Phase Dependency of the Human Primary Motor Cortex and Cholinergic Inhibition Cancelation during Beta tACS

The human motor cortex has a tendency to resonant activity at about 20 Hz so stimulation should more readily entrain neuronal populations at this frequency. We investigated whether and how different interneuronal circuits contribute to such resonance by using transcranial magnetic stimulation (TMS) during transcranial alternating current stimulation (tACS) at motor (20 Hz) and a nonmotor resonance frequency (7 Hz). We tested different TMS interneuronal protocols and triggered TMS pulses at different tACS phases. The effect of cholinergic short-latency afferent inhibition (SAI) was abolished by 20 Hz tACS, linking cortical beta activity to sensorimotor integration. However, this effect occurred regardless of the tACS phase. In contrast, 20 Hz tACS selectively modulated MEP size according to the phase of tACS during single pulse, GABAAergic short-interval intracortical inhibition (SICI) and glutamatergic intracortical facilitation (ICF). For SICI this phase effect was more marked during 20 Hz stimulation. Phase modulation of SICI also depended on whether or not spontaneous beta activity occurred at ~20 Hz, supporting an interaction effect between tACS and underlying circuit resonances. The present study provides in vivo evidence linking cortical beta activity to sensorimotor integration, and for beta oscillations in motor cortex being promoted by resonance in GABAAergic interneuronal circuits

Hyper-parameter tuning and feature extraction for asynchronous action detection from sub-thalamic nucleus local field potentials

Introduction: Decoding brain states from subcortical local field potentials (LFPs) indicative of activities such as voluntary movement, tremor, or sleep stages, holds significant potential in treating neurodegenerative disorders and offers new paradigms in brain-computer interface (BCI). Identified states can serve as control signals in coupled human-machine systems, e.g., to regulate deep brain stimulation (DBS) therapy or control prosthetic limbs. However, the behavior, performance, and efficiency of LFP decoders depend on an array of design and calibration settings encapsulated into a single set of hyper-parameters. Although methods exist to tune hyper-parameters automatically, decoders are typically found through exhaustive trial-and-error, manual search, and intuitive experience. Methods: This study introduces a Bayesian optimization (BO) approach to hyper-parameter tuning, applicable through feature extraction, channel selection, classification, and stage transition stages of the entire decoding pipeline. The optimization method is compared with five real-time feature extraction methods paired with four classifiers to decode voluntary movement asynchronously based on LFPs recorded with DBS electrodes implanted in the subthalamic nucleus of Parkinson’s disease patients. Results: Detection performance, measured as the geometric mean between classifier specificity and sensitivity, is automatically optimized. BO demonstrates improved decoding performance from initial parameter setting across all methods. The best decoders achieve a maximum performance of 0.74 ± 0.06 (mean ± SD across all participants) sensitivity-specificity geometric mean. In addition, parameter relevance is determined using the BO surrogate models. Discussion: Hyper-parameters tend to be sub-optimally fixed across different users rather than individually adjusted or even specifically set for a decoding task. The relevance of each parameter to the optimization problem and comparisons between algorithms can also be difficult to track with the evolution of the decoding problem. We believe that the proposed decoding pipeline and BO approach is a promising solution to such challenges surrounding hyper-parameter tuning and that the study’s findings can inform future design iterations of neural decoders for adaptive DBS and BCI

The potential of convolutional neural networks for identifying neural states based on electrophysiological signals: experiments on synthetic and real patient data

Processing incoming neural oscillatory signals in real-time and decoding from them relevant behavioral or pathological states is often required for adaptive Deep Brain Stimulation (aDBS) and other brain-computer interface (BCI) applications. Most current approaches rely on first extracting a set of predefined features, such as the power in canonical frequency bands or various time-domain features, and then training machine learning systems that use those predefined features as inputs and infer what the underlying brain state is at each given time point. However, whether this algorithmic approach is best suited to extract all available information contained within the neural waveforms remains an open question. Here, we aim to explore different algorithmic approaches in terms of their potential to yield improvements in decoding performance based on neural activity such as measured through local field potentials (LFPs) recordings or electroencephalography (EEG). In particular, we aim to explore the potential of end-to-end convolutional neural networks, and compare this approach with other machine learning methods that are based on extracting predefined feature sets. To this end, we implement and train a number of machine learning models, based either on manually constructed features or, in the case of deep learning-based models, on features directly learnt from the data. We benchmark these models on the task of identifying neural states using simulated data, which incorporates waveform features previously linked to physiological and pathological functions. We then assess the performance of these models in decoding movements based on local field potentials recorded from the motor thalamus of patients with essential tremor. Our findings, derived from both simulated and real patient data, suggest that end-to-end deep learning-based methods may surpass feature-based approaches, particularly when the relevant patterns within the waveform data are either unknown, difficult to quantify, or when there may be, from the point of view of the predefined feature extraction pipeline, unidentified features that could contribute to decoding performance. The methodologies proposed in this study might hold potential for application in adaptive deep brain stimulation (aDBS) and other brain-computer interface systems

