Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Disrupted subcortical functional connectome gradient in drug-naïve first-episode schizophrenia and the normalization effects after antipsychotic treatment

Neuropsychopharmacology (2022)Cite this article

Subjects

Abstract

Antipsychotics are thought to improve schizophrenia symptoms through the antagonism of dopamine D2 receptors, which are abundant mainly in subcortical regions. By introducing functional gradient, a novel approach to identify hierarchy alterations by capturing the similarity of whole brain fucntional connectivity (FC) profiles between two voxels, the present study aimed to characterize how the subcortical gradient is associated with treatment effects and response in first-episode schizophrenia in vivo. Two independent samples of first-episode schizophrenia (FES) patients with matched healthy controls (HC) were obtained: the discovery dataset included 71 patients (FES0W) and 64 HC at baseline, and patients were re-scanned after either 6 weeks (FES6W, N = 33) or 12 months (FES12M, N = 57) of antipsychotic treatment, of which 19 patients finished both 6-week and 12-month evaluation. The validation dataset included 22 patients and 24 HC at baseline and patients were re-scanned after 6 weeks. Gradient metrics were calculated using BrainSpace Toolbox. Voxel-based gradient values were generated and group-averaged gradient values were further extracted across all voxels (global), three systems (thalamus, limbic and striatum) and their subcortical subfields. The comparisons were conducted separately between FES0W and HC for investigating illness effects, and between FES6W/FES12M and FES0W for treatment effects. Correlational analyses were then conducted between the longitudinal gradient alterations and the improvement of clinical ratings. Before treatment, schizophrenia patients exhibited an expanded range of global gradient scores compared to HC which indicated functional segregation within subcortical systems. The increased gradient in limbic system and decreased gradient in thalamic and striatal system contributed to the baseline abnormalities and led to the disruption of the subcortical functional integration. After treatment, these disruptions were normalized and the longitudinal changes of gradient scores in limbic system were significantly associated with symptom improvement. Similar illness and treatment effects were also observed in the validation dataset. By measuring functional hierarchy of subcortical organization, our findings provide a novel imaging marker that is sensitive to treatment effects and may make a promising indicator of treatment response in schizophrenia.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Group differences of the group-averaged subcortical gradient scores at global- and system-levels between schizophrenia at baseline and healthy control as well as the longitudinal alterations in 6-week and 12-month follow-up relative to baseline abnormalities.
Fig. 2: Associations of longitudinal subcortical gradient score changes after 12-month treatment and symptom improvement in schizophrenia patients.

References

  1. Lehman AF, Lieberman JA, Dixon LB, McGlashan TH, Miller AL, Perkins DO, et al. Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry. 2004;161:1–56.

    Google Scholar 

  2. Kapur S, Remington G. Dopamine D(2) receptors and their role in atypical antipsychotic action: still necessary and may even be sufficient. Biol Psychiatry. 2001;50:873–83.

    Article  CAS  Google Scholar 

  3. McCutcheon RA, Reis Marques T, Howes OD. Schizophrenia—an overview. JAMA Psychiatry. 2020;77:201–10.

    Article  Google Scholar 

  4. Andersen HG, Raghava JM, Svarer C, Wulff S, Johansen LB, Antonsen PK, et al. Striatal volume increase after six weeks of selective dopamine D(2/3) receptor blockade in first-episode, antipsychotic-naïve schizophrenia patients. Front Neurosci. 2020;14:484.

    Article  Google Scholar 

  5. Yue Y, Kong L, Wang J, Li C, Tan L, Su H, et al. Regional abnormality of grey matter in schizophrenia: effect from the illness or treatment? PLoS ONE. 2016;11:e0147204.

    Article  Google Scholar 

  6. Li M, Chen Z, Deng W, He Z, Wang Q, Jiang L, et al. Volume increases in putamen associated with positive symptom reduction in previously drug-naive schizophrenia after 6 weeks antipsychotic treatment. Psychol Med. 2012;42:1475–83.

    Article  CAS  Google Scholar 

  7. Ebdrup BH, Skimminge A, Rasmussen H, Aggernaes B, Oranje B, Lublin H, et al. Progressive striatal and hippocampal volume loss in initially antipsychotic-naive, first-episode schizophrenia patients treated with quetiapine: relationship to dose and symptoms. Int J Neuropsychopharmacol. 2011;14:69–82.

