Some definitions for clarity. Neuromodulation, stimulating nerves (usually with electricity) to change (hopefully improve) or control their function. Deep Brain Stimulation (DBS) is a form of neuromodulation. Neuromodulation can be invasive, requiring surgery (like DBS) or noninvasive which provides the stimulation on the surface of the skin. Thus noninvasive neuromodulation does not require surgery. Vagal nerve stimulation is an emerging neuromodulation technique with potential benefit to PWP. Simulation of the vagus nerve can be done invasively/surgically; typically abbreviated, simply VNS or noninvasively, not requiring surgery. The nomenclature for nonsurgical vagal nerve stimulation can get confusing. Vagal nerve stimulation, done without surgery is called transcutaneous (over the skin) abbreviated tVNS, or noninvasive abbreviated nVNS. Furthermore, tVNS or nVNS can be applied at the ear, known as auricular vagal nerve stimulation or aVNS or on the front of the cervical spine (neck) abbreviated cVNS. Lastly all forms of vagal nerve stimulation can be delivered to the left nerve (which is the usual side) or more recently to the right nerve abbreviated rVNS. So it is either surgical vs. non-surgical, stimulated at the ear vs. the neck and left sided vs. right sided.
///Intro: What is the relationship between vagus nerve and PD?
The vagus nerve is the longest nerve in the body and most complex of the 12 pairs of cranial nerves that emanate from the brain. It transmits information to or from the brain to tissues and organs elsewhere in the body. 1
The name vagus comes from the Latin term for wandering. This is because the vagus nerve wanders from the brain into organs in the abdomen. 1
The vagus nerve has two bunches of sensory nerve cell bodies, and it connects the brainstem to the body. It allows the brain to monitor and receive information about many of the body’s different functions. There are multiple nervous system functions provided by the vagus nerve and its related parts. The vagus nerve functions contribute to the autonomic nervous system, which consists of the parasympathetic (associated with the gut and digestion) and sympathetic divisions. 1
Gastrointestinal (gut) dysfunctions are common, non-motor symptoms found in Parkinson's disease. Their management is still challenging and new treatment options are needed. 2
In most patients with Parkinson's disease, gastrointestinal (GI) dysfunctions, such as gastroparesis and constipation, are prodromal to the cardinal motor symptoms of the disease. Sporadic Parkinson's disease has been proposed to develop after ingestion of neurotoxicants that affect the brain-gut axis via the vagus nerve, and then travel to higher centers, compromising the substantia nigra pars compacta (SNpc) and, later, the cerebral cortex. 3
While dopaminergic medication is the standard therapy in PD, it provides limited symptomatic relief from non-motor symptoms and non-pharmacological interventions are currently being studied. 4
The microbiota-gut-brain axis (MGBA) refers to the bidirectional communication between the brain and the gut microbiota and recent studies have linked the MGBA to health and disease. 5
Research has so far investigated this axis mainly from microbiota to brain, but less is known about the other direction. One approach to examine the MGBA from brain to microbiota is through understanding if and how neuromodulation might impact microbiota. 5
In Parkinson's disease (PD), α-synuclein has been identified as a culprit protein and the main component for mediating progressive neurodegeneration. In PWP severe pathology is evident in the autonomic nervous system prior to clinical manifestations of PD symptoms. Pathogenic α-synuclein spread thus occurs from the peripheral nervous system through key nuclei, such as the anterior olfactory nucleus and dorsal motor nucleus of the vagal nerves, gradually reaching the brainstem, midbrain and cerebral cortex. 6
Recent studies of Parkinson's disease indicate that dorsal motor nucleus of nerve vagus is one of the earliest brain areas affected by alpha-synuclein and Lewy body pathology. The influence of electrical stimulation of vagus nerve on a number parameter including the elemental composition of dopamine related brain structures has been investigated. 7
Vagus nerve stimulation (VNS) modifies brain rhythms in the locus coeruleus (LC) via the vagal solitary nucleus. Degeneration of the LC in Parkinson's disease (PD) is an early catalyst of the spreading neurodegenerative process, suggesting that stimulating LC output with VNS has the potential to modify this disease progression. 8
Some of the promising and pertinent study findings are discussed.
