Modulation of intrinsic and synaptic excitability during sleep oscillations and electrographic seizures

Le présente mémoire fournit des nouvelles évidences montrant la modulation de l’excitabilité neuronale intrinsèque et synaptique, et la conséquence de cette modulation sur l’activité neuronale durant à la fois, les oscillations lentes du sommeil, et les crises électrographiques in vivo chez des animaux anesthésiés. Nous effectuons des enregistrements intracellulaires simultanés de neurones corticaux et des potentiels de champs locaux au niveau du gyrus suprasylvien à l’intérieur du cortex associatif pariétal (aires : 5, 7 et 21). Nous suggérons que la fluctuation de la concentration extracellulaire du calcium durant les oscillations lentes du sommeil module à la fois, l’excitabilité intrinsèque et synaptique des neurones corticaux, ainsi par conséquent, elle module affecte la relation d’input-output de ces neurones. L’apparition durant les oscillations lentes du sommeil, des crises de type Lennex-Gastaut qui sont générées corticalement, nous a permet d’étudier les propriétés spatio-temporelles des ondes paroxysmiques rapides associées avec ce type de crises. Nous suggérons que les ondes paroxysmiques rapides apparaissent comme des oscillations quasi-indépendantes même dans les localisations corticales voisines, suggérant leur origine focal.The present memoir provides new evidences showing the modulation of intrinsic and synaptic excitability of cortical neurons, and the consequence of this modulation on neuronal activity during both slow sleep oscillations and electrographic seizures in vivo in anaesthetized animals. We performed simultaneous recordings of cortical neurons with local field potentials in suprasylvian gyrus within parietal associative cortex (area 5, 7 and 21). We suggest that the fluctuation of extacellular calcium concentration during slow sleep oscillations, modulates both intrinsic and synaptic excitability cortical neurons, thus by consequence modulates the input-output relationship of these neurons. The occurrence during slow-wave sleep of cortically generated Lennox-Gastaut type of seizures admits us to study the spatio-temporal properties of paroxysmal fast runs associated with this type of seizures. We suggest that fast runs appeared as quasi-independent oscillations even in neighbouring cortical locations suggesting their focal origin

Structural Brain Alterations Associated with Rapid Eye Movement Sleep Behavior Disorder in Parkinson’s Disease

Characterized by dream-enactment motor manifestations arising from rapid eye movement (REM) sleep, REM sleep behavior disorder (RBD) is frequently encountered in Parkinson’s disease (PD). Yet the specific neurostructural changes associated with RBD in PD patients remain to be revealed by neuroimaging. Here we identified such neurostructural alterations by comparing large samples of magnetic resonance imaging (MRI) scans in 69 PD patients with probable RBD, 240 patients without RBD and 138 healthy controls, using deformation-based morphometry (p < 0.05 corrected for multiple comparisons). All data were extracted from the Parkinson’s Progression Markers Initiative. PD patients with probable RBD showed smaller volumes than patients without RBD and than healthy controls in the pontomesencephalic tegmentum, medullary reticular formation, hypothalamus, thalamus, putamen, amygdala and anterior cingulate cortex. These results demonstrate that RBD is associated with a prominent loss of volume in the pontomesencephalic tegmentum, where cholinergic, GABAergic and glutamatergic neurons are located and implicated in the promotion of REM sleep and muscle atonia. It is additionally associated with more widespread atrophy in other subcortical and cortical regions whose loss also likely contributes to the altered regulation of sleep-wake states and motor activity underlying RBD in PD patients

