Biology subjects

Grill, W. M.

Publications and source records attributed to Grill, W. M..

At least 19 recordsLinked to original sources

bioRxiv2026

Computational investigation of circuit mechanisms underlying short-latency responses to cortical stimulation

Transcranial magnetic stimulation (TMS) over the primary motor cortex (M1) elicits a series of high frequency volleys termed D- and I-waves measured epidurally in the corticospinal tract of awake humans. Further, intracortical microstimulation (ICMS) in M1 of non-human primates evokes D- and I-wave responses similar to those observed in TMS. The cortical circuits and mechanisms involved in the generation of D- and I-waves by stimulation of M1 remain unclear. Here, we implemented computational models of cortical columns with laminarly-organized biophysically-based neurons, following existing models published in the literature: (1) M1 - single compartment (SC), (2) M1 - multi-compartment (MC), (3) primary auditory cortex (A1) - MC, and (4) primary somatosensory cortex (S1) - MC. The network connectivity of each model represented wiring found in the respective cortical regions. The direct effects of stimulation-induced electric fields were modeled as activation of different proportions of pyramidal neurons (PNs) across layers, and dose response curves were constructed for layer 5 (L5) PNs. Both the M1 and A1 models reproduced D- and I-waves, with the magnitude of I-waves increasing with higher recruitment of layer 2/3 and layer 5 PNs. The S1-MC model evoked rhythmic firing activity but with timings mismatched to experimental I-waves. The models replicated the experimentally observed effects of pharmacological agents on I-waves, and virtual lesions of specific neural populations across models revealed plausible microcircuit explanations for the first and later I-waves. This comprehensive comparison of models across multiple cortical regions identified consistent mechanisms underlying the cortical response to TMS and contributes to the refinement of computational strategies for optimizing stimulation paradigms.

neuroscience↗

bioRxiv2026

Histologically Informed Multiscale Modeling of the Neuronal Elements Activated by TMS

BackgroundThe primary neural site(s) at which action potentials are initiated by transcranial magnetic stimulation (TMS) remain poorly understood. Multiscale computational models provide biophysically based hypotheses, but model accuracy is constrained by limited histological knowledge of the microscopic organization of neural tissue. Recent high-resolution electron microscopy, in particular the petavoxel H01 dataset, provides novel, detailed axon morphologies and myelination patterns within the human cortex and superficial white matter. ObjectiveTo compare systematically multiple candidates for the neural elements activated by TMS using computer simulations informed by an extensive body of histological measurements, including neuron models directly reconstructed from the H01 dataset. MethodsWe developed a novel modeling pipeline to extract individual morphologically realistic multi-compartment models with exact myelination from serial section electron microscopic segmentations. To assess candidate excitation sites, we simulated the extracted neuron models together with parameterized models of a "ball-and-two-sticks", bifurcation, termination, and bend under uniform electric fields. In addition, smooth and sharply bending myelinated axons were embedded in a realistic human head model to evaluate activation thresholds under anatomically realistic electric field distributions. ResultsAxon terminations were only excitable by TMS when they were fully myelinated, which the histology suggested is unlikely. Partial myelination, even when separated by only 10 {micro}m from the terminal, increased activation thresholds by more than 100%. Reconstructed H01 neurons exhibited correspondingly high activation thresholds at axon terminals due to a lack of myelination. Further, most other candidate structures exhibited low thresholds only for histologically unrealistic parameter choices. In contrast, myelinated axonal bends of fibers transitioning from cortex to superficial white matter consistently showed low activation thresholds for both uniform electric fields and in realistic head model simulations. These thresholds fell within physiologically realistic ranges and, for larger diameter fibers, approached experimentally measured motor thresholds. ConclusionThese results identify myelinated axons bending from cortex into superficial white matter as possible neural targets for transcranial magnetic stimulation, and demonstrate the relevance of detailed histological and biophysical information to support robust modeling results.

neuroscience↗

bioRxiv2026

Identification of low threshold off-target activation pathways during stimulation of carotid baroreceptor afferents in swine.

