Issues in Experimental Design

fMRI Graduate Course

October 26, 2005

Terminology

• Independent vs. Dependent variables• Categorical vs. Continuous variables• Between- vs. Within-subjects

manipulations• Experimental vs. Control conditions• Confounding factors • Randomization, counterbalancing• Parametric vs. subtractive designs

What is fMRI Experimental Design?

• Controlling the timing and quality of cognitive operations (IVs) to influence resulting brain processes (DVs)

• What can we control?– Experimental comparisons (what is to be measured?)– Stimulus properties (what is presented?)– Stimulus timing (when is it presented?)– Subject instructions (what do subjects do with it?)

Goals of Experimental Design

• To maximize the ability to test hypotheses

• To facilitate generation of new hypotheses

What types of hypotheses are possible for fMRI data?

Epiphenomena?

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• Detection: What is active?

• Estimation: How does activity change over time?

Detection vs. Estimation

Detection

• Detection power defined by SNR

• Depends greatly on hemodynamic response shape

SNR = aM/M = hemodynamic changes (unit)

a = measured amplitude

= noise standard deviation

Estimation

• Ability to determine the shape of fMRI response

• Accurate estimation relies on minimization of variance in estimate of HDR at each time point

• Efficiency of estimation is generally independent of HDR form

Optimal Experimental Design

• Maximizing both Detection and Estimation– Maximal variance in stimulus timing

(increases estimation)– Maximal variance in measured signal

(increases detection)

• Limitations– Refractory effects– Signal saturation

fMRI Design Types

1) Blocked Designs

2) Event-Related Designsa) Periodic Single Trial

b) Jittered Single Trial

c) Staggered or Interleaved Single Trial

3) Mixed Designsa) Combination blocked/event-related

b) Variable stimulus probability

1. Blocked Designs

What are Blocked Designs?

• Blocked designs segregate different cognitive processes into distinct time periods

Task A Task B Task A Task B Task A Task B Task A Task B

Task A Task BREST REST Task A Task BREST REST

PET Designs

• Measurements done following injection of radioactive bolus

• Uses total activity throughout task interval (~30s)

• Blocked designs necessary– Task 1 = Injection 1– Task 2 = Injection 2

Choosing Length of Blocks• Longer block lengths allow for stability of extended responses

– Hemodynamic response saturates following extended stimulation• After about 10s, activation reaches max

– Many tasks require extended intervals• Processing may differ throughout the task period

• Shorter block lengths allow for more transitions– Task-related variability increases (relative to non-task) with increasing

numbers of transitions

• Periodic blocks may result in aliasing of other variance in the data– Example: if the person breathes at a regular rate of 1 breath/5sec, and

the blocks occur every 10s

What baseline should you choose?

• Task A vs. Task B– Example: Squeezing Right Hand vs. Left Hand– Allows you to distinguish differential activation

between conditions– Does not allow identification of activity common to

both tasks• Can control for uninteresting activity

• Task A vs. No-task– Example: Squeezing Right Hand vs. Rest– Shows you activity associated with task– May introduce unwanted results

Adapted from Gusnard & Raichle (2001)

Adapted from Gusnard & Raichle (2001)

From Shulman et al., 1997 (PET data)

From Binder et al., 1999

From Huettel et al., 2001 (Change Detection)

From Huettel et al., 2004 (Baseline > Target Detection)

Non-Task Processing

• In many experiments, activation is greater in baseline conditions than in task conditions!– Requires interpretations of significant activation

• Suggests the idea of baseline/resting mental processes– Emotional processes– Gathering/evaluation about the world around you– Awareness (of self)– Online monitoring of sensory information– Daydreaming

Power in Blocked Designs

1. Summation of responses results in large variance

Single, unit amplitude HDR, convolved by 1, 2, 4 ,8, 12, or 16 events (1s apart).

