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A workshop titled “Beyond the Symptom: The Biology of Fatigue” was held virtually September 27-28, 2021. It was jointly organized by the Sleep Research Society and the Neurobiology of Fatigue Working Group of the NIH Blueprint Neuroscience Research Program. For access to the presentations and video recordings, see: https : //neuroscienceblueprint.nih.gov/about/event/beyond-symptom-biology-fatigue. The goals of this workshop were to bring together clinicians and scientists who use a variety of research approaches to understand fatigue in multiple conditions and to identify key gaps in our understanding of the biology of fatigue. This workshop summary distills key issues discussed in this workshop and provides a list of promising directions for future research on this topic. We do not attempt to provide a comprehensive review of the state of our understanding of fatigue, nor to provide a comprehensive reprise of the many excellent presentations. Rather, our goal is to highlight key advances and to focus on questions and future approaches to answering them.

Food security remains a major sustainability challenge in many parts of Sub-Saharan Africa. Food security has numerous determinants that are complex and interlinked, with one of them being social capital. Social capital reflects an individual’s, household’s, or community’s social networks, social interactions, and social support systems that can be mobilized in times of need to maintain, among others, livelihoods or food security. This study aims to further understand how typologies of social capital are associated with household food security in Southern Malawi, with a focus on access to food. We unpack social capital into three typologies, namely bonding, bridging, and linking social capital, and establish which one is most strongly associated with household access to food, and whether this varies by the gender of the household head. To achieve this, we analyze secondary data from 382 households collected through the Malawian Fourth Integrated Household Survey (IHS4), using principal axis factor analysis and logistic regression analysis. Our findings demonstrate that bonding and bridging social capital are associated with better household access to food, while linking social capital was associated with lower household access to food. Bonding social capital was most strongly associated for female-headed households and linking social capital for male-headed households, highlighting that there are differences between such households. This work confirms observations from other related studies in Sub-Saharan Africa exploring the interface of social capital and food security. It also highlights the importance of both acknowledging the gender of the household head and of unpacking social capital into its typologies when considering food security.

Neurofluids is a term introduced to define all fluids in the brain and spine such as blood, cerebrospinal fluid, and interstitial fluid. Neuroscientists in the past millennium have steadily identified the several different fluid environments in the brain and spine that interact in a synchronized harmonious manner to assure a healthy microenvironment required for optimal neuroglial function. Neuroanatomists and biochemists have provided an incredible wealth of evidence revealing the anatomy of perivascular spaces, meninges and glia and their role in drainage of neuronal waste products. Human studies have been limited due to the restricted availability of noninvasive imaging modalities that can provide a high spatiotemporal depiction of the brain neurofluids. Therefore, animal studies have been key in advancing our knowledge of the temporal and spatial dynamics of fluids, for example, by injecting tracers with different molecular weights. Such studies have sparked interest to identify possible disruptions to neurofluids dynamics in human diseases such as small vessel disease, cerebral amyloid angiopathy, and dementia. However, key differences between rodent and human physiology should be considered when extrapolating these findings to understand the human brain. An increasing armamentarium of noninvasive MRI techniques is being built to identify markers of altered drainage pathways. During the three-day workshop organized by the International Society of Magnetic Resonance in Medicine that was held in Rome in September 2022, several of these concepts were discussed by a distinguished international faculty to lay the basis of what is known and where we still lack evidence. We envision that in the next decade, MRI will allow imaging of the physiology of neurofluid dynamics and drainage pathways in the human brain to identify true pathological processes underlying disease and to discover new avenues for early diagnoses and treatments including drug delivery. Evidence level: 1 Technical Efficacy: Stage 3.

