Timing of high-frequency cortical stimulation in a genetic absence model.

INTRODUCTION: Seizure control is one of the ultimate aims of epileptology: here acute and prolonged effects of closed loop high-frequency stimulation of the somatosensory cortex on the expression of spontaneously occurring spike-wave discharges (SWD) were investigated in a genetic absence model. Effects of closed loop stimulation in the experimental group were compared with a yoked control group allowing to investigate the effect of timing related to SWD occurrence, while controlling for amount and intensity of stimulation. METHODS: WAG/Rij rats were implanted with stimulation electrodes in the deep layers of the somatosensory cortex, and recording electrodes in the cortex and thalamus. Closed-loop and yoked stimulation (1 sec trains, biphasic 0.4 msec pulses, 130 Hz) sessions lasted 24h. The stimulation sessions were preceded and followed by baseline and post stimulation 24-h recordings. RESULTS: Closed-loop stimulation interrupted SWD and duration of SWD was shortened. Both types of stimulation resulted in a reduction in SWD number during stimulation sessions. Closed-loop stimulation also resulted in less SWD during the last eight hours of the post-stimulation recording session. Sometimes yoked stimulation induced low-frequency afterdischarges. DISCUSSION: SWD can be aborted by closed-loop stimulation of the somatosensory cortex, and at the same time the number of SWD was reduced. It can be regarded as a relatively safe neuromodulatory technique without habituation. The reduction of SWD during yoked stimulation session might be caused by 3 Hz afterdischarges. The reduction of SWD on the stimulation and post-stimulation sessions demonstrates the critical relevance of timing for the induction of longer lasting neuromodulatory effects: it suggests that absence seizures themselves might be involved in their reoccurrence.

Dynamics of directional coupling underlying spike-wave discharges.

PURPOSE: Spike and wave discharges (SWDs), generated within cortico-thalamo-cortical networks, are the electroencephalographic biomarker of absence epilepsy. The current work aims to identify mechanisms of SWD initiation, maintenance and termination by the analyses of dynamics and directionality of mutual interactions between the neocortex and various functionally different thalamic nuclei. METHODS: Local-field potential recordings of 16 male Wistar Albino Glaxo from Rijswijk (WAG/Rij) rats, equipped with electrodes targeting layer 4-6 of the somatosensory cortex, rostral and caudal reticular thalamic nuclei (rRTN and cRTN), ventro-posteromedial (VPM), anterior (ATN) and posterior (PO) thalamic nuclei, were obtained. 3s epochs prior to SWD onset, after SWD onset, prior to SWD offset and after SWD offset were analyzed with newly developed time-variant adapted nonlinear Granger causality. RESULTS: A gradual increase in coupling toward SWD onset between cortico-cortical pairs appears as early as 2s preictally. Next first unidirectional increase in coupling is noticed in a restricted number of cortico-thalamic and thalamo-cortical channel pairs, which turn into bidirectional coupling approaching SWD onset, and a gradual increase of intrathalamic coupling. Seizure onset is characterized by a coupling decrease for more than a second in a majority of channel pairs, only the cortex kept driving the cRTN. Intrathalamically the cRTN drives the PO, VPM and ATN. Most channel pairs no longer show differences in coupling with baseline during SWD maintenance, a major exception is the unidirectional coupling between cortex and cRTN. Toward the end of SWDs, more and more channel pairs show an increase in often bidirectional coupling, this increase suddenly vanishes at SWD offset. CONCLUSION: The initiation of SWD is due to a gradual increase in intracortical coupling, followed by a selective increase in first unidirectional and later bidirectional coupling between the cortex and thalamus and also intrathalamically. Once the network is oscillating, coupling decreases in most of the channel pairs, although the cortex keeps its influence on the cRTN. The SWD is dampened by a gradual increase in coupling strength and in the number of channel pairs that influence each other; the latter might represent an endogenous brake of SWDs.

Head-to head comparison of mGlu1 and mGlu5 receptor activation in chronic treatment of absence epilepsy in WAG/Rij rats.

