The role of thalamic nuclei in genetic generalized epilepsies.

There is no doubt on the participation of the thalamus in the various types of genetic generalized epilepsies as evidenced by multiple non-invasive imaging studies in humans as well as invasive studies in animal models of GGE. Based on human and mostly animal data gathered in early 2000 a so called 'three compartment model' on seizure generation was proposed conceptualizing the existence of a hyperexcitable cortical seizure onset zone providing excitation to relay cells of the relay thalamus and the inhibitory reticular thalamic nucleus (RTn). The interplay of corticothalamic excitation and feedforward inhibition via RTn is supposed to entrain thalamic relay neurons into synchronous, oscillatory activity for SWD sustainment. With the emergence of more fine-tuned experimental techniques and analyses, however, it becomes apparent that this model is too simplistic as the thalamus cannot be regarded as unity. Rather, different thalamic nuclei, being integrated in different thalamocortical and other subcortical subloops, need to be differentiated, which take over different functions for seizure generation, generalization and maintenance. Moreover, these networks are not necessarily the same for different classes of patients with GGE and can even be antagonistic between seizure types. This review will summarize data concerning different nuclei and their participation in GGE in order to extend this model and create a more detailed concept on seizure generation, generalization and maintenance.

Thalamo-Cortical and Thalamo-Thalamic Coupling During Sleep and Wakefulness in Rats.

Introduction: The thalamus, a heterogeneous brain structure, is involved in the generation of sleep-related thalamo-cortical oscillations. Higher order nuclei might possess a distinct function compared with first-order nuclei in brain communication. Here it is investigated whether this distinction can also be found during the process of falling asleep and deepening of slow-wave sleep. Methods: A nonlinear version of Granger causality was used to describe changes in directed network activity between the somatosensory cortex and rostral reticular thalamic nucleus (rRTN) and caudal reticular thalamic nucleus (cRTN), the higher order posterior (PO)- and anterior-thalamic nuclei (ATN), and the first-order ventral posteromedial thalamic nucleus (VPM) as assessed in local field potential recordings acquired during passive wakefulness (PW), light slow-wave sleep (LSWS), and deep slow-wave sleep (DSWS) in freely behaving rats. Surrogate statistics was used to assess significance. Results: Decreases in cortico-thalamo-cortical couplings were found. In contrast, multiple increases in intrathalamic couplings were observed. In particular, the rRTN increased its inhibition on the ATN from PW to LSWS, and this was further strengthened from LSWS to DSWS. The cRTN increased its coupling to VPM and PO from PW to LSWS, but the coupling from cRTN to VPM weakened at the transition from LSWS to DSWS, while its coupling to PO strengthened. Furthermore, intra-RTN coupling from PW to LSWS was differently changed compared with the change from LSWS to DSWS. Discussion: It can be inferred that higher order (ATN and PO) and first-order nuclei (VPM) are differentially inhibited during DSWS, which might be relevant for a proper functioning of sleep-related processes. Impact statement The functionally heterogeneous thalamus is affected by the different sleep/wake states. Changes in directed functional coupling between the thalamus and cortex and between functional different thalamic nuclei during the process of falling asleep and deepening to slow-wave sleep were investigated. It was revealed that the rostral and caudal subparts of the reticular thalamic nucleus, constituting the major source of intrathalamic inhibition, decouple from each other and show different coupling profiles with other thalamic nuclei. Specifically, higher order nuclei were found to be more inhibited than first-order nuclei during deep slow-wave sleep. These differences might be relevant for a proper coordination of sleep-related processes such as housekeeping, forgetting of irrelevant information, and consolidation of episodic memory.

Pharmacological activation of mGlu5 receptors with the positive allosteric modulator VU0360172, modulates thalamic GABAergic transmission.

