Biology subjects

Bikson, M.

Publications and source records attributed to Bikson, M..

At least 19 recordsLinked to original sources

bioRxiv2026

The Effect of Transcutaneous Auricular Vagus Nerve Stimulation (taVNS) on Cardiorespiratory Physiology: Four Waveforms Trial with Tragus vs Earlobe Stimulation

BackgroundTranscutaneous auricular vagus nerve stimulation (taVNS) depends on activating afferent vagal pathways, leading to central and physiological (parasympathetic) modulation. Explaining how taVNS changes cardiorespiratory physiology requires systematic characterization of the effects of electrode location and stimulation waveform using rigorous experimental controls. ObjectiveTo determine the acute effects of four taVNS stimulation configurations (left unilateral 25 Hz, 100 Hz, burst, and bilateral 25 Hz) on physiological markers of parasympathetic activation compared with configuration-matched earlobe stimulation in healthy subjects at rest. MethodsCustomized 8-mm ear-clip electrodes delivered monophasic 500 s pulses (anode anterior) to the tragus or a configuration-matched earlobe control across four stimulation configurations (left unilateral 25 Hz, 100 Hz, burst, and bilateral 25 Hz). Twenty-five healthy participants completed a randomized, single-blind, within-subject crossover study, undergoing both active and control stimulation for all four configurations (200 sessions total). Each session consisted of five 60-second stimulation blocks (1,000 stimuli total). Heart rate (HR), heart rate variability (HRV; RMSSD), and respiration were recorded continuously. Linear mixed-effects models compared physiological responses between tragus and earlobe stimulation during the first stimulation block (primary analysis), across 5-second HR intervals (secondary analysis), and averaged across all five stimulation blocks (post hoc analysis). ResultsDuring the first stimulation block, HRV was significantly higher during unilateral left 25 Hz tragus stimulation than during the matched earlobe control ({beta} = -10.34, t(33) = -2.63, p = .01, 95% CI [-18.05, -2.64]), consistent with increased parasympathetic activity. No significant differences were observed for HRV with the other stimulation configurations, or for HR or respiration under any configuration. Analysis of 5-second HR intervals likewise revealed no significant temporal effects for block one. Analysis of 5-second heart rate intervals across the five blocks identified differences between tragus and earlobe at discrete time points but did not show a consistent temporal pattern across the stimulation period. Across all five stimulation blocks, unilateral left 25 Hz tragus stimulation remained associated with higher HRV ({beta} = -6.56, t(124) = -3.85, p < .01, 95% CI [-9.90, -3.22]) and also produced an increase in HR relative to earlobe stimulation ({beta} = -1.05, t(24) = -2.57, p = .01, 95% CI [-1.85, -0.24]). Respiration was unaffected throughout. ConclusionIn this systematic study, unilateral left 25 Hz tragus stimulation produced physiological modulation consistent with vagal target engagement. These findings underscore the importance of rigorous dose-specific taVNS studies to establish reproducible physiological biomarkers.

bioengineering↗

bioRxiv2026

Impedance-Derived Heart Rate and Heart Rate Variability from tDCS Output Voltage: Sensorless Physiological Monitoring During Electrical Neuromodulation

