Enhancement of morphine-induced antinociception after electroconvulsive shock in mice.

Electroconvulsive therapy (ECT) has been applied for chronic pain for decades. The amounts of opioids to treat pain are sometimes reduced after a series of ECT. The effect of ECT on morphine-induced analgesia and its mechanism underlying the reduction of morphine requirement has yet to be clarified. Therefore, we administered electroconvulsive shocks (ECS) to mice and investigated the antinociceptive effect of morphine in a hot plate test. We examined the expression level of µ-opioid receptor in the thalami of mice 25 h after administration of ECS compared to the thalami of mice without ECS administration using western blotting. ECS disturbed the development of a decrease in the percentage of maximal possible effect (%MPE), which was observed 24 h after a morphine injection, when ECS was applied 25, 23, 21, and 12 h before the second administration of morphine. We also examined the effect of ECS on the dose-response curve of %MPE to morphine-antinociception. Twenty-five hours after ECS, the dose-response curve was shifted to the left, and the EC50 of morphine given to ECS-pretreated mice decreased by 30.1% compared to the mice that were not pretreated with ECS. We also found that the expression level of µ-opioid receptors was significantly increased after ECS administration. These results confirm previous clinical reports showing that ECT decreased the required dose of opioids in neuropathic pain patients and suggest the hypothesis that this effect of ECT works through the thalamus.

Standardization of Brief Inventory of Social Support Exchange Network (BISSEN) in Japan.

This study describes the Brief Inventory of Social Support Exchange Network (BISSEN) as a standardized brief inventory measuring various aspects of social support. We confirmed the reliability and validity for function and direction of support and standardized the BISSEN. For Sample 1, a stratified random sampling method was used to select 5200 residents in Japan. We conducted mail surveys and responses were retrieved from 2274 participants (collection rate 43.7%). Participants completed a questionnaire packet that included BISSEN, suicidal ideation, depression, support seeking, and Multidimensional Scale of Perceived Social Support (MSPSS). Sample 2 surveys for test-retest reliability were conducted on 23 residents at approximately two-week intervals. Participants were asked about gender, age, and BISSEN. First, we assessed the internal consistency, test-retest reliability, construct, convergent, and concurrent validity. McDonald's omega (.73-.92) and test-retest correlations (.78-.85) demonstrated adequate internal consistency and test-retest reliability. Depression, support seeking, and MSPSS were significantly correlated with all scores of BISSEN. The non-suicidal ideation group had significantly more support compared to the suicidal ideation group. Therefore, function and direction of support in BISSEN had sufficient reliability and validity. Next, we standardized BISSEN using Z-scores and percentile rank with respect to each 12 norm groups by age and gender.

How perceived social support relates to suicidal ideation: a Japanese social resident survey.

BACKGROUND: The loss of social support is one of the major risk factors for suicide. However, there are few empirical studies that have examined how a person's suicide ideation relates to their social support. AIMS: To examine the relationship between social support and suicidal ideation. METHODS: Self-report questionnaires were sent to 2,200 randomly selected adults in Japan. The questionnaire inquired the participants about the severity of suicidal ideation, the details of current perceived social support and their degree of satisfaction with this social support. Social support and related indicators were compared among three groups of participants that varied in severity of suicidal ideation. RESULTS: People in the group that had suicide ideation during their lives reported receiving significantly less support from their family and had greater feelings of dissatisfaction with that support than those in the other groups. Furthermore, people who had suicide ideation during the month immediately preceding the survey reported providing less support to their family, relatives or friends, as well as receiving less support from family than other groups, and having stronger feelings of dissatisfaction with social support. CONCLUSION: Our study identified a strong relationship between the severity of suicidal ideation and perceived social support.

[Pathways from initial symptoms to psychiatric treatment in patients with schizophrenia].

