A brain network for deep brain stimulation induced cognitive decline in Parkinson’s disease

Abstract

Deep brain stimulation (DBS) is an effective treatment for Parkinson’s disease but can be complicated by side-effects such as cognitive decline. There is often a delay before this side-effect is apparent and the mechanism is unknown, making it difficult to identify patients at risk or select appropriate DBS settings. Here, we test whether connectivity between the stimulation site and other brain regions is associated with cognitive decline following DBS. First, we studied a unique patient cohort with cognitive decline following subthalamic DBS for Parkinson’s disease (n = 10) where re-programming relieved the side-effect without loss of motor benefit. Using resting state functional connectivity data from a large normative cohort (n = 1000), we computed connectivity between each stimulation site and the subiculum, an a priori brain region functionally connected to brain lesions causing memory impairment. Connectivity between DBS sites and this same subiculum region was significantly associated with DBS induced cognitive decline (P < 0.02). We next performed a data-driven analysis to identify connnections most associated with DBS induced cognitive decline. DBS sites causing cognitive decline (versus those that did not) were more connected to the anterior cingulate, caudate nucleus, hippocampus, and cognitive regions of the cerebellum (Pfwe< 0.05). The spatial topography of this DBS-based circuit for cognitive decline aligned with an a priori lesion-based circuit for memory impairment (P = 0.017). To begin translating these results into a clinical tool that might be used for DBS programming, we generated a “heatmap” in which the intensity of each voxel reflects the connectivity to our cognitive decline circuit. We then validated this heatmap using an independent dataset of PD patients in which cognitive performance was measured following subthalamic DBS (n = 33). Intersection of DBS sites with our heatmap was correlated with changes in the Mattis dementia rating scale one year after lead implantation (r = 0.39; p = 0.028). Finally, to illustrate how this heatmap might be used in clinical practice, we present a case that was flagged as “high risk” for cognitive decline based on intersection of the patient’s DBS site with our heatmap. This patient had indeed experienced cognitive decline and our heatmap was used to select alternative DBS parameters. At 14 days follow-up the patient’s cognition improved without loss of motor benefit. These results lend insight into the mechanism of DBS induced cognitive decline and suggest that connectivity-based heatmaps may help identify patients at risk and who might benefit from DBS reprogramming.

Resting-state EEG measures cognitive impairment in Parkinson’s disease

“…Future longitudinal studies are needed to explore these aspects. Furthermore, combined with advanced therapies such as adaptive neurostimulation with longterm wireless streaming of neural recordings 47 , EEG-based assessment of cognitive function by LEAPD might help design better feedback signals or select appropriate neurostimulation settings in targeted treatments for mitigating stimulation-related cognitive side effects and identify patients at risk in future studies 9 .…”

Proceedings of the 10th annual deep brain stimulation think tank: Advances in cutting edge technologies, artificial intelligence, neuromodulation, neuroethics, interventional psychiatry, and women in neuromodulation

“…This indicates that at least some NMS may result from hypodopaminergic brain circuit dysfunctions, while others are thought to reflect neurodegenerative loss of function. Deep brain stimulation has been used to explore the pathophysiology of several NMS in a systematic approach by comparing the effect of a levodopa challenge to a targeted intervention in the basal ganglia loop on non-motor readouts ( Dafsari et al, 2018 ; Petry-Schmelzer et al, 2019 ; Reich et al, 2022 ). STN-DBS was shown to have direct impact on a central brain circuit regulating urinary bladder sensation and thereby reducing urinary urgency in PD ( Herzog et al, 2006 ).…”

Lesion network mapping for symptom localization: recent developments and future directions

“…The most direct test would be to conduct a trial positioning DBS electrodes or noninvasive brain stimulation within a hub of a network identified by LNM. However, a more efficient alternative approach would be reprogramming existing active contacts in DBS patients [37]. This way, one could test the efficacy of numerous DBS contact locations, with the hypothesis being that greater symptom improvement will be seen for contacts with connectivity profile best matching the LNM circuits.…”