파킨슨 병.. 미주신경자극기 치료법 탐구

[문형철]

https://www.mayoclinic.org/tests-procedures/vagus-nerve-stimulation/about/pac-20384565

Review

Noninvasive vagus nerve stimulation in Parkinson’s disease: current status and future prospects

Pages 971-984 | Received 04 Jun 2021, Accepted 16 Aug 2021, Published online: 08 Sep 2021

ABSTRACT

Introduction

Parkinson’s disease (PD) is a common progressive neurodegenerative disorder with multifactorial etiology. While dopaminergic medication is the standard therapy in PD, it provides limited symptomatic treatment and non-pharmacological interventions are currently being trialed.

Areas covered

Recent pathophysiological theories of Parkinson’s suggest that aggregated α-synuclein form in the gut and spread to nuclei in the brainstem via autonomic connections. 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. We conducted an unstructured search of the literature for any studies employing nVNS in PD as well as for studies examining the efficacy of nVNS on improving cognitive function and where nVNS has been applied to co-occurring conditions in PD.

Expert opinion

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. The evidence for nVNS as a therapeutic tool is, however, limited and further studies are needed in both brain health and disease.

소개
파킨슨병(PD)은 다인성 원인을 가진 흔한 진행성 신경 퇴행성 질환입니다. 도파민성 약물이 파킨슨병의 표준 치료법이지만, 증상 치료에는 한계가 있으며 현재 비약물학적 개입이 시험되고 있습니다.

다루는 분야
최근 파킨슨병의 병리 생리학적 이론에 따르면 응집된 α-시누클레인이 장에서 형성되어 자율 신경 연결을 통해 뇌간의 핵으로 퍼진다고 합니다. 

이 논문에서는 

구심성 및 구심성 미주신경 돌기를 표적으로 하는 

비침습적 미주신경 자극(nVNS)이 

파킨슨병 환자의 보행 및 인지 조절을 개선하고 

비운동 증상을 개선하는 유망한 치료 도구라는 

새로운 가설을 검토합니다. 

저희는 파킨슨병에 nVNS를 사용한 모든 연구와 인지 기능 개선에 대한 nVNS의 효능을 조사한 연구, 파킨슨병의 동반 질환에 nVNS를 적용한 연구에 대한 비정형 문헌 검색을 실시했습니다.

전문가 의견
PD에서 

보행 개선을 위한 새로운 치료제로서 nVNS의 증거는 예비적이지만, 

초기 징후는 초기 PD의 도파 저항성 보행 특성을 표적으로 삼는 데 

nVNS가 유용할 수 있다는 가능성을 나타냅니다. 

그러나 치료 도구로서 nVNS에 대한 증거는 제한적이며 뇌 건강과 질병 모두에 대한 추가 연구가 필요합니다.

KEYWORDS: 

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1. Introduction

Pharmacological intervention forms the mainstay treatment for many neurodegenerative and neuropsychiatric disorders, but this approach carries unwanted side effects. Non-pharmacological alternatives such as electrical stimulation used mostly as an adjunct therapy, has gained considerable interest. Vagus nerve stimulation (VNS) is a neuromodulation technique involving invasive surgical implantation of a generator subcutaneously, providing direct electrical stimulation of the left cervical vagus nerve [Citation1–3]. Implantable VNS (iVNS) sends intermittent electrical currents through a wire wrapped around the vagus nerve. It is more common that the left vagus nerve is stimulated due to the right vagus nerve having greater connections to the heart [Citation1]. The VNS device conveys signals through neural impulses to the central nervous system (CNS) [Citation1]. iVNS is approved by the U.S. Food and Drug Administration (FDA) as an adjunct treatment for drug-resistant epilepsy [Citation4] and in patients with treatment-resistant depression [Citation5]; iVNS is also approved by the European Medicines Agency (EMA) for the latter. Recent randomized controlled trials have additionally shown the potential benefits of iVNS in upper limb motor recovery after stroke when stimulation is paired with rehabilitation therapy [Citation6].

The efficacy of iVNS in preventing and ameliorating symptoms of neurodegenerative and neuropsychiatric disorders has captured interest across several clinical fields, with the number of publications utilizing VNS steadily rising.

1. 소개
약리학적인 개입은 많은 신경 퇴행성 및 신경 정신과 질환의 주된 치료법이지만, 이 접근법은 원치 않는 부작용을 수반합니다.

주로 보조 요법으로 사용되는

전기 자극과 같은

비약리학적 대안이 상당한 관심을 받고 있습니다.

미주신경 자극(VNS)은

피하로 발전기를 이식하는 침습적 외과적 수술과 관련된 신경 조절 기술로

좌측 경추 미주신경에 직접 전기 자극을 제공합니다[인용1-3].

이식형 VNS(iVNS)는 미주 신경을 감싸는 와이어를 통해 간헐적인 전류를 보냅니다. 오른쪽 미주신경이 심장과 더 많이 연결되어 있기 때문에 왼쪽 미주신경이 자극되는 것이 더 일반적입니다[인용1].

VNS 장치는

신경 자극을 통해 중추신경계(CNS)에 신호를 전달합니다[인용1].

iVNS는

약물 내성 간질[인용4] 및

치료 저항성 우울증[인용5] 환자의 보조 치료제로

미국 식품의약국(FDA)의 승인을 받았으며

유럽 의약품청(EMA)에서도 후자에 대한 승인을 받았습니다.

최근의 무작위 대조 시험에서는

뇌졸중 후 상지 운동 회복에 있어

재활 치료와 함께 자극을 병행할 경우

iVNS의 잠재적 이점이 추가로 밝혀졌습니다[인용6].

https://www.nature.com/articles/s41531-021-00190-x

비침습적 미주신경 자극(nVNS)은 간질, 편두통 및 군발성 두통 치료에 사용되는 확립된 신경 자극 요법입니다. 이 무작위, 이중맹검, 가짜 대조 교차 시험에서는 파킨슨병(PD) 환자의 보행 및 기타 운동 증상 치료에서 nVNS의 역할을 탐구했습니다. 환자 하위 그룹에서 실험적 개입 전후에 혈청 내 일부 뉴로트로핀 수치와 염증 및 산화 스트레스 마커를 측정했습니다. 보행 동결과 관련된 파킨슨병 환자 33명을 무작위로 nVNS 또는 가짜 약물에 배정했습니다. 기준선 평가 후, 환자들은 집에서 한 달 동안 2분씩 6회(총 12분/일) nVNS/가짜 장치(일렉트로코어, 미국)를 자극하도록 지시받았습니다. 그런 다음 환자를 재평가했습니다. 한 달의 휴지기가 지난 후, 동일한 환자를 대체 치료군에 배정하고 동일한 과정을 따랐습니다. 보행 속도, 자세 시간 및 걸음 길이를 포함한 주요 보행 매개변수가 가짜 치료와 비교하여 nVNS를 통해 유의미하게 개선된 것으로 관찰되었습니다. 마찬가지로 전반적인 운동 기능(MDS-UPDRS III)도 nVNS 자극 후 크게 개선되었습니다. 혈청 종양괴사인자(TNF)-α와 글루타치온 수치가 감소하고 뇌유래신경영양인자(BDNF) 수치가 유의하게 증가( p <0.05)했습니다(nVNS 치료 후). 여기에서는 파킨슨병 환자의 보행 및 운동 기능 치료에 있어 nVNS의 효능과 안전성에 대한 최초의 이중맹검 위조 대조 임상시험 증거를 제시합니다.

뇌 영역의 직접 자극 경로. 1&2, 미주신경의 등쪽 운동핵과 솔리타리우스 핵 ; 3, 소체핵; 4&5, 기저핵과 시상; 6, 전뇌 콜린성 핵(메이너트 기저핵 포함). B 미주 신경을 통한 염증성 반사가 구심성 사지를 보여줍니다. 미주신경 자극은 복강 신경절에서 ACh 분비로 이어집니다. ACh는 비장 신경을 자극하여 비장에 직접적인 아드레날린성 신경 분비를 제공합니다. [Ach = 아세틸 콜린, NE = 노르에피네프린/노라드레날린]. C 비장 내부의 세포 및 분자 환경. 비장 신경에서 분비되는 NE는 T 세포를 자극합니다(콜린에스테라아제 양성으로 Ach를 분비). 분비된 신경전달물질은 대식세포 표면의 니코틴성 ACh 수용체의 7-α 서브유닛과 결합하여 TNF-α의 분비를 억제합니다.

신경 퇴행성 및 신경 정신과적 장애의 증상을 예방하고 개선하는 iVNS의 효능은 여러 임상 분야에서 관심을 끌었으며, VNS를 활용한 논문의 수가 꾸준히 증가하고 있습니다.

Due to the potential complications and reported adverse events [Citation7,Citation8], noninvasive VNS (nVNS) devices have also been developed with the aim of stimulating the vagus nerve transcutaneously. With the advent of the noninvasive devices, risk and adverse events associated with the implantable devices such as the cost of medical care accompanying an invasive surgery and intraoperative complications that can include infections, vagus nerve trauma, peritracheal hematoma, damage to the vocal cords and shortness of breath (dyspnea) due to vagus nerve injury [Citation7–9] are minimized or altogether eliminated. Additionally, lead fractures can occur requiring electrode changes [Citation8]. A further advantage of the nVNS devices is that they promote further research in cognitive and clinical neuroscience to objectively identify the technique’s mechanisms of action specifically in healthy populations without requiring invasive surgery [Citation10]. To that end, in the translational setting nVNS is becoming an increasingly preval‎ent tool to assess the effects of this type of neuromodulation on various psychological and physiological processes [Citation10].

In principle, two types of nVNS devices are commercially available. Transcutaneous auricular VNS (taVNS) is used to stimulate structures of the outer ear such as the tragus and cymba conchae, which are innervated by the auricular branch of the vagus nerve (ABVN) [Citation11]. By contrast, transcutaneous cervical VNS (tcVNS) is delivered via a hand-held device while indirectly stimulating the (left) cervical branch of the vagus nerve within the carotid sheath [Citation12]. A pressing issue is to identify the most optimal stimulation parameters such as the current intensity (milliamps [mA]), frequency (Hertz [Hz]), pulse width (microseconds [µs]), waveform shape (sine, rectangular), cycle duration (on/off periods) and optimal dosage. Stimulation parameters used in studies employing the taVNS device vary widely (readers are referred to as an excellent and comprehensive review by Farmer and colleagues [Citation10]). The majority of studies utilize monophasic or biphasic rectangular pulses, with a pulse width between 200 and 300 μs, current intensity at 0.5 mA, and a frequency of 25 Hz [Citation10].

