Biology subjects

Grill, W. M.

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

24 records · Page 2Linked to original sources

bioRxiv2020

Sources of Off-Target Effects of Vagus Nerve Stimulation Using the Helical Clinical Lead in Domestic Pigs

Clinical data suggest that efficacious vagus nerve stimulation (VNS) is limited by side effects such as cough and dyspnea that have stimulation thresholds lower than those for therapeutic outcomes. VNS side effects are putatively caused by activation of nearby muscles within the neck, via direct muscle activation or activation of nerve fibers innervating those muscles. Our goal was to determine the thresholds at which various VNS-evoked effects occur in the domestic pig--an animal model with vagus anatomy similar to human--using the bipolar helical lead deployed clinically. Intrafascicular electrodes were placed within the vagus nerve to record electroneurographic (ENG) responses, and needle electrodes were placed in the vagal-innervated neck muscles to record electromyographic (EMG) responses. Contraction of the cricoarytenoid muscle occurred at low amplitudes ([~]0.3 mA) and resulted from activation of motor nerve fibers in the cervical vagus trunk within the electrode cuff which bifurcate into the recurrent laryngeal branch of the vagus. At higher amplitudes ([~]1.4 mA), contraction of the cricoarytenoid and cricothyroid muscles was generated by current leakage outside the cuff to activate motor nerve fibers running within the nearby superior laryngeal branch of the vagus. Activation of these muscles generated artifacts in the ENG recordings that may be mistaken for compound action potentials representing slowly conducting A{delta}-, B-, and C-fibers. Our data resolve conflicting reports of the stimulation amplitudes required for C-fiber activation in large animal studies (>10 mA) and human studies (<250 {micro}A). After removing muscle-generated artifacts, ENG signals with post-stimulus latencies consistent with A{delta}- and B-fibers occurred in only a small subset of animals, and these signals had similar thresholds to those that caused bradycardia. By identifying specific neuroanatomical pathways that cause off-target effects and characterizing the stimulation dose-response curves for on- and off-target effects, we hope to guide interpretation and optimization of clinical VNS.

neuroscience↗

bioRxiv2019

Functional Vagotopy in the Cervical Vagus Nerve of the Domestic Pig: Implications for Vagus Nerve Stimulation

Given current clinical interest in vagus nerve stimulation, there are surprisingly few studies characterizing the anatomy of the vagus nerve in large animal models as it pertains to on-and off-target engagement of local fibers. We sought to address this gap by evaluating vagal anatomy in the domestic pig, whose vagus nerve organization and size approximates the human cervical vagus nerve. We provide data on key features across the cervical vagus nerve including diameter, number and diameter of fascicles, and distance of fascicles from the epineural surface where stimulating electrodes are placed. We also characterized the relative locations of the superior and recurrent laryngeal branches of the vagus nerve that have been implicated in therapy limiting side effects with common electrode placement. We identified key variants across the cohort that may be important for vagus nerve stimulation with respect to changing sympathetic/parasympathetic tone, such as cross-connections to the sympathetic trunk. We discovered that cell bodies of pseudo-unipolar cells aggregate together to form a very distinct grouping within the nodose ganglion. This distinct grouping gives rise to a larger number of smaller fascicles as one moves caudally down the cervical vagus nerve. This often leads to a distinct bimodal organization, or vagotopy that may be advantageous to exploit in design of electrodes/stimulation paradigms. Finally, we placed our data in context of historic and recent histology spanning mouse, rat, canine, pig, non-human primate and human models, thus providing a comprehensive resource to understand similarities and differences across species.

neuroscience↗

bioRxiv2019

Accuracy of robotic coil positioning during transcranial magnetic stimulation

ObjectiveRobotic positioning systems for transcranial magnetic stimulation (TMS) promise improved accuracy and stability of coil placement, but there is limited data on their performance. This text investigates the usability, accuracy, and limitations of robotic coil placement with a commercial system, ANT Neuro, in a TMS study.\n\nApproach21 subjects underwent a total of 79 TMS sessions corresponding to 160 hours under robotic coil control. Coil position and orientation were monitored concurrently through an additional neuronavigation system.\n\nMain ResultsRobot setup took on average 14.5 min. The robot achieved low position and orientation error with median 1.34 mm and 3.48{degrees}. The error increased over time at a rate of 0.4%/minute for both position and orientation.\n\nSignificanceAfter the elimination of several limitations, robotic TMS systems promise to substantially improve the accuracy and stability of manual coil position and orientation. Lack of pressure feedback and of manual adjustment of all coil degrees of freedom were limitations of this robotic system.

