Healthy Human Subjects Research Articles

Polarization optical coherence tomography optoretinography: verifying light-induced photoreceptor outer segment shrinkage and subretinal space expansion.

Stimulus-evoked intrinsic optical signal (IOS) changes in retinal photoreceptors are critical for functional optoretinography (ORG). Optical coherence tomography (OCT), with its depth-resolved imaging capability, has been actively explored for IOS imaging of retinal photoreceptors. However, recent OCT studies have reported conflicting results regarding light-induced changes in the photoreceptor outer segments (OSs), with both elongation and shrinkage being observed. These discrepancies may stem from the difficulty in reliably identifying OS boundaries, particularly the inner segment/outer segment (IS/OS) junction and OS tip, as well as potential confusion with subretinal space dynamics. Gaining a better understanding of these light-induced OS changes is essential for accurate interpretation of ORG measurements and for optimizing IOS imaging systems to enhance sensitivity. We aim to develop a method for the reliable identification of OS boundaries and to verify light-induced photoreceptor OS shrinkage and subretinal space expansion. We employed a polarization-resolved full-field swept-source optical coherence tomography system capable of sequentially capturing parallel-polarization and cross-polarization OCT signals. The parallel-polarization mode is optimized to detect ballistically reflected photons from well-defined retinal boundaries, such as the IS/OS junction and the photoreceptor tips, whereas cross-polarization primarily captures multiply scattered photons. This differentiation enables parallel-polarization OCT to minimize the interference from scattered photons, enhancing the precision of OCT band quantification. Parallel-polarization OCT revealed photoreceptor OS shrinkage and subretinal space expansion in light conditions compared with dark conditions. Moreover, the overall outer retinal length appeared to swell under light. These observations were consistently confirmed in four healthy adult human subjects. Parallel-polarization OCT provides a reliable method for identifying the IS/OS junction and OS tip, confirming light-induced photoreceptor OS shrinkage and subretinal space expansion.

DOP012 Promising effects of IMU-856, an orally available epigenetic modulator of barrier regeneration - biomarker findings from a Phase 1 clinical study

Abstract Background A dysfunctional intestinal mucosal barrier is a key pathophysiological hallmark and driver of a broad range of gastrointestinal diseases including inflammatory bowel disease (IBD). To date, there are no adequate treatment strategies to ameliorate impaired barrier function. IMU-856 is an orally available and systemically acting small molecule modulator of sirtuin 6 (SIRT6), a histone/non-histone protein deacetylase which serves as a transcriptional regulator of intestinal barrier function and regeneration of bowel epithelium. In preclinical studies, IMU-856´s mechanism of action has been shown to avoid suppression of immune cells. This could present a new approach to treat intestinal barrier function associated diseases without the serious consequences associated with many immunosuppressive therapies. Methods This was a first-in-human, double-blind, randomized, placebo-controlled clinical trial of IMU-856 in healthy volunteers and patients with celiac disease. In the multiple ascending dose part, healthy human subjects were dosed once-daily for 14 consecutive days with IMU-856 at three different dose levels or placebo. Phase 1b was designed to assess safety and tolerability of IMU-856 at two different dose levels in patients with celiac disease during periods of gluten-free diet and a 15-day gluten challenge. Further objectives included pharmacokinetics and the assessment of histological changes. Biomarkers reflecting intestinal enterocyte function, intestinal integrity, nutrient absorption and general gut health were analyzed to assess the effect on the overall protection of gut architecture. Results IMU-856 was safe and well-tolerated with a benign adverse event profile and pharmacokinetics that allow once-daily dosing. There were no systematic clinically relevant findings relative to safety and tolerability. Treatment with IMU-856 improved the mass, metabolic function and health of intestinal enterocytes as measured by nutrient uptake as well as several biomarkers for intestinal function and integrity as well as general gut health [1]. Conclusion IMU-856 is a safe, highly selective and potent epigenetic modulator, showing signals of improving the intestinal barrier function in patients with celiac disease undergoing a gluten challenge.The positive effects of IMU-856 on various biomarkers for intestinal function, overall health and integrity in conjunction with the protection of gut architecture show that IMU-856 may offer extensive potential in other gastrointestinal diseases with compromised intestinal barrier function like IBD.

