The Role of Puberty and Sex on Brain Structure in Adolescents With Anxiety Following Concussion.

BACKGROUND: Adolescence represents a window of vulnerability for developing psychological symptoms following concussion, especially in girls. Concussion-related lesions in emotion regulation circuits may help explain these symptoms. However, the contribution of sex and pubertal maturation remains unclear. Using the neurite density index (NDI) in emotion regulation tracts (left/right cingulum bundle [CB], forceps minor [FMIN], and left/right uncinate fasciculus), we sought to elucidate these relationships. METHODS: No adolescent had a history of anxiety and/or depression. The Screen for Child Anxiety Related Emotional Disorders and Children's Depression Rating Scale were used at scan to assess anxiety and depressive symptoms in 55 concussed adolescents (41.8% girls) and 50 control adolescents with no current/history of concussion (44% girls). We evaluated if a mediation-moderation model including the NDI (mediation) and sex or pubertal status (moderation) could help explain this relationship. RESULTS: Relative to control adolescents, concussed adolescents showed higher anxiety (p = .003) and lower NDI, with those at more advanced pubertal maturation showing greater abnormalities in 4 clusters: the left CB frontal (p = .002), right CB frontal (p = .011), FMIN left-sided (p = .003), and FMIN right-sided (p = .003). Across all concussed adolescents, lower NDI in the left CB frontal and FMIN left-sided clusters partially mediated the association between concussion and anxiety, with the CB being specific to female adolescents. These effects did not explain depressive symptoms. CONCLUSIONS: Our findings indicate that lower NDI in the CB and FMIN may help explain anxiety following concussion and that adolescents at more advanced (vs less advanced) status of pubertal maturation may be more vulnerable to concussion-related injuries, especially in girls.

The role of sleep quality on white matter integrity and concussion symptom severity in adolescents.

BACKGROUND: Sleep problems are common after concussion; yet, to date, no study has evaluated the relationship between sleep, white matter integrity, and post-concussion symptoms in adolescents. Using self-reported quality of sleep measures within the first 10 days of injury, we aimed to determine if quality of sleep exerts a main effect on white matter integrity in major tracts, as measured by diffusion Magnetic Resonance Imaging (dMRI), and further examine whether this effect can help explain the variance in post-concussion symptom severity in 12- to 17.9-year-old adolescents. METHODS: dMRI data were collected in 57 concussed adolescents (mean age[SD] = 15.4[1.5] years; 41.2 % female) with no history of major psychiatric diagnoses. Severity of post-concussion symptoms was assessed at study entry (mean days[SD] = 3.7[2.5] days since injury). Using the Pittsburgh Sleep Quality Index (PSQI), concussed adolescents were divided into two groups based on their quality of sleep in the days between injury and scan: good sleepers (PSQI global score ≤ 5; N = 33) and poor sleepers (PSQI global score > 5; N = 24). Neurite Orientation Dispersion and Dispersion Index (NODDI), specifically the Neurite Density Index (NDI), was used to quantify microstructural properties in major tracts, including 18 bilateral and one interhemispheric tract, and identify whether dMRI differences existed in good vs poor sleepers. Since the interval between concussion and neuroimaging acquisition varied among concussed adolescents, this interval was included in the analysis along with an interaction term with sleep groups. Regularized regression was used to identify if quality of sleep-related dMRI measures correlated with post-concussion symptom severity. Due to higher reported concussion symptom severity in females, interaction terms between dMRI and sex were included in the regularized regression model. Data collected in 33 sex- and age-matched non-concussed controls (mean age[SD] = 15.2[1.5]; 45.5 % female) served as healthy reference and sex and age were covariates in all analyses. RESULTS: Relative to good sleepers, poor sleepers demonstrated widespread lower NDI (18 of the 19 tracts; FDR corrected P < 0.048). This group effect was only significant with at least seven days between concussion and neuroimaging acquisition. Post-concussion symptoms severity was negatively correlated with NDI in four of these tracts: cingulum bundle, optic radiation, striato-fronto-orbital tract, and superior longitudinal fasciculus I. The multiple linear regression model combining sex and NDI of these four tracts was able to explain 33.2 % of the variability in symptom severity (F[7,49] = 4.9, P < 0.001, Adjusted R2 = 0.332). Relative to non-concussed controls, poor sleepers demonstrated lower NDI in the cingulum bundle, optic radiation, and superior longitudinal fasciculus I (FDR corrected P < 0.040). CONCLUSIONS: Poor quality of sleep following concussion is associated with widespread lower integrity of major white matter tracts, that in turn helped to explain post-concussion symptom severity in 12-17.9-year-old adolescents. The effect of sleep on white matter integrity following concussion was significant after one week, suggesting that acute sleep interventions may need this time to begin to take effect. Our findings may suggest an important relationship between good quality of sleep in the days following concussion and integrity of major white matter tracts. Moving forward, researchers should evaluate the effectiveness of sleep interventions on white matter integrity and clinical outcomes following concussion.

