Abstract
Neuroimaging studies of psychotic disorders have demonstrated abnormalities in structural and functional connectivity involving widespread brain networks. However, these group-level observations have failed to yield any biomarkers that can provide confirmatory evidence of a patient’s current symptoms, predict future symptoms, or predict a treatment response. Lack of precision in both neuroanatomical and clinical boundaries have likely contributed to the inability of even well-powered studies to resolve these key relationships. Here, we employed a novel approach to defining individual-specific functional connectivity in 158 patients diagnosed with schizophrenia (n = 49), schizoaffective disorder (n = 37), or bipolar disorder with psychosis (n = 72), and identified neuroimaging features that track psychotic symptoms in a dimension- or disorder-specific fashion. Using individually specified functional connectivity, we were able to estimate positive, negative, and manic symptoms that showed correlations ranging from r = 0.35 to r = 0.51 with the observed symptom scores. Comparing optimized estimation models among schizophrenia spectrum patients, positive and negative symptoms were associated with largely non-overlapping sets of cortical connections. Comparing between schizophrenia spectrum and bipolar disorder patients, the models for positive symptoms were largely non-overlapping between the two disorder classes. Finally, models derived using conventional region definition strategies performed at chance levels for most symptom domains. Individual-specific functional connectivity analyses revealed important new distinctions among cortical circuits responsible for the positive and negative symptoms, as well as key new information about how circuits underlying symptom expressions may vary depending on the underlying etiology and illness syndrome from which they manifest.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Change history
08 February 2021
A Correction to this paper has been published: https://doi.org/10.1038/s41380-018-0340-x
References
Friston KJ, Frith CD. Schizophrenia: a disconnection syndrome? Clin Neurosci. 1995;3:89–97.
McGuire PK, Frith CD. Disordered functional connectivity in schizophrenia. Psychol Med. 1996;26:663–7.
Stephan KE, Friston KJ, Frith CD. Dysconnection in schizophrenia: from abnormal synaptic plasticity to failures of self-monitoring. Schizophr Bull. 2009;35:509–27.
Pettersson-Yeo W, Allen P, Benetti S, McGuire P, Mechelli A. Dysconnectivity in schizophrenia: where are we now? Neurosci Biobehav Rev. 2011;35:1110–24.
Whitfield-Gabrieli S, Ford JM. Default mode network activity and connectivity in psychopathology. Annu Rev Clin Psychol. 2012;8:49–76.
Whitfield-Gabrieli S, Thermenos HW, Milanovic S, Tsuang MT, Faraone SV, McCarley RW, et al. Hyperactivity and hyperconnectivity of the default network in schizophrenia and in first-degree relatives of persons with schizophrenia. Proc Natl Acad Sci USA. 2009;106:1279–84.
Anticevic A, Cole MW, Repovs G, Murray JD, Brumbaugh MS, Winkler AM, et al. Characterizing thalamo-cortical disturbances in schizophrenia and bipolar illness. Cereb Cortex. 2014;24:3116–30.
Woodward ND, Rogers B, Heckers S. Functional resting-state networks are differentially affected in schizophrenia. Schizophr Res. 2011;130:86–93.
Chen YL, Tu PC, Lee YC, Chen YS, Li CT, Su TP. Resting-state fMRI mapping of cerebellar functional dysconnections involving multiple large-scale networks in patients with schizophrenia. Schizophr Res. 2013;149:26–34.
Cole MW, Anticevic A, Repovs G, Barch D. Variable global dysconnectivity and individual differences in schizophrenia. Biol Psychiatry. 2011;70:43–50.
Shenton ME, Dickey CC, Frumin M, McCarley RW. A review of MRI findings in schizophrenia. Schizophr Res. 2001;49:1–52.
Hoptman MJ, Antonius D, Mauro CJ, Parker EM, Javitt DC. Cortical thinning, functional connectivity, and mood-related impulsivity in schizophrenia: relationship to aggressive attitudes and behavior. Am J Psychiatry. 2014;171:939–48.
Walton E, Hibar DP, van Erp TGM, Potkin SG, Roiz-Santianez R, Crespo-Facorro B, et al. Prefrontal cortical thinning links to negative symptoms in schizophrenia via the ENIGMA consortium. Psychol Med. 2018;48:82–94.
Walton E, Hibar DP, van Erp TG, Potkin SG, Roiz-Santianez R, Crespo-Facorro B, et al. Positive symptoms associate with cortical thinning in the superior temporal gyrus via the ENIGMA Schizophrenia consortium. Acta Psychiatr Scand. 2017;135:439–47.
Lui S, Deng W, Huang X, Jiang L, Ma X, Chen H, et al. Association of cerebral deficits with clinical symptoms in antipsychotic-naive first-episode schizophrenia: an optimized voxel-based morphometry and resting state functional connectivity study. Am J Psychiatry. 2009;166:196–205.
Anticevic A, Brumbaugh MS, Winkler AM, Lombardo LE, Barrett J, Corlett PR, et al. Global prefrontal and fronto-amygdala dysconnectivity in bipolar I disorder with psychosis history. Biol Psychiatry. 2013;73:565–73.
