Effect of 40 Hz light flicker on cognitive impairment and transcriptome of hippocampus in right unilateral common carotid artery occlusion mice.

Vascular cognitive impairment caused by chronic cerebral hypoperfusion (CCH) seriously affects the quality of life of elderly patients. However, there is no effective treatment to control this disease. This study investigated the potential neuroprotective effect of the 40 Hz light flicker in a mouse model of CCH. CCH was induced in male C57 mice by right unilateral common carotid artery occlusion (rUCCAO), leading to chronic brain injury. The mice underwent 40 Hz light flicker stimulation for 30 days after surgery. The results showed that 40 Hz light flicker treatment ameliorated memory deficits after rUCCAO and alleviated the damage to neurons in the frontal lobe and hippocampus. Light flicker administration at 40 Hz decreased IL-1ß and TNF-α levels in the frontal lobe and hippocampus, but immunohistochemistry showed that it did not induce angiogenesis in mice with rUCCAO. Gene expression profiling revealed that the induction of genes was mainly enriched in inflammatory-related pathways. Our findings demonstrate that 40 Hz light flicker can suppress cognitive impairment caused by rUCCAO and that this effect may be involved in the attenuation of neuroinflammation.

Volume changes of the subcortical limbic structures in major depressive disorder patients with and without anhedonia.

Anhedonia is a core feature of major depressive disorder (MDD) and the limbic system has been indicated to be associated with anhedonia in MDD due to its crucial role within the reward circuit. However, the relationship between different regions of the limbic system and MDD, particularly anhedonic symptoms, remains unclear. Therefore, the purpose of this study was to investigate volume changes of various parts of the subcortical limbic (ScLimbic) system in MDD with and without anhedonia. A total of 120 individuals, including 30 MDD patients with anhedonia, 43 MDD patients without anhedonia, and 47 healthy controls (HCs) were enrolled in this study. All subjects underwent structural magnetic resonance imaging scans. After that, ScLimbic system segmentation was performed using the FreeSurfer pipeline ScLimbic. Analysis of covariance (ANCOVA) was performed to identify brain regions with significant volume differences among three groups, and then, post hoc tests were calculated for inter-group comparisons. Finally, correlations between volumes of different parts of the ScLimbic and clinical characteristics in MDD patients were further analyzed. The ANCOVA revealed significant volume differences of the ScLimbic system among three groups in the bilateral fornix (Fx), and the right basal forebrain (BF). As compared with HCs, both groups of MDD patients showed decreased volume in the right Fx, meanwhile, MDD patients with anhedonia further exhibited volume reductions in the left Fx and right BF. However, no significant difference was found between MDD patients with and without anhedonia. No significant association was observed between subregion volumes of the ScLimbic system and clinical features in MDD. The present findings demonstrated that MDD patients with and without anhedonia exhibited segregated brain structural alterations in the ScLimbic system and volume loss of the ScLimbic system might be fairly extensive in MDD patients with anhedonia.

Alterations of brainstem volume in patients with first-episode and recurrent major depressive disorder.

BACKGROUND: Major depressive disorder (MDD) is a prevalent mental health condition characterized by recurrent episodes in a substantial proportion of patients. The number of previous episodes is one of the most crucial predictors of depression recurrence. However, the underlying neural mechanisms remain unclear. To date, there have been limited neuroimaging studies investigating morphological changes of the brainstem in patients with first-episode MDD (FMDD) and recurrent MDD (RMDD). This study aimed to examine volumetric changes of individual brainstem regions in relation to the number of previous episodes and disease duration. METHOD: A total of 111 individuals including 36 FMDD, 25 RMDD, and 50 healthy controls (HCs) underwent T1-weighted structural magnetic resonance imaging scans. A Bayesian segmentation algorithm was used to analyze the volume of each brainstem region, including the medulla oblongata, pons, midbrain, and superior cerebellar peduncle (SCP), as well as the whole brainstem volume. Analyses of variance (ANOVA) were performed to obtain brain regions with significant differences among three groups and then post hoc tests were calculated for inter-group comparisons. Partial correlation analyses were further conducted to identify associations between regional volumes and clinical features. RESULTS: The ANOVA revealed significant brainstem volumetric differences among three groups in the pons, midbrain, SCP, and the whole brainstem (F = 3.996 ~ 5.886, adjusted p = 0.015 ~ 0.028). As compared with HCs, both groups of MDD patients showed decreased volumes in the pons as well as the entire brainstem (p = 0.002 ~ 0.034), however, only the FMDD group demonstrated a significantly reduced volume in the midbrain (p = 0.003). Specifically, the RMDD group exhibited significantly decreased SCP volume when comparing to both FMDD (p = 0.021) group and HCs (p = 0.008). Correlation analyses revealed that the SCP volumes were negatively associated with the number of depressive episodes (r=-0.36, p < 0.01) and illness duration (r=-0.28, p = 0.035) in patients with MDD. CONCLUSION: The present findings provided evidence of decreased brainstem volume involving in the pathophysiology of MDD, particularly, volumetric reduction in the SCP might represent a neurobiological marker for RMDD. Further research is needed to confirm our observations and deepen our understanding of the neural mechanisms underlying depression recurrence.

