Abstract
Background:
Environmental noise exposure is a potential trigger, potentially exacerbating migraine through stress-related activation of phosphorylated protein kinase C epsilon (PKCε)-mediated nociceptive pathways. Warmth acupuncture therapy offers a potential complementary treatment. This study investigates the effect of nocturnal noise on PKCε markers and the efficacy of warmth acupuncture in patients with migraine.
Methods:
A retrospective cohort study of 220 patients with migraine was conducted. The patients were divided into two groups based on nocturnal noise exposure: low noise [≤45 dB(A), n = 110] and high noise [>45 dB(A), n = 110]. Both groups received warmth acupuncture. Pain, sleep, anxiety, and biochemical markers (p-PKCε, phosphorylated cyclic adenosine monophosphate (cAMP) response element binding protein and phosphorylated signal transducer and activator of transcription 1) were evaluated before and after 1 month of therapy. Continuous variables were compared using independent t-tests, and categorical variables were compared using chi-square tests. Pearson’s correlation analysis was used to assess relationships between noise levels and PKCε pathway markers.
Results:
After 1 month, the low-noise group was associated with significantly more favorable distribution of migraine symptom severity, lower visual analog scale pain scores, better sleep quality, lower anxiety levels, and lower PKCε pathway marker expression than the high-noise group (P < 0.05 for all). Correlation analysis revealed that higher noise levels were significantly associated with increased PKC pathway markers.
Conclusion:
Lower nocturnal noise levels were associated with greater treatment response to warmth acupuncture and reduced PKCε pathway activation, suggesting that environmental noise may play an important role in migraine pathophysiology.
Keywords: migraine, noise, protein kinase c epsilon, acupuncture therapy, pain management
Qiang Liu and XiaoGuang Qin are co-first authors. These authors contributed equally to this work.
KEY MESSAGES
-
(1)
Lower nocturnal environmental noise exposure was associated with significantly enhanced clinical outcomes from warmth acupuncture therapy in patients with migraine, including greater reductions in pain, migraine frequency/duration, and anxiety, and improved sleep quality.
-
(2)
Higher nocturnal noise levels were correlated with increased activation of the phosphorylated protein kinase C epsilon (PKCε) signaling pathway [p-PKCε, phosphorylated cAMP response element binding protein (p-CREB), and phosphorylated signal transducer and activator of transcription 1 (p-STAT1)], suggesting a potential biochemical mechanism through which noise may exacerbate migraine pathophysiology.
-
(3)
Environmental noise reduction may serve as a beneficial nonpharmacological intervention to enhance the efficacy of complementary migraine treatments like warmth acupuncture by mitigating stress-related nociceptive pathway activation.
INTRODUCTION
Migraine is a debilitating neurological disorder characterized by recurrent episodes of severe headache, often accompanied by nausea, vomiting, and sensitivity to light and sound.[1] It affects approximately 12% of the global population, leading to substantial personal and societal burden due to loss of productivity and diminished quality of life.[2,3] Despite advances in pharmacological treatments, a substantial subset of patients continues to experience refractory symptoms or intolerable side effects, prompting a growing interest in complementary therapies. Among these therapies, acupuncture and environmental modifications, such as noise reduction, have gained attention for their potential to enhance therapeutic outcomes.[4]
Environmental factors, particularly noise pollution, were recognized as significant contributors to migraine pathogenesis. Noise exposure can trigger or exacerbate migraine attacks through mechanisms involving the hypothalamic–pituitary–adrenal (HPA) axis, leading to increased release of stress hormones and activation of inflammatory pathways.[5,6] The World Health Organization has underscored the importance of maintaining low nocturnal noise levels to prevent adverse health effects, suggesting levels below 45 dB(A) during the night.[7] Given the sensitivity of migraine sufferers to sensory stimuli, noise pollution presents a unique challenge and opportunity in migraine management.
The protein kinase C epsilon (PKCε) pathway has recently been implicated in migraine pathophysiology, particularly in mediating pain sensitization and neuroinflammation.[8] PKCε is a serine/threonine kinase involved in nociceptive signaling and inflammatory processes.[9] Its activation is associated with sensitization of nociceptive pathways, making it a potential therapeutic target in migraine and other pain disorders. Environmental stressors like chronic noise exposure may contribute to migraine pathogenesis by activating the PKCε pathway, leading to sensitization of trigeminovascular neurons and heightened pain perception.[10]
Acupuncture, a traditional Chinese medicine technique increasingly integrated into modern practice, may modulate these pathways.[11,12] Warm acupuncture, which combines needle insertion with mild heat application, is proposed to enhance treatment effects by improving local circulation and potentially influencing pain and stress modulation systems.[13,14]
However, limited research has explored the potential link among environmental noise exposure, the PKCε signaling pathway, and the therapeutic effects of warmth acupuncture. This study aims to address this gap by examining the impact of nocturnal environmental noise levels on PKCε pathway markers in patients with migraine and evaluating the efficacy of warmth acupuncture therapy.
