Biology subjects

Peterchev, A. V.

Publications and source records attributed to Peterchev, A. V..

At least 19 recordsLinked to original sources

bioRxiv2026

Variability and Landmark Quality in Anatomical Co-Registration in Neuronavigation for Brain Stimulation

Accurate neuronavigation depends not only on the technical performance of the tracking system but also on the reproducibility with which anatomical landmarks are physically localized. We quantified operator- and landmark-specific variability in repeated facial and cranial landmark localization in 19,630 measurements from 16 participants, four operators, and 13 landmarks under marked and unmarked conditions. Within-operator precision, inter-operator agreement, and marked-unmarked displacement were analyzed separately. Median within-operator precision was 1.60 mm and median inter-operator distance was 2.91 mm, with substantial differences across both operators and landmarks. The left medial canthus showed the greatest within-operator precision (1.43 mm), whereas the pronasale showed the closest inter-operator agreement (2.05 mm). Marking the positions before the procedure did not significantly improve within-operator precision overall but reduced inter-operator distances by 29.2%, which indicates convergence on a shared spatial reference rather than improved intrinsic repeatability. Between-operator differences also contained systematic directional components; signed offsets approached 1.5 mm. Exploratory analyses did not suggest general left--right difference in precision, although the approach side produced systematic spatial shifts for midline landmarks despite comparable repeatability. These findings demonstrate that anatomical landmark localization is both operator- and landmark-specific. Standardized landmark definitions, operator calibration, consistent pointer approach, and the use of multiple well-defined registration features should therefore be considered integral components of neuronavigation quality control.

neuroscience↗

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

Variants of relative frequency methods for determining transcranial magnetic stimulation motor threshold do not provide accurate estimation of threshold

Relative frequency methods such as five-out-of-ten have been used for a long time to determine motor threshold of transcranial magnetic stimulation (TMS), despite known severe limitations both in accuracy and speed. Variants of relative frequency methods have been developed to improve performance, such as adaptive staircasing and the recent RMT-Finder using binary search. However, they do not solve the fundamental problem underlying the use of relative frequencies to approximate the 50% TMS response rate at threshold. We demonstrate that the probability of false decisions using relative frequency due to at least half the pulses resulting in responses at subthreshold intensities or more than half the pulses resulting in no responses at suprathreshold intensity cannot be sufficiently reduced unless an impractically high pulse count is used, which substantially increases the duration of the thresholding procedure. Simulations in a virtual population of 25,000 subjects reveal that the accuracy of relative frequency methods is not improved by the adaptive staircasing or binary search variants. Although these variants reduce the number of pulses required to reach an estimate compared to the conventional relative frequency method, they are still slower and less accurate than more advanced thresholding methods such as stochastic approximation or maximum likelihood estimation. Therefore, these faster and more accurate methods should become the standard for motor thresholding of TMS, and the use of methods based on relative frequency should be discouraged. HighlightsO_LITMS motor thresholding should not use relative-frequency methods. C_LIO_LIRelative-frequency methods have a high probability of making false decisions. C_LIO_LIVariants of relative-frequency methods do not improve threshold accuracy. C_LIO_LIStochastic approximation or maximum-likelihood estimation are faster and more accurate. C_LI

bioengineering↗

bioRxiv2026

Acute Increase of Excitatory Activity in Pyramidal Neurons of Rat Motor Cortex under Static Magnetic Field

ObjectivesTranscranial application of a static magnetic field (SMF) was reported to result in subsequent modulation of neural excitability in the human motor cortex, but the acute mechanisms underlying this effect are unknown. We explore the mechanisms of this phenomenon with patch-clamp recording in rat brain slices during SMF exposure. Materials and MethodsPatch-clamp recording from layer II/III pyramidal neurons in motor cortex of acutely prepared brain slices were conducted during exposure to 0.20-0.35 T SMF or sham. ResultsDuring SMF exposure we observed an increase in the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) as well as miniature excitatory post-synaptic currents (mEPSCs) recorded in the presence of TTX to suppress action potentials and thus also network effects. There was a significant acute increase in sEPSC frequency for SMF exposure duration of both 6 min and 10 min, but not for 10 min sham exposure. After SMF exposure, the sEPSC and mEPSC frequency returned to baseline. The frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) was unaffected by SMF. The amplitude of the postsynaptic currents decreased with time for all recordings regardless of the condition, presumably due to the expected gradual deterioration of the patch clamp seal. ConclusionsThe acute effect of SMF exposure on sEPSC and mEPSC frequency, but not amplitude, is consistent with the assumption of a presynaptic or synaptic site mediating the effect. Furthermore, the consistency of the effect between sEPSCs and mEPSCs suggests that the effect is not related to action potential propagation in the presynaptic axon. The effect of SMF on EPSCs and not IPSCs may be related to the larger length of excitatory axons compared to inhibitory axons, or to effects on extracellular ionic gradients within the slice.

