINGLE STUDY HAS TO DO ALL OF THIS, BUT WE NEED MORE PEOPLE WHO ARE GOING TO BE LOOKING NOT JUST AT THE END POINT DOING CORRELATIONS BUT WE NEED MORE LONGITUDINAL STUDIES, WE NEED TO HAVE MORE UNDERSTANDING OF WHERE WE STARTED SO THAT WE HAVE A BETTER UNDERSTANDING OF WHERE WE GOT TO SO THAT WE CAN HAVE BETTER PROGNOSTIC AND DIAGNOSTIC MARKERS FOR PEOPLE WHO HAVEN'T GOTTEN TO THE END POINT. THAT'S GOING TO BE REALLY CRITICAL, I THINK, WITH RESPECT TO UNDERSTANDING CHRONIC TRAUMATIC ENCEPHALOPATHY AND OTHER RELATED LONG TERM CONSEQUENCES OF NEURODEGENERATION. SO OVERALL TAKE HOME POINTS, THERE ARE SEX DIFFERENCES IN THE NEUROINFLAMMATORY RESPONSE. THE INTERPLAY AMONG SEX NEUROINFLAMMATION AND THE PERIPHERAL INFLAMMATION, IT'S COMPLICATED AND DYNAMIC AND WE NEED TO STUDY IT MORE. NEUROIMAGING CAN BE A USEFUL TOOL TO INVESTIGATE IN VIVO INFLAMMATION, BUT WE NEED TO UNDERSTAND WHAT WE'RE DOING BETTER AND I THINK WE ALSO PROBABLY NEED SOME BETTER TOOLS ALONG THE WAY THAT I'M HOPEFUL THAT SOME FURTHER RESEARCH WILL GIVE US. SO THANK YOU VERY MUCH FOR YOUR ATTENTION. I JUST WANTED TO THANK MY CHIEF MENTORS ALONG THE WAY TO THIS, SO THANKS. [APPLAUSE] >> THANK YOU SO MUCH. WHAT A GREAT DISPLAY OF HOW OTHER TYPES OF IMAGING FROM OTHER DISCIPLINES OR OTHER CONDITIONS CAN REALLY ILLUMINATE WHAT WE'RE LOOKING FOR IN TRAUMATIC BRAIN INJURY. WHAT I'D LIKE TO DO NOW IS INVITE OUR FINAL PANELIST, LYN TURKSTRA FROM MCMASTER UNIVERSITY. SHE'S A SPEECH LANGUAGE PATHOLOGIST BY TRAINING. SHE STUDIES THE LINKS BETWEEN COGNITIVE FUNCTION AND SOCIAL COMMUNICATION IN INDIVIDUALS WITH BRAIN INJURY. AND COLLABORATES ON THE DEVELOPMENT OF INFORMED PRACTICE STANDARDS TO TRANSLATE RESEARCH FIND TOTION CLINICAL PRACTICE. SHE'LL DISCUSS THE IMPACT OF SEX DIFFERENCES IN SOCIAL BEHAVIOR AS IN REHABILITATION AND BEYOND. DR. TURKSTRA. [APPLAUSE] >> HELLO. THANK YOU FOR STICKING WITH THIS PROGRAM ALL THE WAY UNTIL THE END. I FEEL A BIT LIKE I USED TO FEEL, AS A MEMBER OF THE NEUROTRAUMA SOCIETY, SO THIS IS A GROUP OF BENCH RESEARCHER, MOSTLY PRE-CLINICAL RESEARCH, AND I ATTENDED THE CONFERENCES FOR A DECADE AND EVERY YEAR IT WAS 397 RAT RESEARCHERS, ONE NURSING PROFESSOR WHO STUDIED SLEEP, HARVEY LEVIN AND ME. SO I SORT OF FELT THAT WAY THIS CONFERENCE. I'M TALKING ABOUT REHABILITATION TODAY, AND IT'S FUNNY, THE WORD REHABILITATION HAS COME UP A COUPLE OF TIMES BUT AT THIS CONFERENCE, IT'S GENERALLY NOT EVEN ACCEPTED OR ENTERED INTO ANALYSIS AS A NUISANCE VARIABLE, SO I DON'T KNOW WHAT THE CLASSIFICATION IS FOR BELOW NUISANCE VARIABLE OR JUST COMPLETELY IGNORED VARIABLE. IF YOU ASK PEOPLE WHO HAD A BRAIN INJURY, I THINK MOST OF THEM WOULD SAY THAT REHAB MADE A LIFE CHANGING EFFECT, AND SO THE EFFECT SIZE FOR STUDIES OF REHAB OUTCOMES FAR OUTWEIGH EFFECT SIZES FOR ANYTHING ELSE WE'RE LOOKING AT IN TERMS OF UNDERSTANDING BRAIN INJURY AND PREDICTING OUTCOMES, BUT THE FUNDING FOR THAT HAS NOT KEPT PACE WITH ITS IMPORTANCE OR ITS EFFECT, SO I'M VERY HAPPY TODAY TO TALK A LITTLE BIT ABOUT REHAB. AND SO I'M GOING TO USE AS AN EXAMPLE SOME RESEARCH OUT OF MY LAB THAT REVEALED A FACTOR THAT MIGHT HAVE AN EFFECT ON REHAB. I INITIALLY THOUGHT PREPARING FOR THIS TALK THAT I WOULD TALK ABOUT RESEARCH ON SEX DIFFERENCES IN REHAB OUTCOMES. SO WHEN I DID A LITERATURE SEARCH FOR THAT IN PUBMED, I CAME UP WITH 456 PAPERS. WHEN I EXCLUDED PAPERS THAT ONLY USED THE WORDS SEX OR GENDER IN TERMS OF MATCHING PARTICIPANTS œIN THEIR STUDIES, I ENDED UP WITH SIX PAPERS. ONE WAS BY DR. JOHN CORRIGAN WHO WAS HERE, IT WAS PUBLISHED IN 2006. SO WE KNOW ABSOLUTELY NOTHING ABOUT THE EFFECT OF BIOLOGICAL SEX OR GENDER ON OUTCOMES FROM REHABILITATION, AND AS I HOPE I SHOW YOU IN THIS SMALL DATA WAY, I THINK THOSE EFFECTS COULD BE VERY PROFOUND. SO I'M A COLLEGE PROFESSOR, I'M GOING TO START WITH A QUIZ. OH, FIRST I'M GOING TO START WITH THANKING NCMRR FOR FUNDING MY CURRENT R01 THAT'S JUST WRAPPING UP. NOW I'M GOING TO HAVE A QUIZ. SO I WOULD LIKE TO ASK A MALE IN THE AUDIENCE TO TELL ME WHAT HE THINKS IS GOING ON IN THIS PICTURE. BE BRAVE. IT'S THE END OF THE MEETING. JUST SHOUT IT OUT. WHAT DO YOU THINK? IT HAS TO BE A MAN. YES? I'M PICKING ON YOU BECAUSE YOU'RE RIGHT CLOSE TO THE FRONT. WHAT DO YOU THINK IS HAPPENING? >> [INAUDIBLE] >> SO THERE'S A SCHOOL TEACHER LOOKING AT TWO PUPILS AND A GUY LOOKING AT A DESK. SO IS THERE A FEMALE IN THE AUDIENCE IF THEY CAN TELL ME WHAT THEY THINK IS HAPPENING HERE? YOU GUYS UP FRONT, WHAT DO YOU THINK? >> [INAUDIBLE] >> SO IT'S FUNNY BECAUSE ES HE ESPECIALLY PEOPLE OVER -- THIS WAS SHOT BY A GROUP OF TEEP AGERS WE WERE WORKING WITH DEVELOPING OUR RESEARCH STIMULI. YOUNG ADULTS AND TEENAGERS CAN FIGURE THIS OUT IN A NANOSECOND, BUT SOMEHOW ONCE YOU HIT 25, YOU LOSE WHATEVER GENE IT IS THAT I I ALLOWS YOU TO FIGURE THIS OUT. WHAT MOST PEOPLE IN THEIR TEENS AND ESPECIALLY WOMEN IN THEIR TEENS WILL SAY IS THAT THIS GUY LIKED THIS GIRL ON YOUR RIGHT MORE THAN THE GIRL ON THE LEFT. IS THAT WHAT YOU GUYS WERE THINKING BUT YOU DIDN'T WANT TO -- RIGHT? YOU WERE THINKING IT BUT YOU DIDN'T WANT TO SAY IT. THE FIRST TIME I SHOWED THIS WAS IN NEUROSURGERY, GRAND ROUNDS, AND A NEUROSURGEON SAID, MA'AM, I THINK THAT WOMAN IS HIS MOTHER. AND I SAID, AW, HONEY. WE DON'T GET OUT VERY MUCH AND WE WERE WEARING A MASK ALL THE TIME SO WE NEVER GET TO SEE PEOPLE'S FACIAL EXPRESSIONS. SO THIS IS WHAT WE STUDY IN MY LAB, HOW PEOPLE UNDERSTAND THE SOCIAL ENVIRONMENT, HOW THEY UNDERSTAND SOCIAL QUEUES IN OTHER PEOPLE AND I LIKE TO USE THIS SLIDE BECAUSE I THINK IT'S A PLACE WHERE YOU CAN REALLY SEE DIFFERENCES IN MEN AND WOMEN AND HOW THEY PROCESS STIMULI. SOME MALES WILL SAY THE GUY IN THE MIDDLE IS LOOKING AT THAT WOMAN'S BUTT. I'M MINDFUL THAT WE'RE ON VIDEO. OKAY. SO WHAT I'M TALKING ABOUT HERE IS SOCIAL COGNITION, THAT WAS DEFINED A FEW YEARS AGO AS ALL THE COGNITIVE PROCESSES WE USE TO UNDERSTAND THE SOCIAL WORLD, SO TO DECODE AND ENCODE THE SOCIAL WORLD. THIS INCLUDES THINGS THAT WE USE MENTAL FUNCTIONS WE USE TO UNDERSTAND OTHERS, TO UNDERSTAND OURSELVES, AND TO KNOW THE RULES OF THE SOCIAL WORLD. TODAY I'M GOING TO PRESENT SOME DATA JUST ON THIS. AND THEORY OF MIND. IT'S REALLY COMPLICATED WHEN YOU GET TO STUDYING HUMAN BEHAVIOR TO BE CLEAR ABOUT WHAT YOU'RE STUDYING. SO IN SOCIAL BEHAVIOR, THIS IS A PLACE WHERE BIOLOGICAL SEX, CULTURAL GENDER, SELF EXPRESSION, PERSONAL OUTWARD EXPRESSIONS OF IDENTITY, SEXUAL ORIENTATION, ALL THESE THINGS ARE REALLY MIXED TOGETHER SO IT'S DIFFICULT TO SORT OUT. I WOULD GUESS MOST PEOPLE WHO SAY THEY'RE STUDYING BIOLOGICAL SEX ARE NOT DOING GONAD TYPING, I THINK THEY'RE ASKING PEOPLE HOW THEY SELF IDENTIFY OR THEY'RE LOOKING AT A PERSON AND MAKING A DECISION ABOUT WHETHER A PERSON IS A MALE OR A FEMALE PU WHEN IT COMES TO SOCIAL BEHAVIOR, IT'S NOT THAT SIMPLE. SO FOR US, WE'RE USUALLY STUDYING SOME AMALGAMATION OF SOME BIOLOGICAL SEX AND GENDER IDENTITY AND GENDER EXPRESSION. IN MY LAB, WE STUDY BOTH SELF-REPORTED BIOLOGICAL SEX, WE DO NOT DO TYPING, BUT WE ALSO STUDY SELF-REPORTED GENDER, SO WE LOOK AT PEOPLE'S IDENTIFICATION WITH STEREOTYPICAL ATTRIBUTES OF MALES AND FEMALES IN THEIR CULTURE. TODAY I'M JUST GOING TO TALK ABOUT LIE BIOLOGICAL SEX. SO THE STEREOTYPE ABOUT ABOUT BIOLOGICAL SEX IS THAT WOMEN ARE DIFFERENT WHEN IT COMES TO SOCIAL BEHAVIOR, AND THERE MAY BE SOME MALES IN THE ROOM WHO CAN IDENTIFY WITH THIS AS ONE HIGH SCHOOL STUDENT SAID TO ME, A YOUNG MAN SAID TO ME ONCE, MA'AM, WE'RE JUST HAPPY WHEN ANYONE TALKS TO US. SO I THINK THERE IS A GENERAL STEREOTYPE THAT WOMEN HAVE THIS WHOLE OTHER SET OF QUEUES AND SKILLS THAT MALES DO NOT HAVE. HERE'S THE PROTOTYPE. YOU SEE THIS LOOK? I CAN GIVE THIS LOOK FROM THE FRONT OF A ROOM WITH 300 PEOPLE AND PEOPLE IN THE VERY BACK ROW, ESPECIALLY TEENAGE GIRLS, CAN IDENTIFY IT. IT'S A VERY STRONG BIOLOGICAL SIGNAL. SO THAT'S SORT OF THE PROTOTYPE. WOMEN ARE BETTER AT THIS AND THEY HAVE ALL THESE EXTRA NUANCES IN THEIR BEHAVIOR THAT MEN DON'T REALLY HAVE, BUT THE WAY WE'VE STUDIED THIS DOES NOT MATCH AT ALL THAT PUBLIC PERCEPTION ABOUT WHAT SOCIAL BEHAVIOR IS REALLY LIKE. USUALLY WHAT WE DO IS WE SHOW PEOPLE A FACE AND WE ASK THEM TO SAY WHAT EMOTION IS THAT PERSON FEELING? THIS IS THE STANDARD SORT OF WAY WE TEST THE EMOTION RECOGNITION PART OF SOCIAL COGNITION. THAT'S EVOLVED A LITTLE BIT SO NOW PEOPLE ARE USING MORPHS. THIS IS 40% OF THE EXPRESSION, 60% ALL THE WAY UP TO 100%, SO NOW RESEARCHERS ARE STARTING TO SAY, WELL, WE NEED TO DO SOMETHING THAT'S A LITTLE MORE SUBTLE, THAT MIGHT CAPTURE MORE SUBTLE VARIATIONS. SOME PEOPLE ARE STUDYING THEORY OF MIND BY -- WHICH IS HOW YOU UNDERSTAND OTHER PEOPLE HAVE THOUGHTS DIFFERENT FROM YOURS, USING THINGS LIKE STORIES, SO SALLY AND ANNE WERE PLAYING, SALLY PUT A DOLL SOMEWHERE, ANNE LEFT THE ROOM, WHERE WILL SALLY LOOK FOR THE DOLL, SO THESE ARE ALONG SOMETIMES VERY COMPLICATED STORIES. AND YOU CAN IMAGINE JUST HAVING THAT -- SEEING THAT LITTLE GIFY FOR MEAN GIRLS THAT THESE STORIES AND PICTURES ARE NOT GOING TO CAPTURE THE EVERYDAY SOCIAL DEMANDS