Altered acetylcholine modulations and corticoaccumbal pathway in P11-linked social dysfunction.

Bipolar Disorder: Imaging State Versus Trait

Major depressive disorder (MDD) patients exhibit a mood-congruent emotional processing bias within the amygdala toward negative facial stimuli at both unconscious and conscious levels. Therefore, our study aimed to investigate the temporal and spatial dynamics of amygdala along with its interactions with the whole brain during implicit and explicit conditions in MDD. Thirty MDD patients and 26 healthy controls (HCs) underwent magnetoencephalography (MEG) recordings and performed implicit and explicit emotional face recognition tasks with happy, sad, and neutral facial expressions. Using the amygdala as a seed region, time frequency representations (TFR) and functional connectivity (FC) were calculated. Pearson correlation analyses measured the relationship between TFR and FC values with clinical symptoms. During implicit processing, MDD patients exhibited left amygdala activation in the gamma power (60-70Hz) before 250ms in response to sad facial stimuli compared to HCs. In the implicit mode, there were increased FC between the right amygdala and several brain regions in the occipitoparietal lobes, as well as higher FC between the left amygdala and putamen in MDD patients. Additionally, the right amygdala was positively correlated with the severity of depression and anxiety during implicit processing. MDD patients had lateralized amygdala activation in response to sad facial expressions during unconscious emotional recognition of facial stimuli. Our study provided valuable insights into the spatiotemporal dynamics of facial emotional recognition associated with depressive and anxiety-related cognitive bias during implicit and explicit processing.

Previous neuroimaging studies have revealed abnormal brain networks in patients with major depressive disorder (MDD) in emotional processing. While any cognitive task consists of a series of stages, little is yet known about the topology of functional brain networks in MDD for these stages during emotional face recognition. To address this problem, electroencephalography (EEG)-based functional brain networks of MDD patients at different stages of facial information processing were investigated in this study. First, EEG signals were collected from 16 patients with MDD and 18 age-, gender-, and education-matched normal subjects when performing an emotional face recognition task. Second, the global field power (GFP) method was employed to divide group-averaged event-related potentials into different stages. Third, using the phase transfer entropy (PTE) approach, the brain networks of MDD patients and normal individuals were constructed for each stage in negative and positive face processing, respectively. Finally, we compared the topological properties of brain networks of each stage between the two groups using graph theory approaches. The results showed that the analyzed three stages of emotional face processing corresponded to specific neurophysiological phases, namely, visual perception, face recognition, and emotional decision-making. It was also demonstrated that depressed patients showed abnormally decreased characteristic path length at the visual perception stage of negative face recognition and normalized characteristic path length in the stage of emotional decision-making during positive face processing compared to healthy subjects. Furthermore, while both the MDD and normal groups' brain networks were found to exhibit small-world network characteristics, the brain network of patients with depression tended to be randomized. Moreover, for patients with MDD, the centro-parietal region may lose its status as a hub in the process of facial expression identification. Together, our findings suggested that altered emotional function in MDD patients might be associated with disruptions in the topological organization of functional brain networks during emotional face recognition, which further deepened our understanding of the emotion processing dysfunction underlying MDD.

