Concussion Neuroimaging Consortium (CNC) · TBI outcome schema: PTSD, Depression, Addiction Loss...

Concussion Neuroimaging Consortium Concussion Neuroimaging Consortium (CNC)(CNC)

Vision and MissionVision and MissionVision and MissionVision and Missionwww.concussionimaging.orgwww.concussionimaging.org

Presented @ B1G/CIC/Ivy League TBI SummitPresented @ B1G/CIC/Ivy League TBI SummitChicago, July 15 2015Chicago, July 15 2015

@ 2015 CNC

DisclosureDisclosureDisclosureDisclosure

NO Conflict of Interests Memorandum of Understanding between CNC partners is reached and endorsed by ALL participating institutions: NU, Nebraska, MSU, Purdue, PSU, OSU, UCF, North Shore University Health , ySystem;

© 2015 CNC

CNC Equal PartnersCNC Equal PartnersCNC Equal PartnersCNC Equal Partners

Over the last 5 years our CNC members have published over 350 papers thatfocus on TBI, imaging, neurocognitive processes and neuropsychologicaldevelopment © 2015 CNC

CNC Key ObjectivesCNC Key ObjectivesCNC Key ObjectivesCNC Key ObjectivesConsolidation of leading brain science/brain imaging experts and efforts aimed at identification of imaging “biomarkers” of

i d thl t t i k f t ti concussion and athletes at risk for traumatic concussion;

Development of advanced MR imaging techniques to measure physiological and q p y gneuropsychological alterations after concussion;

© 2015 CNC

CNC Key ObjectivesCNC Key ObjectivesCNC Key ObjectivesCNC Key ObjectivesDevelopment of a standardized, MR-evidenced based and platform independent Operational Manual for acquisition and processing brain i i d timaging data;

Integration of neuroimaging measures with g g gmathematical metrics of behavior and other technologically advanced concussion assessment tools to aid medical intervention and prognosis assessment;

© 2015 CNC.

CNC Key ObjectivesCNC Key ObjectivesCNC Key ObjectivesCNC Key ObjectivesLeverage partnerships with MRI vendors, pharmaceutical and other companies as a critical component for research on neurological t t f ti d t t t b i i j d structure, function and treatment brain injured

patients;

Training faculty, postdoctoral fellow, medical residents or graduate in one or more of the core consortium’s initiatives associated with MR assessment and

t f i management of concussion;

© 2015 CNC

Our StatementOur StatementOur StatementOur Statement

CNC members obtained evidence viaadvanced brain imaging studies (fMRI, DTI,MRS, ASL, DWI, EEG) suggests that both) ggstructural and functionalabnormalities are present far beyond 10p ydays post-injury, meaning that themajority of mTBI can be classified asj ycomplicated, at least. This IS NOTconsidered within the scope of lifepreintegration.

© 2015 CNC

An Engineering Model of ConcussionAn Engineering Model of ConcussionAn Engineering Model of ConcussionAn Engineering Model of Concussion

Northeast Blackout (14 Aug 2003): caused by cascading failure in hi h ld b f d h id d which power could not be transferred across the power grid due

to lack of capacity in available power lines.◦ Monitoring had failed

◦ Preventable!

(Getty Images)

Analogous to what we call concussion◦ Injury impairs delivery of sufficient numbers of inputs within necessary

interval (i.e., summation in place/time are weaker)

◦ Symptoms arise after injury, when summation fails and information is not transferred between processing nodes due to altered connectivity © 2015 CNC

In the following presentationIn the following presentationIn the following presentation,In the following presentation,we will explore neurologic and we will explore neurologic and

hi i l ihi i l ipsychiatric sequelae inpsychiatric sequelae inHighHigh--School Athletes, School Athletes, Collegiate Athletes, Collegiate Athletes,

Professional Athletes andProfessional Athletes andMilitary/VeteransMilitary/Veterans

© 2015 CNC

““SymptomsSymptoms”” as as SubsetSubset of of ““InjuryInjury””SymptomsSymptoms as as SubsetSubset of of InjuryInjuryP213 (Season 4)

Pre-Season Concussion! (24 hrs)P121 (Season 2)

Normal ControlNormal Control

High School Athletes

Pre-Season “Healthy”

© 2015 CNC

PNG High School Study (2009PNG High School Study (2009--15):15):6 years, 8 teams, 380 athlete6 years, 8 teams, 380 athlete--seasons, seasons,

1100+ MRI Scans1100+ MRI Scans

Three High Schools: (Boys’) Football & Girls’ SoccerThree High Schools: (Boys ) Football & Girls SoccerPurdue University: Football (Freshmen) & Women’s Soccer

© 2015 CNC

11H MRS: Altered Biochemistry With H MRS: Altered Biochemistry With Exposure to Acceleration EventsExposure to Acceleration Events

MRS measures are f ffsignificantly different

from like-aged Controls before the

season.

