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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