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Baseline brain structural and functional predictors of clinical outcome in the early course of schizophrenia

Molecular Psychiatry (2018) | Download Citation

Abstract

Although schizophrenia is considered a brain disorder, the role of brain organization for symptomatic improvement remains inadequately defined. We investigated the relationship between baseline brain morphology, resting-state network connectivity and clinical response after 24-weeks of antipsychotic treatment in patients with schizophrenia (n = 95) using integrated multivariate analyses. There was no significant association between clinical response and measures of cortical thickness (r = 0.37, p = 0.98) and subcortical volume (r = 0.56, p = 0.15). By contrast, we identified a strong mode of covariation linking functional network connectivity to clinical response (r = 0.70; p = 0.04), and particularly to improvement in positive (weight = 0.62) and anxious/depressive symptoms (weight = 0.49). Higher internal cohesiveness of the default mode network was the single most important positive predictor. Key negative predictors involved the functional cohesiveness of central executive subnetworks anchored in the frontoparietal cortices and subcortical regions (including the thalamus and striatum) and the inter-network integration between the default mode and sensorimotor networks. The present findings establish links between clinical response and the functional organization of brain networks involved both in perception and in spontaneous and goal-directed cognition, thereby advancing our understanding of the pathophysiology of schizophrenia.

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References

  1. 1.

    Murray CJ, Vos T, Lozano R, Naghavi M, Flaxman AD, Michaud, et al. Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380:2197–223.

  2. 2.

    Hafner H, an der Heiden W. The course of schizophrenia in the light of modern follow-up studies: the ABC and WHO studies. Eur Arch Psychiatry Clin Neurosci. 1999;249(Suppl 4):14–26.

  3. 3.

    Rosenbaum B, Valbak K, Harder S, Knudsen P, Koster A, Lajer M, et al. Treatment of patients with first-episode psychosis: 2-year outcome data from the Danish National Schizophrenia Project. World Psychiatry. 2006;5:100–3.

  4. 4.

    Harvey PD, Heaton RK, Carpenter WT Jr., Green MF, Gold JM, et al. Functional impairment in people with schizophrenia: focus on employability and eligibility for disability compensation. Schizophr Res. 2012;140:1–8.

  5. 5.

    Rosenheck RA, Estroff SE, Sint K, Lin H, Mueser KT, Robinson DG, et al. Incomes and outcomes: social security disability benefits in first-episode psychosis. Am J Psychiatry. 2017;174:886–94.

  6. 6.

    Hayes JF, Marston L, Walters K, King MB, Osborn DPJ. Mortality gap for people with bipolar disorder and schizophrenia: UK-based cohort study 2000-14. Br J Psychiatry J Ment Sci. 2017;211:175–81.

  7. 7.

    Saha S, Chant D, McGrath J. A systematic review of mortality in schizophrenia: is the differential mortality gap worsening over time? Arch Gen Psychiatry. 2007;64:1123–31.

  8. 8.

    Davidson L, McGlashan TH. The varied outcomes of schizophrenia. Can J Psychiatry. 1997;42:34–43.

  9. 9.

    Heilbronner U, Samara M, Leucht S, Falkai P, Schulze TG. The longitudinal course of schizophrenia across the lifespan: clinical, cognitive, and neurobiological aspects. Harv Rev Psychiatry. 2016;24:118–28.

  10. 10.

    Conus P, Cotton S, Schimmelmann BG, McGorry PD, Lambert M. Rates and predictors of 18-months remission in an epidemiological cohort of 661 patients with first-episode psychosis. Soc Psychiatry Psychiatr Epidemiol. 2017;52:1089–99.

  11. 11.

    Koutsouleris N, Kahn RS, Chekroud AM, Leucht S, Falkai P, Wobrock T, et al. Multisite prediction of 4 and 52-week treatment outcomes in patients with first-episode psychosis: a machine learning approach. Lancet Psychiatry. 2016;3:935–46.

