Category: Neurology

Categories : Neurology PaediatricsTags :

Newly Identified Lipid in Breast Milk Might Reduce Cerebral Palsy in Infants

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Ten percent of babies born before 32 weeks will develop cerebral palsy resulting from infections that damage white matter, nerve fibres deep in the brain. While it’s known that the white matter loss will lead to neurological deficits, there is currently no treatment to avoid this.

Now, researchers at Duke Health have conducted experiments using neonatal mice and identified a fatty molecule in breast milk that triggers a process in which stem cells in the brain produce cells that create new white matter, reversing the injury.

The study appears in the journal Cell Stem Cell. Corresponding author Eric Benner, MD, PhD, said that further study in a clinical trial is needed, but the finding is promising.

“Developing therapies for children – especially such medically fragile children – is very difficult to do because there are justifiably strict safety concerns,” Benner said. “The fact that this molecule is already found in something that is safe for premature babies – breast milk – is extremely encouraging.

“It’s been known that fats in breast milk benefit a child’s brain development, but there are many types of fats in breast milk,” Benner said. “This work has identified a lipid molecule in breast milk that promotes white matter development. Now, we can begin to develop a therapy that isolates and delivers this lipid in a way that is safe for the unique challenges of these infants.”

Benner is a neonatologist at Duke University and one of the co-founders of Tellus Therapeutics, a Duke spinout company developed with the help of the Duke University Office for Translation & Commercialization to bring this therapy from the bench into the neonatal intensive care unit.

The fatty molecule identified in the study will be administered intravenously to patients in an upcoming clinical trial. This is significant because many of the infants who are part of this vulnerable population also have gastrointestinal issues and cannot safely be given milk or medication by mouth.

The lipid molecule enters the brain and binds with stem cells there, encouraging the stem cells to become or produce a type of cell called oligodendrocytes.

The oligodendrocytes are like a hub that allow for the production of white matter in the central nervous system. This newly produced white matter in pre-term infants prevents the neurological damage that would otherwise impact the child’s ability to move – the hallmarks of cerebral palsy.

“The timing of brain injury is extremely difficult to predict, thus a treatment that could be safely given to all preterm babies at risk would be revolutionary,” said Agnes Chao, MD, a former fellow in the Division of Neonatology and first author of the paper.

“As a neonatologist, I’m so excited that I may be able to offer a treatment to families with babies that are affected by preterm brain injury who would otherwise have no other options,” Chao said.

Source: Duke University Medical Center

Categories : NeurologyTags :

Night-time Fragrances Provide Cognitive Boost that Could Stave off Dementia

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When a fragrance wafted through the bedrooms of older adults for two hours every night for six months, memory recall skyrocketed. Participants in this study experienced a 226% increase in cognitive capacity compared to controls. The researchers say the finding transforms the long-known tie between smell and memory into an easy, non-invasive technique for strengthening memory and potentially deterring dementia. The findings, which appear to pass the ‘sniff test’, are published in the open-access journal Frontiers in Neuroscience.

The project was conducted University of California, Irvine neuroscientists, involving men and women aged 60 to 85 without memory impairment. All were given a diffuser and seven cartridges, each containing a single and different natural oil. People in the enriched group received full-strength cartridges. Control group participants were given the oils in tiny amounts. Participants put a different cartridge into their diffuser each evening prior to going to bed, and it activated for two hours as they slept.

People in the enriched group showed a 226% increase in cognitive performance compared to the control group, as measured by a word list test commonly used to evaluate memory. Imaging revealed better integrity in the brain pathway called the left uncinate fasciculus. This pathway, which connects the medial temporal lobe to the decision-making prefrontal cortex, becomes less robust with age. Participants also reported sleeping more soundly.

Scientists have long known that the loss of olfactory capacity, or ability to smell, can predict development of nearly 70 neurological and psychiatric diseases. These include Alzheimer’s and other dementias, Parkinson’s, schizophrenia and alcoholism. Evidence is emerging about a link between smell loss due to COVID and ensuing cognitive decrease. Researchers have previously found that exposing people with moderate dementia to up to 40 different odours twice a day over a period of time boosted their memories and language skills, eased depression and improved their olfactory capacities. The UCI team decided to try turning this knowledge into an easy and non-invasive dementia-fighting tool.

