The Immunology of Multisystem Inflammatory Syndrome in Children with COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is typically very mild and often asymptomatic in children. A complication is the rare multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19, presenting 4-6 weeks after infection as high fever, organ dysfunction, and strongly elevated markers of inflammation. The pathogenesis is unclear but has overlapping features with Kawasaki disease suggestive of vasculitis and a likely autoimmune etiology. We apply systems-level analyses of blood immune cells, cytokines, and autoantibodies in healthy children, children with Kawasaki disease enrolled prior to COVID-19, children infected with SARS-CoV-2, and children presenting with MIS-C. We find that the inflammatory response in MIS-C differs from the cytokine storm of severe acute COVID-19, shares several features with Kawasaki disease, but also differs from this condition with respect to T cell subsets, interleukin (IL)-17A, and biomarkers associated with arterial damage. Finally, autoantibody profiling suggests multiple autoantibodies that could be involved in the pathogenesis of MIS-C.

Longitudinal humoral analysis in RSV-infected infants identifies pre-existing RSV strain-specific G and evolving cross-reactive F antibodies.

Respiratory syncytial virus (RSV) is among the most common causes of lower respiratory tract infection (LRTI) and hospitalization in infants. However, the mechanisms of immune control in infants remain incompletely understood. Antibody profiling against attachment (G) and fusion (F) proteins in children less than 2 years of age, with mild (outpatients) or severe (inpatients) RSV disease, indicated substantial age-dependent differences in RSV-specific immunity. Maternal antibodies were detectable for the first 3 months of life, followed by a long window of immune vulnerability between 3 and 6 months and a rapid evolution of FcγR-recruiting immunity after 6 months of age. Acutely ill hospitalized children exhibited lower G-specific antibodies compared with healthy controls. With disease resolution, RSV-infected infants generated broad functional RSV strain-specific G-responses and evolved cross-reactive F-responses, with minimal maternal imprinting. These data suggest an age-independent RSV G-specific functional humoral correlate of protection, and the evolution of RSV F-specific functional immunity with disease resolution.

SARS-CoV-2-specific T cell memory with common TCRαß motifs is established in unvaccinated children who seroconvert after infection.

As the establishment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cell memory in children remains largely unexplored, we recruited convalescent COVID-19 children and adults to define their circulating memory SARS-CoV-2-specific CD4+ and CD8+ T cells prior to vaccination. We analyzed epitope-specific T cells directly ex vivo using seven HLA class I and class II tetramers presenting SARS-CoV-2 epitopes, together with Spike-specific B cells. Unvaccinated children who seroconverted had comparable Spike-specific but lower ORF1a- and N-specific memory T cell responses compared with adults. This agreed with our TCR sequencing data showing reduced clonal expansion in children. A strong stem cell memory phenotype and common T cell receptor motifs were detected within tetramer-specific T cells in seroconverted children. Conversely, children who did not seroconvert had tetramer-specific T cells of predominantly naive phenotypes and diverse TCRαß repertoires. Our study demonstrates the generation of SARS-CoV-2-specific T cell memory with common TCRαß motifs in unvaccinated seroconverted children after their first virus encounter.

Lung γδ T Cells Mediate Protective Responses during Neonatal Influenza Infection that Are Associated with Type 2 Immunity.

Compared to adults, infants suffer higher rates of hospitalization, severe clinical complications, and mortality due to influenza infection. We found that γδ T cells protected neonatal mice against mortality during influenza infection. γδ T cell deficiency did not alter viral clearance or interferon-γ production. Instead, neonatal influenza infection induced the accumulation of interleukin-17A (IL-17A)-producing γδ T cells, which was associated with IL-33 production by lung epithelial cells. Neonates lacking IL-17A-expressing γδ T cells or Il33 had higher mortality upon influenza infection. γδ T cells and IL-33 promoted lung infiltration of group 2 innate lymphoid cells and regulatory T cells, resulting in increased amphiregulin secretion and tissue repair. In influenza-infected children, IL-17A, IL-33, and amphiregulin expression were correlated, and increased IL-17A levels in nasal aspirates were associated with better clinical outcomes. Our results indicate that γδ T cells are required in influenza-infected neonates to initiate protective immunity and mediate lung homeostasis.

Immune responses to SARS-CoV-2 infection and vaccination in children.

