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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)
© 2013 - Dr. S. Slobounov - All Rights Reserved.
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.
© 2013 - Dr. S. Slobounov - All Rights Reserved.
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
© 2013 - Dr. S. Slobounov - All Rights Reserved.
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
© 2015 - Dr. S. Slobounov - All Rights Reserved.
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
Dorsolateral Prefrontal Cortex
R 34 22 13 3.43 236
Insula R 34 -18 13 1.68 4
Ant. Cingulate Bilateral 9 18 25 3.01 2481
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
Dorsolateral Prefrontal Cortex
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
Dorsolateral Prefrontal Cortex
R 36 30 28 2.83 412
Insula R 40 -16 9 2.15 240
Ant. Cingulate Bilateral 12 12 51 2.78 3662
Dorsolateral Prefrontal Cortex
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
Thank You.Thank You.
© 2015 CNC