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.

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 (PNS) noninvasively without surgically implanted devices are enabling for fundamental research and clinical translation. Here, it is demonstrated 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. This principle of temporal interference nerve stimulation (TINS) in vivo using the murine sciatic nerve model is validated. Effective actuation is delivered at significantly lower current amplitudes than standard transcutaneous electrical stimulation. Further, how flexible and conformable on-skin multielectrode arrays can facilitate precise alignment of TINS onto a nerve is demonstrated. This method is simple, relying on the repurposing of existing clinically-approved hardware. TINS opens the possibility of precise noninvasive stimulation with depth and efficiency previously impossible with transcutaneous techniques.

ESHO benchmarks for computational modeling and optimization in hyperthermia therapy.

BACKGROUND: The success of cancer hyperthermia (HT) treatments is strongly dependent on the temperatures achieved in the tumor and healthy tissues as it correlates with treatment efficacy and safety, respectively. Hyperthermia treatment planning (HTP) simulations have become pivotal for treatment optimization due to the possibility for pretreatment planning, optimization and decision making, as well as real-time treatment guidance. MATERIALS AND METHODS: The same computational methods deployed in HTP are also used for in silico studies. These are of great relevance for the development of new HT devices and treatment approaches. To aid this work, 3 D patient models have been recently developed and made available for the HT community. Unfortunately, there is no consensus regarding tissue properties, simulation settings, and benchmark applicators, which significantly influence the clinical relevance of computational outcomes. RESULTS AND DISCUSSION: Herein, we propose a comprehensive set of applicator benchmarks, efficacy and safety optimization algorithms, simulation settings and clinical parameters, to establish benchmarks for method comparison and code verification, to provide guidance, and in view of the 2021 ESHO Grand Challenge (Details on the ESHO grand challenge on HTP will be provided at https://www.esho.info/). CONCLUSION: We aim to establish guidelines to promote standardization within the hyperthermia community such that novel approaches can quickly prove their benefit as quickly as possible in clinically relevant simulation scenarios. This paper is primarily focused on radiofrequency and microwave hyperthermia but, since 3 D simulation studies on heating with ultrasound are now a reality, guidance as well as a benchmark for ultrasound-based hyperthermia are also included.

Restoration of breathing after opioid overdose and spinal cord injury using temporal interference stimulation.

Respiratory insufficiency is a leading cause of death due to drug overdose or neuromuscular disease. We hypothesized that a stimulation paradigm using temporal interference (TI) could restore breathing in such conditions. Following opioid overdose in rats, two high frequency (5000 Hz and 5001 Hz), low amplitude waveforms delivered via intramuscular wires in the neck immediately activated the diaphragm and restored ventilation in phase with waveform offset (1 Hz or 60 breaths/min). Following cervical spinal cord injury (SCI), TI stimulation via dorsally placed epidural electrodes uni- or bilaterally activated the diaphragm depending on current and electrode position. In silico modeling indicated that an interferential signal in the ventral spinal cord predicted the evoked response (left versus right diaphragm) and current-ratio-based steering. We conclude that TI stimulation can activate spinal motor neurons after SCI and prevent fatal apnea during drug overdose by restoring ventilation with minimally invasive electrodes.

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.

Limitations of Incident Power Density as a Proxy for Induced Electromagnetic Fields.

The most recent safety guidelines define basic restrictions for electromagnetic field exposure at frequencies more than 6 GHz in terms of spatial- and time-averaged transmitted power density inside the body. To enable easy-to-perform evaluations in situ, the reference levels for the incident power density were derived. In this study, we examined whether compliance with the reference levels always ensures compliance with basic restrictions. This was evaluated at several distances from different antennas (dipole, loop, slot, patch, and helix). Three power density definitions based on integration of the perpendicular real part of the Poynting vector, the real part of its three vector components, and its modulus were compared for averaging areas of λ2 /16, 4 cm2 (below 30 GHz) and 1 cm2 (30 GHz). In the reactive near-field (d < λ/(2π)), the transmitted power density can be underestimated if an antenna operates at the free space exposure limit. This underestimation may exceed 6 dB (4.0 times) and depends on the field source due to different coupling mechanisms. It is frequency-dependent for fixed-size averaging areas (4 and 1 cm2 ). At larger distances, transmission can be larger than the theoretical plane-wave transmission coefficient due to backscattering between the body and field source. Using the modulus of the incident Poynting vector yields the smallest underestimation. © 2020 Bioelectromagnetics Society.

