Mild Traumatic Brain Injury and

Postconcussion Syndrome:
The New Evidence Base for
Diagnosis and Treatment
Michael McCrea, PhD, ABPP-CN
Neuroscience Center, Waukesha Memorial Hospital
Department of Neurology, Medical College of Wisconsin

Objective: MTBI from A to Z

Review and gain a clearer understanding of:
1.
2.
3.
4.

MTBI on the all-Severity TBI Landscape

Basic and Clinical Science of MTBI
The True Natural History of MTBI
Implications for Rethinking Postconcussion
Syndrome
What does the scientific literature tell us?

Unpaid Political Announcement

1. MTBI, more than any other clinical entity, is a
neuropsychological construct
2. The contribution by neuropsychologists to
MTBI research is unmatched by any other
discipline
3. Neuropsychologists are uniquely suited to
evaluate and treat MTBI
4. Neuropsychologists should not limit their role
in MTBI just to neuropsych testing

Concussion Research Consortium (CRC)

Neuropsychology: William Barr, PhD, ABPP
Thomas Hammeke, PhD, ABPP
Michael McCrea, PhD, ABPP
Scott Millis, PhD, ABPP
Christopher Randolph, PhD, ABPP
Neurosurgery:
Robert Cantu, MD
Neurology:
James Kelly, MD
Sports Medicine:
Kevin Guskiewicz, PhD, ATC
Epidemiology: Steve Marshall, PhD

Part 1:
The TBI Landscape
1. Epidemiology and impact of allseverity TBI
2. Zeroing in on MTBI: Epi and Impact
3. Challenges in Defining & Diagnosing
MTBI
4. Advances in MTBI research
methodologies
5. Top 10 Conclusions

Traumatic Brain Injury: The Big Picture

Major public health problem
world wide
1.4-3.0 million cases/yr in US
Leading cause of death &
disability: 50-100K TBI deaths/yr
in U.S.
40+% of all trauma fatalities in US
each year
At risk: very young/very old,
males, minorities, low SES,
substance abusers
Cost: ~ $100 billion/yr in US
The Forgotten Entity

Significance of MTBI: Silent

Epidemic
> 2.5 million MTBI/yr U.S
True incidence unclear:
30-50% no medical
attention; < 10% of ED
MTBI admitted
Total incidence as high as
500/100K population
Few to neuropsychologist

1.2 million MTBI evald in hospital ED/year

Persistent symptoms and

disability (PCS)
Costly public health issue
(> $30 billion)

Challenges in
Defining & Diagnosing MTBI
Classifying TBI severity an
imperfect science
Varied emphasis on acute injury
characteristics
Limitations of traditional methods
(GCS)
Limited reliability, validity,
predictive power of newer
classification methods
Numerous case and administrative
definitions

2005

Defining MTBI: Beyond GCS

Multiple Severity Indicators
Measure

Mild

Severity Classification
Moderate

Glasgow Coma Scale

13-15

9-12

3-8

Loss of Consciousness

< 20 minutes

20 min 36 hours

> 36 hours

Posttraumatic Amnesia

< 24 hours

1-7 days

> 7 days

Severe

MTBI Definitions
ACRM

GCS
13-15

CDC
WHO
DVBIC
AAN

13-15

LOC
< 30

PTA
< 24 hours

Other

< 30

< 24 hours

AMS, amnesia,
symptoms

< 30

< 24 hours

At least 1 symptom;
other causes r/o

At least LOC, PTA,

AMS, neuro deficit

Altered MS, symptoms

Grade 1: AMS, No LOC, Sxs < 15;
Grade 2: AMS, Sxs > 15;
Grade 3: LOC of any duration

CSG

Symptom-based; Simple (7-10 d.) vs. Complex (persistent sxs or recurrent)

Cantu

Grade 1 (mild): No LOC, PTA < 30, Sxs < 24 hours

Grade 2 (moderate): LOC < 1 or PTA > 30 < 24 hrs or Sxs > 24 hrs < 7 d
Grade 3 (severe): LOC > 1 or PTA > 24 hours, Sxs > 7 days

The Elusive MTBI Denominator:

Research Implications

Interpretation of
findings on acute
effects, recovery,
treatment response,
outcome, prevalence
of disability after
MTBI

Too Restrictive?

Too Inclusive?

Under-report true
incidence, impact
and disability of MTBI
and PCS;

Over-report true
incidence, impact
and disability of MTBI
and PCS;

The Elusive MTBI Denominator:

Clinical Implications
Too Restrictive?
Accurate
True cases of MTBI
identification of MTBI overlooked; no
patients
intervention early
when most effective

Too Inclusive?
Unnecessary
resource utilization;
inaccurate Dx that
does not recognize
true cause and
prescribe best
treatment

TBI Prognosis:
Some Things Are Crystal Clear
Injury Severity is Strongest
Predictor of Recovery
after moderate and severe
TBI

Key Distinctions Between Mild and Moderate/Severe TBI

Moderate & Severe
Definitions

Mild TBI

Consistent, anchored in acute injury

characteristics

Varied, symptom-based

Often clearly present and documented;

drivers of critical care management; strongest
predictors or longterm outcome

Varied emphasis on LOC, PTA, mental status

abnormalities, and of symptoms; limited
correlation with outcome

Classification
Systems, Tools

Tried and true methods for classifying injury

severity; strong history of Glasgow Coma
Scale (GCS) validity in grading injury severity
and correlation with outcome

