Graph theoretical analysis of magnetoencephalographic functional connectivity in Alzheimer's disease.

In this study we examined changes in the large-scale structure of resting-state brain networks in patients with Alzheimer's disease compared with non-demented controls, using concepts from graph theory. Magneto-encephalograms (MEG) were recorded in 18 Alzheimer's disease patients and 18 non-demented control subjects in a no-task, eyes-closed condition. For the main frequency bands, synchronization between all pairs of MEG channels was assessed using a phase lag index (PLI, a synchronization measure insensitive to volume conduction). PLI-weighted connectivity networks were calculated, and characterized by a mean clustering coefficient and path length. Alzheimer's disease patients showed a decrease of mean PLI in the lower alpha and beta band. In the lower alpha band, the clustering coefficient and path length were both decreased in Alzheimer's disease patients. Network changes in the lower alpha band were better explained by a 'Targeted Attack' model than by a 'Random Failure' model. Thus, Alzheimer's disease patients display a loss of resting-state functional connectivity in lower alpha and beta bands even when a measure insensitive to volume conduction effects is used. Moreover, the large-scale structure of lower alpha band functional networks in Alzheimer's disease is more random. The modelling results suggest that highly connected neural network 'hubs' may be especially at risk in Alzheimer's disease.

Magnetoencephalographic evaluation of resting-state functional connectivity in Alzheimer's disease.

Statistical interdependencies between magnetoencephalographic signals recorded over different brain regions may reflect the functional connectivity of the resting-state networks. We investigated topographic characteristics of disturbed resting-state networks in Alzheimer's disease patients in different frequency bands. Whole-head 151-channel MEG was recorded in 18 Alzheimer patients (mean age 72.1 years, SD 5.6; 11 males) and 18 healthy controls (mean age 69.1 years, SD 6.8; 7 males) during a no-task eyes-closed resting state. Pair-wise interdependencies of MEG signals were computed in six frequency bands (delta, theta, alpha1, alpha2, beta and gamma) with the synchronization likelihood (a nonlinear measure) and coherence and grouped into long distance (intra- and interhemispheric) and short distance interactions. In the alpha1 and beta band, Alzheimer patients showed a loss of long distance intrahemispheric interactions, with a focus on left fronto-temporal/parietal connections. Functional connectivity was increased in Alzheimer patients locally in the theta band (centro-parietal regions) and the beta and gamma band (occipito-parietal regions). In the Alzheimer group, positive correlations were found between alpha1, alpha2 and beta band synchronization likelihood and MMSE score. Resting-state functional connectivity in Alzheimer's disease is characterized by specific changes of long and short distance interactions in the theta, alpha1, beta and gamma bands. These changes may reflect loss of anatomical connections and/or reduced central cholinergic activity and could underlie part of the cognitive impairment.

Spike cluster analysis in neocortical localization related epilepsy yields clinically significant equivalent source localization results in magnetoencephalogram (MEG).

OBJECTIVE: In magnetoencephalogram (MEG) recordings of patients with epilepsy several types of sharp transients with different spatiotemporal distributions are commonly present. Our objective was to develop a computer based method to identify and classify groups of epileptiform spikes, as well as other transients, in order to improve the characterization of irritative areas in the brain of epileptic patients. METHODS: MEG data centered on selected spikes were stored in signal matrices of C channels by T time samples. The matrices were normalized and euclidean distances between spike representations in vector space R(CxT) were input to a Ward's hierarchical clustering algorithm. RESULTS: The method was applied to MEG data from 4 patients with localization-related epilepsy. For each patient, distinct spike subpopulations were found with clearly different topographical field maps. Inverse computations to selected spike subaverages yielded source solutions in agreement with seizure classification and location of structural lesions, if present, on magnetic resonance images. CONCLUSIONS: With the proposed method a reliable categorization of epileptiform spikes is obtained, that can be applied in an automatic way. Computation of subaverages of similar spikes enhances the signal-to-noise ratio of spike field maps and allows for more accurate reconstruction of sources generating the epileptiform discharges.

A MEG study of sleep.

A 64-channel, whole cortex magnetoencephalographic system was employed to obtain sleep data from three healthy subjects. Based upon visual inspection of the signals and the corresponding power spectra, we were able to discern a number of features characterizing the evolution of sleep. These included: (1) the transition from records dominated by the alpha rhythm to records in which alpha is attenuated and slower waves increase; (2) the appearance of sleep spindles, particularly in the parietal channels; and, perhaps most interesting, (3) a slow wave phase whose multichannel spectral signature is a broad rounded maximum in the frequency region around 0.5 Hz. Topographical features of the sleep record were also studied. In two of our subjects, rough lateral symmetry was apparent. As their sleep deepened, the distribution of signal power over the head changed such that the maximum moved in the forward and lateral directions, with parietal and temporal signals strengthening relative to the occipital. The records of the third subject showed a tendency toward right dominance, while topographic changes with sleep depth were minimal. Only one of the subjects was able to sustain the deep, slow-wave stage. Here, characteristic multi-detector outbursts appeared, lasting between 150 and 500 ms. During these intervals, widespread topographic patterns were sustained over the head (often with striking dipolar or quadrupolar forms), while crude source modeling yielded two persisting dipoles, laterally paired. Thus, these outbursts seem to represent large-scale, quasi-static configurations of brain activity perhaps related to the K-complexes, which occur earlier in sleep. Finally, we compare our results with those of previous investigators, including work on human electroencephalographic data and research reported by Steriade et al. from animal studies.

