Mild Traumatic Brain Injury

Across the Lifespan

Grant L. Iverson, Ph.D.

Professor, Department of Physical Medicine and Rehabilitation,

Harvard Medical School;

Director, MassGeneral Hospital for Children™ Sport Concussion Program; &

Associate Director of the Traumatic Brain Injury Program,

Home Base, Red Sox Foundation and Massachusetts General Hospital

1st Nordic Neurotrauma Conference

Lund, Sweden

November 13, 2017

Funding Disclosure

• US Department of Defense (grants)

• Canadian Institute of Health Research (grants)

• Lundbeck Canada (grant)

• AstraZeneca Canada (grant)

• ImPACT Applications, Inc. (unrestricted philanthropic support)

• CNS Vital Signs

• Psychological Assessment Resources, Inc.

• Tampere University Hospital

• Alcohol Beverage Medical Research Council

• Rehabilitation Research and Development (RR&D) Service of the US Department of Veterans Affairs

• Defense and Veterans Brain Injury Center (former independent contractor; HJF/GD)

• Mooney-Reed Charitable Foundation (unrestricted philanthropic support)

• Heinz Family Foundation (unrestricted philanthropic support)

• INTRuST Posttraumatic Stress Disorder and Traumatic Brain Injury Clinical Consortium funded by the Department of Defense Psychological Health/Traumatic Brain Injury Research Program (X81XWH-07-CC-CSDoD)

• Football Players Health Study, Harvard University (NFLPA Funding)

Other Disclosures

• Speaker honorariums and travel expenses for

conferences and meetings

• Independent practice in forensic

neuropsychology, including athletes

Mild Traumatic Brain Injuries

are Not Created Equally

Spectrum of MTBI

Extremely Mild Structural Damage

(Transient) (Permanent)

Continuum of Pathophysiology

Minor Major Neurometablic & Neurometabolic Pathoanatomical

(e.g., Contusion)

Rate of Day-of-Injury CT

Abnormalities

• Incidence of intracranial abnormalities in MTBI

in Emergency Department studies

–5% to 40% across studies

– It increases with lowering of GCS: 15, 14, 13

• MRI reveals a greater rate

First

Author

Year

Number

Scanned

GCS

Scores

%

Abnormal

Livingston 1991 111 14-15 14

Stein 1992 1,538 13-15 17.2

Jeret 1993 702 15 9.4

Moran 1994 96 13-15 8.3

Borczuk 1995 1,448 13-15 8.2

Iverson 2000 912 13-15 15.8 Thiruppathy 2000 912 13-15 15.8

Stiell 2005 2,171 13-15 12.1

Stiell 2005 1,822 15 8.0

Ono 2007 1,064 14-15 4.7

Saboori 2007 682 15 6.7

Emergency Department Cohort

• Tampere University Hospital, Tampere, Finland

• August 2010-July 2012

• 3,023 patients presenting to ED and underwent

head CT

• 2,766 mild head trauma

• Average Age: 56.4, 50% are between 34 and 77

• Isokuortti et al. (in press)

Tampere ED Mild Head Trauma Cohort

Rates of Complicated MTBI Isokuortti et al. (in press)

10.1

40.7

52

0

10

20

30

40

50

60

GCS=15 GCS=14 GCS=13

Percentage Abnormal Stratified by GCS

Acute (red) and Pre-Existing Lesions (black) Stratified by

Age Group in Suspected or Confirmed MTBI (N=2,766)

4.9%

3.0% 9.9%

7.3% 12.2% 11.4% 22.2%

20.1% 18.6% 17.7%

1.2 %

4.2 %

11.5 %

23.5 %

29.3 % 32.2 %

48.7 %

56.9 %

66.0 %

78.9 %

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

20-29 30-39 40-49 50-54 55-59 60-64 65-69 70-74 75-79 80+

Acute intracranial lesion Pre-existing intracranial abnormality

Are intracranial abnormalities

related to clinical outcomes?