Elevated Plasma Levels of Mature Brain-Derived Neurotrophic Factor in Major Depressive Disorder Patients with Higher Suicidal Ideation.

Several pieces of evidence show that signaling via brain-derived neurotrophic factor (BDNF) and its receptor, tropomycin receptor kinase B (TrkB), as well as inflammation, play a crucial part in the pathophysiology of depression. The purpose of our study was to evaluate plasma levels of BDNF-TrkB signaling, which are inflammatory factors in major depressive disorder (MDD) patients, and assess their associations with clinical performance. This study recruited a total sample of 83 MDD patients and 93 healthy controls (CON). All the participants were tested with the Hamilton Depression Scale (HAMD), the Beck Scale for Suicide Ideation, and the NEO Five-Factor Inventory. The plasma level of selected BDNF-TrkB signaling components (mature BDNF (mBDNF), precursor BDNF (proBDNF), tyrosine kinase B (TrkB), and tissue plasminogen activator (tPA)) and selected inflammatory factors (interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α)) were measured using an enzyme-linked immunosorbent assay (ELISA). Further, we performed correlation analysis to indicate the relationship between the plasma levels of the factors and clinical characteristics. Results: (i) A higher level of mBDNF and lower openness were observed in MDD patients with higher suicidal ideation than patients with lower suicidal ideation. (ii) In MDD patients, mBDNF was positively correlated with the sum score of the Beck Scale for Suicide Ideation (BSS). (iii) The levels of mBDNF, tPA, IL-1 ß and IL-6 were significantly higher in all MDD subjects compared to the healthy controls, while the levels of TrkB and proBDNF were lower in MDD subjects. Conclusion: Our study provides novel insights regarding the potential role of mBDNF in the neurobiology of the association between depression and suicidal ideation and, in particular, the relationship between BDNF-TrkB signaling, inflammatory factors, and clinical characteristics in MDD.

Altered hippocampal subfield volumes in major depressive disorder with and without anhedonia.

BACKGROUND: Previous neuroimaging findings have demonstrated the association between anhedonia and the hippocampus. However, few studies have focused on the structural changes in the hippocampus in major depressive disorder (MDD) patients with anhedonia. Meanwhile, considering that multiple and functionally specialized subfields of the hippocampus have their own signatures, the present study aimed to investigate the volumetric alterations of the hippocampus as well as its subfields in MDD patients with and without anhedonia. METHODS: A total of 113 subjects, including 30 MDD patients with anhedonia, 40 MDD patients without anhedonia, and 43 healthy controls (HCs), were recruited in the study. All participants underwent high-resolution brain magnetic resonance imaging (MRI) scans, and the automated hippocampal substructure module in FreeSurfer 6.0 was used to evaluate the volumes of hippocampal subfields. We compared the volumetric differences in hippocampal subfields among the three groups by analysis of variance (ANOVA, post hoc Bonferroni), and partial correlation was used to explore the association between hippocampal subregion volumes and clinical characteristics. RESULTS: ANOVA showed significant volumetric differences in the hippocampal subfields among the three groups in the left hippocampus head, mainly in the cornu ammonis (CA) 1, granule cell layer of the dentate gyrus (GC-ML-DG), and molecular layer (ML). Compared with HCs, both groups of MDD patients showed significantly smaller volumes in the whole left hippocampus head. Interestingly, further exploration revealed that only MDD patients with anhedonia had significantly reduced volumes in the left CA1, GC-ML-DG and ML when compared with HCs. No significant difference was found in the volumes of the hippocampal subfields between MDD patients without anhedonia and HCs, either the two groups of MDD patients. However, no association between hippocampal subfield volumes and clinical characteristics was found in either the subset of patients with anhedonia or in the patient group as a whole. CONCLUSIONS: These preliminary findings suggest that MDD patients with anhedonia exhibit unique atrophy of the hippocampus and that subfield abnormalities in the left CA1 and DG might be associated with anhedonia in MDD.

