Postictal hypoperfusion/hypoxia provides the foundation for a unified theory of seizure-induced brain abnormalities and behavioral dysfunction.

A recent article by Farrell et al. characterizes the phenomenon, mechanisms, and treatment of a local and severe hypoperfusion/hypoxia event that occurs in brain regions following a focal seizure. Given the well-established role of cerebral ischemia/hypoxia in brain damage and behavioral dysfunction in other clinical settings (e.g., stroke, cerebral vasospasm), we put forward a new theory: postictal hypoperfusion/hypoxia is responsible for the negative consequences associated with seizures. Fortunately, inhibition of two separate molecular targets, cyclooxygenase-2 (COX-2) and l-type calcium channels, can prevent the expression of postictal hypoperfusion/hypoxia. These inhibitors are important experimental tools used to separate the seizure from the resulting hypoperfusion/hypoxia and can allow researchers to address the contribution of this phenomenon to negative outcomes associated with seizures. Herein we address the implications of this postictal stroke-like event in acute behavioral dysfunction (e.g., Todd's paresis) and sudden unexpected death in epilepsy (SUDEP). Moreover, anatomic alterations such as increased blood-brain barrier permeability, glial activation, central inflammation, and neuronal loss could also be a consequence of repeated hypoperfusion/hypoxic events and, in turn, underlie chronic interictal cognitive and behavioral comorbidities (e.g., memory deficits, anxiety, depression, and psychosis) and exacerbate epileptogenesis. Thus these seemingly disparate and clinically important observations may share a common point of origin: postictal hypoperfusion/hypoxia.

Cortical cells are altered by factors including bone morphogenetic protein released from a placental barrier model under altered oxygenation.

Episodes of hypoxia and hypoxia/reoxygenation during foetal development have been associated with increased risk of neurodevelopmental conditions presenting in later life. The mechanism for this is not understood; however, several authors have suggested that the placenta plays an important role. Previously we found both placentas from a maternal hypoxia model and pre-eclamptic placentas from patients release factors lead to a loss of dendrite complexity in rodent neurons. Here to further explore the nature and origin of these secretions we exposed a simple in vitro model of the placental barrier, consisting of a barrier of human cytotrophoblasts, to hypoxia or hypoxia/reoxygenation. We then exposed cortical cultures from embryonic rat brains to the conditioned media (CM) from below these exposed barriers and examined changes in cell morphology, number, and receptor presentation. The barriers released factors that reduced dendrite and astrocyte process lengths, decreased GABAB1 staining, and increased astrocyte number. The changes in astrocytes required the presence of neurons and were prevented by inhibition of the SMAD pathway and by neutralising Bone Morphogenetic Proteins (BMPs) 2/4. Barriers exposed to hypoxia/reoxygenation also released factors that reduced dendrite lengths but increased GABAB1 staining. Both oxygen changes caused barriers to release factors that decreased GluN1, GABAAα1 staining and increased GluN3a staining. We find that hypoxia in particular will elicit the release of factors that increase astrocyte number and decrease process length as well as causing changes in the intensity of glutamate and GABA receptor staining. There is some evidence that BMPs are released and contribute to these changes.

Caffeine Exacerbates Postictal Hypoxia.

A stroke-like event follows seizures which may be responsible for the postictal state and a contributing factor to the development of seizure-induced brain abnormalities and behavioral dysfunction associated with epilepsy. Caffeine is the world's most popular drug with ∼85% of people in the USA consuming it daily. Thus, persons with epilepsy are likely to have caffeine in their body and brain during seizures. This preclinical study investigated the effects of acute caffeine on local hippocampal tissue oxygenation pre and post seizure. We continuously measured local oxygen levels in the CA1 region of the hippocampus and utilized the electrical kindling model in rats. Rats were acutely administered either caffeine, or one of its metabolites, or agonists and antagonists at adenosine sub-receptor types or ryanodine receptors prior to the elicitation of seizures. Acute caffeine administration caused a significant drop in pre-seizure hippocampal pO2. Following a seizure, caffeine, as well as two of its metabolites paraxanthine, and theophylline, increased the time below the severe hypoxic threshold (10 mmHg). Likewise, the specific A2A receptor antagonist, SCH-58261, mimicked caffeine by causing a significant drop in pre-seizure pO2 and the area and time below the severe hypoxic threshold. Moreover, the A2A receptor agonist, CGS-21680 was able to prevent the effect of both caffeine and SCH-58261 adding further evidence that caffeine is likely acting through the A2A receptor. Clinical tracking and investigations are needed to determine the effect of caffeine on postictal symptomology and blood flow in persons with epilepsy.

