Effect of electric stimulation of the dentate nucleus on focal complexes of epileptic activity in the cerebral cortex

Acute experiments on cats were made with the use of an experimental multifocal epileptic complex (MEC) which was created by local application of different concentrations of penicillin to different zones of the neocortex. At the early stages of the MEC the epileptic activity in the seizure foci increased during electrical stimulation (ES, 100-300 Hz) of the contralateral dentate nucleus. As the epileptic activity of the MEC descended up to the disappearance of some of the dependent foci, ES elicited the suppression of the epileptic discharges in the remaining foci. ES of the dentate nucleus did not affect the overall duration of MEC existence. It is inferred that the dentate nucleus belongs to the antiepileptic system of the brain.     

The Responses of Neurons of the Somatosensory Cortex to Stimulation of the Posterior Thalamus (PO) in WAG/Rij Rats Genetically Predisposed to Absence Epilepsy

In genetically predisposed WAG/Rij rats and healthy Wistar rats, we studied functioning of the paralemniscal region of the thalamo-cortical system. The responses of neurons of the somatosensory cortex to single electrical stimulation of the posterior nucleus of the thalamus were recorded in two- to three-monthold rats within the period when the epileptic activity was not developed. We revealed lower number of shortterm inhibitory responses in WAG/Rij rats as compared to Wistar rats. This may create preconditions for the spreading of spike-wave activity in the somatosensory cortex, which is an electrophysiological sign of absence epilepsy.     

A Possible Mechanism of Blocking of Limbic Motor Seizure Reactions Induced by Activation of the Thalamic Reticular Nucleus

Experiments were directed toward elucidation of the role of the thalamic reticular nucleus (R) in the modulation of generalized seizure reactions under kindling conditions and of the mechanisms mediating the effects of stimulation of the above nucleus on seizure activity. It was shown that activation of the thalamic R in rats limits generalization of the seizure reactions both in the course of development of seizures of limbic genesis (evoked by stimulation of the hippocampus) and under conditions of the existence of a pre-formed epileptic nidus. Tetanic stimulation of the R in cats under conditions of acute experiments induced significant facilitation of IPSPs in thalamo-cortical neurons of the ventrolateral thalamic nucleus. This effect is rather long-lasting and may be considered a mechanism providing blocking of generalized seizures under kindling conditions. Neirofiziologiya/Neurophysiology, Vol. 37, No. 4, pp. 352–361, July–August, 2005.     

A study of the action of anticonvulsant drugs on an experimental model of epilepsy

Repeated electrical low intensity stimulation of various regions of the brain has been shown to induce epileptic seizure activity. This experimental model of epilepsy has been used in our laboratory in rats. Male rats, anaesthetized with nembutal (20 mg/kg, i.p.) and ketalar (60 mg/kg, i.p.) were implanted stereotaxically with electrodes in the dorsal hippocampus and neocortex and received 2 hours stimulation sessions via the hippocampal electrodes (1 sec, 60 Hz, 200-800 microA) one stimulus per minute, during which electrographical and behavioral seizures were induced. The effect of anticonvulsant drugs was tested on this model: phenobarbital (40 mg/kg) reduced the quantity of epileptic electrographic activity and abolished the behavioral aspects of the seizures; diphenylhydantoin (20 mg/kg) reduced the quantity of epileptic electrographic activity, but had no effect on the behavioral component of the seizures; diazepam (6 mg/kg) only blocked the behavioral component of the seizures leaving the animal stuporous and immobile, but the electrographical component was unaffected; carbamazepine (10 mg/kg) had no effect on the electrographical epileptic seizures and reduced the behavioral aspects, but to a lesser extent than diazepam.     

Role of limbic structures in the mechanisms of post-traumatic epilepsy]

It was shown in the experiments on rats that intracerebroventricular administration of kainic acid (0.01, 0.05 microgram) after brain trauma, resulted in the occurrence of behavioral and electrographic convulsive disturbances; maximal expression of epileptic activity was obtained in entorhinal cortex and ventral hippocampus. Kainic acid induced epileptic reactions in nontraumatized rats only if injected in dose 0.1 microgram. Brain trauma did not lead to changes in seizures intensity induced by systemic picrotoxin administration. It is concluded that the formation of generator of pathologically enhanced excitation in limbic structures via increase of excitor glutamatergic neurotransmission is the important mechanism of traumatic epilepsy.     