“The reality is that over the age of 60, the olfactory sense and cognition starts to fall off a cliff,” said Michael Leon, professor of neurobiology & behaviour and a CNLM fellow. “But it’s not realistic to think people with cognitive impairment could open, sniff and close 80 odorant bottles daily. This would be difficult even for those without dementia.”

The study’s first author, project scientist Cynthia Woo, said: “That’s why we reduced the number of scents to just seven, exposing participants to just one each time, rather than the multiple aromas used simultaneously in previous research projects. By making it possible for people to experience the odors while sleeping, we eliminated the need to set aside time for this during waking hours every day.”

The researchers say the results from their study bear out what scientists learned about the connection between smell and memory.

“The olfactory sense has the special privilege of being directly connected to the brain’s memory circuits,” said collaborating investigator Michael Yassa, professor and director of CNLM. “All the other senses are routed first through the thalamus. Everyone has experienced how powerful aromas are in evoking recollections, even from very long ago. However, unlike with vision changes that we treat with glasses and hearing aids for hearing impairment, there has been no intervention for the loss of smell.”

The team would next like to study the technique’s impact on people with diagnosed cognitive loss. The researchers also say they hope the finding will lead to more investigations into olfactory therapies for memory impairment. A product based on their study and designed for people to use at home is expected to come onto the market later this year.

Source: University of California – Irvine

Categories : NeurologyTags :

A Curious Mindset Helps Memory More than an Urgent One

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New research from Duke University found that shifting to a curious mindset helps memory – such as video game players who imagined being a thief scouting a virtual art museum in preparation for a heist. This mindset resulted in better recalling the paintings there. Adopting a high-pressure mindset, such as players trying to execute the heist, resulted in fewer paintings being recalled.

These subtle differences in motivation – urgent, immediate goal-seeking versus curious exploration for a future goal – have big potential for framing real-world challenges such encouraging vaccination. The findings appeared in PNAS.

Alyssa Sinclair, PhD ’23, a postdoctoral researcher working in the lab of Duke Institute for Brain Sciences director Alison Adcock, PhD, MD, recruited 420 adults to pretend to be art thieves for a day. The participants were then randomly assigned to one of two groups and received different backstories.

“For the urgent group, we told them, ‘You’re a master thief, you’re doing the heist right now. Steal as much as you can!’,” Sinclair said. “Whereas for the curious group, we told them they were a thief who’s scouting the museum to plan a future heist.”

After getting these different backstories, however, participants in the two groups played the exact same computer game, scored the exact same way. They explored an art museum with four coloured doors, representing different rooms, and clicked on a door to reveal a painting from the room and its value. Some rooms held more valuable collections of art. No matter which scenario they were pretending to be in, everyone earned real bonus money by finding more valuable paintings.

The impact of this difference in mindset was most apparent the following day. When participants logged back in, they were met with a pop quiz about whether they could recognise 175 different paintings (100 from the day before, and 75 new ones). If participants flagged a painting as familiar, they also had to recall how much it was worth.

Sinclair and her co-author, fellow Duke psychology & neuroscience graduate student Candice Yuxi Wang, were gratified after they graded the tests to see their predictions had played out.

“The curious group participants who imagined planning a heist had better memory the next day,” Sinclair said. “They correctly recognized more paintings. They remembered how much each painting was worth. And reward boosted memory, so valuable paintings were more likely to be remembered. But we didn’t see that in the urgent group participants who imagined executing the heist.”

Urgent group participants, however, had a different advantage. They were better at figuring out which doors hid more expensive pieces, and as a result snagged more high value paintings. Their stash was appraised at about $230 more than the curious participants’ collection.

The difference in strategies (curious versus urgent) and their outcomes (better memory versus higher-valued paintings) doesn’t mean one is better than the other, though.

“It’s valuable to learn which mode is adaptive in a given moment and use it strategically,” Dr Adcock said.

For example, being in an urgent, high-pressure mode might be the best option for a short-term problem.

“If you’re on a hike and there’s a bear, you don’t want to be thinking about long-term planning,” Sinclair said. “You need to focus on getting out of there right now.”

Opting for an urgent mindset might also be useful in less grisly scenarios that require short-term focus, Sinclair explained, like prompting people to get a COVID vaccine.

For encouraging long-term memory or action, stressing people out is less effective.

