Non-inferiority of intermittent theta burst stimulation over the left V1 vs. classical target for depression: A randomized, double-blind trial.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) targeting the visual cortex (VC) has shown antidepressant effects for major depressive disorder (MDD) in sham-controlled trials, but comparisons with rTMS targeting the left dorsolateral prefrontal cortex (DLPFC) are lacking. We aimed to determine the non-inferiority of intermittent theta-burst stimulation (iTBS) over VC vs DLPFC for MDD. METHODS: Participants randomly received navigated iTBS over the left V1 or the left DLPFC twice daily for 14 days with a 3-month follow-up. The primary outcome was change in Hamilton Depression Rating Scale (HAMD-17) score from baseline to treatment end, with 2.5 points as the non-inferiority margin. Secondary outcomes included: improvement in Montgomery-Asberg Depression Rating Scale (MADRS), Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA); response and remission rates; suicidal ideation and adverse events. RESULTS: Of 75 randomized patients, 67 completed full treatment, including 52 first-episode patients and 15 relapsers. The primary outcome indicated the non-inferiority of VC (adjusted difference 1.14, lower 97.5 % CI -1.24; p = .002), confirmed by improvements in objective cognitive task and protein levels, as did most secondary outcomes. Reduced suicidal ideation after treatment, incidence of eye discomfort and pain score were lower in the VC group. CONCLUSIONS: Left VC iTBS has the potential to be non-inferior to DLPFC iTBS in most first-episode MDD in improving depressive symptoms and cognitive function, with less suicidal ideation and adverse events. LIMITATIONS: Given the limited sample size, the lack of a sham control and the use of antidepressants, the findings should be interpreted with caution.

Selective activation of ABCA1/ApoA1 signaling in the V1 by magnetoelectric stimulation ameliorates depression via regulation of synaptic plasticity.

Emerging evidence suggests that dysfunction of the visual cortex may be involved in major depressive disorder (MDD). However, the underlying mechanisms remain unclear. We previously established that combined magnetic stimulation system treatment (c-MSST) resulted in an antidepressant effect in mice. In the present study, we found that V1-targeted c-MSST induced significant antidepressant effects in chronic unpredictable mild stress (CUMS)- and lipopolysaccharide (LPS)-treated mice. Proteomic screening investigation and repeatable validation revealed that expression of the V1 neuronal ATP-binding cassette transporter A1 (ABCA1) and apolipoprotein A-1 (ApoA1) was downregulated in CUMS mice, an effect that was normalized by c-MSST. Neuron-specific knockdown of ABCA1 in V1 blocked c-MSST's antidepressant effects. Mechanistically, CUMS reduced dendritic spine density and long-term plasticity in V1, and these deficits were reversed by c-MSST. V1-targeted c-MSST was found to induce rapid antidepressant effects that are mediated by alterations in synaptic plasticity via the ABCA1/ApoA1 signaling pathway in V1.

Abnormal brain gray matter volume in patients with major depressive disorder: Associated with childhood trauma?

BACKGROUND: Patients with major depressive disorders (MDD) have abnormalities in the frontal-limbic structures of the brain. Childhood trauma is a risk factor for both structural brain alterations and MDD. However, the relationships among the three have not been confirmed. METHODS: Sixty-four patients with MDD and sixty-one healthy controls (HC) were checked by using MRI, the Hamilton Depression Scale (HAMD) and Childhood Trauma Questionnaire (CTQ). Voxel-based morphometry (VBM) was used to compare gray matter volume (GMV) differences between the two groups. Moreover, partial correlation and mediation analyses were conducted to test for potential associations between CTQ scores, different GMV, and clinical variables. RESULTS: Compared to the HC group, the MDD patients showed decreased GMV in the right middle frontal gyrus (rMFG) and right precentral gyrus (rPreCG). In the patient group, reduced GMV in rMFG was associated with CTQ scores (r = -0.30, P = 0.019) and HAMD scores (r = -0.53, P < 0.001). Finally, in the patient group, mediation analysis revealed that the indirect effect of rMFG GMV in CTQ scores and HAMD scores was 0.115 and the proportion of indirect effect to total effect was 23.86%. LIMITATIONS: This study used a cross-sectional collection, and it is unclear whether at the longitudinal level the brain GMV mediates the relationship between childhood trauma and depression. CONCLUSIONS: Abnormalities in the frontal GMV were presented in the MDD patients. It is possible that childhood traumatic experiences cause inefficient GMV and ultimately lead to an increased susceptibility to depression.

