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PubMed2006

Molecular characterization of T-type calcium channels.

Molecular cloning of the low voltage-gated, T-type, calcium channel family opened new avenues of research into their structure-function, distribution, pharmacology, and regulation. Cloning of mammalian cDNAs led to the identification of three T-channel genes: CACNA1G, encoding Cav3.1; CACNA1H, encoding Cav3.2; and CACNA1I, encoding Cav3.3. This allowed sequencing of these genes in absence epilepsy patients, and the identification of single nucleotide polymorphisms (SNPs) that alter channel activity. Their distribution in thalamic nuclei, coupled with the physiological role they play in thalamic oscillations, leads to the conclusion that SNPs in T-channel genes may contribute to neurological disorders characterized by thalamocortical dysrhythmia, such as generalized epilepsy. This section reviews the structure of T-channels, how splicing affects structure and function, how SNPs alter channel activity, and how high voltage-activated auxiliary subunits affect T-channels.

Alternative Splicing↗
PubMed2006

Molecular pathways underlying the modulation of T-type calcium channels by neurotransmitters and hormones.

Low-voltage-activated T-type calcium channels are expressed in various tissues, especially in the brain, where they promote neuronal firing and are involved in slow wave sleep and absence epilepsy. While the transduction pathways by which hormones and neurotransmitters modulate high-voltage-activated calcium channels are beginning to be unraveled, those implicated in T-type calcium channel regulation remain obscure. Several neurotransmitters and hormones regulate native T-type calcium channels, although some contradictory data have been reported depending on the cell type studied. This review focuses on the short-term (minutes range) modulation of T-type calcium channels by neurotransmitters and hormones and on the roles of G proteins and protein kinases in these modulatory effects. Results obtained in different native tissues are discussed and compared with the more recent studies of the three cloned T-type calcium channels CaV3.1, CaV3.2 and CaV3.3 in expression systems.

Animals↗
PubMed2005

Encephalopathy due to carnitine deficiency in an adult patient with gluten enteropathy.

A 48-year-old male patient had two episodes of fever, headache, confusion and seizures following an upper respiratory tract infection. Electroencephalography (EEG) revealed diffuse slowing of background activity. Plasma free carnitine and serum lipid levels were low; fecal fat content and serum antigliadin antibodies were elevated. Duodenal biopsy was compatible with gluten enteropathy. Symptoms improved after the patient was started on a gluten-free diet and carnitine replacement therapy. No recurrence was observed within a four-year follow-up. Carnitine deficiency in adulthood is unusual, and encephalopathy due to carnitine deficiency as a result of celiac disease has not been described previously.

Biopsy↗
PubMed2005

Increase of brain-stem high-frequency SEP subcomponents during light sleep in seizure-free epileptic patients.

OBJECTIVE: Three hertz spike-and-wave (SW) occurrence is caused by the abnormal functioning of the same thalamo-cortical loop generating sleep spindles. In fact, SW preferably occurs during light sleep and transitional phases of the vigilance status. Since high-frequency somatosensory evoked potentials (HF-SEPs) are powerfully modulated by sleep and arousal, we verified whether they can reveal abnormalities of arousal-related structures in two patients having showed sporadic SW discharges during light sleep. METHODS: We recorded right median nerve SEPs in two adult patients who suffered since the infancy from childhood absence epilepsy (CAE). Sleep stage-related changes of HF-SEPs were compared to those observed in five healthy volunteers. RESULTS: HF-SEPs decreased during sleep in controls. By contrast, the amplitude of the subcortical component dramatically increased in CAE patients during phase II NREM sleep. Simultaneous EEG showed normally represented sleep spindles, but not SW discharges. CONCLUSIONS: HF-SEP increase probably reflects the hyperactivation of brain-stem arousal-related structures. During such a hyperactivation no EEG abnormalities were observed. SIGNIFICANCE: We hypothesize that HF-SEP increase might reflect a protective mechanism against seizure occurrence during light sleep.

Adult↗
PubMed2005

Function and dysfunction of synaptic calcium channels: insights from mouse models.

In the past few years several spontaneous or engineered mouse models with mutations in Ca2+ channel genes have become available, providing a powerful approach to defining Ca2+ channel function in vivo. There have been recent advances in outlining the phenotypes and in the functional analysis of mouse models with mutations in genes encoding the pore-forming subunits of Ca(V)2.1 (P/Q-type), Ca(V)2.2 (N-type) and Ca(V)2.3 (R-type) Ca2+ channels, the channels involved in controlling neurotransmitter release at mammalian synapses. These data indicate that Ca(V)2.1 channels have a dominant and efficient specific role in initiating fast synaptic transmission at central excitatory synapses in vivo, and suggest that the Ca(V)2.1 channelopathies are primarily synaptic diseases. The different disorders probably arise from disruption of neurotransmission in specific brain regions: the cortex in the case of migraine, the thalamus in the case of absence epilepsy and the cerebellum in the case of ataxia.

Animals↗
PubMed2005

How reliable are fMRI-EEG studies of epilepsy? A nonparametric approach to analysis validation and optimization.