Acute treatment with positive allosteric modulators (PAMs) of mGlu1 and mGlu5 metabotropic glutamate receptors (RO0711401 and VU0360172, respectively) reduces the incidence of spike-and wave discharges in the WAG/Rij rat model of absence epilepsy. However, from the therapeutic standpoint, it was important to establish whether tolerance developed to the action of these drugs. We administered either VU0360172 (3 mg/kg, s.c.) or RO0711401 (10 mg/kg, s.c.) to WAG/Rij rats twice daily for ten days. VU0360172 maintained its activity during the treatment, whereas rats developed tolerance to RO0711401 since the 3rd day of treatment and were still refractory to the drug two days after treatment withdrawal. In response to VU0360172, expression of mGlu5 receptors increased in the thalamus of WAG/Rij rats after 1 day of treatment, and remained elevated afterwards. VU0360172 also enhanced mGlu5 receptor expression in the cortex after 8 days of treatment without changing the expression of mGlu1a receptors. Treatment with RO0711401 enhanced the expression of both mGlu1a and mGlu5 receptors in the thalamus and cortex of WAG/Rij rats after 3-8 days of treatment. These data were different from those obtained in non-epileptic rats, in which repeated injections of RO0711401 and VU0360172 down-regulated the expression of mGlu1a and mGlu5 receptors. Levels of VU0360172 in the thalamus and cortex remained unaltered during the treatment, whereas levels of RO0711401 were reduced in the cortex at day 8 of treatment. These findings suggest that mGlu5 receptor PAMs are potential candidates for the treatment of absence epilepsy in humans.

Fast, transient cardiac accelerations and decelerations during fear conditioning in rats.

The current study reports on a number of heart rate responses observed in rats subjected to a discriminatory Pavlovian fear conditioning procedure. Rats learned that a series of six auditory pips was followed by a footshock when presented alone, but not when the pip series was preceded by a visual safety signal. Each auditory pip in the series evoked a fast transient (<1s) cardiac deceleration. This was the case on both trials followed by shock and on trials not followed by shock. The onset of the safety light evoked a similar fast deceleration. We propose that these transient decelerations are similar to the human Evoked Cardiac Response 1 (ECR1), a brief modest deceleration evoked by simple sensory stimuli that is thought to reflect an early process of stimulus registration. Immediately following these pip-evoked decelerations, modest fast accelerations were observed. These accelerations were larger when the pip series was followed by shock than when it was not followed by shock. We propose a potential linkage between these accelerations and the human acceleratory ECR2 component, which is associated with more elaborate processing following stimulus registration; something likely to take place when the pip series predicts an aversive event. Both the ECR1- and ECR2-like responses were embedded within a slow, gradual heart rate increase across the entire pip series. This tonic increase was significantly larger on trials with footshock and is therefore probably associated with anticipatory fear of the upcoming shock. An additional special type of cardiac response was found to the first pip in the series not preceded by the safety signal; here, a much larger and more sustained deceleration was apparent. This response appears relatable to the prolonged deceleration reported in humans in response to aversive picture content. We discuss the cardiac responses found in rats in the current study in the context of heart rate responses known in the human literature.

Early onset of age-related changes on neural processing in rats.

Altered perceptual and emotional processing might bind impaired cognitive mechanisms during aging; however the nature of these sensory perception modifications is still unknown. In the present experiment we analyzed in rats, from early to mature life (2 to 11 months old), the response to unattended auditory evoked stimulation (Auditory evoked potential, AEP) and the power spectrum of spontaneous electroencephalogram (EEG), with the aim of unraveling the onset and target functional effects of aging. Somatosensory and cingulate cortex, mediodorsal thalamus and CA3 hippocampus were chosen for examination based on their involvement in sensory processing and age-related deficits. The main finding of this study is the early onset of age-related changes in adult rats as can be established with both AEP's and frequency analyses, and its diversity between brain regions during normal aging.

Protective role for type-1 metabotropic glutamate receptors against spike and wave discharges in the WAG/Rij rat model of absence epilepsy.

