Distinct global brain connectivity alterations in depressed adolescents with subthreshold mania and the relationship with processing speed: Evidence from sBEAD Cohort.

BACKGROUND: Bipolar disorder (BD) is a progressive condition. Investigating the neuroimaging mechanisms in depressed adolescents with subthreshold mania (SubMD) facilitates the early identification of BD. However, the global brain connectivity (GBC) patterns in SubMD patients, as well as the relationship with processing speed before the onset of full-blown BD, remain unclear. METHODS: The study involved 72 SubMD, 77 depressed adolescents without subthreshold mania (nSubMD), and 69 gender- and age-matched healthy adolescents (HCs). All patients underwent a clinical follow-up ranging from six to twelve months. We calculated the voxel-based graph theory analysis of the GBC map and conducted the TMT-A test to measure the processing speed. RESULTS: Compared to HCs and nSubMD, SubMD patients displayed distinctive GBC index patterns: GBC index decreased in the right Medial Superior Frontal Gyrus (SFGmed.R)/Superior Frontal Gyrus (SFG) while increased in the right Precuneus and left Postcentral Gyrus. Both patient groups showed increased GBC index in the right Inferior Temporal Gyrus. An increased GBC value in the right Supplementary Motor Area was exclusively observed in the nSubMD-group. There were opposite changes in the GBC index in SFGmed.R/SFG between two patient groups, with an AUC of 0.727. Additionally, GBC values in SFGmed.R/SFG exhibited a positive correlation with TMT-A scores in SubMD-group. LIMITATIONS: Relatively shorter follow-up duration, medications confounding, and modest sample size. CONCLUSION: These findings suggest that adolescents with subthreshold BD have specific impairments patterns at the whole brain connectivity level associated with processing speed impairments, providing insights into early identification and intervention strategies for BD.

Brain-based graph-theoretical predictive modeling to map the trajectory of anhedonia, impulsivity, and hypomania from the human functional connectome.

Clinical assessments often fail to discriminate between unipolar and bipolar depression and identify individuals who will develop future (hypo)manic episodes. To address this challenge, we developed a brain-based graph-theoretical predictive model (GPM) to prospectively map symptoms of anhedonia, impulsivity, and (hypo)mania. Individuals seeking treatment for mood disorders (n = 80) underwent an fMRI scan, including (i) resting-state and (ii) a reinforcement-learning (RL) task. Symptoms were assessed at baseline as well as at 3- and 6-month follow-ups. A whole-brain functional connectome was computed for each fMRI task, and the GPM was applied for symptom prediction using cross-validation. Prediction performance was evaluated by comparing the GPM to a corresponding null model. In addition, the GPM was compared to the connectome-based predictive modeling (CPM). Cross-sectionally, the GPM predicted anhedonia from the global efficiency (a graph theory metric that quantifies information transfer across the connectome) during the RL task, and impulsivity from the centrality (a metric that captures the importance of a region) of the left anterior cingulate cortex during resting-state. At 6-month follow-up, the GPM predicted (hypo)manic symptoms from the local efficiency of the left nucleus accumbens during the RL task and anhedonia from the centrality of the left caudate during resting-state. Notably, the GPM outperformed the CPM, and GPM derived from individuals with unipolar disorders predicted anhedonia and impulsivity symptoms for individuals with bipolar disorders. Importantly, the generalizability of cross-sectional models was demonstrated in an external validation sample. Taken together, across DSM mood diagnoses, efficiency and centrality of the reward circuit predicted symptoms of anhedonia, impulsivity, and (hypo)mania, cross-sectionally and prospectively. The GPM is an innovative modeling approach that may ultimately inform clinical prediction at the individual level.

Real-world clinical predictors of manic/hypomanic episodes among outpatients with bipolar disorder.

