1. Robert W. McCarley, Presenter Cindy Wible, Marek Kubicki ( generated fMRI data), and Dean Salisbury (generated ERP data) Harvard, VA Boston Healthcare System, Brigham & Women’s Hospital Mismatch Negativity Paradigm for the fBIRN Presentation for fBIRN meeting at ICOSR, March 2003

2. MM Paradigm Desiderata The paradigm should show minimal contributions of other ERP components but at the same time produce a reliable fMRI signal. There are tradeoffs for each of these 2 points. For example, standard and deviant tones with small pitch differences are less likely to produce other components, but also are less likely to show the mismatch response as measured by fMRI. The mismatch task should show deficits in chronic, but not initially in first-episode patients. Progression over time should be evident in first-episode patients. Abnormalities should be associated with structural abnormalities in and near Heschl’s gyrus.

3. ERP & 3T fMRI Conclusions from Pilot Data Summary of Conclusions for 3T 3.0 and 3.15kHz pure tone and pink noise appear excellent in terms of other ERP components and fMRI signal strength but effects in schizophrenia unknown. Original 1 and 1.2 kHz pure tone stimuli also excellent in terms of ERP components and 3T signal strength. ***The proven ability of this stimulus to reveal differences in schizophrenia vs. controls and over time in schizophrenia make it a logical choice.*** In general, pure tones appear to produce better subtraction data. Two Runs are satisfactory on 3T, 13 minutes.

4. Pilot Work: ERP and fMRI (all 3T) Pink noise versus pure tones: reasoning from tonotopic organization, pink noise should produce more fMRI activation than pure tones. Pink noise spans 1/5 octave and is labeled with the center bandwidth. Steve Stufflebeam, MGH MEG lab. 3000 Hz versus 1000 Hz centered tones. (the ear is more sensitive in the 3000 Hz range and this frequency is not similar to the scanner noise (as is the 1,000 Hz tone). ERP experiments will help determine which types of stimuli are desirable in the fMRI experiments. http://splweb.bwh.harvard.edu:8000/pages/projects/BIRN/

5. ERP Pilot Work Dean Salisbury collected ERP Data using pure tone and pink noise stimuli with several different pitch separations. Parametric study. All ERPs are subtraction waveforms, deviant- standard. All stimuli presented with distracter visual task (checkerboard reversal, button press)

6. Original Pure Tone Paradigm, 1 kHz standard, 1.2 kHz deviant First Episode SZ Normal (progression with time) Chronic SZ Abnormal Strong correlation with Heschl’s gyrus Fz Cz Pz N=20 NC

7. Pink Noise 220 Hz standard, 4 octave deviant First Episode SZ ??? Chronic SZ ??? Heschl’s Gyrus ??? Fz Cz Pz N=7 NC P300a

8. Pure Tone, 3.0 kHz standard, 3.5 kHz deviant First Episode SZ ??? Chronic SZ ??? Heschl’s Gyrus ??? Fz Cz Pz N=4 NC P300a ?N2b

9. Pink Noise, 3.0 kHz standard, 3.5 kHz deviant First Episode SZ ??? Chronic SZ ??? Heschl’s Gyrus ??? P300 Fz Cz Pz N=4 NC

10. Fz Cz Pz N=3 NC Pure Tone, 3 kHz standard, 3.15 kHz deviant First Episode SZ ??? Chronic SZ ??? Heschl’s Gyrus ???

11. Fz Cz Pz N=3 NC Pink Noise 3 kHz standard, 3.15 kHz deviant First Episode SZ ??? Chronic SZ ??? Heschl’s Gyrus ???

12. 1.05 kHz deviant 1 kHz standard 1.2 kHz deviant 1.5 kHz deviant 3.15 kHz deviant 3 kHz standard 3.3 kHz deviant 3.5 kHz deviant N = 6 N = 5 N = 20 N = 3 N = 4 Pure tone MMN – long averaging epoch Control subjects’ grand averages Pink Noise MMN – long averaging epoch Control subjects’ grand averages 4 octave deviant 220 Hz standard 3.15 kHz deviant 3 kHz standard 3.3 kHz deviant 3.5 kHz deviant N = 7 N = 3 N = 4

13. ERP Pilot Results Summary 3.0 and 3.15kHz pure tone and pink noise appear good in terms of other components but effects in schizophrenia unknown. Pure tone gives slightly larger amplitude. Original 1 and 1.2 kHz stimuli also good.

14. FMRI Design: General The fMRI experiments used the same stimuli as the ERP experiments including a visual distracter on a GE 3T magnet. The designs shown used 2 control conditions, one presenting the standard tone and the other, the deviant tone. All results are shown with the 2 control conditions combined in the SPM99 analyses A block design was used as shown in the following slide:

15. Typical design: Block with visual distracter task. 3 runs, 4 blocks of the mismatch task usually with the higher frequency tone as the standard (95%) and the lower tone as the deviant (5%). Tones are 100 ms duration with 300 ms ISI. There are 2 types of control condition, one for each of the tones. R MC low R M R C high M R M Run 1: 6 min. 30 sec. R R MC low R M R C high M R M Run 2: 6 min. 30 sec. R R MC high R M R C low M R M Run 3: 6 min. 30 sec. R Control low Control high Mismatch

16. FMRI Pilot Work Task Duration. Each run takes 6 min., 30 seconds. One of the parameters varied was the number of runs, either 1, 2, 3 or 4 runs. On the 3T, we concluded that 2 runs would likely be sufficient for the paradigms tested = 13 minutes.

