Paroxysmal Oscillations Research Articles

Cortical drive and thalamic feed-forward inhibition control thalamic output synchrony during absence seizures.

Behaviorally and pathologically relevant cortico-thalamo-cortical oscillations are driven by diverse interacting cell-intrinsic and synaptic processes. However, the mechanism that gives rise to the paroxysmal oscillations of absence seizures (ASs) remains unknown. Here we report that during ASs in behaving animals, cortico-thalamic excitation drives thalamic firing by preferentially eliciting tonic rather than T-type Ca2+ channels (T-channels)-dependent burst firing in thalamocortical (TC) neurons, and by temporally framing thalamic output via feed-forward reticular thalamic (NRT)-to-TC neuron inhibition. In TC neurons, overall ictal firing is markedly reduced and bursts rarely occur. Moreover, block of T-channels in cortical and NRT neurons suppresses ASs, but in TC neurons has no effect on seizures or on ictal thalamic output synchrony. These results demonstrate ictal bidirectional cortico-thalamic communications and provide the first mechanistic understanding of cortico-thalamo-cortical network firing dynamics during ASs in behaving animals.

Neurotrauma as a factor of epileptogenesis

The presented article deals with traumatic brain injury, which can cause convulsive seizures with the subsequent development of epilepsy, which is especially characteristic of young people. The problems of classification of posttraumatic epileptic seizures, development of their mechanisms, characteristics of diagnosis, as well as the stages of epileptogenesis leading to the development of traumatic epilepsy are considered. The variants of therapy are given in view of traumatic brain injury. It is noted that the use of electrical stimulation during individual phases of paroxysmal oscillations can be an effective method in preventing the development of homeostatic plasticity that is involved in the development of epileptogenesis.

T-type Ca2+ channels in absence epilepsy

Absence epilepsy accompanies the paroxysmal oscillations in the thalamocortical circuit referred as spike and wave discharges (SWDs). Low-threshold burst firing mediated by T-type Ca(2+) channels highly expressed in both inhibitory thalamic reticular nuclei (TRN) and excitatory thalamocortical (TC) neurons has been correlated with the generation of SWDs. A generally accepted view has been that rhythmic burst firing mediated by T-type channels in both TRN and TC neurons are equally critical in the generation of thalamocortical oscillations during sleep rhythms and SWDs. This review examined recent studies on the T-type channels in absence epilepsy which leads to an idea that even though both TRN and TC nuclei are required for thalamocortical oscillations, the contributions of T-type channels to TRN and TC neurons are not equal in the genesis of sleep spindles and SWDs. Accumulating evidence revealed a crucial role of TC T-type channels in SWD generation. However, the role of TRN T-type channels in SWD generation remains controversial. Therefore, a deeper understanding of the functional consequences of modulating each T-type channel subtype could guide the development of therapeutic tools for absence seizures while minimizing side effects on physiological thalamocortical oscillations.

Vulnerability to paroxysmal oscillations in delayed neural networks: a basis for nocturnal frontal lobe epilepsy?

Resonance can occur in bistable dynamical systems due to the interplay between noise and delay (τ) in the absence of a periodic input. We investigate resonance in a two-neuron model with mutual time-delayed inhibitory feedback. For appropriate choices of the parameters and inputs three fixed-point attractors co-exist: two are stable and one is unstable. In the absence of noise, delay-induced transient oscillations (referred to herein as DITOs) arise whenever the initial function is tuned sufficiently close to the unstable fixed-point. In the presence of noisy perturbations, DITOs arise spontaneously. Since the correlation time for the stationary dynamics is ∼τ, we approximated a higher order Markov process by a three-state Markov chain model by rescaling time as t → 2sτ, identifying the states based on whether the sub-intervals were completely confined to one basin of attraction (the two stable attractors) or straddled the separatrix, and then determining the transition probability matrix empirically. The resultant Markov chain model captured the switching behaviors including the statistical properties of the DITOs. Our observations indicate that time-delayed and noisy bistable dynamical systems are prone to generate DITOs as switches between the two attractors occur. Bistable systems arise transiently in situations when one attractor is gradually replaced by another. This may explain, for example, why seizures in certain epileptic syndromes tend to occur as sleep stages change.

