Towards precision medicine in ADHD: longitudinal assessment of visuospatial working memory precision during methylphenidate titration

Introduction

Working memory (WM) is a core cognitive function that is frequently impaired in ADHD and closely linked to functional outcomes and treatment response. Beyond WM capacity, visuospatial WM precision (WMP) has emerged as a sensitive measure of the fidelity of stored representations and is thought to depend on dopaminergic modulation in prefrontal networks.

Methylphenidate (MPH), a first-line treatment for ADHD, increases synaptic dopamine availability and can improve WM performance at optimal doses. However, treatment response and optimal dosage vary substantially between individuals. Identifying cognitive markers sensitive to dose-related changes may support more individualized treatment approaches.

This study investigates longitudinal changes in visuospatial WMP during MPH titration in adults with ADHD, aiming to evaluate WMP as a potential marker for individualized dose optimisation.

Methods

This ongoing longitudinal study aims to include 180 participants aged 18 to 50 years, with data collection currently in progress. Here, we report preliminary findings from the first participants with complete longitudinal data (n = 2 adults with ADHD).

Visuospatial WMP was assessed repeatedly during stepwise MPH dose titration (10-50 mg/day) using a visuospatial localization task in which participants reproduced the position of previously presented stimuli. Performance was quantified as angular deviation between target and response positions. Reaction times were analysed to assess potential speed-accuracy trade-offs.

Participants completed repeated assessments of clinical symptoms, affective state, daily stress, quality of life, and side effects. Analyses focused on descriptive within-subject trajectories and inter-individual variability across dose levels.

Results

Cross-sectional data from an earlier unmedicated sample (ADHD: n = 37; HCS: n = 51) indicated higher angular deviation in individuals with ADHD compared to healthy controls (Cohen’s d = 0.39), however without statistical significance.

Preliminary analyses revealed substantial intra- and inter-individual variability in visuospatial WMP. Both ADHD participants showed changes in WMP across increasing MPH doses, but with distinct response patterns. One participant exhibited pronounced fluctuations across timepoints, whereas the second showed a more stable trajectory with gradual improvement at higher dose levels. No consistent linear dose-response relationship was observed. Mean reaction times remained relatively stable and did not increase during periods of reduced WMP, suggesting that fluctuations were not driven by general slowing or motor-related factors.

Exploratory inspection of questionnaire data indicated distinct individual profiles. In the participant with fluctuating performance, reduced WMP coincided with increased daily stress. In contrast, the participant with more stable improvement showed reductions in depressive symptoms and ADHD severity, along with improved quality of life. Side effects remained relatively stable and were not clearly associated with WMP changes.

Due to the limited sample size, no inferential statistical analyses were conducted.

Conclusions

These preliminary findings suggest that visuospatial WMP is sensitive to within-subject changes during methylphenidate titration while showing marked inter-individual variability. The heterogeneous trajectories may reflect differences in dose sensitivity and interactions between pharmacological effects, affective state, and daily stress.

Together, these findings highlight the potential of combining cognitive and clinical measures to better characterize individualized treatment responses in ADHD and support WMP as a promising candidate marker for dose optimisation.

References

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