Frontal white matter volume and delta EEG sources negatively correlate in awake subjects with mild cognitive impairment and Alzheimer's disease.

OBJECTIVE: A relationship between brain atrophy and delta rhythmicity (1.5-4 Hz) has been previously explored in Alzheimer's disease (AD) subjects [Fernandez A, Arrazola J, Maestu F, Amo C, Gil-Gregorio P, Wienbruch C, Ortiz T. Correlations of hippocampal atrophy and focal low-frequency magnetic activity in Alzheimer disease: volumetric MR imaging-magnetoencephalographic study. Am J Neuroradiol. 2003 24(3):481-487]. In this study, we tested the hypothesis that such a relationship does exist not only in AD patients but also across the continuum of subjects with mild cognitive impairment (MCI) and AD. METHODS: Resting, eyes-closed EEG data were recorded in 34 MCI and 65 AD subjects. EEG rhythms of interest were delta (2-4 Hz), theta (4-8 Hz), alpha 1 (8-10.5 Hz), alpha 2 (10.5-13 Hz), beta 1 (13-20 Hz), and beta 2 (20-30 Hz). EEG cortical sources were estimated by LORETA. Cortical EEG sources were correlated with MR-based measurements of lobar brain volume (white and gray matter). RESULTS: A negative correlation was observed between the frontal white matter and the amplitude of frontal delta sources (2-4 Hz) across MCI and AD subjects. CONCLUSIONS: These results confirmed for the first time the hypothesis that the sources of resting delta rhythms (2-4 Hz) are correlated with lobar brain volume across MCI and AD subjects. SIGNIFICANCE: The present findings support, at least at group level, the 'transition hypothesis' of brain structural and functional continuity between MCI and AD.     

A mating deficient and temperature-sensitive lethal mutant of Schizosaccharomyces pombe defines a new fertility locus

Summary A recessive mutant allele, mef1-84, of a novel locus mapping on the left arm of chromosome I, between ade3 and ura1, 5 cM apart from lys5, confers temperature-sensitive growth and mating deficiency at the nonrestrictive temperatures for growth. Two other mutations suppress the phenotype conferred by mef1-84: sts1-1 suppresses the temperature-sensitive growth only, and smd1-35 suppresses both temperature-sensitive growth and mating deficiency.     

The cellular mechanism of thalamic ponto-geniculo-occipital waves

The cellular mechanisms underlying the genesis of thalamic ponto-geniculo-occipital waves were studied in reserpinized cats under urethane anaesthesia. Simultaneous field potential and intracellular recordings were performed in the lateral geniculate nucleus after acute lesions of retinal and visual cortical inputs. In most relay cells, reserpine-induced ponto-geniculo-occipital waves were associated with a transient depolarization that was often interrupted by a unitary inhibitory postsynaptic potential. The depolarization grew in size with membrane hyperpolarization and was accompanied by an increase in membrane conductance. The inhibitory postsynaptic potential is likely to have resulted from the activation of intrageniculate interneurons since perigeniculate cells were always inhibited during the occurrence of ponto-geniculo-occipital waves. Under reserpine, thalamic ponto-geniculo-occipital waves could also be triggered by peribrachial or auditory stimulation. These evoked ponto-geniculo-occipital waves were associated with intracellular events identical to those occurring spontaneously after reserpine administration. In addition, thalamic spindle oscillations were readily blocked by the occurrence of spontaneous or evoked ponto-geniculo-occipital waves. On the basis of the present results and those already published in the literature, the conclusion is reached that lateral geniculate ponto-geniculo-occipital waves result from a nicotinic activation of relay cells and from a parallel muscarinic inhibition of perigeniculate cells by peribrachial afferents. The functional significance of the ponto-geniculo-occipital activity is discussed on the basis of the antagonistic action of these signals on thalamic oscillations. It is proposed that these signals are the central correlates of orienting reactions elicited by sensory stimuli during waking (the so-called eye movement potentials) and by internally generated drives during paradoxical sleep.     

