The Use of the Velocity Selective Recording Technique to Reveal the Excitation Properties of the Ulnar Nerve in Pigs

Decoding information from the peripheral nervous system via implantable neural interfaces remains a significant challenge, considerably limiting the advancement of neuromodulation and neuroprosthetic devices. The velocity selective recording (VSR) technique has been proposed to improve the classification of neural traffic by combining temporal and spatial information through a multi-electrode cuff (MEC). Therefore, this study investigates the feasibility of using the VSR technique to characterise fibre type based on the electrically evoked compound action potentials (eCAP) propagating along the ulnar nerve of pigs in vivo. A range of electrical stimulation parameters (amplitudes of 50 μA–10 mA and pulse durations of 100 μs, 500 μs, 1000 μs, and 5000 μs) was applied on a cutaneous and a motor branch of the ulnar nerve in nine Danish landrace pigs. Recordings were made with a 14 ring MEC and a delay-and-add algorithm was used to convert the eCAPs into the velocity domain. The results revealed two fibre populations propagating along the cutaneous branch of the ulnar nerve, with mean velocities of 55 m/s and 21 m/s, while only one dominant fibre population was found for the motor branch, with a mean velocity of 63 m/s. Because of its simplicity to provide information on the fibre selectivity and direction of propagation of nerve fibres, VSR can be implemented to advance the performance of the bidirectional control of neural prostheses and bioelectronic medicine applications.

Simplifying the hardware requirements for fast neural EIT of peripheral nerves

Objective: The main objective of this study was to assess the feasibility of lowering the hardware requirements for fast neural EIT in order to support the distribution of this technique. Specifically, the feasibility of replacing the commercial modules present in the existing high-end setup with compact and cheap customized circuitry was assessed. Approach: Nerve EIT imaging was performed on rat sciatic nerves with both our standard ScouseTom setup and a customized version in which commercial benchtop current sources were replaced by custom circuitry. Electrophysiological data and images collected in the same experimental conditions with the two setups were compared. Data from the customized setup was subject to a down-sampling analysis to simulate the use of a recording module with lower specifications. Main results: Compound action potentials (573±287µV and 487±279µV, p=0.28) and impedance changes (36±14µV and 31±16µV, p=0.49) did not differ significantly when measured using commercial high-end current sources or our custom circuitry, respectively. Images reconstructed from both setups showed neglibile (<1voxel, i.e. 40µm) difference in peak location and a high degree of correlation (R2=0.97). When down-sampling from 24 to 16 bits ADC resolution and from 100KHz to 50KHz sampling frequency, signal-to-noise ratio showed acceptable decrease (<-20%), and no meaningful image quality loss was detected (peak location difference <1voxel, pixel-by-pixel correlation R2=0.99). Significance: The technology developed for this study greatly reduces the cost and size of a fast neural EIT setup without impacting quality and thus promotes the adoption of this technique by the neuroscience research community.

SpeedCAP: An Efficient Method for Estimating Neural Activation Patterns Using Electrically-Evoked Compound Action-Potentials in Cochlear Implant Users

Objectives: Electrically-Evoked Compound Action-Potentials (ECAPs) can be recorded using the electrodes in a cochlear implant (CI) and represent the synchronous responses of the electrically-stimulated auditory-nerve. ECAPs can be obtained using a forward-masking method that measures the neural response to a probe and masker electrode separately and in combination. The Panoramic ECAP (PECAP) method measures ECAPs using multiple combinations of masker and probe electrodes and uses a nonlinear optimization algorithm to estimate current spread from each electrode and neural health along the cochlea. However, the measurement of ECAPs from multiple combinations of electrodes is too time-consuming for use in clinics. This study proposes and evaluates a fast version of the PECAP measurements, SpeedCAP, that minimises recording time by exploiting redundancies between multiple ECAP measures, and that can be applied to methods where multiple ECAPs are required. Design: In the first study, 11 users of Cochlear Limited CIs took part. ECAPs were recorded using the forward-masking artefact-cancellation technique at the most comfortable loudness level (MCL) for every combination of masker and probe electrodes for all active electrodes in the users’ MAPs, as per the standard PECAP recording paradigm. The same current levels and recording parameters were then used to collect ECAPs in the same users with the SpeedCAP method. The ECAP amplitudes were then compared between the two conditions, as were the corresponding estimates of neural health and current spread calculated using the PECAP method described by Garcia et al (2021). The second study measured SpeedCAP intra-operatively in 8 CI patients and with all maskers and probes presented at the same current level to assess feasibility. ECAPs for the subset of conditions where the masker and probe were presented on the same electrode were compared to those obtained using the slower approach leveraged by the standard clinical software. Results: Data collection time was reduced from 45 (PECAP) to 8 (SpeedCAP) minutes. There were no significant differences between normalized root mean squared error (RMSE) repeatability metrics for post-operative PECAP and SpeedCAP data, nor for the RMSEs calculated between PECAP and SpeedCAP data. When between-participant differences were removed, both the neural health (r = 0.73) and current spread (r = 0.65) estimates were significantly correlated (p &lt; 0.0001, df = 218) between SpeedCAP and PECAP conditions across all electrodes. Valid ECAPs were obtained in all patients in the second study, demonstrating intra-operative feasibility of SpeedCAP. No significant differences in RMSEs were detectable between post- and intra-operative ECAP measurements. Conclusions: The improved efficiency of SpeedCAP provides time savings facilitating multi-electrode ECAP recordings in routine clinical practice. The SpeedCAP data collection is sufficiently quick to record intra-operatively, and adds no significant error to the ECAP amplitudes. Such measurements could thereafter be submitted to models such as PECAP to provide patient-specific patterns of neural activation to inform programming of clinical MAPs and/or identify causes of poor performance at the electrode-nerve interface of CI users. The speed and accuracy of these measurements also opens up a wide range of additional research questions to be addressed.

