1. Study tests the ‘three-hit’ theory of autism

    March 27, 2017 by Ashley

    From the Rockefeller University press release:

    Since the first case was documented in the United States in 1938, the causes of autism have remained elusive. Hundreds of genes, as well as environmental exposures, have been implicated in these brain disorders. Sex also seems to have something to do with it: About 80 percent of children diagnosed with an autism spectrum disorder are boys.

    This striking bias caught the attention of Rockefeller University’s Donald W. Pfaff. A neurobiologist who studies hormone effects and sex differences in the brain, Pfaff wondered if maleness might somehow amplify the genetic and environmental risk factors for the disease.

    In collaboration with colleagues specializing in child neurology and psychology, he has proposed a “three-hit” theory of autism, which suggests that a genetic predisposition in combination with early stress is more detrimental to boys than to girls, and more likely to produce the social avoidance that is a hallmark of autism disorders. Now, a team in his lab has found evidence in mice supporting this theory.

    “Together, these three hits — genes, environment, and sex — build on one another, such that their combined effect on behavior is much greater than the sum of the three individually,” says Pfaff, head of the Laboratory of Neurobiology and Behavior.

    A test run

    Pfaff and his colleagues formulated the three-hit theory based on studies of animals suggesting that the male hormone testosterone may sensitize the developing brain to stress in a way that can lead to social avoidance, a behavior characteristic of autism. Mice, like humans, are social animals, and in experiments, described in the Proceedings of the National Academy of Sciences, Pfaff’s team looked to see if male mice were more prone to problems with social responses than females when the other two risk factors were present.

    The theory and these experiments focus on the primary aspect of autism spectrum disorders, social problems, but there are others. In addition to social avoidance, autism is associated with difficulties in communication, as well as unusually restricted interests.

    To achieve a genetic hit, the team, led by Sara Schaafsma, a postdoc in the lab, used mice lacking a gene that is frequently mutated in people diagnosed with autism. To evoke stress in the as-yet unborn mice, the researchers prompted the immune systems of their pregnant mothers to react as though under attack from bacteria.

    Changes in brain and behavior

    The researchers later tested the social behavior of these mice in a series of experiments. The most compelling evidence for the three-hit theory came from a test of social recognition. Most of the animals, even those with two risk factors, showed signs of recognizing a once-unfamiliar mouse over multiple encounters. Only mice with all three hits — those that were male, were genetically predisposed to autism, and had experienced stress as embryos — seemed unable to recognize new acquaintances after encountering them multiple times.

    Next, the researchers looked for molecular changes within these rodents’ brains that might help to explain the differences in behavior. They found an increase in the expression of a gene that helps to kick off stress responses, in a brain region called the left hippocampus. With help from C. David Allis’s lab, they looked for chemical alterations in the packaging of DNA that might explain this uptick in gene activity. This effort revealed one particular chemical change in the nerve cell nucleus that encourages the expression of this stress-relevant gene.

    “Neurodevelopmental disorders, including autism, are often attributed to an interaction between genetic ‘nature’ and environmental ‘nurture.’ Our work indicates how male sex comes to be an important component of this dynamic, at least for one major aspect of autism,” Pfaff says. “By collecting a variety of evidence, we have begun to uncover one molecular mechanism, of many, by which these three hits alter sociability.”


  2. Brain cells show teamwork in short-term memory

    March 23, 2017 by Ashley

    From the University of Western Ontario press release:

    Nerve cells in our brains work together in harmony to store and retrieve short-term memory, and are not solo artists as previously thought, Western-led brain research has determined.

    The research turns on its head decades of studies assuming that single neurons independently encode information in our working memories.

    “These findings suggest that even neurons we previously thought were ‘useless’ because they didn’t individually encode information have a purpose when working in concert with other neurons,” said researcher Julio Martinez-Trujillo, based at the Robarts Research Institute and the Brain and Mind Institute at Western University.

    “Knowing they work together helps us better understand the circuits in the brain that can either improve or hamper executive function. And that in turn may have implications for how we work though brain-health issues where short-term memory is a problem, including Alzheimer disease, schizophrenia, autism, depression and attention deficit disorder.”

    Working memory is the ability to learn, retain and retrieve bits of information we all need in the short term: items on a grocery list or driving directions, for example. Working memory deteriorates faster in people with dementia or other disorders of the brain and mind.