Previous studies have shown that injection of the mGlu5 receptor positive allosteric modulator (PAM) VU0360172 into either the thalamus or somatosensory cortex markedly reduces the frequency of spike-and-wave discharges (SWDs) in the WAG/Rij model of absence epilepsy. Here we have investigated the effects of VU0360172 on GABA transport in the thalamus and somatosensory cortex, as possible modes of action underlying the suppression of SWDs. Systemic VU0360172 injections increase GABA uptake in thalamic synaptosomes from epileptic WAG/Rij rats. Consistent with this observation, VU0360172 could also enhance thalamic GAT-1 protein expression, depending on the dosing regimen. This increase in GAT-1 expression was also observed in the thalamus from non-epileptic rats (presymptomatic WAG/Rij and Wistar) and appeared to occur selectively in neurons. The tonic GABAA receptor current present in ventrobasal thalamocortical neurons was significantly reduced by VU0360172 consistent with changes in GAT-1 and GABA uptake. The in vivo effects of VU0360172 (reduction in tonic GABA current and increase in GAT-1 expression) could be reproduced in vitro by treating thalamic slices with VU0360172 for at least 1 h and appeared to be dependent on the activation of PLC. Thus, the effects of VU0360172 do not require an intact thalamocortical circuit. In the somatosensory cortex, VU0360172 reduced GABA uptake but did not cause significant changes in GAT-1 protein levels. These findings reveal a novel mechanism of regulation mediated by mGlu5 receptors, which could underlie the powerful anti-absence effect of mGlu5 receptor enhancers in animal models.

Immediate versus late effects of vigabatrin on spike and wave discharges.

Vigabatrin increases GABA concentrations by inhibiting GABA transaminase. In previous studies, it was shown that vigabatrin increases the incidence of Spike and Wave Discharges (SWD) in the WAG/Rij rat model for absence epilepsy. Since following a single dose of vigabatrin GABA concentrations are known to be increased for several days, the present study sheds light on how the previously described changes in SWD characteristics develop over a longer time frame. To achieve this, we injected adult WAG/Rij rats with 500 mg/kg and recorded their EEG for 48 h. SWD were quantified, and their peak frequencies were calculated. Our results showed three rapid onset effects: a sharp increase in SWD incidence, from 12.5 /hour to 133/hour), this increase lasted only 4.4 h, an increase in mean SWD duration, from 4.6 s to 8.1 s and a drop in peak frequency, from 8 to 6 Hz. Since it takes several hours before GABA concentrations are sufficiently increased, we propose that these immediate effects are caused by direct stimulation of both GABAA and GABAB receptors by the molecule vigabatrin. Next, the mean SWD duration decreased below baseline values after 4.4 h. Hazard rate analysis showed that this is caused by an increased probability of short SWD. We argue that these changes are caused by increased activation of both GABAA and GABAB receptors in the frontal cortex and the thalamus, and more specifically, in the Reticular Thalamic Nucleus (RTN). After approximately 34 h, the probability of short SWD returned to normal. This suggests the occurrence of downregulation of GABA receptors. The decrease in peak frequency was still present 48 h after injection. It has been argued that the balance between GABAA and GABAB receptor-mediated activity in the RTN is crucial for controlling this SWD characteristic. It can be concluded that a single dose of vigabatrin results in remarkable and opposite effects over time: an initial, proabsence effect is followed by an antiabsence effect.

The Brain Network in a Model of Thalamocortical Dysrhythmia.

Sensory information processing and higher cognitive functions rely on the interactions between thalamus and cortex. Many types of neurological and psychiatric disorders are accompanied or driven by alterations in the brain connectivity. In this study, putative changes in functional and effective corticocortical (CC), thalamocortical (TC), and corticothalamic (CT) connectivity during wakefulness and slow-wave sleep (SWS) in a model of thalamocortical dysrhythmia, TRIP8b-/- mice, and in control (wild-type or WT) mice are described. Coherence and nonlinear Granger causality (GC) were calculated for twenty 10 s length epochs of SWS and active wakefulness (AW) of each animal. Coherence was reduced between 4 and ca 20 Hz in the cortex and between cortex and thalamus during SWS compared with AW in WT but not in TRIP8b-/- mice. Moreover, TRIP8b-/- mice showed lower CT coherence during AW compared with WT mice; these differences were no longer present during SWS. Unconditional GC analysis also showed sleep-related reductions in TC and CT couplings in WT mice, while TRIP8b-/- mice showed diminished wake and enhanced sleep CC coupling and rather strong CT-directed coupling during wake and sleep, although smaller during sleep. Conditional GC coupling analysis confirmed the diminished CC and enhanced CT coupling in TRIP8b-/- mice. Our findings indicate that altered properties of hyperpolarization-activated cyclic nucleotide-gated cation channels, characterizing TRIP8b-/- mice, have clear effects on CC, TC, and CT networks. A more complete understanding of the function of the altered communication within these networks awaits detailed phenotyping of TRIP8b-/- mice aimed at specifics of sensory and attentional processes.

