Books & Publications

Contents:

• Acute Effects of Vagal Neuromodulation Approaches in Healthy Individuals

• A Review on the Effect of Vagus Nerve Stimulation on Brain Frequency Bands

• The Effect of Bilateral Transcutenous Auricular Vagus Nerve Stimulation on Working Memory and Neuropsychiatric Profile

• The Impact of the Vagus Nerve on Neurodegenerative and Neuropsychiatric Conditions in Connection with the Oral and Intestinal Microbiome

• Effects of Non-invasive Vagus Nerve Stimulation on Behavioral, Physiological, and Neural Responses to Food in Humans: A Traditional Review

• The Effects of Diet Content on the Vagus Nerve

• Personalized Auricular Non-invasive Vagus Nerve Stimulation System for Inflammatory Bowel Disease Treatment

• Vagus Nerve Stimulation and Pregnancy

• Nursing Roles and Responsibilities in Vagus Nerve Stimulation

• Vagus Nerve Stimulation in School Nurses’ Epilepsy Management: Why is it Necessary to Know?

• The Role of the Vagus Nerve in Rheumatoid Arthritis

Abstract: The autonomic nervous system in our body adapts to changes in the internal and external environment and controls vital structures such as the heart, vessels, intestines, and reproductive organs in our body. It mainly consists of two components: the sympathetic system, which causes the “fight or flight” response, especially in the presence of danger, a threat or in a state of panic, etc.; and the parasympathetic nervous system, whose intrinsic properties shortly referred to as “rest and digest” help to calm down the body, allow growth and development and lower the level of stress.

As the stress factors in our routine life rise, the autonomic nervous system dysfunction may cause numerous disorders and diseases including depression, headaches, gastrointestinal disorders, sleep problems, cardiac problems, and etc. Understanding the autonomic nervous system and its dysfunctions will actually increase your awareness with regard to these problems, and potential solutions.

Author: Ali Veysel Özden, M.D., Ph.D.

Abstract: Although vagus nerve stimulation (VNS) is nowadays frequently used in the treatment of neuropsychiatric disorders including epilepsy, depression, and chronic pain such as migraine, an increasing number of studies mention its peripheral effects. Central effects of VNS as a cranial neuromodulation method can be prioritized, but it can cause physiological changes in many peripheral organs as well by the autonomic nervous system (ANS) activity modification. It can be argued that the peripheral effects of VNS can occur through many mechanisms such as reducing hyperinflammation, regulating circulation, determining the level of muscle tone, and controlling endocrine and exocrine secretions. In addition, the role of the vagus nerve on the gut-brain axis should always be kept in mind. However, the wide distribution of the vagus nerve and its extensive connections including those in the central nervous system complicate our understanding of its peripheral effects. VNS appears to have effects on the body (metabolism, neuronal activity, immune status, etc.) but we need more randomized placebo-controlled studies to fully understand and demonstrate the effects of VNS on peripheral targets. Biofeedback systems can be useful both for testing different stimulation parameters and for better understanding of peripheral effects.

Trigeminal neuralgia is a chronic pain syndrome characterized by sharp and sudden pain on one side of the face, which negatively affects patients’ quality of life. Painkillers and surgical procedures such as nerve blockage are preferred in the treatment, but it requires the application of neuromodulation methods due to its side effects and controversial efficacy. In this current report, we describe a 55-year-old female patient who has been experiencing pain due to trigeminal neuralgia for about 20 years. This case highlights the effectiveness of transcutaneous auricular vagus nerve stimulation (taVNS), one of the neuromodulation methods, on pain. It is emphasized that taVNS is an effective neuromodulation method for the suppression of pain symptoms and an important modality for improving the quality of life of patients.

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OBJECTIVE:  Temporomandibular disorders associated with myofascial pain syndrome cause pain and disability in daily life. The aim of this study was to investigate the effect of auricular vagus nerve stimulation on pain in women with myofascial pain syndrome-related temporomandibular disorder.

METHODS:  A total of 50 women with myofascial pain syndrome-related temporomandibular disorder aged between 18 and 35 years participated in this study. The vagus group (n=25) received auricular vagus nerve stimulation and manual therapy and exercise, and the control group (n=25) received only manual therapy and exercise twice a week for 3 months. The pressure pain threshold was used for the assessment.

RESULTS:  In the vagus group, pressure pain threshold on the masseter, temporalis, sternocleidomastoid, digastricus, trapezius, and levator scapula muscles increased statistically significantly after treatment compared to baseline (p<0.05). In the control group, pressure pain threshold on the masseter and levator scapula muscles increased (p<0.05), while no statistically significant difference was found in the pressure pain threshold on the temporalis, sternocleidomastoid, digastricus, and trapezius muscles (p>0.05). When both groups were compared, vagus group was found to be more effective than control group in increasing pressure pain threshold in the masseter, trapezius, and levator scapula muscles (p<0.05).

CONCLUSION:  Auricular vagus nerve stimulation was found to be effective in increasing pressure pain threshold in patients with myofascial pain syndrome-related temporomandibular disorder. The clinical trial registration number was NCT05500716.

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ABSTRACT:tVNS enhances various memory and learning mechanisms, but there is inconclusive evidence on whether probabilistic learning can be enhanced by tVNS. Here, we tested a simplified version of the probabilistic learning task with monetary rewards in a between-participants design with left and right-sided cymba conchae and tragus stimulation (compared to sham stimulation) in a sample of healthy individuals (n = 80, 64 women, on average 26.38 years old). tVNS enhances overall accuracy significantly (p = 4.09 x 10⁻⁰⁴) and reduces response times (p = 1.1006 x 10⁻⁴⁹) in the probabilistic learning phase. Reinforcement learning modelling of the data revealed that the tVNS group uses a riskier strategy, dedicates more time to stimulus encoding and motor processes and exhibits greater reward sensitivity relative to the sham group. The learning advantage for tVNS relative to sham persists (p = 0.005 for accuracy and p = 9.2501 × 10⁻²⁷ for response times) during an immediate extinction phase with continued stimulation in which feedback and reward were omitted. Our observations are in line with the proposal that tVNS enhances reinforcement learning in healthy individuals. This suggests that tVNS may be useful in contexts where fast learning and learning persistence in the absence of a reward is an advantage, for example, in the case of learning new habits.

Introduction:Vagal modulation is achieved directly by transcutaneous auricular vagus nerve stimulation, whereas breathing exercises stimulate arterial baroreceptors. In this study, we aimed to compare these two methods, which have similar effects.

Methods:88 healthy participants aged 18–35 were randomly divided into breathing exercises (Group BE) and vagus stimulation (Group VNS). Thoracic expansion exercise was performed in the BE group. In the VNS group, biphasic electrical stimulation was applied to both ears with a pulse width of 300 ms, a frequency of 10 Hz, and 20 min. Pulmonary function tests were measured on the first and last days. Heart rate, systolic and diastolic blood pressure, RMSSD, PNN50, LF/HF, LF Power, and HF Power values were measured before and after each of the 10 sessions for both groups.

Results:Heart rate decreased significantly in both groups, with significant superiority in the BE group compared to that in the VNS group. In both groups, blood pressure values decreased significantly. RMSSD, PNN50, and HF values increased significantly in the VNS group, while LF and LF/HF values decreased significantly in the BE group. In pulmonary function test results, the FEV1 value increased significantly in both groups. A significant increase in the FVC value was observed in both groups, but the BE group was superior. The two groups had no significant superiority in the FEV1/FVC value.

Conclusion:As a result, auricular vagus stimulation seems superior to breathing exercises in increasing the parasympathetic system activity, reducing sympathetic activity, and partially increasing respiratory functions.

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Background and Aims:Transcutaneous auricular vagus nerve stimulation (taVNS) is a promising neuromodulation therapy with proved efficacy in treating various conditions, such as migraine, depression, abdominal pain, constipation, stroke, and sleep disorders. However, no randomized controlled trials have evaluated the effects of taVNS in patients with primary dysmenorrhea (PwPD). This study aims to investigate the impact of taVNS on pain, functional and emotional symptoms, and physical performance in PwPD.

Materials and Methods:In this study, conducted over two menstrual cycles, 34 PwPD were randomly assigned (1:1) to the taVNS or Sham groups. The treatment protocol comprised taVNS or sham treatment for five consecutive days, starting five days before the expected second menstrual period. The Numerical Rating Scale (NRS), pressure pain threshold (PPT), the Menstrual Symptom Questionnaire (MSQ), the Functional and Emotional Measure of Dysmenorrhea (FEMD), the Hamilton Anxiety Scale (HAM-A), and the 6-Minute Walking Test (6MWT) were evaluated at the first and subsequent menstrual cycles.

Results:The difference between the groups was significant, favoring the taVNS group in the NRS, PPT, MSQ, FEMD, HAM-A, and 6MWT (for all, p < 0.05). Time, treatment, and time × treatment interaction were found to have significant effects on all treatment parameters except 6MWT (for all, p < 0.05).

Conclusion:PwPD may benefit from taVNS, given it has shown efficacy in alleviating pain and menstrual symptoms while improving physical performance.

