The Subcortical Cocktail Problem; Mixed Signals from the Subthalamic Nucleus and Substantia Nigra

The subthalamic nucleus and the directly adjacent substantia nigra are small and important structures in the basal ganglia. Functional magnetic resonance imaging studies have shown that the subthalamic nucleus and substantia nigra are selectively involved in response inhibition, conflict processing, and adjusting global and selective response thresholds. However, imaging these nuclei is complex, because they are in such close proximity, they can vary in location, and are very small relative to the resolution of most fMRI sequences. Here, we investigated the consistency in localization of these nuclei in BOLD fMRI studies, comparing reported coordinates with probabilistic atlas maps of young human participants derived from ultra-high resolution 7T MRI scanning. We show that the fMRI signal reported in previous studies is likely not unequivocally arising from the subthalamic nucleus but represents a mixture of subthalamic nucleus, substantia nigra, and surrounding tissue. Using a simulation study, we also tested to what extent spatial smoothing, often used in fMRI preprocessing pipelines, influences the mixture of BOLD signals. We propose concrete steps how to analyze fMRI BOLD data to allow inferences about the functional role of small subcortical nuclei like the subthalamic nucleus and substantia nigra.