A common variant of the NOTCH4 gene modulates functional connectivity of the occipital cortex and its relationship with schizotypal traits.

BACKGROUND: Schizotypal traits are considered as inheritable traits and the endophenotype for schizophrenia. A common variant in the NOTCH4 gene, rs204993, has been linked with schizophrenia, but the neural underpinnings are largely unknown. METHODS: In present study, we compared the differences of brain functions between different genotypes of rs204993 and its relationship with schizotypal traits among 402 Chinese Han healthy volunteers. The brain function was evaluated with functional connectivity strength (FCS) using the resting-state functional magnetic resonance image(rs-fMRI). The schizotypal traits were measured by the schizotypal personality questionnaire (SPQ). RESULTS: Our results showed that carriers with the AA genotype showed reduced FCS in the left occipital cortex when compared with carriers with the AG and GG genotypes, and the carriers with the AG genotype showed reduced FCS in the left occipital cortex when compared with carriers with the GG genotype. The FCS values in the left occipital lobe were negatively associated with the SPQ scores and its subscale scores within the carriers with the GG genotype, but not within the carriers with AA or AG genotype. CONCLUSION: Our results suggested that the common variant in the NOTCH4 gene, rs204993, modulates the function of the occipital cortex, which may contribute to schizotypal traits. These findings provide insight for genetic effects on schizotypal traits and its potential neural substrate.

Functional plasticity of the dorsomedial prefrontal cortex in depression reorganized by electroconvulsive therapy: Validation in two independent samples.

Previous studies have implied a key role for the prefrontal cortex in the antidepressive effect of electroconvulsive therapy (ECT). However, there is still ubiquitous inconsistency across these studies, partly due to several confounding effects induced by the use of different samples. Studies with independent samples are necessary for validations to minimize confounding effects. In the current study, resting-state magnetic resonance imaging of 84 participants was collected using two scanners and two types of scanning parameters. One sample consisted of 28 patients and 23 healthy controls, and the other sample consisted of 33 patients. The local activity (indexed by the amplitude of low-frequency fluctuations) and functional connectivity were used to examine functional plasticity in the two independent samples before and after ECT. Both samples showed increased local activity of the dorsomedial prefrontal cortex (DMPFC) and enhanced connectivity of the DMPFC with the posterior cingulate cortex (PCC) following ECT. The enhanced connectivity between the DMPFC and PCC was positively associated with clinical improvement for both samples. These findings provide relatively strong evidence to support the functional plasticity of the dorsomedial prefrontal cortex and reorganization by ECT. The functional plasticity of the DMPFC-PCC may underlie the antidepressive effect of ECT.

Resting-State Functional Connectivity Between Centromedial Amygdala and Insula as Related to Somatic Symptoms in Depressed Patients: A Preliminary Study.

OBJECTIVE: Somatic symptoms are prevalent in patients with depression. The centromedial amygdala (CMA) is a key brain region that mediates autonomic and somatic responses. Abnormal function in the CMA may contribute to the development of somatic symptoms in depressed patients. METHODS: We compared the resting-state functional connectivity (RSFC) based on the seed of the left and right CMA between 37 patients with depression and 30 healthy controls. The severity of depressive and somatic symptoms was assessed using the Hamilton Depression Rating Scale (HDRS) and the 15-item somatic symptom severity scale of the Patient Health Questionnaire (PHQ-15). Correlation analysis was performed to investigate the relationship between the RSFC and clinical variables (HDRS and PHQ-15) in depressed patients. RESULTS: Compared with healthy controls, patients with depression exhibited decreased RSFC between the CMA and insula, and superior temporal gyrus. In addition, functional connectivity between the left CMA and left insula was negatively correlated with PHQ-15 (r = -0.348, p = .037) in depressed patients. No significant relation was found between the RSFC and HDRS in depressed patients. CONCLUSIONS: Functional connectivity between the CMA and insula is reduced in depressive patients, which is associated with the severity of somatic symptoms. Our findings may provide a potential neural substrate to interpret the co-occurrence of depression with somatic symptoms.

Reviving Bistable Perception in Patients With Depression by Decreasing the Overestimation of Prior Precision.

