Marom Bikson - US grants

[unreadable] DESCRIPTION (provided by applicant): There is a growing interest in the use of chronic deep brain stimulation (DBS) for the treatment of medically refractory movement disorders and other neurological and psychiatric conditions. Fundamental questions remain about the physiologic effects of DBS. It is also unclear what stimulation parameters are optimal for the present or future uses of DBS. Previous basic research studies have focused on the direct polarization of neuronal membranes by electrical stimulation. The proposal aims to determine if DBS can indirectly affect brain function (neuronal polarization) through: 1) joule heating of tissue; or 2) electro-permeation of the blood-brain barrier. It is well established that electric current can induce tissue heating and membrane electroporation; however, it remains unclear if the electric fields induced during clinical DBS are sufficient to induce these effects. The overall goal of the proposal is to determine the potential scale of DBS induced temperature and permeability changes by using a bio-heat transfer model and an in vitro endothelial barrier model, respectively. Even small and transient changes in brain temperature or blood-brain barrier permeability can have profound effects on neuronal function and hence on DBS efficacy or safety. This study will provide the-first insight into the role of these novel 'indirect' DBS mechanisms and thus advance improvements in clinical DBS protocols/technology. Relevance to Public Health: Deep Brain Stimulation (DBS) is a highly promising technology for the treatment of neurological disorders such as Parkinson's disease and tremor. This proposal will determine if Deep Brain Stimulation is affecting brain function by raising local temperature or changing the permeability of the blood- brain barrier. These results will improve the success and safety of DBS. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Transcranial Direct Current Stimulation (tDCS) is a non-invasive electrical stimulation technique investigated for a broad range of medical and performance indications. Understanding the cellular mechanisms of tDCS will increase the rigor of ongoing studies and provide a rational basis for dose optimization. Prior mechanistic studies have focused exclusively on direct polarization of neuronal membranes by direct current stimulation (DCS). We propose to test the hypothesis that tDCS directly and transiently modulates blood-brain-barrier (BBB) function, which in turn would modulate neuronal activity. Our approach is to use state-of-the-art animal and tissue models and characterization to determine if a new-class of cellular targets, namely endothelial cells, respond to DCS. These approaches including multi-photon transcranial quantitative imaging of vascular permeability during and after DCS and isolation of molecular and generic responses of endothelial barriers. Because understanding every cellular target of stimulation is required for a comprehensive mechanism, the modulation of BBB by tDCS, in conjunction with direct neuronal effects, is novel and critical to research. This study will be the first to establish the feasibility of direct BBB actions by tDCS as well as quantitatively predict the impact of these changes on neuronal function.

DESCRIPTION (provided by applicant): Tissue ischemia is a major cause of wound dehiscence or anastomotic leakage resulting in significant morbidity and mortality and occurs at a rate of 15 to 25%. Although measurement of systemic blood oxygenation status by pulse oximetry on the finger is a mandatory requirement for every single patient while in the hospital, there are no devices or methods available to measure tissue oxygenation following complex surgical resections and reconstructions in the operating room. Increasingly, surgical procedures are performed by minimally invasive techniques, which add complexity to the problem, as surgeons do not have the opportunity to directly touch, feel or visualize the organs. In a collaboration between The City College of New York (CCNY) bioengineering design team and Memorial Sloan-Kettering Cancer Center (MSKCC) surgeons, we have successfully designed, constructed and tested a novel wireless, handheld intraoperative oximetry (WiPOX) device, which provides real-time, accurate, and convenient intraoperative monitoring of the tissue oxygenation ensuring tissue viability thereby improving surgical outcomes, decreasing mortality, patient hospitalization and the associated costs. In this R03 proposal, based on the feedback from the ongoing clinical trial, we will enhance device performance and accuracy through two further innovations: incorporation of onboard pressure sensors to allow reliable tissue contact and enhancement of S/N through wireless integration with a systemic pulse oximeter. A pipeline for preclinical and clinical testing is in place. These innovative modifications are crucial for surgeons to take the next step of this device utility - to modify the surgical procedure based on tissue oxygenation.

