Focusing on the mechanism itself can be highly complex. Craver and Bechtel [5] describe four dimensions of mechanisms: (1) a phenomenal dimension—a mechanism does things. For music the human ear offers a basic mechanism illustration. The ear translates compression and decompression of air molecules into the conscious perception of sound. (2) A componential dimension—a mechanism has components. In a simplified description the ear has components including the ear drum, the malleus, incus, stapes, and cochlea that transmit the vibration to the cilia which translate the physical vibration to an electrical signal for the auditory nerve. (3) A causal dimension—components interact to make the phenomenon happen. The components of the ear turn the air compressions into electrical signals transmitted through the auditory nerve to the internal perceptual processing system (a complex mechanism in itself). (4) An organizational dimension—components are organized in space and time. There is a particular organization of the components of the ear and how they interact that causes vibration to be perceived as sound.

The basic question of what are the mechanisms of how people enjoy music illustrates a very important aspect of the challenge of studying mechanisms—the ear is essential in the perception of music but it is only a start to the understanding of the cascade of mechanisms or causes of music enjoyment. That understanding would involve further definition of the auditory nuclei in the brainstem, the role and function of the thalamus, the means of transmission to the auditory cortex, the role of memory in the perceptual process, the interaction of expectation with neurotransmitters like dopamine and their role in the perceived response, and so on. Similarly, the question of how does low frequency sound stimulates blood circulation leads to an examination of endothelial cell response resulting in nitric oxide release and its effect on blood flow and so on.

The crucial point here, and an important caveat for this paper, is that research into the mechanisms of the effect of music on health is nascent and in most cases focused on the most obvious components of what can be presumed to be a complex system [6,7]. This paper will, therefore, attempt to point in the direction of potential mechanisms that appear to be emerging for further study rather than serve as a detailed explication of a set of defined mechanisms.

A starting point to study mechanisms is to try to categorize by type of stimulus and type of response. One of the difficult pivots in the thinking of many health researchers is to differentiate between “music” and “sound vibration” as the stimulus. The bulk of research by cognitive neuroscientists focuses on “music” and often with little control of the parameters of that music since the assumption is that the effect stems only from the cognitive processing of that music [8,9].

Within the broad category of “music” as stimulus, the response focus can be on the general effects like arousal, mood, emotion, relaxation, stress, etc., and with the assumption that these responses result from enjoyment or aversion reactions, memory associations, or some inherent neurological process [8]. All of these responses can be attributed to learned schemas, processes, and associations developed through socially mediated cultural immersion from the very earliest days of exposure to music [10].

A second category of mechanisms within “music” is to look at the effect of music cognition on the activation of neural circuits and specific neural functions. This has been most clearly defined in relation to rehabilitation [11,12].

When music or audible sound is considered for its vibratory (rhythmicity) effects, a third category of response mechanism emerges and its focus becomes primarily cellular [10]. The most basic and oldest use of vibratory effect is the mechanical “shaking” of the body and more recently specific areas and cells. Another more specific category of cellular response is the effect of driving a neural modulatory response. The importance of rhythmic brain activity, and the potential for sensory stimulation to drive it, has not received much attention until recently [13,14]. However, for music as a vibratory phenomenon this is an important mechanism to study.

Fundamental to vibratory effects is the rhythmicity of music. It can be thought of as events per second and seconds per event [15]. When there are more than 16 events per second cognitive event fusion changes from individual event perception to hearing pitch frequencies. The rhythmic stimulation effect on cells, however, continues to be related to the events per second even, for example, at 40 or 60 events per second (Hz). If the events are slower than about 10 s per event, long-term memory may allow perception as functional units of musical form but these will not be heard as individual events. Body rhythm cycles, like the 10 s baroreceptor control loop, may still be response to entrainment by recurring events at this frequency and influence these Mayer waves to release endothelial derived nitric oxide [16]. Between 16 events per second and 10 s per event lies the area where short-term memory allows cognitive perception of the individual events as notes, patterns, or melodic groupings. In this category people align physical movement like running, walking, dancing, foot or finger tapping, or mental tracking with the beat. This category of cognitively tracked rhythmicity has known effects of neural, cardiac, and breath entrainment and is used therapeutically, for example, in rhythmic auditory stimulation (RAS) [11]. However, it also has direct effects on cells through mechanical movement.