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Objectives: This study aims to examine the effects of transcutaneous auricular vagus nerve stimulation (taVNS) on social cognition.
The research aims to investigate the effects of transcutaneous auricular vagus nerve stimulation (taVNS) on social cognition,
specifically focusing on its potential to enhance social cognition abilities, strengthen the relationship between social skills, and
influence the connection between Theory of Mind (ToM) and empathy.
Methods: One hundred volunteers (50 female, 50 male), aged between 18 and 45 years, with no psychiatric conditions and who
were suitable for vagus nerve stimulation, participated in the study. An intergroup design was employed, with participants first
completing a social interest scale. The experimental group received taVNS stimulation, while the control group received sham
stimulation. After a 20-minute stimulation period, participants completed the Reading the Mind in the Eyes Test (RMET) and the
Questionnaire of Cognitive and Affective Empathy (QCAE).
Results: The ToM results showed improvement with taVNS. However, no significant differences were observed between groups for
empathy scores, except in the peripheral responsivity subdimension, where the experimental group scored lower than the control group.
Conclusion: According to polyvagal theory, activation of the parasympathetic nervous system promotes a sense of safety, thereby
fostering social engagement. A bidirectional relationship exists between vagal activity and social behavior. The results indicate that
increased vagal activation enhanced participants’ theory of mind (ToM). This sense of security frees cognitive resources, allowing
individuals to focus on understanding others’ mental states rather than self-protection. taVNS appears to improve theory of mind
but has no significant effect on empathy or its subdimensions, except for peripheral responsivity.

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Introduction:Fibromyalgia Syndrome (FMS) is a complex disease characterized by widespread pain, fatigue, emotional disturbances, and autonomic dysfunction. Transcutaneous Auricular Vagus Nerve Stimulation (taVNS) has emerged as a potential noninvasive approach to modulate FMS-related symptoms.

Purpose:To compare the effects of left and bilateral taVNS on pain, mood, functionality, and autonomic nervous system (ANS) activity in individuals with FMS.

Methods:Forty female individuals with FMS were assigned to either a left (n = 20) or a bilateral (n = 20) taVNS group. Both received 11 sessions of taVNS targeting the tragus and concha regions (30 minutes each, 25 Hz, 300 µs) over nonconsecutive days, excluding weekends and menstrual periods. Visual Analog Scale (VAS), Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), and Fibromyalgia Impact Questionnaire (FIQ) were assessed. ANS activity was evaluated via heart rate variability (HRV). After 11 sessions of taVNS, a 2-week follow-up was performed.

Results:No significant differences were observed between groups except for FIQ and BAI on day 28 (p = .002–0.008). Both groups showed significant within-group improvements in VAS (r = 0.87–0.94; p < .001), BDI (r = 0.46–0.71; p < .001), FIQ (r = 0.95–0.99; p < .001), and BAI (r = 0.69–0.94; p < .001) scores. Parasympathetic Nervous System (PNS) (p = .365–0.776) and Sympathetic Nervous System (SNS) (p = .598–0.880) indices, which are the subparameters of HRV, showed no significant between-group differences, with small effect sizes (r < 0.15).

Conclusion:Both stimulation protocols effectively reduced pain and improved mood and functionality in fibromyalgia, indicating a safe, noninvasive adjunctive treatment option.
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Background:Transcutaneous auricular vagus nerve stimulation (TAVNS) stands out as a neuromodulation method that shows therapeutic potential thanks to its ability to regulate autonomic responses. However, the role of TAVNS in the management of bruxism-related clinical parameters has not been sufficiently investigated.

Objective:This study aimed to investigate the holistic effects of TAVNS added to exercise therapy on bruxism-related clinical parameters in patients with clinically based bruxism.

Methods:This randomised, controlled, single-blind experimental clinical study included 40 individuals diagnosed with clinically based bruxism, who were randomly assigned to two groups: the TAVNS group (n = 20) and the control group (n = 20). Both groups performed the Rocabado exercise program for 8 weeks, while the TAVNS group additionally performed TAVNS. Oral health-related quality of life, sleep quality, perceived stress level, pain intensity, pain threshold, biomechanical properties of masticatory muscles, masseter muscle activation and autonomic parameters were evaluated before and after treatment.

Results:The TAVNS group showed significantly better results in oral health-related quality of life, stress levels, masseter muscle functional parameters (resting activation, tonus, stiffness), and autonomic parameters (pulse rate, respiratory rate, sympathetic activity, sympathovagal balance) compared to the control group (p < 0.05).

Conclusion:This study revealed that TAVNS added to exercise therapy provided significant improvements in key clinical parameters associated with bruxism, including both local symptoms (muscle activation and biomechanical properties) and systemic parameters (autonomic parameters, stress, oral health-related quality of life) in bruxism. Although our findings support the clinical potential of TAVNS as a non-invasive complementary option for managing bruxism-related dysfunctions, these effects need to be confirmed in larger samples and long-term follow-ups.
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Aim:Transcutaneous auricular vagus nerve stimulation (taVNS) has recently emerged as an effective neuromodulation method. A preliminary evaluation based on heart rate variability (HRV) could predict those who would benefit most from taVNS. This study investigated the efficacy of taVNS in healthy subjects according to the baseline activity range of the parasympathetic (PNS) and sympathetic nervous system (SNS) indexes.

Methods:76 healthy participants were enrolled in the study. HRV, pulse rate, and systolic and diastolic blood pressure (SBP and DBP) were measured at baseline and after taVNS. The procedure was repeated after 48–72 h.

Results:In the first intervention, the PNS index increased in group 1 (p <0.001), and the SNS index decreased in groups 1 and 3 (p <0.001). In the second intervention, the PNS index increased in groups 1, 2, and 4 (p = 0.001, p = 0.018, and p = 0.003, respectively), while the SNS index decreased in groups 1 and 3 (both p = 0.001). SBP and DBP decreased in all groups after both interventions. After the first intervention, the PNS index was higher in group 1 than in groups 3 and 4 (p = 0.001 and p <0.001, respectively), and the SNS index and SBP were lower in group 1 than in group 3 (both p <0.05). After the second intervention, the PNS index was higher and the SNS index was lower in group 1 than in group 3 (p <0.05).

Conclusions:Subjects with low parasympathetic or high sympathetic activity may be more responsive to taVNS.
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ABSTRACT

Autism spectrum disorder (ASD) is a multifactorial neurodevelopmental condition defined by social deficits, stereotypical or repetitive behaviors, and anxiety. This study evaluates the therapeutic potential of transauricular vagal nerve stimulation (tVNS) in a valproic acid (VPA)-induced mouse model of ASD. The study comprised three groups: the control + sham (saline-treated offsprings receiving sham stimulation), the autistic + sham (VPA-treated offspring receiving sham stimulation), and the autistic + tVNS (VPA-treated offsprings receiving tVNS). Male C57BL/6 mice exposed to VPA on embryonic day 12.5 were evaluated for behavioral and neurobiological alterations. tVNS was applied twice weekly for 3 weeks to investigate its effects on sociability, anxiety-like behaviors, neurogenesis markers, and apoptosis pathways. Behavioral testing, including the three-chamber test, mirrored chamber test, open field test, and elevated plus maze, revealed that tVNS significantly improved sociability and social preference indices, reduced social anxiety, and decreased general anxiety-like behaviors in VPA-induced mice. Histological and immunohistochemical analyses have shown a decrease in neuron density, brain-derived neurotrophic factor (BDNF), and doublecortin (DCX) expression in the hippocampus, amygdala, and prefrontal cortex of VPA-induced mice. Additionally, the increase in caspase-3 immunoreactivity indicates increased apoptosis. tVNS treatment restored BDNF and DCX levels, promoting neurogenesis and synaptic plasticity while significantly reducing caspase-3-mediated apoptosis in affected brain regions. These findings suggest that tVNS may counteract the neural and behavioral deficits associated with ASD by modulating neurogenesis, neuronal plasticity, and apoptosis. The study highlights tVNS as a potential therapeutic intervention for ASD, emphasizing its role in targeting both behavioral alterations and underlying neurobiological mechanisms.

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Purpose: This study aimed to compare the acute effects of vagus nerve stimulation (VNS), transcutaneous electrical nerve stimulation (TENS), and the backup stimulation device (Backup) on pain, sympathetic, and parasympathetic nervous system functions in fibromyalgia patients.
Methods: Thirty fibromyalgia patients (aged 20-45) from a hospital in Bursa were randomly assigned to three groups: VNS, TENS, and Backup stimulation device. Each group received a 30-minute session once weekly for five sessions. Pain was assessed using the visual analog scale (VAS), and sympathetic and parasympathetic functions were measured with the Elite heart rate variability device. Parameters included heart rate, root mean square of successive differences, proportion of NN50 divided by total RR intervals, low-frequency/high-frequency (LF/HF) power, and LF/HF ratio.
Results: No significant post-intervention changes were found in autonomic parameters across groups (p>0.05). However, all groups showed a significant reduction in VAS scores (p<0.05), indicating effective pain relief. Heart rate significantly decreased only in the Backup group (p<0.05), suggesting a shift toward parasympathetic dominance. Between-group analysis revealed significant differences in VAS scores between the TENS and VNS groups, and the VNS and Backup groups (p<0.05), indicating variability in pain response.
Conclusion: TENS, VNS, and Backup stimulation devices effectively reduce pain in fibromyalgia patients. The heart rate reduction in the Backup group suggests a potential effect on autonomic regulation, which may offer a beneficial approach for managing fibromyalgia symptoms. Although autonomic parameters showed no significant changes overall, further research is needed to understand the long-term effects and clinical relevance of these treatments.