    In the past, researchers have believed this executive function was the job of single neurons acting independently from one another — the brain’s version of a crowd of people in a large room all singing different songs in different rhythms and different keys. An outsider trying to decipher any tune in all that white noise would have an extraordinarily difficult task.

    This research, however, suggests many in the neuron throng are singing from the same songbook, in essence creating chords to strengthen the collective voice of memory. With neural prosthetic technology — microchips that can “listen” to many neurons at the same time — researchers are able to find correlations between the activity of many nerve cells. “Using that same choir analogy, you can start perceiving some sounds that have a rhythm, a tune and chords that are related to each other: in sum, short-term memories,” said Martinez-Trujillo, who is also an associate professor at Western’s Schulich School of Medicine & Dentistry.

    And while the ramifications of this discovery are still being explored, “this gives us good material to work with as we move forward in brain research. It provides us with the necessary knowledge to find ways to manipulate brain circuits and improve short term memory in affected individuals,” Martinez-Trujillo said.

    “The microchip technology also allows us to extract signals from the brain in order to reverse-engineer brain circuitry and decode the information that is in the subject’s mind. In the near future, we could use this information to allow cognitive control of neural prosthetics in patients with ALS or severe cervical spinal cord injury,” said Adam Sachs, neurosurgeon and associate scientist at The Ottawa Hospital and assistant professor at the University of Ottawa Brain and Mind Research Institute.


  3. Adults with autism overcome childhood language challenges

    March 21, 2017 by Ashley

    From the Johns Hopkins Medicine press release:

    Results of a small study of adults with autism at Johns Hopkins has added to evidence that their brains can learn to compensate for some language comprehension challenges that are a hallmark of the disorder in children.

    Studies analyzing electrical activity in the brains of children with autism have shown that they have difficulty sorting out pairs of words that are unrelated — like “clock” and “frog” — from those that are related — like “baby” and “bottle” — making it hard for them to process written or spoken language. Moreover, investigators believed that for most children with autism, this struggle with language persisted throughout their lives.

    Results of the new research from specialists at Johns Hopkins Medicine, published in the March issue of the Journal of Autism and Developmental Disorders, suggests that at least some adults with autism process unrelated words as well as adults without the disorder and their brains use distinct learning strategies to do so.

    “There is often an assumption that people with autism will always have problems understanding the meaning of language,” says Emily Coderre, Ph.D., a postdoctoral fellow in neurology at the Johns Hopkins University School of Medicine. “But our results suggest that adults with autism seem to use an alternative mechanism to process language that results in a different pattern in the brain.”

    For the study, the researchers recruited 20 adults with autism spectrum disorder, considered mild to moderate. All participants had “normal” verbal abilities, according to standardized tests. Those with autism spectrum disorder were diagnosed by a specialist on the team based on their score on the Autism Diagnostic Observation Schedule. Some participants were diagnosed early in life, and others not until adulthood. Many participants went to regular schools with special education tracks. Some participants had graduated high school, and some went through college. The research team also recruited a matching group of 20 participants without autism to serve as a comparative control group. Participants overall ranged in age from 18 to 69. Six were female, 35 were white, one was Asian, two were African-American, one was Hispanic and one was mixed race.

    All participants completed a 90-minute computer task that asked them to decide whether two pictures or two words were related (e.g., baby and bottle) or unrelated (e.g., frog and clock). The task designers chose 400 pairs of tangible nouns, half of them in the form of words and the other half displayed as pictures.

    One hundred of the noun pairs were related words, 100 were related pictures, 100 were unrelated words and 100 were unrelated pictures. The screen showed a picture or a word for 1 second and after a brief pause displayed the second picture or word.

    While the participants completed the task, the researchers monitored their brain’s electrical activity using an electroencephalogram (EEG) that recorded activity from 256 electrodes. For their analyses, the researchers looked at the brain activity from nine small clusters of electrodes on the front left, middle and right of the head over the frontal cortex; in the left, middle and right of the top of the head over the central brain; and on the left, right and middle part of the back top of the head, where the parietal lobe is located.

    When analyzing unrelated pictures or words, people with typical development have a spike on the EEG during the 200- to 800-millisecond window following the second word or photo, known as an N400 response. Researchers believe the N400 response reflects the brain’s ability to recognize that something is “off” and that two words or pictures aren’t related in a meaningful way.

