Enhancing Cardiovascular Autonomic Regulation in Parkinson’s Disease Through Non-Invasive Interventions
Abstract
1. Introduction
2. Materials and Methods
2.1. Search Strategy
2.2. Search Terms
2.3. Inclusion and Exclusion Criteria
- Original, peer-reviewed human studies published between January 2014 and December 2024 to capture the most recent evidence in emerging neuromodulation protocols.
- PD patients undergoing non-invasive interventions targeting cardiovascular autonomic function.
- Quantitative assessment of BRS or related cardiovascular outcomes (e.g., heart rate variability (HRV), blood pressure responses).
- Presence of an active treatment arm (single-arm or controlled design).
- Animal or in vitro studies.
- Reviews, meta-analyses or conference abstracts without full quantitative data.
- Studies evaluating exclusively invasive or pharmacological therapies.
- Interventions lacking a defined therapeutic component (e.g., observational, or purely diagnostic studies).
- Investigations including mixed patient cohorts with comorbidities other than PD, without separate PD-specific analysis.
- Participant populations outside adult age ranges (i.e., <18 years).
2.4. Screening and Selection
- Title and Abstract Screening: Two reviewers independently assessed titles and abstracts to exclude clearly irrelevant studies (e.g., those not involving PD, non-invasive interventions, or cardiovascular outcomes). Discrepancies were resolved by discussion.
- Full-Text Review: Full texts of potentially eligible articles were obtained and evaluated against the predefined inclusion and exclusion criteria (Section 2.3). Each study was confirmed to involve adult PD patients, non-invasive therapeutic interventions, and quantitative measures of BRS or related cardiovascular outcomes.
2.5. Risk of Bias Assessment
- Selection Bias: Assessed random sequence generation and allocation concealment methods.
- Performance and Detection Bias: Evaluated blinding of participants, personnel, and outcome assessors.
- Attrition Bias: Reviewed completeness of outcome data and the handling of missing data, as reported by studies (e.g., use of intention-to-treat analyses or specific imputation methods).
- Reporting Bias: Checked for selective outcome reporting by comparing published methods with reported results.
2.6. Data Extraction and Synthesis
- Participant Characteristics: Mean age, gender distribution, sample size, disease duration, and Hoehn and Yahr classification.
- Intervention Details: Type of non-invasive modality, study design (e.g., randomized controlled trial, single arm), intervention frequency and duration, stimulation or exercise parameters, and comparator conditions.
- Outcome Measures: Primary metrics of BRS (e.g., sequence method, transfer function analysis), secondary cardiovascular autonomic indices (e.g., HRV, low-frequency/high-frequency (LF/HF) ratio), and any reported adverse events.
3. Results
3.1. Articles Retrieved
3.2. Participants Characteristics
3.3. Rehabilitation Characteristics
- Effective Stimulation (ES): A randomized clinical trial (RCT) delivered four 6 s sessions of ES (total 2 min) in a single visit [16].
- Resistance Training (RT): In a 12-week RCT, participants completed 24 sessions (twice weekly) of progressive RT [21].
- Automated Mechanical Somatosensory Stimulation (AMSS): An interventional cohort study administered AMSS over 12 days, with two sessions per week (five total sessions) [17].
- Partial Weight-Supported Treadmill Training (PWSTT): A 4-week RCT comprised 16 sessions (four times weekly, 30 min each) [20].
- Dry Immersion (DI): A 4-week controlled clinical trial involved seven 45 min DI sessions (twice weekly) [19].
- Whole-Body Cryostimulation (WBC): A one-week pilot study delivered ten 2 min WBC sessions (twice daily) [18].
- Head-Up Tilt Sleeping (HUTS): A case report described daily HUTS without a specified session duration [24].
- Rigorous study designs: Most interventions (RT, PWSTT, DI) employed randomized clinical trials to strengthen evidence quality.
- Extended training periods: Interventions such as RT and RMT spanned 12 weeks, underscoring the necessity of sustained training for meaningful autonomic adaptation.
- Protocol diversity: Session lengths varied from seconds (ES, WBC) to weeks (RMT), complicating direct efficacy comparisons but illustrating the breadth of non-invasive approaches.