Traditional scales (e.g., GCS) of limited utility

due to ceiling effect and limited sensitivity;
GCS not initially intended for classification of
MTBI; minimal penetration of any specific tool
for standardized assessment of MTBI

Neuroimaging Studies

Imaging studies of critical diagnostic

importance to identifying neurosurgical
emergencies; significant advances in both
structural and functional neuroimaging of
moderate and severe TBI, correlated with
clinical measures and outcome

In a clinical setting, neuroimaging negative and

equivocal in overwhelming majority of cases;
lack of objective findings restricts the medical
legitimacy of MTBI; some indication that
complicated MTBI with structural injury (and
abnormal imaging) distinct from
uncomplicated MTBI with no structural injury

Natural History

Well defined and empirically-delineated

Not well-understood; limited to no consensus

Outcome

AICs best predictor of outcome

Most often predicted by non-injury factors such

as premorbid psychosocial issues,
psychological comorbidities, postinjury
stressors, substance abuse, litigation, etc.

Persistent Disability

More clearly attributed to the severity,

functional neuroanatomy of injury, and
resulting impairments in most cases

Debated as to whether due to neurologic vs.

psychological factors; true epidemiology,
etiology of Post-Concussion Syndrome unclear

Acute Injury
Characteristics

 And Some Things Are Not So Clear

MTBI is a
Different Animal
All Together
All MTBI Are Not Created Equally
Grant Iverson, 2005

Acute MTBI
Research Limitations

Lack of witness account of injury

Immediate accessibility to injured patients
Neuropsychological testing impractical in ER
Lack of objective measures under constraints
Lack of premorbid baseline measures
Multitude of non-injury factors: alcohol/drugs,
other injuries, litigation, others

MTBI Unknowns & Clinical Challenges

Diagnosis: Minimum threshold for injury (i.e., was there indeed an
MTBI?) Defining characteristics? Other causes for symptoms?

Recovery: How long should it take to recovery after MTBI? What is the
expected natural course of this injury?

Prognosis: What are the acute and subacute predictors of positive and
negative outcomes after MTBI?

Complications: To what extent are neurologic versus psychological

factors contributing to symptoms and deficits?

Treatment: Given all this, what approach to treatment gives my patient

the best chance for recovery?

Outcome: What are the best methods to assess recovery and functional
outcome after MTBI?

Streaker Suffers
Concussion
If you're planning to streak at an NHL game, at least wear a pair of
skates. In the third period of Thursday's Bruins-Flames game in
Calgary, a male streaker (wearing only red socks and a smile)
scaled the low glass near the scorers table and jumped onto the
playing surface. The naked stranger quickly lost his

balance, falling backwards and hitting his head on

the ice, knocking himself unconscious. After a sixminute delay, the streaker was covered up and carted off the ice
on a stretcher, waving to cheering fans.

Causes of TBI
MVA

Other
43%

Sports

20%

28%

Assaults
9%

Sports-Related Head Injuries: 300,000 per year in U. S.

Recreation TBI Deaths: > 500 per year
Centers for Disease Control and Prevention, 2000

TBI Landscape: Main Conclusions

1. TBI a major public health problem worldwide
2. > 80% classified as MTBI (500/100K population)
3. Young/old, male, minorities of low SES at risk
4. Nothing mild about the total impact of MTBI
5. What works for moderate/severe may not for MTBI
6. Traditional MTBI research hampered by many issues
7. New innovative approaches to prospective researchers
8. New groundbreaking findings to date
9. Poised to answer: What is natural history of MTBI?
10. MTBI science extends our understanding of PCS

Part 2: Basic & Clinical Science of MTBI

1. Biomechanics
2. Neurophysiology
3. Neuroimaging

Biomechanics of MTBI:
Establishing a minimal biomechanical threshold

How much is enough to cause brain injury?

Accelerometry Instrumentation

Measures and records

blows to the head:
- Impact location
- Impact magnitude
- Impact duration
- Linear and angular
acceleration components
- Exact times of impacts

*Validated against Wayne State Hybrid III

University of North Carolina

HITS Study Methods
60 College football players equipped with HITS
system
Impacts recorded, analyzed for all exposures (games,
practice)
Analysis of impact frequency, magnitude data
Correlation with clinical assessment measures
Look at biomechanical risk x position, other factors

HITS Study Results

> 27,000 impacts recorded

9 concussions observed in HITS equipped players
Average magnitude of concussion impacts: 95 g
67% of concussions (6/9) > 95 g
< 1 % of non-concussive impacts > 95 g
Range of concussion impact 60-120 g

Pellman et al: peak acceleration-concussion 98 g (+/- 28), non-concuss 60 g (+/- 24)

Zhang (2004): Probability of MTBI 25% at 66g, 50% at 82g, 80% at 106g
Brolinson (2006): Average peak acceleration 103.3 g (range 56-118 g)

Cannot underestimate confluence of rotational forces

Neurophysiology of MTBI
Diffuse Axonal Injury (DAI) prominent in
moderate and severe TBI, not in MTBI
The pathophysiology of MTBI renders neurons
dysfunctional, but not destroyed

Serum Biomarkers of MTBI

Potential diagnostic, prognostic utility?
S-100 proteins, neuron specific enolase (NSE)
and cleaved Tau protein (CTP)
S-100 B most extensively studied
S-100 B sensitivity 80-100%, specificity 40-80%;
poor PPV (13-40); NPV 95-100
Risk of false positives (diagnosis, prognosis)