See Panenka et al. (2015) for a

Review (Table 1)

Cognitive Outcomes

• Those with intracranial abnormalities performed more poorly on neuropsychological testing (Table 1, 11 of 19 studies—58%)

• In several of these studies the relationship is modest (small to medium effect sizes)

• Usually on a small number of the cognitive tests

Functional Outcomes

• In 4 of 13 studies, complicated MTBI patients had greater problems as measured by the

– Glasgow Outcome Scale,

– Functional Independence Measure,

– Global Adaptive Functioning Scale,

– Return to work.

• Most studies, however, have not found a significant difference in functional outcomes.

Symptom Reporting

• Paradoxically some studies in the literature

suggest that complicated MTBI patients report

fewer symptoms.

• The most consistent finding is that these two

groups are not different on symptom reporting

(9 of the 13 studies).

To date, macroscopic structural injuries are

not strongly related to clinical outcomes in

MTBI studies

More refined imaging studies might show stronger associations

Personality and psychosocial factors can be vey important

Continuum of

Biological & Psychological

Vulnerability

Extremely Hardy/Resilient Extremely Vulnerable

Patients with mTBI and

moderate-to-high resilience

reported significantly fewer

post-concussion symptoms,

less fatigue, insomnia,

traumatic stress, and

depressive symptoms, and

better quality of life, than

the patients with low

resilience.

Pre-Existing Health Problems

Possible Vulnerability Factor

Emergency Department Cohort

• Tampere University Hospital, Tampere, Finland

• August 2010-July 2012

• 3,023 patients presenting to ED and underwent

head CT

• Average Age: 56.4, 50% are between 34 and 77

• Isokuortti et al. (in press)

Pre-Injury Health Problems 3,023 Patients Undergoing Head CT in the ED

Isokuortti et al. (in press)

• Cardiovascular Diseases: 39.4%

• Mental and Behavioral Disorders: 25.8%

– Chronic Detrimental Alcohol Use: 18.4%

– Affective Disorder: 10.3%

• Diseases of the Nervous System: 23.7%

– Stroke of Transient Ischemic Attack: 10.0%

– Cerebral Atrophy and/or Extensive WMHIs: 6.8%

– Neurodegenerative Disease: 8.3%

• Prior Brain Injury: 10.3%

• Mental Disorders OR Diseases of the Nervous System: 43.8%

There is no simple, reasonably

explanatory model for good or poor

outcome

Biopsychosocial Model

• Pre-Injury – Genetics

– Personality

– Resilience/hardiness

– Vulnerability

– Mental Health

– Prior brain injuries

• Post-Injury – Traumatic axonal injury

– Neurophysiological / neurometabolic disturbance

– Social psychological factors (expectations, good-old-days bias)

– Depression, anxiety, traumatic stress

– Chronic bodily pain and/or headaches

Post-

Concussion

-Like

Symptoms

Personality

Characteristics or

Disorders

Biopsychosocial

Resilience/Hardiness

Biopsychosocial

Vulnerability

Pre-Existing Mental

Health Problems

Previous Brain Injuries

Narcissistic

Dependent

Histrionic

Passive-

Aggressive

ADHD

Learning Disability

Genetics Relating to

Injury Vulnerability

Depression

Anxiety

Genetic

Vulnerability

Cognitive

Diminishment

Mental Health Problems

Social

Psychological

Factors

Insomnia

Chronic Headaches

or Bodily Pain

Depression

Traumatic

Axonal Injury

Altered

Neurotransmitter

Systems

Expectations

Diagnosis Threat

Nocebo Effect

Lifestyle & Family

Dynamics Changes

Anger/Bitterness

Justification/Entitlement

Litigation Stress

Anxiety/Stress/Worry

PTSD

Biopsychosocial Model for Poor Outcome

Copyright © 2010, Grant Iverson, Ph.D.

Pre-Injury Factors

Recovery from Concussion in

Sports

By definition, a sport-related

concussion is a mild traumatic brain

injury.

By consensus, sport-related

concussions are characterized by

normal structural neuroimaging.

Is sport-related concussion a benign

injury?

Results from meta-analyses

Adverse Effects of Sport Concussion on Cognition

Pathophysiology

• Complex interwoven cellular and vascular changes

• Multilayered Neurometabolic Cascade

• Under certain circumstances, cells degenerate and die

Primary Mechanisms

• Ionic shifts

• Abnormal energy metabolism

• Diminished cerebral blood flow

• Impaired neurotransmission

Fortunately, the brain undergoes

dynamic restoration

Assessment Timeline

Sideline Post-

Game

24 Hours

First Week

Second Week

Third Week

At Risk!