Slower perceptual alternations, a notable perceptual effect observed in psychiatric disorders, can be alleviated by antidepressant therapies that affect serotonin levels in the brain. While these phenomena have been well documented, the underlying neurocognitive mechanisms remain to be elucidated. Our study bridges this gap by employing a computational cognitive approach within a Bayesian predictive coding framework to explore these mechanisms in depression. We fitted a prediction error (PE) model to behavioral data from a binocular rivalry task, uncovering that significantly higher initial prior precision and lower PE led to a slower switch rate in patients with depression. Furthermore, serotonin-targeting antidepressant treatments significantly decreased the prior precision and increased PE, both of which were predictive of improvements in the perceptual alternation rate of depression patients. These findings indicated that the substantially slower perception switch rate in patients with depression was caused by the greater reliance on top-down priors and that serotonin treatment's efficacy was in its recalibration of these priors and enhancement of PE. Our study not only elucidates the cognitive underpinnings of depression, but also suggests computational modeling as a potent tool for integrating cognitive science with clinical psychology, advancing our understanding and treatment of cognitive impairments in depression.

Electroconvulsive therapy enhances degree centrality in the orbitofrontal cortex in depressive rumination.

Depressive rumination has been implicated in the onset, duration, and treatment response of refractory depression. Electroconvulsive therapy (ECT) is remarkably effective in treatment of refractory depression by modulating the functional coordination between brain hubs. However, the mechanisms by which ECT regulates depressive rumination remain unsolved. We investigated degree centrality (DC) in 32 pre- and post-ECT depression patients as well as 38 matched healthy controls. An identified brain region was defined as the seed to calculate functional connectivity (FC) in whole brains. Rumination was measured by the Ruminative Response Scale (RRS) and its relationships with identified DC and FC alterations were examined. We found a significant negative correlation between DC of the right orbitofrontal cortex (rOFC) before ECT and brooding level before and after treatment. Moreover, rOFC DC increased after ECT. DC of the left superior temporal gyrus (lSTG) was positively correlated with reflective level before intervention, while lSTG DC decreased after ECT. Patients showed elevated FC in the rOFC with default mode network. No significant association was found between decreased RRS scores and changes in DC and FC. Our findings suggest that functional changes in rOFC and lSTG may be associated with the beneficial effects of ECT on depressive rumination.

Altered brain entropy and functional connectivity patterns in generalized anxiety disorder patients.

BACKGROUND: Generalized anxiety disorder (GAD) is a highly prevalent disease characterized by chronic, pervasive, and intrusive worry. Previous resting-state functional MRI (fMRI) studies on GAD have mainly focused on conventional static linear features. Entropy analysis of resting-state functional magnetic resonance imaging (rs-fMRI) has recently been adopted to characterize brain temporal dynamics in some neuropsychological or psychiatric diseases. However, the nonlinear dynamic complexity of brain signals has been rarely explored in GAD. METHODS: We measured the approximate entropy (ApEn) and sample entropy (SampEn) of the resting-state fMRI data from 38 GAD patients and 37 matched healthy controls (HCs). The brain regions with significantly different ApEn and SampEn values between the two groups were extracted. Using these brain regions as seed points, we also investigated whether there are differences in whole brain resting-state function connectivity (RSFC) pattern between GADs and HCs. Correlation analysis was subsequently conducted to investigate the association between brain entropy, RSFC and the severity of anxiety symptoms. A linear support vector machine (SVM) was used to assess the discriminative power of BEN and RSFC features among GAD patients and HCs. RESULTS: Compared to the HCs, patients with GAD showed increased levels of ApEn in the right angular cortex (AG) and increased levels of SampEn in the right middle occipital gyrus (MOG) as well as the right inferior occipital gyrus (IOG). Contrarily, compared to the HCs, patients with GAD showed decreased RSFC between the right AG and the right inferior parietal gyrus (IPG). The SVM-based classification model achieved 85.33 % accuracy (sensitivity: 89.19 %; specificity: 81.58 %; and area under the receiver operating characteristic curve: 0.9018). The ApEn of the right AG and the SVM-based decision value was positively correlated with the Hamilton Anxiety Scale (HAMA). LIMITATIONS: This study used cross-sectional data and sample size was small. CONCLUSION: Patients with GAD showed increased level of nonlinear dynamical complexity of ApEn in the right AG and decreased linear features of RSFC in the right IPG. Combining the linear and nonlinear features of brain signals may be used to effectively diagnose psychiatric disorders.

