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Abstract

Objective:

The aim of this study was to investigate sonographic measurements of the vagus nerve in a healthy sample and determining reference values at four cross-sectional area (CSA) landmarks. In addition, a further assessment was made of the relationships between demographic and anthropometric variables, compared to the vagus nerve measurements.

Materials and Methods:

The sample comprised 59 healthy individuals (27 men and 32 women). An ultrasound equipment system and a 12L-RS linear transducer were used for the evaluation. The vagus nerve was visualized at two key anatomical sites: prior to the bifurcation point of the common carotid artery (e.g., proximal landmark) and at the inferior border of the thyroid gland (e.g., distal landmark). Bilateral measurements of both anterior-posterior and transverse diameters at these landmarks were collected, to determine the CSA values.

Results:

Gender-specific variations were observed, with men exhibiting significantly larger proximal and distal nerve CSA values on the right side compared to women. In addition, in this cohort, a positive correlation was noted comparing the body mass index (BMI) with the proximal left and right nerve CSAs. Furthermore, neck circumference was found to be significantly positively associated with proximal left, proximal right, and distal right nerve CSAs, within this cohort.

Conclusion:

The results of this cohort study help to build reference values for the vagus nerve, at essential anatomical sites, and highlight potential gender-specific variations.

Keywords

Nerve cross-sectional area nerve reference values sonography vagus nerve

Sonography has become increasingly prevalent, as a noninvasive technique that can be used as a diagnostic tool for neurological pathologies and has been used in several studies, to assess changes in the vagus nerve.^1–3 Cross-sectional area (CSA) measurements of the vagus nerve are commonly used as sonographic reference values, to evaluate changes within the nerve, due to consistent clinical application, across numerous studies.⁴ In addition, as the vagus nerve changes, due to inflammation or atrophy, it may indicate potential markers of disease detection and progression.¹ This underscores the critical importance of understanding the CSA measurement of the vagus nerve, as a reference value.

To further explore the variance in the vagus nerve and better understand disease pathology, it is necessary to establish accurate reference values, in a healthy population. Standardized healthy vagus nerve CSA reference values has the potential to offer greater insight in the detection of vagus nerve aberrations and may guide the development of more targeted interventions. Several studies have published vagus nerve CSA measurements, in regards to neurological pathologies that include: Guillain-Barré Syndrome,¹ amyotrophic lateral sclerosis,² Parkinson’s disease,⁵ and diabetic peripheral neuropathy.³ However, there is currently limited sonographic evidence with regard to standardized reference values of the healthy vagus nerve. Prior studies have reported vagus nerve CSA reference values of healthy cohorts ranging between 1.4 and 5.7 mm².^1,3,6–9 Small sample sizes (n = 12-60), different age groups, and discrepancies in measurement protocols have contributed to these varying findings. Therefore, larger sample sizes and diverse participants are needed to advance our diagnostic assessment.⁸ In this regard, Fisse et al¹⁰ conducted a meta-analysis including four studies (n = 420) reporting a mean vagus nerve CSA of 2.2 mm² (95% confidence interval [CI]: 1.5-2.9 mm²). In addition, more information about the impact of various demographic and anthropometric variables on vagus nerve CSA is required, as some studies have shown that factors such as body mass index (BMI), gender, and age may influence the nerve CSA. ^9,11,12

Furthermore, knowledge of the anatomic variation in the course of the vagus nerve and its CSA may play an important role in reducing the risk of injury to the nerve, during surgical procedures such as carotid endarterectomy, thyroidectomy, and aortic arch aneurysm correction, that can lead to potential post-surgical complications.^13,14 Accordingly, establishing vagus nerve CSA standard reference values, among a healthy population, is essential due to risk of neuronal injury during surgery, as well as the importance of investigating the pathogenesis of various neurological disorders.

Therefore, the aim of this study was to investigate sonographic measurements of the vagus nerve by determining CSA reference values at four landmarks, in addition to further assessing relationships between vagus nerve measurements, gender differences, demographics, and anthropometric variables.