经颅磁刺激对癫痫病灶脑电相关维数的影响

利用脑功能指标——大鼠病灶区脑电的相关维数,研究低频经颅磁刺激对慢性颞叶癫痫大鼠脑功能改善的作用。对一组颞叶癫痫大鼠施予频率为0．5Hz、强度为0．4T、20次／日、连续一周的低频重复性经颅磁刺激(rTMS)．在rTMS前后,分别测取颞叶癫痫大鼠责任病灶区皮层和海马区的脑电,重构时间延迟吸引子,用G-P算法估算反映对应脑区功能状态的相关维数。研究结果显示：施予适量的rTMS(0.4T、20次／日、连续一周),使颞叶癫痫大鼠海马和相应皮层脑电的相关维数比刺激前明显升高。研究表明适量的rTMS有抑制癫痫的作用。     

Epileptiform activity in the somatosensory cortex of rats with trigeminal neuralgia]

It was shown in experiments on rats that penicillin 1 microliter microinjection (100 U) into the caudal nucleus of the spinal tract of the trigeminal nerve, accounting for formation of a generator of pathologically enhanced excitation (GREE), brings about in rats the pain syndrome with characteristic for trigeminal neuralgia behavioural manifestations and the emergence of epileptiform activity in the somatosensory cortex, especially pronounced in the contralateral hemisphere. The emergence of this activity reflects, on the one hand, the action of the GREE in the caudal nucleus of the trigeminal nerve and, on the other hand, the involvement of the somatosensory cortex taking over stimulation from the hyperactive caudal nucleus, into formation of a pathological algic system of this form of trigeminal neuralgia.     

Negative occurrence between hippocampal rhythmic slow activity and epileptiform spikes: influence of the striatum

The effects of caudate and septal stimulation on hippocampal activity were studied. Sodium penicillin was intravenously injected in order to induce a steady rate of interictal epileptic activity. Penicillin injection caused significant reduction of the rate of occurrence and duration of hippocampal rhythmic slow activity (RSA). Spontaneous RSA as well as RSA-eliciting caudate and septal stimulation induced a marked inhibition on frequency of epileptiform complexes. Lesions of the medial septal nucleus made it impossible to record RSA or to observe any sort of influence on hippocampal epileptiform activity by caudate stimulation. This result suggests that the septum is important for RSA genesis in the striato-hippocampal pathway or in the reciprocal septo-hippocampal connections.     

Role of globus pallidus in mechanisms of antiepileptic caudate- cortical effects]

The experiments on rats have shown that striatal electrostimulation influences inhibiting cortex epileptic activity decrease under conditions of globus pallidus destruction. Besides, it is noted that globus pallidus lesion exerts a pronounced antiepileptic effect on development of the neocortical epileptic activity complexes. Globus pallidus stimulation enhanced the neocortex interictal seizure activity and transformed it to ictal discharges. The results are discussed in terms of the role of pale globe in mechanisms of caudate inhibitory action on neocortex epileptic activity.     

Activation of thalamic ventroposteriolateral neurons by phrenic nerve afferents in cats and rats.

It has been demonstrated that phrenic nerve afferents project to somatosensory cortex, yet the sensory pathways are still poorly understood. This study investigated the neural responses in the thalamic ventroposteriolateral (VPL) nucleus after phrenic afferent stimulation in cats and rats. Activation of VPL neurons was observed after electrical stimulation of the contralateral phrenic nerve. Direct mechanical stimulation of the diaphragm also elicited increased activity in the same VPL neurons that were activated by electrical stimulation of the phrenic nerve. Some VPL neurons responded to both phrenic afferent stimulation and shoulder probing. In rats, VPL neurons activated by inspiratory occlusion also responded to stimulation on phrenic afferents. These results demonstrate that phrenic afferents can reach the VPL thalamus under physiological conditions and support the hypothesis that the thalamic VPL nucleus functions as a relay for the conduction of proprioceptive information from the diaphragm to the contralateral somatosensory cortex.     

