Presentation delivered at University of Michigan Injury Center Sport Concussion Summit, Ann Arbor, September 24, 2015

1. Future Directions in TBI Research:
Leveraging Sports Concussion Research
Toward a Neurobiopsychosocial Model
Michael McCrea, PhD, ABPP
Professor of Neurosurgery and Neurology
Director of Brain Injury Research
Medical College of Wisconsin
Clement Zablocki VA Medical Center
Member, NFL Head, Neck and Spine Committee
Neuropsychology Consultant, Green Bay Packers

2. Old Problem New Awareness
Better Science

3. In Vivo Study of Acute Brain Injury
Alternative Paradigms for mTBI Research

4. 4
Evidence-based Injury Assessment,
Management and Return to Play
Science Driving Best Practice!
New Frontiers in the Assessment and Management
of Sport-Related Concussion

5. “Translational Research”
Advancing the Science to Benefit all Populations at Risk of mTBI
SRC Civilian mTBI Military mTBI

6. Where Do We Go From Here?

7. Future Directions in TBI Research:
Acute Effects, Recovery, & Outcome
TRUE NATURAL HISTORY OF INJURY
In Pursuit of the Perfect “Biomarker”
Clinical Recovery:
How long does it take for signs &
symptoms to recover?
Physiological Recovery:
How long does it take for the
brain to recover?
+
Giza & Hovda, 2010

8. How Long Does it Take to Recover?
Is Symptom Recovery Really Recovery?
Rate of Postinjury Recovery
in HS and College Athletes (n=790)
Total (%) Cumulative
Total (%)
Rapid (< 1 day) 21.1 21.1
Gradual (> 1 day, < 7 days) 64.3 85.4
Prolonged (1 week – 1 month) 11.9 97.3
Persistent (> 1 month) 2.7 100.0

9. Effect Sizes: 0.2 Small, 0.5 Medium, 0.8 Large
< 0.3 Difficult to detect in individual patients;
large overlap b/n patients and control group
Effect
Sizes
(d)
“Biomarkers” of Days Past
-1.6
-1.4
-1.2
-1
-0.8
-0.6
-0.4
-0.2
0
< 24 hours 1-6 Days 7-30 Days 30-90 Days
Meta-Analytic Studies and Reviews:
Frencham, 2004; Belanger et al., 2005; Schretlin & Shapiro, 2005; Broglio et al 2008; Iverson, 2011; Rohling et al 2011
Adapted from Iverson, 2011
Effect Sizes: 0.2 Small, 0.5 Medium, 0.8 Large
< 0.3 Difficult to Detect in Individual Patients; large
overlap b/n patients and control group

10. New Frontiers in Brain Injury Science
How Long Does it Take for the Brain to Recover?

11. A Prospective Study of Advanced MRI
Biomarkers to Determine Acute Physiological
Effects and Longitudinal Recovery after
Sport-Related Concussion
PI: M. McCrea
Co-I: A. Nencka, K. Koch, T. Muftuler, Y. Wang, S. Li, T.
Hammeke, K. Guskiewicz, T. McAllister

12. Clinical
Recovery
Physiological
Recovery
Full Clinical &
Physiological
Recovery
PRE-
INJURY:
Normal
Cerebral
Function
ACUTE
IMPAIRED:
Elevated symptoms,
functional impairment,
physiological dysfunction
CONCUSSIVE
EVENT
COMPENSATORY:
Full clinical recovery, but
persistent physiological
dysfunction
POST-ACUTE
(Common Time Point for
Return to Play)
FULL
COMPLETE:
Full clinical recovery, normal
physiological function
Prevention-based
Return to Activity
Integrated mTBI Recovery Model
Injury Management: How Long is Long Enough?

13. TBI Biomarkers:
Same Ole Burning Questions
SENSITVITY:
• Will modern
“biomarkers” prove
more sensitive than
existing clinical
measures as the
objective “marker” of
injury and measure of
recovery?
• Will neuroimaging
prove to be the elusive
physiological marker of
Postconcussion
syndrome?
SPECIFICITY:
• How unique to mTBI are the
“abnormalities” detected on
biomarkers?
• How are biomarker results
influenced by non-injury
factors?
• What is the likelihood of
false positives (e.g.,
depression, anxiety, PTSD,
AODA, etc.?)
• What is the incremental
value of biomarkers at the
individual case level?
Translational Significance? Clinical Utility at the Individual Case Level

14. TBI Pathophysiology: Chasing Moving Targets
Axonal Injury
Synaptic Injury Markers
(Sypt -1)
Microgliosis -
Neuroinflammation
Markers
(EAMP -II)
Vascular injury
Markers (N-CAM)
UCH-L1 SBDP150 SBDP120GFAP(Banyan) CNPase . MAP2
Acute markers Subacute markers
BA-0293
Chronic markers
Demyelination
Neuronal cell
body damage
Dendritic injuryGliosis / Glial Injury
1
Demyelination
MBP fragment

15. • 10% take > 7 days to recover
• Acute severity predicts subacute
recovery (LOC, PTA, 24 hr GSC)
• 2.5% symptomatic > 45 days
• No impairment on objective measures at
Day 45 relative to BL
Predicting Risk and Recovery

16. Real Life Neurobiopsychosocial Model
Cumulative Incidence of Recovery
by Pre-Injury Somatic Symptoms (SOMPRE)
PercentofSubjectsRecovered
0
20
80
60
40
100
Number of Days Post-Injury
0 10 403020
Low SOMPRE
High SOMPRE
a.
Nelson et al., 2015, in preparation
PercentofSubjectsRecovered
0
20
80
60
40
100
Number of Days Post-Injury
0 10 403020
Cumulative Incidence of Recovery
by Acute Post-Concussive Symptoms (CONPOST)
Low CONPOST
High CONPOST
b.
Neurobiological Psychosocial
2,055 athletes baseline tested; 127 concussed athletes re-evaluated
with detailed clinical assessment battery < 24 hours and days 8, 15, and 45) after injury.