Altered task modulation of global signal topography in the default-mode network of unmedicated major depressive disorder.

BACKGROUND: Altered global signal (GS) topography features in the resting-state fMRI of major depressive disorder (MDD), showing abnormally strong global signal representation in the default-mode network (DMN). Whether the abnormal local to global change also shapes activity during task states, and how it relates to psychopathological symptoms, e.g., abnormally slow time speed of motor, cognitive, and affective symptoms, remains unknown. METHODS: We investigated fMRI-based GS with its topographical representation during task states in unmedicated 51 MDD subjects and 28 healthy subjects. Task-related global signal correlation (GSCORR) was probed by a novel paradigm testing the processing of negative/neutral emotions during different time speeds, i.e., slow and fast. RESULTS: We observed a significant interaction between time speed and emotion of GSCORR in various DMN regions in healthy subjects. Next, we showed that MDD exhibits reduced task-related GSCORR in various DMN regions during specifically the fast processing of negative emotions. Finally, we demonstrated that GSCORR in DMN and other brain regions (motor-related regions, inferior frontal cortex) correlated with the degree of psychomotor retardation especially during the fast emotional stimuli. LIMITATIONS: The measurement of interoceptive variables like respiration rate or heart rate were not included in our fMRI acquisition. CONCLUSION: Together, we demonstrated the functional relevance of GS topography by showing reduced GSCORR in DMN during specifically the fast processing of negative emotions in MDD, suggesting the abnormal slowness, i.e., reduced time speed, to be a key feature of both brain and symptoms in MDD.

Potential of Antithrombin III as a Biomarker of Antidepressive Effect in Major Depressive Disorder.

Background: The evaluation of treatment response to antidepressant therapy commonly depends on neuropsychologic assessments, as there are currently no suitable biomarkers. Previous research has identified a panel of increased proteins in patients with major depressive disorder (MDD), including antithrombin III (ATIII), as potential biomarkers of depression. Methods: A total of 90 MDD patients were recruited. Of these, 74 patients received occipital repetitive transcranial magnetic stimulation (rTMS) as individualized, standard, or sham treatment for 5 days, and underwent the complete procedure, including clinical assessments, blood collection, and protein measurement. Results: After treatment, ATIII was significantly decreased in both the individualized and standard groups (both p < 0.001) relative to the sham group. In the individualized group, reduction in ATIII was associated with improvements in several neuropsychological assessments. Furthermore, ATIII at baseline in the standard group and after individualized rTMS showed good performance for evaluating or predicting the response to five-day treatment (AUC = 0.771, 95% CI, 0.571-0.971; AUC = 0.875, 95% CI, 0.714-1.000, respectively) and remission at follow-up (AUC = 0.736, 95% CI, 0.529-0.943; AUC = 0.828, 95% CI, 0.656-1.000, respectively). Lastly, both baseline ATIII and change in ATIII showed good predictive value for the 24-item Hamilton Depression Rating Scale at follow-up (p = 0.024 and 0.023, respectively). Conclusion: Our study revealed a reduction in ATIII after occipital rTMS in MDD patients and a relationship between change in ATIII and therapeutic response. Taken together, these findings provide evidence for the potential of ATIII as a biomarker for the evaluation and prediction of antidepressive effects.

Non-coding RNAs in depression: Promising diagnostic and therapeutic biomarkers.

