Criticality and synchrony of fluctuations in rhythmical brain activity: pretransitional effects in epileptic patients

In extending our previous results demonstrating critical fluctuations in electropathophysiological brain activity prior to onset of partial epileptic seizures, we used once again Hakens approach to self-organized complex systems, which resorts to identifying an order parameter. A renormalized density in phase space and a renormalized differential density were defined and substituted for the Lerner density, which we used previously. Fluctuations in electropathophysiological activity, consisting of periods of high activity recorded from both depth and scalp electrodes in six presurgical patients, were characterized on different time scales. Extension in space of the fluctuations was characterized by observing their synchronous occurrence in different areas of the brain. By simultaneously establishing the fluctuations criticality, we were observing synchronous instabilities. Criticality followed from characterizing the time course of the synchronously arising fluctuations, when approaching seizure onset (i) by their slowing, for the longer-lasting ones (up to about 2 min), and (ii) by their increase in rate of production, for those of shorter duration (up to 20–30 s). Critical behavior may be displayed in favorable cases over more than 1 h prior to seizure onset. Other effects are also described that in some cases may interfere with the simple time course of fluctuations and must be given further consideration, particularly with a view to application to seizure anticipation. Because periods of high activity are involved, any marker of increased electropathophysiological activity in the brain may, in principle, play the role of an order parameter or of an approximate order parameter, e.g., a signals root-mean-square amplitude, or its excess energy content. Such markers may be put to use for the fluctuations they display or merely for their average time evolution prior to seizure onset. We compared the time evolution, prior to onset, of the excess production rate of synchronies and of the signals excess energy content, both averaged over signal sections of a chosen duration. In view of potential noninvasive applications, those scalp electrodes showing effects similar to the observations we made at the epileptogenic focus were identified, and the time course of their order parameters prior to seizure onset was analyzed.     

Nonlinear analysis of epileptic activity in rabbit neocortex

We report on the nonlinear analysis of electroencephalogram (EEG) recordings in the rabbit visual cortex. Epileptic seizures were induced by local penicillin application and triggered by visual stimulation. The analysis procedures for nonlinear signals have been developed over the past few years and applied primarily to physical systems. This is an early application to biological systems and the first to EEG data. We find that during epileptic activity, both global and local embedding dimensions are reduced with respect to nonepileptic activity. Interestingly, these values are very low () and do not change between preictal and tonic stages of epileptic activity, also the Lyapunov dimension remains constant. However, between these two stages the manifestations of the local dynamics change quite drastically, as can be seen, e.g., from the shape of the attractors. Furthermore, the largest Lyapunov exponent is reduced by a factor of about two in the second stage and characterizes the difference in dynamics. Thus, the occurrence of clinical symptoms associated with the tonic seizure activity seems to be mainly related to the local dynamics of the nonlinear system. These results thus seem to give a strong indication that the dynamics remains much the same in these stages of behavior, and changes are due to alterations in model parameters and consequent bifurcations of the observed orbits. Received: 5 February 1997 / Accepted in revised form: 18 September 1997     

Transport Ca-ATPase activity of brain synaptic membranes in rats with korazol-induced epileptic activity

Changes in the activity of transport Ca-ATPase in osmotically disrupted synaptosomes were studied in corazol-induced generalized epileptic activity (EA) monitored by electrocorticogram. The enzyme activity was found to be unchanged at the beginning of the latent period, but significantly diminished towards the end of the latent period and further reduced at the peak of EA. After ET was no longer observed the enzyme activity returned to normal. The activity of transport Ca-ATPase in synaptic junction fraction was found to be 3 times higher than in osmotically disrupted synaptosomes. A possible role of the inactivation of membrane Ca pump in synaptic brain structures is discussed in relation to pathological hyperactivity of neurons.     

Glutamate release by primary brain tumors induces epileptic activity

Epileptic seizures are a common and poorly understood comorbidity for individuals with primary brain tumors. To investigate peritumoral seizure etiology, we implanted human-derived glioma cells into severe combined immunodeficient mice. Within 14-18 d, glioma-bearing mice developed spontaneous and recurring abnormal electroencephalogram events consistent with progressive epileptic activity. Acute brain slices from these mice showed marked glutamate release from the tumor mediated by the system x(c)(-) cystine-glutamate transporter (encoded by Slc7a11). Biophysical and optical recordings showed glutamatergic epileptiform hyperexcitability that spread into adjacent brain tissue. We inhibited glutamate release from the tumor and the ensuing hyperexcitability by sulfasalazine (SAS), a US Food and Drug Administration-approved drug that blocks system x(c)(-). We found that acute administration of SAS at concentrations equivalent to those used to treat Crohn's disease in humans reduced epileptic event frequency in tumor-bearing mice compared with untreated controls. SAS should be considered as an adjuvant treatment to ameliorate peritumoral seizures associated with glioma in humans.     