This paper will not focus on music as “music”; it will focus exclusively on the rhythmicity of music and sound as vibration. In many cases the focus is on the effect of single frequencies although these frequencies may be imbedded in music and heard by the recipient simply as music.

It is common to encounter studies of the effect of vibration and low frequency sound in industrial-oriented research. These studies typically focus on the potentially negative effects of specific work environments, use of particular equipment, and primarily exposure to low frequency vibration and noise [17,18]. However, there is also a long history of interest in the positive effects of vibration. Carriage rides on rough cobblestones came to be associated with positive health effects and mechanical “chairs” emulating these rides were created. In the 18th century the Abbéde St. Pierre created the tré moussoir or fauteuil de poste as a vibrating chair to help patients with melancholia, liver disease, and other conditions that seemed to respond to carriage rides [19]. The 19th century saw considerable interest in vibration and the development of vibrating tools including the chair created by Dr. Jégu after seeing Parkinson’s disease (PD) symptoms calmed by a carriage ride [19,20]. Dr. Jean-Martin Charcot, the most noted neurologist of that century, began studying PD with the chair but acknowledged an earlier physician, M. Vigoroux, who in 1878 used a sounding box with a very large attached tuning fork played with a bow to successfully treat patients with hemianesthesia and locomotor ataxia [21]. Charcot also described treatment of neuraglia and migraines by Dr. Boudet of Paris with tuning forks mounted on small boards. Gilles de la Tourette, Charcot’s assistant, applied the idea of vibration therapy to the brain [19,20,21] with a metal helmet he devised with a motor on top causing the helmet to vibrate at 10Hz. It was found to have a positive effect on insomnia, migraines, and depression and other vague conditions [21].

Whole body vibration (WBV), also referred to as whole body periodic acceleration (WBPA) is one type of application that grew out of the 18th and 19th century interest in vibration. WBV, a mechanical vibration typically created with stand-on oscillating platforms, developed largely in response to concerns about the effect of weightlessness in space on bone and muscle and then was quickly applied in sports [22]. Although current WBV platforms can produce vibration frequencies up to 100 Hz, frequencies below 30 Hz are most commonly used. The past 20 years has seen growing interest in the effects of WBV on bone density, orthopaedic, and neurological concerns [23,24].

More in keeping with the early uses of tuning forks for sensory stimulation is the practice of low frequency sound therapy (and most closely related to music therapy) that has developed in the past 50 years and is now commonly known as vibroacoustic therapy (VAT). WBV typically uses frequencies below 30 Hz while VAT uses 30–120 Hz. Olav Skille in Norway and Petri Lehikoinen in Finland were the leaders in this use of sinusoidal sound to stimulate the body for therapeutic purposes. Skille placed particular emphasis on single pitches at 40, 52, 68, and 86 Hz modulated with a steady rise and fall of amplitude at a rate of about 6.8 s from peak to peak. A noteworthy application of this method in research was done by Wigram [25,26]. Instead of single frequencies, Lehikoinen used constant frequency scanning with the intent to treat muscles at their particular resonance frequency, slow power pulsation to prevent muscle contraction, and at times directional movement of the sound [27]. Lehikoinen developed the NextWave chair system that was Federal Drug Administration (FDA) and British Standards Institution (BSI) approved in 1996 for three claims related to physioacoustic therapy: increased blood and lymphatic circulation, decreased pain and stress, and increased muscle relaxation and mobility [28]. Numerous devices that include chairs, chair backs, beds, mats, pillows, backpacks, and smaller hand-held units have been developed since then.

To review the literature related to vibration, one of the fundamental questions requiring clarification is whether the stimulation of the body with sound waves is different in some way from mechanical vibration. Since people hear sound waves and feel mechanical vibrations, an easy conclusion is that the two are categorically different. However, sound in essence is mechanical vibration that transmits through a medium [29]. In the medium of air, the sound actuator creates a vibration that results in regular compressions and decompressions of air molecules that travel to the receiving surface on the body such as the ear’s tympanic membrane or the mechanoreceptors in the skin. In water a rapidly oscillating membrane would create compressions and decompressions of water molecules. Once in contact with the body, the compression and decompression of the surface of the body is transmitted through bone and tissue and may be sensed by a set of mechanoreceptors or by our auditory system.

