/
Imaging In Traumatic Brain Injury: Imaging In Traumatic Brain Injury:

Imaging In Traumatic Brain Injury: - PowerPoint Presentation

tatyana-admore
tatyana-admore . @tatyana-admore
Follow
560 views
Uploaded On 2016-09-17

Imaging In Traumatic Brain Injury: - PPT Presentation

What Have We Learned A Functional and Molecular Neuroimaging Perspective Emily Stern MD Director Functional Neuroimaging Laboratory Director Functional and Molecular Neuroimaging Departments of Radiology and Psychiatry ID: 467522

brain tbi function imaging tbi brain imaging function fmri functional 2015 pet injury neuroinflammation molecular state neuroimaging resting doi

Share:

Link:

Embed:

Download Presentation from below link

Download Presentation The PPT/PDF document "Imaging In Traumatic Brain Injury:" is the property of its rightful owner. Permission is granted to download and print the materials on this web site for personal, non-commercial use only, and to display it on your personal computer provided you do not modify the materials and that you retain all copyright notices contained in the materials. By downloading content from our website, you accept the terms of this agreement.


Presentation Transcript

Slide1

Imaging In Traumatic Brain Injury:What Have We Learned? A Functional and Molecular Neuroimaging Perspective

Emily Stern,

MD

Director, Functional Neuroimaging Laboratory

Director, Functional and Molecular NeuroimagingDepartments of Radiology and PsychiatryAssociate Professor of Radiology

Brigham and Women

s Hospital

Harvard Medical SchoolSlide2

Disclosures

I have NO RELEVANT financial disclosureSlide3

OutlineBeyond structure: what can functional and molecular neuroimaging tell usIntroduction to methodologies

TBI and brain function (as assessed by fMRI)

Where we are: frontal lobe function, resting stateTBI

pathophysiology: the role of neuroinflammation

as assessed by PETINTRuST DOD pilot studyAdditional future directionsWhere we need to go SummarySlide4

OutlineBeyond structure: what can functional and molecular neuroimaging tell usIntroduction to methodologies

TBI and brain function (as assessed by fMRI

)Where we are: frontal lobe function, resting state

TBI

pathophysiology: the role of neuroinflammation as assessed by PETINTRuST DOD pilot studyAdditional future directionsWhere we need to go SummarySlide5

Functional Brain MappingSlide6

Functional Brain MappingThe use of functional magnetic resonance imaging (fMRI) or positron emission tomography (PET) as a marker of neuronal activityCan identify focal areas of increased or decreased neuronal activity in different mental conditions or disease states

Can identify areas of dysfunction in the absence of structural changeSlide7

18

F-FDG PET

H

215O PET

BOLD fMRIArterial Spin Tagging fMRI BLOOD VOLUMEBLOOD OXYGENATION

11

CO PET

Gadolinium DTPA fMRI

Functional Imaging Method

(PET and fMRI)Slide8

fMRI: Measuring BOLD activity at every point in the brain (voxel) over time

HOPELESS

HOPELESS

[Ex. Hopeless]Slide9

Types of fMRI StudiesSymptom capture (e.g. hallucinations, tics)

Activation studiesprobe

cognitive process and / or neural system

of interest for particular

disordersPre- and post-treatment evaluationResting state assessment Connectivity analyses Assess how brain regions function in concert with each otherSlide10

Can correlate fMRI data directly with:Structural imagingExtensive standardized clinical ratingsNeurobehavioral data

Genetics allelic variants/single nucleotide polymorphisms to identify imaging endophenotypes associated with core clinical features, and that can serve as predictors of differential treatment response

Physiological Measures e.g. cortisol, skin conductance response

Eye trackingIntracranial and surface EEG

Fluid BiomarkersMetabolomics, proteomics, lipidomics, immunomicsSkin Conductance ResponseSlide11

Ex: Abnormal frontolimbic functionCorrelations between BOLD activity and cortisol change prescan to postscan

(Root et al,

Neuroreport, 2009)

