Exploring the variability of single trials in somatosensory evoked responses using constrained source extraction and RMT.

This paper describes the theoretical background of a new data-driven approach to encephalographic single-trial (ST) data analysis. Temporal constrained source extraction using sparse decomposition identifies signal topographies that closely match the shape characteristics of a reference signal, one response for each ST. The correlations between these ST topographies are computed for formal Correlation Matrix Analysis (CMA) based on Random Matrix Theory (RMT). The RMT-CMA provides clusters of similar ST topologies in a completely unsupervised manner. These patterns are then classified into deterministic set and noise using well established RMT results. The efficacy of the method is applied to EEG and MEG data of somatosensory evoked responses (SERs). The results demonstrate that the method can recover brain signals with time course resembling the reference signal and follow changes in strength and/or topography in time by simply stepping the reference signal through time.

Involvement of the thalamocortical system in epileptic loss of consciousness.

Experiments on putative neuronal mechanisms underlying absence seizures as well as clinical observations are critically reviewed for their ability to explain apparent "loss of consciousness." It is argued that the initial defect in absences lies with corticothalamic (CT) neuronal mechanisms responsible for selective attention and/or planning for action, rather than with those establishing either the states or the contents of consciousness. Normally, rich thalamocortical (TC)-CT feedback loops regulate the flow of information to the cortex and help its neurons to organize themselves in discrete assemblies, which through high-frequency (>30 Hz) oscillations bind those distributed processes of the brain that are considered important, so that we are able to focus on what is needed from moment to moment and be aware of this fact. This ability is transiently lost in absence seizures, because large numbers of CT loops are recruited for seconds in much stronger, low-frequency ( approximately 3 Hz) oscillations of EPSP/IPSP sequences, which underlie electroencephalographic (EEG) spike-and-wave discharges (SWDs). These oscillations probably result from a transformation of the normal EEG rhythm of sleep spindles on an abnormal increase of cortical excitability that results in strong activation of inhibitory neurons in the cortex and in nucleus reticularis thalami. The strong general enhancement of CT feedback during SWDs may disallow the discrete feedback, which normally selects specific TC circuits for conscious perception and/or motor reaction. Such a mechanism of SWD generation allows variability in the extent to which different TC sectors are engaged in the SWD activity and thus explains the variable ability of some patients to respond during an absence, depending on the sensory modality examined.

Modeling of evoked field potentials in hippocampal CA1 area describes their dependence on NMDA and GABA receptors.

A computer model of the hippocampal CA1 area, which receives synaptic inputs from CA3 neurons via the Schaffer collaterals, was constructed. Pyramidal cells (PC) and two types of interneurons were represented by compartmental models, and mechanisms of feed-forward inhibition (FFI) and recurrent inhibition were incorporated. Four types of receptor mediated synaptic conductances were used in the model: those of AMPA, GABA(A), GABA(B) and N-methyl-D-aspartate (NMDA). The output of the model, i.e. the field potential calculated at various points in space, was able to qualitatively reproduce the main features of field potentials, which were recorded in hippocampal slices maintained in vitro for both subthreshold and suprathreshold stimulation. In both the experiments and the model, the influence of NMDA and GABA synaptic currents affected mostly the late, decaying phase of evoked field potentials. The modeled interaction of NMDA and GABA components could explain the enhancement of the field potential late phase, which was observed experimentally during paired-pulse stimulation.

Spike-and-wave discharges of absence seizures as a transformation of sleep spindles: the continuing development of a hypothesis.

OBJECTIVES: This review aims to offer a critical account of recent scientific developments relevant to the hypothesis which Pierre Gloor proposed in the 1970s for the generation of spike and wave discharges (SWDs) of primary generalized absence seizures. RESULTS: According to this hypothesis SWDs develop in the same circuits, which normally generate sleep spindles, by an initially cortical transformation of one every two or more spindle waves to a 'spike' component of SWDs, while the next one or more spindle waves are eliminated and replaced by a slow negative wave. This hypothesis was based on experiments in feline generalized penicillin epilepsy showing the possibility of transition from spindles to SWDs, when cortical neurons become hyper-responsive to thalamocortical volleys, which normally induce spindles, and thus engage feedback cortical inhibition, rebound excitation, recurrent intracortical dissemination of excitation during the 'spike' and strong excitation of thalamus for further augmentation of a brain wide synchronous oscillation. In the 1980s, electrophysiological studies in vitro and in vivo revealed the basic features of spindle rhythm generation by neurons in nucleus reticularis thalami and thalamocortical-corticothalamic oscillatory reverberations. CONCLUSIONS: In the light of this knowledge, experimental studies in several genetic and pharmacological animal models of absence seizures, clinical observations and theoretical studies in computer models have considered, tested, modified and challenged this hypothesis. It may still be found useful in the era of dynamic digital EEG analysis of SWDs and its current sources.

Novel approach to a quantitative treatment of the quantal transmitter release at the frog neuromuscular junction.