BackgroundTranscranial direct current stimulation (tDCS) devices adjust output voltage to maintain the target current despite varying impedance. Pulsatile blood flow produces beat-synchronous changes in tissue impedance. ObjectiveTo determine whether impedance-derived heart rate (IHR), heart rate variability (IHRV), and respiration (IDR) can be estimated from tDCS output voltage without additional physiological sensors. MethodsA custom analog front-end acquires the tDCS output voltage across its full dynamic DC range and superimposed AC fluctuations with high precision. Beats detected from the AC-coupled signal yielded normal-to-normal intervals for HR, HRV, and interval-derived respiration. Accuracy was quantified as mean absolute error (MAE) in 10 healthy laboratory participants against ECG and respiration-monitor references, and against chest-strap RR intervals in 19 at-home sessions from 10 participants with mild-to-moderate depression. ResultsLaboratory MAEs versus ECG were 0.57 bpm for HR, 9.40 ms for SDNN, and 18.90 ms for RMSSD (r = 0.995, 0.859, and 0.778; N = 10); respiratory-rate MAE was 1.36 breaths/min (r = 0.852; N = 6). Across 1-5 mA of tDCS, the cardiac voltage {Delta}Vcardiac(t) amplitude scaled linearly with current (slope, 0.073 mV/mA; p < 0.001). The pulsatile impedance {Delta}Zcardiac(t) = ({Delta}Vcardiac(t)/Iapplied) amplitude averaged 0.080 {+/-} 0.029 {Omega} (mean {+/-} SD) across 50 participant-current observations, with no significant dependence on intensity (slope, -0.002 {Omega}/mA; p = 0.086). At-home MAEs were 1.43 bpm for HR, 8.86 ms for SDNN, and 24.92 ms for RMSSD (r = 0.995, 0.767, and 0.680; 19 sessions). ConclusionstDCS output voltage contains a recoverable cardiac-synchronous signal arising from pulsatile impedance, enabling HR, HRV, and respiratory monitoring without additional physiological sensors.

bioengineering↗

bioRxiv2026

Self-powered electronics-free Wearable Disposable Electrotherapy (WDE) platform for accelerated wound healing

Electrical stimulation accelerates wound repair by modulating endogenous bioelectric signals that regulate inflammation, angiogenesis, extracellular matrix remodeling, and cellular responses within the wound microenvironment. However, clinical translation has been hindered by cumbersome devices with procedures that disrupt standard wound-care workflows, direct electrode contact with the wound bed, and/or limited stimulation output. Wearable Disposable Electrotherapy (WDE) integrates an electronics-free printed electrochemical architecture into an mm-thick patch that looks and is applied like a conventional bandage. The device is self- powered and delivers a single electrotherapy dose simply by application to the skin. Device dose-control (electrochemical performance) and efficacy were evaluated in a full-thickness excisional wound model in rats, compared with a sham device and a conventional Constant Current (CC) stimulator. WDE or control treatments were applied daily from day 1 through day 13, with endpoint evaluation on day 14. WDE delivered electrical stimulation comparable to CC while reducing the time required to achieve 50% wound closure by 2.08 days ([~]29%) relative to sham treatment. Histological and immunofluorescence analyses at day 14 demonstrated enhanced tissue remodeling, including increased collagen deposition ([~]25%), tissue cellularity ([~]73%), myofibroblast-associated SMA expression ([~]2.6-fold), angiogenesis-associated CD31 expression ([~]2.0-fold), and increased expression of both M2- (CD206, [~]2.0-fold) and M1- associated (iNOS, [~]1.7-fold) markers compared with sham. A novel cellular-resolution dosimetry model, leveraging charge-based boundary element method accelerated with the fast multipole method (BEM-FMM), provides a biophysical framework linking electrical stimulation with wound microenvironment and tissue repair mechanisms. Together, these findings establish WDE as a practical bioelectric wound dressing that accelerates wound healing and tissue remodeling, with the simplicity and scalability of disposable bandages.

bioengineering↗

bioRxiv2026

Direct Reconstruction of DC Cortical Conductivity from Large-Scale Electron Microscopy Data

