INTRODUCTION
Tic disorders are relatively common neuropsychiatric conditions that affect 1%-5% of children. These disorders are characterized by involuntary repetitive muscle movements or vocalizations that typically begin during childhood or adolescence. Tic disorders are frequently accompanied by comorbid neuropsychiatric conditions such as attention deficit hyperactivity disorder (ADHD) and obsessive-compulsive disorder. The clinical course of tic disorders is often chronic and marked by periods of remission and exacerbation, which complicates our understanding of their neurophysiological underpinnings. For some individuals, symptoms persist into adulthood, significantly impairing daily and social functioning and reducing the quality of life of patients and their families [1]. Although previous studies have identified clinical predictors of symptom progression, such as the association of higher initial tic severity with worse outcomes [2] and early tic suppression predicting a better short-term prognosis [3], these studies have primarily focused on clinical rather than biological variables. Given the neurobiological basis of tic disorders, further exploration of physiological markers is required to deepen our understanding of the mechanisms underlying tic progression and associated symptoms. Additionally, tic disorders are often influenced by stress and are strongly linked to autonomic dysregulation [4].
Heart rate variability (HRV) is a key physiological marker of autonomic nervous system (ANS) balance. HRV measures the variation in the time interval between heartbeats and offer insight into autonomic function. Lower HRV is typically associated with stress, emotional dysregulation, and poor autonomic control, whereas higher HRV indicates adaptive flexibility and resilience [5,6]. Furthermore, HRV analysis may have clinical implications for treatment development, including biofeedback and stress management therapies designed to restore ANS balance.
Although HRV has been studied in relation to stress and emotional regulation under other condition, its role in tic disorders remains unexplored, leaving a critical gap in our understanding of its physiological mechanisms. Considering the chronic stress and emotional challenges often faced by patients with tic disorders, HRV serves as a valuable, non-invasive biomarker for assessing autonomic function in this population. In addition, tracking changes in HRV over time could elucidate the chronicity and progression of autonomic dysfunction in this population. Despite its potential, longitudinal research on HRV in tic disorders remains scarce, limiting our ability to understand the evolution of autonomic function over time and its impact on symptom progression.
This study examined the changes in HRV parameters in adolescents with tic disorders compared to healthy controls over a 1-year follow-up period. We hypothesized that adolescents with tic disorders would exhibit lower HRV parameters than healthy controls, reflecting autonomic dysregulation. Additionally, we predicted that greater tic severity would be associated with more pronounced reductions in HRV, suggesting a link between autonomic dysfunction and clinical symptoms. In addition, we investigated the relationship between HRV changes and clinical tic severity to provide a comprehensive view of the interactions between ANS function and tic symptoms. This study aimed to elucidate how HRV evolves in patients with tics and its potential clinical significance in tic symptomatology using a longitudinal design and extensive data collection. Furthermore, we investigated the correlation between HRV parameters, tic severity, and quality of life measures.
METHODS
Participants and study design
This study analyzed data previously collected from a cohort of 39 children and adolescents with tic disorders at baseline and 30 age-matched healthy controls recruited from the Department of Psychiatry at Korea University Guro Hospital. All participants were aged 6-17 years. Many participants were lost to the study during the 1-year follow-up. As a result, 19 people participated in the 1-year follow-up. Healthy controls were recruited by advertisement from a community mental health center. They were screened to exclude any psychiatric or neurological conditions, including head trauma, brain tumors, or seizures. They were required to be free of psychotropic medication for at least three weeks prior to participation.
The demographic and clinical characteristics of the participants are described in Table 1. Tic disorder diagnosis was confirmed through clinical evaluation and the Yale Global Tic Severity Scale (YGTSS) [7]. The tic disorder and control groups were compared to identify significant autonomic and clinical patterns. This study also analyzed differences in HRV parameters and clinical scales between baseline and endpoint measurements over 1-year. As only the patient group underwent follow-up assessments, the control group’s endpoint data were not re-collected. For comparative consistency, the baseline values of the control group were presented again at the endpoint in Table 2. Variables demonstrating significant differences were selected for further investigation, particularly those showing strong correlations with the severity of tic disorders. All data sets presented in this study are available upon request from the corresponding author.
Ethical approval for this study was granted by the Institutional Review Board of Korea University Guro Hospital (2021GR0275), and written informed consent was obtained from all participants and their guardians.
Clinical measures
This study analyzed both clinical scales to explore psychological functioning in the participants. The participants also completed several assessments to evaluate clinical and physiological variables.
