Dr. Kevin Pelphrey is a Harrison-Wood Jefferson Scholars Foundation Professor of Neurology at the University of Virginia. A leader in groundbreaking autism research, Dr. Pelphrey uses neuroscience to develop tools for detection and autism treatment and to continue helping people like his two children, who are both diagnosed with autism. His research aims to understand the underlying basis behind autism to create the right treatment for specific individuals. He has done heavy genetics work to understand how different genes can affect brain development and has developed ways of predicting autism in children. Some of his research publications include, Combining Pivotal Response Treatment with Intranasal Oxytocin to Improve Social Reciprocity in children with ASD and Visual Scanning of Faces in Autism (2002). After speaking with him for an hour and a half, I truly gained such a greater understanding and overall valued the time he took to meet with me.

The Real Spectrum: Why did you decide to go into autism research?

Dr. Kevin Pelphrey: There were actually two “starts” to my autism research career. The first one was when I was a graduate student in child psychology studying infant development in about 1999. As a part of that, the classic problem with studying infants was getting them to do stuff so you could understand how their brain works. We built an eye tracker that allowed us to see where they were looking. Joe Piven, a researcher at UNC today, came to our lab [at UNC] and saw the eye tracker that we had built and after doing a demo for him, he asked if I wanted to do a study of autism. The opportunity to use the eye tracker with people with ASD was there because of Dr. Piven, who arranged for us to recruit research participants; we had five participants that came in for our study and we showed them faces. We knew from the diagnostic criteria of autism that people with the disorder look less at faces. At UNC, these five participants became almost the “Famous Five” since all of the researchers at the university used them for their autism studies. I remember meeting each of the five and being struck by how different each person was. You could see commonalities that I understand to be the key characteristics of autism. We found some really cool findings: infants with autism look less at the eyes. We submitted that for publication and that was the beginning of my autism research career in the sense that it was the first paper to use eye tracking to use autism. It actually reached Ami Klin, a very famous autism researcher who ran the autism program at Yale, through peer review. About the same time, he had been working on an eye-tracking study and submitted the first paper from his group. He was stunned since he didn’t know anyone else was studying this topic. 

How does the Autism Centers of Excellence Program at UVA achieve their goals to determine causes and treatments of ASD?

Dr. Micah Mazurek was recruited at UVA. UVA used money from their strategic investment fund to give to certain university specialties that they felt could be really strong. One of them was autism research. I’m obviously all for that. Dr. Mazurek developed the clinical infrastructure to make UVA a center for rigorous diagnostic testing and treatments for individuals on the spectrum internationally and nationally. As a medical school professor, I can access all of those resources and contact information for research participants. Every patient that Dr. Mazurek sees will be in a research database, just like SPARK (as mentioned in a previous article post). The STAR (Supporting Transformative Autism Research) program at UVA – which aims to improve the quality of life of individuals with autism through research – has a yearly community meeting where we present our research and it is really geared towards a family audience. 

You have done a lot of research on the effects of intranasal administration of oxytocin and how it increased activity in certain regions of the brain in individuals with ASD. Kindness is shown to improve the wellbeing of individuals with ASD and a lot of it has to do with levels of oxytocin. Is there anything you can say on the science of kindness and how it can affect someone with ASD?

Yes, I could see multiple ways where that could be relevant. On one hand, we should understand how to bring about kindness but also through understanding people’s perspectives. I think from the autism self-advocacy point of view, there is the notion that the environment needs to understand people with autism and adapt to the specific accommodations they need. Kindness also is highlighted in autism in the sense that we have the saying that if you met one person with autism, you only met one person with autism because of the heterogeneity of the disorder. I think kindness also inherently involves treating each person as an individual without preconceptions. When observing individuals with autism, most typically developing people make assumptions, have implicit biases, and think they understand others perspectives, therefore predicting the behavior of others. It really comes down to having normal conversations with individuals with autism without having these preconceptions. Additionally, the oxytocin system improves your treatment and trust of your ingroup but it also reduces trust and kindness to the outgroup, whatever you consider that to be. It’s a strange double-edged sword in that it is a molecule that upregulates systems of social functioning that help you with people you already like but also push people away that you don’t really like. For individuals with autism, it’s hard to identify who the ingroup can be. It is unreasonable to think that simply giving someone oxytocin will work, even though we know it’ll alter their brain activity to look more typical in social activities. If you don’t supplement that oxytocin with a meaningful social learning environment, it’s not going to work.