Altered regional cerebral blood flow in idiopathic hypersomnia

Objectives Idiopathic hypersomnia is characterized by excessive daytime sleepiness despite normal or long sleep time. Its pathophysiological mechanisms remain unclear. This pilot study aims at characterizing the neural correlates of idiopathic hypersomnia using single photon emission computed tomography. Methods Thirteen participants with idiopathic hypersomnia and sixteen healthy controls were scanned during resting wakefulness using a high-resolution single photon emission computed tomography scanner with 99mTc-ethyl cysteinate dimer to assess cerebral blood flow. The main analysis compared regional cerebral blood flow distribution between the two groups. Exploratory correlations between regional cerebral blood flow and clinical characteristics evaluated the functional correlates of those brain perfusion patterns. Significance was set at p <0.05 after correction for multiple comparisons. Results Idiopathic hypersomnia participants showed regional cerebral blood flow decreases in medial prefrontal cortex, posterior cingulate cortex and putamen, as well as increases in amygdala and temporo-occipital cortices. Lower regional cerebral blood flow in the medial prefrontal cortex was associated with higher daytime sleepiness. Conclusions These preliminary findings suggest that idiopathic hypersomnia is characterized by functional alterations in brain areas involved in the modulation of vigilance states, which may contribute to the daytime symptoms of this condition. The distribution of regional cerebral blood flow changes was reminiscent of the patterns associated with normal non-rapid-eye-movement sleep, suggesting the possible presence of incomplete sleep-wake transitions. These abnormalities were strikingly distinct from those induced by acute sleep deprivation, suggesting that the patterns seen here might reflect a trait associated with idiopathic hypersomnia rather than a non-specific state of sleepiness

Sleep spindles may predict response to cognitive behavioral therapy for chronic insomnia

Background While cognitive-behavioral therapy for insomnia constitutes the first-line treatment for chronic insomnia, only few reports have investigated how sleep architecture relates to response to this treatment. In this pilot study, we aimed at determining whether sleep spindle density at pre-treatment predicts treatment response to cognitive behavioral therapy for insomnia. Methods Twenty-four participants with chronic primary insomnia took part in a 6-week cognitive behavioral therapy for insomnia performed in groups of 4 to 6 participants. Treatment response was assessed using the Pittsburgh Sleep Quality Index and the Insomnia Severity Index measured at pre- and post-treatment and at 3- and 12-months follow-up assessments. Secondary outcome measures were extracted from sleep diaries over seven days and one overnight polysomnography, obtained at pre- and post-treatment. Spindle density during stages N2-N3 sleep was extracted from polysomnography at pre-treatment. Hierarchical linear modeling analysis assessed whether sleep spindle density predicted response to cognitive behavioral therapy. Results After adjusting for age, sex and education level, lower spindle density at pre-treatment predicted poorer response over the 12-months follow-up, as reflected by smaller reduction in Pittsburgh Sleep Quality Index over time. Reduced spindle density also predicted lower improvements in sleep diary sleep efficiency and wake after sleep onset immediately after treatment. There were no significant associations between spindle density and changes in the Insomnia Severity Index or polysomnography variables over time. Conclusion These preliminary results suggest that inter-individual differences in sleep spindle density in insomnia may represent an endogenous biomarker predicting responsiveness to cognitive behavioral therapy. Insomnia with altered spindle activity might constitute an insomnia subtype characterized by a neurophysiological vulnerability to sleep disruption associated with impaired responsiveness to cognitive behavioral therapy

The role of pontomesencephalic cholinergic neurons and their neighboring GABAergic and putative glutamatergic neurons in modulating cortical activity and sleep-wake states