Electrical conductivity of cortical gray matter governs the magnitude and spatial distribution of electric fields generated by brain stimulation and intrinsic neuronal activity measured with M/EEG and intracortical recordings. However, reported macroscopic conductivity values vary by more than threefold, limiting the fidelity of bioelectromagnetic models and leaving unresolved whether this variability reflects measurement uncertainty or genuine structural heterogeneity of cortical tissue. Here, we present a multiscale computational framework that, for the first time, attempts to derive mesoscale conductivity maps of mouse visual cortex at 50-{micro}m resolution directly from large-volume, segmented nanometer-scale electron microscopy data. The Minnie 65 subvolume of the MICrONS dataset is accurately subdivided into 1,224 50-{micro}m cubic blocks. Each block contains, on average, 40-50 million membrane facets of a highly convoluted and dense cellular structure. Three orthogonal electrode pairs are applied to each isolated block to estimate the three principal components of the conductivity tensor. Quasistatic electric modeling is enabled by an iterative boundary-element fast multipole method (BEM-FMM) under the approximation of non-conducting membranes (DC conductivity). Spatially averaged conductivity values predicted by our framework agree well with prior low-resolution measurements in rats, validating the approach. At the same time, the resulting mesoscale maps reveal pronounced conductivity granularity at 50-100 {micro}m scales as well as significant variations in both radial and tangential directions. These results indicate that mesoscale conductivity heterogeneity could be an intrinsic structural property of the cortex. Limitations and extensions of this study are discussed in detail.

neuroscience↗

bioRxiv2026

Neuronavigation-free and MRI-free Localization of Deep Brain Targets

Emerging non-invasive brain stimulation modalities, including transcranial focused ultrasound and transcranial interferential stimulation, offer the promise of safely and non-invasively modulating deep brain structures. Accurate targeting of these regions typically involves subject-specific MRI, limiting widespread deployment. Here, we introduce an MRI-free, neuronavigation-free method for localizing deep brain targets using only three simple scalp measurements. These measures define an affine transformation that maps the MNI152 standard head model to an individuals head geometry. We evaluated our approach on 50 healthy adults, comparing our model{square}predicted coordinates against ground-truth coordinates obtained via MRI-based nonlinear normalization. Across ten deep brain targets, our method achieved a mean localization error of 3.82 mm demonstrating a more accessible and cost-efficient alternative than MRI- or neuronavigation-based approaches.

neuroscience↗

bioRxiv2026

Are Synaptic Clefts Directionally Oriented?

Synapses are fundamental building blocks of cortical circuits, yet their geometry is typically regarded as a local property, independent of mesoscale architecture. The prevailing assumption is that synaptic clefts are isotropically oriented in space. Here, we test this assumption by analyzing approximately 117 million synaptic clefts from two independent 1 mm3 electron microscopy datasets: the human H01 middle temporal gyrus and the mouse MICrONS primary visual cortex, using three independent cleft-extraction methods. Across both volumes, we observe that synaptic cleft orientations are not randomly distributed, but instead show statistically significant and spatially coherent directional biases across cortical layers. This mesoscale anisotropy is conserved across species, yet is stronger and more consistent in human association cortex than in mouse sensory cortex, a difference that may reflect the expanded dendritic arbors and greater integrative demands of human pyramidal neurons. We propose that cleft orientation bias is a geometric consequence of the axonal and dendritic architecture that shapes synapse formation, representing a new candidate organizational feature of cortical microarchitecture with potential implications for circuit computation and neuromodulation. These findings motivate targeted physiological studies to determine whether synaptic orientation contributes causally to cortical function.

neuroscience↗

bioRxiv2026

Morphological bias of the MNI152 brain

The MNI152 template is widely treated as a representative average brain in neuroimaging, computational modeling, and neuromodulation research, yet its fidelity to true population morphology has not been systematically evaluated. In this study, we compared the MNI152 template to 430 individual MRI scans from a publicly available dataset spanning Asian, Black, and White participants. We additionally generated an alternative template using ANTsPy to assess whether a modern diffeomorphic approach yields a more anatomically representative average. We conducted affine registrations and deformation-based morphometry to detect and quantify gross morphological differences as well as local voxel-level deformations. Across all racial groups, the MNI152 template required consistent global contraction, and its Jacobian fields revealed spatially heterogeneous deformations, indicating systematic mismatches in both size and shape. In contrast, the ANTsPy template showed mean scaling and deformation values near 1.0, reflecting closer correspondence to real human anatomy. These findings demonstrate that the MNI152 template does not accurately represent the morphology of the studied population and that linear registration alone cannot correct its inherent biases. Reliance on MNI152 may therefore introduce unintended distortions in applications requiring anatomically realistic head models. More robust, unbiased template-generation pipelines, and potentially demographic-specific templates, may be necessary for improved accuracy.

