Aims CLARITY is a novel technique which enables three‐dimensional visualization of immunostained tissue for the study of circuitry and spatial interactions between cells and molecules in the brain. In this study, we aimed to compare methodological differences in the application of CLARITY between rodent and large human post mortem brain samples. In addition, we aimed to investigate if this technique could be used to visualize Lewy pathology in a post mortem Parkinson's brain.MethodsRodent and human brain samples were clarified and immunostained using the passive version of the CLARITY technique. Samples were then immersed in different refractive index matching media before mounting and visualizing under a confocal microscope.ResultsWe found that tissue clearing speed using passive CLARITY differs according to species (human vs. rodents), brain region and degree of fixation (fresh vs. formalin‐fixed tissues). Furthermore, there were advantages to using specific refractive index matching media. We have applied this technique and have successfully visualized Lewy body inclusions in three dimensions within the nucleus basalis of Meynert, and the spatial relationship between monoaminergic fibres and Lewy pathologies among nigrostriatal fibres in the midbrain without the need for physical serial sectioning of brain tissue.ConclusionsThe effective use of CLARITY on large samples of human tissue opens up many potential avenues for detailed pathological and morphological studies.

Voluntary limb movements are associated with increases in trunk muscle activity, some of which occur within a time window considered too fast to be induced by sensory feedback; these increases are termed anticipatory postural adjustments (APAs). Although it is known that the function of APAs is to maintain postural stability in response to perturbations, excitability of the corticospinal projections to the trunk muscles during the APAs remains unclear. Thirty-four healthy subjects performed rapid shoulder flexion in response to a visual cue in standing and lying positions. Transcranial magnetic stimulation (TMS) was delivered over the trunk motor cortex to examine motor evoked potentials (MEPs) in erector spinae (ES) and in rectus abdominis (RA) muscles at several time points prior to the rise in electromyographic activity (EMG) of anterior deltoid (AD) muscle. TMS was also used to assess short-interval intracortical inhibition (SICI) and cervicomedullary MEPs (CMEPs) in ES in the standing position. MEPs in ES were larger at time points closer to the rise in AD EMG in both standing and lying positions, whereas MEPs in RA did not differ over the time course examined. Notably, SICI was reduced at time points closer to the rise in AD EMG, with no change in CMEPs. Our results demonstrate that increasing excitability of corticospinal projections to the trunk muscles prior to a voluntary limb movement is likely to be cortical in origin and is muscle specific.

Study Objectives We sought to examine the impact of digital cognitive behavioral therapy (dCBT) for insomnia on both self-reported cognitive impairment and objective cognitive performance. Methods The Defining the Impact of Sleep improvement on Cognitive Outcomes (DISCO) trial was an online, two-arm, single-blind, randomized clinical trial of dCBT versus wait-list control. Participants were aged 25 years and older, met DSM-5 diagnostic criteria for insomnia disorder, and reported difficulties with concentration or memory. Assessments were carried out online at baseline, and 10 and 24 weeks post-randomization. The primary outcome measure was self-reported cognitive impairment, assessed with the British Columbia Cognitive Complaints Inventory (BC-CCI). Secondary outcomes included tests of cognitive performance, insomnia symptoms, cognitive failures, fatigue, sleepiness, depression, and anxiety. Results Four hundred and ten participants with insomnia were recruited and assigned to dCBT (N = 205) or wait-list control (N = 205). At 10 weeks post-randomization the estimated adjusted mean difference for the BC-CCI was −3.03 (95% CI: −3.60, −2.47; p < 0.0001, d = −0.86), indicating that participants in the dCBT group reported less cognitive impairment than the control group. These effects were maintained at 24 weeks (d = −0.96) and were mediated, in part, via reductions in insomnia severity and increased sleep efficiency. Treatment effects in favor of dCBT, at both 10 and 24 weeks, were found for insomnia severity, sleep efficiency, cognitive failures, fatigue, sleepiness, depression, and anxiety. We found no between-group differences in objective tests of cognitive performance. Conclusions Our study shows that dCBT robustly decreases self-reported cognitive impairment at post-treatment and these effects are maintained at 6 months.

Interactions between the mammalian host and commensal microbiota are enforced through a range of immune responses that confer metabolic benefits and promote tissue health and homeostasis. Immunoglobulin A (IgA) responses directly determine the composition of commensal species that colonize the intestinal tract but require substantial metabolic resources to fuel antibody production by tissue-resident plasma cells. Here, we demonstrate that IgA responses are subject to diurnal regulation over the course of a circadian day. Specifically, the magnitude of IgA secretion, as well as the transcriptome of intestinal IgA + plasma cells, was found to exhibit rhythmicity. Oscillatory IgA responses were found to be entrained by time of feeding and were also found to be in part coordinated by the plasma cell–intrinsic circadian clock via deletion of the master clock gene Arntl . Moreover, reciprocal interactions between the host and microbiota dictated oscillatory dynamics among the commensal microbial community and its associated transcriptional and metabolic activity in an IgA-dependent manner. Together, our findings suggest that circadian networks comprising intestinal IgA, diet, and the microbiota converge to align circadian biology in the intestinal tract and to ensure host-microbial mutualism.