The tcVNS device emits a low-voltage 5 kHz sine wave electrical signal bursts lasting 1 ms via two flat stimulation contact surfaces, which permeates the skin and subcutaneous structures [Citation12]. These bursts repeat once every 40 ms (25 Hz frequency) for 120 seconds. Stimulation intensity can be adjusted by the patient, and stimulation can be repeated up to 12 times per day. According to the manufacturer (ElectroCore, Basking Ridge, NJ, USA) their gammaCore® device uses sine waves since these produce less unpleasant skin sensations and are thus better tolerated compared to square waves. tcVNS is currently licensed for the treatment of primary headache, epilepsy, depression, and anxiety.

The most common adverse events related to the use of the noninvasive devices include headaches, nasopharyngitis, dizziness, oropharyngeal, and neck pain, skin irritation [Citation13,Citation14]. The attrition rate due to adverse events is approximately 2.6% in studies employing nVNS [Citation14].

Parkinson’s disease (PD) is a neurodegenerative disorder that affects the central, peripheral, and enteric nervous systems and is characterized by both motor and non-motor symptoms of which gait and cognitive impairment are common manifestations [Citation15,Citation16]. Gait and cognition are interrelated both in the general population and in PD [Citation15,Citation16]. Gait problems are observed in all gait domains according to a validated gait model in PD [Citation17,Citation18], while cognitive dysfunction is noted in several cognitive domains including visuospatial, attention, and memory [Citation19]. Deficits in both gait and cognition are consistently associated with falls, reductions in health-related quality of life, healthcare costs, and increased caregiver burden [Citation20,Citation21]. Although dopaminergic (DA) medication is the current gold standard treatment for PD, compelling evidence has shown that patients respond selectively to DA treatment, and both gait and cognitive function continue to progressively decline with time [Citation17,Citation22,Citation23], thus suggesting an alternative pathological basis.

Novel non-pharmacological interventions mitigating both PD-associated gait and cognitive impairments are urgently needed. Due to its clinical properties and widespread effects on Central and Autonomic Nervous Systems (CNS/ANS), VNS may be a suitable therapy in PD as highlighted below in the main body of our manuscript. The effects of nVNS on gait problems in human participants with PD has been demonstrated in three recent publications [Citation24–26]. Furthermore, some recent studies have investigated the clinical efficacy of VNS for reducing symptoms that often occur in PD, including fatigue [Citation27] and gastrointestinal symptoms [Citation28,Citation29], neuropsychiatric disorders [Citation30,Citation31], dementia [Citation32,Citation33] and essential tremor [Citation34] providing further theoretical support. Therefore, the aim of this review was to summarize the current literature on nVNS in PD and provide narrative accounts of its therapeutic potential with an emphasis on its efficacy in improving gait and cognitive control, and the mechanisms of action that may mediate these improvements in this disorder.

여러 연구에 따르면 경피적 미주신경 자극(tVNS)이 침습적 방법인 미주신경 자극(VNS)과 유사한 치료 효과를 이끌어낼 수 있는 것으로 나타났습니다. VNS는 우울증과 뇌전증 치료를 위해 FDA 승인을 받은 치료법이지만, 장치 이식과 관련된 수술 전후 위험으로 인해 2차 또는 3차 치료 옵션으로서 더 심각하고 개입에 저항하는 사례의 관리에만 제한적으로 사용됩니다. 반면, tVNS는 특정 위치에 표면 전극을 통해 전류를 가하는 비침습적 기술로, 가장 일반적으로 목의 미주신경의 귀가지(ABVN)와 미주신경의 경추 가지를 표적으로 합니다. tVNS가 불안 및 기분 조절과 관련된 뇌의 다양한 영역에서 저활성화 및 과활성화를 유도하는 것으로 밝혀졌지만, 그 작용 메커니즘과 자극 매개변수가 임상 결과에 미치는 영향은 주로 가설에 머물러 있습니다. 이러한 가정은 주로 미주 신경의 신경생물학과 신경 활동에 미치는 영향 사이의 상관관계에 근거하고 있습니다. 그러나 귀와 목의 미주 신경을 표적으로 삼아 이명, 편두통, 통증 등 여러 다른 질환에 대해서도 tVNS가 연구되고 있습니다. 설명된 대부분의 방법은 적용되는 매개변수와 프로토콜이 다르기 때문에, 현재 특정 질환에 가장 큰 치료 효과를 제공하는 tVNS의 최적 위치나 자극 매개변수에 대한 확실한 증거는 없습니다. 이 리뷰에서는 자극 매개변수, 자극 부위 및 사용 가능한 장치에 중점을 두고 tVNS의 현재 상태를 소개합니다. tVNS가 비침습적이고 임상과 관련된 치료법으로서 잠재력을 최대한 발휘하려면 작용 메커니즘과 최적의 자극 양식을 밝히기 위한 체계적인 연구가 필수적입니다.

잠재적인 합병증과 보고된 부작용[인용7,인용8]으로 인해 미주 신경을 경피적으로 자극하는 비침습적 VNS(nVNS) 장치도 개발되었습니다.

비침습적 장치의 등장으로

침습적 수술에 수반되는 의료 비용과 감염,

미주신경 외상,

기관 주위 혈종,

성대 손상,

미주신경 손상으로 인한 호흡 곤란(호흡 곤란) 등 수술 중 합병증[Citation7-9] 등

이식형 장치와 관련된 위험과 부작용이 최소화되거나 완전히 제거되었습니다.

또한 전극을 교체해야 하는 납 골절이 발생할 수 있습니다[인용8]. nVNS 장치의 또 다른 장점은 침습적 수술 없이 건강한 사람을 대상으로 이 기술의 작용 메커니즘을 객관적으로 규명하기 위한 인지 및 임상 신경과학 분야의 추가 연구를 촉진한다는 점입니다[인용10]. 이를 위해 번역 환경에서 nVNS는 다양한 심리적, 생리적 과정에 대한 이러한 유형의 신경조절 효과를 평가하는 도구로 점점 더 널리 사용되고 있습니다[인용10].

원칙적으로 두 가지 유형의 nVNS 장치가 시판되고 있습니다. 경피적 귀 VNS(taVNS)는 미주신경의 귀 가지(ABVN)에 의해 자극되는 이소골 및 심바소체와 같은 외이의 구조를 자극하는 데 사용됩니다[인용11]. 이와 대조적으로 경피 경추 VNS(tcVNS)는 경동맥 피복 내의 미주 신경의 (왼쪽) 경추 가지를 간접적으로 자극하면서 휴대용 장치를 통해 전달됩니다[인용12]. 가장 시급한 문제는 전류 강도(밀리암페어[mA]), 주파수(헤르츠[Hz]), 펄스 폭(마이크로초[µs]), 파형 형태(사인, 직사각형), 주기 지속 시간(온/오프 주기) 및 최적 용량과 같은 최적의 자극 파라미터를 식별하는 것입니다. taVNS 장치를 사용하는 연구에 사용된 자극 매개변수는 매우 다양합니다(독자들은 Farmer와 동료들의 훌륭하고 포괄적인 리뷰를 참조하세요[인용10]).

대부분의 연구는

단상 또는 2상 직사각형 펄스를 사용하며,

펄스 폭은 200~300μs,

전류 강도는 0.5mA,

주파수는 25Hz입니다[인용10].

tcVNS 장치는 두 개의 평평한 자극 접촉면을 통해 1ms 동안 지속되는 저전압 5kHz 사인파 전기 신호 버스트를 방출하여 피부와 피하 구조에 침투합니다[인용12]. 이러한 버스트는 120초 동안 40ms(25Hz 주파수)마다 한 번씩 반복됩니다.

자극 강도는 환자가 조절할 수 있으며

하루에 최대 12회까지 자극을 반복할 수 있습니다.

제조업체(미국 뉴저지주 베스킹리지에 위치한 일렉트로코어)에 따르면 감마코어® 기기는 사인파를 사용하기 때문에 불쾌한 피부 감각을 덜 유발하고 사각파에 비해 내약성이 우수합니다. tcVNS는 현재 원발성 두통, 간질, 우울증 및 불안 치료용으로 허가되어 있습니다.

비침습적 기기 사용과 관련된 가장 흔한 부작용으로는

두통, 비인두염, 어지러움, 구인두 및 목 통증, 피부 자극 등이

있습니다[인용13,인용14].

nVNS를 사용한 연구에서 부작용으로 인한 이탈률은 약 2.6%입니다[인용14].

파킨슨병(PD)은

중추, 말초 및 장 신경계에 영향을 미치는 신경 퇴행성 질환으로,

보행 및 인지 장애가 흔한 증상인 운동 및 비운동 증상이 모두 특징입니다[인용15,인용16].

보행과 인지는 일반 인구와 PD 모두에서 상호 연관되어 있습니다[인용15,인용16]. PD의 검증된 보행 모델에 따르면 모든 보행 영역에서 보행 문제가 관찰되며[인용17,인용18], 인지 기능 장애는 시공간, 주의력, 기억력 등 여러 인지 영역에서 나타납니다[인용19]. 보행 및 인지 기능의 결함은 낙상, 건강 관련 삶의 질 저하, 의료 비용, 간병인 부담 증가와 일관되게 연관되어 있습니다[인용20,인용21].

도파민성(DA) 약물 치료가 현재 파킨슨병의 표준 치료법이지만,

환자가 DA 치료에 선택적으로 반응하고

보행과 인지 기능이 시간이 지남에 따라 점진적으로 감소한다는

강력한 증거[인용17,인용22,인용23]가 제시되어

다른 병리학적인 근거를 제시하고 있습니다[인용22,인용23].

파킨슨병과 관련된 보행 및 인지 장애를 완화하는 새로운 비약물적 개입이 시급히 필요합니다. 임상적 특성과 중추 및 자율 신경계(CNS/ANS)에 대한 광범위한 효과로 인해, 아래 본문에 강조된 바와 같이 VNS는 PD에 적합한 치료법이 될 수 있습니다.

