神經電刺激

01-27

去年找工作的時候老闆的面試題目就是讓我了解神經電刺激，於是花了一些時間了解這個領域，做了一點東西，今天正好有時間就自己回顧了一下，因為不算是工作保密內容，所以發出來給大家看看，限於時間關係，之前做的英文註解不一一翻譯了。

大家可能了解人的大腦、心臟和內髒的電生理活動其實是非常活躍的，通過調節不同系統之間電信號的傳導，可以影響人的身體機能及感受，這是神經電刺激作為一個重要醫療器械領域的生理基礎。

神經電刺激器械全球市場規模為$49億美元，主要分為脊神經電刺激、迷走神經電刺激、腦深部電刺激及骶神經電刺激四大類，不同的刺激部位及刺激方式對應不同的疾病----這裡面有很多疾病都是目前其他方式無法進行干預或效果不好的。

The largest market currently is SCS for the treatment ofnback pain, emerging technologies in peripheral nerve stimulation will play anpivotal role in opening up new applications and driving double-digit growth fornmany years to come. The pipeline is rich withnproducts designed to address a growing number of patients with long-term painnand other chronic conditions, many of whom have no other treatment options.nThese emerging devices are taking aim at some large and highly unpenetratednmarkets desperate for new, more effective therapies to treat a variety ofncomplex conditions.

幾種主要的神經電刺激方式對應的刺激部位以及想要治療的疾病如下：

與其他現有藥物治療相比，神經電刺激的優點如下：

Advantage of Neuromodulation over Drug Therapy:

?Side Effects – Reversible at any time (not for renal denervation).

?Patience Compliance – Less or no governance at all.

?Resistance to Drugs – For refractory disease, diabetes, Parkinson』s and migraine.

神經電刺激這一領域截至去年6月已經獲得FDA批准的公司如下（對應功能及刺激部位見英文注釋）：

Medtronic: RestoreSensorn(Posture AdaptivenStimulation, SCS) Activa (MRI Compatible, DBS) InterStim II (For Incontinence, SNS)

BostonnScientific: PrecisionnSpectra (FDA Clearance First in Apr. 2004, and this product is in Apr. 2013,nSCS)

St.nJude Medical: Protégé (FDA Clearance in Apr. 2014,nFirst Upgradable SCS, SCS) EonnMini (Recalled)

NervonCorp: Senza (FDA Clearance in May 2015, NonParesthesia for HF Technology, SCS)

StimWave: Freedom-4n(FDA Clearancenin Dec. 2014, Targeting dorsal ramus nerve, SCS)

NeuroPace: RNS (FDA Clearance in Nov. 2013,nResponsive, Closed Loop for Epilepsy, DBS)

Cyberonics: VNS (FDA Clearance in 1997, Leadernin VNS for epilepsy, VNS) AspireSR (FDA Clearance in June, 2015,nFirst of its kind, capable of administering responsive stimulation to heartnrate increases that are associated with seizures in epileptic patients, VNS)

EnteroMedics: Maestro (FDA Clearance in Jan.n2015, For Obesity, VNS)

Cogentix: Urgent PC (FDA Clearance in Aug.n2007, For Bladder, SNS)

Bioness Inc: StimRouter (FDA Clearance in Feb. 2015,nTargeting intractable pain of peripheral nerve origin, PNS)

CVRx Inc: Barostim neo legacy (FDA Clearance innDec. 2014 Under Humanitarian Device Exemption, HDE, For Blood Pressure Control,nCarotid Sinus)

在幾種主要的神經電刺激方式中，迷走神經(Vagus Nerve)電刺激是目前研究最為活躍的領域，國內也有一家公司剛剛取得迷走神經電刺激治療癲癇的許可證。

早期迷走神經電刺激主要研究領域都在癲癇治療領域，後來Cyberonics在臨床試驗中偶然發現其對於抑鬱具有一定的緩解作用，因此又申請了其在抗抑鬱領域的應用。

VagusnNerve:

The vagus nerve is the 10th cranial nerve,nor the Wandering Nerve (vagus is Latin for wandering)nextending from the brain stem all the way to the viscera with a number ofnbranching nerves to the heart, lungs, voice box, stomach, and ears, among othernorgans. It contains motor and sensory fibers and, because it passes through thenneck and thorax to the abdomen, has the widest distribution in the body.

VNS History:

In 1882, Corning suggested thatnelectrical stimulation of the vagus nerve might provide the samenbenefit he had discovered from carotid massage for the management of epilepsy.nEarlynresearches had proposed that VNS affect the blood flow.