    Article  CAS  Google Scholar 

  8. Chopra S, Francey SM, O’Donoghue B, Sabaroedin K, Arnatkeviciute A, Cropley V, et al. Functional connectivity in antipsychotic-treated and antipsychotic-naive patients with first-episode psychosis and low risk of self-harm or aggression: a secondary analysis of a randomized clinical trial. JAMA Psychiatry. 2021;78:994–1004.

    Article  Google Scholar 

  9. Lui S, Li T, Deng W, Jiang L, Wu Q, Tang H, et al. Short-term effects of antipsychotic treatment on cerebral function in drug-naive first-episode schizophrenia revealed by “resting state” functional magnetic resonance imaging. Arch Gen Psychiatry. 2010;67:783–92.

    Article  Google Scholar 

  10. Han S, Becker B, Duan X, Cui Q, Xin F, Zong X, et al. Distinct striatum pathways connected to salience network predict symptoms improvement and resilient functioning in schizophrenia following risperidone monotherapy. Schizophr Res. 2020;215:89–96.

    Article  Google Scholar 

  11. Szulc A, Galinska-Skok B, Waszkiewicz N, Bibulowicz D, Konarzewska B, Tarasow E. Proton magnetic resonance spectroscopy changes after antipsychotic treatment. Curr Med Chem. 2013;20:414–27.

    CAS  Google Scholar 

  12. Kubota M, Moriguchi S, Takahata K, Nakajima S, Horita N. Treatment effects on neurometabolite levels in schizophrenia: a systematic review and meta-analysis of proton magnetic resonance spectroscopy studies. Schizophr Res. 2020;222:122–32.

    Article  Google Scholar 

  13. Li W, Li K, Guan P, Chen Y, Xiao Y, Lui S, et al. Volume alteration of hippocampal subfields in first-episode antipsychotic-naive schizophrenia patients before and after acute antipsychotic treatment. Neuroimage Clin. 2018;20:169–76.

    Article  Google Scholar 

  14. Howes OD, McCutcheon R, Agid O, de Bartolomeis A, van Beveren NJ, Birnbaum ML, et al. Treatment-resistant schizophrenia: Treatment Response and Resistance in Psychosis (TRRIP) Working Group Consensus Guidelines on Diagnosis and Terminology. Am J Psychiatry. 2017;174:216–29.

    Article  Google Scholar 

  15. Vos de Wael R, Benkarim O, Paquola C, Lariviere S, Royer J, Tavakol S, et al. BrainSpace: a toolbox for the analysis of macroscale gradients in neuroimaging and connectomics datasets. Commun Biol. 2020;3:103.

    Article  Google Scholar 

  16. Burt JB, Demirtaş M, Eckner WJ, Navejar NM, Ji JL, Martin WJ, et al. Hierarchy of transcriptomic specialization across human cortex captured by structural neuroimaging topography. Nat Neurosci. 2018;21:1251–9.

    Article  CAS  Google Scholar 

  17. Margulies DS, Ghosh SS, Goulas A, Falkiewicz M, Huntenburg JM, Langs G, et al. Situating the default-mode network along a principal gradient of macroscale cortical organization. Proc Natl Acad Sci USA. 2016;113:12574–9.

    Article  CAS  Google Scholar 

  18. Wang XJ. Macroscopic gradients of synaptic excitation and inhibition in the neocortex. Nat Rev Neurosci. 2020;21:169–78.

    Article  CAS  Google Scholar 

  19. Huntenburg JM, Bazin PL, Margulies DS. Large-scale gradients in human cortical organization. Trends Cogn Sci. 2018;22:21–31.

    Article  Google Scholar 

  20. Marquand AF, Haak KV, Beckmann CF. Functional corticostriatal connection topographies predict goal directed behaviour in humans. Nat Hum Behav. 2017;1:0146.

    Article  Google Scholar 

  21. Vos de Wael R, Larivière S, Caldairou B, Hong SJ, Margulies DS, Jefferies E, et al. Anatomical and microstructural determinants of hippocampal subfield functional connectome embedding. Proc Natl Acad Sci USA. 2018;115:10154–9.

    Article  Google Scholar 

  22. Tian Y, Zalesky A, Bousman C, Everall I, Pantelis C. Insula functional connectivity in schizophrenia: subregions, gradients, and symptoms. Biol Psychiatry Cogn Neurosci Neuroimaging. 2019;4:399–408.

    Google Scholar 

  23. Singh SP, Cooper JE, Fisher HL, Tarrant CJ, Lloyd T, Banjo J, et al. Determining the chronology and components of psychosis onset: The Nottingham Onset Schedule (NOS). Schizophr Res. 2005;80:117–30.

