Altered resting-state functional connectivity (rsFC) has been noted in large-scale functional networks in attention-deficit/hyperactivity disorder (ADHD). However, identifying consistent abnormalities of functional networks is difficult due to varied methods and results across studies. To integrate rsFC alterations and search for coherent patterns of intrinsic functional network impairments in ADHD, this research conducts a coordinate-based meta-analysis of voxel-wise seed-based rsFC studies comparing rsFC between ADHD patients and healthy controls. A total of 25 datasets from 21 studies including 700 ADHD patients and 580 controls were analyzed. We extracted the coordinates of seeds and between-group effects. Each seed was then categorized into a seed-network by its location within priori 7-network parcellations. Then, pooled meta-analyses were conducted for the default mode network (DMN), frontoparietal network (FPN) and affective network (AN) separately, but not for the ventral attention network (VAN), dorsal attention network (DAN), somatosensory network (SSN) and visual network due to a lack of primary studies. The results showed that ADHD was characterized by hyperconnectivity between the FPN and regions of the DMN and AN as well as hypoconnectivity between the FPN and regions of the VAN and SSN. These findings not only support the triple-network model of pathophysiology associated with ADHD but also extend this model by highlighting the involvement of the SSN and AN in the mechanisms of network interactions that may account for motor hyperactivity and impulsive symptoms.

BackgroundAlthough dysfunction of amygdala-related circuits is centrally implicated in major depressive disorder (MDD), little is known about how this dysfunction differs between adult and adolescent MDD patients.MethodsVoxel-wise meta-analyses of abnormal amygdala resting-state functional connectivity (rsFC) were conducted in adult and adolescent groups separately, followed by a quantitative meta-analytic comparison of the two groups.FindingsNineteen studies that included 665 MDD patients (392 adults and 273 adolescents) and 546 controls (341 adults and 205 adolescents) were identified in the current study. Adult-specific abnormal amygdala rsFC in MDD patients compared to that in controls was located mainly within the affective network, including increased connectivity with the right hippocampus/parahippocampus and bilateral ventromedial orbitofrontal cortex and decreased connectivity with the bilateral insula and the left caudate. Adolescent MDD patients specifically demonstrated decreased amygdala rsFC within the cognitive control network encompassing the left dorsolateral prefrontal cortex and imbalanced amygdala rsFC within the default mode network, which was manifested as hyperconnectivity in the right precuneus and hypoconnectivity in the right inferior temporal gyrus. Additionally, direct comparison between the two groups showed that adult patients had strengthened amygdala rsFC with the right hippocampus/parahippocampus as well as the right inferior temporal gyrus and weakened amygdala rsFC with the bilateral insula compared to that in adolescent patients.InterpretationDistinct impairments of amygdala-centered rsFC in adult and adolescent patients were related to different network dysfunctions in MDD. Adult-specific amygdala rsFC dysfunction within the affective network presumably reflects emotional dysregulation in MDD, whereas adolescent-specific amygdala rsFC abnormalities in networks involved in cognitive control might reflect the neural basis of affective cognition deficiency that is characteristic of adolescent MDD.FundThis study was supported by a grant from the National Natural Science Foundation of China (81671669) and by a Sichuan Provincial Youth Grant (2017JQ0001).