  12. 12.

    Menezes NM, Arenovich T, Zipursky RB. A systematic review of longitudinal outcome studies of first-episode psychosis. Psychol Med. 2006;36:1349–62.

  13. 13.

    Samara MT, Leucht C, Leeflang MM, Anghelescu IG, Chung YC, Crespo-Facorro B, et al. Early improvement as a predictor of later response to antipsychotics in schizophrenia: a diagnostic test review. Am J Psychiatry. 2015;172:617–29.

  14. 14.

    Birur B, Kraguljac NV, Shelton RC, Lahti AC. Brain structure, function, and neurochemistry in schizophrenia and bipolar disorder-a systematic review of the magnetic resonance neuroimaging literature. NPJ Schizophr. 2017;3:15.

  15. 15.

    van Erp TG, Hibar DP, Rasmussen JM, Glahn DC, Pearlson GD, Andreassen OA, et al. Subcortical brain volume abnormalities in 2028 individuals with schizophrenia and 2540 healthy controls via the ENIGMA consortium. Mol Psychiatry. 2016;21:585.

  16. 16.

    Van Erp TG, Walton E, Hibar DP, Schmaal L, Jiang W, Glahn DC et al. Cortical brain abnormalities in 4474 individuals with schizophrenia and 5098 controls via the ENIGMA consortium. Biol Psychiatry. 2018. https://doi.org/10.1016/j.biopsych.2018.04.023. (paper in press- no volume or page available yet)

  17. 17.

    Dong D, Wang Y, Chang X, Luo C, Yao D. Dysfunction of large-scale brain networks in schizophrenia: a meta-analysis of resting-state functional connectivity. Schizophr Bull. 2018;44:168–81.

  18. 18.

    Lee WH, Doucet GE, Leibu E, Frangou S. Resting-state network connectivity and metastability predict clinical symptoms in schizophrenia. Schizophr Res. 2018;pii: S0920-9964(18)30242-1.

  19. 19.

    Doucet G, Rider R, Taylor N, Skidmore C, Sharan A, Sperling M et al. Pre-surgery resting-state local graph-theory measures predict neurocognitive outcomes after brain surgery in temporal lobe epilepsy. Epilepsia. 2015;56:517–26.

  20. 20.

    Willette AA, Calhoun VD, Egan JM, Kapogiannis D, Alzheimers Disease Neuroimaging I. Prognostic classification of mild cognitive impairment and Alzheimer’s disease: MRI independent component analysis. Psychiatry Res. 2014;224:81–88.

  21. 21.

    Lieberman J, Chakos M, Wu H, Alvir J, Hoffman E, Robinson D, et al. Longitudinal study of brain morphology in first episode schizophrenia. Biol Psychiatry. 2001;49:487–99.

  22. 22.

    Lieberman J, Jody D, Geisler S, Alvir J, Loebel A, Szymanski S, et al. Time course and biologic correlates of treatment response in first-episode schizophrenia. Arch Gen Psychiatry. 1993;50:369–76.

  23. 23.

    Molina V, Reig S, Sarramea F, Sanz J, Francisco Artaloytia J, Luque R, et al. Anatomical and functional brain variables associated with clozapine response in treatment-resistant schizophrenia. Psychiatry Res. 2003;124:153–61.

  24. 24.

    Nieuwenhuis M, Schnack HG, van Haren NE, Lappin J, Morgan C, Reinders AA, et al. Multi-center MRI prediction models: predicting sex and illness course in first episode psychosis patients. Neuroimage. 2017;145(Pt B):246–53.

  25. 25.

    Palaniyappan L, Marques TR, Taylor H, Handley R, Mondelli V, Bonaccorso S, et al. Cortical folding defects as markers of poor treatment response in first-episode psychosis. JAMA Psychiatry. 2013;70:1031–40.

  26. 26.