Discussion on Spatial and Time Averaging Restrictions Within the Electromagnetic Exposure Safety Framework in the Frequency Range Above 6 GHz for Pulsed and Localized Exposures.

Both the current and newly proposed safety guidelines for local human exposure to millimeter-wave frequencies aim at restricting the maximum local temperature increase in the skin to prevent tissue damage. In this study, we show that the application of the current and proposed limits for pulsed fields can lead to a temperature increase of 10°C for short pulses and frequencies between 6 and 30 GHz. We also show that the proposed averaging area of 4 cm2 , that is greatly reduced compared with the current limits, does not prevent high-temperature increases in the case of narrow beams. A realistic Gaussian beam profile with a 1 mm radius can result in a temperature increase about 10 times higher than the 0.4°C increase the same averaged power density would produce for a plane wave. In the case of pulsed narrow beams, the values for the time and spatial-averaged power density allowed by the proposed new guidelines could result in extreme temperature increases. Bioelectromagnetics. 2020;41:164-168. © 2019 Bioelectromagnetics Society.

Feasibility and relevance of discrete vasculature modeling in routine hyperthermia treatment planning.

Purpose: To investigate the effect of patient specific vessel cooling on head and neck hyperthermia treatment planning (HTP). Methods and materials: Twelve patients undergoing radiotherapy were scanned using computed tomography (CT), magnetic resonance imaging (MRI) and contrast enhanced MR angiography (CEMRA). 3D patient models were constructed using the CT and MRI data. The arterial vessel tree was constructed from the MRA images using the 'graph-cut' method, combining information from Frangi vesselness filtering and region growing, and the results were validated against manually placed markers in/outside the vessels. Patient specific HTP was performed and the change in thermal distribution prediction caused by arterial cooling was evaluated by adding discrete vasculature (DIVA) modeling to the Pennes bioheat equation (PBHE). Results: Inclusion of arterial cooling showed a relevant impact, i.e., DIVA modeling predicts a decreased treatment quality by on average 0.19 °C (T90), 0.32 °C (T50) and 0.35 °C (T20) that is robust against variations in the inflow blood rate (|ΔT| < 0.01 °C). In three cases, where the major vessels transverse target volume, notable drops (|ΔT| > 0.5 °C) were observed. Conclusion: Addition of patient-specific DIVA into the thermal modeling can significantly change predicted treatment quality. In cases where clinically detectable vessels pass the heated region, we advise to perform DIVA modeling.

Efficient and Reliable Assessment of the Maximum Local Tissue Temperature Increase at the Electrodes of Medical Implants under MRI Exposure.

Standard risk evaluations posed by medical implants during magnetic resonance imaging (MRI) includes (i) the assessment of the total local electromagnetic (EM) power (P) absorbed in the vicinity of the electrodes and (ii) the translation of P into a local in vivo tissue temperature increase ∆T (P2∆T) in animal experiments or simulations. We investigated the implant/tissue modeling requirements and associated uncertainties by applying full-wave EM and linear bioheat solvers to different implant models, incident field conditions, electrode configurations, and tissue models. Results show that the magnitude of the power is predominately determined by the lead, while the power distribution, and the P2∆T conversion, is determined by the electrode and surrounding tissues. P2∆T is strongly dependent on the size of the electrode, tissue type in contact with the electrode, and tissue inhomogeneity (factor of >2 each) but less on the modeling of the lead (<±10%) and incident field distribution along the lead (<±20%). This was confirmed by means of full-wave simulations performed with detailed high-resolution anatomical phantoms exposed to two commonly used MRI clinical scenarios (64 and 128 MHz), resulting in differences of less than 6%. For the determination of P2∆T, only the electrode and surrounding tissues must be modeled in great detail, whereas the lead can be modeled as a computationally efficient simplified structure exposed to a uniform field. The separate assessments of lead and electrode reduce the overall computational effort by several orders of magnitude. The errors introduced by this simplification can be considered by uncertainty terms. Bioelectromagnetics. 2019;40:422-433. © 2019 Bioelectromagnetics Society.