At a cellular or molecular level in the body there is probably no difference between activation by air molecules applying regular sine wave pressure on the body, by a surface applying oscillatory pressure stemming from a rotating motor shaft, or by the body itself moving against gravity on an oscillating platform. Another way to understand this can be in comparing the application of sound to produce vibration and the application of vibration to produce sound. Sound, which propagates through a material can vibrate the material and be physically felt like a massage, such as in a vibroacoustic device [30]. Mechanical vibration can also produce sound. Bone conduction headphones are commercially available and are built to be positioned along the skull. The mechanical vibration of the bones of the skull propagate to the inner ear and are perceived as sound [31]. Therefore, the interchange of sound and mechanical vibration demonstrate that they are in essence the same thing.

Clarification is needed about the vocabulary used in this field. We have already explained VAT and WBV. Another term used is rhythmic sensory stimulation (RSS) and is inclusive of multiple types of pulsed (rhythmic) stimulation. RSS includes whole body rhythmic movement, vibrotactile stimulation of all or part of the body, auditory pulses delivered as individual sound units (like hits on a drum, plucks of a string, interaction “waves” resulting from binaural detunement, or isochronous amplitude modulated sound trains) or as molecular compressions that create continuous sound (research usually focusing on low frequency sound 20–130 Hz), and visual light flashes or flicker. Pulsed ultrasound can also be regarded as a type of vibrational mechanical stimulation and is typically applied in 2 ms bursts but with varying ratios of sound to silence from 1:1 (250 Hz) to 1:20 (45 Hz).

When considering the use of rhythmic pulses to stimulate to the body, one question is whether electric stimulation and pulsed ultrasound are comparable to mechanical vibration. Bartel et al. [32] drew parallels between pulsation frequencies used in electric stimulation and pulsed ultrasound with frequencies for VAT. Many years ago Charcot postulated that the vibration stimulation was not unlike electric stimulation and showed similar results [21]. In this paper the review of specific mechanisms activated by vibration will be restricted to studies using various sonic and mechanical vibratory means from general body vibration to focused points of vibration delivered with pencil-like probes. However, a future more extensive review of the mechanisms activated by pulsed stimulation might include electrical and pulsed ultrasound stimulation as well.

A final question is whether whole body vibration (WBV) is fundamentally different from vibroacoustic therapy (VAT) and, therefore, WBV studies cannot be mixed with VAT in the examination of mechanisms. First, although many applications of WBV use frequencies in the level of infrasound (1–15 Hz) they also use higher frequencies (e.g., 20–40 Hz) in the same range that VAT frequently uses. Music stimulation and VAT can employ pulsed sound units at 1–15 Hz and, in fact, “rhythm” in music is primarily in that frequency. So, there is no set frequency that makes it one or the other. Secondly, the axis of the applied vibration may be a discriminator between approaches (e.g., vertical (axial), horizontal, or multidirectional) but at the mechanism level there does not appear to be strict differentiation. For example, with blood flow slow axial (direction of the spine) WBV creates pulsatile stress on endothelial cells and so enhances blood flow at 1 or 2 Hz [33] but also with sound stimulation at 50 Hz [34]. Rhythmic driving of oscillatory coherence happens with rhythmic pulses at 1 or 2 Hz (delta entrainment, e.g., RAS effects) and at 10 Hz (alpha), 20 Hz beta, or 40 Hz gamma, etc. Consequently, at the level of the mechanism, WBV and VAT will be considered within the same domain of pulsed stimulation.