    Cahn W, van Haren NE, Hulshoff Pol HE, Schnack HG, Caspers E, Laponder DA, et al. Brain volume changes in the first year of illness and 5-year outcome of schizophrenia. Br J Psychiatry J Ment Sci. 2006;189:381–2.

  27. 27.

    Prasad KM, Sahni SD, Rohm BR, Keshavan MS. Dorsolateral prefrontal cortex morphology and short-term outcome in first-episode schizophrenia. Psychiatry Res. 2005;140:147–55.

  28. 28.

    Milev P, Ho BC, Arndt S, Nopoulos P, Andreasen NC. Initial magnetic resonance imaging volumetric brain measurements and outcome in schizophrenia: a prospective longitudinal study with 5-year follow-up. Biol Psychiatry. 2003;54:608–15.

  29. 29.

    Bodnar M, Harvey PO, Malla AK, Joober R, Lepage M. The parahippocampal gyrus as a neural marker of early remission in first-episode psychosis: a voxel-based morphometry study. Clin Schizophr Relat Psychoses. 2011;4:217–28.

  30. 30.

    Bodnar M, Malla AK, Joober R, Lord C, Smith E, Pruessner J, et al. Neural markers of early remission in first-episode schizophrenia: a volumetric neuroimaging study of the parahippocampus. Psychiatry Res. 2012;201:40–47.

  31. 31.

    Molina V, Martin C, Ballesteros A, de Herrera AG, Hernandez-Tamames JA. Optimized voxel brain morphometry: association between brain volumes and the response to atypical antipsychotics. Eur Arch Psychiatry Clin Neurosci. 2011;261:407–16.

  32. 32.

    Nejad AB, Madsen KH, Ebdrup BH, Siebner HR, Rasmussen H, Aggernaes B, et al. Neural markers of negative symptom outcomes in distributed working memory brain activity of antipsychotic-naive schizophrenia patients. Int J Neuropsychopharmacol. 2013;16:1195–204.

  33. 33.

    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.

  34. 34.

    Sarpal DK, Argyelan M, Robinson DG, Szeszko PR, Karlsgodt KH, John M, et al. Baseline striatal functional connectivity as a predictor of response to antipsychotic drug treatment. Am J Psychiatry. 2016;173:69–77.

  35. 35.

    Andreasen NC, Carpenter WT Jr., Kane JM, Lasser RA, Marder SR, et al. Remission in schizophrenia: proposed criteria and rationale for consensus. Am J Psychiatry. 2005;162:441–9.

  36. 36.

    Karow A, Naber D, Lambert M, Moritz S, Initiative E. Remission as perceived by people with schizophrenia, family members and psychiatrists. Eur Psychiatry. 2012;27:426–31.

  37. 37.

    Russo M, Levine SZ, Demjaha A, Di Forti M, Bonaccorso S, Fearon P, et al. Association between symptom dimensions and categorical diagnoses of psychosis: a cross-sectional and longitudinal investigation. Schizophr Bull. 2014;40:111–9.

  38. 38.

    Esteghamati A, Khalilzadeh O, Anvari M, Ahadi MS, Abbasi M, Rashidi A. Metabolic syndrome and insulin resistance significantly correlate with body mass index. Arch Med Res. 2008;39:803–8.

  39. 39.

    Johnson W, Bouchard TJ Jr., Krueger RF, McGue M, Gottesman II. Just one g: consistent results from three test batteries. Intelligence. 2004;32:95–107.

  40. 40.

    Plomin R, Deary IJ. Genetics and intelligence differences: five special findings. Mol Psychiatry. 2015;20:98–108.

  41. 41.

    Moser DA, Doucet GE, Lee WH, Rasgon A, Krinsky H, Leibu E, et al. Multivariate associations among behavioral, clinical and multimodal imaging phenotypes in psychosis. JAMA Psychiatry. 2018;75:386–95.

  42. 42.

    Hermes E, Nasrallah H, Davis V, Meyer J, McEvoy J, Goff D, et al. The association between weight change and symptom reduction in the CATIE schizophrenia trial. Schizophr Res. 2011;128:166–70.

