EEG Sleep Slow-Wave Activity as a Mirror of Cortical Maturation

Deep (slow wave) sleep shows extensive maturational changes from childhood through adolescence, which is reflected in a decrease of sleep depth measured as the activity of electroencephalographic (EEG) slow waves. This decrease in sleep depth is paralleled by massive synaptic remodeling during adolescence as observed in anatomical studies, which supports the notion that adolescence represents a sensitive period for cortical maturation. To assess the relationship between slow-wave activity (SWA) and cortical maturation, we acquired sleep EEG and magnetic resonance imaging data in children and adolescents between 8 and 19 years. We observed a tight relationship between sleep SWA and a variety of indexes of cortical maturation derived from magnetic resonance (MR) images. Specifically, gray matter volumes in regions correlating positively with the activity of slow waves largely overlapped with brain areas exhibiting an age-dependent decrease in gray matter. The positive relationship between SWA and cortical gray matter was present also for power in other frequency ranges (theta, alpha, sigma, and beta) and other vigilance states (theta during rapid eye movement sleep). Our findings indicate a strong relationship between sleep EEG activity and cortical maturation. We propose that in particular, sleep SWA represents a good marker for structural changes in neuronal networks reflecting cortical maturation during adolescenc

Sleep in the Human Hippocampus: A Stereo-EEG Study

Background. There is compelling evidence indicating that sleep plays a crucial role in the consolidation of new declarative, hippocampus-dependent memories. Given the increasing interest in the spatiotemporal relationships between cortical and hippocampal activity during sleep, this study aimed to shed more light on the basic features of human sleep in the hippocampus. Methodology/Principal Findings. We recorded intracerebral stereo-EEG directly from the hippocampus and neocortical sites in five epileptic patients undergoing presurgical evaluations. The time course of classical EEG frequency bands during the first three NREM-REM sleep cycles of the night was evaluated. We found that delta power shows, also in the hippocampus, the progressive decrease across sleep cycles, indicating that a form of homeostatic regulation of delta activity is present also in this subcortical structure. Hippocampal sleep was also characterized by: i) a lower relative power in the slow oscillation range during NREM sleep compared to the scalp EEG; ii) a flattening of the time course of the very low frequencies (up to 1 Hz) across sleep cycles, with relatively high levels of power even during REM sleep; iii) a decrease of power in the beta band during REM sleep, at odds with the typical increase of power in the cortical recordings. Conclusions/Significance. Our data imply that cortical slow oscillation is attenuated in the hippocampal structures during NREM sleep. The most peculiar feature of hippocampal sleep is the increased synchronization of the EEG rhythms during REM periods. This state of resonanc

Cortical glucose metabolism correlates negatively with delta-slowing and spike-frequency in epilepsy associated with tuberous sclerosis

The mechanism of altered glucose metabolism seen on positron emission tomography (PET) in focal epilepsy is not fully understood. We determined the association between interictal glucose metabolism and interictal neuronal activity, using PET and electrocorticography (ECoG) measures derived from 865 intracranial electrode sites in 11 children with focal epilepsy associated with tuberous sclerosis complex (TSC) (age: 0.5–16 years) undergoing epilepsy surgery. A multiple linear regression analysis was applied to each patient, to determine whether the glucose uptake at each electrode site on interictal PET was predicted by ECoG amplitude powers and interictal spike-frequency measured in the given electrode site. The regression slopes as well as R -square values (an indicator of fitness of the regression models) were finally averaged across the 11 patients. The mean regression slope for delta amplitude power was −0.0025 (95% CI: −0.0045 to −0.0004; P = 0.02 based on one-sample t -test) and that for spike frequency was −0.023 (95% CI: −0.042 to −0.0038; P = 0.02). On the other hand, the mean regression slopes for the remaining ECoG amplitude powers (theta, alpha, sigma, beta, and gamma activities) were not significantly different from zero. The mean R -square value was 0.39. These results suggest that increased delta-slowing and frequent spike activity were independently and additively associated with glucose hypometabolism in children with focal epilepsy associated with TSC. Association between frequent interictal spike activity and low glucose metabolism may be attributed to slow-wave components following spike discharges on ECoG recording, and a substantial proportion of the variance in regional glucose metabolism on PET could be explained by electrophysiological traits derived from conventional subdural ECoG recording. Hum Brain Mapp, 2008. © 2007 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/61224/1/20461_ftp.pd