    When looking at related and unrelated pictures, the people with autism had the same N400 spike on the EEG readout as the people without autism.

    Contrary to findings from earlier studies in children with autism, adults with autism also had the N400 spike in electrical activity on the EEG when looking at related and unrelated words. In the controls, the response occurred at 250 to 500 milliseconds in the front of the head and from approximately 400 to 800 milliseconds over the top and top rear of the head. The response in the adults with autism started later, from 400 to 800 milliseconds in both the top and top rear of the head.

    From 400 to 800 milliseconds, the N400 spike was relatively evenly distributed over left and right sides of the head for the control participants, whereas in adults with autism, the spike was stronger over the right side of the head. Coderre says that these differences between the groups — an earlier onset of the N400 response for controls and a more right-sided N400 response for the adults with autism — suggest that the two groups used different strategies to think about the meaning of the words. She points out that overall, the adults with autism showed a similar N400 response to the controls, suggesting that they weren’t impaired at teasing apart the unrelated from the related words, contrary to previous studies in children with autism. “It appears that although the adults with autism in our study have brains that are ‘wired’ differently than those without autism, our findings strongly suggest this different wiring can still enable them to achieve good cognitive and language abilities, at least on this one measure,” she says.

    “It is possible that some adults with mild or moderate forms of autism may have developed compensatory learning strategies that allow them to process language as well as people without autism,” says Coderre. She plans to repeat this experiment in children with mild to moderate autism to verify that the differences seen between adults and children are due to learned responses.

    “If we can understand those compensatory strategies better, then teachers can use this information in language programs for children or those with more severe language deficits to help them develop these alternative strategies faster and earlier,” she adds. “I hope our study sends a hopeful message to people with autism or their parents.”

    Coderre says that one limitation of her study is that they used single words for their analysis, simplifying it, whereas others in previous studies used full sentences in their study design, which may have affected the results. She also points out that they asked participants to think about whether the two words were related or not, which may have prompted them to use more explicit compensatory strategies. In future studies, she plans to repeat this experiment using an “implicit” task, in which participants aren’t told to think about the relationship between the words, allowing her to verify whether these results were due to learned compensatory strategies in adults with autism.

    About 3.5 million people in the U.S. have autism, according to the National Institutes of Health, and about a quarter of those are nonverbal. Those with speech have difficulty with complex language processing, like understanding meaning, emotional states in the voice or metaphors.


  4. Sensory links between autism and synesthesia pinpointed

    March 20, 2017 by Ashley

    From the University of Sussex press release:

    Concrete links between the symptoms of autism and synaesthesia have been discovered and clarified for the first time, according to new research by psychologists at the University of Sussex.

    The study, conducted by world-leading experts in both conditions at Sussex and the University of Cambridge and published in the journal Scientific Reports, found that both groups experience remarkably similar heightened sensory sensitivity, despite clear differences in communicative ability and social skills.

    Two previous studies had found an increased prevalence of synaesthesia in autistic subjects, suggesting that although they are not always found in conjunction, the two conditions occur together more often than would be expected by chance alone. However, this is the first study that has attempted to draw a definitive symptomatic link between the two.

    Synaesthesia and autism seem on the surface to be rather different things, with synaesthesia defined as a ‘joining of the senses’ in which music may trigger colours or words may trigger tastes, and autism defined by impaired social understanding and communication.

    The new research shows that both groups report heightened sensory sensitivity, such as an aversion to certain sounds and lights, as well as reporting differences in their tendency to attend to detail. However, the synaesthetes tended not to report difficulties on the traditional communicative symptoms that usually define autism. While the research shows that there are certainly links between the two conditions, these appear to be sensory rather than social.

    The study was led by Professor Jamie Ward, Professor of Cognitive Neuroscience and Co-Director Sussex Neuroscience group, alongside Sussex Psychology colleague, Professor Julia Simner; and Professor Simon Baron-Cohen, Professor of Developmental Psychopathology at the University of Cambridge and Director of the Autism Research Centre.

    Commenting on the research, Prof Ward said: “Synaesthesia has traditionally been considered more of a gift than an impairment, whereas the opposite could often be said of autism. Our research suggests that the two have much more in common than was previously thought, and that many of the sensory traits that autistic people possess are also found in those who experience synaesthesia.

