Abstract
BACKGROUND: In order to elucidate the neuromodulatory mechanisms underlying therapeutic subthalamic deep brain stimulation (DBS), we here reverse-translate a methodological pipeline that integrates neurostimulation effect parameterization and molecular imaging. METHODS: (18)F-fluorodeoxyglucose positron emission tomography was performed in a human-mimicking A53T alpha-synuclein Parkinson's disease rat model and in control rats under both stimulation ON and OFF conditions, with additional CT scans acquired for each rat. Patient-derived approaches-including electrode modeling, electric field estimation, and volume of tissue activated measurement-were applied to assess stimulation effects at the stimulation spot. RESULTS: We revealed consistent hypometabolism in the ipsilateral subthalamic nucleus, substantia nigra, zona incerta, cerebellum, and entopeduncular nucleus, alongside hypermetabolism in the ipsilateral lateral caudate putamen and globus pallidus externus in A53T rats at the OFF condition. Subthalamic DBS improved motor dysfunction and induced specific metabolic responses that differentiated from controls, including increased metabolism in the ipsilateral subthalamic nucleus, substantia nigra, and zona incerta, and decreased metabolism in the bilateral primary motor and somatosensory area, lateral caudate putamen, and contralateral secondary motor area. CONCLUSIONS: Therapeutic subthalamic DBS activates the target region and modulates global brain function by restoring OFF-state hypometabolism in the ipsilateral subthalamic-substantia nigra loop and by reducing metabolic activity in the bilateral cortico-striatal circuitry. A reverse-translational pipeline is established to study stimulation-induced modulation of brain function, integrating a novel positron emission tomography template aligned with the Waxholm space of Sprague-Dawley rats.