Potassium model for slow (2-3 Hz) in vivo neocortical paroxysmal oscillations

In slow neocortical paroxysmal oscillations, the de- and hyperpolarizing envelopes in neocortical neurons are large compared with slow sleep oscillations. Increased local synchrony of membrane potential oscillations during seizure is reflected in larger electroencephalographic oscillations and the appearance of spike- or polyspike-wave complex recruitment at 2- to 3-Hz frequencies. The oscillatory mechanisms underlying this paroxysmal activity were investigated in computational models of cortical networks. The extracellular K(+) concentration ([K(+)](o)) was continuously computed based on neuronal K(+) currents and K(+) pumps as well as glial buffering. An increase of [K(+)](o) triggered a transition from normal awake-like oscillations to 2- to 3-Hz seizure-like activity. In this mode, the cells fired periodic bursts and nearby neurons oscillated highly synchronously; in some cells depolarization led to spike inactivation lasting 50-100 ms. A [K(+)](o) increase, sufficient to produce oscillations could result from excessive firing (e.g., induced by external stimulation) or inability of K(+) regulatory system (e.g., when glial buffering was blocked). A combination of currents including high-threshold Ca(2+), persistent Na(+) and hyperpolarization-activated depolarizing (I(h)) currents was sufficient to maintain 2- to 3-Hz activity. In a network model that included lateral K(+) diffusion between cells, increase of [K(+)](o) in a small region was generally sufficient to maintain paroxysmal oscillations in the whole network. Slow changes of [K(+)](o) modulated the frequency of bursting and, in some case, led to fast oscillations in the 10- to 15-Hz frequency range, similar to the fast runs observed during seizures in vivo. These results suggest that modifications of the intrinsic currents mediated by increase of [K(+)](o) can explain the range of neocortical paroxysmal oscillations in vivo.     

Spontaneous and artificial activation of neocortical seizures

The aim of this study is to disclose the mechanisms underlying the recruitment of neocortical networks during slow-wave sleep oscillations evolving into spike-wave (SW) seizures. 1) We investigated the activation of SW seizures in a seizure-prone neocortex by means of electrical stimuli applied within the frequency range of spontaneous sleep oscillations. Stimuli were grouped in bursts of 10 Hz, similar to sleep spindles, and repeated every 2 s, to reproduce their rhythmic recurrence imposed by the slow (<1 Hz) sleep oscillation. Either cortical or thalamic stimuli, which were applied while the cortex displayed sleeplike activity, gradually induced paroxysmal responses in intracellularly recorded neocortical neurons, which were virtually identical to those of spontaneous seizures and consisted of a progressive buildup of paroxysmal depolarizing shifts (PDSs). 2) The ability of cortical networks to follow stimuli was tested at various stimulation frequencies (1-3 Hz) and quantified by calculating the entropy of the ensuing oscillation. Rhythmic PDSs were optimally induced, and the lowest entropy was generated, at a stimulation frequency around 1.5 Hz. Fast runs at 10-15 Hz, which often override PDSs, thus contributing to the polyspike-wave pattern of seizures, were induced by cortical stimuli, but were disturbed by thalamic stimuli. Spontaneous seizures generally evolved toward an accelerated discharge of PDSs. It is suggested that these accelerating trends during SW seizures act as protective mechanisms by provoking the uncoupling of cortical networks and eventually arresting the seizure.     

Focal synchronization of ripples (80-200 Hz) in neocortex and their neuronal correlates

Field potentials from different neocortical areas and intracellular recordings from areas 5 and 7 in acutely prepared cats under ketamine-xylazine anesthesia and during natural states of vigilance in chronic experiments, revealed the presence of fast oscillations (80-200 Hz), termed ripples. During anesthesia and slow-wave sleep, these oscillations were selectively related to the depth-negative (depolarizing) component of the field slow oscillation (0.5-1 Hz) and could be synchronized over ~10 mm. The dependence of ripples on neuronal depolarization was also shown by their increased amplitude in field potentials in parallel with progressively more depolarized values of the membrane potential of neurons. The origin of ripples was intracortical as they were also detected in small isolated slabs from the suprasylvian gyrus. Of all types of electrophysiologically identified neocortical neurons, fast-rhythmic-bursting and fast-spiking cells displayed the highest firing rates during ripples. Although linked with neuronal excitation, ripples also comprised an important inhibitory component. Indeed, when regular-spiking neurons were recorded with chloride-filled pipettes, their firing rates increased and their phase relation with ripples was modified. Thus besides excitatory connections, inhibitory processes probably play a major role in the generation of ripples. During natural states of vigilance, ripples were generally more prominent during the depolarizing component of the slow oscillation in slow-wave sleep than during the states of waking and rapid-eye movement (REM) sleep. The mechanisms of generation and synchronization, and the possible functions of neocortical ripples in plasticity processes are discussed.     