MATERIALS AND METHODS
Study Design
This retrospective cohort study encompassed 220 patients who received treatment for migraines between October 2022 and December 2023. All data, including nocturnal environmental noise levels, clinical scale assessments, and biomarker levels, were retrieved retrospectively from Gansu University of Traditional Chinese Medicine Affiliated Hospital’s medical record system. Stratified sampling was employed based on demographic information, and general patient information was retrieved from the medical record system. Patients were included in the study if they met the following criteria: (1) fulfillment of the diagnostic criteria for migraine,[15] (2) age of 18 years or older, (3) an average headache frequency of at least once per week, and (4) possession of complete clinical records. The exclusion criteria consisted of the following: (1) having undergone acupuncture treatment or taken medications for migraine prevention within the past month; (2) experiencing secondary headaches such as those due to intracranial hemorrhage, cerebral infarction, or arteriosclerosis; (3) severe impairment of heart, liver, kidney, or other organ functions; (4) cognitive or psychiatric disorders; and (5) hearing impairments [Figure 1].
Figure 1.
Participant flow diagram. PKCε = protein kinase C epsilon.
This study was approved by the Institutional Review Board and Ethics Committee of Gansu University of Traditional Chinese Medicine Affiliated Hospital (No. [2023]52). Informed consent was obtained from all participants involved in this study.[16]
Environmental Noise
The mean noise level (equivalent continuous sound level, Leq) calculated from seven nights of monitoring was used to represent each patient’s exposure. All included patients with migraine were hospitalized, and they underwent standardized nocturnal noise detection in the hospital ward during the treatment period, ensuring consistent exposure to the measured ward noise levels throughout the study. The relevant data were completely recorded in the medical record system. The detection specifications were as follows: Professional portable noise-measuring equipment (model: AWA5688, manufactured by Hangzhou Aihua Instrument Co., Ltd.) conforming to international noise measurement standards was used for continuous noise monitoring. The monitoring was conducted continuously for a period of seven nights in the central area of the hospital ward (at a height of 1.2–1.5 m above the ground, with no obstructions within a 3.5 m radius) during the period from 22:00 PM to 06:00 AM every night. The recorded data were subsequently exported and analyzed using statistical software to calculate the noise levels for each patient. A noise level of 45 dB(A) or below was considered low, based on thresholds commonly adopted in environmental noise standards (e.g., the Chinese GB 3096-2008 standard for residential areas) and prior clinical studies linking nighttime noise above 45 dB to sleep disruption.[17,18,19] Based on the level of nighttime environmental noise, patients were categorized into two groups: a low-noise group (n = 110) and a high-noise group (n = 110).
Variation in noise levels between wards is expected due to factors like location (e.g., proximity to nursing stations, entrances, or equipment), occupancy, and time of night. Using the mean level over seven consecutive nights aimed to provide a representative estimate of exposure and minimize the impact of nightly fluctuations.
Treatment Method
The acupoints Taichong and Yanglingquan were utilized in the treatment protocol. The patients were instructed to sit upright in a natural posture. A 25-mm filiform needle was inserted, with the tip slightly angled toward the affected side, reaching a depth of 12 to 22 mm. Upon needle insertion, the practitioner sought to elicit the characteristic needling sensation (deqi), which was reported by the patient as a feeling of soreness, numbness, fullness, or heaviness. Upon confirmation of this sensation by the patient, the warm-needle moxibustion technique was applied. Concurrently, firm pressure was applied with the left thumb on the area below the acupoint to guide the needle sensation along the affected side toward the forehead. The needle remained in place for 15 minutes. This treatment was conducted three times a week over a span of 4 consecutive weeks. The patients were instructed not to receive any other acute migraine medications or preventive drugs during the treatment period. Nonpharmacological interventions were prohibited. Any deviations from this protocol were recorded, and adjustments were made in the data analysis to account for these factors. The patients’ pain levels, sleep quality, anxiety levels, and biomarker levels were evaluated on the first day and 1 month following the treatment. These assessments aimed to determine the immediate and short-term effects of the warm-needle moxibustion technique and the impact of noise exposure.
Symptom Improvement Assessment
The Headache Impact Test-6 (HIT-6) scale evaluates the degree of symptom improvement in patients before treatment and 1 month after treatment.[20] A Likert-type frequency rating scale is used as follows: never (6 points), rarely (8 points), sometimes (10 points), very often (11 points), and always (13 points). The total score is calculated by summing the scores of all items (range: 36–78 points), with the following severity classifications: severe impact (≥60 points), substantial impact (56–59 points), moderate impact (50–55 points), and minimal/no impact (≤49 points). HIT-6 has demonstrated good reliability in assessing headache impact, with a Cronbach’s alpha coefficient of 0.89.[21]
Pain Score
The visual analog scale (VAS) was used to evaluate pain levels in both groups before treatment and 1 month after treatment.[22] Pain was categorized as follows: no pain (0 points), mild pain (1–3 points), moderate pain (4–6 points), severe pain (7–9 points), and acute severe pain (10 points). The reliability of VAS, as measured by Cronbach’s alpha, was 0.94.[23]
Migraine Degree Assessment
Migraine characteristics, including average attack duration per day and frequency per week, were assessed based on patient headache diaries maintained during the study period.