///Vagal Nerve Stimulation Basic Science
The major surgical treatment for Parkinson's disease (PD) is deep brain stimulation (DBS), but a less invasive treatment is desired. Vagus nerve stimulation (VNS) is a relatively safe treatment without cerebral invasiveness. 9
In several central nervous system diseases, it has been reported that inflammation may be related to the etiologic process, therefore, therapeutic strategies are being implemented to control inflammation. As the nervous system and the immune system maintain close bidirectional communication in physiological and pathological conditions, the modulation of inflammation through the cholinergic anti-inflammatory reflex has been proposed. This review summarizes the evidence supporting vagus nerve stimulation as therapeutic strategies in the treatment of various central nervous system pathologies, and their effect on inflammation. 7
Nicotinic acetylcholine receptors (nAChRs) are master regulators of immune functions via the cholinergic anti-inflammatory pathway and are expressed in microglia, the brain's resident immune cells. There is an extensive dialogue between the neurons and the glial cells around them from which microglia are tasked with monitoring, nurturing, and defending their microenvironment. Dysregulation of any of these processes can have devastating and long-lasting consequences involving microglia-mediated neuroinflammation associated with neurodegenerative diseases such as Parkinson's disease. Furthermore, cholinergic modulation of neuroinflammation is a promising avenue for treatment. 10
According to epidemiologic studies, smoking appears to downregulate the prevalence of Parkinson's disease (PD), possibly due to anti-inflammatory mechanisms via activation of α7 nicotinic acetylcholine receptors (α7 nAChRs). This receptor also appears to play a role in T-cell differentiation. 11
Recently, it has become apparent that the innate immune system participates in PD pathogenesis. The aim of this study was to evaluate the effects of auricular vagus nerve stimulation (aVNS) on substantia nigra (SN) dopaminergic neurodegeneration and the associated neuroinflammation and immune responses in a rat PD model. 11
Following motor behavioral tests, the expression of tyrosine hydroxylase (TH) in the SN and the levels of inflammatory cytokines in the ventral midbrain were evaluated. 11
Compared with 6-OHDA treats rats, aVNS treatment significantly improved motor deficits, increased TH and α7 nAChR expression, and reduced the levels of inflammatory cytokines (tumor necrosis factor-a (TNF-α) and interleukin-1β (IL-1β). 11
Additionally, aVNS increased the numbers of regulatory T (Treg) cells while decreasing T helper (Th)17 cells indicating an immune shift away from auto-immune dysfunction. aVNS exerted neuroprotective effects against dopaminergic damage, possibly by suppressing the evolution of inflammation and modulating innate immune responses. Thus, aVNS may be a potential promising therapy in the future. 11
Parkinson's disease (PD) is a common movement disorder disease. Left vagus nerve stimulation (LVNS) is a potential treatment option for PD. Compared with the left vagus nerve, the right vagus nerve is more closely connected with the midbrain dopaminergic neurons, which are the lesion locations of PD. However, whether right vagus nerve stimulation (RVNS) has a therapeutic effect on PD has not yet been studied. 12
The cuff electrodes were implanted into the right cervical vagal carotid sheaths of the rats. The right vagus nerve was continuously stimulated for 14 days using a radio stimulation system. 12
A remarkable increase in distance traveled and rearing number was observed in the rotenone + RVNS group after stimulation. RVNS markedly up-regulated TH expression level. The expression of α-synuclein was lower in the rotenone + RVNS group. rVNS significantly up-regulated VMAT2 expression. 12
The improved motor behavior and neuroprotective effects on the midbrain dopaminergic neurons in the PD rat model suggest that RVNS could be used as a potential treatment for PD. 12
It was found that statistically significant differences between the animals with electrical stimulation of vagus nerve and the control are observed in the left side of corpus striatum. The mass fractions of these elements are increased in the group for which the electrical stimulation of vagus nerve was performed. 7
These researchers previously showed in a lesion PD model that VNS delivered twice daily reduced neuroinflammation and motor deficits, and attenuated tyrosine hydroxylase (TH)-positive cell loss. 8
The goal of this additional study was to characterize the differential effects of three clinically-relevant VNS paradigms in a PD lesion model.
