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Objective: This work aims to reduce the acoustic noise level of transcranial magnetic stimulation (TMS) coils. TMS requires high currents (several thousand amperes) to be pulsed through the coil, which generates a loud acoustic impulse whose peak sound pressure level (SPL) can exceed 130 dB(Z). This sound poses a risk to hearing and elicits unwanted neural activation of auditory brain circuits. Methods: We propose a new double-containment coil with enhanced winding mounting (DCC), which utilizes acoustic impedance mismatch to contain and dissipate the impulsive sound within an air-tight outer casing. The coil winding is potted in a rigid block, which is mounted to the outer casing by its acoustic nodes that are subject to minimum vibration during the pulse. The rest of the winding block is isolated from the casing by an air gap, and sound is absorbed by foam within the casing. The casing thickness under the winding center is minimized to maximize the coil electric field output. Results: Compared to commercial figure-of-eight TMS coils, the DCC prototype has 10-33 dB(Z) lower SPL at matched stimulation strength, whilst providing 22% higher maximum stimulation strength than equally focal commercial coils. Conclusion: The DCC design greatly reduces the acoustic noise of TMS while increasing the achievable stimulation strength. Significance: The acoustic noise reduction from our coil design is comparable to that provided by typical hearing protection devices. This coil design approach can enhance hearing safety and reduce auditory co-activations in the brain and other detrimental effects of TMS sound., 8 pages, 5 figures

ObjectiveTemporal interference stimulation (TIS) was proposed as a non-invasive, focal, and steerable deep brain stimulation method. However, the mechanisms underlying experimentally-observed suprathreshold TIS effects are unknown, and prior simulation studies had limitations in the representations of the TIS electric field (E-field) and cerebral neurons. We examined the E-field and neural response characteristics for TIS and related transcranial alternating current stimulation modalities.ApproachUsing the uniform-field approximation, we simulated a range of stimulation parameters in biophysically realistic model cortical neurons, including different orientations, frequencies, amplitude ratios, amplitude modulation, and phase difference of the E-fields, and obtained thresholds for both activation and conduction block.Main resultsFor two E-fields with similar amplitudes (representative of E-field distributions at the target region), TIS generated an amplitude-modulated total E-field. Due to the phase difference of the individual E-fields, the total TIS E-field vector also exhibited rotation where the orientations of the two E-fields were not aligned (generally also at the target region). TIS activation thresholds (75–230 V/m) were similar to those of high-frequency stimulation with or without modulation and/or rotation. For E-field dominated by the high-frequency carrier and with minimal amplitude modulation and/or rotation (typically outside the target region), TIS was less effective at activation and more effective at block. Unlike amplitude-modulated high-frequency stimulation, TIS generated conduction block with some orientations and amplitude ratios of individual E-field at very high amplitudes of the total E-field (>1700 V/m).SignificanceThe complex 3D properties of the TIS E-fields should be accounted for in computational and experimental studies. The mechanisms of suprathreshold cortical TIS appear to involve neural activity block and periodic activation or onset response, consistent with computational studies of peripheral axons. These phenomena occur at E-field strengths too high to be delivered tolerably through scalp electrodes and may inhibit endogenous activity in off-target regions, suggesting limited significance of suprathreshold TIS.

The brain is an inherently dynamic system, and much work has focused on the ability to modify neural activity through both local perturbations and changes in the function of global network ensembles. Network controllability is a recent concept in network neuroscience that purports to predict the influence of individual cortical sites on global network states and state changes, thereby creating a unifying account of local influences on global brain dynamics. While this notion is accepted in engineering science, it is subject to ongoing debates in neuroscience as empirical evidence linking network controllability to brain activity and human behavior remains scarce. Here, we present an integrated set of multimodal brain–behavior relationships derived from fMRI, diffusion tensor imaging, and online repetitive transcranial magnetic stimulation (rTMS) applied during an individually calibrated working memory task performed by individuals of both sexes. The modes describing the structural network system dynamics showed direct relationships to brain activity associated with task difficulty, with difficult-to-reach modes contributing to functional brain states in the hard task condition. Modal controllability (a measure quantifying the contribution of difficult-to-reach modes) at the stimulated site predicted both fMRI activations associated with increasing task difficulty and rTMS benefits on task performance. Furthermore, fMRI explained 64% of the variance between modal controllability and the working memory benefit associated with 5 Hz online rTMS. These results therefore provide evidence toward the functional validity of network control theory, and outline a clear technique for integrating structural network topology and functional activity to predict the influence of stimulation on subsequent behavior. SIGNIFICANCE STATEMENT The network controllability concept proposes that specific cortical nodes are able to steer the brain into certain physiological states. By applying external perturbation to these control nodes, it is theorized that brain stimulation is able to selectively target difficult-to-reach states, potentially aiding processing and improving performance on cognitive tasks. The current study used rTMS and fMRI during a working memory task to test this hypothesis. We demonstrate that network controllability correlates with fMRI modulation because of working memory load and with the behavioral improvements that result from a multivisit intervention using 5 Hz rTMS. This study demonstrates the validity of network controllability and offers a new targeting approach to improve efficacy.