Insomnia is a common comorbidity symptom in major depressive disorder (MDD) patients. Abnormal brain activities have been observed in both MDD and insomnia patients, however, the central pathological mechanisms underlying the co-occurrence of insomnia in MDD patients are still unclear. This study aimed to explore the differences of spontaneous brain activity between MDD patients with and without insomnia, as well as patients with different level of insomnia. A total of 88 first-episode drug-naïve MDD patients including 44 with insomnia (22 with high insomnia and 22 with low insomnia) and 44 without insomnia, as well as 44 healthy controls (HC), were enrolled in this study. The level of depression and insomnia were evaluated by HAMD-17, adjusted HAMD-17 and its sleep disturbance subscale in all subjects. Resting-state functional and structural magnetic resonance imaging data were acquired from all participants and then were preprocessed by the software of DPASF. Regional homogeneity (ReHo) values of brain regions were calculated by the software of REST and were compared. Finally, receiver operating characteristic (ROC) curves were conducted to determine the values of abnormal brain regions for identifying MDD patients with insomnia and evaluating the severity of insomnia. Analysis of variance showed that there were significant differences in ReHo values in the left middle frontal gyrus, left pallidum, right superior frontal gyrus, right medial superior frontal gyrus and right rectus gyrus among three groups. Compared with HC, MDD patients with insomnia showed increased ReHo values in the medial superior frontal gyrus, middle frontal gyrus, triangular inferior frontal gyrus, calcarine fissure and right medial superior frontal gyrus, medial orbital superior frontal gyrus, as well as decreased ReHo values in the left middle occipital gyrus, pallidum and right superior temporal gyrus, inferior temporal gyrus, middle cingulate gyrus, hippocampus, putamen. MDD patients without insomnia demonstrated increased ReHo values in the left middle frontal gyrus, orbital middle frontal gyrus, anterior cingulate gyrus and right triangular inferior frontal gyrus, as well as decreased ReHo values in the left rectus gyrus, postcentral gyrus and right rectus gyrus, fusiform gyrus, pallidum. In addition, MDD patients with insomnia had decreased ReHo values in the left insula when compared to those without insomnia. Moreover, MDD patients with high insomnia exhibited increased ReHo values in the right middle temporal gyrus, and decreased ReHo values in the left orbital superior frontal gyrus, lingual gyrus, right inferior parietal gyrus and postcentral gyrus compared to those with low insomnia. ROC analysis demonstrated that impaired brain region might be helpful for identifying MDD patients with insomnia and evaluating the severity of insomnia. These findings suggested that MDD patients with insomnia had wider abnormalities of brain activities in the prefrontal-limbic circuits including increased activities in the prefrontal cortex, which might be the compensatory mechanism underlying insomnia in MDD. In addition, decreased activity of left insula might be associated with the occurrence of insomnia in MDD patients and decreased activities of the frontal-parietal network might cause more serious insomnia related to MDD.

Several psychiatric disorders increase the risk of cardiovascular disease, including posttraumatic stress disorder and major depression. While the precise mechanism for this association has not yet been established, it has been shown that certain disorders promote an unfavorable lipid profile. To study the interaction of stress and lipid dysregulation, we utilized chronic social defeat stress (CSDS), a mouse model of chronic stress with features of posttraumatic stress disorder and major depression. Following exposure to CSDS, mice were given access to either regular chow or a Western-style diet high in fat and cholesterol (HFD). The combination of social stress and HFD resulted in significant perturbations in lipid regulation, including two key features of the metabolic syndrome: increased plasma levels of non-HDL cholesterol and intrahepatic accumulation of triglycerides. These effects were accompanied by a number of changes in the expression of hepatic genes involved in lipid regulation. Transcriptional activity of LXR, SREBP1c, and ChREBP were significantly affected by exposure to HFD and CSDS. We present CSDS as a model of social stress induced lipid dysregulation and propose that social stress alters lipid metabolism by increasing transcriptional activity of genes involved in lipid synthesis.

Accumulating studies have been conducted to identify risk genes and relevant biological mechanisms underlying major depressive disorder (MDD). In particular, transcriptomic analyses in brain regions engaged in cognitive and emotional processes, e.g., the dorsolateral prefrontal cortex (DLPFC), have provided essential insights. Based on three independent DLPFC RNA-seq datasets of 79 MDD patients and 75 healthy controls, we performed differential expression analyses using two alternative approaches for cross-validation. We also conducted transcriptomic analyses in mice undergoing chronic variable stress (CVS) and chronic social defeat stress (CSDS). We identified 12 differentially expressed genes (DEGs) through both analytical methods in MDD patients, the majority of which were also dysregulated in stressed mice. Notably, the mRNA level of the immediate early gene FOS (Fos proto-oncogene) was significantly decreased in both MDD patients and CVS-exposed mice, and CSDS-susceptible mice exhibited a greater reduction in Fos expression compared to resilient mice. These findings suggest the potential key roles of this gene in the pathogenesis of MDD related to stress exposure. Altered transcriptomes in the DLPFC of MDD patients might be, at least partially, the result of stress exposure, supporting that stress is a primary risk factor for MDD.

