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Anatomical and Functional Brain Abnormalities in Drug-Naive First-Episode Schizophrenia
Wenting Ren, M.S.; Su Lui, M.D., Ph.D.; Wei Deng, M.D.; Fei Li, M.D.; Mingli Li, M.D.; Xiaoqi Huang, M.D.; Yuqing Wang, Ph.D.; Tao Li, M.D.; John A. Sweeney, Ph.D.; Qiyong Gong, M.D., Ph.D.
Am J Psychiatry 2013;170:1308-1316. doi:10.1176/appi.ajp.2013.12091148
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Wenting Ren and Wei Deng contributed equally to this study.

Dr. Sweeney has been on advisory boards for Bristol-Myers Squibb, Eli Lilly, Pfizer, Roche, and Takeda and has received grant support from Janssen. The other authors report no financial relationships with commercial interests.

Supported by National Natural Science Foundation (grants 81222018, 81030027, 81227002, and 81220108013); the Distinguished Professorship awarded to Dr. Qiyong Gong by the China Medical Board administered by the Institute of International Education, Washington, D.C.; the Program for Changjiang Scholars and Innovative Research Team in University of China; and the National Key Technologies R&D Program of China (program 2012BAI01B03).

From the Huaxi MR Research Center, Department of Radiology, Center for Medical Imaging, West China Hospital of Sichuan University, China; the Department of Radiation Oncology, Cancer Hospital (Institute), Chinese Academy of Medical Science/Peking Union Medical College, Beijing; the Department of Psychiatry, Stat Key Lab of Biotherapy, West China Hospital of Sichuan University, Chengdu, China; and the Departments of Psychiatry and Pediatrics, University of Texas Southwestern Medical Center, Dallas.

Address correspondence to Dr. Lui (lusuwcums@tom.com) or Dr. Gong (qiyonggong@hmrrc.org.cn).

Copyright © 2013 by the American Psychiatric Association

Received September 02, 2012; Revised November 13, 2012; Revised February 04, 2013; Accepted March 04, 2013.

Abstract

Objective  The authors sought to explore whether anatomical and functional brain deficits are present in similar or different brain regions early in the course of schizophrenia, before antipsychotic treatment, and whether these deficits are more severe or otherwise different in patients with prominent negative symptoms.

Method  A total of 100 drug-naive first-episode schizophrenia patients and 100 matched healthy comparison subjects underwent structural and resting-state functional MRI scanning. Gray matter volume and amplitude of low-frequency fluctuations during resting-state functional studies were measured.

Results  Group comparisons of gray matter volume showed significant differences mainly in thalamo-cortical networks, while alterations in the amplitude of low-frequency fluctuations were observed in fronto-parietal and default mode networks. Thus, different brain regions had alterations in gray matter volume and resting state physiology. These changes did not correlate with the duration of untreated illness, nor with acute clinical symptom severity. Patients with prominent negative symptoms had greater regional alterations in brain anatomy, particularly in the left dorsolateral prefrontal cortex, while the pattern of functional alterations was unrelated to severity of negative symptoms.

Conclusions  Anatomical and resting-state functional deficits were observed in different brain regions, indicating that anatomical and functional brain abnormalities are significantly dissociated in the early course of schizophrenia. The lack of association of these abnormalities with illness duration and episode severity suggests that these anatomical and functional changes may be early-evolving features of the illness that are relatively stable early in the course of illness. The different structural deficits of regional gray matter observed in patients with prominent negative symptoms may provide unique insight into the early regional neuropathology of this symptom dimension in schizophrenia.

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FIGURE 1. Differences in Gray Matter Volume Between Drug-Naive First-Episode Schizophrenia Patients and Healthy Comparison Subjectsa

a Significant group differences were identified by t test (p<0.05 corrected for multiple comparisons with false discovery rate). The regions in blue indicate areas with decreased gray matter volume in first-episode schizophrenia, including the left postcentral gyrus extending to the paracentral lobule and the left inferior parietal gyrus; regions in red indicate areas with increased gray matter volume in first-episode schizophrenia, including the left and right thalamus, anterior cingulate cortex, insula, and orbital frontal gyrus.

FIGURE 2. Differences in the Amplitude of Low-Frequency Fluctuation During Resting-State Functional Imaging Between Drug-Naive First-Episode Schizophrenia Patients and Healthy Comparison Subjectsa

a Significant group differences were identified by t test (p<0.05 corrected for multiple comparisons with the AlphaSim program). The regions in blue showed a decreased amplitude of low-frequency fluctuation in first-episode schizophrenia, seen mainly in the right inferior and left superior frontal gyrus, the medial frontal gyrus, and the left and right inferior parietal lobule and precuneus; regions in red indicate areas with an increased amplitude in first-episode schizophrenia, including the left and right putamen and occipital regions. ALFF=amplitude of low-frequency fluctuation.

FIGURE 3. Differences in Gray Matter Volume Between Healthy Comparison Subjects and Drug-Naive First-Episode Schizophrenia Patients With and Without Prominent Negative Symptomsa

a The regions in blue denote areas with decreased gray matter volume and those in yellow indicate increased gray matter volume in the comparisons indicated (p<0.05 corrected with false discovery rate). Relative to healthy comparison subjects, patients with prominent negative symptoms showed significantly decreased gray matter volume in the right postcentral gyrus and the left inferior parietal lobule and increased gray matter volume in the left and right thalamus, insula, and dorsolateral prefrontal cortex. Relative to healthy comparison subjects, patients without prominent negative symptoms showed significantly decreased gray matter volume in regions including the right middle temporal gyrus, left middle frontal gyrus, left postcentral gyrus, and right middle occipital gyrus, and increased gray matter volume in the left and right thalamus, insula, anterior cingulate cortex, and left inferior frontal gyrus. The direct comparisons between patients without and with prominent negative symptoms revealed smaller gray matter volume in the left and right middle frontal gyrus and the left superior frontal gyrus in patients without prominent negative symptoms.

FIGURE 4. Differences in the Amplitude of Low-Frequency Fluctuation Between Healthy Comparison Subjects and Drug-Naive First-Episode Schizophrenia Patients With and Without Prominent Negative Symptomsa

a The regions in blue denote decreased and those in yellow denote increased amplitude of low-frequency fluctuation in the comparisons indicated (p<0.05 corrected with false discovery rate). Patients with and without prominent negative symptoms showed similar patterns of decreased amplitude of low-frequency fluctuation, mainly in the left and right middle and inferior frontal gyrus and the right inferior parietal lobule, and increased amplitude in the left and right putamen and occipital regions.

Anchor for Jump
TABLE 1.Differences in Gray Matter Volume and Amplitude of Low-Frequency Fluctuation Between Drug-Naive First-Episode Schizophrenia and Healthy Comparison Subjectsa
Table Footer Note

a Differences are significant at p<0.05 with correction for multiple comparisons.

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