In the next section we will present a narrative review of research literature that tries to map the basic “lay of the land” of vibration stimulated mechanisms and what health conditions may be affected. This is not a systematic critical review of research methodology, but rather a “cataloguing” effort to describe applications of vibration and mechanisms of effect. This effort was motivated by the perception that this has not been done to date. Researchers working on the mechanisms of vibration effect have essentially worked in silos. We determined to look for commonalities among the silos by looking not at the vibratory device, frequency, or context of application, but rather at mechanisms involved. Consequently, our search for studies to include was an emergent process from general to specific with the intent to identify categories of mechanism and then the specifics within the categories. We used a basic strategy to locate candidate studies: an electronic database search including PubMed, Scopus, and Google Scholar. Initial searches included terms such as “Vibration and Health”, “Vibration mechanism”, and “Vibration treatments” from years 1975 to 2021. We filtered based on number of citations and considered the more cited work first. After an initial collection of literature and, as researchers starting with the greatest awareness of VAT where the 1996 FDA claims for blood circulation, pain reduction (neurological), and mobility (musculoskeletal) effects were established, we decided to focus on three central concepts of vibration mechanisms for further searches: the effects of vibration on the blood, the nerves/brain, and bone/muscle. A further refined search included terms like “vibration and blood mechanism”, “vibration and neuron mechanism”, “vibration and brain”, “vibration and bone/muscle mechanism”, etc., followed by specific mechanism like endothelial stimulation or mechanoreceptor response. The identification and selection of papers was driven primarily by an attempt to describe the “field”, the “lay of the land” of vibration research. Further, our focus was closely held to mechanism and not evidence-based clinical research related to vibration without attention to mechanism. Papers were chosen based on whether we believed them to add to our understanding of the effects of vibration on health via those areas.

The auditory and vibrotactile stimulation from low frequency sound shows effects that are essentially the result of two categories of mechanisms: (1) physical, through muscular and cellular means, and (2) neurological, through sensory-based stimulation of nerves and receptors. At the physical level sound vibration is sensed by tactile receptors in the outer skin (Merkel disks—sensing vibratory strength and responding most to 5–15 Hz), inner skin (Meisner corpuscles—sensing vibratory frequency and responding most to 20–50 Hz), and in deeper tissues (Pacinian corpuscles—sensing acceleration and responding most to 60–400 Hz) [35,36]. To avoid numbing of these sensors, VAT is usually constantly varied in amplitude (power pulsation) and/or frequency (scanning). A physical therapeutic effect can be obtained at a cellular and lymphatic level due to increased fluid and cellular waste transport, increased cellular metabolism [37,38], increased blood circulation, and muscular relaxation due to a resonance response. Within the brain, vibration hypothetically enhances flow of cerebrospinal fluid and speeds removal of metabolic waste [39]. Most research with VAT has not explored neural oscillatory effects but recent studies show [40,41,42,43,44] potential brain effects, especially through prolonged application of a single frequency (e.g., 40 Hz).

In 1996 the Federal Drug Administration (FDA) reviewed the Next Wave Physioacoustic Chair designed for medical purposes with six imbedded subwoofer speakers used to apply low frequency sound vibration to the body from knees to shoulders at frequencies from 20 to 130 Hz. The FDA approved three claims for the treatment at the time called physioacoustic therapy [28]: (1) increased blood circulation, (2) decreased pain, and (3) increased mobility. Although no evidence was provided at the time for mechanisms of action, the three areas generally pointed to hemodynamic effects, to neurological effects, and to musculoskeletal effects. This FDA approval is important and noteworthy because it appears to be the earliest vibration device approved for multiple claims. Although whole body vibration (WBV) devices have been used for many years with the intent of developing bone and muscle strength, FDA approval was not granted [45]. More recently specific limited application devices using vibration have been cleared for sale [46,47]. However, the effects claimed for WBV and the recent devices fit into the original categories of claim from 1996. Further the general broad categories for the claims for physioacoustic therapy encompass the vast majority of mechanisms we discovered in the literature. The exceptions were primarily in the effects of mechanical shaking related to phlegm and mucous [48] or orthodontics [49].

