Subsecond multichannel magnetic control of select neural circuits in freely moving flies.

Precisely timed activation of genetically targeted cells is a powerful tool for the study of neural circuits and control of cell-based therapies. Magnetic control of cell activity, or 'magnetogenetics', using magnetic nanoparticle heating of temperature-sensitive ion channels enables remote, non-invasive activation of neurons for deep-tissue applications and freely behaving animal studies. However, the in vivo response time of thermal magnetogenetics is currently tens of seconds, which prevents precise temporal modulation of neural activity. Moreover, magnetogenetics has yet to achieve in vivo multiplexed stimulation of different groups of neurons. Here we produce subsecond behavioural responses in Drosophila melanogaster by combining magnetic nanoparticles with a rate-sensitive thermoreceptor (TRPA1-A). Furthermore, by tuning magnetic nanoparticles to respond to different magnetic field strengths and frequencies, we achieve subsecond, multichannel stimulation. These results bring magnetogenetics closer to the temporal resolution and multiplexed stimulation possible with optogenetics while maintaining the minimal invasiveness and deep-tissue stimulation possible only by magnetic control.

Field Distribution of Transcranial Static Magnetic Stimulation in Realistic Human Head Model.

OBJECTIVE: The objective of this work was to characterize the magnetic field (B-field) that arises in a human brain model from the application of transcranial static magnetic field stimulation (tSMS). MATERIALS AND METHODS: The spatial distribution of the B-field magnitude and gradient of a cylindrical, 5.08 cm × 2.54 cm NdFeB magnet were simulated in air and in a human head model using the finite element method and calibrated with measurements in air. The B-field was simulated for magnet placements over prefrontal, motor, sensory, and visual cortex targets. The impact of magnetic susceptibility of head tissues on the B-field was quantified. RESULTS: Peak B-field magnitude and gradient respectively ranged from 179-245 mT and from 13.3-19.0 T/m across the cortical targets. B-field magnitude, focality, and gradient decreased with magnet-cortex distance. The variation in B-field strength and gradient across the anatomical targets largely arose from the magnet-cortex distance. Head magnetic susceptibilities had negligible impact on the B-field characteristics. The half-maximum focality of the tSMS B-field ranged from 7-12 cm3 . SIGNIFICANCE: This is the first presentation and characterization of the three-dimensional (3D) spatial distribution of the B-field generated in a human brain model by tSMS. These data can provide quantitative dosing guidance for tSMS applications across various cortical targets and subjects. The finding that the B-field gradient is high near the magnet edges should be considered in studies where neural tissue is placed close to the magnet. The observation that susceptibility has negligible effects confirms assumptions in the literature.

The development and modelling of devices and paradigms for transcranial magnetic stimulation.

Magnetic stimulation is a non-invasive neurostimulation technique that can evoke action potentials and modulate neural circuits through induced electric fields. Biophysical models of magnetic stimulation have become a major driver for technological developments and the understanding of the mechanisms of magnetic neurostimulation and neuromodulation. Major technological developments involve stimulation coils with different spatial characteristics and pulse sources to control the pulse waveform. While early technological developments were the result of manual design and invention processes, there is a trend in both stimulation coil and pulse source design to mathematically optimize parameters with the help of computational models. To date, macroscopically highly realistic spatial models of the brain, as well as peripheral targets, and user-friendly software packages enable researchers and practitioners to simulate the treatment-specific and induced electric field distribution in the brains of individual subjects and patients. Neuron models further introduce the microscopic level of neural activation to understand the influence of activation dynamics in response to different pulse shapes. A number of models that were designed for online calibration to extract otherwise covert information and biomarkers from the neural system recently form a third branch of modelling.

A Closed Formalism for Anatomy-Independent Projection and Optimization of Magnetic Stimulation Coils on Arbitrarily Shaped Surfaces.