Spontaneous field potentials influence the activity of neocortical neurons during paroxysmal activities in vivo

Field-potential recordings with macroelectrodes, and extra- and intracellular potentials with micropipettes were used to determine the influence of spontaneous field potentials on the activity of neocortical neurons during seizures. In vivo experiments were carried out in cats under anesthesia. Strong negative field fluctuations of up to 20 mV were associated with electroencephalogram "spikes" during spontaneously occurring paroxysmal activities. During paroxysmal events, action potentials displayed an unexpected behavior: a more hyperpolarized firing threshold and smaller amplitude than during normal activity, as determined with intracellular recordings referenced to a distant ground. Considering the transmembrane potential (the difference between extra- and intracellular potential) qualified this observation: firing threshold determined from the transmembrane potential did not decrease, and smaller action-potential amplitude was associated with depolarized firing threshold. The hyperpolarization of intracellular firing threshold was thus related to the field potentials. Similar field-potential effects on neuronal activities were observed when the paroxysmal events included very fast oscillations or ripples (80-200 Hz) that represent rapid fluctuations of field potentials (up to 5 mV in <5 ms). Neuronal firing was phase-locked to those oscillations. These results demonstrate that: (a) strong spontaneous field potentials influence neuronal behavior, and thus play an active role during paroxysmal activities; and (b) transmembrane potentials have to be used to accurately describe the behavior of neurons in conditions in which field potentials fluctuate strongly. Since neuronal activity is presumably the main generator of field potentials, and in return these potentials may increase neuronal excitability, we propose that this constitutes a positive feedback loop that is involved in the development and spread of paroxysmal activities, and that a similar feedback loop is involved in the generation of neocortical ripples. We propose a mechanism for seizure initiation involving these phenomena.     

Slow sleep oscillation, rhythmic K-complexes, and their paroxysmal developments

This paper presents the relations between the slow (< 1 Hz) oscillation (characterizing the activity of corticothalamic networks during quiescent sleep in cats and humans), sleep K-complexes, and some paroxysmal developments of sleep patterns. At the cellular level, the slow oscillation is built up by rhythmic membrane depolarizations and hyperpolarizations of cortical neurons. The EEG expression of this activity is marked by periodic K-complexes which reflect neuronal excitation. The slow oscillation triggers, groups and synchronizes other sleep rhythms, such as thalamically generated spindles as well as thalamically and cortically generated delta oscillations. We discuss the distinctness of the slow (< 1 Hz) and delta (1–4 Hz) oscillations. We also show that the slow cortical oscillation underlies the onset of spike-wave seizures during sleep by transforming the periodic K-complexes into recurrent paroxysmal spike-wave complexes.     

Synaptic responsiveness of neocortical neurons to callosal volleys during paroxysmal depolarizing shifts

Based on intracellular recordings in vivo, we investigated the responsiveness of cat neocortical neurons to callosal volleys during different phases of spontaneously occurring or electrically induced electrographic seizures, compared with control periods of slow sleep-like oscillations. Overt seizures, with spiking, triggered by pulse-trains to the callosal pathway, started with a latency of approximately 20 s after cessation of stimulation, thus contrasting with paroxysmal activity elicited by ipsilateral cortical or thalamic stimulation that is initiated immediately after electrical stimulation. During the rather long preparatory period to callosally triggered seizures, cortical neurons displayed subthreshold depolarizing runs at 4-7 Hz, associated with increased amplitudes of excitatory postsynaptic potentials. The sequential analysis of neuronal responsiveness during different components of spike-wave complexes revealed progressively increased amplitudes of callosally evoked postsynaptic excitatory responses in regular-spiking and fast-rhythmic-bursting neurons, over a period of approximately 20 ms prior to the generation of paroxysmal depolarizing shifts. These data support the concept that seizures consisting of spike-wave complexes originate within the neocortex through a progressive synaptic buildup and that their synchronization is achieved, at least partially, by cortical commissural synaptic linkages.     

Self-sustained rhythmic activity in the thalamic reticular nucleus mediated by depolarizing GABAA receptor potentials

Intracellular recordings from reticular thalamic (RE) neurons in vivo revealed inhibitory postsynaptic potentials (IPSPs) between RE cells that reversed and became depolarizing at the hyperpolarized membrane potentials that occur during sleep. These excitatory IPSPs can directly trigger low-threshold spikes (LTSs). The oscillatory mechanisms underlying IPSP-triggered LTSs crowned by spike bursts were investigated in models of isolated RE networks. In a one-dimensional network model, external stimulation evoked waves of excitation propagating at a constant velocity of 25-150 cells per second. In a large-scale, two-dimensional model of the reticular nucleus, the network showed transient or self-sustained oscillations controlled by the maximum conductance of the low-threshold calcium current and the membrane potential. This model predicts that the isolated reticular nucleus could initiate sequences of spindle oscillations in thalamocortical networks in vivo.