Scientific theories regarding acupuncture
Numerous scientific studies have been conducted concerning the principles underlying the mechanism of action and efficacy of acupuncture.

# Scientific theories
A number of scientific theories have been proposed to account for the principles of action in acupuncture therapy.

## Nerve-reflex theory
The nerve-reflex theory (developed by Ishikawa and Fujita et al. in the 1950s) proposed the reflex interactions between the periphery and the autonomic nervous system. The skin (cutaneous) surface and internal organs (visceras) are intimately connected by these reflexes  "viscera-cutaneous reflex" and "cutaneous-viscera reflex." Abnormalities of the internal organs can manifest themselves in the body surface (such as spasms, redness and referred pain (e.g., heart attack is felt as chest pain on the skin but not heartache in the heart)) through the "viscera-cutaneous reflex." At the same time, stimulation of the body surface (such as skin or muscle) can cause vasodilation or vasoconstriction that changes the blood and lymph flow of the internal organs, activating the endocrine (hormonal) and immune systems via the "cutaneous-viscera reflex."
These reflexes can be related to the neuroendocrine-autonomic responses, which is mediated partly by the hypothalamic-pituitary-adrenal axis (HPA axis). HPA axis is a complex set of feedback interactions between the hypothalamus (located in the midbrain), the pituitary (located beneath the brain) and the adrenal glands (located in the kidneys). The HPA axis is a major part of the neuroendocrine system that regulates stress responses and maintains the homeostatic condition of autonomic responses directly or indirectly, such as circulation regulation, breathing regulation, feeding behavior, weight control and digestion, immune responses, pain responses, acute stresses and chronic stresses, mood states, sexual/reproductive responses, growth, fluid balance and metabolic energy balances.
Recently, a broad sense hypothalamus-pituitary-adrenal (BS-HPA axis) model was proposed to confirm the analgesic effect of acupuncture based on observed neuroimaging (brain scanning) results using fMRI (functional resonance magnetic imaging) technique. The model incorporated the stress-induced HPA axis model together with neuro-immune interaction including the cholinergic anti-inflammatory model. The results, coupled with accumulating evidence, suggested that the central nervous system (CNS) is essential for the processing of these acupuncture-induced effects via its modulation of the autonomic nervous system (ANS), neuroimmune system and hormonal regulation.
These responses all require complex feedback cycles, including positive feedback and negative feedback where perturbations in any part of the system can result in major re-adaptation of the system. Thus, acupuncture is considered as a systemic stimulation therapy activating these autonomic reflexes to restore the homeostatic balance of the body via the neuroendocrine and immune systems. In systems theory, a dynamical system is a system that responds to these perturbations using these feedback loops for adaptation because a real-world system is constantly confronted with perturbations; breaking these feedback loops can often result in uncontrollable conditions (called disease state in biology and medicine). (For example, the uncontrollable movement in Parkinson's disease is due to the feedback loop being broken by the degenerated dopamine neurons in the basal ganglia in the brain.)
Theory of control systems also shows that small changes to the system could result in profound changes to the overall system because every part of the system will have to re-adjust to the new conditions. Muscle cramp is a classic example to show how such feedback system operates in the body by the pain reflex neural circuitry. When muscle spasms contract the muscle, pinching the nerve as a result, the pain signal is sent to the spinal cord, which responds with contracting the muscle further, causing more pain, and results in a vicious cycle in this pain-reflex loop. Such cramp can be relieved by simply stretching the muscle, which results in reducing the pain signal from the pinched nerve, and the spinal cord would respond by reducing its contraction signal to the muscle, and eventually stops the uncontrollable cramp automatically. This shows a small stimulus (a simple stretch) can produce profound re-adaptation in the body, stopping both pain and muscle cramp simultaneously.