Working memory is the ability to perform mental operations on information that is stored in a flexible, limited capacity buffer. The ability to manipulate information in working memory is central to many aspects of human cognition, but also declines with healthy aging. Given the profound importance of such working memory manipulation abilities, there is a concerted effort towards developing approaches to improve them. The current study tested the capacity to enhance working memory manipulation with online repetitive transcranial magnetic stimulation in healthy young and older adults. Online high frequency (5Hz) repetitive transcranial magnetic stimulation was applied over the left dorsolateral prefrontal cortex to test the hypothesis that active repetitive transcranial magnetic stimulation would lead to significant improvements in memory recall accuracy compared to sham stimulation, and that these effects would be most pronounced in working memory manipulation conditions with the highest cognitive demand in both young and older adults. Repetitive transcranial magnetic stimulation was applied while participants were performing a delayed response alphabetization task with three individually-titrated levels of difficulty. The left dorsolateral prefrontal cortex was identified by combining electric field modeling to individualized functional magnetic resonance imaging activation maps and was targeted during the experiment using stereotactic neuronavigation with real-time robotic guidance, allowing optimal coil placement during the stimulation. As no accuracy differences were found between young and older adults, the results from both groups were collapsed. Subsequent analyses revealed that active stimulation significantly increased accuracy relative to sham stimulation, but only for the hardest condition. These results point towards further investigation of repetitive transcranial magnetic stimulation for memory enhancement focusing on high difficulty conditions as those most likely to exhibit benefits.

OBJECTIVE: Sham TMS coils isolate the ancillary effects of their active counterparts, but typically induce low-strength electric fields (E-fields) in the brain, which could be biologically active. We measured the E-fields induced by two pairs of commonly-used commercial active/sham coils. APPROACH: E-field distributions of the active and sham configurations of the Magstim 70 mm AFC and MagVenture Cool-B65 A/P coils were measured over a 7-cm-radius, hemispherical grid approximating the cortical surface. Peak E-field strength was recorded over a range of pulse amplitudes. MAIN RESULTS: The Magstim and MagVenture shams induce peak E-fields corresponding to 25.3% and 7.72% of their respective active values. The MagVenture sham has an E-field distribution shaped like its active counterpart. The Magstim sham induces nearly zero E-field under the coil’s center, and its peak E-field forms a diffuse oval 3–7 cm from the center. Electrical scalp stimulation paired with the MagVenture sham is estimated to increase the sham E-field in the brain up to 10%. SIGNIFICANCE: Different commercial shams induce different E-field strengths and distributions in the brain, which should be considered in interpreting outcomes of sham stimulation.