P0173 The impact of dietary composition on metallothionein gene expression in the intestinal epithelium by exclusive enteral nutrition

Abstract Background The mechanism by which exclusive enteral nutrition (EEN) is effective in the treatment of Crohn’s disease remains elusive. Epidemiologic studies have shown that a substantial proportion of patients with Crohn’s disease are deficient in micronutrients such as zinc, which has been shown to play an important role in the integrity of intestinal epithelial barrier function. Zinc plays a critical role in the transcriptional regulation of metallothioneins (MT), cysteine rich binding proteins that regulate both epithelial and immune function where they are generally believed to play a beneficial role in reducing disease. Methods Transcriptomic analyses were performed by both bulk RNAseq as well as GeoMx spatial transcriptomics. Enzymatic food digests using both bile acids and pancreatic enzymes, analyzed by Proton NMR metabolomics, were used to generate cell culture media for studies in intestinal epithelial cells. Results RNAseq of rectal biopsies obtained from healthy human subjects consuming EEN (Modulen-IBD, Nestlé Health Science) vs. an omnivore diet revealed a very specific induction of genes involved in mineral transport, namely MTs such as MT1G and MT2A. Spatial transcriptomics revealed that the induction of MTs was specific to the colonic epithelium. To develop a cellular model to characterize the mechanism underlying this response, we investigated the impact of animal protein, vegetable, and EEN based foods on the transcriptome of intestinal epithelial cells in culture by both RNAseq and targeted quantitative RT-PCR. This model involved the development of a physiologically relevant modality to digest whole food to generate serum-free cell culture media that was characterized using NMR-based metabolomics. Animal protein and EEN diets induced the expression of specific MTs whereas vegetable diets reduced their expression. We also show that zinc induced MT gene expression in intestinal epithelial cells whereas phytic acid, a phytochemical with known anti-nutrient properties that chelates zinc, reduces the ability of protein-based foods and EEN to induce MT gene expression. Conclusion The consumption of EEN leads to a very specific transcriptomic signature of MT gene expression in the rectal epithelium of humans that can be reproduced in cell culture by exposure to both animal protein-based foods and EEN. By contrast, vegetable-based foods inhibit MT gene expression possibly through the chelation of zinc. These results are consistent with the notion that the exclusion of plant-based foods through the consumption of EEN may have beneficial effects in the treatment of Crohn’s disease by reducing exposure to anti-nutrient phytochemicals that reduce the absorption of beneficial micronutrients such as zinc.

Impaired macroscopic CSF flow by sevoflurane in humans - both during and after anesthesia.

According to the model of the glymphatic system, the directed flow of cerebrospinal fluid (CSF) is a driver of waste clearance from the brain. In sleep, glymphatic transport is enhanced, but it is unclear how it is affected by anesthesia. Animal research indicates partially opposing effects of distinct anesthetics but corresponding results in humans are lacking. Thus, this study aims to investigate the effect of sevoflurane anesthesia on CSF flow in humans, both during and after anesthesia. Using data from a functional magnetic resonance imaging (fMRI) experiment in 16 healthy human subjects before, during, and 45 minutes after sevoflurane mono-anesthesia of 2vol%, we related grey matter blood-oxygenation-level dependent (BOLD) signals to CSF flow, indexed by fMRI signal fluctuations, across the basal cisternae. Specifically, CSF flow was measured by CSF fMRI signal amplitudes, global grey matter (gGM) functional connectivity by the median of inter-regional GM fMRI Spearman rank correlations, and gGM-CSF basal cisternae coupling by Spearman rank correlations of fMRI signals. Anesthesia decreased cisternal CSF peak-to-trough amplitude (median difference Mdn-diff = 1.00, 95% CI [0.17 1.83], p = .013), disrupted the global, cortical BOLD-fMRI-based connectivity (Mdn-diff = 1.5, 95% CI [0.67, 2.33], p < 0.001) and, global grey matter (gGM)-CSF coupling (Mdn-diff = 1.19, 95% CI [0.36, 2.02], p = 0.002). Remarkably, the impairments of global connectivity (Mdn-diff = 0.94, 95% CI [0.11, 1.77], p = 0.022) and gGM-CSF coupling (Mdn-diff = 1.06, 95% CI [0.23, 1.89], p = 0.008) persisted after re-emergence from anesthesia. Collectively, our data show that sevoflurane impairs macroscopic CSF flow via a disruption of coherent gGM activity. This effect persists, at least for a short time, after regaining consciousness. Future studies need to elucidate whether this contributes to the emergence of postoperative neurocognitive symptoms, especially in older patients or those with dementia.

