Altered thalamic functional connectivity and cerebral blood flow in insomnia disorder: a resting-state functional magnetic resonance imaging study


      • The aberrant thalamus-based connectivity pattern of insomnia patients was detected.
      • Insomnia patients showed altered connectivity in precentral gyrus, MFG, SPL, SFG and CPL.
      • Connectivity between thalamus and Crus Ⅰ was significantly correlated with MoCA.


      Background and purpose

      The thalamus plays a crucial role in sleep regulation, but few studies have examined functional connectivity of the thalamus in insomnia disorder. This study aimed to investigate the connectivity patterns and perfusion of the thalamus in patients with insomnia disorder using resting-state functional connectivity and three-dimensional arterial spin labeling (3D ASL).

      Materials and methods

      In total, 56 patients with insomnia disorder and 59 healthy control participants with a similar age-, gender-, and education lever distribution underwent resting-state functional magnetic resonance imaging (rs-fMRI) and 3D-ASL. The thalamus was selected as the seed region. Whole-brain connectivity was assessed using rs-fMRI. Cerebral blood flow (CBF) of the bilateral thalamus was measured with 3D-ASL using region-of-interest (ROI) analysis. All participants completed a series of neuropsychological assessments. Sleep parameters were assessed via polysomnography (PSG). The relationships between imaging parameters and clinical variables were assessed with Pearson correlation analysis.


      Compared with healthy controls, patients with insomnia disorder exhibited increased connectivity between the left thalamus and right precentral gyrus, and right thalamus and left middle frontal gyrus (MFG), right superior parietal lobule (SPL) and right superior frontal gyrus (SFG). Whereas decreased connectivity was noted between the right thalamus and left posterior cerebellar lobe including Crus I, Crus II, and VII b/VII. Connectivity between the right thalamus and left Crus I was positively correlated with MoCA scores (r = 0.286, P = 0.036) in insomnia disorder.


      Our findings illustrate functional abnormalities in brain connectivity and their relationship with cognitive impairments in insomnia disorder, providing novel insight into the neural mechanisms of insomnia disorder.


      3D ASL (three-dimensional arterial spin labeling), rs-fMRI (resting-state functional magnetic resonance imaging), CBF (cerebral blood flow), ROI (region-of-interest), PSQI (Pittsburgh Sleep Quality Index), ISI (Insomnia Severity Index), ESS (Epworth Sleepiness Score), MMSE (Mini-Mental State Examination), MoCA (Montreal Cognitive Assessment), HAMA (Hamilton Anxiety Scale), HAMD (Hamilton Depression Scale), DSM-V (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition), MRI (magnetic resonance imaging), PSG (polysomnography), EPI (echo-planar imaging), TR (repetition time), TE (echo time), FOV (field of view), FA (flip angle), 3D BRAVO (three-dimensional brain volume imaging), DPABI (Data Processing Analysis of Brain Imaging), SPM (Statistical Parametric Mapping), FD (frame-wise displacement), MNI (Montreal Neurological Institute), AAL (automated anatomical labeling), TFCE (Threshold Free Cluster Enhancement), ICC (intra-class correlation coefficient), CPL (cerebellum posterior lobe), ALFF (amplitude of low-frequency fluctuations), SPL (superior parietal lobule), SFG (right superior frontal gyrus), MCI (mild cognitive impairment)


