Cognitive, Behavioral, and Circadian Rhythm Interventions for Insomnia Alter Emotional Brain Responses.

BACKGROUND: The highest risk of depression is conveyed by insomnia. This risk can be mitigated by sleep interventions. Understanding brain mechanisms underlying increased emotional stability following insomnia treatment could provide insight relevant to the prevention of depression. Here, we investigated how different sleep interventions alter emotion-related brain activity in people with insomnia at high risk of developing depression. METHODS: Functional magnetic resonance imaging was used to assess how the amygdala response to emotional stimuli (negative facial expression) in 122 people with insomnia disorder differed from 36 control subjects and how the amygdala response changed after 6 weeks of either no treatment or internet-based circadian rhythm support (CRS), cognitive behavioral therapy for insomnia (CBT-I), or their combination (CBT-I+CRS). Effects on depression, insomnia and anxiety severity were followed up for 1 year. RESULTS: Only combined treatment (CBT-I+CRS) significantly increased the amygdala response, compared with no treatment, CBT-I, and CRS. Individual differences in the degree of response enhancement were associated with improvement of insomnia symptoms directly after treatment (r = -0.41, p = .021). Moreover, exclusively CBT-I+CRS enhanced responsiveness of the left insula, which occurred in proportion to the reduction in depressive symptom severity (r = -0.37, p = .042). CONCLUSIONS: This functional magnetic resonance imaging study on insomnia treatment, the largest to date, shows that a combined cognitive, behavioral, and circadian intervention enhances emotional brain responsiveness and might improve resilience in patients with insomnia who are at high risk of developing depression.

The role of brain white matter in depression resilience and response to sleep interventions.

Insomnia poses a high risk for depression. Brain mechanisms of sleep and mood improvement following cognitive behavioural therapy for insomnia remain elusive. This longitudinal study evaluated whether (i) individual differences in baseline brain white matter microstructure predict improvements and (ii) intervention affects brain white matter microstructure. People meeting the Diagnostic and Statistical Manual of Mental Disorders-5 criteria for Insomnia Disorder (n = 117) participated in a randomized controlled trial comparing 6 weeks of no treatment with therapist-guided digital cognitive behavioural therapy for insomnia, circadian rhythm support or their combination (cognitive behavioural therapy for insomnia + circadian rhythm support). Insomnia Severity Index and Inventory of Depressive Symptomatology-Self Report were assessed at baseline and followed up at Weeks 7, 26, 39 and 52. Diffusion-weighted magnetic resonance images were acquired at baseline and Week 7. Skeletonized white matter tracts, fractional anisotropy and mean diffusivity were quantified both tract-wise and voxel-wise using tract-based spatial statistics. Analyses used linear and mixed effect models while correcting for multiple testing using false discovery rate and Bonferroni for correlated endpoint measures. Our results show the following: (i) tract-wise lower fractional anisotropy in the left retrolenticular part of the internal capsule at baseline predicted both worse progression of depressive symptoms in untreated participants and more improvement in treated participants (fractional anisotropy × any intervention, PFDR = 0.053, Pcorr = 0.045). (ii) Only the cognitive behavioural therapy for insomnia + circadian rhythm support intervention induced a trend-level mean diffusivity decrease in the right superior corona radiata (PFDR = 0.128, Pcorr = 0.108), and individuals with a stronger mean diffusivity decrease showed a stronger alleviation of insomnia (R = 0.20, P = 0.035). In summary, individual differences in risk and treatment-supported resilience of depression involve white matter microstructure. Future studies could target the role of the left retrolenticular part of the internal capsule and right superior corona radiata and the brain areas they connect.

Actigraphy in studies on insomnia: Worth the effort?