One of the effects of vibration applied to the body acknowledged by the FDA in 1996 was an increase in blood circulation [28]. The question is by what mechanism does vibration affect blood flow. A crucial signaling molecule that has a pivotal role in regulating blood flow and oxygenation of tissues is nitric oxide (NO). Nitric oxide is produced and released into the blood by the endothelial cells that line the blood vessels and lymphatic vessels. Vibration stimulates the endothelial cells to produce and release NO in several forms of which the isoform endothelial nitric oxide synthase (eNOS) is of particular importance for the generation of NO from endothelial cells. Although the detailed mechanisms of how sound affects the mechanosensors in the endothelium to control eNOS is not yet completely understood, it appears that the endothelial cells mechanosensor-proteins, Syndecan-4 (Syn4) vascular endothelial growth factor (VEGF), and Krüppel-like Factor 2 (KLF2) translate the physical force from the vibration into biochemical signals. Studies have shown that vibroacoustic stimulation can induce Syn4 and VEGF [50,51]. NO regulates blood flow and vascular tone by affecting the vascular smooth muscle with the activation of the enzyme guanylate cyclase (sGC) [52] and the phosphorylation of extracellular signal-regulated kinase (ERK1/2) [53]. Although the purpose of stimulation, mode of vibration delivery, and frequency of vibration varies, endothelial cell stimulation releases NO and induces blood flow. The effect has been observed with whole body periodic acceleration using a platform (pGz) at 2 Hz [54], with microcirculation in the skin at 47 Hz [55], externally applied vibration to the arm at 50 Hz [34], sonic vibration applied to the chest at 100 Hz [56], and at various body surfaces at 150–250 Hz [57].

In addition to the release of nitric oxide, the vibratory stimulation of endothelial cells has been shown to release the cell protecting mediator, adrenomedullin (AM). It may function as a hormone in controlling circulation and vasodilation but also serves to stimulate angiogenesis—the growth of new blood vessels—and combats oxidative stress in cells. In this way AM can have a positive effect in cardiovascular disease including hypertension, myocardial infarction, and chronic obstructive pulmonary disease. However, in its function to extend blood supply in cells it may be a negative factor in relation to cancer. Martínez et al. [64] conducted an animal study to examine the effect of one hour of pGz stimulation on AM and found that immediately after the stimulation blood pressure was significantly reduced (from 115 ± 10 to 90 ± 8) and AM level was significantly increased and remained so for 3 h (from 776 ± 176 pg/mL baseline to 1584 ± 160 pg/mL, p < 0.01).

Many disease conditions are linked to oxidative stress. These include cancer, Alzheimer’s and Parkinson’s disease, diabetes, and cardiovascular conditions like high blood pressure, atherosclerosis, and stroke. Release of nitric oxide into circulation is known to have some antioxidant properties. Uryash et al. [65], in a study with mice with high oxidative stress, specifically looked for the effect of pGz on eNOS and antioxidants. The subjects were given pGz for an hour a day and tissue was tested after one, two, and four weeks. The pulsed stimulation resulted in significant expression of antioxidants including glutathioneperoxidase-1 (GPX-1), catalase (CAT), superoxide, and superoxide dismutase 1 (SOD1). It also decreased reactive oxygen species (ROS).

To study the effect of mechanically pulsating a blood clot Hoffman and Gill [66] conducted an in-vitro study (outside the body) placing a one-hour-old blood clot into a solution of the medication Heparin typically used as a blood thinner to treat heart attacks or angina. The vessel holding the blood clot was then vibrated at 50 Hz for 20 min with a very low amplitude to simulate the amount of vibration that might be transferred into the body from a surface vibration. The result showed significantly better clot dissolution with vibration (25%) versus no vibration (5%). Hoffman and Gill [67] then basically replicated the study but applying the vibration externally through a 4 cm slab of meat as simulation of human body structure and varying the vibration to 50 Hz applied in short bursts of one per second. In addition to Heparin, they did a sample with Streptokinase, a medication specifically designed to break down clots. They again found the vibration very significantly increased clot dissolution, and with greater effect in the Streptokinase group attributed to enhanced mixing and penetration (or in a sense “drug delivery”) of the lytic agent, which was originally disposed from the clot.

One context where vibration is associated with stroke treatment is the “drip and ship” situation where a patient is started on a drip of recombinant tissue-type plasminogen activator (rtPA) and then transported to a hospital in a helicopter. The helicopter typically presents an unavoidable vibration in the range of 0.5–120 Hz. Researchers [68,69] have been concerned that the vibrating transport might have a negative effect on outcomes and so studied the effects finding that there is no negative effect. However, they did not consider that there might be a positive outcome and did not record the dominant vibration frequencies or control for them. Most recently Dhanesha et al. [70] did consider the possibility of a positive effect and noted vibration frequency, used a ground-based vibration simulation arm in the study along with the no vibration control and the actual helicopter flight. They found that the animals receiving the rtPA and the simulated vibration had significantly smaller infarctions (areas of tissue death from a blood clot) and increased positive neurological outcomes (86% vs. 28%). Oddly, the actual helicopter flight group did not have significantly positive outcomes which the researchers speculate could be due to the 20–30 Hz band of vibration was attenuated in this helicopter flight. Dhanesha et al. concluded that low frequency vibration is synergistic with rtPA and that application of vibration might be a safe and simple intervention for stroke.

