A pilot randomized controlled trial of transcranial direct current stimulation adjunct to moderate-intensity aerobic exercise in hypertensive individuals.

Background: Hypertension is a global issue that is projected to worsen with increasingly obese populations. The central nervous system including the parts of the cortex plays a key role in hemodynamic stability and homeostatic control of blood pressure (BP), making them critical components in understanding and investigating the neural control of BP. This study investigated the effects of anodal transcranial direct current stimulation (tDCS) associated with aerobic physical exercise on BP and heart rate variability in hypertensive patients. Methods: Twenty hypertensive patients were randomized into two groups: active tDCS associated with aerobic exercise or sham tDCS associated with aerobic exercise. BP and heart rate variability were analyzed before (baseline) and after twelve non-consecutive sessions. After each tDCS session (2 mA for 20 min), moderate-intensity aerobic exercise was carried out on a treadmill for 40 min. Results: A total of 20 patients were enrolled (53.9 ± 10.6 years, 30.1 ± 3.7 Kg/m2). There were no significant interactions between time and groups on diastolic BP during wake, sleep, over 24 and 3 h after the last intervention. Heart rate variability variables showed no significant difference for time, groups and interaction analysis, except for HF (ms2) between groups (p < 0.05). Conclusion: Anodal tDCS over the temporal cortex associated with aerobic exercise did not induce improvements in BP and heart rate variability. Clinical trial registration: https://ensaiosclinicos.gov.br/rg/RBR-56jg3n/1, identifier: RBR-56jg3n.

Transcranial electric stimulation modulates firing rate at clinically relevant intensities.

BACKGROUND: Notwithstanding advances with low-intensity transcranial electrical stimulation (tES), there remain questions about the efficacy of clinically realistic electric fields on neuronal function. OBJECTIVE: To measure electric fields magnitude and their effects on neuronal firing rate of hippocampal neurons in freely moving rats, and to establish calibrated computational models of current flow. METHODS: Current flow models were calibrated on electric field measures in the motor cortex (n = 2 anesthetized rats) and hippocampus. A Neuropixels 2.0 probe with 384 channels was used in an in-vivo rat model of tES (n = 4 freely moving and 2 urethane anesthetized rats) to detect effects of weak fields on neuronal firing rate. High-density field mapping and computational models verified field intensity (1 V/m in hippocampus per 50 µA of applied skull currents). RESULTS: Electric fields of as low as 0.35 V/m (0.25-0.47) acutely modulated average firing rate in the hippocampus. At these intensities, firing rate effects increased monotonically with electric field intensity at a rate of 11.5 % per V/m (7.2-18.3). For the majority of excitatory neurons, firing increased for soma-depolarizing stimulation and diminished for soma-hyperpolarizing stimulation. While more diverse, the response of inhibitory neurons followed a similar pattern on average, likely as a result of excitatory drive. CONCLUSION: In awake animals, electric fields modulate spiking rate above levels previously observed in vitro. Firing rate effects are likely mediated by somatic polarization of pyramidal neurons. We recommend that all future rodent experiments directly measure electric fields to insure rigor and reproducibility.

Cytoskeletal Remodeling and Gap Junction Translocation Mediates Blood-Brain Barrier Disruption by Non-invasive Low-Voltage Pulsed Electric Fields.

