Biology subjects

Cassara, A.

Publications and source records attributed to Cassara, A..

9 recordsLinked to original sources

bioRxiv2026

Accurate Hippocampal Electric Field Modeling for Electroconvulsive Therapy: Numerical Accuracy and Convergence

Accurate hippocampal electric field (E-field) prediction is important for individualized electroconvulsive therapy (ECT) dosing and emerging deep-brain stimulation approaches such as temporal interference. Because hippocampal fields are far weaker than those beneath the stimulation electrodes, they are highly sensitive to tissue interfaces, conductivity contrasts, and numerical discretization, so numerical error can rival the physical uncertainties of anatomy and conductivity. We investigate this numerical component of hippocampal dosimetry using individualized head models from eleven ECT patients. Identical head40 segmentations, comprising 40 tissue compartments including the bilateral hippocampi, were simulated with three independent numerical methods: a charge-based boundary-element fast multipole method (BEM-FMM), a voxel-based hexahedral finite-element solver, and a conformal tetrahedral finite-element solver. For each, resolution was increased systematically and convergence assessed from the average hippocampal E-field magnitude. At the highest attainable resolutions, the three methods agreed closely, differing by 6%-7% in the left hippocampus and 9%-12% in the right. At default or coarse resolutions, however, they disagreed by 28.8% on average and up to 50.3% in the right hippocampus. Numerical convergence should therefore be established before differences are attributed to anatomical or conductivity uncertainty, and independent-solver agreement provides a practical basis for reliable hippocampal dosimetry.

neuroscience↗

bioRxiv2025

Shaping a Collaborative, Sustainable, Accessible, and Reproducible Future for Computational Modeling

The o2S2PARC platform is an open-source, extensible, and scalable cloud-based platform developed in the context of the U.S. National Institutes of Health SPARC program to support collaborative, sustainable, FAIR (findable, accessible, interoperable, reusable) and reproducible computational modeling and analysis. This publication presents the main features of o2S2PARC, its underlying approaches and philosophy, innovative aspects of the developed technologies, while also drawing attention to its rapid adoption. The paper showcases a variety of applications and use cases enabled by the platform. These include hybrid electromagnetic-electrophysiology simulations of neural interfaces, personalized brain and spinal cord stimulation planning, in silico device safety assessments, the training and application of AI systems (e.g., for model-predictive control and medical image segmentation), hybridized surrogate modeling and multi-objective optimization in high-dimensional parameter spaces, sensitive and unbiased validation of measurement devices, and interactive data analysis as paper supplements.

neuroscience↗

bioRxiv2024

Simulation Insights on the Compound Action Potential in Multifascicular Nerves

ObjectiveDevelop an efficient method for simulating evoked compound action potential (eCAP) signals from complex nerves to help optimize and interpret eCAP recordings; validate it through comparison with measured vagus nerve eCAP recordings; elucidate the subtle interplay giving rise to specific eCAP signal shapes and magnitudes. ApproachWe developed an extended reciprocity theorem approach to model neuron signals in heterogeneous environments, and use it to study analytically the single fibre action potential. We then established a semi-analytic model that also uses hybrid electromagnetic-electrophysiological simulations to model eCAP signals from complex nerves populated with heterogeneous fiber populations of fibers. A cuff electrode was used to measure activity induced by vagus nerve stimulation in in vivo porcine experiments; these measurements were compared with signals produced by the model. Main ResultsThe semi-analytic model produces signals that approximate the shape and amplitude of in vivo measurements. Partially activated fascicles contribute substantially to the signal, as eCAP contributions from smoothly varying fiber calibers in fully activated ones partially cancel. As a result, eCAP magnitude does not depend monotonically on the stimulation current and recruitment level. Because the eCAP is sensitive to the degree of activation in individual fascicles, and to the location of the recording electrodes with respect to individual fascicles, the contributions of different fascicles to the recorded eCAP signals vary significantly with changes in the shape and placement of the stimulus and the recording electrodes. SignificanceOur method can be used to rapidly assess new stimulation and recording setups involving complex nerves and neurovascular bundles, e.g., to maximize signal information content, for closed-loop control in bioelectronic medicine applications, and potentially to non-destructively reconstruct structural and functional nerve topologies through inverse problem solving.

neuroscience↗

bioRxiv2024

BlueRecording: A Pipeline for the efficient calculation of extracellular recordings in large-scale neural circuit models

