Reward deficits and associated striatal circuitry disturbances have been implicated in the onset and progression of major depressive disorder (MDD). However, no studies have been conducted to ...investigate how the striatal circuitry changes during standard antidepressant, which is important for development of novel and targeted treatments for MDD. We examined the seed‐to‐whole‐brain functional connectivity (FC) for six striatal subregions based on resting‐state fMRI data of 23 MDD patients before and after 8‐week duloxetine, a serotonin, and noradrenaline reuptake inhibitor. Twenty‐three healthy controls (HCs) were also scanned twice with an 8‐week interval. After the analysis of covariance, we observed significant group‐by‐time interaction on FC of the dorsal caudate (DC), ventral striatum (VS), and putamen seeds. Post hoc analyses revealed that the FC between several right striatal seeds and left superior frontal gyrus (SFG), between right DC and left precuneus, between right superior VS and left inferior parietal lobe, were significantly higher in MDD patients compared to HCs at baseline and were reduced after treatment. Conversely, the FC between right inferior VS and left cerebellum was lower in MDD patients and was increased after treatment. Patients with larger reduction in right superior VS—left SFG FC exhibited larger alleviation of rumination. These findings suggest that duloxetine modulates the striatal FC with dorsolateral prefrontal cortex, posterior default mode network, and cerebellum, and partly, these changes underlie symptomatic improvement. This study adds to our understanding of antidepressant mechanism and future therapeutic development might benefit from considering these striatal circuitry as potential targets.
Previous neuroimaging studies have revealed abnormal functional connectivity of brain networks in patients with major depressive disorder (MDD), but findings have been inconsistent. A recent big‐data ...study found abnormal intrinsic functional connectivity within the default mode network in patients with recurrent MDD but not in first‐episode drug‐naïve patients with MDD. This study also provided evidence for reduced default mode network functional connectivity in medicated MDD patients, raising the question of whether previously observed abnormalities may be attributable to antidepressant effects. The present study (ClinicalTrials.gov identifier: NCT03294525) aimed to disentangle the effects of antidepressant treatment from the pathophysiology of MDD and test the medication normalization hypothesis. Forty‐one first‐episode drug‐naïve MDD patients were administrated antidepressant medication (escitalopram or duloxetine) for 8 weeks, with resting‐state functional connectivity compared between posttreatment and baseline. To assess the replicability of the big‐data finding, we also conducted a cross‐sectional comparison of resting‐state functional connectivity between the MDD patients and 92 matched healthy controls. Both Network‐Based Statistic analyses and large‐scale network analyses revealed intrinsic functional connectivity decreases in extensive brain networks after treatment, indicating considerable antidepressant effects. Neither Network‐Based Statistic analyses nor large‐scale network analyses detected significant functional connectivity differences between treatment‐naïve patients and healthy controls. In short, antidepressant effects are widespread across most brain networks and need to be accounted for when considering functional connectivity abnormalities in MDD.
The present study aimed to disentangle the effects of antidepressant treatment from the pathophysiology of MDD and test the medication normalization hypothesis. Both Network‐Based Statistic analyses and large‐scale network analyses revealed intrinsic functional connectivity decreases in extensive brain networks after treatment, while no significant functional connectivity differences were found between treatment‐naïve patients and healthy controls. These results indicate that antidepressant effects are widespread across most brain networks and need to be accounted for when considering functional connectivity abnormalities in MDD.
Exploring the neural basis related to different mood states is a critical issue for understanding the pathophysiology underlying mood switching in bipolar disorder (BD), but research has been scarce ...and inconsistent.
Resting-state functional magnetic resonance imaging data were acquired from 162 patients with BD: 33 (hypo)manic, 64 euthymic, and 65 depressive, and 80 healthy controls (HCs). The differences of large-scale brain network functional connectivity (FC) between the four groups were compared and correlated with clinical characteristics. To validate the generalizability of our findings, we recruited a small longitudinal independent sample of BD patients (n = 11). In addition, we examined topological nodal properties across four groups as exploratory analysis.
A specific strengthened pattern of network FC, predominantly involving the default mode network (DMN), was observed in (hypo)manic patients when compared with HCs and bipolar patients in other mood states. Longitudinal observation revealed an increase in several network FCs in patients during (hypo)manic episode. Both samples evidenced an increase in the FC between the DMN and ventral attention network, and between the DMN and limbic network (LN) related to (hypo)mania. The altered network connections were correlated with mania severity and positive affect. Bipolar depressive patients exhibited decreased FC within the LN compared with HCs. The exploratory analysis also revealed an increase in degree in (hypo)manic patients.