Eleven days after noradrenergic lesion, rats were implanted with VNS devices, and received either low-frequency VNS, standard-frequency VNS, or high-frequency microburst VNS. 8
At higher VNS frequencies, specifically microburst VNS, greater improvements occurred in motor function, attenuation of TH-positive cell loss in SN and LC, and norepinephrine concentration in the PFC. Additionally, higher VNS frequencies resulted in lower α-synuclein accumulation and glial density in the SN. 8
///PD more than a movement disorder. Non-Motor Symptoms
Neuromodulation encompasses a wide range of stimulation techniques and is used to treat neurological, psychiatric and metabolic disorders, like Parkinson's Disease, depression and obesity. 5
Parkinson's disease (PD) is associated with severe motor symptoms attributable to loss of dopamine neurons in the Substantia Nigra. However, several non-motor symptoms (NMS) typically predate the expression of motor signs and symptoms. A substantial reduction of norepinephrine (NE) levels in various brain regions reflecting an extensive loss of innervation from the LC has been assumed as causal for the development of NMS and specifically of attentional impairments in PD. 13
Transcutaneous auricular vagus nerve stimulation (taVNS) is a new, non-invasive neurostimulation method postulated to modulate the LC-NE system in humans. In this current opinion paper, the authors introduce taVNS as a systemic approach to directly affect NE neurotransmission in clinical populations and discuss its potential as therapeutic option for the treatment of NMS, specifically cognitive deficits, in patients with PD. 13
In PWP, locus coeruleus noradrenergic (LC-NE) neurons degenerate prior to substantia nigra dopaminergic (SN-DA) neurons. Vagus nerve stimulation (VNS) activates LC neurons, and decreases pro-inflammatory markers, allowing improvement of LC targets, making it a potential PD therapeutic. 14
Here, they first describe the LC-NE system and discuss how LC-NE dysfunction might affects cognition in PD before detailing the mode of action of taVNS and proposing its use to modulate cognitive deficits in these patients. 13
At this time, a subset of rats also had vagus cuffs implanted. After eleven days, rats received a precise VNS regimen twice a day for ten days, and locomotion was measured during each afternoon session. 14 Immediately following final stimulation, rats were euthanized, and left dorsal striatum, bilateral SN and LC were sectioned for immunohistochemical detection of monoaminergic neurons (tyrosine hydroxylase, TH), α-synuclein, astrocytes (GFAP) and microglia (Iba-1). 14
VNS significantly increased locomotion of lesioned rats. VNS also resulted in increased expression of TH in striatum, SN, and LC; decreased SN α-synuclein expression; and decreased expression of glial markers in the SN and LC of lesioned rats. suggest VNS has potential as a novel PD therapeutic. 14
Vagus nerve stimulation (VNS) is being explored as a potential therapeutic for Parkinson's disease (PD). VNS is less invasive than other surgical treatments and has beneficial effects on behavior and brain pathology. It has been suggested that VNS exerts these effects by increasing brain-derived neurotrophic factor (BDNF) to enhance pro-survival mechanisms of its receptor, tropomyosin receptor kinase-B (TrkB). 15
We have previously shown that striatal BDNF is increased after VNS in a lesion model of PD. 15
At this time, the left vagus nerve was cuffed for stimulation. Eleven days later, rats received VNS twice per day for ten days, with daily locomotor assessment. 15
While ANA-12 did not avert behavioral improvements of VNS, and only partially prevented VNS-induced attenuation of neuronal loss in the locus coeruleus, it did stop neuronal and anti-inflammatory effects of VNS in the nigrostriatal system, indicating a role for TrkB in mediating VNS efficacy. However, our data also suggest that BDNF-TrkB is not the sole mechanism of action for VNS in PD. 15
///GUT
Along with this is the potential use of vagus nerve neuromodulation for treatment of early disease symptoms like dysautonomia, for modulating sympatho-vagal imbalances and easing severe comorbidities of the disease. 6
This study identified a pathway that connects the brainstem vagal nuclei and the Substantia Nigra (SN) and determined whether this pathway is compromised in a model of Parkinsonism. 3
A functional connection between the SN and the Gut was suggested from the observation that simulation of the SN increased gastric tone and motility via activation of dopamine receptors in the dorsal vagal complex. In a model of Parkinsonism, this nigro-vagal pathway was compromised during the early stages of motor deficit development. 3
This randomized double-blind pilot study enrolled patients suffering from Parkinson's disease with gastroenteric complaints.