Recovery Time in Athletes

Some evidence that biological recovery

might take longer than clinical recovery

in some athletes.

Pennsylvania High School Football

Cohort

• 2,141 players

• 3-year prospective cohort study

• 134 concussions

• Players followed until recovered

Collins, Lovell, Iverson, Ide, Maroon (2006)

Recovery Curve (N = 134)

91%

46%

Days Post Injury

Recovery Curves (N = 134)

Days Post Injury

94%

84%

Studies over the past decade illustrate

that the large majority of athletes appear

to recover clinically within one month.

Some have persistent symptoms beyond a month. There might be multiple underlying causes and contributors to those persistent symptoms.

Possible Predictors or Effect Modifiers of

Clinical Outcome

• Pre-injury differences

• Sex

• Age

• Genetics

• Neurodevelopmental conditions (e.g., ADHD, LD)

• Migraine history (personal or family)

• Mental Health history (personal or family)

• Concussion History

• Initial injury severity/acute symptoms (e.g., LOC, PTA, retrograde

amnesia)

• Post-injury clinical differences

• Severity of cognitive deficits

• Development of headaches, migraines, depression

• Dizziness and/or oculomotor functioning

Predictors of Clinical Recovery and Persistent

Symptoms in Children and Adolescents

Multi-Center Canadian Study

5P Sites

Derivation Study Design

• Multicenter, prospective cohort study

– 10 AM – 10 PM daily, 7 days/week

– Real-time data collection: iPads into

– Enrollment: August 2013 – September 2014

• Follow up survey (web or phone):

– 1, 2, 4, 8, and 12 weeks

• Neuropsychological testing

– 1 month and 3 months

Patient Population

Inclusion Criteria

• 5 - 17.9 years old

• Have a concussion

• Had initial injury in

previous 48 hours

• GCS 14+

• English or French

Exclusion Criteria

• CT(+) brain injuries

• Multi-system injuries

• Previous CNS disease

• Intoxication

• No clear trauma history as

primary event (e.g., seizure,

syncope or migraine)

• Previously enrolled

Primary Outcome

• Proportion of children with PCS at one month

• PCS definition based-on ICD-10

– Increase in pre-concussion baseline in 3+ symptoms

• Post-Concussion Symptom Inventory (PCSI)

– Developmentally specific versions (5-7, 8-12, 13-18)

Results

3,063 patients were enrolled (n=2,006 in the

derivation cohort; n=1,057 in the validation cohort)

2,584 completed follow-up at 28 days after the injury

Total Sample (Derivation and

Validation Cohorts) 30-33%

Demographic Variables Mechanism of Injury Ages 5-7 17.9 Sports or Recreational Injury 30.3 Ages 8-12 26.3** Non-Sports-Related Injury or Fall 28.2

Ages 13-17 39.9** Motor Vehicle Collision (only 34 subjects) 47.1

Boys 23.1 Assault (only 19 subjects) 26.3 Girls 41.1** Injury Severity Characteristics and Clinical

Features

Health History GCS=15 29.7 No Prior Concussions 28.4 GCS=14 (only 19 subjects) 36.8 1 or More Prior Concussions 35.1* Loss of Consciousness 36.2*

Prior Concussion with

Symptoms ≥ 1 week 46.1** Appears Dazed and Confused 33.5*

Physician Diagnosed

Migraine History 42.6** Appears Confused About Events 34.2*

Learning Disability 37.9* Answers Questions Slowly 36.6**

ADHD 34.2 Repeats Questions 37.1* Prior History of Anxiety 37.4* Forgetful of Recent Information 37.1* Prior History of Depression 52.8* BESS Tandem Stance ≥ 4 points or unable 54.3**

*Significant predictors. Headache 31.9**

**Multivariate predictors Sensitivity to Noise 40.7**

Fatigue 33.5**

Results

• 45 candidate variables with univariate

association with primary outcome

– Acceptable inter-rater agreement (K>0.6)