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Background/Objectives: We aimed to examine the acute effects of deep breathing exercise and transcutaneous auricular vagus nerve stimulation (taVNS) on autonomic nervous system activation and the characteristics of certain muscle groups and to compare these two methods. 

Methods: 60 healthy adults between the ages of 18 and 45 were randomly divided into two groups to receive a single session of taVNS and deep breathing exercises. Acute measurements of pulse, blood pressure, perceived stress scale, autonomic activity, and muscle properties were performed before and after the application. 

Results: A significant decrease was detected in the findings regarding the perceived stress scale, pulse, and blood pressure values as a result of a single session application in both groups (p < 0.05). In addition, it was determined that the findings regarding autonomic measurement values increased in favor of the parasympathetic nervous system in both groups (p < 0.05). In measurements of the structural properties of the muscle, the stiffness values of the muscles examined in both groups decreased (p < 0.05), while the findings regarding relaxation increased (p < 0.05), except for the masseter in the deep breathing (DB) group. As a result of the comparative statistical evaluation between the groups, the increase in parasympathetic activity was found to be greater in the DB group according to root mean square of differences in successive RR intervals (RMSSD), the percent of differences in adjacent RR intervals > 50 ms (pNN50), and stress index parameters (p < 0.05). In the measurements made with the Myoton^®PRO device, the increase in the relaxation value was higher in the gastrocnemius muscle of the VNS group (p < 0.05). 

Conclusions: It has been observed that both methods can increase parasympathetic activity and muscle relaxation in healthy people in a single session. However, DB appears to be slightly superior in increasing parasympathetic activity, and VNS appears to be slightly superior in increasing relaxation.

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Abstract: In this paper, single side body impedance spectroscopy is performed between wrist and ankle in response to auricular transcutaneous electrical vagus stimulation, to obtain the Cole parameters Ro, R∞ and fc. Following a resting period of 5 minutes in supine position, left ear vagus nerve was stimulated for 3 minutes and BIS performed every 10 seconds, on 8 healthy subjects with age: 23,6+1,5 years, height:
175+8,3 cm; weight: 69,5+18,7 kg and BMI: 22,6+5,5 kg/cm2. Cole circles moved to the right (inreased Ro and R∞ ) with stimulation while the centers shifted upwards. Intracellular and extracellular resistances and the capacitance Cm all increased at the onset of vagus stimulation; resulting in a decrease of 3,4+1.33% in fc. Changes in Ri mainly indicate water shift between cells and extracellular fluid; physiological changes
occurred on cell membrane. fc independent of the participants’ anthropomorphic factors could be used as an indicator to vagus nerve stimulation, without further normalization. This preliminary study was realized with a limited number of participants; however, to reach statistically meaningful results measurements will be performed over a larger sample size.

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Objective: This study aimed to investigate and compare the effectiveness of transcutaneous auricular vagus nerve stimulation
(taVNS) and transcutaneous auricular trigeminal nerve stimulation (taTNS) in the autonomic nervous system in healthy
individuals.
Materials and Methods: The study included 18 healthy participants (41 female, 39 male) aged between 20 and 50 years,
without any acute or chronic illness. Participants were randomized to four groups as taVNS (n = 20), taTNS (n = 20), sham-taVNS (n = 20), and sham-taTNS (n = 20). taVNS and taTNS protocols were designed as follows: duration of bilateral auricular stimulation 30 minutes, current amplitude 250 microseconds, frequency 25 Hz, and current intensity 0.13 to 50 mA above threshold.The sham-taVNS and taTNS groups were designed so that the current intensity remained at 0 mA after the electrodes were
placed and the device was switched on. Heart rate variability (HRV), pulse rate, and systolic (SBP) and diastolic blood pressure (DBP) were recorded at baseline and after interventions.
Results: Heart rate decreased in the taVNS and taTNS groups, and SBP decreased only in the taVNS group compared with
baseline (p < 0.05). Root mean square of consecutive differences (RMSSD) increased significantly in taVNS and taTNS groups (p <0.05). The post hoc analysis showed that taVNS was more effective at increasing RMSSD than was taTNS (p < 0.05). DBP was not changed in all groups (p < 0.05). No parameter changes were found in the sham groups (p < 0.05).
Conclusions: This study showed that taVNS was more effective in decreasing SBP and increasing RMSSD than were taTNS and sham stimulation. More predictive insights into taVNS and taTNS will come from different stimulation areas and results from longer-term studies in future.

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Abstract:Transcutaneous auricular Vagus Nerve Stimulation (taVNS) has emerged as a promising non-invasive method for modulating the Autonomic Nervous System (ANS). However, its impact on cardiac autonomic regulation during acute stress remains underexplored. This study investigates taVNS effects on Heart Rate Variability (HRV) indices in response to psychological stress in healthy individuals across time and frequency domains. Sixty participants were randomly assigned to three groups: control, sham, and stimulation. Each underwent a three-phase experimental protocol: pre-stress, stress induction, and post-stress. Time domain (RR interval, pNN50, SDNN, RMSSD), frequency domain (HF, LF, LF/HF) were computed from ECG signals and analyzed using repeated-measures comparisons. Results revealed that stimulation group exhibited a sharper drop in RR intervals (753 ms pre-stress, 648 ms stress, and 745 ms post-stress), pNN50 (11.1% → 4.3% → 8.7%), and LF/HF rose from (0.6) under stress to (1.1) in recovery, suggesting enhanced vagal reactivation. While the sham group showed limited improvement, the control group demonstrated minimal restoration in pNN50. SDNN values for the stimulation group increased steadily (48.7 ms → 56.8 ms → 63.9 ms), indicating broader autonomic adaptability. These results indicate a targeted influence of taVNS on cardiac vagal tone and overall autonomic regulation, potentially promoting parasympathetic engagement under stress.

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Background:Post-COVID syndrome (PCS) is a condition that occurs after COVID-19 infection that lasts for more than three months and adversely affects the autonomic nervous system (ANS). The aim of this study was to investigate and compare the effectiveness of transcutaneous auricular vagus nerve stimulation (taVNS) and sham taVNS in fatigue in individuals with PCS.

Methods:Forty-two patients (20 male, 22 female) with PCS participated in this study. The severity of fatigue was assessed with the fatigue severity scale (FSS). Heart rate variability (HRV) was measured in participants at baseline and after taVNS. The participants were randomly divided into two groups (taVNS and sham taVNS). taVNS was applied for 20 consecutive days for 30 min each (10 Hz, 300 μs).

Results:The groups were similar in FSS and HRV at baseline (p > 0.05). After the intervention, FSS decreased in taVNS (p = 0.018) and sham taVNS (p = 0.036). RMSSD increased in taVNS (p = 0.010), with no change in sham taVNS (p > 0.05) from baseline to after treatment. Stress index showed no change in both groups (p > 0.05). PNS index increased in taVNS (p = 0.007) and sham taVNS (p = 0.049). The SNS index and low frequency (LF) power decreased in taVNS (p = 0.001, p = 0.017, respectively), with no change in sham taVNS (p > 0.05). High frequency (HF) power showed no change within groups (p > 0.05). LF/HF decreased in taVNS (p = 0.002), with no change in sham taVNS (p > 0.05). Pre- and Post-tests showed taVNS was more effective than sham taVNS in decreasing FSS (p = 0.022) and LF power (p = 0.029), in increasing PNS index (p = 0.016). There was a difference in HF power between groups after treatment (p = 0.042).

Conclusion:Both taVNS and sham taVNS were effective in reducing the severity of fatigue, with sham taVNS being superior to taVNS. The observed effect size was smaller than anticipated. This suggests that larger-sample-size studies are required to verify these results.

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Abstract: Inflammatory bowel disease (IBD) encompasses Crohn's disease (CD) and ulcerative

colitis (UC), is a major health problem on a global scale and its treatment is unsatisfactory. We aimed to investigate the effects of transauricular vagal nerve stimulation (tVNS) on inflammation in rats with IBD induced by trinitrobenzene sulfonic acid (TNBS). A total of 36 adult female Sprague–Dawley rats were given TNBS, or vehicle, and tVNS, or sham, every other day for 30 min for 10 days. Postmortem macroscopic and microscopic colon morphology were evaluated by histological staining.

Additionally, IL-1β, IL-6, IL-10, and TNF-α cytokine levels in the colon and the brain

were evaluated by immunohistochemistry and western blotting analysis. TNBS induced epithelial damage, inflammation, ulceration, and thickened mucosal layer in the colonic tissues. Administration of tVNS significantly ameliorated the severity of TNBS-induced tissue damage and inflammatory response. TNBS also alters proinflammatory and anti-inflammatory balance in the brain tissue. TVNS application significantly suppressed the protein levels of pro-inflammatory cytokines, namely IL-1β,IL-6, and TNF- α while augmenting the level of anti-inflammatory cytokine IL-10 in the colonic and the brain tissue. We have shown that TNBS-mediated colonic inflammation and tissue damage are associated with neuroinflammatory responses in the brain tissue. Also demonstrated for the first time that neuroinflammatory response in the gut-brain axis is suppressed by tVNS in the IBD model. Non-invasive tVNS stands out as a new potential treatment option for types of IBD.

