Parkinson’s disease (PD) is the second most common yet complex neurodegenerative disease characterized by motor symptoms such as bradykinesia, postural instability, resting tremor, and rigidity. Additionally, non-motor symptoms such as olfactory dysfunction, sleep disturbance, and psychiatric symptoms can occur due to dopamine deficiency in the brain. These PD symptoms are caused by dopaminergic neuron impairment in the substantia nigra pars compacta (SNpc), a decrease in dopamine concentration in the basal ganglia, and an abnormal accumulation of alpha-synuclein protein in the Lewy bodies, which results in neurotoxicity [1,2]. PD is the fastest-growing neurodegenerative disorder, with an expected 14.2 million people affected worldwide by 2040 [3]. The prevalence and incidence of PD are especially increasing in rapidly aging societies such as South Korea [4].

In general, PD patients are treated with drugs such as levodopa, monoamine oxidase-B (MAO-B) inhibitors, and dopamine agonists. These drugs can alleviate Parkinsonian symptoms but cannot slow or stop the progression of PD [5]. In addition, standard oral levodopa administration involves intermittent dosing, leading to peaks and troughs in plasmatic dopamine levels that can be translated into abnormally oscillating striatal dopamine levels. This non-physiological fluctuation in dopamine levels can cause disorderly stimulation of dopamine receptors and aberrant firing patterns in striatal neurons, resulting in motor complications such as dyskinesia [6]. Moreover, dizziness, nausea, mental symptoms, hypotension, and daytime sleepiness are potential side effects of such drugs [7]. Aside from the increasing awareness of problems with existing treatments, there is currently an unmet treatment need for PD patients because there are no disease-modifying medications or definite long-term sustainable interventions for PD [8]. Therefore, various complementary and alternative medicines are being investigated to slow disease progression, relieve symptoms, and improve the quality of life in PD patients [9].

Acupuncture and exercise are two main complementary treatments being investigated in PD patients. Compared to conventional treatment alone, acupuncture combined with conventional treatment is more effective at relieving Parkinsonian symptoms and alleviating the Unified Parkinson’s Disease Rating Scale (UPDRS) score [10]. Different exercise therapies, such as aerobic, balancing, complex, strength, and walking exercises, can also help PD patients with motor symptoms [11]. Both acupuncture and exercise therapies are relatively safe and effective when carried out over a long period [12,13]. In particular, it has been suggested that exercise training may have disease-modifying effects in patients with PD [13]. In this study, we intended to achieve the simultaneous synergistic effect of acupuncture and exercise therapy by blending them into the Meridian Activation Remedy System (MARS). Although there is rigorous research on acupuncture and exercise therapy for PD patients, and their effectiveness has been proven, these treatments have been carried out only separately. To date, no studies have been conducted simultaneously on acupuncture and exercise therapies for PD patients. Therefore, in this prospective observational study, we aimed to confirm the effectiveness of MARS for alleviating motor symptoms in PD patients.

1. Study type and subjects

This single-center, prospective, single-arm, observational study was conducted at Daejeon Korean Medicine Hospital of Daejeon University. This study aimed to assess the effectiveness and safety of 8 weeks of MARS intervention in PD patients. A meta-analysis revealed that sufficient effects were achieved in various exercise intervention studies targeting PD patients, with 9-70 people per intervention group [11]. Because this was a pilot, observational study, there was no need to calculate the sample size. After taking into account the number of subjects who could be recruited during the study period, the expected dropout rate (20%), the statistical analysis, and ethical considerations, we set the target number of subjects at 13. We received approval from the Institutional Review Board (IRB) of Daejeon Korean Medicine Hospital of Daejeon University before the start of the study (IRB number: DJDSKH-21-BM-02; date of approval: 24 Feb 2021). This study was registered with the Clinical Research Information Service (CRIS) of the Korea Centers for Disease Control and Prevention (KCT0005986). Subject registration started on March 9, 2021, and ended on October 27, 2021. Participants were recruited using posters inside and outside the hospital. The study was conducted in accordance with the Declaration of Helsinki, and informed consent was obtained from all the subjects involved in the study.

2. Patient selection

PD patients with Hoehn and Yahr stages of 3 or less who could understand and sign a written informed consent form were considered eligible for enrollment in this study. Patients with Parkinson’s plus syndromes, neuropsychiatric disorders, or unstable medical conditions were excluded from the study. The detailed inclusion and exclusion criteria were as follows:

Inclusion criteria

• Age ≥ 20 years

• Patients diagnosed with PD according to the UK Parkinson’s Disease Society Brain Bank criteria and have parkinsonian motor symptoms (bradykinesia combined with tremor, rigidity, and/or postural instability).

• Hoehn and Yahr stage ≤ 3 [14]

• Korean version of the Mini-Mental State Examination (MMSE-K) score ≥ 24 [15]

• Patients who voluntarily consented to the written informed consent form by themselves or by his/her legal representative.

Exclusion criteria

• Patients who are diagnosed with or suspected of having Parkinson’s plus disease.