THAT PEOPLE ARE DEALING WITH. SO IF YOU LOOK AT DATA FROM ALL OF THOSE STUDIES THAT HAVE BEEN DONE ON SEX DIFFERENCE, THERE REALLY AREN'T THE DIFFERENCES THAT YOU SEE IN THE POPULAR LITERATURE. SO THIS IDEA THAT MALES AND FEMALES ARE HUGELY DIFFERENT, THAT WOMEN HAVE THIS WHOLE OTHER SET OF SKILLS AND THAT MEN ARE BASICALLY OBLIVIOUS, MY APOLOGIES TO THE MEN IN THE ROOM, THE DATA -- OR I SHOULDN'T APOLOGIZE. I'M SAYING THE DATA DON'T SUPPORT THE IDEA THAT MEN ARE OBLIVIOUS. IF YOU'VE BEEN USING THAT AS AN EXCUSE, IT'S NO LONGER EFFECTIVE. VERY SMALL DIFFERENCES. THOSE DIFFERENCES ARE PRESENT FROM BIRTH TILL DEATH, SO EVEN BABY GIRLS SEEM TO HAVE A SLIGHT ADVANTAGE OVER BABY BOYS IN RECOGNIZING MOTIONS. AND THIS IS -- THESE ARE SOME DATA FROM KESSLES, ONE OF THE LABS THAT GENERATED SOME PHOTOS, AND YOU CAN SEE BASICALLY THE SAME TREND, THERE ARE TINY DIFFERENCES BETWEEN BOYS AND GIRLS HERE, TINY DIFFERENCES BETWEEN MEN AND WOMEN, AND THEY'RE REALLY ONLY ON SOME EMOTIONS. THESE ARE THE EMOTIONS THAT ARE HARDER TO DIFFERENTIATE ANYWAY. ANYONE CAN TELL HAPPEN BUT IT'S HARDER TO TELL THE DIFFERENCE SOMETIMES BETWEEN FEAR, ANGER, SO REALLY THE DIFFERENCES ARE PRETTY SMALL. THE IMAGING DIFFERENCES ARE PRETTY SMALL IN FMRI STUDIES TO DATE, BUT WHAT YOU DO SEE IS THIS QUOTE JUST CRACKED ME UP, I HAD TO PUT IT IN HERE, WOMEN DID NOT TEND TO USE ANY CONSISTENT NEURAL CIRCUITS FOR PROCESSING EMOTIONAL STIMULI. I KNOW SOMEONE IS GOING TO INTERPRET THAT TO MEAN WOMEN ARE UNSTABLE. I JUST KNOW SOMEONE WILL SAY THAT. SO YOU SEE MORE VARIABILITY AMONG WOMEN IN IMAGING RESEARCH, IN BEHAVIORAL RESEARCH, AND A SLIGHT ADVANTAGE FOR WOMEN OVER MEN. IN MY LAB, WE'VE BEEN VERY INTERESTED IN THE EFFECTS OF CONTEXT ON SOCIAL THINKING. THIS IS A STUDY THAT WAS -- WE REPLICATED FROM AN IMAGING STUDY PUBLISHED IN 2012, WHERE PEOPLE SEE A SENTENCE THAT MAKES A COMMENT ABOUT A PERSON. SHE THINKS YOU ARE COMPETENT, SHE THINKS YOU ARE INCOMPETENT, THEN THEY SEE AFTER THAT A BRIEF PRESENTATION OF A FACE, ALL THE FACES ARE NEUTRAL, THEY'RE NORMED AS NEUTRAL, THEN THEY RATE THE FACIAL EXPRESSION FROM VERY NEGATIVE TO VERY POSITIVE. SO ALL THE RATINGS SHOULD BE ZERO BECAUSE ALL THE FACES ARE PEOPLE DO HAVE A RANGE OF RATINGS FROM POSITIVE TO NEGATIVE DEPENDING ON THE SENTENCE. SO THE EMOTIONS THAT YOU DETECT, YOUR JUDGMENTS OF EMOTION ARE DEPENDENT ON THINGS GOING ON IN THE ENVIRONMENT BEFOREHAND, SO YOU MIGHT SEE THE SAME FACE AND THINK THE PERSON IS ANGRY BECAUSE THEY JUST SAID SOMETHING RUDE. VERSUS HAPPY. AND HERE, I PUT THIS UP BECAUSE YOU CAN SEE HERE, THIS IS WOMEN, THIS IS MEN, I THOUGHT THAT WOMEN MIGHT BE MORE SENSITIVE TO ENVIRONMENTAL SOCIAL QUEUES THAN MEN, BUT WE HAVEN'T SEEN THAT SUPPORTED. BUT WE HAVE SEEN MORE VARIABILITY IN WOMEN AGAIN. SOCIAL COGNITION HAS BECOME A GROWING INTEREST IN THE TBI WORLD. I WOULD SAY OVER THE PATHS 20 YEARS, THERE'S AN ACCUMULATED REALLY LARGE BODY OF WORK ON SOCIAL THINKING AND PEOPLE WITH BRAIN INJURY. IT'S NOT REALLY SURPRISING, SOCIAL PROBLEMS, SOCIAL CHALLENGES ARE COMMONLY REPORTED IN PEOPLE WITH BRAIN INJURY. ALSO IT TURNS OUT A LOT OF THE PARTS OF THE BRAIN THAT HAVE BEEN IMPLICATED IN SOCIAL THINKING ARE ALSO PARTS THAT ARE DAMAGED IN TBI. WE LOOKED IN OUR LAB, FOR EXAMPLE, AT EMOTION RECOGNITION IN TAXICAB. THIS IS USING THAT MORPH TASK I SHOWED YOU EARLIER. EVEN AT 80 OR 100% OF A FACIAL EXPRESSION, SOME PEOPLE WITH BRAIN INJURY ARE STILL NOT ACHIEVING 100% PERFORMANCE. THERE'S AN ESTIMATE ABOUT 30% OF PEOPLE WITH BRAIN INJURY WILL HAVE TROUBLE READING EMOTIONS IN OTHER PEOPLE AND THAT MORE INFORMATION DOES NOT MEAN BETTER FER FOREMAN'S. WE HAVE FOUND SEX-BASED DIFFERENCES HERE AS WELL, AND I SHOW THIS AS A PATTERN THAT WE'VE SEEN SEVERAL TIMES, SO THERE IS THIS SLIGHT FEMALE ADVANTAGE IN NORMAL CONTROLS WHERE YOU SEE WOMEN ARE A LITTLE BIT BETTER AT DETECTING EMOTIONS THAN MEN ARE, BUT WHAT WE SEE HERE IS A SLIGHT DROP IN WOMEN WITH BRAIN INJURY -- I'M SORRY, IT SAYS MODERATE TO SEVERE TBI, NOT MILD. WE SEE A SLIGHT DROP IN WOMEN BUT WE SEE THE SIGNIFICANT DROP IN MEN. AND THIS IS THIS THEME THAT I WOULD LIKE TO POINT OUT ACROSS ALL OF THESE STUDIES WHICH IS THAT MEN MAY LOOK THE SAME ON DIFFERENT TYPES OF TASKS WE'RE USING BUT IF YOU PUSH THE SYSTEM A LITTLE BIT, THAT'S WHERE YOU MIGHT SEE DIFFERENCES IN CHALLENGE BETWEEN MEN AND WOMEN. THEY OVERLAP ALMOST COMPLETE LE ON STANDARD EMOTION TASKS, THAT MALES ARE MORE VULNERABLE TO DAMAGE AND FEMALES HAVE AN ADVANTAGE ON MORE COMPLEX NUANCED EMOTION TASKS, SO WE DO SEE THIS OVER AND OVER, THIS PATTERN WHERE MEN SHOW MORE PROBLEMS AFTER BRAIN INJURY. WE DEVELOPED THIS THEORY OF MIND TASK THAT INVOLVES A VIDEO WHERE YOU WATCH AND MAKE A JUDGMENT ABOUT A MENTAL STATE, HAVE A DISTRACTER, HAVE ANOTHER JUDGMENT ABOUT A MENTAL STATE, SO THIS IS A THEORY OF MIND TASK. AGAIN YOU CAN SEE WHAT I JUST REPORTED THIS, IS A DIFFERENT COHORT ALL TOGETHER, YOU CAN SEE HERE NOT A DIFFERENCE BETWEEN MEN AND WOMEN BUT YOU SEE THERE'S THIS MALE TBI GROUP THAT'S COMING UP AS THE LOWEST GROUP. I SHOULD SAY IN OUR SAMPLES, WE'RE 50/50 MALES AND FEMALES, SO WITH THE -- HERE IS 124, AND OF THE 62 PEOPLE WITH BRAIN INJURY, 31-31. SO FOR WHATEVER UNFORTUNATE REASON, WE HAVE A LOT OF WOMEN WITH BRAIN INJURY IN THE MIDWEST, AND SO OUR SAMPLES GENERALLY HAVE A LOT OF WOMEN. AND HERE'S THE SAME THING AGAIN, YOU CAN SEE AT THE VERY BEGINNING, WHICH IS WATCHING THIS VIDEO, THERE'S NOT MUCH DIFFERENCE BETWEEN TYPICAL MEN AND WOMEN AND BETWEEN WOMEN WITH AND WITHOUT TBI, BUT YOU SEE THIS GROUP DOWN HERE OF MEN WITH BRAIN INJURY, AND IT'S NOT UNTIL YOU INCREASE THE WORKING MEMORY LOAD THAT YOU SEE DROPS IN BOTH MEN AND WOMEN WITH BRAIN INJURY. SO IT SEEMS THAT DIFFERENT THINGS ARE OPERATING FOR WOMEN, THE DECLINE IN PERFORMANCE SEEMS TO ARE KNOW MORE RELATED TO COGNITIVE FUNCTIONS AND TO MEN RELATED TO PERHAPS NOT HAVING AS STRONG A SYSTEM FOR READING EMOTIONS IN OTHER PEOPLE. THIS HAS BEEN SHOWN AS WELL AS MUCH AS YOU CAN HAVE A RAT VERSION OF SOCIAL COGNITION, IN RATS AS WELL. SO WHY DOES THIS MATTER IN REHAB AND BEYOND? WE HAVE A SMALL ADVANTAGE IN WOMEN, MAYBE WE HAVE SOME RESISTANCE TO BRAIN INJURY IN WOMEN, SO THAT THEY HAVE BETTER OUTCOMES IN BEING ABLE TO READ THE SOCIAL WORLD. WELL, YOU KNOW, IN LIFE, IT'S NOT JUST WHAT YOU DO BUT IT'S ALSO WHAT OTHER PEOPLE EXPECT, AND I THINK THAT THERE MAY BE DIFFERENT EXPECTATIONS BY MEN AND WOMEN FOR SOCIAL BEHAVIOR AND DIFFERENT EXPECTATIONS OF MEN AND WOMEN FOR SOCIAL BEHAVIOR. WE DID A STUDY WHERE WE GAVE THIS QUESTIONNAIRE ABOUT SOCIAL BEHAVIOR TO A BUNCH OF UNDERGRAD STUDENTS, SO THIS WAS DEVELOPED IN AUSTRALIA BY DOUGLAS, AND IT LISTS A BUNCH OF SOCIAL COMMUNICATION PROBLEMS. SO WE ASKED UNDERGRDGRADUATES, IF YOU HAVE THIS LIST, IS IT OKAY IF WOMEN DO THESE THINGS AND IS IT OKAY IF MEN DO THESE THINGS? SO WE ASKED WOMEN AND WE ASKED MEN. THIS IS -- THESE ARE THE EXAMPLES OF QUESTIONS. SO OFF OUR GROUP, SO WE HAD HALF MALES, HALF FEMALES ANSWER THIS SURVEY. WE LOOKED AT GENDER SELF IDENTIFICATION IN THIS GROUP AND WE SAW A VERY TYPICAL GENDER PATTERN THAT YOU SEE IN THE GENERAL YOUNG ADULT POPULATION, WHICH IS VERY -- MOST MALES SELF-IDENTIFY AS MASCULINE, A FEW MALES WILL SELF IDENTIFY AS AN DROJ NUSS AND -- ON THE FEMALE SIDES, MOST AS AN DROJNESS OR MASCULINE BECAUSE THOSE VALUES ARE VALUED MORE HIGHLY IN OUR CULTURE SO WOMEN ARE MORE LIKELY TO SELF-RATE THEMSELVES AS BEING ASSERTIVE AND ALL THESE STEREO TYPICALLY IDENTIFIED AS GOOD QUALITIES, SO THIS IS A PRETTY TYPICAL POPULATION, TYPICAL SAMPLE OF STUDENTS. SO WHAT HAPPENED WAS THAT EVERYONE AGREED ON A SET OF FIVE THINGS THAT IS NEVER GOOD FOR ANYONE TO DO. SO THERE'S GOOD AGREEMENT BETWEEN MALES AND FEMALES OF WHAT NOUN WITH YOU NO ONE SHOULD DO. EVERYONE NEEDS TO KNOW WHEN TO TALK AND WHEN TO LISTEN, GIVE PEOPLE INFORMATION THAT IS CORRECT, KEEP TRACK OF THE MAIN DETAILS IN A CONVERSATION, ET CETERA. BUT THE MORE INTERESTING FINDING WAS THIS ONE. SO WHEN WE HAD UNDERGRADUATE FEMALE STUDENTS RATE, THEY IDENTIFIED ALMOST TWICE AS MANY BEHAVIORS AS PROBLEMATIC IF ANYONE DIDN'T DO THEM WELL AS MEN DID. IN OTHER WORDS, THEY WERE PICKIER. SO WOMEN HAD HIGHER STANDARDS FOR ACCEPTABLE BEHAVIOR THAN MEN DID. FOLKLORE AROUND THIS, BUT IT'S BEEN MY MISSION FOR THE LAST 15 OR SO YEARS TO AVOID THE PROBLEM IN REHAB OF GIRL THERAPISTS EXPECTING GIRL BEHAVIOR FROM BOY PATIENTS. SO SOMEONE PRESENTED YESTERDAY THE DIFFERENCE AND INCIDENCE IN PREVALENCE IN NEUROLOGICAL DISORDERS IN MALES VERSUS FEMALES, WE ALL KNOW THE TBI STATISTICS AND YOU PROBABLY ALSO KNOW THE THERAPIST STATISTICS WHICH IS BY AND LARGE, MOST THERAPISTS ARE WOMEN AND BY AND LARGE, MOST PATIENTS WITH BRAIN INJURY ARE MEN. SO WHEN YOU TAKE THIS COMBINATION OF FACTORS, WHICH IS A MALE DOMINATED POPULATION, FEMALE DOMINATED GROUP OF CLINICIAN, AND SOCIAL PROBLEMS BEING CALLED THE HALLMARK PROBLEM OF BRAIN INJURY, I THINK YOU HAVE TO ASK YOURSELF, IS THERE ANY INFLUENCE OF THE RATER ON THAT PERCEPTION OF THE PROBLEM? THE SECOND THING