Biomedical subjects

Gilles van Luijtelaar

Publications and source records attributed to Gilles van Luijtelaar.

At least 19 recordsLinked to original sources

PubMed2006

Midfrequency cortico-thalamic oscillations and the sleep cycle: genetic, time of day and age effects.

WAG/Rij rats have various types of mid frequency cortico-thalamic oscillations, such as anterior and posterior sleep spindles and two types of spike-wave discharges (SWD). The generalized SWD (type I) preferentially occur at transitions from wake to sleep, type II can be found at the occipital cortex during quite wakefulness. In the present experiment sleep spindles, SWD and sleep cycle characteristics of 6-month-old WAG/Rij rats were studied and compared with those of younger WAG/Rij rats with much less SWD and age-matched control (ACI) rats. EEG recordings were made during the beginning (morning) and end (afternoon) of the light period in these four groups of rats. Quantitative characteristics of SWD, sleep spindles and the sleep cycle were determined. There were strain-related and age-dependent effects in the various cortico-thalamic oscillations, older WAG/Rij had more SWDs than younger WAG/Rij rats (both types I and II) and there were more type I SWDs at the end of the light period compared to the beginning. Large strain, age and time of day effects on the sleep cycle were found. The duration of non-REM sleep and the sleep cycle was shorter in WAG/Rij rats but only at the end of the light period and only in older WAG/Rij rats. It can be concluded that the various phasic events and the length of the sleep cycle are under genetic control, and that the sleep cycle length is also controlled by time of day, age and genetic factors. Non-REM sleep and the sleep cycle are disrupted by absence seizures but only in fragile periods when drowsiness and light slow wave sleep dominate.

Aging↗

PubMed2006

Cortical and thalamic coherence during spike-wave seizures in WAG/Rij rats.

The study examines cortico-cortical and cortico-thalamic network synchronization at the onset of spike-wave discharges (SWD) in a genetic model of absence epilepsy, WAG/Rij rats. Coherence was measured between multiple cortical areas (intracortical), reticular and rely thalamic nuclei (intrathalamic) and between the cortex and the thalamus. SWD-related increase of coherence (5-60 Hz) was found in all investigated pairs. The highest increase of coherence was around the mean frequency of SWD (8-11.5 Hz) and in the harmonic band 16-21.5 Hz with two central maxima around 10 and 20 Hz. The frequency profile of coherence was different in different intracortical networks, therefore latter were divided into local, global and transhemispheric networks. The presumable source of SWD in the somatosensory cortex and its closest surroundings formed a minimal (local) circuit, in which occurrence of SWD was facilitated by a consistent shift of network synchrony from delta to alpha/beta frequencies. Transhemispheric coherence revealed the largest increase with an additional 16 Hz peak, suggesting a crucial involvement of the corpus callosum in the pathophysiology of absence seizures. The increase in interhemispheric coherence was largest between relatively remote somatosensory or frontal areas, supporting the assumption that SWD originate from the lateral fronto-parietal cortical area.

Analysis of Variance↗

PubMed2006

Effect of systemic and intracortical administration of phenytoin in two genetic models of absence epilepsy.

1. Spontaneous 7-10 Hz spike-wave discharges (SWDs) are the electroencephalographic hallmark of absence seizures, as can be observed in WAG/Rij as well as in GAERS, two commonly used well-validated genetic rat models of absence epilepsy. A local upregulation of sodium channels within the perioral region of the primary somatosensory cortex indicated an initiation site for SWDs in WAG/Rij rats, in line with a new theory that assumes that SWDs have a cortical focal origin in the perioral region of the somatosensory cortex. We tested whether bilateral microinfusion at this focal site of the sodium channel blocker phenytoin, which is known to aggravate SWDs after systemic administration, reduces SWDs in both models. 2. WAG/Rij rats and GAERS, chronically provided with cortical EEG electrodes and bilateral cortical cannula's, were used. The EEGs were recorded before and after or systemic or bilateral infusion of phenytoin. 3. Microinfusion of phenytoin at the perioral region of the somatosensory cortex produced an immediate cessation of seizure activity in WAG/Rij rats, while systemic injection produced an increase in both genetic models. Microinfusion of the same and higher concentrations of phenytoin in GAERS at the same stereotactic coordinates showed no effect. Phenytoin was effective in GAERS 2 mm more posteriorly.4. The data suggest that both genetic models have a cortical area at which diametrically opposite effects of phenytoin can be found compared to systemic injections: a decrease after local microinfusion and aggravation after systemic administration, although the exact cortical location may be different. Moreover, a deficit in sodium channels might be an ethiological factor underlying an increased probability for the initiation of SWDs in the somatosensory cortex.

