Clinical phenotype and musculoskeletal characteristics of patients with aggrecan deficiency.

Aggrecan is a proteoglycan within the physeal and articular cartilage. Aggrecan deficiency, due to heterozygous mutations in the ACAN gene, causes dominantly inherited short stature and, in many patients, early-onset osteoarthritis and degenerative disc disease. We aimed to further characterize this phenotypic spectrum with an emphasis on musculoskeletal health. Twenty-two individuals from nine families were enrolled. Histories and examinations focused on joint health, gait analysis, joint specific patient reported outcomes, and imaging studies were performed. All patients had dominantly inherited short stature, with the exception of a de novo mutation. Short stature was worse in adults versus children (median height -3.05 SD vs. -2.25 SD). ACAN mutations were not always associated with bone age advancement (median advancement +1.1 years, range 0 to +2 years). Children had subtle disproportionality and clinically silent joint disease-25% with osteochondritis dissecans (OD). Adults had a high prevalence of joint symptomatology-decline in knee function, disability from spinal complaints, and lower physical activity on outcome measures. Osteoarthritis (OA) and OD was detected in 90% of adults, and orthopedic surgeries were reported in 60%. Aggrecan deficiency leads to short stature with progressive decline in height SD, mild skeletal dysplasia, and increasing prevalence of joint pathology over time. Optimal musculoskeletal health and quality of life can be attained with timely identification of pathology and intervention.

Attention-Deficit/Hyperactivity Disorder Status and Sex Moderate Mild Traumatic Brain Injury Symptom Severity in Children and Adolescents: Implications for Clinical Management.

OBJECTIVE: To investigate the impact of pediatric mild traumatic brain injury (mTBI), using a broad parent-reported measure, and to determine whether parent-ratings of mTBI symptoms are higher among those with premorbid attention-deficit/hyperactivity disorder (ADHD) and females. DESIGN: Retrospective case-control. SETTING: Hospital-based sports medicine clinic. PARTICIPANTS: The retrospective chart review included 1346 (age: M = 13.11 years, SD = 2.6; 61.7% male) pediatric patients with (n = 209) and without (n = 1137) ADHD. INDEPENDENT VARIABLES: Group membership (ADHD vs non-ADHD) and sex (male vs female). MAIN OUTCOME MEASURES: Baseline and current Post-Concussion Symptom Inventory-Parent Report Form (PCSI-P) Physical, Emotional, Cognitive, and Fatigue subscale scores. This study used a retrospective chart review; therefore, the hypotheses reported for the current study were formed after data were collected. RESULTS: Controlling for patient age and days from mTBI, patients with ADHD had significantly higher retrospective parent-reported pre-mTBI ratings of physical, emotional, and cognitive symptoms (ds = 0.17-0.62) and higher post-mTBI ratings across all 4 symptom domains (ds = 0.18-0.57) than those without ADHD. There was no group × time interaction for any of the PCSI-P subscales. Females overall had higher retrospective parent-reported pre-injury Fatigue and Emotional symptoms (ds = 0.13-0.19) and higher post-mTBI symptoms in all 4 PCSI-P symptom domains (ds = 0.23-0.35), relative to males. CONCLUSIONS: Attention-deficit/hyperactivity disorder-related postinjury exacerbations in parent-reported symptoms can be explained, in part, by elevated retrospective parent-reported ADHD-related pre-mTBI ratings. These results highlight the importance of assessing a patient's baseline symptoms post-mTBI. These data also indicate that ADHD status and sex should be considered when interpreting mTBI symptom severity during clinical evaluation of concussion.

Altered brain microstructure in association with repetitive subconcussive head impacts and the potential protective effect of jugular vein compression: a longitudinal study of female soccer athletes.

