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TMS in animal models: D Methods and Applications O N Electric current O Magnetic field Electric Coil T field C O P Y Alexander Rotenberg, M.D., Ph.D. Director, Neuromodulation Program Boston Childrens Hospital Conflict of

  1. TMS in animal models: D Methods and Applications O N Electric current O Magnetic field Electric Coil T field C O P Y Alexander Rotenberg, M.D., Ph.D. Director, Neuromodulation Program Boston Children’s Hospital

  2. Conflict of Interest Disclosure D O Alexander Rotenberg N O Current: T Neuro’motion Inc. (technology for improving emotional control; co-founder) NeuroRex (medical advisor) Brainsway Inc. (research support [equipment and personnel]) C Soterix Medical Inc. (research support [equipment]) Neuroelectrics Inc. (research support [equipment]) O Journal of Central Nervous System Diseases (EIC) NIH NIMH, DoD, CIMIT, ERF, TRP (research grants) P Past: Y Neuropace Inc. (research grant and equipment) Nexstim Inc. (consultant) Sage Therapeutics Inc. (consultant) Fisher Family Fund and Fisher-Wallace Inc. (research support [unrestricted gift and equipment])

  3. TMS in animals D O N O T C O P Y

  4. Why TMS studies in animals? D O – Basic Science N – Translational O Research T C O P Y Poma et al., 2006

  5. Advantages of animal subject D O • Subject homogeneity N • Available histology O • Genetic / disease models T C O P Y Liebetanz et al., 2003

  6. Translational Relevance D O • Disease modeling N • TMS safety O • Neuronal connectivity T • Synaptic plasticity C O • Cortical organization P Y Charlet de Sauvage et al. 2007

  7. Induced dysfunction: neglect-like syndrome in cats D O N O T C O P Y Valero Cabre et al., 2005

  8. Frequency-Dependent 14 C-2DG uptake modulated in cat D O N 20 Hz on-line O T C 1 Hz on-line O P Y 20 Hz off-line Valero-Cabre et al. 2006

  9. No injury after prolonged TMS D O • Counter, 1995: N – No deleterious effect on AEP after 1000 pulses at 1Hz n O rabbits • Nishikiori, 1996: T – No cortical or brainstem lesions after ~1 month of daily C TMS in rabbits O • Liebetanz et al., 2003: P – No MRS or histologic changes after 5 days of 1 Hz rTMS Y • Charlet de Sauvage et al., 2007 – No DNA damage after 2000 TMS pulses

  10. Most translational research is with rodents D O • Well-described disease models N • Inexpensive O • Experiments may be translated to clinical care T • TMS effect can be examined at multiple levels: C whole animal, brain slice, single cell, etc. O Kistsen et al., P in progress Y

  11. Disadvantages of rat model D – Compromised stimulus focality O – Slightly more difficult EEG N – Required restraint or anesthesia O T C O P Y Kamida et al., 1998 Luft et al., 2001

  12. Stimulation protocols D O N O T C O P Y Frye, Rotenberg, et al. Child Neurol 2007

  13. Off-Center Coil D O EMG EMG N O T C O P Ground Rotenberg et al., 2009 Y

  14. Lateralized brachioradialis MEP D O N O T C O P Y

  15. Lateralized TMS in Rats D O N O T C O P Y

  16. Stimulation protocols D O N O T C O P Y Frye, Rotenberg, et al. Child Neurol 2007

  17. Measures of Cortical Excitability by Paired-Pulse TMS (ppTMS) D O Conditioning TMS Control N 1 Test TMS 2 O SICI; 2 ms ISI T C O ICF; 12 ms ISI 0.5 mV P 25 ms Y LICI; 200 ms ISI 0.5 mV 50 ms Rotenberg and Pascual-Leone, 2010

  18. Paired-Pulse Inhibition in rats D O N O T C O P Y Vahabzadeh et al., 2011

  19. Inhibition in rats preserved with anesthesia D O N O T C O P Y Vahabzadeh et al., 2011

  20. Inhibition lost with GABA-A antagonist / seizures D O N O T C O P Y Vahabzadeh et al., 2011

  21. PTZ Effects on MEP Inhibition by ppTMS A D O N O T C B O P Y

  22. Detection of cortical inhibition by MMG and ppTMS in unanesthetized rats D O MMG (Mechanomyography) N O T C O P Y Accelerometer

  23. EMG v.s MMG D O Input–output curve of MMG 0.15 0.10 N MMG (V) 0.05 0.00 -0.05 O 50ms -0.10 60%MO 70%MO 80%MO 90%MO 100%MO -0.15 T C O P EMG (Tibia anterior m.) Y MMG

  24. MMG testing during TMS D O N O T C O P Y Awake rat

  25. GABA A -mediated cortical inhibition following pentobarbital (PB) and pentylenetetrazole (PTZ) D O • reduced inhibition with PTZ and increased inhibition with PB N 200ms ISI Saline O PB 80 * PTZ * * % of unconditioned MMG T 60 C O 40 P 20 *** *** *** Y Left Right Ave (L+R) Pre P10 P60 Pre P10 P60 Pre P10 P60 Condition