Healthy subjects: threatening stimuli

RLSlide12

Positron Emission Tomography(PET)Slide13

Positron Emission Tomography (PET)A functional, nuclear medicine technique that allows imaging of cellular and molecular processesTag a biologically active molecule with small amount of radioactivity (similar amount to diagnostic radiological test) and observe binding

Choose radiotracer to target particular molecular function of interest (e.g. glucose metabolism; neuroinflammation)Slide14

PET Procedurehttp://www.sepscience.com/Sectors/Pharma/Articles/429-/Radio-IC-for-Quality-Control-in-PET-Diagnosticshttp://www.slideshare.net/tmhnehru/handout-rmnlectureapplication-of-radiationinmedicineandresearch30122013

http://www.fz-juelich.de/inm/inm-4/EN/Home/_Fokus/Informationen/_node.html

1.

3.

2.4.Slide15

Example: 18F-FDG and 11C-PK11195 PETNeuroinflammation in Patient with Epilepsy Due to Focal Cortical Dysplasia

Ictal

18

F-FDG PET Interictal

18F-FDG PET 11C-PK11195 PET (Butler et al, 2011) RLSlide16

OutlineBeyond structure: what can functional and molecular neuroimaging tell us

Introduction to methodologiesTBI and brain function (as assessed by

fMRI)Where we are: frontal lobe function, resting state

TBI

pathophysiology: the role of neuroinflammation as assessed by PETINTRuST DOD pilot studyAdditional future directionsWhere we need to go SummarySlide17

fMRI and TBI to date:Activation Study Examples Majority focused on probingExecutive function: comprises multiple higher order functions including planning, execution, reasoning, working memory, problem solving

Spatial planning/”

Tower of London”

task in NFL players:

hyperactivation and hypoconnectivity dorsolateral frontal and frontopolar; correlated with # of times removed from play (Hampshire et al, 2013)

(Hampshire et al, 2013)

Inhibitory

function:

Correct inhibitions:

increased

ACC

and

OFC

; incorrect inhibitions:

increased

caudate

and

cerebellum

(Fischer et al, 2014)

frontal lobe function, e.g.Slide18

fMRI and TBI to date:

Activation Study Examples

Majority focused on probing frontal lobe function, e.g.

Working memory: system responsible for transient holding and processing of new and already-stored information; important for reasoning, comprehension, learning and memory updating.

Caudate dysfunction (decreased activation) during encoding (Newsome et al 2015;Increased posterior cingulate activation

(Wylie et al 2015)

Widespread

hyperactivation

– B

visual encoding

, B

frontoparietal

WM network regions, L

temporal

during successful encoding

(Gillis et al, 2014)

Increased WM load: altered (

increased

and

decreased

depending on specific aspect of

taskactivation

DLPFC

and

parietal

, in 9-15

y.o

.

(

Sinopoli

et al 2014)Slide19

fMRI and TBI to date:Activation Study Examples What about emotional function?Emotional dysfunction/psychiatric disease well known

sequelae of TBI, e.g. PTSD: prevalence in TBI uncertain (1-50%); 2008 Rand Report: 7% of troops from Iraq and Afghanistan had TBI with co-morbid PTSD or depression

(

Tanev et al, 2015)Other neuropsychiatric disease: depressed mood, anxiety, impulsive/aggressive behavior, sleep disturbance,

delerium (Bhalerao et al, 2015)Many fewer functional neuroimaging studies, e.g.Decreased facial affect recognition with associated decreased activity in R fusiform gyrus (Neumann et al, 2015)TBI + MDD c/w TBI alone, emotional face matching task: increased B amygdala, decreased

cognitive control regions (

DLPFC

)

(Matthews et al, 2011)Slide20

Most fMRI activation studies have focused on frontal lobe functionFindings include abormalities in a range of regions, including frontal, parietal, temporal, subcorticalVariability could be due to differences in activation tasks, chronicity

and site of injuryVery few studies to date targeting in other regions or other functions (in particular emotional function)

