Combining cardiac monitoring with actigraphy aids nocturnal arousal detection during ambulatory sleep assessment in insomnia.

STUDY OBJECTIVES: The objective assessment of insomnia has remained difficult. Multisensory devices collecting heart rate (HR) and motion are regarded as the future of ambulatory sleep monitoring. Unfortunately, reports on altered average HR or heart rate variability (HRV) during sleep in insomnia are equivocal. Here, we evaluated whether the objective quantification of insomnia improves by assessing state-related changes in cardiac measures. METHODS: We recorded electrocardiography, posture, and actigraphy in 33 people without sleep complaints and 158 patients with mild to severe insomnia over 4 d in their home environment. At the microscale, we investigated whether HR changed with proximity to gross (body) and small (wrist) movements at nighttime. At the macroscale, we calculated day-night differences in HR and HRV measures. For both timescales, we tested whether outcome measures were related to insomnia diagnosis and severity. RESULTS: At the microscale, an increase in HR was often detectable already 60 s prior to as well as following a nocturnal chest, but not wrist, movement. This increase was slightly steeper in insomnia and was associated with insomnia severity, but future EEG recordings are necessary to elucidate whether these changes occur prior to or simultaneously with PSG-indicators of wakefulness. At the macroscale, we found an attenuated cardiac response to sleep in insomnia: patients consistently showed smaller day-night differences in HR and HRV. CONCLUSIONS: Incorporating state-related changes in cardiac features in the ambulatory monitoring of sleep might provide a more sensitive biomarker of insomnia than the use of cardiac activity averages or actigraphy alone.

Treating Insomnia with High Risk of Depression Using Therapist-Guided Digital Cognitive, Behavioral, and Circadian Rhythm Support Interventions to Prevent Worsening of Depressive Symptoms: A Randomized Controlled Trial.

INTRODUCTION: The global disease burden of major depressive disorder urgently requires prevention in high-risk individuals, such as recently discovered insomnia subtypes. Previous studies targeting insomnia with fully automated eHealth interventions to prevent depression are inconclusive: dropout was high and likely biased, and depressive symptoms in untreated participants on average improved rather than worsened. OBJECTIVE: This randomized controlled trial aimed to efficiently prevent the worsening of depressive symptoms by selecting insomnia subtypes at high risk of depression for internet-based circadian rhythm support (CRS), cognitive behavioral therapy for insomnia (CBT-I), or their combination (CBT-I+CRS), with online therapist guidance to promote adherence. METHODS: Participants with an insomnia disorder subtype conveying an increased risk of depression (n = 132) were randomized to no treatment (NT), CRS, CBT-I, or CBT-I+CRS. The Inventory of Depressive Symptomatology - Self Report (IDS-SR) was self-administered at baseline and at four follow-ups spanning 1 year. RESULTS: Without treatment, depressive symptoms indeed worsened (d = 0.28, p = 0.041) in high-risk insomnia, but not in a reference group with low-risk insomnia. Therapist-guided CBT-I and CBT-I+CRS reduced IDS-SR ratings across all follow-up assessments (respectively, d = -0.80, p = 0.001; d = -0.95, p < 0.001). Only CBT-I+CRS reduced the 1-year incidence of clinically meaningful worsening (p = 0.002). Dropout during therapist-guided interventions was very low (8%) compared to previous automated interventions (57-62%). CONCLUSIONS: The findings tentatively suggest that the efficiency of population-wide preventive strategies could benefit from the possibility to select insomnia subtypes at high risk of developing depression for therapist-guided digital CBT-I+CRS. This treatment may provide effective long-term prevention of worsening of depressive symptoms. TRIAL REGISTRATION: the Netherlands Trial Register (NL7359).

Internet-guided cognitive, behavioral and chronobiological interventions in depression-prone insomnia subtypes: protocol of a randomized controlled prevention trial.

BACKGROUND: Major depressive disorder is among the most burdening and costly chronic health hazards. Since its prognosis is poor and treatment effectiveness is moderate at best, prevention would be the strategy of first choice. Insomnia may be the best modifiable risk factor. Insomnia is highly prevalent (4-10%) and meta-analysis estimates ±13% of people with insomnia to develop depression within a year. Among people with insomnia, recent work identified three subtypes with a particularly high lifetime risk of depression. The current randomized controlled trial (RCT) evaluates the effects of internet-guided Cognitive Behavioral Therapy for Insomnia (CBT-I), Chronobiological Therapy (CT), and their combination on insomnia and the development of depressive symptoms. METHODS: We aim to include 120 participants with Insomnia Disorder (ID) of one of the three subtypes that are more prone to develop depression. In a two by two factorial repeated measures design, participants will be randomized to CBT-I, CT, CBT-I + CT or treatment as usual, and followed up for one year. The primary outcome is the change, relative to baseline, of the severity of depressive symptoms integrated over four follow-ups spanning one year. Secondary outcome measures include a diagnosis of major depressive disorder, insomnia severity, sleep diaries, actigraphy, cost-effectiveness, and brain structure and function. DISCUSSION: Pre-selection of three high-risk insomnia subtypes allows for a sensitive assessment of the possibility to prevent the development and worsening of depressive symptoms through interventions targeting insomnia. TRIAL REGISTRATION: Netherlands Trial Register (NL7359). Registered on 19 October 2018.

