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Neuromodulation therapies such as electroconvulsive therapy (ECT) are used to treat several neuropsychiatric disorders, including major depressive disorder (MDD). Recent work has highlighted the use of combined transcranial magnetic stimulation and electroencephalography (TMS-EEG) to evaluate the therapeutic effects of neuromodulation; particularly, the phase locking factor (PLF) and phase locking value (PLV) can reportedly assess neuromodulation-induced functional changes in cortical networks. To examine changes in TMS-induced PLV and PLF before and after ECT, and their relationship with depression severity in patients with MDD, TMS-EEG and the Montgomery–Åsberg Depression Rating Scale (MADRS; depression severity) were implemented before and after ECT in 10 patients with MDD. Single-pulse TMS was applied to the visual and motor areas to induce phase propagation in the visuo-motor network at rest. Functional changes were assessed using PLF and PLV data. Pre-ECT TMS-induced alpha band (9–12 Hz) PLV was negatively correlated with depression severity, and increments of post-ECT from pre-ECT TMS-induced alpha band PLV were positively correlated with the reduction in depression severity. Moreover, we found a negative correlation between pre-ECT TMS-induced PLF at TMS-destination and depression severity. Finally, differences in post-ECT TMS-induced PLF peak latencies between visual and motor areas were positively correlated with depression severity. TMS-EEG-based PLV and PLF may be used to assess the therapeutic effects of neuromodulation and depressive states, respectively. Furthermore, our results provide new insights about the neural mechanisms of ECT and depression.

Several studies have reported that the pandemic of coronavirus disease 2019 (COVID-19) influenced cognitive function in the elderly. However, the effect of COVID-19-related fear on brain atrophy has not been evaluated. In this study, we evaluated the relation between brain atrophy and the effect of COVID-19-related fear by analysing changes in brain volume over time using magnetic resonance imaging (MRI). Participants were 25 Japanese patients with mild cognitive impairment (MCI) or subjective cognitive decline (SCD), who underwent 1.5-tesla MRI scan twice, once before and once after the pandemic outbreak of COVID-19, and the Fear of Coronavirus Disease 2019 Scale (FCV-19S) assessment during that period. We computed regional brain atrophy per day between the 1st and 2nd scan, and evaluated the relation between the FCV-19S scores and regional shrinkage. There was significant positive correlation between the total FCV-19S score and volume reduction per day in the right posterior cingulate cortex. Regarding the subscales of FCV-19S, we found significant positive correlation between factor 2 of the FCV-19S and shrinkage of the right posterior cingulate cortex. There was positive correlation between the FCV-19S score and regional brain atrophy per day. Although it is already known that the psychological effects surrounding the COVID-19 pandemic cause cognitive function decline, our results further suggest that anxiety and fear related to COVID-19 cause regional brain atrophy.

Anorexia nervosa (AN) is a fatal condition associated with extreme underweight and undernutrition. It is more common in young females, with a female-to-male ratio of 10 : 1. Focal cortical dysplasia (FCD) is characterized by dysplasia of the cerebral cortex and is a common cause of pharmacoresistant epilepsy. However, FCD associated with AN has never been reported. We report the first case of AN in a 12-year-old male diagnosed with FCD-type 2 on head magnetic resonance imaging (MRI). He became concerned about lower abdominal distention and began reducing his food intake. He was admitted to our hospital after weight loss of 10 kg in a 1 year. Head MRI showed a localized high-signal area from the cortex to the white matter of the fusiform gyrus near the left hippocampus, with no associated decreased blood flow or electroencephalography (EEG) abnormalities. These findings were characteristic of FCD type II. In males with AN, the search for underlying disease is particularly important. The pathophysiology of the association between AN and FCD is unclear. However, both conditions are reportedly associated with autism spectrum disorder. Further cases are needed to clarify whether FCD is associated with eating disorders.

