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. 2024 Nov 1;69(12):4405–4415. doi: 10.1007/s10620-024-08694-1

Abnormal Autonomic Nervous Regulation in Patients with Globus Pharyngeus

Peter Liptak 1, Zuzana Visnovcova 2, Nikola Ferencova 2,3, Martin Duricek 1, Peter Banovcin 1,✉, Ingrid Tonhajzerova 3
PMCID: PMC11602782  PMID: 39487381

Abstract

Background

Globus pharyngeus could be described as a benign sensation of lump or foreign object in the throat. The etiology of the globus as a solitary syndrome is still unknown, but it is proposed that stress could have an important role in symptom emergence.

Aims

To evaluate the autonomic nervous regulation in patients with globus compared to healthy controls in reaction to stress.

Methods

Patients included in the study were diagnosed based on ROME IV criteria for Disorders of Gut Brain Interaction. Besides globus, the patients did not suffer any other substantial medical condition. As a control group, measurement of healthy volunteers was performed. Both groups underwent the same stress protocol assessment in the same laboratory settings. The protocol consist of two types of stressors: cold pressor test and mental arithmetic test to test different types of autonomic reactivity.

Results

Baroreflex sensitivity was significantly decreased in patients compared to controls in all phases of the protocol. Low-frequency band of systolic blood pressure variability was significantly increased during both stress phases in patients compared to controls. High-frequency band of heart rate variability was significantly decreased in patients compared to controls during the both of the stress phases.

Conclusion

The results of this study shows discrete abnormalities in complex autonomic reflex control which are predominantly manifested in response to stressful stimuli indicating altered neurocardiac regulation as a reaction to stress associated with globus pharynegus. This fact could have an important role in the personalized management of globus patients such as biofeedback.

Keywords: Globus, ANS, Stress, Pathophysiology, Etiology

Introduction

Globus represents a symptom with various definitions. The most common description of globus could be a sensation of lump or foreign object in the throat. Important character of globus is that it is nonpainful, occurs with dry swallowing and disappears with meal ingestion. It could be constant or intermittent [1]. The typical area of sensation is in aboral region from the cricoid region to the proximal edge of sternum, roughly around fossa jugularis [2]. It could occur and be associated with dysphagia, odynophagia, heartburn or chronic cough [1] or as a solitary symptom without known etiological factor and thus known as the Globus syndrome [3].

The globus sensation was first described approximately 2500 years ago and for a long period of time was coined as “globus hystericus” and was inaccurately considered to be associated with women with hysterical personality [4]. Only in the past 50 years the more proper term globus pharyngeus became the normative description of the condition [5].

The prevalence is not exactly known due to the lack of relevant published studies but varies between 0.1 and 21% [1]. The recent study suggest that the worldwide prevalence is 0.9% in females and 0.7% in males [6].The sex difference is not clearly established but several studies reported its more frequent occurrence in women [1].

The etiology of the globus pharyngeus as a solitary syndrome is still unknown. The diagnosis is based on fulfilling the symptomatic ROME IV criteria [7] with normal findings on the upper endoscopy [8] and with gastroesophageal reflux disease (GERD) ruled out as a triggering factor [7]. Solitary report suggest non acidic proximal reflux as a possible contributing factor for globus symptoms [9]. Several pathophysiological mechanisms has been proposed with stress as a possible main contributing factor [10].

Autonomic nervous system (ANS) represents a principal regulatory mechanism in homeostasis. In particular, cardiovascular system is extremely sensitive to sympathetic and parasympathetic regulatory inputs. While heart rate variability (HRV), i.e., oscillations of the heart rate around it mean value, is predominantly under cardiac parasympathetic control, blood pressure variability (BPV) provides important information about sympathetic vasomotor regulatory mechanisms [11]. Moreover, short-term regulation of blood arterial pressure and heart rate is mediated by the cardiac baroreceptor reflex mechanism [12, 13]. The normal functioning of sympathovagal reflex control and dynamic balance is crucial for the adaptability and flexibility of the organism. There is an emerging evidence that the brain gut axis model, describing the bidirectional relationship between gut and central, autonomic and enteral neuronal system and exogenous noxes such as stress, could be applied to the esophageal neuromotility disorders such as functional heart burn, functional dypshagia, or globus pharynegus [14].Thus, autonomic imbalance toward sympathetic overactivity associated with vagal underactivity represents potential pathophysiological pathway leading to arise and continuation of symptoms of this group of disorders [15]. However, the studies concerning ANS and globus pharyngeus are scarce. Therefore, we present here results of a study of the autonomic nervous regulatory mechanisms in patients with globus pharyngeus syndrome related to the various types of stress stimuli.