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        • Buysse D.J.
        • Rush A.J.
        • Reynolds III, C.F.
        Clinical management of insomnia disorder.
        JAMA. 2017; 318: 1973-1974
        • Yan C.Q.
        • Wang X.
        • Huo J.W.
        • et al.
        Abnormal global brain functional connectivity in primary insomnia patients: a resting-state functional MRI study.
        Front Neurol. 2018; 9: 856
        • Fernandez-Mendoza J.
        • Vgontzas A.N.
        • Bixler E.O.
        • et al.
        Clinical and polysomnographic predictors of the natural history of poor sleep in the general population.
        Sleep. 2012; 35: 689-697
        • Peter-Derex L.
        • Yammine P.
        • Bastuji H.
        • et al.
        Sleep and Alzheimer's disease.
        Sleep Med Rev. 2015; 19: 29-38
        • Gan-Or Z.
        • Alcalay R.N.
        • Rouleau G.A.
        • et al.
        Sleep disorders and parkinson disease; lessons from genetics.
        Sleep Med Rev. 2018; 41: 101-112
        • Thomas S.J.
        • Calhoun D.
        Sleep, insomnia, and hypertension: current findings and future directions.
        J Am Soc Hypertens. 2017; 11: 122-129
        • Li M.
        • Zhang X.W.
        • Hou W.S.
        • et al.
        Insomnia and risk of cardiovascular disease: a meta-analysis of cohort studies.
        Int J Cardiol. 2014; 176: 1044-1047
        • Kilic K.
        • Karatas H.
        • Donmez-Demir B.
        • et al.
        Inadequate brain glycogen or sleep increases spreading depression susceptibility.
        Ann Neurol. 2018; 83: 61-73
        • Chan W.S.
        • Levsen M.P.
        • McCrae C.S.
        A meta-analysis of associations between obesity and insomnia diagnosis and symptoms.
        Sleep Med Rev. 2018; 40: 170-182
        • Tan X.
        • Chapman C.D.
        • Cedernaes J.
        • et al.
        Association between long sleep duration and increased risk of obesity and type 2 diabetes: a review of possible mechanisms.
        Sleep Med Rev. 2018; 40: 127-134
        • Akerstedt T.
        • Ghilotti F.
        • Grotta A.
        • et al.
        Sleep duration, mortality and the influence of age.
        Eur J Epidemiol. 2017; 32: 881-891
        • Fortier-Brochu E.
        • Beaulieu-Bonneau S.
        • Ivers H.
        • et al.
        Insomnia and daytime cognitive performance: a meta-analysis.
        Sleep Med Rev. 2012; 16: 83-94
        • Kyle S.D.
        • Morgan K.
        • Espie C.A.
        Insomnia and health-related quality of life.
        Sleep Med Rev. 2010; 14: 69-82
        • Ma N.
        • Dinges D.F.
        • Basner M.
        • et al.
        How acute total sleep loss affects the attending brain: a meta-analysis of neuroimaging studies.
        Sleep. 2015; 38: 233-240
        • Baglioni C.
        • Battagliese G.
        • Feige B.
        • et al.
        Insomnia as a predictor of depression: a meta-analytic evaluation of longitudinal epidemiological studies.
        J Affect Disord. 2011; 135: 10-19
        • Sivertsen B.
        • Krokstad S.
        • Overland S.
        • et al.
        The epidemiology of insomnia: associations with physical and mental health. The HUNT-2 study.
        J Psychosom Res. 2009; 67: 109-116
        • Kessler R.C.
        • Berglund P.A.
        • Coulouvrat C.
        • et al.
        Insomnia and the performance of US workers: results from the America insomnia survey.
        Sleep. 2011; 34: 1161-1171
        • Palagini L.
        • Mauri M.
        • Banfi T.
        • et al.
        Daytime rumination as a feature of insomnia disorder: sleep related cognition is not merely a problem of the night.
        Arch Ital Biol. 2015; 153: 239-247
        • Kang J.M.K.
        • Joo S.W.J.
        • Son Y.D.S.
        • et al.
        Low white-matter integrity between the left thalamus and inferior frontal gyrus in patients with insomnia disorder.
        J Psychiatry Neurosci. 2018; 43: 366-374
        • Li M.
        • Wang R.
        • Zhao M.
        • et al.
