Global Functional Connectivity Deficits in Schizophrenia Depend on Behavioral State

Schizophrenia is a devastating psychiatric illness characterized by deterioration of cognitive and emotional processing. It has been hypothesized that aberrant cortical connectivity is implicated in the disease (Friston, 1998), yet previous studies of functional connectivity (FC) in schizophrenia have shown mixed results (Garrity et al., 2007; Jafri et al., 2008; Lynall et al., 2010). We measured FC using fMRI in human schizophrenia patients and healthy controls during two different tasks and a rest condition, and constructed a voxel-based global FC index. We found a striking FC decrease in patients compared with controls. In the task conditions, relatively weaker FC was specific to regions of cortex not active during the task. In the rest condition, the FC difference between patients and controls was larger and allowed a case-by-case separation between individuals of the two groups. The results suggest that the relative reduction of FC in schizophrenia is dependent on the state of cortical activity, with voxels not activated by the task showing higher levels of FC deficiency. This novel finding may shed light on previous reports of FC in schizophrenia. Whether this neural characteristic is related to the development of the disorder remains to be established.

[1]  I. Nimmo-Smith,et al.  Hypofrontality in schizophrenia: a meta‐analysis of functional imaging studies , 2004, Acta psychiatrica Scandinavica.

[2]  E. Bullmore,et al.  Functional Connectivity and Brain Networks in Schizophrenia , 2010, The Journal of Neuroscience.

[3]  Yuan Zhou,et al.  Schizophrenic patients and their unaffected siblings share increased resting-state connectivity in the task-negative network but not its anticorrelated task-positive network. , 2012, Schizophrenia bulletin.

[4]  Pia Rotshtein,et al.  Diminished neural sensitivity to irregular facial expression in first‐episode schizophrenia , 2009, Human brain mapping.

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

[6]  Karl J. Friston,et al.  Functional Connectivity: The Principal-Component Analysis of Large (PET) Data Sets , 1993, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[7]  E. D. Adrian,et al.  THE ORIGIN OF THE BERGER RHYTHM , 1935 .

[8]  I. Fried,et al.  Interhemispheric correlations of slow spontaneous neuronal fluctuations revealed in human sensory cortex , 2008, Nature Neuroscience.

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

[10]  Karl J. Friston,et al.  Reduced frontotemporal functional connectivity in schizophrenia associated with auditory hallucinations , 2002, Biological Psychiatry.

[11]  J B Poline,et al.  Evidence for abnormal cortical functional connectivity during working memory in schizophrenia. , 2001, The American journal of psychiatry.

[12]  Karl J. Friston The disconnection hypothesis , 1998, Schizophrenia Research.

[13]  T. Murata,et al.  Quantitative EEG in never-treated schizophrenic patients , 1995, Biological Psychiatry.

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

[15]  M. Schölvinck,et al.  Neural basis of global resting-state fMRI activity , 2010, Proceedings of the National Academy of Sciences.

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

[17]  E. Merrin,et al.  Negative symptoms and EEG alpha activity in schizophrenic patients , 1992, Schizophrenia Research.

[18]  Edward T. Bullmore,et al.  Overall brain connectivity maps show cortico subcortical abnormalities in schizophrenia , 2011 .

[19]  C. Frith,et al.  Disordered functional connectivity in schizophrenia , 1996, Psychological Medicine.

[20]  S. Potkin,et al.  Therapeutic effects of individualized alpha frequency transcranial magnetic stimulation (alphaTMS) on the negative symptoms of schizophrenia. , 2005, Schizophrenia bulletin.

[21]  Rafael Malach,et al.  Stimulus-free thoughts induce differential activation in the human default network , 2011, NeuroImage.

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

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

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

[25]  A. Meyer-Lindenberg,et al.  Regionally specific disturbance of dorsolateral prefrontal-hippocampal functional connectivity in schizophrenia. , 2005, Archives of general psychiatry.

[26]  Yehezkel Yeshurun,et al.  Widespread functional connectivity and fMRI fluctuations in human visual cortex in the absence of visual stimulation , 2006, NeuroImage.

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

[28]  Lisa T. Eyler,et al.  Review of longitudinal functional neuroimaging studies of drug treatments in patients with schizophrenia , 2005, Schizophrenia Research.

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

[30]  Dominique Lamy,et al.  Involvement of the Intrinsic/Default System in Movement-Related Self Recognition , 2009, PloS one.

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

[32]  V. Haughton,et al.  Mapping functionally related regions of brain with functional connectivity MR imaging. , 2000, AJNR. American journal of neuroradiology.

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

[34]  M. Torrens Co-Planar Stereotaxic Atlas of the Human Brain—3-Dimensional Proportional System: An Approach to Cerebral Imaging, J. Talairach, P. Tournoux. Georg Thieme Verlag, New York (1988), 122 pp., 130 figs. DM 268 , 1990 .

[35]  P. Matthews,et al.  White matter abnormalities and brain activation in schizophrenia: A combined DTI and fMRI study , 2007, Schizophrenia Research.

[36]  D. Manoach Prefrontal cortex dysfunction during working memory performance in schizophrenia: reconciling discrepant findings , 2003, Schizophrenia Research.

[37]  Dinesh Bhugra,et al.  The Global Prevalence of Schizophrenia , 2005, PLoS medicine.

[38]  E. Merrin,et al.  Negative symptoms and EEG alpha in schizophrenia: a replication , 1996, Schizophrenia Research.

[39]  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.

[40]  S. Sponheim,et al.  Clinical and biological concomitants of resting state EEG power abnormalities in schizophrenia , 2000, Biological Psychiatry.