Materials and Methods

Subjects

The studied cohort consists of 15 patients (4 males – average age: 43.7 ± 14.0yrs.) with globus and 12 healthy subjects (control group, 9 males – average age: 28.7 ± 4.3yrs.). Basic group characteristics is summarized in the Table 1. The patients suffering from globus included in this study were recruited from the outpatients treated in the Clinic of Internal Medicine- Gastroeneterology of Jessenius Faculty of Medicine and University Hospital in Martin. The diagnosis was performed according to ROME IV criteria which are stated as follows: All criteria should be present for the preceding 3 months and the symptom should have started at least 6 months prior to diagnosis. Symptoms should be present at least once per week and are presented as persistent or intermittent, painless sensation of a lump or foreign body in the throat with no structural lesion identified on physical examination, laryngoscopy or endoscopy. Furthermore they occurre between meals in the absence of dysphagia or odynophagia and absence of a gastric inlet patch in the proximal oesophagus. For the diagnosis is also important to evaluate the absence of evidence that gastro-oesophageal reflux or eosinophilic oesophagitis is causing symptoms and the absence of major oesophageal motor disorders (achalasia gastro-oesophageal junction obstruction, diffuse oesophageal spasm, jackhammer oesophagus, absent peristalsis [16]. All patients underwent upper endoscopy (to ensure the absence of gastric inlet patch, signs of reflux disease inflammation, or neoplasia), esophageal high resolution manometry (to ensure the absence of major esophageal motor disturbances), and 24 h pH monitoring with impedance (to ensure the absence of gastroesophageal reflux disease that could lead to disturbances in cardiac autonomic response and thus influence the measured parameters [17]). Also, all of the patients included in the study did not take any medication that could affect cardiovascular and/or neurological system including neuromodulants, calcium channels blocators, beta blocators. They did not suffer from any known cardiovascular, endocrine, psychiatric, metabolic, or neurological disorder. The volunteers in both case and control group were chosen according to following exclusion criteria: no history of neurological, metabolic, endocrine, respiratory, and cardiovascular diseases, without acute infection, and abnormal weight (underweight and obesity). Next, for at least 12 h before the examination, all participants were instructed to refrain from substances influencing activity of the autonomic nervous system (e.g., cigarettes, caffeine, drug). The study was approved by the Ethics Committee of Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava (protocol code: EK 1767/65). All volunteers were thoroughly instructed about the study protocol and confirmed their participation by written informed consent prior to examination.

Table 1.

Basic characteristics

Case control p-value
N (male/female) 15(4/11) 12(9/3) -
Age (years) 43.7 ± 14.0 28.7 ± 4.3 0.002
BMI (kg.m−2) 23.6 ± 3.5 26.1 ± 4.4 0.204
CPT-Likert scale 6.4 ± 2.0 5.9 ± 2.2 0.539
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Data are expressed as average ± SD; BMI Body Mass index, CPT Cold Pressor Test

Values p < 0.05 are considered as statistically significant

Study Protocol

The participants were examined in the psychophysiological laboratory (Biomedical Centre Martin, Jessenius Faculty of Medicine in Martin) under standard conditions (a quiet room, minimization of stimuli, temperature 23 °C, humidity around 50%, in the morning between 9:00 and 11:00 a.m. after light breakfast). After a brief overview of the research protocol and the signing of the informed consent, the anthropometric body analysis was measured using the multi-segmental and multi-frequency (20/100 kHz) bioimpedance device InBody 120 (Biospace Co. Ltd, Seoul, Korea). Following, the participants were comfortably seated in a special armchair, and sensors for continuous recordings of the R-R intervals (Polar V800, Polar Electro, Kempele, Finland) and blood pressure (Finometer Midi Model II, Finapress Medical System, Amsterdam, Netherlands) were applied. Consequently, the study protocol was performed after 10 min relaxation period used to avoid the potential effects of stress. Study protocol consisted of five 6 min-long periods in order rest phase, mental arithmetic test phase, recovery phase (rest phase after mental arithmetic test), cold pressor test phase, and recovery phase (rest phase after cold pressor test) (see Fig. 1). The difference between groups (case – patients with Globus, and healthy controls), the reactivity to selected stressors (rest – mental arithmetic test – recovery and rest – cold pressor test – recovery) within groups and changes between applied stressors (mental arithmetic test and cold pressure test) within groups were analyzed.

Fig. 1.

