1. New possibility of studying how Alzheimer’s disease affects the brain at different ages

    September 16, 2017 by Ashley

    From the Lund University press release:

    Alzheimer’s disease can lead to several widely divergent symptoms and, so far, its various expressions have mainly been observed through the behaviour and actions of patients. Researchers at Lund University in Sweden have now produced images showing the changes in the brain associated with these symptoms — a development which increases knowledge and could facilitate future diagnostics and treatment.

    Symptoms vary in cases of Alzheimer’s disease and often relate to the phase of life in which the disease first occurs. People who become ill before the age of 65 often suffer early on from diminished spatial perception and impaired orientation. Elderly patients more often suffer the symptoms traditionally associated with the disease: above all, memory impairment.

    “Now we have a tool which helps us to identify and detect various sub-groups of Alzheimer’s disease. This facilitates the development of drugs and treatments adapted to various forms of Alzheimer’s,” explains Michael Schöll, researcher at Lund University and the University of Gothenburg.

    Diagnostics could also be facilitated, mainly among younger patients in whom it is particularly difficult to arrive at a correct diagnosis.

    Confident in approval for clinical use

    The findings, published in the journal Brain, are based on studies of around 60 Alzheimer’s patients at Skåne University Hospital and a control group consisting of 30 people with no cognitive impairment.

    Once Alzheimer’s disease has taken hold, it gradually results in the tau protein, present in the brain, forming lumps and destroying the transport routes of the neurons. This can be clearly detected with the new imaging method.

    The method includes a device known as a PET camera and a trace substance, a particular molecule, which binds to tau. The imaging method is currently only used in research, where the current study is one of several contributing to increased knowledge about the disease:

    “The changes in the various parts of the brain that we can see in the images correspond logically to the symptoms in early onset and late onset Alzheimer’s patients respectively,” explains Oskar Hansson, professor of neurology at Lund University and consultant at Skåne University Hospital.

    Oskar Hansson believes that the imaging method will be in clinical use within a few years.


  2. When making decisions, monkeys use different brain areas to weigh value and availability

    by Ashley

    From the Cell Press press release:

    There are many calculations at play in our minds when we make a decision, whether we are aware of them or not. Seventeenth-century mathematician Blaise Pascal first introduced the idea of expected value, which is reached by multiplying the value of something (how much it’s wanted or needed) with the probability that we might be able to obtain it. Now some very 21st century research is showing for the first time in monkeys which parts of the brain are involved in the two-pronged decision-making process that determines this expected value. The study appears August 30 in Neuron.

    “For a long time we thought that representations of value and probability were being evaluated in the same, single part of the brain,” says Peter Rudebeck, an assistant professor of neuroscience and psychiatry at the Icahn School of Medicine at Mount Sinai and the lead author of the new study. “What’s exciting here is that we’re showing that it’s being done in two different parts of the brain, which are separate both functionally and anatomically.”

    The researchers focused on two areas of the brain, the orbital frontal cortex (OFC) and the ventrolateral prefrontal cortex (VLPFC). Studies of people who have had their OFCs damaged due to injury or disease have indicated that injuries to that region of the brain resulted in impaired decision-making abilities. “But when we tried to duplicate this effect experimentally in monkeys by creating lesions in their OFCs, we didn’t see the same result,” Rudebeck explains.

    Further examination revealed that the difference came from how much of the brain was damaged. “When surgeons remove a tumor from the OFC, they remove not only the gray matter, the cortex of the brain, but will also inadvertently affect the white matter, which carries the connections between different parts of the brain,” he says. “We knew the VLPFC sits right next to the OFC, so we decided to look at that as well.”

    Two sets of experiments were devised: the first looked at how the monkeys weighed probability when making decisions, and the second looked at how they weighed value.

    In the first set, monkeys played a sort of slot machine game, where they were shown images on a touch screen and had to determine which image was most likely to get them a reward — a banana-flavored pellet. The researchers periodically changed the probability, but the control monkeys were able to adjust their choices accordingly. Animals with OFC and VLPFC lesions were then given the same task: those with OFC lesions performed the same as the control animals, whereas the monkeys with VLPFC lesions lost the ability to track probability.

