Chronotherapy for patients with a depressive episode treated in a public outpatient mental healthcare clinic in Norway: protocol for a randomised controlled trial.

INTRODUCTION: Depression is highly prevalent in outpatients receiving treatment for mental disorders. Treatment as usual (TAU) usually consists of either psychotherapy and/or antidepressant medication and often takes several weeks before clinical effect. Chronotherapy, consisting of sleep deprivation, sleep-wake phase advancement and stabilisation, and light therapy, is a possible addition to TAU that may decrease the time to treatment response. This randomised controlled trial will examine the benefits of adding chronotherapy to TAU compared with TAU alone. METHODS AND ANALYSIS: The trial will include 76 participants with a depressive episode who initiate outpatient treatment at a secondary mental healthcare outpatient clinic at St. Olavs University Hospital. Participants will be randomly allocated 1:1 to either chronotherapy in addition to TAU or TAU alone. Assessments will be performed at baseline, day 3, day 4, day 7, day 14 and weeks 4, 8, 24 and 52, in addition to longer-term follow ups. The main outcome is difference in levels of depressive symptoms after week 1 using the Inventory of Depressive Symptomatology Self-Report. Secondary outcomes include levels of depressive symptoms at other time points, as well as anxiety, health-related quality of life and sleep assessed through subjective and objective measures. ETHICS AND DISSEMINATION: The study protocol has been approved by the Regional Committee for Medical Research Ethics Central Norway (ref: 480812) and preregistered at ClinicalTrials.gov (ref: NCT05691647). Results will be published via peer-reviewed publications, presentations at research conferences and presentations for clinicians and other relevant groups. The main outcomes will be provided separately from exploratory analysis. TRIAL REGISTRATION NUMBER: NCT05691647.

Dysfunctional beliefs and attitudes about sleep (DBAS) mediate outcomes in dCBT-I on psychological distress, fatigue, and insomnia severity.

OBJECTIVE/BACKGROUND: Digital cognitive behavioral therapy for insomnia (dCBT-I) improves several sleep and health outcomes in individuals with insomnia. This study investigates whether changes in Dysfunctional Beliefs and Attitudes about Sleep (DBAS) during dCBT-I mediate changes in psychological distress, fatigue, and insomnia severity. PATIENTS/METHODS: The study presents a secondary planned analysis of data from 1073 participants in a randomized control trial (Total sample = 1721) of dCBT-I compared with patient education (PE). Self-ratings with the Dysfunctional Beliefs and Attitudes about Sleep (DBAS), the Hospital Anxiety Depression Scale (HADS), the Chalder Fatigue Scale (CFQ), and the Insomnia Severity Index (ISI) were obtained at baseline and 9-week follow-up. Hayes PROCESS mediation analyses were conducted to test for mediation. RESULTS AND CONCLUSION: sDBAS scores were significantly reduced at 9-week follow-up for those randomized to dCBT-I (n = 566) compared with PE (n = 507). The estimated mean difference was -1.49 (95% CI -1.66 to -1.31, p < .001, Cohen's d. = 0.93). DBAS mediated all the effect of dCBT-I on the HADS and the CFQ, and 64% of the change on the ISI (Estimated indirect effect -3.14, 95% CI -3.60 to -2.68) at 9-week follow-up compared with PE. Changes in the DBAS fully mediated the effects of dCBT-I on psychological distress and fatigue, and the DBAS partially mediated the effects on insomnia severity. These findings may have implications for understanding how dCBT-I works and highlights the role of changing cognitions in dCBT-I.

Digital cognitive behaviour therapy for insomnia in individuals with self-reported insomnia and chronic fatigue: A secondary analysis of a large scale randomized controlled trial.

Insomnia is associated with fatigue, but it is unclear whether response to cognitive behaviour therapy for insomnia is altered in individuals with co-occurring symptoms of insomnia and chronic fatigue. This is a secondary analysis using data from 1717 participants with self-reported insomnia in a community-based randomized controlled trial of digital cognitive behaviour therapy for insomnia compared with patient education. We employed baseline ratings of the Chalder Fatigue Questionnaire to identify participants with more or fewer symptoms of self-reported chronic fatigue (chronic fatigue, n = 592; no chronic fatigue, n = 1125). We used linear mixed models with Insomnia Severity Index, Short Form-12 mental health, Short Form-12 physical health, and the Hospital Anxiety and Depression Scale separately as outcome variables. The main covariates were main effects and interactions for time (baseline versus 9-week follow-up), intervention, and chronic fatigue. Participants with chronic fatigue reported significantly greater improvements following digital cognitive behaviour therapy for insomnia compared with patient education on the Insomnia Severity Index (Cohen's d = 1.36, p < 0.001), Short Form-12 mental health (Cohen's d = 0.19, p = 0.029), and Hospital Anxiety and Depression Scale (Cohen's d = 0.18, p = 0.010). There were no significant differences in the effectiveness of digital cognitive behaviour therapy for insomnia between chronic fatigue and no chronic fatigue participants on any outcome. We conclude that in a large community-based sample of adults with insomnia, co-occurring chronic fatigue did not moderate the effectiveness of digital cognitive behaviour therapy for insomnia on any of the tested outcomes. This may further establish digital cognitive behaviour therapy for insomnia as an adjunctive intervention in individuals with physical and mental disorders.

