Molecular basis underlying changes of brain entropy and functional connectivity in major depressive disorders after electroconvulsive therapy

BACKGROUNDMajor depressive disorder (MDD) tends to have a high incidence and high suicide risk. Electroconvulsive therapy (ECT) is currently a relatively effective treatment for MDD. However, the mechanism of efficacy of ECT is still unclear.AIMTo investigate the changes in the amplitude of low-frequency fluctuations in specific frequency bands in patients with MDD after ECT.METHODSTwenty-two MDD patients and fifteen healthy controls (HCs) were recruited to this study. MDD patients received 8 ECT sessions with bitemporal placement. Resting-state functional magnetic resonance imaging was adopted to examine regional cerebellar blood flow in both the MDD patients and HCs. The MDD patients were scanned twice (before the first ECT session and after the eighth ECT session) to acquire data. Then, the amplitude of low-frequency fluctuations (ALFF) was computed to characterize the intrinsic neural oscillations in different bands (typical frequency, slow-5, and slow-4 bands).RESULTSCompared to before ECT (pre-ECT), we found that MDD patients after the eighth ECT (post-ECT) session had a higher ALFF in the typical band in the right middle frontal gyrus, posterior cingulate, right supramarginal gyrus, left superior frontal gyrus, and left angular gyrus. There was a lower ALFF in the right superior temporal gyrus. Compared to pre-ECT values, the ALFF in the slow-5 band was significantly increased in the right limbic lobe, cerebellum posterior lobe, right middle orbitofrontal gyrus, and frontal lobe in post-ECT patients, whereas the ALFF in the slow-5 band in the left sublobar region, right angular gyrus, and right frontal lobe was lower. In contrast, significantly higher ALFF in the slow-4 band was observed in the frontal lobe, superior frontal gyrus, parietal lobe, right inferior parietal lobule, and left angular gyrus.CONCLUSIONOur results suggest that the abnormal ALFF in pre- and post-ECT MDD patients may be associated with specific frequency bands.

The hippocampus has been widely reported to be involved in the neuropathology of major depressive disorder (MDD). All the previous researches adopted group-level hippocampus subregions atlas to investigate abnormal functional connectivities in MDD in absence of capturing individual variability. In addition, the molecular basis of functional impairments of hippocampal subregions in MDD remains elusive. We aimed to reveal functional disruptions and recovery of individual hippocampal subregions in MDD patients before and after ECT and linked these functional connectivity differences to transcriptomic profiles to reveal molecular mechanism. we used group guided individual functional parcellation approach to define individual subregions of hippocampus for each participant. Resting-state functional connectivity (FC) analysis of individual hippocampal subregions was conducted to investigate functional disruptions and recovery in MDD patients before and after ECT. Spatial association between functional connectivity differences and transcriptomic profiles was employed to reveal molecular mechanism. MDD patients showed increased FCs of the left tail part of hippocampus with dorsolateral prefrontal cortex and middle temporal gyrus while decreased FC with primary visual cortex. These abnormal FCs in MDD patients were normalized after ECT. In addition, we found that functional disruptions of the left tail part of hippocampus in MDD were mainly related to synaptic signaling and transmission, ion transport, cell-cell signaling and neurogenesis. Our findings provide initial evidence for functional connectome disruption of individual hippocampal subregions and their molecular basis in MDD.

Individual large-scale functional network mapping for major depressive disorder with electroconvulsive therapy

Haematological markers of inflammation in major depressive disorder (MDD) patients with suicidal behaviour: A systematic review and meta-analysis.

Background: Major depressive disorder (MDD) patients are often associated with inhibition deficits in the visual cortex. Most previous research has focused on visual inhibition in MDD patients during acute and remission phases, with little research on first-episode and drug-naïve (FEDN) patients. To fill this gap, we psychophysically investigated the inhibitory process of visual motion in patients with FEDN MDD. Methods: Two psychophysical tasks: Center-Surround Suppression (CSS) and Motion Repulsion (MR) were utilized to investigate the presence of visual perceptual inhibition deficits in patients with FEDN MDD. We collected data from 74 patients with FEDN MDD and 68 healthy controls (HCs) matched for age, years of education, and gender. We also measured the Hamilton Depression Rating Scale, 17-item (HAMD-17) for each patient to assess the severity of depressive symptoms. Results: The results showed that CSS was significantly deteriorated in FEDN MDD patients (p=0.001), but it did not correlate with the HAMD score (p > 0.05). In addition, no significant differences were observed between the two groups of subjects in terms of gender, age, and education level (all p > 0.05). Analysis of two previously published datasets using the same CSS task involving MDD patients in different illness stages revealed that the levels of CSS reduction in our FEDN patients were also significantly distinguishable from those in acute and recovered MDD patients (all p < 0.01). This quantitative comparison indicates that CSS impairments are dynamic over the course of illness development. Moreover, the magnitudes of MR showed no significant differences between MDD patients and HCs (all p > 0.05). Conclusions: Our study was the first to demonstrate the deteriorated CSS in patients with FEDN MDD. Notably, inhibitory deficits in MDD are also highly specific, as MDD affects only the CSS, but not the MR. Therefore, the discrepancy between these two psychophysical tasks suggests CSS may serve as a feasible early marker in MDD. These findings offer new insights into the specific visual cortical deficits in patients with FEDN MDD. Limitation: The current study lacks imaging data to support the perceptual phenomenon we observed.

