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1.  Development of Surrogate Spinal Cords for the Evaluation of Electrode Arrays Used in Intraspinal Implants 
We report the development of a surrogate spinal cord for evaluating the mechanical suitability of electrode arrays for intraspinal implants. The mechanical and interfacial properties of candidate materials (including silicone elastomers and gelatin hydrogels) for the surrogate cord were tested. The elastic modulus was characterized using dynamic mechanical analysis, and compared with values of actual human spinal cords from the literature. Forces required to indent the surrogate cords to specified depths were measured to obtain values under static conditions. Importantly, to quantify surface properties in addition to mechanical properties normally considered, interfacial frictional forces were measured by pulling a needle out of each cord at a controlled rate. The measured forces were then compared to those obtained from rat spinal cords. Formaldehyde-crosslinked gelatin, 12 wt% in water, was identified as the most suitable material for the construction of surrogate spinal cords. To demonstrate the utility of surrogate spinal cords in evaluating the behavior of various electrode arrays, cords were implanted with two types of intraspinal electrode arrays (one made of individual microwires and another of microwires anchored with a solid base), and cord deformation under elongation was evaluated. The results demonstrate that the surrogate model simulates the mechanical and interfacial properties of the spinal cord, and enables in vitro screening of intraspinal implants.
PMCID: PMC3799967  PMID: 23358939
Functional electrical stimulation; gelatin; mechanical properties; silicone elastomers; spinal cord injury
2.  An Implantable Neural Stimulator for Intraspinal MicroStimulation 
This paper reports on a wireless stimulator device for use in animal experiments as part of an ongoing investigation into intraspinal stimulation (ISMS) for restoration of walking in humans with spinal cord injury. The principle behind using ISMS is the activation of residual motor-control neural networks within the spinal cord ventral horn below the level of lesion following a spinal cord injury. The attractiveness to this technique is that a small number of electrodes can be used to induce bilateral walking patterns in the lower limbs. In combination with advanced feedback algorithms, ISMS has the potential to restore walking for distances that exceed that produced by other types of functional electrical stimulation. Recent acute animal experiments have demonstrated the feasibility of using ISMS to produce the coordinated walking patterns. Here we described a wireless implantable stimulation system to be used in chronic animal experiments and for providing the basis for a system suitable for use in humans. Electrical operation of the wireless system is described, including a demonstration of reverse telemetry for monitoring the stimulating electrode voltages.
PMCID: PMC3795508  PMID: 23366038
3.  Intraspinal microstimulation for the recovery of function following spinal cord injury 
Progress in brain research  2011;194:227-239.
Spinal cord injury is a devastating neurological trauma, often resulting in the impairment of bladder, bowel, and sexual function as well as the loss of voluntary control of muscles innervated by spinal cord segments below the lesion site. Research is ongoing into several classes of therapies to restore lost function. These include the encouragement of neural sparing and regeneration of the affected tissue, and the intervention with pharmacological and rehabilitative means to improve function. This review will focus on the application of electrical current in the spinal cord in order to reactivate extant circuitry which coordinates and controls smooth and skeletal muscle below the injury. We first present a brief historical review of intraspinal microstimulation (ISMS) focusing on its use for restoring bladder function after spinal cord injury as well as its utilization as a research tool for mapping spinal cord circuits that coordinate movements. We then present a review of our own results related to the use of ISMS for restoring standing and walking movements after spinal cord injury. We discuss the mechanisms of action of ISMS and how they relate to observed functional outcomes in animal models. These include the activation of fibers-in-passage which lead to the transsynaptic spread of activation through the spinal cord and the ability of ISMS to produce fatigue-resistant, weight-bearing movements. We present our thoughts on the clinical potential for ISMS with regard to implantation techniques, stability, and damage induced by mechanical and electrical factors. We conclude by suggesting improvements in materials and techniques that are needed in preparation for a clinical proof-of-principle and review our current attempts to achieve these.
PMCID: PMC3245977  PMID: 21867807
Electrical stimulation; lumbosacral enlargement; locomotor networks; standing; walking; muscle fatigue
4.  The Effects of Intraspinal Microstimulation on Spinal Cord Tissue in the Rat 
Biomaterials  2010;31(21):5552-5563.
Intraspinal microstimulation (ISMS) involves the implantation of microwires into the spinal cord below the level of an injury to excite neural networks involved in the control of locomotion in the lower limbs. The goal of this study was to examine the potential spinal cord damage that might occur with chronic ISMS. We employed functional measures of force recruitment and immunohistochemical processing of serial spinal cord sections to evaluate any damage induced by spinal transection, implantation of ISMS arrays, and electrical stimulation of 4 hours/day for 30 days. Functional measurements showed no change in force recruitment following transection and chronic ISMS, indicating no changes to underlying neural networks. The implantation of sham intraspinal microwires produced a spatially-limited increase in the density of microglia/macrophages and GFAP+ astrocytes adjacent to the microwire tracks, indicating a persistent immune response. Most importantly, these results were not different from those around microwires that were chronically pulsed with charge levels up to 48 nC/phase. Likewise, measurements of neuronal density indicated no decrease in neuronal cell bodies in the ventral grey matter surrounding ISMS microwires (243.6/mm2 ± 35.3/mm2) compared to tissue surrounding sham microwires (207.8/mm2 ± 38.8/mm2). We conclude that the implantation of intraspinal microwires and chronic application of ISMS are well tolerated by spinal cord tissue.