Nose-to-brain delivery of DHA-loaded nanoemulsions: A promising approach against Alzheimer's disease.

Reduced docosahexaenoic acid (DHA) concentrations seem to be associated with an increased risk of Alzheimer's disease (AD), and DHA accretion to the brain across the blood-brain-barrier (BBB) can be modulated by various factors. Therefore, there is an urgent need to identify an efficient and non-invasive method to ensure brain DHA enrichment. In the present study, a safe and stable DHA-enriched nanoemulsion, designed to protect DHA against oxidation, was designed and administered intranasally in a transgenic mouse model of AD, the J20 mice. Intranasal treatment with nanoformulated DHA significantly improved well-being and working spatial memory in six-months-old J20 mice. These behavioral effects were associated with a reduction of amyloid deposition, oxidative stress, and neuroinflammation in brain tissues, which may be partially due to DHA-induced inactivation of the pleiotropic kinase GSK3β. In conclusion, intranasal DHA administration exhibited strong therapeutic effects and disease-modifying benefits in the J20 AD model. Given that DHA has already shown safety and tolerability in healthy human subjects, our results further support the need for clinical trials to assess the potential of this approach in Alzheimer's patients.

Verifying the Accuracy of Hemodynamic Analysis Using High Spatial Resolution 3D Phase-contrast MR Imaging on a 7T MR System: Comparison with a 3T System

Hemodynamics is important in the initiation, growth, and rupture of intracranial aneurysms. Since intracranial aneurysms are small, a high-field MR system with high spatial resolution and high SNR is desirable for this hemodynamic analysis. The purpose of this study was to investigate whether the accuracy of MR fluid dynamic (MRFD) results based on 3D phase-contrast MR (3D PC MR, non-electrocardiogram[ECG]-gated 4D Flow MRI) data from a human cerebrovascular phantom and human healthy subjects obtained by a 7T MR system was superior to those by a 3T MR system. 3D PC MR and 3D time of flight MR angiography (3D TOF MRA) imaging were performed on a 3T MR system and a 7T MR system for a human cerebrovascular phantom and 10 healthy human subjects, and MRFD analysis was performed using these data. The MRFD results from each MR system were then compared with the following items based on the computational fluid dynamics (CFD) results: 3D velocity vector field; correlation coefficient (R), angular similarity index (ASI), and magnitude similarity index (MSI) of blood flow velocity vectors. In the MRFD results of 3D velocity vectors of the cerebrovascular phantom, noise-like vectors were observed near the vascular wall on the 3T MR system, but no noise was observed on the 7T MR system, showing results similar to those of CFD. In the MRFD results of the cerebrovascular phantom and healthy subjects, the correlation coefficients R, ASI, and MSI of the 7T MR system were higher than those of the 3T MR system, and ASI and MSI of healthy human subjects were significantly different between the two systems. The accuracy of high spatial resolution MRFD using the 7T MR system exceeded that of the 3T MR system.

Neurophysiological and Cognitive Changes Induced by the Acute Head-Down Tilt.

