Alterations of Intrinsic Connectivity Networks in Antipsychotic-Naïve First-Episode Schizophrenia

Simon Anhøj, Mette Ødegaard Nielsen, Maria Høj Jensen, Kristin Ford, Birgitte Fagerlund, Peter Williamson, Birte Glenthøj, Egill Rostrup, Simon Anhøj, Mette Ødegaard Nielsen, Maria Høj Jensen, Kristin Ford, Birgitte Fagerlund, Peter Williamson, Birte Glenthøj, Egill Rostrup

Abstract

Background: The investigation of large-scale intrinsic connectivity networks in antipsychotic-naïve first-episode schizophrenia increases our understanding of system-level cerebral dysfunction in schizophrenia while enabling control of confounding effects of medication and disease progression. Reports on functional connectivity in antipsychotic-naïve patients have been mixed and the relation between network alterations, psychopathology and cognition is unclear.

Methods: A total number of 47 patients with first-episode schizophrenia who had never received antipsychotic medication and 47 healthy controls were scanned with functional magnetic resonance imaging under resting conditions. Main outcome measures were differences in functional connectivity between groups and the relationship between network alterations, psychopathology and cognition.

Results: Altered connectivity was found between right central executive network (CEN) and right ventral attention network (VAN) (patients > controls, P = .001), left CEN and left VAN (P = .002), and between posterior default mode network and auditory network (P = .006). Association between network connectivity and clinical characteristics was found as interactions between the effects of group and sustained attention (P = .005) and between group and processing speed (P = .007) on the connectivity between right CEN and right VAN.

Conclusions: Our findings suggest that the early phase of schizophrenia is characterized by increased connectivity between fronto-parietal networks suggested to be involved in the control of cognitive and sensory functions. Moreover, the present study suggests that the problem of not disengaging the VAN leads to difficulties with attention and possibly subjective awareness.

Trial registration: ClinicalTrials.gov NCT01154829.

Figures

Fig. 1.
Fig. 1.
Networks of interest. Default mode network (DMN), salience network (SN), central executive network (CEN), ventral attention network (VAN), dorsal attention network (DAN), and auditory network.
Fig. 2.
Fig. 2.
Group differences in pairwise correlations between networks of interest. The lines indicate stronger mean pairwise correlations in patients compared to controls, false discovery rate (FDR) corrected.
Fig. 3.
Fig. 3.
Interaction between group and cognitive measures on pairwise correlations between networks of interest. The lines indicate a significant interaction between group and the specific cognitive measures on the pairwise correlation between networks, false discovery rate (FDR) corrected. Full line = sustained attention (RVP). Dotted line = processing speed (symbol coding).

