Reduced Working Memory Precision in adult ADHD – A Window into the Abnormal Cortical Signal-to-Noise Ratio

• Applicant: Dr. Catherine Barnes-Scheufler
• Subject Area: Biological Psychiatry
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 563229130

Attention-Deficit/Hyperactivity disorder (ADHD) is characterized by cognitive and behavioral dysfunction, which on the neurophysiological level appear to result from a reduced signal-to-noise ratio (SNR) in prefrontal cortex. Stimulant medications targeting dopamine have been shown to improve behavioral symptoms as well as the cortical SNR. However, reliable biomarkers guiding stimulant dosing to decrease the risk of side-effects including cognitive impairment are lacking. The proposed project aims to investigate the suitability of visuospatial working memory precision (WMP) and the cortical SNR as behavioral and neurophysiological markers for ADHD stimulant treatment. Working memory impairment is highly relevant to functional outcome and quality of life in ADHD. Specifically, the cognitive construct of spatial WMP is closely related to prefrontal dopaminergic neurotransmission and the cortical SNR. It can be easily and reliably measured with continuous response tasks and its neurophysiological correlates have been characterized extensively. Therefore, we expect WMP to be ideally suited as the basis for the development of biomarkers for stimulant dosing in adult ADHD. To this end, we plan to conduct functional magnetic resonance imaging (fMRI) scans while patients with adult ADHD and matched control subjects perform a visuospatial WMP paradigm. Patients will abstain from stimulant medication for 24 or 48 hours, depending on their medication. A combination of population receptive field (pRF) mapping and multivariate inverted encoding models will be employed to estimate BOLD activity for memorized positions in both visual and prefrontal areas ('signal') as well as BOLD activity for other parts of the visual field ('noise') and to compute the cortical SNR. We expect to observe a significant behavioral deficit in WMP in adult ADHD, as well as a corresponding reduction in the cortical SNR due to increased noise and a decreased signal. Because ADHD is a complex genetic disorder, the impact of polygenic risk scores (PRS) and dopaminergic gene-sets on behavioral and neurophysiological parameters will be investigated. We expect ADHD-PRS and dopaminergic gene-set scores to correlate with WMP performance and the cortical SNR in both patients and controls. The results of the project could greatly aid the development of a precision medicine approach for stimulant treatment in adult ADHD. This project will combine the expertise of multiple distinguished mentors at highly renowned research institutes to provide the applicant with outstanding training environment for state-of-the-art translational neuroscience techniques: Prof. Dr. Andreas Reif, University Hospital Frankfurt, expert in adult ADHD, Dr. Rosanne Rademaker, Ernst Strüngmann Institute (ESI) for Neuroscience in Cooperation with Max Planck Society, Frankfurt for the fMRI analyses, and Prof. Barbara Franke, the Donders Institute for Brain, Cognition and Behaviour, Nijmegen, for the genetic analyses.

• DFG Programme: Research Grants
• International Connection: Netherlands
• Cooperation Partner: Professorin Barbara Franke, Ph.D.