physiologic basis of fmri signals focus on perfusion mri
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Physiologic Basis of fMRI Signals Focus on Perfusion MRI. John A. Detre, M.D. Center for Functional Neuroimaging Cognitive Rehabilitation Research Consortium University of Pennsylvania Moss Rehabilitation Institute Philadelphia, PA. - PowerPoint PPT PresentationTRANSCRIPT
Physiologic Basis of fMRI SignalsFocus on Perfusion MRI
John A. Detre, M.D.John A. Detre, M.D.Center for Functional NeuroimagingCenter for Functional Neuroimaging
Cognitive Rehabilitation Research ConsortiumUniversity of Pennsylvania
Moss Rehabilitation InstitutePhiladelphia, PA
MEG+ERP
OpticalDyes
Single Unit
Patch Clamp
LightMicroscopy
PET
Lesions
2-deoxyglucose
Microlesions
fMRI
Brain
Map
Column
Layer
Neuron
Dendrite
Synapse
Millisecond Second Minute Hour Day
Log Time
Lo
g S
ize
Week
Spatiotemporal Scales for Neuroscience MethodsSpatiotemporal Scales for Neuroscience Methodsadapted from Churchlandadapted from Churchland
Imaging Physiological Correlates of Neural Imaging Physiological Correlates of Neural FunctionFunction
electrical activity- excitatory- inhibitory- soma action potential
metabolic response
- glucose consumption- oxygen consumption
hemodynamic response- blood flow- blood volume- blood oxygenation
FDG PET
H215O PET
fMRIfMRIEEG
MEG
optical imaging
electrophysiology
- ATP tightly regulated
Brain Mapping with fMRIBrain Mapping with fMRI• Hemodynamic/metabolic response used as surrogate Hemodynamic/metabolic response used as surrogate
marker for neural activitymarker for neural activity
• BOLD fMRI signal represents a complex interaction BOLD fMRI signal represents a complex interaction between CBF, CBV, CMRObetween CBF, CBV, CMRO22::
CBF >> CBF >> CMROCMRO22 lessless deoxyhemoglobin with activation deoxyhemoglobin with activation
CBF is monitored CBF is monitored indirectlyindirectly
– ““Tracer” is Tracer” is venousvenous (though T2* effects can extend beyond vein) (though T2* effects can extend beyond vein)
• Both Both magnitudemagnitude and and temporaltemporal patternpattern are modeled in are modeled in fMRI data analysisfMRI data analysis
• Potentially affected by normal physiology, Potentially affected by normal physiology, pathophysiology, pharmacologypathophysiology, pharmacology
Activation-Flow CouplingActivation-Flow Coupling• Blood flow and metabolism changes accompany brain activationBlood flow and metabolism changes accompany brain activation• First described in late 1800’s by Mosso (Italy) and Sherrington (England)First described in late 1800’s by Mosso (Italy) and Sherrington (England)• Physiological basis remains poorly understood todayPhysiological basis remains poorly understood today
Sir Charles Sherrington
Mosso, Atti R. Accad. Lincei 1880 (Italian)
Sherrington and Roy, J. Physiol. 1890
Physiology of Functional ActivationPhysiology of Functional Activation
neuronneuronarteriolearteriole
venulevenule
capillarycapillary
receptorsreceptors
ion channelsion channels
energetics
glucoseglucose
oxygenoxygen
??????
