Sports-related concussion (SRC) is defined as a mild traumatic brain injury (mTBI) leading to complex impairment(s) in neurological function with many seemingly hidden or difficult to measure impairments that can deteriorate rapidly without any prior indication. Growing numbers of SRCs in professional and amateur contact sports have prompted closer dialog regarding player safety and welfare. Greater emphasis on awareness and education has improved SRC management, but also highlighted the difficulties of diagnosing SRC in a timely manner, particularly during matches or immediately after competition. Therefore, challenges exist in off-field assessment and return to play (RTP) protocols, with current traditional (subjective) approaches largely based on infrequent snapshot assessments. Low-cost digital technologies may provide more objective, integrated and personalized SRC assessment to better inform RTP protocols whilst also enhancing the efficiency and precision of healthcare assessment. To fully realize the potential of digital technologies in the diagnosis and management of SRC will require a significant paradigm shift in clinical practice and mindset. Here, we provide insights into SRC clinical assessment methods and the translational utility of digital approaches, with a focus on off-field digital techniques to detect key SRC metrics/biomarkers. We also provide insights and recommendations to the common benefits and challenges facing digital approaches as they aim to transition from novel technologies to an efficient, valid, reliable, and integrated clinical assessment tool for SRC. Finally, we highlight future opportunities that digital approaches have in SRC assessment and management including digital twinning and the “digital athlete”. The incidence of SRC has grown in many contact sports. For example, in rugby union, the incidence can be as high as one concussion per game3. Accordingly, SRC presents notable health risks to those participating in contact sports where the intensity of e.g., high impact collisions are commonplace with considerable challenges in diagnosis and monitoring to inform return to play/participation (RTP)6.Direct impact(s) to the head or neck during contact sport are major contributors to individuals sustaining Sports-Related Concussion, SRC4. Appropriate SRC management ensures participants do not RTP prematurely as this can lead to a secondary brain injury5. The second impact can have serious consequences including increased intracranial pressure and in extreme cases, death6. Hence, diagnosing SRC through timely and accurate assessment is of crucial importance to minimize short-term health risks. This is reinforced by evidence highlighting the potential long-term impacts of inappropriate SRC management on brain health and chronic traumatic encephalopathy (CTE)8. Long-term neurological deficits associated with head trauma have increased public health concerns (across many sports), driving demand for evidence-based monitoring and treatment9.Timely identification of SRC is of critical importance to SRC management, to avoid adverse neurological implications11. Thus, accurate recognition of SRC is particularly challenging in environments with limited medical support such as amateur teams/sports, where there may be one coach or first aider only. In rugby union environments with reduced medical provision, the conservative approach of “Recognize & Remove and if in doubt, sit them out” is adopted12. That involves permanently removing players identified as being involved in possible head injury-related events  or if they display signs and symptoms associated with SRC there is no return to sporting activity until a medical assessment is performed. That aims to reduce occurrences of missed or misdiagnosed SRC in low-resource/amateur environments.Immediate and accurate (on-field) recognition and management of SRC remain difficult. This includes professional teams/sports that often possess sufficient medical staff to monitor for suspicious mechanisms of injury which may lead to a SRC13. Therefore, challenges remain in the subsequent (off-field) assessment and RTP protocols following SRC. This is confounded by traditional approaches used to diagnose and monitor SRC often occurring during infrequent snapshot assessments. The most widely used approach in SRC assessment is the Sports Concussion Assessment Tool (SCAT) which tests aspects of cognition, balance, and vision via a paper-based questionnaire administered by a health professional14. The manual but subjective nature of tests like SCAT, means formal SRC diagnosis, rehabilitation, and RTP is based solely on clinical judgment with information gathered from self-reported assessment techniques15. This is problematic as research shows SRC is a dynamic and complex pathological process with difficult to measure impairments that can change or deteriorate rapidly without any prior indication16. This presents challenges for the safety, rehabilitation, and RTP.SRC presentation is heterogeneous with a wide variety of signs and symptoms, some of which are subtle and easily missed or may only become apparent in the following hours and days after injury13 reinforces a need for more objective approaches through robust development and provision of diagnostic and prognostic biomarkers to better assess the presence/severity and recovery of SRC, respectively. Digital imaging technologies such as functional MRI (fmRI) or pET scanners are (reference standards) already used to assess the severity of damage such as skull fractures and bleeding on the brain in more severe traumatic injuries. However, their effectiveness and practicality when used in isolation for SRC diagnosis is yet be proven, with only a minority of mTBI such as SRC displaying distinguishable structural changes immediately post concussion17. In addition, not all players suspected of SRC require hospital assessment and of those attending Accident and Emergency (A&E) Departments, only those presenting the most severe signs and symptoms will be sent for imaging20. Thus, those reference technologies are not typically deployed for routine SRC assessment.The Concussion Consensus Statement21. Such approaches could provide scalable robust data for more informed and integrated SRC diagnosis to better inform RTP, enhancing the efficiency and precision of healthcare assessment23. In this narrative review, we examine SRC clinical assessment methods in four key areas , providing insights into the translational utility of readily attainable digital methods. We examine common benefits and challenges facing those digital approaches as they aim to transition from novel technologies to efficient, valid, reliable, and integrated clinical tools for SRC. We highlight future opportunities that attainable digital tools can have in SRC diagnosis and monitoring with a systems-science-based management approach including digital twinning and the “digital athlete”. We provide recommendations on how this field should develop.Recently, lower-cost  technologies have been developed to measure and monitor outcomes for more informed assessments18. Mistry et al.20 highlight the main objective of SRC assessment in A&E is to triage the player/patient, identifying any readily obvious brain injury symptoms/signs that require e.g., surgical intervention. That approach, although it may improve efficiency, omits thorough assessment of many other subtle SRC impairments such as cognitive, motor/functional , and visual deficits24. Thus, current SRC assessments are often binary snapshots, ignoring the interconnected nature and heterogeneity among individuals. Most post-discharge management involves information for the player regarding red flag signs/symptoms and/or provision of head injury information leaflets. Furthermore, outside of professional environments, there is often no physician assessment or follow-up until returning to full contact training25.The rise in SRC cases presented at A&E/ED has prompted closer discussion about improved assessment and management, including calls for the development of national guidelines27 As such reliance on subjective non-specific measures such as symptoms make it extremely difficult to confidently know when it is safe for players to RTP. This highlights the need for valid, objective tools to aid diagnosis, monitoring, and RTP in SRC20.As such current SRC management and rehabilitation protocols rely on self-reported measures/symptoms to determine readiness to play. Therefore, SRC recovery times and prognosis is highly variable and varies dramatically across different age groups and gender. Indeed some individuals can take significantly longer than expected to RTP (3-4 weeks) and experience chronic symptoms even after returning to play28. Pen-and-paper tests include the short-blessed test, digit span (forward and/or reverse) and the Standardised Assessment of Concussion (SAC), now incorporated into the fifth version of the SCAT (SCAT5). Despite widespread clinical use, these tests carry considerable challenges including manual score calculation hindering automated or immediate comparison of scores across different individuals and time points29. Fortunately, progression to using digital neurocognitive testing has overcome some of these limitations.Comprehensive assessment of cognitive function outside of sport typically includes detailed interviews, exploring the history of a patient’s health, education, and social background. In contrast, SRC focuses on more specific areas of cognitive functioning only such as short-term memory, working memory and executive-level function30. Immediate Post-Concussion Assessment and Cognitive Test (ImPACT) is an example of a scalable computerized neurocognitive tool that assesses verbal memory, reaction time, visual-motor speed, and visual memory32. ImPACT tests are complemented with the integration of demographic data and a post-concussion symptom scale for players and staff. Research shows ImPACT is sensitive post concussion in the acute phase (within the first few days) with measurable differences in verbal memory, visual memory, and slower reaction times34. However, there is mixed evidence for neurocognitive testing in subacute and chronic concussion35. Indeed, the international consensus statement of concussion states that “tests should not be seen as the sole basis for the management of decisions”4.The introduction of digital-based cognitive assessments offers a number of advantages over pen-and- paper methods including objective cognitive metrics , randomization of test trials with automation of data collection and analysis33, which may partly explain the reluctance to adopt technology in SRC assessment.Despite the value of digital neurocognitive testing in acute SRC cognitive testing, challenges remain for pragmatic deployment in low-resource environments. The high cost of initial software licenses or fixed yearly subscriptions can be prohibitive to amateur sports teams with limited budgets. Often these commercially orientated companies rarely permit independent validation of their technologies or algorithms used to interpret raw data or outputs. This lack of an open-source or transparent approach makes it very difficult for governing bodies to make evidence-based decisions about which test or technology to endorse/promote. Other pragmatic limitations on a single approach are the reliance on baseline data, where it isn’t always feasible to gather pre-injury data due to e.g., players moving between clubs/teams. Without baseline information, it is difficult to ascertain if an athlete’s post-concussion neurocognitive scores are the result of a concussion or individual variability. Consequently, no single cognitive test/technology has proven capable for standalone use. This has placed greater responsibility on clinicians to have prior experience and use clinical judgment when managing SRC36. SRC can cause impairments in visual and oculomotor speed, with research showing oculomotor dysfunction present in up to 90% of SRC cases37. Traditional subjective visual assessment includes eye-tracking tests e.g., Visual Occulomotor Assessment (VOMS), which assesses impairments via self-report. This test includes a baseline measurement where players verbally rate changes in headache, dizziness, and nausea symptoms compared with their immediate baseline