Multimodal Exercises to Improve Leg Function After Spinal Cord Injury

• Robotic body weight supported treadmill training (Device), also known as Lokomat: 30-minute sessions will be conducted 3-4 times per week for a total of 48 sessions over 12 to 16 weeks.
• Harness-supported multimodal balance training (Other), also known as balance exercises, skilled hand exercises: 30-minute sessions will be conducted 3-4 times per week for a total of 48 sessions over 12 to 16 weeks.

Primary outcomes

• Change in Motor Evoked Potential (MEP) Amplitude in the Tibialis Anterior Muscle at the End of Training. [Eval #1 at baseline; Eval #2 at end of training (48 sessions, average 3-4 months)]: Change between baseline and Evaluation #2 in motor evoked potential area in the tibialis anterior muscle.

Secondary outcomes

• Change From Baseline in ISNCSCI Lower Extremity Motor Score. [Eval #1 at baseline; Eval #2 at end of training (48 sessions, average 3-4 months)]: Change between baseline and Evaluation #2 in lower extremity motor score derived from the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI). Range of scores 0-50, higher is better.
• Change From Baseline in Berg Balance Scale Sitting With Back Unsupported Score. [Eval #1 at baseline; Eval #2 at end of training (48 sessions, average 3-4 months)]: Change between baseline and Evaluation #2 in Berg sitting unsupported subscore. Range 0-4, higher better.
• Change in Leg Spasticity on Modified Ashworth Scale [Eval #1 at baseline; Eval #2 at end of training (48 sessions, average 3-4 months)]: Change between baseline and Evaluation #2 in modified Ashworth Scale. 0-4 score, lower is better.
• Change in Gait Speed on 10-meter Walk Test. [Eval #1 at baseline; Eval #2 at end of training (48 sessions, average 3-4 months)]: Change between baseline and Evaluation #2 in gait speed during 10-meter walk test.
• Change From Baseline in Walking Index for Spinal Cord Injury II (WISCI II) Scale. [Eval #1 at baseline; Eval #2 at end of training (48 sessions, average 3-4 months)]: Change between baseline and Evaluation #2 in WISCI II score. Scores range 0-20, higher is better.
• Change From Baseline in Total Number of Steps Taken by Both Feet During Seated 10-second Step Test. [Eval #1 at baseline; Eval #2 at end of training (48 sessions, average 3-4 months)]: Change between baseline and Evaluation #2 in steps taken during 10-second step test.
• Change in Subjective Pain as Determined by McGill Pain Questionnaire (Short Form). [Eval #1 at baseline; Eval #2 at end of training (48 sessions, average 3-4 months)]: Change between baseline and Evaluation #2 in McGill Pain Questionnaire (Subjective Domain). Total scale 0-45, lower is better.
• Change From Baseline in Endpoint Excursion and Directional Control Parameters Achieved During Seated Limits of Stability Testing. [Time Frame: Eval #1 at baseline; Eval #2 at end of training (48 sessions, average 3-4 months)]: Seated posturography performed using the "Limits of Stability" module of the Smart EquiTest apparatus (Neurocom) while seated. Directional Control measure.
• Change From Baseline in Soleus H-reflex Facilitation. [Time Frame: Eval #1 at baseline; Eval #2 at end of training (48 sessions, average 3-4 months)]: Change between baseline and Evaluation #2 in soleus H-reflex facilitation by transcranial magnetic stimulation (TMS). Short-interval 0-20ms.
• Changes From Baseline in Survey: Spinal Cord Injury - Spasticity Evaluation Tool (SCI-SET) [Eval #1 at baseline; Eval #2 at end of training (48 sessions, average 3-4 months)]: Change between baseline and Evaluation #2 in SCI-SET score. Range of scores -105 to +105. Higher is better.

Sex: All, ages: 21 Years to 65 Years

Inclusion Criteria:

* Males or females age 21-65 years;
* SCI duration > 12 months;
* SCI level C2-T12;
* All SCI severity eligible for baseline testing;
* For exercise protocol, must have severity of Grade C or D on American Spinal Injury Association (ASIA) Impairment Scale, or volitional strength of at least 1/5 in two or more key lower extremity muscles, as well as at least 3/5 in both shoulder and elbow muscles;
* Able to tolerate upright position with support;
* Morphologically capable of fitting a weight-support harness and robotic treadmill system;
* Ability to give informed consent.

