114 https://doi.org/10.1590/0004-282X-anp-2020-0088 ARTICLE ABSTRACT Background: Parkinson’s disease (PD) produces autonomic changes, indicating lower parasympathetic modulation and global variability, but these changes need further studying regarding geometric methods. Objective: To investigate the autonomic modulation in individuals with PD using heart rate variability (HRV) indices obtained through geometric methods. Methods: This is a cross-sectional study that assessed 50 individuals, split into two groups: PD group (PDG; n=26; 75.36±5.21 years) and control group (CG; n=24; 75.36±5.21 years). We evaluated the autonomic modulation by measuring the heart rate beat-to-beat for 30 min with the individual in supine rest using a heart rate monitor and assessed geometric indices (RRtri, TINN, SD1, SD2, SD1/SD2 ratio, and qualitative analysis of the Poincaré plot). Results: Significant reductions were found in RRtri, TINN, SD1, and SD2 indices among PDG compared to CG. Regarding the SD1/SD2 ratio, no significant changes were detected between the groups. The Poincaré plot demonstrated that individuals with PD had lower beat-to-beat dispersion in RR intervals, in addition to greater long-term dispersion of RR intervals compared to CG. Conclusions: The results suggest a reduction in the parasympathetic autonomic modulation and global variability in individuals with PD compared to controls, regardless of sex, age, and body mass index. Keywords: Parkinson Disease; Autonomic Nervous System; Primary Dysautonomias; Neurodegenerative Diseases. RESUMO Introdução: A doença de Parkinson (DP) produz alterações autonômicas, que indicam menor modulação parassimpática e variabilidade global, mas que devem ser investigadas quanto aos métodos geométricos. Objetivo: Investigar a modulação autonômica em indivíduos com DP, por meio de índices de variabilidade da frequência cardíaca (VFC) obtidos pelos métodos geométricos. Métodos: Estudo transversal, no qual foram avaliados 50 voluntários, divididos em dois grupos: o grupo doença de Parkinson (GDP; n=26; 75,36±5,21 anos) e o grupo controle (GC; n=24; 75,36±5,21 anos). Para a avaliação da modulação autonômica a frequência cardíaca foi captada batimento a batimento por meio de um cardiofrequencímetro com os indivíduos em decúbito dorsal por 30 min e índices geométricos da VFC foram avaliados (RRtri, TINN, SD1, SD2 e plot de Poincaré). Resultados: Houve reduções nos índices RRtri, TINN, SD1 e SD2 para o GDP em comparação ao GC. Para a relação SD1/SD2, diferenças significantes não foram observadas entre os grupos. O plot de Poincaré mostrou que indivíduos com DP têm menor dispersão batimento a batimento dos intervalos RR, bem como maior dispersão dos intervalos RR a longo prazo em relação ao GC. Conclusão: Os resultados sugerem haver diminuição da modulação autonômica parassimpática e da variabilidade global em indivíduos com DP em relação a indivíduos sem a doença, as quais são independentes de sexo, idade e índice de massa corporal. Palavras-chave: Doença de Parkinson; Sistema Nervoso Autônomo; Disautonomias Primárias; Doenças Neurodegenerativas. Parkinson’s disease effect on autonomic modulation: an analysis using geometric indices Efeito da doença de Parkinson na modulação autonômica: análise por meio de índices geométricos Mileide Cristina STOCO-OLIVEIRA1, Ana Laura RICCI-VITOR1, Laís Manata VANZELLA1, Heloisa Balotari VALENTE1, Vitor Eduardo dos Santos SILVA1, Larissa Borba ANDRÉ1, Augusto Cesinando de CARVALHO1, David Matthew GARNER2, Luiz Carlos Marques VANDERLEI1 1Universidade Estadual Paulista “Júlio de Mesquita Filho”, Faculdade de Ciências e Tecnologia, Departamento de Fisioterapia, Presidente Prudente, São Paulo, Brazil. 