Marked MRS changes occur at beginning

and during the season.

(PNG Season 4)

(V.N. Poole et al., Dev Neuropsychol, 2014)

© 2015 CNC

DMN Connectivity Changes with DMN Connectivity Changes with Exposure to Acceleration EventsExposure to Acceleration Events

(K Abbas et al Brain Connectivity 2014)(K. Abbas et al., Brain Connectivity, 2014) (K. Abbas et al., Dev Neuropsychol, 2015)

DMN connectivity is different from like-aged Controls at “Baseline”, and reliably decreases during periods of heavy hitting Behavior after season reliably decreases during periods of heavy hitting. Behavior after season

suggests “Baseline” may already be abnormal. (PNG Seasons 3 & 4)

© 2015 CNC

PNG Season 6 Flagging ObservationsPNG Season 6 Flagging ObservationsPNG Season 6 Flagging ObservationsPNG Season 6 Flagging Observations16 neurophysiological assessments @ 5 time-points◦ ImPACT (omnibus), SAC, task-based fMRI, rs-fMRI, CVR, DTI, MRS

(DLPFC & M1: [Ins], [NAA], [tCho], [tCr], [Glx])

◦ “Flagged” if outside Healthy Noncollision-Sport Control 95% CI%flag0% 2 5% 2 5% 0 0% 0 0% 8 20% 4 13%

CONTROLSIn1 In2 Post1 Post2Pre0% 2 5% 2 5% 0 0% 0 0% 8 20% 4 13%6% 2 9% 1 8% 2 5% 2 5% 8 40% 13 55%13% 9 30% 3 15% 6 18% 8 24% 12 70% 6 74%19% 5 41% 10 40% 3 25% 8 44% 7 88% 2 81%25% 8 59% 10 65% 10 48% 5 56% 2 93% 3 90%31% 8 77% 7 83% 11 73% 9 78% 2 98% 2 97%31% 8 77% 7 83% 11 73% 9 78% 2 98% 2 97%38% 4 86% 4 93% 11 98% 4 88% 1 100% 1 100%44% 4 95% 1 95% 1 100% 2 93% 0 100% 0 100%50% 1 98% 1 98% 0 100% 3 100% 0 100% 0 100%56% 0 98% 1 100% 0 100% 0 100% 0 100% 0 100%

Aggregate measures highlight accrual of injury (w/o clear symptoms!) during the season. [cf. Baugh et al. 2015]

63% 1 100% 0 100% 0 100% 0 100% 0 100% 0 100%

“Healthy” status not present until 4-5 months afterparticipation ends. Do the kids get enough rest??

© 2015 CNC

DefaultDefault--mode Network Connectivitymode Network ConnectivityAlteration in Collegiate AthletesAlteration in Collegiate Athletesgg

ty (R

)0.450.5

nnec

tivit

0.350.4

MN

Con

0 20.250.3

ConcussedControl

vera

ll D

0 10.150.2

Ov

00.050.1

Day 1 Day 7 Day 300

Zhu et al. J Neurotrauma. 2015 Mar 1;32(5):327-41.

Case studyCase studyThe functional and structural connectivity to left isthmus of ycingulate cortex of a concussed subject over one month (correlation R > 0.4 and connectivity distribution > 1000).

Day 1 Day 7 Day 30structural

Seed regions

functional

Red: overlap regions.Green: functional seedOrange: structural seed

The above functional connectivity alteration from Day 1 to Day 7

Orange: structural seed

was seen in 8 of our 9 concussed cases. This points toward the possibility of clinically relevant radiographic biomarkers.

fMRI Spatial Memory StudyfMRI Spatial Memory Studyp y yp y y

Pre-Injury Post-Injury

Question of Neurocompensation

Pre Injury Post Injury

© 2013 - Dr. S. Slobounov - All Rights Reserved.