Understanding ultrasound neuromodulation using a computationally efficient and interpretable model of intramembrane cavitation.

OBJECTIVE: Low-intensity focused ultrasound stimulation (LIFUS) emerges as an attracting technology for noninvasive modulation of neural circuits, yet the underlying action mechanisms remain unclear. The neuronal intramembrane cavitation excitation (NICE) model suggests that LIFUS excites neurons through a complex interplay between microsecond-scale mechanical oscillations of so-called sonophores in the plasma membrane and the development of a millisecond-scale electrical response. This model predicts cell-type-specific responses that correlate indirectly with experimental data, but it is computationally expensive and difficult to interpret, which hinders its potential validation. Here, we introduce a multi-scale optimized neuronal intramembrane cavitation (SONIC) model to achieve fast, accurate simulations and confer interpretability in terms of effective electrical response. APPROACH: The NICE system is recast in terms of smoothly evolving differential variables affected by cycle averaged internal variables that are a function of sonophore size and charge density, stimulus frequency and pressure amplitude. Problem separation allows to precompute lookup tables for these functions, which are interpolated at runtime to compute coarse-grained, electrophysiologically interpretable and spatially distributed predictions of neural responses. MAIN RESULTS: The SONIC model accelerates computation by more than three orders of magnitude, accurately captures millisecond-scale electrical responses of various cortical and thalamic neurons and offers an increased interpretability to the effects of ultrasonic stimuli in terms of effective membrane dynamics. Using this model, we explain how different spiking behaviors can be achieved in cortical neurons by varying LIFUS parameters, and interpret predictions of spike amplitude and firing rate in light of the effective electrical system. We demonstrate the substantial influence of sonophore size on excitation thresholds, and use a nanoscale spatially extended SONIC model to suggest that partial sonophore membrane coverage has a limited impact on neuronal excitability. SIGNIFICANCE: By providing an electrophysiologically interpretable description, the SONIC model clarifies cell-type-specific LIFUS neuromodulation according to the intramembrane cavitation hypothesis.

Targeted neurotechnology restores walking in humans with spinal cord injury.

Spinal cord injury leads to severe locomotor deficits or even complete leg paralysis. Here we introduce targeted spinal cord stimulation neurotechnologies that enabled voluntary control of walking in individuals who had sustained a spinal cord injury more than four years ago and presented with permanent motor deficits or complete paralysis despite extensive rehabilitation. Using an implanted pulse generator with real-time triggering capabilities, we delivered trains of spatially selective stimulation to the lumbosacral spinal cord with timing that coincided with the intended movement. Within one week, this spatiotemporal stimulation had re-established adaptive control of paralysed muscles during overground walking. Locomotor performance improved during rehabilitation. After a few months, participants regained voluntary control over previously paralysed muscles without stimulation and could walk or cycle in ecological settings during spatiotemporal stimulation. These results establish a technological framework for improving neurological recovery and supporting the activities of daily living after spinal cord injury.

Theoretical and numerical assessment of maximally allowable power-density averaging area for conservative electromagnetic exposure assessment above 6 GHz.

The objective of this paper is to determine a maximum averaging area for power density (PD) that limits the maximum temperature increase to a given threshold for frequencies above 6 GHz. This maximum area should be conservative for any transmitter at any distance >2 mm from the primary transmitting antennas or secondary field-generating sources. To derive a generically valid maximum averaging area, an analytical approximation for the peak temperature increase caused by localized exposure was derived. The results for a threshold value of 1 K temperature rise were validated against simulations of a series of sources composed of electrical and magnetic elements (dipoles, slots, patches, and arrays) that represented the spectrum of relevant transmitters. The validation was successful for frequencies in which the power deposition occurred superficially (i.e., >10 GHz). In conclusion, the averaging area for a PD limit of 10 W/m2 that conservatively limits the temperature increase in the skin to less than 1 K at any distance >2 mm from the transmitters is frequency dependent, increases with distance, and ranges from 3 cm2 at <10 GHz to 1.9 cm2 at 100 GHz. In the far-field, the area depends additionally on distance and the antenna array aperture. The correlation was found to be worse at lower frequencies (<10 GHz) and very close to the source, the systematic evaluation of which is part of another study to investigate the effect of different coupling mechanisms in the reactive near-field on the ratio of temperature increase to incident power density. The presented model can be directly applied to any other PD and temperature thresholds. Bioelectromagnetics. 39:617-630, 2018. © 2018 Wiley Periodicals, Inc.

