In this podcast we talk to Ana Maria Portugal, Developmental Neuroscientist and postdoctoral researcher in developmental behaviour genetics at the Centre of Neurodevelopmental Disorders at the Karolinska Institute in Stockholm.
Ana was the first author of the recent Open Access JCPP paper, ‘Pupil size and pupillary light reflex in early infancy: heritability and link to genetic liability to schizophrenia’
Ana sets the scene with a summary of the paper highlighting what is currently known about the link between pupillary light reflex and hereditary neurodevelopmental conditions.
Ana discusses the methodology, key findings, including some surprising results relating to the association between the pupil measures and the polygenic score for autism. Plus of course Ana looks at the implications that the study has for researchers and clinicians, and what the next phase for research will be.
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Ana is a developmental neuroscientist who moved to Stockholm in Sweden early in 2020 to join the Development and Neurodiversity Lab at the Karolinska Institutet and Uppsala University. She is interested in how individual (i.e., genetic susceptibilities) and environmental factors (e.g., training, society) shape social, cognitive, and brain development early in life and beyond. She really enjoys science dissemination and exchange with the public, from small discussions with parents and practitioners to busy museum workshops with children.
Jo Carlowe: Hello, welcome to the In Conversation podcast series for the Association for Child and Adolescent Mental Health or ACAMH for short. I’m Jo Carlow, a freelance journalist with a specialism in psychology.
And I have with me Developmental Neuroscientist Ana Maria Portugal who is a postdoctoral researcher in developmental behaviour genetics at the Centre of Neurodevelopmental Disorders at the Karolinska Institute in Stockholm. Ana was the first author of the paper, pupil size and pupillary light reflex in early infancy, heredability and linked genetic liability to schizophrenia. Recently published in the Journal of Child Psychology and Psychiatry.
The JCPP is one of the three journals produced by the Association for Child and Adolescent Mental Health. ACAMH also produces JCPP Advances and the CAMH. And this paper will be the focus of today’s podcast.
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Ana, welcome, nice to meet you. Can you start with a brief introduction about who you are and what you do?
Ana Maria Portugal: I do. Thank you so much for having me. It’s a pleasure to be here. I am a postdoctoral scientist at the Karolinska Institutet in Sweden. So in Stockholm. I see myself primarily as a neuroscientist because I have a background in both biology and psychology. And I tend to focus my research on brain, mind, and formation during the very first few years of life– so during infancy and toddlerhood. I am particularly interested in cognitive and social development and the regulation of behaviour. So I tend to research attention processes and executive functions.
Jo Carlowe: Great, thank you. Ana, let’s turn to the paper, pupil size and pupillary light reflex in early infancy, heritability and linked to genetic liability to schizophrenia published in the JCPP. Before telling us more about your findings, can you set the scene for us? What is currently known about the link between pupillary light reflex and hereditary neurodevelopmental conditions?
Ana Maria Portugal: Yeah, that’s a good question. So I think it would be good if I first start to explain what the pupillary light reflex is. This is like a reflex and response that your pupil does pretty much automatically to respond to a sudden increase or decrease in light. So our pupils quickly constrict or dilate to modulate the amount of light that reaches our eyes and our retina. It does a very basic function of sensory modulation and of our own reactivity to the light in our environment.
So we know that in general, sensory processing atypicalities, such as an hyper response to stimuli in the environment, as loud sounds or lights, are very common if not a hallmark of irritable neurodevelopmental conditions such as autism. For this reason, the pupillary light reflex has been studied in the context of autism in children, adolescents, and adults with the diagnosis and hypersensitive response, so a reduced response to this light– these sudden light onsets, have been shown and have been found to be associated continuously with the traits– with autism traits. In contrast, very early in life, so before symptoms onset, a hypersensitive response, so an increased response, has been seen in infants that later receive a diagnosis of autism. And it has also been associated continuously with greater symptoms of autism.
Further, atypical pupillary light reflex responses have also been described in schizophrenia, where a hypersensitive response has been found in adults with the condition and in association with more symptoms. As far as we know though, no studies with infants and children have been reported. Which is not surprising, since schizophrenia is not usually studied at these early times.
Jo Carlowe: Thank you. That’s really helpful. What did you look at in this study? Can you give us a summary of the paper?
Ana Maria Portugal: So we, in our paper, we looked at this responsive, at the pupillary light reflex, in the terms of the amplitude of the response. So how big or small your response is, and also the speed of the response. As well as our pupil size at resting. So before this light onset. A special part of our study was that we measure these response in five-month-old twins. We did so, because we wanted to the extent to which this response is heritable, and the extent to which is explained by common environment, which is the environment that siblings and family share, which range from factors from the environment that, like the level of noise in the room, or in the home, or the air quality. We are also interested in knowing the extent to which this pupil response and the pupil size share or have some genetic or environmental factors overlap.
Jo Carlowe: Before we turn to the findings, can you say anything more about the methodology that you used?
Ana Maria Portugal: We used an eye tracker, which is a special camera that measures the pupil in a very short time scales, in the order of milliseconds. We also use the twin design, as I mentioned before. So twins are very useful for behavioural genetic research. So they– you know that twins can be identical. So they share all their DNA. Or they can be fraternal twins, which on average share 50% of their DNA, like regular siblings. So by studying the level of similarity between twins separately for these two groups, we can find out the– we can measure the extent to which a phenotype or trait is explained by heritability or is explained by shared environmental influences such as the ones that I mentioned before, because we genotyped our twins. We also got their gene code. And with this gene code, we could measure something that we call a genome-wide polygenic score, which is a score that basically sums up for a particular condition. In our case, we studied autism and schizophrenia. So for these particular conditions, we measure how many variants they had that were previously been associated with these conditions in another population.