IS, THERE IS A LITTLE BIT OF DATA SHOWING THAT YOUR SOCIAL BEHAVIOR IN REHAB AFFECT YOUR OUTCOME. THE THIRD THING IS, WHEN WE DO STUDIES OF AWARENESS OF DEFICITS, IT'S ALMOST ALWAYS FEMALES RATING MALES. BECAUSE IT'S SPOUSES WHO ARE STILL AROUND OF MALES WITH BRAIN INJURY RATING FEMALES. AND IN A STUDY WE PUBLISHED IN A SPECIAL ISSUE, WE SHOWED THAT RATINGS WERE CLOSE BETWEEN WOMEN WITH BRAIN INJURY RATING THEIR OWN SOCIAL SKILLS AND THEIR FAMILY MEMBERS RATING THEM, BUT THERE WAS A SIGNIFICANT DIFFERENCE BETWEEN MEN RATING AND THEIR FAMILY MEMBERS RATING. AND I JUST HAVE BEEN WONDERING IF PART OF THIS LACK OF AWARENESS LITERATURE COMES FROM A DIFFERENCE IN EXPECTATIONS FOR SOCIAL BEHAVIOR, IT ALSO COMES FROM A DIFFERENCE IN AWARENESS BUT WHEN WE'RE THINKING ABOUT SEX BASED DIFFERENCES, IT'S GOOD TO THINK ABOUT THE WHOLE LANDSCAPE SOCHT IN SUMMARY, THE STEREOTYPE IS SORT OF TRUE, WOMEN ARE SLIGHTLY BETTER THAN MEN AT RECOGNIZING AT LEAST BASE UK EMOTIONS AND INFERRING OTHER THOUGHTS. TBI AFFECTS BOTH AND IT MIGHT AFFECT THAT IN MEN MORE THAN WOMEN. WE HAVE NO IDEA HOW THAT LOOKS IN THE WORLD BECAUSE OUR LABORATORY TESTS ARE SO UNDERREPRESENTATIVE OF MEAN GIRLS AND THE SOCIAL WORLD IN GENERAL. AND SO FOR RESEARCH, I THINK EVEN AT THIS MEETING, IT'S BEEN STRIKING, PEOPLE ARE STILL USING SEX AND GENDER WORDS INTERCHANGEABLY, SO I THINK WE NEED TO HAVE A REALLY CLEAR DEFINITIONS ABOUT SEX AND AS CLEAR AS WE CAN BE ABOUT GENDER IN A SORT OF MURKY WORLD. ALSO WHAT OTHER PEOPLE ARE EXPECTING OF THEM, WE NEED TO GET OUT OF THE LAB AND WE NEED TO BE THINKING ABOUT REHAB, BECAUSE IT COUNTS FOR MOST PEOPLE WHO HAVE A BRAIN INJURY AND SO IT'S NOT JUST A NUISANCE VARIABLE IN OUR OUTCOME STUDIES. I WILL END WITH THE STEREOTYPE OF THE OBLIVIOUS PLEAL MALE AND MALE AND T HE WOMAN GIVING HIM A SARCASTIC LOOK, WHICH IS PRETTY GOOD AT 9 MONTHS. [APPLAUSE] >> TAN TAS TICK, DR. TURKSTRA. I COULD NOT AGREE MORE ABOUT THE NEED FOR REHABILITATION. I'LL INVITE THE PANEL BACK UP FOR OUR QUESTION SERIES. WE HAVE ABOUT -- BECAUSE OF THEIR STELLAR WORK, ABOUT 18 MINUTES FOR QUESTIONS. SO YOU'LL ASK FOIX TO BE AT THE FOLKS TO B E AT THE MICROPHONES HERE. I'LL REMARK THEY WERE ON TIME OR EARLY TO MAKE SURE WE HAD TIME FOR QUESTIONS SO KUDOS TO THEM. KUDOS. SO STEWART, WE'LL START WITH YOU. >> HI. THIS IS STU HOFFMAN FROM THE OFFICE OF RESEARCH AND DEVELOPMENT AT THE V.A. I HAVE A QUESTION FOR JEFF. WITH YOUR STUDY, YOU'RE LOOKING AT -- WITH YOUR RESULTS, MADE ME THINK BACK TO A PAPER BY SARAH CUTLER ON PROGESTERONE WITHDRAWAL, SO EVEN THOUGH YOUR LUTEAL PHASE LEVELS ARE PROBABLY NOT AT A THERAPEUTIC LEVEL THAT WOULD BE, YOU KNOW, BENEFICIAL FOR TBI, YOU TAKE THAT INTO ACCOUNT WITH POSSIBLE BUT TEU TRI DAMAGE AND OXIDATIVE STRESS WHICH DISRUPTS ENZYMES, YOU'RE PROBABLY CAUSING A MASSIVE STOP IN PRODUCTION IN PROGESTERONE AND OTHER STEROIDS, AND OTHER HORMONES. SO DO YOU THINK YOU MIGHT BE SEEING MORE OF A PROGESTERONE WITHDRAWAL EFFECT IN THESE WOMEN PATIENTS WITH TBI AS OPPOSED TO A LACK OF A BENEFICIAL PROTECTIVE EFFECT OF THE LUTEAL PHASE? >> THANKS, STEWART. APPRECIATE THAT QUESTION. I THINK THAT'S A REASONABLE HYPOTHESIS AND THAT'S WHAT JESSICA, GILL AND I WERE TRYING TO EXPLORE WHILE LOOKING AT PROGESTERONE SERIALLY. THAT'S WHAT KIND OF HAPPENS DURING THAT PHASE, PROGESTERONE DROPS REALLY QUICKLY SO FORGET ABOUT TBI, BUT IT DROPS REALLY QUICKLY AND THEN WOMEN FEEL CRABBY AND THE SYMPTOMS ARE VERY SIMILAR, SO I MEAN, THAT WOULD BE A POSSIBILITY. I THINK IF WE COULD MEASURE PROGESTERONE KIND OF DAILY AFTER TBI, WE COULD TEST THAT, AND I THINK THAT WOULD BE A REASONABLE THING TO THINK ABOUT. SO DURING THAT FIRST PHASE, WHERE PROGESTERONE IS LOW, IT CAN'T GET ANY LOWER, SO I GUESS YOU DON'T GET THAT WITHDRAWAL EFFECT. AND I THINK THAT'S ONE POSSIBILITY BUT AFTER I HEARD DR. RASMUSSEN SPEAK YESTERDAY, I COULD TELL THINGS WERE A LITTLE MORE COMPLICATED, BUT I THINK THAT'S SOMETHING WE'D LIKE TO PURSUE. THANKS. SPEAKING OF DR. RASMUSSEN. >> YOU INVITED ME TO THE PARTY, RIGHT? APPRECIATE IT. ANNE RASMUSSEN. SO I'M AT THE NATIONAL CENTER FOR PTSD, AND FOCUS MOSTLY ON PTSD BUT OBVIOUSLY IT'S BEEN VERY CLEAR THAT TBI AND PTSD ARE VERY OFTEN CO-PREVALENT. BUT ACTUALLY THE QUESTION I HAD FOR YOU FIRST IS, DID YOU RATE THE SYMPTOMS IN THE FOLLOW-UP PERIOD IN THE SAME MENSTRUAL PHASE AS WHEN THEY INCURRED THE INJURY, OR DID YOU DOCUMENT IT? IT'S A HARD THING TO DO IN FOLLOW-UP, SO I WAS JUST CURIOUS ABOUT HOW YOU DID THAT. OR IF YOU TRIED TO DO IT IN THE SAME, WERE THEY IN THAT LUTEAL PHASE WHEN THEY GOT IT AND IN THE LUTEAL PHASE WHEN THEY WERE RE-TESTED FOR THEIR WELL-BEING? >> ANNE, YOU JUST STOLE MY QUESTION. >> THERE'S A THROWDOWN BETWEEN THE AISLES. >> WE DIDN'T. WE DIDN'T ASK THEM ABOUT THEIR MENSTRUAL FUNCTION AT THAT TIME OF FOLLOW-UP OR MEASURE ANYTHING ANYTHING. >> SO WAS IT EXACTLY A MONTH LATER OR WAS IT PRETTY VARIABLE? >> OH, NO, IT WAS EXACTLY A MONTH LATER. THE INITIAL TYPING OF PHASE WAS DONE WITHIN SIX HOURS OF INJURY, SO WE HAD BLOOD WITHIN SIX HOURS OF INJURY TO SAY OKAY, YOU WERE DEFINITELY IN THIS PHASE OR THAT PHASE. >> AND WHEN YOU FOLLOWED UP? >> THE WAY WE ASKED THEM AGNOSTIC TO THEIR -- >> BUT IT WAS LIKE FOUR WEEKS LATER, IT WASN'T FOUR WEEKS PLUS OR MINUS TWO WEEKS OR FOUR WEEKS PLUS OR MINUS ONE WEEK? >> IT MAY HAVE BEEN FOUR WEEKS PLUS OR MINUS A DAY OR TWO. >> OKAY. SO THAT'S HELPFUL IN UNDERSTANDING IT. SO IT'S I GUESS THEN IMPORTANT TO APPRECIATE THAT THEY MIGHT JUST LOOK MORE SYMPTOMATIC IN THE LUTEAL PHASE COMPARED TO THE FOLLICULAR PHASE. YOU KNOW, WOMEN OFTEN COMPLAIN MORE OF PSYCHIATRIC SYMPTOMS, ANXIETY, DEPRESSION, ET CETERA. SO -- AND I THINK THAT SORT OF GOES TO THE POINT THAT MANY HAVE OBSERVED THAT WOMEN MAY APPEAR TO HAVE, YOU KNOW, HIGHER LEVEL OF SYMPTOMS BEFORE THEY GET THE TRAUMATIC BRAIN INJURY, SO IT WOULD JUST BE IMPORTANT TO CONTROL IN STUDIES, MAYBE TEST THEM AGAIN IN THE FOLLICULAR PHASE, BECAUSE THERE MAY BE THIS KIND OF THING GOING ON, BUT ANYWAY, THAT ASIDE, YOU ALLUDED TO THERE MAY BE MORE COMPLEXITY, AND SO I WAS JUST GOING TO TAKE THIS OPPORTUNITY TO ENTERTAIN THE AUDIENCE WITH A LITTLE BIT MORE OF THE COMPLEXITY WHICH WILL PROBABLY BE REALLY HELPFUL TO US, SO IN THE LUTEAL PHASE, ESTROGEN IS UP, SO IS PROGESTERONE. ESTROGEN -- ESTRODILE ENHANCES THE FUNCTIONING OF THE JEAN THAT CONVERTS -- SO THAT SHOULD GO UP AND IN MOST PEOPLE IT DOES GO UP SORT OF LOCK STEP, SO IT GOES UP IN THE CSF2 TO THREE TIMES IN THE LUTEAL PHASE, IN THE BLOOD IT GOES UP ABOUT 9 TIMES, BOTH, SO THEY'RE VERY MUCH MORE PRECURSOR, MORE ALOE. IN THE PTSD, THE PROGESTERONE GOES UP MAYBE MUCH MORE, THE ALOE DOESN'T GO UP, SO THE ESTROGEN IS GOING UP, SOME PEOPLE A LITTLE LESS, THEY MAY BE MORE AT RISK. SO IT WOULD BE VERY IMPORTANT THEN, NOT JUST TO MEASURE THE PROGESTERONE, BUT TO SEE IF IT'S BEING CONVERTED, THAT WOULD BE ONE IMPORTANT POINT. ALSO IN THE PTSD LITERATURE, THERE'S THIS COOL FINDING WHERE PAY CAP RECEPTOR, MAYBE NOBODY HAS HEARD OF THAT, BUT IT CONFERS RISK FOR PTSD IN WOMEN, NOT MEN, AS OPPOSED TO THAT HORMONE I TALKED ABOUT THAT CONFERS RISK FOR PTSD IN MEN BUT NOT WOMEN, THAT HAS AN ESTROGEN SENSITIVE PROMOTER, AND THERE'S A POLYMORPHISM RIGHT THERE IN THE WOMEN THAT THEN HAS A GREATER RISK FOR PTSD AND WORSE PTSD, SO THERE CAN BE ESTROGEN-SENSITIVE THINGS THAT CONFER GREATER RISK, AND THEN THAT PAYCAP IS ACTUALLY INVOLVED IN THE PATHWAY THAT LEADS TO ALO, SO NOT ONLY DO YOU NOT GET ALL THIS GOOD CYCLIC AMP GOING ON AND ALL THE STUFF ATTENDANT WITH THAT, ABOUT BUT ALSOS YOU DON'T GET THE ALO PRO DUCK, BUT THAT WOULD BE SOMEBODY WITH AN ESTROGEN-SENSITIVE PROBLEM BUT YOU COULD STILL END UP WITH A LOW ALO. SO IN WOMEN, HEALTHY WOMEN DO BETTER IN THE LUTEAL PHASE, SO I JUST WANTED TO SORT OF POINT OUT THAT WE'RE ALWAYS LOOKING AT MEANS AND THERE MIGHT BE A MEAN DIFFERENCE FOR WOMEN IN THE LUTEAL PHASE BUT SOME WOMEN MAY BE RECOVERING BETTER IF IT HAPPENS AND OTHERS RECOVERING MUCH LESS WELL, BECAUSE THEY'RE THE GROUP THAT GETS PROGESTERONE AND CAN'T CONVERT IT, BUT WOMEN THAT CAN DO MUCH BETTER. SO I THINK WE WANT TO LOOK AT THAT VARIABILITY. LIKE SOME PEOPLE ARE RESILIENT AND OTHER PEOPLE DON'T RECOVER, SO IT WON'T BE A SORT OF ONE SIZE FITS ALL KIND OF STORY. THAT'S ALL. SO IF WE DIG INTO THAT, WE'LL PRO BLI FIGURE OUT THESE LITTLE PHENOTYPES THAT WOULD CONFER RISK AND WE'D KNOW WHAT TO DO A BIT BETTER. THAT'S MY POINT. >> THANK YOU. I KNEW I WAS NOT A PITUITARY EXPERT AND YOU JUST PROVED IT RIGHT THERE. >> WELL, WE'VE BEEN WORKING AT IT FOR A WHILE. >> SO I THINK THAT IS FANTASTIC. WHAT I'D LIKE TO DO BECAUSE WE HAVE TWO OTHER FOLKS AT THE MICROPHONE AND WE HAVE ABOUT NINE MINUTES IS GIVE SOME OTHER FOLKS AN OPPORTUNITY, BUT I DO THINK THIS POINTS OUT THE NEED FOR COLLABORATION ACROSS DIFFERENT DISCIPLINES AS WITH RESPECT TO WOMEN. >> GOOD MORNING. I'M JESSICA SCHWARTZ. I AM ONE A NATIONAL SPOKESWOMAN FORT AMERICAN PHYSICAL THERAPY ASSOCIATION AND ALSO A BRAIN INJURY SURVIVOR. SO I KNOW THREE QUARTERS OF OUR PANEL APPEARS