‘Longitudinal association between externalising behaviour and frontoamygdalar resting-state functional connectivity’ – Dr. Sandra Thijssen

In this podcast we talk to Dr. Sandra Thijssen, who was Assistant Professor of the Department of Psychology, Education and Child Studies at Erasmus University, and is now part of the Department of Pedagogical and Educational Sciences at Radboud University.

Sandra begins with a brief overview of how the frontoamygdalar brain circuitry functions and its role in emotional regulation. She then discusses the research and findings from her paper published in the JCPP ‘The longitudinal association between externalizing behavior and frontoamygdalar resting-state functional connectivity in late adolescence and young adulthood‘.

Moreover, Sandra talks about future research projects, including learning more about what experiences may amplify the progression of externalising or antisocial behaviours.

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In my work, I use an evolutionary approach to study the association between the early child family environment and child development, specifically focussing on child brain development. Besides studying effects of the family environment, I am interested in child behavior, specifically externalizing behavior. I am particularly interested in studying normative variation in environment and behavior, because understanding normative development is vital to understand aberrant development.

Transcript

Interviewer: Hello, welcome to the In-Conversation Podcast Series for the Association for Child and Adolescent Mental Health, or ACAMH for short. I’m Jo Carlowe, a freelance journalist with a specialism in psychology. Today I’m interviewing Assistant Professor Dr Sandra Thijjsen of the Department of Psychology, Education and Child Studies at Erasmus University, Rotterdam. Sandra is a co-author on the paper, the longitudinal association between externalising behaviour and frontoamygdalar resting-state functional connectivity in late adolescence and young adulthood, published in the Journal of Child Psychology and Psychiatry. The JCPP in September 2020.

If you’re a fan of our In-Conversation series please subscribe on iTunes or your preferred streaming platform. Let us know how we did with a rating or review and do share with friends and colleagues. Sandra, thank you for joining me. Can you start with an introduction of who you are and what you do?

Dr. Sandra Thijssen: Of course. First of all, thank you, Jo, for inviting me to discuss our paper on the ACAMH podcast. My name is Sandra Thijjsen. I’m an Assistant Professor of Clinical Child and Family Studies at the Erasmus University of Rotterdam, but coming next month I’ll join the Radboud University of Nijmegen, and I’m a neuroscientist interested in neurobiology of externalising behaviour such as aggression, substance abuse, but also dishonest behaviour. In my research I study brain structure and function underlying mostly normative variation in externalising behaviour, and more recently I’ve also become interested in examining the role that the early family environment plays in determining the brain correlates of externalising behaviours, but also internalising behaviours such as depression and anxiety.

Interviewer: Sandra, how did you come to be interested in child and adolescent mental health?

Dr. Sandra Thijssen: That’s a good question. Thank you. I experienced my own adolescence as a tumultuous period with lots of extreme emotions. I was insecure about the way I looked, the way I behaved, and I don’t think my experience differs a great deal from the experience of others, but I think it did at the time spark my interest for mental health. I wondered why do I feel the way I do and why do others appear more stable and it was those questions that made me decide to study psychology, and during my studies I got enthused for child and adolescent development because the childhood and adolescent peers are so important for shaping how we function as adults, and I believe that if we can improve child and adolescent well-being we’re also helping future adults to feel happier and healthier and thereby indirectly impact also our future society.

Interviewer: As I mentioned in the intro, we’re going to focus on your paper published in the JCPP, but before we go into details, can you give a brief overview of how the frontoamygdalar brain circuitry functions and also its role in emotional regulation?

Dr. Sandra Thijssen: Yeah, sure. So the frontoamygdalar circuitry consists of the amygdala on the one hand and regions of the prefrontal cortex on the other hand. The amygdala is a subcortical brain structure that was originally thought to play a large role in negative emotions, like fear and anger, but more recently the amygdala has been linked also to positive emotions and is now suggested to play a role more so in ensuring [s.l. 03:35] detection and emotional learning. So in a matter of speaking if something of importance happens your amygdala sort of starts shouting and urges you to pay attention, and the prefrontal cortex, on the other hand, is a higher order brain region and some of its sub-parts, in particular structures like the orbital frontal cortex and the anterior cingulate cortex are thought to regulate or calm this initial emotional response by the amygdala.