High-voltage pulsed electric fields (HV-PEF) delivered with invasive needle electrodes for electroporation applications is known to induce off-target blood-brain barrier (BBB) disruption. In this study, we sought to determine the feasibility of minimally invasive PEF application to produce BBB disruption in rat brain and identify the putative mechanisms mediating the effect. We observed dose-dependent presence of Evans Blue (EB) dye in rat brain when PEF were delivered with a skull mounted electrode used for neurostimulation application. Maximum region of dye uptake was observed while using 1500 V, 100 pulses, 100 µs and 10 Hz. Results of computational models suggested that the region of BBB disruption was occurring at thresholds of 63 V/cm or higher; well below intensity levels for electroporation. In vitro experiments recapitulating this effect with human umbilical vein endothelial cells (HUVEC) demonstrated cellular alterations that underlie BBB manifests at low-voltage high-pulse conditions without affecting cell viability or proliferation. Morphological changes in HUVECs due to PEF were accompanied by disruption of actin cytoskeleton, loss of tight junction protein-ZO-1 and VE-Cadherin at cell junctions and partial translocation into the cytoplasm. Uptake of propidium iodide (PI) in PEF treated conditions is less than 1% and 2.5% of total number of cells in high voltage (HV) and low-voltage (LV) groups, respectively, implying that BBB disruption to be independent of electroporation under these conditions. 3-D microfabricated blood vessel permeability was found to increase significantly following PEF treatment and confirmed with correlative cytoskeletal changes and loss of tight junction proteins. Finally, we show that the rat brain model can be scaled to human brains with a similar effect on BBB disruption characterized by electric field strength (EFS) threshold and using a combination of two bilateral HD electrode configurations.

Transcranial electric stimulation modulates firing rate at clinically relevant intensities.

Notwithstanding advances with low-intensity transcranial electrical stimulation (TES), there remain questions about the efficacy of clinically realistic electric fields on neuronal function. We used Neuropixels 2.0 probe with 384 channels in an in-vivo rat model of TES to detect effects of weak fields on neuronal firing rate. High-density field mapping and computational models verified field intensity (1 V/m in hippocampus per 50 µA of applied skull currents). We demonstrate that electric fields below 0.5 V/m acutely modulate firing rate in 5% of neurons recorded in the hippocampus. At these intensities, average firing rate effects increased monotonically with electric field intensity at a rate of 7 % per V/m. For the majority of excitatory neurons, firing increased for cathodal stimulation and diminished for anodal stimulation. While more diverse, the response of inhibitory neurons followed a similar pattern on average, likely as a result of excitatory drive. Our results indicate that responses to TES at clinically relevant intensities are driven by a fraction of high-responder excitatory neurons, with polarity-specific effects. We conclude that transcranial electric stimulation is an effective neuromodulator at clinically realistic intensities.

Multi-scale multi-physics model of brain interstitial water flux by transcranial Direct Current Stimulation.

Objective. Transcranial direct current stimulation (tDCS) generates sustained electric fields in the brain, that may be amplified when crossing capillary walls (across blood-brain barrier, BBB). Electric fields across the BBB may generate fluid flow by electroosmosis. We consider that tDCS may thus enhance interstitial fluid flow.Approach. We developed a modeling pipeline novel in both (1) spanning the mm (head),µm (capillary network), and then nm (down to BBB tight junction (TJ)) scales; and (2) coupling electric current flow to fluid current flow across these scales. Electroosmotic coupling was parametrized based on prior measures of fluid flow across isolated BBB layers. Electric field amplification across the BBB in a realistic capillary network was converted to volumetric fluid exchange.Main results. The ultrastructure of the BBB results in peak electric fields (per mA of applied current) of 32-63Vm-1across capillary wall and >1150Vm-1in TJs (contrasted with 0.3Vm-1in parenchyma). Based on an electroosmotic coupling of 1.0 × 10-9- 5.6 × 10-10m3s-1m2perVm-1, peak water fluxes across the BBB are 2.44 × 10-10- 6.94 × 10-10m3s-1m2, with a peak 1.5 × 10-4- 5.6 × 10-4m3min-1m3interstitial water exchange (per mA).Significance. Using this pipeline, the fluid exchange rate per each brain voxel can be predicted for any tDCS dose (electrode montage, current) or anatomy. Under experimentally constrained tissue properties, we predicted tDCS produces a fluid exchange rate comparable to endogenous flow, so doubling fluid exchange with further local flow rate hot spots ('jets'). The validation and implication of such tDCS brain 'flushing' is important to establish.

Bioheat Model of Spinal Column Heating During High-Density Spinal Cord Stimulation.