PRE-CLINICAL, SO IT'S GOING TO FAVOR TO LYN A LITTLE BIT BUT I'M PLANTING THE SEEDS FOR THE AUDIENCE AS WELL. WHAT WE'RE FINDING IN A REHABILITATIVE STANDPOINT, THE NUMBER ONE THING I'M HEARING ARE QUESTIONS ABOUT DOSING AND WHAT ARE WE DOING FOR THESE PATIENTS. AS LYN HAD REMARKED, OUR BRAIN INJURY SURVIVORS, WE GET BACK TO LIFE WITH REHAB. SO ARE THERE ANY CONVERSATIONS OR ANY THINGS KIND OF GOING ON WITH THE WORKING WITH ALL THIS RESEARCH THAT'S GOING ON, ESSENTIALLY THE NUMBER ONE THING THAT WE'RE HEARING FROM REHAB PROVIDERS ARE PT SPEECH AND OT BROTHERS AND SISTERS, DOSING FREQUENCY, WHAT ARE WE DOING FOR THESE PATIENTS. AND WE DON'T REALLY HAVE ANSWER FOR THAT. IS THERE ANY WORK GOING TO BE COMING OUT OR DERIVING -- AND I KNOW I'M PLANTING SEEDS FOR EVERYONE HERE, AGAIN, WE DON'T HAVE CLINICAL PREDICTION GUIDELINES, I KNOW THE INJURY IS HETEROGENOUS, BUT HOW DO WE KIND OF GET THERE WITH ALL THE DATA THAT WE'RE COLLECTING AND NOW MAKE THIS FUNCTIONAL? I KNOW DR. FLANAGAN AT NYU STATES THE DIFFERENCE BETWEEN CONCUSSION AND BRAIN INJURY AND MUSCULOSKELETAL INJURY IS THE COGNITIVE AND BEHAVIORAL STANDPOINT. AT A PHYSIOAND BRAIN INJURY STUR VIEFER I ALSO STATE IT'S COMPLETELY ENVIRONMENTAL AS WELL. SO WE GET FOLKS BACK WITH REHAB TECHNIQUES TO GET THEM BACK INTO FUNCTIONING LIFE. SO IS THERE ANY TALK OR COLLABORATION OR ANYTHING COMING OUT THERE FOR ANY KIND OF RYE HABL TAITION REHABILITATION GUIDELINES BECAUSE IT'S SO NEEDED? >> LYN? >> THERE ARE EXCELLENT REHABILITATION GUIDELINES OUT THERE, BUT I THINK THE -- ESPECIALLY VA DOD GUIDELINES ARE REALLY EXCELLENT BUT WE HAVE NOT REALLY A WAY OF SYSTEMATICALLY LOOKING AT FACTORS LIKE DOSE IN REHABILITATION, EVEN THOUGH THAT'S PART OF THE -- GUIDELINES TO LOOK AT FACTORS, TREATMENT INTENSITY AND DOSE, I'M PART OF A GROUP WITH JOHN WHITE AND MARCEL AND TESSA HART, MULTIDISCIPLINARY PROJECT FUNDED BY P PCORI. >> THEY'RE OPEN FOR BUSINESS BECAUSE THEY'RE NON-FEDERAL BUT GO AHEAD. >> OH, GOOD. SO ANYWAY, THAT WE DEVELOPED A SYSTEM FOR SPECIFYING REHAB TREATMENTS ACROSS DISCIPLINES SO WE CAN LOOK AT THINGS LIKE DOSE, OVERALL DOSE, SO IT'S AN ODD SITUATION IN REHAB RIGHT NOW AT LEAST IN NORTH AMERICA THAT THE KNOWLEDGE WE HAVE ABOUT DOSE IS EXACTLY OPPOSITE TO THE BUDGET CUTS IN TIME SPENT IN REHABILITATION, SO ALL THE DOSE FOR REHAB IS EARLY AND ALL THE GOOD EFFICACY DATA ARE LATER, SO I THINK THAT'S A GREAT SEED TO PLANT. >> AND THAT'S KIND OF WHAT WE'RE SEEING IS THAT IRRESPECTIVE OF -- I AM A QUOTE-UNQUOTE VESTIBULAR THERAPIST, IT DOESN'T MATTER BECAUSE WHEN WE'RE WORK AREING WITH THIS TBI POPULATION, 24 TO 48 HOURS LATER, THEN THEY'RE OUT OF OUR CARE, SO THEN WE'RE MAKING BUDGET CUTS AND WE'RE HAVING PTO TMPLET ONE TO TWO TIMES A WEEK WHEN THEY MAY DO BETTER THREE TO FIVE DAYS A WEEK. SO AGAIN, SEEDS ARE PLANTED, THANK YOU GUYS FOR ALL YOUR WORK. >> SINCE FUNDERS ARE HERE -- NOT FUNDERS BUT REPRESENTATIVES OF FUNDERS ARE HERE, THERE WAS A FUNDING MECHANISM MANY YEARS AGO WHERE A REHAB INSTITUTE COULD PARTNER WITH CENTERS FOR MEDICARE AND MEDICAID AND PROPOSED AN ALTERNATIVE REIMBURSEMENT SCHEME AND TEST IT, BUT I DON'T THINK ANYONE TOOK ADVANTAGE OF IT BECAUSE YOU HAD TO HAVE A REALLY HIGH NUMBER OF PATIENTS GOING THROUGH YOUR REHAB SETTING TO QUALIFY FOR IT, BUT I FEEL LIKE THAT'S WHAT WE NEED. WE NEED CMS FOR EXAMPLE OR SOMEONE LIKE THAT TO PARTNER WITH A RESEARCH GROUP TO SAY LET'S FLIP THE DOSE. >> AND WE'VE 100% SEE THIS. I WAS SPEAKING WITH RON ABOUT THIS YESTERDAY, WE'VE ACTUALLY SEEN THIS WITH PEDIATRIC HIV AND AIDS PATIENTS, SO WE'VE ACTUALLY BEEN ABLE TO -- BOSTON WAS THE NUMBER ONE THAT SENT OUT -- IN THE SOUTH BRONX AND NO, WAS NEW YORK CITY WAS THE SECOND TO FOLLOW UP WITH THIS AND IT ACTUALLY WORKS. SO IF WE'RE LOOK AT A FEICK FROO SEE PERSPECTIVE, SENDING SENDING OUT -- CUT FUNDING AND EMERGENCY VITS IT'S FROM $250,000 A YEAR BILL TO UNDER 30. SO I THINK IF WE'RE LOOK AT THAT FROM A DOSAGE STANDPOINT, I THINK IT CARRIES OVER. IT'S THE SAME YOU THEME, SO I THINK IF WE CAN GET THE CONVERSATION STARTED, I THINK IT WOULD BE A GREAT CONVERSATION, MORE BETTER THAN HERE. >> THERE IS ONE YOUNG WOMAN PATIENTLY STANDING THEN SAT BACK DOWN, STOOD BACK UP. I'M GOING TO INVITE YOU TO STAND BACK UP AND THEN THE OTHER PERSON WHO SAT BACK DOWN IS GOING NEXT. THEN WE'LL GO TO LUNCH. >> I ACTUALLY DON'T -- I DON'T NECESSARILY HAVE A QUESTION, I DO HAVE A COMMENT TO MAKE. I'M A STUDENT IN DR. BAZARIAN'S LAB, AND WHAT I WANTED TO COMMENT ON IS THE FACT THAT WE'RE ALL HERE, WE'RE ALL -- I GUESS WHICH CAN WE CAN SAY WE'RE ALL LIKE MINDED IN THE SCIENCE WORLD TRYING TO DO RESEARCH AND PUBLISH, BUT I THINK WHAT'S REALLY MISSING IS THIS INFORMATION IS NOT NECESSARILY DISPERSED TO THE INJURED POPULATION. I HAVE A FRIEND WHO JUST SUSTAINED A CONCUSSION IN JULY, AND HAS SEVERE POST CONCUSSION SYMPTOMS AND IS TRYING TO RECOVER. BUT WHEN SHE GOOGLED -- SHE HAD TO SELF DIAGNOSE FIRST AND FOREMOST, AND SECONDLY WHEN SHE GOOGLED RESOURCES, THERE WAS NOTHING TO BE FOUND. SHE TEXTED ME YESTERDAY WHILE AT THIS CONFERENCE AND WHEN I GOOGLED, THE MOST AMOUNT OF INFORMATION I FOUND WAS FROM THE CANADIAN WEBSITE. MOST INTERESTINGLY. AND IT JUST WOULD BE GREAT IF WE COULD PERHAPS TRANSLATE AWFUL THIS INFORMATION INTO A WAY THAT THE CONSUMER CAN ESSENTIALLY BE ABLE TO GET QUITE EASILY RATHER THAN GOING TO A CANADIAN WEBSITE WHICH MAY NOT BE GENERAL GENERALIZABLE TO THEM. SO JUST A COMMENT. >> LAST QUESTION. >> HI, I'M MOLLY, I'M ACTUALLY A HIGH SCHOOL STUDENT COMING HERE FOR AN INTERN, I WANTED TO ADD A COMMENT JUST LIKE HER, IT'S FASCINATING WHAT YOU GUYS ARE DOING IN OPENING THE POSSIBILITIES FOR NEUROIMAGING, REHABILITATION, ET CETERA, AND I JUST WANTED TO GIVE THANKS TO THE YOUTH ESPECIALLY, BECAUSE YOUR RESEARCH ARTICLES OPENED UP OPPORTUNITIES AT SUCH A YOUNG AGE FOR ALL OF US TO CONDUCT OUR OWN RESEARCH. SO THANK YOU. >> AWESOME. AND ON THAT INSPIRATIONAL NOTE, I WILL PASS IT ON TO OUR INSPIRATIONAL LEADER, DR. DR. PATRICK WHO WILL GIVE US OUR LUNCH ORDERS. >> HI, EVERYONE. THANK YOU. WELCOME BACK. WE WERE BREAKOUT SESSION 2, TBI AS A CONSEQUENCE OF INTIMATE PARTNER VIOLENCE. THE FIRST QUESTION THAT WE ADDRESSED WAS, CAN RESEARCH PROGRESS ON IPV TBI BEGIN WITH AN INTERROGATION OF LARGE ONGOING CLINICAL TRIALS SUCH AS THE TRACT TBI AURORA -- CARE. >> SO WHAT WE ASSUMED AND GUESSED WHAT WE KNEW ABOUT THOSE BIG DATASETS IS THAT THE QUESTIONS THAT WE THINK ARE CRITICAL TO DOING THE RESEARCH THAT WE WANT TO DO IN IPV TBI WORK ARE NOT THERE, SO IT WOULD BE VERY DIFFICULT TO REALLY GET MUCH OUT OF THAT. IF ANYONE DOING THAT WORK KNOWS THAT THERE ARE PARTICULAR QUESTIONS THAT MAY GET AT THAT, LET US KNOW, BUT AS FAR AS WE CAN TELL, IT'S PROBABLY NOT SOMETHING THAT'S VERY FEASIBLE OR POSSIBLE. WE TOYED WITH THE IDEA OF SEEING IF THERE WAS THE POSSIBILITY OF ADDING A FEW QUESTIONS TO SOMEBODY'S PROTOCOL, BUT I KNOW THAT'S EXTREMELY DIFFICULT, AND EVEN THAT WOULD PROBABLY GIVE MINIMAL GAINS, BUT THAT'S SORT OF WHAT WE CAME UP WITH, WITH RESPECT TO THAT QUESTION. BUT IF SOMEBODY KNOWS SOMETHING ELSE ABOUT THE DATASETS THAT THEY THINK WOULD BE HELPFUL, WE'RE CERTAINLY OPEN TO HEARING ABOUT IT. >> AND EVEN WITHIN THE GROUP OF PEOPLE FROM THIS RESEARCH& CONFERENCE THAT CAME TO TALK ABOUT THIS, THERE WERE JUST HUGE GAPS WITHIN WHAT WE EACH KNEW ABOUT WHAT EACH OTHER WAS DOING, SO WE'RE GOING TO PULL TOGETHER AS A COMMUNITY AND BE ABLE TO PRESENT THE NEXT OPPORTUNITY WHAT WE KNOW ABOUT OURSELVES, AND THEN FIGURE OUT WHAT'S BEING DONE OUT THERE THAT COULD HELP THIS RESEARCH TO MOVE FORWARD. >> THE NEXT QUESTION IS, WHAT AREAS OR GAPS SHOULD BE PRIORITIZED IN RESEARCH ON IPV POPULATIONS, IE, NATURAL HISTORY STUDY, CROSS-SECTIONAL STUDY, AND HOW CAN RESEARCHERS CONTROL FOR COMORBIDITIES. >> SO IN TERMS OF CONTROLLING FOR COMORBIDITIES, THAT'S JUST ONE OF THE EASIER THINGS I THINK TO DEAL WITH, IS WE CONTROL THEM BY ASSESSING THE VARIABLES THAT WE KNOW ARE IMPORTANT WITH RESPECT TO THIS GROUP AND POPULATION OF WOMEN. SO WE CAN GET MEASURES OF THINGS THAT WE KNOW ARE GOING TO BE ISSUES POTENTIALLY: DEPRESSION, ANXIETY, PTSD SYMPTOMATOLOGY, CHILDHOOD ABUSE. THE VARIOUS RANGE OF THINGS WE KNOW ARE GOING TO BE IMPORTANT. AND THEN POTENTIALLY OTHER VARIABLES THAT MAY BE RELEVANT TO THE METHODOLOGY, AND THEN WE CAN USE THOSE AS COVARIANTS IN >> IN TERMS OF GAPS IN THE LITERATURE, IT'S REALLY A GAP, THE WHOLE IPV TBI AREA IS "THE GAP" IN THE LITERATURE. THERE'S NOT ANYTHING SPECIFIC ABOUT IT. WE KNOW VERY LITERALLY ABOUT IT, THERE'S A HANDFUL OF STUDIES, LOOKING AT IPV RELATED TBI SPECIFICALLY. AS I WAS SAYING YESTERDAY, THE ONLY IMAGING STUDY THAT I KNOW OF AT ALL THAT'S EVER BEEN CONDUCTED LOOKING AT THIS IS THE ONE THAT I PRESENTED ON YESTERDAY. SO IN CONTRAST TO THE MILLIONS OR HUNDREDS, YOU KNOW, OF PEOPLE WORKING IN THESE OTHER TBI AREAS, AND PUTTING OUT STUDIES AND STUFF, THERE'S REALLY NOTHING -- I MEAN, LITERATURE REVIEW WOULD BE SUPER, SUPER EASY BECAUSE THERE'S ONE STUDY FOR IMAGING AND THERE'S NOTHING ON BIOMARKERS, SO