Imaging Cognitive States and Traits Imaging Cognitive States and Traits with BOLD and Perfusion fMRIwith BOLD and Perfusion fMRI

John A. Detre, M.D.John A. Detre, M.D.

Director, Center for Functional NeuroimagingDirector, Center for Functional Neuroimaging

University of PennsylvaniaUniversity of Pennsylvania

NeuroimagingNeuroimaging

• Allows noninvasive assessment of brain Allows noninvasive assessment of brain structure and functionstructure and function

• Is the primary means of assessing regional Is the primary means of assessing regional brain function in humansbrain function in humans

• Provides a critical link between animal Provides a critical link between animal models and human brainmodels and human brain

• Complements lesion-based inferences on Complements lesion-based inferences on brain-behavior correlationsbrain-behavior correlations

Imaging is Critical for Human Brain ResearchImaging is Critical for Human Brain Research

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Some Guy

Physiology of Functional ActivationPhysiology of Functional Activation

Magistretti, Brain Res. 2000

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PET CBF, CMRPET CBF, CMRGluGlu, and CMRO, and CMRO22 during Activation during ActivationFox and Raichle, Fox and Raichle, PNASPNAS 1986 1986

• Increase in CBF and CMRIncrease in CBF and CMRGluGlu with minimal change in CMRO with minimal change in CMRO22

• Suggests uncoupling of oxidative metabolism during activationSuggests uncoupling of oxidative metabolism during activation

Magnetic Resonance (Magnetic Resonance (11H)H)

structurestructure

fiber tractsfiber tracts

task activationtask activation

blood flowblood flow

metabolitesmetabolites

++ ++

++

==

Brain Mapping with fMRIBrain Mapping with fMRI

• Noninvasive; Ideal for serial studiesNoninvasive; Ideal for serial studies

• Comparatively inexpensive, widely availableComparatively inexpensive, widely available

• Time-series data provides improved sensitivity within Time-series data provides improved sensitivity within individual subjects (vs. PET pseudosubject)individual subjects (vs. PET pseudosubject)

• Group sensitivity (Random Effects Model) similar to PETGroup sensitivity (Random Effects Model) similar to PET

• Fundamentally correlative (does not prove necessity or Fundamentally correlative (does not prove necessity or sufficiency)sufficiency)

• Hemodynamic/metabolic response used as surrogate Hemodynamic/metabolic response used as surrogate marker for neural activity (same as PET) marker for neural activity (same as PET)

Contrast Mechanisms for fMRIContrast Mechanisms for fMRI• Blood Oxygenation Level Dependent (Blood Oxygenation Level Dependent (BOLDBOLD) fMRI) fMRI

– represents a complex interaction between CBF, CBV, CMROrepresents a complex interaction between CBF, CBV, CMRO22

CBF >> CBF >> CMROCMRO22 lessless deoxyhemoglobin with activation deoxyhemoglobin with activation

– Qualitative: only differences between conditions can be measuredQualitative: only differences between conditions can be measured

• Arterial spin labeling (Arterial spin labeling (ASLASL) provides an endogenous flow ) provides an endogenous flow tracer for perfusion MRItracer for perfusion MRI• Directly analogous to Directly analogous to 1515O-HO-H22O in PETO in PET

– Allow both resting CBF and CBF changes to be measured Allow both resting CBF and CBF changes to be measured

– Quantitative: provides CBF in ml/100g/minQuantitative: provides CBF in ml/100g/min

– CBF obtained by modeling image intensity with and without ASLCBF obtained by modeling image intensity with and without ASL CBF changes may be better localized than BOLDCBF changes may be better localized than BOLD CBF changes may be more linearly coupled with neural activity than BOLDCBF changes may be more linearly coupled with neural activity than BOLD ASL/Control scheme yields “white” noise, provides temporal stability and ASL/Control scheme yields “white” noise, provides temporal stability and

other benefitsother benefits

T2*-weightedSnapshot

Image

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

Perfusion MRI with Arterial Spin Labeling (ASL)Perfusion MRI with Arterial Spin Labeling (ASL)