False-Positive Rates and Associated Risk Factors on the Vestibular-Ocular Motor Screening and Modified Balance Error Scoring System in US Military Personnel.

CONTEXT: In 2018, the US military developed the Military Acute Concussion Evaluation-2 (MACE-2) to inform the acute evaluation of mild traumatic brain injury (mTBI). However, researchers have yet to investigate false-positive rates for components of the MACE-2, including the Vestibular-Ocular Motor Screening (VOMS) and modified Balance Error Scoring System (mBESS), in military personnel. OBJECTIVE: To examine factors associated with false-positive results on the VOMS and mBESS in US Army Special Operations Command (USASOC) personnel. DESIGN: Cross-sectional study. SETTING: Military medical clinic. PATIENTS OR OTHER PARTICIPANTS: A total of 416 healthy USASOC personnel completed the medical history, VOMS, and mBESS evaluations. MAIN OUTCOME MEASURE(S): False-positive rates for the VOMS (≥2 on VOMS symptom items, >5 cm for near point of convergence [NPC] distance) and mBESS (total score >4) were determined using χ2 analyses and independent-samples t tests. Multivariable logistic regressions (LRs) with adjusted odds ratios (aORs) were performed to identify risk factors for false-positive results on the VOMS and mBESS. The VOMS item false-positive rates ranged from 10.6% (smooth pursuits) to 17.5% (NPC). The mBESS total score false-positive rate was 36.5%. RESULTS: The multivariable LR model supported 3 significant predictors of VOMS false-positives, age (aOR = 1.07; 95% CI = 1.02, 1.12; P = .007), migraine history (aOR = 2.49; 95% CI = 1.29, 4.81; P = .007), and motion sickness history (aOR = 2.46; 95% CI = 1.34, 4.50; P = .004). Only a history of motion sickness was a significant predictor of mBESS false-positive findings (aOR = 2.34; 95% CI = 1.34, 4.05; P = .002). CONCLUSIONS: False-positive rates across VOMS items were low and associated with age and a history of mTBI, migraine, or motion sickness. False-positive results for the mBESS total score were higher (36.5%) and associated only with a history of motion sickness. These risk factors for false-positive findings should be considered when administering and interpreting VOMS and mBESS components of the MACE-2 in this population.

Resting State Functional Connectivity between Dorsal Attentional Network and Right Inferior Frontal Gyrus in Concussed and Control Adolescents.

Concussion among adolescents continues to be a public health concern. Yet, the differences in brain function between adolescents with a recent concussion and adolescents with no history of concussion are not well understood. Although resting state functional magnetic resonance imaging (fMRI) can be a useful tool in examining these differences, few studies have used this technique to examine concussion in adolescents. Here, we investigate the differences in the resting state functional connectivity of 52 adolescents, 38 with a concussion in the previous 10 days (mean age = 15.6; female = 36.8%), and 14 controls with no concussion history (mean age = 15.1; female = 57.1%). Independent component analysis and dual regression revealed that control adolescents had significantly greater functional connectivity between the dorsal attention network (DAN) and right inferior frontal gyrus (RIFG) compared to concussed adolescents (p-corrected < 0.001). Specifically, there was a positive DAN-RIFG connectivity in control, but not concussed, adolescents. Our findings indicate that concussion is associated with disrupted DAN-RIFG connectivity, which may reflect a general, nonspecific response to injury.

