Subthalamic Nucleus

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) or globus pallidum internus (GPi) improves motor functions in patients with Parkinson's disease (PD) but may cause a decline in specific cognitive domains. The aim of this systematic review and meta-analysis was to assess the long-term (1-3 years) effects of STN or GPi DBS on four cognitive functions: (i) memory (delayed recall, working memory, immediate recall), (ii) executive functions including inhibition control (Color-Word Stroop test) and flexibility (phonemic verbal fluency), (iii) language (semantic verbal fluency), and (iv) mood (anxiety and depression). Medline and Web of Science were searched, and studies published before July 2021 investigating long-term changes in PD patients following DBS were included. Random-effects model meta-analyses were performed using the R software to estimate the standardized mean difference (SMD) computed as Hedges' g with 95% CI. 2522 publications were identified, 48 of which satisfied the inclusion criteria. Fourteen meta-analyses were performed including 2039 adults with a clinical diagnosis of PD undergoing DBS surgery and 271 PD controls. Our findings add new information to the existing literature by demonstrating that, at a long follow-up interval (1-3 years), both positive effects, such as a mild improvement in anxiety and depression (STN, Hedges' g = 0,34, p = 0,02), and negative effects, such as a decrease of long-term memory (Hedges' g = -0,40, p = 0,02), verbal fluency such as phonemic fluency (Hedges' g = -0,56, p < 0,0001), and specific subdomains of executive functions such as Color-Word Stroop test (Hedges' g = -0,45, p = 0,003) were observed. The level of evidence as qualified with GRADE varied from low for the pre- verses post-analysis to medium when compared to a control group.

Deep brain stimulation 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 deep brain stimulation settings. Here, we test whether connectivity between the stimulation site and other brain regions is associated with cognitive decline following deep brain stimulation. First, we studied a unique patient cohort with cognitive decline following subthalamic deep brain stimulation for Parkinson's disease (n = 10) where reprogramming 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 deep brain stimulation sites and this same subiculum region was significantly associated with deep brain stimulation induced cognitive decline (P < 0.02). We next performed a data-driven analysis to identify connections most associated with deep brain stimulation induced cognitive decline. Deep brain stimulation 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 deep brain stimulation-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 deep brain stimulation programming, we generated a 'heat map' in which the intensity of each voxel reflects the connectivity to our cognitive decline circuit. We then validated this heat map using an independent dataset of Parkinson's disease patients in which cognitive performance was measured following subthalamic deep brain stimulation (n = 33). Intersection of deep brain stimulation sites with our heat map was correlated with changes in the Mattis dementia rating scale 1 year after lead implantation (r = 0.39; P = 0.028). Finally, to illustrate how this heat map 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 deep brain stimulation site with our heat map. This patient had indeed experienced cognitive decline and our heat map was used to select alternative deep brain stimulation parameters. At 14 days follow-up the patient's cognition improved without loss of motor benefit. These results lend insight into the mechanism of deep brain stimulation induced cognitive decline and suggest that connectivity-based heat maps may help identify patients at risk and who might benefit from deep brain stimulation reprogramming.

Subthalamic nucleus (STN) beta-triggered adaptive deep brain stimulation (ADBS) has been shown to provide clinical improvement comparable to conventional continuous DBS (CDBS) with less energy delivered to the brain and less stimulation induced side effects. However, several questions remain unanswered. First, there is a normal physiological reduction of STN beta band power just prior to and during voluntary movement. ADBS systems will therefore reduce or cease stimulation during movement in people with Parkinson's disease and could therefore compromise motor performance compared to CDBS. Second, beta power was smoothed and estimated over a time period of 400 ms in most previous ADBS studies, but a shorter smoothing period could have the advantage of being more sensitive to changes in beta power, which could enhance motor performance. In this study, we addressed these two questions by evaluating the effectiveness of STN beta-triggered ADBS using a standard 400 ms and a shorter 200 ms smoothing window during reaching movements. Results from 13 people with Parkinson's disease showed that reducing the smoothing window for quantifying beta did lead to shortened beta burst durations by increasing the number of beta bursts shorter than 200 ms and more frequent switching on/off of the stimulator but had no behavioural effects. Both ADBS and CDBS improved motor performance to an equivalent extent compared to no DBS. Secondary analysis revealed that there were independent effects of a decrease in beta power and an increase in gamma power in predicting faster movement speed, while a decrease in beta event related desynchronization (ERD) predicted quicker movement initiation. CDBS suppressed both beta and gamma more than ADBS, whereas beta ERD was reduced to a similar level during CDBS and ADBS compared with no DBS, which together explained the achieved similar performance improvement in reaching movements during CDBS and ADBS. In addition, ADBS significantly improved tremor compared with no DBS but was not as effective as CDBS. These results suggest that STN beta-triggered ADBS is effective in improving motor performance during reaching movements in people with Parkinson's disease, and that shortening of the smoothing window does not result in any additional behavioural benefit. When developing ADBS systems for Parkinson's disease, it might not be necessary to track very fast beta dynamics; combining beta, gamma, and information from motor decoding might be more beneficial with additional biomarkers needed for optimal treatment of tremor.

Movement-related gamma activity (> 60 Hz) in cortico-basal ganglia networks reflects pro-kinetic synchronization dynamics. While in the cortex these temporal dynamics are known to unfold spatially across topographically distributed networks, it remains unclear whether a similar spatial propagation occurs within the basal ganglia, and how such spatial encoding may contribute to both physiological and disease-related mechanisms. The subthalamic nucleus (STN) is a key integrative hub for motor processing within the basal ganglia-cortical circuitry. At rest, STN activity is topographically distributed according to its spectral frequency components. To assess whether this spectral topography is dynamic and underlies movement encoding, we dissected the spatiotemporal properties of STN local field potentials recorded intraoperatively at rest and during movement across 63 hemispheres from patients with Parkinson's disease. Using multi-contact deep brain stimulation leads, we captured high-resolution anatomical signal dynamics and contrasted a broad frequency spectrum (60-400 Hz), including high-gamma, fast-gamma, slow high-frequency oscillations and fast high-frequency oscillations. Moreover, we compared these signals to upper limb muscle activity and movement-related beta desynchronization, and examined their association with clinical impairment and levodopa responsiveness. All sub-bands exhibited significant movement-related synchronization in both the contralateral and ipsilateral STN, however, with distinct magnitude and temporal dynamics. The presence and degree of temporal locking to muscle activity and inverse relationship to movement-related beta desynchronization also varied by sub-band. Importantly, each sub-band exhibited spatially segregated hotspots located within the STN that propagate primarily along the inferior-superior axis, yet in band-specific directions. This spatial propagation evolved throughout the movement period but temporally decoupled from synchronization magnitude, indicating that spatial dynamics reflect a distinct property relevant for motor encoding. Notably, propagation of frequencies above 110 Hz inversely correlated with dopamine-related motor improvement, suggesting that exaggerated spatial dynamics may reflect compensatory mechanisms secondary to neurodegeneration. These findings demonstrated that synchronization within the basal ganglia is not a spatially static phenomenon but rather unfolds in space which expands on the current understanding of the basal ganglia mechanism. Propagation of movement-related activity may serve as a potential marker for motor impairment in Parkinson's disease, opening new avenues for spectro-behavioural research and spatially informed neuromodulation strategies.