Browsing by Author "Kawata, Keisuke"
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Item Alterations in mitochondrial energy metabolites following acute subconcussive head impacts among athletes with and without ADHD(Elsevier, 2025-05-28) Ellis, Gage; Nowak, Madeleine K.; Kronenberger, William G.; Recht, Grace O.; Ogbeide, Osamudiamen; Klemsz, Lillian M.; Quinn, Patrick D.; Wilson, Landon; Berryhill, Taylor; Barnes, Stephen; Newman, Sharlene D.; Kawata, Keisuke; Psychiatry, School of MedicineAttention-deficit/hyperactivity disorder (ADHD) is prevalent among contact sports athletes, who may regularly incur repetitive head impacts. This study investigated the effects of acute head impacts on mitochondrial function by analyzing tricarboxylic acid (TCA) cycle metabolites and the potential modulatory role of ADHD. Fifty adult soccer players (ADHD n = 25; non-ADHD n = 25) participated, undergoing ten soccer headers using a controlled heading model. TCA metabolites were assessed at pre-heading baseline, and 2 and 24 h post-heading. Baseline analysis revealed elevated levels of TCA metabolites, including oxaloacetate, citrate, and isocitrate, in the ADHD group. Following head impacts, both groups exhibited significant decreases in these metabolites, yet the magnitude of decrease was more pronounced in the ADHD group. Pyruvate, alpha-ketoglutarate, and fumarate levels increased after headers in both groups. These findings suggest that ADHD is associated with elevated baseline metabolites initiating the TCA cycle, while acute head impacts induce mitochondrial dysfunction, regardless of ADHD.Item Association Between Head Impact Exposure, Psychological Needs, and Indicators of Mental Health Among U.S. High School Tackle Football Players(Elsevier, 2023) Kercher, Kyle A.; Steinfeldt, Jesse A.; Rettke, Devin J.; Zuidema, Taylor R.; Walker, Miata J.; (Martinez) Kercher, Vanessa M.; Silveyra, Patricia; Seo, Dong-Chul; Macy, Jonathan T.; Hulvershorn, Leslie A.; Kawata, Keisuke; Psychiatry, School of MedicinePurpose: Age of first exposure to tackle football and head impact kinematics have been used to examine the effect of head impacts on mental health outcomes. These measures coupled with retrospective and cross-sectional designs have contributed to conflicting results. The purpose of this study was to identify the effect of one season of head impact exposure, age of first exposure to football, and psychological need satisfaction on acute mental health outcomes in adolescent football players. Methods: This prospective single-season cohort study used sensor-installed mouthguards to collect head impact exposure along with surveys to assess age of first exposure to football, psychological satisfaction, depressive symptoms, anxiety symptoms, and thriving from football players at four high schools (n = 91). Linear regression was used to test the association of head impact exposure, age of first exposure, and psychological satisfaction with acute mental health outcomes. Results: A total of 9,428 impacts were recorded with a mean of 102 ± 113 impacts/player. Cumulative head impact exposure and age of first exposure were not associated with acute mental health outcomes at postseason or change scores from preseason to postseason. Greater psychological satisfaction was associated with fewer depressive symptoms (β = -0.035, SE = 0.008, p = < .001), fewer anxiety symptoms (β = -0.021, SE = 0.008, p = .010), and greater thriving scores (β = 0.278, SE = 0.040, p = < .001) at postseason. Discussion: This study does not support the premise that greater single-season head impact exposure or earlier age of first exposure to tackle football is associated with worse acute mental health indicators over the course of a single season in adolescent football players.Item Association Between Proteomic Blood Biomarkers and DTI/NODDI Metrics in Adolescent Football Players: A Pilot Study(Frontiers Media, 2020-11-16) Kawata, Keisuke; Steinfeldt, Jesse A.; Huibregtse, Megan E.; Nowak, Madeleine K.; Macy, Jonathan T.; Kercher, Kyle; Rettke, Devin J.; Shin, Andrea; Chen, Zhongxue; Ejima, Keisuke; Newman, Sharlene D.; Cheng, Hu; Medicine, School of MedicineWhile neuroimaging and blood biomarker have been