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.

Examining 3-month test-retest reliability and reliable change using the Cambridge Neuropsychological Test Automated Battery.

The Cambridge Neuropsychological Test Automated Battery (CANTAB) is a battery of computerized neuropsychological tests commonly used in Europe in neurology and psychiatry studies, including clinical trials. The purpose of this study was to investigate test-retest reliability and to develop reliable change indices and regression-based change formulas for using the CANTAB in research and practice involving repeated measurement. A sample of 75 healthy adults completed nine CANTAB tests, assessing three domains (i.e., visual learning and memory, executive function, and visual attention) twice over a 3-month period. Wilcoxon signed-rank tests showed significant practice effects for 6 of 14 outcome measures with effect sizes ranging from negligible to medium (Hedge's g: .15-.40; Cliff's delta: .09-.39). The Spatial Working Memory test, Attention Switching Task, and Rapid Visual Processing test were the only tests with scores of adequate test-retest reliability. For all outcome measures, Pearson's and Spearman's correlation coefficients ranged from .39 to .79. The measurement error surrounding difference scores was large, thus requiring large changes in performance (i.e., 1-2 SDs) in order to interpret a change score as reliable. In the regression equations, test scores from initial testing significantly predicted retest scores for all outcome measures. Age was a significant predictor in several of the equations, while education was a significant predictor in only two of the equations. The adjusted R2 values ranged between .19 and .67. The present study provides results enabling clinicians to make probabilistic statements about change in cognitive functions based on CANTAB test performances.

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.

Poor sleep quality is associated with greater negative consequences for cognitive control function and psychological health after mild traumatic brain injury than after orthopedic injury.

OBJECTIVE: To test the hypothesis that poor sleep quality has a stronger negative effect on cognitive control function and psychological health after mild traumatic brain injury (mTBI) than after orthopedic injury. METHOD: Patients with mTBI (n = 197) and trauma controls with orthopedic injuries (n = 82) were included in this prospective longitudinal study. The participants (age 16-60) completed three computerized neurocognitive tests assessing response speed and accuracy at 2 weeks and 3 months after injury, as well as questionnaires and interviews assessing sleep quality and psychological distress at 2 weeks, 3 months, and 12 months after injury. Separate Linear Mixed Models (LMMs) for each of the outcome measures (response speed, response accuracy, psychological distress) were performed. RESULTS: We observed a significant interaction effect between poor sleep quality and group (mTBI vs. trauma controls) in the response speed (p = .028) and psychological distress (p = .001) models, driven by a greater negative impact of poor sleep quality on response speed and psychological distress in the mTBI group. We found no such interaction effect for response accuracy (p = .825), and poor sleep quality was associated with worse accuracy to a similar extent for both groups. CONCLUSIONS: Our findings show that poor sleep quality has a more negative impact on cognitive control function and psychological outcome in patients with mTBI, compared to trauma controls. This indicates an increased vulnerability to poor sleep quality in patients who have suffered an mTBI. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Digital cognitive-behavioural therapy for insomnia compared with digital patient education about insomnia in individuals referred to secondary mental health services in Norway: protocol for a multicentre randomised controlled trial.

