Rimmei Fukuda

Modulation of activity in temporal cortex during generation of inner speech.

Monitoring ones thoughts (in the verbal modality) is thought to be critically dependent on the interaction between areas that generate and perceive inner speech in the frontal and temporal cortex, respectively. We used functional magnetic resonance imaging (fMRI) to examine the relationship between activity in these areas while the rate of inner speech generation was varied experimentally. The faster rate was associated with activation in the left inferior frontal gyrus, the right pre‐ and postcentral gyri and both superior temporal gyri. Thus, temporal cortical activation was associated with increasing the rate of covert articulation, in the absence of external auditory input, suggesting that there is effective fronto‐temporal connectivity. Furthermore, this may provide support for the existence of feed forward models, which suggest that activity in regions responsible for verbal perception is modulated by activity in areas that generate inner speech. Hum. Brain Mapping 16:219–227, 2002.

C677T polymorphism in methylenetetrahydrofolate reductase gene and psychoses

A common missense mutation of the methylenetetrahydrofolate reductase (MTHFR) gene (C677T) has been shown to be a risk factor for premature cardiovascular disease and neural tube defect. Deficient activity of MTHFR has also been implicated in the pathogenesis of psychiatric conditions such as schizophrenia and affective disorders. Arinami et al1 found an increased frequency of homozygosity for the mutated type (T677) of the MTHFR gene in schizophrenia and depression. We tried to replicate this finding in a sample of 343 patients with schizophrenia, 143 with bipolar disorder, 71 with unipolar depression, and 258 controls; however, there was no significantly increased frequency of homozygosity for the T677 allele in any of the diagnostic groups, compared to the controls. Our results suggest that homozygosity for the T677 allele of the MTHFR gene is unlikely to play a major role in the pathogenesis of schizophrenia or affective disorders in our sample.

1H-MR spectroscopy and gray matter volume of the anterior cingulate cortex in schizophrenia.

Schizophrenic and normal control subjects were examined using both 1H-magnetic resonance spectroscopy (MRS) and structural MR imaging, in order to accurately assess the partial volume within the spectroscopic volume of interest (VOI) in the anterior cingulate cortex. The gray matter volume within VOI correlated positively with the N-acetyl-aspartate (NAA) to choline (Cho) ratio in schizophrenics only, not in controls. Schizophrenic patients had a reduced NAA/Cho ratio and an elevated Cho/creatine ratio compared to controls after the partial volume effect was eliminated. There was a significant negative correlation between the NAA/Cho ratio and the severity of blunted affect symptom in schizophrenics. These results provide further support to the idea that the measures of 1H-MRS indicate not only neuronal loss but also neuronal dysfunction in schizophrenia.

A study of the association between schizophrenia and the dopamine D3 receptor gene

A study of the genetic association between schizophrenia and aBalI polymorphism in exon 1 of the dopamine D3 (DRD3) gene, a candidate gene for schizophrenia, was conducted. The polymorphism was examined in 91 patients whose symptoms satisfied DSM-III-R for schizophrenia and 90 controls. There were no significant differences between the groups in allele frequencies or genotype counts. Contrary to a previous report, the patients were no more likely to be homozygous than controls. Moreover, no association with the presence of illness could be demonstrated when the patients were grouped according to sex, age of onset, history of admission to psychiatric institutions or positive family history.

Neurotrophin-3 gene polymorphism associated with schizophrenia.

The recent possible neurodevelopmental etiology of schizophrenia makes the neurotrophin‐3 (NT‐3) gene an interesting candidate locus. We studied the allelic distributions of dinucleotide repeat polymorphism at the NT‐3 gene locus in 70 patients with schizophrenia and in 70 controls. A highly significant difference between the two groups was observed at the allele A3. Even Bonferronis correction was used, the difference was still significant. Individuals with homozygous or heterozygous for the allele A3 had a 2.4‐fold increased risk of schizophrenia. Determination of NT‐3 genotype may help to identify those at greater risk of schizophrenia. Furthermore, this finding supports evidence implicating neurodevelopmental deficit in the pathogenesis of this disorder.