Fig. 1

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The study protocol. A Example of continuous record of monitoring parameters during whole examined protocol: HR – heart rate (blue line), DBP – diastolic blood pressure (yellow line), SBP – systolic blood pressure (red line), and BRS – baroreflex sensitivity (pink dots); B device for continual blood pressure parameters (Finometer Midi Model II, Finapress Medical System, Amsterdam, Netherlands) and heart rate (Polar V800, Polar Electro, Kempele, Finland) monitoring; C the timeline of examined protocol consisting of five phases: 1st. rest phase, 2nd. mental stress test (mental arithmetic test), 3rd. recovery phase after stress period, 4th. cold stress test (cold pressor test), and 5th. recovery phase after stress period

Stress Tests

The mental arithmetic test as well as the cold pressor test are among the most commonly used stressors, where the goal is to measure changes in autonomic functions by assessing heart rate and blood pressure responses [18].

Mental Arithmetic Test

The mental arithmetic test represents a standard mental stressor of moderate intensity to assess changes in the ANS [19]. The arithmetic test is non-verbal to minimize the change in the breathing pattern by talking. It consists of sixty different three-digit numbers that were sequentially displayed at different locations on the PC screen after the participant´s response without time limit. Role of volunteers was calculating these three-digit numbers into one-digit number (e.g., three-digit number: 258, calculation: 2 + 5 + 8 = 15 (two-digit number), continue the calculation: 1 + 5 = 6 (one-digit number represents the result)). Next, the volunteer´s task was decided if the one-digit results were odd or even by pushing the arrows with dominant hand on the keyboard (odd-left, even-right) (Fig. 1).

Cold Pressor Test

The basic principle of test was immersing of volunteer´s hand (the whole arm approximately 10 cm above the elbow) in a container of water and ice (Fig. 1). The water had about 4 °C. In case of any complications, the test is stopped, but all volunteers enrolled in the study completed the entire interval. The evaluation of pain perception resulted from cold was measured by the Likert scale.

Evaluated Parameters

Cardiovascular Parameters

Before the analysis, all records (continuous R-R intervals and blood pressure) were carefully checked and the artifacts were manually removed. The 5 min long time series were used for analysis according to recommendation for short-term analysis [20]. Firstly, continuous R-R intervals were measured by Polar V800 (Polar Electro, Kempele, Finland) with a sampling frequency of 1000 Hz. The average heart rate (beat per minute; bpm) was calculated from a 5 min continuous recording.. Next, Beat-to-beat blood pressure (BP) signals were recorded using the Finometer® MIDI Model II (Finapres Medical System, Amsterdam, Netherlands) with a sampling frequency of 200 Hz. A high sensor was used to eliminate the influence of hydrostatic pressure on the finger cuff (i.e., the first part of height´s sensor was placed on finger cuff, the second part at heart level; this allows the arterial pressure to be reconstructed without the influence of altitude). The built-in height-correction system allowed reconstruction of brachial artery pressure. The recordings were analyzed using BeatScope Easy software (Finapres Medical System, Amsterdam, Netherlands). Baroreflex sensitivity (BRS, ms/mmHg) was calculated from continuous beat-to-beat arterial pressure waveforms recordings using the sequential cross-correlation method [21]. BRS reflects changes in the interbeat interval (ms) in response to simultaneous differences in BP (mmHg) and the sensitivity of vagally-mediated heart rate to BP deviations [22, 23].

Spectral Analysis Parameters of Autonomic Control

The spectral-domain analysis of heart rate variability was assessed by resampling of 5 min artifact-free time series of R-R intervals using cubic spline interpolation with the frequency 4 Hz and by detrending through a smoothing parameter Λ = 500 [24]. Spectral power in the high-frequency band of HRV (HF-HRV; 0.15 – 0.40 Hz) was analyzed using an autoregressive model with the Burg periodogram [25]. HF-HRV serves as an index of respiratory sinus arrhythmia (RSA) and cardiac vagal activity [26]. Next, artifact-free beat-to-beat systolic BP series used in the frequency analysis of systolic blood pressure variability (SBPV) were resampled at 2 Hz using cubic spline interpolation through the autoregressive model with Burg periodogram. Consecutively, an absolute spectral power in the low-frequency band (LF, 0.075—0.15 Hz) of SBPV (LF-SBPV) reflecting sympathetic-alpha-adrenoreceptor vasomotor function was evaluated [27].

Statistical Analysis

The data were explored and analyzed in jamovi version 1.2.27 (Sydney, Australia). Data distributions (Gaussian/non-Gaussian) were evaluated using the Shapiro–Wilk normality test and graphically by quantile–quantile plot. The HF-HRV and LF-SBPV were logarithmically transformed because of high inter-individual differences. All examined parameters were normally distributed. Therefore, the repeated measures ANOVA with effect of group (case, control), effect of period (rest, mental arithmetic test, recovery after test, cold pressor test, recovery after test), and mixed effect of group x period was used for all evaluated parameters with Bonferoni post hoc test controlling the false discovery rate as well as family rise error rate for evaluated data. Additional, Cohen´s d was calculated for evaluation the effect size of the study. Basic data were expressed as mean ± SD; physiological parameters were expressed as mean ± SEM. The results are considered statistically significant if p < 0.05.

