Functional MRI: techniques and applicationsFunctional Magnetic Resonance Imaging (FMRI) • MRI...
Transcript of Functional MRI: techniques and applicationsFunctional Magnetic Resonance Imaging (FMRI) • MRI...
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Functional MRI: techniques and applications
Susan Bookheimer, Ph.D.
UCLA Center for Cognitive Neurosciences
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Disclosures
• none
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Outline
• Basis of fMRI signal; how it works, what it
measures
• fMRI experimental design
• New techniques
• Clinical applications
• Research applications
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Introduction to Functional
Imaging
• Neurovascular Coupling: Increased local
brain activity leads to:
– Increased glucose utilization
– Increased cerebral blood flow
– Increased cerebral blood volume
– Minimal increase in oxygen utilization
– Increased deoxyhemoglobin concentration
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Functional Magnetic Resonance
Imaging (FMRI)
• MRI scanning of brain function (vs. structure)
• An indirect measure of increased regional
cerebral blood flow during neural activity
• During increased brain activity, MRI signal
intensity (“brightness”) increases with the
increase in oxyhemoglobin concentration
• Tells us which brain regions are “working”
during task performance
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Principles of fMRI
• Indirect measure of blood flow
– Measures changes in magnetic susceptibility due
to change in ratio of oxygenated vs. deoxygenated
blood that accompanies increased neural activity
• Relative measure
– change across states (rest, activity) of arbitrary
units of signal intensity
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Change in oxyhemoglobin concentration
during increase blood flow
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Visual Stimulation in Occipital cortex
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Time Series analysis: Changes in
MRI signal intensity during activation
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Assumptions in fMRI
• Assumes relatively intact blood flow
response
• Permits relative, activation based
measurements only
• Requires adequate task performance
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fMRI techniques
• Fast- scanning: Echoplanar (EPI) imaging
– Gradient echo EPI: susceptibility weighted
– Spin echo or asymmetric spin echo EPI
– Spiral
– Arterial spin labeling
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Hemodynamic response to
activation tasks
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Image processing
• Image reconstruction into a time series of
volumes
• Test the extent to which the MR signal
intensity conforms to the predicted
hemodynamic response
• Present results in an accessible format
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Practical issues
• Getting people in the scanner
• Stimulus presentation
• Head motion
– restraint
– Mathematical correction (eg AIR)
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MRI Scanner
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MRI Compatible Video Goggles
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Conceptual and methodogical
aspects of experimental design • There are two aspects of fMRI design that are important to
distinguish
• Conceptual design
– How do we design tasks to properly measure the processes of interest?
– The issues here are very similar to those in cognitive psychology
• Methodological design
– How can we construct a task paradigm to optimize our ability to measure the effects of interest, within the specific constraints of the fMRI scanning environment?
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fMRI experimental design: A basic plan
Define mental process
to examine
Define tasks to manipulate
that process
Measure fMRI data
during tasks
Compare fMRI data
between tasks
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Control
Ex B
Ex A - }
- }
Hierarchical Common
baseline
Ex B Ex A
Control
Parallel
Ex B Ex A
Ex A Ex B >
>
Parametric
A< A < A < A
Tailored Baseline
Ex A > Ctl A
Ex B > Ctl B >}
Selective
attention
A B C
A B C
A B C
Factorial Designs
Ex A Ex B
AxB
Mixed, Nested Designs
Conjunction Designs
Priming/Adaptation Designs
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The subtraction method
• Acquire data under two
conditions
– These conditions
putatively differ only in
the cognitive process of
interest
• Compare brain images
acquired during those
conditions
• Regions of difference
reflect activation due to the
“subtracted” process of
interest
Petersen et al., 1988
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Hierarchical subtraction example from Petersen, 1991
• Rest Control
• Auditory words vs. rest: A1, word recognition centers
• Visual words vs rest: visual areas, word form areas
• Reading or repeating words vs passive words: motor areas
• Generating words vs. repeating: semantic (language) areas
- }
- }
- } Semantic
Motor
Sensory
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Experimental design models • Hierarchical designs
– Eg: Peterson et al language study
– Sensory control (see words)
– Output control (read words aloud)
– Language task (generate associates)
• Use a cognitive subtraction model
– Equate demands on all factors except one
• Rely on theory of additive factors
– active areas remain the same throughout the hierarchy
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– One level of hierarchy
– Test for violation of additivity assumption
– Allows you to see common areas active for A
and B
– Assumes A and B have similar psychometric
properties (ie, level of difficulty, variation, and
distribution in the population)
– Need additional approach to see unique areas
Ex B Ex A
Control
Common Baseline
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HOUSE
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Directed Attention Models
• All stimuli identical in all conditions
• Direct attention towards different features
• Implicit or explicit
• Assumes process is modified by directed attention
• Assumes passive processing does not capture your variable of interest
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Example: implicit selective
attention with parallel comparisons
• Subjects hear pairs of sentences.