Modulation of thalamocortical oscillations by TRIP8b, an auxiliary subunit for HCN channels.

Hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channels have important functions in controlling neuronal excitability and generating rhythmic oscillatory activity. The role of tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b) in regulation of hyperpolarization-activated inward current, I h, in the thalamocortical system and its functional relevance for the physiological thalamocortical oscillations were investigated. A significant decrease in I h current density, in both thalamocortical relay (TC) and cortical pyramidal neurons was found in TRIP8b-deficient mice (TRIP8b-/-). In addition basal cAMP levels in the brain were found to be decreased while the availability of the fast transient A-type K+ current, I A, in TC neurons was increased. These changes were associated with alterations in intrinsic properties and firing patterns of TC neurons, as well as intrathalamic and thalamocortical network oscillations, revealing a significant increase in slow oscillations in the delta frequency range (0.5-4 Hz) during episodes of active-wakefulness. In addition, absence of TRIP8b suppresses the normal desynchronization response of the EEG during the switch from slow-wave sleep to wakefulness. It is concluded that TRIP8b is necessary for the modulation of physiological thalamocortical oscillations due to its direct effect on HCN channel expression in thalamus and cortex and that mechanisms related to reduced cAMP signaling may contribute to the present findings.

Modeling spike-wave discharges by a complex network of neuronal oscillators.

PURPOSE: The organization of neural networks and the mechanisms, which generate the highly stereotypical for absence epilepsy spike-wave discharges (SWDs) is heavily debated. Here we describe such a model which can both reproduce the characteristics of SWDs and dynamics of coupling between brain regions, relying mainly on properties of hierarchically organized networks of a large number of neuronal oscillators. MODEL: We used a two level mesoscale model. The first level consists of three structures: the nervus trigeminus serving as an input, the thalamus and the somatosensory cortex; the second level of a group of nearby situated neurons belonging to one of three modeled structures. RESULTS: The model reproduces the main features of the transition from normal to epileptiformic activity and its spontaneous abortion: an increase in the oscillation amplitude, the emergence of the main frequency and its higher harmonics, and the ability to generate trains of seizures. The model was stable with respect to variations in the structure of couplings and to scaling. The analyzes of the interactions between model structures from their time series using Granger causality method showed that the model reproduced the preictal coupling increase detected previously from experimental data. CONCLUSION: SWDs can be generated by changes in network organization. It is proposed that a specific pathological architecture of couplings in the brain is necessary to allow the transition from normal to epileptiformic activity, next to by others modeled and reported factors referring to complex, intrinsic, and synaptic mechanisms.

The anti-absence effect of mGlu5 receptor amplification with VU0360172 is maintained during and after antiepileptogenesis.

PURPOSE: Ethosuximide (ETX) is the drug of choice for the treatment of patients with absence seizures - taking into account both its efficacy, tolerability and antiepileptogenic properties. However, 47% of subjects failed in ETX-therapy, and most antiepileptic drugs have cognitive side effects. VU0360172, a positive allosteric modulator (PAM) of mGluR5, has been proposed as a new anti-absence drug. Here it is investigated whether anti-epileptogenesis induced by ETX alters the sensitivity of VU0360172, and whether cognition is affected during and after chronic ETX treatment. METHOD: EEG's were recorded before and after a challenge with VU0360172 in chronic ETX and in control WAG/Rij rats during and after treatment. Rats were also exposed to a cue discrimination learning task in a Y-maze both during and after treatment. At the end of the experiment, mGlu5 receptors were quantified by Western Blot analysis. RESULTS: Antiepileptogenesis was successfully induced by ETX and VU0360172 showed a time and dose dependent anti-absence action in the control group. VU0360172 kept its anti-absence action in chronic ETX treated rats both during and after treatment, without time and dose dependency. This anti-absence effect of VU0360172 in both groups matched the lack of differences in mGluR5 expression. Chronic ETX enhanced the number of completed trials, the number of correct choices in the Y-maze and the number of consumed sucrose pallets. SIGNIFICANCE: VU0360172 maintains its anti-absence effects after chronic treatment; as such, VU0360172 can also be used as a adjunctive therapy in patients with absence epilepsy. The enhanced motivation and cognitive performance by ETX might be mediated by the antidepressant action of ETX as expressed by an increase in the rewarding properties of sucrose pallets.

