Note: I am not currently accepting new graduate students.
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.
In related studies, we have been exploring the origin of spreading depolarizations (SD) in the brains of mammals and insects.
This mass loss of membrane potential spreads across gray matter, quieting the brain during trauma or stroke, but also quickly leading to neuronal death. The electrical and molecular details of this mechanism have remained a mystery, but we are gaining insight not previously considered by researchers. Unravelling this story will provide considerable insight as to how to protect neurons from loss of blood flow during cardiac arrest, stroke and head trauma.
C U R R I C U L U M V I T A E (short)
NAME Robert David ANDREW
POSITIONS HELD Assistant Professor, appointed 1982
MRC Scholarship, July 1983 - June 1988
Associate Professor, appointed 1988
Tenure awarded, 1988
Professor, appointed 1993
CONTACTS Department of Biomedical and Molecular Sciences
and the Centre for Neuroscience Studies
Queen's University, Kingston, Ontario K7L 3N6.
Cell: (613) 453-1380
Office: (613) 533-2860
UNIVERSITY EDUCATION B.Sc. (Hon.), University of Western Ontario, Dept. Zoology
London, Canada, 1973.
M.Sc., University of Western Ontario, Dept. Zoology
London, Canada, 1975.
Ph.D., Dept. Biology, York University,
Toronto, Canada, 1979.
POSTDOCTORAL Post-doctoral Fellow, Dept. Zoology,
University of Toronto, Toronto, July 1979 - June 1980.
Post--doctoral Fellow, Dept. Physiology,
Tulane Medical School, New Orleans, July 1980 - August 1982.
MRC Postdoctoral Fellowship, July 1980 - June 1982
CURRENT RESEARCH SUPPORT
New Frontiers in Research Fund – Exploration Award. `The early molecular events setting up acute brain injury`.
Funded April 2021 to March 2023. $100K per year + $25K indirect costs.
NSERC Operating Grant. ‘Converting the Na/K pump into a shutdown channel’. Funded 2017-2023, $26K per year.
Heart and Stroke Foundation of Canada Operating Grant. ”Activation and opening of the channel that kills neurons during ischemia” Funded July 2019-June 2021 $96K per year. Extended to June 2022.
Currently supervising two post-docs, three MSc students and three summer project students.
Graduated a total of 1`0 doctoral students and 32 MSc students.
Supervised 32 fourth-year project students.
ANAT 312/812* Functional Neuroanatomy
NSCI 429/829* Disorders of the Nervous System - Course Coordinator
NSCI 499 Research Projects in Neuroscience
NSCI 444/844* Controversies in Neuroscience - Course Coordinator
PEER-REVIEWED PUBLICATIONS (past 10 years)
Andrew RD, Hartings JA, Ayata C, Brennan KC, Dawson-Scully KD, Farkas E, Herreras O, Kirov SA, Müller M, Ollen-Bittle N, Reiffurth C, Revah O, Robertson RM, Shuttleworth CW, Ullah G, Dreier JP. (2022). The critical role of spreading depolarizations in early brain injury: Consensus and contention. Neurocritical Care https://doi.org/10.1007/s12028-021-01429-4
Andrew RD, Farkas E, Hartings JA, Herreras O, Müller M, Kirov SA, Ayata C, Ollen-Bittle N, Brennan KC, , , , , Reiffurth C, Revah O, Robertson RM, Shuttleworth CW, Dawson-Scully KD, Ullah G, Dreier JP (2022) Questioning glutamate excitotoxicity in acute brain damage: the importance of spreading depolarization. Neurocritical Care https://doi.org/10.1007/s12028-021-01431-w
Hellas J and Andrew RD. (2021) Neuronal swelling: A non-osmotic consequence of spreading depolarization. Neurocritical Care https://doi.org/10.1007/s12028-021-01326-w.
