Nader Pouratian, Ph.D. - US grants

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. N/A

DESCRIPTION (provided by applicant): Blood Oxygen Level Dependent (BOLD) functional magnetic resonance imaging (fMRI) is used ubiquitously to map the human brain, both in health and disease. Instead of directly measuring neuronal activity, BOLD fMRI detects perfusion-dependent signals that are coupled to neuronal activity. The accurate interpretation of BOLD fMRI signals is compromised by an incomplete understanding of the precise relationship between electrophysiological activity, functional anatomy, and function perfusion. The overall goal of this research program is to examine the precise relationship between electrophysiology, connectivity, and BOLD fMRI signals across tasks, cortices, and disease states. Candidate: Given his solid neuroscience training, thorough general and sub-specialty (functional) neurosurgical training, and quality research experiences, Dr. Nader Pouratian has already published extensively in the field of human brain mapping. This career development and research proposal represents a natural extension of his previous work which employed multimodality imaging to characterize the etiology, limitations, and capacities of perfusion-dependent brain mapping signals in humans using fMRI, optical imaging, and electrocortical stimulation mapping (ESM). In an environment rich in imaging expertise, the immediate goals are to develop and ensure the breadth and the depth to function as THE imaging expert on a grant proposal. Specific career development goals of this proposal are (1) to gain expertise in additional brain mapping methodologies (electrocorticography and diffusion tractography) in order to become a more comprehensive and well-rounded brain mapping expert (2) to gain facility with and proficiency in complex statistics and signal and image analyses (3) to augment the candidate's fund of knowledge in advanced systems neuroscience (4) to obtain advanced training in the scientific method and (5) to ensure continued training in the ethical conduct of research. These goals will be accomplished by means of hands-on laboratory experience, mentorship and guidance of world-renowned leaders (Drs. Arthur Toga, Susan Bookheimer, Itzhak Fried, Robert Knight, and Jeffrey Ojemann) both within and outside of UCLA and dedicated coursework and seminars. The candidate's long-term research focus is devoted to the precise and accurate mapping and interpretation of human brain function that can be used both to advance systems-level characterization of motor and language systems and to develop restorative neurosurgical interventions. Environment: Research and career development activity will primarily be conducted at UCLA, which ranks among the nations top ten research universities and has a record of excellence which is attributable to a strong network of resources, research, education and collaborative opportunities. The state-of-the-art image acquisition and analysis facilities including the UCLA Laboratory of Neuro Imaging (LONI) and the Ahmanson-Lovelace Brain Mapping Center provide an unparalleled and enriched environment for career development that is particularly suited for career enhancement in the field of neuroimaging and clinical neuroscience. Research within LONI is focused on improving the understanding of the brain in health and disease by using computational approaches for the comprehensive mapping of brain structure and function. UCLA's institutional environment promises to promote the candidate to a new level of academic excellence. Research: The overriding hypothesis is that BOLD fMRI signal characteristics are determined by a complex combination of integrated electrophysiological activity (i.e., multiple field potential bands) that vary across cortices and tasks and are modulated by system capacities, limitations, and buffers. We hypothesize that functionally significant signals can be differentiated from non-specific activations based on unique response profiles and patterns of anatomic connectivity. In Specific Aim 1, we will specifically investigate the electrophysiologic basis of the spatial extent of BOLD fMRI signals across cortices, tasks, and task complexity by comparing BOLD and ECoG signals within subjects using finely-tuned motor and language tasks and multivariate analyses. We hypothesize that BOLD spatial extent is electrophysiologically-determined but dependent upon the extent of low-frequency field potential activity rather than high-frequency activity and that a neurovascular buffer exists such that not all electrophysiological changes instigate changes in perfusion. In Specific Aim 2, we critically analyze the electrophysiologic determinants of BOLD signal intensities, with detailed BOLD-ECoG comparisons designed to determine the variability of these relationships across cortices, tasks, and disease states, whether electrophysiologic and BOLD signals respect similar rules of additivity and adaptation, and how BOLD ceiling responses relate to electrophysiology. In Specific Aim 3, we address the hypothesis that functionally relevant brain mapping signals can be differentiated based on distinctive connectivity based biomarkers. Using multimodality comparisons, we will critically scrutinize the relationship between BOLD signals, ESM, DTI tractography, and BOLD and ECoG signal coherence to elucidate the role of connectivity in delineating significant BOLD fMRI activations. Summary: This career development grant combines key elements from the candidate's background and unique and outstanding institutional resources with the development of the skills required to achieve the goal of becoming an independent investigator with a locally unique Neurosurgical Brain Mapping and Restoration Lab at UCLA.

