Action at a distance: laser acupuncture and the brain

Chapter 36

Action at a distance: laser acupuncture and the brain Nicholas Alexander Wise Department of Physical Medicine and Rehabilitation, UNC Chapel Hill School of Medicine, Chapel Hill, NC, United States

36.1

Background

One of the more mysterious applications of the (already somewhat mysterious) field of photobiomodulation therapy (PBMT) is laser acupuncture (LA). Defined as the nonthermal stimulation of traditional acupuncture or reflex points with a low-level laser, LA differs from the broader field of PBMT in that the irradiated points are not necessarily the target of the intended effect but, instead, are chosen based on traditional Chinese medicine (TCM) theory or an associated bodily system, usually to achieve a nonlocal or systemic result. Despite its increasing popularity in the West (Cui et al., 2017), relative safety (Chan et al., 2017), and rapidly expanding body of research showing clinical efficacy for many conditions (Vickers et al., 2018; Xiang et al., 2017; Lin et al., 2017; Kung et al., 2017; Li et al., 2017), the lack of a clear mechanism of action through which acupuncture exerts its effects on human physiology is a significant hurdle, and for LA, that hurdle is even larger, for as many questions that have been answered, many more arise. While an exhaustive exploration of acupuncture theory and literature is beyond the scope of this chapter, a brief description will be helpful to provide context for the discussion of the effects of the modern development of LA and its unique ability to influence the function of the brain.

36.1.1

Acupuncture and meridian theory

Acupuncture is a nearly 3000-year-old system of healthcare that is still one of the most widely-used treatments in the world. As the centerpiece of TCM, it developed and evolved empirically over several millennia to include many diverse concepts and theories, such as the opposing forces of yin and yang, and the five elements (wood, fire, earth, metal, and water). These terms may sound outdated or out of place in a discussion of modern neuroscience, however they can be interpreted as early attempts to describe the concepts of homeostasis and human phenotypes. A consistent theme running throughout the history of TCM, is that animals and humans contain discrete pathways, called meridians, that originate on the extremities and terminate in the internal organs from which they derive their name (Zhou and Benharash, 2014a). Meridians are thought to exist close to the surface of the skin and act as biological ley lines, allowing the system-wide transfer of vital energy (qi) over a network that seemingly exists outside of recognized hardwired or neurological pathways. There are 12 principal meridians in classical acupuncture theory that are bilateral and symmetrical, plus 2 midline meridians, and 361 specific points (acupoints) that act as nodes through which one can interface with the qi network (Pacific, 1993); in addition, many other secondary points have been found to lie outside of the main meridian network which effectively doubles that number. It is thought that sufficient stimulation of the correct acupoint(s) can normalize either a local excess or deficiency of qi, and allow the meridian, and subsequently the body, to return to homeostasis and restore health.

36.1.2

Physical properties of meridians and acupoints

Despite the long history and empirical development of the methods used, the anatomical underpinnings of acupuncture have only recently begun to be explored. In fact, many questions remain about the physical composition of meridians Photobiomodulation in the Brain. DOI: https://doi.org/10.1016/B978-0-12-815305-5.00036-1 © 2019 Elsevier Inc. All rights reserved.

