Accelerated Aging after Traumatic Brain Injury: An ENIGMA Multi-Cohort Mega-Analysis.

OBJECTIVE: The long-term consequences of traumatic brain injury (TBI) on brain structure remain uncertain. Given evidence that a single significant brain injury event increases the risk of dementia, brain-age estimation could provide a novel and efficient indexing of the long-term consequences of TBI. Brain-age procedures use predictive modeling to calculate brain-age scores for an individual using structural magnetic resonance imaging (MRI) data. Complicated mild, moderate, and severe TBI (cmsTBI) is associated with a higher predicted age difference (PAD), but the progression of PAD over time remains unclear. We sought to examine whether PAD increases as a function of time since injury (TSI) and if injury severity and sex interacted to influence this progression. METHODS: Through the ENIGMA Adult Moderate and Severe (AMS)-TBI working group, we examine the largest TBI sample to date (n = 343), along with controls, for a total sample size of n = 540, to replicate and extend prior findings in the study of TBI brain age. Cross-sectional T1w-MRI data were aggregated across 7 cohorts, and brain age was established using a similar brain age algorithm to prior work in TBI. RESULTS: Findings show that PAD widens with longer TSI, and there was evidence for differences between sexes in PAD, with men showing more advanced brain age. We did not find strong evidence supporting a link between PAD and cognitive performance. INTERPRETATION: This work provides evidence that changes in brain structure after cmsTBI are dynamic, with an initial period of change, followed by relative stability in brain morphometry, eventually leading to further changes in the decades after a single cmsTBI. ANN NEUROL 2024;96:365-377.

Chronic immunosuppression across 12 months and high ability of acute and subacute CNS-injury biomarker concentrations to identify individuals with complicated mTBI on acute CT and MRI.

BACKGROUND: Identifying individuals with intracranial injuries following mild traumatic brain injury (mTBI), i.e. complicated mTBI cases, is important for follow-up and prognostication. The main aims of our study were (1) to assess the temporal evolution of blood biomarkers of CNS injury and inflammation in individuals with complicated mTBI determined on computer tomography (CT) and magnetic resonance imaging (MRI); (2) to assess the corresponding discriminability of both single- and multi-biomarker panels, from acute to chronic phases after injury. METHODS: Patients with mTBI (n = 207), defined as Glasgow Coma Scale score between 13 and 15, loss of consciousness < 30 min and post-traumatic amnesia < 24 h, were included. Complicated mTBI - i.e., presence of any traumatic intracranial injury on neuroimaging - was present in 8% (n = 16) on CT (CT+) and 12% (n = 25) on MRI (MRI+). Blood biomarkers were sampled at four timepoints following injury: admission (within 72 h), 2 weeks (± 3 days), 3 months (± 2 weeks) and 12 months (± 1 month). CNS biomarkers included were glial fibrillary acidic protein (GFAP), neurofilament light (NFL) and tau, along with 12 inflammation markers. RESULTS: The most discriminative single biomarkers of traumatic intracranial injury were GFAP at admission (CT+: AUC = 0.78; MRI+: AUC = 0.82), and NFL at 2 weeks (CT+: AUC = 0.81; MRI+: AUC = 0.89) and 3 months (MRI+: AUC = 0.86). MIP-1ß and IP-10 concentrations were significantly lower across follow-up period in individuals who were CT+ and MRI+. Eotaxin and IL-9 were significantly lower in individuals who were MRI+ only. FGF-basic concentrations increased over time in MRI- individuals and were significantly higher than MRI+ individuals at 3 and 12 months. Multi-biomarker panels improved discriminability over single biomarkers at all timepoints (AUCs > 0.85 for admission and 2-week models classifying CT+ and AUC ≈ 0.90 for admission, 2-week and 3-month models classifying MRI+). CONCLUSIONS: The CNS biomarkers GFAP and NFL were useful single diagnostic biomarkers of complicated mTBI, especially in acute and subacute phases after mTBI. Several inflammation markers were suppressed in patients with complicated versus uncomplicated mTBI and remained so even after 12 months. Multi-biomarker panels improved diagnostic accuracy at all timepoints, though at acute and 2-week timepoints, the single biomarkers GFAP and NFL, respectively, displayed similar accuracy compared to multi-biomarker panels.

