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Abnormal voxel-wise whole-brain functional connectivity in first-episode, drug-naïve adolescents with major depression disorder

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Abstract

Major depression disorder (MDD) is one of the most common psychiatric disorders. Previous studies have demonstrated structural and functional abnormalities in adult depression. However, the neurobiology of adolescent depression has not been fully understood. The aim of this study was to investigate the intrinsic dysconnectivity pattern of voxel-level whole-brain functional networks in first-episode, drug-naïve adolescents with MDD. Resting-state functional magnetic resonance imaging data were acquired from 66 depressed adolescents and 47 matched healthy controls. Voxel-wise degree centrality (DC) analysis was performed to identify voxels that showed altered whole-brain functional connectivity (FC) with other voxels. We further conducted seed-based FC analysis to investigate in more detail the connectivity patterns of the identified DC changes. The relationship between altered DC and clinical variables in depressed adolescents was also analyzed. Compared with controls, depressed adolescents showed lower DC in the bilateral hippocampus, left superior temporal gyrus and right insula. Seed-based analysis revealed that depressed adolescents, relative to controls, showed hypoconnectivity between the hippocampus to the medial prefrontal regions and right precuneus. Furthermore, the DC values in the bilateral hippocampus were correlated with the Hamilton Depression Rating Scale score and duration of disease (all P < 0.05, false discovery rate corrected). Our study indicates abnormal intrinsic dysconnectivity patterns of whole-brain functional networks in drug-naïve, first-episode adolescents with MDD, and abnormal DC in the hippocampus may affect the association of prefrontal-hippocampus circuit. These findings may provide new insights into the pathophysiology of adolescent-onset MDD.

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Data availability statement

The fMRI data used to support the findings of this study are restricted by the research ethical committee of the First Affiliated Hospital of Zhengzhou University, to protect patient privacy.

References

  1. Anticevic A, Brumbaugh MS, Winkler AM, Lombardo LE, Barrett J, Corlett PR, Kober H, Gruber J, Repovs G, Cole MW, Krystal JH, Pearlson GD, Glahn DC (2013) Global prefrontal and fronto-amygdala dysconnectivity in bipolar I disorder with psychosis history. Biol Psychiatry 73:565–573

    Article  PubMed  Google Scholar 

  2. Ashburner J (2007) A fast diffeomorphic image registration algorithm. Neuroimage 38:95–113

    Article  PubMed  Google Scholar 

  3. Biswal B, Zerrin Yetkin F, Haughton VM, Hyde JS (1995) Functional connectivity in the motor cortex of resting human brain using echo-planar MRI. Magn Reson Med 34:537–541

    Article  CAS  PubMed  Google Scholar 

  4. Brooks SJ, Kutcher S (2001) Diagnosis and measurement of adolescent depression: a review of commonly utilized instruments. J Child Adolesc Psychopharmacol 11:341–376

    Article  CAS  PubMed  Google Scholar 

  5. Buckner RL, Sepulcre J, Talukdar T, Krienen FM, Liu H, Hedden T, Andrews-Hanna JR, Sperling RA, Johnson KA (2009) Cortical hubs revealed by intrinsic functional connectivity: mapping, assessment of stability, and relation to Alzheimer’s disease. J Neurosci 29:1860–1873

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Burgess GC, Kandala S, Nolan D, Laumann TO, Power JD, Adeyemo B, Harms MP, Petersen SE, Barch DM (2016) Evaluation of denoising strategies to address motion-correlated artifacts in resting-state functional magnetic resonance imaging data from the Human Connectome Project. Brain Connect 6:669–680

    Article  PubMed  PubMed Central  Google Scholar 

  7. Cao X, Liu Z, Xu C, Li J, Gao Q, Sun N, Xu Y, Ren Y, Yang C, Zhang K (2012) Disrupted resting-state functional connectivity of the hippocampus in medication-naïve patients with major depressive disorder. J Affect Disord 141:194–203

    Article  PubMed  Google Scholar 

  8. Catani M, Dell’acqua F, Thiebaut de Schotten M (2013) A revised limbic system model for memory, emotion and behaviour. Neurosci Biobehav Rev 37:1724–1737

    Article  PubMed  Google Scholar 

  9. Cheng YQ, Xu J, Chai P, Li HJ, Luo CR, Yang T, Li L, Shan BC, Xu XF, Xu L (2010) Brain volume alteration and the correlations with the clinical characteristics in drug-naive first-episode MDD patients: a voxel-based morphometry study. Neurosci Lett 480:30–34