Sleep Quality
The patients were evaluated using the Pittsburgh Sleep Quality Index (PSQI) before treatment and 1 month after treatment. PSQI assesses various sleep dimensions such as sleep quality, sleep latency (time taken to fall asleep), sleep duration, and sleep efficiency (ratio of sleep time to total time in bed). Each item was rated on a scale from 0 to 3, with the overall score ranging up to a maximum of 21. Higher scores suggest poorer sleep quality. The scale demonstrated a Cronbach’s alpha reliability coefficient of 0.791.[24]
Anxiety Score
The patients’ anxiety levels were evaluated using the Hamilton Anxiety Rating Scale (HAMA) before treatment and 1 month post-treatment. HAMA consists of 14 items, each defined by a series of symptoms. Each item is scored on a scale of 0 (not present) to 4 (severe), with a total score range of 0 to 56. Scores of 0 to 7 were deemed normal, 8 to 14 suggest mild anxiety, 15 to 21 indicate moderate anxiety, and scores above 22 denote severe anxiety. HAMA demonstrated a Cronbach’s alpha reliability coefficient of 0.92.[25]
Enzyme-Linked Immunosorbent Assay
Two milliliters of fasting venous blood were drawn from the patients before treatment and 1 month after treatment and collected in vacuum tubes containing ethylenediaminetetraacetic acid as an anticoagulant. Plasma was separated by centrifugation at 3000 rpm for 15 minutes at 4°C and stored at −80°C until analysis. The expression levels of p-PKCε (ab309278, Abcam, UK), phosphorylated cAMP response element-binding protein [p-CREB (ab279763, Abcam, UK)], and phosphorylated signal transducer and activator of transcription 1 [p-STAT1 (ab126454, Abcam, UK)] were determined using commercially available enzyme-linked immunosorbent assay kits in accordance with the manufacturers’ instructions. The optical density values for all samples were normalized and expressed as a percentage relative to a pooled plasma sample from 50 age- and sex-matched healthy volunteers with no history of migraine or other chronic pain conditions to standardize the measurements across experiments and facilitate biological interpretation. This reference sample was defined as 100% and included on each assay plate. All kits have been validated for specificity, sensitivity, and reproducibility by the manufacturer for human plasma samples. All reagents, standard dilutions, controls, and test samples were prepared at room temperature. The assay employed a quantitative sandwich enzyme immunoassay technique. Optical density was measured using a microplate reader (ELX 800, BioTek, USA) at wavelengths between 450 and 570 nm.
Statistical Analysis
Data were analyzed using SPSS statistical software (version 29.0, SPSS Inc., Chicago, IL, USA). Categorical data were represented as n (%). For between-group comparisons of categorical variables, the chi-square test was employed using the basic formula and denoted by χ2. For within-group comparisons of the same categorical variables, the McNemar–Bowker test was used. Continuous variables were initially assessed for normal distribution using the Shapiro–Wilk test. For normally distributed continuous data, results were presented as mean ± standard deviation. Between-group comparisons were performed using independent sample t-tests. Within-group comparisons of normally distributed continuous variables were analyzed using the paired-sample t-test. Pearson’s correlation analysis was utilized to examine relationships between the variables. Multivariable regression analyses were performed using linear regression models with baseline adjustment to further investigate the association between nocturnal noise exposure and migraine outcomes while controlling for potential confounders. Results were presented as adjusted mean differences (aMDs) with 95% confidence intervals (CIs). A P-value of less than 0.05 was considered indicative of statistical significance.
RESULTS
Demographic and Basic Data
The low-noise group (n = 110) and the high-noise group (n = 110) did not show statistically significant differences across a range of variables [Table 1]. Specifically, age, gender distribution, body mass index (BMI), hypertension, diabetes, smoking and drinking history, family history of headache, headache types, lateralization, response to painkillers, employment status, and educational level were similar, as indicated by nonsignificant P-values (P > 0.05) for each parameter. The defining characteristic differentiating the two groups was the noise level exposure, with the high-noise group experiencing significantly higher mean nocturnal noise levels than the low-noise group, with a t-value of 38.674 and a highly significant P-value (P < 0.001). This difference in environmental noise exposure served as the basis for the subsequent analyses of its association with migraine-related biochemical pathways and response to warmth acupuncture.
Table 1.
