Fernando Lopes da Silva

• MD, PhD
• Professor Emeritus at University of Amsterdam

An overview of the pathophysiology of absence seizures is given, focusing on computational modelling where recent neurophysiological experimental evidence is incorporated. The main question addressed is what is the dynamical process by which the same brain can produce sustained bursts of synchronous spike-and-wave discharges (SWDs) and normal, larg...

Abstract The human brain, largely accepted as the most complex biological system known, is still far from being understood in its parts or as a whole. More specifically, biological mechanisms of epileptic states and state transitions are not well understood. Here, we explore the concept of the epilepsy as a manifestation of a multistate network co...

A stimulation-based measurement paradigm is proposed that can provide a biomarker, which we call “separatrix proximity marker”, able to assess how close is a neural system from an epileptic transition. We use a distributed network of potentially multi-stable local systems that can have different levels of susceptibility for transitions to oscillato...

It is not fully understood how seizures terminate and why some seizures are followed by a period of complete brain activity suppression, postictal generalized EEG suppression. This is clinically relevant as there is a potential association between postictal generalized EEG suppression, cardiorespiratory arrest and sudden death following a seizure....

Microarray experiments with RNA from brain regions obtained at different time points after electrically- or pharmacologically-induced status epilepticus in the rat, point to inflammation as a possible contributing epileptogenic factor. The overwhelming acute inflammatory response is reflected in a general and time dependent activation of multiple g...

Background: Neurological disorders are often characterized by an excessive and prolonged imbalance between neural excitatory and inhibitory processes. An ubiquitous finding among these disorders is the disrupted function of inhibitory GABAergic interneurons. Objective: The objective is to propose a novel stimulation procedure able to evaluate th...

Rationale. Automated monitoring and alerting for adverse events in patients with epilepsy can provide higher security and quality of life for those who suffer from this debilitating condition. Recently we explored the relation between clonic slowing at the end of a convulsive seizure and the occurrence and duration of a subsequent period of post-ic...

Epilepsy is a condition in which periods of ongoing normal EEG activity alternate with periods of oscillatory behavior characteristic of epileptic seizures. The dynamics of the transitions between the two states are still unclear. Computational models provide a powerful tool to explore the underlying mechanisms of such transitions, with the purpose...

Automated monitoring and alerting for adverse events in people with epilepsy can provide higher security and quality of life for those who suffer from this debilitating condition. Recently, we found a relation between clonic slowing at the end of a convulsive seizure (CS) and the occurrence and duration of a subsequent period of postictal generaliz...

doi: 10.1142/S0129065714500208

In this study, we investigate the correspondence between dynamic patterns of behavior in two types of computational models of neuronal activity. The first model type is the realistic neuronal model; the second model type is the phenomenological or analytical model. In the simplest model set-up of two interconnected units, we define a parameter spac...

To understand dynamic cognitive processes, the high time resolution of EEG/MEG is invaluable. EEG/MEG signals can play an important role in providing measures of functional and effective connectivity in the brain. After a brief description of the foundations and basic methodological aspects of EEG/MEG signals, the relevance of the signals to obtain...

The main objective of this paper is to examine evidence for the concept that epileptic activity should be envisaged in terms of functional connectivity and dynamics of neuronal networks. Basic concepts regarding structure and dynamics of neuronal networks are briefly described. Particular attention is given to approaches that are derived, or relate...

We aim to derive fully autonomous seizure suppression paradigms based on reactive control of neuronal dynamics. A previously derived computational model of seizure generation describing collective degrees of freedom and featuring bistable dynamics is used. A novel technique for real-time control of epileptogenicity is introduced. The reactive contr...

Epilepsy is a dynamic disease of neuronal networks. To understand how epileptic seizures occur, it is necessary to take into account that the brain of epileptic subjects is able to function in two very distinct modes: a normal state and a state characterized by abnormal oscillations, i.e., epileptic seizures. A main question is how the transition (...

