Non-invasive approaches to functional recovery after spinal cord injury: Therapeutic targets and multimodal device interventions.

This paper is an interdisciplinary narrative review of efficacious non-invasive therapies that are increasingly used to restore function in people with chronic spinal cord injuries (SCI). First presented are the secondary injury cascade set in motion by the primary lesion and highlights in therapeutic development for mitigating the acute pathophysiologic process. Then summarized are current pharmacological strategies for modulation of noradrenergic, serotonergic, and dopaminergic neurotransmission to enhance recovery in bench and clinical studies of subacute and chronic SCI. Last examined is how neuromechanical devices (i.e., electrical stimulation, robotic assistance, brain-computer interface, and augmented sensory feedback) could be comprehensively engineered to engage efferent and afferent motosensory pathways to induce neuroplasticity-based neural pattern generation. Emerging evidence shows that computational models of the human neuromusculoskeletal system (i.e., human digital twins) can serve as functionalized anchors to integrate different neuromechanical and pharmacological interventions into a single multimodal prothesis. The system, if appropriately built, may cybernetically optimize treatment outcomes via coordination of heterogeneous biosensory, system output, and control signals. Overall, these rehabilitation protocols involved neuromodulation to evoke beneficial adaptive changes within spared supraspinal, intracord, and peripheral neuromuscular circuits to elicit neurological improvement. Therefore, qualitatively advancing the theoretical understanding of spinal cord neurobiology and neuromechanics is pivotal to designing new ways to reinstate locomotion after SCI. Future research efforts should concentrate on personalizing combination therapies consisting of pharmacological adjuncts, targeted neurobiological and neuromuscular repairs, and brain-computer interfaces, which follow multimodal neuromechanical principles.

Functional organization of motor networks in the lumbosacral spinal cord of non-human primates.

Implantable spinal-cord-neuroprostheses aiming to restore standing and walking after paralysis have been extensively studied in animal models (mainly cats) and have shown promising outcomes. This study aimed to take a critical step along the clinical translation path of these neuroprostheses, and investigated the organization of the neural networks targeted by these implants in a non-human primate. This was accomplished by advancing a microelectrode into various locations of the lumbar enlargement of the spinal cord, targeting the ventral horn of the gray matter. Microstimulation in these locations produced a variety of functional movements in the hindlimb. The resulting functional map of the spinal cord in monkeys was found to have a similar overall organization along the length of the spinal cord to that in cats. This suggests that the human spinal cord may also be organized similarly. The obtained spinal cord maps in monkeys provide important knowledge that will guide the very first testing of these implants in humans.

Developing a hippocampal neural prosthetic to facilitate human memory encoding and recall.

OBJECTIVE: We demonstrate here the first successful implementation in humans of a proof-of-concept system for restoring and improving memory function via facilitation of memory encoding using the patient's own hippocampal spatiotemporal neural codes for memory. Memory in humans is subject to disruption by drugs, disease and brain injury, yet previous attempts to restore or rescue memory function in humans typically involved only nonspecific, modulation of brain areas and neural systems related to memory retrieval. APPROACH: We have constructed a model of processes by which the hippocampus encodes memory items via spatiotemporal firing of neural ensembles that underlie the successful encoding of short-term memory. A nonlinear multi-input, multi-output (MIMO) model of hippocampal CA3 and CA1 neural firing is computed that predicts activation patterns of CA1 neurons during the encoding (sample) phase of a delayed match-to-sample (DMS) human short-term memory task. MAIN RESULTS: MIMO model-derived electrical stimulation delivered to the same CA1 locations during the sample phase of DMS trials facilitated short-term/working memory by 37% during the task. Longer term memory retention was also tested in the same human subjects with a delayed recognition (DR) task that utilized images from the DMS task, along with images that were not from the task. Across the subjects, the stimulated trials exhibited significant improvement (35%) in both short-term and long-term retention of visual information. SIGNIFICANCE: These results demonstrate the facilitation of memory encoding which is an important feature for the construction of an implantable neural prosthetic to improve human memory.

The Evolution of Neuroprosthetic Interfaces.

