리뷰 논문 Acupuncture Effect and Central Autonomic Regulation - 수련의

[문형철]

neuromodulation에 대한 탐구가 이어지고 있음.

침치료로 자율신경계의 균형을 잡아 많은 내과질환, 대사질환을 치료할 수 있다는 리뷰논문

panic bird..

Acupuncture is a therapeutic technique and part of traditional Chinese medicine (TCM). Acupuncture has clinical efficacy

on various autonomic nerve-related disorders, such as cardiovascular diseases, epilepsy, anxiety and nervousness, circadian rhythm disorders, polycystic ovary syndrome (PCOS) and subfertility. An increasing number of studies have demonstrated that acupuncture can control autonomic nerve system (ANS) functions including blood pressure, pupil size, skin conductance, skin temperature,muscle sympathetic nerve activities, heart rate and/or pulse rate, and heart rate variability. Emerging evidence indicates that acupuncture treatment not only activates distinct brain regions in different kinds of diseases caused by imbalance between the sympathetic and parasympathetic activities, but also modulates adaptive neurotransmitter in related brain regions to alleviate autonomic response.This review focused on the central mechanism of acupuncture in modulating various autonomic responses, which might provide neurobiological foundations for acupuncture effects.

- 침치료는 다양한 자율신경 관련 질환 "심혈관질환, 간질, 불안, 긴장, circadian 리듬 질환, polycystic ovary syndrome, subfertility 등에 효과가 있다고 연구되고 있음. 

- 많은 연구에서 침치료는 자율신경계 기능을 조절할 수 있어 혈압, 동공크기, 피부 전도, 피부온도, 근육 교감신경 활성, 심장박동수 등을 조절함. 침치료는 교감신경과 부교감 신경사이 불균형에 의해 유발되는 질환에서 서로다른 명백한 대뇌영역 활성화뿐 아니라 적응성 신경전달물질의 조절을 통해 교감신경 반응을 완화할 수 있음. 이 논문은 침치료가 다양한 자율신경 반응을 조절함에 초점을 맞추고 있음. 

1. Introduction

Acupuncture has been practiced for over 3000 years with

beneficial clinical effects on many disorders [1]. There is

sufficient evidence of the value of acupuncture to expand

its application into conventional medicine and to encourage

further studies of its physiological and clinical values

[2]. According to traditional Chinese medicine (TCM),

“acupuncture is believed to restore the balance between

Yin and Yang.” This can be translated into the Western

medicine terminology as “acupuncturemodulates the imbalance

between the parasympathetic and sympathetic activity

[3].” Acupuncture has been effectively used in various

autonomic nerve-related disorders, such as cardiovascular

diseases, epilepsy, anxiety and nervousness, circadian rhythm

disorders, polycystic ovary syndrome (PCOS), and subfertility

[4–8]. It could influence some known indicators of

autonomic activities, such as blood pressure [9–11], pupil size

[12], skin conductance [13], skin temperature [14], muscle

sympathetic nerve activities [15], heart rate and/or pulse

rate [16], and heart rate variability [17, 18]. Acupuncture

has been proposed to treat autonomic nerve-related diseases

through modulating the imbalance between the sympathetic

and parasympathetic activities [19]. Previous study has shown

that changes in parasympathetic nervous activity are correlated

with the amount of De-Qi (i.e., arrival of Qi) sensations

during acupuncture manipulation [20]. On the other hand,

the affecting degree of acupuncture on the autonomic nerve

is still unknown because part of the acupuncture effects is

dependent on the De-Qi sensation [21].

A literature review was conducted using PubMed,

EBSCOhost, and the China National Knowledge Infrastructure

(CNKI). Keywords used in the searching were “acupuncture,”

“brain” or “cerebrum” and “sympathetic,” “vagus,” “autonomic,”

or “parasympathetic.” Articles were collected from

December 2007 to present in each database.Theidentified 44

publications in this search were related to acupuncture basic

study and central autonomic regulation. Among these 44

articles whichmet the criteria, 35 articles are in English and 9

articles are in Chinese. In this review, the underlying central

mechanism of acupuncture-induced autonomic modulation

is discussed based on basic studies that have been published

in the past 5 years.We will, in particular, focus on two aspects

as follows: (1) the brain region which plays an important role

in initiating autonomic responses during acupuncture; (2)

neurohumoral autonomic modulation of acupuncture in the

central autonomic nerve system (ANS).

2. Acupuncture Effect and Central

Autonomic Structures

Several studies have demonstrated that the autonomic

dimension of the acupuncture stimulation was mediated by

a mesencephalic and brainstem network [22, 23] (Figure 1),

which is comprised of the hypothalamus, medulla oblongata,

ventrolateral periaqueductal gray, and the dorsomedial prefrontal

cortex.All of these areas are involved in the autonomic

regulation [24–26].