wastewaste
membrane membrane potential & potential & firingfiring
• CBF with task activationCBF with task activation
• Linear with metabolismLinear with metabolism– vs. BOLD (see Hyder)vs. BOLD (see Hyder)
Coupling of CBF, CMRCoupling of CBF, CMRGluGlu, and CMR, and CMRO2O2 during Functional Activationduring Functional Activation
• Uncoupling of CBF, CMRGlu, and CMRO2Uncoupling of CBF, CMRGlu, and CMRO2Fox and Raichle, PNAS 1996Fox and Raichle, PNAS 1996 CBF=CBF=CMRGlu>>CMRGlu>>CMRO2CMRO2
– Predicts reduction in deoxyhemoglobin with activationPredicts reduction in deoxyhemoglobin with activation
• No increase in activated CBF with hypoglycemiaNo increase in activated CBF with hypoglycemiaPowers et al., Am. J. Physiol. 1996Powers et al., Am. J. Physiol. 1996
– Suggests Suggests CBF is not required to supply glucose substrateCBF is not required to supply glucose substrate
• No increase in activated CBF with hypoxiaNo increase in activated CBF with hypoxiaMintun et al., PNAS 2001Mintun et al., PNAS 2001
– Suggests Suggests CBF is not required to supply O2 substrateCBF is not required to supply O2 substrate
BOLDBOLDcontrastcontrast
bloodbloodflowflow
bloodbloodvolumevolume
oxygenoxygenutilizationutilization
structural lesionsstructural lesions(compression)(compression)
autoregulationautoregulation(vasodilation)(vasodilation)
cerebrovascularcerebrovasculardiseasedisease
medicationsmedications
hypoxiahypoxia
anemiaanemia
smokingsmoking
hypercarbiahypercarbia
degenerative degenerative diseasedisease
volume statusvolume status
anesthesia/sleepanesthesia/sleep biophysical effectsbiophysical effects
Potential Physiological Influences on fMRI Signal Potential Physiological Influences on fMRI Signal
• Activation-Flow CouplingActivation-Flow Coupling– Hemodynamic responses used as surrogate marker for neural Hemodynamic responses used as surrogate marker for neural
activity in functional neuroimagingactivity in functional neuroimaging
• Blood Oxygenation Level Dependent (BOLD) fMRIBlood Oxygenation Level Dependent (BOLD) fMRI– represents a complex interaction between CBF, CBV, CMROrepresents a complex interaction between CBF, CBV, CMRO22
– ““Tracer” is Tracer” is venousvenous (though T2* effects can extend beyond vein) (though T2* effects can extend beyond vein) CBF is monitored CBF is monitored indirectlyindirectly
– Qualitative: only differences between conditions can be measuredQualitative: only differences between conditions can be measured
• Arterial spin labeling (ASL) Perfusion MRIArterial spin labeling (ASL) Perfusion MRI– ASL = endogenous flow tracer (analogous to 15O-H2O in PET)ASL = endogenous flow tracer (analogous to 15O-H2O in PET)
– Quantitative: provides CBF in ml/100g/min (classical units)Quantitative: provides CBF in ml/100g/min (classical units)
– Allows both resting CBF and CBF changes to be measuredAllows both resting CBF and CBF changes to be measured
– Harder to implement and has lower SNR compared to BOLDHarder to implement and has lower SNR compared to BOLD
Brain Mapping with fMRI - DefinitionsBrain Mapping with fMRI - Definitions
Direct MRI Measurement of Cerebral Blood FlowDirect MRI Measurement of Cerebral Blood Flowwith Arterial Spin Labeling (ASL)with Arterial Spin Labeling (ASL)
• Uses electromagnetically labeled arterial blood water as an Uses electromagnetically labeled arterial blood water as an endogenous flow tracerendogenous flow tracer
• Provides quantifiable CBF in classical unitsProvides quantifiable CBF in classical units
• Effects of ASL are measured by interleaved subtractive comparison Effects of ASL are measured by interleaved subtractive comparison with control labelingwith control labeling
T1 relaxation
arterialspin labeling
O infusionor inhalation
15
α decay
PET or SPECT Steady State Method
MRI PERFUSION Steady State Method
arteriallabeling
controllabeling
imagingslice
Detre et al., 1992 and ffDetre et al., 1992 and ff
behavior neural function
metabolism
blood flow
BOLD fMRI
biophysics***
ASL CBF MRI
***BOLD contrast includes contributions from biophysical effects such as magnetic field strength homogeneity and orientation of vascular structures.
Physiological Basis of fMRIPhysiological Basis of fMRI
disease
ASL fMRI measures changes in CBF directly, and hence measured signal changes may be more directly coupled to neural activity
ASL orT2*-weighted
SnapshotImage
AverageDifference
Image
StatisticalSignificance
Image
ThresholdedStatistical
Image
Overlay onT1 Anatomic
Image
Brain Activation AnalysisBrain Activation Analysis
TIME SERIESTIME SERIES
TA
SK
TA
SK
fMR
I S
IGN
AL
fMR
I S
IGN
AL
OFFOFF
ONON
fMRI with BOLD ContrastfMRI with BOLD Contrasttask activationtask activation
