Transcript BOLD and FAIR MRI with CO2 and Visual Stimuli Hoge et al

Imaging Cognitive States and Traits
with BOLD and Perfusion fMRI
John A. Detre, M.D.
Director, Center for Functional Neuroimaging
University of Pennsylvania
Neuroimaging
• Allows noninvasive assessment of brain
structure and function
• Is the primary means of assessing regional
brain function in humans
• Provides a critical link between animal
models and human brain
• Complements lesion-based inferences on
brain-behavior correlations
Imaging is Critical for Human Brain Research
?
Some Guy
Physiology of Functional Activation
???
Magistretti, Brain Res. 2000
PET CBF, CMRGlu, and CMRO2 during Activation
Fox and Raichle, PNAS 1986
• Increase in CBF and CMRGlu with minimal change in CMRO2
• Suggests uncoupling of oxidative metabolism during activation
Magnetic Resonance (1H)
+
+
=
+
structure
fiber tracts
blood flow
task activation
metabolites
Brain Mapping with fMRI
• Noninvasive; Ideal for serial studies
• Comparatively inexpensive, widely available
• Time-series data provides improved sensitivity within
individual subjects (vs. PET pseudosubject)
• Group sensitivity (Random Effects Model) similar to PET
• Fundamentally correlative (does not prove necessity or
sufficiency)
• Hemodynamic/metabolic response used as surrogate
marker for neural activity (same as PET)
Contrast Mechanisms for fMRI
• Blood Oxygenation Level Dependent (BOLD) fMRI
– represents a complex interaction between CBF, CBV, CMRO2
– CBF >> CMRO2  less deoxyhemoglobin with activation
– Qualitative: only differences between conditions can be measured
• Arterial spin labeling (ASL) provides an endogenous flow
tracer for perfusion MRI
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Directly analogous to 15O-H2O in PET
Allow both resting CBF and CBF changes to be measured
Quantitative: provides CBF in ml/100g/min
CBF obtained by modeling image intensity with and without ASL
 CBF changes may be better localized than BOLD
 CBF changes may be more linearly coupled with neural activity than BOLD
 ASL/Control scheme yields “white” noise, provides temporal stability and
other benefits
Brain Activation Analysis
fMRI SIGNAL
TIME SERIES
TASK
T2*-weighted Average
Snapshot Difference
Image
Image
ON
OFF
Statistical Thresholded Overlay on
Significance Statistical T1 Anatomic
Image
Image
Image
FMRI with BOLD Contrast
task activation
Photic Stimulation
calcarine cortex
Verbal Fluency Task
Broca’s area
Wernicke’s area
Perfusion MRI with Arterial Spin Labeling (ASL)
• Uses magnetically labeled
arterial blood water as an
endogenous flow tracer
• Provides quantifiable CBF in
classical units (ml/g/min)
• Effects of ASL are measured
by interleaved subtractive
comparison with control
labeling
• ASL effects can be
measured with any imaging
sequence
• CBF calculated using model
(diffusible tracer)
MRI PERFUSION
Ste ady State M e thod
PET or SPECT
Ste ady State M e thod
 de cay
arte r ial
s pin labe ling
15 O infus ion
or inhalation
T1 r e laxation
Perfusion in the Steady State
from J.H. Wood (ed.) Cerebral Blood Flow
• Requires tracer with decay  (such as 15-O for PET)
0
dCt/dt = F.Ca - F.Cv - Ct
dCt/dt =
F.Ca -
F.Ct/
- Ct = 0
f= /(Ca/Ct - 1/)
dM b M b-M b
=
+ fM a - fM v
dt
T1
dMb M0b -Mb
=
+ fMa - f Mb
dt
T1

M0b - Mssb
f=  .