Non-coding RNAs (ncRNAs), including microRNAs, circular RNAs, and long non-coding RNAs, are important regulators of normal biological processes and their abnormal expression may be involved in the pathogenesis of human diseases including depression. Multiple studies have demonstrated a significantly increased or reduced ncRNAs expression in depressed patients compared with healthy subjects and that antidepressant therapy can alter the aberrant expression of ncRNAs in depressed patients. Although the existing evidence is important, it is also mixed and a comprehensive review to guide an effective clinical translation is lacking. Focused on human research, this review summarizes clinical findings of ncRNAs in depression, including those in brain tissues and peripheral samples. We outlined the characteristics and functions of ncRNAs and highlighted their performance in the diagnosis and treatment of depression. Although their precise roles in depression remain uncertain, ncRNAs have shown potential value as biomarkers for diagnosis and therapy in depressed patients.

Sleep disturbance-related neuroimaging features as potential biomarkers for the diagnosis of major depressive disorder: A multicenter study based on machine learning.

BACKGROUND: Objective biomarkers are crucial for overcoming the clinical dilemma in major depressive disorder (MDD), and the individualized diagnosis is essential to facilitate the precise medicine for MDD. METHODS: Sleep disturbance-related magnetic resonance imaging (MRI) features was identified in the internal dataset (92 MDD patients) using the relevance vector regression algorithm, which was further verified in 460 MDD patients of an independent, multicenter dataset. Subsequently, using these MRI features, the eXtreme Gradient Boosting classification model was constructed in the current multicenter dataset (460 MDD patients and 470 normal controls). Meanwhile, the association between classification outputs and the severity of depressive symptoms was also investigated. RESULTS: In MDD patients, the combination of gray matter density and fractional amplitude of low-frequency fluctuation can accurately predict individual sleep disturbance score that was calculated by the sum of item 4 score, item 5 score, and item 6 score of the 17-Item Hamilton Rating Scale for Depression (HAMD-17) (R2 = 0.158 in the internal dataset; R2 = 0.110 in multicenter dataset). Furthermore, the classification model based on these MRI features distinguished MDD patients from normal controls with 86.3% accuracy (area under the curve = 0.937). Importantly, the classification outputs significantly correlated with HAMD-17 scores in MDD patients. LIMITATION: Lacking some specialized tools to assess the personal sleep quality, e.g. Pittsburgh Sleep Quality Index. CONCLUSION: Neuroimaging features can reflect accurately individual sleep disturbance manifestation and serve as potential diagnostic biomarkers of MDD.

Potential clinical value of circular RNAs as peripheral biomarkers for the diagnosis and treatment of major depressive disorder.

BACKGROUND: circular RNAs (circRNAs) are expressed abundantly in the brain and are implicated in the pathophysiology of neuropsychiatric disease. However, the potential clinical value of circRNAs in major depressive disorder (MDD) remains unclear. METHODS: RNA sequencing was conducted in whole-blood samples in a discovery set (7 highly homogeneous MDD patients and 7 matched healthy controls [HCs]). The differential expression of circRNAs was verified in an independent validation set. The interventional study was conducted to assess the potential effect of the antidepressive treatment on the circRNA expression. FINDINGS: in the validation set, compared with 52 HCs, significantly decreased circFKBP8 levels (Diff: -0.24; [95% CI -0.39 ~ -0.09]) and significantly elevated circMBNL1 levels (Diff: 0.37; [95% CI 0.09 ~ 0.64]) were observed in 53 MDD patients. The expression of circMBNL1 was negatively correlated with 24-item Hamilton Depression Scale (HAMD-24) scores in 53 MDD patients. A mediation model indicated that circMBNL1 affected HAMD-24 scores through a mediator, serum brain-derived neurotrophic factor. In 53 MDD patients, the amplitude of low-frequency fluctuations in the right orbital part middle frontal gyrus was positively correlated with circFKBP8 and circMBNL1 expression. Furthermore, the interventional study of 53 MDD patients demonstrated that antidepressive treatment partly increased circFKBP8 expression and the change in expression of circFKBP8 was predictive of further reduced HAMD-24 scores. INTERPRETATION: whole-blood circFKBP8 and circMBNL1 may be potential biomarkers for the diagnosis of MDD, respectively, and circFKBP8 may show great potential for the antidepressive treatment.