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and acupoints, not the least of which is, do they actually exist? The first systematic review to examine the anatomical nature of acupoints was performed in 1980 by Chan, and the conclusion was that anatomical structures at acupoints did not differ in any significant way from nonacupoints, and the effect must be primarily neurologically mediated (Chan, 1984). In addition, many acupoints are indeed located on meridians that overlie major neural pathways, such as the distal pericardium (PC) meridian over the median nerve, the bladder (BL) meridian following the sciatic nerve up the back of the leg, and points on the stomach meridian (ST36, 37) that follow the path of the deep peroneal nerve. Many other acupoints have no clear spatial relationship to large neural pathways, however, and numerous other anatomically-based theories have attempted to explain the presence of meridians. These include: a unique form of vessels called Bonghan corpuscles (Liu et al., 2013), fascial plane lines as guides for meridians (Langevin and Yandow, 2002; Bai et al., 2011), channels of polarized molecules (Lo, 2002), and most simply, acupoints as merely myofascial trigger points (Melzack et al., 1977). The mechanism for the specificity of acupoints has been attributed to nearby dense peripheral nerve bundles (Chan, 1984), supporting a neurological route for acupuncture effects; increased density of mast cells at acupoints, which provides a mechanism for the immunological influence seen clinically (Zhou and Benharash, 2014a; Cheng et al., 2009; Wang et al., 2014a); and areas of viscerally-referred cutaneous neurogenic inflammation (Kim et al., 2017), which suggests the existence of a somatotopic reflex system as an organizing principle of the human body. The biophysical properties of acupoints have also been extensively explored. Acupoints have been repeatedly demonstrated to possess specific electrical properties, such as high conductance and potential, low impedance and resistance, increased capacitance, as well as increased power spectral density (Ahn and Martinsen, 2007; Zhou et al., 2014). Thermal differences (Yang et al., 2007a,b, 2017), channels of low hydraulic resistance (Zhang et al., 2008), enhanced acoustic/vibratory characteristics (Lee et al., 2004), and most intriguingly perhaps for the topic of LA, unique optical properties have also been demonstrated in human and animal meridians (Sang Min et al., 2001; Yang et al., 2007b; Yang et al., 2009; Jovani´c et al., 2009; Zhong et al., 2010). Yang et al. (2009) showed that 633 nm light attenuates less along a 1.0 cm distance of the PC meridian (78.8 6 6.4%) than along the same distance in nonmeridian directions (87.1% 6 3.0%) (P , .05; n 5 20). Employing an advanced biomedical diagnostic technique called optical coherence tomography (OCT), Zhong et al. (2010) successfully distinguished acupoints from nonacupoints. They used OCT to show a significant increase in the optical attenuation coefficients of acupoint PC8 after 10 minutes of irradiation with a 100 mW 808 nm laser probe compared with sham LA. In addition, there have been attempts to update acupuncture theory by incorporating modern scientific concepts such as quantum entanglement (DeSmul, 1996; Wang et al., 2017a), holographic theory (Dale, 1999; Curtis and Hurtak, 2004), and biophotonics (Wang et al., 2014b; Schlebusch et al., 2005; Pokorny et al., 2012). These theories are intriguing and perhaps someday will be able to be scientifically tested, but at present, a clear picture of the biological basis of meridians and acupoints has yet to emerge.

36.1.3

Microsystems

In addition to the full-body meridian macrosystem, there is evidence for numerous somatotopic microsystems located on circumscribed locations throughout the body (Dale, 1999). Beginning with Dr. Paul Nogier’s discovery and introduction of the auriculotherapy (ear) microsystem to the West in the early 1950s, numerous other examples have been documented and used, such as foot and hand reflexology (Miura et al., 2013; Nakamaru et al., 2008), Korean hand acupuncture (Park and Cha, 2012; Litscher, 2002), Su Jok therapy, ECIWO (embryo containing the information of the whole organism) therapy (Zhang, 1987), Yamamoto new scalp acupuncture (YNSA), cranial reflex therapy (Wise, 2007), oral (dental/tongue/gum) acupuncture (Gleditsch, 1978 #7933) (Simma et al., 2009), and iridodiagnostics (Ma, 2015). While the true nature of microsystem activity is unclear, they are thought to be cutaneous projections of the nervous system and largely modulated through the autonomic nervous system. Laser stimulation has been reportedly used successfully on several of these microsystems, including auriculotherapy (Round et al., 2013), Su Jok (Nedeljkovic et al., 2008), YSNA (Yamamoto et al., 2007), and chiropractic cranial reflexes (Wise, 2010), indicating that they may work through whatever mechanism it is that governs LA.

36.1.4

Acupuncture methods

Stimulation is traditionally performed by inserting and manipulating thin needles into specific acupoints, either individually or, more commonly, in groups. The needles are usually inserted to a depth of 1/4 to 1/2 in. below the surface of the skin, or until a specific sensation called deqi is felt. Deqi is often described as a dull heaviness, numbness or a tingle, and it is thought by many to be an important component of the acupuncture experience, and perhaps the most important influence on therapeutic efficacy (Lundeberg, 2013; Hori et al., 2010). While actual puncture with needles is

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still the most common form of stimulation in TCM, effective noninvasive methods, like acupressure, which is the application of manual or physical stimulation of acupoints, and moxibustion, the application of heat though burning herbs (traditionally mugwort) on or near the acupoint, have been used for centuries (Chen and Wang, 2014; Mehta et al., 2017). The modern era brought the use of electroacupuncture (EA) in the 1950s and LA in the 1970s as effective alternatives to needling (Jun et al., 2015). Many studies have validated the increasing use and efficacy of EA. EA can be performed either as an addition to traditional acupuncture, where the current is conducted through an inserted needle, or performed noninvasively via direct application of the current to the skin by an EA device. The electrical current used in EA may be pulsed at different frequencies, which may lead to different physiological effects via the release of different endogenous analgesic compounds (Mayor, 2013; Qiu et al., 2015; Lee and Kim, 2017). Guo et al. (1996) showed that low-frequency EA stimulation (2 Hz) caused the release of enkephalin precursor proteins, whereas high-frequency stimulation (100 Hz) increased expression of dynorphin precursors. Xiang et al. (2014) showed that 2 Hz but not 100 Hz EA evoked a significant increase in mu-opioid receptor binding potential in the anterior cingulate cortex (ACC), the caudate nucleus, the putamen, the temporal lobe, the somatosensory cortex, and the amygdala in rhesus monkeys. A 2018 systematic review and meta-analysis of EA for depression concluded that EA performed equally to antidepressants, but with a decreased risk of adverse events (Li et al., 2018).