ObjectiveElectrical stimulation of the baroreceptors pathways at the carotid sinus bulb - known as baroreflex activation therapy (BAT) - is intended to change autonomic tone and ultimately reduce blood pressure and heart rate. BAT is pre-market approved by the United States Food and Drug Administration (FDA) for the treatment of heart failure and received an FDA humanitarian device exemption for drug resistant hypertension. However, responder rates are limited by side-effects including numbness in the head and neck, altered speech, respiratory constriction, dry cough, vomiting, and altered sensory and motor function of the tongue. We hypothesized that these side-effects are driven by activation of other nearby nerve fibers of similar or lower threshold than the carotid sinus nerve. In this study, we sought to identify the neural sources responsible for off-target muscle activation contributing to these side-effects. These sources would inform strategies mitigating off-target activation in BAT therapy. MethodsDomestic swine were used in this work as the diameter and thickness of the swine carotid artery are closer to human than those of canine models. A monopolar disk electrode mimicking the clinical CVRx(R) Neo electrode was surgically placed proximal to the carotid bifurcation with the position optimized for stimulation dose responsive changes in blood pressure. Evoked responses were recorded during dose response testing from multiple neck muscles, and the corresponding off-target nerve pathways were identified by sequential transection of nearby nerves. ResultsThe following activated off-target muscle groups and their corresponding nerve pathways were verified which included 1) the cricoarytenoid via recurrent laryngeal nerve, 2) cricothyroid via superior laryngeal nerve, 3) sternocleidomastoid via accessory nerve, and 4) the tongue via hypoglossal nerve. The constrictor muscle group was also activated through a more complex neural pathway. ConclusionWe identified multiple sources of therapy-limiting side-effects of BAT in the swine model. These results will help guide the design of improved stimulation electrodes, surgical placement, and parameter programming to reduce BAT-associated side-effects while increasing on-target activation in patients.

bioengineering↗

bioRxiv2025

Single pointwise samples of electric field on a neuron model cannot predict activation threshold by brain stimulation

BackgroundSome computational models of neural activation by transcranial magnetic stimulation overestimate the electric field (E-field) threshold compared to in vivo measurements. A recent study proposed a statistical method to account for the influence of microscopic perturbations to the E-field. The method, however, relies on the unsubstantiated assumption that thresholds can be predicted by single pointwise samples of the E-field strength along neural cables. ObjectiveWe analyzed neural responses to E-field with microscopic perturbations and demonstrate via theoretical derivation and simulations that neural activation is not determined by pointwise E-field amplitude but rather by spatial integration of the E-field along the neural cable. Therefore, the influence of microscopic E-field perturbations is negligible due to the spatiotemporal filtering by the neural membrane and axoplasm. MethodsWe derive the axial and transmembrane currents in a neural cable for an imposed E-field with microscopic perturbations. We simulate neural activation thresholds of unmyelinated and myelinated axons in two stimulation scenarios and compare thresholds for E-field activation with and without perturbations. ResultsIn the theoretical derivation, the perturbation terms average out to zero on larger spatial scales indicating that they do not influence neural activation thresholds. Simulated thresholds with the E-field spatial perturbations present had negligible differences (< 3.4%) compared to those without. ConclusionSingle point samples of the microscopic E-field on a neural cable cannot predict neural activation thresholds. Neural simulations should be used to determine any influence of the E-field spatial perturbations. The latter, however, are unlikely to account for the difference between experimental and simulated E-field thresholds.

bioengineering↗

bioRxiv2024

Circuits and mechanisms for TMS-induced corticospinal waves: Connecting sensitivityanalysis to the network graph