The cyclic AMP pathway is a sex-specific modifier of glioma risk in type I neurofibromatosis patients.

Identifying modifiers of glioma risk in patients with type I neurofibromatosis (NF1) could help support personalized tumor surveillance, advance understanding of gliomagenesis, and potentially identify novel therapeutic targets. Here, we report genetic polymorphisms in the human adenylate cyclase gene adenylate cyclase 8 (ADCY8) that correlate with glioma risk in NF1 in a sex-specific manner, elevating risk in females while reducing risk in males. This finding extends earlier evidence of a role for cAMP in gliomagenesis based on results in a genetically engineered mouse model (Nf1 GEM). Thus, sexually dimorphic cAMP signaling might render males and females differentially sensitive to variation in cAMP levels. Using male and female Nf1 GEM, we found significant sex differences exist in cAMP regulation and in the growth-promoting effects of cAMP suppression. Overall, our results establish a sex-specific role for cAMP regulation in human gliomagenesis, specifically identifying ADCY8 as a modifier of glioma risk in NF1.

A pilot study for evaluation of hypotonia in children with neurofibromatosis type 1.

There are currently no objective criteria to evaluate pediatric hypotonia. The purpose of this pilot study was to identify diagnostic criteria for assessing hypotonia in children with neurofibromatosis type 1. Fifty-five subjects between the ages of 1 and 7 years with a diagnosis of neurofibromatosis type 1 were evaluated. A physical therapist recorded a subjective tone assessment and objective tone metrics, including ankle dorsiflexion, knee extension, hip abduction, triceps fat percentage, grip strength, and head lag during a pull-to-sit test. Multivariate logistic regression analysis showed the presence of head lag paired with increased hip range of motion was a significant predictor of hypotonia. The presence of head lag on a pull-to-sit test paired with increased hip range of motion is an accurate predictor of hypotonia in children with neurofibromatosis type 1. These objective measures should be prospectively evaluated in other pediatric populations for their ability to predict hypotonia.

The association between hypotonia and brain tumors in children with neurofibromatosis type 1.

Children with the neurofibromatosis type 1 (NF1) inherited tumor predisposition syndrome are at risk for the development of brain tumors. In addition, children with neurofibromatosis type 1 often exhibit low tone (hypotonia). In this study, the authors explored the hypothesis that hypotonia could be a clinical indicator of glioma in children with neurofibromatosis type 1. A total of 56 children between 1 and 7 years of age with a confirmed diagnosis of neurofibromatosis type 1 were evaluated. Brain magnetic resonance imaging (MRI) was available for 19 of these children. Chi-square analysis demonstrated a statistically significant correlation between hypotonia and glioma in children with neurofibromatosis type 1 (90% sensitivity and 78% specificity). These results suggest that hypotonia might be a clinically useful indicator of brain tumor in this at-risk population.

Predictive value of café au lait macules at initial consultation in the diagnosis of neurofibromatosis type 1.

OBJECTIVE: To evaluate the predictive utility of the number and morphologic appearance of isolated café au lait macules (CALMs) in establishing the diagnosis of neurofibromatosis type 1 (NF1) in a cohort of children referred to an NF1 subspecialty clinic. DESIGN: Retrospective study of patients seen between the years 2004 and 2007. SETTING: Tertiary care neurofibromatosis referral clinic at St Louis Children's Hospital. Patients The study population comprised 110 patients who presented with CALMs and no other diagnostic features of NF1. The median number of CALMs at initial presentation was 6, while the median age of the patients was 33 months. The median age at the last follow-up examination was 76.5 months. MAIN OUTCOME MEASURES: Number and morphologic appearance of CALMs and diagnosis of NF1. RESULTS: Thirty-four of the children met diagnostic criteria for NF1 during the study period. Thirty-two children met criteria prior to age 72 months, and 2 children met criteria after 72 months. The mean number of CALMs at presentation in children eventually diagnosed as having NF1 (11.8 CALMs) was significantly higher than the mean number of CALMs in children not diagnosed as having NF1 (4.6 CALMs). Of the 44 children who had 6 or more typical CALMs at presentation, 34 children met criteria for NF1. Sixty-eight patients had CALMs described as "typical," while 42 patients had "atypical" CALMs. Only 2 patients with atypical CALMs met criteria for NF1. Conclusion The majority of patients with 6 or more CALMs will eventually meet diagnostic criteria for NF1, typically by age 6 years, and this likelihood increases with increasing number and typical morphologic appearance of CALMs.

Gliomas in patients with neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1) is an inherited autosomal dominant disorder characterized by numerous cutaneous features, including café-au-lait macules, skinfold freckling and iris hamartomas. In addition, individuals with NF1 are prone to the development of both benign and malignant tumors. The most common CNS tumor in children and adults with NF1 is the glioma. In childhood, gliomas are primarily located in the optic pathway, and less frequently in the hypothalamus and brainstem. Regular ophthalmologic evaluations in children are essential for the effective management of these tumors in patients with NF1. Adults, in contrast, are more likely to develop higher grade gliomas, which are treated in a similar fashion as their sporadic counterparts.