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Timely and comprehensive analyses of causes of death stratified by age, sex, and location are essential for shaping effective health policies aimed at reducing global mortality. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023 provides cause-specific mortality estimates measured in counts, rates, and years of life lost (YLLs). GBD 2023 aimed to enhance our understanding of the relationship between age and cause of death by quantifying the probability of dying before age 70 years (70q0) and the mean age at death by cause and sex. This study enables comparisons of the impact of causes of death over time, offering a deeper understanding of how these causes affect global populations. GBD 2023 produced estimates for 292 causes of death disaggregated by age-sex-location-year in 204 countries and territories and 660 subnational locations for each year from 1990 until 2023. We used a modelling tool developed for GBD, the Cause of Death Ensemble model (CODEm), to estimate cause-specific death rates for most causes. We computed YLLs as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. Probability of death was calculated as the chance of dying from a given cause in a specific age period, for a specific population. Mean age at death was calculated by first assigning the midpoint age of each age group for every death, followed by computing the mean of all midpoint ages across all deaths attributed to a given cause. We used GBD death estimates to calculate the observed mean age at death and to model the expected mean age across causes, sexes, years, and locations. The expected mean age reflects the expected mean age at death for individuals within a population, based on global mortality rates and the population's age structure. Comparatively, the observed mean age represents the actual mean age at death, influenced by all factors unique to a location-specific population, including its age structure. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 250-draw distribution for each metric. Findings are reported as counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2023 include a correction for the misclassification of deaths due to COVID-19, updates to the method used to estimate COVID-19, and updates to the CODEm modelling framework. This analysis used 55 761 data sources, including vital registration and verbal autopsy data as well as data from surveys, censuses, surveillance systems, and cancer registries, among others. For GBD 2023, there were 312 new country-years of vital registration cause-of-death data, 3 country-years of surveillance data, 51 country-years of verbal autopsy data, and 144 country-years of other data types that were added to those used in previous GBD rounds. The initial years of the COVID-19 pandemic caused shifts in long-standing rankings of the leading causes of global deaths: it ranked as the number one age-standardised cause of death at Level 3 of the GBD cause classification hierarchy in 2021. By 2023, COVID-19 dropped to the 20th place among the leading global causes, returning the rankings of the leading two causes to those typical across the time series (ie, ischaemic heart disease and stroke). While ischaemic heart disease and stroke persist as leading causes of death, there has been progress in reducing their age-standardised mortality rates globally. Four other leading causes have also shown large declines in global age-standardised mortality rates across the study period: diarrhoeal diseases, tuberculosis, stomach cancer, and measles. Other causes of death showed disparate patterns between sexes, notably for deaths from conflict and terrorism in some locations. A large reduction in age-standardised rates of YLLs occurred for neonatal disorders. Despite this, neonatal disorders remained the leading cause of global YLLs over the period studied, except in 2021, when COVID-19 was temporarily the leading cause. Compared to 1990, there has been a considerable reduction in total YLLs in many vaccine-preventable diseases, most notably diphtheria, pertussis, tetanus, and measles. In addition, this study quantified the mean age at death for all-cause mortality and cause-specific mortality and found noticeable variation by sex and location. The global all-cause mean age at death increased from 46·8 years (95% UI 46·6-47·0) in 1990 to 63·4 years (63·1-63·7) in 2023. For males, mean age increased from 45·4 years (45·1-45·7) to 61·2 years (60·7-61·6), and for females it increased from 48·5 years (48·1-48·8) to 65·9 years (65·5-66·3), from 1990 to 2023. The highest all-cause mean age at death in 2023 was found in the high-income super-region, where the mean age for females reached 80·9 years (80·9-81·0) and for males 74·8 years (74·8-74·9). By comparison, the lowest all-cause mean age at death occurred in sub-Saharan Africa, where it was 38·0 years (37·5-38·4) for females and 35·6 years (35·2-35·9) for males in 2023. Lastly, our study found that all-cause 70q0 decreased across each GBD super-region and region from 2000 to 2023, although with large variability between them. For females, we found that 70q0 notably increased from drug use disorders and conflict and terrorism. Leading causes that increased 70q0 for males also included drug use disorders, as well as diabetes. In sub-Saharan Africa, there was an increase in 70q0 for many non-communicable diseases (NCDs). Additionally, the mean age at death from NCDs was lower than the expected mean age at death for this super-region. By comparison, there was an increase in 70q0 for drug use disorders in the high-income super-region, which also had an observed mean age at death lower than the expected value. We examined global mortality patterns over the past three decades, highlighting-with enhanced estimation methods-the impacts of major events such as the COVID-19 pandemic, in addition to broader trends such as increasing NCDs in low-income regions that reflect ongoing shifts in the global epidemiological transition. This study also delves into premature mortality patterns, exploring the interplay between age and causes of death and deepening our understanding of where targeted resources could be applied to further reduce preventable sources of mortality. We provide essential insights into global and regional health disparities, identifying locations in need of targeted interventions to address both communicable and non-communicable diseases. There is an ever-present need for strengthened health-care systems that are resilient to future pandemics and the shifting burden of disease, particularly among ageing populations in regions with high mortality rates. Robust estimates of causes of death are increasingly essential to inform health priorities and guide efforts toward achieving global health equity. The need for global collaboration to reduce preventable mortality is more important than ever, as shifting burdens of disease are affecting all nations, albeit at different paces and scales. Gates Foundation.