    “Though further research is required, our understanding of autism in the context of synaesthetic abilities may help us unlock the secrets of some of the more positive aspects of autism, such as savantism, while also uncovering further neurological links between the two conditions.”

    Another research paper by the group of researchers, looking more closely at the question of savantism in people with autism, is also due to be published soon.

    Reinforcing their initial research, it shows that synaesthesia tends to be particularly prevalent in people with autism who also have unexpected ‘savant’ abilities, such as superior abilities in arithmetic, memory and art.

    Prof Ward added: “Though some theories propose a causal link between increased sensory sensitivity and impaired social functioning in people with autism, our research so far demonstrates the value of considering synaesthesia on the same spectrum as autism from a sensory point of view.

    We hope in future to be able to continue to explore the relationship between perceptual, cognitive and social symptoms and abilities in autistic and synaesthetic people.”


  5. Protein called GRASP1 is needed to strengthen brain circuits

    March 15, 2017 by Ashley

    From the Johns Hopkins University press release:

    Learning and memory depend on cells’ ability to strengthen and weaken circuits in the brain. Now, researchers at Johns Hopkins Medicine report that a protein involved in recycling other cell proteins plays an important role in this process.

    Removing this protein reduced mice’s ability to learn and recall information. “We see deficits in learning tasks,” says Richard Huganir, Ph.D., professor and director of the neuroscience department at the Johns Hopkins University School of Medicine.

    The team also found mutations in the gene that produces the recycling protein in a few patients with intellectual disability, and those genetic errors affected neural connections when introduced into mouse brain cells. The results, reported in the March 22 issue of Neuron, suggest that the protein could be a potential target for drugs to treat cognitive disorders such as intellectual disability and autism, Huganir says.

    The protein, known as GRASP1, short for GRIP-associated protein 1, was previously shown to help recycle certain protein complexes that act as chemical signal receptors in the brain. These receptors sit on the edges of neurons, and each cell continually shuttles them between its interior and its surface. By adjusting the balance between adding and removing available receptors, the cell fortifies or weakens the neural connections required for learning and memory.

    Huganir says most previous research on GRASP1 was conducted in laboratory-grown cells, not in animals, while the new study was designed to find out what the protein does at the behavioral level in a living animal.

    To investigate, his team genetically engineered so-called knockout mice that lacked GRASP1 and recorded electrical currents from the animals’ synapses, the interfaces between neurons across which brain chemical signals are transmitted. In mice without GRASP1, neurons appeared to spontaneously fire an average of 28 percent less frequently than in normal mice, suggesting that they had fewer synaptic connections.

    Next, Huganir’s team counted protrusions on the mice’s brain cells called spines, which have synapses at their tips. The average density of spines in knockout mice was 15 percent lower than in normal mice, perhaps because defects in receptor recycling had caused spines to be “pruned” or retracted. Neurons from mice without GRASP1 also showed weaker long-term potentiation, a measure of synapse strengthening, in response to electrical stimulation.

    The team then tested the mice’s learning and memory. First, the animals were placed in a tub of milky water and trained to locate a hidden platform. The normal mice needed five training sessions to quickly find the platform in the opaque water, while the knockout mice required seven; the next day, the normal mice spent more time swimming in that location than in other parts of the tub, but the knockout mice seemed to swim around randomly.

    Second, the mice were put in a box with light and dark chambers and given a slight shock when they entered the dark area. The next day, the normal mice hesitated for an average of about four minutes before crossing into the dark chamber, while the knockout mice paused for less than two minutes. “Their memory was not quite as robust,” Huganir says.

    To assess the importance of GRASP1 in humans, the team identified two mutations in the gene that produce the protein in three young male patients with intellectual disabilities, who had an IQ of less than 70 and were diagnosed at an early age. When the researchers replaced the rodent version of the normal GRASP1 gene with the two mutated mouse versions in mouse brain cells, the spine density decreased by 11 to 16 percent, and the long-term potentiation response disappeared.

    Huganir speculates that defects in GRASP1 might cause learning and memory problems because the cells aren’t efficiently recycling receptors back to the surface. Normally, GRASP1 attaches to traveling cellular compartments called vesicles, which carry the receptors, and somehow helps receptors get transferred from ingoing to outgoing vesicles.