## Gate-control theory of pain
The "gate control theory of pain" (developed by Ronald Melzack and Patrick Wall in 1962 and in 1965) proposed that pain perception is not simply a direct result of activating pain fibers, but modulated by interplay between excitation and inhibition of the pain pathways. The "gating of pain" is controlled by the inhibitory action on the pain pathways. That is, the perception of pain can be altered (gated on or off) by a number of means physiologically, psychologically and pharmacologically. The gate-control theory was developed in neuroscience independent of acupuncture, which later was proposed as a mechanism to account for the analgesic action of acupuncture in the brainstem reticular formation by a German neuroscientist in 1976. (With the advance in modern-day technology, stimulation of these pathways can be demonstrated to alter pain perception using electrical stimulations or magnetic stimulations, such as transcranial magnetic stimulation (TMS) or pulsed electromagnetic field (PEMF) therapy for pain.)
It is well-documented in neuroscience that pain blockade can be achieved at multiple levels in the central nervous system (i.e., the brain and spinal cord). At the spinal cord level, pain transmission via the pain fibers can be blocked by surround inhibition of the neighboring nerve fibers that merge at the substantia gelatinosa in the spinal cord. That is to say, stimulation of the surrounding neurons can cause a reduction of pain when the center excitatory pain fibers are inhibited by the surrounding cutaneous (touch) fibers. This phenomenon is an all-too-common experience that, when we bump our head, pain can be relieved by rubbing the surrounding skin area (activating the surround inhibitory neural circuitry physiologically). Blockade of pain at this level suppresses the physical pain (i.e., hurt) rather than the emotional pain (i.e., suffering) because it blocks the pain signal from the periphery. Furthermore, pain blocking by this cutaneous stimulus only lasts for a short period of time, whereas the effect of pain relief by acupuncture lasts for an extended period of time, sometimes months after the needle was removed.
This leads to the theory of central control of pain gating, i.e., pain blockade at the brain (i.e., central to the brain rather than at the spinal cord or periphery) via the release of endogenous opioid (natural pain killers in the brain) neurohormones, such as endorphins and enkephalins (naturally occurring morphines).

## Neurohormonal theory
Pain transmission can also be modulated at many other levels in the brain along the pain pathways, including the periaqueductal gray, thalamus, and the feedback pathways from the cortex back to the thalamus. Each of these brain structure processes different aspect of the pain  from experiencing emotional pain to the perception of what the pain feels like to the recognition of how harmful the pain is to localizing where the pain is coming from. Pain blockade at these brain locations are often mediated by neurohormones, especially those that bind to the opioid receptors (pain-blockade site). Pain relief by morphine drug (exogenous opioid) is acting on the same opioid receptor (where pain blockade occurs) as endorphins (endogenous opioids) that the brain produces and releases.
The discovery of endorphins and opioid receptors in the 1970s played a key role in establishing the validity of acupuncture in mainstream science. Analgesic (pain-killing) action of acupuncture was demonstrated to be mediated by stimulating the release of natural endorphins in the brain. This can be proven scientifically by blocking the action of endorphins (or morphine) using a drug called naloxone. When naloxone is administered to the patient, the analgesic effects of morphine can be reversed, causing the patient to feel pain again. When naloxone is administered to an acupunctured patient, the analgesic effect of acupuncture can also be reversed, leaving the patient with intense pain again. This demonstrates that the site of action of acupuncture is mediated through the natural release of endorphins by the brain, which can be reversed by naloxone. Similar results were also obtained in experiments with animals showing that the analgesic effect is not due to subjective psychological placebo effect, but real physiological phenomenon. Such analgesic effect can also be shown to last more than an hour after acupuncture stimulation by recording the neural activity directly in the thalamus (pain processing site) of the monkey's brain. Furthermore, there is a large overlap between the nervous system and acupuncture trigger points (points of maximum tenderness in myofascial pain syndrome).
The sites of action of acupuncture induced analgesia are also confirmed to be mediated through the thalamus (where emotional pain/suffering is processed) using modern-day powerful non-invasive fMRI (functional magnetic resonance imaging) and positron emission tomography (PET) brain imaging techniques, and via the feedback pathway from the cerebral cortex (where cognitive feedback signal to the thalamus distinguishing whether the pain is noxious (painful) or innocuous (non-harmful)) using electrophysiological recording of the nerve impulses of neurons directly in the cortex, which shows inhibitory action when acupuncture stimulus was applied.