“Sometimes you want to motivate people to seek information and remember it in the future, which might have longer term consequences for lifestyle changes,” Sinclair said. “Maybe for that, you need to put them in a curious mode so that they can actually retain that information.”

Sinclair and Wang are now following up on these findings to see how urgency and curiosity activate different parts of the brain. Early evidence suggests that, by engaging the amygdala, an almond-shaped brain region best known for its role in fear memory, “urgent mode” helps form focused, efficient memories. Curious exploration, however, seems to shuttle the learning-enhancing neurochemical dopamine to the hippocampus, a brain region crucial for forming detailed long-term memories.

With these brain results in mind, Dr Adcock is exploring how her lab’s research might also benefit the patients she sees as a psychiatrist.

“Most of adult psychotherapy is about how we encourage flexibility, like with curious mode” Dr Adcock said. “But it’s much harder for people to do since we spend a lot of our adult lives in an urgency mode.”

These thought exercises may give people the ability to manipulate their own neurochemical spigots and develop “psychological manoeuvres,” or cues that act similar to pharmaceuticals, Dr Adcock explained.

“For me, the ultimate goal would be to teach people to do this for themselves,” Dr Adcock said. “That’s empowering.”

Source: Duke University

Categories : Immunology NeurologyTags :

Study Reveals How The Brain Detects and Regulates Inflammation

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Source: CC0

A study published in the journal Neuron has revealed the existence of a circuit in the brain that senses and regulates the anti-inflammatory response, including the triggering of behaviours associated with sickness and releasing cortisone, a potent negative regulator of immune responses. This circuit embodies a two-way connection between the brain and immune system.

Whenever infections or injuries occur, the immune system is triggered to control the infection and repair damaged tissue. This process involves the release of pro-inflammatory mediators that inform the brain of the body’s immune status and coordinate the immune response. In response to this signal, the brain sets off a complex reaction known as ‘sickness behaviour’ whose purpose is to reassign energy to the body’s different systems. This state is associated with behavioural changes including social avoidance and lethargy, metabolic adjustments such as fever and loss of appetite, and the release of hormones such as cortisone, to increase resistance to infection while also regulating immune responses.

In this study, a multidisciplinary group consisting of neurobiologists and immunologists from the Institut Pasteur, Inserm and the CNRS discovered a novel circuit used by the brain to measure inflammation levels in the blood and, in response to this, regulate inflammation. A region of the brainstem known as the vagal complex directly detects levels and types of inflammatory hormones in the bloodstream. This information is then relayed to neurons in another region of the brainstem called the parabrachial nucleus, which also receives information related to pain and certain aversive or traumatic memories. In turn, these neurons activate neurons in the hypothalamus leading to a rapid increase in cortisone in the blood.

The scientists used state-of-the-art neuroscience approaches to identify this circuit, which enabled them to individually observe the neurons involved during inflammation. The experts observed how the activity of specific neurons in the parabrachial nucleus could regulate the production of white blood cells involved in the immune response. “This research demonstrates that neural activity in the brain alone can have a powerful effect on the development of immune responses during infection or injury. It therefore provides a clear example of the powerful two-way connection between the body and brain. It also fuels our ambition to discover the impact of our brain on the way we interact with microbes, fight off pathogens and heal wounds,” explains Gérard Eberl, Head of the Institut Pasteur’s Microenvironment and Immunity Unit.

The discovery of this circuit opens up new opportunities for research that will jointly contribute to the fields of neurobiology and immunology: “This study gives us additional tools to better understand the impact of systemic inflammation on our brain, mood and on certain neurodegenerative processes,” adds Gabriel Lepousez, a neurobiologist in the Perception and Memory Unit (Institut Pasteur/CNRS).

Given the established role of the parabrachial nucleus in aversive memory processes, potential infectious threats could be averted if this circuit is reactivated by the memory of past inflammatory or aversive experiences. Drawing on this neuro-immune communication, the immune system could therefore benefit from the brain’s ability to predict and anticipate threats in our environment.

Source: Institut Pasteur

Categories : Neurology PaediatricsTags :

Concussions don’t Lower Children’s IQs, Study Finds

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The angst parents feel when their children sustain injuries is surely one of the universal conditions of parenthood. That anxiety is heightened greatly when those injuries involve concussions. But a new study led out of the University of Calgary, published today in the medical journal Pediatrics, may set worried parental minds slightly at ease.

