Latest / The Biological Psychiatry Podcast / Pubertal Timing and the Developing Brain
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- Elvisha Dhamala: From the Biological Psychiatry family of journals, this is the Biological Psychiatry podcast, ⁓ where we discuss the latest research on psychiatric disorders and their treatments. ⁓ Thank you for joining us. I'm your host and Social Media Editor, Elvisha Dhamala. ⁓ Adolescence is a period of biological and psychological change, and at the center of that transformation is puberty. We know that the timing of puberty, whether a young person matures earlier or later than their peers, has been consistently linked to mental health outcomes. We also know that this developmental period is accompanied by substantial reorganization of functional brain networks. But what is unclear is how variation in pubertal timing relates to those brain network changes. And whether those changes might explain why some adolescents go on to develop depression. A new study analyzed data from over 9,000 youth to try and understand these relationships between pubertal timing, brain connectivity, and depressive symptoms. Joining me to discuss this work is Dr. Nasia Matoki from the University of Pennsylvania, who was previously at the Washington University in St. Louis when she did this work under the supervision of Professors Deanna Barch and Nico Dosenbach. Dr. Matoki is the first author of a new study in biological psychiatry, cognitive neuroscience and neuroimaging, titled Functional Brain Network Correlates of Pubertal Timing and Depressive Symptoms in Pre-adolescence. Dr. Matoki, welcome to the Biological Psychiatry Podcast. Nasia Metoki: Yeah, thank you so much for having me. Elvisha Dhamala: So let's start with some background. Puberty is a universal experience, but there's a lot of variability in terms of when it happens. What do you mean when you say pubertal timing and why is it so important? Nasia Metoki: So, pubertal timing is really about where you are in your pubertal development compared with other people that are your age and sex. So we could have two 10-year-old girls, for example, and they can be the exact same chronological age, but at very different points in puberty. So one may be relatively early compared with her peers, and the other relatively late. And that matters because puberty doesn't happen in isolation. So at the same time that the body is changing, the brain is also developing very rapidly. Social relationships are becoming more complicated and emotional systems are changing. So going through these changes earlier than your peers may create a different developmental context than going through them at an average or later time. And that is one reason why pubertal timing has become a pretty important individual. individual difference variable in adolescent mental health research. Elvisha Dhamala: So there's a well established literature linking earlier pubertal timing to depression risks, particularly in girls. Can you tell us what we know about that association and where the gaps in our understanding were? Nasia Metoki: Right, so we already know from a fairly large literature that young people who mature earlier than their peers they do tend to show more internalizing or like depressive symptoms, if you will. And in some studies they also show earlier onset or a more persistent course of these symptoms. So historically that association has often been stronger and more consistent in girls, while in boys we've mostly seen Mixed results. So what we understood much less is why that happens. So we knew that puberty was related to depression, and independently we did know that puberty was a period of substantial brain development, brain change, but we didn't have a clear picture of whether earlier pubertal timing was associated with change in large-scale brain organization. and whether those brain changes might actually help explain that increased depression risk. Elvisha Dhamala: So as you mentioned, along with all of the psychological and hormonal changes that are happening during puberty, there's also a lot of reorganization happening in the brain, particularly in terms of how functional networks are connected. Can you tell us a bit more about what's happening in the brain during this period? Nasia Metoki: tremendous amount that is happening in the brain during puberty. it is important to point that the brain is not simply becoming more connected or less connected, it's literally being reorganized. It's a very plastic period in a person's life. connections strengthen, others weaken, networks become increasingly specialized, so there's a tremendous amount that is happening in the brain during puberty. It is an important it's important to point that the brain is not simply becoming more connected or less connected. it's literally being reorganized. It's a very plastic period in a person's life. some brain connections strengthen, others weaken, and networks become increasingly specialized. While also changing the way that they communicate with each other. Changing the way that they communicate with each other. So that includes brain systems that are involved in sensory, motor processing, cognitive control, and self-referential processing. So puberty is occurring right in the middle of that reorganization, and one of the big questions is whether differences in when puberty occurs are associated with these differences in the time. or a pattern of that dream reorganization. Elvisha