Ketamine produces antidepressant effects in patients with treatment-resistant depression, but its usefulness is limited by its psychotropic side effects. Ketamine is thought to act via NMDA receptors and HCN1 channels to produce brain oscillations that are related to these effects. Using human intracranial recordings, we found that ketamine produces gamma oscillations in prefrontal cortex and hippocampus, structures previously implicated in ketamine’s antidepressant effects, and a 3 Hz oscillation in posteromedial cortex, previously proposed as a mechanism for its dissociative effects. We analyzed oscillatory changes after subsequent propofol administration, whose GABAergic activity antagonizes ketamine’s NMDA-mediated disinhibition, alongside a shared HCN1 inhibitory effect, to identify dynamics attributable to NMDA-mediated disinhibition versus HCN1 inhibition. Our results suggest that ketamine engages different neural circuits in distinct frequency-dependent patterns of activity to produce its antidepressant and dissociative sensory effects. These insights may help guide the development of brain dynamic biomarkers and novel therapeutics for depression.

Functional magnetic resonance imaging (fMRI) has proven to be a powerful tool for noninvasively measuring human brain activity; yet, thus far, fMRI has been relatively limited in its temporal resolution. A key challenge is understanding the relationship between neural activity and the blood-oxygenation-level-dependent (BOLD) signal obtained from fMRI, generally modeled by the hemodynamic response function (HRF). The timing of the HRF varies across the brain and individuals, confounding our ability to make inferences about the timing of the underlying neural processes. Here we show that resting-state fMRI signals contain information about HRF temporal dynamics that can be leveraged to understand and characterize variations in HRF timing across both cortical and subcortical regions. We found that the frequency spectrum of resting-state fMRI signals significantly differs between voxels with fast versus slow HRFs in human visual cortex. These spectral differences extended to subcortex as well, revealing significantly faster hemodynamic timing in the lateral geniculate nucleus of the thalamus. Ultimately, our results demonstrate that the temporal properties of the HRF impact the spectral content of resting-state fMRI signals and enable voxel-wise characterization of relative hemodynamic response timing. Furthermore, our results show that caution should be used in studies of resting-state fMRI spectral properties, as differences can arise from purely vascular origins. This finding provides new insight into the temporal properties of fMRI signals across voxels, which is crucial for accurate fMRI analyses, and enhances the ability of fast fMRI to identify and track fast neural dynamics.

Objective. Regeneration of damaged nerves is required for recovery following nervous system injury. While neural cell behavior may be modified by neuromodulation techniques, the impact of static direct current (DC) magnetic stimulation remains unclear. Approach. This study quantifies the effects of DC magnetostimulation on primary neuronal outgrowth in vitro. The extension of neurites of dorsal root ganglia (DRG) subjected to two different low-strength (mT) static magnetic flux configurations was investigated. Main results. After 3 d of 1 h in-plane (IP) magnetic field stimulation, a 62.5% increase in neurite outgrowth area was seen relative to unstimulated controls. The combined action of in-plane + out-of-plane (IP + OOP) magnetic field application produced a directional outgrowth bias parallel to the IP field direction. At the same time, the diverse magnetic field conditions produced no changes in two soluble neurotrophic factors, nerve growth factor and brain-derived neurotrophic factor, released from resident glia. Significance. These results demonstrate the potential for DC magnetostimulation to enhance neuronal regrowth and improve clinical outcomes.

Purpose: The purpose of this study is to explore the experiences of parents of children with type 1 diabetes mellitus (T1DM) who are living in rural areas. Individuals living in rural areas face barriers to accessing health care that lead to significant health disparities with increased morbidity and mortality. There is a need to understand the unique experiences of those living in rural communities to support their health needs. Methods: In this qualitative study, a convenience sample of 11 parents of children who were diagnosed with T1DM in the last 10 years living in Vermont were recruited through connections with local health professionals and family support networks and interviewed about their experiences. Interviews were transcribed verbatim and analyzed using Braun and Clarke’s 6-step approach to reflexive thematic analysis. Results: Five themes were identified to capture the experience of parenting a child with T1DM in a rural community, including enduring emotional traumas, living life on call, adapting to everyday challenges, lacking a safety net for support, and finding a rhythm. Conclusions: Although findings echo many themes found in previous studies on experiences of parents of children with T1DM, participants also identified unique barriers such as physical distance from formal and informal support systems, unreliable and/or insufficient technological resources, and lack of understanding of T1DM by their communities, including among child care and schools. Diabetes care and education specialists working with families living in rural areas must explore ways to educate key supports to these families to minimize isolation, stigma, and burnout among parents.

