Dániel Fabó

Laminar analysis of slow wave activity in humans

Brain electrical activity is largely composed of oscillations at characteristic frequencies. These rhythms are hierarchically organized and are thought to perform important pathological and physiological functions. The slow wave is a fundamental cortical rhythm that emerges in deep non-rapid eye movement sleep. In animals, the slow wave modulates delta, theta, spindle, alpha, beta, gamma and ripple oscillations, thus orchestrating brain electrical rhythms in sleep. While slow wave activity can enhance epileptic manifestations, it is also thought to underlie essential restorative processes and facilitate the consolidation of declarative memories. Animal studies show that slow wave activity is composed of rhythmically recurring phases of widespread, increased cortical cellular and synaptic activity, referred to as active- or up-state, followed by cellular and synaptic inactivation, referred to as silent- or down-state. However, its neural mechanisms in humans are poorly understood, since the traditional intracellular techniques used in animals are inappropriate for investigating the cellular and synaptic/transmembrane events in humans. To elucidate the intracortical neuronal mechanisms of slow wave activity in humans, novel, laminar multichannel microelectrodes were chronically implanted into the cortex of patients with drug-resistant focal epilepsy undergoing cortical mapping for seizure focus localization. Intracortical laminar local field potential gradient, multiple-unit and single-unit activities were recorded during slow wave sleep, related to simultaneous electrocorticography, and analysed with current source density and spectral methods. We found that slow wave activity in humans reflects a rhythmic oscillation between widespread cortical activation and silence. Cortical activation was demonstrated as increased wideband (0.3-200 Hz) spectral power including virtually all bands of cortical oscillations, increased multiple- and single-unit activity and powerful inward transmembrane currents, mainly localized to the supragranular layers. Neuronal firing in the up-state was sparse and the average discharge rate of single cells was less than expected from animal studies. Action potentials at up-state onset were synchronized within +/-10 ms across all cortical layers, suggesting that any layer could initiate firing at up-state onset. These findings provide strong direct experimental evidence that slow wave activity in humans is characterized by hyperpolarizing currents associated with suppressed cell firing, alternating with high levels of oscillatory synaptic/transmembrane activity associated with increased cell firing. Our results emphasize the major involvement of supragranular layers in the genesis of slow wave activity.

Phase Segregation of Medial Septal GABAergic Neurons during Hippocampal Theta Activity

Septo-hippocampal GABAergic neurons immunoreactive for parvalbumin are thought to play a crucial role in the generation of hippocampal theta oscillations associated with a specific stage of memory formation. Here we use in vivo juxtacellular recording and filling in the medial septum followed by immunocytochemical identification of the recorded cells containing parvalbumin to determine their firing pattern, phase relationship with hippocampal theta, morphology, and to thereby reveal their involvement in the generation of hippocampal theta activity. We have demonstrated that GABAergic medial septal neurons form two distinct populations exhibiting highly regular bursting activity that is tightly coupled to either the trough (178°) or the peak (330°) of hippocampal theta waves. Additionally, different types of bursting as well as nonbursting activity patterns were also observed. The morphological reconstruction of theta-bursting neurons revealed extensive axon arbors of these cells with numerous local collaterals establishing symmetrical synapses; thus, synchrony among the septal pacemaker units may be brought about by their recurrent collateral interactions. Long projecting axons could also be found running dorsally toward the hippocampus and ventrally in the direction of basal forebrain regions. We conclude that GABAergic neurons in the medial septum, which are known to selectively innervate hippocampal interneurons, are in a position to induce rhythmic disinhibition in the hippocampus and other theta-related subcortical areas at two different phases of hippocampal theta.

Twenty-four hours retention of visuospatial memory correlates with the number of parietal sleep spindles.