In the past decades, actigraphy has emerged as a promising, cost-effective, and easy-to-use tool for ambulatory sleep recording. Polysomnography (PSG) validation studies showed that actigraphic sleep estimates fare relatively well in healthy sleepers. Additionally, round-the-clock actigraphy recording has been used to study circadian rhythms in various populations. To this date, however, there is little evidence that the diagnosis, monitoring, or treatment of insomnia can significantly benefit from actigraphy recordings. Using a case-control design, we therefore critically examined whether mean or within-subject variability of actigraphy sleep estimates or circadian patterns add to the understanding of sleep complaints in insomnia. We acquired actigraphy recordings and sleep diaries of 37 controls and 167 patients with varying degrees of insomnia severity for up to 9 consecutive days in their home environment. Additionally, the participants spent one night in the laboratory, where actigraphy was recorded alongside PSG to check whether sleep, in principle, is well estimated. Despite moderate to strong agreement between actigraphy and PSG sleep scoring in the laboratory, ambulatory actigraphic estimates of average sleep and circadian rhythm variables failed to successfully differentiate patients with insomnia from controls in the home environment. Only total sleep time differed between the groups. Additionally, within-subject variability of sleep efficiency and wake after sleep onset was higher in patients. Insomnia research may therefore benefit from shifting attention from average sleep variables to day-to-day variability or from the development of non-motor home-assessed indicators of sleep quality.

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.

Insomnia disorder: State of the science and challenges for the future.

Insomnia disorder comprises symptoms during night and day that strongly affect quality of life and wellbeing. Prolonged sleep latency, difficulties to maintain sleep and early morning wakening characterize sleep complaints, whereas fatigue, reduced attention, impaired cognitive functioning, irritability, anxiety and low mood are key daytime impairments. Insomnia disorder is well acknowledged in all relevant diagnostic systems: Diagnostic and Statistical Manual of the American Psychiatric Association, 5th revision, International Classification of Sleep Disorders, 3rd version, and International Classification of Diseases, 11th revision. Insomnia disorder as a chronic condition is frequent (up to 10% of the adult population, with a preponderance of females), and signifies an important and independent risk factor for physical and, especially, mental health. Insomnia disorder diagnosis primarily rests on self-report. Objective measures like actigraphy or polysomnography are not (yet) part of the routine diagnostic canon, but play an important role in research. Disease concepts of insomnia range from cognitive-behavioural models to (epi-) genetics and psychoneurobiological approaches. The latter is derived from knowledge about basic sleep-wake regulation and encompass theories like rapid eye movement sleep instability/restless rapid eye movement sleep. Cognitive-behavioural models of insomnia led to the conceptualization of cognitive-behavioural therapy for insomnia, which is now considered as first-line treatment for insomnia worldwide. Future research strategies will include the combination of experimental paradigms with neuroimaging and may benefit from more attention to dysfunctional overnight alleviation of distress in insomnia. With respect to therapy, cognitive-behavioural therapy for insomnia merits widespread implementation, and digital cognitive-behavioural therapy may assist delivery along treatment guidelines. However, given the still considerable proportion of patients responding insufficiently to cognitive-behavioural therapy for insomnia, fundamental studies are highly necessary to better understand the brain and behavioural mechanisms underlying insomnia. Mediators and moderators of treatment response/non-response and the associated development of tailored and novel interventions also require investigation. Recent studies suggest that treatment of insomnia may prove to add significantly as a preventive strategy to combat the global burden of mental disorders.

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).

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.

Brain structural correlates of insomnia severity in 1053 individuals with major depressive disorder: results from the ENIGMA MDD Working Group.

It has been difficult to find robust brain structural correlates of the overall severity of major depressive disorder (MDD). We hypothesized that specific symptoms may better reveal correlates and investigated this for the severity of insomnia, both a key symptom and a modifiable major risk factor of MDD. Cortical thickness, surface area and subcortical volumes were assessed from T1-weighted brain magnetic resonance imaging (MRI) scans of 1053 MDD patients (age range 13-79 years) from 15 cohorts within the ENIGMA MDD Working Group. Insomnia severity was measured by summing the insomnia items of the Hamilton Depression Rating Scale (HDRS). Symptom specificity was evaluated with correlates of overall depression severity. Disease specificity was evaluated in two independent samples comprising 2108 healthy controls, and in 260 clinical controls with bipolar disorder. Results showed that MDD patients with more severe insomnia had a smaller cortical surface area, mostly driven by the right insula, left inferior frontal gyrus pars triangularis, left frontal pole, right superior parietal cortex, right medial orbitofrontal cortex, and right supramarginal gyrus. Associations were specific for insomnia severity, and were not found for overall depression severity. Associations were also specific to MDD; healthy controls and clinical controls showed differential insomnia severity association profiles. The findings indicate that MDD patients with more severe insomnia show smaller surfaces in several frontoparietal cortical areas. While explained variance remains small, symptom-specific associations could bring us closer to clues on underlying biological phenomena of MDD.

