Abstract: Thalamocortical circuitry has a substantial impact on emotion and cognition. Previous studies have demonstrated alterations in thalamocortical functional connectivity (FC), characterized by region-dependent hypo- or hyper-connectivity, among individuals with major depressive disorder (MDD). However, the dynamical reconfiguration of the thalamocortical system over time and potential abnormalities in dynamic thalamocortical connectivity associated with MDD remain unclear. Hence, we analyzed dynamic FC (dFC) between ten thalamic subregions and seven cortical subnetworks from resting-state functional magnetic resonance images of 48 patients with MDD and 57 healthy controls (HCs) to investigate time-varying changes in thalamocortical FC in patients with MDD. Moreover, dynamic laterality analysis was conducted to examine the changes in functional lateralization of the thalamocortical system over time. Correlations between the dynamic measures of thalamocortical FC and clinical assessment were also calculated. We identified four dynamic states of thalamocortical circuitry wherein patients with MDD exhibited decreased fractional time and reduced transitions within a negative connectivity state that showed strong correlations with primary cortical networks, compared with the HCs. In addition, MDD patients also exhibited increased fluctuations in functional laterality in the thalamocortical system across the scan duration. The thalamo-subnetwork analysis unveiled abnormal dFC variability involving higher-order cortical networks in the MDD cohort. Significant correlations were found between increased dFC variability with dorsal attention and default mode networks and the severity of symptoms. Our study comprehensively investigated the pattern of alteration of the thalamocortical dFC in MDD patients. The heterogeneous alterations of dFC between the thalamus and both primary and higher-order cortical networks may help characterize the deficits of sensory and cognitive processing in MDD.

重度抑郁障碍患者丘脑皮层环路的动态功能连接异常

[1]AggarwalCC,HinneburgA,KeimDA,2001.On the surprising behavior of distance metrics in high dimensional space.Database Theory—ICDT 2001, Berlin, Heidelberg. Springer Berlin Heidelberg, p.420-434.

[2]AllenEA,DamarajuE,PlisSM,et al.,2014.Tracking whole-brain connectivity dynamics in the resting state.Cereb Cortex,24(3):663-676.

[3]ArbabshiraniMR,DamarajuE,PhlypoR,et al.,2014.Impact of autocorrelation on functional connectivity.NeuroImage,102(Part2):294-308.

[4]AvantsB,TustisonNJ,SongG,2009.Advanced Normalization Tools: V1.0. Insight J, July-December.

[5]BehrensTEJ,Johansen-BergH,WoolrichMW,et al.,2003.Non-invasive mapping of connections between human thalamus and cortex using diffusion imaging.Nat Neurosci,6(7):750-757.

[6]BosDJ,OranjeB,AchterbergM,et al.,2017.Structural and functional connectivity in children and adolescents with and without attention deficit/hyperactivity disorder.J Child Psychol Psychiatry,58(7):810-818.

[7]BrownEC,ClarkDL,HasselS,et al.,2017.Thalamocortical connectivity in major depressive disorder.J Affect Disord,217:125-131.

[8]BruderGE,StewartJW,McGrathPJ,2017.Right brain, left brain in depressive disorders: clinical and theoretical implications of behavioral, electrophysiological and neuroimaging findings.Neurosci Biobehav Rev,78:178-191.

[9]CalhounVD,MillerR,PearlsonG,et al.,2014.The chronnectome: time-varying connectivity networks as the next frontier in fMRI data discovery.Neuron,84(2):262-274.

[10]ChenFF,LvXY,FangJL,et al.,2021.Body-mind relaxation meditation modulates the thalamocortical functional connectivity in major depressive disorder: a preliminary resting-state fMRI study.Transl Psychiatry,11:546.

[11]ChenQL,BeatyRE,CuiZX,et al.,2019.Brain hemispheric involvement in visuospatial and verbal divergent thinking.NeuroImage,202:116065.

[12]ChenSY,LangleyJ,ChenXC,et al.,2016.Spatiotemporal modeling of brain dynamics using resting-state functional magnetic resonance imaging with Gaussian Hidden Markov model.Brain Connect,6(4):326-334.

[13]ChoeAS,NebelMB,BarberAD,et al.,2017.Comparing test-retest reliability of dynamic functional connectivity methods.NeuroImage,158:155-175.

[14]ChoiJ,JeongB,LeeSW,et al.,2013.Aberrant development of functional connectivity among resting state-related functional networks in medication-naive ADHD children.PLoS ONE,8(12):e83516.