Dhamala: So a few prior studies have tried to link pubertal timing, brain connectivity, and depression, but the findings have been mixed. What were the key limitations of that earlier work that motivated your study? Nasia Metoki: One limitation was that a lot of the previous research started with a specific hypothesis about a particular circuit, for example, connections involving the amygdala or the hippocampus, and they only examined those connections. And that's reasonable, it's a hypothesis-driven approach, and it means that if you're looking very specifically at what you've decided in advance to look. And the existing findings were mixed, like you said. Some studies linked earlier puberty to corticolimbic connectivity and depression, while others did not find those relationships. And another issue was that some studies were also relatively small, and some combined observations across time in ways that made it difficult to separate concurrent relationships from truly longitudinal ones. So we wanted to take a step back and and ask the broader question if we look across the whole brain connectome without making assumptions beforehand about where the effect should be, so what would that relationship between pubertal timing and functional so we wanted to stay to take a step back and ask the broader question, if we look across the whole brain connectome without making assumptions beforehand about where the effect should be, what would that relationship between pubertal timing and functional connectivity actually look like? Elvisha Dhamala: So your study uses data from the ABCD study, which is one of the largest developmental neuroimaging datasets in the world. Can you tell us about the sample and what made this dataset particularly well suited for this question? Nasia Metoki: So the ABCD study stands for the Adolescent Brain Cognitive Development Study. It's a very large longitudinal study of children and adolescents in the United States. The full baseline cohort, so the first instance of t taking these kids and doing interviews and imaging. included almost 12,000 children, initially around the ages of 9 to 11 years. And these kids are being followed repeatedly as they move through adolescence. So it was a pretty ideal cohort for a few reasons. So, first of all, the kids entered the study right around the beginning of that critical pubertal window. Second, we did have repeated measures of both behavior and depressive symptoms and brain imaging. And also the sample is Enormous in neuroimaging standards. So in our study, we had more than 9,000 participants for the longitudinal depression analyses. There was about 7,500 with the baseline resting state functional connectivity, and about 3,000 with the longitudinal imaging data that we needed for the brain change in our study, we had more than 9,000 participants for the longitudinal depression analyses. there was about seven and a half thousand with the baseline resting state functional connectivity, and about three thousand with the longitudinal imaging data that we needed for the brain change and mediation analyses. So that was particularly important because brain behavior associations tend to be small and heterogeneous, so large samples give us much greater ability to characterize the effect that we want to characterize reliably. Elvisha Dhamala: So we've talked a little bit about pubertal timing and in this study you use the puberty age graph to measure pubertal timing. Can you explain what that is and why you use that approach? Nasia Metoki: So the basic idea is to ask: given someone's physical signs of puberty, how old would we predict them to be? And how does that predicted pubertal age, quote unquote, compare with their actual chronological age? So we used physical indicators from the pubertal development scale, which is a questionnaire, and it asks questions about we used physical indicators from the pubertal development scale, which is a questionnaire, and it asks questions about growth of of growth or body hair or skin changes and also sex-specific changes such as breast development or voice changes for boys, and we estimate pubertal age separately for males and females, and then compare body hair or skin changes, and also sex-specific changes, such as breast development or voice changes for boys. And we estimate pubertal age separately for males and females, and then compare that predicted age with chronological age. So a positive puberty age gap means that someone is physically more mature than we'd expect for someone their age. So that means that they we would characterize them as having earlier pubertal timing. Elvisha Dhamala: So let's get into your findings. At the broadest level, Nasia Metoki: Yeah. Elvisha Dhamala: did you find a global association between pubertal timing and resting state functional connectivity, or was it a bit more complicated than that? Nasia Metoki: So an interesting finding was that there was no global association, so we didn't see evidence that earlier puberty simply makes the brain on average more connected or less connected. we found a pretty network-specific relationship. So some network pairs showed greater connectivity with earlier pubertal timing, while others showed lower connectivity and many showed So some network pairs showed greater connectivity with earlier pubertal timing, while others showed lower connectivity and many showed very little relationship. very little relationship and that made me think that the more