최근 발표된 세 편의 논문[인용24-26]에서 PD 환자의 보행 문제에 대한 nVNS의 효과가 입증되었습니다. 또한 최근 일부 연구에서는 피로[인용27] 및 위장 증상[인용28,인용29], 신경정신과적 장애[인용30,인용31], 치매[인용32,인용33], 본태성 진전[인용34] 등 PD에서 흔히 발생하는 증상을 완화하는 데 VNS의 임상적 효능을 조사하여 추가적인 이론적 근거를 제공했습니다.

따라서

본 리뷰의 목적은

파킨슨병에서 nVNS에 대한 최신 문헌을 요약하고

보행 및 인지 조절 개선에 대한 효능과

이 장애에서 이러한 개선을 매개할 수 있는 작용 메커니즘에 중점을 두고

치료 잠재력에 대한 서술적 설명을 제공하는 것이었습니다.

2. The vagus nerve: mechanisms of action and importance in Parkinson’s disease

The vagus nerve is the tenth cranial nerve and is composed of 20% motor efferent and 80% sensory afferent fibers [Citation35]. It is located on both the right and left side of the body and acts as a bidirectional channel between the CNS and ANS relaying sensory and motor information between systems [Citation35]. The descending fibers of the vagus nerve traverse and innervate directly or indirectly major internal organs including the heart, spleen, and the gastrointestinal tract, regulating cardiovascular function, inflammatory response, and gastric emptying efferent effects, respectively [Citation36–38]. The vagus nerve is therefore essential in the maintenance of parasympathetic system function and homeostasis.

The motor symptoms of PD emerge due to dysfunction of afferent projection terminals within the striatum and a progressive loss of nigral DA neurons associated with intracellular Lewy bodies (LBs) containing aggregated α-synuclein [Citation39]. Interest in the vagus nerve in PD is relatively longstanding, with Braak and colleagues [Citation40,Citation41] postulating that α-synuclein pathology may spread via the vagus nerve from the GI tract to the midbrain. However, the transfer of LB pathology may not be random but may spread from the medulla oblongata in the brainstem and olfactory nuclei in the caudo-rostral direction to further susceptible structures within the brainstem, limbic system, and finally neocortical regions [Citation41]. This was supported by recent work in a mouse model of PD, where pathogenic α-synuclein injected into an area of the gut richly innervated by the vagus nerve, was found to spread to the dorsal motor nucleus of the vagus (DMNV), locus coeruleus (LC), amygdala, substantia nigra (SN) and, subsequently, the cortex over time [Citation42]. This was associated with degeneration of DA neurons, as well as motor and non-motor symptoms. Truncal vagotomy precluded the symptoms, neurodegeneration and α-synuclein pathology within the brain. However, one recent postmortem study did not demonstrate a difference between intestinal α-synuclein in PD patients and control participants [Citation43], which may challenge this rationale. Potential explanations for the discrepancy between the studies include sampling from different areas of the GI tract, diverse peripheral neuroanatomy in the different populations, and different immunohistochemical staining techniques.

A further contentious issue is where Lewy pathology begins within the brain. This was the subject of a recent multimodal imaging study with the authors proposing ‘brain-first versus body-first’ PD subtypes [Citation44]. Based on the model proposed by Horsager and colleagues, the trajectory of LB pathology described above is considered as the ‘body-first’ subtype. By contrast, the reverse trajectory characterizes the ‘brain-first’ subtype where aggregated α-synuclein may arise in the olfactory tubercle within the brain and descend into the peripheral ANS via structures of the brainstem including the LC [Citation44]. Both subtypes seem to demonstrate alterations in structures and functions subserved by the vagus nerve. There is some evidence that the structural integrity of the vagus nerve, measured using high-resolution ultrasound, may be altered in PD. Some studies have found that both left and right vagus nerves are significantly smaller in patients relative to age-matched controls [Citation45–47], while others have shown a comparable size of the vagus nerve between patients and controls [Citation48–51].

Further alterations associated with cardinal symptoms of PD including gait problems and cognitive dysfunction arise due to alterations in cholinergic neurotransmission in the cholinergic basal forebrain, particularly in the nucleus basalis of Meynert (nbM) and the pedunculopontine nucleus (PPN) in the brainstem [Citation52–54], and serotonergic neurons in the raphe nuclei [Citation55], decreased neurotropic factor signaling in the SN and basal ganglia [Citation56] and possibly due to an abnormal inflammatory response in the brain [Citation57]. This suggests that PD is underpinned by multi-system pathology subserved by several neurotransmitter systems in addition to age-related neurodegeneration that may be related to the function of the vagus nerve.

2. 미주 신경: 파킨슨병에서의 작용 메커니즘과 중요성

미주신경은 10번째 뇌신경으로 20%의 운동 구심성 섬유와 80%의 감각 구심성 섬유로 구성되어 있습니다[인용35].

미주신경은

신체의 오른쪽과 왼쪽에 모두 위치하며,

시스템 간에 감각 및 운동 정보를 전달하는

CNS와 ANS 사이의 양방향 채널 역할을 합니다[인용35].

미주신경의 하행 섬유는

심장, 비장, 위장관을 포함한 주요 내부 장기를 직간접적으로 통과하여

신경을 전달하며 심혈관 기능, 염증 반응, 위 배출 원심성 효과를 각각 조절합니다[인용36-38].

따라서

미주신경은

부교감신경계 기능 및 항상성 유지에 필수적입니다.

PD의 운동 증상은

선조체 내 구심성 투사 단자의 기능 장애와

응집된 α-시누클레인을 포함하는 세포 내 루이체(LB)와 관련된

흑질 DA 뉴런의 점진적 손실로 인해 나타납니다[인용39].

PD에서 미주신경에 대한 관심은 비교적 오래전부터 있어 왔으며,

Braak과 동료들은 [인용40,인용41]

α-시누클린 병리가

미주신경을 통해

위장관으로부터 중뇌로 퍼질 수 있다고 가정했습니다.

그러나

LB 병리의 전이는 무작위적인 것이 아니라

뇌간의 수질과 후각 핵에서 꼬리-등 방향의 후각 핵에서 뇌간, 변연계,

최종적으로 신피질 영역 내의 더 취약한 구조로 퍼질 수 있습니다[Citation41].

이는

미주신경이 풍부하게 신경을 분포하는 장 부위에

병원성 α-시누클레인을 주입한 후

시간이 지남에 따라 미주 등쪽 운동핵(DMNV), 소교차(LC), 편도체, 흑질(SN), 피질로 퍼지는 것으로 밝혀진

PD 마우스 모델의 최근 연구에 의해 뒷받침되었습니다[인용42].

이는 DA 뉴런의 퇴화뿐만 아니라 운동 및 비운동 증상과도 관련이 있습니다. 트렁크 질 절제술은 뇌의 증상, 신경 퇴화 및 α- 시누클레인 병리를 예방했습니다. 그러나 최근의 한 사후 연구에서는 PD 환자와 대조군 참가자의 장내 α-시누클레인 사이에 차이가 없음을 입증하지 못했는데[인용43], 이는 이러한 근거에 이의를 제기할 수 있습니다. 연구 간의 불일치에 대한 잠재적 설명으로는 위장관 내 다른 부위에서 채취한 샘플, 집단마다 다른 말초 신경 해부학, 다른 면역 조직 화학 염색 기법 등이 있습니다.

또 다른 논쟁의 여지가 있는 문제는

루이소체 병리가

뇌의 어느 부위에서 시작되는지입니다.

이는 '뇌 우선 대 신체 우선' PD 하위 유형을 제안한 최근의 다중 모드 이미징 연구의 주제였습니다[인용44]. Horsager와 동료들이 제안한 모델에 따르면, 위에서 설명한 LB 병리의 궤적은 '신체 우선' 하위 유형으로 간주됩니다. 반면, 그 반대 궤적은 응집된 α-시누클레인이 뇌 내의 후각 결절에서 발생하여 LC를 포함한 뇌간 구조를 통해 말초 ANS로 내려가는 '뇌 우선' 하위 유형의 특징입니다 [인용44]. 두 아형 모두 미주신경이 지배하는 구조와 기능에 변화를 보이는 것으로 보입니다. 고해상도 초음파를 사용하여 측정한 미주 신경의 구조적 완전성이 PD에서 변경될 수 있다는 증거가 있습니다. 일부 연구에서는 환자의 좌측 및 우측 미주신경이 연령이 일치하는 대조군에 비해 현저히 작다는 사실을 발견한 반면[인용45-47], 다른 연구에서는 환자와 대조군 간에 미주신경의 크기가 비슷한 것으로 나타났습니다[인용48-51].

보행 문제 및 인지 기능 장애를 포함한

PD의 주요 증상과 관련된 추가적인 변화는

콜린성 기저 전뇌, 특히

뇌간의 메이너트 기저핵(nbM)과 페두쿨로폰틴 핵(PPN)에서

콜린성 신경 전달의 변화로 인해 발생합니다 [인용52-54], 및 래프핵의 세로토닌성 뉴런[인용55], SN 및 기저핵의 신경자극 인자 신호 감소[인용56], 뇌의 비정상적인 염증 반응[인용57] 때문일 가능성이 있습니다.

이는

PD가 미주신경의 기능과 관련이 있을 수 있는

노화 관련 신경 퇴화 외에도

여러 신경전달물질 시스템에 의해 뒷받침되는

다중 시스템 병리에 의해 뒷받침된다는 것을 시사합니다.

2.1. Imaging and VNS in humans

The neural correlates of VNS remain enigmatic, and imaging studies have produced somewhat inconsistent results. The low temporal and spatial resolutions of the imaging modalities used, varying stimulation parameters, limited sample sizes, and the clinical populations assessed are all potentially confounding factors. In healthy volunteers undergoing nVNS, the aim is to measure changes in the blood oxygenation level dependent (BOLD) response in vagal afferent pathway target regions. To date, at least eight studies using whole-brain exploratory analysis have been reported [Citation58–65]. Using taVNS, some [Citation59–62] but not others [Citation58,Citation63] showed increased BOLD response in the nucleus tractus solitarius (NTS) and LC. Conversely, Kraus and colleagues [Citation59] reported decreased BOLD response in both regions during taVNS. Across these studies, increased activity (during taVNS relative to rest or sham stimulation) has been found in regions encompassing salience (insula, anterior cingulate), basal ganglia (caudate nucleus, putamen), thalamic, and cerebellar brain networks. By contrast, deactivation was observed in the limbic system and temporal lobe when sham stimulation has been compared to active stimulation. It is noteworthy that the exact neural connections of the ABVN are not known. The tragus is innervated, for example, only by the great auricular nerve and the auriculotemporal nerve, not the vagus nerve [Citation66].