## Electric conductance theory

### Surface bioelectric field
Understanding of the biological mechanisms underlying the meridian system and acupuncture points requires knowledge of biophysics and mathematical theory. Most cells in the body are electrically charged. The most well-known cells that use electrical charge for their function are neurons, which generate electrical nerve impulses (action potentials) for communication among neurons. Neurons can generate 70 mV voltage difference across the cell membrane. Other cells such as glial cells (that support the function of neurons) are also electrically charged.
Of particular important to acupuncture is that epithelial cells, which are also electrically charged. These epithelial layers (that line the body surface or organs) maintain a 30-100 mV voltage difference across themselves (i.e., across cell layers, not across individual cell's membrane). This gives rise to the phenomenon that there are electrically conducting pathways in the body that are not necessarily identifiable distinctly by morphology. Unlike the nervous system, where the electrical pathways are localized anatomically by nerve fibers, these electrically conducting pathways do not have any anatomical/morphological structure associated with them because they are electrical in nature. That is why these amorphic bioelectric fields within the body had been ignored or undiscovered until recently.

### Electric conductance
To understand these phenomena, electric conductance is crucial to reveal the underlying mechanism of action that promotes many biological processes, such as cell growth, cell repair, cell and nerve regeneration, morphogenesis, etc. (Electrical conductance is a term used to quantify the opposite of electrical resistance. Insulators, such as plastic, have high electrical resistance because they resist the passage of electricity, which is why they are called "electrical resistance." On the other hand, metal wires and salt water have high electrical conductance because they "conduct" electricity easily (rather than resisting it).)
Body fluid that fills the space between cells also tends to be highly conductive electrically, even though they don't form any distinct structure in the body. Therefore, electrical conductance is essential in identifying the electrical pathways in the body that do not have any physical appearance.
Furthermore, gap junctions between cells are the locations where two cells are connecting with each other electrically, promoting the flow of electricity between them. These are microscopic structures that cannot be seen macroscopically or easily identified as anatomical pathways, and are often ignored by most casual observers.

### Role of electric field in directing growth and morphogenesis
There is a variety of cells that are sensitive to electric fields of physiological strength. For instance, somite fibroblasts migrate to the negative pole in a voltage gradient as small as 7 mV/mm. Asymmetric calcium influx is crucial in this migration, which can be blocked or even reversed by calcium channel blockers and ionophores.
Cell growth are often enhanced toward cathode (positive pole) while reduced cell growth toward anode (negative pole) in electric fields of physiological strength. Fast growing cells tend to have relative negative polarity, attracting to the positive electric field. Thus, cells tend to grow toward positive electric field. The negative polarity in growing cells is created by the increased negative membrane potential generated by the mitochondria at high rate of energy metabolism.
The direction of growth pattern in lower animals can be reversed by imposing an electric field, creating a polarization of blastomeres, resulting in a reversal of anterior-posterior polarity and dorsal-ventral polarity in animal morphogenesis (cell growth, differentiation and development).
This shows how cell growth and repair can be directed and re-directed by electric fields, following along the path of electric conductance and strong electric field strengths. The importance of electric field in cellular function leads to the identification of these crucial morphogenetic singular points in the body, as well as the understanding of why reversing the electrical polarity of the electrode in electroacupuncture can produce opposite effect in the body.

## Morphogenetic singularity theory
"Morphogenetic singularity theory" was developed over the last two decades to explain the cellular mechanisms in acupuncture that is beyond the neurohumoral theory.
Understanding the concept of convergence and divergence in a system is crucial to appreciate how acupuncture points are chosen at strategical locations to alter specific bodily functions. A convergent system is a "stable" system where all things will naturally merge/flow into the same point. A valley or a well is a good example. It will always lead to a stable equilibrium because water will automatically sink to the bottom and stay there. In contrast, a divergent system (such as a separatrix) is an "unstable" system where things can go either way. A ridge or a peak is an example. It will lead to instability because water can't stay there for long, it will flow to either side of a mountain with no way to predict which side it may fall. A separatrix is essentially a ridge that separates a continental divide into two watersheds; once water starts falling down one side, there is no point of return, and water cannot go back to the other side.
Electric current flows similarly, which means the body will respond very differently depending on whether acupuncture stimulation is applied to an electrical ridge (separatrix) or a sink hole (singular point), and may have no effect if applied to a flat plain (non-trigger point).