BACKGROUND: Bipolar disorder is a mental illness in which manic and depressive states are repeated, causing psychosocial dysfunction. Manic/hypomanic episodes cause problems with interpersonal, social and financial activities, but there is limited evidence regarding the predictors of manic/hypomanic episodes in real-world clinical practice. METHODS: The multicenter treatment survey on bipolar disorder (MUSUBI) in Japanese psychiatric clinics was administered in an observational study that was conducted to accumulate evidence regarding bipolar disorder in real-world clinical practice. Psychiatrists were asked to complete a questionnaire about patients with bipolar disorder who visited 176 member clinics of the Japanese Association of Neuro-Psychiatric Clinics by conducting a retrospective medical record survey. Our study extracted baseline patient characteristics from September to October 2016, including comorbidities, mental status, duration of treatment, Global Assessment of Functioning (GAF) score, and pharmacological treatment details. We investigated the presence or absence of manic/hypomanic episodes over the course of one year from baseline to September-October 2017. RESULTS: In total, 2231 participants were included in our study, 29.1% of whom had manic/hypomanic episodes over the course of one year from baseline. Binomial logistic regression analysis revealed that the presence of manic/hypomanic episodes was correlated with lower baseline GAF scores, rapid cycling, personality disorder, bipolar I disorder, and a mood state with manic or mixed features. Substance abuse was also a risk factor for manic episodes. There was no significant association between a baseline antidepressant prescription and manic/hypomanic episodes. CONCLUSIONS: In Japan, 29.1% of outpatients with bipolar disorder had manic/hypomanic episodes over the course of one year. Our study suggested that a low GAF score, rapid cycling, personality disorder, bipolar I disorder, substance abuse, and baseline mood state could be predictors of manic/hypomanic episodes. Based on our findings, an antidepressant prescription is not a predictor of manic/hypomanic episodes.

The effects of childhood emotional maltreatment and alexithymia on depressive and manic symptoms and suicidal ideation in females with bipolar disorder: emotion dysregulation as a mediator.

OBJECTIVES: The relations of childhood emotional maltreatment and alexithymia to the clinical course of bipolar disorder (BD) have been widely recognised. Difficulties in regulating emotions may explain these relationships. The current study evaluated the effects of childhood emotional maltreatment and alexithymia on depressive and manic symptoms as well as suicidal ideation in female patients with BD. Emotion dysregulation was evaluated as a mediating factor. METHODS: Three hundred hospitalised female patients with a diagnosis of BD provided information regarding their history of childhood emotional maltreatment, alexithymia, difficulties in emotion regulation, depressive and manic symptoms, and suicidal ideation. A series of structural equation models (SEMs) were calculated to assess the associations between these variables. RESULTS: Childhood emotional abuse and difficulty in identifying feelings were indirectly associated with depressive and manic symptoms as well as suicidal ideation. This association was mediated by emotion dysregulation. This association remained significant after depressive and manic symptoms were controlled in the model. CONCLUSIONS: This study indicates that patients with BD who experienced emotional abuse during childhood and have difficulties identifying emotions report greater emotion dysregulation. These individuals, in turn, are more likely to experience more severe depressive and manic symptoms as well as suicidal ideation.Key pointsChildhood emotional maltreatment and emotional and clinical factors in bipolar disorder were assessed.Childhood emotional abuse indirectly affected clinical factors via emotion dysregulation.Difficulty in identifying feelings was linked to clinical factors via emotional dysregulation.Emotional dysregulation affected the links of childhood emotional maltreatment and difficulty in identifying feelings on suicidal ideation after controlling for clinical symptoms.Emotional dysregulation dimensions of impulse, strategies, and goals emerge in relation to suicidal ideation.

Altered dynamic functional connectivity across mood states in bipolar disorder.

BACKGROUND: This study aims to identify how the large-scale brain dynamic functional connectivity (dFC) differs between mood states in bipolar disorder (BD). The authors analyzed dFC in subjects with BD in depressed and euthymic states using resting-state functional magnetic resonance imaging (rsfMRI) data, and compared these states to healthy controls (HCs). METHOD: 20 subjects with BD in a depressive episode, 23 euthymic BD subjects, and 31 matched HCs underwent rsfMRI scans. Using an existing parcellation of the whole brain, we measured dFC between brain regions and identified the different patterns of brain network connections between groups. RESULTS: In the analysis of whole brain dFC, the connectivity between the left Superior Temporal Gyrus (STG) in the somatomotor network (SMN), the right Middle Temporal Gyrus (MTG) in the default mode network (DMN) and the bilateral Postcentral Gyrus (PoG) in the DMN of depressed BD was greater than that of euthymic BD, while there was no significant difference between euthymic BD and HCs in these brain regions. Euthymic BD patients had abnormalities in the frontal-striatal-thalamic (FST) circuit compared to HCs. CONCLUSIONS: Differences in dFC within and between DMN and SMN can be used to distinguish depressed and euthymic states in bipolar patients. The hyperconnectivity within and between DMN and SMN may be a state feature of depressed BD. The abnormal connectivity of the FST circuit can help identify euthymic BD from HCs.

Associations between hypomania proneness and attentional bias to happy, but not angry or fearful, faces in emerging adults.