state on a scale from 0 (none) to 10 (severe) to determine if each test provokes symptoms38. Other visual tests include the King-Devick (K-D), which is an indirect measurement of rapid eye movements, language function, and attention. The K-D test has demonstrated moderate sensitivity (60%) but poor specificity (39%) in identifying players diagnosed with concussion35. It is also unclear how training and learning effects can influence participant scores, and to date, there is an absence in clinically significant change scores/data. Indeed a recent paper outlined that current eye-tracking tests (such as K-D) were no better than traditional off-field screening alternatives35. This is confounded by deficiencies and heterogeneity in current cognitive testing protocols and environments, making comparisons between studies and decisions on the choice of test difficult39. As such the paper advised that current tests should not be routinely incorporated in SRC assessment.Normal vision correlates with healthy cerebral activity and brain functionIn addition to suboptimal sensitivity, current tests rely heavily on baseline data collection which are not feasible to implement in low-resource environments, where there is often insufficient staff/funding to perform baseline screening. Hence there is significant demand for more sensitive, objective, and scalable solutions for visual assessment in the form of wearable digital eye trackers and/or mobile technologies.40 in a variety of research paradigms ranging from neuroscience to social science41. Despite this rapid rise in the availability of technologies, there are several barriers to clinical deployment. Stuart et al.42 outlined current state of the art and challenges in mTBI visual assessment, finding most studies do not adequately address or report the validity or reliability of eye trackers, making a comparison or clinical interpretation difficult. To translate these technologies into clinical application there is a need for more routine validation, standardization in testing paradigms, and transparency on their use, including algorithms and data analysis methods44.Non-invasive digital technologies such as eye trackers can objectively monitor eye movements during laboratory tasks, assessing visual and cognitive processing45. The latter shines a light onto the eye causing a reflection, a high-resolution camera then captures an image of the eye with reflections which is then used to calculate gaze direction. Research has found the accuracy of the Tobii EyeX to offer sufficient accuracy and precision in gaze direction46. This is consistent with research testing other technologies such as the Eye-Sync which offer good-excellent levels of sensitivity (88%) and specificity (87%) in smooth pursuit assessment48. Overall digital technologies offer high-resolution quantitative data and value over traditional approaches such as the VOMS. Despite promising results of accuracy in academic research, there has yet to be clinical research investigating thresholds or measures that can be applied to a meaningful change that can be widely used for SRC assessment.For the few studies with adequately reported information, Khalife et al. highlight the benefits of investigating rapid, reliable eye-movement impairment in SRC assessment with the Tobii eye-tracker51. The Balance Error Scoring System (BESS) test is a balance and postural stability assessment that is widely used for examining impairments by asking participants to specific adopt stances aimed to challenge their motor and vestibular system54. However, the BESS is assessed subjectively, through manually recording errors  and timed using a stopwatch. As a consequence, the BESS sensitivity is greatly influenced by assessor experience and research suggests only sensitive in the acute phase (within first 2 days of injury)55. These inherent limitations of subjective assessment make it difficult to apply in sporting environments, where there is demand for precise and sensitive clinical measurements. As outlined by Johnson et al., traditional balance assessments “are subjective in nature, do not adequately challenge high functioning athletes and may not be capable of detecting subtle balance disturbances following a concussive event”56. This raises questions surrounding the accuracy in diagnosis, RTP protocol and crucially, paradigms by which SRC is assessed. Indeed gait and postural deficits may in fact be impaired for long periods beyond, typical timeframes of recovery58. Therefore, traditional assessment of motor function carries significant limitations yet remain extremely prevalent across the clinical practice. Opportunities for improvement may be afforded by adopting digital approaches such as inertial sensor-based wearables discussed in the next section.Balance and gait/walking impairments are associated with neurological conditions, including concussion, and therefore forms a key component of clinical assessment60. These studies do show attempts to instrument traditional tests and provide objective digital SRC biomarkers from a single wearable sensor. Recently, Celik et al.61 adopted a multi-wearable approach towards a comprehensive instrumentation of SCAT5. By using eight inertial wearables  to segment-specific components  a wealth of spatial and temporal data associated with each SCAT5 component with excellent/millisecond resolution. Moreover, the study showed how wearables can automatically and more accurately calculate, recognize balance and gait errors during tasks compared to clinical observation, also highlighted by Johnston et al.62. Beyond instrumentation of traditional assessment, research with inertial wearables shows SRC and mTBI impacts balance, gait, and turning66, including under longitudinal assessment55.The development of wearables equipped with inertial sensors (accelerometers and gyroscopes) has facilitated pragmatic instrumented testing of traditional approaches such as the Timed-Up-and-Go (iTUG) and BESS68. However, a necessary precursor to longitudinal free-living remote balance and gait assessment is verified and validated digital SRC biomarkers enabling trust and better understanding by clinicians and patients43.Despite laboratory research showing motor impairments can be strongly associated with SRC, it is not yet known exactly what clinical gait or turning assessment techniques are sensitive for SRC. Therefore, barriers remain in clinical validation and how to translate some novel inertial measures  into clinical endpoints or biomarkers. Indeed, the episodic nature of current laboratory assessments may be supplemented beyond the clinic/hospital during real-world/free-living remote assessment69.Despite rapid and extensive development in the availability of different tests to assess SRC, the symptom checklist and severity indices are retained as the cornerstone for most decisions around readiness to return to play. This includes the Post-Concussion Symptom Scale (PCSS), which assesses a variety of symptoms (0-6 of increasing severity) to give an overall score and has been adapted and abridged into 5th edition of the SCAT (SCAT5)69. Moreover, the severity of symptoms/signs reported by players following a SRC varies significantly (immediate or delayed onset) which can hinder confidence for clinicians and players/patients when assessing readiness to return to play70. In addition, some studies report that players can manipulate self-reported baseline symptom scores, allowing them to mitigate any poorer performance of scores post concussion71. For example, only 17% of athletes self-reported symptoms of SRC, although nearly half of this cohort (48%) sustained a head injury and associated signs of SRC71. Relying on self-reported data may be particularly challenging in competitive environments where there is societal or financial gain in staying injury-free.Although common due to their ease of use, studies have examined the sensitivity of symptom scales in SRC and found suboptimal sensitivity and specificity72. Therefore, challenges remain in providing approaches to more efficiently document SRC injury characteristics across both low- and high-resource environments. The growth in usage and availability of smartphones and affiliated commercial digital technologies means players and clinicians already have widespread access and familiarity with use. A move toward mobile digital applications may serve to overcome some limitations of symptom assessment, data storage, and analytics compared to self-reported pen-and-paper methods.Alongside the challenges of subjectivity in self-reported symptomatology, there are significant practical and logistical barriers. Current pen-and-paper-based SRC assessment methods can take 10–15 min/player which is not always achievable in environments with only one medical practitioner to complete player assessment 73. To the author’s knowledge, CSX has yet to be fully deployed into amateur sports. However, C3 has been used to collect some concussion data in college and professional rugby72. Linder et al. found that use of an Electronic Injury Reporting (IR) app provides a useful digital platform for injury-related demographic analysis72. App advantages include the capacity for players to complete (in their own time) symptom recording as frequently as required with more regularity and consistency in the absence of clinicians.Several smartphone/mobile digital applications/apps are available to track injuries and monitor SRC recovery through symptom reporting. Apps include CSX  and the Cleveland Clinic Concussion Application (C3) which records data on reaction time, memory, vision and information processing35. Moving toward digital symptom recording may allow greater understanding and co-investigation with other SRC impairments.The current reliance on traditional non-digital approaches such as the SCAT5 and lack of robust databases means the progression and recovery of SRC symptoms is unclearDigital approaches and technologies could provide objective information, generating useful and reliable data for improved data presentation, analysis, and insights for SRC management. From this narrative review, Fig. Implementing digital approaches in sports medicine and SRC care could transform how player data is captured, analyzed, and communicated. Current SRC approaches are restricted by the reliance of subjective self-reported assessment under direct observation of a clinician. Thus, outcomes are often reliant on a player informing the clinician and the clinician’s clinical judgment or interpretation. Objective approaches in SRC are often confined to bespoke or professional environments, limiting deployment and accessibility to amateur or adolescent players. In addition, there is considerable focus on traditional in-person assessment at episodic “snapshot” assessments with little to no remote/habitual data collected on those who sustain a SRC during contact sports. The addition of digital or remote assessment approaches such as wearables may augment, and supplement data gathered in traditional assessment visits under the supervision of healthcare professionals.74. Although testing in the latter would be conducted in less controlled conditions, there is considerable value in conducting testing in remote, real-world/free-living as they would be within habitual conditions76.Presently, digital cognitive testing only offers a snapshot assessment. Yet, testing could be better utilized through constant remote evaluation via apps. This would mitigate the need for clinicians to be present and would allow a higher frequency of testing within the players routine environment21. However, capturing reliable data on impaired eye movement outside of controlled/laboratory conditions generates many complications. Thus, challenges remain in the refinement and optimization of eye-tracking as a future SRC diagnostic tool. These include minimum and maximum testing times, choice of eye-tracking tests, lack of standardized protocols to detect SRC eye-movement impairments as well as the complexity of analyzing big data. Overcoming these challenges will require the development and refinement of protocols and data processing methods/algorithms.The use of current eye-tracking approaches in SRC is not currently supported. However, there are opportunities for use of digital eye-tracking outside of the clinic or