YGTSS
The severity of tic disorder symptoms was measured using the YGTSS, which assesses tic symptoms and their severity across the motor and vocal dimensions [7].
Kiddie Schedule for Affective Disorders and Schizophrenia-Present and Lifetime Version
Psychiatric comorbidities were assessed using the Kiddie Schedule for Affective Disorders and Schizophrenia-Present and Lifetime Version (K-SADS-PL) [8]. This semi-structured diagnostic interview was designed to ascertain current and past episodes of psychopathology according to the Diagnostic and Statistical Manual of Mental Disorders criteria, making it a reliable tool for longitudinal and developmental psychiatric studies. The K-SADS-PL comprehensively addresses affective, psychotic, and behavioral disorders.
KIDSCREEN-27
Participant quality of life was assessed using the Korean version of the KIDSCREEN-27 questionnaire [9,10]. The KIDSCREEN-27 evaluates health-related quality of life across domains, including physical well-being, autonomy, and social support [11]. Higher scores indicate a better quality of life. In addition to the total scores, we also obtained scores for the following dimensions: dimension 2 (KID 2): physical well-being, dimension 3 (KID 3): psychological well-being, dimension 4 (KID 4): social support and peers, dimension 5 (KID 5): autonomy and parental relations, and dimension 6 (KID 6): school environment.
Korean ADHD Rating Scale
ADHD symptoms were evaluated using the Korean ADHD Rating Scale (K-ARS) [12], which quantifies the symptoms of attention deficit and hyperactivity.
Children’s Depression Inventory
The Children’s Depression Inventory (CDI) measures depressive symptoms in children and adolescents, with higher scores indicating greater severity of depressive symptoms.
Intelligence quotient
Intelligence quotient (IQ), measured using a standardized intelligence assessment, was also included to account for cognitive variability. Specifically, we used the Korean version of the Wechsler Intelligence Scale for Children-Fourth Edition to assess IQ. This standardized tool is widely used in clinical and research settings in Korea and provides reliable and valid estimates of cognitive ability in children and adolescents.
HRV measurements
This study analyzed HRV parameters to explore autonomic functioning in adolescents. Electrocardiograms (ECGs) were recorded for 5 minutes for each participant, and the HRV parameters were subsequently calculated. To ensure accurate results, the participants were instructed to abstain from consuming tea, coffee, or other caffeine-containing beverages for at least 3 hours before the recordings. During the ECG recording, the participants were instructed to remain still and avoid any movement. Data were collected using an MP36R system (BioPac Systems Inc., Goleta, CA, USA) at a sampling rate of 500 samples for the 5-minute duration. The ECG data were filtered using finite impulse response bandpass filter (1-35 Hz), followed by the R-peak detection algorithm. HRV indices were computed using the detected R peaks. Recordings with severe noise or calculation failure were excluded from the analysis. In addition, recordings containing non-sinus beats exceeding 1% of the total beats were discarded. Premature beats and artifacts were carefully removed using a combination of automatic processing and manual visual inspection at all RR intervals. HRV parameters were assessed to measure ANS activity. ECGs were obtained under resting conditions using a standardized protocol [13].
HRV parameters were derived for both time- and frequency-domain measures. For the time domain, the standard deviation of the normal-to-normal intervals (SDNN) was used to assess the long-term HRV components, whereas the root mean square of successive differences (RMSSD) was computed to evaluate short-term variability through statistical measurements. The standard deviation of the average NN intervals (SDANN) was also calculated over 5-minutes segments to capture the long-term HRV components. SDANN provides insights into the long-term components of HRV, such as low-frequency (L/F) oscillations, which are often linked to overall autonomic function and chronic stress responses.
Analysis of the frequency-domain included very low-frequency (VLF) (0.00-0.04 Hz), LF (0.05-0.15 Hz), and high frequency (HF) (0.16-0.40 Hz), as outlined by the Task Force of the European Society of Cardiology and North American Society of Pacing and Electrophysiology. The LF and HF power values were initially recorded in absolute terms, and their ratios (LF/HF) were subsequently calculated. This ratio served as a composite indicator of the combined influence of sympathetic and parasympathetic modulation.
