Unveiling the dynamics of B lymphocytes in systemic lupus erythematosus patients treated with belimumab through longitudinal single-cell RNA sequencing.

OBJECTIVES: Unraveling the mechanisms underlying treatment response for targeted therapeutics in systemic lupus erythematosus (SLE) patients is challenging due to the limited understanding of diverse responses of circulating immune cells, particularly B cells. We investigated B lymphocyte dynamics during anti-BAFF treatment, utilizing longitudinal single-cell transcriptome data. METHODS: We conducted single-cell RNA sequencing on PBMCs in four Korean SLE patients before and after belimumab treatment at the following time points: 2 weeks, 1, 3, 6, and 12 months. RESULTS: Analyzing over 73 000 PBMCs, we identified 8 distinct subsets of B cells and plasmablasts and analyzed dynamic changes within these cell subsets: initial declines in naive and transitional B cells followed by an increase at three months, contrasted by an initial increase and subsequent decrease in memory B cells by the third month. Meanwhile, plasmablasts exhibited a consistent decline throughout treatment. B cell activation pathways, specifically in naive and memory B cells, were downregulated during the third and sixth months. These findings were validated at the protein level throughout the first four weeks of treatment using flow cytometry. Comparative analysis with bulk transcriptome data from 22 Japanese SLE patients showed increased NR4A1 expression six months post-belimumab treatment, indicating its role in restricting self-reactive B cells, thereby contributing to the biological responses of anti-BAFF treatment. CONCLUSION: The observed B cell dynamics provided insights into the immunological mechanisms underlying the therapeutic effects of anti-BAFF in SLE patients. Furthermore, it underscores the need for research in predicting drug responses based on immune profiling.

Key factors in the cortical response to transcranial electrical Stimulations-A multi-scale modeling study.

Transcranial electrode stimulation (tES), one of the techniques used to apply non-invasive brain stimulation (NIBS), modulates cortical activities by delivering weak electric currents through scalp-attached electrodes. This emerging technique has gained increasing attention recently; however, the results of tES vary greatly depending upon subjects and the stimulation paradigm, and its cellular mechanism remains unclear. In particular, there is a controversy over the factors that determine the cortical response to tES. Some studies have reported that the electric field's (EF) orientation is the determining factor, while others have demonstrated that the EF magnitude itself is the crucial factor. In this work, we conducted an in-depth investigation of cortical activity in two types of electrode montages used widely-the conventional (C)-tES and high-definition (HD)-tES-as well as two stimulation waveforms-direct current (DC) and alternating current (AC). To do so, we constructed a multi-scale model by coupling an anatomically realistic human head model and morphologically realistic multi-compartmental models of three types of cortical neurons (layer 2/3 pyramidal neuron, layer 4 basket cell, layer 5 pyramidal neuron). Then, we quantified the neuronal response to the C-/HD-tDCS/tACS and explored the relation between the electric field (EF) and the radial field's (RF: radial component of EF) magnitude and the cortical neurons' threshold. The EF tES induced depended upon the electrode montage, and the neuronal responses were correlated with the EF rather than the RF's magnitude. The electrode montages and stimulation waveforms caused a small difference in threshold, but the higher correlation between the EF's magnitude and the threshold was consistent. Further, we observed that the neurons' morphological features affected the degree of the correlation highly. Thus, the EF magnitude was a key factor in the responses of neurons with arborized axons. Our results demonstrate that the crucial factor in neuronal excitability depends upon the neuron models' morphological and biophysical properties. Hence, to predict the cellular targets of NIBS precisely, it is necessary to adopt more advanced neuron models that mimic realistic morphological and biophysical features of actual human cells.

Is electric field strength deterministic in cortical neurons' response to transcranial electrical stimulation?

Transcranial electrical stimulation (tES), which modulates cortical excitability via electric currents, has attracted increasing attention because of its application in treating neurologic and psychiatric disorders. To obtain a better understanding of the brain areas affected and stimulation's cellular effects, a multi-scale model was proposed that combines multi-compartmental neuronal models and a head model. While one multi-scale model of tES that used straight axons reported that the direction of electric field (EF) is a determining factor in a neuronal response, another model of transcranial magnetic stimulation (TMS) that used arborized axons reported that EF magnitude is more crucial than EF direction because of arborized axons' reduced sensitivity to the latter. Our goal was to investigate whether EF magnitude remains a crucial factor in the neuronal response in a multi-scale model of tES into which an arborized axon is integrated. To achieve this goal, we constructed a multi-scale model that integrated three types of neurons and a realistic head model, and then simulated the neuronal response to realistic EF. We found that EF magnitude was correlated with excitation threshold, and thus, it may be one of the determining factors in cortical neurons' response to tES.Clinical Relevance-This multi-scale model based on biophysical and morphological properties and realistic brain geometry may help elucidate tES's neural mechanisms. Moreover, given its clinical applications, this model may help predict a patient's neuronal response to brain stimulation effectively.

Morphological Influence and Electric Field Direction's Influence on Activation of Cortical Neurons in Electrical Brain Stimulation: a Computational Study.

Electrical brain stimulation (EBS) has been actively researched because of its clinical application and usefulness in brain research. However, its effect on individual neurons remains uncertain, as each neuron's response to EBS is highly variable and dependent on its morphology and the axis in which a neuron lies. Hence, our goal was to investigate the way that neuronal morphology affects the cellular response to extracellular stimulation from multiple directions. In this computational study, we observed that the varying neuronal morphology and direction of applied electrical field (EF) had some influence on the excitation threshold, which generates an action potential. Further, change of the excitation threshold depending on EF directions was observed.Clinical Relevance- These findings would help us to understand the variability in the modulatory effects of EBS at the cellular level and would be the basis for understanding the packed fibers' responses to EBS. Ultimately, considering EBS' clinical application, it may also help to predict patient's results from EBS treatment.