Cognitive Considerations in Major Depression: Evaluating the Effects of Pharmacotherapy and ECT on Mood and Executive Control Deficits.

Deficits in the executive control of attention greatly impact the quality of life of patients diagnosed with major depressive disorder (MDD). However, attentional deficits are often underemphasized in clinical contexts compared with mood-based symptoms, and a comprehensive approach for specifically evaluating and treating them has yet to be developed. The present study evaluates the efficacy of bifrontal electroconvulsive therapy (ECT) combined with drug therapy (DT) in alleviating mood-related symptomatology and executive control deficits in drug-refractory MDD patients and compares these effects with those observed in MDD patients undergoing DT only. The Hamilton Rating Scale for Depression and the Lateralized Attentional Network Test-Revised were administered across two test sessions to assess treatment-related changes in mood-based symptoms and conflict processing, respectively, in patients undergoing ECT + DT (n = 23), patients undergoing DT (n = 33), and healthy controls (n = 40). Although both groups showed an improvement in mood-based symptoms following treatment and a deficit in conflict processing estimated on error rate, a post-treatment reduction of an executive control deficit estimated on RT was solely observed in the ECT + DT patient group. Furthermore, Bayesian correlational analyses confirmed the dissociation of mood-related symptoms and of executive control measures, supporting existing literature proposing that attentional deficits and mood symptoms are independent aspects of MDD. The cognitive profile of MDD includes executive control deficits, and while both treatments improved mood-based symptoms, only ECT + DT exerted an effect on both measures of the executive control deficit. Our findings highlight the importance of considering the improvement in both mood and cognitive deficits when determining the efficacy of therapeutic approaches for MDD.

Nodal degree changes induced by electroconvulsive therapy in major depressive disorder: Evidence in two independent cohorts.

OBJECTIVE: Electroconvulsive therapy (ECT), a rapidly acting treatment for major depressive disorder (MDD), has been reported to regulate brain networks. Nodes and their connections are the main components of the brain network and are essential for establishing and maintaining effective information transmission. This study aimed to evaluate the role of nodes in mediating antidepressant effects of ECT. METHODS: Voxel-based nodal degree analysis was performed in 42 patients with MDD receiving ECT and 42 matched healthy controls at two time points to identify the nodal changes induced by ECT. Verification analysis was evaluated in a second, independent cohort of 23 MDD patients. RESULTS: MDD patients showed improved nodal degree of the bilateral angular cortex (AG), precuneus, inferior frontal gyrus (IFG) and the right superior frontal gyrus (SFG) after ECT, and the increased nodal degree index (IND) rate of the AG and precuneus were negatively correlated to the depressive changes following ECT. Furthermore, validation analysis revealed a similar pattern of IND abnormalities in the first and second cohort of MDD patients. CONCLUSION: ECT regulates the disrupted nodal degree of the AG and precuneus to achieve an antidepressant effect. This study may provide further insights into the pathogenesis of depression and provide potential targets for antidepressant pharmacotherapies.

Amplitude of Low-Frequency Fluctuation With Different Clinical Outcomes in Patients With Generalized Tonic-Clonic Seizures.

Background: Generalized tonic-clonic seizures (GTCS) are associated with significant disability and sudden unexpected death when they cannot be controlled. We aimed to explore the underlying neural substrate of the different responses to antiseizure drugs between the seizure-free (SF) and non-seizure-free (NSF) patients with GTCS through the amplitude of low-frequency fluctuation (ALFF) method. Methods: We calculated ALFF among the SF group, NSF group, and healthy controls (HCs) by collecting resting-state functional magnetic resonance imaging (rs-fMRI) data. One-way ANOVA was used to compare the ALFF of the three groups, and post-hoc analysis was done at the same time. Pearson's correlation analysis between ALFF in the discrepant brain areas and the clinical characteristics (disease course and age of onset of GTCS) was calculated after then. Results: A significant group effect was found in the right fusiform gyrus (R.FG), left fusiform gyrus (L.FG), left middle occipital gyrus (L.MOG), right inferior frontal gyrus (R.IFG), right precentral gyrus (R.PreG), right postcentral gyrus (R.PostG), and left calcarine sulcus (L.CS). The SF and NSF groups both showed increased ALFF in all discrepant brain areas compared to HCs except the R.IFG in the NSF group. Significantly higher ALFF in the bilateral FG and lower ALFF in the R.IFG were found in the NSF group compared to the SF group. Conclusions: Higher ALFF in the bilateral FG were found in the NSF group compared to the SF and HC groups. Our findings indicate that abnormal brain activity in the FG may be one potential neural substrate to interpret the failure of seizure control in patients with GTCS.

