The Effects of Acupuncture on Cerebral and Muscular Microcirculation: A Systematic Review of Near-Infrared Spectroscopy Studies

Acupuncture produces physiological effects via stimulating acupoints, proximal or distal to the region of effect. Near-infrared spectroscopy (NIRS) noninvasively measures tissue-level hemodynamics in real time. We review the literature investigating the effect of acupuncture on muscular and/or cerebral microcirculation. As the basis, we queried PubMed in June 2014 for articles mentioning both acupuncture and NIRS in title/abstract. The reviewed papers investigated either cerebral (n = 11) or muscular hemodynamics (n = 5) and, based on STRICTA for reporting acupuncture methodology, were overall poor in quality. Acupuncture was found to influence regional oxygen saturation in cerebral and muscular tissue. The cortical response in healthy subjects varied across studies. For subjects with stroke or cerebrovascular dementia, findings suggest that acupuncture may modulate dysfunction in cerebral autoregulation. The muscular response to pressure techniques was more intense than that to needling or laser. Probe proximity could impact measurement sensitivity. No one study simultaneously investigated the direct and remote responses. Research utilizing NIRS to investigate the hemodynamics of acupuncture presently lacks in scope and quality. Improved designs, for example, placebo-controlled, randomized trials, and standardized intervention reporting will raise study quality. Exploiting NIRS in clinical settings, such as stroke, migraine, or other pain conditions, is worthwhile.


Introduction
Acupuncture is the practice of stimulating specific points of the body (acupoints), most commonly by needling, with roots in traditional Chinese medicine, and aims to treat a wide range of ailments [1]. Physiological responses include analgesic and hemodynamic responses. The analgesic response, a reflection of the influence on the autonomic system, has been documented, although not without controversy [2][3][4]. The hemodynamic response is also of clinical interest. Reflexive responses include erythema, a local, relatively benign effect around the stimulation site, and syncope, a systemic, serious adverse effect in poorly compromised subjects [5][6][7][8]. These are rare but well known to acupuncturists. More commonly, the response is therapeutic and able to modulate autoregulation under pathological status, such as stroke and migraine [9][10][11].
Modes of acupuncture are several. Modern practice generally applies stainless steel needles. Variations are application of electricity to the needles, the use of laser at the acupuncture points, manual pressure at the points (acupressure), or moxibustion. Auricular acupuncture involves a collection of points/regions on the ear theorized in 1957 by Nogier [12][13][14]. Point locations may then be categorized by location (and tissue type): body (muscle/tendon), ear (cartilage), and scalp (subcutaneous tissue). Furthermore, the intended effects of acupuncture stimulation are generally proximal or distal. The distal effects depend on the meridian theory, while the proximal effects follow the theory of A Shi points, per Chinese traditional medicine [15][16][17][18]. The scientific mechanisms behind acupuncture have long been and still are mysterious in large part because the needling locations are often remote from the intended area of effect. Such responses to needling stimuli most likely arise from interactions within the nervous system, particularly the brain. Recent tools have made it easier to study these interactions in both muscular and cerebral tissues, from multiple angles. Near-infrared spectroscopy (NIRS) is one such tool that observes the hemodynamics at the tissue level. The muscular hemodynamics reflects the direct response, while the cerebral hemodynamics reflects the remote response to acupuncture stimulation. NIRS observes tissue hemodynamics by using nearinfrared light to monitor blood oxygenation in real time. It is a safe, noninvasive technique but has limited reading depth, while the breadth of the monitored region depends on the number and placement of probes [19][20][21]. Nonetheless, its portability, ease of use, and high temporal resolution are significant advantages over the more spatially comprehensive BOLD-fMRI (blood oxygenation level-dependent functional magnetic resonance imaging), while its ease of use and focus on microcirculation make it an attractive alternative to transcranial Doppler ultrasound (TCD), which focuses on blood flow, usually in specific arteries [10,[22][23][24][25].
These advantages lend themselves well to monitoring the immediate hemodynamic response in cerebral or muscular tissues to acupuncture stimulation. Our aim is to review the studies reporting the use of NIRS in investigating acupuncture, its effectiveness, and its mechanisms.

Materials and Methods
We queried the PubMed database as of June 9, 2014, for all articles mentioning both acupuncture and NIRS in title or abstract, regardless of language. We included all original articles and excluded reviews. Any reviews were combed for relevant citations not found in the database search. For analysis, we focused on articles written in English or Chinese. Analysis of articles written in other languages was limited to abstracts and provided data and figures. All articles marked for analysis were obtained ( Figure 1).

