Transcranial Magnetic Stimulation of the Default Mode Network to Improve Sleep in Individuals With Insomnia Symptoms: Protocol for a Double-Blind Randomized Controlled Trial.

BACKGROUND: Cortical hyperarousal and ruminative thinking are common aspects of insomnia that have been linked with greater connectivity in the default mode network (DMN). Therefore, disrupting network activity within the DMN may reduce cortical and cognitive hyperarousal and facilitate better sleep. OBJECTIVE: This trial aims to establish a novel, noninvasive method for treating insomnia through disruption of the DMN with repetitive transcranial magnetic stimulation, specifically with continuous theta burst stimulation (cTBS). This double-blind, pilot randomized controlled trial will assess the efficacy of repetitive transcranial magnetic stimulation as a novel, nonpharmacological approach to improve sleep through disruption of the DMN prior to sleep onset for individuals with insomnia. Primary outcome measures will include assessing changes in DMN functional connectivity before and after stimulation. METHODS: A total of 20 participants between the ages of 18 to 50 years with reported sleep disturbances will be recruited as a part of the study. Participants will then conduct an in-person screening and follow-on enrollment visit. Eligible participants then conduct at-home actigraphic collection until their first in-residence overnight study visit. In a double-blind, counterbalanced, crossover study design, participants will receive a 40-second stimulation to the left inferior parietal lobule of the DMN during 2 separate overnight in-residence visits. Participants are randomized to the order in which they receive the active stimulation and sham stimulation. Study participants will undergo a prestimulation functional magnetic resonance imaging scan and a poststimulation functional magnetic resonance imaging scan prior to sleep for each overnight study visit. Sleep outcomes will be measured using clinical polysomnography. After their first in-residence study visit, participants conduct another at-home actigraphic collection before returning for their second in-residence overnight study visit. RESULTS: Our study was funded in September 2020 by the Department of Defense (W81XWH2010173). We completed the enrollment of our target study population in the October 2022 and are currently working on neuroimaging processing and analysis. We aim to publish the results of our study by 2024. Primary neuroimaging outcome measures will be tested using independent components analysis, seed-to-voxel analyses, and region of interest to region of interest analyses. A repeated measures analysis of covariance (ANCOVA) will be used to assess the effects of active and sham stimulation on sleep variables. Additionally, we will correlate changes in functional connectivity to polysomnography-graded sleep. CONCLUSIONS: The presently proposed cTBS protocol is aimed at establishing the initial research outcomes of the effects of a single burst of cTBS on disrupting the network connectivity of the DMN to improve sleep. If effective, future work could determine the most effective stimulation sites and administration schedules to optimize this potential intervention for sleep problems. TRIAL REGISTRATION: ClinicalTrials.gov NCT04953559; https://clinicaltrials.gov/ct2/show/NCT04953559. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/51212.

Intraindividual variability in sleep duration and college degree attainment.

The objective of the current study was to examine the relationship between sleep characteristics and college degree attainment. Participants were 968 college students (72% female; mean age 19.7 [1.7]). Participants completed a psychosocial and sleep questionnaire battery followed by one week of daily sleep diaries. Academic degree completion data was obtained from the university registrar 10 years later. Logistic regression examined whether mean and variability in sleep duration and sleep efficiency and insomnia symptoms predicted degree attainment, adjusting for age, gender, semester, grade point average (GPA), and perceived stress. The strongest predictors of degree attainment were female gender (OR = 0.67), greater age (OR = 1.32), GPA (OR = 1.97), and lower intraindividual variability in sleep duration (OR = 0.99). Results highlight the importance of examining variability in sleep duration in addition to mean sleep duration in predicting college retention. Future research should use a combination of objective and subjective measures to explore the impact of sleep factors, including variability, on degree completion and other academic metrics.

Functional connectivity of the default mode network predicts subsequent polysomnographically measured sleep in people with symptoms of insomnia.

Insomnia is often accompanied by excessive pre-sleep rumination. Such ruminative thinking is also associated with increased connectivity of the default mode network (DMN). It is likely that DMN connectivity and associated rumination contribute to the pathogenesis of insomnia. We hypothesized that resting state functional connectivity (rsFC) between the DMN and other brain regions prior to bedtime would predict objectively measured sleep among individuals with insomnia. Twenty participants (12 female; M age = 26.9, SD = 6.6 years) with symptoms of insomnia underwent an rsFC scan in the early evening followed by a night of polysomographically (PSG) measured sleep. Connectivity of the DMN with other brain regions was regressed against several PSG sleep metrics, including time in wake, N1, N2, N3, REM, total sleep time (TST), and sleep efficiency (SE) at a cluster corrected false discovery rate (FDR) correction P < 0.05. The connectivity between DMN and cortical regions was negatively correlated with PSG indices of poorer sleep including time in wake (right angular gyrus) and N1 (precuneus) but positively correlated with time in REM (orbitofrontal cortex), TST (insula, orbitofrontal cortex, superior frontal gyrus, paracingulate gyrus), SE (orbitofrontal cortex). Connectivity between DMN and the pons was negatively correlated with SE. Among individuals with symptoms of insomnia, better sleep was predicted by rsFC between the DMN and cortical regions involved in executive functioning, consciousness, and complex cognition. Findings raise the possibility that future interventions aimed at suppressing pre-sleep DMN activation may weaken synergy between pre-sleep ruminative worry and complex cognitions, potentially ameliorating problems falling asleep.

A non-pharmacological multi-modal therapy to improve sleep and cognition and reduce mild cognitive impairment risk: Design and methodology of a randomized clinical trial.