During the three years since SARS-CoV-2 infections were first described a wealth of information has been gathered about viral variants and their changing properties, the disease presentations they elicit and how the many vaccines developed in record time protect from COVID-19 severe disease in different populations. A general theme throughout the pandemic has been the observation that children and young people in general fare well, with mild symptoms during acute infection and full recovery thereafter. It has also become clear that this is not universally true, as some children develop severe COVID-19 hypoxic pneumonia and even succumb to the infection, while another group of children develop a rare but serious multisystem inflammatory syndrome (MIS-C) and some other children experience prolonged illness following acute infection, post-COVID. Here I will discuss some of the findings made to explain these diverse disease manifestations in children and young people infected by SARS-CoV-2. I will also discuss the vaccines developed at record speed and their efficacy in protecting children from disease.

Hemispheric functional organization, as revealed by naturalistic neuroimaging, in pediatric epilepsy patients with cortical resections.

Functional changes in the pediatric brain following neural injuries attest to remarkable feats of plasticity. Investigations of the neurobiological mechanisms that underlie this plasticity have largely focused on activation in the penumbra of the lesion or in contralesional, homotopic regions. Here, we adopt a whole-brain approach to evaluate the plasticity of the cortex in patients with large unilateral cortical resections due to drug-resistant childhood epilepsy. We compared the functional connectivity (FC) in patients' preserved hemisphere with the corresponding hemisphere of matched controls as they viewed and listened to a movie excerpt in a functional magnetic resonance imaging (fMRI) scanner. The preserved hemisphere was segmented into 180 and 200 parcels using two different anatomical atlases. We calculated all pairwise multivariate statistical dependencies between parcels, or parcel edges, and between 22 and 7 larger-scale functional networks, or network edges, aggregated from the smaller parcel edges. Both the left and right hemisphere-preserved patient groups had widespread reductions in FC relative to matched controls, particularly for within-network edges. A case series analysis further uncovered subclusters of patients with distinctive edgewise changes relative to controls, illustrating individual postoperative connectivity profiles. The large-scale differences in networks of the preserved hemisphere potentially reflect plasticity in the service of maintained and/or retained cognitive function.

A comprehensive demographic profile of the US evicted population.

Millions of American renter households every year are threatened with eviction, an event associated with severe negative impacts on health and economic well-being. Yet we know little about the characteristics of individuals living in these households. Here, we link 38 million eviction court cases to US Census Bureau data to show that 7.6 million people, including 2.9 million children, faced the threat of eviction each year between 2007 and 2016. Overall, adult renters living with at least one child in their home were threatened with eviction at an annual rate of 10.4%, twice that of adults without children (5.0%). We demonstrate not only that the average evicted household includes one child, but that the most common age to experience eviction in America is during childhood. We also find that previous studies have underestimated racial disparities in eviction risk: Despite making up only 18.6% of all renters, Black Americans account for 51.1% of those affected by eviction filings and 43.4% of those evicted. Roughly one in five Black Americans living in a renter household is threatened with eviction annually, while one in ten is evicted. Black-White disparities persist across levels of income and vary by state. In providing the most comprehensive description to date of the population of US renters facing eviction, our study reveals a significant undercount of individuals impacted by eviction and motivates policies designed to stabilize housing for children and families.

Excess risk in infant mortality among populations living in flood-prone areas in Bangladesh: A cluster-matched cohort study over three decades, 1988 to 2017.

The Ganges-Brahmaputra-Meghna river basin, running through Tibet, Nepal, Bhutan, Bangladesh, and northern India, is home to more than 618 million people. Annual monsoons bring extensive flooding to the basin, with floods predicted to be more frequent and extreme due to climate change. Yet, evidence regarding the long-term impacts of floods on children's health is lacking. In this analysis, we used high-resolution maps of recent large floods in Bangladesh to identify flood-prone areas over the country. We then used propensity score techniques to identify, among 58,945 mothers interviewed in six demographic population-based surveys throughout Bangladesh, matched cohorts of exposed and unexposed mothers and leverage data on 150,081 births to estimate that living in flood-prone areas was associated with an excess risk in infant mortality of 5.3 (95% CI 2.2 to 8.4) additional deaths per 1,000 births compared to living in non-flood-prone areas over the 30-y period between 1988 and 2017, with higher risk for children born during rainy (7.9, 95% CI: 3.3 to 12.5) vs. dry months (3.1, 95% CI: -1.1 to 7.2). Finally, drawing on national-scale, high-resolution estimates of flood risk and population distribution, we estimated an excess of 152,753 (64,120 to 241,386) infant deaths were attributable to living in flood-prone areas in Bangladesh over the past 30 y, with marked heterogeneity in attributable burden by subdistrict. Our approach demonstrates the importance of measuring longer-term health impacts from floods and provides a generalizable example for how to study climate-related exposures and long-term health effects.