THE WHOLE -- IT'S BASICALLY A FREE FOR ALL FOR ANYBODY WHO WANTS TO STUDY THIS WILL, BECAUSE THERE'S NOTHING OUT THERE. SO ONE OF THE THINGS WE TALKED ABOUT DOING WAS APPROACHING THIS AS WE GO TO AN IPV POPULATION BASED STUDY AND WE JUST SAY WE'RE GOING TO -- THIS IS WHAT THIS IS ABOUT, WE'RE GOING TO GET AS MUCH INFORMATION AS WE CAN,, TRY TO PUT TOGETHER IMAGING, BIOMARKERS, CLINICAL HISTORY, AND WITH APPROPRIATE COMORBIDITIES ADDRESSING THEM, AND THEN I THINK WE CAN START TO UNCOVER WHAT'S GOING ON HERE AND HOW THERE MAY BE AN INTERSECTION BETWEEN PTSD AND DEPRESSION AND TBI, BUT MOST CRITICALLY HOW TBI, WHICH IS THIS THING THAT'S BEEN COMPLETELY OVERLOOKED IN THIS POPULATION, IS PLAYING A ROLE IN WHAT WE SEE. >> THAT MOVES ON TO OUR THIRD AND FINAL QUESTION, WHAT TYPE OF STUDIES AND RESEARCH STRATEGIES ARE THE MOST VALUABLE AND THE MOST FEASIBLE, ESPECIALLY SINCE WE HAVE A POPULATION THAT COULD BE VERY TRANSIENT OR ALSO IN DANGER, AND HOW CAN WE DO STUDIES THAT ARE VALUABLE AND FEASIBLE WITH THIS GROUP? >> SO IN TERMS OF FEASIBILITY, I MEAN, OBVIOUSLY WE NEED MONEY. THERE IS DEPARTMENT OF DEFENSE AND THERE'S NIH, THERE'S A LOT OF DIFFERENT, YOU KNOW, SOURCES OF FUNDING FOR TBI, I THINK IN SPORTS AND IN THE MILITARY, MORE GENERAL TBI-RELATED STUFF, BUT I MEAN, AND MAYBE IT'S BECAUSE NO ONE HAS SOUGHT THIS SPECIFIC TYPE OF FUNDING YET. I HAVE RECENTLY, AND SO HOPEFULLY I WILL EVENTUALLY GET IT, BUT ULTIMATELY REVIEWERS AND REVIEW SECTIONS NEED TO SEE THAT THIS IS AN IMPORTANT AREA OF RESEARCH. WE CANNOT JUST TAKE WHAT WE KNOW FROM THE MILITARY STUDIES THAT WE HAVE, MILITARY PERSONNEL OR FROM WHAT WE KNOW ABOUT SPORTS AND SAY, OH, WELL, YOU KNOW, WE CAN JUST APPLY THAT TO THIS GROUP OF WOMEN. WE SIMPLY CAN'T DO THAT. THERE ARE SO MANY DIFFERENT VARIABLES THAT MAKE THIS POPULATION VERY UNIQUE THAT WE NEED TO SPECIFICALLY STUDY THESE WOMEN. >> SO WE'RE GOING TO HAVE TO MOVE ON BECAUSE IT'S ONLY 45 MINUTES AND WE HAVE SIX GROUPS. SO THAT WAS GREAT, AND THEN WHAT WE'LL DO IS WE CAN TAKE THE NOTES FROM EACH OF THE GROUPS AND WE'LL COORDINATE THE NOTES AND MAKE BULLET POINTS AND SO DON'T WORRY IF YOU DIDN'T GET TO SOMETHING YOU REALLY WANTED TO. THE NEXT GROUP WOULD BE SESSION 1, WHICH LISA IS GOING TO PRESENT. >> THANK YOU. I WANTED TO THANK OUR SMALL GROUP THAT CAME UP WITH THESE IDEAS AND TO REINFORCE BECAUSE OF THE TIME, I WON'T BE ABLE TO GET TO EVERYTHING BUT IT WILL BE CAPTURED BECAUSE WE DID HAVE OUR NICE SKETCHES. SO IN TERMS OF THE QUESTION -- THE OVERALL QUESTION WAS SEX DIFFERENCES IN TBI ACROSS THE LIFESPAN, THE FIRST SUBQUESTION WAS, HOW DO EXPERTS WHO STU TI SEX DIFFERENCES BE ENCOURAGED TO COLLABORATE IN TBI WORK, THE FIRST THING WE THOUGHT OF WERE WORKSHOPS SUCH AS THIS, SMALL GROUPS, WHERE YOU CAN REALLY BUILD ON THE INTERDISCIPLINARY, WE DEFINED THAT AS ACROSS VARIOUS DISCIPLINES, PROMOTING THE COMMON PROSPECTUS AND CON CONSENSUS. WE ALSO GOT INTO A TRAINING COMPONENT BECAUSE OF THE FUTURE GENERATIONS AND THE WHOLE ISSUE OF REVIEW IN JOURNAL ARTICLES, THERE'S SOME VERY GOOD EXAMPLES, I WANTED TO GIVE A SHOUT OUT TO OUR CANADIAN COLLEAGUES THAT HAVE SEX GENDER CHAMPIONS ON EACH OF THEIR APPLICATIONS, AND IT'S INTENDED TO BE -- HOW WOULD THIS PERSON BE SUPPORTED IF THE GRANT IS FUNDED. SO IT'S ACTUALLY GOT TO BE MEANINGFUL. ANOTHER ONE WAS THE ANALYTICAL STRATEGIES WHERE YOU'RE AGAIN INTERDISCIPLINARY GROUPS, AND NEED TO DO SEX-SPECIFIC ANALYSIS AND MAKE IT SO IT'S AN EXPECTATION THAT THESE STRATEGIES ARE FOLLOWED AND SO FORTH. NUMBER TWO QUESTION IS, CAN LIFESPAN QUESTIONS BE BETTER ADDRESSED BY COLLABORATIONS BETWEEN GROUPS CURRENTLY COLLECTING TBI DATA, THEN THERE'S ANOTHER SUBQUESTION I'LL GET TO IN A MOMENT. THIS, WE WANTED TO ADD "AGED AND AGING" AND ALL THE WAY DOWN TO PEDIATRIC TBI. THIS IS WHERE WE MENTION THE ACE STUDIES, ADVERSE CHILDHOOD EVENTS, ALL BRAIN INJURIES, THE WHOLE THING OF ACCELERATED AGING. IT ALSO GOES INTO METHODS, BUT SOME OF THE DATA LOOKED AT 50 TO 60-YEAR-OLD WOMEN, HISTORY OF HEAD INJURY FROM ANY SOURCE, HOW THE QUESTIONS HAVE TO BE MUCH MORE CAREFULLY WORDED BECAUSE YOU'RE LOOKING AT REPETITIVE EXPOSURES. ANY INJURY, CUMULATIVE KINDS OF TRAUMA, THEN THE LONG-TERM EFFECTS OF PEDIATRIC TBI, WHICH OUR GROUP FELT WAS REALLY GROSSLY UNDERSTUDIED. THEN IN TERMS OF THE SUBQUESTION THERE, HOW CAN COLLABORATIONS BE FACILITATED, THERE'S A LOT OF -- WHILE THE FIELD IS SMALL, THERE'S A LOT OF PEOPLE WITH THEIR OWN DATABASES, CAN THERE BE SOME PROMOTION, SECONDARY ANALYSIS OR COLLABORATION ACROSS THE GROUPS FOR MINING DATA, HAVING GRAD STUDENTS, PREDOCS AND SO FORTH WORK ON THE DATA, SO THAT COULD BE ENCOURAGED. QUESTION NUMBER THREE, WHAT ADDITIONAL MEASURES NEED TO BE INCLUDED TO BEST ADDRESS SEX DIFFERENCES IN NATURAL HISTORY STUDYIES IN TBI. WE HAD A TON OF INFORMATION HERE IN TERMS OF AGAIN SEX-SPECIFIC, PROBING THE ORIGIN OF THE INJURY MORE. THIS IS WHERE INTENTIONALITY WOULD COME IN. HORMONES AND HORMONAL DISRUPTION, AND THE NEED TO BRING IN THE VARIOUS DISCIPLINES SO THAT YOU'RE COLLECTING DATA CORRECTLY. IF THERE'S A FALL INVOLVED WITH THE INJURY, FIND OUT MORE ABOUT IT. TBI IN THE SEX RELATIONSHIP, AGAIN, INTENTIONALITY. UTILIZATION OF COMMUNITY RESOURCES LIKE REHABILITATION, SO INCREASING AWARENESS, SO IT'S MORE THAN JUST RESEARCH, YOU WANT TO GET THE RESOURCES UTILIZED. THERE WAS ALSO A NOTE HERE FOR THE VICTIM ASSISTANCE FUNDS. VICTIMS OF CRIME ASSISTANCE, VOCA, WHICH IS A FEDERAL PROGRAM WHICH ACTUALLY WOULD HELP PAY FOR REHABILITATION COSTS. THIS MIGHT BE PARTICULARLY IMPORTANT TO WOMEN. HISTORY OF AND WE ALSO WANTED THE PATIENT PERSPECTIVE. I DON'T KNOW IF THE YOUNG WOMAN WHO TALKED ABOUT BEING A PARATROOPER, THAT INFORMATION IS REALLY VITAL SO WE FEEL THAT THE PATIENT PERSPECTIVE NEEDS TO BE BUILT IN ACROSS THE BOARD, ACROSS THE CONTINUUM, SO WE WANTED TO ENCOURAGE THAT. AND THEN MEASURES OF CAREGIVING AND SO FORTH. AGAIN, LIFESPAN. >> GREAT, THANKS, LISA. NEXT IS THE TRANSLATIONAL GROUP. >> SO I'M GOING TO READ FROM MY NOTES. WHICH ARE HERE. I THINK THE TWO OVERWHELMING MESSAGES THAT THIS GROUP HAD ON THE QUESTION OF HOW WE CAN RECONCILE TRANSLATIONAL CHALLENGES FACED BY TBI RESEARCHERS IN BOTH DIRECTIONS IS REALLY THE QUESTION THAT ANIMAL MODELS ARE VERY HOMOGENEOUS WHEREAS TBI ENCOMPASSES A HUGE SWELT OF WEALTH OF PATIENTS, ANIMAL MODELS THAT IS THE CLINICAL SIDE OF TBI. ONE WAY, PERHAPS, TO ADDRESS THIS IS WITH MULTICENTER ANIMAL TRIALS, THIS WAS RAISED YESTERDAY BY DAVE WRIGHT, AND POSSIBLY -- AND THIS SORT OF FEEDS INTO THE SECOND QUESTION, WHAT CAN FUNDING AGENCIES DO, POSSIBLY WITH NIH OVERSIGHT. SO IN THE SAME WAY THAT AS WE HAVE CLINICAL RESEARCH NETWORKS THAT ARE USUALLY COOPERATIVE AGREEMENTS WITH A GREAT DEAL OF INPUT FROM THE PROJECT SCIENTISTS AT NIH, IS IT MAY BE POSSIBLE TO SET UP A SIMILAR SYSTEM OF MULTICENTER ANIMAL TRIALS WITH SOME NIH OVERSIGHT. THE NEXT QUESTION THAT WAS RAISED IS -- IT WAS REALLY A COMMENT THAT FUNCTIONAL OUTCOME IS A BIOMARKER IN AND OF ITSELF, AND IF WE CONTINUE TO LOOK FOR BIOMARKERS, WE SHOULD AT LEAST USE THIS BIOMARKER BUT EVEN THOUGH IT IS A BIOMARKER OF OUTCOMES OF TBI, IT USES VERY BLUNT MEASURES, ON, OFF, YES, NO, SEVERE, MODERATE. THE FUNCTIONAL OUTCOME NEEDS ADDRESS THE NUANCES OF THE CLINICAL SITUATION. THERE'S ALSO A PROBLEM IN TRANSLATION IN THAT THE MILD, MODERATE AND SEVERE CATEGORIES OF BRAIN INJURY THAT WE USE IN HUMANS DOES NOT EASILY TRANSLATE INTO THE MOUSE OR RAT MODEL. ONE EXAMPLE THAT WAS GIVEN WAS MICE CAN HAVE A SMALL AMOUNT OF HEMORRHAGE IN THE BRAIN AND IT CAN STILL BE CONSIDERED A MILD BRAIN INJURY, WHEREAS OF COURSE IN HUMANS, YOU COULD NEVER CONSIDER SOMEBODY WHO HAD ANY KIND OF BLEEDING IN THE BRAIN TO HAVE A MILD TBI. SO THERE'S A QUESTION THERE ON HOW WE CAN TRANSLATE WHAT WE'RE FINDING IN THE ANIMALS INTO HUMANS, AGAIN, BECAUSE WE ARE -- BECAUSE HUMANS ARE SO DIFFICULT AND ARE SUBJECT TO SO MANY DIFFERENT THINGS, IT'S JUST VERY HARD TO TRANSLATE ONE FOR THE OTHER. IT WAS ALSO SUGGESTED THAT WE USE COMMON DATA ELEMENTS FOR ANIMAL STUDIES JUST AS WE HAVE BEEN USING IN HUMAN STUDIES, AND I THINK THIS IS A REALLY INTERESTING OPPORTUNITY TO DISCUSS THAT FURTHER, AND THE QUESTION THAT HAS BEEN PLAGUING THE LITERATURE FOR A LONG TIME AND IT'S NOT JUST IN THIS FIELD BUT IN SEVERAL OTHERS TOO IS THE LACK OF DETAIL IN MANY PUBLICATIONS TO ALLOW FOR REPLICATION OF STUDIES. WITHOUT THOSE DETAILS COMING FROM THE PUBLICATIONS, IT'S REALLY DIFFICULT TO SAY WHETHER THE FINDING IS GENERAL AND CAN BE BUILT UPON. IN TERMS OF -- SO THERE WAS ALSO A VERY GOOD POINT THAT WAS RAISED WHICH IS WE NEED ACCESS TO NEGATIVE DATA. THIS OF COURSE IS NOT -- DOESN'T JUST ONLY APPLY IN THE TBI AREA, IT PLAGUES CLINICAL RESEARCH AND IT PLAGUES ANY KIND OF RESEARCH THAT YOU COULD THINK ABOUT IN MEDICINE. THERE JUST ISN'T ACCESS TO NEGATIVE DATA, AND THIS IS A QUESTION THAT I THINK NEEDS TO BE ADDRESSED TOWARDS THOSE WHO PRODUCE THE JOURNALS BUT IT'S SOMETHING THAT WILL HELP MOVE THE FIELD IN TRANSLATION FORWARD IN A VERY RAPID WAY. IT WAS