Migraine and risk of atrial fibrillation: A 9-year follow-up based on the Trøndelag Health Study.

BACKGROUND: Data from some population-based studies have indicated an increased risk of atrial fibrillation (AF) among patients with migraine, particularly among individuals with migraine with aura. The present study aimed to assess the association between primary headache disorders and AF. METHODS: In a population-based 9-year follow-up design, we evaluated the questionnaire-based headache diagnosis, migraine and tension-type headache (TTH) included, collected in the Trøndelag Health Study (HUNT3) conducted in 2006-2008, and the subsequent risk of AF in the period until December 2015. The population at risk consisted of 39,340 individuals ≥20 years without AF at HUNT3 baseline who answered headache questionnaire during HUNT3. The prospective association was evaluated by multivariable Cox proportional hazard models with 95% confidence intervals (CIs). RESULTS: Among the 39,340 participants, 1524 (3.8%) developed AF during the 9-year follow up, whereof 91% of these were ≥55 years. In the multivariable analyses, adjusting for known confounders, we did not find any association between migraine or TTH and risk of AF. The adjusted hazard ratios (HRs) were respectively 0.84 (95% CI = 0.64-1.11) for migraine, 1.16 (95% CI = 0.86-1.27) for TTH and 1.04 (95% CI = 0.86-1.27) for unclassified headache. However, in sensitivity analyses of individuals aged ≥55 years, a lower risk of AF was found for migraine (HR = 0.53; 95% CI = 0.39-0.73). CONCLUSIONS: In this large population-based study, no increased risk of AF was found among individuals with migraine or TTH at baseline. Indeed, among individuals aged ≥55 years, migraine was associated with a lower risk for AF.

Poorer sleep health is associated with altered brain activation during cognitive control processing in healthy adults.

This study investigated how proactive and reactive cognitive control processing in the brain was associated with habitual sleep health. BOLD fMRI data were acquired from 81 healthy adults with normal sleep (41 females, age 20.96-39.58 years) during a test of cognitive control (Not-X-CPT). Sleep health was assessed in the week before MRI scanning, using both objective (actigraphy) and self-report measures. Multiple measures indicating poorer sleep health-including later/more variable sleep timing, later chronotype preference, more insomnia symptoms, and lower sleep efficiency-were associated with stronger and more widespread BOLD activations in fronto-parietal and subcortical brain regions during cognitive control processing (adjusted for age, sex, education, and fMRI task performance). Most associations were found for reactive cognitive control activation, indicating that poorer sleep health is linked to a "hyper-reactive" brain state. Analysis of time-on-task effects showed that, with longer time on task, poorer sleep health was predominantly associated with increased proactive cognitive control activation, indicating recruitment of additional neural resources over time. Finally, shorter objective sleep duration was associated with lower BOLD activation with time on task and poorer task performance. In conclusion, even in "normal sleepers," relatively poorer sleep health is associated with altered cognitive control processing, possibly reflecting compensatory mechanisms and/or inefficient neural processing.

Frequency and predictors of headache in the first 12 months after traumatic brain injury: results from CENTER-TBI.