Many Ways to Take a Look Under the Hood

Method Description

+/-

Comment

CT

Structural

R/O neurosurgerical
emergency; poor sensitivity
to smaller lesions

5-20% MTBI
positive

MRI

Structural

25-50% greater sensitivity

than CT

10-40%
positive

DTI

Images water molecule

diffusion in many directions;
Fractional Anisotropy (FA)
marker of WM integrity

Sensitive to reduced WM FA
after TBI; specificity unclear;
more effective in DAI

Mixed
samples TBI
severity

MTI/
MSI

Magnetic Transfer/Magnetic
Source Imaging; improvement
from T1, T2 weighted imaging;
combines MEG with MR

Suggested sensitivity in
MTBI; specificity unclear

Limited data
to evaluate

MRS

Measures altered metabolic

ratios in critical ROI

Sensitive, non-specific;
Weak association w/ injury
assessment, outcome

Limited data
to evaluate

Many Ways to Take a Look Under the Hood

Method Description

+/-

fMRI

Functional imaging of
neuronal activation
(and dysfunction)

Better temporal/spatial
resolution and better brain
mapping than others; data
on neurophysiological
effects, recovery

SPECT

Functional imaging of
regional blood flow

Sensitivity (60-90% > CT),

but unclear specificity

PET

Functional imaging of
blood flow, oxygen,
glucose metabolism
(different from SPECT)

Comment
Largest
literature of
any; guides
natural hx
research; rehab
applications

MTBI Basic & Clinical Science: Main Conclusions

1. Major advances in biomechanics, neurophysiology,
functional neuroanatomy of MTBI
2. Suggestion of minimal BM threshold 80-100 g; informative
to clinical practice
3. Clear pathophysiology: Neurometabolic cascade with time
course similar to natural clinical course
4. CT still acute imaging of choice
5. MRI more sensitive than CT for structural lesion
6. Complicated MTBI indicates more severe gradient of
injury, but not a perfect predictor of recovery, outcome
7. Functional imaging techniques show great promise, require
further study of Sensitivity, Specificity, Prognostic Value

Part 3:
What is the true
natural history
of MTBI?

Part 3:
Natural History of MTBI
1.
2.
3.
4.
5.
6.
7.
8.

Acute symptoms and symptom recovery

Acute cognitive effects and early recovery
Neuropsychological recovery
Influence of acute injury characteristics on recovery
Measuring neurophysiological recovery
Functional outcome after MTBI
Exceptions to the rule: Longterm effects of MTBI?
Top 10 Conclusions

Can we measure the immediate effects of injury?

What does earliest recovery look like?

The Scientific & Standardization Movements

Sports Concussion Publications
200
175
150
125
100
75
50
25
0

1960's

1970's

1980's

All Sports Concussion

1990's

2000's

Neuropsychological

(PubMed: 1960-2005; per W. Barr)

JAMA 2003; 290:2556-2563

Research Supported by: NCAA, NOCSAE, NAN, NFL Charities, NFHS, Green Bay Packers Foundation,
WMH Foundation, MCW Functional Imaging Research Center
Investigators hold no relevant financial interest or conflict in the research methods, materials, or findings

NCAA, Project Sideline & CDC Concussion Studies

NCAA

Project SL

CDC

25

20

124

4,251

3,279

9,094

196

87

375

AAN Grade 1-2

AAN Grade 3

93.2%
6.8%

82.1%
17.9%

80.7%
9.3%

LOC

6.8%

17.9%

9.3%

PTA

19.1%

37.3%

21.9%

RGA

7.4%

29.9%

17.3%

No LOC/PTA

77.8%

49.1%

64.5%

84%

98%

80%

Teams
Player Seasons
Concussions

% Complete Protocol

Totals: 16,624 Player Seasons, 658 Concussions Studied (3.9% IR)

Methods
Main Outcome Measures: Concussion Symptom Inventory
(CSI), Standardized Assessment of Concussion (SAC), Balance Error
Scoring System (BESS), Neuropsychological Test Battery, (fMRI)

Injury Follow-up: Injured player & matched control

Data Analyses: Longitudinal regression - GEE (GROUP),

standard regression based (SRB) indices of change (INDIVIDUAL)

Sports Concussion Research Protocol
Preseason
Baseline
History
GSC
SAC
BESS
NP Test

Time
of
Injury
GSC
SAC
BESS

PostGame/
Day 1
PostPractice
GSC
GSC
SAC
SAC
BESS
BESS
NP Test
fMRI

Day 2
GSC
SAC
BESS
NP Test

Day 3
GSC
SAC
BESS

Day 5
GSC
SAC
BESS

Day 6/7
GSC
SAC
BESS
NP Test

Neuropsychological testing on days 1, 8, & 45 for HS, days 2, 7, and 90 for college; fMRI in high school only

Day
45/90
GSC
SAC
BESS
NP Test
fMRI

Immediate Symptoms
100
90
80
70
60
50
40
30
20
10
0

Percentage of Subjects Endorsing Symptom

Day 3 Symptoms
100
90
80
70
60
50
40
30
20
10
0

Percentage of Subjects Endorsing Symptom

Day 7 Symptoms
100
90
80
70
60
50
40
30
20
10
0

Percentage of Subjects Endorsing Symptom

85 % of subjects full symptom recovery within 1 week

Orientation:
Day, Month, Date,
Year, Time

Immediate
Memory:
Repeated List
Learning Paradigm

Neurologic
Exam:
Strength, Sensation,
Coordination
Record LOC, PTA

Concentration:
Digits Backward
Months Backward

Delayed Recall:
Word List Recall

Exertional
Maneuvers:
Provocative
conditions

Total Score (30)