• In the case of a generally unstable medical condition (according to the standard work instructions, the research doctor judges based on the results of vital signs and clinical pathology).

• Those whose aspartate transaminase (AST) or alanine transferase (ALT) blood level is 3 times or more than the normal upper limit.

• Patients under treatment for uncontrolled hypertension (over 160/100 mmHg).

• Having a history of neuropsychiatric disorder.

• Having an allergic reaction to stainless steel needles and metals.

• Participation in other clinical research for at least 4 weeks.

• Those whom the researcher deems unsuitable for this study.

• Expectant mother, lactating woman, fertile woman.

3. Research methods

Volunteers who expressed interest in participating in this study were informed about the study’s purpose, treatment method, testing method, procedure, compliance, side effects, inconveniences, compensation, confidentiality, rights, and precautions. Only those who manually signed the written informed consent form could participate in the study. Applicants were chosen and qualified based on the inclusion and exclusion criteria using a demographic survey, vital sign measurement, medical history, treatment history survey, clinical pathology test, and Korean version of the Mini-Mental State Examination (MMSE-K).

The selected subjects were treated with the MARS intervention twice a week for 8 weeks, a total of 16 times, for 20 minutes per session. The Movement Disorder Society-Sponsored Revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part I, II, III, IV, functional near-infrared spectroscopy (fNIRS), GAITRite, 10 M walk test (10MWT), timed up and go test (TUG), 360-degree turn test, Berg Balance Scale (BBS), Fall Efficacy Scale (FES), EuroQol five-dimensional scale (EQ-5D), and Parkinson’s Disease Questionnaire-39 (PDQ-39) scores were measured at the first visit and 8 weeks after the last visit (Supplementary Table S1). The acupoints used in this study were constructed based on the clinical practice guidelines for PD developed by the Center for Clinical Practice Guidelines of Korean Medicine of the National Institute for Korean Medicine Development in 2020 [16].

4. MARS intervention

The MARS intervention comprised intradermal acupuncture and 20 minutes of exercise. First, acupoints LI4, SI3, TE5, PC6, ST36, BL60, GB34, and KI3 were stimulated by attaching 0.18 × 1.3 × 1.5 mm intradermal acupuncture (T-press needle DB130, Dongbang Medical, Boryeong, South Korea) to the patient’s skin. Supplementary Table S2 shows how the acupuncture treatment was carried out in accordance with the STRICTA (2010) guidelines [17]. After acupuncture, a 20-minute exercise sequence was applied (Fig. 1). The detailed MARS intervention method was described in another paper [18].

Figure 1. Examples of actions of MARS (Meridian Activation Remedy System). All acupoints are located in the arms and legs. Exercises consist of actions that activate the (A) three hand-yin meridians, (B) three hand-yang meridians, (C) three foot-yin meridians, and (D) three foot-yang meridians.

Typically, patients with PD complain of both motor and non-motor symptoms. To improve the patient’s non-motor symptoms, such as sleep disturbance, constipation, and digestive symptoms, three hand-yin meridians (shǒu sān yīn jīng) and three hand-yang meridians (shǒu sān yáng jīng) were stimulated. The hand reached forward alternately in internal and external rotation, and the hand reached upward alternately in internal and external rotation 10 times each to stimulate the three hand-yin meridians (Fig. 1A). Next, to stimulate the three hand-yang meridians, punching movements diagonally left and right were performed ten times each (Fig. 1B). Then, to improve motor symptoms such as gait disturbance and postural instability, exercise sequences were used to stimulate the three foot-yin meridians (zú sān yīn jīng) and three foot-yang meridians (zú sān yáng jīng). For the three-foot-yin meridians exercise, the left and right legs were alternately lifted with the outer and inner sides facing up 10 times (Fig. 1C). For the three-yang meridians exercise, forward and jegi kick motions were performed 10 times each (Fig. 1D) [19].

5. Evaluation

The primary outcome variable was the UPDRS III score, and the secondary outcome variables were the UPDRS I, II, IV, fNIRS, GAITRite, 10MWT, TUG, 360-degree turn test, BBS, FES, and EQ-5D scores. All assessments were performed at the first visit (baseline) and after 8 weeks of MARS intervention (endpoint). For safety evaluation, clinical laboratory examinations were performed at baseline and the endpoint, and adverse reactions were investigated at every visit. The detailed schedule of the study is shown in Supplementary Table S1.

1) MDS-UPDRS

The UPDRS is the most widely used scale in clinical practice as a tool to determine the degree of disability in PD patients. In this study, the MDS-UPDRS was used. The MDS-UPDRS Part I (possible range: 0-52, a higher score indicates a worse clinical progression, 0-10: mild, 11-21: moderate, 22+: severe) evaluates the non-motor impact of PD on patients’ daily living experiences; Part II (possible range: 0-52, a higher score indicates a worse clinical progression, 0-12: mild, 13-29: moderate, 39+: severe) assesses the motor impact of PD on patients’ daily living experiences; Part III (possible range: 0-132, a higher score indicates a worse clinical progression, 0-32: mild, 33-58: moderate, 59+: severe) examines motor signs; and Part IV (possible range: 0-24, a higher score indicates a worse clinical progression, 0-4: mild, 5-12: moderate, 13+: severe) evaluates the degree of motor complications [20,21].