Transcriptomics for child and adolescent tuberculosis.

Tuberculosis (TB) in humans is caused by Mycobacterium tuberculosis (Mtb). It is estimated that 70 million children (<15 years) are currently infected with Mtb, with 1.2 million each year progressing to disease. Of these, a quarter die. The risk of progression from Mtb infection to disease and from disease to death is dependent on multiple pathogen and host factors. Age is a central component in all these transitions. The natural history of TB in children and adolescents is different to adults, leading to unique challenges in the development of diagnostics, therapeutics, and vaccines. The quantification of RNA transcripts in specific cells or in the peripheral blood, using high-throughput methods, such as microarray analysis or RNA-Sequencing, can shed light into the host immune response to Mtb during infection and disease, as well as understanding treatment response, disease severity, and vaccination, in a global hypothesis-free manner. Additionally, gene expression profiling can be used for biomarker discovery, to diagnose disease, predict future disease progression and to monitor response to treatment. Here, we review the role of transcriptomics in children and adolescents, focused mainly on work done in blood, to understand disease biology, and to discriminate disease states to assist clinical decision-making. In recent years, studies with a specific pediatric and adolescent focus have identified blood gene expression markers with diagnostic or prognostic potential that meet or exceed the current sensitivity and specificity targets for diagnostic tools. Diagnostic and prognostic gene expression signatures identified through high-throughput methods are currently being translated into diagnostic tests.

Routine SARS-CoV-2 vaccination for all children.

The SARS-CoV-2 pandemic has resulted in unprecedented health and economic losses. Children generally present with less severe disease from this virus compared with adults, yet neonates and children with COVID-19 can require hospitalization, and older children can develop severe complications, such as the multisystem inflammatory syndrome, resulting in >1500 deaths in children from COVID-19 since the onset of the pandemic. The introduction of effective SARS-CoV-2 vaccines in school-age children and adult populations combined with the emergence of new, more highly transmissible SARS-CoV-2 variants has resulted in a proportional increase of infections in young children. Here, we discuss (1) the current knowledge on pediatric SARS-CoV-2 infection and pathogenesis in comparison with adults, (2) the data on vaccine immunogenicity and efficacy in children, and (3) the benefits of early life SARS-CoV-2 vaccination.

The impact of anorexia nervosa and BMI polygenic risk on childhood growth: A 20-year longitudinal population-based study.

Growth deviating from the norm during childhood has been associated with anorexia nervosa (AN) and obesity later in life. In this study, we examined whether polygenic scores (PGSs) for AN and BMI are associated with growth trajectories spanning the first two decades of life. AN PGSs and BMI PGSs were calculated for participants of the Avon Longitudinal Study of Parents and Children (ALSPAC; n = 8,654). Using generalized (mixed) linear models, we associated PGSs with trajectories of weight, height, body mass index (BMI), fat mass index (FMI), lean mass index (LMI), and bone mineral density (BMD). Female participants with AN PGSs one standard deviation (SD) higher had, on average, 0.004% slower growth in BMI between the ages 6.5 and 24 years and a 0.4% slower gain in BMD between the ages 10 and 24 years. Higher BMI PGSs were associated with faster growth for BMI, FMI, LMI, BMD, and weight trajectories in both sexes throughout childhood. Female participants with both a high AN PGS and a low BMI PGS showed slower growth compared to those with both a low AN PGS and a low BMI PGS. We conclude that AN PGSs and BMI PGSs have detectable sex-specific effects on growth trajectories. Female participants with a high AN PGS and low BMI PGS likely constitute a high-risk group for AN, as their growth was slower compared to their peers with high PGSs on both traits. Further research is needed to better understand how the AN PGS and the BMI PGS co-influence growth during childhood and whether a high BMI PGS can mitigate the effects of a high AN PGS.

Long-term Cost-effectiveness of Case Finding and Mass Screening for Celiac Disease in Children.

