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APPLICATIONS OF REAL TIME FMRI: PAIN TREATMENT AND SUBSTANCE ABUSE TREATMENT

APPLICATIONS OF REAL TIME FMRI: PAIN TREATMENT AND SUBSTANCE ABUSE TREATMENT. MARCH 2007 THIS WORK SUPPORTED BY NIH:. SPECIAL THANKS FOR HELP AND GUIDANCE Nora Volkow, NIDA Ro Nemeth, NIDA Dave Thomas, NIDA Larry Stanford, NIDA Linda Porter, NINDS. COLLABORATIVE TEAM. TALK OUTLINE.

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APPLICATIONS OF REAL TIME FMRI: PAIN TREATMENT AND SUBSTANCE ABUSE TREATMENT

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  1. APPLICATIONS OF REAL TIME FMRI:PAIN TREATMENT AND SUBSTANCE ABUSE TREATMENT MARCH 2007 THIS WORK SUPPORTED BY NIH: SPECIAL THANKS FOR HELP AND GUIDANCE Nora Volkow, NIDA Ro Nemeth, NIDA Dave Thomas, NIDA Larry Stanford, NIDA Linda Porter, NINDS

  2. COLLABORATIVE TEAM

  3. TALK OUTLINE

  4. DESCARTES VIEW OF BRAIN, AND PAIN

  5. IS IT POSSIBLE TO VISUALIZE THE MECHANISMS UNDERLYING PERCEPTION IN REAL TIME? fMRI

  6. CAN MRI BECOME A THERAPEUTIC MODALITY? Diagnostic Radiology DIAGNOSTIC • MRI provides answer • Very broad application 3T MRI Today

  7. CAN MRI BECOME A THERAPEUTIC MODALITY? Diagnostic Radiology Neuroimaging Therapy DIAGNOSTIC • MRI provides answer • Very broad application THERAPEUTIC • MRI provides patient improvement • Application in areas of severe need 3T MRI Today Tomorrow?

  8. RTFMRI AS A POTENTIAL NEW INTERFACE TO THE NERVOUS SYSTEM + Wires + Wires + Wires + Wires

  9. RTFMRI AS A POTENTIAL NEW INTERFACE TO THE NERVOUS SYSTEM + Wires + Wires + Wires + Wires + Photons

  10. Slice Thickness e.g., 6 mm MRI: IMAGES OF ANATOMY –PHYSICAL STRUCTURE OBLIQUE SLICES Number of Slices e.g., 10 Consecutive Slices Through SPACE

  11. ~2s fMRI: IMAGES OF PHYSIOLOGY –FUNCTION fMRI FUNCTIONAL IMAGES ARE DERRIVED FROM CHANGES IN T2*-SENSITIVE LOW-RESOLUTION IMAGES OVER TIME Same Spatial Slice Followed Through TIME ... 10 min of data collection

  12. ~2s Condition 1 Condition 2 fMRI FUNCTIONAL IMAGES ARE DERRIVED FROM DEVIATIONS IN LOW-RESOLUTION ANATOMICAL IMAGES Statistical Map superimposed on anatomical MRI image Same Spatial Slice Followed Through TIME Hours/days of analysis ... 10 min of data collection

  13. ~2s Condition 1 Condition 2 fMRI FUNCTIONAL IMAGES ARE DERRIVED FROM DEVIATIONS IN LOW-RESOLUTION ANATOMICAL IMAGES Region of interest (ROI) Statistical Map superimposed on anatomical MRI image Same Spatial Slice Followed Through TIME Hours/days of analysis ... 10 min of data collection

  14. ROI Time Course fMRI Signal (% change) ~2s Condition Time Condition 1 Condition 2 fMRI FUNCTIONAL IMAGES ARE DERRIVED FROM DEVIATIONS IN LOW-RESOLUTION ANATOMICAL IMAGES Region of interest (ROI) Statistical Map superimposed on anatomical MRI image Same Spatial Slice Followed Through TIME Hours/days of analysis ... 10 min of data collection

  15. OVERVIEW OF METHOD MRI acquires real time fMRI data (spiral or EPI) Real time fMRI analysis • Motion correction • Temporal filtering • Spatial filtering • Event-related averages • Pattern comparison Subjects (or patients or clinicians) watch their cognitive processes unfold ‘live’, depicted as simulated displays Image from story courtesy