PURPOSE: To (1) quantify white matter (WM) alterations in female high school athletes during a soccer season and characterise the potential for normalisation during the off-season rest period, (2) determine the association between WM alterations and exposure to repetitive subconcussive head impacts, and (3) evaluate the efficacy of a jugular vein compression collar to prevent WM alterations associated with head impact exposure. METHODS: Diffusion tensor imaging (DTI) data were prospectively collected from high school female soccer participants (14-18 years) at up to three time points over 9 months. Head impacts were monitored using accelerometers during all practices and games. Participants were assigned to a collar (n=24) or non-collar group (n=22). The Tract-Based Spatial Statistics approach was used in the analysis of within-group longitudinal change and between-group comparisons. RESULTS: DTI analyses revealed significant pre-season to post-season WM changes in the non-collar group in mean diffusivity (2.83%±2.46%), axial diffusivity (2.58%±2.34%) and radial diffusivity (3.52%±2.60%), but there was no significant change in the collar group despite similar head impact exposure. Significant correlation was found between head impact exposure and pre-season to post-season DTI changes in the non-collar group. WM changes in the non-collar group partially resolved at 3 months off-season follow-up. DISCUSSION: Microstructural changes in WM occurred during a season of female high school soccer among athletes who did not wear the collar device. In comparison, there were no changes in players who wore the collar, suggesting a potential prophylactic effect of the collar device in preventing changes associated with repetitive head impacts. In those without collar use, the microstructural changes showed a reversal towards normal over time in the off-season follow-up period.

Performance Times for the King-Devick Test in Children and Adolescents.

OBJECTIVE: To establish the King-Devick test (KD) performance values for children and adolescents. DESIGN: Prospective cohort. SETTING: Pediatric sports medicine clinics. PARTICIPANTS: Five hundred seven athletes presenting to a pediatric sports medicine clinic for non-concussion-related evaluations. INDEPENDENT VARIABLES: Age, sex, and risk factors for abnormal concussion recovery. MAIN OUTCOME MEASURES: The King-Devick test time. RESULTS: Four hundred eighty-three participants were included in the final analysis, which included 60.5% girls (n = 292) and 39.5% boys (n = 191). The KD test performance varied by age with a steady decrease in test time yearly from 8 years through 14 years of age, where some plateauing occurred. Baseline scores changed approximately 31 seconds over ages 8 to 18. Analysis of variance results revealed a strong effect of age on overall mean KD time (P < 0.001). The KD test performance was not associated with sex or other studied concussion risk factors or comorbid conditions. CONCLUSIONS: The KD test performance was reported in a cohort of youth aged 8 to 18 years, allowing for comparison of performance in individuals who may not have a baseline assessment. If baseline testing is desired, at least yearly intervals seems to be appropriate through childhood and early adolescence.

White matter alterations over the course of two consecutive high-school football seasons and the effect of a jugular compression collar: A preliminary longitudinal diffusion tensor imaging study.

The cumulative effects of repetitive subclinical head impacts during sports may result in chronic white matter (WM) changes and possibly, neurodegenerative sequelae. In this pilot study, we investigated the longitudinal WM changes over the course of two consecutive high-school football seasons and explored the long-term effects of a jugular vein compression collar on these WM alterations. Diffusion tensor imaging data were prospectively collected both pre- and postseason in the two consecutive seasons. Participants were assigned into either collar or noncollar groups. Tract-based spatial statistics (TBSS) approach and region of interest-based approach were used to quantify changes in WM diffusion properties. Despite comparable exposure to repetitive head impacts, significant reductions in mean, axial, and/or radial diffusivity were identified in Season 1 in multiple WM regions in the noncollar group but not in the collar group. After an 8- to 9-month long off-season, these changes observed in the noncollar group partially and significantly reversed but also remained significantly different from the baseline. In Season 2, trend level WM alterations in the noncollar group were found but located in spatially different regions than Season 1. Last, the WM integrity in the collar group remained unchanged throughout the four time points. In conclusion, we quantitatively assessed the WM structural changes and partial reversal over the course of two consecutive high-school football seasons. In addition, the mitigated WM alterations in athletes in the collar group might indicate potential effect of the collar in ameliorating the changes against repetitive head impacts. Hum Brain Mapp 39:491-508, 2018. © 2017 Wiley Periodicals, Inc.