Association of apolipoprotein E4 with sporadic Alzheimer's disease is more pronounced in early onset type

Apolipoprotein E genotypes in 88 unrelated Japanese patients with NINCDS-ADRDA sporadic Alzheimers disease (AD) were examined and compared with those of 93 healthy controls. Frequency of epsilon 4 allele was increased in patients with AD (31%) compared with controls (10%), as was reported previously. Individuals homozygous or heterozygous for the allele epsilon 4 had a 5.9-fold increased risk of AD. This tendency was more pronounced in early onset sporadic (= non-familial) type than late onset type. The relative risk was also greater for early onset type (RR = 11.7; 95% CI, 4.9-28.3) than late onset type (RR = 4.3; 95% CI, 2.1-8.8). Moreover, patients with homozygote for the allele epsilon 4 had a 14.7-fold increased risk of early onset sporadic AD (P < 0.005, chi 2 = 9.0, df = 1, 95% CI, 2.5-85.1). Our findings indicated that association of apolipoprotein epsilon 4 with sporadic Alzheimers disease is more pronounced in early onset type than in late onset type.

Changes of Immunological Functions after Acute Exacerbation in Schizophrenia

We investigated the changes of immunological functions in 14 schizophrenic patients (DSM-III-R; six men and eight women) who were hospitalized due to acute exacerbation of schizophrenia. The following immunological functions were studied on admission, 4 and 8 weeks after admission: serum immunoglobulins (Ig)G, A, and M; serum complement CH50; lymphocyte responses to mitogens (phytohemagglutinin, concanavalin A, and pokeweed mitogen); lymphocyte subpopulations (CD3%, 4%, 8%, 16%, 20%, 25%, and 56%); and natural killer cell (NK) activity. Psychological status of the patients, which was assessed by using Brief Psychiatric Rating Scale, improved gradually after admission. Changes in immune functions were analyzed using one-way analysis of variance and a randomized block analysis of variance with multiple comparison. NK activity on admission was significantly lower than those at 4 and 8 weeks after admission (p < .03). Serum IgG levels on admission and at 4 weeks after admission were significantly decreased as compared with those at 8 weeks after admission (p < .05); they were also lower than those in controls (p < .05). CD56% on admission and CD25% 4 weeks after admission were significantly increased as compared with controls (p < .05). These results indicate that several immunological functions might change related to time course after acute exacerbation. It is suggested that clinical conditions be carefully taken into consideration to evaluate immunological studies in schizophrenia.

Genes for interleukin‐2 receptor β chain, interleukin‐1 β, and schizophrenia: No evidence for the association or linkage

We studied a CA repeat polymorphism of the interleukin-2 receptor beta chain (IL-2RB) gene and a C/-514/T variation of the interleukin-1 beta (IL-1B) gene in Japanese schizophrenia patients. Both a case-control association study (54 patients and 54 controls) and a linkage study using six multiplex families (the number of the affected > or =4 in each family) were employed. No evidence for the association or the linkage was obtained either for the IL-2RB or IL-1B gene.

Linkage studies between affective disorder and dopamine D2, D3, and D4 receptor gene loci in four Japanese pedigrees

Dopamine antagonists are effective in the treatment of episodes of acute mania. Conversely, drugs which increase dopamine activity can induce a switch to mania. Therefore, disturbances in dopamine transmission and dopamine receptors might be implicated in the pathophysiology of bipolar affective disorder. We have carried out linkage studies between the susceptibility gene for effective disorder and polymorphisms of dopamine DRD2, DRD3, and DRD4 receptor genes in four Japanese pedigrees. Linkages of both DRD2 and DRD3 have been excluded, at least for dominant and intermediate models. The result for DRD2 was consistent with previous studies. For DRD3 this is the first exclusion of affective disorder from this locus in the 3q13.3 where DRD3 has been localized. On the other hand, our data could not exclude linkage of DRD4.

Pericentric region of chromosome 9 is a possible candidate region for linkage study of schizophrenia

We have undertaken a systematic G-banding survey to find structural chromosomal abnormalities among patients with schizophrenia. Of 120 patients with DSM-III-R schizophrenia, four (3.3%) had a pericentric inversion of chromosome 9 and three (2.5%) had a X/XX mosaicism. The frequency of pericentric inversion of chromosome 9 among patients with schizophrenia was statistically higher than those among newborns and Asian populations. Our results indicate that the pericentric region of chromosome 9 might be one of the potential regions of interest for linkage analysis of schizophrenia.