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Since the discovery of aquaporins, it has become clear that the various mammalian aquaporins play critical physiological roles in water and ion balance in multiple tissues. Aquaporin-4 (AQP4), the principal aquaporin expressed in the central nervous system (CNS, brain and spinal cord), has been shown to mediate CNS water homeostasis. In this review, we summarize new and exciting studies indicating that AQP4 also plays critical and unanticipated roles in synaptic plasticity and memory formation. Next, we consider the role of AQP4 in Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), multiple sclerosis (MS), neuromyelitis optica (NMO), epilepsy, traumatic brain injury (TBI), and stroke. Each of these conditions involves changes in AQP4 expression and/or distribution that may be functionally relevant to disease physiology. Insofar as AQP4 is exclusively expressed on astrocytes, these data provide new evidence of "astrocytopathy" in the etiology of diverse neurological diseases., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Normal nervous system function is critically dependent on the balance of water and ions in the extracellular space (ECS). Pathological reduction in brain interstitial osmolarity results in osmotically-driven flux of water into cells, causing cellular edema which reduces the ECS and increases neuronal excitability and risk of seizures. Astrocytes are widely considered to be particularly susceptible to cellular edema due to selective expression of the water channel aquaporin-4 (AQP4). The apparent resistance of pyramidal neurons to osmotic swelling has been attributed to lack of functional water channels. In this study we report rapid volume changes in CA1 pyramidal cells in hypoosmolar ACSF (hACSF) that are equivalent to volume changes in astrocytes across a variety of conditions. Astrocyte and neuronal swelling was significant within 1 min of exposure to 17 or 40% hACSF, was rapidly reversible upon return to normosmolar ACSF, and repeatable upon re-exposure to hACSF. Neuronal swelling was not an artifact of patch clamp, occurred deep in tissue, was similar at physiological vs. room temperature, and occurred in both juvenile and adult hippocampal slices. Neuronal swelling was neither inhibited by TTX, nor by antagonists of NMDA or AMPA receptors, suggesting that it was not occurring as a result of excitotoxicity. Surprisingly, genetic deletion of AQP4 did not inhibit, but rather augmented, astrocyte swelling in severe hypoosmolar conditions. Taken together, our results indicate that neurons are not osmoresistant as previously reported, and that osmotic swelling is driven by an AQP4-independent mechanism.

Approximately 1% of the global population suffers from epilepsy, a class of disorders characterized by recurrent and unpredictable seizures. Of these cases roughly one-third are refractory to current antiepileptic drugs, which typically target neuronal excitability directly. The events leading to seizure generation and epileptogenesis remain largely unknown, hindering development of new treatments. Some recent experimental models of epilepsy have provided compelling evidence that glial cells, especially astrocytes, could be central to seizure development. One of the proposed mechanisms for astrocyte involvement in seizures is astrocyte swelling, which may promote pathological neuronal firing and synchrony through reduction of the extracellular space and elevated glutamate concentrations. In this review, we discuss the common conditions under which astrocytes swell, the resultant effects on neural excitability, and how seizure development may ultimately be influenced by these effects., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Multiple sclerosis (MS) patients are three to six times more likely to develop epilepsy compared to the rest of the population. Seizures are more common in patients with early onset or progressive forms of the disease and prognosticate rapid progression to disability and death. Gray matter atrophy, hippocampal lesions, interneuron loss, and elevated juxtacortical lesion burden have been identified in MS patients with seizures; however, translational studies aimed at elucidating the pathophysiological processes underlying MS epileptogenesis are limited. Here, we report that cuprizone-mediated chronically demyelinated (9-12weeks) mice exhibit marked changes to dorsal hippocampal electroencephalography (EEG) and evidence of overt seizure activity. Immunohistochemical (IHC) analyses within the hippocampal CA1 region revealed extensive demyelination, loss of parvalbumin (PV + ) interneurons, widespread gliosis, and changes in aquaporin-4 (AQP4) expression. Our results suggest that chronically demyelinated mice are a valuable model with which we may begin to understand the mechanisms underlying demyelination-induced seizures., (Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.)

Background: Cortical hyperexcitability due to abnormal fast-spiking inhibitory interneuron function has been documented in fmr1 KO mice, a mouse model of the fragile X syndrome which is the most common single gene cause of autism and intellectual disability., Methods: We collected resting state dense-array electroencephalography data from 21 fragile X syndrome (FXS) patients and 21 age-matched healthy participants., Results: FXS patients exhibited greater gamma frequency band power, which was correlated with social and sensory processing difficulties. Second, FXS patients showed increased spatial spreading of phase-synchronized high frequency neural activity in the gamma band. Third, we observed increased negative theta-to-gamma but decreased alpha-to-gamma band amplitude coupling, and the level of increased theta power was inversely related to the level of resting gamma power in FXS., Conclusions: Increased theta band power and coupling from frontal sources may represent a mechanism providing compensatory inhibition of high-frequency gamma band activity, potentially contributing to the widely varying level of neurophysiological and behavioral abnormalities and treatment response seen in full-mutation FXS patients. These findings extend preclinical observations and provide new mechanistic insights into brain alterations and their variability across FXS patients. Electrophysiological measures may provide useful translational biomarkers for advancing drug development and individualizing treatments for neurodevelopmental disorders with associated neuronal hyperexcitability.

Maintenance of glutamate and water homeostasis in the brain is crucial to healthy brain activity. Astrocytic glutamate transporter-1 (GLT1) and aquaporin-4 (AQP4) are the main regulators of extracellular glutamate and osmolarity, respectively. Several studies have reported colocalization of GLT1 and AQP4, but the existence of a physical interaction between the two has not been well studied. Therefore, we used coimmunoprecipitation to determine whether a strong interaction exists between these two important molecules in mice on both a CD1 and C57BL/6 background. Furthermore, we used Western blot and immunohistochemistry to examine GLT1 levels in AQP4 knockout (AQP4 -/- ) mice. An AQP4-GLT1 precipitate was not detected, suggesting the lack of a strong physical interaction between AQP4 and GLT1. In addition, GLT1 protein levels remained unaltered in tissue from CD1 and C57BL/6 AQP4 -/- mice. Finally, immunohistochemical analysis revealed that AQP4 and GLT1 do colocalize, but only in a region-specific manner. Taken together, these findings suggest that AQP4 and GLT1 do not have a strong physical interaction between them and are, instead, differentially regulated.

