J Clin Med. 2024 Dec 30;14(1):153. doi: 10.3390/jcm14010153.

ABSTRACT

Background: The role of autonomic nervous system (ANS) modulation in chronic neck pain remains elusive. Transcutaneous vagus nerve stimulation (t-VNS) provides a novel, non-invasive means of potentially mitigating chronic neck pain. This study aimed to assess the effects of ANS modulation on heart rate variability (HRV), pain perception, and neck disability. Methods: In this double-blind randomized clinical trial, 102 participants with chronic neck pain were randomly allocated to one of three groups: t-VNS plus standard-care physiotherapy (SC-PT), heart rate variability biofeedback (HRV-BF) with SC-PT, or SC-PT alone. Interventions were administered three times weekly for 6 weeks. The following outcome measures were assessed at baseline and after 6 weeks: HRV, the visual analog scale (VAS), the pressure pain threshold (PPT), and the neck disability index (NDI). Results: The t-VNS group exhibited significant improvements compared to the HRV-BF and SC-PT groups. Specifically, t-VNS increased the RR interval (mean difference [MD] = 35.0 ms; p = 0.037) and decreased the average heart rate (MD = -5.4 bpm; p = 0.039). Additionally, t-VNS reduced the VAS scores (versus HRV-BF: MD = -0.8 cm, p = 0.044; SC-PT: MD = -0.9 cm, p = 0.018), increased the PPT (versus HRV-BF: MD = 94.4 kPa, p < 0.001; SC-PT (MD = 56.2 kPa, p = 0.001)), and lowered the NDI scores (versus HRV-BF: MD = -4.0, p = 0.015; SC-PT: MD = -5.9, p < 0.001). Conclusions: t-VNS demonstrated superior effectiveness compared to HRV-BF and SC-PT in regulating HRV, alleviating pain, and enhancing functional capabilities in individuals with chronic neck pain.

PMID:39797236 | DOI:10.3390/jcm14010153

Psychophysiology. 2025 Jan;62(1):e14739. doi: 10.1111/psyp.14739.

ABSTRACT

Transcutaneous vagus nerve stimulation (tVNS) offers a non-invasive method to enhance noradrenergic neurotransmission in the human brain, thereby increasing cognitive control. Here, we investigate if changes in cognitive control induced by tVNS are mediated through locus coeruleus-induced modifications of neural activity in the anterior cingulate cortex. Young healthy participants engaged in a simple cognitive control task focusing on response inhibition and a more complex task that involved both response inhibition and working memory, inside a magnetic resonance imaging scanner. The tasks were executed using a randomized within-subject design, with participants undergoing auricular tVNS and sham stimulation in separate sessions. tVNS significantly changed performance in the simple control task reflected in a greater propensity to respond. Furthermore, we observed a significant increase in neural activity in the anterior cingulate cortex during the simple cognitive control task under tVNS. Functional connectivity analyses revealed positive coupling between neural activity in the locus coeruleus and anterior cingulate cortex, however, this was not modulated by tVNS. The findings suggest that non-invasive stimulation of the vagus nerve can modulate neural activity in the anterior cingulate cortex. While these neural effects suggest an impact of tVNS in a key region involved in conflict monitoring and cognitive control, the behavioral effects are more indicative of a shift in response bias rather than enhanced cognitive control.

PMID:39780300 | PMC:PMC11711293 | DOI:10.1111/psyp.14739

Elife. 2025 Jan 9;13:RP100088. doi: 10.7554/eLife.100088.

ABSTRACT

BACKGROUND: Subarachnoid hemorrhage (SAH) is characterized by intense central inflammation, leading to substantial post-hemorrhagic complications such as vasospasm and delayed cerebral ischemia. Given the anti-inflammatory effect of transcutaneous auricular vagus nerve stimulation (taVNS) and its ability to promote brain plasticity, taVNS has emerged as a promising therapeutic option for SAH patients. However, the effects of taVNS on cardiovascular dynamics in critically ill patients, like those with SAH, have not yet been investigated. Given the association between cardiac complications and elevated risk of poor clinical outcomes after SAH, it is essential to characterize the cardiovascular effects of taVNS to ensure this approach is safe in this fragile population. Therefore, this study assessed the impact of both acute and repetitive taVNS on cardiovascular function.

