Disruptive changes of cerebellar functional connectivity with the default mode network in schizophrenia

The default mode network (DMN) plays an important role in the physiopathology of schizophrenia. Previous studies have suggested that the cerebellum participates in higher-order cognitive networks such as the DMN. However, the specific contribution of the cerebellum to the DMN abnormalities in schizophrenia has yet to be established. In this study, we investigated cerebellar functional connectivity differences between 60 patients with schizophrenia and 60 healthy controls from a public resting-state fMRI database. Seed-based correlation analysis was performed by using seeds from the left Crus I, right Crus I and Lobule IX, which have previously been identified as being involved in the DMN. Our results revealed that, compared with the healthy controls, the patients showed significantly reduced cerebellar functional connectivity with the thalamus and several frontal regions including the middle frontal gyrus, anterior cingulate cortex, and supplementary motor area. Moreover, the positive correlations between the strength of frontocerebellar and thalamocerebellar functional connectivity observed in the healthy subjects were diminished in the patients. Our findings implicate disruptive changes of the fronto-thalamo-cerebellar circuit in schizophrenia, which may provide further evidence for the "cognitive dysmetria" concept of schizophrenia.

[1]  K. Kiehl,et al.  Rostral anterior cingulate cortex dysfunction during error processing in schizophrenia. , 2003, Brain : a journal of neurology.

[2]  S. Heckers,et al.  Functional resting-state networks are differentially affected in schizophrenia , 2011, Schizophrenia Research.

[3]  M. Glickstein,et al.  Visual pontocerebellar projections in the macaque , 1994, The Journal of comparative neurology.

[4]  Christian Gaser,et al.  Default mode network activity in schizophrenia studied at resting state using probabilistic ICA , 2012, Schizophrenia Research.

[5]  Antipsychotic drug effects in schizophrenia: a review of longitudinal FMRI investigations and neural interpretations. , 2013, Current medicinal chemistry.

[6]  Thierry d'Amato,et al.  Thalamus abnormalities during working memory in schizophrenia. An fMRI study , 2011, Schizophrenia Research.

[7]  D Timmann,et al.  The influence of focal cerebellar lesions on the control and adaptation of gait. , 2008, Brain : a journal of neurology.

[8]  Carsten Schmidt-Samoa,et al.  Reduced size of the pre-supplementary motor cortex and impaired motor sequence learning in first-episode schizophrenia , 2006, Schizophrenia Research.

[9]  J. Ragland,et al.  Alterations of fronto-temporal connectivity during word encoding in schizophrenia , 2007, Psychiatry Research: Neuroimaging.

[10]  A. Meyer-Lindenberg,et al.  Investigation of Anatomical Thalamo-Cortical Connectivity and fMRI Activation in Schizophrenia , 2012, Neuropsychopharmacology.

[11]  Marisa O. Hollinshead,et al.  The organization of the human cerebral cortex estimated by intrinsic functional connectivity. , 2011, Journal of neurophysiology.

[12]  Jeremy D. Schmahmann,et al.  Functional topography in the human cerebellum: A meta-analysis of neuroimaging studies , 2009, NeuroImage.

[13]  Marie-Odile Krebs,et al.  The Role of the Cerebellum in Schizophrenia: an Update of Clinical, Cognitive, and Functional Evidences , 2007, Schizophrenia bulletin.

[14]  P. Mcguire,et al.  The effects of antipsychotics on the brain: what have we learnt from structural imaging of schizophrenia?--a systematic review. , 2009, Current pharmaceutical design.

[15]  Martijn P. van den Heuvel,et al.  FUNCTIONAL CONNECTIVITY IN SCHIZOPHRENIA , 2010, Schizophrenia Research.

[16]  Lei Wang,et al.  Abnormalities of thalamic activation and cognition in schizophrenia. , 2006, The American journal of psychiatry.

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

[18]  E. G. Jones,et al.  Synchrony in the Interconnected Circuitry of the Thalamus and Cerebral Cortex , 2009, Annals of the New York Academy of Sciences.

[19]  Katherine E. Prater,et al.  Distinct Cerebellar Contributions to Intrinsic Connectivity Networks , 2009, NeuroImage.

[20]  Fenna M. Krienen,et al.  Segregated Fronto-Cerebellar Circuits Revealed by Intrinsic Functional Connectivity , 2009, Cerebral cortex.

[21]  F. Schneider,et al.  Modulation of the default mode network is task-dependant in chronic schizophrenia patients , 2011, Schizophrenia Research.

[22]  Ovidiu Lungu,et al.  The incidence and nature of cerebellar findings in schizophrenia: a quantitative review of fMRI literature. , 2013, Schizophrenia bulletin.