    When Huganir’s team introduced GRASP1 mutations into mouse cells, receptors accumulated inside recycling compartments instead of being shuttled to the surface.

    Huganir cautions that the results don’t prove that the GRASP1 mutations caused the patients’ intellectual disability. But the study may encourage geneticists to start testing other patients for mutations in this gene, he says. If more cases are found, researchers may be able to design drugs that target the pathway. Huganir’s team is now studying GRASP1’s role in the receptor recycling process in more detail.


  6. MRIs predict which high-risk babies will develop autism as toddlers

    February 16, 2017 by Ashley

    From the University of North Carolina Health Care media release:

    autism_stairsUsing magnetic resonance imaging (MRI) in infants with older siblings with autism, researchers from around the country were able to correctly predict 80 percent of those infants who would later meet criteria for autism at two years of age.

    The study, published in Nature, is the first to show it is possible to identify which infants — among those with older siblings with autism — will be diagnosed with autism at 24 months of age.

    “Our study shows that early brain development biomarkers could be very useful in identifying babies at the highest risk for autism before behavioral symptoms emerge,” said senior author Joseph Piven, MD, the Thomas E. Castelloe Distinguished Professor of Psychiatry at the University of North Carolina-Chapel Hill. “Typically, the earliest an autism diagnosis can be made is between ages two and three. But for babies with older autistic siblings, our imaging approach may help predict during the first year of life which babies are most likely to receive an autism diagnosis at 24 months.”

    This research project included hundreds of children from across the country and was led by researchers at the Carolina Institute for Developmental Disabilities (CIDD) at the University of North Carolina, where Piven is director. The project’s other clinical sites included the University of Washington, Washington University in St. Louis, and The Children’s Hospital of Philadelphia. Other key collaborators are McGill University, the University of Alberta, the University of Minnesota, the College of Charleston, and New York University.

    This study could not have been completed without a major commitment from these families, many of whom flew in to be part of this,” said first author Heather Hazlett, PhD, assistant professor of psychiatry at the UNC School of Medicine and a CIDD researcher. “We are still enrolling families for this study, and we hope to begin work on a similar project to replicate our findings.”

    People with Autism Spectrum Disorder (or ASD) have characteristic social deficits and demonstrate a range of ritualistic, repetitive and stereotyped behaviors. It is estimated that one out of 68 children develop autism in the United States. For infants with older siblings with autism, the risk may be as high as 20 out of every 100 births. There are about 3 million people with autism in the United States and tens of millions around the world.

    Despite much research, it has been impossible to identify those at ultra-high risk for autism prior to 24 months of age, which is the earliest time when the hallmark behavioral characteristics of ASD can be observed and a diagnosis made in most children.

    For this Nature study, Piven, Hazlett, and researchers from around the country conducted MRI scans of infants at six, 12, and 24 months of age. They found that the babies who developed autism experienced a hyper-expansion of brain surface area from six to 12 months, as compared to babies who had an older sibling with autism but did not themselves show evidence of the condition at 24 months of age. Increased growth rate of surface area in the first year of life was linked to increased growth rate of overall brain volume in the second year of life. Brain overgrowth was tied to the emergence of autistic social deficits in the second year.

    Previous behavioral studies of infants who later developed autism — who had older siblings with autism -revealed that social behaviors typical of autism emerge during the second year of life.

    The researchers then took these data — MRIs of brain volume, surface area, cortical thickness at 6 and 12 months of age, and sex of the infants — and used a computer program to identify a way to classify babies most likely to meet criteria for autism at 24 months of age. The computer program developed the best algorithm to accomplish this, and the researchers applied the algorithm to a separate set of study participants.

    The researchers found that brain differences at 6 and 12 months of age in infants with older siblings with autism correctly predicted eight out of ten infants who would later meet criteria for autism at 24 months of age in comparison to those infants with older ASD siblings who did not meet criteria for autism at 24 months.

    “This means we potentially can identify infants who will later develop autism, before the symptoms of autism begin to consolidate into a diagnosis,” Piven said.

    If parents have a child with autism and then have a second child, such a test might be clinically useful in identifying infants at highest risk for developing this condition. The idea would be to then intervene ‘pre-symptomatically’ before the emergence of the defining symptoms of autism.