Astrocytes regulate extracellular glutamate and water homeostasis through the astrocyte-specific membrane proteins glutamate transporter-1 (GLT1) and aquaporin-4 (AQP4), respectively. The role of astrocytes and the regulation of GLT1 and AQP4 in epilepsy are not fully understood. In this study, we investigated the expression of GLT1 and AQP4 in the intrahippocampal kainic acid (IHKA) model of temporal lobe epilepsy (TLE). We used real-time polymerase chain reaction (RT-PCR), Western blot, and immunohistochemical analysis at 1, 4, 7, and 30days after kainic acid-induced status epilepticus (SE) to determine hippocampal glial fibrillary acidic protein (GFAP, a marker for reactive astrocytes), GLT1, and AQP4 expression changes during the development of epilepsy (epileptogenesis). Following IHKA, all mice had SE and progressive increases in GFAP immunoreactivity and GFAP protein expression out to 30days post-SE. A significant initial increase in dorsal hippocampal GLT1 immunoreactivity and protein levels were observed 1day post SE and followed by a marked downregulation at 4 and 7days post SE with a return to near control levels by 30days post SE. AQP4 dorsal hippocampal protein expression was significantly downregulated at 1day post SE and was followed by a gradual return to baseline levels with a significant increase in ipsilateral protein levels by 30days post SE. Transient increases in GFAP and AQP4 mRNA were also observed. Our findings suggest that specific molecular changes in astrocyte glutamate transporters and water channels occur during epileptogenesis in this model, and suggest the novel therapeutic strategy of restoring glutamate and water homeostasis., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Over the course of the development of deep brain stimulation (DBS) into a well-established therapy for Parkinson's disease, essential tremor, and dystonia, its utility as a potential treatment for autonomic dysfunction has emerged. Dysfunction of autonomic processes is common in neurological diseases. Depending on the specific target in the brain, DBS has been shown to raise or lower blood pressure, normalize the baroreflex, to alter the caliber of bronchioles, and eliminate hyperhidrosis, all through modulation of the sympathetic nervous system. It has also been shown to improve cortical control of the bladder, directly induce or inhibit the micturition reflex, and to improve deglutition and gastric emptying. In this review, we will attempt to summarize the relevant available studies describing these effects of DBS on autonomic function, which vary greatly in character and magnitude with respect to stimulation target., Competing Interests: The authors declare no conflict of interest.

The immune privileged nature of the CNS can make it vulnerable to chronic and latent infections. Little is known about the effects of lifelong brain infections, and thus inflammation, on the neurological health of the host. Toxoplasma gondii is a parasite that can infect any mammalian nucleated cell with average worldwide seroprevalence rates of 30%. Infection by Toxoplasma is characterized by the lifelong presence of parasitic cysts within neurons in the brain, requiring a competent immune system to prevent parasite reactivation and encephalitis. In the immunocompetent individual, Toxoplasma infection is largely asymptomatic, however many recent studies suggest a strong correlation with certain neurodegenerative and psychiatric disorders. Here, we demonstrate a significant reduction in the primary astrocytic glutamate transporter, GLT-1, following infection with Toxoplasma. Using microdialysis of the murine frontal cortex over the course of infection, a significant increase in extracellular concentrations of glutamate is observed. Consistent with glutamate dysregulation, analysis of neurons reveal changes in morphology including a reduction in dendritic spines, VGlut1 and NeuN immunoreactivity. Furthermore, behavioral testing and EEG recordings point to significant changes in neuronal output. Finally, these changes in neuronal connectivity are dependent on infection-induced downregulation of GLT-1 as treatment with the ß-lactam antibiotic ceftriaxone, rescues extracellular glutamate concentrations, neuronal pathology and function. Altogether, these data demonstrate that following an infection with T. gondii, the delicate regulation of glutamate by astrocytes is disrupted and accounts for a range of deficits observed in chronic infection.

Unlabelled: Sensory processing deficits are common in autism spectrum disorders, but the underlying mechanisms are unclear. Fragile X Syndrome (FXS) is a leading genetic cause of intellectual disability and autism. Electrophysiological responses in humans with FXS show reduced habituation with sound repetition and this deficit may underlie auditory hypersensitivity in FXS. Our previous study in Fmr1 knockout (KO) mice revealed an unusually long state of increased sound-driven excitability in auditory cortical neurons suggesting that cortical responses to repeated sounds may exhibit abnormal habituation as in humans with FXS. Here, we tested this prediction by comparing cortical event related potentials (ERP) recorded from wildtype (WT) and Fmr1 KO mice. We report a repetition-rate dependent reduction in habituation of N1 amplitude in Fmr1 KO mice and show that matrix metalloproteinase-9 (MMP-9), one of the known FMRP targets, contributes to the reduced ERP habituation. Our studies demonstrate a significant up-regulation of MMP-9 levels in the auditory cortex of adult Fmr1 KO mice, whereas a genetic deletion of Mmp-9 reverses ERP habituation deficits in Fmr1 KO mice. Although the N1 amplitude of Mmp-9/Fmr1 DKO recordings was larger than WT and KO recordings, the habituation of ERPs in Mmp-9/Fmr1 DKO mice is similar to WT mice implicating MMP-9 as a potential target for reversing sensory processing deficits in FXS. Together these data establish ERP habituation as a translation relevant, physiological pre-clinical marker of auditory processing deficits in FXS and suggest that abnormal MMP-9 regulation is a mechanism underlying auditory hypersensitivity in FXS., Significance: Fragile X Syndrome (FXS) is the leading known genetic cause of autism spectrum disorders. Individuals with FXS show symptoms of auditory hypersensitivity. These symptoms may arise due to sustained neural responses to repeated sounds, but the underlying mechanisms remain unclear. For the first time, this study shows deficits in habituation of neural responses to repeated sounds in the Fmr1 KO mice as seen in humans with FXS. We also report an abnormally high level of matrix metalloprotease-9 (MMP-9) in the auditory cortex of Fmr1 KO mice and that deletion of Mmp-9 from Fmr1 KO mice reverses habituation deficits. These data provide a translation relevant electrophysiological biomarker for sensory deficits in FXS and implicate MMP-9 as a target for drug discovery., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Aquaporin-4 (AQP4) is the predominant water channel expressed by astrocytes in the central nervous system (CNS). AQP4 is widely expressed throughout the brain, especially at the blood-brain barrier where AQP4 is highly polarized to astrocytic foot processes in contact with blood vessels. The bidirectional water transport function of AQP4 suggests its role in cerebral water balance in the CNS. The regulation of AQP4 has been extensively investigated in various neuropathological conditions such as cerebral edema, epilepsy, and ischemia, however, the functional role of AQP4 in synaptic plasticity, learning, and memory is only beginning to be elucidated. In this review, we explore the current literature on AQP4 and its influence on long term potentiation (LTP) and long term depression (LTD) in the hippocampus as well as the potential relationship between AQP4 and in learning and memory. We begin by discussing recent in vitro and in vivo studies using AQP4-null and wild-type mice, in particular, the impairment of LTP and LTD observed in the hippocampus. Early evidence using AQP4-null mice have suggested that impaired LTP and LTD is brain-derived neurotrophic factor dependent. Others have indicated a possible link between defective LTP and the downregulation of glutamate transporter-1 which is rescued by chronic treatment of β-lactam antibiotic ceftriaxone. Furthermore, behavioral studies may shed some light into the functional role of AQP4 in learning and memory. AQP4-null mice performances utilizing Morris water maze, object placement tests, and contextual fear conditioning proposed a specific role of AQP4 in memory consolidation. All together, these studies highlight the potential influence AQP4 may have on long term synaptic plasticity and memory.

