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From the Center for Advancement of Perioperative Health, Departments of *Anesthesiology, Diagnostic Imaging, Neurosurgery, Pediatrics, and ||Child Psychiatry, Yale University School of Medicine, New Haven, Connecticut.
Address correspondence and reprint requests to Shu-Ming Wang, MD, Department of Anesthesiology, Yale School of Medicine, 333 Cedar St., New Haven, CT 06510. Address e-mail to shu-ming.wang{at}yale.edu.
Abstract
BACKGROUND: There are conflicting data regarding clinical efficacy of acupuncture applied while patients are under general anesthesia. We hypothesize that these conflicting data are a result of the inhibitory effect of anesthesia on acupuncture-induced central nervous system activity that can be demonstrated using magnetic resonance imaging.
METHODS: Using a crossover study design, volunteers received standardized Stomach 36 manual acupuncture in two experimental conditions: while undergoing a propofol-based general anesthetic, and while awake. Functional magnetic resonance imaging was conducted during both experimental sessions. Paired-t-test analyses were performed to examine the differences in acupuncture-induced blood oxygenation level-dependent (BOLD) signals between awake and anesthesia conditions. A secondary analysis was performed to account for the changes in regional cerebral blood flow at six regions of interest (thalamus, red nucleus, insula, periaqueductal gray, retrosplenial cingular gyri, and the inferior temporal region).
RESULTS: Using BOLD, we found significant differences between the two experimental sessions in brain areas, including postcentral gyri, retrosplenial cingular area, left posterior insula, bilateral precuneus, thalamus, red nuclei, and substantia nigra (cluster 100, P < 0.01). A secondary analysis correcting for background cerebral blood flow found that BOLD signal differences between experimental conditions were not directly caused by changes in regional blood flow.
DISCUSSION: Propofol-based anesthesia reduces the neurophysiological response to acupuncture stimulation as measured by acupuncture-induced BOLD signals. Further work should be conducted to determine the clinical significance of these findings.
Although many clinicians currently promote the use acupuncture and related techniques in perioperative settings, the efficacy of these techniques is unclear. Specifically, inconsistencies in the efficacy of acupuncture for intraoperative analgesia (1,2), postoperative analgesia (3,4), and postoperative nausea and vomiting have been reported (5–12). Imaging techniques, such as positron emission tomography and functional magnetic resonance imaging (f MRI), have demonstrated that the clinical effects of both general anesthesia and acupuncture are modulated by the central nervous system (CNS) (13–17). After careful consideration of this literature, we suggest that some of these inconsistencies may be related to the inhibitory effects of general anesthesia on acupuncture-related activity within the CNS.
Among all imaging modalities, f MRI is of special utility in the study of anesthesia and acupuncture because it allows for the assessment of brain activities without the need for exogenous contrast material. That is, f MRI provides a measure of brain activity by evaluating differences in blood oxygenation levels under controlled experimental conditions. These differences in blood oxygenation levels are quantified by gradient echo-planar imaging blood oxygenation level-dependent (BOLD) contrast. BOLD contrast is the net result of oxygen consumption (cerebral metabolic rate of O2 consumption) and the hemodynamic response to changes in O2 demand.
In consideration of our hypothesis regarding the inhibitory effects of general anesthesia on acupuncture-related CNS activities and previous reports involving f MRI of the brain and acupuncture stimulation, we decided to examine the impact of propofol-based general anesthesia on acupuncture-induced BOLD signals.
METHODS
The Human Investigation Committee at Yale School of Medicine approved the study. All subjects provided informed consent. Healthy, right-handed, ASA physical status I volunteers were enrolled in this crossover study that included an awake-session and a general-anesthesia-session. Exclusion criteria included a recent history of acute illness, history of substance abuse, pregnancy, and previous experience with acupuncture. All volunteers received a small monetary compensation for their time and effort. Volunteers were instructed to avoid caffeine and alcohol consumption for a period of 24 h before the study and to follow standard ASA recommended NPO guidelines (i.e., NPO for solid food after midnight and NPO for clear liquid up to 2 h before study session).
Experimental Protocol
On the day of the experiment, an anesthesiologist (D.F.) obtained a preanesthesia history, conducted a standard screening questionnaire for metal, and completed a physical examination. All volunteers underwent two separate f MRI scanning sessions, once while awake and once while anesthetized. The sessions were conducted at least 4 h apart to minimize carryover effects. The general anesthesia session always began at 8:00 am and the awake session always followed at 12:00 pm.