  16. RTFMRI SETUP

  17. RTFMRI-BASED TRAINING – A MORE PRECISE, ANATAMICALLY TARGETED MEASURE THAN TRADITIONAL AUTONOMIC ‘BIOFEEDBACK’

  18. RTFMRI-BASED TRAINING – A MORE PRECISE, ANATAMICALLY TARGETED MEASURE THAN TRADITIONAL AUTONOMIC ‘BIOFEEDBACK’

  19. CHALLENGES WITH fMRI AS A MEASURE OF BRAIN FUNCTION “Neurophysiologist reaction”

  20. CHALLENGES WITH fMRI AS A MEASURE OF BRAIN FUNCTION

  21. RTFMRI AND COGNITIVE TRAINING TAKE-HOME EXERCISE

  22. RTFMRI AND COGNITIVE TRAINING TAKE-HOME EXERCISE

  23. RTFMRI AND COGNITIVE TRAINING TAKE-HOME EXERCISE

  24. REAL TIME FMRI TRAINING OF BRAIN FUNCTION Pre Post R L R L Activation target Learned regulation of spatially localized brain activation using real-time fMRI. NeuroImage (2004) 21, 436-443 deCharms, R. C., Christoff, K., Glover, G. H., Pauly, J. M., Whitfield, S., and Gabrieli, J. D.

  25. IMPACT OF RTFMRI TRAINING ON BRAIN ACTIVATION A) Pre-Training BOLD Individual C) Average 2 .6 .4 1 % signal Δ .2 -1 0 -2 B) Post-Training BOLD Individual D) Average 2 .6 .4 1 % signal Δ .2 -1 0 -2 E) Concurrent EMG 0 60s 1 mV 0 -1 60 120 180 240s 0 Time (s)

  26. TIME COURSE OF TRAINING EFFECT AND CONTROLS Whole brain control Sham Training, ROI Motor Task, ROI Post-Training Test, ROI Training, ROI .5 A) B) C) D) E) % signal Δ 0 Experimental + Feedback - Feedback Session III Session III Session III Sham Session II Session II Session II Session I Session I Session I

  27. CAN THIS APPROACH BE USED IN CLINICALLY IMPORTANT AREAS?

  28. 10 9 8 7 6 5 4 3 2 1 pain 0 10 8 0 2 4 6 stimulus TRANSLATING BASIC RESEARCH IN PAIN INTO A NEW POTENTIAL THERAPEUTIC APPLICATION AREA: NEUROIMAGING Rainville…Bushnell, Science 1997

  29. POTENTIAL TARGETS IN THE PAIN CONTROL SYSTEM Invasive Electrical Neurostimulation Provides Pain Relief Anterior Cingulate Rostral ACC Lateral Orbito- Frontal MI/SMA Potential Target Insula Amygdala Periaqueductal Gray SI/SII Pons/ Parabrachial nucleus Internal capsule Thalamus VPL/VPM Rostral Ventromedial Medulla Spinal Cord Dorsal Horn DCN Ascending Pain Perception System Descending Pain Control System

  30. RTFMRI TRAINING PROTOCOL IN HEALTHY SUBJECTS CYCLE, (3 blocks, 150s total) BLOCK DESIGN Rest 30s Increase 60s Decrease 60s Pain Pain Control over brain activation and pain learned by using real-time functional MRI.  Proceedings of the National Academy of Sciences (2005) deCharms, R. C., Maeda, F., Glover, G. H., Ludlow, D., Pauly, J. M., Soneji, D., Gabrieli, J. D., and Mackey, S. C.

  31. RTFMRI TRAINING PROTOCOL IN HEALTHY SUBJECTS CYCLE, (3 blocks, 150s total) BLOCK DESIGN Rest 30s Increase 60s Decrease 60s Pain Pain Briefing Pre-Tests Anatomicals Cycle 1 150s Cycle 2 150s Cycle 3 150s Cycle 4 150s Cycle 5 150s After Scan Ratings Debrief RUN, (5 cycles + ratings, 13min). 1-5 RUNS per TRAINING DAY) Control over brain activation and pain learned by using real-time functional MRI.  Proceedings of the National Academy of Sciences (2005) deCharms, R. C., Maeda, F., Glover, G. H., Ludlow, D., Pauly, J. M., Soneji, D., Gabrieli, J. D., and Mackey, S. C.

