Dynamic changes in perivascular space morphology predict signs of spaceflight-associated neuro-ocular syndrome in bed rest.

During long-duration spaceflight, astronauts experience headward fluid shifts and expansion of the cerebral perivascular spaces (PVS). A major limitation to our understanding of the changes in brain structure and physiology induced by spaceflight stems from the logistical difficulties of studying astronauts. The current study aimed to determine whether PVS changes also occur on Earth with the spaceflight analog head-down tilt bed rest (HDBR). We examined how the number and morphology of magnetic resonance imaging-visible PVS (MV-PVS) are affected by HDBR with and without elevated carbon dioxide (CO2). These environments mimic the headward fluid shifts, body unloading, and elevated CO2 observed aboard the International Space Station. Additionally, we sought to understand how changes in MV-PVS are associated with signs of Spaceflight Associated Neuro-ocular Syndrome (SANS), ocular structural alterations that can occur with spaceflight. Participants were separated into two bed rest campaigns: HDBR (60 days) and HDBR + CO2 (30 days with elevated ambient CO2). Both groups completed multiple magnetic resonance image acquisitions before, during, and post-bed rest. We found that at the group level, neither spaceflight analog affected MV-PVS quantity or morphology. However, when taking into account SANS status, persons exhibiting signs of SANS showed little or no MV-PVS changes, whereas their No-SANS counterparts showed MV-PVS morphological changes during the HDBR + CO2 campaign. These findings highlight spaceflight analogs as models for inducing changes in MV-PVS and implicate MV-PVS dynamic compliance as a mechanism underlying SANS. These findings may lead to countermeasures to mitigate health risks associated with human spaceflight.

Perivascular Space Burden and Cerebrospinal Fluid Biomarkers in US Veterans With Blast-Related Mild Traumatic Brain Injury.

Blast-related mild traumatic brain injury (mTBI) is recognized as the "signature injury" of the Iraq and Afghanistan wars. Sleep disruption, mTBI, and neuroinflammation have been individually linked to cerebral perivascular space (PVS) dilatation. Dilated PVSs are putative markers of impaired cerebrospinal fluid (CSF) and interstitial fluid exchange, which plays an important role in removing cerebral waste. The aim of this cross-sectional, retrospective study was to define associations between biomarkers of inflammation and MRI-visible PVS (MV-PVS) burden in Veterans after blast-related mTBI (blast-mTBI) and controls. The CSF and plasma inflammatory biomarker concentrations were compared between blast-mTBI and control groups and correlated with MV-PVS volume and number per white matter cm3. Multiple regression analyses were performed with inflammatory biomarkers as predictors and MV-PVS burden as the outcome. Correction for multiple comparisons was performed using the Banjamini-Hochberg method with a false discovery rate of 0.05. There were no group-wise differences in MV-PVS burden between Veterans with blast-mTBI and controls. Greater MV-PVS burden was significantly associated with higher concentrations of several proinflammatory biomarkers from CSF (i.e., eotaxin, MCP-1, IL-6, IL-8) and plasma (i.e., MCP-4, IL-13) in the blast-mTBI group only. After controlling for sleep time and symptoms of post-traumatic stress disorder, temporal MV-PVS burden remained significantly associated with higher CSF markers of inflammation in the blast-mTBI group only. These data support an association between central, rather than peripheral, neuroinflammation and MV-PVS burden in Veterans with blast-mTBI independent of sleep. Future studies should continue to explore the role of blast-mTBI related central inflammation in MV-PVS development, as well as investigate the impact of subclinical exposures on MV-PVS burden.

Longitudinal MRI-visible perivascular space (PVS) changes with long-duration spaceflight.