36.2

Laser acupuncture

The advent of medical laser technology in the late 1960s inspired the use of low-level laser as an alternate method of stimulating acupuncture points. There was early evidence that LA was effective and could achieve similar results to needle acupuncture (NA), but with the significant advantages of being completely noninvasive, painless, and requiring shortened treatment times (Whittaker, 2004). LA is generally regarded to be clinically comparable to traditional NA. A systematic review by Baxter et al. (2008) and a follow-up by Law et al. (2015) concluded that LA is an effective treatment for musculoskeletal pain and dysfunction, but with two very important qualifications: an appropriate treatment dosage was necessary, and results were best at long-term follow-up. Unfortunately heterogeneity of the pooled data did not allow the authors of either review to determine an effective dose from the meta-analysis, however Baxter concluded that power outputs of at least 10 mW and dosages of at least 0.5 J point are advisable in LA (Baxter, 2009).

36.2.1

Potential mechanisms of laser acupuncture

The mechanism through which LA exerts its homeostatic effects is currently unknown. It is possible that a mechanism inherent in the PBM effect is amplified and works synergistically with some unique feature of acupoints. Perhaps the answer lies in the higher skin nitric oxide (NO) concentration and expression of neuronal nitric oxide synthesis (nNOS) in acupoints, compared to control points (Liang et al., 2008; Lundeberg, 2013; Ma, 2017). One of the known effects of PBM is a local increase in the release of NO, which acts as a potent vasodilator and cell signaling molecule (Hamblin, 2017). A recent study compared the dose-dependent release of NO from irradiated acupoints (PC4, PC5) and nonacupoints (Jiang et al., 2017b). LA was performed using 658 nm near-infrared laser with the power of 12, 24, 48 mW for 20, 40, 60 minutes. They found that the NO released at the nonacupoint following 40 minutes of laser stimulation only increased slightly, perhaps due to the normal effect of PBM on NO, which happens in any tissue; however the 24 and 48 mW LA more than doubled the NO production at PC4 and PC5 compared to the nonacupoint (P , .05), and peak efficiency in NO production was noted at 24 mW. This finding indicates that the LA-induced release of NO is specific to acupoints, and is dose-dependent. A follow-up study by the same authors found that LA stimulation of PC6 on one side increases NO production on the contralateral side as well, and that releases of NO from both LPC6 and RPC6 after LA at RPC6 are greater than those of after LA LPC6, which may indicate that the acupoint has lateralized specificity (Jiang et al., 2017a).

36.2.2

The deqi question

The imperceptibility of LA raises the question of the importance of deqi in regards to clinical efficacy. If indeed the deqi sensation is one of the most important components of NA, one might wonder how LA can be clinically effective without it? Deqi is thought to involve all nerve fiber types, from the fast-conducting myelinated Aβ fibers to the slowconducting unmyelinated C fibers, although the slower conducting fibers in the musculotendinous layers are likely to be behind most of the sensation (Hui et al., 2007; Zhou and Benharash, 2014b). PBMT has numerous documented

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inhibitory and analgesic effects on peripheral pain nerves via disruption of microtubule arrays and fast axonal flow (Chow et al., 2011), however this effect may be dose-dependent and wavelength dependent. In a study with implications for LA, Chow et al. found that irradiating a single point overlying the rat sciatic nerve (and presumably the BL meridian) with 808 nm infrared laser for 120 seconds (54 J, 18 J/cm2) increased somatosensory-evoked potential (SSEP) amplitudes when compared with delivery of the same total energy to four points, which caused decreased SSEP amplitudes and conduction block (Chow et al., 2012). Irradiation with red (650 nm) laser for 30 or 120 seconds caused no change in SSEPs. These findings are contrary to their own previous findings which showed significant neuronal inhibition with both red and infrared wavelengths (Yan et al., 2011 #7954), but consistent with the biphasic effect of hyperpolarization followed by depolarization. If the primary effect of LA is neurologically mediated, many questions still remain about the differing effects of dose, wavelength, frequency, and irradiance on neural tissue and acupoints.