INTRODUCTION: Transcranial magnetic stimulation (TMS) is a popular method for the noninvasive stimulation of neurons in the brain. It has become a standard instrument in experimental brain research and has been approved for a range of diagnostic and therapeutic applications. These applications require appropriately shaped coils. Various applications have been established or approved for specific coil designs with their corresponding spatial electric field distributions. However, the specific coil implementation may no longer be appropriate from the perspective of available material and manufacturing opportunities or considering the latest understanding of how to achieve induced electric fields in the head most efficiently. Furthermore, in some cases, field measurements of coils with unknown winding or a user-defined field are available and require an actual implementation. Similar applications exist for magnetic resonance imaging coils. OBJECTIVE: This work aims at introducing a complete formalism free from heuristics, iterative optimization, and ad-hoc or manual steps to form practical stimulation coils with individual turns to either equivalently match an existing coil or produce a given field. The target coil can reside on practically any sufficiently large or closed surface adjacent to or around the head. METHODS: The method derives an equivalent field through vector projection exploiting the well-known Huygens' and Love's equivalence principle. In contrast to other coil design or optimization approaches recently presented, the procedure is an explicit forward Hilbert-space vector projection or basis change. For demonstration, we map a commercial figure-of-eight coil as one of the most widely used devices and a more intricate coil recently approved clinically for addiction treatment (H4) onto a bent surface close to the head for highest efficiency and lowest field energy. RESULTS: The resulting projections are within ≤4% of the target field and reduce the necessary pulse energy by more than 40%.

Comments on "Identifiability Analysis and Noninvasive Online Estimation of the First-Order Neural Activation Dynamics in the Brain With Closed-Loop Transcranial Magnetic Stimulation".

Presents corrections to the paper, (Identifiability Analysis and Noninvasive Online Estimation of the First-Order Neural Activation Dynamics in the Brain With Closed-Loop Transcranial Magnetic Stimulation).

Salivary uric acid dynamics are associated with stress response hormones among African Americans in an urban sample.

Acute physiological responses to psychosocial stressors are a potential pathway underlying racial disparities in stress-related illnesses. Uric acid (UA) is a potent antioxidant that has been linked to disparities in stress-related illnesses, and recent research has shown that UA is responsive to acute social stress. However, an examination of the relationships between the purinergic system and other commonly measured stress systems is lacking. Here, we measure and characterize associations of salivary uric acid (sUA) with markers of hypothalamic-pituitary-adrenal (HPA) axis activation, sympathetic-adreno-medullar (SAM) axis activation, and acute inflammation. A community sample of 103 African Americans (33 male, 70 female) completed the Trier Social Stress Test to induce social-evaluative threat. Passive drool collected before, during, and after the stressor task provided salivary reactivity measures of UA (sUA), cortisol, dehydroepiandrosterone sulfate (DHEAS), salivary alpha amylase (sAA - a surrogate marker of SAM activity) and C-reactive protein (sCRP). Multiple regressions revealed that total activation of cortisol, DHEAS, and sCRP were each positively associated with higher total activation of sUA. Additionally, DHEAS reactivity was positively associated with sUA reactivity. Relationships between HPA-axis markers and sUA were especially observed among younger and male participants. Overall, findings suggest potential coordination of stress systems with sUA in response to acute stress, which may further the contributions of biological stress processes to racial health disparities.

Scalp surface estimation and head registration using sparse sampling and 3D statistical models.

Registering the head and estimating the scalp surface are important for various biomedical procedures, including those using neuronavigation to localize brain stimulation or recording. However, neuronavigation systems rely on manually-identified fiducial head targets and often require a patient-specific MRI for accurate registration, limiting adoption. We propose a practical technique capable of inferring the scalp shape and use it to accurately register the subject's head. Our method does not require anatomical landmark annotation or an individual MRI scan, yet achieves accurate registration of the subject's head and estimation of its surface. The scalp shape is estimated from surface samples easily acquired using existing pointer tools, and registration exploits statistical head model priors. Our method allows for the acquisition of non-trivial shapes from a limited number of data points while leveraging their object class priors, surpassing the accuracy of common reconstruction and registration methods using the same tools. The proposed approach is evaluated in a virtual study with head MRI data from 1152 subjects, achieving an average reconstruction root-mean-square error of 2.95 mm, which outperforms a common neuronavigation technique by 2.70 mm. We also characterize the error under different conditions and provide guidelines for efficient sampling. Furthermore, we demonstrate and validate the proposed method on data from 50 subjects collected with conventional neuronavigation tools and setup, obtaining an average root-mean-square error of 2.89 mm; adding landmark-based registration improves this error to 2.63 mm. The simulation and experimental results support the proposed method's effectiveness with or without landmark annotation, highlighting its broad applicability.