Incessant transitions between active and silent states in cortico-thalamic circuits and altered neuronal excitability lead to epilepsy

La ligne directrice de nos expériences a été l'hypothèse que l'apparition et/ou la persistance des fluctuations de longue durée entre les états silencieux et actifs dans les réseaux néocorticaux et une excitabilité neuronale modifiée sont les facteurs principaux de l'épileptogenèse, menant aux crises d’épilepsie avec expression comportementale. Nous avons testé cette hypothèse dans deux modèles expérimentaux différents. La déafférentation corticale chronique a essayé de répliquer la déafférentation physiologique du neocortex observée pendant le sommeil à ondes lentes. Dans ces conditions, caractérisées par une diminution de la pression synaptique et par une incidence augmentée de périodes silencieuses dans le système cortico-thalamique, le processus de plasticité homéostatique augmente l’excitabilité neuronale. Par conséquent, le cortex a oscillé entre des périodes actives et silencieuses et, également, a développé des activités hyper-synchrones, s'étendant de l’hyperexcitabilité cellulaire à l'épileptogenèse focale et à des crises épileptiques généralisées. Le modèle de stimulation sous-liminale chronique (« kindling ») du cortex cérébral a été employé afin d'imposer au réseau cortical une charge synaptique supérieure à celle existante pendant les états actifs naturels - état de veille ou sommeil paradoxal (REM). Dans ces conditions un mécanisme différent de plasticité qui s’est exprimé dans le système thalamo-corticale a imposé pour des longues périodes de temps des oscillations continuelles entre les époques actives et silencieuses, que nous avons appelées des activités paroxysmiques persistantes. Indépendamment du mécanisme sous-jacent de l'épileptogenèse les crises d’épilepsie ont montré certaines caractéristiques similaires : une altération dans l’excitabilité neuronale mise en évidence par une incidence accrue des décharges neuronales de type bouffée, une tendance constante vers la généralisation, une propagation de plus en plus rapide, une synchronie augmentée au cours du temps, et une modulation par les états de vigilance (facilitation pendant le sommeil à ondes lentes et barrage pendant le sommeil REM). Les états silencieux, hyper-polarisés, de neurones corticaux favorisent l'apparition des bouffées de potentiels d’action en réponse aux événements synaptiques, et l'influence post-synaptique d'une bouffée de potentiels d’action est beaucoup plus importante par rapport à l’impacte d’un seul potentiel d’action. Nous avons également apporté des évidences que les neurones néocorticaux de type FRB sont capables à répondre avec des bouffées de potentiels d’action pendant les phases hyper-polarisées de l'oscillation lente, propriété qui peut jouer un rôle très important dans l’analyse de l’information dans le cerveau normal et dans l'épileptogenèse. Finalement, nous avons rapporté un troisième mécanisme de plasticité dans les réseaux corticaux après les crises d’épilepsie - une diminution d’amplitude des potentiels post-synaptiques excitatrices évoquées par la stimulation corticale après les crises - qui peut être un des facteurs responsables des déficits comportementaux observés chez les patients épileptiques. Nous concluons que la transition incessante entre des états actifs et silencieux dans les circuits cortico-thalamiques induits par disfacilitation (sommeil à ondes lentes), déafférentation corticale (épisodes ictales à 4-Hz) ou par une stimulation sous-liminale chronique (activités paroxysmiques persistantes) crée des circonstances favorables pour le développement de l'épileptogenèse. En plus, l'augmentation de l’incidence des bouffées de potentiels d’actions induisant une excitation post-synaptique anormalement forte, change l'équilibre entre l'excitation et l'inhibition vers une supra-excitation menant a l’apparition des crises d’épilepsie.The guiding line in our experiments was the hypothesis that the occurrence and / or the persistence of long-lasting fluctuations between silent and active states in the neocortical networks, together with a modified neuronal excitability are the key factors of epileptogenesis, leading to behavioral seizures. We addressed this hypothesis in two different experimental models. The chronic cortical deafferentation replicated the physiological deafferentation of the neocortex observed during slow-wave sleep (SWS). Under these conditions of decreased synaptic input and increased incidence of silent periods in the corticothalamic system the process of homeostatic plasticity up-regulated cortical cellular and network mechanisms and leaded to an increased excitability. Therefore, the deafferented cortex was able to oscillate between active and silent epochs for long periods of time and, furthermore, to develop highly synchronized activities, ranging from cellular hyperexcitability to focal epileptogenesis and generalized seizures. The kindling model was used in order to impose to the cortical network a synaptic drive superior to the one naturally occurring during the active states - wake or rapid eye movements (REM) sleep. Under these conditions a different plasticity mechanism occurring in the thalamo-cortical system imposed long-lasting oscillatory pattern between active and silent epochs, which we called outlasting activities. Independently of the mechanism of epileptogenesis seizures showed some analogous characteristics: alteration of the neuronal firing pattern with increased bursts probability, a constant tendency toward generalization, faster propagation and increased synchrony over the time, and modulation by the state of vigilance (overt during SWS and completely abolished during REM sleep). Silent, hyperpolarized, states of cortical neurons favor the induction of burst firing in response to depolarizing inputs, and the postsynaptic influence of a burst is much stronger as compared to a single spike. Furthermore, we brought evidences that a particular type of neocortical neurons - fast rhythmic bursting (FRB) class - is capable to consistently respond with bursts during the hyperpolarized phase of the slow oscillation, fact that may play a very important role in both normal brain processing and in epileptogenesis. Finally, we reported a third plastic mechanism in the cortical network following seizures - a decreasing amplitude of cortically evoked excitatory post-synaptic potentials (EPSP) following seizures - which may be one of the factors responsible for the behavioral deficits observed in patients with epilepsy. We conclude that incessant transitions between active and silent states in cortico-thalamic circuits induced either by disfacilitation (sleep), cortical deafferentation (4-Hz ictal episodes) and by kindling (outlasting activities) create favorable circumstances for epileptogenesis. The increase in burst-firing, which further induce abnormally strong postsynaptic excitation, shifts the balance of excitation and inhibition toward overexcitation leading to the onset of seizures