Materials and Methods

This study was conducted in accordance with the 1964 Helsinki Declaration and its later amendments. Informed consent was obtained from all individual participants included in the study. This study was approved by the ethics committee of the host university (024-7087-7008). A total of 63 healthy participants were recruited for the study. All participants provided informed and written consent during the enrollment process. Inclusion criteria required all participants to be at least 18 years of age and have the capacity to provide informed consent. Exclusion criteria consisted of reported history of significant neurological or medical disorders, in addition to prior surgical history.

Height and weight for each participant was measured, and BMI was calculated. Neck circumference was additionally obtained following protocols established by Vatier et al.¹⁵

Sonographic Protocol and Parameters

The sonographic examination was conducted with each participant seated on an exam bed that was adjusted to a 45° incline. This specific angle and position were chosen to ensure the comfort of the participant, maintain stability during the procedure, and provide optimal imaging of the vagus nerve and surrounding neck structures.

An InSite (GE Healthcare, Wausaukee, WI) ultrasound equipment system was used with a 12L-RS linear transducer. The ultrasound frequency was set at 5 MgHz, a setting that provides a balance between image resolution and depth of penetration. The sonographic protocol and parameters were standardized to ensure consistency across all measurements and participants. Intra-rater reliability was determined by reassessing five participants by the same examiner. Moreover, two additional examiners approved the vagus nerve diameter measurements, for each participant examined. The vagus nerve was visualized prior to the bifurcation point of the common carotid artery (CCA), between the internal jugular vein and the CCA, within the carotid sheath (e.g., proximal landmark). It was also noted at the inferior border of the thyroid gland between the medial border of the vagus nerve and the lateral edge of the inferior border of the thyroid gland (e.g., distal landmark). The bifurcation of the CCA was specifically chosen as the proximal landmark, as it is widely considered to be a standard landmark used by most researchers. The inferior border of the thyroid gland was chosen as the distal landmark, as it is a reasonable distance away from the CCA bifurcation and clearly identifiable with sonography. The distance between the vagus nerve and the thyroid gland was additionally measured. Bilateral measurements of both anterior-posterior and transverse diameters at the proximal and distal landmarks were collected to determine a total of four CSA values for each participant. Sonograms were dynamically reviewed, recorded, and saved for subsequent analysis (See Figure 1A and B).

Figure 1.

(A). A transverse sonographic view is provided of the vagus verve, which is taken at the proximal anatomical landmark. (B). A transverse sonographic view of the vagus nerve to assess the cross-sectional area. IJV = internal jugular vein; CCA: common carotid artery; 1 = anterior-posterior diameter; 2 = transverse diameter.

Statistical Analysis

All statistical analyses were conducted using R (version 3.5.1). Data were winsorized to 3 standard deviations (n = 4, 3 men and 1 woman). Demographic and anthropometric variables were assessed using t-tests and chi-squared tests. Sonographic measurements of the vagus nerve CSA were based on formula calculations from Walter and Tsiberidou¹⁶ (e.g., CSA = (d1 × d1 × π)/4). A moderator analysis was performed for demographic measures with vagus nerve CSA measures using analysis of variance (ANOVA). Neither age nor race influenced vagus nerve CSA measures; however, proximal right CSA (F = 8.89, p = .004) and distal right CSA (F = 12.75, p < .001) were impacted by gender differences. A general linear hypothesis test was run to investigate group comparisons (2 levels: men, women) for CSAs and effect sizes were calculated using Cohen’s d. Post hoc Spearman correlations were performed to investigate potential associations between vagus nerve CSA measures and both demographic (age and race) and anthropometric (neck circumference and BMI) variables for all participants in addition to separately within groups. All p-value were corrected using a false discovery rate (FDR) across all CSA measures with an adjusted significance threshold of q < .05.