• Uses magnetically labeled Uses magnetically labeled arterial blood water as an arterial blood water as an endogenous flow tracerendogenous flow tracer

• Provides quantifiable CBF in Provides quantifiable CBF in classical units (ml/g/min)classical units (ml/g/min)

• Effects of ASL are measured by Effects of ASL are measured by interleaved subtractive interleaved subtractive comparison with control labelingcomparison with control labeling

• ASL effects can be measured ASL effects can be measured with any imaging sequencewith any imaging sequence

• CBF calculated using model CBF calculated using model (diffusible tracer)(diffusible tracer)

T1 relaxation

arterial spin labeling

O infusion

or inhalation

15

decay

PET or SPECT Steady State Method

MRI PERFUSION Steady State Method

• Requires tracer with decay Requires tracer with decay (such as 15-O for PET) (such as 15-O for PET)

Perfusion in the Steady StatePerfusion in the Steady Statefrom J.H. Wood (ed.) Cerebral Blood Flowfrom J.H. Wood (ed.) Cerebral Blood Flow

dCt/dt = F.Ca - F.Cv - Ct

dCt/dt = F.Ca - F.Ct/ - Ct = 0

f= /(Ca/Ct - 1/)

f = T1app

. Mb

0 - Mbss

2 Mb0

dMb

dt=

Mb0-Mb

T1+ fMa - fMv

dMbdt

= Mb

0-Mb

T1 + fMa - f

Mb

Quantification of regional CBF with ASL• Requires a model for determining CBF from measured signals• Other key parameters are T1blood, T1brain, arterial transit time,

– Some models also require (blood:brain partition coefficient)

• Single compartment model (Detre 1992)– Assumes ASL in well-mixed equilibrium with brain (Kety-Schmidt)

• Two compartment model (Alsop 1996)– Includes arterial blood water compartment with arterial transit time

• Modified two compartment model (Chalela 2000)– *Assumes labeled spins remain in vasculature (relax with T1blood)

• Three compartment model (Parkes 2002)– Includes limited diffusion and venous component

• Identical results with kinetic model (Buxton 1998)• Microsphere analogy (Buxton 2005)

– Emphasizes rapid tracer decay

ASL in Human Brain: 2 Comparment ModelASL in Human Brain: 2 Comparment Model

• Flow is exponentially dependent on transit timeFlow is exponentially dependent on transit time• Transit times in human brain are comparable to T1Transit times in human brain are comparable to T1• Postlabeling delay allows labeled water to reach tissuePostlabeling delay allows labeled water to reach tissue

arterial spin tagging imaging

TR TE

delay

Alsop and Detre, JCBFM 1996Alsop and Detre, JCBFM 1996Roberts et al., PNAS 1994Roberts et al., PNAS 1994

Wiliams et al., PNAS 1992Wiliams et al., PNAS 1992

Rat Brain

Human Brain

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 LabelingDetre et al., Detre et al., Magn. Reson. Med.Magn. Reson. Med. 1992 and ff 1992 and ff

Single SliceSingle SlicePerfusion ImagePerfusion Imageabout 1% effectabout 1% effect

Control - Label Control - Label

CBF in “classical” units of ml/100g/minCBF in “classical” units of ml/100g/min

1515O-PET Validation of CASL (2 compartment)O-PET Validation of CASL (2 compartment)Ye et al., Magn Reson Med 2000Ye et al., Magn Reson Med 2000

CASLCASL PETPET

Key Technical Advances in ASLKey Technical Advances in ASL• Initial demonstration of ASL (pseudocontinuous saturation in rat)Initial demonstration of ASL (pseudocontinuous saturation in rat)

– Detre et al., MRM 1992Detre et al., MRM 1992

• Continuous inversion ASL (velocity driven adiabatic inversion=CASL)Continuous inversion ASL (velocity driven adiabatic inversion=CASL)– Williams et al., PNAS 1992Williams et al., PNAS 1992