In space, under weightlessness conditions, human brain activity is changed due to the shifting of body fluid and blood toward the cephalic region. This shifting leads to changes in cerebral hemodynamics and, consequently, neurophysiological function, which impacts mental functions like cognition and decision-making capabilities of space travelers. The present study reports the effect of acute exposure to simulated microgravity on cognitive functions and event-related potentials. There were 18 healthy human subjects who participated in a 1-h 6° head-down tilt (HDT) bed rest to simulate physiological conditions during microgravity. Subjects were instructed to perform event-related potential tasks and cognitive tasks with a simulator sickness questionnaire to evaluate their performance, attention, and alertness during weightlessness, at baseline, after microgravity exposure, and after a recovery of 30 min. A significant change was found in the latency of P300 as compared to the baseline. The amplitude of the P300 wave was changed during HDT. The mean reaction time of contingent negative variation increased significantly as compared to the baseline. A significant increase in choice reaction time was observed during HDT vs. baseline. The values recovered partially after 30 min of exposure. It was concluded that simulated microgravity impacts mental functions as evidenced by alterations in choice reaction time and event-related potential latencies and reaction time. The study has applied value for understanding neurophysiological responses and optimization of cognitive performance in space conditions. Sharma M, Gaur S, Pawar H, Yadav N, Thondala B, Kumar S, Kishore K, Ray K, Panjwani U. Neurophysiological and cognitive changes induced by the acute head-down tilt. Aerosp Med Hum Perform. 2025; 96(1):45-52.

Swarm-initialized adaptive controller with beetle antenna searching of wearable lower limb exoskeleton for sit-to-stand and walking motions.

In recent years, exoskeleton robots have attracted great interest from researchers in the area of robotics due to their ability to assist human functionality improvement. A wearable lower limb exoskeleton is aimed at supporting the limb functionality rehabilitation process and to assist physical therapists. Development of a stable and robust control system for multi-joint rehabilitation robots is a challenging task due to their non-linear dynamic systems. This paper presents the development of a Swarm-Initialized Adaptive (SIA) based controller, which is a combination of a swarm-based intelligence, named Swarm Beetle Antenna Searching (SBAS), and an adaptive Lyapunov-based controller. The SBAS initializes the parameters of SIA to efficiently improve the performance of the control system and then these controller parameters are updated by an adaptive controller. The control system is validated in a lower limb exoskeleton prototype with four degrees of freedom, using a healthy human subject for sit-to-stand and walking motions. The experimental results show the applicability of the proposed method and demonstrate that our approach obtained efficient control performance in terms of steady-state error and robustness and can be used for a lower limb exoskeleton to improve human mobility.

In silico validation of non-invasive arterial compliance estimation and potential determinants of its variability.

Arterial compliance (AC) is an important cardiovascular parameter characterizing mechanical properties of arteries. AC is significantly influenced by arterial wall structure and vasomotion, and it markedly influences cardiac load. A new method, based on a two-element Windkessel model, has been recently proposed for estimating AC as the ratio of the time constant T of the diastolic blood pressure decay and peripheral vascular resistance derived from clinically available stroke volume measurements and selected peripheral blood pressure parameters which are less prone to peripheral distortions. The aim of this study was to validate AC estimation using a virtual population generated by in silico model of the systemic arterial tree. In the second part of study, we analysed causal coupling between AC oscillations and variability of its potential determinants - systolic blood pressure and heart rate in healthy young human subjects. The pool of virtual subjects (n=3818) represented an extensive AC distribution. AC was estimated from the peripheral blood pressure curve and by the standard method from the aortic blood pressure curve. The proposed method slightly overestimated AC set in the model but both ACs were strongly correlated (r=0.94, p<0.001). In real data, we observed that AC dynamics was coupled with basic cardiovascular parameters variability independently of the autonomic nervous system state. In silico analysis suggests that AC can be reliably estimated by noninvasive method. The analysis of short-term AC variability together with its determinants could improve our understanding of factors involved in AC dynamics potentially improving assessment of AC changes associated with atherosclerosis process. Key words Arterial compliance, Cardiovascular model, Arterial blood pressure, Causal analysis, Volume-clamp photoplethysmography.