Inclusion criteria are as follows:
(i) being in PubMed database, up to June 9, 2014, (ii) mentioning "acupuncture" in title/abstract or as a MeSH term and "near-infrared spectroscopy (NIRS)" in title/abstract, (iii) being an original article, (iv) having no restriction on language, (v) having, for analysis, language restricted to English or Chinese.
Exclusion criteria are as follows: (i) it is a review; (ii) for analysis, languages other than English or Chinese were excluded, aside from abstract, tables, and figures.

Methods of Analysis.
To assess study quality, we adapted the checklist for STRICTA (standards for reporting interventions in clinical trials of acupuncture) [26] (Table 1). Information  on study designs, population, interventions, hemodynamic  measures, and outcomes was organized in the tables (Tables  2-4). A summary table is also provided (Table 5).

Quality of Studies according to STRICTA.
By STRICTA, the quality of studies under review may be considered poor in their reporting of acupuncture. We took a broad interpretation of acupuncture to include laser needling, moxibustion, and acupressure ( Table 1). Details of needling, particularly number of needle insertions, depth of insertion, clarity between unilateral and bilateral application, and response sought to stimulation, were not reported in 44% of the studies (7 of 16) ( Table 1, Item 2). Depth of insertion and response sought may not be applicable to some of these studies, since laser stimulation, electric stimulation, moxibustion, and acupressure were included, yet four (three) investigated manual needling among the seven underreporting depths of insertion (response sought) ( Table 1, Items 2c and 2d). The number of needle insertions was often obscured from lack of distinction between unilateral and bilateral application. Regarding treatment regimen, the frequency of sessions, or time between sessions, was not reported in the majority of the studies (63%, 10 of 16) largely because most of these studies involved only one session (  manual, laser [27] ear electropuncture [32] manual acupuncture [33] cerebrovascular dementia [34] neonates, laser [37] trigger points [35] Chinese (n = 2): stroke [28] electromoxibustion [29] German (n = 3): manual, laser [30] intracranial pressure [38] manual acupuncture [31] English (n = 5): trapezius (n = 2): de-qi not induced [40]; neck pain, tender points [42] knee, acupressure (n = 1) [39] forearm, laser (n = 1) [41] hands, perfusion imaging  one of two to record rCBV as the principal NIRS parameter [28]. The other investigated single-point electric moxibustion in 20 healthy subjects, aged 25-53, with mean 46 [29]. The principal oxyhemoglobin parameter in the remaining three studies was O 2 Hb measured by the NIRO 300 and involved healthy subjects aged 19-38. Two involved brief needle stimulations (20 s), with a retention time of 5 or 10 min [27,30]. The other used continuous electrical stimulation on auricular acupuncture points, finding steady increase in O 2 Hb during each 15-minute stimulation of 100 Hz that persisted on level in the periods between stimulations [32].
It is likely that rCBV is synonymous with, or at least closely related to, total hemoglobin, as defined in Table 4. The interstudy populations assessed by rCBV were not comparable-one suffering stroke, the other, healthy-although both were older (age ranges: 41-75, 25-53) than the participants in the studies mentioned below [28,29]. Among the studies finding increased oxygenation, one recorded the maximum amplitude of the changes in response to seven types of acupuncture stimulation (164 total) randomly distributed among 88 subjects [27]. The other two involved one or two subjects [30,32]. All of these volunteers were healthy and aged 19-38. The stimulation times are comparable to the ones used in the studies finding oxygenation decreases. This complicates any attempt to draw a correlation between age and the cerebral hemodynamic response to acupuncture on healthy subjects.
Excepting the cerebrovascular dementia case, the populations are young and somewhat comparable in size (20, 20, and 16); also, the number of acupuncture points used is single to a few [31,35,37]. Manual needling showed quick response among healthy adults, but response to laser in neonates only emerged after the laser was turned off [31,35,37]. Also, needling stimulation was brief, comparable to the multipletype acupuncture study finding increase in oxygenation, discussed above [27]. In spite of some common points among the studies investigating acupuncture in healthy young adults, the findings appear inconsistent: some found oxygenation increase; others found oxygenation decrease [27,[30][31][32]35].
Evidence-Based Complementary and Alternative Medicine 5      Table 3. † † Maximum amplitude of the changes in oxyhemoglobin and deoxyhemoglobin. * On midpoint between the C7 spinous process, near neck tender points; * * near and 50 mm away from Jianjing GB 21 stimulation point.

