Subcortical structures, which include the basal ganglia and parts of the limbic system, have key roles in learning, motor control and emotion, but also contribute to higher-order executive functions. Prior studies have reported volumetric alterations in subcortical regions in schizophrenia. Reported results have sometimes been heterogeneous, and few large-scale investigations have been conducted. Moreover, few large-scale studies have assessed asymmetries of subcortical volumes in schizophrenia. Here, as a work completely independent of a study performed by the ENIGMA consortium, we conducted a large-scale multisite study of subcortical volumetric differences between patients with schizophrenia and controls. We also explored the laterality of subcortical regions to identify characteristic similarities and differences between them. T1-weighted images from 1680 healthy individuals and 884 patients with schizophrenia, obtained with 15 imaging protocols at 11 sites, were processed with FreeSurfer. Group differences were calculated for each protocol and meta-analyzed. Compared with controls, patients with schizophrenia demonstrated smaller bilateral hippocampus, amygdala, thalamus and accumbens volumes as well as intracranial volume, but larger bilateral caudate, putamen, pallidum and lateral ventricle volumes. We replicated the rank order of effect sizes for subcortical volumetric changes in schizophrenia reported by the ENIGMA consortium. Further, we revealed leftward asymmetry for thalamus, lateral ventricle, caudate and putamen volumes, and rightward asymmetry for amygdala and hippocampal volumes in both controls and patients with schizophrenia. Also, we demonstrated a schizophrenia-specific leftward asymmetry for pallidum volume. These findings suggest the possibility of aberrant laterality in neural pathways and connectivity patterns related to the pallidum in schizophrenia.

These results show the distribution of difference score in patients with schizophrenia. These findings may contribute to assessing the severity of estimated cognitive decline and identifying patients with schizophrenia who suffer from cognitive decline.

We could differentiate between MDD and BD subjects in terms of gamma band ASSR. Our data suggest that the 40-Hz ASSR may be a potential biomarker for differentiation between MDD and BD patients.

Abnormalities in prenatal brain development contribute to schizophrenia vulnerability. Orbitofrontal cortex sulcogyral patterns are largely determined during prenatal development, and four types of orbitofrontal cortex sulcogyral patterns have been classified in humans. Altered orbitofrontal cortex patterns have been reported in individuals with schizophrenia using magnetic resonance imaging; however, sample sizes of previous studies were small–medium effects for detection, and gender manifestation for orbitofrontal cortex sulcogyral patterns is unclear. The present study investigated orbitofrontal cortex patterns of 155 patients with schizophrenia and 375 healthy subjects. The orbitofrontal cortex sulcogyral pattern distributions of schizophrenia were significantly different compared with healthy subjects in the left hemisphere (χ 2 = 14.55, p = 0.002). In female schizophrenia, post-hoc analyses revealed significantly decreased Type I expression (χ 2 = 6.76, p = 0.009) and increased Type II expression (χ 2 = 11.56, p = 0.001) in the left hemisphere. The present study suggested that female schizophrenia showed altered orbitofrontal cortex patterns in the left hemisphere, which may be related to neurodevelopmental abnormality.

Although intranasal oxytocin is expected to be a novel therapy for the core symptoms of autism spectrum disorder, which has currently no approved medication, the efficacy of repeated administrations was inconsistent, suggesting that the optimal dose for a single administration of oxytocin is not optimal for repeated administration. The current double-blind, placebo-controlled, multicentre, crossover trial (ClinicalTrials.gov Identifier: NCT03466671) was aimed to test the effect of TTA-121, a new formulation of intranasal oxytocin spray with an enhanced bioavailability (3.6 times higher than Syntocinon® spray, as assessed by area under the concentration–time curve in rabbit brains), which enabled us to test a wide range of multiple doses, on autism spectrum disorder core symptoms and to determine the dose–response relationship. Four-week administrations of TTA-121, at low dose once per day (3 U/day), low dose twice per day (6 U/day), high dose once per day (10 U/day), or high dose twice per day (20 U/day), and 4-week placebo were administered in a crossover manner. The primary outcome was the mean difference in the reciprocity score (range: 0–14, higher values represent worse outcomes) on the Autism Diagnostic Observation Schedule between the baseline and end point of each administration period. This trial with two administration periods and eight groups was conducted at seven university hospitals in Japan, enrolling adult males with high-functioning autism spectrum disorder. Enrolment began from June 2018 and ended December 2019. Follow-up ended March 2020. Of 109 males with high-functioning autism spectrum disorder who were randomized, 103 completed the trial. The smallest P-value, judged as the dose–response relationship, was the contrast with the peak at TTA-121 6 U/day, with inverted U-shape for both the full analysis set (P = 0.182) and per protocol set (P = 0.073). The Autism Diagnostic Observation Schedule reciprocity score, the primary outcome, was reduced in the TTA-121 6 U/day administration period compared with the placebo (full analysis set: P = 0.118, mean difference = −0.5; 95% CI: −1.1 to 0.1; per protocol set: P = 0.012, mean difference = −0.8; 95% CI: −1.3 to −0.2). The per protocol set was the analysis target population, consisting of all full analysis set participants except those who deviated from the protocol. Most dropouts from the full analysis set to the per protocol set occurred because of poor adherence to the test drug (9 of 12 in the first period and 8 of 15 in the second period). None of the secondary clinical and behavioural outcomes were significantly improved with the TTA-121 compared with the placebo in the full analysis set. A novel intranasal spray of oxytocin with enhanced bioavailability enabled us to test a wide range of multiple doses, revealing an inverted U-shape dose–response curve, with the peak at a dose that was lower than expected from previous studies. The efficacy of TTA-121 shown in the current exploratory study should be verified in a future large-scale, parallel-group trial.