two of the most active areas of research in the neurotrauma community, these fields rarely intersect to delineate subconcussive brain injury. The aim of the study was to examine the association between diffusion MRI techniques [diffusion tensor imaging (DTI) and neurite orientation/dispersion density imaging (NODDI)] and brain-injury blood biomarker levels [tau, neurofilament-light (NfL), glial-fibrillary-acidic-protein (GFAP)] in high-school football players at their baseline, aiming to detect cumulative neuronal damage from prior seasons. Twenty-five football players were enrolled in the study. MRI measures and blood samples were obtained during preseason data collection. The whole-brain, tract-based spatial statistics was conducted for six diffusion metrics: fractional anisotropy (FA), mean diffusivity (MD), axial/radial diffusivity (AD, RD), neurite density index (NDI), and orientation dispersion index (ODI). Five players were ineligible for MRIs, and three serum samples were excluded due to hemolysis, resulting in 17 completed set of diffusion metrics and blood biomarker levels for association analysis. Our permutation-based regression model revealed that serum tau levels were significantly associated with MD and NDI in various axonal tracts; specifically, elevated serum tau levels correlated to elevated MD (p = 0.0044) and reduced NDI (p = 0.016) in the corpus callosum and surrounding white matter tracts (e.g., longitudinal fasciculus). Additionally, there was a negative association between NfL and ODI in the focal area of the longitudinal fasciculus. Our data suggest that high school football players may develop axonal microstructural abnormality in the corpus callosum and surrounding white matter tracts, such as longitudinal fasciculus. A future study is warranted to determine the longitudinal multimodal relationship in response to repetitive exposure to sports-related head impacts.Item Association of Auditory Interference and Ocular-Motor Response with Subconcussive Head Impacts in Adolescent Football Players(Mary Ann Liebert, 2024-05-31) Bellini, Zachary S.; Recht, Grace O.; Zuidema, Taylor R.; Kercher, Kyle A.; Sweeney, Sage H.; Steinfeldt, Jesse A.; Kawata, Keisuke; Pediatrics, School of MedicineThe aim of this study was to examine whether neuro-ophthalmological function, as assessed by the King-Devick test (KDT), alters during a high school football season and to explore the role of auditory interference on the sensitivity of KDT. During the 2021 and 2022 high school football seasons, football players' neuro-ophthalmological function was assessed at five time points (preseason, three in-season, postseason), whereas control athletes were assessed at preseason and postseason. Two-hundred ten football players and 80 control athletes participated in the study. The year 1 cohort (n = 94 football, n = 10 control) was tested with a conventional KDT, whereas the year 2 cohort (n = 116 football, n = 70 control) was tested with KDT while listening to loud traffic sounds to induce auditory interference. There were improvements in KDT during a season among football players, regardless of conventional KDT (preseason 53.4 ± 9.3 vs. postseason 46.4 ± 8.5 sec; β = -1.7, SE = 0.12, p < 0.01) or KDT with auditory interference (preseason 52.3 ± 11.5 vs. postseason 45.1 ± 9.5 sec; β = -1.7, SE = 0.11, p < 0.001). The degree of improvement was similar between the tests, with no significant group-by-time interaction (β = -0.08, SE = 0.17, p = 0.65). The control athletes also improved KDT performance at a similar degree as the football cohorts in both KDT conditions. Our data suggest that KDT performance improves during a season, regardless of auditory interference or head impact exposure. KDT performance was not impacted by a noisy environment, supporting its sideline utility for screening more severe forms of injury.Item Association of Frequent Sexual Choking/Strangulation With Neurophysiological Responses: A Pilot Resting-State fMRI Study(Mary Ann Liebert, 2023) Hou, Jiancheng; Huibregtse, Megan E.; Alexander, Isabella L.; Klemsz, Lillian M.; Fu, Tsung-Chieh; Fortenberry, J. Dennis; Herbenick, Debby; Kawata, Keisuke; Pediatrics, School of MedicineBeing choked or