Tamer S. Ibrahim - US grants

DESCRIPTION (provided by applicant): This grant proposes the development and testing of a highly advanced neural interface system that incorporates the best features of modern neural interfaces into a single system. The Micro Neural Interface (MNI) system is comprised of up to 100 independent, wireless, biological sensors with on-board signal conditioning and spike detection. Each probe communicates with and is powered via a 2.4 GHz wireless RF transceiver. Individual probes can be implanted within cortical and subcortical structures. The MNI system has two operating modes: time stamp and streaming. In time stamp mode, each MNI probe is queried sequentially such that data from all probes is collected every 1000 5s. Each probe is independently programmed with two threshold settings to provide basic spike discrimination. In the streaming mode, a single probe transmits neural data that is digitized with 8 bits of resolution at 10 KHz to a basestation. This mode allows the user to examine the spike waveforms and perform manual spike sorting on an external PC, but it can address only a single probe at a time. Threshold crossings are also transmitted during the streaming mode to allow functional verification. Two specific aims are proposed for this research SA1) Development of wireless Micro-Neural Interface (MNI) probes and basestation. SA2) In-vivo testing of the MNI system in rodents. PUBLIC HEALTH RELEVANCE: Narrative The significance of this work to human health is that it will result in a highly novel neural interface design. First, the MNI system will provide researchers and potentially clinicians with unparalleled access to neural activity across cortical and subcortical structures. This access will allow scientist to understand distributed neural processing and provide a tool for more in-depth understanding of neurological disorders. Second, the MNI system may be used as a Brain Machine Interface.

DESCRIPTION (provided by applicant): The potential of magnetic resonance imaging/spectroscopy (MRI/S) for whole-body applications at high (e 3 tesla) fields and of head applications at ultrahigh (e7 tesla) fields appears to be limitless. It is;however, hindered by significant challenges including safety concerns regarding exceeding radiofrequency (RF) power deposition in tissue and large image inhomogeneity/voids due to "undesired" RF field inhomogeneity across the anatomy. It is widely accepted that parallel (multi) transmission approaches where the MRI RF coil/array is excited at multiple of its elements using, what-appear-to-be, arbitrarily RF pulses are the solutions for alleviating these challenges. The widespread implementation of these approaches into a full scale scientific and clinical research using these MRI/S systems has been hampered by significant obstacles such as significant subject-to-to-subject sensitivity, SNR losses, and unclear safety concerns regarding the assurance of the multi-transmit experiment. The objective of this work is to design and implement a new and novel class of multi-transmit RF arrays and methodologies that will make parallel-transmission approaches practical in current and future MRI scanners;enhancing their capabilities into new levels of SNR and sensitivity. We will design and implement a new multi-transmit 7 tesla head arrays that are coupled (with significant SNR enhancement and RF field overlapping,) and subject-insensitive. The performance of the proposed RF arrays are minimally affected by differences in the subjects and therefore provides safe operation and eliminates the need for RF field mapping, pre-scanning, and preparation time. To evaluate the usefulness of these arrays on practical MRI applications, we will use our multi-transmit capable 7 tesla human scanner to evaluate the visual cortex and the hippocampus and frontal lobes in the context of Alzheimer's disease. At the end of this project we will provide our findings and the designs of the subject-insensitive RF arrays and the associated RF field maps to the scientific community. As the proposed RF arrays are subject-insensitive, the designs and the RF field maps can be directly implemented on any 7 tesla human MRI system without the need for a stand alone multi-transmission capability. PUBLIC HEALTH RELEVANCE: This project will result in significant improvements in high field magnetic resonance imaging (MRI.) The project will advance the safety and performance of the MRI technology impacting research in medicine in general and in Alzheimer's disease in particular.

