PVARF FEATURED RESEARCHER
Dr. Miranda Lim is a Staff Physician in the Sleep Disorders Clinic at the VA Portland Health Care System, in the Division of Hospital & Specialty Medicine, Section of Pulmonary & Critical Care Medicine. She is board certified in both Neurology and Sleep Medicine. She is also an Assistant Professor of Medicine at Oregon Health & Science University, with secondary appointments in Neurology, Behavioral Neuroscience, and the Oregon Institute of Occupational Health Sciences.
Dr. Lim completed her MD/PhD at Emory University, her neurology residency at Washington University in Saint Louis, and fellowship in sleep medicine at University of Pennsylvania prior to arrival at the VA Portland in 2013 as a junior investigator. Her research program focuses on three primary areas:
1. Examine the mechanisms underlying sleep-wake disturbances in traumatic brain injury (TBI): Despite the fact that sleep-wake disturbances are highly prevalent and a major source of disability in patients with chronic TBI, the reasons for this are unknown. We established a mouse model of mild TBI that showed persistent sleep-wake disturbances, including the inability to sustain long wake bouts and increased sleep fragmentation, persisting up to 4 weeks after a single mild injury (Lim et al., 2013, Sci Transl Med). We also identified a neuropeptide system in the hypothalamus, orexin (also known as hypocretin), that was chronically impaired after mild TBI (Willie*, Lim* et al., 2012, J Neurotrauma; Lim et al., 2013, Sci Transl Med). Orexin is a relevant target because it is also implicated in human narcolepsy, which shares some clinical features of excessive daytime sleepiness in TBI.
2. Identify and evaluate novel therapeutic agents in TBI: There is a critical need for more effective treatments for the neurocognitive sequelae after TBI. As poor sleep can exacerbate memory, attention and mood, potentially some of these neurocognitive and mood symptoms could be improved by sleep interventions. We recently identified a promising new dietary therapy consisting of branched chain amino acids (BCAA: L-leucine, L-isoleucine, L-valine). Mice that received BCAA supplementation in the drinking water 48 hours after TBI showed a dramatic reversal of sleep-wake deficits (Lim et al., 2013, Sci Transl Med), as well as memory deficits in a learning task (Elkind*, Lim* et al., 2015, Front Neurol). What do BCAAs do in the brain? BCAAs are the building blocks for the excitatory neurotransmitter glutamate; we showed that they also restore functionality to orexin neurons after TBI. We are now currently collaborating on an exploratory clinical trial of BCAA therapy in sports-related concussion (Clinicaltrials.gov, NCT01860404).
3. Identify novel biomarkers for diagnosis and prognosis of TBI: One of the major challenges in advancing clinical care in mild TBI is the lack of objective diagnostic and prognostic markers which can help identify those who will continue to experience persistent disability (e.g., post-concussive syndrome). We are currently analyzing the brain electroencephalogram (EEG) during sleep and wake states in both mouse and human subjects with TBI to identify novel EEG-based markers, using quantitative EEG analyses (i.e., cross-frequency coupling). This research project was recently funded by the American Sleep Medicine Foundation.
Dr. Lim is the recipient of a VA Career Development Award entitled “Sleep-wake disturbances in traumatic brain injury.” She also is the research mentor for a post-doctoral researcher funded by the VA OAA Nursing Fellowship, Dr. Kristianna Weymann, RN, PhD, who will be conducting clinical research on Veterans with sleep disorders andTBI/PTSD.
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