Patients were randomized to use either a sham-device or to stimulate the vagal nerve with an electric device over the course of four weeks with four stimulations per day. 2
Clinical outcome was evaluated using the Gastrointestinal Symptom Rating Scale whereas gastrointestinal motility was measured with the 13C-octanoic acid breath test. 2
In the treatment group, vagal nerve stimulation improved the Gastrointestinal Symptom Rating Scale comparing before and after stimulation. This improvement was not observed in the sham group . 2
In the 13C-octanoic acid breath test no significant changes were detectable. 2
Vagal nerve stimulation is well tolerated with no side effects and may be a promising non-invasive therapy option to improve gastroenteric symptoms in Parkinson's disease. 2
Neuromodulation was associated with changes in relative gut bacterial abundances, but not with (changes in) α-diversity or β-diversity. 5
Summarizing, currently reported findings suggest that neuromodulation interventions are associated with moderate changes in the gut microbiome. 5
///Pd Motor Symptoms
With the development of medical technology, vagus nerve stimulation (VNS) has been approved by the Food and Drug Administration (FDA) as an alternative treatment for refractory epilepsy, refractory depression, cluster headaches, and migraines. 16
Furthermore, current evidence showed promising results towards the treatment of more brain diseases, such as Parkinson's disease PD. 16
In this paper, we review the novel hypothesis that noninvasive vagus nerve stimulation (nVNS), targeting efferent and afferent vagal projections, is a promising therapeutic tool to improve gait and cognitive control and ameliorate non-motor symptoms in people with Parkinson's. 4
Evidence of nVNS as a novel therapeutic to improve gait in PD is preliminary, but early signs indicate the possibility that nVNS may be useful to target dopa-resistant gait characteristics in early PD. 4
This is the first experiment reporting a systematic evaluation of taVNS in PD. In this sample of patients with mild-to-moderate PD, the taVNS in add-on to levodopa improved several objective gait parameters. Despite direct data on duration not being collected, the putative taVNS effect persisted for the time duration of the UPDRS motor assessment, the flanker test (mean completion time 52 13.7 seconds), and two consecutive gait assessments (single 10mTUG test mean completion time 28 7.3 seconds). 17
The latter might give useful information for future biomarker (eg, neurophysiological) studies. Preclinical studies showed that VNS can improve structural and functional aspects of PD. Even though its mechanism of action is still debated, VNS can entrain the ascending cholinergic and noradrenergic pathways which are involved in cognitive processing and in locomotor abilities. In this study, taVNS improved some dopamine-dependent gait parameters (eg, stride length). 17
In the active group tVNS, step time and step length variability decreased whereas an increase was identified in the sham group with step length variability reaching significance (5.6 vs. 25.4% change for active vs. control group, p=0.045). This exploratory study provides preliminary data suggesting dopa-resistant gait characteristics may improve with nVNS. 18
Freezing of gait (FOG) is a common, disabling symptom of Parkinson's disease (PD), but the mechanisms and treatments of FOG remain great challenges for clinicians and researchers. 19
In the risk factor section, gait disorders, PIGD phenotype, lower striatal DAT uptake were found to be independent risk factors of FOG with consistent evidence. 19
Two drugs that showed promise for FOG include istradefylline and rasagiline. 19
Non-pharmacological treatments encompass noninvasive vagus nerve stimulation (tVNS), and physiotherapeutic approaches including cues and other training strategies. 19
Several novel therapeutic strategies seem to be effective, such as rTMS over supplementary motor area (SMA), spinal cord stimulation (SCS) and VNS. 19
// Stimulation with surgery vs. surface stimulation vs. ointment
Several studies have illustrated that transcutaneous vagus nerve stimulation (tVNS) can elicit therapeutic effects that are similar to those produced by its invasive counterpart, vagus nerve stimulation (VNS). Surgical VNS is an FDA-approved therapy for the treatment of both depression and epilepsy, but it is limited to the management of more severe, intervention-resistant cases as a second or third-line treatment option due to perioperative risks involved with device implantation. 20
