Prognostic Value of Spreading Depolarizations in Patients With Severe Traumatic Brain Injury.

Importance: Advances in treatment of traumatic brain injury are hindered by the inability to monitor pathological mechanisms in individual patients for targeted neuroprotective treatment. Spreading depolarizations, a mechanism of lesion development in animal models, are a novel candidate for clinical monitoring in patients with brain trauma who need surgery.

Objective: To test the null hypothesis that spreading depolarizations are not associated with worse neurologic outcomes.

Safety and Reliability of Bedside, Single Burr Hole Technique for Intracranial Multimodality Monitoring in Severe Traumatic Brain Injury.

Background: We aimed to provide a systematic description of our 2-year experience using a standardized bedside, single burr hole approach to intracranial multimodality monitoring (MMM) in patients with severe traumatic brain injury (sTBI), focusing on safety and probe reliability.

Methods: We performed this observational cohort study at a university-affiliated, Level I trauma center with dedicated 20-bed neuroscience intensive care unit. We included 43 consecutive sTBI patients who required MMM to guide clinical care based on institutional protocol and had a four-lumen bolt placed to measure intracranial pressure, brain tissue oxygen, regional cerebral blood flow, brain temperature, and intracranial electroencephalography.

Terminal spreading depolarization and electrical silence in death of human cerebral cortex.

Objective: Restoring the circulation is the primary goal in emergency treatment of cerebral ischemia. However, better understanding of how the brain responds to energy depletion could help predict the time available for resuscitation until irreversible damage and advance development of interventions that prolong this span. Experimentally, injury to central neurons begins only with anoxic depolarization.

Subarachnoid blood acutely induces spreading depolarizations and early cortical infarction.

See Ghoshal and Claassen (doi:10.1093/brain/awx226) for a scientific commentary on this article. Early cortical infarcts are common in poor-grade patients after aneurysmal subarachnoid haemorrhage.

The continuum of spreading depolarizations in acute cortical lesion development: Examining Leão's legacy.

A modern understanding of how cerebral cortical lesions develop after acute brain injury is based on Aristides Leão's historic discoveries of spreading depression and asphyxial/anoxic depolarization. Treated as separate entities for decades, we now appreciate that these events define a continuum of spreading mass depolarizations, a concept that is central to understanding their pathologic effects. Within minutes of acute severe ischemia, the onset of persistent depolarization triggers the breakdown of ion homeostasis and development of cytotoxic edema.

Recording, analysis, and interpretation of spreading depolarizations in neurointensive care: Review and recommendations of the COSBID research group.

Spreading depolarizations (SD) are waves of abrupt, near-complete breakdown of neuronal transmembrane ion gradients, are the largest possible pathophysiologic disruption of viable cerebral gray matter, and are a crucial mechanism of lesion development. Spreading depolarizations are increasingly recorded during multimodal neuromonitoring in neurocritical care as a causal biomarker providing a diagnostic summary measure of metabolic failure and excitotoxic injury. Focal ischemia causes spreading depolarization within minutes.

Direct current electrocorticography for clinical neuromonitoring of spreading depolarizations.

Spreading depolarizations cause cortical electrical potential changes over a wide spectral range that includes slow potentials approaching the direct current (or 0 Hz) level. The negative direct current shift (<0.05 Hz) is an important identifier of cortical depolarization and its duration is a measure of potential tissue injury associated with longer lasting depolarizations.

Excitotoxicity and Metabolic Crisis Are Associated with Spreading Depolarizations in Severe Traumatic Brain Injury Patients.

Cerebral microdialysis has enabled the clinical characterization of excitotoxicity (glutamate >10 μM) and non-ischemic metabolic crisis (lactate/pyruvate ratio [LPR] >40) as important components of secondary damage in severe traumatic brain injury (TBI). Spreading depolarizations (SD) are pathological waves that occur in many patients in the days following TBI and, in animal models, cause elevations in extracellular glutamate, increased anaerobic metabolism, and energy substrate depletion. Here, we examined the association of SD with changes in cerebral neurochemistry by placing a microdialysis probe alongside a subdural electrode strip in peri-lesional cortex of 16 TBI patients requiring neurosurgery.

Real-time monitoring of extracellular adenosine using enzyme-linked microelectrode arrays.

Throughout the central nervous system extracellular adenosine serves important neuroprotective and neuromodulatory functions. However, current understanding of the in vivo regulation and effects of adenosine is limited by the spatial and temporal resolution of available measurement techniques. Here, we describe an enzyme-linked microelectrode array (MEA) with high spatial (7500 µm(2)) and temporal (4 Hz) resolution that can selectively measure extracellular adenosine through the use of self-referenced coating scheme that accounts for interfering substances and the enzymatic breakdown products of adenosine.

Assessment of Cerebrovascular Autoregulation Using Regional Cerebral Blood Flow in Surgically Managed Brain Trauma Patients.