Methods of automated absence seizure detection, interference by stimulation, and possibilities for prediction in genetic absence models.

BACKGROUND: Genetic rat models for childhood absence epilepsy have become instrumental in developing theories on the origin of absence epilepsy, the evaluation of new and experimental treatments, as well as in developing new methods for automatic seizure detection, prediction, and/or interference of seizures. METHOD: Various methods for automated off and on-line analyses of ECoG in rodent models are reviewed, as well as data on how to interfere with the spike-wave discharges by different types of invasive and non-invasive electrical, magnetic, and optical brain stimulation. Also a new method for seizure prediction is proposed. RESULTS: Many selective and specific methods for off- and on-line spike-wave discharge detection seem excellent, with possibilities to overcome the issue of individual differences. Moreover, electrical deep brain stimulation is rather effective in interrupting ongoing spike-wave discharges with low stimulation intensity. A network based method is proposed for absence seizures prediction with a high sensitivity but a low selectivity. Solutions that prevent false alarms, integrated in a closed loop brain stimulation system open the ways for experimental seizure control. CONCLUSIONS: The presence of preictal cursor activity detected with state of the art time frequency and network analyses shows that spike-wave discharges are not caused by sudden and abrupt transitions but that there are detectable dynamic events. Their changes in time-space-frequency characteristics might yield new options for seizure prediction and seizure control.

The effect of acupuncture on mood and working memory in patients with depression and schizophrenia.

BACKGROUND: In patients with depression, as well as in patients with schizophrenia, both mood and working memory performance are often impaired. Both issues can only be addressed and improved with medication to some extent. OBJECTIVE: This study investigates the mood and the working memory performance in patients with depression or schizophrenia and whether acupuncture can improve these. DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: A pragmatic clinical trial design was used. The study was conducted in a psychiatric clinic. Fifty patients with depression and 50 with schizophrenia were randomly divided into an experimental and a waiting-list group. Additionally, 25 healthy control participants were included. Twelve weeks of individualized acupuncture treatment was used as the clinical intervention. MAIN OUTCOME MEASURES: All patients were tested before (T1) and after (T2) acupuncture treatment on a mood scale (Beck Depression Inventory-II, BDI-II), a simple working memory task (digit span), and a complex working memory task (letter-number sequencing); the healthy controls were tested at T1 only. RESULTS: Patients with depression scored worse than the others on the BDI-II, and patients with schizophrenia scored worse than the healthy controls. On the digit span, patients with schizophrenia did not differ from healthy controls whereas they scored worse of all on the letter-number sequencing. With respect to the acupuncture findings, first, the present study showed that the use of acupuncture to treat patients with schizophrenia was both practical and safe. Moreover, acupuncture had a positive effect on the BDI-II for the depression group, but acupuncture had no effect on the digit span and on the letter-number sequencing performance for the two clinical groups. CONCLUSION: The clinical improvement in patients with depression after acupuncture treatment was not accompanied by any significant change in a simple working memory task or in a more complex working memory task; the same was true for the patients with schizophrenia. TRIAL REGISTRATION: Dutch Trial Register NTR3132.

Anti-absence activity of mGlu1 and mGlu5 receptor enhancers and their interaction with a GABA reuptake inhibitor: Effect of local infusions in the somatosensory cortex and thalamus.