Mania, the core feature of bipolar disorder, is associated with heightened and positive emotion responding. Yet, little is known about the underlying cognitive processes that may contribute to heightened positive emotionality observed. Additionally, while previous research has investigated positive emotion biases in non-clinical samples, few if any, account for subthreshold clinical symptoms or traits, which have reliably assessed psychopathological risk. The present study compared continuous scores on a widely used self-report measure of hypomania proneness (HPS-48) with a dot-probe task to investigate attentional biases for happy, angry, fearful, and neutral faces among 66 college student participants. Results suggested that hypomania proneness was positively associated with attentional bias towards happy, but not angry or fearful faces. Results remained robust when controlling for positive affect and did not appear to be affected by negative affect or current symptoms of depression, anxiety, and stress. Findings provide insight into potential behavioural markers that co-occur with heightened positive emotional responding and hypomania in emerging adults.

Synaptotagmin-7 deficiency induces mania-like behavioral abnormalities through attenuating GluN2B activity.

Synaptotagmin-7 (Syt7) probably plays an important role in bipolar-like behavioral abnormalities in mice; however, the underlying mechanisms for this have remained elusive. Unlike antidepressants that cause mood overcorrection in bipolar depression, N-methyl-d-aspartate receptor (NMDAR)-targeted drugs show moderate clinical efficacy, for unexplained reasons. Here we identified Syt7 single nucleotide polymorphisms (SNPs) in patients with bipolar disorder and demonstrated that mice lacking Syt7 or expressing the SNPs showed GluN2B-NMDAR dysfunction, leading to antidepressant behavioral consequences and avoidance of overcorrection by NMDAR antagonists. In human induced pluripotent stem cell (iPSC)-derived and mouse hippocampal neurons, Syt7 and GluN2B-NMDARs were localized to the peripheral synaptic region, and Syt7 triggered multiple forms of glutamate release to efficiently activate the juxtaposed GluN2B-NMDARs. Thus, while Syt7 deficiency and SNPs induced GluN2B-NMDAR dysfunction in mice, patient iPSC-derived neurons showed Syt7 deficit-induced GluN2B-NMDAR hypoactivity that was rescued by Syt7 overexpression. Therefore, Syt7 deficits induced mania-like behaviors in mice by attenuating GluN2B activity, which enabled NMDAR antagonists to avoid mood overcorrection.

Bipolar Disorder Among Patients Diagnosed With Frontotemporal Dementia.

OBJECTIVE: Previous studies have documented manic and hypomanic symptoms in behavioral variant frontotemporal dementia (bvFTD), suggesting a relationship between bipolar disorder and bvFTD. METHODS: The investigators conducted a literature review as well as a review of the psychiatric histories of 137 patients with bvFTD, and patients with a prior diagnosis of bipolar disorder were identified. The clinical characteristics of patients' bipolar disorder diagnosis, family history, features of bvFTD, and results from fluorodeoxyglucose positron emission tomography (FDG-PET), as well as autopsy findings, were evaluated. RESULTS: Among the 137 patients, 14 (10.2%) had a psychiatric diagnosis of bipolar disorder, eight of whom met criteria for bipolar disorder (type I, N=6; type II, N=2) 6-12 years preceding onset of classic symptoms of progressive bvFTD. Seven of the eight patients with bipolar disorder had a family history of mood disorders, four had bitemporal predominant hypometabolism on FDG-PET, and two had a tauopathy involving temporal lobes on autopsy. Three additional patients with late-onset bipolar I disorder proved to have a nonprogressive disorder mimicking bvFTD. The remaining three patients with bvFTD had prior psychiatric symptoms that did not meet criteria for a diagnosis of bipolar disorder. The literature review and the findings for one patient further suggested a shared genetic mutation in some patients. CONCLUSIONS: Manic or hypomanic episodes years before other symptoms of bvFTD may be a prodrome of this dementia, possibly indicating anterior temporal involvement in bvFTD. Other patients with late-onset bipolar disorder exhibit the nonprogressive frontotemporal dementia phenocopy syndrome. Finally, a few patients with bvFTD have a genetic predisposition for both disorders.

