Long-Biao Cui1, Yi-Bin Xi1, and Hong Yin1
1Xijing Hospital, Fourth Mililtary Medical University, Xi'an, China, People's Republic of
Synopsis
Our results suggest an association of abnormal regional
function in the putamen and prefrontal cortex and hyperconnectivity between
them with AVHs in SZ. The functional interaction of the putamen with DLPFC
and Broca’s area seems to be crucial for AVHs in SZ. Additionally, the putamen-related regional
and network functional deficits may also serve as a potential diagnostic biomarker
of AVHs in SZ based on the direct evidence in vivo we
found. In SZ patients, there
is an extensive hypoconnectivity within cortical-striatal-cerebellar networks,
which further supports the current thinking about disconnection hypothesis of SZ.Objective: Auditory verbal hallucinations (AVHs) are one of
the cardinal symptoms of schizophrenia (SZ). Cerebral functional deficits may
represent pathophysiological underpinnings of neuromodulation behind AVHs in SZ.
However, the regional and network functional deficits for AVHs in SZ remain to
be identified.
Methods:
Seventeen medication-naïve first-episode SZ patients with AVHs, 15 without AVHs,
and 19 healthy controls (HCs) were studied using resting-state functional
magnetic resonance imaging. We compared the amplitude of low-frequency
fluctuation (ALFF) and regional homogeneity (ReHo) among these subjects. Areas
with both ALFF and ReHo alterations were used as seeds in functional
connectivity (FC) analysis. Then we performed correlation analysis between
image measures and symptoms and receiver operating characteristic (ROC)
analysis.
Results: One-way analysis of variance showed
significant differences of ALFF and ReHo in the bilateral putamen, thereby
being used as seeds. SZ patients with AVHs showed decreased ALFF in the left
putamen, increased ReHo in the right dorsolateral prefrontal cortex (DLPFC),
and increased right putamen-seeded FC with the left DLPFC and Broca’s area
relative to those without AVHs. Furthermore, the increased strength of the
connectivity between the right putamen and the left Broca’s area correlated
with the severity of SZ symptoms. Both patient groups demonstrated
hypoconnectivity within cortico-striatal-cerebellar networks.
Discussion: Our results suggest that SZ patients
with AVHs show abnormal local neurophysiological activity and interregional integration,
primarily involving the putamen and prefrontal cortex. Specifically, as
compared with those without AVHs, SZ patients with AVHs exhibited decreased
ALFF in the left putamen and increased ReHo in the right middle frontal gyrus
(DLPFC), as well as enhanced FC between the right putamen and the left middle
and inferior frontal gyri (DLPFC and Broca’s area). From the perspective of
structure and function, the putamen and middle and inferior frontal gyri (DLPFC
and Broca’s area) have ever been linked
to AVHs in SZ. van Tol et al studied whole-brain voxel-based morphometry of
gray matter and showed lower gray matter volume of the left putamen in SZ patients
with AVHs relative to those without AVHs (1).
In line with the volumetric study, we found regional functional deficits in the
left putamen using ALFF. Compared with SZ patients without AVHs, the right
putamen in SZ patients with AVHs was functionally connected to the left middle
and inferior frontal gyri, which represent DLPFC and Broca’s area and are known
to be involved in AVHs in SZ. A coordinate-based meta-analysis by Jardri et al included
ten positron emission tomography or fMRI studies and identified cortical activations
during AVHs in SZ patients, including the left Broca’s area (2).
In FC study by Hoffman et al (3),
intriguingly, the left Broca’s area-seeded FC with the putamen demonstrated
significantly greater when SZ patents with AVHs were compared with SZ patients
without AVHs, suggesting that the putamen and Broca’s area reciprocally
interacted no matter which one is used as seed area. Meanwhile, elevated bilateral
Wernicke’s area-seeded FC with the putamen was also found in this study,
suggesting aberrant functional interaction of the putamen with speech areas
might contribute to AVHs in SZ.
Conclusion:
AVHs in SZ have
abnormal regional function in the putamen and prefrontal cortex, as well as
hyperconnectivity between them. The putamen-related regional and network
functional deficits may serve as potential diagnostic biomarkers of AVHs in SZ.
Furthermore, dysconnectivity within cortico-striatal-cerebellar networks might
subserve the pathogenesis of SZ.
Acknowledgements
This study was supported by the National Key Basic Research and Development Program (973)
(2011CB707805). The authors thank Dr. Yang Liao and Peng Huang from School of Medical
Psychology, Fourth Military Medical University and Dr. Yuan-Qiang Zhu from School
of Life Sciences and Technology, Xidian University for their assistance with
the data analysis. The authors declare no competing financial interests.References
1. van Tol, M.J., van der Meer,
L., Bruggeman, R., Modinos, G., Knegtering, H., Aleman, A., 2014. Voxel-based
gray and white matter morphometry correlates of hallucinations in
schizophrenia: The superior temporal gyrus does not stand alone. Neuroimage
Clin 4, 249-257.
2. Jardri, R., Pouchet, A., Pins, D., Thomas, P., 2011. Cortical
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