Data-driven method to infer the seizure propagation patterns in an epileptic brain from intracranial electroencephalography

Surgical interventions in epileptic patients aimed at the removal of the epileptogenic zone have success rates at only 60-70%. This failure can be partly attributed to the insufficient spatial sampling by the implanted intracranial electrodes during the clinical evaluation, leading to an incomplete picture of spatio-temporal seizure organization in the regions that are not directly observed. Utilizing the partial observations of the seizure spreading through the brain network, complemented by the assumption that the epileptic seizures spread along the structural connections, we infer if and when are the unobserved regions recruited in the seizure. To this end we introduce a data-driven model of seizure recruitment and propagation across a weighted network, which we invert using the Bayesian inference framework. Using a leave-one-out cross-validation scheme on a cohort of 45 patients we demonstrate that the method can improve the predictions of the states of the unobserved regions compared to an empirical estimate that does not use the structural information, yet it is on the same level as the estimate that takes the structure into account. Furthermore, a comparison with the performed surgical resection and the surgery outcome indicates a link between the inferred excitable regions and the actual epileptogenic zone. The results emphasize the importance of the structural connectome in the large-scale spatio-temporal organization of epileptic seizures and introduce a novel way to integrate the patient-specific connectome and intracranial seizure recordings in a whole-brain computational model of seizure spread.     

Astrocytes in the epileptic brain

The roles that astrocytes play in the evolution of abnormal network excitability in chronic neurological disorders involving brain injury, such as acquired epilepsy, are receiving renewed attention due to improved understanding of the molecular events underpinning the physiological functions of astrocytes. In epileptic tissue, evidence is pointing to enhanced chemical signaling and disrupted linkage between water and potassium balance by reactive astrocytes, which together conspire to enhance local synchrony in hippocampal microcircuits. Reactive astrocytes in epileptic tissue both promote and oppose seizure development through a variety of specific mechanisms; the new findings suggest several novel astrocyte-related targets for drug development.     

Liquid chromatographic analysis of catecholamines routine assay for regional brain mapping

A thoroughly tested and highly reliable catecholamine assay is described which routinely determines 20–100 picograms of norepinephrine and dopamine in small punches of brain tissue weighing 0.50 to 50 mg. The assay was designed for regional brain mapping. It employs liquid chromatography with electrochemical detection and involves a minimum of sample pretreatment. Its realistic performance is illustrated by typical experimental data. Modifications for larger or whole brain samples as well as details of construction and operation of this system are given.     

Effects of extremely-low-frequency electric fields on neuronal activity in rat brain

The effects of 50-, 30-, and 15-Hz electric field exposure on the activity of spontaneously firing neurons in the brain of anaesthetized rats were studied. Exposure to fields of 100 V/m (peak-to-peak, in air) produced no effect on the overall rate of neuronal firing, but some synchronicity with the period of the exposure waveform was seen with 15- and 30-Hz electric fields.     

Androgens alter electric organ discharge pulse duration despite stability in electric organ discharge frequency.

Weakly electric fish in the genus Sternopygus emit a sinusoidal, individually distinct, and sexually dimorphic electric organ discharge (EOD) that is used in electrolocation and communication. Systemically applied androgens decrease EOD frequency, which is set by a medullary pacemaker nucleus, and increase pulse duration, which is determined by the cells of the electric organ (the electrocytes), in a coordinated fashion. One possibility is that androgens broaden the EOD pulse duration by acting on the pacemaker neurons, thereby effecting a change in pacemaker firing frequency, and that the change in EOD pulse duration is due to an activity-dependent process. To determine whether androgens can alter pulse duration despite a stable pacemaker nucleus firing frequency, we implanted small doses of dihydrotestosterone in the electric organ. We found that androgen implants increased EOD pulse duration, but did not influence EOD frequency. In addition, using immunocytochemistry, we found that electrocytes label positively with an androgen receptor antibody. While it is not known on which cells androgens act directly, together these experiments suggest that they likely act on the electrocytes to increase EOD pulse duration. Since pulse duration is determined by electrocyte action potential duration and ionic current kinetics, androgens may therefore play a causative role in influencing individual variation and sexual dimorphism in electrocyte electrical excitability, an important component of electrocommunicatory behavior.