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The discovery that electroencephalography (EEG) contains useful information at frequencies above the traditional 80Hz limit has had a profound impact on our understanding of brain function. In epilepsy, high-frequency oscillations (HFOs, >80Hz) have proven particularly important and useful. This literature review describes the morphology, clinical meaning, and pathophysiology of epileptic HFOs. To record HFOs, the intracranial EEG needs to be sampled at least at 2,000Hz. The oscillatory events can be visualized by applying a high-pass filter and increasing the time and amplitude scales, or EEG time-frequency maps can show the amount of high-frequency activity. HFOs appear excellent markers for the epileptogenic zone. In patients with focal epilepsy who can benefit from surgery, invasive EEG is often required to identify the epileptic cortex, but current information is sometimes inadequate. Removal of brain tissue generating HFOs has been related to better postsurgical outcome than removing the seizure onset zone, indicating that HFOs may mark cortex that needs to be removed to achieve seizure control. The pathophysiology of epileptic HFOs is challenging, probably involving populations of neurons firing asynchronously. They differ from physiological HFOs in not being paced by rhythmic inhibitory activity and in their possible origin from population spikes. Their link to the epileptogenic zone argues that their study will teach us much about the pathophysiology of epileptogenesis and ictogenesis. HFOs show promise for improving surgical outcome and accelerating intracranial EEG investigations. Their potential needs to be assessed by future research., (Copyright © 2012 American Neurological Association.)

Neuronal synchronisation at gamma frequencies (30-100 Hz) has been implicated in cognition and memory. Gamma oscillations can be studied in various in vitro models, but their in vivo validity and their relationship with reference memory remains to be proven. By using the natural variation of wild type C57bl/6J mice, we assessed the relationships between reference memory and gamma oscillations recorded in hippocampal area CA3 in vivo and in vitro. Local field potentials (LFPs) were recorded from area CA3 in behaviourally-characterised freely moving mice, after which hippocampal slices were prepared for recordings in vitro of spontaneous gamma oscillations and kainate-induced gamma oscillations in CA3. The gamma-band power of spontaneous oscillations in vitro correlated with that of CA3 LFP oscillations during inactive behavioural states. The gamma-band power of kainate-induced oscillations correlated with the activity-dependent increase in CA3 LFP gamma-band power in vivo. Kainate-induced gamma-band power correlated with Barnes circular platform performance and object location recognition, but not with object novelty recognition. Kainate-induced gamma-band power was larger in mice that recognised the aversive context, but did not correlate with passive avoidance delay. The correlations between behavioural and electrophysiological measures obtained from the same animals show that the gamma-generating capacity of the CA3 network in vitro is a useful index of in vivo gamma strength and supports an important role of CA3 gamma oscillations in spatial reference memory., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Sixty years ago the clinical neurophysiology of epilepsy had progressed to the stage that it posed questions that could be addressed by major advances in cellular electrophysiology made around the that time. However, it took about 25-30 years to build up serious momentum in understanding the mechanisms of epileptic discharges. Over the past 2-3 decades developments in pharmacology and molecular biology have substantially increased the depth and complexity of our insights into the nervous system in general and the epileptic brain in particular. One of the biggest advances in our understanding of the brain is in its plasticity in the adult - that is its ability to modify its structure and function. The current state of play is that for most chronic epileptic foci it is possible to identify multiple differences from normal brain tissue in both the structure and function of neurons, neuronal networks and glia. This review will chart some of this progress to give an idea of the pace of advances over the decades., (Copyright © 2010 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Brain stimulation is currently used as an experimental treatment for patients with medically refractory epilepsy. However, the results of such stimulation are still less than optimal. A major factor is the lack of understanding of the mechanisms of applied stimuli. Herein we review evidence on the effects of stimulation in models of epileptic seizures. We show that the effects of stimulation during epileptic seizures can differ from those observed under normal conditions. Several studies suggest a potentially greater beneficial therapeutic effect of strong depolarizing and overactivating stimulations than hyperpolarizing ones in the treatment of seizures. The potential relevance of these results to other therapeutic stimulation protocols is discussed.