OBJECTIVE: Glutamate and γ-aminobutyric acid (GABA) are the key neurotransmitter systems in the cortical-thalamocortical network, involved in normal and pathologic oscillations such as spike-wave discharges (SWDs), which characterize different forms of absence epilepsy. Metabotropic glutamate (mGlu) and GABA receptors are widely expressed within this network. Herein, we examined the effects of two selective positive allosteric modulators (PAMs) of mGlu1 and mGlu5 receptors, the GABA reuptake inhibitor, tiagabine, and their interaction in the somatosensory cortex and thalamus on SWDs in WAG/Rij rats. METHODS: Male WAG/Rij rats were equipped with bilateral cannulas in the somatosensory cortex (S1po) or the ventrobasal (VB) thalamic nuclei, and with cortical electroencephalography (EEG) electrodes. Rats received a single dose of the mGlu1 receptor PAM, RO0711401, or the mGlu5 receptor PAM, VU0360172, various doses of tiagabine, or VU0360172 combined with tiagabine. RESULTS: Both PAMs suppressed SWDs regardless of the site of injection. Tiagabine enhanced SWDs when injected into the thalamus, but, unexpectedly, suppressed SWDs in a dose-dependent manner when injected into the cortex. Intracortical co-injection of VU0360172 and tiagabine produced slightly larger effects as compared to either VU0360172 or tiagabine alone. Intrathalamic co-injections of VU0360172 and subthreshold doses of tiagabine caused an antiabsence effect similar to that exhibited by VU0360172 alone in the first 10 min. At 30 min, however, the antiabsence effect of VU0360172 was prevented by subthreshold doses of tiagabine, and the combination produced a paradoxical proabsence effect at 40 and 50 min. SIGNIFICANCE: These data (1) show that mGlu1 and mGlu5 receptor PAMs reduce absence seizures acting at both thalamic and cortical levels; (2) demonstrate for the first time that tiagabine, despite its established absence-enhancing effect, reduces SWDs when injected into the somatosensory cortex; and (3) indicate that the efficacy of VU0360172 in the thalamus may be critically affected by the availability of (extra)synaptic GABA.

Application of adaptive nonlinear Granger causality: disclosing network changes before and after absence seizure onset in a genetic rat model.

BACKGROUND: Advanced methods of signal analysis of the preictal and ictal activity dynamics characterizing absence epilepsy in humans with absences and in genetic animal models have revealed new and unknown electroencephalographic characteristics, that has led to new insights and theories. NEW METHOD: Taking into account that some network associations can be considered as nonlinear, an adaptive nonlinear Granger causality approach was developed and applied to analyze cortico-cortical, cortico-thalamic and intrathalamic network interactions from local field potentials (LFPs). The outcomes of adaptive nonlinear models, constructed based on the properties of electroencephalographic signal and on statistical criteria to optimize the number of coefficients in the models, were compared with the outcomes of linear Granger causality. RESULTS: The nonlinear adaptive method showed statistically significant preictal changes in Granger causality in almost all pairs of channels, as well as ictal changes in cortico-cortical, cortico-thalamic and intrathalamic networks. Current results suggest rearrangement of interactions in the thalamo-cortical network accompanied the transition from preictal to ictal phase. COMPARISON WITH EXISTING METHOD(S): The linear method revealed no preictal and less ictal changes in causality. CONCLUSIONS: Achieved results suggest that this proposed adaptive nonlinear method is more sensitive than the linear one to dynamics of network properties. Since changes in coupling were found before the seizure-related increase of LFP signal amplitude and also based on some additional tests it seems likely that they were not spurious and could not result from signal to noise ratio change.

Sleep ameliorating effects of acupuncture in a psychiatric population.

The interest of psychiatric patients for complementary medicine, such as acupuncture, is stable, but effect studies in psychiatry remain scarce. In this pilot study, the effects of 3 months of acupuncture treatment on sleep were evaluated and compared between a group of patients with schizophrenia (n = 16) and a group with depression (n = 16). Healthy controls were included in order to establish reference values (n = 8). Patients with schizophrenia and depression were randomly assigned to either a waiting list or a treatment condition. The Pittsburgh Sleep Quality Inventory was completed before and after the acupuncture treatment (individualized and according to traditional Chinese medicine principles) or the waiting list condition. Both acupuncture groups showed significant lower scores on the sleep inventory, which was not the case for the waiting list condition. Moreover, it was found that the effectiveness of the acupuncture treatment was higher in the patients with schizophrenia than in the patients with depression. Acupuncture seems able to improve sleep in this convenient sample of patients with long-lasting psychiatric problems and may be a suitable and cost-effective add-on treatment for this group, particularly if conducted group-wise.

