Noninvasive Deep Brain Stimulation via Temporally Interfering Electric Fields.

We report a noninvasive strategy for electrically stimulating neurons at depth. By delivering to the brain multiple electric fields at frequencies too high to recruit neural firing, but which differ by a frequency within the dynamic range of neural firing, we can electrically stimulate neurons throughout a region where interference between the multiple fields results in a prominent electric field envelope modulated at the difference frequency. We validated this temporal interference (TI) concept via modeling and physics experiments, and verified that neurons in the living mouse brain could follow the electric field envelope. We demonstrate the utility of TI stimulation by stimulating neurons in the hippocampus of living mice without recruiting neurons of the overlying cortex. Finally, we show that by altering the currents delivered to a set of immobile electrodes, we can steerably evoke different motor patterns in living mice.

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.

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.

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.

Benchmark problems for transcranial ultrasound simulation: Intercomparison of compressional wave models.

Computational models of acoustic wave propagation are frequently used in transcranial ultrasound therapy, for example, to calculate the intracranial pressure field or to calculate phase delays to correct for skull distortions. To allow intercomparison between the different modeling tools and techniques used by the community, an international working group was convened to formulate a set of numerical benchmarks. Here, these benchmarks are presented, along with intercomparison results. Nine different benchmarks of increasing geometric complexity are defined. These include a single-layer planar bone immersed in water, a multi-layer bone, and a whole skull. Two transducer configurations are considered (a focused bowl and a plane piston operating at 500 kHz), giving a total of 18 permutations of the benchmarks. Eleven different modeling tools are used to compute the benchmark results. The models span a wide range of numerical techniques, including the finite-difference time-domain method, angular spectrum method, pseudospectral method, boundary-element method, and spectral-element method. Good agreement is found between the models, particularly for the position, size, and magnitude of the acoustic focus within the skull. When comparing results for each model with every other model in a cross-comparison, the median values for each benchmark for the difference in focal pressure and position are less than 10% and 1 mm, respectively. The benchmark definitions, model results, and intercomparison codes are freely available to facilitate further comparisons.

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.

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.

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.

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.

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.

Pregnant women models analyzed for RF exposure and temperature increase in 3T RF shimmed birdcages.

PURPOSE: MRI is increasingly used to scan pregnant patients. We investigated the effect of 3 Tesla (T) two-port radiofrequency (RF) shimming in anatomical pregnant women models. THEORY AND METHODS: RF shimming improves B1+ uniformity, but may at the same time significantly alter the induced current distribution and result in large changes in both the level and location of the absorbed RF energy. In this study, we evaluated the electrothermal exposure of pregnant women in the third, seventh, and ninth month of gestation at various imaging landmarks in RF body coils, including modes with RF shimming. RESULTS: Although RF shimmed configurations may lower the local RF exposure for the mother, they can increase the thermal load on the fetus. In worst-case configurations, whole-body exposure and local peak temperatures-up to 40.8°C-are equal in fetus and mother. CONCLUSIONS: Two-port RF shimming can significantly increase the fetal exposure in pregnant women, requiring further research to derive a very robust safety management. For the time being, restriction to the CP mode, which reduces fetal SAR exposure compared with linear-horizontal polarization modes, may be advisable. Results from this study do not support scanning pregnant patients above the normal operating mode. Magn Reson Med 77:2048-2056, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Virtual population-based assessment of the impact of 3 Tesla radiofrequency shimming and thermoregulation on safety and B1 + uniformity.