INTRODUCTION: High-density (HD) spinal cord stimulation (SCS) delivers higher charge per time by increasing frequency and/or pulse duration, thus increasing stimulation energy. Previously, through phantom studies and computational modeling, we demonstrated that stimulation energy drives spinal tissue heating during kHz SCS. In this study, we predicted temperature increases in the spinal cord by HD SCS, the first step in considering the potential impact of heating on clinical outcomes. MATERIALS AND METHODS: We adapted a high-resolution computer-aided design-derived spinal cord model, both with and without a lead encapsulation layer, and applied bioheat transfer finite element method multiphysics to predict temperature increases during SCS. We simulated HD SCS using a commercial SCS lead (eight contacts) with clinically relevant intensities (voltage-controlled: 0.5-7 Vrms) and electrode configuration (proximal bipolar, distal bipolar, guarded tripolar [+-+], and guarded quadripolar [+--+]). Results were compared with the conventional and 10-kHz SCS (current-controlled). RESULTS: HD SCS waveform energy (reflecting charge per second) governs joule heating in the spinal tissues, increasing temperature supralinearly with stimulation root mean square. Electrode configuration and tissue properties (an encapsulation layer) influence peak tissue temperature increase-but in a manner distinct for voltage-controlled (HD SCS) compared with current-controlled (conventional/10-kHz SCS) stimulation. Therefore, depending on conditions, HD SCS could produce heating greater than that of 10-kHz SCS. For example, with an encapsulation layer, using guarded tripolar configuration (500-Hz, 250-µs pulse width, 5-Vpeak HD SCS), the peak temperature increases were 0.36 °C at the spinal cord and 1.78 °C in the epidural space. CONCLUSIONS: As a direct consequence of the higher charge, HD SCS increases tissue heating; voltage-controlled stimulation introduces special dependencies on electrode configuration and lead encapsulation (reflected in impedance). If validated with an in vivo measurement as a possible mechanism of action of SCS, bioheat models of HD SCS serve as tools for programming optimization.

Computational modeling of posteroanterior lumbar traction by an automated massage bed: predicting intervertebral disc stresses and deformation.

Spinal traction is a physical intervention that provides constant or intermittent stretching axial force to the lumbar vertebrae to gradually distract spinal tissues into better alignment, reduce intervertebral disc (IVD) pressure, and manage lower back pain (LBP). However, such axial traction may change the normal lordotic curvature, and result in unwanted side effects and/or inefficient reduction of the IVD pressure. An alternative to axial traction has been recently tested, consisting of posteroanterior (PA) traction in supine posture, which was recently shown effective to increase the intervertebral space and lordotic angle using MRI. PA traction aims to maintain the lumbar lordosis curvature throughout the spinal traction therapy while reducing the intradiscal pressure. In this study, we developed finite element simulations of mechanical therapy produced by a commercial thermo-mechanical massage bed capable of spinal PA traction. The stress relief produced on the lumbar discs by the posteroanterior traction system was investigated on human subject models with different BMI (normal, overweight, moderate obese and extreme obese BMI cases). We predict typical traction levels lead to significant distraction stresses in the lumbar discs, thus producing a stress relief by reducing the compression stresses normally experienced by these tissues. Also, the stress relief experienced by the lumbar discs was effective in all BMI models, and it was found maximal in the normal BMI model. These results are consistent with prior observations of therapeutic benefits derived from spinal AP traction.

Computational Modeling of Deep Tissue Heating by an Automatic Thermal Massage Bed: Predicting the Effects on Circulation.

Automatic thermal and mechanical massage beds support self-managed treatment, including reduction of pain and stress, enhanced circulation, and improved mobility. As the devices become more sophisticated (increasing the degrees of freedom), it is essential to identify the settings that best target the desired tissue. To that end, we developed an MRI-derived model of the lower back and simulated the physiological effects of a commercial thermal-mechanical massage bed. Here we specifically estimated the tissue temperature and increased circulation under steady-state conditions for typical thermal actuator settings (i.e., 45-65°C). Energy transfer across nine tissues was simulated with finite element modeling (FEM) and the resulting heating was coupled to blood flow with an empirically-guided model of temperature-dependent circulation. Our findings indicate that thermal massage increases tissue temperature by 3-8°C and 1-3°C at depths of 2 and 3 cm, respectively. Importantly, due to the rapid (non-linear) increase of circulation with local temperature, this is expected to increase blood flow four-fold (4x) at depths occupied by deep tissue and muscle. These predictions are consistent with prior clinical observations of therapeutic benefits derived from spinal thermal massage.