36.3

Acupuncture and the brain

Modern brain research methods have delivered much information and insight into the neural correlates of the myriad clinical effects of acupuncture. This body of research has grown rapidly since the first study in the mid-1990s (Yoshida et al., 1995); for example, a PubMed search of “(acupuncture or EA) and (fMRI or PET or EEG)” produced more than 882 references as of May 2018. However, relatively few studies have specifically examined the brain effects of LA. A similar search for (LA and (fMRI or PET or EEG or NIRS)) (and excluding nonrelevant topics like laser-evoked pain) produced 37 results. In order to delineate the unique effects of LA on brain function, we will first briefly summarize some interesting issues and findings from what we know about the brain effects of NA and EA.

36.3.1

Functional magnetic resonance imaging

Functional magnetic resonance imaging (fMRI) is an important form of brain imaging that is used to detect changes in cerebral hemodynamics under certain task conditions. fMRI studies show correlative increases or decreases in a bloodoxygen-level-dependent (BOLD) signal, which can be interpreted as activation or deactivation of specific brain areas. fMRI has excellent spatial resolution (B1 2 mm) but poor temporal resolution: peak BOLD signal is seen B6 9 seconds after onset of the neural activity (Fro¨hlich, 2016). fMRI studies have demonstrated robust effects of NA on brain activity and revealed that acupuncture’s effects are largely (but not completely) explained as being mediated by the central nervous system. Although more recent studies have benefitted from more rigorous design and statistical analysis, it should be noted that the methodology and validity of some early fMRI acupuncture studies are in question (Cho et al., 1998; Qiu et al., 2016). Issues such as publication bias, unsuitable controls, neglected carryover effects of block design, overly generous interpretation of activation/deactivation, and questionable point specificity have resulted in a heterogenous body of lower-quality evidence about which it is often difficult to make conclusions (Beissner and Henke, 2011). With that caveat, let us take a look at what is out there. A systematic review of NA and fMRI studies was conducted by He et al. (2015). They analyzed 82 studies from 2008 to 2014, comprising a total of 2263 subjects and a variety of designs and methods. They summarize that “acupuncture could not only evoke brain activation in sensorimotor brain areas and widespread deactivation in the limbic paralimbic neocortical network, but also modulate the connectivity of several brain regions, including antinociceptive, memory and affective brain regions, within DMN, SMN and amygdale-associated brain network. These regions process information in circuits that could broadly be assumed to engage: the affective (amygdala, hippocampus), sensory (thalamus, primary and secondary somatosensory cortices), cognitive (ACC, anterior insula) and inhibitory (PAG, hypothalamus) processing during the experience of pain. Most fMRI studies of acupuncture show it may recruit distributed cortical and subcortical brain networks that are also implicated in both inhibitory and facilitating effects in the pain-modulation system for both sensation and affective pain perception. However, correlation between other therapeutic effects induced by acupuncture and the corresponding neuroimaging changes has not been well studied.” In their summary, they describe a wide variety of responses in regard to point specificity in the included studies: some results were completely consistent with the idea that disorder-specific acupoints evoke hemodynamic changes in disorderimplicated brain areas, while others failed to replicate those results. They also emphasize that most of the studies were performed on a single point on healthy subjects, which is unlike real-world clinical practice, since (1) clinical acupuncture usually involves stimulation of multiple points simultaneously and (2) acupuncture is thought to play a homeostatic role, and the effects on brain activation may be quite different between healthy subjects and those with a pathological imbalance. They point out other factors such as small sample size, gender differences, psychological state, and carryover effects that increase the heterogeneity of the analysis and make the results difficult to interpret.

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fMRI investigations of the neural correlates of the deqi sensation by Asghar et al. (2010) and Hui et al. (2010). Hui et al. (2010) found that deqi was associated with significant deactivation in the limbic paralimbic neocortical network, which is closely related to the default mode network (DMN). The DMN is a group of brain regions that are active when the brain is in a resting state, that is, not performing any specific task, and is mentioned frequently in the acupuncture literature and seems to play a significant role in the brain effects of acupuncture. A recent systematic review reported that verum acupuncture usually increases DMN and sensorimotor network connectivity with pain-, affectiveand memory-related brain areas (Cai et al., 2018), making this an issue that requires further study. Future studies are needed to determine if LA modulates the DMN in a similar fashion. The central tenet of point specificity appears to be supported by many later studies that have demonstrated the effective uniqueness of acupoints compared to the surrounding tissue and sham (nonacupoints) (Xing et al., 2013; Campbell, 2006; Wang et al., 2012; Qin et al., 2011; Li et al., 2012, 2016). This being acupuncture, however, the literature is not without its share of contradictory results. The first study to demonstrate point specificity with fMRI was eventually retracted, as several of the authors decided they no longer could support the concept after failure to replicate the original finding (Cho et al., 1998). This may be due to the use of NA on nonacupoints as a control. Brain imaging studies that have used real stimulation on sham acupoints as a control have demonstrated that there may not be such a thing as a totally inert point on the body, which makes using verum acupuncture on a true control point rather difficult (QuahSmith et al., 2010; Dincer and Linde, 2003). The choice of controls in fMRI studies is a very important consideration due to the fact that a needle inserted into the skin may trigger certain brain activity that may be misinterpreted as point-specific. A 2013 meta-analysis of 28 fMRI studies sought to explore the question of point specificity by analyzing the brain activation patterns that could be attributed solely to the insertion of a needle into the body (Chae et al., 2013). They showed that needle stimulation without regard to location evoked brain activation in the so-called pain matrix (insula, thalamus, ACC, somatosensory cortex, primary visual cortex, inferior frontal cortex, superior temporal cortex, superior temporal gyrus, and cerebellum), and caused significant deactivation in the DMN (medial prefrontal cortex, subgenual ACC, caudate, amygdala, posterior cingulate cortex, thalamus, parahippocampus, and cerebellum). Hui et al. (2010) also reported that when acupuncture induced sharp pain, the deactivation in the DMN was attenuated or reversed in direction. On its face, this does not seem very surprising: a painful sensation (however small) would theoretically cause the brain to wake up from its resting state. However, it does illustrate some of the issues present in interpreting brain activation patterns with NA and fMRI—issues that LA conveniently avoids completely.