Comparison of Demographic and Basic Data between Two Groups.
| Parameters | Low Noise Group (n = 110) | High Noise Group (n = 110) | t/χ 2 | P |
|---|---|---|---|---|
| Age (years) | 47.58 ± 5.83 | 48.18 ± 3.64 | 0.921 | 0.358 |
| Gender (female, %) | 79 (71.82%) | 86 (78.18%) | 1.188 | 0.276 |
| BMI (kg/m2) | 23.28 ± 1.26 | 23.15 ± 1.03 | 0.843 | 0.400 |
| Hypertension [n (%)] | 26 (23.64%) | 31 (28.18%) | 0.592 | 0.442 |
| Diabetes [n (%)] | 20 (18.18%) | 22 (20.00%) | 0.118 | 0.732 |
| Smoking history [n (%)] | 11 (10%) | 10 (9.09%) | 0.053 | 0.819 |
| Drinking history [n (%)] | 15 (13.64%) | 14 (12.73%) | 0.040 | 0.842 |
| Family history of headache [n (%)] | 46 (41.82%) | 42 (38.18%) | 0.303 | 0.582 |
| Types [n (%)] | 0.440 | 0.803 | ||
| -Chronic tension | 23 (20.91%) | 24 (21.82%) | ||
| -Migraine with aura | 62 (56.36%) | 65 (59.09%) | ||
| -Migraine without aura | 25 (22.73%) | 21 (19.09%) | ||
| Lateralization [n (%)] | 0.335 | 0.563 | ||
| -Unilateral | 77 (70.00%) | 73 (66.36%) | ||
| -Bilateral | 33 (30.00%) | 37 (33.64%) | ||
| Response to painkiller [n (%)] | 59 (53.64%) | 65 (59.09%) | 0.665 | 0.415 |
| Employment status [n (%)] | 1.145 | 0.285 | ||
| -Employed | 88 (80.00%) | 94 (85.45%) | ||
| -Unemployed | 22 (20.00%) | 16 (14.55%) | ||
| Education level [n (%)] | 0.104 | 0.748 | ||
| -High school or lower | 84 (76.36%) | 86 (78.18%) | ||
| -University or higher | 26 (23.64%) | 24 (21.82%) | ||
| Noise level (dB[A]) | 40.12 ± 2.17 | 53.28 ± 2.83 | 38.674 | <0.001 |
BMI = body mass index
Symptom Assessment
Table 2 shows the comparison results of the impact degree of symptoms between the two groups. Before treatment, no significant differences were observed in symptom severity distribution between the two groups across all categories (P > 0.05).
Table 2.
Comparison of Symptom Assessment between Two Groups.
| Efficacy | Low-Noise Group (n = 110) | High-Noise Group (n = 110) | χ 2 | P |
|---|---|---|---|---|
| Before treatment | 0.773 | 0.856 | ||
| Minimal impact | 12 (10.91%) | 11 (10.00%) | ||
| Moderate impact | 16 (14.55%) | 12 (10.91%) | ||
| Substantial impact | 38 (34.55%) | 41 (37.27%) | ||
| Severe impact | 44 (40.00%) | 46 (41.82%) | ||
| After treatment 1 month | 9.260 | 0.026 | ||
| Minimal impact | 31 (28.18%) | 18 (16.36%) | ||
| Moderate impact | 34 (30.91%) | 25 (22.73%) | ||
| Substantial impact | 22 (20.00%) | 35 (31.82%) | ||
| Severe impact | 23 (20.91%) | 32 (29.09%) | ||
| χ2 | 25.724 | 9.244 | ||
| P | <0.001 | 0.026 |
The within-group comparisons were analyzed using the McNemar–Bowker test for paired categorical data. The categories and scoring ranges of HIT-6 were as follows: severe impact (≥60 points), substantial impact (56–59 points), moderate impact (50–55 points), and minimal/no impact (≤49 points).
However, 1 month after treatment, significant differences were noted in the distribution of symptom severity between the two groups (χ2 = 9.26, P = 0.026). From the perspective of data distribution, the proportions of substantial and severe impact in the high-noise group were higher than those in the low-noise group. Meanwhile, the proportions of minimal impact and moderate impact in the low-noise group were higher than those in the high-noise group, suggesting that lower noise exposure was associated with more favorable symptom improvements. The within-group analyses using the McNemar–Bowker test (χ2 = 25.724, P < 0.001 for the low-noise group and χ2 = 9.244, P = 0.026 for the high-noise group) further support the significant improvement in outcomes associated with reduced noise levels.
Visual Analog Scale
Before treatment, both groups showed similar VAS scores (P = 0.667, Table 3). However, by 1 month post-treatment, a significant difference emerged: the low-noise group’s VAS scores significantly decreased compared with the high-noise group’s scores. This difference was highly statistically significant with a t-value of 9.907 (P < 0.001). The within-group analyses highlighted significant reductions in pain, with t-values of 22.701 for the low-noise group and 12.434 for the high-noise group, both with corresponding P-values <0.001. These findings indicate that lower nocturnal noise exposure was associated with greater pain reductions in patients with migraine receiving warmth acupuncture therapy.
Table 3.
Comparison of Visual analog scale between Two Groups.
| Parameters | Low-Noise Group (n = 110) | High-Noise Group (n = 110) | t | P |
|---|---|---|---|---|
| Before treatment | 4.68 ± 0.45 | 4.65 ± 0.48 | 0.431 | 0.667 |
| After treatment 1 month | 3.24 ± 0.49 | 3.87 ± 0.45 | 9.907 | <0.001 |
| t | 22.701 | 12.434 | ||
| P | <0.001 | <0.001 |
Migraine Degree
Before treatment, the duration of migraine episodes per day did not differ significantly between the groups (t = 1.346, P = 0.180, Table 4). At 1 month post-treatment, a notable reduction was observed in the low-noise group, where the duration significantly decreased compared with that in the high-noise group, resulting in a significant between-group difference (t = 5.592, P < 0.001). The within-group analysis confirmed significant reductions for both groups, with t-values of 11.523 (P < 0.001) for the low-noise group and 6.254 (P < 0.001) for the high-noise group.