2) fNIRS

fNIRS (NIRScout 1624, NIRx Medical Technology, Berlin, Germany) was used to observe cortical hemodynamic changes. The arrangement of 15 sources and 15 detectors was based on the international 10–20 electrode system. In this study, we wanted to explore the effectiveness of a MARS intervention for improving motor symptoms in PD patients, so we measured the prefrontal, frontal, and motor cortex regions of the patients. Motor symptoms in PD patients are thought to be caused primarily by dopaminergic cell damage in the substantia nigra of the midbrain, but fNIRS can only measure the cortical region. As a result, we focused on the frontal and motor cortex regions, which are associated with motor output and control, among the areas that can be measured with fNIRS equipment. The optode configuration resulted in 47 channels that included the motor and prefrontal cortices. Starting from standing, standing for 30 seconds, and walking for 30 seconds were repeated for a total of 150 seconds on a treadmill. The data were analyzed using the open-source Homer3 (v1.33) package (http://github.com/BUNPC/Homer3). After converting the raw data to optical density data, motion artifacts were removed using the Savitzky–Golay filtering method with default parameters. Then, the optical density was bandpass filtered between 0.01 and 0.5 Hz. Subsequently, the optical density was converted to concentration data using the modified Beer–Lambert law. Finally, the hemodynamic response function in each channel was estimated with GLM (‘hmrR_GLM’) for –2 to 35 sec of treadmill walking, and the total average of each hemodynamic response was calculated for each region of interest. The concentration data were reconstructed on atlas anatomy utilizing the AtlasViewer (v2.16) Toolbox [22]. T-statistic maps were plotted onto a standard brain template for group analysis. Differences in oxyhemoglobin concentrations were considered significant at an uncorrected p < 0.05.

3) Gait analysis

GAITRite is a gait analysis device that measures spatiotemporal gait variables by measuring the pressure of foot touches. When walking on a slab with a sensor, spatiotemporally quantified values of each variable can be obtained, and the information obtained in this way is known to show similar accuracy as the results of 4D gait analysis [23]. First, to exclude the effects of acceleration and deceleration at the start and end of walking, a 3.66 M long GAITRite^® system (CIR System Inc., USA) device was placed in the center during 10 M walking, and the subject was asked to walk at the same speed as usual. This process was carried out 3 times. Simultaneously, the time to walk a 10 M straight line at a normal speed was measured. This 10MWT was also carried out 3 times. Through GAITRite, the temporal gait variables step time, cycle time, stance time, swing time, single support time, spatial gait variables such as step length and stride length, and variables representing the ratio of the gait cycle such as single support phase, double support phase, swing phase, stance phase, cadence (steps per minute) and gait velocity (walking speed) were measured. The outcome variables for the GAITRite parameters were evaluated using paired t-tests. The level of significance for determining statistical significance was set at 0.05.

4) TUG

The TUG test measures balance and mobility. It is a test used to evaluate gait to predict fall risk [24]. It is also a test method for confirming dynamic balance and functional gait [25]. The patients sat on a chair with armrests, stood up, walked a distance of 3 meters, circled the return sign, returned to the chair by walking a distance of 3 meters again, and sat down. The procedure was repeated 3 times to measure the average time the patient took from standing up to returning to the chair and sitting down. The TUG score is associated with the UPDRS score in PD patients. In addition, according to Yoo et al.’s research, TUG time can be used as a prodromal marker to predict the risk of PD development. The average TUG time in the 66-year-old Korean group was 8.3 ± 2.8 seconds, and a TUG time of 10 seconds was in the 74.2th percentile. There were more PD patients in the group with a TUG time of 10 seconds or more than in the group with a TUG time of less than 10 seconds [26].

5) 360° turn test

A normal elderly person takes fewer than six steps to turn in place, whereas PD patients take up to 20 steps due to freezing and motor instability [27]. As a result, the number of steps required to turn 360 degrees in place was measured in this study to assess the motor ability of the patients. The procedure was repeated three times to calculate the average value.

6) BBS

The BBS (possible range: 0-56, a higher score indicates the ability to maintain good balance, 0-20 indicates balance impairment, 21-40 indicates acceptable balance, 41-56 indicates good balance) is a test used to assess balance ability. It comprises 14 items that assess static and dynamic balance in daily life [28]. Each item is scored from 0 to 4, with a higher score indicating a better balance function.

7) FES

The FES (possible range: 10-100; a higher score indicates that the respondent is more confident and capable of avoiding falls) is a scale used to assess people’s fear of falling in everyday situations. It evaluates the efficacy of falls for home activities. It contains ten items scored from 1 to 10 [29]. The lower the score for each item on a scale of 1 to 10, the greater the respondent’s confidence and fall efficacy.

