Microbiota alterations in proline metabolism impact on depression through GABA and ECM homeostasis

Abstract The microbiota-gut-brain axis has emerged as a novel target in depression, a disorder with low treatment efficacy. However, the field is dominated by underpowered studies focusing on major depression not addressing microbiome functionality, compositional nature, or confounding factors. We applied a multi-omics approach combining pre-clinical models with three human cohorts including mild-depressed patients. Microbial functions and metabolites converging into glutamate/GABA metabolism, particularly proline, were linked to depression. Whole-brain dynamics revealed rich club network disruptions associated with depression and circulating proline. Proline supplementation in mice exacerbated depression along with microbial translocation. Human microbiota transplantation induced an emotional-impaired phenotype in mice and alterations in GABA-, proline-, and extracellular matrix-related pre-frontal cortex genes. Targeting the microbiome and dietary proline may open new windows for an efficient depression treatment.

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Whole-Brain Dynamics in Aging: Disruptions in Functional Connectivity and the Role of the Rich Club

Cerebral Cortex ◽

10.1093/cercor/bhaa367 ◽

2020 ◽

Author(s):

Anira Escrichs ◽

Carles Biarnes ◽

Josep Garre-Olmo ◽

José Manuel Fernández-Real ◽

Rafel Ramos ◽

...

Keyword(s):

Functional Connectivity ◽

Resting State ◽

Functional Network ◽

Brain Dynamics ◽

Whole Brain ◽

Rich Club ◽

Brain Functional Network ◽

Age Related ◽

Age Range ◽

The Brain

Abstract Normal aging causes disruptions in the brain that can lead to cognitive decline. Resting-state functional magnetic resonance imaging studies have found significant age-related alterations in functional connectivity across various networks. Nevertheless, most of the studies have focused mainly on static functional connectivity. Studying the dynamics of resting-state brain activity across the whole-brain functional network can provide a better characterization of age-related changes. Here, we employed two data-driven whole-brain approaches based on the phase synchronization of blood-oxygen-level-dependent signals to analyze resting-state fMRI data from 620 subjects divided into two groups (middle-age group (n = 310); age range, 50–64 years versus older group (n = 310); age range, 65–91 years). Applying the intrinsic-ignition framework to assess the effect of spontaneous local activation events on local–global integration, we found that the older group showed higher intrinsic ignition across the whole-brain functional network, but lower metastability. Using Leading Eigenvector Dynamics Analysis, we found that the older group showed reduced ability to access a metastable substate that closely overlaps with the so-called rich club. These findings suggest that functional whole-brain dynamics are altered in aging, probably due to a deficiency in a metastable substate that is key for efficient global communication in the brain.

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Identification of ephrinB2 positive vessels in non-Hodgkin lymphoma subtypes.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.e19542 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. e19542-e19542

Author(s):

Kenneth Stuart Cohen ◽

Mina Jamali ◽

Elizabeth Hyjek

Keyword(s):

Tumor Biology ◽

Tyrosine Kinase Signaling ◽

Eph Receptor ◽

Follicular Hyperplasia ◽

Reverse Signaling ◽

Tissue Sections ◽

Non Hodgkin Lymphoma ◽

Clinical Models ◽

Novel Target ◽

The University

e19542 Background: Current anti-angiogenic therapies for tumors target signaling pathways such as VEGF. However, the role of alternative vascular pathways in tumor biology in general, and lymphoma biology specifically, are less well understood. Recently, the Eph receptor tyrosine kinase signaling pathway has emerged as a novel target for therapeutic inhibition. The EphB family member EphB4, and its reverse signaling ligand ephrinB2, are indispensible for developmental angiogenesis. Inhibition of ephrinB2 signaling results in impaired tumor growth in pre-clinical models. We therefore sought to determine if ephrinB2 is expressed in the microenvironment of human lymphomas and thereby represents a novel therapeutic target. Methods: We evaluated by immunohistochemistry on paraffin tissue sections expression of ephrinB2, CD34 (endothelial cells) and CD163 (macrophages) in LN biopsies from 12 cases of FL and 11 cases of DLBCL retrieved from the archives of the Department of Pathology at the University of Chicago (2000-2011). Eleven cases of follicular hyperplasia or quiescent LNs were used as controls (Cs). Slides were digitally scanned and examined both semi-quantitatively and by digital image analysis. Stained cells were quantified both in internal areas and at lymphoma-fat interfaces. Results: CD34+ microvessel densities were comparable between DLBCL and C groups but showed a significantly higher trend of interface angiogenic sprouts in FLs. Interface recruited CD163+ cell numbers were significantly higher in DLBCLs than in both FLs and Cs (p<0.0001). EphrinB2-expressing blood vessels were significantly increased in FLs but not in DLBCL. Conclusions: FLs demonstrate an increase in ephrinB2+/CD34+ vessels at the lymphoma-fat interface. In contrast, DLBCLs demonstrate no increase in ephrinB2+ vessels versus controls. However, DLBCLs were notable for increased recruitment of CD163+ macrophages at the tumor/host interface. These data represent the first analysis of ephrinB2 expression in human lymphomas and demonstrate heterogeneity between locations within a lymphoma and between histologic subtypes. Analysis of ephrinB2 in human lymphomas reveals marked heterogeneity in lymphoma microenvironmental domains.