Table 4.
Comparison of Migraine Degree between Two Groups.
| Parameters | Time | Low-Noise Group (n = 110) | High-Noise Group (n = 110) | t | P |
|---|---|---|---|---|---|
| Duration of migraine a day (h) | Before treatment | 7.34 ± 1.56 | 7.08 ± 1.23 | 1.346 | 0.180 |
| After treatment 1 month | 5.23 ± 1.12 | 6.08 ± 1.14 | 5.592 | <0.001 | |
| t | 11.523 | 6.254 | |||
| P | <0.001 | <0.001 | |||
| Frequency of migraine a week (days/week) | Before treatment | 3.15 ± 0.37 | 3.21 ± 0.32 | 1.377 | 0.170 |
| After treatment 1 month | 2.24 ± 0.26 | 2.96 ± 0.37 | 16.882 | <0.001 | |
| t | 21.105 | 5.360 | |||
| P | <0.001 | <0.001 |
Similarly, the frequency of migraine episodes per week showed no significant difference between the groups before treatment (t = 1.377, P = 0.170). At 1 month post-treatment, the low-noise group demonstrated a significant decrease in frequency compared with the high-noise group (t = 16.882, P < 0.001). The within-group analyses indicated significant reductions in frequency, with t-values of 21.105 (P < 0.001) for the low-noise group and 5.360 (P < 0.001) for the high-noise group. These results suggest that lower nocturnal environmental noise exposure was associated with greater reductions in the duration and frequency of migraines in patients receiving warmth acupuncture therapy.
Sleep Quality
Before treatment, no significant differences were observed in the PSQI total score between the groups (t = 0.508, P = 0.612, Table 5). However, at 1 month post-treatment, the low-noise group exhibited a greater improvement than the high-noise group (t = 2.968, P = 0.003).
Table 5.
Comparison of Sleep Quality between Two Groups.
| Parameters | Time | Low Noise Group (n = 110) | High Noise Group (n = 110) | t | P |
|---|---|---|---|---|---|
| PSQI total score | Before treatment | 10.08 ± 1.75 | 10.19 ± 1.58 | 0.508 | 0.612 |
| After treatment 1 month | 6.59 ± 1.24 | 7.11 ± 1.35 | 2.968 | 0.003 | |
| t | 17.066 | 15.544 | |||
| P | <0.001 | <0.001 | |||
| Sleep quality | Before treatment | 2.21 ± 0.34 | 2.25 ± 0.37 | 0.820 | 0.413 |
| After treatment 1 month | 1.65 ± 0.61 | 1.83 ± 0.49 | 2.363 | 0.019 | |
| t | 8.410 | 7.174 | |||
| P | <0.001 | <0.001 | |||
| Sleep latency | Before treatment | 2.21 ± 0.41 | 2.24 ± 0.42 | 0.658 | 0.511 |
| After treatment 1 month | 1.76 ± 0.37 | 1.91 ± 0.45 | 2.689 | 0.008 | |
| t | 8.546 | 5.623 | |||
| P | <0.001 | <0.001 | |||
| Sleep duration | Before treatment | 2.18 ± 0.42 | 2.14 ± 0.38 | 0.863 | 0.389 |
| After treatment 1 month | 1.72 ± 0.35 | 1.85 ± 0.41 | 2.626 | 0.009 | |
| t | 8.825 | 5.441 | |||
| P | <0.001 | <0.001 | |||
| Sleep efficiency | Before treatment | 2.03 ± 0.43 | 2.07 ± 0.44 | 0.700 | 0.485 |
| After treatment 1 month | 1.58 ± 0.45 | 1.75 ± 0.32 | 3.061 | 0.003 | |
| t | 7.583 | 6.169 | |||
| P | <0.001 | <0.001 |
PSQI = Pittsburgh Sleep Quality Index
In terms of specific sleep parameters, the sleep quality scores improved significantly over 1 month in both groups. However, more pronounced changes were noticed in the low-noise group (t = 8.410, P < 0.001), with an after-treatment score of 1.65 ± 0.61 compared with 1.83 ± 0.49 in the high-noise group (t = 2.363, P = 0.019). Sleep latency, duration and efficiency showed significant improvements after 1 month. The low-noise group exhibited improvements in sleep latency, sleep duration and sleep efficiency, each with highly significant within-group reductions over time (P < 0.001). In comparison, the high-noise group’s improvements remained statistically significant but less substantial (sleep latency: t = 2.689, P = 0.008; sleep duration: t = 2.626, P = 0.009; sleep efficiency: t = 3.061, P = 0.003). These findings indicate that lower noise exposure was associated with greater improvements in the sleep quality of patients with migraine receiving warmth acupuncture therapy.