Transcranial magnetic stimulation (TMS) is a non-invasive, FDA-cleared treatment for neuropsychiatric disorders with broad potential for new applications, but the neural circuits that are engaged during TMS are still poorly understood. Recordings of neural activity from the corticospinal tract provide a direct readout of the response of motor cortex to TMS, and therefore a new opportunity to model neural circuit dynamics. The study goal was to use epidural recordings from the cervical spine of human subjects to develop a computational model of a motor cortical macrocolumn through which the mechanisms underlying the response to TMS, including direct and indirect waves, could be investigated. An in-depth sensitivity analysis was conducted to identify important pathways, and machine learning was used to identify common circuit features among these pathways. Sensitivity analysis identified neuron types that preferentially contributed to single corticospinal waves. Single wave preference could be predicted using the average connection probability of all possible paths between the activated neuron type and L5 pyramidal tract neurons (PTNs). For these activations, the total conduction delay of the shortest path to L5 PTNs determined the latency of the corticospinal wave. Finally, there were multiple neuron type activations that could preferentially modulate a particular corticospinal wave. The results support the hypothesis that different pathways of circuit activation contribute to different corticospinal waves with participation of both excitatory and inhibitory neurons. Moreover, activation of both afferents to the motor cortex as well as specific neuron types within the motor cortex initiated different I-waves, and the results were interpreted to propose the cortical origins of afferents that may give rise to certain I-waves. The methodology provides a workflow for performing computationally tractable sensitivity analyses on complex models and relating the results to the network structure to both identify and understand mechanisms underlying the response to acute stimulation. AUTHOR SUMMARYUnderstanding circuit mechanisms underlying the response to transcranial magnetic stimulation remains a significant challenge for translational and clinical research. Computational models can reconstruct network activity in response to stimulation, but basic sensitivity analyses are insufficient to identify the fundamental circuit properties that underly an evoked response. We developed a data-driven neuronal network model of motor cortex, constrained with human recordings, that reproduced the corticospinal response to magnetic stimulation. The model supported several hypotheses, e.g., the importance of stimulating incoming fibers as well as neurons within the cortical column and the relevance of both excitatory and inhibitory neurons. Following a sensitivity analysis, we conducted a secondary structural analysis that linked the results of the sensitivity analysis to the network using machine learning. The structural analysis pointed to anatomical mechanisms that contributed to specific peaks in the response. Generally, given the anatomy and circuit of a neural region, identifying strongly connected paths in the network and the conduction delays of these paths can screen for important contributors to response peaks. This work supports and expands on hypotheses explaining the response to transcranial magnetic stimulation and adds a novel method for identifying generalizable neural circuit mechanisms.

neuroscience↗

bioRxiv2024

Optogenetic fMRI reveals therapeutic circuits of subthalamic nucleus deep brain stimulation

While deep brain stimulation (DBS) is widely employed for managing motor symptoms in Parkinsons disease (PD), its exact circuit mechanisms remain controversial. To identify the neural targets affected by therapeutic DBS in PD, we analyzed DBS-evoked whole brain activity in female hemi-parkinsonian rats using function magnetic resonance imaging (fMRI). We delivered subthalamic nucleus (STN) DBS at various stimulation pulse repetition rates using optogenetics, allowing unbiased examinations of cell-type specific STN feed-forward neural activity. Unilateral STN optogenetic stimulation elicited pulse repetition rate-dependent alterations of blood-oxygenation-level-dependent (BOLD) signals in SNr (substantia nigra pars reticulata), GP (globus pallidus), and CPu (caudate putamen). Notably, these manipulations effectively ameliorated pathological circling behavior in animals expressing the kinetically faster Chronos opsin, but not in animals expressing ChR2. Furthermore, mediation analysis revealed that the pulse repetition rate-dependent behavioral rescue was significantly mediated by optogenetically induced activity changes in GP and CPu, but not in SNr. This suggests that the activation of GP and CPu are critically involved in the therapeutic mechanisms of STN DBS.

neuroscience↗

bioRxiv2023

Neural mechanisms of the temporal response of cortical neurons to intracortical microstimulation

