Graduate student, California Institute of Technology
Simulating electrical activity due to spinal cord stimulation to model and predict patient outcomes
Epidural spinal cord stimulation (SCS) is a promising therapy for spinal cord injury (SCI), in which electrode arrays are implanted over the spinal cord to deliver electrical signals to neurons. This approach enables paraplegic patients to stand, regain partial control of leg movements, and make gains in lost autonomic function. Several parameters of the stimulation may be modified, including the choice of active electrodes and their polarities, and the amplitude, frequency, and pulse width of the pulse trains applied to the active electrodes; these must be optimized for each patient individually and may also vary with time. Our work links computational models of SCS to experimental data obtained by testing paraplegic patients’ standing performance under a range of stimuli; such analysis may help to clarify some of the mechanisms underlying the success of SCS and suggest new methods to guide the selection of effective stimuli for each patient.
Via finite element analysis, we simulate sets of stimulation parameters used in clinical experiments to estimate the electrical activity in the spinal cord and surrounding tissue. A feature set is then constructed from the electrical response in tissue voxel grids of several granularities. Random forest and elastic net regression enable us to show that these features can predict subjects’ empirical responses. Further, we show that Gaussian process regression can effectively model a probability distribution on the performance of candidate stimuli, enabling more informative performance prediction for untested stimuli.
We also apply feature selection methodology to identify the features that most likely influence subject responses. We find that key electric field features are anatomically structured and align with neural activation theory. Using kernel density estimation, the feature values corresponding to more desirable patient responses are then estimated. We investigate techniques such as clustering the feature space and searching for groups of potentially-co-activated spinal tissue locations, which could enable estimation of a patient’s optimal stimulating field. Further applications of this work include developing algorithms to optimize stimulation for SCI patients, determining optimal electrode placement, and considering novel electrode array designs.
Some preliminary results appear in our paper in the Proceedings of the 2017 IEEE Conference in Neural Engineering: http://ieeexplore.ieee.org/document/8008363/
Abstract: Locomotor behavior is controlled by specific neural circuits called central pattern generators primarily located at the lumbosacral spinal cord. These locomotor-related neuronal circuits have a high level of automaticity; that is, they can produce a "stepping" movement pattern also seen on electromyography (EMG) in the absence of supraspinal and/or peripheral afferent inputs. These circuits can be modulated by epidural spinal-cord stimulation and/or pharmacological intervention. Such interventions have been used to neuromodulate the neuronal circuits in patients with motor-complete spinal-cord injury (SCI) to facilitate postural and locomotor adjustments and to regain voluntary motor control. Here, we describe a novel non-invasive stimulation strategy of painless transcutaneous electrical enabling motor control (pcEmc) to neuromodulate the physiological state of the spinal cord. The technique can facilitate a stepping performance in non-injured subjects with legs placed in a gravity-neutral position. The stepping movements were induced more effectively with multi-site than single-site spinal-cord stimulation. From these results, a multielectrode surface array technology was developed. Our preliminary data indicate that use of the multielectrode surface array can fine-tune the control of the locomotor behavior. As well, the pcEmc strategy combined with exoskeleton technology is effective for improving motor function in paralyzed patients with SCI. The potential impact of using pcEmc to neuromodulate the spinal circuitry has significant implications for furthering our understanding of the mechanisms controlling locomotion and for rehabilitating sensorimotor function even after severe SCI.
Pub.: 25 Jul '15, Pinned: 01 Oct '17
Abstract: Enabling motor control by epidural electrical stimulation of the spinal cord is a promising therapeutic technique for the recovery of motor function after a spinal cord injury (SCI). Although epidural electrical stimulation has resulted in improvement in hindlimb motor function, it is unknown whether it has any therapeutic benefit for improving forelimb fine motor function after a cervical SCI. We tested whether trains of pulses delivered at spinal cord segments C6 and C8 would facilitate the recovery of forelimb fine motor control after a cervical SCI in rats. Rats were trained to reach and grasp sugar pellets. Immediately after a dorsal funiculus crush at C4, the rats showed significant deficits in forelimb fine motor control. The rats were tested to reach and grasp with and without cervical epidural stimulation for 10weeks post-injury. To determine the best stimulation parameters to activate the cervical spinal networks involved in forelimb motor function, monopolar and bipolar currents were delivered at varying frequencies (20, 40, and 60Hz) concomitant with the reaching and grasping task. We found that cervical epidural stimulation increased reaching and grasping success rates compared to the no stimulation condition. Bipolar stimulation (C6- C8+ and C6+ C8-) produced the largest spinal motor-evoked potentials (sMEPs) and resulted in higher reaching and grasping success rates compared with monopolar stimulation (C6- Ref+ and C8- Ref+). Forelimb performance was similar when tested at stimulation frequencies of 20, 40, and 60Hz. We also found that the EMG activity in most forelimb muscles as well as the co-activation between flexor and extensor muscles increased post-injury. With epidural stimulation, however, this trend was reversed indicating that cervical epidural spinal cord stimulation has therapeutic potential for rehabilitation after a cervical SCI.