Development and Clinical Validation of a Finite Element Method Model Mapping Focal Intracranial Cooling.

Therapeutic hypothermia (TH) is a common and effective technique to reduce inflammation and induce neuroprotection across a variety of diseases. Focal TH of the brain can avoid the side effects of systemic cooling. The degree and extent of focal TH are a function of cooling probe design and local brain thermoregulation processes. To refine focal TH probe design, with application-specific optimization, we develop precise computational models of brain thermodynamics under intense local cooling. Here, we present a novel multiphysics in silico model that can accurately predict brain response to focal cooling. The model was parameterized from previously described values of metabolic activity, thermal conductivity, and temperature-dependent cerebral perfusion. The model was validated experimentally using data from clinical cases where local cooling was induced intracranially and brain temperatures monitored in real-time with MR thermometry. The validated model was then used to identify optimal design probe parameters to maximize volumetric TH, including considering three stratifications of cooling (mild, moderate, and profound) to produce Volume of Tissue Cooled (VOTC) maps. We report cooling radius increases in a nearly linear fashion with probe length and decreasing probe surface temperature.

Neurocapillary-Modulation.

OBJECTIVES: We consider two consequences of brain capillary ultrastructure in neuromodulation. First, blood-brain barrier (BBB) polarization as a consequence of current crossing between interstitial space and the blood. Second, interstitial current flow distortion around capillaries impacting neuronal stimulation. MATERIALS AND METHODS: We developed computational models of BBB ultrastructure morphologies to first assess electric field amplification at the BBB (principle 1) and neuron polarization amplification by the presence of capillaries (principle 2). We adapt neuron cable theory to develop an analytical solution for maximum BBB polarization sensitivity. RESULTS: Electrical current crosses between the brain parenchyma (interstitial space) and capillaries, producing BBB electric fields (EBBB) that are >400x of the average parenchyma electric field (EBRAIN), which in turn modulates transport across the BBB. Specifically, for a BBB space constant (λBBB) and wall thickness (dth-BBB), the analytical solution for maximal BBB electric field (EABBB) is given as: (EBRAIN × λBBB)/dth-BBB. Electrical current in the brain parenchyma is distorted around brain capillaries, amplifying neuronal polarization. Specifically, capillary ultrastructure produces ∼50% modulation of the EBRAIN over the ∼40 µm inter-capillary distance. The divergence of EBRAIN (Activating function) is thus ∼100 kV/m2 per unit EBRAIN. CONCLUSIONS: BBB stimulation by principle 1 suggests novel therapeutic strategies such as boosting metabolic capacity or interstitial fluid clearance. Whereas the spatial profile of EBRAIN is traditionally assumed to depend only on macroscopic anatomy, principle 2 suggests a central role for local capillary ultrastructure-which impact forms of neuromodulation including deep brain stimulation (DBS), spinal cord stimulation (SCS), transcranial magnetic stimulation (TMS), electroconvulsive therapy (ECT), and transcranial electrical stimulation (tES)/transcranial direct current stimulation (tDCS).

High-resolution computational modeling of the current flow in the outer ear during transcutaneous auricular Vagus Nerve Stimulation (taVNS).