BackgroundIntracortical microstimulation (ICMS) is used to map neuronal circuitry in the brain and restore lost sensory function, including vision, hearing, and somatosensation. The temporal response of cortical neurons to single pulse ICMS is remarkably stereotyped and comprises short latency excitation followed by prolonged inhibition and, in some cases, rebound excitation. However, the neural origin of the different response components to ICMS are poorly understood, and the interactions between the three response components during trains of ICMS pulses remains unclear. ObjectiveWe used computational modeling to determine the mechanisms contributing to the temporal response to ICMS in model cortical pyramidal neurons. MethodsWe built a biophysically based computational model of a cortical column comprising neurons with realistic morphology and synapses and quantified the temporal response of cortical neurons to different ICMS protocols. We characterized the temporal responses to single pulse ICMS across stimulation intensities and inhibitory (GABA-B/GABA-A) synaptic strengths. To probe interactions between response components, we quantified the response to paired pulse ICMS at different inter-pulse intervals and the response to short trains at different stimulation frequencies. Finally, we evaluated the performance of biomimetic ICMS trains in evoking a sustained neural response. ResultsSingle pulse ICMS evoked short latency excitation followed by a period of inhibition, but model neurons did not exhibit post-inhibitory rebound excitation. The strength of short latency excitation increased and the duration of inhibition increased with increased stimulation amplitude. Prolonged inhibition resulted from both after-hyperpolarization currents and GABA-B synaptic transmission. During the paired pulse protocol, the strength of short latency excitation evoked by a test pulse decreased marginally compared to those evoked by a single pulse for interpulse intervals (IPI) <100 ms. Further, the duration of inhibition evoked by the test pulse was prolonged compared to single pulse for IPIs < 40ms and was not predicted by linear superposition of individual inhibitory responses. For IPIs>40 ms, the duration of inhibition evoked by the test pulse was comparable to those evoked by a single pulse. Short ICMS trains evoked repetitive excitatory responses against a background of inhibition. However, the strength of the repetitive excitatory response declined during ICMS at higher frequencies. Further, the duration of inhibition at the cessation of ICMS at higher frequencies was prolonged compared to the duration following a single pulse. Biomimetic pulse trains evoked comparable neural response between the onset and offset phases despite the presence of stimulation induced inhibition. ConclusionsThe cortical column model replicated the short latency excitation and long-lasting inhibitory components of the stereotyped neural response documented in experimental ICMS studies. Both cellular and synaptic mechanisms influenced the response components generated by ICMS. The non-linear interactions between response components resulted in dynamic ICMS-evoked neural activity and may play an important role in mediating the ICMS-induced precepts. HIGHLIGHTSO_LIImplemented a biophysically based computational model of the cortical column to study the temporal response of neurons to intracortical microstimulation (ICMS) C_LIO_LITemporal response of model neurons comprised short latency excitation followed by a long-lasting inhibition but did not include rebound excitation. C_LIO_LIExcitation was mediated by both direct (antidromic) and indirect synaptic mechanisms and inhibition by both cellular (after-hyperpolarizing currents) and synaptic (GABAergic) mechanisms. C_LIO_LIThe temporal dynamics of the response to ICMS should be considered when designing paradigms for sensory prosthetic applications. C_LI

neuroscience↗

bioRxiv2023

Attenuating midline thalamus bursting to mitigate absence epilepsy

Advancing the mechanistic understanding of absence epilepsy is crucial for developing new therapeutics, especially for patients unresponsive to current treatments. Utilizing a recently developed mouse model of absence epilepsy carrying the BK gain-of-function channelopathy D434G, here we report that attenuating the burst firing of midline thalamus (MLT) neurons effectively prevents absence seizures. We found that enhanced BK channel activity in the BK-D434G MLT neurons promotes synchronized bursting during the ictal phase of absence seizures. Modulating MLT neurons through pharmacological reagents, optogenetic stimulation, or deep brain stimulation effectively attenuates burst firing, leading to reduced absence seizure frequency and increased vigilance. Additionally, enhancing vigilance by amphetamine, a stimulant medication, or physical perturbation also effectively suppresses MLT bursting and prevents absence seizures. These findings suggest that the MLT is a promising target for clinical interventions. Our diverse approaches offer valuable insights for developing new therapeutics to treat absence epilepsy. HighlightsThe midline thalamus (MLT) is a key thalamic region for absence seizure pathogenesis MLT neurons exhibit synchronized bursting during ictal phase. BK channel contributes to MLT burst firing Attenuating MLT bursting increases vigilance and suppresses absence seizures

neuroscience↗

bioRxiv2023

Towards a more accurate quasi-static approximation of the electric potential for neurostimulation with kilohertz-frequency sources