  32. RTFMRI TRAINING PROTOCOL IN HEALTHY SUBJECTS CYCLE, (3 blocks, 150s total) BLOCK DESIGN Rest 30s Increase 60s Decrease 60s Pain Pain Briefing Pre-Tests Anatomicals Cycle 1 150s Cycle 2 150s Cycle 3 150s Cycle 4 150s Cycle 5 150s After Scan Ratings Debrief RUN, (5 cycles + ratings, 13min). 1-5 RUNS per TRAINING DAY) ROI TARGET: rostral Anterior Cingulate Cortex

  33. RTFMRI TRAINING PROTOCOL IN HEALTHY SUBJECTS CYCLE, (3 blocks, 150s total) BLOCK DESIGN Rest 30s Increase 60s Decrease 60s Pain Pain Briefing Pre-Tests Anatomicals Cycle 1 150s Cycle 2 150s Cycle 3 150s Cycle 4 150s Cycle 5 150s After Scan Ratings Debrief RUN, (5 cycles + ratings, 13min). 1-5 RUNS per TRAINING DAY) ROI TARGET: rostral Anterior Cingulate Cortex SUBJECT INSTRUCTIONS: Written text describing cognitive modulation of pain • Attend to pain vs. attend away • Perceive the pain as more intense vs. less intense • Perceive the pain as harmful vs. only a tactile sensation

  34. 4 3 2 1 0 -1 RTFMRI TRAINING PROTOCOL IN HEALTHY SUBJECTS CYCLE, (3 blocks, 150s total) BLOCK DESIGN Rest 30s Increase 60s Decrease 60s Pain Pain Briefing Pre-Tests Anatomicals Cycle 1 150s Cycle 2 150s Cycle 3 150s Cycle 4 150s Cycle 5 150s After Scan Ratings Debrief RUN, (5 cycles + ratings, 13min). 1-5 RUNS per TRAINING DAY) ROI TARGET: rostral Anterior Cingulate Cortex SUBJECT INSTRUCTIONS: Written text describing cognitive modulation of pain • Attend to pain vs. attend away • Perceive the pain as more intense vs. less intense • Perceive the pain as harmful vs. only a tactile sensation SUBJECT DISPLAYS fMRI BOLD difference 0 50 100s

  35. rtfMRI-BASED TRAINING LEADS TO SPATIALLY-SPECIFIC CHANGES IN BRAIN ACTIVATION MEASURE: Thresholded T-statistic, (INCREASE – DECREASE) last run VS. (INCREASE – DECREASE) first run

  36. HEALTHY SUBJECTS LEARN INCREASED CONTROL OVER BRAIN ACTIVATION THROUGH THE COURSE OF TRAINING 0.6 * † 0.5 0.4 rACC activation (BOLD) 0.3 0.2 0.1 0 Training run 1 Training run 2 Training run 3 Final test run 4 MEASURE: Brain Activation, BOLD % Signal Change, (Increase Period – Decrease Period) from each pair of blocks, Averaged over N=8 Subjects

  37. HEALTHY SUBJECTS LEARN INCREASED CONTROL OVER PAIN THROUGH THE COURSE OF TRAINING 50 * * † 40 30 Pain intensity rating (% difference) 20 10 0 -10 Training run 1 Training run 2 Training run 3 Final test run 4 MEASURE: Pain Intensity Rating % Difference, (Increase Period Rating – Decrease Period Rating)/Average from each pair of blocks, Averaged over N=8 Subjects

  38. THE TIMECOURSE OF LEARNING OF CONTROL OVER BRAIN ACTIVATION MIRRORS THE TIME COURSE FOR CONTROL OVER PAIN 0.6 * † 0.5 0.4 rACC activation (BOLD) 0.3 0.2 0.1 0 Training run 1 Training run 2 Training run 3 Final test run 4 50 * * † 40 30 Pain intensity rating (% difference) 20 10 0 -10 Training run 1 Training run 2 Training run 3 Final test run 4

  39. LEARNED CONTROL OVER BRAIN ACTIVATION IN RACC LEADS TO CORRESPONDING CHANGES IN PAIN INTENSITY RATINGS FOR A CONCURRENT THERMAL STIMULUS 100 80 60 40 Pain intensity (% difference) 20 0 y=28.167x + 7.013 R=0.368 p<0.00076 -20 -40 -0.5 0 0.5 1 1.5 rACC activation (BOLD)

