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Y P O C Intensive Course in Transcranial Magnetic Stimulation T O N O D E The cause of, and solution to, some of TMSs variability S And a way to potentially increase its selectivity and efficacy A E Peter J. Fried, Ph.D. L

  1. Y P O C Intensive Course in Transcranial Magnetic Stimulation T O N O D E “The cause of, and solution to, some of TMS’s variability S And a way to potentially increase its selectivity and efficacy” A E Peter J. Fried, Ph.D. L P October, 2017

  2. Y P O C T  What is ‘state-dependency’? O  Single Pulse TMS (specificity) N  Repetitive TMS (meta-plasticity, variability) O  Implications for study design D E S A E L P 2

  3. Y P O C T O Input N O The basal or ongoing state of the brain Something D in the influences the outcome of stimulation middle E S A E L Output P 3

  4. Y P O C Test pulse Conditioning Pulse T (alone) + Test Pulse O N Intracortical Inhibition O (ISI = 1-6ms) D Intracortical E Facilitation (ISI = 8-30ms) S A E L P Modified from: Kobayashi & Pascual-Leone, 2003 (Lancet Neurology) 4

  5. Y P O C T  What is ‘state-dependency’? O  Single Pulse TMS (specificity) N  Adaptation & Priming O  Repetitive TMS (meta-plasticity) D  Implications for study design E S A E L P 5

  6. Y P O C T O Adaptation: Prolonged prior exposure to stimulus reduces N neural activity and response to subsequent presentation O D Priming: Transient prior exposure to stimulus increases E neural activity and response to subsequent S presentation A E L P 6

  7. Y P O C T O N O + D E S A E L P

  8. Y P O C T O N O + D E S A E L P

  9. Y P O C T Relative neural activity O N O D Baseline After adaptation to red After TMS E S A E Modified from: Silvanto et al., 2008 (Trends in Cognitive Sciences) L P 9

  10. Y P O C T O N O D E S A E L P Cattaneo & Silvanto, 2008 (NeuroReport) 10

  11. Y P O C T O N O D E S A E L P Cattaneo et al., 2008 (European Journal of Neuroscience) 11

  12. Y P O C T   neural activity =  TMS susceptibility O N  Adaptation/Priming can O improve selectivity of TMS D E  “Functionally independent, spatially S A overlapping populations of neurons” E L P 12

  13. Y P O C T  What is ‘state-dependency’? O  Single Pulse TMS (specificity) N  Repetitive TMS (meta-plasticity) O  Inter-individual variability D  Altered impact in disorders E S  Preconditioning, multiple sessions A  Implications for study design E L P 13

  14. Y P O C T O N O D E S A E L P 14

  15. Y P O C T O 1600 pulses 240 pulses N O D E S A E L P

  16. Y P O C 100% T Spatial Accuracy O 100% 95% N * 95% O 90% D 90% 85% E 85% S A 80% 80% E Baseline Post-rTMS L 75% P 70% Modified from Fried et al., 2014 Baseline Post-rTMS

  17. Y P O C T O Impact of 1Hz rTMS on Motor-Evoked Potential (MEP), Intracortical Facilatition and Inhibition N O D E S A E L Brighina et al., 2005 (Experimental Brain Research) P 18

  18. Y P O C Iezzi E et al., 2008 (J Neurophysio) T O N O D E S A E L P 21

  19. Y P O C T O N O D E S A E L P 22

  20. Y P O C Impact of tDCS/rTMS on Motor-Evoked Potential (MEP) amplitude T O N O D E S A E L Siebner et al., 2004 (Journal of Neuroscience) P 23

  21. Y P O C T O N O D E S A E L P 24

  22. Y P O C Impact of daily 1Hz rTMS on visuo-spatial detection T O Impact of rTMS on Motor-Evoked Potentials N O D E S A E Maeda et al., 2000 (Clinical Neurophysiology) L P Valero-Cabré et al., 2008 (European Journal of Neuroscience) 26

  23. Y P O C T O Impact of TBS on Motor-Evoked Potential (MEP) Amplitude Cumulative Impact of Back-to-Back TBS N 5 Log Transformed "time to baseline" values 4.5 O 4 3.5 ASD D 3 FXS 2.5 E 2 Control 1.5 S 1 A 0.5 0 E 1 2 Session Number L Oberman et al., 2012 (European Journal of Neuroscience) Oberman et al., 2016 (J Child Adolescent Psychopharm) P 27