Inactivation of the Somatosensory Cortex Prevents Paroxysmal Oscillations in Cortical and Related Thalamic Neurons in a Genetic Model of Absence Epilepsy

Absence seizures consist of bilateral spike-and-wave discharges (SWDs) occurring over widespread cortical and thalamic regions. In genetic models of absence epilepsy, recent in vivo investigations indicate that SWDs emerge first in the facial somatosensory cortex and then propagate via the corticothalamocortical loop. The specific involvement of this cortical region in ictogenic processes remained to be established and the participation of its related thalamocortical system in seizure initiation remained unclear. Here, using electrocorticographic (ECoG) and intracellular recordings in vivo from cortex and thalamus in the Genetic Absence Epilepsy Rat from Strasbourg (GAERS), we obtained novel evidence for the cortical focus theory of absence epilepsy. We report that blockade of action potential discharge and synaptic activities in facial somatosensory cortical neurons, by topical application of tetrodotoxin, prevents the occurrence of paroxysmal activities in local and distant cortical neurons and ECoGs, as well as in thalamocortical neurons in register with the somatosensory cortex. In contrast, pharmacological inhibition of a remote motor cortical region or of the related thalamic nuclei did not suppress ictal activities in the somatosensory cortex. This study demonstrates that SWDs in GAERS have a focal origin within the facial somatosensory cortex, which is sufficient and necessary to generate ictal activities.

Rhythmic bursting in the cortico-subthalamo-pallidal network during spontaneous genetically determined spike and wave discharges.

Absence seizures are characterized by impairment of consciousness associated with bilaterally synchronous spike-and-wave discharges (SWDs) in the electroencephalogram (EEG), which reflect paroxysmal oscillations in thalamocortical networks. Although recent studies suggest that the subthalamic nucleus (STN) provides an endogenous control system that influences the occurrence of absence seizures, the mechanisms of propagation of cortical epileptic discharges in the STN have never been explored. The present study provides the first description of the electrophysiological activity in the cortico-subthalamo-pallidal network during absence seizures in the genetic absence epilepsy rats from Strasbourg, a well established model of absence epilepsy. In corticosubthalamic neurons, the SWDs were associated with repetitive suprathreshold depolarizations correlated with EEG spikes. These cortical paroxysms were reflected in the STN by synchronized, rhythmic, high-frequency bursts of action potentials. Intracellular recordings revealed that the intraburst pattern in STN neurons was sculpted by an early depolarizing synaptic potential, followed by a short hyperpolarization and a rebound of excitation. The rhythmic hyperpolarizations in STN neurons during SWDs likely originate from a subpopulation of pallidal neurons exhibiting rhythmic bursting temporally correlated with the EEG spikes. The repetitive discharges in STN neurons accompanying absence seizures might convey powerful excitation to basal ganglia output nuclei and, consequently, may participate in the control of thalamocortical SWDs.

Potassium model for slow (2-3 Hz) in vivo neocortical paroxysmal oscillations.

In slow neocortical paroxysmal oscillations, the de- and hyperpolarizing envelopes in neocortical neurons are large compared with slow sleep oscillations. Increased local synchrony of membrane potential oscillations during seizure is reflected in larger electroencephalographic oscillations and the appearance of spike- or polyspike-wave complex recruitment at 2- to 3-Hz frequencies. The oscillatory mechanisms underlying this paroxysmal activity were investigated in computational models of cortical networks. The extracellular K(+) concentration ([K(+)](o)) was continuously computed based on neuronal K(+) currents and K(+) pumps as well as glial buffering. An increase of [K(+)](o) triggered a transition from normal awake-like oscillations to 2- to 3-Hz seizure-like activity. In this mode, the cells fired periodic bursts and nearby neurons oscillated highly synchronously; in some cells depolarization led to spike inactivation lasting 50-100 ms. A [K(+)](o) increase, sufficient to produce oscillations could result from excessive firing (e.g., induced by external stimulation) or inability of K(+) regulatory system (e.g., when glial buffering was blocked). A combination of currents including high-threshold Ca(2+), persistent Na(+) and hyperpolarization-activated depolarizing (I(h)) currents was sufficient to maintain 2- to 3-Hz activity. In a network model that included lateral K(+) diffusion between cells, increase of [K(+)](o) in a small region was generally sufficient to maintain paroxysmal oscillations in the whole network. Slow changes of [K(+)](o) modulated the frequency of bursting and, in some case, led to fast oscillations in the 10- to 15-Hz frequency range, similar to the fast runs observed during seizures in vivo. These results suggest that modifications of the intrinsic currents mediated by increase of [K(+)](o) can explain the range of neocortical paroxysmal oscillations in vivo.

Role of Glial Cells in Seizures and Epilepsy: Intracellular Calcium Oscillations sn Spatial Buffering.