Sleep-related epileptic behaviors and non-REM-related parasomnias: Insights from stereo-EEG

During the last decade, many clinical and pathophysiological aspects of sleep-related epileptic and non-epileptic paroxysmal behaviors have been clarified. Advances have been achieved in part through the use of intracerebral recording methods such as stereo-electroencephalography (S-EEG), which has allowed a unique "in vivo" neurophysiological insight into focal epilepsy. Using S-EEG, the local features of physiological and pathological EEG activity in different cortical and subcortical structures have been better defined during the entire sleep-wake spectrum. For example, S-EEG has contributed to clarify the semiology of sleep-related seizures as well as highlight the specific epileptogenic networks involved during ictal activity. Moreover, intracerebral EEG recordings derived from patients with epilepsy have been valuable to study sleep physiology and specific sleep disorders. The occasional co-occurrence of NREM-related parasomnias in epileptic patients undergoing S-EEG investigation has permitted the recordings of such events, highlighting the presence of local electrophysiological dissociated states and clarifying the underlying pathophysiological substrate of such NREM sleep disorders. Based on these recent advances, the authors review and summarize the current and relevant S-EEG literature on sleep-related hypermotor epilepsies and NREM-related parasomnias. Finally, novel data and future research hypothesis will be discussed

The thalamic mGluR1-PLC??4 pathway is critical in sleep architecture

The transition from wakefulness to a nonrapid eye movement (NREM) sleep state at the onset of sleep involves a transition from low-voltage, high-frequency irregular electroencephalography (EEG) waveforms to large-amplitude, low-frequency EEG waveforms accompanying synchronized oscillatory activity in the thalamocortical circuit. The thalamocortical circuit consists of reciprocal connections between the thalamus and cortex. The cortex sends strong excitatory feedback to the thalamus, however the function of which is unclear. In this study, we investigated the role of the thalamic metabotropic glutamate receptor 1 (mGluR1)-phospholipase C ??4 (PLC??4) pathway in sleep control in PLC??4-deficient (PLC??4-/-) mice. The thalamic mGluR1-PLC??4 pathway contains synapses that receive corticothalamic inputs. In PLC??4-/- mice, the transition from wakefulness to the NREM sleep state was stimulated, and the NREM sleep state was stabilized, which resulted in increased NREM sleep. The power density of delta (??) waves increased in parallel with the increased NREM sleep. These sleep phenotypes in PLC??4-/- mice were consistent in TC-restricted PLC??4 knockdown mice. Moreover, in vitro intrathalamic oscillations were greatly enhanced in the PLC??4-/- slices. The results of our study showed that thalamic mGluR1-PLC??4 pathway was critical in controlling sleep architecture.ope