BACKGROUND & AIMS: Celiac disease (CD) is a common yet underdiagnosed autoimmune disease with substantial long-term consequences. High-accuracy point-of-care tests for CD antibodies conducted at youth primary health care centers may enable earlier identification of CD, but evidence about the cost-effectiveness of such strategies is lacking. We estimated the long-term cost-effectiveness of active case finding and mass screening compared with clinical detection in the Netherlands. METHODS: A decision tree and Markov model were used to simulate a cohort of 3-year-old children with CD according to each strategy, taking into account their impact on long-term costs (from a societal perspective) and quality-adjusted life-years (QALYs). Model parameters incorporated data from the GLUTENSCREEN project, the Dutch Celiac Society, the Dutch Pediatric Surveillance Unit, and published sources. The primary outcome was the incremental cost-effectiveness ratio (ICER) between strategies. RESULTS: Mass-screening produced 7.46 more QALYs and was €28,635 more costly compared with current care (ICER: €3841 per QALY), and case finding produced 4.33 more QALYs and was €15,585 more costly compared with current care (ICER: €3603 per QALY). At a willingness to pay of €20,000 per QALY, both strategies were highly cost-effective compared with current care. Scenario analyses indicated that mass screening is likely the optimal strategy, unless no benefit in detecting asymptomatic cases is assumed. CONCLUSIONS: An earlier identification of CD through screening or case finding in children using a point-of-care tests leads to improved health outcomes and is cost-effective in the long-term compared with current care. If the feasibility and acceptability of the proposed strategies are successful, implementation in Dutch regular care is needed.

Age-related transcript changes in type I interferon signaling in children and adolescents with long COVID.

SARS-CoV-2 typically causes mild symptoms in children, but evidence suggests that persistent immunopathological changes may lead to long COVID (LC). To explore the interplay between LC and innate immunity, we assessed the type I interferon (IFN-I) response in children and adolescents with LC symptoms (LC; n = 28). This was compared with age-matched SARS-CoV-2 recovered participants without LC symptoms (MC; n = 28) and healthy controls (HC; n = 18). We measured the mRNA expression of IFN-I (IFN-α/ß/ε/ω), IFN-I receptor (IFNAR1/2), and ISGs (ISG15, ISG56, MxA, IFI27, BST2, LY6E, OAS1, OAS2, OAS3, and MDA5) in PBMCs collected 3-6 months after COVID-19. LC adolescents (12-17 years) had higher transcript levels of IFN-ß, IFN-ε, and IFN-ω than HC, whereas LC children (6-11 years) had lower levels than HC. In adolescents, increased levels of IFN-α, IFN-ß, and IFN-ω mRNAs were found in the LC group compared with MC, while lower levels were observed in LC children than MC. Adolescents with neurological symptoms had higher IFN-α/ß mRNA levels than MC. LC and MC participants showed decreased expression of ISGs and IFNAR1, but increased expression of IFNAR2, than HC. Our results show age-related changes in the expression of transcripts involved in the IFN-I signaling pathway in children and adolescents with LC.

Immune-epithelial cell cross-talk enhances antiviral responsiveness to SARS-CoV-2 in children.

The risk of developing severe COVID-19 rises dramatically with age. Schoolchildren are significantly less likely than older people to die from SARS-CoV-2 infection, but the molecular mechanisms underlying this age-dependence are unknown. In primary infections, innate immunity is critical due to the lack of immune memory. Children, in particular, have a significantly stronger interferon response due to a primed state of their airway epithelium. In single-cell transcriptomes of nasal turbinates, we find increased frequencies of immune cells and stronger cytokine-mediated interactions with epithelial cells, resulting in increased epithelial expression of viral sensors (RIG-I, MDA5) via IRF1. In vitro, adolescent peripheral blood mononuclear cells produce more cytokines, priming A549 cells for stronger interferon responses to SARS-CoV-2. Taken together, our findings suggest that increased numbers of immune cells in the airways of children and enhanced cytokine-based interactions with epithelial cells tune the setpoint of the epithelial antiviral system. Our findings shed light on the molecular basis of children's remarkable resistance to COVID-19 and may suggest a novel concept for immunoprophylactic treatments.

Estimating the key outcomes and hepatocellular carcinoma risk in patients in immune-tolerant phase of chronic hepatitis B virus infection: A systematic review and meta-analysis.