Epilepsy is a neurological disorder characterized by sudden, often unexpected transitions from normal to pathological behavioral states called epileptic seizures. Some of these seizures are accompanied by uncontrolled, often rhythmic movements of body parts when seizure activity propagates to brain areas responsible for the initiation and control o...

High frequency oscillations (HFO) in stereo electroencephalographic (SEEG) signals have been recently the focus of attention as biomarkers that can have potential predictive power for the spatial location and possibly the timing of the onset of epileptic seizures. In this work we present a case study where we compare two quantitative paradigms for...

Rationale: The goal of this study is to evaluate the electroencephalographic (EEG) events, prior to clonic phases of epileptic motor seizures. Analyzing video sequences we were able to detect these special phases of motor seizures, by image features. This can be used for an early detection and alerting for these events. In the study we analyzed 42...

A phenomenological neural network model with bi-stable oscillatory units is used to model up- and down-states. These states have been observed in vivo in biological neuronal systems and feature oscillatory, limit cycle type of behavior in the up-states. A network is formed by a set of interconnected units. Two different types of network layouts are...

Het geheugen is een heterogeen verschijnsel. Psychologisch onderzoek bij de mens en gedragsonderzoek bij verschillende diersoorten, heeft aangetoond dat verschillende vormen van het geheugen onderscheiden kunnen worden. Er bestaat een soort‘confederatie’ van geheugensystemen (Willingham 1997), of in andere woorden: er bestaan meervoudige geheugensy...

Previously we found that benzodiazepines not only provoke beta-activity in the EEG, but also higher frequency activity. Knowing the origin of this high frequency activity is crucial if localisation of epileptogenic brain tissue is the query. We attempt to differentiate cerebral from muscular origin of such activity. We postulate that EEG and MEG ha...

High frequency oscillations (HFOs) constitute a novel trend in neurophysiology that is fascinating neuroscientists in general, and epileptologists in particular. But what are HFOs? What is the frequency range of HFOs? Are there different types of HFOs, physiological and pathological? How are HFOs generated? Can HFOs represent temporal codes for cog...

High frequency oscillations (HFO) have a variety of characteristics: band-limited or broad-band, transient burst-like phenomenon or steady-state. HFOs may be encountered under physiological or under pathological conditions (pHFO). Here we review the underlying mechanisms of oscillations, at the level of cells and networks, investigated in a variety...

High-frequency oscillations (HFOs) are EEG field potentials with frequencies higher than 30 Hz; commonly the frequency band between 30 and 70 Hz is denominated the gamma band, but with the discovery of activities at frequencies higher than 70 Hz a variety of terms have been proposed to describe the latter (Gotman and Crone, 2011). In general we may...

The most important quest of cognitive neuroscience may be to unravel the mechanisms by which the brain selects, links, consolidates, and integrates new information into its neuronal network, while preventing saturation to occur. During the past decade, neuroscientists working within several disciplines have observed an important involvement of the...

Characteristically within the resting brain there are slow fluctuations (around 0.1Hz) of EEG and NIRS-(de)oxyhemoglobin ([deoxy-Hb], [oxy-Hb]) signals. An interesting question is whether such slow oscillations can be related to the intention to perform a motor act. To obtain an answer we analyzed continuous blood pressure (BP), heart rate (HR), pr...

Motor dominance is well established, but sensory dominance is much less clear. We therefore studied the cortical evoked magnetic fields using magnetoencephalography (MEG) in a group of 20 healthy right handed subjects in order to examine whether standard electrical stimulation of the median and ulnar nerve demonstrated sensory lateralization. The g...

Photosensitive epilepsy (PSE) offers a highly reproducible model to investigate whether changes in neuronal activity preceding the transition to an epileptic photoparoxysmal response (PPR) may be detected. We investigated this possibility in patients with idiopathic PSE using MEG, as well as normal controls and non-photosensitive epileptic patients...

The transition between the interictal and ictal states may be characterised in terms of the dynamics of a complex system. Seizures may emerge because of a change in system parameters, but these parameters may be invisible to passive observation. Therefore, a number of investigators have developed methods to probe the system using stimulation; these...

