Major depressive disorder (MDD) is one of the most prevalent, chronic, recurrent, and burdensome psychiatric disorders characterized by depressed mood, social isolation and anhedonia (Dudek et al., 2021; Auerbach et al., 2015). Specifically, anhedonia, the decreased interest and ability to experience pleasure, is conceptualized as a core feature of MDD (Treadway and Zald 2011). Anhedonia is highly prevalent among individuals with MDD (Cao et al., 2019), which often develops into a residual symptom when other symptoms remit, resulting in an increased inter-episode functional impairment (Di Nicola et al. 2013). To date, accumulating lines of evidence suggest that anhedonia is linked to greater overall illness severity and recurrent illness course in MDD (Gabbay et al., 2015). Anhedonia has also been reported to be a risk factor of suicidality independent from depression severity (Ducasse et al., 2021). Furthermore, several studies have pointed out that in patients with MDD, greater levels of anhedonia at the outset of management predict poorer responsiveness to a range of interventions, including antidepressant treatments, cognitive behavioral therapy (CBT), and repetitive transcranial magnetic stimulation (rTMS) (Whitton and Pizzagalli 2022). Taken together, the present evidence has suggested that MDD with anhedonic symptoms may be treated as a specific phenotype (Hasler et al., 2004), although the pathophysiology underlying remains unknown.

Until now, most studies have discovered that anhedonia is mainly due to functional and structural abnormalities of brain regions involving in the reward circuit (Hanuka et al., 2022). As an important nexus for emotion processing and hedonic experience, the most consistently described reward circuit mainly refers to the neural pathways between the frontal cortex and limbic structures(Cooper et al., 2018; Westbrook et al., 2020). Previous magnetic resonance imaging (MRI) studies have elucidated that MDD with anhedonia may be associated with functional connectivity alterations of the fronto-striato-limbic circuits and cortical networks (Hu et al., 2023). In recent studies, it has also been found that reduced activity in limbic regions, such as the ventral striatum and caudate nucleus, while hyperactivity in cortical regions, for example, the ventromedial frontal cortex and dorsolateral prefrontal cortex, may be associated with anhedonia in patients with MDD (Faramarzi et al., 2022; Young et al., 2016). In addition, striatal volume atrophy and decreased white matter integrity of the reward-related brain regions have been reported to be implicated in MDD with anhedonia as well (Enneking et al., 2019; Lu et al., 2022c; Pizzagalli et al., 2009; Yang et al., 2017).

Being an important circuit for instinct and emotion generation, the limbic system supports multiple functions and behaviors, and its various subdivisions can process different emotions and feelings, motivation and will, cognition and attention, and even memory (Heimer and Van Hoesen 2006). From an anatomical perspective, the limbic system has, in turn, been divided into cortical and subcortical regions for further investigation (Greve et al., 2021). The olfactory cortex, hippocampus, caudal orbitofrontal, medial frontal, temporopolar, anteroventral insular, cingulate, retrosplenial, and parahippocampal gyrus are contained within the cortical regions, while the hypothalamus, amygdala, the extended amygdala, nucleus accumbens (NAc), ventral pallidum, association thalamic nuclei, basal forebrain, septal nuclei, cerebellum, fornix, and the reticular formation of the brainstem belong to the subcortical regions (Fischl et al., 2004; Heimer and Van Hoesen 2006). The associations of anhedonia with structural and functional abnormalities in cortical areas of the limbic system have been revealed in recent studies, especially the hippocampus and cingulate gyrus (Yu et al., 2021; Lally et al., 2015; Faramarzi et al., 2022). Meanwhile, functional abnormalities in ScLimbic system have also been implicated in MDD with anhedonia, as previously reported, functional alterations of Nac subregions, ventral pallidum and hypothalamus may mediate the association between MDD and anhedonia (Hu et al., 2023; Keller et al., 2013; Jenkins et al., 2018), however, a key gap in our understanding of the morphometric correlates of anhedonia in MDD is the lack of explorations of structural alterations in the subcortical limbic (ScLimbic) system. Structural abnormalities of the ScLimbic system have been reported to contribute to the pathophysiology of MDD in previous studies, for instance, patients with MDD exhibited regional volume reductions in the ScLimbic system, including the thalamus, pallidum, and NAc (Ancelin et al., 2019), as well as myelin impairments in the fornix (Hou et al., 2021). The NAc, pallidum, and fornix are the major sites in subcortical structures that play key roles in reward and motivation (Brown and Winocur 1973; LeGates et al., 2018; Ancelin et al., 2019). In this context, the relationship between anhedonia and structural alterations of the ScLimbic system deserves careful study in future.

The development of accurate localization and segmentation of anatomical structures in the ScLimbic system has enabled us to further elucidate the neurobiology of MDD, specifically the anhedonic symptoms. Recently, an easy-to-use tool was developed, tested, and validated to automatically segment several ScLimbic structures, including the hypothalamus (HTh), mammillary bodies (MB), basal forebrain (BF), septal nuclei (SepN), fornix (Fx), and NAc, from T1-weighted anatomical imagings (Greve et al., 2021). This tool provides an unmet need, and the clinical utility of this tool has been demonstrated by applying it to Alzheimer's disease (AD) and multiple sclerosis (Greve et al., 2021; Abuaf et al., 2022). Thus, the purpose of this study was to investigate volume changes of various parts of the ScLimbic system in MDD patients with and without anhedonia by using the automatic segmentation toolbox. We hypothesized that altered volumes in certain brain regions of the ScLimbic system would be observed which could be used to discriminating MDD with anhedonia from MDD without anhedonia, or healthy individuals.