Disruption of synaptic networks has been advocated in the pathogenesis of psychiatric diseases like schizophrenia. The majority of synaptic proteins involved in neuronal communications are localized in lipid rafts. These rafts form the platform for coordinating neuronal signal transduction, by clustering interacting partners. The PAG1 protein is a transmembrane adaptor protein in the lipid raft signaling cluster that regulates Src family kinases (SFKs), a convergent point for multiple pathways regulating N -methyl- d -aspartate (NMDA) receptors. Reports of de novo missense mutations in PAG1 and SFK mediated reductions in tyrosine phosphorylation of NMDA receptor subunit proteins in schizophrenia patients, point to a putative role in schizophrenia pathogenesis. To evaluate this, we resequenced the entire coding region of PAG1 in Japanese schizophrenia patients ( n  = 1,140) and controls ( n  = 1,140). We identified eight missense variants, of which four were previously unreported. Case–control genetic association analysis of these variants in a larger cohort ( n  = 4,182) showed neither a statistically significant association of the individual variants with schizophrenia, nor any increased burden of the rare alleles in the patient group. Expression levels of PAG1 in post-mortem brain samples from schizophrenia patients and controls also showed no significant differences. To assess the precise role of PAG1 in schizophrenia, future studies with larger sample sizes are needed.

Mice with the C3H background show greater behavioral propensity for schizophrenia, including lower prepulse inhibition (PPI), than C57BL/6 (B6) mice. To characterize as‐yet‐unknown pathophysiologies of schizophrenia, we undertook proteomics analysis of the brain in these strains, and detected elevated levels of Mpst, a hydrogen sulfide (H 2 S)/polysulfide‐producing enzyme, and greater sulfide deposition in C3H than B6 mice. Mpst ‐deficient mice exhibited improved PPI with reduced storage sulfide levels, while Mpst ‐transgenic (Tg) mice showed deteriorated PPI, suggesting that “sulfide stress” may be linked to PPI impairment. Analysis of human samples demonstrated that the H 2 S/polysulfides production system is upregulated in schizophrenia. Mechanistically, the Mpst‐ Tg brain revealed dampened energy metabolism, while maternal immune activation model mice showed upregulation of genes for H 2 S/polysulfides production along with typical antioxidative genes, partly via epigenetic modifications. These results suggest that inflammatory/oxidative insults in early brain development result in upregulated H 2 S/polysulfides production as an antioxidative response, which in turn cause deficits in bioenergetic processes. Collectively, this study presents a novel aspect of the neurodevelopmental theory for schizophrenia, unraveling a role of excess H 2 S/polysulfides production. Synopsis This study proposes a novel concept that excess hydrogen sulfide production (sulfide stress) underlies a schizophrenia pathophysiology in the realm of neurodevelopmental hypothesis of the disease. Targeting the metabolic pathway of hydrogen sulfide provides a novel therapeutic approach. Mpst‐deficient mice exhibited improved prepulse inhibition (PPI), a typical schizophrenia‐relevant endophenotype, with reduced sulfide levels, while Mpst‐transgenic mice showed deteriorated PPI. Postmortem brains and iPS‐derived cells from a subset of schizophrenia patients displayed evidence for sulfide stress. Sulfide stress condition stemmed from insults in developing brain in mouse models and elicited dampened energy metabolism. MPST expression level in hair follicles has a potential to stratify schizophrenia patients with sulfide stress. Graphical Abstract This study proposes a novel concept that excess hydrogen sulfide production (sulfide stress) underlies a schizophrenia pathophysiology in the realm of neurodevelopmental hypothesis of the disease. Targeting the metabolic pathway of hydrogen sulfide provides a novel therapeutic approach.

We previously identified frequent deletion/insertion polymorphisms in the 20-alanine homopolymer stretch of PHOX2B (PMX2B), the gene for a transcription factor that plays important roles in the development of oculomotor nerves and catecholaminergic neurons and regulates the expression of both tyrosine hydroxylase and dopamine beta-hydroxylase genes. An association was detected between gene polymorphisms and overall schizophrenia, and more specifically, schizophrenia with ocular misalignment. These prior results implied the existence of other schizophrenia susceptibility genes that interact with PHOX2B to increase risk of the combined phenotype. ASCL1 was considered as a candidate interacting partner of PHOX2B, as ASCL1 is a transcription factor that co-regulates catecholamine-synthesizing enzymes with PHOX2B. The genetic contributions of PHOX2B and ASCL1 were examined separately, along with epistatic interactions with broader candidate phenotypes. These phenotypes included not only schizophrenia, but also bipolar affective disorder and Parkinson's disease (PD), each of which involve catecholaminergic function. The current case-control analyses detected nominal associations between polyglutamine length variations in ASCL1 and PD (P=0.018), but supported neither the previously observed weak association between PHOX2B and general schizophrenia, nor other gene-disease correlations. Logistic regression analysis revealed the effect of ASCL1 dominant x PHOX2B additive (P=0.008) as an epistatic gene-gene interaction increasing risk of PD. ASCL1 controls development of the locus coeruleus (LC), and accumulating evidence suggests that the LC confers protective effects against the dopaminergic neurodegeneration inherent in PD. The present genetic data may thus suggest that polyglutamine length polymorphisms in ASCL1 could influence predispositions to PD through the fine-tuning of LC integrity.