Short Sleep and Adolescents' Performance on a Concussion Assessment Battery: An Experimental Sleep Manipulation Study.

OBJECTIVE: Correlational studies have linked short sleep to adolescents' report of postconcussion symptoms and cognitive performance during concussion assessments. This study tested whether those are cause-effect relationships. DESIGN: Three-week randomly counterbalanced, within-subjects, crossover experiment. SETTING: Adolescents slept at home with weekly visits to an outpatient clinic for sleep monitor uploads and outcome assessments. PARTICIPANTS: Twenty-four healthy 14- to 17.9-year-olds. CONDITIONS: After an initial sleep-stabilization period, adolescents experienced 5-night spans of short sleep (SS; 6.5 hours/night in bed) versus Healthy Sleep Opportunity (HS; 9.5 hours/night in bed). MAIN OUTCOME MEASURES: Cognitive indexes and the postconcussion symptom scale (PCSS) from the Immediate PostConcussion Assessment and Cognitive Testing. RESULTS: Adolescents reported significantly worse symptoms on the PCSS after SS than HS, even after excluding items manifestly related to sleep. Verbal memory was also worse after SS than HS, though the effect was small. The manipulation did not significantly affect other cognitive indexes. CONCLUSIONS: A realistic "dose" of short sleep, similar to what many adolescents experience regularly on school nights, can cause or contribute to symptom reports during concussion assessments. Consistent with previous sleep research, one-on-one cognitive tests seem to be less sensitive than measures of emotional and behavioral functioning to the effects of short sleep.

Structural Connectivity Related to Persistent Symptoms After Mild TBI in Adolescents and Response to Aerobic Training: Preliminary Investigation.

OBJECTIVE: To quantify structural connectivity abnormalities in adolescents with mild traumatic brain injury (mTBI) and to investigate connectivity changes following aerobic training using graph theory and diffusion tensor imaging tractography. SETTING: Outpatient research setting. PARTICIPANTS: Twenty-two children (age: 15.83 ± 1.77 years, 10 females) with 4 to 16 weeks of persistent symptoms after mTBI and a matched healthy comparison group. DESIGN: Randomized clinical trial of aerobic training and stretching comparison combined with case-control comparison. MAIN MEASURES: (1) Five global network measures: global efficiency (Eglob), mean local efficiency, modularity, normalized clustering coefficient (γ), normalized characteristic path length (λ), and small-worldness (σ). (2) The self-reported Post-Concussion Symptom Inventory score. RESULTS: At initial enrollment, adolescents with mTBI had significantly lower Eglob and higher γ, λ, and σ (all P < .05) than healthy peers. After the intervention, significantly increased Eglob and decreased λ (both P < .05) were found in the aerobic training group. Improvement in Post-Concussion Symptom Inventory scores was significantly correlated with the Eglob increase and λ decrease in the aerobic training and λ decrease in the stretching comparison group (all P < .05). CONCLUSION: This pilot study showed initial evidence that structural connectivity analysis was sensitive to brain network abnormalities and may serve as an imaging biomarker in children with persistent symptoms after mTBI.

Aerobic Exercise for Adolescents With Prolonged Symptoms After Mild Traumatic Brain Injury: An Exploratory Randomized Clinical Trial.