In deaf children, huge emphasis was given to language; however, emotional cues decoding and production appear of pivotal importance for communication capabilities. Concerning neurophysiological correlates of emotional processing, the gamma band activity appears a useful tool adopted for emotion classification and related to the conscious elaboration of emotions. Starting from these considerations, the following items have been investigated: (i) whether emotional auditory stimuli processing differs between normal-hearing (NH) children and children using a cochlear implant (CI), given the non-physiological development of the auditory system in the latter group; (ii) whether the age at CI surgery influences emotion recognition capabilities; and (iii) in light of the right hemisphere hypothesis for emotional processing, whether the CI side influences the processing of emotional cues in unilateral CI (UCI) children. To answer these matters, 9 UCI (9.47 ± 2.33 years old) and 10 NH (10.95 ± 2.11 years old) children were asked to recognize nonverbal vocalizations belonging to three emotional states: positive (achievement, amusement, contentment, relief), negative (anger, disgust, fear, sadness), and neutral (neutral, surprise). Results showed better performances in NH than UCI children in emotional states recognition. The UCI group showed increased gamma activity lateralization index (LI) (relative higher right hemisphere activity) in comparison to the NH group in response to emotional auditory cues. Moreover, LI gamma values were negatively correlated with the percentage of correct responses in emotion recognition. Such observations could be explained by a deficit in UCI children in engaging the left hemisphere for more demanding emotional task, or alternatively by a higher conscious elaboration in UCI than NH children. Additionally, for the UCI group, there was no difference between the CI side and the contralateral side in gamma activity, but a higher gamma activity in the right in comparison to the left hemisphere was found. Therefore, the CI side did not appear to influence the physiologic hemispheric lateralization of emotional processing. Finally, a negative correlation was shown between the age at the CI surgery and the percentage of correct responses in emotion recognition and then suggesting the occurrence of a sensitive period for CI surgery for best emotion recognition skills development.

Abnormalities in emotion recognition (ER) are frequently reported in depression, with lower recognition accuracy in patients with major depressive disorder (MDD) when compared to healthy individuals. Mindfulness was found to directly impact the severity of depressive symptoms, by recognizing negative cognitions and dysfunctional reactions. The aims of this study were to compare ER and mindfulness levels between MDD patients and healthy controls (HCs), as well as to examine whether ER and mindfulness are related to symptom severity in MDD patients. Sixty-eight patients with MDD and 93 HCs participated in the study. A sociodemographic form, reading the mind in the eyes test (RMET), five facet mindfulness questionnaire-short form (FFMQ-S) and the Montgomery-Asberg depression scale (MADRS) were administered. Group comparison in ER and mindfulness was performed using the multivariate analysis of covariance (MANCOVA). Bivariate correlations and hierarchical linear regression analyses were performed to assess the associations between depression severity, ER and mindfulness in the patient group. Higher level of mindfulness was found in HCs relative to MDD group, however, no ER difference was present between the groups. A positive association between depression severity and the non-reactivity facet of mindfulness was found. On the other hand, ER was not significantly associated with symptom severity among individuals with MDD. Non-reactivity, unlike other dimensions of mindfulness, seems to increase with the severity of depressive symptoms among MDD patients. A particular focus on this subdimension in mindfulness techniques may yield better outcomes in alleviation of depressive symptoms.