So by regulating the amygdala response, the prefrontal cortex is involved in emotion regulation and this process is measured by examining frontal amygdala functional connectivity, which is the correlation between the activity in the amygdala and the activity in the prefrontal structures, like the anterior cingulate cortex and the orbital frontal cortex, which are the structures we examined in our study.

Interviewer: Great, thank you, and your paper focussed on the association between adolescents and young adult externalising behaviour, such as aggression and rule breaking and frontoamygdalar functional connectivity when the brain is at rest. Why was it important to look at the brain at rest and what was the aim of the study?

Dr. Sandra Thijssen: That’s a great question. Most studies examining the neural correlates of externalising behaviour have used task-based FMRI. So in such studies participants lie in the scanner and perform a specific task. For example, they could be asked to view emotional faces or emotional scenes, or they’re asked to solve moral puzzles, and these studies teach us a lot about how individuals who show high levels of externalising behaviour respond to these specific circumstances and what studies about the brain and rest add to this knowledge is that they provide insights on how the brains of these individuals function in the absence of stimulation or when they are addressed.

And this activation and rest is important because although at rest the brain is not idle, resting activity is assumed to take up about 20% of the body’s energy, despite the brain being only 2% of the body’s mass, and the way the brain behaves in the absence of stimulation may actually determine how it responds when stimulation does occur. So therefore, the aim of our study was to examine the relationship between adolescent self-reported externalising behaviour and amygdala anterior cingulate cortex and amygdala orbital frontal cortex functional connectivity in the brain at rest and we also wanted to examine how this relationship might change over adolescence and young adulthood.

Interviewer: And how did you go about this? What was the methodology used?

Dr. Sandra Thijssen: This study was conducted at the University of Minnesota. I was a visiting scholar there from 2017 to 2019, and the data were actually drawn from a larger study of adolescent brain and behavioural development directed by Monica Luciana’s laboratory, and our analysis were conducted in a sample of over 100 adolescents and young adults from the general population, and participants were 11 to 25 at the start of our study and were seen up to four times over two year intervals, and at all for visits we measured externalising behaviour using the Achenbach Youth and Adults Self-Report questionnaires.

These questionnaires ask individuals to report on the extent to which they engage in aerobic and behaviours as well as aggression, and we examined frontoamygdalar functional connectivity using the resting state functional MRI. So, as I explained before, this means that we measured participant’s brain activation in the absence of a task. Participants were instructed to lay in the scanner with their eyes closed, but to resist falling asleep and using these resting state scans we examined the degree of co-activation between the amygdala on the one hand and two regions of the prefrontal cortex on the other hand, namely the anterior cingulate cortex and the orbital frontal cortex.

So the measure was the extent to which increases in activation of the amygdala are related to increases in activation of the anterior cingulate or orbital frontal cortex and vice-versa. Okay, so we examined differences in externalising behaviour between individuals as well as differences within individuals over time were related to amygdala anterior cingulate cortex functional connectivity and amygdala orbital frontal cortex functional connectivity, and we also examined whether this relationship depended on age.

Interviewer: And what can you say about the findings?

Dr. Sandra Thijssen: We found that individuals who show higher levels of externalising behaviour have a higher degree of functional connectivity between the amygdala and the anterior cingulate cortex and orbital frontal cortex? And this association was independent of age, which means that between adolescents and young adulthood, we found a higher degree of functional connectivity in those who were high externalisers and lower degrees of functional connectivity in those who were low externalisers and this difference in functional connectivity between the high and low externalisers did not change over the course of development.

Interviewer: So can I check, in layman’s terms do your findings suggest that adolescents with higher externalising behaviours are in a state of hyper-vigilance?

Dr. Sandra Thijssen: I think it’s hard to interpret exactly what is high degree of functional connectivity between the amygdala and the anterior cingulate cortex and orbital frontal cortex means hyper-vigilance as a psychological state is more typically associated with states of anxiety, and because we scanned our participants while they were at rest we cannot make use of stimulus material or participant behaviour to interpret the meaning of our findings as a somewhat more possible in task-based FMRI, but our results do suggest that the amygdala and anterior cingulate cortex and orbital frontal cortex show a strong connection in that when the amygdala becomes activate, so does the anterior cingulate cortex and the orbital frontal cortex and vice-versa.