BACKGROUND: Headache is a prevalent and debilitating symptom following traumatic brain injury (TBI). Large-scale, prospective cohort studies are needed to establish long-term headache prevalence and associated factors after TBI. This study aimed to assess the frequency and severity of headache after TBI and determine whether sociodemographic factors, injury severity characteristics, and pre- and post-injury comorbidities predicted changes in headache frequency and severity during the first 12 months after injury. METHODS: A large patient sample from the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) prospective observational cohort study was used. Patients were stratified based on their clinical care pathway: admitted to an emergency room (ER), a ward (ADM) or an intensive care unit (ICU) in the acute phase. Headache was assessed using a single item from the Rivermead Post-Concussion Symptoms Questionnaire measured at baseline, 3, 6 and 12 months after injury. Mixed-effect logistic regression analyses were applied to investigate changes in headache frequency and associated predictors. RESULTS: A total of 2,291 patients responded to the headache item at baseline. At study enrolment, 59.3% of patients reported acute headache, with similar frequencies across all strata. Female patients and those aged up to 40 years reported a higher frequency of headache at baseline compared to males and older adults. The frequency of severe headache was highest in patients admitted to the ICU. The frequency of headache in the ER stratum decreased substantially from baseline to 3 months and remained from 3 to 6 months. Similar trajectory trends were observed in the ICU and ADM strata across 12 months. Younger age, more severe TBI, fatigue, neck pain and vision problems were among the predictors of more severe headache over time. More than 25% of patients experienced headache at 12 months after injury. CONCLUSIONS: Headache is a common symptom after TBI, especially in female and younger patients. It typically decreases in the first 3 months before stabilising. However, more than a quarter of patients still experienced headache at 12 months after injury. Translational research is needed to advance the clinical decision-making process and improve targeted medical treatment for headache. TRIAL REGISTRATION: ClinicalTrials.gov NCT02210221.

Forecasting migraine with machine learning based on mobile phone diary and wearable data.

INTRODUCTION: Triggers, premonitory symptoms and physiological changes occur in the preictal migraine phase and may be used in models for forecasting attacks. Machine learning is a promising option for such predictive analytics. The objective of this study was to explore the utility of machine learning to forecast migraine attacks based on preictal headache diary entries and simple physiological measurements. METHODS: In a prospective development and usability study 18 patients with migraine completed 388 headache diary entries and self-administered app-based biofeedback sessions wirelessly measuring heart rate, peripheral skin temperature and muscle tension. Several standard machine learning architectures were constructed to forecast headache the subsequent day. Models were scored with area under the receiver operating characteristics curve. RESULTS: Two-hundred-and-ninety-five days were included in the predictive modelling. The top performing model, based on random forest classification, achieved an area under the receiver operating characteristics curve of 0.62 in a hold-out partition of the dataset. DISCUSSION: In this study we demonstrate the utility of using mobile health apps and wearables combined with machine learning to forecast headache. We argue that high-dimensional modelling may greatly improve forecasting and discuss important considerations for future design of forecasting models using machine learning and mobile health data.

Workplace Factors Associated With Return to Work After Mild-to-Moderate Traumatic Brain Injury.

OBJECTIVE: Sociodemographic and injury-related predictors for return to work (RTW) after mild-to-moderate traumatic brain injury (TBI) have been extensively explored. However, there is a knowledge gap regarding work-related predictors of RTW. The main aim of this study was to explore work-related predictors of work participation 6 and 12 months after mild-to-moderate TBI. SETTING: Data were collected at baseline 8 to 12 weeks after injury, and 3, 6, and 12 months after baseline, at a specialized TBI rehabilitation outpatient clinic at Oslo University Hospital, Oslo, Norway. PARTICIPANTS: Eligible patients had suffered a mild-to-moderate TBI 8 to 12 weeks previously, were employed 50% or more at time of injury, were between 18 and 60 years of age, and sick listed 50% or more at time of inclusion due to symptoms of TBI (based on the Rivermead Post-Concussion Symptoms Questionnaire). In total, 116 patients were included in a randomized controlled trial, of whom 113 were included in the 1-year analysis. DESIGN: Patients were originally included in a randomized controlled trial. There were no between-group differences in RTW after 1 year. Thus, the participants were evaluated as one cohort in this study. MAIN MEASURES: The primary outcome measure was work participation 1 year after study inclusion. Work-related predictors were chosen on the basis of previous research and expert opinion and entered into a multivariable linear regression model. The model controlled for sociodemographic and injury-related factors. RESULTS: The best-fitting model explained 25% of variation in work participation at 1 year. Significant predictors were predictability, quantitative demands and rewards (recognition) at the workplace, private or public employment, symptom burden at baseline, and sex. CONCLUSION: In this study, several work-related predictors outperformed some of the established sociodemographic and injury-related predictors of RTW after TBI, thus stressing the need for further focus and research on amendable predictors of RTW after mild-to-moderate TBI.