Task-related functional magnetic resonance imaging-based neuronavigation for the treatment of depression by individualized repetitive transcranial magnetic stimulation of the visual cortex.

To determine whether repetitive transcranial magnetic stimulation (rTMS) of the visual cortex (VC) provides effective and well-tolerated treatment and whether magnetic resonance imaging (MRI) measures functional change of the VC as a biomarker of therapeutic effect in major depressive disorder (MDD), we performed a sham-controlled, double-blind, randomized, three-arm VC rTMS treatment study in 74 MDD patients. Neuronavigated rTMS (10 Hz, 90% of resting motor threshold, 1,600 pulses over 20 min twice per day) was performed over the VC for five days. Clinical outcome was measured by Hamilton Depression Rating Scale (HAMD-24) at days 0, 1, 3, 5 and after terminating rTMS, with follow-up at four weeks. MRI was measured at days 0 and 5. The individualized group exhibited the greatest change in HAMD-24 scores after VC rTMS for 5 days (F=5.53, P=0.005), which were maintained during follow-up period (F=4.22, P=0.016). All patients reported good tolerance. Changes in VC task-related functional MRI correlated with symptomatic reduction in the individualized group. Treatment reduced the initially abnormal increase in resting state functional connectivity from the VC to the pre/subgenual anterior cingulate cortex at day 5, especially in the individualized group. We demonstrated therapeutic potential and good tolerance of VC rTMS in MDD patients, indicated by biomarkers of fMRI measurement.

The reduced left hippocampal volume related to the delayed P300 latency in amnestic mild cognitive impairment.

BACKGROUND: Amnestic mild cognitive impairment (aMCI) is characterized by delayed P300 latency and reduced grey matter (GM) volume, respectively. The relationship between the features in aMCI is unclear. This study was to investigate the relationship between the altered P300 latency and the GM volume in aMCI. METHODS: Thirty-four aMCI and 34 well-matched normal controls (NC) were studied using electroencephalogram during a visual oddball task and scanned with MRI. Both tests were finished in the same day. RESULTS: As compared with the NC group, the aMCI group exhibited delayed P300 latency in parietal cortex and reduced GM volumes in bilateral temporal pole and left hippocampus/parahippocampal gyrus. A remarkable negative correlation was found between delayed P300 latency and reduced left hippocampal volume only in the aMCI group. Interestingly, the mediating analysis found P300 latency significantly mediated the association between right supramarginal gyrus volume and information processing speed indicated by Stroop Color and Word Test A scores. CONCLUSIONS: The association between delayed P300 latency and reduced left hippocampal volume in aMCI subjects suggests that reduced left hippocampal volume may be the potential structural basis of delayed P300 latency.

Identifying Plasma Biomarkers with high specificity for major depressive disorder: A multi-level proteomics study.

BACKGROUND: There are currently no objective diagnostic biomarkers for major depressive disorder (MDD) due to the biological complexity of the disorder. The existence of blood-based biomarkers with high specificity would be convenient for the clinical diagnosis of MDD. METHODS: A comprehensive plasma proteomic analysis was conducted in a highly homogeneous cohort [7 drug-naïve MDD patients and 7 healthy controls (HCs)], with bioinformatics analysis combined with machine learning used to screen candidate proteins. Verification of reproducibility and specificity was conducted in independent cohorts [60 HCs and 74 MDD, 42 schizophrenia (SZ) and 39 bipolar I disorder (BD-I) drug-naïve patients]. Furthermore, verification of consistency was accomplished by proteomic analysis of postmortem brain tissue from 16 MDD patients and 16 HCs. RESULTS: Levels of C-reactive protein (CRP), antithrombin III (ATIII), inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4) and vitamin D-binding protein (VDB) were significantly higher in MDD patients, both in the discovery cohort and independent replication cohort. In comparison with SZ or BD-I patients, two proteins (VDB and ITIH4) were significantly elevated only in MDD patients. In addition, increased VDB and ITIH4 were observed consistently in both plasma and postmortem dorsolateral prefrontal cortex tissues of MDD patients. Furthermore, a panel consisting of all four plasma proteins was able to distinguish MDD patients from HCs or SZ or BD-I patients with the highest accuracy. CONCLUSION: Plasma ITIH4 and VDB may be potential plasma biomarkers of MDD with high specificity. The four-protein panel is more suitable as a potential clinical diagnostic marker for MDD.

