Children who experience Attention Deficit Hyperactivity Disorder may have symptoms that last, come and go, or disappear completely as they grow older. A recent study published in Nature Mental Health revealed that these different symptom pathways are physically reflected in brain development during adolescence, particularly the growth and thinning of certain areas of the brain. This study highlights the potential of using brain scans to predict future symptom changes and emphasizes the need for long-term monitoring even after treatment begins.
Attention Deficit Hyperactivity Disorder, commonly known as ADHD, affects approximately 5% of children and adolescents worldwide. This developmental condition often results in a variety of clinical outcomes as children grow into teenagers and young adults. Some people continue to have symptoms into adulthood, while others go through a period of remission when their symptoms fade significantly. Still, some people take a new path where their behavioral problems actually get worse over time.
It remains extremely difficult to predict which young people will take which path. A major reason for this difficulty is the lack of long-term brain imaging data that shows exactly how the adolescent brain matures. The physical development of the brain during this transition period is accompanied by intense structural changes, including a major biological process called synaptic pruning.
During synaptic pruning, the brain naturally eliminates unused neural connections to increase mental efficiency. This normal trimming process causes the outer layer of the brain, known as the cerebral cortex, to thin over time. Differences in how quickly or slowly this thinning occurs can have fundamental effects on how people process information, pay attention, and regulate their emotions later in life.
Qiang Luo, a researcher at Fudan University in China, led an international team of scientists to investigate how typical brain maturation maps to attention deficit hyperactivity disorder. The research team wanted to know whether specific physical changes in the brain correspond to different developmental symptom pathways. They also assessed whether standard medications prescribed for this condition alter their physical brain developmental pathways.
The research team examined longitudinal data from studies of cognitive development in the adolescent brain. This large-scale ongoing project follows thousands of young people in the United States over many years, measuring environmental, physical, and mental health factors. The research team focused on a diverse and inclusive group of 7,436 adolescents who underwent their first brain scan at approximately age 10.
The researchers divided the youth into four different groups based on behavioral assessments provided over the next two years. There was no increase in psychiatric symptoms in the large control group. A much smaller persistence group had higher symptom levels at the beginning and end of the 2-year period. The remission group started with strong symptoms but eventually fell below the diagnostic threshold. Finally, the emergency group started with mild symptoms that eventually worsened to clinical levels.
Evaluation of brain scans over time revealed different physical characteristics in each group. The persistent group had faster rates of cortical thinning in certain frontal regions of the brain compared to the healthy control group. These specific frontal regions are typically associated with executive functions such as complex decision making and cognitive control. Accelerated hair thinning is associated with a lack of these everyday cognitive skills.
Changes in the rate of brain development were also observed in the emergent group. Those whose symptoms worsened over time showed a slower rate of cortical thinning in the right posterior cingulate cortex. This region is a key component of the brain’s default mode network, which helps control mind wandering and inner thoughts. By holding on to connections that would normally be cut out, the developing brain can have a hard time shifting focus outward when needed in classrooms or social settings.
On the other hand, the remission group showed completely different biological characteristics. The adolescent whose symptoms disappeared experienced a rapid expansion of the physical volume of the left hippocampus. The hippocampus is a deeper, more primitive brain structure deeply involved in memory formation and emotional regulation. As the region grew faster, adolescents showed corresponding behavioral improvements in school participation, prosocial behavior, and sleep quality.
To understand why these structural brain changes occurred, the researchers compared local brain maps to spatial gene expression databases. They analyzed which genes were naturally highly activated in these specific changing brain regions. They found strong overlap with genes that organize cell synapses and manage chemical messengers such as dopamine and serotonin.
This genetic overlap provides a deep biological basis for the observed changes in external behavior. This suggests that the physical volume changes seen in brain scans are linked to fundamental cellular processes that control how local neurons communicate with each other. Tracking these physical parameters essentially allows scientists to observe genetic activity unfolding on a large scale.
The researchers then investigated the role of ongoing drug use in these developmental outcomes. They matched young people with similar symptom severity at the start of the study who either received or did not receive treatment. The analysis showed that taking a prescription drug initially was not statistically significant in predicting an individual’s eventual entry into a remission trajectory.
The lack of association between medication and duration of remission is an unexpected finding. Medical treatments for attention-deficit hyperactivity disorder are widely recognized to be highly effective in managing immediate behavioral symptoms. However, it may not be possible to fundamentally change the fundamental physical development of the brain over the long term. The researchers noted that even people who experienced remission of symptoms still had sleep disturbances and emotional regulation problems.
Following the initial physical analysis, the team tested whether these newly discovered brain signatures could predict future behavior. They fed baseline brain scan data and behavioral scores into a machine learning computer model. The model accurately predicted participants’ symptom severity three years later at age 13. Physical brain measurements improved the accuracy of predictions compared to using a simple behavioral checklist alone.
The team then validated the predictive model using a completely separate group of study participants. One validation group consisted of 23-year-olds who participated in a European neuroscience study. The researchers were able to reproduce the specific association between hippocampal enlargement and symptom resolution both in the young adult group and in two other independent clinical samples. Observing this exact same pattern of brain expansion in different age groups increases confidence in the initial findings.
The current study has several limitations that should be noted. Because this study is observational, it cannot prove that physical changes in the cortex or hippocampus directly cause improvement or worsening of symptoms. The findings only show that there is a strong correlation between specific physical rates of brain development and symptom pathways that change over time.
Additionally, different datasets use different questionnaires to measure participants’ behavioral symptoms, which slightly complicates accurate comparisons between separate groups. The information available regarding participants’ complete medication history was also somewhat limited. Researchers cautioned against drawing definitive conclusions about long-term drug effects based solely on parental reports of recent drug use.
In the future, scientists will need to conduct brain scans more frequently and over longer periods of time to capture the true fluid dynamics of brain development. Focusing on lifestyle interventions that naturally influence continued hippocampal growth, such as continued aerobic exercise, may aid in the development of new non-drug treatments. By identifying physical brain markers of these symptom pathways, researchers established a biological roadmap for developing targeted interventions aimed at producing long-term symptom remission.
The study, “Cortical thinning and hippocampal expansion as brain manifestations of the symptom trajectory of attention-deficit hyperactivity disorder,” is published in Nature Mental Health and is authored by Wenjie Hou, Daqian Zhu, Barbara J. Sahakian, Samuele Cortese, Christelle Langley, Lizhu Luo, Qingyang Li, Zixin Gu, Luolong Cao, Gareth J. Barker, and Arun LW. Bokde, Rüdiger Brühl, Sylvane Desivieres, Herta Flor, Hugh Galavan, Penny Gauland, Antoine Grygis, Andreas Heinz, Jean-Luc Martinot, Marie-Laure Payerre Martinot, Eric Artige, Frauk Nice, Dimitri Papadopoulos-Orfanos, Louise Pustka, Michael N. Smolka, Sarah Homan, Nathalie Holz, Nilakshi Vaidya, Henrik Walter, Robert Whelan, Gunter Schumann, Li Yang, Tobias Banaschewski, Qiang Luo, and the IMAGEN consortium.
