Takehisa Araki

Microglial activation by epileptic activities through the propagation pathway of kainic acid-induced hippocampal seizures in the rat

We studied the distribution of activated microglia in the brain during kainic acid-induced acute hippocampal seizures in rats. Although no microglial activation was observed 4 h after seizure induction, activation was detected in the primary focus and also in other selected structures in the limbic and non-limbic structures after 8 and 24 h, in the absence of any obvious morphological changes in the neurons. The structures with activated microglia were highly consistent with those included in the propagation pathways of the hippocampal seizures. These findings thus suggest that the microglial cells are activated through the propagation pathways by the seizure activities that propagate transynaptically from the primary focus, even without any apparent neuronal injury.

Propagation of hippocampal seizure activity arising from the hippocampus: a local cerebral blood flow study

We studied the propagation of spike discharges and the changes in local cerebral blood flow (LCBF) by means of the electroencephalogram (EEG) and autoradiographs to elucidate the underlying mechanism and the propagation pathway in rats with limbic seizures. Seizures were induced by the unilateral microinjection of kainic acid (KA) into the dorsal hippocampus during which behavioral, EEG and LCBF changes were documented. Overall, the results indicate an initial spreading to the contralateral hippocampus from the ipsilateral hippocampus, followed by activation of the ipsilateral amygdala, other limbic structures, striatum and sensorimotor cortex. Finally, seizure activity spreads to the ipsilateral globus pallidus, substantia nigra, subthalamic nucleus, thalamus, septum and parietal cortex. The activation of the contralateral hippocampus in the KA model studied here occurs earlier than in the acute amygdaloid seizure model. Elucidation of the mechanisms underlying this difference in the propagation pathway will require the application in parallel of techniques examining these and other aspects of seizure activity.

Inferior Temporal Sulcus as a Site of Corticotomy: Magnetic Resonance Imaging Analysis of Individual Sulcus Patterns

OBJECTIVE Transcortical approaches to the inferior horn often result in quadrant hemianopsia attributable to the injury to the optic radiation. The inferior temporal sulcus (ITS) has received little attention as an entrance point for the transsulcal approach. We used the method of detecting the ITS with magnetic resonance imaging (MRI) scans and investigated the sulcus pattern of ITS, its incidence rate, and the availability of the ITS to the corticotomy for selective amygdalohippocampectomy. METHODS The sulcus patterns of the ITS of 100 temporal lobes in 50 healthy individuals were classified according to the number of interruptions by gyral bridges, and the localization of the ITS was characterized in relation to the outer surface by means of the surface anatomy scan of MRI. RESULTS Most of the ITS was interrupted by one to three gyral bridges (0 bridges, 8%; one bridge, 27%: two bridges, 37%; three bridges, 20%; more than four bridges or no apparent ITS, 8%). When the ITS was present, it was located 15 mm above the orbitotragus line at a point 20 mm anterior to the tragus. The number of gyral bridges was significantly larger in the left temporal lobes than in the right temporal lobes, regardless of the sex of the subject. CONCLUSION The ITS was clearly identified in 72% of the temporal lobes by the oblique sagittal view of MRI scans; thus, in such cases, the ITS was considered to be a candidate for an entrance point of a small temporal corticotomy. The preoperative observation of the ITS in relation to the orbitotragus line by means of MRI may improve the planning of the transsulcal approaches to deeply seated mesial temporal lesions, such as hippocampal sclerosis.

Limbic seizures originating in the olfactory bulb: an electro-behavioral annd glucose metabolism study

We studied seizures which were induced by a microinjection of kainic acid (KA) into the unilateral olfactory bulb (OB) in the rats. The first epileptiform discharge appeared in the OB, was then propagated to the amygdala and the hippocampus unilaterally, and finally propagated to the unilateral sensori-motor cortex. Consistent graded behavioral changes, almost identical to those of the amygdaloid and hippocampal seizures, occurred during the development of the seizures, and three stages were classified: stage 1 was staring, stage 2 consisted of masticatory movement and stage 3 demonstrated rearing and rearing and falling. Local cerebral glucose utilization (LCGU) measured with the [14C]2-deoxyglucose method revealed a graded propagation of seizure activities at each stage in the unilateral structures. At stage 1, the increased activities propagated from the OB localized in the anterior olfactory nucleus; at stage 2, the endopiriform nucleus, the nucleus accumbens, the entorhinal cortex, the ventral globus pallidus and the globus pallidus were all activated; at stage 3, the thalamic nuclei (mediodorsal, ventrolateral, ventromedial and centromedian nuclei), the substantia nigra pars reticulata, the entopeduncular nucleus and the sensorimotor cortex were also activated. The globus pallidus, which receives afferent fibers from the nucleus accumbens, was the first structure that was activated metabolically among the extralimbic structures. No metabolic activation occurred in the amygdala and the hippocampus in spite of the early propagation of epileptiform discharges to these structures on EEG. These results suggest that OB seizures involve the limbic structures, while the amygdala and the hippocampus have a little contribution to OB seizures. In addition, the nucleus accumbens plays an important role as a functional interface between the limbic and the motor system in OB seizures.