Project Summary/Abstract: Depression (target disease of this proposal) affects 34 million Americans including 2 million seniors per year. It is a leading cause of morbidity and mortality in older adults (target population of this proposal). The vascular depression hypothesis (proposed in 1998) remains the most salient theory explaining the onset and perpetuation of depression in older adults. This model is based on the observation that in older adults, white matter hyperintensities (a hallmark of small vessel disease, SVD) are associated with depression onset and perpetuation. Progress in understanding the relationship of small vessel disease with late-life depression has been stymied in part by lack of specificity of white matter hyperintensities which can represent components of edema, gliosis, ischemia, and inflammation. Traditional MR imaging is unable to distinguish between these components, and thus the specific mechanisms that contribute to depression remain unclear. The emergence of ultrahigh field MR imaging allows for greater specificity of the WMH lesions, and other components of small vessel disease. Bringing 7 tesla (T) imaging into mainstream clinical use will be accomplished through 1) having exclusive (over 1.5/3T) application(s) and 2) achieving robust, safe, consistent, and homogenous high-quality images. Through a consortium consisting of experts at University of Pittsburgh combined with collaboration at FDA, University of Minnesota, and Quality Electrodynamics Inc., our goal is to enhance our understanding of the neuropathophysiology, treatment, and management of depression in older adults. We will achieve this goal through the development of robust radiofrequency methodology, as well as pulse sequences that produce 7T images with the aforementioned necessary attributes. This will be paired with complementary 3T MRI at baseline. We will use our recently developed (as well as a proposed) custom designed 7T radiofrequency coil system and pulse sequences that are already being used in disease/patient studies. Based on our preliminary results, the proposed RF solution will provide unprecedented homogeneity and consistency among different subjects/patients, and therefore excellent signal to noise ratio and contrast to noise ratio for detection of components of small vessel disease. The study will examine two cohorts 1) a group of 30 older adults recruited through the Alzheimer's Disease Research Center (ADRC) for developing an MRI to histopathology statistical model of SVD and 2) 60 older adults with late-life depression who will undergo scanning at baseline and after 2 years. The longitudinal 7T MRI and SVD model will be used to help characterize the small vessel changes associated with depression in older adults. In summary, this study develops an emerging and timely technology (high-performance ultrahigh field MRI) to study a critical pathophysiological process (cerebral small vessel disease) in a clinically relevant population (Late-Life Depression). This project will further advance all of these three domains.

ABSTRACT Through the mechanism of a pre-doctoral T32 interdisciplinary training program, the Departments of Bioengineering (BIOE) and Psychiatry at the University of Pittsburgh (UPitt) are seeking NIH support for bioengineering pre-docs to train as mental health researchers. The program is aimed at educating talented students with engineering and other quantitative sciences background for careers in mental health research. Consistent with the NIMH strategic, we envision an increasing role for quantitative and computational science in psychiatric research. The trainees (6 per year) of this program will be uniquely qualified to help lead development and use new technical bioengineering approaches to address mental health research challenges. This training program capitalizes on the breadth of bioengineering in psychiatry research at UPitt and provides students with access to the clinical presentation and treatment of psychiatric disorders. PhD trainees will take foundational courses in bioengineering, cognitive and computational neuroscience, psychopathology, and ethics and will be complemented by electives. Students are exposed to clinical environments via a longitudinal clinical experience and two 1-week intensive clinical observerships. A diverse group of research-active mentors (16 in Psychiatry and 16 in Bioengineering) comprised of basic scientists, clinicians, and engineers, serve as advisors to guide students in their doctoral research efforts where each mentee will have 2 principle co-mentors (1 in BIOE and 1 in Psychiatry). Finally, students participate in several program-specific activities throughout their graduate school years, designed to enhance interactions and exchange of information (student-student and student-faculty) and to facilitate professional and career development. Each student receives extensive research training in the laboratories of the training faculty. There are three integrated focus areas of this pre-doctoral training program: (1) Neuroimaging, (2) Neurostimulation, and (3) Neural Engineering. All of these tracks are heavily utilized in a wide variety of mental health research including mood disorder, anxiety disorder, psychotic disorder, suicide, and cognitive impairment where currently there is a critical mass of researchers at UPitt addressing these disorders. This training program will provide a unique educational and research experience aimed at training bioengineering scientists to develop careers in mental health research.