BACKGROUND: Transcutaneous auricular Vagus Nerve Stimulation (taVNS) applies low-intensity electrical current to the ear with the intention of activating the auricular branch of the Vagus nerve. The sensitivity and selectivity of stimulation applied to the ear depends on current flow pattern produced by a given electrode montage (size and placement). OBJECTIVE: We compare different electrodes designs for taVNS considering both the predicted peak electric fields (sensitivity) and their spatial distribution (selectivity). METHODS: Based on optimized high-resolution (0.47 mm) T1 and T2 weighted MRI, we developed an anatomical model of the left ear and the surrounding head tissues including brain, CSF/meninges, skull, muscle, blood vessels, fat, cartilage, and skin. The ear was further segmented into 6 regions of interest (ROI) based on various nerve densities: cavum concha, cymba concha, crus of helix, tragus, antitragus, and earlobe. A range of taVNS electrode montages were reproduced spanning varied electrodes sizes and placements over the tragus, cymba concha, earlobe, cavum concha, and crus of helix. Electric field across the ear (from superficial skin to cartilage) for each montage at 1 mA or 2 mA taVNS, assuming an activation threshold of 6.15 V/m, 12.3 V/m or 24.6 V/m was predicted using a Finite element method (FEM). Finally, considering every ROI, we calculated the sensitivity and selectivity of each montage. RESULTS: Current flow patterns through the ear were highly specific to the electrode montage. Electric field was maximal at the ear regions directly under the electrodes, and for a given total current, increases with decreasing electrode size. Depending on the applied current and nerves threshold, activation may also occur in the regions between multiple anterior surface electrodes. Each considered montage was selective for one or two regions of interest. For example, electrodes across the tragus restricted significant electric field to the tragus. Stimulation across the earlobe restricted significant electric field to the earlobe and the antitragus. Because of this relative selectivity, use of control ear montages in experimental studies, support testing of targeting. Relative targeting was robust across assumptions of activation threshold and tissue properties. DISCUSSION: Computational models provide additional insight on how details in electrode shape and placement impact sensitivity (how much current is needed) and selectivity (spatial distribution), thereby supporting analysis of existing approaches and optimization of new devices. Our result suggest taVNS current patterns and relative target are robust across individuals, though (variance in) axon morphology was not represented.

Adaptive current-flow models of ECT: Explaining individual static impedance, dynamic impedance, and brain current density.

BACKGROUND: Improvements in electroconvulsive therapy (ECT) outcomes have followed refinement in device electrical output and electrode montage. The physical properties of the ECT stimulus, together with those of the patient's head, determine the impedances measured by the device and govern current delivery to the brain and ECT outcomes. OBJECTIVE: However, the precise relations among physical properties of the stimulus, patient head anatomy, and patient-specific impedance to the passage of current are long-standing questions in ECT research and practice. To this end, we develop a computational framework based on diverse clinical data sets. METHODS: We developed anatomical MRI-derived models of transcranial electrical stimulation (tES) that included changes in tissue conductivity due to local electrical current flow. These "adaptive" models simulate ECT both during therapeutic stimulation using high current (∼1 A) and when dynamic impedance is measured, as well as prior to stimulation when low current (∼1 mA) is used to measure static impedance. We modeled two scalp layers: a superficial scalp layer with adaptive conductivity that increases with electric field up to a subject-specific maximum (σSS¯), and a deep scalp layer with a subject-specific fixed conductivity (σDS). RESULTS: We demonstrated that variation in these scalp parameters may explain clinical data on subject-specific static impedance and dynamic impedance, their imperfect correlation across subjects, their relationships to seizure threshold, and the role of head anatomy. Adaptive tES models demonstrated that current flow changes local tissue conductivity which in turn shapes current delivery to the brain in a manner not accounted for in fixed tissue conductivity models. CONCLUSIONS: Our predictions that variation in individual skin properties, rather than other aspects of anatomy, largely govern the relationship between static impedance, dynamic impedance, and ECT current delivery to the brain, themselves depend on assumptions about tissue properties. Broadly, our novel modeling pipeline opens the door to explore how adaptive-scalp conductivity may impact transcutaneous electrical stimulation (tES).

Tissue Temperature Increases by a 10 kHz Spinal Cord Stimulation System: Phantom and Bioheat Model.