Early intervention is essential for improving the long-term prognosis of schizophrenic patients. With the objective of contributing to early treatment in communities in the future, we retrospectively investigated patient data, including the pathway to psychiatric care, the course prior to consultation, and initial symptoms. An interview survey was conducted involving a total of 125 patients receiving treatment for a diagnosis of schizophrenia and 74 family members using two questionnaire sheets to collect data on the pathway to psychiatric care, age at onset, time between onset and the initiation of treatment, initial symptoms, and the necessary information. For the pathway to psychiatric care, facilities were classified into : psychiatric clinic, psychiatric hospital, psychiatric department of a general hospital, and general practices, and tendencies were investigated. As for the initial symptoms, differences between those recognized by the patients themselves and their families were investigated. The results showed that approximately 80% of patients had first visited medical facilities, while the remaining patients had consulted psychologists, school nurses, teachers, or public health centers. The mean time from onset to initial psychiatric consultation was 24.7 ± 3.3 months, with a median period of 6.0 months. This duration was particularly long among patients who first visited general practitioners. As the initial symptoms, 70% of patients had psychiatric symptoms as subjective symptoms, and more than 70% of family members equally noticed psychiatric symptoms. On the other hand, 40% of patients had positive symptoms, but only 20% of family members had noticed the positive symptoms. A total of 30% of patients had been aware of somatic symptoms, and these patients were significantly more likely to initially visit physicians in a department other than the psychiatric department. As for delay in consultation, patients who had onsets at an early age tended to take longer to make the initial visit. The above findings confirmed the necessity of disease education at schools, given that onset can occur in school-age children, as well as the establishment of a mental health network, understanding of psychiatric diseases among primary care physicians and their cooperation with psychiatrists, and increased public awareness regarding psychiatric diseases.

Paradox of schizophrenia genetics: is a paradigm shift occurring?

BACKGROUND: Genetic research of schizophrenia (SCZ) based on the nuclear genome model (NGM) has been one of the most active areas in psychiatry for the past two decades. Although this effort is ongoing, the current situation of the molecular genetics of SCZ seems disappointing or rather perplexing. Furthermore, a prominent discrepancy between persistence of the disease at a relatively high prevalence and a low reproductive fitness of patients creates a paradox. Heterozygote advantage works to sustain the frequency of a putative susceptibility gene in the mitochondrial genome model (MGM) but not in the NGM. METHODS: We deduced a criterion that every nuclear susceptibility gene for SCZ should fulfill for the persistence of the disease under general assumptions of the multifactorial threshold model. SCZ-associated variants listed in the top 45 in the SZGene Database (the version of the 23rd December, 2011) were selected, and the distribution of the genes that could meet or do not meet the criterion was surveyed. RESULTS: 19 SCZ-associated variants that do not meet the criterion are located outside the regions where the SCZ-associated variants that could meet the criterion are located. Since a SCZ-associated variant that does not meet the criterion cannot be a susceptibility gene, but instead must be a protective gene, it should be linked to a susceptibility gene in the NGM, which is contrary to these results. On the other hand, every protective gene on any chromosome can be associated with SCZ in the MGM. Based on the MGM we propose a new hypothesis that assumes brain-specific antioxidant defenses in which trans-synaptic activations of dopamine- and N-methyl-d-aspartate-receptors are involved. Most of the ten predictions of this hypothesis seem to accord with the major epidemiological facts and the results of association studies to date. CONCLUSION: The central paradox of SCZ genetics and the results of association studies to date argue against the NGM, and in its place the MGM is emerging as a viable option to account for genomic and pathophysiological research findings involving SCZ.

Schizophrenia: maternal inheritance and heteroplasmy of mtDNA mutations.

Role of mitochondrial pathology in schizophrenia has not been fully clarified. We searched for distinctive variants in mtDNA extracted from the gray matter of postmortem brains and from peripheral blood samples. We screened mtDNA region containing 5 genes encoding subunits of cytochrome c oxidase and ATPases. Polymorphisms not already reported in databases are recorded as unregistered rare variants. Four unregistered, non-synonymous rare variants were detected in 4 schizophrenic samples. Seven registered non-synonymous variants were not previously detected in non-psychotic Japanese samples registered in the mtSNP database. These variants may contribute to disease pathophysiology. In one family, compound mutations showed co-segregation with schizophrenia. MtDNA mutations could confer a risk for schizophrenia in the Japanese population, although further analyses are needed.

Improvements in both psychosis and motor signs in Parkinson's disease, and changes in regional cerebral blood flow after electroconvulsive therapy.