In 1934, Soma Weiss proposed thatncompression of the carotid sinus produced a direct cerebral response, causingnsyncope in human beings that is different from the effects of this stimulationnon blood pressure or heart rate.

In 1938, Bailey and Bremernreported that vagal stimulationncaused electro-encephalogram changes.

Dell and Olson in 1951, showednthat stimulation of the cut cervical vagus nerve evoked responses in the ventroposterior complex and intralaminar regions of the thalamus. Sincenthen, various experimental studies have established the effects of vagus nerve stimulation on the brain.

In 1952, DrnAlberto Zanchetti, an Italian cardiologist,ndemonstrated that VNS was affecting the electrical currents in the nerves, notnthe vascular system.

In 1985, Zabara et al. reported that electricalnstimulation from the vagus nerve produces inhibitionnof the neural processes, which can alter brain electrical activity andnterminate seizures in dogs. Since this research, vagus nerve stimulation has been usednfor patient benefit in various clinical conditions.

In 1988 Penry et al. performed the first humannimplant of a vagal stimulating device into a human.

Whatnis Epilepsy:

Epilepsy is a condition of thenbrain causing seizures. Anseizure is a disruption of the electrical communication between neurons. Thenseizures in epilepsy may be related to a brain injury or a family tendency, butnmost of the time the cause is unknown. Thenhuman brain is the source of human epilepsy. Although the symptoms of a seizurenmay affect any part of the body, the electrical events that produce thensymptoms occur in the brain. The location of that event, how it spreads and hownmuch of the brain is affected, and how long it lasts all havenprofound effects. These factors determine the character of a seizurenand its impact on the individual.

Epilepsy is the 4th (migraine, stroke andnAlzheimer』s disease occurs more frequently) most common neurological conditionnand affects more than 65nmillion people worldwide.

Epilepsy Diagnosis:

According to International League AgainstnEpilepsy (ILAE),na person is considered to havenepilepsy if they meet any of the following conditions:

?At least two unprovoked seizuresnoccur more than 24 hours apart

?One unprovoked seizure occurs butnthere is a probability of further seizures (approximately 75% or more) based onninterictal EEG and epilepsy syndrome

?At least two seizures occur in ansetting of reflex epilepsy.

Epilepsy Treatment:

?Anti-seizure drugs known asnantiepileptic drugs (AEDs)

?Certain diet changes:nKetogenicnDiet (A high-fat, low-carbohydrate dietnthat, although followed temporarily, is thought to have long-term benefits)

?Brain surgery

?DevicenTreatment: DBS, VNS, and Responsive Neural Stimulation

About 2/3 of patients withnepilepsy will achieve seizure control with medications. However, fornAT LEAST 1 million people in thenUnited States have uncontrolled epilepsy which cannot be treated withndrugs. Among these people, 25% - 80% can benefit from surgery.

VNS Therapy for Epilepsy:

In 1997, the U.S. Food and DrugnAdministration (FDA) approved vagus nerve stimulation as a (adjunctive) therapeutic intervention fornintractable focal or partialnepilepsy in people 12 years of age andnover. About 70,000 patients had been treated with VNS in the past 15 years.

去年FDA最新批准的VNS對於肥胖治療的產品為EneroMedics公司的Maestro：

其中最讓我覺得有前景的是一家叫SetPoint的公司，他們正在研發VNS用於炎症相關疾病的治療，目前主要針對類風濕性關節炎和Crohn氏病，其理論基礎在於Kevin Tracey炎症反射弧理論的發現及建立，希望他們早日成功。

Inflammationnand Neurology:

Inflammation is a participant innmany disease, including Alzheimer』s and other neurodegenerative brain disease,nas well as inflammatory bowel disease, congestive heart failure,natherosclerosis, Rheumatoid arthritis andndiabetes.

Untiln1990s,nit was dogmatic that the immunensystem is self-regulatingnthrough humoral and cellular pathways that are essentially autonomous. Immunenfunctions were presumed to be independent from neuronal control, their effectornmechanisms operating outside of neurological mechanisms that establishnhomeostasis in other organs.

Furthernconsideration reveals that these humoral and cellular mechanisms are inherentlynlimited in several aspects. First, their response time to a rapidly changingnenvironment is relatively slow becausenof the reliance on the production of mediators, cell trafficking, and thendistribution of mediators and cells by the circulatory system. Second, thesensystems are inefficientnfor integrating biological responses to numerous stimulating inputs across anwidely distributed network of immune tissues. Third, as these regulatorynsystems rely on the circulatory system to operate systemically, they inherentlynlack the means to exert efficientnregulatory responses in a regional or tissue specific fashion. Thus, humoralnand cellular counter-regulatory mechanisms do not provide all the essentialnfeatures required to fully maintain immunological homeostasis in vivo.