    Research could then begin to examine the effect of interventions on children during a period before the syndrome is present and when the brain is most malleable. Such interventions may have a greater chance of improving outcomes than treatments started after diagnosis.

    “Putting this into the larger context of neuroscience research and treatment, there is currently a big push within the field of neurodegenerative diseases to be able to detect the biomarkers of these conditions before patients are diagnosed, at a time when preventive efforts are possible,” Piven said. “In Parkinson’s for instance, we know that once a person is diagnosed, they’ve already lost a substantial portion of the dopamine receptors in their brain, making treatment less effective.

    Piven said the idea with autism is similar; once autism is diagnosed at age 2-3 years, the brain has already begun to change substantially.

    “We haven’t had a way to detect the biomarkers of autism before the condition sets in and symptoms develop,” he said. “Now we have very promising leads that suggest this may in fact be possible.”


  7. Increased reaction to stress linked to gastrointestinal issues in children with autism

    January 6, 2017 by Ashley

    From the University of Missouri-Columbia media release:

    One in 45 American children lives with autism spectrum disorder, according to the Centers for Disease Control and Prevention.

    Many of these children also have significant gastrointestinal issues, but the cause of these symptoms is unknown. Now, researchers from the University of Missouri School of Medicine suggest that the gastrointestinal issues in these individuals with autism may be related to an increased reaction to stress. It’s a finding the researchers hope could lead to better treatment options for these patients.

    “We know that it is common for individuals with autism to have a more intense reaction to stress, and some of these patients seem to experience frequent constipation, abdominal pain or other gastrointestinal issues,” said David Beversdorf, M.D., associate professor in the departments of radiology, neurology and psychological sciences at MU and the MU Thompson Center for Autism and Neurodevelopmental Disorders. “To better understand why, we looked for a relationship between gastrointestinal symptoms and the immune markers responsible for stress response. We found a relationship between increased cortisol response to stress and these symptoms.”

    Cortisol is a hormone released by the body in times of stress, and one of its functions is to prevent the release of substances in the body that cause inflammation. These inflammatory substances — known as cytokines — have been associated with autism, gastrointestinal issues and stress. The researchers studied 120 individuals with autism who were treated at MU and Vanderbilt University. The individuals’ parents completed a questionnaire to assess their children’s gastrointestinal symptoms, resulting in 51 patients with symptoms and 69 without gastrointestinal symptoms.

    To elicit a stress response, individuals took a 30-second stress test. Cortisol samples were gathered through participants’ saliva before and after the test. The researchers found that the individuals with gastrointestinal symptoms had greater cortisol in response to the stress than the participants without gastrointestinal symptoms.

    When treating a patient with autism who has constipation and other lower gastrointestinal issues, physicians may give them a laxative to address these issues,” Beversdorf said. “Our findings suggest there may be a subset of patients for which there may be other contributing factors. More research is needed, but anxiety and stress reactivity may be an important factor when treating these patients.”

     


  8. Impaired recycling of mitochondria in autism?

    October 31, 2016 by Ashley

    From the Boston Children’s Hospital media release:

    memory neuronsTuberous sclerosis complex (TSC), a genetic disorder that causes autism in about half of those affected, could stem from a defect in a basic system cells use to recycle their mitochondria, report scientists at Boston Children’s Hospital. The scientists believe their findings, published online October 18 by Cell Reports, open new treatment possibilities not just for TSC, but possibly for other forms of autism and some neurologic disorders.

    Mitochondria, the organelles responsible for cellular energy production and metabolism, constantly get recycled. Through a process known as autophagy (“self-eating”), cells literally digest their damaged or aging mitochondria, clearing the way for healthy replacements. (Research on how autophagy works earned a Nobel Prize earlier this month.)

    The new study, led by Mustafa Sahin, MD, PhD, and co-first authors Darius Ebrahimi-Fakhari, MD, PhD, a resident at Boston Children’s Hospital, and medical student Afshin Saffari, in Boston Children’s F.M. Kirby Neurobiology Center, shows that autophagy is defective in TSC. The scientists further showed that two existing classes of drugs counter the defect: the epilepsy drug carbamazepine, and drugs known as mTOR inhibitors. When treated, the dysfunctional neurons were able to clear damaged mitochondria and replenish healthy mitochondria, restoring a normal turnover.