PURPOSE: Psychotic symptoms in Parkinson's disease (PD) are relatively common and, in addition to creating a disturbance in patients' daily lives, have consistently been shown to be associated with poor outcome. The use of anti-PD medications has been the most widely identified risk factor for PD psychosis (PDP). However, the pathophysiology of PDP remains unclear. Although the efficacy of electroconvulsive therapy (ECT) for PD had been pointed out, only one study has demonstrated the effectiveness of ECT on both psychotic symptoms and motor symptoms. The aim of this study was to examine the acute effectiveness of ECT on PD and to identify the brain areas associated with PDP. METHODS: The study was conducted at Juntendo University Hospital in Tokyo. Eight patients with L-DOPA- or dopamine (DA) agonist-induced PDP, who were resistant to quetiapine treatment, were enrolled. Severity of PD was evaluated using the Hoehn and Yahr stage. Psychotic symptoms were evaluated using multiple measures from the Scale for the Assessment of Positive Symptoms (SAPS). Technetium-99m ethyl cysteinate dimer single photon emission computed tomography (99mTc ECD SPECT) was used to assess regional cerebral blood flow (rCBF) before and after a course of ECT. A voxel-by-voxel group analysis was performed using Statistical Parametric Mapping (SPM5). RESULTS: Our study clearly demonstrated that PDP was significantly less severe after ECT than before ECT, as indicated by change in mean SAPS total domain score (t=7.2, P=0.0002). Furthermore, the patients showed significant improvement in Hoehn and Yahr stage after ECT (t=11.7, P<0.0001). A further notable observation was significant increase in rCBF in the right middle frontal gyrus after ECT. CONCLUSION: We conclude that a course of ECT produced notable improvements not only in PDP but also in the severity of PD. The findings of change in rCBF suggest implications for dysfunction in the middle frontal region for patients with PDP.

Brain perfusion in fibromyalgia patients and its differences between responders and poor responders to gabapentin.

INTRODUCTION: The aim of the present study was to determine the brain areas associated with fibromyalgia, and whether pretreatment regional cerebral blood flow (rCBF) can predict response to gabapentin treatment. METHODS: A total of 29 women with fibromyalgia and 10 healthy women (without pain) matched for age were finally enrolled in the study. Technetium-99m ethyl cysteinate dimer single photon emission computed tomography ((99m)Tc-ECD SPECT) was performed in the fibromyalgia patients and controls. A voxel-by-voxel group analysis was performed using Statistic Parametric Mapping 5 (SPM5). After treatment with gabapentin, 16 patients were considered 'responders', with decrease in pain of greater than 50% as evaluated by visual analogue scale (VAS). The remaining 13 patients were considered 'poor responders'. RESULTS: We observed rCBF abnormalities, compared to control subjects, in fibromyalgia including hypoperfusion in the left culmen and hyperperfusion in the right precentral gyrus, right posterior cingulate, right superior occipital gyrus, right cuneus, left inferior parietal lobule, right middle temporal gyrus, left postcentral gyrus, and left superior parietal lobule. Compared to responders, poor responders exhibited hyperperfusion in the right middle temporal gyrus, left middle frontal gyrus, left superior frontal gyrus, right postcentral gyrus, right precuneus, right cingulate, left middle occipital gyrus, and left declive. The right middle temporal gyrus, left superior frontal gyrus, right precuneus, left middle occipital gyrus, and left declive exhibited high positive likelihood ratios. CONCLUSIONS: The present study revealed brain regions with significant hyperperfusion associated with the default-mode network, in addition to abnormalities in the sensory dimension of pain processing and affective-attentional areas in fibromyalgia patients. Furthermore, hyperperfusion in these areas was strongly predictive of poor response to gabapentin.

A case of adult-onset type II citrullinemia with comorbid epilepsy even after liver transplantation.

The current study using single case voxel-based morphometry (VBM) of magnetic resonance imaging (MRI) and ¹H-MR-spectroscopy (¹H-MRS) explores the neural background of unexplained seizure attacks and electroencephalography (EEG) abnormalities persisting even after liver transplantation in a patient with adult-onset type II citrullinemia (CTLN2). Although the MRI had shown no gross abnormality, the VBM revealed significantly smaller-than-normal regional volume in the left hippocampus of the patient as compared with 111 age-matched controls. ¹H-MRS further indicated reduction of all metabolite concentrations in the left hippocampus compared with those in the right homolog region, with the single exception of elevated glutamate concentration. These results are similar to those of patients with mesial temporal lobe epilepsy (TLE), although CTLN2-complicated mesial TLE has rarely been reported. In contrast to TLE, periictal asterixis and interictal slow activities on EEG support another possibility that the patient might have slight metabolic encephalopathy even after the liver transplantation.