2Oxford Brookes University, Faculty of Health and Life Sciences, Department of Biological and Medical Sciences, Oxford, United Kingdom. Mileide Cristina STOCO-OLIVEIRA http://orcid.org/0000-0002-8685-2786; Ana Laura RICCI-VITOR https://orcid.org/0000-0002-3654-8532; Laís Manata VANZELLA https://orcid.org/0000-0002-9494-3143; Heloisa Balotari VALENTE https://orcid.org/0000-0003-3975-1904; Vitor Eduardo dos Santos SILVA https://orcid.org/0000-0002-9008-3086; Larissa Borba ANDRÉ https://orcid.org/0000-0002-0525-8735; Augusto Cesinando de CARVALHO https://orcid.org/0000-0002-3858-5740; David Matthew GARNER https://orcid.org/0000-0002-8114-9055; Luiz Carlos Marques VANDERLEI https://orcid.org/0000-0002-1891-3153 Correspondence: Heloisa Balotari Valente; E-mail: helobalov@hotmail.com Support: This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES) – Finance Code 001. Conflict of interest: There is no conflict of interest to declare. Authors’ contribution: Study conception and design: Mileide Cristina Stoco-Oliveira and Luiz Carlos Marques Vanderlei; Data collection: Mileide Cristina Stoco-Oliveira, Heloisa Balotari Valente, Vitor Eduardo dos Santos Silva, Larissa Borba André, and Augusto Cesinando de Carvalho; Data analysis: Ana Laura Ricci-Vitor, Laís Manata Vanzella, and David M. Garner; Manuscript drafting: Mileide Cristina Stoco-Oliveira, Luiz Carlos Marques Vanderlei, Ana Laura Ricci-Vitor, and Laís Manata Vanzella. Received on March 7, 2020; Received in its final form on June 15, 2020; Accepted on June 25, 2020. https://doi.org/10.1590/0004-282X-anp-2020-0088 http://orcid.org/0000-0002-8685-2786 https://orcid.org/0000-0002-3654-8532 https://orcid.org/0000-0002-9494-3143 https://orcid.org/0000-0003-3975-1904 https://orcid.org/0000-0002-9008-3086 https://orcid.org/0000-0002-0525-8735 https://orcid.org/0000-0002-3858-5740 https://orcid.org/0000-0002-8114-9055 https://orcid.org/0000-0002-1891-3153 mailto:helobalov@hotmail.com 115Stoco-Oliveira MC et al. Parkinson’s disease effect on autonomic modulation INTRODUCTION The autonomic nervous system (ANS) is divided into three parts: sympathetic, parasympathetic, and enteric1. Dysfunctions in these systems can cause distinct signs and symptoms, such as parasympathetic cholinergic failure, lead- ing to urinary retention; sympathetic cholinergic failure, pro- moting a decline in sweating; sympathetic noradrenergic failure, causing orthostatic hypotension; enteric dysfunction, reducing peristalsis and, therefore, resulting in constipation2. Several of these changes are found in Parkinson’s disease (PD). The ANS dysfunctions2 identified in PD may occur due to the presence of Lewy bodies at different parts of sympa- thetic and parasympathetic components of the ANS, such as the mid-lateral spine, the sympathetic paravertebral ganglia, the adrenal medulla, and the dorsal vagal nucleus3. Given the changes promoted by PD in the ANS, the use of simple and non-invasive tools should be encouraged. Thus, the heart rate variability (HRV) can be adopted to eval- uate these changes through interval oscillations between consecutive heart beats (RR intervals), showing the influence of ANS on the sinus node, as well as identify the individual’s physiological health status4. The HRV analysis can be per- formed in numerous ways, including geometric methods (tri- angular index — RRtri; triangular interpolation of RR inter- val histogram — TINN; and Poincaré plot), which convert the RR intervals into geometric patterns and allow analyzing the HRV by its geometric or graphic properties5. TINN and RRtri are computed from the construction of a histogram density of normal RR intervals, with all possible RR values in the x-axis and their frequency in the y-axis. The union of histogram points forms a shape similar to a triangle from which these indices are constructed4,5. The Poincaré plot is a two-dimensional graphic strategy of consecutive RR intervals4,5. Its analysis can be visual, by eval- uating the figure formed by its attractor, demonstrating the level of complexity of RR intervals, or quantitative, by adjust- ing the elliptical figure formed by the attractor, using the indi- ces: SD1 (standard deviation of instantaneous beat-to-beat variability), SD2 (long-term standard deviation of continu- ous RR intervals), and SD1/SD2 ratio4. Many authors con- sider the Poincaré plot analysis to be grounded in