in static situations. As these methods do not require active participation of the wearer, they overcome many potential issues of adherence allowing participants to wear these technologies as part of their daily life79. Yet the true utility of inertial technologies may be their use beyond the clinic with the provision of habitual balance and gait data67. Such wearables should become more accepted and the standard for gathering continuous, high-resolution free-living data due to their discrete attachment and low wearer burden. Technical validation of inertial wearables has led to the development of a conceptual gait model80, providing a framework for clinicians to better utilize gait data to make more informed clinical decisions. For example, a similar modeling approach78 has been applied in chronic (non-sporting) mTBI providing enhanced gait analysis, which could be a means to assess response to interventions and better understand underlying impairments. Future research should apply and evaluate conceptual models in acute mTBI and SRC from free-living gait data to provide better insight to habitual player recovery, better informing RTP.Use of  wearables within mTBI has shown considerable promise for measuring balance and gait impairments82. However, digital monitoring may not easily lend itself within free-living due to the requirement for players' attention. Yet by collecting longitudinal  symptom data, a deeper understanding of the rate of progression of symptoms could be determined, supporting the transition and deployment of other digital approaches. Clinicians could deploy apps to measure symptoms beyond snapshot testing points but would need to account for testing conditions. Adoption of mobile technologies to support symptom documentation would allow integration with other digital approaches, providing holistic systems-based approaches to SRC management. If used routinely, such approaches may have capacity to provide alert systems to healthcare professionals for missed SRC or injuries within squads, which could standardize and systematize injury severity through evaluation of red flags via structured and personalized assessment.Symptoms post SRC are thought to be closely linked to improvements in physiological recovery and should therefore remain a cornerstone of assessment83. Therefore, step changes to understand, diagnose and manage SRC will require multi-scalar approaches which could be built around a systems-science framework to shift research into practice. Achieving this will require cross-disciplinary collaborations and the adoption of novel approaches with shared repositories to facilitate and intensify collaboration.Measuring and monitoring a single impairment is unlikely to reveal meaningful new insights into SRC. There is a need for a multidimensional/multimodal approach with digital diagnostic and prognostic models/frameworks to improve outcomes84. A digital twin can represent a back-up/copy to a person’s physical state before an intervention, providing retrospective or real-time monitoring of a wide range of parameters85. The application of wearables to create a digital twin of baseline health information for a player participating in contact sport would provide objective data, providing opportunities for remote monitoring and evaluation86. This leads to the concept of the digital athlete  and big data. It has been applied to complex systems and in medicine to provide a framework to create a virtual representation of players based on the integration of data from digital devices, omics, imaging, and electronic medical recordsete Fig.  where anRoutine engagement with sport-specific stakeholders on how digital tools could advance SRC diagnosis and monitoring.Development of open-source athlete digital monitoring approaches for routine integration of data streams.An expert, multidisciplinary consensus on the use of fit-for-purpose digital SRC tools within and/or across sports.Transparency of all digital tools in SRC assessment .Digital approaches could have tangible objective improvements in SRC diagnosis and monitoring. However, there are notable application and deployment challenges pertaining to sports , funding, environments , and education. This will demand different approaches to ensure correct adherence and implementation as well as robust data collection protocols to ensure adequate monitoring. Likewise, there are privacy (security), ethical (remote and/or continuous monitoring), and trust considerations  when collecting SRC data. To better understand these demands, there is a need for independent and multidisciplinary research with diverse stakeholders  with transparency in findings and conclusions drawn. To support behavior change for routine digital adoption in SRC, there must be the development of multidisciplinary standardized frameworks and agreement in validated/reliable tools to ensure trustworthy technologies that are fit-for-purpose. Accordingly, high-level recommendations include:The increasing incidence of SRC and challenges of current diagnosis approaches has illuminated the scale of the problem facing clinicians for routine diagnosis and monitoring. Although traditional and subjective approaches will remain a crucial component of SRC assessment, they are unable to reliably provide an evidence-based approach to the detection, monitoring, and management to inform RTP. Digital approaches have the potential to transform the way player/participant data can be objectively captured, processed, and analyzed, enhancing current healthcare practice in SRC. Informative digital biomarkers from habitual behaviors could be routinely captured providing reliable (big) data that can support the development of other novel SRC biomarkers. Adopting free-living assessment is feasible with some current wearables but future considerations should be given to integration with IoT platforms for a multi-model, remote and holistic player assessment. Digital-based approaches coupled with novel concepts/frameworks from other research domains  provide a persuasive and timely route to addressing ongoing limitations in SRC. Recommendations provided here could help modernize (digitize) SRC diagnosis and monitoring to protect athletes and their sport.


Drosophila, CRY is receptive to blue light and resets the circadian rhythm. CRY also influences membrane potential dynamics that regulate neural activity of circadian clock neurons in Drosophila, including the temporal structure in sequences of spikes, by interacting with subunits of the voltage-dependent potassium channel. Moreover, several core clock molecules interact with voltage-dependent/independent channels, channel-binding protein, and subunits of the electrogenic ion pump. These components cooperatively regulate mechanisms that translate circadian photoreception and the timing of clock genes into changes in membrane excitability, such as neural firing activity and polarization sensitivity. In clock neurons expressing CRY, these mechanisms also influence synaptic plasticity. In this review, we propose that membrane potential dynamics created by circadian photoreception and core clock molecules are critical for generating the set point of synaptic plasticity that depend on neural coding. In this way, membrane potential dynamics drive formation of baseline sleep architecture, light-driven arousal, and memory processing. We also discuss the machinery that coordinates membrane excitability in circadian networks found in Drosophila, and we compare this machinery to that found in mammalian systems. Based on this body of work, we propose future studies that can better delineate how neural codes impact molecular/cellular signaling and contribute to sleep, memory processing, and neurological disorders.The circadian rhythm is a fundamental process that regulates the sleep–wake cycle. This rhythm is regulated by core clock genes that oscillate to create a physiological rhythm of circadian neuronal activity. However, we do not know much about the mechanism by which circadian inputs influence neurons involved in sleep–wake architecture. One possible mechanism involves the photoreceptor cryptochrome (CRY). In  Drosophila. For example, period (PER) and timeless (TIM) oscillate to create transcription–translation feedback loops , which is typically shown as mean firing rate , 16, firRegardless of whether spiking activity is used for information representation, the “membrane potential dynamics” of neurons is the essence of neuronal information representation , 33. In Drosophila, and we will compare this machinery to that found in mammalian systems.In this review, we propose that membrane potential dynamics produced by circadian photoreception and core clock molecules are critical for generating synaptic plasticity based on the fixed point of neural coding. In this way, these dynamics drive the formation of architecture that support baseline sleep, light-driven arousal, and processing of memory. We will also discuss the machinery that regulates the circadian rhythm and organizes internal  and external  membrane excitability in In mammals, the master of circadian clock networks is the suprachiasmatic nucleus (SCN) . The SCNDrosophila, specialized clock neurons are enriched with core clock genes that cooperatively drive circadian-dependent activity  anticipate evening activity . They also found that the mammalian homolog of WAKE  cotransporter. Because Quasimodo is involved in multiple components, further studies need to elucidate the interactive mechanism that modulates the membrane potential dynamics of l-LNvs. Shal/Kv4, a voltage-gated potassium channel, was sufficient to modulate sleep–wake transitions by suppressing time-specific rates of neuronal firing  and a novel sodium/potassium ATPase β subunit, which are upregulated at night under clock and WAKE control. Upregulation of KCa activity leads to a deeper after hyperpolarization of DN1p spikes, which slows firing during periods of increased input. Conversely, sodium/potassium ATPase activity accelerates spike onset, which maintains spiking during periods of reduced input. The combination of increased KCa and sodium/potassium ATPase activity promotes spike morphologies with faster onset and deeper afterhyperpolarization, which leads to regular firing and greater sleep quality at night .Tabuchi et al. also demonstrated a causal role for temporal coding in sleep behavior. They found that circadian-dependent changes in the spiking pattern of DN1p clock neurons encodes arousal and regulates sleep . HoweverThese studies further our knowledge about how neurons can modulate output behaviors through changes in physiology. The circadian clock may modulate behavior through multiple mechanisms in which clock-dependent molecules influence membrane excitability and temporal spike codes. More circadian-driven behaviors could be modulated through temporal spiking patterns because clock neurons may use multiple distinct codes. However, further studies are needed to closely assess how environmental light can modulate membrane excitability and temporal spike codes.