Enhanced cerebral blood flow similarity of the somatomotor network in chronic insomnia: Transcriptomic decoding, gut microbial signatures and phenotypic roles.

Chronic insomnia (CI) is a complex disease involving multiple factors including genetics, gut microbiota, and brain structure and function. However, there lacks a unified framework to elucidate how these factors interact in CI. By combining data of clinical assessment, sleep behavior recording, cognitive test, multimodal MRI (structural, functional, and perfusion), gene, and gut microbiota, this study demonstrated that enhanced cerebral blood flow (CBF) similarities of the somatomotor network (SMN) acted as a key mediator to link multiple factors in CI. Specifically, we first demonstrated that only CBF but not morphological or functional networks exhibited alterations in patients with CI, characterized by increases within the SMN and between the SMN and higher-order associative networks. Moreover, these findings were highly reproducible and the CBF similarity method was test-retest reliable. Further, we showed that transcriptional profiles explained 60.4 % variance of the pattern of the increased CBF similarities with the most correlated genes enriched in regulation of cellular and protein localization and material transport, and gut microbiota explained 69.7 % inter-individual variance in the increased CBF similarities with the most contributions from Negativicutes and Lactobacillales. Finally, we found that the increased CBF similarities were correlated with clinical variables, accounted for sleep behaviors and cognitive deficits, and contributed the most to the patient-control classification (accuracy = 84.4 %). Altogether, our findings have important implications for understanding the neuropathology of CI and may inform ways of developing new therapeutic strategies for the disease.

Functional MRI-based biomarkers of insomnia with objective short sleep duration phenotype.

BACKGROUND: Insomnia disorder with objective short sleep duration (ISS) phenotype is a more serious biological subtype than insomnia with objective normal sleep duration (INS) phenotype, and the neuroimaging data is helpful to understand the pathophysiology of the ISS phenotype. This study was to compare the amplitude of low-frequency fluctuation (ALFF), regional homogeneity (ReHo), and functional connectivity (FC) between the ISS phenotype and the INS phenotype. METHODS: In this cross-sectional study, 55 patients with insomnia disorder were recruited, and 22 of them were defined as the ISS phenotype by the objective cardiopulmonary coupling (CPC) technique. The blood oxygen level-dependent (BOLD) sequences of all participants were obtained using the 3.0 T magnetic resonance imaging system. We analyzed and compared the ALFF, ReHo, and FC between the ISS phenotype and the INS phenotype. We also conducted Pearson's correlation analysis between significant neuroimaging biomarkers and the CPC parameters. RESULTS: The differences were not significant in ALFF (PFWE-corr＞0.05) or ReHo (PFWE-corr＞0.05) between the ISS phenotype and the INS phenotype. For the FC analysis, the ISS phenotype had a Hub-node of the left inferior occipital gyrus (IOG.L), with significantly decreased connections (p＜0.001) in the bilateral occipital, parietal, and temporal regions. The significant FCs were closely related to sleep parameters. CONCLUSION: The left inferior occipital gyrus (IOG.L), as a Hub-node with decreased functional connections, may be a potential fMRI-based biomarker of the ISS phenotype.

Multimodal neuroimaging exploration of the mechanisms of sleep quality deterioration after SARS-CoV-2 Omicron infection.