And I think the vice-versa part is important because it could be that prefrontal areas are actually calling upon the amygdala to alert itself as opposed to a more bottom up sequence of activation. So because these regions seem more attuned, even in the absence of emotional stimuli, this could suggest that this frontal amygdala circuit is in a less activated state in those with lower levels of externalising behaviour, but again, we do not know exactly what this lower degree of connectivity in the absence of stimulation or reaction means.

We would need to relate this measure of connectivity to a measure of vigilance or to test it in the context of a task that demands actual behaviour in order to make more substantiated claims about the meaning of this functional connectivity effect.

Interviewer: Sandra, in your study, no association was found between externalising behaviour and age. Was that surprising and how do you account for that?

Dr. Sandra Thijssen: Yeah, that was surprising. Prior literature, but maybe even more so our general conception of adolescence suggests that externalising behaviours and then especially rule breaking behaviours peaked during adolescence. The adolescent period is characterised, of course, by importance of challenges such as changing relationship with parents, exploration of new roles, experience of intimate partnerships and it seems unsurprising that for some individuals, more than for others, these challenges are met with acting out behaviours, but our sample did not support this prediction, perhaps because of the relatively high functioning nature of our sample.

Our study was conducted in a sample from the general population, and while it did include several participants showing clinical levels of externalising behaviours, most individuals showed lower average levels of externalising problems. So while we did expect externalising babies to increase over age, at least over adolescence, more recent literature on the development of externalising behaviour is more mixed with some studies showing increases over adolescence, while others show stable patterns of externalising behaviour, and our findings seem to support the idea that externalising tendencies represent stable traits, and indeed it does have considerable support in the literature also.

Interviewer: There were developmental changes in the frontal amygdala brain circuitry. What did you find in this respect and what does it mean?

Dr. Sandra Thijssen: Yeah, so as I mentioned before, the amygdala is a subcortical brain region involved in detection and emotion and compared to the cortex, which continues to mature well into the early 20s, the amygdala is thought to reach a mature state earlier in development. There are several theories on adolescence which suggests that adolescents act out the way they do because they’re subcortical emotional regions mature before the higher order cortex does, and the cortex, therefore, is not able to fully regulate these emotional subcortical regions.

And our study shows that amygdala orbital frontal cortex, functional connectivity and to a lesser extent amygdala anterior cingulate cortex functional connectivity increased with age. This could mean that as the frontal cortex develops it becomes better attuned to the amygdala and as a consequence becomes better able to regulate the amygdala, and I realise that interpretation seems to counteract our findings of increased functional connectivity in high externalising individuals and the increased functional connectivity between prefrontal regions and the amygdala that we observe in the context of higher externalising could mean that the prefrontal cortex is working more strongly to successfully regulate behaviour in those individuals.

And of course, because the prefrontal cortex continues to develop through adolescence, connectivity between the prefrontal cortex and the amygdala becomes stronger over time in both a low externalising as well as in high externalising individuals, leaving a theory to better emotion regulation, and I think it’s important to emphasise that our study did not include large numbers of individuals with extreme levels of externalising tendencies. So it may be that people with very high levels of externalising behaviour but the integrity of the survey would break down as behaviour regulation fails and therefore future studies should attempt to replicate these findings in a group of high externalisers which would help to expand upon these interpretations.

Interviewer: That will be really interesting. Sandra, your findings provide insight into the neural underpinning of externalising behaviours. How might that be translated into clinical practice? So, for example, could it lead to better targeted interventions?

Dr. Sandra Thijssen: I think for now it’s too early to expect direct translations of most neuroimaging research in non-clinical samples to the clinical practice. I also want to be very careful not to overstate the clinical reach of these findings, given that our sample was a largely healthy sample, but I do think that studies like ours help solve a piece of the puzzle of understanding the neural circuits that mediate behaviour regulation. I think what our results suggest is that even in the absence of stimulation, individuals who show relatively high levels of externalising behaviour show a different pattern of activation within circuitry relevant for emotional and behavioural regulation.