+ l-LNvs and s-LNvs, as well as LNds and DN1s , distinct populations of clock neurons drive the circadian rhythm at different times of day. As evening descends, the driving force of activity becomes the responsibility of LNds in the presence of light, illustrating the rearrangement of neuronal circuits according to the photoperiod . Thus, CThe circadian clock may have strong implications in proper memory consolidation. In humans, chronic disruption in the circadian clock has been linked to mild cognitive impairment and even dementia and Alzheimer's disease , 184. ThDrosophila also supports plastic mechanisms shaped by astrocytes and clock neurons (The hippocampus has long been implicated in long-term memory (LTM) and may modulate LTM through sleep. Recently, researchers proposed that sharp wave-ripples are important for the consolidation process of LTM that contributes to deficits in emotional memory , sequent neurons .Drosophila, specific regions of the brain regulate learning and memory pathways. For example, MBs are located in the protocerebrum of the brain, where they are organized into five lobes that process olfactory learning and memory. Furthermore, MBs may also participate in the interplay between sleep regulation and memory centers  neurons in mice . This apLight, or the absence of light, could also maintain robust LTM. In human studies, certain light exposure can affect cortical areas that are important for cognition. For example, differing wavelengths of light affected memory and attention –206. In + l-LNvs. Inami et al. used a memory paradigm involving courtship conditioning to assess how consolidated memory is maintained and how environmental light participates in this process  and core clock signaling regulate membrane potential dynamics to modulate synaptic plasticity that depends on neural coding, as well as circuitry, memory, and sleep architecture. Moreover, recent work in At the molecular level, computation in the brain starts with proteins, such as voltage-gated ion channels and receptors that can change their structural and functional state in response to environmental changes, such as light. These molecular mechanisms have been adapted into increasingly more complex computational frameworks. In synapses and neurons, local membrane potentials shaped by ion channels and receptors are temporally and spatially integrated. Furthermore, individual neurons are interconnected into networks and circuits, and the circuits are assembled into a brain capable of abstract thought. Not surprisingly, electronic computing has mirrored the same pattern in the engineering world, starting from transistors and integrated circuits to microprocessors and computers. When combined with voltage-gated sodium channels, voltage-gated potassium channels have a crucial function in generating action potentials at the molecular level. To generate action potentials with a specific shape and firing pattern, a neuron needs these voltage-gated ionic channels in appropriate subcellular locations.Drosophila and melanopsin in mammals) could be a mechanism that functionally makes some voltage-gated channels unable to simultaneously participate in generating membrane potential dynamics. Therefore, such a decreased cooperativity of these channels must enhance the hysteresis effect and, thus, may lead to the higher-order temporal structure of membrane potential dynamics. Light signaling adds a powerful mechanism for sensing light and controlling the history-dependency of membrane potentials, which is critical for generating specific patterns of spike trains.How light-induced signaling impacts voltage-gated channels to regulate membrane potential dynamics is unclear. In this review, we propose that a decreased cooperativity of the voltage-gated potassium channel state change timing is vital to generating the higher-order temporal structure of membrane potential dynamics. Mathematically, this state change can be defined as an integrator/differentiator that converts the sum of input signals into an output signal over time, while the output decays steadily. This light-induced state change (mediated by CRY in As we elucidate clearer connections between light, the circadian clock, and clock-driven behaviors, we can make meaningful efforts to use pharmaceuticals or simply light as a form of treatment against circadian pathologies.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Affiliate stigma may increase the risks of negative parenting and psychological and depressive problems in caregivers of children with attention-deficit/hyperactivity disorder (ADHD). Evaluating affiliate stigma and determining how to reduce it are crucial to promoting mental health in caregivers and their children with ADHD. The aim of this study was to examine the associations of stress-coping orientations and parental child-rearing styles with the risk of high affiliate stigma in caregivers of children with ADHD in Taiwan. Affiliate stigma, stress-coping orientations, and parental child-rearing styles were assessed. The results of univariate logistic regression analysis indicated that caregivers’ gender, depressive symptoms, four orientations of stress coping, and two parenting styles, and children’s high severities of internalizing, externalizing, and ADHD symptoms were significantly associated with high affiliate stigma. The results of multivariate logistic regression analysis indicated that after controlling for caregivers’ gender, depressive symptoms, and children’s severity of internalizing, externalizing, and ADHD symptoms, caregivers with high orientation of seeking social support were less likely to have high affiliate stigma than those with low orientation of seeking social support; the caregivers with high care and affection parenting were less likely to have high affiliate stigma than those with low care and affection parenting, whereas the caregivers with high overprotection parenting were more likely to have high affiliate stigma than those with low overprotection parenting. Intervention programs targeting caregiver affiliate stigma must consider various coping orientations and parental child-rearing styles in their approach. Affiliate stigma refers to the self-stigma of caregivers of people with mental illnesses; this stigma entails a caregiver perceiving stigmatizing attitudes being directed at them from others and internalizing these negative attitudes . AffiliaAccording to the ecological systems theory , caregivParker developed the Parental Bonding Instrument to measure three factors of parental child-rearing, namely care and affection, overprotection, and authoritarianism . A high The aim of this study was to examine the associations between stress-coping orientations and parental child-rearing styles with affiliate stigma in caregivers of children with ADHD in Taiwan. We hypothesized that various stress-coping orientations and parental child-rearing styles have various associations with affiliate stigma in caregivers of children with ADHD.The procedure of recruiting participants at baseline in the Study on Affiliate stigma in Caregivers of Children with ADHD in Taiwan has been described elsewhere . In brieWe used the 22-item self-administrated Affiliate Stigma Scale (ASS)  to measuWe used the 53-item self-administrated COPE to assess caregivers’ stress-coping strategies . Every iThe original PBI measures how each adult remembers and represents their own parents’ attitudes and behaviors towards them during their infancy . Gau andThe Chinese Version of the Child Behavior Checklist for Ages 6–18 (CBCL/6-18) is a 112-item standardized caregiver-reported measure of behavioral problems in children ,28,29. WThe 20-item Mandarin Chinese version of the Center for Epidemiological Study-Depression Scale (CES-D) was used to assess the severity of depressive symptoms in caregivers ,31. CareCaregivers’ gender, age, length of education, and marital status, and children’s gender and age were collected at baseline.p value of <0.05 were used to present statistical significance. We defined the OR that was higher than 1.5, 2.5, and 4 or lower than 0.667, 0.4, and 0.25 as having a small, medium, and large effect, respectively [Descriptive results are presented as percentages for categorical variables and as mean and standard deviation (SD) for continuous variables. The associations of caregivers’ demographic characteristics, depressive symptom, high orientation of stress-coping strategies, and child-rearing styles, and children’s demographic characteristics, and severe behavioral and ADHD symptoms (independent variables) with high affiliate stigma (dependent variable) were firstly examined by using univariate logistic regression analysis. Variables that were significantly associated with high affiliate stigma in univariate logistic regression analysis were further selected for multivariate logistic regression analysis, serving as the independent variables. The associations of various coping orientations and parental bonding with high affiliate stigma were examined separately in two logistic regression models, controlling for demographic characteristics, caregivers’ depressive symptoms, and the children’s behavioral and ADHD symptoms. Odds ratio (OR), its 95% confidence interval (CI), and a two-tailed ectively ,33.n = 322, 80.5%).Variables that were significantly associated with high affiliate stigma in univariate logistic regression analysis were further selected for multivariate logistic regression analysis. Caregivers’ gender and depressive symptoms and children’s internalizing, externalizing, and ADHD symptoms were used as the covariates. The study revealed that various types of stress-coping orientations and parental childrearing styles had varying relationships with high affiliate stigma among caregivers of children with ADHD.Parents may experience multiple sources of stress when taking care of children with ADHD such as managing their children’s behaviors, supervising the completion of their children’s daily routines, maintaining relationships among family members, and craving social support . The typIn addition to seeking socioemotional support, the coping strategy of changing cognition such as positive reinterpretation, acceptance of stressors, and perceived growth in the process of managing stress may diminish the negative emotional consequences of stressful events ,9. BecauThe results of this study demonstrated that caregivers with high care and affection parenting were less likely to have high affiliate stigma than those with low care and affection parenting, whereas the caregivers with high overprotection parenting were more likely to have high affiliate stigma than those with low overprotection parenting. Research has demonstrated that high levels of caregiver care and affection significantly correlate with reduced inattention and psychiatric comorbidities in their children . CharbonFurthermore, overprotective parenting reflects denial of their children’s psychological autonomy . ResearcAlthough the cross-sectional study design limited the possibility to determine the causal relationship between affiliate stigma, stress-coping orientations, and parental child-rearing styles, mental health professionals must assist the caregivers of children with ADHD in identifying the most suitable stress-coping strategies, especially seeking of social support, and advising against less effective coping strategies. Moreover, intervention programs targeting caregiver affiliate stigma must consider parental styles in their approach. Affiliate stigma, stress-coping strategies, and parental child-rearing styles may be the results of interactions between caregivers and environments. Not only caregivers’ psychological and cognitive mechanisms but also the interactions with people in caregivers’ microsystem and mesosystem should be assessed.This study surveyed the association between affiliate stigma and stress-coping orientations and parental child-rearing styles by a cross-sectional design, which limited the possibility of determining the causal relationships among the variables. Moreover, this study collected the data from caregivers but no other information source. The single data source may have resulted in common-method variance. This study did not collect data on children’s treatment for ADHD and thus could not determine the possible influence of ADHD treatment. Further study is needed to support the categorization of the COPE used in this study.This study demonstrated that seeking social support may be an adaptive stress-coping strategy to protect caregivers of children with ADHD from aggravated affiliate stigma. Moreover, adopting the parental style of care and affection may contribute to low affiliate stigma, whereas adopting the parental style of overprotection may increase the risk for caregivers perceiving public stigma and internalizing the negative attitudes. The results of this study indicate that caregivers of children with ADHD need help to develop the coping strategy of seeking social support. Intervention programs targeting caregiver affiliate stigma must consider parental styles in their approach. Further study is needed to examine the mechanism accounting for the associations of seeking social support and the parental style of care and affection and overprotection with affiliate stigma in caregivers of children with ADHD. Mental health professionals should develop the intervention programs to enhance caregivers’ adaptive stress-coping strategies and parental child-rearing styles; the effects of intervention programs on reducing affiliate stigma also warrant study.