    “Our findings point to possible treatments for enhancing mitophagy for some neurodevelopmental and neurodegenerative diseases,” says Sahin, who is also director of the Translational Neuroscience Center at Boston Children’s and senior author on the paper.

    Out with the old, in with the new

    Defects in mitophagy, or autophagy of mitochondria, have already been implicated in a number of neurologic disorders such as Parkinson’s disease and Alzheimer’s disease. Mitochondria have also been studied in autism for years, but the findings have been largely anecdotal and inconclusive, in part because the autism population is diverse and hard to define.

    We decided to use tuberous sclerosis, a genetically defined disorder that has a high incidence of autism, as a model to understand the role of mitochondrial dynamics,” says Sahin.

    Sahin, Ebrahimi-Fakhari and colleagues studied both rat neurons and patient-derived neurons (created from induced pluripotent stem cells) affected by TSC and used live-cell imaging to examine the distribution and dynamics of mitochondria. They found that the TSC neurons as a whole had more mitochondria, and in particular more fragmented and dysfunctional mitochondria.

    Axons take the hit

    Then they examined the neurons’ axons, the projections that send messages to other cells. Mitochondria play a critical role in axons, and are found in high numbers at presynaptic sites — the tips of axons that form synapses or junctions with other neurons and release neurotransmitters. But the axons of both rat neurons and neurons from TSC patients were depleted of mitochondria.

    “We think this could have implications for how neurons talk to each other,” says Ebrahimi-Fakhari. “Synapses that lose the support of mitochondria might be releasing neurotransmitters too much or too little.”

    Diving deeper, they found that while mitophagy was increased in the body of the cell, it was reduced in the axons. Although proteins involved in the early steps of mitophagy increased in the axons, autophagosomes and lysosomes — the organelles that do the digesting — failed to appear around the damaged mitochondria. Instead, the mitochondria were being shuttled out of the axons, back to the body of the cell, without being replaced.

    Therapeutic opportunity?

    The researchers were able to restore normal mitophagy and replenish functioning mitochondria — in both neurons in a dish and in live mice — in several ways:

    • by reintroducing a healthy copy of the gene mutated in TSC
    • by adding rapamycin, an mTOR inhibitor that the Sahin lab has shown to improve TSC in animal models and that is currently in clinical trials
    • with carbamazepine, a common anti-seizure medication, that enhances autophagy through a different mechanism of action than mTOR inhibitors.

    Most notably, mitochondria were replenished at presynaptic sites, where their presence is most critical.

    The findings shed intriguing light on what is already known about TSC and autism. Growing evidence, including from previous studies in the Sahin lab, shows that autism, intellectual disability and seizures in many patients with TSC may result, at least in part, from synaptic dysfunction. Autism itself is increasingly seen as a disorder of synapses — and this study hints at one possible way synapses might go awry.

    “Our work defines mitochondrial homeostasis as a therapeutic target for TSC, and may also have implications for other neurological diseases that involve mitochondrial dysfunction,” says Ebrahimi-Fakhari.


  9. Researchers identify new autism blood biomarker

    May 4, 2016 by Ashley

    From the UT Southwestern Medical Center media release:

    autism metaphorResearchers at UT Southwestern Medical Center have identified a blood biomarker that may aid in earlier diagnosis of children with autism spectrum disorder, or ASD.

    Early intervention is the key to the best treatment for ASD, which affects about 1 in 70 children. Unfortunately, most children are not diagnosed until about age 4, when communication and social disabilities become apparent. This neurodevelopmental disorder is characterized by social interaction and communication challenges, and restricted and repetitive patterns of behavior.

    In a recent edition of Scientific Reports, UT Southwestern researchers reported on the identification of a blood biomarker that could distinguish the majority of ASD study participants versus a control group of similar age range. In addition, the biomarker was significantly correlated with the level of communication impairment, suggesting that the blood test may give insight into ASD severity.

    “Numerous investigators have long sought a biomarker for ASD,” said Dr. Dwight German, study senior author and Professor of Psychiatry at UT Southwestern. “The blood biomarker reported here along with others we are testing can represent a useful test with over 80 percent accuracy in identifying ASD.”