Heterogeneity in warm-season land-atmosphere coupling over the U.S. Southern Great Plains.

Heterogeneity in warm-season (May-August) land-atmosphere (LA) coupling is quantified with the long-time, multiple-station measurements from the U.S. Department of Energy Atmospheric Radiation Measurement (ARM) program and the moderate-resolution imaging spectroradiometer (MODIS) satellite remote sensing at the Southern Great Plains (SGP). We examine the coupling strength at 7 additional locations with the same surface type (i.e., pasture/grassland) as the ARM SGP central facility (CF). To simultaneously consider multiple factors and consistently quantify their relative contributions, we apply a multiple linear regression method to correlate the surface evaporative fraction (EF) with near-surface soil moisture (SM) and leaf area index (LAI). The observations show moderate to weak terrestrial segment LA coupling with large heterogeneity across the ARM SGP domain in warm-season. Large spatial variabilities in the contributions from SM and LAI to the EF changes are also found. The coupling heterogeneities appear to be associated with differences in land use, anthropogenic activities, rooting depth, and soil type at different stations. Therefore, the complex LA interactions at the SGP cannot be well represented by those at the CF/E13 based on the metrics applied here. Overall, the LAI exerts more influence on the EF than does the SM due to its overwhelming impacts on the latent heat flux. This study complements previous studies based on measurements only from the CF and has important implications for modeling LA coupling in weather and climate models. The multiple linear regression provides a more comprehensive measure of the integrated impacts on LA coupling from several different factors.

Compounding Impacts of Human-Induced Water Stress and Climate Change on Water Availability.

The terrestrial phase of the water cycle can be seriously impacted by water management and human water use behavior (e.g., reservoir operation, and irrigation withdrawals). Here we outline a method for assessing water availability in a changing climate, while explicitly considering anthropogenic water demand scenarios and water supply infrastructure designed to cope with climatic extremes. The framework brings a top-down and bottom-up approach to provide localized water assessment based on local water supply infrastructure and projected water demands. When our framework is applied to southeastern Australia we find that, for some combinations of climatic change and water demand, the region could experience water stress similar or worse than the epic Millennium Drought. We show considering only the influence of future climate on water supply, and neglecting future changes in water demand and water storage augmentation might lead to opposing perspectives on future water availability. While human water use can significantly exacerbate climate change impacts on water availability, if managed well, it allows societies to react and adapt to a changing climate. The methodology we present offers a unique avenue for linking climatic and hydrologic processes to water resource supply and demand management and other human interactions.

Competing influences of anthropogenic warming, ENSO, and plant physiology on future terrestrial aridity.

The 2011-2016 Californian drought illustrates that drought-prone areas do not always experience relief once a favorable phase of El Niño-Southern Oscillation (ENSO) returns. In the 21st century, such an expectation is unrealistic in regions where global warming induces an increase in terrestrial aridity larger than the aridity changes driven by ENSO variability. This premise is also flawed in areas where precipitation supply cannot offset the global warming-induced increased evaporative demand. Here, atmosphere-only experiments are analyzed to identify land regions in which aridity is currently sensitive to ENSO, and where projected future changes in mean aridity exceed the range caused by ENSO variability. Insights into the drivers of these aridity changes are obtained in simulations with incremental addition of three different factors to current climate: ocean warming, vegetation response to elevated CO2 levels, and intensified CO2 radiative forcing. The effect of ocean warming overwhelms the range of ENSO-driven temperature variability worldwide, increasing potential evapotranspiration (PET) in most ENSO-sensitive regions. Additionally, ~39% of the regions currently sensitive to ENSO receive less precipitation in the future, independent of the ENSO phase. Aridity increases consequently in 67-72% of the ENSO-sensitive area. When both radiative and physiological effects are considered, the area affected by aridity rises to 75-79% when using PET-derived measures of aridity, but declines to 41% when total soil moisture aridity indicator is employed. This reduction mainly occurs because plant stomatal resistance increases under enhanced CO2 concentrations, which results in improved plant water use efficiency, and hence reduced evapotranspiration and soil desiccation. Imposing CO2-invariant stomatal resistance may overestimate future drying in PET-derived indices.