OBJECTIVES: Abnormal task-related activation and connectivity is present in schizophrenia. The aim of this study was the analysis of functional networks in schizophrenia patients in remission after the first episode. EXPERIMENTAL DESIGN: Twenty-nine male patients in remission after the first episode of schizophrenia and 22 healthy controls underwent examination by functional magnetic resonance during verbal fluency tasks (VFT). The functional connectivity of brain networks was analyzed using independent component analysis. RESULTS: The patients showed lower activation of the salience network during VFT. They also showed lower deactivation of the default mode network (DMN) during VFT processing. Spectral analysis of the component time courses showed decreased power in slow frequencies of signal fluctuations in the salience and DMNs and increased power in higher frequencies in the left frontoparietal cortex reflecting higher fluctuations of the network activity. Moreover, there was decreased similarity of component time courses in schizophrenia—the patients had smaller negative correlation between VFT activated and deactivated networks, and smaller positive correlations between DMN subcomponents. CONCLUSIONS: There is still an abnormal functional connectivity of several brain networks in remission after the first episode of schizophrenia. The effect of different treatment modalities on brain connectivity, together with temporal dynamics of this functional abnormality should be the objective of further studies to assess its potential as a marker of disease stabilization.

Department of Psychiatry Masaryk University and University hospital Brno Czech Republic

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Amunts K, Weiss PH, Mohlberg H, Pieperhoff P, Eickhoff S, Gurd JM, Marshall JC, Shah NJ, Fink GR, Zilles K ( 2004): Analysis of neural mechanisms underlying verbal fluency in cytoarchitectonically defined stereotaxic space—the roles of Brodmann areas 44 and 45. Neuroimage 22: 42–56. PubMed

Andreasen NC, Carpenter WT Jr, Kane JM, Lasser RA, Marder SR, Weinberger DR ( 2005): Remission in schizophrenia: Proposed criteria and rationale for consensus. Am J Psychiatry 162: 441–449. PubMed

Birn RM, Diamond JB, Smith MA, Bandettini PA ( 2006): Separating respiratory‐variation‐related fluctuations from neuronal‐activity‐related fluctuations in fMRI. Neuroimage 31: 1536–1548. PubMed

Boksman K, Theberge J, Williamson P, Drost DJ, Malla A, Densmore M, Takhar J, Pavlosky W, Menon RS, Neufeld RW ( 2005): A 4.0‐T fMRI study of brain connectivity during word fluency in first‐episode schizophrenia. Schizophr Res 75: 247–263. PubMed

Calhoun VD, Adali T, Pearlson GD, Pekar JJ ( 2001): A method for making group inferences from functional MRI data using independent component analysis. Hum Brain Mapp 14: 140–151. PubMed PMC

Calhoun VD, Adali T, Pekar JJ ( 2004): A method for comparing group fMRI data using independent component analysis: application to visual, motor and visuomotor tasks. Magn Reson Imaging 22: 1181–1191. PubMed

Calhoun VD, Eichele T, Pearlson G ( 2009a): Functional brain networks in schizophrenia: A review. Front Hum Neurosci 3: 17. PubMed PMC

Calhoun VD, Liu J, Adali T ( 2009b): A review of group ICA for fMRI data and ICA for joint inference of imaging, genetic, and ERP data. Neuroimage 45( 1 Suppl): S163–S172. PubMed PMC

Camchong J, MacDonald AW III, Bell C, Mueller BA, Lim KO ( 2011): Altered functional and anatomical connectivity in schizophrenia. Schizophr Bull 37: 640–650. PubMed PMC

Ceskova E, Prikryl R, Kasparek T, Ondrusova M ( 2005): Psychopathology and treatment responsiveness of patients with first‐episode schizophrenia. Neuropsychiatr Dis Treat 1: 179–185. PubMed PMC

Ceskova E, Prikryl R, Kasparek T, Kucerova H ( 2007): One‐year follow‐up of patients with first‐episode schizophrenia (comparison between remitters and non‐remitters): Neuropsychiatr Dis Treat 3: 153–160. PubMed PMC

Costafreda SG, Fu CH, Lee L, Everitt B, Brammer MJ, David AS ( 2006): A systematic review and quantitative appraisal of fMRI studies of verbal fluency: Role of the left inferior frontal gyrus. Hum Brain Mapp 27: 799–810. PubMed PMC

Curtis VA, Bullmore ET, Brammer MJ, Wright IC, Williams SC, Morris RG, Sharma TS, Murray RM, McGuire PK ( 1998): Attenuated frontal activation during a verbal fluency task in patients with schizophrenia. Am J Psychiatry 155: 1056–1063. PubMed