Background: Bipolar disorder (BD) is a mental disorder characterized by mood fluctuations between an acute episodic state of either mania or depression and a clinically remitted state. Dysfunction of large-scale intrinsic brain networks has been demonstrated in this disorder, but it remains unknown whether those network alterations are related to different states. Methods: In the present study, we performed a meta-analysis of whole-brain seed-based resting-state functional connectivity (rsFC) studies in BD patients to compare the intrinsic function of brain networks between episodic and remitted states. Thirty-nine seed-based voxel-wise rsFC datasets from thirty publications (1047 BD patients vs 1081 controls) were included in the meta-analysis. Seeds were categorized into networks by their locations within a priori functional networks. Seed-based d mapping analysis of between-state effects identified brain systems in which different states were associated with increased connectivity or decreased connectivity within and between each seed network. Findings: We found that BD patients presented decreased connectivity within the affective network (AN) in acute episodes but not in the remitted state of the illness. Similar decreased connectivity within the defaultmode network (DMN) was also found in the acute state, but it was replaced by increased connectivity in the remitted state. In addition, different patterns of between-network dysconnectivity were observed between the acute and remitted states. Interpretation: This study is the first to identify different patterns of intrinsic function in large-scale brain networks between the acute and remitted states of BD through meta-analysis. The findings suggest that a shift in network function between the acute and remitted states may be related to distinct emotional and cognitive dysfunctions in BD, which may have important implications for identifying clinically relevant biomarkers to guide alternative treatment strategies for BD patients during active episodes or remission.

Previous resting-state functional magnetic resonance imaging (rs-fMRI) studies of obsessive-compulsive disorder (OCD) have facilitated our understanding of OCD pathophysiology based on its intrinsic activity. However, whether the group difference derived from univariate analysis could be useful for informing the diagnosis of individual OCD patients remains unclear. We aimed to apply multivariate pattern analysis of different rs-fMRI parameters to distinguish drug-naive patients with OCD from healthy control subjects (HCS). Fifty-four drug-naive OCD patients and 54 well-matched HCS were recruited. Four different rs-fMRI parameter maps, including the amplitude of low-frequency fluctuations (ALFF), fractional amplitude of low-frequency fluctuations (fALFF), regional homogeneity (ReHo) and functional connectivity strength (FCS), were calculated. Training of a support vector machine (SVM) classifier using rs-fMRI maps produced voxelwise discrimination maps. Overall, the classification accuracies were acceptable for the four rs-fMRI parameters. Excellent performance was achieved when ALFF maps were employed (accuracy, 95.37%, p < 0.01), good performance was achieved by using ReHo maps, weaker performance was achieved by using fALFF maps, and fair performance was achieved by using FCS maps. The brain regions showing the greatest discriminative power included the prefrontal cortex, anterior cingulate cortex, precentral gyrus, and occipital lobes. The application of SVM to rs-fMRI features may provide potential power for OCD classification.

The hippocampus and amygdala are important structures in the posttraumatic stress disorder (PTSD); however, the exact relationship between these structures and stress or PTSD remains unclear. Moreover, they consist of several functionally distinct subfields/subregions that may serve different roles in the neuropathophysiology of PTSD. Here we present a subregional profile of the hippocampus and amygdala in 145 survivors of a major earthquake and 56 non‐traumatized healthy controls (HCs). We found that the bilateral hippocampus and left amygdala were significantly smaller in survivors than in HCs, and there was no difference between survivors with (n = 69) and without PTSD (trauma‐exposed controls [TCs], n = 76). Analyses revealed similar results in most subfields/subregions, except that the right hippocampal body (in a head‐body‐tail segmentation scheme), right presubiculum, and left amygdala medial nuclei (Me) were significantly larger in PTSD patients than in TCs but smaller than in HCs. Larger hippocampal body were associated with the time since trauma in PTSD patients. The volume of the right cortical nucleus (Co) was negatively correlated with the severity of symptoms in the PTSD group but positively correlated with the same measurement in the TC group. This correlation between symptom severity and Co volume was significantly different between the PTSD and TCs. Together, we demonstrated that generalized smaller volumes in the hippocampus and amygdala were more likely to be trauma‐related than PTSD‐specific, and their subfields/subregions were distinctively affected. Notably, larger left Me, right hippocampal body and presubiculum were PTSD‐specific; these could be preexisting factors for PTSD or reflect rapid posttraumatic reshaping.