To our knowledge, only one study has investigated the dynamic, online changes in brain function during tcVNS. Frangos and Komisaruk [Citation65] placed two electrodes over the right cervical vagus nerve in 13 healthy participants undergoing fMRI imaging. In comparison to pre-nVNS rest and reference stimulation (placed on the right sternocleidomastoid muscle), 2 min of continuous tcVNS elicited increased BOLD response in several regions of the forebrain that contain cholinergic neurons or receive dense cholinergic projections from the nbM including bilateral dorsolateral prefrontal cortex (DLPFC), caudate nucleus, and thalamus, left (contralateral) visceral area of the postcentral gyrus, and cerebellum (see Figure 1). During an analysis focused on the lower brainstem, greater BOLD response was noted in the ipsilateral nucleus of solitary tract (NTS, ipsilateral to the stimulation), bilateral parabrachial complex (PB), as well as in SN and ventral tegmental area (VTA) during stimulation relative to control. This study additionally showed that activity in the SN (the source of the nigrostriatal pathway transmitting DA from SN to caudate and putamen; an area severely affected in PD) and VTA (from which DA is transmitted to ventral striatum [mesolimbic pathway] and to PFC [mesocortical pathway]; an area less affected in PD) outlasted the period of tcVNS stimulation. As such, tcVNS may be better suited for targeting key regions of neurodegeneration in PD that underpin gait and cognitive impairments. Further studies are, however, warranted.

2.1. 인간의 영상과 VNS

VNS의 신경학적 상관관계는 여전히 수수께끼로 남아 있으며, 영상 연구에서도 다소 일관되지 않은 결과가 나왔습니다. 사용된 영상 기법의 낮은 시간적 및 공간적 해상도, 다양한 자극 매개변수, 제한된 샘플 크기, 평가된 임상 집단은 모두 잠재적으로 혼란을 야기할 수 있는 요인입니다.

nVNS를 받는 건강한 지원자의 경우, 미주 구심성 경로 표적 영역에서 혈중 산소화 수준 의존적(BOLD) 반응의 변화를 측정하는 것이 목표입니다. 현재까지 전뇌 탐색 분석을 사용한 최소 8건의 연구가 보고되었습니다[인용58-65]. 일부[인용59-62]는 taVNS를 사용했지만 다른 일부[인용58,인용63]는 그렇지 않았는데, 핵핵(NTS)과 LC에서 BOLD 반응이 증가한 것으로 나타났습니다. 반대로, 크라우스와 동료들[인용59]은 taVNS 동안 두 영역 모두에서 BOLD 반응이 감소했다고 보고했습니다. 이러한 연구 전반에서, (휴식 또는 가짜 자극에 비해 taVNS 동안의) 활동 증가는 두드러기(insula, 전대상회), 기저핵(꼬리핵, 퍼타멘), 시상 및 소뇌 네트워크를 포괄하는 영역에서 발견되었습니다. 반면, 가짜 자극을 실제 자극과 비교했을 때는 변연계와 측두엽에서 비활성화가 관찰되었습니다. ABVN의 정확한 신경 연결은 알려져 있지 않다는 점이 주목할 만합니다. 예를 들어, 삼차신경은 미주신경이 아닌 대이개신경과 귀두측두신경에 의해서만 자극을 받습니다 [인용66].

우리가 아는 한, tcVNS 중 뇌 기능의 동적 온라인 변화를 조사한 연구는 단 한 건뿐입니다. 프랜고스와 코미사룩[인용65]은 13명의 건강한 참가자를 대상으로 오른쪽 경추 미주신경 위에 두 개의 전극을 배치하여 fMRI 영상을 촬영했습니다. nVNS 전 휴식 및 기준 자극( 우측 흉쇄유돌근에 위치)과 비교하여, 2분 동안의 지속적인 tcVNS는 콜린성 뉴런을 포함하거나 양측 배측 전전두피질(DLPFC)을 포함하여 nbM으로부터 밀집된 콜린성 투사를 받는 전뇌의 여러 영역에서 BOLD 반응의 증가를 이끌어냈습니다, 꼬리핵, 시상, 좌측(반대측) 내장 영역인 후중격의 내장 영역, 소뇌(그림 1 참조)를 포함합니다. 하부 뇌간에 초점을 맞춘 분석에서, 자극 시 대조군에 비해 자극의 동측 시상핵(NTS, 자극의 동측), 양측 시상하부 복합체(PB), 그리고 SN과 복측 분절 영역(VTA)에서 더 큰 BOLD 반응이 관찰되었습니다. 이 연구는 또한 SN(SN에서 꼬리 및 꼬리겉질로 DA를 전달하는 흑질 경로의 근원, PD에서 심하게 영향을 받는 영역)과 VTA(DA가 복측 선조체[중변연계 경로]와 PFC[중피질 경로]로 전달되는 영역, PD에서 덜 영향을 받는 영역)의 활동이 tcVNS 자극 기간보다 더 오래 지속된다는 사실을 추가로 보여주었습니다. 따라서 보행 및 인지 장애를 뒷받침하는 PD의 주요 신경 퇴행 부위를 표적으로 삼는 데 tcVNS가 더 적합할 수 있습니다. 그러나 추가 연구가 필요합니다.

Figure 1. VNS mechanisms of action and physiological effects. Abbr. ACh, acetylcholine; Amy, amygdala; BOLD, blood oxygenation level dependant; Cd, caudate; DMNV, dorsal motor nucleus of the vagus; DLFPC, dorsolateral prefrontal cortex; Hp, hippocampus; HRV, heart-rate variability; LC, locus coeruleus; nbM, nucleus basalis of Meynert; NE, norepinephrine; NTS, nucleus tractus solitarius; PPN, pedunculopontine nucleus; S1, primary somatosensory cortex; Thal, thalamus; TNF- α, tumor necrosis factor-α; VNS, vagus nerve stimulation; Note, the figure is partly adapted from [Citation36] and [Citation92]. Icons used in the figure are provided gratis by https://www.freepik.com

그림 1. VNS 작용 메커니즘 및 생리적 효과. Abbr. ACh, 아세틸콜린; Amy, 편도체; BOLD, 혈액 산소화 수준 의존적; Cd, 꼬리; DMNV, 미주 등쪽 운동핵; DLFPC, 배측 전전두피질; Hp, 해마; HRV, 심박수 변동성; LC, 유전자좌; nbM, Meynert의 기저핵; NE, 노르에피네프린; NTS, 소상핵; PPN, 소상핵; S1, 일차 체성 감각 피질; Thal, 시상; TNF- α, 종양 괴사인자-α; VNS, 미주 신경 자극; 참고, 그림은 [ 인용36 ] 및 [ 인용92 ]에서 부분적으로 수정한 것입니다. 그림에 사용된 아이콘은 https://www.freepik.com 에서 무료로 제공했습니다 .

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2.2. VNS and norepinephrine

Alterations in the complex interplay between DA, norepinephrine (NE), and serotonergic systems, in addition to cholinergic neurotransmission, have been attributed to both motor and non-motor functions in PD [Citation40,Citation67,Citation68]. This is supported by post mortem studies that have revealed profound cell loss and LBs in the LC [Citation69,Citation70] leading to the theory that neurodegeneration of LC in addition to the raphe nuclei – containing serotonergic neurons – may precede that of DA-SN neurons in some cases [Citation40].

VNS may modulate LC-NE neurons via afferent projections to the NTS [Citation71], a sensory nucleus located in the brainstem medulla [Citation1]. According to George [Citation1], the NTS relays afferent sensory information to cortical and subcortical brain structures using an autonomic feedback loop, via direct projections to nuclei in the medulla and through arising pathways via the LC and PB that terminate in the forebrain [Citation1]. The LC is the main site for synthesis of NE in the brain with a neuroprotective role [Citation72,Citation73]. Transient, intensity-dependent increase in brain NE is observed following iVNS [Citation74,Citation75].

The LC projects to all levels of the forebrain, including limbic structures (thalamus, amygdala, hippocampus) [Citation76]. These regions play a central role in higher cognitive and affective processes [Citation76]. Visceral information from the vagus nerve is furthermore relayed to the hypothalamus, insular cortex, and the anterior cingulate cortex [Citation1]. The LC additionally has reciprocal connections with the PFC and is therefore believed to play a putative role in PFC cognitive functions such as working memory [Citation77]. VNS has been shown to induce mood and emotion enhancing effects potentially due to LC’s extensive connections with limbic structures, particularly the amygdala, in addition to the amygdala’s main output pathway, the bed nucleus of stria terminalis [Citation76]. LC-NE projections also reach the cholinergic nbM in the basal forebrain [Citation78] which may cause the upregulation of ACh via stimulation of excitatory α1- and β1- adrenoceptors [Citation79].

2.2. VNS와 노르에피네프린

콜린성 신경전달과 더불어

DA,

노르에피네프린(NE),

세로토닌 시스템 간의

복잡한 상호 작용의 변화는

PD의 운동 및 비운동 기능 모두에 기인합니다[인용40,인용67,인용68].

이는 LC에서 심각한 세포 손실과 LB를 발견한 사후 연구에 의해 뒷받침됩니다[인용69,인용70]

세로토닌성 뉴런을 포함하는 라페핵과 더불어 LC의 신경 퇴행이

일부 경우 DA-SN 뉴런의 신경 퇴행보다

선행할 수 있다는 이론으로 이어집니다[인용40].

VNS는

뇌간 수질에 위치한 감각 핵인 NTS[인용71]로의 구심성 돌출을 통해

LC-NE 뉴런을 조절할 수 있습니다[인용1].

George [인용1]에 따르면,

NTS는 자율 피드백 루프를 사용하여

수질의 핵에 직접 투영하고

전뇌에서 종결되는 LC와 PB를 통해 발생하는 경로를 통해

구심성 감각 정보를 피질 및 피질하 뇌 구조에 전달합니다 [인용1].

LC는

뇌에서 신경 보호 역할을 하는

NE의 주요 합성 부위입니다[인용72,인용73].