8) EQ-5D

The EuroQol group developed the EQ-5D, a tool for measuring health-related quality of life. It is designed to assess five dimensions of exercise ability, namely, self-management, daily activities, pain and discomfort, anxiety, and depression (each number is summed to produce a total score between 5 and 15, with a higher total score indicating lower quality of life), and overall health according to the visual analog scale (VAS, score between 0 and 100) [30]. Each of the five dimensions is worth 1 to 3 points, and a higher score indicates a lower health-related quality of life, while a higher VAS score indicates a higher health status.

9) PDQ-39

The PDQ-39 (possible range: 0-156; the higher the score is, the more severe the decline in PD patients’ quality of life) is a widely used clinical tool for assessing the quality of life of PD patients [31]. The PDQ-39 assesses the overall quality of life of PD patients. The PDQ-39 consists of 8 items and 39 questions, including 10 questions about movement, 6 questions about daily activities, 6 questions about emotional well-being, 4 questions about stigma, 3 questions about social support, and 3 questions about physical discomfort [32]. Each item is scored from 0 to 4, with higher scores indicating lower quality of life.

6. Statistics

Continuous variables are expressed as the mean and standard deviation (mean ± SD), and the statistical significance level was set at 0.05. To evaluate the fNIRS and GAITRite outcomes, t-statistics were used. The Wilcoxon signed-rank test was used to evaluate the remaining outcome variables (primary outcome variable: MDS-UPDRS Part III; secondary or exploratory outcome variables: MDS-UPDRS Parts I, II, IV, 10MWT, TUG, 360-degree turn test, BBS, FES, EQ-5D, EQ-5D (VAS), and PDQ-39) using R software version 4.2.1 (R Foundation for Statistical Computing, Vienna, Austria). Graphs were drawn using Python version 3.7.0 (Python Software Foundation, Wilmington, DE, United States).

1. Demographic characteristics

Four out of seventeen people who applied for this study dropped out during the screening process, leaving 13 enrolled. Six (46.2%) were male, seven (53.8%) were female, and the average age was 63.8 ± 8.0 years. All 13 participants completed the 8-week MARS intervention successfully. The demographic characteristics of the participants are shown in Table 1.

base. = baseline; end. = endpoint; HY = Hoehn and Yahr stage; LED = Levodopa equivalent dose; MDS-UPDRS = The Movement Disorder Society-Sponsored Revision of the unified Parkinson’s Disease Rating Scale; PD = Parkinson’s disease..

&md=tbl&idx=1' data-target="#file-modal"">Table 1

Demographic characteristics.

Subject number	Gender/age	HY	PD duration (years)	LED (mg)	Comorbidity	MDS-UPDRS II (base.)	MDS-UPDRS II (end.)	MDS-UPDRS III (base.)	MDS-UPDRS III (end.)
1	F/60s	2	4	200	Depression, osteoarthritis	31	15	31	8
2	M/60s	2	1	0	N/A	3	2	17	4
3	F/50s	1	8	440	Hypertension	17	5	3	3
4	F/60s	2	11	870	N/A	11	16	21	17
5	F/60s	1	7	830	N/A	17	10	18	7
6	F/50s	2	7	1280	Panic disorder	9	12	12	5
7	M/70s	2	7	525	Insomnia, constipation	6	8	22	9
8	F/50s	2	4	460	N/A	24	16	8	2
9	F/60s	2	4	0	Depression, osteoarthritis	23	10	39	18
10	M/70s	2	5	925	Diabetes	11	18	15	10
11	M/70s	1	4	820	N/A	16	16	12	8
12	M/50s	1	8	0	N/A	5	9	18	6
13	M/70s	2	8	250	Benign prostatic hyperplasia	27	33	44	18

base. = baseline; end. = endpoint; HY = Hoehn and Yahr stage; LED = Levodopa equivalent dose; MDS-UPDRS = The Movement Disorder Society-Sponsored Revision of the unified Parkinson’s Disease Rating Scale; PD = Parkinson’s disease..

2. Effectiveness evaluation

The results of the effectiveness evaluation are shown in Supplementary Table S3.

1) MDS-UPDRS

The MDS-UPDRS scores of the subjects before and after the intervention were compared. The subjects’ average MDS-UPDRS Part I scores before and after 8 weeks of MARS intervention were 16.0 ± 8.1 and 16.1 ± 8.0, respectively (p > 0.05, Fig. 2A). The nonmotor impact of PD on patients’ daily living experiences did not change significantly after 8 weeks of treatment. Before and after 8 weeks of intervention, the subjects’ average MDS-UPDRS Part II scores were 15.4 ± 8.9 and 13.1 ± 7.6, respectively (p > 0.05, Fig. 2B). After 8 weeks of treatment, the motor impact of PD on the patients’ daily living experiences did not change significantly. The subjects’ average MDS-UPDRS Part III scores significantly improved from 20.0 ± 11.8 to 8.8 ± 5.5 after 8 weeks of MARS intervention (p = 0.003, Fig. 2C), indicating that there was a significant improvement in motor signs in the patients. Finally, before and after 8 weeks of treatment, the subjects’ average MDS-UPDRS Part IV scores were 7.3 ± 4.0 and 5.0 ± 3.3, respectively (p > 0.05, Fig. 2D). The degree of motor complications did not change significantly after 8 weeks of treatment.