Vestibular/ocular motor symptoms in concussed adolescents are linked to retrosplenial activation.

Following concussion, adolescents often experience vestibular and ocular motor symptoms as well as working memory deficits that may affect their cognitive, academic and social well-being. Complex visual environments including school activities, playing sports, or socializing with friends may be overwhelming for concussed adolescents suffering from headache, dizziness, nausea and fogginess, thus imposing heightened requirements on working memory to adequately function in such environments. While understanding the relationship between working memory and vestibular/ocular motor symptoms is critically important, no previous study has examined how an increase in working memory task difficulty affects the relationship between severity of vestibular/ocular motor symptoms and brain and behavioural responses in a working memory task. To address this question, we examined 80 adolescents (53 concussed, 27 non-concussed) using functional MRI while performing a 1-back (easy) and 2-back (difficult) working memory tasks with angry, happy, neutral and sad face distractors. Concussed adolescents completed the vestibular/ocular motor screening and were scanned within 10 days of injury. We found that all participants showed lower accuracy and slower reaction time on difficult (2-back) versus easy (1-back) tasks (P-values < 0.05). Concussed adolescents were significantly slower than controls across all conditions (P < 0.05). In concussed adolescents, higher vestibular/ocular motor screening total scores were associated with significantly greater differences in reaction time between 1-back and 2-back across all distractor conditions and significantly greater differences in retrosplenial cortex activation for the 1-back versus 2-back condition with neutral face distractors (P-values < 0.05). Our findings suggest that processing of emotionally ambiguous information (e.g. neutral faces) additionally increases the task difficulty for concussed adolescents. Post-concussion vestibular/ocular motor symptoms may reduce the ability to inhibit emotionally ambiguous information during working memory tasks, potentially affecting cognitive, academic and social functioning in concussed adolescents.

Predictors of poor reading performance in student-athletes following sport-related concussion.

The goal of the current study was to determine which sport/recreation-related concussion (SRC) assessments predict academic reading performance following SRC. The study included 70 concussed students aged 14-22 years (M = 16.21, SD = 1.90) evaluated 2-30 days (M = 8.41, SD = 5.88) post-injury. SRC assessments included: Post-Concussion Symptom Scale, Immediate Post-Concussion Assessment and Cognitive Testing, Vestibular/Ocular Motor Screening, and King-Devick test. The Nelson-Denny Reading Test (NDRT) comprehension subtest measured academic reading accuracy and rate. Pearson correlations examined relationships among SRC assessments and reading accuracy/rate; those assessments that significantly correlated with the NDRT were included in multiple regressions (MRs) predicting reading accuracy and reading rate. Results supported positive correlations between visual motor speed and reading accuracy (r = .31, p = .01), and near point of convergence (NPC) and reading rate (r = .30, p = .01). The MRs for reading accuracy (F = 4.61, p = .01) and reading rate (F = 4.61, p = .01) were significant, and predicted approximately 40% of the variance, with visual motor speed and NPC as the only significant predictors in both models. Symptoms were not predictive of reading accuracy or rate. The present study indicates that visual motor speed and NPC are predictive of academic reading performance after SRC, suggesting clinicians should consider these clinical outcomes to better inform academic accommodations.

Lower post-injury psychological resilience is associated with increased recovery time and symptom burden following sport-related concussion.

