Language Lateralization by Passive Auditory fMRI in Presurgical Assessment for Temporal Lobe Epilepsy: A Single-Center Retrospective Study.

Background: In temporal lobe epilepsy (TLE), estimating the potential risk of language dysfunction before surgery is a necessary procedure. Functional MRI (fMRI) is considered the most useful to determine language lateralization noninvasively. However, there are no standardized language fMRI protocols, and several issues remain unresolved. In particular, the language tasks normally used are predominantly active paradigms that require the overt participation of patients, making assessment difficult for pediatric patients or patients with intellectual disabilities. In this study, task-based fMRI with passive narrative listening was applied to evaluate speech comprehension to estimate language function in Japanese-speaking patients with drug-resistant TLE. Methods: Twenty-one patients (six with intellectual disabilities) participated. Patients listened to passive auditory stimuli with combinations of forward and silent playback, and forward and backward playback. The activation results were extracted using a block design, and lateralization indices were calculated. The obtained fMRI results were compared to the results of the Wada test. Results: The concordance rate between fMRI and the Wada test was 95.2%. Meaningful responses were successfully obtained even from participants with intellectual disabilities. Conclusions: This passive fMRI paradigm can provide safe and easy presurgical language evaluation, particularly for individuals who may not readily engage in active paradigms.

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 mu3B, a subunit of AP-3B. mu3B-/- mice suffered from spontaneous epileptic seizures. Morphological abnormalities were observed at synapses in these mice. Biochemical studies demonstrated the impairment of gamma-aminobutyric acid (GABA) release because of, at least in part, the reduction of vesicular GABA transporter in mu3B-/- 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.

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.

BACKGROUND: To 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/DESIGN: This 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). DISCUSSION: The present study is designed to evaluate the effectiveness of the community-based suicide prevention program in the seven participating areas. TRIAL REGISTRATION: UMIN Clinical Trials Registry (UMIN-CTR) UMIN000000460.

[Psychiatric and Psychological Comorbidities in Epilepsy: Clinical Features and Psychiatric Management].

Psychiatric comorbidities, including mood, anxiety, psychotic disorders, and autism spectrum disorder are common in patients with epilepsy (PWE), often occurring at rates 2-3-fold or higher than in the general population without epilepsy. Furthermore, an attention should be paid to psychiatric symptoms together with those caused by antiepileptic drug therapy, epilepsy surgery, and vagus nerve stimulation because these therapies sometimes induce psychiatric comorbidities. It is important to differentiate psychogenic non epileptic seizures (PNES) from epilepsy, and to provide patients with psychiatric treatment. We focused on the process and certainty of diagnosis and the managements of PNES. An accurate, undistorted understanding of the relationship between mental status and epilepsy is essential to ensure appropriate therapy and avoid misconceptions and unnecessary treatment. Psychiatric and psychological states should be evaluated at the time of the first visit in every PWE and patients should be provided adequate psychiatric therapy if necessary within the overall therapeutic plan.

Ictal dipole source analysis based on a realistic scalp-skull-brain head model in localizing the epileptogenic zone.

The objective of this study is to examine whether dipole modeling based on a realistic scalp-skull-brain head model (SSB/DT) is useful to localize the epileptogenic zone. Eight patients with surgically treated temporal lobe epilepsy were studied. Dipole locations and vector moments of ictal epileptiform activities were calculated by inverse solution methods. Accuracy of dipole locations were assessed by comparing with intracranial EEG. The patterns of ictal epileptiform activities were correlated with the dipole location and vector moment. Dipole locations of the peaks of ictal epileptiform activities estimated by SSB/DT showed good agreement with the epileptogenic foci determined by intracranial EEG. SSB/DT was able to discriminate between medial and lateral temporal epileptogenic foci. Two distinctive types of dipole vector moments, vertical and horizontal were noted. Vertical dipole vector moments corresponded to the medial temporal dipole source and horizontal dipole vector moments were corresponded to the lateral temporal dipole source. Useful clues to differentiate between medial and lateral temporal lobe epilepsy by the visual inspection of scalp EEG were found. SSB/DT is useful tool in the presurgical evaluation of patients with intractable epilepsy.

Transient gamma-band response is dissociated from sensory memory as reflected by MMN.