Associations between executive functions, intelligence and adaptive behaviour in children and adolescents with mild intellectual disability.

Background: The purpose of this study was to explore the role of everyday executive functions in relation to intelligence and adaptive behaviour in children and adolescents with mild intellectual disability. Method: A group of children and adolescents, previously diagnosed with mild intellectual disability were assessed according to intelligence, everyday executive functions and adaptive behaviour. The association between everyday executive functions and intelligence was examined, and it was explored whether intelligence or everyday executive functions would best predict adaptive behaviour. Results: Adaptive behaviour was significantly predicted by executive functions, but not by intelligence. Nor was intelligence significantly related to everyday executive functions in this group. Conclusions: Although fundamental in diagnosing intellectual disability, intelligence cannot predict adaptive behaviour. Assessing everyday executive functions and adaptive behaviour, as well as acknowledging the strong association between them, provides valuable information in the process of optimizing developmental support for children and adolescents with mild intellectual disability.

ENIGMA brain injury: Framework, challenges, and opportunities.

Traumatic brain injury (TBI) is a major cause of disability worldwide, but the heterogeneous nature of TBI with respect to injury severity and health comorbidities make patient outcome difficult to predict. Injury severity accounts for only some of this variance, and a wide range of preinjury, injury-related, and postinjury factors may influence outcome, such as sex, socioeconomic status, injury mechanism, and social support. Neuroimaging research in this area has generally been limited by insufficient sample sizes. Additionally, development of reliable biomarkers of mild TBI or repeated subconcussive impacts has been slow, likely due, in part, to subtle effects of injury and the aforementioned variability. The ENIGMA Consortium has established a framework for global collaboration that has resulted in the largest-ever neuroimaging studies of multiple psychiatric and neurological disorders. Here we describe the organization, recent progress, and future goals of the Brain Injury working group.

The Relationship of Psychiatric Symptoms with Performance-Based and Self-Reported Cognitive Function After Ischemic Stroke.

OBJECTIVE: Findings on the relationship of psychiatric symptoms with performance-based and self-reported cognitive function post-stroke are inconclusive. We aimed to (1) study the relation of depression and anxiety to performance-based cognitive function and (2) explore a broader spectrum of psychiatric symptoms and their association with performance-based versus self-reported cognitive function. METHOD: Individuals with supratentorial ischemic stroke performed neuropsychological examination 3 months after stroke. For primary analyses, composite scores for memory and attention/executive function were calculated based on selected neuropsychological tests, and the Hospital Anxiety and Depression Scale (HADS) was used. Psychiatric symptoms and self-reported cognitive function for secondary aims were assessed using the Symptom-Checklist-90 - Revised (SCL-90-R). RESULTS: In a sample of 86 patients [mean (M) age: 64.6 ± 9.2; Mini-Mental State Examination (MMSE), 3-7 days post-stroke: M = 28.4 ± 1.7; National Institutes of Health Stroke Scale (NIHSS) after 3 months: M = 0.7 ± 1.6] depressive symptoms (HADS) were associated with poorer memory performance after controlling for age, sex, and education (p ≤ .01). In a subsample (n = 41; Age: M = 65.7 ± 8.1; MMSE: M = 28.4 ± 1.8; NIHSS: M = 1.0 ± 1.9), symptoms of phobic anxiety (SCL-90-R) were associated with poorer performance-based memory and attention/executive function, and symptoms of anxiety (SCL-90-R) with lower attention/executive function. Higher levels of self-reported cognitive difficulties were associated with higher scores in all psychiatric domains (p ≤ .05). CONCLUSION: Even in relatively well-functioning stroke patients, depressive symptoms are associated with poorer memory. The results also suggest that various psychiatric symptoms are more related to self-reported rather than to performance-based cognitive function. Screening for self-reported cognitive difficulties may not only help to identify patients with cognitive impairment, but also those who need psychological treatment.