Orientation
Im. Memory
Concentration
Delayed Recall

/5
/15
/5
/5

SAC Clinical Database

> 750 Concussions

Grade 1, 2, 3 Concussions
Youth, HS, College, Pro Athletes
Follow-up: minutes, days,
weeks, months
With & Without Previous
Baseline
All gradients of concussion:
LOC, PTA, Neither
Sensitivity/Specificity: RCIs,
GEEs, SRB modeling
Studies of non-sports MTBI

Complexity of Neuropsychological Testing

Interpreting Neuropsychological Recovery

Simple Group Comparisons/RMANOVA: injured vs.

control performance; confounded by baseline performance,

practice effects, RTTM, other serial testing factors, mult comps
Generalized Estimating Equations (GEE): longitudinal
regression estimating mean group differences between
concussion and controls adjusted for baseline score, age,
education, history
Standard regression based (SRB): empirical method to
detect meaningful change at individual case level with
correction for practice effects & regression to the mean;
(Obtained-Predicted/SE prediction) larger than criterion (translated 90% CI)

Clinical Decision-Making Influenced by

method applied to measure recovery

SIMPLE GROUP COMPARISONS*

HVLT Immediate Memory
HVLT Delayed Recall
HVLT Recognition
WMS-3 Letter-Number Sequencing
Trails A
Trails B
SDMT
SDMT Recall
Stroop Word
Stroop Color
Stroop Color-Word

Day 1-2

Day 6-7

Day 45-90

COWAT
: CC < NC (p > .05)

: CC< NC (p < .10)

* Without controlling for BL, multiple comparisons

G.E.E MODELING*
HVLT Immediate Memory
HVLT Delayed Recall
HVLT Recognition
WMS-3 Letter-Number Sequencing
Trails A
Trails B
SDMT
SDMT Recall
Stroop Word
Stroop Color
Stroop Color-Word

Day 1-2

Day 6-7

Day 45-90

COWAT
: CC < NC (p > .05)

: CC < NC (p < .10)

* Controlling for covariates (BL, education, history)

Meta-analysis: 21 studies,
790 concussions, 2014 controls

Acute effects (w/n 24 hrs)

greatest for delayed memory
(d=1.00), memory acquisition
(d=1.03), and global cognitive
functioning (d=1.42)
No residual neuropsych
impairment > 7 days
postinjury
Findings moderated by
cognitive domain,
comparison group (control vs.
Overall ES (d=0.49) comparableself-control)
to non-sports (d=0.54)

Neuropsychological Recovery after MTBI:

The Meta-Analytic Age

A Quantitative Review of the Effects of Traumatic

Brain Injury on Cognitive Functioning
Schretlin, David & Shapiro, Ann
(International Review of Psychiatry, 2003, 15, 341-349)
Factors Moderating Neuropsychological Outcomes
Following MTBI: A Meta-Analysis
Belanger, Curtiss, Demery, Lebowitz, & Vanderploeg
(JINS, 2005, 11, 215-227)
Outcomes from Mild Traumatic Brain Injury
Iverson, Grant
(Current Opinion in Psychiatry, 2005, 18, 301-317)

Summary
39 studies, 48 MTBI (n=1716) vs.
control (n=1164) comparisons;
Moderate in overall cognitive
functioning <7 days post-injury
(d=.41)

Learning/memory, RT, and attention

show greatest acute effects
Effects diminish by 7-29 days (.29),
disappear by 30-89 days (.08) post
Recovery of overall functioning
follows a logarithmic course

 Meta-analysis: 39 studies, 1463

MTBI cases, 1191 controls
Overall effect of MTBI on
neuropsychological functioning
moderate (d=.54)
Acute: greatest affect on
memory (d=1.03), fluency (d
=.89)
Unselected or prospective
samples: No residual NP effects
by 3 mos. (d=.04)
Clinic samples (.74) & litigants
(.78) at 3 mos.
Litigation associated with stable
or worsening cognition

 Extensive literature review;

excellent MTBI shelf reference
Little doubt about abnormal
neurophysiology as cause of
sxs, dysfunction acutely
Maximal sxs first 72 hours,
rapid improvement over 1st
week
Delayed recovery often
largely related to other
comorbidities (e.g., depression,
pain, PTSD, etc.)
All MTBI not created equally
Clearly, the estimate of 10-20% of patients with MTBIs
not recoverying by 6-12 months is much too high

Putting Tests to the Test

How sensitive is standardized testing in
detecting real abnormalities in the
asymptomatic player who says Im fine and
would otherwise be returned to play?

Classifying Individual Impairment

SRB Model: Linear regression on
control BL scores to generate
formula to predict scores at T2...
Regression coefficient, intercept of
regression line used with BL score
to predict score for each subject at
T2 and subsequent time points
Meaningful change: (ObtainedPredicted/SE prediction) JINS
> ,criterion
2005, 11, 1-12
(translated 90% CI)
Empirical method to detect true
impairment/recovery; correction for
practice effects, RTTM

Added Value of
Neuropsychological Testing

100
90

Specificity

80

NP Testing

Sensitivity

70

Brief Battery

60

Sensitivity: refers to probability

of individual player abnormal on
any measure (Specificity > 84%)

Brief Battery: GSC, BESS, SAC

50

Neuropsychological Testing:

40

minimal increase (5%) in

sensitivity over brief battery on
Day 2, but more than doubles
sensitivity on Day 7 (14% to 30%)