How seizures start is a major question in epilepsy research. Preictal EEG changes occur in both human patients and animal models, but their underlying mechanisms and relationship with seizure initiation remain unknown. Here we demonstrate the existence, in the hippocampal CA1 region, of a preictal state characterized by the progressive and global increase in neuronal activity associated with a widespread buildup of low-amplitude high-frequency activity (HFA) (>100 Hz) and reduction in system complexity. HFA is generated by the firing of neurons, mainly pyramidal cells, at much lower frequencies. Individual cycles of HFA are generated by the near-synchronous (within approximately 5 ms) firing of small numbers of pyramidal cells. The presence of HFA in the low-calcium model implicates nonsynaptic synchronization; the presence of very similar HFA in the high-potassium model shows that it does not depend on an absence of synaptic transmission. Immediately before seizure onset, CA1 is in a state of high sensitivity in which weak depolarizing or synchronizing perturbations can trigger seizures. Transition to seizure is characterized by a rapid expansion and fusion of the neuronal populations responsible for HFA, associated with a progressive slowing of HFA, leading to a single, massive, hypersynchronous cluster generating the high-amplitude low-frequency activity of the seizure.

High-frequency electrographic activity (HFA) has a frequency of 80-600Hz. It can be observed interictally in epileptic foci and also at the onset of epileptic seizures. There are several hypotheses about how HFA is generated, and it has been suggested that the underlying mechanisms may play an important role in epileptogenesis and ictogenesis. The high specificity of HFA for epileptic foci is now used during presurgical evaluation to help localize epileptic focus. In this article we review the current state of knowledge regarding this phenomenon and challenges for the future studies focusing on HFA., (Copyright 2009 Elsevier B.V. All rights reserved.)

Powerline contamination of recorded signals represents a major source of noise in electrophysiology and impairs the use of recordings for research. In this article we present simple and effective method for cancelling 50 Hz (or 60 Hz) noise using a reference noise signal and average noise cycle subtraction. This method is capable of reliably removing not only the fundamental powerline frequency but also its harmonic frequencies. The efficiency of this method appears to be superior to other commonly used methods such as notch filtering or adaptive filtering. Our experience and results show that this method can be efficiently used with very low signal-to-noise ratios, while preserving original signal waveform.

The patho-physiological hypothesis of mental retardation caused by the deficiency of the RhoGAP Oligophrenin1 (OPHN1), relies on the well-known functions of Rho GTPases on neuronal morphology, i.e. dendritic spine structure. Here, we describe a new function of this Bin/Amphiphysin/Rvs domain containing protein in the control of clathrin-mediated endocytosis (CME). Through interactions with Src homology 3 domain containing proteins involved in CME, OPHN1 is concentrated to endocytic sites where it down-regulates the RhoA/ROCK signaling pathway and represses the inhibitory function of ROCK on endocytosis. Indeed disruption of Ophn1 in mice reduces the endocytosis of synaptic vesicles and the post-synaptic alpha-amino-3-hydroxy-5-methylisoazol-4-propionate (AMPA) receptor internalization, resulting in almost a complete loss of long-term depression in the hippocampus. Finally, pharmacological inhibition of this pathway by ROCK inhibitors fully rescued not only the CME deficit in OPHN1 null cells but also synaptic plasticity in the hippocampus from Ophn1 null model. Altogether, we uncovered a new patho-physiological mechanism for intellectual disabilities associated to mutations in RhoGTPases linked genes and also opened new directions for therapeutic approaches of congenital mental retardation.

Neuronal synchronization at gamma frequency, implicated in cognition, can be evoked in hippocampal slices by pharmacological activation. We characterized spontaneous small-amplitude gamma oscillations (SgammaO) recorded in area CA3 of mouse hippocampal slices and compared it with kainate-induced gamma oscillations (KgammaO). SgammaO had a lower peak frequency, a more sinusoidal waveform and was spatially less coherent than KgammaO, irrespective of oscillation amplitude. CA3a had the smallest oscillation power, phase-led CA3c by approximately 4 ms and had the highest SgammaO frequency in isolated subslices. During SgammaO CA3c neurons fired at the rebound of inhibitory postsynaptic potentials (IPSPs) that were associated with a current source in stratum lucidum, whereas CA3a neurons often fired from spikelets, 3-4 ms earlier in the cycle, and had smaller IPSPs. Kainate induced faster/larger IPSPs that were associated with an earlier current source in stratum pyramidale. SgammaO and KgammaO power were dependent on alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, gap junctions and gamma-aminobutyric acid (GABA)(A) receptors. SgammaO was suppressed by elevating extracellular KCl, blocking N-methyl-d-aspartate (NMDA) receptors or muscarinic receptors, or activating GluR5-containing kainate receptors. SgammaO was not affected by blocking metabotropic glutamate receptors or hyperpolarization-activated currents. The adenosine A(1) receptor antagonist 8-cyclopentyl-1,3-dimethoxyxanthine (8-CPT) and the CB1 cannabinoid receptor antagonist N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251) increased SgammaO power, indicating that endogenous adenosine and/or endocannabinoids suppress or prevent SgammaO in vitro. SgammaO emerges from a similar basic network as KgammaO, but differs in involvement of somatically projecting interneurons and pharmacological modulation profile. These observations advocate the use of SgammaO as a natural model for hippocampal gamma oscillations, particularly during less activated behavioural states.