Project Summary/Abstract Action initiation and withholding are key parts of everyday behavior, and underlying these is action suppression. This includes (1) suppressing competing actions when selecting one action from alternatives (2) suppressing all responses when presented with conflicting information until a proper decision can be made and (3) suppressing a response when the environment rapidly changes indicating a pre-planned response must be stopped. The literature suggests that these three functions are supported by distinct fronto-basal ganglia (BG) circuits. Yet the evidence for this is only piecemeal as few studies simultaneously record from both cortical and subcortical regions with sufficient spatial, temporal, and spectral resolution while subjects perform multiple tasks. We hypothesize that suppression during selection, conflict and stopping involve dissociable fronto-BG circuits ? that different frontal cortical regions causally communicate with different BG regions. We will test this over-arching hypothesis by taking advantage of the unique opportunity of deep brain stimulation (DBS) surgery for Parkinson?s disease, to obtain multi-focal cortical and BG recordings across 3 action suppression tasks (self-paced movement, Eriksen Flanker task, and stop signal). We will record across multiple scales ? single unit activity, local field potentials, and fMRI - the only way to attain spatio-temporal data sufficient to test the hypothesis. In Specific Aim 1, we aim to demonstrate that spatially, temporally, and spectrally dissociable circuits mediate distinct types of action suppression using the very high spatial and temporal precision of unit activity and local field potentials (LFPs) recorded from the subthalamic nucleus (STN) and globus pallidus internus (GPi) and simultaneously recorded, spectrally rich electrocorticography (ECoG) from 3 cortical regions (pre- and primary motor, pre-supplementary motor, and right inferior frontal gyrus). In Specific Aim 2, we will use invasive brain stimulation to further characterize the separability of these fronto-BG circuits. We hypothesize that DBS-induced patterns of impairment/improvement across different suppression tasks relates to differences in fronto-BG network recruitment relative to the site of stimulation. We will use concurrent fMRI with DBS to evaluate disparate effects of DBS on brain activity across tasks. We will also examine how DBS at different STN foci evokes distinct brain networks using fMRI in patients undergoing asleep MR-guided DBS implants. These studies will guide invasive neurophysiological recordings with intraoperative stimulation during DBS surgery. In Specific Aim 3, we will adapt a dynamic biologically-grounded computational model of action choice to add an action suppression function. We will fit this model to the electrophysiological data and evaluate several computational theories of action withholding and choice. The impact is widespread, including the basic science of action regulation, the role of separate but parallel long-range human brain networks for action regulation, understanding how DBS differentially modulates action suppression functions, and ultimately for circuit-specific implants that modulate human action in various disorders.

