Computational modeling of autonomic nerve stimulation: Vagus et al.

Computational models of electrical stimulation, block and recording of autonomic nerves enable analysis of mechanisms of action underlying neural responses and design of optimized stimulation parameters. We reviewed advances in computational modeling of autonomic nerve stimulation, block, and recording over the past five years, with a focus on vagus nerve stimulation, including both implanted and less invasive approaches. Few models achieved quantitative validation, but integrated computational pipelines increase the reproducibility, reusability, and accessibility of computational modeling.

Circuits and mechanisms for TMS-induced corticospinal waves: Connecting sensitivity analysis 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.

Reverse-engineered models reveal differential membrane properties of autonomic and cutaneous unmyelinated fibers.

Unmyelinated C-fibers constitute the vast majority of axons in peripheral nerves and play key roles in homeostasis and signaling pain. However, little is known about their ion channel expression, which controls their firing properties. Also, because of their small diameters (~ 1 μm), it has not been possible to characterize their membrane properties using voltage clamp.

Highly efficient modeling and optimization of neural fiber responses to electrical stimulation.

Peripheral neuromodulation has emerged as a powerful modality for controlling physiological functions and treating a variety of medical conditions including chronic pain and organ dysfunction. The underlying complexity of the nonlinear responses to electrical stimulation make it challenging to design precise and effective neuromodulation protocols. Computational models have thus become indispensable in advancing our understanding and control of neural responses to electrical stimulation.

Quasistatic approximation in neuromodulation.

We define and explain the quasistatic approximation (QSA) as applied to field modeling for electrical and magnetic stimulation. Neuromodulation analysis pipelines include discrete stages, and QSA is applied specifically when calculating the electric and magnetic fields generated in tissues by a given stimulation dose. QSA simplifies the modeling equations to support tractable analysis, enhanced understanding, and computational efficiency.

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.

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

Background: Intracortical 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.

Computational models of compound nerve action potentials: Efficient filter-based methods to quantify effects of tissue conductivities, conduction distance, and nerve fiber parameters.

Background: Peripheral nerve recordings can enhance the efficacy of neurostimulation therapies by providing a feedback signal to adjust stimulation settings for greater efficacy or reduced side effects. Computational models can accelerate the development of interfaces with high signal-to-noise ratio and selective recording. However, validation and tuning of model outputs against in vivo recordings remains computationally prohibitive due to the large number of fibers in a nerve.

Quasistatic approximation in neuromodulation.

We define and explain the quasistatic approximation (QSA) as applied to field modeling for electrical and magnetic stimulation. Neuromodulation analysis pipelines include discrete stages, and QSA is applied specifically when calculating the electric and magnetic fields generated in tissues by a given stimulation dose. QSA simplifies the modeling equations to support tractable analysis, enhanced understanding, and computational efficiency.

At home adaptive dual target deep brain stimulation in Parkinson's disease with proportional control.

Continuous deep brain stimulation (cDBS) of the subthalamic nucleus (STN) or globus pallidus is an effective treatment for the motor symptoms of Parkinson's disease. The relative benefit of one region over the other is of great interest but cannot usually be compared in the same patient. Simultaneous DBS of both regions may synergistically increase the therapeutic benefit.

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

Our 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.We 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.We first show that the potentials generated by sources of unbalanced pulses exhibit different transients as compared to those of charge-balanced pulses, and this is disregarded by the quasi-static assumption.

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

Background: Transcranial 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.

Objective: To quantify neuronal polarization generated by tDCS in a multi-scale computational model.

Optimization of patient-specific stereo-EEG recording sensitivity.

Stereo-EEG is a minimally invasive technique used to localize the origin of epileptic activity (the epileptogenic zone) in patients with drug-resistant epilepsy. However, current stereo-EEG trajectory planning methods are agnostic to the spatial recording sensitivity of implanted electrodes. In this study, we used image-based patient-specific computational models to design optimized stereo-EEG electrode configurations.

Temporally non-regular patterns of deep brain stimulation (DBS) enhance assessment of evoked potentials while maintaining motor symptom management in Parkinson's disease (PD).

Background: Traditional deep brain stimulation (DBS) at fixed regular frequencies (>100 Hz) is effective in treating motor symptoms of Parkinson's disease (PD). Temporally non-regular patterns of DBS are a new parameter space that may help increase efficacy and efficiency.