Aging populations are at increased risk of sleep deficiencies (e.g., insomnia) that are associated with a variety of chronic health risks, including Alzheimer's disease and related dementias (ADRD). Insomnia medications carry additional risk, including increased drowsiness and falls, as well as polypharmacy risks. The recommended first-line treatment for insomnia is cognitive behavioral therapy for insomnia (CBTi), but access is limited. Telehealth is one way to increase access, particularly for older adults, but to date telehealth has been typically limited to simple videoconferencing portals. While these portals have been shown to be non-inferior to in-person treatment, it is plausible that telehealth could be significantly improved. This work describes a protocol designed to evaluate whether a clinician-patient dashboard inclusive of several user-friendly features (e.g., patterns of sleep data from ambulatory devices, guided relaxation resources, and reminders to complete in-home CBTi practice) could improve CBTi outcomes for middle- to older-aged adults (N = 100). Participants were randomly assigned to one of three telehealth interventions delivered through 6-weekly sessions: (1) CBTi augmented with a clinician-patient dashboard, smartphone application, and integrated smart devices; (2) standard CBTi (i.e., active comparator); or (3) sleep hygiene education (i.e., active control). All participants were assessed at screening, pre-study evaluation, baseline, throughout treatment, and at 1-week post-treatment. The primary outcome is the Insomnia Severity Index. Secondary and exploratory outcomes span sleep diary, actiwatch and Apple watch assessed sleep parameters (e.g., efficiency, duration, timing, variability), psychosocial correlates (e.g., fatigue, depression, stress), cognitive performance, treatment adherence, and neurodegenerative and systemic inflammatory biomarkers.

Internal consistency reliability of mental health questionnaires in college student athletes.

OBJECTIVES: To examine the internal consistency reliability and measurement invariance of a questionnaire battery designed to identify college student athletes at risk for mental health symptoms and disorders. METHODS: College student athletes (N=993) completed questionnaires assessing 13 mental health domains: strain, anxiety, depression, suicide and self-harm ideation, sleep, alcohol use, drug use, eating disorders, attention deficit hyperactivity disorder (ADHD), bipolar disorder, post-traumatic stress disorder (PTSD), gambling and psychosis. Internal consistency reliability of each measure was assessed and compared between sexes as well as to previous results in elite athletes. Discriminative ability analyses were used to examine how well the cut-off score on the strain measure (Athlete Psychological Strain Questionnaire) predicted cut-offs on other screening questionnaires. RESULTS: Strain, anxiety, depression, suicide and self-harm ideation, ADHD, PTSD and bipolar questionnaires all had acceptable or better internal consistency reliability. Sleep, gambling and psychosis questionnaires had questionable internal consistency reliability, although approaching acceptable for certain sex by measure values. The athlete disordered eating measure (Brief Eating Disorder in Athletes Questionnaire) had poor internal consistency reliability in males and questionable internal consistency reliability in females. CONCLUSIONS: The recommended mental health questionnaires were generally reliable for use with college student athletes. To truly determine the validity of the cut-off scores on these self-report questionnaires, future studies need to compare the questionnaires to a structured clinical interview to determine the discriminative abilities.

"Generalized unsafety" as fear inhibition to safety signals in adults with and without childhood trauma.

The Generalized Unsafety Theory of Stress posits that low heart rate variability contributes to a perception of "generalized unsafety" (i.e., constantly perceiving oneself to be unsafe), independent of stressful events or stress-related symptomatology. We tested this claim by examining if resting heart rate variability, trait worry, posttraumatic stress symptoms, trauma history, and age of onset predicted fear inhibition, a measure of generalized unsafety. A Pavlovian discriminant conditioning paradigm was used to assess fear inhibition level by comparing eyeblink startle potentiation to a threat cue (presented with air blast) with startle potentiation to a safety signal (never presented with air blast). Survey and laboratory responses were collected from 42 adults who were 20 years old on average, 86% Women, and 76% White. Heart rate variability did not independently predict variation in fear inhibition, as hypothesized. Rather, higher levels of posttraumatic stress symptoms and greater cumulative interpersonal trauma predicted lower fear inhibition. Individuals reporting childhood trauma had higher trait worry, which predicted more severe posttraumatic stress symptoms. These findings highlight the role of attenuated inhibitory learning in stress-related symptomatology and developmentally disruptive trauma. Ability to distinguish threat from safety is a plausible biobehavioral mechanism by which adversity impacts development.

Sex and region-specific effects of variable stress on microglia morphology.

Major Depressive Disorder (MDD) is a common and debilitating mood disorder that is more prevalent in women than men. In humans, PET imaging of microglia activation is currently being explored as a potential biomarker of MDD and suicidal ideation. Stress is a trigger for many mood disorders, including MDD. Microglial changes in morphology and activation state in response to stress has been reported in various brain regions, but most studies only examined male subjects. Here we report changes in microglia morphology in the nucleus accumbens (NAc) and subregions of the hippocampus (HPC) in both male and female mice following variable stress of 6 or 28 days in duration. Our data demonstrate that after 6 days of stress, microglia in the female NAc and dentate gyrus have a reduction in homeostatic associated morphology and an increase in primed microglia. After 28 days some of these sex specific stress effects were still present in microglia within the NAc but not the dentate gyrus. There were no effects of stress in either sex at either timepoint in CA1. In female mice, anti-inflammatory activation of microglia using rosiglitazone promoted sociability behavior after 6 days of stress. Furthermore, both drug and stress have impact on microglia morphology and activation state in the NAc. These data suggest that microglia morphology and activation state are altered by 6 days of variable stress in a region-specific manner and may contribute to, or potentially compensate for, the onset of stress susceptibility rather than impacting long term exposure to stress.