Journal Article

Dose‐Dependent Effects of Catecholaminergic Modulation on Interference Control: Role of Baseline GABA and Glx in Cortico‐Subcortical Networks

Roessner, Veit, Stock, Ann‐Kathrin, Werner, Annett, Koyun, Anna Helin, Kuntke, Paul, Beste, Christian

2025

Overview

Cognitive control, which is critical for goal‐directed behavior, involves resolving conflicts between competing stimuli and is influenced by neurotransmitter interactions within cortico‐subcortical areas. This study investigated the relationship between baseline amino acid transmitter levels and interference control, focusing on the effects of experimentally enhancing catecholaminergic signaling. Using a double‐blind, placebo‐controlled crossover design with two dosage groups, n = 71 healthy human adults underwent proton magnetic resonance spectroscopy once to assess baseline GABA+ and Glx levels in the anterior cingulate cortex (ACC), striatum, and supplementary motor area (SMA). Participants then performed a subliminally primed flanker task inducing different scales of conflict twice while EEG was recorded: once after receiving a placebo (lactase) and once more under either low (0.25 mg/kg) or medium (0.50 mg/kg) doses of methylphenidate (MPH), which modulates the catecholaminergic and amino acid transmitter systems driving cognitive and interference control. Medium MPH doses were more effective than low doses at reducing subliminal interference effects, highlighting dose‐specific behavioral improvements. Higher striatal GABA+ levels led to better interference control at low doses, while lower ACC GABA+ and GABA+/Glx levels were associated with better interference control at medium doses, suggesting a dose‐dependent shift from striatal to ACC dominance in conflict resolution. Neurophysiological (EEG data) analyses revealed increased theta‐band (TBA) and alpha‐band activity (ABA) overlapping in the mid‐superior‐frontal and inferior‐frontal clusters under conditions of heightened cognitive control demands. The findings highlight that whether and how amino acid transmitter levels in cognitive control‐relevant regions modulate interference conflicts depends on the degree of catecholaminergic signaling. We found medium methylphenidate doses (0.5 mg/kg) to be more effective than low doses (0.25 mg/kg) at reducing subliminal interference effects, with higher striatal GABA+ levels leading to better interference control at low doses, while lower ACC GABA+ and GABA+/Glx levels led to better interference control at medium doses.

• Publisher: John Wiley & Sons, Inc
• Subject: Abscisic acid / Adult / Amino acids / Catecholamines / Central Nervous System Stimulants - administration & dosage / Central Nervous System Stimulants - pharmacology / Communications equipment / Conflict management / Conflict resolution / Conflict, Psychological / Corpus Striatum - diagnostic imaging / Corpus Striatum - drug effects / Corpus Striatum - metabolism / Cortex (cingulate) / Cross-Over Studies / Dose-Response Relationship, Drug / Double-Blind Method / EEG / Electroencephalography / Executive Function - drug effects / Executive Function - physiology / Female / Females / GABA / gamma-Aminobutyric Acid - metabolism / Glutamic Acid - metabolism / Glutamine / Glx / Gyrus Cinguli - diagnostic imaging / Gyrus Cinguli - drug effects / Gyrus Cinguli - metabolism / Humans / interference control / Lactase / Magnetic resonance spectroscopy / Male / Methylphenidate / Methylphenidate - administration & dosage / Methylphenidate - pharmacology / Motor Cortex - diagnostic imaging / Motor Cortex - drug effects / Motor Cortex - metabolism / MRS / Neostriatum / Nerve Net - diagnostic imaging / Nerve Net - drug effects / Nerve Net - metabolism / Neurophysiology / Nuclear magnetic resonance spectroscopy / Placebos / Proton magnetic resonance / Proton Magnetic Resonance Spectroscopy / Spectrum analysis / Supplementary motor area / Young Adult / γ-Aminobutyric acid