Humans are exposed to extreme environmental stressors during spaceflight and return with alterations in brain structure and shifts in intracranial fluids. To date, no studies have evaluated the effects of spaceflight on perivascular spaces (PVSs) within the brain, which are believed to facilitate fluid drainage and brain homeostasis. Here, we examined how the number and morphology of magnetic resonance imaging (MRI)-visible PVSs are affected by spaceflight, including prior spaceflight experience. Fifteen astronauts underwent six T1-weighted 3 T MRI scans, twice prior to launch and four times following their return to Earth after ~ 6-month missions to the International Space Station. White matter MRI-visible PVS number and morphology were calculated using an established, automated segmentation algorithm. We validated our automated segmentation algorithm by comparing algorithm PVS counts with those identified by two trained raters in 50 randomly selected slices from this cohort; the automated algorithm performed similarly to visual ratings (r(48) = 0.77, p < 0.001). In addition, we found high reliability for four of five PVS metrics across the two pre-flight time points and across the four control time points (ICC(3,k) > 0.50). Among the astronaut cohort, we found that novice astronauts showed an increase in total PVS volume from pre- to post-flight, whereas experienced crewmembers did not (p = 0.020), suggesting that experienced astronauts may exhibit holdover effects from prior spaceflight(s). Greater pre-flight PVS load was associated with more prior flight experience (r = 0.60-0.71), though these relationships did not reach statistical significance (p > 0.05). Pre- to post-flight changes in ventricular volume were not significantly associated with changes in PVS characteristics, and the presence of spaceflight associated neuro-ocular syndrome (SANS) was not associated with PVS number or morphology. Together, these findings demonstrate that PVSs can be consistently identified on T1-weighted MRI scans, and that spaceflight is associated with PVS changes. Specifically, prior spaceflight experience may be an important factor in determining PVS characteristics.

Emfit Bed Sensor Activity Shows Strong Agreement with Wrist Actigraphy for the Assessment of Sleep in the Home Setting.

PURPOSE: Wrist-worn actigraphy via research-grade devices, a well-established approach to the assessment of rest-activity, is limited by poor compliance, battery life, and lack of direct evidence for time spent physically in the bed. A non-invasive bed sensor (Emfit) may provide advantages over actigraphy for long-term sleep assessment in the home. This study compared sleep-wake measurements between this sensor and a validated actigraph. PATIENTS AND METHODS: Thirty healthy subjects (6 to 54 years) underwent simultaneous monitoring with both devices for 14 days and filled out a daily sleep diary. Parameters included bed entry time, sleep start, sleep end, bed exit time, rest interval duration, and wake after sleep onset (WASO). The agreement between the two devices was measured using Bland-Altman plots and inter-class correlation coefficients (ICC). In addition, sensitivity, specificity, and accuracy were obtained from epoch-by-epoch comparisons of Emfit and actigraphy. RESULTS: Fifteen percent of the subjects reported that wearing the actigraph was a burden. None reported that using the bed sensor was a burden. The minimal detectable change between Emfit and actigraphy was 11 minutes for bed entry time, 14 minutes for sleep start, 14 minutes for sleep end, 10 minutes for bed exit time, 20 minutes for rest interval duration, and 110 minutes for WASO. Inter-class correlation coefficients revealed an excellent agreement for all sleep parameters (ICC=0.99, 95% CI 98-99) except for WASO (ICC=0.46, 95% CI 0.33-0.56). Sensitivity, specificity, and accuracy were 0.62, 0.93, and 0.88, respectively. Kappa correlation analysis revealed a moderate correlation between the two devices (κ=0.55, p<0.0001). CONCLUSION: Emfit is an acceptable alternative to actigraphy for the estimation of bed entry time, sleep start, sleep end, bed exit time, and rest interval duration. However, WASO estimates are poorly correlated between the two devices. Emfit may offer methodological advantages in situations where actigraphy is challenging to implement.

Simultaneous Heart Rate Variability and Electroencephalographic Monitoring in Children in the Emergency Department.

Changes in heart rate variability (HRV) and electroencephalographic (EEG) background are promising tools for risk stratification and outcome prediction in children seen in the Emergency Department (ED). Novel monitoring technologies offer an opportunity for determining the clinical value of these physiologic variables, however, studies evaluating these measurements obtained in the Pediatric ED are sparse. The current study used a single center, prospective, observational cohort study of HRV and EEG as early predictors of outcome in children with acute trauma. ECG and HRV data were successfully collected in 167 subjects and simultaneous collection of ECG and EEG data using a wireless monitoring device was piloted in 17 patients with 15 patients having EEG data rated as appropriate for clinical interpretation. The mean time from ED arrival to ECG and EEG recording start was 7.5 (SD 11.6) and 34.5 (SD 15.5) minutes, respectively. The mean time required for EEG electrode placement was 9.3 min (SD 5.8 min). Results showed recording early HRV and EEG is feasible in children with acute injury seen in the ED. This study suggests that high consent rates are possible with the adequate research infrastructure and physiologic variables may offer an early, non-invasive marker for injury stratification and prognosis in children.