• Forward stepwise, binary logistic regression

– Pin=0.05, Pout=0.10

5P Prediction Model

Covariate

aOR

95% CI P Value

Lower Upper

Age group

5 to 7 0.000

8 to 12 1.54 1.09 2.19

13 to 18 2.31 1.62 3.32

Sex Male 0.000

Female 2.24 1.78 2.82

Longest symptom

duration

No prior concussion

or <1 week 0.011

1+ week 1.53 1.10 2.13

Personal history of

migraine

No 0.001

Yes 1.73 1.24 2.43

Answers questions

slowly

No 0.008

Yes 1.37 1.08 1.74

Tandem stance

0-3 0.022

4+ or unable 1.31 1.04 1.66

Headache No 0.013

Yes 1.66 1.11 2.48

Sensitivity to noise No 0.002

Yes 1.47 1.15 1.87

Fatigue No 0.000

Yes 1.84 1.37 2.46

5P Prediction Model

Risk Factor Categories Points

Age Group 5 to 7

8 to 12

13 to 18

0

1

2

Sex Male

Female

0

2

Longest Symptom Duration No Prior or <1 week

1+ week

0

1

Personal History of Migraine No

Yes

0

1

Answers Questions Slowly No

Yes

0

1

Tandem Stance 0-3

4+, or unable to do test

0

1

Headache No

Yes

0

1

Sensitivity to Noise No

Yes

0

1

Fatigue No

Yes

0

2

5P Points: Risk

Point total

Estimate

of Risk

Lower

95% CI

Upper

95% CI

Observed %

with PCS-4 Weeks

0 0.04 0.02 0.07 0/6 (0%)

1 0.06 0.04 0.09 6/37 (16%)

2 0.08 0.06 0.13 11/98 (11%)

3 0.12 0.08 0.18 15/156 (10%)

4 0.16 0.12 0.22 41/239 (17%)

5 0.22 0.17 0.30 71/289 (25%)

6 0.30 0.23 0.38 90/299 (30%)

7 0.38 0.30 0.47 96/243 (40%)

8 0.48 0.39 0.57 80/172 (47%)

9 0.57 0.48 0.66 58/103 (56%)

10 0.66 0.57 0.74 30/43 (70%)

11 0.74 0.66 0.82 9/13 (69%)

12 0.81 0.75 0.88 3/3 (100%)

Predictors of clinical recovery from

concussion: a systematic review

Objective

Review the factors that might be associated with,

or influence, clinical recovery from concussion.

Clinical Recovery – a return to normal activities,

including school and sports, following injury.

Encompasses resolution of symptoms and return to

normal balance and cognitive functioning.

Methodological Differences in the

Literature Methodological differences in:

– Outcomes (e.g., symptom resolution, cognition, balance,

return to sports, return to school)

– Time between injury and outcome (e.g., days to several

months)

– Settings (e.g., high school, college, specialty clinic,

emergency department)

– Number of modifiers examined in each study (e.g., 1-47)

• Univariate

• Multivariate

Considerations:

Greater Pre-Injury/Baseline Symptom Reporting

• Females (Brown et al., 2015; Iverson et al., 2015)

• Athletes with a history of ADHD (Iverson et al., 2015; Nelson et al, 2015),

learning disability (Zuckerman et al., 2013; Elbin et al., 2013), mental health

treatment (Iverson, 2015), substance use treatment (Iverson et al., 2015),

migraine treatment (Iverson et al., 2015), headache treatment (Brooks

et al., 2016).

• Individuals with multiple prior concussions (Iverson et al., 2015;

Brooks et al., 2016).

• Some athletes without any of these prior conditions report

concussion-like symptoms in their daily lives (Iverson et al., 2015),

potentially related to stress (Edman et al., 2012), depression (Covassin et al., 2012),

or insufficient sleep (McClure et al., 2014).

PRISMA • 7,648 initially identified

• 4,777 after duplicate removals

• 101 full-text articles and 13

conference abstracts ultimately

included

Study Inclusion Criteria

1. Published by June 2016

2. Examined clinical recovery

from concussion

Caveats for Interpreting Results

• Results of all predictors were mixed.