Yeo BT, Krienen FM, Sepulcre J, Sabuncu MR, Lashkari D,Hollinshead M, et al. The organization of the human cerebral cortex estimated by intrinsic functional connectivity. J Neurophysiol. 2011;106:1125–65.
Laumann TO, Gordon EM, Adeyemo B, Snyder AZ, Joo SJ, Chen MY, et al. Functional system and areal organization of a highly sampled individual human brain. Neuron. 2015;87:657–70.
Gordon EM, Laumann TO, Gilmore AW, Newbold DJ, Greene DJ, Berg JJ, et al. Precision functional mapping of individual human brains. Neuron. 2017;95:791–.e797.
Glasser MF, Coalson TS, Robinson EC, Hacker CD, Harwell J, Yacoub E, et al. A multi-modal parcellation of human cerebral cortex. Nature. 2016;536:171–8.
Power JD, Cohen AL, Nelson SM, Wig GS, Barnes KA, Church JA, et al. Functional network organization of the human brain. Neuron. 2011;72:665–78.
Wig GS, Laumann TO, Cohen AL, Power JD, Nelson SM, Glasser MF, et al. Parcellating an individual subject’s cortical and subcortical brain structures using snowball sampling of resting-state correlations. Cereb Cortex. 2014;24:2036–54.
Choi EY, Yeo BT, Buckner RL. The organization of the human striatum estimated by intrinsic functional connectivity. J Neurophysiol. 2012;108:2242–63.
Ji JL, Spronk M, Kulkarni K, Repovs G, Anticevic A, Cole MW. Mapping the human brain's cortical-subcortical functional network organization. NeuroImage (in press).
Kraguljac NV, White DM, Hadley N, Hadley JA, ver Hoef L, Davis E, et al. Aberrant hippocampal connectivity in unmedicated patients with schizophrenia and effects of antipsychotic medication: a longitudinal resting state functional MRI study. Schizophr Bull. 2016;42:1046–55.
Mueller S, Wang D, Fox MD, Yeo BT, Sepulcre J, Sabuncu MR, et al. Individual variability in functional connectivity architecture of the human brain. Neuron. 2013;77:586–95.
Langs G, Wang D, Golland P, Mueller S, Pan R, Sabuncu MR, et al. Identifying shared brain networks in individuals by decoupling functional and anatomical variability. Cereb Cortex. 2016;26:4004–14.
Braga RM, Buckner RL. Parallel interdigitated distributed networks within the individual estimated by intrinsic functional connectivity. Neuron. 2017;95:457–71.e455.
Wang D, Buckner RL, Fox MD, Holt DJ, Holmes AJ, Stoecklein S, et al. Parcellating cortical functional networks in individuals. Nat Neurosci. 2015;18:1853–60.
Van Dijk KR, Sabuncu MR, Buckner RL. The influence of head motion on intrinsic functional connectivity MRI. Neuroimage. 2012;59:431–8.
Baker JT, Holmes AJ, Masters GA, Yeo BT, Krienen F, Buckner RL, et al. Disruption of cortical association networks in schizophrenia and psychotic bipolar disorder. JAMA Psychiatry. 2014;71:109–18.
Buckner RL, Krienen FM, Castellanos A, Diaz JC, Yeo BT. The organization of the human cerebellum estimated by intrinsic functional connectivity. J Neurophysiol. 2011;106:2322–45.
Lui S, Zhou XJ, Sweeney JA, Gong Q. Psychoradiology: the frontier of neuroimaging in psychiatry. Radiology. 2016;281:357–72.
Sun H, Chen Y, Huang Q, Lui S, Huang X, Shi Y, et al. Psychoradiologic utility of MR imaging for diagnosis of attention deficit hyperactivity disorder: a radiomics analysis. Radiology. 2017;287:620–30.
Port JD. Diagnosis of attention deficit hyperactivity disorder by using mr imaging and radiomics: a potential tool for clinicians. Radiology. 2018;287:631–2.
Kuhn S, Musso F, Mobascher A, Warbrick T, Winterer G, Gallinat J. Hippocampal subfields predict positive symptoms in schizophrenia: first evidence from brain morphometry. Transl Psychiatry. 2012;2:e127.
Rotarska-Jagiela A, Oertel-Knoechel V, DeMartino F, van de Ven V, Formisano E, Roebroeck A, et al. Anatomical brain connectivity and positive symptoms of schizophrenia: a diffusion tensor imaging study. Psychiatry Res. 2009;174:9–16.
Seok JH, Park HJ, Chun JW, Lee SK, Cho HS, Kwon JS, et al. White matter abnormalities associated with auditory hallucinations in schizophrenia: a combined study of voxel-based analyses of diffusion tensor imaging and structural magnetic resonance imaging. Psychiatry Res. 2007;156:93–104.
Cheung V, Chiu CP, Law CW, Cheung C, Hui CL, Chan KK, et al. Positive symptoms and white matter microstructure in never-medicated first episode schizophrenia. Psychol Med. 2011;41:1709–19.