36.4 36.4.1

Laser acupuncture and the brain Animal studies

Relatively few animal studies examining the brain effects of LA have been published in English. Jittiwat showed that LA at GV20 significantly decreased the brain infarct volume in cortical and subcortical areas in cerebral ischemic rats (Jittiwat, 2017). In addition, LA increased the catalase, glutathione peroxidase, and superoxide-dismutase (SOD). A decreased infarct volume plus increased SOD are strongly associated with reduced neurological deficit after stroke. Sutalangka et al. examined LA at HT7 (a point associated with learning and memory) or sham in an animal model of Alzheimer’s disease (Sutalangka et al., 2013). LA was performed once a day for 14 days with a violet laser (405 nm,100 mW, spot diameter of 500 mm, 10 minutes). The rats who received verum LA showed a cognitive enhancement effect compared to sham, as well as elevation of acetylcholine (ACh) in the hippocampus. ACh plays an important role in learning and memory and the authors suggest that LA at HT7 may improve cholinergic function in the hippocampus, which in turn gives rise to enhanced spatial memory. The same point (HT7) was examined for its effects on animal models of autism in two studies by Khongrum et al. (Khongrum and Wattanathorn, 2015, 2017). In both studies, LA was performed once daily for 10 minutes at HT7 on both the left and the right sides (405 nm, 100 mW (0.100 J/s), diameter of 500 mm). The results of the first study showed that LA at HT7 improved behavioral outcomes as well as markers of oxidative stress in the cerebral cortex, striatum, and hippocampus. In the second study (2017), they examined the histological changes in the cerebellum induced by the same LA at HT7 protocol. Compared to sham, the LA rats had significantly decreased oxidative stress, as well as decreased levels of the pro-inflammatory cytokine IL-6 in the cerebellum. In addition, they found enhanced Purkinje cell survival and increased GABAergic function as a result of the improvements in oxidative stress status and inflammation induced by LA at HT7. The behavioral and biomarker improvements evoked by LA in these animal models of neurodegenerative diseases make this an exciting area for future studies.

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36.4.2

Laser acupuncture and functional magnetic resonance imaging

The first evidence of LA’s effectiveness at modulating human brain activity (and point specificity) using fMRI came from a 2002 study (n 5 10) that examined laser stimulation of a point on the left little toe; bladder 67 (BL67) which is traditionally used to treat a variety of eye disorders (Siedentopf et al., 2002). The laser parameters reported were 10 mW power output and a wavelength of 670 nm. Compared to the sham LA condition, they found significant activation of the visual cortex within Brodmann’s area (BA) 18 (cuneus) and BA19 (occipital cortex) in the left hemisphere, areas which are involved in higher order visual processing, and no activation within corresponding areas of the right hemisphere. They conclude that the brain activity found “is not due to peripheral afferent input from the dermal mechanoreceptors because our brain activation map present only ipsilateral activity within BA 18 and 19. Due to these findings, we assume that the Merkel and Ruffini corpuscles, which are augmented at acupoints, are not involved in the underlying mechanism of acupuncture.” One of the strengths of this early study, and LA in general, is the ability to use sham LA as a true control: there was no tactile stimulation from the laser and therefore no noise generated in the somatosensory cortex or pain matrix. To investigate the potential difference in brain activation on fMRI between traditional NA and LA, Siedentopf et al. (2005) performed LA on gall bladder 43 (GB43) in 22 healthy male volunteers. The acupoint chosen for this study is a point traditionally used for deafness, dizziness, tinnitus, ear diseases, headache and migraine. GB43 is located on the foot between the fourth and fifth toe, which is far enough away from the MRI scanner to avoid creating artifacts—a significant concern for fMRI investigations of NA. Laser parameters were 670 nm (red) and 10 mW power output. The results indicated that LA of the left GB43 acupoint activated the left thalamus, left nucleus rubber, and the brainstem, with no activation in the right hemisphere. LA of the right GB43 point activated the central midbrain, extending paramedially to the right, and the placebo group (sham LA) showed no significant brain activations for either side. Of particular interest in both of these studies is (1) the point specificity of BL67 and GB43, activating areas associated with visual and auditory processing, respectively, and (2) the fact that LA of a single point activated ipsilateral brain regions only. If LA stimulation was solely transmitted to the brain via the neurological route from skin mechanoreceptors to the afferent somatosensory pathway, contralateral activation would be expected, as those tracts crossover at the brainstem. Together these findings both support the existence of an alternate informational path from the periphery to the brain that does not cross the midline (e.g., meridians).