        Abnormalities of thalamus volume and resting state functional connectivity in primary insomnia patients.
        Brain Imaging Behav. 2019; 13: 1193-1201
        • Altena E.
        • Vrenken H.
        • Van Der Werf Y.D.
        • et al.
        Reduced orbitofrontal and parietal gray matter in chronic insomnia: a voxel-based morphometric study.
        Biol Psychiatry. 2010; 67: 182-185
        • Venkatraman V.
        • Chuah Y.M.
        • Huettel S.A.
        • et al.
        Sleep deprivation elevates expectation of gains and attenuates response to losses following risky decisions.
        Sleep. 2007; 30: 603-609
        • Riemann D.
        • Voderholzer U.
        • Spiegelhalder K.
        • et al.
        Chronic insomnia and MRI-measured hippocampal volumes: a pilot study.
        Sleep. 2007; 30: 955-958
        • Campabadal A.
        • Abos A.
        • Segura B.
        • et al.
        Disruption of posterior brain functional connectivity and its relation to cognitive impairment in idiopathic REM sleep behavior disorder.
        NeuroImage Clin. 2019; 25102138
        • Shang C.Y.
        • Lin H.Y.
        • Gau S.S.
        Effects of the dopamine transporter gene on striatal functional connectivity in youths with attention-deficit/hyperactivity disorder.
        Psychol Med. 2020; : 1-11
        • Wackerhagen C.
        • Veer I.M.
        • Erk S.
        • et al.
        Amygdala functional connectivity in major depression - disentangling markers of pathology, risk and resilience.
        Psychol Med. 2019; : 1-11
        • Maiti B.
        • Koller J.M.
        • Snyder A.Z.
        • et al.
        Cognitive correlates of cerebellar resting-state functional connectivity in parkinson disease.
        Neurology. 2019;
        • Sherman S.M.
        Thalamus plays a central role in ongoing cortical functioning.
        Nat Neurosci. 2016; 19: 533-541
        • Tononi G.
        • Cirelli C.
        Sleep and the price of plasticity: from synaptic and cellular homeostasis to memory consolidation and integration.
        Neuron. 2014; 81: 12-34
        • Elvsashagen T.
        • Mutsaerts H.J.
        • Zak N.
        • et al.
        Cerebral blood flow changes after a day of wake, sleep, and sleep deprivation.
        Neuroimage. 2019; 186: 497-509
        • Edinger J.D.
        • Bonnet M.H.
        • Bootzin R.R.
        • et al.
        Derivation of research diagnostic criteria for insomnia: report of an American Academy of sleep medicine work group.
        Sleep. 2004; 27: 1567-1596
        • Chao-Gan Y.
        • Yu-Feng Z.
        DPARSF: a MATLAB toolbox for "Pipeline" data analysis of resting-state fMRI.
        Front Syst Neurosci. 2010; 4: 13
        • Song X.W.
        • Dong Z.Y.
        • Long X.Y.
        • et al.
        REST: a toolkit for resting-state functional magnetic resonance imaging data processing.
        PloS one. 2011; 6e25031
        • Zhao L.
        • Wang Y.
        • Jia Y.
        • et al.
        Microstructural abnormalities of basal ganglia and thalamus in bipolar and unipolar disorders: a diffusion kurtosis and perfusion imaging study.
        Psychiatry Investig. 2017; 14: 471-482
        • Wang T.
        • Li S.
        • Jiang G.
        • et al.
        Regional homogeneity changes in patients with primary insomnia.
        Eur Radiol. 2016; 26: 1292-1300
        • Liu C.H.
        • Liu C.Z.
        • Zhang J.
        • et al.
        Reduced spontaneous neuronal activity in the insular cortex and thalamus in healthy adults with insomnia symptoms.
        Brain Res. 2016; 1648: 317-324
        • Killgore W.D.
        • Schwab Z.J.
        • Kipman M.
        • et al.
        Insomnia-related complaints correlate with functional connectivity between sensory-motor regions.
        Neuroreport. 2013; 24: 233-240
        • Kim N.
        • Won E.
        • Cho S.
        Thalamocortical functional connectivity in patients with insomnia using resting-state fMRI.
        46. 2021 (E639-E646)
        • Gao L.
        • Bai L.
        • Zhang Y.
        • et al.
        Frequency-dependent changes of local resting oscillations in sleep-deprived brain.