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Background/Objectives: Transcutaneous auricular vagus nerve stimulation (TaVNS) is a
non-invasive method of electrical stimulation used to autonomic neuromodulation. Position and
form of the electrodes are important for the effectiveness of autonomic modulation. This study was aimed to investigate the effect of TaVNS in-ear and behind-ear on autonomic variables. Methods: A total of 76 healthy participants (male: 40, female: 36) were randomized into four groups as in-ear TaVNS, behind-ear TaVNS, in-ear sham, and behind-ear sham. The TaVNS protocol included bilateral auricular stimulation for 20 min, 25 hertz frequency, a pulse width of 250 μs, and a suprathreshold current (0.13-50 mA). Heart rate (HR), systolic and diastolic blood pressure (SBP and DBP), and heart rate variability (HRV) were measured baseline and after stimulation. The parameters RMSSD (root mean square of consecutive differences between normal heartbeats), LF power (low-frequency), and HF power (high-frequency) were assessed in the HRV analysis.

Results: HR decreased in the in-ear TaVNS after intervention (p < 0.05), but did not change in
behind-ear TaVNS and sham groups compared to baseline (p > 0.05). SBP and DBP decreased and
RMSSD increased in the in-ear and behind-ear TaVNS groups (p < 0.05), but did not change in sham groups compared to baseline (p > 0.05). There was no significant difference in LF and HF power after TaVNS compared to baseline in all groups (p > 0.05). SBP was lower and RMSSD was higher in-ear TaVNS than behind-ear TaVNS after intervention (p < 0.05). Conclusions: In-ear TaVNS appears to be more effective than behind-ear TaVNS in modulating SBP and RMSSD, but this needs to be studied in larger populations.

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Abstract:Vagus nerve stimulation (VNS) is the subject of exploration as an adjunct treatment for neurological disorders such as epilepsy, chronic migraine, pain, and depression. A non-invasive form of VNS is transcutaneous auricular VNS (taVNS).Combining animal models and positron emission tomography (PET) may lead to a better understanding of the elusive mechanisms of taVNS. We evaluated the acute effect of electrical stimulation of the left vagus nerve via the ear on brain synaptic vesicle glycoprotein 2A (SV2A) as a measure of presynaptic density and glucose metabolism in naïve rats. Female Sprague–Dawley rats were imaged with [11C]UCB-J (n=11) or [18F]fluorodeoxyglucose ([18F]FDG) PET (n=13) on two separate days, (1) at baseline, and (2) after acute unilateral left taVNS or sham stimulation (30min). We calculated the regional volume of distribution (VT) for [11C]UCB-J and standard uptake values (SUV) for [18F]FDG. We observed regional reductions of [11C]UCB-J binding in response to taVNS ranging from 36% to 59%. The changes in taVNS compared to baseline were significantly larger than those induced by sham stimulation. The differences were observed bilaterally in the frontal cortex, striatum, and midbrain. The [18F]FDG PET uptake remained unchanged following acute taVNS or sham stimulation compared to baseline values. This proof-of-concept study shows for the first time that acute taVNS for 30min can modulate in vivo synaptic SV2A density in cortical and subcortical regions of healthy rats. Preclinical disease models and PET ligands of different targets can be a powerful combination to assess the therapeutic potential of taVNS.

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Background: Current inflammatory bowel disease (IBD) treatments often fail to achieve lasting remission and have adverse effects. Vagus nerve stimulation (VNS) offers a promising therapy due to its anti-inflammatory effects. Its invasive nature, however, has led to the development of non-invasive methods like transcutaneous auricular VNS (taVNS). This study assesses taVNS’s impact on acute colitis progression, inflammatory, anti-inflammatory, and apoptosis-related markers.

Methods: Male C57BL/6 mice (11–12 weeks) were used for dextran sulfate sodium (DSS)- and dinitrobenzene sulfonic acid (DNBS)-induced colitis studies. The administration of taVNS or no stimulation (anesthesia without stimulation) for 10 min per mouse began one day before colitis induction and continued daily until sacrifice. Ulcerative colitis (UC)- like colitis was induced by administering 5% DSS in drinking water for 5 days, after which the mice were sacrificed.

Crohn’s disease (CD)-like colitis was induced through a single intrarectal injection of DNBS/ethanol, with the mice sacrificed after 3 days. Disease activity index (DAI), macroscopic evaluations, and histological damage were assessed.Colon, spleen, and blood samples were analyzed via qRT-PCR and ELISA. One-way or two-way ANOVA with Bonferroni and Šídák tests were applied.

Results: taVNS improved DAI, macroscopic, and histological scores in DSS colitis mice, but only partially mitigated weight loss and DAI in DNBS colitis mice. In DSS colitis, taVNS locally decreased colonic inflammation by downregulating pro-inflammatory markers (IL-1β, TNF-α, Mip1β, MMP 9, MMP 2, and Nos2) at the mRNA level and upregulating anti-inflammatory TGF-β in non-colitic conditions at both mRNA and protein levels and IL-10 mRNA levels in both non-colitic and colitic conditions. Systemically, taVNS decreased splenic TNF-α in non-colitic mice and increased serum levels of TGF-β in colitic mice and splenic levels in non-colitic and colitic mice. Effects were absent in DNBS-induced colitis. Additionally, taVNS decreased pro-apoptotic markers (Bax, Bak1, and caspase 8) in non-colitic and colitic conditions and increased the pro-survival molecule Bad in non-colitic mice.

Conclusions: This study demonstrates that taVNS has model-dependent local and systemic effects, reducing inflammation and apoptosis in UC-like colitis while offering protective benefits in non-colitic conditions. These findings encourage further research into underlying mechanisms and developing adjunct therapies for UC.

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Background: This study investigated the effects of diet, exercise, and vagus nerve stimulation (VNS) methods on body composition, functional capacity, and blood parameters in the short term.
Methods: We performed our research in obese individuals(N:90) aged 18-65 years, who were stage I, II, and III according to WHO. Laboratory measurements and evaluation scales of individuals in the Diet, Exercise, and VNS groups were compared. Anthropometric changes were recorded as well as changes in functional capacity (6-minute walk test(6MWT)), muscle strength (hand grip strength test); stair climbing test(SCT), food choice (Excessive food
cravings Questionnaire(FCQ), Visual analog scale(VAS), and quality of life(The 36-Item Short Form Health Survey questionnaire(SF-36)).
Results: A weight loss of 4%-10% in total body weight (4.7–10.4 kg) in a 4-week period improved anthropometric features, functional capacity, and quality of life (p <0.05). Considering the parameters and tests examined in the study, although there were no statistically significant differences between the groups, it was observed that there was a positive effect on health status in all 3 groups compared to the beginning of the study. Weight loss was statistically significant in DG compared to other groups (p <0.05). Percentage distribution of weight loss, respectively, Diet Group(DG): 10%; Exercise Group(EG): 6%; VNS Group: 4%.
Conclusion: 3 different methods - diet, exercise, and VNS - that we have examined in a 4-week period were effective in creating weight loss. Although there is no significant weight loss with auricular VNS, it has been observed as a result of the scale data that there may be a behavioral change in terms of appetite/food choice orientation. We think that auricular VNS can be used alone or in addition to other weight loss methods in the treatment of obesity. There is a need for long-term research on this three methods related to body weight change.

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Abstract: Vagus nerve signals from the gut to brain carry information about nutrients and drive food reward. Such signals are disrupted by consuming large amounts of high-calorie foods, necessitating greater food intake to elicit a similar neural response. Non‐invasive vagus nerve stimulation (nVNS) via a branch innervating the ear is a candidate treatment for obesity in humans. There is disagreement on the optimal location of nVNS in the ear for experimental and clinical studies. There are also no studies comparing nVNS in hungry and full states. We aimed to compare ear position(s) for nVNS and explore the effects of nVNS during hungry and full states on proxies for autonomic outflow (heart-rate variability) and efferent metabolism (gastric frequency and resting energy expenditure).

Objectives: Auricular vagus nerve stimulation (VNS) is a non-invasive treatment
modality. Opinions that it can be used in the treatment of various clinical problems
have gained importance in recent years. In this study, it was aimed to lay the
groundwork for the use of the auricular VNS in different ears.
Methods: Healthy individuals (n = 90) were divided into three groups: unilateral
left (n = 30), unilateral right (n = 30), and bilateral (n = 30) auricular VNS.
Electroencephalography (EEG) and electromyography (EMG) measurements
were performed before and after auricular VNS (10 Hz, 300 μs, 20 min) for a
single session.
Results: An increase in wrist extensor muscles activation was detected on the
contralateral side of the auricular VNS application side. It has been observed that
there is a general decrease in the power of high-frequency waves and an increase
in the power of lower-medium frequency waves in various parts of the brain.
Conclusion: Our findings suggest that the projection of the auricular VNS in the
central nervous system may also affect the corticospinal tracts.

Abstract: Loss of the sense of taste and smell is a common side effect of Covid 19. It is thought that transcutaneous ear vagus nerve stimulation may affect taste and smell as a result of neural connections. We present a 27-year-old female participant diagnosed with loss of taste and smell for more than 1 year. The Connecticut Chemosensory Clinical Research Center (CCCRC) olfactory test was used to test the sense of smell. To test the sense of taste, 3 drops of taste test were applied. It was found that during the application period of 1 session per day for 15 days, there was a progressive improvement in the sense of taste and smell.