Traumatic brain injury (TBI), the foremost cause of morbidity and mortality in persons under 45 years of age worldwide, leads to about 200,000 victims requiring hospitalization and approximately 52,000 deaths per year in the United States. TBI is characterized by cerebral edema leading to raised intracranial pressure, brain herniation, and subsequent death. Current therapies for TBI treatment are often ineffective, thus novel therapies are needed. Recent studies have shown that an osmotic transport device (OTD) is capable of reducing brain water content and improving survival in mice with severe cerebral edema. Here we compare the effects of a craniectomy and an OTD plus craniectomy on neurological function in mice after TBI. Animals treated with a craniectomy plus an OTD had significantly better neurological function 2 days after TBI compared with those treated with craniectomy only. This study suggests that an OTD for severe brain swelling may improve patient functional outcome. Future studies include a more comprehensive neurological examination, including long-term memory tests.

Aquaporin-4 (AQP4) is a bidirectional water channel that is found on astrocytes throughout the central nervous system. Expression is particularly high around areas in contact with cerebrospinal fluid, suggesting that AQP4 plays a role in fluid exchange between the cerebrospinal fluid compartments and the brain. Despite its significant role in the brain, the overall spatial and region-specific distribution of AQP4 has yet to be fully characterized. In this study, we used Western blotting and immunohistochemical techniques to characterize AQP4 expression and localization throughout the mouse brain. We observed AQP4 expression throughout the forebrain, subcortical areas, and brainstem. AQP4 protein levels were highest in the cerebellum with lower expression in the cortex and hippocampus. We found that AQP4 immunoreactivity was profuse on glial cells bordering ventricles, blood vessels, and subarachnoid space. Throughout the brain, AQP4 was expressed on astrocytic end-feet surrounding blood vessels but was also heterogeneously expressed in brain tissue parenchyma and neuropil, often with striking laminar specificity. In the cerebellum, we showed that AQP4 colocalized with the proteoglycan brevican, which is synthesized by and expressed on cerebellar astrocytes. Despite the high abundance of AQP4 in the cerebellum, its functional significance has yet to be investigated. Given the known role of AQP4 in synaptic plasticity in the hippocampus, the widespread and region-specific expression pattern of AQP4 suggests involvement not only in fluid balance and ion homeostasis but also local synaptic plasticity and function in distinct brain circuits., (© The Author(s) 2015.)

Cellular edema (cell swelling) is a principal component of numerous brain disorders including ischemia, cortical spreading depression, hyponatremia, and epilepsy. Cellular edema increases seizure-like activity in vitro and in vivo, largely through nonsynaptic mechanisms attributable to reduction of the extracellular space. However, the types of excitability changes occurring in individual neurons during the acute phase of cell volume increase remain unclear. Using whole-cell patch clamp techniques, we report that one of the first effects of osmotic edema on excitability of CA1 pyramidal cells is the generation of slow inward currents (SICs), which initiate after approximately 1 min. Frequency of SICs increased as osmolarity decreased in a dose-dependent manner. Imaging of real-time volume changes in astrocytes revealed that neuronal SICs occurred while astrocytes were still in the process of swelling. SICs evoked by cell swelling were mainly nonsynaptic in origin and NMDA receptor-dependent. To better understand the relationship between SICs and changes in neuronal excitability, recordings were performed in increasingly physiological conditions. In the absence of any added pharmacological reagents or imposed voltage clamp, osmotic edema induced excitatory postsynaptic potentials and burst firing over the same timecourse as SICs. Like SICs, action potentials were blocked by NMDAR antagonists. Effects were more pronounced in adult (8-20 weeks old) compared with juvenile (P15-P21) mice. Together, our results indicate that cell swelling triggered by reduced osmolarity rapidly increases neuronal excitability through activation of NMDA receptors. Our findings have important implications for understanding nonsynaptic mechanisms of epilepsy in relation to cell swelling and reduction of the extracellular space., (© The Author(s) 2015.)

Optical coherence tomography (OCT) is a high resolution, minimally invasive imaging technique, which can produce depth-resolved cross-sectional images. In this study, OCT was used to detect changes in the optical properties of cortical tissue in vivo in mice during the induction of global (pentylenetetrazol) and focal (4-aminopyridine) seizures. Through the use of a confidence interval statistical method on depth-resolved volumes of attenuation coefficient, we demonstrated localization of regions exhibiting both significant positive and negative changes in attenuation coefficient, as well as differentiating between global and focal seizure propagation.

Traumatic brain injury (TBI) is significant, from a public health standpoint, because it is a major cause of the morbidity and mortality of young people. Cerebral edema after a TBI, if untreated, can lead to devastating damage of the remaining tissue. The current therapies of severe TBI (sTBI), as outlined by the Brain Trauma Foundation, are often ineffective, thus a new method for the treatment of sTBI is necessary. Herein, the reduction of cerebral edema, after TBI, using an osmotic transport device (OTD) was evaluated. Controlled cortical impact (CCI) was performed on adult female CD-1 mice, and cerebral edema was allowed to form for 3 h, followed by 2 h of treatment. The treatment groups were craniectomy only, craniectomy with a hydrogel, OTD without bovine serum albumin (BSA), and OTD. After CCI, brain water content was significantly higher for animals treated with a craniectomy only, craniectomy with a hydrogel, and OTD without BSA, compared to that of control animals. However, when TBI animals were treated with an OTD, brain water content was not significantly higher than that of controls. Further, brain water content of TBI animals treated with an OTD was significantly reduced, compared to that of untreated TBI animals, TBI animals treated with a craniectomy and a hydrogel, and TBI animals treated with an OTD without BSA. Here, we demonstrate the successful reduction of cerebral edema, as determined by brain water content, after TBI using an OTD. These results demonstrate proof of principle for direct water extraction from edematous brain tissue by direct osmotherapy using an OTD.

Cerebral edema develops in response to a variety of conditions, including traumatic brain injury and stroke, and contributes to the poor prognosis associated with these injuries. This study examines the use of optical coherence tomography (OCT) for detecting cerebral edema in vivo. Three-dimensional imaging of an in vivo water intoxication model in mice was performed using a spectral-domain OCT system centered at 1300 nm. The change in attenuation coefficient was calculated and cerebral blood flow was analyzed using Doppler OCT techniques. We found that the average attenuation coefficient in the cerebral cortex decreased over time as edema progressed. The initial decrease began within minutes of inducing cerebral edema and a maximum decrease of 8% was observed by the end of the experiment. Additionally, cerebral blood flow slowed during late-stage edema. Analysis of local regions revealed the same trend at various locations in the brain, consistent with the global nature of the cerebral edema model used in this study. These results demonstrate that OCT is capable of detecting in vivo optical changes occurring due to cerebral edema and highlights the potential of OCT for precise spatiotemporal detection of cerebral edema.

