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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.

Aim Studies have reported that cognitive decline occurs after the onset of schizophrenia despite heterogeneity in cognitive function among patients. The aim of this study was to investigate the degree of estimated cognitive decline in patients with schizophrenia by comparing estimated premorbid intellectual functioning and current intellectual functioning. Methods A total of 446 patients with schizophrenia (228 male, 218 female), consisting of three sample sets obtained from 11 psychiatric facilities, and 686 healthy controls participated in this study. The Wechsler Adult Intelligence Scale-III (WAIS-III) was used to measure the participants’ current full-scale IQ (FSIQ). The premorbid IQ was estimated using the Japanese Adult Reading Test-25. Estimated cognitive decline (difference score) was defined as the difference between the estimated premorbid IQ and the current FSIQ. Results Patients with schizophrenia showed greater estimated cognitive decline, a lower FSIQ, and a lower premorbid IQ compared with the healthy controls. The mean difference score, FSIQ, and estimated premorbid IQ were −16.3, 84.2, and 100.5, respectively, in patients with schizophrenia. Furthermore, 39.7% of the patients had a difference score of 20 points or greater decline. A discriminant analysis showed that the difference score accurately predicted 81.6% of the patients and healthy controls. Conclusion 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.

© 2016 Macmillan Publishers Limited, part of Springer Nature. All rights reserved. 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.

Background The auditory steady-state response (ASSR) elicited by gamma band neural oscillations has received considerable interest as a biomarker of psychiatric disorders. Although recent ASSR studies have reported that patients with bipolar disorder (BD) show altered ASSRs, little is known about ASSRs in patients with major depressive disorder (MDD). The aim of this study was to evaluate whether ASSRs in MDD subjects differed from those in BD subjects or normal controls (NC). Method We analyzed ASSRs in 14 MDD patients, 19 BD patients, and 29 normal control subjects. We used whole-head 306-channel magnetoencephalography to evaluate ASSR power and phase-locking factors (PLF) elicited by 20-, 30-, 40-, and 80-Hz click trains. We determined optimal sensitivity and specificity of ASSR power and PLF for the diagnosis of MDD or BD via receiver operating characteristic (ROC) curve analysis using a nonparametric approach. Results MDD patients exhibited no significant differences in ASSR power or PLF compared with NC subjects, while BD patients showed deficits on the ASSR measures. MDD patients showed significantly larger ASSR power and PLF for 30-, 40-, and 80-Hz stimuli compared with BD patients. The area under the curve (AUC) for the ROC analysis (MDD vs. BD) was 0.81 [95% CI=0.66–0.96, p=0.003] concerning 40-Hz ASSR power. Limitations We could not exclude the effect of medication and the sample size of the current study is relatively small. Conclusions 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 (χ2 = 14.55, p = 0.002). In female schizophrenia, post-hoc analyses revealed significantly decreased Type I expression (χ2 = 6.76, p = 0.009) and increased Type II expression (χ2 = 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.

Studies have reported that cognitive decline occurs after the onset of schizophrenia despite heterogeneity in cognitive function among patients. The aim of this study was to investigate the degree of estimated cognitive decline in patients with schizophrenia by comparing estimated premorbid intellectual functioning and current intellectual functioning.A total of 446 patients with schizophrenia (228 male, 218 female), consisting of three sample sets obtained from 11 psychiatric facilities, and 686 healthy controls participated in this study. The Wechsler Adult Intelligence Scale-III (WAIS-III) was used to measure the participants' current full-scale IQ (FSIQ). The premorbid IQ was estimated using the Japanese Adult Reading Test-25. Estimated cognitive decline (difference score) was defined as the difference between the estimated premorbid IQ and the current FSIQ.Patients with schizophrenia showed greater estimated cognitive decline, a lower FSIQ, and a lower premorbid IQ compared with the healthy controls. The mean difference score, FSIQ, and estimated premorbid IQ were -16.3, 84.2, and 100.5, respectively, in patients with schizophrenia. Furthermore, 39.7% of the patients had a difference score of 20 points or greater decline. A discriminant analysis showed that the difference score accurately predicted 81.6% of the patients and healthy controls.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.