ALSO MENTIONED THAT WE NEED BETTER TEACHING OF STATISTICS TO YOUNG INVESTIGATORS, SEVERAL OF THE PEOPLE AROUND THE TABLE WERE -- COMMENTED THANK YOU HOW POORLY POSTDOCS WERE COMING TO THEM WITH TRAINING IN STATISTICS. FINALLY, WHEN WE TALK ABOUT THE ROAFL FUNDING ROLE OF FUNDING AGENCIES, ONE OF THE VERY STRONG MESSAGES WAS THAT NIH SHOULD CLARIFY WHAT IT WANTS FROM RESEARCHERS, MEANING DO WE NEED -- ARE WE LOOKING FOR A MECHANISM BEFORE WE TEST -- BEFORE WE MOVE FORWARD OR ARE WE FIRST LOOKING FOR TESTING OF SAFETY AND EFFICACY, SEEING IF THE PRODUCT IS ACTUALLY SAFE AND WORKS, BEFORE WE THEN GO BACK AND SAY YES, IT SEEMS TO WORK, NOW LET'S LOOK AT ITS MECHANISM. SO THIS IS A QUESTION I THINK THAT REALLY ADDRESSES BOTH THE REVIEWERS WHO COME FROM THE COMMUNITY TO ADDRESS THIS AND ALSO TO GET CLARIFICATION FROM NIH AS TO WHICH OF THESE DIRECTIONS IT WANTS TO MOVE IN. I THINK THE TRUTH IS THAT NIH IS NOT A SINGLE INSTITUTION AND EACH IC HAS ITS OWN PATH AND ITS OWN WAY FORWARD IN THESE AREAS AND IT'S GOING TO BE VERY DEPENDENT ON WHERE YOU'RE APLOOG FOR FUNDING. SINCE THE VAST MAJORITY OF HERE I THINK WOULD GET NINDS FUNDING, THE MESSAGE FROM THEM IS WE NEED TO CLARIFY WHAT IT IS EXACTLY WE WANT FROM RESEARCHERS IN ORDER TO ALLOW THEM TO MOVE FORWARD IN TRANSLATION. THAT'S IT. >> THANK YOU, JEREMY. THE NEXT IS THE SPORTS GROUP. YOU SHOULD PROBABLY INTRODUCE YOURSELF. >> THANK YOU. MY NAME IS DONNA DUFFEY, I'M FROM THE UNIVERSITY OF NORTH CAROLINA AT GREENSBORO. I WAS IN THE BREAKOUT GROUP THAT FOCUSED ON SEX DIFFERENCES FOLLOWING SPORTS-RELATED TBI. SO THIS IS SUCH AN IMPORTANT OPPORTUNITY FOR US TO BE ABLE TO TALK ABOUT THESE THINGS, SO I WOULD LIKE TO ALSO ASK FOR HELP FROM MY BREAKOUT GROUP, IF I FORGET ANYTHING OR I DON'T WANT TO MISREPRESENT ANYTHING THAT WE SAID, SO HELP IF I START TO GO DOWN THAT ROAD. IN TERMS OF THE GAPS OF KNOWLEDGE REGARDING SEX DIFFERENCES THAT CURRENTLY EXIST IN SPORT-RELATED TBI, ONE OF THE THINGS WE TALKED ABOUT WAS MAKING SURE WE HAD A BROADER PERSPECTIVE OF DIFFERENT AGE GROUPS AS WELL AS DIFFERENT SPORTS, SO YOU KNOW, NOT JUST FOCUSING ON SORT OF THE NCAA SPORTS OR HIGH SCHOOL SPORTS THAT WE ALL KNOW PROBABLY WELL, WHETHER WE WERE AN ATHLETE OR KNOW SOMEONE WHO IS AN ATHLETE. WE EVEN TALKED ABOUT EXTREME SPORTS AND ACTION SPORTS. WE TALKED ABOUT A CONTINUED FOCUS ON HORMONES AND THE NEED FOR CONTINUED WORK IN RESEARCH IN THOSE AREAS. TALKED ABOUT NOT TAKING A SORT OF ONE SIZE FITS ALL APPROACH AND REALLY FOCUSING ON THIS IDEA OF WHAT IS DEVELOPMENTALLY AN AGE-APPROPRIATE IN TERMS OF TREATMENT, REHABILITATION, ET CETERA. WE DID TALK ABOUT THE NEED FOR A LARGER, MORE COMPREHENSIVE DATASET WHERE WOMEN AROUND JUST CONSIDERED A COHORT OR SUBCOHORT OF A SPECIFIC DATASET. WE TALKED ABOUT A CONTINUED FOCUS ON THE PSYCHOLOGICAL AND PSYCHIATRIC OUTCOMES OF TBI AMONG WOMEN IN SPORT ENVIRONMENTS, AND THIS IDEA OF TREATMENT CONSISTENCY FROM ONE PROVIDER TO ANOTHER. WE DID TALK A LITTLE BIT ABOUT FOCUSING ON WHETHER OR NOT CLINICAL BIAS MAY BE A VARIABLE THAT NEEDS TO BE CONSIDERED WHEN WE START TO EVEN JUST THINK ABOUT THE DISSEMINATION OF WHAT WE'RE PUBLISHING AND HOW WE'RE TALKING ABOUT THESE THINGS TO PEOPLE IN A VARIETY OF DIFFERENT CONTEXTS AND ENVIRONMENTS. WE ALSO DID TALK ABOUT THE IDEA OF DISSEMINATION, EDUCATION, AND HOW DO WE MAKE SURE THAT WE ARE GETTING THE INFORMATION TO THE PEOPLE WHO NEED IT IN THE MOST TIMELY MANNER. WHAT DO YOU THINK, BREAKOUT GROUP? AM I GOOD? >> THE ONLY TWO THINGS I WOULD ADD IS WE ALSO JUST LIKE THE LAST GROUP, WE TALKED ABOUT THE NEED FOR OBJECTIVE MEASURES BECAUSE CONCUSSIONS ARE GENERALLY SELF-REPORTED SO THE DEVELOPMENT OF OBJECTIVE BIOLOGICAL MEASURES FOR ASSESSING CONCUSSION AND WE TALKED ABOUT ONE WAY TO GET PAST SOME OF THESE HURDLES IS THERE'S NOT CONSISTENT CARE, WHICH IS WHAT WAS DISCUSSED, THERE'S NOT CONSISTENT CARE ACROSS THE COUNTRY. SO THERE IS THE IOM REPORT, WE COULD RECONVENE AT SOME LEVEL JUST TO START TO SEE IF IT'S STILL UP TO DATE, AND THEN THE GROUP TALKED ABOUT THE NEED THEN FOR COMPARATIVE EFFECTIVENESS RESEARCH TO DISCUSS HOW DO YOU TREAT PEOPLE ACROSS THE AGE SPECTRUM, GIRLS AND BOYS, FOR MILD TBI PARTICULARLY RELATED TO SPORTS. >> IN TERMS OF WHAT INFORMATION SHOULD BE COLLECTED IN CLINICAL TBI RESEARCH IN ORDER TO INTERROGATE DATA FOR SEX DIFFERENCES, ONE OF THE THINGS THAT WE HAD TALKED ABOUT, WE WERE ASKED TO THINK ABOUT IN SOME OF THESE SMALLER STUDIES THAT RK ARE BEING CONDUCTED, MAKING SURE THE RIGHT CONTROLS ARE IN PLACE, WE WERE ALSO ASKED TO THINK ABOUT WHETHER OR NOT WE NEED TO DO SEX-SPECIFIC -- EXCLUSIVE SEX-SPECIFIC STUDIES AND MAYBE FOR A MOMENT GET AWAY FROM THE COMPARATIVE STUDIES. THERE WAS A QUESTION ABOUT WHETHER OR NOT WE'RE MISSING SOMETHING THERE IN THOSE COMPARATIVE STUDIES. SHARED DATASETS, TAKING ADVANTAGE OF ALREADY LARGE DATASETS THAT MAY BE ALREADY IN EXISTENCE, AND OF COURSE THE IDEA OF COLLABORATION IS SOMETHING THAT WE HAD TALKED ABOUT AS WELL. >> THAT'S GREAT, THANK YOU. >> WE ALSO TALKED -- JUST FOR A POSITIVE NOTE, BEING THE CO-DIRECTOR, WE TALKED ABOUT THERE'S QUITE A BIT OF DATA IN FITPR THAT WILL SHED SOME INITIAL INFORMATION ON THESE QUESTIONS. SO THE NEXT GROUP WAS THE VETERANS GROUP. DR. DON MARION IS GOING TO PRESENT WHAT THEY DISCUSSED. >> OUR GROUP WAS ASKED TO TALK ABOUT MILITARY -- GENDER DIFFERENCES IN MILITARY TBI. WE HAD TWO QUESTIONS. THE FIRST QUESTION WAS DOES CURRENT KNOWLEDGE OF TBI WARRANT A DIFFERENTIAL APPROACH TO THE DIAGNOSIS, PROGNOSIS AND TREATMENT OF MEN AND WOMEN IN THE ACTIVE DUTY VETERAN POPULATION AND MILITARY. AND THEN THE SECOND QUESTION WAS YOU KNOW, IF WE COULD, HOW -- WHAT WOULD THE GAPS BE AND HOW WOULD WE ADDRESS THOSE GAPS. SO STARTING OUT OF THE GATE, WE FELT THERE WASN'T CURRENTLY ENOUGH DATA SO THAT WE COULD RELIABLY THINK IN TERMS OF TRADING MALE VERSUS FEMALE WHO CAME TO OUR OFFICE WITH A MILITARY-RELATED TBI. HOWEVER, I THINK THE GROUP IN GENERAL THOUGHT THAT WE NEEDED TO BE SURE TO ASK APPROPRIATE QUESTIONS AND GET AN APPROPRIATE HISTORY AND PHYSICAL THINKING IN TERMS OF WHERE YOU ARE IN YOUR MENSTRUAL CYCLE, IF YOU'RE A WOMAN, AND HORMONAL CHANGES MIGHT AFFECT SOME OF THESE SYMPTOMS AND SIGNS THAT CAN MIMIC POST CONCUSSION SYNDROME, ASKING NEGATIVE VERSUS POSITIVE PREDICTER OF INDICATORS OF PRE-EXISTING FACTORS AND KEEPING TRACK OF THOSE. WE THOUGHT THE CURRENT KNOWLEDGE MAY ASSIST US WITH A MORE -- YEAH. ALL RIGHT. WE FELT THE CURRENT KNOWLEDGE MAY ASSIST US WITH MORE SENSITIVITY OR BETTER SCREENING FOR WOMEN VERSUS MEN WITH TBI. DIFFERENT DISCIPLINES MAY NEED TO HAVE DIFFERENT CRY TIER CRITERIA FOR DIAGNOSING AND TREATING PATIENTS THAT IS PHYSICAL THERAPISTS, FOR EXAMPLE, OR OCCUPATIONAL THERAPISTS, PSYCHOLOGISTS, AND SO FORTH. AND WE THOUGHT WE COULD DO A BETTER JOB IN THE MILITARY FOR EDUCATION OF THE DIFFERENCES OF HOW MEN AND WOMEN RESPOND TO A CONCUSSION. FOR EXAMPLE, WHAT ABOUT DIFFERENCES IN DEPRESSION OR PTSD AND WHAT ABOUT THE DIFFERENT CAUSES FOR PTSD IN WOMEN AND MEN. SO THOSE WERE KIND OF OUR THOUGHTS ABOUT THE CURRENT STATE OF AFFAIRS. SO WHAT INFORMATION WILL ADVANCE THE FIELD TOWARD UNDERSTANDING AND ADDRESSING THESE DIFFERENCES IN TREATMENT, DIAGNOSIS AND. ONE OF THE FIRST THINGS WE THOUGHT WAS THAT WE REALLY DO NEED MORE LONGITUDINAL STUDIES, AND THOSE ARE OBVIOUSLY DIFFICULT, OTHERWISE THEY WOULD HAVE BEEN DONE ALREADY. DIFFICULT I THINK BECAUSE WOMEN COMPRISE A MINORITY OF MEMBERS OF THE MILITARY. HOWEVER, IT WAS POINTED OUT, AND APPROPRIATELY SO, I THINK, THAT THE MAJORITY OF TBI IN THE MILITARY ACTUALLY OCCURS IN GARRISON RATHER THAN ON THE BATTLEFIELD, AND SO WOMEN ARE VERY FREQUENTLY AFFECTED AND CAN BE STUDIED AND THERE NEEDS TO AB BETTER FOCUS. SO BLAST IS NOT AS COMMON A CAUSE OF TBI ANYMORE AS IT ONCE WAS. THERE NEEDS TO BE RESEARCH ON BETTER OUT COME MEASURES, OF INTERMEDIATE OUTCOMES, THIS MIGHT INVOLVE BIOMARKERS, EITHER IMAGING OR SERUM BIOMARKERS, BUT IT ALSO NEEDS TO INVOLVE PHYSICAL OUTCOME MEASURES BETTER THAN SELF-REPORTED MEASURES. WE NEED TO LOOK AT FUNCTIONAL OUTCOME MEASURES SUCH AS JOB, HOME, SENSE OF WELLBEING, ARE YOU BACK TO DOING WHAT YOU WANT TO BE DOING WAS A COMMON THEME, I THINK. WE NEED TO WIDEN THE VALUE -- THE OUTCOME MEASURES FOR FEMALE VERSUS MALE PATIENTS TO DETERMINE WHAT IS THEIR DESIRED OUTCOME. WE TALKED ABOUT THAT ALREADY. THE FOCUS ON WHAT THEY WANT TO ACCOMPLISH. NEED TO EXPLORE HOW TO EDUCATE PATIENTS THAT SOME SYMPTOMS ARE NORMAL, SOMETIMES YOU'RE JUST GULF COAST TO HAVE A HEADACHE AND IT MAY NOT BE RELATED TO YOUR TRAUMA. SOME OF THE MEMBERS OF OUR GROUP THOUGHT IT WOULD BE GREAT IF THERE WERE FEMALE-SPECIFIC CLINICS OR UNITS IN THE V.A., IN PARTICULAR, THE V.A. NEEDS TO PAY PARTICULAR ATTENTION TO HAVE HAVING FEMALE FRIENDLY WARDS OR AT LEAST AREAS FOR INPATIENT CARE. WE NEED TO FOLLOW THE MODEL OF THE HEADACHE MEDICINE IN TERMS OF OVERALL TREATMENT, MORE SENSITIVE, DEPLOYABLE IMAGING TECHNIQUES THAT CAN BE ABLE TO CORRELATE WHAT WE SEE ON THE SCAN TO FUNCTIONAL OUTCOMES, WE'D LIKE TO SEE RESEARCH