8
Evidence-Based Complementary and Alternative Medicine is calculated during maximal exertion of trapezius conducted once before and again one day after needling. Needles angled perpendicularly. See Table 4 for definition. c Two probes: one 2 cm from the stimulation point at Xiyangguan (GB 33) and the other on the opposite side of the patella. d The stimulation site, Neiguan (Pe 6), is located 2 cm proximal to the midpoint of the carpal fold between the tendons of M. flexor carpi radialis and M. palmaris longus. Two of 11 observed either a slight increase or no significant changes in oxyhemoglobin. Both of these also used transcranial Doppler ultrasound (TCD) to measure blood flow in the middle cerebral artery (MCA). The one finding no significant change in oxygenation generally found increased mean blood flow velocity in the left and right MCA (and, to a lesser degree, reduced pulsatility index) but no change in blood pressure parameters in response to (needle, pressure, or laser) stimulation of acupuncture points known to increase intracranial pressure in 34 healthy subjects, aged 20-35 (mean 25.2) [38]. The other study also found increased mean blood flow in the right MCA in response to an acupuncture scheme designed for "general increase of Qi-energy" in 12 subjects, aged 26-41 (mean 35.2) [33]. Aside from using both TCD and NIRS, too many parameters differ between the two to infer anything substantial.
In summary, the findings above indicate that the cerebral tissue oxygenation response to acupuncture, even in healthy young adults, varies widely, with no clear correlation to any single factor. Further research is required to investigate whether the variation in response carries over to subjects exhibiting dysfunction in cerebral autoregulation, as in stroke or migraine, since acupuncture has been found to have modulating effects [10,47]. We recommend that future investigations consider the following for control: population age and fitness/health level; acupuncture type and intensity of stimulation (number of sessions, frequency, and duration); and NIRS machine model and recorded parameters and the number and positioning of probe(s).

The Muscular Hemodynamic
Response. The response in the trapezius muscle was mixed between the two relevant studies. One found an increase in regional tissue oxygenation in the site of stimulation starting with needling, which stayed constant at least 5 min after stimulation ended, and identified no changes in a region centered 50 mm away [40]. The implication is that the direct oxygenation response to needling is detectable in the region surrounding the stimulation site, but not so in a region less than 1 cm away. The other found no increase but even a slight decrease in the ratio of oxyhemoglobin to total hemoglobin in the recorded region, which was located amidst six needles angled obliquely under the probe [41]. Some of the key differences between the two studies were population type (healthy versus "neck pain"), number of needles (1 versus 6), needling location (Jianjing GB 21 versus tender points), needling angle (vertical versus oblique), needle retention (2 versus 15 min), and NIRS parameters (oxyhemoglobin versus ratio of oxyhemoglobin to total hemoglobin).
A significant response in tissue oxygenation from acupressure stimulation of Xiyangguan GB33 was detected in the knee tissues on the stimulated side, while no significant response registered on the opposite side of the knee [39]. Acupressure may have a wider range of impact on muscular tissue oxygenation compared to manual or laser needling, simply owing to the nature of the techniques (pressure from the thumb versus needling at a point).
No significant response in tissue oxygenation was detected in the forearm from laser needle stimulation at Neiguan Pe 6, located 2 cm proximal to the middle point of the carpal fold between the tendons of M. flexor carpi radialis and M. palmaris longus [42]. The NIRS probe was located on M. flexor carpi ulnaris. Increased blood flow in a nearby region (5 cm proximal to the middle point of the carpal fold between the tendons of M. flexor carpi radialis and M. palmaris longus) was detected by laser Doppler spectroscopy. It is possible the NIRS probe was too distant from the site of stimulation or that laser needling may not have a strong enough effect for NIRS to detect a significant response. A significant change in the perfusion rates of the hands was found in response to the first session of manual needling of Hegu LI 4 and Houxi SI 3. However, at the third session five days after, the responses failed to register significance. The baseline perfusion rates from the first to the third trial increased in one subject, but not the other [36]. This may reflect an acclimatization of muscular tissue perfusion to repeated acupuncture (three 10-minute sessions over 5 days). The study only has two subjects of different gender and age. No firm conclusions can be drawn from this study.
In summary of the MH studies, the technique of stimulation and proximity of the probe to the stimulation site appear to have a discernible impact on the detection and intensity of a response in the muscle and connective tissues. The findings suggest that in muscular tissue, acupressure has a greater impact on regional oxygenation than acupuncture, which in turn exceeds that of laser stimulation. Oxygenation has not been found to decrease in response to acupuncture, but the number of studies is few.

Conclusion
Research using NIRS to investigate the hemodynamic effects of acupuncture is presently lacking in scope, number, and quality. Further studies may exploit the ease of use and realtime capacity of NIRS to monitor regional, tissue-level blood oxygenation to examine the concurrent response locally in the muscular tissue and remotely in the cerebral tissue. Improved study designs, accounting for the limitations of NIRS, placebo-controlled RCTs, and standardized reporting on interventions, such as adherence to STRICTA, will raise the quality of studies. Although the hemodynamic response to acupuncture varied widely among healthy subjects, it is worthwhile to extend the use of NIRS to clinical settings, such as stroke, neck pain, migraine, or other pain conditions.