[15]DingYD,YangR,YanCG,et al.,2021.Disrupted hemispheric connectivity specialization in patients with major depressive disorder: evidence from the REST-meta-MDD Project.J Affect Disord,284:217-228.

[16]DoronKW,BassettDS,GazzanigaMS,2012.Dynamic network structure of interhemispheric coordination.Proc Natl Acad Sci USA,109(46):18661-18668.

[17]DuHH,ShenX,DuXY,et al.,2022.Altered visual cortical excitability is associated with psychopathological symptoms in major depressive disorder.Front Psychiatry,13:844434.

[18]DupireA,KantP,MonsN,et al.,2013.A role for anterior thalamic nuclei in affective cognition: interaction with environmental conditions.Hippocampus,23(5):392-404.

[19]FischlB,2012.FreeSurfer.NeuroImage,62(2):774-781.

[20]FoxMD,SnyderAZ,VincentJL,et al.,2005.The human brain is intrinsically organized into dynamic, anticorrelated functional networks.Proc Natl Acad Sci USA,102(27):9673-9678.

[21]FoxMD,ZhangDY,SnyderAZ,et al.,2009.The global signal and observed anticorrelated resting state brain networks.J Neurophysiol,101(6):3270-3283.

[22]GotlibIH,JonidesJ,BuschkuehlM,et al.,2011.Memory for affectively valenced and neutral stimuli in depression: evidence from a novel matching task.Cognit Emotion,25(7):1246-1254.

[23]GrohA,KriegerP,MeaseRA,et al.,2018.Acute and chronic pain processing in the thalamocortical system of humans and animal models.Neuroscience,387:58-71.

[24]GüntürkünO,StröckensF,OcklenburgS,2020.Brain lateralization: a comparative perspective.Physiol Rev,100(3):1019-1063.

[25]HakimdavoodiH,AmirmazlaghaniM,2020.Using autoregressive-dynamic conditional correlation model with residual analysis to extract dynamic functional connectivity.J Neural Eng,17(3):035008.

[26]HamiltonJP,ChenMC,WaughCE,et al.,2015.Distinctive and common neural underpinnings of major depression, social anxiety, and their comorbidity.Soc Cogn Affect Neurosci,10(4):552-560.

[27]HamiltonM,1967.Development of a rating scale for primary depressive illness.Br J Soc Clin Psychol,6(4):278-296.

[28]HutchisonRM,WomelsdorfT,GatiJS,et al.,2013.Resting-state networks show dynamic functional connectivity in awake humans and anesthetized macaques.Hum Brain Mapp,34(9):2154-2177.

[29]IglesiasJE,InsaustiR,Lerma-UsabiagaG,et al.,2018.A probabilistic atlas of the human thalamic nuclei combining ex vivo MRI and histology.NeuroImage,183:314-326.

[30]KaiserRH,Andrews-HannaJR,WagerTD,et al.,2015.Large-scale network dysfunction in major depressive disorder: a meta-analysis of resting-state functional connectivity.JAMA Psychiatry,72(6):603-611.

[31]KangLJ,ZhangAX,SunN,et al.,2018.Functional connectivity between the thalamus and the primary somatosensory cortex in major depressive disorder: a resting-state fMRI study.BMC Psychiatry,18:339.

[32]KlingnerCM,LangbeinK,DietzekM,et al.,2014.Thalamocortical connectivity during resting state in schizophrenia.Eur Arch Psychiatry Clin Neurosci,264(2):111-119.

[33]KongQM,QiaoH,LiuCZ,et al.,2018.Aberrant intrinsic functional connectivity in thalamo-cortical networks in major depressive disorder.CNS Neurosci Ther,24(11):1063-1072.

[34]LenoskiB,BaxterLC,KaramLJ,et al.,2008.On the perform

[35]ance of autocorrelation estimation algorithms for fMRI analysis.IEEE J Sel Top Signal Process,2(6):828-838.

[36]LindquistMA,XuYT,NebelMB,et al.,2014.Evaluating dynamic bivariate correlations in resting-state fMRI: a comparison study and a new approach.NeuroImage,101:531-546.

[37]LiuF,WangYF,LiML,et al.,2017.Dynamic functional network connectivity in idiopathic generalized epilepsy with generalized tonic-clonic seizure.Hum Brain Mapp,38(2):957-973.

