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:

– 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

– 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

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

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

- }

- }

- } Semantic

Motor

Sensory

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

– 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

HOUSE

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

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?

• 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

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

Timing

Blocked vs. Event-Related fMRI

BLOCKED:

SPACED MIXED TRIAL:

RAPID MIXED TRIAL:

From R. Buckner, HBM2001

Experimental Paradigm

Block Length = 32.5 sec Total Scan Time = 4:53 min

“Match” “Label” Control

Susan Y. Bookheimer,

Ph.D.

Match

Affect

Hariri et al., 1999 From Hariri et al 1999

Label Affect

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)

ISI = 500-1500 ms

Jitter = 0-500 ms

2 s

2 s

2 s

+

+

+

TR = 3 s

TR = 3 s

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

% c

orr

ect

Match Label Control0

20

40

60

80

100

High-Functioning

Autistic Boys

Normal Adults

Accuracy

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

– Surgical planning

– AD/AD risk

– Drug interventions

– Psychiatric disorders

Clinical Applications:

Neurosurgical planning

• Goal: Identify critical areas

• Task specificity issues

• Disruption by the lesion

• Language performance

Recording

Strips

Stimulation

Points- 1 cm

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

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

Pre-Treatment

Post-Treatment

Donepezil Treatment- Mild AD

Related Paired-Associate Learning vs. Rest

fMRI in Psychiatric populations

• 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)

Threat

Disgust

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