Background: Impairment of cerebrovascular autoregulation is a risk factor for ischemic damage following severe brain injury. Autoregulation can be assessed indirectly using intracranial pressure monitoring as a surrogate of cerebral blood volume, but this measure may not be applicable to patients following decompressive craniectomy. Here, we describe assessment of autoregulation using regional cerebral blood flow (rCBF).

Spreading depolarizations mediate excitotoxicity in the development of acute cortical lesions.

Spreading depolarizations (SD) are mass depolarizations of neurons and astrocytes that occur spontaneously in acute brain injury and mediate time-dependent lesion growth. Glutamate excitotoxicity has also been extensively studied as a mechanism of neuronal injury, although its relevance to in vivo pathology remains unclear. Here we hypothesized that excitotoxicity in acute lesion development occurs only as a consequence of SD.

Spreading depression in continuous electroencephalography of brain trauma.

Objective: Cortical spreading depolarizations are a pathophysiological mechanism and candidate target for advanced monitoring in acute brain injury. Here we investigated manifestations of spreading depolarization in continuous electroencephalography (EEG) as a broadly applicable, noninvasive method for neuromonitoring.

Methods: Eighteen patients requiring surgical treatment of traumatic brain injury were monitored by invasive electrocorticography (ECoG; subdural electrodes) and noninvasive scalp EEG during intensive care.

Inverse neurovascular coupling to cortical spreading depolarizations in severe brain trauma.

Cortical spreading depolarization causes a breakdown of electrochemical gradients following acute brain injury, and also elicits dynamic changes in regional cerebral blood flow that range from physiological neurovascular coupling (hyperaemia) to pathological inverse coupling (hypoperfusion). In this study, we determined whether pathological inverse neurovascular coupling occurred as a mechanism of secondary brain injury in 24 patients who underwent craniotomy for severe traumatic brain injury. After surgery, spreading depolarizations were monitored with subdural electrode strips and regional cerebral blood flow was measured with a parenchymal thermal diffusion probe.

Detection of spreading depolarization with intraparenchymal electrodes in the injured human brain.

Background: Spreading depolarization events following ischemic and traumatic brain injury are associated with poor patient outcome. Currently, monitoring these events is limited to patients in whom subdural electrodes can be placed at open craniotomy. This study examined whether these events can be detected using intra-cortical electrodes, opening the way for electrode insertion via burr hole.

Disruptions in the regulation of extracellular glutamate by neurons and glia in the rat striatum two days after diffuse brain injury.

Disrupted regulation of extracellular glutamate in the central nervous system contributes to and can exacerbate the acute pathophysiology of traumatic brain injury (TBI). Previously, we reported increased extracellular glutamate in the striatum of anesthetized rats 2 days after diffuse brain injury. To determine the mechanism(s) responsible for increased extracellular glutamate, we used enzyme-based microelectrode arrays (MEAs) coupled with specific pharmacological agents targeted at in vivo neuronal and glial regulation of extracellular glutamate.

Substantia nigra vulnerability after a single moderate diffuse brain injury in the rat.

Dementia and parkinsonism are late-onset symptoms associated with repetitive head injury, as documented in multiple contact-sport athletes. Clinical symptomatology is the likely phenotype of chronic degeneration and circuit disruption in the substantia nigra (SN). To investigate the initiating neuropathology, we hypothesize that a single diffuse brain injury is sufficient to initiate SN neuropathology including neuronal loss, vascular disruption and microglial activation, contributing to neurodegeneration and altered dopamine regulation.

Hypersensitive glutamate signaling correlates with the development of late-onset behavioral morbidity in diffuse brain-injured circuitry.

In diffuse brain-injured rats, robust sensory sensitivity to manual whisker stimulation develops over 1 month post-injury, comparable to agitation expressed by brain-injured individuals with overstimulation. In the rat, whisker somatosensation relies on thalamocortical glutamatergic relays between the ventral posterior medial (VPM) thalamus and barrel fields of somatosensory cortex (S1BF). Using novel glutamate-selective microelectrode arrays coupled to amperometry, we test the hypothesis that disrupted glutamatergic neurotransmission underlies the whisker sensory sensitivity associated with diffuse brain injury.

Targeted over-expression of glutamate transporter 1 (GLT-1) reduces ischemic brain injury in a rat model of stroke.

Following the onset of an ischemic brain injury, the excitatory neurotransmitter glutamate is released. The excitotoxic effects of glutamate are a major contributor to the pathogenesis of a stroke. The aim of this study was to examine if overexpression of a glutamate transporter (GLT-1) reduces ischemic brain injury in a rat model of stroke.

Diffuse brain injury elevates tonic glutamate levels and potassium-evoked glutamate release in discrete brain regions at two days post-injury: an enzyme-based microelectrode array study.

Traumatic brain injury (TBI) survivors often suffer from a wide range of post-traumatic deficits, including impairments in behavioral, cognitive, and motor function. Regulation of glutamate signaling is vital for proper neuronal excitation in the central nervous system. Without proper regulation, increases in extracellular glutamate can contribute to the pathophysiology and neurological dysfunction seen in TBI.