accurate picture is that pubertal timing is associated with a pretty selective reorganization of particular functional systems rather than like a global And that made me think that more the more accurate picture is that pubertal timing is associated with a pretty selective reorganization of particular functional systems rather than like a global shift of brain connectivity. Elvisha Dhamala: One particularly interesting aspect of your results were the sex differences. So you found that earlier pubertal timing was associated with widespread and heterogeneous connectivity patterns in females, but that effect was much more limited in males. How should we interpret that difference? Nasia Metoki: Okay, so disclaimer, I would be cautious about interpreting that as saying that puberty somehow affects the female brain more. So there's a very important developmental issue here. Our participants were only 9 to 11 years old at baseline, and at that age, many girls have already entered or progressed substantially through puberty, while many boys are still at relatively early stages. and in fact, females in our sample showed a much broader distribution So pubertal timing may simply be capturing more meaningful variation in biological maturation in girls at this particular age. And pretty consistently with that idea, we did see some cross-sectional effects in males, but they didn't persist longitudinally. So it is possible that if we followed the boys farther down into adolescence, stronger or more distributed patterns would emerge later. So I see that finding partly as a sex difference, but more importantly as a difference in developmental time. Yeah. Elvisha Dhamala: longitudinally, earlier pubertal timing in females Nasia Metoki: Mm. Elvisha Dhamala: predicted reductions in functional connectivity at the follow-up. What does that tell us about how puberty might be shaping brain development over time? Nasia Metoki: So we were not just asking whether earlier maturing children already had different brains. asked whether pubertal timing at baseline predicted some subsequent changes in connectivity while accounting for where their connectivity started. In We asked whether pubertal timing at baseline predicted some subsequent changes in connectivity while accounting for where their connectivity started. In females it did. earlier pubertal timing predicted changes two years later across a reproducible set of network connections, and most of those effects reflected reductions in connectivity over time. So they were particularly concentrated in basal ganglia, the thalamus, and sensory motor systems, and the ventral attention network. So one interpretation would be that earlier maturation may be associated. with an earlier timetable of network specialization. Again, we should emphasize that this is like observational. We cannot for certain, say that puberty caused those brain changes. Elvisha Dhamala: You also found that earlier pubertal timing was associated with higher depressive symptoms, both concurrently and prospectively. Was that consistent across the sexes? Nasia Metoki: It was this is something that has been shown in the literature time and time again, earlier pubertal timing being associated with higher depressive symptoms, and we found that too, and that relationship did not significantly differ between males and females. Elvisha Dhamala: Despite finding associations between pubertal timing and brain connectivity, as well as between pubertal timing and depression, the connectivity changes did not mediate the link to depression. How should we interpret this finding? Nasia Metoki: So I think it suggests that the pathway from earlier puberty to depression is more complex than a single sequence in which puberty changes connectivity and those changes lead to depressive So I think it suggests that the pathway from earlier puberty to depression is more complex than a single sequence in which puberty changes connectivity and those changes lead to depressive symptoms. it's also possible that we're looking relatively early development, so that's why it might not have come up as a significant result. So some of these brain behavior relationships may become stronger or more detectable in adolescence as puberty progresses and depressive symptoms become more prevalent. And other factors, interestingly, may be shaping all these three processes. For instance, there's evidence for early life adversity or chronic stress. For instance, there's evidence for early life adversity or chronic stress. That could increase vulnerability That could increase vulnerability to depression and influence brain development and also be associated with to depression and influence brain development and also be associated with earlier pubertal maturation. And some developmental models have proposed an alternate sequence in which adversity and emotional symptoms could emerge first, followed by changes in brain function and potentially then earlier pubertal maturation. So I think the The broader message would be that resting state connectivity is likely only one piece of a larger biological, social and psychological process. And we should be generally speaking cautious about assuming we already know the direction or the mechanism Elvisha Dhamala: So there's a bunch of different ways that we can assess pubertal development, and here you use parent report rather than hormonal assessments or self-report. What are the trade-offs of of that approach and how might incorporating