Transcranial magnetic stimulation input-output curve slope differences suggest variation in recruitment across muscle representations in primary motor cortex.

Measurement of the input-output (IO) curves of motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS) can be used to assess corticospinal excitability and motor recruitment. While IO curves have been used to study disease and pharmacology, few studies have compared the IO curves across the body. This study sought to characterize IO curve parameters across the dominant and non-dominant sides of upper and lower limbs in healthy participants. Laterality preferences were assessed in eight healthy participants and IO curves were measured bilaterally for the first dorsal interosseous (FDI), biceps brachii (BB), and tibialis anterior (TA) muscles. Results show that FDI has lower motor threshold than BB which is, in turn, lower than TA. In addition, both BB and TA have markedly shallower logarithmic IO curve slopes from small to large MEP responses than FDI. After normalizing these slopes by their midpoints to account for differences in motor thresholds, which could result from geometric factors such as the target depth, large differences in logarithmic slopes remain present between all three muscles. The differences in slopes between the muscles could not be explained by differences in normalized IO curve spreads, which relate to the extent of the cortical representation and were comparable across the muscles. The IO curve differences therefore suggest muscle-dependent variations in TMS-evoked recruitment across the primary motor cortex, which should be considered when utilizing TMS-evoked MEPs to study disease states and treatment effects.

Reduced Auditory Perception and Brain Response with Quiet TMS Coil.

BACKGROUND: Electromagnetic forces in transcranial magnetic stimulation (TMS) coils generate a loud clicking sound that produces confounding auditory activation and is potentially hazardous to hearing. To reduce this noise while maintaining stimulation efficiency similar to conventional TMS coils, we previously developed a quiet TMS double containment coil (qTMS-DCC). OBJECTIVE: To compare the stimulation strength, perceived loudness, and EEG response between qTMS-DCC and a commercial TMS coil. METHODS: Nine healthy volunteers participated in a within-subject study design. The resting motor thresholds (RMTs) for qTMS-DCC and MagVenture Cool-B65 were measured. Psychoacoustic titration matched the Cool-B65 loudness to qTMS-DCC pulsed at 80, 100, and 120% RMT. Event-related potentials (ERPs) were recorded for both coils. The psychoacoustic titration and ERPs were acquired with the coils both on and 6 cm off the scalp, the latter isolating the effects of airborne auditory stimulation from body sound and electromagnetic stimulation. The ERP comparisons focused on a centro-frontal region that encompassed peak responses in the global signal. RESULTS: RMT did not differ significantly between the coils, with or without the EEG cap on the head. qTMS-DCC was perceived to be substantially quieter than Cool-B65. For example, qTMS-DCC at 100% coil-specific RMT sounded like Cool-B65 at 34% RMT. The general ERP waveform and topography were similar between the two coils, as were early-latency components, indicating comparable electromagnetic brain stimulation in the on-scalp condition. qTMS-DCC had a significantly smaller P180 component in both on-scalp and off-scalp conditions, supporting reduced auditory activation. CONCLUSIONS: The stimulation efficiency of qTMS-DCC matched Cool-B65, while having substantially lower perceived loudness and auditory-evoked potentials. Highlights: qTMS coil is subjectively and objectively quieter than conventional Cool-B65 coilqTMS coil at 100% motor threshold was as loud as Cool-B65 at 34% motor thresholdAttenuated coil noise reduced auditory N100 and P180 evoked response componentsqTMS coil enables reduction of auditory activation without masking.

Social status moderates the relationship between facial structure and aggression.

A growing body of evidence has linked individual differences in facial structure-in particular, the facial width-to-height ratio (FWHR)-to social behaviors, including aggression, cheating, and nonreciprocation of trust. In the research reported here, we extended this work by demonstrating that the association between FWHR and aggression is moderated by subjective and objective measures of social status. In Study 1 (N = 237 college students), FWHR was positively correlated with aggressive behavior, but only among men reporting relatively low social status. In Study 2 (N = 891 professional hockey players), FWHR was positively correlated with penalty minutes, but only among players who earned relatively low salaries. Collectively, these studies provide compelling evidence for the role of social status in moderating the relationship between facial structure and aggression, indicating that FWHR is a robust predictor of aggressive behavior, but only in the context of relatively low social status.