BackgroundTranscranial magnetic stimulation (TMS) is a noninvasive brain stimulation technique used for research and clinical applications. Existent TMS coils are limited in their precision of spatial targeting (focality), especially for deeper targets.ObjectiveThis paper presents a methodology for designing TMS coils to achieve optimal trade-off between the depth and focality of the induced electric field (E-field), as well as the energy required by the coil.MethodsA multi-objective optimization technique is used for computationally designing TMS coils that achieve optimal trade-offs between stimulation focality, depth, and energy (fdTMS coils). The fdTMS coil winding(s) maximize focality (minimize stimulated volume) while reaching a target at a specified depth and not exceeding predefined peak E-field strength and required coil energy. Spherical and MRI-derived head models are used to compute the fundamental depth–focality trade-off as well as focality–energy trade-offs for specific target depths.ResultsAcross stimulation target depths of 1.0–3.4 cm from the brain surface, the stimulated volume can be theoretically decreased by 42%–55% compared to existing TMS coil designs. The stimulated volume of a figure-8 coil can be decreased by 36%, 44%, or 46%, for matched, doubled, or quadrupled energy. For matched focality and energy, the depth of a figure-8 coil can be increased by 22%.ConclusionComputational design of TMS coils could enable more selective targeting of the induced E-field. The presented results appear to be the first significant advancement in the depth–focality trade-off of TMS coils since the introduction of the figure-8 coil three decades ago, and likely represent the fundamental physical limit.DECLARATION OF INTERESTThe fdTMS technology described in this paper is subject to a provisional patent application by Duke University with the authors as inventors. Additionally: L.J.G. is inventor on a patent pertaining to the design of focal multicoil TMS systems. S.M.G. is inventor on patents and patent applications; he has received royalties from Rogue Research, TU Muenchen, and Porsche; furthermore, he has been provided with research support and patent fee reimbursement from Magstim Co. A.V.P. is inventor on patents and patent applications, and has received research and travel support as well as patent royalties from Rogue Research; research and travel support, consulting fees, as well as equipment loan from Tal Medical / Neurex; patent application and research support from Magstim; and equipment loans from MagVenture, all related to technology for transcranial magnetic stimulation.

Objective: To develop a pipeline for realistic head models of nonhuman primates (NHPs) for simulations of noninvasive brain stimulation, and use these models together with empirical threshold measurements to demonstrate that the models capture individual anatomical variability. Methods: Based on structural MRI data, we created models of the electric field (E-field) induced by right unilateral (RUL) electroconvulsive therapy (ECT) in four rhesus macaques. Individual motor threshold (MT) was measured with transcranial electric stimulation (TES) administered through the RUL electrodes in the same subjects. Results: The interindividual anatomical differences resulted in 57% variation in median E-field strength in the brain at fixed stimulus current amplitude. Individualization of the stimulus current by MT reduced the E-field variation in the target motor area by 27%. There was significant correlation between the measured MT and the ratio of simulated electrode current and E-field strength ( $r^{2} = 0.95$ , $p = 0.026$ ). Exploratory analysis revealed significant correlations of this ratio with anatomical parameters including of the superior electrode-to-cortex distance, vertex-to-cortex distance, and brain volume ( $r^{2} > 0.96$ , $p ). The neural activation threshold was estimated to be $0.45 \pm 0.07$ V/cm for 0.2-ms stimulus pulse width. Conclusion: These results suggest that our individual-specific NHP E-field models appropriately capture individual anatomical variability relevant to the dosing of TES/ECT. These findings are exploratory due to the small number of subjects. Significance: This study can contribute insight in NHP studies of ECT and other brain stimulation interventions, help link the results to clinical studies, and ultimately lead to more rational brain stimulation dosing paradigms.

Electroconvulsive therapy (ECT) and magnetic seizure therapy (MST) are conventionally applied with a fixed stimulus current amplitude, which may result in differences in the neural stimulation strength and focality across patients due to interindividual anatomical variability. The objective of this study is to quantify the effect of head anatomical variability associated with age, sex, and individual differences on the induced electric field characteristics in ECT and MST. Six stimulation modalities were modeled including bilateral and right unilateral ECT, focal electrically administered seizure therapy (FEAST), and MST with circular, cap, and double-cone coils. The electric field was computed using the finite element method in a parameterized spherical head model representing the variability in the general population. Head tissue layer thicknesses and conductivities were varied to examine the impact of interindividual anatomical differences on the stimulation strength, depth, and focality. Skull conductivity most strongly affects the ECT electric field, whereas the MST electric field is independent of tissue conductivity variation in this model but is markedly affected by differences in head diameter. Focal ECT electrode configurations such as FEAST is more sensitive to anatomical variability than that of less focal paradigms such as BL ECT. In MST, anatomical variability has stronger influence on the electric field of the cap and circular coils compared to the double-cone coil, possibly due to the more superficial field of the former. The variability of the ECT and MST electric fields due to anatomical differences should be considered in the interpretation of existing studies and in efforts to improve dosing approaches for better control of stimulation strength and focality across patients, such as individualization of the current amplitude. The conventional approach to individualizing dosage by titrating the number of pulses cannot compensate for differences in the spatial extent of stimulation that result from anatomical variability.