Results

Characteristics of the Patients End Controls

27 probands were included in study, from which were 15 patients and 12 controls. The basic characteristics are more detailedly described in Table 1.

Evaluated Parameters During Stress Protocol

The repeated measured ANOVA revealed significant effect of group for parameters: ln_LF-SBPV, HR, ln_HF-HRV, and BRS (F[1] = 21.50, p < 0.001; F[1] = 12.60, p = 0.002; F[1] = 19.60, p < 0.001; F[1] = 105.00, p < 0.001; respectively); significant effect of period for parameters: SBP, DBP, HR, ln_HF-HRV, and BRS (F[4] = 41.84, p < 0.001; F[4] = 36.28, p < 0.001; F[4] = 64.26, p < 0.001; F[4] = 6.78, p < 0.001; F[4] = 10.36, p < 0.001; respectively); and significant effect of group x period interaction for parameters: ln_LF-SBPV, HR, and BRS (F[4] = 4.01, p = 0.005; F[4] = 2.69, p = 0.035; F[4] = 3.50, p = 0.011; respectively).

Between Groups Comparisons of Evaluated Parameters

During the 1st rest period (RP1) the BRS parameter (case: 7.1 ± 0.7 ms/mmHg vs. control: 19.5 ± 1.8 ms/mmHg) was significantly decreased in case group compared to control group (p < 0.001). No significant changes were found in remaining evaluated parameters. The second phase, the mental arithmetic test (MA) the parameters ln_HF-HRV (case: 3.3 ± 0.4 ms2 vs. control: 5.3 ± 0.3 ms2), and BRS (case: 5.1 ± 0.5 ms/mmHg vs. control: 14.8 ± 0.9 ms/mmHg) were significantly decreased, and HR (case: 87.2 ± 2.8 vs. control: 71.9 ± 2.2), ln_LF-SBPV (case: 15.0 ± 0.3 mmHg2 vs. control: 13.6 ± 0.2 mmHg2) significantly increased in case group compared to controls (p = 0.006; p < 0.001; p < 0.001; p = 0.007; respectively). No significant changes were found in remaining evaluated parameters. Second rest period (RP2) shows BRS parameter (case: 7.1 ± 0.6 ms/mmHg vs. control: 16.1 ± 1.2 ms/mmHg) to be significantly decreased and parameter ln_LF-SBPV (case: 14.9 ± 0.2 mmHg2 vs. control: 13.7 ± 0.2 mmHg2) significantly increased in case group compared to controls (p < 0.001; p = 0.004; respectively). No significant changes were found in remaining evaluated parameters. After the second rest period the cold pressor test was performed and shows parameters ln_HF-HRV (case: 4.2 ± 0.4 ms2 vs. control: 6.0 ± 0.3 ms2), and BRS (case: 6.5 ± 0.4 ms/mmHg vs. control: 17.2 ± 1.2 ms/mmHg) to be significantly decreased and index ln_LF-SBPV (case: 14.9 ± 0.2 mmHg2 vs. control: 13.7 ± 0.1 mmHg2) significantly increased in case group compared to control group (p = 0.019; p < 0.001; p = 0.008; respectively). No significant changes were found in remaining evaluated parameters. Finally, during the third rest period parameters ln_HF-HRV (case: 4.2 ± 0.3 ms2 vs. control: 6.0 ± 0.2 ms2) and BRS (case: 7.2 ± 0.5 ms/mmHg vs. control: 20.7 ± 1.5 ms/mmHg) were significantly decreased in case group compared to control group (p = 0.017; p < 0.001; respectively). No significant changes were found in remaining evaluated parameters.

Comparison of the Individual Periods of the Protocol (RP1 vs. MA) Within Case and Control Groups Case Group

Parameters SBP (MA: 143.0 ± 4.3 mmHg vs. RP1: 122.0 ± 3.9 mmHg), DBP (MA: 86.9 ± 2.2 mmHg vs. RP1: 76.7 ± 2.7 mmHg), and HR (MA: 87.2 ± 2.8 bpm vs. RP1: 74.7 ± 2.2 bpm) were significantly increased during MA compared to RP1 period in case group (p < 0.001 for all). No significant changes were found in remaining evaluated parameters.