neuroscience↗

bioRxiv2025

Electrophysiological Characteristics of Epidural Spinal Signals in Preclinical Models of Spinal Cord Stimulation

ObjectivesEpidural stimulation of the spinal cord evokes distinct electrophysiological responses that can be recorded epidurally. Here, we characterized evoked compound action potentials (ECAPs), doublets (secondary or tertiary ECAPs, likely of different physiological origin than primary ECAPs), evoked synaptic activity potentials (ESAPs), and electromyographic (EMG) signals in preclinical models. Our objective was to clarify the features and distinct physiological origins of these signals, in order to advance mechanistic studies and support clinical applications of spinal cord stimulation (SCS) therapy. Materials and MethodsAdult male Sprague-Dawley rats (300-440 g) were implanted with two epidural leads (caudal and rostral; each with eight electrodes) and received monopolar, biphasic stimulation (200 s pulse width) at 2 and 50 Hz, with current increased stepwise to motor threshold. Rhesus macaques (11.5 and 10.2 kg) were implanted with a single 12-electrode epidural lead and stimulated using either tripolar, triphasic pulses at 10 Hz (100 s) or tripolar, biphasic pulses at 3 Hz (80 s) up to 3xECAP threshold. Recordings were taken from non-stimulating electrodes. ResultsECAPs and EMG signals were recorded across multiple spinal segments in both rats (L1-T7) and macaques (L2-T11). Doublets presented as complex waveforms with multiple negative peaks, two in rats and three in macaques, likely representing distinct ECAPs at T11-T6 in a rat and L1-T11 in macaques. ESAPs, detectable in rats, showed anatomical specificity, over the L1/T13 vertebrae with peak responses at L1. Signal analysis included activation thresholds, amplitudes, latencies, and conduction velocities. ConclusionsThis study outlines electrophysiological signals evoked by SCS in terms of their waveform, recruitment thresholds, and putative physiological origins. We propose that, to the extent these signals reflect different aspects of spinal processing and may serve as biomarkers of dysregulated nociceptive pathways, as well as indicators of SCS efficacy or potential side effects.

neuroscience↗

bioRxiv2025

High-Capacity transcranial Direct Current Stimulation (HC-tDCS)

BackgroundEnhancing tDCS technology can support the delivery of higher current intensities, enabling broader dose-response studies in human trials. MethodsHigh-Capacity tDCS (HC-tDCS) integrates novel electrodes and adaptive current/voltage controlled electronics. Multi-layer HC electrodes include polarity-specific redox layers and designed hydrogel interfaces, shaped for a bifrontotemporal montage. The stimulator design includes adaptive ramps with hybrid voltage-current control and low (7.5 V) compliance voltage. Scanning electron microscopy (SEM) and electrical impedance spectroscopy (EIS) were used to characterize electrode properties. Tolerability of HD-tDCS was tested for target currents 1-6 mA (in 1 mA increments) for 30 min on 5 healthy subjects, and compared with conventional tDCS using 2 mA F3-F4 sponge-electrodes. MRI-derived computational models predicted cortical electric fields. Tolerability was assessed according to the 100 mm visual analogue scale for pain (VASP-100), skin erythema assessment, thermal imaging, and adverse event questionnaires. ResultsThe electrode design including high-roughness polarity-specific capacity, electrochemically supports high-charge direct current stimulation. In all subjects, HC-tDCS was well tolerated at all tested doses (1-6 mA) with minor transient adverse events and average VASP-100 less than 15. VASP-100 during sponge-electrode tDCS at 2 mA was comparable to 5 and 6 mA HC-tDCS. HC-tDCS operates at significantly lower voltage than sponge-tDCS, impacting tolerability and efficiency. Modeling predicts peak frontal electric fields of 0.65-1.08 V/m for 2 mA HC-tDCS and 1.95-3.25 V/m for 6 mA HC-tDCS, compared to 0.49-0.95 V/m for 2 mA sponge-tDCS. ConclusionsHC-tDCS allows increased cortical stimulation; at 6 mA achieving double the 1 V/m electric field threshold in all subjects. Enabled by pre-stimulation procedures, specialized electrodes, and adaptive low-voltage stimulators, HC-tDCS is well tolerated at intensities up to at least 6 mA.