In previous studies we showed that autonomous absence seizure generation and termination can be explained by realistic neuronal models eliciting bi-stable dynamics. In these models epileptic seizures are triggered either by external stimuli (reflex epilepsies) or by internal fluctuations. This scenario predicts exponential distributions of the dura...

This study examined whether chronic neuropathic pain, modulated by a local anesthetic block, is associated with cortical magnetic field changes. In a group of 20 patients with pain caused by unilateral traumatic peripheral nerve injury, a local block with lidocaine 1% was administered and the cortical effects were measured and compared with a contr...

Objectives. The goal of the present work is to apply a modified version previously developed method for detection of areas involved in epileptogenic circuits and the assessment of the therapeutic effects of Low Frequency Intracranial Theta- burst Electric Neuronal Stimulation (LFITNES). Methods. We use a novel paradigm for stimulation of the brain...

We focus on the implications that the underlying neuronal dynamics might have on the possibility of anticipating seizures and designing an effective paradigm for their control. Transitions into seizures can be caused by parameter changes in the dynamic state or by interstate transitions as occur in multi-attractor systems; in the latter case, only...

The existence of the electrical activity of the brain (i.e. the electroencephalogram or EEG) was discovered more than a century ago by Caton. After the demonstration that the EEG could be recorded from the human scalp by Berger in the 1920s, it made a slow start before it became accepted as a method of analysis of brain functions in health and dise...

The scalp electroencephalogram (EEG)/magnetoencephalogram (MEG) occupies an important position as a diagnostic and research tool because of four main characteristics: (1) it has an exceedingly high time resolution, (2) it is noninvasive, (3) it is simple to record and it is inexpensive, and (4) it is the only technique by means of which the dynamic...

Theta oscillations (4-12 Hz) are associated with learning and memory and are found in the hippocampus and the entorhinal cortex (EC). The spatio-temporal organization of rhythmic activity in the hippocampal-EC complex was investigated in vitro. The voltage sensitive absorption dye NK3630 was used to record the changes in aggregated membrane voltage...

We clinically tested a quantitative EEG method to localize abnormal variations in benzodiazepine-induced fast rhythms to localize focal epileptogenic lesions, assuming altered quality/quantity of GABA receptors in the lesions. During a 64-channel-EEG (sampled at 1 kHz) recording benzodiazepines were administered to five patients with localization r...

In EEG/fMRI correlation studies it is common to consider the fMRI BOLD as filtered version of the EEG alpha power. Here the question is addressed whether other EEG frequency components may affect the correlation between alpha and BOLD. This was done comparing the statistical parametric maps (SPMs) of three different filter models wherein either the...

In this paper, we investigate the origin of the large inter-subject-variability of EEG-fMRI correlation patterns. For that purpose, a simplified representation of the fMRI signal is obtained by using a hierarchical clustering algorithm detecting spatial patterns of mutually correlated voxels. The general-linear model is subsequently used to determi...

Absence seizures are paroxysmal losses of consciousness of abrupt onset and offset, accompanied by bilaterally synchronous spike-and-wave (SW) discharges in the EEG. It is currently considered that the mechanisms underlying SW discharges may be related to the thalamocortical mechanisms of sleep spindle generation. The cellular mechanisms for the ge...

It has been shown that the analysis of electroencephalographic (EEG) signals submitted to an appropriate external stimulation (active paradigm) is efficient with respect to anticipating epileptic seizures [S. Kalitzin, Clin. Neurophysiol. 116, 718 (2005)]. To better understand how an active paradigm is able to detect properties of EEG signals by me...

A change in neuronal network excitability within the hippocampus is one of the hallmarks of temporal lobe epilepsy (TLE). In the dentate gyrus (DG), however, neuronal loss and mossy fiber sprouting are associated with enhanced inhibition rather than progressive hyperexcitability. The aim of this study was to investigate how alterations in excitabil...

