Non-invasive temporal interference electrical stimulation of the human hippocampus.

Deep brain stimulation (DBS) via implanted electrodes is used worldwide to treat patients with severe neurological and psychiatric disorders. However, its invasiveness precludes widespread clinical use and deployment in research. Temporal interference (TI) is a strategy for non-invasive steerable DBS using multiple kHz-range electric fields with a difference frequency within the range of neural activity. Here we report the validation of the non-invasive DBS concept in humans. We used electric field modeling and measurements in a human cadaver to verify that the locus of the transcranial TI stimulation can be steerably focused in the hippocampus with minimal exposure to the overlying cortex. We then used functional magnetic resonance imaging and behavioral experiments to show that TI stimulation can focally modulate hippocampal activity and enhance the accuracy of episodic memories in healthy humans. Our results demonstrate targeted, non-invasive electrical stimulation of deep structures in the human brain.

The effect of body position change on noninvasively acquired intracranial pulse waves.

Objective. Craniospinal compliance (CC) is an important metric for the characterization of space-occupying neurological pathologies. CC is obtained using invasive procedures that carry risks for the patients. Therefore, noninvasive methods for acquiring surrogates of CC have been proposed, most recently based on changes in the head's dielectric properties during the cardiac cycle. Here, we have tested whether changes in body position, which are known to influence CC, are reflected in a capacitively acquired signal (hereinafter referred to as W) originating from dynamic changes of the head's dielectric properties.Approach. eighteen young healthy volunteers were included in the study. After 10 min in supine position, subjects were tilted head-up (HUT), back to 0° (horizontal, control), and then head-down (HDT). Metrics related to cardiovascular action were extracted from W, including AMP, the peak-to-valley amplitude of the cardiac modulation of W. Computational electromagnetic simulations were performed to probe the association between intracranial volume change and W.Main results. AMP decreased during HUT (0°: 2869 ± 597 arbitrary units (au); +75°: 2307 ± 490 au,P= 0.002) and increased during HDT (-30°: 4403 ± 1428 au,P< 0.0001). The same behavior was predicted by the electromagnetic model.Significance. tilting affects the distribution of CC between cranial and spinal compartments. Cardiovascular action induces compliance-dependent oscillatory changes in the intracranial fluid composition, which causes corresponding variations in the head's dielectric properties. These manifest as increasing AMP with decreasing intracranial compliance, which suggests that W may contain information related to CC, and that it might be possible to derive CC surrogates therefrom.

Coverage factors for efficient demonstration of compliance of low-frequency magnetic near-field exposures with basic restrictions.

Objective. Regulators require that wireless power transfer (WPT) systems and other strong magnetic field sources are compliant with the basic restrictions (BR) defined as the limits of the fields induced in the human body, i.e. the induced electric field/current density/specific absorption rate limits. This can be achieved by demonstrating compliance with the reference levels (RL) defined in air without the human body, i.e. the incident electric/magnetic field limits. Local sources, such as WPT transmitters, generate non-uniform fields that can locally exceed the RL while the induced fields are still well below the BR. In these cases, robust compliance with BR can be demonstrated, generally requiring a large number of simulations. In this study, we proposed an efficient evaluation using a homogeneous phantom and applying a coverage factor to account for the local field enhancements caused by the dielectric contrasts of the highly inhomogeneous human tissues.Approach. The generally applicable coverage factors were derived from a statistical analysis of the field enhancements observed on four magnetic near-field sources placed at different separation distances (2-80 mm) and locations on the back of 12 anatomical models. The field enhancements were characterized by the ratios between the peak induced fields in the anatomical models and those in the homogeneous half-space phantom (ϵr= 55,σ= 0.75 S m-1,ρ= 1,000 kg m-3) at the same distance.Main results. The resulting 99th percentile coverage factors range from 1 and 9 depending on the dosimetric quantity.Significance. The use of these coverage factors reduces the compliance testing effort from hundreds of simulations to only one, and makes experimental testing feasible without the support of simulations. The study also demonstrates that running only a few use-case simulations with anatomical models may underestimate the exposure by more than 10 dB.

Noninvasive Monitoring of Intracranial Pulse Waves.