• Many older studies examined outcome during the

first 2 weeks post injury, while more recent

studies examined those who are slow to recover

(e.g., > 1 month).

Mixed Evidence For All Potential Predictors

Predictor of Clinical Recovery Studies supporting it as

a predictor of recovery

Studies not supporting it

as a predictor of

recovery

Age (younger age) 7 24

Sex (female sex) 17 27

History of Concussions 20 21

Prior Psychiatric History 7 1

Personal Migraine History 1 9

Family Migraine History 1 2

ADHD 1 10

Learning Disability 1 7

Loss of Consciousness 9 22

Post-Traumatic Amnesia 9 16

Retrograde Amnesia 5 5

Greater Acute/Subacute Symptoms 21 3

Younger Age

Yes Chermann (2014) 25741414; Field (2003) 12756388; Terwilliger (2016) 26421452; Covassin (2012) 22539534; Majerske (2008) 18523563; Pellman (2006) 16462480; Zuckerman (2012) 23227435

No Lau (2012) 21841522; Hang (2015) 26430968; McDevett (2015) 26502998; Nelson (2016) 26974186; Asplund (2004) 15523205; Chrisman (2013) 23252433; Vargas (2015) 25643158; Nelson (2016) 26974186; Morgan 2015 25745949; Meehan 2010 20716683; Meehan (2013), 23628374; McCrea 2013, 23058235; Lee (2013) 24063601; Baker (2015) 26084537; Greenhill (2016) 27005467; Nelson (2016) 27164666; Corwin (2014) 25262302; Preiss-Farzenagan (2009) 19627902; Heyer (2016) 27056449; Kontos (2012) 22503738; Kriz (2016) 26781190; Miller (2016) 26684762; Ellis 2015 26359916

Age

• There is some, but not definitive, support for a gradient age and

level of play effect with clinical recovery being fastest in

professional athletes, followed by college athletes, followed by

high school athletes.

• No age effects in several studies, including some large scale

studies (Nelson, Guskiewicz, et al., 2016; Nelson, Tarima, et al., 2016).

• In the large multicenter Canadian study (Zemek et al., 2016), children

presenting to the ED following injury, the rates of those having

persistent symptoms > 4 weeks:

• Ages 5-7=17.9%, ages 8-12=26.3%, ages 13-17=39.9%.

Female Sex

Yes Baker (2016) 26378093; Berz 2013 23703518; Henry 2016 26445375; Kostyun 2015 25553213; Bock 2015; 26243160; Zuckerman 2014 24206343; Covassin 2012 22539534; Covassin 2013 24197616; Covassin 2016 26950073; Majerske 2008 18523563; Colvin 2009 19460813; Eisenberg 2013 23753087; Ellis 2015 26359916; Miller 2016 26684762; Preiss-Farzenagan (2009) 19627902 (in adults); Heyer (2016) 27056449

No Chermann 2014 25741414; Moor 2015 25883871; Hang 2015 26430968; Nelson 2016 26974186; Mayers 2013 23686028; Asplund 2004 15523205; Black 2016 26862834; Chrisman 2013 23252433; Zuckerman 2016 27032916; Zuckerman 2012 23030348; Vargas 2015 25643158; Terwilliger 2016 26421452; Morgan 2015 25745949; Frommer 2011 21214354; Baker 2015 26084537; McDevett 2015 26502998; Nelson (2016) 27164666; Lax (2015) 26362811; Ono (2016) 26672026; Preiss-Farzenagan (2009) 19627902 (in children/adolescents); Covassin (2007) 17762747; Kontos (2012) 22503738; Wasserman (2015) 26546304; Yang (2015) 25649775

Sex

• Comparable number of studies show positive and negative

findings that worse outcomes are associated with female

sex.

• Some large-scale and epidemiological studies indicate that

girls and young women are at greater risk for having

symptoms that persist for more than a month (e.g., Wasserman et al.,

2016; Zemek,et al., 2016; Kostyun et al., 2016).

• The extent to which recovery is slower/outcomes are worse

for females is still unclear.