Aimed at revolutionizing our understanding of the brain, the BRAIN initiative calls for ?improvement of existing non-invasive neuromodulation? techniques. There is presently great interest in transcranial Direct Current Stimulation (tDCS), which is deployable, well tolerated, and carries the promise of targeted neuromodulation. Computational models of tDCS predict individual brain current flow for a given electrode configuration (?montage?), and predict that optimized targeting montages can achieve more focal cortical stimulation. Through three innovations, this proposal removes existing barriers limiting access to computational models that will allow researchers to individually tailor electrode montages for desired cortical targets so as to optimize clinical outcomes and address specific research hypotheses. First, a decade of technical innovation in automated image segmentation and high- throughput current flow modeling will be enhanced and encoded in cloud-enabled open-source. Second, state-of-the-art MRI mapping of tDCS current distribution will validate and refine model methods. Third, stand-alone and web-based modeling client software will be deployed with computationally demanding steps implemented on servers. Only as a result of algorithmic optimization can the modeling process be divided into two steps: a cloud-based computationally intensive processing on servers, and then simulations taking just seconds by researchers using client software on conventional PC. These innovations result in a process that previously required extensive expertise and labor, super-computers and numerous iterations instead being reduced to a single step, requiring seconds on a conventional PC. In addition, we will supply the MRI protocol for in vivo mapping of tDCS current flow. In an exploratory aim, MRI mapping will test modeling predictions on deep structure targeting with tDCS. Directly responsive to the RFA, the outcome of this proposal is a toolbox for the optimization of tDCS spatial precision to enhance the rigor of tDCS research aimed at understanding the brain and for treating disease. Our approach is unique in integrating the scalability, rigor, and transparency of opens-source (server side) with highly assessable GUI control software (client side), while being exceptionally robust (e.g. non-ideal scan quality) and flexible (e.g. conventional pad or High-Definition electrodes).

PROJECT SUMMARY Transcranial Direct Current Stimulation (tDCS) is investigated to treat a broad range of brain disorders and to change cognition in healthy individuals. The scale and breadth of tDCS human trials has outpaced understanding of cellular mechanisms. The flexibility of tDCS derives from use in combination with a training task, with the goal to enhance ?neuronal capacity? for plasticity (learning) on the specific task. tDCS is thus applied either during or before a task, to produce an acute or persistent change in neural capacity. The rational advancement of tDCS as a clinical/neuroscience tool requires knowing the cellular targets of stimulation, and linking their activation with changes in neuronal capacity during and after tDCS. Neurons, and to a lesser extent glia, have been studied as tDCS cellular targets. Endothelial cells of the blood-brain barrier (BBB) have been unaddressed until recently by our team. Yet BBB function is well known to be sensitive to other forms of electrical stimulation, and that changes in BBB will alter brain function. Indeed BBB stimulation is consistent with the concept of tDCS acting to generally prime the brain (e.g. changing excitability or metabolic capacity). This proposal addresses a novel hypothesis and scientific premise for how BBB modulation may enhance neural capacity during or after tDCS. We propose that the conductive vascular network across the brain shunts current and in the process generates electric fields across the BBB higher than around neurons. We believe that BBB polarization by tDCS alters the transport of water and solutes across the BBB (during stimulation) and activates the expression of genes leading to the production of neuroactive chemicals (including NO) by the blood vessels of the BBB (after stimulation), all of which modulate the microenvironment of neurons and neuronal capacity. Given a natural bias toward interpreting any tDCS actions as reflecting direct neuron activation (and thus BBB response as secondary/epiphenomena) we require state-of-the-art modeling and experimental tools to quantify the direct stimulation of BBB by tDCS. We present substantial preliminary data from in silico, in vitro, and in vivo studies that support our overall premise. This data reflects a successful R21 collaboration by our team; having shown feasibly of a novel cellular target, this RO1 establishes the mechanism and potential impact of direct BBB activation by tDCS. Aim 1: We will develop a multi-scale (from head anatomy to micro-vasculature) multi-physics (coupling electric fields with electro-diffusion filtration transport) model. Aim 2: We will validate acute (during DCS) changes in water and molecule permeability using a specially designed in vitro BBB model system where the absence of neurons establishes a direct action of current on the BBB, as well as test the activation of nitric oxide (NO) and other neuro-active genes (neurotrophins) by DCS in the absence of neurons. Aim 3: Using multi-photon brain imaging for determining BBB permeability in a rat model, we will analyze the persistent (minutes) BBB permeability changes induced by tDCS and their dependence on NO.