Amygdala is an important locus of dysfunction implicated in major depressive disorder(MDD). Aberrant amygdala networks(AN) had been reported in resting-state functional magnetic resonance imaging (rs-fMRI) study. The safety and efficacy of acupuncture treatment for MDD have been verified in previous clinical studies. This study is aimed to investigate whether acupuncture at GV20 could modulate the abnormal AN of patients with the first-episode, drug-naïve MDD by using rs-fMRI combined with functional connectivity (FC) method. Thirty MDD patient underwent 6-min rs-fMRI scans respectively before and after 20-min electro-acupuncture stimulate(EAS) at GV20. Twenty-nine healthy subjects underwent only a 6-min rs-fMRI scan. Based on the amygdala as the seed region, FC method was adopted to examine abnormal AN in patients by comparing with healthy subjects and to evaluate the influence of EAS on intrinsic connectivity within the AN in patients with MDD. Compared to healthy subjects, MDD patients had aberrant intrinsic AN which mainly showed increased FC between amygdala and hippocampus, precuneus, precentral gyrus and angular gyrus, as well as decreased FC between amygdala and orbital frontal cortex(OFC). Moreover, our results indicated that EAS at GV20 induced increased/decreased FC between amygdala and certain regions in MDD patients. In addition, the intrinsic amygdala FC within other certain brain regions in MDD patients were regulated by EAS at GV20. The abnormal AN of MDD patients could be modulated by EAS at GV20. Our findings may further provide the potential imaging evidence to support the modulatory mechanisms of acupuncture on MDD.

The role of distinct limbic areas in emotion regulation has been largely inferred from neuroimaging studies. Recently, the opportunity for intracranial recordings from limbic areas has arisen in patients undergoing deep brain stimulation (DBS) for neuropsychiatric disorders including major depressive disorder (MDD) and obsessive compulsive disorder (OCD). Here we test the hypothesis that distinct temporal patterns of local field potential (LFP) activity in the human limbic system reflect disease state and symptom severity in MDD and OCD patients. To this end, we recorded LFPs via implanted DBS electrodes from the bed nucleus of stria terminalis (BNST area) in 12 patients (5 OCD, 7 MDD) and from the subgenual cingulate cortex in 7 MDD patients (CG25 area). We found a distinct pattern of oscillatory activity with significantly higher α-power in MDD compared with OCD in the BNST area (broad α-band 8-14 Hz; P<0.01) and a similar level of α-activity in the CG25 area as in the BNST area in MDD patients. The mean α-power correlated with severity of depressive symptoms as assessed by the Beck depression inventory in MDD (n=14, r=0.55, P=0.042) but not with severity of obsessive compulsive symptoms in OCD. Here we show larger α-band activity in MDD patients compared with OCD recorded from intracranial DBS targets. Our results suggest that α-activity in the limbic system may be a signature of symptom severity in MDD and may serve as a potential state biomarker for closed loop DBS in MDD.

