Non-invasive brain stimulation for post-COVID-19 conditions: a systematic review.

Alongside the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic, the number of patients with persistent symptoms following acute infection with SARS-CoV-2 is of concern. It is estimated that at least 65 million people worldwide meet criteria for what the World Health Organization (WHO) defines as "post-COVID-19 condition" - a multisystem disease comprising a wide range of symptoms. Effective treatments are lacking. In the present review, we aim to summarize the current evidence for the effectiveness of non-invasive or minimally invasive brain stimulation techniques in reducing symptoms of post-COVID-19. A total of nineteen studies were identified, one using transcutaneous vagus nerve stimulation (tVNS), another using transorbital alternating current stimulation (toACS), six studies on transcranial magnetic stimulation (TMS) and eleven studies on transcranial direct current stimulation (tDCS) for the treatment of post-COVID-19 symptoms. Existing studies report first promising results, illustrating improvement in clinical outcome parameters. Yet, the mechanistic understanding of post-COVID-19 and how brain stimulation techniques may be benefitial are limited. Directions for future research in the field are discussed.

Vagus nerve stimulation in lesional and Non-Lesional Drug-Resistant focal onset epilepsies.

PURPOSE: Drug-resistant epilepsy (DRE) affects one-third of patients with focal epilepsy. A large portion of patients are not candidates for epilepsy surgery, thus alternative options, such as vagus nerve stimulation (VNS), are proposed. Our objective is to study the effect of vagus nerve stimulation on lesional versus non-lesional epilepsies. METHODS: This is a retrospective cohort study in a single center in London, Ontario, which includes patients with DRE implanted with VNS, implanted between 1997-2018 and the date of analysis is December 2023. PARTICIPANTS: Patients implanted with VNS were classified by lesional (VNS-L) and non-lesional (VNS-NL) based on their MRI head findings. We further subdivided the VNS groups into patients with VNS alone versus those who also had additional epilepsy surgeries. RESULTS: A total of 29 patients were enrolled in the VNS-L, compared to 29 in the VNS-NL. The median age of the patients in the study was 31.8 years, 29.31 % were men (N = 17). 41.4 % (n = 12) of the patients were VNS responders (≥50 % seizure reduction) in the VNS-L group compared to 62.0 % (n = 18) in the VNS-NL group (p = 0.03). When other epilepsy surgeries were combined with VNS in the VNS-L group, the median rate of seizure reduction was greater (72.4 (IQR 97.17-45.88) than the VNS-NL group 53.9 (IQR 92.22-27.92); p = 0.27). CONCLUSIONS: VNS is a therapeutic option for patients with lesional epilepsy, with slightly inferior results compared to patients with non-lesional epilepsy. Patients implanted with VNS showed higher seizure reduction rates if they had previous epilepsy surgeries. This study demonstrates that VNS in lesional epilepsies can be an effective treatment.

Treating heart failure by targeting the vagus nerve.

Increased sympathetic and reduced parasympathetic nerve activity is associated with disease progression and poor outcomes in patients with chronic heart failure. The demonstration that markers of autonomic imbalance and vagal dysfunction, such as reduced heart rate variability and baroreflex sensitivity, hold prognostic value in patients with chronic heart failure despite modern therapies encourages the research for neuromodulation strategies targeting the vagus nerve. However, the approaches tested so far have yielded inconclusive results. This review aims to summarize the current knowledge about the role of the parasympathetic nervous system in chronic heart failure, describing the pathophysiological background, the methods of assessment, and the rationale, limits, and future perspectives of parasympathetic stimulation either by drugs or bioelectronic devices.

Outcomes of surgical resection and vagus nerve stimulation in patients with medically refractory epilepsy and glutamic acid decarboxylase 65 antibody positivity.

