Background Insomnia Disorder (ID) is the second-most prevalent mental disorder and a primary risk factor for depression. Inconsistent clinical and biomarker findings suggest heterogeneity and unrecognized subtypes. Previous top-down proposed subtypes had insufficient validity. The present large-scale study aimed to reveal robust subtypes using data-driven analyses on a high-dimensional set of biologically based traits. Methods Netherlands Sleep Registry participants (N=4,322; 2,224 with probable ID) completed up to 34 trait questionnaires. ID subtypes were identified using latent class analyses. Validity was evaluated in an independent sample and by assessing within-subject stability over years. Clinical relevance was extensively assessed in all subtypes for the development of sleep complaints, comorbidities including depression and response to benzodiazepines, and in two subtypes for an EEG biomarker and effectiveness of cognitive behavioral therapy. To facilitate implementation, a concise subtype questionnaire was constructed and validated in an independent sample. Outcomes Five novel ID subtypes were identified: one labelled as highly distressed, two as moderately distressed with either intact or weak responses to pleasurable emotions, and two as low distressed with either high or low reactivity to environment and life time events. A participant could be classified with high probability to only one subtype, and also in an independent replication sample five subtypes were again optimal (posterior probabilities 0•91-1•00). Participants reassessed 4•8±1•6 years later (N=215) maintained their subtype with high probability (0•87); indicating high stability. Clinical relevance showed from subtype differences in developmental etiology, response to treatment, an EEG biomarker, and up to five-fold differing risk of depression. Interpretation High-dimensional data-driven subtyping of people with insomnia solved an unmet need of heterogeneity reduction. Subtyping facilitates progress in finding mechanisms, developing personalized treatment, and selecting cases with the highest risk of depression for inclusion in preventive trials. Funding European Research Council (ERC-ADG-2014-671084-INSOMNIA); Netherlands Organization for Scientific Research (VICI-453-07-001). 4322 Sleep Registry database search for ISI and one additional questionnaire completed 2224 probable ID; Latent Class Analysis 2098 excluded ISI < 10 control reference values 1046 probable ID; subtype profiles and interpretation 1178 excluded for interpretation completed < 10 questionnaires 215 probable ID; Latent Transition Analysis 831 lost to follow-up 614 Sleep Registry database search for completed Insomnia Type Questionnaire and ISI 251 independent non-overlapping probable ID; Latent Class Analysis 363 excluded were included in original probable ID sample to develop model 244 received DSM-5 face-to-face diagnosis to validate ISI cutoff

People with insomnia show insufficient adaptation of their brain responses to the ever-present heartbeats. Abnormalities in the neural circuits involved in interoceptive awareness including the salience network may be of key importance to the pathophysiology of insomnia.

Insomnia and chronic pain are highly prevalent conditions and are often comorbid. Somatic complaints other than pain are also often observed in insomnia. Poor sleep and pain are known to mutually reinforce each other. However, it is unknown whether the habitual severity of insomnia modulates the acute effect of a particularly bad night's sleep on the next day's pain severity, and whether it modulates the acute effect of pain on the following night's sleep quality. Using data from 3,508 volunteers (2,684 female, mean age 50.09 y), we addressed these questions in addition to the associations between the habitual severity of insomnia, somatic complaints, and pain. Results indicated that people suffering from more severe habitual insomnia showed stronger mutual acute within-day reactivity of pain and poor sleep quality. The same increased reactivity was found in people with more severe habitual pain. Interestingly, the acute within-day mutual reactivity of pain and sleep quality showed consistent asymmetry. Pain worsened more after a particularly bad night's sleep than it improved after a particularly good night's sleep. Likewise, sleep worsened more after a day with more-than-usual pain than it improved after a day with less-than-usual pain. Future interventions may profit from addressing this asymmetric mutual reactivity especially in people with severe comorbid insomnia and chronic pain.