INTRODUCTION: Insomnia is highly prevalent in outpatients receiving treatment for mental disorders. Cognitive-behavioural therapy for insomnia (CBT-I) is a recommended first-line intervention. However, access is limited and most patients with insomnia who are receiving mental healthcare services are treated using medication. This multicentre randomised controlled trial (RCT) examines additional benefits of a digital adaptation of CBT-I (dCBT-I), compared with an online control intervention of patient education about insomnia (PE), in individuals referred to secondary mental health clinics. METHODS AND ANALYSIS: A parallel group, superiority RCT with a target sample of 800 participants recruited from treatment waiting lists at Norwegian psychiatric services. Individuals awaiting treatment will receive an invitation to the RCT, with potential participants undertaking online screening and consent procedures. Eligible outpatients will be randomised to dCBT-I or PE in a 1:1 ratio. Assessments will be performed at baseline, 9 weeks after completion of baseline assessments (post-intervention assessment), 33 weeks after baseline (6 months after the post-intervention assessment) and 61 weeks after baseline (12 months after the post-intervention assessment). The primary outcome is between-group difference in insomnia severity 9 weeks after baseline. Secondary outcomes include between-group differences in levels of psychopathology, and measures of health and functioning 9 weeks after baseline. Additionally, we will test between-group differences at 6-month and 12-month follow-up, and examine any negative effects of the intervention, any changes in mental health resource use, and/or in functioning and prescription of medications across the duration of the study. Other exploratory analyses are planned. ETHICS AND DISSEMINATION: The study protocol has been approved by the Regional Committee for Medical and Health Research Ethics in Norway (Ref: 125068). Findings from the RCT will be disseminated via peer-reviewed publications, conference presentations, and advocacy and stakeholder groups. Exploratory analyses, including potential mediators and moderators, will be reported separately from main outcomes. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT04621643); Pre-results.

Examining the Subacute Effects of Mild Traumatic Brain Injury Using a Traditional and Computerized Neuropsychological Test Battery.

This study investigates subacute cognitive effects of mild traumatic brain injury (MTBI) in the Trondheim Mild TBI Study, as measured, in part, by the neuropsychological test battery of the Collaborative European NeuroTrauma Effectiveness Research in TBI (CENTER-TBI) program, including computerized tests from the Cambridge Neuropsychological Test Automated Battery (CANTAB) and traditional paper-and-pencil tests. We investigated whether cognitive function was associated with injury severity: intracranial traumatic lesions on neuroimaging, witnessed loss of consciousness (LOC), or post-traumatic amnesia (PTA) >1 h. Further, we explored which of the tests in the CENTER-TBI battery might be associated with the largest subacute effects of MTBI (i.e., at 2 weeks post-injury). We recruited 177 patients with MTBI (16-59 years of age) from a regional trauma center and an outpatient clinic,79 trauma control participants, and 81 community control participants. The MTBI group differed from community controls only on one traditional test of processing speed (coding; p = 0.009, Cliff's delta [Δ] = 0.20). Patients with intracranial abnormalities performed worse than those without on a traditional test (phonemic verbal fluency; p = 0.043, Δ = 0.27), and patients with LOC performed differently on the Attention Switching Task from the CANTAB (p = 0.020, Δ = -0.20). Patients with PTA >1 h performed worse than those with <1 h on 10 measures, from traditional tests and the CANTAB (Δ = 0.33-0.20), likely attributable, at least in part, to pre-existing differences in intellectual functioning between groups. In general, those with MTBI had good neuropsychological outcome 2 weeks after injury and no particular CENTER-TBI computerized or traditional tests seemed to be more sensitive to subtle cognitive deficits.

Methodology Matters: Comparing Approaches for Defining Persistent Symptoms after Mild Traumatic Brain Injury.

Some people experience persistent post-concussion symptoms (PPCS) after mild traumatic brain injury (mTBI). A meaningful clinical classification and scientific progress are hampered by a lack of consensus regarding the phenomenology, assessment, and operationalization of PPCS. Here we demonstrate and evaluate how the methodology used to assess and define persistent symptoms after mTBI influences PPCS as a binary outcome. We present empirical data from 15 classification methods reflecting procedures found in the literature and clinical practice. In total, 221 patients with mTBI, 73 patients with orthopedic injuries, and 77 community controls were included in the study. The prevalence rate of PPCS in the mTBI group varied between 10% and 47%, depending on the method used to assess and define unfavorable outcome. There was generally low positive agreement between the different methods; even the two methods yielding the most similar prevalence rates (89.2% overall proportion agreement) agreed on less than half (45.5% positive agreement) of the PPCS cases. Using a liberal but not uncommon threshold for symptom severity, there was a considerable misclassification rate of PPCS in both comparison groups. Our results highlight the importance for researchers to be aware of the limitations of using binary approaches for classification of PPCS. The poor agreement between methods should be considered when (1) interpreting the heterogeneity in the existing PPCS literature and (2) developing new improved methods. An empirically informed consensus regarding classification of PPCS should be a priority for the research community.

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.

Developing Cognition Endpoints for the CENTER-TBI Neuropsychological Test Battery.