METHODS: In this randomized clinical trial, 24 SAH patients were assigned to either a taVNS treatment or a sham treatment group. During their stay in the intensive care unit, we monitored patient electrocardiogram readings and vital signs. We compared long-term changes in heart rate, heart rate variability (HRV), QT interval, and blood pressure between the two groups. Additionally, we assessed the effects of acute taVNS by comparing cardiovascular metrics before, during, and after the intervention. We also explored acute cardiovascular biomarkers in patients exhibiting clinical improvement.

RESULTS: We found that repetitive taVNS did not significantly alter heart rate, QT interval, blood pressure, or intracranial pressure (ICP). However, repetitive taVNS increased overall HRV and parasympathetic activity compared to the sham treatment. The increase in parasympathetic activity was most pronounced from 2 to 4 days after initial treatment (Cohen’s d = 0.50). Acutely, taVNS increased heart rate, blood pressure, and peripheral perfusion index without affecting the corrected QT interval, ICP, or HRV. The acute post-treatment elevation in heart rate was more pronounced in patients who experienced a decrease of more than one point in their modified Rankin Score at the time of discharge.

CONCLUSIONS: Our study found that taVNS treatment did not induce adverse cardiovascular effects, such as bradycardia or QT prolongation, supporting its development as a safe immunomodulatory treatment approach for SAH patients. The observed acute increase in heart rate after taVNS treatment may serve as a biomarker for SAH patients who could derive greater benefit from this treatment.

FUNDING: The American Association of Neurological Surgeons (ALH), The Aneurysm and AVM Foundation (ALH), The National Institutes of Health R01-EB026439, P41-EB018783, U24-NS109103, R21-NS128307 (ECL, PB), McDonnell Center for Systems Neuroscience (ECL, PB), and Fondazione Neurone (PB).

CLINICAL TRIAL NUMBER: NCT04557618.

PMID:39786346 | PMC:PMC11717364 | DOI:10.7554/eLife.100088

Am J Physiol Endocrinol Metab. 2025 Jan 9. doi: 10.1152/ajpendo.00184.2024. Online ahead of print.

ABSTRACT

The current study aimed to propose a method to directly measure right cervical vagal nerve activity (cVNA) alongside renal sympathetic nerve activity (RSNA) in conscious rats. The right cervical vagus nerve was surgically exposed and fitted with a bipolar electrode to record cVNA. A microcatheter was used to administer levobupivacaine to selectively block afferent cVNA. Upon levobupivacaine administration, cVNA reduced by 84%, enabling the exclusive assessment of efferent cVNA. Intravenous and intraperitoneal administration of cholecystokinin-8 (CCK-8) demonstrated that peripherally acting CCK-8 influences the central nervous system through afferent cVNA without affecting the RSNA or efferent cVNA. This technique can be highly applicable for quantifying the dynamic changes in the interaction between vagal and sympathetic nerve activities, thereby shedding light on their roles in maintaining homeostasis and developing autonomic dysfunction, as in obesity and diabetes.

PMID:39787315 | DOI:10.1152/ajpendo.00184.2024

Epilepsy Res. 2025 Jan 2;210:107499. doi: 10.1016/j.eplepsyres.2024.107499. Online ahead of print.

ABSTRACT

Lennox-Gastaut syndrome (LGS) is a severe developmental and epileptic encephalopathy characterized by multiple drug-resistant seizure types, cognitive impairment, and distinctive electroencephalographic patterns. Neuromodulation techniques, including vagus nerve stimulation (VNS), deep brain stimulation (DBS), and responsive neurostimulation (RNS), have emerged as important treatment options for patients with LGS who do not respond adequately to antiseizure medications. This review, developed with input from the Pediatric Epilepsy Research Consortium (PERC) LGS Special Interest Group, provides practical guidance for clinicians on the use of these neuromodulation approaches in patients with LGS. We discuss patient selection criteria, expected seizure and non-seizure outcomes, potential complications, and device management considerations for each technique. The review also covers initiation and titration strategies, ongoing care requirements, and emerging data on combining multiple neuromodulation modalities. While all three approaches can reduce seizure frequency in patients with LGS, with commonly reported responder rates ranging from 50 % to 60 %, their impacts on cognition, behavior and quality of life are more variable. Careful patient selection, individualized programming, and long-term follow-up are essential to optimize outcomes with neuromodulation in this challenging patient population. Further research is needed to identify optimal candidates, determine the ideal timing during patients’ clinical course to consider neuromodulation, develop standardized outcome measures, and evaluate the comparative effectiveness and cost-effectiveness of different neuromodulation techniques for LGS.