Results

As demonstrated in Table 1, there were a total of 59 participants (e.g., 27 men and 32 women) included. No significant differences between the gender groups were reported for age, gender, race, and BMI, except for men having larger neck circumferences compared to women (p < .001) (See Table 1).

Table 1.

Demographic Characteristics of Male and Female Participants.

Demographics	M (n= 27)		F (n= 32)
	N		N		χ²	p-value
Race (C/B/A/O)	3/2/13/9		5/4/19/4		3.82	.282
	Mean	SD	Mean	SD	F	p-value
Age (years)	21.70	2.4	22.53	2.4	1.76	.191
BMI	25.85	3.0	25.34	7.2	0.12	.713
Neck circumference (cm)	38.54	2.6	32.74	2.5	76.28	<.001

M, male; F, female; C, caucasian; B, black; A, asian; O, other/mixed; SD, standard deviation.

Vagus Nerve Measurements

Calculated vagus nerve CSA measurements are provided in Table 2. No significant differences were observed between left and right landmarks regarding anterior-posterior diameter, transverse diameter, and calculated CSA values, at the proximal and distal sites. Cross-sectional area measurements, at the distal site, based on the proximal location (i.e., the inferior border of the thyroid landmark) were closer on the left side, compared to the right (p < .001).

Table 2.

Vagus Nerve Measurements.

	Proximal			Distal
Vagus Nerve	Left	Right	p-value	Left	Right	p-value
AP (mm)	1.28 (0.3)	1.32 (0.3)	0.476	1.41 (0.3)	1.34 (0.3)	0.173
Transverse (mm)	1.74 (0.3)	1.66 (0.3)	0.116	1.76 (0.3)	1.73 (0.3)	0.582
Proximal to thyroid (mm)	-	-	-	8.36 (2.6)	10.1 (2.0)	<0.001
CSA (mm²)	2.54 (0.9)	2.32 (0.8)	0.258	2.58 (1.2)	2.7 (1.0)	0.753

AP, anterior-posterior diameter; CSA, cross-sectional area.

Demographic and Anthropometric Associations

No significant associations were observed between CSA landmarks and demographic variables (p > .11). Body mass index had a significant weakly positively association with proximal left (r = 0.29, q = .037) and right CSA (r = .33, q = .024). Neck circumference had a significant weakly positive association with proximal left (r = .33, q = .024), proximal right (r = .38, q = .013), and distal right (r = .38, q = .013) CSAs.

Between-Group Differences

Men had significantly larger proximal (d = 0.77, q = .008) and distal (d = 0.93, q = .004) CSA values compared to women on the right side (See Figures 2 and 3).

Figure 2.

The graph provides the effect sizes for vagal nerve CSA differences between the cohort’s men and women. The circles indicate the Cohen’s d and horizontal lines indicate 95% CI. CSA, cross-sectional area; DR_CSA, distal right cross-sectional area; DL_CSA, distal left cross-sectional area; PR_CSA, proximal right cross-sectional area; PL_CSA, proximal left cross-sectional area.

Figure 3.

A box plot graph of the study cohort’s gender differences in vagus nerve CSA.

Demographic and Anthropometric Associations Between Groups

No significant associations were observed between CSA landmarks and demographic variables for men (p > .16) and women (p > .08). Body mass index had a positive moderate association with only the proximal right CSA in females (r = .41, p = .019, q = .156). Neck circumference had a significant strongly positive association with only the distal left CSA in men (r = .69, p < .001, q < .001) (See Figure 4).

Figure 4.

The correlation plot indicates the level of association between the distal left CSA vegus nerve, and neck circumference. The neck circumference was positively associated with distal left vegal nerve CSA in males. CSA, cross-sectional area; DL CSA, distal left cross-sectional area; M, males; F, females.