BACKGROUND: To evaluate the neurological alterations induced by Omicron infection, to compare brain changes in chronic insomnia with those in exacerbated chronic insomnia in Omicron patients, and to examine individuals without insomnia alongside those with new-onset insomnia. METHODS: In this study, a total of 135 participants were recruited between January 11 and May 4, 2023, including 26 patients with chronic insomnia without exacerbation, 24 patients with chronic insomnia with exacerbation, 40 patients with no sleep disorder, and 30 patients with new-onset insomnia after infection with Omicron (a total of 120 participants with different sleep statuses after infection), as well as 15 healthy controls who were never infected with Omicron. Neuropsychiatric data, clinical symptoms, and multimodal magnetic resonance imaging data were collected. The gray matter thickness and T1, T2, proton density, and perivascular space values were analyzed. Associations between changes in multimodal magnetic resonance imaging findings and neuropsychiatric data were evaluated with correlation analyses. RESULTS: Compared with healthy controls, gray matter thickness changes were similar in the patients who have and do not have a history of chronic insomnia groups after infection, including an increase in cortical thickness near the parietal lobe and a reduction in cortical thickness in the frontal, occipital, and medial brain regions. Analyses showed a reduced gray matter thickness in patients with chronic insomnia compared with those with an aggravation of chronic insomnia post-Omicron infection, and a reduction was found in the right medial orbitofrontal region (mean [SD], 2.38 [0.17] vs. 2.67 [0.29] mm; P < 0.001). In the subgroups of Omicron patients experiencing sleep deterioration, patients with a history of chronic insomnia whose insomnia symptoms worsened after infection displayed heightened medial orbitofrontal cortical thickness and increased proton density values in various brain regions. Conversely, patients with good sleep quality who experienced a new onset of insomnia after infection exhibited reduced cortical thickness in pericalcarine regions and decreased proton density values. In new-onset insomnia patients post-Omicron infection, the thickness in the right pericalcarine was negatively correlated with the Self-rating Anxiety Scale (r = - 0.538, P = 0.002, PFDR = 0.004) and Self-rating Depression Scale (r = - 0.406, P = 0.026, PFDR = 0.026) scores. CONCLUSIONS: These findings help us understand the pathophysiological mechanisms involved when Omicron invades the nervous system and induces various forms of insomnia after infection. In the future, we will continue to pay attention to the dynamic changes in the brain related to insomnia caused by Omicron infection.

Altered morphometric similarity networks in insomnia disorder.

Previous studies on structural covariance network (SCN) suggested that patients with insomnia disorder (ID) show abnormal structural connectivity, primarily affecting the somatomotor network (SMN) and default mode network (DMN). However, evaluating a single structural index in SCN can only reveal direct covariance relationship between two brain regions, failing to uncover synergistic changes in multiple structural features. To cover this research gap, the present study utilized novel morphometric similarity networks (MSN) to examine the morphometric similarity between cortical areas in terms of multiple sMRI parameters measured at each area. With seven T1-weighted imaging morphometric features from the Desikan-Killiany atlas, individual MSN was constructed for patients with ID (N = 87) and healthy control groups (HCs, N = 84). Two-sample t-test revealed differences in MSN between patients with ID and HCs. Correlation analyses examined associations between MSNs and sleep quality, insomnia symptom severity, and depressive symptoms severity in patients with ID. The right paracentral lobule (PCL) exhibited decreased morphometric similarity in patients with ID compared to HCs, mainly manifested by its de-differentiation (meaning loss of distinctiveness) with the SMN, DMN, and ventral attention network (VAN), as well as its decoupling with the visual network (VN). Greater PCL-based de-differentiation correlated with less severe insomnia and fewer depressive symptoms in the patients group. Additionally, patients with less depressive symptoms showed greater PCL de-differentiation from the SMN. As an important pilot step in revealing the underlying morphometric similarity alterations in insomnia disorder, the present study identified the right PCL as a hub region that is de-differentiated with other high-order networks. Our study also revealed that MSN has an important potential to capture clinical significance related to insomnia disorder.

Analysis of functional connectivity changes in attention networks and default mode networks in patients with depression and insomnia.

PURPOSE: Major Depressive Disorder (MDD) and Insomnia Disorder (ID) are prevalent psychiatric conditions often occurring concurrently, leading to substantial impairment in daily functioning. Understanding the neurobiological underpinnings of these disorders and their comorbidity is crucial for developing effective interventions. This study aims to analyze changes in functional connectivity within attention networks and default mode networks in patients with depression and insomnia. METHODS: The functional connectivity alterations in individuals with MDD, ID, comorbid MDD and insomnia (iMDD), and healthy controls (HC) were assessed from a cohort of 174 participants. They underwent rs-fMRI scans, demographic assessments, and scale evaluations for depression and sleep quality. Functional connectivity analysis was conducted using region-of-interest (ROI) and whole-brain methods. RESULTS: The MDD and iMDD groups exhibited higher Hamilton Depression Scale (HAMD) scores compared to HC and ID groups (P < 0.001). Both ID and MDD groups displayed enhanced connectivity between the left and right orbital frontal cortex compared to HC (P < 0.05), while the iMDD group showed reduced connectivity compared to HC and ID groups (P < 0.05). In the left insula, reduced connectivity with the right medial superior frontal gyrus was observed across patient groups compared to HC (P < 0.05), with the iMDD group showing increased connectivity compared to MDD (P < 0.05). Moreover, alterations in functional connectivity between the left thalamus and left temporal pole were found in iMDD compared to HC and MDD (P < 0.05). Correlation analyses revealed associations between abnormal connectivity and symptom severity in MDD and ID groups. CONCLUSIONS: Our findings demonstrate distinct patterns of altered functional connectivity in individuals with MDD, ID, and iMDD compared to healthy controls. These findings contribute to a better understanding of the pathophysiology of depression and insomnia, which could be used as a reference for the diagnosis and treatments of these patients.