    Article  CAS  PubMed  Google Scholar 

  10. Cole J, Costafreda SG, McGuffin P, Fu CH (2011) Hippocampal atrophy in first episode depression: a meta-analysis of magnetic resonance imaging studies. J Affect Disord 134:483–487

    Article  PubMed  Google Scholar 

  11. Connolly CG, Wu J, Ho TC, Hoeft F, Wolkowitz O, Eisendrath S, Frank G, Hendren R, Max JE, Paulus MP, Tapert SF, Banerjee D, Simmons AN, Yang TT (2013) Resting-state functional connectivity of subgenual anterior cingulate cortex in depressed adolescents. Biol Psychiatry 74:898–907

    Article  PubMed  PubMed Central  Google Scholar 

  12. Cullen KR, Gee DG, Klimes-Dougan B, Gabbay V, Hulvershorn L, Mueller BA, Camchong J, Bell CJ, Houri A, Kumra S, Lim KO, Castellanos FX, Milham MP (2009) A preliminary study of functional connectivity in comorbid adolescent depression. Neurosci Lett 460:227–231

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Davey CG, Harrison BJ, Yücel M, Allen NB (2012) Regionally specific alterations in functional connectivity of the anterior cingulate cortex in major depressive disorder. Psychol Med 42:2071–2081

    Article  CAS  PubMed  Google Scholar 

  14. Di Martino A, Zuo XN, Kelly C, Grzadzinski R, Mennes M, Schvarcz A, Rodman J, Lord C, Castellanos FX, Milham MP (2013) Shared and distinct intrinsic functional network centrality in autism and attention-deficit/hyperactivity disorder. Biol Psychiatry 74:623–632

    Article  PubMed  PubMed Central  Google Scholar 

  15. First MSR, Gibbon M, Williams J (1997) Structured clinical interview for DSM-IV axis I disorders. American Psychiatric Publishing, Washington, DC

    Google Scholar 

  16. Gabbay V, Ely BA, Li Q, Bangaru SD, Panzer AM, Alonso CM, Castellanos FX, Milham MP (2013) Striatum-based circuitry of adolescent depression and anhedonia. J Am Acad Child Adolesc Psychiatry 52:628-641.e613

    Article  PubMed  PubMed Central  Google Scholar 

  17. Gasquoine PG (2013) Localization of function in anterior cingulate cortex: from psychosurgery to functional neuroimaging. Neurosci Biobehav Rev 37:340–348

    Article  PubMed  Google Scholar 

  18. Geng H, Wu F, Kong L, Tang Y, Zhou Q, Chang M, Zhou Y, Jiang X, Li S, Wang F (2016) Disrupted structural and functional connectivity in prefrontal-hippocampus circuitry in first-episode medication-naïve adolescent depression. PLoS ONE 11:e0148345

    Article  PubMed  PubMed Central  Google Scholar 

  19. Genovese CR, Lazar NA, Nichols T (2002) Thresholding of statistical maps in functional neuroimaging using the false discovery rate. Neuroimage 15:870–878

    Article  PubMed  Google Scholar 

  20. Han S, Cui Q, Wang X, Li L, Li D, He Z, Guo X, Fan YS, Guo J, Sheng W, Lu F, Chen H (2020) Resting state functional network switching rate is differently altered in bipolar disorder and major depressive disorder. Hum Brain Mapp 41:3295–3304

    Article  PubMed  PubMed Central  Google Scholar 

  21. Han S, He Z, Duan X, Tang Q, Chen Y, Yang Y, Pang Y, Nan X, Cui Q, Chen H (2019) Dysfunctional connectivity between raphe nucleus and subcortical regions presented opposite differences in bipolar disorder and major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry 92:76–82

    Article  PubMed  Google Scholar 

  22. Ho TC, Wu J, Shin DD, Liu TT, Tapert SF, Yang G, Connolly CG, Frank GK, Max JE, Wolkowitz O, Eisendrath S, Hoeft F, Banerjee D, Hood K, Hendren RL, Paulus MP, Simmons AN, Yang TT (2013) Altered cerebral perfusion in executive, affective, and motor networks during adolescent depression. J Am Acad Child Adolesc Psychiatry 52:1076-1091.e1072

    Article  PubMed  Google Scholar 

  23. Ho TC, Yang G, Wu J, Cassey P, Brown SD, Hoang N, Chan M, Connolly CG, Henje-Blom E, Duncan LG, Chesney MA, Paulus MP, Max JE, Patel R, Simmons AN, Yang TT (2014) Functional connectivity of negative emotional processing in adolescent depression. J Affect Disord 155:65–74