Trajectories of Persistent Postconcussion Symptoms and Factors Associated With Symptom Reporting After Mild Traumatic Brain Injury.

OBJECTIVE: To examine the trajectories of persistent postconcussion symptoms (PPCS) after mild traumatic brain injury (MTBI) and to investigate which injury-related and personal factors are associated with symptom reporting. DESIGN: Prospective longitudinal cohort study. Follow-up at 3 and 12 months postinjury. SETTING: A level 1 trauma center and an emergency outpatient clinic. PARTICIPANTS: Patients with MTBI (n=358), trauma controls (n=75), and community controls (n=78). MAIN OUTCOME MEASURES: Symptoms were assessed with the British Columbia Postconcussion Symptom Inventory (BC-PSI). Participants were categorized as having moderate to severe PPCS (msPPCS) when reporting ≥3 moderate/severe symptoms or a BC-PSI total score of ≥13. BC-PSI total scores were compared between the groups and were further used to create cutoffs for reliable change by identifying uncommon and very uncommon change in symptoms in the community control group. Associations between symptom reporting and 25 injury-related and personal factors were examined. RESULTS: The MTBI group had a similar prevalence of msPPCS at 3 and 12 months (21%) and reported more symptoms than the control groups. Analyses of individual trajectories, however, revealed considerable change in both msPPCS and BC-PSI total scores in the MTBI group, where both worsening and improvement was common. Intracranial lesions on computed tomography were associated with a greater likelihood of improving from 3 to 12 months. Those with msPPCS at both assessments were more likely to be women and to have these personal preinjury factors: reduced employment, pain, poor sleep, low resilience, high neuroticism and pessimism, and a psychiatric history. CONCLUSIONS: Group analyses suggest a stable prevalence of msPPCS the first year postinjury. However, there was considerable intraindividual change. Several personal factors were associated with maintaining symptoms throughout the first year.

ENIGMA-Sleep: Challenges, opportunities, and the road map.

Neuroimaging and genetics studies have advanced our understanding of the neurobiology of sleep and its disorders. However, individual studies usually have limitations to identifying consistent and reproducible effects, including modest sample sizes, heterogeneous clinical characteristics and varied methodologies. These issues call for a large-scale multi-centre effort in sleep research, in order to increase the number of samples, and harmonize the methods of data collection, preprocessing and analysis using pre-registered well-established protocols. The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) consortium provides a powerful collaborative framework for combining datasets across individual sites. Recently, we have launched the ENIGMA-Sleep working group with the collaboration of several institutes from 15 countries to perform large-scale worldwide neuroimaging and genetics studies for better understanding the neurobiology of impaired sleep quality in population-based healthy individuals, the neural consequences of sleep deprivation, pathophysiology of sleep disorders, as well as neural correlates of sleep disturbances across various neuropsychiatric disorders. In this introductory review, we describe the details of our currently available datasets and our ongoing projects in the ENIGMA-Sleep group, and discuss both the potential challenges and opportunities of a collaborative initiative in sleep medicine.

Personal Factors Associated With Postconcussion Symptoms 3 Months After Mild Traumatic Brain Injury.