The question of whether patients in the immune-tolerant (IT) phase of chronic hepatitis B virus (HBV) infection should undergo antiviral therapy and determine the optimal regimen remains unclear. A comprehensive search of PubMed, Embase, MEDLINE, Cochrane Library, and Wanfang Data from inception to 5 December 2023, was conducted. Studies reporting on key outcomes such as HBV DNA undetectability, HBeAg loss or seroconversion, HBsAg loss or seroconversion, and hepatocellular carcinoma (HCC) incidence in patients in the IT phase of chronic HBV infection were included. In total, 23 studies were incorporated. Approximately 4% of patients in the IT phase achieved spontaneous HBeAg loss over 48 weeks of follow-up. Antiviral therapy demonstrated a favourable impact on HBV DNA negative conversion (Children: risk ratios [RR] = 6.83, 95% CI: 2.90-16.05; Adults: RR = 25.84, 95% CI: 6.47-103.31) and HBsAg loss rates (Children: RR = 9.49, 95% CI: 1.74-51.76; Adults: RR = 7.35, 95% CI: 1.41-38.27) for patients in the IT phase. Subgroup analysis revealed that in adult patients in the IT phase, interferon plus nucleos(t)ide analogues (NA)-treated patients exhibited a higher pooled rate of HBsAg loss or seroconversion than those treated with NA monotherapy (9% vs. 0%). Additionally, the pooled annual HCC incidence for patients in the IT phase was 3.03 cases per 1000 person-years (95% CI: 0.99-5.88). Adult patients in the IT phase had a significantly lower HCC incidence risk than HBeAg-positive indeterminate phase patients (RR = 0.46, 95% CI: 0.32-0.66), with no significant differences observed between IT and immune-active phases. Presently, there is insufficient evidence solely based on reducing the risk of HCC incidence, to recommend treating patients in the IT phase of chronic HBV infection. However, both adult and paediatric patients in the IT phase responded well to antiviral therapy, showing favourable rates of HBsAg loss or seroconversion.

Autologous bone marrow mononuclear cells to treat severe traumatic brain injury in children.

Autologous bone marrow mononuclear cells (BMMNCs) infused after severe traumatic brain injury have shown promise for treating the injury. We evaluated their impact in children, particularly their hypothesized ability to preserve the blood-brain barrier and diminish neuroinflammation, leading to structural CNS preservation with improved outcomes. We performed a randomized, double-blind, placebo-sham-controlled Bayesian dose-escalation clinical trial at two children's hospitals in Houston, TX and Phoenix, AZ, USA (NCT01851083). Patients 5-17 years of age with severe traumatic brain injury (Glasgow Coma Scale score ≤ 8) were randomized to BMMNC or placebo (3:2). Bone marrow harvest, cell isolation and infusion were completed by 48 h post-injury. A Bayesian continuous reassessment method was used with cohorts of size 3 in the BMMNC group to choose the safest between two doses. Primary end points were quantitative brain volumes using MRI and microstructural integrity of the corpus callosum (diffusivity and oedema measurements) at 6 months and 12 months. Long-term functional outcomes and ventilator days, intracranial pressure monitoring days, intensive care unit days and therapeutic intensity measures were compared between groups. Forty-seven patients were randomized, with 37 completing 1-year follow-up (23 BMMNC, 14 placebo). BMMNC treatment was associated with an almost 3-day (23%) reduction in ventilator days, 1-day (16%) reduction in intracranial pressure monitoring days and 3-day (14%) reduction in intensive care unit (ICU) days. White matter volume at 1 year in the BMMNC group was significantly preserved compared to placebo [decrease of 19 891 versus 40 491, respectively; mean difference of -20 600, 95% confidence interval (CI): -35 868 to -5332; P = 0.01], and the number of corpus callosum streamlines was reduced more in placebo than BMMNC, supporting evidence of preserved corpus callosum connectivity in the treated groups (-431 streamlines placebo versus -37 streamlines BMMNC; mean difference of -394, 95% CI: -803 to 15; P = 0.055), but this did not reach statistical significance due to high variability. We conclude that autologous BMMNC infusion in children within 48 h after severe traumatic brain injury is safe and feasible. Our data show that BMMNC infusion led to: (i) shorter intensive care duration and decreased ICU intensity; (ii) white matter structural preservation; and (iii) enhanced corpus callosum connectivity and improved microstructural metrics.

Differential neural correlates underlying visuospatial versus semantic reasoning in autistic children.