Objective To study the resting-state functional connectivity(FC) changes of anterior cingulate cortex(ACC) and amygdala in adolescent patients with medication-naive first-episode major depressive disorder(MDD). Methods Medication-naive first-episode MDD adolescents(n=30) and pair-wise matched healthy controls(HCs, n=29) underwent resting-state functional magnetic resonance images(fMRI). To study whether there were different in FC changes between amygdala and ACC and whole brain regions, and whether abnormal FC was related to clinical characteristics. Results Compared with HCs, the adolescent MDD patients showed decreased FC between the left amygdala and right thalamus(MNI x, y, z: 15, -21, 18)(t=-2.85)and increased FC between the left amygdala and the bilateral temporal middle gyrus, left occipital gyrus, right medial prefrontal cortex(MPFC)(MNI x, y, z: 9, 66, 15)(t=2.80). The right amygdale showed decreased FC with bilateral middle frontal gyrus, left caudate(MNI x, y, z: -15, -9, 21)(t=-2.53), right thalamus(MNI x, y, z: 12, -36, 12)(t=-3.01), right cerebellum(MNI x, y, z: 3, -84, -33)(t=-2.45) and increased FC with right temporal middle gyrus, right MPFC(MNI x, y, z: 6, 69, 12)(t=2.41). The left ACC showed decreased FC with left cerebellum(MNI x, y, z: 12, -87, -24)(t=-2.36), left frontal inferior triangle gyrus, right frontal inferior orbital gyrus and increased FC with right frontal middle orbital gyrus.The right ACC showed decreased FC with left caudate(MNI x, y, z: -15, 21, 6)(t=-2.29), right temporal middle gyrus, right MPFC(MNI x, y, z: 9, 54, 36)(t=-2.29), right frontal inferior orbital gyrus, right angular(MNI x, y, z: 45, -51, 21)(t=-3.01), left dorsolateral prefrontal cortex(MNI x, y, z: -21, 33, 36)(t=-2.61). The increased FC between the left amygdale and bilateral temporal middle gyrus showed positive correlation with the score of HAMD(r=0.50, P<0.05; r=0.45, P<0.05). And the FC between the right amygdale and right middle frontal gyrus was positive correlation with duration of disease(r=0.63, P<0.05). Conclusion There is widespread FC disorder in amygdala and ACC in adolescents patients with first-episode depression.Abnormal FC changes may be the neuropathological mechanism of depression. Key words: Adolescent major depressive disorder; Resting-state fMRI; Functional connectivity; Amygdala; Anterior cingulated cortex

Major depressive disorder (MDD) is a prevalent mental disorder characterized by impairments in affect, behaviour and cognition. Previous studies have indicated that the anterior cingulate cortex (ACC) may play an essential role in the pathophysiology of depression. In this study, we systematically identified changes in functional connectivity (FC) for ACC subdivisions that manifest in MDD and further investigated the relationship between these changes and the clinical symptoms of depression. Sub-regional ACC FC was estimated in 41 first-episode medication-naïve MDD patients compared to 43 healthy controls. The relationships between depressive symptom severity and aberrant FC of ACC subdivisions were investigated. In addition, we conducted a meta-analysis to generate the distributions of MDD-related abnormal regions from previously reported results and compared them to FC deficits revealed in this study. In MDD patients, the subgenual and perigenual ACC demonstrated decreased FC with the posterior regions of the default network (DN), including the posterior inferior parietal lobule and posterior cingulate cortex. FC of these regions was negatively associated with the Automatic Thoughts Questionnaire scores and largely overlapped with previously reported abnormal regions. In addition, reduced FC between the caudal ACC and precuneus was negatively correlated with the Hamilton Anxiety Scale scores. We also found increased FC between the rostral ACC and dorsal medial prefrontal cortex. Our findings confirmed that functional interaction changes in different ACC sub-regions are specific and associated with distinct symptoms of depression. Our findings provide new insights into the role of ACC sub-regions and DN in the pathophysiology of MDD.

Background: Major depressive disorder (MDD) has demonstrated abnormalities of static intrinsic brain activity measured by amplitude of low-frequency fluctuation (ALFF). Recent studies regarding the resting-state functional magnetic resonance imaging (rs-fMRI) have found the brain activity is inherently dynamic over time. Little is known, however, regarding the temporal dynamics of local neural activity in MDD. Here, we investigated whether temporal dynamic changes in spontaneous neural activity are influenced by MDD.Methods: We recruited 81 first-episode, drug-naive MDD patients and 64 age-, gender-, and education-matched healthy controls who underwent rs-fMRI. A sliding-window approach was then adopted for the estimation of dynamic ALFF (dALFF), which was used to measure time-varying brain activity and then compared between the two groups. The relationship between altered dALFF variability and clinical variables in MDD patients was also analyzed.Results: MDD patients showed increased temporal variability (dALFF) mainly focused on the bilateral thalamus, the bilateral superior frontal gyrus, the right middle frontal gyrus, the bilateral cerebellum posterior lobe, and the vermis. Furthermore, increased dALFF variability values in the right thalamus and right cerebellum posterior lobe were positively correlated with MDD symptom severity.Conclusions: The overall results suggest that altered temporal variability in corticocerebellar–thalamic–cortical circuit (CCTCC), involved in emotional, executive, and cognitive, is associated with drug-naive, first-episode MDD patients. Moreover, our study highlights the vital role of abnormal dynamic brain activity in the cerebellar hemisphere associated with CCTCC in MDD patients. These findings may provide novel insights into the pathophysiological mechanisms of MDD.