Objective To explore birth stories of autistic women to understand how they make sense of the experience of childbirth. Design Narrative analysis. Setting Online interviews. Participants Sixteen women on the autism spectrum shared 19 birth stories. Methods Participants were recruited from online autism forums and were invited to share their birth stories via online asynchronous interviews. Using Burke’s approach to narrative analysis, we identified five elements within each story, including Scene (when/where), Agents (who), Act (what), Agency (how), and Purpose (why). We explored parts of the narratives where two or more elements were out of balance with each other. Results Tension most often occurred when actions taken by the health care team (Act) were out of balance with their approach to care (Agency), which left participants feeling that their concerns were minimized, their wishes were ignored, and they were left out of critical communication and education. Participants also struggled when their own autistic traits (Agent), such as sensory sensitivities, were out of balance with the birth environment (Scene), which impaired their ability to communicate with providers and participate in the birth. Conclusion Poor communication, untreated pain, and sensory overload dominated the birth narratives of participants. Nurses should trust women’s reports of pain and anxiety because autistic women may appear calm even when in severe distress. Environmental adjustments, such as dimming the lights, can help minimize sensory overload. Nurses need to provide thorough and nonjudgmental education about the birth process to ensure that autistic women feel safe and in control and do not withdraw from care.

Sleep is essential for brain function in a surprisingly diverse set of ways. In the short term, lack of sleep leads to impaired memory and attention; in the longer term, it produces neurological dysfunction or even death. This review article discusses recent advances in understanding how sleep maintains the physiological health of the brain, via interconnected systems of neuronal activity and fluid flow. The neural dynamics that appear during sleep are intrinsically coupled to its consequences for blood flow, cerebrospinal fluid dynamics, and waste clearance. Recognizing these linked causes and consequences of sleep has shed new light on why sleep is important for such disparate aspects of brain function.

Sleep research has evolved considerably since the first sleep electroencephalography (EEG) recordings in the 1930s and the discovery of well-distinguishable sleep stages in the 1950s. While electrophysiological recordings have been used to describe the sleeping brain in much detail, since the 1990s neuroimaging techniques are applied to uncover the brain organization and functional connectivity of human sleep with greater spatial resolution. The combination of EEG with different neuroimaging modalities such as Positron Emission Tomography (PET), structural MRI (sMRI) and functional Magnetic Resonance Imaging (fMRI) impose several challenges for sleep studies. For instance, difficulties maintaining and consolidating sleep in an unfamiliar and restricted environment, scanner-related distortions with physiological artifacts may contaminate polysomnography recordings, and the necessity to account for all physiological changes throughout the sleep cycles to better data interpretability. Here, we review the field of sleep neuroimaging in healthy non-sleep-deprived populations, from early findings to more recent developments, discuss the challenges of applying concurrent EEG and imaging techniques to sleep, and possible future directions the field will greatly benefit from.

Simultaneous EEG-fMRI is a powerful multimodal technique for imaging the brain, but its use in neurofeedback experiments has been limited by EEG noise caused by the MRI environment. Neurofeedback studies typically require analysis of EEG in real time, but EEG acquired inside the scanner is heavily contaminated with ballistocardiogram (BCG) artifact, a high-amplitude artifact locked to the cardiac cycle. Although techniques for removing BCG artifacts do exist, they are either not suited to real-time, low-latency applications, such as neurofeedback, or have limited efficacy. We propose and validate a new open-source BCG removal software called EEG-LLAMAS (Low Latency Artifact Mitigation Acquisition Software), which adapts and advances existing artifact removal techniques for low-latency experiments. We first used simulations to validate LLAMAS in data with known ground truth. We found that LLAMAS performed better than the best publicly-available real-time BCG removal technique, optimal basis sets (OBS), in terms of its ability to recover EEG waveforms, power spectra, and slow wave phase. To determine whether LLAMAS would be effective in practice, we then used it to conduct real-time EEG-fMRI recordings in healthy adults, using a steady state visual evoked potential (SSVEP) task. We found that LLAMAS was able to recover the SSVEP in real time, and recovered the power spectra collected outside the scanner better than OBS. We also measured the latency of LLAMAS during live recordings, and found that it introduced a lag of less than 50ms on average. The low latency of LLAMAS, coupled with its improved artifact reduction, can thus be effectively used for EEG-fMRI neurofeedback. This platform enables closed-loop experiments which previously would have been prohibitively difficult, such as those that target short-duration EEG events, and is shared openly with the neuroscience community.