Modifications in glutamatergic transmission after dopamine depletion of the nucleus accumbens. A combined in vivo/in vitro electrophysiological study in the rat.

The interaction between the glutamatergic and dopaminergic input in the nucleus accumbens was examined by studying the effects of dopamine depletion of the nucleus accumbens on the local field potentials, and the L-glutamate elicited responses of the nucleus accumbens in anaesthetized rats in vivo. A characteristic field potential in the nucleus accumbens is evoked by electrical stimulation of the fornix/fimbria fibres, with a monosynaptic positive peak at 10 ms (P10). Rats were unilaterally injected with 6-hydroxydopamine in the nucleus accumbens. The contralateral accumbens was sham lesioned. The rats were divided into short-term and long-term survival groups of one to two weeks and 24 weeks, respectively. In the short-term group, a striking increase (up to three times) of the amplitude of the P10 components, at the site of the lesion, compared with the sham lesioned contralateral accumbens and untreated rats, was found. The long-term group could still display a slight increase although on average this was not significantly different from controls. In the short-term group, at the centre of the lesion, the paired-pulse facilitation ratio was significantly smaller than at the more ventral, less denervated, border of the accumbens. These differences were no longer visible in the long-term group. Single-unit activity of the accumbens, elicited by the iontophoretical application of L-glutamate showed, in controls, a maximal firing frequency ranging from 5 to 40 Hz (mean 25 Hz), whereas in the short-term group more than 50% of the accumbens neurons fired with higher frequencies, reaching up to 90 Hz (mean 55 Hz). In the long-term group the firing frequency varied from 5 to 60 Hz (mean 41 Hz). No changes in threshold ejection glutamate current were found for both lesioned groups. In control rats the L-glutamate elicited responses of six cells tested could be suppressed by dopamine whereas in lesioned rats three of the six cells tested were unresponsive to dopamine. Intracellular recordings of accumbens cells in slices in 6-hydroxydopamine and sham lesioned rats, showed no significant changes in the intrinsic membrane properties, e.g. resting membrane potential, input resistance, spike threshold, action potential amplitude or duration. We conclude that dopamine denervation leads to an increase of excitability of the principal accumbens neurons. This is reflected by the increase of the firing frequency of these cells and of the amplitude of the evoked field potentials. The former is more likely of postsynaptic origin whereas the latter may also have a presynaptic contribution. These effects cannot be attributed to changes in intrinsic membrane properties of the cells.

Responses of the nucleus accumbens following fornix/fimbria stimulation in the rat. Identification and long-term potentiation of mono- and polysynaptic pathways.

The nucleus accumbens occupies a strategic position as an interface between limbic cortex and midbrain structures involved in motor performance. The fornix-fimbria carries limbic inputs to the ventral striatum, namely by way of fibers originating in the CA1/subiculum and projecting to the nucleus accumbens. It also carries fibers arising in the septal area that project to the hippocampal formation, and projection fibers to other areas of the rostral forebrain from Ammon's horn. Electrical stimulation of this bundle causes characteristic field potentials both in the nucleus accumbens and in the subiculum. In rats, under halothane anesthesia, the responses evoked by fornix/fimbria stimulation in the nucleus accumbens consist of two main positive peaks (at 10 and 25 ms, referred to as P10 and P25, respectively). P10 represents monosynaptic activation. We hypothesized that P25 reflects the activation of a polysynaptic loop, i.e. a fornix-fimbria hippocampal loop in series with the fibers that arise in the subiculum and project to the nucleus accumbens. To test this hypothesis, we reversibly blocked the fibers projecting caudally to the hippocampus by a local anesthetic (lidocaine) and the glutamatergic transmission through the CA1/subiculum by a local injection of kynurenic acid. Both manipulations yielded a reversible depression of about 90% of the P25 component while P10 remained unaffected as expected. In concert a strong reduction (to 24-31%) of control values of the responses evoked in the subiculum was seen. The dynamics of the mono- and polysynaptic pathways differ markedly. The synaptic responses through both pathways are enhanced by paired-pulse stimulation, but the polysynaptic pathway is facilitated in a much stronger way. Following a tetanus (50 Hz, 2 s duration) applied to the fornix/fimbria, the P10 component of the nucleus accumbens responses showed an immediate increase by a factor of about 2 followed by a phase of gradual decrement with half-decay time of about 10 min, after which a persistent long-term potentiation of about 25% above control level was maintained for the rest of the experiment (max 90 min). The P25 component showed a transient 10-fold potentiation with return to control values after about 10 min. In contrast to the P25 elicited by a conditioning stimulus, the P25 component elicited by a second stimulus delivered at an interval of 100 ms (test stimulus) showed a persistent long-term potentiation.(ABSTRACT TRUNCATED AT 400 WORDS)