Control Group

Parameters SBP (MA: 133.0 ± 4.9 mmHg vs. RP1: 118.0 ± 4.8 mmHg), DBP (MA: 80.9 ± 2.6 mmHg vs. RP1: 71.3 ± 3.0 mmHg), and HR (MA: 71.9 ± 2.2 mmHg vs. RP1: 65.8 ± 2.3 mmHg) were significantly increased and parameter BRS (MA: 14.8 ± 0.9 ms/mmHg vs. RP1: 19.5 ± 1.8 ms/mmHg) significantly decreased during MA compared to RP1 period in control group (p < 0.001; p < 0.001; p < 0.001; p = 0.013; respectively). No significant changes were found in remaining evaluated parameters.

Comparison of the Individual Periods of the Protocol (MA vs. RP2) Within Case and Control Groups Case Group

Parameters SBP (MA: 143.0 ± 4.3 mmHg vs. RP2: 129.0 ± 3.9 mmHg), DBP (MA: 86.9 ± 2.2 mmHg vs. RP2: 79.3 ± 2.3 mmHg), and HR (MA: 87.2 ± 2.8 mmHg vs. RP2: 77.0 ± 2.6 mmHg) were significantly increased during MA compared to RP2 period in case group (p < 0.001 for all). No significant changes were found in remaining evaluated parameters.

Control Group

Parameter HR (MA: 71.9 ± 2.2 bpm vs. RP2: 65.7 ± 1.9 bpm) was significantly increased during MA compared to RP2 period in control group (p < 0.001). No significant changes were found in remaining evaluated parameters.

Comparison of the Individual Periods of the Protocol (RP2 vs. CPT) Within Case and Control Groups Case Group

Parameters SBP (CPT: 146.0 ± 4.6 mmHg vs. RP2: 129.0 ± 3.9 mmHg) and DBP (CPT: 87.6 ± 2.4 mmHg vs. RP2: 79.3 ± 2.3 mmHg) were significantly increased during CPT compared to RP2 period in case group (p < 0.001 for both). No significant changes were found in remaining evaluated parameters.

Control Group

Parameters SBP (CPT: 138.0 ± 5.0 mmHg vs. RP2: 126.0 ± 4.5 mmHg) and DBP (CPT: 83.7 ± 2.8 mmHg vs. RP2: 75.9 ± 2.8 mmHg) were significantly increased during CPT compared to RP2 period in control group (p < 0.001 for both). No significant changes were found in remaining evaluated parameters.

Comparison of the Individual Periods of the Protocol (CPT vs. RP3) Within Case and Control Groups Case Group

Parameters SBP (CPT: 146.0 ± 4.6 mmHg vs. RP3: 132.0 ± 3.8 mmHg) and DBP (CPT: 87.6 ± 2.4 mmHg vs. RP3: 80.2 ± 2.2 mmHg) were significantly increased during CPT compared to RP3 period in case group (p < 0.001; p = 0.005; respectively). No significant changes were found in remaining evaluated parameters.

Control Group

No significant changes were found for all evaluated parameters.

Comparison of the Individual Periods of the Protocol (MA vs. CPT) Within Case and Control Groups Case Group

Parameter HR (MA: 87.2 ± 2.8 bpm vs. CPT: 76.1 ± 2.4 bpm) was significantly increased during MA compared to CPT period in case group (p < 0.001). No significant changes were found in remaining evaluated parameters in case group.

Control Group

Parameter HR (MA: 71.9 ± 2.2 bpm vs. CPT: 64.4 ± 2.3 bpm) was significantly increased and parameter ln_HF-HRV (MA: 5.3 ± 0.3 ms2 vs. CPT: 6.0 ± 0.3 ms2) significantly decreased during MA compared to CPT period in control group (p < 0.001; p = 0.040; respectively). No significant changes were found in remaining evaluated parameters in control group.

All results are summarized in Table 2, Table 3 and Fig. 2.

Table 2.