Physiotherapy can include both device-guided slow breathing (DGSB) and nondevice-guided slow breathing (NDGSB) in the treatment of systemic arterial hypertension.The aim of this study is to summarize the effects of DGSB on blood pressure levels of patients with hypertension based on the published literature to date.A systematic search of all published randomized controlled trials (RCTs) on the effects of device-guided and nondevice-guided slow breathing in patients with hypertension, without language restriction, was carried out up to a publication date of January 2020 in nine databases: PubMed/MEDLINE, Latin American and Caribbean Health Sciences Literature (LILACS), EMBASE, CENTRAL , Physiotherapy Evidence Database (PEDro), CINAHL , Scopus, Web of Science, and Livivo. Clinical trial records databases , and bases for the open gray literature, including Gray Literature Report and ProQuest Central , were also searched for potentially eligible RCTs. The quality assessment of the included studies will be performed using the Cochrane Risk of Bias Tool for Randomized Trials. The overall quality of the evidence for each outcome will be assessed using the GRADE  system.As of December 2021, the review was completed and all data from continuous variables referring to blood pressure values (mmHg) were synthesized.This systematic review will provide a summary of the current evidence on the effects of both DGSB and NDGSB on blood pressure levels. This information can contribute to decision-making by health professionals related to the use of these interventions in patients with hypertension.PROSPERO  CRD42020147554; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=147554RR1-10.2196/33579 Hypertension is a multifactorial chronic disease, and is the main risk factor for the development of cardiovascular diseases and chronic kidney disease. Hypertension affects 32% of adults and more than 60% of the elderly, being responsible for half of the deaths from cardiovascular disease (CVD) in Brazil . In addiConsidering the high prevalence rates, the treatment of hypertension is necessary, not only to reduce blood pressure levels but also to prevent the development of CVD, cerebrovascular diseases, and kidney diseases. This treatment can be medication, which will be determined according to the blood pressure values obtained either in medical consultations or at home; cardiovascular risk factors; and the presence of target organ damage identified during anamnesis. Nonpharmacological treatment has also been shown to be effective in reducing blood pressure levels in patients with hypertension -4, incluThe physiotherapy prescription for the treatment of hypertension may include both exercise and device-guided slow breathing (DGSB) or nondevice-guided slow breathing (NDGSB). These breathing exercises consist of slow and deep breathing with 6 to 10 breaths per minute, and can be performed with or without a guiding device. Isometric exercises have been shown to be effective in reducing blood pressure levels, along with aerobic and dynamic exercises -6. HowevThe American Heart Association reported that there is no strong evidence on the effectiveness of DGSB, whereas the 8th Brazilian Hypertension Guidelines reported a IIa degree of recommendation, level of evidence A ,4. A revpranayama) for 4 weeks in patients with prehypertension and hypertension. The review included 17 studies, with systolic blood pressure reported in 1017 subjects and diastolic blood pressure reported in 964 subjects. Although interesting, this review did not specifically include patients with hypertension and exclusively compared DGSB to pranayama. Therefore, a systematic review of the antihypertensive effects of DGSB or NDGSB applied by physical therapists is necessary to provide the best evidence available to clinical physical therapists and patients with hypertension. In addition, it is also important to summarize the evidence on the effectiveness of DGSB or NDGSB compared to usual care.Recommendations for the use of DGSB or NDGSB in clinical practice should be guided by a systematic, high-quality literature review. Recently, Chaddha et al  publisheAccordingly, the aim of this systematic review and meta-analysis is to summarize the effects of DGSB on blood pressure levels of patients with hypertension compared with control conditions , other interventions (NDGSB), and when used as an adjunct to other treatments (medication). Thus, the research question for this systematic review of randomized controlled trials (RCTs) is: What are the effects of the prolonged use of device-guided or nondevice-guided slow breathing compared to usual care on the blood pressure values of patients with hypertension?The design of this systematic review is inspired by the recommendations of the Cochrane Handbook of Systematic Reviews  and the The articles were selected based on inclusion criteria according to the type of study, participants, and intervention.RCTs published up to January 2020 were included in this systematic review, without language or year of publication restrictions.Studies including patients with hypertension, with or without comorbidity, who were over 18 years old, of both sexes, and with or without antihypertensive medication treatment were included for review.Interventions considered had to involve DGSB and NDGSB compared to control conditions  and interventions as an adjunct to other treatments (medication). Any dosage of device-guided breathing treatment was accepted. Regarding the follow-up time, studies with a duration of a minimum of 8 weeks were considered.RCTs that also used other interventions along with DGSB/NDGSB, such as physical activity ; salt reduction and salt substitution; stress control ; dietary interventions, including a dietary approach to stop hypertension, low-carbohydrate diet, Mediterranean diet, high-protein diet, low-fat diet, vegetarian diet, paleolithic diet, and low index glycemic/load; and lifestyle interventions  were excluded since it was not possible to identify the specific effect of DGSB/NDGSB in such studies.The primary outcome was the systolic blood pressure and diastolic blood pressure values , expressed in mmHg, measured after the interventions, as well as their variations. The secondary outcome was a reduction in the quantity/dosage of drugs administered to control hypertension, if relevant.A systematic search of all published RCTs on the effects of device and nondevice-guided slow breathing in patients with hypertension, without language restriction, was carried out until January 2020 in nine databases: Pubmed/MEDLINE, Latin American and Caribbean Health Sciences Literature (LILACS), EMBASE, CENTRAL , Physiotherapy Evidence Database (PEDro), CINAHL , Scopus, Web of Science, and Livivo. Clinical trial record databases , and sites for the open grey literature, such as Gray Literature Report and ProQuest Central , were also searched. Completed and ongoing RCTs were searched up to January 2020 and, when possible, only peer-review papers were included, because the grey literature was also searched.An example of the search strategy used in PubMed/MEDLINE is shown in Two reviewers independently analyzed all titles and abstracts retrieved with the search. When there was agreement on a particular record, the full text was analyzed by both reviewers, according to the eligibility criteria. In the presence of disagreement between the reviewers, a third reviewer was convened. When additional information was needed, the authors of the potentially eligible studies were contacted.Hypertension [Mesh: NoExp], hypertensi*, high blood pressure, high blood pressures, blood pressure [Mesh], blood pressure, arterial pressures, arterial tension, arterial tensions, Arterial Pressure [Mesh], Arterial pressure, arterial blood pressure, arterial blood pressures, elevated blood pressure, acute hypertension, arterial hypertension, cardiovascular hypertension, controlled hypertension, hypertensive disease, systemic hypertension, increased blood pressure, artery blood pressure, artery pressure, systemic arterial pressure, systemic artery pressure, Hypertension [Mesh: NoExp] OR hypertensi* OR high blood pressure OR high blood pressures OR blood pressure [Mesh] OR blood pressure OR arterial pressures OR arterial tension OR arterial tensions OR Arterial Pressure [Mesh] OR Arterial pressure OR arterial blood pressure OR arterial blood pressures OR elevated blood pressure OR acute hypertension OR arterial hypertension OR cardiovascular hypertension OR controlled hypertension OR hypertensive disease OR systemic hypertension OR increased blood pressure OR artery blood pressure OR artery pressure OR systemic arterial pressure OR systemic artery pressure, Breathing Exercises [Mesh: NoExp], breathing exercises, respiratory muscle training, device-guided breathing, loaded breathing, slow breathing exercises, paced breathing, controlled breathing, breathing exercise, breathing therapy, chest physical therapy, chest physiotherapy, respiration exercise, respiration therapy, respiratory exercise, respiratory physiotherapy, deep inspiration, deep respiration, deep breathing, Breathing Exercises [Mesh: NoExp] OR breathing exercises OR respiratory muscle training OR device-guided breathing OR loaded breathing OR slow breathing exercises OR paced breathing OR controlled breathing OR breathing exercise OR breathing therapy OR chest physical therapy OR chest physiotherapy OR respiration exercise OR respiration therapy OR respiratory exercise OR respiratory physiotherapy OR deep inspiration OR deep respiration OR deep breathing OR deep respiration OR deep breathing, Hypertension [Mesh: NoExp] OR hypertensi* OR high blood pressure OR high blood pressures OR blood pressure [Mesh] OR blood pressure OR arterial pressures OR arterial tension OR arterial tensions OR Arterial Pressure [Mesh] OR Arterial pressure OR arterial blood pressure OR arterial blood pressures OR elevated blood pressure OR acute hypertension OR arterial hypertension OR cardiovascular hypertension OR controlled hypertension OR hypertensive disease OR systemic hypertension OR increased blood pressure OR artery blood pressure OR artery pressure OR systemic arterial pressure OR systemic artery pressure AND Breathing Exercises [Mesh: NoExp] OR breathing exercises OR respiratory muscle training OR device-guided breathing OR loaded breathing OR slow breathing exercises OR paced breathing OR controlled breathing OR breathing exercise OR breathing therapy OR chest physical therapy OR chest physiotherapy OR respiration exercise OR respiration therapy OR respiratory exercise OR respiratory physiotherapy OR deep inspiration OR deep respiration OR deep breathing OR deep respiration OR deep breathingTwo reviewers independently extracted the following data from the included trials: author, publication date, country of publication, study type, sample size, participant characteristics , use or not of antihypertensive medications, presence of comorbidities, categories of blood pressure, details of intervention , details for blood pressure measurement , and outcome measures (systolic and diastolic blood pressure). A third reviewer was called in case of disagreement. When necessary, the authors of RCTs included were contacted to provide additional information.The quality assessment of the included studies was conducted using the Cochrane Risk of Bias Tool for Randomized Trials (RoB2) , which iAll data from continuous variables referring to blood pressure values (mmHg) will be synthesized according to the mean difference and respective 95% CIs. Standard deviations were also extracted from the studies for analysis.The effects of interventions