Mehder RH, Bennett BM, Andrew RD. (2021) Age-related neuronal deterioration specifically within the dorsal hippocampus in a mouse model of late onset Alzheimer's disease. J Alzheimer`s Disease.79: 1547–1561. DOI 10.3233/JAD-201024
Ghoweria AO, Gagolewicz P, Fraziera HE, Ganta JC, Andrew RD, Bennett BM, Thibault O. (2020) Neuronal calcium imaging, excitability, and plasticity changes in the Aldh2–/– mouse model of sporadic Alzheimer’s disease. J Alzheimer`s Disease 77:1623–1637. DOI 10.3233/JAD-200617
Lowry CA, Golod ME, Andrew RD, Bennett BM (2020) Expression of neuronal Na+/K+-ATPase a subunit isoforms in the mouse brain following genetically programmed or behaviorally induced oxidative stress. Neuroscience 442: 202-215.
Shuttleworth CW, Andrew RD, Akbari Y, Ayata C, Brennan KC, et al. (2020). Which spreading depolarizations are deleterious to brain tissue? Neurocritical Care 32 (1), 317-322.doi: 10.1007/s12028-019-00776-7.PMID: 31388871
Mehder RH, Bennett BM, Andrew RD. (2020) Morphometric analysis of hippocampal and neocortical pyramidal neurons in a mouse model of late onset Alzheimer's disease. J Alzheimer`s Dis. doi: 10.3233/JAD-191067.
Robertson RM, Dawson-Scully KD, Andrew RD. (2020) Neural shutdown under stress: an evolutionary perspective on spreading depolarization. J Neurophysiol. 123(3):885-895. doi: 10.1152/jn.00724.2019. Epub 2020 Feb 5 PMID: 32023142
Petrin D, Gagolewicz PJ, Mehder RH, Bennett BM, Jin AY, Andrew RD. (2019). Spreading depolarization and neuronal damage or survival in mouse neocortical brain slices immediately and 12 hours following middle cerebral artery occlusion. J Neurophysiol.121(5): 1650-1663. PMID: 30811255
Ventura, NM, Li TY Tse, MY, Richard L, Tayade C, Jin AY, Andrew RD, Pang SC. (2018). Developmental origins of pregnancy-induced cardiac changes: Establishment of a novel model using the atrial natriuretic peptide gene-disrupted mice. Mol Cell Biochem. 2018 Dec;449(1-2):227-236. doi: 10.1007/s11010-018-3359-z.
Andrew RD, Hsieh YT, Brisson CD. (2017) Spreading depolarization triggered by elevated potassium is weak or absent in the rodent lower brain., 7-2016 (e-pub), J Cereb Blood Flow Metab. 2017 May;37(5):1735-1747. doi: 10.1177/0271678X16657344.
Hartings JA, Shuttleworth CW, Kirov SA, Ayata C, Hinzman JM, Foreman B, Andrew RD et al., (2017) The continuum of spreading depolarizations in acute cortical lesion development: Examining Leao's legacy., J Cereb Blood Flow Metab. 2017 May;37(5):1571-1594. doi: 10.1177/0271678X16654495.
Dreier JP, Fabricius M, Ayata C, ...Andrew RD et al. (2017) Recording, analysis, and interpretation of spreading depolarizations in neurointensive care: Review and recommendations of the COSBID research group. J Cereb Blood Flow Metab. 2017 May;37(5):1595-1625. doi: 10.1177/0271678X16654496.
Spong KE, Andrew RD, Robertson RM, (2016) Mechanisms of spreading depolarization in vertebrate and insect central nervous systems., 10-2016, J. Neurophysiology, Vol. 116(3):1117-27.
Hubel N, Andrew RD, Ullah G, (2016) Large extracellular space leads to neuronal susceptibility to ischemic injury in a Na+/K+ pumps-dependent manner., 5-2016, J. Neurophysiology, Vol. 40(2):177-92
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
Ventura NM, Jin AY, Tse MY, Peterson NT, Andrew RD, Pang SC. (2015). Onset and Regression of Pregnancy-Induced Cardiovascular Alterations in Gestationally-Hypertensive Mice: The Role of the Natriuretic Peptide System. Biol. Reprod. Dec; 93(6):142. doi: 10.1095/biolreprod.115.132696.