Multi-channel electroencephalography recordings have shown that a visual cue, indicating right hand, left hand or foot motor imagery, can induce a short-lived brain state in the order of about 500 ms. In the present study, 10 able-bodied subjects without any motor imagery experience (naive subjects) were asked to imagine the indicated limb movement...

Considering that there are several theoretical reasons why fMRI data is correlated to variations in heart rate, these correlations are explored using experimental resting state data. In particular, the possibility is discussed that the "default network", being a brain area that deactivates during non-specific general tasks, is a hemodynamic effect...

Pharmacoresistance is a major problem in the treatment of epilepsy. We showed previously that pharmacoresistance, at least partially, is due to an up-regulation of the multidrug transporter (MDT) P-glycoprotein (P-gp): inhibition of P-gp improves seizure control in phenytoin-treated epileptic rats (poststatus epilepticus rat model for temporal lobe...

Photosensitive epilepsy (PSE) is the most common form of reflex epilepsy. Usually, to find out whether a patient is sensitive, he/she is stimulated visually with, e.g. a stroboscopic light stimulus at variable frequency and intensity until a photo paroxysmal response (PPR) occurs. The research described in this work aims to find whether photosensit...

EEG coherence is decreased in Alzheimer's disease (AD), suggesting decreased interaction between brain areas. Nonlinear EEG analysis in AD points to decreased complexity of brain dynamics, implicating increased interaction. To clarify these apparently paradoxical findings from linear and nonlinear analysis, we calculated global coherence and global...

This overview covers recent advances in the field of EEG/MEG signal processing and modeling in epilepsy regarding both interictal and ictal phenomena. In the first part, the main methods used in the analysis of interictal EEG/MEG epileptiform spikes are presented and discussed. Source and volume conductor models are passed in review, namely the equ...

Gangliogliomas (GG) constitute the most frequent tumor entity in young patients undergoing surgery for intractable epilepsy. The histological composition of GG, with the presence of dysplastic neurons, corroborates their maldevelopmental origin. However, their histogenesis, the pathogenetic relationship with other developmental lesions, and the mol...

Unlabelled: This study explores differences in cognitive outcome after a standard resection (SR) or tailored (TR) in 100 patients with left temporal lobe epilepsy, controlling for extent in the three lateral gyri. Comparing preoperative to 6-month postoperative performance on a battery of intelligence, language and verbal memory tests revealed the...

In this paper we investigate the mechanisms underlying transitions in epilepsy and cognition by exploring intermittency in simple recurrent neural network models. We demonstrate that neural activity can change dynamical phases without requiring plasticity or reliance on external cues. However, we also demonstrate that the characteristic of the resu...

Considering that the role of colour in photosensitive epilepsy (PSE) remains unclear, we designed a study to determine the potential of different colours, colour combinations and white light to trigger photoparoxysmal responses (PPRs) under stringent controlled conditions. After assessing their photosensitivity to stroboscopic white light and black...

We investigated the involvement of the complement cascade during epileptogenesis in a rat model of temporal lobe epilepsy (TLE), and in the chronic epileptic phase in both experimental as well as human TLE. Previous rat gene expression analysis using microarrays indicated prominent activation of the classical complement pathway which peaked at 1 we...

In this study, the effects of vigabatrin on spike-and-wave discharges (SWDs) were measured in WAG/Rij rats, an animal model of absence epilepsy. Vigabatrin was used with the aim of enhancing GABAergic neurotransmission, and in this way to investigate the role of this process in the properties of SWDs. The study was carried out both in the rat, in v...

Mesial temporal lobe epilepsy patients often display shrinkage of the entorhinal cortex, which has been attributed to neuronal loss in medial entorhinal cortex layer III (MEC-III). MEC-III neuronal loss is reproduced in chronic epileptic rats after kainate-induced (KA) status epilepticus. Here we examined, in vitro, functional changes in superficia...

EEG was recorded during fMRI scanning of 16 normal controls in resting condition with eyes closed. Time variations of the occipital alpha band amplitudes were correlated to the fMRI signal variations to obtain insight into the hemodynamic correlates of the EEG alpha activity. Contrary to earlier studies, no a priori assumptions were made on the exp...

