Takahiro Ishimoto

Convulsive seizures induced by N-methyl-d-aspartate microinjection into the mesencephalic reticular formation in rats

Effects of microinjections of a single 2 or 10 nmol dose of N-methyl-D-aspartate (NMDA) into the unilateral mesencephalic reticular formation (MRF) on behavior and electroencephalogram were examined in rats (n=18) during a 15 min period (Exp. 1), and subsequent effects of sound stimulation with key jingling applied at 15, 30, and 45 min after the injections were observed (Exp. 2). The microinjections of 2 nmol dose of NMDA (n=10) induced hyperactivity (9 of 10 rats) and running/circling (8 of 10 rats) in Exp. 1, and hyperactivity (3 of 10 rats) in Exp. 2. Moreover, the microinjections of 10 nmol dose of NMDA (n=8) induced not only hyperactivity (8 of 8 rats) and running/circling (7 of 8 rats) but also generalized tonic-clonic seizures (GTCS) (5 of 8 rats) in Exp. 1; these seizure patterns were also elicited by sound stimulation in Exp. 2. The seizure patterns were accompanied by electroencephalographic seizure discharges in the MRF and the motor cortex. In contrast, the control group rats (n=10) which received a single dose of saline microinjection into the unilateral MRF showed no behavioral or electroencephalographic changes in both Exp. 1 and 2. These findings suggest that the MRF has an important role in the development of GTCS, which follows hyperactivity and running/circling, and that potentiation of excitatory neurotransmission in the MRF participates in the development of audiogenic seizures as well as GTCS.

Kindling of the midbrain periaqueductal gray in rats

We investigated the role of midbrain periaqueductal gray matter (PAG) in the manifestation of generalized seizures by administering electrical stimulation to this area in rats. Electrical stimulation of 60 Hz biphasic square pulses of a 1-s duration administered to the PAG-induced convulsive responses in the following order: (1) Type I, running (stimulus intensity; range 50--200 microA, mean 73.1 microA) without afterdischarge (AD), (2) Type IIa, running (stimulus intensity; range 50--300 microA, mean 111.8 microA) with AD at the PAG and the amygdala (AMY), and (3) Type IIb, generalized tonic--clonic seizures (GTCS) (stimulus intensity; range 50--250 microA, mean 182.1 microA) with AD at the PAG and AMY. Twenty daily PAG stimulations at the non-GTCS inducing threshold failed to produce kindling. However, 20 daily PAG stimulations at the GTCS threshold produced progressive AD spread involving the motor cortex, and progressive changes in the behavioral seizure pattern. These findings indicate that the PAG can be effectively kindled. However, PAG kindling has no apparent influence on subsequent AMY kindling.

Biperiden-induced delirium model in rats: a behavioral and electroencephalographic study.

AIMS AND METHODS In order to elucidate the neural mechanisms of delirium, we administered the anticholinergic drug, biperiden (40 mg/kg i.p.), to 10 adult male Wistar rats and examined the resulting polygraphic recordings, including electroencephalography (EEG), electrooculography (EOG), and electromyography (EMG), for 60 min following injection. EEG data were investigated quantitatively by power spectrum analyses using fast Fourier transformation. Ten male Wistar rats receiving saline (i.p.) were used as the control group. RESULTS Treated rats demonstrated two types of alternating behavioral change: a hyperactive and hypoactive state. In the hyperactive state, rapid walking, excessive random sniffing, and retropulsion were observed, with EEG desynchronization (significantly increased alpha1 (8.0-10.0 Hz), alpha2 (10.0-13.0 Hz), and beta (13.0-30.0 Hz) power values), as well as EEG slowing (significantly increased delta (0.5-4.0 Hz) and theta1 (4.0-6.0 Hz) power values): significantly marked rapid eye movement, and increased EMG activity. In the hypoactive state, motor arrest and drowsiness were observed, with prominent EEG slowing (significantly increased delta and theta1 power values): significantly decreased rapid eye movement and moderately decreased EMG activity. On the other hand, the control group did not show any behavioral or polygraphic changes. CONCLUSIONS The behavioral and polygraphic changes induced by biperiden administration in rats are similar to those of delirium in humans. Therefore, it is proposed that biperiden-treated rats are a good delirium model and the anticholinergic mechanism is one of the potent factors in the development of delirium in humans.