OBJECTIVE: To describe the methodology and report primary outcomes of an exploratory randomized clinical trial (RCT) of aerobic training for management of prolonged symptoms after a mild traumatic brain injury (mTBI) in adolescents. SETTING: Outpatient research setting. PARTICIPANTS: Thirty adolescents between the ages of 12 and 17 years who sustained a mTBI and had between 4 and 16 weeks of persistent symptoms. DESIGN: Partially blinded, pilot RCT of subsymptom exacerbation aerobic training compared with a full-body stretching program. MAIN MEASURES: The primary outcome was postinjury symptom improvement assessed by the adolescent's self-reported Post-Concussion Symptom Inventory (PCSI) repeated for at least 6 weeks of the intervention. Parent-reported PCSI and adherence are also described. RESULTS: Twenty-two percent of eligible participants enrolled in the trial. Repeated-measures analysis of variance via mixed-models analysis demonstrated a significant group × time interaction with self-reported PCSI ratings, indicating a greater rate of improvement in the subsymptom exacerbation aerobic training group than in the full-body stretching group (F = 4.11, P = .044). Adherence to the home exercise programs was lower in the subsymptom exacerbation aerobic training group compared with the full-body stretching group (mean [SD] times per week = 4.42 [1.95] vs 5.85 [1.37], P < .0001) over the duration of the study. CONCLUSION: Findings from this exploratory RCT suggest subsymptom exacerbation aerobic training is potentially beneficial for adolescents with persistent symptoms after an mTBI. These findings and other recent research support the potential benefit of active rehabilitation programs for adolescents with persistent symptoms after an mTBI. Larger replication studies are needed to verify findings and improve generalizability. Future work should focus on determining the optimal type, timing, and intensity of active rehabilitation programs and characteristics of individuals most likely to benefit.

Analysis of head impact exposure and brain microstructure response in a season-long application of a jugular vein compression collar: a prospective, neuroimaging investigation in American football.

BACKGROUND: Historical approaches to protect the brain from outside the skull (eg, helmets and mouthpieces) have been ineffective in reducing internal injury to the brain that arises from energy absorption during sports-related collisions. We aimed to evaluate the effects of a neck collar, which applies gentle bilateral jugular vein compression, resulting in cerebral venous engorgement to reduce head impact energy absorption during collision. Specifically, we investigated the effect of collar wearing during head impact exposure on brain microstructure integrity following a competitive high school American football season. METHODS: A prospective longitudinal controlled trial was employed to evaluate the effects of collar wearing (n=32) relative to controls (CTRL; n=30) during one competitive football season (age: 17.04±0.67 years). Impact exposure was collected using helmet sensors and white matter (WM) integrity was quantified based on diffusion tensor imaging (DTI) serving as the primary outcome. RESULTS: With similar overall g-forces and total head impact exposure experienced in the two study groups during the season (p>0.05), significant preseason to postseason changes in mean diffusivity, axial diffusivity and radial diffusivity in the WM integrity were noted in the CTRL group (corrected p<0.05) but not in the collar group (p>0.05). The CTRL group demonstrated significantly larger preseason to postseason DTI change in multiple WM regions compared with the collar group (corrected p<0.05). DISCUSSION: Reduced WM diffusivity alteration was noted in participants wearing a neck collar after a season of competitive football. Collar wearing may have provided a protective effect against brain microstructural changes after repetitive head impacts. TRIAL REGISTRATION NUMBER: NCT02696200.

Does central nervous system dysfunction underlie patellofemoral pain in young females? Examining brain functional connectivity in association with patient-reported outcomes.

Patellofemoral pain (PFP) is defined as retro- or peri-patellar knee pain without a clear structural abnormality. Unfortunately, many current treatment approaches fail to provide long-term pain relief, potentially due to an incomplete understanding of pain-disrupted sensorimotor dysfunction within the central nervous system. The purposes of this study were to evaluate brain functional connectivity in participants with and without PFP, and to determine the relationship between altered brain functional connectivity in association with patient-reported outcomes. Young female patients with PFP (n = 15; 14.3 ± 3.2 years) completed resting-state functional magnetic resonance imaging (rs-fMRI) and patient-reported outcome measures. Each patient with PFP was matched with two controls (n = 30, 15.5 ± 1.4 years) who also completed identical rs-fMRI testing. Six bilateral seeds important for pain and sensorimotor control were created, and seed-to-voxel analyses were conducted to compare functional connectivity between the two groups, as well as to determine the relationship between connectivity alterations and patient-reported outcomes. Relative to controls, patients with PFP exhibited altered functional connectivity between regions important for pain, psychological functioning, and sensorimotor control, and the connectivity alterations were related to perceived disability, dysfunction, and kinesiophobia. The present results support emergent evidence that PFP is not localized to structural knee dysfunction, but may actually be resultant to altered central neural processes. Clinical significance: These data provide potential neuro-therapeutic targets for novel therapies aimed to reorganize neural processes, improve neuromuscular function, and restore an active pain-free lifestyle in young females with PFP.