As the size and complexity of network simulations accessible to computational neuroscience grows, new avenues open for research into extracellularly recorded electric signals. Biophysically detailed simulations permit the identification of the biological origins of the different components of recorded signals, the evaluation of signal sensitivity to different anatomical, physiological, and geometric factors, and selection of recording parameters to maximize the signal information content. Simultaneously, virtual extracellular signals produced by these networks may become important metrics for neuro-simulation validation. To enable efficient calculation of extracellular signals from large neural network simulations, we have developed BlueRecording, a pipeline consisting of standalone Python code, along with extensions to the Neurodamus simulation control application, the CoreNEURON computation engine, and the SONATA data format, to permit online calculation of such signals. In particular, we implement a general form of the reciprocity theorem, which is capable of handling non-dipolar current sources, such as may be found in long axons and recordings close to the current source, as well as complex tissue anatomy, dielectric heterogeneity, and electrode geometries. To our knowledge, this is the first application of this generalized (i.e., non-dipolar) reciprocity-based approach to simulate EEG recordings. We use these tools to calculate extracellular signals from an in silico model of the rat somatosensory cortex and hippocampus and to study signal contribution differences between regions and cell types.

neuroscience↗

bioRxiv2024

Improved Temporal and Spatial Focality of Non-invasive Deep-brain Stimulation using Multipolar Single-pulse Temporal Interference with Applications in Epilepsy

Temporal Interference (TI) is an emerging method to non-invasively stimulate deep brain structures. This innovative technique is increasingly recognized for its potential applications in the treatment of various neurological disorders, including epilepsy, depression, and Alzheimers disease. However, several drawbacks to the TI method exist that we aim to improve upon. To begin, the applied electric field in the TI target is not much higher than what non-invasive transcranial alternating current stimulation (TACS) provides in the cortex. Additionally, the TI stimulation onset is dependent on the envelope of the amplitude modulated (AM) signal, where for example 1 Hz and 100 Hz envelopes have significantly different rise times to reach maximum envelope amplitude - unlike square biphasic pulses. This limitation in turn prevents classic TI, from applying bursts of pulses. Finally, the electric field intensity of TI cannot be increased or decreased at the target without dramatically altering the spatial profile of the stimulation focus. In the work presented here, we efficiently address all three of these limitations. First, we performed two-photon calcium imaging to show that individual neurons selectively respond to the TI envelope frequency, providing evidence that TI modulates neural activity with temporal specificity. This marks a significant advancement, representing the first empirical demonstration of neuronal activation at the {Delta}f frequency within the context of TI and in an imaging modality. Subsequently, we compared the AM signals of TI with phase-shift keying (PSK) modulated signals to highlight the superior effectiveness of noninvasive pulses in contrast to the traditional TI method, particularly in inducing epileptic activity (after-discharges) in mice. We also added a multipolar configuration to create a significant increase in the electric field at the target without significantly altering the spatial profile and applied Fourier components to replicate classic biphasic bursts of square pulses - all transcranially, without the use of penetrating electrodes. These innovations aim to enhance the precision and efficacy of TI stimulation, to advance its application in neurological research and therapy. Key Points / HighlightsO_LINon-invasive temporal interference stimulation modulates the activity of individual neurons at the envelope frequency. C_LIO_LIA non-invasive multi-pulse TI stimulation paradigm improves both temporal and spatial focality in the deep target neural tissue when compared to traditional continuous wave (amplitude-modulated) TI stimulation. C_LIO_LIPulse TI paradigms can stimulate deep neural targets with reduced amplitude of the topical high-frequency stimulation, decreasing off-target stimulation when compared to continuous wave TI patterns. As a consequence, pulse TI stimulation reduces the risk of undesired side effects such as high-frequency conduction block in off-target tissues or cortical areas. C_LIO_LIBoth temporal and spatial focality of the TI stimulation pattern positively correlate with the efficacy of the stimulation to induce seizures in the mouse hippocampus. C_LI

neuroscience↗

bioRxiv2023

Obstructive Sleep Apnea Improves with Non-invasive Hypoglossal Nerve Stimulation using Temporal Interference

BackgroundPeripheral nerve stimulation is used in both clinical and fundamental research for therapy and exploration. At present, non-invasive peripheral nerve stimulation still lacks the penetration depth to reach deep nerve targets and the stimulation focality to offer selectivity. It is therefore rarely employed as the primary selected nerve stimulation method. We have previously demonstrated that a new stimulation technique, temporal interference stimulation, can overcome depth and focality issues. MethodsHere, we implement a novel form of temporal interference, bilateral temporal interference stimulation, for bilateral hypoglossal nerve stimulation in rodents and humans. Pairs of electrodes are placed alongside both hypoglossal nerves to stimulate them synchronously and thus decrease the stimulation amplitude required to activate hypoglossal-nerve controlled tongue movement. ResultsComparing bilateral temporal interference stimulation with unilateral temporal interference stimulation, we show that it can elicit the same behavioral and electrophysiological responses at a reduced stimulation amplitude. Traditional transcutaneous stimulation evokes no response with equivalent amplitudes of stimulation. ConclusionsDuring first in-man studies, temporal interference stimulation was found to be well-tolerated, and to clinically reduce apnea-hypopnea events in a subgroup of female patients with obstructive sleep apnea. These results suggest a high clinical potential for the use of temporal interference in the treatment of obstructive sleep apnea and other diseases as a safe, effective, and patient-friendly approach. Trial registrationThe protocol was conducted with the agreement of the International Conference on Harmonisation Good Clinical Practice (ICH GCP), applicable United States Code of Federal Regulations (CFR) and followed the approved BRANY IRB File # 22-02-636-1279.