Neurons within the brainstem pontomescencephalic tegmentum (PMT) are suggested to play a critical role in influencing cortical activity and behavior across sleep-wake states. Cholinergic neurons in the PMT form part of the ascending activating system and are thought to participate in stimulating cortical activation during both waking (W) and paradoxical sleep (PS). They are also suggested to trigger PS with muscle atonia through their descending projections into the brainstem reticular formation. Yet in the laterodorsal tegmental and pedunculopontine tegmental nuclei (LDT and PPT), they lie intermingled with GABAergic and glutamatergic neurons, which could also modulate cortical activity and sleep–wake states.In the present work, by immunohistochemical identification of recorded and labeled single cells in urethane-anesthetized and natural sleeping/waking rats, I described the activity profiles of LDT and PPT cholinergic neurons, in addition to GABAergic and putative glutamatergic neurons, first, under anesthesia in relation to cortical activity, and second, during natural sleep-wake states in relation to state, cortical activity and muscle tone. In anesthetized rats, I found that all LDT/PPT cholinergic neurons increased their discharge in association with cortical activation evoked by somatic stimulation. They could thus function to stimulate this cortical activation. In contrast, LDT/PPT GABAergic and putative glutamatergic neurons were heterogeneous: they could either increase or decrease their discharge in relation to cortical activation. They could thus work differently to stimulate cortical activation or to dampen behavioral arousal. In natural sleeping/waking rats, I found that a cholinergic neuron was active during both W and PS, as a W/PS-max active neuron. LDT/PPT Cholinergic neurons could thus function to stimulate cortical activation during W and during PS, and trigger motor inhibition and muscle atonia associated with PS. In contrast, LDT/PPT GABAergic and putative glutamatergic neurons were heterogeneous in their sleep-wake discharge profiles. Some were active during both W and PS and were considered as W/PS-max active neurons. They could thus participate in stimulating cortical activation during both W and PS. Others were maximally active during PS, as PS-max active neurons, and could thus participate in dampening behavioral arousal and muscle tone during PS. Some putative glutamatergic neurons were maximally active during W, as W-max active neurons, and could thus participate in stimulating behavioral arousal with muscle tone during wakefulness.Together, these findings indicate that different LDT/PPT neurons are working in coordination to either mediate cortical activation during W and PS, to dampen behavioral arousal and muscle tone during PS or to stimulate behavioral arousal and muscle tone during wakefulness.Les neurones situés dans le tronc cérébral au niveau du pontomescencephalic tegmentum (PMT) ont été suggérés de jouer un role critique pour influencer l'activité corticale et comportementale durant les états de veille et de sommeil ou états, dits, de vigilance. Les neurones cholinergiques dans le PMT font partie du système d'activation ascendant qui contribue à la genèse de l'activation corticale durant l'éveil (E) et le sommeil paradoxal (SP). Ils sont aussi suggérés promouvoir l'état de SP accompagné d'atonie musculaire via leurs projections descendantes vers la formation réticulaire du tronc cérébral. Dans les noyaux laterodorsal tegmentale et pédonculopontin tegmentale (LDT et PPT), ces neurones cholinergiques sont entremêlés avec d'autres neurones GABAergiques et glutamatergiques, qui peuvent à leur tour contribuer à la modulation de l'activité corticale et donc aux états de vigilance.Dans le présent travail, des cellules ont été enregistrées, marquées et identifiées immunohistochimiquement comme des neurones cholinergiques, GABAergiques ou présumés glutamatergiques dans le LDT et le PPT chez des rats anesthésiés à l'uréthane et chez des rats qui dorment et se réveillent naturellement. Premièrement, sous anesthésie, nous avons déterminé l'activité de ces neurones en relation avec l'activation corticale. Deuxièmement, à travers les différents états de veille et de sommeil, nous avons déterminé l'activité de ces neurones en relation avec ces états de veille et de sommeil, les activités corticales pertinentes caractérisant ces états et le tonus musculaire. Chez les rats anesthésiés, j'ai constaté que tous les neurones cholinergiques du LDT / PPT augmentaient leur décharge en association avec l'activation corticale évoquéepar une stimulation somatique. Ils pourraient donc participer à cette activation corticale. Les neurones GABAergiques et les neurons présumés glutamatergiques, quant a eux, étaient hétérogènes. Soit, ils augmentaient ou ils diminuaient leur décharge en relation avec l'activation corticale. Ils pourraient ainsi contribuer différemment soit pour stimuler l'activation corticale ou au contraire freiner l'éveil comportemental. Chez des rats qui dorment et se réveillent naturellement, j'ai constaté qu'un neurone cholinergique est actif au cours des deux états de vigilance l'éveil et SP, il est considéré comme étant un neurone E/SP-max. Les neurones cholinergiques de LDT/PPT pourraient ainsi stimuler l'activation corticale lors de l'éveil et du SP, comme ils pourraient également promouvoir l'inhibition motrice et l'induction de l'atonie musculaire associée au SP. En revanche, les neurons GABAergiques et les neurones présumés glutamatergiques du LDT/PPT sont hétérogènes dans leurs profils de décharge. Certains, sont actifs pendant l'éveil et le SP, comme étant des neurones E/SP-max. Comme pour les neurones cholinergiques, ils pourraient également stimuler l'activation corticale au cours de l'éveil et du SP. D'autres, sont actifs au maximum pendant le SP, comme étant des neurones SP-max. Ils pourraient éventuellement participer à freiner l'éveil comportemental ainsi que le tonus musculaire au cours du SP. Quelques neurones présumés glutamatergiques sont actifs au maximum pendant l'éveil. Ils pourraient participer à stimuler l'éveil comportemental ainsi que le tonus musculaire au cours de l'éveil.L'ensemble de ces travaux montre que les différents neurones du LDT/PPT travaillent en coordination pour soit influencer l'activation corticale pendant l'éveil et le SP, soit freiner l'éveil comportemental et le tonus musculaire au cours du SP ou au contraire stimuler l'éveil comportemental et le tonus musculaire au cours de l'éveil