Simultaneously acquired functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) data hold great promise for localizing the spatial source of epileptiform events detected in the EEG trace. Despite a number of studies applying this method, there has been no independent and systematic validation of the approach. The present study uses a nonparametric method to show that interictal discharges lead to a blood oxygen level dependent (BOLD) response that is significantly different to that obtained by examining random 'events'. We also use this approach to examine the optimization of analysis strategy for detecting these BOLD responses. Two patients with frequent epileptiform events and a healthy control were studied. The fMRI data for each patient were analyzed using a model derived from the timings of the epileptiform events detected on EEG during fMRI scanning. Twenty sets of random pseudoevents were used to generate a null distribution representing the level of chance correlation between the EEG events and fMRI data. The same pseudoevents were applied to control data. We demonstrate that it is possible to detect blood oxygen level-dependent (BOLD) changes related to interictal discharges with specific and independent knowledge about the reliability of this activation. Biologically generated events complicate the fMRI-EEG experiment. Our proposed validation examines whether identified events have an associated BOLD response beyond chance and allows optimization of analysis strategies. This is an important step beyond standard analysis. It informs clinical interpretation because it permits assessment of the reliability of the connection between interictal EEG events and the BOLD response to those events.

Analysis of Variance↗
PubMed2004

Dynamics of non-convulsive epileptic phenomena modeled by a bistable neuronal network.

It is currently believed that the mechanisms underlying spindle oscillations are related to those that generate spike and wave (SW) discharges. The mechanisms of transition between these two types of activity, however, are not well understood. In order to provide more insight into the dynamics of the neuronal networks leading to seizure generation in a rat experimental model of absence epilepsy we developed a computational model of thalamo-cortical circuits based on relevant (patho)physiological data. The model is constructed at the macroscopic level since this approach allows to investigate dynamical properties of the system and the role played by different mechanisms in the process of seizure generation, both at short and long time scales. The main results are the following: (i) SW discharges represent dynamical bifurcations that occur in a bistable neuronal network; (ii) the durations of paroxysmal and normal epochs have exponential distributions, indicating that transitions between these two stable states occur randomly over time with constant probabilities; (iii) the probabilistic nature of the onset of paroxysmal activity implies that it is not possible to predict its occurrence; (iv) the bistable nature of the dynamical system allows that an ictal state may be aborted by a single counter-stimulus.

Animals↗
PubMed2004

Abnormal motor behavior and vestibular dysfunction in the stargazer mouse mutant.

In stargazer mutant mice, a mutation in the gene encoding stargazin results in absence epilepsy, cerebellar ataxia, and a characteristic abnormal motor syndrome. The main goal of the current studies was to characterize the nature and source of the abnormal motor behavior. Because the stargazer motor syndrome resembles that of other rodents with vestibular dysfunction, the motor abnormalities were compared with those of normal mice treated with toxins known to damage the vestibular system. Quantitative open field assessments revealed that the stargazer mice display a motor syndrome very similar to that exhibited by mice with toxin-induced vestibulopathy. However, stargazer mice also displayed several additional behaviors, such as ataxic gait and sustained extensor movements of the neck. In addition, stargazer mice performed worse than mice with toxin-induced vestibulopathy in most standard tests of motor function. Motor function was also impaired on each of four behavioral tests sensitive to vestibular function. Because of the close associations between the vestibular and auditory systems, tests of auditory function were also employed. The stargazer mutants exhibited relatively normal auditory brainstem evoked responses but no apparent acoustic startle reflex. Histological examination of vestibular sensory epithelium at the light and electron microscopic levels confirmed the existence of abnormalities in the stargazer mutants. These results imply a previously unrecognized role for stargazin in the normal functions of the vestibular system and indicate that some, but not all, of the abnormal motor syndrome of stargazer mice can be attributed to vestibular dysfunction.

Acoustic Stimulation↗
PubMed2005

The role of the environment on the development of spike-wave discharges in two strains of rats.

Recently, we demonstrated that Type 1 and 2 spike-wave discharges (SWD) in the EEG of juvenile WAG/Rij rats were affected differently by housing before the period at which SWD start to occur. Here we consider possible sensitive periods by analyzing strain and housing influences before and after age of SWD onset. The effects of environment in WAG/Rij and ACI rats were investigated by manipulating housing during the period in which SWD become fully manifested in WAG/Rij rats. Rats were first housed from weaning in either an impoverished or enriched environment. Housing changed for half of the rats at three months, while for the other half housing stayed the same. EEG recordings at six months showed that enriched housing led to a worsening of seizure activity. The occurrence, number and mean duration of both types of discharges were influenced differently by strain, housing and age. Our data strengthen the strong genetic dependence of Type 1 SWD, but the mean duration seems to remain sensitive to housing during development. Type 2 SWD are more sensitive to environmental influences, especially in WAG/Rij rats. Moreover, the period after three months seems a sensitive period for housing effects on Type 2 SWD in this strain. Finally, our data further support the idea that Type 1 and 2 SWD are different phenomena, with their number and mean duration controlled by distinct mechanisms.