on blood pressure values will be analyzed separately. The data will be evaluated according to the type of intervention (DGSB or NDGSB); however, only studies lasting at least 8 weeks will be considered for meta-analysis . Results where there was an intention-to-treat analysis will be used whenever possible.2I statistic. The quality of the evidence will be considered inconsistent if considerable heterogeneity between the groups (2I>50%) is observed. When sufficient evidence is available, a funnel graph will be used to investigate possible publication bias.The presence of statistical heterogeneity between RCTs will be assessed using the 2I>50%), indirectness , imprecision (<400 participants in the comparison for continuous outcomes), and publication bias . For each factor not met, the quality of the evidence is reduced by one level . Single trial comparisons (<400 participants for continuous results) were found to be inconsistent and inaccurate, providing “low quality evidence,” which could be downgraded to “very low quality evidence” if limitations are identified in relation to the risk of bias [The overall quality of the evidence for each outcome will be assessed using the GRADE   system,  of bias .The quality of the evidence will be categorized as follows: the evidence is of high quality if the results are consistent in ≥75% of the participants, with a low risk of bias, without publication bias, and with consistent direct and accurate data; further research is unlikely to alter the estimate or confidence in such results. The evidence will be considered to be of moderate quality when one of the five classification factors above is met; further research can alter the estimated effect and impact confidence in the effect in this case. The evidence will be considered to be of poor quality when two of the five classification factors are not met. In this situation, future research is likely to alter the estimated effect and have a significant impact on confidence in the effect. The evidence will be considered to be of very low quality when three of the five classification factors are not met, as any estimate of effect is uncertain in this case .As of December 2021, the review is complete and all data from continuous variables referring to blood pressure values (in mmHg) have been synthesized.This systematic review aims to provide the best available evidence on the effectiveness of DGSB or NDGSB in patients with hypertension, as well as whether DGSB/NDGSB allows for a reduction in the amount/dosage of antihypertensive medication administration. All recommendations in the Cochrane Manual of Systematic Reviews will be followed to ensure that the review is of high quality. It is believed that the results of this systematic review will be important because both DGSB and NDGSB are accessible and can be performed even at home, as long as the use is prescribed and guided by a physical therapist.pranayama on the blood pressure of patients with hypertension, since this type of intervention is routinely used in a physiotherapist’s clinical practice, following a completely different method from that adopted in yoga. Therefore, this evidence will inform health care professionals and patients about the potential benefits of this intervention. This review may also identify gaps in the literature that can be addressed in future studies.In addition, this review is the first to assess NDGSB unrelated to the effect of


The basal ganglia network is represented by an interconnected group of subcortical nuclei traditionally thought to play a crucial role in motor learning and movement execution. During the last decades, knowledge about basal ganglia physiology significantly evolved and this network is now considered as a key regulator of important cognitive and emotional processes. Accordingly, the disruption of basal ganglia network dynamics represents a crucial pathogenic factor in many neurological and psychiatric disorders. The striatum is the input station of the circuit. Thanks to the synaptic properties of striatal medium spiny neurons (MSNs) and their ability to express synaptic plasticity, the striatum exerts a fundamental integrative and filtering role in the basal ganglia network, influencing the functional output of the whole circuit. Although it is currently established that the immune system is able to regulate neuronal transmission and plasticity in specific cortical areas, the role played by immune molecules and immune/glial cells in the modulation of intra-striatal connections and basal ganglia activity still needs to be clarified. In this manuscript, we review the available evidence of immune-based regulation of synaptic activity in the striatum, also discussing how an abnormal immune activation in this region could be involved in the pathogenesis of inflammatory and degenerative central nervous system (CNS) diseases. The basal ganglia network operates for appropriate context-dependent cognitive, behavioral and emotional responses.Bidirectional plastic changes of striatal synapses allow input integration and input-output associations in the basal ganglia network.Astrocytes gate striatal excitatory synaptic transmission and orchestrate striatal pathways and subnetworks activation.Soluble immune molecules may influence striatal glutamatergic transmission acting on both pre- and post-synaptic sites.Pathological activation of striatal astrocytes and microglia could influence the synaptic bases of basal ganglia network functioning, leading to cognitive and behavioral abnormalities during neurological disorders.The extensive research performed during the last years has made it clear the crucial role of the immune system in the field of cognitive and behavioral sciences. Human behavioral, cognitive and social traits could be deeply influenced by the activation of immune cells in both physiological and pathological conditions. The classical concept of the central nervous system (CNS) as an immune-privileged site has significantly evolved during the last years, acknowledging the presence of functional meningeal lymphatic vessels and a complex neuro-immune cross-talk involving innate and adaptive immunity, as well as resident immune cells within the CNS , 2. IndeA prototypical example of the neuromodulatory role of the immune system is represented by the shift in an individual’s behavior and perceptions frequently accompanying infectious diseases. Indeed, a reduced interest in social interactions and unnecessary physical activity could represent a protective evolutionistic response aimed at limiting pathogen spreading in a social community. These complex cognitive and behavioral responses are thought to be caused by pro-inflammatory mediators released by immune cells counteracting the infection . If the The cortico-striato-thalamo-cortical network was originally described as an essential circuit for locomotor activity and movement execution . Still, The complex microstructural organization of the striatum, characterized by multiple inhibitory and excitatory synaptic connections among various neuronal subtypes, highlights the activity of this structure as an input integrator. Functional or structural alterations of such synaptic connections can powerfully influence the final output and tuning of the whole basal ganglia network . DespiteThe functional anatomy of the basal ganglia can be described as a closed-loop network with two different pathways canonically considered as parallel and opposed, one favoring (direct) and another inhibiting (indirect) the activation of cortical brain areas. The main input of the basal ganglia network is represented by glutamatergic excitatory projections from cortical and thalamic areas, making synaptic contact with striatal medium spiny neurons (MSNs) and aspiny interneurons , 17. SucThe extensive net of intra-striatal inter-neuronal connections, integrating various cortical and sub-cortical inputs, makes the striatum a crucial station from which the information is filtered and channeled through the direct and indirect pathways Figure 1The classical “push–pull”, direct–indirect dichotomous view of striatal output pathways has been challenged by the evidence that both pathways are activated during the initiation/stopping of actions or behavioral sequences , 43–45 aOverall, basal ganglia seem to be involved in a wide range of behavioral, cognitive and affective functions, leading to the execution of a specific response out of the different choices continuously arising during daily living. Basal ganglia activity could be involved both in conscious goal-directed behavior and in habitual unconscious actions, representing two possible decision-making performances , 55. VenAccording to the critical roles played by the basal ganglia circuit in brain physiology, its dysfunctional activity could lead to a wide range of behavioral/cognitive/emotional consequences. The selection process mediated by the circuit could become altered, since basal ganglia malfunction could be followed by an excessive impulsivity in high-conflict decisions , lowerinSince their discovery, long-lasting and activity-dependent plastic changes of synaptic transmission have been considered a plausible biological process underlying brain ability to translate experiences into memories –70. SynaIn this scenario, the synaptic plastic changes described at excitatory corticostriatal connections , 71–73 ain vivo activation of the two striatal pathways was found to be concurrent  concentration , could deeply influence the basal ganglia action-outcome synaptic associations. Accordingly, altered astrocytic activity has been linked to enhanced reward-seeking behavior and to the pathological intake of drugs of abuse . In rodevia direct synaptic phagocytosis and in cooperation with microglial cells, tagging synapses for elimination through the secretion of transforming growth factor-β (TGF-β)  , 145.Microglia can account for 5%–12% of total cellular elements in the CNS, representing the main element of the resident CNS immune system with critical roles in organizing rapid responses against different kinds of tissue injury –148. Act3CL1, which could be secreted or expressed as a membrane-tethered protein, is thought to represent a synaptic tagging mechanism through which neuronal cells may attract resident CX3CR1-expressing microglia   or neuroMurine microglial cells display a spectrum of distinct anatomical features, lysosome content and membrane properties across basal ganglia nuclei, suggesting that region-specific local cues could shape the functional state of these cells . A recenMoreover, microglial cells could modulate goal-directed and drug-seeking behavior through a molecular pathway, yet to be fully characterized, involving a Toll-like receptor 4 (TLR4)-induced modulation of NMDAR-dependent synaptic plasticity in MSNs of NAc , or throIncreasing evidence suggests that soluble products of inflammation can influence learning/memory processes and human behavior through the modulation of synaptic transmission and plasticity in different neural networks , 172. InOn the other side, less is known about the potential effects of such molecules on subcortical network activity. It has been suggested that IL-1β could be involved in the modulation of striatal neurotransmission during both physiological and pathological conditions. Indeed, the exposure of murine corticostriatal slices to IL-1β is followed by an enhanced frequency of spontaneous excitatory transmission, an effect potentially caused by the activation of transient receptor potential vanilloid 1 (TRPV1) channels located in striatal pre-synaptic terminals  togetherAnother pro-inflammatory cytokine, TNF-α, has