PURPOSE: To assess the effect of radiofrequency (RF) shimming of a 3 Tesla (T) two-port body coil on B1 + uniformity, the local specific absorption rate (SAR), and the local temperature increase as a function of the thermoregulatory response. METHODS: RF shimming alters induced current distribution, which may result in large changes in the level and location of absorbed RF energy. We investigated this effect with six anatomical human models from the Virtual Population in 10 imaging landmarks and four RF coils. Three thermoregulation models were applied to estimate potential local temperature increases, including a newly proposed model for impaired thermoregulation. RESULTS: Two-port RF shimming, compared to circular polarization mode, can increase the B1 + uniformity on average by +32%. Worst-case SAR excitations increase the local RF power deposition on average by +39%. In the first level controlled operating mode, induced peak temperatures reach 42.5°C and 45.6°C in patients with normal and impaired thermoregulation, respectively. CONCLUSION: Image quality with 3T body coils can be significantly increased by RF shimming. Exposure in realistic scan scenarios within guideline limits can be considered safe for a broad patient population with normal thermoregulation. Patients with impaired thermoregulation should not be scanned outside of the normal operating mode. Magn Reson Med 76:986-997, 2016. © 2015 Wiley Periodicals, Inc.

Rapid method for thermal dose-based safety supervision during MR scans.

To maximize diagnostic accuracy and minimize costs, magnetic resonance imaging (MRI) scanners expose patients to electromagnetic exposure levels well above the established maximum, but in a well-controlled environment. In this paper, we discuss a novel safety assessment model that offers maximum flexibility while ensuring no local tissue damage due to radiofrequency induced heating occurs. This model is based on the cumulative equivalent minutes at 43 °C (CEM43) thermal dose concept, which naturally considers exposure duration, tissue sensitivity and the transient nature of heating, and permits rapid assessment of exposure safety of a given MRI scan using information about the transient specific absorption rate (SAR). It builds upon theoretical considerations (e.g., relating peak temperatures in the presence and absence of local thermoregulation) as well as data extracted from simulations involving anatomical models (e.g., to determine the characteristic time of temperature changes). The model is capable of predicting CEM43 for patients with either uncompromised thermoregulation or absent thermoregulation. The model predictions approximate detailed simulations well and results illustrate the importance of adequately considering changes in perfusion. The model presented herein offers an MRI safety assessment approach that overcomes problems associated with traditional SAR-based limits. Its limitations and the associated uncertainties are discussed together with remaining open questions.

Whole-body and local RF absorption in human models as a function of anatomy and position within 1.5T MR body coil.

PURPOSE: Radiofrequency energy deposition in magnetic resonance imaging must be limited to prevent excessive heating of the patient. Correlations of radiofrequency absorption with large-scale anatomical features (e.g., height) are investigated in this article. THEORY AND METHODS: The specific absorption rate (SAR), as the pivotal parameter for quantifying absorbed radiofrequency, increases with the radial dimension of the patient and therefore with the large-scale anatomical properties. The absorbed energy in six human models has been modeled in different Z-positions (head to knees) within a 1.5T bodycoil. RESULTS: For a fixed B1+ incident field, the whole-body SAR can be up to 2.5 times higher (local SAR up to seven times) in obese adult models compared to children. If the exposure is normalized to 4 W/kg whole-body SAR, the local SAR can well-exceed the limits for local transmit coils and shows intersubject variations of up to a factor of three. CONCLUSIONS: The correlations between anatomy and induced local SAR are weak for normalized exposure, but strong for a fixed B1+ field, suggesting that anatomical properties could be used for fast SAR predictions. This study demonstrates that a representative virtual human population is indispensable for the investigation of local SAR levels.

Thermal tissue damage model analyzed for different whole-body SAR and scan durations for standard MR body coils.