neuroscience↗

bioRxiv2018

Simulation of transcranial magnetic stimulation in head model with morphologically-realistic cortical neurons

Transcranial magnetic stimulation (TMS) enables non-invasive modulation of brain activity with both clinical and research applications, but fundamental questions remain about the neural types and elements it activates and how stimulation parameters affect the neural response. We integrated detailed neuronal models with TMS-induced electric fields in the human head to quantify the effects of TMS on cortical neurons. TMS activated with lowest intensity layer 5 pyramidal cells at their intracortical axonal terminations in the superficial gyral crown and lip regions. Layer 2/3 pyramidal cells and inhibitory basket cells may be activated too, whereas direct activation of layers 1 and 6 was unlikely. Neural activation was largely driven by the field magnitude, contrary to theories implicating the field component normal to the cortical surface. Varying the induced currents direction caused a waveform-dependent shift in the activation site and provided a mechanistic explanation for experimentally observed differences in thresholds and latencies of muscle responses. This biophysically-based simulation provides a novel method to elucidate mechanisms and inform parameter selection of TMS and other forms of cortical stimulation.

bioengineering↗

bioRxiv2018

Biophysically Realistic Neuron Models for Simulation of Cortical Stimulation

1.ObjectiveWe implemented computational models of human and rat cortical neurons for simulating the neural response to cortical stimulation with electromagnetic fields.\n\nApproachWe adapted model neurons from the library of Blue Brain models to reflect biophysical and geometric properties of both adult rat and human cortical neurons and coupled the model neurons to exogenous electric fields (E-fields). The models included 3D reconstructed axonal and dendritic arbors, experimentally-validated electrophysiological behaviors, and multiple, morphological variants within cell types. Using these models, we characterized the single-cell responses to intracortical microstimulation (ICMS) and uniform E-field with dc as well as pulsed currents.\n\nMain resultsThe strength-duration and current-distance characteristics of the model neurons to ICMS agreed with published experimental results, as did the subthreshold polarization of cell bodies and axon terminals by uniform dc E-fields. For all forms of stimulation, the lowest threshold elements were terminals of the axon collaterals, and the dependence of threshold and polarization on spatial and temporal stimulation parameters was strongly affected by morphological features of the axonal arbor, including myelination, diameter, and branching.\n\nSignificanceThese results provide key insights into the mechanisms of cortical stimulation. The presented models can be used to study various cortical stimulation modalities while incorporating detailed spatial and temporal features of the applied E-field.

bioengineering↗

bioRxiv2018

Coupling magnetically induced electric fields to neurons: longitudinal and transverse activation

We present a theory and computational models to couple the electric field induced by magnetic stimulation to neuronal membranes. The response of neuronal membranes to induced electric fields is examined under different time scales, and the characteristics of the primary and secondary electric fields from electromagnetic induction and charge accumulation on conductivity boundaries, respectively, are analyzed. Based on the field characteristics and decoupling of the longitudinal and transverse field components along the neural cable, quasi-potentials are a simple and accurate approximation for coupling of magnetically induced electric fields to neurons and a modified cable equation provides theoretical consistency for magnetic stimulation. The conventional and modified cable equations are used to simulate magnetic stimulation of long peripheral nerves by circular and figure-8 coils. Activation thresholds are obtained over a range of lateral and vertical coil positions for two nonlinear membrane models representing unmyelinated and myelinated axons and also for undulating myelinated axons. For unmyelinated straight axons, the thresholds obtained with the modified cable equation are significantly lower due to transverse polarization, and the spatial distributions of thresholds as a function of coil position differ significantly from predictions by the activating function. For myelinated axons, the transverse field contributes negligibly to activation thresholds, whereas axonal undulation can increase or decrease thresholds depending on coil position. The analysis provides a rigorous theoretical foundation and implementation methods for the use of the cable equation to model neuronal response to magnetically induced electric fields. Experimentally observed stimulation with the electric fields perpendicular to the nerve trunk cannot be explained by transverse polarization alone and is likely due to nerve fiber undulation and other geometrical inhomogeneities.

bioengineering↗