36.4.3

The frequency question

Many laser devices used in LA and PBMT have the ability to modulate their output at different pulse frequencies, and the question of whether there are frequency-specific pulsing effects in LA (like EA) is an interesting and complex one. While it has been shown in vitro and in vivo, PBMT studies that are pulsing the laser at different frequencies can cause different physiological effects (Ando et al., 2011; Ilic et al., 2006; Hashmi et al., 2010), the exact mechanism of pulsing in LA is, yet again, unclear, as traditional PBMT does not cause neural membrane depolarization and firing the way that EA does. A fascinating study in 2010 by Hsieh et al. set out to examine whether different stimulation modes of LA on the same point would activate different brain areas in the similar fashion to EA. Using fMRI to look at BOLD signals, they compared the effects of a continuous wave (CW) laser stimulation and one that was modulated at 10 Hz with rest period and sham LA. The team demonstrated that even though the laser was the same (30 mW, 808 nm), and the acupoint was the same (left Kidney 1, K1), the 10 Hz modulation activated distinct brain areas when compared to CW. The CW LA showed significant activation of the inferior parietal lobule in the left parietal lobe, and the 10 Hz LA uniquely activated the left inferior parietal lobule and the left supramarginal gyrus, areas related to attention and memory. This study raises some obvious questions of the importance of frequency modulation in LA, such as: how does frequency modulation in LA actually work? Will different frequencies activate different brain regions? Can brainwaves be modulated for even entrained rom the periphery by pulsed LA? Clearly, more studies are needed to answer these frequency-related questions.

36.4.4

Laser acupuncture and depression

Acupuncture has long been used as a treatment for depression. The 2018 Cochrane review of acupuncture and depression states that “acupuncture may result in a moderate reduction in the severity of depression when compared with treatment as usual or no treatment. Use of acupuncture may lead to a small reduction in the severity of depression when compared with control acupuncture. Effects of acupuncture versus medication and psychological therapy are uncertain