Reduced coupling between global signal and cerebrospinal fluid inflow in patients with depressive disorder: A resting state functional MRI study.

BACKGROUND: Depressed patients often suffer from sleep disturbance, which has been recognized to be responsible for glymphatic dysfunction. The purpose of this study was to investigate the coupling strength of global blood­oxygen-level-dependent (gBOLD) signals and cerebrospinal fluid (CSF) inflow dynamics, which is a biomarker for glymphatic function, in depressed patients and to explore its potential relationship with sleep disturbance by using resting-state functional MRI. METHODS: A total of 138 depressed patients (112 females, age: 34.70 ± 13.11 years) and 84 healthy controls (29 females, age: 36.6 ± 11.75 years) participated in this study. The gBOLD-CSF coupling strength was calculated to evaluate glymphatic function. Sleep disturbance was evaluated using the insomnia items (item 4 for insomnia-early, item 5 for insomnia-middle, and item 6 for insomnia-late) of The 17-item Hamilton Depression Rating Scale for depressed patients, which was correlated with the gBOLD-CSF coupling strength. RESULTS: The depressed patients exhibited weaker gBOLD-CSF coupling relative to healthy controls (p = 0.022), possibly due to impairment of the glymphatic system. Moreover, the gBOLD-CSF coupling strength correlated with insomnia-middle (r = 0.097, p = 0.008) in depressed patients. Limitations This study is a cross-sectional study. CONCLUSION: Our findings shed light on the pathophysiology of depression, indicating that cerebral waste clearance system deficits are correlated with poor sleep quality in depressed patients.

Electroencephalography connectome changes in chronic insomnia disorder are correlated with neurochemical signatures.

STUDY OBJECTIVES: This study aimed to investigate the alterations in resting-state electroencephalography (EEG) global brain connectivity (GBC) in patients with chronic insomnia disorder (CID) and to explore the correlation between macroscale connectomic variances and microscale neurotransmitter distributions. METHODS: We acquired 64-channel EEG from 35 female CID patients and 34 healthy females. EEG signals were source-localized using individual brain anatomy and orthogonalized to mitigate volume conduction. Correlation coefficients between band-limited source-space power envelopes of the DK 68 atlas were computed and averaged across regions to determine specific GBC values. A support vector machine (SVM) classifier utilizing GBC features was employed to differentiate CID patients from controls. We further used Neurosynth and a 3D atlas of neurotransmitter receptors/transporters to assess the cognitive functions and neurotransmitter landscape associated with CID cortical abnormality maps, respectively. RESULTS: CID patients exhibited elevated GBC within the medial prefrontal cortex and limbic cortex, particularly at the gamma carrier frequency, compared to controls (pFDR < .05). GBC patterns were found to effectively distinguish CID patients from controls with a precision of 90.8% in the SVM model. The cortical abnormality maps were significantly correlated with meta-analytic terms like "cognitive control" and "emotion regulation." Notably, GBC patterns were associated with neurotransmitter profiles (pspin < .05), with neurotransmitter systems such as norepinephrine, dopamine, and serotonin making significant contributions. CONCLUSIONS: This work characterizes the EEG connectomic profile of CID, facilitating the cost-effective clinical translation of EEG-derived markers. Additionally, the linkage between GBC patterns and neurotransmitter distribution offers promising avenues for developing targeted treatment strategies for CID.

Larger hypothalamic subfield volumes in patients with chronic insomnia disorder and relationships to levels of corticotropin-releasing hormone.