Ten years ago, we published a position paper in this journal, criticizing reductionist claims of neurobiology related to mental disorders and important theoretical concepts like free will. Our interdisciplinary group of experts highlighted the need for and the challenges of integrating different approaches and system levels in neuroscience. We argued-and still argue-that such an integrative and multi-perspective approach is an important precondition for progress in the understanding and treatment of neuro-psychiatric disorders. We now review the progress towards an integrative neuroscience during the past decade in five steps: First, we examine the social and institutional context of brain research that has enabled tremendous technical developments and insights. Nevertheless, many research programs remain reductionist and fail to acknowledge differences between different system levels, their complex interactions, and domain-specific languages. We argue that scientific discourse largely lacks any critical account on the very nature of neurobiological explanations and interdisciplinary interfaces. Second, these conceptual weaknesses lead us to highlight the need for establishing an interdisciplinary neurophilosophy which tackles the challenging multiplicity of perspectives and approaches in modern neurosciences. The task is not just a collaboration between philosophers and neuroscientists, but rather the development of a critical philosophical stance within the neurosciences themselves. Third, based on this, we plead for the importance of the emerging science of complex systems, which is particularly helpful to integrate interdisciplinary knowledge and develop new strategies for modeling multi-level relations and phenomena. We suggest the application of systemic approaches in the mind sciences. Fourth, in line with this holistic view, we present an ecological perspective on human beings. The still dominating cephalocentric paradigm in neurosciences is severely limited without understanding the brain as a regulative organ in a situated organism and-in case of humans-an acting person "extended" to tools, technologies, and social structures. Fifth, in our final section, we illustrate our view using the debate about free will. We argue that any position respecting the complexity and irreducibility of mental phenomena will escape inappropriate reductionist and deterministic assumptions while fully acknowledging scientific evidence. We conclude with the demand for stronger efforts towards an institutionalized, interdisciplinary, systems-oriented neurophilosophy.
Long COVID is increasingly recognized as a multisystem condition involving persistent inflammation, autonomic dysregulation, and metabolic disturbance. The vagus nerve-mediated cholinergic anti-inflammatory pathway (CAP) provides a biologically plausible link between neural regulation and immune homeostasis, while metabolic pathways involving AMP-activated protein kinase (AMPK), sirtuin 1 (SIRT1), and peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) are closely related to mitochondrial function and energy balance. In this review, we synthesize evidence from neuroscience, immunology, and metabolic research to investigate how electroacupuncture (EA) may modulate vagal-cholinergic signaling and the downstream inflammatory and metabolic processes associated with long COVID. Experimental studies indicate that EA can influence CAP-related mechanisms, including α7 nicotinic acetylcholine receptor (α7nAChR)-mediated inhibition of NF-κB/NLRP3-related inflammatory signaling, and may also regulate AMPK-SIRT1-PGC-1α-associated metabolic pathways. Although clinical evidence is more indirect, it suggests that electroacupuncture may affect autonomic function, inflammatory markers, symptom burden, and neurophysiological regulation. To support a balanced interpretation, we organize the evidence in this review into a framework based on levels of evidence, which distinguishes direct preclinical findings from indirect clinical indicators and associations used to generate hypotheses. This framework highlights the potential convergence of vagal-cholinergic anti-inflammatory regulation and metabolic recovery pathways, while recognizing that several proposed connections-particularly those linking CAP-related signaling to improvements in long COVID symptoms-require further validation. Overall, this review provides a structured basis for future mechanistic studies and phenotype-oriented clinical trials evaluating EA as a neuromodulatory strategy for long COVID and related chronic inflammatory conditions.
