Angel V. Peterchev, Ph.D. - US grants

[unreadable] DESCRIPTION (provided by applicant): This proposal responds to PA-06-278 (Neurotechnology Research, Development, and Enhancement) which calls for "significant enhancement of existing technologies ... to study the brain or behavior in basic or clinical research." We present a novel device design that substantially expands the functionality of transcranial magnetic stimulation (TMS) as a noninvasive probe of brain function with therapeutic potential by introducing continuous user-control of pulse shape. TMS modulates brain activity through the induction of cerebral currents by brief magnetic pulses. TMS has demonstrated significant antidepressant effects, but the dosing parameters associated with the best clinical outcome have yet to be identified and optimized. Although neural response is known to be highly sensitive to the shape of the stimulating pulse, existing TMS devices allow only limited control over stimulus waveform. Conventional TMS devices induce sinusoidal-exponential cerebral current pulses, while studies suggest that rectangular pulses will be more efficient. Further, high-frequency TMS devices used in clinical applications induce bidirectional current flow, while research suggests that unipolar currents would be more effective. Finally, pulse width is known to influence the efficiency of stimulation, but this parameter cannot be controlled in conventional TMS devices. We aim to design, simulate, implement, bench test and characterize a novel TMS device with controllable pulse shape (cTMS), capable of inducing approximately rectangular, predominately unipolar cerebral currents with controllable pulse width and shape. The cTMS device switches the stimulating coil between a positive and a negative capacitor bank, using newly available high-power semiconductor devices. We present simulations supporting the feasibility of the cTMS system, and the increased efficiency of rectangular pulses. The first TMS device with rectangular pulse shape with controllable width and directionality will facilitate optimization of TMS as a probe of brain function and as a potential therapeutic intervention more closely matched to the physiology of the human brain. TMS holds promise for studying and treating psychiatric and neurological illnesses such as depression and schizophrenia, but its effectiveness has been constrained in part by device limitations. The proposed electronic device expands the functionality of this technique, helping to bring its substantial clinical therapeutic potential to fruition. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): This translational project will develop a novel framework to optimize the dosing of seizure therapies for the treatment of medication resistant disorders. Despite advances in antidepressant interventions, none has replaced electroconvulsive therapy (ECT) in its acute efficacy and spectrum of action. However, ECT carries the risk of significant cognitive side effects, some of which are lasting. Major improvements in the risk/benefit ratio of ECT have been made over the past few decades, including the introduction of more focal stimulation with magnetic seizure therapy (MST), yet our knowledge of the optimal dosing of seizure therapies remains relatively rudimentary. Lacking an understanding of the biophysical and physiological mechanisms, refinements in ECT/MST technique must rely exclusively on time-consuming and costly clinical trials. Consequently, key questions remain unanswered, such as: (1) how to position the electrode or coil to TARGET stimulation to specific brain areas, (2) how best to INDIVIDUALIZE the dosage for each patient, and (3) how to OPTIMIZE stimulus parameters for efficient seizure induction. Answers to these questions could lead to substantial advances in the tolerability of the treatment and would inform clinical decision-making. Addressing this knowledge gap, we propose a new platform for the rational dosing of electric and magnetic seizure therapy that couples computational modeling with empirical validation to inform the targeting, individualization, and optimization of ECT/MST technique. This 5-year collaborative project spanning the disciplines of engineering and psychiatry entails two interrelated lines of work: computational modeling, and in vivo testing to physiologically calibrate the model and empirically determine the dynamic interaction between pulse train characteristics and seizure initiation. This proposal has 3 aims: (AIM 1) to inform TARGETING, we will simulate the strength and focality of neural stimulation as a function of ECT electrode and MST coil configuration using realistic head models calibrated through empirical neural threshold measurement in vivo;(AIM 2) to guide the INDIVIDUALIZATION of dosage, we will titrate pulse amplitude for efficient seizure induction in vivo and evaluate it as a means of controlling the focality of stimulation;and (AIM 3) to OPTIMIZE train parameters, we will empirically determine the most efficient frequency and directionality of pulse trains for seizure induction. This approach accounts for tissue conductivity and the anisotropy of white matter as measured by diffusion tensor imaging, it includes physiological calibration of field maps relative to neural activation thresholds, and it evaluates relatively ignored parameters which are central to controlling the focality and physiological action of seizure therapies. Pilot data supporting each of the aims demonstrate that lowering pulse amplitude improves focality and seizure induction is more efficient with lower frequencies and unidirectional pulse trains. This work provides a basis for rational dosing of seizure therapies that could help improve their risk/benefit ratio and guide the development of safer alternatives for severely ill patients. PUBLIC HEALTH RELEVANCE: Clinical depression affects upwards of 34 million US citizens, but only about one third of those are effectively treated with medications. For the remainder, electroconvulsive therapy (ECT) is an effective option but it carries a risk of side effects. This project couples state-of-the-art engineering methods with the latest developments in clinical psychiatry to inform the dosing of existing and novel seizure therapies so that persons with severe depression and other disabling disorders will have more effective and safer treatment options.