To explain the discrepancy between estimates of parameters of quantal transmitter release received by different techniques the paper postulates a novel concept for quanta mobilization, which assumes that a quantum emitted by a vesicle transiently acquires a transition state in which it is immediately available for release. The working particle model is formulated in terms of probabilities of inter-state quanta transitions. The parameters of the model are determined by fitting solutions to the experimental curves representing short-term changes of synaptic efficacy at the frog neuromuscular junction as well as taking into account the morphologically estimated number of releasable vesicles. The value of the model is demonstrated by successful prediction of the estimates of the parameters of the quantal transmitter release suggested by evidence received from different lines of research.

Stochastic particle formulation of the vesicle hypothesis. Relevance to short-term phenomena.

Based on the vesicle hypothesis, the modes of elementary quantum-vesicle interactions have been formulated in terms of probabilities of induced and spontaneous interstate quanta transitions and generalized within the framework of the previously developed theory of the double barrier synapse. Among the three allowed states for a quantum, the transition state is a novel formulation for the fraction of immediately available quanta governed by both vesicle and presynaptic membranes. The parameters of the model were determined by fitting solutions to the experimental curves representing effects of single pulse and short train activation on transmitter release at the frog neuromuscular junction. Qualitative differences in particle physics of transmitter release found under low quantal outputs on one hand and normal transmission on the other allowed the formulation of the uncertainty hypothesis and the quantum condition of synaptic homeostasis.

Mediastinal cystic hygroma: report of a case with review of the literature.

Cystic hygroma is a developmental malformation of the lymphatic system. It is very uncommon for this type of tumor to arise from and grow exclusively in the mediastinum. Enlargement of such a lesion within this region often produces alarming respiratory symptoms requiring immediate medical attention.

The tottering mouse: a critical review of its usefulness in the study of the neuronal mechanisms underlying epilepsy.

The tottering mouse resulted from a recessively inherited, autosomal, single-locus mutation which produces a very characteristic neurological and cellular phenotype. Almost simultaneously and late in the development of this mutant appears a triad of symptoms: frequent episodes of absence seizures with spike-and-wave discharges; more rarely occurring episodes of focal motor seizures; and ataxia. Electrographic, behavioural and pharmacological similarities to absence epilepsy in man make the tottering mouse a useful animal model for testing new anti-absence drugs. It also affords a unique opportunity to study the effects of multiple alleles on epileptic behaviour. The neuronal mechanisms underlying the generation of absence seizures in this mutant are apparently a combination of a generalized noradrenergic hyperactivity in the brain and some gene-linked, but unknown, conditions prevailing in an earlier phase of development at specific brain areas which induce the generalized forebrain hyper-innervation by locus coeruleus terminals. Several biochemically, microscopically and electrophysiologically identified cellular differences between normal and tottering mice are potential aspects of this primary developmental defect. Research into these gene-linked neuronal characteristics co-inherited with seizures in this mutant makes the tottering mouse a powerful tool in the study of cellular mechanisms underlying genetically determined factors in epileptogenesis.

Possible mechanisms underlying hyperexcitability in the epileptic mutant mouse tottering.

Tottering mice present a useful experimental model of genetically determined generalized epilepsy of the absence type. In electrophysiological recordings from hippocampal slices in vitro we found that the postsynaptic excitability (firing threshold) of pyramidal neurons in the CA1 area of tg/tg slices was significantly higher than that of normal slices. In spite of this hyperexcitability, in vitro epileptiform discharges were not observed spontaneously, or upon provocation by intracellular depolarizing pulses, or in response to moderate elevations (+2 mM) in extracellular potassium. The latter elevations actually induced significantly smaller increases in the CA1 synaptic responses of tg/tg as compared to normal slices. The hyperexcitability of tottering neurons could not be explained in terms of altered membrane electrical properties or any reduction of synaptic inhibition or increased capacity for long-term potentiation. Responses to noradrenaline, histamine and adenosine, as well as to the release of N-methyl-D-aspartate channels--by eliminating Mg(2+)--were comparable in tg/tg and normal slices. These studies show that hyperexcitability can be co-inherited with epilepsy and in this model its expression can be maintained in vitro. The neuronal mechanism of this expression remains elusive, as it does not appear to include some features known to be shared by experimental models of chemically or electrically induced epilepsy.

Effects of adenosine and adenine nucleotides on synaptic transmission in the cerebral cortex.

Adenosine and the adenine nucleotides have a potent depressant action on cerebral cortical neurons, including identified corticospinal cells. Other purine and pyrimidine nucleotides were either weakly depressant (inosine and guanosine derivatives) or largely inactive (xanthine, cytidine, thymidine, uridine derivatives). The 5'-triphosphates and to a lesser extent the 5'-diphosphates of all the purine and pyrimidines tested had excitant actions on cortical neurons. Adenosine transport blockers and deaminase inhibitors depressed the firing of cortical neurons and potentiated the depressant actions of adenosine and the adenine nucleotides. Methylxanthines (theophylline, caffeine, and isobutylmethylxanthine) antagonized the depressant effects of adenosine and the adenine nucleotides and enhanced the spontaneous firing rate of cerebral cortical neurons. Intracellular recordings showed that adenosine 5'-monophosphate hyperpolarizes cerebral cortical neurons and suppresses spontaneous and evoked excitatory postsynaptic potentials in the absence of any pronounced alterations in membrane resistance or of the threshold for action potential generation. It is suggested that adenosine depresses spontaneous and evoked activity by inhibiting the release of transmitter from presynaptic nerve terminals. Furthermore, the depressant effects of potentiators and excitant effects of antagonists of adenosine on neuronal firing are consistent with the hypothesis that cortical neurons are subject to control by endogenously released purines.