Spatial Buffering During Slow and Paroxysmal Sleep Oscillations in Cortical Networks of Glial Cells In Vivo Amzica F, Massimini M, Manfridi A J Neurosci 2002;22:1042–1053 The ability of neuroglia to buffer local increases of extracellular K+ has been known from in vitro studies. This property may confer on these cells an active role in the modulation and spreading of cortical oscillatory activities. We addressed the question of the spatial buffering in vivo by performing single and double intraglial recordings, together with measures of the extracellular K+ and Ca2+ concentrations ([K+]out and [Ca2+]out) in the cerebral cortex of cats under ketamine and xylazine anesthesia during patterns of slow sleep oscillations and spike-wave seizures. In addition, we estimated the fluctuations of intraglial K+ concentrations ([K+]in). Measurements obtained during the slow oscillation indicated that glial cells phasically take up part of the extracellular K+ extruded by neurons during the depolarizing phase of the slow oscillation. During this condition, the redistribution of K+ appeared to be local. Large steady increases of [K+]out and phasic potassium accumulations were measured during spike-wave seizures. In this condition, [K+]in rose before [K+]out if the glial cells were located at some distance from the epileptic focus, suggesting faster K+ diffusion through the interglial syncytium. The simultaneously recorded [Ca2+]out dropped steadily during the seizures to levels incompatible with efficient synaptic transmission, but also displayed periodic oscillations, in phase with the intraseizure spike-wave complexes. In view of this fact, and considering the capability of K+ to modulate neuronal excitability both at the presynaptic and postsynaptic levels, we suggest that the K+ long-range spatial buffering operated by glia is a parallel synchronizing and/or spreading mechanism during paroxysmal oscillations. Calcium Oscillations in Neocortical Astrocytes under Epileptiform Conditions Tashiro A, Goldberg J, Yuste R J Neurobiol 2002;50:45–55 Morphological and functional alterations in astrocytic glia are often found in epileptic syndromes, although the exact role of astrocytes in epilepsy is poorly understood. During calcium imaging of epileptiform events in juvenile neocortical slices we previously discovered cells with spontaneous oscillations in their intracellular free calcium concentration ([Ca(2+)](i)). We have now characterized these oscillations using two in vitro models of epilepsy and find that they are produced by astrocytes. Astrocytic oscillations are widespread throughout the imaged territories, are remarkably regular and have long periods, averaging 100 s, which become shorter during development. Astrocytic oscillations are uncorrelated among themselves and with epileptiform events, are blocked by internal release antagonists and are stimulated by caffeine. Astrocytic calcium oscillations could mediate reactive astrogliosis, contribute to the pathogenesis of chronic epileptic syndromes, and be used as a diagnostic test for epileptic tissue.

Cortical hyperpolarization-activated depolarizing current takes part in the generation of focal paroxysmal activities.

During paroxysmal neocortical oscillations, sudden depolarization leading to the next cycle occurs when the majority of cortical neurons are hyperpolarized. Both the Ca(2+)-dependent K(+) currents (I(K(Ca))) and disfacilitation play critical roles in the generation of hyperpolarizing potentials. In vivo experiments and computational models are used here to investigate whether the hyperpolarization-activated depolarizing current (I(h)) in cortical neurons also contributes to the generation of paroxysmal onsets. Hyperpolarizing current pulses revealed a depolarizing sag in approximately 20% of cortical neurons. Intracellular recordings from glial cells indirectly indicated an increase in extracellular potassium concentration ([K(+)](o)) during paroxysmal activities, leading to a positive shift in the reversal potential of K(+)-mediated currents, including I(h). In the paroxysmal neocortex, approximately 20% of neurons show repolarizing potentials originating from hyperpolarizations associated with depth-electroencephalogram positive waves of spike-wave complexes. The onset of these repolarizing potentials corresponds to maximal [K(+)](o) as estimated from dual simultaneous impalements from neurons and glial cells. Computational models showed how, after the increased [K(+)](o), the interplay between I(h), I(K(Ca)), and a persistent Na(+) current, I(Na(P)), could organize paroxysmal oscillations at a frequency of 2-3 Hz.

