Amygdala substructure volumes and serotonin transporter in first-episode, drug- naïve major depressive disorder: A pilot study
Introduction
Major depressive disorder (MDD) is a common and burden mental illness that deeply interferes with daily life and causes significant disability in millions of humankind globally (James et al., 2018). Recognizing the underlying mechanisms of MDD development is requisite to lower its adverse influence on mental health. The MDD etiology composes multifaceted interactions with other brain regions. Several pathophysiological mechanisms have been reported, including brain morphological changes and neurotransmitter dysregulation.
The amygdala, nestled in the medial temporal lobe, plays a fundamental role in the processing of emotion, state of affection/mood, fear conditioning, and extinction and social behaviors (Duvarci and Pare, 2014; Steuber et al., 2021) and projects to several cortical and subcortical structures that are implicated in MDD, including the hippocampus, anterior cingulated cortex, and medial prefrontal cortex (Duvarci and Pare, 2014). Additionally, the amygdala is a paired structure that is comprised of distinct functional substructures (nuclei) that allow signals to project/receive from multiple brain areas. The amygdala nuclei can be divided into three groups, namely, laterobasal, centromedial, and superficial (DE OLMOS and Heimer, 1999). Overall, the lateral nucleus (LA) is an entrance of the amygdala, which receives inhibitory and stimulatory inputs that are projected from different cortical regions (Šimić et al., 2021). The superficial nuclei participate in the affective and olfactory information processing throughout the brain's limbic lobe (Šimić et al., 2021). The centromedial group of nuclei is considered as a role in physiological and behavioral responses converted from sensory stimulation (Ciocchi et al., 2010; Linley et al., 2017, 2017i; Šimić et al., 2021). Quantification volume for the amygdala and separate nucleus segmentation is available by performing Freesurfer software (Saygin et al., 2017).
Recent imaging studies on the amygdala and its substructures in MDD have been strikingly inconsistent. Bigger (Roddy et al., 2021), smaller (Kronenberg et al., 2009), and no significant differences (Brown et al., 2019;Delaparte et al., 2017;Tesen et al., 2021) in the whole amygdala or nuclei volumes have been studied in MDD cohorts compared to control subjects. Inconsistencies may reflect participant characteristics, depression definition, and methodological differences (Nolan et al., 2020; Saygin et al., 2017). Furthermore, heterogeneity within and between study groups and predominated confounding factors have been mentioned as reasons for disparate outcomes. An aforesaid confounding factor is the various numbers of depressive episodes and the percentage of patients who are recently taking antidepressants currently while recruited in the study. Investigating the amygdala volume alteration related to MDD susceptibility in drug-naïve patients during their first-episode is interesting due to established evidence for the neurotoxicity impact in recurrent depressive episodes and the neurotrophic effects of antidepressants on the amygdala volume (Nolan et al., 2020).
The function of serotonin (5-HT) in MDD originated from pharmacological studies on the antidepressant properties of selective serotonin reuptake inhibitors (SSRIs) by suppressing the serotonin transporter (SERT). The SERT is an integral membrane protein that terminates serotonergic activity by eliminating and reabsorbing 5-HT from the synapse calf, which is a sophisticated component for 5-HT activity balance. Postmortem meta-analyses have shown that patients with MDD have decreased SERT availability compared to healthy controls (Gryglewski et al., 2014; Kambeitz and Howes, 2015). Furthermore, in vitro animal study has found that 5-HT concentration is associated with SERT density (Dewar et al., 1991). Changes in SERT availability in the human brain may be considered as a representation in the serotonergic system, and SERT availability evaluation in MDD may further contribute valuable insight into MDD pathophysiology. However, SERT availability results in MDD were often inconsistent (Gryglewski et al., 2014). As mentioned above, the conflicting findings might originate from the high heterogeneity of the recruited samples from the study. Hence, investigating SERT availability in more homogenous participants with adequate control of covariates is valuable to obtain a more vigorous outcome.
Several lines of evidence have suggested that 5-HT may potentially regulate the activity of the amygdala to influence emotional processing (Bigos et al., 2008; Jans et al., 2007). Drugs that block the SERT (e.g., SSRIs) are the most common pharmacotherapy for depression treatment that modulates the amygdala to emotional stimuli (Bigos et al., 2008). Moreover, genetic variations in the SERT influence the SERT expression and amygdala activation to aversive stimuli (Scherk et al., 2009). SERT knockout mice revealed increased depressive-like behavior after frequent exposure to forced swim stress, accompanied by a morphological amygdala abnormality (Wellman et al., 2007). Finally, amygdala lesions may take part in the depressive behaviors that are modulated by SERT or the SERT modulated depressive behaviors have been shown to disappear in amygdala injury mice (Sur et al., 1996). The evidence suggests a close relationship between amygdala and SERT in MDD. So far, no study has concurrently examined both the amygdala substructural volumes and the SERT availability in MDD. This study concomitantly explored the amygdala substructural volumes and SERT availability in patients with first-episode, drug-naïve MDD, and healthy controls (HCs), respectively. We further assessed their inter-relationships and correlation with depression severity in patients with MDD.
Section snippets
Methods
Following the Declaration of Helsinki, revised in 1989; all participants gave informed consent to attend the study. The study protocol was got permission by the institutional ethical board of the Taipei Veteran General Hospital.
Results
The study included 27 patients with MDD (mean age = 45.3 ± 11.5 years) and 27 age- and gender-matched HCs (mean age = 45.3 ± 10.9 years). Age and gender were not significantly different between groups. Other characteristics, such as education, were also homogeneous between groups as shown in Table 1. No significant difference was found in the amygdala substructure volume and SERT availability between the two groups, respectively (Table 2).
Both the volumes of the right medial nucleus and
Discussion and conclusion
This study concurrently investigated both the brain amygdala volumes and the SERT availability in first-episode and drug-naïve MDD, which exhibited the following four remarkable findings: 1) no significant difference in the amygdala total or any nuclei volumes between MDD and HCs; 2) the SERT availability insignificantly different between groups; 3) no association between amygdala substructure volume and SERT availability in patients with MDD; 4) lack of associations of the MADRS scores with
CRediT authorship contribution statement
Ching-Wen Chen, Mu-N Liu, Yuan-Hwa Chou, and Ying-Jay Liou conceptualized the study and edited the manuscript for critical intellectual content. Ching-Wen Chen, Mu-N Liu, Wen-Chi Hsieh, and Li-Yu Hu collected and analyzed the data and drafted the manuscript. All authors were involved in editing the manuscript for critical intellectual content, and all approved the final version to be published and took responsibility for the accuracy of the data.
Declaration of competing interest
The authors declare that there is no conflict of interest.
Acknowledgments
We appreciated all participants taking part in this study. We also appreciated the staff in the nuclear medicine department who helped with the SPECT imaging of this study and the investigators for contributing to data acquisition. This work was supported by project CI-107-2 from the Yen Tjing Ling Medical Foundation and Taipei Veterans General Hospital-National Yang-Ming University Excellent Physician Scientists Cultivation Program.
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