Sex difference in latency for cervical vestibular-evoked myogenic potential (VEMP) has been reported in Brown Norway rats. Human investigations of sex difference in VEMP latency have shown inconsistent results, although there are indicators of sexual dimorphism in vestibular function and a higher reporting rate for vestibular disorder in women than in men. Sex effects in human VEMP were re-evaluated here using a procedure adapting clinical protocols for higher sensitivity. VEMP was compared between 24 women and 24 men using a novel procedure that (1) controlled neck tension with biofeedback and a padded head bar; (2) used body-conducted stimuli to eliminate sound exposure concerns and collect appreciably more data than is feasible with air-conducted stimuli; which in turn (3) increased statistical power because there were sufficient data for a linear mixed effects regression modelling analysis. Women had significantly shorter VEMP peak to trough latency than men. The sex difference of 2.4 ms (95% CI [-0.9, -3.9], p = 0.0020) was 21% of the mean 11.4 ms VEMP peak to trough latency measured across women and men. There was no significant sex difference in VEMP peak to trough amplitude. These findings are a reversal of several prior studies in humans, reviewed here with a simulation indicating the studies may have been underpowered. Findings are consistent with those in Brown Norway Rats, for which a study design featuring a custom rodent holder to control neck tension, extension of test sequences in comparison to those typically used in VEMP protocols for humans, and insertion of electrodes subcutaneously will have increased sensitivity compared to that achievable with clinical VEMP protocols for humans. Findings are interpreted as sex hormones affecting myelination or synaptic response; sexual dimorphism in neck/head size may also have contributed. The vestibular periphery and brainstem are highly conserved across vertebrates with similar findings in rat and human supporting use of VEMP as a reliable, non-invasive indicator of vestibular function. VEMP measures in humans may require higher sensitivity than is achievable using current clinical protocols in order to produce consistent results.
Consciousness remains one of the central challenges in contemporary neuroscience, in part due to the absence of an explicit framework describing the temporal constraints required for integrative processing. While influential models such as Integrated Information Theory and the Free Energy Principle characterize structural and functional aspects of conscious systems, they remain largely agnostic regarding the minimum temporal windows necessary for information to become phenomenologically accessible. We propose that temporal integration constitutes a biologically invariant constraint operating across multiple organizational scales. Drawing on recent experimental evidence of memory formation in non-neuronal cells, we introduce the concept of a minimal bioelectrical/biochemical temporal window (ΔT_b) governing cellular information consolidation. We propose that this foundational temporal constraint may contribute to organismic basal coherence (γ) through bioelectric and autonomic mechanisms, which in turn modulate higher-order perceptual and phenomenological integration. Within the Emergent Flow Theory framework, classical findings from the Libet paradigm are reinterpreted not as evidence against agency, but as reflecting necessary delays associated with multilevel temporal integration. By linking cellular memory, bioelectric signaling, vagal-autonomic regulation, and cortical dynamics, this work outlines a unified temporal architecture of conscious processing that is biologically grounded, mechanistically plausible, and empirically testable using multimodal neurophysiological protocols. The proposed pathway linking cellular temporal integration (ΔT_b) to organismic autonomic coherence (γ) is classified as mechanistically plausible, requiring empirical validation within the EFT framework.
Cancer is a debilitating disease with an often chronic course. One of the most taxing and prevalent sequelae in this context is cancer-related fatigue (CRF) resulting from the disease and/or associated treatments. Over the last years mindfulness-based interventions such as eurythmy therapy (ERYT), a mindful-movement therapy from anthroposophic medicine, have emerged as promising adjunct therapies in oncology. This prospective study investigated an online implementation of ERYT for CRF using a single arm repeated-measures design based on two consecutive studies. Study 1 consisted of an initial assessment before, during, after, and at follow up of a 6-week online ERYT-based program in a mixed sample of N = 165 adults with or without cancer diagnosis. Study 2 involved a similar design with an adapted 8-week online ERYT-based program in a sample of N = 125 adults who had been diagnosed with cancer. Outcomes were assessed using the Functional Assessment of Chronic Illness Therapy-Fatigue, Perceived Stress Scale, Mindful Attention Awareness Scale, and Insomnia Severity Index (for Study 1 all, for Study 2 only the former three). We additionally performed an exploratory analysis regarding practice frequency and duration. Data were analyzed using Linear Mixed-Effect Models per outcome; ANOVA was used for practice times. For Study 1, mixed-effects model estimates showed no significant effect on fatigue, but pointed to significantly improved emotional and physical well-being, reduced stress, as well as increased mindfulness (mixed subjects). Functional and social well-being or sleep quality did not change significantly. Study 2 model estimates on the other hand showed significantly improved CRF in conjunction with the ERYT-based online intervention, as well as improved stress and mindfulness scores (cancer-diagnosed subjects). Taken together, while our results should be interpreted with caution given the single-arm design and relatively high dropout, they suggest online ERYT may be associated with a reduction in fatigue for individuals diagnosed with cancer, an increase in mindfulness, and benefits for stress and certain well-being indicators. The online group format is advantageous in view of affordability and accessibility, the latter being particularly relevant for individuals who due to high symptom severity cannot leave their homes. Randomized-controlled studies will be needed to confirm these findings.
