Paired stimulation to enhance spared circuit function after SCI

Transcription

1 Paired stimulation to enhance spared circuit function after SCI TMS Noam Y. Harel, MD, PhD James J. Peters VA Medical Center Icahn School of Medicine at Mt. Sinai CES

2 Disclosures No financial or other conflicts of interest. Funding acknowledgments: VA RR&D B9212-C, B0881-W NYSCIRB C30599 Neilsen Foundation Mount Sinai Neurology

3 Clinically complete Anatomically complete There is tissue left to work with >50% of Complete SCI patients retain evidence for intact fibers Stroke TBI Bunge 1993 Kakulas 1999 Dimitrijevic (many papers) SCI

4 Activity-Dependent Recovery through Rerouting, Plasticity Not Regeneration Targeted exercises Electromagnetic stim

5 Various forms of neurostimulation Modality: magnetic vs electric vs tactile Site: brain vs cord vs peripheral nerve vs muscle Route: invasive vs non-invasive Timing: phasic vs repetitive vs continuous (direct) Intensity: subthreshold vs suprathreshold Combinations: single-site vs multi-site stimulation Loops: open vs closed Other: approx other factors to consider

6 Cervical electrical stimulation (CES) Non-invasive; phasic (not direct) C4-C5 T2-T4

7 Cervical electrical stimulation (CES) Potential advantages: Non-invasive, can be applied during exercise (TMS) Can measure mechanistic outcomes (DCS) Multiple levels Both sides simultaneously (TMS) Potential disadvantages: Non-invasive à less focal Risk of cervical complications eg autonomic dysreflexia?

8 Cervical electrical stimulation (CES) Preliminary testing 15 able-bodied volunteers, 9 C-SCI, 5 ALS Exclusions: recent autonomic dysreflexia, seizures, implanted electrical devices, tracheostomy, etc Biphasic 2ms pulses, cathode posterior >150 CES sessions completed so far, no SAEs Several SCI subjects elevated SBP from 90s to 150s-160s clinicaltrials.gov NCT

9 SCI Subjects Gender Age Trauma /NT DOI Level Grade CES Threshold (ma) TMS Threshold (%MSO) M 29 T 3yr C8 C M 52 T 17yr C8 C M 64 T 14yr C4 D M 57 T 12yr C4 D M 40 T 14yr C4 D 19* 68 M 43 T 14yr C5 D M 54 T 6yr C5 C F 52 T 16yr C4 B F 22 NT 1yr C5* C 3 37 Screen Failures: M 36 T 7yr C5 D nd 69 M 54 T 4yr C4 D nd M 35 T 12yr C4 B M 36 T 11yr C3 C 46 F 61 T 20yr C2 D 5.5

10 CES pathways Efferent (non-synaptic) vs Afferent (trans-synaptic) root stim CES CES Peripheral conduction time Non-synaptic Trans-synaptic C4-C5 T2-T4 40 ms clinicaltrials.gov NCT

11 Paired stimulation to strengthen cervical synaptic circuits TMS Antidromic (PNS) Root stim (CES) Other supraspinal AFFERENT (CES) UMN (CST) LMN (CES) (PNS) (TMS) Taylor and Martin, 2009 Bunday and Perez, 2012

12 Paired stim - Immediate Effects Test combinations of TMS and CES TMS 120%, CES SUB-threshold Paired pulses timed for TMS arrival at cervical synapses either ms prior or 10 ms after arrival of CES MEP amp (measured on a pulse-to-pulse basis) TMS (120% MT) Subthreshold CES TMS-pre-CES 1-5 ms CES-pre-TMS 10 ms

13 Paired stim - Immediate Effects Sub-threshold CES facilitates ensuing APB MEP Timing-dependent TMS 120% CES 80-90% clinicaltrials.gov NCT

14 Paired stim - Immediate Effects Sub-threshold CES facilitates ensuing ADM MEP Timing-dependent TMS 120% CES 80-90% clinicaltrials.gov NCT

15 CES so far Safety: no SAEs; some asymptomatic increased BP Distribution: Activates multiple upper extremity myotomes bilaterally Mechanism: Root activation; sensory afferents at lower intensity, motor efferents at higher intensity Paired SUB-threshold CES with TMS: CES facilitates ensuing MEP via timing-dependent convergent synaptic firing TMS 120% CES 80-90%

16 Next steps Analyze more outcomes and stimulus intervals Cortical silent period; F-wave persistence; H-reflexes; etc Model electric fields, effects of injury/surgery/ hardware Repetitive stimulation/lasting effects Autonomic effects? Combine with exercise and/or meds Closed loop stimulation (EMG-controlled) See poster by Yu-Kuang Wu

17 Thanks! Pierre Asselin Eric Bailey William Bauman Denis Doyle-Green Kenlys Fajardo Kenny Guber Henry Hauser Jasmeen Hussain Shivani Kastuar Steven Knezevic Stephen Kornfeld James LiMonta Matt Maher Stephanie Martinez Nunu Nguyen Angelica Romero Sana Saeed Tiffany Santiago Ann Spungen Melissa Veale Jill Wecht Yu-Kuang Wu Ajax Yang Lok Yung William Zerbarini SINAI Thomas Bryce Marcel Dijkers Miguel Escalon Joseph Herrera Vince Huang Allan Kozlowski David Putrino Stuart Sealfon Chung-ying Tsai Junqian Xu ELSEWHERE Marom Bikson Jason Carmel Maria Knikou Jack Martin Gale Whiteneck