Anna Szűcs

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.

Correction of vitamin D deficiency improves seizure control in epilepsy: A pilot study

There is growing interest concerning the role of vitamin D in various medical conditions such as diabetes and oncological, cardiovascular and central nervous system disorders. Although vitamin D deficiency is known to be highly prevalent among epilepsy patients, only a single study, published nearly forty years ago, assessed the effect of vitamin D on seizure control. Here, we measured serum 25-hydroxy-vitamin D (25(OH)D) levels and normalized it by administration of vitamin D3 in 13 patients with pharmacoresistant epilepsy. To see if vitamin D3 has an impact on seizure frequency, we compared seizure numbers during a 90-day period before and after treatment onset. We found that seizure numbers significantly decreased upon vitamin D3 supplementation. Median seizure reduction was 40%. We conclude that the normalization of serum vitamin 25(OH)D level has an anticonvulsant effect.

The role of NREM sleep micro-arousals in absence epilepsy and in nocturnal frontal lobe epilepsy.

The article summarises the role of input and consequent phasic events in the dynamism of non-rapid eye movement (NREM) sleep and in homeostatic slow-wave economy during sleep. Then, an overview of the mechanism of how micro-arousals in NREM sleep gate epileptic events in absence epilepsy (AE) and in sporadic and autosomal dominant nocturnal frontal lobe epilepsy (NFLE/ADNFLE) is presented. The ictal type of generalised spike-wave discharges (SWDs) are associated with a special vigilance level in between NREM, rapid-eye movement (REM) and wake state. This transitional state is characterised by input-driven bidirectional fluctuations. Among them, SWDs are linked to A1 type A phases of CAP and therefore seem to be associated with shifts towards NREM sleep (sleep induction). In ADNFLE (and presumably in NFLE), micro-arousals release epileptic events in NREM sleep probably due to epileptic sensitisation of the cholinergic arousal system by the known acetylcholine (ACh) receptor mutations affecting the arousal system, giving rise to the epileptic (and also parasomniac) episodes. In both kinds of these system epilepsies (AE and NFLE), epileptic events can be released by phasic events during NREM sleep. The difference is that absences are activated in reactive states with a sleep-promoting, antiarousal effect, while in NFLE the epileptic disorder is interwoven with the cholinergic arousal function. The role of arousal/antiarousal in NFLE and AE fits nicely with the hypothesis that these epilepsies are disorders of two antagonistic thalamo-frontal systems involved in functions NREM sleep and wakefulness.

Physiopathogenetic Interrelationship between Nocturnal Frontal Lobe Epilepsy and NREM Arousal Parasomnias

Aims. To build up a coherent shared pathophysiology of NFLE and AP and discuss the underlying functional network. Methods. Reviewing relevant published data we point out common features in semiology of events, relations to macro- and microstructural dynamism of NREM sleep, to cholinergic arousal mechanism and genetic aspects. Results. We propose that pathological arousals accompanied by confused behavior with autonomic signs and/or hypermotor automatisms are expressions of the frontal cholinergic arousal function of different degree, during the condition of depressed cognition by frontodorsal functional loss in NREM sleep. This may happen either if the frontal cortical Ach receptors are mutated in ADNFLE (and probably also in genetically not proved nonlesional cases as well), or without epileptic disorder, in AP, assuming gain in receptor functions in both conditions. This hypothesis incorporates the previous “liberation theory” of Tassinari and the “state dissociation hypothesis” of Bassetti and Terzaghi). We propose that NFLE and IGE represent epileptic disorders of the two antagonistic twin systems in the frontal lobe. NFLE is the epileptic facilitation of the ergotropic frontal arousal system whereas absence epilepsy is the epileptic facilitation of burst-firing working mode of the spindle and delta producing frontal thalamocortical throphotropic sleep system. Significance. The proposed physiopathogenesis conceptualize epilepsies in physiologically meaningful networks.

Generalised paroxysmal fast activity (GPFA) is not always a sign of malignant epileptic encephalopathy

PURPOSE Generalised paroxysmal fast activity (GPFA) consists of 8-26 (most frequently around 10 Hz), 2-50 seconds (usually below 10 seconds) bursts of generalised rhythmic discharges with frontal predominance, appearing most frequently during NREM sleep. The pattern is traditionally linked to Lennox-Gastaut (LGS) or late LGS (LLGS) syndrome and associated with tonic-axial seizures, pharmaco-resistency and poor prognosis including mental deterioration. We present here four patients with GPFA, who had neither LGS/LLGS syndrome, nor mental deterioration, two of them are seizure-free, two had infrequent seizures on medication. METHODS All the patients had neurological work-up and high resolution MRI studies. They were followed for years including repeated EEGs in awake state and during sleep. RESULTS The main seizure-type was generalised tonic-clonic seizure in three patients and absence in one. Onset of epilepsy varied from 7 to 21 years. No MRI lesion was found. All of them had generalised spike-and-wave discharges during the course of their epilepsy but some had also focal clinical or EEG features, were more difficult to treat, as atypical features compared to the classic generalised epilepsies with generalised spike-wave pattern. CONCLUSIONS Although GPFA should remain an important diagnostic feature of both the classical and late variant of LGS, our cases clearly demonstrate that GPFA could represent a possible electrographic variant in certain generalised epilepsies showing atypical features; better treatability and outcome than in LGS and no mental deterioration.