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Whole-brain dynamics in aging: disruptions in functional connectivity and the role of the rich club

10.1101/2020.06.29.164343 ◽

2020 ◽

Author(s):

Anira Escrichs ◽

Carles Biarnes ◽

Josep Garre-Olmo ◽

José Manuel Fernández-Real ◽

Rafel Ramos ◽

...

Keyword(s):

Functional Connectivity ◽

Resting State ◽

Resting State Fmri ◽

Brain Dynamics ◽

Whole Brain ◽

Rich Club ◽

Brain Functional Network ◽

Age Related ◽

Age Range ◽

The Brain

AbstractNormal aging causes disruptions in the brain that can lead to cognitive decline. Resting-state fMRI studies have found significant age-related alterations in functional connectivity across various networks. Nevertheless, most of the studies have focused mainly on static functional connectivity. Studying the dynamics of resting-state brain activity across the whole-brain functional network can provide a better characterization of age-related changes. Here we employed two data-driven whole-brain approaches based on the phase synchronization of blood-oxygen-level-dependent (BOLD) signals to analyze resting-state fMRI data from 620 subjects divided into two groups (‘middle-age group’ (n=310); age range, 50-65 years vs. ‘older group’ (n=310); age range, 66-91 years). Applying the Intrinsic-Ignition Framework to assess the effect of spontaneous local activation events on local-global integration, we found that the older group showed higher intrinsic ignition across the whole-brain functional network, but lower metastability. Using Leading Eigenvector Dynamics Analysis, we found that the older group showed reduced ability to access a metastable substate that closely overlaps with the so-called rich club. These findings suggest that functional whole-brain dynamics are altered in aging, probably due to a deficiency in a metastable substate that is key for efficient global communication in the brain.

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Treating Depression and other Serotonin Deficiency Brain Disorders with Tryptophan

Current Psychopharmacologye ◽

10.2174/2211556010666211202104548 ◽

2021 ◽

Vol 10 ◽

Author(s):

Darakhshan Jabeen Haleem

Keyword(s):

Treatment Efficacy ◽

Essential Amino Acid ◽

Tryptophan Hydroxylase ◽

Depression Treatment ◽

Brain Disorders ◽

Serotonin Synthesis ◽

Brain Disorder ◽

Psychiatric Illnesses ◽

Serotonin Deficiency ◽

Rate Limiting

: Deficits of brain serotonin (5-hydroxytryptamine; 5-HT) are implicated in a number of psychiatric illnesses including depression. Treatment efficacy of this highly prevalent brain disorder is not adequate largely because serotonin stores are depleted. Tryptophan an essential amino acid is the sole precursor of serotonin; its systemic or oral administration increases serotonin synthesis because tryptophan hydroxylase, the rate limiting enzyme of 5-HT biosynthesis, is physiologically unsaturated with its substrate. The present article targets importance of tryptophan supplementation in treating serotonin deficiency and improving therapeutic intervention in depression and other serotonin deficiency brain disorders.