The ideal neuroprosthetic interface permits high-quality neural recording and stimulation of the nervous system while reliably providing clinical benefits over chronic periods. Although current technologies have made notable strides in this direction, significant improvements must be made to better achieve these design goals and satisfy clinical needs. This article provides an overview of the state of neuroprosthetic interfaces, starting with the design and placement of these interfaces before exploring the stimulation and recording platforms yielded from contemporary research. Finally, we outline emerging research trends in an effort to explore the potential next generation of neuroprosthetic interfaces.

A neurorobotic platform for locomotor prosthetic development in rats and mice.

OBJECTIVES: We aimed to develop a robotic interface capable of providing finely-tuned, multidirectional trunk assistance adjusted in real-time during unconstrained locomotion in rats and mice. APPROACH: We interfaced a large-scale robotic structure actuated in four degrees of freedom to exchangeable attachment modules exhibiting selective compliance along distinct directions. This combination allowed high-precision force and torque control in multiple directions over a large workspace. We next designed a neurorobotic platform wherein real-time kinematics and physiological signals directly adjust robotic actuation and prosthetic actions. We tested the performance of this platform in both rats and mice with spinal cord injury. MAIN RESULTS: Kinematic analyses showed that the robotic interface did not impede locomotor movements of lightweight mice that walked freely along paths with changing directions and height profiles. Personalized trunk assistance instantly enabled coordinated locomotion in mice and rats with severe hindlimb motor deficits. Closed-loop control of robotic actuation based on ongoing movement features enabled real-time control of electromyographic activity in anti-gravity muscles during locomotion. SIGNIFICANCE: This neurorobotic platform will support the study of the mechanisms underlying the therapeutic effects of locomotor prosthetics and rehabilitation using high-resolution genetic tools in rodent models.

[Visual prostheses]. / Sehprothesen.

Sensory neuroprostheses for restoration of vision are a technical approach for treatment of previously untreatable blindness. These systems consist of a technical sensor such as a camera and an implanted multi-electrode array within the visual system. The image information from the sensor is processed with specially designed integrated circuits in such a way that the stimulation pulses can be determined and presented to the implanted multi-electrode matrix. Energy supply and the transfer of the stimulus pulse information is realized either via direct cable connections within the site of the implant or by telemetric inductive links. Currently, two retinal implant systems are approved in the European Union (EU) to be used in blind patients with retinitis pigmentosa. With both systems basic visual functions can be restored. The complication rate is relatively low given the complexity of the surgical procedure. Other systems are still under development but approval studies by several manufacturers and consortia are already in preparation.

Current challenges to the clinical translation of brain machine interface technology.

Development of neural prostheses over the past few decades has produced a number of clinically relevant brain-machine interfaces (BMIs), such as the cochlear prostheses and deep brain stimulators. Current research pursues the restoration of communication or motor function to individuals with neurological disorders. Efforts in the field, such as the BrainGate trials, have already demonstrated that such interfaces can enable humans to effectively control external devices with neural signals. However, a number of significant issues regarding BMI performance, device capabilities, and surgery must be resolved before clinical use of BMI technology can become widespread. This chapter reviews challenges to clinical translation and discusses potential solutions that have been reported in recent literature, with focuses on hardware reliability, state-of-the-art decoding algorithms, and surgical considerations during implantation.

Application of carbon nanotubes in neurology: clinical perspectives and toxicological risks.

Nanomedicine is an emerging field that proposes the application of precisely engineered nanomaterials for the prevention, diagnosis and therapy of certain diseases, including neurological pathologies. Carbon nanotubes (CNT) are a new class of nanomaterials, which have been shown to be promising in different areas of nanomedicine. In this review, the application of CNT interfacing with the central nervous system (CNS) will be described, and representative examples of neuroprosthetic devices, such as neuronal implants and electrodes will be discussed. Furthermore, the possible application of CNT-based materials as regenerative matrices of neuronal tissue and as delivery systems for the therapy of CNS will be presented.

Determination of relevant neuron-neuron connections for neural prosthetics using time-delayed mutual information: tutorial and preliminary results.