nonlinear dynamics6. This assumption has gained attention, given the physiological evidence that the mechanisms involved in car- diovascular regulation interact with each other in a nonlin- ear and complex way7. These studies can provide important physiological interpretations of HRV6, as well as an improved understanding of the fluctuations that occur in the human body, both in health and disease8. Investigations have shown that PD causes autonomic changes9, among which a lower parasympathetic modula- tion and global variability stand out10. A better understand- ing of this imbalanced condition is vital, since the ANS con- trols part of the body’s internal functions. Searches in the relevant scientific literature revealed few studies assessing the autonomic modulation using the measurable analysis of the Poincaré plot, no articles evaluating the plot qualitatively with individuals at rest, and no investigations that adopted RRtri and TINN in their analyses. Thus, this work aims at contributing to the literature on the current theme by evaluating the autonomic modula- tion in individuals with PD through HRV indices obtained by geometric methods (RRtri, TINN, and Poincaré plots). We hypothesize that HRV indices from these methods can identify changes in the autonomic modulation of individu- als with PD. This information is crucial for researchers and clinicians working with this population group, as it allows a better understanding of ANS dysfunctions in these subjects, which is central to explaining treatment strategies that can lessen these changes. METHODS This is a cross-sectional study, and all procedures were approved by the Research Ethics Committee of the Universidade Estadual Paulista, School of Science and Technology. All subjects were informed about the procedures and purposes of the study, and after agreement, they signed a confidential written informed consent form. Population and selection criteria The subjects were recruited at health clinics in the city of Presidente Prudente, São Paulo, Brazil. Individuals with PD should have been diagnosed with the disease at any time and be classified into stages 1 to 3, according to the Hoehn and Yahr (HY) Disability Stage Scale11. Participants with- out the disease were assigned to the control group (CG) and paired by age and sex to the subjects with PD. Additionally, to ensure the understanding of the procedures performed, only individuals without cognitive deficits, as assessed by the Mini-Mental State Examination (MMSE)12, were considered for both groups. Smokers, alcoholics, individuals with infections and car- diovascular and respiratory diseases known to interfere with cardiac autonomic control, and those who did not sign the informed consent form were excluded. Likewise, we excluded subjects who presented more than 5% of errors in the series of RR intervals. Experimental protocol The datasets were collected in two phases, with intervals ranging from 24 hours to one week between them, all per- formed during the “on” period of levodopa for PD subjects13. The first stage involved gathering personal data and perform- ing physical and clinical evaluations. In the second period, the autonomic assessment was completed, and the partici- pants were released. 116 Arq Neuropsiquiatr 2021;79(2):114-121 The datasets were recorded in a room with a tempera- ture between 21 and 23°C and humidity of 40 to 60% between 08:00 and 12:00 a.m. to minimize the influence of the circa- dian rhythm14. The individuals were asked to avoid consum- ing alcoholic beverages and/or stimulants, such as coffee, tea, or chocolate, in the preceding 12 hours and to use their medi- cation as usual. The evaluations were carried out individually. Physical and clinical evaluations After individual data collection, the subjects were assessed for body composition (body weight, height, and body mass index — BMI), cardiovascular parameters, the stage of PD, and cognition. Body weight was measured with a digital scale (Welmy R/I 200, Santa Bárbara D’Oeste, São Paulo, Brazil), and