Acupuncture
The first author (S.M.W.) performed acupuncture stimulations at the left ST 36 acupoint, traditionally known as the Zusanli acupoint (Fig. 1). This acupuncture point is located on the anterior aspect of the leg in the tibialis anterior muscle, just below the tibia tuberosity and 1.5 "cun"1 lateral to the tibia. We choose the ST 36 site because previous imaging studies involving this acupuncture point have demonstrated its effects on the CNS (17–19). For example, Wu et al. (17) showed that acupuncture stimulations at ST 36 and LI 4 enhanced BOLD signals (activation) of descending antinociceptive pathways, whereas at the same time lessening BOLD signals (deactivation) at multiple limbic areas involved in processing of pain signals. ST 36 is also one of the most frequently studied acupoints for initiation of acupuncture-induced analgesia (20). As this acupuncture point is located in the leg, it poses little risk in interfering with the f MRI imaging process.
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Acupuncture stimulation was performed with a sterile, single use, individually wrapped acupuncture needle (0.3 mm [multi] 3 cm; SEIRIN, OMS Medical Supplies, Braintree, MA). To assure that the acupuncture stimulation paradigm was uniform for every volunteer in every experimental condition, a paradigm was programmed and projected on a screen visible to the acupuncturist. When the projection screen showed "acupuncture on," the acupuncturist manipulated the needle by twirling it approximately 90° and lifting-thrusting it approximately 0.6–1.0 cm. This was done in a balanced, reinforcing, and reducing manner at about 1 Hz for 20 s (17). When the projection screen showed "acupuncture off," the acupuncturist stopped the acupuncture stimulation for 20 s. The experimental paradigm called for eight cycles consisting of 20-s periods of acupuncture stimulation, alternating with 20-s periods of no stimulation. The difference in BOLD signal between these two states constituted the acupuncture-stimulated BOLD signal used in the analysis.
Since volunteers could not report the subjective "De Qi" sensation (soreness, numbness, heaviness) while undergoing general anesthesia, the acupuncturist used the widely used technique of "needle grasp" akin to that of a "fish taking bait," to determine that she was applying the appropriate acupuncture stimulation. This needle grasp sensation is accepted in the literature as a biomechanical phenomenon that involves connective tissue (21–23). It is important to note that the acupuncturist relied on the needle grasp sensation in applying the stimulation in both awake and anesthetized experimental sessions.
General Anesthesia Session
For the propofol general anesthesia session, an IV cannula was inserted when the patients was in the holding area and an infusion of lactated Ringer’s solution at 40 mL/h was initiated. Each participant was monitored with Bispectral Index (BIS) (Aspect, Boston, MA) and MRI compatible-standard ASA monitors (electrocardiography, arterial blood pressure, Spo2, and ETco2). General anesthesia was induced using 1–2 mg/kg IV propofol administered over a period of 3 min to achieve a BIS value of 40 ± 10. A continuous propofol infusion of was then started at 120–150 µg · kg–1 · min–1. All participants were kept in the holding area for 15 min to assure that vital signs were stable and that the BIS was maintained at 40–60. The BIS target range was selected based on data associating this BIS value with general anesthesia (24,25). All participants were breathing spontaneously with O2 saturation 
95% in room air without airway intervention. The participants were closely monitored. If any of the participants had required an oral airway insertion, the study would have been aborted.
Next, the BIS monitor was removed and volunteers were transported into the MRI scanner with continuous ASA standard monitors and a continuous propofol infusion at a rate that was shown to maintain BIS at 40 ± 10. While in the scanner, the propofol infusion was continued at the same rate and participants were continually monitored using the ASA standard monitors as described above. The acupuncture intervention, auditory stimulations, and the sequence of image data acquisition were performed as described below. After completion of the general anesthesia session, all participants were transported to a recovery area equipped with standard monitors and staffed by an anesthesiologist.
Awake Session
In the afternoon, at least 4-h later, participants underwent the same acupuncture intervention and f MRI sequence of image data acquisitions as in the morning general anesthesia session. After the completion of the awake session, all participants were asked about "De Qi" sensations and the IV line was then removed.