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5878728/

수십 년 동안 알츠하이머병(AD)과 파킨슨병(PD) 모두에서 뇌의 주요 노르아드레날린성 핵인 소상체(LC)의 퇴화가 발생한다는 사실이 알려져 왔지만, 그다지 주목받지 못했습니다. 이제 LC의 고인산화 타우는 인간 뇌에서 최초로 발견되는 AD 유사 신경 병리이며, LC의 α-시누클레인 내포물은 PD의 초기 단계를 나타내며, 실험적 LC 병변은 동물 모델에서 신경 병리 및 인지/행동 결함을 악화시킨다는 사실이 인식되고 있습니다. 이 리뷰의 목적은 LC 병리, 기능 장애 및 퇴행의 원인과 결과, 그리고 조기 발견 및 치료에 대한 의미를 고려하는 것입니다.

알츠하이머병과 파킨슨병의 궤상체 기능 개요 이 도식에는 질병 진행에 따른 LC 뉴런의 병리, 활동, 형태 및 생존에 대한 가상의 모델이 간략하게 설명되어 있습니다. 각 단계 위에 해당되는 인지 및 행동 표현형이 나열되어 있고, 아래에 잠재적 치료법이 나열되어 있습니다. 그림은 알츠하이머병의 진행을 나타내며(다음 참조), PD의 경우 타우/신경섬유 엉킴 대신 α-시누클레인/루이소체 병리가 발생한다는 차이점이 있지만 유사한 과정이 가설로 가정되어 있습니다. 질병이 없다는 것은 정상적인 인지 및 행동과 함께 정상적인 LC 활동과 관련이 있습니다. 알츠하이머병의 초기 전구 단계에서는 고인산화된 "프리탱글" 형태의 타우(pτ)가 LC에 나타나 신경세포 과잉 활동과 그에 따른 행동 표현형을 유발합니다. 이 단계에서 NE 전달을 약화시키는 치료법으로 과잉 활동을 억제할 수 있습니다. 프리탱글 타우가 응집되기 시작하고 더 진행된 형태(예: 신경섬유 엉킴, τ)로 진행됨에 따라 LC 섬유와 말단이 퇴화하기 시작하여 LC 활동 조절 장애, 혼합 행동 표현형, 경도 인지 장애(MCI)가 발생합니다. 특정 개인의 특정 증상 발현에 따라 신경교세포 전달을 감소시키거나 증가시키는 치료법이 적용될 수 있습니다. 말기 질환에서는 솔직한 LC 변성이 발생합니다. 인지 및 각성의 심각한 결손은 신경전달을 증가시키는 치료법으로 치료할 수 있습니다.

뇌 NE의 일시적, 강도 의존적 증가는 iVNS 이후 관찰됩니다 [인용74,인용75].

LC는 변연계 구조(시상, 편도체, 해마)를 포함한 모든 수준의 전뇌에 투사됩니다[인용76]. 이러한 영역은 더 높은 인지 및 정서적 과정에서 중심적인 역할을 합니다[인용76]. 미주 신경의 내장 정보는 시상하부, 섬 피질, 전대상피질로 전달됩니다[인용1]. 또한 LC는 PFC와 상호 연결되므로 작업 기억과 같은 PFC 인지 기능에 추정적인 역할을 하는 것으로 여겨집니다[인용77]. VNS는 편도체의 주요 출력 경로인 선조체의 기저핵 외에도 변연계 구조, 특히 편도체와의 광범위한 연결로 인해 기분과 감정을 향상시키는 효과를 유도하는 것으로 나타났습니다[인용76]. LC-NE 투영은 또한 기저 전뇌의 콜린성 nbM에 도달하여[인용78] 흥분성 α1- 및 β1- 아드레날린 수용체의 자극을 통해 ACh의 상향 조절을 유발할 수 있습니다[인용79].

2.3. VNS cholinergic activity and inflammation

There is some evidence from animal models implicating acetylcholine (ACh) as a mechanism of action in VNS [Citation80,Citation81]. Attenuation of VNS following the application of the muscarinic agonist scopolamine in a rat model [Citation80] and after lesioning the nucleus basalis of Meynert (nbM) [Citation82] corroborates this.

ACh is a neurotransmitter and a neuromodulator that is pivotal for various cognitive, sensory, and motor functions [Citation83,Citation84], and is thought to mitigate the production of pro-inflammatory cytokines [Citation85]. ACh acts through two receptors in the CNS, ionotropic nicotinic receptors (nAChRs) and metabotropic muscarinic receptors (mAChRs) [Citation84].

Increased density of astrocytes and active microglia have been observed in PD, which supports the theory that PD may be a disorder of neuroinflammation [Citation57,Citation86]. When neuroinflammation begins in PD relative to neurodegeneration is unsubstantiated [Citation57], but neurodegeneration is exacerbated under persistent neuroinflammation [Citation57,Citation87]. Vagal efferents originate in the DMNV, which lies in the medulla, adjacent to the NTS and receives the majority of processed NTS sensory signals [Citation88]. The primary neurotransmitter of DMNV neurons is ACh, and DMNV neurons together with ACh play a key role in inhibiting neuroinflammation via the cholinergic anti-inflammatory pathway [Citation36–38,Citation89]. It is therefore not surprising that the vagus nerve is sensitive to pro-inflammatory cytokines such as interleukin-1β (IL-1β), IL-6 and IL-18 and tumor necrosis factor-α (TNF-α) but not IL-10 [Citation85] and that VNS has anti-inflammatory effects possibly by upregulating cholinergic neurotransmission, inhibiting the production of both IL and TNF-α [Citation38,Citation85]. It has also been theorized that this process occurs in the spleen via the vagus nerve using ACh (through α7nAChR subtype) and a vagosympathetic interaction [Citation36,Citation90,Citation91] – see Figure 1. Another example of the anti-inflammatory effects of VNS occurs in the GI tract [Citation36,Citation92]. These effects are also mediated via the α7nAChR subtype [Citation85,Citation93]. However, the exact mechanisms underpinning the interaction between the vagus nerve, spleen, and GI tract is debated [Citation36] and the evidence in PD is limited [Citation37]. We refer the reader to Bonaz and colleagues [Citation36] and Pavlov and Tracey [Citation92] for an excellent discussion on this topic.

In PD, DMNV neurons are highly susceptible to neurodegeneration, and contain phosphorylated α-synuclein [Citation40] leading to neuroinflammatory processes [Citation94]. Farrand and colleagues [Citation95–97] showed that VNS reduced the number of astrocytes and microglia, as well as reverting microglia back to their inactive state in a rat model of PD. Furthermore, the authors showed that VNS reduced aggregated α-synuclein in the SN. These effects are most strongly induced during high-frequency microburst VNS and restores neurodegenerative and anti-inflammatory effects to levels comparable to un-lesioned control animals [Citation96]. The evidence on how these effects are exerted is limited but increased brain-derived neurotrophic factor (BDNF) and an activation of central α7nAChRs has been suggested [Citation93,Citation95]. Jiang and colleagues [Citation98] furthermore showed that taVNS in PD model rats reduced levels of TNF-α and IL-1β (pro-inflammatory) cytokines and increased levels of α7nAChRs. In humans, one study demonstrated that following tcVNS for 26-days, patients with Sjögren’s syndrome demonstrated significant reduction of cytokines in blood including TNF-α and IL-1β [Citation27]. Findings from a recent study suggests that repeated tcVNS stimulation over a 30-day period reduces TNF-α and increases the concentration of BDNF in blood serum in human PD participants [Citation26].

The evidence presented above lends credence to the proposal that VNS may boost the cholinergic system and modulate neuroinflammation in PD.

2.3. VNS 콜린성 활동과 염증

아세틸콜린(ACh)이

VNS의 작용 메커니즘으로 작용한다는 동물 모델의 증거가 일부 있습니다[인용80,인용81].

쥐 모델에서

무스카린 작용제 스코폴라민을 투여한 후[인용80]와

메이너트 기저핵(nbM)을 병변시킨 후[인용82]의

VNS 약화는 이를 뒷받침합니다.

ACh는

다양한 인지, 감각 및 운동 기능에 중추적인 역할을 하는

신경전달물질이자 신경 조절제로서[인용83,인용84],

전 염증성 사이토카인의 생성을 완화하는 것으로 알려져 있습니다[인용85].

ACh는

CNS의 두 가지 수용체, 즉

이온성 니코틴 수용체(nAChR)와

대사성 무스카린 수용체(mAChR)를 통해 작용합니다[Citation84].

PD에서

성상교세포와 활성 미세아교세포의 밀도 증가가 관찰되었으며,

이는 PD가 신경염증 장애일 수 있다는 이론을 뒷받침합니다[인용57,인용86].

PD에서

신경염증이 신경퇴행과 관련하여 시작되는 시기는 입증되지 않았지만[인용57],

지속적인 신경염증 하에서 신경퇴행이 악화됩니다[인용57,인용87].

미주 원심은

NTS에 인접한 수질에 있는 DMNV에서 유래하며,

처리된 대부분의 NTS 감각 신호를 수신합니다[인용88].

DMNV 뉴런의 주요 신경전달물질은

ACh이며,

DMNV 뉴런은 ACh와 함께 콜린성 항염증 경로를 통해 신경염증을 억제하는 데 중요한 역할을 합니다[인용36-38,인용89].

따라서

미주신경이

인터루킨-1β(IL-1β), IL-6, IL-18, 종양괴사인자-α(TNF-α)와 같은

전 염증성 사이토카인에 민감하지만

IL-10에는 민감하지 않은 것은 놀라운 일이 아니며[Citation85],

VNS가 콜린성 신경 전달을 상향 조절하여

IL과 TNF-α의 생산을 모두 억제함으로써 항염 효과를 갖는다는 것은

아마도 [Citation38,Citation85] 당연한 일입니다.

또한 이 과정은 ACh(α7nAChR 아형을 통한)와 미주 신경을 통해 비장에서 발생한다는 이론도 있습니다[인용36,인용90,인용91] - 그림 1 참조.

VNS의 항염증 효과의 또 다른 예는

위장관에서 발생합니다[인용36,인용92].

이러한 효과는 또한 α7nAChR 아형을 통해 매개됩니다[인용85,인용93]. 그러나 미주신경, 비장, 위장관 간의 상호작용을 뒷받침하는 정확한 메커니즘은 논쟁의 여지가 있으며[인용36], PD에 대한 증거는 제한적입니다[인용37]. 이 주제에 대한 훌륭한 논의는 Bonaz와 동료들[인용36], Pavlov와 Tracey[인용92]를 참조하시기 바랍니다.