Three novel methods for determining motor threshold with transcranial magnetic stimulation outperform conventional procedures.

Objective. Thresholding of neural responses is central to many applications of transcranial magnetic stimulation (TMS), but the stochastic aspect of neuronal activity and motor evoked potentials (MEPs) challenges thresholding techniques. We analyzed existing methods for obtaining TMS motor threshold and their variations, introduced new methods from other fields, and compared their accuracy and speed.Approach. In addition to existing relative-frequency methods, such as the five-out-of-ten method, we examined adaptive methods based on a probabilistic motor threshold model using maximum-likelihood (ML) or maximuma-posteriori(MAP) estimation. To improve the performance of these adaptive estimation methods, we explored variations in the estimation procedure and inclusion of population-level prior information. We adapted a Bayesian estimation method which iteratively incorporated information of the TMS responses into the probability density function. A family of non-parametric stochastic root-finding methods with different convergence criteria and stepping rules were explored as well. The performance of the thresholding methods was evaluated with an independent stochastic MEP model.Main Results. The conventional relative-frequency methods required a large number of stimuli, were inherently biased on the population level, and had wide error distributions for individual subjects. The parametric estimation methods obtained the thresholds much faster and their accuracy depended on the estimation method, with performance significantly improved when population-level prior information was included. Stochastic root-finding methods were comparable to adaptive estimation methods but were much simpler to implement and did not rely on a potentially inaccurate underlying estimation model.Significance. Two-parameter MAP estimation, Bayesian estimation, and stochastic root-finding methods have better error convergence compared to conventional single-parameter ML estimation, and all these methods require significantly fewer TMS pulses for accurate estimation than conventional relative-frequency methods. Stochastic root-finding appears particularly attractive due to the low computational requirements, simplicity of the algorithmic implementation, and independence from potential model flaws in the parametric estimators.

Identifiability Analysis and Noninvasive Online Estimation of the First-Order Neural Activation Dynamics in the Brain With Closed-Loop Transcranial Magnetic Stimulation.

BACKGROUND: Neurons demonstrate very distinct nonlinear activation dynamics, influenced by the neuron type, morphology, ion channel expression, and various other factors. The measurement of the activation dynamics can identify the neural target of stimulation and detect deviations, e.g., for diagnosis. This paper describes a tool for closed-loop sequential parameter estimation (SPE) of the activation dynamics through transcranial magnetic stimulation (TMS). The proposed SPE method operates in real time, selects ideal stimulus parameters, detects and processes the response, and concurrently estimates the input-output (IO) curve and the first-order approximation of the activated neural target. OBJECTIVE: To develop a method for concurrent SPE of the first-order activation dynamics and IO curve with closed-loop TMS. METHOD: First, identifiability of an integrated model of the first-order neural activation dynamics and IO curve is assessed, demonstrating that at least two IO curves need to be acquired with different pulse widths. Then, a two-stage SPE method is proposed. It estimates the IO curve by using Fisher information matrix (FIM) optimization in the first stage and subsequently estimates the membrane time constant as well as the coupling gain in the second stage. The procedure continues in a sequential manner until a stopping rule is satisfied. RESULTS: The results of 73 simulation cases confirm the satisfactory estimation of the membrane time constant and coupling gain with average absolute relative errors (AREs) of 6.2% and 5.3%, respectively, with an average of 344 pulses (172 pulses for each IO curve or pulse width). The method estimates the IO curves' lower and upper plateaus, mid-point, and slope with average AREs of 0.2%, 0.7%, 0.9%, and 14.5%, respectively. The conventional time constant estimation method based on the strength-duration (S-D) curve leads to 33.3% ARE, which is 27.0% larger than 6.2% ARE obtained through the proposed real-time FIM-based SPE method in this paper. CONCLUSIONS: SPE of the activation dynamics requires acquiring at least two IO curves with different pulse widths, which needs a controllable TMS (cTMS) device with adjustable pulse duration. SIGNIFICANCE: The proposed SPE method enhances the cTMS functionality, which can contribute novel insights in research and clinical studies.

Closed-loop optimal and automatic tuning of pulse amplitude and width in EMG-guided controllable transcranial magnetic stimulation.