Epilepsy associated with high-titer glutamic acid decarboxylase 65 (GAD65) IgG is often refractory to immunotherapies and antiseizure medication. This study sought to determine the efficacy of vagus nerve stimulation (VNS) and surgical resection in patients with drug-resistant epilepsy associated with GAD65-IgG. We retrospectively identified 15 patients with drug-resistant epilepsy and high serum GAD65 antibody titers (>20 nmol·L-1) who underwent VNS implantation (n = 6), surgical resection (n = 7), or both (n = 2). A responder to VNS was defined as someone with a ≥50% reduction in seizure frequency, and a favorable surgical outcome was defined as Engel I-II. Of the eight patients who underwent VNS implantation, three (37.5%) were initially responders, but this was not sustained in two. Of the nine patients who underwent surgical resection, three (33.3%) had a favorable outcome; however, only one patient was seizure-free at last follow-up. Pathology was available in six patients, and only one had evidence of inflammation; this patient had seizure onset 1 year prior to surgery. Favorable seizure outcome correlated with older age at time of resective surgery, with a trend favoring later age of seizure onset. Taken together, surgical resection and VNS implantation may have limited efficacy in this patient population but can be considered in carefully selected cases.

The Effect of In-Ear and Behind-Ear Transcutaneous Auricular Vagus Nerve Stimulation on Autonomic Function: A Randomized, Single-Blind, Sham-Controlled Study.

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.

Brain Perception of Different Oils on Appetite Regulation: An Anorectic Gene Expression Pattern in the Hypothalamus Dependent on the Vagus Nerve.

(1) Background: We examined the effect of the acute administration of olive oil (EVOO), linseed oil (GLO), soybean oil (SO), and palm oil (PO) on gastric motility and appetite in rats. (2) Methods: We assessed food intake, gastric retention (GR), and gene expression in all groups. (3) Results: Both EVOO and GLO were found to enhance the rate of stomach retention, leading to a decrease in hunger. On the other hand, the reduction in food intake caused by SO was accompanied by delayed effects on stomach retention. PO caused an alteration in the mRNA expression of NPY, POMC, and CART. Although PO increased stomach retention after 180 min, it did not affect food intake. It was subsequently verified that the absence of an autonomic reaction did not nullify the influence of EVOO in reducing food consumption. Moreover, in the absence of parasympathetic responses, animals that received PO exhibited a significant decrease in food consumption, probably mediated by lower NPY expression. (4) Conclusions: This study discovered that different oils induce various effects on parameters related to food consumption. Specifically, EVOO reduces food consumption primarily through its impact on the gastrointestinal tract, making it a recommended adjunct for weight loss. Conversely, the intake of PO limits food consumption in the absence of an autonomic reaction, but it is not advised due to its contribution to the development of cardiometabolic disorders.

The nucleus of solitary tract (NTS) synchronizes sleep-wake-state-dependent cortical activity through the parabrachial nucleus (PB) in rat.

BACKGROUND: The medullary nucleus of solitary tract (NTS) and its afferents of vagus nerve have long been investigated in regulation of cortical activity and sleep promotion. However, the underlying neural circuit by which the NTS regulates electroencephalogram (EEG) and sleep remain unclear. As the NTS has a strong projection to the pontine arousal site, the parabrachial nucleus (PB), we proposed the NTS via the pontine parabrachial nucleus (PB) regulates cortical activity and sleep. METHODS: We bilaterally and directly stimulated the NTS neurons by chemogenetic approach and NTS terminals in the PB by optogenetic approach and examined changes in EEG and sleep in rats. RESULTS: Opto- and chemo-stimulation of the NTS and NTS-PB pathway altered neither sleep amounts nor patterns; however, both stimulations consistently increased EEG delta (0.5-4.0 Hz) EEG power during non-rapid-eye-movement (NREM) sleep and alpha-beta (10-30 Hz) EEG power during wake and REM sleep. CONCLUSION: Our results indicate that the NTS via its projections to the PB synchronizes low frequency EEG during NREM sleep and high frequency EEG during wake and REM sleep. This pathway may serve the neural foundation for the vagus nerve stimulation (VNS) treating cortical disorders.