    Since other studies have found abnormalities in the immune systems of autistic children, researchers set out to search for antibodies in the blood related to ASD. In this study, researchers found that boys with ASD had significantly reduced levels of a serum IgG1 antibody. Investigating further, researchers analyzed 25 peptoid compounds that bound to IgG1 and zeroed in on one — ASD1 — that was 66 percent accurate in diagnosing ASD. When combined with thyroid stimulating hormone level measurements, the ASD1-binding biomarker was 73 percent accurate at diagnosis.

    More testing, including analysis of blood samples from girls with ASD, is needed to further validate the findings, Dr. German said. Girls made up a small ratio of the study group, and the biomarker did not correlate as strongly with ASD diagnosis as with boys.


  10. ‘I care for you,’ says the autistic moral brain

    March 31, 2016 by Ashley

    From the International School of Advanced Studies (SISSA) media release:

    autism lonely child“Autistic people are cold and feel no empathy.” True? It is a pervasive stereotype, but when analyzed through the lens of science, reality turns out to be quite different.

    According to a study at SISSA, carried out in collaboration with the University of Vienna, when autistic people are placed in “moral dilemma” situations, they show an empathic response similar to the general population. The myth of coldness in autism is likely due to the presence of the subclinical trait of alexithymia, which is often associated with autism, but is distinct and can be present in the general population, and is characterized by the inability to recognize one’s own, or others’ emotions. The study was published in the journal Scientific Reports.

    According to a Facebook post by a group called Families Against Autistic Shooters, “[Autistic people] are cold, calculating killing machines with no regard to human life.” The group was created in response to the collective hysteria provoked by yet another mass shooting in an American school last October, in this case by a 26-year-old boy who was later reported to be affected by autism. The social stigma towards people with autism remains strong — these individuals are often described as cold, antisocial, and disinterested in others, which only worsens their isolation.

    But is it actually true that a person with autism does not care about the suffering of others? “According to our studies, it is quite the opposite: the autistic trait is associated with a normal empathic concern for others and is actually associated with greater tendency to avoid causing harm to others,” says SISSA researcher, Indrajeet Patil, first author of a recently-published study in Scientific Reports. “The mistaken stereotype is most likely due to another personality construct, which is often found in the autistic population, but can also be found in those who are not afflicted, called alexithymia.”

    Autism is a neuropsychiatric disorder with a wide spectrum shared by individuals with varying degrees of cognitive skills (ranging from people with significant delays to those of above-average intelligence). Diagnostic criteria have changed over the decades (becoming more and more specific). Alexithymia, on the other hand, is a “subclinical” condition (as opposed to a disease), which can be found in the general as well as the autistic population (with an incidence rate of approximately 50% in the latter) and is characterized by an inability to understand one’s own emotions and the emotions of others. “For a long time, the alexithymia trait in patients was confused with autistic symptoms, but today we know that they are distinct,” says Giorgia Silani, former SISSA neuroscientist, now of the University of Vienna, who led the study. “In alexithymia, there is a lack of understanding emotions. In autism, however, we know that what is reduced is the theory of the mind, or the ability to attribute thoughts and mental states to others.”

    Moral Dilemmas

    In the study, Patil, Silani and colleagues subjected people with high-functioning autism (high IQ) to moral dilemmas. A moral dilemma is a hypothetical situation where a decision must be made which could save lives of some individuals by sacrificing others’. In the classic moral dilemma one must decide whether or not to voluntarily take an action that will cause the death of one person, and, in so doing, save a large number of others, or do nothing, which means not killing anyone directly, but resulting in the death of other people. A “purely” rational attitude encourages the voluntary action (utilitarian), but an “empathic” attitude prevents most people from choosing to kill voluntarily.

    The current investigation used advanced statistical modelling techniques to dissociated effect of autistic and alexithymic traits to see how they related to moral judgments. The results revealed that alexithymia is related to utilitarian choices on account of reduced empathic concern, while the autistic trait is linked to opposition to utilitarian choices due to increased personal distress. “Autism is associated with strong emotional stress in response to situations in which the individual tends to avoid performing harmful actions,” says Patil.

    The authors agree that tools for identifying and distinguishing between alexithymia and autistic disorders must be further enhanced. Their work, they add, is only an initial step in trying to define a model that can explain the complex relationship between various mutually-dependent personality traits and points to exciting new avenues for further research.