Parkinson's disease as a somato-cognitive action network disorder

Parkinson's disease (PD) is an incurable neurological disorder that often begins insidiously with sleep disturbances and somatic symptoms, progressing to whole-body motor and cognitive symptoms^1-5. Dysfunction of the somato-cognitive action network (SCAN)-which is thought to control action execution^6,7 by coordinating arousal, organ physiology and whole-body motor plans with behavioural motivation-is a potential contributor to the diverse clinical manifestations of PD. To investigate the role of the SCAN in PD pathophysiology and treatments (medications, deep-brain stimulation (DBS), transcranial magnetic stimulation (TMS) and MRI-guided focused ultrasound stimulation (MRgFUS)), we built a large (n = 863), multimodal, multi-intervention clinical imaging dataset. Resting-state functional connectivity revealed that the substantia nigra and all PD DBS targets (subthalamic nucleus, globus pallidus and ventral intermediate thalamus) are selectively connected to the SCAN rather than to effector-specific motor regions. Importantly, PD was characterized by specific hyperconnectivity between the SCAN and the subcortex. We therefore followed six PD cohorts undergoing DBS, TMS, MRgFUS and levodopa therapy using precision resting-state functional connectivity and electrocorticography recording. Efficacious treatments reduced SCAN-to-subcortex hyperconnectivity. Targeting the SCAN instead of effector regions doubled the efficacy of TMS treatments. Focused ultrasound treatment benefits increased when the target was closer to the thalamic SCAN sweet spot. Thus, SCAN hyperconnectivity is central to PD pathophysiology and its alleviation is a hallmark of successful neuromodulation. Targeting functionally defined subcortical SCAN nodes may improve existing therapies (DBS, MRgFUS), whereas cortical SCAN targets offer effective non-invasive or minimally invasive neuromodulation for PD.