Modulation of synaptic transmission in neocortex by network activities

Neocortical neurons integrate inputs from thousands of presynaptic neurons that fire in vivo with frequencies that can reach 20 Hz. An important issue in understanding cortical integration is to determine the actual impact of presynaptic firing on postsynaptic neuron in the context of an active network. We used dual intracellular recordings from synaptically connected neurons or microstimulation to study the properties of spontaneous and evoked single-axon excitatory postsynaptic potentials (EPSPs) in vivo, in barbiturate or ketamine)xylazine anaesthetized cats. We found that active states of the cortical network were associated with higher variability and decrease in amplitude and duration of the EPSPs owing to a shunting effect. Moreover, the number of apparent failures markedly increased during active states as compared with silent states. Single-axon EPSPs in vivo showed mainly paired-pulse facilitation, and the paired-pulse ratio increased during active states as compare to silent states, suggesting a decrease in release probability during active states. Raising extracellular Ca2+ concentration to 2.5–3.0 mm by reverse microdialysis reduced the number of apparent failures and significantly increased the mean amplitude of individual synaptic potentials. Quantitative analysis of spontaneous synaptic activity suggested that the proportion of presynaptic activity that impact at the soma of a cortical neuron in vivo was low because of a high failure rate, a shunting effect and probably dendritic filtering. We conclude that during active states of cortical network, the efficacy of synaptic transmission in individual synapses is low, thus safe transmission of information requires synchronized activity of a large population of presynaptic neurons

Focal generation of paroxysmal fast runs during electrographic seizures

Purpose:  A cortically generated Lennox-Gastaut type seizure is associated with spike-wave/poly-spike-wave discharges at 1.0–2.5 Hz and fast runs at 7–16 Hz. Here we studied the patterns of synchronization during runs of paroxysmal fast spikes. Methods:  Electrographic activities were recorded using multisite intracellular and field potential recordings in vivo from cats anesthetized with ketamine-xylazine. In different experiments, the recording electrodes were located either at short distances (<1 mm) or at longer distances (up to 12 mm). The main experimental findings were tested in computational models. Results:  In the majority of cases, the onset and the offset of fast runs occurred almost simultaneously in different recording sites. The amplitude and duration of fast runs could vary by orders of magnitude. Within the fast runs, the patterns of synchronization recorded in different electrodes were as following: (1) synchronous, in phase, (2) synchronous, with phase shift, (3) patchy, repeated in phase/phase shift transitions, and (4) nonsynchronous, slightly different frequencies in different recording sites or absence of oscillatory activity in one of the recording sites; the synchronous patterns (in phase or with phase shifts) were most common. All these patterns could be recorded in the same pair of electrodes during different seizures, and they were reproduced in a computational network model. Intrinsically bursting (IB) neurons fired more spikes per cycle than any other neurons suggesting their leading role in the fast run generation. Conclusions:  Once started, the fast runs are generated locally with variable correlations between neighboring cortical foci

