Thursday, June 8, 2017

Could a Single Brain Scan Predict Which Infants Will Eventually be Diagnosed with Autism?

Differences in a baby’s brain activity patterns at 6 months of age can predict which children will develop autism at 2 years of age, according to a study published this week by the NIH- funded, multi-site Infant Brain Imaging Study (IBIS) network, which includes CHOP’s Center for Autism Research.

CHOP researchers are part of a national network using brain imaging
to detect the earliest signs of autism in infants.
Using a safe brain imaging procedure called functional connectivity magnetic resonance imaging (fcMRI), the research team studied brain activity during waking tasks and natural sleep in 59 six-month-old infants who were at high risk for autism spectrum disorder (ASD). They then applied a computer algorithm to analyze the pattern of activity across tens of thousands of neural signals across the entire brain. This combination of techniques allowed scientists to identify with more than 96% accuracy which children would go on to be diagnosed with the neurodevelopmental condition by two years of age, and which would not.  The study is the fourth in a series of findings published this year by the IBIS researchers.

“2017 has been a breakthrough year for decades of research aimed at detecting the earliest changes in the brain that are associated with autism,” said Robert T. Schultz, Ph.D., who leads the CHOP research site. “This current study reveals the foundational patterns of brain function at age 6 months, which set in motion developmental processes that yield behavioral symptoms of autism by age 24 months.  This is an astounding observation that could fundamentally change clinical practice.”

Robert T. Schultz, PhD, directs
the CHOP study site for the NIH
multi-site infant brain imaging study.
All of the science to date shows that early diagnosis and intervention for autism is the best way to reduce the severity of symptoms over the course of a lifetime. However, until now, clinicians have not had rigorous ways to diagnose children before the behaviors of autism emerge, typically between ages 2 and 4- and even this requires a highly specialized clinician and can involve long wait times.

Although this latest study was a small one, researchers are encouraged that this growing body of evidence will mean that in the future, neuroimaging may be a useful tool to diagnose autism or help health care providers evaluate a child’s risk of developing the disorder. “The ability to detect who will develop autism before there are any clear outward manifestations should enable earlier diagnoses and better long term outcomes for scores of children who develop autism,” said Dr. Schultz.

The authors propose that a neuroimaging scan at age 6 months can accurately predict autism among high-risk infants, but caution that the findings need to be replicated in a larger group. 

The results were published in the June 7th issue of Science Translational Medicine, and the study’s lead author was Dr. Robert Emerson at University of North Carolina, Chapel Hill.

Learn more about the study results from the NIH press release and Spectrum article.

Monday, May 15, 2017

CHOP and Mt. Sinai Hospital Expand Partnership to Include Autism Research

First Joint Research Symposium between CHOP’s Center for Autism Research and Mt. Sinai’s Seaver Autism Center for Research and Treatment “Exceeds Expectations”

A rainy April morning didn’t dampen the enthusiasm of a group of cross-disciplinary autism clinicians and researchers who convened at the New York Academy of Medicine for the first in a series of “meeting of the minds” between two of the country’s leading autism research centers- the Seaver Autism Center of Mount Sinai Hospital and the Center for Autism Research (CAR) at Children’s Hospital of Philadelphia.

The nearly fifty experts met to share the most recent developments in their work, with the shared goal of advancing the progress of science to discover the causes of autism spectrum disorder (ASD), identify the mechanisms underlying its signature symptoms, develop drug and behavioral therapies, and improve medical and legislative policies related to access to and delivery of services.

As an outgrowth of CHOP and Mount Sinai’s formal clinical alliance announced in 2015, this autism research collaboration between CAR and the Seaver Center is a move toward integrating the two health care networks’ significant research capital. Spearheaded by CAR’s scientific director, Robert Schultz, PhD, and the Seaver Center’s director, Joseph Buxbaum, PhD, the autism research partnership merges not only the expertise of CHOP and Mt. Sinai researchers, but the Icahn School of Medicine and the University of Pennsylvania as well.

L-R: Alexander Kolevzon, MD, Clinical Director of Mt. Sinai's
Seaver Center, Joseph Buxbaum, PhD, Director of Mt. Sinai's
Seaver Center, and Robert Schultz, PhD, Director of CHOP's
Center for Autism Research
In opening remarks, Dr. Schultz and Dr. Buxbaum referenced the numerous visits each has made to the other’s Center over the course of the last decade and were pleased that the official partnership between CHOP and Mount Sinai presented an opportunity to collaborate more closely on autism research.

“One of the hallmarks of autism- and the greatest challenge to autism researchers- is its heterogeneity. There are myriad combinations of genetic variants, brain changes, and behavioral outcomes that could present as autism spectrum disorder in any one individual- and that has slowed progress for devising new, effective interventions,” said Dr. Schultz. ” Breakthroughs will only come from being able to see the patterns of genetics, neurobiology, and behavior across a large group of individuals with autism and related conditions. A partnership between CAR and Seaver brings us much closer to achieving this.”

During the morning session of the symposium, each of the clinicians and researchers were asked to present an “Ignite” talk explaining a current project or body of work and its potential impact on the understanding of ASD or developing interventions. These abbreviated “TED”- style talks were intended to spark ideas for where researchers might join forces to apply novel research approaches or combine data sets for more robust research opportunities.

Mt. Sinai and CHOP faculty developed the foundations of
several new research projects for NIH funding proposals

During the afternoon session, the attendees were challenged to form small groups based on these opportunities for connection, and develop a realistic proposal outline for a coveted NIH R01 grant. For the day’s final session, each group had to present their proposal to a mock-panel of NIH reviewers. Amidst a palpable sense of urgency and competition, the four teams did not disappoint.

“The plans that emerged from this exercise exceeded our expectations,” said Dr. Buxbaum.”In just a few hours, our clinical and research faculty identified several real targets for promising lines of research that could begin almost immediately. We each left feeling challenged and inspired by the rich partnership that began to take shape today.” 

The next joint research day is planned for the Fall in Philadelphia. Over the next six months, the investigators will continue to refine their mock proposals with the aim of turning them into funded collaborative research projects. 

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.