T1app 2 M0
b
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 Model
Rat Brain
• Flow is exponentially dependent on transit time
• Transit times in human brain are comparable to T1
• Postlabeling delay allows labeled water to reach tissue
TE
TR
arter ial spin tagging
delay
im aging
Wiliams et al., PNAS 1992
Human Brain
Roberts et al., PNAS 1994
Alsop and Detre, JCBFM 1996
Perfusion MRI with Arterial Spin Labeling
Detre et al., Magn. Reson. Med. 1992 and ff
Control - Label
B Field Gradient
Control Inversion
Plane
Imaging Slice
Arterial Tagging
Plane
Continuous Adiabatic
Inversion Geometry
Single Slice
Perfusion Image
about 1% effect
CBF in “classical” units of ml/100g/min
15O-PET
Validation of CASL (2 compartment)
Ye et al., Magn Reson Med 2000
CASL
PET
Key Technical Advances in ASL
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Initial demonstration of ASL (pseudocontinuous saturation in rat)
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Continuous inversion ASL (velocity driven adiabatic inversion=CASL)
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Wang et al, MRM 2005
Snapshot 3D Imaging (FSE and GRASE)
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Wang et al., MRM 2002
Wang et. Al., Radiology 2004
Multicoil/Parallel Imaging (hybrid coil)
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Ye et al., MRM 2000
High Field Benefits - T1 and SNR (1.5T vs. 4T)
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Alsop and Detre, Radiology 1998
Background suppression (nulling static signal)
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Alsop and Detre, JBCFM 1998
Multislice (amplitude modulated control inversion)
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Roberts et al., PNAS 1994
Transit time correction (postlabeling delay)
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Williams et al., PNAS 1992
Human ASL (single slice CASL)
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•
Detre et al., MRM 1992
Duhamel and Alsop, ISMRM abstracts 2004
Fernandez-Seara et al., MRM 2005
Improved Labeling (Pseudocontinuous ASL)
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Garcia et al., ISMRM abstracts 2005
• Total ~10X SNR Gains over the past decade
Physiological Basis of fMRI
behavior
neural function
disease
biophysics***
BOLD fMRI
metabolism
ASL MRI
blood volume
blood flow
***site/scan effects
ASL vs. BOLD
Localization of Functional Contrast
Perfusion
Perfusion Activation
BOLD Activation
BOLD
Cortical Localization; Rat Forepaw Stimulation
Duong et al., Magn. Reson. Med., 2000
Mn++
BOLD
CBF
BOLD-CBF
OVERLAP
BOLDMn++
CBF-Mn++
1
2
12
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 sensitivity
from Huppert et al., NeuroImage 2006
BOLD vs. ASL: Noise Spectra
Aguirre, NeuroImage 2002
Statistical power as a function of
Observed power spectra
frequency of experimental design
normalized power
delta value
12
0.15
10
BOLD
perfusion
8
BOLD
perfusion
0.1
6
perfusion fMRI is
superior to BOLD
perfusion fMRI
for detecting
observations are
neural activity that
independent in time
evolves over 60
seconds or greater
4
0.05
2
0
000
0.025
0.025
0.05
0.05
0.075
0.075
freq(Hz)
(Hz)
freq
0.1
0.1
0.125
0.125
Concurrent ASL and BOLD
Wong et al., NMR Biomed 1997 and ff
• ASL with GE EPI
– Control-tag=CBF
– Control+tag=BOLD
Perfusion vs. BOLD: Very Low Task Frequency
Wang et al., MRM 2002
ASL
24 hr
ASL Perfusion fMRI vs. BOLD
Improved Intersubject Variability vs. BOLD
Single Subject
Group (Random Effects)
Aguirre et al., NeuroImage 2002
ASL fMRI of Motor Learning
Olson et al., Brain and Cognition 2005
Right premotor
Right inferior parietal
• Motor sequence learning (SRT)
• N=10, 3 X 25 min runs/subject
Right superior temporal
fixation1
2.5min
sequence learning
15min
2.5min
transfer
fixation2
5min
Developmental Changes in CBF
Wang 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 Stress
Wang et al., PNAS 2005
• 25 Subjects
• 4 x 8min CASL perfusion scans:
1.
2.
3.
4.
Rest
Low stress (Counting backward)
High stress (Serial subtraction by 13)
Rest
• Self rating of stress, anxiety and
salivary cortisol with each scan
• Heart rate continuously recorded
Correlation of CBF and Perceived Stress: RPFC
Wang et al., Soc Cog Affect Neurosci 2007
Imaging Genotype: 5-HTTLPR
Hariri et al., Science 2002
• Allelic variations in serotonin transporter genes are associated with anxietyrelated traits and risk of depression (short allele carries greater risk)
• BOLD fMRI demonstrates that carriers of s allele (vs. l/l) show greater amygdala
activation in response to fearful faces
Resting Brain Function vs.5-HTTLPR Genotype
Rao et al., Biol Psychiatry 2007
• N=26 healthy volunteers
• rCBF vs. 5-HTTLRP Genotype
fMRI Studies of the Neural Substrate for Risk
• Risk is a ubiquitous phenomenon
– Risk may be assumed or environmental
• Some amount of risk-taking is likely beneficial to
advancement
– Excessive risk-taking may underlie impulse-control
disorders such as drug abuse and gambling
• Behavioral economics is a “hot” area in social
neurobiology that considers human decisionmaking according to principles of risk and
reward.