  26. TMS in Experimental Epilepsy D O • Diagnostic N – Measure of cortical excitability O – Assessment of drug (or other intervention) effect T C • Therapeutic O – Anticonvulsant (seizure termination) P Y – Antiepileptic (seizure prevention)

  27. Fluid Percussion Injury: a post-traumatic epilepsy model D O N O T C O P Nature Protocols, 2011 Y McIntosh et al., 1989

  28. Reduced cortical inhibition in TBI: a marker for epileptogenesis? D O • Rats with TBI show less ppTMS-MMG inhibition relative to sham-TBI controls 6 weeks after injury, when post-traumatic N epilepsy develops. O Normal rats 120 T Chronic TBI rats * ** 100 % of unconditioned MMG C * * 80 O 2mm P 60 Y 40 20 0 L R L R L R 50ms ISI 200ms ISI 100ms ISI

  29. Loss of cortical inhibition after TBI D O 200ms ISI 100ms ISI 1.0 1.0 Sham control Sham control * N * TBI TBI * * * 0.8 * 0.8 ** O ** * * 0.6 0.6 T Ratio Ratio 0.4 0.4 C O 0.2 0.2 P 0.0 0.0 Pre 1WK 2WKS 3WKS 4WKS 5WKS 6WKS Pre 1WK 2WKS 3WKS 4WKS 5WKS 6WKS Y Time Time  Gradual decrease in LICI reaches significance at 1 week after TBI as compared to pre-values. More detailed data compared between sham and TBI group in LICI at 100 ms (C) and 200 ms ISI (D) following TBI. (*p<0.05, **p<0.01) Hsieh et al., ECCN 2011 abstr.

  30. General cortical architecture was not affected by TBI Sham control TBI (contra-lesion) TBI (lesion) D 2 4 6 2 4 6 2 4 6 NeuN I O II/III N O V T VI C O NeuN Layer V thickness P Y

  31. Parvalbumin (PV) interneurons are the major sub-type of cortical inhibitory neuron… D and vulnerable to oxidative stress O N O T C O P Y Gonchar et al., 2007, Front Neuroanat.

  32. Gradual loss of parvalbumin (PV)-cells after TBI D Post-TBI (contra-lesion) Sham control Post-TBI (peri-lesion) O 2 4 2 4 6 2 4 6 6 PV I N II/III O V T VI C Peri-lesion Contra-lesion O * *** P n.s. n.s. * *** Y

  33. Delayed increase in oxidative stress after TBI D Sham control Post-TBI (peri-lesion) Post-TBI (contra-lesion) 2 4 6 2 4 6 2 4 6 O 8-oxo-dG I N II/III O V T VI C Peri-lesion Contra-lesion O *** n.s. ** *** n.s. P Y n.s.

  34. Implications for Therapy D Antioxidant O (N-acetylcysteine) Neuroprotection N Oxidative stress (Otx2) O T ↓ Otx2 ↓ Perineuronal nets Impaired inhibition C O TBI Loss of PV-cells P PTE Y Epileptic seizure Lee et al., 2013

  35. D O N O T C O P Y

  36. Ceftriaxone treatment prophylaxes against posttraumatic seizures D O N O T C O P Y

  37. ppTMS as a biomarker in TBI treatment D O ppTMS-MMG at 200ms ISI Saline CTX 1.2 N O p=0.002 1.0 p=0.05 Ratio of unconditioned MMG p=0.04 T 0.8 p=0.07 C 0.6 O 0.4 P n=7 (saline) n=3 (saline) n=7 (saline) n=6 (CTX) n=3 (CTX) 0.2 Y n=7 (CTX) 0.0 Time Pre 1W 2W 3W 4W 5W 6W Hameed et al., 2014

  38. Stimulation protocols D O N O T C O P Y Frye, Rotenberg, et al. Child Neurol 2007

  39. Therapeutic TMS D O • Three potential targets: N O – Seizure T – Epilepsy C – Epileptogenesis O P Y

  40. Rat TMS-EEG methods D O N O EEG EKG T C O P Y Rotenberg, et al., 2005 Ives et al., 2006

  41. Spike Provocation by TMS in Rats D O N O T C O P Y Rotenberg, Brain Topogr 2010

  42. Rat “ deep ” TMS during seizure D O electric current magnetic field coil N electric field O T C O EEG analysis torso strap restraints P (seizure detection) Y

  43. Kainate (KA) Model Status Epilepticus D O • Three-Stage Effect: N – Acute 2-3 hour prolonged seizure O – Subacute 6-9 week seizure-free period T – Chronic daily recurrent seizures C O P Y

  44. Terminated KA seizure D O N O T C O P Y Ives, Rotenberg et al., Clin Neurophys2006

  45. Refractory KA Seizure D O N O T C O P Y 5 sec

  46. rTMS during KA seizure D O N O T C O P Y Rotenberg et al., Clin Neurophys 2008

  47. rTMS during KA seizures 150% D O Relative Average Seizure Duration 125% N (% untreated control) 100% O * T * 75% C O 50% P Y 25% 0% untreated active sham untreated active sham untreated active sham 0.25 Hz 0.5 Hz 0.75 Hz Rotenberg et al., 2008

  48. Reduced c-Fos expression D (and excitotoxicity?) O with 0.5 Hz rTMS N O T C O P Y KA only Control KA + TMS Rotenberg et al., AES abstr 2005

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