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 |
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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 | |
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 |