Slobounov et al., (fMRI study. Experimental Brain Research, 202(2), 341

MTBI: Brain Imaging (rsFMRI)MTBI: Brain Imaging (rsFMRI)g g ( )g g ( )

Disruption of inter-hemispheric hippocampal f i l i i ( l i DLPFC) functional connectivity (also seen in DLPFC); another potential biomarker

Slobounov et al., (2010) NeuroImage

Default Mode NetworkDefault Mode NetworkDefault Mode NetworkDefault Mode NetworkWe reported reduced magnitude and number of significant

i b i ROI h k h connections between primary ROIs that make up the default mode network (DMN) [(i.e., PCC, medial prefrontal cortex, medial lateral and inferior parietal p pcortex (Raichle et al., 2001)] and other ROIs including DLPFC and bilateral parietal cortex.

Johnson et al. (2011). NeuroImage (multiple MTBI)


Default Mode NetworkDefault Mode NetworkDefault Mode NetworkDefault Mode NetworkZhang, Slobounov et al. (2012). Journal of Neurotrauma 29, 756-765.

J h Sl b t l (2011) Ne oI a e 59 511 518Johnson, Slobounov et al. (2011). NeuroImage, 59, 511-518.

Slobounov et al. (2011). NeuroImage, 55(4), 1716-27.


¹¹HH--MRS Normal Controls vs. MTBIMRS Normal Controls vs. MTBICSI l j b CCCSI l j b CCCSI placement just above CCCSI placement just above CC

Johnson, Slobounov et al. (2012).N i L tt 10(509) 5 8


Neuroscience Letters, 10(509), 5-8.

O lO l M D f A d M D f A d OcularOcular--Motor Deficits: in Acute and Motor Deficits: in Acute and SubSub--Acute Phases of ConcussionAcute Phases of ConcussionJohnson, Hallett, Slobounov (2015) Johnson, Hallett, Slobounov (2015) Brain Imaging & BehaviorBrain Imaging & Behavior, , NeurologyNeurology

FEFEF

precuneus SEF


Gray matter density abnormalities in a cohort of ex-NFL Players

ex-NFL (n=9) > Healthy (n=10)Region Hemisphere X Y Z Peak z Volume, mm3

Dorsolateral Prefrontal R No DifferencesCortex

Insula R 38 -3 -6 2.95 1215

Ant. Cingulate Bilateral 0 3 48 2.44 631

Dorsolateral Prefrontal Cortex

L -38 27 16 2.50 662

Insula L -44 0 -6 1.9 24

Healthy (n=10) > ex-NFL (n=10)Healthy (n=10) > ex-NFL (n=10)Region Hemisphere X Y Z Peak z Volume, mm3


R 34 22 13 3.43 236

Insula R 34 -18 13 1.68 4


Dorsolateral Prefrontal C

L -32 20 30 2.18 462Cortex

Insula L -30 23 -12 2.07 27

p=0.05 with small volume correction using network mask for multiple comparisons , age used as a co-variate

Gray matter density abnormalities in a cohort of exGray matter density abnormalities in a cohort of ex--NFL PlayersNFL PlayersPink = Network Mask: dorsolateral prefrontal cortex, insula and anterior cingulate

Yellow = ex-NFL > Healthy Blue = Healthy > ex-NFL

AnteriorAnteriorCingulate

CortexDorsolateralPrefrontal

Cortex

RightInsula

Funded by Edward Hines Jr., VA Hospital, Center for Innovation in Complex Chronic Healthcare, Locally Initiated Project #42-129 and pilot funds from Northwestern University’s Center for Translational Imaging to Theresa Pape, Todd Parrish, Amy Herrold, Brett Harton, Xue Wang

Gray matter density differences between ex-NFL Players & Veteransex-NFL (n=9) > Veteran (n=7)

Region Hemisphere X Y Z Peak z Volume, mm3

Dorsolateral Prefrontal C t

R No DifferencesCortex

Insula R No Differences

Ant. Cingulate Bilateral No Differences


L No Differences

Insula L -42 15 -12 2.72 142

Veteran (n=7) > ex-NFL (n=9)Veteran (n=7) > ex-NFL (n=9)Region Hemisphere X Y Z Peak z Volume, mm3