The body’s proprioception system gathers and processes information about changes in the position of joints and limbs and, therefore, is strongly involved in the control of posture and movement. Proprioceptors are mechanosensory neurons in the skin (Merkel disks and Meissner’s and Pacinian corpuscles), muscles (spindles), tendons (Golgi tendon organs), and joints. This proprioception system involving receptors, nerves, spinal cord, and pathways of the central nervous system terminates within the thalamus and cerebral cortex [36].

The proprioception system is very sensitive to vibration and, since it is an important factor in motor control, the effect of vibration has been the subject of considerable research, especially the effect of whole body vibration on the rehabilitation of neurological disorders [80]. The stimulation or sensitization of the proprioception system appears to engage a mechanism that retrains the body-mind strategies of motor control or establishes greater consonance between input from the senses and output to the motor system at the cortical level [81]. Perhaps pointing to a cascade effect in this proprioceptive mechanism, which is not fully understood, Delecluse et al. [82] propose that vibration may enhance corticospinal cell connectivity to spinal motor neurons.

The vagus nerve, one of the 12 cranial nerves, serves as a major parasympathetic (efferent) component of the autonomic nervous system and importantly transmits sensory information from much of the body to the brain [84]. It plays a key role in cardiac and gastrointestinal function, in muscle control of mouth and throat, in the neuroendocrine-immune system, and in the regulation of emotion including anxiety and depression. Vagus nerve stimulation (VNS) [84] is a recognized practice commonly done with manual massage or compression, electrical stimulation, or vibration including with the voice or gargling throat or with external vibrotactile devices. However, the spleen has nerve fibers that are integrated with the vagus nerve and studies [85,86] show that anti-inflammatory effects of the vagus nerve rely somewhat on the splenic nerve to the extent that stimulation of the splenic nerve results in immunosuppressive effects comparable to VNS [87]. Vibration at the abdominal level [88] may then be stimulating the splenic–vagal nerve system. Specific applications of VNS include refractory epilepsy, depression, and decreasing inflammation. One of the known mechanisms by which stimulation of the vagus nerve has its effect is the release of the neurotransmitter acetylcholine.

One of the submechanisms of the general mechanism of nerve stimulation but a basic mechanism of analgesia is focused on the function of the substantia gelatinosa in the dorsal horn and is commonly known as gate control. The theory for this pain mechanism was proposed by Melzack and Wall [109] and postulates that the substantia gelatinosa modulates sensory information being transmitted to the spinal cord and the brain. Specifically, signals from pain receptors are carried to the dorsal horn by small diameter afferent A-delta and C fibers. The signal transmission from the pain receptors can be modulated (inhibited) by the large afferent A-alpha and A-beta fibers transmitting sensory signals from skin sensation such as touch or vibration [78,96,109]. This mechanism known as gate control theory has been subject of considerable criticism and aspects have been questioned [110,111] and enhanced by Melzack’s neuromatrix of pain theory [112] but its fundamental function remains.

Salter and Henry [113] specifically explored the response of wide dynamic range (WDR) spinal neurons in the lumbar dorsal horn to vibration at different amplitudes and frequencies to determine how they might play a role in analgesic effects. They tried a variety of frequencies and intensities and found that WDR neurons entrained to the vibratory frequencies below 80 Hz. Their findings suggest that pain reduction is accomplished by the effect of vibration on Pacinian corpuscle afferents and the WDR neuron response in the dorsal horn but that frequency, location, and intensity of the vibratory stimulus is a factor that needs further clarification.

An alternative medical practice that has growing scientific evidence for its effect on the central nervous system and regulating autonomic responses is acupuncture [114]. The clinical efficacy of acupuncture may reside in its neurobiological foundations and in its purported effect of creating biochemical changes in the body and brain that control the autonomic nervous system’s functions such as blood pressure, heart rate variability, skin temperature, and perception of pain. The detailed explanation of mechanisms is still needed.