DESCRIPTION (provided by applicant): Transcranial magnetic stimulation (TMS) is a non-invasive method for probing and modulating human brain function. It is approved for the treatment of depression and pre-surgical cortical mapping; it also shows promise in other neurological and psychiatric disorders. Exactly what TMS does to neuronal activity, however, remains unknown. This gap in our knowledge precludes us from biologically-based, rational design of TMS protocols. To fill this gap, we need a better mechanistic understanding of the effect of TMS on cerebral neurons and a database of dose-response curves that describe how the selection of TMS parameters (the dose) relates to changes of neuronal activity (the response). Our project aims to contribute such mechanistic insight and empirical data. Our interdisciplinary team has developed a novel repertoire of tools and techniques that permit us to manipulate the TMS stimulus parameters, model the resulting electromagnetic fields and neuronal responses, and record from cerebral neurons while TMS is applied. In our first set of experiments (Aim 1), we will vary the temporal parameters of TMS. Using a custom TMS pulse generator, we will systematically change what the individual pulses look like (the pulse waveform) and how they are applied sequentially (the pulse train). Concomitant recordings in the zone of stimulation will determine how the various parameters modulate the firing rates of axons, excitatory neurons, and inhibitory neurons. Second (Aim 2), we will vary the spatial parameters of TMS using various coil locations and types of stimulation coils, including macaque-scaled approximations to conventional figure-8 coils as well as less focal coils recently approved for depression treatment (H coils). With simultaneous targeted recordings in the brain we will map the neural response in various cortical regions. In parallel to these empirical studies, we will construct individual, realistic, MRI-based head models coupled with neural response models to simulate, respectively, the electric field spatial distribution and the resultin response of various neuron types. The simulations will both guide and be informed by the empirical neural recordings, enhancing our understating of the mechanisms of TMS and providing a novel simulation tool that could inform TMS dosage. The end result of this project will be to discover how TMS influences the brain at the level of single neurons and simple circuits. The outcome should be transformative in helping researchers and clinicians to navigate the vast parametric space of TMS so that it may be used more effectively as a probe in neuroscience, and as a clinical treatment.