Objectives: To evaluate the effect of auricular vagus nerve stimulation (VNS) applied in addition to ischemic compression and stretching exercises on pain, trigger point (TP) sensitivity, grip strength, quality of life and autonomic functions in patients with myofascial pain syndrome (MPS).

Methods: Sixty patients, who had neck pain, met the diagnostic MPS criteria of Travell and Simons were included in the study. The subjects were randomly divided into VNS group (n = 30) or control group (n = 30). Each group performed 10 sessions of TP ischemic compression and stretching exercises (5 days/week). Ten sessions of 30-minute long auricular VNS were added to the treatment in VNS group. Pain severity [Visual Analogue Scale (VAS)], TP sensitivity (algometer), grip strength (Jamar dynamometer), quality of life [Short Form-36 (SF-36)] and autonomic function [Composite Autonomic Symptom Scale-31 (Compass-31)] were evaluated before and after 10 sessions of treatment.

Results: The VAS, algometer and Jamar measurements showed significant improvement in both groups. A statistically significant improvement was found in orthostatic intolerance, secretomotor and pupillomotor subscales of Compass-31 scale in the VNS group following the treatment (p < 0.05) while no significant difference was observed in the control group (p > 0.05). The control group showed significant improvement in all parameters of SF-36 scale, while the VNS group showed significant improvement in physical function, social functionality and pain parameters (p < 0.05). The changes in the VAS, algometer, Jamar scores and secretomotor subscale of the Compass-31 scale were statistically higher in the VNS group than in the control group (p < 0.001, p < 0.001, p = 0.001 and p = 0.011, respectively).

Conclusions: It can be argued that auricular VNS increases the effectiveness of ischemic compression and stretching exercises in patients with MPS. Further and detailed studies are needed in which the effect of VNS alone or in combination with other treatments in patients with MPS is examined and the physiological mechanisms are investigated.

Keywords: Myofascial pain syndrome, auricular vagus nerve stimulation, ischemic compression, autonomic nervous system, quality of life

Background: This study is to investigate the effect of non-invasive auricular VNS on cycle ergometer test and physiological parameters in healthy individuals.

Methods: 46 people participated in the study. The participants were randomly divided into 3 groups as Above Threshold, Under Threshold and Control according to the sensation of electrical current on ears. The participants were evaluated 3 times; before the application, after the first and second bicycle exercises. Numerical pain scale, pulse rate, blood pressure, respiratory rate, and distance travelled during exercise for cycle ergometer test.

Results: There was no significant difference in 1st measurement, 2nd measurement, 3rd measurement of pulse rate, saturation value and performance in the control group, sub-threshold group and above threshold group (p ˃ 0.05). The 2nd measurement of NPS value was significantly lower in the above threshold group than in the control group and the below threshold group (p ˂ 0.05). The 1st measurement, 2nd measurement, 3rd measurement respiratory rate and 3rd measurement diastolic pressure values were significantly higher in the sub-threshold group (p ˂ 0.05).

Conclusion: In healthy individuals, short-term non-invasive auricular VNS does not affect cycle ergometer test during exercise. This may be due to the fact that the application time is kept short and the application is a single time. In VNS application, feeling the current and/or current intensity may affect parameters such as respiratory rate and blood pressure.

Abstract: Vagus nerve stimulation (VNS) has been used in the treatment of epilepsy and depression for more than 20 years. Although the invasive cervical method is the most preferred application, side effects such as cough, voice change and hoarseness can be seen due to negative effects on the recurrent laryngeal nerve (a branch of the vagus nerve). Auricular VNS has been preferred recently due to its non-invasiveness, but uncertainty about the stimulation parameters continues. We tested the hypothesis that auricular VNS can affect voice and its features indirectly via afferent nerve connections reaching the nucleus tractus solitarius. Two patients previously using auricular VNS device for different diseases were requested to record their voices before and after the stimulation. Their devices (Vagustim) were changed with new version to check the usage of the patients. Sound recordings at different VNS frequencies (1-150 Hz) were collected by a mobile phone and analyzed with Praat and our MATLAB algorithm. Fundamental frequency (f0), jitter, shimmer, and harmonic to noise ratio (HNR) owere evaluated. The alteration was highest at 100 Hz and 30 Hz VNS for the male and female patients respectively. Audio recordings before and after 30 Hz (for female) and 100 Hz (for male) VNS at different durations (5-30 min) on different days were repeated and compared by Praat and our algorithm. Some discrepancy between the parameters jitter, shimmer, and HNR are detected between the algorithms, which is accounted to the fact that it is not standardized whether the algorithm uses only a specific part of the input signal or the whole signal. However, when the ratio of change of these parameters are considered, fundamental frequency and the HNR were found to be highly consistent for developing an algorithm to govern the stimulation parameters in an automated way. Furthermore, the same ratios for jitter and shimmer are also promising after some improvement to be included in such an algorithm. These results suggest that auricular VNS can affect voice and its parameters, but this change is related with stimulation parameters. It seems necessary to develop specific software and algorithms that can detect this change well.

Authors: Ali Veysel Özden, Tayfun Tatar

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Abstract: In this paper, we propose multifrequency body impedance measurement technique for monitoring the onset of vagus nerve stimulation. In response to transcutaneous electrical vagus stimulation, changes occur in body fluids i.e. fluid shifts in extracellular and intracellular media that can be assessed by Cole parameters Re and Ri before and after stimulus, by measuring single side impedance spectroscopy (from 3 kHz to 1MHz) between wrist and ankle. Following a resting period of 5 minutes in supine position, auricular vagus nerve was stimulated for 3 minutes and BIS performed every 10 seconds, on 23-27 years old, 5 healthy subjects. During the stimulation phase, either an increase or a decrease was observed in extracellular and intracellular fluids. In 3 of the subjects, an ECF decrease of 0.02% per kg was compensated by 0.02 to 0.06% per kg increase in ICF; with a correlation coefficient of -0,70 to -0,79; suggesting fluid shifts between ECF and ICF. With the other 2 subjects, both ECF and ICF decreased by about 0.02% per kg. The study was performed with a limited number of participants; to reach statistically meaningful results measurements will be performed over a larger sample size.

Authors: Y. Ülgen, B. Büyüksaraç, B. Tunç and H. Solmaz

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Abstract: The purpose of this study is to evaluate the impact of auricular vagus nerve stimulation, applied in conjunction with an exercise treatment program, on pain and life quality in patients with fibromyalgia syndrome (FMS). To achieve the study objectives, 60 female patients between the ages 18 and 50, with diagnosed FMS according to the American College of Rheumatology (ACR) 2010 diagnostic criteria, were randomly divided into 2 groups of 30. The first group was assigned 20 sessions of a home-based exercise program, while the second group was assigned 20 sessions of auricular vagus nerve stimulation and 20 sessions of a home-based exercise program. Patients were assessed before and after the treatments using the Visual Analog Scale (VAS) for pain, Beck Depression Scale for depression, Beck Anxiety Scale for anxiety, Fibromyalgia Impact Questionnaire (FIQ) for functional evaluation, and Short Form-36 (SF-36) for life quality. In this randomized controlled trial, comparisons within the groups revealed that both groups had statistically significant improvements in pain, depression, anxiety, functionality, and life quality scores (p < 0.05), while comparisons across the groups revealed that the group experiencing the vagus nerve stimulation had no statistically significant differences between the baseline scores, except for those of SF-36’s subparameters of physical function, social functionality, and pain. In fact, comparisons across the groups after the interventions revealed that the group experiencing the vagus nerve stimulation had better scores but not statistically significant. From the analysis of this data, we observed that vagus nerve stimulation in FMS treatment did not give additional benefit together with exercise, except for three subparameters of SF-36. It was identified that further studies which separately investigate the effects of vagus nerve stimulation and exercise on FMS with longer follow-up periods and an increased number of patients are needed.

Authors: Nazlı Kutlu, Ali Veysel Özden, Hasan Kerem Alptekin, Jülide Öncü Alptekin

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Objective: The aim of this study is to investigate the effect of non-invasive auricular VNS (Vagus Nerve Stimulation) on sportive performance and physiological parameters in healthy individuals.

Material and Method: 46 healthy young individuals aged 19.2(±1.5) years participated in the study. The participants were randomly divided into 3 groups as Above Threshold Group (n:15; 10 females, 5 males), Under Threshold Group (n:15; 10 females, 5 males), and Control Group (no stimulation) (n:16; 11 females, 5 males) according to the sensation of electrical current on ears. The participants were evaluated 3 times; before the application, after the first and second bicycle exercises. Numerical pain scale (NPS), pulse rate, blood pressure, respiratory rate, and distance traveled during exercise for sportive performance were recorded in kilometers as the evaluation method. The stimulation was done during the first bicycle exercise with 5 minutes of duration. The Kruskal-wallis, mann-whitney u test were used for the quantitative independent data obtained. In the analysis of qualitative independent data, chi-squared test was used.

Author: Sefa Haktan Atık

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Abstract: Paroxysmal hemicrania is characterised by severe short-term unilateral headaches that are associated with ipsilateral cranial autonomic symptoms. A rare headache type, paroxysmal hemicrania is included in the trigeminal autonomic cephalgia group of primary headache. The relationship between paroxysmal hemicrania and sleep apnoea has not been previously reported in the literature. Her headaches temporarily regressed with positive airway pressure treatments and positively responded to transauricular vagus nerve stimulation. We evaluated the stimulatory effect of this treatment by examining the patient’s sympathetic skin responses.