Imaging Data Acquisition
f MRI was performed using a 1.5 T field strength, whole body MRI scanner (Siemens Sonata, Erlangen, Germany). Each study session began with a three-plane localizer scan (20 s) to position the brain within the scanner. After the sagittal localizer was applied, baseline images were obtained through inversion recovery of T1-weighted scan (TI/TE/TR = 800/11/1800, 256 x 192 x 2 nex) every 3 mm thick, skip 0.5 mm, FOV = 22 cm. A total of 16 slices were obtained. This acquisition was used to define the ac–pc line for prescription of the anatomic T1 images and functional images in the following series. Axial-oblique T1-weighted images were recorded and used as basic anatomic images that were later registered to the 3D high-resolution acquisition obtained at the end of the study. TI/TE/TR = 800/11/1800 ms, 256 x 192 x 2 nex, 5 mm thick, skip 0 mm, FOV = 22 cm, 22 slices. FMRI using gradient echo echo-planar imaging BOLD contrast was then run during the task. As described above, the task consisted of three paradigms of eight cycles alternating between 20 s of "acupuncture on" followed by 20 s of "acupuncture off." After the acupuncture task was completed, an auditory stimulation paradigm was run as a control task. The auditory stimulation paradigm consisted of eight blocks of 30 s of auditory stimuli presented binaurally. The 30 s of auditory stimuli consisted of random tones presented for 250 ms with an interstimulus interval of 750 ms, such that 30 random tones were presented per block. The tones were randomly selected from a set of six pure tones (frequencies of 200, 400, 600, 1000, 1200 Hz). The echo-planar imaging parameters were, flip angle = 80°, TE = 45 ms, TR = 1800 ms, matrix 64 x 64, 108 images per slice.
Analysis of fMRI Data
Data motion was corrected using SPM-99 and Gaussian blurring function with FWHM 6.25 mm. General Linear Model was used to examine the response to the stimulus, and a spatially varying autoregressive (AR(p)) model for the temporal errors. The minimum variance estimator of the parameters b of the General Linear Model (Y = Xb + e), was obtained by least squares after prewhitening the errors. The prewhitening was achieved by multiplying the measurement vector Y and the model matrix X by a matrix A such that the variance of the resulting errors was proportional to the identity matrix as described by Worsley et al. (26). Modeling the errors as an AR process permits efficient computation of the whitening matrix, A. Contrasts between the b parameters can then be tested for the null hypothesis that there is no effect of propofol general anesthesia. ß Maps were stored and converted into the multisubject data space using our registration software (27). Correction for multiple comparisons was performed using the cluster-size threshold (100 for this particular study) approach described by Forman et al. (28) and similar to that implemented in AFNI (http://afni.nimh.nih.gov/afni/). The Talairach coordinate system was defined in this common brain space such that all activations were reported using Broadman’s area definitions and Talairach coordinates. Group data were analyzed in a second-level analysis where baseline absolute cerebral blood flow (CBF) was taken into consideration. Such second level analysis allows the influence of baseline CBF changes caused by propofol to be dissociated from signal changes associated with acupuncture stimulation (P < 0.01).
Regional-of-Interest Delineation
Six regional-of-interests (ROIs) were selected for analysis based on the preliminary examination of the results. Anatomical structures were designated according to coordinates from the brain atlas implemented in the program used for area localization. A paired t-test was used to compare results between acupuncture awake and acupuncture under propofol general anesthesia conditions (cluster 100, P < 0.05).
RESULTS
Eleven right-handed volunteers, nine men and two women, aged 28 ± 4 yr, completed the experimental protocol described above. None of the volunteers required any airway intervention while under propofol general anesthesia and none experienced Spo2 below 95%. Arterial blood pressure and heart rate values did not differ significantly between the preintervention period, intraintervention period, and postintervention period (P = ns). The average BIS value was 47 ± 6 in the holding area before transferring to the f MRI scanner with a continuous propofol infusion rate of 120–150 µg · kg–1 · min–1 throughout the scanning process. No subject reported any recall during the general anesthesia session. De Qi sensations were reported by all subjects while undergoing the awake-session during acupuncture stimulation, including numbness with and without radiation (2 of 11), aching (4 of 11), discomfort (4 of 11), and stinging sensation (3 of 11). As indicated above, the acupuncturist experienced the traditional needle grasp sensation in all acupuncture interventions during both awake and general anesthesia sessions.