Role of the pulvinar-lateralis posterior nucleus complex (P-LP) in the experimental epilepsy of the cat

The ability of the pulvinar-lateralis posterior nucleus complex (P-LP) to evoke epileptic activity when stimulated, was studied in 20 adult cats. Twelve animals were analyzed after they recovered from the surgical procedure (chronic model). In seven of them a cannula with electrodes was implanted in the P-LP and one twisted bipolar electrode was placed ipsilaterally in the following structures: hippocampus, superior colliculus, caudate nucleus and cerebral cortex. Through the cannula Na penicillin was injected. The electrodes allowed both to stimulate and to record the electrical activity. In the remaining five cats, the cannula was implanted in hippocampus in order to compare its sensitivity to generate epileptic activity to that of P-LP. Another group of eight cats were surgically implanted and studied in the same day (acute model). In four of them the cannula was placed in the P-LP through the temporal pathway, to avoid crossing the hippocampus and the ventricle. In another four, penicillin was injected in the P-LP after suctioning the cerebral cortex and the hippocampus overlying the former structure. Epileptic activity could be induced in P-LP and it spread rapidly to hippocampus and after a while to the other implanted structures. This was observed both with penicillin and electrical stimulation. The sensitivity of P-LP to generate epileptic activity was lower than that of the hippocampus. In particular, it was necessary to use two to ten times more penicillin and three times the electrical current intensity in the P-LP as compared to the values needed in the hippocampus. These results are discussed in view of the controversial problem about the ability of the thalamus to generate and spread epileptic activity.     

Effect of Acute Stress on the Development of Seizures in a Kindling Model in Rats

We studied the effect of acute stress induced by nociceptive stimulation of the limbs on the duration of ECoG epileptiform activity and manifestation of generalized motor convulsive reactions under conditions of a kindling model of epilepsy in rats. Two and four weeks after termination of the kindling procedure, test stimulations of the hippocampus evoked intense attacks of epileptic activity. Short-lasting pain-inducing stimulation (intense electrical stimulation of the limbs) resulted in noticeable limitation of both ECoG and motor behavioral manifestations of epileptic activity determined by the formation of an epileptogenic nidus. The antiepileptic effect of acute stress was limited in time; manifestations of this effect reached their maximum about 3 h after painful stimulation, while about 6 h after such stimulation they became smoothed to a considerable extent.     

Sudden unexpected death in epileptics following sudden,intense, increases in geomagnetic activity: Prevalence of effect and potential mechanisms

Abrupt, intense increases in global geomagnetic activity during the local night may precipitate a significant proportion of sudden unexpected (or unexplained) deaths (SUD) in epileptics. Over a 2-year period SUD in healthy chronic epileptic rats occurred when the average daily geomagnetic activity exceeded 50 nT (nanoTesla) and suddenly began during local night. Other experiments demonstrated that epileptic rats displayed more spontaneous seizures per night if there had been sudden increases in geomagnetic activity. Analyses of previously published data indicated that the number of SUDs/month in a population of human epileptics was positively associated with the number of days/month when the average geomagnetic activity exceeded 50 nT. The results support the hypothesis that suppression of the nocturnal concentrations of the endogenous anticonvulsant melatonin by sudden increases in geomagnetic activity may encourage fatal cardiac arrhythmias by uncoupling the insular/amygdaloid-paraventricular hypothalamic-solitary nucleus pathways.     

Features of the morphofunctional state of the organs of the thymico-lymphatic system during various adaptive reactions induced by electric stimulation of emotiogenic structures of the brain

Weak electrical stimulation of emotiogenic brain structures was found to lead to the development of different general non-specific adaptation reactions. Stimulation of nucleus lateralis septi was found to evoke mainly the development of activation reaction, while stimulation of globus pallidum caused primarily the development of training reactions. Stress reactions were considerably less frequent in electrical stimulation of both kinds of structures than in the control. This can be explained by small values of the electrical current applied. Morphofunctional activity of thymus lymphatic system depended not only on the type of non-specific reaction but also on the character of the stimulated emotiogenic structure--the functional activity was higher with the stimulation of nucleus lateralis-septi. However, the functional activity of thymus lymphatic system in rats with globus pallidum stimulation was higher than in control rats that were not subject to any stimulation.     