A 69-year-old woman with no family history of mental or neurologic diseases or hypoxic episodes began to show gradual progressive apathy and difficulties in household work at about 50 years of age, followed by emotional blunting. At 68 years of age, she developed catatonia-like signs with little or no spontaneous movement, mutism, and refusal to eat or drink. Frontotemporal dementia (FTD) was suspected because of the bilateral frontal and temporal atrophy shown by an MRI study. At that time, her family found that her symptoms were temporarily resolved with zolpidem without sleepiness. Medical examinations, including a complete blood cell count, and liver, renal, and thyroid function tests, showed no abnormalities. EEG showed dominant α rhythm with occasional slow waves, without any evidence of disturbance of consciousness. Psychotropic agents including zopiclone, lorazepam, brotizolam, alprazolam, diazepam, quazepam, quetiapine, fluvoxamine, lamotrigine, mirtazapine, and amantadine did not resolve her catatonia-like signs. No psychological tests could be performed because of her catatonic state. About 30 minutes after the oral administration of zolpidem (5 mg), her catatonia-like signs gradually ameliorated, and the effect lasted for a few hours. Psychological tests following zolpidem administration demonstrated that her Mini-Mental State Examination score was 21/30, showing disturbances in orientation, attention, and calculation, while the Frontal Assessment Battery score was 11/18 with signs of perseveration that indicated the hypofunction of the frontal lobe. The Bush-Francis Catatonia Rating Scale score changed from 26 to 3 (table). Brain perfusion scans were performed before and after the administration of zolpidem (figure). In both scans, a severe perfusion decrease was observed in bilateral high-frontal lobes, and a mild decrease was observed in bilateral temporal lobes, which was compatible with FTD. After the oral administration of zolpidem, the perfusion was decreased in the brainstem and improved in the thalamus and some cortical areas, including the left parieto-temporal lobe and left cerebellar cortex. The anticatatonic effect of zolpidem has been observed for these 2 years without any side effect.

Although there has been great technological development in the computer field, improved cost performance is still required in order to accurately and quickly solve the partial differential equation which represents the complicated dynamics of sliding pressure operation of a supercritical once-through boiler. To obtain the solution using software, the following ideas are proposed in this paper. (1) Pressure and entropy as state variables are chosen to represent dynamics instead of temperature which cannot be independent of pressure in the saturated steam region. (2) The partial differential equation system is transformed into an ordinary one by the characteristic curve method. (3) High speed steam table is introduced instead of the international steam table formula. The simulation methods have been successfully applied not only to build the simulator for control system design but also to model the built-in-simulator of optimal control system.

When a feedback control system model is obtained mathematically or physically, a parallel learning system can be composed by copying the model to i (i=1, 2, …, k) systems corresponding to learning times. In the copied systems, the actuating signal of the i- 1-th model is added to the actuating signal of the i-th model. Thus obtained k-th learning model is equivalent to the system which has a filter as series compensator composed by the sum of i (i=0, 1, 2, …, k) multiple of the left side of the characteristic equation. This paper calls the sum "multiple eigenvalue filter", and shows that the multiple eigenvalue filter is applicable in actual plant control systems, to eliminate control variable deviation without losing stability when disturbance is added to the systems. It is demonstrated that control deviation becomes to zero by first learning in the control systems including integral action such as level control. Although controlled systems have an inverse response characteristics which is found in boiler drum level behaviour, the proposed parallel learning method is a powerful way to control the level stably as well as precisely.

The proposed control system is based on the super-real-time simulation in which a physical model is introduced to present the controlled system dynamics. The optimal actuating signals have been obtained by solving the physical model equation so that control variables are kept constant at every specified time interval with the aid of parallel microprocessors. It is shown by computer simulation that the method has been successfully applied to level control of a cascaded tank system. The following results have been obtained by the calculation of the SRTC transfer function. (1) Feedforward compensation by the target control variable is added to the actuating signal. (2) SRTC yields proportional feedback control. (3) SRTC compensates the lag of the plant transfer function. (4) SRTC also compensates disturbance to the plant.

This paper deals with the eigenvalue problem of the multiple eigenvalue filter which was proposed in the previous paper, "Parallel Learning in Control Systems (Derivation of Multiple Eigen value Filter)". The system with proposed filter derived by means of parallel learning not only reduces control variable deviation without decreasing stability, but also has PID (Proportional, Integral and Derivative) control action although the original control system before learning has just proportional control action. In this paper, the reason is shown from the view point of eigenvalue problem and Nyquist stability theory.