• Human ASL (single slice CASL)Human ASL (single slice CASL)– Roberts et al., PNAS 1994Roberts et al., PNAS 1994

• Transit time correction (postlabeling delay)Transit time correction (postlabeling delay)– Alsop and Detre, JBCFM 1998Alsop and Detre, JBCFM 1998

• Multislice (amplitude modulated control inversion)Multislice (amplitude modulated control inversion)– Alsop and Detre, Radiology 1998Alsop and Detre, Radiology 1998

• Background suppression (nulling static signal)Background suppression (nulling static signal)– Ye et al., MRM 2000Ye et al., MRM 2000

• High Field Benefits - T1 and SNR (1.5T vs. 4T)High Field Benefits - T1 and SNR (1.5T vs. 4T)– Wang et al., MRM 2002Wang et al., MRM 2002– Wang et. Al., Radiology 2004Wang et. Al., Radiology 2004

• Multicoil/Parallel Imaging (hybrid coil)Multicoil/Parallel Imaging (hybrid coil)– Wang et al, MRM 2005Wang et al, MRM 2005

• Snapshot 3D Imaging (FSE and GRASE)Snapshot 3D Imaging (FSE and GRASE)– Duhamel and Alsop, ISMRM abstracts 2004Duhamel and Alsop, ISMRM abstracts 2004– Fernandez-Seara et al., MRM 2005Fernandez-Seara et al., MRM 2005

• Improved Labeling (Pseudocontinuous ASL)Improved Labeling (Pseudocontinuous ASL)– Garcia et al., ISMRM abstracts 2005Garcia et al., ISMRM abstracts 2005

• Total ~10X SNR Gains over the past decadeTotal ~10X SNR Gains over the past decade

behavior neural function

metabolism

blood flow

biophysics***

***site/scan effects

Physiological Basis of fMRIPhysiological Basis of fMRI

disease

blood volume

BOLD fMRIBOLD fMRIASL MRIASL MRI

ASL vs. BOLDASL vs. BOLDLocalization of Functional ContrastLocalization of Functional Contrast

Perfusion Activation

BOLD Activation

PerfusionPerfusion

BOLDBOLD

Cortical Localization; Rat Forepaw StimulationDuong et al., Magn. Reson. Med., 2000

MnMn++++

BOLDBOLD

CBFCBF

OVERLAPOVERLAP

BOLD-CBFBOLD-CBF BOLD-MnBOLD-Mn++++ CBF-MnCBF-Mn++++ 11221122

Temporal Characteristics of Perfusion fMRI

• Control/Label pair typically every 4-8 sec– “Turbo” ASL (Wong) can increase resolution by ~50%

– Qualitative CBF (no control) in ~2 sec

– S:N much lower than BOLD for event-related fMRI

• Control/Label pair eliminates drift effects– White noise (instead of 1/f)

– Stable over long durations (learning, behavioral state changes, pharmacological challenge etc.)

– Sinc subtraction eliminates BOLD derivative

Event-Related ASL• Event-related ASL possible

– e.g. Yang NeuroImage 2000 and ff

• Nominally less sensitive than BOLD– However, CBF>> BOLD signal

– BS-ASL provides improved sensitivity

• Temporal resolution lower than BOLD– Can use label-only for CBF

– Can use “turbo” ASL (Wong) for limited slice coverage

• Activation peaks faster than BOLD– Demonstrated with jittered acquisition

– Consistent with capillary/tissue sensitivityfrom Huppert et al., NeuroImage 2006

perfusion

freq (Hz)

0 0.025 0.05 0.075 0.1 0.125

0.15

0.1

0.05

0

norm

aliz

ed p

ower

Observed power spectra

BOLD

perfusion fMRI observations are independent in time

BOLD vs. ASL: Noise SpectraAguirre, NeuroImage 2002

perfusion fMRI is superior to BOLD for detecting neural activity that evolves over 60 seconds or greater

freq (Hz)0 0.025 0.05 0.075 0.1 0.125

12

10

8

6

4

2

0

delta

val

ue

BOLD

Statistical power as a function offrequency of experimental design

perfusion

Concurrent ASL and BOLDConcurrent ASL and BOLDWong et al., NMR Biomed 1997 and ffWong et al., NMR Biomed 1997 and ff