calcarine cortexcalcarine cortex Broca’s areaBroca’s area Wernicke’s areaWernicke’s area
Photic StimulationPhotic Stimulation Verbal Fluency TaskVerbal Fluency Task
Imaging SliceImaging Slice
Arterial TaggingArterial TaggingPlanePlane
Continuous Adiabatic Continuous Adiabatic Inversion GeometryInversion Geometry
Control Inversion Control Inversion Plane Plane
B F
ield
Gra
die
ntB
Fie
ld G
radi
ent
Perfusion MRI with Arterial Spin LabelingPerfusion MRI with Arterial Spin Labeling
Single SliceSingle SlicePerfusion ImagePerfusion Image(about 1% effect)(about 1% effect)
Control - Label Control - Label
Key Improvements in ASL MRIKey Improvements in ASL MRI• Transit time correctionTransit time correction
– (Alsop and Detre, 1998)(Alsop and Detre, 1998)
• MultisliceMultislice– (Alsop and Detre, 1998)(Alsop and Detre, 1998)
• Background suppressionBackground suppression– (Ye et al., 2000)(Ye et al., 2000)
• High FieldHigh Field– (Wang et al., 2002)(Wang et al., 2002)
• Multicoil/Parallel ImagingMulticoil/Parallel Imaging– (Wang et al, 2005)(Wang et al, 2005)
• Snapshot 3D ImagingSnapshot 3D Imaging– (Duhamel and Alsop, 2004)(Duhamel and Alsop, 2004)– (Fernandez-Seara et al., 2005)(Fernandez-Seara et al., 2005)
• Improved LabelingImproved Labeling– (Garcia et al., 2005)(Garcia et al., 2005)
SNR gains exceeding approaching 1000% over the past decade
Data from David Alsop, BIDC
Perfusion Perfusion fMRIfMRI using ASL using ASL
• Observe CBF changesObserve CBF changes directly directly– CBF changes are more linearly coupled to neural activity than BOLD effectsCBF changes are more linearly coupled to neural activity than BOLD effects
• RestingResting and and activatedactivated CBF in absolute units (ml/g/min) CBF in absolute units (ml/g/min)– Pathological conditions may affect resting CBFPathological conditions may affect resting CBF
• Despite reduced sensitivity vs. BOLD, advantages for:Despite reduced sensitivity vs. BOLD, advantages for:– Spatial resolution (localizes to brain rather than vein)Spatial resolution (localizes to brain rather than vein)
– Low frequency designs (behavioral states)Low frequency designs (behavioral states)
– Group analyses (? reduced intersubject variability)Group analyses (? reduced intersubject variability)
– Regions of high static susceptibility gradient (non-GE EPI)Regions of high static susceptibility gradient (non-GE EPI)
– Statistical advantages (white noise)Statistical advantages (white noise)
Localization of Functional ContrastLocalization of Functional Contrast
Perfusion Activation
BOLD Activation
PerfusionPerfusion
BOLD*BOLD*
*1.5T/Gradient Echo*1.5T/Gradient Echo
drainingdrainingveinvein
Temporal Characteristics of Perfusion fMRITemporal Characteristics of Perfusion fMRI
• Control/Label pair typically every 4-8 secControl/Label pair typically every 4-8 sec– ““Turbo” ASL (Wong) can increase resolution by ~50%Turbo” ASL (Wong) can increase resolution by ~50%
– Qualitative Qualitative CBF (no control) in ~2 secCBF (no control) in ~2 sec
– S:N much lower than BOLD for event-related fMRIS:N much lower than BOLD for event-related fMRI
• Control/Label pair eliminates drift effectsControl/Label pair eliminates drift effects– White noise (instead of 1/f)White noise (instead of 1/f)
– Stable over long durations (learning, behavioral state changes, Stable over long durations (learning, behavioral state changes, pharmacological challenge etc.)pharmacological challenge etc.)
– Sinc subtraction eliminates BOLD derivativeSinc subtraction eliminates BOLD derivative
Perfusion vs. BOLD: Very Low Task FrequencyPerfusion vs. BOLD: Very Low Task FrequencyWang et al., Wang et al., MRMMRM 2002 2002
Onl
y pe
rfus
ion
fMR
I ca
n de
tect
act
ivat
ion
with
O
nly
perf
usio
n fM
RI
can
dete
ct a
ctiv
atio
n w
ith
task
and
con
trol
sep
arat
ed b
y 24
hou
rsta
sk a
nd c
ontr
ol s
epar
ated
by
24 h
ours
ASL Perfusion fMRI vs. BOLDASL Perfusion fMRI vs. BOLDImproved Improved IntersubjectIntersubject Variability vs. BOLD Variability vs. BOLD
Aguirre et al., NeuroImage 2002
Single SubjectSingle Subject Group (Random Effects)Group (Random Effects)
Utility of ASL Perfusion fMRIUtility of ASL Perfusion fMRIin Clinical Researchin Clinical Research
• Quantify CBF in cerebrovascular disordersQuantify CBF in cerebrovascular disorders– Perfusion imaging may reveal “functional” deficits without a structural correlatePerfusion imaging may reveal “functional” deficits without a structural correlate
– Baseline CBF is a critical determinant of the capacity for activation-flow coupling Baseline CBF is a critical determinant of the capacity for activation-flow coupling with a taskwith a task