Pervasive feelings of social isolation and loneliness have been longstanding among up to half of older adults, and have received increased attention amid the COVID-19 pandemic. Programs to address loneliness and facilitate meaningful connections are vital for physical and mental wellbeing. The purpose of this study was to explore older adults' experiences participating as volunteers in the

The spontaneous dynamics of the brain modulate its function from moment to moment, shaping neural computation and cognition. Functional MRI (fMRI), while classically used as a tool for spatial localization, is increasingly being used to identify the temporal dynamics of brain activity. fMRI analyses focused on the temporal domain have revealed important new information about the dynamics underlying states such as arousal, attention, and sleep. Dense temporal sampling – either by using fast fMRI acquisition, or multiple repeated scan sessions within individuals – can further enrich the information present in these studies. This review focuses on recent developments in using fMRI to identify dynamics across brain states, particularly vigilance and sleep states, and the potential for highly temporally sampled fMRI to answer these questions.

This research was supported by a Harvard Mind Brain Behavior Interfaculty Initiative Graduate Student Award and a Harvard GSAS Predissertation Summer Fellowship to L.S.L; Japan Society for the Promotion of Science KAKENHI Grants 19H01772 and 20H05000 to F.K.; European Research Council Synergy Grant 609819 SOMICS to J.C.; and European Commission Marie Skłodowska-Curie Fellowship MENTALIZINGORIGINS to C.K. Social animals must carefully track consequential events and opportunities for social learning. However, the competing demands of the social world produce trade-offs in social attention, defined as directed visual attention towards conspecifics. A key question is how socioecology shapes these biases in social attention over evolution and development. Chimpanzees, Pan troglodytes, and bonobos, Pan paniscus, provide ideal models for addressing this question because they have large communities with fission–fusion grouping, divergent sex-based dominance hierarchies and occasional intergroup encounters. Using noninvasive eye-tracking measures, we recorded captive apes’ attention to side-by-side images of familiar and unfamiliar conspecifics of the same sex. We tested four competing hypotheses about the influence of taxonomically widespread socioecological pressures on social attention, including intergroup conflict, dominance, dispersal and mating competition. Both species preferentially attended to familiar over unfamiliar conspecifics when viewing the sex that typically occupies the highest ranks in the group: females for bonobos, and males for chimpanzees. However, they did not demonstrate attentional biases between familiar and unfamiliar members of the subordinate sex. Findings were consistent across species despite differences in which sex tends to be more dominant. These results suggest that sex-based dominance patterns guide social attention across Pan. Our findings reveal how socioecological pressures shape social attention in apes and likely contribute to the evolution of social cognition across primates. Postprint

The moment of awakening from sleep reflects a profound transformation in neural activity and behavior. The thalamus is a key controller of arousal state, but whether its diverse nuclei exhibit coordinated or distinct activity at transitions in behavioral arousal state is not known. Using fast fMRI at ultra-high field (7 Tesla), we measured sub-second activity across thalamocortical networks and within nine thalamic nuclei to delineate these dynamics during spontaneous transitions in behavioral arousal state. We discovered a stereotyped sequence of activity across thalamic nuclei that preceded behavioral arousal after a period of inactivity, followed by widespread cortical deactivation. These thalamic dynamics were linked to whether participants remained awake or fell back asleep, with unified thalamic activation reflecting subsequent maintenance of awake behavior. These results provide an outline of the complex interactions across thalamocortical circuits that orchestrate arousal state transitions, and additionally, demonstrate that fast fMRI can resolve sub-second subcortical dynamics in the human brain.