The widespread high power in a broad beta band reported previously during sleep in insomnia is present as well during eyes closed wakefulness, suggestive of a round-the-clock hyperarousal. Low power in the upper alpha band during eyes open is consistent with low cortical inhibition and attentional filtering. The fine-grained HD-EEG findings suggest that, while more feasible than PSG, wake EEG of short duration with a few well-chosen electrodes and frequency bands, can provide valuable features of insomnia.

Quantification of sleep stage dynamics revealed a particular vulnerability of stage N2 in insomnia. The feature characterizes insomnia better than-and independently of-any conventional sleep parameter.

Summary 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.

The complaints of people suffering from Insomnia Disorder (ID) concern both sleep and daytime functioning. However, little is known about wake brain temporal dynamics in people with ID. We therefore assessed possible alterations in Long-Range Temporal Correlations (LRTC) in the amplitude fluctuations of band-filtered oscillations in electroencephalography (EEG) recordings. We investigated whether LRTC differ between cases with ID and matched controls. Within both groups, we moreover investigated whether individual differences in subjective insomnia complaints are associated with LRTC. Resting-state high-density EEG (256-channel) was recorded in 52 participants with ID and 43 age- and sex-matched controls, during Eyes Open (EO) and Eyes Closed (EC). Detrended fluctuation analysis was applied to the amplitude envelope of band-filtered EEG oscillations (theta, alpha, sigma, beta-1, beta-2) to obtain the Hurst exponents (H), as measures of LRTC. Participants rated their subjective insomnia complaints using the Insomnia Severity Index (ISI). Through general linear models, we evaluated whether H, aggregated across electrodes and frequencies, differed between cases and controls, or showed within-group associations with individual differences in ISI. Additionally, we characterized the spatio-spectral profiles of group differences and associations using non-parametric statistics. H did not differ between cases with ID and controls in any of the frequency bands, neither during EO nor EC. During EO, however, within-group associations between H and ISI indicated that individuals who experienced worse sleep quality had stronger LRTC. Spatio-spectral profiles indicated that the associations held most prominently for the amplitude fluctuations of parietal theta oscillations within the ID group, and of centro-frontal beta-1 oscillations in controls. While people suffering from insomnia experience substantially worse sleep quality than controls, their brain dynamics express similar strength of LRTC. In each group, however, individuals experiencing worse sleep quality tend to have stronger LRTC during eyes open wakefulness, in a spatio-spectral range specific for each group. Taken together, the findings indicate that subjective insomnia complaints involve distinct dynamical processes in people with ID and controls. The findings are in agreement with recent reports on decreasing LRTC with sleep depth, and with the hypothesis that sleep balances brain excitability.

People with Insomnia Disorder (ID) not only experience abundant nocturnal mentation, but also report altered spontaneous mental content during daytime wakefulness, such as an increase in bodily experiences (heightened somatic awareness). Previous studies have shown that resting-state EEG can be temporally partitioned into quasi-stable microstates, and that these microstates form a small number of canonical classes that are consistent across people. Furthermore, the microstate classes have been associated with individual differences in resting mental content including somatic awareness. To address the hypothesis that altered resting mental content in ID would be reflected in an altered representation of the corresponding EEG microstates, we analyzed resting-state high-density EEG of 32 people with ID and 32 age- and sex-matched controls assessed during 5-min eyes-closed wakefulness. Using data-driven topographical k-means clustering, we found that 5 microstate classes optimally explained the EEG scalp voltage map sequences across participants. For each microstate class, 3 dynamic features were obtained: mean duration, frequency of occurrence, and proportional coverage time. People with ID had a shorter mean duration of class C microstates, and more frequent occurrence of class D microstates. The finding is consistent with previously established associations of these microstate properties with somatic awareness, and increased somatic awareness in ID. EEG microstate assessment could provide objective markers of subjective experience dimensions in studies on consciousness during the transition between wake and sleep, when self-report is not possible because it would interfere with the very process under study. Addressing somatic awareness may benefit psychotherapeutic treatment of insomnia.