The Neuroimmune Interactions in Depression, Addiction and Pain (NIDAP) Research Program has 2 main goals:
- To increase understanding of how bi-directional relations between the immune system and the central nervous system enhance susceptibility to depression and pain states, and their combined risk for prescription drug abuse
- To develop a practical approach to translating this information into clinical care.
This program seeks to bridge translational research gaps by developing novel in-vivo human research paradigms and strategies to validate results previously obtained from similar basic research studies involving neuroimmune interactions in animal models of depressive behavior and pain states. These in-vivo research strategies employ molecular neuroimaging techniques in an innovative way to study mind-body relationships in humans suffering with symptoms of pain and depression. Success with these novel research paradigms will lead to far less reliance on animal models for drug development and subsequently, to more clinically effective treatments and significant reductions in drug development time.
Until recently, in-vivo human studies of neuroimmune interactions involving the brain relied heavily on basic research in animal models and post-mortem studies in humans, with little in-vivo evidence in humans. As a consequence, when otherwise promising immune-based pharmaceuticals developed to treat human pain and depression were trialed in real-life clinical settings in humans, substantial treatment resistance (and many drug failures) occurred. Subsequent human “biomarker” studies suggest that inter-individual clinical (and biological) heterogeneity in humans often underlies treatment resistance in pain and/or depression. The traditional “one size fits all” drug treatment strategy is far more applicable to a homogeneous population than for the vast heterogeneity seen in humans with varying degrees of pain, depression, and frequent co-morbidities (e.g. prescription drug abuse, cardiovascular disease, etc.).
The approach taken in the NIDAP Research Program focuses on enhancing three critical components in pain and depression research:
- Tools/Technologies: The NIDAP Research Program develops (or adapts in an innovative manner) various stress (emotional, painful) induction PET imaging research paradigms to facilitate investigation of specific neuroimmune interactions in-vivo in humans. Examples of such paradigms include a standardized deep-tissue pain challenge, mood induction paradigm, and a novel Virtual Reality based paradigm. The novel VR paradigm leverages portable VR technologies and study-tailored scripts to facilitate in-vivo dynamic PET imaging of stress-related moderation of neuroimmune interactions in depression and pain states. These research paradigms are designed to fit within the framework of traditional neuroimaging scans using both Positron Emission Tomography (PET) and Magnetic Resonance Imaging (MRI). NIDAP has collaborated, via the Interdisciplinary PET Research Working Group, to guide local production of 2 radiotracer ligands (C11-PBR-28 and C11-Carfentanil) specifically designed to enable brain imaging of microglial density and endogenous opioid functioning. Additional work is underway in designing and testing novel research paradigms that utilize Ultra-Small Paramagnetic Iron Oxide Nanoparticles (USPIO) within a framework of Dynamic Contrast MRI imaging to quantify macrophage/dendritic cell density in peripheral tissues and of brain microglia in subjects with existing blood brain barrier disruption. Imaging (both PET and MRI) components of the program’s projects are completed within the Texas Medical Center at various partner locations including (UT MD Anderson Cancer Center, UTHealth, Houston Methodist Research Institute, Chi Baylor St. Luke’s Medical Center, and the Texas Heart Institute). Much of the program’s day-to-day activities (data processing, analyses, etc.) are completed within dedicated computing space. NIDAP houses considerable computing infrastructure with a new server grade Mac Pro (Apple, CA) including a 2.7 GHz Intel 12 core (24 threaded) Xeon E5 processor with 30 MB of L3 cache, 64 GB of RAM, 2 TB of solid state memory for active processing and analyses, Gigabit LAN connection with access to multiple TB of longer term storage space, Thunderbolt 2 expandability, and dual D300 AMD Firepro graphics processors (each with 2GB of GDDR5 VRAM) for high speed GPU processing. The MacPro is accessed within the lab via 4 Apple Displays connected directly to the console and 4 MacbookPro laptops via gigabit ethernet and wifi connections. Additional external solid state drives (connected via high speed Thunderbolt 2) provide additional 2 TB of swap space, used to process and analyze data from specific neuroimaging projects involving 1500 distinct brain scans, obtained from collaborators. The NIDAP Program makes considerable attempts to reduce those measurement errors that are often attributed to deficient research practices. To reduce biological variance attributed to temperature variation, all samples are temporarily stored and transported in a portable battery operated, programmable cooling/freezing unit. Quantification results from multiplex assays of biological proteins (particularly IL-1 family cytokines) are frequently obscured by both low detection sensitivity and substantial lab staff variability, rendering much scientific data unusable. Dr. Prossin has substantial experience with ELISA assay technique (training under Dr. Elisa Koch at the University of Michigan) and has direct access to ELISA technology both internally (Department of Psychiatry) and externally at various local facilities which he uses as needed. However, in an attempt to enhance results of biological protein assays, all protein assays are completed using individual ELISA assays. By collaborating with an external partner, who maintains a very high ELISA throughput in a single user lab, the NIDAP Research Program reduces potential confounds. These examples offer a glimpse into the attention to detail taken within the NIDAP Research Program.
- Mechanisms: Dr. Prossin’s research program seeks to understand how brain chemicals (e.g. opioid neurotransmitters), cells (e.g. microglia), and proteins (inflammatory cytokines) interact with the humoral immune system (and vice versa) to facilitate development and maintenance of depression and pain states. The NIDAP Program also seeks to understand how variance factors (specific genetic polymorphisms, sex, age, coping style, etc.) moderate various “neuroimmune” interactions during painful and emotionally stressful conditions and how these effects facilitate maintenance of negative affective states (depression, pain) and enhance risk for (or progression of) co-morbid medical illnesses (prescription drug abuse, cardiovascular disease, etc.). The dimensional approach (focusing on behavioral symptoms rather than diagnoses) taken in Dr. Prossin’s research facilitates broader application across a spectrum of psychiatric and medical illnesses (i.e. addictive behaviors, mood disorders, personality disorders, pain disorders, fibromyalgia, arthritis, heart disease, stroke, lung cancer, etc.) rather than being applied to one specific diagnosis (i.e. Major Depressive Disorder). These dimensional approaches to psychiatric/behavioral research are consistent with the thematic of new research strategies developed by the National Institute of Mental Health, making Dr. Prossin’s program an early adopter of these innovative strategies.
- Application: The NIDAP Program seeks to enhance medical precision in depression and pain states in an individualized manner. The goal of personalized medicine is to tailor delivery of healthcare to the individual patient so as to enhance treatment efficacy and reduce treatment resistance. The research paradigms developed and piloted in the NIDAP program are ideally suited to the evolving field of personalized, precision medicine. Using in vivo molecular neuroimaging strategies throughout a range of research studies, the NIDAP program is learning how to apply these technologies to guide treatment selection and delivery in a clinically meaningful and truly individualized manner. These technological advances and applications have great promise in optimizing medical precision in delivery of care to individuals with co-morbid pain and depression, specifically targeting those at greatest risk of treatment resistance and development of prescription drug abuse. To further facilitate translation into the real world clinic setting, the NIDAP utilizes direct access to an on-site treatment research clinic with adjacent on-site pharmacy resources to manage treatment trials.
Alan Prossin, M.B.B.S.
Director, Neuroimmune Interactions in
Depression, Addiction, and Pain (NIDAP)
Behavioral and Biomedical Services Building (BBSB)
1941 East Road
Houston, TX 77054