HDR Estimation: Blocked Designs

Power in Blocked Designs

2. Transitions between blocks

Simulation of single run with either 2 or 10 blocks.

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Power in Blocked Designs

2. Transitions between blocks

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Addition of linear drift within run.

Power in Blocked Designs

2. Transitions between blocks

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Addition of noise (SNR = 0.67)

Deeper concept…

We want the changes evoked by the task to be at different parts of the frequency spectrum than non-task-evoked changes.

Limitations of Blocked Designs

• Very sensitive to signal drift – Sensitive to head motion, especially when only a few

blocks are used.

• Poor choice of baseline may preclude meaningful conclusions

• Many tasks cannot be conducted repeatedly

• Difficult to estimate the HDR

2. Event-Related Designs

What are Event-Related Designs?

• Event-related designs associate brain processes with discrete events, which may occur at any point in the scanning session.

Why use event-related designs?

• Some experimental tasks are naturally event-related

• Allows studying of trial effects

• Improves relation to behavioral factors

• Simple analyses– Selective averaging– General linear models

Buckner et al., (1996)

Word-stem completion task. Blocked design: 30s on/off. Event-related design: 15s ISI.

Buckner et al., (1996)

McCarthy et al., (1997)

McCarthy et al., (1997)

Dale and Buckner (1997)

2a. Periodic Single Trial Designs

• Stimulus events presented infrequently with long interstimulus intervals

500 ms 500 ms 500 ms 500 ms

18 s 18 s 18 s

Trial Spacing Effects: Periodic Designs

20sec

8sec 4sec

12sec

From Bandettini and Cox, 2000

ISI: Interstimulus Interval

SD: Stimulus Duration

2b. Jittered Single Trial Designs

• Varying the timing of trials within a run

• Varying the timing of events within a trial

Effects of Jittering on Stimulus Variance

From Hopfinger et al., 2000

Effects of ISI on Power

Birn et al, 2002

2c. Staggered Single Trial

• By presenting stimuli at different timings, relative to a TR, you can achieve sub-TR resolution

• Significant cost in number of trials presented – Resulting loss in experimental power

• Very sensitive to scanner drift and other sources of variability

• Also called Interleaved Stimulus Presentation

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Two of the phases are normal.

But, one has a change in one trial (e.g., head motion)

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Post-Hoc Sorting of Trials

From Konishi, et al., 2000

Data from old/new episodic memory test.

Limitations of Event-Related Designs

• Differential effects of interstimulus interval– Long intervals do not optimally increase

stimulus variance– Short intervals may result in refractory effects

• Detection ability dependent on form of HDR

• Length of “event” may not be known

3. Mixed Designs

3a. Combination Blocked/Event

• Both blocked and event-related design aspects are used (for different purposes)– Blocked design is used to evaluate state-dependent

effects – Event-related design is used to evaluate item-related

effects

• Analyses are conducted largely independently between the two measures– Cognitive processes are assumed to be independent

… …

Mixed Blocked/Event-related Design

Target-related Activity (Phasic)

Blocked-related Activity (Tonic)

Task-Initiation Activity (Tonic)

Task-Offset Activity (Tonic)

3b. Variable Stimulus Probability

• Stimulus probability is varied in a blocked fashion – Appears similar to the combination design

• Mixed design used to maximize experimental power for single design

• Assumes that processes of interest do not vary as a function of stimulus timing– Cognitive processing– Refractory effects

Random and Semi-Random Designs

From Liu et al., 2001

Summary of Experiment Design• Main Issues to Consider

– What design constraints are induced by my task?– What am I trying to measure?– What sorts of non-task-related variability do I want to avoid?

• Rules of thumb– Blocked Designs:

• Powerful for detecting activation• Useful for examining state changes

– Event-Related Designs: • Powerful for estimating time course of activity• Allows determination of baseline activity• Best for post hoc trial sorting

– Mixed Designs• Best combination of detection and estimation• Much more complicated analyses