The hypothalamus is a well-established core structure in the sleep-wake cycle. While previous studies have not consistently found whole hypothalamus volume changes in chronic insomnia disorder (CID), differences may exist at the smaller substructural level of the hypothalamic nuclei. The study aimed to investigate the differences in total and subfield hypothalamic volumes, between CID patients and healthy controls (HCs) in vivo, through an advanced deep learning-based automated segmentation tool. A total of 150 patients with CID and 155 demographically matched HCs underwent T1-weighted structural magnetic resonance scanning. We utilized FreeSurfer v7.2 for automated segmentation of the hypothalamus and its five nuclei. Additionally, correlation and causal mediation analyses were performed to investigate the association between hypothalamic volume changes, insomnia symptom severity, and hypothalamus-pituitary-adrenal (HPA) axis-related blood biomarkers. CID patients exhibited larger volumes in the right anterior inferior, left anterior superior, and left posterior subunits of the hypothalamus compared to HCs. Moreover, we observed a positive association between blood corticotropin-releasing hormone (CRH) levels and insomnia severity, with anterior inferior hypothalamus (a-iHyp) hypertrophy mediating this relationship. In conclusion, we found significant volume increases in several hypothalamic subfield regions in CID patients, highlighting the central role of the HPA axis in the pathophysiology of insomnia.

Glymphatic system dysfunction in middle-aged and elderly chronic insomnia patients with cognitive impairment evidenced by diffusion tensor imaging along the perivascular space (DTI-ALPS).

BACKGROUND: Chronic insomnia impairs the glymphatic system and may lead to cognitive impairment and dementia in elderly population. The diffusion tensor image analysis along the perivascular space (DTI-ALPS) has been proposed as a non-invasive method to measure the activity of human brain glymphatic. We aim to explore whether glymphatic function is impaired in middle-aged and elderly chronic insomnia individuals and to identify the relationships between glymphatic dysfunction and cognitive impairment. METHODS: A total of 33 chronic insomnia patients (57.36 ± 5.44 years, 30 females) and 20 age- and sex-matched healthy controls (57.95 ± 5.78 years, 16 females) were prospectively enrolled between May 2022 and January 2023. All participants completed MRI screening, cognition and sleep assessments, and DTI-ALPS index analysis. RESULTS: Our findings revealed that the DTI-ALPS index was significantly difference among the chronic insomnia patients with impaired cognition group (1.32 ± 0.14), with normal cognition group (1.46 ± 0.09), and healthy controls (1.61 ± 0.16) (p = 0.0012, p < 0.0001, p = 0.0008, respectively). Mini-Mental State Examination (MMSE) scores of chronic insomnia patients with cognitive impairment were positively correlated with the DTI-ALPS index (Partial correlation analyses after correction for age, sex, education level and duration of chronic insomnia: r = 0.78, p = 0.002). DTI-ALPS had moderate accuracy in distinguishing chronic insomnia patients with cognitive impairment from those with normal cognition. DATA CONCLUSION: The glymphatic system dysfunction is involved in chronic insomnia among middle-aged and elderly individuals, and it has been found to be correlated with cognitive decline.

Altered orientation dispersion index of white matter in individuals with insomnia during the COVID-19 pandemic: A study combining neuroimaging technique and Mendelian randomization.

STUDY OBJECTIVES: Coronavirus disease 2019 (COVID-19) can lead to insomnia. However, associations between COVID-19-caused insomnia and white matter (WM) changes are unclear. METHODS: All subjects had ever been infected with COVID-19. We investigated 89 insomniacs (29 chronic insomniacs, 33 new-onset insomniacs, 27 aggravated insomniacs) and 44 matched non-insomnia participants. Neurite orientation dispersion and density imaging (NODDI) was performed to identify micro-structural alterations of WM, and twelve scales related to sleeping status, memory, attention, learning, emotional status, and executive functions were used. Then, correlations between insomnia/cognitive-behavioral functions and diffusion metrics were tested. To eliminate influence of pre-COVID-19 factors on insomnia, causal relationships between COVID-19 and WM changes were validated by Mendelian randomization (MR) analysis. The significant brain regions of COVID-19-caused insomnia were intersected results of tract-based spatial statistics (TBSS) and MR analyses. RESULTS: Compared to non-insomnia group, insomnia group and its subgroups including post-COVID-19 aggravated or unchanged chronic insomnia group had higher orientation dispersion index (ODI) in extensive brain regions. The left superior longitudinal fasciculus (SLF), left posterior thalamic radiation (PTR), and left cingulate gyrus (CG) were specific brain regions in COVID-19-induced insomnia aggravation. After Bonferroni correction, partial correlation analyses within insomnia group showed that ODI in left SLF was positively correlated with Pittsburgh sleep quality index (PSQI), insomnia severity index (ISI), and self-rating anxiety scale (SAS) scores; ODI in the left PTR was positively correlated with PSQI and ISI scores. CONCLUSIONS: This study is a continuation of our previous research, which provided potential biomarkers for COVID-19-induced insomnia.