Value of peripheral neurotrophin levels for the diagnosis of depression and response to treatment: A systematic review and meta-analysis.

The neurotrophin hypothesis indicates that neurotrophic factors are important for the pathophysiology of major depressive disorder (MDD), with alterations in peripheral neurotrophin levels having potential clinical application for MDD. The present meta-analysis aimed to investigate the diagnostic value for MDD of peripheral neurotrophin levels in cross-sectional studies and the association between peripheral neurotrophin levels and the response to antidepressant treatment in longitudinal studies. Published studies in the PubMed and Web of Science databases were systematically searched up to February 2020. The search terms included depressive disorder, neurotrophic factor, serum/plasma and their synonyms. Human studies reporting on BDNF, GDNF, IGF-2, VEGF, NGF, FGF-2, and S100B levels in MDD patients were included. Data comparing MDD patients and healthy controls, and/or between responders and non-responders before and after antidepressant treatment were extracted. A random effects model was used to calculate standardized mean differences. A total of 177 original studies were identified, including 139 cross-sectional and 38 longitudinal studies. Significantly reduced BDNF and NGF levels and significantly elevated IGF-1, VEGF, and S100B levels were reported in MDD patients compared with healthy controls, while GDNF and FGF-2 levels were not significantly different. Furthermore, compared with non-responders, S100B levels at baseline and BDNF levels following treatment were significantly elevated in responders. In addition, there was a significantly elevated level of VEGF after treatment in responders only. In conclusions, alterations in peripheral neurotrophins levels were strongly associated with the biology and the treatment response of MDD. Further investigations are required to examine potential sources of heterogeneity.

Plasma Circular RNA DYM Related to Major Depressive Disorder and Rapid Antidepressant Effect Treated by Visual Cortical Repetitive Transcranial Magnetic Stimulation.

BACKGROUND: Reduced plasma circular RNA DYM (circDYM) has been detected in patients with major depressive disorder (MDD). Mechanism research has demonstrated that circDYM, acting as a microRNA-9 sponge, suppressed microglial activation by increasing Heat Shock Protein 90 ubiquitination, indicating that circDYM could be a potential biomarker of MDD. METHODS: Thirty-two normal controls (NCs) and 60 MDD patients were recruited. Enrolled patients were randomly allocated to the real or sham repetitive transcranial magnetic stimulation (rTMS) group, followed by continuous five-day visual cortical rTMS or sham treatment. All participants underwent multidimensional neuropsychological assessments and detection of circDYM levels. RESULTS: Initial scores on all emotional and psychosocial assessments in MDD were significantly different from those of NCs. As compared with the NC group, baseline plasma circDYM levels in MDD patients decreased remarkably (p=0.030) and showed significant positive correlations with the scores of the 24-item Hamilton Depression Rating Scale (r=0.318, p=0.031) and retardation subscale (r=0.323, p=0.029). The increase in circDYM was noteworthy after rTMS (p=0.006), while downregulation with no statistical significance was observed after sham treatment (p=0.170). LIMITATIONS: It was not estimated on the correlation between plasma circDYM levels and long-term efficacy of rTMS. The mechanism of upregulated circDYM expression in response to visual cortical rTMS remained unrevealed, and the sample size was relatively small. CONCLUSIONS: This study verified the reduced circDYM levels in MDD patients, and further determined the upregulated circDYM expression after rTMS treatment, revealing the potential of circDYM as a biomarker for MDD diagnosis and antidepressant effect of visual cortical rTMS.