We explored the differences in spontaneous activity between MDD and SD subjects and HCs using Rs-fMRI data and the fALFF analysis approach. Our findings indicated alterations in the fALFF in the right lateral prefrontal frontal lobes (PFC), the default mode networks (DMN) and the fusiform areas. In addition, there was a positive correlation between the fALFF value and the HAMA score in the right fusiform gyrus and a positive correlation between the fALFF value and the PANNS score in the right middle frontal gyrus in MDD patients. Moreover, a negative correlation was revealed between fALFF values and the BDI score in the right inferior frontal gyrus in SD subjects. These data provide new insights into the neural mechanisms of SD and MDD.
We observed many prefrontal, occipital and parietal areas with fALFF alterations in MDD patients compared with those in SD patients, including the fusiform gyri, right prefrontal gyri, cuneus and precuneus. The fusiform gyrus, a common component of visual recognition circuits, is thought to be involved in facial processing [28]. Similar to previous studies [29, 30], increased fALFF was found in the bilateral fusiform gyri in first-episode, treatment-naive patients with MDD in our study. It is suggested that the recognition of facial expressions in MDD is altered as a result of this compensatory increase. In addition, previous studies reported a negative emotional bias related to the right fusiform gyrus in MDD [31–33] and conversely to the left fusiform gyrus in SD subjects [34]. There was a positive correlation between depressive symptom severity and fALFF in the right fusiform in the MDD subjects in our study. In line with these results, we suggest that the fALFF values of the fusiform might be a biomarker for distinguishing MDD from SD.
Of note, MDD subjects exhibited decreased fALFF in multiple areas of the right PFC in the present study. The PFC areas have been most consistently identified as being closely related to MDD [35, 36], and each distinct subregion of the PFC plays a different critical role in the cognitive bias of MDD [30]. The altered PFC regions in our study mainly consisted of the dorsal lateral prefrontal cortex (DLPFC), ventrolateral prefrontal cortex (VLPFC) and the premotor areas. The VLPFC, including the inferior frontal gyrus, is a critical region in cognitive processing, and the DLPFC is a component of the cinguloopercular network [37] and plays an important role in executive control [38]. In addition to individuals with MDD, SD subjects have shown reduced gray matter volume and white matter in the PFC [39, 40] and have displayed negative-word processing in the prefrontal lobe [41]. Moreover, in the correlation analysis, we found a positive correlation between the fALFF values of the right middle frontal gyrus and depressive symptom severity in the MDD group. This indicates that the right middle frontal gyrus may be vital to and plays a role in executive function, and its fALFF values can also be used as a biomarker for differentiating MDD and SD. Interestingly, our results showed a negative correlation between fALFF values in the inferior frontal cortex and BDI scores in SD subjects. The inferior frontal cortex has been linked to premotor cortical areas and related to executive function in depression [42]. Thus, we speculate that this area might be a target area for a treatment strategy for executive function recovery in preventing SD from developing into MDD.
Apart from the PFC, we observed decreased fALFF in the left cuneus in MDD subjects compared with that in SD subjects. The cuneus is a part of the visual recognition circuit [43], and its dysfunctional connectivity has been a target of antidepressant treatment effects [44]. MDD patients also exhibit decreased gray matter volume in the cuneus [45]. In contrast to a previous study that revealed increased fALFF in the left cuneus in MDD compared with that of control subjects [43], we observed decreased fALFF in the left cuneus in MDD subjects compared with that in SD subjects. We speculate that this may represent a compensatory increased function of visual recognition in SD subjects. As expected, we observed decreased fALFF in the precuneus in MDD and SD subjects. The precuneus is a core node in the DMN [46], is involved in the processing of self-relevant information [47] and is associated with deficits in general autobiographical memory [48]. Previous studies have shown that the fALFF values in the right precuneus have a negative correlation with the number of depressive episodes [49]. Our findings support the role of the DMN in the neural mechanisms of both SD and MDD. Compared with that of MDD subjects and HCs, the precuneus of SD subjects presented consistent abnormal fALFF. This indicates the key role of the DMN in the neural basis of SD.
Consistent with a previous study [30], our findings demonstrated an increased fALFF in the left cerebellum in MDD patients compared with that of HCs. The cerebellum was reported to play a role in emotional and cognitive processes in recent depression studies [50–53] and to have connections with the limbic regions [54]. Moreover, frontocerebellar dysregulation has been found in adolescents with MDD [55]. Increased activation in the cerebellum at rest [55, 56] and during reduced activity were reported in the frontal regions in MDD patients [57]. Specifically, the anterior cerebellum may be related to the depression remitted process [51, 53, 58]. The neurological mechanism of cerebellar dysfunction is not completely understood, and future functional and structural connectivity analyses will be helpful in identifying the correlation between the cerebellum and other brain areas.
In addition to a relatively small sample size, other limitations should be noted. First, we only recruited young adults in the present study, and it is unclear whether the findings observed here will generalize to older or younger samples. Second, given that the clinical and subclinical conditions are different, we used different rating scales to assess their depressive severity within the groups. Therefore, the difference in the rating scales may influence the results. Third, as a cross-sectional study, we cannot ensure the clinical consistency of the MDD patients because the patients were all in the first episode of their illness, and some of them may develop bipolar disorder in subsequent years. Similarly, the relatively mild depressive symptoms of the SD subjects are not stable and might transform over time; thus, a longitudinal study is required to better address the results.