  43. 43.

    Ventura J, Subotnik KL, Guzik LH, Hellemann GS, Gitlin MJ, Wood RC, et al. Remission and recovery during the first outpatient year of the early course of schizophrenia. Schizophr Res. 2011;132:18–23.

  44. 44.

    Witten DM, Tibshirani R, Hastie T. A penalized matrix decomposition, with applications to sparse principal components and canonical correlation analysis. Biostatistics. 2009;10:515–34.

  45. 45.

    Breiman L, Friedman JH. Predicting multivariate responses in multiple linear regression. J R Stat Soc Ser B Stat Methodol. 1997;59:3–54.

  46. 46.

    Klami A, Virtanen S, Kaski S. Bayesian canonical correlation analysis. J Mac Learn Res. 2013;14:965–1003.

  47. 47.

    Association AP. Diagnostic and statistical manual of mental disorders. Arlington, VA: American Psychiatric Publishing; 2013.

  48. 48.

    First MB, Williams JBW, Karg RS, Spitzer RL. Structured clinical interview for DSM-5, research version. American Psychiatric Association, Arlington, VA; 2015.

  49. 49.

    Wechsler D. Wechsler Abbreviated Scale of Intelligence. 2nd ed. San Antonio, TX: NCS Pearson; 2011.

  50. 50.

    Wells R, Swaminathan V, Sundram S, Weinberg D, Bruggemann J, Jacomb I, et al. The impact of premorbid and current intellect in schizophrenia: cognitive, symptom, and functional outcomes. NPJ Schizophr. 2015;1:15043.

  51. 51.

    Ventura J, Green MF, Shaner A, Liberman RP. Training and quality assurance with the Brief Psychiatric Rating Scale. Int J Methods Psychiatr Res. 1993;3:221–44.

  52. 52.

    Kopelowicz A, Ventura J, Liberman RP, Mintz J. Consistency of Brief Psychiatric Rating Scale factor structure across a broad spectrum of schizophrenia patients. Psychopathology. 2008;41:77–84.

  53. 53.

    Gardner DM, Murphy AL, O’Donnell H, Centorrino F, Baldessarini RJ. International consensus study of antipsychotic dosing. Am J Psychiatry. 2010;167:686–93.

  54. 54.

    Leucht S, Cipriani A, Spineli L, Mavridis D, Orey D, Richter F, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet. 2013;382:951–62.

  55. 55.

    Tiihonen J, Wahlbeck K, Lonnqvist J, Klaukka T, Ioannidis JP, Volavka J, et al. Effectiveness of antipsychotic treatments in a nationwide cohort of patients in community care after first hospitalisation due to schizophrenia and schizoaffective disorder: observational follow-up study. BMJ. 2006;333:224.

  56. 56.

    Desikan RS, Segonne F, Fischl B, Quinn BT, Dickerson BC, Blacker D, et al. An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest. Neuroimage. 2006;31:968–80.

  57. 57.

    Doucet GE, Rasgon N, McEwen BS, Micali N, Frangou S. Elevated body mass index is associated with increased integration and reduced cohesion of sensory-driven and internally guided resting-state functional brain networks. Cereb Cortex. 2018;28:988–97.

  58. 58.

    Gu S, Satterthwaite TD, Medaglia JD, Yang M, Gur RE, Gur RC, et al. Emergence of system roles in normative neurodevelopment. Proc Natl Acad Sci USA. 2015;112:13681–6.

  59. 59.

    Zalesky A, Fornito A, Harding IH, Cocchi L, Yucel M, Pantelis C, et al. Whole-brain anatomical networks: does the choice of nodes matter? Neuroimage. 2010;50:970–83.

  60. 60.

    Crossley NA, Mechelli A, Vertes PE, Winton-Brown TT, Patel AX, Ginestet CE, et al. Cognitive relevance of the community structure of the human brain functional coactivation network. Proc Natl Acad Sci USA. 2013;110:11583–8.