(Note regarding severe TBI and disorders of consciousness)fMRI

and TBI to date:Activation studies summarySlide21

fMRI and TBI to date:Resting State Study Examples Spontaneous low-frequency fluctuations in BOLD activity result in patterns of correlated activity between brain regions (

Biswal et al, 1995)Can be thought of as the

“idling” brain

Default mode network (DMN) is well-known example: medial PFC (TOM),

posterior cingulate (integration), precuneus (episodic memory, self reflection), parietalMedial temporal lobe (memory)(Fox et al, 2005)Slide22

Large number of recent studies, esp mild TBI:Increased FC between sub-thalamic regions and sensory cortical regions and DMN, [<10d post TBI]

(Sours et al, 2015)

Increased FC in regions of the DMN and between cerebellum and SMA; [<1 yr post TBI]

(Nathan et al, 2015)Decreased

FC in bilat somatosensory and motor cortices, but only when proximal to blast (<10m), [<1yr-~5yr post deployment] (Robinson et al, 2015)Veterans with TBI and increased re-experiencing PTSD sxs: decreased FC in network engaged in gating of working memory, [time post TBI NA] (Spielberg et al, 2015).Possible reasons for variability: differences in chronicity; differences in sites of injuryfMRI and TBI to date:Resting State Study Examples Slide23

OutlineBeyond structure: what can functional and molecular neuroimaging tell us

Introduction to methodologiesTBI and brain function (as assessed by

fMRI)

Where we are: frontal lobe function, resting state

TBI pathophysiology: the role of neuroinflammation as assessed by PETINTRuST DOD pilot studyAdditional future directionsWhere we need to go SummarySlide24

DOD INTRuSt ConsortiumINjury and TR

aumatic ST

ress

Novel Functional and Structural Biomarkers of Neuroinflammation and White Matter Change in TBI: a Potential New Diagnostic and Therapeutic Approach

M. Shenton, PhD E. Stern, MD R. Zafonte, DOSlide25

The role of neuroinflammation in TBI RationaleIn addition to better understanding the pathophysiology underlying the phenotype (

fMRI), it is critical to address the molecular processes that occur after TBI

Prerequisite for developing new treatment targets Slide26

The role of neuroinflammation in TBIAimIdentification of novel

neuroinflammatory and white matter biomarkers of TBI

BackgroundMild TBI: difficult to predict which pts

will go on to have persistent cognitive/emotional sxs

Therefore important to examine pathophysiological processes that occur subsequent to injuryEvolving belief that pathophysiological changes after TBI include significant inflammatory and immunological componentsSlide27

Microglia and the TSPO proteinMicroglia are brain’s resident immune cell: become activated almost immediately after injury; can be chronically activated; Serve as major antigen-presenting cells in brain, phagocytosis/clearance: crucial for

neuroinflammatory cascade; sythesize immune mediators (cytokines,

chemokines, complement activation proteins)

PET radioligand [

11C]-PK11195 binds to TSPO (translocator) protein expressed on mitochondria of activated microglia  sensitive to neuroinflammationConcept of harmful vs. beneficial inflammation (Neurotoxic vs. neuroprotective )Prolonged microglial activation may lead to excessive, poorly-reglulated inflammation and can be cytotoxic

(Gentleman et al, 2004; Bal-Price et al, 2001)

Evidence for time-dependent role for different

microglial

phenotypes

(

Febinger

et al, 2015)

Implications: Anti-inflammatory treatment

At time of trauma; longer term;

prophylactically

?