Circadian and homeostatic modulation of sleep spindles in the human electroencephalogram

Sleep spindles are transient EEG oscillations of about 12-16 Hz. Together with slow waves, they hallmark the human non-REM sleep EEG. Sleep spindles originate in the thalamus and are suggested to have a sleep protective function by reducing sensory transmission to the cortex. Other evidence points to an involvement of sleep spindles in brain plasticity processes during sleep. Previous studies have shown that sleep spindles are both under homeostatic (sleep-wake dependent) and circadian (time of day-dependent) control. Furthermore, frequency-specific topographical distribution of power density within the spindle frequency range has been reported. The aim of this thesis was to assess homeostatic and circadian influences on spectral spindle frequency activity (SFA) and spindle parameters in different brain regions. Healthy young volunteers participated in both a 40-h sleep deprivation (SD) and a 40-h multiple nap paradigm. The recovery nights after the SD and the nap protocol served to assess the effect of enhanced and reduced homeostatic sleep pressure, respectively. The multiple nap paradigm revealed the modulation of sleep spindles across the circadian cycle. Two different methodological approaches were used to analyze the EEGs: classical spectral analysis (Fast Fourier Transform, FFT) and a new method for instantaneous spectral analysis (Fast Time Frequency Transform, FTFT), developed as a part of this thesis project in collaboration with Wim Martens from TEMEC, The Netherlands. Slow wave activity (SWA, spectral power density in the 0.75-4.5 Hz range) and spindle frequency activity (SFA, spectral power density in the spindle frequency range) in the high frequency range (13.75-16.5 Hz) were oppositely affected by the differential levels of sleep pressure (Chapter 2). These effects strongly depended on brain location. After SD, the SWA increase compared to the baseline night was most pronounced in the beginning of the night and in the fronto-central region. Power density in the high spindle frequency range was reduced in the centro-parietal brain region. After the nap protocol, when sleep pressure was reduced, power density in the SWA range was decreased at the beginning of the night. SFA was generally increased after the nap protocol. The data indicate that the balance between SWA and high-frequency spindle activity may represent a sensitive marker for the level of homeostatic sleep pressure. The new method of FTFT revealed that spindle density was reduced after SD (Chapter 3). This reduction was particularly apparent in the frontal derivation, and most pronounced in the first half of the night. The reduction of spindle density with its temporal and local specificity confirms the inverse homeostatic regulation of slow waves and sleep spindles. Sleep spindles had a lower frequency and a higher amplitude after SD. Within an individual spindle, frequency variability was reduced, which indicates that sleep spindles were more stable and homogenous after SD. The increase in spindle amplitude and the reduced intra-spindle frequency variability suggests a higher degree of synchronization in thalamocortical neurons under high homeostatic sleep pressure. EEGs during the nap paradigm were analyzed to compare SFA and sleep spindle characteristics during and outside the circadian phase of melatonin secretion (the “biological night” and “biological day”, respectively) (Chapter 4). In naps occurring during the phase of melatonin secretion, lower spindle frequencies were promoted, indexed as a reduction in mean spindle frequency (i.e. slowing of sleep spindles) and an increase in spindle amplitude and SFA in the low-frequency range (up to ~14.25 Hz) paralleled by a reduction in the high-frequency range (~ 14.5-16 Hz). Furthermore, spindle density was increased, and intra-spindle frequency variability reduced during the night. Thus, the circadian pacemaker is likely to promote low-frequency, high amplitude and homogenous sleep spindles during the biological night. The circadian modulation of sleep spindles may be a way by which the circadian system modulates and times sleep consolidation. This circadian modulation clearly depended on brain location such that it was maximal in the parietal and minimal in the frontal derivation. Taken together, the segregated analysis of different spindle parameters by the new high-time and high-frequency resolution spindle analysis provides new insights into sleep spindles and their regulation. Both homeostatic and circadian processes affected sleep spindles characteristics in a topography-specific manner. These statedependent local aspects provide further evidence that sleep is a dynamic phenomenon which reflects use-dependent recovery or reactivation processes

