Childhood ADHD is linked to distinct developmental changes in brain white matter

An analysis of ABCD study data found that children with ADHD showed signs of reduced glial cellularity (measured as reduced restricted normalized isotropic diffusion) in 20 white matter tracts at 9 years of age. They also noticed signs of reduced axonal organization (measured as reduced restricted normalized directional diffusion) of nerve fibers in 16 white matter tracts between ages 9 and 14. The paper was published in Biological Psychiatry: Cognitive Neuroscience and Neuroimaging.

Attention-deficit/hyperactivity disorder, or ADHD, is a neurodevelopmental condition that affects attention, impulse control, and activity levels. It usually begins in childhood, although many people continue to experience symptoms in adolescence and adulthood. Some people with ADHD mainly struggle with distractibility, forgetfulness, and organization, while others are more affected by restlessness and impulsive behavior. Many experience a combination of both patterns.

ADHD symptoms are persistent and interfere with everyday functioning. They can affect school or work performance, relationships, time management, and the ability to complete routine tasks. In fact, ADHD is frequently diagnosed when a child starts school because its symptoms often conflict with classroom expectations. It is estimated to affect approximately 3-10% of children.

Study author L. Nate Overholtzer and his colleagues note that white matter—the tissue in the brain made mainly of nerve fibers—facilitates efficient communication between brain regions, thereby supporting higher-order cognitive processes. These processes are commonly impaired in ADHD. With this in mind, they conducted a study aiming to characterize the relationship between ADHD and white matter microarchitecture across early adolescence. They also evaluated how these associations were affected by three classes of ADHD medications: amphetamine-based, methylphenidate-based, and nonstimulant medications.

They analyzed data from the Adolescent Brain and Cognitive Development Study (ABCD Study). The ABCD study is a large, long-term U.S. research project following thousands of children into adulthood to understand how brain development relates to health, behavior, and life experiences.

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The analyses used data collected at enrollment (2016-2018), 2 years (2018-2020), and 4 years (2020-2022) after the start of the study. The total number of participants for whom data were available at the start of the study was 9,426. In year 2, it was 6,745, and it was down to 2,483 participants in year 4. At the start of the study, 1,150 participants (12.2%) had ADHD (658 of whom were taking ADHD medication). In year 2, there were 763 participants with ADHD (11.3%), and in year 4, there were 294 (11.8%).

The researchers used advanced diffusion magnetic resonance imaging (MRI) scans of the participants’ brains. Participants who were using non-ADHD psychiatric medications were excluded from the analysis to prevent pharmacological confounds. The study authors identified whether participants had ADHD based on caregiver responses to the computerized Kiddie Schedule for Affective Disorders and Schizophrenia (KSADS) and the Medication Inventory Survey (MIS). The latter assessment also served to identify the type of ADHD medication participants were taking.

Results indicated that children with ADHD tended to show decreased restricted normalized isotropic diffusion in 20 white matter tracts at age 9, indicating reduced glial cellularity. The analyses also showed that ADHD was associated with enduring decreases in restricted normalized directional diffusion in 16 white matter tracts between the ages of 9 and 14, indicating reduced axonal organization. Additionally, an exploratory analysis indicated that the narrowing of isotropic diffusion differences between children with and without ADHD across early adolescence paralleled an overall age-related drop in ADHD symptoms across the participants.

Restricted normalized isotropic diffusion (RNI) and restricted normalized directional diffusion (RND) are advanced MRI measures that describe how water movement is restricted within brain tissue.

RNI reflects restriction that is similar in all directions and serves as an indicator of glial cellularity—the presence and morphology of support cells like astrocytes, microglia, and myelin-producing cells.

RND reflects restriction along a particular direction and, in brain white matter, provides information about the organization, packing, and alignment of nerve fibers (axons).

“Altogether, ADHD was robustly associated with reductions in isotropic diffusion in white matter tracts, suggestive of atypical glial cellularity during late childhood. Complementary reductions in directional diffusion of select tracts may suggest atypical axonal organization enduring across early adolescence,” the study authors concluded.

The study contributes to the scientific knowledge about the neural basis of ADHD. However, the study was limited by smaller sample sizes in later waves—partially because Year 4 data collection was still ongoing at the time of the data release, and because children with ADHD had higher exclusion rates due to factors like moving during MRI scans or taking other psychiatric medications. This could limit the generalizability of the results to the broader ADHD population.

The paper, “Developmental Differences in White Matter Microarchitecture in Youth with ADHD: Longitudinal Findings from the ABCD Study,” was authored by L. Nate Overholtzer, Katherine L. Bottenhorn, Hedyeh Ahmadi, Sarah L. Karalunas, Bradley S. Peterson, and Megan M. Herting.