Neurotrophic factors in bipolar disorders patients with manic episode

Background/aim: Neurotrophins are one of the most important molecule groups affecting cerebral neuroplasticity. The amount of evidence about the role of changes in neuroplasticity in the pathophysiology of bipolar disease is growing. Materials and methods: We measured serum levels of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-3 (NT-3), glial cell-line derived neurotrophic factor (GDNF), vascular endothelial growth factor (VEGF), insulin-like growth factor-1 (IGF-1), fibroblast growth factor (FGF)-2, neuritin 1 (Nrn 1) in bipolar 1 manic episode patients (n = 45) and healthy control group. Results: When controlled for age, BMI and cortisol, it was found that the serum levels of BDNF, NGF, NT-3, VEGF and FGF-2 of bipolar manic episode patients were not statistically different compared to those of the control group. GDNF level and Nrn 1 levels were significantly lower (P = 0.003 and P = 0.025 respectively) while IGF-1 levels were significantly higher than the control group (P = 0.0001). ROC analysis was performed and the area under the the curve was calculated as 0.737, 0.766 for GDNF, IGF-1 respectively. Conclusion: The changes in the levels of GDNF, IGF-1 and Nrn 1 might be involved in pathopysiology of bipolar disorder, and GDNF, IGF-1 may be considered as state markers in bipolar manic episode.

Delirious mania as a frequent and recognizable neuropsychiatric syndrome in patients with anti-NMDAR encephalitis.

BACKGROUND: Previous case reports showed that delirious mania could be one of the many neuropsychiatric presentations of Anti-N-methyl-d-aspartate receptor encephalitis (ANMDARE). OBJECTIVE: To evaluate the frequency of delirious mania and its associated factors in ANMDARE. METHOD: A prospective study, including all patients with ANMDARE admitted to the National Institute of Neurology and Neurosurgery of Mexico, from January 2014 to April 2019. The diagnosis of delirious mania was established when diagnostic criteria for mania and delirium were fulfilled simultaneously. RESULTS: 79 patients with definitive ANMDARE were included. Delirious mania was identified in 20 (25.3%) of these patients. Catatonia, psychomotor agitation, disinhibition, impulsivity, and grandiose delusions were significantly associated with delirious mania. Also, a lower frequency of EEG abnormalities, absence of extreme delta brush, and a shorter hospital stay was observed in these patients. CONCLUSION: Delirious mania proved to be a frequent neuropsychiatric presentation of ANMDARE, and its presence should warn the physician about the possibility of this diagnosis. It was mainly associated with higher rates of catatonia, psychomotor agitation, disinhibition, and psychotic symptoms. The lack of recognition of delirious mania as a neuropsychiatric presentation in ANMDARE may be a source of diagnostic and therapeutic errors, as most physicians associate this with bipolar disorder.

The structure of mania: An overview of factorial analysis studies.

BACKGROUND: Operational definitions of mania are based on expert consensus rather than empirical data. The aim of this study is to identify the key domains of mania, as well as the relevance of the different signs and symptoms of this clinical construct. METHODS: A review of latent factor models studies in manic patients was performed. Before extraction, a harmonization of signs and symptoms of mania and depression was performed in order to reduce the variability between individual studies. RESULTS: We identified 12 studies fulfilling the inclusion criteria and comprising 3039 subjects. Hyperactivity was the clinical item that most likely appeared in the first factor, usually covariating with other core features of mania, such as increased speech, thought disorder, and elevated mood. Depressive-anxious features and irritability-aggressive behavior constituted two other salient dimensions of mania. Altered sleep was frequently an isolated factor, while psychosis appeared related to grandiosity, lack of insight and poor judgment. CONCLUSIONS: Our results confirm the multidimensional nature of mania. Hyperactivity, increased speech, and thought disorder appear as core features of the clinical construct. The mood experience could be heterogeneous, depending on the co-occurrence of euphoric (elevated mood) and dysphoric (irritability and depressive mood) emotions of varying intensity. Results are also discussed regarding their relationship with other constitutive elements of bipolar disorder, such as mixed and depressive states.

Opposing Changes in the Functional Architecture of Large-Scale Networks in Bipolar Mania and Depression.