f MRI obtained during the awake session showed areas of acupuncture-induced activation in bilateral postcentral gyri corresponding to the primary and secondary somatosensory cortices (SI and II), left superior temporal gyrus, thalamus, left posterior insula, left pallidum, left inferior temporal gyrus, mesencephalon, red nuclei, substantia nigra, and right basis pedunculi (cluster 100, P < 0.01) (Fig. 2). In contrast, during the general anesthesia session, areas of acupuncture-induced activation were observed in the right precentral gyrus corresponding to the motor cortex, left frontal pole, and right occipital gyrus. Additionally, there were areas of acupuncture-induced deactivation in the left postcentral gyrus corresponding to SI and SII, right cerebellar hemisphere, and right inferior temporal gyrus (cluster 100, P < 0.01) (Fig. 3).
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Paired-t-test analysis of awake versus anesthetized acupuncture sessions found significant differences in bilateral postcentral gyri, cingular gyrus, left inferior frontal gyrus, retrosplenial area, left posterior insula, bilateral precuneus, thalamus, red nuclei, substantia nigra, right basis pedunculi, and left middle temporal regions (cluster 100, P < 0.01) (Fig. 4). The Talairach coordinates of these areas are presented in Table 1.
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After preliminary examination of the results, six ROIs were selected for direct comparison between BOLD signal induced by acupuncture stimulation under awake and general anesthesia conditions. These six ROIs were the thalamus, red nucleus, insula, periaqueductal gray (PAG), retrosplenial cingular gyri, and inferior temporal region. In addition, BOLD signals and regional CBF (rCBF) of the auditory cortices were also analyzed for control purposes. Relative differences in these regions in both BOLD signals and rCBF can be seen in Figure 5. After incorporating the baseline CBF of the awake and general anesthesia sessions into a secondary level of analysis, we found that both the differences of auditory and acupuncture-induced brain activities between awake and under general anesthesia states cannot be attributed solely to changes in baseline CBF.
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DISCUSSION
Under the conditions of this study, we found that acupuncture administrated to volunteers who were awake induced a unique neurophysiological response that was demonstrated by f MRI. These findings are in line with previous publications in this area (15,16,18). We also demonstrated that this acupuncture-related neurophysiological response was significantly reduced by general anesthesia, and that this effect was not attributed to changes in baseline rCBF.
The limbic system is of great interest in acupuncture research. Hui et al. (18) performed an f MRI study that examined the effects of ST 36 acupuncture on the cerebellar and limbic systems. These investigators found a predominance of deactivations, when subjects experienced the De Qi sensation during acupuncture stimulation. Our findings of deactivation in the retrosplenial cortices, right cerebellar hemisphere, and inferior temporal cortex are consistent with their data. Interestingly, our data differ from their findings in that we observed activation of the insula, whereas Hui et al. found deactivation of the insula. We also recorded increased activity in the PAG area, whereas Hui et al. did not note any changes in that region. These discrepancies between the findings are likely due to significant differences in the f MRI protocols used in both studies and the threshold used for data analysis.
The insula is associated with higher functions of pain perception; it receives input from the thalamus, which, in turn, receives input from the spinal–thalamic tract that carries nociceptive input. Our results indicate activation in the left posterior insula in the awake acupuncture setting, which is consistent with its function in processing noxious and somatesthetic stimuli. This activation has been demonstrated in other studies in that only true acupuncture (not sham acupuncture) activates the insula ipsilateral to the stimulation (29,30). Activation of the insula was also observed in other acupuncture studies using positron emission tomography and f MRI (13,29,30). In addition, the anterior insula is thought to be associated with the anticipation of painful stimulation (31). The lack of activation in the anterior insula in the awake acupuncture session also indicates the absence of a confounding factor in the form of anticipation among the subjects. Indeed, all participants in the study were acupuncture naive and none of these participants had any recall of receiving acupuncture during the general anesthesia session. Our study also demonstrated acupuncture-induced activation in the PAG area in the awake condition. Notably, Hui et al. did not record this data point. The role of the PAG in analgesia is quite complex, involving multiple neurotransmitter systems and it has extensive connections with several regions of the brain that are involved in the interpretation of sensory data. The PAG activation we observed does correlate with a finding by Liu et al. (16) that acupuncture at LI 4 activates the PAG, whereas nonacupoint stimulation actually causes a deactivation.
