Research paperLongitudinal changes of amplitude of low-frequency fluctuations in MDD patients: A 6-month follow-up resting-state functional magnetic resonance imaging study
Introduction
Major depressive disorder (MDD) is a common, debilitating mental disorder whose pathophysiology is both complex and poorly understood (Eshel and Roiser, 2010). MDD, like all the other psychiatric disorders, is currently diagnosed on the basis of physician's subjective assessment of clinical symptomatology (Malhi and Mann, 2018). This symptom-based diagnostic framework covers hundreds of thousands of unique symptom combinations, resulting in extensive heterogeneity in the clinical MDD syndrome (Fried and Nesse, 2015; Park et al., 2017). Moreover, despite many efforts characterizing the brain, behavior, and physiology of individuals with MDD, unlike diagnostic biomarkers in other areas of biology and medicine (Rosell et al., 2013), we still lack biomarker candidates for consistently differentiating MDD patients from healthy subjects, partly because of a huge gap between the diagnostic labels and neurobiological substrates (Drysdale et al., 2017; Gururajan et al., 2016).
Resting-state functional magnetic resonance imaging (rsfMRI) is a potentially effective method to explore the spontaneous neural activities and functional connectivity networks underlying the pathogenesis of MDD (Hasler and Northoff, 2011). The amplitude of low-frequency fluctuations (ALFF), measuring the spontaneous fluctuations in the BOLD signal at a given voxel, is one of most frequently used rsfMRI metrics to quantify the spontaneous, intrinsic local neuronal activities (Zuo et al., 2010). Results from various rsfMRI studies suggested that ALFF is one of the most reliable and reproducible rsfMRI parameters in healthy individuals or patients with mental disorders (Xia et al., 2019; Zuo and Xing, 2014). Considering the high test-retest reliability of ALFF (Zuo and Xing, 2014), it has been widely used to detect brain function abnormalities in various mental disorders, such as MDD (Drysdale et al., 2017), schizophrenia (Li et al., 2016), attention-deficient hyperactivity disorder (Li et al., 2014), and posttraumatic stress disorder (Disner et al., 2018).
To date, many studies have cross-sectionally examined ALFF characteristics in MDD patients. A resting-state fMRI study reported that increased ALFF in the right ventral median frontal gyrus and higher ALFF in the right putamen could be trait-related biomarkers for MDD (Jing et al., 2013). Another study of treatment-naive MDD patients showed increased ALFF primarily in the forebrain while decreased ALFF in posterior brain regions (Liu et al., 2014). Recently, a meta-analysis of first-episode drug-naive MDD patients found increased ALFF, mainly in para-hippocampal gyrus extending to the hippocampus (Wang et al., 2017). Another meta-analysis found decreased ALFF activity of the cerebellum in drug-naive MDD patients, and increased ALFF activity in the anterior cingulate cortex may be associated with good response to antidepressant treatment (Zhou et al., 2017). Numerous ALFF studies have been performed with relatively small sample sizes to detect brain intrinsic activities; however, most of these studies are cross-sectional, and the inconsistent results have hindered our understanding of the exact pathophysiology related to MDD (Liu et al., 2017; Yang et al., 2018). As a result, large-scale longitudinal studies with similar measurement instruments are needed to overcome these shortcomings.
Given that MDD residua may serve as an important predictor of recurrence or relapse (Hardeveld et al., 2010), identification of state-independent neural abnormalities in remitted MDD subjects may help us better understand the pathophysiology of recurrence or relapse in MDD. However, most of the current studies have investigated ALFF changes after short-time antidepressant treatment (usually within three months) (Emam et al., 2019; Fang et al., 2015; Wang et al., 2014). Few longitudinal studies have been conducted to evaluate if the aberrant neural substrates at baseline are modified by antidepressant treatment.
The present study recruited 149 medication-free MDD patients and 122 healthy control subjects at baseline. All patients received an open-label antidepressant treatment for 6 months. RsfMRI was used to evaluate regional brain function in both HCs, acute and remitted MDD patients. The aims of the study are to determine the ALFF abnormalities at baseline in MDD patients and whether these abnormalities will be corrected after 6 months’ efficient antidepressant treatment.
Section snippets
Patients and study design
We recruited 235 patients with MDD and 163 HCs from the inpatient and outpatient departments of Zhumadian Psychiatric Hospital and its nearby communities. Current unipolar major depressive episode (MDE) was assessed by two professional psychiatrists using the Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version (SCID-I-RV). Demographic and clinical characteristics of all participants at baseline were assessed by a self-designed socio-demographic questionnaire, the 24-item
Clinical Characteristics of MDD, MDD-R and HC groups
The clinical characteristics of each group were shown in Table 1. No significant differences were observed in age, gender, or educational level between MDD and HC groups. No significant differences were found in the number of episodes, age of onset, current illness duration, total illness duration or treatment between MDD group and the MDD-R subgroup at baseline, as shown in Table 2.
Alterations in ALFF in MDD and their changes in remission
Compared to HCs, significantly reduced ALFF was found in the right precuneus (PCUN), posterior cingulate cortex
Discussion
To the best of our knowledge, this is the first long-term longitudinal study using large samples to identify trait biomarkers for MDD based on whole-brain ALFF. This study found that medication-free patients with MDD had significantly decreased ALFF in the right PCUN/PCC compared to control subjects. In addition, the decreased ALFF is persistent in remitted patients after 6-month antidepressant treatment. Therefore, the altered intrinsic regional spontaneous brain activation may represent a
Limitations and future considerations
However, several important limitations of this study should be noted. First, the dropout rate (47%) is high in the study, mainly owing to loss of contact or moving to other cities for work, data of whom were not analyzed. Second, we did not follow up the HCs for the second MRI scan for 6 months. It is not known whether the ALFF of HCs will change during the six months. Future studies should be conducted to address this question. Third, the decreased ALFF in the right PCUN/PCC have been
Conclusions
We conducted a longitudinal MRI study in a relatively large MDD sample. Our results showed that MDD shows reduced ALFF in the PCUN/PCC, which persists into clinical remission, indicating that the decreased ALFF in the PCUN/PCC may serve as a trait marker of MDD.
Author statement
This paper is new and neither the entire manuscript nor any part of its content has been published or has been accepted elsewhere. It is not in submission at any other journals. All authors have approved of the final version of this manuscript.
CRediT authorship contribution statement
Mi Wang: Conceptualization, Data curation, Formal analysis, Investigation, Writing - original draft, Writing - review & editing. Yumeng Ju: Data curation, Investigation, Writing - review & editing. Xiaowen Lu: Data curation, Investigation. Jinrong Sun: Data curation, Investigation. Qiangli Dong: Data curation, Investigation. Jin Liu: Data curation, Investigation. Liang Zhang: Data curation, Investigation. Yan Zhang: Investigation, Project administration, Writing - review & editing. Shuai Zhang:
Declaration of Competing Interest
None.
Acknowledgments
We thank all participants for participating in this study. We thank Dr. Ziwei Liu for his statistical advice.
Funding
This study was supported by the National Science and Technologic Program of China (2015BAI13B02), the Defense Innovative Special Region Program (17-163-17-XZ-004-005-01), the National Natural Science Foundation of China (81171286, 91232714 and 81601180).
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