Abnormal regional spontaneous neural activity in first-episode, treatment-naive patients with late-life depression: A resting-state fMRI study

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Abstract

Background

The previous resting perfusion or task-based studies have provided evidence of functional changes in the brains of patients with late-life depression (LLD). Little is known, so far, about the changes in the spontaneous brain activity in LLD during the resting state. The aim of this study was to investigate the spontaneous neural activity in first-episode, treatment-naive patients with LLD by using resting-state functional magnetic resonance imaging (fMRI).

Methods

A novel analytical method, coherence-based regional homogeneity (Cohe-ReHo), was used to assess regional spontaneous neural activity during the resting state in 15 first-episode, treatment-naive patients with LLD and 15 age- and gender-matched healthy controls.

Results

Compared to the healthy controls, the LLD group showed significantly decreased Cohe-ReHo in left caudate nucleus, right anterior cingulate gyrus, left dorsolateral prefrontal cortex, right angular gyrus, bilateral medial prefrontal cortex, and right precuneus, while significantly increased Cohe-ReHo in left cerebellum posterior lobe, left superior temporal gyrus, bilateral supplementary motor area, and right postcentral gyrus (p < 0.005, corrected for multiple comparisons).

Conclusions

These findings indicated abnormal spontaneous neural activity was distributed extensively in first-episode, treatment-naive patients with LLD during the resting state. Our results might supply a novel way to look into the underlying pathophysiology mechanisms of patients with LLD.

Highlights

► Cohe-ReHo method detects different brain activity between patients with LLD and HC. ► Patients with LLD have widespread Cohe-ReHo alterations. ► The Cohe-ReHo method may be a tool for understanding the pathophysiology of LLD.

Introduction

Late-life depression (LLD) is associated with emotional suffering, cognitive impairment, disability and poor compliance with medical treatments (Alexopoulos, 2005, Charney et al., 2003). As one of the most common mental disorders and the most important precursor of suicide in the old people, LLD leads to a decline in both well-being and daily functioning (Taki et al., 2005). At present, the diagnosis of depression is mainly dependent on clinical signs and symptoms, and the exact neural basis underlying LLD is still not fully understood.

Recent advances in imaging techniques open the way to provide a greater understanding of the neuropathology of depression. Functional neuroimaging approaches make it feasible to explore the changes of brain function that can be responsible for variability in mood and cognitive responses to treatment (Gunning and Smith, 2011). Therefore, thoughtful use of functional neuroimaging techniques can guide treatment decisions of depression. During the past years, ample evidence from functional neuroimaging studies has described changes of cerebral activity in patients with depression. A recent positron emission tomography (PET) study demonstrates that cerebral glucose metabolism is increased in patients with LLD relative to healthy control subjects in superior frontal gyrus and precuneus (PCU) regions (Smith et al., 2009). In addition, Kumar and colleagues reveal that the depressed subjects showed significant reductions in the regional cerebral metabolic rate of glucose in the subcortical and paralimbic regions (Kumar et al., 1993). Moreover, hypoactivation of the dorsal anterior cingulate cortex (ACC) and the hippocampus are detected in patients with geriatric depression during a word activation task (de Asis et al., 2001). Recently, functional magnetic resonance imaging (fMRI) has appeared as a popular technology due to its advantage of non-invasive and not requiring exposure to radioactive tracers and thus may provide new insights into the pathophysiology of depression. An fMRI study has found that activation in the ACC is significantly decreased in elderly patients who have experienced multiple depressive episodes when performed a verbal fluency task (Takami et al., 2007). Further, Aizenstein et al. observe decreased dorsolateral prefrontal cortex (DLPFC) while increased caudate nucleus (CAU) activation in response to an explicit sequence-learning task (Aizenstein et al., 2005). Although aforementioned studies have demonstrated functional abnormalities in patients with LLD, there are fewer consensuses on the changes in functional brain activity. Confounds associated with illness chronicity, such as the number of episode and prolonged exposure to antidepressants, may lead to the inconsistency across studies (Guo et al., 2011a, Zou et al., 2010). Compared with studies using chronic patients, relatively few studies have investigated first-episode, treatment-naive patients with LLD. The study of the first-episode, treatment-naive patients with LLD may be significant for elucidating the core pathogenesis of this illness. Besides, another issue pertains that the task-related functional neuroimaging studies require patients to follow relatively complicated cognitive tasks and thus the performance may confounds the results (Callicott et al., 2003).

