1. Laboratory for Magnetic Brain Stimulation Felipe Fregni, MD, PhD Assistant Professor Harvard Medical School Neuromodulation for chronic pain

2. Why neuromodulation for the treatment of chronic pain? What do we know about chronic pain?

3. Chronic pain has a different pathophysiology as compared to acute pain syndromes It is associated with plastic changes in the nervous system - leading to the phenomenon of central and peripheral sensitization

4. Development of spontaneous activity in primary afferents Increase of mechanosensitiviy Activation of protein kinase C facilitates the response to sensory neurons to capsaicin Inflammation - production of multiple mediators - bind to G-protein receptors - activation of second messengers (alterations in gene expression and receptors Primary nociceptors mostly terminate in the spinal cord - second-order neurons exhibit plasticity dependent activity - repetitive activity induces long- lasting facilitation in the output system Brain activation - SI, SII - discrimation and intensity of pain; anterior cingulate cortex, insula and frontal cortex - emotional aspects of pain

5. In chronic pain, usually, there is no (or little) peripheral damage, injury or inflammation - it is a result of nervous system dysfunction Chronic pain is a result of maladaptive plasticity

6. Clinical examples Clinical conditions of chronic pain in which the pathophysiology is maladaptive plastic mechanisms -Phantom limb pain -Fybromyalgia -Pain in spinal cord injury -Pain in stroke

7. How to revert nervous system dysfunction associated with chronic pain? TENS Melzack and Wall - gate theory Spinal cord stimulation Vagal nerve stimulation? Deep Brain Stimulation Cortical stimulation - noninvasive and invasive techniques

8. Cortical Stimulation for the treatment of pain Initial experience with invasive stimulation - epidural stimulation of motor cortex is effective to reduce chronic pain (Tsubokawa, 1993) Animal study - the spinal cord was transected - hyperactivity in the thalamus that was decreased by motor cortex stimulation, but not sensory stimulation (Tsubokawa, 1991) Neuroimaging study - thalamic modulation associated with M1 stimulation (Garcia-Larrea, 1999)

9. PET scan after MCS

10. M1 stimulation for chronic pain

11. Noninvasive techniques of cortical stimulation Repetitive transcranial magnetic stimulation Transcranial direct current stimulation

12. Transcranial magnetic stimulation basic principles Magnetic field TMS coil Electric current

14. Transcranial Direct Current Stimulation

15. tDCS model Wagner & Fregni, 2007

16. Clinical studies

17. Initial experience - rTMS Cross-over study in which 60 patients with neuropathic pain received a single session of active and sham rTMS 10Hz (1000 pulses) rTMS of the primary motor cortex - single session Lefaucheur et al., JNNP, 2004

18. Khedr et al. - JNNP - 2005 Long-lasting effects 48 patients - post- stroke pain and trigeminal neuralgia 20Hz rTMS of the primary motor cortex - 5 consecutive sessions

19. rTMS for chronic visceral pain Initial study - site and parameters of stimulation (1Hz - right and left SII (secondary somatosensory area; 20 Hz - right and left SII; sham rTMS) Main outcome = %VAS reduction + % Medication reduction Fregni et al., Annals of Neurology, 2005

20. BaselineL-1HzR-1HzR-ShamL-20HzL-shamR-20Hz Opioid use during treatment

21. 2 weeks of rTMS for chronic visceral pain

22. Other strategies rTMS for migraine - site of stimulation (left DLPFC ) - preliminary studies with significant reduction of migraine attacks and medication use (Brighina, 2004) Other sites of stimulation - comparison of M1, SI, SMA and PM - pain reduction only after M1 stimulation (Hirayama, 2006) Prediction tool for epidural stimulation (Andre-Obadia, 2006)

23. Pooled analysis - meta-analysis Studies investigating M1 stimulation for chronic pain (rTMS and tDCS) 12 studies using nonivasive brain stimulation Risk ratio (responders rate) - active vs. sham rTMS - 2.64, 95% C.I., 1.63 – 4.30

24. Invasive vs. noninvasive brain stimulation 12 studies using non-invasive brain stimulation and 22 for invasive brain stimulation (open studies) Weighted responders rate: –72.6% (95% C.I., 67.7 – 77.4) invasive stimulation studies –45.3% (95% C.I., 39.2 – 51.4) noninvasive stimulation studies (36.8% (95% C.I., 30.5 – 43.0) for the rTMS studies and 71.4% (95% C.I., 52.1– 90.7) for tDCS studies)

25. Find a marker for pain changes - glutamate levels? Figure 4 - Areas that were studied in our preliminary MRS study (left and right SII) and the diagram below shows the concentration levels of each neurotransmitter (according to the ppm of the chemical substances).