Our findings identify a distributed pattern of large-scale network disturbances in the unique context of (hypo)mania and thus provide new evidence for our understanding of the neural mechanism of BD.
The evaluation tools included HAMD-17 total scores, HAMA total scores, and Clinical Global Impressions Severity Subscale (CGI-S) score. ...short form-12 (SF-12) physical component score (PCS) and ...mental component score (MCS) were used to assess the quality of life of these patients. ...230 patients completed the 6-week follow-up, including 128 patients with early-improvement and 102 early-unimproved patients. According to the logistic regression analysis, the results revealed that the combination with sedative-hypnotic drugs was a significant predictor of early improvement in week 2. Benzodiazepines are primarily used as a sedative-hypnotics in patients with MDD to alleviate anxiety symptom and insomnia, and they might contribute to the response to antidepressants in the first two weeks because they produce a faster onset of effect on anxiety symptoms than antidepressants alone. ...it may be justifiable to combine benzodiazepines as a short-term treatment in patients with MDD and high-level anxiety.
Summary
Objective
Growing evidence has implicated dysfunction of the thalamus and its projection cortical targets in depression. However, the anatomical specificity of thalamo‐cortical connectivity ...in major depressive disorder (MDD) remains unknown due to the regional heterogeneity of the thalamus and limited methods to examine this.
Methods
Resting‐state fMRI was collected on 70 MDD patients and 70 healthy controls. The thalamus was parcellated based on connectivity with six predefined cortical regions of interest (ROIs). The segmented thalamic nuclei were used as seeds to map connectivity with the rest of the whole brain. The cortical‐to‐thalamus connectivity values and thalamus‐based connectivity maps were compared between groups.
Results
The cortical ROIs demonstrated correlations with spatially distinct zones within the thalamus. We found a trend toward reduced parietal ROI‐to‐thalamus connectivity in MDD. Importantly, MDD patients demonstrated reduced connectivity between prefrontal and parietal thalamus ROIs and bilateral middle frontal gyrus (MFG) and the right posterior default mode network (DMN) and between the prefrontal and motor thalamus ROIs and lateral temporal regions. Conversely, increased connectivity emerged between the motor thalamus ROI and right MFG and right medial frontal gyrus/anterior cingulate; between motor/somatosensory thalamus ROIs and right posterior DMN; between prefrontal/somatosensory thalamus ROIs and cerebellum; and between the parietal thalamus ROI and left insula.
Conclusions
This study is the first to examine the anatomical specificity of thalamo‐cortical connectivity disturbances in MDD. Subjects with MDD demonstrated altered thalamo‐cortical connectivity characterized by a complex pattern of region‐dependent hypo‐ or hyperconnectivity. We therefore speculate that selectively modulating the connectivity of thalamo‐cortical circuitry may be a potential novel therapeutic mechanism for MDD.
Quantization has been widely employed in analog-to-digital conversion (ADC) for the acquisition of digital data, which are further utilized for prognostics. However, quantization errors are ...inevitable during ADC, resulting in bias in the subsequent prognosis results. Compared to the numerous researches on prognosis considering measurement noises, slight attention has been paid on remaining useful life (RUL) for degrading devices incorporating quantization errors. In this study, a Wiener-process-based model incorporating mixed random noise is utilized to describe the degradation process involving quantization errors. In order to mitigate the impact of quantization errors, a parameter identification approach and a degradation state estimation method are proposed, which integrate maximum likelihood estimation, particle filter, and Bayesian inference. Subsequently, the results of RUL prediction with and without considering quantization errors are derived, respectively. Finally, numerical examples and a case study of the control moment gyroscopes (CMG) and batteries are provided to demonstrate the proposed method.
•Prognosis for stochastic degrading devices incorporating quantization is investigated.•A prognosis method involving both measurement and quantization errors is proposed.•Offline and online parameters identification methods are presented.•The PDFs of the RUL prediction incorporating quantization are derived.