bioengineering↗

bioRxiv2026

Amplitude-Modulated Kilohertz Stimulation Targeting Beta-Band Activity Disrupts Motor Learning

Sensorimotor learning is associated with the modulation of neural rhythms in the primary motor cortex (M1). Beta-band activity ("beta"; 15-30 Hz) is suppressed during learning, while delta oscillations (1-4 Hz) become increasingly correlated with movement kinematics as skill improves. These observations have been complemented by experimental manipulations designed to perturb oscillatory activity with externally applied electric fields (E-fields). In non-human primates, invasive beta stimulation has been shown to disrupt motor learning whereas delta stimulation enhanced motor recovery in a stroke model. Causal evidence in humans remains limited, partly because established non-invasive methods cannot achieve continuous, narrowband E-fields at sufficient amplitude in the brain. To address this gap, we employed kilohertz transcranial magnetic perturbation (kTMP), a non-invasive magnetic induction technique that delivers continuous narrowband kilohertz E-fields which can be amplitude-modulated (AM) to target cortical rhythms. We applied AM-kTMP to test the functional relevance of beta and delta activity in human motor learning. In a double-blind mixed design, 40 participants performed a force-control task while receiving AM-kTMP at E-field amplitudes of 8 V/m in M1. We targeted either beta or delta, each paired with a sham condition. AM-kTMP influenced motor performance in a frequency-dependent manner: Beta-kTMP suppressed performance gains relative to both delta-kTMP and sham, whereas delta-kTMP showed no effect. These results suggest that increased beta activity in human M1 can interfere with motor learning. More broadly, kTMP offers a novel approach to probe frequency-specific cortical dynamics.

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

Understanding the mechanisms of lateral parietalmemory modulation in Mild Cognitive Impairment

The application of transcranial magnetic stimulation (TMS) to lateral parietal cortex has shown promise in improving episodic memory in older adults with Mild Cognitive Impairment (MCI). Previous work has suggested that such improvements are achieved by activating hippocampus at a distance with TMS, though this explanation is incomplete. We hypothesized that the mnemonic benefits arise from an additional mechanism: the modulation of semantic representations. Nineteen participants with amnestic MCI received either active intermittent theta-burst stimulation (iTBS) to angular gyrus or control vertex stimulation over three consecutive days while viewing object stimuli and completing relational memory encoding tasks during fMRI, followed by conceptual and perceptual recognition memory tests. We found that active TMS (relative to control TMS) significantly modulated conceptual memory performance. Using Representational Similarity Analysis with semantic embeddings derived from a large language model, we examined how TMS affects neural representations in inferior parietal lobule and hippocampus. We found that TMS enhanced semantic representational strength in inferior parietal lobule and reduced representational strength in hippocampus. Surprisingly, both effects supported successful memory. Neural pattern similarity analyses suggested that reduced hippocampal similarity supported successful memory, perhaps by promoting pattern separation mechanisms. These findings demonstrate that parietal TMS modulates semantic processing in a region-specific manner, by strengthening semantic integration at the stimulation site while promoting representational differentiation in medial temporal regions. This work advances our mechanistic understanding of memory neuromodulation and has implications for the optimization of therapeutic interventions in age-related memory disorders. Significance StatementTranscranial Magnetic Stimulation (TMS) applied to parietal cortex can improve memory in patients with Mild Cognitive Impairment (MCI), a population at high risk for Alzheimers Disease, yet the mechanisms underlying this benefit remain poorly understood. Using fMRI and Representational Similarity Analysis (RSA), we examined how TMS alters the neural representation of semantic stimulus information in parietal cortex and hippocampus during memory encoding. Our results show that TMS selectively modulates semantic representations at the stimulation site and in hippocampus, and that these representational changes predict memory improvement. These findings advance our mechanistic understanding of parietal memory neuromodulation and lay the groundwork for more targeted and effective TMS-based interventions for age-related memory disorders.

