In a groundbreaking study published in Translational Psychiatry, researchers have unveiled compelling evidence that cortical gyrification—a measure of the brain’s surface folding patterns—can serve as a powerful predictor of initial treatment response in adults diagnosed with Attention Deficit Hyperactivity Disorder (ADHD). This discovery represents a substantial leap forward in personalized medicine approaches to ADHD, a neurodevelopmental disorder affecting millions globally and notoriously heterogeneous in treatment outcomes. The implications of these findings extend beyond clinical psychiatry, touching on the very architecture of the brain and its influence on complex behavioral and cognitive phenotypes.
Attention Deficit Hyperactivity Disorder is characterized by pervasive patterns of inattention, impulsivity, and hyperactivity, symptoms that often persist into adulthood and severely impact daily functioning and quality of life. While pharmacological treatments like stimulants remain the mainstay of therapy, patient responses vary widely, with some individuals experiencing remarkable symptomatic relief and others showing disappointing or negligible improvements. Until now, predicting who would benefit from treatment—and tailoring interventions accordingly—has remained a clinical challenge, largely due to the lack of reliable biological biomarkers.
The study’s authors addressed this challenge by focusing on the gyrification index, a neuroanatomical feature reflecting the degree of cortical folding in the human brain. Cortical gyrification develops dynamically during early brain maturation, influenced by genetic, epigenetic, and environmental factors. Abnormal gyrification patterns have previously been implicated in several psychiatric conditions, including schizophrenia and autism spectrum disorder, providing a tantalizing hint that these structural parameters might also predict therapeutic responses in neurodevelopmental disorders like ADHD.
Leveraging advanced neuroimaging techniques and sophisticated computational algorithms, the researchers quantified cortical gyrification across the cerebral cortex in a cohort of adult ADHD patients prior to treatment initiation. The study population underwent rigorous clinical evaluations to characterize symptom severity and functional impairments before being administered standard ADHD pharmacotherapies. Subsequent assessments after initial treatment phases allowed for correlation analyses between baseline gyrification patterns and clinical outcomes.
What emerged from the data was a robust association: individuals exhibiting distinct gyrification patterns within specific cortical regions demonstrated significantly better initial responses to ADHD medications. Notably, regions linked to executive functioning and attentional control—such as the prefrontal cortex and anterior cingulate—showed the most pronounced gyrification differences correlating with positive treatment effects. These findings suggest that the microarchitectural landscape of the brain might underpin the efficacy of pharmacological interventions targeting neurotransmitter systems implicated in ADHD pathology.
This study’s methodological innovations deserve attention. Employing high-resolution magnetic resonance imaging (MRI), the researchers extracted precise cortical folding metrics, which were then subjected to rigorous statistical modeling to isolate predictive markers. Incorporation of machine learning algorithms enhanced predictive accuracy, highlighting the promise of combining neuroimaging with artificial intelligence to personalize psychiatric treatment strategies. Such a paradigm might transform current symptom-based approaches into predictive models grounded in objective neurobiological data.
Furthermore, the researchers ensured careful control for confounding variables such as age, sex, medication history, and comorbid psychiatric conditions, bolstering the validity of their findings. The multi-site nature of the study further strengthens generalizability, addressing one of the recurrent limitations in neuropsychiatric research. This robustness underscores cortical gyrification as a candidate biomarker ready for subsequent validation in larger, more diverse populations.
Beyond its clinical ramifications, the study opens intriguing questions about the developmental trajectories leading to varied gyrification patterns in ADHD brains. Since gyrification is highly susceptible to early-life influences, including prenatal environment and childhood adversity, future research may decode how these factors interact with genetic predispositions to shape treatment responsiveness. This perspective encourages a more integrative model encompassing neurodevelopmental biology, environmental exposures, and lifelong brain plasticity.
The translational impact of these results is significant. If gyrification indices can reliably forecast treatment responsiveness, clinicians could employ neuroimaging scans to tailor ADHD therapies from the outset, minimizing trial-and-error prescribing and reducing patient burden. This precision approach would lead to optimized therapeutic outcomes, enhance adherence, and potentially mitigate long-term negative consequences of untreated or inadequately treated ADHD symptoms.
Critically, while this study emphasizes initial treatment response, it prompts exploration into whether gyrification patterns also predict sustained therapeutic effectiveness and functional recovery over extended periods. Incorporation of longitudinal designs and multimodal imaging could refine understanding of how cortical structure relates to dynamic treatment trajectories. These insights could further refine guidelines for pharmacological and adjunctive behavioral interventions.
Attention must also be paid to the biological mechanisms linking gyrification and treatment response. Altered cortical folding might reflect underlying variations in neuronal connectivity, synaptic density, or neurochemical signaling within pivotal brain circuits targeted by ADHD medications. Experimental studies dissecting these neural substrates may illuminate novel targets for pharmacological development, with the ultimate goal of enhancing treatment efficacy beyond current standards.
Importantly, this work contributes to a growing movement challenging conventional diagnostic frameworks that rely solely on symptom clusters. By anchoring psychiatric diagnoses in neurobiological substrates, such research catalyzes the shift toward a neuroscience-informed psychiatric nosology. This reframing is essential for resolving heterogeneity in clinical presentations and forging stratified intervention pathways.
Moreover, the integration of cortical gyrification metrics into clinical workflows could be facilitated by advances in imaging technology and analytic pipelines, making such assessments increasingly accessible and cost-effective. Collaborations between neuroscientists, clinical psychiatrists, and data scientists will be pivotal in translating these findings from research settings into practical clinical tools.
In sum, this exciting study highlights the immense potential of cortical gyrification as a biomarker for predicting initial treatment response in adults with ADHD. It sets the stage for future investigations aimed at verifying these markers across populations, elucidating their biological underpinnings, and embedding them within precision psychiatry frameworks. As we continue to unravel brain-behavior relationships, such advances promise to elevate patient care by delivering more targeted, effective, and personalized interventions for complex neurodevelopmental disorders.
The path ahead calls for multidisciplinary efforts to not only replicate and expand upon these findings but also to integrate cortical morphometric data with genomic, cognitive, and environmental datasets. Harnessing this rich confluence of information could usher in a new era of individualized medicine in ADHD and beyond, transforming decades of elusive treatment challenges into opportunities for unequivocal clinical progress.
Subject of Research: Cortical gyrification as a biomarker to predict initial treatment response in adults with ADHD.
Article Title: Cortical gyrification predicts initial treatment response in adults with ADHD.
Article References:
Laatsch, J., Stein, F., Maier, S. et al. Cortical gyrification predicts initial treatment response in adults with ADHD. Transl Psychiatry 15, 406 (2025). https://doi.org/10.1038/s41398-025-03681-0
DOI: https://doi.org/10.1038/s41398-025-03681-0