Stress-sensitive neural circuits change the gut microbiome via duodenal glands.

Negative psychological states impact immunity by altering the gut microbiome. However, the relationship between brain states and microbiome composition remains unclear. We show that Brunner's glands in the duodenum couple stress-sensitive brain circuits to bacterial homeostasis. Brunner's glands mediated the enrichment of gut Lactobacillus species in response to vagus nerve stimulation. Cell-specific ablation of the glands markedly suppressed Lactobacilli counts and heightened vulnerability to infection. In the forebrain, we mapped a vagally mediated, polysynaptic circuit connecting the central nucleus of the amygdala to Brunner's glands. Chronic stress suppressed central amygdala activity and phenocopied the effects of gland lesions. Conversely, excitation of either the central amygdala or parasympathetic vagal neurons activated Brunner's glands and reversed the effects of stress on the gut microbiome and immunity. The findings revealed a tractable brain-body mechanism linking psychological states to host defense.

Complications and Mortality Rate of Vagus Nerve Stimulation for Drug-Resistant Epilepsy.

OBJECTIVE: The goal of this study is to evaluate the complications and mortality associated with vagus nerve stimulation (VNS). METHODS: We retrospectively reviewed medical records of patients who underwent VNS implantation for the treatment of drug-resistant epilepsy (DRE) between 2000 and 2023. The mean follow-up time was 10.6 years, ranging from three months to 22 years. RESULTS: In total, 55 adult and pediatric patients received VNS therapy with 117 procedures performed over 23 years. The most common early complications were hoarseness and cough which were reported in eight adult patients (6.8%). Four children with intellectual disability (ID) had infection (3.4%), eight patients had lead breakage (6.8%), and two had device migration (1.7%). Four of all patients (7.3%) demonstrated late complications due to chronic nerve stimulation including vocal cord dysfunction, late-onset severe AV block, and obstructive sleep apnea (OSA). Three patients (5.5%) had VNS deactivated permanently due to complications and/or lack of efficacy. Two patients died from probable sudden unexpected death in epilepsy (SUDEP) with an incidence of 3.4/1000 person-years. CONCLUSIONS: VNS therapy is safe over long-term follow-up but not without risks. Most post-operative complications are minor and transient for adults. Children with ID tend to have infection and device migration. Late-onset cardiac complications and OSA can develop in some patients during VNS therapy and should not be overlooked. The SUDEP rate may decrease with VNS therapy over time.

Vagus nerve electroneurogram-based detection of acute kainic acid induced seizures.

Seizures produce autonomic symptoms, mainly sympathetic but also parasympathetic in origin. Within this context, the vagus nerve is a key player as it carries information from the different organs to the brain and vice versa. Hence, exploiting vagal neural traffic for seizure detection might be a promising tool to improve the efficacy of closed-loop Vagus Nerve Stimulation. This study developed a VENG detection algorithm that effectively detects seizures by emphasizing the loss of spontaneous rhythmicity associated with respiration in acute intrahippocampal Kainic Acid rat model. Among 20 induced seizures in six anesthetized rats, 13 were detected (sensitivity: 65%, accuracy: 92.86%), with a mean VENG-detection delay of 25.3 ± 13.5 s after EEG-based seizure onset. Despite variations in detection parameters, 7 out of 20 seizures exhibited no ictal VENG modifications and remained undetected. Statistical analysis highlighted a significant difference in Delta, Theta and Beta band evolution between detected and undetected seizures, in addition to variations in the magnitude of HR changes. Binomial logistic regression analysis confirmed that an increase in delta and theta band activity was associated with a decreased likelihood of seizure detection. This results suggest the possibility of distinct seizure spreading patterns between the two groups which may results in differential activation of the autonomic central network. Despite notable progress, limitations, particularly the absence of respiration recording, underscore areas for future exploration and refinement in closed-loop stimulation strategies for epilepsy management. This study constitutes the initial phase of a longitudinal investigation, which will subsequently involve reproducing these experiments in awake conditions with spontaneous recurrent seizures.