bioengineering↗

bioRxiv2025

MRI-free Virtual Neuronavigation for TMS

Methods to determine coil position are paramount in TMS. Existing approaches are limited to scalp heuristics or depend on some combination of neuronavigation hardware, average brain templates, as well as subject MRI and/or evoked responses. We developed head-model guided TMS virtual neuronavigation without subject MRI, specialized hardware, or evoked responses. The MRI-free virtual neuronavigation involves three scalp measurements which are then used to generate an individualized head model by applying ellipsoid-based affine transformations to the MNI standard head model. Virtual neuronavigation is then performed on this individualized head model for any brain target. The coil position is then provided to the operator in simple geodesic measurements. We simulated this process on MRI data of fifteen subjects showing a mean error of 2.75 mm, outperforming the accuracy of scalp heuristic targeting approaches.

bioengineering↗

bioRxiv2024

Frequency-dependent and capacitive tissue electrical properties in spinal cord stimulation models

BackgroundModels of spinal cord stimulation (SCS) simulate the electric fields (E-fields) generated in targeted tissues, which in turn can predict physiological and then behavioral outcomes. Notwithstanding increasing sophistication and use in optimizing therapy, SCS models typically calculate E-fields using the quasi-static approximation (QSA). QSA, as implemented in neuromodulation models, neglects the frequency dispersion of tissue conductivity, as well as propagation, capacitive, and inductive effects on the E-field. The reliability of QSA specifically for SCS has not been considered in detail, especially for higher-frequency SCS. MethodsWe implemented a frequency-dependent finite element method (FEM) and solved a high- resolution RADO-SCS model with voltage-controlled (VC) and current-controlled (CC) stimulation to assess the impact of frequency-dependent conductivity (dispersion) and permittivity of spinal tissues on E-fields generated at three different spinal column locations (epidural space, spinal cord, and root) for frequencies spanning from 1 Hz to 10 MHz. Results were compared with predictions of QSA method, with varied conductivity values of purely resistive tissues. We further assessed the impact of frequency-dependent and capacitive tissue properties on spinal heating and distortion of the E-field waveform. ResultsTissue-specific electric properties around the energized leads and mode of stimulation-control impacted the magnitude of E-fields. In the spinal cord, the VC-SCS E-field generated with the frequency-dependent and capacitive properties was comparable to the QSA with 2X epidural fat conductivity, whereas the CC-SCS generated E-field was minimally impacted by frequency- dependent and capacitive properties up to 10 kHz. Spinal cord heating predicted by frequency- dependent and capacitive tissue properties was comparable to the QSA conditions with VC-SCS, whereas with CC-SCS, there was no impact of the frequency-dependent and capacitive tissue properties in spinal cord heating. E-field waveform distortion in the spinal cord, with CC-SCS at 1 kHz-specific electrical properties, was significant when fat capacitance (permittivity) was increased by 10X, whereas with VC-SCS, there was no effect of tissue capacitance. ConclusionRegardless of the mode of SCS, QSA was still valid in predicting SCS-induced E-field and heating at the spinal tissues- across and {beta} dispersion region of spinal tissues dielectric spectrum for VC-SCS and up to 10 kHz for CC-SCS.

bioengineering↗

bioRxiv2024

Statistical method accounts for microscopic electric field distortions around neurons when simulating activation thresholds