Discussion

This study obtained measurements of the vagus nerve CSA, within the carotid sheath at two reference points: proximally just prior to the bifurcation of the CCA and distally in line with the inferior border of the thyroid gland. Overall, vagus nerve CSA values (proximal left: 2.54 ± 0.9 mm², proximal right: 2.32 ± 0.8 mm², distal left: 2.58 ± 1.2 mm², and distal right: 2.7 ± 1.0 mm²) were slightly higher than the mean pooled CSA of 2.2 mm² (95% CI: 1.5-2.9 mm²), as reported by Fisse et al.¹⁰ However, as the mean values remain within the established confidence interval, the present findings aligned with the established normative ranges. The slight discrepancy may, in part, be attributed to the relatively younger age of the current participants (e.g., mean = 22.03 years) compared to Fisse et al’s¹⁰ mean age of 42.7 years. Prior sonographic studies have demonstrated that vagus nerve CSA tends to decrease with advancing age.^9,17 Specifically, Pelz et al⁹ reported a mean age of 49.7 years (range of 22-76 years) and stratified that cohort into two age groups (e.g., above and below 50 years). They found higher vagus nerve CSA values in the younger members of their cohort. In contrast, Bedewi et al,¹⁸ reported a mean age group of 42.1 years (range: 22-66 years), but reported no significant association between age and vagus nerve CSA.

While several studies have reported the vagal CSA to be larger on the right side,^5,7–9,16 this study found that the mean vagal CSA values were larger on the right side, specifically in men compared to women.

The present findings similarly align with Curcean et al⁷ who measured the vagal CSA at the bifurcation of the CCA (mean 2.14 ± 0.79 mm² on the left and 2.86 ± 1.27 mm² on the right) and at the level of the omohyoid muscle (mean 2.10 ± 0.06 mm² on the left and 2.43 ± 0.08 mm² on the right). The sample size included 21 participants (12 females and 9 males, mean age 25 ± 2 years) which, although smaller in number, was similar in age to the present sample size and with comparable CSA values. This is further supported by Pelz et al⁹ who measured the vagal CSA proximally at the level of the carotid sinus and distally at the thyroid gland (proximal: 2.1 ± 0.5 mm² on the left and 2.7 ± 0.6 mm² on the right; distal: 1.9 ± 0.4 mm² on the left and 2.6 ± 0.6 mm² on the right) in 60 participants (35 women and 25 men, mean age 49.7 ± 19.7 years). While the mean age, in this sample size was middle-aged, which is relatively older than the present sample, the CSA values are still comparable. Bedewi et al¹⁸ measured vagus nerve CSA within the carotid sheath, between the CCA and IJV, and reported lower CSA values, with a mean of 1.9 ± 0.6 mm² on the left side and 2.1 ± 0.5 mm² on the right side in 43 participants (e.g., 28 women and 15 men, mean age: 42.1 ± 10.7). In addition, Dörschner et al⁸ reported lower CSA values with a mean of 1.2 ± 0.4 mm² for the left side and 1.5 ± 0.4 mm² for the right side. However, the sample size was only 12 participants (e.g., nine women and three men), with a mean age of 88.4 ± 8.5 years. By comparison to this study, their participants were much older and smaller in number. As some studies^9,17 have suggested that vagal CSA decreases with increasing age, this may partly account for this variation.

While these studies have all reported vagus nerve CSA values to be larger on the right side, no gender-specific differences were found. Significantly larger right-sided vagus nerve CSA values were observed in males compared to females. These findings are strengthened by a histopathological study conducted by Moriyama et al,¹² comparing myelinated axons in peripheral nerves between males and females. The study found significantly larger average circularity ratio of myelinated axons in the vagus nerve in males compared to females.¹² Conversely, Walter & Tsiberidou¹⁶ found CSA values to be larger on the right side in females in their ultrasonographic study. However, the mean age of 44.8 ± 19.9 years is relatively older than this study sample size, which may be a potential factor influencing the discrepancy in results. Furthermore, this is the first ultrasonographic study to report larger vagal CSA values in males compared to females in a healthy population, and further studies are warranted to validate these results.