The long-standing practice of using manualized inventories and observational assessments to diagnose and track motor function in autism overlooks critical data invisible to the naked eye. This subjective approach can introduce biases and hinder the translation of research into clinical applications that rely on objective markers of brain-body connections. Meanwhile, we are experiencing a digital healthcare revolution, marked by innovations in the collection and analysis of electronic health records, personal genomes, and diverse physiological measurements. Advanced technologies, including current wearable devices, integrate both active and passive (sensor-based) data collection, providing a more comprehensive view of human health. Despite advances in sensors, wearables, algorithms, machine learning, and agentic AI, autism research remains siloed, with many tools inaccessible to affected families and care teams. There is a pressing need to merge these technological advances and expedite their translation into accessible, scalable tools and solutions to diversify scientific understanding. In response, this Perspective introduces the Move Initiative, a coalition spearheaded by the nonprofit 2 m Foundation, composed of self-advocates, families, clinicians, researchers, entrepreneurs, and investors who aim to advance and refine the measurement of movement in autism. Move will make motor screenings more dynamic and longitudinal while supporting continuous assessment of targeted interventions. By fostering cross-disciplinary collaboration, Move seeks to accelerate the integration of the expanding knowledge base into widespread practice. Deep, longitudinal, multi-modal profiling of individuals with Autism Spectrum Disorder offers an opportunity to address gaps in current data and methods, enabling new avenues of inquiry and a more comprehensive understanding of this complex, heterogeneous condition.
Pain is a complex phenomenon influenced by psychosocial variables, including the placebo effect. The effectiveness of mindfulness-based interventions (MBIs) for pain has been demonstrated in experimental studies and systematic reviews, but the mechanisms of action are only starting to be established. Whether the expectations of individuals experiencing pain can be manipulated during MBIs remains to be systematically evaluated, and what role placebo effects might play remains to be explored. To evaluate the literature analyzing placebo effects in MBIs for pain, we performed a systematic review based on searches conducted in PubMed, Web of Science, and SCOPUS databases. Our search revealed a total of 272 studies, of which only 19 studies were included (10 acute pain and nine chronic pain), considering the inclusion and exclusion criteria related to expectations and placebo effects. From the 19 included studies, six measured placebo effects only in relation to the pharmacological intervention used in the study and not to an MBI. The results of the few studies that focused on the placebo effects of the MBIs indicate that placebo and expectations play a role in the MBIs' effects on pain. Although expectations and placebo effects are frequently discussed in the context of mindfulness and pain research, these results show that these factors are still not routinely considered in experimental designs. However, the results of the few studies included in this systematic review highlight a clear role for placebo and expectancy effects in the overall effects of MBIs for both acute and chronic pain, suggesting that routine measurement and further consideration in future studies are warranted. Additional research in this fascinating and challenging field is necessary to fully understand the connection between MBIs, placebo/expectations, and their effects on pain relief.
Peripheral nerve injury (PNI) imposes significant burdens, requiring therapies targeting both mechanical compression and inflammatory pathophysiology. While neurolysis addresses extrinsic compression and methylcobalamin promotes intrinsic nerve repair, their combined potential is underexplored. This study compared the efficacy of neurolysis monotherapy, methylcobalamin monotherapy, and combination therapy across functional, electrophysiological, and inflammatory outcomes in PNI. Ninety PNI patients were randomized to three groups (n = 30/group): neurolysis alone, methylcobalamin alone (0.5 mg tid), or combination therapy. Outcomes at 60 days comprised functional recovery (Carroll Scale), nerve conduction velocities (MCV, SCV, AMP, LAT), joint mobility (AROM/PROM), pain severity (Global Pain Scale), and serum cytokines (NF-κB, TNF-α, IL-6 via ELISA). The combination group demonstrated significantly higher total therapeutic efficacy (86.67%) compared to neurolysis alone (50.00%) and methylcobalamin alone (53.33%; P < 0.05). All groups showed significant post-treatment improvements in nerve conduction velocities, joint mobility parameters, pain scores, and inflammatory cytokine levels (P < 0.05). However, combination therapy yielded superior outcomes: it produced the greatest improvements in active and passive range of motion, the most significant reductions in pain scores across all assessed domains, and the lowest post-treatment levels of inflammatory cytokines (NF-κB, TNF-α, IL-6; P < 0.05 versus either monotherapy). The combination of neurolysis and methylcobalamin synergistically enhances functional recovery, nerve conduction, joint mobility, pain relief, and anti-inflammatory effects in PNI, demonstrating superior clinical efficacy compared to either treatment administered alone.