Ventura NM, Jin AY, Tse MY, Peterson NT, Andrew RD, Mewburn JD, Pang SC. (2015). Maternal hypertension programs increased cerebral tissue damage following stroke in adult offspring. Molecular and Cellular Biochemistry 408(1): 223-233.
D'Souza Y, Elharram A, Soon-Shiong R, Andrew RD, Bennett BM. (2015). Characterization of Aldh2-/- mice as an age-related model of cognitive impairment and Alzheimer's Disease. Molecular Brain 8:27. doi: 10.1186/s13041-015-0117-y.
Brisson CD, Jin AY, Andrew RD. (2014) Brainstem neurons resist the same acute ischemia that injures higher neurons: Insight to the persistent vegetative state. PLoS ONE. 9(5): e96585. doi:10.1371/journal.pone.0096585
Ventura NM, Jin AY, Peterson NT, Tse MY, Andrew RD, Pang SC. (2014) Molecular adaptations in vasoactive systems during acute stroke in salt-induced hypertension. Molecular and Cellular Biochemistry: 399(1-2):39-47.
Brisson CD, Lukewich MK, Andrew RD. (2013) A distinct boundary between the higher brain`s susceptibility to ischemia and the lower brain`s resistance. PLoS ONE. 8(11): e79589. doi:10.1371/journal.pone.0079589
Brisson CD, Andrew RD. (2012) A neuronal population that dramatically resists acute ischemic injury independent of blood supply. J Neurophysiol 108: 419-430.
White SH, Brisson CD, Andrew RD. (2012) Examining protection from anoxic depolarization by the drugs dibucaine and carbetapentane using whole-cell recording from CA1 neurons. J Neurophysiol 107:2083-2095.
Douglas HA, Callaway JK, Sword J, Kirov SA, Andrew RD. (2011) Potent inhibition of anoxic depolarization by the sodium channel blocker dibucaine. J Neurophysiol 105:1482-94.
RECENT ABSTRACTS (past 15 years)
Mehder RH and Andrew RD (2019) Surviving neurons in the ischemic core following focal stroke in mice.
iCSD meeting, Yokahama, Japan, July 2019.
Mehder RH, Bennett BM, Andrew RD (2018) .Morphometric Analysis of Dorsal Hippocampal Neurons in a Mouse Model of Sporadic Alzheimer's Disease. Canadian Assoc Neuroscience. Vancouver, Canada.
Andrew RD, Gagolewicz PJ (2018) A Putative Channel Driving Spreading Depolarization. Invited Workshop "Mathematical Modeling of Cortical Spreading Depression and Related Phenomena,” held at the Institute for Mathematics and its Applications., Minneapolis, USA.