The auditory gamma-band transient oscillatory response has been considered to reflect early cognitive processing and attention triggering, as has been suggested of the mismatch negativity (MMN). We examined whether the auditory gamma-band response was related to sensory memory as reflected by MMN. During the electroencephalogram (EEG) recordings, approximately 2000 click sounds were presented to nine healthy adult subjects with constant SOA of 120 or 170 ms in an ignored condition. At a probability of 10%, a click sound was randomly omitted from the stimulus sequence. EEG epochs responding to omitted clicks and to click sounds were averaged for analysis, respectively, and then those were convoluted by Gabor wavelet for the gamma-band response calculation. The MMN to a deviant omission in a sequence of click sounds was elicited with SOA of 120 ms which was shorter than the duration of temporal window of integration, whereas no MMN was elicited with SOA of 170 ms. In contrast with the MMN, the transient gamma-band response clearly commenced after the stimuli but not after the omissions, regardless whether SOA was short or long. The findings indicate that the brain process underlying the transient gamma-band response should be dissociated from the sensory memory function.

Genetics of epilepsy: current status and perspectives.

Epilepsy affects more than 0.5% of the world's 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.

Involvement of highly polysialylated neural cell adhesion molecule (PSA-NCAM)-positive granule cells in the amygdaloid-kindling-induced sprouting of a hippocampal mossy fiber trajectory.

The mossy fiber system in the hippocampus of amygdaloid-kindled rats was examined by using highly polysialylated neural cell adhesion molecule (PSA-NCAM) as a marker for immunohistochemical detection of immature dentate granule cells and mossy fibers in combination with bromodeoxyuridine (BrdU) labeling of newly generated granule cells. Statistically significant increases in BrdU-labeled cells and PSA-NCAM-positive cells occurred in the dentate gyrus following kindling. The increase in PSA-NCAM-immunoreactive neurites was confined to the entire stratum lucidum of CA3. Immunoelectron-microscopic examination also revealed that PSA-NCAM-positive immature synaptic terminals of the sprouting mossy fibers increased in the stratum lucidum of CA3 in the kindled rats. The increase in the numbers of PSA-NCAM-positive granule cells correlated well with the increase in the immunopositive neurites and synaptic terminals on the mossy fiber trajectory. The increase in these PSA-NCAM-immunopositive structures is thought to reflect the enhancement of sprouting and synaptogenesis of mossy fibers by a subset of granule cells newly generated during amygdaloid-kindling and suggests that the reorganization of the mossy fiber system on the normal trajectory at least in part contributes to the acquisition and maintenance of an epileptogenic state.

Different patterns of dipole source localization in gelastic seizure with or without a sense of mirth.

Dipole source localization corresponding to interictal spikes were estimated using EEG dipole tracing with a realistic three-shell head model in three patients with cryptogenic gelastic epilepsy. The dipole sources in two patients, whose gelastic seizures were accompanied by a subjective feeling of mirth, were estimated in the right or left medio-basal temporal regions. In the other patient, with gelastic seizures without a sense of mirth, the dipole sources were localized in the right frontal region corresponding to the anterior cingulate. The results suggest that the neural activities in hippocampal regions are involved with the generation of gelastic seizures with a sense of mirth and those in the cingulate might be associated with the motor act of laughter.

[Mechanisms of interaction between adenosine receptor subtypes on hippocampal serotonin release].

To clarify the mechanisms of interaction between adenosine receptor subtypes (A1R and A2R) on 5-HT release, the present study determined the effects of adenosine receptor subtypes on voltage-sensitive Ca(2+)-channels (VSCCs), protein-kinases (PKs) and synaptic-proteins (SNAREs) related 5-HT release using microdialysis in freely moving rat. A1R-antagonists increased basal 5-HT release, which was reduced by inhibitors of N-VSCC, PKC and syntaxin predominantly, and by inhibitors of PKA and synaptobrevin weakly, but was not affected by P-VSCC inhibitor. In the presence of A1R-antagonist, A2R-agonists increased basal 5-HT release, whose action was inhibited by P-VSCC, PKA and synaptobrevin inhibitors predominantly and reduced by N-VSCC, PKC and syntaxin inhibitors weakly. Under the condition of adenylate-cyclase activation in the absence of A1R-antagonists, A2R-agonists increased basal 5-HT release. K(+)-evoked 5-HT release was enhanced by A1R-antagonist and A2R-agonist, whose actions were inhibited by P-VSCC, PKA and synaptobrevin inhibitors predominantly. These results suggest that an activation of A1R suppresses 5-HT release via an inhibition of N-VSCC/PKC/syntaxin and P-VSCC/PKA/synaptobrevin, and an activation of A2-R stimulates 5-HT release via an enhancement of P-VSCC/PKA/synaptobrevin. Therefore PKA activity plays an important role in the interaction between A1R and A2R on hippocampal 5-HT release.

Effectiveness of a multimodal community intervention program to prevent suicide and suicide attempts: a quasi-experimental study.

