This study aimed to investigate the relationship between MDD and asymmetrical abnormalities in Rs-FC by calculating PAS scores. Our results revealed significant differences in PAS scores between MDD patients and HCs, particularly in the left IFG and Bi-PCC regions. A decrease in the PAS score of the left IFG indicated reduced hemispheric asymmetry, whereas an increase in the PAS score of the Bi-PCC suggested enhanced hemispheric asymmetry. These findings emphasize the association between irregular hemispheric FC asymmetry in the left IFG and Bi-PCC regions and MDD.
A wealth of research highlights the relationship between MDD and abnormalities in the structure and function of the fronto-limbic system [55–58]. This complex network plays a crucial role in regulating emotions, motivation, and reward-related stimuli processing [59, 60]. The system encompasses several specific brain regions, including the prefrontal cortex (PFC), amygdala, hippocampus, and striatum. The observed deviations within this system are consistent with the characteristic symptoms of MDD, such as persistent sadness, reduced interest in pleasurable activities, cognitive challenges, and disturbances in sleep patterns [15, 61].
The conclusions of this study align with some of the findings from our previous meta-analysis, which was conducted on an extensive sample of MDD patients from 25 consortia [22]. However, the observed asymmetry changes did not entirely coincide with those from MDD patients without comorbid gastrointestinal symptoms[23]. These discrepancies could be attributed to diverse inclusion criteria, research focuses, sample sizes, clinical symptoms, medication statuses, data analysis methods, and demographic characteristics across these studies.
The prefrontal and cingulate cortex are crucial brain regions involved in cognitive control and emotion regulation, and any alterations in neural circuits within these areas can considerably impact cognition[62]. Individuals exhibiting hypofunction in the prefrontal cortex typically experience cognitive and emotional impairments[63]. Therefore, it is common for patients with MDD to present diminished executive control abilities, such as impaired memory and attention [64]. The left IFG is often characterized as a 'multifunctional' area instrumental in emotional, behavioural, and cognitive control. It plays key roles in semantic understanding, production, and inhibition [65]. Numerous studies suggest that a dysfunctional semantic perception, potentially indicative of impaired left IFG functioning, may be associated with depressive symptoms such as low mood, disinterest, and social withdrawal [66]. Furthermore, the left IFG is known to play a crucial role in various functions including emotional regulation, self-control, inhibitory control, language processing, attention, and working memory [67]. Importantly, as a component of the mental reasoning network and mirror neuron system, the left IFG contributes to our understanding of others' thoughts and emotions, thereby enhancing social interactions [68].
The posterior cingulate cortex (PCC), located within Brodmann's area 23/31, has numerous structural connections with different brain regions and is part of the default mode network [69]. Notably, the PCC is among the most active regions in the human brain during rest and is instrumental in recalling episodic memories, processing self-relevant information, and regulating emotions [65, 70, 71]. Some research, such as the work by Maddock et al., proposed that abnormal FC in the PCC could be linked to feelings of hopelessness often seen in depression[72]. This suggests that asymmetrical abnormalities in the connectivity of these brain regions could potentially contribute to the onset and progression of depressive symptoms. However, there were also divergent views on these findings [10, 73, 74].
This study demonstrated that TSH levels in individuals with MDD were significantly lower compared to those in healthy controls (HCs), aligning with several prior investigations [36, 39, 75]. However, we found no significant correlation between changes in thyroid-stimulating hormone levels and alterations in the PAS of the left IFG. Although various studies suggest a connection between abnormal thyroid function and depression's onset and progression, this doesn't necessarily imply a direct correlation between fluctuations in TSH levels and altered brain FC. In fact, the relationship between TSH level changes and altered brain connectivity is likely multifaceted, influenced by diverse biological and environmental factors. TSH's impact on functional connectivity is typically mediated through thyroxine, suggesting a possibly indirect relationship [76, 77]. Modifications in FC might involve various biological mechanisms, including neurotransmitter levels, neuronal activity, and synaptic function, indicating that a single biomarker (such as TSH) may not entirely capture the scope of altered brain FC [78]. As Drevets et al. suggested, shifts in FC might involve numerous factors such as genetics, environment, psychological stress, and developmental stage, which can interact and collectively impact FC [79]. Therefore, while alterations in TSH levels might be associated with abnormal thyroid function, they could represent just one among multiple factors influencing FC asymmetry.
Plasma cholesterol must bind to apolipoprotein, forming lipoprotein, to cross the blood-brain barrier. Consequently, cholesterol's action is affected by lipoproteins of varying densities, such as high-density lipoprotein (HDL) and low-density lipoprotein (LDL)[80]. In this study, we found no significant difference in serum CHOL levels between MDD patients and healthy controls, consistent with Huang's findings[81]. We also observed no significant correlation with brain asymmetry abnormalities. Many studies have reported typical cholesterol dysregulation in MDD patients, characterized by decreased HDL, increased LDL, and elevated LDL/HDL ratios[82–84]. This suggests that CHOL levels in MDD patients may not directly contribute to disease development, indicating that CHOL might not directly influence FC. Therefore, future studies exploring the relationship between CHOL and MDD should consider both HDL and LDL levels.
Several limitations should be considered when interpreting this study's results. First, the sample size was relatively small, possibly reducing the statistical power and generalizability of the findings. Second, the cross-sectional design of the study limits our ability to determine the causal relationship between brain asymmetry and MDD. Longitudinal studies with larger samples are required to confirm these findings and assess the potential impact of treatment on brain connectivity and hemispheric asymmetry. Additionally, the influence of medication status on the observed results should be taken into account, as antidepressant treatments may have confounding effects on brain connectivity measures. Finally, future studies should consider the potential impact of other factors that may contribute to the observed alterations in brain connectivity, such as genetic predisposition or environmental stressors.