    Article  PubMed  Google Scholar 

  24. Hu L, Xiao M, Ai M, Wang W, Chen J, Tan Z, Cao J, Kuang L (2019) Disruption of resting-state functional connectivity of right posterior insula in adolescents and young adults with major depressive disorder. J Affect Disord 257:23–30

    Article  PubMed  Google Scholar 

  25. Hua K, Wang T, Li C, Li S, Ma X, Li C, Li M, Fu S, Yin Y, Wu Y, Liu M, Yu K, Fang J, Wang P, Jiang G (2018) Abnormal degree centrality in chronic users of codeine-containing cough syrups: a resting-state functional magnetic resonance imaging study. Neuroimage Clin 19:775–781

    Article  PubMed  PubMed Central  Google Scholar 

  26. Jiang X, Wang X, Jia L, Sun T, Kang J, Zhou Y, Wei S, Wu F, Kong L, Wang F, Tang Y (2021) Structural and functional alterations in untreated patients with major depressive disorder and bipolar disorder experiencing first depressive episode: a magnetic resonance imaging study combined with follow-up. J Affect Disord 279:324–333

    Article  PubMed  Google Scholar 

  27. Kessler RC, Walters EE (1998) Epidemiology of DSM-III-R major depression and minor depression among adolescents and young adults in the national comorbidity survey. Depress Anxiety 7:3–14

    Article  CAS  PubMed  Google Scholar 

  28. Kim JH, Suh SI, Lee HJ, Lee JH, Lee MS (2019) Cortical and subcortical gray matter alterations in first-episode drug-naïve adolescents with major depressive disorder. NeuroReport 30:1172–1178

    Article  PubMed  PubMed Central  Google Scholar 

  29. LeGates TA, Kvarta MD, Tooley JR, Francis TC, Lobo MK, Creed MC, Thompson SM (2018) Reward behaviour is regulated by the strength of hippocampus-nucleus accumbens synapses. Nature 564:258–262

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Li H, Li L, Shao Y, Gong H, Zhang W, Zeng X, Ye C, Nie S, Chen L, Peng D (2016) Abnormal intrinsic functional hubs in severe male obstructive sleep apnea: evidence from a voxel-wise degree centrality analysis. PLoS ONE 11:e0164031

    Article  PubMed  PubMed Central  Google Scholar 

  31. Li J, Gong H, Xu H, Ding Q, He N, Huang Y, Jin Y, Zhang C, Voon V, Sun B, Yan F, Zhan S (2019) Abnormal voxel-wise degree centrality in patients with late-life depression: a resting-state functional magnetic resonance imaging study. Front Psychiatry 10:1024

    Article  CAS  PubMed  Google Scholar 

  32. Li M, Das T, Deng W, Wang Q, Li Y, Zhao L, Ma X, Wang Y, Yu H, Li X, Meng Y, Palaniyappan L, Li T (2017) Clinical utility of a short resting-state MRI scan in differentiating bipolar from unipolar depression. Acta Psychiatr Scand 136:288–299

    Article  CAS  PubMed  Google Scholar 

  33. Li S, Ma X, Huang R, Li M, Tian J, Wen H, Lin C, Wang T, Zhan W, Fang J, Jiang G (2016) Abnormal degree centrality in neurologically asymptomatic patients with end-stage renal disease: a resting-state fMRI study. Clin Neurophysiol 127:602–609

    Article  PubMed  Google Scholar 

  34. Lisman J, Buzsáki G, Eichenbaum H, Nadel L, Ranganath C, Redish AD (2017) Viewpoints: how the hippocampus contributes to memory, navigation and cognition. Nat Neurosci 20:1434–1447

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. MacQueen GM (2009) Magnetic resonance imaging and prediction of outcome in patients with major depressive disorder. J Psychiatry Neurosci 34:343–349

    PubMed  PubMed Central  Google Scholar 

  36. Murphy K, Fox MD (2017) Towards a consensus regarding global signal regression for resting state functional connectivity MRI. Neuroimage 154:169–173

    Article  PubMed  Google Scholar 

  37. Myers K, Winters NC (2002) Ten-year review of rating scales. I: overview of scale functioning, psychometric properties, and selection. J Am Acad Child Adolesc Psychiatry 41:114–122

    Article  PubMed  Google Scholar 

  38. Myers K, Winters NC (2002) Ten-year review of rating scales. II: Scales for internalizing disorders. J Am Acad Child Adolesc Psychiatry 41:634–659

    Article  PubMed  Google Scholar 

  39. Namkung H, Kim SH, Sawa A (2017) The insula: an underestimated brain area in clinical neuroscience, psychiatry, and neurology. Trends Neurosci 40:200–207