30
20
10

Neurocognitive Impairment:

0
CC

PG

D1 D2 D3 D5
Assessment Point

D7

Delayed memory, processing

speed, verbal fluency

Added Value of Neuropsycholgocial Testing

Day 2

Day 7

SxImpaired

Controls
Impaired

SxImpaired

Controls
Impaired

(n=68)

(n=56)

(n=85)

(n=56)

BESS

37%

9%

8%

7%

SAC

16%

7%

7%

7%

NP Battery

15%

8%

16%

9%

(true +)

(false +)

(true +)

(false +)

NP Net Gain

7% Detection

7% Detection

(TP-FP)

Impaired relative to own pre-injury baseline performance on each measure

Added Value of Neuropsychological Testing

Collie et al (2006): Cognitive testing in symptomatic vs.
asymptomatic athletes within 11 days after concussion
Symptomatic athletes (n=36): Impaired on 3 of 9 cognitive
measures 2.2 days post injury
Asymptomatic athletes (n=25): Impaired on 1 of 9 cognitive
measures 3.5 days post injury; Improved on 2/9
Group mean change from baseline, not individual rates of
impairment; no report of false positive impairment rate

Schatz et al (2006): ImPACT cognitive and symptom score

sensitivity 81.9%, specificity 89.4% < 72 hr post; 85% correctly

classified; no report of cognitive predictor independent of symptoms

Van Kampen (2006): NP testing increased sensitivity from 64%

to 83% over symptoms alone; 30% false + rate

Evolution of Neuropsychological Testing

in Sports Concussion
1997: Development of a standardized
neuropsychological test battery is recommended to detect
impairment associated with concussion
(AAN Practice Parameter)
1999: The usefulness of neuropsychological assessment
in clinical decision making should not be short-changed
(AOSSM Concussion Workshop Group)
2001: Neuropsychological Testing is one of the
cornerstones of concussion evaluation
(CISG, Vienna Agreement Statement)

Evolution of Neuropsychological Testing

2004: Neuropsychological testing should not be done
while the athlete is symptomatic because it adds nothing
to return-to-play decisions and may contaminate the
testing process by allowing practice effects to confound
results
recommended that neuropsychological testing remain
one of the cornerstones of concussion evaluation in
complex concussionis not currently regarded as
important in the evaluation of simple concussion
should not be the sole basis for management decisions,
either for continued time out or return to play decisions
(CISG, Prague Agreement Statement)

Influence of Acute Injury

Characteristics on Recovery

Acute Injury Characteristics: Frequency & Influence

NCAA

Project SL

CDC

196

87

375

AAN Grade 1-2

AAN Grade 3

93.2%
6.8%

82.1%
17.9%

80.7%
9.3%

LOC

6.8%

17.9%

9.3%

PTA

19.1%

37.3%

21.9%

RGA

7.4%

29.9%

17.3%

No LOC/PTA

77.8%

49.1%

64.5%

84%

98%

80%

Concussions

% Complete Protocol

Median Duration: LOC 10 sec., PTA < 60 minutes

35

Figure 4. Symptom Recovery by LOC/PTA

GSC Total Score

30
25
20
15
10
5
0
BL
Control

CC

PG

D1

No PTA/LOC

D2

D3

D5

PTA/No LOC

D6

D45
LOC+PTA

Figure 5. Cognitive Recovery by LOC/PTA

30

SACTotal Score

28
26
24
22
p < .001

20
BL

CC

Control

PG

D1

No PTA/LOC

D2

D3

D5

PTA/No LOC

D6

D45
LOC+PTA

LOC vs. NO LOC

HVLT Immediate Memory
HVLT Delayed Recall
HVLT Recognition
WMS-3 Letter-Number Sequencing
Trails A
Trails B
SDMT
SDMT Recall
Stroop Word
Stroop Color
Stroop Color-Word

Day 1-2

Day 6-7

Day 45-90

COWAT
: LOC < No LOC (p > .05)

: LOC < No LOC (p < .10)

* Without controlling for multiple comparisons

PTA vs. NO PTA

HVLT Immediate Memory
HVLT Delayed Recall
HVLT Recognition
WMS-3 Letter-Number Sequencing
Trails A
Trails B
SDMT
SDMT Recall
Stroop Word
Stroop Color
Stroop Color-Word

Day 1-2

Day 6-7

Day 45-90

COWAT
: PTA < No PTA (p > .05)

: PTA < No PTA (p < .10)

* Without controlling for multiple comparisons

Measuring Neurophysiological Effects & Recovery

After MTBI
30
29
28
27
26
25
24
BL CC PG D1 D2 D3 D5 D7

When and how does the brain recover?