• ASL with GE EPIASL with GE EPI– Control-tag=CBFControl-tag=CBF– Control+tag=BOLDControl+tag=BOLD

Perfusion vs. BOLD: Very Low Task FrequencyWang et al., MRM 2002

24 hr24 hr

ASLASL

ASL Perfusion fMRI vs. BOLDImproved Intersubject Variability vs. BOLD

Single SubjectSingle Subject Group (Random Effects)Group (Random Effects)

Aguirre et al., NeuroImage 2002

ASL fMRI of Motor LearningOlson et al., Brain and Cognition 2005

fixation1 sequence learning transfer fixation2

2.5min 15min 5min 2.5min

• Motor sequence learning (SRT)Motor sequence learning (SRT)• N=10, 3 X 25 min runs/subjectN=10, 3 X 25 min runs/subject

Right superior temporal Right inferior parietal

Right premotor

Developmental Changes in CBFDevelopmental Changes in CBFWang et al., JMRI 2003 and ffWang et al., JMRI 2003 and ff

Mean CBF images for:•child group (age 5-10, n=31)

•adolescent group (age 11-16, n=33)•young adult group (age 18-30, n=26)

Age-related regional CBF changes in cingulate, angular, hippocampus,

and frontal cortex.

A multicenter, longitudinal and cross-sectional study of ages 7-16 was recently funded

ASL Perfusion of Psychological StressWang et al., PNAS 2005

• 25 Subjects25 Subjects

• 4 x 8min CASL perfusion scans:4 x 8min CASL perfusion scans:1.1. RestRest

2.2. Low stress (Counting backward)Low stress (Counting backward)

3.3. High stress (Serial subtraction by 13)High stress (Serial subtraction by 13)

4.4. RestRest

• Self rating of stress, anxiety and Self rating of stress, anxiety and salivary cortisol with each scansalivary cortisol with each scan

• Heart rate continuously recordedHeart rate continuously recorded

Correlation of CBF and Perceived Stress: RPFC

Wang et al., Soc Cog Affect Neurosci 2007

Imaging Genotype: 5-HTTLPRImaging Genotype: 5-HTTLPRHariri et al., Science 2002Hariri et al., Science 2002

• Allelic variations in serotonin transporter genes are associated with anxiety-Allelic variations in serotonin transporter genes are associated with anxiety-related traits and risk of depression (short allele carries greater risk)related traits and risk of depression (short allele carries greater risk)

• BOLD fMRI demonstrates that carriers of BOLD fMRI demonstrates that carriers of ss allele (vs. l/l) show greater amygdala allele (vs. l/l) show greater amygdala activation in response to fearful facesactivation in response to fearful faces

Resting Brain Function vs.5-HTTLPR GenotypeRao et al., Biol Psychiatry 2007

• N=26 healthy volunteersN=26 healthy volunteers• rCBF vs. 5-HTTLRP GenotyperCBF vs. 5-HTTLRP Genotype

fMRI Studies of the Neural Substrate for RiskfMRI Studies of the Neural Substrate for Risk

• Risk is a ubiquitous phenomenonRisk is a ubiquitous phenomenon

– Risk may be assumed or environmentalRisk may be assumed or environmental

• Some amount of risk-taking is likely beneficial to Some amount of risk-taking is likely beneficial to advancementadvancement

– Excessive risk-taking may underlie impulse-control Excessive risk-taking may underlie impulse-control disorders such as drug abuse and gamblingdisorders such as drug abuse and gambling

• Behavioral economics is a “hot” area in social Behavioral economics is a “hot” area in social neurobiology that considers human decision-neurobiology that considers human decision-making according to principles of risk and reward.making according to principles of risk and reward.