Persistence criteria for susceptibility genes for schizophrenia: a discussion from an evolutionary viewpoint.

BACKGROUND: The central paradox of schizophrenia genetics is that susceptibility genes are preserved in the human gene-pool against a strong negative selection pressure. Substantial evidence of epidemiology suggests that nuclear susceptibility genes, if present, should be sustained by mutation-selection balance without heterozygote advantage. Therefore, putative nuclear susceptibility genes for schizophrenia should meet special conditions for the persistence of the disease as well as the condition of bearing a positive association with the disease. METHODOLOGY/PRINCIPAL FINDINGS: We deduced two criteria that every nuclear susceptibility gene for schizophrenia should fulfill for the persistence of the disease under general assumptions of the multifactorial threshold model. The first criterion demands an upper limit of the case-control difference of the allele frequencies, which is determined by the mutation rate at the locus, and the prevalence and the selection coefficient of the disease. The second criterion demands an upper limit of odds ratio for a given allele frequency in the unaffected population. When we examined the top 30 genes at SZGene and the recently reported common variants on chromosome 6p with the criteria using the epidemiological data in a large-sampled Finnish cohort study, it was suggested that most of these are unlikely to confer susceptibility to schizophrenia. The criteria predict that the common disease/common variant hypothesis is unlikely to fit schizophrenia and that nuclear susceptibility genes of moderate effects for schizophrenia, if present, are limited to 'rare variants', 'very common variants', or variants with exceptionally high mutation rates. CONCLUSIONS/SIGNIFICANCE: If we assume the nuclear DNA model for schizophrenia, it should have many susceptibility genes of exceptionally high mutation rates; alternatively, it should have many disease-associated resistance genes of standard mutation rates on different chromosomes. On the other hand, the epidemiological data show that pathogenic genes, if located in the mitochondrial DNA, could persist through sex-related mechanisms.

[Electroconvulsive therapy for neurological disorders].

Electroconvulsive therapy (ECT) recovers the brain function through generalized convulsion induced by electrical stimulation of the brain. While the primary targets of ECT are psychiatric disorders such as depression, schizophrenia, and schizoaffective disorder, it has been well documented that ECT has therapeutic effects on muscular rigidity of Parkinson's disease and neuroleptics-induced malignant syndrome. Recently we demonstrated that ECT reduces intractable pain and allodynia associated with deafferentation pain disorders by recovering the function of the thalamic nucleus. ECT, if applied on appropriate clinical assessments, may contribute to the therapeutics of neuropsychiatric disorders.

A resistance gene in disguise for schizophrenia?

We examined the hypothesis that -485 T, a novel polymorphism in the promoter region of the neuropeptide Y gene which was shown to be associated with schizophrenia in our previous paper, confers susceptibility to the disease. For a case-control association study, 331 unrelated Japanese schizophrenics (S(1): milder cases in the previous study, n = 212; and S(2): additional severer cases, n = 119) and 199 unrelated normal controls were recruited. Contribution of -485 T to the risk and the severity of the illness was examined by (1) comparing the risk in each genotype in the general population, (2) testing correlations between the gene-dose of -485 T, and the severity of chronic outcome in S(2) assessed with the Positive and Negative Symptom Scale, and (3) comparing the distribution of age at onset in S(1) + S(2) among the three genotypes. -485 T was significantly associated with schizophrenia in S(1) + S(2). Significant negative correlations were observed between the gene-dose and the symptom assessment scores in all items. The homozygote of -485 T showed a second peak frequency in the late-onset group both in males and females, while the homozygote of the alternative allele showed a single peak in the early-onset group. The higher risk of schizophrenia in the heterozygote than in the homozygote of -485 T in the general population did not support the possibility of linkage disequilibrium with a susceptibility gene. -485 T most likely confers resistance but not susceptibility to schizophrenia. An interaction between a nuclear resistance gene and a presumptive pathogenic gene in the mitochondrial DNA was suggested.

Persistence problem in schizophrenia and mitochondrial DNA.