Effect of Barodenervation on Cardiovascular Responses Elicited from the Hypothalamic Arcuate Nucleus of the Rat

We have previously reported that chemical stimulation of the hypothalamic arcuate nucleus (ARCN) in the rat elicited increases as well as decreases in blood pressure (BP) and sympathetic nerve activity (SNA). The type of response elicited from the ARCN (i.e., increase or decrease in BP and SNA) depended on the level of baroreceptor activity which, in turn, was determined by baseline BP in rats with intact baroreceptors. Based on this information, it was hypothesized that baroreceptor unloading may play a role in the type of response elicited from the ARCN. Therefore, the effect of barodenervation on the ARCN-induced cardiovascular and sympathetic responses and the neurotransmitters in the hypothalamic paraventricular nucleus (PVN) mediating the excitatory responses elicited from the ARCN were investigated in urethane-anesthetized adult male Wistar rats. Bilateral barodenervation converted decreases in mean arterial pressure (MAP) and greater splanchnic nerve activity (GSNA) elicited by chemical stimulation of the ARCN with microinjections of N-methyl-D-aspartic acid to increases in MAP and GSNA and exaggerated the increases in heart rate (HR). Combined microinjections of NBQX and D-AP7 (ionotropic glutamate receptor antagonists) into the PVN in barodenervated rats converted increases in MAP and GSNA elicited by the ARCN stimulation to decreases in MAP and GSNA and attenuated increases in HR. Microinjections of SHU9119 (a melanocortin 3/4 receptor antagonist) into the PVN in barodenervated rats attenuated increases in MAP, GSNA and HR elicited by the ARCN stimulation. ARCN neurons projecting to the PVN were immunoreactive for proopiomelanocortin, alpha-melanocyte stimulating hormone (alpha-MSH) and adrenocorticotropic hormone (ACTH). It was concluded that increases in MAP and GSNA and exaggeration of tachycardia elicited by the ARCN stimulation in barodenervated rats may be mediated via release of alpha-MSH and/or ACTH and glutamate from the ARCN neurons projecting to the PVN.     

Transient changes of cortical interhemispheric responses after repeated caffeine administration in immature rats

Repeated postnatal caffeine treatment of rat pups led to transient developmental changes in cortical epileptic afterdischarges. To know if physiological cortical functions are also affected transcallosal evoked potentials were studied. Rat pups of the Wistar strain were injected daily with caffeine (10 or 20 mg/kg s.c.) from postnatal day (P) 7 to P11, control siblings received saline. Cortical interhemispheric responses were tested at P12, 18, 25 and in young adult rats. Amplitude of initial monosynaptic components was evaluated in averaged responses. Single pulses as well as paired and frequency (five pulses) stimulations were used. Developmental rules - highest amplitude of responses in 25-day-old rats, potentiation with paired and frequency stimulation present since P18 - were confirmed. Caffeine-treated rats exhibited transient changes: single responses were augmented in P25 if high stimulation intensity was used, paired-pulse and frequency responses were higher in experimental than in control animals at P12, the opposite change was observed in 18- and more markedly in 25-day-old rats. No significant changes were found in adult animals, monosynaptic transcallosal responses represent a simple and robust system. The developmental profile of described changes did not exactly correspond to changes in epileptic afterdischarges supporting the possibility that afterdischarges did not arise from early monosynaptic components of responses. In spite of transient nature of changes they can reflect delayed or more probably modified brain development.     

