Introduction

Despite the remarkable developments in Western Medicine in modern times, public interest in Traditional, Complementary and Alternative Medicine (TCAM), such as acupuncture, remains high [1], [2]. This may be because TCAM is perceived as holistic and relatively free of adverse effects. However, these treatments sit uncomfortably alongside scientific medicine because of strikingly different explanatory systems and the empirical tests applied by each discipline. In order to bridge the gulf between high public acceptability and the lack of empirical evidence for many of these treatments, it is important to reconcile them with modern scientific concepts. Our focus here is on laser acupuncture, and we address the question whether laser acupuncture produces brain effects that are biologically plausible.

There have been many studies [3]–[20] some of which have involved functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) of the brain effects of needle acupuncture. Some neuroimaging and neuroendocrine studies have suggested that needle acupuncture affects hypothalamic as well as extrahypothalamic functions and modulates mood [3], [5]–[9]. Needling of the leg acupoint ST36 and the hand acupoint LI4 was shown to activate the hypothalamus and nucleus accumbens and deactivate the rostral anterior cingulate cortex (rACC) [3]. Superficial needling (i.e. needling that did not produce the classical de qi sensation - tingling, numbness or other sensations that occur after an acupuncture needle has been properly placed in the body) and non-acupoints (i.e. points on the skin that do not lie on recognized meridians in Traditional Chinese Medicine [TCM]) did not activate the hypothalamus [7]. Stimulation of the acupoint PC6, located above the wrist, recommended for a wide range of conditions from nausea to stress management, resulted in activation of the cerebellum, dorsomedial nucleus of the thalamus, anterior cingulate gyrus and left superior frontal gyrus [8]. All of these studies have used needle acupuncture which, although more traditional, is invasive.

While laser acupuncture has become an increasingly common clinical method, particularly in primary care, its empirical basis has been less well studied to date. Whereas needle acupuncture studies have shown activation and deactivation of the somatosensory cortex [3], [4], [6], [7], [11]–[14], superficial needling and laser intervention appear to stimulate cortical and subcortical structures other than the somatosensory cortex [11], [19], [20]. This is consistent with the observation that low intensity laser stimulation does not produce a skin sensation. For example, laser acupuncture of a foot acupoint, classically used for treating visual problems, was demonstrated to cause activation of the occipital cortex [19].

This study has used laser delivered at low intensity as used in primary care. Other studies have reported high intensity lasers can produce de qi sensation [21]. High intensity laser is not commonly used in primary care situations and therefore was not used in the current study. Further, as low intensity laser does not result in sensory sensation it is ideal for double blind randomized controlled studies where the subjects could not differentiate between placebo (laser off) and verum laser (laser on).

The evidence suggests that cortical activation does occur with acupuncture and this activation may be specific to certain brain regions in relation to the site and type of stimulation [11]–[14]. In practice, acupoint efficacy is not specific, and one acupoint can be used for several different conditions, just as one medical condition can be managed with several acupoint locations. For instance, the antidepressant effect of laser acupuncture [22] has been attributed to a group of acupoints - CV14, LR14, LR8 and HT7 (see fig.1 for anatomical location), however there are other acupoint combinations that are also applicable for the management of depression. The neurological effects of stimulation of these acupoints CV14, LR14, HT7 and LR8 in combination have yet to be investigated.

In this study, we examined the blood oxygen level dependant (BOLD) functional magnetic resonance imaging (fMRI) response to laser simulation on the above mentioned acupoints CV14, LR14, LR8 and HT7. We chose laser acupuncture as it permits blinding of application because of the lack of a local sensation at low intensity, together with the previously mentioned increases in practical usage and limited understanding of its mechanisms. We reasoned that if laser acupuncture is altering a person's mental state a neurological effect should be observable. Further, if the effect differs dependent on the site of stimulation, then the neural locus of the activity should also differ.

Materials and Methods

Choice of acupoints and control point

The acupoints were selected based on results from our previous study [22] and the TCM for mood disorders [23], [24]. These acupoints lay on the classically named liver (LR), heart (HT) and conception vessel (CV) meridians. The selected points, labelled LR8, LR14, HT7 and CV14 in TCM, are shown in Figure 1. LR8 is in the medial knee region, between the insertions of the sartorius and semitendinosus muscles. LR14 is in the vicinity of the 6th intercostal space on the mid clavicular line. HT7 is at the wrist crease, in the vicinity of the radial side of the flexor carpi ulnaris. CV14 is in the anterior midline, approximately 5 cm below the xiphisternum. A control non-acupoint was selected on the abdominal surface, midway between SP15 (four cun from the umbilicus) and ST25 (two cun from the umbilicus) away from the abdominal meridians.

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Figure 1. Selected acupoints relevant to mood and depression.

In Traditional Chinese Medicine, the Liver (LR) meridian is used to treat depression. Two LR points were used: LR14 and LR 8. Two other acupoints considered important in depression were also used (CV 14 and HT 7). The control point (sham point or non acupoint) was located midway between SP15 and ST 25 acupoints.

https://doi.org/10.1371/journal.pone.0012619.g001

Results

Group analysis

At the group level, there were significant increases (activation) in BOLD levels in some brain regions for acupoints LR14, CV14, LR8 and the control point compared to all the other points (verum laser per point > all others, p<0.001; see Table 1). Further, there were significant decreases (deactivation) in BOLD levels for acupoints LR14, LR8 and the control point compared to all the other points (all others > verum laser per point, p<0.001; see Table 1) in other brain regions.