Statistical analysis
Data were analyzed using IBM SPSS Statistics for Windows, version 27.0, and Python, version 2.2.3. Our sample size was carefully chosen based on earlier studies investigating HRV in populations with tic disorders. Previous researches in this area were referenced [14,15]. We performed a power analysis based on the pre-assumed effect sizes to validate this further. This analysis showed that a sample size of 70 participants was necessary to achieve adequate power (0.8) with an alpha of 0.05 and a beta of 0.2, using the LF index as the critical parameter of our analysis. Our sample size was adequately powered to identify significant differences.
Baseline and endpoint measures were compared to assess changes over time. The normality of the distributions was evaluated using the Shapiro-Wilk test. Paired t-tests and nonparametric Mann-Whitney U tests were conducted for normally and non-normally distributed data, respectively. For each comparison, normality and variance homogeneity were tested. Depending on the outcome, either an independent-samples t-test or Mann-Whitney U test was applied.
Correlations between HRV parameters and clinical outcomes were explored using Pearson’s and Spearman’s correlation coefficients. Parameters demonstrating significant changes were selected for their implications in autonomic regulation and clinical manifestations of tic disorders.
RESULTS
Group characteristics and clinical measurements
Group characteristics and clinical measurements are presented in Table 1. The patient group comprised 39 individuals, 19 of whom were followed up after 1 year. The control group included 30 individuals. Although patients with tic disorders showed lower IQ scores than the control group (96.65±11.40 vs. 103.30±10.63, p<0.05), the scores in both groups were within the normal range. Patients with tic disorders showed higher CDI scores (9.63±5.74 vs. 5.43±5.61, p<0.05), reflecting greater emotional and cognitive challenges. Quality of life, as measured using the KIDSCREEN-27 questionnaire, was consistently lower in patients with tic disorders. Specifically, the scores for psychological well-being (KID 3) were 27.65±5.26 in patients compared to 30.27±3.88 in controls (p<0.05), those for autonomy and parent relations (KID 5) were 27.47±4.72 vs. 30.00±3.74 (p<0.05), and the total KIDSCREEN-27 scores were 106.03±15.12 vs. 114.63±13.36 (p<0.05), respectively [11].
The K-ARS scores revealed a higher prevalence of ADHD symptoms in patients with tic disorders. The mean K-ARS score in patients with tic disorders was 13.23±9.93, compared with 5.90±5.00 in the control group (p<0.01). These results align with the established comorbidity between tic disorders and ADHD, highlighting the broader cognitive and behavioral challenges faced by individuals with tic disorders.
HRV measurements in patients with tic disorders and controls at baseline and the endpoint
HRV measurements in patients with tic disorders and controls at baseline and the endpoint are presented in Table 2. At baseline, the patient group exhibited a significantly higher SDANN than the control group (23.19±12.30 ms vs. 16.97±8.23 ms, p<0.05), indicating differences in long-term autonomic variability. Among frequency-domain measures, both LF (16.52±11.98×10-3 ms2 vs. 19.78±10.53×10-3 ms2) and HF (15.52±16.54×10-3 ms2 vs. 20.79±11.49×10-3 ms2) were lower in patients with tic disorders, although these differences were not statistically significant. The LF/HF ratio was higher in patients with tic disorders (1.86±1.80) than in the control group (1.18±0.80), reflecting a tilt toward sympathetic dominance [16].
At the endpoint, LF was significantly reduced in patients with tic disorder compared with the control group (12.74±8.99×10-3 ms2 vs. 19.78±10.53×10-3 ms2, p<0.05), reflecting diminished sympathetic activity. SDANN remained higher in patients with tic disorder (23.00±13.25 ms) than in the control group (16.97±8.23 ms, p<0.05), consistent with the baseline findings. Other frequency-domain measures, such as HF and VLF, tended to be lower in the patient group, but without statistical significance.
Comparison of clinical scales and HRV measurement between baseline and the endpoint in patients with tic disorders
Comparisons of clinical scales and HRV parameters between the baseline and the endpoint in the patient group after 1-year follow-up were shown in Table 3. At baseline, the K-ARS score was 13.84±10.72, reflecting mild to moderate ADHD-related symptoms. Among HRV parameters, the SDNN was 59.63±25.52 ms, showing moderate overall variability, while the RMSSD was 44.34±27.44 ms, indicating parasympathetic activity. In the frequency-domain, LF was 16.52±11.98×10-3 ms2, HF was 15.52±16.54×10-3 ms2, and LF/HF was 1.86±1.80, suggesting slight sympathetic predominance.
