Biology subjects

Aberra, A. S.

Publications and source records attributed to Aberra, A. S..

11 recordsLinked to original sources

bioRxiv2026

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

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

neuroscience↗

bioRxiv2025

Simulation of evoked responses to transcranial magnetic stimulation using a multiscale cortical circuit model

BackgroundTranscranial magnetic stimulation (TMS) is a widely used non-invasive brain stimulation technique, but the neural circuits activated by TMS remain poorly understood. Previous modeling approaches have been limited to either simplified point-neuron networks or isolated single-cell models that lack synaptic connectivity. ObjectiveTo develop and validate a multiscale cortical circuit model that integrates morphologically-realistic neurons with accurate TMS-induced electric field distributions and to investigate mechanisms underlying cortical responses to stimulation. MethodsWe constructed a network model of a cortical column comprising 10,000 biophysically realistic neurons (excitatory pyramidal cells and inhibitory interneurons) across layers 2/3, 5, and 6 with over 10 million synaptic connections. The model incorporated thalamic and non-specific corticocortical inputs to generate physiological firing rates. TMS-induced electric fields were calculated using finite element modeling and coupled to individual neurons through the extracellular mechanism. We validated model predictions against experimental recordings of TMS-evoked local field potentials (LFPs) and multiunit activity. ResultsThe model reproduced key experimental observations including the dose-dependent N50 LFP component and multiphasic multi-unit responses, consisting of an (excitatory) increase followed by a (inhibitory) decrease in firing rates. The early excitatory response exhibited dual-peak dynamics reflecting distinct contributions from directly and indirectly activated neuronal populations, and the subsequent inhibitory phase reflected activation of feedback GABAergic circuits through both GABAA and GABAB conductances. Spatial analysis across 30 cortical columns distributed across the precentral gyrus revealed orientation-dependent evoked responses. ConclusionThis validated multiscale model provides mechanistic insights into TMS-evoked cortical dynamics, demonstrating how direct neuronal activation cascades through synaptic networks to generate characteristic population responses. The framework establishes a computational platform for optimizing stimulation protocols in research and clinical applications. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=124 SRC="FIGDIR/small/673790v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@1028145org.highwire.dtl.DTLVardef@1751714org.highwire.dtl.DTLVardef@3e2c06org.highwire.dtl.DTLVardef@1bc756e_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2025

Bridging macroscopic and microscopic modeling of electric field by brain stimulation

BackgroundModeling the electric field (E-field) on the microscopic scale improves our understanding of brain stimulation modalities and modeling methods but requires careful consideration of the conductivity values and correction of the field amplitudes to match conventional models on the macroscopic scale. ObjectiveWe analyze the correction step and discuss its relevance and implications for E-field modeling efforts bridging the macroscopic and microscopic scales. MethodsWe provide the theoretical framework for comparing microscopic and macroscopic models and describe approaches for effectively and efficiently matching the E-field amplitude and tissue conductivity. ResultsConsistent results can be obtained for brain stimulation models on different scales with appropriately selected conductivity and E-field amplitudes. ConclusionMicroscopic E-field models enable numerical estimation of conductivity of macroscopic homogenous neural tissue from microscopically realistic brain samples and exploration of the effect of microscopic E-field perturbations on neural activation threshold by brain stimulation, therefore improving modeling accuracy.

bioengineering↗

bioRxiv2025

Subthreshold electric fields bidirectionally modulate neurotransmitter release through axon polarization

1.Subthreshold electric fields modulate brain activity and demonstrate potential in several therapeutic applications. Electric fields are known to generate heterogenous membrane polarization within neurons due to their complex morphologies. While the effects of somatic and dendritic polarization in postsynaptic neurons have been characterized, the functional consequences of axonal polarization on neurotransmitter release from the presynapse are unknown. Here, we combined noninvasive optogenetic indicators of voltage, calcium and neurotransmitter release to study the subcellular response within single neurons to subthreshold electric fields. We first captured the detailed spatiotemporal polarization profile produced by uniform electric fields within individual neurons. Small polarization of presynaptic boutons produces rapid and powerful modulation of neurotransmitter release, with the direction - facilitation or inhibition - depending on the direction of polarization. We determined that subthreshold electric fields drive this effect by rapidly altering the number of synaptic vesicles participating in neurotransmission, producing effects which resemble short-term plasticity akin to presynaptic homeostatic plasticity. These results provide key insights into the mechanisms of subthreshold electric fields at the cellular level. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=86 SRC="FIGDIR/small/639625v1_ufig1.gif" ALT="Figure 1"> View larger version (14K): org.highwire.dtl.DTLVardef@cf9016org.highwire.dtl.DTLVardef@fcc601org.highwire.dtl.DTLVardef@12b9a52org.highwire.dtl.DTLVardef@1a08232_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2023