OBJECTIVE: To describe personal factors in patients with mild traumatic brain injury (MTBI) and 2 control groups and to explore how such factors were associated with postconcussion symptoms (PCSs). DESIGN: Prospective cohort study. SETTING: Level 1 trauma center and outpatient clinic. PARTICIPANTS: Participants (N=541) included patients with MTBI (n=378), trauma controls (n=82), and community controls (n=81). MAIN OUTCOME MEASURES: Data on preinjury health and work status, personality, resilience, attention deficit/hyperactivity, and substance use. Computed tomography (CT) findings and posttraumatic amnesia were recorded. Symptoms were assessed at 3 months with the British Columbia Postconcussion Symptom Inventory and labeled as PCS+ if ≥3 symptoms were reported or the total score was ≥13. Predictive models were fitted with penalized logistic regression using the least absolute shrinkage and selection operator (lasso) in the MTBI group, and model fit was assessed with optimism-corrected area under the curve (AUC) of the receiver operating characteristic curve. RESULTS: There were few differences in personal factors between the MTBI group and the 2 control groups without MTBI. Rates of PCS+ were 20.8% for the MTBI group, 8.0% for trauma controls, and 1.3% for community controls. In the MTBI group, there were differences between the PCS+ and PCS- group on most personal factors and injury-related variables in univariable comparisons. In the lasso models, the optimism-corrected AUC for the full model was 0.79, 0.73 for the model only including personal factors, and 0.63 for the model only including injury variables. Working less than full time before injury, having preinjury pain and poor sleep quality, and being female were among the selected predictors, but also resilience and some personality traits contributed in the model. Intracranial abnormalities on CT were also a risk factor for PCS. CONCLUSIONS: Personal factors convey important prognostic information in patients with MTBI. A vulnerable work status and preinjury health problems might indicate a need for follow-up and targeted interventions.

Post-concussion symptoms three months after mild-to-moderate TBI: characteristics of sick-listed patients referred to specialized treatment and consequences of intracranial injury.

Objective: To present pre-injury, injury-related, work-related and post-injury characteristics, and to compare patients with and without traumatic intracranial abnormalities, in a treatment-seeking sample with persistent post-concussion symptoms (PPCS) after mild-to-moderate TBI.Methods: Cross-sectional design in the context of a specialized TBI outpatient clinic. Eligible patients were aged 18-60 years, employed ≥ 50% at time of injury, and sick listed ≥ 50% at inclusion due to PPCS. Data were collected 8-12 weeks after injury through review of medical records, semi-structured interviews, questionnaires, and neuropsychological screening.Results: The study included 116 patients, of whom 60% were women, and predominantly white-collar workers in full-time positions. Ninety-four percent had a mild TBI, and 23% had intracranial abnormalities. The full sample reported high somatic, emotional, and cognitive symptom burden, and decreased health-related quality of life. Patients with normal CT/MRI results reported higher overall symptom burden, while patients with intracranial abnormalities had worse memory function.Conclusion: Injury severity and traumatic intracranial radiological findings should not be the sole ground for planning of rehabilitation service provision in patients with PPCS, as subjective complaints do not necessarily co-vary with these variables.

Biofeedback Treatment App for Pediatric Migraine: Development and Usability Study.

OBJECTIVE: The objective of this study was to develop and investigate the usability of a biofeedback treatment smartphone app for adolescent migraine sufferers. BACKGROUND: Biofeedback is effective in treating pediatric migraine. However, biofeedback is not widely used due to the necessity of a trained therapist and specialized equipment. Emerging digital technology, including smartphones and wearables, enables new ways of administering biofeedback. METHODS: In a prospective open-label development and usability study, 10 adolescent migraine sufferers used a newly developed biofeedback app with wearable sensors that measured their muscle tension, finger temperature, and heart rate. Three iterative rounds of usability testing, including a 2-week home testing period, were completed. A biofeedback algorithm, combining and optimizing the 3 physiological modalities, and several algorithms for sham-treatment were created. Usability was evaluated statistically and summarized thematically. RESULTS: Five of ten participants completed all 3 rounds of usability testing. A total of 72 biofeedback sessions were completed. Usability scoring was consistently high, with median scores ranging from 3.5 to 4.5 on a 5-point scale. The biofeedback optimization algorithm correlated excellently to the raw physiological measurements (r = 0.85, P < .001). The intervention was safe and tolerable. CONCLUSION: We developed an app for young migraine sufferers to receive therapist-independent biofeedback. The app underwent a rigorous development process as well as usability and feasibility testing. It is now ready for clinical trials.

Cognitive Reserve Moderates Cognitive Outcome After Mild Traumatic Brain Injury.