Optimized SNR-based ECAP threshold determination is comparable to the judgement of human evaluators

In cochlear implant (CI) users, measurements of electrically evoked compound action potentials (ECAPs) prove the functionality of the neuron-electrode interface. Objective measures, e.g., the ECAP threshold, may serve as a basis for the clinical adjustment of the device for the optimal benefit of the CI user. As for many neural responses, the threshold determination often is based on the subjective assessment of the clinical specialist, whose decision-making process could be aided by autonomous computational algorithms. To that end, we extended the signal-to-noise ratio (SNR) approach for ECAP threshold determination to be applicable for FineGrain (FG) ECAP responses. The new approach takes advantage of two features: the FG stimulation paradigm with its enhanced resolution of recordings, and SNR-based ECAP threshold determination, which allows defining thresholds independently of morphology and with comparably low computational power. Pearson’s correlation coefficient r between the ECAP threshold determined by five experienced evaluators and the threshold determined with the FG-SNR algorithm was in the range of r = 0.78–0.93. Between evaluators, r was in a comparable range of 0.84–0.93. A subset of the parameters of the algorithm was varied to identify the parameters with the highest potential to improve the FG-SNR formalism in the future. The two steps with the strongest influence on the agreement between the threshold estimate of the evaluators and the algorithm were the removal of undesired frequency components (denoising of the response traces) and the exact determination of the two time windows (signal and noise and noise only).”The parameters were linked to the properties of an ECAP response, indicating how to adjust the algorithm for the automatic detection of other neurophysiological responses.

Evidence That ITPR2-Mediated Intracellular Calcium Release in Oligodendrocytes Regulates the Development of Carbonic Anhydrase II + Type I/II Oligodendrocytes and the Sizes of Myelin Fibers

Myelination of neuronal axons in the central nervous system (CNS) by oligodendrocytes (OLs) enables rapid saltatory conductance and axonal integrity, which are crucial for normal brain functioning. Previous studies suggested that different subtypes of oligodendrocytes in the CNS form different types of myelin determined by the diameter of axons in the unit. However, the molecular mechanisms underlying the developmental association of different types of oligodendrocytes with different fiber sizes remain elusive. In the present study, we present the evidence that the intracellular Ca2+ release channel associated receptor (Itpr2) contributes to this developmental process. During early development, Itpr2 is selectively up-regulated in oligodendrocytes coinciding with the initiation of myelination. Functional analyses in both conventional and conditional Itpr2 mutant mice revealed that Itpr2 deficiency causes a developmental delay of OL differentiation, resulting in an increased percentage of CAII+ type I/II OLs which prefer to myelinate small-diameter axons in the CNS. The increased percentage of small caliber myelinated axons leads to an abnormal compound action potentials (CAP) in the optic nerves. Together, these findings revealed a previously unrecognized role for Itpr2-mediated calcium signaling in regulating the development of different types of oligodendrocytes.