    In the second set of experiments, the monkeys had a choice of two rewards when they played a game — peanuts or M&Ms. These rewards were hidden under objects that the monkeys had previously learned predicted either of the two rewards. Because monkeys generally like peanuts and M&Ms equally, they turn over objects overlying peanuts and M&Ms at the same rate. But to shift the value toward one treat over the other, in favor of the peanuts, the monkeys were given M&Ms immediately before the experiment. Having already had their fill of M&Ms, the control monkeys favored the objects overlying peanuts, as expected. Those with VLPFC lesions had the same inclination. The monkeys with OFC lesions, however, showed a preference for the objects overlying M&Ms.

    “We’ve known for a long time that these two parts of the brain are highly interconnected,” Rudebeck says. “They both send connections to another area of the frontal lobe, the ventromedial prefrontal cortex (VMPFC). Imaging studies with fMRI suggested that the VMPFC may be where choices ultimately get made.”

    The investigators tested this in a separate set of experiments, where they induced lesions in that area. “The animals were able to make a decision based on probability or value alone, but when they had to combine the two, they were less able to do that,” Rudebeck concludes. “This lines up with what we’ve seen in humans, because we know that people who have brain damage in that area also have trouble with making decisions.”


  3. Study suggests placebo effectiveness may hinge on ability to control emotions

    September 13, 2017 by Ashley

    From the University of Luxembourg press release:

    In a pioneering study, researchers at the University of Luxembourg used fMRI technology to show that a person’s ability to reinterpret negative events and to control feelings influences how strongly a placebo will work to reduce pain. Dr Marian van der Meulen gave us additional input.

    “Brain scans showed researchers that specific regions in the brain react when a person receives a placebo and as a result experiences less pain,” explains Dr Marian van der Meulen, neuropsychologist at the University of Luxembourg. “The regions in the brain that process pain become less active, which demonstrates that the placebo effect is real. But the psychological mechanism is still very little understood, and it is unclear why some people show a much stronger placebo response than others. We suspected that the way we can regulate our emotions plays a role and set out to investigate this.”

    Why is it important to better understand the placebo effect?

    “It’s important to understand that the placebo effect is not only an imagined improvement when we believe we receive a medication.

    The placebo effect had traditionally a negative reputation. During the last decade however, researchers have investigated the placebo effect itself. They have shown that placebos can trigger real biological changes in the body, including the brain, and that the placebo effect plays a role every time we receive a medical treatment. The placebo effect not only happens when administering a bogus treatment, but is a part of every medical procedure. It is triggered by the presence of a white coat and other signs of medical authority, verbal suggestions of improvement and previous experiences with a treatment. Clinicians or psychiatrists may be able to improve the outcome of a medical intervention by optimising the contribution of the placebo effect.”

    How was the study carried out, and key findings

    “The study was conducted in collaboration with the ZithaKlinik and uses fMRI (functional magnetic resonance imaging) of the brain to show a relationship between the regions in the brain that respond to a placebo and the ability to regulate emotions.

    First, we assessed participants’ ability for ‘cognitive reappraisal‘, which means how well they can reinterpret negative emotions. Participants looked at images that create negative emotions. Their task was to come up with ideas or interpretations that made them feel more positive about an image and we measured how well they managed to do this. At the ZithaKlinik, participants were then put in the MRI scanner and they received painful heat stimuli on their arms. They were then told that they received a powerful pain-relieving cream, which in reality was just a simple skin moisturiser.

    All participants reported less pain: the placebo effect was working. Interestingly, those with a higher capacity to control their negative feelings showed the largest responses to the placebo cream in the brain. Their activity in those brain regions that process pain was most reduced. This suggests that your ability to regulate emotions affects how strong your response to a placebo will be.”

    Which role does brain imaging play?

    “When a brain area is more active, it consumes more oxygen and more blood will flow to this area. fMRI measures this change in blood flow and detects which areas of the brain are involved in a certain mental process. In our research we were able to detect decreases in activation in pain-processing regions but also increases in an area involved in emotion regulation.

    This is the first study using functional brain imaging that was conducted in Luxembourg. Our next research project will use fMRI to assess, amongst others, the placebo effect in elderly people. We know that older people perceive and report pain differently than young people, yet why this is the case remains poorly understood. With improved understanding, clinicians and caretakers may be able to better diagnose and treat pain conditions in elderly people.”