Treatment of Drug-Resistant Epilepsy With Right-Sided Vagus Nerve Stimulation.

Vagus nerve stimulation (VNS) has been used as an adjunctive therapeutic option for drug-resistant epilepsy for decades. Traditionally, the left vagus nerve is used for stimulation, while the right vagus nerve is rarely used. The long-term efficacy and safety of the right VNS (R-VNS) in humans are unknown. We presented three patients who were treated with R-VNS over a follow-up period of up to eight years. All three patients tolerated R-VNS well with minimal complications. R-VNS displayed reasonable effectiveness in all three patients. One patient had an excellent response and became seizure-free. The other two patients demonstrated a less favorable response to R-VNS compared to their previous left VNS therapy.

Stimulated Vocal Fold Immobility After Vagal Nerve Stimulator Placement: A Case Series.

INTRODUCTION: Vagal nerve stimulator (VNS) implantation is a vital therapy for epilepsy refractory to other treatments; however, it is associated with a very high rate of voice changes. Relatively few of these patients are evaluated for vocal fold motion impairments. In this series, we evaluate 5 such patients with a novel phenotype of forced abduction with VNS stimulation. METHODS: Retrospective case series. RESULTS: Five patients with a VNS implant who underwent operative direct or in-office rigid laryngoscopy and had vocal fold motion impairment associated with VNS activation are included. All 5 patients had vocal fold mobility with VNS off and a fixed with activation. All patients exhibited vocal fold abduction with VNS activation. Patient 2 has since undergone laryngeal reinnervation, which helped her intermittent dysphonia but left a small glottic gap. A type 1 thyroplasty corrected this gap and improved her voice further. Patient 3 has undergone laryngeal reinnervation for which early results show improvement in perceptual and patient reported outcomes. Patients 4 and 5 have both undergone laryngeal reinnervation with improvement in voice. CONCLUSION: Previous reported cases of stimulated immobility associated with VNS use describe only adduction of the vocal fold. This series expands the previous work showing the VNS activation can also cause stimulated immobility in an abducted position, for which reinnervation and other medialization procedures offer promising treatment.

Preoperative vagal activity predicts clinical outcomes after total knee replacement.

Total knee replacement (TKR) surgery carries with it significant surgical trauma and activates complex inflammatory pathways, which initially assist healing. However, impaired regulation of inflammatory pathways can cause tissue damage and postoperative complications. The vagus nerve regulates inflammation, the activity of which is indexed by heart-rate variability (HRV), which predicts postoperative pain, longer hospitalization and improved recovery during the postoperative period. The present study examined the relationship between presurgical HRV, inflammation and complications after TKR. The present study assessed data from 41 patients undergoing TKR. A retrospective design was used, where preoperative electrocardiograms were scanned to determine HRV. Outcome measures included inflammation [C-reactive protein (CRP) levels] over four postoperative days, length of stay (LOS), and complications. Preoperative HRV predicted the trajectory of postoperative CRP levels. The low HRV group demonstrated higher overall postoperative CRP and a longer time to recover than patients with high HRV. Furthermore, the magnitude of inflammatory decline between postoperative days two and four was associated with LOS. However, HRV did not predict postoperative complications. In conclusion, patients with lower presurgical vagal activity had a worse postoperative inflammatory profile than those with high vagal tone. In the age of personalized medicine, such findings may have implications for identifying and preparing patients before surgery.

Neuromicrobiology Comes of Age: The Multifaceted Interactions between the Microbiome and the Nervous System.

The past decade has seen an explosion in our knowledge about the interactions between gut microbiota, the central nervous system, and the immune system. The gut-brain axis has recently gained much attention due to its role in regulating host physiology. This review explores recent findings concerning potential pathways linking the gut-brain axis to the initiation, pathophysiology, and development of neurological disorders. Our objective of this work is to uncover causative factors and pinpoint particular pathways and therapeutic targets that may facilitate the translation of experimental animal research into practical applications for human patients. We highlight three distinct yet interrelated mechanisms: (1) disruptions of both the intestinal and blood-brain barriers, (2) persistent neuroinflammation, and (3) the role of the vagus nerve.