17. Risks of Persistent Symptoms After SRC
36.6%
25.7%
15.8%
6.9%
3.0%
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
50%
> 7 Days > 10 Days > 15 Days > 30 Days > 45 Days
Self-Report Symptom Recovery Predictors of Persistent
Symptoms >45 Days:
Pre-injury Baseline
BSI-18 Somatization Index Score
(p=.004)
(N=72)
McCrea 2014 Unpublished
 Faintness or dizziness
 Pains in heart or chest
 Nausea or upset stomach
 Trouble getting your breath
 Numbness or tingling in parts of your
body
 Feeling weak in parts of your body
After Controlling for BL BSI-18 (SOM)
Acute Injury Characteristics, Assessment
Results Not Predictive of Persistent Symptoms

18. Neurobiological
Pre-Injury
Factors
- Genetics
- Neurologic
Vulnerabilities
Trauma Burden
- Injury Severity
- Repetitive
Exposure
- Polytrauma
Biomarkers
- Structural/
Functional
Imaging
- Blood
Biomarkers
Psychosocial
Psychological
Function
- Premorbid
- Post-injury
Comorbidities
Environmental
Factors
- Social Support
- Life Stressors
- Iatrogenesis
Motivational
Factors
- Expectation
- Secondary Gain
Multi-Domain Predictor Variables
Neurobiopsychosocial Model of mTBI:
Multidimensional Prediction of Risk & Recovery
Neurocognitive
Function
Neurobehavioral
Function
Psychological Health
and Wellness
Life Function &
Quality
Neurologic Health
Multi-Dimensional Outcome
In A Single Study Design?

19. CARE Consortium
Sponsored by United States
Department of Defense (DoD)
& National Collegiate Athletic
Association (NCAA)
3 Years, $28M

20. Advanced Research Core (ARC)
Medical College of Wisconsin
(McCrea, PI)
Virginia Tech
PI’s: Duma & Rowson
UNC
PI’s: Guskiewicz & Mihalik
UCLA
PI’s: Giza & DiFiori
Head Impact
Measurement
(HIM)
Co-Leaders:
Duma, Stemper
Advanced
Neuroimaging
(MRI)
Co-Leaders:
Koch, Saykin
Biomarkers
& Genetics
(BIOGEN)
Co-Leaders:
Foroud, Giza
ARC Scientific Concentrations
Wisconsin
PI: Brooks
ARC Performance Sites
ARC Coordinating Center
NCAA-DoD Grand Alliance – CARE Consortium
Clinical
Outcomes
(CLIN)
Co-Leaders:
Broglio, Guskiewicz
Senior Scientific Advisory Panel
Iverson, Jordan, Kelly, Marshall, Saykin,
Smith, Talavage, Wallace, Xu
CARE Consortium investigators and SSAP members engaged with respective ARC Scientific Concentrations

21. ARC Overview: Specific Aim
CARE Aim 3:
Utilize the framework of the CSC (Aim 2) to conduct advanced
scientific studies which integrate biomechanical, clinical,
neuroimaging, neurobiological and genetic markers of injury to
advance our understanding of neurophysiological effects and
recovery after SRC in college athletes.

22. Toward Integration:
Neurobiopsychosocial Study of SRC
Understanding the True Natural History of Acute Injury & Recovery

23. Looking to Science for Answers
Concussion
news worries
parents
OTL survey finds 57 percent of
parents less likely to allow kids to
play football
August 26, 2012, 9:13 AM ET
By Paula Lavigne | ESPN.com
Outside the Lines" survey finds that a
majority of parents are concerned
enough about news reports of
concussions from playing football to
keep their children away from the
sport.
?
At a Crossroads

24. Thank You
Michael McCrea, PhD, ABPP
Professor of Neurosurgery
Director of Brain Injury Research
Medical College of Wisconsin
Office: 414-955-7302
Email: mmccrea@mcw.edu

25. Real Life Neurobiopsychosocial Model:
NFL Combine
Physical Attributes
(height, weight, wings)
Vulnerabilities
(prior injury/exposure)
Biometrics
(laboratory results)
Performance
(speed, strength, agility)
Intelligence
(aptitude, academics)
Personality/EQ
(emotional intelligence)
Social Maturity
(“off-field factors”)
Individual Factors
(background/history)
Objective: Multi-Dimensional Model to Predict Outcome

26. Post-injury
Premorbid
Structural
Brain
Damage
Neuro-
metabolic
Factors
Depression
/ Anxiety
PTSD /
Stress
Ortho /
Chronic
Pain
Personality
Factors
Medication
Effects
Iatrogenic
Effects
Nocebo Effect /
Dx Threat
TBI Symptom
Recovery,
Functional
Outcome
“Good Ole
Days” Bias
Reinforced
Role Behavior
Expectations &
Misattribution
Symptom
Exaggeration
Malingering,
2ndary Gain
Factors Influencing Recovery and Outcome After TBI
Adapted from Iverson, Zasler, Lange, 2008
Somatiz-
ation
Methods to
Assess
Injury-Related
Factors
Psychological
Comorbidities
Social
Factors
Motivational
Factors

27. Bringing It All Together
In A Single Study Design?
Pathophysiology
Diagnostics
Injury
Management
Long-range
Risks
PH: Education and
Prevention
Injury
Biomechanics
Recovery
&
Outcome

28. SPORT CONCUSSION
SUMMIT
September 24, 2015#uminjuryctr