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Experimental design of fMRI studies

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Experimental design of fMRI studies

Klaas Enno Stephan Laboratory for Social and Neural Systems Research

Institute for Empirical Research in Economics

University of Zurich

Functional Imaging Laboratory (FIL)

Wellcome Trust Centre for Neuroimaging

University College London

With many thanks for slides & images to:

FIL Methods group,

particularly Christian Ruff

Methods & models for fMRI data analysis12 November 2008

Statistical parametric map (SPM)

Design matrix

Image time-series

Kernel

Realignment

Smoothing

General linear model

Gaussian

field theory

Statistical

inference

Normalisation

p <0.05

Template

Parameter estimates

Overview

- Categorical designs
- Subtraction - Pure insertion, evoked / differential responses
- Conjunction - Testing multiple hypotheses
- Parametric designs
- Linear - Adaptation, cognitive dimensions
- Nonlinear - Polynomial expansions, neurometric functions
- Factorial designs
- Categorical - Interactions and pure insertion
- Parametric - Linear and nonlinear interactions
- - Psychophysiological Interactions

- Neuronal structures computing face recognition?

Cognitive subtraction- Aim:
- Neuronal structures underlying a single process P?

- Procedure:
- Contrast: [Task with P] – [control task without P ] = P
- the critical assumption of „pure insertion“

- P implicit in control task ?

„Queen!“ „Aunt Jenny?“

- Same stimuli, different task

- Interaction of process and task?

Name Person! Name Gender!

Cognitive subtraction: Baseline problems- „Distant“ stimuli

- Several components differ!

Evoked responses

SPM{F} testing for evoked responses

Parahippocampal responses to words

- “Baseline” here corresponds to session mean
- Estimation depends crucially on inclusion of null events or long SOAs
- “Cognitive” interpretation difficult, but useful to define regions generally involved in the task

BOLD EPI fMRI at 2T, TR 3.2sec. Words presented every 16 secs; (i) studied words or (ii) new words

Differential responses

SPM{F} testing for evoked responses

Parahippocampal responses to words

SPM{F} testing for differences

studied words

new words

BOLD EPI fMRI at 2T, TR 3.2sec. Words presented every 16 secs; (i) studied words or (ii) new words

Peri-stimulus time {secs}

A categorical analysis

Experimental design

Word generation G

Word repetition R

R G R G R G R G R G R G

G - R = Intrinsic word generation

…under assumption of pure insertion

Overview

- Categorical designs
- Subtraction - Pure insertion, evoked / differential responses
- Conjunction - Testing multiple hypotheses
- Parametric designs
- Linear - Adaptation, cognitive dimensions
- Nonlinear - Polynomial expansions, neurometric functions
- Factorial designs
- Categorical - Interactions and pure insertion
- Parametric - Linear and nonlinear interactions
- - Psychophysiological Interactions

Conjunctions

- One way to minimise the baseline/pure insertion problem is to isolate the same process by two or more separate comparisons, and inspect the resulting simple effects for commonalities
- A test for such activation common to several independent contrasts is called “conjunction”
- Conjunctions can be conducted across a whole variety of different contexts:
- tasks
- stimuli
- senses (vision, audition)
- etc.

- Note: the contrasts entering a conjunction must be orthogonal !

Viewing Naming

A1

A2

Objects Colours

Stimuli (A/B)

B1

B2

Common object

recognition response (R)

Price et al. 1997

ConjunctionsExample: Which neural structures support object recognition, independent of task (naming vs viewing)?

Visual Processing V

Object Recognition R

Phonological Retrieval P

Object viewing V,R

Colour viewing V

Object naming P,V,R

Colour naming P,V

(Object - Colour viewing) [1 -1 0 0]

&

(Object - Colour naming) [0 0 1 -1]

[ V,R - V ] & [ P,V,R - P,V ] = R & R = R

A1-A2

Two types of conjunctions

- Test of global null hypothesis: Significant set of consistent effects
- “Which voxels show effects of similar direction (but not necessarily individual significance) across contrasts?”
- Null hypothesis: No contrast is significant: k = 0
- does not correspond to a logical AND !
- Test of conjunction null hypothesis: Set of consistently significant effects
- “Which voxels show, for each specified contrast, significant effects?”
- Null hypothesis: Not all contrasts are significant: k < n
- corresponds to a logical AND

p(A1-A2) <

+

+

p(B1-B2) <

Friston et al.(2005). Neuroimage, 25:661-667.

Nichols et al. (2005). Neuroimage, 25:653-660.

SPM offers both conjunctions

specificity

specificity

Global null:

k = 0

Conjunction null:

k < n

Friston et al. 2005, Neuroimage, 25:661-667.

F-test vs. conjunction based on global null

Friston et al. 2005, Neuroimage, 25:661-667.

Using the conjunction null is easy to interpret, but can be very conservative

Friston et al. 2005, Neuroimage, 25:661-667.