A screen shot of BART.

Balloon Analog Risk Task (BART)Lejuez et al., J Exp Psychol Appl 2002

• Developed as a behavioral index to predict risky behaviors

- Correlates with real-world risky behavior e.g. smoking, seat belt use etc.

• Participants are told to press the “pump” button to inflate the balloon.

• The balloon will explode at some point (between 1st – fill the screen, e.g., 128th).

• Typically 30 balloons

• Participants earn 5¢ per pump placed to a temporary bank.

• If balloon explode, participants lose all money in temporary bank

• Participants hit collect button to earn the money in temporary bank

• Participants were paid an amount proportional to what they earn

fMRI BART

Pump

End with explosion -- lose

End without explosion -- win

Pump

End with explosion -- lose

End without explosion -- win

Wager: XXX Total: XXX

• Modified for fMRI with improved graphics, reduced trials, increasing Modified for fMRI with improved graphics, reduced trials, increasing risk/rewardrisk/reward

• Active and passive modesActive and passive modes

• Can segregate trial effects from risk/reward covariateCan segregate trial effects from risk/reward covariate

Neural Correlates on Voluntary and Involuntary RiskRao et al;., Neuroimage 2008

Neural Correlates of Individual Differences in Risk Tolerance

R L

Resting CBF Predicts Risk ToleranceResting CBF Predicts Risk Tolerance

• N=12 healthy controls (of 14 studied for fMRI)N=12 healthy controls (of 14 studied for fMRI)• pCASL acquired prior to fMRI taskpCASL acquired prior to fMRI task

15 young, healthy right-handed adults 15 young, healthy right-handed adults (23 ± 4 years, 8 male) (23 ± 4 years, 8 male)

Pseudo-continuous ASL with TR = 4 Pseudo-continuous ASL with TR = 4 s, labeling time = 1.8 s, post-labeling s, labeling time = 1.8 s, post-labeling delay = 1 sdelay = 1 s

20 min PVT flanked by 5 min rest20 min PVT flanked by 5 min rest Visual analog ratings of subjective Visual analog ratings of subjective

fatigue prior to and immediately after fatigue prior to and immediately after the PVT scanthe PVT scan

rest1 rest220 m PVT4m 4m

Example of quantitative CBF Example of quantitative CBF image from one subjectimage from one subject

ASL fMRI: Pyschomotor Vigilance TaskASL fMRI: Pyschomotor Vigilance TaskRao et al., ISMRM 2008Rao et al., ISMRM 2008

Behavioral Results

• Significant TOT effects were observed during the PVT:Significant TOT effects were observed during the PVT:

• Mental fatigue (MF) scores increased from 3.7 before the task to Mental fatigue (MF) scores increased from 3.7 before the task to

5.1 after the task (36% change; p < 0.001)5.1 after the task (36% change; p < 0.001)

• Reaction times increased from 284ms for the first 10min to 302 ms Reaction times increased from 284ms for the first 10min to 302 ms

for the second 10 min (6.3%; p = 0.002) for the second 10 min (6.3%; p = 0.002)

MF Score

0

2

4

6

8

Pre-task Post-task

RT (ms)

250

300

350

0-10min 10-20min

Mean RT (ms)

250

275

300

325

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

Time on Task (min)

MRI Results: Regional CBF Changes PVT vs. Rest

PVT vs. Rest (FDR p < 0.05)PVT vs. Rest (FDR p < 0.05)

A right parietal-cingulate-frontal A right parietal-cingulate-frontal network, the left sensorimotor network, the left sensorimotor

cortex, and bilateral basal ganglia cortex, and bilateral basal ganglia were activated by the PVT task.were activated by the PVT task.

