Engaging Cervical Spinal Cord Networks to Reenable Volitional Control of Hand Function in Tetraplegic Patients

Abstract

Background: Paralysis of the upper limbs from spinal cord injury results in an enormous loss of independence in an individual's daily life. Meaningful improvement in hand function is rare after 1 year of tetraparesis. Therapeutic developments that result in even modest gains in hand volitional function will significantly affect the quality of life for patients afflicted with high cervical injury. The ability to neuromodulate the lumbosacral spinal circuitry via epidural stimulation in regaining postural function and volitional control of the legs has been recently shown. A key question is whether a similar neuromodulatory strategy can be used to improve volitional motor control of the upper limbs, that is, performance of motor tasks considered to be less "automatic" than posture and locomotion. In this study, the effects of cervical epidural stimulation on hand function are characterized in subjects with chronic cervical cord injury.

Objective: Herein we show that epidural stimulation can be applied to the chronic injured human cervical spinal cord to promote volitional hand function.

Methods and results: Two subjects implanted with a cervical epidural electrode array demonstrated improved hand strength (approximately 3-fold) and volitional hand control in the presence of epidural stimulation.

Conclusions: The present data are sufficient to suggest that hand motor function in individuals with chronic tetraplegia can be improved with cervical cord neuromodulation and thus should be comprehensively explored as a possible clinical intervention.

Keywords: cervical spinal cord; epidural stimulation; hand function; neuromodulation; spinal cord injury.

© The Author(s) 2016.

Figures

Fig. 1. Subject Radiographic and Clinical Profiles

The location of the cervical spinal cord injury for (A) subjects is shown on sagittal T2 magnetic resonance imaging (MRI) to be at approximately the C5 spinal level. The injury location exhibits a high intensity T2 signal corresponding to a glial scar formation. Spinal cord tissue distal and proximal to the injury locus has a normal appearance without evidence of post-traumatic syrinx formation. (B) International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) examination of subjects before and after intervention. ISNCSCI scores were assessed at the start of the study without stimulation and at the conclusion of the study with stimulation. (C) Clinically significant increases of 23 and 16 points for the upper extremity motor score were observed for Subjects 1 and 2, respectively. The minimal clinically detectable change has been reported to be 1 for this motor score. The spinal cord independence measure (SCIM), version 3, was used to assess the activities of daily living by in both subjects at the beginning and conclusion of the study. (D) Improvement in all categories was observed in both subjects. An overall improvement of 28 and 31 points, respectively, were recorded. The scores represent the subject’s state at home in a non-stimulated condition.

Fig. 2. Improvement in hand function with intervention

Subjects 1 and 2 were assessed for hand function over a period of at least 12 weeks prior to implantation. (A) A session-by-session comparison of the grip force generated by subjects shows the stability of baseline performance (A, left panel), and the gradual improvement of grip force in sessions with and without stimulation following implantation for both subjects (A, right panel). X-axis shows each testing session, all of which were conducted weekly except for the implanted phase in A2, in which the sessions were conducted daily. Box-plots of maximum contraction force by session for both subjects. Lines reflect best linear fit across baseline sessions and 3rd order polynomial fits across implanted sessions with and without stimulation. Stimulation parameters varied in each session with electrode pairs of −13+14 (Subject 1) and −22+26 (Subject 2) unless stated otherwise. (B) Average peak forces as measured by handgrip device. (C) The ARAT examination was used to assess hand function in everyday tasks. (D, E) Hand endurance and control were assessed by a repetition and accuracy task, respectively. (F) Representative sinusoidal traces of accuracy task with scores are displayed on the left. Note that F1 and F2 are scaled differently. (G) Representative traces of a rapid oscillatory task over 10 seconds with the number of threshold crossings are displayed on the left. For all assessments shown (B–E), scores from all examinations in each situation (Baseline, Implanted (No stim), Implanted (With stim)) were averaged to demonstrate the overall effects. *, **: indicate significant differences from Baseline and Implanted (No stim), respectively, at P < 0.05.

