Neuroimaging in insomnia: Review and reconsiderations.

Over the last decades, neuroimaging has become a substantial component of insomnia research. While theoretical underpinnings of different studies vary just like methodological choices and the experimental design, it is suggested that major features of insomnia disorder rely on the impaired function, structure, metabolism and connectivity of brain areas involved in sleep generation, emotion regulation, self-processing/-awareness and attentional orientation. However, neuroimaging research on insomnia often suffers from small sample sizes, heterogeneous methodology and a lack of replicability. With respect to these issues, the field needs to address the questions: (1a) how sufficiently large sample sizes can be accumulated within a reasonable economic framework; (1b) how effect sizes in insomnia-related paradigms can be amplified; (2a) how a higher degree of standardisation and transparency in methodology can be provided; and (2b) how an adequate amount of flexibility/complexity in study design can be maintained. On condition that methodological consistency and a certain degree of adaptability are given, pooled data/large cohort analyses can be considered to be one way to answer these questions. Regarding experimental single-centre trials, it might be helpful to focus on insomnia-related transdiagnostic concepts. In doing so, expectable effect sizes (in between-subjects designs) can be increased by: (a) comparing groups that are truly distinct regarding the variables examined in a concept-specific paradigm; and (b) facilitated, intensified and precise elicitation of a target symptom.

Associations between sleep health and grey matter volume in the UK Biobank cohort (n = 33 356).

As suggested by previous research, sleep health is assumed to be a key determinant of future morbidity and mortality. In line with this, recent studies have found that poor sleep is associated with impaired cognitive function. However, to date, little is known about brain structural abnormalities underlying this association. Although recent findings link sleep health deficits to specific alterations in grey matter volume, evidence remains inconsistent and reliant on small sample sizes. Addressing this problem, the current preregistered study investigated associations between sleep health and grey matter volume (139 imaging-derived phenotypes) in the UK Biobank cohort (33 356 participants). Drawing on a large sample size and consistent data acquisition, sleep duration, insomnia symptoms, daytime sleepiness, chronotype, sleep medication and sleep apnoea were examined. Our main analyses revealed that long sleep duration was systematically associated with larger grey matter volume of basal ganglia substructures. Insomnia symptoms, sleep medication and sleep apnoea were not associated with any of the 139 imaging-derived phenotypes. Short sleep duration, daytime sleepiness as well as late and early chronotype were associated with solitary imaging-derived phenotypes (no recognizable pattern, small effect sizes). To our knowledge, this is the largest study to test associations between sleep health and grey matter volume. Clinical implications of the association between long sleep duration and larger grey matter volume of basal ganglia are discussed. Insomnia symptoms as operationalized in the UK Biobank do not translate into grey matter volume findings.

Sleep health dimensions and shift work as longitudinal predictors of cognitive performance in the UK Biobank cohort.

STUDY OBJECTIVES: The long-term effects of sleep health and shift work on cognitive performance are unclear. In addition, research has been limited by small sample sizes and short follow-up periods. We conducted one of the largest examinations of the longitudinal influence of sleep health dimensions and shift work on cognitive performance in people of middle and old age using data from the UK Biobank. The hypothesis was that poor sleep health and shift work would predict lower cognitive performance. METHODS: Self-reported sleep duration, daytime sleepiness, insomnia symptoms, chronotype, and shift work status were assessed as predictors at baseline. Cognitive performance was operationalized by a touchscreen test battery at follow-up between 7.4 ±â€…2.2 and 9.0 ±â€…0.9 years after baseline assessment, depending on the specific task. Models were performed for each cognitive domain including relevant confounders (e.g. depression). The alpha level was set at p < 0.01 for all analyzes. RESULTS: The study sample comprised 9394 participants for the reasoning task, 30 072 for the reaction time task, 30 236 for the visual memory task, 2019 for the numeric memory task, and 9476 for the prospective memory task. Shift work without night shifts (ß = -2.0 × 10-1 ± 6.5 × 10-2, p = 0.002) and with night shifts (ß = -1.9 × 10-1 ± 7.2 × 10-2, p = 0.010) predicted a significantly reduced performance in the reasoning task. Short sleep duration (ß = -2.4 × 10-1 ± 7.9 × 10-2, p = 0.003) and shift work without night shifts (ß = -3.9 × 10-1 ± 1.2 × 10-1, p = 0.002) predicted a significantly lower performance in the task probing prospective memory. CONCLUSIONS: Our results suggest that, after controlling for confounding variables, shift work, and short sleep duration are important predictors for cognitive performance in people of middle and old age. Further work is required to examine causal mechanisms of the observed associations.

