Nanthia A. Suthana - US grants

Project Summary/Abstract Decades of research and clinical observations have established that episodic memory, the ability to remember recently experienced events, depends on the hippocampus and associated structures in the medial temporal lobe (MTL), including entorhinal, perirhinal and parahippocampal cortices [1, 2]. It is thought that the neuronal mechanisms supporting episodic memory for spatial context involves place and grid cells found in the MTL that increase in firing rate when an animal is in a specific location during navigation [3-7]. Furthermore, successful formation and retrieval of spatial memory is thought to be dependent upon the integration of MTL structures through coordinated oscillatory activity related to spike timing dependent plasticity [8-15]. The proposed project will investigate the relationship between spatial navigation, human memory, oscillatory activity, and spatially selective cells using intracranial single-unit and local field potential (LFP) recordings in humans. We will examine patients who are implanted with the Neuropace Responsive Neurostimulator (RNS®) or DEPTH electrodes for clinical evaluation and treatment of epilepsy. The RNS device will allow us to stimulate and record LFP activity from the MTL during real world and virtual reality (VR) spatial navigation using simultaneous full body motion capture and immersive VR headset technology. The DEPTH electrodes will allow us to stimulate and record single-unit and LFP activity during immersive VR spatial navigation. Together these studies will have access to over 30 subjects over the project period through an interdepartmental collaboration among clinical and basic science leaders at UCLA. Since our studies address basic questions about the role of oscillations and single neurons in memory, it is anticipated that such basic studies will contribute to bridging of findings between species and laying the scientific foundation for helping future patients with diseases where memory is impaired such as Alzheimer's disease and epilepsy.

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.

Project Summary/Abstract Accumulating evidence from studies in rodents suggests that emotional reactions to threatening stimuli rely on neurophysiological changes within an anxiety-processing network that includes the medial prefrontal cortex (mPFC), basolateral amygdala (BLA), and ventral hippocampus (vHPC) [1]. Since rodent studies often use laboratory animal models (similar to healthy humans) it is unclear whether findings will translate to the human mPFC-BLA-vHPC network especially in individuals with various levels of anxiety such as post-traumatic stress disorder (PTSD) or generalized anxiety disorder (GAD). The proposed project will implement a first-of-its-kind platform for intracranial electroencephalographic (iEEG) recording and intracranial electrical stimulation (iES) of mPFC-BLA-vHPC oscillatory activity during laboratory and naturalistic fear-based tasks using immersive virtual reality (VR) technology and wearable biometric sensors capable of recording physiology (eye-blinks, heart rate variability [HRV], skin conductance response [SCR], and pupil size). Through an interdisciplinary collaboration between UCLA and the Veteran?s Administration Greater Los Angeles Healthcare System (VAGLAHS) the proposed project will have access to 80 epilepsy participants implanted with mPFC, BLA, and/or vHPC depth electrodes with varying levels of dysregulatory anxiety-related processing. Since our studies address basic questions about the role of mPFC-BLA-vHPC oscillations in human fear and anxiety, the results will bridge findings across species and lay the scientific foundation for helping future patients with debilitating anxiety disorders.

Project Summary/Abstract Alzheimer?s Disease (AD) affects millions of people in the US and worldwide, and is becoming an increased burden on individual and society. Individuals with amnestic mild cognitive impairment (aMCI) are at greater risk for development of AD. A reliable method of treatment for individuals with aMCI could help not only to improve the lives of elderly individuals with memory impairment, but also potentially prevent or delay the development of AD. Theta burst transcranial magnetic stimulation (TBS) is a non-invasive neuromodulation method that shows promise for improving memory and may be applied to brain areas that are functionally connected to the hippocampus in order to restore memory function. Because the ability to apply stimulation to modify memory functions depends on the application of stimulation at distinct and specific sites in the complex neuronal circuitry underlying these functions, neuroimaging guided targeting of TBS treatment will provide individualized tailoring of therapeutic intervention needed for maximum efficacy. The proposed project will therefore implement a novel high-resolution functional magnetic resonance imaging (fMRI) guided TBS method to improve hippocampal-cortical connectivity and consequent episodic memory in elderly aMCI individuals with and without genetic risk for AD. Functional MRI, scalp electroencephalography (EEG), and genetic testing will also be used to characterize brain network changes and genetic factors that are associated with TBS related memory restoration. The implications of TBS related memory restoration to patients affected with disorders of memory is of great significance and of urgent need. The proposed project will therefore develop a novel method for memory enhancement, characterize associated brain changes, contribute to the understanding of hippocampal-cortical networks and their role in memory, and ultimately provide a novel therapeutic approach to human memory disorders. The data from this project will demonstrate a proof-of-concept that TBS can be used to improve memory in aMCI, and will launch an emerging and pivotal area of research that will provide therapeutic interventions for patients afflicted with life debilitating cognitive disorders.