strangled during partnered sex is an emerging sexual behavior, prevalent among young adult women. The goal of this study was to test whether, and to what extent, frequently being choked or strangled during sex is associated with cortical surface functioning and functional connectivity. This case-control study consisted of two groups (choking vs. choking-naïve). Women who were choked 4 or more times during sex in the past 30 days were enrolled into the choking group, whereas those without were assigned to the choking-naïve group. We collected structural and resting-state functional magnetic resonance imaging (fMRI) data and analyzed the data for amplitude of low-frequency fluctuation (ALFF) and regional homogeneity (ReHo) using cortical surface-based resting-state fMRI analysis, followed by static and dynamic resting-state fMRI connectivity analysis. Forty-one participants (choking n = 20; choking-n-aïve n = 21) contributed to the analysis. An inter-hemispheric imbalance in neuronal activation pattern was observed in the choking group. Specifically, we observed significantly lower ALFF and ReHo in the left cortical regions (e.g., angular gyrus, orbitofrontal gyrus) and higher ALFF and ReHo in the right cortical regions (e.g., pre-central/post-central gyri) in the choking group compared with the choking-naïve group. A significant group difference was found in static functional connectivity between the bilateral angular gyrus and the whole brain, in which the choking group's angular gyrus showed hyperconnectivity with, for example, the post-central gyrus, pre-central gyrus, and Rolandic operculum, relative to the choking-naïve group. The dynamic analysis revealed hyperconnectivity between the left angular gyrus and the bilateral postcentral gyrus in the choking group compared with the choking-naïve group. Taken together, our data show that multiple experiences of sexual choking/strangulation are associated with an inter-hemispheric imbalance in neural activation pattern and hyperconnectivity between the angular gyrus and brain regions related to motor control, consciousness, and emotion. A longitudinal study using multi-modal neurological assessments is needed to clarify the acute and chronic consequences of sexual choking/strangulation.Item Association of Plasma Tau With Mortality and Long-term Neurocognitive Impairment in Survivors of Pediatric Cerebral Malaria and Severe Malarial Anemia(American Medical Association, 2021-12) Datta, Dibyadyuti; Bangirana, Paul; Opoka, Robert O.; Conroy, Andrea L.; Co, Katrina; Bond, Caitlin; Zhao, Yi; Kawata, Keisuke; Saykin, Andrew J.; John, Chandy C.; Biostatistics and Health Data Science, School of MedicineImportance: Cerebral malaria (CM) and severe malarial anemia (SMA) are associated with persistent neurocognitive impairment (NCI) among children in Africa. Identifying blood biomarkers of acute brain injury that are associated with future NCI could allow early interventions to prevent or reduce NCI in survivors of severe malaria. Objective: To investigate whether acutely elevated tau levels are associated with future NCI in children after CM or SMA. Design, setting, and participants: This prospective cohort study was conducted at Mulago National Referral Hospital in Kampala, Uganda, from March 2008 to October 2015. Children aged 1.5 to 12 years with CM (n = 182) or SMA (n = 162) as well as community children (CC; n = 123) were enrolled in the study. Data analysis was conducted from January 2020 to May 2021. Exposure: CM or SMA. Main outcomes and measures: Enrollment plasma tau levels were measured using single-molecule array detection technology. Overall cognition (primary) and attention and memory (secondary) z scores were measured at 1 week and 6, 12, and 24 months after discharge using tools validated in Ugandan children younger than 5 years or 5 years and older. Results: A total of 467 children were enrolled. In the CM group, 75 (41%) were girls, and the mean (SD) age was 4.02 (1.92) years. In the SMA group, 59 (36%) were girls, and the mean (SD) age was 3.45 (1.60) years. In the CC group, 65 (53%) were girls, and the mean (SD) age was 3.94 (1.92) years. Elevated plasma tau levels (>95th percentile in CC group; >6.43 