  4. Origins of autism: Abnormalities in sensory processing at six months

    by Ashley

    From the McGill University press release:

    The origins of autism remain mysterious. What areas of the brain are involved, and when do the first signs appear? New findings published in Biological Psychiatry brings us closer to understanding the pathology of autism, and the point at which it begins to take shape in the human brain. Such knowledge will allow earlier interventions in the future and better outcomes for autistic children.

    Scientists used a type of magnetic resonance imaging (MRI), known as diffusion weighted imaging, to measure the brain connectivity in 260 infants at the ages of 6 and 12 months, who had either high or low risks of autism. The lengths and strengths of the connections between brain regions was used to estimate the network efficiency, a measure of how well each region is connected to other regions. A previous study with 24-month-old children found that network efficiency in autistic children was lower in regions of the brain involved in language and other behaviours related to autism. The goal of this new study was to establish how early these abnormalities occur.

    Lead author John Lewis, a researcher at the Montreal Neurological Institute and Hospital of McGill University and the Ludmer Centre for Bioinformatics and Mental Health, found network inefficiencies had already been established in six-month-old infants who went on to be diagnosed with autism. Inefficiencies in the six-month-olds appeared in the auditory cortex. He also found the extent of the inefficiency at six months of age was positively related to the severity of autistic symptoms at 24 months. As the children aged, areas involved in processing of vision and touch, as well as a larger set of areas involved in sound and language, also showed such a relation between inefficiency and symptom severity.

    Identifying the earliest signs of autism is important because it may allow for diagnosis before behavioural changes appear, leading to earlier intervention and better prospects for a positive outcome. By pinpointing the brain regions involved in processing sensory inputs as the earliest known locations of neural dysfunction related to autism, researchers narrow down the genetic factors and mechanisms that could be responsible for its development. The fact that neurological signs are already present at six months also eliminates some environmental factors as potential causes of the disorder.

    “Our goal was to discover when and where in the brain the network inefficiencies first appeared,” says Lewis. “The results indicate that there are differences in the brains of infants who go on to develop autism spectrum disorder even at six months of age, and that those early differences are found in areas involved in processing sensory inputs, not areas involved in higher cognitive functions. We hope that these findings will prove useful in understanding the causal mechanisms in autism spectrum disorder, and in developing effective interventions.”

    The research comes from the Infant Brain Imaging Study (IBIS), a collaborative effort by investigators at the Montreal Neurological Institute, and four clinical sites in the United States, coordinated to conduct a longitudinal brain imaging and behavioural study of infants at high risk for autism.


  5. Brain changes linked to physical, mental health in functional neurological disorder

    by Ashley

    From the Massachusetts General Hospital press release:

    An imaging study by Massachusetts General Hospital (MGH) investigators has identified differences in key brain structures of individuals whose physical or mental health has been most seriously impaired by a common but poorly understood condition called functional neurological disorder (FND). In their report published online in the Journal of Neurology, Neurosurgery and Psychiatry, the research team describes reductions in the size of a portion of the insula in FND patients with the most severe physical symptoms and relative volume increases in the amygdala among those most affected by mental health symptoms.

    “The brain regions implicated in this structural neuroimaging study are areas involved in the integration of emotion processing, sensory-motor and cognitive functions, which may help us understand why patients with functional neurological disorder exhibit such a mix of symptoms,” says David Perez, MD, MMSc, of the MGH Departments of Neurology and Psychiatry, lead and corresponding author of the report. “While this is a treatable condition, many patients remain symptomatic for years, and the prognosis varies from patient to patient. Advancing our understanding the pathophysiology of FND is the first step in beginning to develop better treatments.”

    One of the most common conditions bringing patients to neurologists, FND involves a constellation of neurologic symptoms — including weakness, tremors, walking difficulties, convulsions, pain and fatigue — not explained by traditional neurologic diagnoses. This condition has also been called conversion disorder, reflecting one theory that patients were converting emotional distress into physical symptoms, but Perez notes that this now appears to be an oversimplified view of a complex neuropsychiatric condition. The research team hopes that advancing the neurobiological understanding of FND will increase awareness and decrease the stigma — including skepticism about the reality of patients’ symptoms — often associated with this condition.