Targeting HIF2α-ARNT hetero-dimerisation as a novel therapeutic strategy for pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a destructive disease of the pulmonary vasculature often leading to right heart failure and death. Current therapeutic intervention strategies only slow disease progression. The role of aberrant hypoxia-inducible factor (HIF)2α stability and function in the initiation and development of pulmonary hypertension (PH) has been an area of intense interest for nearly two decades. Here we determine the effect of a novel HIF2α inhibitor (PT2567) on PH disease initiation and progression, using two pre-clinical models of PH. Haemodynamic measurements were performed, followed by collection of heart, lung and blood for pathological, gene expression and biochemical analysis. Blood outgrowth endothelial cells from idiopathic PAH patients were used to determine the impact of HIF2α-inhibition on endothelial function. Global inhibition of HIF2a reduced pulmonary vascular haemodynamics and pulmonary vascular remodelling in both su5416/hypoxia prevention and intervention models. PT2567 intervention reduced the expression of PH-associated target genes in both lung and cardiac tissues and restored plasma nitrite concentration. Treatment of monocrotaline-exposed rodents with PT2567 reduced the impact on cardiovascular haemodynamics and promoted a survival advantage. In vitro, loss of HIF2α signalling in human pulmonary arterial endothelial cells suppresses target genes associated with inflammation, and PT2567 reduced the hyperproliferative phenotype and overactive arginase activity in blood outgrowth endothelial cells from idiopathic PAH patients. These data suggest that targeting HIF2α hetero-dimerisation with an orally bioavailable compound could offer a new therapeutic approach for PAH. Future studies are required to determine the role of HIF in the heterogeneous PAH population

Cyclic intensive light exposure induces retinal lesions similar to age-related macular degeneration in APPswe/PS1 bigenic mice

<p>Abstract</p> <p>Background</p> <p>Intensive light exposure and beta-amyloid (Aβ) aggregates have been known as a risk factor for macular degeneration and an important component in the pathologic drusen structure involved in this disorder, respectively. However, it is unknown whether Aβ deposition mediates or exacerbates light exposure-induced pathogenesis of macular degeneration. Several studies including the one from us already showed accumulation of Aβ deposits in the retina in Alzheimer's transgenic mice. Using histopathological analysis combined with electroretinographic functional assessment, we investigated the effects of cyclic intensive light exposure (CILE) on the architecture of retina and related function in the APPswe/PS1bigenic mouse.</p> <p>Results</p> <p>Histopathological analysis has found significant loss of outer nuclear layer/photoreceptor outer segment and outer plexiform layer along with abnormal hypo- and hyper-pigmentation in the retinal pigment epithelium (RPE), remarkable choroidal neovascularization (CNV), and exaggerated neuroinflammatory responses in the outer retina of APPswe/PS1 bigenic mice following cyclic intensive light exposure (CILE), whereas controls remained little change contrasted with age-matched non-transgenic littermates. CILE-induced degenerative changes in RPE are further confirmed by transmission electron microcopy and manifest as formation of basal laminar deposits, irregular thickening of Bruch's membrane (BrM), deposition of outer collagenous layer (OCL) in the subretinal space, and vacuolation in the RPE. Immunofluorescence microscopy reveals drusenoid Aβ deposits in RPE as well as neovessels attached which are associated with disruption of RPE integrity and provoked neuroinflammatory response as indicated by markedly increased retinal infiltration of microglia. Moreover, both immunohistochemistry and Western blots detect an induction of vascular endothelial growth factor (VEGF) in RPE, which corroborates increased CNV in the outer retina in the bigenic mice challenged by CILE.</p> <p>Conclusions</p> <p>Our findings demonstrate that degenerative changes in the outer retina in the APPswe/PS1 bigenic mouse induced by CILE are consistent with these in AMD. These results suggest that an Alzheimer's transgenic animal model with accumulation of Aβ deposits might be an alternative animal model for AMD, if combined with other confounding factors such as intensive light exposure for AMD.</p

Differential expression and correlation of immunoregulation related piRNA in rheumatoid arthritis