OBJECTIVE: The clinical management of several neurological disorders benefits from the assessment of intracranial pressure and craniospinal compliance. However, the associated procedures are invasive in nature. Here, we aimed to assess whether naturally occurring periodic changes in the dielectric properties of the head could serve as the basis for deriving surrogates of craniospinal compliance noninvasively. METHODS: We designed a device and electrodes for noninvasive measurement of periodic changes of the dielectric properties of the human head. We characterized the properties of the device-electrode-head system by measurements on healthy volunteers, by computational modeling, and by electromechanical modeling. We then performed hyperventilation testing to assess whether the measured signal is of intracranial origin. RESULTS: Signals obtained with the device on volunteers showed characteristic cardiac and respiratory modulations. Signal oscillations can be attributed primarily to changes in resistive properties of the head during cardiac and respiratory cycles. Reduction of end-tidal CO2, through hyperventilation, resulted in a decrease in the signal amplitude associated with cardiovascular action. CONCLUSION: Given the higher CO2 reactivity of intracranial vessels compared to extracranial ones, the results of hyperventilation testing suggest that the acquired signal is, in part, of intracranial origin. SIGNIFICANCE: If confirmed in larger cohorts, our observations suggest that noninvasive capacitive acquisition of changes in the dielectric properties of the head could be used to derive surrogates of craniospinal compliance.

Theory for a non-invasive diagnostic biomarker for craniospinal diseases.

Monitoring intracranial pressure (ICP) and craniospinal compliance (CC) is frequently required in the treatment of patients suffering from craniospinal diseases. However, current approaches are invasive and cannot provide continuous monitoring of CC. Dynamic exchange of blood and cerebrospinal fluid (CSF) between cranial and spinal compartments due to cardiac action transiently modulates the geometry and dielectric properties of the brain. The resulting impedance changes can be measured and might be usable as a non-invasive CC surrogate. A numerically robust and computationally efficient approach based on the reciprocity theorem was developed to compute dynamic impedance changes resulting from small geometry and material property changes. The approach was successfully verified against semi-analytical benchmarks, before being combined with experimental brain pulsation data to study the information content of the impedance variation. The results indicate that the measurable signal is dominated by the pulsatile displacement of the cortical brain surface, with minor contributions from the ventricular surfaces and from changes in brain perfusion. Different electrode setups result in complementary information. The information content from the investigated three electrode pairs was employed to successfully infer subject-specific brain pulsation and motion features. This suggests that non-invasive CC surrogates based on impedance monitoring could be established.

Mechanism of Capacitive Coupling of Proximal Electromagnetic Sources With Biological Bodies.

This study investigates the absorption of the induced E-field in homogeneous biological tissue exposed to highly localized field sources in proximity of the body, such as the charged tips of antennas, where E-field coupling dominates. These conditions are relevant for compliance testing of modern mobile phones where exposure is evaluated at small separation between radiators and the body. We derive an approximation that characterizes the decay of the induced E-field in the tissue as a function of distance. The absorption is quantified in terms of the local specific absorption rate (SAR) at the tissue surface as a function of the charge at the antenna tip. The approximation is based on the analytical evaluation of the E-fields of a charged disk under quasi-static conditions. We validate this approximation using full-wave simulations of dipoles. We demonstrate that the coupling mechanism of the E-field is dominated by the perpendicular field component and that wave propagation need not be considered for the characterization of the exposure. The surface SAR decreases approximately with the fourth power of the distance and with the square of the ratio of the permittivities of the tissue and free-space. The approximation predicts the induced maximum E-field with an accuracy of better than 1.5 dB. © 2022 Bioelectromagnetics Society.

Rapid SAR optimization for hyperthermic oncology: combining multi-goal optimization and time-multiplexed steering for hotspot suppression.