Derived from data on emergency room visits in children’s hospitals in Canada and the US, the findings show that IQ and intelligence is not affected in a clinically meaningful way by paediatric concussions.

The study compares 566 children diagnosed with concussion to 300 with orthopaedic injuries. The children range in age from eight to 16 and they were recruited from two cohort studies. In the five Canadian hospitals that participated, patients completed IQ tests three months postinjury.

The US cohort was conducted at two children’s hospitals in Ohio, wherein patients completed IQ tests three to 18 days, postinjury.

“Obviously there’s been a lot of concern about the effects of concussion on children, and one of the biggest questions has been whether or not it affects a child’s overall intellectual functioning,” says Dr. Keith Yeates, PhD, a professor in UCalgary’s Department of Psychology and senior author of the Pediatrics paper. Yeates is a renowned expert on the outcomes of childhood brain disorders, including concussion and traumatic brain injuries.

“The data on this has been mixed and opinions have varied within the medical community,” says Yeates. “It’s hard to collect big enough samples to confirm a negative finding. The absence of a difference in IQ after concussion is harder to prove than the presence of a difference.”

Combining the Canadian and U.S. cohorts gave the Pediatrics study an abundant sample and it allowed Yeates and his co-authors to test patients with a wide range of demographics and clinical characteristics.

“We looked at socioeconomic status, patient sex, severity of injuries, concussion history, and whether there was a loss of consciousness at the time of injury,” says Yeates. “None of these factors made a difference. Across the board, concussion was not associated with lower IQ.”

The children with concussion were compared to children with orthopaedic injuries other than concussion to control for other factors that that might affect IQ, such as demographic background and the experience of trauma and pain. This allowed the researchers to determine whether the children’s IQs were different than what would be expected minus the concussion.

The findings of the study are important to share with parents, says Dr Ashley Ware, PhD, a professor at Georgia State University and lead author of the paper.

“Understandably, there’s been a lot of fear among parents when dealing with their children’s concussions,” Ware says. “These new findings provide really good news, and we need to get the message to parents.”

Dr Stephen Freedman, PhD, co-author of the paper and a professor of paediatrics and emergency medicine, agrees. “It’s something doctors can tell children who have sustained a concussion, and their parents, to help reduce their fears and concerns,” says Freedman. “It is certainly reassuring to know that concussions do not lead to alterations in IQ or intelligence.”

Another strength of the Pediatrics research is that incorporates the two cohort studies, one testing patients within days of their concussions and the other after three months.

“That makes our claim even stronger,” says Ware. “We can demonstrate that even in those first days and weeks after concussion, when children do show symptoms such as a pain and slow processing speed, there’s no hit to their IQs. Then it’s the same story three months out, when most children have recovered from their concussion symptoms. Thanks to this study we can say that, consistently, we would not expect IQ to be diminished from when children are symptomatic to when they’ve recovered.”

She adds: “It’s a nice ‘rest easy’ message for the parents.”

Source: University of Calgary

Categories : NeurologyTags :

Simple Oxygen Therapy can Boost Motor Skills Rehabilitation

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Scientists studying the impact of oxygen supplementation on motor learning have found a promising treatment that could help patients who have experienced neurological trauma recover lost motor skills.

“A simple and easy to administer treatment with 100% oxygen can drastically improve human motor learning processes,” said Dr Marc Dalecki, now at the German University of Health and Sports in Berlin, senior author of the study in Frontiers in Neuroscience.

Repurposing a frontline treatment

Brains have a high oxygen demand, and hypoxia causes cognitive function to decrease, while in high-oxygen contexts it recovers, and the delivery of 100% oxygen is already used to help preserve as much of the brain as possible in patients with neurological injuries.

Motor learning is particularly dependent on oxygen-reliant information processing and memory functions: humans learn by trial and error, so the ability to remember and integrate information from previous trials is critical to efficient and effective motor learning. So could supplementing oxygen while learning a motor task help people learn faster and more effectively, offering hope for neurorehabilitation patients?

“I had this idea in my mind for almost a decade and promised myself to investigate it once I got my own research lab,” said Dalecki, who led the experimental research at the School of Kinesiology at Louisiana State University. “And with Zheng Wang, now Dr Zheng Wang, I had the perfect doctoral student to run it – a keen physiotherapist with a clinical background and stroke patient experience.”