Ultrasonographically measured atrophy of vagus nerve in Parkinson's Disease: clinical and pathogenetic insights plus systematic review and meta-analysis.

INTRODUCTION: According to the current Parkinson's Disease (PD) pathogenesis hypotheses, the vagus nerve (VN) is essential for disease development. It has been identified as a main entry point for misfolded α-synuclein to the central nervous system, and surgical vagotomy appears to limit disease progress both in animal models and in humans. A recent approach tried to assess VN size in PD patients via neck ultrasonography, but the clinical value of this method is yet to be established. STATE OF THE ART: A systematic search of the MEDLINE, Scopus, and Web of Science databases was conducted, and 12 case- -control studies were included. Meta-analysis revealed a modest reduction in VN size in PD (effect size - 0.79 SD (95%CI [-1.34, -0.25] p = 0.004)). The atrophy was more pronounced on the right side, and the nerve was smaller in females. In PD patients, VN reduction correlated with cardiac parasympathetic function decline and with advances in motor ratings. The discrimination potential for PD diagnosis, and any association with other non-motor domains, remains unclear. CLINICAL IMPLICATIONS: VN atrophy in PD could be detected by ultrasound imaging. However, the clinical significance of this phenomenon has yet to be clarified. Size reduction is not readily apparent and is individually variable. However, it may be considered a promising means to improve early PD diagnosis and the recognition of autonomic dysfunction. FUTURE DIRECTIONS: With more extensive research, VN sonography could provide useful evidence regarding disease origins. Imaging should be performed together with a profound clinical assessment and biomarker testing to establish the role to be played by this method in future practice.

Presentation of Arteria Lusoria with Non Recurent Laryngeal Nerve.

Non-recurrent laryngeal nerve (NRLN) is an anatomic variation seen in about 0.52-0.7% patients, generally on right side. It exits the vagus nerve having a direct route to the larynx, unlike usual recurrent laryngeal nerve, supplying intrinsic laryngeal muscles except cricothyroid. It is sited over left side on extremely rare occasions, that is, 0.04% of the cases. Some cases of NRLN co-exists with aberrant right subclavian artery which courses behind the esophagus, also known as 'arteria lusoria'. Here we present a case of 60-years old patient, diagnosed as goiter presented to us in june 2023 at the department of head and neck surgery at a tertiary care setup of Karachi Pakistan. Intra-operatively, non-recurrent nerve was encountered, whose association was found with arteria lusoria, observed in pre-operative CT-scan. The nerve was saved and no post-operative complications were seen in patient. The association of arteria lusoria in this case emphasize its importance in predicting NRLN via pre-operative imaging techniques which can prevent its injury intra-operatively.

An Unusual Case of Anterior Displacement of the Vagus Nerve during Total Thyroidectomy: A Surgical Dilemma.

We present a case report describing an unexpected anomaly encountered during a total thyroidectomy for a patient with papillary carcinoma of the left lobe of the thyroid with retrosternal extension. Intraoperatively, we discovered that the left lobe of the thyroid gland had extended posteriorly, invading the carotid space and displacing the carotid sheath anteriorly. The vagus nerve was identified as a cord-like structure abutting the anterior surface of the tumor, in close relation to the strap muscles. This case highlights the importance of careful dissection and identification of anatomical structures during thyroidectomy procedures to avoid inadvertent nerve injury. We discuss the significance of meticulous dissection-wide exposure and advocate for greater awareness and vigilance among surgeons.

Genetic labeling of the nucleus of tractus solitarius neurons associated with electrical stimulation of the cervical or auricular vagus nerve in mice.

