Junichiro Yoshimoto

Protein phosphorylation, a key regulator of cellular processes, plays a central role in brain function and is implicated in neurological disorders. Information on protein phosphorylation is expected to be a clue for understanding various neuropsychiatric disorders and developing therapeutic strategies. Nonetheless, existing databases lack a specific focus on phosphorylation events in the brain, which are crucial for investigating the downstream pathway regulated by neurotransmitters. To overcome the gap, we have developed a web-based database named “Kinase-Associated Neural PHOspho-Signaling (KANPHOS).” This paper presents the design concept, detailed features, and a series of improvements for KANPHOS. KANPHOS is designed to support data-driven research by fulfilling three key objectives: (1) enabling the search for protein kinases and their substrates related to extracellular signals or diseases; (2) facilitating a consolidated search for information encompassing phosphorylated substrate genes, proteins, mutant mice, diseases, and more; and (3) offering integrated functionalities to support pathway and network analysis. KANPHOS is also equipped with API functionality to interact with external databases and analysis tools, enhancing its utility in data-driven investigations. Those key features represent a critical step toward unraveling the complex landscape of protein phosphorylation in the brain, with implications for elucidating the molecular mechanisms underlying neurological disorders. KANPHOS is freely accessible to all researchers at https://kanphos.jp.

Background Phenotyping analysis that includes time course is useful for understanding the mechanisms and clinical management of postoperative delirium. However, postoperative delirium has not been fully phenotyped. Hypothesis-free categorization of heterogeneous symptoms may be useful for understanding the mechanisms underlying delirium, although evidence is currently lacking. Therefore, we aimed to explore the phenotypes of postoperative delirium following invasive cancer surgery using a data-driven approach with minimal prior knowledge. Methods We recruited patients who underwent elective invasive cancer resection. After surgery, participants completed 5 consecutive days of delirium assessments using the Delirium Rating Scale-Revised-98 (DRS-R-98) severity scale. We categorized 65 (13 questionnaire items/day × 5 days) dimensional DRS-R-98 scores using unsupervised machine learning (K-means clustering) to derive a small set of grouped features representing distinct symptoms across all participants. We then reapplied K-means clustering to this set of grouped features to delineate multiple clusters of delirium symptoms. Results Participants were 286 patients, of whom 91 developed delirium defined according to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, criteria. Following the first K-means clustering, we derived four grouped symptom features: (1) mixed motor, (2) cognitive and higher-order thinking domain with perceptual disturbance and thought content abnormalities, (3) acute and temporal response, and (4) sleep–wake cycle disturbance. Subsequent K-means clustering permitted classification of participants into seven subgroups: (i) cognitive and higher-order thinking domain dominant delirium, (ii) prolonged delirium, (iii) acute and brief delirium, (iv) subsyndromal delirium-enriched, (v) subsyndromal delirium-enriched with insomnia, (vi) insomnia, and (vii) fit. Conclusion We found that patients who have undergone invasive cancer resection can be delineated using unsupervised machine learning into three delirium clusters, two subsyndromal delirium clusters, and an insomnia cluster. Validation of clusters and research into the pathophysiology underlying each cluster will help to elucidate the mechanisms of postoperative delirium after invasive cancer surgery.

<title>Abstract</title>Scintillators emit visible luminescence when irradiated with X-rays. Given the unlimited tissue penetration of X-rays, the employment of scintillators could enable remote optogenetic control of neural functions at any depth of the brain. Here we show that a yellow-emitting inorganic scintillator, Ce-doped Gd₃(Al,Ga)₅O₁₂ (Ce:GAGG), can effectively activate red-shifted excitatory and inhibitory opsins, ChRmine and GtACR1, respectively. Using injectable Ce:GAGG microparticles, we successfully activated and inhibited midbrain dopamine neurons in freely moving mice by X-ray irradiation, producing bidirectional modulation of place preference behavior. Ce:GAGG microparticles are non-cytotoxic and biocompatible, allowing for chronic implantation. Pulsed X-ray irradiation at a clinical dose level is sufficient to elicit behavioral changes without reducing the number of radiosensitive cells in the brain and bone marrow. Thus, scintillator-mediated optogenetics enables minimally invasive, wireless control of cellular functions at any tissue depth in living animals, expanding X-ray applications to functional studies of biology and medicine.

Our current understanding of melancholic depression is shaped by its position in the depression spectrum. The lack of consensus on how it should be treated—whether as a subtype of depression, or as a distinct disorder altogethe—interferes with the recovery of suffering patients. In this study, we analyzed brain state energy landscape models of melancholic depression, in contrast to healthy and non-melancholic energy landscapes. Our analyses showed significant group differences on basin energy, basin frequency, and transition dynamics in several functional brain networks such as basal ganglia, dorsal default mode, and left executive control networks. Furthermore, we found evidences suggesting the connection between energy landscape characteristics (basin characteristics) and depressive symptom scores (BDI-II and SHAPS). These results indicate that melancholic depression is distinguishable from its non-melancholic counterpart, not only in terms of depression severity, but also in brain dynamics.