R 36 30 28 2.83 412

Insula R 40 -16 9 2.15 240



L -38 21 28 1.95 118Cortex

Insula L -30 11 -17 2.09 203

p=0.05 with small volume correction using network mask for multiple comparisons , age & time since injury used as co-variates

Pink = Network Mask: dorsolateral prefrontal cortex, insula and anterior cingulate

Gray matter density differences between ex-NFL Players & Veterans

Yellow = ex-NFL > Veterans Blue = Veteran > ex-NFL

L ft Anterior DorsolateralP f t lLeft

Insula

AnteriorCingulate

Cortex

PrefrontalCortex

Funded by Edward Hines Jr., VA Hospital, Center for Innovation in Complex Chronic Healthcare, Locally Initiated Project #42-129 and pilot funds from Northwestern University’s Center for Translational Imaging to Theresa Pape, Todd Parrish, Amy Herrold, Brett Harton, Xue Wang

Three Step Schema For Trauma Consequences?Three Step Schema For Trauma Consequences?Medial Temporal Cortex NAc/VS sgACC PAC Insula/CaudateMedial Temporal Cortex(Hippocampus-Amygdala)(PTSD, Anxiety)

NAc/VS, sgACC, PAC(Depressive Sx’s)

Insula/Caudate(SUD, Addiction)

A i

Prefrontal Cortex

ApproximateTime Course

f EffPrefrontal Cortex

MDD

Suicide

nal Concussive

SyndromeEmergenceOf Frontal

Disconnection

EmergenceOf Psychiatric

Symptoms

of Effects

PTSD

MDD

of F

unct

ion

Illne

ss

DisconnectionBehavior

Symptoms

Ti ( k )

SUD

ympt

oms

oB

rain

Time (wks-yrs)

0 3 6 9 N

Sy

© 2015 CNC

TBI outcome schema: PTSD, Depression, Addiction

Loss PTSDD i (MDD)

Mild-TBI or CTE

Mild-TBI in soldiers leads to shearing of tracts connecting2

3

Keypress In

PGP2 IAPS KEYPRESS (First 9x9 picture set), No. 22

Slope of

Loss Aversion Depression (MDD)

Addiction (SUD)

CTE

Relative Preference Theory Mapping of Reward/Aversion

gPPC and PFC, & affecting working memory (WM)

4 50H+, H‐

-20 0 20 40 60 80 100 120

-3

-2

-1

0

1

Mean Keypress Intensity

Shannon Entropy of

Avoidance

Slope of Approach

Loss Aversio

n

=

Circles on SLF. Figure from Shah et al., Brain Injury, 2012

Information load capacity is negatively affected3.00

3.50

4.00

4.50

Hplus

βL

0

10050

1 3 5 7

# correct

# items

# wrong

0

10050

1 3 5 7# items

2.00

2.50

0.010.501.001.502.002.503.003.504.004.505.005.506.00

Hminus Beta

Cobb Douglas Function 1 3 5 7 1 3 5 7Hitc = δ1,1 + δ1,2e-δ1,3X FAc = δ2,1 + δ2,2eδ2,3X

β /H+ & H−

Cobb-Douglas FunctionRelating Signal Detection

To Reward/Aversion

βL= zHTc /zFAc/Signal Detection Threshold (β) H± = aβ bK±

c K+ & K−

β

© 2013 - Dr. H. Breiter - All Rights Reserved.

ConclusionsConclusionsConclusionsConclusionsAdvanced MRI has potential as a clinical biomarker

di TBI Thi h b f ll lid dregarding mTBI. This has to be fully validated.

If this is confirmed, it could lead the way to return to yplay considerations and possibly treatment strategy studies.

Additional advanced technology, once validated as clinical relevant and when used as extension of the li i l ld h l id lif i i clinical exam could help guide life reintegration

decisions and possibly retirement decisions for student and professional athletes.p

© 2015 CNC

CNC Recent InitiativesCNC Recent InitiativesCNC Recent InitiativesCNC Recent Initiatives

A Call to Arms: The Need to Create an Inter-Institutional Concussion Neuroimaging Consortium…g g

NIH R21 grant in review, June 2015

© 2015 CNC

Concussion Neuroimaging Consortium (CNC) · TBI outcome schema: PTSD, Depression, Addiction Loss...

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