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.