Recent evidence suggests that the sleep-dependent consolidation of declarative memories relies on the non-rapid eye movement (NREM) rather than the rapid eye movement (REM) phase of sleep. Moreover, a few studies both at the cellular and the behavioural levels have suggested the involvement of sleep spindles, the most synchronous oscillatory waveforms during NREM sleep stage 2, in this process. Our previous study showed that overnight verbal memory retention correlates with the total number of sleep spindles in left frontocentral areas, while spindling in other regions did not correlate with mnemonic retention. In the present study, we show that retention of visuospatial memories over a 24-h period correlates with the total number of sleep spindles detected over parietal regions during the intervening night-time sleep. This result provides further evidence for the association between sleep spindle activity and declarative memory consolidation, and suggests that visuospatial and verbal memory retention differ in the topographic distribution of the NREM spindle activity with which they are associated.

In vivo laminar electrophysiology co-registered with histology in the hippocampus of patients with temporal lobe epilepsy.

Laminar multiple microelectrodes have been developed to sample cortical and hippocampal activity in animals. If these measurements are adequately co-registered with the anatomy of the region, they can yield important information about its function and structure. In vivo laminar electrophysiological recordings from the human epileptic hippocampus are rare. However, histological and immunohistochemical analyses are widely used to determine the structural changes associated with temporal lobe epilepsy (TLE). Here we present data obtained by a combined approach: intraoperative recording of laminar field potentials, single and multiple unit activity under anesthesia, accompanied by histology and immunohistochemistry from the same hippocampal region of epileptic patients undergoing temporal lobectomy for drug-resistant TLE. The stability of the electrophysiology and the accuracy of its co-registration with histology were tested successfully. We have found large field potential spikes associated with bursting single units in CA1. Intracortical and subdural strip recordings from the lateral temporal cortex showed similar field potential activation patterns. A prominent oscillatory activity was present in the dentate gyrus with highly localized field potential gradient and multiple unit activity. This pattern could be used as a landmark defining the position of the electrode in the hippocampus. Our findings indicate that some aspects of the local and network epileptiform activity in the hippocampal formation are likely preserved under anesthesia. Electrophysiological identification of the functional state of the hippocampus together with its local structural correlates could further enhance our understanding of this disease.

Complex Propagation Patterns Characterize Human Cortical Activity during Slow-Wave Sleep

Cortical electrical activity during nonrapid eye movement (non-REM) sleep is dominated by slow-wave activity (SWA). At larger spatial scales (∼2–30 cm), investigated by scalp EEG recordings, SWA has been shown to propagate globally over wide cortical regions as traveling waves, which has been proposed to serve as a temporal framework for neural plasticity. However, whether SWA dynamics at finer spatial scales also reflects the orderly propagation has not previously been investigated in humans. To reveal the local, finer spatial scale (∼1–6 cm) patterns of SWA propagation during non-REM sleep, electrocorticographic (ECoG) recordings were conducted from subdurally implanted electrode grids and a nonlinear correlation technique [mutual information (MI)] was implemented. MI analysis revealed spatial maps of correlations between cortical areas demonstrating SWA propagation directions, speed, and association strength. Highest correlations, indicating significant coupling, were detected during the initial positive-going deflection of slow waves. SWA propagated predominantly between adjacent cortical areas, albeit spatial noncontinuities were also frequently observed. MI analysis further uncovered significant convergence and divergence patterns. Areas receiving the most convergent activity were similar to those with high divergence rate, while reciprocal and circular propagation of SWA was also frequent. We hypothesize that SWA is characterized by distinct attributes depending on the spatial scale observed. At larger spatial scales, the orderly SWA propagation dominates; at the finer scale of the ECoG recordings, non-REM sleep is characterized by complex SWA propagation patterns.

Current use of imaging and electromagnetic source localization procedures in epilepsy surgery centers across Europe

In 2014 the European Union–funded E‐PILEPSY project was launched to improve awareness of, and accessibility to, epilepsy surgery across Europe. We aimed to investigate the current use of neuroimaging, electromagnetic source localization, and imaging postprocessing procedures in participating centers.

Current practices in long-term video-EEG monitoring services: A survey among partners of the E-PILEPSY pilot network of reference for refractory epilepsy and epilepsy surgery.

