The site of stimulation moderates neuropsychiatric symptoms after subthalamic deep brain stimulation for Parkinson's disease

Abstract

Deep brain stimulation of the subthalamic nucleus for Parkinson's disease is an established advanced therapy that addresses motor symptoms and improves quality of life. However, it has also been associated with neuropsychiatric symptoms such as impulsivity and hypomania. When significant, these symptoms can be distressing, necessitating psychiatric intervention. However, a comprehensive analysis of neurocognitive and neuropsychiatric outcomes with reference to the site of subthalamic stimulation has not been undertaken. We examined this matter in a consecutive sample of 64 persons with Parkinson's disease undertaking subthalamic deep brain stimulation. Participants were assessed with a battery of neuropsychiatric instruments at baseline and at repeated postoperative intervals. A psychiatrist identified patients with emergent, clinically-significant symptoms due to stimulation. The site of the active electrode contact and a simulated volume of activated tissue were evaluated with reference to putative limbic, associative and motor subregions of the subthalamic nucleus. We studied anatomical correlates of longitudinal neuropsychiatric change and delineated specific subthalamic regions associated with neuropsychiatric impairment. We tested the ability of these data to predict clinically-significant symptoms. Subthalamic stimulation within the right associative subregion was associated with inhibitory errors on the Excluded Letter Fluency task at 6-weeks (p = 0.023) and 13-weeks postoperatively (p = 0.0017). A cluster of subthalamic voxels associated with inhibitory errors was identified in the right associative and motor subregions. At 6-weeks, clinically-significant neuropsychiatric symptoms were associated with the distance of the active contact to the right associative subregion (p = 0.0026) and stimulation within the right associative subregion (p = 0.0009). At 13-weeks, clinically-significant symptoms were associated with the distance to the right (p = 0.0027) and left (p = 0.0084) associative subregions and stimulation within the right associative subregion (p = 0.0026). Discrete clusters of subthalamic voxels associated with high and low likelihood of postoperative neuropsychiatric symptoms were identified in ventromedial and dorsolateral zones, respectively. When a classifier was trained on these data, clinically-significant symptoms were predicted with an accuracy of 79%. These data underscore the importance of accurate electrode targeting, contact selection and device programming to reduce postoperative neuropsychiatric impairment. The ability to predict neuropsychiatric symptoms based on subthalamic data may permit anticipation and prevention of these occurrences, improving safety and tolerability.

Keywords: Deep brain stimulation; Impulsivity; Neuropsychiatry; Parkinson's disease; Subthalamic nucleus.

Figures

Graphical abstract

Fig. 1

A: Timeline of participant assessments during the investigation. All participants underwent a multidisciplinary assessment at baseline prior to DBS, which included a psychiatric assessment. Participants also undertook a battery of neuropsychiatric instruments prior to DBS and at four postoperative intervals. Between postoperative assessments, participants received standard neurology and psychiatry follow up, with surveillance for the evolution of clinically-significant neuropsychiatric symptoms attributable to DBS. The interval of interest for this investigation was between the assessments at 6 and 13-weeks post-DBS. B: Statistical flowchart illustrating the modelling of candidate neuropsychiatric and anatomical variables, controlling for disease and demographic factors, following by the identification of subthalamic voxel clusters significantly associated with neuropsychiatric impairment.

Fig. 2

Image processing pipeline for the identification of electrode contact points and volume activated tissue (VAT). A: MPRAGE, FLAIR and CT images were co-registered and manually checked for accuracy, with an accurately-sited electrode indexed in the right STN. B and C: Spatial normalisation into common template space using DARTEL. D: Coronal view of the active electrode contact (asterisk) with reference to the limbic (yellow), associative (blue) and motor (maroon) subregions of the STN. E: Axial view of both electrode trajectories with reference to the STN and its subregions. Within each STN limbic = yellow, associative = blue and motor = maroon subregions. F: Oblique sagittal view with simulated VAT in each hemisphere (red sphere). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 3

Stimulation predominates in the dorsolateral aspect of the STN across the cohort. Hemispheric VATs for each participant were concatenated and thresholded to identify the highest frequency of overlapping voxels at 6-weeks (A and B) and 13-weeks (C and D). The subthalamic atlas is overlaid on a T2-weighted image in ICBM_2009b nonlinear asymmetric space. Within each STN limbic = yellow, associative = blue and motor = maroon subregions. A and C: Top 25% of overlapping voxels in the axial plane. B and D: Top 25% of overlapping voxels in the coronal plane. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 4

Clusters of subthalamic voxels in the right associative and motor subregions are associated with inhibitory deficits 6- and 13-weeks after subthalamic DBS. Within each STN limbic = yellow, associative = blue and motor = maroon subregions. At 6-weeks, a small cluster of FWE-corrected subthalamic voxels significantly associated with ELF rule violations is observed in the right motor subregion (pink). At 13-weeks this cluster is larger and predominates in the right associative subregion, extending into the right motor subregion (blue). A: Axial view at 6-weeks, B: oblique view at 13-weeks, C: axial view at 13-weeks, D: coronal view at 13-weeks. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 5

Distinct clusters of subthalamic voxels are associated with high and low likelihood of developing clinically-significant neuropsychiatric symptoms after STN-DBS for Parkinson's disease. Within each STN limbic = yellow, associative = blue and motor = maroon subregions. Green: a cluster of FWE-corrected voxels significantly associated with being a non-case can be identified in the dorsolateral aspect of the right STN. Red: a cluster of FWE-corrected voxels significantly associated with being a case are identified in the ventromedial aspect of both the right and left STN. Significant clusters are found in both the right and left STN, corresponding with the known anatomy of this nucleus, with motor representations in the dorsolateral aspect of this nucleus and cognitive-associative circuits in the ventromedial region. A: Axial view, B: Coronal view, C: Oblique view. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Supplementary Fig. 1

The distribution of original and imputed data is compared to ensure plausible values are generated. The distribution of the original, non-missing data for each variable is displayed in blue and the results of 5 datasets of imputed values (each comprised of 50 iterations of imputation) are overlaid in red. The distribution of each imputed dataset is similar to the original, non-missing data, suggesting that imputed values are plausible.

Supplementary Fig. 2

Gradient Boosting classification of post-DBS ‘cases’ using subthalamic data. At both 6 and 13-weeks the overlap of the stimulation field in relation to the right associative STN subregion (VAT.Overlap.R.Assoc) has the greatest predictive power in the training set. At 6-weeks (Fig. 2a), this anatomical variable is the dominant factor in classification. At 13-weeks, (Fig. 2b) the distance of the active electrode contact to the right and left associative subregions are also important factors.