Translational Neurophysiology Lab

The Clinical Neurophysiology Lab studies spreading depolarizations (SD), a class of pathologic waves that occur in cerebral gray matter and are fundamental in understanding the development of brain lesions from acute injuries. As the largest known disturbance of still living tissue, their disruptive impact is seen at all levels of cellular and tissue function, including neurochemistry, organelle ultrastructure, blood-brain barrier, microvascular flow, and metabolism. Based on studies of ischemic stroke in rodents, SDs have long been recognized as the central mechanism driving the toxic changes, including neuronal edema and intracellular Ca2+ loading, that lead to infarction. However, SDs also occur in other conditions of acute injury, including contusion, subdural hematoma, intracerebral hemorrhage, and subarachnoid hemorrhage, and appear to be a requisite mechanism of tissue damage across these conditions.

We study SDs in patients using the technique, pioneered by Anthony Strong, MD (King’s College London) in 2002, of placing electrode strips on the brain of patients who require neurosurgical intervention after severe brain trauma. By making recordings for several days in the intensive care unit, we find that 50-60% of patients exhibit SDs, and SDs often recur in a repetitive pattern for days. In some cases, they cause deterioration of brain activity to the point of isoelectricity (flat-line). In a multi-center effort, we are presently using depth electrodes and EEG to determine whether these results generalize to the more common brain trauma patient that does not require neurosurgery. We also collaborate internationally with other medical centers in the Co-Operative Studies on Brain Injury Depolarization (COSBID) to study SDs in patients after aneurysm rupture, intracerebral hemorrhage and ischemic stroke. Collectively, our aim is to determine how monitoring of SDs can be used to guide treatments and neuroprotective inteventions in patients, following the principle of precision medicine, and thus achieve better outcomes.

In parallel to clinical studies, we utilize animal models to better understand the mechanisms and consequences of SD. Rodent models include focal (middle cerebral artery occlusion) and global (4-vessel occlusion) cerebral ischemia, acute subdural hematoma, and brain contusion (fluid percussion). However, the gyrencephalic (folded) nature of the human cerebral cortex appears to be critically relevant to how SDs are triggered and propagate in patients. Therefore, we also study brain injury in large animal models (swine), which, similar to humans, have more complex neuroanatomy including sulci and gyri. A further advantage of this approach is that clinical neuromonitoring equipment can be used, thus increasing translational relevance of research results. Importantly, the conduct of parallel clinical and laboratory studies enables bi-directional translation, with laboratory investigations often driven by novel clinical findings. 

The Translational Neurophysiology Lab is led by Jed A. Hartings, PhD, working closely with Laura Ngwenya, MD, PhD and Brandon Foreman, MD and collaborating across several departments and institutions both nationally and internationally.  

Resources and Links

Co-Operative Studies on Brain Injury Depolarization

Brain Tsunamis

Documentary Film: COSBID and the Clinical Discovery of Spreading Depolarizations  

News and Media

The Dana Foundation, “The End Comes as a Wave”. Sophie Fessl, Sept 26, 2018.

Kate Sheridan. Does a dying brain mean death? Some cellular changes may be reversible, new evidence shows. Newsweek February 27, 2018.

WVXU, Ann Thompson reporting, March 12, 2018: “The sounds inside your brain right before death.”

Mayfield Clinic Short Film, “Research – In the Long Run” 

“Watch Out for That Brain Tsunami”, M.J. Gertner, The Atlantic

Key Publications

Dreier JP, Major S, Foreman B, et al. Terminal spreading depolarization and electrical silence in death of human cerebral cortex. Ann Neurol 2018;83:295-310.1.      

Hartings JA. Spreading depolarization monitoring in neurocritical care of acute brain injury. Curr Opin Crit Care 2017;23:94-102.

Hartings JA, York J, Carroll CP, et al. Subarachnoid blood acutely induces spreading depolarizations and early cortical infarction. Brain 2017;140:2673-90.

Hinzman JM, DiNapoli VA, Mahoney EJ, Gerhardt GA, Hartings JA. Spreading depolarizations mediate excitotoxicity in the development of acute cortical lesions. Exp Neurol 2015.

Hartings JA, Shuttleworth CW, Kirov SA, et al. The continuum of spreading depolarizations in acute cortical lesion development: Examining Leao's legacy. J Cereb Blood Flow Metab 2017;37:1571-94.

Dreier JP, Fabricius M, Ayata C, et al. Recording, analysis, and interpretation of spreading depolarizations in neurointensive care: Review and recommendations of the COSBID research group. J Cereb Blood Flow Metab 2017;37:1595-625.

Hartings JA, Wilson JA, Hinzman JM, et al. Spreading depression in continuous electroencephalography of brain trauma. Ann Neurol 2014;76:681-94.

Hartings JA, Bullock MR, Okonkwo DO, et al. Spreading depolarisations and outcome after traumatic brain injury: a prospective observational study. Lancet Neurol 2011;10:1058-64.