Effects of levetiracetam on hippocampal kindling in Noda epileptic rats

In order to clarify the seizure susceptibility of Noda epileptic rat (NER) and the antiepileptic effects of levetiracetam (LEV), we performed electrical hippocampal kindling in NERs compared with Wistar rats (experiment 1), and hippocampal kindling in NERs with LEV administration (experiment 2). In experiment 1, electrical stimulation was administered to the right dorsal hippocampus of NERs and Wistar rats once per day. In experiment 2, NERs were randomly assigned to group L (LEV administration) and C (saline administration). Following daily administration of LEV (240 mg/kg, i.p.) to group L and saline to group C, hippocampal kindling was performed from the 5th day of consecutive LEV or saline administration. As a result of experiment 1, all NERs exhibited stage 5 (falling) or stage 6 seizure (running/jumping, subsequent seizure) from the first electrical stimulation. In experiment 2, LEV suppressed development of hippocampal kindling, increased the afterdischarge threshold of the hippocampus and inhibited stage 6 seizures in NER. Although LEV prolonged the afterdischarge duration at the first stage 5 seizure significantly, there was a tendency to prolong the latency to generalization by LEV. These findings indicate that NER is susceptible not only to limbic seizures but also to brainstem seizures. Furthermore, LEV may have inhibitory effects not only on the hippocampus but also on other neuronal pathways to secondary generalization in this rat model.

Convulsive seizures induced by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid microinjection into the mesencephalic reticular formation in rats

Effects of microinjections of a single 2 or 10 nmol dose of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) into the unilateral mesencephalic reticular formation (MRF) on behavior and on the electroencephalogram were examined in rats (n=30) over a 15-min period (Exp. 1); subsequent effects of sound stimulation with key jingling applied at 15, 30, and 45 min after the injection were observed (Exp. 2). The microinjections of a 2 nmol dose of AMPA (n=15) induced hyperactivity (15 of 15 rats) and running/circling (10 of 15 rats) in Exp. 1, and hyperactivity (5 of 15 rats) in Exp. 2. Moreover, the microinjections of a 10 nmol dose of AMPA (n=15) induced hyperactivity (15 of 15 rats), running/circling (13 of 15 rats), generalized tonic-clonic seizures (GTCS) (4 of 15 rats), and amygdala kindling-like seizures (AMKS) (8 of 15 rats) in Exp. 1; electroencephalographic seizure discharges were predominantly observed in the MRF during hyperactivity, running/circling and GTCS, while those predominantly observed in the amygdala were during AMKS. In Exp. 2, hyperactivity (15 of 15 rats), running/circling (14 of 15 rats) and GTCS (6 of 15 rats) were elicited by sound stimulation, although AMKS were not. The control group of rats (n=15) which received a single dose of saline microinjection into the unilateral MRF showed no behavioral or electroencephalographic changes in both Exp. 1 and 2. These findings suggest that potentiation of excitatory amino acid neurotransmission induced by AMPA injection into the MRF plays an important role not only in the development of hyperactivity, running/circling, GTCS and AMKS, but also in the development of audiogenic seizures.

A case of insufficient sleep syndrome

Abstract All night polysomnographic evaluation (PSG) soon after admission and at the late period of admission revealed an atypically high sleep efficiency and a prolonged total sleep time. Sleep onset latency and distribution of REM and NREM sleep stages were like those of normal sleepers. On REM latency, while it was remarkably reduced (25.0 min) soon after admission and sleep onset REM period (SOREMP) was found, at the late period of admission it was prolonged and SOREMP was not found. Giving multiple sleep latency test with polysomnography, soon after admission subjective excessive daytime sleepiness had already improved and mean sleep latency (13.2 min) was within normal range. However, SOREMP appeared twice in five tests. We considered that the appearance at the early period of admission was the result of REM pressure growing.

Nature and Consequences of Seizures Originating in the Brainstem

Experimental studies suggest that the brainstem, particularly the brainstem reticular formation (RF), is involved in the secondary generalization of partial seizures originating in the forebrain. Electrolytic lesioning of the midbrain involving the medial part of the mesencephalic RF (MRF) prior to amygdala (AM) kindling retards the development of AM kindling.10 Extensive midline bisection of the brainstem (the midbrain to the pons) can inhibit the development of a stage 5 AM kindled seizure.8 In feline AM kindling, the emergence of afterdischarge (AD) in the ipsilateral and then contralateral midbrain reticular formation precedes generalization and synchronization of AD leading to the final stage 6 generalized convulsion.45 In addition, a unilateral lesion (ipsilateral to the kindled AM) in the midbrain reticular formation not only elevates the established generalized seizure triggering threshold but also prevents recalling the kindled stage 6 seizures in cats.45, 47 However, bisection of the forebrain commissures does not prevent stage 6 convulsive development.46 In prefrontal kindling in epileptic Senegalese baboons, Papio papio, bisynchronous electroencephalographic discharges in the bulbar RF are associated with photically induced generalized convulsions and AM kindled generalized seizures.44