INTRODUCTION: Vagus nerve stimulation (VNS) is clinically useful for treating epilepsy, depression, and chronic pain. Currently, cervical VNS (cVNS) treatment is well-established, while auricular VNS (aVNS) is under development. Vagal stimulation regulates functions in diverse brain regions; therefore, it is critical to better understand how electrically-evoked vagal inputs following cVNS and aVNS engage with different brain regions. OBJECTIVE: As vagus inputs are predominantly transmitted to the nucleus of tractus solitarius (NTS), we directly compared the activation of NTS neurons by cVNS or aVNS and the brain regions directly projected by the activated NTS neurons in mice. METHODS: We adopted the targeted recombination in active populations method, which allows for the activity-dependent, tamoxifen-inducible expression of mCherry-a reporter protein-in neurons specifically associated with cVNS or aVNS. RESULTS: cVNS and aVNS induced comparable bilateral mCherry expressions in neurons within the NTS, especially in its caudal section (cNTS). However, the numbers of mCherry-expressing neurons within different subdivisions of cNTS was distinctive. In both cVNS and aVNS, anterogradely labeled mCherry-expressing axonal terminals were similarly observed across different areas of the forebrain, midbrain, and hindbrain. These terminals were enriched in the rostral ventromedial medulla, parabrachial nucleus, periaqueductal gray, thalamic nuclei, central amygdala, and the hypothalamus. Sex difference of cVNS- and aVNS-induced labeling of NTS neurons was modest. CONCLUSION: The central projections of mCherry-expressing cNTS terminals are comparable between aVNS and cVNS, suggesting that cVNS and aVNS activate distinct but largely overlapping projections into the brain through the cNTS.

Baseline characteristics and predictors for early implantation of vagus nerve stimulation therapy in people with drug-resistant epilepsy: Observations from an international prospective outcomes registry (CORE-VNS).

OBJECTIVE: Vagus nerve stimulation (VNS) Therapy is routinely indicated for people with drug-resistant epilepsy (DRE). We analyzed the baseline characteristics of individuals receiving the recently released VNS models and identified factors associated with early or late implantation. METHODS: The Comprehensive Outcomes Registry of subjects with Epilepsy (CORE-VNS), a prospective observational study evaluating the clinical and psychosocial outcomes of VNS Therapy®, is following participants for up to 60 months after VNS implantation. In this analysis, we used Cox proportional hazards model to identify baseline characteristics associated with the time from diagnosis to first implantation. RESULTS: Of the 819 enrolled, 792 (96.7%) participants implanted with a VNS device were evaluated. 529 (64.6%) underwent the first implantation and 263 (32.1%) a re-implantation. Participants' median age at first implant was 24 years; 492 (62.1%) were ≥18 years old and 166 (20.3%) were < 12 years old. The average number of failed ASMs prior to VNS implantation was 7.1, and 145 (17.7%) had undergone previous epilepsy-related surgery. Epilepsy was classified as focal in 47.7% of participants, generalized in 16.1% and combined focal and generalized in 34.2%. Many of the participants (40.9%) had epilepsy of unknown etiology. The median time from diagnosis to first implantation was 10.33 years and was significantly shorter in participants with combined focal and generalized epilepsy compared to those with focal epilepsy alone, and in participants with genetic and immune epilepsy compared to those with unknown etiologies. SIGNIFICANCE: In people with DRE, VNS Therapy is provided after multiple failures of ASMs and after failure of epilepsy surgery in one in six individuals. Time from diagnosis to first implantation is associated with epilepsy type and etiology, likely reflecting variable treatment pathways. Clearer guidelines on when and how non-drug therapies should be deployed in people with DRE related to different epilepsy factors are needed. PLAIN LANGUAGE SUMMARY: Neuromodulation can be a very helpful treatment in people who have seizures that do not respond to medications. The most widely utilized neuromodulation therapy is vagus nerve stimulation (VNS). We present data from a large, global study to show that people use an average of seven anti-seizure medications before attempting VNS Therapy and that it takes about 10 years for people to get their first VNS implant. We advocate for clearer treatment guidelines on how and when to consider VNS Therapy in people with seizures that are resistant to medication.