This paper proposes an efficient algorithm for automatic and optimal tuning of pulse amplitude and width for sequential parameter estimation (SPE) of the neural membrane time constant and input-output (IO) curve parameters in closed-loop electromyography-guided (EMG-guided) controllable transcranial magnetic stimulation (cTMS). The proposed SPE is performed by administering a train of optimally tuned TMS pulses and updating the estimations until a stopping rule is satisfied or the maximum number of pulses is reached. The pulse amplitude is computed by the Fisher information maximization. The pulse width is chosen by maximizing a normalized depolarization factor, which is defined to separate the optimization and tuning of the pulse amplitude and width. The normalized depolarization factor maximization identifies the critical pulse width, which is an important parameter in the identifiability analysis, without any prior neurophysiological or anatomical knowledge of the neural membrane. The effectiveness of the proposed algorithm is evaluated through simulation. The results confirm satisfactory estimation of the membrane time constant and IO curve parameters for the simulation case. By defining the stopping rule based on the satisfaction of the convergence criterion with tolerance of 0.01 for 5 consecutive times for all parameters, the IO curve parameters are estimated with 52 TMS pulses, with absolute relative estimation errors (AREs) of less than 7%. The membrane time constant is estimated with 0.67% ARE, and the pulse width value tends to the critical pulse width with 0.16% ARE with 52 TMS pulses. The results confirm that the pulse width and amplitude can be tuned optimally and automatically to estimate the membrane time constant and IO curve parameters in real-time with closed-loop EMG-guided cTMS.

Writing about justice and injustice: Complex effects on affect, performance, threat, and biological responses to acute social stress among african American women and men.

OBJECTIVE: Brief, culturally-tailored, and scalable stress coping interventions are needed to address a broad range of stress-related health disparities, including among African Americans. In this study, we develop two brief justice writing interventions and demonstrate a methodological approach for evaluating how prompting African Americans to think about justice and injustice can alter responses to acute social stress. METHODS: African American women and men were randomized to a neutral writing condition or one of two justice-based writing interventions, which prompted them to recall past experiences of personal justice - with (adjunctive injustice) or without (personal justice-only) recalling and writing about injustice. Participants then completed a modified Trier Social Stress Test, during which they received feedback on poor performance. We measured cognitive performance, affect, and perceived threat in response to task feedback. We also measured blood pressure and salivary cortisol stress responses. RESULTS: Men experienced more positive emotion, performed better on the stressor task, and were less threatened by poor performance feedback in the personal justice-only condition. Men also had lower systolic blood pressure reactivity in the justice writing conditions compared to control. Women experienced less positive emotion, performed worse on the stressor task, and were more threatened by feedback in the personal justice-only condition. Women also had lower cortisol recovery after the stressor task in the adjunctive injustice condition. CONCLUSION: Thinking about justice and injustice may alter performance, affect, threat, and biological responses to acute social stress. Still, gender differences highlight that justice thinking is likely to produce heterogeneous and complex stress coping responses among African Americans.

Optimized monophasic pulses with equivalent electric field for rapid-rate transcranial magnetic stimulation.

Objective.Transcranial magnetic stimulation (TMS) with monophasic pulses achieves greater changes in neuronal excitability but requires higher energy and generates more coil heating than TMS with biphasic pulses, and this limits the use of monophasic pulses in rapid-rate protocols. We sought to design a stimulation waveform that retains the characteristics of monophasic TMS but significantly reduces coil heating, thereby enabling higher pulse rates and increased neuromodulation effectiveness.Approach.A two-step optimization method was developed that uses the temporal relationship between the electric field (E-field) and coil current waveforms. The model-free optimization step reduced the ohmic losses of the coil current and constrained the error of the E-field waveform compared to a template monophasic pulse, with pulse duration as a second constraint. The second, amplitude adjustment step scaled the candidate waveforms based on simulated neural activation to account for differences in stimulation thresholds. The optimized waveforms were implemented to validate the changes in coil heating.Main results.Depending on the pulse duration and E-field matching constraints, the optimized waveforms produced 12%-75% less heating than the original monophasic pulse. The reduction in coil heating was robust across a range of neural models. The changes in the measured ohmic losses of the optimized pulses compared to the original pulse agreed with numeric predictions.Significance.The first step of the optimization approach was independent of any potentially inaccurate or incorrect model and exhibited robust performance by avoiding the highly nonlinear behavior of neural responses, whereas neural simulations were only run once for amplitude scaling in the second step. This significantly reduced computational cost compared to iterative methods using large populations of candidate solutions and more importantly reduced the sensitivity to the choice of neural model. The reduced coil heating and power losses of the optimized pulses can enable rapid-rate monophasic TMS protocols.