### Singular points in bioelectric field
Acupuncture points have high density of gap junctions and local maximum for electrical conductance. That is, they allow the most electricity to pass through with ease compared to the surroundings. They have the maximum electric current density in a region, serving as a converging point of surface current. It is a singular point of abrupt change in electric current flow. (A "singular point" is a point of discontinuity as defined in mathematics.) It indicates an abrupt transition from one state to another. Thus, small perturbations around singular points can have decisive (crucial) effects on a system (or the body).

### Electrical singular point and acupuncture points
It can be shown that acupuncture point GV20 Baihui is a "singular point" at the surface magnetic field using SQUID (Superconducting QUantum Interference Device) to detect the pattern of electromagnetic field on the human scalp. It shows that it is the location where the surface magnetic flux trajectories converge and enter the inside of the body.
The midline Governor Vessel meridian is a converging pathway for magnetic flux (magnetic flow) on the scalp, and also a separatrix which divides the surface magnetic field into two symmetrical domains of different flow directions. A separatrix is a trajectory or boundary between spatial domains in which other trajectories have different behavior.

### Morphogenetic singularity theory and the meridian system
Morphologically, the Governor Vessel is also the axis of symmetry on the scalp. That is, it divides the scalp into two symmetrical flow patterns (like a continental divide dividing two watersheds). This pattern is consistent with the pattern of the meridian system, but different from the distribution of any major nerve, lymphatic or blood vessel on the scalp because it is amorphic (with no shape or form) electrical pathway, flowing along the path of least resistance. This morphogenetic singularity theory suggests that the meridian system is related to the bioelectric field in morphogenesis and growth control.
Thus, meridian signal transduction is embedded into the activity of other physiological systems. It is suggested acupuncture may activate these bioelectrochemical oscillations for signal transduction since many other non-excitable cells have electrochemical oscillations for long-range intercellular communication.

# Mechanisms of action

## Organizing centers, electric conductance points and acupuncture points
Acupuncture points are high electric conductance points on the body surface highly correlated with "organizing centers" in cellular development. Organizing centers are the regions where a small group of cells determines the fate how cells will develop within that region. (Example of organizing centers can be found in the embryonic amphibian blastopore  the classic organizing center which has high electric conductance and current density. Higher vertebrates also have similar organizing center with high electric conductance and density and high gap junction density.)
At the macroscopic level, organizing centers are singular points in the morphogen gradient and electromagnetic field. Any disruption of electric field at these organizing centers can cause malformation. Changes in electric activity at the organizing centers often precede morphological changes, which are also correlated with acupuncture stimulation. (For example, in embryonic development, outward current can be detected at the limb bud (embryonic future-limb outgrowth)  an organizing center  several days before the first cell growth.)
Various stimuli (such as mechanical injury and injection of chemicals) can also induce morphogenesis (cell growth and repair) at organizing centers. Thus, therapeutic effect of acupuncture can be achieved by a variety of stimuli applied to these organizing centers either mechanically with a needle or electrically with an electrode in electroacupuncture.

### Origin of meridian system
The origin of meridians can be traced back to the undifferentiated cell differentiation in embryonic development. Meridians are separatrices to an under-differentiated interconnected cellular network that regulates growth and physiology. At early stages of embryogenesis, gap junction-mediated cell-cell communication is usually diffusely-distributed, which results in the entire embryo becoming linked as a syncytium. As development progresses, gap junctions become restricted at discrete boundaries. This leads to the subdivision of the embryo into communication compartment domains.

