Wednesday, March 15, 2017

Excess Brain Fluid May Be Early Indicator of Autism in Infants

A research team from The Children's Hospital of Philadelphia's Center for Autism Research (CAR) and colleagues from a national collaboration have made another discovery about the development of the brain in babies and toddlers who go onto have autism. Bob Schultz, PhD, Director of CAR and his team, have contributed to each of these studies as a member site within the NIH-funded Infant Brain Imaging Study network. 

The investigative team found that some infants who go on to develop autism by age 2 have an abundance of brain fluid- called cerebrospinal fluid - between the brain and the skull in the first year of life.  

The study was published in the journal Biological Psychiatry and is among a trio of articles the team has published in recent months pointing to very early brain changes- or biomarkers- in infancy that may signal the development of autism spectrum disorder (ASD). 

All three studies used brain imaging and diagnostic testing to follow infants who had an older sibling with an autism diagnosis. Having an older sibling with ASD places these infants at a twenty-times-higher risk for developing the disorder themselves. The two other studies found that the younger siblings who went on to develop autism by age two showed more rapid brain growth and differences in the atypical patterns of neural activity in the first year of life.

Significantly, the brain areas pinpointed in each of these studies, are known to be involved with the regulation of social behavior, a key component of ASD.  Each of the three biomarkers the study teams identified was able to predict who which babies would go on to receive a diagnosis of autism at age 24 months, with overall accuracy ranging from over 90% to about 70%.  

"We've been working in partnership with the families who volunteer to be a part of this work, and with an incredible network of colleagues across the country, for the better part of a decade in order to learn from younger siblings about changes in the brain that might signal autism years before a behavioral diagnosis can be made," explained Schultz, who leads the IBIS research at CHOP. "With these latest findings, we are getting very close to being able to confidently identify which babies are likely to develop autism, and this will allow us to begin earlier interventions that we hope will blunt the severity autism symptoms as the child grows older. The discoveries also point to biological processes and mechanisms that lead to autism, deepening our understanding of the origins and timing of the emergence of autism.”

The researchers are particularly encouraged by the most recent findings regarding excess brain fluid, because it is the very first study of early markers of autism that has been independently validated or replicated in two different studies.The research team hopes more such successes will follow suit. 

A longer article about these findings was recently published on the Simons Foundation’s Spectrum News blog.

Saturday, January 28, 2017

Frankly, My Dear. That's Clear: An Expert Q&A on 'Frank' Presentations in Autism

Ashley de Marchena, PhD (left) and Judith Miller, PhD (right)
There is an adage that goes, “If you’ve met one person on the autism spectrum, you’ve met one person on the autism spectrum.” Autism spectrum disorder (ASD) is so varied in its manifestation of behavioral and social differences that it is hard to make any blanket assumptions about any individual’s abilities, impairments, or interests based on that diagnosis. But one thing that a lot of individuals on the spectrum have in common is that their autism sometimes seems immediately obvious to clinicians who specialize in ASD when they meet them — even before they begin a diagnostic evaluation.

Researchers from the Center for Autism Research (CAR) at Children’s Hospital of Philadelphia recently acknowledged and evaluated this phenomenon for the first time in the scientific literature with a paper published in October in the journal Autism Research. Ashley de Marchena, PhD, who trained as a fellow at CAR and is now on the faculty at the University of the Sciences, and Judith Miller, PhD, a psychologist in CAR and assistant professor of Psychology in Psychiatry at CHOP and the Perelman School of Medicine at the University of Pennsylvania, co-authored the study in which they surveyed experienced clinicians about the concept of what they call “frank” presentations of ASD. They sought to understand and report on the informal understanding these clinicians developed about a perception that does not currently exist explicitly in any formal diagnostic tool.

To get a better sense of what this concept of “frank” presentation could mean for diagnosing and understanding ASD, Cornerstone asked Drs. de Marchena and Miller to tell us more about the idea and their study. The edited Q&A follows below.