Spatial Buffering during Slow and Paroxysmal Sleep Oscillations in Cortical Networks of Glial CellsIn Vivo

The ability of neuroglia to buffer local increases of extracellular K(+) has been known from in vitro studies. This property may confer on these cells an active role in the modulation and spreading of cortical oscillatory activities. We addressed the question of the spatial buffering in vivo by performing single and double intraglial recordings, together with measures of the extracellular K(+) and Ca(2+) concentrations ([K(+)](out) and [Ca(2+)](out)) in the cerebral cortex of cats under ketamine and xylazine anesthesia during patterns of slow sleep oscillations and spike-wave seizures. In addition, we estimated the fluctuations of intraglial K(+) concentrations ([K(+)](in)). Measurements obtained during the slow oscillation indicated that glial cells phasically take up part of the extracellular K(+) extruded by neurons during the depolarizing phase of the slow oscillation. During this condition, the redistribution of K(+) appeared to be local. Large steady increases of [K(+)](out) and phasic potassium accumulations were measured during spike-wave seizures. In this condition, [K(+)](in) rose before [K(+)](out) if the glial cells were located at some distance from the epileptic focus, suggesting faster K(+) diffusion through the interglial syncytium. The simultaneously recorded [Ca(2+)](out) dropped steadily during the seizures to levels incompatible with efficient synaptic transmission, but also displayed periodic oscillations, in phase with the intraseizure spike-wave complexes. In view of this fact, and considering the capability of K(+) to modulate neuronal excitability both at the presynaptic and postsynaptic levels, we suggest that the K(+) long-range spatial buffering operated by glia is a parallel synchronizing and/or spreading mechanism during paroxysmal oscillations.

Cortical coupling in sleep and paroxysmal oscillations

Intracellular and electroencephalographic (EEG) studies in animals and humans show that a major sleep rhythm, the slow oscillation (0.5–1 Hz), is generated and synchronized within intracortical circuits. This cortical oscillation triggers thalamic neurons, and thus, produces complex wave-sequences that include sleep spindles (7–15 Hz). These findings emphasize that the neocortex and thalamus are a unified oscillatory machine. Under special circumstances, such as the reduction in the inhibitory constraint, the slow sleep oscillation may develop into paroxysmal oscillations, consisting of spike-wave (SW) and polyspike-wave (PSW) complexes at 2–3 Hz, which are often associated with fast runs at 10–15 Hz, as in the Lennox–Gastaut syndrome. The SW/PSW seizures are initiated in neocortex and they spread to the thalamus only after a few seconds. During cortical SW seizures, most thalamocortical neurons are hyperpolarized and display phasic inhibitory postsynaptic potentials due to the activity of GABAergic thalamic reticular neurons that faithfully follow the paroxysmal depolarizing shifts arising in cortical neurons.

LTS cells in cerebral cortex and their role in generating spike-and-wave oscillations

Some types of epileptic seizures involve both thalamus and cerebral cortex, while other types can be evoked in the cerebral cortex without thalamic participation. We investigated the possible role of low-threshold spike (LTS) cortical neurons in the genesis of these intracortical seizures. We found LTS cortical neurons in cat area 5–7 in vivo, the properties of which could be modeled based on relatively weak densities of the T-type calcium channel. At the network level, a small minority of LTS pyramidal cells was sufficient to generate paroxysmal oscillations with spike-and-wave (SW) field potentials. These oscillations reproduce the properties of intracortical SW paroxysms observed in athalamic cats, such as the slow frequency (1.8– 2.5 Hz ). We suggest that calcium-mediated rebound mechanisms intrinsic to cerebral cortex can explain the genesis of intracortical SW activity.

Neuronal and Glial Membrane Potentials during Sleep and Paroxysmal Oscillations in the Neocortex

This study investigated the fluctuations in the membrane potential of cortical neurons and glial cells during the slow sleep oscillation and spike-wave (SW) seizures. We performed dual neuron-glia intracellular recordings together with multisite field potential recordings from cortical suprasylvian association areas 5 and 7 of cats under ketamine-xylazine anesthesia. Electrical stimuli applied to the cortex elicited responses consisting of a biphasic depolarization in glial cells, which was associated with an EPSP-IPSP sequence in neurons. During the slow (<1 Hz) oscillation, extracellular measurements of the potassium concentration revealed periodic increases with an amplitude of 1-2 mm, similar in shape to glial activities. We suggest that, through their uptake mechanisms, glia cells modulate the neuronal excitability and contribute to the pacing of the slow oscillation. The slow oscillation often evolved into SW paroxysms, mimicking sleep-triggered seizures. This transition was associated with increased coupling between the depolarizing events in neurons and glial cells. During seizures, the glial membrane potential displayed phasic negative events related to the onset of the paroxysmal depolarizing shifts in neurons. These events were not voltage dependent and increased their incidence and amplitude with the development of the seizure. It is suggested that the intraglial transient negativities represent field reflections of synchronized neuronal potentials. We propose that the mechanisms underlying the neuron-glia communication include, besides the traditional neurotransmitter- and ion-mediated pathways, field effects crossing their membranes as a function of the state of the cortical network.