Overview very conservative

- Categorical designs
- Subtraction - Pure insertion, evoked / differential responses
- Conjunction - Testing multiple hypotheses
- Parametric designs
- Linear - Adaptation, cognitive dimensions
- Nonlinear - Polynomial expansions, neurometric functions
- Factorial designs
- Categorical - Interactions and pure insertion
- Parametric - Linear and nonlinear interactions
- - Psychophysiological Interactions

Parametric designs very conservative

- Parametric designs approach the baseline problem by:
- Varying the stimulus-parameter of interest on a continuum, in multiple (n>2) steps...
- ... and relating measured BOLD signal to this parameter

- Possible tests for such relations are manifold:
- Linear
- Nonlinear: Quadratic/cubic/etc. (polynomial expansion)
- Model-based (e.g. predictions from learning models)

Quadratic very conservative

Linear

SPM{F}

Parametric modulation of regressorsF-contrast [0 1 0] on

quadratic parameter

→ inverted ‘U’ response to

increasing word presentation

rate in the DLPFC

Polynomial expansion:

f(x) ~ b1 x + b2 x2 + b3 x3 ...

SPM5 offers polynomial expansion as option for parametric modulation of regressors

Büchel et al. 1996, NeuroImage 4:60-66

Parametric modulation of regressors by time very conservative

Büchel et al. 1998, NeuroImage 8:140-148

“User-specified” parametric modulation of regressors very conservative

Polynomial expansion

&

orthogonalisation

Büchel et al. 1998, NeuroImage 8:140-148

Investigating neurometric functions very conservative(= relation between a stimulus property and the neuronal response)

Stimulus

awareness

Stimulus

intensity

Pain

intensity

Pain threshold: 410 mJ

- P0-P4: Variation of intensity of a laser stimulus applied to the right hand (0, 300, 400, 500, and 600 mJ)

P3

P2

P1

P4

Büchel et al. 2002, J. Neurosci. 22:970-976

Stimulus intensity very conservative

Stimulus presence

Pain intensity

Neurometric functionsBüchel et al. 2002, J. Neurosci. 22:970-976

Model-based regressors very conservative

- general idea:generate predictions from a computational model, e.g. of learning or decision-making
- Commonly used models:
- Rescorla-Wagner learning model
- temporal difference (TD) learning model

- use these predictions to define regressors
- include these regressors in a GLM and test for significant correlations with voxel-wise BOLD responses

TD model of reinforcement learning very conservative

- appetitive conditing with pleasant taste reward
- activity in ventral striatum and OFC correlated with TD prediction error at the time of the CS

O‘Doherty et al. 2003, Neuron

Overview very conservative

- Categorical designs
- Subtraction - Pure insertion, evoked / differential responses
- Conjunction - Testing multiple hypotheses
- Parametric designs
- Linear - Adaptation, cognitive dimensions
- Nonlinear - Polynomial expansions, neurometric functions
- Factorial designs
- Categorical - Interactions and pure insertion
- Parametric - Linear and nonlinear interactions
- - Psychophysiological Interactions

Task (1/2) very conservative

Viewing Naming

A1

A2

Objects Colours

Stimuli (A/B)

B1

B2

Main effects and interactions- Main effect of task: (A1 + B1) – (A2 + B2)
- Main effect of stimuli: (A1 + A2) – (B1 + B2)
- Interaction of task and stimuli:Can show a failure of pure insertion
- (A1 – B1) – (A2 – B2)

interaction effect

(Stimuli x Task)

Colours Objects Colours Objects

Viewing

Naming

V+ very conservative

V-

V+

V-

V+

V-

V+

V-

A+

A-

A+

A-

Parametric interactionsRescorla-Wagner learning

curves (=0.075):

Primary visual cortex

Significant four-way interaction in V1 and putamen:

V1

- during learning, predictive tones
- increasingly activate V1 & PUT in the absence of predicted visual stimuli,
- increasingly deactivate V1 & PUT in the presence of predicted vis. stimuli

PUT

p < 0.05, corrected

random effects, n=16

den Ouden et al. 2009, Cereb. Cortex

Task factor very conservative

Task B

Task A

TA/S1

TB/S1

Stim 1

Stimulus factor

Stim 2

TB/S2

TA/S2

Psycho-physiological interactions (PPI)

GLM of a 2x2 factorial design:

main effect

of task

main effect

of stim. type

interaction

main effect

of task

We can replace one main effect in the GLM by the time series of an area that shows this main effect.

E.g. let's replace the main effect of stimulus type by the time series of area V1:

V1 time series main effect

of stim. type

psycho-

physiological

interaction

SPM{Z} very conservative

V5 activity

time

V1

V5

V5

attention

V5 activity

no attention

V1 activity

PPI example: attentional modulation of V1→V5Attention

=

V1 x Att.

Friston et al. 1997, NeuroImage 6:218-229

Büchel & Friston 1997, Cereb. Cortex 7:768-778

V1 very conservative

V5

V5

V1

attention

attention

PPI: interpretationTwo possible interpretations of the PPI term:

V1

V1

Modulation of V1V5 by attention

Modulation of the impact of attention on V5 by V1.

Thank you very conservative

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