Functional MRI
ADVANTAGES:
Non-invasive
Better spatial/temporal resolution
than PET/SPECT
No radiation exposure multiple
studies
More methodologically
appropriate for studying effects of
treatment and rehabilitation
MR technology access
Low cost compared to PET
Measuring Meaningful
Cerebral Change

Sternberg Task
Remember: 4 7 3 8

Encode: 2.5 sec

Load Dependent
Memory Scanning Task

(Set size 2,4,6)

Maintain : 2.5, 5.0, 7.5 sec

Time
7

Rest interval: 2.5, 5.0, 7.5 sec

Retrieve: 2.5 sec

Theoretical Curve Sternberg Task & Cerebral Blood Flow

2.5 sec

IR F

IR F

5.0 sec

0.0

7.5 sec

0.0

2.5

5.0

7.5

10.0

12.5

15.0

17.5

20.0

22.5

25.0

0.0

2.5

5.0

7.5

10.0

12.5

15.0

17.5

20.0

22.5

25.0

IR F

Maintenance delay

Encode Maintain Retrieve Rest

SECONDS

10

15
20
seconds

25

Predicted blood flow pattern during Encoding, Maintenance, Retrieval, Rest

Differential Activation Change with Increasing Task Load

Figure 7. Brain Activation associated with increasing activation related to
Set Size on Day 1 (Encode Phase, threshold p <.01, vol > 200ul).
Left Lateral

Left Medial

Right Medial

Left

Right

Concussed

Right Lateral

Control
Concussion Effects: Lack of normal cerebral recruitment in response to cognitive demand

Day 1 Encode: Control minus Injured

T-test exceeding threshold at p < .0005; cluster size > 200 ml

Z = -6

Z=9

Z = 21

Z = 36

Z = 47

Principal Areas of Group

Activation Differences:
- Basal Ganglia (L)
- Post. Cing/Retrosplenial
- Precentral Gyrus (L)

Control > Concussed

Concussed > Control

Encoding Phase
Left SMA/PreSMA

P=1.5x10-5
vol=371 uL
alpha=0.05

CM RL, AP, IS: 0, -6, 46

Vol: 2880 uL

Encode SS6 AUC SMA/PreSMA

Day 1: Encode ROI1 (SMA/PreSMA) SS6

+ SE

MRI Percent Signal Change

0.8
Control
Injured
0.6

0.4

0.2

MRI AUC Percent Signal Change

+ SE

1.0

0.8

Injured
Controls

0.6

0.4

0.2

0.0

Day 1

Day 45

Imaging Session
0.0

-0.2
1

Image Number

Day X Grp X Session Interaction p= .07

Day 1 AUC correlates RT: r = -.44 p = .01
Day 1 AUC correlates slope: r = -.39 p = .03
Regression: Day1 AUC = RT + Movement 46%v

Day 1: Encoding Phase

Left SMA/PreSMA

P=1.5x10-5
vol=371 uL
alpha=0.05

CM RL, AP, IS: 0, -6, 46

Vol: 2880 uL

MRI Percent Signal Change

0.8

0.6

Control no loc
Control loc
Injured no loc
Injured loc

0.4

MRI AUC Percent Signal Change

Day 1: ROI1 SMA/PreSMA

Encode SS6 + SE

Day 1: Encode SS6 AUC

1.0
Control no LOC
Control LOC
Injured no LOC
Injured LOC

0.8

0.6

0.4

0.2

0.0
0

Control and Injured Subgroups

0.2

0.0

-0.2

Image Number

Oneway Grp, p < .005;

Grp covary rms1post, p = .02
Grp covary rms1pre, p = 07
Grp 2 vrs Grp 4, p = .01

Day 45 Encode: Control minus Injured

T-test exceeding threshold at p < .0005; cluster size > 200 ml
Z = -6

Z=9

Z = 21

Z = 36

Z = 47

LL

Minimal Areas of Group

Activation Differences
(noise)

R
R

Control > Concussed

Concussed > Control

Functional Model of MTBI

Measuring Clinically Meaningful Cerebral Change

Acute Injury:

Neuronal Activation

Brain injured sufficiently to dysregulate

consistent neuronal recruitment
(decreased fMRI activation)

Recovery/Rehabilitation:
Allows/facilitates recruitment of additional
neuronal resources to maintain functional
standard (increased functional activation)

15

30

45

Recovery Period (days)

(Moderate/Severe TBI: Implications for amplitude/course/reversibility)

Functional Outcome After MTBI

Overwhelming majority of MTBI resume normal
independent social, occupational, educational function
within days to weeks of injury
Highly variable methods on RTW research
Non-injury factors associated with poor functional
outcome
Higher risk of depression, anxiety (12-44%), which
receive insufficient attention

Science of MTBI
Recovery
Clear, sound evidence
Kids: rapid recovery, no
residual cognitive,
behavioral, academic
deficits
Adults: rapid symptom,
cognitive recovery; no
impairments 3-12 mos
Non-injury factors predict
persistent symptoms

Exceptions to the Rule?

Single, uncomplicated concussion
a benign neurologic event, but.
Complicated MTBI
Repeat Concussion: Immediate,
mid-range, longterm risks
Second Impact Syndrome:
- Mechanism, pathology, risk
Chronic effect on symptoms and
cognition
Longterm Effects: What happens
when they get old?

30
Control

Symptom Severity

25

Concussion

CRITICAL FIRST WEEK:

Average of 7 days for full recovery (91%)

75% of repeat concussions within first 7 days
92% of repeat concussions within first 10 days

20

15

10

Assessment Point

What about chronic symptoms or

functional impairments after
repeat concussion?

Center for the Study of

Retired Athletes

2001 Health Survey of Retired NFL Players

History of concussion from participating in
professional football: 61% of all respondents
Ave no. concussions during pro football career: 2.1
24% of respondents sustained 3 or more concussions
12% of respondents sustained 5 or more concussions
71% reported having returned to play on the same day as
their concussion (18% reported this occurrence 3+ times)
16% reported that concussions have a permanent effect on
thinking/ memory skills as they get older

Is recurrent concussion a longterm risk for depression?