Neurocognitive and Quality of Life Improvements Associated With Aerobic Training for Individuals With Persistent Symptoms After Mild Traumatic Brain Injury: Secondary Outcome Analysis of a Pilot Randomized Clinical Trial.

Objective: To report secondary neurocognitive and quality of life outcomes for a pilot randomized clinical trial (RCT) of aerobic training for management of prolonged symptoms after a mild traumatic brain injury (mTBI) in adolescents. Setting: Outpatient research setting. Participants: Thirty adolescents between the ages of 12 and 17 years who sustained a mTBI and had between 4 and 16 weeks of persistent post-concussive symptoms. Design: Secondary outcome analysis of a partially masked RCT of sub-symptom exacerbation aerobic training compared with a full-body stretching program highlighting cognitive and quality of life outcomes. Main Measures: The secondary outcomes assessed included neurocognitive changes in fluid and crystallized age-adjusted cognition using the National Institutes of Health (NIH) toolbox and self and parent-reported total quality of life using the Pediatric Quality of Life Inventory. Results: Twenty-two percent of eligible participants enrolled in the trial. General linear models did not reveal statistically significant differences between groups. Within group analyses using paired t-tests demonstrated improvement in age-adjusted fluid cognition [t (13) = 3.39, p = 0.005, Cohen's d = 0.61] and crystallized cognition [t (13) = 2.63, p = 0.02, Cohen's d = 0.70] within the aerobic training group but no significant improvement within the stretching group. Paired t-tests demonstrated significant improvement in both self-reported and parent-reported total quality of life measures in the aerobic training group [self-report t (13) = 3.51, p = 0.004, Cohen's d = 0.94; parent-report t (13) = 6.5, p < 0.0001, Cohen's d = 1.80] and the stretching group [self-report t (14) = 4.20, p = 0.0009, Cohen's d = 1.08; parent-report t (14) = 4.06, p = 0.0012, Cohen's d = 1.045]. Conclusion: Quality of life improved significantly in both the aerobic exercise and stretching groups; however, this study suggests that only sub-symptom exacerbation aerobic training was potentially beneficial for neurocognitive recovery, particularly the fluid cognition subset in the NIH Toolbox. Limited sample size and variation in outcomes measures limited ability to detect between group differences. Future research should focus on developing larger studies to determine optimal timing post-injury and intensity of active rehabilitation to facilitate neurocognitive recovery and improve quality of life after mTBI. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT02035579.

Neck Collar with Mild Jugular Vein Compression Ameliorates Brain Activation Changes during a Working Memory Task after a Season of High School Football.

Emerging evidence indicates that repetitive head impacts, even at a sub-concussive level, may result in exacerbated or prolonged neurological deficits in athletes. This study aimed to: 1) quantify the effect of repetitive head impacts on the alteration of neuronal activity based on functional magnetic resonance imaging (fMRI) of working memory after a high school football season; and 2) determine whether a neck collar that applies mild jugular vein compression designed to reduce brain energy absorption in head impact through "slosh" mitigation can ameliorate the altered fMRI activation during a working memory task. Participants were recruited from local high school football teams with 27 and 25 athletes assigned to the non-collar and collar group, respectively. A standard N-Back task was used to engage working memory in the fMRI at both pre- and post-season. The two study groups experienced similar head impact frequency and magnitude during the season (all p > 0.05). fMRI blood oxygen level dependent (BOLD) signal response (a reflection of the neuronal activity level) during the working memory task increased significantly from pre- to post-season in the non-collar group (corrected p < 0.05), but not in the collar group. Areas displaying less activation change in the collar group (corrected p < 0.05) included the precuneus, inferior parietal cortex, and dorsal lateral prefrontal cortex. Additionally, BOLD response in the non-collar group increased significantly in direct association with the total number of impacts and total g-force (p < 0.05). Our data provide initial neuroimaging evidence for the effect of repetitive head impacts on the working memory related brain activity, as well as a potential protective effect that resulted from the use of the purported brain slosh reducing neck collar in contact sports.