  24. Y P O C T O N O D E S A E L P Fried et al., 2017 (Frontiers in Aging Neuroscience) 28

  25. Y P O C T O N O D E S A E L P Fried et al., 2017 (Frontiers in Aging Neuroscience) 29

  26. Y P O C T O N O D E S A E L P Fried et al., 2017 (Frontiers in Aging Neuroscience) 30

  27. Y P O C T  Impact of rTMS not absolute O  Low/High Hz doesn’t always suppress/enhance N  Can be influenced by disorder O  Assess reliability/stability of outcome variable D  Presence of “homeostatic” forces E  Very short interval (≤ 1 s)  basis of rTMS S  Back-to-back regimens  likely to cancel out A E  Daily sessions  build up facilitation L  Meta-plastic effects might last up to a week P 31

  28. Y P O C T  What is ‘state-dependency’? O  Single Pulse TMS (specificity) N  Repetitive TMS (meta-plasticity) O  Implications for study design D  Follow the three C’s E S  Predicting Therapeutic Outcome A  To sham or not to sham E L P 32

  29. Y P O C T Easy to control Less Easy to Control O  Caffeine, Rx  Amount of sleep N  Prior stimulation  Menstrual cycle O  Time of day  Stress, mood D  Food intake  Disease heterogeneity E  Handedness  Baseline activity S A  Concomitant activity  Expectation E  DNA L P 33

  30. Y P O C T  Modulates NMDAR-dependent plasticity O  Activity-dependent release at synapses N O pro-BDNF D Mature BDNF E S A 65%: val66val E 35%: val66met (less efficient) L Single substitution of Guanine for Adenine results in an P amino acid switch from Valine (Val) to Methionine (Met)

  31. Y P O C T  Produced by astrocytes, microglia (in CNS) O  Transports cholesterol & fat-soluble vitamins N to neurons O  Three major isoforms: D  ApoE2 (cys112, cys158): ~7% E S  ApoE3 (cys112, arg158): ~79% A  ApoE4 (arg112, arg158): ~14% E ▪ E3,E4 & E4,E4: Higher risk for Alzheimer’s disease L P 35

  32. Y P O p = 0.0537 p = 0.0051* C Effect size = 0.35 Effect size = 0.52 T BDNF Val/Met & ApoE ε3/ε4 All subjects excluded O 80 MEP Amplitude (% ∆ from baseline) N 60 O 40 D E 20 S 0 A OHC DM2 OHC DM2 E -20 L Unpublished work – please do not share P For full study, see Fried et al., 2016 (J Alzheimer’s Disease)

  33. Y P O C T O N O D E S A E L P Fried et al., 2017 (Frontiers in Aging Neuroscience) 37

  34. Y P O C T  Collect / Correlate O N  Control / Counter-balance O D  Co-opt / Capitalize E S A E L P 38

  35. Y P O C T O N O D E S A E L P Eschweiler et al., 2000 (Psychiatry Res.: Neuroimaging) Weiduschat and Dubin, 2013 (J Affective Disorders) 39

  36. Y P O C T O N O D E S A E L P Fox et al., 2012 (Biological Psychiatry) Mottaghy et al., 2002 (Psychiatry Res.: Neuroimaging) 40

  37. Y P O C T O N O D E S A Li et al., 2016 (Cerebral Cortex) E L P 41

  38. Y P O C T  Individualized targeting O  Single node vs. network N  Prime sub-populations of neurons O  Intrinsic vs. extrinsic engagement D  Assess efficacy online E S  Custom dose A  Leverage placebo effect E L P 42

  39. Y P O C T  Only ~14% of randomized sham-controlled O trials report blinding success (Broadbent et al. 2011, World J N Bio Psychiatry) O D  Patients correctly guessed Tx condition above E chance (Berlim et al. 2013, Int J Neuropsychopharm) S A E L P 43

  40. Y P O C T O real sham Pros: N Easy, fast, cheap O No switching coils D Similar sensations E S Cons: A Might induce current E Won’t fool non-naïve L P 44

  41. Y P O C T O real sham Pros: N Similar look and feel O Tech getting better D E Cons: S Slow, expensive A Must switch coils E Still doesn’t feel the same L P 45

  42. Y P O C T O real vertex Pros: N Easy, fast, cheap O Same sensations D E Cons: S Will control site have A real effects? E Laterality of sensations L P 46

  43. Y P O C T O Left hemisphere Right hemisphere Pros: N Easy, fast, cheap O Same sensations D Greater explanatory E power S A Cons: E More difficult study design L P 47

  44. Y P O C T O N What state- O dependency? D E S A E L P 48

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