Experimental Design for Functional MRI

1. Experimental Designfor Functional MRI David Glahn Updated by JLL

2. General Experimental Design- Neuropsychology - • What is the question? • What are appropriate controls? • Which imaging modality? • Study style?

3. Experimental Design: Terminology • Variables • Independent vs. Dependent • Categorical vs. Continuous • Contrasts • Experimental vs. Control • Parametric vs. subtractive • Comparisons of subjects • Between- vs. Within-subjects • Confounding factors • Randomization, counterbalancing From Scott Huettel, Duke

4. Donder’s Method: Subtraction Example: How long does it take to choose between alternatives? (Mental Chronometry) • A random series of A’s and B’s presented and the subject must: • Task 1 - Respond whenever event A or B occurs (RT1) • Task 2 - Respond only to A not to B (RT2) • Task 3 - Respond X to A and Y to B (RT3) RT = reaction time • RT1 = T-detect + T-response • RT2 = T-detect + T-discrimination + T-response • RT3 = T-detect + T-discrimination + T-choice + T-response • T-discrimination = RT2 - RT1 • T-choice = RT3 - RT2

5. Criticisms of Donder • Assumes that adding components does not affect other components (i.e. assumption of pure insertion) • One should pick tasks that differ along same dimension (time in our example) • Although resting baseline is good to include, it may limit inference (e.g. Sternberg, 1964)

6. What types of hypotheses are possible for fMRI data? From Scott Huettel, Duke

7. Experimental Design for fMRI Must Account for Hemodynamic Response (HR) Savoy et al., 1995

8. Linear Systems Analysis Boynton et al. 1996 • The linear transform model of fMRI hypothesizes that responses are proportional to local average neural activity averaged over a period of time. • fMRI responses in human primary visual cortex (V1) depend on both stimulus timing (8 Hz) and stimulus contrast (black/white). • Responses to long-duration stimuli can be predicted from a hemodynamic response function (HRF) derived from shorter duration stimuli. • The noise in the fMRI data is independent of stimulus contrast and stimulus temporal period. • Because the linear transform model is consistent with our data, we proceeded to estimate the temporal fMRI response function and the underlying (presumably neural) contrast response function using HRF… • Assumption is that HRF is linear and shift-invariant!

9. Sync each differential response to start of trial Linearity of BOLD response Dale & Buckner, 1997 Reversing Checkerboard (8 Hz) One-trial = 1 stimulus Two-trial – 2 stimuli Three-trial = 3 stimuli Stim duration (SD) = 1 s Inter-stim interval (ISI) = 2 s Not quite linear but good enough for first order approximations

10. fMRI Design Types • Blocked Designs • Event-Related Designs • Periodic Single Trial • Jittered Single Trial • Mixed Designs - Combination blocked/event-related

11. Blocked Designs

12. What are Blocked Designs? • Blocked designs segregate different cognitive tasks into distinct time periods (blocks) Paradigm – pattern or model; detailed plan for the experiment Task A Task B Task A Task B Task A Task B Task A Task B Task A REST Task B REST Task A REST Task B REST fMRI brain images acquired continuously

13. “Loose” vs. “Tight” Block Designs • Loose: 1 Task, 1 contrast (with Baseline) • Tight: more than 1 Task, multiple contrasts (including baseline)

14. Types of Blocked Design • Task A vs. Task B (… vs. Task C…) • 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 (… vs. Task C…) • Example: Squeezing Right Hand vs. Rest • Shows you activity associated with task • May introduce unwanted results if not matched properly (example would be if rest acquired with eyes closed but task had eyes open)

15. (E - Bad Control Design) Adapted from Gusnard & Raichle (2001)

16. A True Baseline? Different Areas may have different baselines Cerebral Blood Flow Cerebral Metabolic Rate of O2 Oxygen Extraction Fraction Adapted from Gusnard & Raichle (2001) Depends on what is measured!

17. Power in Blocked Designs • Summation of responses results in large signals then plateaus (~10 sec) • Response Duration does not plateau and onset does not change Stimulus duration and interval compared with HRF ISI = 1 sec

18. Choosing Length of Blocks • Longer block lengths allow for stability of extended responses • Hemodynamic response saturates following extended stimulation • After about 10s, activation reaches plateau • Many tasks require extended intervals • Brain processing may differ throughout the task period • Shorter block lengths move your signal to higher temporal frequencies • Away from low-frequency noise: scanner drift, etc. • Not possible in O-15 PET rCBF studies • Periodic blocks may result in aliasing of other periodic signals in the data • Example: if the person breathes at a regular rate of 12 per min and the blocks are 10s long (6 blocks/min) • Could be problem if the aliased signal falls within the range of desired signals From Scott Huettel, Duke

19. What are the temporal limits? • What is the shortest stimulus duration that fMRI can detect? • Blamire et al. (1992) – 2 sec • Bandettini (1993): 0.5 sec • Savoy et al (1995): 34 msec • With enough averaging, anything seems possible. • Assume that the shape of the HRF is predictable. • Event-related potentials (ERPs) are based on averaging small responses over many trials. • Can we do the same thing with fMRI?