Why did you study this question? Why now?

de Marchena: From early on in my clinical training, I recognized that expert ASD specialist clinicians, Judi included, often alluded to “instantly diagnosable” children with ASD. As a beginner, I usually didn’t see it, but as I gained knowledge and experience, I started to understand what my mentors were talking about. But the strange thing was, they weren’t actually talking about it, just alluding to it as a given. I also never saw anything written about this phenomenon in any chapter or article about ASD, and never heard it discussed at a conference. No one was talking about it — except Judi!

Judi coined the term and got many of us at CAR talking about the construct of “frank” presentations as potentially orthogonal to severity, and maybe even as a novel dimension of behavior in ASD altogether. I was intrigued by how she was thinking and talking about this as-yet-undescribed phenomenon, so we decided to work on it together.

Miller: This is a concept clinicians have been talking about informally for years. For the past couple of decades, however, it has been really important to widen our view and understand the full “spectrum” of ASD, and figure out where the diagnostic boundaries lie. Now that we understand how broad the spectrum really is, we need ways to make sense of it. We had begun talking about the idea of “frank” features within our group and realized that there was no literature out there describing it. We developed several ideas for how to begin, and then Ashley suggested we start with a survey of the clinical community. This really helped flesh out the concept, and in the end made sure it reflects what the wider community use as “frank” rather than if it were based solely on our own ideas.

Can you briefly summarize the most significant findings?

de Marchena: To me, the two most significant findings are, first, there was an overwhelming consensus among surveyed clinicians that “frank” presentations of ASD are a real phenomenon — i.e., in some people with ASD, the diagnosis is almost immediately apparent. Second, clinicians estimated that only a subset of people with ASD have frank presentations. While diagnosis is immediately apparent in about 40 percent of people with ASD, the majority of people with ASD do not have frank, instantly recognizable autism.

Miller: As a clinician with 15-plus years’ experience in ASD, I can’t help but wonder what the “rate” of frank presentations might have been a decade or two ago. It seems as if there are a lot more complex, and sometimes complicated, clinical presentations today than back when I was training. I think a lot of clinicians are experiencing this. This might be due to increased awareness — more families and more professionals are including ASD on their list of possible concerns, and thus more individuals with subtle presentations are showing up for evaluations. Usually, you expect your job to get easier with practice, but in many ways it is more challenging now than ever.

What excites you most about the findings?

de Marchena: The findings are exciting to me for two main reasons. The first is that it’s possible we are describing a new behavioral construct that could help us subtype the heterogeneity of ASD and even influence diagnostic assessment. The second is related to a personal soapbox: Both my clinical intuition (having diagnosed hundreds of kids with ASD at this point) and my behavioral researcher’s eye for observation tell me that there are clearly qualitative differences in behavior among people with ASD that are very significant, and have been woefully under-described. (This is in part because they are by definition highly challenging to quantify). Our clinician data on behaviors associated with frank presentations is in line with this perspective. Many of the features (though not all) described by our clinicians reflect qualitative differences such as awkwardness or “something about…” the way people hold their bodies, approach the examiner, make eye contact, etc. These findings provide an extra impetus for me to really dig deep into these qualitative differences to better understand them.

Are there any immediate practical implications for clinicians?

de Marchena: The field of social psychology has taught us again and again that first impressions, while often right, can also often be misleading and even harmful. We encourage clinicians to attend to their impressions of frank presentations, but not, as one of our respondents put it, to “let their first impression be their last impression.” More work needs to be done!

Where do you see this research going next?

de Marchena: Our participants brought up some really great points about how attention to frank presentations can and should be (cautiously) integrated into the diagnostic process. Judi is already developing some tools to figure out how to do this. As a behavioral/communication researcher, I’m very interested in figuring out what aspects of behavior lead to frank presentations, and I’m already hard at work designing some experiments to start answering this question.

Miller: Right now, a lot of ASD tools — and most of the ASD science  — is about ASD as a whole, rather  than on individual symptoms. But maybe if we studied a very specific autism behavior in greater detail, we could really home in on the underlying brain mechanism. That would be a new approach. At our center, we are developing a set of tools and experiments to start looking at some of these small, but highly specific behaviors, with a variety of experimental and behavioral measures.