Aquaporin-4 (AQP4) is the major water channel expressed in the central nervous system (CNS) and is primarily expressed in glial cells. Many studies have shown that AQP4 regulates the response of the CNS to insults or injury, but far less is known about the potential for AQP4 to influence synaptic plasticity or behavior. Recent studies have examined long-term potentiation (LTP), long-term depression (LTD), and behavior in AQP4 knockout (KO) and wild-type mice to gain more insight into its potential role. The results showed a selective effect of AQP4 deletion on LTP of the Schaffer collateral pathway in hippocampus using an LTP induction protocol that simulates pyramidal cell firing during theta oscillations (theta-burst stimulation; TBS). However, LTP produced by a different induction protocol was unaffected. There was also a defect in LTD after low frequency stimulation (LFS) in AQP4 KO mice. Interestingly, some slices from AQP4 KO mice exhibited LTD after TBS instead of LTP, or LTP following LFS instead of LTD. These data suggest that AQP4 and astrocytes influence the polarity of long-term synaptic plasticity (potentiation or depression). These potentially powerful roles expand the influence of AQP4 and astrocytes beyond the original suggestions related to regulation of extracellular potassium and water balance. Remarkably, AQP4 KO mice did not show deficits in basal transmission, suggesting specificity for long-term synaptic plasticity. The mechanism appears to be related to neurotrophins and specifically brain-derived neurotrophic factor (BDNF) because pharmacological blockade of neurotrophin trk receptors or scavenging ligands such as BDNF restored plasticity. The in vitro studies predicted effects in vivo of AQP4 deletion because AQP4 KO mice performed worse using a task that requires memory for the location of objects (object placement). However, performance on other hippocampal-dependent tasks was spared. The results suggest an unanticipated and selective role of AQP4 in synaptic plasticity and spatial memory, and underscore the growing appreciation of the role of glial cells in functions typically attributed to neurons. Implications for epilepsy are discussed because of the previous evidence that AQP4 influences seizures, and the role of synaptic plasticity in epileptogenesis., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

It is estimated that one in 26 people will develop epilepsy in their lifetime, amounting to almost 12 million people in the United States alone (Hesdorffer et al., 2011). Epilepsy is a group of conditions characterized by sporadic occurrence of seizures and unconsciousness. This severely limits the ability to perform everyday tasks and leads to increased difficulty with learning and memory, maintenance of steady employment, driving, and overall socioeconomic integration. A greater understanding of the cellular and molecular mechanisms underlying seizures and epilepsy is necessary, as it may lead to novel antiepileptic treatments. In this chapter, we will review the current literature surrounding the involvement of glial cells in epilepsy with particular emphasis on review of human tissue studies and some possible underlying mechanisms. Based on the current evidence and hypotheses of glial mechanisms in epilepsy, novel therapeutic opportunities for the treatment of epilepsy will also be presented., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Laser-based diagnostics and therapeutics show promise for many neurological disorders. However, the poor transparency of cranial bone (calvaria) limits the spatial resolution and interaction depth that can be achieved, thus constraining opportunity in this regard. Herein, we report preliminary results from efforts seeking to address this limitation through use of novel transparent cranial implants made from nanocrystalline yttria-stabilized zirconia (nc-YSZ). Using optical coherence tomography (OCT) imaging of underlying brain in an acute murine model, we show that signal strength is improved when imaging through nc-YSZ implants relative to native cranium. As such, this provides initial evidence supporting the feasibility of nc-YSZ as a transparent cranial implant material. Furthermore, it represents a crucial first step towards realization of an innovative new concept we are developing, which seeks to eventually provide a clinically-viable means for optically accessing the brain, on-demand, over large areas, and on a chronically-recurring basis, without need for repeated craniectomies., From the Clinical Editor: In this study, transparent nanocrystalline yttria-stabilized-zirconia is used as an experimental "cranium prosthesis" material, enabling the replacement of segments of cranial bone with a material that allows for optical access to the brain on a recurrent basis using optical imaging methods such as OCT., (© 2013.)

Great effort has been made toward defining and characterizing the pre-ictal state. Many studies have pursued the idea that there are recognizable electrographic (EEG-based) features which occur before overt clinical seizure activity. However, development of reliable EEG-based seizure detection and prediction algorithms has been difficult. In this review, we discuss the concepts of seizure detection vs. prediction and the pre-ictal "clinical milieu" and "EEG milieu". We proceed to discuss novel concepts of seizure detection based on the pre-ictal "physiological milieu"; in particular, we indicate some early evidence for the hypothesis that pre-ictal cell swelling/extracellular space constriction can be detected with novel optical methods. Development and validation of optical seizure detection technology could provide an entirely new translational approach for the many patients with intractable epilepsy., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Potassium (K(+)) ions released into brain extracellular space (ECS) during neuroexcitation are efficiently taken up by astrocytes. Deletion of astrocyte water channel aquaporin-4 (AQP4) in mice alters neuroexcitation by reducing ECS [K(+)] accumulation and slowing K(+) reuptake. These effects could involve AQP4-dependent: (a) K(+) permeability, (b) resting ECS volume, (c) ECS contraction during K(+) reuptake, and (d) diffusion-limited water/K(+) transport coupling. To investigate the role of these mechanisms, we compared experimental data to predictions of a model of K(+) and water uptake into astrocytes after neuronal release of K(+) into the ECS. The model computed the kinetics of ECS [K(+)] and volume, with input parameters including initial ECS volume, astrocyte K(+) conductance and water permeability, and diffusion in astrocyte cytoplasm. Numerical methods were developed to compute transport and diffusion for a nonstationary astrocyte-ECS interface. The modeling showed that mechanisms b-d, together, can predict experimentally observed impairment in K(+) reuptake from the ECS in AQP4 deficiency, as well as altered K(+) accumulation in the ECS after neuroexcitation, provided that astrocyte water permeability is sufficiently reduced in AQP4 deficiency and that solute diffusion in astrocyte cytoplasm is sufficiently low. The modeling thus provides a potential explanation for AQP4-dependent K(+)/water coupling in the ECS without requiring AQP4-dependent astrocyte K(+) permeability. Our model links the physical and ion/water transport properties of brain cells with the dynamics of neuroexcitation, and supports the conclusion that reduced AQP4-dependent water transport is responsible for defective neuroexcitation in AQP4 deficiency.

Optical coherence tomography (OCT) is a biomedical imaging technique with high spatial-temporal resolution. With its minimally invasive approach OCT has been used extensively in ophthalmology, dermatology, and gastroenterology. Using a thinned-skull cortical window (TSCW), we employ spectral-domain OCT (SD-OCT) modality as a tool to image the cortex in vivo. Commonly, an opened-skull has been used for neuro-imaging as it provides more versatility, however, a TSCW approach is less invasive and is an effective mean for long term imaging in neuropathology studies. Here, we present a method of creating a TSCW in a mouse model for in vivo OCT imaging of the cerebral cortex.

The most common technology for seizure detection is with electroencephalography (EEG), which has low spatial resolution and minimal depth discrimination. Optical techniques using near-infrared (NIR) light have been used to improve upon EEG technology and previous research has suggested that optical changes, specifically changes in near-infrared optical scattering, may precede EEG seizure onset in in vivo models. Optical coherence tomography (OCT) is a high resolution, minimally invasive imaging technique, which can produce depth resolved cross-sectional images. In this study, OCT was used to detect changes in optical properties of cortical tissue in vivo in mice before and during the induction of generalized seizure activity. We demonstrated that a significant decrease (P < 0.001) in backscattered intensity during seizure progression can be detected before the onset of observable manifestations of generalized (stage-5) seizures. These results indicate the feasibility of minimally-invasive optical detection of seizures with OCT.