Understanding the relationship between the stimulus parameters of electroconvulsive therapy (ECT) and the electric field characteristics could guide studies on improving risk/benefit ratio. We aimed to determine the effect of current amplitude and electrode size and spacing on the ECT electric field characteristics, compare ECT focality with magnetic seizure therapy (MST), and evaluate stimulus individualization by current amplitude adjustment.Electroconvulsive therapy and double-cone-coil MST electric field was simulated in a 5-shell spherical human head model. A range of ECT electrode diameters (2-5 cm), spacing (1-25 cm), and current amplitudes (0-900 mA) was explored. The head model parameters were varied to examine the stimulus current adjustment required to compensate for interindividual anatomical differences.By reducing the electrode size, spacing, and current, the ECT electric field can be more focal and superficial without increasing scalp current density. By appropriately adjusting the electrode configuration and current, the ECT electric field characteristics can be made to approximate those of MST within 15%. Most electric field characteristics in ECT are more sensitive to head anatomy variation than in MST, especially for close electrode spacing. Nevertheless, ECT current amplitude adjustment of less than 70% can compensate for interindividual anatomical variability.The strength and focality of ECT can be varied over a wide range by adjusting the electrode size, spacing, and current. If desirable, ECT can be made as focal as MST while using simpler stimulation equipment. Current amplitude individualization can compensate for interindividual anatomical variability.

Background: Various transcranial magnetic stimulation (TMS) coil designs are available or have been proposed. However, key coil characteristics such as electric field focality and attenuation in depth have not been adequately compared. Knowledge of the coil focality and depth characteristics can help TMS researchers and clinicians with coil selection and interpretation of TMS studies. Objective: To quantify the electric field focality and depth of penetration of various TMS coils. Methods: The electric field distributions induced by 50 TMS coils were simulated in a spherical human head model using the finite element method. For each coil design, we quantified the electric field penetration by the half-value depth, d1/2, and focality by the tangential spread, S1/2, defined as the half-value volume (V1/2) divided by the half-value depth, S1/2 = V1/2/d1/2. Results: The 50 TMS coils exhibit a wide range of electric field focality and depth, but all followed a depth–focality tradeoff: coils with larger half-value depth cannot be as focal as more superficial coils. The ranges of achievable d1/2 are similar between coils producing circular and figure-8 electric field patterns, ranging 1.0–3.5 cm and 0.9–3.4 cm, respectively. However, figure-8 field coils are more focal, having S1/2 as low as 5 cm2 compared to 34 cm2 for circular field coils. Conclusions: For any coil design, the ability to directly stimulate deeper brain structures is obtained at the expense of inducing wider electrical field spread. Novel coil designs should be benchmarked against comparison coils with consistent metrics such as d1/2 and S1/2.

Lowering and individualizing the current amplitude in electroconvulsive therapy (ECT) has been proposed as a means to produce stimulation closer to the neural activation threshold and more focal seizure induction, which could potentially reduce cognitive side effects. However, the effect of current amplitude on the electric field (E-field) in the brain has not been previously linked to the current amplitude threshold for seizure induction. We coupled MRI-based E-field models with amplitude titrations of motor threshold (MT) and seizure threshold (ST) in four nonhuman primates (NHPs) to determine the strength, distribution, and focality of stimulation in the brain for four ECT electrode configurations (bilateral, bifrontal, right-unilateral, and frontomedial) and magnetic seizure therapy (MST) with cap coil on vertex. At the amplitude-titrated ST, the stimulated brain subvolume (23-63%) was significantly less than for conventional ECT with high, fixed current (94-99%). The focality of amplitude-titrated right-unilateral ECT (25%) was comparable to cap coil MST (23%), demonstrating that ECT with a low current amplitude and focal electrode placement can induce seizures with E-field as focal as MST, although these electrode and coil configurations affect differently specific brain regions. Individualizing the current amplitude reduced interindividual variation in the stimulation focality by 40-53% for ECT and 26% for MST, supporting amplitude individualization as a means of dosing especially for ECT. There was an overall significant correlation between the measured amplitude-titrated ST and the prediction of the E-field models, supporting a potential role of these models in dosing of ECT and MST. These findings may guide the development of seizure therapy dosing paradigms with improved risk/benefit ratio.