PMCID: PMC2875271  PMID: 20430436
5.  Muscle Plasticity in Rat Following Spinal Transection and Chronic Intraspinal Microstimulation 
Intraspinal microstimulation (ISMS) employs electrical stimulation of the ventral grey matter to reactivate paralyzed skeletal muscle. This work evaluated the transformations in the quadriceps muscle that occurred following complete transection and chronic stimulation with ISMS or a standard nerve cuff (NCS). Stimulation was applied for 30 days, 4 hours/day. Both methods induced significant increases in time-to-peak tension (ISMS 35%, NCS 25%) and ½ rise-time (ISMS 39%, NCS 25%) compared to intact controls (IC). Corresponding increases in type-IIA myosin heavy chain (MHC) and decreases in type-IID MHC were noted compared to IC. These results were unexpected because ISMS recruits motor units in a near-normal physiological order while NCS recruits motor units in a reversed order. Spinal cord transection and 30 days of stimulation did not alter either recruitment profile. The slope of the force recruitment curves obtained through ISMS following transection and 30 days of stimulation was similar to that obtained in intact animals, and 3.4-fold shallower than that obtained through NCS. The transformations observed in the current work are best explained by the near maximal level of motor unit recruitment, the total daily time of activity and the tonic nature of the stimulation paradigm.
PMCID: PMC3037113  PMID: 20813653
Functional electrical stimulation; muscle plasticity; spinal motoneurons
6.  Afferent inputs to mid- and lower-lumbar spinal segments are necessary for stepping in spinal cats 
Afferent inputs are known to modulate the activity of locomotor central pattern generators, but their role in the generation of locomotor patterns remains uncertain. This study sought to investigate the importance of afferent input for producing bilateral, coordinated hindlimb stepping in adult cats. Following complete spinal transection, animals were trained to step on the moving belt of a treadmill until proficient, weight-bearing stepping of the hindlimbs was established. Selective dorsal rhizotomies of roots reaching various segments of the lumbosacral enlargement were then conducted, and hindlimb stepping capacity was reassessed. Depending on the deafferented lumbosacral segments, stepping was either abolished or unaffected. Deafferentation of mid-lumbar (L3/L4) or lower-lumbar (L5-S1) segments abolished locomotion. Locomotor capacity in these animals could not be restored with the administration of serotonergic or adrenergic agonists. Deafferentation of L3, L6, or S1 had mild effects on locomotion. This suggested that critical afferent inputs pertaining to hip position (mid-lumbar) and limb loading (lower-lumbar) play an important role in the generation of locomotor patterns after spinal cord injury.
PMCID: PMC2885015  PMID: 20536916
central pattern generation; hip position; limb loading; afferent input; locomotion
7.  Management of Spasticity After Spinal Cord Injury: Current Techniques and Future Directions 
Spasticity, resulting in involuntary and sustained contractions of muscles, may evolve in patients with stroke, cerebral palsy, multiple sclerosis, brain injury, and spinal cord injury (SCI). The authors critically review the neural mechanisms that may contribute to spasticity after SCI and assess their likely degree of involvement and relative significance to its pathophysiology. Experimental data from patients and animal models of spasticity as well as computer simulations are evaluated. The current clinical methods used for the management of spasticity and the pharmacological actions of drugs are discussed in relation to their effects on spinal mechanisms. Critical assessment of experimental findings indicates that increased excitability of both motoneurons and interneurons plays a crucial role in pathophysiology of spasticity. New interventions, including forms of spinal electrical stimulation to suppress increased neuronal excitability, may reduce the severity of spasticity and its complications.
PMCID: PMC2860542  PMID: 19723923
spasticity; spasms; spinal cord injury; upper motor neuron syndrome; rehabilitation; neurological disorder
8.  Restoring Stepping After Spinal Cord Injury Using Intraspinal Microstimulation and Novel Control Strategies 
Conference Proceedings  2011;2011:5798-5801.
The overall objective of this project is to develop a feedback-driven intraspinal microstimulation (ISMS) system. We hypothesize that ISMS will enhance the functionality of stepping by reducing muscle fatigue and producing synergistic movements by activating neural networks in the spinal cord. In the present pilot study, the controller was tested with ISMS and external sensors (force plates, gyroscopes, and accelerometers). Cats were partially supported in a sling and bi-laterally stepped overground on a 4-m instrumented walkway. The walkway had variable friction. Limb angle was controlled to within 10° even in the presence of variable friction. Peak ground reaction forces in each limb were approximately 12% of body weight (12.5% was full load bearing in this experimental setup); rarely, the total supportive force briefly decreased to as low as 4.1%. Magnetic resonance images were acquired of the excised spinal cord and the implanted array. The majority of electrodes (75%) were implanted successfully into their target regions. This represents the first successful application of ISMS for overground walking.
PMCID: PMC3276678  PMID: 22255658

Results 1-8 (8)