Since the pivotal studies of neurophysiologists in the early 20th century, research on brain functions in non-human primates has provided valuable insights into the neural mechanisms subserving neurological function. By using data acquired on non-human primates as a reference, important progress in knowledge of the human brain and its functions has been achieved. The translational impact allowed by this scientific effort must be recognized in the implementation of the current surgical techniques particularly in support of the neurosurgical approach to brain tumors. In the surgical treatment of brain tumors, the ability to maximally extend the resection allows an improvement in overall survival, progression-free survival, and quality of life of patients. The main goal, and, at the same time, the main challenge, of oncological neurological surgery is to avoid permanent neurological deficit while reaching maximal resection, particularly when the tumor infiltrates the neural network subserving motor functions. Brain mapping techniques were developed using neurophysiological probes to identify the areas and tracts subserving sensorimotor function, ensuring their preservation during the resection. During the last 20 years, starting from the classical "Penfield" technique, brain mapping has been progressively implemented. Among the major advancements was the introduction of high-frequency direct electrical stimulation. Its refinement, along with the complementary use of low-frequency stimulation, allowed a further refinement of stimulation protocols. In this narrative review, we propose an analysis of the process through which the knowledge acquired through experiments on non-human primates influenced and changed the current approach to neurosurgical procedures. We then describe the main brain mapping techniques used in the resection of tumors located within sensorimotor circuits. We also detail how these techniques allowed the acquisition of new data on the properties of areas and tracts underlying sensorimotor control, in turn fostering the design of new tools to navigate within cortical and subcortical areas, that were before deemed to be "sacred and untouchable."
This study aimed to investigate the neural mechanisms that differentiate mind-body practices from aerobic physical activities and elucidate their effects on cognition and healthy aging. We examined functional brain connectivity in older adults (age > 60) without pre-existing uncontrolled chronic diseases, comparing Tai Chi with Water Aerobics practitioners. We conducted a cross-sectional, case-control fMRI study involving two strictly matched groups (n = 32) based on gender, age, education, and years of practice. Seed-to-voxel analysis was performed using the Salience, and Frontoparietal Networks as seed regions in Stroop Word-Color and N-Back tasks and Resting State. During Resting State condition and using Salience network as a seed, Tai Chi group exhibited a stronger correlation between Anterior Cingulate Cortex and Insular Cortex areas (regions related to interoceptive awareness, cognitive control and motor organization of subjective aspects of experience). In N-Back task and using Salience network as seed, Tai Chi group showed increased correlation between Left Supramarginal Gyrus and various cerebellar regions (related to memory, attention, cognitive processing, sensorimotor control and cognitive flexibility). In Stroop task, using Salience network as seed, Tai Chi group showed enhanced correlation between Left Rostral Prefrontal Cortex and Right Occipital Pole, and Right Lateral Occipital Cortex (areas associated with sustained attention, prospective memory, mediate attention between external stimuli and internal intention). Additionally, in Stroop task, using Frontoparietal network as seed, Water Aerobics group exhibited a stronger correlation between Left Posterior Parietal Lobe (specialized in word meaning, representing motor actions, motor planning directed to objects, and general perception) and different cerebellar regions (linked to object mirroring). Our study provides evidence of differences in functional connectivity between older adults who have received training in a mind-body practice (Tai Chi) or in an aerobic physical activity (Water Aerobics) when performing attentional and working memory tasks, as well as during resting state.
