Stroke is among the leading causes of death and disability worldwide. Restoring blood flow through recanalization is currently the only acute treatment for cerebral ischemia. Unfortunately, many patients that achieve a complete recanalization fail to regain functional independence. Recent studies indicate that activation of peripheral immune cells, particularly neutrophils, may contribute to microcirculatory failure and futile recanalization. Stroke primarily affects the elderly population, and mortality after endovascular therapies is associated with advanced age. Previous analyses of differential gene expression across injury status and age identify ischemic stroke as a complex age-related disease. It also suggests robust interactions between stroke injury, aging, and inflammation on a cellular and molecular level. Understanding such interactions is crucial in developing effective protective treatments. The global stroke burden will continue to increase with a rapidly aging human population. Unfortunately, the mechanisms of age-dependent vulnerability are poorly defined. In this review, we will discuss how neutrophil-specific gene expression patterns may contribute to poor treatment responses in stroke patients. We will also discuss age-related transcriptional changes that may contribute to poor clinical outcomes and greater susceptibility to cerebrovascular diseases.

Fragile X syndrome (FXS) is the most common single-gene cause of intellectual disability and autism spectrum disorder. Individuals with FXS present with a wide range of severity in multiple phenotypes including cognitive delay, behavioral challenges, sleep issues, epilepsy, and anxiety. These symptoms are also shared by many individuals with other neurodevelopmental disorders (NDDs). Since the discovery of the FXS gene, FMR1, FXS has been the focus of intense preclinical investigation and is placed at the forefront of clinical trials in the field of NDDs. So far, most studies have aimed to translate the rescue of specific phenotypes in animal models, for example, learning, or improving general cognitive or behavioral functioning in individuals with FXS. Trial design, selection of outcome measures, and interpretation of results of recent trials have shown limitations in this type of approach. We propose a new paradigm in which all phenotypes involved in individuals with FXS would be considered and, more importantly, the possible interactions between these phenotypes. This approach would be implemented both at the baseline, meaning when entering a trial or when studying a patient population, and also after the intervention when the study subjects have been exposed to the investigational product. This approach would allow us to further understand potential trade-offs underlying the varying effects of the treatment on different individuals in clinical trials, and to connect the results to individual genetic differences. To better understand the interplay between different phenotypes, we emphasize the need for preclinical studies to investigate various interrelated biological and behavioral outcomes when assessing a specific treatment. In this paper, we present how such a conceptual shift in preclinical design could shed new light on clinical trial results. Future clinical studies should take into account the rich neurodiversity of individuals with FXS specifically and NDDs in general, and incorporate the idea of trade-offs in their designs.

Background Neurodevelopmental disorders (NDD) cause individuals to have difficulty in learning facts, procedures, or social skills. NDD has been linked to several genes, and several animal models have been used to identify potential therapeutic candidates based on specific learning paradigms for long-term and associative memory. In individuals with NDD, however, such testing has not been used so far, resulting in a gap in translating preclinical results to clinical practice. Objective We aim to assess if individuals with NDD could be tested for paired association learning and long-term memory deficit, as shown in previous animal models. Methods We developed an image-based paired association task, which can be performed at different time points using remote web-based testing, and evaluated its feasibility in children with typical development (TD), as well as NDD. We included 2 tasks: object recognition as a simpler task and paired association. Learning was tested immediately after training and also the next day for long-term memory. Results We found that children aged 5-14 years with TD (n=128) and with NDD of different types (n=57) could complete testing using the Memory Game. Children with NDD showed deficits in both recognition and paired association tasks on the first day of learning, in both 5-9–year old (P<.001 and P=.01, respectively) and 10-14–year old groups (P=.001 and P<.001, respectively). The reaction times to stimuli showed no significant difference between individuals with TD or NDD. Children with NDD exhibited a faster 24-hour memory decay for the recognition task than those with TD in the 5-9–year old group. This trend is reversed for the paired association task. Interestingly, we found that children with NDD had their retention for recognition improved and matched with typically developing individuals by 10-14 years of age. The NDD group also showed improved retention deficits in the paired association task at 10-14 years of age compared to the TD group. Conclusions We showed that web-based learning testing using simple picture association is feasible for children with TD, as well as with NDD. We showed how web-based testing allows us to train children to learn the association between pictures, as shown in immediate test results and those completed 1 day after. This is important as many models for learning deficits in NDD target both short- and long-term memory for therapeutic intervention. We also demonstrated that despite potential confounding factors, such as self-reported diagnosis bias, technical issues, and varied participation, the Memory Game shows significant differences between typically developing children and those with NDD. Future experiments will leverage this potential of web-based testing for larger cohorts and cross-validation with other clinical or preclinical cognitive tasks.