Lack of structural brain alterations associated with insomnia: findings from the ENIGMA-Sleep Working Group.

Existing neuroimaging studies have reported divergent structural alterations in insomnia disorder (ID). In the present study, we performed a large-scale coordinated meta-analysis by pooling structural brain measures from 1085 subjects (mean [SD] age 50.5 [13.9] years, 50.2% female, 17.4% with insomnia) across three international Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA)-Sleep cohorts. Two sites recruited patients with ID/controls: Freiburg (University of Freiburg Medical Center, Freiburg, Germany) 42/43 and KUMS (Kermanshah University of Medical Sciences, Kermanshah, Iran) 42/49, while the Study of Health in Pomerania (SHIP-Trend, University Medicine Greifswald, Greifswald, Germany) recruited population-based individuals with/without insomnia symptoms 75/662. The influence of insomnia on magnetic resonance imaging-based brain morphometry using an insomnia brain score was then assessed. Within each cohort, we used an ordinary least-squares linear regression to investigate the link between the individual regional cortical and subcortical volumes and the presence of insomnia symptoms. Then, we performed a fixed-effects meta-analysis across cohorts based on the first-level results. For the insomnia brain score, weighted logistic ridge regression was performed on one sample (Freiburg), which separated patients with ID from controls to train a model based on the segmentation measurements. Afterward, the insomnia brain scores were validated using the other two samples. The model was used to predict the log-odds of the subjects with insomnia given individual insomnia-related brain atrophy. After adjusting for multiple comparisons, we did not detect any significant associations between insomnia symptoms and cortical or subcortical volumes, nor could we identify a global insomnia-related brain atrophy pattern. Thus, we observed inconsistent brain morphology differences between individuals with and without insomnia across three independent cohorts. Further large-scale cross-sectional/longitudinal studies using both structural and functional neuroimaging are warranted to decipher the neurobiology of insomnia.

Associations between insomnia symptoms and functional connectivity in the UK Biobank cohort (n = 29,423).

An increasing number of studies harness resting-state fMRI functional connectivity analysis to investigate the neurobiological mechanisms of insomnia. The results to date are inconsistent and the detection of minor and widely distributed alterations in functional connectivity requires large sample sizes. The present study investigated associations between insomnia symptoms and resting-state functional connectivity at the whole-brain level in the largest sample to date. This cross-sectional analysis used resting-state imaging data from the UK Biobank, a large scale, population-based biomedical database. The analysis included 29,423 participants (age: 63.1 ± 7.5 years, 54.3% female), comprising 9210 with frequent insomnia symptoms and 20,213 controls without. Linear models were adjusted for relevant clinical, imaging, and socio-demographic variables. The Akaike information criterion was used for model selection. Multiple comparisons were corrected using the false discovery rate with a significance level of q < 0.05. Frequent insomnia symptoms were associated with increased connectivity within the default mode network and frontoparietal network, increased negative connectivity between the default mode network and the frontoparietal network, and decreased connectivity between the salience network and a node of the default mode network. Furthermore, frequent insomnia symptoms were associated with altered functional connectivity between nodes comprising sensory areas and the cerebellum. These functional alterations of brain networks may underlie dysfunctional affective and cognitive processing in insomnia and contribute to subjectively and objectively impaired sleep. However, it must be noted that the item that was used to assess frequent insomnia symptoms in this study did not assess all the characteristics of clinically diagnosed insomnia.

Comparative effectiveness of three versions of a stepped care model for insomnia differing in the amount of therapist support in internet-delivered treatment: study protocol for a pragmatic cluster randomised controlled trial (GET Sleep).