Prior Concussions

Yes Hang (2015) 26430968; Nelson (2016) 26974186; Guskiewicz (2003) 14625331; Castile (2011) 22144000; Chrisman (2013) 23252433 (football only); Zuckerman (2016) 27032916; Morgan (2015) 25745949; Covassin (2013) 23959963; Kerr (2014) 26535354; Colvin (2009) 19460813; Iverson (2006) 16537266; Miller (2016) 26684762; Wasserman (2015) 26546304; Slobounov (2007) 17762746; Benson (2011) 21502355; Corwin (2014) 25262302

No Asken (2016) 27111584; Barlow (2011) 21904694; Moor (2015) 25883871; Brown (2014) 24394679; Lau (2012) 21841522; Mautner (2015) 25353721; McDevett (2015) 26502998; Vargas (2015) 25643158; Terwilliger (2016) 26421452; McCrea (2013) 23058235; Erlanger (2003) 12650417; Majerske (2008) 18523563; Baker (2015) 26084537; Ellis (2015) 26359916; Field (2003) 12756388; Makdissi (2013) 23479491; Pellman (2006) 16462480; Gibson (2013) 23758286; Heyer (2016) 27056449; Miller (2016) 26684762; Chrisman (2013) 23252433 (non-football only)

Prior Concussions

• Many studies find an association between prior concussions and

worse clinical outcomes.

• A greater number of studies have not found that prior concussions

are associated with worse outcomes.

• Still likely a significant modifier because:

• Prior history of concussion is a risk factor for future

concussions (Abrahams et al., 2012)

• Prior concussions are associated with greater pre-injury

symptom reporting in some athletes (Abrahams et al., 2012; Iverson et al.,

2015)

• Some large-scale studies show an association between

concussion history and increased risk for symptoms lasting

more than four weeks (e.g., Castile et al., 2012; Miller et al., 2016; Wasserman et al.,

2016)

Health History

• Mental Health History

– Almost all studies suggest worse outcome.

• ADHD History

– Almost all studies do not suggest worse outcome.

• Learning Disability History

– Almost all studies do not suggest worse outcome.

• Personal Migraine History

– Almost all studies do not suggest worse outcome.

– One large well-designed study reported that a personal history of

migraine is associated with risk for symptoms lasting more than

four weeks (Zemek et al., 2016).

Injury Severity

• Loss of consciousness

– Some studies report positive findings that LOC is

associated with worse outcomes, but most do not find an

association with LOC.

• Post-traumatic amnesia/“amnesia”

– Mixed, but more studies do not find association with

worse outcomes.

• Retrograde amnesia

– Less frequently studied.

– Consistently associated with worse outcome in the first 10

days following injury.

Greater Acute Symptoms

Yes Chermann (2014) 25741414; Brown (2014) 24394679; Hang (2015) 26430968; Resch (2015) 26565424; Castile (2011) 22144000; Chrisman (2013) 23252433; Zuckerman (2016) 27032916; Meehan (2014) 25381296; Meehan (2013) 23628374; McCrea (2013) 23058235; Benson (2011) 21502355; Greenhill (2016) 27005467; Makdissi (2013) 23479491; Nelson (2016) 27164666; Merritt (2015) 25685959; Prichep (2013) 22588360; Heyer (2016) 27056449; Iverson (2007) 17304003

No Barlow (2011) 21904694; Moor (2015) 25883871; Morgan (2015) 25745949

Acute Clinical Findings

• Acute/sub-acute symptom burden

– Associated with worse outcome

– Of all possible predictors, it was the most

consistently associated with worse outcome.

• Acute/Subacute Post-injury Headaches

– Almost all studies suggest worse outcome.

Conclusions

• Strongest/most consistent predictor of slow recovery: more

severe acute/subacute symptoms after injury.

• Those with preinjury mental health problems or migraines

seem to be at a slightly increased risk for persistent symptoms.

• Those with ADHD/learning disabilities do not seem to be at an

increased risk for persistent symptoms.

• Teenagers may be at the highest risk for persistent symptoms.

• Girls have a higher likelihood of prolonged recovery.