Gagolewicz PJ and Andrew RD (2017) The elusive channel driving ischemic spreading depolarization. Society for Neuroscience, United States
Mehder RH, Petrin D, Gagolewicz PJ, Bennett BM, Jin AY, Andrew RD (2017) Survival of pyramidal neurons within the ischemic core of 12-hour post-MCAo mice. Society for Neuroscience, Washington DC
Andrew RD, Hsieh Y-T and Brisson.CD (2016) Spreading depression is weak or absent in the rodent lower brain. Canadian Association for Neuroscience 2016, Toronto, Canada
Gagolewicz PJ and Andrew RD. (2016) Still unidentified: The channel driving spreading depolarization during ischemia. Canadian Association for Neuroscience 2016, Toronto, Canada
El-Kerdawy H, Carr J and Andrew RD. (2016) Mechanisms underlying neuronal swelling during acute osmotic or acute ischemic stress. Canadian Association for Neuroscience 2016, Toronto, Canada
Andrew RD. (2015) Spreading Depression and Migraine Pain as Evolutionary Epiphenomena of TBI. Co-operative Studies on Brain Injury Depolarizations 2015, Copenhagen, Denmark
Brisson CD, Andrew RD. (2014) Spreading depolarization strength during ischemia determines higher brain susceptibility and lower brain resistance to acute injury. Society for Neuroscience 2014, Washington, United States
Andrew RD and Kim.D (2014) Does ischemia induce spreading depolarization by converting the Na+/K+ pump into a channel? Co-operative Studies on Brain Injury Depolarizations 2014, Boston, United States
Andrew RD. (2014) Spreading depolarization strength during ischemia determines higher brain susceptibility and lower brain resistance to acute injury. Workshop on Cortical Spreading Depression and Related Neurological
Phenomena. Toronto, Canada
Andrew RD, Britton R, McQueen SA, Kim D, Jin AY (2013) Could the failing Na+/K+ pump convert to a channel during stroke? Soc Neurosci Abstracts 2013
Andrew RD and Brisson CD (2013) Single neuron properties promote onset of the persistent vegetative state. Canad Assoc Neurosci 2013. Toronto
Petrin D, Ventura NM, Peterson N, Andrew RD, Tse MY, Pang SC,Jin AY (2013) Spreading depolarization is attenuated post-stroke and may involve isoform-specific altered sodium-potassium ATPase function. Canad Assoc Neurosci 2013. Toronto
Petrin D, Ventura NM, Peterson N, Andrew RD, Tse MY, Pang SC,Jin AY (2013) Spreading depolarization after stroke is supported by the alpha-1 isoform of Na+/K+-ATPase. Canadian Stroke Congress, Montreal.
Ventura NM, Peterson NY, Tse MY, Wong PG, Jin AY, Andrew RD, Pang SC (2013) Molecular effects of salt-induced hypertension on the development of acute ischemic stroke in the heterozygous ANP+/- gene-disrupted mice. Canadian Stroke Congress, Montreal.
Petrin D, Andrew RD, Jin AY (2013) Endogenous and exogenous alteration of spreading depolarization in the post-stroke brain. European Stroke Conference 2013.
Ventura NM, Peterson NT, Tse MY, Jin AY, Andrew RD, Pang SC. (2013) A novel model for ischemic stroke–the ANP gene disrupted (ANP−/−) mouse: molecular effects of hypertension in the development of stroke. Exper Biol `13.
Andrew RD, Hsieh Y-T, Brisson CD (2012) Projection neurons in brainstem and hypothalamus intrinsically resist acute stroke injury while projection neurons in cortex, striatum and thalamus die. .Soc Neurosci Abstracts 2012
Brisson CD, Hsieh Y-T, Andrew RD (2012) Robust neuronal resistance to acute ischemic depolarization and swelling in midbrain-pons assessed with intracellular electrophysiology and two-photon microscopy. Soc Neurosci Abstracts 2012
Foreman-Mackey A., Peterson, N., Andrew, RD, Kaur, J., Singh, S., Jin, AY (2011) Acute stroke opens neuronal pannexin1 channels. Int. Stroke Conf., New Orleans, Feb 2012.
Andrew, RD, CD Brisson (2011) Trauma trumps stroke: Why is our higher brain inept at dealing with blocked blood flow? Vasospasm 2011: The 11th International Conference on Neurovascular Events after Subarachnoid Hemorrhage. Cincinatti, Ohio.
Brisson CD, Andrew RD (2011) Brainstem neurons in solitary nucleus resist ischemic stress compared to cortical pyramidal neurons. Soc. Neurosci. Abstr. 2011.
Andrew, R D (2010) When does `personhood`begin? Understanding neural development can inform the abortion issue. Neuroethics Society.
Pang, S. C., C.W. Reifel, L.W. MacKenzie, R.A. Easteal, R.D. Andrew, R.E. Hunt, S. Virk. (2010) Establishment of an internet-accessible, scalable gross anatomy and histology image catalogue (SGAHIC) for modern medical and health science education. Annual meeting of the Canadian Health Libraries Association.