Figure 2. Effectiveness evaluation of MARS using MDS-UPDRS. The subjects’ (n = 13) (A) average (mean ± SD) MDS-UPDRS Part I scores before (16.0 ± 8.1) and after (16.1 ± 8.0) 8 weeks of MARS intervention, p > 0.05. (B) Average MDS-UPDRS part II scores before (15.4 ± 8.9) and after (13.1 ± 7.6) 8 weeks of intervention, p > 0.05. (C) Average MDS-UPDRS part III scores before (20.0 ± 11.8) and after (8.8 ± 5.5) 8 weeks of intervention, **p = 0.003. (D) Average MDS-UPDRS part IV scores before (7.3 ± 4.0) and after (5.0 ± 3.3) 8 weeks of intervention, p > 0.05. MARS = Meridian Activation Remedy System; MDS-UPDRS = The Movement Disorder Society-Sponsored Revision of the unified Parkinson’s Disease Rating Scale.

2) fNIRS

Fig. 3 shows cortical activation and the average hemodynamic changes in oxyhemoglobin (HbO) and deoxyhemoglobin (HbR) in the cerebral cortex measured by fNIRS. Compared to baseline, the HbO concentration increased in the peripheral channels (10, 11, 12, 13, 19, 22, and 28) after 8 weeks of MARS intervention. Although cortical activation increased, the difference was not statistically significant (p > 0.05, Fig. 3A). Similarly, in the mapping results, high cortical activity was shown in the S4 and D7 regions, which are areas related to walking, and the prefrontal cortex region, which are areas related to decision making, after MARS intervention compared to baseline. However, the results were not statistically significant (p > 0.05, Fig. 3B).

Figure 3. Cortical activation measured by fNIRS. (A) Compared with the baseline, HbO concentration in the time series increased in the above channels (10, 11, 12, 13, 19, 22, and 28) after 8 weeks of intervention, however, without statistical significance (p > 0.05). (B) Mapping changes in the cerebral cortex. After 8 weeks of MARS intervention, cortical activities near S4 and D7 regions were higher compared to the baseline. The results, however, were not statistically significant (p > 0.05). fNIRS = functional near-infrared spectroscopy.

3) Gait analysis

GAITRite parameters, which were measured a total of 3 times per subject per visit, were averaged and then compared using paired t tests. There was no significant difference in the gait parameters before and after the intervention when measured in the middle of the 10-meter walk. Meanwhile, the subjects’ 10MWTs at baseline and the endpoint were 9.5 ± 1.8 seconds and 8.7 ± 1.3 seconds, respectively. After treatment, the 10MWT of the patients was significantly reduced (p = 0.040, Fig. 4A). Unlike the significant change in the 10MWT, the absence of a velocity change in the GAITRite test indicated that there was no difference in velocity in the middle of the gait cycle, but there was a change in velocity either at the start or at the end of the gait cycle after treatment.

Figure 4. Effectiveness evaluation of MARS using other secondary outcomes. Average changes (mean ± SD) in (A) 10-meter walk test time (10MWT); (9.5 ± 1.8 seconds at the baseline, 8.7 ± 1.3 seconds at the endpoint, *p = 0.040). (B) Timed up and go time (TUG); (9.8 ± 1.8 seconds at the baseline, 8.9 ± 1.4 seconds at the endpoint, *p = 0.040). (C) 360-degree turn test (8.5 ± 1.7 steps at the baseline, 7.9 ± 1.6 steps at the endpoint, p > 0.05). (D) Berg balance scale score (BBS); (55.7 ± 0.5 at the baseline, 55.9 ± 0.3 at the endpoint, p > 0.05). (E) Falls efficacy scale score (FES); (77.8 ± 21.8 at the baseline, 87.7 ± 15.9 at the endpoint, p > 0.05). (F) EuroQol five-dimensional questionnaire 5 dimensions score (EQ-5D); (9.7 ± 3.5 at the baseline, 9.2 ± 2.1 at the endpoint, p > 0.05). (G) EuroQol five-dimensional questionnaire VAS score (EQ-5D [VAS]); (61.5 ± 16.7 at the baseline, 63.8 ± 15.1 at the endpoint, p > 0.05). (H) Parkinson’s Disease Questionnaire-39 score (PDQ-39); (52.2 ± 26.1 at the baseline, 45.0 ± 25.3 at the endpoint, p > 0.05) of 13 PD patients as a result of 8-week MARS intervention. MARS = Meridian Activation Remedy System.

4) TUG

The subjects’ TUG time was 9.8 ± 1.8 seconds at baseline. After 8 weeks of MARS, the subjects’ TUG time was 8.9 ± 1.4 seconds. The TUG time was significantly reduced after 8 weeks of MARS intervention (p = 0.040, Fig. 4B).