IntroductionAbnormalities in emotion recognition (ER) are frequently reported in depression, with lowered recognition accuracy in patients with major depressive disorder (MDD) when compared to healthy individuals. Mindfulness was found to directly impact the severity of depressive symptoms, by negative cognition and dysfunctional reaction recognition.ObjectivesThe aims of this study were to compare ER and mindfulness levels between MDD patients and healthy controls (HC), as well as to examine whether ER and mindfulness are related to symptom severity in MDD patients.Methods68 patients with MDD and 93 HC participated in the study. A sociodemographic form, Reading the Mind in the Eyes Test (RMET), Five Facet Mindfulness Questionnaire-Short Form (FFMQ-S) and the Montgomery Asperg Depression Scale (MADRS) were administered. Group comparison in ER and mindfulness was assessed using the Multivariate analysis of covariance (MANCOVA). Bivariate correlations and multiple linear regression analyses were performed to assess the associations between depression severity, ER and mindfulness in the patient group.ResultsBetter ER and higher levels of mindfulness were found in HCs relative to the MDD group. A positive association between depression severity and the non-reactivity facet of mindfulness was found, indicating that in the MDD group non-reactivity was a significant predictor for depression severity. On the other hand, ER was not significant in predicting symptom severity.ConclusionsNon-reactivity, unlike other dimensions of mindfulness, seems to increase with the severity of depressive symptoms among MDD patients. To particularly focus on this subdimension in mindfulness techniques may yield better outcomes in alleviation of depressive symptoms.DisclosureNo significant relationships.

Major depressive disorder skews the recognition of emotional prosody

Background: Major depressive disorder (MDD) patients face an increased risk of developing cognitive impairments. One of the prominent cognitive impairments in MDD patients is verbal fluency deficit. Nonetheless, it is not clear which vulnerable brain region in MDD is interactively linked to verbal fluency deficit. It is important to gain an improved understanding for verbal fluency deficit in MDD.Methods: Thirty-four MDD patients and 34 normal controls (NCs) completed resting-state fMRI (rs-fMRI) scan and a set of verbal fluency tests (semantic VFT and phonemic VFT). Fourteen brain regions from five brain networks/systems (central executive network, default mode network, salience network, limbic system, cerebellum) based on their vital role in MDD neuropathology were selected as seeds for functional connectivity (FC) analyses with the voxels in the whole brain. Finally, correlations between the z-score of the FCs from clusters showing significant between-group difference and z-score of the VFTs were calculated using Pearson correlation analyses.Results: Increased FCs in MDD patients vs. NCs were identified between the bilateral posterior cingulate cortex (PCC) and the right inferior frontal gyrus (triangular part), in which the increased FC between the right PCC and the right inferior frontal gyrus (triangular part) was positively correlated with the z score of phonemic VFT in the MDD patients. Moreover, decreased FCs were identified between the right hippocampal gyrus and PCC, as well as left cerebellum Crus II and right parahippocampal gyrus in MDD patients vs. NCs.Conclusions: The MDD patients have altered FCs among key brain regions in the default mode network, the central executive network, the limbic system, and the cerebellum. The increased FC between the right PCC and the right inferior frontal gyrus (triangular part) may be useful to better characterize pathophysiology of MDD and functional correlates of the phonemic verbal fluency deficit in MDD.

