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.

We propose a novel method for multiple clustering, which is useful for analysis of high-dimensional data containing heterogeneous types of features. Our method is based on non-parametric Bayesian mixture models in which features are automatically partitioned (into views) for each clustering solution. This feature partition works as feature selection for a particular clustering solution, which screens out irrelevant features. To make our method applicable to high-dimensional data, a co-clustering structure is newly introduced for each view. Further, the outstanding novelty of our method is that we simultaneously model different distribution families, such as Gaussian, Poisson, and multinomial distributions in each cluster block, which widens areas of application to real data. We apply the proposed method to synthetic and real data, and show that our method outperforms other multiple clustering methods both in recovering true cluster structures and in computation time. Finally, we apply our method to a depression dataset with no true cluster structure available, from which useful inferences are drawn about possible clustering structures of the data.

In diagnostic applications of statistical machine learning methods to brain imaging data, common problems include data high-dimensionality and co-linearity, which often cause over-fitting and instability. To overcome these problems, we applied partial least squares (PLS) regression to resting-state functional magnetic resonance imaging (rs-fMRI) data, creating a low-dimensional representation that relates symptoms to brain activity and that predicts clinical measures. Our experimental results, based upon data from clinically depressed patients and healthy controls, demonstrated that PLS and its kernel variants provided significantly better prediction of clinical measures than ordinary linear regression. Subsequent classification using predicted clinical scores distinguished depressed patients from healthy controls with 80% accuracy. Moreover, loading vectors for latent variables enabled us to identify brain regions relevant to depression, including the default mode network, the right superior frontal gyrus, and the superior motor area.

Background: Advance in high-throughput technologies in genomics, transcriptomics, and metabolomics has created demand for bioinformatics tools to integrate high-dimensional data from different sources. Canonical correlation analysis (CCA) is a statistical tool for finding linear associations between different types of information. Previous extensions of CCA used to capture nonlinear associations, such as kernel CCA, did not allow feature selection or capturing of multiple canonical components. Here we propose a novel method, two-stage kernel CCA (TSKCCA) to select appropriate kernels in the framework of multiple kernel learning. Results: TSKCCA first selects relevant kernels based on the HSIC criterion in the multiple kernel learning framework. Weights are then derived by non-negative matrix decomposition with L1 regularization. Using artificial datasets and nutrigenomic datasets, we show that TSKCCA can extract multiple, nonlinear associations among high-dimensional data and multiplicative interactions among variables. Conclusions: TSKCCA can identify nonlinear associations among high-dimensional data more reliably than previous nonlinear CCA methods.

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.

This paper presents a variational Bayes (VB) method for normalized Gaussian network, which is a mixture model of local experts. Based on the Bayesian framework, we introduce a meta-learning mechanism to optimize the prior distribution and the model structure. In order to search for the optimal model structure efficiently, we also develop a hierarchical model selection method. The performance of our method is evaluated by using function approximation problems and an system identification problem of a nonlinear dynamical system. Experimental results show that our Bayesian framework results in the reduction of generalization error and achieves better function approximation than existing methods within the finite mixtures of experts family whim the number of training data is fairly small.

Corticostriatal synapse plasticity of medium spiny neurons is regulated by glutamate input from the cortex and dopamine input from the substantia nigra. While cortical stimulation alone results in long-term depression (LTD), the combination with dopamine switches LTD to long-term potentiation (LTP), which is known as dopamine-dependent plasticity. LTP is also induced by cortical stimulation in magnesium-free solution, which leads to massive calcium influx through NMDA-type receptors and is regarded as calcium-dependent plasticity. Signaling cascades in the corticostriatal spines are currently under investigation. However, because of the existence of multiple excitatory and inhibitory pathways with loops, the mechanisms regulating the two types of plasticity remain poorly understood. A signaling pathway model of spines that express D1-type dopamine receptors was constructed to analyze the dynamic mechanisms of dopamine- and calcium-dependent plasticity. The model incorporated all major signaling molecules, including dopamine- and cyclic AMP-regulated phosphoprotein with a molecular weight of 32 kDa (DARPP32), as well as AMPA receptor trafficking in the post-synaptic membrane. Simulations with dopamine and calcium inputs reproduced dopamine- and calcium-dependent plasticity. Further in silico experiments revealed that the positive feedback loop consisted of protein kinase A (PKA), protein phosphatase 2A (PP2A), and the phosphorylation site at threonine 75 of DARPP-32 (Thr75) served as the major switch for inducing LTD and LTP. Calcium input modulated this loop through the PP2B (phosphatase 2B)-CK1 (casein kinase 1)-Cdk5 (cyclin-dependent kinase 5)-Thr75 pathway and PP2A, whereas calcium and dopamine input activated the loop via PKA activation by cyclic AMP (cAMP). The positive feedback loop displayed robust bi-stable responses following changes in the reaction parameters. Increased basal dopamine levels disrupted this dopamine-dependent plasticity. The present model elucidated the mechanisms involved in bidirectional regulation of corticostriatal synapses and will allow for further exploration into causes and therapies for dysfunctions such as drug addiction.

Reinforcement learning (RL) has been applied to constructing controllers for nonlinear systems in recent years. Since RL methods do not require an exact dynamics model of the controlled object, they have a higher flexibility and potential for adaptation to uncertain or nonstationary environments than methods based on traditional control theory. If the target system has a continuous state space whose dynamic characteristics are nonlinear, however, RL methods often suffer from unstable learning processes. For this reason, it is difficult to apply RL methods to control tasks in the real world. In order to overcome the disadvantage of RL methods, we propose an RL scheme combining multiple controllers, each of which is constructed based on traditional control theory. We then apply it to a swinging-up and stabilizing task of an acrobot with a limited torque, which is a typical but difficult task in the field of nonlinear control theory. Our simulation result showed that our method was able to realize stable learning and to achieve fairly good control. © ISAROB 2005.

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.