Is current medical education adequately preparing future physicians to manage concussion: an initial evaluation.

OBJECTIVES: In 2010, there were 2.5 million hospitalizations, emergency room visits, or deaths associated with concussions in the United States.[1] Knowledge deficits exist among physicians regarding concussion management, which can lead to severe repercussions, including poor patient outcomes, poor patient satisfaction, and potential medical-legal issues. While concussion is a prevalent condition evaluated in the medical field, medical students continue to have a knowledge deficit regarding concussion diagnosis, prognosis, medical management, and return to play guidelines. METHODS: Medical students from a mid-western medical school completed a survey on concussion diagnosis, prognosis, medical management, and return to play guidelines. RESULTS: The response rate was 40%. The data suggests that the vast majority of medical students are able to define concussion; however, most reported never having a lecture dedicated to concussion during medical school and also lacked clinical experience with acute concussion and post-concussive syndrome. There are clear areas of deficiency as noted by the inability of students to correctly identify symptoms and appropriate management of concussion. CONCLUSION: The current study indicates that at an individual, mid-western, top 50 medical school, current medical trainees may not be adequately educated to identify and manage concussion. Future research is warranted to determine the optimal guidelines to educate future physicians as it pertains to concussion diagnosis, management, prognosis, and return to play guidelines.

The Effects of External Jugular Compression Applied during Head Impact Exposure on Longitudinal Changes in Brain Neuroanatomical and Neurophysiological Biomarkers: A Preliminary Investigation.

OBJECTIVES: Utilize a prospective in vivo clinical trial to evaluate the potential for mild neck compression applied during head impact exposure to reduce anatomical and physiological biomarkers of brain injury. METHODS: This project utilized a prospective randomized controlled trial to evaluate effects of mild jugular vein (neck) compression (collar) relative to controls (no collar) during a competitive hockey season (males; 16.3 ± 1.2 years). The collar was designed to mildly compress the jugular vein bilaterally with the goal to increase intracranial blood volume to reduce risk of brain slosh injury during head impact exposure. Helmet sensors were used to collect daily impact data in excess of 20 g (games and practices) and the primary outcome measures, which included changes in white matter (WM) microstructure, were assessed by diffusion tensor imaging (DTI). Specifically, four DTI measures: fractional anisotropy, mean diffusivity (MD), axial diffusivity, and radial diffusivity (RD) were used in the study. These metrics were analyzed using the tract-based Spatial Statistics (TBSS) approach - a voxel-based analysis. In addition, electroencephalography-derived event-related potentials were used to assess changes in brain network activation (BNA) between study groups. RESULTS: For athletes not wearing the collar, DTI measures corresponding to a disruption of WM microstructure, including MD and RD, increased significantly from pre-season to mid-season (p < 0.05). Athletes wearing the collar did not show a significant change in either MD or RD despite similar accumulated linear accelerations from head impacts (p > 0.05). In addition to these anatomical findings, electrophysiological network analysis of the degree of congruence in the network electrophysiological activation pattern demonstrated concomitant changes in brain network dynamics in the non-collar group only (p < 0.05). Similar to the DTI findings, the increased change in BNA score in the non-collar relative to the collar group was statistically significant (p < 0.01). Changes in DTI outcomes were also directly correlated with altered brain network dynamics (r = 0.76; p < 0.05) as measured by BNA. CONCLUSION: Group differences in the longitudinal changes in both neuroanatomical and electrophysiological measures, as well as the correlation between the measures, provide initial evidence indicating that mild jugular vein compression may have reduced alterations in the WM response to head impacts during a competitive hockey season. The data indicate sport-related alterations in WM microstructure were ameliorated by application of jugular compression during head impact exposure. These results may lead to a novel line of research inquiry to evaluate the effects of protecting the brain from sports-related head impacts via optimized intracranial fluid dynamics.