The purpose of this study was to compare athletes with high and low resilience scores on concussion outcomes, and identify significant predictors associated with protracted recovery (>30 days). Forty-five adolescent and young adult athletes (28 males; aged 15.13 ± 2.74; range of 11-22) were diagnosed with an SRC within 14 days of injury (M = 4.9 days) and grouped as high or low resilience based on score on the Connor-Davidson Resilience Scale-10 (CD-RISC-10). Primary dependent measures included days to full clearance, Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT), Depression Anxiety and Stress Scale-21 (DASS-21), and Vestibular/Ocular Motor Screening (VOMS). The low resilience group (n = 22) had a longer recovery (36.0 ± 27.6 vs 17.8 ± 11.2 days), endorsed more mood symptoms (PCSS Affective cluster; 3.8 ± 0.8 vs 0.9 ± 0.7), and were more likely to have VOMS scores above cut off (p = 0.01-0.02), compared to those with high psychological resilience (n = 23). Logistic regression found low resilience scores was the only significant predictor for protracted recovery among injury characteristics and risk factors. Psychological resilience is a critical factor associated with recovery time following sport-related concussions. Low resilience was also associated with other poor clinical outcomes, greater subjective symptom report, more severe vestibular dysfunction, and elevated levels of mood symptoms following injury.

Utility of a Postural Stability/Perceptual Inhibition Dual Task for Identifying Concussion in Adolescents.

CONTEXT: Research in the area of dual-task paradigms to assess sport-related concussion (SRC) status is growing, but additional assessment of this paradigm in adolescents is warranted. DESIGN: This case-control study compared 49 adolescent athletes aged 12-20 years with diagnosed SRC to 49 age- and sex-matched controls on visual-spatial discrimination and perceptual inhibition (PIT) reaction time tasks performed while balancing on floor/foam pad conditions. METHODS: The SRC group completed measures at a single time point between 1 and 10 days postinjury. Primary outcomes were dual-task reaction time, accuracy, and sway. General linear models evaluated differences between groups (P < .05). Logistic regression identified predictors of concussion from outcomes. Area under the curve evaluated discriminative ability of identifying SRC. RESULTS: Results supported significantly higher anterior-posterior (AP) sway values in concussed participants for visual-spatial discrimination and PIT when balancing on the floor (P = .03) and foam pad (P = .03), as well as mediolateral sway values on the floor during visual-spatial discrimination (P = .01). Logistic regression analysis (R2 = .15; P = .001) of all dual-task outcomes identified AP postural sway during the PIT foam dual task as the only significant predictor of concussed status (ß = -2.4; P = .004). Total symptoms (area under the curve = 0.87; P < .001) and AP postural sway on foam (area under the curve = 0.70; P = .001) differentiated concussed from controls. CONCLUSION: The AP postural sway on foam during a postural stability/PIT dual task can identify concussion in adolescents between 1 and 10 days from injury.

White Matter Abnormalities Associated With Prolonged Recovery in Adolescents Following Concussion.

Background: Concussion symptoms in adolescents typically resolve within 4 weeks. However, 20 - 30% of adolescents experience a prolonged recovery. Abnormalities in tracts implicated in visuospatial attention and emotional regulation (i.e., inferior longitudinal fasciculus, ILF; inferior fronto-occipital fasciculus, IFOF; uncinate fasciculus; UF) have been consistently reported in concussion; yet, to date, there are no objective markers of prolonged recovery in adolescents. Here, we evaluated the utility of diffusion MRI in outcome prediction. Forty-two adolescents (12.1 - 17.9 years; female: 44.0%) underwent a diffusion Magnetic Resonance Imaging (dMRI) protocol within the first 10 days of concussion. Based on days of injury until medical clearance, adolescents were then categorized into SHORT (<28 days; N = 21) or LONG (>28 days; N = 21) recovery time. Fractional anisotropy (FA) in the ILF, IFOF, UF, and/or concussion symptoms were used as predictors of recovery time (SHORT, LONG). Forty-two age- and sex-matched healthy controls served as reference. Higher FA in the ILF (left: adjusted odds ratio; AOR = 0.36, 95% CI = 0.15 - 0.91, P = 0.030; right: AOR = 0.28, 95% CI = 0.10 - 0.83, P = 0.021), IFOF (left: AOR = 0.21, 95% CI = 0.07 - 0.66, P = 0.008; right: AOR = 0.30, 95% CI = 0.11 - 0.83, P = 0.020), and UF (left: AOR = 0.26, 95% CI = 0.09 - 0.74, P = 0.011; right: AOR = 0.28, 95% CI = 0.10 - 0.73, P = 0.010) was associated with SHORT recovery. In additional analyses, while adolescents with SHORT recovery did not differ from HC, those with LONG recovery showed lower FA in the ILF and IFOF (P < 0.014). Notably, inclusion of dMRI findings increased the sensitivity and specificity (AUC = 0.93) of a prediction model including clinical variables only (AUC = 0.75). Our findings indicate that higher FA in long associative tracts (especially ILF) might inform a more objective and accurate prognosis for recovery time in adolescents following concussion.