PURPOSE: Healthy tissue hotspots are a main limiting factor in administering deep hyperthermia cancer therapy. We propose an optimization scheme that uses time-multiplexed steering (TMPS) among minimally correlated (nearly) Pareto-optimal solutions to suppress hotspots without reducing tumor heating. Furthermore, tumor heating homogeneity is maximized, thus reducing toxicity and avoiding underexposed tumor regions, which in turn may reduce recurrence. MATERIALS AND METHODS: The novel optimization scheme combines random generation of steering parameters with local optimization to efficiently identify the set of (Pareto-) optimal solutions of conflicting optimization goals. To achieve simultaneous suppression of hotspots, multiple steering parameter configurations with minimally correlated hotspots are selected near the Pareto front and combined in TMPS. The performance of the novel scheme was compared with that of a multi-goal Genetic Algorithm for a range of simulated treatment configurations involving a modular applicator heating a generic tumor situated in the bladder, cervix, or pelvic bone. SAR cumulative histograms in tumor and healthy tissue, as well as hotspot volumes are used as metrics. RESULTS: Compared to the non-TMPS optimization, the proposed scheme was able to reduce the peak temperature in healthy tissue by 0.2 °C-1.0 °C (a thermal dose reduction by at least 26%) and, importantly, the hotspot volume above 42 °C in healthy tissue by 41%-86%. At the same time, tumor heating homogeneity was maintained or improved. CONCLUSIONS: The extremely rapid optimization (5 s for TMPS part, on a standard PC) permits closed-loop treatment reoptimization during treatment administration, and empowers physicians with a selection of optimal treatment scenarios reflecting different weighting of conflicting treatment goals.

Radio-frequency exposure of the yellow fever mosquito (A. aegypti) from 2 to 240 GHz.

Fifth generation networks (5G) will be associated with a partial shift to higher carrier frequencies, including wavelengths comparable in size to insects. This may lead to higher absorption of radio frequency (RF) electromagnetic fields (EMF) by insects and could cause dielectric heating. The yellow fever mosquito (Aedes aegypti), a vector for diseases such as yellow and dengue fever, favors warm climates. Being exposed to higher frequency RF EMFs causing possible dielectric heating, could have an influence on behavior, physiology and morphology, and could be a possible factor for introduction of the species in regions where the yellow fever mosquito normally does not appear. In this study, the influence of far field RF exposure on A. aegypti was examined between 2 and 240 GHz. Using Finite Difference Time Domain (FDTD) simulations, the distribution of the electric field in and around the insect and the absorbed RF power were found for six different mosquito models (three male, three female). The 3D models were created from micro-CT scans of real mosquitoes. The dielectric properties used in the simulation were measured from a mixture of homogenized A. aegypti. For a given incident RF power, the absorption increases with increasing frequency between 2 and 90 GHz with a maximum between 90 and 240 GHz. The absorption was maximal in the region where the wavelength matches the size of the mosquito. For a same incident field strength, the power absorption by the mosquito is 16 times higher at 60 GHz than at 6 GHz. The higher absorption of RF power by future technologies can result in dielectric heating and potentially influence the biology of this mosquito.

MorphoSONIC: A morphologically structured intramembrane cavitation model reveals fiber-specific neuromodulation by ultrasound.

Low-Intensity Focused Ultrasound Stimulation (LIFUS) holds promise for the remote modulation of neural activity, but an incomplete mechanistic characterization hinders its clinical maturation. Here we developed a computational framework to model intramembrane cavitation (a candidate mechanism) in multi-compartment, morphologically structured neuron models, and used it to investigate ultrasound neuromodulation of peripheral nerves. We predict that by engaging membrane mechanoelectrical coupling, LIFUS exploits fiber-specific differences in membrane conductance and capacitance to selectively recruit myelinated and/or unmyelinated axons in distinct parametric subspaces, allowing to modulate their activity concurrently and independently over physiologically relevant spiking frequency ranges. These theoretical results consistently explain recent empirical findings and suggest that LIFUS can simultaneously, yet selectively, engage different neural pathways, opening up opportunities for peripheral neuromodulation currently not addressable by electrical stimulation. More generally, our framework is readily applicable to other neural targets to establish application-specific LIFUS protocols.

Induced radiofrequency fields in patients undergoing MR examinations: insights for risk assessment.

