Spinal Evoked Compound Action Potentials in Rats With Clinically Relevant Stimulation Modalities.

OBJECTIVES: Rats are commonly used for translational pain and spinal cord stimulation (SCS) research. Although many SCS parameters are configured identically between rats and humans, stimulation amplitudes in rats are often programmed relative to visual motor threshold (vMT). Alternatively, amplitudes may be programmed relative to evoked compound action potential (ECAP) thresholds (ECAPTs), a sensed measure of neural activation. The objective of this study was to characterize ECAPTs, evoked compound muscle action potential thresholds (ECMAPTs), and vMTs with clinically relevant SCS modalities. MATERIALS AND METHODS: We implanted ten anesthetized rats with two quadripolar epidural SCS leads: one for stimulating in the lumbar spine, and another for sensing ECAPs in the thoracic spine. We then delivered two SCS paradigms to the rats. The first used 50-Hz SCS with 50-, 100-, 150-, and 200-µs pulse widths (PWs), whereas the second used a 50-Hz, 150-µs PW low-rate program (LRP) multiplexed to a 1200-Hz, 50-µs PW high-rate program (HRP). We increased SCS amplitudes up to the vMT in the first paradigm, and in the second, we increased HRP amplitudes up to the HRP ECAPT with a fixed amplitude (70% of the vMT) LRP. For each test case, we captured ECAPTs, ECMAPTs, and vMTs from each rat. RESULTS: vMTs were 3.0 ± 0.7 times greater than ECAPTs, with vMTs marginally (3.0 ± 3.6%) greater than ECMAPTs (mean ± SD) across all PWs with the first paradigm. With the second paradigm, we noted a negligible increase (3.6 ± 6.2%) on the LRP ECAP as HRP amplitudes were increased. CONCLUSIONS: Our results demonstrate reasonable levels of neural activation in anesthetized rats with SCS amplitudes appropriately programmed relative to vMT or ECMAPT when using clinically relevant SCS modalities. Furthermore, we demonstrate the feasibility of ECAP recording in rats with multiplexed HRP SCS.

Categorical Signaling of the Strongest Stimulus by an Inhibitory Midbrain Nucleus.

The nucleus isthmi pars magnocellularis (Imc), a group of inhibitory neurons in the midbrain tegmentum, is a critical component of the spatial selection network in the vertebrate midbrain. It delivers long-range inhibition among different portions of the space map in the optic tectum (OT), thereby mediating stimulus competition in the OT. Here, we investigate the properties of relative strength-dependent competitive interactions within the Imc, in barn owls of both sexes. We find that when Imc neurons are presented simultaneously with one stimulus inside the receptive field and a second, competing stimulus outside, they exhibit gradual or switch-like response profiles as a function of relative stimulus strength. They do so both when the two stimuli are of the same sensory modality (both visual) or of different sensory modalities (visual and auditory). Moreover, Imc neurons signal the strongest stimulus in a dynamically flexible manner, indicating that Imc responses reflect an online comparison between the strengths of the competing stimuli. Notably, Imc neurons signal the strongest stimulus more categorically, and earlier than the OT. Paired recordings at spatially aligned sites in the Imc and OT reveal that although some properties of stimulus competition, such as the bias of competitive response profiles, are correlated, others such as the steepness of response profiles, are set independently. Our results demonstrate that the Imc is itself an active site of competition, and may be the first site in the midbrain selection network at which stimulus competition is resolved.SIGNIFICANCE STATEMENT This work sheds light on the functional properties of a small group of inhibitory neurons in the vertebrate midbrain that play a key part in how the brain selects a target among competitors. A better understanding of the functioning of these neurons is an important building block for the broader understanding of how distracters are suppressed, and of spatial attention and its dysfunction.

Response features across the auditory midbrain reveal an organization consistent with a dual lemniscal pathway.