height was obtained using a stadiometer (Sanny, São Paulo, Brazil). Based on these measurements, the BMI was calculated by the mathematical formula: weight/height2 (kg/m2), leading to the classification of body composition15. Body fat percentage and lean mass were obtained through the Maltron BF 906 Body Fat Analyzer (Maltron, UK) bio- impedance equipment with the participant in a supine posi- tion on a non-conductive surface lacking metallic contacts and focused on remaining at rest during the procedure16. Systolic and diastolic blood pressures were confirmed with an aneroid sphygmomanometer (WelchAllyn – Tycos, New York, USA) and a stethoscope (Littman, Saint Paul, Minnesota, USA). The pressures were indirectly measured in the left arm and classified according to the criteria established by the VII Brazilian Guideline of Arterial Hypertension17. The resting heart rate (HR) was recorded with the same HR monitor used to eval- uate the HRV (Polar RS800CX, Polar Electro, Kempele, Finland). The disease stage assessment was performed based on the HY scale, which evaluates the individual’s disability accord- ing to their signs and symptoms11. The cognitive evaluation involved the administration of the MMSE, which assesses this function based on the following domains: spatial orien- tation, temporal memory, immediate memory, recall, calcu- lation, language-naming, repetition, comprehension, script, and diagram reproduction12. Autonomic system assessment For the investigation of autonomic modulation, the HR beat-to-beat was obtained by an HR monitor (Polar RS800CX, Polar Electro, Kempele, Finland). To this end, the subjects rested in the supine position on a stretcher for 30 minutes. They were asked to stay awake, breathe spontaneously, and avoid conversation throughout the procedure. The datasets collected were transferred to the Polar Precision Performance SW software (v. 4.01.029). The series of RR intervals initially obtained underwent digital filtering performed by the software with a moderate filter4, followed by manual filtering in the Microsoft Excel software to elimi- nate premature ectopic beats and artifacts. Only series with more than 95% of sinus beats were included in the study18. The autonomic modulation analysis consisted of sections with 1000 consecutive RR intervals19, and the Kubios® HRV software, version 3.125, was used to calculate HRV indices. Geometric methods were adopted to analyze HRV, and the following indices were obtained: RRtri, TINN, and indices extracted from the Poincaré plot (SD1, SD2, SD1/SD2 ratio). RRtri was calculated from the density histogram of nor- mal RR intervals, involving the histogram integral (the total number of RR intervals) divided by the maximum of the den- sity distribution (modal frequency of RR intervals), measured on a discrete scale with sections of 7.8125 ms (1/128 s)20. TINN consists of the baseline width of the distribution mea- sured as the basis of a triangle, and the least-squares differ- ence was used to determine the triangle20. The Poincaré plot is a map of points in Cartesian coordi- nates, with each RR interval represented on the x-axis by the previous RR interval and on the y-axis by the following inter- val, a figure that allows quantitative and qualitative analysis. The Poincaré plot was quantitatively investigated using the following indices: SD1, SD2, and SD1/SD2 ratio20. The qualita- tive analysis of the plot was performed based on the shapes formed by the attractor, which were described by Tulppo et al.21 as: 1) Figure in which the RR interval dispersion increases with increase in the RR intervals, characteristic of a normal plot; 2) Figure with low overall beat-to-beat dispersion and no increase in RR interval dispersion in the long term. Data analysis Descriptive statistical techniques were applied to describe the population profile data, and results were pre- sented as mean, standard deviation, and percentage. To match the HRV geometric indices in the CG and PDG and in stages 1–2 and 3 of HY, analyses of covariance (ANCOVA) were carried out and adjusted for potential con- founding factors controlled by their direct relationship with autonomic modulation. These adjustment factors were: gen- der, age, and BMI. We used the Fisher’s test to investigate whether there was a difference between the medications of the groups. The qualitative analysis of the Poincaré plot was per- formed using a scatter plot from the Microsoft Excel software, including all volunteers. The assessment of data normality was determined by the Shapiro-Wilk test. We measured the effect size of the differences between groups by eta squared. Effect sizes were considered small from ≥0.01 to <0.06, mod- erate from ≥0.06 to <0.14, and high when ≥0.142822. The sig- nificance level was set at 5% for all tests and the confidence interval at 95%. We used the SPSS statistical software (v. 13.0; SPSS Inc., Chicago, IL, USA) for the statistical assessments. The power of the study was calculated in the software from the website www.lee.dante.br. For the SD1 index http://www.lee.dante.br 117Stoco-Oliveira MC et al. Parkinson’s disease effect on autonomic modulation variable, it assumed a significant difference of 7 ms and standard deviation of 6 ms, based on the number of sub- jects analyzed and the 5% significance level (two-tailed) established at a power greater than 80% to detect changes between variables. RESULTS Figure 1 illustrates the subject’s distribution and sample loss throughout the stages. Table 1 presents the group features. Significant differ- ences were detected in the diastolic blood pressure, BMI, and MMSE variables (p<0.05), but not in the variables age, systolic blood pressure, HR, body fat, lean mass, body weight, and height (p>0.05). Overweight15, prehypertension17, absence of cognitive deficits12, and PDG individuals were identified in stage two of PD11. Significant differences were revealed in Table 2 with regard to dopamine antagonists, levodopa, and antidepressants. Table 3 compares the geometric HRV indices between CG and PDG. Statistically significant reductions were found in Figure 1. Sample loss flowchart. Table 1. Characterization of the control and Parkinson’s disease groups evaluated in the study. CG (n=24) PDG (n=26) p-value Age (years) 70.25±8.02 72.76±7.64 0.261 SBP (mmHg) 130.41±13.34 126.15±12.02 0.241 DBP (mmHg) 86.66±8.68 79.61±10.38 0.013 HR (bpm) 62.75±12.93 64.92±9.10 0.493 Body fat (%) 32.08±9.54 33.04±8.62 0.712 Lean mass (%) 67.83±9.48 66.95±8.62 0.732 Body weight (kg) 78.25±10.77 72.94±13.74 0.137 Height (m) 1.63±0.06 1.63±0.09 0.783 BMI 29.42±4.04 27.02±4.01 0.044 MMSE 26.87±3.12 24.57±4.47 0.042 Diagnosis time (years) ----- 6.57±5.27 ---- HY Scale ----- 2.34±0.62 ---- Mean±standard deviation. CG: control group; PDG: Parkinson’s disease group; SBP: systolic blood pressure; DBP: diastolic blood pressure; HR: heart rate; BMI: body mass index; HY: Hoehn and Yahr Disability Stage Scale; MMSE: Mini-Mental State Examination; mmHg: millimeters of mercury; bpm: beats per minute; %: percentage; kg: kilograms; m: meters. 118 Arq Neuropsiquiatr 2021;79(2):114-121 Table 2. Medication used by volunteers of the control and Parkinson’s disease groups evaluated in the study. Medication (%) CG (n=24) PDG (n=26) p-value Dopamine antagonists 0.0 30.8 0.004 Platelet antiaggregant 20.8 23.1 1.0 Antiarrhythmic drugs 0.0 11.5 0.23 Anticholinergic 0.0 7.7 0.49 Antidepressants 4.2 30.8 0.024 Beta-blocker 8.3 19.2 0.42 Biguanides 16.7 19.2 1.0 Ca+ channel blocker 8.3 7.7 1.0 Angiotensin II receptor blockers 41.7 34.6 0.77 Ciprofibrate 0.0 3.8 1.0 Amantadine Hydrochloride 0.0 15.4 0.11 Diuretic 25.0 15.4 0.49 Entacapone 0.0 7.7 0.49 Statins 29.2 23.1 0.75 Gliclazide 8.3 7.7 1.0 ACE inhibitor 12.5 0.0 0.10 MAO inhibitor 0.0 15.4 0.11 Levodopa 0.0 69.2 0.000 Others 66.7 69.2 1.0 Vasodilator 4.2 15.4 0.35 CG: control group; PDG: Parkinson’s disease group; %: percentage; Ca+: calcium; ACE: angiotensin-converting enzyme; MAO: monoamine oxidase. Table 3. Comparison of the geometric indices of heart rate variability between the control