Recovery from Mild Traumatic Brain Injury

in Civilians

Subjects

• Tampere University Hospital, ED, Finland

• 49 patients with MTBIs

• No history of medical, mental health, or substance

abuse problems

• All underwent MRI for clinical or research purposes:

24.5% Abnormal

• First Research Visit, SCAT2; M = 30.4 hours (SD =

27.3) and all within 5 days

One Month Outcome

• ICD-10 Postconcussional Syndrome, Mild in

Severity =

23% of the MTBI sample

12% of the Community Control sample with

remote ankle injuries

Acute Predictors of One-Month

Post-Concussion Syndrome

• Loss of Consciousness: No

• Retrograde Amnesia: No

• Post-Traumatic Amnesia: No

• Abnormal MRI: No

• High Symptom Reporting in first few days: Yes

• Acute Psychological Distress: Yes (strongest predictor)

Most people recover functionally within 3 months

following injury.

Examples of Neuropsychology Meta-Analyses

Most people return to work within 3 months.

Return to work rates are highly variable across studies

and are likely influenced by many factors separate from

the injury to the brain.

Are there Microstructural White Matter

Abnormalities?

Cannot see on standard CT or MRI

If present, are these abnormalities associated with

persistent symptoms?

Why is White Matter

Vulnerable?

1. Anatomy

2. Physics & Forces

Traumatic Axonal Injury

• In general, unless exposed to very serious

forces, axons do not “shear” at the point of

injury.

• Stretch causes a temporary deformation of an

axon that gradually returns to the original

orientation and morphology even though

internal damage might have been sustained

Traumatic Axonal Injury

• In summary, a single acceleration/deceleration event might result in:

– (a) no apparent change in structure or function,

– (b) functional or metabolic change,

– (c) eventual structural change in the axon, or

– (d) frank separation of the axon into proximal and distal segments.

• These outcomes are dependent on the force applied to the brain.

Diffusion Tensor Imaging (DTI)

• DTI measures both the directionality and the

magnitude of water diffusion in white matter.

• Often considered proxy measures for the microstructural integrity of white matter in the human brain.

Common Analyses

• Region of Interest

• Tract-Based Spatial Statistics

• Tractography

• Emerging: Multivariate ROIs (Atlas-Based Approach)

Review of 50 DTI Studies in MTBI (Wäljas et al., 2014)

Findings Yes No Not

Reported

Abnormal White Matter 88% 12% ---

Correlated with:

Return to Work 0% 2% 98%

Post-Concussion Symptoms 12% 6% 82%

Cognitive Functioning 54% 8% 38%

Mental Health Problems 6% 8% 86%

DTI is interesting and has advanced

knowledge in TBI.

Remember, however, white matter

abnormalities are present in many

conditions—even in healthy adults.

And many of these conditions are present before injury or sometimes in

the years after injury.

ADHD

Learning Disability/Dyslexia

Depression

Hypertension

Non-Traumatic TMJ Disorder

Migraine

Marijuana & Alcohol Abuse in

Adolescents

More Bad News for Smokers

These data suggest that smoking affects the microstructural

integrity of cerebral white matter and support previous data

that smoking is associated with impaired cognition.

CONCLUSIONS: We document lower cognitive

performance and reductions in brain structural integrity

among adolescents with Metabolic Syndrome, thus

suggesting that even relatively short-term impairments in

metabolism, in the absence of clinically manifest vascular

disease, may give rise to brain complications.

Isolated White Matter Hyperintensities

in Healthy Adults

Examining DTI in a Civilian

Biopsychosocial Outcome from

MTBI Study

Prospective Study of One Year

Outcome from Civilian MTBI

Tampere, Finland

Recruited from the Emergency Department

Imaging and Clinical Assessment at 3-4 Weeks

Clinical Assessment at 1 Year

Wäljas M, Iverson GL, Lange RT, Hakulinen U, Dastidar P, Huhtala H, Liimatainen S, Hartikainen K, Öhman J. A prospective biopsychosocial study of the persistent post-concussion symptoms following mild traumatic brain injury. J Neurotrauma. 2015 Apr 15;32(8):534-47.