Inhibitory control is a core cognitive function that is primarily associated with activation in the prefrontal cortex (PFC) and is the cognitive function that inhibits impulses, thoughts, and suppresses irrelevant information to an identified goal or task. Prior research suggests that bilingualism may affect brain activity related to inhibitory control, yet few studies have compared functional activity between monolingual and bilingual children. The current study used functional near-infrared spectroscopy (fNIRS) to examine region of interest comparisons and task-state functional connectivity across the PFC during an interference suppression Simon task with 13 bilingual (East Asian or Ibero-romance paired with English) and 13 age-matched English monolingual preschoolers. Results showed no significant differences in behavioral measures of interference suppression. However, bilingual preschoolers showed lower oxygenated hemoglobin activation and more localized patterns of connectivity within the PFC, suggesting more efficient processing during suppression compared to their monolingual peers. This may reflect the bilingual experience of regularly suppressing their second language when not in use, thus facilitating neural efficiency. These findings contribute to the growing body of literature on bilingual cognitive development suggesting that functional connectivity during executive function may differ in bilingual children, even at a young age, despite no observable behavioral differences. This highlights the importance of integrating neuroimaging with behavioral data to gain a more comprehensive understanding of bilingual cognitive development.
This article presents the theoretical foundation of two well established movement-based methods that represent a fundamental departure from most current interventions and are applied globally with children and adults experiencing diverse motoric, cognitive, and social challenges as well as with high functioning individuals: the Feldenkrais method and Anat Baniel Method® NeuroMovement®. These methods are based on leveraging neuroplasticity through the utilization of movement, not as "exercise" or externally imposed motor sequences, but as a means for effective, two-way felt communication with the recipient and their brain. Through connecting with the recipient, starting where they are-motorically, emotionally, and cognitively, we follow their unique responses, moment-by-moment, creating a dance-like dyadic process of self-discovery that mimics the spontaneous, organic way typically developing children play, learn, and grow. Practitioners in these methods, by joining and creating mutual connection with the recipient, help turn the subjective experience of the recipient into a reliable means of attaining spontaneous, mutually generated emergent learning in the recipient. In this process the autonomy of the recipient is respected and enhanced. Our work will be described through direct applications to autism seen as a neuro-motor-sensing disorder where those challenges can be transcended through the dyadic dance embodied in our techniques. Since 87% of children with autism spectrum disorder have significant movement challenges, we propose that movement, as a means for effective two-way communication with the child and their brain, needs to play a central role in autism intervention. In this article we outline how our interventions take place through case studies, vignettes and discussion, separately for each of the two methods. This article will also include recommendations for conducting investigations that characterize some of the basic components of these two methods, utilizing experimental designs and recently developed technologies and biometrics that generate unique individual profiles of both the receiver and the provider of the intervention, and of the interbrain synchrony, correlate them with changes in movement organization, cognitive functioning and coherence, and track changes in the signal-to-noise ratio. These methods should enable refinement and scalability of tracking and assessing the mechanisms and effectiveness of the interventions.
Chronic stress is known to impair emotional regulation and adaptive behavioral responses through neuroinflammatory activation, oxidative imbalance, and dysregulation of neuroplasticity-related genes. Kiperin Mind Focus, a nootropic nutraceutical containing L-theanine, citicoline, phosphatidylserine, Rhodiola rosea, Ginkgo biloba, caffeine, and Lion's Mane mushroom extract has been formulated to support stress resilience, mood regulation and neural health. This study aimed to investigate the neuroprotective and neuroregulatory effects of the combined formulation on behavioral, biochemical, histopathological, and molecular parameters in rats exposed to chronic unpredictable mild stress (CUMS). Thirty-two adult male Wistar rats were randomized into four groups (n = 8): Control, Stress, Kiperin Mind Focus (MF), and Stress + Mind Focus (SMF). CUMS was applied for 45 days, and the combined formulation was administered by oral gavage (130 mg/kg/day). Behavioral outcomes were evaluated using the sucrose preference (SPT), open field (OFT), elevated plus maze (EPM), and forced swim (FST) tests. Serum and tissue cytokine levels (IL-1β, IL-6, IL-10, TNF-α) and oxidative stress index (TOS/TAS ratio) were measured. Hippocampal and prefrontal gene expression of FOS, DBH, NMB, BDNF, CREB1, GRIN2A, and GABRB1 was assessed via qPCR, and histopathological changes were semi-quantitatively scored. Chronic stress induced anhedonia, anxiety-like behavior, and behavioral despair, accompanied by elevated proinflammatory cytokines, oxidative imbalance, and neuronal degeneration in the hippocampus and prefrontal cortex. The supplementation significantly improved SPT, OFT, EPM, and FST performance, normalized cytokine and oxidative parameters, and reduced neuronal injury scores. At the molecular level, supplementation attenuated stress-induced upregulation of FOS, DBH, and NMB while maintaining neurotrophic (BDNF, CREB1) and GABAergic (GABRB1) expression near control levels. Kiperin Mind Focus exerted robust neuroprotective, anti-inflammatory, and antioxidant effects under chronic stress, restoring molecular homeostasis and stabilizing stress-related behavioral outcomes. These findings support its role as a stress-buffering and mood-stabilizing supplement, that promotes emotional regulation and adaptive exploratory behavior under prolonged stress conditions.