Animals↗
PubMed2005

Clinical experience with levetiracetam in childhood epilepsy: an add-on and mono-therapy trial.

We examined the efficacy, optimum dosage and adverse effects of levetiracetam in two prospective trials in children with epilepsy. In the add-on trial, 67 children between 6 months and 16 years were included. In the mono-therapy trial, 10 children between 4 years and 16 years were included. Levetiracetam was titrated up to an optimal dosage for every individual patient, depending on efficacy and tolerability, and reflecting clinical practice. The range of dosages used was between 12 and 62 mg/kg/day, with a median of 33 mg/kg/day. Overall, 20 weeks after the start of levetiracetam, there was a median seizure reduction of 60% (add-on trial 50%; mono-therapy trial 81%). Levetiracetam was equally effective for partial and generalized seizures. Side effects were less common in the mono-therapy trial. Tiredness (7.8%) and aggressiveness (5%) were the most common side effects, and were dose-related, but were no reason to discontinue levetiracetam. In 25% of the children, a positive effect was seen on behaviour and/or alertness. This could not be related directly to seizure control. Overall, these two clinical trials confirm that levetiracetam is a broad spectrum anti-epileptic drug with a favourable safety profile. The positive effect on behaviour needs further quantitative study.

Adolescent↗
PubMed2005

The neural correlate of (un)awareness: lessons from the vegetative state.

Consciousness has two main components: wakefulness and awareness. The vegetative state is characterized by wakefulness without awareness. Recent functional neuroimaging results have shown that some parts of the cortex are still functioning in 'vegetative' patients. External stimulation, such as a painful stimulus, still activates 'primary' sensory cortices in these patients but these areas are functionally disconnected from 'higher order' associative areas needed for awareness. Such studies are disentangling the neural correlates of the vegetative state from the minimally conscious state, and have major clinical consequences in addition to empirical importance for the understanding of consciousness.

Agnosia↗
PubMed2004

Clinical efficacy of galvanic skin response biofeedback training in reducing seizures in adult epilepsy: a preliminary randomized controlled study.

We investigated the effect of galvanic skin response (GSR) biofeedback training on seizure frequency in patients with treatment-resistant epilepsy. Eighteen patients with drug-refractory epilepsy were randomly assigned either to an active GSR biofeedback group (n = 10) or to a sham control biofeedback group (n = 8). Biofeedback training significantly reduced seizure frequency in the active biofeedback group (P = 0.017), but not the control group (P > 0.10). This was manifest as a significant between-group difference in seizure reduction (P 0.01). Furthermore, there was a correlation between degree of improvement in biofeedback performance and reduction of seizure frequency (rho = 0.736, P = 0.001), confirming that the effect of biofeedback treatment was related to physiological change. Our findings highlight the potential therapeutic value of GSR biofeedback in reducing seizure frequency in patients with drug-resistant epilepsy.

Adult↗
PubMed1977

Reaction time variability in epileptic and brain-damaged patients.

Median reaction times and intra-individual variability were studied in epileptic (N = 63), brain-damaged (non-epileptic) (N = 25) and control patients (N = 25) using a six and one half minute visual, continuous reaction time task. Epileptic and brain-damaged groups were significantly slower than control patients on median reaction times at the 10th, 50th, and 90th percentiles and on the differences between the 10th and 90th percentiles. Thus both general slowing and greater intra-individual variability were found in the epileptic and brain-damaged patients. Reaction times were not related to presence, type and severity of EEG abnormality or to age of onset of epilepsy. Grand mal patients did have significantly greater variability than other types of seizure patients. Epileptic and brain-damaged patients did not differ significantly on any reaction time variables. Both groups were discriminated significantly from the controls on all reaction time measures, especially on the intra-individual variability measure.

Adolescent↗
PubMed1980

Effects of evoked spike-wave discharges upon short term memory in patients with epilepsy.

Memory for digits was examined during EEG examination in five female children suffering from light sensitive epilepsy. Sequences of random digits equal to the patients' digit span, span-less-one and span-less-two were presented, followed by a 2 sec. interval, after which recall of the digits was required. The 2 sec. interval could be filled in any of four possible ways by: a burst of photic stimulation which evoked a paroxysm of generalised spike-wave in the EEG; a burst of slow (3 Hz) photic stimulation having no discernible effect upon the EEG; a burst of fast (30 Hz) stimulation, again having no observable effect; or a period of silence with no photic stimulation. It was found that recall of digits series of all three lengths was impaired if a paroxysm of spike-wave had been generated between the end of presentation and the beginning of recall. There were no significant differences in correctness of recall when the slow, fast and no-stimulation photic conditions were compared. It was found that the last two digits in the digit span were more vulnerable to recall failure than were the first two. On the basis of recent work in human experimental psychology, the initial and final digit pairs appear to be retrieved from functionally different storage systems. It is tentatively suggested therefore, that since different parts of the digit span are dislocated to different extents by spike-wave activity, they may depend upon different neural substrates.

Adolescent↗