Hiroto Iwasa

Effect of localization of missense mutations in SCN1A on epilepsy phenotype severity

Background and Methods: Many missense mutations in the voltage-gated sodium channel subunit gene SCN1A were identified in patients with generalized epilepsy with febrile seizures plus (GEFS+) and severe myoclonic epilepsy of infancy (SMEI), although GEFS+ is distinct from SMEI in terms of clinical symptoms, severity, prognosis, and responses to antiepileptic drugs. The authors analyzed the localization of missense mutations in SCN1A identified in patients with GEFS+ and SMEI to clarify the phenotype-genotype relationships. Results: Mutations in SMEI occurred more frequently in the “pore” regions of SCN1A than did those in GEFS+. These SMEI mutations in the “pore” regions were more strongly associated than mutations in other regions with the presence of ataxia and tendency to early onset of disease. The possibility of participation of ion selectivity dysfunction of the channel in the pathogenesis of SMEI was suggested by a mutation in the pore region (R946C) identified in a SMEI patient. Conclusions: There was a significant phenotype-genotype relationship in generalized epilepsy with febrile seizures plus and severe myoclonic epilepsy of infancy with SCN1A missense mutations. More severe sodium channel dysfunctions including abnormal ion selectivity that are caused by mutations in the pore regions may be involved in the pathogenesis of SMEI.

Defective function of GABA-containing synaptic vesicles in mice lacking the AP-3B clathrin adaptor

AP-3 is a member of the adaptor protein (AP) complex family that regulates the vesicular transport of cargo proteins in the secretory and endocytic pathways. There are two isoforms of AP-3: the ubiquitously expressed AP-3A and the neuron-specific AP-3B. Although the physiological role of AP-3A has recently been elucidated, that of AP-3B remains unsolved. To address this question, we generated mice lacking μ3B, a subunit of AP-3B. μ3B−/− mice suffered from spontaneous epileptic seizures. Morphological abnormalities were observed at synapses in these mice. Biochemical studies demonstrated the impairment of γ-aminobutyric acid (GABA) release because of, at least in part, the reduction of vesicular GABA transporter in μ3B−/− mice. This facilitated the induction of long-term potentiation in the hippocampus and the abnormal propagation of neuronal excitability via the temporoammonic pathway. Thus, AP-3B plays a critical role in the normal formation and function of a subset of synaptic vesicles. This work adds a new aspect to the pathogenesis of epilepsy.

Genetics of epilepsy: current status and perspectives

Epilepsy affects more than 0.5% of the worlds population and has a large genetic component. The most common human genetic epilepsies display a complex pattern of inheritance and the susceptibility genes are largely unknown. However, major advances have recently been made in our understanding of the genetic basis of monogenic inherited epilepsies. Progress has been particularly evident in familial idiopathic epilepsies and in many inherited symptomatic epilepsies, with the discovery that mutations in ion channel subunits are implicated, and direct molecular diagnosis of some phenotypes of epilepsy is now possible. This article reviews recent progress made in molecular genetics of epilepsy, focusing mostly on idiopathic epilepsy, and some types of myoclonus epilepsies. Mutations in the neuronal nicotinic acetylcholine receptor alpha4 and beta2 subunit genes have been detected in families with autosomal dominant nocturnal frontal lobe epilepsy, and those of two K(+) channel genes were identified to be responsible for underlying genetic abnormalities of benign familial neonatal convulsions. The voltage-gated Na(+) -channel (alpha1,2 and beta1 subunit), and GABA receptor (gamma2 subunit) may be involved in the pathogenesis of generalized epilepsy with febrile seizure plus and severe myoclonic epilepsy in infancy. Mutations of Ca(2+)-channel can cause some forms of juvenile myoclonic epilepsy and idiopathic generalized epilepsy. Based upon these findings, pathogenesis of epilepsy as a channelopathy and perspectives of molecular study of epilepsy are discussed.

The synchronization between brain areas under motor inhibition process in humans estimated by event-related EEG coherence.

To investigate the functional connection of brain areas under motor inhibition, the event-related coherence (ERCoh) of the electroencephalogram (EEG) was calculated for 10 subjects who were asked to perform a visual discrimination (GO/NO-GO) task. The subjects were instructed to push (GO) or not to push (NO-GO) a micro-switch according to different visual stimuli. Twenty-one-channel scalp EEGs were recorded and the surface Laplacians were calculated at F3, F4, C3, C4, P3 and P4 using the source derivation method. The time-courses of the inter- and intra-hemispheric coherence were calculated using the fast Fourier transform for each condition (GO or NO-GO), and were compared statistically between the two conditions. The results suggest that the ERCoh under the NO-GO condition consisted of two components; alpha band synchronization between bilateral frontal areas and theta band synchronization among bilateral frontal, central and parietal areas. It is likely that the former is related directly to the decision not to move, and the latter is related to the motor inhibition process.