and Parkinson’s disease groups, adjusted for gender, age, and body mass index. CG (n=24) PDG (n=26) F-value p-value Eta squared Effect sizeMean (SE) Mean (SE) RRtri 6.60 (0.47) 4.31 (0.45) 11.732 0.001 0.207 High TINN 146.95 (9.73) 80.57 (9.33) 23.117 0.000 0.339 High SD1 17.02 (1.20) 10.95 (1.16) 12.527 0.001 0.218 High SD2 31.76 (2.31) 17.69 (2.22) 18.292 0.000 0.289 High SD1/ SD2 1.90 (0.10) 1.67 (0.09) 2.346 0.133 0.050 Low BMI: body mass index; CG: control group; PDG: Parkinson’s disease group; SE: standard error; F: Coefficient of the measure of variance between groups by the variance within groups; RRtri: triangular index; TINN: triangular interpolation of RR interval histogram; SD1: standard deviation of instantaneous beat-to-beat variability; SD2: long-term standard deviation of continuous RR intervals. Figure 2. Scatter plot representing the qualitative analysis of Poincaré plot observed in control (Graphic A) and Parkinson’s disease (Graphic B) groups. the PDG for RRtri, TINN, SD1, and SD2 indices (p<0.05), but not in SD1/SD2 ratio (p>0.05). Figure 2 displays the visual representation of the Poincaré plot pattern of the evaluated groups. This representation required the RR intervals of all subjects examined in the study to plot the chart. Table 4 shows the comparison of geometric HRV indices between participants with PD stages 1–2 and 3 according to 119Stoco-Oliveira MC et al. Parkinson’s disease effect on autonomic modulation the HY Disability Stage Scale. No significant difference was identified between the groups (p>0.05). DISCUSSION The results obtained by the Poincaré plot visual analy- sis and the geometric HRV indices confirmed that PD indi- viduals presented reduced global variability and parasym- pathetic modulation, irrespective of possible confounding factors, such as gender, age, and BMI. Furthermore, no dif- ferences were found in the autonomic modulation of par- ticipants with stages 1–2 and 3 of the HY Disability Stage Scale. Consequently, all PD individuals were allocated in the PDG. In the description of PDG subjects, the analyzed par- ticipants represent the general PD population, given the high proportion of males24 and older adults25. The subjects had a mean time of diagnosis of 6.57±5.27 years, which can be considered low considering the variation from 1 to 30 years described in the medical literature26. The results obtained by the HY scale11 showed that most subjects pre- sented impairment on both sides of the body but no bal- ance deficit11. Regardless of the pharmacotherapy, a substantial differ- ence was found between PDG and CG concerning the classes of dopamine antagonists and levodopa, which are specific for the treatment of PD. Also, the groups showed a significant dif- ference as to classes of antidepressants. In PDG, 30.8% of sub- jects used this medication, while its use in CG corresponded to 4.2% of subjects; this difference is in agreement with the Table 4. Comparison between Parkinson’s disease participants in disease stages 1–2 and 3 according to the Hoehn and Yahr Disability Stage Scale. HY (1–2) HY (3) F-value p-value Eta squared Effect sizeMean (SE) Mean (SE) RRtri 4.64 (1.22) 3.46 (1.43) 3.06 0.094 0.127 Moderate TINN 85.06 (29.17) 70.20 (21.75) 1.00 0.328 0.046 Small SD1 11.86 (4.26) 8.82 (4.03) 1.58 0.222 0.070 Moderate SD2 18.80 (7.35) 14.13 (5.83) 1.92 0.180 0.084 Moderate SD1/ SD2 1.70 (0.54) 1.62 (0.38) 0.32 0.572 0.015 Small HY: Hoehn and Yahr Disability Stage Scale; SE: standard error; F: Coefficient of the measure of variance between groups by the variance within groups; RRtri: triangular index; TINN: triangular interpolation of RR interval histogram; SD1: standard deviation of instantaneous beat-to-beat variability; SD2: long-term standard deviation of continuous RR intervals. literature, which describes depression as very common in subjects with PD27. In addition, although some studies indi- cate a negative influence of antidepressants on autonomic modulation, the literature only reports evidence against the class of tricyclic