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
A screen shot of BART.
fMRI BART
Pump
End with explosion -- lose
Pump
End without explosion -- win
End with explosion -- lose
Wager: XXX
Total: XXX
End without explosion -- win
• Modified for fMRI with improved graphics, reduced trials, increasing
risk/reward
• Active and passive modes
• Can segregate trial effects from risk/reward covariate
Neural Correlates on Voluntary and Involuntary Risk
Rao et al;., Neuroimage 2008
Neural Correlates of Individual Differences in Risk Tolerance
R
L
Resting CBF Predicts Risk Tolerance
• N=12 healthy controls (of 14 studied for fMRI)
• pCASL acquired prior to fMRI task
ASL fMRI: Pyschomotor Vigilance Task
Rao et al., ISMRM 2008
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15 young, healthy right-handed adults
(23 ± 4 years, 8 male)
Pseudo-continuous ASL with TR = 4 s,
labeling time = 1.8 s, post-labeling
delay = 1 s
20 min PVT flanked by 5 min rest
Visual analog ratings of subjective
fatigue prior to and immediately after
the PVT scan
20 m PVT
4m
rest1
4m
rest2
Example of quantitative CBF
image from one subject
Behavioral Results
MF Score
RT (ms)
Mean RT (ms)
8
325
6
300
350
300
4
275
2
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
Pre-task
•
250
250
0
Post-task
Time on Task (min)
0-10min
10-20min
Significant TOT effects were observed during the PVT:
•
Mental fatigue (MF) scores increased from 3.7 before the task to
5.1 after the task (36% change; p < 0.001)
•
Reaction times increased from 284ms for the first 10min to 302 ms
for the second 10 min (6.3%; p = 0.002)
MRI Results: Regional CBF Changes PVT vs. Rest
PVT vs. Rest
15
CBF(%)
10
5
0
ACC
IPL
MFC
Tha
-5
A right parietal-cingulate-frontal
network, the left sensorimotor
cortex, and bilateral basal ganglia
were activated by the PVT task.
PVT vs. Rest (FDR p < 0.05)
Regional CBF: Predictors of RT Change
ACC Activity
Thalamus Activity
20
15
10
5
0
-5
r = 0.56, p = 0.04
RT%
RT%
r = 0.67, p = 0.009
-20
0
20
CBF% (PVT-Rest)
40
20
15
10
5
0
-5
0
5
10
15
20
25
CBF% (PVT-Rest)
During PVT, regional CBF changes (CBF%) in thalamus and ACC
correlated with the performance decline (RT%)
MRI Results: Post-task rest vs. Pre-task rest
RT%
ACC Activity
r = -0.74, p = 0.002
20
15
10
5
0
-5
-40
-20
0
20
CBF%
R_IPL Activity
RT%
r = -0.66, p = 0.01
20
15
10
5
0
-5
-20
-10
0
10
20
CBF%
The parietal-cingulate-frontal network was
deactivated after prolonged PVT task, and the
deactivations correlated with RT%.
RT%
R_MFC Activity
r = -0.59, p = 0.03
20
15
10
5
0
-5
-25
-20
-15
-10
-5
CBF% (Rest2-Rest1)
0
5
Regional CBF at Baseline: Predictors of RT
(Brain State/Phenotype)
R_MFC Activity
r = -0.59, p = 0.03
20
15
10
5
0
-5
RT%
RT%
Thalamus Activity
0.8
1
1.2
rCBF
1.4
r = 0.68, p = 0.008
20
15
10
5
0
-5
1
1.2
1.4
1.6
rCBF
Before the PVT task, regional CBF activity (normalized to global
CBF) in thalamus and right MFC predicted the subsequent
performance decline (RT%).
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 Timescales
Complementary Utility of BOLD and ASL
ASL fMRI
BOLD fMRI
EVENT
100 msec
BLOCK
10 sec
BEHAVIORAL STATE
1 hr
TRAIT
1 day
log time
15O-PET
FDG-PET
• 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”
• Richness of neuroimaging data allow
brain-behavior correlations to be
detected through statistical analysis
without a hypothesis
– Can examine structure and/or function
– ASL provides ideal functional modality for
this – not constrained by task
Gene Chip Array
• Analogous to approach used in
molecular biology to find gene/function
or gene/disorder correlations
– For brain imaging data, added benefit of
meaningful spatial organization
A Priori Knowledge of
Local and Distributed
Networks