Cardiovascular parameters

case control p-value (Cohen´s d)
Rest period 1st. (baseline)
HR (beats per min) 74.7 ± 2.2 65.8 ± 2.3 0.370
SBP (mmHg) 122.0 ± 3.9 118.0 ± 4.8 0.999
DBP (mmHg) 76.7 ± 2.7 71.3 ± 3.0 0.999
BRS (ms/mmHg) 7.1 ± 0.7 19.5 ± 1.8  < 0.001 (2.81)
Mental arithmetic test
HR (beats per min) 87.2 ± 2.8 71.9 ± 2.2 0.007 (− 1.59)
SBP (mmHg) 143.0 ± 4.3 133.0 ± 4.9 0.999
DBP (mmHg) 86.9 ± 2.2 80.9 ± 2.6 0.999
BRS (ms/mmHg) 5.1 ± 0.5 14.8 ± 0.9  < 0.001 (4.02)
Recovery period after test
HR (beats per min) 77.0 ± 2.6 65.7 ± 1.9 0.208
SBP (mmHg) 129.0 ± 3.9 126.0 ± 4.5 0.999
DBP (mmHg) 79.3 ± 2.3 75.9 ± 2.8 0.999
BRS (ms/mmHg) 7.1 ± 0.6 16.1 ± 1.2  < 0.001 (3.00)
Cold pressor test
HR (beats per min) 76.1 ± 2.4 64.4 ± 2.3 0.102
SBP (mmHg) 146.0 ± 4.6 138.0 ± 5.0 0.999
DBP (mmHg) 87.6 ± 2.4 83.7 ± 2.8 0.999
BRS (ms/mmHg) 6.5 ± 0.4 17.2 ± 1.2  < 0.001 (3.76)
Recovery period after test
HR (beats per min) 73.2 ± 2.3 61.9 ± 2.0 0.120
SBP (mmHg) 132.0 ± 3.8 133.0 ± 4.5 0.999
DBP (mmHg) 80.2 ± 2.2 79.6 ± 2.6 0.999
BRS (ms/mmHg) 7.2 ± 0.5 20.7 ± 1.5  < 0.001 (3.67)
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The bold emphasize that the p value in each particular case means statistical significance. This could be p < 0.05, p < 0.01 or p < 0.001

Data are expressed as average ± SEM; HR Heart Rate; SBP Systolic Blood Pressure; DBP Diastolic Blood Pressure; and BRS Baroreflex Sensitivity

Values p < 0.05 are considered as statistically significant. Data in parenthesis “()” represent Cohen´s d

Table 3.

Spectral analysis parameters of autonomic control (ln_HF-HRV – parasympathetic regulation; ln_LF-SBPV – sympathetic regulation)

case control p-value (Cohen´s d)
Rest period 1st. (baseline)
ln_HF-HRV (ms2) 4.3 ± 0.4 5.9 ± 0.2 0.070
ln_LF-SBPV (mmHg2) 14.4 ± 0.2 14.0 ± 0.1 0.999
Mental arithmetic test
ln_HF-HRV (ms2) 3.3 ± 0.4 5.3 ± 0.3 0.006 (2.00)
ln_LF-SBPV (mmHg2) 15.0 ± 0.3 13.6 ± 0.2  < 0.001 (− 1.53)
Recovery period after test
ln_HF-HRV (ms2) 4.4 ± 0.3 5.5 ± 0.2 0.631
ln_LF-SBPV (mmHg2) 14.9 ± 0.2 13.7 ± 0.2 0.004 (− 1.33)
Cold pressor test
ln_HF-HRV (ms2) 4.2 ± 0.4 6.0 ± 0.3 0.019 (1.99)
ln_LF-SBPV (mmHg2) 14.9 ± 0.2 13.7 ± 0.1 0.008 (− 1.53)
Recovery period after test
ln_HF-HRV (ms2) 4.2 ± 0.3 6.0 ± 0.2 0.017 (2.60)
ln_LF-SBPV (mmHg2) 14.6 ± 0.1 13.9 ± 0.2 0.200
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The bold emphasize that the p value in each particular case means statistical significance. This could be p < 0.05, p < 0.01 or p < 0.001

Data are expressed as average ± SEM; ln_HF-HRV – logarithmic transformation of heart rate variability in high-frequency band; and ln_LF-SBPV – logarithmic transformation of systolic blood pressure variability in low-frequency band

Values p < 0.05 are considered as statistically significant. Data in parenthesis “()” represent Cohen´s d

Fig. 2.

Fig. 2

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Evaluated parameters during stress protocol within case and control groups. Data are expressed as average ± SEM; SBP – systolic blood pressure; DBP – diastolic blood pressure; ln_LF-SBPV – logarithmic transformation of systolic blood pressure variability in low-frequency band; HR – heart rate; ln_HF-HRV – logarithmic transformation of heart rate variability in high-frequency band; and BRS – baroreflex sensitivity. Orange color bars represent case group; blue bars – control group. Star (*) represents significant changes during stress protocol within case group, hangtag (#) significant changes within control group. P-values < 0.05 are considered as statistically significant; three identical marks: p < 0.001; two identical marks – p < 0.01; and one mark – p < 0.05

Discussion

Globus is a disorder with complex pathophysiology based on brain-gut axis disarray rather than psychosomatic disorder [28]. As in other Disorders of Gut-Brain Interaction (DGBIs) such as irritable bowel syndrome and functional dyspepsia one of the contributing factors to globus symptom could be visceral hypersensitivity [29]. In general, it can be stated that the most important functions of the digestive tract affected by DGBIs are sensory perceptions and motility. Sensory-motor dysfunction is highly likely to be related to alterations in neural processing of the brain-gut axis [30] and to visceral reflex pathways [31]. Multiple studies have observed a rise in stressful life events before symptom onset [16], implying that life stress could play a role in both the development and worsening of symptoms. It was observed that up to 96% of globus patients experienced heightened symptoms during periods of intense emotions [10]. However, other reports have noted no differences in the psychological states of globus patients compared to normal controls [32].