Recent studies have implicated glial cells in modulation of synaptic transmission, so it is plausible that glial cells may have a functional role in the hyperexcitability characteristic of epilepsy. Indeed, alterations in distinct astrocyte membrane channels, receptors, and transporters have all been associated with the epileptic state. This review focuses on the potential roles of the glial water channel aquaporin-4 (AQP4) in modulation of brain excitability and in epilepsy. We will review studies of mice lacking AQP4 (Aqp4(-/-) mice) or α-syntrophin (an AQP4 anchoring protein) and discuss the available human studies demonstrating alterations of AQP4 in human epilepsy tissue specimens. We will conclude with new studies of AQP4 regulation and discuss the potential role of AQP4 in the development of epilepsy (epileptogenesis). While many questions remain unanswered, the available data indicate that AQP4 and its molecular partners may represent important new therapeutic targets., (Copyright © 2012 Wiley Periodicals, Inc.)

Object: Cerebral edema is a significant cause of morbidity and mortality in many disease states. Current therapies of cerebral edema are often ineffective in treating severe edema. Here, the authors develop a hollow fiber-hydrogel device (HFHD) for direct surface contact-based treatment of severe cerebral edema., Methods: Brain edema was induced in adult mice via water intoxication by intraperitoneal water administration (30% body weight). Control mice received no treatment. A distinct group of mice was treated with craniectomy but no device application (craniectomy only). A third experimental group was treated with craniectomy and HFHD application. The HFHD contained a lumen solution of 350 g/L bovine serum albumin in room-temperature artificial CSF at pH 7.4. Survival and brain water content were assessed as end points., Results: Craniectomy and application of the HFHD enhanced survival in animals with severe cerebral edema. Animals treated with a craniectomy and HFHD (n = 5) survived up to 5 hours longer than animals treated with craniectomy only (n = 5) (p < 0.001) or no treatment (n = 5) (p < 0.001). Animals treated with craniectomy and HFHD (n = 5) had a survival rate of 80% within the observation period (360 minutes), whereas no animal treated with craniectomy only (n = 5) or no treatment (n = 5) survived longer than 50 and 33 minutes, respectively. Statistical significance was observed for the survival rate between the animals treated with a craniectomy + HFHD (n = 5) versus those treated with craniectomy only (n = 5) (p < 0.001), and craniectomy + HFHD versus no treatment (n = 5) (p < 0.001). Histological analysis demonstrated no significant cell loss in the cortex subjacent to HFHD application., Conclusions: Here, the authors demonstrate the feasibility of their HFHD to treat cerebral edema in this model. These results indicate that controlled water extraction from edematous brain tissue can be performed and can lead to increased survival compared with craniectomy only. Further studies remain to be performed to further optimize the HFHD and to test it in more clinically relevant models, such as traumatic brain injury.

Recent evidence suggests that astrocytes may be a potential new target for the treatment of epilepsy. The glial water channel aquaporin-4 (AQP4) is expressed in astrocytes, and along with the inwardly-rectifying K(+) channel K(ir)4.1 is thought to underlie the reuptake of H(2)O and K(+) into glial cells during neural activity. Previous studies have demonstrated increased seizure duration and slowed potassium kinetics in AQP4(-/-) mice, and redistribution of AQP4 in hippocampal specimens from patients with chronic epilepsy. However, the regulation and role of AQP4 during epileptogenesis remain to be defined. In this study, we examined the expression of AQP4 and other glial molecules (GFAP, K(ir)4.1, glutamine synthetase) in the intrahippocampal kainic acid (KA) model of epilepsy and compared behavioral and histologic outcomes in wild-type mice vs. AQP4(-/-) mice. Marked and prolonged reduction in AQP4 immunoreactivity on both astrocytic fine processes and endfeet was observed following KA status epilepticus in multiple hippocampal layers. In addition, AQP4(-/-) mice had more spontaneous recurrent seizures than wild-type mice during the first week after KA SE as assessed by chronic video-EEG monitoring and blinded EEG analysis. While both genotypes exhibited similar reactive astrocytic changes, granule cell dispersion and CA1 pyramidal neuron loss, there were an increased number of fluorojade-positive cells early after KA SE in AQP4(-/-) mice. These results indicate a marked reduction of AQP4 following KA SE and suggest that dysregulation of water and potassium homeostasis occurs during early epileptogenesis. Restoration of astrocytic water and ion homeostasis may represent a novel therapeutic strategy., (Copyright © 2012 Elsevier Inc. All rights reserved.)

We investigated the role of aquaporin-4 in the development of cerebral edema following kainic acid-induced status epilepticus (SE) using specific gravimetry and T2 MRI techniques at 6 h, 1 day, 4 days and 7 days after SE. Our results indicate significantly greater tissue edema and T2 MRI changes in AQP4(-/-) compared to AQP4(+/+) mice that peaks at about 1 day after SE (greater in hippocampus relative to cortex). These results have implications for the mechanisms of edema formation and clearance following intense seizure activity., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Aquaporin-4 (AQP4) is the main water channel in the brain and primarily localized to astrocytes where the channels are thought to contribute to water and K(+) homeostasis. The close apposition of AQP4 and inward rectifier K(+) channels (Kir4.1) led to the hypothesis of direct functional interactions between both channels. We investigated the impact of AQP4 on stimulus-induced alterations of the extracellular K(+) concentration ([K(+)](o)) in murine hippocampal slices. Recordings with K(+)-selective microelectrodes combined with field potential analyses were compared in wild type (wt) and AQP4 knockout (AQP4(-/-)) mice. Astrocyte gap junction coupling was assessed with tracer filling during patch clamp recording. Antidromic fiber stimulation in the alveus evoked smaller increases and slower recovery of [K(+)](o) in the stratum pyramidale of AQP4(-/-) mice indicating reduced glial swelling and a larger extracellular space when compared with control tissue. Moreover, the data hint at an impairment of the glial Na(+)/K(+) ATPase in AQP4-deficient astrocytes. In a next step, we investigated the laminar profile of [K(+)](o) by moving the recording electrode from the stratum pyramidale toward the hippocampal fissure. At distances beyond 300 μm from the pyramidal layer, the stimulation-induced, normalized increases of [K(+)](o) in AQP4(-/-) mice exceeded the corresponding values of wt mice, indicating facilitated spatial buffering. Astrocytes in AQP4(-/-) mice also displayed enhanced tracer coupling, which might underlie the improved spatial re- distribution of [K(+)](o) in the hippocampus. These findings highlight the role of AQP4 channels in the regulation of K(+) homeostasis., (Copyright © 2011 Wiley-Liss, Inc.)