This project will develop a low-noise transcranial magnetic stimulation (TMS) system. TMS is a technique for non-invasive brain stimulation using strong, brief magnetic pulses. TMS is widely used as a tool for probing brain function and is an FDA approved treatment for depression. A significant limitation of TMS, however, is that the magnetic pulse delivery is associated with a loud clicking sound as high as 140 dB resulting from electromagnetic forces. The loud noise significantly impedes both basic research and clinical applications of TMS. First, it effectively makes TMS less focal since every click activates auditory cortex, brainstem, and other connected regions, synchronously with the magnetic pulse. Second, the repetitive clicking sound, both by itself or paired with synchronous activation at the TMS target site, can induce neuromodulation that can interfere with and confound the intended effects at the TMS target. Third, the clicking noise can compromise blinding of TMS studies and necessitates the use of sham conditions that replicate the sound but that could induce undesirable sound-mediated modulation effects as well. Finally, there are known safety concerns regarding hearing loss and induction of tinnitus, especially in vulnerable populations, as well as tolerability considerations, since TMS noise may contribute to headache and cause discomfort in some patients. Addressing this need, we propose a quiet TMS (qTMS) device that incorporates two key concepts: First, the dominant frequency of the TMS pulse sound (typically 2?5 kHz) will be shifted to higher frequencies that are above the human hearing upper threshold of about 20 kHz. This will be accomplished by making the magnetic pulse ultrabrief, and shaping it so that its fundamental frequency is above 20 kHz. Due to the strength?duration properties of the neural response, ultrabrief pulses require higher amplitude to achieve neural stimulation, but the total pulse energy is actually lower than for conventional pulses. Second, the TMS coil will be redesigned electrically and mechanically to generate suprathreshold electric field pulses while minimizing the sound emitted at audible frequencies (< 20 kHz). This will require the coil to sustain pulses with higher voltage and current but of briefer duration than conventional pulses, while minimizing the electromagnetic energy that is converted to and emitted as acoustic energy at frequencies below 20 kHz. The enhanced acoustic properties of the coil will be accomplished with a novel, layered coil design. We will design and build a qTMS device based on these concepts, aiming at an initial reduction of the acoustic noise of 40 dB compared to a conventional device. The neural and acoustic stimulation produced by qTMS will be characterized in bench-top measurements and a proof-of-concept human study. We present pilot data from a low-amplitude qTMS prototype already demonstrating reduction of noise by 19 dB with ultrabrief pulses, as well as data from a human study showing comparable neural activation with amplitude-adjusted brief versus long pulses. Thus, qTMS technology could enable more precise, effective, safe, and tolerable TMS.

This project will develop transcranial magnetic stimulation coils with improved focality and depth (fdTMS). TMS is a technique for noninvasive brain stimulation using strong, brief magnetic pulses. TMS is widely used in the neurosciences as a tool for probing brain function and connectivity. Presently, TMS is FDA-approved for the treatment of depression and for pre-surgical cortical mapping, and is under study for other psychiatric and neurological disorders. A significant limitation of TMS, however, is that the induced electric field stimulates a relatively large area of cortex, especially when the targets are deep. Low focality entails co-activation outside the desired target, which reduces the precision of stimulation, may increase the risk of side-effects including seizures, and may reduce efficacy via antagonistic responses. Thus, fdTMS coil technology could enable more selective, safe, and effective stimulation. Conventional TMS coil design has relied on simple heuristics to determine the shape of the coil windings. Because the winding shape is related in a complex way to the electric field induced in the brain, the spatial stimulation characteristics of available coils are generally suboptimal. Consequently, while coils intended specifically for deep TMS have been commercialized, their tradeoff between depth and focality is not better than that of conventional figure-8 and double-cone configurations. Addressing this limitation, we propose to develop fdTMS coils to obtain maximal focality for a given depth of stimulation or specific anatomical target. Unlike conventional approaches, our method specifies the required electric field characteristics in the brain and deploys novel computational optimization algorithms to determine the coil winding shape and placement to meet these specifications within practical energy limits. We present preliminary data demonstrating that for any target depth our approach outperforms existing coils with increase in focality up to 100%. Using this approach, we will design, implement, and validate two types of fdTMS coils. First, we will develop a series of general-purpose coil designs corresponding to a range of practical depths. The coils will be optimized for maximal focality in a spherical head model, reflecting the intended use for various targets and therefore being anatomy-independent. Like most conventional coils, they will be freely moveable on the head surface. Second, we will optimize coils for specific anatomical brain targets using state-of-the-art MRI-based head models. This approach accounts for the effects on the induced electric field of anatomical features such as gyral shape and current flow through the highly conducting sulci. We will validate experimentally the fdTMS coils via measurements of induced electric field maps as well as human motor responses. The human study will quantify stimulation focality and depth through mapping of muscle representations at various locations and depths in the primary motor cortex using electromyography.