Emotional Aspects of Pediatric Post-Intensive Care Syndrome Following Traumatic Brain Injury.

Children with traumatic brain injury (TBI) requiring neurocritical care are at risk for neurocognitive, emotional, physical, and psychosocial difficulties, collectively known as Post-Intensive Care Syndrome. Our study assessed parent-reported emotional functioning and identified risk factors for emotional sequelae in the acute recovery phase. Fifty-three children between 5 and 18 years old hospitalized for TBI were assessed 1-month following discharge. Relevant injury-, child-, and family-specific variables were collected. Emotional functioning was assessed using PROMIS Parent Proxy Report Short Forms for Anxiety and Depressive Symptoms. We used Chi-square tests to evaluate differences between children with and without elevations in anxiety and depressive symptoms. Logistic regression determined predictors of elevations in symptoms among significant variables. Parents frequently endorsed moderate or worse anxiety (45.2%) and depressive (32.1%) symptoms among children. Mechanism of injury and elevated parent post-traumatic stress disorder (PTSD) symptoms were associated with elevated anxiety and depressive symptoms, while direct family involvement in the accident/injury was associated only with elevated anxiety symptoms. Results from logistic regression indicated that only elevated parent PTSD symptoms were a significant predictor for child anxiety and depressive symptoms. Anxiety and depressive symptoms are prevalent in the acute recovery phase of TBI. Consistent with previous research, elevations in anxiety and depressive symptoms were more related to psychosocial factors than injury severity. High levels of parent PTSD symptoms and their relationship with children's internalizing symptoms highlight the need for mental health treatment for TBI patients and their families.

Link between Mild Traumatic Brain Injury, Poor Sleep, and Magnetic Resonance Imaging: Visible Perivascular Spaces in Veterans.

Impaired clearance of perivascular waste in the brain may play a critical role in morbidity after mild traumatic brain injury (mTBI). We aimed to determine the effect of mTBI on the burden of magnetic resonance imaging (MRI)-visible perivascular spaces (PVSs) in a cohort of U.S. military veterans and whether sleep modulates this effect. We also investigated the correlation between PVS burden and severity of persistent post-concussive symptoms. Fifty-six Iraq/Afghanistan veterans received 3 Tesla MRI as part of a prospective cohort study on military blast mTBI. White matter PVS burden (i.e., number and volume) was calculated using an established automated segmentation algorithm. Multi-variate regression was used to establish the association between mTBIs sustained in the military and PVS burden. Covariates included age, blood pressure, number of impact mTBIs outside the military, and blast exposures. Correlation coefficients were calculated between PVS burden and severity of persistent post-concussive symptoms. There was a significant positive relationship between the number of mTBIs sustained in the military and both PVS number and volume (p = 0.04). A significant interaction was found between mTBI and poor sleep on PVS volume (p = 0.04). A correlation was found between PVS number and volume, as well as severity of postconcussive symptoms (p = 0.03). Further analysis revealed a moderate correlation between PVS number and volume, as well as balance problems (p < 0.001). In Iraq/Afghanistan veterans, mTBI is associated with an increase in PVS burden. Further, an interaction exists between mTBI and poor sleep on PVS burden. Increased PVS burden, which may indicate waste clearance dysfunction, is associated with persistent post-concussive symptom severity.

The relationship between depressive symptoms, somatic complaints, and concussion history with poor sleep in collegiate athletes.