One question that arises in relation to acupuncture is whether the specific acupoints must be punctured with needles or whether vibratory sound stimulation might have the same effect. Xu et al. [115] explored this question by looking for microcirculation using laser Doppler flowmetry at meridian acupoints while stimulating the points with low frequency sound waves between 16 and 160 Hz. They found different points respond optimally to different sound frequencies. For example, the point Yin Ling Quan: A0 responded to 29.14 Hz, Zusanli A1 responded best to 58.27 Hz, and Tianjing A2 to 110.00 Hz. Brătilă and Moldovan [116] used an electrical input output model to determine optimal frequencies for the lung meridian (124 Hz) and kidney meridian (120 Hz). Weber et al. [117] explored the use of a simultaneous sound combination (32, 48, and 64 Hz) for its effectiveness to reduce perceived pain intensity and pain threshold compared to a single frequency sound stimulation and a sham. They applied electromagnetic transducers to five acupoints indicated for relief of pain and anxiety and subjected 13 pain-free participants to a cold pressor test. Results showed that both multifrequency and single frequency sound stimulation significantly improved pain tolerance and reduce intensity of pain.

Unpacking the complexity of the role of neurotransmitters and neuromodulators on the body and brain is beyond the scope of this paper. However, research has shown instances in which neurotransmitters are stimulated by vibration and these will be described here.

In relation to vibratory analgesia, Salter and Henry [118] examined specifically the vibratory activation of P₁-purinergic receptors in the dorsal horn by the neurotransmitter adenosine. In a study with cats, vibration was applied at 80 Hz in 2.5–3.5 s trains every 20–25 s for 10 min. This resulted in a vibration-induced depression of lower lumbar nociceptive neurons and remained in effect for up to 4 h after the stimulation. Various agents used to attenuate the depression of these neurons revealed that adenosine was responsible for the analgesic effect. The study suggests that the effect earlier described as gate control may be mediated by the release of adenosine resulting from vibration.

Several neurotransmitters not specifically related to pain have already been discussed in other contexts above. Assuming vibration can stimulate the vagus nerve and the related splenic nerve as discussed above, vibration then has the effect of releasing acetylcholine, which plays a key role in synapses and especially at the location where nerves and muscles connect. It also plays a role in controlling the autonomic nervous system and a particularly important role in the cognitive system and in regulating heart rate. Additionally, stimulation of the splenic nerve causes the induction of norepinephrine. Nitric oxide, extensively discussed above, is also a neurotransmitter serving to regulate and mediate processes of the nervous, immune, and cognitive systems.

Gamma-aminobutyric acid (GABA) is a prominent neurotransmitter in the brain and the central nervous system. It plays a crucial role reducing the activity of neurons and especially in control of fear and anxiety. Safarov and Kerimov [119,120] in two separate animal studies explored the effect of low frequency vibration (20 Hz) on GABA levels and its metabolism. The found that vibration, regardless of duration, increased GABA level in the brain stem, the large hemispheres, and the cerebellum as well as activity of the glutamate decarboxylase enzyme, which produces GABA. However, they found the effect more marked with 30 min stimulation than with long periods like 7 h. The implication is that one of the mechanisms creating the relaxation effect of vibroacoustic stimulation may be the boost in neurotransmitter GABA.

Some mechanism for vibratory analgesia were explained above under gate control. However, there is pain that does not appear to stem from nociception and where the application of vibratory stimulation cannot be affecting only the dorsal horn neurons because the frequency is above the primary response level of Pacinian corpuscles and the rapidly adapting mechanoreception system. Such pain may then be neurogenic, stemming from neural circuit dysrhythmias or disconnections. Hollins et al. [97] explores this and determines that in some cases the vibratory analgesia must stem from cortical dynamics and specifically from an interaction of Brodmann areas 3a and 3b/1. Fallon et al. [138] observed that in Fibromyalgia (FM) patients there was increased theta power in the prefrontal and anterior cingulate cortices consistent with TCD characteristics. This increased frontal theta activity was significantly correlated measured tenderness and tiredness scores. Jensen et al. [139] used brain imaging to examine brain connectivity in FM patients and found less connectivity between the rostral anterior cingulate cortex (rACC) (known to play a role in inhibiting pain) and the hippocampus extending into the part of the brain stem known to modulate pain.

