Download Functional MRI: techniques and applications

Functional MRI:
techniques and applications
Susan Bookheimer, Ph.D.
UCLA Center for Cognitive Neurosciences
Disclosures
• none
Outline
• Basis of fMRI signal; how it works, what it
measures
• fMRI experimental design
• New techniques
• Clinical applications
• Research applications
Introduction to Functional
Imaging
• Neurovascular Coupling: Increased local
brain activity leads to:
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Increased glucose utilization
Increased cerebral blood flow
Increased cerebral blood volume
Minimal increase in oxygen utilization
Increased deoxyhemoglobin concentration
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
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
Change in oxyhemoglobin concentration
during increase blood flow
Visual Stimulation in Occipital cortex
Time Series analysis: Changes in
MRI signal intensity during activation
Assumptions in fMRI
• Assumes relatively intact blood flow
response
• Permits relative, activation based
measurements only
• Requires adequate task performance
fMRI techniques
• Fast- scanning: Echoplanar (EPI) imaging
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Gradient echo EPI: susceptibility weighted
Spin echo or asymmetric spin echo EPI
Spiral
Arterial spin labeling
Hemodynamic response to
activation tasks
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
Practical issues
• Getting people in the scanner
• Stimulus presentation
• Head motion
– restraint
– Mathematical correction (eg AIR)
MRI Scanner
MRI Compatible Video Goggles
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?
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
Hierarchical
Ex B
}
Ex A
- }
Control
Tailored Baseline
Common
baseline
Ex A
Parallel
Ex B
Control
Parametric
Ex A > Ctl A
>}
Ex B > Ctl B
Factorial Designs
Ex A
Ex B
AxB
A< A < A <
A
Ex B
> Ex A
Ex A
> Ex B
Selective
attention
A B C
A B C
A B C
Mixed, Nested Designs
Conjunction Designs
Priming/Adaptation Designs
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
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
- }
Sensory
- }
Motor
- }
Semantic
Experimental design models
• Hierarchical designs
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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
Ex A
Ex B
Common Baseline
Control
– 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
HOUSE
Directed Attention Models
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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
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
EG Corbetta et al
Selective attention to shape, color,
motion
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.
Dapretto and Bookheimer, Neuron, 1999
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
Boynton et al., 1996
Cohen et al., 1996
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
Can adaptation fMRI characterize
neural representations?
Two stimuli: can neurons tell the
difference?
• A voxel containing neurons that respond to all
politicians, irrespective of party
• A voxel containing some specifically
Democratic neurons, and other specifically
Republican neurons.
From R. Raizada
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
From R. Raizada
Different, fresh neurons:
It’s a Democrat
Timing
Blocked vs. Event-Related fMRI
BLOCKED:
SPACED MIXED TRIAL:
RAPID MIXED TRIAL:
From R. Buckner, HBM2001
Experimental Paradigm
“Match”
Block Length = 32.5 sec
“Label”
Control
Total Scan Time = 4:53 min
Match
Affect
Label Affect
Y. Bookheimer,
FromSusan
Hariri
et al 1999
Ph.D.
Hariri et al., 1999
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
Directed vs. averted gaze
Event-Related fMRI Design
Optimized Random Sequence
(Wager & Nichols 2003)
TR = 3 s
TR = 3 s
2s
+
+
2s
+
2s
ISI = 500-1500 ms
Jitter = 0-500 ms
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
Left Hippocampus Anatomic ROI
Two-Group Designs
• Two-group designs
– Hypothesis: groups differ in activation vs
control comparisons
– Different from resting state differences ala
FDG
– Performance confounds
Accuracy
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Directed vs. averted gaze
TD: Directed vs Averted Gaze
(negative emotions)
Amygdala,
hippocampus,
Medial PFC,
lateral PFC
Visual and HC
ASD
Visual and HC
No task
modulation
Between-group direct
comparisons
Direct
TD > ASD
Averted
TD > ASD
Functional Connectivity in fMRI
Functional Connectivity
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
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
Group Analysis: Effect of Genotype
5HTT and imaging
Amygdala response:
5HTT short allele > Long allele
Cohort 1
Cohort 2
Applications
• Mapping normal functions: within group
• Clinical applications: between group
designs
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Surgical planning
AD/AD risk
Drug interventions
Psychiatric disorders
Clinical Applications:
Neurosurgical planning
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Goal: Identify critical areas
Task specificity issues
Disruption by the lesion
Language performance
Stimulation
Points- 1 cm
Recording
Strips
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
Color of grass
“nose”
“green”
– Finding a name; comprehension, expression
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.
Areas of conjunction
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
Donepezil Treatment- Mild AD
Pre-Treatment
Post-Treatment
Related Paired-Associate Learning vs. Rest
fMRI in Psychiatric populations
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Panic disorder
Social anxiety
ADHD
Autism
Bipolar
Panic Disorder- symptom provocation
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
Amygdala
hyperarousal in
social anxiety
disordered
children
Susan Y. Bookheimer, Ph.D.
Disgust and Threat Responses in
OCD (Shapira et al, Biol Psychiatry. 2003)
Disgust
Threat
Control
OCD
Susan Y. Bookheimer, Ph.D.
Bipolar Disorder- Mania
Altshuler et al 2005
Summary
• Numerous applications for fMRI in
translational research
• Elucidate normal brain systems
• Help identify circuits impaired in patient
populations
• Numerous new techniques