5) 360° turn test

The number of steps during the 360-degree turn test was 8.5 ± 1.7 and 7.9 ± 1.6 before and after 8 weeks of MARS intervention, respectively. The number of steps to turn 360 degrees decreased after the treatment, but the difference was not statistically significant (p > 0.05, Fig. 4C).

6) BBS

The BBS score before the MARS intervention was 55.7 ± 0.5, and the BBS score after 8 weeks of MARS intervention was 55.9 ± 0.3, indicating no significant change (p > 0.05, Fig. 4D). Regarding BBS scores, four patients in Visit 1 had 55 points, and all others had 56 points, while one patient in Visit 16 had 55 points, and all others had 56 points. Because the maximum BBS score was 56 points, the patients in this study had normal initial balance ability.

7) FES

The FES score before the MARS intervention was 77.8 ± 21.8, and the score after the MARS intervention was 87.7 ± 15.9. There was an increase in the FES score after MARS, but it was not statistically significant (p > 0.05, Fig. 4E).

8) EQ-5D

The five dimensions of the EQ-5D and the VAS score at baseline were 9.7 ± 3.5 and 61.5 ± 16.7, respectively. The five dimensions and VAS scores after 8 weeks of MARS intervention were 9.2 ± 2.1 and 63.8 ± 15.1, respectively. There were no significant changes in the five dimensions or VAS scores before and after MARS treatment (p > 0.05, Fig. 4F and 4G).

9) PDQ-39

The PDQ-39 score before MARS was 52.2 ± 26.1, and the PDQ-39 score after 8 weeks of MARS was 45.0 ± 25.3. There was a decrease in the PDQ-39 score after MARS, indicating some improvements, but the difference was not statistically significant (p > 0.05) (Fig. 4H).

3. Safety evaluation

Adverse reactions due to MARS were investigated at each visit. Among a total of 13 subjects, none had MARS-related adverse reactions. There were 0 subjects with abnormal values in clinical pathology tests performed at screening and after the end of the study (Supplementary Table S4).

1. Summary of findings

To summarize, MARS intervention twice weekly for 8 weeks improved motor symptoms and functions in PD patients. However, due to the small number of study participants, no significant effect on cerebral cortex hemodynamics or quality of life was found in PD patients. As a limitation of this study, patients were allowed to use any other combination of treatments to reflect the characteristics of the real clinical environment, making it difficult to determine whether the effects of improving motor symptoms and functions observed in this study were the effects of MARS intervention or the results of the other treatments. In addition, due to the small number of subjects, there was no significant range of score deviation when evaluating the effect of MARS intervention on PD. Moreover, the lack of a control group is another limitation of this study. However, the average -11.2-point improvement in the MDS-UPDRS Part III score of the patients after the intervention was encouraging. For detecting minimal improvement, the minimal clinically important difference (MCID) for the MDS-UPDRS Part III is estimated to be -3.25 points [33]. In addition, 10.7 to 10.8 points on the UPDRS Part III score indicate a large clinically important difference [34]. Therefore, MARS intervention was effective in alleviating motor signs in PD patients.

Due to the small sample size of 13 people in this study, the results for each individual are also displayed in a bar chart for the MDS-UPDRS Part III, TUG time, and 10MWT, where significant changes were observed (Supplementary Fig. S1). It was confirmed that the overall values for all three variables measured in Visit 16 decreased compared to those measured in Visit 1. In the case of the MDS-UPDRS Part III, it was confirmed that all subjects’ scores improved at Visit 16, with the exception of one subject (PD Patient 3), who initially had low scores from baseline (Visit 1). Furthermore, patients with higher MDS-UPDRS Part III scores and more severe motor symptoms at baseline demonstrated greater improvement in scores at Visit 16. As a result, for patients who started with low MDS-UPDRS Part III scores, there may not have been a large difference in the before-and-after comparison because the room for improvement was initially limited.

2. Detailed findings

In this study, the MDS-UPDRS, the most widely used scale in clinical trials, was used to evaluate the degree of disability in PD patients. The UPDRS Part I assesses the non-motor impact of PD on patients’ daily living experiences, Part II examines the motor impact of PD on patients’ daily living experiences, Part III assesses motor signs, and Part IV evaluates the degree of motor complications [20]. We used the UPDRS Part II and Part III scores as primary endpoints to evaluate the effect of MARS intervention on the motor symptoms of PD patients. After 8 weeks of MARS intervention, there were improvements in UPDRS Part II scores, but the changes were not statistically significant (Table 1 and Fig. 2B). After 8 weeks of MARS intervention, a significant improvement in the score on the UPDRS Part III, an objective motility test, was observed from 20.0 ± 11.8 to 8.8 ± 5.5 (Table 1 and Fig. 2C). Therefore, after 8 weeks of MARS, there was an objective improvement in motor function in PD patients. In the case of the UPDRS Part II, which surveys motility symptoms in daily life, the lack of statistical significance despite a change in score can be attributed to the small number of study subjects. In addition, since the recruited subjects were at an early stage of PD progression (Hoehn and Yahr Scale stage 1 or 2), there were no significant differences in UPDRS Part I and Part IV scores before and after MARS intervention. There were only a few subjects who reported motor symptom complications. As a result, there was little room for change in the UPDRS Part I and Part IV scores before and after the MARS intervention in this study. In future studies, it will be necessary to observe changes in the UPDRS Part I and Part IV scores as a result of MARS intervention in patients with more severe PD.