    Previous functional MRI studies have suggested that a group of brain structures forming part of what is called the salience network — which are involved in detecting important bodily and environmental stimuli, as well as integrating emotional, cognitive and sensory-motor experiences — showed increased activity in FND patients during a variety of behavioral and emotion-processing tasks. The current study is one of the first to examine structural relationships between components of the salience network and the physical and mental health of patients with FND.

    The researchers compared whole-brain structural MRI scans of 26 FND patients with those of 27 healthy control participants, looking for associations between the size of salience-network structures and participants’ reports of their physical health, mental health and symptoms of anxiety and depression. While there were no whole-brain structural differences between FND patients and healthy controls, patients reporting the greatest levels of physical impairment were found to have decreased volume in the left anterior insula, while those reporting the greatest mental health impairments and highest anxiety levels had increased volume within the amygdala.

    “The association among FND patients between the severity of impairments in physical functioning and reduced left anterior insular volume is intriguing, given that the anterior insula has been implicated in self- and emotional awareness,” says Perez, who is a dual trained neurologist-psychiatrist and an assistant professor of Neurology at Harvard Medical School.

    He adds, “Little attention has been given to FND to date, which is striking given its prevalence and the health care expenses driven by patients suffering with FND. I hope that advancing the neurobiological understanding of FND will help decrease the stigma often associated with this condition and increase public awareness of the unmet needs of this patient population.”


  6. Eating triggers endorphin release in the brain

    September 12, 2017 by Ashley

    From the University of Turku press release:

    Finnish researchers have revealed how eating stimulates brain’s endogenous opioid system to signal pleasure and satiety.

    The recent results obtained by researchers from Turku PET Centre have revealed that eating leads to widespread opioid release in the brain, likely signalling feelings of satiety and pleasure.

    Eating a delicious pizza led to significant increase of pleasant feelings, whereas consumption of calorie-matched nutritional drink did not. However, both types of meals induced significant release of endogenous opioids in the brain.

    Opioids are associated with pleasure and euphoria. The study revealed that a significant amount of endorphins is released in the entire brain after eating the pizza and, surprisingly, even more are released after the consumption of the tasteless nutritional drink. The magnitude of the opioid release was independent of the pleasure associated with eating. According to the researchers, it is likely that the endogenous opioid system regulates both feelings of pleasure and satiety.

    -The opioid system regulates eating and appetite, and we have previously found that its dysfunctions are a hallmark of morbid obesity. The present results suggest that overeating may continuously overstimulate the opioid system, thus directly contributing to development of obesity. These findings open new opportunities for treating overeating and the development of obesity, says Professor Lauri Nummenmaa from Turku PET Centre.

    – It was a surprise that endorphins are released in the entire brain and that the nutritional drink had a larger impact. This creates a basis for future research and hopefully we will find ways to study and describe the development and predictors of addiction, obesity and eating disorders, says Researcher, M.D., PhD. Jetro Tuulari.

    The study was conducted using positron emission tomography (PET). The participants were injected with a radioactive compound binding to their brain’s opioid receptors. Radioactivity in the brain was measured three times with the PET camera: after a palatable meal (pizza), after a non-palatable meal (liquid meal) and after an overnight fast.

    The research was funded by the Academy of Finland.


  7. Noninvasive eye scan could detect key signs of Alzheimer’s disease years before patients show symptoms

    by Ashley

    From the Cedars-Sinai press release:

    Cedars-Sinai neuroscience investigators have found that Alzheimer’s disease affects the retina — the back of the eye — similarly to the way it affects the brain. The study also revealed that an investigational, noninvasive eye scan could detect the key signs of Alzheimer’s disease years before patients experience symptoms.

    Using a high-definition eye scan developed especially for the study, researchers detected the crucial warning signs of Alzheimer’s disease: amyloid-beta deposits, a buildup of toxic proteins. The findings represent a major advancement toward identifying people at high risk for the debilitating condition years sooner.

    The study, published in JCI Insight, comes amid a sharp rise in the number of people affected by the disease. Today, more than 5 million Americans have Alzheimer’s disease. That number is expected to triple by 2050, according to the Alzheimer’s Association.

    “The findings suggest that the retina may serve as a reliable source for Alzheimer’s disease diagnosis,” said the study’s senior lead author, Maya Koronyo-Hamaoui, PhD, a principal investigator and associate professor in the departments of Neurosurgery and Biomedical Sciences at Cedars-Sinai.