Overexpression of BDNF in the ventrolateral periaqueductal gray regulates the behavior of epilepsy-migraine comorbid rats.

OBJECTIVE: To investigate the effects of brain-derived neurotrophic factor (BDNF) overexpression in the ventrolateral periaqueductal gray (vlPAG) on behavioral changes in epilepsy-migraine comorbid rats. METHOD: We used an adeno-associated virus (AAV)-mediated vector to supplement BDNF in the vlPAG area prior to the establishment of a pilocarpine-nitroglycerin (Pilo-NTG) combination-induced comorbid model of epilepsy and migraine. Seizure- and migraine-related behaviors were analyzed. Cell loss and apoptosis in vlPAG were detected through hematoxylin-eosin (HE) and TUNEL staining. Immunofluorescence staining analyses were employed to detect expressions of BDNF and its receptor, tyrosine kinase B (TrkB), in vlPAG. Immunohistochemical staining was conducted to detect expressions of c-Fos and calcitonin gene-related peptide (CGRP) in the trigeminal nucleus caudalis (TNC) and trigeminal ganglion (TG). RESULTS: Comparing to control group, AAV-BDNF injected comorbid group showed lower pain sensitivity, scratching head, and spontaneous seizures accompanied by the downregulation of c-Fos labeling neurons and CGRP immunoreactivity in the TNC and TG. However, these changes were still significantly higher in the comorbid group than those in both epilepsy and migraine groups under the same intervention. CONCLUSION: These data demonstrated that supplying BDNF to vlPAG may protect structural and functional abnormalities in vlPAG and provide an antiepileptic and analgesic therapy.

Decreased Resting-State Functional Connectivity of Periaqueductal Gray in Temporal Lobe Epilepsy Comorbid With Migraine.

Objective: Patients with temporal lobe epilepsy (TLE) are at high risk for having a comorbid condition of migraine, and these two common diseases are proposed to have some shared pathophysiological mechanisms. Our recent study indicated the dysfunction of periaqueductal gray (PAG), a key pain-modulating structure, contributes to the development of pain hypersensitivity and epileptogenesis in epilepsy. This study is to investigate the functional connectivity of PAG network in epilepsy comorbid with migraine. Methods: Thirty-two patients with TLE, including 16 epilepsy patients without migraine (EwoM) and 16 epilepsy patients with comorbid migraine (EwM), and 14 matched healthy controls (HCs) were recruited and underwent resting functional magnetic resonance imaging (fMRI) scans to measure the resting-state functional connectivity (RsFC) of PAG network. The frequency and severity of migraine attacks were assessed using the Migraine Disability Assessment Questionnaire (MIDAS) and Visual Analog Scale/Score (VAS). In animal experiments, FluoroGold (FG), a retrograde tracing agent, was injected into PPN and its fluorescence detected in vlPAG to trace the neuronal projection from vlPAG to PPN. FG traced neuron number was used to evaluate the neural transmission activity of vlPAG-PPN pathway. The data were processed and analyzed using DPARSF and SPSS17.0 software. Based on the RsFC finding, the excitatory transmission of PAG and the associated brain structure was studied via retrograde tracing in combination with immunohistochemical labeling of excitatory neurons. Results: Compared to HCs group, the RsFC between PAG and the left pedunculopontine nucleus (PPN), between PAG and the corpus callosum (CC), was decreased both in EwoM and EwM group, while the RsFC between PAG and the right PPN was increased only in EwoM group but not in EwM group. Compared to EwoM group, the RsFC between PAG and the right PPN was decreased in EwM group. Furthermore, the RsFC between PAG and PPN was negatively correlated with the frequency and severity of migraine attacks. In animal study, a seizure stimulation induced excitatory transmission from PAG to PPN was decreased in rats with chronic epilepsy as compared to that in normal control rats. Conclusion: The comorbidity of epilepsy and migraine is associated with the decreased RsFC between PAG and PPN.

