Aberrant intrinsic brain activity and cognitive deficit in first-episode treatment-naive patients with schizophrenia

Background Given the important role of the default mode network (DMN) in cognitive function and the well-known neurocognitive deficit in schizophrenia, it is intriguing to examine systematically the relationship between neurocognitive dysfunction and aberrant intrinsic activities, and also functional connectivity, of the DMN in patients with schizophrenia. Method First-episode, treatment-naive patients with schizophrenia (FES) (n = 115) and healthy controls (n = 113) underwent resting-state functional magnetic resonance imaging (fMRI) scans and neurocognitive tests. Intrinsic neural activities evaluated by using the fragment amplitude of low-frequency fluctuations (fALFF) and the resting-state functional connectivity assessed by seed-based correlational analysis were compared between patients and controls. Aberrant intrinsic activities and DMN connectivity in patients were then correlated to neurocognitive performance and clinical symptoms. Results Compared to controls, patients with FES showed decreased fALFF in the bilateral medial prefrontal cortex (MPFC) and the orbitofrontal cortex (OFC), and increased fALFF in the bilateral putamen. Increased functional connectivity with the DMN was observed in the left insula and bilateral dorsolateral PFC (DLPFC) in patients with FES. In patients, aberrant fALFF in the bilateral OFC were correlated with cognitive processing speed; fALFF in the left OFC and right putamen were correlated with the clinical factors excited/activation and disorganization; and increased DMN functional connectivity in the left insula was correlated with the clinical factors positive, excited/activation, disorganization and neurocognitive deficit in the domain of sustained attention. Conclusions These associations between neurocognitive dysfunction and aberrant intrinsic activities, and also functional connectivity, of the DMN in patients with schizophrenia may provide important insights into the neural mechanism of the disease.

[1]  S. Faraone,et al.  Neurocognition in first-episode schizophrenia: a meta-analytic review. , 2009, Neuropsychology.

[2]  V. Calhoun,et al.  Aberrant "default mode" functional connectivity in schizophrenia. , 2007, The American journal of psychiatry.

[3]  F. Castellanos,et al.  Spontaneous attentional fluctuations in impaired states and pathological conditions: A neurobiological hypothesis , 2007, Neuroscience & Biobehavioral Reviews.

[4]  Kwang-Hyuk Lee,et al.  A functional magnetic resonance imaging study of social cognition in schizophrenia during an acute episode and after recovery. , 2006, The American journal of psychiatry.

[5]  G L Shulman,et al.  INAUGURAL ARTICLE by a Recently Elected Academy Member:A default mode of brain function , 2001 .

[6]  R. Hu.  Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) , 2003 .

[7]  Jonathan D. Cohen,et al.  Lateral and medial hypofrontality in first-episode schizophrenia: functional activity in a medication-naive state and effects of short-term atypical antipsychotic treatment. , 2005, The American journal of psychiatry.

[8]  S. Debener,et al.  Default-mode brain dysfunction in mental disorders: A systematic review , 2009, Neuroscience & Biobehavioral Reviews.

[9]  K. Vogeley,et al.  Resting-state functional network correlates of psychotic symptoms in schizophrenia , 2010, Schizophrenia Research.

[10]  Tianzi Jiang,et al.  Decreased regional homogeneity in schizophrenia: a resting state functional magnetic resonance imaging study , 2006, Neuroreport.

[11]  Mert R. Sabuncu,et al.  The influence of head motion on intrinsic functional connectivity MRI , 2012, NeuroImage.

[12]  Alessandra Bertoldo,et al.  The impact of schizophrenia on frontal perfusion parameters: a DSC-MRI study , 2011, Journal of Neural Transmission.

[13]  N. Andreasen,et al.  Insular cortex abnormalities in schizophrenia: a structural magnetic resonance imaging study of first-episode patients , 2000, Schizophrenia Research.

[14]  R. Bonelli,et al.  Structural neuroimaging of the basal ganglia in schizophrenic patients: a review , 2007, Wiener Medizinische Wochenschrift.

[15]  Wei Deng,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. , 2010, Archives of general psychiatry.

[16]  S. Haber,et al.  Increased synaptic dopamine function in associative regions of the striatum in schizophrenia. , 2010, Archives of general psychiatry.

[17]  M. Fox,et al.  Spontaneous fluctuations in brain activity observed with functional magnetic resonance imaging , 2007, Nature Reviews Neuroscience.

[18]  Yuan Zhou,et al.  Functional disintegration in paranoid schizophrenia using resting-state fMRI , 2007, Schizophrenia Research.

[19]  P. Fransson.  Spontaneous low‐frequency BOLD signal fluctuations: An fMRI investigation of the resting‐state default mode of brain function hypothesis , 2005, Human brain mapping.

[20]  Todd S. Woodward,et al.  Aberrant connectivity during self–other source monitoring in schizophrenia , 2011, Schizophrenia Research.

[21]  V. Calhoun,et al.  Modulation of temporally coherent brain networks estimated using ICA at rest and during cognitive tasks , 2008, Human brain mapping.

[22]  R. Norman,et al.  Course of cognitive functioning in first episode schizophrenia spectrum disorders , 2004, Expert review of neurotherapeutics.

[23]  Yong He,et al.  Disrupted small-world networks in schizophrenia. , 2008, Brain : a journal of neurology.

