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Table 1 Summary of various bioelectronic interventions to improve neurologic function after spinal cord injury

From: Neurorestorative interventions involving bioelectronic implants after spinal cord injury

Intervention Type of data Target/goal of intervention Specific target(s) of action Details of implant Animal model/clinical trial Results of studies References
Tonic electrochemical neuromodulation for hindlimb function Preclinical Infralesional
Improve hindlimb function
Lumbosacral cord Stainless steel wires secured at midline over L2 and S1 to provide tonic epidural electrical stimulation (EES); 40 Hz
s.c. or i.p. administration of pharmacologic agents
Rat: complete transection at T7
Rat: left lateral over-hemisection at T7 and right lateral hemisection at T10
Rat: severe contusion at T9 (250 kDyn) sparing < 10% tissue at lesion epicenter
EES + serotonergic agonists could generate weight-bearing leg movements as soon as 1 week after SCI
Tonic electrochemical neuromodulation + daily training resulted in ability of rats to initiate and sustain full weight-bearing bipedal locomotion during electrochemical neuromodulation; recovery translated to other unpracticed tasks (i.e., swimming)
Courtine et al. 2009
Musienko et al. 2011
van den Brand et al. 2012
Asboth et al. 2018
Clinical Infralesional
Improve leg function
Lumbosacral cord 16-electrode array implanted over midline of spinal cord segments L1-S1/2; pulse generator in abdominal pouch
Stimulation parameters (frequency, amplitude) empirically driven via ad hoc observation
Chronic SCI patients (AIS A/B) Intense locomotor training combined with epidural stimulation
AIS B patients able to walk over ground with assistive devices and electrical stimulation; AIS A patients demonstrated some independent stepping on treadmill with body-weight support except one patient able to walk over ground and independently stand during stimulation
Angeli et al. 2018
Gill et al. 2018
Tonic electrical neuromodulation for autonomic function Clinical Infralesional
Improve autonomic function
Lumbosacral cord 16-electrode array implanted at T11-L1 vertebral levels over spinal cord segments L1-S1
Parameters of stimulation optimized empirically
Chronic SCI patients (AIS A/B) Reduced blood pressure drop with orthostatic stress test (transitioning from supine to sitting) with EES
Resolution of orthostatic-induced symptoms (i.e., dizziness, poor concentration) and prevention of decrease in MCA blood flow
Persistent hypotension evident in some patients resolved with EES
West et al. 2018
Aslan et al. 2018
Harkema et al. 2018a
Harkema et al. 2018b
Darrow et al. 2019
Multi-directional robotic gravity assist Preclinical/Clinical Improve locomotor ability by facilitating training N/A Multidirectional robotic support system; three translational axes in Cartesian frame and one rotational axis; suspension system fabricated with spring assembly to decouple inertia of robotic structure from subject
Real-time control of propulsion, lateral balance, and body-weight support along four degrees of freedom
Rat: cortical stroke, moderate, and severe SCI
Human: stroke, SCI, normal subjects
Enabled skilled motor control after stroke and coordinated locomotion on staircase after moderate (lateral hemisection) and severe SCI (staggered lateral hemisection) in rats
Human gravity-assist algorithm: supervised machine learning approach that predicted optimal upward support forces for each patient based on collected kinematic variables; simulations guided personalization of forward force for patient-specific needs
Algorithm optimized upward and forward forces to facilitate locomotion depending on patient needs
Dominici et al. 2012
Mignardot et al. 2017
Spatiotemporal electrical stimulation paradigms Preclinical Infralesional
Improve hindlimb function
Lumbosacral cord Epidural implant fabricated with UV photolithographic patterning of photosensitive polyimide; microelectroforming to create gold electrodes and embedded gold interconnects; contact interface over-molded with thin layer of medical grade silicone to improve biointegration Rat: complete transection T8
Rat: dorsal contusion T9
Delivery of stimulation at spatial “hot spots” (motor pools innervating different hindlimb muscles) for flexion and extension in the cord
Closed-loop stimulation delivered based on angular displacement of hindlimb endpoint around its center of rotation
Spatiotemporal neuromodulation gait patterns closer to intact rats than with continuous stimulation after SCI
Wenger et al. 2016
Clinical Infralesional
Improve leg function
Lumbosacral cord 16-electrode paddle array implanted over lumbosacral cord segments; connected to pulse generator in abdomen
Rostro-caudal positioning of electrode array optimized based on EMG responses to single-pulse EES intra-operatively
Chronic SCI patients (AIS C/D) Simulations based on patient MRI and CT scans of the spine guided identification of optimal electrode configurations leg muscle recruitment
Closed-loop triggering of EES based on foot trajectory
Spatiotemporal EES enabled overground locomotion within one week; patients able to increase step elevation 3- to 5-fold when asked, during EES delivery
Continuous EES enhanced muscle activity but poorly facilitated overground locomotion
Wagner et al. 2018