pg/mL) were observed in 100 children (55%) with CM and 69 children (43%) with SMA (P < .001). In children with CM who were younger than 5 years, elevated plasma tau levels were associated with increased mortality (odds ratio [OR], 3.06; 95% CI, 1.01-9.26; P = .048). In children with CM who were younger than 5 years at both CM episode and follow-up neurocognitive testing, plasma tau levels (log10 transformed) were associated with worse overall cognition scores over 24-month follow-up (β = -0.80; 95% CI, -1.32 to -0.27; P = .003). In children with CM who were younger than 5 years at CM episode and 5 years or older at follow-up neurocognitive testing, plasma tau was associated with worse scores in attention (β = -1.08; 95% CI, -1.79 to -0.38; P = .003) and working memory (β = -1.39; 95% CI, -2.18 to -0.60; P = .001). Conclusions and relevance: In this study, plasma tau, a marker of injury to neuronal axons, was elevated in children with CM or SMA and was associated with mortality and persistent NCI in children with CM younger than 5 years.Item Associations between repetitive head impact exposure and midlife mental health wellbeing in former amateur athletes(Frontiers Media, 2024-05-28) Buddenbaum, Claire V.; Recht, Grace O.; Rodriguez, Adriana K.; Newman, Sharlene D.; Kawata, Keisuke; Pediatrics, School of MedicineIntroduction: Repetitive head impacts (RHI) have been suggested to increase the risk of developing a neurodegenerative disease, and many of these individuals develop a preceding mental health diagnosis. Given the lack of studies among amateur athletes, this study aimed to examine mental health outcomes in middle-aged amateur athletes who have been exposed to RHI through contact sport participation. Methods: This is a single site, cohort study involving former amateur athletes aged between 30 and 60 with at least 10 years of organized contact or non-contact sport participation. All participants completed demographic and mental health questionnaires. Mental health outcomes included symptoms related to depression, anxiety, post-traumatic stress disorder (PTSD), attention deficit hyperactive disorder (ADHD), and aggression. Self-reported data on mental health diagnoses and associated prescription were elicited and used to estimate odds ratios (OR). Results: Data from 41 contact athletes and 22 age/sex-matched non-contact athletes were available for analysis. The contact group exhibited a 2.25-fold higher likelihood of being diagnosed with mental health disorders and 1.29-fold higher likelihood of using associated medications compared to the non-contact group. The contact group reported significantly higher PTSD-related symptoms [4.61 (0.03,9.2), p=0.05] compared to the non-contact control group. While not statistically significant, the contact group showed increased depressive [2.37 (0.05, 4.79), p=0.07] and ADHD symptoms [4.53 (0.51, 9.57), p=0.08] compared to controls. In a secondary analysis, a distinct trend emerged within the contact group, revealing pronounced elevations in mental health symptoms among individuals with lower socioeconomic status (<$50,000/year) compared to higher income subgroups, and these symptoms decreased as income levels rose [depression: -3.08 (-4.47, -1.7), p<0.001; anxiety: -1.95 (-3.15, -0.76), p=0.002; ADHD: -4.99 (-8.28, -1.69), p=0.004; PTSD: -4.42 (-7.28, -1.57), p=0.003; aggression: -6.19 (-11.02, -1.36), p=0.01]. This trend was absent in the non-contact control group. Discussion: Our data suggest that even individuals at the amateur level of contact sports have an increased likelihood of being diagnosed with mental health disorders or experiencing mental health symptoms compared to non-contact athletes. Our findings indicate that socioeconomic status may have an interactive effect on individuals' mental health, particularly among those with a long history of RHI exposure.Item Blood biomarkers of neuronal injury in paediatric cerebral malaria and severe malarial anaemia(Oxford University Press, 2023-11-27) Datta, Dibyadyuti; Gopinadhan, Adnan; Soto, Alejandro; Bangirana, Paul; Opoka, Robert O.; Conroy, Andrea L.; Saykin, Andrew J.; Kawata, Keisuke; John, Chandy C.; Pediatrics, School of MedicinePersistent neurodisability