BACKGROUND
Major depressive disorder (MDD) is associated with disrupted brain structural integration. Morphometric similarity offers a means to capture the coordinated patterns of various structural features. However, it remains unknown whether MDD-related changes can be detected in cortical morphometric similarity through the Morphometric Inverse Divergence (MIND) network. Additionally, the role of brain connectivity in shaping these alterations, and their links to neuroreceptors and gene expression, have yet to be investigated.


METHODS
Using the T1-weighted MRI data from 71 patients with first-episode, treatment-naïve MDD and 69 healthy controls, we constructed the MIND network for all participants. We then performed between-group comparisons to investigate abnormalities in the network and spatial relationships between the observed patterns of MIND disruption and the patterns of neuroreceptors were estimated. Network-based spreading was utilized to explore the abnormalities constrained by brain connectivity based on structural, functional, and transcriptional connectome architecture and to further identify potential epicenters of MDD. In addition, partial least squares regression was conducted to examine the associations of gene expression profiles with MIND changes in MDD.


RESULTS
Patients with MDD showed significantly increased MIND in regions associated with sensation and cognition compared with healthy controls, with this altered pattern being influenced by a combination of transcriptional and structural connectivity, and potential epicenters of MDD were identified in the frontal, parietal, and paracentral cortices. Furthermore, the cortical map of case-control differences in MIND was spatially correlated with the cannabinoid CB1 receptor and the brain-wide expression of a weighted combination of genes. These genes were enriched for neurobiologically relevant pathways and preferentially expressed in different cell classes and cortical layers.


CONCLUSION
These results highlight the abnormal pattern of morphometric similarity observed in MDD, shedding light on the complex interplay between disrupted macroscale coordinated morphology and microscale molecular organization in MDD.

Brain connectivity and transcriptomic similarity inform abnormal morphometric similarity patterns in first-episode, treatment-naïve major depressive disorder

Self-face recognition is a vital aspect of self-referential processing, which is closely related to affective states. However, neuroimaging research on self-face recognition in adults with major depressive disorder is lacking. This study aims to investigate the alteration of brain activation during self-face recognition in adults with first-episode major depressive disorder (FEMDD) via functional magnetic resonance imaging (fMRI); FEMDD (n = 59) and healthy controls (HC, n = 36) who performed a self-face-recognition task during the fMRI scan. The differences in brain activation signal values between the two groups were analyzed, and Pearson correlation analysis was used to evaluate the relationship between the brain activation of significant group differences and the severity of depressive symptoms and negative self-evaluation; FEMDD showed significantly decreased brain activation in the bilateral occipital cortex, bilateral fusiform gyrus, right inferior frontal gyrus, and right insula during the task compared with HC. No significant correlation was detected between brain activation with significant group differences and the severity of depression and negative self-evaluation in FEMDD or HC. The results suggest the involvement of the malfunctioning visual cortex, prefrontal cortex, and insula in the pathophysiology of self-face recognition in FEMDD, which may provide a novel therapeutic target for adults with FEMDD.

Hypoactive Visual Cortex, Prefrontal Cortex and Insula during Self-Face Recognition in Adults with First-Episode Major Depressive Disorder

Adolescents with major depressive disorder (MDD) experience significant difficulties in emotion regulation. This study aimed to explore emotion regulation in adolescents with depression using an emotion regulation paradigm combined with event-related potentials (ERP) while investigating the relationship between maternal emotion regulation and adolescent depressive symptoms through a mediation model. Overall, 38 healthy controls (HC) and 57 adolescents with depression (MDD) rated the pictures they saw according to aversive reappraisal (reappraisal of an aversive picture or down-regulate aversive emotions), aversive watch, and neutral conditions. Adolescents with depression gave more negative ratings to aversive images, and the emotional regulation success index (ERSI) of adolescents with depression was lower than that of healthy individuals. ERP data revealed an elevation in late positive potential (LPP) amplitude during the aversive reappraisal and aversive watch conditions compared with that in the neutral condition in the MDD group. Compared with the HC group, adolescents with depression showed larger LPP amplitudes under aversive watch conditions. The aversive reappraisal condition evoked a larger LPP than that in the other conditions in the HC group in the late time windows. The ΔLPP (separating the variability in the ERP wave associated with emotion regulation) was larger in the HC group than in the MDD group. Mediation analysis revealed that maternal emotion regulation influenced adolescent depression levels through its effect on the adolescent's emotion regulation. These findings provide important insights into the emotion regulation process in adolescents with depression and offer suggestions for clinical interventions. 

Maternal emotion regulation abilities affect adolescent depressive symptoms by mediating their emotion regulation ability: An ERP study

Altered stimulus generalization has been well-documented in anxiety disorders; however, there is a paucity of research investigating this phenomenon in the context of depression. Depression is characterized by impaired reward processing and heightened attention to negative stimuli. It is hypothesized that individuals with depression exhibit reduced generalization of reward stimuli and enhanced generalization of loss stimuli. Nevertheless, no study has examined this process and its underlying neural mechanisms. In the present study, we recruited 25 participants with subthreshold depression (SD group) and 24 age-matched healthy controls (HC group). Participants completed an acquisition task, in which they learned to associate three distinct pure tones (conditioned stimuli, CSs) with a reward, a loss, or no outcome. Subsequently, a generalization session was conducted, during which similar tones (generalization stimuli, GSs) were presented, and participants were required to classify them as a reward tone, a loss tone, or neither. The results revealed that the SD group exhibited reduced generalization errors in the early phase of generalization, suggesting a diminished ability to generalize reward-related stimuli. The event-related potential (ERP) results indicated that the SD group exhibited decreased generalization of positive valence to reward-related GSs and heightened generalization of negative valence to loss-related GSs, as reflected by the N1 and P2 components. However, the late positive potential (LPP) was not modulated by depression in reward generalization or loss generalization. These findings suggested that individuals with subthreshold depression may have a blunted or reduced ability to generalize reward stimuli, shedding light on potential treatment strategies targeting this particular process. 

Reduced generalization of reward among individuals with subthreshold depression: Behavioral and EEG evidence.

Abstract Despite the critical role of self-disturbance in psychiatric diagnosis and treatment, its diverse behavioral manifestations remain poorly understood. This investigation aimed to elucidate unique patterns of self-referential processing in affective disorders and first-episode schizophrenia. A total of 156 participants (41 first-episode schizophrenia [SZ], 33 bipolar disorder [BD], 44 major depressive disorder [MDD], and 38 healthy controls [HC]) engaged in a self-referential effect (SRE) task, assessing trait adjectives for self-descriptiveness, applicability to mother, or others, followed by an unexpected recognition test. All groups displayed preferential self- and mother-referential processing with no significant differences in recognition scores. However, MDD patients showed significantly enhanced self-referential recognition scores and increased bias compared to HC, first-episode SZ, and BD. The present study provides empirical evidence for increased self-focus in MDD and demonstrates that first-episode SZ and BD patients maintain intact self-referential processing abilities. These findings refine our understanding of self-referential processing impairments across psychiatric conditions, suggesting that it could serve as a supplementary measure for assessing treatment response in first-episode SZ and potentially function as a discriminative diagnostic criterion between MDD and BD. 

Behavioral evidence of impaired self-referential processing in patients with affective disorders and first-episode schizophrenia

Behavioral and electrophysiological analyses of self-referential neural processing in major depressive disorder.

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Behavioral and electrophysiological analyses of self-referential neural processing in major depressive disorder.