### Meridian system and separatrix-boundary between muscle groups
These boundaries are major pathways of bioelectric currents, and divide the body into domains of different electric current directions. Separatrices can be folds on the surface or boundaries between different structures, and often connect singular points. The attributes of separatrix is consistent with the observation in the classic view of Nei Jing (prenatal/inborn) that meridians lie at the boundaries between different muscles or along conductive paths of connective tissues.
For example, part of the Lung Meridian runs along the borders of biceps and brachioradialis muscles. Part of Pericardium Meridian runs between palmaris longus and flexor carpi radialis muscles. Part of Gallbladder Meridian runs between sternocleidomastoid and trapezius muscles. Trigger points also tend to locate at the boundaries of muscles.
The midline posterior meridian (Governor Vessel)and the midline anterior meridian (Conception Vessel) are the axes of symmetry of the body surface and the boundaries of many different structures. They are also regarded as the convergence of all meridians in traditional acupuncture. It is consistence with the under-differentiation of the meridians that most apical (tip) part of folds in embryos remain undifferentiated in morphogenesis, including organizing centers such as apical ectodermal ridge.

### High density of acupuncture points: auricles, convex and concave points
Distribution of acupuncture points and organizing centers is closely related to the morphology of the body. In particular, the auricle (ear lobe) has the most complex surface morphology, and also has the highest density of acupuncture points. Although an auricle has no important nerves or blood vessels, and it has no significant physiological function other than sound collection, abnormality in its morphology is one of the most sensitive signs of malformations in other organs. Auricular malformation has been observed in many clinical syndromes, including Turner syndrome, Potter syndrome, Treacher-Collins syndrome, Patau syndrome, Edwards syndrome, Noonan syndrome, maternal diabetes, atherosclerosis, Goldenharr syndrome, Beckwith syndrome, DiGeorge syndrome, Cri-du-chat syndrome and fragile X syndrome. Standard textbook of pediatrics suggests any auricular anomaly should initiate a search for malformations in other parts of the body.
Based on the phase gradient model in developmental biology, many organizing centers are at the extreme points of curvature on the body surface, such as the locally most convex points (e.g., the apical ectodermal ridge and other growth tips) or concave points (e.g., the zone of polarizing activity). Similarly, almost all the extreme points of the body surface curvature are acupuncture points.
Examples of convex points are: EX-UE11 Shixuan, EX-LE12 Qiduan, ST17 Ruzhong, ST42 Chongyang, ST45 Lidui, SP1 Yinbai, SP10 Xuehai, GV25 Suliao, EX-HN3 Yintang.
Examples of concave points are: CV17 Danzhong, KI1 Yongquan, LI5 Yangxi, LU 5 Chize, LU7 Lieque, LU8 Jingqu, LU10 Yuji, SI19 Tinggong, TE21 Ermen, GB20 Fengchi, GB30 Huantiao, BL40 Weizhong, HT1 Jiquan, SI18 Quanliao, BL1 Jingming, CV8 Shenque, ST35 Dubi.

## Long-term biological effects of acupuncture
Long-term effects induced by acupuncture can be observed in gene expression in many areas of the brain and spinal cord. An increase of gene expression of proto-oncogene c-fos for adrenocorticotropic hormone (stress hormone) and endorphin (pain-killer) can be found in both hypothalamus and pituitary. This demonstrated the long-term effect of activating the hypothalamo-pituitary-adrenocortical HPA axis (see above) by acupuncture in response to stress and pain. Gene expression induced by acupuncture is also found in numerous brainstem nuclei (including periaqueductal gray, involved in pain gating, and locus coeruleus, implicated in stress, anxiety and heroin withdrawal) and in the spinal cord (including the dorsal horn, involved in pain transmission). This demonstrated the long-term effect of acupuncture-induced changes in the brain in response to pain-regulation and other autonomic regulations.

# Diagnostic vs. treatment models

## Unifying Ryodoraku diagnostic model and meridian system
Ryodoraku (ryo = good, do = electro-conductive, raku = line) system (developed by Yoshio Nakatani in Japan) is a lesser-known meridian system similar to the traditional meridian system. It is a set of highly electrically conductive points (low electrical resistance) running longitudinally up and down the body. It is discovered independently by physiological measurements of skin conductance rather than by traditional acupuncture dogmas (such as yin, yang or qi). It is considered as contemporary Asian medicine (CAM) rather than traditional Oriental medicine.