• Task: judge if the sentences mean the same thing
• Implicit Manipulation: sentences differ on semantic or syntactic basis
– “The boy went to the store- The boy went to the market”
– “The city is east of the lake. East of the city is the lake”
• Comparisons:
– Common baseline: each vs. rest
– Parallel comparisons: semantic vs syntax and reverse
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EG Corbetta et al
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Selective attention to shape, color,
motion
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Implicit Directed attenion
• EG Dapretto et al
• Instructions are the same; process required to
reach a response differs
• Syntax vs semantics: sentence comprehension
task.
– Do the sentences mean the same thing (Y N)
– The boy has gone to the market. The boy has gone to
the store
– The city is east of the lake. East of the lake is the city.
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Dapretto and Bookheimer, Neuron, 1999
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Parametric designs
• Employs continuous variation in a stimulus/task parameter
– E.g., working memory load, stimulus contrast
• Inference:
– Modulation of activity reflects sensitivity to the modulated parameter
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Boynton et al., 1996
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Cohen et al., 1996
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Priming/adaptation designs
• Presentation of an item multiple times leads to changes in
activity
– Usually decreased activity upon repetition
• Inference:
– Regions showing decreased activity are sensitive to (i.e. represent)
whatever stimulus features were repeated
• Requires version of pure modulation assumption
– Assumes that processing of specific features is reduced but that the
task is otherwise qualitatively the same
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Can adaptation fMRI characterize
neural representations?
• A voxel containing neurons that respond to all
politicians, irrespective of party
• A voxel containing some specifically
Democratic neurons, and other specifically
Republican neurons.
Two stimuli: can neurons tell the
difference?
From R. Raizada
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Neural adaptation to repeated stimuli does show the difference:
What counts as repetition for neurons in a voxel?
It’s a politician Same neurons, adapting:
It’s a politician again
It’s a
Republican
Different, fresh neurons:
It’s a Democrat From R. Raizada
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Timing
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Blocked vs. Event-Related fMRI
BLOCKED:
SPACED MIXED TRIAL:
RAPID MIXED TRIAL:
From R. Buckner, HBM2001
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Experimental Paradigm
Block Length = 32.5 sec Total Scan Time = 4:53 min
“Match” “Label” Control
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Susan Y. Bookheimer,
Ph.D.