In contrast, tVNS is a non-invasive technique that involves the application of electrical currents through surface electrodes at select locations, most commonly targeting the auricular branch of the vagus nerve (ABVN) and the cervical branch of the vagus nerve in the neck. 20
tVNS has been investigated for several other disorders, including tinnitus, migraine and pain, by targeting the vagus nerve at sites in both the ear and the neck.20
tVNS is a non-invasive technique that involves the application of electrical currents through surface electrodes at select locations, most commonly targeting the auricular branch of the vagus nerve (ABVN) and the cervical branch of the vagus nerve in the neck. It has been shown that tVNS elicits hypo- and hyperactivation in various regions of the brain associated with anxiety and mood regulation. 21
The aim of this study was to assess whether aural stimulation with ointment containing capsaicin improves swallowing function in elderly patients with dysphagia. 22
Twenty elderly dysphagic patients with a history of cerebrovascular disorder or Parkinson's disease were randomly divided into two groups: 10 receiving aural stimulation with 0.025% capsaicin ointment and 10 stimulated with placebo. The ointments were applied to the external auditory canal with a cotton swab. Then, swallowing of a bolus of blue-dyed water was recorded using transnasal videoendoscopy, and the swallowing function was evaluated according to both endoscopic swallowing scoring and Sensory-Motor-Reflex-Clearance (SMRC) scale. 22
The sum of endoscopic swallowing scores was significantly decreased 30 and 60 min after a single administration in patients treated with capsaicin, but not with placebo. Reflex score, but not Sensory, Motion and Clearance scores, of the SMRC scale was significantly increased 5, 30 and 60 min after single administration in patients treated with capsaicin, but not with placebo. No patient showed signs of adverse effects. 22
As capsaicin is an agonist of the transient receptor potential vanilloid 1 (TRPV1), these findings suggest that improvement of the swallowing function, especially glottal closure and cough reflexes, in elderly dysphagic patients was due to TRPV1-mediated aural stimulation of vagal Arnold's nerve with capsaicin, but not with a nonspecific mechanical stimulation with a cotton swab. 22
///refs
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3. Anselmi, L., Toti, L., Bove, C., Hampton, J. & Travagli, R. A. A Nigro-Vagal Pathway Controls Gastric Motility and Is Affected in a Rat Model of Parkinsonism. Gastroenterology 153, 1581–1593 (2017).
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5. Korenblik, V. et al. Are neuromodulation interventions associated with changes in the gut microbiota? A systematic review. Neuropharmacology 223, 109318 (2023).
6. Ko, D. W. K. Transcutaneous vagus nerve stimulation (tVNS) as a potential therapeutic application for neurodegenerative disorders - A focus on dysautonomia in Parkinson’s disease. Auton. Neurosci. Basic Clin. 235, 102858 (2021).
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14. Farrand, A. Q. et al. Vagus nerve stimulation improves locomotion and neuronal populations in a model of Parkinson’s disease. Brain Stimulat. 10, 1045–1054 (2017).
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18. Morris, R. et al. Noninvasive vagus nerve stimulation to target gait impairment in Parkinson’s disease. Mov. Disord. Off. J. Mov. Disord. Soc. 34, 918–919 (2019).
19. Gao, C., Liu, J., Tan, Y. & Chen, S. Freezing of gait in Parkinson’s disease: pathophysiology, risk factors and treatments. Transl. Neurodegener. 9, 12 (2020).
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21. Yap, J. Y. Y. et al. Critical Review of Transcutaneous Vagus Nerve Stimulation: Challenges for Translation to Clinical Practice. Front. Neurosci. 14, 284 (2020).
22. Kondo, E. et al. Aural stimulation with capsaicin ointment improved swallowing function in elderly patients with dysphagia: a randomized, placebo-controlled, double-blind, comparative study. Clin. Interv. Aging 12, 1921–1928 (2017).
Transcranial Magnetic Stimulation (TMS)
Anyone taking these drugs?
Anyone heard of this? Caloric vestibular stimulation 