Brisson, D.C., R. D. Andrew (2010) Magnocellular neuroendocrine cells dramatically resist stroke-like injury in live brain slices compared to neocortical pyramidal neurons. Soc. Neurosci. Abstr. 2010.
Ranepura N, C.D. Brisson and R. D. Andrew (2010) Neurons that resist osmotic volume change in brain slices and when dissociated. Soc. Neurosci. Abstr. 2010.
Brisson, D.C., N. Ranepura, M. Lukewich, R. D. Andrew (2009) Anoxic depolarization in hypothalamic and brainstem slices. Soc. Neurosci. Abstr.2009.
Andrew, R. D. (2008) When does `personhood` begin? Teaching how neural development might inform the abortion issue. Soc. Neurosci. Abstr.
White, S. H. and R. D. Andrew (2008) Whole cell recording from CA1 neurons to explain ischemia protection by dibucaine and carbetapentane. Soc. Neurosci. Abstr.
Andrew, R. D., W.C. Risher and S.A. Kirov (2008) Real-time volume responses of astrocytes to osmotic and ischemic stressing vivo and in cortical slices revealed by 2-photon microscopy. Canadian Physiological Society Meetings, Lake Louise, Alberta.
White, S. H. and R. D. Andrew (2008) Whole cell recording from pyramidal neurons help explain ischemia protection by a sodium channel blocker. Canadian Physiological Society Meetings, Lake Louise, Alberta.
Kirov, S. A. and R. D. Andrew, (2007) Real-time volume responses of astrocytes to osmotic and ischemic stress in cortical brain slices. Canad. J. Neurolog. Sci. 34 (Suppl 3), S67.
Andrew, R.D. and S. A. Kirov (2007) Two photon microscopy reveals real-time volume responses by astrocytes to osmotic and ischemic stress. Canadian Physiological Society Meetings, Quebec City, P.Q.
Scott, C.A., R. D. Andrew, J. P. Rossiter, and A. C. Jackson (2007) Marked injury to neuronal processes in an experimental mouse model of rabies using YFP transgenic mice. ACV?
Kirov, S. A. and Andrew, (2006) CNS neurons withstand osmotic but not ischemic stress. The 50th Biophysical Society Annual Meeting, Salt Lake City, Utah
Andrew, R.D. S. E. Boehnke and S. A. Kirov (2006) Physiological evidence that pyramidal neurons lack water channels. Canadian Physiological Society Meetings, Lake Louise, Alberta
Douglas, H.A., G. Yang, R. D. Andrew and S. A. Kirov (2006) Two-photon microscopical study of pyramidal neurons protected from ischemic stress by dibucaine. Soc. Neurosci. Abstr. 2006
Kirov, S.A., S. E. Boehnke and R. D. Andrew (2006) Real-time volume responses of astrocytes to osmotic and ischemic stress in cortical brain slices. Soc. Neurosci. Abstr. 2006
CURRENT RESEARCH SUPPORT
NSERC Operating Grant. ‘Converting the Na/K pump into a shutdown channel’. Funded 2017 to 2022, $26K per year.
Heart and Stroke Foundation of Canada Operating Grant ”Activation and opening of the channel that kills neurons during ischemia” Funded July 2019-June 2021 $90K per year.
RECENT INVITED Symposia Participation (not yet updated)
February 12-16, 2018 Lecture: ‘A Putative Channel Driving Spreading Depolarization’. Invited Workshop "Mathematical Modeling of Cortical Spreading Depression and Related Phenomena,” held at the Institute for Mathematics and its Applications. Minneapolis, USA.
April 2018.CBC Radio interview on the hazards of the poison Palytoxin.
July 2016. York University, Toronto Ontario. Our brain: Wired for God and Country. Biology Dept. seminar. May 2016.
July 2014. International Workshop Speaker. Cortical Spreading Depression and Related Neurological Phenomena. Fields Institute, University of Toronto.
October 2014. Speaker. Cooperative Studies on Brain Injury Depolarization Annual meeting. Boston MA.