What techniques (e.g. studying genetics, brain imaging) have proved most effective for you in studying the neurological abnormalities of ASD?

From my perspective, everything in development is a complex interplay between levels of the organism. So, like a convenient level in understanding a human being would be genetics and brain structure and function. Then, there is the social context like interpersonal relationships and the broader societal context. I see all of those as bidirectionally influencing each other. There was a time when we thought that genetics drives everything – if we just look for candidate genes, we’ll figure out autism. We actually found about 70 high-confidence candidate genes, where if you have a mutation in that gene, you have a higher risk for autism. However, we haven’t found a gene that is solely responsible for autism development. Other times in science, we have thought everything is environmental and genetics was a blank slate. Now we know that autism development has to do with the environment, epigenetics, genetics itself, and behaviors. Any question that I answer regarding autism diagnosis, I try to apply all of those methods of thinking. The newest for me is the microbiome, which I used to roll my eyes at when people brought it up. However, it is actually important and relevant. I have been more interested recently in animal system models, whether it be c.elegans, zebrafish, monkeys, or mice. David Amaral was the first researcher to find a link between the mother monkey having the flu and then subsequent altered amygdala development in the baby monkey. 

One study you conducted found that ASD-derived organoids exhibited an overproduction of GABAergic inhibitory neurons. I found evidence that has suggested that potential deficits in GABAergic inhibitory interneurons as well as in glutamate signaling are the pathophysiological mechanism of autism. What has your research shown you about this topic?

From a wide variety of perspectives, it looks like one of the neurological pathways responsible for autism is the GABA-glutamate imbalance as one way to think about it. It makes a lot of sense in that respect as to why people with autism would be more susceptible to developing epilepsy. Most of the genes we have identified as candidate genes for autism have something to do with modulating GABA and/or glutamate and are heavily involved in that type of modulation. GABA, in particular, is interesting because it has different roles in the body depending on the stage of development. Early on, it’s excitatory and then it becomes inhibitory. We think that autism is emerging out of brain developmental events that are happening in early fetal development. The subsequent imbalance that we see and the imbalance that we see when we create induced pluripotent stem cell-derived organoids suggests that that is a strong characteristic of autism and can be a target for treatment. One can imagine identifying the subgroup of people with autism for whom that [GABA imbalance] is a clear mechanism of their autism and treating them early to avoid the development of seizures, which would help the incidence of intellectual disability – since seizures themselves can bring about intellectual disability. So, from one respect I think what we’ll end up finding is that there is a subgroup of kids for whom this is a key mechanism if not the mechanism, and other kids it will be other things. What we have found also most recently is that the GABA-glutamate aspect and the excitatory/inhibitory imbalance is intertwined with an inflammatory aspect that is related to microglial development – another potential mechanism that may help explain the heterogeneity of autism. You could have an inflammatory event – like Mom having a viral infection during pregnancy – that may also contribute. Then, that alters the functioning of genes involved in the inflammatory response in the brain and then you have a cascade that occurs throughout development. Oxytocin also reduces inflammation so this could prove to be helpful to this concept. 

Along with other researchers, you have found reduced connectivity between the amygdala and ventrolateral prefrontal cortex. What do you think of the role of the amygdala in the severity of social deficits of ASD.

I think it’s incredibly important. The abnormal development of the amygdala is likely to be really significant. It is a central part of the story. For connectivity, in particular, what can be very hopeful and exciting is that we have also shown that we can modulate an increased connectivity between the ventrolateral prefrontal cortex through cognitive behavioral therapy (something that works for depression), reducing anxiety and increasing the ability to emotionally regulate (something that this connection is responsible for). As the patient shows more success on a primary behavioral outcome, you see increased prefrontal-amygdala connectivity. The insula, a fold of cortex that almost touches the amygdala, is also really important in this story since it has implications with the amygdala.