Purpose. To characterize and quantify the induced radiofrequency (RF) electric (E)-fields andB1+rmsfields in patients undergoing magnetic resonance (MR) examinations; to provide guidance on aspects of RF heating risks for patients with and without implants; and to discuss some strengths and limitations of safety assessments in current ISO, IEC, and ASTM standards to determine the RF heating risks for patients with and without implants.Methods. InducedE-fields andB1+rmsfields during 1.5 T and 3 T MR examinations were numerically estimated for high-resolution patient models of the Virtual Population exposed to ten two-port birdcage RF coils from head to feet imaging landmarks over the full polarization space, as well as in surrogate ASTM phantoms.Results. Worst-caseB1+rmsexposure greater than 3.5µT (1.5 T) and 2µT (3 T) must be considered for all MR examinations at the Normal Operating Mode limit. Representative inducedE-field and specific absorption rate distributions under different clinical scenarios allow quick estimation of clinical factors of high and reduced exposure.B1shimming can cause +6 dB enhancements toE-fields along implant trajectories. The distribution and magnitude of inducedE-fields in the ASTM phantom differ from clinical exposures and are not always conservative for typical implant locations.Conclusions.Field distributions in patient models are condensed, visualized for quick estimation of risks, and compared to those induced in the ASTM phantom. InducedE-fields in patient models can significantly exceed those in the surrogate ASTM phantom in some cases. In the recent 19ε2revision of the ASTM F2182 standard, the major shortcomings of previous versions have been addressed by requiring that the relationship between ASTM test conditions andin vivotangentialE-fields be established, e.g. numerically. With this requirement, the principal methods defined in the ASTM standard for passive implants are reconciled with those of the ISO 10974 standard for active implantable medical devices.

Feasibility of Temperature Control by Electrical Impedance Tomography in Hyperthermia.

We present a simulation study investigating the feasibility of electrical impedance tomography (EIT) as a low cost, noninvasive technique for hyperthermia (HT) treatment monitoring and adaptation. Temperature rise in tissues leads to perfusion and tissue conductivity changes that can be reconstructed in 3D by EIT to noninvasively map temperature and perfusion. In this study, we developed reconstruction methods and investigated the achievable accuracy of EIT by simulating HT treatmentlike scenarios, using detailed anatomical models with heterogeneous conductivity distributions. The impact of the size and location of the heated region, the voltage measurement signal-to-noise ratio, and the reference model personalization and accuracy were studied. Results showed that by introducing an iterative reconstruction approach, combined with adaptive prior regions and tissue-dependent penalties, planning-based reference models, measurement-based reweighting, and physics-based constraints, it is possible to map conductivity-changes throughout the heated domain, with an accuracy of around 5% and cm-scale spatial resolution. An initial exploration of the use of multifrequency EIT to separate temperature and perfusion effects yielded promising results, indicating that temperature reconstruction accuracy can be in the order of 1 ∘C. Our results suggest that EIT can provide valuable real-time HT monitoring capabilities. Experimental confirmation in real-world conditions is the next step.

The SPARC DRC: Building a Resource for the Autonomic Nervous System Community.

The Data and Resource Center (DRC) of the NIH-funded SPARC program is developing databases, connectivity maps, and simulation tools for the mammalian autonomic nervous system. The experimental data and mathematical models supplied to the DRC by the SPARC consortium are curated, annotated and semantically linked via a single knowledgebase. A data portal has been developed that allows discovery of data and models both via semantic search and via an interface that includes Google Map-like 2D flatmaps for displaying connectivity, and 3D anatomical organ scaffolds that provide a common coordinate framework for cross-species comparisons. We discuss examples that illustrate the data pipeline, which includes data upload, curation, segmentation (for image data), registration against the flatmaps and scaffolds, and finally display via the web portal, including the link to freely available online computational facilities that will enable neuromodulation hypotheses to be investigated by the autonomic neuroscience community and device manufacturers.

Reflection Properties of the Human Skin From 40 to 110 GHz: A Confirmation Study.

Several recent theoretical dosimetric studies above 6 GHz apply generic layered skin models. For this frequency range, new experimental phantoms for over-the-air performance of wireless devices were proposed that simulate the impedance matching effects of the stratum corneum layer (SCL) with a low-loss coating layer. The aim of this study was to verify the skin models by comparing their reflection coefficients S11 with measurements of 37 human volunteers (21 males, 16 females, 5-80 years) at 21 body locations (10 at palm, 11 at arm/face) with different SCL thicknesses, using waveguides covering frequencies from 40 to 110 GHz. Such measurements were also carried out with the phantom material. The statistical analysis showed strong evidence that S11 depends on the SCL thickness and no evidence that S11 depends on sex. The measured S11 values for thin and thick skin can be represented by SCL layers of 15 and 140 µm, respectively. These values correspond well to the assumptions of previous studies. (The cohort did not include volunteers doing heavy manual work.) The phantom material mimics the matching effect of the SCL with deviations from the waveguide measurements of less than 0.85 dB (22%), which confirms the suitability of layered phantoms to represent the electromagnetic reflection/absorption of human skin. © 2021 Bioelectromagnetics Society.