PMID:39778379 | DOI:10.1016/j.eplepsyres.2024.107499

Psychophysiology. 2025 Jan;62(1):e14754. doi: 10.1111/psyp.14754.

ABSTRACT

Transcutaneous auricular vagus nerve stimulation (taVNS) has been tested as a strategy to facilitate fear extinction learning based on the hypothesis that taVNS increases central noradrenergic activity. Four studies out of six found taVNS to enhance extinction learning especially at the beginning of extinction. Facilitatory effects of taVNS were mainly observed in US expectancy, less in fear-potentiated startle (FPS), and not in the skin conductance response (SCR). Suboptimal stimulation parameters may explain the reported mixed results. Also, variability in selected fear conditioning paradigms and statistical power impedes the comparability between studies. This study sought to further test whether taVNS accelerates fear extinction learning as indexed by US expectancy, FPS, and SCR. Similar to most previous studies, we employed a differential fear conditioning paradigm. The left ear of 79 healthy participants was stimulated with either sham (earlobe) or taVNS (cymba concha) during extinction learning. To maximize the beneficial effects of taVNS, the stimulation of the left cymba concha was administered continuously at the maximum level below the pain threshold. Results of the pre-registered frequentist and exploratory Bayesian analyses indicate that taVNS did not accelerate extinction learning in any of the outcomes. The null results indicate that taVNS with commonly used stimulation parameters does not reliably optimize fear extinction learning. More research is needed to test if the stimulation protocol determines the efficacy of taVNS in optimizing fear extinction learning.

PMID:39775931 | DOI:10.1111/psyp.14754

Int J Older People Nurs. 2025 Jan;20(1):e70006. doi: 10.1111/opn.70006.

ABSTRACT

BACKGROUND: A high number of stroke patients cannot recover fully from motor impairment despite early rehabilitation. Auricular therapies, usually given by acupuncture doctors or nurses, have been widely used among these post-stroke patients. Potential benefits of auricular therapies were shown in recent clinical trials.

OBJECTIVES: The purpose of this review was to systematically evaluate the clinical effects of auricular therapy in the treatment of post-stroke motor impairment.

METHODS: PubMed, Embase, Web of Science, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Cochrane Library, Chinese Biological Medicine (CBM), Chinese National Knowledge Infrastructure (CNKI) and Wanfang databases were searched from their inception to May 2023. Randomised controlled trials of auricular therapy for the treatment of post-stroke motor impairment met the screening criteria. The primary outcome was the Fugl-Meyer Assessment Scale (FMA). The secondary outcomes included the Fugl-Meyer Assessment Upper Extremity Scale (FMA-UE), Chinese Stroke Scale (CSS), clinical efficacy and the Barthel Index Scale (BI). Meta-analysis was carried out using RevMan software 5.3.

RESULTS: Twenty-eight RCTs with 1993 patients were included. The meta-analysis results suggested that compared with conventional treatment, auricular therapy combined with conventional treatment significantly improved the FMA score (MD: 15.07, 95% CI, 12.56 to 17.59), the FMA-UE score (MD: 6.49, 95% CI, 5.54 to 7.45), the clinical efficacy (RR: 1.20, 95% CI, 1.12 to 1.29) and the BI score (MD: 10.26, 95% CI, 9.11 to 11.40), while the combination treatment significantly decreased the CSS score (MD: -2.98, 95% CI, -4.38 to -1.59).

CONCLUSION: Auricular therapy, as an adjunctive treatment to the conventional treatment, improved post-stroke motor impairment and self-care ability. Early auricular therapy of the patients in the early disease stage may lead to better improvement. Further well-designed, large-size clinical studies are needed.

IMPLICATIONS FOR PRACTICE: This study suggested that auricular therapy could be used as a complementary therapy with conventional treatment for improving motor impairment and self-care ability among post-stroke patients with motor impairment in hospitals, long-term care facilities and homes.

PMID:39777988 | DOI:10.1111/opn.70006

Sleep Breath. 2025 Jan 7;29(1):69. doi: 10.1007/s11325-024-03203-0.

ABSTRACT

PURPOSE: The effect of allergic rhinitis (AR) on autonomic nervous system in patients with obstructive sleep apnea (OSA) remains unclear. We utilized heart rate variability (HRV) analysis to assess cardiac autonomic activity in patients with OSA, comparing those with and without allergic rhinitis (AR).

METHODS: We enrolled 182 patients who visited our sleep clinic complaining of habitual snoring or apnea during sleep. All patients underwent full-night polysomnography (PSG) and multiple allergen simultaneous tests. We calculated the HRV extracted from the electrocardiography of the PSG. Participants were divided into a normal group and an AR group, and HRV indices were compared according to OSA severity in each group.