[23]  E. Bullmore,et al.  Functional dysconnectivity in schizophrenia associated with attentional modulation of motor function. , 2005, Brain : a journal of neurology.

[24]  Dewen Hu,et al.  Discriminative analysis of resting-state functional connectivity patterns of schizophrenia using low dimensional embedding of fMRI , 2010, NeuroImage.

[25]  Mark S. Cohen,et al.  Decreased small-world functional network connectivity and clustering across resting state networks in schizophrenia: an fMRI classification tutorial , 2013, Front. Hum. Neurosci..

[26]  P. Liddle The Symptoms of Chronic Schizophrenia , 1987, British Journal of Psychiatry.

[27]  Christopher L. Asplund,et al.  The organization of the human cerebellum estimated by intrinsic functional connectivity. , 2011, Journal of neurophysiology.

[28]  S. Paradiso,et al.  "Cognitive dysmetria" as an integrative theory of schizophrenia: a dysfunction in cortical-subcortical-cerebellar circuitry? , 1998, Schizophrenia bulletin.

[29]  J. Schmahmann From movement to thought: Anatomic substrates of the cerebellar contribution to cognitive processing , 1996, Human brain mapping.

[30]  M. Raichle,et al.  Searching for a baseline: Functional imaging and the resting human brain , 2001, Nature Reviews Neuroscience.

[31]  P. Strick,et al.  Cerebellar Projections to the Prefrontal Cortex of the Primate , 2001, The Journal of Neuroscience.

[32]  Fabio Sambataro,et al.  Treatment with Olanzapine is Associated with Modulation of the Default Mode Network in Patients with Schizophrenia , 2010, Neuropsychopharmacology.

[33]  H. Johansen-Berg,et al.  Distinct and overlapping functional zones in the cerebellum defined by resting state functional connectivity. , 2010, Cerebral cortex.

[34]  Susanne M. Jaeggi,et al.  Resting state cortico-cerebellar functional connectivity networks: a comparison of anatomical and self-organizing map approaches , 2012, Front. Neuroanat..

[35]  P. Skudlarski,et al.  Brain Connectivity Is Not Only Lower but Different in Schizophrenia: A Combined Anatomical and Functional Approach , 2010, Biological Psychiatry.

[36]  T. Wassink,et al.  Defining the phenotype of schizophrenia: cognitive dysmetria and its neural mechanisms , 1999, Biological Psychiatry.

[37]  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.

[38]  Hae-Jeong Park,et al.  Medial prefrontal default-mode hypoactivity affecting trait physical anhedonia in schizophrenia , 2009, Psychiatry Research: Neuroimaging.

[39]  Jack C. Rogers,et al.  Combination of Resting State fMRI, DTI, and sMRI Data to Discriminate Schizophrenia by N-way MCCA + jICA , 2013, Front. Hum. Neurosci..

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

[41]  R. Buckner,et al.  Self-projection and the brain , 2007, Trends in Cognitive Sciences.

[42]  Stefan Golaszewski,et al.  Brain activation patterns during a selective attention test — a functional MRI study in healthy volunteers and unmedicated patients during an acute episode of schizophrenia , 2007, Psychiatry Research: Neuroimaging.

[43]  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.

[44]  Kristina M. Visscher,et al.  Ventral Tegmental Area/Midbrain Functional Connectivity and Response to Antipsychotic Medication in Schizophrenia , 2014, Neuropsychopharmacology.

[45]  Christopher J. Bell,et al.  Altered functional and anatomical connectivity in schizophrenia. , 2011, Schizophrenia bulletin.

[46]  S. Taylor,et al.  Low-frequency BOLD fluctuations demonstrate altered thalamocortical connectivity in schizophrenia. , 2010, Schizophrenia bulletin.

[47]  P. Strick,et al.  Cerebellar Loops with Motor Cortex and Prefrontal Cortex of a Nonhuman Primate , 2003, The Journal of Neuroscience.

[48]  Stephan Heckers,et al.  Anterior cingulate cortex activation during cognitive interference in schizophrenia. , 2004, The American journal of psychiatry.

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

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

[51]  D. Yurgelun-Todd,et al.  Morphometry of individual cerebellar lobules in schizophrenia , 2000, NeuroImage.

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

[53]  René S. Kahn,et al.  Impaired Cerebellar Functional Connectivity in Schizophrenia Patients and Their Healthy Siblings , 2011, Front. Psychiatry.

[54]  Yul-Wan Sung,et al.  Functional magnetic resonance imaging , 2004, Scholarpedia.