BACKGROUND Chatbots have been increasingly considered for applications in the health and social care fields. Currently, it remains unclear how a chatbot could engage users coping with complex health needs, such as parents of individuals with neurodevelopmental disorders (NDDs), who often need frequent and ongoing support. One approach to enhancing user engagement is the use of game elements in non-game contexts, known as gamification. To be effective, gamification needs to be tailored to users. OBJECTIVE We sought to identify which gamification elements would be the most useful in a chatbot that focuses on supporting families of children and youths with NDDs. METHODS We performed a narrative literature review of gamification elements and their current implementation. We then used a qualitative approach, which included a series of focus groups and interviews with caregivers of individuals with NDDs (N = 21) to identify potential gamification elements that could be well-suited for a chatbot focused on NDDs. Transcripts were analyzed for emerging themes. RESULTS From our 21 participants, we identified 3 main themes: 1) parents of individuals with NDDs were familiar and had positive experiences with gamification; 2) specific gamification element (goal setting) was considered an important feature for a chatbot for NDDs, whereas others (customization, rewards, and unlockable content) received more mixed opinions; and 3) although social networking was viewed positively, it is a complex feature to implement due to the pertaining issue of medical fact-checking. CONCLUSIONS We show for the first time that prospective users (parents of individuals with NDDs) support the use of gamification in a chatbot for NDDs. Our study illustrates the importance of adopting a user-centred design when deciding which gamification elements to include, as some commonly used elements were perceived negatively by this specific group of users.

BACKGROUND Understanding memory development has fascinated scientists for over 100 years, with important insights in genetics and molecular mechanisms being provided from animal model testing in the last 3 decades. Nonetheless, unlike for animals, testing memory can be challenging in children, especially when they have neurodevelopmental disorders (NDD). In order to leverage those genetic discoveries to develop precise treatment, it was important to develop a test which would allow for easy repeated testing over time, would be done in a comfortable environment for children, and could be done on a large scale to adjust for the important neurodiversity in NDD. OBJECTIVE MISSING METHODS We developed The Memory Game, an online test administered on a tablet, allowing remote testing at longer intervals. We used only pictures to avoid issues with reading and language ability. We also included two types of tasks to dissect the memory circuits involved in NDD: paired associative memory (hippocampus-dependent) and recognition (hippocampus-independent). RESULTS We observed significant performance differences between children with NDD compared to ones with typical development. We also showed more heterogeneous scores in children with NDD and differences in memory decay over time. CONCLUSIONS Our findings show how remote testing can identify developmental differences in learning and memory between individuals with typical development and developmental disorders. Therefore, the Memory Game could prove critical in remote testing as part of clinical trials. Future testing of individuals with gene specific diagnoses will also further our understanding of brain function.

Background Chatbots have been increasingly considered for applications in the health care field. However, it remains unclear how a chatbot can assist users with complex health needs, such as parents of children with neurodevelopmental disorders (NDDs) who need ongoing support. Often, this population must deal with complex and overwhelming health information, which can make parents less likely to use a software that may be very helpful. An approach to enhance user engagement is incorporating game elements in nongame contexts, known as gamification. Gamification needs to be tailored to users; however, there has been no previous assessment of gamification use in chatbots for NDDs. Objective We sought to examine how gamification elements are perceived and whether their implementation in chatbots will be well received among parents of children with NDDs. We have discussed some elements in detail as the initial step of the project. Methods We performed a narrative literature review of gamification elements, specifically those used in health and education. Among the elements identified in the literature, our health and social science experts in NDDs prioritized five elements for in-depth discussion: goal setting, customization, rewards, social networking, and unlockable content. We used a qualitative approach, which included focus groups and interviews with parents of children with NDDs (N=21), to assess the acceptability of the potential implementation of these elements in an NDD-focused chatbot. Parents were asked about their opinions on the 5 elements and to rate them. Video and audio recordings were transcribed and summarized for emerging themes, using deductive and inductive thematic approaches. Results From the responses obtained from 21 participants, we identified three main themes: parents of children with NDDs were familiar with and had positive experiences with gamification; a specific element (goal setting) was important to all parents, whereas others (customization, rewards, and unlockable content) received mixed opinions; and the social networking element received positive feedback, but concerns about information accuracy were raised. Conclusions We showed for the first time that parents of children with NDDs support gamification use in a chatbot for NDDs. Our study illustrates the need for a user-centered design in the medical domain and provides a foundation for researchers interested in developing chatbots for populations that are medically vulnerable. Future studies exploring wide range of gamification elements with large number of potential users are needed to understand the impact of gamification elements in enhancing knowledge mobilization.