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Summary: Fever suffered during the first trimester of pregnancy can lead to facial deformities and heart defects in the fetus, a new study reveals.

Source: UC Berkeley.

Fevers in a mother’s first trimester of pregnancy increase the baby’s risk for some heart defects and facial deformities such as cleft lip or palate, but exactly how this happens is unclear. Scientists have debated whether a virus or other infection causes the defects, or if fever alone is the problem.

UC Berkeley researchers have helped find evidence indicating that the fever itself, not its cause, is what interferes with the development of the heart and jaw during the first three to eight weeks of pregnancy. The findings, demonstrated in animal embryos, were published Oct. 10 in the journal Science Signaling.

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The work, a collaboration with scientists at Duke University, provides new leads as scientists continue investigating heart defects, which affect 1 percent of live births in the U.S., and cleft lip or palate, affecting about 4,000 infants per year.

“Congenital heart and cranial facial defects are very common in live births, but most of the time they have unknown causes,” said senior author Chunlei Liu, an associate professor of neuroscience and electrical engineering and computer sciences at Berkeley. “Our study identified a specific molecular pathway that links maternal fever directly to some of those defects.”

The results suggest a portion of congenital birth defects could be prevented if fevers are treated through the judicious use of acetaminophen during the first trimester, said co-senior author Eric Benner, a neonatologist and assistant professor of pediatrics at Duke.

“My hope is that right now, as women are planning to become pregnant and their doctors advise them to start taking prenatal vitamins and folic acid, their doctor also informs them if they get a fever, they should not hesitate to call and consider taking a fever reducer, specifically acetaminophen (Tylenol), which has been studied extensively and determined to be safe during the first trimester,” Benner said. “While doctors advise most women to avoid any drug during pregnancy, there may be benefits to taking acetaminophen to reduce fever. Women should discuss all risks and benefits with their doctors.”

Benner cautions that nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, naproxen and aspirin also reduce fevers, but should not be used during pregnancy. There is also ongoing debate over whether sustained use of acetaminophen is safe during pregnancy to manage ongoing conditions such as arthritis, Benner said.

“However, its judicious use for an acute problem such as fever is considered safe. These findings suggest we can reduce the risk of birth defects that otherwise could lead to serious health complications requiring surgery,” he said.

To observe how fever impacts a developing fetus, the researchers studied zebrafish and chicken embryos. Among their discoveries, the scientists found that neural crest cells — cells that are critical building blocks for the heart, face and jaw — contain temperature-sensitive properties.

The researchers engineered a noninvasive magnet-based technology to create fever-like conditions in two specific temperature-sensitive ion channels called TRPV1 and TRPV4 in the neural crest cells involved in developing the heart and face. When those neural crest cells were subjected to conditions mimicking a transient fever, the embryos developed craniofacial irregularities and heart defects, including double outlet right ventricle, Tetralogy of Fallot and other outflow obstructions.

“With electrical magnetic waves coupled with engineered ion channel proteins, we are able to impact specific biological cells remotely without affecting other biochemical environments,” Liu said. “The technique can be applied to study many different cell types and their roles at various developmental stages.”

Liu is also part of team that was recently awarded $13.4 million to develop new MRI techniques and instruments to boost the resolution by a factor of 20.

The type of birth defect depends on whether the fever occurs during heart development or head and face development. What researchers still do not know is whether or how the severity or duration of a fever impacts development. Besides laboratory experiments, future epidemiological and clinical studies are also needed to evaluate those factors.

Funding: The research was supported by the Jean and George Brumley Jr. Neonatal Perinatal Research Institute, the Zeist Foundation, the Hartwell Foundation, the Mandel Foundation, the Duke Health Scholars Award, the American Heart Association (16GRNT30980012), and the National Institutes of Health (NIMH R01MH096979, NHLBI R21HL122759, and NIBIB P41EB015897), including grants specifically from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (K12HD043494, T32HD043728), and the National Institute of Biomedical Imaging and Bioengineering (T32EB001040).