Compliance Assessment of the Epithelial or Absorbed Power Density Below 10 GHz Using SAR Measurement Systems.

The introduction of new dosimetric quantities, in particular, epithelial or absorbed power density for frequencies above 6 GHz, in exposure guidelines and safety standards requires the development of new experimental assessment procedures for compliance testing. In this study, we propose to approximate the peak spatial-average absorbed power density (psSab ) using the same measured data and algorithms that are used for determining the peak spatial-average specific absorption rate psSAR, which is currently limited to frequencies up to 10 GHz. The uncertainty component for the transformation of psSAR to psSab was evaluated as less than 0.55 dB (13.5%) for any source as close as 0.02 λ from the tissue simulating media. The approach is easy to implement and allows determining compliance with the basic restrictions of the latest safety guidelines. In the next project, we will expand dosimetric probes, phantoms, and procedures for frequencies above 10 GHz. © 2021 Bioelectromagnetics Society.

Radiofrequency-induced heating of broken and abandoned implant leads during magnetic resonance examinations.

PURPOSE: The risks of RF-induced heating of active implantable medical device (AIMD) leads during MR examinations must be well understood and realistically assessed. In this study, we evaluate the potential additional risks of broken and abandoned (cut) leads. METHODS: First, we defined a generic AIMD with a metallic implantable pulse generator (IPG) and a 100-cm long lead containing 1 or 2 wires. Next, we numerically estimated the deposited in vitro lead-tip power for an intact lead, as well as with wire breaks placed at 10 cm intervals. We studied the effect of the break size (wire gap width), as well as the presence of an intact wire parallel to the broken wire, and experimentally validated the numeric results for the configurations with maximum deposited in vitro lead-tip power. Finally, we performed a Tier 3 assessment of the deposited in vivo lead-tip power for the intact and broken lead in 4 high resolution virtual population anatomic models for over 54,000 MR examination scenarios. RESULTS: The enhancement of the deposited lead-tip power for the broken leads, compared to the intact lead, reached 30-fold in isoelectric exposure, and 16-fold in realistic clinical exposures. The presence of a nearby intact wire, or even a nearby broken wire, reduced this enhancement factor to <7-fold over the intact lead. CONCLUSION: Broken and abandoned leads can pose increased risk of RF-induced lead-tip heating to patients undergoing MR examinations. The potential enhancement of deposited in vivo lead-tip power depends on location and type of the wire break, lead design, and clinical routing of the lead, and should be carefully considered when performing risk assessment for MR examinations and MR conditional labeling.

The impact of CT image parameters and skull heterogeneity modeling on the accuracy of transcranial focused ultrasound simulations.

Objective. Low-intensity transcranial ultrasound stimulation (TUS) is a promising non-invasive brain stimulation (NIBS) technique. TUS can reach deeper areas and target smaller regions in the brain than other NIBS techniques, but its application in humans is hampered by the lack of a straightforward and reliable procedure to predict the induced ultrasound exposure. Here, we examined how skull modeling affects computer simulations of TUS.Approach. We characterized the ultrasonic beam after transmission through a sheep skull with a hydrophone and performed computed tomography (CT) image-based simulations of the experimental setup. To study the skull model's impact, we varied: CT acquisition parameters (tube voltage, dose, filter sharpness), image interpolation, segmentation parameters, acoustic property maps (speed-of-sound, density, attenuation), and transducer-position mismatches. We compared the impact of modeling parameter changes on model predictions and on measurement agreement. Spatial-peak intensity and location, total power, and the Gamma metric (a measure for distribution differences) were used as quantitative criteria. Modeling-based sensitivity analysis was also performed for two human head models.Main results. Sheep skull attenuation assignment and transducer positioning had the most important impact on spatial peak intensity (overestimation up to 300%, respectively 30%), followed by filter sharpness and tube voltage (up to 20%), requiring calibration of the mapping functions. Positioning and skull-heterogeneity-structure strongly affected the intensity distribution (gamma tolerances exceeded in>80%, respectively>150%, of the focus-volume in water), necessitating image-based personalized modeling. Simulation results in human models consistently demonstrate a high sensitivity to the skull-heterogeneity model, attenuation tuning, and transducer shifts, the magnitude of which depends on the underlying skull structure complexity.Significance. Our study reveals the importance of properly modeling the skull-heterogeneity and its structure and of accurately reproducing the transducer position. The results raise red flags when translating modeling approaches among clinical sites without proper standardization and/or recalibration of the imaging and modeling parameters.