The role of

neuroinflammation

in TBI

Background (continued)Slide28

The role of neuroinflammation in TBI HypothesesAcutely, will observe inflammatory changes 1-2 weeks post TBI with 11C-PK11195 PET, particularly in region of injury

Pts with greater inflammation, DAI, and micro-hemorrahagic

changes at 1-2 wks will show greater impairment on neuropsychological measures at 3 monthsChronically

, at 3 months, inflammatory change will be present, in different pattern than acute changes, reflecting secondary microglial

activity in sites adjacent to and more distally connected to original site of injury, due to remodeling, Wallerian degeneration, etc.Slide29

The role of neuroinflammation in TBI MethodsImaging: PET with [

11C]-PK11195:

novel translocator

(TSPO) protein receptor

ligand binds to mitochondria of activated microglia in the brainmarker of neuroinflammationStructural MRI, diffusion tensor imaging (DTI) and Susceptibility Weighted Imaging (SWI) also obtainedTiming of measurements: 1-2 weeks post TBI and 3 months post TBIBased on animal literature for neuroinflammation in TBI

and human literature for

neuroinflammation

in stroke

(with PK1195)Slide30

Unpublished data removedSlide31

OutlineBeyond structure: what can functional and molecular neuroimaging tell us

Introduction to methodologiesTBI and brain function (as assessed by

fMRI)

Where we are: frontal lobe function, resting state

TBI pathophysiology: the role of neuroinflammation as assessed by PETINTRuST DOD pilot studyAdditional future directionsWhere we need to go SummarySlide32

Functional and Molecular Neuroimaging in TBI: Next steps to keep in mind for the fieldMore extensive examination of biological aspects of brain function after TBI based uponClinical phenotypesTake advantage of what we know about

cognitive and emotional (including psychiatric dysfunction) to probe additional brain areas and brain structures with

fMRI

(b) to

panic related words controlled for neutral words, over time (early vs late)

(a) to

PTSD related words

controlled for neutral words, over time (early

vs

late)

(y= -3) p<0.01.

(

Protopopescu

et al,

Biol

Psych 2005)

Example: Abnormal

Frontolimbic

Function

Amygdala

response in PTSD

vs

NL subjects

Time and stimulus specificitySlide33

Functional and Molecular Neuroimaging in TBI: Next steps to keep in mind for the fieldMore extensive examination of biological aspects of brain function after TBI:Incorporate additional information into our modelsGenotype (imaging can act as an “

endophenotype”)

Proteomics, metabolomics

, immunomics

, etc.Better stratify studies based upon severity and chronicitySlide34

Translational approachIntegration of different imaging modalitiesConduct studies pre- and post-intervention

Functional and Molecular Neuroimaging in TBI: Next steps to keep in mind for the field

Scanning

before treatment

Patterns of brain activity that correlate with/predict treatment responseScanning after treatmentPatterns of brain activity that correlate with successful treatmentPost- vs. Pretreatment scansChanges in patterns of brain activity associated with treatment responseSlide35

OutlineBeyond structure: what can functional and molecular neuroimaging tell us

Introduction to methodologiesTBI and brain function (as assessed by

fMRI)

Where we are: frontal lobe function, resting state

TBI pathophysiology: the role of neuroinflammation as assessed by PETINTRuST DOD pilot studyAdditional future directionsWhere we need to go SummarySlide36

Summary and ConclusionsfMRI is a powerful tool to examine brain function after TBI, though has not been used extensively yet. While most work to date has focused on working memory and the resting state, future work should be tied to the broader range of clinical phenotypes that exist after TBI.Molecular processes that occur after injury, such as inflammation, can be examined

in vivo with PET. These may be particularly important for determining novel interventions.

There are a number of ways to advance the field,including

incorporating additional sources of information(e.g. genotyping, proteomics, etc.), further integrating the results of different imaging modalities, and imaging pre- and post-tx

.Slide37

Summary and ConclusionsfMRI is a powerful tool to examine brain function after TBI, though has not been used extensively yet. While most work to date has focused on working memory and the resting state, future work should be tied to the broader range of clinical phenotypes that exist after TBI.Molecular processes that occur after injury, such as inflammation, can be examined in vivo with PET. These may be particularly important for determining novel interventions.

There are a number of ways to advance the

field,including incorporating additional sources of information(e.g. genotyping, proteomics, etc.), further integrating the results of different imaging modalities, and imaging pre- and post-

tx.Slide38

Summary and ConclusionsfMRI is a powerful tool to examine brain function after TBI, though has not been used extensively yet. While most work to date has focused on working memory and the resting state, future work should be tied to the broader range of clinical phenotypes that exist after TBI.Molecular processes that occur after injury, such as inflammation, can be examined in vivo with PET. These may be particularly important for determining novel interventions.