Volumetric Alterations of the Hippocampal Subfields in Major Depressive Disorder with and without Suicidal Ideation.

Major depressive disorder (MDD) is often accompanied with suicidal ideation (SI). Previous studies suggested that MDD patients who experienced suicidal attempts (SA) exhibited smaller hippocampal volume than those without SA. The hippocampus consists of several subfields that are histologically and functionally unique respectively. However, few studies have been designed to investigate the relationship between suicide and volumetric changes of the hippocampal subfields in MDD. A total of 92 participants, including 24 MDD patients with SI (MDD-SI), 30 MDD patients without SI (MDD-nSI), and 38 healthy controls (HC) were recruited in this study. High-resolution structural magnetic resonance images (MRI) were obtained and analyzed by using the automated hippocampal substructure module in FreeSurfer 7.3.2 Analyses of variance (ANOVA) were performed to obtain hippocampal subfields with significant differences among three groups and then post hoc tests were calculated for inter-group comparisons. Finally, the relationships between volumes of the hippocampal subfields and clinical characteristics were assessed using correlation analyses. The ANOVA revealed significant volumetric differences of the hippocampal subfields among three groups in the bilateral cornu ammonis (CA) 1 head, CA4, granule cell layer of the dentate gyrus (GC-ML-DG), molecular layer (ML), the right hippocampus-amygdala transition area (HATA), and the right subiculum (Sub) body. Relative to HC, both groups of MDD showed decreased volumes in the CA1 head, CA4, GC-ML-DG head, ML head, and whole hippocampal head of the left hippocampus, the right HATA, and bilateral whole hippocampal body and whole hippocampus. Meanwhile, the MDD-SI group further exhibited diminished volume in the CA1 head, GC-ML-DG head, ML head, CA4 body, Sub body, and whole hippocampal head of the right hippocampus, as well as bilateral GC-ML-DG body and ML body. Additionally, the MDD-SI group also showed decreased volumes in the right GC-ML-DG body, ML body, and Sub body when comparing to MDD-nSI group. However, no significant association was observed between hippocampal subfield volumes and clinical features in MDD. The present findings suggested that SI in MDD might be attributed to subfield abnormalities in the subiculum and DG-dominant circuit of the right hippocampus.

Increased plasma levels of IL-6 are associated with striatal structural atrophy in major depressive disorder patients with anhedonia.

Background: Anhedonia, as the core endophenotype of major depressive disorder (MDD), is closely related to poor prognosis, but the mechanism of this feature remains to be understood. The aim of this study was to investigate the inflammatory factors and brain structural alterations in MDD patients with anhedonia and evaluate the relationship between these factors. Methods: We assessed the plasma levels of interleukin-1 beta (IL-1ß), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) in MDD patients with anhedonia (n = 22), MDD patients without anhedonia (n = 20), and age- and sex-matched healthy controls (HCs, n = 20) by enzyme-linked immunosorbent assay kits. All participants underwent high-resolution brain magnetic resonance imaging (MRI) scans, and voxel-based morphometry (VBM) was used to evaluate their gray matter volume (GMV). We compared inflammatory factors and GMV among the three groups and explored their relationships in MDD patients with anhedonia. Results: Compared with those of HCs, plasma levels of IL-1ß were increased in patients with MDD independent of anhedonia features, while plasma levels of IL-6 were elevated in MDD patients with anhedonia only. Meanwhile, MDD patients with anhedonia exhibited reduced GMV in the left striatal structures compared to MDD patients without anhedonia and HCs. Moreover, a significant association was observed between increased plasma levels of IL-6 and decreased GMV of the left putamen in MDD patients with anhedonia. Conclusions: The present research outcomes suggest that anhedonia is associated with increased plasma levels of IL-6 and decreased GMV in the left striatal structures. In addition, this study demonstrates that GMV loss in the left putamen is related to increased plasma levels of IL-6 in MDD with anhedonia, which provides further insights into the possible mechanisms of anhedonia.