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Pan F, Xu Y, Zhou W, Chen J, Wei N, Lu S, Shang D, Wang J, Huang M (2020) Disrupted intrinsic functional connectivity of the cognitive control network underlies disease severity and executive dysfunction in first-episode, treatment-naive adolescent depression. J Affect Disord 264:455–463

    Article  PubMed  Google Scholar 

  41. Peng W, Chen Z, Yin L, Jia Z, Gong Q (2016) Essential brain structural alterations in major depressive disorder: a voxel-wise meta-analysis on first episode, medication-naive patients. J Affect Disord 199:114–123

    Article  PubMed  Google Scholar 

  42. Peng X, Lin P, Wu X, Gong R, Yang R, Wang J (2018) Insular subdivisions functional connectivity dysfunction within major depressive disorder. J Affect Disord 227:280–288

    Article  PubMed  Google Scholar 

  43. Redlich R, Opel N, Bürger C, Dohm K, Grotegerd D, Förster K, Zaremba D, Meinert S, Repple J, Enneking V, Leehr E, Böhnlein J, Winters L, Froböse N, Thrun S, Emtmann J, Heindel W, Kugel H, Arolt V, Romer G, Postert C, Dannlowski U (2018) The limbic system in youth depression: brain structural and functional alterations in adolescent in-patients with severe depression. Neuropsychopharmacology 43:546–554

    Article  PubMed  Google Scholar 

  44. Revah-Levy A, Birmaher B, Gasquet I, Falissard B (2007) The Adolescent Depression Rating Scale (ADRS): a validation study. BMC Psychiatry 7:2

    Article  PubMed  PubMed Central  Google Scholar 

  45. Reynolds S, Carrey N, Jaworska N, Langevin LM, Yang XR, Macmaster FP (2014) Cortical thickness in youth with major depressive disorder. BMC Psychiatry 14:83

    Article  PubMed  PubMed Central  Google Scholar 

  46. Shad MU, Muddasani S, Rao U (2012) Gray matter differences between healthy and depressed adolescents: a voxel-based morphometry study. J Child Adolesc Psychopharmacol 22:190–197

    Article  PubMed  PubMed Central  Google Scholar 

  47. Shen T, Qiu M, Li C, Zhang J, Wu Z, Wang B, Jiang K, Peng D (2014) Altered spontaneous neural activity in first-episode, unmedicated patients with major depressive disorder. NeuroReport 25:1302–1307

    Article  CAS  PubMed  Google Scholar 

  48. Shen Y, Yao J, Jiang X, Zhang L, Xu L, Feng R, Cai L, Liu J, Wang J, Chen W (2015) Sub-hubs of baseline functional brain networks are related to early improvement following two-week pharmacological therapy for major depressive disorder. Hum Brain Mapp 36:2915–2927

    Article  PubMed  PubMed Central  Google Scholar 

  49. Smitha KA, Akhil Raja K, Arun KM, Rajesh PG, Thomas B, Kapilamoorthy TR, Kesavadas C (2017) Resting state fMRI: a review on methods in resting state connectivity analysis and resting state networks. Neuroradiol J 30:305–317

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Song XW, Dong ZY, Long XY, Li SF, Zuo XN, Zhu CZ, He Y, Yan CG, Zang YF (2011) REST: a toolkit for resting-state functional magnetic resonance imaging data processing. PLoS ONE 6:e25031

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Straub J, Brown R, Malejko K, Bonenberger M, Grön G, Plener PL, Abler B (2019) Adolescent depression and brain development: evidence from voxel-based morphometry. J Psychiatry Neurosci 44:237–245

    Article  PubMed  PubMed Central  Google Scholar 

  52. Straub J, Metzger CD, Plener PL, Koelch MG, Groen G, Abler B (2017) Successful group psychotherapy of depression in adolescents alters fronto-limbic resting-state connectivity. J Affect Disord 209:135–139

    Article  CAS  PubMed  Google Scholar 

  53. Uddin LQ, Nomi JS, Hébert-Seropian B, Ghaziri J, Boucher O (2017) Structure and function of the human insula. J Clin Neurophysiol 34:300–306

    Article  PubMed  PubMed Central  Google Scholar 

  54. Wang JH, Zuo XN, Gohel S, Milham MP, Biswal BB, He Y (2011) Graph theoretical analysis of functional brain networks: test–retest evaluation on short- and long-term resting-state functional MRI data. PLoS ONE 6:e21976

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Whitfield-Gabrieli S, Ford JM (2012) Default mode network activity and connectivity in psychopathology. Annu Rev Clin Psychol 8:49–76