References

    1. Buckner RL, Krienen FM, Yeo BT. Opportunities and limitations of intrinsic functional connectivity MRI. Nat Neurosci. 2013;16:832–837.
    1. Fox MD, Raichle ME. Spontaneous fluctuations in brain activity observed with functional magnetic resonance imaging. Nat Rev Neurosci. 2007;8:700–711.
    1. Williamson P. Are anticorrelated networks in the brain relevant to schizophrenia?Schizophr Bull. 2007;33:994–1003.
    1. Buckner RL, Andrews-Hanna JR, Schacter DL. The brain’s default network: anatomy, function, and relevance to disease. Ann N Y Acad Sci. 2008;1124:1–38.
    1. Menon V. Large-scale brain networks and psychopathology: a unifying triple network model. Trends Cogn Sci. 2011;15:483–506.
    1. Palaniyappan L, Liddle PF. Does the salience network play a cardinal role in psychosis? An emerging hypothesis of insular dysfunction. J Psychiatry Neurosci. 2012;37:17–27.
    1. Palaniyappan L, White TP, Liddle PF. The concept of salience network dysfunction in schizophrenia: from neuroimaging observations to therapeutic opportunities. Curr Top Med Chem. 2012;12:2324–2338.
    1. Northoff G, Qin P. How can the brain’s resting state activity generate hallucinations? A ‘resting state hypothesis’ of auditory verbal hallucinations. Schizophr Res. 2011;127:202–214.
    1. Williamson PC, Allman JM. A framework for interpreting functional networks in schizophrenia. Front Hum Neurosci. 2012;6:184.
    1. Karbasforoushan H, Woodward ND. Resting-state networks in schizophrenia. Curr Top Med Chem. 2012;12:2404–2414.
    1. He Z, Deng W, Li M et al. . Aberrant intrinsic brain activity and cognitive deficit in first-episode treatment-naive patients with schizophrenia. Psychol Med. 2013;43:769–780.
    1. Lui S, Deng W, Huang X 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.
    1. Li M, Deng W, He Z et al. . A splitting brain: Imbalanced neural networks in schizophrenia. Psychiatry Res. 2015;232:145–153.
    1. Lui S, Li T, Deng W 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;67:783–792.
    1. Sheffield JM, Barch DM. Cognition and resting-state functional connectivity in schizophrenia. Neurosci Biobehav Rev. 2016;61:108–120.
    1. Düring S, Glenthøj BY, Andersen GS, Oranje B. Effects of dopamine D2/D3 blockade on human sensory and sensorimotor gating in initially antipsychotic-naive, first-episode schizophrenia patients. Neuropsychopharmacology. 2014;39:3000–3008.
    1. Ebdrup BH, Raghava JM, Nielsen MO, Rostrup E, Glenthoj B. Frontal fasciculi and psychotic symptoms in antipsychotic-naive patients with schizophrenia before and after 6 weeks of selective dopamine D2/3 receptor blockade. J Psychiatry Neurosci. 2015;41:150030.
    1. Nielsen MO, Rostrup E, Wulff S et al. . Improvement of brain reward abnormalities by antipsychotic monotherapy in schizophrenia. Arch Gen Psychiatry. 2012;69: 1195–1204.
    1. Nielsen MØ, Rostrup E, Wulff S et al. . Alterations of the brain reward system in antipsychotic naïve schizophrenia patients. Biol Psychiatry. 2012;71:898–905.
    1. Nielsen MO, Rostrup E, Wulff S, Glenthoj B, Ebdrup BH. Striatal reward activity and antipsychotic-associated weight change in patients with schizophrenia undergoing initial treatment. JAMA Psychiatry. 2016;73:121–128.
    1. Nordholm D, Poulsen HE, Hjorthøj C et al. . Systemic oxidative DNA and RNA damage are not increased during early phases of psychosis: A case control study. Psychiatry Res. 2016;241:201–206.
    1. Wulff S, Pinborg LH, Svarer C et al. . Striatal D(2/3) binding potential values in drug-naïve first-episode schizophrenia patients correlate with treatment outcome. Schizophr Bull. 2015;41:1143–1152.
    1. Wing JK, Babor T, Brugha T et al. . SCAN. Schedules for Clinical Assessment in Neuropsychiatry. Arch Gen Psychiatry. 1990;47:589–593.
    1. Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull. 1987;13:261–276.
    1. Oldfield RC. The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia. 1971;9:97–113.