Prospective Outcome Study on MTBI

(N = 126 at one month and 103 at one year) Wäljas et al. (2015)

ICD-10 Mild Post-Concussion Syndrome

• MTBI One Month: 59% MTBI One Year: 38%

• Healthy Controls: 31%

Abnormal Structural MRI and/or DTI Variable from days to weeks post injury (Average = 1 month)

• Abnormal structural MRI = 12.1%

• Diffusion Tensor Imaging (DTI): Multifocal areas

of unusual white matter

– MTBI Group = 50.7%

– Healthy Controls =12.4%

Predictors of the Post-Concussion

Syndrome

• One Month: pre-injury mental health problems

and bodily injuries.

• Being symptomatic at one month was a

significant predictor of being symptomatic at

one year.

• Depression was significantly related to PCS at

both one month and one year.

• Structural MRI abnormalities and

microstructural white matter findings (DTI)

were not significantly associated with greater

post-concussion symptom reporting, and they

were not significant predictors of PCS at one-

month or one-year following injury.

Participants and Procedures

• 62 adults with MTBIs

• 31 complicated and 31 uncomplicated

• Neurocognitive testing (many tests)

• Symptom Ratings

– British Columbia Postconcussion Symptom Inventory

– Beck Depression Inventory-Second Edition

– Beck Anxiety Inventory

• DTI on a 3T MRI scanner approximately 6-8

weeks post injury.

Reduced FA in body and genu of the corpus callosum and the

left frontal corona radiata and

Increased radial diffusivity in genu of the corpus callosum

and left frontal corona radiata

No Significant Differences

• Symptoms

• Broad range of neuropsychological tests

Biopsychosocial Model Continued:

Persistent Symptoms

Depression, Anxiety, Traumatic Stress,

Chronic Pain, and the Post-Concussion Syndrome

Vestibular

Injury

Brain

Injury

Chronic

Headaches

Chronic

Bodily

Pain

Insomnia/

Sleep

Disturbance

Life Stress

Anxiety/

Cognitive

Hypochondriasis

Post-Traumatic

Stress

Depression

Cognitive

Difficulty

& PCS

Symptoms

Many clinical

conditions are

associated with

symptoms.

Pre-injury

health and

mental

health is

important.

Personality

characteristics

and social-

environmental

factors can be

important.

A

biopsychosocial

model is most

appropriate.

Civilians who sustain an MTBI are at substantially

increased risk for experiencing depression in the

first year following injury.

The etiology of depression is likely individualized

and multifactorial.

Post-concussion-like symptoms can be mimicked or

magnified by traumatic stress, anxiety, pain, depression,

sleep disturbance, and social psychological factors at any

point in the recovery trajectory.

115

Symptoms

Mild TBI

Depression

Anxiety

Traumatic stress

Life stressors

Insomnia

Chronic

Pain

Individuals who are symptomatic at 3-6 months are

at considerable risk for being symptomatic at 1-2

years post injury.

Factors Affecting Recovery Time

• General health

• Previous concussions / neurological problems

• Pre-injury mental health problems

• Mechanism of Injury: MVA vs. Sports

• Acute Psychological Distress in the first few days

• Severity of concussion symptoms in the first week

• Post-Acute co-occurring conditions (depression, PTSD,

chronic pain)

• Personality Characteristics

• Motivation

• Litigation

Conclusions

• Mild TBIs are heterogeneous.

• Most athletes appear to recover within one month and

most civilians appear to recover within three months.

• Macroscopic intracranial lesions are not strongly related

to outcome.

• Microstructural differences as measured by DTI are not

strongly related to outcome.

• A biopsychosocial model helps conceptualize good and

poor outcome in individual cases.

Careful and Comprehensive Assessment

= Targets for Treatment and

Rehabilitation

Reduce Symptoms; Improve Function

• Sleep Disturbance

• Stress & Anxiety

• Depression

• Deconditioning

• Headaches

• Bodily Pain

Vestibular

Injury

Brain

Injury

Chronic

Headaches

Chronic

Bodily

Pain

Insomnia/

Sleep

Disturbance

Life Stress

Anxiety/

Cognitive

Hypochondriasis

Post-Traumatic

Stress

Depression

Cognitive

Difficulty

& PCS

Symptoms

Treat

what you

can treat.

Success

begets

success.

Reduce

symptoms.

Improve

functioning.

Thank You