Jo Carlowe: And what did you find? What are the key findings that you can share with us?
Ana Maria Portugal: So first, we showed that infants’ pupil size and the amplitude of the pupil response to light were highly heritable phenotypes. We did not find any evidence for influences from the shared environment on these measures.
Further, we showed that the variance in these two phenotypes was also explained by unique genetic influences on each phenotype. So in other words, their genetic correlation was quite modest, which can suggest that they are partly explained by different gene sets and potentially explained by different brain processes.
Finally, we observed a link between the infant’s pupil size at resting and the polygenic score to schizophrenia. While no such association was found for the amplitude of the pupil response or the polygenic score to autism.
Jo Carlowe: Can you say anything about the implications?
Ana Maria Portugal: Yes. So I think, finding a reliable, and objective, and quickly measured response, such as the one that we get with the pupillary measurements can sound very interesting in the sense of screening or assessing quickly in the population risk for certain conditions. And I think, although that’s always a long-term future aim of the kind of research that I do, the study is still a very preliminary piece of evidence and doesn’t get us very close of that goal.
So the link, for example, the link that we find between the pupil size and the genetics of schizophrenia is an interesting– and it’s a significant link. But this link alone does not explain the variance in these measures. Which means that the pupil size according to our data would not be a sensitive or specific predictor of this risk. But I believe that the implication for at least in the short-term, our findings add to the understanding of the brain mechanisms and systems that are implicated in psychiatric conditions and potentially highlights the importance of looking at these processes from very early on in infancy.
So schizophrenia, for example, is not very often studied by looking at this time early in life. And that’s because it’s a condition that is diagnosed much later in development. But I think, I hope that maybe by using these polygenic scores that we have now in infants, we can perhaps shed light on some very early stage atypicalities that can unfold into later symptoms throughout life.
Jo Carlowe: So it sounds unlikely that you’re advocating for early physiological responses such as pupillary light reflex to be used to screen or assess for later psychiatric risk.
Ana Maria Portugal: Yeah. I think at this moment, our data is not enough to advocate for that. Also, I think it’s an important– maybe an important thing to highlight, is that we are using, as I said, polygenic scores for these conditions. And polygenic scores, they are a very interesting method. But I think clinicians and other professionals need to be aware that they only capture common genetic variants linked to these conditions in one population. So they might not explain many other things that are influencing that diagnosis. So they don’t explain much of that diagnosis, or they don’t explain the totality of the diagnosis. The polygenic score itself is not a good predictor of whether a person will have that diagnosis or not. And we are using that to establish a link to our previous measure. And I think that’s– it’s a very small proportion that we are explaining in an end diagnosis of someone. So I think, we are very limited by that.
Jo Carlowe: Yeah. So it sounds like your findings are extremely relevant for research, but the implications for mental health professionals working with children and young people is just to hold it in mind as something to watch.
Ana Maria Portugal: Yeah. If there was any, they would be very speculative, I guess. And I think they are more helpful to the understanding of the mechanisms behind these conditions and their development rather than practical implications in clinical settings.
Jo Carlowe: Yeah. Thank you. And is there anything else in the paper that you would like to highlight?
Ana Maria Portugal: So I think, and for I think it could be interesting to mention, and actually it follows up on our just brief discussion just now, that it is somehow surprising that we did not find any association between the pupil measures and the polygenic score for autism in our study. And this is surprising, since the link between pupil measures and autism is a bit more established now. And there is also another report that came just at the same time of ours, which has found a link between these.
So I think what I would like to emphasise again is the limitations that we have in testing this link, and the fact that our results do not exclude the possibility that the pupil reflex is indeed implicated in autism. I think it’s more likely that we need a stronger polygenic scores for autism to become available.
And that maybe more rare genetic variants associated with autism and other factors associated that are not captured by the polygenic score, they might be the ones associated with these pupil phenotypes. So I guess, as in all research, more and bigger studies are needed.
Jo Carlowe: And what are your plans? Are you planning some follow-up research that you’d like to mention, or is there anything else in the pipeline that you can share with us?
Ana Maria Portugal: Yes, sure. So I think, so in these infant twins study that I mentioned and that our results are based on, we also have other interesting phenotypes that we are looking at and that are very much related to eye movements, and regulation, or selection of environmental visual input. So for example, I hope to report soon on face [INAUDIBLE], which is a very interesting phenotype in the context of autism research, as the listeners might know. We are also planning some future experimental studies to study these pupil dynamics in response to different environmental cues in the context of autism research and other neuropsychiatric conditions. So I think there’s more to follow up on. [LAUGHTER]
Jo Carlowe: Right, thank you. Finally, Anna, what is your take-home message for those listening to our conversation?
Ana Maria Portugal: I think the take-away message, it’s just on the importance of considering in research, and funding, and potentially on the explanations that clinicians might have, how early life– how these early life very fine-grained and basic measurements of sensory processing and attention are important in the context of mental health research. So these phenotypes are usually not very easily observable by the naked eye. But they might have a role in the developmental cascades that lead to psychiatric and psychological traits that we observe much later in adolescence and adulthood. So I hope that by identifying these early targets during research, where deviations start, we might be able to understand these pathways better and how to best support certain populations in the future.
Jo Carlowe: Brilliant. Ana, thank you so much. For more details on Ana Maria Portugal, please visit the ACAMH website, www.acamh.org, and Twitter @acamh. ACAMH is spelled A-C-A-M-H. And don’t forget to follow us on your preferred streaming platform. Let us know if you enjoyed the podcast with a rating or review. And do share with friends and colleagues.