    1. Wechsler D. WAIS-III Administration and Scoring Manual. San Antonio TX: Psychol Corp; 1997.
    1. Keefe RS, Goldberg TE, Harvey PD, Gold JM, Poe MP, Coughenour L. The Brief Assessment of Cognition in Schizophrenia: reliability, sensitivity, and comparison with a standard neurocognitive battery. Schizophr Res. 2004;68:283–297.
    1. Sahakian BJ, Owen AM. Computerized assessment in neuropsychiatry using CANTAB: discussion paper. J R Soc Med. 1992;85:399–402.
    1. Jenkinson M, Bannister P, Brady M, Smith S. Improved optimization for the robust and accurate linear registration and motion correction of brain images. Neuroimage. 2002;17:825–841.
    1. Paul Mazaika FH, Glover GH, Reiss AL. Methods and Software for fMRI analysis for clinical subjects. Neuroimage. 2009;47:S58.
    1. Andersson JL, Jenkinson M, Smith S.. Non-linear optimisation FMRIB Technial Report TR07JA1. 2007. . Accessed December 1, 2017.
    1. Andersson JL, Jenkinson M, Smith S.. Non-linear registration, aka Spatial normalisation FMRIB Technial Report TR07JA2. 2007. . Accessed December 1, 2017.
    1. Beckmann CF, Smith SM. Probabilistic independent component analysis for functional magnetic resonance imaging. IEEE Trans Med Imaging. 2004;23:137–152.
    1. Beckmann CF, DeLuca M, Devlin JT, Smith SM. Investigations into resting-state connectivity using independent component analysis. Philos Trans R Soc Lond B Biol Sci. 2005;360:1001–1013.
    1. Filippini N, MacIntosh BJ, Hough MG et al. . Distinct patterns of brain activity in young carriers of the APOE-epsilon4 allele. Proc Natl Acad Sci U S A. 2009;106:7209–7214.
    1. Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Statist Soc B. 1995;57:289–300.
    1. Corbetta M, Shulman GL. Control of goal-directed and stimulus-driven attention in the brain. Nat Rev Neurosci. 2002;3:201–215.
    1. Pu W, Rolls ET, Guo S et al. . Altered functional connectivity links in neuroleptic-naïve and neuroleptic-treated patients with schizophrenia, and their relation to symptoms including volition. Neuroimage Clin. 2014;6:463–474.
    1. Amico F, O’Hanlon E, Kraft D et al. . Functional connectivity anomalies in adolescents with psychotic symptoms. PLoS One. 2017;12:e0169364.
    1. Anticevic A, Hu X, Xiao Y et al. . Early-course unmedicated schizophrenia patients exhibit elevated prefrontal connectivity associated with longitudinal change. J Neurosci. 2015;35:267–286.
    1. Cole MW, Repovš G, Anticevic A. The frontoparietal control system: a central role in mental health. Neuroscientist. 2014;20:652–664.
    1. Menon V, Uddin LQ. Saliency, switching, attention and control: a network model of insula function. Brain Struct Funct. 2010;214:655–667.
    1. Vincent JL, Kahn I, Snyder AZ, Raichle ME, Buckner RL. Evidence for a frontoparietal control system revealed by intrinsic functional connectivity. J Neurophysiol. 2008;100:3328–3342.
    1. Bartolomeo P. Attention disorders after right brain damage: living in halved worlds. London, New York: Springer; 2014.
    1. Corbetta M, Patel G, Shulman GL. The reorienting system of the human brain: from environment to theory of mind. Neuron. 2008;58:306–324.
    1. Decety J, Lamm C. The role of the right temporoparietal junction in social interaction: how low-level computational processes contribute to meta-cognition. Neuroscientist. 2007;13:580–593.
    1. Krall SC, Rottschy C, Oberwelland E et al. . The role of the right temporoparietal junction in attention and social interaction as revealed by ALE meta-analysis. Brain Struct Funct. 2015;220:587–604.
    1. Raichle ME, MacLeod AM, Snyder AZ, Powers WJ, Gusnard DA, Shulman GL. A default mode of brain function. Proc Natl Acad Sci U S A. 2001;98:676–682.
    1. Gusnard DA, Akbudak E, Shulman GL, Raichle ME. Medial prefrontal cortex and self-referential mental activity: relation to a default mode of brain function. Proc Natl Acad Sci U S A. 2001;98:4259–4264.