is a known complication in paediatric survivors of cerebral malaria and severe malarial anaemia. Tau, ubiquitin C-terminal hydrolase-L1, neurofilament-light chain, and glial fibrillary acidic protein have proven utility as biomarkers that predict adverse neurologic outcomes in adult and paediatric disorders. In paediatric severe malaria, elevated tau is associated with mortality and neurocognitive complications. We aimed to investigate whether a multi-analyte panel including ubiquitin C-terminal hydrolase-L1, neurofilament-light chain, and glial fibrillary acidic protein can serve as biomarkers of brain injury associated with mortality and neurodisability in cerebral malaria and severe malarial anaemia. In a prospective cohort study of Ugandan children, 18 months to 12 years of age with cerebral malaria (n = 182), severe malarial anaemia (n = 158), and asymptomatic community children (n = 118), we measured admission blood levels of ubiquitin C-terminal hydrolase-L1, neurofilament-light chain, and glial fibrillary acidic protein. We investigated differences in biomarker levels, associations with mortality, blood–brain barrier integrity, neurodeficits and cognitive Z-scores in survivors up to 24-month follow-up. Admission ubiquitin C-terminal hydrolase-L1 levels were elevated >95th percentile of community children in 71 and 51%, and neurofilament-light chain levels were elevated >95th percentile of community children in 40 and 37% of children with cerebral malaria and severe malarial anaemia, respectively. Glial fibrillary acidic protein was not elevated in disease groups compared with controls. In cerebral malaria, elevated neurofilament-light chain was observed in 16 children who died in hospital compared with 166 survivors (P = 0.01); elevations in ubiquitin C-terminal hydrolase-L1 levels were associated with degree of blood–brain barrier disruption (P = 0.01); and the % predictive value for neurodeficits over follow-up (discharge, 6-, 12-, and 24 months) increased for ubiquitin C-terminal hydrolase-L1 (60, 67, 72, and 83), but not neurofilament-light chain (65, 68, 60, and 67). In cerebral malaria, elevated ubiquitin C-terminal hydrolase-L1 was associated with worse memory scores in children <5 years at malaria episode who crossed to over 5 years old during follow-up cognitive testing [β −1.13 (95% confidence interval −2.05, −0.21), P = 0.02], and elevated neurofilament-light chain was associated with worse attention in children ≥5 years at malaria episode and cognitive testing [β −1.08 (95% confidence interval −2.05, −1.05), P = 0.03]. In severe malarial anaemia, elevated ubiquitin C-terminal hydrolase-L1 was associated with worse attention in children <5 years at malaria episode and cognitive testing [β −0.42 (95% confidence interval −0.76, −0.07), P = 0.02]. Ubiquitin C-terminal hydrolase-L1 and neurofilament-light chain levels are elevated in paediatric cerebral malaria and severe malarial anaemia. In cerebral malaria, elevated neurofilament-light chain is associated with mortality whereas elevated ubiquitin C-terminal hydrolase-L1 is associated with blood–brain barrier dysfunction and neurodeficits over follow-up. In cerebral malaria, both markers are associated with worse cognition, while in severe malarial anaemia, only ubiquitin C-terminal hydrolase-L1 is associated with worse cognition.Item Cerebral Cortical Surface Structure and Neural Activation Pattern Among Adolescent Football Players(American Medical Association, 2024-02-05) Zuidema, Taylor R.; Hou, Jiancheng; Kercher, Kyle A.; Recht, Grace O.; Sweeney, Sage H.; Chenchaiah, Nishant; Cheng, Hu; Steinfeldt, Jesse A.; Kawata, Keisuke; Pediatrics, School of MedicineImportance: Recurring exposure to head impacts in American football has garnered public and scientific attention, yet neurobiological associations in adolescent football players remain unclear. Objective: To examine cortical structure and neurophysiological characteristics in adolescent football players. Design, setting, and participants: This cohort study included adolescent football players and control athletes (swimming, cross country, and tennis) from 5 high school athletic programs, who were matched with age, sex (male), and