20. Assumption of steady-state dynamics. For block designs we assume that the BOLD effect remains constant across the epoch of interest. For PET this assumption is valid given the half-life of the radiotracer used for CBF studies, task designs, and the time period for the image acquisition. But the BOLD response is much more transient and more importantly may vary according to brain regions and stimulus durations and maybe even stimulus types. Savoy et al., 1995

21. Limitations of Blocked Designs • Sensitive to signal drift or MR instability • Poor choice of conditions/baseline may preclude meaningful conclusions • Many tasks cannot be conducted well repeatedly

22. Non-Task Brain Processing • In experiments activation can be greater in baseline conditions than in task conditions! • Requires different processing for interpretation • Suggests the idea of baseline/resting mental processes • Gathering/evaluation about the world around you • Awareness (of self) • Online monitoring of sensory information • Daydreaming • Neurons that are wired together fire together • This collection of resting state brain processes is often called the “Default Mode Network” (DMN)

23. Default Mode! Resting State Networks (RSNs) Vision. Frontal Parietal Damoiseaux 2006 analyzed separate 10-subject resting-state data sets, using Independent Components analysis (ICA).

24. Event-Related Designs

25. Buckner et al., 1998 Event Related

26. What are Event-Related Designs? • Event-related designs associate brain processes with discrete events, which may occur at any point in the scanning session. • Can detect transient BOLD responses • Supports adapting task to response such as changing difficulty based on error rate

27. Why use event-related designs? • Some experimental tasks are naturally event-related (future stimuli based on response) • Allows studying within-trial effects • Improves relation to behavioral factors (behavior changes within blocks may be masked) • Simple analyses • Selective averaging • General linear models (GLM)

28. Same Event Averaging • Sorting Into Common Groups • Behavior • Physiological Measure • Outlier Rejection • Transient vs. Task level Responses

29. 500 ms 500 ms 500 ms 500 ms 18 s 18 s 18 s Periodic Single Trial Designs • Stimulus events presented infrequently with long inter-stimulus intervals (ISIs)

30. ISI = 12sec (15 trials) ISI = 8sec (~12 trials) ISI = 4sec (~45 trials) Trial Spacing Effects: Periodic Designs ISI = 20sec (9 trials) A20 A12 A4 A8 Want to maximize amplitude times number of trials per study

31. Bandettini & Cox, 2000 • The optimal inter-stimulus interval (ISI) for a stimulus duration (SD), was determined. • Empirical Observation: For SD=2sec, ISI=12 to 14 sec. • Theory Predicts: For SD<=2 sec, the optimal repetition interval (RI=ISI+SD) • Theory Predicts: For SD>2sec, RI = 8+(2*SD). • The statistical power of ER-fMRI relative to blocked-design was determined • Empirical: For SD=2 sec, ER-fMRI was ~35% lower than that of blocked-design • Simulations that assumed a linear system demonstrated estimate ~65% reduction in power • Difference suggest that the ER-fMRI amplitude is greater than that predicted by a linear shift-invariant system models.

32. Jittered Single Trial Designs • Varying the timing of trials within a run • Varying the timing of events within a trial 1 event 2 events 3 events 2 events Trial 1 Trial 2 Trial 3 Trial 4

33. Effects of Jittering on Response Stimulus Response Jittering allows us to sample BOLD response in more states

34. Effects of ISI on Detectability Jittered ISI Detectability Constant ISI Max when ½ stims are task state and ½ stims are control state Estimated Accuracy of HRF Birn et al, 2002

35. Detecting Using Selective Averaging Visual stim duration = 1 s; acquisition 240 sec Trials subtracted then correlation analysis with predicted response Large Response Most samples Mid Response More Samples Low Response Fewer Samples Dale and Buckner (1997)

36. Variability of HRF: Evidence • Aguirre, Zarahn & D’Esposito, 1998 • HRF shows considerable variability between subjects different subjects • Within subjects, responses are more consistent, although there is still some variability between sessions same subject, same session same subject, different session

37. Variability of HRF: Implications • Aguirre, Zarahn & D’Esposito, 1998 • Generic HRF models (gamma functions) account for 70% of variance • Subject-specific models account for 92% of the variance (22% more!) • Poor modeling reduces statistical power • Less of a problem for block designs than event-related (do you know why?) • Biggest problem with delay tasks where an inappropriate estimate of the initial and final components contaminates the delay component • Possible solution: model the HRF individually for each subject • Possible caveat: HRF may also vary between areas, not just subjects • Buckner et al., 1996: • noted a delay of 0.5-1 sec between visual and prefrontal regions • vasculature difference? • processing latency? • Bug or feature? • Menon & Kim – mental chronometry

38. Post-Hoc Sorting of Trials True Memory Formation vs. False Memory Formation Using information about fMRI activation at memory encoding to predict behavioral performance at memory retrieval. From Kim and Cabeza, 2007

39. Limitations of Event-Related Designs • Low power (maybe) • Collecting lots of data, many runs • The key issues are: • Can my subjects perform the task as designed? • Are the processes of interest independent from each other (in time, amplitude, etc.)?

40. Mixed Designs

41. Mixed: Combination Blocked/Event • Both blocked and event-related design aspects are used (for different purposes) • Blocked design: state-dependent effects • Event-related design: item-related effects • Analyses can model these as separate phenomena, if cognitive processes are independent. • “Memory load effects” vs. “Item retrieval effects” • Or, interactions can be modeled. • Effects of memory load on item retrieval activation.

42. You can model a block with events… Event-related model reaches peak sooner… Blocked (solid) Event-Related (dashed) … and returns to baseline more slowly. In this study, some language-related regions were better modeled by event-related. From Mechelli, et al., 2003

43. Mixed Design

44. 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

45. What is fMRI Experimental Design? • Controlling the timing and quality of cognitive operations to influence brain activation • What can we control? • Stimulus properties (what is presented?) • Stimulus timing (when is it presented?) • Subject instructions (what do subjects do with it?) • What are the goals of experimental design? • To test specific hypotheses (i.e., hypothesis-driven) • To generate new hypotheses (i.e., data-driven)

46. Experimental Designfor Functional MRI David Glahn Updated by JLL