TRANSMISSION COEFFICIENT OF POWER DENSITY INTO SKIN TISSUE BETWEEN 6 AND 300 GHZ.

The latest electromagnetic safety guidelines define transmitted or epithelial power density as the basic restriction above 6 GHz. In this note, we derive an approximation for a conservative transmission coefficient for quasi plane wave incidence as a function of the frequency for the normal component of the Poynting vector with respect to the evaluation plane or tissue surface |Sz inc| and for its modulus ||Sinc||. The maximum transmission coefficient for the normal component of the Poynting vector ${\boldsymbol{T}}_{\mathbf{z}}^{\mathbf{max}}$ is 1 independent of tissue composition and frequency. Approximations of ${\boldsymbol{T}}_{\mathbf{total}}^{\mathbf{max}}$ normalized to ||Sinc|| for thin and thick stratum corneum are provided allowing higher exposures. These approximations allow to conservatively demonstrate compliance with basic restrictions when quasi plane-wave conditions are locally satisfied and enhancement effects of standing waves between source and body can be neglected. The reported results are important to regulators and standardization bodies regarding revisions of compliance requirements and safety guidelines.

Quantification of clinically applicable stimulation parameters for precision near-organ neuromodulation of human splenic nerves.

Neuromodulation is a new therapeutic pathway to treat inflammatory conditions by modulating the electrical signalling pattern of the autonomic connections to the spleen. However, targeting this sub-division of the nervous system presents specific challenges in translating nerve stimulation parameters. Firstly, autonomic nerves are typically embedded non-uniformly among visceral and connective tissues with complex interfacing requirements. Secondly, these nerves contain axons with populations of varying phenotypes leading to complexities for axon engagement and activation. Thirdly, clinical translational of methodologies attained using preclinical animal models are limited due to heterogeneity of the intra- and inter-species comparative anatomy and physiology. Here we demonstrate how this can be accomplished by the use of in silico modelling of target anatomy, and validation of these estimations through ex vivo human tissue electrophysiology studies. Neuroelectrical models are developed to address the challenges in translation of parameters, which provides strong input criteria for device design and dose selection prior to a first-in-human trial.

Effects of pulse-modulated radiofrequency magnetic field (RF-EMF) exposure on apoptosis, autophagy, oxidative stress and electron chain transport function in human neuroblastoma and murine microglial cells.

The use of body-worn wireless devices with different communication protocols and rapidly changing exposure scenarios is still multiplying and the need to identify possible health effects of radiofrequency electromagnetic field (RF-EMF) exposure with extremely low-frequency (ELF) modulation envelops. In this study, effects of ELF-modulated 935 MHz RF-EMF on apoptosis, autophagy, oxidative stress and electron exchange in N9 microglial and SH-SY5Y neuroblastoma cells were investigated. Cells were exposed at 4 W/kg or sham-exposed for 2 and 24 h. RF-EMF exposure of both cell types did not alter apoptosis, the number of living cells nor the apoptosis-inducing factor (AIF), irrespective of the exposure duration. RF-EMF exposure for 24, but not for 2 h, increased protein levels of the autophagy marker ATG5, whereas LC3B-I and II and pERK were not altered in both cell types and exposure times investigated. A transient increase in glutathione (GSH), but not hydrogen peroxide and cytochrome c oxidase was found only in SH-SY5Y cells, indicating that short-time RF-EMF at SAR levels accepted by today's safety guidelines might cause autophagy and oxidative stress with the effect being dependent on cell type and exposure duration. Further studies are needed to evaluate possible underlying mechanisms involved in pulse-modulated RF-EMF exposure.