ObjectiveOur goal was to determine the conditions for which a more precise calculation of the electric potential than the quasi-static approximation may be needed in models of electrical neurostimulation, particularly for signals with kilohertz-frequency components. ApproachWe conducted a comprehensive quantitative study of the differences in nerve fiber activation and conduction block when using the quasi-static and Helmholtz approximations for the electric potential in a model of electrical neurostimulation. Main resultsWe first show that the potentials generated by sources of unbalanced pulses exhibit different transients as compared to those of energy-balanced pulses, and this is disregarded by the quasi-static assumption. Secondly, the relative errors for current-distance curves were below 3%, while for strength-duration curves the variations ranged between 1-17%, but could be improved to less than 3% across the range of pulse duration by providing a corrected quasi-static conductivity. Third, we extended our analysis to trains of pulses and reported a "congruence area" below 700 Hz, where the fidelity of fiber responses is maximal for suprathreshold stimulation. Further examination of waveforms and polarities revealed similar fidelities in the congruence area, but significant differences were observed beyond this area. However, the spike-train distance revealed differences in activation patterns when comparing the response generated by each model. Finally, in simulations of conduction-block, we found that block thresholds exhibited errors above 20% for repetition rates above 10 kHz. Yet, employing a corrected value of the conductivity improved the agreement between models, with errors no greater than 8%. SignificanceOur results emphasize that the quasi-static approximation cannot be naively extended to electrical stimulation with high-frequency components, and notable differences can be observed in activation patterns. As well, we introduce a methodology to obtain more precise model responses using the quasi-static approach, which can be a valuable resource in computational neuroengineering.

neuroscience↗

bioRxiv2023

Multi-scale model of axonal and dendritic polarization by transcranial direct current stimulation in realistic head geometry

1.BackgroundTranscranial direct current stimulation (tDCS) is a non-invasive brain stimulation modality that can alter cortical excitability. However, it remains unclear how the subcellular elements of different neuron types are polarized by specific electric field (E-field) distributions. ObjectiveTo quantify neuronal polarization generated by tDCS in a multi-scale computational model. MethodsWe embedded layer-specific, morphologically-realistic cortical neuron models in a finite element model of the E-field in a human head and simulated steady-state polarization generated by conventional primary-motor-cortex-supraorbital (M1-SO) and 4x1 high-definition (HD) tDCS. We quantified somatic, axonal, and dendritic polarization of excitatory pyramidal cells in layers 2/3, 5, and 6, as well as inhibitory interneurons in layers 1 and 4 of the hand knob. ResultsAxonal and dendritic terminals were polarized more than the soma in all neurons, with peak axonal and dendritic polarization of 0.92 mV and 0.21 mV, respectively, compared to peak somatic polarization of 0.07 mV for 1.8 mA M1-SO stimulation. Both montages generated regions of depolarization and hyperpolarization beneath the M1 anode; M1-SO produced slightly stronger, more diffuse polarization peaking in the central sulcus, while 4x1 HD produced higher peak polarization in the gyral crown. Simulating polarization by uniform local E-field approximated the spatial distribution of tDCS polarization but produced large errors in some regions. ConclusionsPolarization of pre- and postsynaptic compartments of excitatory and inhibitory cortical neurons may play a significant role in tDCS neuromodulation. These effects cannot be predicted from the E-field distribution alone but rather require calculation of the neuronal response.

bioengineering↗

bioRxiv2022

Optimized Monophasic Pulses with Equivalent Electric Field for Rapid-Rate Transcranial Magnetic Stimulation