2.1. Hypothalamus. Hypothalamus is the most important

brain center that controls the ANS [27]. As the site of

autonomic regulation, hypothalamus has been proved to be

involved in the pathway of electroacupuncture (EA) attenuating

sympathetic activity. Impulses generated in sensory

fibres in the skin connect with interneurons to modulate

activities of the motoneurons hypothalamus to change

autonomic functions [28]. Increased sympathetic activity

in hypertension may act as a stimulus for nitric oxide

(NO) release in the hypothalamus. EA application on ST36

could effectively modulate the activity and expression‎ of

neuronal nitric oxide synthase (nNOS) in the hypothalamus

of spontaneously hypertensive rats (SHR). The effect may

through its connections to sympathetic and parasympathetic

nervous system and also through its control of endocrine

organs [29]. However, which part of the hypothalamus that

participates in the mechanism of action is still remained

unclear. Effects on decreased neuropeptide Y (NPY) production

due to stimulation on the paraventricular nucleus

(PVN) of hypothalamus [30] is one of the several hypotheses

which have been proposed in the literature regarding

the action mechanism. The PVN of hypothalamus is

a cell group that plays an important role in the regulation

of sympathetic vasomotor tone and autonomic stress

responses [31, 32]. Acupuncture could decrease NPY [33]

and corticotropin-releasing hormone [34] expressions in

the PVN and produce some specific effects on suppressing

the sympathetic outflow in response to chronic stressors

[35].

Arcuate (ARC) nucleus projects to other brain regions

that regulate the sympathetic outflow include the dorsomedial

hypothalamus, midbrain periaqueductal grey, rostral

ventrolateral medulla (rVLM), and the nucleus of the

solitary tract [36]. Neurons in the ARC nucleus projecting

to the rVLM potentially participate in EA inhibition of

reflex cardiovascular sympathoexcitation [37]. Ventrolateral

periaqueductal gray (vlPAG) projections from the ARC are

required for EA regulation of sympathoexcitatory presympathetic

rVLM activity and the cardiovascular excitatory

reflex responses, while a direct pathway between the ARC

and rVLM might serve as a source of endorphins for EA

cardiovascular modulation.

2.2. Medulla Oblongata. Specific regions of the medulla

oblongata mediate central control of autonomic function. In

the central nervous system (CNS), the rVLM is an important

part of the sympathetic efferent limb of cardiovascular reflex

activity and, as such, it is important in the maintenance of

arterial blood pressure [38]. It projects to the intermediolateral

columns of the thoracic spinal cord, which is the origin

of sympathetic preganglionic neurons [39]. Inhibition of

neuronal function in this nucleus results in large decreasing

of blood pressure [40]. EA could inhibit cardiovascular

autonomic responses through modulating rVLM neurons

[41, 42]. Moreover, opioids and gamma-aminobutyric acid

(GABA) participate in the long-term EA-related inhibition

of sympathoexcitatory cardiovascular responses in the rVLM

[43]. Activation of the nucleus raphe pallidus (NRP) attenuates

sympathoexcitatory cardiovascular reflexes through

a mechanism involving serotonergic neurons and 5-HT1A

receptors in the rVLM during EA. Serotonergic projections

from the NRP to the rVLM contribute to the EAcardiovascular

responses [44].

The nucleus ambiguus (NAmb), located in the ventrolateral

division of the hindbrain, is considered to be an  important site of origin of preganglionic parasympathetic

vagal motor neurons that ultimately regulate autonomic

function through the releasing of acetylcholine [45]. The

recent study of that neurons colabeled with c-Fos and choline

acetyltransferase (ChAT) were activated in the EA-treated

animals instead of sham EA group indicates that someNAmb

neurons activated by EA are preganglionic vagal neurons

[18]. It is suggested that stimulation on a special acupoint

is crucial to achieve modulate effect on autonomic function

by activating NAmb neurons. It is consistent with TCM

theory that genuine acupoints treatment is more effective

than nonacupoints treatment based on specific physiological

effects related to meridians and collections of meridian Qi .

2.3. Midbrain.  Ventrolateral periaqueductal gray (vlPAG) is

an essential midbrain nuclei that process information from

somatic afferents during EA [46]. Caudal vlPAG is a significant

region in the long-loop arcuate-rVLM pathway for the

EA-cardiovascular response, while the rostral vlPAG plays a

major role in the reciprocal arcuate-vlPAGpathway that helps

to prolong EA-cardiovascular modulation [47]. Excitation of

vlPAG neurons enhances the arcuate response to splanchnic

stimulation, while blockade of vlPAG neurons limits excitation

of arcuate neurons by EA. These observations indicate

that EA-induced excitation of arcuate neurons requires input

from the vlPAG, and the reciprocal reinforcement between

themidbrain and the ventral hypothalamus serves to prolong

the influence of EA on the baseline blood pressure [48].

2.4. Dorsomedial Prefrontal Cortex (DMPFC).  Theprefrontal

cortex (PFC) is vital for mediating behavioral and somatic

responses to stress in the autonomic centers via projections

[49]. A near-infrared spectroscopy (NIRS) study found that

the rightPFC activity predominantlymodulated sympathetic

effects during a mental stress task [50]. Acupuncture stimulation

might decrease sympathetic activity and increase

parasympathetic activity through its inhibitory effects on dorsomedial

PFC activity [51]. This might be beneficial to treat

chronic pain induced by hyperactivity of the sympathetic

nervous system. However, Sakatani et al. found no significant

correlation between the PFC activity and ANS function

during acupuncture. One of the possible explanations of the

poor correlationsmight be that the PFC activity induced by

acupuncture is not closely linked with ANS function [52].