Prion diseases are heterogeneous in clinical presentation, suggesting that different prion diseases have distinct pathophysiological changes. To understand the pathophysiology specific to variant Creutzfeldt-Jakob Disease (vCJD), in vitro electrophysiological studies were performed in a mouse model in which human-derived vCJD prions were transmitted to transgenic mice expressing human instead of murine prion protein. Paired-pulse stimulation of the Schaffer collaterals evoked hypersynchronous bursting in the hippocampus of vCJD-inoculated mice; comparable bursts were never observed in control or Prnp knockout mice, or in mice inoculated with a strain of prion associated with classical CJD. Furthermore, NMDA receptor-mediated excitation was increased in vCJD-inoculated mice. Using pharmacological experiments and computer simulations, we demonstrate that the increase in NMDA receptor-mediated excitation is necessary and sufficient to explain the distinctive bursting pattern in vCJD. These pathophysiological changes appear to result from a prion strain-specific gain-of-function and may explain some of the distinguishing clinical features of vCJD.

Neuronal population oscillations in the hippocampus have an important effect in the information processing in the brain and the generation of epileptic seizures. In this paper, we investigate the neuronal population oscillations in the hippocampus of epileptic rats in vivo using an empirical mode decomposition (EMD) method. A neuronal population oscillation can be decomposed into several relaxation oscillations, which possess a recovery and release phase, with the different frequencies that ranges from 0 to 600 Hz. The natures of relaxation oscillations at the pre-ictal, seizure onset and ictal states are distinctly different. The analysis of relaxation oscillations show that the gamma wave is a lead relaxation oscillation at the pre-ictal stage, then it moves to beta oscillation or theta oscillation while the ictal stage starts; the fast relaxation oscillations are associated with the slow relaxation oscillations in the CA1 or CA3, in particular, the fast relaxation oscillations are associated on the recovery phase of the slow relaxation oscillations during the pre-ictal interval, however move to the release phase of the slow relaxation oscillations during the ictal interval. Comparison of the relaxation oscillations in CA1 and CA3 shows that the neurons in the CA1 are more active during the epileptic seizures than during the pre-ictal stage. These findings demonstrate that this method is very helpful to decompose neuronal population for understanding the underlying mechanism of epileptic seizures.

High-frequency activity has been described as having a role in the initiation of epileptic seizures. The case of a patient with refractory bitemporal epilepsy is presented. Extraoperative monitoring with depth and subdural electrodes revealed an ictal pattern with a build-up of high-frequency (> 80 Hz) activity originating in the cortex, with spread to both hippocampi. This observation was only revealed with the use of high-pass filtering, and represented crucial information that significantly influenced the decision about the side, localization and extent of resection. Removal of the cortex generating high-frequency activity, led to cessation of seizures in this patient. Current knowledge about the role of high-frequency activity and the case presented here support the importance of recording with equipment capable of detecting fast activity during the presurgical invasive monitoring. An active search for a high-frequency seizure onset zone in patients with structurally-unaffected hippocampi may improve the outcome beyond that possible with conventional bandwidth, invasive EEG recordings.