The central auditory system has traditionally been divided into lemniscal and nonlemniscal pathways leading from the midbrain through the thalamus to the cortex. This view has served as an organizing principle for studying, modeling, and understanding the encoding of sound within the brain. However, there is evidence that the lemniscal pathway could be further divided into at least two subpathways, each potentially coding for sound in different ways. We investigated whether such an interpretation is supported by the spatial distribution of response features in the central nucleus of the inferior colliculus (ICC), the part of the auditory midbrain assigned to the lemniscal pathway. We recorded responses to pure tone stimuli in the ICC of ketamine-xylazine-anesthetized guinea pigs and used three-dimensional brain reconstruction techniques to map the location of the recording sites. Compared with neurons in caudal-and-medial regions within an isofrequency lamina of the ICC, neurons in rostral-and-lateral regions responded with shorter first-spike latencies with less spiking jitter, shorter durations of spiking responses, a higher proportion of spikes occurring near the onset of the stimulus, lower thresholds, and larger local field potentials with shorter latencies. Further analysis revealed two distinct clusters of response features located in either the caudal-and-medial or the rostral-and-lateral parts of the isofrequency laminae of the ICC. Thus we report substantial differences in coding properties in two regions of the ICC that are consistent with the hypothesis that the lemniscal pathway is made up of at least two distinct subpathways from the midbrain up to the cortex.

Neural integration and enhancement from the inferior colliculus up to different layers of auditory cortex.

While the cochlear implant has successfully restored hearing to many deaf patients, it cannot benefit those without a functional auditory nerve or an implantable cochlea. As an alternative, the auditory midbrain implant (AMI) has been developed and implanted into deaf patients. Consisting of a single-shank array, the AMI is designed for stimulation along the tonotopic gradient of the inferior colliculus (ICC). Although the AMI can provide frequency cues, it appears to insufficiently transmit temporal cues for speech understanding because repeated stimulation of a single site causes strong suppressive and refractory effects. Applying the electrical stimulation to at least two sites within an isofrequency lamina can circumvent these refractory processes. Moreover, coactivation with short intersite delays (<5 ms) can elicit cortical activation which is enhanced beyond the summation of activity induced by the individual sites. The goal of our study was to further investigate the role of the auditory cortex in this enhancement effect. In guinea pigs, we electrically stimulated two locations within an ICC lamina or along different laminae with varying interpulse intervals (0-10 ms) and recorded activity in different locations and layers of primary auditory cortex (A1). Our findings reveal a neural mechanism that integrates activity only from neurons located within the same ICC lamina for short spiking intervals (<6 ms). This mechanism leads to enhanced activity into layers III-V of A1 that is further magnified in supragranular layers. This integration mechanism may contribute to perceptual coding of different sound features that are relevant for improving AMI performance.

Transcutaneous Auricular Vagus Nerve Stimulation (tAVNS) Delivered During Upper Limb Interactive Robotic Training Demonstrates Novel Antagonist Control for Reaching Movements Following Stroke.

Implanted vagus nerve stimulation (VNS) delivered concurrently with upper limb rehabilitation has been shown to improve arm function after stroke. Transcutaneous auricular VNS (taVNS) offers a non-invasive alternative to implanted VNS and may provide similar therapeutic benefit. There is much discussion about the optimal approach for combining VNS and physical therapy, as such we sought to determine whether taVNS administered during robotic training, specifically delivered during the premotor planning stage for arm extension movements, would confer additional motor improvement in patients with chronic stroke. Thirty-six patients with chronic, moderate-severe upper limb hemiparesis (>6 months; mean Upper Extremity Fugl-Meyer score = 25 ± 2, range 13-48), were randomized to receive 9 sessions (1 h in length, 3x/week for 3 weeks) of active (N = 18) or sham (N = 18) taVNS (500 ms bursts, frequency 30 Hz, pulse width 0.3 ms, max intensity 5 mA, ∼250 stimulated movements per session) delivered during robotic training. taVNS was triggered by the onset of a visual cue prior to center-out arm extension movements. Clinical assessments and surface electromyography (sEMG) measures of the biceps and triceps brachii were collected during separate test sessions. Significant motor improvements were measured for both the active and sham taVNS groups, and these improvements were robust at 3 month follow-up. Compared to the sham group, the active taVNS group showed a significant reduction in spasticity of the wrist and hand at discharge (Modified Tardieu Scale; taVNS = -8.94% vs. sham = + 2.97%, p < 0.05). The EMG results also demonstrated significantly increased variance for the bicep peak sEMG amplitude during extension for the active taVNS group compared to the sham group at discharge (active = 26.29% MVC ± 3.89, sham = 10.63% MVC ± 3.10, mean absolute change admission to discharge, p < 0.01), and at 3-month follow-up, the bicep peak sEMG amplitude was significantly reduced in the active taVNS group (P < 0.05). Thus, robot training improved the motor capacity of both groups, and taVNS, decreased spasticity. taVNS administered during premotor planning of movement may play a role in improving coordinated activation of the agonist-antagonist upper arm muscle groups by mitigating spasticity and increasing motor control following stroke. Clinical Trial Registration: www.ClinicalTrials.gov, identifier (NCT03592745).