PD에서 DMNV 뉴런은 신경 퇴행에 매우 취약하며 인산화 α-시누클레인[인용40]을 함유하고 있어 신경 염증 과정을 유발합니다[인용94]. Farrand와 동료들[인용95-97]은 VNS가 성상교세포와 미세아교세포의 수를 감소시킬 뿐만 아니라 PD의 쥐 모델에서 미세아교세포를 비활성 상태로 되돌린다는 사실을 보여주었습니다. 또한 저자들은 VNS가 SN에서 응집된 α-시누클레인을 감소시키는 것으로 나타났습니다. 이러한 효과는 고주파 마이크로버스트 VNS 동안 가장 강력하게 유도되며 신경 퇴행성 및 항염증 효과를 병변이 없는 대조 동물과 비슷한 수준으로 회복시킵니다[인용96]. 이러한 효과가 어떻게 발휘되는지에 대한 증거는 제한적이지만 뇌유래신경영양인자(BDNF)의 증가와 중추 α7nAChR의 활성화가 제안되었습니다[인용93,인용95]. Jiang과 동료들[인용98]은 PD 모델 쥐의 taVNS가 TNF-α 및 IL-1β(전 염증성) 사이토카인의 수치를 감소시키고 α7nAChR의 수치를 증가시킨다는 사실을 추가로 보여주었습니다. 사람의 경우, 한 연구에 따르면 쇼그렌 증후군 환자에게 26일 동안 tcVNS를 투여한 결과 TNF-α와 IL-1β를 포함한 혈액 내 사이토카인이 현저히 감소한 것으로 나타났습니다[인용27]. 최근 연구에 따르면 30일 동안 반복적인 tcVNS 자극이 인간 PD 참가자의 혈청 내 TNF-α를 감소시키고 BDNF의 농도를 증가시키는 것으로 나타났습니다[인용26].

위에 제시된 증거는

VNS가 콜린성 시스템을 강화하고

PD의 신경 염증을 조절할 수 있다는 제안에 신빙성을 부여합니다.

3. VNS may mitigate gait problems in PD

Gait impairments in PD appear early in the course of the disease, progressively worsen with disease severity, and respond only selectively to treatment [Citation17,Citation99]. They have significant consequences, as discrete gait characteristics predict future falls even in those who are falls naïve [Citation100]. Progression of discrete gait impairments (such as step time variability and step length variability) are evident in early disease despite optimal dopaminergic treatment [Citation23]. This reflects the contemporary view of PD as a complex multisystem disorder in which core impairments are underpinned by deficits in multiple neurotransmitter systems, as well as age-related neurodegeneration.

Cognitive impairment contributes to early gait deficits [Citation101], and conversely, gait impairments predict cognitive decline in early PD [Citation102]. Both cognitive deficit and gait impairment in PD may be in part underpinned by systematic alterations in cholinergic neurotransmission [Citation53,Citation103–106] in addition to neurodegeneration of the nigrostriatal DA pathway [Citation103]. The cholinergic nbM and PPN in addition to intrinsic cholinergic neurons in the hippocampus, striatum, cortex, the medial habenula, and cerebellum constitute the principal sources of cholinergic projections in the brain [Citation107–109]. Loss of cholinergic neurons in both the nbM and PPN in PD is extensive [Citation110,Citation111]. Improvements in gait and postural control in PD are observed following deep-brain stimulation (DBS) of the nbM and PPN [Citation112,Citation113] Furthermore, acetylcholinesterase inhibitors (AChEI), aimed at boosting the output of cholinergic neurons within the nbM, are under investigation in the management of gait impairments in PD [Citation114].

3. VNS는 파킨슨병의 보행 문제를 완화

파킨슨병의 보행 장애는

질병 진행 초기에 나타나고

질병의 중증도에 따라 점진적으로 악화되며

치료에 선택적으로만 반응합니다[인용17,인용99].

이산 보행 특성은 낙상이 없는 환자에서도 향후 낙상을 예측할 수 있기 때문에 중요한 결과를 가져옵니다[인용100]. 이산 보행 장애 discrete gait impairments (예: 걸음 시간 변동성 및 걸음 길이 변동성)의 진행은 최적의 도파민성 치료에도 불구하고 초기 질환에서 분명하게 나타납니다[인용23]. 이는 PD를 여러 신경전달물질 시스템의 결함과 노화와 관련된 신경 퇴행으로 인해 핵심 장애가 뒷받침되는 복잡한 다중 시스템 장애로 보는 현대적 관점을 반영합니다.

보행은 운동 및 인지 기능을 포함한 광범위한 중추 신경계 네트워크에 의해 뒷받침되는 다양한 특성으로 설명되는 복잡한 현상입니다. 그럼에도 불구하고 개별 보행 특성의 신경 기질은 제대로 이해되지 않아 노화와 질병으로 인한 보행 장애에 대한 이해가 제한되어 있습니다. 이 구조화된 검토는 독립적인 보행 영역을 반영하는 사전 지정된 모델에서 정의된 보행 특성을 노인의 뇌 영상 매개변수에 매핑하는 것을 목표로 합니다. 38,029건의 연구 결과 52건을 검토했습니다. 연구 결과 보행 평가를 신경 기질에 매핑할 때 일관되지 않은 접근 방식이 나타나 결론을 제한하는 것으로 나타났습니다. 보행 장애는 일반적으로 뇌 기능 저하, 특히 회백질 위축 및 백질 무결성 손실과 관련이 있습니다. 보행 제어의 전반적인 척도인 보행 속도는 전두엽 및 기저핵 영역에서 이러한 영상 마커와 가장 자주 연관되었으며, 그 감소는 백질 부피 및 완전성 측정으로 예측할 수 있었습니다. 추가적인 보행 측정이나 기능적 이미징 매개변수를 평가한 연구는 거의 없었습니다. 향후에는 건강과 질병의 이동성을 더 잘 이해하기 위해 다중 프로세스 네트워크 관점을 취하는 연구를 포함하여 보행의 지역적 신경해부학적 및 기능적 상관관계를 매핑하는 연구가 필요합니다.

인지 장애는 초기 보행 결손에 기여하고[인용101], 반대로 보행 장애는 초기 PD의 인지 저하를 예측합니다[인용102]. PD의 인지 결손과 보행 장애는 부분적으로 흑색질 DA 경로의 신경 퇴화 [인용53,인용103-106] 외에도 콜린성 신경 전달의 체계적 변화 [인용103]에 의해 뒷받침될 수 있습니다 [인용103]. 해마, 선조체, 피질, 내측 하베눌라 및 소뇌의 고유 콜린성 뉴런과 더불어 콜린성 nbM 및 PPN은 뇌에서 콜린성 투사의 주요 원천을 구성합니다 [인용107-109]. PD에서 nbM과 PPN 모두에서 콜린성 뉴런의 손실은 광범위합니다[인용110,인용111]. nbM과 PPN의 심부 뇌 자극(DBS) 후 PD의 보행 및 자세 제어가 개선되는 것이 관찰됩니다 [인용112,인용113] 또한 nbM 내 콜린성 뉴런의 출력을 높이는 것을 목표로 하는 아세틸콜린에스테라제 억제제(AChEI)가 PD의 보행 장애 관리에서 연구되고 있습니다 [인용114].

3.1. VNS and locomotion in animals

At least five studies have assessed the effects of VNS on gait in animal models of PD. These have shown that chronic iVNS [Citation95–97,Citation115] or taVNS [Citation98] improves locomotion or locomotor asymmetry relative to animals receiving no VNS (indexed by the cylinder test assessing forelimb akinesia and increased total distance traveled [Citation95–97,Citation115], increased latency to time to fall using the rotarod task, and time to traverse on the beam-walking test [Citation98]). In these studies, the improvement in locomotion coincided with a reduction in markers of neuroinflammation, increased density of Tyrosine Hydroxylase (TH)-positive cells – an enzyme which aids in the conversion of L-tyrosine to L-DOPA – in both SN and LC [Citation95–98,Citation115] in addition to reduced α-synuclein in SN [Citation95–98]. In relation to this, VNS was also used in conjunction with forearm training in non-parkinsonian rats [Citation82]. This study showed that VNS paired with training led to increased cortical motor maps relative to untrained animals – an indicator of neuroplasticity. By contrast, in animals with selective lesions of cholinergic nbM neurons, VNS paired with forearm training did not lead to increased cortical representation of the forelimb area indicating that cholinergic pathways are critical for this reorganization to occur [Citation82]. One caveat of this study, however, was that motor performance in both groups (lesioned and non-lesioned nbM) was similar, suggesting that forelimb cortical representation cannot solely explain functional activity.

Farrand and colleagues assessed three stimulation frequencies and cycle durations in PD animal models [Citation96] (see Table 1 for further details). The three stimulation parameters included low-frequency VNS, high-frequency VNS, and microburst biomimetic VNS. All groups received identical current intensity of 0.75 mA. In short, all groups (relative to the sham group receiving no stimulation) showed improvements in all assessments, but a trend for the microburst biomimetic VNS to have the greatest effects [Citation96].

Table 1. Stimulation location, parameters and duration for all studies assessing the efficacy of VNS in people with Parkinson’s and Parkinson’s model rats

In a recent study by another group, Kin and colleagues [Citation115] used variable stimulation intensity but identical pulse frequency, pulse width, and cycle duration (see Table 1) with stimulation administered for 14 days. Results indicated that VNS had the greatest effect in animals who received moderate intensity stimulation (0.25 and 0.5 mA) since these animals showed less forelimb akinesia relative to animals receiving low or high-intensity stimulation. In this study [Citation115], stimulation of the VN was initiated immediately following lesioning (using 6-OHDA, a neurotoxin affecting DA and NE neurons in the brain). In contrast, Farrand and colleagues used a double lesion approach and mimicked the PD pathology trajectory first by causing LC-NE depletion (DSP-6, another neurotoxin) followed by SN-DA lesioning (6-OHDA) 7 days later. VNS therapy then began 11 days following the SN-DA lesioning [Citation95–97].

