Effects of childhood maltreatment and major depressive disorder on functional connectivity in hippocampal subregions.

Major Depressive Disorder (MDD) with childhood maltreatment is a prevalent clinical phenotype. Prior studies have observed abnormal hippocampal activity in MDD patients, considering the hippocampus as a single nucleus. However, there is limited research investigating the static and dynamic changes in hippocampal subregion functional connectivity (FC) in MDD patients with childhood maltreatment. Therefore, we employed static and dynamic FC analyses using hippocampal subregions, including the anterior hippocampus and posterior hippocampus, as seed regions to investigate the neurobiological alterations associated with MDD resulting from childhood maltreatment. This study involved four groups: MDD with (n = 48) and without childhood maltreatment (n = 30), as well as healthy controls with (n = 57) and without (n = 46) childhood maltreatment. Compared to MDD patients without childhood maltreatment, those with childhood maltreatment exhibit altered FC between the hippocampal subregion and multiple brain regions, including the anterior cingulate gyrus, superior frontal gyrus, putamen, calcarine gyrus, superior temporal gyrus, angular gyrus, and supplementary motor area. Additionally, dynamic FC between the right medial-2 hippocampal head and the right calcarine gyrus shows a positive correlation with childhood maltreatment across all its subtypes. Moreover, dFC between the right hippocampal tail and the left angular gyrus moderates the relationship between childhood maltreatment and the depression severity. Our findings of distinct FC patterns within hippocampal subregions provide new clues for understanding the neurobiological basis of MDD with childhood maltreatment.

The role of the thalamic subregions in major depressive disorder with childhood maltreatment: Evidences from dynamic and static functional connectivity.

BACKGROUND: Major depressive disorder (MDD) with a history of childhood maltreatment represents a highly prevalent clinical phenotype. Previous studies have demonstrated functional alterations of the thalamus among MDD. However, no study has investigated the static and dynamic changes in functional connectivity (FC) within thalamic subregions among MDD with childhood maltreatment. METHODS: This study included four groups: MDD with childhood maltreatment (n = 48), MDD without childhood maltreatment (n = 30), healthy controls with childhood maltreatment (n = 57), and healthy controls without childhood maltreatment (n = 46). Sixteen thalamic subregions were selected as seed to investigate group-differences in dynamic FC (dFC) and static FC (sFC). Correlation analyses were performed to assess the associations between abnormal FC and maltreatment severity. Eventually, moderation analyses were employed to explore the moderating role of abnormal FC in the relationship between maltreatment and depressive severity. RESULTS: MDD with childhood maltreatment exhibit abnormal thalamic subregions FC compared to MDD without childhood maltreatment, characterized by abnormalities with the sFC of the rostral anterior cingulate cortex, with the dFC of the calcarine, middle cingulate cortex, precuneus cortex and superior temporal gyrus. Furthermore, sFC with the rostral anterior cingulate cortex and dFC with the middle cingulate cortex were correlated with the severity of maltreatment. Additionally, dFC with the superior temporal gyrus moderates the relationship between maltreatment and depression severity. LIMITATIONS: The cross-sectional designs fail to infer causality. CONCLUSIONS: Our findings support thalamic dysfunction as neurobiological features of childhood maltreatment as well as vulnerability to MDD.

Effects of childhood neglect on regional brain activity and corresponding functional connectivity in major depressive disorder and healthy people: Risk factor or resilience?

BACKGROUND: Childhood neglect is a high risk factor for major depressive disorder (MDD). However, the effects of childhood neglect on regional brain activity and corresponding functional connectivity in MDD patients and healthy populations remains unclear. METHODS: Regional homogeneity, amplitude of low-frequency fluctuations (ALFF), fractional ALFF, degree centrality, and voxel-mirrored homotopic connectivity were extensively calculated to explore intraregional brain activity in MDD patients with childhood neglect and in healthy populations with childhood neglect. Functional connectivity analysis was then performed using regions showing abnormal brain activity in regional homogeneity/ALFF/fractional ALFF/degree centrality/voxel-mirrored homotopic connectivity analysis as seed. Partial correlation analysis and moderating effect analysis were used to explore the relationship between childhood neglect, abnormal brain activity, and MDD severity. RESULTS: We found decreased brain function in the inferior parietal lobe and cuneus in MDD patients with childhood neglect. In addition, we detected that childhood neglect was significant associated with abnormal cuneus brain activity in MDD patients and that abnormal cuneus brain activity moderated the relationship between childhood neglect and MDD severity. In contrast, higher brain function was observed in the inferior parietal lobe and cuneus in healthy populations with childhood neglect. CONCLUSIONS: Our results provide new evidence for the identification of neural biomarkers in MDD patients with childhood neglect. More importantly, we identify brain activity characteristics of resilience in healthy populations with childhood neglect, providing more clues to identify neurobiological markers of resilience to depression after suffering childhood neglect.

Intrinsic brain abnormalities in female major depressive disorder patients with childhood trauma: A resting-state functional magnetic resonance imaging study.

Objective: Childhood trauma is a strong predictor of major depressive disorder (MDD). Women are more likely to develop MDD than men. However, the neural basis of female MDD patients with childhood trauma remains unclear. We aimed to identify the specific brain regions that are associated with female MDD patients with childhood trauma. Methods: We recruited 16 female MDD patients with childhood trauma, 16 female MDD patients without childhood trauma, and 20 age- and education level-matched healthy controls. All participants underwent resting-state functional magnetic resonance imaging (MRI). Regional brain activity was evaluated as the amplitude of low-frequency fluctuation (ALFF). Furthermore, functional connectivity (FC) analyses were performed on areas with altered ALFF to explore alterations in FC patterns. Results: There was increased ALFF in the left middle frontal gyrus (MFG) and the right postcentral gyrus (PoCG) in MDD with childhood trauma compared with MDD without childhood trauma. The areas with significant ALFF discrepancies were selected as seeds for the FC analyses. There was increased FC between the left MFG and the bilateral putamen gyrus. Moreover, ALFF values were correlated with childhood trauma severity. Conclusion: Our findings revealed abnormal intrinsic brain activity and FC patterns in female MDD patients with childhood trauma, which provides new possibilities for exploring the pathophysiology of this disorder in women.

Tyrosine phosphorylation of integrin beta3 regulates kindlin-2 binding and integrin activation.

Kindlins are essential for integrin activation in cell systems and do so by working in a cooperative fashion with talin via their direct interaction with integrin ß cytoplasmic tails (CTs). Kindlins interact with the membrane-distal NxxY motif, which is distinct from the talin-binding site within the membrane-proximal NxxY motif. The Tyr residues in both motifs can be phosphorylated, and it has been suggested that this modification of the membrane-proximal NxxY motif negatively regulates interaction with the talin head domain. However, the influence of Tyr phosphorylation of the membrane-distal NxxY motif on kindlin binding is unknown. Using mutational analyses and phosphorylated peptides, we show that phosphorylation of the membrane-distal NITY(759) motif in the ß(3) CT disrupts kindlin-2 recognition. Phosphorylation of this membrane-distal Tyr also disables the ability of kindlin-2 to coactivate the integrin. In direct binding studies, peptides corresponding to the non-phosphorylated ß(3) CT interacted well with kindlin-2, whereas the Tyr(759)-phosphorylated peptide failed to bind kindlin-2 with measurable affinity. These observations indicate that transitions between the phosphorylated and non-phosphorylated states of the integrin ß(3) CT determine reactivity with kindlin-2 and govern the role of kindlin-2 in regulating integrin activation.