    “One of the major advantages of analyzing the retina is the repeatability, which allows us to monitor patients and potentially the progression of their disease.”

    Yosef Koronyo, MSc, a research associate in the Department of Neurosurgery and first author on the study, said another key finding from the new study was the discovery of amyloid plaques in previously overlooked peripheral regions of the retina. He noted that the plaque amount in the retina correlated with plaque amount in specific areas of the brain.

    “Now we know exactly where to look to find the signs of Alzheimer’s disease as early as possible,” said Koronyo.

    Keith L. Black, MD, chair of Cedars-Sinai’s Department of Neurosurgery and director of the Maxine Dunitz Neurosurgical Institute, who co-led the study, said the findings offer hope for early detection when intervention could be most effective.

    “Our hope is that eventually the investigational eye scan will be used as a screening device to detect the disease early enough to intervene and change the course of the disorder with medications and lifestyle changes,” said Black.

    For decades, the only way to officially diagnose the debilitating condition was to survey and analyze a patient’s brain after the patient died. In recent years, physicians have relied on positron emission tomography (PET) scans of the brains of living people to provide evidence of the disease but the technology is expensive and invasive, requiring the patient to be injected with radioactive tracers.

    In an effort to find a more cost-effective and less invasive technique, the Cedars-Sinai research team collaborated with investigators at NeuroVision Imaging, Commonwealth Scientific and Industrial Research Organisation, University of Southern California, and UCLA to translate their noninvasive eye screening approach to humans.

    The published results are based on a clinical trial conducted on 16 Alzheimer’s disease patients who drank a solution that includes curcumin, a natural component of the spice turmeric. The curcumin causes amyloid plaque in the retina to “light up” and be detected by the scan. The patients were then compared to a group of younger, cognitively normal individuals.

    Koronyo-Hamaoui and Koronyo also were key authors of the original results, published in the journal Neuroimage in 2011 and first presented at the Alzheimer’s Association’s International Conference in 2010.


  8. New light on link between gut bacteria and anxiety-like behaviours

    September 8, 2017 by Ashley

    From the Biomed Central press release:

    Research published in the open access journal Microbiome sheds new light on how gut bacteria may influence anxiety-like behaviors. Investigating the link between gut bacteria and biological molecules called microRNAs (miRNAs) in the brain; researchers at the APC Microbiome Institute at University College Cork, which is funded by Science Foundation Ireland, found that a significant number of miRNAs were changed in the brains of microbe-free mice. These mice are reared in a germ-free bubble and typically display abnormal anxiety, deficits in sociability and cognition, and increased depressive-like behaviors.

    Dr Gerard Clarke, the corresponding author said: “Gut microbes seem to influence miRNAs in the amygdala and the prefrontal cortex. This is important because these miRNAs may affect physiological processes that are fundamental to the functioning of the central nervous system and in brain regions, such as the amygdala and prefrontal cortex, which are heavily implicated in anxiety and depression.”

    miRNAs are short sequences of nucleotides (the building blocks of DNA and RNA), which can act to control how genes are expressed. miRNA dysregulation or dysfunction is believed to be an underlying factor contributing to stress-related psychiatric disorders, neurodegenerative diseases and neurodevelopmental abnormalities. miRNA changes in the brain have been implicated in anxiety-like behaviors.

    Dr Clarke said: “It may be possible to modulate miRNAs in the brain for the treatment of psychiatric disorders but research in this area has faced several challenges, for example, finding safe and biologically stable compounds that are able to cross the blood-brain barrier and then act at the desired location in the brain. Our study suggests that some of the hurdles that stand in the way of exploiting the therapeutic potential of miRNAs could be cleared by instead targeting the gut microbiome.”

    The researchers found that levels of 103 miRNAs were different in the amygdala and 31 in the prefrontal cortex of mice reared without gut bacteria (GF mice) compared to conventional mice. Adding back the gut microbiome later in life normalized some of the changes to miRNAs in the brain.

    The findings suggest that a healthy microbiome is necessary for appropriate regulation of miRNAs in these brain regions. Previous research demonstrated that manipulation of the gut microbiome affects anxiety-like behaviors but this is the first time that the gut microbiome has been linked to miRNAs in both the amygdala and prefrontal cortex, according to the authors.