neuroscience↗

bioRxiv2025

High-Power Dual-Channel Chamber for High-Frequency Magnetic Neuromodulation

ObjectiveSeveral novel methods, including magnetogenetics and magnetoelectric stimulation, use high frequency alternating magnetic fields to precisely manipulate neural activity. To quantify the behavioral effects of such interventions in a freely moving mouse, we developed a dual-channel magnetic chamber, specifically designed for rate-sensitive magnetothermal-genetic stimulation, and adaptable for other uses of alternating magnetic fields. ApproachThrough an optimized coil design, the system allows independent control of two spatially orthogonal uniform magnetic fields delivered at different frequencies within a 10 x 10 x 6 cm3 chamber suitable for mouse studies. The two channels have nominal frequencies of 50 and 550 kHz with peak magnetic field strengths of 88 and 12.5 mT, achieved with resonant coil drives having peak voltages of 1.6 and 1.8 kV and currents of 1.0 and 0.26 kA, respectively. Additionally, a liquid cooling system enables magnetic field generation for second-level durations, and an observation port and camera allow video capture of the animals behavior within the chamber. Main ResultsThe system generates high-amplitude magnetic fields across two widely separated frequency channels with negligible interference (< 1%). Relatively uniform magnetic field distribution ({+/-}10% across 94% of the chamber volume) is maintained throughout the chamber, and temperature increase of the inner side of the coil enclosure during the operation is limited to < 0.35 {degrees}C/s to ensure in vivo safety. Using cobalt-doped and undoped iron oxide nanoparticles, we demonstrate channel-specific heating rates of 3.5 {degrees}C/s and 1.5 {degrees}C/s, respectively, validating frequency-selectivity. Both channels can run continuously for 4 seconds stably. SignificanceWe present a novel magnetic stimulation platform that combines high-frequency, high-power capability with two independently-controlled channels generating different frequencies, along with a real-time behavioral observation system for freely moving animals. The system supports frequency-multiplexed stimulation strategies for precise modulation of neural activity, making it a versatile tool for advancing magnetogenetics, neural circuit interrogation, and noninvasive stimulation approaches in neuroscience and bioengineering.

bioengineering↗

bioRxiv2025

Practical TMS coils with maximum focality and various stimulation depths

Conventional transcranial magnetic stimulation (TMS) coils generate a diffuse and shallow electric field (E-field) in the brain. This results in limited spatial targeting precision (focality). Previously, we developed a methodology for designing theoretical TMS coils to achieve optimal trade-off between the depth and focality of the induced E-field, as well as the energy required by the coil. This paper presents methods for the practical design and implementation of such focal-deep TMS (fdTMS) coils. First, we consider how the coils shape affects energy requirements and design a curved "hat" former that enables a wide range of coil placements while improving energy efficiency compared to flat formers. Second, we introduce a hybrid layer winding implementation to improve energy efficiency by using multi-layer windings in some regions of the coil and a single layer in others. Using simulations with a spherical head model, we benchmark the focality of the fdTMS E-field in the brain and the scalp, as well as the required energy, against conventional TMS coils. We then implement two fdTMS coil designs using copper wire wound inside a 3d-printed plastic former. The E-field of the prototype fdTMS coils and two conventional figure-8 counterparts is measured with a robotic probe to validate the designs. The experimental measurements corroborate the simulations, demonstrating that the fdTMS coils produce a more compact E-field relative to standard figure-8 coils. One potential disadvantage of the fdTMS coil prototypes is wider spread of the scalp E-field and increased energy loss due to the additional windings. Nonetheless, the presented fdTMS coils could offer advantages for precise mapping studies, and the design framework could be leveraged for other coil optimizations.

