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Background Maintenance of ion homeostasis is essential for normal brain function. Inhalational anesthetics are known to act on various receptors, but their effects on ion homeostatic systems, such as sodium/potassium-adenosine triphosphatase (Na+/K+-ATPase), remain largely unexplored. Based on reports demonstrating global network activity and wakefulness modulation by interstitial ions, the hypothesis was that deep isoflurane anesthesia affects ion homeostasis and the key mechanism for clearing extracellular potassium, Na+/K+-ATPase. Methods Using ion-selective microelectrodes, this study assessed isoflurane-induced extracellular ion dynamics in cortical slices of male and female Wistar rats in the absence of synaptic activity, in the presence of two-pore-domain potassium channel antagonists, during seizures, and during spreading depolarizations. The specific isoflurane effects on Na+/K+-ATPase function were measured using a coupled enzyme assay and studied the relevance of the findings in vivo and in silico. Results Isoflurane concentrations clinically relevant for burst suppression anesthesia increased baseline extracellular potassium (mean ± SD, 3.0 ± 0.0 vs. 3.9 ± 0.5 mM; P < 0.001; n = 39) and lowered extracellular sodium (153.4 ± 0.8 vs. 145.2 ± 6.0 mM; P < 0.001; n = 28). Similar changes in extracellular potassium and extracellular sodium and a substantial drop in extracellular calcium (1.5 ± 0.0 vs. 1.2 ± 0.1 mM; P = 0.001; n = 16) during inhibition of synaptic activity and two-pore-domain potassium suggested a different underlying mechanism. After seizure-like events and spreading depolarization, isoflurane greatly slowed extracellular potassium clearance (63.4 ± 18.2 vs. 196.2 ± 82.4 s; P < 0.001; n = 14). Na+/K+-ATPase activity was markedly reduced after isoflurane exposure (greater than 25%), affecting specifically the α2/3 activity fraction. In vivo, isoflurane-induced burst suppression resulted in impaired extracellular potassium clearance and interstitial potassium accumulation. A computational biophysical model reproduced the observed effects on extracellular potassium and displayed intensified bursting when Na+/K+-ATPase activity was reduced by 35%. Finally, Na+/K+-ATPase inhibition with ouabain induced burst-like activity during light anesthesia in vivo. Conclusions The results demonstrate cortical ion homeostasis perturbation and specific Na+/K+-ATPase impairment during deep isoflurane anesthesia. Slowed potassium clearance and extracellular accumulation might modulate cortical excitability during burst suppression generation, while prolonged Na+/K+-ATPase impairment could contribute to neuronal dysfunction after deep anesthesia. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Background and Purpose— The diagnosis of transient ischemic attack is challenging. Evidence of acute ischemia on MRI diffusion-weighted imaging is highly variable and confirmed in only about one-third of patients. This study investigated the significance of blood-brain barrier dysfunction (BBBD) mapping in patients with transient neurological deficits, as a diagnostic and prognostic biomarker required for risk stratification and stroke prevention. Methods— We used dynamic contrast-enhanced MRI to quantitatively map BBBD in a prospective cohort study of 57 patients diagnosed with transient ischemic attack/minor stroke and 50 healthy controls. Results— Brain volume with BBBD was significantly higher in patients compared with controls ( P =0.002). BBBD localization corresponded with the clinical presentation in 41 patients (72%) and was more extensive in patients with acute infarct on diffusion-weighted imaging ( P =0.05). Patients who developed new stroke during follow-up had a significantly greater BBBD at the initial presentation ( P =0.03) with a risk ratio of 5.35 for recurrent stroke. Conclusions— This is the first description of the extent and localization of BBBD in patients with transient ischemic attack/minor stroke. We propose BBBD mapping as a valuable tool for detection of subtle brain ischemia and a promising predictive biomarker required for risk stratification and stroke prevention.

IntroductionConcussion has been studied with increasing scrutiny in recent years, including evaluation of diagnostic technologies to detect structural damage to the brain. Previous studies in our laboratories using a number of TBI biomarkers have demonstrated the potential of blood biomarkers Neurogranin (NRGN), Oligodendrocyte myelin glycoprotein (OMG), and Synuclein beta (SNCB) as indicators of damage after concussion. This study was designed to evaluate the relationship of blood biomarkers with concussion history.MethodsELISA assays were developed to detect Aldolase C (ALDOC), Brain derived neurotrophic factor (BDNF), GFAP, Metallothionein-3 (MT3), NRGN, Neuron specific enolase (NSE), OMG, and SNCB. Serum concentrations were determined in replicate assays. Three cohorts were studied: mild TBI patients (HeadSMART; n = 139, Johns Hopkins University); healthy controls (n = 52, Baylor College of Medicine); and semi-professional football players (n = 31; Ben-Gurion University). Serum biomarker values were analyzed by Spearman's pairwise correlation to identify associations with prior concussion number, age, and years of play. Modeling in logistic regression was used to assess risk of PCS at 3 months.ResultsPrior concussion number was correlated with NRGN (p = 0.58), SNCB (p = 0.42), and ALDOC (p = 0.64) in players during the active season. Post-season, NRGN (p = 0.53) and ALDOC (p = 0.37) remain associated with concussion number. ALDOC and NRGN also correlated during the active season (p = 0.68), and ALDOC levels correlated with OMG (0.66), BDNF (−0.51) and NSE (−0.38). In HeadSMART mild-TBI, NRGN was correlated with ALDOC (p = 0.44), and SNCB and BDNF (p = −0.33), and OMG and NSE (p = −0.33) were weakly correlated. ALDOC, BDNF, GFAP, and OMG were associated with age, including decreasing ALDOC and NRGN with age. Classifier models confirmed the utility of these markers for predicting risk of ongoing symptoms (PCS) after mTBI.ConclusionBlood levels of NRGN and SNCB are consistently associated with concussion and have been shown to be useful for mTBI diagnosis. These markers, and ALDOC, are promising biomarkers for further development in sports-related concussion.