IntroductionNotwithstanding advances in computational models of neuromodulation, there are mismatches between simulated and experimental activation thresholds. Transcranial Magnetic Stimulation (TMS) of the primary motor cortex generates motor evoked potentials (MEPs). At the threshold of MEP generation, whole-head models predict macroscopic (at millimeter scale) electric fields (50-70 V/m) which are considerably below conventionally simulated cortical neuron thresholds (175-350 V/m). MethodsWe hypothesize that this apparent contradiction is in part a consequence of electrical field warping by brain microstructure. Classical neuronal models ignore the physical presence of neighboring neurons and microstructure and assume that the macroscopic field directly acts on the neurons. In previous work, we performed advanced numerical calculations considering realistic microscopic compartments (e.g., cells, blood vessels), resulting in locally inhomogeneous (micrometer scale) electric field and altered neuronal activation thresholds. Here we combine detailed neural threshold simulations under homogeneous field assumptions with microscopic field calculations, leveraging a novel statistical approach. ResultsWe show that, provided brain-region specific microstructure metrics, a single statistically derived scaling factor between microscopic and macroscopic electric fields can be applied in predicting neuronal thresholds. For the cortical sample considered, the statistical methods match TMS experimental thresholds. ConclusionsOur approach can be broadly applied to neuromodulation models, where fully coupled microstructure scale simulations may not be computationally tractable.

neuroscience↗

bioRxiv2024

Electromagnetic Modeling within a Microscopically Realistic Brain - Implications for Brain Stimulation

Modeling brain stimulation at the microscopic scale may reveal new paradigms for various stimulation modalities. We present the largest map to date of extracellular electric field distributions within a layer L2/L3 mouse primary visual cortex brain sample. This was enabled by the automated analysis of serial section electron microscopy images with improved handling of image defects, covering a volume of 250 x 140 x 90 m3. The map was obtained by applying a uniform brain stimulation electric field at three different polarizations and accurately computing microscopic field perturbations using the boundary element fast multipole method. We used the map to identify the effect of microscopic field perturbations on the activation thresholds of individual neurons. Previous relevant studies modeled a macroscopically homogeneous cortical volume. Our result shows that the microscopic field perturbations - an electric field spatial noise with a mean value of zero - only modestly influence the macroscopically predicted stimulation field strengths necessary for neuronal activation. The thresholds do not change by more than 10% on average. Under the stated limitations and assumptions of our method, this result justifies the conventional theory of "invisible" neurons embedded in a macroscopic brain model for transcranial magnetic and transcranial electrical stimulation. However, our result is solely sample-specific and largely neglects the effect of the microcapillary network. Furthermore, we only considered the uniform impressed field and a single- pulse stimulation time course. Significance statementThis study is arguably the first attempt to model brain stimulation at the microscopic scale, enabled by automated analysis of modern scanning electron microscopy images of the brain. It concentrates on modeling microscopic perturbations of the extracellular electric field caused by the physical cell structure and is applicable to any type of brain stimulation. Data availability statementPost-processed cell CAD models (383, stl format), microcapillary CAD models (34, stl format), post-processed neuron morphologies (267, swc format), extracellular electric field and potential distributions at different polarizations (267x3, MATLAB format), *.ses projects files for biophysical modeling with Neuron software (267x2, Neuron format), and computed neuron activating thresholds at different conditions (267x8, Excel tables, without the sample polarization correction from Section 2.8) are made available online through BossDB, a volumetric open-source database for 3D and 4D neuroscience data.

neuroscience↗

bioRxiv2024

Dorsal horn dendrite polarization during Spinal Cord Stimulation (SCS) predicted using the quasi-uniform-mirror assumption.