Repetitive transcranial magnetic stimulation (rTMS) has been widely used as an alternative treatment for obsessive-compulsive disorder (OCD). However, the most effective rTMS parameters, such as the targets and stimulation frequencies, remain controversial. Therefore, we aimed to compare and rank the efficacy and tolerability of different rTMS strategies for OCD treatment. We searched five electronic databases from the date of their inception to March 25, 2020. Pairwise meta-analyses and network meta-analyses were performed to synthesize data. We assessed the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework. Twenty-two eligible randomized controlled trials (RCTs) were included. For efficacy, low-frequency (LF) rTMS over the dorsolateral prefrontal cortex (DLPFC; mean difference (MD) 6.34, 95% credible interval (CrI) 2.12–10.42) and supplementary motor area (MD 4.18, 95% CrI 0.83–7.62), and high-frequency rTMS over the DLPFC (MD 3.75, 95% CrI 1.04–6.81) were more effective than sham rTMS. Regarding tolerability, all rTMS treatment strategies were similar to the sham rTMS. The estimated ranking probabilities of treatments showed that LF-rTMS over the DLPFC might be the most effective intervention among all rTMS strategies. However, the quality of evidence regarding efficacy was evaluated as very low. Current evidence suggested a marginal advantage for LF-rTMS over the DLPFC on OCD treatment. High-quality RCTs with low selection and performance bias are needed to further verify the efficacy of specific rTMS strategies for the OCD treatment.

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Background/Aims: Erinacine, which is extracted from the medicinal mushroom Hericium erinaceus, is known to play anticancer roles in human cancers. The following study aims to investigate the role of erinacine in the opening of the mitochondrial permeability transition pore (MPTP) in hepatocellular carcinoma (HCC) through the PI3K/Akt/GSK-3β signaling pathway and highlights the applicability of erinacine in HCC treatments. Methods: HCC and paracancerous tissues were obtained from 85 HCC patients who’ve undergone surgical resection. Immunohistochemistry was adopted to detect positive expression of PI3K, Akt, and GSK-3β. Treatment of HepG-2 with LY294002 (an inhibitor of the PI3K/Akt/GSK-3β signaling pathway) and different concentration of erinacine was performed to determine the involvement of LY294002 in erinacine action. The expressions of PI3K, Akt, GSK-3β, CyclinD1, Vimentin, β-catenin, Bcl-2, E-cadherin, Bax, and caspase-9 were determined by RT-qPCR and Western blot analysis. Cell viability, colony formation rate, migration, invasion, cycle, and apoptosis were detected by MTT, colony formation, wound healing assay, Transwell assay, and flow cytometry, respectively. The size and weight of xenograft tumors were observed in nude mice. Mitochondrial membrane potential in HepG-2 was determined using laser scanning confocal microscopy following JC-1 staining. Mitochondrial Ca²⁺ indicator Rhod-2, AM was used to detect the changes of mitochondrial Ca²⁺, while western blot analysis was employed to detect the presence levels of cytochrome C (cyt-C). Results: The results revealed that PI3K, Akt, and GSK-3β were up-regulated in HCC tissues. Erinacine or LY294002 led to a decrease in mitochondrial membrane potential, increase in intracellular mitochondrial Ca²⁺, and the release of cyt-C in mitochondria. In addition, Erinacine was found to decrease the mitochondrial membrane potential, expression of PI3K, Akt, GSK-3β, CyclinD1, Vimentin, β-catenin, and Bcl-2, cell proliferation, colony formation ability, migration, invasion, and xenograft tumor size, while E-cadherin, Bax, and caspase-9 expression, and cell apoptosis were elevated in a dose-dependent manner. Erinacine also stimulated the effects of LY294002 on the HCC. Following the addition of 500 μM Erinacine and MPTP opening inhibitor CsA, we found that the mitochondrial membrane potential level increased, while mitochondrial Ca2+ and Cyt-C decreased from the mitochondria. Conclusion: The results from the study demonstrated that erinacine induced MPTP opening, facilitates the release of cyt-C, and inhibited cell proliferation, migration, and invasion, while it promotes apoptosis by inactivating the PI3K/Akt/GSK-3β signaling pathway, preventing the progression of HCC.