OBJECTIVE: Ongoing exploration of factors related to poor sleep in collegiate athletes is important as understanding of the risks and consequences of poor sleep in this specific population increases. DESIGN: Retrospective cohort study. SETTING: University in the Pacific Northwest. PARTICIPANTS: One-hundred thirty-seven male and female collegiate athletes across 5 collision, contact, and limited contact team sports. MEASUREMENTS: Depressive symptoms (Patient Health Questionnaire 9; PHQ-9), anxiety symptoms (General Anxiety Disorder 7; GAD-7), and somatic complaints (Patient Health Questionnaire 15; PHQ-15). Sleep quality (Pittsburgh Sleep Quality Index; PSQI) used both a cutoff score ≥6 and a cutoff score of ≥8, indicating "poor sleep quality" to reduce threats to divergent validity. RESULTS: Poor sleep quality as defined by PSQI ≥ 6 was present in 53% of athletes, and as defined by PSQI ≥ 8 was identified in 33.5% of the cohort. There were no differences in the incidence of poor sleepers between sport, race/ethnicity, or sex. Multiple regression analysis revealed that depressive symptoms, somatic complaints, Caucasian race, male sex, and number of concussions were significant predictors of poor sleep (P < .05). The model accounted for 43% of the variance in PSQI and primarily by depressive symptoms explaining 9% of reported sleep quality variability. Anxiety symptoms, sport category, and history of migraines were not significant predictors of poor sleep quality. CONCLUSIONS: A high incidence of poor sleep among collegiate athletes was observed regardless of sport, and may be related to depressive symptoms, somatic complaints, Caucasian race, male sex, and historical number of concussions.

Sleep disturbances after pediatric traumatic brain injury: a systematic review of prevalence, risk factors, and association with recovery.

STUDY OBJECTIVES: Sleep is vital for brain development and healing after injury, placing children with sleep-wake disturbances (SWD) after traumatic brain injury (TBI) at risk for worse outcomes. We conducted a systematic review to quantify SWD after pediatric TBI including prevalence, phenotypes, and risk factors. We also evaluated interventions for SWD and the association between SWD and other posttraumatic outcomes. METHODS: Systematic searches were conducted in MEDLINE, PsychINFO, and reference lists for English language articles published from 1999 to 2019 evaluating sleep or fatigue in children hospitalized for mild complicated, moderate, or severe TBI. Two independent reviewers assessed eligibility, extracted data, and assessed risk of bias using the Newcastle-Ottowa Score for observational studies. RESULTS: Among 966 articles identified in the search, 126 full-text articles were reviewed, and 24 studies were included (11 prospective, 9 cross-sectional, and 4 case studies). Marked heterogeneity was found in study populations, measures defining SWD, and time from injury to evaluation. Studies showed at least 20% of children with TBI had trouble falling or staying asleep, fatigue, daytime sleepiness, and nightmares. SWD are negatively correlated with posttraumatic cognitive, behavioral, and quality of life outcomes. No comparative intervention studies were identified. The risk of bias was moderate-high for all studies often related to lack of validated or objective SWD measures and small sample size. Heterogeneity precluded meta-analyses. CONCLUSIONS: SWD are important morbidities after pediatric TBI, though current data are limited. SWD have implications for TBI recovery and may represent a modifiable target for improving outcomes after pediatric TBI.

Sleep Measure Validation in a Pediatric Neurocritical Care Acquired Brain Injury Population.

BACKGROUND/OBJECTIVE: Lingering morbidities including physical, cognitive, emotional, and psychosocial sequelae, termed the Post-Intensive Care Syndrome, persist years after pediatric neurocritical care (PNCC) hospitalization. Sleep disturbances impact other Post-Intensive Care Syndrome domains and are under-evaluated to date due to a lack of appropriate measurement tools. The present study evaluated the validity of the Sleep Disturbance Scale for Children (SDSC) to address the growing need for assessing sleep problems after PNCC. METHODS: We conducted a prospective observational study of youth aged 3-17 years with acquired brain injury (N = 69) receiving care through longitudinal PNCC programs at two tertiary academic medical centers. Parents completed the SDSC and provided proxy reports of internalizing symptoms, health-related quality of life (HRQOL), fatigue, pain behavior, and cognitive function within 3 months of hospital discharge. Evidence for the validity of the SDSC was established by utilizing the full sample for psychosocial measure comparisons and by comparing SDSC outcomes by severity (Low Risk, Mild-Moderate Risk, and High Risk defined by reported standardized T-scores). RESULTS: Internal consistency of the SDSC was good (α = .81). Within the full sample, increased sleep disturbances on the SDSC were significantly correlated with Post-Intensive Care Syndrome measures, including worse physical (r = .65), psychological (r = .62), and cognitive (r = - .74) sequelae. Youth in the High Risk group evidenced greater dysfunction in mental acuity, pain behavior, internalizing symptoms, and social engagement. Findings revealed both statistically and clinically significant impacts of sleep disturbances as measured by the SDSC on HRQOL. CONCLUSIONS: The SDSC is a valid and reliable measure for assessing sleep disturbances in children after PNCC. Results support the use of the SDSC to measure sleep disturbances after PNCC. Targeted interventions for sleep disturbances may be key to overall patient recovery.