In this paper, we present a rigorous, general definition of the nonlinear association index, known as h2. Proving equivalence between different definitions we show that the index measures the best dynamic range of any nonlinear map between signals. We present also a construction for removing the influence of one signal from another, providing, thus...

Previous findings on changes in K+-induced GABA release from hippocampal slices during kindling epileptogenesis were reinvestigated using physiological electrical stimulation. For that purpose, a procedure was developed enabling neurochemical monitoring of GABA release locally in the CA1 region of rat hippocampal slices upon tetanic stimulation of...

The purpose of this paper is to update the state of knowledge with respect to long-term monitoring (LTM) in epilepsy and to formulate recommendations regarding the application of LTM in clinical practice. LTM is an established technique in use both in a hospital setting and, increasingly, in an ambulatory and more recently in a community-based sett...

We investigated expression of genes involved in the proteolytic process during epileptogenesis in a rat model of temporal lobe epilepsy (TLE). In a previous microarray study we found prominent activation of this process, which reached highest expression during the acute and latent phase (1 week after SE) in CA3 and entorhinal cortex (EC). Detailed...

To get insight into the mechanisms that may lead to progression of temporal lobe epilepsy, we investigated gene expression during epileptogenesis in the rat. RNA was obtained from three different brain regions [CA3, entorhinal cortex (EC), and cerebellum (CB)] at three different time points after electrically induced status epilepticus (SE): acute...

To assess the long-term effects of temporal lobe epilepsy surgery on verbal memory. We assessed verbal memory performance as measured by a verbal learning test ("15 Words Test," a Dutch adaptation of Rey's Auditory Verbal Learning Test) before surgery and at three specific times after surgery: 6 months, 2 years, and 6 years in 85 patients (34 left...

: The hippocampal system, consisting of the hippocampus, subiculum, and adjacent parahippocampal region, is known to play an important role in learning and memory processes. It is also known that the originally proposed trisynaptic circuit is a simplified representation of the organization of this system. In this paper, we present evidence, both an...

We studied the reactivity of EEG rhythms (mu rhythms) in association with the imagination of right hand, left hand, foot, and tongue movement with 60 EEG electrodes in nine able-bodied subjects. During hand motor imagery, the hand mu rhythm blocked or desynchronized in all subjects, whereas an enhancement of the hand area mu rhythm was observed dur...

Recording of EEG during fMRI scanning is a recent technique that provides new perspectives on the underlying generators of classical EEG phenomena appearing in spontaneous brain activity, such as the alpha rhythm, interictal spikes and sleep spindles. The theoretical principle, on which the method is based, is quite simple. By making a statistical...

In this paper, we investigate the dynamical scenarios of transitions between normal and paroxysmal state in epilepsy. We assume that some epileptic neural network are bistable i.e., they feature two operational states, ictal and interictal that co-exist. The transitions between these two states may occur according to a Poisson process, a random wal...

The understanding of neurobiological mechanisms of epileptogenesis is essential for rational approaches for a possible disease modification as well as treatment of underlying causes of the epilepsies. More effort is necessary to translate results from basic investigations into new approaches for clinical research and to better understand a relation...

Simultaneous recording of electroencephalogram/functional magnetic resonance images (EEG/fMRI) was applied to identify blood oxygenation level-dependent (BOLD) changes associated with spontaneous variations of the alpha rhythm, which is considered the hallmark of the brain resting state. The analysis was focused on inter-subject variability associa...

The main topic of this overview is an analysis of the concepts of phase and synchrony, as used in neurophysiology, in their various meanings. A number of notions related to the concepts of phase and synchrony, which are incorporated in contemporary neurophysiology, particularly in the domain of neuro-cognitive physiology are discussed. These notion...

Contralateral somatosensory evoked fields (SEF) by whole head MEG after unilateral median and ulnar nerve stimulation of both hands were studied in 10 healthy right-handed subjects. Major parameters describing cortical activity were examined to discriminate median and ulnar nerve evoked responses. Somatic sensitivity showed high similarity in the 4...