[pursuant to NOT-AG-18-008 submission instructions, this Supplement Abstract reflects the relevance of the proposed research to AD/ADRD and so is updated from the parent-grant Abstract. However, the scope of the parent-grant is unchanged as funded. In the Supplement Abstract, additions from the parent grant abstract in RED] Abstract The BRAIN initiative aiming to revolutionize understanding of the brain requires ?improvement of existing non-invasive neuromodulation? (RFA-MH-16-810). Arguably no existing technique in humans has generated more interest than transcranial Direct Current Stimulation (tDCS). tDCS applications span Alzheimer's Disease and its related Dementias (AD/ADRD). For the value of ongoing and future to be maximized, computational models must be adapted to tDCS in older individuals. Computational models of tDCS predict brain current-flow in individual subjects, and support the development of targeted montages. In older adults with brain atrophies highly conducting cerebrospinal fluid fills the void and significantly alters current flow in the brain. Through three innovations, this proposal removes barriers limiting access to computational models by tDCS researcher for this population. First, a decade of technical innovation in automated image segmentation and high-throughput current-flow modeling will be enhanced and encoded in cloud- enabled open-source. Through this supplement, we will further enhance reliability in modeling older adults. Second, state-of-the-art MRI mapping of tDCS current distribution will validate and refine model methods. Through this supplement, we will empirically validate altered current flow in adults with brain atrophy. Third, stand-alone and web-based modeling software will be deployed, with computationally demanding steps implemented on servers. Ongoing and future work testing tDCS for AD/ADRD will directly benefit. Directly responsive to the parent RFA, the outcome of this proposal is a toolbox for the optimization of tDCS spatial precision to enhance the rigor of tDCS research aimed at understanding the brain and treating disease. Directly responsive to the supplement RFA, the enhancements described here will stimulate additional activity leading to progress in AD/ADRD treatments using tDCS. While the supplement focuses on AD/ADRD, the work proposed is within the scope of the active award.

Project Summary/Abstract LaGuardia Community College?s ?Bridges to the Baccalaureate Research Training Program? has demonstrated high graduation and high transfer rates for our students, conclusively demonstrating that a community college can take the lead in administering a successful Bridges program. Our program has formed a consortium with three exceptional four-year colleges?the City College of New York, Hunter College, and Queens College?to provide challenging research experiences in the biomedical and behavioral sciences for our underrepresented college students: women, minorities, the disabled, and those from economically disadvantaged backgrounds. LaGuardia proposes to place 10 students in hands-on, mentored research experiences each year of the grant period. These students will choose from a list of research projects and will be engaged in preliminary, preparatory research at LaGuardia, under the tutelage of the LaGuardia Faculty Research Mentors. This experience gained will then be utilized during the summer, as the Bridges students become involved in more intensive research at our three linking colleges, Brookhaven National Laboratories, and SUNY downstate Medical Center. The Bridges program also features a number of activities designed to support the students: monthly research student seminars, tutoring, transfer counseling, opportunities to present their research results at local and national conferences, instruction in the Responsible Conduct of Research, Rigor and Reproducibility, instructional workshops on bio-statistics, leadership and self-management skills, bioinstrumentation, research paper critique, library research, research design, data science, introduction to Python, and poster presentation and the use of ePortfolios. The ePortfolio will be used by Bridges students to collect their academic work, progress report and to reflect on their learning and career goals. The program will also offer LaGuardia faculty the opportunity to participate in effective mentoring workshop offered at the university of Wisconsin and Bridges students will also enroll in the National Research Mentoring Network (NRMN). The monthly research seminars are notable in that they feature progress reports and formal final reports by the students themselves, presentations by CUNY faculty and outside speakers, information from the program?s transfer counselor, a session on developing and delivering professional presentations using PowerPoint, and an Alumni Homecoming Day where Bridges alumni return to share their successes and research with current Bridges students. Bridges students will also use an adapted version of myIDP (Individual Development Plan) to explore careers in biomedical, sciences, and bioengineering.