Anxiety Score
Before treatment, the anxiety scores were comparable between the low- and high-noise groups, with no significant difference (t = 0.126, P = 0.900, Table 6). However, at 1 month post-treatment, the low-noise group exhibited a more substantial reduction in anxiety scores than the high-noise group. This difference was statistically significant (t = 2.966, P = 0.003). The within-group analysis confirmed these reductions as highly significant, with the low-noise group showing greater improvement (t = 5.458, P < 0.001) than the high-noise group (t = 2.973, P = 0.003). These results suggest that lower noise exposure was associated with greater reductions in the anxiety levels of patients with migraine receiving warmth acupuncture therapy.
Table 6.
Comparison of Anxiety Score between Two Groups.
| Parameters | Low-Noise Group (n = 110) | High-Noise Group (n = 110) | t | P |
|---|---|---|---|---|
| Before treatment | 8.84 ± 3.56 | 8.78 ± 3.57 | 0.126 | 0.900 |
| After treatment 1 month | 6.64 ± 2.28 | 7.57 ± 2.34 | 2.966 | 0.003 |
| t | 5.458 | 2.973 | ||
| P | <0.001 | 0.003 |
Protein Kinase C Epsilon Pathway Markers
For p-PKC (% of control), both groups exhibited reductions at 1 month post-treatment, but the low-noise group demonstrated a more pronounced decrease than the high-noise group, resulting in a highly significant difference (t = 5.773, P < 0.001, Table 7). The within-group analysis showed significant reductions in both groups (t = 16.911 for low noise, t = 12.404 for high noise, both P < 0.001).
Table 7.
Comparison of Protein Kinase C Epsilon Pathway Markers between Two Groups.
| Parameters | Time | Low-Noise Group (n = 110) | High-Noise Group (n = 110) | t | P |
|---|---|---|---|---|---|
| p-PKC (% of control) | Before treatment | 115.28 ± 15.38 | 118.67 ± 16.34 | 1.584 | 0.115 |
| After treatment 1 month | 85.47 ± 10.26 | 94.36 ± 12.47 | 5.773 | <0.001 | |
| t | 16.911 | 12.404 | |||
| P | <0.001 | <0.001 | |||
| p-CREB (% of control) | Before treatment | 124.36 ± 13.18 | 122.69 ± 13.67 | 0.922 | 0.357 |
| After treatment 1 month | 84.15 ± 10.42 | 96.48 ± 11.34 | 8.398 | <0.001 | |
| t | 25.101 | 15.477 | |||
| P | <0.001 | <0.001 | |||
| p-STAT1 (% of control) | Before treatment | 106.24 ± 10.36 | 107.26 ± 11.12 | 0.702 | 0.483 |
| After treatment 1 month | 83.54 ± 10.21 | 96.45 ± 10.13 | 9.419 | <0.001 | |
| t | 16.368 | 7.537 | |||
| P | <0.001 | <0.001 |
% of control indicates that values are expressed as percentage relative to a pooled plasma sample from healthy volunteers defined as 100%; p-CREB = phosphorylated cAMP response element binding protein, p-PKC = phosphorylated protein kinase C, p-STAT1 = phosphorylated signal transducer and activator of transcription 1
Similarly, the p-CREB measurements (% of control) indicated a greater reduction in the low-noise group. This difference was highly significant (t = 8.398, P < 0.001), with within-group t-values indicating significant changes (t = 25.101 for low noise, t = 15.477 for high noise, both P < 0.001).
In the case of p-STAT1 (% of control), both groups started with similar levels before treatment and experienced reductions at 1 month post-treatment. However, the low-noise group’s values decreased more significantly than the high-noise group’s values, with a significant between-group difference (t = 9.419, P < 0.001). The reductions were significant within both groups (t = 16.368 for low noise, t = 7.537 for high noise, both P < 0.001). These findings suggest that reduced nocturnal environmental noise was associated with more substantial modulations in PKCε pathway markers, highlighting the enhanced efficacy of warmth acupuncture therapy in less noisy environments for patients with migraine.
Correlation Analysis between Noise Level and Protein Kinase C Epsilon Pathway Markers
The correlation coefficient (r) for p-PKC (% of control) was 0.352, indicating a moderate positive correlation with noise levels, and this relationship was statistically significant (P < 0.001, Figure 2). Similarly, p-CREB (% of control) showed a stronger positive correlation with noise levels, with an r of 0.487 (P < 0.001), suggesting that higher noise levels were significantly associated with higher p-CREB levels. The strongest correlation was observed for p-STAT1 (% of control), with an r of 0.496, demonstrating a significant and robust positive association (P < 0.001). These findings indicate that higher nocturnal noise levels were correlated with increased levels of these PKCε pathway markers, suggesting a potential mechanistic link between environmental noise exposure and biological pathways influencing migraine pathophysiology.
Figure 2.