Project Summary/Abstract The pathophysiology underlying the motor symptoms of Parkinson?s disease (PD) remains incompletely understood with recent conflicting reports of changes in neuronal activity in distinct nodes within the basal ganglia-thalamocortical (BGTC) motor circuit. A unified approach that accounts for conflicting results is needed. Emphasizing the relatively underexplored dynamic relationship between nodes in the circuit, we build upon the hypothesis that exaggerated network-level coupling is the pathophysiologic process underlying the rigidity and bradykinesia of PD by impeding effective information flow. Accordingly, we propose that modulation of network coupling is the common therapeutic mechanism across pharmacologic and surgical therapies; other physiologic sequelae are specific to the target of therapeutic intervention and account for disparate results in the literature. We will simultaneously assess cortical and subcortical physiology in relation to clinical symptoms and in response to deep brain stimulation (DBS), cortical stimulation and pharmacologic therapy in patients undergoing DBS implantation surgery. This approach enables superior investigation of spatially specific cortical phenomena compared to extraoperative studies. We propose that it is critically important to understand the functional connectivity of the extended BGTC network, including not only the motor cortex with subthalamic nucleus (STN) as most studies do, but also connectivity with globus pallidus internus (GPi, the final common output of the basal ganglia) and the supplementary motor area (SMA) and dorsal premotor cortex (PMd), which are to where pallidal-receiving thalamic regions dominantly project. Moreover, our analyses will focus on the differential physiological significance of low vs high ? oscillations with respect to normal motor function, disease, and therapeutic intervention. In Specific Aim 1, we aim to understand the clinical correlates of the untreated BGTC motor network in PD both at rest and with movement, taking specific advantage of temporal variation in disease symptomatology (as measured with objective clinical rating scales and comprehensive kinematics) with simultaneously recorded measures of network connectivity. In Specific Aim 2, we will use subcortical and cortical stimulation to specifically perturb distinct nodes in the BGTC motor network, in order to confirm that network coupling is the common mechanism underlying therapeutic brain stimulation, regardless of target, and to also identify target specific effects that can account for known clinical differences in DBS at STN vs GPi. Finally, in Specific Aim 3, we will evaluate pharmacologic modulation of the BGTC motor network, with an aim to understand the temporal relationships between symptom amelioration and network modulation. Taken together, we will significantly enhance the existing BGTC motor network wiring diagram by elucidating the role of motor network coupling in PD. Addressing this fundamental knowledge gap will facilitate therapeutic innovations, including identification of control signals that can be used for closed loop DBS as well as provide a wiring diagram of the BGTC motor circuit that could guide pharmacologic innovation.

ABSTRACT The public health burden of Treatment Resistant Depression (TRD) has prompted clinical trials of deep brain stimulation (DBS) that have, unfortunately, produced inconsistent outcomes. Potential gaps and opportunities include a need: (1) to better understand the neurocircuitry of the disease; (2) for precision DBS devices that can target brain networks in a clinically and physiologically validated manner; and (3) for greater insight into stimulation dose-response relationships. These needs are based on our overarching hypothesis that network- guided neuromodulation is critical for the efficacy of DBS in TRD. This project aims to address the unmet need of TRD patients by identifying brain networks critical for treating depression and to use next generation precision DBS with steering capability to engage these targeted networks and develop a new therapy for TRD. We use the Boston Scientific (BS) Vercise DBS system, which offers a segmented steerable lead with multiple independent current sources that allows true directional steering. Moreover, this system integrates stimulation field modeling (SFM) with MR tractography to predict network engagement. We use an innovative approach of targeting both subgenual cingulate (SGC) and ventral capsule/ventral striatum (VC/VS), which we term corticomesolimbic DBS. These targets are hubs in distinct yet partially overlapping depression networks and emerging basic science literature implicates them in bidirectional modulation of depression circuits. We also apply a paradigm-shifting approach using intracranial stereo-EEG (sEEG) subacutely after DBS implant to evaluate the clinical reliability of steering, SFMs, and tractography and to define and then target the networks mediating symptoms of depression. In Aim 1, in the Epilepsy Monitoring Unit (EMU), we investigate the capability of Vercise to selectively engage distinct brain networks and compare the spatial distribution of evoked network activity and modulation with that predicted by SFM and tractography. In Aim 2, we conduct further studies in the EMU to delineate depression-relevant networks and show behavioral changes with network-targeted stimulation. We use a variety of tasks to probe different symptom domains and novel assessment tools (Computerized Adaptive Testing and Automated Facial Affect Recognition) to enhance classification and model algorithms to optimize stimulation patterns. In Aim 3, we bring the results from Aims 1 and 2 together, to test the therapeutic potential of corticomesolimbic DBS in 12 subjects with TRD, with a focus on safety, feasibility, and preliminary efficacy in a 8-month open label trial with a subsequent randomized, blinded withdrawal of stimulation to assess efficacy. The impact of this proposal includes physiological validation of current ?steering? DBS technology to target specific networks, insights into effects of stimulation parameters on network physiology, an improved understanding of the pathophysiology of depression, and, perhaps most importantly, a novel approach for treating TRD. This research will also pioneer a novel and high-yield test bed for DBS therapy development consistent with BRAIN priorities.