BACKGROUND: Multilevel and multimodal interventions have been suggested for suicide prevention. However, few studies have reported the outcomes of such interventions for suicidal behaviours. METHODS: We examined the effectiveness of a community-based multimodal intervention for suicide prevention in rural areas with high suicide rates, compared with a parallel prevention-as-usual control group, covering a total of 631,133 persons. The effectiveness was also examined in highly populated areas near metropolitan cities (1,319,972 persons). The intervention started in July 2006, and continued for 3.5 years. The primary outcome was the incidence of composite outcome, consisting of completed suicides and suicide attempts requiring admission to an emergency ward for critical care. We compared the rate ratios (RRs) of the outcomes adjusted by sex, age group, region, period and interaction terms. Analyses were performed on an intention-to-treat basis and stratified by sex and age groups. FINDINGS: In the rural areas, the overall median adherence of the intervention was significantly higher. The RR of the composite outcome in the intervention group decreased 7% compared with that of the control group. Subgroup analyses demonstrated heterogeneous effects among subpopulations: the RR of the composite outcome in the intervention group was significantly lower in males (RR = 0.77, 95% CI 0.59-0.998, p = 0.0485) and the RR of suicide attempts was significantly lower in males (RR = 0.39, 95% CI 0.22-0.68, p = 0.001) and the elderly (RR = 0.35, 95% CI 0.17-0.71, p = 0.004). The intervention had no effect on the RR of the composite outcome in the highly populated areas. INTERPRETATION: Our findings suggest that this community-based multimodal intervention for suicide prevention could be implemented in rural areas, but not in highly populated areas. The effectiveness of the intervention was shown for males and for the elderly in rural areas. TRIAL REGISTRATION: ClinicalTrials.gov NCT00737165 UMIN Clinical Trials Registry UMIN000000460.

Development of individualized medicine for epilepsy based on genetic information.

Despite the continuous development and release of new anti-epileptic drugs (AEDs), almost one in four patients are resistant to AED therapy. Current therapy requires trial and error to determine the most effective AED and dosage for a patient. The development of individualized medicine for epilepsy is critical for improving AED treatment, particularly that based on genetic information. However, several crucial issues remain to be resolved before the development of AED therapy can proceed further. The epilepsy genes responsible for common phenotypes have not yet been identified and ongoing pharmacogenetic studies continue to search for an explanation as to why 20-25% of patients do not respond to AEDs. There is no convincing clinical evidence that P-glycoprotein at the blood-brain barrier limits the uptake of AEDs into the brain of epileptic patients and contributes to the development of the drug-resistant phenotype. This article provides a critical review of the status and perspectives for the development of individualized medicine for epilepsy, based on genetic polymorphisms/mutations in relation to three major components: the pharmacodynamic pathway, the pharmacokinetic pathway and the mechanisms of action of AEDs. The development of multiplex assay technologies, together with the generation of epilepsy animal models bearing human epilepsy genes, are also discussed.

Genetic identifiers of epilepsy.

Epilepsy affects >0.5% of the world's population and has a large genetic component. The most common human genetic epilepsies display a complex pattern of inheritance, and the identity of the susceptibility genes is largely unknown despite recent advances in molecular biology. However, genetic identifiers of certain types of epilepsy with neurodegenerative characteristics and of a small number of familial idiopathic epilepsies have been uncovered to date. This article reviews recent progress made in molecular genetics of epilepsy, focusing mostly on idiopathic epilepsy together with our own discovery of novel mutations in the genes of autosomal dominant nocturnal frontal lobe epilepsy and benign familial neonatal convulsions (BFNCs), and the genetic locus of benign adult familial myoclonic epilepsy. Pathogenesis of epilepsy as a channelopathy and of BFNC also is discussed.

Physical and psychomotor development in the offspring born to mothers with epilepsy.

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.

Marital status of patients with epilepsy with special reference to the influence of epileptic seizures on the patient's married life.

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. METHODS: We examined the marital status of adult patients with epilepsy who did not have mental retardation and had been treated at Hirosaki University Hospital, Hirosaki, Japan, for >5 years. The present study included 278 patients (142 men and 136 women) ranging from age 20 to 60 years. RESULTS: Sixty-six men and 52 women were single. Seventy-six males and 84 females had been married. The present study investigated the proportion of patients in whom seizures were controlled at the time of marriage. Percentages were only 30% for men and 22% for women. This result showed that in many patients, seizures were not controlled when they were married, which suggests that seizures themselves may not markedly inhibit marriage. Thirteen men and 16 women (total, 29 patients) had experienced divorce. Epilepsy was the cause of divorce in seven of the 29 patients who had been divorced. Of these seven patients, only one patient had informed the spouse of the disease before marriage. In the remaining six patients, seizures were witnessed after marriage or the disease was revealed by medication, which resulted in divorces. CONCLUSIONS: Concerning the association between marriage and the job, a close relation was found between the presence or absence of marriage and the presence or absence of a job among male patients.