Authors: Metin, Kübra Mehel; Meriç, Olcay Tosun; İnan, Levent Ertuğrul; Yoldaş, Tahir Kurtuluş

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Abstract: During sports and exercise, the cardiovascular system, respiratory system, musculoskeletal system, nervous system, endocrine system, and immune system play an active role. With the start of exercise, sympathetic activity in the body increases and parasympathetic activity is suppressed. With the end of the exercise, sympathetic activity decreases, while parasympathetic activity increases and contributes to the recovery process of the individual. The contribution of the parasympathetic system to the restructuring/recovery during the rest period is important in terms of reducing the fatigue of the athletes and enabling them to recover in the early period. Stimulation of the vagus nerve, which is the main branch of the parasympathetic system, can affect many cardiovascular, pulmonary, and metabolic parameters both during rest and exercise. Our article aims to evaluate the potential benefits and effects of using auricular vagus nerve stimulation (VNS) for sports purposes on the recovery and performance of athletes in light of the literature. Recovery after exercise can be accelerated with auricular VNS. The negativities caused by overload and excessive training can be reduced. Thanks to better rest and early recovery, the performance in the following training program can be increased. Injuries that may occur due to insufficient recovery can be prevented or injuries can be reduced. We can expect that the auricular VNS method will be used soon in light of sufficient scientific data due to its effects that cannot be considered doping.

Authors: Ali Veysel Özden, Kerem Alptekin, Mehmet Unal

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Objectives: This study aims to investigate the effects of transcutaneous auricular vagus nerve stimulation (taVNS) on visual memory performance and fatigue in healthy individuals.

Methods: Between April 10, 2022 and May 25, 2022, a total of 60 physical therapy and rehabilitation students (27 males, 33 females; mean age: 20.6±1.6 years; range, 18 to 24 years) were included in the study. The individuals were divided into two groups as the experimental group (n=30) and the control group (n=30). The experimental group received taVNS, mobile device supported games, and low-medium intensity aerobic exercises, while the control group received mobile device supported games and aerobic exercises. The personal information form was applied to all participants. The level of fatigue was measured using a computer-based evaluation and Fatigue Severity Scale (FSS) to analyze the visual memory performance.

Results: All parameters used to evaluate visual memory performance showed a significant difference, while the FSS scores showed no significant difference (p>0.05). Only one sub-parameter in the control group was significantly different, while none of the other sub-parameters or FSS scores were significantly different (p>0.05). There was a significant difference between the two groups in terms of two of the visual memory sub-parameters, although no significant difference was found for the results of one parameter and the FSS (p>0.05).

Conclusion: Our study results show that taVNS can produce positive effects on visual memory performance, although it does not apparently affect fatigue.

Authors: Rıdvan Yıldız, Ali Veysel Özden, Onur Seçgin Nişancı, Zeynep Yıldız Kızkın, Bedriye Cansu Demirkıran

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Background: The anti-inflammatory impacts of stimulating the vagus nerve as a part of the gut-brain axis on intestinal macrophage activity and inflammatory cytokine production have been documented. While vagus nerve stimulation until now has been chiefly invasive, non-invasive auricular vagus nerve stimulation (NitaVNS) has no adverse effects associated with invasive stimulation. The NitaVNS-mediated activation of brainstem nuclei can exert anti-inflammatory effects directly on the colon or indirectly through the spleen via a macrophage-acetylcholine-dependent pathway.

Methods: Thirty C57BL/6 mice aged 11 to 12 weeks were divided into four groups: control (CTRL)-NitaVNS, CTRL-Sham, dextran sulphate sodium (DSS)-NitaVNS and DSS-Sham. Pre-set stimulation parameters (10 minutes duration, 10 V voltage, 500 s pulse width, and 20 Hz frequency) were applied for NitaVNS or sham-paw stimulation. 5% DSS was administered to induce colitis for five consecutive days, whereas CTRL mice received regular water. Weight loss, stool consistency, blood in the feces, and disease activity index were evaluated daily. Rectal bleeding, colon bleeding, and fecal consistency were determined as a composite macroscopic score upon sacrifice. Collected colon and blood samples were assessed for pro-inflammatory parameters such as interleukin (IL)-1β, tumor necrosis factor (TNF)-α, IL-6, C-reactive protein (CRP), matrix metalloproteinase (MMP)-2, macrophage inflammatory protein (Mip)-1α and β, and anti-inflammatory cytokine tumor growth factor (TGF)-β using qRT-PCR and ELISA.

Results: Compared to colitic-sham mice, colitic NitaVNS mice demonstrated a delayed onset and a significantly lower clinical disease severity. Colitis induced significant weight loss, rectal bleeding, and stool consistency loss, and NitaVNS significantly abolished these effects. In colitic conditions, NitaVNS decreased the disease activity index significantly compared to the colitic sham group. Colitis increased the macroscopic scores, and NitaVNS decreased them significantly. Conversely, colon length was significantly reduced in colitic conditions, but NitaVNS abrogated that deleterious effect. mRNA expression levels of IL-1β and TNF-α were significantly increased in colitic mice and NitaVNS decreased them significantly. Whereas Mip-1α and 1β were not modified in colitic conditions, NitaVNS significantly decreased these markers. MMP2 mRNA expression and colonic IL-6 and IL-1β protein levels were not altered in all conditions. However, colitis induced a significant decrease in colonic TGF-β levels, but NitaVNS did not amplify that effect. Interestingly, in the serum of colitic mice, NitaVNS significantly increased and decreased TGF-β and CRP levels, respectively.

Conclusion:These findings suggest that NitaVNS possess some spatial anti-inflammatory effects in acute colitis through the up or downregulation of anti- or pro-inflammatory markers.

Authors: F Hesampour, D Tshikudi, A Veysel Özden, C N Bernstein, J -E Ghia

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Objectives: The purpose of this study was to investigate the efficacy of noninvasive auricular vagus nerve stimulation (AVNS) on sports performance.

Methods: The intervention group (n = 30) received a single session of AVNS, while the control group (n = 30) received a single session of sham AVNS. Pre- and post-treatment isometric quadriceps muscle strength, heart rate, lower extremity balance, and grip strength were measured.

Results: It was ascertained that the differences in heart rate (-0.73 pulse/min, p = 0.032) and modified Star Balance Test scores (anterior 2.72 cm, p = 0.000, posterolateral 3.65 cm, p = 0.000 and posteromedial 2.43 cm, p = 0.000) before and after AVNS were significant in subjects in the experimental group. The results of the one-way ANOVA analysis show that the differences obtained in all measurement parameters are not statistically significant (p > 0.05). Considering the partial eta squared (η2) obtained from the measurements, a small descriptive effect in favor of experimental group was obtained for the quadriceps strength (0.016) and anterior balance (0.054) measurements.

Conclusion:This study demonstrates that a single AVNS session compared to sham AVNS shows a modest benefit though not statistically significant improvement in athletic performance. Single-use of AVNS seems not effective in improving athletic performance.

Authors: Adem Çalι, Ali Veysel Özden, İsmail Ceylan

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Abstract: Vagus nerve signals from the gut to brain carry information about nutrients and drive food reward. Such signals are disrupted by consuming large amounts of high-calorie foods, necessitating greater food intake to elicit a similar neural response. Non-invasive vagus nerve stimulation (nVNS) via a branch innervating the ear is a candidate treatment for obesity in humans. There is disagreement on the optimal location of nVNS in the ear for experimental and clinical studies. There are also no studies comparing nVNS in hungry and post-prandial states. We aimed to compare ear position(s) for nVNS and explore the effects of nVNS during hungry and post-prandial states on proxies for autonomic outflow (heart-rate variability) and efferent metabolism (gastric wave frequency and resting energy expenditure). In a within-subject design, 14 participants (10 women, on average 29.4 +/- 6.7 years old) received nVNS in four different locations (cymba conchae, tragus, earlobe, or tragus AND cymba conchae) on separate days. In each session, participants were asked to consume a palatable chocolate flavored milk. With electrography on the abdomen and indirect calorimetry in a canopy, we measured electro-cardiogram, electro-gastrogram and resting energy expenditure for 15 min before and at least 35 min after consumption of the palatable drink. We also collected ratings of the palatable drink and internal and other states. Pre-drink consumption (in a hungry state) we observed no differences in the effect of location of acute nVNS on resting energy expenditure and gastric wave measures. However, nVNS in cymba conchae decreases heart-rate variability (relative to sham) and ratings of how much participants want to consume the drink (relative to tragus AND cymba conchae and a trend relative to sham). After drink consumption and with continued nVNS, gastric wave frequency is unchanged, and resting energy expenditure increases regardless of stimulation location. Heart-rate variability decreases in all locations, except cymba conchae. We also observe a trend for an increase in gastric wave amplitude in late post-drink consumption time-points in cymba conchae. We observe no support for the combined stimulation of tragus AND cymba conchae being more effective than either of the individual locations. These results suggest that nVNS in the cymba conchae in a hungry state has a similar acute effect on vagal tone as food consumption: to decrease heart rate variability. This effect then negates the usual postprandial effects of a decrease in heart rate variability as seen in the other nVNS locations. These preliminary observations suggest that nVNS in cymba conchae may act primarily on vagal afferent autonomic (and only modestly on metabolic output) in a similar way as food consumption does.

