Abnormal dynamic functional connectivity of hippocampal subregions associated with working memory impairment in melancholic depression.

BACKGROUND: Previous studies have demonstrated structural and functional changes of the hippocampus in patients with major depressive disorder (MDD). However, no studies have analyzed the dynamic functional connectivity (dFC) of hippocampal subregions in melancholic MDD. We aimed to reveal the patterns for dFC variability in hippocampus subregions - including the bilateral rostral and caudal areas and its associations with cognitive impairment in melancholic MDD. METHODS: Forty-two treatment-naive MDD patients with melancholic features and 55 demographically matched healthy controls were included. The sliding-window analysis was used to evaluate whole-brain dFC for each hippocampal subregions seed. We assessed between-group differences in the dFC variability values of each hippocampal subregion in the whole brain and cognitive performance on the MATRICS Consensus Cognitive Battery (MCCB). Finally, association analysis was conducted to investigate their relationships. RESULTS: Patients with melancholic MDD showed decreased dFC variability between the left rostral hippocampus and left anterior lobe of cerebellum compared with healthy controls (voxel p < 0.005, cluster p < 0.0125, GRF corrected), and poorer cognitive scores in working memory, verbal learning, visual learning, and social cognition (all p < 0.05). Association analysis showed that working memory was positively correlated with the dFC variability values of the left rostral hippocampus-left anterior lobe of the cerebellum (r = 0.338, p = 0.029) in melancholic MDD. CONCLUSIONS: These findings confirmed the distinct dynamic functional pathway of hippocampal subregions in patients with melancholic MDD, and suggested that the dysfunction of hippocampus-cerebellum connectivity may be underlying the neural substrate of working memory impairment in melancholic MDD.

The prevalence and characteristics of MCCB cognitive impairment in unmedicated patients with bipolar II depression and major depressive disorder.

BACKGROUND: Cognitive impairment has been acknowledged as a core clinical manifestation of bipolar disorder (BD) as well as major depressive disorder (MDD). Determining the prevalence and characteristics of cognitive impairment is important for clinical interventions. This study investigated the prevalence and characteristics of cognitive impairment based on the Measurement and Treatment Research to Improve Cognition Schizophrenia Consensus Cognitive Battery (MCCB) in both BD and MDD. METHOD: One hundred and forty-nine BD II depression, 147 MDD, and 124 demographically matched healthy controls (HC) underwent MCCB cognitive assessment. The prevalence of MCCB cognitive impairment and group difference comparisons were performed. Additionally, association analysis was performed to investigate the relationship between cognitive performance and clinical variables. RESULTS: Compared to the HC group, both BD II depression and MDD groups had a significantly reduced performance for all MCCB cognitive domains (all p < 0.05). The numerical scores for visual learning were lower in the BD II depression group compared to the MDD group. 32.89% of the BD II depression patients had clinically significant impairment (>1.5 SD below the normal mean) in two or more MCCB domains compared to 23.13% for MDD patients. CONCLUSIONS: A high percent of patients in the BD II depression and MDD group exhibited MCCB cognitive impairments with clinical significance. Cognitive impairments were more common in BD II depression patients compared to MDD patients, particularly for visual learning. These findings suggest that clinicians should be aware of the severe cognitive impairment in mood disorders and establish effective cognitive screening and intervention strategies.

Childhood trauma history is linked to abnormal brain metabolism of non-medicated adult patients with major depressive disorder.

OBJECTIVES: Childhood trauma is a risk factor that may lead to persistent brain metabolic abnormalities, predisposing individuals to major depressive disorder (MDD). To better elucidate the pathogenesis of MDD, we investigated the neurometabolic changes in unmedicated MDD patients who had experienced childhood trauma (CT). METHODS: In this study, 37 unmedicated MDD patients with CT, 35 unmedicated MDD patients without CT, and 30 healthy control participants underwent high-resolution proton magnetic resonance spectroscopy (1H-MRS) examination. Bilateral metabolic ratios of N-acetylaspartate (NAA)/creatine (Cr) and choline (Cho)/Cr in the prefrontal white matter (PWM), anterior cingulate cortex (ACC), putamen, and cerebellum were obtained. RESULTS: MDD patients showed neurometabolic changes in the cortico-striato-cerebellar (CSC) circuit. Furthermore, MDD patients showed significantly lower NAA/Cr and higher Cho/Cr ratio in the bilateral ACC and putamen, and higher NAA/Cr and lower Cho/Cr ratio in the cerebellum. Childhood trauma reduced the Cho/Cr ratio in the left ACC, which played an important role in longer and more episodes of depression. CONCLUSION: Early childhood trauma has a long-lasting impact on the metabolism of adult MDD patients, leading to abnormal choline metabolism of the left ACC. Abnormal biochemical metabolism in the CSC circuit may be an underlying pathophysiology of MDD. LIMITATION: As this is a small cross-sectional study, the impact of childhood trauma on the different stages of depression has not been observed.

Associations between executive function impairment and biochemical abnormalities in depressed adolescents with non-suicidal self-injury.