ALONG THOSE LINES. SPECIFICALLY WE'VE SEEN IN THE LAST COUPLE OF DAYS AND ACTUALLY IN THE LAST SEVERAL YEARS VERY ELEGANT MRI STUDYIES, A QUESTION I THINK A LOT OF US WERE CONCERN ABOUT, THOUGH, IS HOW DO YOU RELATE THE FINDINGS, FOR EXAMPLE, DTI FINDINGS, F.A. FINDINGS TO TO SYMPTOMS, SO THERE NEEDS TO BE MUCH MORE RESEARCH ON THAT. BETTER INTERFACE BETWEEN THE DOD AND V.A. IN TERMS OF EMR. OUR GROUP THOUGHT THAT A REAL STUMBLING BLOCK IN TERMS OF SMOOTH LONGITUDINAL STUDY WAS THE ABILITY TO SEAMLESSLY MOVE EMR DATA FROM THE ACTIVE DUTY DOD SIDE TO THE V.A. SIDE, AND THAT NEEDS TO CHANGE. INCREASED RESEARCH ON OCULAR MOTOR ASSESSMENTS, INCREASED VETERAN ASSESSMENT ON OTHER CAUSE OF CONCUSSION, FOR EXAMPLE, FALLS, AND SPORT CONCUSSION, NOT JUST BLAST. WE NEED TO CAPTURE DIAGNOSIS OF TBI AND BETTER CODING FOR TBI. THERE WAS CONCERN THAT CURRENTLY THE DIAGNOSIS OR THE DEFINITION OF TBI IS NOT AS CLEAR AS IT COULD BE, AND PEOPLE THAT HAVE GONE BACK TO CHARTS AND TRIED TO LOOK AT THESE LONGITUDINAL STUDIES AND SURVEILLANCE HAVE BEEN FRUSTRATED THAT CODING IS ALL OVER THE MAP AND IT'S NOT VERY TIGHT, SO THAT NEEDS TO BE IMPROVED. THERE NEEDS TO BE HEIGHTENED AWARENESS OF THE CAUSES OF TBI AND DOCUMENTATION AND POST-TRAUMATIC DIAGNOSIS, BERT UNDERSTANDING OR KNOWLEDGE OF WHO RESPONDS BEST TO CERTAIN INTERVENTIONS, AND FINALLY, STUDIES ON ANTIDEPRESCIENT EFFICACY, ESPECIALLY IN TERMS OF WOMEN WITH TBI. HOW DO WE KNOW WE ARE COLLECTING DATA ON LIFETIME EXPOSURE TO TBI, NEED BETTER INFORMATION ON THAT, AND THEN BETTER STUDIES ON BIOMARKERS. >> THANKS, DR. MARION. AND THEN LAST BUT NOT LEAST -- >> NEVER LEAST, TRUST ME. SO WHAT INFORMATION SHOULD BE INCLUDED TO ACCOUNT FOR SEX DIFFERENCES WHEN DIFFERENT MODALITYINGS OF BIOMARERS ARE BEING DEVELOPED AND ANALYZED. I'M GOING TO RESTRICT MY COMMENTS TO THINGS UNIQUE TO OUR GROUP, MENSTRUAL CYCLE I THINK HAS ALREADY BEEN STATED. I THINK THE BIGGEST DISCUSSION WE HAD WAS ENSURING THE DISTINGUISHMENT BETWEEN -- AND OUTCOME. IN TERMS OF PARTICULARLY IN SYMPTOMS FOR MILD TRAUMATIC BRAIN INJURY, WE USED THEM BOTH AS A PREDICTER AND AN OUTCOME, SO THAT ESSENTIALLY CONFIRMS THAT ANY OTHER PIECE OF THAT WITH MENSTRUAL SYMPTOMS, MANY OF THE LANDMARK STUDIES RELATED TO SYMPTOMS IN MILD TRAUMATIC BRAIN INJURY, THERE WAS NO ACCOUNTING FOR MENSTRUAL SYMPTOMS SO THAT COULD BE A POTENTIAL CONFOUNDER FOR USING THEM FOR BOTH. THEN THE OTHER IS THAT FOR BIOMARKERS WREELY SHOULD BE LOOKING AT DR. MANNIX POINTED OUT WHERE SEX WAS A BIOLOGICAL VARIABLE, SUCH AS IN ALZHEIMER'S DISEASE AND STROKE, IN THE PERFORMANCE OF THOSE BIOMARKERS AND LOOK AT OTHER POTENTIAL EFFECTS OF THOSE WITH RESPECT TO EPIGENETICS OR PROTEIN EXPRESSION OR OTHER THINGS THAT WERE RAISED DURING THE COURSE OF THIS MEETING. WHEN WE TALKED ABOUT OUTCOMES AS WELL FOR BIOMARKERS, THE OTHER THING THAT HAS NOT BEEN LOOKED AT IN BRAIN INJURY IS IN GYNECOLOGICAL HEALTH OND REPRODUCTIVE HEALTH FOR MEN AND WOMEN. SO WE DON'T KNOW -- WHAT THE EFFECTS ARE OR GYNECOLOGICAL HEALTH MORE BROADLY OUTSIDE OF THE MENSTRUAL CYCLE AND WE DON'T KNOW WHAT THE EFFECTS ARE POTENTIALLY IN FERTILITY IN THE YOUNGER STAGES AND/OR EARLY MENOPAUSE OR OTHER RELATIONSHIPS TO THE FEMALE CYCLES. SO THESE WERE SOME THINGS WE TALKED ABOUT WHEN WE WERE TALKING ABOUT BIOMARKERS. THE OTHER THING IS DEFINING WHAT A BIOMARKER IS, SO THERE WAS SOME QUESTION AS TO WHETHER SOMETHING WAS A FUNCTIONAL OUTCOME VERSUS A BIOMARKER. AND COMING UP WITH A BETTER UNDERSTANDING OF IF A FUNCTIONAL MARKER THAT WAS MORE QUANTITATIVE IN NATURE WOULD BE CONSIDERED A BIOMARKER OR NOT. SO FOR EXAMPLE IN THE AREAS OF VISION AND VESTIBULAR WHERE THERE ARE SOME SEX DIFFERENCES EMERGING WITH RESPECT TO MEASUREMENT OF OUTCOMES AND/OR PROGNOSTIC MARKERS, ARE THERE SEX DIFFERENCES THERE, AND MORE OUT COME RELATED DATA. THERE WERE HUGE GAPS IDENTIFIED IN TRAUMATIC BRAIN INJURY REHABILITATION WITH VERY FEW PUBLICATIONS NOTED. EVEN THE BASIC LITERATURE REVIEW AVAILABLE DATA LOOKING AT WHERE SEX WAS ACTUALLY USED AS A COMPARATOR AND NOT JUST AN KTDING OF GENDER WOULD BE -- ACCOUNTING FOSH SEX IN THE POPULATION WOULD BE BETTER. WE TALKED A LOT ABOUT OTHER THINGS THAT MAY BE CONSIDERED IN TERMS OF OUTCOMES, AND ALSO RELATED TO STAGES OF LIFE, SO DEVELOPMENTAL STAGES MAY BE VERY APPROPRIATE AS WE KNOW THERE'S A -- DISTRIBUTION IN THE INCIDENCE OF TBI, EARLY AGE AND OLDER AGE, AND THERE'S A PAUCITY OF DATA IN OLDER WOMEN, BOTH WITH RESPECT TO THEIR OUTCOMES AND MANAGEMENT. WE ALSO TALKED ABOUT AN INITIAL MANAGEMENT THAT WE DON'T UNDERSTAND, EACH SOME OF THE MOST COMMONLY PRESCRIBED MEDICATIONS WHEN IT COMES TO TRAUMATIC BRAIN INJURY, ESPECIALLY AS IT RELATES TO SEX AS A VARIABLE RESPONSE, SO EVEN SOMETHING AS BASIC AS IBUPROFEN THAT'S BEING PROVIDED TO LOTS OF PEOPLE AFTER MILD TRAUMATIC BRAIN INJURY, THERE'S NO STUDYS THAT REALLY LOOK AT SEX AS A BIOLOGICAL VARIABLE IN TERMS OF THE RESPONSE TO MANAGEMENT WITH RESPECT TO. THEN FINALLY WHEN WE TALKED ABOUT LONG TERM OUTCOMES, WE TALKED ABOUT SOME OF THE REAL PROBLEMS IN OUTCOMES MEASUREMENT IN TRAUMATIC BRAIN INJURY, THE LACK OF PRECISION, BUT ALSO THE LACK OF PRECISION RELATED TO WOMEN'S SOCIAL ROLES, AND LOOKING AT NEW ECONOMIC MODELS TO DETERMINE INSTEAD OF RETURN TO WORK, GIVEN SOME WOMEN'S SOCIAL ROLES; IT BET INVENTORY TALK ABOUT RELATIVE CONTRIBUTION TO INCOME OR RELATIVE CONTRIBUTION TO MANAGEMENT OF COMMUNITY OR HOME, OR THE LEVEL OF COGNITIVE DEMAND PLACED ON A PERSON DURING THE DAY FOR BASIC TASKS. SO THOSE WERE JUST SOME DIFFERENT WAYS THAT WE TALKED ABOUT IN TERMS OF LOOKING AT SOCIAL OUTCOMES AND WORK OUTCOMES BECAUSE THOSE TEND TO BE THE ONES THAT ARE MOST ASSOCIATED WITH THE OUTCOMES OF REHABILITATION. SO WE WILL STOP THERE AND I WILL TURN IT BACK OVER -- >> LET'S GIVE A HAND TO OUR PANELISTS WILL -- I JUST WANTED TO AGAIN THANK OUR PARTNERS, CNRM, OR WH, FOR THEIR SUPPORT OF THE MEETING, I HOPE YOU ALL JOIN ME IN THANKING DIANA CUMMINGS WHO DID THE BIGGEST LOAD FOR HAD THIS MEETING, MAKING IT WORK SO WELL. SO TO FINISH UP OUR MEETING, WE'RE GOING TO HEAR FROM THE DIRECTOR OF NINDS, DR. WALTER KOROSHETZ. >> BECAUSE I HAVE ATTENTION DEFICIT DISORDER, I HAVE TO TAKE NOTES TO PAY ATTENTION TO THINGS SO I'M GOING TO SHARE THOSE WITH YOU NOW. VERY QUICKLY, JUST A COUPLE OF REFLECTIONS ON WHAT'S HAPPENED OVER THE LAST COUPLE OF DAYS, AND A BIG THANK YOU TO EVERYONE. I GUESS THE FIRST THING IS THAT THE NIH HAD A GOOD IDEA THAT MAYBE PEOPLE SHOULD BE PAYING MORE ATTENTION TO SEX AS A BIOLOGICAL VARIABLE. WE'VE HEARD SO MANY DIFFERENT EXAMPLES OF THAT. I THINK IT'S PRETTY CLEAR THAT WE SAW LOTS OF EVIDENCE THAT TBI IN WOMEN IS A PUBLIC HEALTH PROBLEM THAT NEEDS TO BE BETTER UNDERSTOOD AND THERE'S DEFINITELY SOME DIFFERENCES THAT BETWEEN MEN AND WOMEN THAT WE HAVE TO TAKE INTO ACCOUNT. SOME TAKE HOME POINTS IS THAT ED VISITS FOR TBI ARE INCREASING, CLOSE TO 50% NOW IF -- ACTUALLY PREDOMINATE IN THESE VISITS. SO TRYING TO PREVENT AND TREAT THIS RISING PROBLEM I THINK IS SOMETHING THAT CAME OUT FROM THE MEETING. DEATH DUE TO TRAUMATIC BRAIN INJURY IS FALLING AND THAT'S A GREAT THING. SO I THINK THIS IS ONE AREA WHERE I THINK THERE HAS BEEN PROGRESS. THIS IS A MAJOR IMPROVEMENT IN DEATH RATES, MAYBE DUE TO SEAT BELTS, BUT -- OR BETTER CARE, BUT SOMETHING THAT SHOULD BE TAUTED AS SOMETHING THAT SCIENCE CAN REALLY CHANGE THE PUBLIC HEALTH IN TBI. WE HEARD ABOUT INTIMATE PARTNER VIOLENCE AS ALI BIG PROBLEM IN THIS COUNTRY, AND THE ROLE THAT TRAUMATIC BRAIN INJURY PLAYS IN THE SYMPTOMS AND I THINK TEASING THOSE APART FROM THE OTHER PROBLEMS IN THIS AREA ARE GOING TO BE DIFFICULT, BUT ONE THING THAT CAME TO MIND IS THAT WHEN LITTLE KIDS COME IN WITH INJURY, THEY GET SCREENED FOR DOMESTIC VIOLENCE IN THE HOUSE RELATED TO THE KID, SIMILAR SCREENING METHODS COULD PROBABLY BE TAKEN INTO THE EMERGENCY ROOM FOR INTIMATE PARTNER VIOLENCE AND IF WE HAVE SOMETHING LIKE A MARKER, TAU, BLOOD TEST THAT INDICATES THAT THERE HAS BEEN SIGNS OF INJURY IN A PERSON, THAT THOSE COULD POTENTIALLY BE DEVELOPED TO IMPROVE THE SCREENING, ESPECIALLY WHEN PEOPLE WANT TO TALK ABOUT WHAT THE CAUSE OF THE TRAUMA WAS. A LOT OF TALK ABOUT SPORTS-RELATED CONCUSSIONS IN WOMEN THIS IS A GROWING PROBLEM. MORE AND MORE WOMEN ARE ENGAGING IN SPORTS THAT WILL PUT THEM AT RISK FOR HEAD INJURY. AND AGAIN I THINK WE HEARD FROM THE DATA THAT TRYING TO PREVENT THAT SECOND HIT OR THAT SECOND CONCUSSION IS SO IMPORTANT, BECAUSE THE THINGS THAT SEEM TO DETERMINE SEVERITY IS OFTEN TIMES THE NUMBER OF PREVIOUS CONCUSSIONS. AND SO HOW DO WE DO BETTER THERE, I THINK THE DOUBLE DOWN ON PREVENTION, AND TO TRY TO TAKE ADVANTAGE OF THE PROGRESS THAT'S BEEN SEEN CERTAINLY AT THE NCAA LEVEL IN TERMS OF RETURN TO PLAY, PRACTICES KIND OF SCALED UP TO GREATER HEALTH, GOING TO BRING THOSE OUT TO THE WIDESPREAD ATHLETIC COMMUNITY, I THINK WOULD BE VERY HELPFUL. IN TERMS OF FOCUSING, IT LOOKS LIKE WOMEN'S SOCCER IS CERTAINLY AN AREA TO FOCUS ON WHERE THE NUMBERS ARE INCREASING AND POTENTIALLY MORE CONCUSSION IN WOMEN THAN MEN. THE