    Article  PubMed  Google Scholar 

  56. Wiles N, Thomas L, Abel A, Ridgway N, Turner N, Campbell J, Garland A, Hollinghurst S, Jerrom B, Kessler D, Kuyken W, Morrison J, Turner K, Williams C, Peters T, Lewis G (2013) Cognitive behavioural therapy as an adjunct to pharmacotherapy for primary care based patients with treatment resistant depression: results of the CoBalT randomised controlled trial. Lancet 381:375–384

    Article  PubMed  Google Scholar 

  57. Wise T, Radua J, Via E, Cardoner N, Abe O, Adams TM, Amico F, Cheng Y, Cole JH, de Azevedo Marques Périco C, Dickstein DP, Farrow TFD, Frodl T, Wagner G, Gotlib IH, Gruber O, Ham BJ, Job DE, Kempton MJ, Kim MJ, Koolschijn P, Malhi GS, Mataix-Cols D, McIntosh AM, Nugent AC, O’Brien JT, Pezzoli S, Phillips ML, Sachdev PS, Salvadore G, Selvaraj S, Stanfield AC, Thomas AJ, van Tol MJ, van der Wee NJA, Veltman DJ, Young AH, Fu CH, Cleare AJ, Arnone D (2017) Common and distinct patterns of grey-matter volume alteration in major depression and bipolar disorder: evidence from voxel-based meta-analysis. Mol Psychiatry 22:1455–1463

    Article  CAS  PubMed  Google Scholar 

  58. Woolrich MW, Ripley BD, Brady M, Smith SM (2001) Temporal autocorrelation in univariate linear modeling of FMRI data. Neuroimage 14:1370–1386

    Article  CAS  PubMed  Google Scholar 

  59. Yan C-G, Wang X-D, Zuo X-N, Zang Y-F (2016) DPABI: data processing and analysis for (resting-state) brain imaging. Neuroinformatics 14:339–351

    Article  PubMed  Google Scholar 

  60. Yang H, Luo X, Yu H, Guo M, Cao C, Li Y, Fan G (2020) Altered resting-state voxel-level whole-brain functional connectivity in multiple system atrophy patients with cognitive impairment. Clin Neurophysiol 131:54–62

    Article  PubMed  Google Scholar 

  61. Zhang FF, Peng W, Sweeney JA, Jia ZY, Gong QY (2018) Brain structure alterations in depression: psychoradiological evidence. CNS Neurosci Ther 24:994–1003

    Article  PubMed  PubMed Central  Google Scholar 

  62. Zhang H, Li L, Wu M, Chen Z, Hu X, Chen Y, Zhu H, Jia Z, Gong Q (2016) Brain gray matter alterations in first episodes of depression: a meta-analysis of whole-brain studies. Neurosci Biobehav Rev 60:43–50

    Article  PubMed  Google Scholar 

  63. Zhang J, Wang J, Wu Q, Kuang W, Huang X, He Y, Gong Q (2011) Disrupted brain connectivity networks in drug-naive, first-episode major depressive disorder. Biol Psychiatry 70:334–342

    Article  PubMed  Google Scholar 

  64. Zimmerman M, Martinez JH, Young D, Chelminski I, Dalrymple K (2013) Severity classification on the Hamilton Depression Rating Scale. J Affect Disord 150:384–388

    Article  PubMed  Google Scholar 

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Acknowledgements

This research study was supported by the Natural Science Foundation of China (nos. 81601467, 81871327, 81601472).

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Authors and Affiliations

  1. Functional and Molecular Imaging Key Laboratory of Henan Province, Department of Magnetic Resonance Imaging, The First Affiliated Hospital of Zhengzhou University, Henan, People’s Republic of China

    Ruiping Zheng, Yuan Chen, Yu Jiang, Bingqian Zhou, Shaoqiang Han, Yarui Wei, Caihong Wang & Jingliang Cheng

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  1. Ruiping Zheng
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  2. Yuan Chen
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Contributions

RZ, YC, and SH conceived and designed the study. RZ and YC supervised the conduct of the study. YC, YJ, and BZ are responsible for data acquisition. RZ, BZ, and YC analyzed the data. RZ, YC, YJ, and YW assisted with literature review. RZ, YC, and SH drafted the initial manuscript, and JC, YZ, SH, YW, and CW reviewed and revised the manuscript. RZ and YC takes responsibility for the paper. All the authors read and approved the final manuscript.

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Correspondence to Jingliang Cheng.

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Zheng, R., Chen, Y., Jiang, Y. et al. Abnormal voxel-wise whole-brain functional connectivity in first-episode, drug-naïve adolescents with major depression disorder. Eur Child Adolesc Psychiatry 32, 1317–1327 (2023). https://doi.org/10.1007/s00787-022-01959-y

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