Dawson N, Thompson RJ, McVie A, Thomson DM, Morris BJ, Pratt JA (in press): Modafinil reverses phencyclidine‐induced deficits in cognitive flexibility, cerebral metabolism, and functional brain connectivity. Schizophr Bull. PubMed PMC

Dye SM, Spence SA, Bench CJ, Hirsch SR, Stefan MD, Sharma T, Grasby PM ( 1999): No evidence for left superior temporal dysfunction in asymptomatic schizophrenia and bipolar disorder. PET study of verbal fluency. Br J Psychiatry 175: 367–374. PubMed

Elvevag B, Weinstock DM, Akil M, Kleinman JE, Goldberg TE ( 2001): A comparison of verbal fluency tasks in schizophrenic patients and normal controls. Schizophr Res 51: 119–126. PubMed

Falkai P, Wobrock T, Lieberman J, Glenthoj B, Gattaz WF, Moller HJ ( 2006): World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of schizophrenia, Part 2: Long‐term treatment of schizophrenia. World J Biol Psychiatry 7: 5–40. PubMed

Fletcher PC, Frith CD, Grasby PM, Friston KJ, Dolan RJ ( 1996): Local and distributed effects of apomorphine on fronto‐temporal function in acute unmedicated schizophrenia. J Neurosci 16: 7055–7062. PubMed PMC

Ford JM, Mathalon DH, Whitfield S, Faustman WO, Roth WT ( 2002): Reduced communication between frontal and temporal lobes during talking in schizophrenia. Biol Psychiatry 51: 485–492. PubMed

Fox MD, Snyder AZ, Vincent JL, Raichle ME ( 2007): Intrinsic fluctuations within cortical systems account for intertrial variability in human behavior. Neuron 56: 171–184. PubMed

Friston K ( 2009): Causal modelling and brain connectivity in functional magnetic resonance imaging. PLoS Biol 7: e33. PubMed PMC

Friston KJ, Frith CD ( 1995): Schizophrenia: A disconnection syndrome? Clin Neurosci 3: 89–97. PubMed

Frith CD, Friston KJ, Liddle PF, Frackowiak RS ( 1991): A PET study of word finding. Neuropsychologia 29: 1137–1148. PubMed

Frith CD, Friston KJ, Herold S, Silbersweig D, Fletcher P, Cahill C, Dolan RJ, Frackowiak RS, Liddle PF ( 1995): Regional brain activity in chronic schizophrenic patients during the performance of a verbal fluency task. Br J Psychiatry 167: 343–349. PubMed

Fu CH, Morgan K, Suckling J, Williams SC, Andrew C, Vythelingum GN, McGuire PK ( 2002): A functional magnetic resonance imaging study of overt letter verbal fluency using a clustered acquisition sequence: Greater anterior cingulate activation with increased task demand. Neuroimage 17: 871–879. PubMed

Fu CH, Suckling J, Williams SC, Andrew CM, Vythelingum GN, McGuire PK ( 2005): Effects of psychotic state and task demand on prefrontal function in schizophrenia: An fMRI study of overt verbal fluency. Am J Psychiatry 162: 485–494. PubMed

Garrity AG, Pearlson GD, McKiernan K, Lloyd D, Kiehl KA, Calhoun VD ( 2007): Aberrant "default mode" functional connectivity in schizophrenia. Am J Psychiatry 164: 450–457. PubMed

Greicius MD, Krasnow B, Reiss AL, Menon V ( 2003): Functional connectivity in the resting brain: A network analysis of the default mode hypothesis. Proc Natl Acad Sci USA 100: 253–258. PubMed PMC

Gurd JM, Amunts K, Weiss PH, Zafiris O, Zilles K, Marshall JC, Fink GR ( 2002): Posterior parietal cortex is implicated in continuous switching between verbal fluency tasks: An fMRI study with clinical implications. Brain 125( Pt 5): 1024–1038. PubMed

Hampson M, Driesen NR, Skudlarski P, Gore JC, Constable RT ( 2006): Brain connectivity related to working memory performance. J Neurosci 26: 13338–13343. PubMed PMC

Himberg J, Hyvarinen A, Esposito F ( 2004): Validating the independent components of neuroimaging time series via clustering and visualization. Neuroimage 22: 1214–1222. PubMed

Jafri MJ, Pearlson GD, Stevens M, Calhoun VD ( 2008): A method for functional network connectivity among spatially independent resting‐state components in schizophrenia. Neuroimage 39: 1666–1681. PubMed PMC