BackgroundThis study examines the strength and spatial distribution of the electric field induced in the brain by electroconvulsive therapy (ECT) and magnetic seizure therapy (MST).MethodsThe electric field induced by standard (bilateral, right unilateral, and bifrontal) and experimental (focal electrically administered seizure therapy and frontomedial) ECT electrode configurations as well as a circular MST coil configuration was simulated in an anatomically realistic finite element model of the human head. Maps of the electric field strength relative to an estimated neural activation threshold were used to evaluate the stimulation strength and focality in specific brain regions of interest for these ECT and MST paradigms and various stimulus current amplitudes.ResultsThe standard ECT configurations and current amplitude of 800–900 mA produced the strongest overall stimulation with median of 1.8–2.9 times neural activation threshold and more than 94% of the brain volume stimulated at suprathreshold level. All standard ECT electrode placements exposed the hippocampi to suprathreshold electric field, although there were differences across modalities with bilateral and right unilateral producing respectively the strongest and weakest hippocampal stimulation. MST stimulation is up to 9 times weaker compared to conventional ECT, resulting in direct activation of only 21% of the brain. Reducing the stimulus current amplitude can make ECT as focal as MST.ConclusionsThe relative differences in electric field strength may be a contributing factor for the cognitive sparing observed with right unilateral compared to bilateral ECT, and MST compared to right unilateral ECT. These simulations could help understand the mechanisms of seizure therapies and develop interventions with superior risk/benefit ratio.

Electroconvulsive therapy (ECT) at conventional current amplitudes (800–900 mA) is highly effective but carries the risk of cognitive side effects. Lowering and individualizing the current amplitude may reduce side effects by virtue of a less intense and more focal electric field exposure in the brain, but this aspect of ECT dosing is largely unexplored. Magnetic seizure therapy (MST) induces a weaker and more focal electric field than ECT; however, the pulse amplitude is not individualized and the minimum amplitude required to induce a seizure is unknown. We titrated the amplitude of long stimulus trains (500 pulses) as a means of determining the minimum current amplitude required to induce a seizure with ECT (bilateral, right unilateral, bifrontal, and frontomedial electrode placements) and MST (round coil on vertex) in nonhuman primates. Furthermore, we investigated a novel method of predicting this amplitude-titrated seizure threshold (ST) by a non-convulsive measurement of motor threshold (MT) using single pulses delivered through the ECT electrodes or MST coil. Average STs were substantially lower than conventional pulse amplitudes (112–174 mA for ECT and 37.4% of maximum device amplitude for MST). ST was more variable in ECT than in MST. MT explained 63% of the ST variance and is hence the strongest known predictor of ST. These results indicate that seizures can be induced with less intense electric fields than conventional ECT that may be safer; efficacy and side effects should be evaluated in clinical studies. MT measurement could be a faster and safer alternative to empirical ST titration for ECT and MST.

Mouse models are widely used in studies of various forms of transcranial electric stimulation (TES). However, there is limited knowledge of the electric field distribution induced by TES in mice, and computational models to estimate this distribution are lacking. This study examines the electric field and current density distribution in the mouse brain induced by TES. We created a high-resolution finite element mouse model incorporating ear clip electrodes commonly used in mouse TES to study, for example, electroconvulsive therapy (ECT). The electric field strength and current density induced by an ear clip electrode configuration were computed in the anatomically realistic, inhomogenous mouse model. The results show that the median electric field strength induced in the brain at 1 mA of stimulus current is 5.57 V/m, and the strongest field of 20.19 V/m was observed in the cerebellum. Therefore, to match the median electric field in human ECT at 800 mA current, the electrode current in mouse should be set to approximately 15 mA. However, the location of the strongest electric field in posterior brain regions in the mouse does not model well human ECT which targets more frontal regions. Therefore, the ear clip electrode configuration may not be a good model of human ECT. Using high-resolution realistic models for simulating TES in mice may guide the establishment of appropriate stimulation parameters for future in vivo studies.