Top-down and bottom-up alterations of connectivity patterns of the suprachiasmatic nucleus in chronic insomnia disorder.

The importance of the suprachiasmatic nucleus (SCN, also called the master circadian clock) in regulating sleep and wakefulness has been confirmed by multiple animal research. However, human studies of SCN in vivo are still nascent. Recently, the development of resting-state functional magnetic resonance imaging (fMRI) has made it possible to study SCN-related connectivity changes in patients with chronic insomnia disorder (CID). Hence, this study aimed to explore whether sleep-wake circuitry (i.e., communication between the SCN and other brain regions) is disrupted in human insomnia. Forty-two patients with CID and 37 healthy controls (HCs) underwent fMRI scanning. Resting-state functional connectivity (rsFC) and Granger causality analysis (GCA) were performed to find abnormal functional and causal connectivity of the SCN in CID patients. In addition, correlation analyses were conducted to detect associations between features of disrupted connectivity and clinical symptoms. Compared to HCs, CID patients showed enhanced rsFC of the SCN-left dorsolateral prefrontal cortex (DLPFC), as well as reduced rsFC of the SCN-bilateral medial prefrontal cortex (MPFC); these altered cortical regions belong to the "top-down" circuit. Moreover, CID patients exhibited disrupted functional and causal connectivity between the SCN and the locus coeruleus (LC) and the raphe nucleus (RN); these altered subcortical regions constitute the "bottom-up" pathway. Importantly, the decreased causal connectivity from the LC-to-SCN was associated with the duration of disease in CID patients. These findings suggest that the disruption of the SCN-centered "top-down" cognitive process and "bottom-up" wake-promoting pathway may be intimately tied to the neuropathology of CID.

Preliminary investigation of the interactive role of physiological arousal and insomnia complaints in gray matter volume alterations in chronic widespread pain.

STUDY OBJECTIVES: Brain regions involved in insomnia and chronic pain are overlapping and diffuse. The interactive role of physiological arousal in associations between insomnia symptoms and neural regions is unknown. This preliminary study examined whether arousal interacted with sleep in associations with gray matter volume of frontal (dorsolateral prefrontal cortex, anterior cingulate cortex) and temporal (right/left hippocampus) regions in adults with chronic widespread pain and insomnia complaints. METHODS: Forty-seven adults with chronic widespread pain and insomnia (mean age = 46.00, standard deviation = 13.88, 89% women) completed 14 daily diaries measuring sleep onset latency (SOL), wake time after sleep onset, and total sleep time (TST), as well as Holter monitor assessments of heart rate variability (measuring physiological arousal), and magnetic resonance imaging. Multiple regressions examined whether average SOL, wake time after sleep onset, or TST were independently or interactively (with arousal/heart rate variability) associated with dorsolateral prefrontal cortex, anterior cingulate cortex, and left/right hippocampus gray matter volumes. RESULTS: Shorter TST was associated with lower right hippocampus volume. TST also interacted with arousal in its association with right hippocampal volume, Specifically, shorter TST was associated with lower volume at highest and average arousal levels. SOL interacted with arousal in its association with anterior cingulate cortex volume, such that, among individuals with lowest arousal, longer SOL was associated with lower volume. CONCLUSIONS: Preliminary findings highlight the interactive roles of physiological arousal and insomnia symptoms in associations with neural structure in chronic widespread pain and insomnia. Individuals with the highest physiological arousal may be particularly vulnerable to the impact of shorter TST on hippocampal volume loss. Reducing SOL may only impact anterior cingulate cortex volume in those with lower physiological arousal. CITATION: Curtis AF, Nair N, Hayse B, et al. Preliminary investigation of the interactive role of physiological arousal and insomnia complaints in gray matter volume alterations in chronic widespread pain. J Clin Sleep Med. 2024;20(2):293-302.