Action Potentials↗

PubMed2006

Global and focal aspects of absence epilepsy: the contribution of genetic models.

The cortico-reticular theory of absence epilepsy explains the origin of the bilateral generalized spike-wave discharges (SWDs) characterizing absence seizures via a subcortical pacemaker that is responsible for both normal sleep spindles and pathological SWDs. This pacemaker is the reticular thalamic nucleus (RTN); it produces spontaneous oscillations together with thalamic relay cells and the cortex in an assembled thalamo-cortico-thalamic network. Recently, Meeren et al. [2002. Cortical focus drives widespread corticothalamic networks during spontaneous absence seizures in rats. Journal of Neuroscience 22, 1480-1495.] proposed a focal theory of absence epilepsy based on experimental findings in the WAG/Rij rat, a genetic model of absence epilepsy: the somatosensory cortex contains a focus that initiates a cascade of events that ultimately leads to the occurrence of the bilateral and generalized SWDs if the state of the thalamo-cortical circuitry is favorable. Pharmacological, neurochemical, and neurophysiological data are presented and reviewed here that suggest SWDs might emerge from spontaneous oscillating neurons in the somatosensory cortex during both wakefulness and drowsiness. There is evidence for a variety of neurobiological changes, including a deficient global (parvalbumin) and local GABA-ergic (neurophysiological) system in the neocortex, which may explain why specifically the perioral region of the somatosensory cortex is hyperexcitable and the initiation site of 10Hz oscillations. The neuronal cortical and subcortical circuitry that produces SWDs is part of a large oscillatory system involved in generating cerebral rhythms associated with vibrissal movements. It needs to be established whether similar or comparable pathophysiological processes are also present in humans. Our hypothesis can be readily tested in other models and in humans considering that it is very specific and can be subjected to experimental verification.

Animals↗

PubMed2006

NMDA-NR1 and AMPA-GluR4 receptor subunit immunoreactivities in the absence epileptic WAG/Rij rat.

From an age of 2-3 months onwards, the WAG/Rij rat, a genetic model for absence epilepsy, develops spike-wave discharges (SWD). SWD start in the peri-oral somatosensory cortex (POsc), whereas the rostral reticular thalamic nucleus (rRTN) contributes to synchronizing the thalamo-cortical oscillations. We hypothesize that N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoazolepropionic acid (AMPA) receptors in the POsc and rRTN are involved in, respectively, the initiation and synchronization of SWD activity. As a first step to test this hypothesis, 3 months old non-epileptic and 6 months old absence epileptic WAG/Rij rats were compared with age-matched non-epileptic ACI control rats. The presence of NMDA and AMPA receptors was assessed by quantifying immunostaining for the NMDA-NR1 subunit and the AMPA-GluR4 subunit, respectively. In the POsc, WAG/Rij rats of both ages showed less NMDA-NR1 (-14.7%) and AMPA-GluR4 (-8.7%) subunit staining than ACI rats. From 3 to 6 months, AMPA-GluR4 subunit staining more strongly increased in the rRTN of WAG/Rij rats than of ACI rats. Further studies should support our assumption that in the POsc of the WAG/Rij rat, SWD start as a result of reduced NMDA- and AMPA-mediated glutamatergic stimulation, and that AMPA-GluR4 containing neurons in the rRTN of this rat strain contribute to synchronization of thalamic and cortical neurons.

Aging↗

PubMed2006

Time-frequency analysis of spike-wave discharges using a modified wavelet transform.