Hand-eye coordination

Dalecki and Wang recruited 40 participants, 20 of whom received 100% oxygen at normobaric pressure and 20 of whom received medical air (21% oxygen) through a nasal cannula during the “adaptation” or learning phase of a task.

Dalecki and Wang selected a simple visuomotor task which involved drawing lines between different targets on a digital tablet with a stylus. The task was designed to test how quickly the participants were able to integrate information from the eye and hand, a crucial part of motor learning. After the task had been learned, the alignment of the cursor and the stylus was altered to see how effectively the participants adapted to the inconsistency, and then realigned for a final session to see how they adapted to the realignment.

“The oxygen treatment led to substantially faster and about 30% better learning in a typical visuomotor adaptation task,” said Wang, first author of the study and now at the Mayo Clinic in Rochester. “We also demonstrate that the participants were able to consolidate these improvements after the termination of the oxygen treatment.”

Oxygen improved learning by 30%

The scientists found that the participants who had received oxygen learned faster and performed better, improvements which extended into later sessions of the task when oxygen was not administered.

The oxygen group moved the pen more smoothly and more accurately, and when the cursor was adjusted in a deliberate attempt to throw them off, they adapted more quickly. They also made bigger mistakes when the alignment of the stylus was corrected, suggesting they had integrated the previous alignment more thoroughly than the other group.

Dalecki and Wang plan to investigate the long-term effects of this supplementation on learning and test the intervention with other motor learning tasks: it is possible that the relevant brain functions for this task in particular benefit from high ambient oxygen levels, leading to the observed advantages in performance. They also hope to bring the oxygen treatment to elderly and injured people, in the hope that it will help them re-learn motor skills.

“Our future plan is to investigate whether this treatment can also improve motor recovery processes following brain trauma,” said Dalecki. “Since it worked in the young healthy brain, we expect that the effects may even be larger in the neurologically impaired, more vulnerable brain.”

Source: Medical Xpress

Categories : Neurology PaediatricsTags :

Children with Autism Have Memory Impairments, Study Finds

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Children with autism have memory challenges that hinder not only their memory for faces but also their ability to remember other kinds of information, according to new research. These impairments are reflected in distinct connection patterns children’s brains, the study found.

Published in Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, the study findings clarify a debate about memory function in children with autism, showing that their memory struggles surpass their ability to form social memories. The finding should prompt broader thinking about autism in children and about treatment of the developmental disorder, according to the scientists who conducted the study.

“Many high-functioning kids with autism go to mainstream schools and receive the same instruction as other kids,” said lead author Jin Liu, PhD at Stanford University. Memory is a key predictor of academic success, said Liu, adding that memory challenges may academically disadvantage children with autism.

The study’s findings also raise a philosophical debate about the neural origins of autism, the researchers said. Social challenges are recognised as a core feature of autism, but it’s possible that memory impairments might significantly contribute to the ability to engage socially.

“Social cognition can not occur without reliable memory,” said senior author Vinod Menon, PhD.

“Social behaviours are complex, and they involve multiple brain processes, including associating faces and voices to particular contexts, which require robust episodic memory,” Menon said. “Impairments in forming these associative memory traces could form one of the foundational elements in autism.”

Comprehensive memory tests

Affecting about one in every 36 children, autism is characterised by social impairments and restricted, repetitive behaviours. The condition exists on a wide spectrum, with those on one end having severe intellectual disability and about a third of people with autism have intellectual impairments. On the other end of the spectrum, many people with high-functioning autism have normal or high IQ, complete higher education and work in a variety of fields.

Children with autism are known to have difficulty remembering faces. Some small studies have also suggested that children with autism have broader memory difficulties. They included children with wide ranges of age and IQ, both of which influence memory.

To clarify the impact of autism on memory, the new study included 25 children with high-functioning autism and normal IQ who were 8 to 12 years old, and a control group of 29 typically developing children with similar ages and IQs.

All participants completed a comprehensive evaluation of their memory skills, including their ability to remember faces; written material; and non-social photographs, or photos without any people. The scientists tested participants’ ability to accurately recognise information (identifying whether they had seen an image or heard a word before) and recall it (describing or reproducing details of information they had seen or heard before). The researchers tested participants’ memory after delays of varying lengths. All participants also received fMRI scans of their brains to evaluate how memory-associated regions are connected to each other.