ObjectiveTranscranial magnetic stimulation (TMS) with monophasic pulses achieves greater changes in neuronal excitability but requires higher energy and generates more coil heating than TMS with biphasic pulses, and this limits the use of monophasic pulses in rapid-rate protocols. We sought to design a stimulation waveform that retains the characteristics of monophasic TMS but significantly reduces coil heating, thereby enabling higher pulse rates and increased neuromodulation effectiveness. ApproachA two-step optimization method was developed that uses the temporal relationship between the electric field (E-field) and coil current waveforms. The model-free optimization step reduced the ohmic losses of the coil current and constrained the error of the E-field waveform compared to a template monophasic pulse, with pulse duration as a second constraint. The second, amplitude adjustment step scaled the candidate waveforms based on simulated neural activation to account for differences in stimulation thresholds. The optimized waveforms were implemented to validate the changes in coil heating. Main resultsDepending on the pulse duration and E-field matching constraints, the optimized waveforms produced 12% to 75% less heating than the original monophasic pulse. The reduction in coil heating was robust across a range of neural models. The changes in the measured ohmic losses of the optimized pulses compared to the original pulse agreed with numeric predictions. SignificanceThe first step of the optimization approach was independent of any potentially inaccurate or incorrect model and exhibited robust performance by avoiding the highly nonlinear behavior of neural responses, whereas neural simulations were only run once for amplitude scaling in the second step. This significantly reduced computational cost compared to iterative methods using large populations of candidate solutions and more importantly reduced the sensitivity to the choice of neural model. The reduced coil heating and power losses of the optimized pulses can enable rapid-rate monophasic TMS protocols.

bioengineering↗

bioRxiv2022

Rapid estimation of cortical neuron activation thresholds by transcranial magnetic stimulation using convolutional neural networks

BackgroundTranscranial magnetic stimulation (TMS) can modulate neural activity by evoking action potentials in subpopulations of cortical neurons. The TMS-induced electric field (E-field) can be simulated in subject-specific head models derived from MR images, but the spatial distribution of the E-field alone does not predict the physiological response. Coupling E-field models to populations of biophysically realistic neuron models yields insights into the activation mechanisms of TMS, but the significant computational cost associated with these models limits their use and eventual translation to clinically relevant applications. ObjectiveThe objective was to develop computationally efficient estimators of the activation thresholds of multi-compartmental cortical neuron models in response to TMS-induced E-field distributions. MethodsMulti-scale models combining anatomically accurate finite element method (FEM) simulations of the TMS E-field with layer-specific representations of cortical neurons were used to generate a large dataset of activation thresholds. 3D convolutional neural networks (CNNs) were trained on these data to predict the activation threshold of specific model neurons given the local E-field distribution. Using training and test data from different head models, the CNN estimator was compared to an approach using the uniform E-field approximation to estimate thresholds in the non-uniform TMS-induced E-field. ResultsThe 3D CNNs were more accurate than the uniform E-field approach, with mean absolute percent error (MAPE) on the test dataset below 2.5% compared to 5.9 - 9.8% with the uniform E-field approach. Further, there was a strong correlation between the CNN predicted and actual thresholds for all cell types (R2 > 0.96) compared to the uniform E-field approach (R2 = 0.62 - 0.91). The CNNs estimate thresholds with a 2 - 4 orders of magnitude reduction in the computational cost of the multi-compartmental neuron models. Conclusion3D CNNs can estimate rapidly and accurately the TMS activation thresholds of biophysically realistic neuron models using sparse samples of the local E-field, enabling simulating responses of large neuron populations or parameter space exploration on a personal computer.

bioengineering↗

bioRxiv2022

Spatially selective stimulation of the pig vagus nerve to modulate target effect versus side effect

Electrical stimulation of the cervical vagus nerve using implanted electrodes (VNS) is FDA-approved for the treatment of drug-resistant epilepsy, treatment-resistant depression, and most recently, chronic ischemic stroke rehabilitation. However, VNS is critically limited by the unwanted stimulation of nearby neck muscles - a result of non-specific stimulation activating motor nerve fibers within the vagus. Prior studies suggested that precise placement of small epineural electrodes can modify VNS therapeutic effects, such as cardiac responses. However, it remains unclear if placement can alter the balance between intended effect and limiting side effect. We used an FDA investigational device exemption approved six-contact epineural cuff to deliver VNS in pigs and quantified how epineural electrode location impacts on- and off-target VNS activation. Detailed post-mortem histology was conducted to understand how the underlying neuroanatomy impacts observed functional responses. Here we report the discovery and characterization of clear neuroanatomy-dependent differences in threshold and saturation for responses related to both effect (change in heart rate) and side effect (neck muscle contractions). The histological and electrophysiological data were used to develop and validate subject-specific computation models of VNS, creating a well-grounded quantitative framework to optimize electrode location-specific activation of nerve fibers governing intended effect versus unwanted side effect.