Authors: Zeynep Altınkaya, Lina Öztürk, İlkim Büyükgüdük, Hüseyin Yanık, Dilan Deniz Yılmaz, Berçem Yar, Evren Değirmenci, Uğur Dal, Maria Geraldine Veldhuizen

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Objectives: The aim of this study is to investigate the effects of non-invasive vagus nerve stimulation (VNS) on tremor in Parkinson’s disease (PD)

Methods: This single-center, prospective, and implementation study with before-after design included five participants diagnosed with PD. Auricular VNS was applied to each participant 3 times on different days. VNS was applied to the participants as the right ear, left ear, and bilateral ear. The cardiovascular parameters of the participants were evaluated with Kubios HRV Standard and tremor with UPDRS tremor subscale and smartphone application before and after the intervention

Results: A significant decrease in diastolic blood pressure (p=0.043) was found in participants who underwent bilateral auricular VNS. Although there was no significant change in the UPDRS tremor subscale, decreases in the maximum tremor amplitude in the x (p=0.043) and y (0.014) planes were detected in the measurements made with the smartphone application.

Conclusion: In this study, a decrease in the tremor amplitude measured in the 3D plane with auricular VNS was found in patients with PD.

Authors: Ahmet Kivanc Menekseoglu, Merve Damla Korkmaz, Enes Efe Is, Ceyhun Basoglu, Ali Veysel Ozden

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Aims: This study aims to evaluate the effects of transcutaneous auricular vagus nerve stimulation (taVNS) on sustained attention and depression in individuals with suspected attention deficit hyperactivity disorder (ADHD).

Methods: Between May 1, 2022 and September 25, 2022, the study included 60 students (9 males, 51 females; mean age: 21.11±1.6 years; range, 18 to 24
years) identified as being at high risk for attention deficit hyperactivity disorder (ADHD). Participants were randomly assigned to either the intervention or control groups. Each group consisted of 30 individuals. The intervention group received taVNS in conjunction with mobile-assisted games and relaxation exercises, while the control group received mobile-assisted games and relaxation exercises alone. The data were collected using a descriptive information form, the Beck Depression Inventory, and mobile-assisted assessment parameters. Data were analyzed using the Wilcoxon signed-rank test, t-test, and MannWhitney U test. Results: Significant differences were observed in the intervention group concerning the sub-parameters used to measure attention and depression scale scores; however, in the control group, all but one of the attention sub-parameters showed significant differences. A comparison between the two groups revealed significant differences in reaction times and Beck Depression Inventory scores in favor of the intervention group.

Conclusion: This study revealed that taVNS can effectively
improve attention (cognitive function) and alleviate symptoms of depression.

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Purpose: This study aims to investigate the effects of transcutaneous auricular vagus nerve stimulation (taVNS) on key parameters, including nerve conduction velocity, grip strength, pain, and upper extremity functionality in individuals with carpal tunnel syndrome (CTS).

Methods: The study involved 51 patients (90 hands) diagnosed with carpal tunnel syndrome, comprising 12 males and 39 females, ranging in age from 18 to 58 years. Participants were divided into groups by random randomization method. Sensory branch conduction velocity of the median nerve was assessed via electromyography (EMG), hand grip strength was measured using a digital dynamometer, and pain intensity was quantified with a visual analog scale (VAS); additionally, upper extremity functionality was evaluated using the Upper Extremity Functional Index (UEFI) scale before and after the treatment. In the experimental group, in addition to the conventional physiotherapy program, 10 sessions of auricular vagus nerve stimulation were administered; for the sham and control groups, the conventional physiotherapy program alone was conducted over the course of 10 sessions.

Results: The analysis revealed no statistically significant differences between the groups concerning variables such as body mass index (BMI), age, gender, educational background, and smoking status (p>0.05). However, within-group evaluations exhibited significant differences compared to baseline values in terms of nerve conduction velocity, pain perception, and upper extremity functionality, with no such difference observed in grip strength (p<0.05). The intergroup comparisons indicated a significant difference in favor of the experimental group across all parameters, except for grip strength (p<0.05); conversely, no substantial differences were observed between the sham and control groups (p>0.05).

Conclusion: The findings suggest that the adjunctive use of taVNS alongside conventional rehabilitation programs in individuals diagnosed with CTS results in increased sensory nerve conduction velocity and enhanced upper extremity functional capacity, accompanied by a reduction in pain; nevertheless, grip strength remains unaffected.

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Abstract: Inflammatory bowel disease (IBD) is a chronic relapsing clinic condition whose cure could be very difficult even with new treatments. Although tremendous changes have occured in IBD treatment; there is an unmet need for a low-cost, easy-to-access treatment associated with low side effects. Possible dysfunction of interaction between the microbiome-gut-brain axis and autonomic nervous system; expecially vagus nerve dysfunction can be targeted for a new therapy. Given this, vagus nerve stimulation (VNS) camoes to the fore. Using present literature, we reviewed pathophysiology of IBD and anti inflammatory effect of VNS and the current aim of this review is to provide a comprehensive understanding of the effect of VNS on gut inflammation and the potential of personalized auricular VNS on IBD management. In the field of precision medicine these days, when digital transformation in health comes to the fore, personalized auricular VNS which uses machine learning algortims may be an complementary treatment of IBD.

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Abstract: The aim of our study is to find out whether the return rate of parasympathetic activity (PA) can be accelerated with auricular transcutaneous vagus nerve stimulation (TVNS). Pulmonary function test, ANS activity, pulse and blood pressure measurements were made. Individuals ran for 15 minutes. Those in the TVNS group received 5 minutes of auricular VNS. In the control group, headphones were attached but no current was given. After the end of their procedures, they were compared with pre-exercise. In the TVNS group, the pulse parameter was higher than in the initial measurement (p=0.001). There was a significant (p=0.007) rise in the FEV1 value in the VNS group. The sympathetic nervous system (SNS) index (p<0.05) increased in both groups when compared to the initial measurement, although there was no significant difference in the index values between the groups. The TVNS group showed an increase from the first measurement (p<0.05), but there was no significant difference in the parasympathetic nervous system (PNS) Index between the groups (p>0.05). The groups’ values for the first and second measures were equal (p>0.05), and the root mean square of the successive differences (RMSSD) values did not reveal a significant difference. TVNS can improve respiratory parameters in healthy individuals in the acute period after exercise, and it seems that it can also increase activation in both the sympathetic and parasympathetic system. It can be stated that TVNS may lead to variable results in different circumstances in sports.

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Background: In recent years, human and animal studies have provided increasing evidence that vagus nerve stimulation (VNS) can produce analgesic effects as well as alleviating resistant epilepsy and depression. Our study was designed to compare the efficacy of transcutaneous auricular vagus nerve stimulation with conventional low back rehabilitation in patients with chronic low back pain (CLBP).

Methods: Sixty patients with LBP were randomly divided into two groups. Group 1 received conventional rehabilitation and home exercise, and Group 2 received transcutaneous auricular VNS and home exercise. Both groups received treatment five days a week for three weeks. Trunk mobility (Modified Schober test, fingertip-to-floor test), muscle strength (CSMI-Cybex Humac-Norm isokinetic dynamometer and Lafayette manual muscle strength measuring device), trunk endurance, balance tests, Visual Analog Scale, Beck Depression Scale, Pittsburgh Sleep Quality Index, Oswestry Disability Index were evaluated.

Results: At the end of three weeks, within-group assessment results showed positive effects on mobility, functional status, depression and sleep in all groups (p < 0.05). Pain level, endurance time and flexion trunk muscle strength results showed more improvement in Group 2 (p < 0.05). Some parameters of isokinetic lower extremity quadriceps muscle strength and fall risk scores showed a significant improvement in Group 1 (p < 0.05).

Discussion: VNS has been observed to be more effective on pain, trunk muscle strength and endurance duration and sleep status. Auricular VNS may be included in the treatment of patients with CLBP in whom conventional physical therapy is inadequate or not applicable.

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Introduction: Inflammatory bowel disease is a chronic and idiopathic disease of the digestive tract. The disease also affects the liver and pancreas. Our aim in the study was to examine the effect of transcutaneous auricular vagal nerve stimulation (TAVNS) on the healing of liver and pancreas damage.

Material and Method: 36 rats in 4 groups were included in this study. The Sham group was intracolonic injected with saline and TAVNS was not applied. The Sham+ TAVNS group was injected intracolonically with saline and TAVNS was applied. The TNBS+Sham group was injected with TNBS (trinitrobenzene sulfonic acid) intracolonically and TAVNS was not applied. In TNBS+ TAVNS group, both TNBS was injected and TAVNS was applied. Liver tissue and pancreas tissue were examined histologically and histomorphometrically. Results: In our study, the final body weights of TNBS+Sham and TNBS+ TAVNS groups were found to be significantly lower than Sham and Sham+TAVNS groups. The liver and pancreas histopathological scores of the TNBS injected groups were significantly higher. In the liver hepatocytes of rats in TNBS+Sham group, necrotic areas, vacuolar degeneration, and sinusoidal congestion were observed in some regions. Degenerative findings in liver sections of group TNBS+ TAVNS group were also partially reduced. The number and area of Langerhans islets in the pancreas of the animals in TNBS+Sham and TNBS+ TAVNS groups were found to be lower than in Sham and Sham+ TAVNS groups.