OBJECTIVE: Manic and depressive phases of bipolar disorder (BD) show opposite symptoms in psychomotor, thought, and affective dimensions. Neuronally, these may depend on distinct patterns of alterations in the functional architecture of brain intrinsic activity. Therefore, the study aimed to characterize the spatial and temporal changes of resting-state activity in mania and depression, by investigating the regional homogeneity (ReHo) and degree of centrality (DC), in different frequency bands. METHODS: Using resting-state functional magnetic resonance imaging (fMRI), voxel-wise ReHo and DC were calculated-in the standard frequency band (SFB: 0.01-0.10 Hz), as well as in Slow5 (0.01-0.027 Hz) and Slow4 (0.027-0.073 Hz)-and compared between manic (n = 36), depressed (n = 43), euthymic (n = 29) patients, and healthy controls (n = 112). Finally, clinical correlations were investigated. RESULTS: Mania was mainly characterized by decreased ReHo and DC in Slow4 in the medial prefrontal cortex (as part of the default-mode network [DMN]), which in turn correlated with manic symptomatology. Conversely, depression was mainly characterized by decreased ReHo in SFB in the primary sensory-motor cortex (as part of the sensorimotor network [SMN]), which in turn correlated with depressive symptomatology. CONCLUSIONS: Our data show a functional reconfiguration of the spatiotemporal structure of intrinsic brain activity to occur in BD. Mania might be characterized by a predominance of sensorimotor over associative networks, possibly driven by a deficit of the DMN (reflecting in internal thought deficit). Conversely, depression might be characterized by a predominance of associative over sensorimotor networks, possibly driven by a deficit of the SMN (reflecting in psychomotor inhibition).

Disorders of human consciousness in the Tri-partite synapses.

Conscious Action Theory extends quantum theory to macroscopic phenomena and suggests physical correlates of consciousness occur at the intersection of external measurement signals and internally generated signals from memories that model the outside world. This physical theory predicts conscious phenomena happen at all scales and differ only by the size and complexity of material organizations involved. At the scale of the human "Brain" consciousness is predicted to happen where the processing loop of activity in the Glial network interfaces with the real world input-output processing loop of the Nuronal network. This happens at the Tripartite synapses creating an intersection plenum in biological systems that produces the experience of empty space and the objects it contains. Analysis of the transmitter-receptor strengths implementing the control and feedback between the Glial and Neuronal networks indicate imbalances can be directly related to schizophrenia, mania, epilepsy, and depression. This paper addresses three topics supporting the above mechanisms for normal consciousness functioning and its medical deviations. First we preset the architecture of a pan-psychic physical theory, which supports the hypothesis that tri-partite synapses are the location of human conscious experience. Second we discuss the inner workings of the Glial network to support long term memory and control functions corresponding to the inner feeling of the "I" self. Third, we consider the relation between psychiatric conditions and the balance states between the number of neuronal transmitters and astrocytic receptors.

Nitrated meat products are associated with mania in humans and altered behavior and brain gene expression in rats.

Mania is a serious neuropsychiatric condition associated with significant morbidity and mortality. Previous studies have suggested that environmental exposures can contribute to mania pathogenesis. We measured dietary exposures in a cohort of individuals with mania and other psychiatric disorders as well as in control individuals without a psychiatric disorder. We found that a history of eating nitrated dry cured meat but not other meat or fish products was strongly and independently associated with current mania (adjusted odds ratio 3.49, 95% confidence interval (CI) 2.24-5.45, p < 8.97 × 10-8). Lower odds of association were found between eating nitrated dry cured meat and other psychiatric disorders. We further found that the feeding of meat preparations with added nitrate to rats resulted in hyperactivity reminiscent of human mania, alterations in brain pathways that have been implicated in human bipolar disorder, and changes in intestinal microbiota. These findings may lead to new methods for preventing mania and for developing novel therapeutic interventions.

Blackberry extract improves behavioral and neurochemical dysfunctions in a ketamine-induced rat model of mania.

Bipolar disorder is a chronic mood disorder characterized by episodes of mania and depression. The aim of this study was to investigate the effects of blackberry extract on behavioral parameters, oxidative stress and inflammatory markers in a ketamine-induced model of mania. Animals were pretreated with extract (200 mg/kg, once a day for 14 days), lithium chloride (45 mg/kg, twice a day for 14 days), or vehicle. Between the 8th and 14th days, the animals received an injection of ketamine (25 mg/kg) or vehicle. On the 15th day, thirty minutes after ketamine administration, the animals' locomotion was assessed using open-field apparatus. After the experiments, the animals were euthanized and cerebral structures were removed for neurochemical analyses. The results showed that ketamine treatment induced hyperlocomotion and oxidative damage in the cerebral cortex, hippocampus and striatum. In contrast, pretreatment with the extract or lithium was able to prevent hyperlocomotion and oxidative damage in the cerebral cortex, hippocampus, and striatum. In addition, IL-6 and IL-10 levels were increased by ketamine, while the extract prevented these effects in the cerebral cortex. Pretreatment with the extract was also effective in decreasing IL-6 and increasing the level of IL-10 in the striatum. In summary, our findings suggest that blackberry consumption could help prevent or reduce manic episodes, since this extract have demonstrated neuroprotective properties as well as antioxidant and anti-inflammatory effects in the ketamine-induced mania model.