Aberrant interhemispheric functional connectivity in major depressive disorder with and without anhedonia.

OBJECTIVE: Anhedonia is a core feature of major depressive disorder (MDD), and as a subtype of depression, MDD with anhedonia may have exceptional neurobiological mechanisms. However, the neuropathology of anhedonia in MDD remains unclear. Thus, this study aimed to investigate the brain functional differences between MDD with and without anhedonia. METHODS: A total of 62 individuals including 22 MDD patients with anhedonia, 20 MDD patients without anhedonia, and 20 healthy controls (HCs) were recruited for this study. All participants underwent 3.0-T functional magnetic resonance imaging scan. Voxel-mirrored homotopic connectivity (VMHC) was employed to quantitatively describe bilateral functional connectivity. Analyses of variance (ANOVA) were performed to obtain brain regions with significant differences among three groups and then post hoc tests were calculated for inter-group comparisons. RESULTS: The ANOVA revealed significant VMHC differences among three groups in the bilateral middle temporal gyrus (MTG), superior frontal gyrus (SFG), and inferior parietal lobule (IPL) (F = 10.47 ~ 15.09, p < 0.05, AlphaSim corrected). Relative to HCs, MDD with anhedonia showed significantly decreased VMHC in the bilateral MTG (t = -5.368, p < 0.05, AlphaSim corrected), as well as increased VMHC in the bilateral SFG (t = -4.696, p < 0.05, AlphaSim corrected). Compared to MDD without anhedonia, MDD with anhedonia showed significantly decreased VMHC in the bilateral MTG and IPL (t = -5.629 ~ -4.330, p < 0.05, AlphaSim corrected), while increased VMHC in the bilateral SFG (t = 3.926, p < 0.05, AlphaSim corrected). However, no significant difference was found between MDD without anhedonia and HCs. CONCLUSION: The present findings suggest that MDD with and without anhedonia exhibit different patterns of interhemispheric connectivity. Anhedonia in MDD is related to aberrant interhemispheric connectivity within brain regions involved in the frontal-temporal-parietal circuit.

The impacts of anhedonia on brain functional alterations in patients with major depressive disorder: A resting-state functional magnetic resonance imaging study of regional homogeneity.

BACKGROUND: Anhedonia, as one of the core manifestations of major depressive disorder (MDD), has an effect on prognosis of the disease. However, the neuropathology of MDD is complex and the neural basis of anhedonia remains unclear. The aim of the present study was to investigate the impacts of anhedonia on brain functional alterations in patients with MDD. METHODS: A total of 62 individuals including MDD patients with anhedonia (n = 22), MDD patients without anhedonia (n = 20), and healthy controls (HCs, n = 20) were recruited. All participants underwent resting-state functional magnetic resonance imaging scanning and intrinsic brain function was explored by using regional homogeneity (ReHo) method. A two-sample t-test was performed to explore ReHo differences between MDD patients and HCs, then analysis of variance (ANOVA) was introduced to obtain brain regions with significant differences among three groups, and finally post hoc tests were calculated for inter-group comparisons. Correlations between ReHo values of each survived area and clinical characteristics in MDD patients were further analyzed. RESULTS: Compared with HCs, MDD showed increased ReHo in the left superior temporal gyrus (STG) and bilateral inferior frontal gyrus (IFG), as well as decreased ReHo in the left superior frontal gyrus (SFG). Interestingly, this relationship was attenuated and no longer significant after consideration for the effect of anhedonia in MDD patients. MDD patients with anhedonia were more likely to exhibit decreased ReHo in the left SFG and left middle cingulate gyrus (MCG) when comparing to HCs. No significant difference was found between MDD patients without anhedonia and HCs, either the two groups of MDD patients. There was no significant association between ReHo values of each survived area and clinical characteristics in MDD patients. CONCLUSIONS: The present results suggest that the impacts of anhedonia on brain functional alterations in MDD should be emphasized and disturbed intrinsic brain function in the frontal-limbic regions may be associated with anhedonia in MDD patients.