[38]LiuPH,TuHW,ZhangAX,et al.,2021.Brain functional alterations in MDD patients with somatic symptoms: a resting-state fMRI study.J Affect Disord,295:788-796.

[39]LiuX,ZhangNY,ChangC,et al.,2018.Co-activation patterns in resting-state fMRI signals.NeuroImage,180:485-494.

[40]LlinásRR,ParéD,1991.Of dreaming and wakefulness.Neuroscience,44(3):521-535.

[41]LlinásRR,RibaryU,JeanmonodD,et al.,1999.Thalamocortical dysrhythmia: a neurological and neuropsychiatric syndrome characterized by magnetoencephalography.Proc Natl Acad Sci USA,96(26):15222-15227.

[42]LlinásRR,UrbanoFJ,LeznikE,et al.,2005.Rhythmic and dysrhythmic thalamocortical dynamics: GABA systems and the edge effect.Trends Neurosci,28(6):325-333.

[43]LongYC,CaoHY,YanCG,et al.,2020.Altered resting-state dynamic functional brain networks in major depressive disorder: findings from the REST-meta-MDD consortium.NeuroImage Clin,26:102163.

[44]LuFM,ChenYC,CuiQ,et al.,2023.Shared and distinct patterns of dynamic functional connectivity variability of thalamo-cortical circuit in bipolar depression and major depressive disorder.Cereb Cortex,33(11):6681-6692.

[45]LuiS,WuQZ,QiuLH,et al.,2011.Resting-state functional connectivity in treatment-resistant depression.Am J Psychiatry,168(6):642-648.

[46]LundTE,MadsenKH,SidarosK,et al.,2006.Non-white noise in fMRI: does modelling have an impact?NeuroImage,29(1):54-66.

[47]McLeodKR,LangevinLM,GoodyearBG,et al.,2014.Functional connectivity of neural motor networks is disrupted in children with developmental coordination disorder and attention-deficit/hyperactivity disorder.NeuroImage Clin,4:566-575.

[48]MillerKD,PintoDJ,SimonsDJ,2001.Processing in layer 4 of the neocortical circuit: new insights from visual and somatosensory cortex.Curr Opin Neurobiol,11(4):‍488-497.

[49]MurataY,ColonneseMT,2018.Thalamus controls development and expression of arousal states in visual cortex.J Neurosci,38(41):8772-8786.

[50]OtteC,GoldSM,PenninxBW,et al.,2016.Major depressive disorder.Nat Rev Dis Primers,2:16065.

[51]PrattJA,MorrisBJ,2015.The thalamic reticular nucleus: a functional hub for thalamocortical network dysfunction in schizophrenia and a target for drug discovery.J Psychopharmacol,29(2):127-137.

[52]PurdonPL,WeisskoffRM,1998.Effect of temporal autocorrelation due to physiological noise and stimulus paradigm on voxel-level false-positive rates in fMRI.Hum Brain Mapp,6(4):239-249.

[53]RosenAFG,RoalfDR,RuparelK,et al.,2018.Quantitative assessment of structural image quality.NeuroImage,169:407-418.

[54]SaalmannYB,2014.Intralaminar and medial thalamic influence on cortical synchrony, information transmission and cognition.Front Syst Neurosci,8:83.

[55]SacchetMD,HoTC,ConnollyCG,et al.,2016.Large-scale hypoconnectivity between resting-state functional networks in unmedicated adolescent major depressive disorder.Neuropsychopharmacology,41(12):2951-2960.

[56]SanacoraG,TreccaniG,PopoliM,2012.Towards a glutamate hypothesis of depression: an emerging frontier of neuropsychopharmacology for mood disorders.Neuropharmacology,62(1):63-77.

[57]SchaeferA,KongR,GordonEM,et al.,2018.Local-global parcellation of the human cerebral cortex from intrinsic functional connectivity MRI.Cereb Cortex,28(9):‍3095-3114.

[58]SendiMSE,ZendehrouhE,SuiJ,et al.,2021.Abnormal dynamic functional network connectivity estimated from default mode network predicts symptom severity in major depressive disorder.Brain Connect,11(10):838-849.

[59]ShermanSM,2007.The thalamus is more than just a relay.Curr Opin Neurobiol,17(4):417-422.

[60]ShineJM,2019.Neuromodulatory influences on integration and segregation in the brain.Trends Cogn Sci,23(7):‍572-583.

[61]SteinerL,FederspielA,SlavovaN,et al.,2020.Functional topography of the thalamo-cortical system during development and its relation to cognition.NeuroImage,223:117361.

