Biology subjects

Brydges, C. R.

Publications and source records attributed to Brydges, C. R..

3 recordsLinked to original sources

bioRxiv2022

Gut microbiome-linked metabolites in the pathobiology of depression and anxiety - a role for bile acids

BackgroundThe gut microbiome may play a role in the pathogenesis of neuropsychiatric diseases including major depressive disorder (MDD). Bile acids (BAs) are steroid acids that are synthesized in the liver from cholesterol and further processed by gut-bacterial enzymes, thus requiring both human and gut microbiome enzymatic processes in their metabolism. BAs participate in a range of important host functions such as lipid transport and metabolism, cellular signaling and regulation of energy homeostasis. BAs have recently been implicated in the pathophysiology of Alzheimers and several other neuropsychiatric diseases, but the biochemical underpinnings of these gut microbiome-linked metabolites in the pathophysiology of depression and anxiety remains largely unknown. MethodUsing targeted metabolomics, we profiled primary and secondary BAs in the baseline serum samples of 208 untreated outpatients with MDD. We assessed the relationship of BA concentrations and the severity of depressive and anxiety symptoms as defined by the 17-item Hamilton Depression Rating Scale (HRSD17) and the 14-item Hamilton Anxiety Rating Scale (HRSA-Total), respectively. We also evaluated whether the baseline metabolic profile of BA informs about treatment outcomes. ResultsThe concentration of the primary BA chenodeoxycholic acid (CDCA) was significantly lower at baseline in both severely depressed (log2 fold difference (LFD)= -0.48; p=0.021) and highly anxious (LFD= -0.43; p=0.021) participants compared to participants with less severe symptoms. The gut bacteria-derived secondary BAs produced from CDCA such as lithocholic acid (LCA) and several of its metabolites, and their ratios to primary BAs, were significantly higher in the more anxious participants (LFDs range=[0.23,1.36]; ps range=[6.85E-6,1.86E-2]). The interaction analysis of HRSD17 and HRSA-Total suggested that the BA concentration differences were more strongly correlated to the symptoms of anxiety than depression. Significant differences in baseline CDCA (LFD= -0.87, p=0.0009), isoLCA (LFD= -1.08, p=0.016) and several BA ratios (LFDs range [0.46, 1.66], ps range [0.0003, 0.049]) differentiated treatment failures from remitters. ConclusionIn patients with MDD, BA profiles representing changes in gut microbiome compositions are associated with higher levels of anxiety and increased probability of first-line treatment failure. If confirmed, these findings suggest the possibility of developing gut microbiome-directed therapies for MDD characterized by gut dysbiosis.

neuroscience↗

bioRxiv2020

Indoxyl sulfate, a gut microbiome-derived uremic toxin, is associated with psychic anxiety and its functional magnetic resonance imaging-based neurologic signature

BackgroundIt is unknown whether indoles, metabolites of tryptophan that are derived entirely from bacterial metabolism in the gut, are associated with symptoms of depression and anxiety. MethodsSerum samples (baseline, 12 weeks) were drawn from participants (n=196) randomized to treatment with cognitive behavioral therapy (CBT), escitalopram, or duloxetine for major depressive disorder. ResultsBaseline indoxyl sulfate abundance was positively correlated with severity of psychic anxiety and total anxiety and with resting state functional connectivity to a network that processes aversive stimuli (which includes the subcallosal cingulate cortex (SCC-FC), bilateral anterior insula, right anterior midcingulate cortex, and the right premotor areas). The relation between indoxyl sulfate and psychic anxiety was mediated only through the metabolites effect on the SCC-FC with the premotor area. Baseline indole abundances were unrelated to post-treatment outcome measures, which suggests that CBT and antidepressant medications relieve anxiety via mechanisms unrelated to gut microbiota. ConclusionsA peripheral gut microbiome-derived metabolite was associated with altered neural processing and with psychiatric symptom (anxiety) in humans, which provides further evidence that gut microbiome disruption can contribute to neuropsychiatric disorders that may require different therapeutic approaches.

neuroscience↗

bioRxiv2018

Fast trial-by-trial fronto-parietal cortical dynamics of conflict detection and context updating in a flanker task

The traditional N2 and P3 components of the human event-related potential (ERP) have been associated with cognitive control. However, recent research has found that the traditional target P3 consists of a mixture of stimulus-locked, response-locked, and latency variable P3-like positivities that can be functionally and topographically dissociated from one another. The current study aimed to extend previous results by examining target N2 and P3-like subcomponents indexing conflict detection and context updating at both low- and high-order levels in the neural hierarchy during control of target detection in a flanker task. Electroencephalographic (EEG) signals were recorded from 45 young adults while they completed a hybrid go/nogo flanker task, and Residue Iteration Decomposition (RIDE) was applied to functionally dissociate these peaks and establish their roles in conflict detection and context updating. Frequentist and Bayesian analyses showed a stimulus-locked frontal N2 revealing early conflict detection and fast categorization of nogo, congruous and incongruous trials, resulting in subsequent frontal P3-like activity (high-order context updating) elicited by infrequent nogo trials in the latency-variable RIDE cluster, and by the perceptually difficult incongruous trials in the response-locked cluster. In turn, the perceptually easier and more frequent congruous trials did not elicit frontal P3-like activity, although all trial types did elicit parietally distributed P3-like activity (low-order context updating), mostly within the latency-variable cluster. These novel findings support the presence of up to three distinct high-order task-set units regulating performance in our flanker task, as indexed by split-second, dynamic information transmission across frontal and parietal scalp regions.

neuroscience↗