Goghari VM, Sponheim SR, MacDonald AW. The functional neuroanatomy of symptom dimensions in schizophrenia: a qualitative and quantitative review of a persistent question. Neurosci Biobehav Rev. 2010;34:468.
Khadka S, Meda SA, Stevens MC, Glahn DC, Calhoun VD, Sweeney JA, et al. Is aberrant functional connectivity a psychosis endophenotype? A resting state functional magnetic resonance imaging study. Biol Psychiatry. 2013;74:458–66.
Meda SA, Gill A, Stevens MC, Lorenzoni RP, Glahn DC, Calhoun VD, et al. Differences in resting-state fMRI functional network connectivity between schizophrenia and psychotic bipolar probands and their unaffected first-degree relatives. Biol Psychiatry. 2012;71:881–9.
Benoit A, Bodnar M, Malla AK, Joober R, Lepage M. The structural neural substrates of persistent negative symptoms in first-episode of non-affective psychosis: a voxel-based morphometry study. Front Psychiatry. 2012;3:42.
Li Y, Li WX, Xie DJ, Wang Y, Cheung EF, Chan RC. Grey matter reduction in the caudate nucleus in patients with persistent negative symptoms: an ALE meta-analysis. Schizophr Res. 2018;192:9–15.
Kim G-W, Kim Y-H, Jeong G-W. Whole brain volume changes and its correlation with clinical symptom severity in patients with schizophrenia: a DARTEL-based VBM study. PLoS ONE. 2017;12:e0177251.
Adler CM, Adams J, DelBello MP, Holland SK, Schmithorst V, Levine A, et al. Evidence of white matter pathology in bipolar disorder adolescents experiencing their first episode of mania: a diffusion tensor imaging study. Am J Psychiatry. 2006;163:322–4.
Martino M, Magioncalda P, Saiote C, Conio B, Escelsior A, Rocchi G, et al. Abnormal functional-structural cingulum connectivity in mania: combined functional magnetic resonance imaging-diffusion tensor imaging investigation in different phases of bipolar disorder. Acta Psychiatr Scand. 2016;134:339–49.
Pomarol-Clotet E, Moro N, Sarro S, Goikolea JM, Vieta E, Amann B, et al. Failure of de-activation in the medial frontal cortex in mania: evidence for default mode network dysfunction in the disorder. World J Biol Psychiatry. 2012;13:616–26.
Li M, Huang C, Deng W, Ma X, Han Y, Wang Q, et al. Contrasting and convergent patterns of amygdala connectivity in mania and depression: a resting-state study. J Affect Disord. 2015;173:53–8.
Çetin MS, Christensen F, Abbott CC, Stephen JM, Mayer AR, Cañive JM, et al. Thalamus and posterior temporal lobe show greater inter-network connectivity at rest and across sensory paradigms in schizophrenia. Neuroimage. 2014;97:117–26.
Bassett DS, Nelson BG, Mueller BA, Camchong J, Lim KO. Altered resting state complexity in schizophrenia. Neuroimage. 2012;59:2196–207.
Repovs G, Csernansky JG, Barch DM. Brain network connectivity in individuals with schizophrenia and their siblings. Biol Psychiatry. 2011;69:967–73.
Satterthwaite TD, Vandekar SN, Wolf DH, Bassett DS, Ruparel K, Shehzad Z, et al. Connectome-wide network analysis of youth with Psychosis-Spectrum symptoms. Mol Psychiatry. 2015;20:1508.
Fair DA, Cohen AL, Power JD, Dosenbach NU, Church JA, Miezin FM, et al. Functional brain networks develop from a “local to distributed” organization. PLoS Comput Biol. 2009;5:e1000381.
Acknowledgements
This work was supported by the NIH grants K01MH111802, K23MH104515, 1R01NS091604, P50MH106435, Beijing Municipal Science and Technology Commission No. Z161100002616009, National Natural Science Foundation of China grants No. 81790652.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Rights and permissions
About this article
Cite this article
Wang, D., Li, M., Wang, M. et al. Individual-specific functional connectivity markers track dimensional and categorical features of psychotic illness. Mol Psychiatry 25, 2119–2129 (2020). https://doi.org/10.1038/s41380-018-0276-1
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41380-018-0276-1
This article is cited by
-
Multivariate patterns of brain functional connectome associated with COVID-19-related negative affect symptoms
Translational Psychiatry (2024)
-
Personalized functional network mapping for autism spectrum disorder and attention-deficit/hyperactivity disorder
Translational Psychiatry (2024)
-
A meta-analysis and systematic review of single vs. multimodal neuroimaging techniques in the classification of psychosis
Molecular Psychiatry (2023)
-
Individual-specific functional connectivity improves prediction of Alzheimer’s disease’s symptoms in elderly people regardless of APOE ε4 genotype
Communications Biology (2023)
-
Individualized functional connectome identified generalizable biomarkers for psychiatric symptoms in transdiagnostic patients
Neuropsychopharmacology (2023)