bioengineering↗

bioRxiv2022

Responses of Model Cortical Neurons to Temporal Interference Stimulation and Other Transcranial Alternating Current Stimulation Modalities

ObjectiveTemporal interference stimulation (TIS) was proposed as a non-invasive, focal, and steerable deep brain stimulation method. However, the mechanisms underlying experimentally-observed suprathreshold TIS effects are unknown, and prior simulation studies had limitations in the representations of the TIS electric field (E-field) and cerebral neurons. We examined the E-field and neural response characteristics for TIS and related transcranial alternating current stimulation modalities. ApproachUsing the uniform-field approximation, we simulated a range of stimulation parameters in biophysically realistic model cortical neurons, including different orientations, frequencies, amplitude ratios, amplitude modulation, and phase difference of the E-fields, and obtained thresholds for both activation and conduction block. Main resultsFor two E-fields with similar amplitudes (representative of E-field distributions at the target region), TIS generated an amplitude-modulated total E-field. Due to the phase difference of the individual E-fields, the total TIS E-field vector also exhibited rotation where the orientations of the two E-fields were not aligned (generally also at the target region). TIS activation thresholds (75-230 V/m) were similar to those of high-frequency stimulation with or without modulation and/or rotation. For E-field dominated by the high-frequency carrier and with minimal amplitude modulation and/or rotation (typically outside the target region), TIS was less effective at activation and more effective at block. Unlike amplitude-modulated high-frequency stimulation, TIS generated conduction block with some orientations and amplitude ratios of individual E-field at very high amplitudes of the total E-field (>1700 V/m). SignificanceThe complex 3D properties of the TIS E-fields should be accounted for in computational and experimental studies. The mechanisms of suprathreshold cortical TIS appear to involve neural activity block and periodic activation or onset response, consistent with computational studies of peripheral axons. These phenomena occur at E-field strengths too high to be delivered tolerably through scalp electrodes and may inhibit endogenous activity in off-target regions, suggesting limited significance of suprathreshold TIS.

bioengineering↗

bioRxiv2021

Characterizing the short-latency evoked response to intracortical microstimulation across a multi-electrode array

ObjectivePersons with tetraplegia can use brain-machine interfaces to make visually guided reaches with robotic arms. Without somatosensory feedback, these movements will likely be slow and imprecise, like those of persons who retain movement but have lost proprioception. Intracortical microstimulation (ICMS) has promise for providing artificial somatosensory feedback. If ICMS can mimic naturally occurring neural activity, afferent interfaces may be more informative and easier to learn than interfaces that evoke unnaturalistic activity. To develop such biomimetic stimulation patterns, it is important to characterize the responses of neurons to ICMS. ApproachUsing a Utah multi-electrode array, we recorded activity evoked by single pulses, and short (~0.2 s) and long (~4 s) trains of ICMS at a wide range of amplitudes and frequencies. As the electrical artifact caused by ICMS typically prevents recording for many milliseconds, we deployed a custom rapid-recovery amplifier with nonlinear gain to limit signal saturation on the stimulated electrode. Across all electrodes after stimulation, we removed the remaining slow return to baseline with acausal high-pass filtering of time-reversed recordings. With these techniques, we could record ~0.7 ms after stimulation offset even on the stimulated electrode. Main resultsWe recorded likely transsynaptically-evoked activity as early as ~0.7 ms after single pulses of stimulation that was immediately followed by suppressed neural activity lasting 10-150 ms. Instead of this long-lasting inhibition, neurons increased their firing rates for ~100 ms after trains. During long trains, the evoked response on the stimulated electrode decayed rapidly while the response was maintained on non-stimulated channels. SignificanceThe detailed description of the spatial and temporal response to ICMS can be used to better interpret results from experiments that probe circuit connectivity or function of cortical areas. These results can also contribute to the design of stimulation patterns to improve afferent interfaces for artificial sensory feedback.

neuroscience↗

bioRxiv2021

Fascicles split or merge every ~560 microns within the human cervical vagus nerve