Kay SR, Fiszbein A, Opler LA ( 1987): The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 13: 261–276. PubMed

Kim DI, Manoach DS, Mathalon DH, Turner JA, Mannell M, Brown GG, Ford JM, Gollub RL, White T, Wible C, Belger A, Bockholt HJ, Clark VP, Lauriello J, O'Leary D, Mueller BA, Lim KO, Andreasen N, Potkin SG, Calhoun VD ( 2009): Dysregulation of working memory and default‐mode networks in schizophrenia using independent component analysis, an fBIRN and MCIC study. Hum Brain Mapp 30: 3795–3811. PubMed PMC

Kiviniemi V, Kantola JH, Jauhiainen J, Hyvarinen A, Tervonen O ( 2003): Independent component analysis of nondeterministic fMRI signal sources. Neuroimage 19( 2 Pt 1): 253–260. PubMed

Kubicki M, McCarley R, Westin CF, Park HJ, Maier S, Kikinis R, Jolesz FA, Shenton ME ( 2007): A review of diffusion tensor imaging studies in schizophrenia. J Psychiatr Res 41: 15–30. PubMed PMC

Lancaster JL, Woldorff MG, Parsons LM, Liotti M, Freitas CS, Rainey L, Kochunov PV, Nickerson D, Mikiten SA, Fox PT ( 2000): Automated Talairach atlas labels for functional brain mapping. Hum Brain Mapp 10: 120–131. PubMed PMC

Lawrie SM, Buechel C, Whalley HC, Frith CD, Friston KJ, Johnstone EC ( 2002): Reduced frontotemporal functional connectivity in schizophrenia associated with auditory hallucinations. Biol Psychiatry 51: 1008–1011. PubMed

Leucht S, Barnes TR, Kissling W, Engel RR, Correll C, Kane JM ( 2003): Relapse prevention in schizophrenia with new‐generation antipsychotics: A systematic review and exploratory meta‐analysis of randomized, controlled trials. Am J Psychiatry 160: 1209–1222. PubMed

Li YO, Adali T, Calhoun VD ( 2007): Estimating the number of independent components for functional magnetic resonance imaging data. Hum Brain Mapp 28: 1251–1266. PubMed PMC

Lui S, Li T, Deng W, Jiang LJ, Wu QZ, Tang HH, Yue QA, Huang XQ, Chan RC, Collier DA, Meda SA, Pearlson G, Mechelli A, Sweeney JA, Gong QY ( 2010): 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 67: 783–792. PubMed

Meda SA, Stevens MC, Folley BS, Calhoun VD, Pearlson GD ( 2009): Evidence for anomalous network connectivity during working memory encoding in schizophrenia: An ICA based analysis. PLoS ONE 4: e7911. PubMed PMC

Meyer‐Lindenberg AS, Olsen RK, Kohn PD, Brown T, Egan MF, Weinberger DR, Berman KF ( 2005): Regionally specific disturbance of dorsolateral prefrontal‐hippocampal functional connectivity in schizophrenia. Arch Gen Psychiatry 62: 379–386. PubMed

Pihlajamaki M, Tanila H, Hanninen T, Kononen M, Laakso M, Partanen K, Soininen H, Aronen HJ ( 2000): Verbal fluency activates the left medial temporal lobe: A functional magnetic resonance imaging study. Ann Neurol 47: 470–476. PubMed

Pomarol‐Clotet E, Salvador R, Sarro S, Gomar J, Vila F, Martinez A, Guerrero A, Ortiz‐Gil J, Sans‐Sansa B, Capdevila A, Cebamanos JM, McKenna PJ ( 2008): Failure to deactivate in the prefrontal cortex in schizophrenia: Dysfunction of the default mode network? Psychol Med 38: 1185–1193. PubMed

Ragland JD, Gur RC, Valdez J, Turetsky BI, Elliott M, Kohler C, Siegel S, Kanes S, Gur RE ( 2004): Event‐related fMRI of frontotemporal activity during word encoding and recognition in schizophrenia. Am J Psychiatry 161: 1004–1015. PubMed PMC

Raichle ME, MacLeod AM, Snyder AZ, Powers WJ, Gusnard DA, Shulman GL ( 2001): A default mode of brain function. Proc Natl Acad Sci USA 98: 676–682. PubMed PMC

Rossell SL ( 2006): Category fluency performance in patients with schizophrenia and bipolar disorder: The influence of affective categories. Schizophr Res 82: 135–138. PubMed

Rotarska‐Jagiela A, van de Ven V, Oertel‐Knochel V, Uhlhaas PJ, Vogeley K, Linden DE ( 2010): Resting‐state functional network correlates of psychotic symptoms in schizophrenia. Schizophr Res 117: 21–30. PubMed