There are a number of ways to advance the

field,including incorporating additional sources of information(e.g. genotyping, proteomics, etc.), further integrating the results of different imaging modalities, and imaging pre- and post-

tx.Slide39

Summary and ConclusionsfMRI is a powerful tool to examine brain function after TBI, though has not been used extensively yet. While most work to date has focused on working memory and the resting state, future work should be tied to the broader range of clinical phenotypes that exist after TBI.Molecular processes that occur after injury, such as inflammation, can be examined in vivo with PET. These may be particularly important for determining novel interventions.

There are a number of ways to advance the field,including incorporating additional sources of information(e.g. genotyping, proteomics, etc.), further integrating the results of different imaging modalities, and imaging pre- and post-

tx.Slide40

Citations

1.

Bal-Price, A. and G.C. Brown,

Inflammatory neurodegeneration mediated by nitric oxide from activated glia

-inhibiting neuronal respiration, causing glutamate release and excitotoxicity. J Neurosci., 2001. 21(17): p. 6480-91.2. Bhalerao, S.U., et al., Understanding the neuropsychiatric consequences associated with significant traumatic brain injury. Brain Inj, 2013. 27(7-8): p. 767-74. doi: 10.3109/02699052.2013.793396.3. Biswal, B., et al., Functional connectivity in the motor cortex of resting human brain using echo-planar MRI. Magn Reson Med., 1995. 34(4): p. 537-41.4. Butler, T., et al., Imaging inflammation in a patient with epilepsy due to focal cortical dysplasia. J Neuroimaging., 2013. 23(1): p. 129-31. doi

: 10.1111/j.1552-6569.2010.00572.x.

Epub

2011 Jan 11.

5.

Febinger

, H.Y., et al.,

Time-dependent effects of CX3CR1 in a mouse model of mild traumatic brain injury.

J

Neuroinflammation

., 2015.

12

(1): p. 154.

doi

: 10.1186/s12974-015-0386-5.

6. Fischer, B.L., et al.,

Default mode network interference in mild traumatic brain injury - a pilot resting state study.

J

Neurotrauma

., 2014.

31

(2): p. 169-79.

doi

: 10.1089/neu.2013.2877.

Epub 2013 Nov 1.7. Fox, M.D., et al., The human brain is intrinsically organized into dynamic, anticorrelated functional networks.

Proc Natl Acad Sci U S A., 2005. 102(27): p. 9673-8. Epub

2005 Jun 23.8. Gentleman, S.M., et al., Long-term intracerebral inflammatory response after traumatic brain injury. Forensic Sci Int., 2004.

146(2-3): p. 97-104.9. Gillis, M.M. and B.M. Hampstead, Close-range blast exposure is associated with altered functional connectivity in Veterans independent of concussion symptoms at time of exposure. Brain Imaging

Behav, 2014. 7: p. 7.Slide41

Citations

10. Matthews, S.C., et al.,

A multimodal imaging study in U.S. veterans of Operations Iraqi and Enduring Freedom with and without major depression after blast-related concussion.

Neuroimage., 2011. 54

(Suppl 1): p. S69-75. doi: 10.1016/j.neuroimage.2010.04.269. Epub 2010 May 6.11. Nathan, D.E., et al., Imaging brain plasticity after trauma. Brain Connect., 2015. 5(2): p. 102-14. doi: 10.1089/brain.2014.0273. Epub 2014 Dec 22.12. Neumann, D., et al., Cognitive Improvement after Mild Traumatic Brain Injury Measured with Functional Neuroimaging during the Acute Period. Brain Imaging Behav, 2015. 4: p. 4.13. Neumann, D., et al., Neurobiological mechanisms associated with facial affect recognition deficits after traumatic brain injury. Brain Imaging Behav, 2015. 4: p. 4.14. Newsome, M.R., et al., Neurobiological mechanisms associated with facial affect recognition deficits after traumatic brain injury. Neuroimage

Clin

., 2015.