    1. Fornito A, Bullmore ET. Reconciling abnormalities of brain network structure and function in schizophrenia. Curr Opin Neurobiol. 2015;30:44–50.
    1. Pettersson-Yeo W, Allen P, Benetti S, McGuire P, Mechelli A. Dysconnectivity in schizophrenia: where are we now?Neurosci Biobehav Rev. 2011;35:1110–1124.
    1. Guo W, Liu F, Chen J et al. . Using short-range and long-range functional connectivity to identify schizophrenia with a family-based case-control design. Psychiatry Res. 2017;264:60–67.
    1. Guo W, Liu F, Chen J et al. . Hyperactivity of the default-mode network in first-episode, drug-naive schizophrenia at rest revealed by family-based case-control and traditional case-control designs. Medicine (Baltimore). 2017;96:e6223.
    1. Li F, Lui S, Yao L et al. . Longitudinal changes in resting-state cerebral activity in patients with first-episode schizophrenia: a 1-year follow-up functional MR Imaging Study. Radiology. 2016;279:867–875.
    1. Li T, Wang Q, Zhang J et al. . Brain-wide analysis of functional connectivity in first-episode and chronic stages of schizophrenia. Schizophr Bull. 2017;43:436–448.
    1. Martino M, Magioncalda P, Yu H et al. . Abnormal resting-state connectivity in a substantia nigra-related striato-thalamo-cortical network in a large sample of first-episode drug-naive patients with schizophrenia. Schizophr Bull. 2018;44:419–431.
    1. Wang S, Zhan Y, Zhang Y et al. . Abnormal long- and short-range functional connectivity in adolescent-onset schizophrenia patients: a resting-state fMRI study. Prog Neuropsychopharmacol Biol Psychiatry. 2018;81:445–451.
    1. Hasenkamp W, James GA, Boshoven W, Duncan E. Altered engagement of attention and default networks during target detection in schizophrenia. Schizophr Res. 2011;125:169–173.
    1. Schneider FC, Royer A, Grosselin A et al. . Modulation of the default mode network is task-dependant in chronic schizophrenia patients. Schizophr Res. 2011;125:110–117.
    1. Whitfield-Gabrieli S, Thermenos HW, Milanovic S et al. . Hyperactivity and hyperconnectivity of the default network in schizophrenia and in first-degree relatives of persons with schizophrenia. Proc Natl Acad Sci U S A. 2009;106:1279–1284.
    1. Patel GH, Yang D, Jamerson EC, Snyder LH, Corbetta M, Ferrera VP. Functional evolution of new and expanded attention networks in humans. Proc Natl Acad Sci U S A. 2015;112:9454–9459.
    1. Mantini D, Corbetta M, Romani GL, Orban GA, Vanduffel W. Evolutionarily novel functional networks in the human brain?J Neurosci. 2013;33:3259–3275.
    1. Shulman GL, Astafiev SV, McAvoy MP, d’Avossa G, Corbetta M. Right TPJ deactivation during visual search: functional significance and support for a filter hypothesis. Cereb Cortex. 2007;17:2625–2633.
    1. Webb TW, Igelström KM, Schurger A, Graziano MS. Cortical networks involved in visual awareness independent of visual attention. Proc Natl Acad Sci U S A. 2016;113:13923–13928.
    1. Viviani R, Graf H, Wiegers M, Abler B. Effects of amisulpride on human resting cerebral perfusion. Psychopharmacology (Berl). 2013;229:95–103.
    1. Power JD, Barnes KA, Snyder AZ, Schlaggar BL, Petersen SE. Spurious but systematic correlations in functional connectivity MRI networks arise from subject motion. Neuroimage. 2012;59:2142–2154.
    1. Satterthwaite TD, Wolf DH, Loughead J et al. . Impact of in-scanner head motion on multiple measures of functional connectivity: relevance for studies of neurodevelopment in youth. Neuroimage. 2012;60:623–632.
    1. Van Dijk KR, Sabuncu MR, Buckner RL. The influence of head motion on intrinsic functional connectivity MRI. Neuroimage. 2012;59:431–438.
    1. Pruim RH, Mennes M, Buitelaar JK, Beckmann CF. Evaluation of ICA-AROMA and alternative strategies for motion artifact removal in resting state fMRI. Neuroimage. 2015;112:278–287.

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