Brain damage (BD) caused by stroke, traumatic brain injury (TBI), or neurodegenerative conditions often results in persistent cognitive, motor, and emotional impairments. Music-based interventions (MI) have been explored as adjunctive rehabilitation strategies; however, the evidence remains fragmented. This systematic review and meta-analysis synthesize available research on the effects of MI on functional recovery following BD, due to acquired brain injury (ABI), including both TBI and non-TBI. From a total of 868 publications screened in PubMed, Embase, Scopus, Cochrane Library, Web of Science, and ClinicalTrials.gov, 90 were included, of which 41 met the criteria for quantitative evaluation and meta-analysis, to assess the state-of-the-art of research on music and BD in the fields of neuropsychology and cognitive sciences. The reviewed studies span a range of methodologies, including randomized controlled trials and qualitative research, and incorporate diverse MI strategies, such as active music-making, structured listening, and improvisational techniques. The findings indicate that music supports recovery across motor, cognitive, and, albeit to a lesser extent, communicative and psychosocial domains. The findings suggest beneficial effects of MI, particularly in gait function (z = 3.46, P < 0.01), upper extremity function (z = 6.11, P < 0.01; UEF), communication (z = 3.21, P < 0.01), cognitive rehabilitation (z = 3.29, P < 0.01), and emotional, behavioral, and social outcomes (z = 2.35, P = 0.02); notably, these effects were often supported by consistent statistical significance across multiple subgroup analyses (e.g., gait, UEF). This study highlights the therapeutic potential of music in neurorehabilitation and supports its integration into multidisciplinary treatment programs. Despite these promising findings, methodological heterogeneity, small sample sizes, and short intervention durations limit the generalizability of results. The evidence suggests that music may modulate key neurobiological pathways in BD, supporting its integration into evidence-based neurorehabilitation programs.
While the autism diagnosis emphasizes "deficits" in social communication, the article advances that sensory-movement differences underpin autism through a review of the following sources of evidence. This account critically challenges "autistic regression", with evidence that sensory-movement features appear by birth as the earliest signs of autism and underlie the behavioral differences used for diagnosis, which may reflect adaptations to inherent differences and misunderstandings from others. Sensory and motor differences are salient to autistic people, but they often go underrecognized by others. They cause cascading effects in infancy on behavior and communication through differences in sensorimotor learning, automatic imitation, eye contact, sensory perception, and interests. The article then explains how sensory processing differences may influence reduced perceptual narrowing, which involves a bottom-up information processing style grounded in the surrounding environment. Furthermore, this bottom-up processing may grow from reduced sensory integration in feedback loops potentially involving the cerebellum of the brain. The article then moves into implications for the widespread consequences of these inherent differences on quality of life. The article closes with implications for autism as a construct (including underestimated empathy and pain), testing the theory, providing sensory-sensitive support and acceptance of autistic people, and applications to diverse autistic people. The theory may apply particularly well to autistic women and girls, autistic people with speech divergence, autistic people with ADHD, and autistic people with co-occurring sensory and motor-related neurodivergences. Throughout the article, the theory also provides clinical, neurological, and experiential evidence for sensory and motor differences as lifelong, challenging the notion of "losing" (an) autism (diagnosis) as instead reflecting (risky and not necessarily "successful") camouflaging.
Arecoline, a biologically active alkaloid extracted from the areca nut, serves as the primary psychoactive ingredient in betel quid, one of the most widely consumed psychoactive substances worldwide. Despite its extensive use, the central nervous system (CNS) effects of arecoline remain inadequately understood. This study aims to investigate the central actions of arecoline through a comprehensive, multi-dimensional approach that integrates behavioral assays, neuroimaging techniques, calcium signaling analysis, and transcriptomic profiling. Our findings demonstrate dose-dependent addictive properties of arecoline, alongside distinct behavioral alterations that highlight its potential for addiction. Neuroimaging and calcium signaling data revealed region-specific alterations in neural activity, particularly in areas associated with learning, memory, and reward processing. Furthermore, transcriptomic analysis identified significant changes in gene expression, particularly in pathways related to synaptic plasticity, calcium signaling, and metal ion transport. These results provide valuable insights into the addictive potential of arecoline and its underlying neurobiological mechanisms, offering crucial information for understanding its broader impact on CNS function. The study's findings hold significant implications for informing public health strategies aimed at addressing arecoline misuse and its potential role in addiction-related disorders.