Thalamic stimulation in absence epilepsy.

PURPOSE: The site specific effects of two different types of electrical stimulation of the thalamus on electroencephalic epileptic activity as generated in the cortico-thalamo-cortical system were investigated in genetic epileptic WAG/Rij rats, a well characterized and validated absence model. METHODS: First, 12 male rats received low frequency (double-pulse pairs of 2.5Hz, 150 µA intensity and 30s inter-pair-interval) open-loop stimulation to either the Ventral-Postero-Medial (VPM) or the Anterior Thalamic Nucleus (ATN) for 8h. Second, rats received high frequency (130Hz, pulse train of 1s) closed-loop stimulation applied to either VPM or ATN whenever a spike-wave discharge (SWD) was automatically detected. RESULTS: Low frequency stimulation induced 8Hz SWD-like afterdischarges (AD). AD were frequently seen in VPM but rarely in ATN stimulated rats. AD, recorded in cortex and thalamus, showed a strong temporal coherence (visually assessed) and opposite spike polarities. Properties of AD and spontaneous SWD were equally affected by the stimulation. Closed-loop high frequency stimulation disrupted spontaneous SWD with no difference between ATN and VPM stimulated rats. 89% of SWD could be disrupted leading to a decrease in average SWD duration from 9 to 1.5s. CONCLUSION: Low frequency stimulation induced AD, which strongly mimic SWD. Moreover, the effects were site-specific. High frequency thalamic stimulation disrupts ongoing SWD probable by interfering with the slow firing pattern of cortico-thalamo-cortical neurons seen during SWD cycle. The absence of stimulation site specificity for high frequency stimulation might be due to the fact that stimulation only started on average 1s after SWD onset when SWD are already fully expressed in the bidirectional cortico-thalamo-cortical resonance system.

Peri-ictal network dynamics of spike-wave discharges: phase and spectral characteristics.

PURPOSE: The brain is a highly interconnected neuronal assembly in which network analyses can greatly enlarge our knowledge on seizure generation. The cortico-thalamo-cortical network is the brain-network of interest in absence epilepsy. Here, network synchronization is assessed in a genetic absence model during 5 s long pre-ictal->ictal transition periods. METHOD: 16 male WAG/Rij rats were equipped with multiple electrodes targeting layer 4 to 6 of the somatosensory-cortex, rostral and caudal RTN, VPM, anterior-(ATN) and posterior (Po) thalamic nucleus. Local field potentials measured during pre-ictal->ictal transition and during control periods were subjected to time-frequency and pairwise phase consistency analysis. RESULTS: Pre-ictally, all channels showed spike-wave discharge (SWD) precursor activity (increases in spectral power), which were earliest and most pronounced in the somatosensory cortex. The caudal RTN decoupled from VPM, Po and cortical layer 4. Strong increases in synchrony were found between cortex and thalamus during SWD. Although increases between cortex and VPM were seen in SWD frequencies and its harmonics, boarder spectral increases (6-48Hz) were seen between cortex and Po. All thalamic nuclei showed increased phase synchronization with Po but not with VPM. CONCLUSION: Absence seizures are not sudden and unpredictable phenomena: the somatosensory cortex shows highest and earliest precursor activity. The pre-ictal decoupling of the caudal RTN might be a prerequisite of SWD generation. Po nucleus might be the primary thalamic counterpart to the somatosensory-cortex in the generation of the cortico-thalamic-cortical oscillations referred to as SWD.

On the origin and suddenness of absences in genetic absence models.