Factors affecting spiking related to sleep and wake states in temporal lobe epilepsy (TLE)

The aim of the study was to investigate the influence of different clinical factors on spiking during sleep and wakefulness in temporal lobe epilepsy. The study included 38 temporal lobe epilepsy (TLE) patients who underwent long-term electroencephalography (EEG) monitoring. In addition to traditional sleep scoring, waking was subdivided into eyes opened (WEO) and eyes closed (WEC) states. The following spike measures were investigated: spiking rates for each state, mean spike rate, spiking stability across wake and sleep states and relative spike density for each state. These measures were investigated according to clinical variables, such as age, age at epilepsy onset, duration of epilepsy, seizure frequency, the presence of secondarily generalised tonic-clonic (SGTC) seizures and the data on epileptogenic lesions based on MRI. Spiking rates during most states and spiking stability showed a significant positive correlation with epilepsy duration. Relative spike density during sleep stage NREM3,4 significantly increased with age at epilepsy onset. Relative spike density during WEC was significantly higher in the presence of hippocampal sclerosis (HS). Spiking rate during REM was significantly higher if a patient had SGTC seizures. Our data provide evidence that different aspects of spiking are associated with different aspects of TLE. We suggest that spike behaviour analysis offer new aspects both for diagnosis and research.

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.

Leukoencephalopathy, cerebral calcifications and cysts: A family study

We present a clinical, neuro-radiological and genetic study on a family with members suffering from an autosomal dominantly inherited syndrome characterised by epilepsy, cerebral calcifications and cysts, bone abnormalities; progressive neuro-cognitive deterioration and paranasal sinusitis. This syndrome shares several features with leukoencephalopathy with calcifications and cysts also called Labrune syndrome and the condition of cerebroretinal microangiopathy with calcifications and cysts (CRMCC; Coats plus syndrome). Genetic studies in this family did not reveal mutations in the CTC1 gene defected in CRMCC. We interpret our results as those supporting recent findings that despite clinical similarities, late-onset Labrune and Coats plus syndrome might be distinct entities. This family may have Labrune syndrome or a yet unclassified entity; exploration of similar cases could help classifying this one, and related conditions.

Sleep EEG Detects Epileptiform Activity in Alzheimer’s Disease with High Sensitivity

BACKGROUND The reported prevalence of epilepsy in Alzheimers disease (AD) is variable, probably due to the different methodological approaches. OBJECTIVE We aimed to define the optimal electroencephalogram (EEG) settings for reliable detection of epileptiform discharges in AD patients. METHODS We analyzed 24-h EEGs of 5 patients living with AD and epilepsy. The sensitivity of various length EEGs in detecting epileptiform discharges in different periods of the day, the diurnal distribution of the discharges, and their relation to sleep-stages were calculated. RESULTS Significant high correlation was identified between the sensitivity of EEG and the length of recordings (r = 0.972, p = 0.005). The sensitivity of a 30-min EEG-epoch recorded between 8:00 and 16:00 was 0.0375 compared to 0.7 between 0:00 and 8:00 (p = 0.005). The average sensitivity of an 8-h EEG-epoch was≥0.8. 82% of epileptiform discharges occurred during sleep, mainly related to non-REM sleep (p < 0.001). CONCLUSION 8-h awake-, or 1-h sleep-EEG provide sufficient sensitivity in detecting epileptiform activity in AD. This needs to be considered in studies on AD-related epilepsy. Recognizing epilepsy in AD patients is essential because it might compromise cognitive functions and accelerate the progression of the disease.

Peri-ictal water drinking in temporal lobe epilepsy: Is it a reliable lateralizing sign?

Peri-ictal water drinking has been reported to be a lateralizing sign to the right side in temporal lobe epilepsy (TLE). As peri-ictal water drinking is relatively common in our own patients with TLE, we wanted to evaluate its lateralization value for ourselves. We reviewed the data for 55 adult patients with TLE who had undergone epilepsy surgery with a favorable postoperative outcome in our center. Eight patients exhibited peri-ictal water drinking behavior. Five of them had a left temporal and three a right temporal epileptogenic region. We also analyzed cases of peri-ictal water drinking in the literature and found that the reported data do not support this behavior as a laterality indicator. In conclusion, we could not find any evidence for the lateralization value of peri-ictal water drinking in TLE.