    The researchers used next-generation-sequencing (NGS) to find out which miRNAs were present in the amygdala and the prefrontal cortex of groups of 10-12 control mice with a normal gut microbiota, GF mice and ex-GF mice — which had been colonized with bacteria by housing them with the control mice — and adult rats whose normal microbiota had been depleted with antibiotics.

    They found that depleting the microbiota of adult rats with antibiotics impacted some miRNAs in the brain in a similar way to the GF mice. This suggests that even if a healthy microbiota is present in early life, subsequent changes in adulthood can impact miRNAs in the brain relevant to anxiety-like behaviors, according to the authors.

    The authors note that the exact mechanism by which the gut microbiota is able to influence the miRNAs in the brain remains unclear. Even though the study shows that effects of the microbiota on miRNAs are present in more than one species (mice and rats), further research into the possible connection between gut bacteria, miRNAs and anxiety-like behaviors is needed before the findings can be translated to a clinical setting.

    Dr Clarke said: “This is early stage research but the possibility of achieving the desired impact on miRNAs in specific brain regions by targeting the gut microbiota — for example by using psychobiotics — is an appealing prospect.”


  9. Artificial neural networks decode brain activity during performed and imagined movements

    September 5, 2017 by Ashley

    From the University of Freiburg press release:

    Filtering information for search engines, acting as an opponent during a board game or recognizing images: Artificial intelligence has far outpaced human intelligence in certain tasks. Several groups from the Freiburg excellence cluster BrainLinks-BrainTools led by neuroscientist private lecturer Dr. Tonio Ball are showing how ideas from computer science could revolutionize brain research. In the scientific journal Human Brain Mapping they illustrate how a self-learning algorithm decodes human brain signals that were measured by an electroencephalogram (EEG).

    It included performed movements, but also hand and foot movements that were merely thought of, or an imaginary rotation of objects. Even though the algorithm was not given any characteristics ahead of time, it works as quickly and precisely as traditional systems that have been created to solve certain tasks based on predetermined brain signal characteristics, which are therefore not appropriate for every situation.

    The demand for such diverse intersections between human and machine is huge: At the University Hospital Freiburg, for instance, it could be used for early detection of epileptic seizures. It could also be used to improve communication possibilities for severely paralyzed patients or an automatic neurological diagnosis.

    “Our software is based on brain-inspired models that have proven to be most helpful to decode various natural signals such as phonetic sounds,” says computer scientist Robin Tibor Schirrmeister. The researcher is using it to rewrite methods that the team has used for decoding EEG data: So-called artificial neural networks are the heart of the current project at BrainLinks-BrainTools. “The great thing about the program is we needn’t predetermine any characteristics. The information is processed layer for layer, that is in multiple steps with the help of a non-linear function. The system learns to recognize and differentiate between certain behavioral patterns from various movements as it goes along,” explains Schirrmeister. The model is based on the connections between nerve cells in the human body in which electric signals from synapses are directed from cellular protuberances to the cell’s core and back again. “Theories have been in circulation for decades, but it wasn’t until the emergence of today’s computer processing power that the model has become feasible,” comments Schirrmeister.

    Customarily, the model’s precision improves with a large number of processing layers. Up to 31 were used during the study, otherwise known as “Deep Learning.” Up until now, it had been problematic to interpret the network’s circuitry after the learning process had been completed. All algorithmic processes take place in the background and are invisible. That is why the researchers developed the software to create cards from which they could understand the decoding decisions. The researchers can insert new datasets into the system at any time. “Unlike the old method, we are now able to go directly to the raw signals that the EEG records from the brain. Our system is as precise, if not better, than the old one,” says head investigator Tonio Ball, summarizing the study’s research contribution. The technology’s potential has yet to be exhausted — together with his team, the researcher would like to further pursue its development: “Our vision for the future includes self-learning algorithms that can reliably and quickly recognize the user’s various intentions based on their brain signals. In addition, such algorithms could assist neurological diagnoses.”


  10. Gut microbes may talk to the brain through cortisol

    September 4, 2017 by Ashley

    From the University of Illinois College of Agricultural, Consumer and Environmental Sciences press release:

    Gut microbes have been in the news a lot lately. Recent studies show they can influence human health, behavior, and certain neurological disorders, such as autism. But just how do they communicate with the brain? Results from a new University of Illinois study suggest a pathway of communication between certain gut bacteria and brain metabolites, by way of a compound in the blood known as cortisol. And unexpectedly, the finding provides a potential mechanism to explain the characteristics of autism.

