Descoberta de alvos de estimulação cerebral não-invasiva para o Freezing da marcha na Doença de Parkinson integrando estudos de lesões, estimulação cerebral profunda e ressonância magnética individualizada

Objective 1: Elucidating Shared Connectivity of FOG-Related Brain Lesions and DBS Stimulation Sites. Although FOG is frequently associated with neurodegenerative disorders, it can emerge due to 1) brain lesions (for instance, a consequence of stroke or brain trauma) or 2) side effects of Deep Brain Stimulation. These uncommon causes of FOG share the same clinical phenomenology as neurodegenerative FOG and provide causal scenarios to understand FOG. With lesion and DBS network mapping, the 3D volume of a brain lesion or the Volume of Tissue Activated (VTA) from DBS is mapped onto a reference brain. The average activity on the location of each lesion/VTA is correlated to the activity of every other brain voxel on each individual from a normative resting state functional MRI dataset (~1000 subjects). A final network map of each lesion/VTA is obtained by averaging the results across all the individuals in the normative connectome. Three different cohorts will be explored: 1) FOG inducing lesions obtained from a systematic review of the literature, 2) PD patients with DBS-related improvement vs. no change on FOG, 3) dystonia patients with stimulation-induced FOG vs. no FOG. Each individual map, and cross-group comparison will allow us to identify key brain regions related to FOG. Objective 2: Individualized Mapping of DBS-Induced Changes in FOG Networks. While treating DBS stimulation sites as seed in connectivity analysis informs FOG networks, this strategy overlooks how changes in stimulation, such as frequency, affect individual network activity. In fact, reducing DBS frequency reduces FOG (Preliminary Data Fig. 3) with no change of the VTA. We will collect resting-state fMRI in PD patients with subthalamic nucleus Deep Brain Stimulation while undergoing both low-frequency (60Hz) and high-frequency (130 Hz) stimulation (LFS and HFS, respectively), assessing the clinical response of FOG to DBS. Patients will wear a set of wearable inertial measurement units (IMUs) fixed to different body parts to better characterize gait and FOG episodes. Whole-brain seed-based connectivity maps with VTAs as seeds will be computed in each patient for each experimental condition and the maps will be compared to identify connectivity nodes and networks that might be specific of each condition. Connectivity between VTAs and the regions of interest identified in aim 1 will be compared across the three experimental conditions. These functional connectivity maps specific of each condition will be used in a modelling approach with clinical assessment to identify state correlates of FOG severity. This map will be compared with those identified in Aim 1 to further validate functional regions and define targets for non-invasive brain stimulation. Objective 3: Testing refined brain stimulation to reduce FOG. Non-invasive neuromodulation tools can manipulate dysfunctional circuits and significantly reduce symptoms. With the identification of a shared FOG network in previous taks, optimal target selection for brain stimulation can be performed. We will conduct a proof-of-concept trial where patients will be randomized to real or sham rTMS on a preselected set of regions identified on imaging studies. We will assess longitudinal improvement of FOG by standard clinical assessments and using state-of-art inertial sensors-based kinematics. Changes in activity in motor networks of these patients will be assessed using pre and post-intervention fMRI.