Schizophrenia, a major psychosis with a strong genetic component, persists over generations despite a clearly reduced reproductive fitness of the patients. This 'persistence' problem has puzzled scientists for long years. A hypothesis of 'balanced polymorphism' proposed by Huxley et al. that the incidence could be sustained by a higher fertility in the siblings of the patients has not been supported by most epidemiological studies. Multiple-genes model, which most geneticists today accept, explains that the loss of susceptibility alleles resulting from the lower fertility of the patients would have a negligible effect on the overall gene pool in the population. We carefully examined the multiple-genes model and proved it cannot account for the persistence problem without unrealistic assumptions and hence the contribution of multiple genes in the nuclear DNA to the heredity of schizophrenia should be considerably limited. We demonstrated a pathogenic gene with a low penetrance, if located in the mitochondrial DNA, could be sustained given a higher fertility of the 'female' siblings and/or a decreased male-female ratio in the offspring of the susceptible females. This hypothesis, coupled with the report which suggests mitochondrial dysfunction in schizophrenia, may encourage a new direction in genetic study of this puzzling disorder.

Electroconvulsive therapy after coil embolization of cerebral aneurysm: a case report and literature review.

We report a case of an uneventful course after electroconvulsive therapy (ECT) of a patient who had undergone coil embolization for an intracranial aneurysm 37 days earlier. There have been no reports until now of ECT after coil embolization. According to histopathologic examinations, it takes approximately 2 weeks after coil embolization for the aneurysm to become fixed. The ECT can be a therapeutic option even in patients with a previous history of coil embolization, as long as it is performed under proper anesthetic management.

Resting hypofrontality in schizophrenia: A study using near-infrared time-resolved spectroscopy.

Hypofrontality has been a major finding obtained from functional neuroimaging studies on schizophrenia, although there have also been contradictory results that have questioned the reality of hypofrontality. In our previous study, we confirmed the existence of activation hypofrontality by using a 2-channel continuous-wave-type (CW-type) near-infrared spectroscopy (NIRS) instrument. In this study, we employed a single-channel time-resolved spectroscopy (TRS) instrument, which can quantify hemoglobin (Hb) concentrations based on the photon diffusion theory, to investigate resting hypofrontality. A pair of incident and detecting light guides was placed on either side of the forehead at approximately Fp2-F8 or Fp1-F7 alternately in 14 male schizophrenic patients and 16 age-matched male control subjects to measure Hb concentrations at rest. The patients were also measured with a 2-channel CW-type NIRS instrument during the performance of a random number generation (RNG) task. A reduced total hemoglobin concentration (t-Hb) less than 60 microM (the mean value of the control subjects-1.5 SD) was observed bilaterally in 4 patients and only in the left side in 3 patients. Activation hypofrontality was more manifest in these patients than in the remaining 7 patients despite the same task performance. This decreased t-Hb was related to the duration of illness, and it was not observed in patients whose duration of illness was less than 10 years. These results indicate that resting hypofrontality is a chronically developed feature of schizophrenia. This does not necessarily represent frontal dysfunction, but may reflect anatomical and/or functional changes in frontal microcirculation.

Electroconvulsive therapy improves severe pain associated with fibromyalgia.

The pathophysiology of fibromyalgia remains unknown. Several reports have recently suggested the novel concept that fibromyalgia is due to the central nervous system becoming hyper-responsive to a peripheral stimulus. The effect of electroconvulsive therapy (ECT) as pain remedication in cases of fibromyalgia without major depressive disorder was studied in a prospective trial lasting three months. All of the patients taking part in the study fulfilled the American College of Rheumatology diagnostic criteria for fibromyalgia. Technetium-99m ethyl cysteinate dimer single photon emission computed tomography was used to assess regional cerebral blood flow (rCBF) before and after a course of ECT. Pain assessment in the patients was undertaken by use of the visual analog scale (VAS) and by evaluation of tender points (TPs). Beck's depression inventory (BDI) was further used to assess depressive mood change in the patients. Our study clearly demonstrated that pain was significantly less severe after ECT, as indicated by the VAS scale for pain and the evaluation of TPs. A further notable observation was that thalamic blood flow was also improved. We conclude that a course of ECT produced notable improvements in both intractable severe pain associated with fibromyalgia and also in terms of thalamic blood flow.