The Effect of Exercise on Nonmotor Symptoms in Parkinson's Disease with Deep Brain Stimulation

Parkinson's disease (PD) is a progressive neurodegenerative disease, leading to waning effectiveness of oral medications and development of motor and nonmotor fluctuations, prompting use of deep brain stimulation (DBS). While DBS can provide considerable motor benefit, effects on nonmotor symptoms (NMS) are mixed. ¹ , ² Aerobic exercise (AE) has emerged as an effective therapeutic intervention in PD, improving physical fitness, motor and non‐motor symptoms. ³ Although the effects of AE on various NMS of PD have been investigated, most studies do not include participants with DBS. ⁴ Given the benefits of AE in early disease, we hypothesized exercise may be a valuable adjunct intervention for those with more advanced disease following DBS placement. We enrolled non‐exercising PD participants with subthalamic nucleus (STN) DBS in a 12‐week graduated AE pilot program and present a secondary analysis of changes in NMS.

Inclusion criteria included a diagnosis of PD, STN DBS, age >18, H&Y stage 1–3 with medication and stimulation on, and able to safely tolerate an exercise program. Regular exercisers (at least 30 min of AE ≥4 times/week) were excluded. ⁵ At the baseline visit, participants underwent fitness assessments to determine baseline percentage of heart rate max (HRmax) they were able to maintain for 30 min. Participants were trained on the exercise regimen by a PT with expertise in PD. To increase participation, acceptability, and accessibility, any modality of AE was allowed eg, treadmill, stationary bike, etc. We allowed for variability in since we used HR goals and trained participants on the Borg scale. The exercise regimen was adjusted biweekly, with a 5–10% increase in heart rate reserve (HRR) each visit until reaching a HRR of 70% of HRmax. Compliance was confirmed during biweekly phone calls between in‐person visits. NMS were assessed at baseline and at the end of the 12‐week intervention with the Movement Disorders Society‐Nonmotor Scale (MDS‐NMS), Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), Apathy Evaluation Scale (AES), and Epworth Sleepiness Scale (ESS). Median and inter‐quartile range (IQR) or mean and range were used to summarize ordinal scores and continuous variables. Count and percentage were used to summarize categorical variables. The Wilcoxon signed‐rank test was used to assess the change of score from baseline to final assessment. Effect size was reported as the change in mean score from baseline to final assessment divided by standard deviation at baseline. ⁶ The magnitude of effect sizes were interpreted as small (d = 0.2), medium (d = 0.5), and large (d = 0.8) based on commonly accepted benchmarks. All statistical tests were two sided with a significance level of 0.05.

Eleven participants were screened for participation and 9 were enrolled. One participant withdrew due to worsening anxiety and depression. Median age was 67 years (IQR 58–71), with mean disease duration since diagnosis of 8.75 years (range 3–14 years). Mean duration since DBS surgery was 3.63 years (range 1–9 years). All participants racially self‐identified as White with 33.3% as Hispanic/Latino. One (11.1%) participant was female. Most participants elected to use a combination of stationary bicycle and walking outdoors.

Eight participants completed the study. Adherence was ≥80% in 55.6% (95% CI: 21.2, 86.3) of participants (ie, at least 30 min of aerobic exercise at least 3 times per week). There were no significant changes in scores in compliant or noncompliant participants. There was a medium effect of exercise on NMS overall in compliant participants (Table 1). In compliant participants, exercise had a large effect on depression, psychosis, impulse control, and pain, and a small to medium effect in nearly all other domains of the MDS‐NMS. Of note, baseline NMS in most domains were low and sensitivity may have been limited by a floor effect. In domains with a baseline score >1 on the MDS‐NMS (cognition, sleep, pain, gastrointestinal and urinary symptoms), there were medium to large effects of exercise in compliant participants. This suggests current results may be underpowered to detect significant changes. Larger studies to evaluate effects of exercise on NMS are needed. Additionally, more symptom‐specific assessments may be valuable.

TABLE 1.

Non‐motor outcomes at baseline and post‐intervention

	Baseline	Post‐intervention	Change	P‐value	Effect size	Effect size 80% compliant
No of participants	N = 9	N = 7	N = 7		N = 7	N = 5
Depression subscore	1 (0, 2)	0 (0, 2.5)	0 (−0.5, 1.5)	0.58	0.95	1.00
Anxiety subscore	1 (0, 4)	0 (0, 1.5)	0 (−2, 0.5)	0.58	−0.28	a
Apathy subscore	0 (0, 1)	1 (0, 2.5)	1 (−0.5, 2.5)	0.28	2.34	−0.43
Psychosis subscore	0 (0, 0.2)	1 (0.5, 2.5)	0.5 (0, 3.2)	0.27	1.59	0.87
Impulse control subscore	0 (0, 1)	2 (0, 4)	0 (0, 3.5)	0.27	2.54	1.31
Cognition subscore	16 (12, 24)	15 (10, 28)	−6 (−9.5, 7.5)	>0.99	−0.05	−0.42
Orthostatic hypotension Subscore	0 (0, 2)	2 (1, 3)	2 (0, 3)	0.59	0.06	a
Urinary subscore	4 (0, 6)	3 (0, 5.5)	0 (−0.5, 1)	>0.99	−0.10	−0.57
Sexual subscore	0 (0, 0)	0 (0, 9)	0 (−6.5, 0)	0.42	−0.24	−0.39
Gastrointestinal subscore	10 (3, 12)	7 (2, 8)	−2 (−4.5, 0)	0.22	−0.45	−0.51
Sleep subscore	10 (5, 14)	8 (4, 13.5)	0 (−3.5, 3)	0.59	−0.22	−0.31
Pain subscore	8 (8, 9)	8 (4, 21.5)	4 (−2, 11)	0.25	1.40	1.88
Other subscore	6 (4, 16)	17 (6.5, 20.5)	2 (−2, 8)	0.29	0.61	0.19
MDS‐NMS total score	80 (63, 103)	65 (43.5, 116)	−12 (−21.5, 23)	>0.99	0.08	−0.43