OBJECTIVE: A recently introduced Spinal Cord Stimulation (SCS) system operates at 10 kHz, faster than conventional SCS systems, resulting in significantly more power delivered to tissues. Using a SCS heat phantom and bioheat multi-physics model, we characterized tissue temperature increases by this 10 kHz system. We also evaluated its Implanted Pulse Generator (IPG) output compliance and the role of impedance in temperature increases. MATERIALS AND METHODS: The 10 kHz SCS system output was characterized under resistive loads (1-10 KΩ). Separately, fiber optic temperature probes quantified temperature increases (ΔTs) around the SCS lead in specially developed heat phantoms. The role of stimulation Level (1-7; ideal pulse peak-to-peak of 1-7mA) was considered, specifically in the context of stimulation current Root Mean Square (RMS). Data from the heat phantom were verified with the SCS heat-transfer models. A custom high-bandwidth stimulator provided 10 kHz pulses and sinusoidal stimulation for control experiments. RESULTS: The 10 kHz SCS system delivers 10 kHz biphasic pulses (30-20-30 µs). Voltage compliance was 15.6V. Even below voltage compliance, IPG bandwidth attenuated pulse waveform, limiting applied RMS. Temperature increased supralinearly with stimulation Level in a manner predicted by applied RMS. ΔT increases with Level and impedance until stimulator compliance was reached. Therefore, IPG bandwidth and compliance dampen peak heating. Nonetheless, temperature increases predicted by bioheat multi-physic models (ΔT = 0.64°C and 1.42°C respectively at Level 4 and 7 at the cervical segment; ΔT = 0.68°C and 1.72°C respectively at Level 4 and 7 at the thoracic spinal cord)-within ranges previously reported to effect neurophysiology. CONCLUSIONS: Heating of spinal tissues by this 10 kHz SCS system theoretically increases quickly with stimulation level and load impedance, while dampened by IPG pulse bandwidth and voltage compliance limitations. If validated in vivo as a mechanism of kHz SCS, bioheat models informed by IPG limitations allow prediction and optimization of temperature changes.

Role of skin tissue layers and ultra-structure in transcutaneous electrical stimulation including tDCS.

BACKGROUND: During transcranial electrical stimulation (tES), including transcranial direct current stimulation (tDCS) and transcranial alternating current stimulation (tACS), current density concentration around the electrode edges that is predicted by simplistic skin models does not match experimental observations of erythema, heating, or other adverse events. We hypothesized that enhancing models to include skin anatomical details, would alter predicted current patterns to align with experimental observations. METHOD: We develop a high-resolution multi-layer skin model (epidermis, dermis, and fat), with or without additional ultra-structures (hair follicles, sweat glands, and blood vessels). Current flow patterns across each layer and within ultra-structures were predicted using finite element methods considering a broad range of modeled tissue parameters including 78 combinations of skin layer conductivities (S m-1): epidermis (standard: 1.05 × 10-5; range: 1.05 × 10-6 to 0.465); dermis (standard: 0.23; range: 0.0023 to 23), fat (standard: 2 × 10-4; range: 0.02 to 2 × 10-5). The impact of each ultra-structures in isolation and combination was evaluated with varied basic geometries. An integrated final model is then developed. RESULTS: Consistent with prior models, current flow through homogenous skin was annular (concentrated at the electrode edges). In multi-layer skin, reducing epidermis conductivity and/or increasing dermis conductivity decreased current near electrode edges, however no realistic tissue layer parameters produced non-annular current flow at both epidermis and dermis. Addition of just hair follicles, sweat glands, or blood vessels resulted in current peaks around each ultrastructure, irrespective of proximity to electrode edges. Addition of only sweat glands was the most effective approach in reducing overall current concentration near electrode edges. Representation of blood vessels resulted in a uniform current flow across the vascular network. Finally, we ran the first realistic model of current flow across the skin. CONCLUSION: We confirm prior models exhibiting current concentration near hair follicles or sweat glands, but also exhibit that an overall annular pattern of current flow remains for realistic tissue parameters. We model skin blood vessels for the first time and show that this robustly distributes current across the vascular network, consistent with experimental erythema patterns. Only a state-of-the-art precise model of skin current flow predicts lack of current concentration near electrode edges across all skin layers.