While fronto-posterior underconnectivity has often been reported in autism, it was shown that different contexts may modulate between-group differences in functional connectivity. Here, we assessed how different task paradigms modulate functional connectivity differences in a young autistic sample relative to typically developing children. Twenty-three autistic and 23 typically developing children aged 6 to 15 years underwent functional magnetic resonance imaging (fMRI) scanning while completing a reasoning task with visuospatial versus semantic content. We observed distinct connectivity patterns in autistic versus typical children as a function of task type (visuospatial vs. semantic) and problem complexity (visual matching vs. reasoning), despite similar performance. For semantic reasoning problems, there was no significant between-group differences in connectivity. However, during visuospatial reasoning problems, we observed occipital-occipital, occipital-temporal, and occipital-frontal over-connectivity in autistic children relative to typical children. Also, increasing the complexity of visuospatial problems resulted in increased functional connectivity between occipital, posterior (temporal), and anterior (frontal) brain regions in autistic participants, more so than in typical children. Our results add to several studies now demonstrating that the connectivity alterations in autistic relative to neurotypical individuals are much more complex than previously thought and depend on both task type and task complexity and their respective underlying cognitive processes.

Olfactory function after mild traumatic brain injury in children-a longitudinal case control study.

The prevalence of posttraumatic olfactory dysfunction in children after mild traumatic brain injury ranges from 3 to 58%, with potential factors influencing this variation, including traumatic brain injury severity and assessment methods. This prospective longitudinal study examines the association between mild traumatic brain injury and olfactory dysfunction in children. Seventy-five pediatric patients with mild traumatic brain injury and an age-matched healthy control group were enrolled. Olfactory function was assessed using the Sniffin' Sticks battery, which focuses on olfactory threshold and odor identification. The study found that children with mild traumatic brain injury had impaired olfactory function compared with healthy controls, particularly in olfactory threshold scores. The prevalence of olfactory dysfunction in the patient group was 33% and persisted for 1 yr. No significant association was found between traumatic brain injury symptoms (e.g. amnesia, loss of consciousness) and olfactory dysfunction. The study highlights the importance of assessing olfactory function in children after mild traumatic brain injury, given its potential impact on daily life. Although most olfactory dysfunction appears transient, long-term follow-up is essential to fully understand the recovery process. The findings add valuable insights to the limited literature on this topic and urge the inclusion of olfactory assessments in the management of pediatric mild traumatic brain injury.

Shared Minds, Shared Feedback: tracing the influence of parental feedback on shared neural patterns.

Parental feedback affects children in multiple ways. However, little is known about how children, family, and feedback types affect parental feedback neural mechanisms. The current study used functional near-infrared spectroscopy-based hyperscanning to observe 47 mother-daughter pairs's (mean age of mothers: 35.95 ± 3.99 yr old; mean age of daughters: 6.97 ± 0.75 yr old) brain synchronization in a jigsaw game under various conditions. Between parental negative feedback and praise conditions, mother-daughter brain in supramarginal gyrus, left dorsolateral prefrontal cortex, right inferior frontal gyrus, and right primary somatic (S1) differed. When criticized, conformity family-communication-patterned families had much worse brain synchronization in S1, left dorsolateral prefrontal cortex, and right Wernicke's region than conversational families. Resilient children had better mother-child supramarginal gyrus synchronicity under negative feedback. This study supports the importance of studying children's neurological development in nurturing environments to assess their psychological development.

Volleyball training improves working memory in children aged 7 to 12 years old: an fNIRS study.

This study aimed to investigate the effect of a 12-wk extracurricular volleyball training on working memory from both behavioral and cerebral aspects. A total of 80 children were randomized assigned to (i) the experimental group, who engaged in extracurricular volleyball training for 60 min, thrice a week for 12 wk, and (ii) the control group, who maintained their regular daily routine. Working memory was evaluated in both groups using the N-back task before and after the intervention. Furthermore, functional near-infrared spectroscopy was employed to monitor the level of oxygenated hemoglobin in the prefrontal cortex. The experimental group performed better in the behavioral task than the control group, as evidenced by a shorter response time and a higher correct rate. The functional near-infrared spectroscopy results suggested that the activation of the left dorsolateral prefrontal cortex was significantly higher in the experimental group than in the control group. In addition, correlation analyses showed that the enhancement of left dorsolateral prefrontal cortex activation was significantly correlated with decreasing response time and improving response accuracy in the N-back task. These findings suggest that the left dorsolateral prefrontal cortex is likely the neural substrate for improved working memory performance elicited by 12-wk open skill exercise.