Unilateral and Bilateral Subthalamic Deep Brain Stimulation Differently Favour Apathy in Parkinson's Disease

Abstract

The link between subthalamic nucleus deep brain stimulation (STN-DBS) and apathy in patients with Parkinson's disease (PD) remains a controversial topic. The literature is mixed and the most supported explanation is the reduction of dopaminergic treatment. Yet a body of clinical and experimental evidences suggest that STN-DBS itself can also promote apathy in certain patients. However, the parameters accounting for apathy heterogeneity in stimulated patients along with the mechanisms underlying apathy induced by STN-DBS remain to be investigated. Whether bilateral and unilateral STN-DBS have the same influence on apathy is for instance unknown. We previously and separately showed in patients and rodents that bilateral STN-DBS can promote apathy per se. Here, we compare the effect of bilateral versus unilateral STN-DBS both in patients and in rodents. We conducted a clinical follow-up of patients with Parkinson's disease undergoing unilateral or bilateral STN-DBS and assessing apathy 3 months before and after STN-DBS. In parallel, we applied chronic and uninterrupted unilateral or bilateral DBS in rodents and extract longitudinal motivational changes with a battery of behavioural tests. While bilateral STN-DBS promotes apathy in patients and induces a loss of motivation in rodents, we found that unilateral STN-DBS did not exert such an effect both in patients and in rats. These data show that bilateral but not unilateral STN-DBS promotes apathy. This not only substantiate the induction of neuropsychiatric effects by STN-DBS but also suggest that this might be circumvented if STN-DBS is applied unilaterally instead of bilaterally.

Keywords: Parkinson's disease; apathy; motivation; subthalamic nucleus deep brain stimulation.

FIGURE 1

Bilateral but not unilateral STN‐DBS promotes apathy in Parkinson's disease patients. (A) Bilateral STN‐DBS promotes apathy, highlighted by a significant increase of the Apathy Evaluation Scale (AES) score (pre–STN‐DBS: 30.9 ± 1.2, STN‐DBS: 39.2 ± 1.8, Wilcoxon signed rank test, p = 0.002), and permit a significant Unified Parkinson's Disease Rating Scale III (UPDRS III) score improvement (pre–STN‐DBS: 31.1 ± 3.7, STN‐DBS: 14.3 ± 2.6, Wilcoxon signed rank test p = 0.007), along a significant levodopa‐equivalent daily doses (LEDD) reduction (pre–STN‐DBS: 1200.0 ± 123.1, STN‐DBS: 796.7 ± 179.0, Wilcoxon signed rank test p = 0.02). (B) Unilateral STN‐DBS does not only promote apathy, as shown by a similar AES score before and after DBS (pre–STN‐DBS: 27.4 ± 2.1, STN‐DBS: 27.1 ± 2.0, Wilcoxon signed rank test p = 0.82), but also permits a significant UPDRS III score improvement (pre–STN‐DBS: 26 ± 3.6, STN‐DBS: 11.1 ± 2.6, Wilcoxon signed rank test p = 0.0011) and LEDD reduction (1162.0 ± 160.9, STN‐DBS: 589.0 ± 91.2, Wilcoxon signed rank test, p = 0.0011). Unilateral, n = 11, bilateral, n = 12. Data shown as means ± SEM. *p < 0.05, **p < 0.01.

FIGURE 2

Bilateral but not unilateral STN‐DBS reduces reward motivation. (A) Bilateral STN‐DBS decreases reward seeking, highlighted by a decrease of the number of delivered reward (sham, baseline: 61.5 ± 4.9 rewards, STN‐DBS: 63.6 ± 6.6 rewards; paired t test, sham: t ₁₀ = 0.2964, p = 0.7730; STN‐DBS, baseline: 67.2 ± 8.6 rewards; STN‐DBS: 34.6 ± 7.6 rewards; paired t test, STN‐DBS: t ₁₂ = 4.876, p = 0.0004). (B) Bilateral STN‐DBS do not alter preference for sucrose over water in a two‐bottle choice test (sham: 91.9% ± 3.0, bilateral STN‐DBS: 90.4% ± 1.8; t test: t ₁₇ = 0.4120, p = 0.6855). (C) Unilateral STN‐DBS does not decrease the number of delivered reward in the self‐administration task (sham, baseline: 66.0 ± 11.7 rewards, STN‐DBS: 54.8 ± 12.4 rewards; paired t test: t ₅ = 0.7815, p = 0.4699; STN‐DBS, baseline: 65.0 ± 12.1 rewards; STN‐DBS: 57.9 ± 10.2 rewards; paired t test: t ₆ = 0.02022, p = 0.9845). (D) Unilateral STN‐DBS does not alter preference for sucrose over water (sham: 95.9% ± 1.0, STN‐DBS: 94.9% ± 1.4; t test: t ₁₁ = 0.5485, p = 0.5943). Bilateral: sham: n = 7–13, STN‐DBS: n = 6–13; Unilateral: sham: n = 6, STN‐DBS: n = 7. Data shown as means ± SEM. ***p < 0.001.

FIGURE 3

Bilateral but not unilateral STN‐DBS reduces basal activity. (A) Bilateral STN‐DBS tends to induce hypoactivity in rats during an open area test and decreases the total travelled distance (sham: 4184.4 ± 906.8 cm; STN‐DBS: 2179.6 ± 484.9 cm; t test: t ₁₁ = 1.853, p = 0.0908), (B) but does not alter the fine motor skills of front limbs as demonstrated by adjusting steps in the course of the stepping test (sham: 5.7 ± 0.6 adjusting steps, STN‐DBS: 6.1 ± 0.9 adjusting steps; RM 1 way ANOVA, STN‐DBS effect: F _{1, 3} = 0.6834, p = 0.4690; trials effect: F _{1, 1} = 2.533, p = 0.3571). (C) Unilateral STN‐DBS does not modify behavioural activity in the open area test (sham: 3156.9 ± 663.9 cm; STN‐DBS: 3421.0 ± 609.6 cm; t test: t ₁₁ = 0.2932, p = 0.7748), or (D) the stepping test performances (sham: 6.2 ± 0.2 adjusting steps, STN‐DBS: 6.6 ± 0.3 adjusting steps; RM 1 way ANOVA, STN‐DBS effect: F _{1, 3} = 0.9981, p = 0.3914; trials effect: F _{1, 1} = 0.9529, p = 0.5077). Bilateral: sham: n = 7–8, STN‐DBS: n = 6–11; Unilateral: sham: n = 6, STN‐DBS: n = 7. Data shown as means ± SEM.