• Correlate “resting” CBF with cognitive deficits in cohortCorrelate “resting” CBF with cognitive deficits in cohort– Allows functional localization of affected regionsAllows functional localization of affected regions
– Avoids confound of impaired task performance during fMRIAvoids confound of impaired task performance during fMRI
– Avoids need for cognitively impaired subject to perform during fMRIAvoids need for cognitively impaired subject to perform during fMRI
• CBF should be a stable biomarker across space and timeCBF should be a stable biomarker across space and time– Ideal for multisite or longitudinal studiesIdeal for multisite or longitudinal studies
– This advantage has yet to be formally proven in a clinical studyThis advantage has yet to be formally proven in a clinical study
Perfusion MRI in Cerebrovascular DiseasePerfusion MRI in Cerebrovascular DiseaseIntracranial Stenosis with Intracranial Stenosis with BilateralBilateral Cognitive Deficits Cognitive Deficits
Jefferson et al., Jefferson et al., AJNRAJNR 2006 2006
T2-weighted structural MRI:T2-weighted structural MRI:R>L ischemic changesR>L ischemic changes
Preop Perfusion MRI:Preop Perfusion MRI:Bilateral (R>L) hypoperfusionBilateral (R>L) hypoperfusion
L Hemisphere CBF= 27 ml/100g/min*L Hemisphere CBF= 27 ml/100g/min*R Hemisphere CBF= 20 ml/100g/minR Hemisphere CBF= 20 ml/100g/min Normal CBF= 50 ml/100g/minNormal CBF= 50 ml/100g/min
Postop Perfusion MRI:Postop Perfusion MRI:Bilateral increase in perfusionBilateral increase in perfusion
L Hemisphere CBF= 56 ml/100g/minL Hemisphere CBF= 56 ml/100g/minR Hemisphere CBF= 53 ml/100g/minR Hemisphere CBF= 53 ml/100g/min
Perfusion MRI correlated better with cognitive deficits than structural MRI
Cognitive Correlations using Resting Perfusion MRI Cognitive Correlations using Resting Perfusion MRI in Alzeimer’s Dementiain Alzeimer’s Dementia
• 17 Patients with clinical Alzheimer’s Disease17 Patients with clinical Alzheimer’s Disease• Noninvasive perfusion MRI in 5 mm slicesNoninvasive perfusion MRI in 5 mm slices• Correlation of CBF with cognitive performance on:Correlation of CBF with cognitive performance on:
– Semantic Category Membership JudgmentSemantic Category Membership Judgment– Confrontation Naming Confrontation Naming – Semantically-guided Category Naming FluencySemantically-guided Category Naming Fluency– Sentence ComprehensionSentence Comprehension
SEMANTIC CATEGORY SEMANTIC CATEGORY MEMEBERSHIP JUDGEMENTMEMEBERSHIP JUDGEMENT
CONFRONTATION NAMINGCONFRONTATION NAMING SEMANTICALLY-GUIDED SEMANTICALLY-GUIDED CATEGORY NAMING FLUENCYCATEGORY NAMING FLUENCY
SENTENCE SENTENCE COMPREHENSIONCOMPREHENSION
RAW PERFUSION DATARAW PERFUSION DATA
This approach to localization of dysfunction also avoids having patient perform a task during MRI
Dissociation of Activation-Flow CouplingDissociation of Activation-Flow CouplingPatient with Left Intracranial Carotid StenosisPatient with Left Intracranial Carotid Stenosis
BOLD fMRIBOLD fMRI Perfusion MRIPerfusion MRI
Markedly decreased Markedly decreased left hemispheric left hemispheric perfusion at restperfusion at rest
Lack of left hemispheric activation during motor task most likely reflects low resting CBF rather than any
reorganization of neural function
Considerations in Task-Activation fMRIConsiderations in Task-Activation fMRI(Summary)(Summary)
hemodynamic change
RR & HR
pathophysiology
noisephysics
pathologyneural function
fMRI signal
behavior &performance
motion
diagnostic fMRI
Neuroscience fMRI
clinical fMRI
ConclusionsConclusions• FMRI is measures neural activity FMRI is measures neural activity indirectlyindirectly
– BOLD qualitatively reflects CBF and metabolismBOLD qualitatively reflects CBF and metabolism– ASL quantitatively reflect CBFASL quantitatively reflect CBF
• Clinical FMRI poses special challengesClinical FMRI poses special challenges– Task performance effects must be consideredTask performance effects must be considered– Underlying pathophysiology may alter coupling of activation and flowUnderlying pathophysiology may alter coupling of activation and flow
• FMRI identifies FMRI identifies putativeputative regions supporting task function regions supporting task function– Does not establish necessityDoes not establish necessity– Correlation with outcome, lesions, or TMS lesions can disambiguateCorrelation with outcome, lesions, or TMS lesions can disambiguate
• Many fMRI applications in neurorehabilitationMany fMRI applications in neurorehabilitation– Mechanisms of neuroplasticityMechanisms of neuroplasticity– Biomarker for therapyBiomarker for therapy– Prediction of outcomePrediction of outcome– Bionic interfacesBionic interfaces