And given this different at rest, our study could suggest that intervention efforts could focus not only on things like stimulus processing, but also on the individual state when they’re not stimulated. However, our results provide no information on how to shape such intervention or on the effectiveness of such interventions, and again our study was designed to capture normative behavioural developments, and I think it would be useful to determine the extent to which the patterns that we observed here in a largely healthy sample generalised to a clinical population and also to examine to what extent these structures are susceptible to intervention before making any strong suggestion with regards to clinical intervention. So for now, I think it’s too early to translate our findings to clinical practice.

Interviewer: You may not be able to answer this next question then in relation to what you’ve just said, but I wondered if there are any implications of your findings.

Dr. Sandra Thijssen: I think there are not so much for the neuroimaging findings, but our findings do suggest that externalising tendencies are relatively stable over time and I think that part of our findings suggest that identification of individuals at risk can occur early in childhood and interventions at the behavioural level should perhaps begin early in life, perhaps during the childhood period, but whether such interventions would change the course of neuro development, of course, is an open question.

Interviewer: Sandra, is there anything else you want to highlight from this research?

Dr. Sandra Thijssen: Yeah, to summarise, we found that higher levels of externalising behaviour were associated with increased amygdala anterior cingulate cortex functional connectivity and the orbital frontal cortex functional connectivity, and in longitudinal studies such effects can be explained by differences between individuals as well as differences within individuals over time, and our follow up analysis revealed that for both amygdala anterior cingulate cortex functional connectivity and amygdala orbital frontal cortex functional connectivity, the effects for finding could be explained by differences in externalising behaviour between individuals, but only for orbital frontal cortex functional connectivity.

The association with externalising behaviour could be explained by within person fluctuations in externalising behaviour over time, and this means that only amygdala orbital frontal cortex functional connectivity seems to change when the externalising behaviour of the individual changes, and its difference in effect could be explained in different ways. For example, between force and effect of amygdala anterior cingulate cortex functional connectivity that could be the result of characteristics that are related to externalising behaviour, but are not the effect of externalising behaviour itself and therefore subtle within changes in externalising behaviour do not associate with changes in functional connectivity.

Another explanation is that amygdala orbital frontal cortex functional connectivity is more sensitive to subtle changes in externalising behaviour than amygdala anterior cingulate cortex functional connectivity is, and if this latter interpretation is the case perhaps the orbital frontal cortex functional connectivity is more receptive to interventions then the amygdala anterior cingulate cortex functional  connectivity is.

Interviewer: Are you planning some follow up research that you can reveal to us?

Dr. Sandra Thijssen: Yes. As a researcher in child and family studies I am convinced that externalising behaviour problems do not typically occur in isolation. The family environment is such an important predictor of adolescent and young adult mental health, and therefore I’m working on a project that looks into types and timing of stress exposure within the family and its effects on neural underpinnings of externalising behaviours. The project is still very much in the early phase, so I can’t provide any results as of yet.

But I’m very excited to embark on this project and learn more about what experiences may amplify the progression of externalising or antisocial behaviours.

Interviewer: And any other research projects. Is there anything else in the pipeline that you’d like to mention?

Dr. Sandra Thijssen: Yeah, most of my current projects focus on the early child environment and its relation with neural development. So if you’re interested in how parenting or early stress may affect brain development, please keep an eye out for my work.

Interviewer: And finally, Sandra, what is your takeaway message for those listening to our conversation?

Dr. Sandra Thijssen: My takeaway message for those listening to our conversation is that adolescents and young adults show variations in frontal amygdala, functional connectivity addressed as a function of age and as a function of their level of externalising behaviour, and these were independent effects. Our study underscores, I believe, the importance of studying longitudinal samples, although we did not find different developmental patterns of frontal amygdala functional connectivity for high externalisers relative to low externalisers. Our longitudinal data do show that associations between externalising behaviour and functional connectivity that are found when comparing different individuals may not be found when you compare the same individuals over time.

Our ultimate aim is to better understand factors that contribute to better mental health in children and adolescents, we are looking for markers that are sensitive to such changes over time, and I believe only longitudinal studies will help us find those.

Interviewer: Sandra, thank you ever so much. For more details on Dr Sandra Thijjsen please visit the ACAMH website www.acamh.org and Twitter at ACAMH. ACAMH is spelt ACAMH, and don’t forget to follow us on iTunes or your preferred streaming platform. Let us know if you enjoyed the podcast with a rating or review and do share with friends and colleagues.