After 1-year, the K-ARS score had improved to 11.05±7.33. The HRV measures showed notable changes, with the SDNN and RMSSD decreasing to 51.07±20.53 ms and 33.41±16.63 ms, respectively, reflecting reduced autonomic function. LF decreased significantly from 16.52±11.98×10-3 ms2 to 12.74±8.99×10-3 ms2 (p<0.05), whereas HF fell slightly to 13.71±16.28×10-3 ms2. LF/HF shifted marginally to 1.71±1.53, indicating a trend toward parasympathetic dominance [16].
Correlations of KIDSCREEN-27, K-ARS, and HRV measurements in patients with tic disorders and controls
Correlations between HRV measurements and clinical rating scales were performed in Table 4. Among patients with tic disorders, HRV parameters were significantly related to quality of life measures at baseline. KID 2 was significantly negatively correlated with VLF (r=-0.412, p<0.05), indicating that lower physical well-being was associated with higher VLF values, reflecting potential autonomic dysregulation [11,17]. KID 4 showed strong positive correlations with SDNN (r=0.517, p<0.01), SDANN (r=0.481, p<0.01), and RMSSD (r=0.474, p<0.01), suggesting that better social support is linked to improved overall HRV and parasympathetic activity [11,17]. Similarly, KID 5 was positively correlated with SDNN (r=0.352, p<0.05) and RMSSD (r=0.348, p<0.05) but negatively correlated with VLF (r=-0.412, p<0.05), indicating that a better school environment was associated with both improved short-term HRV and reduced long-term autonomic fluctuations [11,17].
At the endpoint, patients with tic disorders showed correlations with varying strengths and directions. While these differences were not statistically significant. These patterns differed from those observed in the control group. KID 3 was negatively correlated with SDNN (r=-0.399, p<0.05), whereas KID 5 was negatively correlated with both SDNN (r=-0.475, p<0.01) and RMSSD (r=-0.443, p<0.05), suggesting that better quality of life scores in these areas was linked to lower HRV.
DISCUSSION
This study investigated differences in HRV between adolescents with tic disorders and healthy controls over a 1-year follow-up period, focusing on the relationship of HRV parameters with clinical severity, tic symptoms, and quality of life. These findings provide insights into ANS dysregulation in tic disorders and its association with clinical and quality of life metrics.
At baseline, HRV parameters differed significantly between the patient and control groups. Although SDANN was higher, the LF and HF values were significantly lower in the patient group. The elevated SDANN in the patient group may reflect heightened long-term autonomic variability owing to the chronic nature of tic symptoms, which involve sustained physiological arousal and heightened autonomic demands [13,18,19]. This contrasts with reduced LF and HF values, which indicate impaired sympathetic and parasympathetic activity [16], likely stemming from ANS dysregulation caused by tic disorders. The discrepancy between elevated SDANN and reduced LF/HF suggests that while long-term autonomic variability is maintained, the short-term regulatory capacity of the ANS is diminished in patients with tics disorders, particularly in response to acute stressors or the tics themselves. This may reflect compensatory mechanisms in the ANS that attempt to regulate chronic dysregulation but fail to normalize short-term autonomic responses [20].
Significant changes were observed in HRV parameters of patients with tic disorder over the 1-year follow-up period. LF, which was significantly lower at baseline than that in the controls, showed a further reduction at the endpoint, whereas the HF and VLF trends did not reach statistical significance. The progressive reduction in LF may reflect worsening sympathetic dysfunction over time [16], which is potentially exacerbated by chronic tic severity and associated psychological and social stressors. The lack of significant changes in HF and VLF suggests that parasympathetic and long-term autonomic activities remain relatively stable [16]. This stability may result from the chronic nature of tic disorders, in which autonomic adjustments stabilize over time but fail to recover or normalize. These findings highlight the need for targeted interventions to address the progressive deterioration of sympathetic activity in children with tics.
However, HRV has certain limitations. For instance, HRV indirectly reflects autonomic function through parasympathetic modulation and may not fully capture the complexity of ANS regulation or its relationship with psychiatric and physiological states [21]. This limitation could explain the lack of significant changes in HF and VLF, because HRV may not directly reflect the full spectrum of autonomic activity or chronic stress responses. Additionally, HRV measures are sensitive to internal psychiatric states and other confounding variables, suggesting the need for further investigation using complementary methodologies such as neuroendocrine markers (e.g., cortisol) or psychophysiological assessments (e.g., skin conductance and EEG) to provide a more comprehensive understanding of autonomic dysregulation in tic disorders [22]. The findings of the present study also highlight the need for targeted interventions to address the progressive deterioration of sympathetic activity in children with tic disorders, along with refined tools for assessing ANS function and its clinical implications.
