The Hyperarousal Mechanism Underlying Insomnia

Insomnia disorder is the most common sleep disorder,and has become the second most prevalent mental disorder.One-third of the general population reports insomnia complaints and the diagnostic criteria for insomnia disorder are met by 10% of individuals.However,the pathophysiological mechanism underlying insomnia disorder has not been clarified.The clinical diagnoses of insomnia disorder are currently based on subjective reports during clinical interviews or on responses to self-report questionnaires,there is still no robust and reliable objective measures.As the core feature of insomnia,“hyperarousal” may be a key perspective to understand the pathophysiology of insomnia and promotes to obtain the objective measures.Therefore,the present thesis aimed to explore and determine the factors related to hyperarousal in insomnia disorder and then ascertain the reliable and convincing electrophysiological evidence associated with hyperarousal.We expected that the results would help to understandard the relationship between insomnia and hyperarousal,develop the objective assessment and diagnosis for insomnia disorder,and thus provide new hyperarousal-based treatment targets.The concept of hyperarousal covers cognitive or subjective indicators like worry,tention and rumination,as well as physiological indicators of somatic and cortical activity.Thus hyperarousal means a state of heightened tension and activity in cognitive,somatic,and cortical domains.The neurocognitive model speculates that three factors related to the hyperarousal of insomnia(predisposing factors,precipitating event and perpetuating factors),and the sleep interfering-interpreting process model proposes that several factors may directly lead to or be permissive of hyperarousal and these factors include arousibility,stimulus-arousal associations,behavioral and cognitive coping strategies and interpersonal relations.Other factors like attributions,perfectionism,beliefs about sleep,and daytime functioning may indirectly lead to hyperarousal through the sleep interpreting process.However,these hypotheses are still in the theoretical level and lack of empirical evidence.In addition,the neurocognitive model posits that cortical arousal is central to the pathophysiology of insomnia and exerts its deleterious effects on sleep initiation or maintenance through enhanced sensory processing and information processing.To address the above issues,this thesis designs 7 studies to investigate the psychophysiological factors related to hyperarousal,the resting-state electroencephalography(EEG)features of cortical hyperarousal and the role of cortical hyperarousal on attention control in insomnia individuals.The first part of the thesis examined the psychophysiological factors of hyperarousal in insomnia individuals by means of multiple linear regression analysis and network analysis.Based on the hypothesis-driven perspective and the results of previous studies,study 1 confirmed several important variables related to hyperarousal,including emotional factors like anxiety and depression,emotion regulation ability,perceived stress level,rumination,perfectionism and gender.The results of step-wise linear regression indicated that the significant predicting factors for hyperarousal included gender,perfectionism,rumination,and dysfunctional beliefs and attitudes about sleep.Perceived stress and emotional factors like anxiety and depression had no significant predictive effect on hyperarousal.Although we found the psychophysiological factors related to hyperarousal in study 1,it’s still unclear how these independent variables interact with each other and their interaction effect on dependent variables.Since linear regression should have to control the multicollinearity between independent variables,only a limited number of variables can be included into the linear model.Therefore,based on the data-driven perspective,we adopted the network analysis in study 2 to further explore how the predisposing,precipitating and perpetuating factors interact with each other,and further evaluate the role of hyperarousal in the overall network model.The results of study 2 indicated that the nodes that directly and positively correlated with hyperarousal included rumination,self-consciousness,perfectionism,fatigue,insomnia response to stress and dysfunctional beliefs and attitudes about sleep.The node with negative correlation was the type of circadian rhythms.There was no direct correlations between hyperarousal and the other variables,and the indirect relationship can be achieved by the moderation of rumination and self-related factors.As a hub node in the network model,hyperarousal played a pivotal influence in the overall network.Due to the possible overfitting of the linear model and the lack of robustness of the network model,we adopted another independent sample to validate the results,which indicated that the current results are reliable and convincing.In summary,the results of study 1 and study2 suggested that the psychophysiological factors related to hyperarousal included gender,more depression-related rumination,higher private and public self-consciousness,more perfectionism and fatigue,higher insomnia response to stress and dysfunctional beliefs and attitudes about sleep and late circadian rhythm.Hyperarousal interacted with these psychophysiological factors and formed the mutually reinforcing feedback loops.Although cortical arousal is central to the pathophysiology of insomnia,no effective and reliable objective measures had ever been obtained to assess it.Therefore,we conducted 2 studies to assess the power spectral features across different stages of sleep and wakefulness in patients with insomnia disorder,and to investigate the resting-state related EEG evidence for hyperarousal.The aim of study 3 was to explore the spectral features in patients with different insomnia duration during pre-sleep wakefulness.Results indicated that compared with good sleepers,patients with insomnia duration longer than 3 years presented decreased power spectral density in theta,alpha and beta,but patients with