Source: Brett Israel – UC Berkeley
Image Source: NeuroscienceNews.com images is credited to Liu, et al.
Original Research: Abstract for “Temperature-activated ion channels in neural crest cells confer maternal fever–associated birth defects” by Mary R. Hutson, Anna L. Keyte, Miriam Hernández-Morales, Eric Gibbs, Zachary A. Kupchinsky, Ioannis Argyridis, Kyle N. Erwin, Kelly Pegram, Margaret Kneifel, Paul B. Rosenberg, Pavle Matak, Luke Xie, Jörg Grandl, Erica E. Davis, Nicholas Katsanis, Chunlei Liu, and Eric J. Benner in Science Signaling. Published online October 10 2017 doi:10.1126/scisignal.aal4055

Abstract

Temperature-activated ion channels in neural crest cells confer maternal fever–associated birth defects

Birth defects of the heart and face are common, and most have no known genetic cause, suggesting a role for environmental factors. Maternal fever during the first trimester is an environmental risk factor linked to these defects. Neural crest cells are precursor populations essential to the development of both at-risk tissues. We report that two heat-activated transient receptor potential (TRP) ion channels, TRPV1 and TRPV4, were present in neural crest cells during critical windows of heart and face development. TRPV1 antagonists protected against the development of hyperthermia-induced defects in chick embryos. Treatment with chemical agonists of TRPV1 or TRPV4 replicated hyperthermia-induced birth defects in chick and zebrafish embryos. To test whether transient TRPV channel permeability in neural crest cells was sufficient to induce these defects, we engineered iron-binding modifications to TRPV1 and TRPV4 that enabled remote and noninvasive activation of these channels in specific cellular locations and at specific developmental times in chick embryos with radio-frequency electromagnetic fields. Transient stimulation of radio frequency–controlled TRP channels in neural crest cells replicated fever-associated defects in developing chick embryos. Our data provide a previously undescribed mechanism for congenital defects, whereby hyperthermia activates ion channels that negatively affect fetal development.

“Temperature-activated ion channels in neural crest cells confer maternal fever–associated birth defects” by Mary R. Hutson, Anna L. Keyte, Miriam Hernández-Morales, Eric Gibbs, Zachary A. Kupchinsky, Ioannis Argyridis, Kyle N. Erwin, Kelly Pegram, Margaret Kneifel, Paul B. Rosenberg, Pavle Matak, Luke Xie, Jörg Grandl, Erica E. Davis, Nicholas Katsanis, Chunlei Liu, and Eric J. Benner in Science Signaling. Published online October 10 2017 doi:10.1126/scisignal.aal4055

Source: Imperial College London.

Patients taking psilocybin to treat depression show reduced symptoms weeks after treatment following a ‘reset’ of their brain activity.

The findings come from a study in which researchers from Imperial College London used psilocybin – the psychoactive compound that occurs naturally in magic mushrooms – to treat a small number of patients with depression in whom conventional treatment had failed.

In a paper, published today in the journal Scientific Reports, the researchers describe patient-reported benefits lasting up to five weeks after treatment, and believe the psychedelic compound may effectively reset the activity of key brain circuits known to play a role in depression.

Comparison of images of patients’ brains before and one day after they received the drug treatment revealed changes in brain activity that were associated with marked and lasting reductions in depressive symptoms.

The authors note that while the initial results of the experimental therapy are exciting, they are limited by the small sample size as well as the absence of a control group – such as a placebo group – to directly contrast with the patients.

Dr Robin Carhart-Harris, Head of Psychedelic Research at Imperial, who led the study, said: “We have shown for the first time clear changes in brain activity in depressed people treated with psilocybin after failing to respond to conventional treatments.

“Several of our patients described feeling ‘reset’ after the treatment and often used computer analogies. For example, one said he felt like his brain had been ‘defragged’ like a computer hard drive, and another said he felt ‘rebooted’. Psilocybin may be giving these individuals the temporary ‘kick start’ they need to break out of their depressive states and these imaging results do tentatively support a ‘reset’ analogy. Similar brain effects to these have been seen with electroconvulsive therapy.”

Over the last decade or so, a number of clinical trials have been conducted into the safety and effectiveness of psychedelics in patients with conditions such as depression and addictions, yielding promising results.

In the recent Imperial trial, the first with psilocybin in depression, 20 patients with treatment-resistant form of the disorder were given two doses of psilocybin (10 mg and 25 mg), with the second dose a week after the first.

Nineteen of these underwent initial brain imaging and then a second scan one day after the high dose treatment. Carhart-Harris and team used two main brain imaging methods to measure changes in blood flow and the crosstalk between brain regions, with patients reporting their depressive symptoms through completing clinical questionnaires.

Immediately following treatment with psilocybin, patients reported a decrease in depressive symptoms – corresponding with anecdotal reports of an ‘after-glow’ effect characterised by improvements in mood and stress relief.

Functional MRI imaging revealed reduced blood flow in areas of the brain, including the amygdala, a small, almond-shaped region of the brain known to be involved in processing emotional responses, stress and fear. They also found increased stability in another brain network, previously linked to psilocybin’s immediate effects as well as to depression itself.