Realistic anatomically detailed open-source spinal cord stimulation (RADO-SCS) model.

OBJECTIVE: Computational current flow models of spinal cord stimulation (SCS) are widely used in device development, clinical trial design, and patient programming. Proprietary models of varied sophistication have been developed. An open-source model with state-of-the-art precision would serve as a standard for SCS simulation. APPROACH: We developed a sophisticated SCS modeling platform, named Realistic Anatomically Detailed Open-Source Spinal Cord Stimulation (RADO-SCS) model. This platform consists of realistic and detailed spinal cord and ancillary tissues anatomy derived based on prior imaging and cadaveric studies. In our finite element model of the T9-T11 spine levels, we represented the following tissues: vertebrae, intervertebral disc, epidural space, epidural space vasculature, dura mater, dural sac, intraforaminal tissue, cerebrospinal fluid (CSF), whitematter, spinal cord vasculature, Lissauer's tract, gray matter, dorsal and ventral roots and rootlets, dorsal root ganglion (DRG), sympathetic chain (trunk and ganglion), thoracic aorta and its branching, peripheral vasculature, and soft tissues (thorax). As an exemplary application to illustrate the model workflow, we simulated a bipolar SCS montage and calculated the corresponding activation thresholds for individual axons populating the spinal cord. MAIN RESULTS: RADO-SCS provides state-of-the-art precision across 19 tissue compartments. The resulting model calculations of the electric fields generated in the white-matter and gray matter, and the axonal activation thresholds are broadly consistent with prior simulations. SIGNIFICANCE: The RADO-SCS can be used to simulate any SCS approach with both unprecedented resolution (precision) and transparency (reproducibility). Freely-available online, the RADO-SCS will be updated continuously with version control.

Bio-Heat Model of Kilohertz-Frequency Deep Brain Stimulation Increases Brain Tissue Temperature.

OBJECTIVES: Early clinical trials suggest that deep brain stimulation at kilohertz frequencies (10 kHz-DBS) may be effective in improving motor symptoms in patients with movement disorders. The 10 kHz-DBS can deliver significantly more power in tissue compared to conventional frequency DBS, reflecting increased pulse compression (duty cycle). We hypothesize that 10 kHz-DBS modulates neuronal function through moderate local tissue heating, analogous to kilohertz spinal cord stimulation (10 kHz-SCS). To establish the role of tissue heating in 10 kHz-DBS (30 µs, 10 kHz, at intensities of 3-7 mApeak ), a decisive first step is to characterize the range of temperature changes during clinical kHz-DBS protocols. MATERIALS AND METHODS: We developed a high-resolution magnetic resonance imaging-derived DBS model incorporating joule-heat coupled bio-heat multi-physics to establish the role of tissue heating. Volume of tissue activated (VTA) under assumptions of activating function (for 130 Hz) or heating (for 10 kHz) based neuromodulation are contrasted. RESULTS: DBS waveform power (waveform RMS) determined joule heating at the deep brain tissues. Peak heating was supralinearly dependent on stimulation RMS. The 10 kHz-DBS stimulation with 2.3 to 5.4 mARMS (corresponding to 3 to 7 mApeak ) produced 0.10 to 1.38°C heating at the subthalamic nucleus (STN) target under standard tissue parameters. Maximum temperature increases were predicted inside the electrode encapsulation layer (enCAP) with 2.3 to 5.4 mARMS producing 0.13 to 1.87°C under standard tissue parameters. Tissue parameter analysis predicted STN heating was especially sensitive (ranging from 0.44 to 1.35°C at 3.8 mARMS ) to decreasing enCAP electrical conductivity and decreasing STN thermal conductivity. CONCLUSIONS: Subject to validation with in vivo measurements, neuromodulation through a heating mechanism of action by 10 kHz-DBS can indicate novel therapeutic pathways and strategies for dose optimization.