PVT vs. Rest

-5

0

5

10

15

ACC IPL MFC Tha

CB

F(%

)

Regional CBF: Predictors of RT Change

Thalamus Activity

-505

101520

-20 0 20 40

CBF% (PVT-Rest)

RT

%

ACC Activity

-505

101520

0 5 10 15 20 25

CBF% (PVT-Rest)

RT

%

During PVT, regional CBF changes (CBF%) in thalamus and ACC During PVT, regional CBF changes (CBF%) in thalamus and ACC correlated with the performance decline (RT%)correlated with the performance decline (RT%)

r = 0.67, p = 0.009 r = 0.56, p = 0.04

MRI Results: Post-task rest vs. Pre-task rest

The parietal-cingulate-frontal network was The parietal-cingulate-frontal network was deactivated after prolonged PVT task, and the deactivated after prolonged PVT task, and the

deactivations correlated with RT%.deactivations correlated with RT%.

ACC Activity

-505

101520

-40 -20 0 20

CBF%

RT

%

R_IPL Activity

-505

101520

-20 -10 0 10 20

CBF%

RT

%

r = -0.74, p = 0.002

r = -0.66, p = 0.01

R_MFC Activity

-505

101520

-25 -20 -15 -10 -5 0 5

CBF% (Rest2-Rest1)

RT

%

r = -0.59, p = 0.03

Regional CBF at Baseline: Predictors of RT(Brain State/Phenotype)

Thalamus Activity

-505

101520

0.8 1 1.2 1.4

rCBF

RT

%

R_MFC Activity

-505

101520

1 1.2 1.4 1.6

rCBF

RT

%

Before the PVT task, regional CBF activity (normalized to global Before the PVT task, regional CBF activity (normalized to global CBF) in thalamus and right MFC predicted the subsequent CBF) in thalamus and right MFC predicted the subsequent performance decline (RT%).performance decline (RT%).

r = -0.59, p = 0.03 r = 0.68, p = 0.008

ASL CBF as a Biomarker of Brain Function

• Can measure “function” during rest, state, or task– Can measure cognitive, affective, or pharmacological state

– Also shows correlations with genotype/phenotype (traits)

– Complementary to BOLD fMRI studies of “events”

• Quantifies a biological parameter (CBF)– CBF coupled to neural activity (both magnitude and location)

– CBF is better localized than BOLD (so far only for animal studies)

– Theoretically insensitive to scanning parameters, scanner platform, and field strength - should be ideal for multisite or longitudinal studies

• Future Directions– Optimization of the “resting” state

– Ultra-high field ASL to improve sensitivity

Functional Imaging TimescalesComplementary Utility of BOLD and ASL

100 msec100 msec 10 sec10 sec 1 hr1 hr 1 day1 day

EVENTEVENT BLOCKBLOCK BEHAVIORAL STATEBEHAVIORAL STATE TRAITTRAIT

BOLD fMRIBOLD fMRI ASL fMRIASL fMRI

FDG-PETFDG-PET1515O-PETO-PET

log timelog time

• BOLD fMRI optimal for events and short blocks (< few min)– Unable to characterize states except as manifested in event/block activation

• ASL fMRI optimal for behavioral ‘states’ or stable ‘traits’– Independent of biophysical effects - should be stable across time, platform– Less well suited to characterizing events due to lower SNR

““Brainomics”Brainomics”

Gene Chip ArrayGene Chip Array

A Priori Knowledge ofA Priori Knowledge of Local and Distributed Local and Distributed

NetworksNetworks

• Richness of neuroimaging data allow brain-Richness of neuroimaging data allow brain-behavior correlations to be detected through behavior correlations to be detected through statistical analysis without a hypothesisstatistical analysis without a hypothesis– Can examine structure and/or functionCan examine structure and/or function– ASL provides ideal functional modality for this – ASL provides ideal functional modality for this –

not constrained by tasknot constrained by task

• Analogous to approach used in molecular Analogous to approach used in molecular biology to find gene/function or gene/disorder biology to find gene/function or gene/disorder correlationscorrelations– For brain imaging data, added benefit of For brain imaging data, added benefit of

meaningful spatial organizationmeaningful spatial organization