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Table 1. Significant brain activation patterns from laser acupuncture to LR14, CV14, LR8 and control point.

https://doi.org/10.1371/journal.pone.0012619.t001

With LR8, activation of ipsilateral limbic cortex (cingulate gyrus) and deactivation of bilateral frontal cortices (middle frontal gyrus), (contralateral superior frontal gyrus), contralateral temporal cortex (middle temporal gyrus) and contralateral caudate occurred. Stimulation at the LR14 acupoint resulted in activation of contralateral frontal cortex (superior and middle frontal gyrii), contralateral parietal cortex (postcentral gyrus) and deactivation of contralateral cerebellum (cerebellar tonsil) and contralateral occipital cortex (precuneus). Acupoint CV14 produced activation of the left limbic cortex in the posterior cingulate and there was no significant deactivation in the grey matter. HT7 had no significant activation or deactivation. The control point (non acupoint or sham point), activated the contralateral parietal cortex (postcentral gyrus). It also deactivated the contralateral limbic cortex (parahippocampal gyrus).

Discussion

This is the first fMRI study to examine the effects of laser stimulation of a suite of acupoints found to be efficacious in a clinical condition (depression). A salient feature of this study was that four acupoints and a control non-acupoint (sham point) were stimulated in a random design. The subjects were unaware of the relative significance of different acupoints. The use of low level laser acupuncture, which does not produce a skin sensation, permitted the blinding of subjects to verum or placebo stimulation, something difficult to achieve with needle acupuncture.

The main finding of our study was that each acupoint or control point resulted in a different pattern of brain activity when contrasted against all the other acupoints or control point. The acupoints we investigated in this study were those that have been used in our previous treatment study for depression [22]. This finding suggests that although these acupoints are all used in the treatment of depression, the neural locus of this effect differs depending upon the site stimulated. The efficacy of these acupoints in the treatment of depression may vary greatly between patients and site stimulated, and our findings may shed some light on these effects [26].

The neuroanatomical basis of depression is not completely understood, however a number of studies have implicated abnormalities in certain brain regions, in particular the medial and dorsolateral prefrontal cortex, the cingulate gyrus and the so-called limbic brain regions (hippocampus, parahippocampal gyrus, amygdala, septal nuclei, insula, thalamus) and paralimbic regions (orbitofrontal cortex, anterior temporal lobe) [26]–[29]. There is converging evidence from drug treatment, cognitive-behavior therapy and brain stimulation techniques that antidepressant treatments work by modulating frontal-subcortical neuronal circuits. The most consistently reported finding is that antidepressant treatments lead to a normalization of activity in the dorsolateral prefrontal cortex, with additional changes in the subgenual cingulate region, the posterior cingulate, parahippocampal gyrus and insula [29]. Whether the change in prefrontal cortex is a primary event or secondary to changes in subcortical nuclei is unclear, but the relationship of treatment response to this suggests that it is biologically plausible that laser acupuncture could be an effective antidepressant treatment through its effects on the above brain regions.

The results show this combination of acupoints activating frontal cortex, limbic cortex and subcortical caudate. The trend is for ipsilateral activation suggestive of neurological circuitry outside the dorsal spinal columns and more likely to be autonomically driven [30]–[32]. Most of the deactivations were contralateral. Also LR14 and control point activations included primary somatosensory cortical activations (SSI). None of the deactivations involved SSI, however they did include the regions as described earlier that could collectively be called the affective cortex (the frontal, limbic and temporal cortices as well as the subcortical caudate). This combination of ipsilateral and contralateral activations and deactivations may perhaps be representative of the combined actions of both the spinal and autonomic nervous systems during laser acupuncture.

In classical acupuncture, there are primary and secondary acupoints for the treatment of any disorder. The approach to acupoint selection can be variable, with primary acupoints being considered essential and secondary acupoints additive for some patients. In our study, we cannot predict from these results whether any acupoint should be preferred over others for clinical use, even though LR8 deactivated more brain regions (middle and superior frontal gyrus, middle temporal gyrus and the subcortical caudate) than all the other points. These are results from a sample of healthy subjects. The question of whether the results would be different in a sample of clinically depressed subjects, needs to still be answered. Further studies are required to explore the relative value of different acupoints, the final test for which naturally lies in a clinical trial. It also cannot be stated from our study whether the treatment response can be achieved with stimulation at one point alone, or if multiple points are necessary.

There is conflicting evidence regarding acupoint specificity and whether that specificity is relative rather than absolute for any particular disorder [33]–[38]. Furthermore, it is debatable whether the clinical effects of acupuncture are restricted to stimulation on points that lie on the classical meridians in TCM. Our finding that laser stimulation of a non-acupoint produced some brain activation suggest that there is unlikely to be a completely neutral control non-acupoint, and this should prompt a re-examination of the use of sham points (in needle acupuncture studies) as control hence minimizing the true statistical effects of any acupoint [36]–[39]. It is also interesting that laser acupuncture in this study appeared to preferentially activate the limbic cortex ipsilaterally and deactivate the limbic cortex contralaterally. It has been suggested that laser stimulation preferentially activates unmyelinated afferent fibers that project ipsilaterally to the insula [40]–[42], which might also explain the differences from needle acupuncture.

This laser acupuncture fMRI study demonstrated the central effects of stimulation of a suite of acupoints found to be efficacious in treating depression in a primary care setting. The multiple acupoints each activated different groupings of frontal-limbic-striatal brain regions, suggesting some acupoint specificity but also a commonality in the regions affected. There was a trend for the limb acupoints to cause ipsilateral activation and contralateral de-activation. The results of the study suggest that laser acupuncture is a biologically plausible anti-depressant treatment. Its efficacy and the relative merits of the different proposed acupoints must be empirically examined.

Acknowledgments

The authors would like to thank Dr Ron Shnier (Radiologist) for his contribution and Ms Angie Russell for assistance with manuscript preparation and submission.