Affect and Arousal in Insomnia: Through a Lens of Neuroimaging Studies.

PURPOSE OF REVIEW: Previous research has struggled with identifying clear-cut, objective counterparts to subjective distress in insomnia. Approaching this discrepancy with a focus on hyperarousal and dysfunctional affective processes, studies examining brain structures and neural networks involved in affect and arousal are reviewed and conclusions for an updated understanding of insomnia are drawn. RECENT FINDINGS: Recent studies found that amygdala reactivity, morphometry and adaptation in insomnia are altered, indicating that processing of negative stimuli is intensified and more lasting. Also, patients with insomnia show aberrant connectivity in the default mode network (DMN) and the salience network (SN), which is associated with subjective sleep disturbances, hyperarousal, maladaptive emotion regulation and disturbed integration of emotional states. The limbic circuit is assumed to play a crucial role in enhanced recall of negative experiences. There is reason to consider insomnia as a disorder of affect and arousal. Dysregulation of the limbic circuit might perpetuate impaired connectivity in the DMN and the SN. However, the interplay between the networks is yet to be researched.

ENIGMA MDD: seven years of global neuroimaging studies of major depression through worldwide data sharing.

A key objective in the field of translational psychiatry over the past few decades has been to identify the brain correlates of major depressive disorder (MDD). Identifying measurable indicators of brain processes associated with MDD could facilitate the detection of individuals at risk, and the development of novel treatments, the monitoring of treatment effects, and predicting who might benefit most from treatments that target specific brain mechanisms. However, despite intensive neuroimaging research towards this effort, underpowered studies and a lack of reproducible findings have hindered progress. Here, we discuss the work of the ENIGMA Major Depressive Disorder (MDD) Consortium, which was established to address issues of poor replication, unreliable results, and overestimation of effect sizes in previous studies. The ENIGMA MDD Consortium currently includes data from 45 MDD study cohorts from 14 countries across six continents. The primary aim of ENIGMA MDD is to identify structural and functional brain alterations associated with MDD that can be reliably detected and replicated across cohorts worldwide. A secondary goal is to investigate how demographic, genetic, clinical, psychological, and environmental factors affect these associations. In this review, we summarize findings of the ENIGMA MDD disease working group to date and discuss future directions. We also highlight the challenges and benefits of large-scale data sharing for mental health research.

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.

Consistent altered internal capsule white matter microstructure in insomnia disorder.

STUDY OBJECTIVES: Suggested neural correlates of insomnia disorder have been hard to replicate. Even the most consistent finding, altered white matter microstructure in the anterior limb of the internal capsule, is based on handful studies. The urge for replicable targets to understand the underlying mechanisms of insomnia made us study white matter fractional anisotropy (FA) across three samples of cases and controls. METHODS: 3-Tesla MRI diffusion tensor imaging data of three independent samples were combined for analysis, resulting in n = 137 participants, of whom 73 were diagnosed with insomnia disorder and 64 were matched controls without sleep complaints. Insomnia severity was measured with the Insomnia Severity Index (ISI). White matter microstructure was assessed with FA. White matter tracts were skeletonized and analyzed using tract-based spatial statistics. We performed a region-of-interest analysis using linear mixed-effect models to evaluate case-control differences in internal capsule FA as well as associations between internal capsule FA and insomnia severity. RESULTS: FA in the right limb of the anterior internal capsule was lower in insomnia disorder than in controls (ß = -9.76e-3; SE = 4.17e-3, p = .034). In the entire sample, a higher ISI score was associated with a lower FA value of the right internal capsule (ß = -8.05e- 4 FA/ISI point, SE = 2.60e- 4, p = .008). Ancillary whole brain voxel-wise analyses showed no significant group difference or association with insomnia severity after correction for multiple comparisons. CONCLUSIONS: The internal capsule shows small but consistent insomnia-related alterations. The findings support a circuit-based approach to underlying mechanisms since this tract connects many brain areas previously implicated in insomnia.