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 that work 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. I have collaborated with Dr. Sergei Kirov 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 are 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 spreading depression (SD), 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. A related aspect is a process similar to spreading depression termed 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. My Neurologist colleague Dr. Al Jin and I collaborate to investigate drugs that reduce such damage in brain slices by blocking the AD. They also inhibit SD. We consider AD and PID inhibition to be the key targets for improving patient outcome following stroke or traumatic brain injury.
Most recently we are carrying out single channel recordings in mammalian neurons undergoing ischemia to discover the fundamental molecular mechanisms underlying acute neuronal death that can quickly develop following spreading depolarization (SD) in the gray matter of the higher brain. By identifying the channel that opens to drive SD, we are now able to search for an SD `activator` released by the ischemic gray matter that evokes that opening to generate SD and the neuronal injury that follows in its wake.
Three Recent Reviews Published
Our first recent review provides an overview of research into spreading depolarization. (doi.org/10.1007/s12028-021-01431-w). When a patient arrives in the emergency department following a stroke, a traumatic brain injury, or sudden cardiac arrest, there is no therapeutic drug available to help protect their jeopardized neurons. One crucial reason is that we have not identified the molecular mechanisms leading to electrical failure, neuronal swelling, and blood vessel constriction in newly injured gray matter. All three result from a process termed spreading depolarization (SD). Because we only partially understand SD, we lack molecular targets and biomarkers to help neurons survive after losing their blood flow and then undergoing recurrent SD.
In this review, we first introduce SD as a single or recurring event, generated in gray matter following lost blood flow, which compromises the Na+/K+ pump. Electrical recovery from each SD event requires so much energy that neurons often die over minutes and hours following initial injury, independent of extracellular glutamate. We discuss how SD has been investigated (with various pitfalls) and how overtaxing of the Na+/K+ ATPase elicits SD. We then turn to the properties of SD itself, focusing on its initiation and propagation as well as on computer modeling. Finally, we summarize points of consensus and contention among the authors as well as where SD research may be heading. In an accompanying review, we critique the role of the glutamate excitotoxicity theory, how it has shaped SD research, and its fading relevance to the study of early brain injury (compared with SD theory).
Youtube videos of spreading depolarization:
Our second new review (doi: 10.1007/s12028-021-01429-4.) challenges more than 40 years of dogma regarding how and why brain cells die when deprived of blood (ischemia) as follows stroke, traumatic brain injury, or cardiac arrest. The textbook explanation identifies an excess of glutamate release as the great destroyer of ischemic brain tissue by hyper-exciting the neurons (“glutamate excitotoxicity”). Yet the basic and clinical science supporting that concept is surprisingly weak.
Our revisionist view argues that a more dynamic process of brain injury has been largely ignored, that of recurring spreading depolarizations (SDs). Within minutes of lost blood flow to the brain, an SD event initiates and propagates across the deprived gray matter, killing neurons. Where blood flow is only partially reduced in neighboring regions, recurring SD events reduce blood flow, stressing and injuring the neurons over the ensuing hours and days, This sequence provides a therapeutic window to attempt to inhibit recurrent SD and so rescue neurons. Glutamate release has only a minor role in this scenario, which is why we challenge the accepted story of glutamate excitotoxicity being the initiator of human brain injury, not only in stroke but in other proposed neurodegenerative diseases.
Our third review also questions that status quo, but this time involving neuronal swelling during early ischemia (doi.org/10.1007/s12028-021-01326-w). Counter-intuitively, recent research argues that ischemic swelling of neurons is non-osmotic, involving ion/water cotransporters as well as at least one known amino acid water pump. While incompletely understood, these mechanisms argue against the dogma that neuronal swelling involves water uptake driven by an osmotic gradient with aquaporins as the conduit. Promoting clinical recovery from neuronal cytotoxic edema evoked by spreading depolarizations requires a far better understanding of molecular water pumps and ion/water cotransporters that act to rebalance water shifts during brain ischemia.