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

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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

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ntB

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radi

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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

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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