Brain-computer interface Preclinical Improve hindlimb function M1; lumbosacral cord Rat:
32-channel microelectrode array in layer V of leg region of right motor cortex
Wire electrodes sutured to dura over dorsal aspect of L2 and S1 to deliver EES (tonic, 40 Hz)
Rhesus monkey:
96-channel microelectrode array implanted into M1; custom-made spinal implant (see “Spatiotemporal electrical stimulation paradigms”) inserted into T13-L1 vertebral level; decoded swing and stance from neural activity and triggered stimulation protocols wirelessly
Rat: dorsal contusion at T9-T10 (250 kDyn)
Rhesus monkey: lateral CST lesion T7/8
Rat proportional BSI:
Normalized cumulative firing in motor cortex resulted in delivery of stimulation burst over electrode at L2 (amplitude based on linear relationship)
Compared to continuous stimulation, proportional BSI enabled rats to produce gait patterns resembling intact rats and also resulted in better locomotor performance with rehabilitation
Within 1 week post-SCI and without training, BSI in monkey restored weight-bearing locomotion on treadmill and overground
Bonizzato et al. 2018
Capogrosso et al. 2016
Brain-computer interface Clinical Improve upper limb movement M1 with prosthetic limb Microelectrode array implanted in M1 to decode motor intention based on neural spiking activity
Movement of prosthetic limb (i.e., DLR Light-Weight Robot III) based on decoded motor intention
Chronic tetraplegia secondary to brainstem stroke, spino-cerebellar degeneration Subjects able to use robotic arm to reach and grasp foam ball targets; able to grasp bottle and drink coffee through a straw
Able to control prosthetic limb freely in 3D space and after training, perform coordinate reach and grasp movements
Hochberg et al. 2012 Collinger et al. 2013
Clinical Improve upper limb movement M1 with neuro-muscular electrical stimulator (NMES) Microelectrode array implanted in M1; subject trained to use motor cortical neuronal activity to control NMES, which delivers electrical stimulation to arm muscles via percutaneous electrodes Chronic tetraplegia secondary to SCI Regained volitional movement via intracortical signals linked to neuromuscular stimulation in real time
Able to perform grasping of bottle, pouring into a jar, and stirring with a stick; drinking mug of coffee and feeding self with paralyzed arm
Bouton et al. 2016
Ajiboye et al. 2017
Clinical Improve upper limb sensation S1 Microelectrode array implanted in S1, wired to external connector attached to skull Chronic tetraplegia secondary to SCI Intracortical microstimulation evoked sensations with projected fields in the fingers
Using Modular Prosthetic Limb, increase in motor torque when limb touched linearly converted to stimulation amplitude; subject able to identify the finger touched
Flesher et al. 2016
Deep brain stimulation Preclinical Supra-lesional
Improve hindlimb function
MLR 000-gauge stainless steel needle soldered to screw connector implanted stereotactically in MLR and secured with dental cement to the skull Rat: incomplete SCI with scalpel blade and iridectomy scissors Increasing stimulation intensity resulted in rat walking to galloping and increase in swimming speed in intact animals
4 weeks after SCI, increase in walking speed with increase in MLR stimulation intensity; reduction in paw drag
Bachmann et al. 2013
Preclinical Supra-lesional
Improve hindlimb function
NRM Microelectrode implanted stereotactically in the NRM; programmed to give 5 min of 8 Hz stimulation alternated with 5 min of rest for 12 daytime hours followed by 12 h of rest Rat: contusion T8 Reduction of mechanical allodynia in forepaws 6 weeks after injury; reduction in astrogliosis at 15 weeks in the spinal cord Hentall and Burns 2009
Vagal nerve stimulation Preclinical Supra-lesional
Improve forelimb function
Vagus nerve Vagus nerve cuff electrode placed around left cervical branch of vagus nerve; closed-loop delivery of stimulation on trials in which pull forces of rat forelimb fall within the top quintile of previous trials Rat: right (200 kDyn) or midline (225 kDyn) C6 dorsal contusion Compared to rehabilitation alone, closed-loop VNS stimulation significantly improved recovery of forelimb strength Ganzer et al. 2018
Motor cortex stimulation Preclinical Supra-lesional
Improvement of limb function
Corticospinal tract Electrode insertion for stimulation of pyramidal tract or motor cortex Rat: unilateral pyramidal tract lesion Continuous stimulation for 10 days significantly augmented strength of ipsilateral motor responses (recorded in the deep radial nerve); increase in density of corticospinal tract projections Carmel and Martin 2014
Clinical Supra-lesional
Improvement of limb function
M1 Repetitive transcranial magnetic stimulation of M1; frequency ranging between 5 and 20 Hz for between 5 and 15 sessions Subacute and chronic SCI patients (AIS A-D) Limited and variable improvements in sensory and motor function Tazoe and Perez 2015
  1. AIS American Spinal Injury Association Impairment Scale, i.p. intraperitoneal; BSI Brain-spine interface, EES Epidural electrical stimulation, EMG Electromyogram, M1 Primary motor cortex, MCA Middle cerebral artery, MLR Mesencephalic locomotor region, NMES Neuromuscular electrical stimulator, NRM Nucleus raphe magnus, S1 primary sensory cortex, s.c. subcutaneous