Correlation analysis between noise level and PKCε pathway markers: (a) p-PKC and noise level, (b) p-CREB and noise level, and (c) p-STAT1 and noise level. ⚫ indicates data points included in the analysis. p-CREB = phosphorylated cAMP response element binding protein, p-PKC = phosphorylated protein kinase C, p-STAT1 = phosphorylated signal transducer and activator of transcription 1.
Multivariable Regression Analyses
Multivariable regression analyses were performed to control for potential confounding variables. The multivariable linear regression models, adjusting for baseline values, age, gender, and BMI, confirmed the significant associations between higher noise exposure and less improvement in continuous outcomes post-treatment. The results, expressed as aMDs between the high- and low-noise groups for post-treatment values with 95% CIs, are presented in Table 8. After adjustment for these potential confounders, exposure to higher nocturnal noise levels remained significantly associated with less improvement in all measured clinical and biomarker outcomes following warmth acupuncture therapy.
Table 8.
Adjusted Analysis of Treatment Outcomes Based on Noise-Exposure Group.
| Outcome Measure | Adjusted Mean Difference (aMD)* | 95% CI | P-Value |
|---|---|---|---|
| VAS score | 0.58 | 0.42–0.74 | <0.001 |
| PSQI total score | 0.61 | 0.25–0.97 | 0.001 |
| HAMA score | 0.94 | 0.32–1.56 | 0.003 |
| p-PKCε (% of control) | 9.12 | 6.25–11.99 | <0.001 |
| p-CREB (% of control) | 12.58 | 9.84–15.32 | <0.001 |
| p-STAT1 (% of control) | 13.05 | 10.21–15.89 | <0.001 |
Positive aMD values indicate worse outcome (higher score/level) in the high-noise group than in the low-noise group after adjustment for baseline value, age, gender, and BMI; aMD = adjusted mean difference, HAMA, Hamilton anxiety rating scale, p-CREB = phosphorylated cAMP response element binding protein, p-PKCε = phosphorylated protein kinase C epsilon, PSQI = Pittsburgh Sleep Quality Index, p-STAT1 = phosphorylated signal transducer and activator of transcription 1, VAS = visual analog scale
DISCUSSION
This retrospective cohort study explored the complex interplay between nocturnal environmental noise levels and their influence on PKCε pathway markers, as well as the efficacy of warmth acupuncture therapy in mitigating migraine manifestations. The absence of significant baseline differences between the groups in terms of demographics, clinical features, or biomarker levels suggests that the subsequent divergence in outcomes is likely attributable to the differential noise exposure during the treatment period rather than pre-existing disparities.
The significant improvement in clinical outcomes, including pain reduction, improved sleep quality, and lower anxiety scores, and the parallel, more pronounced reduction in PKCε pathway markers (p-PKCε, p-CREB, and p-STAT1) observed in the low-noise group suggest that the therapeutic efficacy of warmth acupuncture is enhanced in a quieter environment. This integrated effect may be attributed to reduced environmental stress, which mitigates nociceptive sensitization and facilitates the treatment’s neuromodulatory actions. The significant finding that decreased nocturnal noise levels lead to improved treatment outcomes highlights the sensitivity of migraine sufferers to environmental noise, suggesting that noise pollution should be considered a critical factor in migraine management strategies. Environmental noise is known to cause physiological stress, which can exacerbate migraine episodes.[26,27] The body’s response to stress often involves the activation of the HPA axis, leading to the release of cortisol and other stress hormones.[28,29] Such activation may potentiate inflammatory pathways and increase nociceptive sensitivity, which are acknowledged triggers for migraines.[30] The reduction in migraine frequency and intensity observed in the low-noise group may be attributed to decreased environmental stress, mitigating these pathways and enhancing the body’s response to complementary therapies like warmth acupuncture.
The observed correlation between decreased noise exposure and reduced levels of p-PKCε pathway markers further supports the hypothesis that noise impacts migraine pathogenesis through biochemical pathways. The PKCε signaling pathway is a crucial mediator of cellular responses to stress and pain.[31,32] Its activation is implicated in the sensitization of pain pathways, particularly in response to repeated or chronic stressors, as found in persistent noise exposure.[33] The findings of the present study suggest that environmental noise may drive PKCε activation, thereby enhancing migraine pathophysiology. The more pronounced reduction in PKCε pathway markers in the low-noise group may indicate that warmth acupuncture counteracts this activation more effectively in a quieter environment, facilitating its therapeutic efficacy.
Another critical observation was the lesser reduction in PKCε, p-CREB, and p-STAT1 markers within the high-noise group, which may explain the decreased efficacy of warmth acupuncture for patients exposed to high noise levels. This finding can be attributed to the theory of stress-induced resistance to treatment, where chronic exposure to environmental stressors, such as noise, leads to adaptive mechanisms that blunt the body’s responsiveness to therapy. This study hypothesized that chronic noise exposure may sustain increased baseline levels of stress and inflammatory markers, potentially leading to adaptive mechanisms that reduce the body’s relative responsiveness to therapy aimed at similar pathways. These adaptive changes could explain the attenuated treatment effects observed in the high-noise group.[34] Consequently, warmth acupuncture’s ability to modulate pain and anxiety may be attenuated under such circumstances, underscoring the importance of optimizing environmental factors to enhance therapy outcomes.