INTRODUCTION: It is unclear how internet-delivered cognitive-behavioural therapy for insomnia (CBT-I) can be integrated into healthcare systems, and little is known about the optimal level of therapist guidance. The aim of this study is to investigate three different versions of a stepped care model for insomnia (IG1, IG2, IG3) versus treatment as usual (TAU). IG1, IG2 and IG3 rely on treatment by general practitioners (GPs) in the entry level and differ in the amount of guidance by e-coaches in internet-delivered CBT-I. METHODS AND ANALYSIS: In this randomised controlled trial, 4268 patients meeting International Classification of Diseases, Tenth Revision (ICD-10) criteria for insomnia will be recruited. The study will use cluster randomisation of GPs with an allocation ratio of 3:3:3:1 (IG1, IG2, IG3, TAU). In step 1 of the stepped care model, GPs will deliver psychoeducational treatment; in step 2, an internet-delivered CBT-I programme will be used; in step 3, GPs will refer patients to specialised treatment. Outcomes will be collected at baseline, and 4 weeks, 12 weeks and 6 months after baseline assessment. The primary outcome is insomnia severity at 6 months. An economic evaluation will be conducted and qualitative interviews will be used to explore barriers and facilitators of the stepped care model. ETHICS AND DISSEMINATION: The study protocol was approved by the Ethics Committee of the Medical Centre-University of Freiburg. The results of the study will be published irrespective of the outcome. TRIAL REGISTRATION NUMBER: DRKS00021503.

Associations Between Sleep Health and Amygdala Reactivity to Negative Facial Expressions in the UK Biobank Cohort.

BACKGROUND: Sleep health (SH) is considered a key determinant of human physiological and psychological well-being. In line with this, previous studies have found that poor sleep is associated with various psychiatric disorders, in particular, with anxiety and depression. Although little is known about the neural mechanisms underlying these associations, recent findings suggest that essential dimensions of SH are associated with altered amygdala reactivity (AR); however, evidence to date is inconsistent and reliant on small sample sizes. METHODS: To address this problem, the current preregistered study investigated associations between SH and AR to negative facial expressions in the UK Biobank cohort (25,758 participants). Drawing on a large sample size and consistent data acquisition, 5 dimensions of SH (insomnia symptoms, sleep duration, daytime sleepiness, chronotype, and sleep medication) were examined. RESULTS: Exploratory analyses revealed that short sleep duration was associated with decreased AR. The remaining SH dimensions and a composite measure of all SH dimensions were not associated with AR. CONCLUSIONS: To our knowledge, this is the largest study to test associations between SH and AR. Habitual short sleep duration may be associated with decreased AR, possibly indicating compensation for impaired prefrontal processes and hampered emotion regulation.

To Regulate or Not to Regulate: Emotion Regulation in Participants With Low and High Impulsivity.

Successful emotion regulation plays a key role in psychological health and well-being. This study examines (1) whether cognitive control and corresponding neural connectivity are associated with emotion regulation and (2) to what extent external instructions can improve emotion regulation in individuals with low vs. high cognitive control capacity. For this, emotion regulation capabilities and the impact of emotion regulation on a subsequent emotional Stroop task was tested in participants with low (N = 25) vs. high impulsivity (N = 32). The classification according to impulsivity is based upon the stable correlation between high impulsivity and reduced cognitive control capacity. A negative emotion inducing movie scene was presented with the instruction to either suppress or allow all emotions that arose. This was followed by an emotional Stroop task. Electromyography (EMG) over the corrugator supercilii was used to assess the effects of emotion regulation. Neurophysiological mechanisms were measured using functional near-infrared spectroscopy over frontal brain areas. While EMG activation was low in the low-impulsive group independent of instruction, high-impulsive participants showed increased EMG activity when they were not explicitly instructed to suppress arising emotions. Given the same extent of functional connectivity within frontal lobe networks, the low-impulsive participants controlled their emotions better (less EMG activation) than the high-impulsive participants. In the Stroop task, the low-impulsive subjects performed significantly better. The emotion regulation condition had no significant effect on the results. We conclude that the cognitive control network is closely associated with emotion regulation capabilities. Individuals with high cognitive control show implicit capabilities for emotion regulation. Individuals with low cognitive control require external instructions (= explicit emotion regulation) to achieve similarly low expressions of emotionality. Implications for clinical applications aiming to improve emotion regulation are discussed.

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.