Fig. 3. Motor performance relative to ES parameters

(A1) Subject 1 was implanted with one 16-channel cervical epidural stimulation paddle array spanning spinal cord levels C5-T1. (B1) All stimulation was conducted at electrodes #13 and #14 (shaded in the schematic diagram). (A2) Subject 2 was implanted with two parallel, temporary, percutaneous linear 16-channel cervical epidural stimulation electrodes spanning spinal cord levels C4-T1. (B2) All stimulation was conducted at electrodes #22 and #26. Stimulation locations were selected based on optimized evoked responses recorded for different electrode pairs. Grip strength (maximum voluntary contraction) was assessed over different frequencies (C) and intensities (D) of stimulation. Force output from the device was collected with the subject at rest (Baseline) and during voluntary contraction (Voluntary). Note that there was no observed tonic contraction during baseline phase for Subject 2 (C2, D2). (C) Tests of different frequencies were conducted at a constant intensity of 1.0 mA for Subject 1 and at 2.8 mA for Subject 2. (D) Tests of different stimulation intensities were conducted at a constant frequency of 20 Hz for both subjects. (E) To assess hand control, the ability to accurately follow a targeted sine wave was assessed with several stimulation frequencies applied during the test (5, 10, 20, and 30 Hz) during each test session which was preceded (Pre) and followed (Post) by testing without stimulation. (F) Time to actuate the handgrip device (Response) was assessed at different stimulation frequencies and intensities. For both subjects and all assessments, the mean values (±SEM, three trials for each condition) are shown.

Fig. 4. Handgrip force and evoked potential

(A, B) Handgrip force and EMG during a maximum handgrip performed without (A) and with (B) ES of the cervical spinal cord (electrodes −13+14, 10 Hz, 1.0 mA for Subject 1 and electrodes −22+26, 10 Hz, 5.5 mA for Subject 2). The performance with ES is segmented into three distinct phases of activity: the initial stimulation phase without any voluntary effort (blue shaded area), the voluntary contraction phase (red shaded area), and the relaxation phase of the voluntary effort (green shaded area). (C) The effect of stimulation frequency on the average evoked potentials and force patterns for three seconds during the initial stimulation phase was determined both before any voluntary effort (blue traces) and during the voluntary contraction phase (red traces) in each muscle. (D) Evoked potentials were collected during the three phases of activity. More than 20 potentials evoked in each muscle were averaged. (E) The rising pattern of force along with the two corresponding components of the total FD iEMG signal (μV•sec). Pulse synchronized EMG at 10 Hz (red triangles) vs. the remainder of the total EMG signal (i.e., non-synchronized potentials, green squares) during the initial phase of the contraction is shown. The presence (blue diamonds) or absence (green plus signs) of the lower synchronized signal was not correlated with the force generated during a given time bin. ER, evoked response; FD, flexor digitorum; ED, extensor digitorum; Brac, brachioradialis; H. Thenar, hypothenar; iEMG, integrated EMG.

Fig. 5. Handgrip forces and evoked responses at different percentage volitional efforts

(A) Handgrip force measurements consisted of a maximum contraction at the beginning of testing (100% Pre) followed by seven consecutive contractions labeled on the x-axis at 10 (black), 25 (purple), 75 (orange) % effort, and a maximum contraction at the end (100% Post). The subjects were given five seconds of rest between each contraction, and five minutes of rest between different efforts without stimulation. Maximal forces (100% Pre and 100% Post stimulation) were conducted after a 5-minute rest interval. (C) Fifteen minutes after the completion of A, the same series of contractions at different % maximum efforts were repeated in the presence of increasing intensities of stimulation. (E) The experiments with stimulation were repeated on another day (without the No Stimulation series) to assess possible fatigue effects. (B, D, F) The flexor digitorum integrated EMG (iEMG) for three specific contractions is shown, with the number above the bar referring to the contraction number (1–7) corresponding to the 7 consecutive contractions at different stimulation strengths shown in A, C, and E, respectively. (G) The patterns of evoked potentials at selected percent efforts and at different strengths of stimulation when there was modest (25% effort) or substantial (75% effort) fatigue and when there was no apparent fatigue (10% effort) are shown, corresponding to C and the iEMG in D. While no responses were visible consistently either before or during the fatigued state, synchronized responses were recorded when Subject 1 appeared to recover from fatigue when stimulated at a higher intensity (G1). Subject 2 was asked to continue the series of contractions shown in C2 up to a maximum intensity of 6.0 mA and no indications of fatigue were noted based on the amplitudes of evoked potentials. Subject 2 did not exhibit fatigue (E2 vs C2) and synchronized responses were recorded at all intensities (G2). The stimulation parameters for Subject 1 were an electrode pattern of −13+14, 20 Hz, and 0–1.3 mA. The stimulation parameters for Subject 2 were an electrode pattern of −22+26, 20 Hz, and 0–6.0 mA.