Characterization of the "deqi" response in acupuncture

The study was performed on 20–47 years old (29.0 +/- S.D 7.8), right-handed, acupuncture naïve healthy adult volunteers, 15 male and 27 female, 32 Caucasians, 6 Asians, 2 Hispanics and 2 Africans with informed consent, as approved by the Massachusetts General Hospital Subcommittee on Human Studies. The subjects were screened and excluded for major medical illnesses, history of head trauma, neuropsychiatric disorders, use of medications within one week, and contraindications for exposure to a high magnetic field. The sample size was determined by the minimum number of subjects necessary to detect activation/deactivation differences comparable to what had been observed in our previous fMRI studies, with 80% power.

The subjects were blinded to the procedures and could not see the sites undergoing stimulation from their supine position in the scanner. They were told that the acupuncture performed at different acupoints with different techniques would generate different needling sensations. Tactile (touch) stimulation was performed prior to acupuncture when the subjects were still naïve to acupuncture as a sensory comparison for the acupuncture stimulation. Thus, the comparison stimulation also took into account expectation and its placebo effects. Tactile stimulation and acupuncture were both performed at the same acupoint in 16 subjects each for LI4 and ST36, and 13 subjects for LV3. Three of the 42 subjects received tactile stimulation and acupuncture at all three acupoints; the remaining 39 subjects received acupuncture to all three acupoints, but only the paired tactile stimulation to the first of their acupoints. Analyses comparing tactile stimulation to acupuncture stimulation were performed on the paired sensory – acupuncture datasets. Data from all 3 acupoints for each subject was used in the Spearman's correlation of intensities of sensations in acupuncture.

Acupuncture and tactile stimulation control was delivered to LI4 on the hand, LV3 on the foot and ST36 on the lower leg on the right in randomized order by an acupuncturist with over 25 years of clinical experience (JL). The individual's sensitivity to needle manipulation was pretested, aiming to elicit deqi sensations without noxious pain. The stimulation paradigm is depicted in Figure 1. The needle was rotated approximately 180° in each direction with even motion at the rate of 60 times/min for 2 min during M1 and M2. The needle remained in place during the rest periods R1, R2 and R3. Each procedure lasted a total of ten minutes. In order to avoid excess discomfort, the subject was instructed to raise one finger if any sensation reached the intensity of 7–8 on a scale of 1–10 and 2 fingers in case of any sharp pain. When so signalled, the acupuncturist would adjust the force of stimulation so that the sharp pain would disappear within a few seconds. The acupuncture stimulation procedure was performed twice for each acupoint. Sterile, one-time use only stainless steel needles were used for LV3 (0.20 mm diameter) and ST36 (0.22 mm diameter) (KINGLI Medical Appliance Co. Wuxi, China). Silver needles (0.23 mm diameter) were used for LI4 (Matsuka, Tokyo, Japan). Superficial tactile stimulation was performed by gentle tapping with a size 5.88 von Frey monofilament, a standard method of sensory stimulation, prior to acupuncture with needling. The purpose of this design was to explore how acupuncture sensations might differ from the sensations elicited by the conventional sensory stimulus of touch. At the end of each tactile stimulation or acupuncture procedure, the subject was questioned by another researcher in the team if each of the deqi sensations (aching, pressure, soreness, heaviness, fullness, warmth, cooling, numbness, tingling, dull pain), sharp pain or any other sensations occurred during the stimulation, and to rate its intensity on the scale of 1–10 (1–3 mild, 4–6 moderate, 7–9 strong, 10 unbearable).

The analyses were performed on each dataset from an acupuncture or tactile stimulation procedure. The paired t tests, ANOVA and Fisher's exact tests were performed on the average of the duplicate datasets for the acupuncture and tactile stimulation. Spearman's correlation for intensities of different sensations was performed on the individual datasets with acupuncture stimulation (41, 40, 41 datasets for LI4, ST36 LV3 respectively). The data were analysed both as continuous measures of a sensation, and also as a binary indication of its presence or absence. A sensation was determined to be present if the reported level, averaged over replicates, reached a minimal score of 1.

The datasets were divided into 3 groups 1) deqi, 2) mixed (deqi + sharp pain), and 3) no sensations (neither deqi nor sharp pain) according to the sensations recorded at the end of each experimental procedure. None of the participants experienced acute pain without deqi. While dull pain was included as an important component of deqi, sharp pain of different forms such as stabbing, burning or pricking, was regarded as inadvertent noxious stimulation, and the co-occurrence of sharp pain with deqi was classified as a 'mixed response'. This scheme of categorization was based on the distinct differences in the hemodynamic response of the brain to these two categories of psychophysical response as evidenced by neuroimaging in prior studies. The pain neuromatrix was inhibited in deqi but activated in the presence of sharp pain [7, 8].

We characterized the sensory responses elicited by the stimulation paradigm through a number of statistical approaches as described below. The set of observations and analyses we present are organized in support of three objectives: a) characterization of the prevalence of sensations elicited by the acupuncture stimulation; b) characterization of the uniqueness of the sensations associated with the deqi experience; and c) exploration of characteristic of sensations that could be used as a 'deqi composite', a single-valued summary of the reported simultaneous sensations. Each of these objectives was explored using techniques as described below.

