1. Issues in Experimental Design fMRI Graduate Course October 26, 2005

3. 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

4. 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?)

5. Goals of Experimental Design To maximize the ability to test hypotheses To facilitate generation of new hypotheses

6. What types of hypotheses are possible for fMRI data?

7. Epiphenomena?

8. Detection: What is active? Estimation: How does activity change over time? Detection vs. Estimation

9. Detection Detection power defined by SNR Depends greatly on hemodynamic response shape SNR = aM/  M = hemodynamic changes (unit) a = measured amplitude  = noise standard deviation

10. 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

11. 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

12. fMRI Design Types 1)Blocked Designs 2)Event-Related Designs a)Periodic Single Trial b)Jittered Single Trial c)Staggered or Interleaved Single Trial 3)Mixed Designs a)Combination blocked/event-related b)Variable stimulus probability

13. 1. Blocked Designs

14. What are Blocked Designs? Blocked designs segregate different cognitive processes into distinct time periods Task ATask BTask ATask BTask ATask BTask ATask B Task ATask BREST Task ATask BREST

15. 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

16. 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

20. 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

21. Adapted from Gusnard & Raichle (2001)

23. From Shulman et al., 1997 (PET data) From Binder et al., 1999

24. From Huettel et al., 2001 (Change Detection) From Huettel et al., 2004 (Baseline > Target Detection)

25. 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

26. 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).

27. HDR Estimation: Blocked Designs

28. Power in Blocked Designs 2. Transitions between blocks Simulation of single run with either 2 or 10 blocks.

29. Power in Blocked Designs 2. Transitions between blocks Addition of linear drift within run.

30. Power in Blocked Designs 2. Transitions between blocks Addition of noise (SNR = 0.67)

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

32. 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

33. 2. Event-Related Designs

34. What are Event-Related Designs? Event-related designs associate brain processes with discrete events, which may occur at any point in the scanning session.

35. 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

36. Buckner et al., (1996) Word-stem completion task. Blocked design: 30s on/off. Event-related design: 15s ISI.

37. Buckner et al., (1996)

38. McCarthy et al., (1997)

40. Dale and Buckner (1997)

41. 2a. Periodic Single Trial Designs Stimulus events presented infrequently with long interstimulus intervals 500 ms 18 s

42. Trial Spacing Effects: Periodic Designs 20sec 8sec4sec 12sec

43. From Bandettini and Cox, 2000 ISI: Interstimulus Interval SD: Stimulus Duration

44. 2b. Jittered Single Trial Designs Varying the timing of trials within a run Varying the timing of events within a trial

45. Effects of Jittering on Stimulus Variance

46. From Hopfinger et al., 2000

47. Effects of ISI on Power Birn et al, 2002

48. 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

50. Two of the phases are normal. But, one has a change in one trial (e.g., head motion) +0s +1s +2s

51. Post-Hoc Sorting of Trials From Konishi, et al., 2000 Data from old/new episodic memory test.

52. 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

53. 3. Mixed Designs

54. 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

56. …… Mixed Blocked/Event-related Design Target-related Activity (Phasic) Blocked-related Activity (Tonic) Task-Initiation Activity (Tonic) Task-Offset Activity (Tonic)

58. 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

59. Random and Semi-Random Designs From Liu et al., 2001

60. 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