Project(Summary(/(Abstract! There is a need to understand the mechanisms of neural stimulation technologies (RFA-NS-18-018). The impact of such research increases with both the clinical relevance of a neuromodulation technology and the extent mechanisms are unknown. Spinal Cord Stimulation at kHz frequencies (kHz SCS) has undergone a meteoric clinical and market rise, in the absence of an accepted mechanistic hypothesis. The most peculiar feature of kHz SCS mechanistically is that rapid biphasic stimulation undermines traditional mechanisms of electrical stimulation. But, we note this same feature of rapid pulsing results in high stimulation power leading to our hypothesis that kHz SCS increases tissue temperature. Our proposal that a clinically-established implanted electrical stimulation device would unexpectantly function by joule heating is disruptive and innovative and so requires, as the first step, to establish the degree of temperature increase during kHz SCS. To this end, our research plan develops state-of-the-art tools for multi-physics bioheat modeling (Aim 1), multi-compartment 3D- lattice phantom verification (Aim 2), and validation in a swine model (Aim 3) to methodically test the hypothesis that kHz SCS produces a 0.5-2 oC temperature rise. The multi-physics model (Aim 1) will be state-of-the-at in anatomical resolution, internal lead architecture, and the first to couple joule heat, heat conduction and convection (CSF flow), metabolism, and blood flow perfusion. The heat phantom (Aim 2) will be the first for spinal cord stimulation based on novel 3D-lattice printed compartments. The swine model (Aim 3) is selected for anatomical similarities to the human spinal cord and vertebral canal, and will include a custom fabricated combination lead/sensor array for in vivo temperature mapping. The most peculiar clinical feature of kHz SCS is lack of paresthesia, associated with conventional SCS. We will develop a dorsal horn network model of heating- based analgesia (Aim 4) by integrating experimentally validated temperature increases, pain processing network dynamics, and membrane sensitivity to temperature (Q10). We hypothesize a 0.5-2 0C temperature rise generates pain relief through the same final MoA as conventional SCS (gate-control) but without pacing associated paresthesia. RFA responsive, this ?computational model incorporates cellular heterogeneity?, specifically electrophysiological data on of excitatory vs inhibitory superficial dorsal horn interneurons, including differential responses to heating. While device design, disease models, and clinical trials are explicitly outside RFA scope, establishing a novel MoA and state-of-the-art tools developed in each Aim implicitly drive and underpin such developments. Directly RFA responsive, we ?improve understanding of the neurobiological underpinnings of existing methods and lay the foundation for the next generation technologies by developing models (Aim 1, 4), systems (Aim 2), and procedures (Aim 3) to guide the design of better neuromodulation tools?. Indeed, because the heating MoA is fundamentally innovative, new tools are needed.

Project Summary / Abstract (unchanged from original proposal, except supplement in red) There is a need to understand the mechanisms of neural stimulation technologies (RFA-NS-18-018). The impact of such research increases with both the clinical relevance of a neuromodulation technology and the extent mechanisms are unknown. Spinal Cord Stimulation at kHz frequencies (kHz SCS) has undergone a meteoric clinical and market rise, in the absence of an accepted mechanistic hypothesis. The most peculiar feature of kHz SCS mechanistically is that rapid biphasic stimulation undermines traditional mechanisms of electrical stimulation. But, we note this same feature of rapid pulsing results in high stimulation power leading to our hypothesis that kHz SCS increases tissue temperature. Our proposal that a clinically-established implanted electrical stimulation device would unexpectantly function by joule heating is disruptive and innovative and so requires, as the first step, to establish the degree of temperature increase during kHz SCS. To this end, our research plan develops state-of-the-art tools for multi-physics bioheat modeling (Aim 1), multi-compartment 3D- lattice phantom verification (Aim 2), and validation in a swine model (Aim 3) to methodically test the hypothesis that kHz SCS produces a 0.5-2 oC temperature rise. The multi-physics model (Aim 1) will be state-of-the-at in anatomical resolution, internal lead architecture, and the first to couple joule heat, heat conduction and convection (CSF flow), metabolism, and blood flow perfusion. The heat phantom (Aim 2) will be the first for spinal cord stimulation based on novel 3D-lattice printed compartments. The swine model (Aim 3) is selected for anatomical similarities to the human spinal cord and vertebral canal, and will include a custom fabricated combination lead/sensor array for in vivo temperature mapping. The most peculiar clinical feature of kHz SCS is lack of paresthesia, associated with conventional SCS. We will develop a dorsal horn network model of heating- based analgesia (Aim 4) by integrating experimentally validated temperature increases, pain processing network dynamics, and membrane sensitivity to temperature (Q10). We hypothesize a 0.5-2 0C temperature rise generates pain relief through the same final MoA as conventional SCS (gate-control) but without pacing associated paresthesia. While device design, disease models, and clinical trials are explicitly outside RFA scope, establishing a novel MoA and state-of-the-art tools developed in each Aim implicitly drive and underpin such developments. Directly RFA responsive, we ?improve understanding of the neurobiological underpinnings of existing methods and lay the foundation for the next generation technologies by developing models (Aim 1, 4), systems (Aim 2), and procedures (Aim 3) to guide the design of better neuromodulation tools?. Indeed, because the heating MoA is fundamentally innovative, new tools are needed. Responsive to NOT-NS-21-014, this supplement enhances within-scope resource dissemination of the awarded 1R01NS112996 parent award by developing an open-source SCS modeling tool that predicts current flow and heating.