While the mechanisms of Spinal Cord Stimulation are traditionally assumed to follow pacing of dorsal columns axons, the development of sub-paresthesia SCS and new waveforms has encouraged consideration of different cellular targets. Given their relative proximity to the stimulation electrodes and role in pain processing (e.g., synaptic processing and gate control theory), spinal cord dorsal horn interneurons may be direct targets of stimulation. We developed a novel computational modeling pipeline termed quasi-uniform-mirror assumption and apply it to predict polarization of dorsal horn inter-neuron cell types (Islet type, Central type, Stellate/Radial, Vertical-like) to SCS. The quasi-uniform-mirror assumption allows prediction, for each cell type and location in the dorsal horn, the peak and axis of dendritic polarization as well as the impact of stimulation pulse width. For long pulse (dc), the peak polarization per mA of SCS with a bipolar montage were: Islet type 3.5 mV, Central type 2 mV, Stellate/Radial 1.4 mV, Vertical-like 2.5 mV. For Stellate/Radial the peak dendritic polarization was dorsal-ventral, and for Islet type Central peak dendrite polarization was in the rostral-caudal axis. For Islet type and Central type cells peak dendrite polarization was between stimulation electrodes, while for Stellate/Radial and Vertical-like peak dendrite polarization was under stimulation electrodes. The impact of pulse width depended on cell membrane time constants, which in the quasi-uniform-mirror assumption are uniform first-order. Assuming 1 ms time constant, for a 1 ms or 100 us pulse width, the peak dendrite polarization decreases (from the dc values) by [~]33% and [~]88%. These results suggest, for the conditions modeled, maximum polarization is of islet-cells in the superficial dorsal horn at locations between electrodes; applying 2 mA 1 ms pulse SCS, the peak islet-cell dendrite polarization is [~]4.7 mV. Polarizations of a few mV have been shown to modulate synaptic processing through sub-threshold mechanisms.

bioengineering↗

bioRxiv2023

Frequency-dependent phase entrainment of cortical cell types during tACS: Converging modeling evidence

BackgroundTranscranial alternating current stimulation (tACS) enables non-invasive modulation of brain activity, holding promise for clinical and research applications. Yet, it remains unclear how the stimulation frequency affects various neuron types. ObjectiveTo quantify the frequency-dependent behavior of key neocortical cell types. MethodsWe used both detailed (anatomical multicompartments) and simplified (three compartments) single-cell modeling approaches based on the Hodgkin-Huxley formalism to study neocortical excitatory and inhibitory cells under various-amplitude tACS frequencies within the 5-50 Hz range at rest and during basal 10 Hz activity. ResultsL5 pyramidal cells exhibited the highest polarizability at DC, ranging from 0.21 to 0.25mm and decaying exponentially with frequency. Inhibitory neurons displayed membrane resonance in the 5-15 Hz range with lower polarizability, although bipolar cells had higher polarizability. Layer 5 PC demonstrated the highest entrainment close to 10 Hz, which decayed with frequency. In contrast, inhibitory neurons entrainment increased with frequency, reaching level akin to PC. Results from simplified models could replicate the phase preferences, while amplitudes tend to follow opposite trends in PC. ConclusiontACS-induced membrane polarization is frequency-dependent, revealing observable resonance behavior. This finding motivates further experimental studies of cell-specific frequency-dependent membrane responses to weak electric stimuli. Whilst optimal phase entrainment of sustained activity is achieved in PC when tACS frequency matches the activity, inhibitory neurons tend to be entrained at higher frequencies. Consequently, this presents the potential for precise, cell-specific targeting. O_LISingle-cell models of frequency response to tACS for a wide variety of neurons C_LIO_LISimplified and morphologically accurate models were compared C_LIO_LIPyramidal cells (PC) show resonant-like response close to intrinsic firing frequency C_LIO_LIEntrainement of GABAergic neurons increases with the frequency of tACS C_LIO_LIMembrane polarization resonance in GABAergic neurons within the 5-15 Hz range C_LI

neuroscience↗

bioRxiv2023

Wearable Disposable Electrotherapy

We design and validate a novel electrotherapy platform without electronic components, using printed abundant, environmentally benign materials. Whereas existing electrotherapy devices use an independent power source and electronics to generate and control stimulation currents, our design eliminates the need for these components. Device production relies only on scalable additive manufacturing and common materials, minimizing cost and environmental impact. The disposable single-use platform (as discreet as adhesive bandages) is activated simply by placement on the body. A prescribed electrotherapy discharge is regulated by a flexible 3D electrochemical architecture tailored to each application by a novel operational theory. The single-dose usability of this platform is a categorical shift from existing approaches with durable equipment that require programming and assembly to disposable electrodes for each use. Our Wearable Disposable Electrotherapy technology can be distributed like pharmacotherapy, with indications spanning neuromodulation of brain disorders, wound healing, transcutaneous drug delivery, bioelectronic medicine, and aesthetics.

