Anatomical abnormalities in these schizophrenic patients with marked negative symptoms were most evident in left hemispheric neocortical and limbic regions and related white matter tracts. These data are compatible with models that depict schizophrenia as a supraregional disorder of multiple, distributed brain regions and the axonal connections between them.

In people with schizophrenia who are prone to auditory hallucinations, increasing the demands on the processing of inner speech is associated with attenuated engagement of the brain areas implicated in verbal self-monitoring.

Monitoring one's 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.

We have therefore confirmed previous reports of brain regions involved in olfactory processing in young volunteers and demonstrated decreased activation in elderly volunteers.

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 al 1 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.Methylenetetrahydrofolate reductase (MTHFR; EC 1.5.1.20) catalyses the NADPH-linked reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a cofactor for methylation of homocysteine to methionine and a compound which possibly serves as the methylation of biogenic amines. Frosst et al 2 identified a common mutation (C677T), which converts an alanine to a valine residue. This mutation is associated with MTHFR activity and plasma homocysteine levels; homocysteine levels in individuals homozygous for the mutated type were almost twice the value for heterozygous or homozygous for the wild-type. Furthermore, the mutation has been shown to be a risk factor for premature cardiovascular disease 3,4 and neural tube defect. 5,6 Deficient activity of MTHFR may also be associated with psychiatric conditions such as mental retardation, schizophrenia, 7-9 and affective disorders. 10 In line with this, a recent study of Arinami et al 1 examined the C677T polymorphism for patients with schizophrenia, bipolar disorder, and depression, and found an increased frequency of homozygosity for the T677 allele among schizophrenics (odds ratio 1.9, P = 0.0006) and among patients with unipolar depression (odds ratio 2.8, P = 0.005), but not among patients with bipolar disorder (odds ratio 1.0). In the present study, we tried to replicate these findings. Table 1 shows the genotype distribution and allele frequency for the C677T polymorphism of the MTHFR gene among the patients with schizophrenia, bipolar disorder, unipolar depression, and controls. The genotype distributions were in Hardy-Weinberg equilibrium for the four groups ( 2 = 0.1, df = 1, ns for the schizophrenics; 2 = 0.6, df = 1, ns for the patients with bipolar disorder; 2 = 0.7, df = 1, ns for the patients with unipolar depression; 2 = 0.9, df = 1, ns for the controls). The frequency of the T677 allele in our control subjects was 0.38, which was consistent with two other Japanese studies; Nshio et al 11 investigated 129 men aged 40-59 years and obtained an allele frequency of 0.38 and Arinami et al 1 reported 0.37 ...