3.2. Preliminary evidence for VNS effect on locomotion in PD

Pilot studies in human subjects with PD have explored the use of acute and chronic tcVNS on gait improvement. In one study, 19 participants with mild-to-moderate PD, with and without freezing of gait (FOG) were assessed using an instrumented walkway technology pre- and post-stimulation applied twice to the left side of the neck. Step length, count, velocity, and stride velocity variability were all found to be improved in participants, while in patients with FOG the number of steps taken to turn was significantly reduced [Citation25]. In a recent randomized sham-controlled study, Morris and colleagues [Citation24] studied 30 participants with PD. Participants received either a single dose of active or sham tcVNS to the left side of the neck in addition to their usual treatment. Gait was measured both pre- and post-stimulation. Both step time and step length variability decreased in participants in the active group relative to sham, although only step length variability reached significance. Both gait characteristics have been shown to be DA-treatment resistant [Citation23,Citation116] and potentially cholinergically mediated; thus, improvement may be due to upregulation of neurotransmission in the latter system, possibly in the cholinergic nbM or PPN regions. In both studies, stimulation was well tolerated with no adverse events reported. Finally, a very recent randomized, double-blind sham-controlled crossover trial showed that multi-dose tcVNS over 30 days improved gait velocity, step length, and step time in patients during active stimulation that was not observed following sham stimulation [Citation26]. This study furthermore showed that active stimulation resulted in a significant improvement on the Unified Parkinson’s Disease Rating Scale-III over and above that seen following sham stimulation. It is unclear, however, if any of these effects were mediated by improved cholinergic neurotransmission. Further studies would be needed to clarify this using appropriate methods. The authors of this study reported that no carry-over effects were observed following the intervention. Although no adverse effects were reported following repeated use of the device, a minority of patients withdrew from the study (both during the active and sham conditions) due to discomfort associated with the device use. Reassuringly, a large majority of participants were able to successfully carry out the stimulation at home.

All three studies conducted in people with Parkinson’s employed cervical VNS devices provided by the same manufacturer. All stimulation parameters are hardcoded in the device except the current intensity which can be adjusted by the participant (Table 1). None of these studies reported the average current intensity used by participants.

In summary, tcVNS may have beneficial neuromodulatory effects on treatment-resistant gait characteristics and falls in PD. Potential putative mechanisms could be reduced neuroinflammation, reduced α-synuclein aggregation, increased neurotropic factor signaling and/or upregulated cholinergic neurotransmission. The use of a non-pharmacological adjunct to rehabilitate to improve gait in Parkinson’s is an intriguing development, which merits further exploration. A larger randomized sham-controlled, multi-dose tcVNS study is currently being trialed in our group (ISRCTN19394828).

4. VNS leads to improvement across several cognitive domains

4.1. VNS and cognition in non-PD populations

Both iVNS and nVNS have been found to improve cognitive ability in animal and healthy human subjects. In early animal studies, iVNS increased memory retention in rats [Citation117,Citation118]. This was later replicated in epilepsy patients [Citation119], where iVNS facilitated retention/recognition memory [Citation120–122] and complex executive function [Citation123,Citation124]. Most of the nVNS literature has concentrated on utilization of taVNS [Citation125–131], although one recent study did find improved cognitive performance using the cervical tcVNS approach [Citation132].

There is some evidence that performance in associative memory is improved following taVNS in a group of older adults [Citation125], perhaps attributable to NE neuromodulation. Kaan et al. [Citation126] also found some evidence that taVNS improved memory of item order in healthy young adults.

taVNS can also enhance higher-order executive functions such as cognitive flexibility, which can be thought of as the ability to switch between different mental concepts and produce appropriate responses. Integral to this skill is inhibitory control, whereby a prior attentional focus is ‘switched off’ thus freeing up the capacity to attend to a new task [Citation133]. Active taVNS improved response selection in healthy young adults, and Serial Reaction Time performance; it also enhanced inhibitory control [Citation130]. Earlier work, however, suggested that taVNS might only assist response inhibition when the working memory load is high [Citation127]. A more recent study by Borges and colleagues [Citation129] found that performance on the set-shifting task, but not selective attention or response inhibition, was improved by taVNS.

VNS has additionally been explored in the context of cognitive impairment. The development of PD dementia (PDD) is a frequent and distressing complication of the disease, with a cumulative incidence approaching 80% in community-based studies [Citation134–136]. Mild cognitive impairment in PD (PD-MCI) may be a prodromal stage of PDD and can be present in up to 40% [Citation137]. Although enhanced cognitive function following VNS has not yet been assessed in PD/PDD, there has been some success with its use in Alzheimer’s Disease (AD) [Citation32,Citation33,Citation138]. An initial pilot study [Citation32] recruited 10 AD patients who underwent iVNS over a period of 10 weeks. At the three-month follow-up, improved scores were achieved on the cognitive subset of the Alzheimer’s Disease Assessment Scale (ADAS-cog) and the Mini Mental State Exam (MMSE) in 7/10 and 9/10 patients, respectively. These outcomes were mostly maintained at 6-months, with 7/10 patients still scoring higher on both scales [Citation32]. Later, further seven AD participants were added to the sample and were followed up for 1 year [Citation33]. Improved scores on the ADAS-cog (in 7/17 patients), and MMSE (in 12/17 patients) were sustained at 1 year after implantation. The treatment was well-tolerated, with minimal adverse effects, and no decline was reported in quality of life or mood during the study period. While this preliminary work suggests that iVNS can improve cognitive function in AD, the evidence base is minimal and limited by small participant numbers and a lack of control comparator group.

4.2. VNS in depression and anxiety

Individuals with PD are more likely than the general population to experience neuropsychiatric symptoms [Citation139]. Depression is particularly common, and it has a substantial impact on a PD patient’s ability to carry out daily activities [Citation139–141]. Depression can predate the motor features of PD for up to several years [Citation139], suggesting that psychiatric symptoms are also mediated by the pathophysiology of PD itself.

The management of depression in PD may include optimization of anti-Parkinson medications, the use of antidepressants [Citation139] and psychological therapies [Citation142]. In the general population, VNS has been used and approved for treatment-resistant depression. The scientific basis for this originated from animal studies, which established significant anti-depressant effects of iVNS in rats [Citation5]. In this context, the proposed underlying mechanisms of VNS include: i) changes in areas of the brain that are implicated in depression, ii) enhanced levels of NE and serotonin, and iii) increased BDNF, which may in turn decrease the neuronal loss associated with depressive disorders [Citation71,Citation143]. In human studies, both iVNS [Citation144] and taVNS [Citation145–147] have demonstrated efficacy in reducing depressive symptoms. Similarly, there is work to suggest that both iVNS and tcVNS may be beneficial in improving anxiety [Citation30,Citation31]. Thus far, it is unclear whether these outcomes can be achieved in PD, but there is evidence to suggest VNS can help in the management of depressive disorders and that iVNS improves quality of life in patients with epilepsy [Citation148].

5. Other actions of VNS

VNS has been shown to improve autonomic functions. For example, VNS may modulate heart rate variability (HRV), which is inversely related to the levels of inflammatory markers, and is known to be diminished in PD [Citation149]. It is theorized that VNS can improve autonomic function by reducing the sympathetic and enhancing the parasympathetic tone of the ANS. Furthermore, VNS may be an attractive approach to reduce fatigue and improve gastroparesis, which is also a common feature in PD [Citation150,Citation151].

5.1. Autonomic function

HRV refers to the beat-to-beat alterations in heart rate. Higher resting HRV is associated with good mental health and emotional well-being, whereas reduced HRV and vagus nerve activity have been associated with increased morbidity and mortality, and greater preval‎ence of psychiatric conditions, such as depression and anxiety [Citation146,Citation152].

In healthy adults, preliminary evidence suggests minimal effects of taVNS [Citation153–156] on HRV parameters. An additional layer of complexity relates to the variable stimulation parameters used which differ somewhat between studies in addition to age groups being studied.

In healthy young and middle-aged adults taVNS with a combination of 500 μs pulse width and 10 Hz stimulation frequency, but participant-specific current intensity produced the greatest effect on heart rate relative to sham (electrodes placed on the earlobe) [Citation153]. Another study assessed varying taVNS current intensities (0.5, 1 and 1.5 mA with other parameters held constant: 200–300 μs pulse width, 25 Hz frequency and cycle duration as 30 s on/off) on autonomic function in healthy young adults [Citation129]. This study showed that cardiac vagal activity increased in participants relative to rest, but this increase was not related to stimulation intensity or when intensity was self-controlled versus when it was pre-set by the researchers. Moreover, statistically significant differences in cardiac vagal activity were not reached when comparing active or sham conditions.

The effects of VNS on autonomic function in aging remains elusive and requires further investigation. In one study, healthy older adults underwent continuous stimulation via the vagus using taVNS [Citation157]. The authors showed that a single 15-min session per day for 14 days increased several measures of HRV in participants with some of these effects outlasting the period of stimulation. The authors furthermore showed that lower cardiac vagal activity at rest better predicted increased HRV under stimulation.

Lack of cardiac effects following nVNS may be due to the left side being stimulated, whereas effects may be more pronounced following right-sided stimulation [Citation154]. Using taVNS, De Couck and colleagues [Citation154] assessed effects of laterality (right or left cymba conchae) on measures of HRV in healthy young and middle-aged adults. This study primarily showed that right-sided stimulation resulted in increases of the standard deviation of all beat-to-beat (RR) intervals (SDNN; thought to reflect both sympathetic and parasympathetic output). A trend for similar effects was observed following left-sided stimulation.

Using taVNS, Weise and colleagues [Citation149] studied vagal evoked potentials from the ABVN, integrity of the vagal nuclei complex and heart rate in 50 patients with PD before and during stimulation. Both the left and right tragus of the ear were stimulated (square impulses, pulse width: 0.1 ms, current intensity: 8 mA and frequency: 0.5 Hz). In this study, the authors found no differences between groups in either the latency or the amplitude of ABVN evoked potentials between groups. Furthermore, although the components of HRV were lower in PD relative to matched healthy volunteers at baseline, there was no effect of taVNS on any component [Citation149]. It is likely however that the authors of this study [Citation149] are recording afferent nerve volleys as opposed to cortically generated potentials. Follow-up studies are therefore warranted.