PURPOSE The European Union-funded E-PILEPSY network aims to improve awareness of, and accessibility to, epilepsy surgery across Europe. In this study we assessed current clinical practices in epilepsy monitoring units (EMUs) in the participating centers. METHOD A 60-item web-based survey was distributed to 25 centers (27 EMUs) of the E-PILEPSY network across 22 European countries. The questionnaire was designed to evaluate the characteristics of EMUs, including organizational aspects, admission, and observation of patients, procedures performed, safety issues, cost, and reimbursement. RESULTS Complete responses were received from all (100%) EMUs surveyed. Continuous observation of patients was performed in 22 (81%) EMUs during regular working hours, and in 17 EMUs (63%) outside of regular working hours. Fifteen (56%) EMUs requested a signed informed consent before admission. All EMUs performed tapering/withdrawal of antiepileptic drugs, 14 (52%) prior to admission to an EMU. Specific protocols on antiepileptic drugs (AED) tapering were available in four (15%) EMUs. Standardized Operating Procedures (SOP) for the treatment of seizure clusters and status epilepticus were available in 16 (59%). Safety measures implemented by EMUs were: alarm seizure buttons in 21 (78%), restricted patients ambulation in 19 (70%), guard rails in 16 (59%), and specially designated bathrooms in 7 (26%). Average costs for one inpatient day in EMU ranged between 100 and 2200 Euros. CONCLUSION This study shows a considerable diversity in the organization and practice patterns across European epilepsy monitoring units. The collected data may contribute to the development and implementation of evidence-based recommended practices in LTM services across Europe.

Outcome of vagus nerve stimulation for epilepsy in Budapest.

Vagus nerve stimulation (VNS) is a nonpharmacologic therapeutic option for patients with intractable epilepsy. Better clinical outcomes were recorded in nonfocal and Lennox‐Gastaut syndrome (LGS). We conducted a 2‐year, open label, prospective study to measure the seizure outcome of 26 VNS patients. The seizure numbers were assessed using clinician’s global impression scale (CGI) and patient diaries. The average seizure reduction was 23% at the first year and 22% at the second year. Seizure reduction was more pronounced among patients with nonfocal than with focal epilepsy. The response rate was 50% at first year and 30% at the second year. The best CGI record for clinically significant improvement was 15% in the LGS group. The only statistically significant result was the reduction of the generalized tonic–clonic seizures (GTCS). The side‐effect profile was good; however, the large number of mild and reversible effects influenced the stimulation parameters and thus probably the effectiveness of the therapy. We suggest that VNS is an optional treatment mostly in cases of therapy‐resistant Lennox‐Gastaut syndrome. Patients with GTCS may experience improvement such as reduction of seizure severity. We conclude that VNS is a safe neuromodulatory treatment, but future developments of neuromodulatory approaches are needed.

The risk of paradoxical levetiracetam effect is increased in mentally retarded patients

Purpose: Incidental paradoxical antiepileptic effect of levetiracetam has been described. The aim of the present study was to identify the epilepsy patients at risk.

Increased mesiotemporal delta activity characterizes virtual navigation in humans.

Hippocampal theta or rhythmic slow activity (RSA) occurring during exploratory behaviors and rapid-eye-movement (REM) sleep is a characteristic and well-identifiable oscillatory rhythm in animals. In contrast, controversy surrounds the existence and electrophysiological correlates of this activity in humans. Some argue that the human hippocampal theta occurs in short and phasic bursts. On the contrary, our earlier studies provide evidence that REM-dependent mesiotemporal RSA is continuous like in animals but instead of the theta it falls in the delta frequency range. Here we used a virtual navigation task in 24 epilepsy patients implanted with foramen ovale electrodes. EEG was analyzed for 1-Hz wide frequency bins up to 10 Hz according to four conditions: resting, non-learning route-following, acquisition and recall. We found progressively increasing spectral power in frequency bins up the 4 Hz across these conditions. No spectral power increase relative to resting was revealed within the traditional theta band and above in any of the navigation conditions. Thus the affected frequency bins were below the theta band and were similar to those characterizing REM sleep in our previous studies providing further indication that it is delta rather than theta that should be regarded as a human analog of the animal RSA.