Homeostaticncontrol of immune responses by neural reflex circuits occurs in a time framenthat operates extremely fast relative to humoral and cell-traffickingnmechanisms. Afferent reflex arcs sense pathogenic molecules, cytokines, andnother products of infection and cell injury, thereby activating actionnpotentials that travel rapidly, specifically, and directionally. These incomingnneural signals to brainstem nuclei stimulate efferent action potentials thatntravel to the principal organs of the immune system, including the spleen,nlymph nodes, and reticuloendothelialnorgans. Arrival of action potentials in these innervated immune tissuesnculminates in release of neurotransmitters that interact with specificnreceptors expressed by monocytes, macrophages, lymphocytes, and other cells ofnthe innate and adaptive immune systems. Neurotransmitter receptor-mediatednintracellular signal transduction modulates immune cellular function bynspecific molecular mechanisms, resulting in exquisite, timely, and regionalncontrol of immunity and in establishment of immune homeostasis.

The inflammatory reflex:

Thenprototypical reflex circuit regulating immunity is comprised of afferent andnefferent signals transmitted in the vagusnnerve in response to the molecular products of infection and injury, includingncytokines, eicosanoids, DAMPs, and PAMPs. Stimulation of the vagusnnerve activates adrenergic splenic neurons residing in the celiac ganglion,nwhich travel into the spleen and terminate in synapse-like structures adjacentnto T cells in the white pulp. Norepinephrinenreleased from splenic neurons binds to β2nadrenergic receptor expressed on a subset of T cellsnthat expresses choline acetyltransferase,nthe rate-limiting enzyme in acetylcholine biosynthesis. Acetylcholine interactsnwith α7nnicotinic acetylcholine receptor (α7 nAChR)nexpressed in red pulp and marginal-zone macrophages to inhibit cytokine (TNF,nIL-1, IL-18, HMGB1, and other cytokines) release.

Innhealthy people, the nervous system provides a precise mechanism of checks andnbalances that maintains the levels of TNF within a safe range. But innrheumatoid arthritis, like brake failure in a car barreling down a mountain,nthe neural control exerted by the vagusnnerve fails and the production of TNF goes out of control. The VNS system by SetPointnaims to restore the vagusnnerve signals that are missing in the patients and reestablish safe level ofnTNF.

ThenCAP signal in the vagusnnerve targets:

?splenicnmacrophages and circulating leukocytes through interfacing with the splenicnnerve and a specialized subset of acetylcholine producing T-cells.

?intestinalnmacrophages and dendritic cells through interfacing with nerves of the entericnnervous system.

FornRheumatoidnArthritis:

Atnleast two major effects of this neural mechanism prevent tissue injury: decreasednrelease of TNF and other proinflammatoryncytokines andndecreasednexpression of adhesion molecules, HLA-DR, and other activationnmarkers on monocytes as they transit the spleen en route to the joints or sitenof inflammation.

FornCrohn』s:n

Vagusnnerve stimulation in patients with inflammatory bowel disease may functionnthrough dual mechanisms, including the spleen pathway asnin rheumatoid arthritis, and also by directly modulating inhibitoryncholinergic neural signals to the intestine. Cytokine-producing cells thatnexpress α7 nAChRnreside in the intestinal villi, where they lie in close proximity tonacetylcholine-producing neurons that are regulated by vagusnnerve signals.

除了上述這些需要進行植入的迷走神經電刺激器械，還有一些用於治療偏頭痛的非植入性神經電刺激產品：

Mechanism of Action for electroCore:

The system delivers proprietary electrical signals (pentawave?) to the vagus nerve which activates specific afferent fibers in the vagus nerve bundle, causes the release of inhibitory neurotransmitters within the central nervous system, and reduces the over expression of the excitatory neurotransmitter glutamate.

Mechanismnof Action for Cerbomed:

Transcutaneous vagus nerve stimulator NEMOS consists of a stimulation unitnand a dedicated ear electrode. It uses the fact that a branch of the vagus nerve can be stimulated throughnthe skin (transcutaneous) with electrical impulses, in areas of the outer ear.nThis stimulation passes along particular nerve fibers to reach the brainstemnand activates higher centers of the brain associated with an anticonvulsiven(anti-seizure) effect.The recommended daily stimulationndose is 4 hours and should be reached daily.

目前其他主要的神經電刺激產品研發公司如下：

這個領域未來還有很多路要走，但其前景一定十分廣闊，值得保持關注。