insomnia duration less than 3 years showed similar decreases only in alpha band.The results of study 3 indicated that insomnia duration may be an important factor related to EEG power spectra.But sudy 3 had the limited sample size and failed to investigate the EEG spectral features during sleep.Therefore,in study 4,we adopted a meta-analytic approach to systematically assess existing evidence of EEG spectral features in insomnia disorder during wakefulness and different sleep stages.Hedges’ s g was calculated by 148 effect sizes from 24 studies involving 977 participants.Our results demonstrated that,throughout wakefulness and sleep,patients with insomnia disorder exhibited increased beta band power,although such increases sometimes extended into neighboring frequency bands,which can be regard as the most robust and reliable biomarker for cortical hyperarousal.Patients with insomnia disorder also exhibited increased theta and gamma power during wakefulness,as well as increased alpha and sigma power during rapid eye movement(REM)sleep.In addition,insomnia disorder was associated with decreased delta power and increased theta,alpha,and sigma power during NREM sleep.The EEG measures of absolute and relative power have similar sensitivity in detecting spectral features of insomnia disorder during wakefulness and REM sleep.However,relative power appeared to be a more sensitive biomarker during NREM sleep.In summary,through the 2 studies of this section,we found that insomnia duration had an important effect on spectral features during pre-sleep wakefulness and increased beta activity can be regard as the reliable and convincing EEG biomarker for cortical hyperarousal in patients with insomnia disorder.The current results will accelerate the application of objective diagnosis for hyperarousal in insomnia disorder.In the task-related EEG section,we adopted the behavioral data and ERP method to examine the effect of cortical hyperarousal on attention control during pre-sleep wakefulness.By using different stimulus modality(visual and auditory),larger sample sizes,and finer insomnia subtype,we aimed to investigate the behavioral and ERP evidence related to cortical hyperarousal in Oddball task.The behavioral results of study 5 and 6 indicated no significant between-group difference for the accuracy rate and mean reaction time both in visual and auditory Oddball.The ERP results in study 6suggested that the increase of N100 peak amplitude may be the reliable evidence for the effect of cortical hyperarousal on attention control.However,we found only weak evidence of hyperarousal in N100 peak amplitude,previous studies also reported the ERP components like P200 and P300.The discrepancy may be related to the individual difference in insomnia suffers(i.e.,insomnia heterogeneity).Thus in study 7,we divided the insomnia patients of study 6 into 5 insomnia subtypes: highly distressed(subtype 1),moderately distressed but reward sensitive(subtype 2),moderately distressed and reward insensitive(subtype 3),slightly distressed with high reactivity(subtype 4),slightly distressed with low reactivity(subtype 5).Consistent with our hypothesis,different insomnia subtypes exhibited different Oddball ERP features.Specifically,pre-sleep hyperarousal is one of the most obvious symptoms in subtype 1,subtpe 2 and subtype 3,and this symptom can be measured by the increase of N100 amplitude.Subtype 3 also showed decreased amplitude in P200 and P300,suggesting that this subtype is the most obvious group with hyperarousal and dysfunctional attention control.Subtype 4 showed increased P300 amplitude in standard tones when compared with good sleepers and this ERP feature is consistent with their high reactivity.No significant between-group differences were found in insomnia subtype 5,suggesting the limited hyperarousal effects on attention control in this subtype.Through integrating the results of these three sections,this thesis provides supplementary and new evidence for the hyperarousal mechanism of insomnia.First,based on multiple linear regression and network analysis,we found that the psychophysiological factors related to hyperarousal included gender,more depression-related rumination,higher private and public self-consciousness,more perfectionism and fatigue,higher insomnia response to stress and dysfunctional beliefs and attitudes about sleep and late circadian rhythm.Hyperarousal interacted with these psychophysiological factors and formed the mutually reinforcing feedback loops.Hyperarousal played a pivotal role in the insomnia-related psychophysiological network and was a hub node with higher expected influence.Second,the results of meta-analysis indicated that throughout wakefulness and sleep,patients with ID exhibited increased beta band power,which can be regard as the most robust and reliable biomarker for cortical hyperarousal in insomnia disorder.The results strongly support the notion that insomnia manifest as round-the-clock hyperarousal.Finally,the results of study 5 and study 6 indicated that the behavioral measures were not sensitive enough to detect the hyperarousal effect on attention control.The sensitivity of Oddball ERPs was susceptible to insomnia heterogeneity.When analyzing the Oddball ERPs in different insomnia subtypes,we found that there were indeed ERP evidence for the effect of hyperarousal on attention in subtype 1,subtype 2 and subtype 3.In addition,we also found the ERP evidence of dysfunctional attention control in insomnia subtype 3,and the evidence of high reactivity in insomnia subtype 4.In summary,the thesis systematically investigated the psychophysiological factors related to hyperarousal in insomnia individuals,found the resting state EEG indicators to quantify cortical hyperarousal in insomnia patients,and evaluated the effects of cortical hyperarousal on attentional control.All these results provide empirical evidence and strong supports for the neurocognitive model of insomnia.The thesis will promote the application of hyperarousal-based objective diagnosis and assessment in insomnia disorder,and establish the new treatment targets and evaluations based on hyperarousal.