Objective: To compare the effects of temporally non-regular patterns of DBS to traditional regularly-spaced pulses.

Pathways and parameters of sacral neuromodulation in rats.

The stimulation paradigm for sacral neuromodulation has remained largely unchanged since its inception. We sought to determine, in rats, whether stimulation-induced increases in bladder capacity correlated with the proportion of sensory pudendal (PudS) neurons at each stimulated location (L6, S1). If supported, this finding could guide the choice of stimulation side (left/right) and level (S2, S3, S4) in humans.

The Fifth Bioelectronic Medicine Summit: today's tools, tomorrow's therapies.

The emerging field of bioelectronic medicine (BEM) is poised to make a significant impact on the treatment of several neurological and inflammatory disorders. With several BEM therapies being recently approved for clinical use and others in late-phase clinical trials, the 2022 BEM summit was a timely scientific meeting convening a wide range of experts to discuss the latest developments in the field. The BEM Summit was held over two days in New York with more than thirty-five invited speakers and panelists comprised of researchers and experts from both academia and industry.

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

Background: Transcranial 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.

Objective: To quantify neuronal polarization generated by tDCS in a multi-scale computational model.

Calcium image analysis in the moving gut.

Background: The neural control of gastrointestinal muscle relies on circuit activity whose underlying motifs remain limited by small-sample calcium imaging recordings confounded by motion artifact, paralytics, and muscle dissections. We present a sequence of resources to register images from moving preparations and identify out-of-focus events in widefield fluorescent microscopy.

Methods: Our algorithm uses piecewise rigid registration with pathfinding to correct movements associated with smooth muscle contractions.

Network model of nociceptive processing in the superficial spinal dorsal horn reveals mechanisms of hyperalgesia, allodynia, and spinal cord stimulation.

The spinal dorsal horn (DH) processes sensory information and plays a key role in transmitting nociception to supraspinal centers. Loss of DH inhibition during neuropathic pain unmasks a pathway from nonnociceptive Aβ-afferent inputs to superficial dorsal horn (SDH) nociceptive-specific (NS) projection neurons, and this change may contribute to hyperalgesia and allodynia. We developed and validated a computational model of SDH neuronal circuitry that links nonnociceptive Aβ-afferent inputs in lamina II/III to a NS projection neuron in lamina I via a network of excitatory interneurons.

The Therapeutic Frequency Profile of Subthalamic Nucleus Deep Brain Stimulation in Rats Is Shaped by Antidromic Spike Failure.

The therapeutic mechanisms of subthalamic nucleus (STN) deep brain stimulation (DBS) may depend on antidromic activation of cortex via the hyperdirect pathway. However, hyperdirect pathway neurons cannot reliably follow high-stimulation frequencies, and the spike failure rate appears to correlate with symptom relief as a function of stimulation frequency. We hypothesized that antidromic spike failure contributes to the cortical desynchronization caused by DBS.

Spatiotemporal parameters for energy efficient kilohertz-frequency nerve block with low onset response.

Background: Electrical nerve conduction block has great potential for treatment of disease through reversible and local inactivation of somatic and autonomic nerves. However, the relatively high energy requirements and the presence of undesired excitation at the onset of the kilohertz-frequency (KHF) signals used for block pose obstacles to effective translation. Frequency, electrode geometry, and waveform shape are known to influence block threshold and onset response, but available data provide a limited understanding of how to select these parameters to optimize nerve block.

Validated computational models predict vagus nerve stimulation thresholds in preclinical animals and humans.

We demonstrated how automated simulations to characterize electrical nerve thresholds, a recently published open-source software for modeling stimulation of peripheral nerves, can be applied to simulate accurately nerve responses to electrical stimulation.We simulated vagus nerve stimulation (VNS) for humans, pigs, and rats. We informed our models using histology from sample-specific or representative nerves, device design features (i.

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

Background: Transcranial magnetic stimulation (TMS) can modulate neural activity by evoking action potentials in cortical neurons. TMS neural activation can be predicted by coupling subject-specific head models of the TMS-induced electric field (E-field) to populations of biophysically realistic neuron models; however, the significant computational cost associated with these models limits their utility and eventual translation to clinically relevant applications.

Objective: To develop computationally efficient estimators of the activation thresholds of multi-compartmental cortical neuron models in response to TMS-induced E-field distributions.