Overall deqi response was significantly more frequent in acupuncture than in tactile stimulation control. In terms of sensation prevalence, the frequency of individual sensations was significantly higher in acupuncture than in tactile stimulation control. In addition, acupuncture elicits a unique set of sensations, as the occurrence of each sensation (with the exception of tingling) was distinct between acupuncture and tactile stimulation for each subject. Significant differences were found in the intensity of sensations between acupuncture and tactile stimulation control. Dull pain was significantly more intense in LI4 than in ST36. Aching, soreness and pressure appeared to be most important for the characterization of deqi. Use of the weighted average appeared to provide greater power in detection of the sensations specific to the deqi experience. All three points demonstrated correlation between aching and soreness, between heaviness and pressure, between dull pain and aching or soreness, and between tingling and numbness.

Clinical and experimental data indicate that not all human subjects and animals respond with deqi and benefit from acupuncture treatments. The ratio of responders to non-responders is estimated to be 8:2 or 7:3. The individual variations may be attributed to differences in the levels of endogenous opioids and anti-opioids [10]. The finding of an overall deqi response of 71–73% for all acupoints combined and 62–75% for individual acupoints is consistent with the purported percentage of acupuncture responders.

Among the many components of deqi sensations, aching, soreness and dull pain stood out as the most important characteristics of acupuncture not only because of their high frequency in acupuncture, but also because they were very uncommon in tactile stimulation (Tables 2, 3, 4, 5, Figure 2). They also showed correlation in intensity with one another by Spearman's analysis (Figure 4). These findings are consistent with reports in the literature. Aching was found to be the most frequent sensation in manual acupuncture at ST36 [8] and at LI4 [9]. Soreness correlated with the analgesic action of acupuncture [11]. The sensations demonstrated to be characteristic of deqi are in accord with the list based on a survey conducted among expert acupuncturists [12], although the data were collected with the subject lying in the scanner during fMRI and not under routine clinical conditions. The convergence of findings with a study based on clinical experience lends significant support to the experimental results in this report. Importantly our decision to treat sharp pain of any form to be uncharacteristic of deqi receives support from this survey. Although a "dull" sensation has been described [13], this is perhaps the first report of dull pain being an important component of the deqi response. We found that the dull pain generally occurred in deqi with higher total scores, and significantly more often at LI4, the acupoint known to have the stronger general analgesic actions. It was the only sensation that was not detected in tactile stimulation. Interestingly, the temporal relationship between dull pain and sharp pain was reversed in acupuncture deqi compared with noxious stimulation. The dull pain described in pain literature is often referred to as 'second pain' because it generally follows sharp pain [14], while in acupuncture the dull pain occurs independently or precedes sharp pain. Moreover, repeated fMRI studies have demonstrated that the pain neuromatrix in the limbic system is deactivated by dull pain in deqi, in marked contrast to its activation by noxious stimulation [7, 8]. Based on the characteristics of the dull pain revealed in the present study (Tables 2, 3, 4, 5, 6, 7, 8) and previous fMRI findings, the dull pain in acupuncture is distinct from the dull pain induced by noxious stimulation. The differences could be partly explained by involvement of different nerve fiber systems induced by different procedures. Most experimental studies on pain employed thermal stimulation delivered to the skin surface, while acupuncture needle manipulation delivered mechanical stimulation to nerve fibers at deeper levels.

Many sensations were shared by the deqi response generated at LI4, ST36 and LV3, but more careful examination of the data revealed differences in frequency, intensity and in the weights and rank ordering of individual sensations facilitated by the deqi composite. Consistent with the well-known potency of LI4 in analgesic and modulatory actions, acupuncture at LI4 produced the most prominent response in terms of the overall deqi experience, the number of sensations elicited and their intensities, as well as the prevalence of dull pain, an important characteristic of deqi as mentioned earlier. The differences between acupoints applied not only to acupuncture, but also to tactile stimulation (Table 1).

The differences in the sensory experience between acupoints in both acupuncture and tactile stimulation may be related to differences in the afferent innervations between acupoints. It is known that the dorsum of the hand is highly sensitive to touch, thermal and other sensory stimuli. In addition to the faster conducting myelinated Aβ fibers involved in the transmission of touch, vibration and numbness, hairy skin is supplied with a special C fiber system that delivers an affectionate sensation or 'limbic touch' to the brain [14, 19]. The gentle rhythmic tactile stimulus performed for control could also activate the tactile afferents to deliver sensations with a tranquilizing effect on the brain, although less common than acupuncture.

Compared with simple averages of intensity scores, the weighted averages reduced the variation between acupoints in regard to the differences of intensity between acupuncture and tactile stimulation control. Application of the deqi composite will convert the complex sensation profile of deqi to a single value, which can then be used for more straightforward comparisons between groups of subjects, between acupoints, and between stimulation techniques. These values will be useful for correlating the deqi response to clinical efficacy, and by neuroimaging, to the hemodynamic response of the brain to of acupuncture in future studies.

