Non-Invasive Stimulation for Improving Motor Function

Non-Invasive Stimulation for Improving Motor Function in Spinal Cord Injury

The purpose of this study is to determine if spinal excitability is increased with a Spinal Associative Stimulation (SAS) protocol, and to determine the functional consequences of this technique on motor recovery.

Study Overview

• Status: Unknown
• Conditions: Spinal Cord Injuries
• Intervention / Treatment: Diagnostic test: Paired TMS & Peripheral Nerve Stimulation

Detailed Description

Recovery of motor function continues to be a problem following Spinal Cord Injury. Non-invasive brain stimulation techniques, targeting cortical areas, have been shown to enhance the excitability in the human motor cortex, and these changes in the motor cortex may be of significance for the rehabilitation of brain injured patients. However, little is known about the adaptational changes in the excitability/plasticity of spinal neural circuits in spinal cord injury patients.

The purpose of this study is to investigate the excitability of cortical and spinal inhibitory and excitatory mechanisms before and following a period of repetitive and synchronized dual peripheral nerve and brain stimulation. Repetitive, paired brain and peripheral nerve stimulation as a neuromodulatory tool, paired associative stimulation (PAS), has been well described. In this technique, stimuli are timed such that afferent and efferent volleys interact at the level of the cortex, that lead to a temporary enhancement of Motor Evoked Potential (MEP) amplitude in target muscles, and when applied repeatedly, lead to a sustained effect, outlasting the intervention period. This repetitive technique has been done in healthy subjects and patients with neurological diseases. By modifying the time between paired stimuli, the investigators will generate afferent/efferent interactions in the spinal cord.

The working hypothesis of this study is that the acute facilitation of the H-reflex during Paired TMS and peripheral nerve stimulation, may be harnessed to modulate spinal excitability (sustained increase in the MEP amplitude). That is, the investigators will test if similar to PAS, a change in excitability outlasting the stimulation/intervention period may occur with afferent/efferent interactions, although at the level of the spinal cord rather than the cortex, and be useful to strengthen residual pathways after damage to the spinal cord.

• Study Type: Interventional
• Enrollment (Anticipated): 30
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Mar Cortes, MD; Phone Number: 9143683181; Email: mac2083@med.cornell.edu
• Study Contact Backup: Name: Zoe Tsagaris, MS; Phone Number: 9145972153; Email: kzt3001@med.cornell.edu

Study Locations

• United States
  • New York
    • White Plains, New York, United States, 10605
      • Recruiting
      • Burke Medical Research Institute
      • Contact: Kathleen Friel, PhD; Phone Number: 914-368-3116; Email: braininjuryclinic@med.cornell.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Spinal cord injury subjects with chronic lesions (> 6 months after the injury)
• Motor incomplete lesion, measured by the American Spinal cord Injury Association (ASIA) Impairment Scale (AIS)
• Traumatic cause of lesion; d) Some degree of motor function in the ankle flexor and extensors (Low extremity Motor Score - LEMS≥3).

Exclusion Criteria:

• Motor and sensory complete lesion (AIS A); LEMS < 3;
• Non-traumatic cause of lesion
• Medically unstable condition
• Other concurrent neurological illness
• Presence of a potential TMS risk factor (detailed below)

Potential TMS risk factor:

• Damaged skin at the site of stimulation
• Presence of an electrically, magnetically or mechanically activated implant
• An intracerebral vascular clip, or any other electrically sensitive support system
• Metal in any part of the body, including metal injury to the eye
• A history of medication-resistant epilepsy in the family
• Past history of seizures or unexplained spells of loss of consciousness.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: SAS20; The paired stimulation (SAS) will be comprised of patient adjusted subthreshold TMS (80% of resting motor threshold over optimal site for soleus muscle), delivered 20ms prior to a peripheral nerve stimulus in the popliteal fossa and will be repeated at 0.1 Hz for 15 minutes (90 stimuli pairs).	Diagnostic test: Paired TMS & Peripheral Nerve Stimulation; Method of assessing neurophysiology and activity of the spinal cord
Active Comparator: SAS0; The paired stimulation (SAS) will be comprised of patient adjusted subthreshold TMS (80% of resting motor threshold over optimal site for soleus muscle), delivered 0ms prior to a peripheral nerve stimulus in the popliteal fossa and will be repeated at 0.1 Hz for 15 minutes (90 stimuli pairs).	Diagnostic test: Paired TMS & Peripheral Nerve Stimulation; Method of assessing neurophysiology and activity of the spinal cord
Active Comparator: SAS50; The paired stimulation (SAS) will be comprised of patient adjusted subthreshold TMS (80% of resting motor threshold over optimal site for soleus muscle), delivered 50ms prior to a peripheral nerve stimulus in the popliteal fossa and will be repeated at 0.1 Hz for 15 minutes (90 stimuli pairs).	Diagnostic test: Paired TMS & Peripheral Nerve Stimulation; Method of assessing neurophysiology and activity of the spinal cord

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in H-Reflex Threshold	Assessment of muscle reaction after stimulation of sensory fibers	Baseline compared with immediately after intervention