Laser ablation of the pia mater for insertion of high-density microelectrode arrays in a translational sheep model.

Objective. The safe insertion of high density intracortical electrode arrays has been a long-standing practical challenge for neural interface engineering and applications such as brain-computer interfaces (BCIs). However, the pia mater can be difficult to penetrate and causes deformation of underlying cortical tissue during insertion of high-density intracortical arrays. This can lead to neuron damage or failed insertions. The development of a method to ease insertion through the pia mater would represent a significant step toward inserting high density intracortical arrays.Approach. Here we describe a surgical procedure, inspired by laser corneal ablation, that can be used in translational models to thin the pia mater.Main results. We demonstrate that controlled pia removal with laser ablation over a small area of cortex allows for microelectrode arrays to be inserted into the cortex with less force, thus reducing deformation of underlying tissue during placement of the microelectrodes. This procedure allows for insertion of high-density electrode arrays and subsequent acute recordings of spiking neuron activity in sheep cortex. We also show histological and electrophysiological evidence that laser removal of the pia does not acutely affect neuronal viability in the region.Significance. Laser ablation of the pia reduces insertion forces of high-density arrays with minimal to no acute damage to cortical neurons. This approach suggests a promising new path for clinical BCI with high-density microelectrode arrays.

The Argo: a high channel count recording system for neural recording in vivo.

OBJECTIVE: Decoding neural activity has been limited by the lack of tools available to record from large numbers of neurons across multiple cortical regions simultaneously with high temporal fidelity. To this end, we developed the Argo system to record cortical neural activity at high data rates. APPROACH: Here we demonstrate a massively parallel neural recording system based on platinum-iridium microwire electrode arrays bonded to a CMOS voltage amplifier array. The Argo system is the highest channel count in vivo neural recording system, supporting simultaneous recording from 65 536 channels, sampled at 32 kHz and 12-bit resolution. This system was designed for cortical recordings, compatible with both penetrating and surface microelectrodes. MAIN RESULTS: We validated this system through initial bench testing to determine specific gain and noise characteristics of bonded microwires, followed by in-vivo experiments in both rat and sheep cortex. We recorded spiking activity from 791 neurons in rats and surface local field potential activity from over 30 000 channels in sheep. SIGNIFICANCE: These are the largest channel count microwire-based recordings in both rat and sheep. While currently adapted for head-fixed recording, the microwire-CMOS architecture is well suited for clinical translation. Thus, this demonstration helps pave the way for a future high data rate intracortical implant.

A novel microwire interface for small diameter peripheral nerves in a chronic, awake murine model.

OBJECTIVE: The vagus nerve has been implicated in a variety of immune responses, and the number of studies using mouse models to unravel key mechanisms has increased. However, as of yet, there is no electrode that can chronically record neural activity from the mouse vagus nerve due to its small diameter. Such recordings are critical to understand the role of these biomarkers for translational research. APPROACH: In this study, we developed a methodology for surgically implanting the wrappable microwires onto the vagus nerve of mice. Similar to a cuff electrode, we wrapped de-insulated ends of microwires around the vagus nerve and re-insulated them on the nerve with Kwik-Sil. The recording fidelity of the wrappable microwire on the vagus nerve was validated in an acute, anesthetized model by comparing performance to commercially-available electrodes. A chronic, awake mouse model was then developed to record spontaneous compound action potentials (CAPs). MAIN RESULTS: In an acute setting, the wrappable microwire successfully recorded spontaneous CAPs with similar signal-to-noise ratios (SNR) and peak-to-peak amplitude to commercially available electrodes. In chronic, awake recordings, viable SNRs were obtained from the wrappable microwires between 30 and 60 d (n = 8). Weekly impedance measurements showed no correlation with SNR or time, indicating device stability, and the electrodes recorded CAPs for the duration of the recording period. SIGNIFICANCE: To the best of our knowledge, this is the first reported chronic, awake neural interface with the mouse vagus nerve. This approach can facilitate clinical translation for bioelectronic medicine in preclinical disease models of interest with the creation of more clinically relevant preclinical models.

Closed-loop neuromuscular electrical stimulation using feedforward-feedback control and textile electrodes to regulate grasp force in quadriplegia.