Increasing attention is being paid to the non-motor symptoms of Parkinson's disease (PD). While deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been shown to clearly improve motor symptoms of PD, the effects of STN DBS on autonomic symptoms have not been well studied. We examined 11 patients undergoing STN DBS for PD. Patients were administered a questionnaire by phone to evaluate pre-operative and post-operative function. Three out of the 11 patients reported marked improvement post-DBS in one or more symptoms of autonomic dysfunction (sweating, bladder, or bowel function). All three patients had early-onset PD (EOPD), whereas the eight patients reporting no significant improvement were those with late-onset PD. Thus, we found that some patients experienced marked improvement in sweating and/or bowel and bladder function after STN DBS, with a trend towards a response in patients with EOPD. Our results suggest the utility of a larger prospective study., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Aquaporin-4 (AQP4) is the major water channel in the CNS and is primarily expressed in astrocytes. Little is known about the potential for AQP4 to influence synaptic plasticity, although many studies have shown that it regulates the response of the CNS to injury. Therefore, we evaluated long-term potentiation (LTP) and long-term depression (LTD) in AQP4 knock-out (KO) and wild-type mice. KO mice exhibited a selective defect in LTP and LTD without a change in basal transmission or short-term plasticity. Interestingly, the impairment in LTP in KO mice was specific for the type of LTP that depends on the neurotrophin BDNF, which is induced by stimulation at theta rhythm [theta-burst stimulation (TBS)-LTP], but there was no impairment in a form of LTP that is BDNF independent, induced by high-frequency stimulation. LTD was also impaired in KO mice, which was rescued by a scavenger of BDNF or blockade of Trk receptors. TrkB receptors, which mediate effects of BDNF on TBS-LTP, were not altered in KO mice, but p75NTR, the receptor that binds all neurotrophins and has been implicated in some types of LTD, was decreased. The KO mice also exhibited a cognitive defect, which suggests a new role for AQP4 and astrocytes in normal cognitive function. This defect was evident using a test for location-specific object memory but not Morris water maze or contextual fear conditioning. The results suggest that AQP4 channels in astrocytes play an unanticipated role in neurotrophin-dependent plasticity and influence behavior.

Robert Bentley Todd, who is best remembered for "Todd's paralysis," made many more important contributions to neurology and neuroscience, including the concept of brain electricity and electrical discharges in epilepsy. He was also a pioneering microscopist and we here review his neurohistological studies and his contributions to the application of Schwann's (1839) cell theory to the nervous system and the later neuron doctrine, as described in his textbook The Descriptive and Physiological Anatomy of the Brain, Spinal Cord and Ganglions (Todd, 1845), his Cyclopaedia of Anatomy and Physiology (1847) and his joint textbook with William Bowman The Physiological Anatomy and Physiology of Man (1845). Writing in the mid-1840s, Todd acknowledged that the "vesicles" he observed corresponded to the earlier descriptions of "globules" or "kugeln" by Valentin and which Schwann first interpreted as cell bodies. Todd was among the first to recognize that nerve cell bodies were in continuity with axons ("axis cylinders"), sometimes associated with "the white substance of Schwann" ("tubular" fibers), or sometimes without ("gelatinous" fibers). He also described continuous nerve cell branching processes, later called dendrites. He was the first to recognize the insulating properties of Schwann's "white substance" (myelin) to facilitate conduction. Influenced by his contemporary, Faraday, Todd was also the first to develop the functional concept of dynamic polarization ("nervous polarity") to explain nerve cell conduction.

Mice deficient in the water channel aquaporin-4 (AQP4) demonstrate increased seizure duration in response to hippocampal stimulation as well as impaired extracellular K+ clearance. However, the expression of AQP4 in the hippocampus is not well described. In this study, we investigated (i) the developmental, laminar and cell-type specificity of AQP4 expression in the hippocampus; (ii) the effect of Kir4.1 deletion on AQP4 expression; and (iii) performed Western blot and RT-PCR analyses. AQP4 immunohistochemistry on coronal sections from wild-type (WT) or Kir4.1-/- mice revealed a developmentally-regulated and laminar-specific pattern, with highest expression in the CA1 stratum lacunosum-moleculare (SLM) and the molecular layer (ML) of the dentate gyrus (DG). AQP4 was colocalized with the glial markers glial fibrillary acidic protein (GFAP) and S100β in the hippocampus, and was also ubiquitously expressed on astrocytic endfeet around blood vessels. No difference in AQP4 immunoreactivity was observed in Kir4.1-/- mice. Electrophysiological and postrecording RT-PCR analyses of individual cells revealed that AQP4 and Kir4.1 were co-expressed in nearly all CA1 astrocytes. In NG2 cells, AQP4 was also expressed at the transcript level. This study is the first to examine subregional AQP4 expression during development of the hippocampus. The strikingly high expression of AQP4 in the CA1 SLM and DG ML identifies these regions as potential sites of astrocytic K+ and H2O regulation. These results begin to delineate the functional capabilities of hippocampal subregions and cell types for K+ and H2O homeostasis, which is critical to excitability and serves as a potential target for modulation in diverse diseases., (Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.)

Object: Cerebral edema is a significant cause of morbidity and mortality in diverse disease states. Currently, the means to detect progressive cerebral edema in vivo includes the use of intracranial pressure (ICP) monitors and/or serial radiological studies. However, ICP measurements exhibit a high degree of variability, and ICP monitors detect edema only after it becomes sufficient to significantly raise ICP. The authors report the development of 2 distinct minimally invasive fiberoptic near-infrared (NIR) techniques able to directly detect early cerebral edema., Methods: Cytotoxic brain edema was induced in adult CD1 mice via water intoxication by intraperitoneal water administration (30% body weight intraperitoneally). An implantable dual-fiberoptic probe was stereotactically placed into the cerebral cortex and connected to optical source and detector hardware. Optical sources consisted of either broadband halogen illumination or a single-wavelength NIR laser diode, and the detector was a sensitive NIR spectrometer or optical power meter. In one subset of animals, a left-sided craniectomy was performed to obtain cortical biopsies for water-content determination to verify cerebral edema. In another subset of animals, an ICP transducer was placed on the contralateral cortex, which was synchronized to a computer and time stamped., Results: Using either broadband illumination with NIR spectroscopy or single-wavelength laser diode illumination with optical power meter detection, the authors detected a reduction in NIR optical reflectance during early cerebral edema. The time intervals between water injection (Time Point 0), optical trigger (defined as a 2-SD change in optical reflectance from baseline), and defined threshold ICP values of 10, 15 and 20 mm Hg were calculated. Reduction in NIR reflectance occurred significantly earlier than any of the ICP thresholds (p < 0.001). Saline-injected control mice exhibited a steady baseline optical signal. There was a significant correlation between reflectance change and tissue specific gravity of the cortical biopsies, further validating the dual-fiberoptic probe as a direct measure of cerebral edema., Conclusions: Compared with traditional ICP monitoring, the aforementioned minimally invasive NIR techniques allow for the significantly earlier detection of cerebral edema, which may be of clinical utility in the identification and thus early treatment of cerebral edema.

