Exploring the relationship between dystonia and STN-DBS in Parkinson's disease: insights from a single-centre cohort

Abstract

Introduction: Motor side effects may emerge after deep brain stimulation (DBS) of the subthalamic nucleus (STN) in Parkinson's disease (PD) patients. Out of 60 PD patients, we observed 16 patients displaying de novo dystonic symptoms after the implantation and 11 dystonic PD patients without benefit from the stimulation. We hypothesized that a common neural pathway may cause dystonia in both conditions. Our study aims to investigate the clinical and connectivity substrates of dystonia after STN-DBS.

Methods: We divided our cohort into four groups: 16 patients displaying dystonia after STN-DBS, 11 patients with previously known dystonia not improving after surgery, 14 patients with dystonic symptoms relieved by the stimulation and 19 controls who never experienced dystonia. MANOVA was used to compare clinical data and the distance of the active contact center from the STN border among the four groups. Finally, we reconstructed the "sour" spots for dystonic symptoms and the associated structural and functional connectivity using a Parkinsonian normative connectome.

Results: De novo dystonic and not-improved dystonic patients had a statistically significant longer PD duration before surgery (p = 0.001) and a greater active contact-STN distance (p < 0.001). Moreover, the "sour" spots were similar in both groups and structural and functional connectivity profiles were associated with brain areas correlated with dystonia pathophysiology (cerebellum, midbrain, parietal and temporal cortices).

Conclusions: We formulated a two-hit model for dystonia after STN-DBS: a clinical feature of Parkinsonian patients causes predisposing altered plasticity contributing to dystonic symptoms development when coupled with the stimulation of dystonia-related subcortical and cortical structures.

Keywords: Deep brain stimulation; Dystonia; Movement disorders; Parkinson’s disease; Side effects.

Fig. 1

Group-level reconstruction of patients’ electrodes and sour-spot exploration. All reconstructions are rendered in Lead-DBS 3D viewer with the 7 T MNI 2009b asymmetric T1 as background. Subcortical structures are identified according to DISTAL Atlas: subthalamic nucleus (orange), red nucleus (red), globus pallidum pars interna (green). Panel a: patients’ electrodes reconstruction at group level and their position relative to the subthalamic nucleus. Electrodes are color-coded according to the dystonia status: control patients are colored in red, de novo dystonic patients in yellow, improved pre-dystonic patients in blue, not-improved pre-dystonic patients in green. Panel b: No differences were found between the left and right sides in the two sour-spot. On the left, the sour-spot for de novo dystonic patients is colored in brown; on the right, the sour-spot for pre-dystonic patients without benefit from DBS is colored in yellow. Both sour-spots extend cranially from the STN surface, but the former has a more pronounced anterolateral extension in close contact with fibers negatively associated with clinical outcome in GPi-DBS for cervical dystonia (fasciculus lenticularis, in light green) as described by [19]. Note that the fibers negatively associated with clinical outcome in GPi-DBS for generalized dystonia (striatopallidofugal tracts of the posterior comb system) are located more dorsally than the two sour-spots. Panel c: Sour-spot’s relation with the subcortical structures as depicted by the Zona Incerta Atlas [20]. Both sour-spots get in touch medially with the rostral zona incerta (pink). Note that the caudal zona incerta (blue) resides dorsal to STN

Fig. 2

Structural and functional fingerprint of the two sour-spots. Panel a: Structural connectivity profile of the lateral and medial surfaces of the left hemisphere for the sour-spot of de novo dystonic patients (upper row) and not-improved pre-dystonic patients (lower row). The structural fingerprint of the two sour-spots shows prevalent connections with the brainstem, cerebellum, thalamus, motor and premotor areas, supplementary e pre-supplementary areas, part of the precuneus, the upper part of the primary somatosensory and the posterior parietal areas. Panel b: Functional connectivity profile of the lateral and medial surfaces of the right hemisphere for the sour-spot of de novo dystonic patients (upper row) and not-improved pre-dystonic patients (lower row)