Functional dysconnectivity of the dorsolateral prefrontal cortex in first-episode schizophrenia using resting-state fMRI

doi:10.1016/j.neulet.2007.02.081

Neuroscience Letters

Volume 417, Issue 3, 7 May 2007, Pages 297-302

https://doi.org/10.1016/j.neulet.2007.02.081 Get rights and content

Abstract

The known regional abnormality of the dorsolateral prefrontal cortex (DLPFC) and its role in various neural circuits in schizophrenia has given prominence to its importance in studies on the dysconnection associated with schizophrenia. Abnormal functional connectivities of the DLPFC have been found during various goal-directed tasks; however, the occurrence of the abnormality during rest in patients with schizophrenia has rarely been reported. In the present study, we selected bilateral Brodmann's area 46 as region of interest and analyzed the differences in the DLPFC functional connectivity pattern between 17 patients with first-episode schizophrenia (FES) and 17 matched controls using resting-state fMRI. We found that the bilateral DLPFC showed reduced functional connectivities to the parietal lobe, posterior cingulate cortex, thalamus and striatum in FES patients. We also found enhanced functional connectivity between the left DLPFC and the left mid-posterior temporal lobe and the paralimbic regions in FES patients. Our results suggest that functional dysconnectivity associated with the DLPFC exists in schizophrenia during rest. This may be partially related to disturbance in the intrinsic brain activity.

Section snippets

Acknowledgements

This work was partially supported by the Natural Science Foundation of China, Grant Nos. 30425004, 30530290 and 60121302, and the National Key Basic Research and Development Program (973), Grant No. 2003CB716100.

The authors are grateful to the anonymous referees for their constructive comments. The authors also thank Yihui Hao, Kun Wang, Ming Song and Professor Xiaoping P. Hu for their helpful discussions and Drs. Rhoda E. and Edmund F. Perozzi for editing and English language assistance.

References (32)

N.C. Andreasen et al.
Hypofrontality in schizophrenia: distributed dysfunctional circuits in neuroleptic–naive patients
Lancet
(1997)
W.E. Bunney et al.
Evidence for a compromised dorsolateral prefrontal cortical parallel circuit in schizophrenia
Brain Res. Brain Res. Rev.
(2000)
B. Crespo-Facorro et al.
Insular cortex abnormalities in schizophrenia: a structural magnetic resonance imaging study of first-episode patients
Schizophr. Res.
(2000)
J.H. Fallon et al.
The neuroanatomy of schizophrenia: circuitry and neurotransmitter systems
Clin. Neurosci. Res.
(2003)
W.W. Fleischhacker et al.
EUFEST Steering Committee, The European First Episode Schizophrenia Trial (EUFEST): rationale and design of the trial
Schizophr. Res.
(2005)
K.J. Friston
The disconnection hypothesis
Schizophr. Res.
(1998)
M.J. Lowe et al.
Functional connectivity in single and multislice echoplanar imaging using resting-state fluctuations
Neuroimage
(1998)
D. Malaspina et al.
Resting neural activity distinguishes subgroups of schizophrenia patients
Biol. Psychiatry
(2004)
J.A. Maldjian et al.
An automated method for neuroanatomic and cytoarchitectonic atlas-based interrogation of fMRI data sets
NeuroImage
(2003)
R. Schlosser et al.
Altered effective connectivity during working memory performance in schizophrenia: a study with fMRI and structural equation modeling
Neuroimage
(2003)

K.E. Stephan et al.

Synaptic plasticity and dysconnection in schizophrenia

Biol. Psychiatry

(2006)

L. Tian et al.

Altered resting-state functional connectivity patterns of anterior cingulate cortex in adolescents with attention deficit hyperactivity disorder

Neurosci. Lett.

(2006)

L. Wang et al.

Changes in hippocampal connectivity in the early stages of Alzheimer's disease: evidence from resting state fMRI

Neuroimage

(2006)

S. Achard et al.

A resilient, low-frequency, small-world human brain functional network with highly connected association cortical hubs

J. Neurosci.

(2006)

B. Biswal et al.

Functional connectivity in the motor cortex of resting human brain using echo-planar MRI

Magn. Reson. Med.

(1995)

J. Burns et al.

Structural disconnectivity in schizophrenia: a diffusion tensor magnetic resonance imaging study

Br. J. Psychiatry

(2003)

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Functional dysconnectivity of the dorsolateral prefrontal cortex in first-episode schizophrenia using resting-state fMRI

Abstract

Section snippets

Acknowledgements

Lancet

Brain Res. Brain Res. Rev.

Schizophr. Res.

Clin. Neurosci. Res.

Schizophr. Res.

Schizophr. Res.

Neuroimage

Biol. Psychiatry

NeuroImage

Neuroimage

Biol. Psychiatry

Neurosci. Lett.

Neuroimage

A resilient, low-frequency, small-world human brain functional network with highly connected association cortical hubs

J. Neurosci.

Functional connectivity in the motor cortex of resting human brain using echo-planar MRI

Magn. Reson. Med.

Structural disconnectivity in schizophrenia: a diffusion tensor magnetic resonance imaging study

Br. J. Psychiatry