While several of the prior studies have reported variations in vagal CSA values, several factors including sample size, age, race, variations in vagus nerve anatomical position, differences in procedures for obtaining CSA, and various ultrasonographic landmark references must be considered. The bifurcation of the CCA seems to be a standard landmark for most studies, and in addition to measuring the vagal CSA at this location, this study also obtained measurements at the level of the inferior border of the thyroid gland. Other studies have reported using the thyroid gland as a landmark; however, it has not been stated whether this was at the superior or inferior border.⁹ In an attempt to minimize variations and standardize procedures between different studies, it may be beneficial to use the inferior border of the thyroid gland as a second standard due to its easily identifiable location on ultrasound and reasonable distance away from the CCA bifurcation.

In addition, a significant positive correlation was observed between BMI and vagus nerve CSA measurements, specifically for the proximal left and right CSA values, that aligns with Oura et al¹¹ reported findings, as they reported similar associations in bilateral proximal vagus CSA values.¹¹ In this study, a correlation was detected in the proximal regions, but no association was found between BMI and distal CSA values. One possible explanation is that the proximal vagus nerve may be more influenced by body size, due to its proximity to larger anatomical structures of the neck, whereas distal segments may not exhibit the same proportional relationship to body size. While there is evidence of associations between vagal afferent signaling dysregulation and obesity,¹⁹ as well as vagus nerve therapy associations with weight loss,^20,21 further studies are needed, to better understand how these relate to vagal nerve CSA reference values.

Moreover, a significant positive association was found between neck circumference and the CSA of the proximal left, proximal right, and distal right segments of the vagus nerve. However, no association was identified for the distal left CSA. This lack of association may be attributed to factors such as measurement artifact, small sample size, or potential inherent anatomical differences between vagus nerve segments. To clarify these discrepancies, further studies with larger and more diverse sample sizes are needed.

Limitations

There are several limitations associated with this research, such as the study design that has threats to internal and external validity. Although the cohort has an adequate sample size and well-balanced groups, the cohort was formed by convenience, therefore these results are unique to this group. This sample of participants were predominately comprised of relatively young (mean = 22.03) Asian individuals (n = 34); therefore, this further limits the applicability of these findings. Nevertheless, in this cohort, no associations between race and CSA measurements were found. In addition, the ultrasound equipment system and software did not have a built-in trace or ellipse function, thus vagus nerve CSA measurements were assessed using manual calculations. Although the method’s precision in detecting age and gender-related variations were reported, differences in CSA measurement methods may account for slight discrepancies in values, compared to other published studies. Furthermore, potential motion artifact from pulsations of the CCA and internal jugular vein, during data collection, must be considered as a possible influencing factor in the reported CSA vagal nerve values. It may be important to consider, electrocardiogram gating, to overcome this limitation in measurement comparison.⁷

Conclusion

This study reported the CSA, of the vagus nerve, at essential anatomical sites that were based on a young, healthy cohort. The study results were comparable with those that have been reported in prior studies. These findings may help contribute to the evidence needed to identify various vagal nerve pathologies. Sonography of the vagus nerve is essential in potentially reducing the risk of vagus nerve injury, during surgical procedures. Based on published evidence, this may be the first sonographic study to report significantly larger vagus nerve CSA values on the right side in men compared to women. Further research is needed to validate these findings in larger, and more diverse healthy participants.

Footnotes

Acknowledgements

The authors would like to thank all the individuals who took part in this study.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Ethics Approval

Ethical approval for this study was obtained from Northumbria University Ethics Committee [2024-7087-7008].

Informed Consent

Written informed consent was obtained from all subjects before the study.

Animal Welfare

Guidelines for humane animal treatment did not apply to this study because no animals were used during the study.

Trial Registration

Not applicable.

ORCID iDs

Rachal R. Hegde

Japnit K. Dham

Hannah F. Shoctor

Eugene Choe

Neysa P. Sanghavi

Ivonne N. Y. Meares

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Ultrasonographic Reference Values for Vagus Nerve Cross-sectional Area and Associated Variables in Healthy Individuals