Extracellular Ca2+ fluctuations in vivo affect afterhyperpolarization potential and modify firing patterns of neocortical neurons

Neocortical neurons can be classified in four major electrophysiological types according to their pattern of discharge: regular-spiking (RS), intrinsically-bursting (IB), fast-rhythmic-bursting (FRB), and fast-spiking (FS). Previously, we have shown that these firing patterns are not fixed and can change as a function of membrane potential and states of vigilance. Other studies have reported that extracellular calcium concentration ([Ca2 +]o) fluctuates as a function of the phase of the cortical slow oscillation. In the present study we investigated how spontaneous and induced changes in [Ca2 +]o affect the properties of action potentials (APs) and firing patterns in cortical neurons in vivo. Intracellular recordings were performed in cats anesthetized with ketamine–xylazine during spontaneous [Ca2 +]o fluctuation and while changing [Ca2 +]o with reverse microdialysis. When [Ca2 +]o fluctuated spontaneously according to the phase of the slow oscillation, we found an increase of the firing threshold and a decrease of the afterhyperpolarization (AHP) amplitude during the depolarizing (active, up) phase of the slow oscillation and some neurons also changed their firing pattern as compared with the hyperpolarizing (silent, down) phase. Induced changes in [Ca2 +]o significantly affected the AP properties in all neurons. The AHP amplitude was increased in high calcium conditions and decreased in low calcium conditions, in particular the earliest components. Modulation of spike AHP resulted in notable modulation of intrinsic firing pattern and some RS neurons revealed burst firing when [Ca2 +]o was decreased. We also found an increase in AHP amplitude in high [Ca2 +]o with in vitro preparation. We suggest that during spontaneous network oscillations in vivo, the dynamic changes of firing patterns depend partially on fluctuations of the [Ca2 +]o

Sleep Spindles Predict Stress-Related Increases in Sleep Disturbances

Background and Aim: Predisposing factors place certain individuals at higher risk for insomnia, especially in the presence of precipitating conditions such as stressful life events. Sleep spindles have been shown to play an important role in the preservation of sleep continuity. Lower spindle density might thus constitute an objective predisposing factor for sleep reactivity to stress. The aim of this study was therefore to evaluate the relationship between baseline sleep spindle density and the prospective change in insomnia symptoms in response to a standardized academic stressor. Methods: Twelve healthy students had a polysomnography recording during a period of lower stress at the beginning of the academic semester, along with an assessment of insomnia complaints using the insomnia severity index (ISI). They completed a second ISI assessment at the end of the semester, a period coinciding with the week prior to final examinations and thus higher stress. Spindle density, amplitude, duration, and frequency, as well as sigma power were computed from C4–O2 electroencephalography derivation during stages N2–N3 of non-rapid-eye-movement (NREM) sleep, across the whole night and for each NREM sleep period. To test for the relationship between spindle density and changes in insomnia symptoms in response to academic stress, spindle measurements at baseline were correlated with changes in ISI across the academic semester. Results: Spindle density (as well as spindle amplitude and sigma power), particularly during the first NREM sleep period, negatively correlated with changes in ISI (p < 0.05). Conclusion: Lower spindle activity, especially at the beginning of the night, prospectively predicted larger increases in insomnia symptoms in response to stress. This result indicates that individual differences in sleep spindle activity contribute to the differential vulnerability to sleep disturbances in the face of precipitating factors