- Analogous modalities: ES and AMSS shared similar mechanistic goals of somatosensory activation, while PWSTT and RT both leveraged load-bearing exercise to induce cardiovascular adaptations.
3.4. Study Designs and Protocols
3.5. Rehabilitation Effects
3.6. Statistical Analysis
4. Discussion
4.1. Limitations
- ES: Focused on stimulation site specificity without systematically varying stimulus intensity, limiting insight into dose–response relationships.
- RT: Heterogeneity in concurrent medication regimens and absence of long-term follow-up assessments constrain interpretation of sustained autonomic effects.
- WBC: Small cohort size and lack of a control group reduce statistical power and external validity; age-related variability was not explored.
- PWSTT: Participants were not selected based on OH or impaired BRS, limiting applicability to the target dysautonomia population.
- DI: Recruitment challenges and multimorbidity in older subjects precluded an age-matched control group; the individual contributions of immersion versus thermoneutral temperature (32 °C) were not disaggregated.
- RMT: Absence of randomized, blinded, sham-controlled designs and control-group adherence issues in follow-up studies introduce potential bias; baseline differences in age, disease severity, and duration may confound outcomes.
- AMSS: No control or sham-stimulation arm was included, leaving placebo effects unaddressed.
- HUTS: Case-report design and lack of standardized tilt protocols limit generalizability and dose–response characterization.
4.2. Future Directions
- Standardization and Personalization
- Develop consensus protocols with clearly defined intervention parameters (e.g., stimulation sites, frequencies, durations).
- Incorporate individualized titration of stimulation intensity or exercise load based on patient-specific physiological markers (e.g., baseline BRS, hemodynamic responses).
- Intensive, Multimodal Rehabilitation
- Design studies that combine complementary interventions (e.g., ES + RT or RMT + HUTS) to target multiple facets of autonomic dysfunction simultaneously.
- Evaluate “dose–response” effects by comparing standard versus high-intensity regimens to identify optimal training volumes for maximal autonomic adaptation.
- Mechanistic and Neuromodulatory Investigations
- Pair clinical trials with mechanistic studies (e.g., neuroimaging, autonomic reflex testing) to uncover neural circuits and molecular pathways responsible for observed benefits.
- Explore biomarkers (e.g., neurotrophic factors, inflammatory mediators) to monitor treatment response and guide protocol refinement.
- Long-Term Efficacy and Disease-Modifying Potential
- Conduct extended follow-up assessments (≥12 months) to determine the durability of autonomic improvements and their impact on clinical outcomes such as fall rates and disease progression.
- Investigate whether sustained autonomic rehabilitation can modify the trajectory of PD-related cardiovascular decline or delay the onset of disabling symptoms.
5. Conclusions
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
Abbreviations
PD | Parkinson’s Disease |
OH | Orthostatic Hypotension |
SBP | Systolic Blood Pressure |
DBP | Diastolic Blood Pressure |
BRS | Baroreflex Sensitivity |
UPDRS | Unified Parkinson Disease Rating Scale |
ES | Effective Stimulation |
RT | progressive Resistant Training |
WBC | Whole Body Cryostimulation |
PWSTT | Partial Weight Supported Treadmill Training |
DI | Dry Immersion |
RMT | Respiratory Motor Training |