In this context where FM seems to be related to brain dysregulation and connectivity, where pain appears to be related to brain region interaction, and where there is demonstrated potential for vibration to drive neural coherence, it can be speculated that the positive results from vibratory stimulation on FM patients were due to the mechanism of oscillatory coherence [30,140]. Both studies [30,140] used 40 Hz vibrotactile stimulation of the body, used oscillatory coherence and its relation to connectivity as a premise for effect, but did not establish mechanism with brain imaging. The authors are currently engaged in a study to explore this mechanism.

The specific mechanisms or causes related to neurodegenerative diseases and conditions are not fully understood but one path being explored with some success is that of spontaneous brain oscillation power, synchronization, dysrhythmia, and circuit connectivity.

Dockstader et al. [141] studied the oscillatory power in various frequency bands in brain regions using magnetoencephalography (MEG) imaging in children who had been treated for brain tumors with cranial radiation therapy (CRT). Children treated with CRT consistently are found to have cognitive deficits in attention, processing speed, and memory. The results showed a clear pattern of gamma deficits with a significantly lower gamma oscillation power in the 60–100 Hz range in the resting state.

Stam et al. [142] studied Alzheimer’s patients (AD) and healthy controls with full-head MEG with the purpose of investigating linear and non-linear interdependencies in the MEG signal channels. Results showed that this measure of synchronization was lower in AD in the 10–14 Hz alpha band, 18–22 Hz beta band, and in the 22–40 Hz gamma band. Additionally, studying AD patients with MEG, Ribary et al. [136] looked at 40 Hz oscillatory coherence at cortical and subcortical sites associated with the thalamocortical loop. Results showed that although AD patients had similar activity patterns as healthy patients, the AD patients had reduced gamma activity in the cortical component.

Recent research [42,43,143,144,145] demonstrated that 40Hz auditory, vibrotactile, or visual rhythmic sensory stimulation (RSS) had significantly positive results on AD symptoms. Although none of these studies confirmed the effect on oscillatory coherence in humans, that mechanism can be inferred from the method and results. A possible submechanism of RSS driving oscillatory coherence at 40 Hz was shown by Iaccarino [42]. They demonstrated that in AD mice the effect of the general 40 Hz RSS was to drive fast-spiking parvalbumin-positive-interneurons (at 40 Hz but not at other frequencies) and as a result reducing amyloid-β levels. They also observed a reduction in inflammation, increase in microglia activity, blood vessel lumen size, and cognitive performance.

Lozano and Lipsman [132] review and explain dysfunctional brain circuits and specifically how deep brain stimulation (DBS) can mitigate the effect, for example, of the motor circuit affecting Parkinson’s disease (PD). The role of DBS in relation to the dysfunctional motor circuit in PD is the inhibition of a group of neurons with 130 Hz electrical stimulation. While the widely accepted approach of DBS is an inhibitory one, Neuman et al. [146] point out that DBS modulates the motor circuit but does not restore it functionally. They differentiate the motor circuit pathways more precisely in the basal ganglia and suggest their work may inspire innovative ways to improve the therapeutic efficacy of neuromodulation in PD. Several studies have used sound vibration as a neuromodulatory stimulant with PD patients [44,147]. One study applied 30 Hz and the other 40 Hz. Both had significant positive results and, although no neuroimaging was used to verify effects on circuit function, they pointed to the potential mechanism of vibration therapy with PD.

The discussion above has already identified a vibration mechanism related to major depressive disorder (MDD) under vagal stimulation and under oscillatory coherence and TCD. Decreased connectivity is a clearly identified factor in MDD [148] and so affecting MDD by driving coherence with rhythmic sound and vibration is a possibility. There is a further potential mechanism for MDD related to frontal asymmetry. There is considerable evidence that frontal EEG asymmetry between left and right in the alpha band is a biomarker for depression and anxiety [149] but age, gender, and severity of depression interaction raises a caution on this [150]. However, studies have shown that using music stimulation with depressed participants has resulted in a reduction of frontal asymmetry in the EEG [151,152,153]. These music studies did not use low frequency sound or vibrotactile stimulation. The only known study that has used vibrotactile gamma stimulation [89] did show significant reduction in depression severity. More research into the occurrence of frontal oscillatory asymmetry and vibratory stimulation is needed.