We present an approach for rapidly and quantitatively mapping tissue absorption and scattering spectra in a wide-field, noncontact imaging geometry by combining multifrequency spatial frequency domain imaging (SFDI) with a computed-tomography imaging spectrometer (CTIS). SFDI overcomes the need to spatially scan a source, and is based on the projection and analysis of periodic structured illumination patterns. CTIS provides a throughput advantage by simultaneously diffracting multiple spectral images onto a single CCD chip to gather spectra at every pixel of the image, thus providing spatial and spectral information in a single snapshot. The spatial-spectral data set was acquired 30 times faster than with our wavelength-scanning liquid crystal tunable filter camera, even though it is not yet optimized for speed. Here we demonstrate that the combined SFDI-CTIS is capable of rapid, multispectral imaging of tissue absorption and scattering in a noncontact, nonscanning platform. The combined system was validated for 36 wavelengths between 650-1000 nm in tissue simulating phantoms over a range of tissue-like absorption and scattering properties. The average percent error for the range of absorption coefficients (μa) was less than 10% from 650-800 nm, and less than 20% from 800-1000 nm. The average percent error in reduced scattering coefficients (μs') was less than 5% from 650-700 nm and less than 3% from 700-1000 nm. The SFDI-CTIS platform was applied to a mouse model of brain injury in order to demonstrate the utility of this approach in characterizing spatially and spectrally varying tissue optical properties.

The glial water channel aquaporin-4 (AQP4) is implicated in the control of ion and osmohomeostasis in the sensory retina. Using retinal slices from AQP4-deficient and wild-type mice, we investigated whether AQP4 is involved in the regulation of glial cell volume under altered osmotic conditions. Superfusion of retinal slices with a hypoosmolar solution induced a rapid swelling of glial somata in tissues from AQP4 null mice but not from wild-type mice. The swelling was mediated by oxidative stress, inflammatory lipid mediators, and sodium influx into the cells and was prevented by activation of glutamatergic and purinergic receptors. Distinct inflammatory proteins, including interleukin-1 beta, interleukin-6, and inducible nitric oxide synthase, were up-regulated in the retina of AQP4 null mice compared with control, whereas cyclooxygenase-2 was down-regulated. The data suggest that water flux through AQP4 is involved in the rapid volume regulation of retinal glial (Müller) cells in response to osmotic stress and that deletion of AQP4 results in an inflammatory response of the retinal tissue. Possible implications of the data for understanding the pathophysiology of neuromyelitis optica, a human disease that has been suggested to involve serum antibodies to AQP4, are discussed., ((c) 2010 Wiley-Liss, Inc.)

Objective: Spinal cord injury (SCI) is accompanied by disruption of the blood-spinal cord barrier and subsequent extravasation of fluid and proteins, which results in edema (increased water content) at the site of injury. However, the mechanisms that control edema and the extent to which edema impacts outcome after SCI are not well elucidated., Methods: Here, we examined the role of aquaporin-4 (AQP4) water channels after experimental contusion injury in mice, a clinically relevant animal model of SCI., Results: Mice lacking AQP4 (AQP4(-/-) mice) exhibited significantly impaired locomotor function and prolonged bladder dysfunction compared with wild-type (WT) littermates after contusion SCI. Consistent with a greater extent of functional deterioration, AQP4(-/-) mice showed greater neuronal loss and demyelination, with prominent cyst formation, which is generally absent in mouse SCI. The extent of spinal cord edema, as expressed by percentage water content, was persistently increased above control levels in AQP4(-/-) mice but not WT mice at 14 and 28 days after injury. Immunohistochemical analysis indicated that blood vessels in the vicinity of the lesion core had incomplete barrier function because of sparse tight junctions., Interpretation: These results suggest that AQP4 plays a protective role after contusion SCI by facilitating the clearance of excess water, and that targeting edema after SCI may be a novel therapeutic strategy.

Purpose: Diffusion tensor imaging (DTI) studies have reported substantial white matter abnormalities in patients with temporal lobe epilepsy (TLE). However, limited data exist regarding the extent of white matter tract abnormalities, cognitive effects of these abnormalities, and relationship to clinical factors. The current study examined these issues in subjects with chronic TLE., Methods: DTI data were obtained in 12 TLE subjects and 10 age-matched healthy controls. Voxel-wise statistical analysis of fractional anisotropy (FA) was carried out using tract-based spatial statistics (TBSS). White matter integrity was correlated with cognitive performance and epilepsy-related clinical parameters., Results: Subjects with TLE, as compared to healthy controls, demonstrated four clusters of reduced FA, in anterior temporal lobe, mesial temporal lobe, and cerebellum ipsilateral, as well as frontoparietal lobe contralateral to the side of seizure onset. Mean FA was positively correlated with delayed memory, in anterior temporal lobe; and immediate memory, in mesial temporal lobe. Lower FA values in the posterior region of corpus callosum were related to earlier age of seizure onset., Conclusion: TLE is associated with widespread disturbances in white matter tracts and these changes have important cognitive and clinical consequences.

Object: Prior studies suggest that aura semiology may have localizing value. However, temporal lobe aura characteristics and response to surgery have not been studied in large patient series., Methods: The authors retrospectively analyzed the case records of 182 patients undergoing temporal lobectomy for medically intractable epilepsy at a single institution. They analyzed the frequency and type of auras and seizures preoperatively, and at 3 months and 1 year after temporal lobectomy. Auras were divided into medial semiology (rising epigastric, olfactory/gustatory, experiential, and fear) and lateral semiology (auditory, somatosensory, and visual), or other., Results: Of 182 patients, 150 were included in this study. The preoperative prevalence of auras was 77%. Multiple types of auras were present in 20% of patients. The most common aura was rising epigastric (26% of all auras). Postoperatively, auras were eliminated in 63% of patients at 3 months and in 64% at 1 year. Seventy-seven patients (51%) were seizure-free and aura-free, 22 (15%) were seizure-free with auras, 26 (17%) had seizures but no auras, and 25 (17%) had seizures with auras. Despite having their auras eliminated, 6.7% of patients continued to have complex partial seizures. Lateral temporal auras were more than twice as likely as medial temporal auras to persist after surgery (p < 0.002)., Conclusions: While the majority of patients in the authors' series became seizure- and aura-free, a significant minority still had persistent auras. Patients with lateral temporal auras appear to be at increased risk for having persistent postoperative auras. The discrepancy between aura and seizure outcomes results in a small group of patients having persistent seizures but losing their auras postoperatively.

On the bicentennial of Darwin's birth, we describe the origin of the calcar avis and summarize the debate around this structure, which played a central role in the evolution debate in the mid-19th century. We performed a comprehensive review of relevant neuroanatomic literature, bibliographic sources, and 19th century primary sources. Once known as the hippocampus minor, the structure now known as the calcar avis is an involution of the ventricular wall produced by the calcarine fissure. A heated debate raged between 2 prominent scientific theorists, Sir Richard Owen and Thomas Henry Huxley, over the presence of the hippocampus minor in apes versus humans. Owen put forward the lack of an identifiable hippocampus minor in humans as part of an attempt to debunk evolution. A bitter personal and academic rivalry ensued, as Huxley conducted his own dissections to refute Owen's claims. Huxley ultimately dismantled Owen's premises, securing the epithet "Darwin's bulldog" for his defense of the theory of evolution. Thus, this relatively obscure neuroanatomic landmark served as a pivotal point of contention in the most popularized and acrimonious evolutionary debate of the 19th century.