Analysis of Cerebral Lobar Microbleeds and a Decreased Cerebral Blood Flow in a Memory Clinic Setting

OBJECTIVE Cerebral microbleeds (MBs) have been previously associated with cognitive dysfunction, including Alzheimers disease. In the present study, we aimed to clarify the relationship between cerebral lobar MBs and the regional cerebral blood flow (CBF). METHODS We investigated the data obtained from 122 patients in our memory clinic who were examined by both MRI and (99m)Tc-ethyl cysteinate dimer (ECD)-single photon emission computed tomography (SPECT). Patient brain scans were superimposed and brain regions containing both decreased CBF and MBs were visually identified. For each patient eight brain regions were evaluated, comprising the right and left frontal, temporal, parietal, and occipital lobes. RESULTS Cerebral MBs were detected in 36 of the 122 (29.5%) patients. Of these 36 patients, 23 had detectable lobar MBs, which were primarily distributed in the occipital lobe in 19 of the 46 (41.3%) regions with lobar MBs. The frequency of MBs accompanied by a decreased CBF in the parietal and occipital lobes was significantly higher than that observed in the frontal lobe (73.3% vs. 27.3%, p<0.05, and 73.7% vs. 27.3%, p<0.05, respectively). Additionally, a decreased CBF was observed significantly more frequently in the brain regions with 5 or more MBs compared to the regions with one microbleed (83.3 vs. 25.0%, p<0.0005). Among the 17 patients with observable MBs accompanied by a decreased CBF, none were initially diagnosed with either subjective complaints or mild cognitive impairment. CONCLUSION We determined that the cerebral lobar MBs located in the parietal and occipital lobes, and the lobar regions with a large number of MBs, were significantly more likely to be accompanied by a decreased CBF.

Kainic acid-induced thalamic seizure in cats — a possible model of petit mal seizure

Bipolar depth electrodes were implanted stereotaxically in the thalamus, hippocampus and midbrain reticular formation of cats. Cortical screw electrodes were placed over the bilateral sensorimotor cortex. A guide cannula with an inner injection cannula was inserted unilaterally into the posterolateral ventral nuclei (VPL) of the thalamus. Eight days after the procedures, kainic acid (2.0 micrograms) was injected unilaterally into the VPL via the injection cannula in freely moving animals and electro-clinical observations were made. About 1 h after the kainic acid injection, multiple spikes were observed in the VPL (injection site), which propagated to the subcortical structures. These seizures finally propagated bilaterally to the cortex about 2 h after the injection. About 3-4 h after the injection, small spike and wave complexes repeatedly appeared for a short period of time in cortical leads and cats exhibited behavioral arrest with unresponsiveness during the seizures. About 24 h after the injection, generalized small spike and wave complexes were observed intermittently in cortical and subcortical structures. They persisted for 4-5 s and were associated with behavioral arrest and staring. The results demonstrate that a unilateral microinjection of kainic acid into VPL induced petit mal-like seizure, and suggest that VPL plays an important role in the generation or transfer of spike and wave complexes.

Propagation of Acute Seizure Activities Observed by Local Cerebral Glucose Metabolism

Abstract: We studied the propagation of acute focal seizure activities in animals by means of the [14C]deoxyglucose method. Seizures were induced unilaterally by injecting penicillin in the neocortical area 4 and area 9 in the monkey, and by injecting kainic acid in the hippocampus of the rat and in the ventral posterolateral thalamic nucleus of the cat. The earliest and the most consistent propagation was the one to the target structures of the primary focus, mediated through the “preferential” projection pathways. At a more advanced stage, the propagation to the immediately adjoining brain regions occurred, followed by the secondary propagation to the target structures of the adjoining regions. Propagation to the contralateral homologous structure was not a major one at the early stage unless the structure of the primary focus had its own commissural connections.

Altered GABAergic effects on kainic acid-induced seizures in the presence of hippocampal sclerosis in rats.

Although deficient inhibitory action of GABAergic neurons is frequently implicated in the pathogenesis of epileptic seizures, their exact contribution to the epileptogenicity is still controversial. In the present study, we investigated the effects of GABAergic action on kainic acid (KA)-induced hippocampal seizure in rats with or without hippocampal sclerosis (HS). HS was produced by pretreatment of KA (12 mg/kg i.p.) 3 weeks prior to induction of acute KA seizure (8 mg/kg i.p.). After development of epileptiform activity in the hippocampus, either muscimol (50 ng/microliters, 1.0 microliter) or vehicle (phosphate buffer solution, 1.0 microliter) was applied locally in the left dorsal hippocampus through a cannula and electrobehavioral observation was performed continuously for 6 h. The seizures were divided into four stages according to their severity. 7 days after the induction of acute seizure, the rats were sacrificed and subjected to histological examinations. In the rats without HS, muscimol reduced the seizure severity as well as neuronal damage, whereas muscimol facilitated the severity of both indicators in the presence of HS. Muscimol accelerated the propagation of epileptiform activity and the onset of more advanced seizure stages regardless of presence or absence of HS. Our study suggest that the GABAa function has dual effects on the final severity of KA-induced seizure depending on the presence or absence of HS and that it accelerates the rate of seizure development in either condition. The altered GABAa function in the presence of HS would probably modify seizure activity.