Prion protein (PrP) is a normal component of neurons, which confers susceptibility to prion diseases. Despite its evolutionary conservation, its normal function remains controversial. PrP-deficient (Prnp(0/0)) mice have weaker afterhyperpolarizations (AHPs) in cerebellar and hippocampal neurons. Here we show that the AHP impairment in hippocampal CA1 pyramidal cells is selective for the slow AHP, and is not caused by an impairment of either voltage-gated Ca(2+) channels or Ca(2+)-activated K(+) channels. Instead, Prnp(0/0) neurons have twofold to threefold stronger Ca(2+) buffering and double the Ca(2+) extrusion rate. In Prnp(0/0) neurons thapsigargin abolished the stronger Ca(2+) buffering and extrusion, and thapsigargin or cyclopiazonic acid abolished the weakening of the slow AHPs. These data implicate sarcoplasmic/endoplasmic reticulum calcium ATPase in the enhanced Ca(2+) buffering, and extrusion into the endoplasmic reticulum, which contains substantial amounts of PrP in wild-type mice. Altered Ca(2+) homeostasis can explain several phenotypes identified in Prnp(0/0) mice.

Currently, no treatment can prevent the cognitive and motor decline associated with widespread neurodegeneration in prion disease. However, we previously showed that targeting endogenous neuronal prion protein (PrP(C)) (the precursor of its disease-associated isoform, PrP(Sc)) in mice with early prion infection reversed spongiform change and prevented clinical symptoms and neuronal loss. We now show that cognitive and behavioral deficits and impaired neurophysiological function accompany early hippocampal spongiform pathology. Remarkably, these behavioral and synaptic impairments recover when neuronal PrP(C) is depleted, in parallel with reversal of spongiosis. Thus, early functional impairments precede neuronal loss in prion disease and can be rescued. Further, they occur before extensive PrP(Sc) deposits accumulate and recover rapidly after PrP(C) depletion, supporting the concept that they are caused by a transient neurotoxic species, distinct from aggregated PrP(Sc). These data suggest that early intervention in human prion disease may lead to recovery of cognitive and behavioral symptoms.

The CA1 region of the rat hippocampal slice generates spontaneous electrographic seizures (field bursts) when exposed to ACSF containing < or = 0.2 mM calcium. It has been proposed that, particularly during the early part of a field burst, synchronised activity in small independent aggregates of neurons results in low amplitude irregular population spikes and subsequent fusion of aggregates generates high amplitude, regular discharging spikes. In the present experiments, we have tested the hypothesis that progression from aggregate formation to aggregate fusion requires a critical mass of participating neurons. We found that isolated CA1 segments >2 mm are still able to generate high amplitude, regular discharging population spikes, but when segment length is reduced to 1-2 mm, only 29% generate spikes with these characteristics; in the remainder, the field burst shows a DC shift+/-low amplitude irregular population spikes. No field bursts were seen in segments < 0.7 mm or in 50% of those 0.7-1 mm in length (in the remaining 50%, only the DC component of the field burst was present). Exposing 1-2 mm segments to hypo-osmolar perfusate induced a return of high amplitude rhythmic discharging population spikes in the field burst. We interpret these observations by indicating that progression from aggregate formation to aggregate fusion requires a critical neuronal mass and can be enhanced by reducing osmolarity of the perfusate.

The physical basis for electrical stimulation of excitable tissue, as used by electrophysiological researchers and clinicians in functional electrical stimulation, is presented with emphasis on the fundamental mechanisms of charge injection at the electrode/tissue interface. Faradaic and non-Faradaic charge transfer mechanisms are presented and contrasted. An electrical model of the electrode/tissue interface is given. The physical basis for the origin of electrode potentials is given. Various methods of controlling charge delivery during pulsing are presented. Electrochemical reversibility is discussed. Commonly used electrode materials and stimulation protocols are reviewed in terms of stimulation efficacy and safety. Principles of stimulation of excitable tissue are reviewed with emphasis on efficacy and safety. Mechanisms of damage to tissue and the electrode are reviewed.

Infectious prion diseases may be acquired, sporadic or inherited in their aetiology. Inherited prion diseases are caused by coding mutations in the prion protein (PrP) gene. We investigated whether one of the commonest of these mutations, E200K, results in a functionally inactive prion protein by expressing human PrP 200K in transgenic mice homozygous for murine PrP null alleles. We examined the intrinsic properties of hippocampal CA1 pyramidal cells in these mice by measuring the resting potential, time constants and amplitude of the slow after-hyperpolarisation (AHP). These mice show rescue of the reduced slow AHP electrophysiological phenotype found in PrP null mice. Using the AHP as a marker for PrP function, we conclude that this pathogenic PrP mutation, does not significantly affect the normal neuronal function of PrP.