Research reportClinical, cognitive, and functional connectivity correlations of resting-state intrinsic brain activity alterations in unmedicated depression
Introduction
Major Depressive Disorder (MDD) has been reported as the leading cause of disability in the United States and the second cause of disability worldwide (Ferrari et al., 2013). Despite the availability of different treatment options, the remission rate from MDD is estimated not to be more than 50%, even after one year of treatment (Whiteford et al., 2013). Better understanding of the underlying mechanisms of MDD and development of more effective treatment options are critical for reducing the huge burden of this mental illness for affected patients, their families and society in general.
Neuroimaging has been one of the principal research modalities for investigating the neuropathology of depression. Structural brain imaging studies in MDD have pointed to cortico-striato-limbic neurocircuitries as the anatomical substrates of depression (Ballmaier et al., 2008, Bora et al., 2012, Koolschijn et al., 2009, Kumar et al., 2014, Liao et al., 2013, Sheline, 2003, Tadayonnejad and Ajilore, 2014). Another major line of research in the neuroimaging of depression uses functional magnetic resonance imaging (fMRI) to explore abnormal alterations of brain function in depressed subjects. In those studies, abnormal activity in terms of the blood-oxygen-level dependent (BOLD) signal is examined in patients with MDD during the performance of a cognitive, emotional or reward processing task (Diener et al., 2012, Hamilton et al., 2012, Hasler et al., 2009, Heller et al., 2009, Pizzagalli, 2011).
Recent advances in fMRI have led to the development of resting-state fMRI (rs-fMRI) (Biswal et al., 1995, Fox and Raichle, 2007). In rs-fMRI, brain baseline fluctuations in the BOLD signal are measured when a subject with open or closed eyes is not doing anything in the scanner. Considering the pervasive nature of several depressive symptoms like depressed mood, negative rumination or lack of motivation, rs-fMRI actually might be even a better approach for investigating the abnormal neural mechanisms of depression.
In rs-fMRI, two measures are used commonly to examine the network-related and regional characteristics of low frequency oscillations (LFOs): Functional Connectivity (FC) and Amplitude of Low-Frequency Fluctuation (ALFF). In FC analysis, the temporal correlation (synchronicity) of resting-state BOLD signals of spatially distributed brain areas is calculated as a measure of brain region resting-state functional interaction (Fox and Greicius, 2010, Fox et al., 2005). In ALFF analysis, the baseline intensity or the amplitude of LFOs is quantified as a regional characteristic of resting-state intrinsic neural activity (Zang et al., 2007, Zou et al., 2008, Zuo et al., 2010). Although FC or ALFF analysis have commonly focused on the 0.01 to 0.08 Hz frequency range, some reports have suggested the involvement of higher frequencies range in LFOs characteristics under normal physiological conditions in regions like brain stem, basal ganglia, or amygdala (Salvador et al., 2008, Zuo et al., 2010), during pathological conditions such as pain (Baliki et al., 2011) or after noninvasive cortical stimulation (Chen et al., 2013).
Alterations in ALFF values in depression have been the subject of a few recent rs-fMRI studies. Those studies mainly focused on the pattern of ALFF changes in depression and reported MDD-related ALFF alterations in several brain areas like the frontal cortex, parietal cortex, temporal cortex, limbic system, visual network and cerebellum (Guo et al., 2013, Liu et al., 2014, Wang et al., 2012, Zhang et al., 2014). Clinical and cognitive correlations of ALFF alterations in MDD have not been examined comprehensively. The possible contribution of higher frequency ALFF (0.1–0.25 Hz) changes has also not been tested yet. Furthermore, it has not been investigated that how regions with ALFF changes in depression behave differently in their interactions with other elements of involved networks.
In this study, we aimed to test three hypotheses. First, MDD is related to alterations in ALFF calculated for traditional lower frequency (0.01–0.08 Hz) as well as untested higher frequency (0.1–0.25 Hz) ranges in areas that belong to cortico-striato-limbic circuits. Second, changes in ALFF values in MDD are correlated with depression symptoms severity and cognitive performance. Third, FC between regions with ALFF alterations and other nodes in the related networks are altered in depression.
Section snippets
Participants
For this study, we recruited 45 subjects. Of these, 20 were unmedicated subjects with unipolar major depression (MDD) and 25 were nondepressed comparison subjects (HC). All study subjects were recruited from the local community through advertisements in flyers, newspapers, and radio. The inclusion criteria for all subjects were 30 years of age and older, antidepressant-naive or free of antidepressant use for at least two weeks and no history of unstable cardiac or neurological diseases. The
Demographics
Demographic, clinical and cognitive data of both healthy and depressed subjects are summarized in Table 1. Compared to the healthy controls, patients with MDD had a significantly lower mean age. There were no significant differences between the two groups in gender, education, or MMSE. As expected, depressed subjects scored significantly higher on both measures of depression severity. There were no significant differences in cognitive performance across three domains of EF, AIP and LM.
ALFF group differences
First, we
Discussion
This study revealed alterations of both lower frequency (0.01–0.08 Hz) ALFF in regions belonging to affective networks and corticostriatal neurocircuitry and changes in higher frequency (0.1–0.25 Hz) ALFF in the left thalamus, left motor and somatosensory networks and the right pons. We found that depressive symptoms severity is positively correlated with the LF-fALFF in the right anterior cingulate cortex as well as higher frequency fALFF in the left somatosensory region and right thalamus in
Conclusions
In conclusion, we used the ALFF measure to test the difference in the baseline amplitude of intrinsic brain activity mediated in both lower (0.01–0.08 Hz) and higher (0.1–0.25 Hz) frequency bands of BOLD-based resting-state LFOs in non-medicated patients with depression relative to control subjects. ALFF alterations were found in clusters belonging to affective networks, the corticostriatal system and motor/somatosensory networks. We detected significant correlations between depressive symptom
Role of funding source
The funder (National Institute of Mental Health) had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
Conflict of interest
The authors report no biomedical financial interests or potential conflicts of interest.
Acknowledgments
This work was supported by the National Institute of Mental Health (R01 MH-073989 to AK; K23 MH-081175 to OA).
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