Neuronal activation causes an imbalance in the supply and use of oxygen, which increases the HbO concentration in the blood while decreasing the HbR concentration [35]. After 8 weeks of MARS, the fNIRS results in the time series showed relatively high activation in the areas around S4 and D7 related to walking compared to that at baseline. Furthermore, the mapping revealed a relatively high activation level in the prefrontal cortex region. The difference, however, was neither large nor statistically significant. A previous study using fNIRS to confirm the effects of acupuncture and exercise therapy for PD revealed activation of the cortical region related to walking after treatment [36,37].

Furthermore, the acupoints used in this study were restricted to the arms and legs. The exercise therapy used in this study also differed from those used in previous studies. It was a meridian-stimulating exercise rather than the more commonly studied gait, strength, and aerobic exercises. As a result, while the results from fNIRS measurements were not statistically significant, the improvement in hemodynamic changes was somewhat confirmed. In the future, MARS intervention must be developed as a more personalized treatment for patients, and fNIRS tasks must also be developed into a suitable form for evaluation so that studies can be conducted to observe cortical hemodynamic changes in PD patients after personalized treatment.

In this study, the GAITRite test, 10MWT, TUG test, 360-degree turn test, BBS, and FES were used to observe changes in the motor function of PD patients after MARS intervention. The 10MWT and TUG showed significant changes after 8 weeks of MARS treatment. For instance, the patients’ TUG time at baseline was 9.8 ± 1.8 seconds, which was slightly greater than the average TUG of 66-year-olds in Korea (8.3 ± 2.8 seconds), but this was not a severe condition. The patients’ TUG time improved to 8.9 ± 1.4 after 16 visits, which was still higher than the average TUG value for 66-year-olds in Korea but could be considered an improvement over the baseline [26]. The results suggested that the gait speed, balance ability, and functional gait of PD patients improved after treatment. On the other hand, there was no significant difference before or after the MARS intervention in any of the GAITRite measurements. Nelson et al. [38] suggested that the heel-heel base of support (H-H BoS) of PD patients is generally wider than that of non-impaired individuals. However, the patients enrolled in this study were at a relatively early stage of PD progression, and their H-H BoS was closer to that of the non-impaired individuals than that of the PD patients in Nelson et al.’s study. It is possible that there was little room for change in the GAITRite parameters before and after the MARS intervention in this study.

In previous studies [37,39], PD patients who received acupuncture and exercise therapy each showed significant improvements in cadence in GAITRite measurements. However, in this study, there was no significant difference in cadence after the MARS intervention. The insignificant velocity change during the 3.66 M-long walk on the GAITRite device, in contrast to the significant change in the 10MWT, indicates that there was no difference in velocity in the middle of the gait after treatment, but there was a change in velocity at the start or end of the gait. Gait freezing is common in PD patients, especially during the first three steps of gait initiation [40]. This confirmed that gait freezing at the start and end of gait, which is a gait characteristic of PD patients, improved with MARS intervention. Further studies comparing the characteristics of gait initiation, middle gait, and gait termination, as well as the effect of MARS intervention on each section of gait in PD patients, are necessary.

There was an improvement in the scores on the 360-degree turn test and the FES after 8 weeks of MARS intervention, but the differences were not statistically significant. This can be attributed to the small number of study subjects and the large variation in the numerical values. In addition, because the subjects’ BBS scores at baseline were close to perfect (55.7 ± 0.5), there was only a small amount of room for improvement. To observe a significant improvement in BBS scores after MARS intervention, a study on PD patients with more impaired balance ability will be required in the future.

The PDQ-39 and EQ-5D questionnaires were used to assess the study subjects’ changes in quality of life. The EQ-5D, which assesses general health-related quality of life, showed almost no change. In contrast, the PDQ-39, which assesses PD-specific quality of life, did not show statistical significance but did show some change. MARS intervention could improve patients’ quality of life, particularly in PD-specific areas. However, due to the large intersubject variation in the PDQ-39 score in this study, a more extensive study with a larger number of subjects is required in the future to determine the effect of MARS intervention on improving the quality of life of patients with PD.

The development of MARS intervention is also intended to overcome the limitations of antiparkinsonian drugs. Patients with PD who participated in this study were taking various forms of levodopa and dopamine agonists. However, there was no change in the dose of anti-Parkinson’s medication taken by the subjects over the course of the 8 weeks and 16 visits. Patients with PD typically visit a neurologist for prescriptions every 3 to 6 months, so 8 weeks is considered short to confirm changes in patients’ prescriptions. It is believed that the intervention period should be longer than 6 months to confirm whether the intervention actually changes the prescription of PD patients.