        PloS one. 2015; 10e0120323
        • Van Dort C.J.
        Locus coeruleus neural fatigue: a potential mechanism for cognitive impairment during sleep deprivation.
        Sleep. 2016; 39: 11-12
        • Bellesi M.
        • Tononi G.
        • Cirelli C.
        • et al.
        Region-specific dissociation between cortical noradrenaline levels and the sleep/wake cycle.
        Sleep. 2016; 39: 143-154
        • Li C.
        • Ma X.
        • Dong M.
        • et al.
        Abnormal spontaneous regional brain activity in primary insomnia: a resting-state functional magnetic resonance imaging study.
        Neuropsychiatr Dis Treat. 2016; 12: 1371-1378
        • Zhou F.
        • Huang S.
        • Zhuang Y.
        • et al.
        Frequency-dependent changes in local intrinsic oscillations in chronic primary insomnia: a study of the amplitude of low-frequency fluctuations in the resting state.
        NeuroImage Clin. 2017; 15: 458-465
        • Bruno R.M.
        • Sakmann B.
        Cortex is driven by weak but synchronously active thalamocortical synapses.
        Science (New York, NY). 2006; 312: 1622-1627
        • Li M.
        • Wang R.
        • Zhao M.
        Abnormalities of thalamus volume and resting state functional connectivity in primary insomnia patients.
        • Chen G.
        • Zhao L.
        • Jia Y.
        • et al.
        Abnormal cerebellum-DMN regions connectivity in unmedicated bipolar II disorder.
        J Affect Disord. 2019; 243: 441-447
        • Yu S.
        • Feng F.
        • Zhang Q.
        • et al.
        Gray matter hypertrophy in primary insomnia: a surface-based morphometric study.
        Brain Imaging Behav. 2018;
        • Leerssen J.
        • Wassing R.
        • Ramautar J.R.
        • et al.
        Increased hippocampal-prefrontal functional connectivity in insomnia.
        Neurobiol Learn Mem. 2018;
        • Price N.
        • Born RJTJontojotSfN
        Timescales of sensory- and decision-related activity in the middle temporal and medial superior temporal areas. 30. 2010: 14036-14045
        • G C
        Abnormal cerebellum-DMN regions connectivity in unmedicated bipolar II disorder.
        J Affect Disord. 2019; 243: 441-447
        • B J
        Effect-size seed-based d mapping of resting-state fMRI for persistent insomnia disorder.
        Sleep Breath. 2019;
        • Olivito G.
        • Lupo M.
        • Iacobacci C.
        • et al.
        Structural cerebellar correlates of cognitive functions in spinocerebellar ataxia type 2.
        J Neurol. 2018; 265: 597-606
        • Yk W.
        • Xh S.
        • Yy W.
        • et al.
        Evaluation of the age-related and gender-related differences in patients with primary insomnia by fractional amplitude of low-frequency fluctuation: a resting-state functional magnetic resonance imaging study.
        Medicine. 2020; 99e18786
        • DJ H.
        • OD O.
        Circadian and homeostatic modulation of functional connectivity and regional cerebral blood flow in humans under normal entrained conditions.
        J Cereb Blood Flow Metab. 2014; 34: 1493-1499
        • Zhou F.
        • Huang M.
        • Gu L.
        • et al.
        Regional cerebral hypoperfusion after acute sleep deprivation: a STROBE-compliant study of arterial spin labeling fMRI.
        Medicine. 2019; 98e14008
        • Wu J.C.
        • Gillin J.C.
        • Buchsbaum M.S.
        • et al.
        Frontal lobe metabolic decreases with sleep deprivation not totally reversed by recovery sleep.
        Neuropsychopharmacology. 2006; 31: 2783-2792
        • Wang T.
        • Yan J.
        • Li S.
        • et al.
        Increased insular connectivity with emotional regions in primary insomnia patients: a resting-state fMRI study.
        Eur Radiol. 2017; 27: 3703-3709
        • Stoffers D.
        • Moens S.
        • Benjamins J.
        • et al.
        Orbitofrontal gray matter relates to early morning awakening: a neural correlate of insomnia complaints?.
        Front Neurol. 2012; 3: 105