Deficits in brain default mode network connectivity mediate the relationship between poor sleep quality and anxiety severity.

STUDY OBJECTIVES: Chronic insomnia disorder (CID) is a prevalent sleep disorder that frequently cooccurs with anxiety. The association between insomnia and anxiety has been established; however, the neurobiological basis of this relationship remains unclear. This study aimed to investigate the neural markers of CID patients with and without anxiety and to determine whether specific neural connectivity mediates the relationship between insomnia and anxiety. METHODS: This study included 180 participants, comprising CID patients with anxiety (CID-A), CID patients without anxiety (CID-NA), and good sleep controls. All participants completed self-reported measures of sleep quality and anxiety severity and underwent functional magnetic resonance imaging. Brain functional integration was measured using functional connectivity density (FCD) and resting-state functional connectivity (rsFC). Correlation and mediation analyses were used to examine the relationships among brain connectivity, sleep quality, and anxiety severity. RESULTS: The CID-NA and CID-A groups showed decreased local FCD in the medial prefrontal cortex (mPFC) and disrupted rsFC between the precuneus and other brain regions. Only the CID-A group exhibited altered long-range FCD in the precuneus and the rsFC between the anterior default mode network (DMN, e.g. mPFC) and posterior DMN (e.g. precuneus). Mediation analysis revealed DMN dysconnectivity underlying the association between poor sleep quality and anxiety symptoms. CONCLUSIONS: This study identified shared and distinct brain circuit disruptions in the CID-NA and CID-A groups, with deficits in DMN connectivity as a potential neural mechanism through which disrupted sleep augments anxiety. These findings may facilitate the development of personalized therapies for insomnia and associated anxiety problems.

Neural mechanisms of attentional bias to emotional faces in patients with chronic insomnia disorder.

OBJECTIVE: This study used event-related potential (ERP) and resting-state functional connectivity (rs-FC) approaches to investigate the neural mechanisms underlying the emotional attention bias in patients with chronic insomnia disorder (CID). METHODS: Twenty-five patients with CID and thirty-three demographically matched healthy controls (HCs) completed clinical questionnaires and underwent electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) scans. EEG analysis examined the group differences in terms of reaction times, P3 amplitudes, event-related spectral perturbations, and inter-trial phase synchrony. Subsequently, seed-based rs-FC analysis of the amygdala nuclei (including the central-medial amygdala [CMA] and basolateral amygdala [BLA]) was performed. The relationship between P3 amplitude, rs-FC and clinical symptom severity in patients with CID was further investigated by correlation analysis. RESULTS: CID patients exhibited shorter reaction times than HCs in both standard and deviant stimuli, with the abnormalities becoming more pronounced as attention allocation increased. Compared to HCs, ERP analysis revealed increased P3 amplitude, theta wave power, and inter-trial synchrony in CID patients. The rs-FC analysis showed increased connectivity of the BLA-occipital pole, CMA-precuneus, and CMA-angular gyrus and decreased connectivity of the CMA-thalamus in CID patients. Notably, correlation analysis of the EEG and fMRI measurements showed a significant positive correlation between the P3 amplitude and the rs-FC of the CMA-PCU. CONCLUSION: This study confirms an emotional attention bias in CID, specifically in the neural mechanisms of attention processing that vary depending on the allocation of attentional resources. Abnormal connectivity in the emotion-cognition networks may constitute the neural basis of the abnormal scalp activation pattern.

Towards the neurobiology of insomnia: A systematic review of neuroimaging studies.