The nucleus tractus solitarii (NTS) is a highly conserved brainstem structure that has served as a principal hub for visceral sensory integration across vertebrate evolution. While the NTS has long been described as a relay for cardiovascular and respiratory reflexes, recent work increasingly frames it as an integrative node that transforms diverse afferent signals into adaptive, context-sensitive responses. In this review, we synthesize evidence on the developmental origins of the NTS (including contributions from the dorsal alar plate and epibranchial placodes) and its comparative organization across vertebrate taxa. We argue that many interspecies differences are more plausibly interpreted as functional reweighting within a conserved circuit framework-shaped by species-specific respiratory-feeding strategies and ecological demands-rather than as wholesale rewiring of the core network. Within this comparative context, the extensive supranuclear modulation observed in humans is discussed not as biological "superiority," but as layered control that has become particularly prominent in response to human-specific anatomical constraints and behavioral demands, including those associated with speech and complex social interaction. Clinically, we revisit dysphagia, cough hypersensitivity, and nausea/vomiting as manifestations of network-level dysregulation and gating failure rather than isolated breakdowns of single reflex arcs. Finally, we suggest that neuromodulation strategies, including vagus nerve stimulation, may be best conceptualized as delivering patterned afferent input capable of shaping NTS network plasticity, rather than as non-specific electrical activation.
Context-sensitive behaviors are crucial for the adaptive success of many organisms. Investigating neural processes that facilitate context-sensitive behavior requires knowledge of the molecular signaling and anatomical brain connectivity within and between relevant brain networks. Here, we outline the roles of oxytocin and dopamine signaling systems in context-sensitive singing in songbirds. Additionally, using the recently compiled songbird connectome, we review anatomical connectivity between vocal-motor and social brain networks that may facilitate context-sensitive singing. We present a model for context-sensitive adaptability of singing behavior in songbirds. We propose that the medial preoptic nucleus of the hypothalamus may serve as the output nucleus of the social behavior network, influencing oxytocin-mediated dopamine delivery to the vocal control network, in a context-sensitive manner. As many components of this model are conserved across species, we speculate that this proposed model can be generalized to facilitate context-sensitive motor behaviors across vertebrate species. Overall, we emphasize the importance of investigating each component of our proposed model, within a single species. This perspective aims to uncover how integrated neural mechanisms give rise to behavior.
Anti-metabotropic glutamate receptor 1 (mGluR1) encephalitis is a rare autoimmune disease affecting cerebellar Purkinje cells. Only thirty-nine cases have been reported globally, with inconsistent documentation of treatments and outcomes. A systematic review is needed to identify prognostic factors and expand clinical understanding and treatment options. Observational follow-up data of anti-mGluR1 encephalitis cases were collected. All anti-mGluR1 encephalitis cases published in the PubMed and Google Scholar databases in English before November 1, 2024 were included. Clinical information and possible predictive factors from both current and previously reported cases were statistically analyzed. We present a case of anti-mGluR1 encephalitis successfully treated with ofatumumab. During the patient's initial episode, she partially recovered after first-line treatment. She experienced a relapse 6 months later and was treated with ofatumumab, resulting in complete recovery. Forty cases of anti-mGluR1 encephalitis, including our case, were summarized. The prevalence was similar between men and women, with 50% of patients aged 40-59 years. The most common clinical manifestations were ataxia and dysarthria. Cerebrospinal fluid analysis showed normal white blood cell count and IgG index in 37.1% of patients. Almost half of the patients (48.6%) exhibited cerebellar atrophy on cerebral MRI scans at initial presentation or during follow-up. Only 25% of patients recovered completely. According to the modified Rankin Scale (mRS) scores at the last follow-up, patients with poor outcome (n = 13, 32.5%) had a lower proportion of first-line immunotherapy (62%, P = 0.017) and a longer follow-up time (median 36 months, P = 0.038). The peak incidence of anti-mGluR1 encephalitis occurs between ages of 40-59 years. More than one-third of patients have normal cell counts and IgG index in the cerebrospinal fluid. Therefore, patients suspected of having this encephalitis should be tested for the presence of anti-mGluR1 antibodies in serum and cerebrospinal fluid. Notably, the first-line immunotherapy may be a critical factor influencing clinical outcomes.