Conclusion: In this study, we found that TNBS-induced colitis in rats caused histopathological and histomorphometric changes in the liver and pancreas, causing weight loss, and that TAVNS had therapeutic effects on these changes.

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Abstract:  COVID-19 pandemic has caused unprecedented morbidity, mortality and global disruption. While most COVID-19 patients have mild symptoms and recover within several weeks, more than 50% are left with ongoing symptoms several months later many of which appear autonomic in nature. Autonomic nervous system (ANS) dysfunction may be the underlying mechanism of Post or Long Covid syndrome and appears to be related to its symptoms.

Neuromodulation methods can improve and regulate the activites of the sympathetic and parasympathetic branches. Vagus Nerve Stimulation (VNS) is approved for the treatment of drug refractory epilepsy and depression. Also it has been shown to attenuate hyperinflammation and it carries the potential for correction of the imbalance in ANS. So it can be said that noninvasive VNS can be used as an adjunct therapy in COVID-19 patients. In COVID-19 pneumonia cases, transcutaneous auricular VNS can reduce markedly elevated interleukin-6 levels. In addition, VNS appears to be useful in COVID-19 related respiratory symptoms. However, selective VNS is important to decrease unwanted side effects like bronchoconstriction in COVID-19 caused acute respiratory distress syndrome. VNS can further decrease airway passage by increasing mucus secretion. To prevent this, organ/function-specific stimulation will be better for regulation of the ANS. VNS is also recommended for the treatment of cytokine storm in severe COVID-19 patients and again monitoring of the ANS is suggested for more accurate treatment.Cytokine storm is strongly correlated with sympathetic overactivity and ANS dysfunction. So it can be said that PNS-mediated anti-inflammatory effect is diminished in hyperinflammatory status. Chronic ANS dysfunction in Post-Covid patients probably continues in a vicious circle. Disease-related stress also aggravates the condition. As a safe treatment method, auricular VNS can be preferred as an adjuvant therapy in Covid-19 and similar infectious diseases with hyperinflammation. The ability of VNS to modulate the immune system without impairing specific immunity to infectious agents is highly advantageous in the treatment of inflammatory conditions due to COVID-19 and other infectious agents. Non-invasive neuromodulation methods can be preferred for the management of COVID-19 symptoms both in the active disease period or after it to control long COVID. Non-invasive cranial microcurrent stimulation can reduce vascular dysregulation and improve cognitive impairment in Post Covid patients. Vagus nerve signal disorder and ANS dysfunction are most likely to occur in long COVID. This is often accompanied by an immune system disorder. Fatigue, malaise, brain fog, headaches, sleep problems, muscle pain, tachycardia are commonly seen in Long COVID and all are related with ANS dysfunction. VNS is a method that has been recognized as safe and it can be beneficial for the treatment of postural orthostatic tachycardia syndrome and other symptoms related with Long COVID.

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Abstract: Aims: This study aims to evaluate the effects of transcutaneous auricular vagus nerve stimulation (taVNS) on sustained attention and depression in individuals with suspected attention deficit hyperactivity disorder (ADHD). Methods: Between May 1, 2022 and September 25, 2022, the study included 60 students (9 males, 51 females; mean age: 21.11±1.6 years; range, 18 to 24 years) identified as being at high risk for attention deficit hyperactivity disorder (ADHD). Participants were randomly assigned to either the intervention or control groups. Each group consisted of 30 individuals. The intervention group received taVNS in conjunction with mobile-assisted games and relaxation exercises, while the control group received mobile-assisted games and relaxation exercises alone. The data were collected using a descriptive information form, the Beck Depression Inventory, and mobile-assisted assessment parameters. Data were analyzed using the Wilcoxon signed-rank test, t-test, and Mann-Whitney U test. Results: Significant differences were observed in the intervention group concerning the sub-parameters used to measure attention and depression scale scores; however, in the control group, all but one of the attention sub-parameters showed significant differences. A comparison between the two groups revealed significant differences in reaction times and Beck Depression Inventory scores in favor of the intervention group. Conclusion: This study revealed that taVNS can effectively improve attention (cognitive function) and alleviate symptoms of depression.

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Keywords: auricular; cycling ergometry; recovery; transcutaneous; vagus nerve stimulation.

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Background: Vagus nerve stimulation is the process of applying electrical stimulation to the vagus nerve transcutaneously. The vagus nerve is one of the most commonly used structures for neuromodulation applications due to
its anatomical course. As such, non-invasive applications can be easily performed from areas where the vagal nerve is
superficialized.

Methods: In this study, 30 healthy volunteers underwent a single session of transcutaneous auricular vagus nerve
stimulation (taVNS) for 20 minutes. Heart rate variability (HRV) parameters were assessed with a 5-minute chest measurement
with Polar H7 device.

Results: As a result of the study, when the parameters were compared before and after the taVNS, it was found that
the LF/HF parameter significantly decreased and the RMSSD and HF parameters significantly increased (P<0.05). When
all heart rate variability parameters and changes were compared between men and women, it was found that there was no significant difference between the groups (P>0.05).

Conclusions: Accordingly, it was concluded that taVNS applications can neuromodulate heart rate variability parameters in the direction of parasympathetic activity and that gender is not an effective factor in these changes.,

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Correct Electrode Placement During Sham Stimulation in Transcutaneous Auricular Vagus Nerve Stimulation

Background: The gut epithelium, derived from stem cells, is critical for maintaining gastrointestinal homeostasis. In ulcerative colitis (UC), the epithelial lining is compromised, leading to mucosal alterations and cell proliferation and differentiation disruptions. The therapeutic goal in UC management is to restore gut barrier function for sustained remission. The anti-inflammatory and protective properties of vagus nerve stimulation (VNS) can be delivered via non-invasive transcutaneous auricular VNS (NitaVNS).

Aims: To investigate the impact of NitaVNS on stem cell preservation, proliferative activity, and epithelial cell differentiation using a mouse model mimicking UC.

Methods: Male C57BL/6 mice received a 5-day regimen of 5% dextran sodium sulfate to induce colitis; control groups received regular water. Preventive NitaVNS or sham stimulation started one day before colitis induction and continued for six days. Disease activity index (DAI) was assessed daily, and macroscopic scores were determined upon sacrifice. Distal colonic markers associated with proliferating (leucinerich repeat-containing G-protein coupled receptor 5 [Lgr5]), fetal-like (lymphocyte antigen 6 A [Ly6A]), and quiescent (homeodomain-only protein homeobox [HOPX]) gut stem cells were evaluated using qRT-PCR and immunofluorescence (IF) expression patterns. Epithelial cell differentiation marker cytokeratin 20 (CK20), proliferation marker Ki67, gut-differentiated epithelial cells, tuft cell-associated doublecortin-like kinase 1 (DCLK1), and gobletcell-associated mucin2 (MUC2) were assessed.

Results: NitaVNS significantly ameliorated the DAI and macroscopic scores. In non- and colitic mice, no significant difference in the expression pattern was observed in HOPX and Ly6A and their respective colonic mRNA expression. Although NitaVNS decreased Lgr5 expression pattern and colonic mRNA expression in non-colitic mice, NitaVNS prevented the significant decrease in Lgr5 expression pattern and colonic mRNA expression in colitic mice. In sham colitic mice, CK20, Ki67, and MUC2 expression patterns decreased; however, NitaVNS prevented this deleterious effect. Per se, NitaVNS in non-colitic conditions did not show any effects. No effects were observed on mRNA expression. In sham-colitis mice, DCLK1 expression patterns and mRNA expression were decreased. However, NitaVNS prevented this deleterious effect in colitic mice. Per se, NitaVNS in non-colitic conditions did not show any effects.

Conclusion: NitaVNS preserves the proliferating stem cells responsible for tissue repair and maintains colonic proliferative activity, epithelial cell differentiation, and tuft and goblet cell-associated markers in colitic mice. Identifying the molecular mechanism underlying the protective role of NitaVNS may lead to novel therapeutic targets in UC.

Abstract: Autism is a neurodevelopmental disorder with limited treatment alternatives and which incidence is increasing. Some research suggests that vagus nerve simulation might lead to the reduction of certain symptom. The autism model was induced by oral VPA administration (600 mg·kg⁻¹) to C57BL/6 pregnant mice on E12.5 days. The study included three groups: the VPA Transcutaneous Auricular Stimulation Group (VPA + tVNS), the VPA Control Group (VPA + sham), and the Healthy Control Group (Control + sham). Each group included 16 mice (8 M/8 F). Our results show that serum IL-1β and IL-6 levels were significantly higher in male VPA-exposed mice than controls. However, IL-1β was significantly lower, and IL-6, TNF- α, and IL-22 were not different in female VPA-exposed mice compared to the control group. Brain NLRP3 levels were significantly higher in both sexes in the VPA autism model (P < 0.05). tVNS application increased brain NLRP3 levels in both sexes and reduced serum IL-1β levels in male mice. We conclude that cytokine dysregulation is associated with the VPA-induced adult autism model, and the inflammatory response is more pronounced in male mice. tVNS application altered the inflammatory response and increased brain NLPR3 levels in both sexes. Further studies are needed to understand the beneficial or detrimental role of the inflammatory response in autism and its sexual dimorphism.