The epidemiology of primary headaches in patients with multiple sclerosis.

OBJECTIVE: Recent studies have shown a pathophysiologic link between headache and multiple sclerosis (MS), but the prevalence of primary headaches among patients with MS differs substantially across studies. This meta-analysis aimed to comprehensively gather available evidence to estimate the prevalence of primary headaches among patients with MS. METHOD: We systematically searched the electronic databases including PubMed, Embase, and Scopus for cohort, case-control, cross-sectional studies that measured the prevalence of headache among patients with MS. Two reviewers independently screened titles and abstracts to identify the eligible studies and the full texts of the included studies were reviewed. Newcastle-Ottawa Scale (NOS) was used to assess the risk of bias of the included literatures. We then conducted a meta-analysis using Stata Software 15.0 to calculate the pooled prevalence of headaches among patients with MS and assess the source of heterogeneity. RESULTS: We identified 16 eligible studies covering a total of 3,560 patients with MS. The pooled estimated prevalence of primary headaches among patients with MS was 56%. The statistical heterogeneity was moderate with I2 of 82.1% (p < .001). Both a visual inspection of the funnel plot and Egger' regression tests revealed no significant publication bias (p = .44). The pooled estimated prevalence of migraine (55%) was higher in comparison with that of tension-type headache (20%). The prevalence of migraine subtype was 16% and 10% for migraine without aura and migraine with aura, respectively. The pooled prevalence of primary headache in case-control group (57%) was approximately in line with the cross-sectional group (56%). CONCLUSION: The overall prevalence of primary headaches among patients with MS was considerably high. Clinical screening of headache among patients with MS will be helpful to formulate an individualized treatment plans and alleviate the physical and mental impact of the disease.

Enhanced cerebro-cerebellar functional connectivity reverses cognitive impairment following electroconvulsive therapy in major depressive disorder.

Electroconvulsive therapy (ECT), a rapidly acting and effective treatment for major depressive disorder (MDD), is frequently accompanied by cognitive impairment. Recent studies have documented that ECT reorganizes dysregulated inter/intra- connected cerebral networks, including the affective network, the cognitive control network(CCN) and default mode network (DMN).Moreover, cerebellum is thought to play an important role in emotion regulation and cognitive processing. However, little is known about the relationship between cerebro-cerebellar connectivity alterations following ECT and antidepressant effects or cognitive impairment. We performed seed-based resting-state functional connectivity (RSFC) analyses in 28 MDD patients receiving ECT and 20 healthy controls to identify cerebro-cerebellar connectivity differences related to MDD and changes induced by ECT. Six seed regions (three per hemisphere) in the cerebrum were selected for RSFC, corresponding to the affective network, CCN and DMN, to establish cerebro-cerebellar functional connectivity with cerebellum. MDD patients showed increased RSFC between left sgACC and left cerebellar lobule VI after ECT. Ggranger causality analyses (GCA) identified the causal interaction is from left cerebellar lobule VI to left sgACC. Furthermore, increased effective connectivity from left cerebellar lobule VI to left sgACC exhibited positively correlated with the change in verbal fluency test (VFT) score following ECT (r = 0.433, p = 0.039). Our findings indicate that the enhanced cerebro-cerebellar functional connectivity from left lobule VI to left sgACC may ameliorate cognitive impairment induced by ECT. This study identifies a potential neural pathway for mitigation of cognitive impairment following ECT.

The Comorbid Relationship Between Migraine and Asthma: A Systematic Review and Meta-Analysis of Population-Based Studies.

