Brain network flexibility as a predictor of skilled musical performance.

Interactions between the body and the environment are dynamically modulated by upcoming sensory information and motor execution. To adapt to this behavioral state-shift, brain activity must also be flexible and possess a large repertoire of brain networks so as to switch them flexibly. Recently, flexible internal brain communications, i.e. brain network flexibility, have come to be recognized as playing a vital role in integrating various sensorimotor information. Therefore, brain network flexibility is one of the key factors that define sensorimotor skill. However, little is known about how flexible communications within the brain characterize the interindividual variation of sensorimotor skill and trial-by-trial variability within individuals. To address this, we recruited skilled musical performers and used a novel approach that combined multichannel-scalp electroencephalography, behavioral measurements of musical performance, and mathematical approaches to extract brain network flexibility. We found that brain network flexibility immediately before initiating the musical performance predicted interindividual differences in the precision of tone timbre when required for feedback control, but not for feedforward control. Furthermore, brain network flexibility in broad cortical regions predicted skilled musical performance. Our results provide novel evidence that brain network flexibility plays an important role in building skilled sensorimotor performance.

Discovery of 6-[5-(4-fluorophenyl)-3-methyl-pyrazol-4-yl]-benzoxazin-3-one derivatives as novel selective nonsteroidal mineralocorticoid receptor antagonists.

In the course of our study on selective nonsteroidal mineralocorticoid receptor (MR) antagonists, a series of novel benzoxazine derivatives possessing an azole ring as the core scaffold was designed for the purpose of attenuating the partial agonistic activity of the previously reported dihydropyrrol-2-one derivatives. Screening of alternative azole rings identified 1,3-dimethyl pyrazole 6a as a lead compound with reduced partial agonistic activity. Subsequent replacement of the 1-methyl group of the pyrazole ring with larger lipophilic side chains or polar side chains targeting Arg817 and Gln776 increased MR binding activity while maintaining the agonistic response at the lower level. Among these compounds, 6-[1-(2,2-difluoro-3-hydroxypropyl)-5-(4-fluorophenyl)-3-methyl-1H-pyrazol-4-yl]-2H-1,4-benzoxazin-3(4H)-one (37a) showed highly potent in vitro activity, high selectivity versus other steroid hormone receptors, and good pharmacokinetic profiles. Oral administration of 37a in deoxycorticosterone acetate-salt hypertensive rats showed a significant blood pressure-lowering effect with no signs of antiandrogenic effects.