12% of retired NFL players have had or
currently have a bout with clinical depression.
Of those with a history of depression:
87% still suffer from depression
46% currently being medically treated
Does depression limit your activities of daily living?
23% = NEVER

64% = SOME

12%=OFTEN

Concussion As Risk for Depression

Lifetime prevelance of
depression

25
20
15
General male population

10
5
0
0-2

Survey N = 2,488
Depression N = 263

3-4
Number of Previous Concussions

5+

Is recurrent concussion a risk factor for

late life cognitive decline or dementia?
Webster was diagnosed in 1999 as having brain damage
caused by repeated head injuries during his playing days.
According to his doctors, several concussions damaged his
frontal lobe causing cognitive dysfunction. His doctors said
the progressively worsening injury caused him to behave
erratically at times.
USA TODAY
9/24/02

Recurrent Concussion as Risk for Dementia?

NFL vs. Normative PAD Age Distribution

Cumulative Percentages

120
100
80

NFL

60

Normative

40
20
0
< 60

< 65

< 70

< 75

< 80

< 83

< 95

Age Cohorts
NFL Mean Age: 71.7 (7.62); Median: 74.0; Range: 52-83

NATURAL HISTORY OF MTBI

MAIN CONCLUSIONS
1. Symptom recovery in days to weeks in most cases
2. Measurable cognitive impairments w/o LOC, PTA, neuro
3. Favorable cognitive recovery overlapping symptom recovery;
no permanent impairment
4. Neurophysiological recovery c/w clinical recovery (days to wks)
5. AICs and focal lesions indicate more severe gradient, not
perfectly predictive of outcome
6. Favorable functional outcome is expected
7. Non-injury factors best predictors of poor outcome
8. Exceptions to the rules: Recurrent MTBI

Implications for
Rethinking Postconcussion
Syndrome

Part 4:
Implications for Rethinking
Postconcussion Syndrome
1.
2.
3.
4.
5.
6.
7.
8.

Defining Postconcussion Syndrome

Non-specificity of PCS Symptoms
Epidemiology of PCS: Another denominator problem
PCS: Neuropsychological Disorder
Psychological Theories of PCS
Interventional Models for PCS
A practical model for clinical management of PCS
Top 10 Conclusions

What is PCS?
ICD-10: F07.2 (part of class of disorders with
a demonstrable etiology in cerebral disease,
brain injury, or other insult leading to cerebral
dysfunction).

Def: A syndrome that occurs following head trauma

(usually sufficiently severe to result in loss of
consciousness) and includes a number of disparate
symptoms such as headache, dizziness, fatigue,
irritability, difficulty in concentration and performing
mental tasks, impairment of memory, insomnia, and
reduced tolerance to stress, emotional excitement, or
alcohol.

What is PCS?
DSM-IV- proposed new category:
A. History of a head trauma that has caused significant
concussion (loc, pta, sz)
B. Evidence from neuropsychological testing of impaired
attention or memory
C. Three or more occur shortly post-injury and persist for at
least 3 months:

Headache
Dizziness
Irritability
Fatigue
Anxiety, depression, or emotional lability
Sleep disturbance
Personality change
Apathy

Non-specificity of PCS symptoms

Symptoms are not specific to concussion/TBI; e.g.:
Trahan et al, 2001: Pts with depression endorse significantly
more PCS Sxs than pts with mTBI.
Lees-Haley et al, 2001: Non-TBI personal injury claimants
endorse PCS symptomatology at high rates, comparable on
many symptoms to mTBI claimants (e.g., concentration
impairments 63% mTBI, 65% other).
Iverson & McKraken, 1997: Chronic pain pts endorse PCS Sxs
at high rate (81% endorsing 3+ symptoms)
Gouvier et al., 1988: High base rates of PCS symptoms in
normal (college) population

Prevalence of PCS Symptoms

Headache

Dizziness

Irritability

Memory
problems

Conc.
problems

College
students1

36%

18%

36%

17%

42%

Chronic
pain2

80%

67%

49%

33%

63%

Depressed3 37%

20%

52%

25%

54%

PI
claimants
(non tbi)4

77%

41%

63%

46%

71%

mTBI5

42%

26%

28%

36%

25%

1. Sawchyn et al., 2000; 2. Radanov et al., 1992; 3.Trahan et al., 2001; 4. Dunn et al., 1995; 5. Ingebrigtsen et al., 1998

Reliability & Validity of PCS Criteria

Boake et al (2004): agreement b/n DSM and ICD symptom
criteria, poor overall agreement because few patients met
criteria for cognitive deficit and clinical significance
Conclusion: limited agreement b/n diagnostic systems
leading to different diagnosis and treatment in the same case
Boake et al. (2005): At 3 mos, higher prevalence of PCS
with ICD-10 (64%) than DSM-IV (11%); 40% of non-TBI
sample met ICD criteria, 7% for DSM;
Conclusion: PCS symptoms are not sufficient to make the
diagnosis of MTBI; linking residual symptoms to TBI is a
major problem
Kashluba et al (2006): ICD-10 PCS symptoms unable to
accurately classify MTBI patients from NCs at 3 months

Whats the incidence of PCS?

Epidemiology?
Frequent citation of influential Alexander (1995
Neurology) review article: at one year after injury
approximately 15% of [mild TBI] patients still
have disabling symptoms
Articles referenced for this figure are Rutherford et al.,
1978; McLean et al., 1983.
This figure and these citations echoed in multiple
publications, but..