Test-retest reliability of the Vestibular Ocular Motor Screening (VOMS) tool and modified Balance Error Scoring System (mBESS) in US military personnel.

The Military Acute Concussion Evaluation 2 (MACE 2), which includes the Vestibular-Ocular Motor Screening (VOMS) tool and the single-leg stance component of the modified Balance Error Scoring System (mBESS), was introduced in 2018 as an assessment of acute mTBI in US military personnel. However, the reliability of the VOMS and mBESS in this population has not been established. OBJECTIVES: The primary purpose of this study was to examine the reliability of the VOMS across a 6-month period in healthy, uninjured US Army Special Operations Command (USASOC) personnel. DESIGN: Active duty/heathy military personnel (n=108) completed the VOMS and mBESS at baseline and follow-up 6 months later (±1 month). METHOD: Cronbach's alpha was used to examine the internal consistency of the VOMS and mBESS at both time points. Two-way mixed intra-class correlation coefficients (ICC) with consistency agreement were used to evaluate test-retest reliability. RESULTS: VOMS demonstrated excellent internal consistency (α=0.99), whereas, the mBESS demonstrated poor internal consistency (α=0.29). Test-retest reliability of VOMS items was moderate-to-good with ICCs ranging from 0.60 to 0.81. Test-retest reliability was moderate for mBESS total score (ICC=0.59) and double-leg stance (ICC=0.73), while single-leg (ICC=0.49) and tandem (ICC=0.02) stances were poor. CONCLUSIONS: The findings suggest that VOMS has high internal consistency and moderate-to-good test-retest reliability. mBESS has poor internal consistency and poor-to-moderate test-retest reliability. The results suggest that VOMS is a reliable addition to the MACE-2, whereas, mBESS single-leg stance is less reliable. As such, mBESS double-leg stance may be a more reliable measure of balance in this population.

Effect of Patient Compliance With Treatment Recommendations on Clinical Outcomes in Chronic mTBI: A TEAM-TBI Study.

INTRODUCTION: Treatment approaches for mild traumatic brain injury (mTBI) have evolved to focus on active and targeted therapies, but the effect of compliance with therapy has not been investigated. The purpose of this study was to examine the role of patient compliance with prescribed therapies on clinical outcomes following mTBI. MATERIALS AND METHODS: Participants were aged 18-60 years with chronic (ie, 6+ months) mTBI symptoms who were previously recalcitrant (n = 66). Participants were diagnosed with a vestibular disorder and were prescribed vestibular and exertion therapies. Participants were instructed to continue the exercise regimen during the 6-month treatment phase at home. Participant compliance was evaluated by clinicians at patients' follow up visit as: (1) high, (2) moderate, or (3) low compliance based on patient report and clinician interview. High-compliance was compared to a combined low- and moderate-compliance group on the outcomes using a 2 (group) × 2 (time) analysis of variance. RESULTS: 39 of the 66 (59%) participants with vestibular disorder returned for a 6-month evaluation and were included in the analyses. Of these 39 participants, 16 (41%) were high-compliance (36.7 ± 10.9 years, 18.8% female), 17 (44%) were moderate-compliance (32.5 ± 5.5 years, 23.5% female), and 6 (15%) were low-compliance (32.7 ± 3.3 years, 0% female). CONCLUSION: High compliance significantly reduced total Vestibular/Ocular Motor Screening scores compared to low/middle compliance (P = .005). Post-Concussion Symptom Scale was reduced by 48% and dizziness symptoms reduced by 31% in the high-compliance cohort. High compliance with prescribed exertion/vestibular rehabilitation therapies enhanced clinical outcomes for previously recalcitrant patients with chronic mTBI-related vestibular disorders.