ABSTRACT The overarching goal of this project is to secure, link, and disseminate BRAIN Initiative data, including electrophysiology, imaging, behavioral, and clinical data with all pertinent recording and imaging parameters, coming from participating sites. Our plan for a Data Archive for the Brain Initiative (DABI) is in response to RFA-MH-17-255. The Laboratory of Neuro Imaging (LONI) at USC has established itself as a hub for delivering effective informatics and analytics solutions in the context of big data for major projects in the study of a range of neurological diseases. LONI has demonstrated and proven experience with variations in data descriptions, data incompleteness, and data harmonization; we have built data portals and query engines for efficient search and utilization, and we have, most importantly, enabled broad data (re-)use toward accelerated discovery. Just as the ADNI (http://adni.loni.usc.edu/) project has been a powerful catalyst for success in biomarker research in Alzheimer's disease, this project has the power to foster a similar and potentially greater level of success for human neurophysiological data. Furthermore, we understand the needs of investigators who have collected these data and their concerns associated with data sharing, in addition to the privacy of the subjects from whom the data are collected. We have the extensive infrastructure in place to handle such large-scale data as well as LONI's Pipeline Processing Environment for streamlined integration of analytic tools. This platform will be designed with the flexibility to integrate input from those awarded grants to address standardization of data (RFA-MH-17-256) as well as those who design tools to interface with archives (RFA-MH-17-257). We will receive and de-identify data of various modalities from the participating sites, incorporating analysis tools previously developed at LONI and elsewhere, managing the data access systems, providing user interfaces to explore, visualize, interpret, and download the data, and provide comprehensive information about the projects and corresponding data through the public website that will be developed specifically for DABI. We aim to provide a tool for investigators that will decrease the burden of archiving the data once it has been generated. We have already created a true community by having established good communication among our group of collaborators from funded BRAIN Initiative programs. Furthermore, we will be working with industry partners that are anticipated major sources of data to specifically streamline methods for data upload from those sources.

Project Summary Blindness in the United States is a large and increasing problem. Any significant vision loss is debilitating, but profound blindness is devastating to an individual?s ability to be independent and to perform everyday tasks and activities. Hundreds of thousands of people in the United States suffer from profound blindness, and most of these currently have no hope of vision recovery. Recently, a retinal prosthesis has become available in Europe, U.S., and Canada for people with profound vision loss from Retinitis Pigmentosa, a degenerative retinal disease. This prosthesis, the Argus® II Retinal Prosthesis System, has been approved by the FDA for commercial use in these patients. However, the Argus II System can only help a small subset of people who are profoundly blind. The goal of this project is to conduct a small scale clinical study with the intent of developing the final version of a visual prosthesis to be placed in the visual cortex ? the part of the brain that processes vision. It will be based on the successful platform of the Argus II System, but modified for implant in the brain. A cortical prosthesis could help restore visual perception to many more profoundly blind people, including people who have lost their vision due to disease or damage to the eyes, optic nerve, or thalamus. This visual cortical prosthesis, called the Orion, will consist of an array of 60 electrodes that is implanted on the surface of the brain, a receiving antenna, and an electronics case. The implant will communicate wirelessly with the external equipment via a transmitting antenna. Other external components include glasses embedded with a small video camera and a video processing unit that the implanted patient wears on a belt or strap. This project will be to conduct a small early feasibility clinical trial of the device in ten people, to evaluate safety, efficacy, reliability and to conduct psychophysics characterization studies. At the end of this grant period, the cortical prosthesis will be completely developed and positioned for testing in a larger group of human subjects.