BackgroundAlthough PIWI-interacting RNAs (piRNAs) have recently been associated with germline development and many human diseases, their expression pattern and relationship in autoimmune diseases remain indistinct. This study aimed to investigate the presence and correlation of piRNAs in rheumatoid arthritis (RA).MethodsWe first analyzed the expression profile of piRNAs using small RNA sequencing in peripheral leukocytes of three new-onset untreated RA patients and three healthy controls (HCs). We then selected piRNAs related to immunoregulation by bioinformatics analysis and verified them in 42 new-onset RA patients and 81 HCs by RT-qPCR. Furthermore, a receiver operating characteristic curve was generated to quantify the diagnostic performance of these piRNAs. A correlation analysis was conducted to observe the link between piRNA expression and RA clinical characteristics.ResultsA total of 15 upregulated and 9 downregulated piRNAs among 1,565 known piRNAs were identified in peripheral leukocytes of RA patients. Dysregulated piRNAs were enriched in numerous pathways related to immunity. After selection and validation, two immunoregulation piRNAs (piR-hsa-27620 and piR-hsa-27124) were significantly elevated in RA patients and have good abilities to distinguish patients from controls, which have the potential to serve as biomarkers. PIWI and other proteins implicated in the piRNA pathway were also associated with RA

The role of ERK1/2 in colitis through regulation of NADPH oxidase and mitochondrial fission

Objective To investigate the role of extracellular signal regulated kinase 1/2 （ERK1/2） in colitis through the regulation of NADPH oxidase and mitochondrial fission. Methods Mice models of acute colitis were induced by 3% dextran sulfate sodium （DSS）. Thirty C57BL/6J mice were randomly divided into six groups by random number table method： control group， 3%DSS group，1% dimethyl sulfoxide （DMSO） group， ERK1/2 inhibitor（PD98059） group， 3%DSS+1%DMSO group and 3%DSS+PD98059 group， with five mice in each group. The changes of body weight， colonic length， disease activity index and colonic histopathological changes of mice in the control and 3%DSS groups were evaluated， and the expression levels of ERK1/2， p-ERK1/2， Nicotinamide adenine dinucleotide phosphate oxidase 1 （Nox1） and Nox2 in colonic mucosa of mice were detected. Mice in 1%DMSO and 3%DSS+1%DMSO groups were intraperitoneally injected with 1%DMSO. Mice in the PD98059 and 3%DSS+PD98059 groups were intraperitoneally injected with PD98059. The colonic histopathological changes were evaluated among four groups， and the expression levels of Nox1， Nox2， Dynamin related protein 1 （DRP1）， p-DRP1-S616 and p-DRP1-S637 mitochondrial fission related proteins were detected. Mitochondrial fission of colonic epithelial cells in the control and 3%DSS groups was observed by transmission electron microscopy. The co-localization of Nox2 and mitochondrial outer membrane translocator enzyme TOM complex （TOMM20） in colonic mucosa of mice in two groups was analyzed by double-immunofluorescence staining. The correlation between relative expression levels of DRP1 and Nox2 mRNA in mouse colonic mucosa was analyzed in two groups. Results Compared with the control group， mice in the 3%DSS group exhibited body weight loss， shortened colonic length， increased disease activity index and increased colonic histopathological score. The expression levels of p-ERK1/2， Nox1， Nox2 in colonic mucosa of mice were significantly up-regulated in the 3%DSS group （all P &lt; 0.05）. In mice with colitis， mitochondrial fission in colonic epithelial cells was increased， and the colonic mucosa co-localization of DRP1 and Nox2 was elevated， and the relative mRNA expression levels of both target genes were positively correlated （r = 0.678， P &lt; 0.05）. ERK1/2 inhibitor PD98059 improved colonic histopathological changes in mice with colitis， and down-regulated the expression levels of Nox1， Nox2， DRP1， p-DRP1-S616 in colonic mucosa. Conclusion Inhibition of ERK1/2 may ameliorate colitis by down-regulating NADPH oxidase expression and alleviating mitochondrial fission

Pitch then power: limitations to acceleration in quadrupeds

Rapid acceleration and deceleration are vital for survival in many predator and prey animals and are important attributes of animal and human athletes. Adaptations for acceleration and deceleration are therefore likely to experience strong selective pressures—both natural and artificial. Here, we explore the mechanical and physiological constraints to acceleration. We examined two elite athletes bred and trained for acceleration performance (polo ponies and racing greyhounds), when performing maximal acceleration (and deceleration for ponies) in a competitive setting. We show that maximum acceleration and deceleration ability may be accounted for by two simple limits, one mechanical and one physiological. At low speed, acceleration and deceleration may be limited by the geometric constraints of avoiding net nose-up or tail-up pitching, respectively. At higher speeds, muscle power appears to limit acceleration