    Article  Google Scholar 

  24. Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull. 1987;13:261–76.

    Article  CAS  Google Scholar 

  25. Aas IH. Guidelines for rating Global Assessment of Functioning (GAF). Ann Gen Psychiatry. 2011;10:2.

    Article  Google Scholar 

  26. Wallwork RS, Fortgang R, Hashimoto R, Weinberger DR, Dickinson D. Searching for a consensus five-factor model of the Positive and Negative Syndrome Scale for schizophrenia. Schizophr Res. 2012;137:246–50.

    Article  CAS  Google Scholar 

  27. Cao H, Wei X, Hu N, Zhang W, Xiao Y, Zeng J, et al. Cerebello-thalamo-cortical hyperconnectivity classifies patients and predicts long-term treatment outcome in first-episode schizophrenia. Schizophr Bull. 2022;48:505–13.

    Article  Google Scholar 

  28. Yang B, Zhang W, Lencer R, Tao B, Tang B, Yang J, et al. Grey matter connectome abnormalities and age-related effects in antipsychotic-naive schizophrenia. EBioMedicine 2021;74:103749.

    Article  CAS  Google Scholar 

  29. Andreasen NC, Pressler M, Nopoulos P, Miller D, Ho BC. Antipsychotic dose equivalents and dose-years: a standardized method for comparing exposure to different drugs. Biol Psychiatry. 2010;67:255–62.

    Article  CAS  Google Scholar 

  30. Yan CG, Wang XD, Zuo XN, Zang YF. DPABI: data processing & analysis for (resting-state) brain imaging. Neuroinformatics. 2016;14:339–51.

    Article  Google Scholar 

  31. Friston KJ, Williams S, Howard R, Frackowiak RS, Turner R. Movement-related effects in fMRI time-series. Magn Reson Med. 1996;35:346–55.

    Article  CAS  Google Scholar 

  32. Tian Y, Margulies DS, Breakspear M, Zalesky A. Topographic organization of the human subcortex unveiled with functional connectivity gradients. Nat Neurosci. 2020;23:1421–32.

    Article  CAS  Google Scholar 

  33. Schaefer A, Kong R, Gordon EM, Laumann TO, Zuo XN, Holmes AJ, et al. Local-global parcellation of the human cerebral cortex from intrinsic functional connectivity MRI. Cereb Cortex. 2018;28:3095–114.

    Article  Google Scholar 

  34. Coifman RR, Lafon S, Lee AB, Maggioni M, Nadler B, Warner F, et al. Geometric diffusions as a tool for harmonic analysis and structure definition of data: diffusion maps. Proc Natl Acad Sci USA. 2005;102:7426–31.

    Article  CAS  Google Scholar 

  35. Tenenbaum JB, de Silva V, Langford JC. A global geometric framework for nonlinear dimensionality reduction. Science. 2000;290:2319–23.

    Article  CAS  Google Scholar 

  36. Langs G, Golland P, Ghosh SS. Predicting activation across individuals with resting-state functional connectivity based multi-atlas label fusion. Med Image Comput Comput Assist Inter. 2015;9350:313–20.

    Google Scholar 

  37. Meng Y, Yang S, Chen H, Li J, Xu Q, Zhang Q, et al. Systematically disrupted functional gradient of the cortical connectome in generalized epilepsy: Initial discovery and independent sample replication. Neuroimage. 2021;230:117831.

    Article  Google Scholar 

  38. Sabaroedin K, Razi A, Chopra S, Tran N, Pozaruk A, Chen Z, et al. Frontostriatothalamic effective connectivity and dopaminergic function in the psychosis continuum. Brain. 2022. https://doi.org/10.1093/brain/awac018.

  39. Howes OD, Kapur S. The dopamine hypothesis of schizophrenia: version III–the final common pathway. Schizophr Bull. 2009;35:549–62.

    Article  Google Scholar 

  40. Chopra S, Fornito A, Francey SM, O’Donoghue B, Cropley V, Nelson B, et al. Differentiating the effect of antipsychotic medication and illness on brain volume reductions in first-episode psychosis: a longitudinal, randomised, triple-blind, placebo-controlled MRI study. Neuropsychopharmacology. 2021;46:1494–501.

