“Memory Enhancement with Modeling, Electrophysiology, and Stimulation (MEMES)”
Principal Investigator: Beth Buffalo
ABSTRACT: The RAM Program seeks to develop new technologies for using brain stimulation to enhance human memory. The MEMES team seeks to achieve this goal via a diverse and experience group of neuroscientists, neurosurgeons and corporate partners that will perform theoretical and empirical studies designed to identify optimal stimulation parameters and methodologies for human memory enhancement. These parameters will be identified and refined via brain recordings in neurosurgical patients. These studies are designed to build towards the end goal of creating an implantable device that can be used by patients with memory disorders. The role of the University of Washington (PI: Elizabeth Buffalo, Ph.D.) in this research program is to oversee research studies regarding the neuronal representation of spatial knowledge in the nonhuman primate brain and the assessment of the ability of direct brain stimulation to enhance these representations. This work will be carried out via collaboration with clinical studies involving human patients, both here ate UW and with neurosurgeons and neurologists at multiple hospitals. The University of Washington’s work in this program consists of several components to support the MEMES research proposal. First, UW will adapt experimental paradigms that are designed to assess how the human brain represents spatial information for use in the nonhuman primate. Second, UW will perform neurophysiological recordings of both single units and network neural activity while monkeys perform tasks of spatial navigation in the presence and absence of direct brain stimulation. This will provide insight into the functional correlates of neural activity and reveal the neurophysiological effects of neuronal stimulation. Third, UW will collaborate with partner institutions in using the ensemble neural data obtained in monkeys to contrain and develop computational models of how direct brain stimulation might be used to alter a patient’s brain state to improve the efficiency of their memory encoding. Fourth, UW will develop and test a novel closed-loop real-time methodology for using brain stimulation to enhance spatial memory performance in monkeys. The overarching goal of all of these studies is to develop and test methodologies in nonhuman primates that can be directly translated into patients in the service of improving memory.
“Impact of cannabis on pathogenesis in treated HIV infection”
Principal Investigator: Nikki Klatt
ABSTRACT: With 35 million HIV-infected individuals worldwide, containment and eventual eradication of the AIDS pandemic remains a top priority in contemporary biomedical research. While antiretroviral therapy (ART) can improve health during HIV infection, a cure is not yet available, and despite suppression of viremia with ART, these individuals still have increased morbidity and mortality compared to uninfected individuals. Indeed, HIV-infected subjects cannot discontinue ART, because residual HIV persists, and virus rebound is inevitable if ART is terminated. The HIV reservoir is complex, and at least two mechanisms drive this latent pool of infected cells, including residual low levels of virus replication in anatomical sanctuaries (such as the gastrointestinal tract), and persistent proviral HIV DNA that is integrated into the host genome in long-lived cellular reservoirs. Furthermore, HIV is closely associated with, and potentially driven by, immune activation and inflammation during HIV infection. The pathology of disease caused by HIV infection is complex and multifaceted. In addition to high levels of systemic viral replication, HIV infection results in a vicious cycle of mucosal damage, chronic inflammation and overall immunological dysfunction, which are closely associated with disease. This chronic immune activation is strongly associated with gastrointestinal (GI) mucosal damage and microbial translocation, which do not resolve completely with ART. While there is a clear positive correlation between measures of immune activation and HIV persistence in ART-suppressed individuals, whether immune activation is a cause, a consequence or both a cause and a consequence of HIV persistence is unknown. Here, we propose a provocative approach to directly evaluate whether decreasing inflammation during ART-suppressed lentiviral infection results in a decreased HIV reservoir, using an extremely novel therapeutic concept.
“Developmental Neurotoxicity of Domoic Acid in Nonhuman Primate Model”
Principal Investigator: Tom Burbacher
Domoic Acid (DA), is a naturally-occurring biotoxin that can contaminate harvestable populations of finfish and shellfish in ocean waters. Exposure to DA is associated with a constellation of clinical symptoms that can include gastrointestinal distress, confusion, transient and permanent memory loss, coma and death. Animal studies have demonstrated a strong fetal sensitivity to this environmental toxin. The toxic algal blooms that produce DA appear to be increasing in frequency and toxicity and pose a growing threat to human health and seafood safety. Very little is known about the effects of chronic, low-dose exposure to DA, a pattern of exposure that would particularly represent coastal-dwelling indigenous communities that rely on the ocean as a vital source of food and cultural identity. Given that episodes of DA contamination are becoming more frequent, a legitimate concern arises as to whether DA may negatively affect fetal development at levels of exposure that do not product overt signs of neurotoxicity or illness in pregnant women. To elucidate the maternal and developmental neurotoxicity of Domoic Acid, we propose to conduct the first study of chronic, low-level, oral DA exposure in a nonhuman primate model with outcome measures that embrace pharmacokinetics, neuropathology, stereology, neuroimaging and neurobehavioral assessment. The results of this study will provide important information on the neurotoxic consequences of DA exposure during pregnancy and the resulting effects on infant health and development.
“CRCNS: Information processing in cerebral cortex for visual-oculomotor behavior”
(CRCNS = Collaborative Research in Computational Neuroscience)
Principal Investigator: Mike Mustari
The primate visual and oculomotor system allows tracking of small visual objects and large moving visual scenes to support optimal visual acuity and visual motor behavior. We use volitional smooth pursuit (SP) eye movements and reflex-like optokinetic (OKR) eye movements to support visual function. Both classes of tracking eye movements require cerebral cortical processing of visual inputs to create initial commands for eye movements. Volitional SP and OKR behaviors offer important perspectives on neural mechanisms that produce sensory-motor behavior, perception and cognitive processing. Our studies focus on the frontal eye fields (FEF) and parietal cortex (MSTd, MSTl, MT), which have been shown to play a role in SP, OKR and perception. However, the information passed between these areas during tracking eye movements remains unknown. Our studies will address this gap in knowledge by providing the first comparative data on visual, eye movement and task related signals carried in feedforward and feedback pathways between frontal and parietal cortex. We will apply novel computational approaches for data analysis, model the functional contributions of frontal and parietal cortex to tracking eye movements, and finally test the model predictions using electrical stimulation and optogenetic techniques to reversibly perturb signaling in this cortical-cortical network. There are extensive cortical-cortical connections between brain regions but we lack specific information about the role of these connections in complex sensory-motor behavior. Our studies are organized under 3 specific aims to experimental and computational approaches that build on information theory and related statistical methods to account for how different signals(e.g., visual, eye movement) are combined and interact to support purposeful behavior. Our experimental work provides novel neurophysiological data taken from frontal and parietal cortical neurons that we identify as projecting from one brain region to another and 2) the experimental results will be directly compared to simulations developed in computational models of cortico-cortical interaction.