Neurobiological effects of deep brain stimulation: A systematic review of molecular brain imaging studies

Deep brain stimulation (DBS) is an established treatment for several brain disorders, including Parkinson's disease, essential tremor, dystonia and epilepsy, and an emerging therapeutic tool in many other neurological and psychiatric disorders. The therapeutic efficacy of DBS is dependent on the stimulation target, but its mechanisms of action are still relatively poorly understood. Investigating these mechanisms is challenging, partly because the stimulation devices and electrodes have limited the use of functional MRI in these patients. Molecular brain imaging techniques, such as positron emission tomography (PET) and single photon emission tomography (SPET), offer a unique opportunity to characterize the whole brain effects of DBS. Here, we investigated the direct effects of DBS by systematically reviewing studies performing an `on' vs `off' contrast during PET or SPET imaging. We identified 62 studies (56 PET and 6 SPET studies; 531 subjects). Approximately half of the studies focused on cerebral blood flow or glucose metabolism in patients Parkinson's disease undergoing subthalamic DBS (25 studies, n = 289), therefore Activation Likelihood Estimation analysis was performed on these studies. Across disorders and stimulation targets, DBS was associated with a robust local increase in ligand uptake at the stimulation site and target-specific remote network effects. Subthalamic nucleus stimulation in Parkinson's disease showed a specific pattern of changes in the motor circuit, including increased ligand uptake in the basal ganglia, and decreased ligand uptake in the primary motor cortex, supplementary motor area and cerebellum. However, there was only a handful of studies investigating other brain disorder and stimulation site combinations (1-3 studies each), or specific neurotransmitter systems, preventing definitive conclusions of the detailed molecular effects of the stimulation in these cases.