Objective: To identify the functional connectivity profile of deep brain stimulation (DBS) sites causing delayed-onset adverse effects such as gait ataxia and cognitive decline.

Background: DBS can be highly effective for essential tremor (ET) and Parkinson’s disease (PD). However, DBS settings that initially appear beneficial can be accompanied by later? side-effects such as progressive gait ataxia and cognitive decline. These side effects are thought to stem from current spread to unintended networks, which might be visualized using functional connectivity.

Methods: We utilized data from two DBS cohorts: 7 patients with ET who experienced delayed onset gait ataxia following DBS to the thalamus (Reich et al. 2017) and 10 patients with PD who experienced cognitive side effects following DBS to the subthalamic nucleus (Frankemolle et al. 2010). All patients experienced side effect improvement after DBS reprogramming without change in motor benefit. The volume of tissue-activated (VTA) was computed for each subject, before and after reprogramming, and combined with publically available human connectome data (resting-state fMRI from 1000 healthy subjects) to identify the network of regions functionally connected to each VTA. Connectivity with VTAs causing side effects were compared to connectivity with VTAs providing side effect relief using paired t-tests and a voxelwise within-subject design.

Results: VTAs causing delayed onset gait ataxia (versus VTAs in the same patients after reprogramming) showed increased functional connectivity to the primary motor areas of the cerebellum (T=6.4, p<0.001), bilateral pallidum (T=5.7, p<0.001) and paramedian ventral pons (T=10.8, p<0.001). VTAs causing cognitive side effects (versus VTAs after reprogramming) showed increased connectivity to the ponto-mesencephalic tegmentum (T=4.6, p<0.001), inferior frontal gyrus (BA 47; T=4.8, p<0.001) and anterior cingulate (T=4.3, p<0.01). All p values of the peak voxels are currently uncorrected for multiple comparisons.

Conclusions: DBS induced side effects appear to be associated with connectivity between the stimulation site and a specific network of other brain regions. Normative connectome data may be used to identify these adverse connectivity profiles based on different VTAs within the same subjects. These results may help identify patients at risk for delayed onset DBS side effects, lend insight into the mechanism of these side effects, and guide reprogramming efforts.

References: 1. Reich MM, Pozzi NG, Brumberg J, Astrom M, Volkmann J, Isaias IU. Reply: Clinical approach to delayed-onset cerebellar impairment following deep brain stimulation for tremor. Brain. 2017;140(5):e28. 2. Frankemolle AM, Wu J, Noecker AM, Voelcker-Rehage C, Ho JC, Vitek JL, et al. Reversing cognitive-motor impairments in Parkinson’s disease patients using a computational modelling approach to deep brain stimulation programming. Brain. 2010;133(Pt 3):746-61.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/connectivity-profile-of-delayed-onset-dbs-side-effects/