The continuous Morlet wavelet transform was used for the analysis of the time-frequency pattern of spike-wave discharges (SWD) as can be recorded in a genetic animal model of absence epilepsy (rats of the WAG/Rij strain). We developed a new wavelet transform that allows to obtain the time-frequency dynamics of the dominating rhythm during the discharges. SWD were analyzed pre- and post-administration of certain drugs. SWD recorded predrug demonstrate quite uniform time-frequency dynamics of the dominant rhythm. The beginning of the discharge has a short period with the highest frequency value (up to 15 Hz). Then the frequency decreases to 7-9 Hz and frequency modulation occurs during the discharge in this range with a period of 0.5-0.7 s. Specific changes of SWD time-frequency dynamics were found after the administration of psychoactive drugs, addressing different brain mediator and modulator systems. Short multiple SWDs appeared under low (0.5 mg/kg) doses of haloperidol, they are characterized by a fast frequency decrease to 5-6 Hz at the end of every discharge. The frequency of the dominant frequency of SWD was not stable in long lasting SWD after 1.0 mg/kg or more haloperidol: then two periodicities were found. Long lasting SWD seen after the administration of vigabatrin showed a stable frequency of the discharge. The EEG after Ketamin showed a distinct 5 s quasiperiodicity. No clear changes of time-frequency dynamics of SWD were found after perilamine. It can be concluded that the use of the modified Morlet wavelet transform allows to describe significant parameters of the dynamics in the time-frequency domain of the dominant rhythm of SWD that were not previously detected.

Algorithms↗

PubMed2006

Environmental manipulations early in development alter seizure activity, Ih and HCN1 protein expression later in life.

Although absence epilepsy has a genetic origin, evidence from an animal model (Wistar Albino Glaxo/Rijswijk; WAG/Rij) suggests that seizures are sensitive to environmental manipulations. Here, we show that manipulations of the early rearing environment (neonatal handling, maternal deprivation) of WAG/Rij rats leads to a pronounced decrease in seizure activity later in life. Recent observations link seizure activity in WAG/Rij rats to the hyperpolarization-activated cation current (Ih) in the somatosensory cortex, the site of seizure generation. Therefore, we investigated whether the alterations in seizure activity between rats reared differently might be correlated with changes in Ih and its channel subunits hyperpolarization-activated cation channel HCN1, 2 and 4. Whole-cell recordings from layer 5 pyramidal neurons, in situ hybridization and Western blot of the somatosensory cortex revealed an increase in Ih and HCN1 in neonatal handled and maternal deprived, compared to control rats. The increase was specific to HCN1 protein expression and did not involve HCN2/4 protein expression, or mRNA expression of any of the subunits (HCN1, 2, 4). Our findings provide the first evidence that relatively mild changes in the neonatal environment have a long-term impact of absence seizures, Ih and HCN1, and suggest that an increase of Ih and HCN1 is associated with absence seizure reduction. Our findings shed new light on the role of Ih and HCN in brain functioning and development and demonstrate that genetically determined absence seizures are quite sensitive for early interventions.

Animals↗

PubMed2006

Amygdala kindling in the WAG/Rij rat model of absence epilepsy.

PURPOSE: The kindling model in rats with genetic absence epilepsy is suitable for studying mechanisms involved in the propagation and generalization of seizure activity in the convulsive and nonconvulsive components of epilepsy. In the present study, we compared the amygdala kindling rate and afterdischarge characteristics of the nonepileptic Wistar control rat with a well-validated model of absence epilepsy, the WAG/Rij rat, and demonstrated the effect of amygdala kindling on spike-and-wave discharges (SWDs) in the WAG/Rij group. METHODS: Electrodes were stereotaxically implanted into the basolateral amygdala of rats for stimulation and recording and into the cortex for recording. After a recovery period, the animals were stimulated at their afterdischarge thresholds. EEG was recorded to analyze SWDs and afterdischarge durations. The seizure severity was evaluated by using Racine's 5-stage scale. RESULTS: All nonepileptic control and four of seven WAG/Rij animals reached a stage 5 seizure state, whereas three animals failed to reach stage 3, 4, or 5 and stayed at stage 2 after application of 30 stimulations. Interestingly, WAG/Rij rats, resistant to kindling, demonstrated a significantly longer duration of SWDs on the first day of the experiment before kindling stimulation than did the kindled WAG/Rij animals. Additionally, the cumulative total duration and the number of SWDs after the kindling stimulation were statistically increased compared with SWDs before kindling stimulation. CONCLUSIONS: The results of our study demonstrate that the progress of amygdala kindling is changed in rats with genetic absence epilepsy, perhaps as a consequence of the hundreds of daily SWDs.