Distinct brain networks drive memory challenges

In line with prior research, children with autism had more difficulty remembering faces than typically developing children, the study found.

The research showed they also struggled to recall non-social information. On tests about sentences they read and non-social photos they viewed, their scores for immediate and delayed verbal recall, immediate visual recall and delayed verbal recognition were lower.

“We thought that behavioural differences might be weak because the study participants with autism had fairly high IQ, comparable to typically developing participants, but we still observed very obvious general memory impairments in this group,” Liu said.

Among typically developing children, memory skills were consistent: If a child had good memory for faces, he or she was also good at remembering non-social information.

This wasn’t the case in autism. “Among children with autism, some kids seem to have both impairments and some have more severe impairment in one area of memory or the other,” Liu said.  

“It was a surprising finding that these two dimensions of memory are both dysfunctional, in ways that seem to be unrelated – and that maps onto our analysis of the brain circuitry,” Menon said.

The brain scans showed that, among the children with autism, distinct brain networks drive different types of memory difficulty.

For children with autism, the ability to retain non-social memories was predicted by connections in a network centred on the hippocampus. But face memory was predicted by a separate set of connections centred on the posterior cingulate cortex, a key region of the brain’s default mode network, which has roles in social cognition and distinguishing oneself from other people.

“The findings suggest that general and face-memory challenges have two underlying sources in the brain which contribute to a broader profile of memory impairments in autism,” Menon said.

In both networks, the brains of children with autism showed over-connected circuits relative to typically developing children. Over-connectivity, likely from insufficient selective pruning of neural circuits, has been found in other studies of brain networks in children with autism.

New autism therapies should account for the breadth of memory difficulties the research uncovered, as well as how these challenges affect social skills, Menon said. “This is important for functioning in the real world and for academic settings.”

Source: Stanford University Medical Center

Categories : NeurologyTags :

Scientists Discover a Neural Signature for Borderline Personality Disorder

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A new study of a brain region called the rostro-medial prefrontal could potentially advance diagnosis and therapies for Borderline Personality Disorder (BPD). Published in the journal Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, the research revealed that the rostro-medial prefrontal specifically becomes more active when people are rejected by others at greater rates. However, individuals with BPD – characterised by interpersonal sensitivity to rejection and emotional instability – do not display rostro-medial prefrontal cortex activity when rejected.

The brain reacts with rostro-medial prefrontal activity to rejection as if there is something “wrong” in the environment. This brain activity may activate an attempt to try to restore and maintain close social ties to survive and thrive. This region of the brain also is activated when humans try to understand other peoples’ behaviour in light of their mental and emotional state.

“Inactivity in the rostro-medial prefrontal cortex during rejection may explain why those with BPD are more sensitive and more distressed by rejection. Understanding why individuals with this debilitating and high risk disorder experience emotional distress to rejection goes awry will help us develop more targeted therapies for BPD,” said psychologist Eric A. Fertuck, associate professor at City College of New York.

On the significance of the study, Fertuck noted that while previous findings in this area have been mixed, “what we’ve done is improve the specificity and resolution of our rejection assessment, which improves on prior studies.”

Research continues with several investigations underway examining the role of social rejection in different mental health problems including post-traumatic stress disorder, depression, and social anxiety.

Source: City College of New York

Categories : NeurologyTags :

New Analysis Strengthens Evidence Linking Autism and the Microbiome

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In spite of burgeoning studies, the biological roots of autism remain elusive. Microbial approaches however have shown some promise, and now a study published in Nature Neuroscience has uncovered a microbial signature associated with autism, which clearly overlaps with metabolic pathways.

The study re-analysed of dozens of previously published datasets and found that they align with a recent, long-term study of autistic individuals that used a microbiome-focused intervention. These findings also underscore the importance of longitudinal studies in elucidating the interplay between the microbiome and complex conditions such as autism.

“We were able to harmonise seemingly disparate data from different studies and find a common language with which to unite them. With this, we were able to identify a microbial signature that distinguishes autistic from neurotypical individuals across many studies,” says Jamie Morton, one of the study’s corresponding authors. “But the bigger point is that going forward, we need robust long-term studies that look at as many datasets as possible and understand how they change when there is a [therapeutic] intervention.”