3. Acupuncture Effect and

Neurohumoral Modulation

 Some neurotransmitters, including serotonin, opioid peptides,

catecholamines, and amino acids in the brain appear to

be participated in themodulationmechanism of acupuncture

for certain ANS [53, 54].

3.1. Endogenous Opioids.  EA was able to restore the impaired

gastric motility and dysrhythmic slow waves by enhancing

vagal activity, which was mediated via the opioid pathway

[55, 56]. Ameliorating effects of EA at ST-36 on gastric

motility might activate the central opioids that, in turn,

inhibit sympathetic outflow [57]. Although acupuncture

produced significant heart rate decreases in pentobarbitalanesthetized

rats, this response is related to the activation

of GABAergic neurons instead of opioid [58]. This opinion

is proved by another study, which indicates that an opioid

receptor-mediated transmission is not responsible for

the present bradycardiac response induced by acupuncturelike

stimulation [59]. These views suggest that acupuncture

treatment on different diseases may be mediated by different

neurotransmitters, which is in accordance with holistic view

of acupuncture treatment in TCM theory.

EA activates enkephalinergic neurons in several brain

areas that regulate sympathetic outflow, including the arcuate

nucleus, rostral ventrolateral medulla, raph´e nuclei, among

others [60, 61]. Consistent with this, Li et al. [62] found

that EA at P5-P6 transiently stimulates the production of

enkephalin in a region of the brain, which regulates sympathetic

outflow. It is suggested that a single brief acupuncture

treatment can increase the expression‎ of this modulatory

neuropeptide.The 𝛽 -endorphin is a key mediator of changes

in autonomic functions [63]. Acupuncture may hypothetically

affect the hypothalamic-pituitary-adrenal (HPA) axis

by decreasing cortisol concentrations and the hypothalamicpituitary-

gonadal (HPG) axis by modulating central 𝛽 -

endorphin production and secretion [64]. Some reports

have also shown that a negative perception of acupuncture

might produce enhanced sympathetic activation to the

acupuncture stimulus [65], which may be mediated through

endorphin pathway [66]. It is conceivable that a specific

neuroendocrine-immune network is crucial to the produce of

acupuncture therapeutic effect. Further studies are required

to reveal involved molecules and underlying mechanisms.

3.2. Amino Acids.  Amino acid sensors could regulate the

activity of vagal afferent fibers [67]. Amino acids are directly

involved in signaling the vagus pathway in the ARC [68].

Recent studies have shown that vesicular glutamate transporter

3 (VGLUT3) in the ARC neurons [69, 70] and

vlPAG [60, 71] were activated by EA at the P5-P6 acupoints.

Glutamate only partially but significantly contributes to the

activation of ARC-vlPAG reciprocal pathways during EA

stimulation of somatic afferents [47]. In addition, reduction

of GABA release disinhibits vlPAG cells, which, in turn,

modulates the activity of rVLM neurons to attenuate the

sympathoexcitatory reflex responses [46]. EA modulates the

sympathoexcitatory reflex responses by decreasing the release

ofGABA in the vlPAG[43], most likely through a presynaptic

CB1 receptor mechanism [72]. Studies conducted so far on

amino acids suggest that glutamate and GABA are involved

in the mechanism of acupuncture for autonomic alteration.

This response is closely related to vlPAG.

3.3. Nerve Growth Factor (NGF).  TheNGF is a neurotrophin,

which regulates the function and survival of peripheral

sensory, sympathetic, and forebrain cholinergic neurons. It

couldmodulate sensory and autonomic activity as amediator

of acupuncture effects in the CNS [73]. The therapeutic

potential of EA could modulate the activity of the ANS

by a long-lasting depression of the sympathetic branch,  which is associated with a peripheral downregulation of

NGF in organs. Manner˚as et al. [74] found that EA could

effectively improve PCOS-related metabolic disorders, alter

sympathetic markers [75], and normalize the DHT-induced

increase of mRNANGF . The data on EA/NGF interaction in

PCOS models further suggested that the decrease of NGF

expression‎ in peripheral organs could benefit EA to modulate

the activity of the ANS [76]. Although NGF in organs has

been proved to be associated with the acupuncture effect on

ANS, there is a lack of sufficient evidence to demonstrate the

relationship between acupuncture effect and NGF in central

autonomic nerve system. 

4. Conclusion

 Emerging evidence indicates that acupuncture treatment not only activates distinct brain regions in different kinds of diseases caused by imbalance between the sympathetic and parasympathetic activities, but also modulates adaptive neurotransmitter in related brain regions to alleviate autonomic response. However, it is not clear whether different pathway is activated by specific acupoint, such as local points and distant points, or the autonomic regulation effect of acupoints from differentmeridians. Further rigorous RCTs are required for the study of this topic. It enables us to understand the importance of acupuncture therapy in the autonomic regulation. Then, acupuncture can be used in the treatment of various autonomic disorders as a novel alternative therapy.