Functional segregation of basal ganglia pathways in Parkinson’s disease

Abstract

Dopamine exerts modulatory signals on cortex-basal ganglia circuits to enable flexible motor control. Parkinson's disease is characterized by a loss of dopaminergic innervation in the basal ganglia leading to complex motor and non-motor symptoms. Clinical symptom alleviation through dopaminergic medication and deep brain stimulation in the subthalamic nucleus likely depends on a complex interplay between converging basal ganglia pathways. As a unique translational research platform, deep brain stimulation allows instantaneous investigation of functional effects of subthalamic neuromodulation in human patients with Parkinson's disease. The present study aims at disentangling the role of the inhibitory basal ganglia pathways in cognitive and kinematic aspects of automatic and controlled movements in healthy and parkinsonian states by combining behavioural experiments, clinical observations, whole-brain deep brain stimulation fibre connectivity mapping and computational modelling. Twenty patients with Parkinson's disease undergoing subthalamic deep brain stimulation and 20 age-matched healthy controls participated in a visuomotor tracking task requiring normal (automatic) and inverted (controlled) reach movements. Parkinsonian patients on and off deep brain stimulation presented complex patterns of reaction time and kinematic changes, when compared to healthy controls. Stimulation of cortico-subthalamic fibres was correlated with reduced reaction time adaptation to task demand, but not kinematic aspects of motor control or alleviation of Parkinson's disease motor signs. By using clinically, behaviourally and fibre tracking informed computational models, our study reveals that loss of cognitive adaptation can be attributed to modulation of the hyperdirect pathway, while kinematic depends on suppression of indirect pathway activity. Our findings suggest that hyperdirect and indirect pathways, converging in the subthalamic nucleus, are differentially involved in cognitive aspects of cautious motor preparation and kinematic gain control during motor performance. Subthalamic deep brain stimulation modulates but does not restore these functions. Intelligent stimulation algorithms could re-enable flexible motor control in Parkinson's disease when adapted to instantaneous environmental demand. Our results may inspire new innovative pathway-specific approaches to reduce side effects and increase therapeutic efficacy of neuromodulation in patients with Parkinson's disease.

Toward a unified connectomic target for deep brain stimulation in obsessive-compulsive disorder

“…Use of normative connectomes has been introduced in other clinical domains where patient-specific MRI data was unavailable, such as stroke [76][77][78] or transcranial magnetic stimulation 79 . In DBS, the technique has been applied before and -as in the present study -has led to models that could be used to predict improvement in out-of-sample data 29,30,80 . In addition to the practical advantage of being applicable in cases where patient-specific data is lacking, normative data also has the theoretical advantage of much better data quality.…”

“…Structural connectivity between VTAs and all other brain areas was calculated based on a normative connectome as similarly done in previous work 29,30,41,44,80,83 . Specifically, a wholebrain connectome based on state-of-the-art multi-shell diffusion-weighted imaging data from 985 subjects of the Human Connectome Project (HCP) 1200 subjects data release 81 was calculated in each patient using Lead-Connectome.…”

Left prefrontal impact links subthalamic stimulation with depressive symptoms

“…Whole-brain structural connectivity profiles seeding from bilateral VTAs or E-Fields were estimated using a PD group connectome that is based on publicly available data (Parkinson's patients (n=90; age 61.38±10.42, 28 female) was priorly computed 24 and has been used in context of DBS multiple times before 2,26,27 . For each patient, fibers passing through the VTA or a non-zero voxel of the E-Field were selected from this normative connectome and projected onto a voxelized volume in standard space (1mm isotropic resolution) while keeping count of the fibers traversing each voxel.…”

“…Third, we used an age-and disease-matched group connectome that was based on data acquired in PD-patients enrolled in the PPMI project, which will not account for individual structural connectivity but instead assumes similar connectivity profiles in all patients. While this assumption might not hold true in all cases, several recent studies have introduced and validated the method within DBS context 2,3,27 . Beyond practical advantages (where patient-specific connectivity data is often not available and cannot be acquired postoperatively), normative connectomes like the one used here comprise a high N of subjects which by averaging lead to high signal-to-noise levels and state-of-the-art data quality.…”

Modulating the human functional connectome using deep brain stimulation

“…This was done with the symmetric diffeomorphic registration algorithm implemented in Advanced Normalization Tools (http://stnava.github.io/ANTs/; Avants et al, 2008) using the "effective (low variance)" preset with subcortical refinement as implemented in Lead-DBS (Horn et al, 2019). This exact normalization method was recently evaluated bestperforming in a large comparative study (Ewert, Horn, et al, 2018) and STN definitions obtained by the method rivaled those of manual expert segmentations in precision.…”