With 43 authors, this study brought together leaders in computational biology, engineering, medicine, autism and the microbiome who hailed from institutions in North America, South America, Europe and Asia. “The sheer number of fields and areas of expertise in this large-scale collaboration is noteworthy and necessary to get a new and consistent picture of autism,” says Rob Knight, the director of the Center for Microbiome Innovation at the University of California San Diego and a study co-author.

Autism is inherently complex, and studies that attempt to pinpoint specific gut microbes involved in the condition have been confounded by this complexity. First, autism presents in heterogeneous ways – autistic individuals differ from each other genetically, physiologically and behaviourally. Second, the microbiome presents unique difficulties. Microbiome studies typically report simply the relative proportions of specific microbes, requiring sophisticated statistics to understand which microbial population changes are relevant to a condition of interest.

This makes it challenging to find the signal amongst the noise. Making matters more complicated, most studies to date have been one-time snapshots of the microbial populations present in autistic individuals. “A single time point is only so powerful; it could be very different tomorrow or next week,” says study co-author Brittany Needham, assistant professor of anatomy, cell biology and physiology at the Indiana University School of Medicine.

“We wanted to address the constantly evolving question of how the microbiome is associated with autism, and thought, ‘let’s go back to existing datasets and see how much information we may be able to get out of them,'” says co-corresponding author Gaspar Taroncher-Oldenburg, director of Therapeutics Alliances at New York University, who initiated the work with Morton while he was a consultant-in-residence for SFARI.

In the new study, the research team developed an algorithm to re-analyse 25 previously published datasets containing microbiome and other “omic” information, such as gene expression, immune system response and diet, from both autistic and neurotypical cohorts. Within each dataset, the algorithm found the best matched pairs of autistic and neurotypical individuals in terms of age and sex, two factors that can typically confound autism studies.

Novel computational methodologies

“Rather than comparing average cohort results within studies, we treated each pair as a single data point, and thus were able to simultaneously analyse over 600 ASD-control pairs corresponding to a de facto cohort of over 1200 children,” says Taroncher-Oldenburg. “From a technical standpoint, this required the development of novel computational methodologies altogether,” he adds. Their new computational approach enabled them to reliably identify microbes that have differing abundances between ASD and neurotypical individuals.

The analysis identified autism-specific metabolic pathways associated with particular human gut microbes. Importantly, these pathways were also seen elsewhere in autistic individuals, from their brain-associated gene expression profiles to their diets. “We hadn’t seen this kind of clear overlap between gut microbial and human metabolic pathways in autism before,” says Morton.

Even more striking was an overlap between microbes associated with autism, and those identified in a recent long-term faecal microbiota transplant study led by James Adams and Rosa Krajmalnik-Brown at Arizona State University. “Another set of eyes looked at this, from a different lens, and they validated our findings,” says Krajmalnik-Brown, who was not involved in this study.

“What’s significant about this work is not only the identification of major signatures, but also the computational analysis that identified the need for future studies to include longitudinal, carefully designed measurements and controls to enable robust interpretation,” says Kelsey Martin, executive vice president of SFARI and the Simons Foundation Neuroscience Collaborations, who was not involved in the study.

“Going forward, we need more long-term studies that involve interventions, so we can get at cause-and-effect,” says Morton. Taroncher-Oldenburg, who cites the compliance issues often faced by traditional long-term studies, suggests that study designs could more effectively take into account the realities of long-term microbiome sampling of autistic individuals. “Practical, clinical restrictions must inform the statistics, and that will inform the study design,” he says. Further, he points out that long-term studies can reveal insights about both the group and the individual, as well as how that individual responds to specific interventions over time.

Importantly, researchers say these findings go beyond autism. The approach set forth here could also be employed across other areas of biomedicine that have long proved challenging. “Before this, we had smoke indicating the microbiome was involved in autism, and now we have fire. We can apply this approach to many other areas, from depression to Parkinson’s to cancer, where we think the microbiome plays a role, but where we don’t yet know exactly what the role is,” says Knight.

Source: EurekAlert!

Categories : Mental Health NeurologyTags :

Neuroscientists Identify a New Subtype of Depression that Resists SSRIs

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In a new study, scientists at Stanford Medicine have described a new category of depression, the cognitive biotype, which accounts for 27% of depressed patients and is not effectively treated by commonly prescribed antidepressants. The findings were reported in JAMA Network.

For these patients, cognitive tasks showed difficulty in planning ahead, self-control, sustaining focus despite distractions and suppressing inappropriate behaviour; imaging showed decreased activity in two brain regions responsible for those tasks.

