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
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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
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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