Jennifer Seifert

Normal Molecular Repair Mechanisms in Regenerative Peripheral Nerve Interfaces Allow Recording of Early Spike Activity Despite Immature Myelination

Clinical use of neurally controlled prosthetics has advanced in recent years, but limitations still remain, including lacking fine motor control and sensory feedback. Indwelling multi-electrode arrays, cuff electrodes, and regenerative sieve electrodes have been reported to serve as peripheral neural interfaces, though long-term stability of the nerve-electrode interface has remained a formidable challenge. We recently developed a regenerative multi-electrode interface (REMI) that is able to record neural activity as early as seven days post-implantation. While this activity might represent normal neural depolarization during axonal regrowth, it can also be the result of altered nerve regeneration around the REMI. This study evaluated high-throughput expression levels of 84 genes involved in nerve injury and repair, and the histological changes that occur in parallel to this early neural activity. Animals exhibiting spike activity increased from 29% to 57% from 7 to 14 days following REMI implantation with a corresponding increase in firing rate of 113%. Two weeks after implantation, numbers of neurofilament-positive axons in the control and REMI implanted nerves were comparable, and in both cases the number of myelinated axons was low. During this time, expression levels of genes related to nerve injury and repair were similar in regenerated nerves, both in the presence or absence of the electrode array. Together, these results indicate that the early neural activity is intrinsic to the regenerating axons, and not induced by the REMI neurointerface.

A wireless system for monitoring transcranial motor evoked potentials.

Intraoperative neurophysiological monitoring (IONM) is commonly used as an attempt to minimize neurological morbidity from operative manipulations. The goal of IONM is to identify changes in the central and peripheral nervous system function prior to irreversible damage. Intraoperative monitoring also has been effective in localizing anatomical structures, including peripheral nerves and sensorimotor cortex, which helps guide the surgeon during dissection. As part of IONM, transcranial motor evoked potentials (TcMEPs), and somatosensory evoked potentials (SSEPs) are routinely monitored. However, current wired systems are cumbersome as the wires contribute to the crowded conditions in the operating room and in doing so not only it limits the maneuverability of the surgeon and assistants, but also places certain demand in the total anesthesia required during surgery, due to setup preoperative time needed for proper electrode placement, due to the number and length of the wires, and critical identification of the lead wires needed for stimulation and recording. To address these limitations, we have developed a wireless TcMEP IONM system as a first step toward a multimodality IONM system. Bench-top and animal experiments in rodents demonstrated that the wireless method reproduced with high fidelity, and even increased the frequency bandwidth of the TcMEP signals, compared to wired systems. This wireless system will reduce the preoperative time required for IONM setup, add convenience for surgical staff, and reduce wire-related risks for patients during the operation.

In-vivo tests of a 16-channel implantable wireless neural stimulator

Wireless stimulation of neural tissue could enable many emerging neural prosthesis designs, and eliminate problems associated with percutaneous wires and connectors. Our laboratory has developed a 16-channel wireless floating microelectrode array (WFMA) for chronic implantation. Here, we report on its first use within in-vivo experiments, using a rat sciatic nerve model. Stimulus currents and associated muscular movements were determined for electrodes of two WFMA devices implanted into four animal subjects.

Chronic sensory-motor activity in behaving animals using regenerative multi-electrode interfaces.

Regenerative peripheral nerve interfaces have been proposed as viable alternatives for the natural control and feel of robotic prosthetic limbs. We have developed a Regenerative Multi-electrode Interface (REMI) that guides re-growing axons through an electrode array deployed in the lumen of a nerve guide. While acute studies have shown the use of the REMI in the rat sciatic nerve, the quality of chronic signal recording has not been reported. Here we show that implantation of this interface in the sciatic nerve is stable with high quality recordings up to 120 days and failures mainly attributable to abiotic factors related to pedestal detachment and wire breakage. We further tested the interfacing of REMI with fascicles of the sciatic nerve that primarily innervate muscles (tibial) and skin (sural). When implanted into the tibial nerve, bursting activity was observed synchronous to stepping. However, implantation of REMI into the sural nerve failed due to its small size. While fascicles smaller than 300 μm are a challenge for regenerative interfacing, we show that a modified REMI can be used in an insertion mode to record sensory signals from skin. In summary, the REMI represents an effective tool for recording firing patterns of specific axon types during voluntary movement, which may be used to improve the motor control and sensory feedback in closed loop control systems for robotic prosthesis.