been hypothesized to modulate glutamatergic neurotransmission in the striatum. Specifically, exposure of murine brain slices to TNF-α was able to induce an alteration of spontaneous excitatory synaptic currents in MSNs, with an increased duration and decay time that could be reversed by the application of anti-TNF receptor (TNFR)–antibodies . InteresOn the other hand, it has been proposed that TNF-α could play a role in the homeostatic maintenance of excitatory synaptic weights around a firing set point, exerting a physiological and adaptive role aimed at limiting the corticostriatal drive during pathological conditions . Specifi2+/Calmodulin(CaM)-dependent protein kinase II (CaMKII)  represent a family of soluble immune mediators exerting pleiotropic immune-modulating effects, with particular regard to immune-surveillance processes against viral infections , 220. In(CaMKII) , known t(CaMKII) , 226. Of(CaMKII) .The last decades have been characterized by an intense investigation of the crucial role played by neuroinflammation in the pathogenesis of several neurodegenerative disorders , 229, inResident immune cells are thought to be involved in these pathological processes. Early reports showed high levels of activated microglia in the midbrain and in the striatum of PD brains , 252, anAs introduced above, the abnormal release of pro-inflammatory soluble mediators within the striatum, together with the loss of the physiological supporting functions exerted by glial cells, could alter the function of the striatal synaptic network during PD development, long before the occurrence of neurodegenerative features Figure 2To date, PD-related synaptopathy has been mainly linked to the synaptic and molecular effects of pathological α-syn aggregates –278. HowThe potential relevance of pathological neuro-immune interactions during PD is supported by a recent study showing that corticostriatal synaptic plasticity can be rescued through the modulation of astrocytic and microglial activation by transcranial magnetic stimulation (TMS) . Specifi2+ signaling, could alter MSNs membrane excitability and disrupt cortico-striatal glutamatergic transmission (Further investigations are required to clearly decipher the potential dysfunction of striatal astrocytes during the course of PD, but findings obtained in research studies on other basal ganglia disorders like HD seem to suggest that the loss of physiological astrocytic properties could be associated with altered action selection, habit formation, impulse inhibition and motor behavior , 293. HDsmission , 293. Susmission , 303, posmission , 304. OvThe functional view of the basal ganglia network slowly moved from the brain motor control station to the decision-maker of appropriate context-dependent cognitive, behavioral and emotional responses. In parallel, the physiological processes underlying the integrative and filtering activity of the basal ganglia started to be deciphered during the last decades. Plastic properties of striatal synaptic connections have been demonstrated as crucial for the integration of multimodal cortical inputs and for conveying a proper basal ganglia output driving an individual’s action selection/inhibition and habit formation. In this scenario, the current evidence on the neuro-modulatory role played by immuno-glial cells in cortical areas suggests that corticostriatal projections and subcortical networks can be influenced by the immune system as well.The characterization of the neuro-immune interactions taking place in the striatum, both in its dorsal and ventral areas, could help to decipher the molecular mechanisms underlying the previously underscored effects of the immune system on motivated and context-dependent human behavior. The identification of cells and soluble immune mediators involved in the striatal neuro-immune cross-talk could lead to a new approach to basal ganglia disorders, disclosing a novel pathophysiological view for motor, behavioral, cognitive and emotional abnormalities accompanying neurological and psychiatric disorders.MDF conceived the review. AM performed the literature review, wrote the manuscript draft and prepared the figures. MDF, VG, LP, and PC reviewed and integrated the manuscript draft and the figures. All authors contributed to the article and approved the submitted version.This work has been supported by the Marlene and Paolo Fresco Institute for Parkinson’s and Movement Disorder, Fresco Parkinson Institute, New York University School of Medicine.AM received travel grants from Biogen, Novartis, Merck, Teva, Almirall and Sanofi to attend national and international conferences. MDF participated on advisory boards for and received speaker or writing honoraria and funding for traveling from Bayer, Biogen Idec, Sanofi, Merck, Mylan, Novartis, Roche and Teva. PC participated on advisory boards for and received funding for traveling, speaker honoraria and research support from AbbVie, Biogen Idec, Merck, Genzyme, Novartis, Prexton, Teva, UCB and Zambon.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Most older adults prefer to age in place rather than moving to a long-term care (LTC) facility, but little is known about the factors that predict entry into LTC. This study sought to utilize administrative claims data to understand the predictors of LTC transitions using de-identified claims data from Medicare Advantage members in the UnitedHealth Group Clinical Discovery Database. We investigated LTC transitions of 250,587 adults  between January 1, 2016 and December 31, 2019. Types of predictors for these transitions include aggregated medical data surrounding chronic conditions and frailty indices, as well as healthcare utilization and demographics in 2016 and 2017. We then fit data of these types to an extreme gradient boosting (XGBoost) model to predict long-term care transitions in 2018 and 2019 . Frailty indicators, such as falls and fractures, mobility problems, dementia, and delirium, as well as osteoporosis are strong predictors of LTC transitions. These findings can be used to design interventions aimed at preventing LTC transitions and enabling older adults to age in place.


Human-parasite co-evolution has endowed parasites with multiple strategies to subvert host immunity in order to establish chronic infections and ensure human-to-human transmission. While much focus has been placed on viral and bacterial infections, intravital microscopy studies during parasitic infections have been comparatively sparse. In this review, we will discuss how in vivo microscopy has provided important insights into the generation of innate and adaptive immunity in various organs during parasitic infections, with a primary focus on Leishmania. We highlight how microscopy-based approaches may be key to providing mechanistic insights into Leishmania persistence in vivo and to devise strategies for better parasite control.Intravital microscopy, such as 2-photon microscopy, is now a mainstay in immunological research to visually characterize immune cell dynamics during homeostasis and pathogen infections. This approach has been especially beneficial in describing the complex process of host immune responses to parasitic infections  To address this, time-lapse intravital microscopy (IVM) has been used to capture cell motility and cell-cell interaction dynamics within physiological tissue environments, where stromal cell networks, physiological blood flow, lymphatic drainage and innervation remain intact. More recently, two-photon microscopy (2P-IVM) has emerged as the gold standard for in vivo imaging and represents an important imaging platform to refine and extend observations derived from cell culture studies. While initial studies focused on cellular dynamics at steady-state or using model antigen systems, more recent 2P-IVM studies have focused on visualizing immunity generation in response to natural infections, solid tumors and evaluating candidate vaccine efficacy in vivo.The immune system must rapidly mobilize immune cells to appropriate tissue sites to eliminate infections, but at the same time, must be tightly regulated to prevent excessive tissue damage. This is largely achieved by the exquisite ability of immune cells to continuously survey most organs in the body, and by coordinating cell-cell communication among different cell types to generate antigen and site-specific immunity. Immune surveillance in vitro imaging studies and static histological analyses that fail to fully capture the biomechanical, physicochemical and immunological aspects of complex tissue environments. Two-photon microscopy is a powerful tool that allows researchers to visually characterize cellular dynamics that dictate the specificity, breadth, and magnitude of immune responses. Pioneering studies using 2P-IVM in intact , and visceral (VL), also known as kala-azar , that modify the phagosome into a parasitophorous vacuole  production to aid in killing intracellular parasites -specific CD4+ T cells at 6 hours post-infection, whereas T cell activation was drastically reduced at 24 hours and completely abolished at 48 hours post-infection , arguing that additional mechanisms are in place that prevent complete parasite clearance in vivo, even in the face of strong cellular immunity induction  are generated during primary infection, yet it is currently not clear whether these cells also require a small pool of parasites for their long-term maintenance (CM) home to secondary lymphoid organs, such as the draining lymph node, where they proliferate and differentiate into effector T cells and migrate back to the lesion sites to mediate effector activities  reactivation  and a studentship from Research Manitoba and University of Manitoba Student Fellowship (RZ). JU is supported by a CIHR Project grant MOP 114932.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Atherosclerosis, the chronic accumulation of cholesterol-rich plaque within arteries, is associated with a broad spectrum of cardiovascular diseases including myocardial infarction, aortic aneurysm, peripheral vascular disease, and stroke. Atherosclerotic cardiovascular disease remains a leading cause of mortality in high-income countries and recent years have witnessed a notable increase in prevalence within low- and middle-income regions of the world. Considering this prominent and evolving global burden, there is a need to identify the cellular mechanisms that underlie the pathogenesis of atherosclerosis to discover novel therapeutic targets for preventing or mitigating its clinical sequelae. Despite decades of research, we still do not fully understand the complex cell-cell interactions that drive atherosclerosis, but new investigative approaches are rapidly shedding light on these essential mechanisms. The vascular endothelium resides at the interface of systemic circulation and the underlying vessel wall and plays an essential role in governing pathophysiological processes during atherogenesis. In this review, we present emerging evidence that implicates the activated endothelium as a driver of atherosclerosis by directing site-specificity of plaque formation and by promoting plaque development through intracellular processes, which regulate endothelial cell proliferation and turnover, metabolism, permeability, and plasticity. Moreover, we highlight novel mechanisms of intercellular communication by which endothelial cells modulate the activity of key vascular cell populations involved in atherogenesis, and discuss how endothelial cells contribute to resolution biology – a process that is dysregulated in advanced plaques. Finally, we describe important future directions for preclinical