A recent study revealed disrupted topological organization of whole-brain networks in patients with major depressive disorder (MDD); however, these results were mostly driven by recurrent MDD ...patients, rather than first-episode drug-naïve (FEDN) patients. Furthermore, few longitudinal studies have explored the effects of antidepressant therapy on the topological organization of whole-brain networks.
We collected clinical and neuroimaging data from 159 FEDN MDD patients and 152 normal controls (NCs). A total of 115 MDD patients completed an eight-week antidepressant treatment procedure. Topological features of brain networks were calculated using graph theory-based methods and compared between FEDN MDD patients and NCs, as well as before and after treatment.
Decreased global efficiency, local efficiency, small-worldness, and modularity were found in pretreatment FEDN MDD patients compared with NCs. Nodal degrees, betweenness, and efficiency decreased in several networks compared with NCs. After antidepressant treatment, the global efficiency increased, while the local efficiency, the clustering coefficient of the network, the path length, and the normalized characteristic path length decreased. Moreover, the reduction rate of the normalized characteristic path length was positively correlated with the reduction rate of retardation factor scores.
The interaction effects of groups and time on the topological features were not explored because of absence of the eighth-week data of NC group.
The topological architecture of functional brain networks is disrupted in FEDN MDD patients. After antidepressant therapy, the global efficiency shifted toward recovery, but the local efficiency deteriorated, suggesting a correlation between recovery of retardation symptoms and global efficiency.
•The topological architecture of functional brain networks was disrupted in first-episode drug-naïve MDD patients.•Nodal degrees, betweenness, and efficiency decreased in several networks compared to normal controls.•After antidepressant therapy, the global efficiency shifted toward recovery, suggesting recovery of retardation symptom.
The early postnatal stage is a critical period of hippocampal neurodevelopment and also a period of high vulnerability to adverse life experiences. Recent evidence suggests that nectin‐3, a cell ...adhesion molecule, mediates memory dysfunction and dendritic alterations in the adult hippocampus induced by postnatal stress. But it is unknown whether postnatal nectin‐3 reduction alone is sufficient to alter hippocampal structure and function in adulthood. Here, we down regulated hippocampal expression of nectin‐3 and its heterophilic adhesion partner nectin‐1, respectively, from early postnatal stage by injecting adeno‐associated virus (AAV) into the cerebral lateral ventricles of neonatal mice (postnatal day 2). We found that suppression of nectin‐3, but not nectin‐1, expression from the early postnatal stage impaired hippocampus‐dependent novel object recognition and spatial object recognition in adult mice. Moreover, AAV‐mediated nectin‐3 knockdown significantly reduced dendritic complexity and spine density of pyramidal neurons throughout the hippocampus, whereas nectin‐1 knockdown only induced the loss of stubby spines in CA3. Our data provide direct evidence that nectins, especially nectin‐3, are necessary for postnatal hippocampal development of memory functions and structural integrity.
Calbindin modulates intracellular Ca2+ dynamics and synaptic plasticity. Reduction of hippocampal calbindin levels has been implicated in early-life stress-related cognitive disorders, but it remains ...unclear how calbindin in distinct populations of hippocampal neurons contributes to stress-induced memory loss. Here we report that early-life stress suppressed calbindin levels in CA1 and dentate gyrus (DG) neurons, and calbindin knockdown in adult CA1 or DG excitatory neurons mimicked early-life stress-induced memory loss. In contrast, calbindin knockdown in CA1 interneurons preserved long-term memory even after an acute stress challenge. These results indicate that the dysregulation of calbindin in hippocampal excitatory, but not inhibitory, neurons conveys susceptibility to stress-induced memory deficits. Moreover, calbindin levels were downregulated by early-life stress through the corticotropin-releasing hormone receptor 1-nectin3 pathway, which in turn reduced inositol monophosphatase levels. Our findings highlight calbindin as a molecular target of early-life stress and an essential substrate for memory.
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•Early-life stress suppresses calbindin levels in the adult mouse hippocampus•Calbindin knockdown in CA1 or DG excitatory neurons impairs spatial memory•Calbindin knockdown in CA1 interneurons preserves long-term spatial memory•Stress downregulates calbindin levels via a corticotropin-releasing hormone receptor
Li et al. demonstrate that early-life stress suppresses hippocampal calbindin levels through the CRHR1-nectin3 system. Reduced calbindin levels in hippocampal excitatory, but not inhibitory, neurons mediate stress-induced spatial memory impairment.
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