EVENT-RELATED DYNAMICS OF THE GAMMA-BAND OSCILLATION IN THE HUMAN BRAIN : INFORMATION PROCESSING DURING A GO/NOGO HAND MOVEMENT TASK

To investigate the gamma band activity relating to the discrimination process and motor behavior in the human brain, the event-related dynamics of the EEG spectrum was calculated during the visual GO/NOGO hand movement task and a control task (the visual element of the GO/NOGO task only) in eight subjects. The subjects were instructed to push (GO) or not to push (NOGO) a microswitch according to different visual stimuli and 21-channel scalp EEGs were recorded. The time courses of the power spectra after the stimuli were calculated using the fast Fourier transform for each condition (GO, NOGO and the control task), and were compared statistically between the conditions. The results suggested that a high gamma band oscillation, occurring at the frontal and left parieto-occipital areas at around 90 ms after the stimuli, relates to the discrimination process. Under the GO condition, this oscillation continued until 140 ms, and a subsequent oscillation occurred over the motor areas at around 200 ms, which seemed to be related to the motor action. On the other hand, under the NOGO condition, a low gamma band oscillation occurred in the central area at around 230 ms, which seemed to be related to the inhibition process.

Changes of Hippocampal Glucose Utilization Subsequent to Amygdaloid-Kindled Generalized Seizures

SUMMARY: Local changes in cerebral glucose utilization during the postictal phase of amygdaloid‐kindled generalized seizures were studied with the quantitative autoradiographic 2‐[14C]deoxyglucose method in conscious rats. Measurement was initiated either just after termination of a behavioral seizure (GS‐I) or 30 s after seizure termination (GS‐II) to determine dynamic metabolic changes in the postictal phase. Although glucose utilization of the neocortex was remarkably depressed in both GS‐I and GS‐II, that of the hippocampus significantly increased in GS‐I and then decreased in GS‐II as compared with control. These changes of hippocampal glucose utilization were observed in all sectors of the pyramidal cell layer (CA 1–4) and in the molecular layer. Because metabolic changes associated with development of amygdaloid‐kindled seizures begin in the limbic structures including the hippocampus, the transient increase in hippocampal glucose utilization observed in the early postictal phase indicates that the hippocampus is one of the key structures not only for initiating and maintaining but also for terminating kindled seizures.

A community intervention trial of multimodal suicide prevention program in Japan: A Novel multimodal Community Intervention program to prevent suicide and suicide attempt in Japan, NOCOMIT-J

BackgroundTo respond to the rapid surge in the incidence of suicide in Japan, which appears to be an ongoing trend, the Japanese Multimodal Intervention Trials for Suicide Prevention (J-MISP) have launched a multimodal community-based suicide prevention program, NOCOMIT-J. The primary aim of this study is to examine whether NOCOMIT-J is effective in reducing suicidal behavior in the community.Methods/DesignThis study is a community intervention trial involving seven intervention regions with accompanying control regions, all with populations of statistically sufficient size. The program focuses on building social support networks in the public health system for suicide prevention and mental health promotion, intending to reinforce human relationships in the community. The intervention program components includes a primary prevention measures of awareness campaign for the public and key personnel, secondary prevention measures for screening of, and assisting, high-risk individuals, after-care for individuals bereaved by suicide, and other measures. The intervention started in July 2006, and will continue for 3.5 years. Participants are Japanese and foreign residents living in the intervention and control regions (a total of population of 2,120,000 individuals).DiscussionThe present study is designed to evaluate the effectiveness of the community-based suicide prevention program in the seven participating areas.Trial registrationUMIN Clinical Trials Registry (UMIN-CTR) UMIN000000460.

The time course of interhemispheric EEG coherence during a GO/NO-GO task in humans

Event-related coherence of the EEG was calculated for 10 subjects performing a visual discrimination GO/NO-GO task. The subjects were instructed to push (GO) or not to push (NO-GO) a button according to visual stimuli. Twenty-one-channel scalp EEGs were recorded and the surface Laplacian was calculated using the source derivation method. The time courses of the coherence between F3 and F4, C3 and C4, and P3 and P4 were calculated using the fast Fourier transform for each task and were compared between conditions. Statistical analysis showed that coherence in the NO-GO condition became significantly higher than that in the GO condition between F3 and F4. The synchronization between bilateral dorsolateral frontal areas might therefore play an important role in the motor inhibition process.

Marital Status of Patients with Epilepsy with Special Reference to the Influence of Epileptic Seizures on the Patient's Married Life

Summary:  Purpose: We investigated the marital status of the patients with epilepsy to clarify the clinical factors impeding improvement of the quality of life in adults with epilepsy.

Physical and Psychomotor Development in the Offspring Born to Mothers with Epilepsy

Summary:  Psychomotor development of 71 children born to mothers with epilepsy was prospectively studied and compared to those of 99 controls matched for age, maternal educational level and age, and socioeconomic status. Intrauterine growth retardation disappeared before age 3 years. Assessment at age 1.5 years revealed that exposure to seizures, high dose of antiepileptic drugs (AEDs) in utero, and small head circumference at birth affected development quotient (DQ) scores of motor or linguistic abilities or both. DQ scores of motor ability of children of mothers with complex partial seizures were lower than those with simple partial seizures when assessed at age 3 years. Assessments at age 1.5 years revealed that the total daily dose of AEDs correlated negatively with DQ scores of motor ability, and at age 3 years, maternal educational level affected DQ scores of some fields, including linguistic ability. The effects of AED exposure in utero and the occurrence of maternal seizures on the development of offspring were found to matter more at the younger age, but later on, the child care environment and, in particular, maternal ability of child‐rearing, became more important. Our findings indicate that careful and regular follow‐ups are needed to monitor the developmental stages of children of mothers with epilepsy, and the introduction of a day nursery should be suggested if necessary.