Biogenetic temperament and character in insomnia and depression

Multi-modal MRI measures reveal sensory abnormalities in major depressive disorder patients: A surface-based study

Approximately two-thirds of major depressive disorder (MDD) patients have pain, which exacerbates the severity of depression. Electroconvulsive therapy (ECT) is an efficacious treatment that can alleviate depressive symptoms; however, treatment for pain and the underlying neural substrate is elusive. We enrolled 34 patients with MDD and 33 matched healthy controls to complete clinical assessments and neuroimaging scans. MDD patients underwent second assessments and scans after ECT. We defined a pain-related network with a published meta-analysis and calculated topological patterns to reveal topologic alterations induced by ECT. Using the amplitude of low-frequency fluctuations (ALFFs), we probed local function aberrations of pain-related circuits in MDD patients. Subsequently, we applied gray matter volume (GMV) to reveal structural alterations of ECT relieving pain. The relationships between functional and structural aberrations and pain were determined. ECT significantly alleviated pain. The neural mechanism based on pain-related circuits indicated that ECT weakened the circuit function (ALFF: left amygdala and right supplementary motor area), while augmenting the structure (GMV: bilateral amygdala/insula/hippocampus and anterior cingulate cortex). The topologic patterns became less efficient after ECT. Correlation analysis between the change in pain and GMV had negative results in bilateral amygdala/insula/hippocampus. Similarity, there was a positive correlation between a change in ALFF in the left amygdala and improved clinical symptoms. ECT improved pain by decreasing brain local function and global network patterns, while increasing structure in pain-related circuits. Functional and structural alterations were associated with improvement in pain.

The relationship between age-related changes in brain structural connectivity (SC) and functional connectivity (FC) with cognition is not well understood. Furthermore, it is not clear whether cognition is represented via a similar spatial pattern of FC and SC or instead is mapped by distinct sets of distributed connectivity patterns. To this end, we used a longitudinal, within-subject, multimodal approach aiming to combine brain data from diffusion-weighted MRI (DW-MRI), and functional MRI (fMRI) with behavioral evaluation, to better understand how changes in FC and SC correlate with changes in cognition in a sample of older adults. FC and SC measures were derived from the multimodal scans acquired at two time points. Change in FC and SC was correlated with 13 behavioral measures of cognitive function using Partial Least Squares Correlation (PLSC). Two of the measures indicate an age-related change in cognition and the rest indicate baseline cognitive performance. FC and SC—cognition correlations were expressed across several cognitive measures, and numerous structural and functional cortical connections, mainly cingulo-opercular, dorsolateral prefrontal, somatosensory and motor, and temporo-parieto-occipital, contributed both positively and negatively to the brain-behavior relationship. Whole-brain FC and SC captured distinct and independent connections related to the cognitive measures. Overall, we examined age-related function-structure associations of the brain in a comprehensive and integrated manner, using a multimodal approach. We pointed out the behavioral relevance of age-related changes in FC and SC. Taken together, our results highlight that the heterogeneity in distributed FC and SC connectivity patterns provide unique information about the variable nature of healthy cognitive aging.

Changes in regional brain activity and functional connectivity (FC) in patients with neurogenic detrusor overactivity (NDO) following spinal cord injury (SCI) remain unclear. This study used resting-state functional magnetic resonance imaging (fMRI) to investigate regional brain activity and FC in NDO patients after SCI. Resting-state fMRI scans were obtained from 20 NDO patients after SCI and 20 healthy controls (HCs). Regional brain activity was measured using regional homogeneity (ReHo). Subsequently, a seed-based whole-brain FC analysis was performed using the regions with significantly different ReHo as seeds. Partial correlation analysis was conducted to examine the relationship between FC values and clinical scores in the NDO patients with SCI. Compared to HC, patients with NDO exhibited significantly decreased ReHo in the right medial frontal gyrus (MFG). Furthermore, compared to HC, NDO patients demonstrated stronger FC between the seed (right MFG) and voxels in the left pyramis, right cerebellum posterior lobe, and left middle temporal gyrus. Weaker FC was observed between the seed (right MFG) and voxels in the right paracentral lobule. Correlation analyses revealed that the Overactive Bladder Symptom Score and urgency urinary incontinence scores were positively correlated with FC values between the right MFG and the left pyramis. SCI-related NDO patients exhibit abnormalities in both regional brain activity and FC, with supraspinal connectivity deviation extent associated with the severity of lower urinary tract symptom. This study contributes to a better understanding of the potential supraspinal neural mechanisms underlying SCI-related NDO.