Amygdala↗

PubMed2005

Reduction of adrenergic neurotransmission with clonidine aggravates spike-wave seizures and alters activity in the cortex and the thalamus in WAG/Rij rats.

The alpha-2 adrenoreceptor agonist clonidine in low dose inhibits the release of noradrenaline and aggravates absence seizures. The present study examines properties of two types of spike-wave discharges (SWD) in a genetic model of absence epilepsy, the WAG/Rij rats. After reduction of noradrenergic neurotransmission with clonidine (0.00625 mg/kg, i.p.), the electrical activity was recorded in the neocortex, the ventroposteromedial nucleus (VPM) and the reticular thalamic nucleus (RTN). Clonidine temporally reduced percentage of wakefulness but did not affect sleep. Clonidine decreased the spectral power of sleep EEG (mostly in the delta band), this effect was found in the cortex and in the VPM. Clonidine increased the incidence of SWD type I (generalized); the spectral power of SWD I was lower in the frontal cortex (mostly in 1-9 and 30-100 Hz) and in the VPM (1-5 Hz), but higher in the RTN (9-14 Hz). Local occipital SWD (type II) had a tendency to be less numerous after clonidine, they had a lower power in the 5-9 Hz band in the occipital cortex, in the VPM and in the RTN. It can be concluded that strengthening of 9-14 Hz activity in the RTN may underlie clonidine-induced aggravation of SWD I.

Adrenergic alpha-Agonists↗

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

Evolving concepts on the pathophysiology of absence seizures: the cortical focus theory.

Four main theories on the pathophysiology of generalized absence seizures have been proposed. The "centrencephalic" theory, proposed in 1954, suggested that discharges originate from a deep-seated diffusely projecting subcortical pacemaker in the midline thalamus. This concept was refined in 1991 with the "thalamic clock" theory, implying that the reticular thalamic nucleus contains the pacemaker cells for the thalamic clock, imposing its rhythm to the cortex. According to other investigators, however, the cortex seems to play a leading role. They suggested that spike-wave discharges have a focal onset in the cortex and are generalized through a rapid propagation. In the "corticoreticular" theory, postulated in 1968, spike-wave discharges are linked to the thalamocortical mechanisms that generate spindles. Rhythmic spindle oscillations generated in the thalamus are transformed into spike-wave discharges when the cortex is hyperexcitable. A 2002 study confirmed in epileptic rats that a functionally intact thalamocortical network is required for the generation of spike-wave discharges. The corticothalamic interrelationships were investigated by means of nonlinear association signal analyses of multiple spike-wave discharges. This showed a consistent focus within the perioral region of the somatosensory cortex. From this focus, seizure activity generalizes rapidly over the cortex. During the first cycles of the seizure the cortex drives the thalamus, while thereafter cortex and thalamus drive each other, thus amplifying and maintaining the rhythmic discharge. In this way the "cortical focus" theory for generalized absence epilepsy bridges cortical and thalamic theories.

Animals↗

PubMed2005

Morphometric Golgi study of cortical locations in WAG/Rij rats: the cortical focus theory.