Midazolam suppresses spike-and-wave rhythm accompanying three different models of epileptic seizures

The action of a water-soluble benzodiazepine midazolam (0.1 and 1 mg/kg i.p.) was tested against three models of spike-and-wave rhythm in rats: rhythmic metrazol activity (a model of human absence seizures), minimal metrazol seizures, and epileptic afterdischarges induced by low-frequency cortical stimulation (probably models of human myoclonic seizures). Midazolam was able to reduce spike-and-wave activity in all three models, but there were quantitative differences: the lower dose was effective only against rhythmic metrazol activity, but its action against two other models was negligible, whereas the higher dose of midazolam resulted in significant effects in all three models. These quantitative differences are not sufficient to prove our hypothesis that the spike-and-wave rhythm represents different phenomena in various models. A spread of epileptic activity into brain structures other than the thalamocortical system determines the type of epileptic seizures.     

Morpho-functional effects of kainic acid injection into the cat's pulvinar-lateralis posterior nucleus complex

The histological, electroencephalographic, behavioral changes as well as the changes in the intensity threshold of stimulation necessary to induce contralateral turning were studied in 16 cats, in which kainic acid (KA) was injected locally into the pulvinar-lateralis posterior nucleus complex (P-LP). In 13 cats a stainless-steel tube with two attached electrodes was implanted in P-LP, and electrodes were also implanted in the ipsilateral dorsal hippocampus, the superior colliculus and the caudate nucleus. KA was injected through the tube using a 10 microliters Hamilton syringe. In other 3 cats, KA was injected stereotaxically through the needle of the Hamilton syringe and two electrodes were implanted in these areas after withdrawal of the syringe. The intensity thresholds of stimulation required to induce turning behavior were controlled before and after KA administration in the 13 cats with an implanted tube and only after KA injections in the three cats without a tube; in these instances the current threshold of the contralateral P-LP served as control. The histological results showed a moderate KA damage of the P-LP, with destruction of neuronal soma and gliosis and additional involvement, in all the experiments, of the dorsal hippocampus; however, passage fibers were spared by the lesions. A dose-dependent epileptic effect of KA was seen, which was slight with the 3 micrograms dose and intense with 6 micrograms. The EEG recording showed a prominent and almost simultaneous epileptic involvement of the hippocampus and the P-LP after KA, with less involvement of the other implanted structures. Turning behavior induced by electrical stimulation of the P-LP was suppressed when the electrode tip was located inside the lesioned area. When the electrode tip was placed inside a slight or moderate damaged tissue, a significative increase in current threshold was found, and finally when the tip of the electrode was outside the lesioned area no change in threshold was observed. These findings do not contradict our previous hypothesis of an intrinsic cholinergic mechanism involved in the turning response evoked by P-LP electrical stimulation, although it cannot be excluded that fibers coming presumably from the superior colliculus or pretectum may contribute to the response.     

Contrasting effects of stimulation of the caudate nucleus and globus pallidus on paroxysmal hippocampal activity in the cat

The different actions exerted by pallidum and caudate nucleus on electrically induced epileptic activity of hippocampus were analyzed. Caudate appeared to inhibit hippocampal after discharges duration (HAD) while the globus pallidus exerted a facilitatory effect on HAD duration. Both effects were maximal when conditioning stimulation immediately preceded hippocampal test stimulation. The results are discussed considering reciprocal functional connections of the two striatal structures.     

Reproduction of passive avoidance reactions after neurotensin microinjection into nucleus accumbens of rat brain against the background of reserpine action

The purpose of the study was to reveal the features of the influence of neurotensin injected into the nucleus accumbens on behaviour of rats after systemic administration of reserpine in the dose of 2 mg/kg. Reprodution of passive avoidance conditioned reactions, painful stimulation aftereffects on locomotor activity in the "open field", and behavior in the elevated plus-maze were studied. It was shown that reserpine administration impaired the reproduction of passive avoidance reactions and weakened the oppressing aftereffect of painful stimulation, which can be due to a decrease in anxiety in rats. Neurotensin prevented disorders in the defensive behavior evoked by reserpine and intensified the state of anxiety in the elevated plus-maze. The positive influence ofneurotensin on the reproduction of passive avoidance can be associated with the recovery of the anxiogenic effect of painful stimulation destroyed by reserpine. Thus, neurotensin injected into the nucleus accumbens could normalize the balance of brain monoaminergic systems.