    “Changes in neurometabolites during infancy can have profound effects on brain development, and it is possible that the microbiome — or collection of bacteria, fungi, and viruses inhabiting our gut — plays a role in this process,” says Austin Mudd, a doctoral student in the Neuroscience Program at U of I. “However, it is unclear which specific gut bacteria are most influential during brain development and what factors, if any, might influence the relationship between the gut and the brain.”

    The researchers studied 1-month-old piglets, which are remarkably similar to human infants in terms of their gut and brain development. They first identified the relative abundances of bacteria in the feces and ascending colon contents of the piglets, then quantified concentrations of certain compounds in the blood and in the brain.

    “Using the piglet as a translatable animal model for human infants provides a unique opportunity for studying aspects of development which are sometimes more difficult or ethically challenging to collect data on in human infants,” Mudd says. “For example, in this study we wanted to see if we could find bacteria in the feces of piglets that might predict concentrations of compounds in the blood and brain, both of which are more difficult to characterize in infants.”

    The researchers took a stepwise approach, first identifying predictive relationships between fecal bacteria and brain metabolites. They found that the bacterial genera Bacteroides and Clostridium predicted higher concentrations of myo-inositol, Butyricimonas positively predicted n-acetylaspartate (NAA), and Bacteroides also predicted higher levels of total creatine in the brain. However, when bacteria in the genus Ruminococcus were more abundant in the feces of the piglets, NAA concentrations in the brain were lower.

    “These brain metabolites have been found in altered states in individuals diagnosed with autism spectrum disorder (ASD), yet no previous studies have identified specific links between bacterial genera and these particular metabolites,” Mudd notes.

    The next step was to determine if these four bacterial genera could predict compounds in the blood. “Blood biomarkers are something we can actually collect from an infant, so it’s a clinically relevant sample. It would be nice to study an infant’s brain directly, but imaging infants is logistically and ethically difficult. We can, however, obtain feces and blood from infants,” says Ryan Dilger, associate professor in the Department of Animal Sciences, Division of Nutritional Sciences, and Neuroscience Program at U of I.

    The researchers found predictive relationships between the fecal microbiota and serotonin and cortisol, two compounds in the blood known to be influenced by gut microbiota. Specifically, Bacteroides was associated with higher serotonin levels, while Ruminococcuspredicted lower concentrations of both serotonin and cortisol. Clostridium and Butyricimonas were not associated strongly with either compound.

    Again, Mudd says, the results supported previous findings related to ASD. “Alterations in serum serotonin and cortisol, as well as fecal Bacteroides and Ruminococcus levels, have been described in ASD individuals.”

    Based on their initial analyses, the researchers wanted to know if there was a three-way relationship between Ruminococcus, cortisol, and NAA. To investigate this further, they used a statistical approach known as “mediation analysis,” and found that serum cortisol mediated the relationship between fecal Ruminococcus abundance and brain NAA concentration. In other words, it appears that Ruminococcus communicates with and makes changes to the brain indirectly through cortisol. “This mediation finding is interesting, in that it gives us insight into one way that the gut microbiota may be communicating with the brain. It can be used as a framework for developing future intervention studies which further support this proposed mechanism,” Dilger adds.

    “Initially, we set out to characterize relationships between the gut microbiota, blood biomarkers, and brain metabolites. But once we looked at the relationships identified in our study, they kept leading us to independently reported findings in the autism literature. We remain cautious and do not want to overstate our findings without support from clinical intervention trials, but we hypothesize that this could be a contributing factor to autism’s heterogenous symptoms,” Mudd says. Interestingly, in the time since the researchers wrote the paper, other publications have also reported relationships between Ruminococcus and measures of brain development, supporting that this might be a promising area for future research.

    Dilger adds, “We admit this approach is limited by only using predictive models. Therefore, the next step is to generate empirical evidence in a clinical setting. So it’s important to state that we’ve only generated a hypothesis here, but it’s exciting to consider the progress that may be made in the future based on our evidence in the pre-clinical pig model.”