The Road Not Taken: What Developmental Psychology Might Learn From Darwin's Insights Concerning Sexual Selection.

Developmental Psychology is the branch of psychology that studies, not only human behavior, but how and why human behavior changes over time. This essay seeks to review to what extent Developmental Psychology has failed to perceive human behavior through the lens of evolutionary theory in general, and in particular sexual selection as first described by Darwin and later elaborated on by many, including Robert Trivers and Geoffrey Miller; the essay asserts that this failure has resulted in many wrong turns and missed opportunities. In some cases, major developmental theorists (e.g., Freud, Erikson) were bedeviled by sex-based differences which they saw but could not explain and which compromised the parsimony of their stage theories. In the case of stage theories of moral development, some major theorists (e.g., Piaget, Kohlberg) were able to offer simpler explanations of moral development only by limiting their studies to male subjects. And, while Developmental Psychology textbooks thoroughly describe sex differences in the timing of morphological changes in puberty, writers seldom discuss why the timing is different in the two sexes, universally, and functionally. On the other hand, several domains of developmental focus, including play, mate choice, parenting, and spatial cognition, have seen successful research efforts that utilized sexually selected predispositions as foundational assumptions. The essay concludes with a discussion of how a more evolutionary and functional view of human behavior might move the field of Developmental Psychology to an even more robust and accurate understanding of how humans change over the course of a lifetime.

Detection of motor-evoked potentials below the noise floor: rethinking the motor stimulation threshold.

Objective. Motor-evoked potentials (MEPs) are among the most prominent responses to brain stimulation, such as supra-threshold transcranial magnetic stimulation and electrical stimulation. Understanding of the neurophysiology and the determination of the lowest stimulation strength that evokes responses requires the detection of even smaller responses, e.g. from single motor units. However, available detection and quantization methods suffer from a large noise floor. This paper develops a detection method that extracts MEPs hidden below the noise floor. With this method, we aim to estimate excitatory activations of the corticospinal pathways well below the conventional detection level.Approach. The presented MEP detection method presents a self-learning matched-filter approach for improved robustness against noise. The filter is adaptively generated per subject through iterative learning. For responses that are reliably detected by conventional detection, the new approach is fully compatible with established peak-to-peak readings and provides the same results but extends the dynamic range below the conventional noise floor.Main results. In contrast to the conventional peak-to-peak measure, the proposed method increases the signal-to-noise ratio by more than a factor of 5. The first detectable responses appear to be substantially lower than the conventional threshold definition of 50µV median peak-to-peak amplitude.Significance. The proposed method shows that stimuli well below the conventional 50µV threshold definition can consistently and repeatably evoke muscular responses and thus activate excitable neuron populations in the brain. As a consequence, the input-output (IO) curve is extended at the lower end, and the noise cut-off is shifted. Importantly, the IO curve extends so far that the 50µV point turns out to be closer to the center of the logarithmic sigmoid curve rather than close to the first detectable responses. The underlying method is applicable to a wide range of evoked potentials and other biosignals, such as in electroencephalography.

A formalism for sequential estimation of neural membrane time constant and input-output curve towards selective and closed-loop transcranial magnetic stimulation.

Objective.To obtain a formalism for real-time concurrent sequential estimation of neural membrane time constant and input-output (IO) curve with transcranial magnetic stimulation (TMS).Approach.First, the neural membrane response and depolarization factor, which leads to motor evoked potentials with TMS are analytically computed and discussed. Then, an integrated model is developed which combines the neural membrane time constant and IO curve. Identifiability of the proposed integrated model is discussed. A condition is derived, which assures estimation of the proposed integrated model. Finally, sequential parameter estimation (SPE) of the neural membrane time constant and IO curve is described through closed-loop optimal sampling and open-loop uniform sampling TMS. Without loss of generality, this paper focuses on a specific case of commercialized TMS pulse shapes. The proposed formalism and SPE method are directly applicable to other pulse shapes.Main results.The results confirm satisfactory estimation of the membrane time constant and IO curve parameters. By defining a stopping rule based on five times consecutive convergence of the estimation parameters with a tolerances of 0.01, the membrane time constant and IO curve parameters are estimated with 82 TMS pulses with absolute relative estimation errors (AREs) of less than 4% with the optimal sampling SPE method. At this point, the uniform sampling SPE method leads to AREs up to 16%. The uniform sampling method does not satisfy the stopping rule due to the large estimation variations.Significance.This paper provides a tool for real-time closed-loop SPE of the neural time constant and IO curve, which can contribute novel insights in TMS studies. SPE of the membrane time constant enables selective stimulation, which can be used for advanced brain research, precision medicine and personalized medicine.