Because depression has traditionally been defined as a mood disorder, doctors commonly prescribe selective serotonin reuptake inhibitors (SSRIs), but these are less effective for patients with cognitive dysfunction. Researchers said that targeting these cognitive dysfunctions with less commonly used antidepressants or other treatments may alleviate symptoms and help restore social and occupational abilities.

The study is part of a broader effort by neuroscientists to find treatments that target depression biotypes, according to the study’s senior author, Leanne Williams, PhD, professor of psychiatry and behavioural sciences.

“One of the big challenges is to find a new way to address what is currently a trial-and-error process so that more people can get better sooner,” Williams said. “Bringing in these objective cognitive measures like imaging will make sure we’re not using the same treatment on every patient.”

Finding the biotype

In the study, 1008 adults with previously unmedicated major depressive disorder were randomly given one of three widely prescribed typical antidepressants: escitalopram (Lexapro) or sertraline (Zoloft), which act on serotonin, or venlafaxine-XR (Effexor), which acts on both serotonin and norepinephrine. Seven hundred and twelve of the participants completed the eight-week regimen.

Before and after treatment with the antidepressants, the participants’ depressive symptoms were measured using two surveys – one, clinician-administered, and the other, a self-assessment, which included questions related to changes in sleep and eating. Measures on social and occupational functioning, as well as quality of life, were tracked as well.

The participants also completed a series of cognitive tests, before and after treatment, measuring verbal memory, working memory, decision speed and sustained attention, among other tasks.

Before treatment, scientists scanned 96 of the participants using functional magnetic resonance imaging as they engaged in a task called the “GoNoGo” that requires participants to press a button as quickly as possible when they see “Go” in green and to not press when they see “NoGo” in red. The fMRI tracked neuronal activity by measuring changes in blood oxygen levels, which showed levels of activity in different brain regions corresponding to Go or NoGo responses. Researchers then compared the participants’ images with those of individuals without depression.

The researchers found that 27% of the participants had more prominent symptoms of cognitive slowing and insomnia, impaired cognitive function on behavioural tests, as well as reduced activity in certain frontal brain regions – a profile they labelled the ‘cognitive biotype’.

“This study is crucial because psychiatrists have few measurement tools for depression to help make treatment decisions,” said Laura Hack, MD, PhD, the lead author of the study and an assistant professor of psychiatry and behavioural sciences. “It’s mostly making observations and self-report measures. Imaging while performing cognitive tasks is rather novel in depression treatment studies.”

Pre-treatment fMRI showed those with the cognitive biotype had significantly reduced activity in the dorsolateral prefrontal cortex and dorsal anterior cingulate regions during the GoNoGo task compared with the activity levels in participants who did not have the cognitive biotype. Together, the two regions form the cognitive control circuit, which is responsible for limiting unwanted or irrelevant thoughts and responses and improving goal selection, among other tasks.

After treatment, the researchers found that for the three antidepressants administered, the overall remission rates were 38.8% for participants with the newly discovered biotype and 47.7% for those without it. This difference was most prominent for sertraline, for which the remission rates were 35.9% and 50% for those with the biotype and those without, respectively.

“Depression presents in different ways in different people, but finding commonalities – like similar profiles of brain function – helps medical professionals effectively treat participants by individualising care,” Williams said.

Depression isn’t one size fits all

Williams and Hack propose that behaviour measurement and imaging could help diagnose depression biotypes and lead to better treatment. A patient could complete a survey on their own computer or in the doctor’s office, and if they are found to display a certain biotype, they might be referred to imaging for confirmation before undergoing treatment.

Researchers under Williams and Hack are studying another drug, guanfacine, that specifically targets the dorsolateral prefrontal cortex region. They believe this treatment could be more effective for patients with the cognitive subtype.

Williams and Hack hope to conduct studies with participants who have the cognitive biotype, comparing different types of medication with treatments such as transcranial magnetic stimulation (TMS) and cognitive behavioural therapy.

“I regularly witness the suffering, the loss of hope and the increase in suicidality that occurs when people are going through our trial-and-error process,” Hack said. “And it’s because we start with medications that have the same mechanism of action for everyone with depression, even though depression is quite heterogeneous. I think this study could help change that.”

Source: Stanford Medicine