In Vivo Modulation of the Blood-Brain Barrier Permeability by Transcranial Direct Current Stimulation (tDCS).

tDCS has been used to treat various brain disorders and its mechanism of action (MoA) was found to be neuronal polarization. Since the blood-brain barrier (BBB) tightly regulates the neuronal microenvironment, we hypothesized that another MoA of tDCS is direct vascular activation by modulating the BBB structures to increase its permeability (P). To test this hypothesis, we used high resolution multiphoton microscopy to determine P of the cerebral microvessels in rat brain. We found that 20 min 0.1-1 mA tDCS transiently increases P to a small solute, sodium fluorescein (MW 376) and to a large solute, Dextran-70k, with a much higher increase in P to the large solute. By pretreating the vessel with a nitric oxide synthase inhibitor, we revealed that the tDCS-induced increase in P is NO dependent. A transport model for the BBB was further employed to predict the structural changes by the tDCS. Comparing model predictions with the measured data suggests that tDCS increases P by temporarily disrupting the structural components forming the paracellular pathway of the BBB. That the transient and reversible increase in the BBB permeability also suggests new applications of tDCS such as a non-invasive approach for brain drug delivery through the BBB.

Prevention of schizophrenia deficits via non-invasive adolescent frontal cortex stimulation in rats.

Schizophrenia is a severe neurodevelopmental psychiatric affliction manifested behaviorally at late adolescence/early adulthood. Current treatments comprise antipsychotics which act solely symptomatic, are limited in their effectiveness and often associated with side-effects. We here report that application of non-invasive transcranial direct current stimulation (tDCS) during adolescence, prior to schizophrenia-relevant behavioral manifestation, prevents the development of positive symptoms and related neurobiological alterations in the maternal immune stimulation (MIS) model of schizophrenia.

Adaptive current tDCS up to 4 mA.

BACKGROUND: Higher tDCS current may putatively enhance efficacy, with tolerability the perceived limiting factor. OBJECTIVE: We designed and validated electrodes and an adaptive controller to provide tDCS up to 4 mA, while managing tolerability. The adaptive 4 mA controller included incremental ramp up, impedance-based current limits, and a Relax-mode where current is transiently decreased. Relax-mode was automatically activated by self-report VAS-pain score >5 and in some conditions by a Relax-button available to participants. METHODS: In a parallel-group participant-blind design with 50 healthy subjects, we used specialized electrodes to administer 3 daily session of tDCS for 11 min, with a lexical decision task as a distractor, in 5 study conditions: adaptive 4 mA, adaptive 4 mA with Relax-button, adaptive 4 mA with historical-Relax-button, 2 mA, and sham. A tablet-based stimulator with a participant interface regularly queried VAS pain score and also limited current based on impedance and tolerability. An Abort-button provided in all conditions stopped stimulation. In the adaptive 4 mA with Relax-button and adaptive 4 mA with historical-Relax-button conditions, participants could trigger a Relax-mode ad libitum, in the latter case with incrementally longer current reductions. Primary outcome was the average current delivered during each session, VAS pain score, and adverse event questionnaires. Current delivered was analyzed either excluding or including dropouts who activated Abort (scored as 0 current). RESULTS: There were two dropouts each in the adaptive 4 mA and sham conditions. Resistance based current attenuation was rarely activated, with few automatic VAS pain score triggered relax-modes. In conditions with Relax-button option, there were significant activations often irrespective of VAS pain score. Including dropouts, current across conditions were significantly different from each other with maximum current delivered during adaptive 4 mA with Relax-button. Excluding dropouts, maximum current was delivered with adaptive 4 mA. VAS pain score and adverse events for the sham was only significantly lower than the adaptive 4 mA with Relax-button and adaptive 4 mA with historical-Relax-button. There was no difference in VAS pain score or adverse events between 2 mA and adaptive 4 mA. CONCLUSIONS: Provided specific electrodes and controllers, adaptive 4 mA tDCS is tolerated and effectively blinded, with acceptability likely higher in a clinical population and absence of regular querying. Indeed, presenting participants with overt controls increases rumination on sensation.