17. Example of varying number of runs. A subject with 4 runs: Pink Noise (3k and 3.5 k)

18. Pink Noise using 3000 Hz and 3500 Hz: 1,2,3 and 4 runs (one subject) 1 run 2 runs 3 runs 4 runs Mismatch Condition (vs. Rest) R L

19. FMRI Pilot Data All of the data in the presentation from this slide forward are analyzed using ONLY 2 RUNS.

20. Subject 4 using 3,000 Hz and 3,150 Hz pure tones.

21. Pure Tones using 3,000 Hz and 3,150 Hz tones (1 sub., 2 runs) Mismatch Condition 3000 k Hz Standard 3150 k Hz Deviant Control Condition 3000 k Hz Standard plus 3150 k Hz Deviant L R

22. Pure Tone 3000Hz and 3150Hz Glass Brains (1 sub, 2 runs) Mismatch Condition 3000 k Hz Standard 3150 k Hz Deviant Control Condition 3000 k Hz Standard plus 3150 k Hz Deviant LR

23. Pure tone using 3,000 Hz and 3,150 Hz: Difference Image (temporal lobe mask) Mismatch minus (Control 1 + Control 2) Masked (1 sub., 2 runs) R L

24. Same Subject: Pink noise data centered at 3.0 and 3.15 kHz.

25. Pink Noise using 3,000 Hz and 3,150 Hz tones (1 sub, 2 runs) Mismatch Condition 3000 k Hz Standard 3150 k Hz Deviant Control Condition 3000 k Hz Standard plus 3150 k Hz Deviant R L

26. Pink Noise 3000Hz and 3150Hz Glass Brains (1 sub, 2 runs) Mismatch Condition 3000 k Hz Standard 3150 k Hz Deviant Control Condition 3000 k Hz Standard plus 3150 k Hz Deviant L R

27. Different Subject (13): Pure Tones using 3,000 and 3,150 Hz tones Data virtually identical to other subject, only difference image shown

28. Pure Tones using 3,000 Hz and 3,150 Hz tones: Difference Image Mismatch minus (Control1 + Control2) Masked (1 sub., 2 runs) R L

29. Same subject using 3,000 Hz and 3,150 Hz pink noise. Data virtually identical to other subject, not shown.

30. 3.0 & 3.15 kHz Group Analyses (Not Masked): Mismatch minus Control (control 3 k + control 3.15 k) Pure Tones, 3 subjects R L R L Pink Noise, 2 Subjects

31. FMRI Pilot Data, 1.0 and 1.2 kHz pure tones 3 subjects using the original pure tones proposed in the grant application. Sample data from one subject (subject 11).

32. Pure Tones using 1,000 Hz and 1,200 Hz tones (1 sub, 2 runs) Mismatch Condition 1000 k Hz Standard 1200 k Hz Deviant Control Condition 1000 k Hz Standard plus 1200 k Hz Deviant R L

33. Pure Tones 1000Hz and 1200Hz Glass Brains (1 sub, 2 runs) Mismatch Condition 1000 k Hz Standard 1200 k Hz Deviant Control Condition 1000 k Hz Standard plus 1200 k Hz Deviant R L

34. FMRI Pilot Data – Other Frequencies Previously we had run 5 subjects using Pink Noise 3.0 and 3.5 kHz tones before ERP data were available. We show a single example (subject 1), and only the difference map.

35. Pink Noise, 3.0 and 3.5 kHz: Mismatch minus Control (control 3 k + control 3.15 k) Temporal Lobe Masked (1 sub., 2 runs) R L

36. FMRI Pilot Data Previously we had also run 2 subjects using the first pink noise stimuli, tones with the 4 octave difference 3,520 Hz and 220 Hz centered pink noise. We also ran 3.0 kHz and 3.25 kHz pink noise and pure tones. fMRI Activation (not shown) not very different from other pink noise data.

37. ERP & 3T fMRI Conclusions from Pilot Data Summary of Conclusions for 3T 3.0 and 3.15kHz pure tone and pink noise appear excellent in terms of other ERP components and fMRI signal strength but effects in schizophrenia unknown. Original 1 and 1.2 kHz pure tone stimuli also excellent in terms of ERP components and 3T signal strength. ***The proven ability of this stimulus to reveal differences in schizophrenia vs. controls and over time in schizophrenia make it a logical choice.*** In general, pure tones appear to produce better subtraction data. Two Runs are satisfactory on 3T, 13 minutes.