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↗

bioRxiv2025

Distinct impacts of sodium channel blockers on the strength-duration properties of human motor cortex neurones

Voltage-gated sodium channels (VGSCs) are essential for regulating axonal excitability in the human brain. While sodium channel blockers are known to modulate neuronal excitability, their in vivo effects on the human cortex remain poorly understood. Here, we employed novel transcranial magnetic stimulation (TMS) measures to investigate the effects of sodium channel blockers, carbamazepine and lacosamide, on the strength-duration behaviour of human cortical neurones, serving as an index of sodium channel function. Our data showed that single doses of both medications elevated resting motor thresholds compared to placebo, indicating reduced excitability; however, their impacts varied according to TMS pulse width. Carbamazepine raised thresholds proportionally across all pulse widths, whereas lacosamide disproportionately influenced thresholds for long-duration pulses. Crucially, lacosamide reduced the strength-duration time constant and increased rheobase, while carbamazepine had minimal effects on both. These results reveal subtle and unexpected differences in cortical neurone behaviour following VGSC-blocking medication administration. Lacosamides response aligns with the proposed mechanism of sodium conductance blockade, while carbamazepines effects suggest distinct VGSC interactions or potential off-target effects. Our findings advance the understanding of VGSC-blocking medication interactions in the human cortex and underscore the importance of employing specific TMS measures to gain deeper insights into medication mechanisms of action in vivo. Such measures could serve as valuable adjuncts in medication development and patient monitoring, enhancing understanding of medication action in clinical settings.

neuroscience↗

bioRxiv2025

Magnetic activation of electrically active cells

Magnetic control of cell activity has applications ranging from non-invasive neurostimulation to remote activation of cell-based therapies. Unlike other methods of regulating cell activity like heat and light, which are based on known receptors or proteins, no magnetically gated channel has been identified to date. As a result, effective approaches for magnetic control of cell activity are based on strong alternating magnetic fields able to induce electric fields or materials that convert magnetic energy into electrical, thermal, or mechanical energy to stimulate cells. In our investigations of magnetic cell responses, we found that a spiking HEK cell line with no other co-factors responds to a magnetic field that reaches a maximum of 500 mT within 200 ms using a permanent magnet. The response is rare, approximately 1 in 50 cells, but is fast and reproducible, generating an action potential within 200 ms of magnetic field stimulation. The magnetic field stimulation is over 10,000 times slower than the magnetic fields used in transcranial magnetic stimulation (TMS) and the induced electric field is more than an order of magnitude lower than necessary for neuromodulation, suggesting that induced electric currents do not drive the cell response. Instead, our calculation suggests that this response depends on mechanoreception pathways activated by the magnetic torque of TRP-associated lipid rafts. Despite the relatively rare response to magnetic stimulation, when cells form gap junctions, the magnetic stimulation can propagate to nearby cells, causing tissue-level responses. As an example, we co-cultured spiking HEK cells with beta-pancreatic MIN6 cells and found that this co-culture responds to magnetic fields by increasing insulin production. Together, these results point toward a method for the magnetic control of biological activity without the need for a material co-factor such as synthetic nanoparticles. By better understanding this mechanism and enriching for magneto-sensitivity it may be possible to adapt this approach to the rapidly expanding tool kit for wireless cell activity regulation.

biophysics↗

bioRxiv2024

Optimal Frequency for Seizure Induction with Electroconvulsive Therapy and Magnetic Seizure Therapy

Electroconvulsive therapy (ECT) and magnetic seizure therapy (MST) are effective in the treatment of medication-resistant depression. Determining the stimulus frequency resulting in the lowest seizure threshold could produce fewer adverse effects by reducing the overall stimulus intensity. To determine the optimal frequency for seizure induction, four male rhesus macaques were titrated with an increasing number of pulses at fixed frequencies ranging from 5 to 240 pulses per second (pps) using ultrabrief-pulse right-unilateral ECT and circular-coil-on-vertex MST. The seizure threshold dependence on stimulus frequency was similar for ECT and MST. While higher frequencies required progressively shorter trains to induce a seizure, the middle frequency range was associated with the fewest pulses (and hence the least charge and energy), with a minimum at 16 pps and similarly low thresholds for 10 and 25 pps. The number of pulses at seizure threshold increased markedly at lower and higher frequencies. The lowest stimulus frequencies, 5 and 10 pps, were associated with the greatest ictal power measured by electroencephalography. While this study did not assess efficacy or side effects, the results highlight the significance of stimulus frequency for seizure induction, suggest efficient titration schedules that minimize exposure to the electrical stimulus, and can inform studies to assess the impact on clinical outcomes.