Rodent models are valuable for preclinical examination of novel therapeutic techniques, including transcranial magnetic stimulation (TMS). However, comparison of TMS effects in rodents and humans is confounded by inaccurate scaling of the spatial extent of the induced electric field in rodents. The electric field is substantially less focal in rodent models of TMS due to the technical restrictions of making very small coils that can handle the currents required for TMS. We examine the electric field distributions generated by various electrode configurations of electric stimulation in an inhomogeneous high-resolution finite element mouse model, and show that the electric field distributions produced by human TMS can be approximated by electric stimulation in mouse. Based on these results and the limits of magnetic stimulation in mice, we argue that the most practical and accurate way to model focal TMS in mice is electric stimulation through either cortical surface electrodes or electrodes implanted halfway through the mouse cranium. This approach could allow much more accurate approximation of the human TMS electric field focality and strength than that offered by TMS in mouse, enabling, for example, focal targeting of specific cortical regions, which is common in human TMS paradigms.

We have proposed that the current amplitude in electroconvulsive therapy (ECT) be lowered to produce stimulation closer to the neural activation threshold and individualized to account for anatomical variability across patients. A novel approach to individualize the ECT current amplitude could be via motor threshold (MT) determination with transcranial electric stimulation (TES) applied through the ECT electrodes instead of the fixed high current approach. This study derives an estimate of the electric field (E-field) neural activation threshold and tests whether individual differences in TES MT are explained by anatomical variability measurements and simulations in individual head models. The E-field distribution induced by a right unilateral (RUL) ECT electrode configuration was computed in subject-specific finite element head models of four nonhuman primates (NHPs) for whom MT was measured. By combining the measured MTs and the computed E-field maps, the neural activation threshold is estimated to be 0.45 ± 0.07 V/cm for 0.2 ms stimulus pulse width. The individual MT was correlated with the electrode-to-cortex distance under the superior electrode (R(2)=.96, p=.022) as well as with the simulated electrode-current/induced-E-field ratio (R(2)=.95, p=.026), indicating that both anatomical measurements and computational models could predict the individual current requirements for transcranial stimulation. These findings could be used with realistic human head models and in clinical studies to explore novel ECT dosing paradigms, and as a new noninvasive means to determine individual dosage requirement with ECT.

This study examines the characteristics of the electric field induced in the brain by electroconvulsive therapy (ECT) with individualized current amplitude. The electric field induced by bilateral (BL), bifrontal (BF), right unilateral (RUL), and frontomedial (FM) ECT electrode configurations was computed in anatomically realistic finite element models of four nonhuman primates (NHPs). We generated maps of the electric field strength relative to an empirical neural activation threshold, and determined the stimulation strength and focality at fixed current amplitude and at individualized current amplitudes corresponding to seizure threshold (ST) measured in the anesthetized NHPs. The results show less variation in brain volume stimulated above threshold with individualized current amplitudes (16-36%) compared to fixed current amplitude (30-62%). Further, the stimulated brain volume at amplitude-titrated ST is substantially lower than that for ECT with conventional fixed current amplitudes. Thus individualizing the ECT stimulus current could compensate for individual anatomical variability and result in more focal and uniform electric field exposure across different subjects compared to the standard clinical practice of using high, fixed current for all patients.

Study objectives We attempted to prevent the development of working memory (WM) impairments caused by sleep deprivation using fMRI-guided repetitive transcranial magnetic stimulation (rTMS). Novel aspects of our fMRI-guided rTMS paradigm included the use of sophisticated covariance methods to identify functional networks in imaging data, and the use of fMRI-targeted rTMS concurrent with task performance to modulate plasticity effects over a longer term. Design Between-groups mixed model. Setting TMS, MRI, and sleep laboratory study. Participants 27 subjects (13 receiving Active rTMS, and 14 Sham) completed the sleep deprivation protocol, with another 21 (10 Active, 11 Sham) non-sleep deprived subjects run in a second experiment. Interventions Our previous covariance analysis had identified a network, including occipital cortex, which demonstrated individual differences in resilience to the deleterious effects of sleep deprivation on WM performance. Five Hz rTMS was applied to left lateral occipital cortex while subjects performed a WM task during 4 sessions over the course of 2 days of total sleep deprivation. Measurements and results At the end of the sleep deprivation period, Sham sleep deprived subjects exhibited degraded performance in the WM task. In contrast, those receiving Active rTMS did not show the slowing and lapsing typical in sleep deprivation, and instead performed similarly to non- sleep deprived subjects. Importantly, the Active sleep deprivation group showed rTMS-induced facilitation of WM performance a full 18 hours after the last rTMS session. Conclusions Over the course of sleep deprivation, these results indicate that rTMS applied concurrently with WM task performance affected neural circuitry involved in WM to prevent its full impact.