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Lower Extremity Motor Score (LEMS)	Assessment of lower extremity strength in key muscles; maximal score of 50 with 20 or less indicating participant likely has limited ambulation.	Baseline, immediately after intervention
Walking Index for Spinal Cord Injury (WISCI II)	This is a functional capacity scale that rank orders ambulation in people with spinal cord injury, by evaluating the amount of physical assistance, braces or devices required to walk 10 meters. Rank scores range from 0-20. A higher score is indicative of more independent ambulation.	Baseline, immediately after intervention
10 Meter Walk Test	Measure of gait speed	Baseline, immediately after intervention
Spinal Cord Independence Measure, Version 3 (SCIM III)	A disability rating scale developed to specifically address the ability of SCI patients to perform basic activities of daily living independently (including self-care, mobility, respiration and sphincter management)	Baseline, immediately after intervention
Muscle Force	Amount of force recorded during maximal voluntary isometric contraction of a grip movement, recorded with a grip strength measurement device.	Baseline, immediately after intervention
Anklebot	Lower extremity robotic device that provides kinematic evaluation data	Baseline, immediately after intervention

Collaborators and Investigators

• Sponsor: Kathleen Friel
• Collaborators: Burke Medical Research Institute
• Investigators: Study Director: Kathleen Friel, PhD, Burke Medical Research Institute

Publications and helpful links

General Publications

• Pascual-Leone A. Disrupting the brain to guide plasticity and improve behavior. Prog Brain Res. 2006;157:315-329. doi: 10.1016/s0079-6123(06)57019-0.
• Deletis V, Schild JH, Beric A, Dimitrijevic MR. Facilitation of motor evoked potentials by somatosensory afferent stimulation. Electroencephalogr Clin Neurophysiol. 1992 Oct;85(5):302-10. doi: 10.1016/0168-5597(92)90106-l.
• Hiersemenzel LP, Curt A, Dietz V. From spinal shock to spasticity: neuronal adaptations to a spinal cord injury. Neurology. 2000 Apr 25;54(8):1574-82. doi: 10.1212/wnl.54.8.1574.
• Kumru H, Vidal J, Kofler M, Benito J, Garcia A, Valls-Sole J. Exaggerated auditory startle responses in patients with spinal cord injury. J Neurol. 2008 May;255(5):703-9. doi: 10.1007/s00415-008-0780-3. Epub 2008 Feb 21.
• Rothwell JC. Techniques and mechanisms of action of transcranial stimulation of the human motor cortex. J Neurosci Methods. 1997 Jun 27;74(2):113-22. doi: 10.1016/s0165-0270(97)02242-5.
• Kofler M, Valls-Sole J, Fuhr P, Schindler C, Zaccaria BR, Saltuari L. Sensory modulation of voluntary and TMS-induced activation in hand muscles. Exp Brain Res. 2008 Jul;188(3):399-409. doi: 10.1007/s00221-008-1372-2. Epub 2008 Apr 18.
• Pascual-Leone A, Tarazona F, Keenan J, Tormos JM, Hamilton R, Catala MD. Transcranial magnetic stimulation and neuroplasticity. Neuropsychologia. 1999 Feb;37(2):207-17. doi: 10.1016/s0028-3932(98)00095-5.
• Serranova T, Valls-Sole J, Munoz E, Genis D, Jech R, Seeman P. Abnormal corticospinal tract modulation of the soleus H reflex in patients with pure spastic paraparesis. Neurosci Lett. 2008 May 23;437(1):15-9. doi: 10.1016/j.neulet.2008.03.068. Epub 2008 Mar 28.
• Boorman G, Becker WJ, Morrice BL, Lee RG. Modulation of the soleus H-reflex during pedalling in normal humans and in patients with spinal spasticity. J Neurol Neurosurg Psychiatry. 1992 Dec;55(12):1150-6. doi: 10.1136/jnnp.55.12.1150.
• Poon DE, Roy FD, Gorassini MA, Stein RB. Interaction of paired cortical and peripheral nerve stimulation on human motor neurons. Exp Brain Res. 2008 Jun;188(1):13-21. doi: 10.1007/s00221-008-1334-8. Epub 2008 Mar 11.
• Stefan K, Kunesch E, Benecke R, Cohen LG, Classen J. Mechanisms of enhancement of human motor cortex excitability induced by interventional paired associative stimulation. J Physiol. 2002 Sep 1;543(Pt 2):699-708. doi: 10.1113/jphysiol.2002.023317.
• Ridding MC, McKay DR, Thompson PD, Miles TS. Changes in corticomotor representations induced by prolonged peripheral nerve stimulation in humans. Clin Neurophysiol. 2001 Aug;112(8):1461-9. doi: 10.1016/s1388-2457(01)00592-2.
• Valls-Sole J, Alvarez R, Tolosa ES. Responses of the soleus muscle to transcranial magnetic stimulation. Electroencephalogr Clin Neurophysiol. 1994 Dec;93(6):421-7. doi: 10.1016/0168-5597(94)90148-1.
• Hoffken O, Veit M, Knossalla F, Lissek S, Bliem B, Ragert P, Dinse HR, Tegenthoff M. Sustained increase of somatosensory cortex excitability by tactile coactivation studied by paired median nerve stimulation in humans correlates with perceptual gain. J Physiol. 2007 Oct 15;584(Pt 2):463-71. doi: 10.1113/jphysiol.2007.140079. Epub 2007 Aug 16.

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2013
• Primary Completion (Anticipated): September 1, 2019
• Study Completion (Anticipated): December 1, 2019

Study Registration Dates

• First Submitted: May 16, 2018
• First Submitted That Met QC Criteria: July 9, 2018
• First Posted (Actual): July 19, 2018

Study Record Updates

• Last Update Posted (Actual): July 10, 2019
• Last Update Submitted That Met QC Criteria: July 8, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Wounds and Injuries; Trauma, Nervous System; Spinal Cord Diseases; Spinal Cord Injuries
• Other Study ID Numbers: BRC391

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: There is no plan to make individual participant data available to other researchers at this time.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: Yes