We examined the contralateral hemispheric cortical activity in MEG (151 ch) after unilateral median nerve stimulation of the right and left hand in twenty healthy right-handed subjects. The goal was to establish parameters to describe cortical activity of the hemispheric responses and to study the potential ability to assess differences in voluntee...

The essence of epilepsy is that a patient displays (long) periods of normal EEG activity (i.e., nonepileptiform) intermingled occasionally with epileptiform paroxysmal activity. The mechanisms of transition between these two types of activity are not well understood. To provide more insight into the dynamics of the neuronal networks leading to seiz...

The study of phase consistency of high frequency EEG/MEG components can reveal properties of neuronal networks that are informative about their excitability state. The clue is that these properties are easier to put in evidence when the response of the neuronal networks is evoked by an adequate stimulation paradigm. The latter may be considered a p...

The characteristic cell loss in layer III of the medial entorhinal area (MEA-III) in human mesial temporal lobe epilepsy is reproduced in the rat kainate model of the disease. To understand how this cell loss affects the functional properties of the MEA, we investigated whether projections from the presubiculum (prS), providing a main input to the...

Iron accumulation in the brain has been associated with neurodegenerative disorders, including epilepsy. In our previous SAGE study, we showed that ferritin, an iron-storage protein, was one of the genes (Ferritin-H) that showed overexpression before the chronic epileptic phase. In this study we used ferritin as indicator for disturbed iron homeost...

Interest in visually induced seizures has increased in recent years as a result of the increasing number of precipitants in our modern environment. This review addresses new developments in this field with special attention given to the emergence of new diagnostic, therapeutic and preventive approaches; it also emphasizes the importance of this con...

We investigated the behavior of short-lasting beta bursts (beta rebound, beta ERS) induced after imagination of hand, foot or tongue movement. Nine able-bodied subjects were asked to imagine one type of movement following the presentation of a visual cue stimulus. EEG was recorded from 60 closely spaced electrodes placed over frontal, central and p...

PURPOSE OF REVIEW: Interest in visually induced seizures has increased in recent years as a result of the increasing number of precipitants in our modern environment. This review addresses new developments in this field with special attention given to the emergence of new diagnostic, therapeutic and preventive approaches; it also emphasizes the imp...

Four main theories on the pathophysiology of generalized absence seizures have been proposed. The "centrencephalic" theory, proposed in 1954, suggested that discharges originate from a deep-seated diffusely projecting subcortical pacemaker in the midline thalamus. This concept was refined in 1991 with the "thalamic clock" theory, implying that the...

After Pokémon viewing triggered an epidemic of seizures in Japan, many efforts have been made to design safety guidelines and systems to protect subjects with photosensitivity. The authors developed a new method based upon nonlinear diffusion techniques capable of filtering the epileptogenic content of a video sequence related to color without alte...

To explore and validate a novel stimulation and analysis paradigm proposed to monitor spatial distribution and temporal changes of the excitability state in patients with temporal lobe epilepsy (TLE). We use intermittent pulse stimulation in the frequency range 10-20Hz. A quantitative measure of spectral phase de-modulation, the relative phase clus...

Magnetoencephalography (MEG) is a relatively novel technique that allows the study of the dynamic properties of cortical activity. The functional localization of brain sources of MEG signals depends on the models used and it always has a certain degree of uncertainty. Nevertheless, MEG can be very useful in assisting the neurosurgeon in planning an...

We investigated whether the functional network properties of the medial entorhinal area (MEA) of the entorhinal cortex were altered in a rat model of chronic epilepsy that is characterized by extensive cell loss in MEA layer III. Responses were evoked in the entorhinal cortex by electrical stimulation of the subiculum in anesthetized chronic epilep...

BACKGROUND: After Pokemon viewing triggered an epidemic of seizures in Japan, many efforts have been made to design safety guidelines and systems to protect subjects with photosensitivity. The authors developed a new method based upon nonlinear diffusion techniques capable of filtering the epileptogenic content of a video sequence related to color...