The complex sensations in deqi involve a wide spectrum of nerve afferents, ranging from the fast conducting, coarsely myelinated Aβ fibers with higher thresholds to the slow conducting fine unmyelinated C fibers with lower thresholds (Table 10). However, there is contention about which types of fibers play the major role in acupuncture deqi and acupuncture analgesia [2‐6]. The results of this study suggested that the majority of the deqi sensations, such as aching, soreness, dull pain, and warmth involved the slower conducting Aδ and C fibers. Pressure may not be a good discriminator because it involves several nerve fiber types. Numbness and tingling, relatively common in acupuncture, involve the Aβ fibers, but they are not as specific for acupuncture as the sensations mentioned above. As a matter of fact, tingling was the most common sensation in tactile stimulation (Table 5, Figure 2). The depth at which acupuncture exerts its action locally is not completely clear. Several conjoint psychophysical, electrophysiological and histological studies in humans indicate that deqi first appears when the needle reaches the muscle layers [2, 5, 6, 10]. Deep tissue afferents, but not cutaneous afferents mediated transcutaneous electrical nerve stimulation-induced antihyperalgesia [16]. However, it has been recently proposed that the more superficial connective tissue layers might be more important, based on the entwining of connective tissue around the acupuncture needle in animal models and ultrasound imaging in humans [17, 18]. The results of the present study suggest that nerve fibers at all levels are involved but the deeper muscle layers with its rich supply of slow conducting fibers may play the major role.

Most studies in the literature employ "non-point" or placebo acupuncture for controls. In this study tactile stimulation was delivered to the acupoints, not as an 'inert' control but for comparison of the response patterns. Many of the sensations comprising deqi in acupuncture also occurred with tactile stimulation, but at a significantly lower frequency and with a different pattern. Aching and soreness, most common in acupuncture, were rare in tactile stimulation, Tingling and numbness showed the highest frequency in tactile stimulation instead. The differences between acupuncture and tactile stimulation could be explained by the greater concentration of slower conducting Aγ, δ fibers in deeper tissue layers than in the skin [5, 6]. This may also explain why as high as 73% of tactile stimulation failed to elicit deqi versus only 2% in acupuncture. The low incidence of deqi in tactile stimulation could also explain why in earlier studies with small sample sizes, the tactile stimulation control might be underpowered to demonstrate the deqi response and the hemodynamic response associated with it [7].

The results also demonstrated differences between acupoints in their sensory response to tactile stimulation. Similar to acupuncture, LI4, ST36 and LV3 ranked in decreasing order with regard to the percentage of deqi response and the number of sensations. When thresholded at a total score of 3, deqi was as common as 37.5% at LI4 and only 7.7% at LV3, with ST36 at an intermediate level. The dorsum of the hand is known to be richer in afferent innervations and more sensitive to touch, thermal and other stimuli than the leg or foot. It could be supplied with the C tactile afferents that deliver a 'limbic' touch to the brain [15, 19]. One might speculate that the gentle rhythmic touch employed for tactile stimulation control could activate similar nerve fiber systems to produce a pleasant and tranquilizing effect on the brain.

One challenge common to most acupuncture research is in the design of a valid control. Since the distribution of nerve structures is ubiquitous, the minimal, superficial, sham, non-point or placebo acupuncture often employed in acupuncture research cannot be interpreted as inert controls [19]. We opted to use tactile stimulation at the acupoint, not for inert control, but for comparison with acupuncture. It would be desirable to compare the response at a 'non-acupuncture point" with classical acupoints in future studies; this was not performed because of time limitations Based on our results, an overlap of sensations between the classical acupoint and the non-point could be anticipated, depending on their tissue types and the distribution of afferent fibers and sensory receptors. It is reported that acupuncture at a non-meridian point elicited deqi sensations similar to those elicited at two classical acupoints, GB 37 and UB 60 [24]. In this study the sensations interview was conducted after a ten minute fMRI scan, within which the subjects had received two sets of two minutes of stimulation, not under typical clinical settings. Applications of these results to clinical settings warrant further investigation. To avoid bias on the part of the acupuncturist, the interview was conducted by another research staff on site. An alternative method would be projecting the questions onto a screen that the subject can view and provide answers by typing on a device while positioned in the scanner. However, the subject would be deprived of opportunities to clarify understanding of the questions and provide more detailed description of the sensations. The grading of the intensities of the individual sensations as well as the setting of a threshold for the deqi response is somewhat subjective. There is at present no reliable method to quantify any of the deqi sensations; it has to depend on subjective perceptions reported by the subject. We have set two thresholds of different astringency for analysis with different purposes. Importantly, the findings are specific to the manual acupuncture technique adopted and to acupoints located in muscle layers, the tissue type to which most acupoints belong. Other techniques such as electroacupuncture and acupoints located in the scalp, perisosteum and other types of tissues with different innervations would require additional investigation.