The use of transcranial magnetic stimulation (TMS) as a therapeutic intervention is FDA-cleared for treating depression, obsessive-compulsive disorder, and migraine, and shows promise for a host of other brain disorders. The appeal of TMS is its safety, non-invasiveness, and well-established capacity for modulating the activity of brain regions. In human subjects, that modulation is assessed only at the gross scale of behavioral, cognitive, or aggregate physiological effects (e.g. EMG, EEG, fMRI). The fine-scale responses and mechanisms of TMS, at the level of biophysical and biological effects on neurons and circuits, remain poorly understood. This knowledge gap hinders rational design of TMS protocols and leaves researchers and clinicians dependent on trial-and-error approaches and inferences from macroscopic data to improve the methodology. The lack of reductionistic insight is particularly detrimental when targeting non-motor areas such as prefrontal cortex where a readout of the immediate neural response is unavailable, for example due to the stimulus artifact in EEG. Our overall goal is to fill in this knowledge gap by studying the neural circuit mechanisms of TMS in the non-human primate brain. The approach integrates neurophysiological experiments featuring direct single-unit and local field potential recordings and multiscale computational simulations of neural circuits in both primary motor cortex and prefrontal cortex. Aim 1 is to establish the circuit mechanisms of acute responses to single and paired TMS pulses. Determining the pulse response of single neural elements and recurrent cortical circuits permits a detailed examination of the biophysics and biology of neural recruitment at a short time scale. A main goal of TMS therapy is to achieve controlled, lasting neuromodulation, however, so in Aim 2 we will extend the same neurophysiological and modeling approaches to the study of responses to repetitive TMS (rTMS). Here the goal of the neurophysiology will be to quantify the effects of rTMS pulse trains on long-lasting changes in neural activity and, accordingly, the neural simulations will incorporate synaptic plasticity. Critically, in both Aims we will conduct the experiments and modeling both in primary motor cortex, where spinal potential recordings and electromyography can supplement direct readout of neural effects in cortex, and prefrontal cortex, where only cortical-level recordings are suited to characterize neuromodulatory effects. The overall product will be an experiment- and model-driven mechanistic understanding of the effect of TMS on cortical circuits, enabling a transformational advance in the interpretation of the effects of TMS. Taken together, the results will promote a more biologically-grounded, rational approach to designing TMS protocols for neuromodulation.

Abstract The ability to noninvasively modulate and image the brain with spatial and temporal precision is highly desirable for understanding brain circuits in health and disease. Transcranial magnetic stimulation (TMS) is a method for stimulating the superficial cortex with high spatial and temporal precision, and its effects can be aimed at deeper targets by leveraging the trans-synaptic connectivity of brain circuits. Functional magnetic resonance imaging (fMRI) has high spatial resolution but limited temporal precision, and the opposite holds for electroencephalography (EEG). These three noninvasive electromagnetic methods have recently been combined to achieve high spatial and temporal precision of concurrent modulation and imaging of the brain. This approach, however, has various significant technical limitations, including mutual electromagnetic artifacts decreasing the signal-to-noise ratio and delaying the acquisition of imaging/EEG data, TMS acoustic noise co- activating auditory pathways, and the inability to adaptively adjust the TMS coil position within the MRI scanner for optimal targeting. The overarching objective of this project is to address these limitations by developing and integrating an array of novel technologies. We will develop a compact, energy efficient, quiet, as well as MRI- and EEG-compatible TMS coil. The TMS coil will be actuated with a custom MRI-compatible robotic system, allowing adaptive optimization of the coil position and orientation based on imaging feedback. The neural circuit responses to the stimulation will be imaged with a newly developed a flexible, head-conforming array of MRI coils combining local magnetic field shimming and RF receiving to achieve high signal-to-noise ratio and fast image acquisition. The brain activity will be simultaneously recorded both before and after TMS with high temporal resolution and low noise using a novel wireless EEG system. To meet the technical challenges of creating such as a system operating inside MRI scanners, our team has developed several breakthrough technologies that will work synergistically to reduce or eliminate couplings between system components and enhance the stimulation precision and imaging speed and sensitivity. Once developed, the robotically-actuated TMS-EEG-fMRI system will enable systematic interrogation of human brain circuits inside an MRI scanner with spatial and temporal flexibility and precision that are impossible to achieve with current technology. The integrated system will be easy-to-use, and platform-agonistic thus having the potential for immediate and scalable impact. First-time adaptive optimization of the TMS coil placement in the MRI scanner will be demonstrated for brain-state-triggered engagement of a deep brain target. In summary, the proposed robotically- actuated TMS-EEG-fMRI system will enable modulation and imaging of brain circuits with enhanced anatomical and functional precision that can lead to advances in neuroscience research and therapeutic interventions.