    Article  CAS  Google Scholar 

  41. Ceraso A, Lin JJ, Schneider-Thoma J, Siafis S, Tardy M, Komossa K, et al. Maintenance treatment with antipsychotic drugs for schizophrenia. Cochrane Database Syst Rev. 2020;8:Cd008016.

    Google Scholar 

  42. Kraguljac NV, McDonald WM, Widge AS, Rodriguez CI, Tohen M, Nemeroff CB. Neuroimaging biomarkers in schizophrenia. Am J Psychiatry. 2021;178:509–21.

    Article  Google Scholar 

  43. Huang XF, Song X. Effects of antipsychotic drugs on neurites relevant to schizophrenia treatment. Med Res Rev. 2019;39:386–403.

    Article  CAS  Google Scholar 

  44. Thornton MA, Hughes EG. Neuron-oligodendroglia interactions: activity-dependent regulation of cellular signaling. Neurosci Lett. 2020;727:134916.

    Article  CAS  Google Scholar 

  45. Molina V, Sanz J, Sarramea F, Benito C, Palomo T. Prefrontal atrophy in first episodes of schizophrenia associated with limbic metabolic hyperactivity. J Psychiatr Res. 2005;39:117–27.

    Article  Google Scholar 

  46. Jones CA, Watson DJ, Fone KC. Animal models of schizophrenia. Br J Pharm. 2011;164:1162–94.

    Article  CAS  Google Scholar 

  47. Lahti AC, Weiler MA, Holcomb HH, Tamminga CA, Cropsey KL. Modulation of limbic circuitry predicts treatment response to antipsychotic medication: a functional imaging study in schizophrenia. Neuropsychopharmacology. 2009;34:2675–90.

    Article  CAS  Google Scholar 

  48. Duan X, Hu M, Huang X, Dong X, Zong X, He C, et al. Effects of risperidone monotherapy on the default-mode network in antipsychotic-naive first-episode schizophrenia: posteromedial cortex heterogeneity and relationship with the symptom improvements. Schizophr Res. 2020;218:201–8.

    Article  Google Scholar 

  49. Tamminga CA, Stan AD, Wagner AD. The hippocampal formation in schizophrenia. Am J Psychiatry. 2010;167:1178–93.

    Article  Google Scholar 

  50. Harrison PJ. The neuropathology of schizophrenia. A critical review of the data and their interpretation. Brain. 1999;122:593–624.

    Article  Google Scholar 

  51. Heckers S, Konradi C. Hippocampal neurons in schizophrenia. J Neural Transm. 2002;109:891–905.

    Article  CAS  Google Scholar 

  52. Blaha CD, Yang CR, Floresco SB, Barr AM, Phillips AG. Stimulation of the ventral subiculum of the hippocampus evokes glutamate receptor-mediated changes in dopamine efflux in the rat nucleus accumbens. Eur J Neurosci. 1997;9:902–11.

    Article  CAS  Google Scholar 

  53. Legault M, Wise RA. Injections of N-methyl-D-aspartate into the ventral hippocampus increase extracellular dopamine in the ventral tegmental area and nucleus accumbens. Synapse. 1999;31:241–9.

    Article  CAS  Google Scholar 

  54. Gill KM, Lodge DJ, Cook JM, Aras S, Grace AA. A novel α5GABA(A)R-positive allosteric modulator reverses hyperactivation of the dopamine system in the MAM model of schizophrenia. Neuropsychopharmacology. 2011;36:1903–11.

    Article  CAS  Google Scholar 

  55. Phillips AG, Ahn S, Howland JG. Amygdalar control of the mesocorticolimbic dopamine system: parallel pathways to motivated behavior. Neurosci Biobehav Rev. 2003;27:543–54.

    Article  CAS  Google Scholar 

  56. Gur RE, Loughead J, Kohler CG, Elliott MA, Lesko K, Ruparel K, et al. Limbic activation associated with misidentification of fearful faces and flat affect in schizophrenia. Arch Gen Psychiatry. 2007;64:1356–66.

    Article  Google Scholar 

  57. Blasi G, Popolizio T, Taurisano P, Caforio G, Romano R, Di Giorgio A, et al. Changes in prefrontal and amygdala activity during olanzapine treatment in schizophrenia. Psychiatry Res. 2009;173:31–8.

    Article  Google Scholar 

  58. Mier D, Schirmbeck F, Stoessel G, Esslinger C, Rausch F, Englisch S, et al. Reduced activity and connectivity of left amygdala in patients with schizophrenia treated with clozapine or olanzapine. Eur Arch Psychiatry Clin Neurosci. 2019;269:931–40.