Purpose: The relative roles of stereotactic radiosurgery (SRS) vs. whole brain radiotherapy (WBRT) in the treatment of patients with brain metastases from breast cancer remain undefined. In this study, we reviewed our experience with these patients., Materials and Methods: We retrospectively reviewed all patients treated between 1991 and 2005 with Gamma Knife SRS for brain metastases from breast cancer. The actuarial survival and freedom from progression endpoints were calculated using the Kaplan-Meier method., Results: Between 1991 and 2005, 176 patients underwent SRS for brain metastases from breast cancer. The median survival time was 16.0 months for 95 newly diagnosed patients and 11.7 months for 81 patients with recurrent brain metastases. In the newly diagnosed patients, omission of upfront WBRT did not significantly affect the MST (p = .20), brain freedom from progression (p = .75), or freedom from new brain metastases (p = .83). Longer survival was associated with age <50 years, Karnofsky performance score >or=70, primary tumor control, estrogen receptor positivity, and Her2/neu overexpression. No association was found between the number of treated brain metastases and the survival time., Conclusion: We have described prognostic factors for breast cancer patients treated with SRS for newly diagnosed or recurrent brain metastases. Most patient subsets had a median survival time of >or=11 months. Unexpectedly, upfront WBRT did not appear to improve brain freedom from progression, and a larger number of brain metastases was not associated with a shorter survival time. Breast cancer might be distinct from other primary sites in terms of prognostic factors and the roles of WBRT and SRS for brain metastases.

Surgery within the third ventricle was a special challenge early in the conception of the discipline of neurosurgery due to a lack of diagnostic methods and difficulty in reaching and removing lesions affecting this vital region. Walter Dandy and Harvey Cushing performed pioneering approaches of the third ventricular region. The authors have reviewed the previously undisclosed efforts of Cushing to approach the third ventricle through a direct review of his available patient records at the Cushing Brain Tumor Registry. The authors compare these efforts to those of Dandy published in Dandy's pioneering work Benign Tumors in the Third Ventricle of the Brain: Diagnosis and Treatment. Based on the review of these records, the authors attempt to examine the foundations of surgery within the third ventricle.

Tumor-associated epilepsy is an important contributor to morbidity in patients with brain tumors. Proposed pathophysiological mechanisms to explain these effects range from neuronal and glial dysfunction to deranged vascular homeostasis, to ionic and pH changes. Perilesional tissue alterations play a vital role in the generation of tumor-associated seizures. Clinical studies have determined that tumor-associated seizures are usually focal with secondary generalization and often resistant to antiepileptic drugs. Tumor histopathological characteristics and location are independent factors that impact seizure burden. Further understanding of the mechanisms of tumor-associated epilepsy may lead to new types of treatments targeted at perilesional tissue alterations.

Astrocytes in different brain regions display variable functional properties. In the hippocampus, astrocytes predominantly express time- and voltage-independent currents, but the underlying ion channels are not well defined. This ignorance is partly attributable to abundant intercellular coupling of these cells through gap junctions, impeding quantitative analyses of intrinsic membrane properties. Moreover, distinct types of cells with astroglial properties coexist in a given brain area, a finding that confused previous analyses. In the present study, we investigated expression of inwardly rectifying (Kir) and two-pore-domain (K2P) K+ channels in astrocytes, which are thought to be instrumental in the regulation of K+ homeostasis. Freshly isolated astrocytes were used to improve space-clamp conditions and allow for quantitative assessment of functional parameters. Patch-clamp recordings were combined with immunocytochemistry, Western blot analysis, and semiquantitative transcript analysis. Comparative measurements were performed in different CA1 subregions of astrocyte-targeted transgenic mice. While confirming weak Ba2+ sensitivity in situ, our data demonstrate that in freshly isolated astrocytes, the main proportion of membrane currents is sensitive to micromolar Ba2+ concentrations. Upregulation of Kir4.1 transcripts and protein during the first 10 postnatal days was accompanied by a fourfold increase in astrocyte inward current density. Hippocampal astrocytes from Kir4.1-/- mice lacked Ba2+-sensitive currents. In addition, we report functional expression of K2P channels of the TREK subfamily (TREK1, TREK2), which mediate astroglial outward currents. Together, our findings demonstrate that Kir4.1 constitutes the pivotal K+ channel subunit and that superposition of currents through Kir4.1 and TREK channels underlies the "passive" current pattern of hippocampal astrocytes.

Neurocysticercosis is the most common parasitic infection in the CNS and a leading cause of epilepsy. Since it is a circumscribed lesional cause of epilepsy, specific locations of neurocysticercal lesions may lead to specific clinical presentations. The authors describe a 17-year-old Hispanic boy who had a single enhancing bilobar mass in the right amygdala. Initially, the patient presented with secondarily generalized tonic-clonic seizures, which resolved with antiepilepsy drug therapy. On further investigation, he was found to have persistent olfactory and déjà vu auras. A right amygdalectomy without hippocampectomy was performed, and both the seizures and auras immediately resolved. Pathological analysis revealed neurocysticercosis. To the authors' knowledge, this case is the first reported instance of 2 distinct mesial temporal aura semiologies associated with localized neurocysticercosis in the amygdala and successfully treated with resection. Uniquely, the case demonstrates that both olfactory and déjà vu auras can emanate from the amygdala.

Object: Parietal lobe epilepsy (PLE) accounts for a small percentage of extratemporal epilepsies, and only a few and mostly smaller series have been reported. Preoperative findings, surgical strategies, pathological bases, and postoperative outcomes for PLE remain to be elucidated., Methods: Patients with PLE were identified by screening a prospective epilepsy surgery database established in 1989 at the University of Bonn. Charts, preoperative imaging studies, surgical reports, and neuropathological findings were reviewed. Seizure outcome was classified according to Engel class (I-IV)., Results: Forty patients (23 females and 17 males) with PLE were identified and had a mean age of 25.0 years and a mean preoperative epilepsy duration of 13.7 years. Nine patients had a significant medical history (for example, trauma, meningitis/encephalitis, or perinatal hypoxia). Preoperative MR imaging abnormalities were identified in 38 (95%) of 40 patients; 26 patients (65%) underwent invasive electroencephalography evaluation. After lesionectomy of the dominant (in 20 patients) or nondominant (in 20 patients) parietal lobe and additional multiple subpial transections (in 11 patients), 2 patients suffered from surgical and 12 from neurological complications, including temporary partial Gerstmann syndrome. There were no deaths. Histopathological analysis revealed 16 low-grade tumors, 11 cortical dysplasias, 9 gliotic scars, 2 cavernous vascular malformations, and 1 granulomatous inflammation. In 1 case, no histopathological diagnosis could be made. After a mean follow-up of 45 months, 27 patients (67.5%) became seizure free or had rare seizures (57.5% Engel Class I; 10% Engel Class II; 27.5% Engel Class III; and 5% Engel Class IV)., Conclusions: Parietal lobe epilepsy is an infrequent cause of extratemporal epilepsy. Satisfactory results (Engel Classes I and II) were obtained in 67.5% of patients in our series. A temporary partial hemisensory or Gerstmann syndrome occurs in a significant number of patients.