Modular multilevel TMS device with wide output range and ultrabrief pulse capability for sound reduction.

Objective.This article presents a novel transcranial magnetic stimulation (TMS) pulse generator with a wide range of pulse shape, amplitude, and width.Approach.Based on a modular multilevel TMS (MM-TMS) topology we had proposed previously, we realized the first such device operating at full TMS energy levels. It consists of ten cascaded H-bridge modules, each implemented with insulated-gate bipolar transistors, enabling both novel high-amplitude ultrabrief pulses as well as pulses with conventional amplitude and duration. The MM-TMS device can output pulses including up to 21 voltage levels with a step size of up to 1100 V, allowing relatively flexible generation of various pulse waveforms and sequences. The circuit further allows charging the energy storage capacitor on each of the ten cascaded modules with a conventional TMS power supply.Main results. The MM-TMS device can output peak coil voltages and currents of 11 kV and 10 kA, respectively, enabling suprathreshold ultrabrief pulses (>8.25µs active electric field phase). Further, the MM-TMS device can generate a wide range of near-rectangular monophasic and biphasic pulses, as well as more complex staircase-approximated sinusoidal, polyphasic, and amplitude-modulated pulses. At matched estimated stimulation strength, briefer pulses emit less sound, which could enable quieter TMS. Finally, the MM-TMS device can instantaneously increase or decrease the amplitude from one pulse to the next in discrete steps by adding or removing modules in series, which enables rapid pulse sequences and paired-pulse protocols with variable pulse shapes and amplitudes.Significance.The MM-TMS device allows unprecedented control of the pulse characteristics which could enable novel protocols and quieter pulses.

Isolating two sources of variability of subcortical stimulation to quantify fluctuations of corticospinal tract excitability.

OBJECTIVE: Investigate the variability previously found with cortical stimulation and handheld transcranial magnetic stimulation (TMS) coils, criticized for its high potential of coil position fluctuations, bypassing the cortex using deep brain electrical stimulation (DBS) of the corticospinal tract with fixed electrodes where both latent variations of the coil position of TMS are eliminated and cortical excitation fluctuations should be absent. METHODS: Ten input-output curves were recorded from five anesthetized cats with implanted DBS electrodes targeting the corticospinal tract. Goodness of fit of regressions with a conventional single variability source as well as a dual variability source model was quantified using a Schwarz Bayesian Information approach to avoid overfitting. RESULTS: Motor evoked potentials (MEPs) through DBS of the corticospinal tract revealed short-term fluctuations in excitability of the targeted neuron pathway reflecting endogenous input-side variability at similar magnitude as TMS despite bypassing cortical networks. CONCLUSION: Input-side variability, i.e., variability resulting in changing MEP amplitudes as if the stimulation strength was modulated, also emerges in electrical stimulation at a similar degree and is not primarily a result of varying stimulation, such as minor coil movements in TMS. More importantly, this variability component is present, although the cortex is bypassed. Thus, it may be of spinal origin, which can include cortical input from spinal projections. Further, the nonlinearity of the compound variability entails complex heteroscedastic non-Gaussian distributions and typically does not allow simple linear averages in statistical analysis of MEPs. As the average is dominated by outliers, it risks bias. With appropriate regression, the net effects of excitatory and inhibitory inputs to the targeted neuron pathways become noninvasively observable and quantifiable. SIGNIFICANCE: The neural responses evoked by artificial stimulation in the cerebral cortex are variable. For example, MEPs in response to repeated presentations of the same stimulus can vary from no response to saturation across trials. Several sources of such variability have been suggested, and most of them may be technical in nature, but localization is missing.