Similar to many anesthetics, propofol has a direct effect on the rCBF of some areas in the brain. Hofbauer et al. reported that a low-plasma concentration of propofol has no effect on rCBF, whereas high-plasma concentration propofol does cause a marked decrease in rCBF in the thalamus and cingulate cortex areas (32). In humans, propofol is reported to enhance pain-evoked responses in the thalamus and anterior cingulated cortex in mild sedation situations, but these pain-evoked responses (both in the thalamus and anterior cigulate cortex) disappear while the response of insula remains when subjects become unconscious (32). In the current study, we observed that acupuncture-induced activity in the insula was completely suppressed under propofol general anesthesia. A possible explanation is that even though both pain and acupuncture stimulations are processed through the insula, they have two distinctive functions. Indeed, the literature indicates that there is a significant overlapping central pathway activated by acupuncture and by pain (13).
To confirm that the suppression of acupuncture-related BOLD signals under propofol general anesthesia is not due to rCBF changes, we performed a second level analysis that accounted for the background rCBF. Our results indicated that the magnitude of the BOLD signal differences between awake and general anesthesia states was not solely explained by the changes in rCBF. Although our study design was not focused on differentiating the suppression of BOLD signals under propofol general anesthesia caused by decreased metabolic activities or uncoupling of blood flow, several articles indicate that changes in CBF caused by propofol are a reflection of the decreased cerebral metabolic requirement (33,34). Thus, the most likely cause of this suppression of acupuncture-induced BOLD signals under propofol general anesthesia is the direct decrease in neuronal activities.
Several methodological limitations of this study should be noted. First, although we understand the importance of a placebo or sham-controlled study, we did not use a placebo or sham stimulation in order to avoid the common limitation that results from an inconsistent control due to varying types of sham acupuncture (17). We therefore performed the true acupuncture stimulation when volunteers were awake and under propofol general anesthesia and compared the different areas of CNS activities seen on f MRI, rather than comparing real acupuncture with sham acupuncture. The reader should note that the experimental paradigm consisted of acupuncture on and acupuncture off, and that the results of our study are derived from the BOLD differences between these two conditions; therefore, we had control of with/without acupuncture brain images. Second, using a crossover design we decided a priori not to randomize the order of sessions but, rather, to do all general anesthesia sessions in the morning and all awake sessions 4 h later. This was done mainly to minimize the NPO period required for the volunteers. In avoiding randomization, however, we may have introduced a confounding effect, as traditional acupuncturists believe flow of energy varies with time of the day. Another potential methodological issue is the possibility of a carryover effect between the morning and afternoon acupuncture sessions. We selected a 4-h time interval between the experimental conditions in order to minimize the potential for carryover. There are data suggesting that acupuncture analgesia decays exponentially with a half-life of about 16 min (35). If this is the case, there should be almost no residual effect by 160 min (10 half-lives). Randomization of experimental sequences would have controlled for any effect of time of day or carryover effects.
In conclusion, we have confirmed our initial hypothesis that propofol general anesthesia has a significant dampening effect on the neurophysiological response to acupuncture, as reflected in the acupuncture-induced BOLD signals. The reader should note, however, the limitations on interpretation of the data introduced by our nonrandomized crossover design. Although our results are not geared toward clinical or functional end-points, our findings may begin to explain the discrepancy observed in earlier research regarding the clinical efficacy of acupuncture in the operative and perioperative period. Future studies should focus on elucidating the impact of various levels of consciousness and different anesthetics on the acupuncture-induced BOLD signal changes in selective CNS areas, as well as the clinical and mechanistic implications of these findings.
Footnotes
1cun: Unit for Chinese length measurement that is equal to body inch; 1 cun is defined as the width of the first interphalangeal joint. 
Accepted for publication May 3, 2007.
Supported by National Institutes of Health, NCCAM, R21AT001613-01 (to S.M.W.) and NICHD, R01HD37007-02 (to Z.N.K.), Bethesda, MD.
REFERENCES
This article has been cited by other articles:
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  S.-M. Wang, S. Escalera, E. C. Lin, I. Maranets, and Z. N. Kain Extra-1 Acupressure for Children Undergoing Anesthesia Anesth. Analg., September 1, 2008; 107(3): 811 - 816. [Abstract] [Full Text] [PDF]
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