The apolipoprotein E (APOE) gene is the strongest genetic risk factor for Alzheimer’s disease (AD); however, how it modulates brain homeostasis is not clear. The apoE protein is a major lipid carrier in the brain transporting lipids such as cholesterol among different brain cell types. Here, we show that APOE deficiency in human iPSC-derived cerebral organoids impacts brain lipid homeostasis by modulating multiple cellular and molecular pathways. Molecular profiling through single cell RNA-sequencing revealed that APOE deficiency leads to changes in cellular composition of isogenic cerebral organoids likely by modulating the EIF2 signaling pathway as these events were alleviated by the treatment of a pathway inhibitor ISRIB. APOE deletion also leads to activation of the Wnt/β-catenin signaling pathway with concomitant decrease of SFRP1 expression in glia cells. Importantly, the critical role of apoE in cell type-specific lipid homeostasis was observed upon APOE deletion in cerebral organoids with a specific upregulation of cholesterol biosynthesis in excitatory neurons and excessive lipid accumulation in astrocytes. Relevant to human AD, APOE4 cerebral organoids show altered neurogenesis and cholesterol metabolism compared to those with APOE3. Our work demonstrates critical roles of apoE in brain homeostasis and offers critical insights into the APOE4-related pathogenic mechanisms.

Over the past decade, noninvasive, restraint-free eye-tracking research with primates has transformed our understanding of primate social cognition. The use of this technology with many primate species allows for the exploration and comparison of how these species attend to and understand social agents and interactions. The ability to compare and contrast the cognitive capacities of various primate species, including humans, provides insight into the evolutionary mechanisms and selective pressures that have likely shaped social cognition in similar and divergent ways across the primate order. In this review, we begin by discussing noninvasive behavioral methods used to measure primate gaze and attention before the introduction of noninvasive, restraint-free eye-tracking methodologies. Next, we focus on findings from recent eye-tracking research on primate social cognition, beginning with simple visual and search mechanisms. We then discuss the results that have built on this basic understanding of how primates view images and videos, exploring discrimination and knowledge of social agents, following social cues, tracking perspectives and predicting behavior, and the combination of eye-tracking and other behavioral and physiological methods. Finally, we discuss some future directions of noninvasive eye-tracking research on primate social cognition and current eye-tracking work-in-progress that builds on these previous studies, investigating underexplored socio-cognitive capacities and utilizing new methodologies.

SummarySubanesthetic doses of ketamine produce rapid and sustained anti-depressant effects in patients with treatment-resistant depression. Unfortunately, the usefulness of ketamine as a treatment is limited by its potential for abuse because of psychotropic side effects such as dissociation. Understanding the brain dynamics and the neural circuits involved in ketamine’s effects could lend insight into improved therapies for depression with fewer adverse effects. It is believed that ketamine acts via NMDA receptor and hyperpolarization-activated cyclic nucleotide-gated 1 (HCN1) channels to produce changes in oscillatory brain dynamics. Here we show, in humans, a detailed description of the principal oscillatory changes in cortical and subcortical structures by administration of a subanesthetic dose of ketamine. Using recordings from intracranial electrodes, we found that ketamine increased gamma oscillations within prefrontal cortical areas and the hippocampus--structures previously implicated in ketamine’s antidepressant effects. Furthermore, our studies provide direct evidence of a ketamine-induced 3 Hz oscillation in posteromedial cortex that has been proposed as a mechanism for its dissociative effects. By analyzing changes in neural oscillations after the addition of propofol, whose GABAergic activity antagonizes ketamine’s NMDA-mediated disinhibition alongside a shared HCN1 inhibitory effect, we identified brain dynamics that could be attributed to NMDA-mediated disinhibition versus HCN1 inhibition. Overall, our results imply that ketamine engages different neural circuits in distinct frequency-dependent patterns of activity to produce its antidepressant and dissociative sensory effects. These insights may help guide the development of novel brain dynamic biomarkers and therapeutics for depression.