Match
Affect
Hariri et al., 1999 From Hariri et al 1999
Label Affect
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Event-Related Designs
• Event-related or single trial experiments
– Have stimuli presented 1 at a time rather than in
blocks
– Adjust for the hemodynamic response function
– Bin like stimuli, obtain averaged HRF
– Compare HRFs across stimulus types
– Long ISI studies (15 seconds) allow for complete
relaxation of HRF (implicit resting control)
– Short ISI studies model additive response of like
stimuli and adjust
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Directed vs. averted gaze
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Event-Related fMRI Design
Optimized Random Sequence
(Wager & Nichols 2003)
ISI = 500-1500 ms
Jitter = 0-500 ms
2 s
2 s
2 s
+
+
+
TR = 3 s
TR = 3 s
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Episodic Retrieval:
R-K Distinction (Eldridge,
Knowlton et al 2000)
• Remember (R) - recognition with conscious
recollection
– Episodic memory
• Know (K) - recognition without recollection
– Non-episodic memory
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Left Hippocampus Anatomic ROI
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Two-Group Designs
• Two-group designs
– Hypothesis: groups differ in activation vs
control comparisons
– Different from resting state differences ala
FDG
– Performance confounds
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% c
orr
ect
Match Label Control0
20
40
60
80
100
High-Functioning
Autistic Boys
Normal Adults
Accuracy
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Directed vs. averted gaze
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TD: Directed vs Averted Gaze
(negative emotions)
Amygdala,
hippocampus,
Medial PFC,
lateral PFC
Visual and HC
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ASD
Visual and HC No task
modulation
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Between-group direct
comparisons
Direct
TD > ASD
Averted
TD > ASD
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Functional Connectivity in fMRI
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Functional Connectivity
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Imaging Genetics
• Growing Field
• Examines differences in brain structure/function/connectivity as a result of possessing different genetic polymorphisms
• Usually chosen for conferring risk for a disorder
• Imaging differences seen in normal populations with different, common polymorphisms in the absence of obvious behavioral or phenotypic differences
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fMRI in normal subjects with
genetic risk for AD Bookheimer, Small, et al, NEJM 2000
• Purpose: use fMRI to identify changes in brain function
prior to significant cognitive decline; predict outcome
• APOE-3 vs E-4 extremely healthy older volunteers
(X=63.5; N=30)
• Memory “stress-test” in cognitively normal elderly
– Memorize unrelated word pairs “justice-club”
– Scans compare learning/retrieval vs. control
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Group Analysis: Effect of Genotype
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5HTT and imaging
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Amygdala response:
5HTT short allele > Long allele
Cohort 1 Cohort 2
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Applications
• Mapping normal functions: within group
• Clinical applications: between group designs
– Surgical planning
– AD/AD risk
– Drug interventions
– Psychiatric disorders
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Clinical Applications:
Neurosurgical planning
• Goal: Identify critical areas
• Task specificity issues
• Disruption by the lesion
• Language performance
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Recording
Strips
Stimulation
Points- 1 cm
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Language Tasks • Object Naming
– Finding a name; expression
– Used in OR; alternate forms; reveals Broca’s area and
Basal temporal language area
• Auditory Naming
Smell with this “nose”
Color of grass “green”
– Finding a name; comprehension, expression
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Conjunction Analysis
• Within task, repeat conditions (3 times)
• Across tasks, find areas of overlap
• Perform separately for receptive, expressive
tasks
• Allows low magnitude activations that are
consistent to show.
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Areas of conjunction
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Pharmaco- fMRI
• Use fMRI to identify brain changes
associated with treatment
• Eg, Acetylcholine agonist treatment may
improve memory in AD
• fMRI Pre- and post-treatment with Aricept
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Pre-Treatment
Post-Treatment
Donepezil Treatment- Mild AD
Related Paired-Associate Learning vs. Rest
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fMRI in Psychiatric populations
• Panic disorder
• Social anxiety
• ADHD
• Autism
• Bipolar
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Panic Disorder- symptom provocation
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Social Anxiety and amygdala
arousal Guyer et al, Arch Gen Psychiatry. 2008 65(11): 1303–1312.
Simulated online “chat” in social anxiety and control adolescents
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Amygdala
hyperarousal in
social anxiety
disordered
children
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Susan Y. Bookheimer, Ph.D.
Disgust and Threat Responses in
OCD (Shapira et al, Biol Psychiatry. 2003)
Threat
Disgust
Control OCD
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Susan Y. Bookheimer, Ph.D.
Bipolar Disorder- Mania Altshuler et al 2005
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Summary
• Numerous applications for fMRI in
translational research
• Elucidate normal brain systems
• Help identify circuits impaired in patient
populations
• Numerous new techniques