Project Summary/Abstract: There is a well-established association between small vessel disease (SVD, microangiopathy) and Alzheimer's disease (AD). The underlying mechanisms for associations between small vessels and the AD cascade remain unclear. Some of the association between SVD and AD is due to the cumulative cognitive burden from independent pathologies (AD and SVD) leading to early manifestation of the clinical syndrome of AD. It is becomingly recognized that another way in which SVD and AD are related is through bi-directional interaction at molecular and cellular levels: e.g., inflammatory factors associated with A? plaques contribute to SVD. Furthermore, an emerging hypothesis is that decreased pulsatility of small arterioles decreases cerebral spinal fluid (CSF) clearance of amyloid, putting someone at risk of AD. A better understanding of the underlying mechanisms relating SVD and AD is especially important as it can identify prevention and treatment targets. This proposed transdisciplinary (Multi-PI) proposal aims to develop advanced MRI methods (hardware, acquisition, and analysis) with 7T human imaging and study the pathways linking small vessel and CSF flow pathophysiology to AD. It will be achieved through a consortium consisting of expertise at 1) U. of Pittsburgh - MRI acquisition and analysis-, and AD; 2) FDA -RF-heating matters in relation guidelines-; 3) U. of Minnesota - MRI acquisition-; 4) Quality Electrodynamics Inc. (QED) -integration of patient friendly hardware-; and Montreal Neurological Institute -MRI analysis-. We will examine small vessel morphology, cerebrovascular reactivity (CVR), and CSF flow, all of which are inter-related components in AD pathophysiology. For instance, small vessel lesions (in part due to amyloid angiopathy) may disrupt CVR, and consequently interfere with A? clearance. The study is designed as a prospective observational study of older adults without dementia: 30 amyloid positive, and 30 amyloid negative (n = 60). We will leverage two ongoing studies (RF1AG025516 & R01AG052446) of AD pathology for recruitment, clinical characterization and PET imaging. Individuals are scanned at baseline (Aim 1) using current state of the art technology. Throughout we will work on MRI development (Aim 2). At 2-year follow up individuals will be scanned again with the same protocol as at baseline, and will also undergo scanning with the newly developed technology (Aim 3). In summary, this study develops, applies and validates advanced imaging of small vessel morphology, CVR, and CSF flow and other traditional MRI biomarkers to characterize pre-clinical AD, and potentially identify targets for prevention and/or treatment. The proposal takes advantage of recent and proposed advances in a timely and recently FDA-approved technology (7T human MRI) and collaborations between: a) scientists, engineers, and clinicians; b) leading 7T human MRI centers and a coil company; and c) a governmental regulatory agency.

SARS-CoV-2 virus displays neurotropism in some infected patients with reports of viral invasion, inflammation, meningoencephalitis, microvascular injury, stroke, delirium and delayed cognitive and psychiatric symptoms. It is unclear if there is any acceleration of neurodegenerative processes and increased risk of Alzheimer?s disease and related dementias (ADRD). Race-, ethnic- minorities and men are known to have a higher risk of dying from COVID and may also have a greater susceptibility to long-term neuropsychiatric sequelae. Ultrahigh field (7T) MRI has increased sensitivity and spatial resolution, compared to 3T MRI and can detect small changes in cortical and white matter structure, integrity and connectivity, inflammation, iron deposition, hippocampal subfields, venular injury and the locus coeruleus. The 7T MRI COVID Consortium is an international collaboration across 5 sites to enroll a diverse, multi-ethnic cohort of 780 persons, aged 55-80. Of these 260 persons will have well-documented SARS-CoV-2 infection (cases) and 260 will be ?illness? controls with a clinically similar non-COVID illness (e.g. pneumonia). Cases and controls will include >25% Hispanic and >25% African-Americans. Both groups will be compared to 260 healthy controls with documented normal cognition and no hospitalization in preceding 2 years. Additional data will be drawn from 40 persons with autosomal dominant early-onset AD and 180 population controls, all imaged with the same 7T MRI protocol. All participants will undergo 2 annual 7T MRI scans and 4 detailed exams comprising neurological, cognitive and psychiatric assessments, smell, gait, blood biomarkers of neurodegeneration (p-tau181, NFL, GFAP, amyloid) and systemic inflammation (CRP, IL6, IL10, TNF-alpha, IL1R) and surveillance for incident MCI, ADRD dementia. These exams will occur at the time of each MRI, and at 36, 48 months post-illness. We propose the following specific aims: Aim 1: Detail the range of (Aim 1a) Early (6-12 months) brain pathology in COVID survivors (Aim 1b) assess if early changes improve, persist or worsen at a delayed 7T MRI (12-18 months) and (Aim 1c) Compare findings in COVID survivors to MRI in preclinical EOAD. Aim 2: Compare cross-sectional prevalence of pre-illness ADRD and vascular injury (VCID) and of cognitive, behavioral, mood and functional outcomes across 3 groups. Aim 3: Relate early and delayed 7T MRI measures to subsequent risk of MCI, dementia and cognitive and gait trajectories. Aim 4: Explore if race/ethnic-, sex- differences, blood biomarkers, genetics, or early SARS-CoV-2 ?treatments? are effect-modifiers, mediators, or neither, of the associations noted in Aims 1-3. Investigators leading this grant are also members of other larger, less detailed COVID consortia permitting harmonized data analyses. Our study will permit a better biological understanding of mechanisms and modifiers of long-term neurological and psychiatric sequelae of COVID. It could also help illuminate the role of viral infections, inflammation and immune response in ADRD.