Transcranial direct current stimulation (tDCS) is a noninvasive neuromodulation technique where weak direct current is administered through electrodes placed on the subject's head. Transcranial magnetic stimulation (TMS) is a noninvasive method for focal brain stimulation where small intracranial currents are induced by a pulsed magnetic field. TMS can be applied simultaneously with tDCS to probe brain excitability or to effect synergistic neuromodulation. Delivering TMS simultaneously with tDCS can induce electric current pulses in the tDCS electrodes even when the tDCS device is turned off or is set to 0 mA output, as long as the electrodes are connected to the tDCS current source. The output impedance of commercial tDCS devices is in the range of 2–5 kΩ which can allow substantial currents to be induced by TMS. In a rat TMS-tDCS setup, the induced currents are comparable to the tDCS current magnitude. To mitigate the induced currents, the area of the loop formed by the tDCS electrode leads should be minimized and the impedance of the tDCS circuit at TMS pulses frequencies (1–10 kHz) should be maximized.

This study investigates the stimulation strength and focality of electroconvulsive therapy (ECT) with individualized current amplitude in a nonhuman primate (NHP) model. We generated an anatomically realistic finite element model of a NHP head incorporating tissue heterogeneity and white matter conductivity anisotropy based on structural magnetic resonance imaging (MRI) and diffusion tensor MRI data. The electric field spatial distributions of three conventional ECT electrode placements (bilateral, bifrontal, and right unilateral) and an experimental frontomedial electrode configuration were simulated. We calibrated the electric field maps relative to an empirical neural activation threshold and evaluated the stimulation strength and focality of the various ECT electrode configurations with individualized current amplitudes corresponding to the motor threshold and seizure threshold assessed in the anesthetized NHP. Understanding the stimulation strength and focality of various forms of ECT could provide insight into the mechanisms of therapeutic seizure induction, and could provide support for the clinical investigation of ECT with individualized current amplitude as an intervention with potentially improved risk/benefit ratio.

The input-output (IO) curve of cortical neuron populations is a key measure of neural excitability and is related to other response measures including the motor threshold which is widely used for individualization of neurostimulation techniques, such as transcranial magnetic stimulation (TMS). The IO curve parameters provide biomarkers for changes in the state of the target neural population that could result from neurostimulation, pharmacological interventions, or neurological and psychiatric conditions. Conventional analyses of IO data assume a sigmoidal shape with additive Gaussian scattering that allows simple regression modeling. However, careful study of the IO curve characteristics reveals that simple additive noise does not account for the observed IO variability. We propose a consistent model that adds a second source of intrinsic variability on the input side of the IO response. We develop an appropriate mathematical method for calibrating this new nonlinear model. Finally, the modeling framework is applied to a representative IO data set. With this modeling approach, previously inexplicable stochastic behavior becomes obvious. This work could lead to improved algorithms for estimation of various excitability parameters including established measures such as the motor threshold and the IO slope, as well as novel measures relating to the variability characteristics of the IO response that could provide additional insight into the state of the targeted neural population.

The goal of this study is to investigate the influence of white matter conductivity anisotropy on the electric field strength induced by electroconvulsive therapy (ECT). We created an anatomically-realistic finite element human head model incorporating tissue heterogeneity and white matter conductivity anisotropy using structural magnetic resonance imaging (MRI) and diffusion tensor MRI data. The electric field spatial distributions of three conventional ECT electrode placements (bilateral, bifrontal, and right unilateral) and an experimental electrode configuration, focal electrically administered seizure therapy (FEAST), were computed. A quantitative comparison of the electric field strength was subsequently performed in specific brain regions of interest thought to be associated with side effects of ECT (e.g., hippocampus and in-sula). The results show that neglecting white matter conductivity anisotropy yields a difference up to 19%, 25% and 34% in electric field strength in the whole brain, hippocampus, and insula, respectively. This study suggests that white matter conductivity anisotropy should be taken into account in ECT electric field models.