HUTS | Head Up Tilt Sleeping |
AMSS | Automated Mechanical Somatosensory Stimulation |
RCT | Randomized Clinical Trial |
ECG | Electrocardiograph |
SAP | Systolic Arterial Pressure |
HRV | Heart Rate Variability |
HR | Heart Rate |
LF | Low Frequency |
HF | High Frequency |
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Author, Year | No. of Participants | Drop Out | Gender (M/F) | Mean Age (Year) | Disease Duration (Year) | BMI (Kg/m2) | Hoehn and Yahr Scale |
---|---|---|---|---|---|---|---|
1. Barbic, Galli et al., 2014 [16] | 16 | NA | 8/8 | 66 ± 3 | 13 ± 1 | 23 ± 1 | 2–3 |
2. Kanegusuku, Silva-Batista et al., 2017 [21] | 30 | 3 | 22/5 | 65 ± 8 | 8.7 ± 4.7 | 25.6 ± 3.6 | 2–3 |
3. Piterà, Cremascoli et al., 2024 [18] | 17 | 4 | 6/7 | 64.5 ± 9 | 5.4 ± 7.3 | 26.18 ± 3.91 | 1–3 |
4. Ganesan, Pal et al., 2014 [20] | 60 | NA | 46/14 | 58.15 ± 8.7 | 5.3 ± 3.4 | 23.57 ± 3.92 | 1–3 |
5. Gerasimova-Meigal, Meigal et al., 2021 [19] | 20 | NA | 13/7 | 61 ± 6 | 4.5 ± 1.1 | 27.42 ± 3.7 | 1–3 |
6. Huang, Lai et al., 2020 [22] | 75 | NA | 29/33 | 64.1 ± 9.9 | 5.4 ± 4.4 | 24.2 ± 4.35 | 2–3 |
7. Huang, Lai et al., 2021 [23] | 75 | 23 | 23/29 | 64.9 ± 9.85 | 5.25 ± | NA | 2–3 |
8. Zamunér, Shiffer et al., 2019 [17] | 23 | 7 | 6/10 | 66.2 ± 9.4 | 7 ± 3.5 | 24.2 ± 2.8 | 2–4 |
9. van der Stam, Shmuely et al., 2024 [24] | 1 | NA | M | 69.00 | 10 | NA | 2 |
Author, Year | Study Design | Intervention | Length of Delivery | No. and Frequency of Sessions | Each Session Time | Quality Rating * |
---|---|---|---|---|---|---|
1. Barbic, Galli et al., 2014 [16] | Randomized Clinical Trial | ES | 2 min | 4; 4 | 6 s | Moderate |
2. Kanegusuku, Silva-Batista et al., 2017 [21] | Randomized Clinical trial | RT | 12 weeks | 24; 2 days/week | NA | High |
3. Piterà, Cremascoli et al., 2024 [18] | Pilot Study | WBC | 1 week | 10; 2/day | 2 min | Moderate |
4. Ganesan, Pal et al., 2014 [20] | Randomized Clinical Trial | PWSTT | 4 weeks | 16; 4 days/week | 30 min | High |
5. Gerasimova-Meigal, Meigal et al., 2021 [19] | Controlled Clinical Trial | DI | 4 weeks | 7; 2/week | 45 min | Moderate |
6. Huang, Lai et al., 2020 [22] | Prospective Case–Control study | RMT | 12 weeks | 120; 2/day | 30 min | Moderate |
7. Huang, Lai et al., 2021 [23] | Prospective Case–Control study | RMT | 12 weeks | 120; 2/day | 30 min | Moderate |
8. Zamunér, Shiffer et al., 2019 [17] | Interventional Model | AMSS | 12 days | 5; 2/week | NA | Moderate |
9. van der Stam, Shmuely et al., 2024 [24] | Case Report | HUTS | ∞ | ∞; 1/day | NA | N/A |
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Suthar, A.; Zemmar, A.; Krassioukov, A.; Ovechkin, A. Enhancing Cardiovascular Autonomic Regulation in Parkinson’s Disease Through Non-Invasive Interventions. Life 2025, 15, 1244. https://doi.org/10.3390/life15081244
Suthar A, Zemmar A, Krassioukov A, Ovechkin A. Enhancing Cardiovascular Autonomic Regulation in Parkinson’s Disease Through Non-Invasive Interventions. Life. 2025; 15(8):1244. https://doi.org/10.3390/life15081244
Chicago/Turabian StyleSuthar, Aastha, Ajmal Zemmar, Andrei Krassioukov, and Alexander Ovechkin. 2025. "Enhancing Cardiovascular Autonomic Regulation in Parkinson’s Disease Through Non-Invasive Interventions" Life 15, no. 8: 1244. https://doi.org/10.3390/life15081244
APA StyleSuthar, A., Zemmar, A., Krassioukov, A., & Ovechkin, A. (2025). Enhancing Cardiovascular Autonomic Regulation in Parkinson’s Disease Through Non-Invasive Interventions. Life, 15(8), 1244. https://doi.org/10.3390/life15081244