What else do we need to learn about frankness before integrating the concept further into diagnosis and research?

de Marchena: One medium-term goal is to figure out if frankness is reliable. That is, are the same kids who I see as frank the same ones who Judi also sees as frank? Are they the same as the kids who a psychiatrist in private practice in North Carolina also sees as frank? If it’s not reliable, then it can’t be valid. If it is reliable, next we’ll want to know if those early impressions of frankness map onto actual ASD diagnosis, as one test of validity. If either of these tests fail, then we’ll have some equally important work to do alerting the clinical community that, even though we seem to agree that this frank ASD phenomenon exists, that we actually don’t agree on which patients have frank ASD, and/or we are wrong about our first impressions. I think either way, it is important to find the truth and spread the word.

Boosting Social Behaviors in People with Autism

Cells of the amygdala (red).

Credit: The lab of Edward Brodkin,

Perelman School of Medicine,
University of Pennsylvania
It may be possible to boost social interaction in people with autism by using a new therapeutic drug target, according to new research from the University of Pennsylvania and the Children's Hospital of Philadelphia. The research team conducted a study in mice to examine a whether a mutation in a specific gene, Protocadherin (PCDH10), affects social behavior. PCDH10 plays a role in the development of axons (the brain's "wires") and cell-to-cell communication, and previous studies have shown that the gene is associated with autism.

While there are medications available to treat some of the common symptoms of autism like anxiety, depression, attention deficit hyperactivity disorder (ADHD), and irritability, there is no drug currently approved to address difficulties with social interactions- a defining feature of autism. "This research could significantly change our understanding of the causes and brain changes in autism and could lead to new treatment approaches for the harder to treat social aspects of ASD," senior author Edward S. Brodkin, MD, said in a press release.

The research team, which also included Robert T. Schultz, PhD, director of The Center for Autism Research at CHOP and Ted Abel, PhD, the Brush Family Professor of Biology at Penn, found that when one of the two copies of PCDH10 was deleted from the mice, they showed decreased social approach behaviors. The investigators also noted that this habit was observed more often in males than females, which seems consistent with understood behaviors of autism in humans.

Importantly, the researchers were also able to pinpoint the brain circuits that are involved in some of the social difficulties associated with autism. The mice with one deleted PCDH10 gene showed differences in the fine structure of the amygdala, a brain region long thought to play a role in autism.

Next, the researchers treated the affected mice with d-cycloserine, an antibiotic used to treat tuberculosis. The drug is known to boost NMDA glutamate receptor function. "By enhancing NMDA receptor signaling, the mice went from social avoidance to more typical social approach behavior," Brodkin observed.

This finding was in line with the results of preliminary clinical studies of d-cycloserine in human patients with autism, which showed that the drug significantly improved social behaviors in older adolescents and adults diagnosed with autism spectrum disorders. However, these studies in humans are too small and need to be replicated on a larger scale in order to validate the treatment. The researchers say this new data on PCDH10 mutations in mice provides a basis to pursue additional studies in people.

Brodkin and his team plan to continue to study mice to understand why the presence or absence of PCDH10 seems to affect males more than females in terms of social behaviors. They will also continue to study the role the amygdala plays in affecting these behaviors, as a clue to better treatment approaches for social behaviors in certain autism spectrum disorder subtypes. 

The findings of the study, “Sociability Deficits and Altered Amygdala Circuits in Mice Lacking Pcdh10, an Autism Associated Gene”, were recently published in the journal Biological Psychiatry.

Note: In addition to their primary academic appointments, Dr. Brodkin and Dr. Abel are collaborating faculty members at The Center for Autism Research at CHOP.

Saturday, December 31, 2016

A pause to reflect, look ahead

As we take a moment to reflect on 2016, we have a lot to be proud of and grateful for!

Thanks to the generous support of families who participate in CAR studies or contribute to our Center's work through financial donations, CAR has continued to meet the needs of families in numerous ways over the past year. 