Major depressive disorder (MDD) patients with anhedonia tend to have a poor prognosis. The underlying imaging basis for anhedonia in MDD remains largely unknown. The relationship between nodal properties and anhedonia in MDD patients need to be further investigated. Herein, this study aims to explore differences of cerebral functional node characteristics in MDD patients with severe anhedonia (MDD-SA) and MDD patients with mild anhedonia (MDD-MA) before and after the antidepressant treatment. Ninety participants with current MDD were recruited in this study. 24-Item Hamilton Depression Scale (HAMD-24) and Snaith-Hamilton Pleasure Scale (SHAPS) were used to assess the severity of depression and anhedonia at baseline and the end of 6-months treatment. The MDD patients who scored above the 25th percentile on the SHAPS were assigned to an MDD-SA group (n=19), while those who scored below the 25th percentile were assigned to an MDD-MA group (n=18). All patients in the 2 groups received antidepressant treatment. Functional magnetic resonance imaging (fMRI) images of all the patients were collected at baseline and the end of 6-months treatment. Graph theory was applied to analyze the patients' cerebral functional nodal characteristics, which were measured by efficiency (ei) and degree (ki). Repeated measures 2-factor ANCOVA showed significant main effects on group on the ei and ki values of left superior frontal gyrus (LSFG) (P=0.003 and P=0.008, respectively), and on the ei and ki values of left medial orbital-frontal gyrus (LMOFG) (P=0.004 and P=0.008, respectively). Compared with the MDD-MA group, the significantly higher ei and ki values of the LSFG (P=0.015 and P=0.021, respectively), and the significantly higher ei and ki values of the LMOFG (P=0.015 and P=0.037, respectively) were observed in the MDD-SA group at baseline. Meanwhile, higher SHAPS scores could result in higher ei and ki values of LSFG (P=0.019 and P=0.026, respectively), and higher ei value of LMOFG (P=0.040) at baseline; higher SHAPS scores could result in higher ei values of LSFG (P=0.049) at the end of 6-months treatment. The multiple linear regression analysis revealed that sex were negatively correlated with the ei and ki values of LSFG (r= -0.014, P=0.004; r=-1.153, P=0.001, respectively). The onset age of MDD was negatively correlated with the ki value of LSFG (r=-0.420, P=0.034) at the end of 6-months treatment. We also found that SHAPS scores at baseline were positively correlated with the HAMD-24 scores (r=0.387, P=0.022) at the end of 6-months treatment. There are obvious differences in nodal properties between the MDD-SA and the MDD-MA patients, such as the high ei of LSFG in the MDD-SA patients, which may be associated with the severity of anhedonia. These nodal properties could be potential biomarkers for the prognosis of MDD. The increased ei and ki values in the LSFG of MDD-SA patients may underlie a compensatory mechanism or protective mechanism. The mechanism may be an important component of the pathological mechanism of MDD-SA. The poor prognosis in the MDD-SA patients suggests that anhedonia may predict a worse prognosis in MDD patients. Sex and onset age of MDD may affect the nodal properties of LSFG at baseline and the end of 6-months treatment.

A Hypothesized Role for Dendritic Remodeling in the Etiology of Mood and Anxiety Disorders

Background: Deficits in reward processing, such as approaching motivation, reward learning and effort-based decision-making, have been observed in patients with schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD). However, little is known about the nature of reward-processing deficits in these 3 diagnostic groups. The present study aimed to compare and contrast amotivation in these 3 diagnostic groups using an effort-based decision-making task. Methods: Sixty patients (19 SCZ patients, 18 BD patients and 23 MDD patients) and 27 healthy controls (HC) were recruited for the present study. The Effort Expenditure for Reward Task (EEfRT) was administered to evaluate their effort allocation pattern. This task required participants to choose easy or hard tasks in response to different levels of reward magnitude and reward probability. Results: Results showed that SCZ, BD, and MDD patients chose fewer hard tasks compared to HC. As reward magnitude increased, MDD patients made the least effort to gain reward compared to the other groups. When reward probability was intermediate, MDD patients chose fewer hard tasks than SCZ patients, whereas BD patients and HC chose more hard tasks than MDD and SCZ patients. When the reward probability was high, all 3 groups of patients tried fewer hard tasks than HC. Moreover, SCZ and MDD patients were less likely to choose hard tasks than BD patients and HC in the intermediate estimated value conditions. However, in the highest estimated value condition, there was no group difference in hard task choices between these 3 clinical groups, and they were all less motivated than HC. Conclusion: SCZ, BD, and MDD patients shared common deficits in gaining reward if the reward probability and estimated value were high. SCZ and MDD patients showed less motivation than BD patients in gaining reward when the reward probability and estimated value was intermediate.

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.