Sleep is a critical factor influencing migraine, and disturbances in sleep quality often exacerbate migraine symptoms.[35] The present study demonstrated that decreased nocturnal noise levels were associated with significant reductions in migraine-related pain, as evidenced by VAS scores. These reductions in pain were likely to contribute to improved sleep quality, as measured by PSQI scores. Sleep disturbances are known to augment pain perception and reduce pain thresholds, creating a feedback loop that exacerbates migraine symptoms.[36,37] By alleviating the severity of migraine pain, warmth acupuncture may break this cycle, allowing for enhanced restorative sleep processes. Therefore, the reduction in environmental noise appears to facilitate more effective pain management, which, in turn, promotes enhanced sleep and further contributes to the overall improvement in migraine treatment outcomes.
Anxiety scores decreased significantly in the low-noise group, suggesting an anxiolytic effect of warmth acupuncture that was potentiated in quieter settings. Anxiety is both a symptom and a trigger of migraines, likely mediated through overlapping neural pathways governing stress and pain.[38] Noise serves as a persistent stressor, likely exacerbating underlying anxiety levels.[39] By providing a calmer nocturnal atmosphere, these pathways could potentially return to baseline more rapidly, thereby reducing anxiety levels and enabling warmth acupuncture to exert its full therapeutic potential.
These observations were not isolated but may be explained through the lens of broader neurophysiological mechanisms. Central sensitization, characterized by heightened responsiveness to sensory stimuli in the central nervous system, is a well-documented feature of migraines.[40] Environmental noise may act as a constant peripheral input, promoting central sensitization and potentially counteracting the desensitization efforts of treatments like warmth acupuncture. The decreased VAS scores and improvements in attack frequency and duration in quieter environments indicate that the modulation of this central sensitization is critical and achievable by minimizing noise exposure.
Additionally, the correlation analysis highlights the robust association between noise levels and PKCε pathway activation, as well as their subsequent impact on migraine severity. These findings suggest that beyond the peripheral and immediate impacts of noise, a deeper, chronic influence exists through biochemical pathways that modulate migraine pathophysiology. Unraveling the exact nature of these biological interactions warrants further investigation but underscores the relevance of considering environmental and lifestyle factors together with traditional treatment modalities.
The limitations of this study must be acknowledged, including its observational nature, which precludes causal inferences. Although this study attempted to control for key demographic and clinical variables, residual confounding by unmeasured factors (e.g., detailed medication adherence, specific room conditions, and other environmental stressors) cannot be ruled out. This approach may introduce variability and potential biases in assessing the true impact of environmental noise on migraine symptoms and treatment outcomes. This study, while primarily retrospective, incorporates a cross-sectional analysis of PKCε pathway markers. This approach is limited by its retrospective nature. Additionally, the study relied on self-reported measures, which, although validated, were subject to bias. Furthermore, a formal mediation analysis was not performed to statistically quantify the role of the PKCε pathway in linking noise exposure to treatment efficacy. Investigating this mediating effect could be a valuable direction for future research with larger sample sizes and tailored designs. Future studies should aim at incorporating longitudinal designs to capture temporal variability and a more extensive biomarker profiling to fully elucidate the mechanistic interactions between environmental noise and migraine pathophysiology.
CONCLUSION
This study underscores the interconnectedness of environmental conditions, physiological stress markers, and therapeutic efficacy in migraine management. It advocates for a comprehensive approach to migraine treatment that includes environmental noise mitigation as a potential non-pharmacological intervention, thereby enhancing the effectiveness of traditional and complementary therapies. Understanding the multifaceted interactions among these factors opens avenues for more personalized migraine management strategies, offering promise for improved quality of life among sufferers.
Availability of data and materials
The datasets used during the present study are available from the corresponding author upon reasonable request.
Author contributions
Liu Q and Qin XG conceptualized and designed the study, and were responsible for data interpretation and manuscript drafting. Luo CL, Zhao ZT, and Xie WJ Zhang supervised patient recruitment and data collection, and conducted noise level measurements and statistical analysis. Qin X and Du XZ Zhang revised the manuscript for critical content. All authors have read and approved the final manuscript.
Ethics approval and consent to participate
This study was reviewed and approved by the ethics committee of Gansu University of Traditional Chinese Medicine Affiliated Hospital (No. [2023]52). Informed consent was obtained from all participants involved in this study.
Financial Support and Sponsorship
This study was supported by the Gansu Provincial Department of Education 2020 Innovation Ability Improvement Project: The Regulation Mechanism of PKCε Pathway in Migraine Model Rats under the Intervention of Wentong Acupuncture Based on the Theory of Pain Sensitivity. PKCε Pathway Regulation Mechanism (No. 2020B-52).
Conflict of Interests
No conflicts of interest exit in the submission of this manuscript.
Acknowledgment
Not applicable.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets used during the present study are available from the corresponding author upon reasonable request.