Sambataro F, Blasi G, Fazio L, Caforio G, Taurisano P, Romano R, Di Giorgio A, Gelao B, Lo Bianco L, Papazacharias A, Popolizio T, Nardini M, Bertolino A ( 2010): Treatment with olanzapine is associated with modulation of the default mode network in patients with Schizophrenia. Neuropsychopharmacology 35: 904–912. PubMed PMC

Spence SA, Liddle PF, Stefan MD, Hellewell JS, Sharma T, Friston KJ, Hirsch SR, Frith CD, Murray RM, Deakin JF, Grasby PM ( 2000): Functional anatomy of verbal fluency in people with schizophrenia and those at genetic risk. Focal dysfunction and distributed disconnectivity reappraised. Br J Psychiatry 176: 52–60. PubMed

Stephan KE, Magnotta VA, White T, Arndt S, Flaum M, O'Leary DS, Andreasen NC ( 2001): Effects of olanzapine on cerebellar functional connectivity in schizophrenia measured by fMRI during a simple motor task. Psychol Med 31: 1065–1078. PubMed

Takizawa R, Kasai K, Kawakubo Y, Marumo K, Kawasaki S, Yamasue H, Fukuda M ( 2008): Reduced frontopolar activation during verbal fluency task in schizophrenia: A multi‐channel near‐infrared spectroscopy study. Schizophr Res 99: 250–262. PubMed

Thomas CG, Harshman RA, Menon RS ( 2002): Noise reduction in BOLD‐based fMRI using component analysis. Neuroimage 17: 1521–1537. PubMed

van Beilen M, Pijnenborg M, van Zomeren EH, van den Bosch RJ, Withaar FK, Bouma A ( 2004): What is measured by verbal fluency tests in schizophrenia? Schizophr Res 69: 267–276. PubMed

Vercammen A, Knegtering H, Liemburg EJ, den Boer JA, Aleman A ( 2010): Functional connectivity of the temporo‐parietal region in schizophrenia: Effects of rTMS treatment of auditory hallucinations. J Psychiatr Res 44: 725–731. PubMed

Watt DC, Katz K, Shepherd M ( 1983): The natural history of schizophrenia: A 5‐year prospective follow‐up of a representative sample of schizophrenics by means of a standardized clinical and social assessment. Psychol Med 13: 663–670. PubMed

Weiss EM, Siedentopf C, Hofer A, Deisenhammer EA, Hoptman MJ, Kremser C, Golaszewski S, Felber S, Fleischhacker WW, Delazer M ( 2003): Brain activation pattern during a verbal fluency test in healthy male and female volunteers: A functional magnetic resonance imaging study. Neurosci Lett 352: 191–194. PubMed

Weiss EM, Hofer A, Golaszewski S, Siedentopf C, Brinkhoff C, Kremser C, Felber S, Fleischhacker WW ( 2004): Brain activation patterns during a verbal fluency test‐a functional MRI study in healthy volunteers and patients with schizophrenia. Schizophr Res 70: 287–291. PubMed

Weissman DH, Roberts KC, Visscher KM, Woldorff MG ( 2006): The neural bases of momentary lapses in attention. Nat Neurosci 9: 971–978. PubMed

Whitfield‐Gabrieli S, Thermenos HW, Milanovic S, Tsuang MT, Faraone SV, McCarley RW, Shenton ME, Green AI, Nieto‐Castanon A, LaViolette P, Wojcik J, Gabrieli JD, Seidman LJ ( 2009): Hyperactivity and hyperconnectivity of the default network in schizophrenia and in first‐degree relatives of persons with schizophrenia. Proc Natl Acad Sci USA 106: 1279–1284. PubMed PMC

Wolf RC, Vasic N, Sambataro F, Hose A, Frasch K, Schmid M, Walter H ( 2009): Temporally anticorrelated brain networks during working memory performance reveal aberrant prefrontal and hippocampal connectivity in patients with schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 33: 1464–1473. PubMed

Yurgelun‐Todd DA, Waternaux CM, Cohen BM, Gruber SA, English CD, Renshaw PF ( 1996): Functional magnetic resonance imaging of schizophrenic patients and comparison subjects during word production. Am J Psychiatry 153: 200–205. PubMed

Zhou Y, Liang M, Tian L, Wang K, Hao Y, Liu H, Liu Z, Jiang T ( 2007): Functional disintegration in paranoid schizophrenia using resting‐state fMRI. Schizophr Res 97: 194–205. PubMed

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