Prebiotics and vitamins enhance gut barrier in a randomized double-blind placebo-controlled trial

Purpose Intestinal mucosa functions as a specialized permeable barrier, facilitating nutrient absorption and safeguarding against external influences. Gut barrier serves as a channel of communication between gastrointestinal and bodily processes. Research investigations have postulated that enhancing gut barrier through microbiota could potentially enhance overall well-being. Hence, this intervention study was designed to assess whether intervention of microbiota modulators delivers intestinal and extra-intestinal benefits. Design/methodology/approach A randomized, double-blind, placebo-controlled trial was devised to examine the impact of two doses (1.5 and 3 g) of intervention, comprising prebiotics and vitamins on gut barrier indicators (faecal IgA and calprotectin) and microbiota markers (lactobacilli and bifidobacteria) of healthy human subjects. In addition, cholera vaccine challenge test was conducted to assess the influence of the barrier improvement on the mucosal response to a stressor. Findings After two weeks of intervention, prebiotics and vitamins resulted in a significant (p = 0.04) enhancement of faecal IgA levels compared to placebo. This enhancement coincided with an increase in levels of faecal lactobacilli and bifidobacteria. A significant (p &lt; 0.001) reduction in faecal calprotectin levels was observed in both intervention groups at the end of intervention, compared to placebo. Following cholera vaccine challenge, a markedly (p &lt; 0.03) heightened response was documented in intervention groups. Research limitations/implications This study illustrated that combination of prebiotics and vitamins could effectively modulate gut barrier and microbiota markers in healthy individuals, which contribute to a good gut health. These findings establish a foundation for delivering optimal bodily functions dwelling from a healthy gut. Originality/value This is one of its kind study which has probed into the physiological response with improvement in gut health markers.

Integrated analysis of metabolome, lipidome, and gut microbiome reveals the immunomodulation of Astragali radix in healthy human subjects

BackgroundAs a typical medicinal food homology species, Chinese herbal medicine Astragali radix (AR) has been widely used to regulate the human immune system worldwide. However, the human immunomodulation of AR and its corresponding mechanisms remain unclear.MethodsFirst, following a fortnight successive AR administration, the changes in immune cytokines and immune cells from 20 healthy human subjects were used as immune indicators to characterize the immunomodulatory effects of AR. Subsequently, ultra-high-performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry (UHPLC-Q-TOF/MS) based lipidomics and metabolomics analysis was performed on human serum, urine, and feces samples to investigate the changes in metabolic profiles. Then, 16S rRNA gene sequencing of feces samples was adopted for the changes of human gut microbiota. Finally, correlation analysis was conducted on the gut microbiome, metabolome/lipidome data, and immune indicators.ResultsAR displayed good safety in clinical use and posed a minor impact on gut microbiota major genera, global metabolic profiles, and immune cells. Meanwhile, AR could significantly up-regulate anti-inflammatory cytokines, down-regulate serum creatinine and pro-inflammatory cytokines, promote the anabolism of arginine, glycerolipid, sphingolipid, and purine, and the catabolism of phenylalanine and glycerophospholipid. Moreover, these AR-induced changes were closely correlated with significantly decreased Granulicatella, slightly higher Bifidobacterium, Ruminococcus, and Subdoligranulum, and slightly lower Blautia.ConclusionThe study clearly demonstrated that AR could modulate the human immune, by modifying the metabolism of amino acids, lipids, and purines in a microbiota-related way.Trial registration ChiCTR, ChiCTR2100054765. Registered 26 December 2021-Prospectively registered, https://www.chictr.org.cn/historyversionpub.html?regno=ChiCTR2100054765

Track-Weighted Dynamic Functional Connectivity Profiles and Topographic Organization of the Human Pulvinar.