  61. 61.

    Moser DA, Doucet GE, Ing A, Dima D, Schumann G, Bilder RM et al. An integrated brain-behavior model for working memory. Mol Psychiatry. 2017. https://doi.org/10.1038/mp.2017.247. (paper in press- no volume or page available yet)

  62. 62.

    Lambert M, Karow A, Leucht S, Schimmelmann BG, Naber D. Remission in schizophrenia: validity, frequency, predictors, and patients’ perspective 5 years later. Dialog Clin Neurosci. 2010;12:393–407.

  63. 63.

    Corbetta M, Kincade JM, Shulman GL. Neural systems for visual orienting and their relationships to spatial working memory. J Cogn Neurosci. 2002;14:508–23.

  64. 64.

    Doucet G, Naveau M, Petit L, Delcroix N, Zago L, Crivello F, et al. Brain activity at rest: a multiscale hierarchical functional organization. J Neurophysiol. 2011;105:2753–63.

  65. 65.

    Fox MD, Snyder AZ, Vincent JL, Corbetta M, Van Essen DC, Raichle ME. The human brain is intrinsically organized into dynamic, anticorrelated functional networks. Proc Natl Acad Sci USA. 2005;102:9673–8.

  66. 66.

    Raichle ME. The brain’s default mode network. Annu Rev Neurosci. 2015;38:433–47.

  67. 67.

    Fair DA, Cohen AL, Dosenbach NU, Church JA, Miezin FM, Barch DM, et al. The maturing architecture of the brain’s default network. Proc Natl Acad Sci USA. 2008;105:4028–32.

  68. 68.

    Andrews-Hanna JR. The brain’s default network and its adaptive role in internal mentation. Neuroscience. 2012;18:251–70.

  69. 69.

    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.

  70. 70.

    Krishnadas R, Ryali S, Chen T, Uddin LQ, Supekar K, Palaniyappan L, et al. Resting state functional hyperconnectivity within a triple network model in paranoid schizophrenia. Lancet. 2014;383:S65.

  71. 71.

    Abel KM, Drake R, Goldstein JM. Sex differences in schizophrenia. Int Rev Psychiatry. 2010;22:417–28.

  72. 72.

    Haynes VS, Zhu B, Stauffer VL, Kinon BJ, Stensland MD, Xu L, et al. Long-term healthcare costs and functional outcomes associated with lack of remission in schizophrenia: a post-hoc analysis of a prospective observational study. BMC Psychiatry. 2012;12:222.

  73. 73.

    Anticevic A, Gancsos M, Murray JD, Repovs G, Driesen NR, Ennis DJ, et al. NMDA receptor function in large-scale anticorrelated neural systems with implications for cognition and schizophrenia. Proc Natl Acad Sci USA. 2012;109:16720–5.

  74. 74.

    Lewis DA, Moghaddam B. Cognitive dysfunction in schizophrenia: convergence of gamma-aminobutyric acid and glutamate alterations. Arch Neurol. 2006;63:1372–6.

  75. 75.

    Keshavan MS, Vinogradov S, Rumsey J, Sherrill J, Wagner A. Cognitive training in mental disorders: update and future directions. Am J Psychiatry. 2014;171:510–22.

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Acknowledgements

This work was supported in part through the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai. Dr. Frangou received support from the National Institutes of Health (R01 MH104284-01A1) and European Unit FP7 program (IMAGEMEND 602450; IMAging GEnetics for MENtal Disorders) projects. Dr. Moser received support from the Swiss National Science Foundation (P300PB_171584).

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  1. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    • Gaelle E. Doucet
    • , Dominik A. Moser
    • , Maxwell J. Luber
    • , Evan Leibu
    •  & Sophia Frangou

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Correspondence to Sophia Frangou.

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https://doi.org/10.1038/s41380-018-0269-0