atherosclerosis research, including epigenetic and targeted therapies, to limit the progression of atherosclerosis in at-risk or affected patients. Atherosclerosis is a chronic inflammatory process in which the accumulation of cholesterol-laden plaque restricts blood flow within the arterial vasculature. The occlusion of arteries by luminal encroachment of expanding plaque or emboli from plaque rupture underlies a spectrum of cardiovascular diseases (CVDs) including myocardial infarction, ischemic cardiomyopathy, stroke, and peripheral vascular disease. Although CVD has remained a leading cause of morbidity and mortality in high-income countries , an epidEndothelial cells (ECs) comprise the vascular endothelium, the inner lining of all blood vessels, which forms the interface between systemic circulation and underlying tissues. The quiescent or non-proliferating endothelium, once considered to be dormant outside the settings of vascular development or disease, is now understood to play an active role in maintaining vascular homeostasis by receiving and generating diverse biochemical  and mechanical signals . The sysThe pathophysiology of atherosclerosis begins with the perturbed endothelium and is mediated by a cascade of intra- and intercellular signaling events that shape the behaviour of cells within the vasculature . VasculaIn this review, we present emerging studies that implicate the vascular endothelium as a driver of atherosclerotic CVD by directing site-specificity of plaque formation and governing plaque progression through intracellular processes. Furthermore, we highlight recent studies that describe intercellular communication between ECs and key vascular cell types involved in atherogenesis , and disThe vascular endothelium is subjected to both tangential  and circumferential forces  that result from circulating blood flow. ECs at this interface convert mechanical stimuli to biochemical signals through mechanotransduction, which modulates key cellular processes in response to fluctuations in the vascular environment, including proliferation and turnover . The devIn the setting of undisturbed laminar flow, nitric oxide (NO) is produced by elevated levels of eNOS in ECs and diffuses across cell membranes to modulate the activity of vascular cells, including SMCs and leukocytes . NO-mediin vivo protection against atherosclerosis under disturbed flow, including inhibition of integrin α5 by cartilage oligomeric matrix protein   , as wellin vitro  are mitigated by circulating endothelial progenitor cells . Atherosin vitro . Hemodynin vitro . For exain vitro . Furtherin vitro , and hypin vitro .Flow-sensitive microRNAs have also been identified as key modulators of endothelial proliferation and turnover in atherosclerosis , includiA robust characterization of the transcriptional and epigenetic regulatory elements that contribute to endothelial dysfunction has remained an important challenge for atherosclerosis research and has been recently addressed with next-generation approaches for global EC profiling. Of note, the integration of chromatin immunoprecipitation, chromatin accessibility, and RNA sequencing has enabled identification of diverse DNA regulatory elements associated with disturbed flow and proinflammatory activation  . MoreoveMetabolic pathways prominently contribute to EC phenotypes in health and disease. Despite direct exposure to oxygen in the blood, ECs do not utilize oxidative phosphorylation as a primary means of energy production, perhaps because this might enhance oxidative stress and would hamper angiogenesis in hypoxic environments . InsteadAltered EC metabolism has been identified as both a consequence of, and a contributor to, endothelial dysfunction in atherosclerosis. In the quiescent endothelium, laminar shear stress reduces glucose uptake and glycolytic and mitochondrial activity in ECs via KLF2 . ConversIn its quiescent state, the vascular endothelium forms a semipermeable barrier between luminal and abluminal environments that allows for selective bidirectional movement of molecules via EC cell-cell junctions, vesicle-mediated transport within ECs, and diffusion between ECs or across endothelial gaps . In pionin vitro and elevated atherosclerotic burden in mice  has emerged as an important research area for the pathogenesis and treatment of atherosclerosis . Three bBeyond the endothelium, EC-EVs regulate both immune and non-immune vascular cell populations involved in the development of atherosclerosis  and circin vitro co-culture towards in vivo tracking approaches to allow for a robust, physiological characterization of EV activity, which will be made possible with advances in the visualization of EV release and uptake  and those which prevent associated complications  . Lipid-lThe NLRP3 inflammasome is now recognized as a key player in the coordination of vascular inflammation and onset of atherogenesis . NLRP3-min vitro by downregulating NFκB-ICAM-1/VCAM-1 signaling  as anti-inflammatory therapies for limiting endothelial inflammation in CVD . Resolviignaling , and attignaling . Beyond ignaling , suggestNotably, the potential therapeutic impact of promoting inflammation resolution through efferocytosis  is being established with preclinical studies, wherein atherosclerotic plaque progression has been attenuated by proefferocytic cluster of differentiation 47 (CD47)-blocking therapies  or activEpigenetic interventions allow for broad targeting of the diverse mechanisms underlying endothelial dysfunction and have shown recent promise as anti-atherosclerotic therapies . The met+/H+ exchanger 1 inhibition  have likewise afforded new opportunities for anti-atherosclerotic therapies that resolve endothelial dysfunction . Vasculahibition . Despitehibition . Importahibition .in vitro and in vivo models of endothelial activation and atherosclerosis remains an important consideration to identify strategies that hold significant therapeutic potential for distinct plaque locations and diverse patient groups. Additionally, the safety, efficacy, timing, and sustained response of candidate treatments must be considered, as the atherosclerotic disease process develops over decades and necessitates long-term intervention. A robust integration of experimental techniques , data sources , and cutting-edge computational methods  will be required for the creation of next-generation biomarkers and therapies that effectively mitigate atherosclerotic CVD in vulnerable patients.An emerging body of literature has implicated the vascular endothelium as an essential driver of atherosclerosis, a disease process that contributes to substantial mortality and healthcare burden among aging populations. These discoveries shed light on diverse cellular mechanisms that underlie endothelial activation, dysfunctional cell-cell communication, and perturbed vascular homeostasis in atherogenesis. Moreover, they highlight novel therapeutic targets and delivery methods with significant potential to prevent or limit plaque development in patients with atherosclerotic CVD. Although a broad spectrum of intra- and intercellular processes has been implicated in preclinical models of endothelial dysfunction and atherosclerosis, several methodological challenges remain to effectively translate this research to clinical practice. First, the generalizability of findings between diverse


Havoc associated with the novel Coronavirus Disease 2019 (COVID-19) pandemic is placing unprecedented pressure on healthcare and public health system worldwide. With medical resources and personnel being directed to battle COVID-19 globally, the pandemic may have grave repercussions in the resurgence of other infectious diseases such as dengue fever, especially in resource-limited countries with both endemic dengue and intense COVID-19 transmission.During the COVID-19 pandemic, dengue cases spiked in Brazil, introducing an added burden on already fragile healthcare systems . ConsidePreventing or reducing dengue virus transmission depends primarily on mosquito vector controls including interrupting human–vector contact. At a time of continuous lockdowns, when public health staff are diverted to control COVID-19 transmission and community engagement focused on the pandemic, routine mosquito vector surveillance and control programs are discontinued or paused in many countries , which wAedes mosquito drastically increased during the COVID-19 lockdown due to paused vector control programs [A study of India found that the immature density of programs , and an programs . During programs . A robusprograms . Conversprograms .The rapid spread of dengue viruses from endemic to nonendemic countries is associated with international airline travel . StringeAedes aegypti populations and lead to dengue outbreaks [Most dengue endemic countries are low- and middle-income countries. Lower socioeconomic conditions with large numbers of people living in densely populated areas in poorly constructed housing without adequate clean water and sanitation tend to promote utbreaks . As the utbreaks , with alutbreaks .Lockdown measures implemented for the COVID-19 pandemic may also have interrupted already incomplete dengue case detection and reporting, especially in poorer endemic countries that lack effective dengue surveillance systems. Passive mechanisms of dengue surveillance and case detection largely depend on dengue-infected individuals presenting to the healthcare system and the provider subsequently reporting the case to authorities. When combined with insufficient access to dengue diagnostic tests, underestimation of cases is likely. Under lockdown measures, people with dengue symptoms, especially if mild, may delay or avoid seeking healthcare , while di month − average monthly number of dengue cases during 2015 to 2019 at i month ~ number of COVID-19 cases at i month). The results suggested that COVID-19 was significantly and positively associated with dengue in Indonesia  and Vietnam  , Indonesia, Thailand, and Vietnam. Dengue incidence rate ratio (IRR)  was calculated to represent and compare the extent of changing incidence of dengue between 2020 and the previous 5 years across the study countries in the context of the COVID-19 pandemic. The incidence rate for COVID-19 in 2020 was calculated to demonstrate the severity of pandemic in different countries . Fig 1 s= 0.000) . No statIn Australia, dengue outbreaks are usually triggered by imported cases from endemic countries, with a subsequent seasonal outbreak that includes local transmission . Public Although this observational analysis may be vulnerable to confounding due to a variety of transmission dynamics and surveillance capacity in different countries, these data support that the pandemic may have impacts on dengue transmission, with different effects across countries. A research conducted in Singapore found an increased dengue transmission during the COVID-19 pandemic , while oAs the world remains focused on managing the global COVID-19 pandemic, we need to remain mindful that the sustained efforts are needed to prevent the resurgence of other infectious diseases. This is of concern for dengue endemic countries in the Asia-Pacific region, considering the monsoon season in the Indian subcontinent and surrounding regions and the serious situation of the COVID-19 pandemic in this region. Based on recent research and our observation in Asia-Pacific region, some very specific points should be taken care of as follows: (1) continuing to monitor and assess the possibility of reimportation and resurgence of dengue where dengue is not endemic, especially during outbreaks of novel serotypes in neighboring countries ; (2) pay