Effects of changes in cortical excitability upon the epileptic bursts in generalized penicillin epilepsy of the cat.

Previous studies had suggested that the epileptic bursts of feline generalized penicillin epilepsy represent the response of hyperexcitable cortex to thalamocortical volleys normally evoking spindles. If this were the case, it should be possible to convert the epileptic bursts of generalized penicillin epilepsy into spindles by decreasing the excitability of cortical neurons. In cats exhibiting the EEG signs of feline generalized penicillin epilepsy cortical excitability was decreased by hypoxia, by the topical application to the cortex of KCl (inducing spreading depression), barbiturates, GABA, AMP or noradrenaline. During generalized penicillin epilepsy, hypoxia and KCl-induced spreading depression abolished epileptic bursts which were replaced by spindles. When spindles and epileptic complexes occurring in the same animal were compared, a direct correlation between the frequencies of these two rhythms could be demonstrated, that of the epileptic complexes being about half that of the spindle waves. These observations support the hypothesis that the epileptic bursts of feline generalized penicillin epilepsy are induced by thalamocortical volleys normally involved in spindle genesis. Topical cortical applications of barbiturates, GABA, AMP and noradrenaline reduced or inverted the negative spikes of the spike and wave complexes, while augmenting the negative slow waves, or revealing them clearly in instances in which they had been poorly developed. This effect is interpreted as being due to a selective inactivation of the superficial cortical layers. That topical cortical application of barbiturates, GABA, AMP and noradrenaline was capable of transforming into typical spike and wave complex epileptic bursts, which had not previously conformed to this pattern, indicates that the intracortical electrophysiological events of typical and atypical epileptic bursts in feline generalized penicillin epilepsy are fundamentally the same and reflect an alternation between excitatory and inhibitory sequences.

On the specificity of histamine H2-receptor antagonists in the rat cerebral cortex.

The effects of iontophoretically applied histamine H2-receptor antagonists and their antagonism of various amines, acetylcholine (ACh), and adenosine 5'-monophosphate (5'-AMP) were studied on spontaneously active rat cerebral cortical neurons. Metiamide selectively blocked the depressant actions of histamine. Burimamide, in amounts necessary for histamine antagonism, also antagonized the depressant effects of noradrenaline, dopamine, and 5-hydroxytryptamine. Neither antagonist affected 5'-AMP-induced depressions, but both reduced or blocked the excitatory actions of ACh. It is concluded that metiamide may be useful as a reliable antagonist of H2 receptors on cerebral cortical neurons.

Microiontophoretic studies of the effects of false transmitter candidates and amphetamine on cerebellar Purkinje cells.

The effects of microiontophoretic applications of equivalent doses (ejection times and currents) of noradrenaline, amphetamine, octopamine and p-hydroxynorephedrine on the spontaneous firing of Purkinje and unidentified cells in the cerebellum of rats were examined. In addition, the effects of amphetamine of Purkinje cells were examined in animals pretreated with the tyrosine hydroxylase inhibitor, alpha-methyltyrosine (alpha-MpT) or with a combination of reserpine plus alpha-MpT. The results indicate that the "false transmitters" are weak agonists when compared to noradrenaline in inhibiting the firing of Purkinje cells. The results of the iontophoretic studies with amphetamine are not consistent with a pre-synaptic releasing effect by amphetamine at noradrenergic synapses in the cns since the efficacy of amphetamine on Purkinje cells was unaltered after pretreatment with alpha-MpT or alpha-MpT plus reserpine.

The effects of dimethylaminoethanol (deanol) on cerebral cortical neurons.

2-Dimethylaminoethanol and acetylcholine were iontophoretically tested on deep, spontaneously firing, neurons of the rat cerebral cortex. All identified corticospinal cells and 71% of the unidentified ones were excited by Deanol. Eight percent of the latter group were inhibited. All but one neuron responded similarly to ACh and Deanol, when both substances were tested on the same neuron. Atropine reversibly blocked these responses. The implications of these observations are discussed with regard to cholinergic synapses in the brain and the rationalization of the therapeutic use of Deanol.

A potent depressant action of adenine derivatives on cerebral cortical neurones.

Adenosine and several adenine nucleotides depress the excitability of cerebral cortical neurones, including identified Betz cells. Cyclic 3',5'-adenosine monophosphate was a less effective depressant than various other adenine nucleotides, including cyclic 2',3'-adenosine monophosphate. Adenine and inosine had only weak depressant activity. An initial excitant action of ATP was observed on several neurones. This was succeeded by a depressant effect when the application of ATP was terminated.