RESULTS: The low-frequency (LF) to high-frequency (HF) ratio (LF/HF; r = 0.336, p < 0.001), LF normalised unit (LFnu; r = 0.345, p < 0.001), and HFnu (r = -0.345, p < 0.001) were significantly correlated with the apnea-hypopnea index. The HRV index comparison between non-severe and severe OSA in the normal group showed significant differences in LFnu (64.7 ± 12.5 in non-severe and 72.4 ± 11.7 in severe, p < 0.001), LF/HF (2.3 ± 1.6 in non-severe and 3.3 ± 2.0 in severe, p = 0.002), and HFnu (35.3 ± 12.5 in non-severe and 27.6 ± 11.7 in severe, p < 0.001). However, in the AR group, LFnu (p = 0.648), LF/HF (p = 0.441), and HFnu (p = 0.648) were comparable between non-severe and severe OSA.

CONCLUSION: Considering that LFnu, HFnu, and LF/HF represent sympathetic activity, parasympathetic activity, and sympathovagal balance, respectively, AR may attenuate the sympathetic predominance and sympathovagal imbalance associated with cardiovascular morbidity in severe OSA.

PMID:39775148 | DOI:10.1007/s11325-024-03203-0

Curr Pain Headache Rep. 2025 Jan 7;29(1):14. doi: 10.1007/s11916-024-01344-1.

ABSTRACT

PURPOSE OF REVIEW: Management of primary headache disorders during pregnancy is limited due to known teratogenicity or unknown safety of many currently available pharmaceutical therapies. Here, we explore the safety and efficacy of non-invasive neuromodulatory devices as another treatment modality for pregnant patients.

RECENT FINDINGS: There are six FDA-cleared, non-invasive neuromodulatory devices currently available for the management of headache that include remote electrical neuromodulation (REN), noninvasive vagal nerve stimulation (nVNS), external trigeminal nerve stimulation (eTNS), single-pulse transcranial magnetic stimulation (sTMS), and external concurrent occipital and trigeminal neurostimulation (eCOT-NS). Neuromodulatory devices are a safe, effective, and well tolerated non-pharmacological option for migraine and other primary headache disorders. Although evidence of safety and tolerability use in pregnancy is limited, they may serve as a therapeutic alternative or adjunct to improve the care of our pregnant patients.

PMID:39777577 | PMC:PMC11706918 | DOI:10.1007/s11916-024-01344-1

Int J Mol Sci. 2024 Dec 10;25(24):13269. doi: 10.3390/ijms252413269.

ABSTRACT

Cognitive impairment is a core feature of neurodevelopmental (schizophrenia) and aging-associated (mild cognitive impairment and Alzheimer’s dementia) neurodegenerative diseases. Limited efficacy of current pharmacological treatments warrants further search for new targets for nootropic interventions. The breakdown of myelin, a phospholipids axonal sheath that protects the conduction of nerve impulse between neurons, was proposed as a neuropathological abnormality that precedes and promotes the deposition of amyloid-β in neuritic plaques. The present review of the recent literature and our own pre- and clinical data suggest (for the first time) that the anthranilic acid (AA)-induced activation of microglial-expressed G-protein coupled receptor (GPR109A) inhibits cytosolic phospholipase A2 (cPLA2), an enzyme that triggers the degradation of myelin and consequently attenuates cognitive impairment. The present review suggests that the up-regulation of AA formation is a sex-specific compensatory (adaptive) reaction aimed to prevent/treat cognitive impairment. The AA-GPR109A-cPLA2-myelin-cognition cascade suggests new nootropic interventions, e.g., the administration of pegylated kynureninase, an enzyme that catalyzes AA formation from Kynurenine (Kyn), a tryptophane catabolite; pegylated interferon-alpha; central and peripheral Kyn aminotransferase inhibitors that increase availability of Kyn as a substrate for AA formation; and vagus nerve stimulation. The cascade predicts nootropic activity of exogenous GPR109A agonists that were designed and underwent clinical trials (unsuccessful) as anti-dyslipidemia agents. The proposed cascade might contribute to the pathogenesis of cognitive impairment. Data on AA in neurodegenerative disorders are scarce, and the proposed cascade needs further exploration in pre- and clinical studies.

PMID:39769034 | PMC:PMC11675959 | DOI:10.3390/ijms252413269