BACKGROUND: Transcutaneous neuromuscular electrical stimulation is routinely used in physical rehabilitation and more recently in brain-computer interface applications for restoring movement in paralyzed limbs. Due to variable muscle responses to repeated or sustained stimulation, grasp force levels can change significantly over time. Here we develop and assess closed-loop methods to regulate individual finger forces to facilitate functional movement. We combined this approach with custom textile-based electrodes to form a light-weight, wearable device and evaluated in paralyzed study participants. METHODS: A textile-based electrode sleeve was developed by the study team and Myant, Corp. (Toronto, ON, Canada) and evaluated in a study involving three able-body participants and two participants with quadriplegia. A feedforward-feedback control structure was designed and implemented to accurately maintain finger force levels in a quadriplegic study participant. RESULTS: Individual finger flexion and extension movements, along with functional grasping, were evoked during neuromuscular electrical stimulation. Closed-loop control methods allowed accurate steady state performance (< 15% error) with a settling time of 0.67 s (SD = 0.42 s) for individual finger contact force in a participant with quadriplegia. CONCLUSIONS: Textile-based electrodes were identified to be a feasible alternative to conventional electrodes and facilitated individual finger movement and functional grasping. Furthermore, closed-loop methods demonstrated accurate control of individual finger flexion force. This approach may be a viable solution for enabling grasp force regulation in quadriplegia. TRIAL REGISTRATION: NCT, NCT03385005. Registered Dec. 28, 2017.

Characterizing Longitudinal Changes in the Impedance Spectra of In-Vivo Peripheral Nerve Electrodes.

Characterizing the aging processes of electrodes in vivo is essential in order to elucidate the changes of the electrode⁻tissue interface and the device. However, commonly used impedance measurements at 1 kHz are insufficient for determining electrode viability, with measurements being prone to false positives. We implanted cohorts of five iridium oxide (IrOx) and six platinum (Pt) Utah arrays into the sciatic nerve of rats, and collected the electrochemical impedance spectroscopy (EIS) up to 12 weeks or until array failure. We developed a method to classify the shapes of the magnitude and phase spectra, and correlated the classifications to circuit models and electrochemical processes at the interface likely responsible. We found categories of EIS characteristic of iridium oxide tip metallization, platinum tip metallization, tip metal degradation, encapsulation degradation, and wire breakage in the lead. We also fitted the impedance spectra as features to a fine-Gaussian support vector machine (SVM) algorithm for both IrOx and Pt tipped arrays, with a prediction accuracy for categories of 95% and 99%, respectively. Together, this suggests that these simple and computationally efficient algorithms are sufficient to explain the majority of variance across a wide range of EIS data describing Utah arrays. These categories were assessed over time, providing insights into the degradation and failure mechanisms for both the electrode⁻tissue interface and wire bundle. Methods developed in this study will allow for a better understanding of how EIS can characterize the physical changes to electrodes in vivo.

Effects of location and timing of co-activated neurons in the auditory midbrain on cortical activity: implications for a new central auditory prosthesis.

OBJECTIVE: An increasing number of deaf individuals are being implanted with central auditory prostheses, but their performance has generally been poorer than for cochlear implant users. The goal of this study is to investigate stimulation strategies for improving hearing performance with a new auditory midbrain implant (AMI). Previous studies have shown that repeated electrical stimulation of a single site in each isofrequency lamina of the central nucleus of the inferior colliculus (ICC) causes strong suppressive effects in elicited responses within the primary auditory cortex (A1). Here we investigate if improved cortical activity can be achieved by co-activating neurons with different timing and locations across an ICC lamina and if this cortical activity varies across A1. APPROACH: We electrically stimulated two sites at different locations across an isofrequency ICC lamina using varying delays in ketamine-anesthetized guinea pigs. We recorded and analyzed spike activity and local field potentials across different layers and locations of A1. RESULTS: Co-activating two sites within an isofrequency lamina with short inter-pulse intervals (<5 ms) could elicit cortical activity that is enhanced beyond a linear summation of activity elicited by the individual sites. A significantly greater extent of normalized cortical activity was observed for stimulation of the rostral-lateral region of an ICC lamina compared to the caudal-medial region. We did not identify any location trends across A1, but the most cortical enhancement was observed in supragranular layers, suggesting further integration of the stimuli through the cortical layers. SIGNIFICANCE: The topographic organization identified by this study provides further evidence for the presence of functional zones across an ICC lamina with locations consistent with those identified by previous studies. Clinically, these results suggest that co-activating different neural populations in the rostral-lateral ICC rather than the caudal-medial ICC using the AMI may improve or elicit different types of hearing capabilities.