Phase-dependent offline enhancement of human motor memory.

BACKGROUND: Skill learning engages offline activity in the primary motor cortex (M1). Sensorimotor cortical activity oscillates between excitatory trough and inhibitory peak phases of the mu (8-12 Hz) rhythm. We recently showed that these mu phases influence the magnitude and direction of neuroplasticity induction within M1. However, the contribution of M1 activity during mu peak and trough phases to human skill learning has not been investigated. OBJECTIVE: To evaluate the effects of phase-dependent TMS during mu peak and trough phases on offline learning of a newly-acquired motor skill. METHODS: On Day 1, three groups of healthy adults practiced an explicit motor sequence learning task with their non-dominant left hand. After practice, phase-dependent TMS was applied to the right M1 during either mu peak or mu trough phases. The third group received sham TMS during random mu phases. On Day 2, all subjects were re-tested on the same task to evaluate offline learning. RESULTS: Subjects who received phase-dependent TMS during mu trough phases showed increased offline skill learning compared to those who received phase-dependent TMS during mu peak phases or sham TMS during random mu phases. Additionally, phase-dependent TMS during mu trough phases elicited stronger whole-brain broadband oscillatory power responses than phase-dependent TMS during mu peak phases. CONCLUSIONS: We conclude that sensorimotor mu trough phases reflect brief windows of opportunity during which TMS can strengthen newly-acquired skill memories.

Regulatory Macrophages Inhibit Alternative Macrophage Activation and Attenuate Pathology Associated with Fibrosis.

Diversity and plasticity are the hallmarks of macrophages. The two most well-defined macrophage subsets are the classically activated macrophages (CAMϕs) and the IL-4-derived alternatively activated macrophages (AAMϕs). Through a series of studies, we previously identified and characterized a distinct population of macrophages with immunoregulatory functions, collectively termed regulatory macrophages (RMϕs). Although considerable advances have been made in understanding these various macrophage subsets, it is not known whether macrophages of one activation state can influence the other. In this study, we examined whether RMϕs capable of inhibiting inflammatory responses of CAMϕs could also inhibit AAMϕs and their profibrotic responses. Our results demonstrated that RMϕs significantly dampened the alternate activation phenotype of AAMϕs generated in vitro and intrinsically occurring AAMϕs from TACI-/- macrophages. Further, RMϕs inhibited AAMϕ-promoted arginase activity and fibroblast proliferation in vitro. This inhibition occurred regardless of the strength, duration, and mode of alternative activation and was only partially dependent on IL-10. In the chlorhexidine gluconate-induced peritoneal fibrosis model, AAMϕs worsened the fibrosis, but RMϕs rescued mice from AAMϕ-mediated pathological conditions. Taken together, our study demonstrates that RMϕs are a specialized subset of macrophages with a nonredundant role in limiting overt proregenerative functions of AAMϕs, a role distinct from their well-defined role of suppression of inflammatory responses by CAMϕs.