BACKGROUND: H protons magnetic resonance spectroscopy (1H-MRS) has been used to detect the biochemical metabolism changes and the mechanism of executive dysfunction in major depressive disorder (MDD). While, finding information associated with non-suicidal self-injury (NSSI) among adolescents with MDD is challenging. The present study aimed to examine the executive function and biochemical metabolism alterations, as well as to elucidate their associations in depressed adolescents with NSSI. METHODS: A total of 86 adolescents with MDD (40 with NSSI, and 46 without NSSI) and 28 healthy controls were recruited in the current study. The executive function was assessed by Digital symbol test (DST), Wisconsin Card Sorting Test (WCST), Trail Making Test, part B (TMT-B), and Verbal fluency (VF). Bilateral metabolite levels of the prefrontal cortex (PFC), anterior cingulated cortex (ACC), lenticular nucleus (LN) of basal ganglia and thalamus were obtained by 1H-MRS at 3.0 T, and then the ratios of N-acetyl aspartate (NAA) and choline-containing compounds (Cho) to creatine (Cr) were determined, respectively. Finally, association analysis was conducted to investigate their relationships. RESULTS: The depressed adolescents with NSSI showed significantly lower VF scores than those without NSSI and healthy controls. We also found significantly higher NAA/Cr ratios in the right thalamus, while significantly lower Cho/Cr ratios in the right thalamus of NSSI group than the MDD without NSSI group and healthy controls. And NSSI group also showed lower NAA/Cr ratio in the right LN than the MDD without NSSI group. For MDD with NSSI, the NAA/Cr ratios of the left thalamus were positively correlated with the time of TMTB and the Cho/Cr ratios of the left ACC were positively correlated with the VF scores. CONCLUSIONS: Depressed adolescents with NSSI may have executive dysfunction and NAA and Cho metabolism abnormalities in the thalamus. And the NAA/Cr ratios of the right LN could distinguish NSSI from depressed adolescents. Further, the executive dysfunction may be associated with the abnormal NAA metabolism in the left thalamus and ACC.

The Effectiveness of Eye Movement Desensitization and Reprocessing Toward Adults With Major Depressive Disorder: A Meta-Analysis of Randomized Controlled Trials.

The practice-based evidence suggests that it is possible to use eye movement desensitization and reprocessing (EMDR) to treat major depressive disorder (MDD), but its specific efficacy is unknown. A systematic search was carried out for randomized controlled trials comparing EMDR with a control condition group in MDD patients. Two meta-analyses were conducted, with symptom reduction as primary outcome and remission as exploratory outcome. Eight studies with 320 participants were included in this meta-analysis. The first meta-analysis showed that EMDR outperformed "No Intervention" in decreasing depressive symptoms (standardized mean difference [SMD] = -0.81, 95% CI = -1.22 to -0.39, p < 0.001, low certainty), but statistically significant differences were not observed in improving remission (risk ratio = 1.20, 95% CI = 0.87-1.66, p = 0.25, very low certainty). The second showed the superiority of EMDR over CBT in reducing depressive symptoms (mean difference [MD] = -7.33, 95% CI = -8.26 to -6.39, p < 0.001, low certainty), and improving remission (risk ratio = 1.95, 95% CI = 1.24-3.06, p = 0.004, very low certainty). Besides, anxiety symptoms and level of functioning could not be included as secondary outcome due to the lack of data. The present meta-analysis suggests that EMDR is more effective in treating MDD than "No Intervention" and CBT, particularly in individuals who have traumatic experience. However, this result should be considered with caution due to small sample size and low quality of trails.

Serum copper and zinc levels correlate with biochemical metabolite ratios in the prefrontal cortex and lentiform nucleus of patients with major depressive disorder.

BACKGROUND: Previous studies have demonstrated that copper and zinc metabolism are associated with the development of major depressive disorder (MDD). Abnormal copper and zinc levels may be related to neurotransmission and biochemical metabolism in the brains of MDD patients, especially in the prefrontal cortex (PFC) and lentiform nucleus (LN). However, the mechanism of how copper and zinc levels contribute to neural metabolism in MDD patients remains to be deciphered. This study aimed to correlate copper and zinc levels with biochemical metabolite ratios in the PFC and LN of MDD patients. METHOD: Twenty-nine MDD patients and thirty-two healthy control (HC) volunteers were enrolled in this study. Proton magnetic resonance spectroscopy (1H-MRS) was used to determine the levels of the N-acetylaspartate (NAA), choline (Cho) and creatine (Cr) in the brain, and specifically in the PFC and LN regions. Serum copper and zinc levels were measured using atomic emission spectrometry (AES). Afterwards, copper and zinc levels were correlated with biochemical metabolite ratios in the PFC and LN regions of the brain. RESULTS: Higher serum copper and lower serum zinc levels with higher copper/zinc ratios were observed in MDD patients. NAA/Cr ratios in the PFC of MDD patients were lower compared to HC volunteers. In MDD patients, serum copper levels were negatively correlated with NAA/Cr ratios in the right PFC and right LN, while copper/zinc ratios were negatively correlated with NAA/Cr ratios in the right LN. No significant differences in serum copper and zinc levels with NAA/Cr ratios in the left PFC and left LN were observed in MDD patients. CONCLUSION: Our findings suggest that higher serum copper and lower serum zinc levels may contribute to neuronal impairment by affecting neuronal biochemical metabolite ratios in the right PFC and right LN of MDD patients. Abnormal copper and zinc levels may play an important role in the pathophysiology of MDD.