    Article  Google Scholar 

  59. Fanselow MS, Dong HW. Are the dorsal and ventral hippocampus functionally distinct structures? Neuron. 2010;65:7–19.

    Article  CAS  Google Scholar 

  60. Strange BA, Witter MP, Lein ES, Moser EI. Functional organization of the hippocampal longitudinal axis. Nat Rev Neurosci. 2014;15:655–69.

    Article  CAS  Google Scholar 

  61. McCutcheon RA, Abi-Dargham A, Howes OD. Schizophrenia, dopamine and the striatum: from biology to symptoms. Trends Neurosci. 2019;42:205–20.

    Article  CAS  Google Scholar 

  62. Haber SN. Corticostriatal circuitry. Dialogues Clin Neurosci. 2016;18:7–21.

    Article  Google Scholar 

  63. Alexander GE, DeLong MR, Strick PL. Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annu Rev Neurosci. 1986;9:357–81.

    Article  CAS  Google Scholar 

  64. Yang S, Meng Y, Li J, Li B, Fan YS, Chen H, et al. The thalamic functional gradient and its relationship to structural basis and cognitive relevance. Neuroimage. 2020;218:116960.

    Article  Google Scholar 

  65. Gong Q, Lui S, Sweeney JA. A selective review of cerebral abnormalities in patients with first-episode schizophrenia before and after treatment. Am J Psychiatry. 2016;173:232–43.

    Article  Google Scholar 

Download references

Funding

This study was supported by the National Key R&D Program of China (Project Nos. 2022YFC2009901 [to SL] and 2022YFC2009900 [to SL]), the National Natural Science Foundation of China (Project Nos. 82120108014 [to SL], 82071908 [to SL], 82101998 [to WZ], 82102007 [to LY], 81761128023 [to QG], 81621003 [to QG] and 81901828 [to ZY]), Chinese Academy of Medical Sciences (Project No. 2021-I2M-C&T-A-022 [to SL]), Sichuan Science and Technology Program (Project No. 2021JDTD0002 [to SL] and 2021YFS0077 [to LY]), 1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University (Project Nos. ZYYC08001 [to SL] and ZYJC18020 [to SL]), and Post-Doctor Research Project, West China Hospital, Sichuan University (Grant No. 2020HXBH005 [to WZ]). SL acknowledges the support from Humboldt Foundation Friedrich Wilhelm Bessel Research Award and Chang Jiang Scholars (Program No. T2019069).

Author information

Author notes

  1. These authors contributed equally: Chengmin Yang, Wenjing Zhang.

Authors and Affiliations

  1. Huaxi MR Research Center (HMRRC), Functional and Molecular Imaging Key Laboratory of Sichuan Province, Department of Radiology, West China Hospital, Sichuan University, Chengdu, China

    Chengmin Yang, Wenjing Zhang, Li Yao, Qiyong Gong & Su Lui

  2. Research Unit of Psychoradiology, Chinese Academy of Medical Sciences, Chengdu, China

    Chengmin Yang, Wenjing Zhang, Li Yao, Qiyong Gong & Su Lui

  3. College of Electronic Engineering, Chengdu University of Information Technology, Chengdu, China

    Jiajun Liu & Zhipeng Yang

  4. Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA

    Jeffrey R. Bishop

  5. Department of Psychiatry and Psychotherapy, University of Lübeck, Lübeck, Germany

    Rebekka Lencer

Authors
  1. Chengmin Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wenjing Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jiajun Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Li Yao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jeffrey R. Bishop
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rebekka Lencer
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Qiyong Gong
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Zhipeng Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Su Lui
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conception: CY, WZ, SL and ZY; Methodological development and statistical analysis: CY, JL and ZY; Data collection, acquisition and interpretation: WZ, LY, SL and QG; Manuscript draft: CY, WZ, JRB and RL; Critical revisions of the manuscript and final approval of this version to be published: all authors.

Corresponding authors

Correspondence to Zhipeng Yang or Su Lui.

Ethics declarations

Competing interests

WZ consulted to VeraSci. JRB has served as a consultant to OptumRx. The remaining authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Yang, C., Zhang, W., Liu, J. et al. Disrupted subcortical functional connectome gradient in drug-naïve first-episode schizophrenia and the normalization effects after antipsychotic treatment. Neuropsychopharmacol. (2022). https://doi.org/10.1038/s41386-022-01512-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41386-022-01512-0

Search

Advanced search

Quick links