Chronic and low charge injection wireless intraneural stimulation in vivo

Functional stability and in-vivo reliability are significant factors determining the longevity of a neural interface. In this ongoing study, we test the performance of a wireless floating microelectrode array (WFMA) over a period of 143 days. The topography of the microelectrodes has allowed for selective stimulation of different fascicles of the rat sciatic nerve. We confirmed that motor evoked thresholds remain stable over time and that the nerve stimulation charges were within tissue safety limits. Importantly, motor evoked responses were elicited at threshold currents in fully awake animals without causing pain or discomfort. These data validate the use of the WFMA system for intraneural interfacing of peripheral nerves for neuroprosthetic and bioelectronics medical applications.

A miniature power-efficient bidirectional telemetric platform for in-vivo acquisition of electrophysiological signals

The need for in vivo wireless acquisition of biological signals is emerging in various medical fields. Electrophysiological applications including recording myoelectric signals in-vivo gastric electrical activity (GEA) to study gastric dysmotility, electrocorticography (ECoG) to study pain, and transcranical motor evoked potentials (TcMEP) for intraoperative neurophysiological monitoring of spinal cord integrity require physically miniaturized devices with low power consumption and capability of implantation. These systems should provide reliable communication in real time with sufficient data rates. We have developed three telemetric systems for GEA, ECoG and TcMEP applications based on a common transceiver platform but with different design considerations. Each has been successfully validated in appropriate animal models, to demonstrate the feasibility of wireless acquisition of key electrophysiological signals.

Atraumatic Spine Distraction Induces Metabolic Distress in Spinal Motor Neurons

Corrective forces during spine deformity surgery, including distraction, impart significant stresses to the spinal cord that may result in permanent injury. Intraoperative neuromonitoring is commonly used by surgeons to recognize possible damage to the spinal cord in cases of evident traumatic or vascular damage to the spinal cord. However, mild insult to the spinal cord that does not result in obvious trauma or electrophysiological changes present a major clinical challenge as the mechanisms of this type of spinal cord injury (SCI) remain largely unknown, and thus preventive strategies are lacking. We used a sustained bidirectional spinal distraction animal model to determine the role of stretch-induced hypoxia in mild SCI. Direct measurement of intraparenchymal oxygen revealed an immediate decrease in partial pressure (47.08 ± 5.79% pO2) distal to the injury site following a 5-mm distraction. This hypoxic insult induced mitochondrial dysfunction as evidenced by an acute increase (216%) in protein oxidation 30 min post-injury, as well as a 37% decrease in perikaryal size and a 42% decrease in nuclear area (pyknosis) in ventral motor neurons at the injury site. These results indicate that hypoxic events during mild spine distraction may lead to cellular metabolic impairments and permanent functional deficits. The development of strategies targeting the prevention of hypoxic injury during spine distraction may be useful in protecting the cellular metabolic damage that may occur during spine surgery in the absence of overt mechanical or vascular SCI.

Electromagnetic interference in intraoperative monitoring of motor evoked potentials and a wireless solution

Intraoperative neurophysiological monitoring (IONM) is utilized to minimize neurological morbidity during spine surgery. Transcranial motor evoked potentials (TcMEPs) are principal IONM signals in which the motor cortex of the subject is stimulated with electrical pulses and the evoked potentials are recorded from the muscles of interest. Currently available monitoring systems require the connection of 40-60 lengthy lead wires to the patient. These wires contribute to a crowded and cluttered surgical environment, and limit the maneuverability of the surgical team. In this work, it was demonstrated that the cumbersome wired system is vulnerable to electromagnetic interference (EMI) produced by operating room (OR) equipment. It was hypothesized that eliminating the lengthy recording wires can remove the EMI induced in the IONM signals. Hence, a wireless system to acquire TcMEPs was developed and validated through bench-top and animal experiments. Side-by-side TcMEPs acquisition from the wired and wireless systems in animal experiments under controlled conditions (absence of EMI from OR equipment) showed comparable magnitudes and waveforms, thus demonstrating the fidelity in the signal acquisition of the wireless solution. The robustness of the wireless system to minimize EMI was compared with a wired-system under identical conditions. Unlike the wired-system, the wireless system was not influenced by the electromagnetic waves from the C-Arm X-ray machine and temperature management system in the OR.