No of subjects	N = 9	N = 8	N = 8		N = 7	N = 5
BAI	9 (3, 10)	5.5 (3, 19)	−1 (−4.5, 3.5)	0.83	0.10	−0.09
BDI	8 (4, 9)	5.5 (2.5, 10.5)	−1 (−3.2, −0.2)	0.4	−0.15	−0.11
AES	45 (38, 46)	41 (38, 46)	2 (−1.5, 4.5)	0.4	0.20	−0.20
ESS	9 (8, 13)	9 (6.5, 11)	0 (−2, 0)	0.34	−0.18	−0.23

Note: Median (IQR) reported. Wilcoxon signed‐rank test for the change of score from baseline to final assessment.

Abbreviations: IQR, interquartile range; MDS‐NMS, movement disorders society nonmotor scale; BAI, Beck anxiety inventory; BDI, Beck depression inventory; AES, apathy evaluation scale; ESS, Epworth sleepiness scale.

^a Standard deviation 0 at baseline.

Conducted in Arizona, the study faced unique recruitment challenges. Many participants were seasonal residents who could not commit to the study's duration, and the clinic's large catchment area created distance barriers for others. Additionally, the decision to exclude participants on beta‐blockers further limited eligible candidates. Future studies should take into account the specific barriers of the local populations. Furthermore, investigating flexibility in exercise selection through randomized designs will yield valuable insights into compliance with exercise regimens. There are mixed results in the literature regarding effect of AE on mood, apathy, and cognition. ⁴ The effects of AE on cognition seem to vary based on the domain assessed with possibly beneficial impact on language and executive function. ⁷ Our study assessed cognition through the MDS‐NMS, which includes six questions on cognitive function that may not capture more nuanced changes in this domain, and still found a medium effect on cognition in compliant participants. Studies are more promising in suggesting improvement in fatigue and sleep—particularly sleep time, sleep efficiency, and sleep architecture. ⁴ , ⁸ , ⁹ However, nearly all AE studies exclude participants with DBS, demonstrating the need for further research. This is particularly important as the burden of NMS increases with advanced disease, with detrimental impact on quality of life. ¹⁰ It is, however, a small pilot study and not powered to evaluate specific NMS. Future studies should include more thorough evaluations of specific NMS.

Author Roles

(1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the first draft, B. Review and Critique.

S.A.: 1A, 1B, 1C, 2A, 2C, 3A

C.H.: 2A, 2B, 2C, 3B

A.W.A.: 2C, 3B

M.O.: 1C, 3B

S.F.: 1C, 3B

F.P.: 2A, 3B

H.S.: 1A, 2C, 3B

Disclosures

Ethical Compliance Statement: This study was approved by the Dignity Health St. Joseph's Hospital and Medical Center/Barrow Neurological Institute IRB. Informed written consent was obtained from all participants. All authors confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

Funding Sources and Conflicts of Interest: This study was funded by the Davis Phinney Foundation. The authors declare there are no conflicts of interest relevant to this work.

Financial Disclosures for the Previous 12 Months: SA, MO, and SF do not have any relevant financial disclosures for the previous 12 months. AWA receives research support from the NIH NICHD. She serves as site investigator for studies sponsored by the Michael J. Fox Foundation for Parkinson's Research, NIH, NeuroNEXT, Aligning Science Across Parkinson's (ASAP) initiative, Parkinson's Study Group, Bial R&D Investments, and Rho, Inc. She has served as consultant for PhotoPharmics, Inc. and Gray Matter Technologies, LLC. HS has received research support from Transposon, NINDS, Parkinson Study Group/UCB, Parkinson's Foundation, MJFF, Jazz Pharmaceuticals, Intra‐cellular Therapeutics and Barrow Neurological Foundation. HS has served as a consultant for AbbVie, Sage/Biogen, Praxis, KeifeRx, Fasikl and Jazz Pharmaceuticals. CH is an employee of University of Arizona, has been on grants/contract in the past year from NIH, DoD, Cystic Fibrosis Foundation, and Translational Sciences, Inc. He has also received honorariums from Pennsylvania Department of Health and Florida Department of Health.

Data Availability Statement

The data that support the findings of this study may be available from the corresponding author upon reasonable request.