Reduced dynamic functional connectivity between salience and executive brain networks in insomnia disorder.

Research into insomnia disorder has pointed to large-scale brain network dysfunctions. Dynamic functional connectivity is instrumental to cognitive functions but has not been investigated in insomnia disorder. This study assessed between-network functional connectivity strength and variability in patients with insomnia disorder as compared with matched controls without sleep complaints. Twelve-minute resting-state functional magnetic resonance images and T1-weighed images were acquired in 65 people diagnosed with insomnia disorder (21-69 years, 48 female) and 65 matched controls without sleep complaints (22-70 years, 42 female). Pairwise correlations between the activity time series of 14 resting-state networks and temporal variability of the correlations were compared between cases and controls. After false discovery rate correction for multiple comparisons, people with insomnia disorder and controls did not differ significantly in terms of mean between-network functional connectivity strength; people with insomnia disorder did, however, show less functional connectivity variability between the anterior salience network and the left executive-control network. The finding suggests less flexible interactions between the networks during the resting state in people with insomnia disorder.

ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries.

This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of "big data" (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA's activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors.

Neuroimaging insights into the link between depression and Insomnia: A systematic review.

BACKGROUND: Insomnia is a common symptom of Major Depressive Disorder (MDD) and genome-wide association studies pointed to their strong genetic association. Although the prevalence of insomnia symptoms in MDD is noticeable and evidence supports their strong bidirectional association, the number of available neuroimaging findings on patients of MDD with insomnia symptoms is limited. However, such neuroimaging studies could verily improve our understanding of their shared pathophysiology and advance corresponding theories. METHODS: Based on the preferred reporting items for systematic reviews and meta-analysis (PRISMA) guideline, we have conducted a literature search using PubMed, EMBASE, and Scopus databases and systematically explored 640 studies using various neuroimaging modalities in MDD patients with different degrees of insomnia symptoms. RESULTS: Despite inconsistencies, current findings from eight studies suggested structural and functional disturbances in several brain regions including the amygdala, prefrontal cortex and anterior cingulate cortex and insula. The aberrant functional connectivity within and between the main hubs of the salience and default mode networks could potentially yield new insights into the link between MDD and insomnia, which needs further assessment. LIMITATIONS: The number of studies reviewed herein is limited. The applied methods for assessing structural and functional neural mechanisms of insomnia and depression were variable. CONCLUSION: Neuroimaging methods demonstrated the overlapping underlying neural mechanisms between MDD and insomnia. Future studies may facilitate better understanding of their pathophysiology to allow development of specific treatment.

Increased hippocampal-prefrontal functional connectivity in insomnia.

Insomnia Disorder (ID) is the second-most common mental disorder and has a far-reaching impact on daytime functioning. A meta-analysis indicates that, of all cognitive domains, declarative memory involving the hippocampus is most affected in insomnia. Hippocampal functioning has consistently been shown to be sensitive to experimental sleep deprivation. Insomnia however differs from sleep deprivation in many aspects, and findings on hippocampal structure and function have been equivocal. The present study used both structural and resting-state functional Magnetic Resonance Imaging in a larger sample than previously reported to evaluate hippocampal volume and functional connectivity in ID. Included were 65 ID patients (mean age = 48.3 y ±â€¯14.0, 17 males) and 65 good sleepers (mean age = 44.1 y ±â€¯15.2, 23 males). Insomnia severity was assessed with the Insomnia Severity Index (ISI), subjective sleep with the Consensus Sleep Diary (CSD) and objective sleep by two nights of polysomnography (PSG). Seed-based analysis showed a significantly stronger connectivity of the bilateral hippocampus with the left middle frontal gyrus in ID than in controls (p = .035, cluster based correction for multiple comparisons). Further analyses across all participants moreover showed that individual differences in the strength of this connectivity were associated with insomnia severity (ISI, r = 0.371, p = 9.3e-5) and with subjective sleep quality (CSD sleep efficiency, r = -0.307, p = .009) (all p FDR-corrected). Hippocampal volume did not differ between ID and controls. The findings indicate more severe insomnia and worse sleep quality in people with a stronger functional connectivity between the bilateral hippocampus and the left middle frontal gyrus, part of a circuit that characteristically activates with maladaptive rumination and deactivates with sleep.