Objective: Recent studies have indicated a pathophysiologic link between migraine and asthma. This meta-analysis aimed to comprehensively estimate the risk ratio for migraine in asthma as well as that of asthma in migraine based on available evidence. Method: We systematically searched the electronic databases including PubMed, Web of Science, and SCOPUS for population-based studies that measured either the odds or the risk of asthma in subjects with migraine as well as that of migraine in subjects with asthma. The titles and abstracts were screened by two independent reviewers to identify eligible studies, and this was followed by full-text review of the included studies. Newcastle-Ottawa Scale (NOS) was used to assess the risk of bias of included literature. A meta-analysis was conducted with Review Manager 5.3 Software to calculate the odds ratio (OR) for case-control and cross-sectional studies and either relative ratio (RR) or hazard ratio (HR) for cohort studies, and the source of heterogeneity was assessed. Subgroup and sensitivity analyses were conducted, and the I2 test were used to assess the source of heterogeneity. The funnel plot, Galbraith plot, and Egger's test were used to evaluate publication bias. Results: Fifteen published studies covering a total of 1,188,780 individuals were identified. Pooled analysis indicated that migraine was associated with increased odds (OR = 1.54; 95% CI: 1.34~1.77) and risk for asthma (HR = 1.42; 95% CI: 1.26~1.60), and asthma associated with increased odds (OR = 1.45; 95% CI: 1.22~1.72) and risk for migraine (HR = 1.47; 95% CI: 1.41~1.52). Conclusion: Migraine is a potential risk indicator for asthma, and vice versa, asthma is a potential risk indicator for migraine. However, future prospective cohort studies are warranted to provide more evidence concerning the detailed association between migraine and asthma.

Common variant of CNTNAP2 gene modulate the social performances and functional connectivity of posterior right temporoparietal junction.

Social deficits are features of autism and highly heritable traits. A common variant in autism-related CNTNAP2 gene, rs2710102, has been linked with social performance, but the neural substrates are largely unknown. We investigated variations in social performance and functional connectivity (static and dynamic) in the subregions of right temporoparietal junction (RTPJ), a key node of brain social network, using resting-state magnetic resonance imaging (n = 399) by genotype at rs2710102 in healthy volunteers. Social performance was evaluated using the social domain of the Autism-Spectrum Quotient (AQ-social; n = 641) and fixation time on eye areas during an eye-tracking task (n = 32). According to previous evidence that the A-allele is the risk allele for social dysfunction, we classified participants into GG and A-allele carriers (AA/AG) groups. The A-allele carriers showed poor social performance (high AQ-social and short fixation time on eye areas) compared with the GG carriers. In the A-allele carriers, decreased stationary functional connectivity between the orbitofrontal cortex and posterior RTPJ (pRTPJ), and decreased dynamic functional connectivity (dFC) between the medial prefrontal cortex (mPFC) and pRTPJ were observed. The fixation time at eye areas positively were correlated with the pRTPJ-mPFC dFC. These findings provided insight for genetic effect on social behavior and its potential neural substrate.

Decreased Connection Between Reward Systems and Paralimbic Cortex in Depressive Patients.

Despite decades of research on depression, the underlying pathophysiology of depression remains incompletely understood. Emerging evidence from task-based studies suggests that the abnormal reward-related processing contribute to the development of depression. It is unclear about the function pattern of reward-related circuit during resting state in depressive patients. In present study, seed-based functional connectivity was used to evaluate the functional pattern of reward-related circuit during resting state. Selected seeds were two key nodes in reward processing, medial orbitofrontal cortex (mOFC) and nucleus accumbens (NAcc). Fifty depressive patients and 57 healthy participants were included in present study. Clinical severity of participants was assessed with Hamilton depression scale and Hamilton anxiety scale. We found that compared with healthy participants, depressive patients showed decreased connectivity of right mOFC with left temporal pole (TP_L), right insula extending to superior temporal gyrus (INS_R/STG) and increased connectivity of right mOFC with left precuneus. Similarly, decreased connectivity of left mOFC with TP_L and increased connectivity with cuneus were found in depressive patients. There is also decreased connectivity of right NAcc with bilateral temporal pole, as well as decreased connectivity of left NAcc with INS_R/STG. In addition, the functional connectivity of right nucleus accumbens with right temporal pole (TP_R) was negatively correlated with clinical severity. Our results emphasize the role of communication deficits between reward systems and paralimbic cortex in the pathophysiology of depression.