At rest, the parameters of the heart rate and blood pressure variability pointed to cardiovascular autonomic regulation without significant alterations in patients suffering from globus pharyngeus. However, baroreflex sensitivity was significantly decreased in the patients indicating abnormal cardiovascular reflex control already at rest. With respect to autonomic regulation, the cardiac baroreflex responds to blood pressure fluctuations by compensatory heart rate adjustment predominantly via the parasympathetic system [12]. Our findings of diminished BRS are in agreement with other studies considering DGBIs. The so far published data clearly points to a disrupted baroreflex mechanism in patients with disorders of gut brain interaction although there are no relevant data on globus pharyngeus to this date to our best knowledge. Significantly lower BRS values ​​were observed in patients with irritable bowel syndrome compared to controls [33–35]. Decreased baroreflex sensitivity values ​​have also been observed in pediatric patients with functional dyspepsia [36].

According to neurovisceral hierarchical integration [37], we suggest that reduced heart rate reflex control could reflect deficient neural coordination of cardiovascular regulation. Moreover, BRS represents major negative prognostic indicator of cardiac arrhythmia [38], which is independent of vagally-mediated HRV [39]. Taken together, it seems that adult globus pharyngeus is characterized by reduced heart rate vagal reflex control as a potential powerful predictor of adverse clinical outcomes [39, 40].

However, both cognitive (mental arithmetic test) and physiological (cold pressor test) stressors were associated with discrete abnormalities in cardiovascular regulatory mechanisms. Our findings revealed that patients with globus pharyngeus showed reduced HRV vagally-mediated parameters (lower HF-HRV, BRS) associated with tachycardia indicating altered reflex cardiac regulation in response to stressors. In line with psychophysiological theories, HRV represents an index of the flexible network of neural structures responsible for both cardiovagal and emotional/social regulation [41, 42]. More precisely, cortical centers such as the prefrontal cortex exert an inhibitory influence on subcortical centers including the amygdala that allows the organism to regulate emotional and behavioral responses. Therefore, this inhibitory cortico-subcortical neural circuit links psychological processes and health-related physiological processes indexed by HRV [43, 44]. Several studies indicate that globus pharyngeus is frequently associated with mental disorders, i.e., globus is considered as a type of conversion or depressive disorder [45]. In this context, the central functional networks partially overlap with the brain regions involved in the neurophysiological basis of anxiety and depression (e.g., prefrontal cortex, amygdala). Neural networks of control for GI physiology embrace four levels. The first level is the myenteric and submucosal plexus and enteric glial cells (EGCs). The second level is the prevertebral ganglia, which modulate the peripheral visceral reflex. The third level consists of neurons of the autonomic nervous system (ANS) in the spinal cord originating from the sympathetic (T5L2) and sacral (S2S4) parasympathetic nervous systems. The fourth level consists of two nuclei of the brainstem: the nucleus tractus solitarius (NTS) and the dorsal motor nucleus of the vagus nerve (DMVN). Both nuclei receive and send signals to the afferent and efferent axons of the vagus nerve, respectively. Upper gastrointestinal tract is under control of DMVN. In addition to the DMNV, the nucleus ambiguus (NAmb) is the origin of the vagal efferent that controls gastrointestinal function. Therefore, while the DMVN innervates the submucosal and enteric plexuses, the NAmb innervates the striated muscles of the larynx, pharynx, and esophagus. This network controls vago-vagal reflexes [46]. Besides, the cardiovascular information is integrated into the DMNV, the NAmb, and NTS. Recent image studies report inhibitory effects of the prefrontal cortex in the regulation of cardio-autonomic functions and emotion [47] and another report that women subjected to a stress test showed changes in brain connectivity and brain activity between the dorsolateral prefrontal cortex and NTS [48]. These studies support the claim of an association between globus pharyngeus mental disorder and cardiovascular function. Thus, we can suggest that the first pathway leading to cardiovascular vagal dysregulation in response to mental and cold stress may include emotional/affective-linked alterations associated with globus pharyngeus at the hierarchical neurobiological basis, as described by a recent study [37]. Concerning sympathetic regulation, our findings of the conceivable vascular sympathetic activation (higher lnLF_SBPV) to both stressors in patients suffering from globus represent a novel aspect of this study. In this context, the higher blood pressure oscillations may lead to damage in the organ system and restricted ability to maintain stable blood flow during perfusion pressure changes [49]. Of note, the increased BPV represents a risk factor for cardiovascular complications, independent of tonic blood pressure [50, 51]. Therefore, the abnormal dynamic sympathovagal pattern toward increased sympathetic vasomotor activity (higher BPV) and reduced cardiac vagal modulation (decreased HRV and BRS) manifested to stress could represent a certain “pre-grade” in globus patients in a trajectory leading to resting deficient sympathetic vasomotor and cardiovagal reflex control manifesting in disease progress.