Background Cancer cell-derived extracellular vesicles (EVs) have previously been shown to contribute to pre-metastatic niche formation. Specifically, aggressive tumors secrete pro-metastatic EVs that travel in the circulation to distant organs to modulate the microenvironment for future metastatic spread. Previous studies have focused on the interface between pro-metastatic EVs and epithelial/endothelial cells in the pre-metastatic niche. However, EV interactions with circulating components such as low-density lipoprotein (LDL) have been overlooked. Results This study demonstrates that EVs derived from brain metastases cells (Br-EVs) and corresponding regular cancer cells (Reg-EVs) display different interactions with LDL. Specifically, Br-EVs trigger LDL aggregation, and the presence of LDL accelerates Br-EV uptake by monocytes, which are key components in the brain metastatic niche. Conclusions Collectively, these data are the first to demonstrate that pro-metastatic EVs display distinct interactions with LDL, which impacts monocyte internalization of EVs.

Autistics are more likely than neurotypicals to be gay, lesbian, bisexual, asexual, and other sexual orientations. Autistics and sexual minorities represent populations at high risk for depression, anxiety, and suicidality. Little is known about the experiences of individuals living at this intersection. In this phenomenology, 67 individuals who identified as autistic sexual minorities participated in online interviews to describe the meaning of their experiences. Six themes emerged, including: self-acceptance is a journey; autistic traits complicate self-identification of sexual orientation; social and sensory stressors affect sexual expression; feeling misunderstood and isolated; challenges finding mutually satisfying relationships; and difficulty recognizing and communicating sexual needs. Autistic sexual minorities experience a "double minority" status that complicates identity formation and increases vulnerability in sexual relationships.

Labor migration has surged in the former Soviet countries such as Kyrgyzstan because of multiple crises that the country faced since the collapse of the Soviet Union. Migration has produced broad impacts on most aspects of life in Kyrgyzstan and is transforming family life in myriad ways. Based on in-depth interviews with members of migrating families, this study explores the impact of labor migration on families from Kyrgyzstan and identifies issues that arise at the intersection of migration and family life. The experiences of migrants and their family members were examined (N = 20). The results revealed that decisions of who would migrate were made jointly among extended families and were driven by economic needs. Migration incurred number of trade-offs and challenges for families, especially separation of family members and additional responsibilities placed on those who remain at home. The study contributes to our understanding of the family level consequences of labor migration, providing a nuanced picture of the benefits and compromises for families.

Effects derived from the simultaneous application of passive, uniform saturating magnetic field and tensile stress during long-time annealing utilizing a unique and simple processing tool, the MultiDriver furnace, are reported. In particular, the evolution of the crystalline structure and the magnetic domain configuration of severely deformed and subsequently annealed equiatomic FeNi alloys were revealed by high-energy synchrotron X-Ray diffraction and Magneto-Optic Kerr Microscopy. These alloys are known to undergo a first-order magnetic phase transformation to a chemically ordered tetragonal (L10) structure in astronomical timeframes. MultiDriver-annealed specimens are found to retain a tetragonal crystallographic state and texture that is similar to that of the precursor deformed state, with a smaller unit cell volume and a larger c/a ratio relative to those of control samples that were annealed under the same conditions but without magnetic field and stress drivers. Magnetic domain images echo these observations: while as-cast FeNi alloys exhibit domain patterns consistent with the presence of a stress-modified cubic magnetocrystalline anisotropy, large areas of domains with uniaxial anisotropy are present in MultiDriver-annealed samples. While no chemical order was demonstrated in these samples, a strategy is proposed for achieving the ordered state by employing a passive magnetic gradient in the MultiDriver furnace to enhance diffusion.

