Abstract
Background Variation in the longitudinal course of childhood attention deficit/hyperactivity disorder (ADHD) coincides with neurodevelopmental maturation of brain structure and function. Prior work has attempted to determine how alterations in white matter (WM) relate to changes in symptom severity, but much of that work has been done in smaller cross-sectional samples using voxel-based analyses. Using standard diffusion-weighted imaging (DWI) methods, we previously showed WM alterations were associated with ADHD symptom remission over time in a longitudinal sample of probands, siblings, and unaffected individuals. Here, we extend this work by further assessing the nature of these changes in WM microstructure by including an additional follow-up measurement (aged 18 – 34 years), and using the more physiologically informative fixel-based analysis (FBA).
Methods Data were obtained from 139 participants over 3 clinical and 2 follow-up DWI waves, and analyzed using FBA in regions-of-interest based on prior findings. We replicated previously reported significant models and extended them by adding another time-point, testing whether changes in combined and hyperactivity-impulsivity (HI) continuous symptom scores are associated with fixel metrics at follow-up.
Results Clinical improvement in HI symptoms over time was associated with more fiber density at follow-up in the left corticospinal tract (lCST) (tmax=1.092, standardized effect[SE]=0.044, pFWE=0.016), and improvement in combined symptoms over time was associated with more fiber cross-section at follow-up in the lCST (tmax=3.775, SE=0.051, pFWE=0.019).
Conclusions Aberrant white matter development involves both lCST micro- and macrostructural alterations and its path may be moderated by preceding symptom trajectory.
Competing Interest Statement
This study sample is from the NeuroIMAGE project. NeuroIMAGE is the longitudinal follow-up study of the Dutch part of the International Multisite ADHD Genetics (IMAGE) project, which was a multi-site, international effort. NeuroIMAGE was supported by an NWO Large Investment Grant 1750102007010 and NWO Brain & Cognition an Integrative Approach Grant (433-09-242) (to J.K.B.), and grants from Radboud University Nijmegen Medical Center, University Medical Center Groningen and Accare, and VU University Amsterdam. Funding agencies had no role in study design, data collection, interpretation or influence on writing. J.N. is supported by an NWO Veni grant (no. VI.Veni.194.032). B.F. receives support from the Netherlands Organization for Scientific Research (NWO), i.e. the Vici Innovation Program (grant 016-130-669). J.K.B. has been in the past 3 years a consultant to / member of advisory board of / and/or speaker for Takeda/Shire, Roche, Medice, Angelini, Janssen, and Servier. He is not an employee of any of these companies, and not a stock shareholder of any of these companies. He has no other financial or material support, including expert testimony, patents, royalties. All other authors report no biomedical financial interests or potential conflicts of interest.
Abbreviations
- ADHD
- attention-deficit hyperactivity disorder
- CSD
- constrained spherical deconvolution
- DTI
- diffusion tensor imaging
- DWI
- diffusion-weighted imaging
- FA
- fractional anisotropy
- FBA
- fixel-based analysis
- FC
- fiber cross-section
- FD
- fiber density
- FDC
- fiber density and cross-section
- FOD
- fiber orientation distribution
- HI
- hyperactivity-impulsivity
- IA
- inattention
- lCST
- left corticospinal tract
- lSLF
- left superior longitudinal fasciculus
- MRI
- magnetic resonance imaging
- ROI
- region of interest
- SE
- standardized effect
- WM
- white matter