bioengineering↗

bioRxiv2024

Using Dual-Coil TMS-EEG to Probe Bilateral Brain Mechanisms in Healthy Aging and Mild Cognitive Impairment

BackgroundA widespread observation in the cognitive neuroscience of aging is that older adults show a more bilateral pattern of task-related brain activation. These observations are based on inherently correlational approaches. The current study represents a targeted assessment of the role of bilaterality using repetitive transcranial magnetic stimulation (rTMS). ObjectiveWe used a novel bilateral TMS-stimulation paradigm, applied to a group of healthy older adults (hOA) and older adults with mild cognitive impairment (MCI), with two aims: First, to elucidate the neurophysiological effects of bilateral neuromodulation, and second to provide insight into the neurophysiological basis of bilateral brain interactions. MethodsElectroencephalography (EEG) was recorded while participants received six forms of transcranial magnetic stimulation (TMS): unilateral and bilateral rTMS trains at an alpha (8 Hz) and beta (18 Hz) frequency, as well as two sham conditions (unilateral, bilateral) mimicking the sounds of TMS. ResultsFirst, time-frequency analyses of oscillatory power induced by TMS revealed that unilateral beta rTMS elicited rhythmic entrainment of cortical oscillations at the same beta-band frequency. Second, both bilateral alpha and bilateral beta stimulation induced a widespread reduction of alpha power. Lastly, healthy older adults showed greater TMS-related reductions in alpha power in response to bilateral rTMS compared to the MCI cohort. ConclusionOverall, these results demonstrate frequency-specific responses to bilateral rTMS in the aging brain, and provide support for inhibitory models of hemispheric interaction across multiple frequency bands.

neuroscience↗

bioRxiv2024

Reduced Auditory Perception and Brain Response with Quiet TMS Coil

BACKGROUNDElectromagnetic forces in transcranial magnetic stimulation (TMS) coils generate a loud clicking sound that produces confounding auditory activation and is potentially hazardous to hearing. To reduce this noise while maintaining stimulation efficiency similar to conventional TMS coils, we previously developed a quiet TMS double containment coil (qTMS-DCC). OBJECTIVETo compare the stimulation strength, perceived loudness, and EEG response between qTMS-DCC and a commercial TMS coil. METHODSNine healthy volunteers participated in a within-subject study design. The resting motor thresholds (RMTs) for qTMS-DCC and MagVenture Cool-B65 were measured. Psychoacoustic titration matched the Cool-B65 loudness to qTMS-DCC pulsed at 80, 100, and 120% RMT. Event-related potentials (ERPs) were recorded for both coils. The psychoacoustic titration and ERPs were acquired with the coils both on and 6 cm off the scalp, the latter isolating the effects of airborne auditory stimulation from body sound and electromagnetic stimulation. The ERP comparisons focused on a centro-frontal region that encompassed peak responses in the global signal. RESULTSRMT did not differ significantly between the coils, with or without the EEG cap on the head. qTMS-DCC was perceived to be substantially quieter than Cool-B65. For example, qTMS-DCC at 100% coil-specific RMT sounded like Cool-B65 at 34% RMT. The general ERP waveform and topography were similar between the two coils, as were early-latency components, indicating comparable electromagnetic brain stimulation in the on-scalp condition. qTMS-DCC had a significantly smaller P180 component in both on-scalp and off-scalp conditions, supporting reduced auditory activation. CONCLUSIONSThe stimulation efficiency of qTMS-DCC matched Cool-B65, while having substantially lower perceived loudness and auditory-evoked potentials. HighlightsO_LIqTMS coil is subjectively and objectively quieter than conventional Cool-B65 coil C_LIO_LIqTMS coil at 100% motor threshold was as loud as Cool-B65 at 34% motor threshold C_LIO_LIAttenuated coil noise reduced auditory N100 and P180 evoked response components C_LIO_LIqTMS coil enables reduction of auditory activation without masking C_LI

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↗

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↗