Deep brain stimulation induced normalization of the human functional connectome in Parkinson’s disease

Neuroimaging has seen a paradigm shift away from a formal description of local activity patterns towards studying distributed brain networks. The recently defined framework of the 'human connectome' enables global analysis of parts of the brain and their interconnections. Deep brain stimulation (DBS) is an invasive therapy for patients with severe movement disorders aiming to retune abnormal brain network activity by local high frequency stimulation of the basal ganglia. Beyond clinical utility, DBS represents a powerful research platform to study functional connectomics and the modulation of distributed brain networks in the human brain. We acquired resting-state functional MRI in 20 patients with Parkinson's disease with subthalamic DBS switched on and off. An age-matched control cohort of 15 subjects was acquired from an open data repository. DBS lead placement in the subthalamic nucleus was localized using a state-of-the art pipeline that involved brain shift correction, multispectral image registration and use of a precise subcortical atlas. Based on a realistic 3D model of the electrode and surrounding anatomy, the amount of local impact of DBS was estimated using a finite element method approach. On a global level, average connectivity increases and decreases throughout the brain were estimated by contrasting on and off DBS scans on a voxel-wise graph comprising eight thousand nodes. Local impact of DBS on the motor subthalamic nucleus explained half the variance in global connectivity increases within the motor network (R = 0.711, P < 0.001). Moreover, local impact of DBS on the motor subthalamic nucleus could explain the degree to how much voxel-wise average brain connectivity normalized towards healthy controls (R = 0.713, P < 0.001). Finally, a network-based statistics analysis revealed that DBS attenuated specific couplings known to be pathological in Parkinson's disease. Namely, coupling between motor thalamus and motor cortex was increased while striatal coupling with cerebellum, external pallidum and subthalamic nucleus was decreased by DBS. Our results show that resting state functional MRI may be acquired in DBS on and off conditions on clinical MRI hardware and that data are useful to gain additional insight into how DBS modulates the functional connectome of the human brain. We demonstrate that effective DBS increases overall connectivity in the motor network, normalizes the network profile towards healthy controls and specifically strengthens thalamo-cortical connectivity while reducing striatal control over basal ganglia and cerebellar structures.