Andrew, R. David - Queen's University - Department of Biomedical and Molecular Sciences

个人简介

My lab is currently studying how our higher brain is incredibly susceptible to global ischemia (as during sudden heart failure), while our brainstem is dramatically resistant. This is best demonstrated by the tragic development of the `persistent vegetative state` where a brain-injured patient is awake but not aware...because only their lower brain is functioning. Studying how the lower brain resists damage should reveal clues as to why our higher brain is so susceptible to injury.

研究领域

My interest in Neuroscience developed while carrying out electron microscopical studies comprising my M.Sc. studies at the University of Western Ontario. Subsequently during Ph.D. research at York University in Toronto, I utilized electrical stimulation of nervous tissue to increase neurohormone release as studied ultrastructurally and biochemically. From these studies I decided to learn more about neurophysiological techniques as research tools. As a post-doc at the Tulane Medical School with Dr. Ed Dudek, I studied the electrophysiology of mammalian neuroendocrine cells and used live hippocampal slices to examine electrotonic coupling among neurons. This approach continued in my own lab, evolving into neurophysiological studies of neuronal swelling caused when neurons are osmotically challenged, become hyperactive (as during epilepsy) or are metabolically challenged (as during stroke). Recording intracellularly from neurons or astrocytes (or extracellularly from neuronal populations) can be combined with simultaneous imaging techniques. For example, imaging light transmittance through live brain slices is a dramatic way to monitor tissue swelling and injury. More recently I have been using 2-photon scanning laser confocal microscopy that reveals volume changes and damage to single neurons and glial in real time. Individual brain cells can be imaged in transgenic rodents engineered so that a few cells are dramatically fluorescent on a dark background in the live state. We have been particularly interested in how neurons and glia respond during the early period of simulated stroke or head trauma. We can then assess potentially therapeutic drugs that reduce or prevent acute neuronal injury. One particular research interest is a phenomenon termed cortical spreading depression (CSD), a migrating depolarization of brain cells that can be imaged in neocortical and hippocampal brain slices. Spreading depression underlies the aura (e.g. flashing lights or numbness) preceding migraine headache and may actually be a cause of migraine pain, rather than just a symptom. Related is a process similar to CSD termed ischemic or anoxic depolarization (AD). As soon as cortical tissue experiences severe metabolic stress (as during stroke or head trauma), AD generation contributes even more stress, damaging neurons wherever it propagates. AD-like events (peri-infarct depolarizations, PIDs) recur and expand brain damage in the hours following stroke or brain trauma. We are currently investigating drugs that reduce such damage in brain slices by blocking the AD. They also inhibit CSD and likely PIDs in vivo. I consider that inhibiting these spreading depolarizations as a key target for potentially improving patient outcome following brain injury, rather than the textbook explanation that blames excessive glutamate release (excitotoxicity). My lab is currently demonstrating that our higher brain is susceptible to global ischemia, while our brainstem is dramatically resistant, despite the fact that all regions are equally lose their blood flow http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0096585. This provides an explanation as to why the brain-injured patient often enters a `persistent vegetative state`: the subject is left with only a functioning hypothalamus and brainstem and so is awake but not aware. We propose that this is because the higher brain has developed a `shutdown` mode (i.e., spreading depolarization) to bypass epileptiform and seizure activity immediately following brain injury. This induces a lie-low response to brain injury that has several advantageous. For example, movement attracting attention immediately post-injury is suppressed.

近期论文

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Andrew RD. (2016). Spreading depression is weak or absent in the rodent lower brain. J Cerebral Blood Flow and Metabolism. In press. Spong KE, Andrew RD, Robertson RM (2016). Mechanisms of spreading depolarization in vertebrate and insect central nervous systems. J Neurophysiol; published ahead of print June 22, 2016, doi:10.1152/jn.00352.2016 Dreier JP…Andrew RD…et al. (2016). Recommendations of the COSBID study group on recording and analysis of spreading depolarizations in neurointensive care. J Cerebral Blood Flow and Metabolism DOI:10.1177/0271678X16654496. Hartings JA…Andrew RD et al. (2016). The continuum of spreading mass depolarizations in acute cortical lesion development: redefining Leao`s legacy. J Cerebral Blood Flow and Metabolism. In press. Hubel N, Andrew RD, Ullah G. (2016). Large extracellular space leads to neuronal susceptibility to ischemic injury in Na+/K+ pumps-dependent manner. J Computational Neuroscience. In press. Andrew RD. (2015).The Persistent Vegetative State: Evidence That the Lower Brain Survives Because Its Neurons Intrinsically Resist Ischemia. M.M. Monti, W.G. Sannita (eds.), Brain Function and Responsiveness in Disorders of Consciousness,© Springer International Publishing Switzerland 2016 DOI 10.1007/978-3-319-21425-2_10