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owing to the very low quality of evidence”(Smith et al., 2018). LA does not have an extensive body of evidence to support its use for depression, but there are three promising studies by Quah-Smith et al. that examined the acute brain effects of LA on a set of acupoints that are traditionally used for mood disorders: left liver 8 (LR8), right liver 14 (LR14), left heart 7 (HT7), and conception vessel 14 (CV14) on the midline, as well as a nonacupoint in the abdomen for a control. Their first study in 2010 performed LA on these points in healthy subjects (n 5 10) with an 808 nm and 25 mW laser delivered though a fiber optic arm (Quah-Smith et al., 2010). A block design of 20 seconds was used in which the subject received either verum or sham (laser off) LA at a single acupoint, and this cycle was repeated four times per acupoint and once per control. Since the laser produces no thermal or other sensations, the subject was successfully blinded as to the treatment phase. Analysis of the BOLD signal showed a trend of point-specific patterns of ipsilateral activation of the frontal cortex, limbic cortex, and subcortical caudate, and deactivation on the contralateral side. Results for individual points included: LR8 activated the ipsilateral limbic cortex, and deactivated the middle frontal gyri bilaterally, as well as the contralateral temporal cortex and caudate. LR14 stimulation activated the contralateral frontal cortex and parietal cortex, and deactivated the contralateral occipital cortex and cerebellum. CV14 activated the left limbic cortex, with no significant deactivations. Stimulation of HT7 caused no significant activation or deactivation, but the control point (nonacupoint) activated the contralateral postcentral gyrus in the parietal cortex and deactivated the contralateral limbic cortex. Interestingly, the contralateral somatosensory cortex was only activated by LR14 and the control point, and not by any of the other points. The same investigators repeated the same LA protocol in 2013, but this time in depressed patients (n 5 10) (QuahSmith et al., 2013b). They used the same laser parameters (808 nm, 25 mW, 4 J per point) on the same set of acupoints (LR8, LR14, HT7, CV14) plus the additional kidney 3 (KI3) to compare their results with the healthy subjects from their 2010 study. What they found, perhaps not unsurprisingly, was that LA activated a much more extensive network of brain regions in the depressed patients compared to the healthy subjects from their previous study. This difference may be due to the relative amount of activation at baseline of the two groups. While both the healthy and depressed subjects showed the most activation in the frontal and temporal lobes, depressed patients also showed significant activation in the inferior parietal lobule (LR14), modulation in the cerebellum with CV12 and LR8, and modulation in brain regions involved in the DMN. While the exact neuroanatomical basis for depression is unclear, abnormal function of the DMN is thought to play a role in depression (Ng et al., 2017). The third trial performed by this team using the same LA protocols for depression was a double-blinded RCT in 2013 in which 47 participants were randomized to receive LA or sham at the same acupoints (LR14, CV14, LR8, HT7, and KI3) (Quah-Smith et al., 2013a). The LA was administered twice a week for 4 weeks and once a week for another 4 weeks, for a total of 12 sessions. The primary outcome was a change in severity of depression at 8 weeks using the Hamilton depression rating scale (HAM-D), and secondary outcomes were the change in severity of depression using the Quick Inventory for Depression-Self Reporting (QID-SR) and the Quick Inventory for Depression-Clinician (QIDSCL). At 8 weeks, participants in the active laser group showed greater improvement on the primary and clinician-rated secondary outcome measures HAM-D (mean 9.28 (SD 6.55) vs mean 14.14 (SD 4.78) P , .001) and QIDS-CL (mean 8.12 (SD 6.61) vs mean 12.68 (SD 3.77) P , .001). The self-report QIDS-SR scores improved in both groups but did not differ significantly between the groups. At 3 months, the QIDS-SR scores of the active laser participants remained significantly lower than baseline.

36.4.5

Laser acupuncture and cerebral blood flow

Litscher et al. have performed many studies exploring the effect of different forms of LA on brain function. In 2000 they conducted a multiparametric examination of the effect of NA and LA on brain circulation and the bispectral index of EEG. They found that both NA and LA (19 mW, 685 nm) of six acupoints (LI4, ST30, BL60, BL65, BL66, BL67) increased the mean blood flow velocity in the posterior cerebral artery in specific brain areas. In 2004 Litscher performed LA on 18 healthy volunteers in a randomized controlled crossover trial using functional multidirectional transcranial ultrasound Doppler sonography (fTCD) (n 5 17) and fMRI (n 5 1) (Litscher et al., 2004). Reported laser parameters were: 30 40 mW power output, 685 nm wavelength; 20-minute irradiation time; beam diameter: 500 μm; energy density of about 4.6 kJ/cm2 at each acupoint and a total sum of 36.8 kJ/cm2 for all acupoints. Simultaneous LA on four acupoints (LI4, ST36, BL60, BL67) resulted in an increase of mean blood flow velocity in the posterior cerebral artery measured by fTCD [before stimulation (mean 6 SE): 42.2 6 2.5; during stimulation: 44.2 6 2.6; after stimulation: 42.3 6 2.4 cm/s, n.s.]. Mean blood flow velocity in the middle cerebral artery decreased insignificantly. The fMRI analysis of one subject showed that bilateral stimulation of the acupoints produced bilateral positive activation over the frontal cortex, as well as an increase of the BOLD signal in the left superior occipital gyrus (BA19). The activation of

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the visual cortex (presumably by the two vision-related acupoints, BL60 and BL67) agrees with the earlier findings by Siedentopf et al. (2002).

36.4.6

Laser acupuncture and brain oscillations

Another insight into brain state and function comes from electroencephalogram (EEG) recordings of cortical oscillations. EEG can detect the minute fluctuations in brain rhythms that give insight into spatial and temporal dynamics of brain activation. The analgesic effect of NA has been shown to be related to reducing the power of gamma oscillations (30 100 Hz) in bilateral prefrontal cortex, mid-cingulate cortex, primary somatosensory cortex, and insula (Hauck et al., 2017). A 2013 randomized trial comparing acupuncture with clonazepam in 80 patients with generalized anxiety disorder used EEG to explore changes in brainwaves at 6 weeks. The NA group showed superior reductions in the HAM-A compared to those in the clonazepam group (P , .05), plus increased alpha power and decreased theta power (Zhou et al., 2013). Unfortunately to date there are few published explorations of LA in humans using EEG. While not strictly LA, one study from 2012 measured differences in brain oscillations before and after using laser stimulation on the palm of the hand (Laser parameters: 6 laser diodes, 830 nm, 7 mW each, and pulse frequency of 10 Hz) (Wu et al., 2012). They found significant activations in the alpha and theta bands, with deactivation of beta, very similar to changes in brain state induced by mindfulness meditation (Lomas et al., 2015). Even though acupoints in the hand were not specifically targets, it is likely that Pericardium 8 (PC8), was stimulated at the very least, which raises the question: what is the effect of incidental acupoint stimulation when performing traditional PBMT? Are the overall effects enhanced by “accidental” acupoint stimulation or is the lack of specificity an issue? EEG is an important method of quantifying brain activity and is sorely underutilized in LA research.