bioengineering↗

bioRxiv2023

Transcranial electric stimulation modulates firing rate at clinically relevant intensities

Notwithstanding advances with low-intensity transcranial electrical stimulation (TES), there remain questions about the efficacy of clinically realistic electric fields on neuronal function. We used Neuropixels 2.0 probe with 384 channels in an in-vivo rat model of TES to detect effects of weak fields on neuronal firing rate. High-density field mapping and computational models verified field intensity (1 V/m in hippocampus per 50 {micro}A of applied skull currents). We demonstrate that electric fields below 0.5 V/m acutely modulate firing rate in 5% of neurons recorded in the hippocampus. At these intensities, average firing rate effects increased monotonically with electric field intensity at a rate of 7 % per V/m. For the majority of excitatory neurons, firing increased for cathodal stimulation and diminished for anodal stimulation. While more diverse, the response of inhibitory neurons followed a similar pattern on average, likely as a result of excitatory drive. Our results indicate that responses to TES at clinically relevant intensities are driven by a fraction of high-responder excitatory neurons, with polarity-specific effects. We conclude that transcranial electric stimulation is an effective neuromodulator at clinically realistic intensities.

neuroscience↗

bioRxiv2023

Novel Evoked Synaptic Activity Potentials (ESAPs) elicited by Spinal Cord Stimulation

Spinal cord stimulation (SCS) evokes fast epidural Evoked Compound Action Potential (ECAPs) that represent activity of dorsal column axons, but not necessarily a spinal circuit response. Using a multimodal approach, we identified and characterized a delayed and slower potential evoked by SCS that reflects synaptic activity within the spinal cord. Anesthetized female Sprague Dawley rats were implanted with an epidural SCS lead, epidural motor cortex stimulation electrodes, an epidural spinal cord recoding lead, an intraspinal penetrating recording electrode array, and intramuscular electromyography (EMG) electrodes in the hindlimb and back. We stimulated the motor cortex or the epidural spinal cord and recorded epidural, intraspinal, and EMG responses. SCS pulses produced characteristic propagating ECAPs (composed of P1, N1, and P2 waves with latencies <2 ms) and an additional wave ("S1") starting after the N2. We verified the S1-wave was not a stimulation artifact and was not a reflection of hindlimb/back EMG. The S1-wave has a distinct stimulation-intensity dose response and spatial profile compared to ECAPs. CNQX (a selective competitive antagonist of AMPA receptors) significantly diminished the S1-wave, but not ECAPs. Furthermore, cortical stimulation, which did not evoke ECAPs, produced epidurally detectable and CNQX-sensitive responses at the same spinal sites, confirming epidural recording of an evoked synaptic response. Finally, applying 50 Hz SCS resulted in dampening of ESAPs, but not ECAPs. Therefore, we hypothesize that the S1-wave is synaptic in origin, and we term the S1-wave type responses: Evoked Synaptic Activity Potentials (ESAPs). The identification and characterization of epidurally recorded ESAPs from the dorsal horn may elucidate SCS mechanisms. Significance StatementSpinal cord stimulation (SCS) is an established treatment for chronic pain and has applications to other disorders and neurorehabilitation. Notwithstanding decades of trials and research, questions remain about SCS mechanisms of action - and indicators thereof. Recent technological developments have enabled the detection of Evoked Compound Action Potential (ECAPs) - reflecting synchronous activity of the dorsal column axons activated by SCS. However, ECAP is not a direct measure of sensory processing in the dorsal horn. Here, we identify and characterize a novel electrophysiological signal that is evoked and detectable by epidural SCS electrodes and reflects spinal synaptic currents. This new signal, termed an Evoked Synaptic Activity Potential (ESAP), is thus a novel means with which to interrogate spinal gray matter circuits during SCS.

neuroscience↗