27. Study design 17 patients with spinal cord injury and refractory chronic pain Randomized (1:2) to receive sham and active tDCS Baseline evaluation (2 weeks before) Treatment (5 days of treatment) Follow-up evaluation (after 2 weeks of treatment)

28. Site of stimulation

29. tDCS of the primary motor cortex for the treatment of central pain due to spinal cord injury - Fregni et al., Pain, 2006 * * * ** * * *

31. tDCS and fibromyalgia Extensive evidence suggests that fibromyalgia is associated with a central nervous system dysfunction: Recent evidence has shown that fibromyalgia is associated with specific brain activity changes. In a recent SPECT study, patients with fibromyalgia as compared to healthy controls showed a decrease in the regional cerebral blood flow in the thalamus, caudate nucleus and pontine tegmentum (1). I In addition it has long been demonstrated that antidepressants, such as tricyclics, improve pain in fibromyalgia (2) and recent studies suggest that centrally acting drugs such as dopaminergic drugs are effective in alleviating the symptoms of fibromyalgia as compared with placebo (3). Finally, this disorder is extremely refractroctory to peripheral treatments such as non-steroidal anti-inflamatory drugs 31

32. Methods Thirty-two patients (females only – mean age of 53.4 ± 8.9 years) participated in this study. The following assessments were made: pain measurement, quality-of-life/other domains of fibromyalgia, psychiatric symptoms, cognitive and safety evaluation and adverse events. Sleep assessment - polysomnography Stimulation - a constant current of 2mA intensity for 20 minutes - 3 groups: Anodal M1 Anodal DLPFC Sham tDCS 32

33. Results - main outcome (pain) The type 3 test of fixed effects revealed a significant effect of time (p<0.0001), group (p=0.007) and interaction term time vs. group (p<0.0001)

34. Results - sleep (1)

35. Results - sleep (2)

36. Questions Long-lasting effect? Efficacy of stimulation to other, non- sensorimotor cortical targets? Optimum timing of the brain stimulation? Brain stimulation for acute pain?

37. What we don’t know about chronic pain? Individual variability - why some individuals develop chronic pain - nature vs. nurture Is there specific neural circuits associated with different chronic pain syndromes - resolution of neuroimaging tools are not suficient Is it possible to cure chronic pain

38. Is it the perfect therapy for chronic pain? Far from it… Effects sizes are still modest Adverse effects associated with long-term use Loss of efficacy Is there a tolerability for brain stimulation?

39. Challenges for the future

40. Redesigning TMS technology Coils that can induce an electric current in deep areas - e.g. cone coils Changing pulse configuration - unidirectional square pulse might improve the efficacy of this method Continuous vs. variable frequency Modeling the electrical current

41. Methods of monitoring TMS treatment Neuroimaging techniques (SPECT, PET, fMRI) - “on-line” Bestmann et al., Neuroimage. 2005 “off-line” (immediate response or long- term treatments such as depression treatment) Fregni et al. Neurology. 2006 (in press) Spectroscopy to measure metabolite changes

42. EEG-guided TMS system EEG system to control TMS parameters Analysis of the TMS response - comparison between motor vs. prefrontal cortex (Kahkonen et al., Psychopharmacology (Berl), 2005) Klimesch et al showed that stimulation at alpha +1Hz frequency induces a larger cognitive performance gain

43. Enhancing rTMS effects - Effects of rTMS might be due to synaptic strengthening (LTP/LTD). - Baseline cortical activity would be an important predictor of the subsequent effects of rTMS Iyer et al., J Neurosci. 2003

44. Preconditioning rTMS with tDCS Siebner et al., Journal of Neuroscience, 2004

45. Theta burst stimulation Theta burst stimulation of the motor cortex produces a long-lasting and powerful effect on motor cortex physiology Huang et al., Neuron, 2005

46. Maintenance therapy - what to do after the induction phase? Recent studies showing that rTMS if applied once every 1 or 2 weeks is effective to maintain the beneficial therapeutic effects O'Reardon JP, Blumner KH, Peshek AD, Pradilla RR, Pimiento PC. Long-term maintenance therapy for major depressive disorder with rTMS.J Clin Psychiatry. 2005 Dec;66(12):1524-8. Li X, Nahas Z, Anderson B, Kozel FA, George MS. Can left prefrontal rTMS be used as a maintenance treatment for bipolardepression?Depress Anxiety. 2004;20(2):98-100. Our experience shows that it is possible to maintain patients in remission for several years using rTMS

47. Brain stimulation for the treatment of pain is not new…

48. Although there are some encouraging results, neuromodulation for chronic pain is still a relatively unexplored field and conclusions regarding its clinical effects at this stage are not yet possible.

49. ffregni@bidmc.harvard.edu Thank you