Hyperfrontality in patients with schizophrenia during saccade and antisaccade tasks: a study with fMRI.

AIMS: Antisaccadic eye movements, requiring inhibition of a saccade toward a briefly appearing peripheral target, are known to be impaired in schizophrenia. Previous neuroimaging studies have indicated that patients with schizophrenia show diminished activations in the frontal cortex and basal ganglia. These studies used target fixation as a baseline condition. However, if the levels of brain activities at baseline are not compatible between patients and healthy subjects, between-group comparison on antisaccade-related activations is consequently invalidated. One possibility is that patients with schizophrenia may present with greater activation during fixation than healthy subjects. In order to examine this possibility, here we investigated brain activities associated with antisaccade in the two groups without using target fixation at baseline. METHODS: Functional brain images were acquired during prosaccades and antisaccades in 18 healthy subjects and 18 schizophrenia patients using a box-car functional magnetic resonance imaging design. Eye movements were measured during scanning. RESULTS: In the patient group, the elevated activities in the dorsolateral prefrontal cortex (DLPFC) and thalamus, normally seen in antisaccade tasks relative to saccade tasks, were no longer observed. Moreover, in normal subjects, activities in the DLPFC and thalamus were greater during the antisaccade task than during the saccade task. In patients, no such difference was observed between the two tasks, suggesting that these brain regions are likely to be highly activated even by a simple task such as fixation. In particular, the DLPFC and thalamus in patients were not activated at a level commensurate with the difficulty of the tasks presented. CONCLUSIONS: From these results, it is suggested that schizophrenia entails dysfunctions in the fronto-striato-thalamo-cortical network associated with motor function control.

Functional MRI mapping of brain activation during visually guided saccades and antisaccades: cortical and subcortical networks.

Antisaccade tasks require a subject to inhibit a saccade toward a briefly appearing peripheral target and instead to immediately generate a saccade to an equivalent point in the opposite hemifield. Using functional magnetic resonance imaging (fMRI), we investigated the neural networks required to inhibit reflexive saccades and to voluntarily generate saccades. The results demonstrated that saccade and antisaccade tasks often bilaterally activate frontal, parietal and supplementary eye fields, lenticular nuclei and occipital cortex. Additional activation of bilateral dorsolateral prefrontal cortices, supramarginal gyri, anterior cingulate cortices and thalamus was observed during antisaccade tasks. These results indicate that fronto-parietal and fronto-striato-thalamo-cortical circuits are involved in antisaccade tasks. The fronto-parietal circuit is thought to be related to the planning of saccadic eye movements that involve attentional control, while the fronto-striato-thalamo-cortical circuits connect to cortical region as a feedback network. We speculate that the abnormalities in spatial attention and eye movement control observed in schizophrenia stem from dysfunctions in the fronto-parietal and fronto-striato-thalamo-cortical circuits.

Mutation screening and association study of the beta-adrenergic receptor kinase 2 gene in schizophrenia families.

Chromosome 22q12 is one of the most promising regions for harboring a risk gene for schizophrenia. We have reported significant linkage of intermediate phenotypes for schizophrenia with markers within or near the beta-adrenergic receptor kinase 2 (ADRBK2, or GRK3) gene, which is highly expressed in dopaminergic pathways in the central nervous system, and mediates homologous desensitization for a variety of neurotransmitters and hormones through phosphorylation of G protein-coupled receptors (GPCRs). A polymorphism in the promoter region of the ADRBK2 was reported to be associated with bipolar disorder. We screened the putative promoter region, and all 21 exonic and flanking intronic regions of the ADRBK2 gene for mutations in 48 schizophrenia probands (including 16 Japanese and 32 Chinese patients), and evaluated the detected polymorphisms and those reported in the JSNP database for associations with schizophrenia in 113 family trios of schizophrenia probands. Four single nucleotide variants in the 5'-UTR/promoter region, and 16 rare variants in exonic and flanking regions, were identified. Among them, the Cys208Ser variant was the only non-synonymous mutation. Cys208Ser was found in one family without cosegregation between the variant and schizophrenia. Moreover, allelic, genotypic and haplotypic analyses provided no evidence for association between alleles at these polymorphisms and schizophrenia. The present study indicates that the ADRBK2 gene is unlikely to contribute strongly to schizophrenia susceptibility in this set of families.

Determining vulnerability to schizophrenia in methamphetamine psychosis using exploratory eye movements.

Patients with methamphetamine (MAP) psychosis whose psychotic symptoms continued after MAP withdrawal were observed at Saitama Prefecture Government Psychiatric Hospital. The purpose of the present study was to ascertain whether some of these MAP psychosis subjects have a vulnerability to schizophrenia. Forty-eight patients with MAP psychosis were divided into three groups based on clinical course: transient type, prolonged type and persistent type. Furthermore, the patients with the persistent type were divided into two groups: one group were moderately disturbed in social adaptive functioning and had Global Assessment Functioning scale (GAF) points >50, and the other group consisted of those who were severely disturbed in social adaptive functioning and who had GAF points of < or =50. These MAP patients were tested for exploratory eye movements, which are the vulnerability marker of schizophrenia, and were compared with 30 patients with schizophrenia and 30 healthy control subjects. The responsive search score of the severely disturbed group of patients of the persistent type was lowest, significantly lower than those of the transient type and the healthy controls. It did not differ from that of the schizophrenic subjects. These results suggest that the severely disturbed group of patients with the persistent type of MAP psychosis have a vulnerability to schizophrenia.

Influence of arousal level for functional magnetic resonance imaging (fMRI) study: simultaneous recording of fMRI and electroencephalogram.

Simultaneous recording of functional MRI (fMRI) and electroencephalogram (EEG) has been applied to several clinical fields, making it possible to monitor the arousal level of the subject during a cognitive task. The study confirmed that activated cerebral areas were different between high and low arousal levels during the smooth-pursuit eye movement task. When arousal level was high, activations in the parietal eye field, frontal eye field (FEF), supplementary eye field (SMA), visual fields (V1) and occipito-temporal junction (V5) were found. In contrast, when arousal level was low, activations were found only in V1 and FEF. The results indicate that the monitoring of the arousal level of subjects using fMRI and EEG recordings simultaneously is crucial for detecting cortical activations during a cognitive task.