OBJECTIVE: To investigate whether cognitive reserve moderates differences in cognitive functioning between patients with mild traumatic brain injury (MTBI) and controls without MTBI and to examine whether patients with postconcussion syndrome have lower cognitive functioning than patients without postconcussion syndrome at 2 weeks and 3 months after injury. DESIGN: Trondheim MTBI follow-up study is a longitudinal controlled cohort study with cognitive assessments 2 weeks and 3 months after injury. SETTING: Recruitment at a level 1 trauma center and at a general practitioner-run, outpatient clinic. PARTICIPANTS: Patients with MTBI (n=160) according to the World Health Organization criteria, trauma controls (n=71), and community controls (n=79) (N=310). MAIN OUTCOME MEASURES: A cognitive composite score was used as outcome measure. The Vocabulary subtest was used as a proxy of cognitive reserve. Postconcussion syndrome diagnosis was assessed at 3 months with the British Columbia Postconcussion Symptom Inventory. RESULTS: Linear mixed models demonstrated that the effect of vocabulary scores on the cognitive composite scores was larger in patients with MTBI than in community controls at 2 weeks and at 3 months after injury (P=.001). Thus, group differences in the cognitive composite score varied as a function of vocabulary scores, with the biggest differences seen among participants with lower vocabulary scores. There were no significant differences in the cognitive composite score between patients with (n=29) and without (n=131) postconcussion syndrome at 2 weeks or 3 months after injury. CONCLUSION: Cognitive reserve, but not postconcussion syndrome, was associated with cognitive outcome after MTBI. This supports the cognitive reserve hypothesis in the MTBI context and suggests that persons with low cognitive reserve are more vulnerable to reduced cognitive functioning if they sustain an MTBI.

Cognitive performance in DSWPD patients upon awakening from habitual sleep compared with forced conventional sleep.

Difficult early morning awakening is one of the defining symptoms of delayed sleep-wake phase disorder. It is accompanied by low cognitive arousal and drowsiness resulting in difficulty concentrating and focusing attention upon awakening. We designed the current study to quantitate cognitive performance (i.e. omissions, commissions, reaction time [average and variability]) and cognitive domains (i.e. focused attention, sustained attention, impulsivity and vigilance) with Conners' Continuous Performance Test II during both habitual and conventional (00:00-07:00 hr) sleep-wake schedule in young adult patients with delayed sleep-wake phase disorder (n = 20, mean age = 24.8 years, SD = 3.0) and controls (n = 16, mean age = 24.4 years, SD = 3.4). Conners' Continuous Performance Test II was administered after awakening and in the afternoon during both habitual and conventional conditions. In-laboratory polysomnography was performed for 2 nights. We assessed sleep, tiredness, chronotype and depression using questionnaires. Saliva was sampled for dim light melatonin onset measurements. Repeated-measures ANOVAs were applied for the Conners' Continuous Performance Test II measures with group (patient/control), time (afternoon/morning) and condition (habitual/conventional schedule) as fixed factors. Patients with delayed sleep-wake phase disorder had reduced reaction times, especially in the morning, greater response speed variability, and made more omission and commission errors compared with controls. Patients with delayed sleep-wake phase disorder also had reduced focused attention, especially upon forced early awakening. The short total sleep time of patients with delayed sleep-wake phase disorder could not statistically explain this outcome. In conclusion, we observed a state-dependent reduced ability to focus attention upon early morning awakening in patients with delayed sleep-wake phase disorder. Patients also had more omissions, longer reaction time and increased RT variability after habitual sleep, suggesting a possible small cognitive trait dysfunction in delayed sleep-wake phase disorder.

Preterm birth leads to hyper-reactive cognitive control processing and poor white matter organization in adulthood.