ABSTRACT The public health burden of Treatment Resistant Depression (TRD) has prompted clinical trials of deep brain stimulation (DBS) that have, unfortunately, produced inconsistent outcomes. Potential gaps and opportunities include a need: (1) to better understand the neurocircuitry of the disease; (2) for precision DBS devices that can target brain networks in a clinically and physiologically validated manner; and (3) for greater insight into stimulation dose-response relationships. These needs are based on our overarching hypothesis that network- guided neuromodulation is critical for the efficacy of DBS in TRD. This project aims to address the unmet need of TRD patients by identifying brain networks critical for treating depression and to use next generation precision DBS with steering capability to engage these targeted networks and develop a new therapy for TRD. We use the Boston Scientific (BS) Vercise DBS system, which offers a segmented steerable lead with multiple independent current sources that allows true directional steering. Moreover, this system integrates stimulation field modeling (SFM) with MR tractography to predict network engagement. We use an innovative approach of targeting both subgenual cingulate (SGC) and ventral capsule/ventral striatum (VC/VS), which we term corticomesolimbic DBS. These targets are hubs in distinct yet partially overlapping depression networks and emerging basic science literature implicates them in bidirectional modulation of depression circuits. We also apply a paradigm-shifting approach using intracranial stereo-EEG (sEEG) subacutely after DBS implant to evaluate the clinical reliability of steering, SFMs, and tractography and to define and then target the networks mediating symptoms of depression. In Aim 1, in the Epilepsy Monitoring Unit (EMU), we investigate the capability of Vercise to selectively engage distinct brain networks and compare the spatial distribution of evoked network activity and modulation with that predicted by SFM and tractography. In Aim 2, we conduct further studies in the EMU to delineate depression-relevant networks and show behavioral changes with network-targeted stimulation. We use a variety of tasks to probe different symptom domains and novel assessment tools (Computerized Adaptive Testing and Automated Facial Affect Recognition) to enhance classification and model algorithms to optimize stimulation patterns. In Aim 3, we bring the results from Aims 1 and 2 together, to test the therapeutic potential of corticomesolimbic DBS in 12 subjects with TRD, with a focus on safety, feasibility, and preliminary efficacy in a 8-month open label trial with a subsequent randomized, blinded withdrawal of stimulation to assess efficacy. The impact of this proposal includes physiological validation of current ?steering? DBS technology to target specific networks, insights into effects of stimulation parameters on network physiology, an improved understanding of the pathophysiology of depression, and, perhaps most importantly, a novel approach for treating TRD. This research will also pioneer a novel and high-yield test bed for DBS therapy development consistent with BRAIN priorities.

PROJECT SUMMARY/ABSTRACT General anesthesia (GA) is a pharmacologically-induced state of unresponsiveness and unconsciousness which millions of people experience every year. Despite its ubiquity, a clear and consistent picture of the brain circuits mediating consciousness and responsiveness has not emerged. Assertions from non-invasive human studies (i.e. EEG and brain imaging), modeling and animal studies implicate key cortical and subcortical brain areas (including cortex, thalamus, and basal ganglia (BG)) during anesthesia. However, studies to date are limited by the lack of direct recordings in humans from both cortical and subcortical regions with sufficient spatial, temporal, and spectral resolution during pharmacologically-induced anesthesia. Our overall hypothesis is that the mesocircuit model of consciousness, which was original proposed to characterize recovery after brain injury, can be generalized to understand mechanisms of consciousness more broadly. The current research proposal focuses on experimentally probing the mesocircuit in neurosurgical patients, taking advantage of differences in patient populations with respect to basal ganglia disease (e.g., Parkinson disease [PD] vs essential tremor [ET]), the ability to synchronously acquire high resolution BG and cortical neurophysiology, and the opportunity to modulate the circuit in a targeted fashion with deep brain stimulation (DBS) to interrogate brain-behavior relationships. We pursue three specific aims: Aim 1: To demonstrate that patients with underlying basal ganglia pathology are more sensitive to propofol than other patients. Specifically, we will use target-controlled infusion of propofol to characterize pharmacokinetic-pharmacodynamic parameters in patients with PD and ET to gain insights into the potential role of BG circuitry in regulating consciousness, bearing on our more generalized model of mesocircuit mediation of consciousness. Aim 2: To correlate temporal evolution of basal ganglia-frontoparietal cortical circuit dynamics with behavioral correlates of induction and emergence from propofol anesthesia. We will use high spatial, temporal, and spectral resolution recordings in human subjects to provide direct evidence of circuit function, temporal evolution, causal circuit flow, and brain-behavior correlates. Aim 3: To evaluate the effects of targeted mesocircuit DBS (including both globus pallidus internus and externus) on propofol induced loss and recovery of consciousness and responsiveness. The research is innovative in its use of natural variations in neurological disease and concurrent invasive recording and stimulation in humans with a mechanistic and causal study design. The proposed research is significant because it will demonstrate a complex interplay of cortical and subcortical networks with partially separable effects of anesthesia, contrary to the most common clinical approach of measuring a single, continuously scaled metric for depth of anesthesia. This program will provide important human data to shed light on the generalizability of the mesocircuit model of regulating consciousness as well as validate a human experimental model for further investigation and characterization of anesthetic effects on the human brain.