[62]SteriadeM,2001.Impact of network activities on neuronal properties in corticothalamic systems.J Neurophysiol,86(1):1-39.

[63]SunWZ,TanZC,MenshBD,et al.,2016.Thalamus provides layer 4 of primary visual cortex with orientation- and direction-tuned inputs.Nat Neurosci,19(2):308-315.

[64]Sweeney-ReedCM,BuentjenL,VogesJ,et al.,2021.The role of the anterior nuclei of the thalamus in human memory processing.Neurosci Biobehav Rev,126:146-158.

[65]TadayonnejadR,YangSL,KumarA,et al.,2015.Clinical, cognitive, and functional connectivity correlations of resting-state intrinsic brain activity alterations in unmedicated depression.J Affect Disord,172:241-250.

[66]VaccarinoAL,SillsTL,EvansKR,et al.,2009.Multiple pain complaints in patients with major depressive disorder.Psychosom Med,71(2):159-162.

[67]WangR,LiuMX,ChengXH,et al.,2021.Segregation, integration, and balance of large-scale resting brain networks configure different cognitive abilities.Proc Natl Acad Sci USA,118(23):e2022288118.

[68]WeelandCJ,VriendC,van der WerfY,et al.,2022a.Thalamic subregions and obsessive-compulsive symptoms in 2,500 children from the general population.J Am Acad Child Adolesc Psychiatry,61(2):321-330.

[69]WeelandCJ,KasprzakS,de JoodeNT,et al.,2022b.The thalamus and its subnuclei—a gateway to obsessive-compulsive disorder.Transl Psychiatry,12:70.

[70]WeiQ,BaiTJ,BrownEC,et al.,2020.Thalamocortical connectivity in electroconvulsive therapy for major depressive disorder.J Affect Disord,264:163-171.

[71]WilliamsJBW,1988.A structured interview guide for the Hamilton Depression Rating Scale.Arch Gen Psychiatry,45(8):742-747.

[72]WuXR,KongXZ,VatanseverD,et al.,2022.Dynamic changes in brain lateralization correlate with human cognitive performance.PLoS Biol,20(3):e3001560.

[73]XueSW,WangD,TanZ,et al.,2019.Disrupted brain entropy and functional connectivity patterns of thalamic subregions in major depressive disorder.Neuropsychiatr Dis Treat,15:2629-2638.

[74]YanCG,ZangYF,2010.DPARSF: a MATLAB toolbox for “pipeline” data analysis of resting-state fMRI.Front Syst Neurosci,4:13.

[75]YaoZJ,ShiJ,ZhangZ,et al.,2019a.Altered dynamic functional connectivity in weakly-connected state in major depressive disorder.Clin Neurophysiol,130(11):2096-2104.

[76]YaoZJ,ZouY,ZhengWH,et al.,2019b.Structural alterations of the brain preceded functional alterations in major depressive disorder patients: evidence from multimodal connectivity.J Affect Disord,253:107-117.

[77]YuYM,ZhengWH,TanXF,et al.,2021.Microstructural profiles of thalamus and thalamocortical connectivity in patients with disorder of consciousness.J Neurosci Res,99(12):3261-3273.

[78]YuanR,DiX,TaylorPA,et al.,2016.Functional topography of the thalamocortical system in human.Brain Struct Funct,221(4):1971-1984.

[79]ZhangDY,SnyderAZ,ShimonyJS,et al.,2010.Noninvasive functional and structural connectivity mapping of the human thalamocortical system.Cereb Cortex,20(5):‍1187-1194.

[80]ZhaoZY,ZhangYH,ChenN,et al.,2022.Altered temporal reachability highlights the role of sensory perception systems in major depressive disorder.Prog Neuropsychopharmacol Biol Psychiatry,112:110426.

[81]ZhengWH,TanXF,LiuTT,et al.,2021.Individualized thalamic parcellation reveals alterations in shape and microstructure of thalamic nuclei in patients with disorder of consciousness.Cereb Cortex Commun,2(2):tgab024.

[82]ZhiDM,CalhounVD,LvLX,et al.,2018.Aberrant dynamic functional network connectivity and graph properties in major depressive disorder.Front Psychiatry,9:339.

[83]ZhuFR,LiuF,GuoWB,et al.,2018.Disrupted asymmetry of inter- and intra-hemispheric functional connectivity in patients with drug-naive, first-episode schizophrenia and their unaffected siblings.eBioMedicine,36:429-435.