Insomnia disorder signifies a major public health concern. The development of neuroimaging techniques has permitted to investigate brain mechanisms at a structural and functional level. The present systematic review aims at shedding light on functional, structural, and metabolic substrates of insomnia disorder by integrating the available published neuroimaging data. The databases PubMed, PsycARTICLES, PsycINFO, CINAHL and Web of Science were searched for case-control studies comparing neuroimaging data from insomnia patients and healthy controls. 85 articles were judged as eligible. For every observed finding of each study, the effect size was calculated from standardised mean differences, statistic parameters and figures, showing a marked heterogeneity that precluded a comprehensive quantitative analysis. From a qualitative point of view, considering the findings of significant group differences in the reported regions across the articles, this review highlights the major involvement of the anterior cingulate cortex, thalamus, insula, precuneus and middle frontal gyrus, thus supporting some central themes in the debate on the neurobiology of and offering interesting insights into the psychophysiology of sleep in this disorder.

Relationship between cognitive function and brain activation in major depressive disorder patients with and without insomnia: A functional near-infrared spectroscopy (fNIRS) study.

BACKGROUND: Patients with major depressive disorder (MDD) frequently present with sleep disturbances and cognitive impairment. The purpose of this study was to investigate whether cognitive impairment is more severe in MDD patients with insomnia, and the underlying neural mechanisms. METHODS: A total of 41 MDD patients with insomnia and 43 MDD patients without insomnia were recruited. We used functional near-infrared spectroscopy (fNIRS) to assess changes in oxyhemoglobin (Oxy-Hb) concentrations in the brain of patients while performing a verbal fluency task (VFT). Sleep quality was assessed by the Pittsburgh Sleep Quality Index (PSQI), cognitive function by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), and severity of depression by the Hamilton Depression Scale (HAMD). RESULTS: Compared to MDD patients without insomnia, those with insomnia had lower scores on the RBANS total and immediate memory, visuospatial/constructional, and delayed memory subscales, as well as lower oxy-Hb concentrations in the bilateral dorsolateral prefrontal cortex (DLPFC) and bilateral medial prefrontal cortex (mPFC).Further correlation analysis showed that there was a significant correlation between the RBANS total score in all brain regions except left mPFC in MDD patients with insomnia(all p < 0.05). Further multiple linear regression showed that Oxy-Hb concentrations of left DLPFC were independently associated with RBANS total score. CONCLUSION: Our study suggests that MDD patients with insomnia have more cognitive impairment, which is associated with impaired frontal brain activity. Our findings may provide new insights to understand the underlying neural mechanisms of both disorders MDD patients and provide potential clinical value for developing treatment strategies for insomnia in MDD patients.

Sex-specific grey matter abnormalities in individuals with chronic insomnia.

Previous studies have reported sex differences in altered brain function in patients with chronic insomnia (CI). However, sex-related alterations in brain morphology have rarely been investigated. This study aimed to investigate sex-specific grey matter (GM) alterations in patients with CI and to examine the relationship between GM alterations and neuropsychological assessments. Ninety-three (65 females and 28 males) patients and 78 healthy (50 females and 28 males) controls were recruited. Structural magnetic resonance imaging data were analysed using voxel-based morphometry to test for interactions between sex and diagnosis. Spearman's correlation was used to assess the associations among structure, disease duration, and sleep-, mood-, and cognition-related assessments. Males with CI showed reduced GM volume in the left inferior parietal lobe, left middle cingulate cortex, and right supramarginal gyrus. Females with CI showed increased GM volume in the right Rolandic operculum. Moreover, mood-related assessments were negatively correlated with GM volumes in the right supramarginal gyrus and left inferior parietal lobe in the male patients, and cognitive-related assessments were positively correlated with GM volumes in the Rolandic operculum in the female patients. Our findings indicate sex-specific alterations in brain morphology in CI, thereby broadening our understanding of sex differences in CI and potentially providing complementary evidence for the development of more effective therapies and individual treatments.

Response inhibition impairment related to altered frontal-striatal functional connectivity in insomnia disorder: A pilot and non-clinical study.