[24]  Peter Williamson,et al.  Are anticorrelated networks in the brain relevant to schizophrenia? , 2007, Schizophrenia bulletin.

[25]  R. Murray,et al.  Factor Structures of the Neurocognitive Assessments and Familial Analysis in First-Episode Schizophrenia Patients, Their Relatives and Controls , 2010, The Australian and New Zealand journal of psychiatry.

[26]  Bharat B. Biswal,et al.  Competition between functional brain networks mediates behavioral variability , 2008, NeuroImage.

[27]  Jason R. Tregellas,et al.  The role of the insula in schizophrenia , 2010, Schizophrenia Research.

[28]  D. Rujescu,et al.  Factor structure and external validity of the PANSS revisited , 2006, Schizophrenia Research.

[29]  E. Bora,et al.  Neuroanatomical abnormalities in schizophrenia: A multimodal voxelwise meta-analysis and meta-regression analysis , 2011, Schizophrenia Research.

[30]  Tao Li,et al.  Localization of cerebral functional deficits in treatment-naive, first-episode schizophrenia using resting-state fMRI , 2010, NeuroImage.

[31]  R. Bluhm,et al.  Spontaneous low-frequency fluctuations in the BOLD signal in schizophrenic patients: anomalies in the default network. , 2007, Schizophrenia bulletin.

[32]  J. Hornak,et al.  Social and emotional functioning following bilateral and unilateral neurosurgical prefrontal cortex lesions. , 2009, Journal of neuropsychology.

[33]  Peter Fransson,et al.  The precuneus/posterior cingulate cortex plays a pivotal role in the default mode network: Evidence from a partial correlation network analysis , 2008, NeuroImage.

[34]  Karl J. Friston,et al.  Schizophrenia: a disconnection syndrome? , 1995, Clinical neuroscience.

[35]  Kevin Murphy,et al.  The impact of global signal regression on resting state correlations: Are anti-correlated networks introduced? , 2009, NeuroImage.

[36]  R. Reitan.  Trail Making Test: Manual for Administration and Scoring , 1992 .

[37]  Michelle Hampson,et al.  Functional connectivity between task-positive and task-negative brain areas and its relation to working memory performance. , 2010, Magnetic resonance imaging.

[38]  Chaozhe Zhu,et al.  An improved approach to detection of amplitude of low-frequency fluctuation (ALFF) for resting-state fMRI: Fractional ALFF , 2008, Journal of Neuroscience Methods.

[39]  Yuan Zhou,et al.  Widespread functional disconnectivity in schizophrenia with resting-state functional magnetic resonance imaging , 2006, Neuroreport.

[40]  Xi-Nian Zuo,et al.  Amplitude of low-frequency oscillations in schizophrenia: A resting state fMRI study , 2010, Schizophrenia Research.

[41]  M. Annett.  A classification of hand preference by association analysis. , 1970, British journal of psychology.

[42]  Abraham Z. Snyder,et al.  Spurious but systematic correlations in functional connectivity MRI networks arise from subject motion , 2012, NeuroImage.

[43]  Nashaat N. Boutros,et al.  The Brain and Behavior: An Introduction to Behavioral Neuroanatomy , 2005 .

[44]  Maurizio Corbetta,et al.  The human brain is intrinsically organized into dynamic, anticorrelated functional networks. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[45]  S. Kapur,et al.  The dopamine hypothesis of schizophrenia: version III--the final common pathway. , 2009, Schizophrenia bulletin.

[46]  H. Möller,et al.  Increase of striatal dopamine transmission in first episode drug-naive schizophrenic patients as demonstrated by [123I]IBZM SPECT , 2009, Psychiatry Research: Neuroimaging.

[47]  J. Gabrieli,et al.  Hyperactivity and hyperconnectivity of the default network in schizophrenia and in first-degree relatives of persons with schizophrenia , 2009, Proceedings of the National Academy of Sciences.

[48]  Mark A. Elliott,et al.  Impact of in-scanner head motion on multiple measures of functional connectivity: Relevance for studies of neurodevelopment in youth , 2012, NeuroImage.

[49]  D. Wechsler.  WAIS-R manual : Wechsler adult intelligence scale-revised , 1981 .

[50]  Angus W. MacDonald,et al.  The functional neuroanatomy of symptom dimensions in schizophrenia: A qualitative and quantitative review of a persistent question , 2010, Neuroscience & Biobehavioral Reviews.

[51]  J. Gold,et al.  Overlooking the obvious: a meta-analytic comparison of digit symbol coding tasks and other cognitive measures in schizophrenia. , 2007, Archives of general psychiatry.

[52]  G. Juckel,et al.  Gray matter abnormalities in subjects at ultra-high risk for schizophrenia and first-episode schizophrenic patients compared to healthy controls , 2009, Psychiatry Research: Neuroimaging.

[53]  Vince D. Calhoun,et al.  A method for functional network connectivity among spatially independent resting-state components in schizophrenia , 2008, NeuroImage.

[54]  M. First,et al.  Structured clinical interview for DSM-IV axis I disorders : SCID-I : clinical version : scoresheet , 1997 .

[55]  R. Salvador,et al.  Failure to deactivate in the prefrontal cortex in schizophrenia: dysfunction of the default mode network? , 2008, Psychological Medicine.