Individuals born preterm with very low birth weight (VLBW; birth weight ≤ 1500 g) are at high risk for perinatal brain injuries and deviant brain development, leading to increased chances of later cognitive, emotional, and behavioral problems. Here we investigated the neuronal underpinnings of both reactive and proactive cognitive control processes in adults with VLBW. We included 32 adults born preterm with VLBW (before 37th week of gestation) and 32 term-born controls (birth weight ≥10th percentile for gestational age) between 22 and 24 years of age that have been followed prospectively since birth. Participants performed a well-validated Not-X continuous performance test (CPT) adapted for use in a mixed block- and event-related fMRI protocol. BOLD fMRI and DTI data was acquired on a 3T scanner. Performance on the Not-X CPT was highly similar between groups. However, the VLBW group demonstrated hyper-reactive cognitive control processing and disrupted white matter organization. The hyper-reactive brain activation signature in VLBW adults was associated with lower gestational age, lower fluid intelligence score, and anxiety problems. Automated Multi-Atlas Tract Extraction (AutoMATE) analyses revealed that this disruption of normal brain function was accompanied by poorer white matter organization in the anterior thalamic radiation and the cingulum, as reflected in both reduced fractional anisotropy and increased mean diffusivity. These findings show that the preterm behavioral phenotype is associated with predominantly reactive-, rather than proactive cognitive control processing, as well as white matter abnormalities, that may underlie common difficulties that many preterm born individuals experience in everyday life.

Magnetic resonance spectroscopy of fiber tracts in children with traumatic brain injury: A combined MRS - Diffusion MRI study.

Traumatic brain injury can cause extensive damage to the white matter (WM) of the brain. These disruptions can be especially damaging in children, whose brains are still maturing. Diffusion magnetic resonance imaging (dMRI) is the most commonly used method to assess WM organization, but it has limited resolution to differentiate causes of WM disruption. Magnetic resonance spectroscopy (MRS) yields spectra showing the levels of neurometabolites that can indicate neuronal/axonal health, inflammation, membrane proliferation/turnover, and other cellular processes that are on-going post-injury. Previous analyses on this dataset revealed a significant division within the msTBI patient group, based on interhemispheric transfer time (IHTT); one subgroup of patients (TBI-normal) showed evidence of recovery over time, while the other showed continuing degeneration (TBI-slow). We combined dMRI with MRS to better understand WM disruptions in children with moderate-severe traumatic brain injury (msTBI). Tracts with poorer WM organization, as shown by lower FA and higher MD and RD, also showed lower N-acetylaspartate (NAA), a marker of neuronal and axonal health and myelination. We did not find lower NAA in tracts with normal WM organization. Choline, a marker of inflammation, membrane turnover, or gliosis, did not show such associations. We further show that multi-modal imaging can improve outcome prediction over a single modality, as well as over earlier cognitive function measures. Our results suggest that demyelination plays an important role in WM disruption post-injury in a subgroup of msTBI children and indicate the utility of multi-modal imaging.

A systematic literature review of psychotherapeutic treatment of prolonged symptoms after mild traumatic brain injury.

BACKGROUND: Mild traumatic brain injuries (mTBI) are the most common of traumatic brain injuries and patients often experience a wide range of symptoms such as headache, fatigue, dizziness, sleep problems and subjective cognitive deficits. While most symptomatic patients recover quickly, a sub-group of ~ 10-20% of patients experience prolonged symptoms. There is currently a lack of evidence-based treatment for these patients. OBJECTIVE: The objective of the present paper was to conduct a systematic review of the literature on psychotherapeutic interventions specifically for patients with prolonged symptoms (> 3 months after injury) after mTBI. METHODS: With a more precise definition of psychotherapy than previous reviews, an extensive literature search was conducted that yielded 2332 hits, of which five were considered to meet the criteria. Only two of the studies were randomized controlled trials. RESULTS AND CONCLUSIONS: Results revealed several methodological limitations in the included studies, leading to the conclusion that it is premature to make any strong recommendations on psychotherapeutic treatment of prolonged symptoms after mTBI. With in-depth methodological analyses of the included studies and comprehensive recommendations for future research, the present review aims to inform clinicians and to encourage scientists to engage in collaborative effort towards increasing the number of methodologically sound clinical trials in the field.