During the study period, there were no MARS-related adverse events among the 13 subjects. In addition, none of the patients had abnormal clinical pathology test results before or after the study. Because we used intradermal acupuncture with minimal stimulation, MARS intervention was unlikely to cause harm to the patients. Furthermore, compared to traditional exercise therapy, the movements we implemented are relatively static. MARS intervention was shorter and simpler than conventional exercise therapy, but it is thought that the synergistic effect could be maximized because it was combined with acupuncture treatment.

3. MARS intervention

PD has been studied extensively since it was first reported by British physician James Parkinson in 1817. Currently, drugs such as levodopa are being used as standard treatments [41], and various other treatments are being tested and studied [42]; however, no definitive treatments for PD have been established. Recent evidence has shown that various forms of exercise treatments may have disease-modifying effects when implemented in the mid-to-long term for PD patients. However, its application in clinical practice is insufficient because there are barriers preventing PD patients from exercising consistently, and there is currently a lack of a sustainable system that can efficiently and systematically support PD patients in engaging in exercise [13]. As a result, it is necessary to develop a special therapeutic exercise method for PD patients that can be performed efficiently by medical personnel and is long-term sustainable.

Although acupuncture and exercise therapies are currently being studied for their efficacy in the treatment of PD [43-45], there has been little research on how these treatments work together. As a result, in this study, we combined acupuncture and exercise treatment with MARS and evaluated its effectiveness and safety in 13 PD patients. Furthermore, before conducting future clinical trials, evidence from a prospective observational study of MARS intervention on the degree of PD-related disability, hemodynamics, motor functions, and quality of life in PD patients is needed. Compared to traditional exercise therapy, the movements we implemented in the MARS intervention were shorter and more straightforward. However, it was combined with acupuncture treatment, and we thought that the synergistic effect could be maximized.

The authors’ other paper describes the MARS intervention and its development in detail [18]. In summary, MARS treatment combines intradermal acupuncture and exercise to (1) improve proprioceptive sensation and motor function in PD patients. MARS intervention aims to improve motor function in PD patients by strengthening proprioceptive signals. (2) MARS incorporates slow and rapid muscle control exercises, balancing slow and fast twitch muscles to improve motor ability and myofiber survival. (3) The combination of acupuncture and exercise in MARS has the potential to alleviate pain in PD patients by leveraging the analgesic effect of acupuncture and the circulation and muscle benefits of exercise. (4) MARS aims to prevent motor learning decline in PD patients by stimulating brain plasticity via the impact of acupuncture on the motor cortex, as evidenced by improved gait and UPDRS scores. (5) Finally, combining acupuncture with exercise can boost the synergistic effect. As the MARS intervention in this study was self-developed by the researchers, its effectiveness and validity need to be further evaluated. A randomized controlled trial will be conducted to determine the efficacy and cost-effectiveness of MARS treatment.

To conclude, from March 9, 2021, to October 27, 2021, a prospective observational study was conducted at Daejeon Korean Medicine Hospital of Daejeon University to confirm the effect of MARS intervention on PD patients, and the following conclusions could be drawn. After twice a week of MARS intervention for 8 weeks, the MDS-UPDRS Part III score, 10MWT, and TUG time of PD patients were significantly decreased, confirming the effect of improving motor symptoms and functions in PD patients. Moreover, the MDS-UPDRS Part II score, fNIRS hemodynamics, 360-degree turn test score, and FES score improved to some extent after the intervention, but the differences were not statistically significant. There was no difference in the MDS-UPDRS Part I or IV score, GAITRite score, BBS score, or EQ-5D score before or after the MARS intervention. The MARS intervention was found to be beneficial and effective in improving motor symptoms and function in PD patients. More research is needed before the intervention can be used as a treatment for PD patients in the future.

None.

Supplementary data to this article can be found online at https://doi.org/10.51507/j.jams.2024.17.2.55.

This research was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HF20C0174).

Conceptualization: IC, SP, MSP, and HY. Methodology: IC, SP, MSP, and HY. Software: IC, SHL, JWS, and MSP. Validation: IC, SP, MSP, and HY. Formal analysis: SHL, JWS, and MSP. Investigation: IC, SP, MSP, and HY. Resources: IC, SP, MSP, and HY. Data curation: IC, SP, SHL, JWS, and MSP. Writing – Original Draft: IC, and MSP. Writing – Review & Editing: IC, SP, SHL, JWS, ICS, YSK, MSP, and HY. Visualization: IC, SHL, and MSP. Supervision: SP, ICS, YSK, and HY. Project administration: IC, and HY. Funding acquisition: HY.

This research was reviewed and approved by the institutional review board of Daejeon Korean Medicine Hospital of Daejeon University (registration number: DJDSKH-21-BM-02). Informed consent was obtained from all participants.

The data that support the findings of this study are available within the article and its supplementary material.

The authors declare no conflict of interest.