The human pulvinar is considered a prototypical associative thalamic nucleus as it represents a key node in several cortico-subcortical networks. Through this extensive connectivity to widespread brain areas, it has been suggested that the pulvinar may play a central role in modulating cortical oscillatory dynamics of complex cognitive and executive functions. Additionally, derangements of pulvinar activity are involved in different neuropsychiatric conditions including Lewy-body disease, Alzheimer's disease, and schizophrenia. Anatomical investigations in nonhuman primates have demonstrated a topographical organization of cortico-pulvinar connectivity along its dorsoventral and rostrocaudal axes; this specific organization shows only partial overlap with the traditional subdivision into subnuclei (anterior, lateral, medial, and inferior) and is thought to coordinate information processing within specific brain networks. However, despite its relevance in mediating higher-order cognitive functions, such a structural and functional organization of the pulvinar in the human brain remains poorly understood. Track-weighted dynamic functional connectivity (tw-dFC) is a recently developed technique that combines structural and dynamic functional connectivity, allowing the identification of white matter pathways underlying the fluctuations observed in functional connectivity between brain regions over time. Herein, we applied a data-driven parcellation approach to reveal topographically organized connectivity clusters within the human pulvinar complex, in two large cohorts of healthy human subjects. Unsupervised clustering of tw-dFC time series within the pulvinar complex revealed dorsomedial, dorsolateral, ventral anterior, and ventral posterior connectivity clusters. Each of these clusters shows functional coupling to specific, widespread cortico-subcortical white matter brain networks. Altogether, our findings represent a relevant step towards a better understanding of pulvinar anatomy and function, and a detailed characterization of his role in healthy and pathological conditions.

Tactile imagery affects cortical responses to vibrotactile stimulation of the fingertip

Mental imagery is a crucial cognitive process, yet its underlying neural mechanisms remain less understood compared to perception. Furthermore, within the realm of mental imagery, the somatosensory domain is particularly underexplored compared to other sensory modalities. This study aims to investigate the influence of tactile imagery (TI) on cortical somatosensory processing. We explored the cortical manifestations of TI by recording EEG activity in healthy human subjects. We investigated event-related somatosensory oscillatory dynamics during TI compared to actual tactile stimulation, as well as somatosensory evoked potentials (SEPs) in response to short vibrational stimuli, examining their amplitude-temporal characteristics and spatial distribution across the scalp. EEG activity exhibited significant changes during TI compared to the no-imagery baseline. TI caused event-related desynchronization (ERD) of the contralateral μ-rhythm, with a notable correlation between ERD during imagery and real stimulation across subjects. TI also modulated several SEP components in sensorimotor and frontal areas, showing increases in the contralateral P100 and P300, contra- and ipsilateral P300, frontal P200, and parietal P600 components. The results clearly indicate that TI affects cortical processing of somatosensory stimuli, impacting EEG responses in various cortical areas. The assessment of SEPs in EEG could serve as a versatile marker of tactile imagery in practical applications. We propose incorporating TI in imagery-based brain-computer interfaces (BCIs) to enhance sensorimotor restoration and sensory substitution. This approach underscores the importance of somatosensory mental imagery in cognitive neuroscience and its potential applications in neurorehabilitation and assistive technologies.

Western Blot Characterization of Human Serum Prestin, an Outer Hair Cell Biomarker.

Western blot analysis of human prestin in the blood reveals multiple bands, rather than a single band. Previously, using the ELISA method, prestin was shown to be a good biomarker of outer hair cell (OHC) health and sensorineural hearing loss that could be measured in the blood. Recently, we found that a Western blot approach in an experimental model demonstrated three prestin bands providing greater insights into prestin in the blood and its origins. This approach has not yet been explored in humans. Serum samples from 25 healthy human subjects were analyzed. An automated Western blot for each sample was generated, and bands were analyzed and compared with transient evoked otoacoustic emission levels (TEOAE). There were five bands at ~32, ~50, ~94, ~139, and ~171 kDa, respectively. Notably, the ~50-kDa band consistently was the most prominent. When the subjects were divided based on TEOAE level, those with high emission levels had a significantly larger ~94-kDa band than those with low emission levels. Western blot characterization of OHC biomarker prestin in humans shows that the band closest to the previously estimated molecular weight of prestin (81 kDa) is related to a functional measure of OHCs. This finding increases confidence in the value of serum prestin as a biomarker. The Western blot method appears to offer higher-resolution information on serum prestin. Future work will be carried out under pathological conditions to inform on the application of this quantitative method in clinical settings.

Ventilatory response to head-down-tilt in healthy human subjects.