VGLL4 targets a TCF4-TEAD4 complex to coregulate Wnt and Hippo signalling in colorectal cancer.

Concerted co-regulation of multiple signalling pathways is crucial for tissue homoeostasis and tumorigenesis. Here we report that VGLL4, a previously identified YAP antagonist, also functions as a regulator of Wnt/ß-catenin signalling. The expression of VGLL4 is significantly downregulated in clinical colorectal carcinoma (CRC) specimens, positively associated with patient survival rate, and inversely correlated with the expression of Wnt target genes in CRCs. Knockdown of VGLL4 enhances proliferation and tumour formation of CRC cells. A designed peptide mimicking the function of VGLL4 effectively inhibits CRC progression in a de novo mouse model. Mechanistically, TEAD4 associates with TCF4 to form a complex and cobind target genes. VGLL4 targets this TEAD4-TCF4 complex to interfere the functional interplay between TEAD4 and TCF4, suppressing the transactivation of TCF4. Collectively, our study indicates that Wnt/ß-catenin and Hippo-YAP signalling are directly linked at transcription factor-level, and VGLL4 can target a TEAD4-TCF4 complex to co-regulate both pathways.

Structural insights into the C1q domain of Caprin-2 in canonical Wnt signaling.

Previously, we have identified Caprin-2 as a new regulator in canonical Wnt signaling through a mechanism of facilitating LRP5/6 phosphorylation; moreover, we found that its C-terminal C1q-related domain (Cap2_CRD) is required for this process. Here, we determined the crystal structures of Cap2_CRD from human and zebrafish, which both associate as a homotrimer with calcium located at the symmetric center. Surprisingly, the calcium binding-deficient mutant exists as a more stable trimer than its wild-type counterpart. Further studies showed that this Caprin-2 mutant disabled in binding calcium maintains the activity of promoting LRP5/6 phosphorylation, whereas the mutations disrupting Cap2_CRD homotrimer did impair such activity. Together, our findings suggested that the C-terminal CRD domain of Caprin-2 forms a flexible homotrimer mediated by calcium and that such trimeric assembly is required for Caprin-2 to regulate canonical Wnt signaling.

Smurf1-mediated axin ubiquitination requires Smurf1 C2 domain and is cell cycle-dependent.

Previously, Smad ubiquitination regulatory factor 1 (Smurf1)-mediated Lys29 (K29)-linked poly-ubiquitination of Axin has been identified as a novel regulatory process in Wnt/ß-catenin signaling. In this work, we discovered that the C2 domain of Smurf1 is critical for targeting Axin for ubiquitination. We found that the C2 domain-mediated plasma membrane localization of Smurf1 is required for Axin ubiquitination, and interfering with that disturbs the co-localization of Smurf1 and Axin around the plasma membrane. Moreover, the C2 domain of Smurf1, rather than its WW domains, is involved in Smurf1's interaction with Axin; and the putative PPXY motifs (PY motif) of Axin are not essential for such an interaction, indicating that Smurf1 binds to Axin in a non-canonical way independent of WW-PY interaction. Further, we found that Smurf1-Axin interaction and Axin ubiquitination are attenuated in the G2/M phase of cell cycle, contributing to an increased cell response to Wnt stimulation at that stage. Collectively, we uncovered a dual role of Smurf1 C2 domain, recruiting Smurf1 to membrane for accessing Axin and mediating its interaction with Axin, and that Smurf1-mediated Axin ubiquitination is subjected to the regulation of cell cycle.

Small-molecule modulation of Wnt signaling via modulating the Axin-LRP5/6 interaction.

The Wnt/ß-catenin signaling pathway has a crucial role in embryonic development, stem cell maintenance and human disease. By screening a synthetic chemical library of lycorine derivatives, we identified 4-ethyl-5-methyl-5,6-dihydro-[1,3]dioxolo[4,5-j]phenanthridine (HLY78) as an activator of the Wnt/ß-catenin signaling pathway, which acts in a Wnt ligand-dependent manner. HLY78 targets the DIX domain of Axin and potentiates the Axin-LRP6 association, thus promoting LRP6 phosphorylation and Wnt signaling transduction. Moreover, we identified the critical residues on Axin for HLY78 binding and showed that HLY78 may weaken the autoinhibition of Axin. In addition, HLY78 acts synergistically with Wnt in the embryonic development of zebrafish and increases the expression of the conserved hematopoietic stem cell (HSC) markers, runx1 and cmyb, in zebrafish embryos. Collectively, our study not only provides new insights into the regulation of the Wnt/ß-catenin signaling pathway by a Wnt-specific small molecule but also will facilitate therapeutic applications, such as HSC expansion.