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Structural Features of the Human Connectome That Facilitate the Switching of Brain Dynamics via Noradrenergic Neuromodulation

Frontiers in Computational Neuroscience ◽

10.3389/fncom.2021.687075 ◽

2021 ◽

Vol 15 ◽

Author(s):

Carlos Coronel-Oliveros ◽

Samy Castro ◽

Rodrigo Cofré ◽

Patricio Orio

Keyword(s):

Structural Connectivity ◽

Structural Features ◽

Global Scale ◽

Brain Dynamics ◽

Connectivity Matrix ◽

Rich Club ◽

Spatial Features ◽

Brain States ◽

The Rich ◽

Meso Scale

The structural connectivity of human brain allows the coexistence of segregated and integrated states of activity. Neuromodulatory systems facilitate the transition between these functional states and recent computational studies have shown how an interplay between the noradrenergic and cholinergic systems define these transitions. However, there is still much to be known about the interaction between the structural connectivity and the effect of neuromodulation, and to what extent the connectome facilitates dynamic transitions. In this work, we use a whole brain model, based on the Jasen and Rit equations plus a human structural connectivity matrix, to find out which structural features of the human connectome network define the optimal neuromodulatory effects. We simulated the effect of the noradrenergic system as changes in filter gain, and studied its effects related to the global-, local-, and meso-scale features of the connectome. At the global-scale, we found that the ability of the network of transiting through a variety of dynamical states is disrupted by randomization of the connection weights. By simulating neuromodulation of partial subsets of nodes, we found that transitions between integrated and segregated states are more easily achieved when targeting nodes with greater connection strengths—local feature—or belonging to the rich club—meso-scale feature. Overall, our findings clarify how the network spatial features, at different levels, interact with neuromodulation to facilitate the switching between segregated and integrated brain states and to sustain a richer brain dynamics.

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Novel target for depression treatment evaluated in open-label trial

The Brown University Psychopharmacology Update ◽

10.1002/pu.30402 ◽

2019 ◽

Vol 30 (3) ◽

pp. 6-6

Keyword(s):

Depression Treatment ◽

Open Label ◽

Open Label Trial ◽

Novel Target

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Depression treatment in women and men with bipolar affective disorder: a comparative study

Neurology neuropsychiatry Psychosomatics ◽

10.14412/2074-2711-2021-3-59-66 ◽

2021 ◽

Vol 13 (3) ◽

pp. 59-66

Author(s):

N. A. Tyuvina ◽

A. E. Stolyarova ◽

V. V. Balabanova ◽

K. M. Bunkova ◽

E. N. Efremova

Keyword(s):

Affective Disorder ◽

Clinical Global Impression ◽

Treatment Efficacy ◽

Rating Scale ◽

Bipolar Affective Disorder ◽

Severe Depression ◽

Severity Of Illness ◽

Depression Treatment ◽

Significant Treatment ◽

Men And Women

Objective: to compare depression treatment efficacy with and without antidepressants (ADs) in men and women with bipolar affective disorder (BAD).Patients and methods. We enrolled 100 patients with BAD (F31.3–F31.5 according to ICD-10), including 50 women aged 33.0 [23.0; 50.2] years and 50 men aged 37.5 [29.5; 47.2] years using prospective and retrospective methods. Various antidepressants, normothymics, antipsychotics combinations were used to treat depression. We performed a comparative analysis of treatment efficacy with and without antidepressants in men and women subgroups. Clinical assessment at the baseline and the end of 1, 2, 4, 6-th week of therapy (or at discharge) included a specially developed clinical examination chart and the following psychometric scales: Montgomery-Asberg Depression Rating Scale (MADRS), Clinical Global Impression – Severity of illness (CGI-S), Clinical Global Impression – Improvement (CGI-I).Results and discussion. Women tended to have a slower improvement in the condition compared to men. Maximum reduction in MADRS score and a CGI-I, CGI-S higher frequency of clinical improvement and remission was observed in men and women who did not receive antidepressants than patients who did not receive antidepressants. When BAD type was included in the analysis, in patients treated with antidepressants, transient symptoms of the opposite pole occurred in 24.7% of patients of both sexes with bipolar affective I disorder (BAD I) and in 16.8% with bipolar affective II disorder (BAD II). There were no significant gender differences in patients with BAD I, while women predominated in BAD II group (22.5% compared to 7.8% men). No significant treatment-emergent affective switch was observed with tricyclic antidepressants and selective serotonin and norepinephrine reuptake inhibitors in both groups (21; 16.7; 16.7% in men and 28; 21.8; 12.5% in women, respectively). The assessment of intermission revealed that women were significantly more likely to have shorter periods between phases (42% compared to 22% in men). In addition, women were significantly more likely to have shorter periods between phases (42% compared to 22% in men) when the intermission duration was included in the analysis. In some patients with severe depression and infective first-line therapy (anticonvulsants and atypical antipsychotics), antidepressants prescription can increase treatment effectiveness. However, several factors should be considered, such as BAD type and variant, depression severity, treatment-emergent affective switch in history, and gender.Conclusion. A decision about antidepressants' dosage and treatment duration requires a dynamic follow-up of the patient in order to discontinue the antidepressants as fast as possible and decrease the risk of treatment-emergent affective switch and shortening of remission period.