Exclusion Criteria:

* Unsuitable cognitive capacity as judged by the study physician;
* Diagnosis of neurological injury other than SCI, such as stroke, traumatic brain injury, or other neurological condition that the study physician considers to be exclusionary;
* Multiple spinal cord lesions;
* History of frequent autonomic dysreflexia;
* History of seizures;
* Use of medications that significantly lower seizure threshold, such as anti-psychotics, tricyclic antidepressants, amphetamines, and bupropion;
* History of implanted brain/spine/nerve stimulators, aneurysm clips, or cardiac pacemaker/defibrillator;
* Deep vein thrombosis in lower extremities of less than 6 months duration;
* Pregnancy;
* (Interventional phase only): Lack of detectable tibialis anterior motor evoked potential (MEP) at baseline even with active facilitation;
* (Interventional phase only): Pressure ulcers greater than stage 1 severity on the foot, ankle, knee and/or pelvic girdle;
* (Interventional phase only): Bone mineral density of the hip (proximal femur) T-score <3.5 standard deviations from age- and gender-matched normative data;
* (Interventional phase only): Any spasticity, contractures, or heterotopic ossification that result in inadequate range of motion of the shoulder, elbow, wrist, fingers, hip, knee, or ankle joints in the judgment of the study physician;
* (Interventional phase only): Inability to cooperate with instructions or unwilling to commit to daily training sessions for 3-4 days per week over 12-16 weeks;
* (Interventional phase only): A diagnosis of coronary artery disease that precludes moderate to intense exercise.

Participant flow

Outcome results

• Change in Motor Evoked Potential (MEP) Amplitude in the Tibialis Anterior Muscle at the End of Training. (Primary), Number, Amplitude percentage of Mmax: Multimodal Training -1.75; Treadmill Training -2.01
• Change From Baseline in ISNCSCI Lower Extremity Motor Score. (Secondary), Mean, units on a scale: Multimodal Training 0.11 +/- 4.81; Treadmill Training -0.30 +/- 4.32
• Change From Baseline in Berg Balance Scale Sitting With Back Unsupported Score. (Secondary), Mean, units on a scale: Multimodal Training 0.10 +/- 0.32; Treadmill Training 0.00 +/- 0.00
• Change in Leg Spasticity on Modified Ashworth Scale (Secondary), Mean, units on a scale: Multimodal Training 0.13 +/- 0.25; Treadmill Training -0.39 +/- 0.89
• Change in Gait Speed on 10-meter Walk Test. (Secondary), Mean, meters per second: Multimodal Training .04 +/- 0; Treadmill Training 0.12 +/- 0.132
• Change From Baseline in Walking Index for Spinal Cord Injury II (WISCI II) Scale. (Secondary)
• Change From Baseline in Total Number of Steps Taken by Both Feet During Seated 10-second Step Test. (Secondary), Mean, steps: Multimodal Training 2.83 +/- 1.14; Treadmill Training -1.08 +/- 1.03
• Change in Subjective Pain as Determined by McGill Pain Questionnaire (Short Form). (Secondary), Mean, units on a scale: Multimodal Training 0.89 +/- 2.76; Treadmill Training -0.93 +/- 3.00
• Change From Baseline in Endpoint Excursion and Directional Control Parameters Achieved During Seated Limits of Stability Testing. (Secondary), Mean, Percentage of perfect path to target: Multimodal Training 1.93 +/- 3.42; Treadmill Training 8.42 +/- 4.02
• Change From Baseline in Soleus H-reflex Facilitation. (Secondary), Mean, percentage of control reflex size: Multimodal Training 6.63 +/- 6.25; Treadmill Training -5.20 +/- 3.35
• Changes From Baseline in Survey: Spinal Cord Injury - Spasticity Evaluation Tool (SCI-SET) (Secondary), Mean, units on a scale: Multimodal Training 2.14 +/- 11.44; Treadmill Training -0.67 +/- 0.82

Adverse events

Time frame: Approx. 6 months or until completion of study participation.

Other adverse events by term

Limitations and caveats: Smaller than expected enrollment, high dropout rate.

• Harel NY, Asselin PK, Fineberg DB, Pisano TJ, Bauman WA, Spungen AM. Adaptation of computerized posturography to assess seated balance in persons with spinal cord injury. J Spinal Cord Med. 2013 Mar;36(2):127-33. doi: 10.1179/2045772312Y.0000000053. PMID 23809527
• Harel NY, Martinez SA, Knezevic S, Asselin PK, Spungen AM. Acute changes in soleus H-reflex facilitation and central motor conduction after targeted physical exercises. J Electromyogr Kinesiol. 2015 Jun;25(3):438-43. doi: 10.1016/j.jelekin.2015.02.009. Epub 2015 Mar 2. PMID 25771437

• Noam Y Harel, MD PhD, Principal investigator, James J. Peters Veterans Affairs Medical Center

NIH grants: 5IK2RX000881-03