Molecular Glucose Imaging Reveals Network Reconfiguration by Subthalamic Deep Brain Stimulation in Parkinsonian Rats

Abstract Background: In order to elucidate the neuromodulatory mechanisms underlying therapeutic subthalamic deep brain stimulation, we here reverse-translate a methodological pipeline that integrates neurostimulation effect parameterization and molecular imaging. Methods: ¹⁸F-fluorodeoxyglucose positron emission tomography is 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—are 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 OFF-stimulated A53T rats. Subthalamic deep brain stimulation improved motor dysfunction and induced specific metabolic responses that differentiated from controls, including increased metabolism in the ipsilateral Subthalamic nucleus, Substantia nigra, Zona incerta, and decreased metabolism in the bilateral Primary motor and somatosensory area, lateral Caudate putamen, and contralateral Secondary motor area. Conclusions: Therapeutic subthalamic deep brain stimulation activates the target region and modulates motor network activity by restoring OFF-state hypometabolism in the ipsilateral Subthalamic–Substantia nigra loop and by reducing metabolic activity in the bilateral cortico-striatal network. A reverse-translational pipeline is established to study stimulation-induced network modulation, integrating a novel positron emission tomography template aligned with the Waxholm space of Sprague-Dawley rats.