OTHER POINT TO MAKE IS AS WE SAW THE RECOVERY GRAPHS, SO THESE ARE BAD PROBLEMS BUT IN THE MAJORITY OF PEOPLE, PEOPLE DO RECOVER OVER FAIRLY RAPID PERIODS OF TIME, BUT THEN IN THE NCAA STUDY, THERE WERE 18% OF DIDN'T RETURN TO PLAY FOR GREATER THAN 28 DAYS. SO FOCUSING ON THE POPULATION THAT IS SUFFERING THE MOST MAY BE AN IMPORTANT AREA TO MOVE INTO AND NOW POTENTIALLY WE HAVE WAYS OF IDENTIFYING WHO THOSE PEOPLE ARE. WE HAVE VERY LITTLE UNDERSTANDING OF WHAT THE BIOLOGY IS IN THAT SPACE. SO IN UNDERSTANDING TBI IN WOMEN, I THINK WE HEARD LOTS OF COMPLICATING FEATURES, AND THIS BASICALLY CRIES OUT FOR A NEED FOR GREATER PRECISION, SO I THINK MARGARET MCCARTHY SAID VERY EARLY ON THAT THE X-X VERSUS THE X-Y IS THE EASY PART BUT THAT'S PROBABLY NOT THE BIGGEST PART. THE HORMONAL EFFECTS SEEM TO BE PROMINENT IN A LOT OF THE BIOLOGY, BUT THEY'RE CHANGING OVER TIME. WE HEARD ABOUT TESTOSTERONE GOING UP IN UTERO, THE CHANGES IN HOMO STATUS IN THE POSTNATAL PERIOD, THE PREPUBERTAL PERIOD WHERE THE MALES AND FEMALES MIGHT BE QUITE SIMILAR, BUT THEN AS PUBERTY OCCURS, EVEN THE GREATER COMPLEXITY BECAUSE WE HAVE DIFFERENT STAGES OF THE MENSTRUAL CYCLE WHICH ARE QUITE DIFFERENT, AND THE USE OF SYNTHETIC PROGESTINS MAY BE ACTUALLY AS IMPORTANT AS THE CYCLE TIME. THE POST-MENOPAUSAL PERIOD ALSO THINKS -- DRAMATICALLY IN TERMS OF HORMONAL FUNCTION, THE PROPENSITY TOWARD VULNERABILITY TO INJURY. IN THE ELDERLY, WE TALKED A LITTLE ABOUT THE INCIDENCE. I GUESS THE OTHER AREA THAT CERTAINLY WE DIDN'T TALK TOO MUCH ABOUT IS THE INFLUENCE ON HEAD INJURY AND DEVELOPING DEMENTIA IN THE ELDERLY. AND THIS IS STILL AN OPEN QUESTION, THE DATA ON HEAD INJURY AND DEVELOPING DEMENTIA, THE DATA IS VARIABLE. AND IT'S AN IMPORTANT GROWING PROBLEM AS OUR POPULATION AGES, IT'S ALSO OF INTEREST IN THAT THERE'S A LOT OF FUNDING THAT'S COME TO DEMENTIA RESEARCH, SO RESEARCH THAT LOOKS AT THE TBI ON THE EFFECTS OF DEVELOPING DEMENTIA WOULD GET A STRONG ENDORSEMENT FROM THE FUNDING PAY LINES WHICH RL OFTENTIMES DOUBLE FOR THAT TYPE OF RESEARCH COMPARED TO OTHER TYPES OF RESEARCH. WE ALSO HEARD ABOUT HOW THE NEUROSTEROID PATHWAYS MAY BE DIFFERENT, EVEN IN PTSD PATIENTS ARE. WE TALKED A LITTLE ABOUT NEUROLOGICAL TRAJECTORIES, I WAS JUST TALKING HERE ABOUT THE DEGENERATION OF THE -- IN THE ELDERLY AND BHA THE IMPACT OF TRAUMATIC BRAIN INJURY MAY BE, BUT ALSO -- IMPORTANT IN GIRLS AND HEAD INJURY IN THAT PERIOD OF TIME BECAUSE IT'S NOT A STATIC -- NEVER QUITE STATIC BUT THAT'S A VERY ROBUST TIME FOR DEVELOPMENT OF THE BRAIN AND HOW BRAIN INJURY AFFECTS THAT PROCESS, PARTICULARLY IN GIRLS THAT IS IMPORTANT. TALKS ABOUT BIOMECHANICS INSIDE THE BRAIN AND ALSO HOW THE HEAD WILL MOVE WITH RESPECT TO A CERTAIN FORCE, AND IT GETS TO THAT QUESTION OF HOW MUCH -- HOW DO WE ACTUALLY KNOW WHAT THE DOSE OF TRAUMATIC BRAIN INJURY IS FOR THE SAME HIT, THE DOSE ON THE BRAIN MAY BE QUITE SUBSTANTIALLY GREATER IN WOMEN THAN IT WOULD BE IN A MAN AT THE SAME AGE, SO HOW TO TAKE INTO ACCOUNT BODY HABITUS IN THE BIOMECHANICS TO GET AT EQUAL DOSES AND TRY TO UNDERSTAND IF THAT'S RELATED TO SOME OF THE DIFFERENCES. WE CERTAINLY KNOW THE PRE-INJURY CHARACTERISTICS ARE COMING OUT AS STRONG MEDIATORS OF THE EFFECTS OF CONCUSSION, SO PRIOR CONCUSSION WE TALKED ABOUT, BUT ALSO HISTORY OF ANXIETY, DEPRESSION, SOMATIZATION SEEM TO BE DRIVERS, SO ONE CAN THINK OF ACTUALLY IN THE FUTURE POTENTIALLY DEVELOPING A CONCUSSION RISK SCORE FOR SOMEONE DEPENDING ON THEIR CHARACTERISTICS, WHAT IS THE CHANCE THAT THEY'RE GOING TO DEVELOP A SIGNIFICANT, YOU KNOW, THREE MONTHS OUT OF SCHOOL SHOULD THEY RETURN TO PLAY AND HAVE ANOTHER CONCUSSION. ANOTHER POINT WHICH I THINK CAME OUT DURING NUMEROUS TALKS WAS THE DIFFERENCE BETWEEN GENDER AND SEX AS A BIOLOGICAL VARIABLE, AND THAT GENDER IS NOT SIMPLY A BLACK AND WHITE BUT IT'S A SPECTRUM, AND CERTAINLY IN ASSESSING BEHAVIORAL OUTCOMES, ONE HAS TO LOOK AT GENDER IN THAT FASHION, AND SO I THINK AS MAR MARGARET MCCARTHY'S COMMENT I QUOTED HERE, BEHAVIOR IS LOOSELY ANCHORED TO YOUR ANATOMY BUT IS BUFFERED BY CONTEXT. THE AREAS OF SCIENCE WHICH DEMONSTRATED SEX DIFFERENCES, THE NEURAL MECHANISMS OF DIFFERENT SYNAPTIC FUNCTION, DIFFERENT CIRCUIT FUNCTION IN MEN VERSUS WOMEN, THE IP FLEUNS OF GONADAL HORMONES, CLEARLY THROUGHOUT MANY DIFFERENT EXAMPLES OF BIOLOGY, THERE'S BIG DIFFERENCES IN THE IMMUNE RESPONSE IN MALES AND FEMALES, AND WE TALKED ABOUT THAT NOT ONLY WITH RESPECT TO THE HUMERAL IMMUNE SYSTEM BUT ALSO THE INNATE IMMUNE SYSTEM IN THE BRAIN. ANATOMICAL DIFFERENCES INSIDE THE BRAIN SUCH AS AXON DIAMETER, AND BRAIN STRUCTURE. WE DIDN'T TALK TOO MUCH ABOUT THE ECONOMIC SYSTEM, I THINK THAT MAY ALSO BE IMPORTANT BECAUSE THERE'S GOOD EVIDENCE THAT THE AUTONOMIC SYSTEM THAT MALES AND FEMALES IS QUITE DIFFERENT SO GIVEN AN INJURY, THAT'S GOING TO AFFECT OUTFLOW TO THE AUTO NO MIBG SYSTEM THAT MAY ALSO INFLUENCE THE FLOW THE BRAIN IS GETTING FROM THE AUTONOMIC SYSTEM, WE DID TALK ABOUT THE DIFFERENCE IN SYMPTOMS BETWEEN MALES AND FEMALES, THE INCREASE IN THE SEVERITY, AND THE CHARACTERISTICS OF THE SYMPTOMS WHICH DIFFER OFTENTIMES BETWEEN MALES AND FEMALES. THESE ARE CERTAINLY VERY IMPORTANT WHEN TRYING TO TREAT THE PATIENT BECAUSE YOU'RE TRYING TO IMPROVE THEIR SYMPTOMS, WORK WITH THEM THROUGH THEIR SYMPTOMS SO TREATING THEM THE FEMALES AND MALES IS DOOMED TO FAILURE BECAUSE THEY'RE DIFFERENT. THE OTHER AREA WHICH I THINK FOR RESEARCH IS OF INTEREST IS THAT IF YOU'RE INTERESTED IN HEADACHE AFTER TRAUMATIC BRAIN INJURY, THEN YOU WOULD PREFERENTIALLY WANT TO STUDY WOMEN BECAUSE THAT'S WHERE YOU'RE GOING TO SEE IT, SO THERE MAY BE REAL ADVANTAGES IN STUDYING THESE KIND OF INTERACTIONS BETWEEN HEADACHE AND TBI, ANXIETY AND TBI, SLEEP AND TBI, ACTUALLY CONCENTRATING ON STUDIES IN WOMEN. IN TERMS OF TRANSLATION, I'D SAY WE HAVE TO GET RID OF THE LOST PART SO IT'S DISCOVERY, THE OPPOSITE OF LOSS IN TRANSLATION, SO WE HAVE CERTAINLY -- AND PEOPLE TALKED ABOUT IT TODAY, COME THROUGH A PERIOD OF TIME AND NOT JUST IN THIS FIELD BUT IN MANY OTHER FIELDS WHERE TREATING THE ANIMAL IS MUCH, MUCH EASIER THAN TREATING PEOPLE, SO YOU GO THROUGH 20 YEARS OF WORK THROUGH CLINICAL TRIAL, FIND THAT IT DIDN'T ACTUALLY HAVE THE OUTCOME YOU WANTED, AND SO HOW DO WE DO IT DIFFERENTLY. THERE'S LOTS OF REASONS WHY THE JUMP FROM THE ANIMAL TO THE HUMAN MAY NOT BE AS EASY AS WE THINK, BUT WE THINK WHAT WE REALLY NEED DO IS DETERMINE HOW TO MAKE MEASURES OF THE PATHOLOGY THAT'S OCCURRING IN HUMANS TO BRIDGE THAT GAP BECAUSE IN THE ANIMAL STUDIES, THE DRUGS ARE FOCUSED AGAINST A CERTAIN PATHOPHYSIOLOGICAL EVENT, AND WHAT YOU'D REALLY LIKE TO KNOW IS WHEN YOU GO INTO PEOPLE, YOU'RE REALLY AFFECTING THAT EVENT OR NOT. MANY OF THE PAST STUDY, WE JUST DON'T KNOW. WE KNOW -- WE DON'T KNOW IF WE HAD THE DOSE WRONG, WE TREATED TOO LATE. THEY'RE PROBABLY MORE IMPORTANT NOW TO DEVELOP MEASURES THAN IT IS TO KIND OF PURSUE ANY ONE SINGLE THERAPY, BECAUSE WE HAVE A MEASURE THAT WE CAN RELY ON, THE MANY THERAPIES THAT ARE COME DOWN THE PIKE TESTED AGAINST THOSE THERAPIES. SO WE CAN'T GIVE UP, WE CAN'T SURRENDER, WE JUST HAVE TO GET CLEVER IN THIS SPACE. TREATMENT IS CERTAINLY THE THING THAT WE'RE ALWAYS FOCUSED ON. AND THAT'S WHAT THE WHOLE GOAL OF THE RESEARCH IS. I WOULD SAY THAT CLEARLY THE DATA KEEPS COMING BACK TO THE POINT THAT BY PREVENTING REPETITIVE TBI, THIS MAY HAVE A SIGNIFICANT PUBLIC HEALTH IMPACT, AND CERTAINLY THE NCAA STUDY SHOWING THAT THE FREQUENCY OF PEOPLE RETURNING TO PLAY, THE SAME DAY, IS ZERO, IS REALLY A TREMENDOUS ADVANCE, AND THE TIME NOW WHERE I THINK IT LOOKS LIKE PEOPLE REALLY ARE BEING VERY CAREFUL ABOUT LIMITING THAT SECOND EVENT IN THAT SHORT TIME FRAME, I THINK IS PROBABLY A SUCCESSFUL OUTCOME OF THE WORK THAT'S BEEN DONE OVER THE LAST COUPLE YEARS. WHEN I STARTED IN THIS IN 1998, WE HAD A CONCUSSION SPORTS PROGRAM, WE WERE TRYING TO TEACH THE COACHES, HOW TO EVALUATE PLAYERS, AT THAT TIME THE ROLE WAS YOU GOT YOUR BELL RUNG, YOU GOT BACK IN AND PLAYED. SO THINGS REALLY DEFINITELY HAVE CHANGED JUST OVER THE LAST TWO DECADES. THEN IN TREATING PEOPLE AS I SAID, BECAUSE THE SYMPTOMS ARE DIFFERENT, THE SEVERITY IS DIFFERENT, ANYBODY WHO TREATS PATIENTS HAS TO KNOW THIS AND TAKE IT INTO ACCOUNT AND SUPPORT THE WHOLE PERSON UNTIL THEY GET BETTER. BUT JUST TO SAY BEFORE WE END THAT WE TALKED A LOT ABOUT THE DIFFERENCES BETWEEN MEN AND WOMEN, BUT THERE'S A LOT OF DATA WHICH SAYS THAT THERE IS DIFFERENCES BUT OFTENTIMES THE TRAJECTORY IS THE SAME, SO THE LESSONS LEARNED FROM BOTH SECTIONS BOTH SEXES ARE GOING TO BE IMPORTANT TO BOTH SEXES. THANKS AGAIN TO PAT, DIANA, TOYA RODGERS AND SPECIAL THANKS TO OUR FRIENDS OF THE OFFICE OF RESEARCH FOR WOMEN'S HEALTH, CNRM, AND AGAIN TO THE PINK CONCUSSIONS GROUP, REALLY HELP SUPPORTING THIS, GETTING PEOPLE TOGETHER, TALKING, AND FOR BRINGING THIS GREAT GROUP THAT THEY HAD AT LUNCH YESTERDAY WHICH BRING HOME WHY WE'RE DOING THIS RESEARCH IN THE FIRST PLACE. SO THANKS VERY MUCH, EVERYONE, AND GOOD LUCK TRAVELING HOME. HOPEFULLY NO POWER OUTAGES