8:543-53.

(

doi

): p. 10.1016/j.nicl.2015.04.024.

eCollection

2015.

15. Protopopescu, X., et al.,

Differential time courses and specificity of

amygdala

activity in posttraumatic stress disorder subjects and normal control subjects.

Biol

Psychiatry., 2005.

57

(5): p. 464-73.

16. Robinson, M.E., et al.,

Exploring variations in functional connectivity of the resting state default mode network in mild traumatic brain injury.

Hum Brain

Mapp

., 2015.

36(3): p. 911-22. doi: 10.1002/hbm.22675. Epub 2014 Nov 4.

17. Root, J.C., et al., Frontolimbic function and cortisol reactivity in response to emotional stimuli. Neuroreport., 2009. 20

(4): p. 429-34. doi: 10.1097/WNR.0b013e328326a031.Slide42

Citations

18.

Sinopoli

, K.J., et al., Imaging "brain strain" in youth athletes with mild traumatic brain injury during dual-task performance. J Neurotrauma

., 2014. 31(22): p. 1843-59. doi: 10.1089/neu.2014.3326. Epub 2014 Sep 11.19. Sinopoli, K.J., et al., Serum Neuron-Specific Enolase Is Related to Cerebellar Connectivity: A Resting-State Functional Magnetic Resonance Imaging Pilot Study. J Neurotrauma., 2014. 31(22): p. 1843-59. doi: 10.1089/neu.2014.3326. Epub 2014 Sep 11.20. Sours, C., et al., Hyper-connectivity of the thalamus during early stages following mild traumatic brain injury. Brain Imaging Behav., 2015. 9(3): p. 550-63. doi: 10.1007/s11682-015-9424-2.21. Sours, C., et al., Chronology and chronicity

of altered resting-state functional connectivity after traumatic brain injury.

Brain Imaging

Behav

., 2015.

9

(2): p. 353-4.

doi

: 10.1007/s11682-014-9310-3.

22. Spielberg, J.M., et al.,

Brain network disturbance related to posttraumatic stress and traumatic brain injury in veterans.

Biol

Psychiatry., 2015.

78

(3): p. 210-6.

doi

: 10.1016/j.biopsych.2015.02.013.

Epub

2015 Feb 18.

23. Tanev, K.S., et al.,

PTSD and TBI co-morbidity: scope, clinical presentation and treatment options.

Brain

Inj

, 2014. 28(3): p. 261-70. doi: 10.3109/02699052.2013.873821.24. Wilde, E.A., et al.,

Advanced neuroimaging applied to veterans and service personnel with traumatic brain injury: state of the art and potential benefits. Brain Imaging Behav, 2015. 8: p. 8.

25. Wylie, G.R., et al., Sex differences in orbitofrontal connectivity in male and female veterans with TBI. PLoS One., 2015. 10(5):

p. e0126110. doi: 10.1371/journal.pone.0126110. eCollection 2015Slide43

AcknowledgementsBWH Functional Neuroimaging Laboratory (FNL)David Silbersweig, MDHong Pan, PhDLorene LeungRachel Cohn

Monica BennettBen CoinerJane Epstein, MDAndrea Field

BWH Psychiatry Neuroimaging Laboratory

Martha Shenton,

PhDMichael ColemanWonderful RAs!

Spaulding RH

Ross Zafonte, DO

BWH Nuclear Medicine

Marie

Kijewksi

,

PhD

Mi-Ae

Park, PhD

Funding :

ForTBI

PET

Neuroinflammation

:

INTRuST

Consortium/DOD

Other current funding

: NIDRR, Epilepsy Foundation, NFL Players Association, Garden Fund, Northeastern University, Gilead Pharmaceutical, Merck Pharmaceutical

BWH Neurology/FNL

Tarun

Singhal

, MDSlide44

Thank you!estern3@partners.ortgwww.functionalneuroimaginglab.orgSlide45