Circadian and homeostatic modulation of sleep spindles in the human electroencephalogram

Sleep spindles are transient EEG oscillations of about 12-16 Hz. Together with slow waves, they hallmark the human non-REM sleep EEG. Sleep spindles originate in the thalamus and are suggested to have a sleep protective function by reducing sensory transmission to the cortex. Other evidence points to an involvement of sleep spindles in brain plasticity processes during sleep. Previous studies have shown that sleep spindles are both under homeostatic (sleep-wake dependent) and circadian (time of day-dependent) control. Furthermore, frequency-specific topographical distribution of power density within the spindle frequency range has been reported. The aim of this thesis was to assess homeostatic and circadian influences on spectral spindle frequency activity (SFA) and spindle parameters in different brain regions. Healthy young volunteers participated in both a 40-h sleep deprivation (SD) and a 40-h multiple nap paradigm. The recovery nights after the SD and the nap protocol served to assess the effect of enhanced and reduced homeostatic sleep pressure, respectively. The multiple nap paradigm revealed the modulation of sleep spindles across the circadian cycle. Two different methodological approaches were used to analyze the EEGs: classical spectral analysis (Fast Fourier Transform, FFT) and a new method for instantaneous spectral analysis (Fast Time Frequency Transform, FTFT), developed as a part of this thesis project in collaboration with Wim Martens from TEMEC, The Netherlands. Slow wave activity (SWA, spectral power density in the 0.75-4.5 Hz range) and spindle frequency activity (SFA, spectral power density in the spindle frequency range) in the high frequency range (13.75-16.5 Hz) were oppositely affected by the differential levels of sleep pressure (Chapter 2). These effects strongly depended on brain location. After SD, the SWA increase compared to the baseline night was most pronounced in the beginning of the night and in the fronto-central region. Power density in the high spindle frequency range was reduced in the centro-parietal brain region. After the nap protocol, when sleep pressure was reduced, power density in the SWA range was decreased at the beginning of the night. SFA was generally increased after the nap protocol. The data indicate that the balance between SWA and high-frequency spindle activity may represent a sensitive marker for the level of homeostatic sleep pressure. The new method of FTFT revealed that spindle density was reduced after SD (Chapter 3). This reduction was particularly apparent in the frontal derivation, and most pronounced in the first half of the night. The reduction of spindle density with its temporal and local specificity confirms the inverse homeostatic regulation of slow waves and sleep spindles. Sleep spindles had a lower frequency and a higher amplitude after SD. Within an individual spindle, frequency variability was reduced, which indicates that sleep spindles were more stable and homogenous after SD. The increase in spindle amplitude and the reduced intra-spindle frequency variability suggests a higher degree of synchronization in thalamocortical neurons under high homeostatic sleep pressure. EEGs during the nap paradigm were analyzed to compare SFA and sleep spindle characteristics during and outside the circadian phase of melatonin secretion (the “biological night” and “biological day”, respectively) (Chapter 4). In naps occurring during the phase of melatonin secretion, lower spindle frequencies were promoted, indexed as a reduction in mean spindle frequency (i.e. slowing of sleep spindles) and an increase in spindle amplitude and SFA in the low-frequency range (up to ~14.25 Hz) paralleled by a reduction in the high-frequency range (~ 14.5-16 Hz). Furthermore, spindle density was increased, and intra-spindle frequency variability reduced during the night. Thus, the circadian pacemaker is likely to promote low-frequency, high amplitude and homogenous sleep spindles during the biological night. The circadian modulation of sleep spindles may be a way by which the circadian system modulates and times sleep consolidation. This circadian modulation clearly depended on brain location such that it was maximal in the parietal and minimal in the frontal derivation. Taken together, the segregated analysis of different spindle parameters by the new high-time and high-frequency resolution spindle analysis provides new insights into sleep spindles and their regulation. Both homeostatic and circadian processes affected sleep spindles characteristics in a topography-specific manner. These statedependent local aspects provide further evidence that sleep is a dynamic phenomenon which reflects use-dependent recovery or reactivation processes