The origin of spike-wave discharges (SWDs), typical for absences, has been debated for at least half a century. While most classical views adhere to a thalamic oscillatory machinery and an active role of the cortex in modifying normal oscillations into pathological SWDs, recent studies in genetic models such as WAG/Rij and GAERS rats have challenged this proposal. It seems now well established that SWDs originate from the deep layers of the somatosensory cortex, that the activity quickly spreads over the cortex and invades the thalamus. The reticular thalamic nucleus and other thalamic nuclei provide a resonance circuitry for the amplification, spreading and entrainment of the SWDs. Conclusive evidence has been found that the changed functionality of HCN1 channels is a causative factor for the changes in local excitability and age-dependent increase in SWD. Furthermore, upregulation of two subtypes of Na+ channels, reduction of GABAB and mGlu 2/3 receptors might also play a role in the local increased excitability in WAG/Rij rats. Signal analytical studies have also challenged the view that SWDs occur suddenly from a normal background EEG. SWDs are recruited cortical responses and they develop from increasing associations within and between cortical layers and subsequently subcortical regions, triggered by the simultaneous occurrence of theta and delta precursor activity in the cortex and thalamus in case both structures are in a favorable condition, and increased directional coupling between cortex and thalamus. It is hypothesized that the cortex is the driving force throughout the whole SWD and is also responsible for its end.

Metabotropic glutamate receptors in the thalamocortical network: strategic targets for the treatment of absence epilepsy.

Metabotropic glutamate (mGlu) receptors are positioned at synapses of the thalamocortical network that underlie the development of spike-and-wave discharges (SWDs) associated with absence epilepsy. The modulatory role of individual mGlu receptor subtypes on excitatory and inhibitory synaptic transmission in the cortico-thalamo-cortical circuitry makes subtype-selective mGlu receptor ligands potential candidates as novel antiabsence drugs. Some of these compounds are under clinical development for the treatment of numerous neurologic and psychiatric disorders, and might be soon available for clinical studies in patients with absence seizures refractory to conventional medications. Herein we review the growing evidence that links mGlu receptors to the pathophysiology of pathologic SWDs moving from the anatomic localization and function of distinct mGlu receptor subtypes in the cortico-thalamo-cortical network to in vivo studies in mouse and rat models of absence epilepsy.

Spike-wave discharges in WAG/Rij rats are preceded by delta and theta precursor activity in cortex and thalamus.

OBJECTIVE: In order to unravel the mechanisms underlying the "sudden" onset of spontaneous absences in genetically prone subjects, we investigated the immediate precursors of spike-wave discharges (SWDs) produced in cortico-thalamo-cortical neuronal networks. METHODS: A time-frequency analysis of the cortical and thalamic ECoG of WAG/Rij rats was accomplished with a continuous wavelet decomposition of SWDs, 3 s prior to the onset of SWDs (pre-SWD), and in control periods devoid of SWDs. RESULTS: The pre-SWD ECoG consisted of delta and theta components in 80-90% of all SWDs simultaneously in cortex and thalamus, the co-occurrence of delta and theta was rare (7%) during control periods. The occurrence of delta and theta events in pre-SWDs in the cortex preceded that in the thalamus. The frequency of theta component in cortex correlated positively with that in thalamus, this correlation was less strong for delta. CONCLUSION: Precursors of SWDs comprise of delta and theta, their co-occurrence is typical for non-epileptic periods. Thalamic and cortical theta are strongly related. Rhythmic precursors appear earlier in cortex than in thalamus, and this is in line with the cortical origin of SWD. SIGNIFICANCE: Simultaneous presence of delta and theta events in EEG is a condition for the occurrence of SWDs.

Does arousal interfere with operant conditioning of spike-wave discharges in genetic epileptic rats?

One of the ways in which brain computer interfaces can be used is neurofeedback (NF). Subjects use their brain activation to control an external device, and with this technique it is also possible to learn to control aspects of the brain activity by operant conditioning. Beneficial effects of NF training on seizure occurrence have been described in epileptic patients. Little research has been done about differentiating NF effectiveness by type of epilepsy, particularly, whether idiopathic generalized seizures are susceptible to NF. In this experiment, seizures that manifest themselves as spike-wave discharges (SWDs) in the EEG were reinforced during 10 sessions in 6 rats of the WAG/Rij strain, an animal model for absence epilepsy. EEG's were recorded before and after the training sessions. Reinforcing SWDs let to decreased SWD occurrences during training; however, the changes during training were not persistent in the post-training sessions. Because behavioural states are known to have an influence on the occurrence of SWDs, it is proposed that the reinforcement situation increased arousal which resulted in fewer SWDs. Additional tests supported this hypothesis. The outcomes have implications for the possibility to train SWDs with operant learning techniques.