These findings provide a new window into what happens in the brains of people after they have ‘come down’ from a psychedelic, where an initial disintegration of brain networks during the drug ‘trip’, is followed by a re-integration afterwards.

Dr Carhart-Harris explained: “Through collecting these imaging data we have been able to provide a window into the after effects of psilocybin treatment in the brains of patients with chronic depression. Based on what we know from various brain imaging studies with psychedelics, as well as taking heed of what people say about their experiences, it may be that psychedelics do indeed ‘reset’ the brain networks associated with depression, effectively enabling them to be lifted from the depressed state.

The authors warn that while the initial findings are encouraging, the research is at an early stage and that patients with depression should not attempt to self-medicate, as the team provided a special therapeutic context for the drug experience and things may go awry if the extensive psychological component of the treatment is neglected. They add that future studies will include more robust designs and currently plan to test psilocybin against a leading antidepressant in a trial set to start early next year.

Professor David Nutt, Edmond J. Safra Professor of Neuropsychopharmacology and director of the Neuropsychopharmacology Unit in the Division of Brain Sciences, and senior author of the paper, added: “Larger studies are needed to see if this positive effect can be reproduced in more patients. But these initial findings are exciting and provide another treatment avenue to explore.”

Funding: The research was supported by the Medical Research Council, the Alex Mosley Charitable Trust and the Safra Foundation.

Source: Ryan O’Hare – Imperial College London
Image Source: NeuroscienceNews.com images is credited to Carhart Harris, R et al. Scientific Reports 2017.
Original Research: Full open access research for “Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms” by Robin L Carhart-Harris, Leor Roseman, Mark Bolstridge, Lysia Demetriou, J Nienke Pannekoek, Matthew B Wall, Mark Tanner, Mendel Kaelen, John McGonigle, Kevin Murphy, Robert Leech, H Valerie Curran & David J Nutt in Scientific Reports. Published online October 13 2017 doi:10.1038/s41598-017-13282-7

Abstract

Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms

Psilocybin with psychological support is showing promise as a treatment model in psychiatry but its therapeutic mechanisms are poorly understood. Here, cerebral blood flow (CBF) and blood oxygen-level dependent (BOLD) resting-state functional connectivity (RSFC) were measured with functional magnetic resonance imaging (fMRI) before and after treatment with psilocybin (serotonin agonist) for treatment-resistant depression (TRD). Quality pre and post treatment fMRI data were collected from 16 of 19 patients. Decreased depressive symptoms were observed in all 19 patients at 1-week post-treatment and 47% met criteria for response at 5 weeks. Whole-brain analyses revealed post-treatment decreases in CBF in the temporal cortex, including the amygdala. Decreased amygdala CBF correlated with reduced depressive symptoms. Focusing on a priori selected circuitry for RSFC analyses, increased RSFC was observed within the default-mode network (DMN) post-treatment. Increased ventromedial prefrontal cortex-bilateral inferior lateral parietal cortex RSFC was predictive of treatment response at 5-weeks, as was decreased parahippocampal-prefrontal cortex RSFC. These data fill an important knowledge gap regarding the post-treatment brain effects of psilocybin, and are the first in depressed patients. The post-treatment brain changes are different to previously observed acute effects of psilocybin and other ‘psychedelics’ yet were related to clinical outcomes. A ‘reset’ therapeutic mechanism is proposed.

“Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms” by Robin L Carhart-Harris, Leor Roseman, Mark Bolstridge, Lysia Demetriou, J Nienke Pannekoek, Matthew B Wall, Mark Tanner, Mendel Kaelen, John McGonigle, Kevin Murphy, Robert Leech, H Valerie Curran & David J Nutt in Scientific Reports. Published online October 13 2017 doi:10.1038/s41598-017-13282-7

Source: Western University.

In one of the largest microbiota studies conducted in humans, researchers at Western University, Lawson Health Research Institute and Tianyi Health Science Institute in Zhenjiang, Jiangsu, China have shown a potential link between healthy aging and a healthy gut.

With the establishment of the China-Canada Institute, the researchers studied the gut bacteria in a cohort of more than 1,000 Chinese individuals in a variety of age-ranges from 3 to over 100 years-old who were self-selected to be extremely healthy with no known health issues and no family history of disease. The results showed a direct correlation between health and the microbes in the intestine.