Eight-month old WAG/Rij rats, which developed spontaneous occurring absence seizures, showed a reduced function of mGlu1 metabotropic glutamate receptors in the thalamus, as assessed by in vivo measurements of DHPG-stimulated polyphosphoinositide hydrolysis, in the presence of the mGlu5 antagonist MPEP as compared to age-matched non-epileptic control rats. These symptomatic 8-month old WAG/Rij rats also showed lower levels of thalamic mGlu1α receptors than age-matched controls and 2-month old (pre-symptomatic) WAG/Rij rats, as detected by immunoblotting. Immunohistochemical and in situ hybridization analysis indicated that the reduced expression of mGlu1 receptors found in symptomatic WAG/Rij rats was confined to an area of the thalamus that excluded the ventroposterolateral nucleus. No mGlu1 receptor mRNA was detected in the reticular thalamic nucleus. Pharmacological manipulation of mGlu1 receptors had a strong impact on absence seizures in WAG/Rij rats. Systemic treatment with the mGlu1 receptor enhancer SYN119, corresponding to compound RO0711401, reduced spontaneous spike and wave discharges spike-wave discharges (SWDs) in epileptic rats. Subcutaneous doses of 10 mg/kg of SYN119 only reduced the incidence of SWDs, whereas higher doses (30 mg/kg) also reduced the mean duration of SWDs. In contrast, treatment with the non-competitive mGlu1 receptor antagonist, JNJ16259685 (2.5 and 5 mg/kg, i.p.) increased the incidence of SWDs. These data suggest that absence epilepsy might be associated with a reduction of mGlu1 receptors in the thalamus, and that compounds that amplify the activity of mGlu1 receptors might be developed as novel anti-absence drugs. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.

N150 in amygdalar ERPs in the rat: is there modulation by anticipatory fear?

The hypothesis was tested whether the amygdalar N150 of rats, a slow, negative component in the event-related potential from the lateral amygdala, is sensitive to a state of anxious anticipation. A conditioning procedure was applied in which a series of six auditory stimuli was followed by a shock when presented alone, but not when the auditory stimuli were preceded by a visual stimulus. Heart rate recordings confirmed that the auditory stimulus train induced a state of increasing anticipatory fear and that this condition was modulated by the visual stimulus. During behavioral training, a N150 appeared in the amygdalar event-related potential evoked by the auditory stimuli, replicating previous findings. However, the amplitude of the N150 was not affected by whether or not the visual stimulus had been presented before. These results failed to support the idea that the N150 is related to the expectancy of an aversive event. An alternative interpretation, emphasizing the increase in arousal and attention that is inherent to aversive learning, is discussed.

Convulsive and nonconvulsive epilepsy in rats: effects on behavioral response to novelty stress.

Behavioral response to a new environment of Wistar and WAG/Rij rats with absence and/or audiogenic seizures (AGSs) was investigated. Behavior was observed in open-field (OF) and light-dark choice (LD) tests. Correlations of test performance with seizure parameters were evaluated. AGS-susceptible Wistar rats exhibited reduced exploration (rearing) in both tests and a tendency toward hyperlocomotion in the OF test. Genetically absence-epileptic WAG/Rij rats demonstrated agitation (increased vertical/horizontal locomotion, enhanced defecation/urination) in the LD test, whereas they exhibited reduced exploration, increased grooming, and hyperlocomotion in the OF test. Anxiety level, as estimated by grooming time in the OF test and latency to first "risk assessment" in the LD test, correlated positively with the propensity for absence seizures in WAG/Rij rats not susceptible to AGSs. It can be concluded that the behavioral response to novelty stress in epileptic subjects depends on the type and severity of seizures.

Neural correlates of sensory gating in the rat: decreased Fos induction in the lateral septum.

In the P(50) gating or conditioning-testing paradigm in the rat, two identical click stimuli are presented with an inter-click interval of 500 ms. The reaction towards the second click, as measured with evoked potentials, is reduced in respect to that towards the first click; this phenomenon is called sensory gating. In the present experiments, the inter-click interval was varied systematically and auditory evoked potentials were measured. Sensory gating was found to occur only at intervals between 500 and 1000 ms, but not at longer intervals. Fos immunohistochemistry was then performed using two groups of rats exposed to double clicks: the inter-click interval was 500 ms in the experimental group and 2500 ms in the control group. Fos induction was analyzed in selected brain structures. In the auditory pathways, Fos-immunoreactive neurons were found in both groups of rats in the inferior colliculus and medial geniculate body. Fos-immunoreactive cells were also examined in the septum and hippocampus. In the ventral part of the lateral septal nucleus, the labeled neurons were significantly fewer in the experimental animals compared to the control group. Smaller and non-significant quantitative differences of Fos-positive neurons were documented in the medial septum and hippocampal CA1 region. These data point out a selective decrease in the lateral septum of Fos induced by auditory sensory gating, and suggest an involvement of this structure, and possibly of other parts of the septo-hippocampal system, in sensory gating mechanisms. The results might be relevant for theories on sensory gating deficits in schizophrenia.