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The effect of external stimulation on functional networks in the aging healthy human brain

10.1101/2021.11.19.469206 ◽

2021 ◽

Author(s):

Anira Escrichs ◽

Yonatan Sanz Perl ◽

Noelia Martinez-Molina ◽

Carles Biarnes ◽

Josep Garre ◽

...

Keyword(s):

In Silico ◽

Brain Area ◽

Resting State Fmri ◽

Brain Dynamics ◽

Healthy Human ◽

Whole Brain ◽

External Stimulation ◽

Rich Club ◽

Brain States ◽

The Brain

Understanding the brain changes occurring during aging can provide new insights for developing treatments that alleviate or reverse cognitive decline. Neurostimulation techniques have emerged as potential treatments for brain disorders and to improve cognitive functions. Nevertheless, given the ethical restrictions of neurostimulation approaches, in silico perturbation protocols based on causal whole-brain models are fundamental to gaining a mechanistic understanding of brain dynamics. Furthermore, this strategy could serve as a more specific biomarker relating local activity with global brain dynamics. Here, we used a large resting-state fMRI dataset divided into middle-aged (N=310, aged < 65 years) and older adults (N=310, aged >= 65) to characterize brain states in each group as a probabilistic metastable substate (PMS) space, each with a probabilistic occurrence and frequency. Then, we fitted the PMS to a whole-brain model and applied in silico stimulations with different intensities in each node to force transitions from the brain states of the older group to the middle-age group. We found that the precuneus, a brain area belonging to the default mode network and the rich club, was the best stimulation target. These findings might have important implications for designing neurostimulation interventions to revert the effects of aging on whole-brain dynamics.

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System-Wide Magnet Therapy in Depression Treatment

Vestnik nevrologii, psihiatrii i nejrohirurgii (Bulletin of Neurology, Psychiatry and Neurosurgery) ◽

10.33920/med-01-2007-01 ◽

2020 ◽

pp. 12-26

Author(s):

Ivan Bakhmutskiy ◽

Viktor Kosenko ◽

Leonid Shulkin ◽

Svetlana Guba ◽

Nikolay Bakhmutskiy

Keyword(s):

Treatment Efficacy ◽

Antidepressant Treatment ◽

Treatment Method ◽

Main Group ◽

Rotating Magnetic Field ◽

Control Group ◽

Depression Treatment ◽

Current Frequency ◽

Number Of Patients ◽

Magnetic Therapy

Study purpose. Study of the system-wide magnetic therapy efficacy in major depressive disorder treatment. Materials and methods. Depression patients were assigned to two groups: the control group and the main one. The control group underwent conventional antidepressant treatment while for the main group conventional treatment was combined with system-wide magnetic therapy. In the course of treatment, patients were exposed to a variable-amplitude rotating magnetic field with 2,2 MT induction and 100 Hz current frequency for 30 minutes. The treatment efficacy was evaluated on the Hamilton scale after 4 weeks of treatment. Results and Conclusion. The number of patients (responders) in remission,  7 points on the Hamilton scale, was significantly greater in the main group than it was in the control one: 18 and 28 in the control group and the main group, respectively (p < 0,01). Significant (by over 50 %) reduction in six symptoms was achieved in the main group: suicidal thoughts (80,65 %), critical attitude to the disease (75,0 %), late insomnia (72,5 %), early insomnia (70,91 %), agitation (53,16 %). Symptoms decreased by 35,84 % and 50,91 % in the control group and the main group, respectively (p < 0,05), by total scores on the Hamilton scale. The treatment efficacy under CNE was 0,643 and 0,491 in the control group and the main group, respectively, and as 0,491 < 0,643, we proved statistically that treatment in the main group is significantly more effective (p = 0,000021). With the procedure being well tolerated and causing no adverse effects during treatment, this depression treatment method can be recommended for clinical practice.

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