Investigation of assumptions underlying current safety guidelines on EM-induced nerve stimulation.

An intricate network of a variety of nerves is embedded within the complex anatomy of the human body. Although nerves are shielded from unwanted excitation, they can still be stimulated by external electromagnetic sources that induce strongly non-uniform field distributions. Current exposure safety standards designed to limit unwanted nerve stimulation are based on a series of explicit and implicit assumptions and simplifications. This paper demonstrates the applicability of functionalized anatomical phantoms with integrated coupled electromagnetic and neuronal dynamics solvers for investigating the impact of magnetic resonance exposure on nerve excitation within the full complexity of the human anatomy. The impact of neuronal dynamics models, temperature and local hot-spots, nerve trajectory and potential smoothing, anatomical inhomogeneity, and pulse duration on nerve stimulation was evaluated. As a result, multiple assumptions underlying current safety standards are questioned. It is demonstrated that coupled EM-neuronal dynamics modeling involving realistic anatomies is valuable to establish conservative safety criteria.

Simulation techniques in hyperthermia treatment planning.

Abstract Clinical trials have shown that hyperthermia (HT), i.e. an increase of tissue temperature to 39-44 °C, significantly enhance radiotherapy and chemotherapy effectiveness [1]. Driven by the developments in computational techniques and computing power, personalised hyperthermia treatment planning (HTP) has matured and has become a powerful tool for optimising treatment quality. Electromagnetic, ultrasound, and thermal simulations using realistic clinical set-ups are now being performed to achieve patient-specific treatment optimisation. In addition, extensive studies aimed to properly implement novel HT tools and techniques, and to assess the quality of HT, are becoming more common. In this paper, we review the simulation tools and techniques developed for clinical hyperthermia, and evaluate their current status on the path from 'model' to 'clinic'. In addition, we illustrate the major techniques employed for validation and optimisation. HTP has become an essential tool for improvement, control, and assessment of HT treatment quality. As such, it plays a pivotal role in the quest to establish HT as an efficacious addition to multi-modality treatment of cancer.

CEM43°C thermal dose thresholds: a potential guide for magnetic resonance radiofrequency exposure levels?

OBJECTIVE: To define thresholds of safe local temperature increases for MR equipment that exposes patients to radiofrequency fields of high intensities for long duration. These MR systems induce heterogeneous energy absorption patterns inside the body and can create localised hotspots with a risk of overheating. METHODS: The MRI + EUREKA research consortium organised a "Thermal Workshop on RF Hotspots". The available literature on thresholds for thermal damage and the validity of the thermal dose (TD) model were discussed. RESULTS/CONCLUSIONS: The following global TD threshold guidelines for safe use of MR are proposed: 1. All persons: maximum local temperature of any tissue limited to 39 °C 2. Persons with compromised thermoregulation AND (a) Uncontrolled conditions: maximum local temperature limited to 39 °C (b) Controlled conditions: TD < 2 CEM43°C 3. Persons with uncompromised thermoregulation AND (a) Uncontrolled conditions: TD < 2 CEM43°C (b) Controlled conditions: TD < 9 CEM43°C The following definitions are applied: Controlled conditions A medical doctor or a dedicated trained person can respond instantly to heat-induced physiological stress Compromised thermoregulation All persons with impaired systemic or reduced local thermoregulation KEY POINTS: • Standard MRI can cause local heating by radiofrequency absorption. • Monitoring thermal dose (in units of CEM43°C) can control risk during MRI. • 9 CEM43°C seems an acceptable thermal dose threshold for most patients. • For skin, muscle, fat and bone,16 CEM43°C is likely acceptable.