Postural fluid shifts may directly affect respiratory control via a complex interaction of baro- and chemo-reflexes, and cerebral blood flow. Few data exist concerning the steady state ventilatory responses during head-down tilt. We examined the cardiorespiratory responses during acute 50° head-down tilt (HDT) in 18 healthy subjects (mean [SD] age 27 [10] years). Protocol 1 (n=8, two female) was 50° HDT from 60° head-up posture sustained for 10min, while exposed to normoxia, normoxic hypercapnia (5% CO2), hypoxia (12% inspired O2) or hyperoxic hypercapnia (95% O2, 5% CO2). Protocol 2 (n=10, four female) was 50° HDT from supine, sustained for 10min, while breathing either medical air or normoxic hypercapnic (5% CO2) gas. Ventilation ( , pneumotachograph), end-tidal O2 and CO2 concentration and blood pressure (Finapres) were measured continuously throughout each protocol. Middle cerebral artery blood flow velocity (MCAv; transcranial Doppler) was also measured during protocol 2. Ventilation increased significantly (P<0.05) compared to baseline during HDT in both hyperoxic hypercapnia (protocol 1 by mean [SD] 139 [26]%) and normoxic hypercapnia (protocol 1 by mean [SD] 131 [21]% and protocol 2 by 129 [23]%), despite no change in or from baseline. No change in was observed during HDT with medical air or hypoxia, and there was no significant change in MCAv during HDT compared to baseline. The absence of change in cerebral blood flow leads us to postulate that the augmented ventilatory response during steep HDT may involve mechanisms related to cerebral venous pressure and venous outflow.

Study while you sleep: using targeted memory reactivation as an independent research project for undergraduates.

Newly acquired information is stabilized into long-term memory through the process of consolidation. Memories are not static; rather, they are constantly updated via reactivation, and this reactivation occurs preferentially during slow-wave sleep (SWS; also referred to as N3 in humans). Here we present a scalable neuroscience research investigation of memory reactivation using low-cost electroencephalogram (EEG) recording hardware and open-source software for students and educators across the K-12 and higher education spectrum. The investigation uses a method called targeted memory reactivation (TMR), whereby auditory cues that were previously associated with learning are represented during sleep, triggering the recall of stored memories and (through this) strengthening these memories. We demonstrated the efficacy of this technique on seven healthy human subjects (19-35 years old, 3 females, four males). The subjects learned to play a spatial memory game on an app where they associated pictures (e.g., a clock) with locations on a grid while they listened to picture-appropriate sounds (e.g., "tic-toc"); next, they took a nap while undergoing EEG recordings. During SWS, half of the sounds from the game were replayed by the app, while half were substituted with nonlearned sounds. Subjects then played the memory game again after waking. Results showed that spatial recall was improved more for cued than uncued memories, demonstrating the benefits of memory replay during sleep and suggesting that one may intervene in this process to boost recall of specific memories. This research investigation takes advantage of the importance of sleep for memory consolidation and demonstrates improved memory performance by cueing sounds during SWS.NEW & NOTEWORTHY Why study when you could just sleep? We demonstrate how students can perform scalable research investigations to manipulate memory processing during sleep. It is a hands-on way to advance students' understanding of sleep-based memory consolidation and the corresponding neural mechanisms using open-source software and do-it-yourself EEG tools.

The first in-human study to evaluate the antiplatelet properties of the clopidogrel conjugate DT-678 in acute coronary syndrome patients and healthy volunteers.