“The aim is to bring novel microbiome diagnostic systems to populations, then use food and probiotics to try and improve biomarkers of health,” said Gregor Reid, PhD, professor at Western’s Schulich School of Medicine & Dentistry and Scientist at Lawson Health Research Institute. “It begs the question – if you can stay active and eat well, will you age better, or is healthy aging predicated by the bacteria in your gut?”

The study, published this month in the journal mSphere, showed that the overall microbiota composition of the healthy elderly group was similar to that of people decades younger, and that the gut microbiota differed little between individuals from the ages of 30 to over 100.

“The main conclusion is that if you are ridiculously healthy and 90 years old, your gut microbiota is not that different from a healthy 30 year old in the same population,” said Greg Gloor, PhD, the principal investigator on the study and also a professor at Western’s Schulich School of Medicine & Dentistry and Scientist at Lawson Health Research Institute. Whether this is cause or effect is unknown, but the study authors point out that it is the diversity of the gut microbiota that remained the same through their study group.

“This demonstrates that maintaining diversity of your gut as you age is a biomarker of healthy aging, just like low-cholesterol is a biomarker of a healthy circulatory system,” Gloor said. The researchers suggest that resetting an elderly microbiota to that of a 30-year-old might help promote health.

“By studying healthy people, we hope to know what we are striving for when people get sick,” said Reid.

The study also found a distinct anomaly in the group aged 19 to 24 that has not been observed in large-scale analyses of other populations and they suspect may be unique to this healthy cohort in China. The distinct gut microbiota of this group was a surprising finding and requires further study.

Source: Crystal Mackay – Western University
Image Source: NeuroscienceNews.com images is in the public domain.
Original Research: Full open access research for “The Gut Microbiota of Healthy Aged Chinese Is Similar to That of the Healthy Young” by Gaorui Bian, Gregory B. Gloor, Aihua Gong, Changsheng Jia, Wei Zhang, Jun Hu, Hong Zhang, Yumei Zhang, Zhenqing Zhou, Jiangao Zhang, Jeremy P. Burton, Gregor Reid, Yongliang Xiao, Qiang Zeng, Kaiping Yang, and Jiangang Li in mSphere. Published online October 2017 doi:10.1128/mSphere.00327-17

Abstract

The Gut Microbiota of Healthy Aged Chinese Is Similar to That of the Healthy Young

The microbiota of the aged is variously described as being more or less diverse than that of younger cohorts, but the comparison groups used and the definitions of the aged population differ between experiments. The differences are often described by null hypothesis statistical tests, which are notoriously irreproducible when dealing with large multivariate samples. We collected and examined the gut microbiota of a cross-sectional cohort of more than 1,000 very healthy Chinese individuals who spanned ages from 3 to over 100 years. The analysis of 16S rRNA gene sequencing results used a compositional data analysis paradigm coupled with measures of effect size, where ordination, differential abundance, and correlation can be explored and analyzed in a unified and reproducible framework. Our analysis showed several surprising results compared to other cohorts. First, the overall microbiota composition of the healthy aged group was similar to that of people decades younger. Second, the major differences between groups in the gut microbiota profiles were found before age 20. Third, the gut microbiota differed little between individuals from the ages of 30 to >100. Fourth, the gut microbiota of males appeared to be more variable than that of females. Taken together, the present findings suggest that the microbiota of the healthy aged in this cross-sectional study differ little from that of the healthy young in the same population, although the minor variations that do exist depend upon the comparison cohort.

IMPORTANCE We report the large-scale use of compositional data analysis to establish a baseline microbiota composition in an extremely healthy cohort of the Chinese population. This baseline will serve for comparison for future cohorts with chronic or acute disease. In addition to the expected difference in the microbiota of children and adults, we found that the microbiota of the elderly in this population was similar in almost all respects to that of healthy people in the same population who are scores of years younger. We speculate that this similarity is a consequence of an active healthy lifestyle and diet, although cause and effect cannot be ascribed in this (or any other) cross-sectional design. One surprising result was that the gut microbiota of persons in their 20s was distinct from those of other age cohorts, and this result was replicated, suggesting that it is a reproducible finding and distinct from those of other populations.

“The Gut Microbiota of Healthy Aged Chinese Is Similar to That of the Healthy Young” by Gaorui Bian, Gregory B. Gloor, Aihua Gong, Changsheng Jia, Wei Zhang, Jun Hu, Hong Zhang, Yumei Zhang, Zhenqing Zhou, Jiangao Zhang, Jeremy P. Burton, Gregor Reid, Yongliang Xiao, Qiang Zeng, Kaiping Yang, and Jiangang Li in mSphere. Published online October 2017 doi:10.1128/mSphere.00327-17