Original citations for the 15% at 1 year

Rutherford et al., 1979 (actually mis-cited in the Alexander

article)
145 consecutive mild TBI cases admitted to hospital in Belfast.
131 followed up at one year, 19 still reporting symptoms (14.5%)
8/19 involved in lawsuits, 6/19 suspected of malingering at 6 weeks
post-injury (overlap of 5)
10/19 pts reporting at least one new symptom not endorsed 6 weeks
post-injury
Age not related to duration of symptoms, but gender was (women
more likely to be symptomatic)
No controls (e.g., ortho injuries)

Original citations for the 15%at 1 year

McLean et al., 1983
11 pts with mild TBI (GCS 13-15)
8 pts with mod TBI (GCS 9-12)
1 pt with severe TBI (GCS=8)

Controls N=52, friends of pts (non-injured)

Groups compared on neurocognitive scores and
symptom checklist at 3 days & 1 month post-injury.
No difference in neurocognitive scores, but more
symptoms in pt group at 1 month.
The moral of the story: Check original sources!

Epidemiology of PCS: Methodological Issues

Ascertainment Bias?
Extremely common, estimated incidence of 1.54 million
concussions with LOC/year in US alone1; perhaps 12-15 times
as many concussions with no LOC.
Only a small percentage of these pts ever seek any form of
medical treatment.
A small percentage of those ever see a neuropsychologist
MTBI patients enrolled in studies represent select subsample
Underscores need for appropriate control groups

True Incidence of PCS: More in the range of 5%

Lower than rate of abnormal imaging?

PCS: Neuropsychological Disorder

Biopsychosocial basis for PCS (Iverson, Zasler, Lange)
In most studies examining predictors of PCS
symptomatology in TBI, injury severity is usually not
predictive (sometimes relationship is found to be
inverse), but non-injury variables are:

Blaming of other(s) for injury, Limited social support

Current levels depression/anxiety
Premorbid psychiatric Hx
Presence of PTSD
Somatization
Motivational factors (exaggeration, malingering)

Implication: Psychological Theory and Treatment

Psychological Theories of PCS

Expectation as Etiology: preformed expectations about
effects of head injury, misattribute common complaints to
head injury
Good Old Days Hypothesis: EAE + consideration that
people attribute all sxs to negative event
Nocebo Effect: expectations of sickness and associated
emotional distress cause the sickness in question
Diasthesis-Stress Model: interaction b/n physiological,
psychological, motivational and iatrogenic factors

Implication: Psychological Intervention

Efficacy of Psychological Intervention

for PCS
Mittenberg et al. (1996): 58 subjects with mTBI,
randomly assigned to 1 of 2 groups:
Treatment: given printed educational material and met
once (1 hr) prior to discharge with therapist
Control- normal hospital treatment and discharge
instructions

6-month follow-up by blinded interviewer (no

baseline Sx differences)

Efficacy of Psychological Intervention

for PCS
Treatment group reported significantly shorter
mean symptom duration (33 vs 51 days), fewer
symptoms, and less severe symptoms
Results suggest that brief, early psychological
intervention can minimize PCS
Additional studies

Efficacy of Psychological Intervention

for PCS
Ponsford et al., (2002): 202 adults with mTBI, 79
assigned to intervention within one week of injury:
Intervention consisted only of informational booklet re
expected natural history of symptoms and coping strategies

At 3 months post-injury, intervention group reported

fewer overall symptoms and less current stress
Similar findings from Minderhoud et al. (1980), Relander
et al. (1972), Wade et al., (1998), Paniak et al., 2000,
Ponsford et al., 2001.

WHO Collaborating
Centre Task Force on Mild
Traumatic Brain Injury
Results of survey of nonsurgical interventions and cost
for mTBI (J Rehabil Med
2004):
Evidence that early intervention
can reduce long-term complaints,
and that this intervention need
not be intensive.

Postconcussion Syndrome: Main Conclusions

1. Sx-Based diagnosis of PCS problematic (poor reliability of
criteria, nonspecificity of sxs)
2. PCS estimates severely inflated; true incidence ~ 1-5%
3. Frequency of structural injury higher than PCS
4. Science to rethink PCS: Neuropsychological Disorder
5. Psychological bases indicates psychological and educational
interventions
6. Effective intervention will improve functional outcome and
reduce disability from PCS
7. Need to rule out motivational factors
8. Neuropsychologists the key component

Warning: Commercial Re-Run

1. MTBI, more than any other clinical entity, is a
neuropsychological construct
2. The contribution by neuropsychologists to MTBI
research is unmatched by any other discipline
3. Neuropsychologists are uniquely suited to evaluate and
treat MTBI
4. Neuropsychologists should not limit their role in
MTBI just to neuropsych testing

Neuropsych Consult: STAT

EMS education
ED consultation
Acute TBI Clinic
Multidisciplinary Approach
Neuropsychology & PM/R
Patient/family education
Supportive follow-up
Outcome research

Neuropsychologys Response
AAN Position Statement: Where are neuropsychology
and rehabilitation psychology?
Military MTBI Task Force: Inter-organizational
collaboration between:
- APA Division 40
- APA Division 22
- American Academy of Clinical Neuropsychology
- National Academy of Neuropsychology

Military, VA, Civilian Psychologists

Position statement and call to action

Anyone up for a drink and some chatter?

Contact Information
Michael McCrea, PhD, ABPP-CN
Neuropsychology Service
Waukesha Memorial Hospital
721 American Avenue, Suite 501
Waukesha Memorial Hospital
Waukesha, WI 53188
Office: 262-928-2156
Fax: 262-928-5580
Email: michael.mccrea@phci.org