This study describes the development and psychometric evaluation of a new self-report measure of social cognition: the Theory of Mind Inventory:Self-report-Adult (ToMI:SR-Adult). Adults with autism (or a suspicion of autism; n = 111) and typically developing adults (n = 109) completed a demographic questionnaire and the ToMI:SR-Adult online. Both quantitative and qualitative self-reports of one’s own theory of mind functioning were collected. The ToMI:SR-Adult performed well under all examinations of reliability and validity (internal consistency, accuracy of classification, contrasting-groups). The qualitative data confirmed impressions of validity and revealed that the adults in our sample had high levels of self-insight regarding their own theory of mind. The ToMI:SR-Adult is offered as a promising research and clinical tool for the assessment of social cognition in adults.

The hematological module of the Athlete Biological Passport (ABP) represents an important tool in the pursuit to detect blood doping in athletes. Currently, collecting blood samples for ABP analysis can be cumbersome, invasive, and expensive, involving a venous blood draw performed by a trained phlebotomist followed by cold-chain monitored shipping to the analysis laboratory. Developing innovative methods to collect and transport ABP blood samples while adhering to strict preanalytical and analytical requirements has the potential to greatly increase testing frequency and, consequently, the effectiveness of the ABP program globally. The focus of this study was to compare venous blood collections with capillary blood collections to determine if capillary samples could be used for ABP analysis without sacrificing the analytical integrity required for antidoping testing procedures. In this study, capillary blood was collected using the Tasso+ EDTA device (Tasso, Inc.), a novel microvolumetric device that collects liquid, whole blood from skin capillaries on the upper arm. Excellent laboratory agreement was observed between venous and capillary blood samples for the three main ABP parameters: HGB, RET%, and OFF-Score. Additionally, the stability of capillary samples after storage at 4°C, similar to what would be required during transport, was acceptable for up to 72 h following collection. Finally, we generated individual ABP profiles using the adaptive model for 10 participants and observed excellent agreement between venous and capillary profiles. These results indicate capillary blood collection is a viable alternative to venous blood collections for ABP analysis.

We implemented a multi-pronged strategy (MAX) involving chronic (2 weeks high carbohydrate [CHO] diet + gut-training) and acute (CHO loading + 90 g·h−1 CHO during exercise) strategies to promote endogenous and exogenous CHO availability, compared with strategies reflecting lower ranges of current guidelines (CON) in two groups of athletes. Nineteen elite male race walkers (MAX: 9; CON:10) undertook a 26 km race-walking session before and after the respective interventions to investigate gastrointestinal function (absorption capacity), integrity (epithelial injury), and symptoms (GIS). We observed considerable individual variability in responses, resulting in a statistically significant (p < 0.001) yet likely clinically insignificant increase (Δ 736 pg·mL−1) in I-FABP after exercise across all trials, with no significant differences in breath H2 across exercise (p = 0.970). MAX was associated with increased GIS in the second half of the exercise, especially in upper GIS (p < 0.01). Eighteen highly trained male and female distance runners (MAX: 10; CON: 8) then completed a 35 km run (28 km steady-state + 7 km time-trial) supported by either a slightly modified MAX or CON strategy. Inter-individual variability was observed, without major differences in epithelial cell intestinal fatty acid binding protein (I-FABP) or GIS, due to exercise, trial, or group, despite the 3-fold increase in exercise CHO intake in MAX post-intervention. The tight-junction (claudin-3) response decreased in both groups from pre- to post-intervention. Groups achieved a similar performance improvement from pre- to post-intervention (CON = 39 s [95 CI 15–63 s]; MAX = 36 s [13–59 s]; p = 0.002). Although this suggests that further increases in CHO availability above current guidelines do not confer additional advantages, limitations in our study execution (e.g., confounding loss of BM in several individuals despite a live-in training camp environment and significant increases in aerobic capacity due to intensified training) may have masked small differences. Therefore, athletes should meet the minimum CHO guidelines for training and competition goals, noting that, with practice, increased CHO intake can be tolerated, and may contribute to performance outcomes.