1. BRAIN PLASTICITY AFTER SPINAL CORD INJURY CORTICAL REORGANIZATION AFTER CHRONIC SCI Mar Cortes Non-invasive Brain Stimulation and Human Motor Control Lab Burke Medical Research Institute Cornell University New York

2. SCI PHASES AND KEY PATHOLOGICAL EVENTS Rowland et al, Neurosurg Focus, 2008

3. Prevention of injury Reduction of secondary damage Replacement of lost cells Strategies to enhance regeneration The development of new circuitry/ rehabiliation of remaining circuitry STRATEGIES FOR SPINAL CORD REPAIR Multiple systems affected - multivariety of approaches Neurophysiology – to understand the underlying mechanisims of dysfunction Neuromodulation - to enhance cortical/spinal cord excitability Training therapies - to enhance/repair motor function

4. MEP at 110% RMT 0.1mV 200ms 0.1 mV 20ms EMG at maximum voluntary contraction (MVC) Healthy Subject SCI Patient Edwards et al, in preparation BRAIN NETWORKS INVOLVED IN MOTOR CONTROL REMAIN RESPONSIVE IN CHRONIC PARALYSIS Motor Power 1/5 5/5

5. Transcranial Magnetic Stimulation: Mapping vertex Right hemisphereLeft hemisphere max

6. REORGANIZATION AND PRESERVATION OF MOTOR CONTROL OF THE BRAIN IN SCI Kotilo et al, J Neurotrauma (2011)

7. CORTICOMOTOR REPRESENTATION OF FOREARM MUSCLES FOLLOWING CERVICAL SCI AIM: Investigate changes in cortical map reorganization of forearm muscles with lack of voluntary activation but corticospinal response in chronic SCI non-invasively Preservation of corticospinal responses of impared muscles Changes in somatotopic localization Differences in map area and volume compared with healthies SIGNIFICANCE : Therapeutic strategies aiming for restoring spinal cord function even with chronic sci can build on a preserved competent brain control

8. CORTICAL REORGANIZATION AFTER CHRONIC SCI PATIENT # GENDERAGE LEVEL OF INJURY ASIA TYPE TIME SINCE INJURY MUSCLE SIDE MOTOR POWER 1F29 C4B2.3 FCRL1 2M31 C5B7.5 FCRL1 3M44 C4C1.8 ECRR1 4F55 C5A2.1 FCRR1 5M54 C6A2.2 FCRR1 6M70 C1D3 ECRR1 7F24 C4B5.8 ECRL1 8M17 C4B4 ECRR1 9M50 C6A29 FCRL0 10M50 C1C3 ECRL1 Presence of MEP > 100uV in forearm muscle, with normal latency range. Motor Power of forearm muscle 0-1/5. Chronic SCI (>1year after injury). Cervical injury. Tetraplegic. Traumatic/non-traumatic. Complete/Incomplete

9. CORTICAL REORGANIZATION AFTER CHRONIC SCI: OPTIMAL SITE LOCATION OF FOREARM MUSCLES Cz Right hemisphere Left hemisphere Healthy subjects (n=18) Chronic tetraplegic SCI (n=10) Cortes et al, in prep

10. CORTICAL REORGANIZATION AFTER CHRONIC SCI: MEDIAL SHIFT OF THE OPTIMAL SITE IN SCI SUBJECTS Cz Right hemisphere Left hemisphere Healthy subjects Chronic tetraplegic SCI

11. EMG BIOFEEDBACK MUSCLE SPECIFIC TRAINING RESTORES NEUROPHYSIOLOGICAL VALUES IN CHRONIC SCI Healthy subject SCI pre trainingSCI post training

12. CONCLUSIONS TMS GUIDED REHABILITATION Muscles that are profoundly affected after SCI, can be identified by TMS GREATER POTENTIAL FOR RECOVERY Muscles with corticospinal response to TMS, despite being clinically silent, may have biological substrate for functional enhancement, even in chronic phase CORTICAL REORGANIZATION AFTER CHRONIC SCI - Changes in cortical organization occurs after SCI - Clinically silent muscles in tetraplegic patients have a medial shift cortical representation, in the direction of the deafferented lower limb - The understanding of the cortical reorganization after chronic SCI may have implications for function recovery, by using therapeutic strategies that specifically target that brain area (brain stimulation protocols…)

13. Neuromodulation to enhance spinal excitability

14. 100μV 20ms TMS 80%RMT Only PNS Only Combined TMS 80%RMT +PNS TMS PNS 20ms Electrical Stimulator Magnetic Stimulator Peripheral stimulation of somatosensory afferents conditioned by TMS, increases spinal excitability, traduced in a larger H-reflex amplitude Cortes et al, Clin Neurophys, 2011

15. 90 paired stimuli PNS TMS 20ms 0.1 Hz 90001040302050890 sec PREPOST INTERVENTION (15 min) H-Reflex RC Neuromodulation paradigm to modulate spinal excitability: Spinal Associative Stimulation protocol

16. Repetitive paired stimulation can induce changes in excitability at the spinal cord level that are sustained after the intervention period H-reflex amplitude progressively increased over the paired pulse intervention period Left shift of the H reflex RC after the intervention period, with a lower threshold H-reflex recruitment curve

17. CONCLUSIONS Non-invasive Brain Stimulation can be used as a neuromodulatory tool to target spinal cord and induce changes and enhance excitability at that level SAS may be useful to strength residual pathways after incomplete injuries. SCI plastic changes outlast intervention period => therapeutic window to apply behavioral training in order to enhance motor recovery

18. FUTURE CONSIDERATIONS TO ENHANCE MOTOR RECOVERY AFTER SCI COMBINED THERAPIES BEHAVIORAL TRAINING NEUROMODULATION TECHNIQUES PHARMACOLOGY CELL TRANSPLANTAION NEUROPHYSIOLY GUIDED REHAB

19. ACKNOWLEDGEMENTS Dylan J Edwards Raj Ratan Bruce Volpe Avrielle Rykman Alvaro Pascual-Leone Gary Thickbroom Josep Valls-Sole

20. Thank you

21. Pre – trainingPost - training Chronic SCI motor performance after Upper limb Robotic Training