It is important to note that globus-linked atypical HRV and BRS pattern was found only to cognitive and physiological stressors, not at rest. Additionally, in recovery phases, the return of the heart rate and blood pressure to basal values was observed on both groups. While the reactivity to mental arithmetic test is influenced by cortical (e.g., prefrontal cortex) as well as subcortical regulatory centers associated predominantly with beta-adrenergic activity [52], cold pressor test is considered as an index for vascular alpha-adrenergic regulation used for screening of hypertension [53]. It seems that discrete abnormalities in the cardiovascular regulatory network were induced by the stress response indicating thus less adaptability and flexibility in globus patients. Moreover, this cardiovascular autonomic response persisted even in both recovery phases (i.e., after mental arithmetic test and cold pressor stress) without returning BPV, BRS, and HRV indices to basal values representing thus increased risk of cardiovascular complications in patients suffering from globus.

Our detailed study of the cardiac autonomic reflex control and vascular responses to different stressors suggests that complex neurophysiological regulatory cortical/subcortical network combined with individual psychological factors could affect final cardiovascular functioning/adaptability to stress in globus patients. It could be important for personalized treatment of globus patients such as biofeedback.

The major limitation of this study include the relatively small sample of patients not age- and gender-matched to controls. In this context, the so far findings regarding the impact of age and gender on resting cardiovascular activity as well as cardiovascular reactivity to mental and cold pressor test are inconclusive. More specifically, with respect to resting cardiovascular activity, Alyahya et al. [54] reported age-dependent greater decline of resting vagally-mediated HRV in males, but not in females. On the other hand, mean arterial pressure (MAP) was reported to be similar in females with respect to age, but higher in older males compared to younger males [55]. Further, baseline HR and vagally-mediated HRV is reported to be greater in females compared to males [56], while blood pressure (BP) is reported to be higher in males compared to females at similar ages, however, after menopause, there is a BP increase in females to higher levels compared to males at similar ages [57]. With respect to cardiovascular reactivity to mental stress, Ross et al. [58] reported similar HR and BP reactivity to mental stress in both men and women, while Sato and Miyake [59] revealed that females exhibit greater HRV reactivity to mental arithmetic test compared to males and similar BP responses in both males and females. With respect to cardiovascular reactivity in response to CPT, young as well as older adults (both females and males) seem to have similar HR and BP reactivity in response to CPT [55, 60–62]. Based on above-mentioned inconsistent findings across the studies, the impact of age and gender on resting cardiovascular activity as well as cardiovascular reactivity to various stressors remains elusive. From this perspective, further research is needed to validate our findings in a larger set of the patients with globus pharyngeus including age- and gender-matched controls. The second limitation is the lack of psychological profiling of the patients and controls. We implemented several questionary based tools for psychological evaluation. But as we found out through the study in two cases of controls and at least one case in patients the probands did not adhere to answering the questions properly and so we decided not to evaluate this aspect as this could affect the final results.

Conclusion

The results of this study shows discrete abnormalities in complex autonomic reflex control which are predominantly manifested in response to stressful stimuli indicating altered neurocardiac regulation as a reaction to stress associated with globus pharynegus. We suggest that altered neurophysiological regulatory cortical/subcortical network combined with individual psychological factors could affect final physiological functioning/adaptability to stress in patients with globus pharynegus. This fact could have an important role in the personalized management of globus patients such as biofeedback.

Author’s contribution

PL: manuscript preparation, data acquisition, study design; ZV: data analysis; NF: data analysis; MD: clinical support; PB: study design; IT: study design and supervision, data analysis, manuscript preparation.

Funding

Open access funding provided by The Ministry of Education, Science, Research and Sport of the Slovak Republic in cooperation with Centre for Scientific and Technical Information of the Slovak Republic. Vedecká Grantová Agentúra MŠVVaŠ SR a SAV,VEGA 1/0048/24.

Data availability

No datasets were generated or analyzed during the current study.

Declarations

Conflict of interest

Authors declare no possible conflict of interest regarding to this study.

Footnotes

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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