BACKGROUND: Identification of functional dependence among neurons is a necessary component in both the rational design of neural prostheses as well as in the characterization of network physiology. The objective of this article is to provide a tutorial for neurosurgeons regarding information theory, specifically time-delayed mutual information, and to compare time-delayed mutual information, an information theoretic quantity based on statistical dependence, with cross-correlation, a commonly used metric for this task in a preliminary analysis of rat hippocampal neurons. METHODS: Spike trains were recorded from rats performing delayed nonmatch-to-sample task using an array of electrodes surgically implanted into the hippocampus of each hemisphere of the brain. In addition, spike train simulations of positively correlated neurons, negatively correlated neurons, and neurons correlated by nonlinear functions were generated. These were evaluated by time-delayed mutual information (MI) and cross-correlation. RESULTS: Application of time-delayed MI to experimental data indicated the optimal bin size for information capture in the CA3-CA1 system was 40 ms, which may provide some insight into the spatiotemporal nature of encoding in the rat hippocampus. On simulated data, time-delayed MI showed peak values at appropriate time lags in positively correlated, negatively correlated, and complexly correlated data. Cross-correlation showed peak and troughs with positively correlated and negatively correlated data, but failed to capture some higher order correlations. CONCLUSIONS: Comparison of time-delayed MI to cross-correlation in identification of functionally dependent neurons indicates that the methods are not equivalent. Time-delayed MI appeared to capture some interactions between CA3-CA1 neurons at physiologically plausible time delays missed by cross-correlation. It should be considered as a method for identification of functional dependence between neurons and may be useful in the development of neural prosthetics.

Toward a convergence of regenerative medicine, rehabilitation, and neuroprosthetics.

No effective therapeutic interventions exist for severe neural pathologies, despite significant advances in regenerative medicine, rehabilitation, and neuroprosthetics. Our current hypothesis is that a specific combination of tissue engineering, pharmacology, cell replacement, drug delivery, and electrical stimulation, together with plasticity-promoting and locomotor training (neurorehabilitation) is necessary to interact synergistically in order to activate and enable all damaged circuits. We postulate that various convergent themes exist among the different therapeutic fields. Therefore, the objective of this review is to highlight the convergent themes, which we believe have a common goal of restoring function after neural damage. The convergent themes discussed in this review include modulation of inflammation and secondary damage, encouraging endogenous repair/regeneration (using scaffolds, cell transplantation, and drug delivery), application of electrical fields to modulate healing and/or activity, and finally modulation of plasticity.

A novel command signal for motor neuroprosthetic control.

BACKGROUND: Neuroprostheses can restore functions such as hand grasp or standing to individuals with spinal cord injury (SCI) using electrical stimulation to elicit movements in paralyzed muscles. Implanted neuroprostheses currently use electromyographic (EMG) activity from muscles above the lesion that remain under volitional control as a command input. Systems in development use a networked approach and will allow for restoration of multiple functions but will require additional command signals to control the system, especially in individuals with high-level tetraplegia. OBJECTIVE: The objective of this study was to investigate the feasibility of using muscles innervated below the injury level as command sources for a neuroprosthesis. Recent anatomical and physiological studies have demonstrated the presence of intact axons across the lesion, even in those diagnosed with a clinically complete SCI; hence, EMG activity may be present in muscles with no sign of movement. METHODS: Twelve participants with motor complete SCI were enrolled and EMG was recorded with surface electrodes from 8 muscles below the knee in each leg. RESULTS: Significant activity was evident in 89% of the 192 muscles studied during attempted movements of the foot and lower limb. At least 2 muscles from each participant were identified as potential command signals for a neuroprosthesis based on 2-state, threshold classification. CONCLUSIONS: Results suggest that voluntary activity is present and recordable in below lesion muscles even after clinically complete SCI.

[Neural prostheses and neuromodulation : Research and clinical practice in therapy and rehabilitation]. / Neuroprothetik und Neuromodulation : Forschungsansätze und klinische Praxis bei Therapie und Rehabilitation.

Stimulation of the nervous system with the aid of electrical active implants has changed the therapy of neurological diseases and rehabilitation of lost functions and has expanded clinical practice within the last few years. Alleviation of effects of neurodegenerative diseases, therapy of psychiatric diseases, the functional restoration of hearing as well as other applications have been transferred successfully into clinical practice. Other approaches are still under development in preclinical and clinical trials. The restoration of sight by implantable electronic systems that interface with the retina in the eye is an example how technological progress promotes novel medical devices. The idea of using the electrical signal of the brain to control technical devices and (neural) prostheses is driving current research in the field of brain-computer interfaces. The benefit for the patient always has to be balanced with the risks and side effects of those implants in comparison to medicinal and surgical treatments. How these and other developments become established in practice depends finally on their acceptance by the patients and the reimbursement of their costs.