Among our most exciting advances in 2016 are several large-scale studies that will broaden our understanding of the great variability of ASD from one person to the next, and pave the way for more personalized treatment strategies. Here are some highlights from the past year:

  • In 2016, CAR ran 23 active studies serving all age ranges from infancy through adulthood.
  • Nearly 3,000 people participated in studies at CAR this year, many of whom received expert clinical guidance and  support.
  • CAR researchers published more than 75 peer-reviewed journal articles to guide new therapies, improve clinical care, and better meet the needs of individuals on the autism spectrum and their families.

2017 will bring some exciting new programs and advances at CAR! We look forward to having you as a partner as we move to our new home at CHOP’s state-of-the-art Roberts Center for Pediatric Care on Schuylkill Avenue in March,  and as we expand our research into more community-based settings, such as schools and camps.

We’re so grateful to you for being a part of our Center, and send our warmest wishes to you and your family for a happy, healthy, and fulfilling 2017. We look forward to seeing you in the new year!

Friday, September 23, 2016

CAR Researcher Dreams of a Better Night's Sleep for Children With Autism, Their Families

Children and adolescents need a healthy sleep pattern to fully develop and to perform their best during the day, but – as many reading this know all to well- sleep difficulties plague as many as  50%-80% of children with autism spectrum disorder (ASD)- and by default, their parents! And the consequences overflow to nearly every aspect of waking life.

Research has shown that children and adolescents with ASD who sleep poorly are more likely to engage in problematic daytime behaviors than children who get enough sleep, and that sleep disturbance is connected to anxiety, heightened sensory responses, aggression and poorer health outcomes in kids with ASD.

CAR researcher and developmental pediatrician Amanda Bennet, MD, MPH, empathized with the parents she’d see in her office, whose children’s sleep troubles were taking a difficult toll on the family over extended periods of time. With support from the Autism Speaks Autism Treatment Network, Dr. Bennett and her team set out to conduct the first large-scale study to look at the prevalence of sleep problems and patterns of sleep medication use in children with ASD patients and their families.

The team collected data from more than 1500 children and their parents, and it revealed a significant “disconnect” between parents and clinicians. Parents reported sleep problems in 71% of the children, but clinicians only diagnosed 30% of the children with a sleep disorder, indicating that parents’ concerns about sleep may not be reflected in the information gathered during a clinical visit.

Of the 30% of children who were diagnosed with a sleep disorder by a doctor, a little less than half (46%) were prescribed at least one medication to support better sleep; but these children who took sleep medications had more troublesome behaviors during the day and poorer quality of life overall.

Given this evidence that sleep concerns are both common and associated with problematic daytime symptoms, it is important that primary care providers be vigilant to sleep concerns voiced by parents,” the researchers wrote in the study.  However, there are barriers to this discussion on both sides of the exam table. Parents may think that sleep problems are “just a part of autism” or might be focused on other “daytime” behavioral concerns that could be the result of poor sleep. On the other side, health care providers may not have received training to implement behavioral sleep interventions for children with ASD, and given a lack of other options, turn to recommending medication when faced with parent’s concerns over a challenging sleep problem.

The causes of sleep difficulties in children with ASD are often complex. They may be related to health conditions like epilepsy or gastroesophageal reflux, which are fairly common in children with ASD; or it may be that challenges unique to autism, like difficulty with transitions or with understanding parent expectations regarding sleep, exacerbate problems with sleep hygiene or pediatric insomnia. Although some children require medications for treatment, a behavioral intervention might be more appropriate for others.   

While the study findings will come as no surprise to families living through this first-hand, Bennett and her colleagues see this study as a starting point for improving support for families and improving screening tools and training for clinicians.

In the meantime, some factors that have been shown to improve quality of sleep include calming bedtime routines and relaxing bedtime environments. Sleep medications can have their benefits, but establishing a nightly routine can ease the anxiety and stress of sleep disturbances. Parents learning sleep education can also help their child develop nighttime routines that ease the difficulties of sleep. Visit the CAR Autism Roadmap ™ for more information and tips on improving sleep for children with ASD.