5.2. Fatigue

A recent study assessed the efficacy of tcVNS in patients with primary Sjögren’s syndrome, which is an immune-mediated inflammatory condition characterized by chronic fatigue [Citation27]. The authors instructed participants to apply stimulation sequentially to the left and right vagus nerves twice daily for 26 days. Results showed that physical fatigue, but not mental fatigue, and daytime sleepiness were reduced at the study endpoint relative to baseline, with significant reductions in certain cytokines, as discussed above [Citation27].

5.3. Gastroparesis

Gastroparesis, or delayed gastric emptying, are common and under-recognized in PD [Citation158], with changes in the DMNV implicated [Citation37]. The efficacy of VNS in resolving gastroparesis has been attributed to the vagus nerve role in the genesis and maintenance of nausea and vomiting, which are two of the cardinal symptoms of gastroparesis [Citation159]. Two studies have thus far provided some evidence of a beneficial effect of nVNS on gastroparesis in non-PD populations [Citation28,Citation29]. Both studies asked participants to apply tcVNS to left and right vagus nerve sequentially for a minimum of three [Citation28] and four [Citation29] weeks. Both studies reported reduced gastroparesis in participants as indicated by reduced scores on the Gastroparesis Cardinal Symptom Index.

6. Conclusion & future prospects

PD is a common neurological condition with a number of motor and non-motor features. Although DA loss is universal, other neurotransmitters and mechanisms are now recognized as underpinning the neurobiology of the disease. Dopaminergic treatment can improve some features, but a number of dopa-resistant characteristics are established, and alternative treatment options are required. VNS is a potential non-pharmacological intervention that has the potential to improve gait, cognition, fatigue, and autonomic function, although further work is required to establish the mechanistic foundation for PD. Potential mechanisms include augmentation of cholinergic transmission, reduction in neuroinflammation and potentiation of NE release. Multi-dose sham-controlled studies are required to determine the proof of concept and feasibility of VNS in PD.

7. Expert opinion

Prevention of falls in older people is a public health priority. Gait disorders are a primary driver of falls and are common manifestations of aging syndromes such as sarcopenia – muscle atrophy – and frailty as well as neurodegenerative diseases. With regard to the latter, PD is a specific architype; where the burden of gait impairments and falls risk is greatest. The impact of gait dysfunction and falls in PD is such that people with PD who voted for them as the number one research priority in a recent James Lind Alliance and Parkinson’s UK priority setting partnership [Citation160].

Over the past 25 years, the global burden of PD has more than doubled due to increasing numbers of older people, longer disease duration, and environmental factors; this has been associated with an increase in disability-adjusted-life-years [Citation161]. nVNS could contribute to understanding the mechanisms of aging and treating age-related diseases such as PD, by exploring novel mechanisms and potential non-pharmacological treatments for gait disorders in PD. Targeting specific gait characteristics that underpin fall risk could conceivably reduce the morbidity and mortality associated with falls in PD, with wider implications for other aging and neurodegenerative conditions if efficacy is demonstrated. The potential benefits of a nonpharmacological, low-cost, simple-to-use, home-delivered electroceutical approach to boost cholinergic function, improve gait parameters, and reduce falls risk in this patient group are immense. If cognitive function were also be improved, as indicated in animal and healthy human studies, this would provide significant additional benefits. Importantly, because nVNS is FDA/MHRA approved for the treatment of common neurological and psychiatric disorders, obstacles to market are reduced and patient benefit may be seen much more promptly than with a novel device.

Although research in humans using nVNS is still in its infancy with research utilizing nVNS beginning around the start of this century, the number of publications and conditions utilizing nVNS are steadily increasing [Citation10]. There are still several technical limitations or parameters that need to be assessed, including the optimal current intensity, frequency, pulse width, cycle duration, and waveform shape from the nVNS device. Even laterality could be reviewed, and studies are needed to determine if left, right or alternating left/right stimulation is superior in terms of neurotransmitter release. Additionally, studies informing the optimal number of dosages and treatment tolerance are needed. Finally, focality of nVNS has not been studied to our knowledge and studies assessing whether nVNS (and in particular tcVNS) activates other surrounding nerves are lacking. However, Yakunina and colleagues [Citation62] showed that stimulation of the tragus and cymba conchae elicit increased BOLD response measured using fMRI in areas that are part of the vagal pathways including the NTS, whereas stimulation of the infero-posterior wall of the ear canal did not.

How the difference in stimulation parameters affects the response to the stimulation is a current hot topic (see some discussion in [Citation10]). Both manufacturers of the most widely used commercially available nVNS devices (NEMOS® and gammaCore®) do not allow adjustment of most stimulation parameters. In both cases only the stimulation intensity can be adjusted by the user. Consequently, custom-built devices stimulating the outer ear (or direct vagal stimulation in animals) are therefore becoming increasingly preval‎ent. In people with Parkinson’s varying stimulation parameters of nVNS devices have not been assessed. Regarding the studies in PD animal models, the critical question of whether these findings can be translated into human patients remains to be answered. Another issue that needs to be disentangled is the effects of nVNS as an adjunct treatment in patients on acetylcholinesterase inhibitors.

Advanced neuroimaging methods such as functional near-infrared spectroscopy and wearable neuroimaging technology employing magnetoencephalography [Citation162] may be used to investigate nVNS underlying mechanisms. Also, nVNS effects on the enteric nervous system, neuropsychological functioning and motor control are currently unclear in humans. Nonetheless, preliminary data from three studies in humans [Citation24–26] have already provided convincing evidence that tcVNS can improve dopaminergic treatment-resistant gait characteristics in early-stage PD, but it is currently unclear if these effects are sustained when participants no longer stimulate themselves. Finally, health economic data would be beneficial to collect, to determine costs and potential savings in relation to other treatments [Citation1]. To date, there are no head-to-head studies of iVNS vs. nVNS, although inherently invasive in nature, potential adverse events and presumed greater costings would favor nVNS.

Finally, a brief discussion on the use of sham stimulation in VNS is merited. When using other neuromodulation techniques such as transcranial magnetic or current stimulation (TMS, tCS) the use of sham stimulation is common and is thought to provide an adequate control condition [Citation163]. However, providing such a control condition is not without its challenges. The TMS coil makes an audible clicking sound when the magnetic pulse is delivered to the scalp followed by some scalp irritation as well as noticeable contraction of some muscles. Consequently, its use as a control condition, by definition, has been criticized [Citation164].

Similar issues are faced when using tCS where the stimulation produces noticeable and often painful sensory perceptions. The most common approach to sham tCS is to ramp the device up to a predetermined intensity before ramping the current down after a few seconds [Citation163]. Nonetheless, these sensory perceptions are substantially more noticeable and frequent during active tCS relative to sham [Citation165] which throw into question its use as a proper control condition in clinical research, especially in randomized controlled crossover trials. Stimulating the vagus nerve may be no different since vagal stimulation can elicit a range of side effects as noted previously [Citation13,Citation14]. Using taVNS it is common to place the stimulating electrodes on the earlobes of participants to not activate fibers of the ABVN. This again may cause issues in studies adopting a crossover design. Related to this gammaCore® sham devices do deliver perceptible electrical stimulation to the skin, but the frequency of pulses is low (0.1 Hz) [Citation26], and this purportedly does not activate vagal fibers and consequently regions of the vagal pathways (i.e. NTS, LC). To that end, the sham stimulation may be considered as a limitation of the technique, making it difficult to blind participants who may be aware of the most common side effects of nVNS. However, as with TMS and tCS, this is the best option we currently have.

In summary, nVNS is an evolving technique with potential applications in a number of symptoms and conditions. Further research to delineate the exact underpinning mechanisms of action, feasibility, and to generate pilot data are required; some of which we hope will be answered in the ISCRTN registered study (ISRCTN19394828).

Article highlights

• The known mechanisms of action of nVNS suggest it may impact brain regions and neurotransmitter systems affected by neurodegeneration in PD.

• Recent pathophysiological theories of PD suggest that neurons with Lewy Body pathology may originate in the gut and spread via the vagus nerve to the midbrain with both motor and non-motor symptoms being associated with this occurrence.

• Preliminary evidence highlights proof of concept for a single dose of nVNS to improve dopa-resistant gait characteristics in PD. Evidence for improved cognition and cognitive function in PD is lacking.

• Early results in other disease areas support nVNS as a promising therapeutic tool to improve other non-motor symptoms in PD, such as neuroinflammation, autonomic function, reduced gastroparesis, and fatigue.

• The translational effects of nVNS is an emerging field of study. Considerable work is needed to accurately determine the stimulation type (trans-auricular or trans-cervical) side (left or right), frequency of the stimulation, stimulation intensity, pulse width, cycle duration and waveform shape. Information on dosages is also needed, and future studies should assess the optimal number of treatments, number of doses per day and treatment tolerance. Finally, studies are needed to disentangle whether and how nVNS treatment interacts with pharmacological therapies such as acetylcholinesterase inhibitors.

Declaration of interest

AJ Yarnall is an NIHR BRC Intermediate Clinical Fellow and has received research grants from Parkinson’s UK, Dunhill Medical Trust, Lewy Body Society, Weston Brain Institute, Intercept Pharmaceuticals, NIHR, Cure Parkinson’s Trust, EU IMI, and Michael J Fox Foundation and Dunhill Medical Trust. For AJ Yarnall’s current research program, ElectroCore, LLC, supplies nVNS devices free of charge but have no intellectual input. AJ Yarnall has received honoraria and support for attending educational meetings from GE Healthcare, Bial, UCB, Abbvie, Britannia, Teva-Lundbeck, and Genus. MR Baker has received research funding from the MRC, NIHR, Ataxia UK, Academy of Medical Sciences, and the William Leech Charity. ElectroCore LLC previously provided gammacore devices to Dr. Baker at no cost and without restriction for experimental studies conducted in his laboratory. J-P Taylor is supported by Newcastle NIHR BRC. He has received speaker fees from GE Healthcare, funding from Sosei-Heptares and has consulted for Kyowa-Kirin. L Rochester’s research program is supported in part by grants from, among others, Parkinson’s UK and Cure Parkinson’s Trust. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers in this manuscript have no relevant financial or other relationships to disclose.

Additional informationFunding

The work is funded by a joint research grant award from Parkinson’s UK (ref: G-1903) and Dunhill Medical Trust (ref: RPGF1906\154) to the senior author.

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References

• George MS, Sackeim HA, Rush AJ, et al. Vagus nerve stimulation: a new tool for brain research and therapy. Biol Psychiatry. 2000;47:287–295.
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