Precision mapping of Parkinson's Disease pathophysiology in the Somato-Cognitive Action Network’s DBS targets - PROJECT SUMMARY: Parkinson’s Disease (PD) is a neurodegenerative disease that causes symptoms such as tremor, bradykinesia, and freezing of gait, as well as sleep disturbance, autonomic dysfunction, and abulia. PD patients particularly struggle to initiate and maintain actions, which causes gait freezing, leading to falls. PD results from dysfunction in motor circuitry, including connections between subcortical structures such as substantia nigra and striatum, as well as primary motor cortex, which drives voluntary movement. Recently, our group rewrote the textbook diagrams of motor circuitry. We described a previously unrecognized Somato-Cognitive Action Network (SCAN) which is interspersed between effector-specific regions of primary motor cortex (foot, hand, mouth) (Gordon et al., Nature, 2023). The SCAN is engaged by coordinated rather than isolated actions, and it is strongly preferentially connected to other cortical regions important for action planning and control, autonomic function, and arousal. Many SCAN functions (drive to act, gait, autonomic control, arousal, motor coordination) are affected in PD. Further, clinical targets for neuromodulation in PD are connected to SCAN. Thus, SCAN dysfunction might be an important aspect of PD pathophysiology and resulting symptoms. Critically, recent technical advances in noninvasive functional neuroimaging allow us for the first time to reliably evaluate the connectivity of motor systems, including SCAN, into the deep subcortical structures most relevant for PD. Using these patient-oriented techniques, we will first test whether PD-relevant subcortical structures—including clinical targets for PD—are connected more strongly to the SCAN circuit than to effector-specific M1 foot, hand, and mouth regions. We will then test whether these subcortical-to-SCAN circuits are altered in PD patients to a greater degree than effector-specific circuits. Finally, we will test whether subcortical-to-SCAN circuits are more strongly associated with different PD symptoms than effector-specific circuits, focusing particularly on action initiation and gait freezing symptoms. This work will advance a new conceptualization of PD as a disorder of SCAN rather than of traditional effector-specific M1, which will revolutionize how we think of the disorder. Localizing PD disruption to specific portions of M1 could aid with evaluation of patients using these advanced, noninvasive fMRI techniques, and can provide precision targets of interest for other imaging modalities. Noninvasive mapping of cortico-subcortical connectivity will enable optimal target definition for neuromodulatory treatment of PD. Reconceptualizing PD as a disorder of SCAN, a system for integrated action, rather than of M1 circuits for isolated movement, may spur development of alternate symptom evaluation tools oriented around this framework. Finally, localizing M1 sites of disruption in PD opens the possibility of treating PD using cortical stimulation, a less-invasive alternative to deep brain stimulation.