PURPOSE: This article investigates the safety of radiofrequency induced local thermal hotspots within a 1.5T body coil by assessing the transient local peak temperatures as a function of exposure level and local thermoregulation in four anatomical human models in different Z-positions. METHODS: To quantize the effective thermal stress of the tissues, the thermal dose model cumulative equivalent minutes at 43°C was employed, allowing the prediction of thermal tissue damage risk and the identification of potentially hazardous MR scan-scenarios. The numerical results were validated by B1 (+) - and skin temperature measurements. RESULTS: At continuous 4 W/kg whole-body exposure, peak tissue temperatures of up to 42.8°C were computed for the thermoregulated model (60°C in nonregulated case). When applying cumulative equivalent minutes at 43°C damage thresholds of 15 min (muscle, skin, fat, and bone) and 2 min (other), possible tissue damage cannot be excluded after 25 min for the thermoregulated model (4 min in nonregulated). CONCLUSION: The results are found to be consistent with the history of safe use in MR scanning, but not with current safety guidelines. For future safety concepts, we suggest to use thermal dose models instead of temperatures or SAR. Special safety concerns for patients with impaired thermoregulation (e.g., the elderly, diabetics) should be addressed.

A review of numerical and experimental compensation techniques for skull-induced phase aberrations in transcranial focused ultrasound.

The development of phased array transducers and their integration with magnetic resonance (MR) guidance and thermal monitoring has established transcranial MR-guided focused ultrasound (tcMRgFUS) as an attractive non-invasive modality for neurosurgical interventions. The presence of the skull, however, compromises the efficiency of transcranial FUS (tcFUS) therapy, as its heterogeneous nature and acoustic characteristics induce significant phase aberrations and energy attenuation, especially at the higher acoustic frequencies employed in tcFUS thermal therapy. These aberrations may distort and shift the acoustic focus as well as induce heating at the patient's scalp and skull bone. Phased array transducers feature hundreds of elements that can be driven individually, each with its own phase and amplitude. This feature allows for compensation of skull-induced aberrations by calculation and application of appropriate phase and amplitude corrections. In this paper, we illustrate the importance of precise refocusing and provide a comprehensive review of the wide variety of numerical and experimental techniques that have been used to estimate these corrections.

Modeling of EEG electrode artifacts and thermal ripples in human radiofrequency exposure studies.

The effects of radiofrequency (RF) exposure on wake and sleep electroencephalogram (EEG) have been in focus since mobile phone usage became pervasive. It has been hypothesized that effects may be explained by (1) enhanced induced fields due to RF coupling with the electrode assembly, (2) the subsequent temperature increase around the electrodes, or (3) RF induced thermal pulsing caused by localized exposure in the head. We evaluated these three hypotheses by means of both numerical and experimental assessments made with appropriate phantoms and anatomical human models. Typical and worst-case electrode placements were examined at 900 and 2140 MHz. Our results indicate that hypothesis 1 can be rejected, as the induced fields cause <20% increase in the 10 g-averaged specific absorption rate (SAR). Simulations with an anatomical model indicate that hypothesis 2 is also not supported, as the realistic worst-case electrode placement results in a maximum skin temperature increase of 0.31 °C while brain temperature elevations remained <0.1 °C. These local short-term temperature elevations are unlikely to change brain physiology during the time period from minutes to several hours after exposure. The maximum observed temperature ripple due to RF pulses is <0.001 °C for GSM-like signals and <0.004 °C for 20-fold higher pulse energy, and offers no support for hypothesis 3. Thus, the mechanism of interaction between RF and changes in the EEG power spectrum remains unknown.

Causal phase-dependent control of non-spatial attention in human prefrontal cortex.

Non-spatial attention is a fundamental cognitive mechanism that allows organisms to orient the focus of conscious awareness towards sensory information that is relevant to a behavioural goal while shifting it away from irrelevant stimuli. It has been suggested that attention is regulated by the ongoing phase of slow excitability fluctuations of neural activity in the prefrontal cortex, a hypothesis that has been challenged with no consensus. Here we developed a behavioural and non-invasive stimulation paradigm aiming at modulating slow excitability fluctuations of the inferior frontal junction. Using this approach, we show that non-spatial attention can be selectively modulated as a function of the ongoing phase of exogenously modulated excitability states of this brain structure. These results demonstrate that non-spatial attention relies on ongoing prefrontal excitability states, which are probably regulated by slow oscillatory dynamics, that orchestrate goal-oriented behaviour.