Recently it was demonstrated that for the absence epilepsy characteristic spike-wave discharges initially emerge from the somatosensory cortex and quickly involve the rest of the cortex and cortico-thalamic network. This has led to the development of the focal theory of absence epilepsy. In this experiment, this theory was further investigated by studying the neuronal organization of the cortical focal zone, a non-focal zone in genetic epileptic WAG/Rij rats and functional related areas in non-epileptic age matched control rats. A classical Golgi staining technique was used to visualize whole cortical neurons with dendritic and axon arborisation. Apical dendrites of pyramidal cells in epileptic rats were often split, declined and were running in non-perpendicular directions. Quantitative differences between the strains were found for the length of neurons, between focal and control areas mainly for dendritic arborization. A significant "strain-zone" interaction was found for the maximal distance between two points of dendritic arborization, the mean length of a dendritic segment and the number of free terminations of apical dendrites. All this demonstrates that properties of dendrites in the cortical focal area of WAG/Rij rats were at variance with dendritic characteristics outside the focal area and with functional similar areas in non-epileptic controls. These features might reflect the hyperexcitability of somatosensory neurons, which underlie the initiation and spreading of spike-wave discharges in WAG/Rij rats. Finally, these results are in line with the cortical focus theory of absence epilepsy.

Animals↗

PubMed2004

On the relationship between anticipatory behaviour in a Pavlovian paradigm and Pavlovian-to-Instrumental Transfer in rats (Rattus norvegicus).

The present rat study assessed the relationship between, and the sensitivity of, two different tests for appetitive conditioned responding to differences in the contingency between a conditioned stimulus (CS) and an unconditioned stimulus (US), and to differences in US magnitude. The first test used a Pavlovian-to-Instrumental Transfer (PIT) paradigm, assessing the capacity of the CS to enhance instrumental responding for food. The second test employed a Pavlovian conditioning paradigm with an extended CS-US interval, and total number of behavioural elements in this interval as a dependent measure. The PIT test proved to be sensitive to contingency but not reward magnitude differences, whereas the reverse was true for the Pavlovian test. Although there was a significant correlation between tests in the magnitude of the CS-induced increase of food-magazine entries, the main dependent measure from PIT (number of lever presses) and that from the Pavlovian test (total number of behavioural elements) did not correlate. It is suggested that in the PIT procedure, the CS induces a chain of behavioural responses of which lever pressing is just a single element and that the Pavlovian test, in principle, is more sensitive.

Animals↗

PubMed2004

Cortical control of generalized absence seizures: effect of lidocaine applied to the somatosensory cortex in WAG/Rij rats.

The role of the somatosensory cortex (SmI) in the incidence of spike-wave discharges (SWDs) was studied in a genetic model of absence epilepsy, WAG/Rij rats. SWDs were recently shown to initiate at the perioral area of the SmI and spread over the cortex and thalamus within a few milliseconds [J. Neurosci. 22 (2002) 1480]. It was hypothesized that functional deactivation of the SmI might reduce the appearance of SWDs. This was tested using unilateral microinjections (1 microl) of 2% lidocaine into the SmI in 13 WAG/Rij rats. Electrocorticogram (ECoG) was recorded in free moving animals from four cortical sites after lidocaine and control (saline) injections. Lidocaine effectively diminished the power of the ECoG spectra mostly in the area surrounding the injection site. Deactivation of the perioral region of the SmI reduced the incidence of SWDs at the entire cortex in both hemispheres. The number of SWDs gradually reached control level at the end of the second hour after injections of lidocaine. These data show that proper functioning of SmI is important for the occurrence of SWDs, supporting the idea that absence seizures might have a focal cortical origin.

Animals↗

PubMed2004

Cortical and limbic excitability in rats with absence epilepsy.

The classical cortico-reticular theory on absence epilepsy suggests that a hyperexcitable cortex is a precondition for the occurrence of absence seizures. In the present experiment seizure thresholds and characteristics of cortical and limbic epileptic afterdischarges (AD) were determined in a comparative cortical stimulation study in young and old adult genetically epileptic WAG/Rij, congenic ACI and Wistar rats. Fifteen-second series of 8Hz stimulation of the sensory-motor cortex were applied in 80- and 180-day-old rats with implanted electrodes. Strain differences were found for the threshold for movements directly induced by stimulation, low frequency spike-and-wave AD, maximal clonic intensity of seizures accompanying direct stimulation, and frequency characteristics of low frequency AD. None of these results agreed with a higher cortical excitability exclusively in WAG/Rij rats. However, WAG/Rij rats had the longest duration of the low frequency AD, and the lowest threshold for the transition to the limbic type of AD. The decrease of this threshold correlated with the increase of the incidence and total duration of spontaneous SWDs in WAG/Rij rats. It is concluded that the elevated excitability of the limbic system or pathways mediating the spread of the epileptic activity into this system can be attributed to the development of genetic epileptic phenotype in WAG/Rij rats.