  40. FOUR CONTROL GROUPS WERE TRAINED USING SIMILAR OR IDENTICAL PROCEDURES BUT IN THE ABSENCE OF RACC RTFMRI INFORMATION

  41. THE LEARNED CONTROL OVER PAIN REQUIRES SPATIALLY-SPECIFIC RTFMRI INFORMATION 50 Pain Intensity 40 30 20 10 Change in pain rating (% difference) 0 -10 -20 -30 -40 rACC exper. group

  42. p<.01 † † p<.001 † † † p<.05 vs. experimental * p<.01 vs. experimental ** p<.001 vs. experimental *** THE LEARNED CONTROL OVER PAIN REQUIRES SPATIALLY-SPECIFIC RTFMRI INFORMATION 50 Pain Intensity 40 30 20 10 Change in pain rating (% difference) 0 -10 -20 -30 † † † † † *** * ** *** -40 rACC exper. group Attention control group I – rtfMRI control group II PCC control group III Yoked control group IV EFFECT CONTROL GROUPS, NO EFFECT

  43. p<.01 † † p<.001 † † † p<.05 vs. experimental * p<.01 vs. experimental ** p<.001 vs. experimental *** THE LEARNED CONTROL OVER PAIN REQUIRES SPATIALLY-SPECIFIC RTFMRI INFORMATION 50 Pain Intensity Unpleasantness 40 30 20 10 Change in pain rating (% difference) 0 -10 -20 -30 † † † † † *** *** * * ** *** *** ** -40 rACC exper. group Attention control group I – rtfMRI control group II PCC control group III Yoked control group IV EFFECT CONTROL GROUPS, NO EFFECT

  44. CAN THE PICTURES OF YOUR HEAD PROVIDE RELIEF?

  45. 4 3 2 1 0 -1 RTFMRI TRAINING PROTOCOL IN PAIN PATIENTS CYCLE, (3 blocks, 150s total) BLOCK DESIGN Rest 30s Increase 60s Decrease 60s Briefing Pre-Tests Anatomicals NO PAINFUL EXTERNAL STIMULI Cycle 1 150s Cycle 2 150s Cycle 3 150s Cycle 4 150s Cycle 5 150s After Scan Ratings Debrief RUN, (5 cycles + ratings, 13min). 1-5 RUNS per TRAINING DAY) ROI TARGET: rostral Anterior Cingulate Cortex SUBJECT INSTRUCTIONS: Written text describing cognitive modulation of pain • Attend to pain vs. attend away • Perceive the pain as more intense vs. less intense • Perceive the pain as harmful vs. only a tactile sensation SUBJECT DISPLAYS fMRI BOLD difference 0 50 100s

  46. PATIENT REPORT OF PAIN MEASURES PRIOR TO SCANNING Pain Rating Index

  47. PATIENT REPORT OF PAIN MEASURES PRIOR TO SCANNING AFTER SCANNING Pain Rating Index Pain Rating Index

  48. CHANGE IN PAIN RATINGS FOLLOWING RTFMRI TRAINING IN CHRONIC PAIN PATIENTS rACC rtfMRI experimental group 80 † † † 70 MPQ 60 VAS † † † p<.001 50 Change in pain rating (%) 40 30 20 10

  49. PATIENTS WHO LEARNED TO CONTROL RACC ACTIVATION SHOWED A CHANGE IN PAIN, OTHERS DID NOT y=0.422x + 0.085. R=0.9170. p<0.01 y=0.376x +0.392. R=0.9173. p<0.01 80 100 70 90 60 80 50 70 40 60 Change in MPQ (%) 30 Change in VAS (%) 50 20 40 10 30 0 20 -10 0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 -0.2 0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 rACC change in activation (BOLD) rACC change in activation (BOLD)

  50. A CONTROL GROUP, TRAINED USING AUTONOMIC BIOFEEDBACK, DID NOT SHOW THE SAME CHANGES IN PAIN rACC rtfMRI experimental group Autonomic feedback control group 80 † † † p<.02 p<.02 70 MPQ 60 VAS † † † p<.001 50 † † † Change in pain rating (%) 40 30 20 10 CONTROL GROUP, NO EFFECT EFFECT

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