DT-678 is a novel antiplatelet prodrug, capable of releasing the antiplatelet active metabolite of clopidogrel (AM) upon exposure to glutathione. In this study, we investigated factors responsible for clopidogrel high on-treatment platelet reactivity (HTPR) in acute coronary syndrome (ACS) patients and evaluated the capacity of DT-678 to overcome HTPR. A total of 300 consecutive ACS patients naive to P2Y12 receptor inhibitors were recruited and genotyped for CYP2C19 alleles. Blood samples were drawn before and after administration of 600-mg clopidogrel. Platelet reactivity index (PRI) and plasma AM concentrations were determined and grouped according to their CYP2C19 genotypes. DT-678 was applied ex vivo to whole blood samples to examine its inhibitory effects. To further examine the antiplatelet effectiveness of DT-678 in vivo, 20 healthy human subjects were recruited in a Phase I clinical trial, and each received a single dose of either 3-mg DT-678 or 75-mg clopidogrel. The pharmacokinetics and pharmacodynamics in different CYP2C19 genotype groups were compared. Statistical analyses revealed that CYP2C19 genotype, body mass index, hyperuricaemia, and baseline PRI were significantly associated with a higher risk of clopidogrel HTPR in ACS patients. The addition of DT-678 ex vivo decreased baseline PRI regardless of CYP2C19 genotypes, overcoming clopidogrel HTPR. This observation was further confirmed in healthy volunteers receiving 3mg of DT-678. These results suggest that DT-678 effectively overcomes clopidogrel HTPR resulting from genetic and/or clinical factors in Chinese ACS patients, demonstrating its potential to improve antiplatelet therapy.

Association between neurovascular coupling and neural signals in the resting state as revealed by a combined fMRI and magnetoencephalography study in humans.

The blood oxygenation level-dependent (BOLD) activation reflects hemodynamic events mediated by neurovascular coupling. During task performance, the BOLD hemodynamic response in a relevant area is mainly driven by the high levels of synaptic activity (reflected in local field potentials, LFPs) but, in contrast, during a task-free, resting state, the contribution to BOLD of such neural events is small, as expected by the comparatively (to the task state) low level of neural events. Concomitant recording of BOLD and LFP at rest in animal experiments has estimated the neural contribution to BOLD to ∼10%. Such experiments have not been performed in humans. As an approximation, we recorded (in the same subject, n = 57 healthy participants) at a task-free, resting state the BOLD signal and, in a different session, the magnetoencephalographic (MEG) signal, which reflects purely neural (synaptic) events. We then calculated the turnover of these signals by computing the successive moment-to-moment difference in the BOLD and MEG time series and retaining the median of the absolute value of the differenced series (BOLD and TMEG, respectively). The correlation between normalized turnovers of BOLD (TBOLD) and turnovers of MEG (TMEG) was r = 0.336 (r2 = 0.113; P = 0.011). These results estimate that 11.3% of the variance in TBOLD can be explained by the variance in TMEG. This estimate is close to the aforementioned estimate obtained by direct recordings in animal experiments. NEW & NOTEWORTHY Here, we report on a weak positive association between turnovers of blood oxygenation level-dependent (TBOLD) and magnetoencephalographic (TMEG) signals in 57 healthy human subjects in a resting, task-free state. More specifically, we found that the purely neural TMEG accounted for 11.1% of the TBOLD, a percentage remarkably close to that found between resting-state local field potentials (LFPs) and BOLD recorded concurrently in animal experiments.

The fecal content of Veillonellaceae family bacteria correlates with cognitive parameters in young healthy human subjects

The fecal content of Veillonellaceae family bacteria correlates with cognitive parameters in young healthy human subjects

Customized stiffness control strategy for a six-bar linkage-based gait rehabilitation robot

Abstract Lower limb rehabilitation robots based on linkage-based mechanisms have recently drawn significant attention in the field due to their numerous advantages. The control of previously proposed linkage-based gait rehabilitation robotic orthoses has been achieved using constant speed control without consideration for the interaction forces. However, such an approach can be harmful to people with stroke since the level of disability varies among individuals, and it may cause potential injuries when excessive force is applied by the robot. To overcome this limitation and improve the rehabilitation process, it is necessary to recognize the force exerted by the person during walking and adjust the robot’s assistive torque accordingly, to provide synchronized motion. Thus, in this work, a human-cooperative approach based on a stiffness control strategy for the six-bar linkage-based gait rehabilitation robot is presented. The proposed methodology can serve as a solid foundation for developing a human-cooperative approach for linkage-based lower limb rehabilitation robotic orthoses. The control was validated and tested with eight healthy human subjects. As a result, customized robotic assistance with this mechanism can be provided during training to meet the individual needs of stroke patients, which can lead to increased engagement and contribution, thus improving treatment outcomes.