Resting-state fMRI has been viewed as a promising way to studying depression because of the persistent and pervasive nature of depressive symptoms (Greicius et al., 2007). The resting-state fMRI, unlike task-based fMRI, is relatively easy to obtain and ask patients nothing but to remain still with eyes closed, which is of more potential applications in clinical studies. So far, by using resting-state fMRI functional connectivity method, Greicius et al. observe the thalamic and subgenual cingulate functional connectivity is significantly greater in the depressed subjects compared with healthy controls (Greicius et al., 2007). With the graph theory analysis, Zhang and colleagues find that the increased nodal centralities are mainly in the CAU and default mode regions, and decreased nodal centralities in the orbital frontal, and temporal regions (Zhang et al., 2011). However, these above-described studies can only reveal the aberrant functional connectivity between two remote areas but not from the perspective of regional activity in the resting state. Although a result of abnormal functional connectivity between two remote regions can be integrative and comprehensive, no conclusion can be drawn about which region is aberrant from such an investigation. Therefore, it is important to explore the regional activity by using other approaches.

Several existing local measurements are complementary to functional connectivity methods. For example, regional homogeneity (ReHo), has been developed to explore that a given voxel is temporally similar to its neighbors within a single region (Zang et al., 2004). ReHo analysis hypothesizes that spatially neighboring voxels should have similar temporal patterns. Abnormal ReHo possibly reflects the changes of temporal aspects of neural activity in the regional area. It has been shown that the major regions of default mode network (DMN) have increased ReHo than other brain regions during resting state (Long et al., 2008). Additionally, the ReHo method has been used to investigate the brain function in healthy subjects (Zang et al., 2004) and psychiatric and neurological disorders (Bai et al., 2008, Guo et al., 2011b, He et al., 2007, Qiu et al., 2011, Wu et al., 2011).

The aforementioned ReHo method uses Kendall's coefficient of concordance (KCC) to measure the similarity or synchronization of the time courses. However, KCC is based on temporal information (particularly rank information) of time series. The KCC value will be decreased if there is time lag among the time courses and be susceptible to random noise induced by phase delay among the time courses. To overcome such limitations, a novel ReHo method, coherence-based ReHo (Cohe-ReHo) is recently proposed to measure the local synchronization of resting-state fMRI signal (Liu et al., 2010a). Moreover, Liu and colleagues demonstrate that Cohe-ReHo is more sensitive to the differences of spontaneous activity between different conditions and between different groups (Liu et al., 2010a).

To the best of our knowledge, Cohe-ReHo has not been used to measure local synchronization in depressed patients, let alone in patients with LLD. Thus, in this resting-state study, we used a well-defined cohort of patients by recruiting merely the first-episode, treatment-naive patients with LLD and carefully matched healthy control subjects. The purpose of the present study was to assess the alteration of regional activity underlying LLD pathophysiology. We hypothesized that patients with LLD may have different local activity when compared with normal controls.

Section snippets

Subjects

Fifteen depressed patients aged from 60 to 79 years old and 15 age- and gender-matched healthy controls were recruited from the Mental Health Institute, the Second Xiangya Hospital, Central South University, China. This study was approved by the local ethical committee, and written informed consent was obtained from all subjects. All patients met the following inclusion criteria: (1) the diagnose of major depressive disorder was made with the structured clinical interview for DSM-IV (SCID) by

Participants

As presented in Table 1, the two groups were matched for age (mean ± SD) (67.53 ± 6.12 years for LLD group; 64.87 ± 3.70 years for normal controls; t = 1.44, df = 28, p = 0.159), gender (both groups have 6 males and 9 females) and head motion differences (mean ± SD) (Translation: 0.06 ± 0.03 for LLD group; 0.07 ± 0.07 for control group; t = 0.73, df = 28, p = 0.47; Rotation: 0.04 ± 0.01 for LLD group; 0.04 ± 0.01 for control group; t = 0.74, df = 28; p = 0.46). Compared with healthy control subjects, patients with LLD showed

Discussion

The present study was an effort in employing Cohe-ReHo method in LLD. The most advantage of the present study is the recruitment of a group of first-episode, treatment-naive patients with LLD. Recent studies demonstrated that the antidepressants could make the brain function of patients with depression more similar to that of healthy controls (Anand et al., 2005, Delaveau et al., 2011, Fu et al., 2007). However, previous studies usually recruited depressed patients on antidepressants; thus

Study limitations

In addition to the limited sample size, several methodological issues should be considered in explaining the results. First, as in all the resting-state fMRI studies, some inevitable physiological noise, such as respiratory and cardiac fluctuations of the subject during scanning may influence the stability of resting-state fMRI signals. Although we tried to correct such noises, we could not fully eliminate the effects of these noises. In future studies, simultaneous cardiac recording may

Conclusion

In summary, in our present study, we observed abnormal local activity in patients with LLD compared to the healthy controls. These results indicated that the altered activity have already existed in the initial stage of LLD, because our case group only included first-episode, treatment-naive patients with LLD. Moreover, such findings shed light on the pathophysiological mechanisms underlying LLD. Further work combining different modalities may contribute to providing more information about this

Acknowledgments

The authors thank the editor and anonymous reviewers for constructive suggestions. This work was supported by the 973 project 2012CB517901, the Natural Science Foundation of China 61125304, 30900483, 81171406 and 91132721, and the Fundamental Research Funds for the Central Universities.

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