antidepressants28, prescribed for only one individual in the PDG, suggesting that this difference did not influence our results. The SD1 index, which reflects the parasympathetic mod- ulation4, was lower in the PDG compared to the CG and had a high effect size. These results confirm that subjects with PD have a reduced parasympathetic modulation. A similar find- ing was identified in the study by Rocha et al.10, who also esti- mated the SD1 index in individuals with PD at rest and dis- covered a reduction in parasympathetic modulation in these subjects compared to individuals without the disease. This decrease in vagal function has been linked to an increase in morbidity and mortality29. The global variability indices RRtri, TINN, and SD2 were also reduced in PD individuals compared to those without the disease and showed a high effect size. The SD2 index is comparable to that of Rocha et al.10, who detected a difference of 14.41 ms between groups of volunteers in 15 minutes rest, a value very similar to the one found in this study — 14.07 ms. No important difference in the SD1/ SD2 ratio was found between the groups, which can be explained by the reduction in both SD1 and SD2 indices in subjects with PD. The decrease in global variability and parasympathetic modulation can be qualitatively detected in the Poincaré plot of the groups evaluated (Figure 2). The Poincaré plot visual analysis confirmed that PD individuals have a lower beat- to-beat RR interval dispersion, as the shape of the plot was linear, indicating that PD subjects have reduced parasympa- thetic modulation when compared to individuals without the disease, as their plot displayed a larger beat-to-beat dis- persion. Moreover, the long-term distribution of RR intervals in the PDG presented a higher concentration of points to the right of the plot, suggesting the presence of RR intervals with higher values in this group. This result corroborates the study by Haapaniemi et al.23, who presented the plot with a 24-hour electrocardiogram (ECG) analysis and detected a lower dis- persion in PD compared to controls. These findings confirm the importance of the inter- vention in individuals with PD so as to promote a superior response of the parasympathetic and global modulation, as well as reduce possible system damage, as in the initial stages of PD, when cardiovagal dysfunction occurs due to the decline in ANS branches30. The current study presents some limitations. Its cross- sectional design makes it impossible to survey the auto- nomic behavior of these subjects, restricting the evaluation of the temporal evolution of the disease. In addition, indi- viduals with PD in phases 4 and 5 of HY were not included. The large number of medications taken by subjects from 120 Arq Neuropsiquiatr 2021;79(2):114-121 both groups should also be considered a study limitation. Furthermore, we must take into account that all PDG par- ticipants were assessed during the levodopa “on” period and that a detailed account should be taken of the medications used by each group. Despite these limitations, this study is, to our knowledge, the first to evaluate RRtri and TINN indices and perform a qualitative analysis of the Poincaré plot in resting individuals with PD. Also, the assessments performed with adjustment for potential confounding factors (gender, age, BMI) can be considered one of the strong points of the study. In summary, the results suggest that individuals with PD present a reduced global variability and parasympathetic modulation compared to individuals without the disease, regardless of likely confounding factors, such as gender, age, and BMI. These findings show the need for prevention and treatment of PD subjects through interventions that may encourage HRV increases in this population. 1. Orimo S, Ghebremedhin E, Gelpi E. Peripheral and central autonomic nervous system: does the sympathetic or parasympathetic nervous system bear the brunt of the pathology during the course of sporadic PD? 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