The results of the correlation analyses between the KIDSCREEN-27 scores and HRV parameters provided additional insights. At baseline, higher quality of life scores (e.g., KID 2 and 5) were associated with lower VLF in the patient group. VLF reflects long-term autonomic regulatory mechanisms, and elevated VLF levels are often linked to chronic stress or systemic instability [23]. Therefore, the observed reduction in VLF with improved quality of life in patients may indicate relief from chronic stress and better autonomic stabilization as psychosocial well-being improves. This finding elucidates the potential of psychosocial interventions to positively influence ANS regulation in children with tic disorders.
Over the 1-year follow-up period, the correlations between HRV measures and the psychological/behavioral scales observed at baseline were altered significantly at the endpoint. The previously observed correlations were no longer significant, and some even shifted directions. For example, the correlation between VLF and the KIDSCREEN dimension five scores was significant at baseline but disappeared at the endpoint 1-year later. This may reflect the effects of treatment and homeostatic adaptation over time. During the 1-year follow-up period, improved psychological well-being and autonomic stability may have reduced the physiological influence of HRV on these domains. The lack of correlation between the clinical rating scales, including the perception of quality of life, the YGTSS, and HRV measures observed at the endpoint, could indicate enhanced resilience and better autonomic regulation as adolescents adapt to treatment or other environmental changes. These findings emphasize the dynamic nature of HRV and its association with psychological outcomes, particularly in the context of longitudinal improvement.
Conversely, in the control group, higher KIDSCREEN scores were generally associated with reduced HRV, including SDNN and RMSSD. While this may initially appear counterintuitive, it likely reflects an “adaptive reduction” in HRV. In healthy individuals, the ANS maintains stability and is less reactive to external stressors, resulting in a more stable and efficient state. Unlike patients with tic disorders, in whom reduced HRV may signify dysfunction, in healthy children, lower HRV in the context of a high quality of life suggests a state of reduced reactivity and efficient autonomic functioning [24]. This highlights the need to interpret HRV in context, as the same trend may signify pathology in one group and healthy adaptation in another.
No significant relationships between clinical severity, as measured by the YGTSS, and HRV parameters were observed at baseline or endpoint. Tic severity, measured using the YGTSS, was not directly linked to HRV changes, suggesting that the relationship between the clinical presentation of tics and HRV parameters is complex and that many variables are likely involved. However, when observed longitudinally, the changes in the correlation patterns over time suggest a dynamic interplay between ANS function and tic severity. These shifts reflect the evolving impact of tic disorders on ANS regulation or changes in physiological adaptation in response to treatment as well as the importance of longitudinal perspectives in understanding the complex interactions between ANS dysregulation and clinical symptoms.
The results of this 1-year longitudinal study highlight significant ANS dysregulation in adolescents with tic disorders and its relationship with clinical severity and quality of life. At baseline, patients with tic disorders showed lower LF and HF values, indicating reduced sympathetic and parasympathetic activity [16], along with higher SDANN scores, suggesting possible chronic stress or compensatory mechanisms [13,18,19]. During the follow-up period, LF further declined, reflecting progressive sympathetic dysfunction, whereas HF and VLF remained relatively stable, emphasizing the chronic nature of ANS dysregulation. Quality of life scores were inversely correlated with VLF in the patient group at baseline, implying reduced chronic stress as psychosocial well-being improved. In contrast, higher quality of life scores in the controls were linked to reduced HRV, possibly reflecting adaptive autonomic stability.
The relatively small sample size at the endpoint may limit statistical power. Additionally, although the patient and control groups were age-matched at baseline, we did not include age as a covariate in the within-subject analyses. Likewise, although data on therapeutic interventions (e.g., medication use) were available, these were not incorporated into the present analysis. These may limit our ability to distinguish disease-related HRV changes from those associated with normal development or treatment effects. Therefore, research findings should be interpreted with caution. Further research with larger, multi-center samples and longitudinal design is warranted.
In conclusion, the results of this study demonstrated that tic disorders are characterized by chronic and progressive ANS dysregulation, which is directly influenced by the patient’s quality of life. Tailored interventions, especially early and personalized therapeutic strategies aimed at improving the quality of life and addressing specific autonomic imbalances, are crucial for achieving better outcomes in this population.
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