The goal of this study is to investigate the regional distribution of the electric field (E-field) strength induced by electroconvulsive therapy (ECT), and to contrast clinically relevant electrode configurations through finite element (FE) analysis. An FE human head model incorporating tissue heterogeneity and white matter anisotropy was generated based on structural magnetic resonance imaging (MRI) and diffusion tensor MRI (DT-MRI) data. We simulated the E-field spatial distributions of three standard ECT electrode placements [bilateral (BL), bifrontal (BF), and right unilateral (RUL)] and an investigational electrode configuration [focal electrically administered seizure therapy (FEAST)]. A quantitative comparison of the E-field strength was subsequently carried out in various brain regions of interests (ROIs) that have putative role in the therapeutic action and/or adverse side effects of ECT. This study illustrates how the realistic FE head model provides quantitative insight in the biophysics of ECT, which may shed light on the differential clinical outcomes seen with various forms of ECT, and may guide the development of novel stimulation paradigms with improved risk/benefit ratio.

The safety of transcranial magnetic stimulation (TMS) in patients with an implanted deep brain stimulation (DBS) systems has not been thoroughly investigated. One potential safety hazard is the induction of significant voltages in the subcutaneous leads in the scalp that could result in unintended electrical currents in the DBS electrode contacts. We measured ex-vivo the TMS-induced voltages and currents in DBS electrodes with the implantable pulse generator (IPG) set in various modes of operation. We show that voltages as high as 100 V resulting in currents as high as 83 mA can be induced in the DBS leads by a TMS pulse in all IPG modes. These currents are an order of magnitude higher than the normal DBS pulses, and could result in tissue damage. When the IPG is turned off, electrode currents flow only if the TMS-induced voltage exceeds 5 V.

The safety of electroconvulsive therapy (ECT) in patients who have deep brain stimulation (DBS) implants represents a significant clinical issue. A major safety concern is the presence of burr holes and electrode anchoring devices in the skull, which may alter the induced electric field distribution in the brain. We simulated the electric field using finite-element method in a five-shell spherical head model. Three DBS electrode anchoring techniques were modeled, including ring/cap, microplate, and burr-hole cover. ECT was modeled with bilateral (BL), right unilateral (RUL), and bifrontal (BF) electrode placements and with clinically-used stimulus current amplitude. We compared electric field strength and focality among the DBS implantation techniques and ECT electrode configurations. The simulation results show an increase in the electric field strength in the brain due to conduction through the burr holes, especially when the burr holes are not fitted with nonconductive caps. For typical burr hole placement for subthalamic nucleus DBS, the effect on the electric field strength and focality is strongest for BF ECT, which runs contrary to the belief that more anterior ECT electrode placements are safer in patients with DBS implants.

We present a quantitative comparison of two metrics-neural stimulation strength and focality-in electrocon-vulsive therapy (ECT) and magnetic seizure therapy (MST) using finite-element method (FEM) simulation in a spherical head model. Five stimulation modalities were modeled, including bilateral ECT, unilateral ECT, focal electrically administered seizure therapy (FEAST), and MST with circular and double-cone coils, with stimulation parameters identical to those applied in clinical practice. We further examine the effect on the stimulation metrics of individual-, sex- and age-related variability in tissue layer thickness and conductivity. Neural stimulation by MST is shown to be more focal and superficial than ECT. This result suggests that it may be advantageous to reduce the current used in ECT. The stimulation strength in MST is also less sensitive to variations in head geometry and tissue conductivity than in ECT. Individualization of pulse amplitude in both ECT and MST could compensate for anatomical variability, which could lead to more consistent clinical outcomes.

We briefly summarized several new stimulation techniques. There are many new methods of human brain stimulation, including modification of already known methods and brand-new methods. In this article, we focused on theta burst stimulation (TBS), repetitive monophasic pulse stimulation, paired- and quadri-pulse stimulation, transcranial alternating current stimulation (tACS), paired associative stimulation, controllable pulse shape TMS (cTMS), and deep-brain TMS. For every method, we summarized the state of the art and discussed issues that remain to be addressed.