1Vagus nerve stimulation (VNS) is FDA approved for stroke rehabilitation, epilepsy, and depression; however, the vagus functional anatomy underlying the implant is poorly understood. We used microCT to quantify fascicular structure and neuroanatomy within human cervical vagus nerves. Fascicles split or merged every ~560 m (17.8 {+/-} 6.1 events/cm). The high degree of fascicular splitting and merging in humans may explain the clinical heterogeneity in patient responses.

neuroscience↗

bioRxiv2021

Stoney vs. Histed: Quantifying the Spatial Effects of Intracortical Microstimulation

BackgroundIntracortical microstimulation (ICMS) is used to map neural circuits and restore lost sensory modalities such as vision, hearing, and somatosensation. The spatial effects of ICMS remain controversial: Stoney and colleagues proposed that the volume of somatic activation increased with stimulation intensity, while Histed et al. suggested activation density, but not somatic activation volume, increases with stimulation intensity. ObjectiveWe used computational modeling to quantify the spatial effects of ICMS intensity and unify the apparently paradoxical findings of Histed and Stoney. MethodsWe implemented a biophysically-based computational model of a cortical column comprising neurons with realistic morphology and representative synapses. We quantified the spatial effects of single pulse ICMS, including the radial distance to activated neurons and the density of activated neurons as a function of stimulation intensity. ResultsAt all amplitudes, the dominant mode of somatic activation was by antidromic propagation to the soma following axonal activation, rather than via trans-synaptic activation. There were no occurrences of direct activation of somata or dendrites. The volume over which antidromic action potentials were initiated grew with stimulation amplitude, while the volume of somatic activations did not. However, the density of somatic activation within the activated volume increased with stimulation amplitude. ConclusionsThe results resolve the apparent paradox between Stoney and Histeds results by demonstrating that the volume over which action potentials are initiated grows with ICMS amplitude, consistent with Stoney. However, the volume occupied by the activated somata remains approximately constant, while the density of activated neurons within that volume increase, consistent with Histed. HIGHLIGHTSO_LIImplemented a biophysically-based computational model of cortical column comprising cortical neurons with realistic morphology and representative synapses. C_LIO_LIQuantified the spatial patterns of neural activation by intracortical microstimulation to resolve the paradoxical findings of Stoney et al., 1968 and Histed et al., 2009. C_LIO_LIThe dominant mode of neural activation near the electrode was direct (i.e., via antidromic propagation from direct activation of the axon) and not trans-synaptic. C_LIO_LIThe dominant effect of increased ICMS intensity was to increase the density of activated neurons but not the volume of activation. C_LI

neuroscience↗

bioRxiv2020

In vivo visualization of pig vagus nerve 'vagotopy' using ultrasound

BackgroundPlacement of the clinical vagus nerve stimulating cuff is a standard surgical procedure based on anatomical landmarks, with limited patient specificity in terms of fascicular organization or vagal anatomy. As such, the therapeutic effects are generally limited by unwanted side effects of neck muscle contractions, demonstrated by previous studies to result from stimulation of 1) motor fibers near the cuff in the superior laryngeal and 2) motor fibers within the cuff projecting to the recurrent laryngeal. ObjectiveThe use of patient-specific visualization of vagus nerve fascicular organization could better inform clinical cuff placement and improve clinical outcomes. MethodsThe viability of ultrasound, with the transducer in the surgical pocket, to visualize vagus nerve fascicular organization (i.e. vagotopy) was characterized in a pig model. Ultrasound images were matched to post-mortem histology to confirm the utility of ultrasound in identifying fascicular organization. ResultsHigh-resolution ultrasound accurately depicted the vagotopy of the pig vagus nerve intra-operatively, as confirmed via histology. The stereotypical pseudo-unipolar cell body aggregation at the nodose ganglion was identifiable, and these sensory afferent fascicular bundles were traced down the length of the vagus nerve. Additionally, the superior and recurrent laryngeal nerves were identified via ultrasound. ConclusionsIntraoperative visualization of vagotopy and surrounding nerves using ultrasound is a novel approach to optimize stimulating cuff placement, avoid unwanted activation of motor nerve fibers implicated in off-target effects, and seed patient-specific models of vagal fiber activation to improve patient outcomes.

neuroscience↗