additional measures of puberty provide more information? Nasia Metoki: Right. Parent-reported pubertal development has some advantages for a study that is this large, like the ABCD dataset. It is relatively easy to collect. it's a questionnaire. It captures multiple visible aspects of physical development. And in younger children, there is evidence that parent reports can actually be preferable to self-reports because children may overestimate their development. And in younger children, there is evidence that parent reports can actually be preferable to self-reports because children may overestimate their development. trade-off, like you said, is that we're measuring the physical expression of puberty, not the underlying endocrine processes directly. Parents may not observe every change accurately, and two young people with similar physical development could still have different hormonal profiles. So hormonal measures could give us a more biologically precise picture of processes such as gonatal or adrenal maturation. So in the future, studies would ideally combine both physical development and repeated hormonal measures, and that's important because hormones fluctuate a lot, so repetition for the hormonal measures is pretty important. So in the future, studies would ideally combine both physical development and repeated hormonal measures, and that's important because hormones fluctuate a lot. So repetition for the hormonal measures is pretty important. So a multimodal approach will help us understand whether some of the heterogeneity that we see in the brain, in those brain development maps, is actually related to a specific biological components of puberty. Elvisha Dhamala: So if the brain connectivity changes you observe do not explain the link between pubertal timing and depression, what else might be going on? Are there other pathways or mechanisms that might be driving this? Nasia Metoki: I'm almost certain that there's there's probably multiple pathways than a single mechanism. so earlier maturing young people are having adult-like physical changes while their same age peers may not be, and that can change how they're treated by peers or parents or So earlier maturing young people are having adult-like physical changes while their same-age peers may not be, and that can change how they're treated by peers or parents or teachers, coaches, in society as a whole. So things like peer relationships or body image or social expectations or exposure to stress. teachers or coaches and society as a whole. So things like peer relationships or body image or social expectations or exposure to stress and the mismatch And the mismatch between the physical maturation and the emotional development may actually all matter very much. And there's, like I mentioned earlier, there's also biological pathways that resting state connectivity may not be able to capture, such as hormonal effects or stress physiology, or structural brain development. So I think. So, what our findings do is pushing us away from looking at one single neural explanation and trying for a more integrated model where we're hopeful, hopefully in the future, looking at biological, physiological, and social changes interacting during puberty. our findings, what they do is pushing us away from looking at one single neural explanation and trying for a more integrated model where we're hopefully in the future looking at biological, physiological, and social changes interacting during puberty. Elvisha Dhamala: So my last question is: what is one t key takeaway that you'd want clinicians, parents, and researchers to take away from this study? Nasia Metoki: I think the main message is that when puberty happens, the relativity to your peers really matters. Earlier maturation is associated with differences in how large-scale brain networks are developing, especially for girls And it's also associated with greater depressive symptoms. Those findings don't collapse into a simple story where one particular brain change depression. Parents and clinicians, especially earlier puberty shouldn't be viewed as a problem or diagnosis. It's not something pathological. I would think of it as a developmental context that may create additional vulnerability for some young people. So pay attention to emotional changes, social So, for parents and clinicians especially, earlier puberty shouldn't be viewed as a problem or a diagnosis. I would think of it as a developmental context that may create additional vulnerability for some young people. Paying attention to emotional changes, social experiences, and the support that a child has. experiences, and having an identifying the support that a child has. While they're navigating puberty, may ultimately be just as important as understanding has or needs while what is changing in the brain. they're navigating Elvisha Dhamala: That's all for today's episode. Thank you to Dr. Matoki for joining us to share her work on puberty, brain development, and mental health. listeners, can find the full paper in Biological Psychiatry, Cognitive Neuroscience, and Neuroimaging, and we'll include the link in our episode description. To learn more about our journals, please visit biologicalpsychiatryjournal.com. You can find The Biological Psychiatry Podcast wherever you get your podcasts. Subscribe now so you don't miss our next episode and follow us on our social media channels for highlights and updates. 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