36.4.7

Laser acupuncture for stroke and neurorehabilitation

There is intriguing evidence from Naeser et al. that LA is effective in assisting the neurorehabilitation of stroke patients with paralysis, including case reports (Naeser, 1997; Naeser et al., 2011), as well as evidence of lesion-site improvement from a CT-scan study (Naeser et al., 1995). In the latter study, Naeser treated seven stroke patients (ages 48 71 years; 5 males), five with hemiplegia, including severely reduced or absent voluntary finger movement, and two patients with hand paresis. The reported laser parameters were: 20 mW, 780 nm NIR CW laser, with a 1-mm-diameter aperture. LA stimulation was performed for 20 seconds per point (51 J/cm2) on the shallower points on the hands and face, and deeper acupuncture points (on the arms and legs) received LA for 40 seconds per point (103 J/cm2). The patients were treated 2 3 times per week for 3 4 months. Overall, five of seven of the patients (71.4%) showed improvement on physical examination by a blinded assessor after conclusion of treatment, including increases in range of motion, grip strength, and hand dexterity tests. Based on the CT scans, they were able to determine that the size of the lesion in the motor pathway areas correlated to whether or not they responded to LA treatment, with the cutoff being at .50% of the brain area (severe paralysis). These results warrant further investigation of LA as a mono- and adjuvant therapy in neurorehabilitation.

36.4.8

The wavelength question

The vast majority of PBMT research studies have used laser devices that fall within the range of red to near infrared (632 1064 nm), and even within that range, there is evidence that physiological effects are not only dose-dependent, but wavelength-specific as well (Albuquerque-Pontes et al., 2015; Ang et al., 2012; Pereira et al., 2014; Santos et al., 2014; Usumez et al., 2014). However, there is some evidence to show that lasers using shorter wavelengths may also evoke specific physiological results on tissue (Wang et al., 2017b; Hwang et al., 2015). Litscher’s research group in Austria has shown the effectiveness of nontraditional wavelengths of light for use in LA. In 2010 they found that violet laser stimulation at GV14 on the upper back increased the blood flow velocity in the basilar artery significantly (P , .001) compared with the reference interval before LA (Litscher et al., 2010). The reported laser parameters were: 405 nm, 110 mW, diameter 500 μm, treatment time of 10 minutes. They also found that the same violet-LA protocol increased peripheral microcirculation (Wang et al., 2011) and skin temperature distribution (Litscher et al., 2011). Litscher has also reported positive results in modulating neurological responses using yellow and green laser light (Litscher et al., 2015, 2018). These initial explorations raise the interesting question of the potential therapeutic aspects of different wavelengths that can be used in LA. Since the depth of penetration of blue, green, and yellow light is

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thought to not be more than a few millimeters deep, how deep are acupoints exactly? We know needles are usually inserted up to 1/2 in. deep, but how deep does laser light need to penetrate in order to get its therapeutic effect? Future LA studies are needed with direct comparison between wavelengths to determine the optimal color for the job in brain stimulation.

36.5

Conclusion

The recent explosion in neuroscience research and advances in brain imaging technology have settled the question of whether or not acupuncture influences brain function. The answer is clearly in the affirmative. It is now clear that acupoint stimulation, whether by needle, laser, or electricity, can modulate brain function and thanks to fMRI technology, we know a lot about where. We just don’t yet know exactly how or why. It is safe to say that the effects of acupuncture cannot be explained away by the placebo effect or an expectation of benefit anymore. However, we also know that the real answer is, of course, complicated, as acupuncture and the placebo response do actually share some similar brain pathways for triggering the release of endogenous opiates. The historical problems that acupuncture has had with hard evidence are partly due to questionable research methods and heterogeneity of results, however it may also be due to the fact that acupuncture truly is a nonlinear approach to a nonlinear system (human physiology), and it needs to be studied as such by improved methodology. The advantages of incorporating modern laser technology in this complex field, such as the ability to use an inactivated laser as a credible true sham in double-blinded RCTs, will go a long way to help solve some of these research problems for the future, and would seem to be clearly required.

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