neuroscience↗

bioRxiv2022

LTP-like noninvasive striatal brain stimulation enhances striatal activity and motor skill learning in humans

The stimulation of deep brain structures has thus far only been possible with invasive methods. Transcranial electrical temporal interference stimulation (tTIS) is a novel, noninvasive technology that might overcome this limitation. The initial proof-of-concept was obtained through modeling, physics experiments and rodent models. Here, we show for the first time successful noninvasive neuromodulation of the striatum via tTIS in humans using computational modeling, fMRI studies and behavioral evaluations. Theta-burst patterned striatal tTIS increased activity in the striatum and associated motor network. Furthermore, striatal tTIS enhanced motor performance, especially in healthy older participants as they have lower natural learning skills than younger subjects. These findings place tTIS as exciting new method to target deep brain structures in humans noninvasively, thus enhancing our understanding of their functional roles. Moreover, our results lay the groundwork for innovative, noninvasive treatment strategies for brain disorders in which deep striatal structures play key pathophysiological roles.

neuroscience↗

bioRxiv2022

Focal Non-invasive Deep-brain Stimulation with Temporal Interference for the Suppression of Epileptic Biomarkers

Neurostimulation applied from deep brain stimulation (DBS) electrodes is an effective therapeutic intervention in patients suffering from intractable drug-resistant epilepsy when resective surgery is contraindicated or failed. Inhibitory DBS to suppress seizures and associated epileptogenic biomarkers could be performed with high-frequency stimulation (HFS), typically between 100 -165Hz, to various deep-seated targets such as for instance the Mesio-temporal lobe (MTL) which leads to changes in brain rhythms, specifically in the hippocampus. The most prominent alterations concern high-frequency oscillations (HFOs), namely increase in ripples, a reduction in pathological Fast Ripples (FRs), and a decrease in pathological interictal epileptiform discharges (IEDs). In the current study, we use Temporal Interference stimulation to provide a non-invasive focal DBS (130 Hz) of the MTL, specifically the hippocampus, which increases physiological ripples, and decreases the number of FRs and IEDs in a mouse model of epilepsy. Similarly, we show the inability of 130 Hz transcranial current stimulation (TCS) to achieve similar results. The method could potentially revolutionize how DBS, certainly in epilepsy, is performed, and we therefore further demonstrate the translatability to human subjects via measurements of the TI stimulation vs TCS in human cadavers. Results show the better penetration of TI fields into the human hippocampus as compared with TCS. Finally, we provide evidence of the efficacy of the specific form of Pulse-width Modulated TI (PWM-TI), implemented with square waves, which is used in this study. One Sentence SummaryA non-invasive deep brain stimulation applied via temporal interference achieves the suppression of biomarkers of epilepsy in mice and is scaled to humans.

neuroscience↗

bioRxiv2021

Noninvasive Stimulation of Peripheral Nerves using Temporally-Interfering Electrical Fields

Electrical stimulation of peripheral nerves is a cornerstone of bioelectronic medicine. Effective ways to accomplish peripheral nerve stimulation noninvasively without surgically implanted devices is enabling for fundamental research and clinical translation. Here we demonstrate how relatively high frequency sine-wave carriers (3 kHz) emitted by two pairs of cutaneous electrodes can temporally interfere at deep peripheral nerve targets. The effective stimulation frequency is equal to the offset frequency (0.5 - 4 Hz) between the two carriers. We validate this principle of temporal interference nerve stimulation (TINS) in vivo using the murine sciatic nerve model. Effective actuation is delivered at significantly lower current amplitudes than standard transcutaneous electrical stimulation. Further, we demonstrate how flexible and conformable on-skin multielectrode arrays can facilitate precise alignment of TINS onto a nerve. Our method is simple, relying on repurposing of existing clinically-approved hardware. TINS opens the possibility of precise noninvasive stimulation with depth and efficiency previously impossible with transcutaneous techniques.

neuroscience↗