BACKGROUND: It is not clear whether and how insomnia disorder (ID) impairs response inhibition ability. Fronto-striatal functional connectivity (FC) plays a critical role in response inhibition and is found be abnormal in patients with ID. In this study, we examined whether insomnia symptoms impair response inhibition in a large non-clinical sample and whether impaired response inhibition is related to abnormal fronto-striatal FC. METHODS: One hundred and fifteen young ID patients and 160 age and sex-matched healthy controls (HC) underwent resting-state functional magnetic response imaging scans and performed the stop-signal task (SST). Performance of SST, Gray Matter Volumes (GMVs), and connections of brain regions related to fronto-striatal circuits was compared between groups. Further examined the association between response inhibition impairment and fronto-striatal FC. RESULTS: The behavioral results showed that patients with ID had significantly longer stop-signal reaction time (SSRT) compared with the HC, reflecting the impaired response inhibition among IDs. Brain imaging results showed IDs had decreased GMVs of the Right Superior Frontal (SFG) and left Supplementary Motor area (SMA). Seed-based FC results showed that compared to HC, the ID showed decreased FC between left SMA and left Paracentral lobule, left SMA and right SMA, and right SFG and right Orbital Middle Frontal gyrus, and increased FC between right SFG and right putamen. Meanwhile, the FC between right SFG and putamen was positively correlated with SSRT in IDs. CONCLUSIONS: The current study found significantly impaired response inhibition among ID and this impairment may be related to abnormal fronto-striatal FC in ID.

Opposing brain signatures of sleep in task-based and resting-state conditions.

Sleep and depression have a complex, bidirectional relationship, with sleep-associated alterations in brain dynamics and structure impacting a range of symptoms and cognitive abilities. Previous work describing these relationships has provided an incomplete picture by investigating only one or two types of sleep measures, depression, or neuroimaging modalities in parallel. We analyze the correlations between brainwide neural signatures of sleep, cognition, and depression in task and resting-state data from over 30,000 individuals from the UK Biobank and Human Connectome Project. Neural signatures of insomnia and depression are negatively correlated with those of sleep duration measured by accelerometer in the task condition but positively correlated in the resting-state condition. Our results show that resting-state neural signatures of insomnia and depression resemble that of rested wakefulness. This is further supported by our finding of hypoconnectivity in task but hyperconnectivity in resting-state data in association with insomnia and depression. These observations dispute conventional assumptions about the neurofunctional manifestations of hyper- and hypo-somnia, and may explain inconsistent findings in the literature.

Abnormal alterations of regional spontaneous neuronal activity and functional connectivity in insomnia patients with difficulty falling asleep: a resting-state fMRI study.

BACKGROUND: Insomnia disorder (ID) seriously affects people's daily life. Difficulty falling asleep is the most commonly reported complaint in patients with ID. However, the mechanism of prolonged sleep latency (SL) is still obscure. The aim of our present study was to investigate the relationship between prolonged SL and alterations in spontaneous neural activity and brain functional connectivity (FC) in ID patients using functional magnetic resonance imaging (fMRI). METHODS: A total of 52 insomniacs with difficulty falling asleep and 30 matched healthy controls (HCs) underwent resting-state fMRI. The amplitude of low-frequency fluctuation (ALFF) was measured and group differences were compared. The peak areas with significantly different ALFF values were identified as the seed regions to calculate FC to the whole brain. SL was assessed by a wrist actigraphy device in ID patients. The Pittsburgh Sleep Quality Index (PSQI), Hamilton Anxiety Rating Scale (HAMA), and Hyperarousal Scale (HAS) were evaluated in both ID patients and HCs. Finally, correlation analyses were performed between the clinical features and FC/ALFF values. RESULTS: ID patients showed higher PSQI, HAMA, HAS scores than HCs. The functional MRI results indicated increased ALFF value in the left insula and right amygdala and decreased ALFF value in the right superior parietal lobe (SPL) in ID patients. The seed-based FC analysis demonstrated increased FC between the left insula and the bilateral precentral gyrus and FC between the right amygdala and the left posterior cingulate cortex (PCC) in patients with ID. Correlation analysis indicated that the increased FC value of the right amygdala-left PCC was positively correlated with SL measured by actigraphy. CONCLUSION: This study revealed abnormal regional spontaneous fluctuations in the right amygdala, left insula, and right SPL, as well as increased FC in the left insula-precentral and right amygdala-left PCC. Moreover, the prolonged SL was positively correlated with the abnormal FC in the right amygdala-left PCC in ID patients. The current study showed the correlation between prolonged SL and the abnormal function of emotion-related brain regions in ID patients, which may contribute to a better understanding of the neural mechanisms underlying difficulty falling asleep in patients with ID. CLINICAL TRIAL REGISTRATION: http://www.chictr.org.cn ., ChiCTR1800015282. Registered on 20th March 2018.