Corticothalamic Inputs Control the Pattern of Activity Generated in Thalamocortical Networks

Absence seizures (3-4 Hz) and sleep spindles (6-14 Hz) occur mostly during slow-wave sleep and have been hypothesized to involve the same corticothalamic network. However, the mechanism by which this network transforms from one form of activity to the other is not well understood. Here we examine this question using ferret lateral geniculate nucleus slices and stimulation of the corticothalamic tract. A feedback circuit, meant to mimic the cortical influence in vivo, was arranged such that thalamic burst firing resulted in stimulation of the corticothalamic tract. Stimuli were either single shocks to mimic normal action potential firing by cortical neurons or high-frequency bursts (six shocks at 200 Hz) to simulate increased cortical firing, such as during seizures. With one corticothalamic stimulus per thalamic burst, 6-10 Hz oscillations resembling spindle waves were generated. However, if the stimulation was a burst, the network immediately transformed into a 3-4 Hz paroxysmal oscillation. This transition was associated with a strong increase in the burst firing of GABAergic perigeniculate neurons. In addition, thalamocortical neurons showed a transition from fast (100-150 msec) IPSPs to slow ( approximately 300 msec) IPSPs. The GABA(B) receptor antagonist CGP 35348 blocked the slow IPSPs and converted the 3-4 Hz paroxysmal oscillations back to 6-10 Hz spindle waves. Conversely, the GABA(A) receptor antagonist picrotoxin blocked spindle frequency oscillations resulting in 3-4 Hz oscillations with either single or burst stimuli. We suggest that differential activation of thalamic GABA(A) and GABA(B) receptors in response to varying corticothalamic input patterns may be critical in setting the oscillation frequency of thalamocortical network interactions.

Chapter 17 Thalamic and thalamocortical mechanisms underlying 3 Hz spike-and-wave discharges

Publisher Summary This chapter reviews the models for thalamic∼3 Hz paroxysmal oscillations and for thalamocortical∼3 Hz oscillations with spike-and-wave field potentials. Experiments reviewed in the introduction show that the thalamus is essential to generate 3 Hz spike-and-wave seizures, and hence thalamic slices display paroxysmal oscillations at∼3 Hz, following the application of GABA, antagonists, as described in the chapter. However, evidence from a number of experimental studies indicates that, this thalamic 3 Hz oscillation is a phenomenon distinct from spike-and-wave seizures. Several mechanisms have been proposed to account for the effects of blocking of GABA, receptors in thalamic circuit. Injections of GABA B antagonists in the thalamus with intact cortex failed to generate spike-and-wave seizures. A thalamocortical network consisting of different layers of cortical and thalamic cells is simulated to explore the impact of this mechanism at the network level.

Complex dynamics and bifurcations in neurology

The neurologist is often faced with patients who exhibit a bewildering array of abnormal oscillations and complex rhythms that pose therapeutic problems. These problems take many forms (Mackey & Milton, 1987; Glass & Mackey, 1988). Most commonly there is an appearance of an oscillation in a neurological control system not normally characterized by a rhythmic process. Examples include ankle clonus in patients with corticospinal tract disease (Dimitrijevic et al., 1978), various movement disorders (e.g. essential and Parkinson's tremors, Marsden, 1984a, b), and the abnormal paroxysmal oscillations in the discharges of neurons which are associated with seizures (Ayala et aL, 1973). There can be a qualitative change in the oscillations produced by an already rhythmic process, for example, gait abnormalities (Beuter & Garfinkel, 1985), Cheyne-Stokes respiration (Cherniack & Longobardo, 1973), altered sleep-wake cycles (Wehr et al., 1982) and rapid cycling manic-depressive illness (Wehr & Goodwin, 1983). In addition, there can be the disappearance of a rhythmic process as occurs in patients with depression in whom there is the disappearance of the diurnal rhythm in cortisol secretion (Hollister et aL, 1980). Finally, some clinical events recur in a seemingly random fashion, for example, seizures in adult epileptics (Milton et al., 1987). The traditional explanation given by the neurologist is to relate the appearance of abnormal dynamical behaviors to pathological processes which destroy or modify neural control mechanisms. The abnormal breathing patterns (Plum & Posner, 1980) and rhythmic movements of the palate (Lapresle & Hamida, 1970) which can occur