Dysfunction of the circadian clock has been implicated in the pathogenesis of cardiovascular disease. The CLOCK protein is a core molecular component of the circadian oscillator, so that mice with a mutated Clock gene ( Clk/Clk ) exhibit abnormal rhythms in numerous physiological processes. However, here we report that chronic kidney disease (CKD)-induced cardiac inflammation and fibrosis are attenuated in Clk/Clk mice even though they have high blood pressure and increased serum angiotensin II levels. A search for the underlying cause of the attenuation of heart disorder in Clk/Clk mice with 5/6 nephrectomy (5/6Nx) led to identification of the monocytic expression of G protein-coupled receptor 68 (GPR68) as a risk factor of CKD-induced inflammation and fibrosis of heart. 5/6Nx induces the expression of GPR68 in circulating monocytes via altered CLOCK activation by increasing serum levels of retinol and its binding protein (RBP4). The high-GPR68-expressing monocytes have increased potential for producing inflammatory cytokines, and their cardiac infiltration under CKD conditions exacerbates inflammation and fibrosis of heart. Serum retinol and RBP4 levels in CKD patients are also sufficient to induce the expression of GPR68 in human monocytes. Our present study reveals an uncovered role of monocytic clock genes in CKD-induced heart failure. Alteration of circadian rhythms is often observed in patients with chronic kidney disease (CKD). Here, the authors show that CKD-induced dysfunction of the circadian clock increases the expression of G protein-coupled receptor 68 in circulating monocytes and that their cardiac infiltration exacerbates inflammation and fibrosis of heart.

PurposeWe compared the outcomes of laparoscopic surgery (LS) with those of open surgery (OS) for unilateral and bilateral pediatric inguinal hernia.MethodsUsing a nationwide claim-based database in Japan, we analyzed data from children younger than 15 years old, who underwent inguinal hernia repair between January 2005 and December 2017. Patient characteristics, incidence of reoperation, postoperative complications, length of hospital stay, and duration of anesthesia were compared between LS and OS for unilateral and bilateral hernia.ResultsAmong 5554 patients, 2057 underwent LS (unilateral 1095, bilateral 962) and 3497 underwent OS (unilateral 3177, bilateral 320). The incidence of recurrence was not significantly different between OS and LS (unilateral: OS 0.2% vs. LS 0.3%, p = 0.44, bilateral: OS 0.6% vs. LS 0.6%, p = 1.00). The incidence of metachronous hernias was significantly higher in the OS group than in the LS group (4.8% vs. 1.0%, p < 0.001). The surgical site infection rate was significantly lower after OS than after LS for unilateral surgeries (0.9% vs. 2.2%, p = 0.002). There was no difference between OS and LS in the length of hospital stay.ConclusionBoth OS and LS had a low incidence of recurrence in children; however, the incidence of metachronous hernias was lower for LS, which may influence operative technique decisions.

BackgroundColorectal endoscopic submucosal dissection (ESD) requires advanced endoscopic skill. For safer and more reliable ESD implementation, various traction devices have been developed in recent years. The purpose of this research was to evaluate whether an ESD training program using a traction device (TD) would contribute to the improvement of trainees’ skill acquisition.MethodsThe differences in treatment outcomes and learning curves by the training program were compared before and after the introduction of TD (control group: January 2014 to March 2016; TD group: April 2016 to June 2018).ResultsA total of 316 patients were included in the analysis (TD group: 202 cases; control group: 114 cases). The number of cases required to achieve proficiency in ESD techniques was 10 in the TD group and 21 in the control group. Compared to the control group, the TD group had a significant advantage in ESD self-completion rate (73.8% vs. 58.8%), dissection speed (19.5 mm2/min vs. 15.9 mm2/min), en bloc resection rate (100% vs. 90%), and R0 resection rate (96% vs. 83%).ConclusionsThe rate of colorectal ESD self-completion by trainees improved immediately after the start of the training program using a traction device compared to the conventional method, and the dissection speed tended to increase linearly with ESD experience. We believe that ESD training using a traction device will help ESD techniques to be performed safely and reliably among trainees.