Age Factors↗

PubMed2004

Corticosterone increases spike-wave discharges in a dose- and time-dependent manner in WAG/Rij rats.

Corticosteroids mediate seizure activity in different epilepsy models or epilepsies. However, for childhood absence epilepsy, a nonconvulsive type of epilepsy, direct evidence for corticosteroid seizure modulation is lacking. Thus, in the present study, we analysed the acute systemic effects of different doses of the corticosteroid corticosterone on seizure activity in a well-validated animal model of childhood absence epilepsy, the WAG/Rij rat. We found a time- and dose-dependent increase in the number of spike-wave discharges (SWD) in the EEG, with 500 microg/kg of corticosterone causing a 327% increase in discharges compared to baseline 15-30 min after administration. No treatment effects were found on mean duration of SWD and behavior. Our data indicate that corticosterone in a physiologically relevant dose can aggravate absence seizures in a rapid but transient way. Regarding the time course of the effect, we suggest that corticosterone is acting nongenomically, possibly via a temporary increase of excitatory amino acids.

Action Potentials↗

PubMed2004

Absence seizures during pregnancy in WAG/Rij rats.

Spontaneously occurring spike-wave discharges (SWDs) and serum concentrations of ovarian steroid hormones were investigated before, during and after pregnancy in WAG/Rij rats, a rat strain with genetically determined absence seizures. Eight groups of rats were included in the assays of progesterone and estradiol: rats at diestrus, at various days of pregnancy and at lactating days. The number of SWDs in cortical EEG of WAG/Rij rats was decreased from the 3rd up to the 18th day of pregnancy and subsequently increased to control level. Thereafter, a new decrease was found 2-3 days after parturition. Serum concentration of progesterone was threefold increased at the 3rd day of pregnancy, remained elevated until the 18th day of pregnancy and returned to control values before delivery. Over measured days, estradiol was significantly elevated only at the 18th day of pregnancy. Results demonstrate that physiological conditions induced by the state of pregnancy lead to suppression of occurrence of SWDs. Changes in plasma progesterone concentration correspond to the changes in number of SWDs: an increased level of progesterone during pregnancy is accompanied by a decreased number of SWDs, while a decrease in circulating progesterone before parturition is paralleled by an increase of SWDs. Of interest, the relationship between SWDs and concentration of progesterone found during pregnancy is diametrically opposite to results obtained in acute administration studies of progesterone in nonpregnant animals.

Animals↗

PubMed2004

Mixed forms of epilepsy in a subpopulation of WAG/Rij rats.

Mixed forms of epilepsy in patients are often refractory. Therefore, animal models of comorbid convulsive and nonconvulsive seizure are needed for experimental research. Susceptibility to audiogenic convulsions was studied in a large group of young and adult WAG/Rij rats with inherited absence epilepsy. In 30% of adult rats, sound stimulation provoked audiogenic seizures of moderate intensity. The seizures had two excitation periods separated by a remarkably stable "arrest" of paroxysmal movements. Up to 20% of young WAG/Rij rats were also susceptible to audiogenic seizures, with a longer latency, lower intensity, and more simple seizure patterns. No difference in manifestations of spike-wave discharges was observed between the WAG/Rij rats with and without audiogenic seizures. This subpopulation of WAG/Rij rats genetically predisposed to absence and audiogenic seizures is proposed as an animal model suitable for investigation of basal mechanisms and pharmacological profiles of this mixed form of epilepsy.

Acoustic Stimulation↗