A Boundary Element Method of Bidomain Modeling for Predicting Cellular Responses to Electromagnetic Fields

ObjectiveCommonly used cable equation-based approaches for determining the effects of electromagnetic fields on excitable cells make several simplifying assumptions that could limit their predictive power. Bidomain or "whole" finite element methods have been developed to fully couple cells and electric fields for more realistic neuron modeling. Here, we introduce a novel bidomain integral equation designed for determining the full electromagnetic coupling between stimulation devices and the intracellular, membrane, and extracellular regions of neurons. MethodsOur proposed boundary element formulation offers a solution to an integral equation that connects the device, tissue inhomogeneity, and cell membrane-induced E-fields. We solve this integral equation using first-order nodal elements and an unconditionally stable Crank-Nicholson time-stepping scheme. To validate and demonstrate our approach, we simulated cylindrical Hodgkin-Huxley axons and spherical cells in multiple brain stimulation scenarios. Main ResultsComparison studies show that a boundary element approach produces accurate results for both electric and magnetic stimulation. Unlike bidomain finite element methods, the bidomain boundary element method does not require volume meshes containing features at multiple scales. As a result, modeling cells, or tightly packed populations of cells, with microscale features embedded in a macroscale head model, is made computationally tractable, and the relative placement of devices and cells can be varied without the need to generate a new mesh. SignificanceDevice-induced electromagnetic fields are commonly used to modulate brain activity for research and therapeutic applications. Bidomain solvers allow for the full incorporation of realistic cell geometries, device E-fields, and neuron populations. Thus, multi-cell studies of advanced neuronal mechanisms would greatly benefit from the development of fast-bidomain solvers to ensure scalability and the practical execution of neural network simulations with realistic neuron morphologies.

biophysics↗

bioRxiv2023

Neuronal FOS reports synchronized activity of presynaptic neurons

The immediate early gene FOS is frequently used as a marker for highly active neurons. Implicit in this use is the assumption that there is a correlation between neuronal spiking and FOS expression. Here we use optogenetic stimulation of hippocampal neurons to investigate the relation between spike frequency and FOS expression, and report several surprising observations. First, FOS expression is cell-type specific, spiking CA2 pyramidal neurons rarely express FOS. Second, FOS has a U-shaped dependence on frequency: Spiking at 0.1 Hz is more effective than high frequency spiking (50 Hz) while intermediate frequencies do not induce FOS. Third, the pathway from spiking to FOS is not cell-autonomous. Instead, transmitter release and metabotropic glutamate receptor (mGluR) activation are required and, at 0.1 Hz, FOS is induced independently of CREB/calcineurin/MEK pathways. We propose that FOS does not primarily encode a neurons own spike frequency but indicates repeated participation in highly synchronized activity, e.g. sharp wave ripples.

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

Activity-driven synaptic translocation of LGI1 controls excitatory neurotransmission

The fine control of synaptic function requires robust trans-synaptic molecular interactions. However, it remains poorly understood how the landscape of trans-synaptic bridges dynamically remodels to reflect functional states of the synapse. Here we developed novel optical tools to visualize in firing synapses the molecular behavior of a particular secreted trans-synaptic protein, LGI1, and its presynaptic receptor, ADAM23, and discovered that neuronal activity acutely rearranges the abundance of these proteins at the synaptic cleft. Surprisingly, LGI1 in synapses was not secreted, as described elsewhere, but exo- and endocytosed through its interaction with ADAM23. Activity-driven translocation of LGI1 facilitated the formation of trans-synaptic connections proportionally to the history of activity of the synapse, adjusting excitatory transmission to synaptic firing rates. Thus, our findings reveal that LGI1 abundance at the synaptic cleft can be acutely remodeled and serves as a critical point of activity-dependent control of synaptic function. Highlights- Neuronal activity translocates LGI1 and ADAM23 to the presynaptic surface - LGI1 and ADAM23 are not located in synaptic vesicles - Stable cleft localization of LGI1 depends on the history of synaptic activity - LGI1 abundance at the synaptic cleft controls glutamate release

neuroscience↗

bioRxiv2022

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

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

bioengineering↗

bioRxiv2022

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

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

bioengineering↗

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↗