Peculiarities of Neurostimulation by Intense Nanosecond Pulsed Electric Fields: How to Avoid Firing in Peripheral Nerve Fibers

Intense pulsed electric fields (PEF) are a novel modality for the efficient and targeted ablation of tumors by electroporation. The major adverse side effects of PEF therapies are strong involuntary muscle contractions and pain. Nanosecond-range PEF (nsPEF) are less efficient at neurostimulation and can be employed to minimize such side effects. We quantified the impact of the electrode configuration, PEF strength (up to 20 kV/cm), repetition rate (up to 3 MHz), bi- and triphasic pulse shapes, and pulse duration (down to 10 ns) on eliciting compound action potentials (CAPs) in nerve fibers. The excitation thresholds for single unipolar but not bipolar stimuli followed the classic strength–duration dependence. The addition of the opposite polarity phase for nsPEF increased the excitation threshold, with symmetrical bipolar nsPEF being the least efficient. Stimulation by nsPEF bursts decreased the excitation threshold as a power function above a critical duty cycle of 0.1%. The threshold reduction was much weaker for symmetrical bipolar nsPEF. Supramaximal stimulation by high-rate nsPEF bursts elicited only a single CAP as long as the burst duration did not exceed the nerve refractory period. Such brief bursts of bipolar nsPEF could be the best choice to minimize neuromuscular stimulation in ablation therapies.

TRPA1 block protects against loss of white matter function during ischaemia in the mouse optic nerve

Oligodendrocytes produce myelin which provides insulation to axons and speeds up neuronal transmission. In ischaemic conditions myelin is damaged, resulting to mental and physical disabilities. Therefore, it is important to understand how the functionality of oligodendrocytes and myelin is affected by ischaemia. Recent evidence suggests that oligodendrocyte damage during ischaemia is mediated by TRPA1, whose activation raises intracellular Ca2+ concentrations and damages compact myelin. Here, we show that TRPA1 is tonically active in oligodendrocytes and the optic nerve, as the specific TRPA1 antagonist, A-967079, decreases basal oligodendrocyte Ca2+ concentrations and increases the size of the compound action potential. Conversely, TRPA1 agonists reduce the size of the optic nerve compound action potential, and this effect is significantly reduced by the TRPA1 antagonist. These results indicate that glial TRPA1 regulates neuronal excitability in the white matter under physiological as well as pathological conditions. Importantly, we find that inhibition of TRPA1 prevents loss of compound action potentials during oxygen and glucose deprivation (OGD) and improves the recovery. TRPA1 block was effective when applied before, during or after OGD, indicating that the damage is occurring during ischaemia, but that therapeutic intervention is possible after the ischaemic insult. These results indicate that TRPA1 has an important role in the brain, and that its block may be effective in treating oligodendrocyte loss and damage in many white matter diseases.

The Panoramic ECAP Method: Estimating Patient-Specific Patterns of Current Spread and Neural Health in Cochlear Implant Users

The knowledge of patient-specific neural excitation patterns from cochlear implants (CIs) can provide important information for optimizing efficacy and improving speech perception outcomes. The Panoramic ECAP (‘PECAP’) method (Cosentino et al. 2015) uses forward-masked electrically evoked compound action-potentials (ECAPs) to estimate neural activation patterns of CI stimulation. The algorithm requires ECAPs be measured for all combinations of probe and masker electrodes, exploiting the fact that ECAP amplitudes reflect the overlapping excitatory areas of both probes and maskers. Here we present an improved version of the PECAP algorithm that imposes biologically realistic constraints on the solution, that, unlike the previous version, produces detailed estimates of neural activation patterns by modelling current spread and neural health along the intracochlear electrode array and is capable of identifying multiple regions of poor neural health. The algorithm was evaluated for reliability and accuracy in three ways: (1) computer-simulated current-spread and neural-health scenarios, (2) comparisons to psychophysical correlates of neural health and electrode-modiolus distances in human CI users, and (3) detection of simulated neural ‘dead’ regions (using forward masking) in human CI users. The PECAP algorithm reliably estimated the computer-simulated scenarios. A moderate but significant negative correlation between focused thresholds and the algorithm’s neural-health estimates was found, consistent with previous literature. It also correctly identified simulated ‘dead’ regions in all seven CI users evaluated. The revised PECAP algorithm provides an estimate of neural excitation patterns in CIs that could be used to inform and optimize CI stimulation strategies for individual patients in clinical settings.

Improved post-stroke spontaneous recovery by astrocytic extracellular vesicles

Spontaneous recovery after a stroke accounts for a major part of the neurological recovery in patients. However limited, the spontaneous recovery is mechanistically driven by axonal restorative processes for which several molecular cues have been previously described. We report the acceleration of spontaneous recovery in a preclinical model of ischemia/reperfusion in rats via a single intracerebroventricular administration of extracellular vesicles released from primary cortical astrocytes. We used MRI, confocal and multiphoton microscopy to correlate the structural remodeling of the corpus callosum and striatocortical circuits with neurological performance over 21 days. We also evaluated the functionality of the corpus callosum by repetitive recordings of compound action potentials to show that the recovery facilitated by astrocytic extracellular vesicles was both anatomical and functional. Our data provide compelling evidence that astrocytes can hasten the basal recovery that naturally occurs post-stroke through the release of cellular mediators contained in extracellular vesicles.