Understanding the neural processes that govern the human gut-brain connection has been challenging due to the inaccessibility of the body′s interior. In this study, we aimed to identify neural responses to gastrointestinal sensation (i.e., the neural basis of ′gut feelings′) in healthy humans using a minimally invasive mechanosensory probe. Combining electroencephalography and electrogastrography with signal detection theory measures, we quantified brain, stomach, and perceptual (button-press) responses following the ingestion of a vibrating capsule. The relationship between vibration strength and perceptual sensitivity was evaluated using two stimulation conditions (normal and enhanced). Most individuals successfully perceived capsule stimulation in both conditions, as evidenced by above chance accuracy scores. Perceptual accuracy improved significantly during the enhanced relative to normal stimulation, which was associated with faster reaction time and reduced reaction time variability. Stomach stimulation induced responses in a cluster of parieto-occipital leads near the midline via a late positive potential emerging 300-600 milliseconds after stimulation onset. Moreover, these ′gastric evoked potentials′ showed dose-dependent increases in amplitude and were significantly correlated with perceptual accuracy. Our findings are consistent with recent neurogastric and optogenetic studies demonstrating a role for posteromedial cortices in gastrointestinal interoception and body dissociation and highlight a unique form of enterically-focused sensory monitoring within the human brain. Overall, these results show that this minimally invasive approach could serve as a useful tool for understanding gut-brain interactions in healthy and clinical populations.
Clinical interpretation of human mitochondrial DNA (mtDNA) variants has been challenging for technical and biological reasons but the involvement of dysfunctional mitochondria in many diseases makes it imperative to have a validated assay for detecting pathogenic variants. We have tested several methods to identify those best suited to detect and confirm mtDNA variants. The choice of methods is dependent on the amount of DNA available for testing and the sensitivity required for detecting low--level heteroplasmies. There is a tradeoff between a polymerase's ability to amplify small amounts of DNA and its ability to generate accurate sequence. We report a simple method to measure heteroplasmy levels of large deletions from NGS data alone without need for qPCR or other methods. Use of HapMap samples for standardization needs to be done with caution as most have novel heteroplasmic sites that have arisen during immortalization/cell culture processes. Different batches of DNA can have variable sequence. In contrast, we observed no de novo heteroplasmies in healthy mother--child pairs studied using blood or saliva though the frequency of pre--existing heteroplasmies often changed dramatically across generations. Long--read nanopore sequencing of individuals with two heteroplasmies suggested a random distribution of variants on single molecules but technical artifacts prevent certainty on this finding. Urine provides an additional readily accessible source of mtDNA that can be used for bone marrow transplant recipients whose saliva/blood mtDNA may be contaminated by the BMT donor's mtDNA. We have characterized cells suspended in urine via expression profiling and shown them to be primarily mucosal cells that are independent of . CC-BY 4.0 International license It is made available under a (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/222109 doi: bioRxiv preprint first posted online 3 blood. Understanding the pitfalls of the various mtDNA sequencing methods allows development of reliable and accurate tests suitable for clinical diagnostics. Author SummaryMitochondrial DNA is important for many diseases but it is present at many copies per cell so is harder to check for mutations compared to nuclear DNA. We have studied mitochondrial DNA in different ways to see how it changes across generations and in different locations in the body. The tests need to be much more sensitive than nuclear DNA tests so that we can detect mutations down to 1%. We have shown that mitochondrial DNA changes when cell lines are used but saliva, blood and cells in the urine can all be used for testing. Cells in the urine originate as mucosal cells and are independent of blood. We developed a new method for analyzing large deletions that means sequencing data alone can be used for measuring the frequency of deletions. We also followed a family with two variable sites to better understand ho...
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