ABSTRACT (Parent Grant) Chronic low back pain (CLBP) is one of the most ubiquitous and intractable problems in medicine and a significant source of patient suffering and disability, leading to opioid misuse and addiction. Previous neuromodulatory therapies for CLBP have focused primarily on spinal etiologies and intra-spinal mechanisms of pain transmission. However, existing pharmacological and neuromodulatory therapies have not been successful in treating CLBP. Potential gaps and opportunities include: (1) a need to better understand the brain networks underlying CLBP, (2) development of DBS devices that can better target the specific brain networks underlying CLBP in a safe and clinically testable manner, and (3) identification of neuroimaging biomarkers of response to DBS for CLBP. Pain can be separated into sensory, cognitive and affect components. Growing neuroimaging evidence shows that chronic pain is associated with widespread changes in brain circuits mediating these components with particular pathological overrepresentation of the affective component. The current proposal aims to address these critical gaps and the unmet therapeutic needs of CLBP patients by using a next- generation DBS device with directional steering capability to engage networks known to mediate the affective component of CLBP. We will use the Abbott Infinity? DBS System, which offers segmented electrodes capable of providing directional current steering technology. In addition, we will utilize patient- specific probabilistic tractography to target the subgenual cingulate cortex (SCC) in order to engage the major fiber pathways mediating the affective component of chronic pain. The SCC region demonstrates structural connectivity to downstream brain structures also known to be involved in the affective component of chronic pain, and DBS of the SCC has been previously shown to improve affect in patients with intractable depression. The objective of this application is to propose an exploratory first-in-human clinical trial of SCC DBS for the treatment of medically refractory CLBP which leverages our multidisciplinary expertise and technical skills. Specifically, we propose the following aims in order to carry out this trial: (1) Assess the preliminary efficacy of DBS of the SCC in the treatment of medically refractory CLBP; (2) Demonstrate the safety and feasibility of SCC DBS for CLBP; and (3) Develop diffusion tensor imaging (DTI)-based blueprints of response to SCC DBS for CLBP. The overall impact of this proof-of-concept pilot trial includes validation of the concept that suffering from CLBP results from pathological activity in affective brain networks, that these networks can be accurately engaged using a next-generation directional DBS device in a safe and feasible manner, and the discovery of neuroimaging biomarkers of response to SCC DBS for CLBP.