school. Neuroimaging assessments were conducted May to July of the 2021 and 2022 seasons. Data were analyzed from February to November 2023. Exposure: Playing tackle football or noncontact sports. Main outcomes and measures: Structural magnetic resonance imaging (MRI) data were analyzed for cortical thickness, sulcal depth, and gyrification, and cortical surface-based resting state (RS)-functional MRI analyses examined the amplitude of low-frequency fluctuation (ALFF), regional homogeneity (ReHo), and RS-functional connectivity (RS-FC). Results: Two-hundred seventy-five male participants (205 football players; mean [SD] age, 15.8 [1.2] years; 5 Asian [2.4%], 8 Black or African American [3.9%], and 189 White [92.2%]; 70 control participants; mean [SD] age 15.8 [1.2] years, 4 Asian [5.7], 1 Black or African American [1.4%], and 64 White [91.5%]) were included in this study. Relative to the control group, the football group showed significant cortical thinning, especially in fronto-occipital regions (eg, right precentral gyrus: t = -2.24; P = .01; left superior frontal gyrus: -2.42; P = .002). Elevated cortical thickness in football players was observed in the anterior and posterior cingulate cortex (eg, left posterior cingulate cortex: t = 2.28; P = .01; right caudal anterior cingulate cortex 3.01; P = .001). The football group had greater and deeper sulcal depth than the control groups in the cingulate cortex, precuneus, and precentral gyrus (eg, right inferior parietal lobule: t = 2.20; P = .004; right caudal anterior cingulate cortex: 4.30; P < .001). Significantly lower ALFF was detected in the frontal lobe and cingulate cortex of the football group (t = -3.66 to -4.92; P < .01), whereas elevated ALFF was observed in the occipital regions (calcarine and lingual gyrus, t = 3.20; P < .01). Similar to ALFF, football players exhibited lower ReHo in the precentral gyrus and medial aspects of the brain, such as precuneus, insula, and cingulum, whereas elevated ReHo was clustered in the occipitotemporal regions (t = 3.17; P < .001; to 4.32; P < .01). There was no group difference in RS-FC measures. Conclusions and relevance: In this study of adolescent athletes, there was evidence of discernible structural and physiological differences in the brains of adolescent football players compared with their noncontact controls. Many of the affected brain regions were associated with mental health well-being.Item Effectiveness of biomedical interventions on the chronic stage of traumatic brain injury: a systematic review of randomized controlled trials(Frontiers Media, 2024-03-18) Kawata, Keisuke; Rettke, Devin J.; Thompson, Christopher; Mannix, Rebekah; Bazarian, Jeffrey J.; Datta, Dibyadyuti; Exercise & Kinesiology, School of Health and Human SciencesTraumatic brain injury (TBI), in any form and severity, can pose risks for developing chronic symptoms that can profoundly hinder patients’ work/academic, social, and personal lives. In the past 3 decades, a multitude of pharmacological, stimulation, and exercise-based interventions have been proposed to ameliorate symptoms, memory impairment, mental fatigue, and/or sleep disturbances. However, most research is preliminary, thus limited influence on clinical practice. This review aims to systematically appraise the evidence derived from randomized controlled trials (RCT) regarding the effectiveness of pharmacological, stimulation, and exercise-based interventions in treating chronic symptoms due to TBI. Our search results indicate that despite the largest volume of literature, pharmacological interventions, especially using neurostimulant medications to treat physical, cognitive, and mental fatigue, as well as daytime sleepiness, have yielded inconsistent results, such that some studies found improvements in fatigue (e.g., Modafinil, Armodafinil) while others failed to yield the improvements after the intervention. Conversely, brain stimulation techniques (e.g., transcranial magnetic stimulation, blue light therapy) and exercise interventions were effective in ameliorating mental health symptoms and cognition. However, given that most RCTs are equipped with small sample sizes, more high-quality, larger-scale RCTs is needed.