<title>Abstract</title>Neurofeedback (NF) aptitude, which refers to an individual’s ability to change its brain activity through NF training, has been reported to vary significantly from person to person. The prediction of individual NF aptitudes is critical in clinical NF applications. In the present study, we extracted the resting-state functional brain connectivity (FC) markers of NF aptitude independent of NF-targeting brain regions. We combined the data in fMRI-NF studies targeting four different brain regions at two independent sites (obtained from 59 healthy adults and six patients with major depressive disorder) to collect the resting-state fMRI data associated with aptitude scores in subsequent fMRI-NF training. We then trained the regression models to predict the individual NF aptitude scores from the resting-state fMRI data using a discovery dataset from one site and identified six resting-state FCs that predicted NF aptitude. Next we validated the prediction model using independent test data from another site. The result showed that the posterior cingulate cortex was the functional hub among the brain regions and formed predictive resting-state FCs, suggesting NF aptitude may be involved in the attentional mode-orientation modulation system’s characteristics in task-free resting-state brain activity.

Recently, the dimensional approach has attracted much attention, bringing a paradigm shift to a continuum of understanding of different psychiatric disorders. In line with this new paradigm, we examined whether there was common functional connectivity related to various psychiatric disorders in an unsupervised manner without explicitly using diagnostic label information. To this end, we uniquely applied a newly developed network-based multiple clustering method to resting-state functional connectivity data, which allowed us to identify pairs of relevant brain subnetworks and subject cluster solutions accordingly. Thus, we identified four subject clusters, which were characterized as major depressive disorder (MDD), young healthy control (young HC), schizophrenia (SCZ)/bipolar disorder (BD), and autism spectrum disorder (ASD), respectively, with the relevant brain subnetwork represented by the cerebellum-thalamus-pallidum-temporal circuit. The clustering results were validated using independent datasets. This study is the first cross-disorder analysis in the framework of unsupervised learning of functional connectivity based on a data-driven brain subnetwork.

In neuroscience, the functional magnetic resonance imaging (fMRI) is a vital tool to non-invasively access brain activity. Using fMRI, the functional connectivity (FC) between brain regions can be inferred, which has contributed to a number of findings of the fundamental properties of the brain. As an important clinical application of FC, clustering of subjects based on FC recently draws much attention, which can potentially reveal important heterogeneity in subjects such as subtypes of psychiatric disorders. In particular, a multiple clustering method is a powerful analytical tool, which identifies clustering patterns of subjects depending on their FC in specific brain areas. However, when one applies an existing multiple clustering method to fMRI data, there is a need to simplify the data structure, independently dealing with elements in a FC matrix, i.e., vectorizing a correlation matrix. Such a simplification may distort the clustering results. To overcome this problem, we propose a novel multiple clustering method based on Wishart mixture models, which preserves the correlation matrix structure without vectorization. The uniqueness of this method is that the multiple clustering of subjects is based on particular networks of nodes (or regions of interest, ROIs), optimized in a data-driven manner. Hence, it can identify multiple underlying pairs of associations between a subject cluster solution and a ROI sub-network. The key assumption of the method is independence among sub-networks, which is effectively addressed by whitening correlation matrices. We applied the proposed method to synthetic and fMRI data, demonstrating the usefulness and power of the proposed method.

Resting-state fMRI has the potential to help doctors detect abnormal behavior in brain activity and to diagnose patients with depression. However, resting-state fMRI has a bias depending on the scanner site, which makes it difficult to diagnose depression at a new site. In this paper, we propose methods to improve the performance of the diagnosis of major depressive disorder (MDD) at an independent site by reducing the site bias effects using regression. For this, we used a subgroup of healthy subjects of the independent site to regress out site bias. We further improved the classification performance of patients with depression by focusing on melancholic depressive disorder. Our proposed methods would be useful to apply depression classifiers to subjects at completely new sites.

Dopamine signaling in the brain is a complex phenomenon that strongly contributes to emotional behaviors. Medium spiny neurons (MSNs) play a major role in dopamine signaling through dopamine D1 receptors (D1Rs) or dopamine D2 receptors (D2Rs) in the striatum. cAMP/protein kinase A (PKA) regulates phosphorylation signals downstream of D1Rs, which affects the excitability of MSNs, leading to reward-associated emotional expression and memory formation. A combination of phosphoproteomic approaches and the curated KANPHOS database can be used to elucidate the physiological and pathophysiological functions of dopamine signaling and other monoamines. Emerging evidence from these techniques suggests that the Rap1 pathway plays a crucial role in the excitability of MSNs, leading to the expression of emotional behaviors.

acrobotは2リンク2関節からなるロボットで, 第2関節のみにアクチュエータが存在する.acrobotは非線形なダイナミックスをもち, 状態変数及び制御変数の空間がともに連続であるために, 強化学習によってこの制御を獲得することは難しい課題の一つである.本論文では, acrobotをバランスする制御に強化学習を応用する.我々の強化学習法はactor-criticアーキテクチャを用いて学習が行われる.actorは現在の状態に対して制御信号を出力し, criticは将来を通して得られる報酬の累積(期待報酬)を予測する.actorとcriticはともに正規化ガウス関数ネットワークによって近似され, オンラインEMアルゴリズムを用いて学習が行われる.また, criticの学習を促進させるための新たな手法を導入する.本手法が少ない試行回数から良い制御を獲得できることを計算機シミュレーションの結果により示す.