Project Summary/Abstract The BRAIN Initiative has made a significant investment in invasive human neuroscientific studies that take advantage of unique neurosurgical opportunities to study basic human neuroscience without therapeutic intent. These non-therapeutic studies are of particular ethical interest due to uncertainty and disagreement about when such studies should be allowed, particularly with respect to risk/benefit assessments. Such ethical issues arise since (1) these investigations expose participants to additional risks beyond that of therapeutic surgery, (2) these risks cannot be offset by any expectation of direct therapeutic benefit, (3) the neurological sequelae may be more consequential than harm to other organs, (4) the rarity of the investigative techniques results in uncertainty of the actual risks, and (5) the benefits or value of such investigations are not explicitly obvious, and given the rapid growth of this field, it may become increasingly unclear what knowledge we should value going forward as society. We hypothesize (i) that patient-participants living with disabling disorders have a unique and valuable perspective on the risks and worth of such research, (ii) that such judgements may contrast with those of investigators and the general public based on differing life experience, and (iii) that understanding these different judgments can advance the ethical design of future studies and critically broaden the field?s discussion of valuing the individual risks against the social benefit of the research. In Aim 1, we seek to understand patient-participant perspectives on risks, benefits, and permissibility of such trials. This population may have unique perspectives based on their history of chronic neurologic disease, which may uniquely influence their assessment of risks and value. We will interview patients across studies with varying degrees of invasiveness to elucidate a wide range of experiences and to evaluate the impact of invasiveness on the relevant perspectives. In Aim 2, we elucidate alternate perspectives from investigators (physicians, engineers, neuroscientists and others) as well as the public, to assess how differing social, life, and occupational experiences impact risk and benefit assessments This data and data from aim 1 will provide a wide-ranging set of comparative narratives about perceptions of risks, benefits, and the evaluations thereof. In Aim 3, we will elucidate perspectives from all three populations on the limits of the risks, benefits, and social worth of future research. Are there limits to what future scientific goals should be pursued with evolving technology in non-therapeutic studies? To address these aims, we bring together a multidisciplinary team of clinicians, ethicists, and psychologists to explore the diverse social values that inform risk/benefit assessments. The proposal is enhanced by an environment with a strong history and current portfolio of non-therapeutic invasive human neuroscientific studies across multiple investigators. Impact. Our goal is to characterize how different stakeholder values can and should be incorporated in the design and assessment of future non-therapeutic invasive human neurophysiological studies, with the anticipation that such perspectives will lead to more consistent, socially inclusive, and ethically rigorous risk/benefit assessments.

We seek sponsorship from the NIH to support the establishment of an innovative and successful training hub in neurotechnology at UCLA ? the UCLA Training in Neurotechnology Translation (TNT) - integrating multidisciplinary expertise in basic, translational, and clinical neurosciences and engineering. The increasing burden of neurologic disease is projected to be significant; it is anticipated that neurotechnology, like prosthetics, imaging, and other devices, will be integral to meeting this unmet need. The overall mission of TNT is to train a new generation of neuroscientists and engineers who will be leaders in the field of translational neurotechnology who have expertise in the longitudinal process of translating technology from bench-to-bedside in clinical neurosciences. The training program builds on the belief that successful translational neuroscientists of the future will require not only mastery of science, but will require specific knowledge and experience in fundamental issues related to translation, including experimental and trial design, statistics, regulatory processes and hurdles, and the business aspects of neurotechnology translation. The specific objectives for TNT include: (1) Understanding the spectrum of translational neurotechnology research (2) Becoming experts in the longitudinal process of clinical translation (3) Learning how to define clinical needs and practicalities for translational research (4) Training in scientific rigor (5) Training in regulatory pathways and business of science, including communication and (6) Exposure and understanding of industry perspectives and regulatory and business hurdles in translational neurotechnology. The program will integrate exposure across disciplines, with key activities in training including: (1) Mentored research in the field of neurotechnology (2) Clinical immersion experience (3) Dual mentorship by a scientist and clinician (4) TNT Seminar Series (5) Core coursework in scientific rigor and the responsible conduct of research (6) Participation in campus-based innovation and/or translational activity and (7) Submission of an individual funding application. At the core of the training program is a multidisciplinary faculty from 13 departments across three schools at UCLA with a strong record of funding, publication, and training success. The training experience is complemented by commitment by multiple industry partners to participate in and provide educational opportunities for trainees. TNT will train 3 predoctoral and 3 postdoctoral trainees (2-year appointment). TNT is both complementary to, and participatory in, existing programs in neurosciences, engineering, innovation, and translation already well established at UCLA.