### History of Ryodoraku system
In 1950, Nakatani discovered that there is a series of points in which electroconductivity was higher than the surrounding area when he measured the skin resistance of edematous patient with nephritis (a kidney disorder). This happened to match the acupuncture Kidney Meridian. He subsequently called these meridian lines, Ryodoten, points of lowered electrical resistance, or electro permeable points (EPP).
He was the first person to measure the electrical activity of acupuncture points, and first to use electrical stimulation to stimulate acupuncture points. In 1966, he introduced a new method of detecting meridian abnormalities, and was the first to formulate diagnostic and treatment criteria (called Ryodoraku Treatment) from these objective measurements that are reflected as autonomic unbalance in skin conductance measurements. He invented the neurometer to measure the skin conductance by injecting small electrical current pulse through the probe into the skin. The computerized version of the instrument is renamed as Electro Meridian Imaging (EMI) or Electronic Pulse Diagnosis.
Coincidentally, changes in skin conductance is also used as one of the criteria used in lie detectors. Lie detectors work by the principle that when someone lies, it usually elicits an autonomic response resulting in sweating (a Galvanic skin response recorded as a change in skin conductance). Polygraph machines essentially measure physiological parameters (skin conductance, heart rate, respiratory rate and blood pressure) that correspond to an anxiety state in lying when asked a pointed question. This shows how stress can trigger immediate responses that interrelate the brain, visceras (internal organs) and the skin by the autonomic nervous system.
The difference between the skin conductance change in lie detection and Ryodoraku measurement is that acupoints are localized in very small, discrete points whereas sweating can occur in any large part of the skin that has sweat glands for lie detection. Furthermore, lying often produces an immediate change in skin conductance via the autonomic nervous system whereas the conductance at acupoints doesn't often change instantly at resting state.

### Localization of acupoints by Ryodoraku skin conductance measurements
A mathematical model of ionic conductance was developed to account for the changes in skin impedance (skin resistance). Recently, an extensive analysis of how electromagnetic field can dissipate inside the body in relation to skin resistance and body conductivity (body fluid compartments) had been worked out theoretically and experimentally. These electrical measurements accounted for the existence of invisible dissipative structure of electromagnetic field that is composed of an interference pattern of standing waves in resonance with the body cavity, consistent with known principles in physics, anatomy, histology, neurology and biochemistry.
Based on the neurometer measurements, Nakatani discovered that most of the traditional acupoints could be located by specific skin conductance more precisely than traditional method, without any knowledge of the complex acupuncture nomenclature, philosophy or mnemonics.

### Diagnostic Ryodoraku skin conductance measurements
Nakatani also discovered that the number of electro permeable points not only varied with disease process but also with the voltage of the detector probe. He also found asymmetric differences between the conductance of the left and right meridians often correspond to disease states in those coresponding internal organs.
Most of the traditional acupoints could be located if current is injected at 21-volt. However if current is injected at 12-volt, there were other electrically conductive points over the body not associated with any specific acupuncture points. He called these Responsive Ryodo-points or reactive electropermeable points (REPPs). These points often correspond to trigger points or Ah Shi (tender to touch) points. He hypothesized that they may be related to the autonomic response and could be indicative of internal disorder or dysfunction. For example, significant difference between the electrical conductance measurements at acupoints can be found in weight reduction.
Thus, Ryodoraku detection and analysis can be applied as an objective, quantifiable method to localize acupoints for electrical stimulation more precisely and empirically, greatly augmenting traditional acupuncture techniques.

# Recent advances
Recent advances in high-tech medical technology also provide robust scientific evidence confirming and verifying the clinical efficacy in acupuncture stimulation. Non-invasive laser needle acupuncture stimulation provides yet another independent method for stimulation that can be quantified by fMRI (functional magnetic resonance imaging technique) and fTCD (functional multidirectional transcranial ultrasound Doppler sonography) and (Doppler perfusion imaging) that demonstrated the increase in microcirculation and cerebral blood flow. True double-blind studies in acupuncture research can be performed using these latest laser technologies where the stimulation cannot be felt by the patients.