Correlation between anxiety-depression symptoms and immune characteristics in inpatients with 2019 novel coronavirus in Wuhan, China.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is widely acknowledged as a severe traumatic event, and depression, anxiety, and psychological distress are common in diagnosed patients. However, the correlations of biological indicators with emotion are rarely reported. The primary objective of this study was to explore the dysfunction of immune-inflammatory characteristics in patients with depression-anxiety symptoms. METHODS: We investigated the mental status of inpatients with COVID-19 in Wuhan and compared the differences in cytokines and lymphocytes between patients with and without depression-anxiety symptoms at admission. After two weeks of treatment, we evaluated the mental conditions and measured the cytokines and lymphocytes of the patients with depression and anxiety symptoms and explored the changes and their associations. RESULTS: Approximately half of the patients with COVID-19 had depression and anxiety symptoms, and the symptoms were related to the ratio of CD4+/CD8+ and the level of CD4+T lymphocytes. When compared with patients without depression-anxiety symptoms, CD4+T lymphocytes level was significantly higher in COVID-19 patients with depression-anxiety symptoms. CONCLUSION: This study provided novel evidence regarding the association between depression and anxiety symptoms and immune characteristics, especially CD4+T lymphocyte levels, in COVID-19 patients. We emphasized the importance of paying attention to the dynamic immune process of patients diagnosed with COVID-19 with depression/anxiety.

The efficacy and safety of sulforaphane as an adjuvant in the treatment of bipolar depressive disorder: Study protocol for a randomized, double-blinded, placebo-controlled, parallel-group clinical trial.

BACKGROUND: Bipolar disorder (BD) is a chronic and disabling psychiatric disorder. The treatment of BD still remains a significant clinical challenge due to the complex nature of the disease. Nutraceutical therapy as adjunctive role is a promising therapy for BD. Sulforaphane (SFN), a broccoli extract, was reported to be effective for emotional problems and cognitive impairment. However, clinical research of SFN in the treatment of BD was rare. Therefore, this study is designed to evaluate the adjuvant role of SFN in the treatment of BD. METHODS: This is a randomized, double-blinded, placebo-controlled, parallel-group clinical trial. A total of 100 patients who meet inclusion criteria will be assigned to receive quetiapine plus SFN or quetiapine plus placebo in a 1:1 ratio. The total duration of the study will be 12 weeks including 5 follow ups. The primary outcome is in the Montgomery-Asberg depression rating scale. The secondary outcomes are the quick inventory of depressive symptomatology-self report, Hamilton anxiety rating scale, young mania rating scale, cognitive function, inflammatory factors, and intestinal flora. Any adverse events will be recorded throughout the trial. DISCUSSION: This trial will provide evidences to evaluate the efficacy and safety of SFN combined with quetiapine in the treatment of BD patients, as well as the adjuvant role of SFN in combination. TRIAL REGISTRATION: This study protocol was registered at the Chinese clinical trial registry (ChiCTR2000028706).

Increased ratio of mature BDNF to precursor-BDNF in patients with major depressive disorder with severe anhedonia.

BACKGROUND: Although studies have shown that severe anhedonia in patients with major depressive disorder (MDD) is associated with poor treatment outcomes, the biological mechanism of this feature is unclear. The aim of this study was to investigate the dysfunction of brain-derived neurotrophic factor (BDNF) metabolism, measured by the ratio of mature BDNF to precursor-BDNF, in MDD patients with severe anhedonia. METHODS: We measured plasma levels of mature BDNF (mBDNF), precursor-BDNF (proBDNF), tissue plasminogen activator (tPA) and tropomyosin-related kinase B (trkB) in outpatients with MDD with anhedonia (n = 26), outpatients with MDD without anhedonia (n = 29) and age- and sex-matched healthy controls (HCs, n = 38) by enzyme-linked immunosorbent assay kits, and we calculated the ratio of mBDNF to proBDNF (M/P). We compared these biological determinants among the three groups and explored the interrelationships between anhedonia severity and BDNF metabolism. RESULTS: The levels of mBDNF, proBDNF, and tPA and the ratio of M/P were identified with highly significant differences among the three groups. Compared with MDD patients without anhedonia and healthy controls, MDD patients with anhedonia showed higher level of the ratio of M/P, and it was positively associated with the SHAPS scores in MDD patients. Compared to healthy controls, the plasma tPA concentrations were higher in MDD patients with anhedonia but were not different from those in MDD patients without anhedonia. CONCLUSION: These results provide novel evidence regarding the relationship between anhedonia and plasma BDNF metabolism. The hypermetabolism of BDNF may be a function of anhedonia rather than other characteristics in MDD.