Pub.: 14 Feb '17, Pinned: 01 Oct '17
Abstract: Epidural electrical stimulation (EES) of lumbosacral segments can restore a range of movements after spinal cord injury. However, the mechanisms and neural structures through which EES facilitates movement execution remain unclear. Here, we designed a computational model and performed in vivo experiments to investigate the type of fibers, neurons, and circuits recruited in response to EES. We first developed a realistic finite element computer model of rat lumbosacral segments to identify the currents generated by EES. To evaluate the impact of these currents on sensorimotor circuits, we coupled this model with an anatomically realistic axon-cable model of motoneurons, interneurons, and myelinated afferent fibers for antagonistic ankle muscles. Comparisons between computer simulations and experiments revealed the ability of the model to predict EES-evoked motor responses over multiple intensities and locations. Analysis of the recruited neural structures revealed the lack of direct influence of EES on motoneurons and interneurons. Simulations and pharmacological experiments demonstrated that EES engages spinal circuits trans-synaptically through the recruitment of myelinated afferent fibers. The model also predicted the capacity of spatially distinct EES to modulate side-specific limb movements and, to a lesser extent, extension versus flexion. These predictions were confirmed during standing and walking enabled by EES in spinal rats. These combined results provide a mechanistic framework for the design of spinal neuroprosthetic systems to improve standing and walking after neurological disorders.
Pub.: 07 Dec '13, Pinned: 01 Oct '17
Abstract: Human lumbar spinal cord networks controlling stepping and standing can be activated through posterior root stimulation using implanted electrodes. A new stimulation method utilizing surface electrodes has been shown to excite lumbar posterior root fibers similarly as with implants, an unexpected finding considering the distance to these target neurons. In the present study we apply computer modeling to compare the depolarization of posterior root fibers by both stimulation techniques. We further examine the potential for additional direct activation of motoneurons within the anterior roots. Using an implant, action potentials are initiated in the posterior root fibers at their entry into the spinal cord or along the longitudinal portions of the fiber trajectories, depending on the cathode position. For transcutaneous stimulation low threshold sites of the same fibers are identified at their exits from the spinal canal in addition to their spinal cord entries. In these exit regions anterior root fibers can also be activated. The simulation results provide a biophysical explanation for the electrophysiological findings of lower limb muscle responses induced by posterior root stimulation. Efficient excitation of afferent spinal cord structures with a simple noninvasive method can become a promising modality in the rehabilitation of people with motor disorders.
Pub.: 09 Dec '10, Pinned: 01 Oct '17
Abstract: Electrical neuromodulation of lumbar segments improves motor control after spinal cord injury in animal models and humans. However, the physiological principles underlying the effect of this intervention remain poorly understood, which has limited the therapeutic approach to continuous stimulation applied to restricted spinal cord locations. Here we developed stimulation protocols that reproduce the natural dynamics of motoneuron activation during locomotion. For this, we computed the spatiotemporal activation pattern of muscle synergies during locomotion in healthy rats. Computer simulations identified optimal electrode locations to target each synergy through the recruitment of proprioceptive feedback circuits. This framework steered the design of spatially selective spinal implants and real-time control software that modulate extensor and flexor synergies with precise temporal resolution. Spatiotemporal neuromodulation therapies improved gait quality, weight-bearing capacity, endurance and skilled locomotion in several rodent models of spinal cord injury. These new concepts are directly translatable to strategies to improve motor control in humans.
Pub.: 19 Jan '16, Pinned: 01 Oct '17
Abstract: Spinal cord injury disrupts the communication between the brain and the spinal circuits that orchestrate movement. To bypass the lesion, brain–computer interfaces1, 2, 3 have directly linked cortical activity to electrical stimulation of muscles, and have thus restored grasping abilities after hand paralysis1, 4. Theoretically, this strategy could also restore control over leg muscle activity for walking5. However, replicating the complex sequence of individual muscle activation patterns underlying natural and adaptive locomotor movements poses formidable conceptual and technological challenges6, 7. Recently, it was shown in rats that epidural electrical stimulation of the lumbar spinal cord can reproduce the natural activation of synergistic muscle groups producing locomotion8, 9, 10. Here we interface leg motor cortex activity with epidural electrical stimulation protocols to establish a brain–spine interface that alleviated gait deficits after a spinal cord injury in non-human primates. Rhesus monkeys (Macaca mulatta) were implanted with an intracortical microelectrode array in the leg area of the motor cortex and with a spinal cord stimulation system composed of a spatially selective epidural implant and a pulse generator with real-time triggering capabilities. We designed and implemented wireless control systems that linked online neural decoding of extension and flexion motor states with stimulation protocols promoting these movements. These systems allowed the monkeys to behave freely without any restrictions or constraining tethered electronics. After validation of the brain–spine interface in intact (uninjured) monkeys, we performed a unilateral corticospinal tract lesion at the thoracic level. As early as six days post-injury and without prior training of the monkeys, the brain–spine interface restored weight-bearing locomotion of the paralysed leg on a treadmill and overground. The implantable components integrated in the brain–spine interface have all been approved for investigational applications in similar human research, suggesting a practical translational pathway for proof-of-concept studies in people with spinal cord injury.
Pub.: 09 Nov '16, Pinned: 01 Oct '17