Background: Measuring cognitive functioning is common in traumatic brain injury (TBI) research, but no universally accepted method for combining several neuropsychological test scores into composite, or summary, scores exists. This study examined several possible composite scores for the test battery used in the large-scale study Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI). Methods: Participants with mild traumatic brain injury (MTBI; n = 140), orthopedic trauma (n = 72), and healthy community controls (n = 70) from the Trondheim MTBI follow-up study completed the CENTER-TBI test battery at 2 weeks after injury, which includes both traditional paper-and-pencil tests and tests from the Cambridge Neuropsychological Test Automated Battery (CANTAB). Seven composite scores were calculated for the paper and pencil tests, the CANTAB tests, and all tests combined (i.e., 21 composites): the overall test battery mean (OTBM); global deficit score (GDS); neuropsychological deficit score-weighted (NDS-W); low score composite (LSC); and the number of scores ≤5th percentile, ≤16th percentile, or <50th percentile. Results: The OTBM and the number of scores <50th percentile composites had distributional characteristics approaching a normal distribution. The other composites were in general highly skewed and zero-inflated. When the MTBI group, the trauma control group, and the community control group were compared, effect sizes were negligible to small for all composites. Subgroups with vs. without loss of consciousness at the time of injury did not differ on the composite scores and neither did subgroups with complicated vs. uncomplicated MTBIs. Intercorrelations were high within the paper-and-pencil composites, the CANTAB composites, and the combined composites and lower between the paper-and-pencil composites and the CANTAB composites. Conclusion: None of the composites revealed significant differences between participants with MTBI and the two control groups. Some of the composite scores were highly correlated and may be redundant. Additional research on patients with moderate to severe TBIs is needed to determine which scores are most appropriate for TBI clinical trials.

The Prevalence and Stability of Sleep-Wake Disturbance and Fatigue throughout the First Year after Mild Traumatic Brain Injury.

In this prospective, longitudinal study, we aimed to determine the prevalence and stability of sleep-wake disturbance (SWD) and fatigue in a large representative sample of patients (Trondheim mild traumatic brain injury [mTBI] follow-up study). We included 378 patients with mTBI (age 16-60), 82 matched trauma controls with orthopedic injuries, and 83 matched community controls. Increased sleep need, poor sleep quality, excessive daytime sleepiness, and fatigue were assessed at 2 weeks, 3 months, and 12 months after injury. Mixed logistic regression models were used to evaluate clinically relevant group differences longitudinally. Prevalence of increased sleep need, poor sleep quality, and fatigue was significantly higher in patients with mTBI than in both trauma controls and community controls at all time points. More patients with mTBI reported problems with excessive daytime sleepiness compared to trauma controls, but not community controls, at all time points. Patients with complicated mTBI (intracranial findings on computed tomography or magnetic resonance imaging) had more fatigue problems compared to those with uncomplicated mTBI, at all three time points. In patients with mTBI who experienced SWDs and fatigue 2 weeks after injury, around half still had problems at 3 months and approximately one third at 12 months. Interestingly, we observed limited overlap between the different symptom measures; a large number of patients reported one specific problem with SWD or fatigue rather than several problems. In conclusion, our results provide strong evidence that mTBI contributes significantly to the development and maintenance of SWDs and fatigue.

Mild to moderate partial sleep deprivation is associated with increased impulsivity and decreased positive affect in young adults.

The effects of mild-moderate partial sleep deprivation on affective and cognitive functioning were evaluated in a naturalistic home environment, mimicking short sleep typically caused by demands from work or society. A total of 52 healthy individuals aged 18-35 was included in an 11-day study protocol. Participants slept at home, and sleep patterns were observed using actigraphs and sleep diaries. After maintaining habitual sleep for 7 days, the participants were asked to sleep 2 hours less than their average sleep duration for the last three nights of the study protocol. A not-X continuous performance test was administered at 9 am (± 90 minutes) on days 1, 4, 8 (habitual sleep), 9 and 11 (sleep deprivation). Performance-based measures included response accuracy and speed. Participant-reported measures included how well the participants felt they performed and how exhausted they were from taking the test, as well as positive and negative affect. There was a significant change in reaction time, number of commission errors, subjective performance, subjective exertion, and positive affect across the visits. Specifically, there was a linear decrease in reaction time, performance, and positive affect throughout the study, and a significant quadratic trend for commissions and exertion (first decreasing, then increasing after sleep deprivation). The univariate tests for omissions and negative affect were not significant. We conclude that sleeping 1.5-2 hours less than usual leads to faster response speed, but more commission errors and decreased positive affect. This indicates that individuals become more impulsive and experience less positive affect after a period of short sleep.

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.