Sleep-Wake Disturbances After Acquired Brain Injury in Children Surviving Critical Care.

BACKGROUND: Sleep-wake disturbances are underevaluated among children with acquired brain injury surviving critical care. We aimed to quantify severity, phenotypes, and risk factors for sleep-wake disturbances. METHODS: We performed a prospective cohort study of 78 children aged ≥3 years with acquired brain injury within three months of critical care hospitalization. Diagnoses included traumatic brain injury (n = 40), stroke (n = 11), infectious or inflammatory disease (n = 10), hypoxic-ischemic injury (n = 9), and other (n = 8). Sleep Disturbances Scale for Children standardized T scores measured sleep-wake disturbances. Overall sleep-wake disturbances were dichotomized as any total or subscale T score ≥60. Any T score ≥70 defined severe sleep-wake disturbances. Subscale T scores ≥60 identified sleep-wake disturbance phenotypes. RESULTS: Sleep-wake disturbances were identified in 44 (56%) children and were classified as severe in 36 (46%). Sleep-wake disturbances affected ≥33% of patients within each diagnosis and were not associated with severity of illness measures. The most common phenotype was disturbance in initiation and maintenance of sleep (47%), although 68% had multiple concurrent sleep-wake disturbance phenotypes. One third of all patients had preadmission chronic conditions, and this increased risk for sleep-wake disturbances overall (43% vs 21%, P = 0.04) and in the traumatic brain injury subgroup (52% vs 5%, P = 0.001). CONCLUSIONS: Over half of children surviving critical care with acquired brain injury have sleep-wake disturbances. Most of these children have severe sleep-wake disturbances independent of severity of illness measures. Many sleep-wake disturbances phenotypes were identified, but most children had disturbance in initiation and maintenance of sleep. Our study underscores the importance of evaluating sleep-wake disturbances after acquired brain injury.

Hospital Mortality and Functional Outcomes in Pediatric Neurocritical Care.

OBJECTIVES: Pediatric neurocritical care (PNCC) outcomes research is scarce. We aimed to expand knowledge about outcomes in PNCC by evaluating death and changes in Functional Status Scale (FSS) from baseline among PNCC diagnoses. METHODS: We conducted a 2-year observational study of children aged 0 to 18 years admitted to the ICU with a primary neurologic diagnosis (N = 325). Primary outcomes were death and change in FSS from preadmission baseline to discharge. New disability was defined as an FSS change of ≥1 from baseline, and severe disability was defined as an FSS change of ≥3. Categorical results are reported as relative risk (RR) with 95% confidence interval (CI). RESULTS: Thirty (9%) patients died. New disability (n = 103; 35%) and severe disability (n = 37; 13%) were common in PNCC survivors. New disability (range 14%-54%) and severe disability (range 3%-33%) outcomes varied significantly among primary diagnoses (lowest in status epilepticus; highest in infectious and/or inflammatory and stroke cohorts). Disability occurred in all FSS domains: mental status (15%), sensory (52%), communication (38%), motor (48%), feeding (40%), and respiratory (12%). Most (64%) patients with severe disability had changes in ≥3 domains. Requiring critical care interventions (RR 2.1; 95% CI 1.5-3.1) and having seizures (RR 1.5; 95% CI 1.1-2.0) during hospitalization were associated with new disability. CONCLUSIONS: PNCC patients have high rates of death and new disability at discharge, varying significantly between PNCC diagnoses. Multiple domains of disability are affected, underscoring the ongoing multidisciplinary health care needs of survivors. Our study quantified hospital outcomes of PNCC patients that can be used to advance future research in this vulnerable population.