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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 A E Peter J. Fried, Ph.D. L P June, 2019 Y P O C T What is

  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 A E Peter J. Fried, Ph.D. L P June, 2019

  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 T Test pulse Conditioning Pulse (alone) O + Test Pulse N Intracortical Inhibition O (ISI = 1-6ms) D Intracortical Facilitation E (ISI = 8-30ms) S A E L Modified from: Kobayashi & Pascual-Leone, 2003 (Lancet Neurology) P 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 O presentation D Priming: Transient prior exposure to stimulus increases E neural activity and response to subsequent presentation S 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 O Relative neural activity 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 Cattaneo & Silvanto, 2008 (NeuroReport) P 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 overlapping populations of neurons” A E L P 12

  13. Y P O C T O N O D E S A E L P Zrenner et al., 2018 (Brain Stimulation) 13

  14. 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 14

  15. Y P O C T  ≥10 Hz rTMS / iTBS O N O D  ~1 Hz rTMS / cTBS E S A E L P 15

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

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

  18. 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 Brighina et al., 2005 (Experimental Brain Research) L P 19

  19. Y P O C T O N O D E S A E L P Iezzi E et al., 2008 (J Neurophysio) 22

  20. Y P O C T O 80 N 60 MEP amplitude (%∆ from baseline) 40 O 20 D 0 Visit-A Visit-B E -20 S -40 A -60 E -80 Baseline T5-T20 T30-T40 T50-T60 L Time relative to iTBS P 23

  21. Y P O C T Impact of tDCS/rTMS on Motor-Evoked Potential (MEP) amplitude O N O D E S A E L Siebner et al., 2004 (Journal of Neuroscience) P 24

  22. Y P O C T O N O D E S A E L P 25

  23. Y P O C T Impact of daily 1Hz rTMS on visuo-spatial detection O N Impact of rTMS on Motor-Evoked Potentials O D E S A E Maeda et al., 2000 (Clinical Neurophysiology) L P Valero-Cabré et al., 2008 (European Journal of Neuroscience) 27

  24. 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 0.5 A 0 1 2 E Session Number L Oberman et al., 2012 (European Journal of Neuroscience) Oberman et al., 2016 (J Child Adolescent Psychopharm) P 28

  25. Y P O C T O N O D E S A E L Fried et al., 2017 (Frontiers in Aging Neuroscience) P 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 O N O D E S A E L P Fried et al., 2017 (Frontiers in Aging Neuroscience) 31

  28. Y P O C T R 24 = .49, p = .012 O N O D E Ratio: AMT/RMT S A E L P Unpublished data – do not share 32

  29. 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 interact A  Daily sessions  build up facilitation E  Meta-plastic effects might last up to a week L P 33

  30. 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  Predicting Therapeutic Outcome S A  To sham or not to sham E L P 34

  31. 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  Concomitant activity A  Expectation E  DNA L P 35

  32. Y P O C T Brain-derived neurotrophic factor (BDNF) Apolipoprotein E (APOE)   O   Modulates NMDAR-dependent plasticity Produced by astrocytes, microglia (in N CNS)  Activity-dependent release at synapses  Transports cholesterol & fat-soluble vitamins to neurons O pro-BDNF Mature BDNF  Three major isoforms: D ▪ ApoE2 (cys112, cys158): ~7% ▪ ApoE3 (cys112, arg158): ~79% E 65%: val66val ▪ ApoE4 (arg112, arg158): ~14% S 35%: val66met (less efficient) ▪ E3,E4 & E4,E4: Higher risk for Alzheimer’s disease A Single substitution of Guanine for Adenine E results in an amino acid switch from Valine (Val) to Methionine (Met) L P

  33. 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 O excluded 80 MEP Amplitude (% ∆ from baseline) N 60 O 40 D E 20 S 0 A OHC DM2 OHC DM2 E -20 L P For full study, see Fried et al., 2016 (J Alzheimer’s Disease)

  34. Y P O C T O N O D E S A E L P Fried et al., 2017 (Frontiers in Aging Neuroscience) 38

  35. Y P O C T  Collect / Correlate O N  Control / Counter-balance O D  Co- opt / Capitalize E S A E L P 39

  36. Y P O C T Perfusion MRI O NIRS N O D ∆ HAM -D E S A E L Eschweiler et al., 2000 (Psychiatry Res.: Neuroimaging) P Weiduschat and Dubin, 2013 (J Affective Disorders) 40

  37. Y P O C Resting-state functional connectivity MRI rCBF (SPECT) T O N O D E S A E L P Fox et al., 2012 (Biological Psychiatry) Mottaghy et al., 2002 (Psychiatry Res.: Neuroimaging) 41

  38. Y P O C T O N O D E S A Li et al., 2016 (Cerebral Cortex) E L P 42

  39. Y P O C T  Individualized targeting O N  Single node vs. network  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 43

  40. 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 44

  41. 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 45

  42. 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 46

  43. 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 47

  44. 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 48

  45. Y P O C T O N What state- O dependency? D E S A E L P 49

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