In this pilot study, we applied an integrative multimodal imaging approach (fMRI and [11C]diprenorphine PET) to investigate the brain mechanisms involved in verum acupuncture stimulation compared with placebo needle stimulation. Interestingly, the two imaging modalities revealed predominantly divergent findings. The fMRI study showed fMRI signal increases during verum acupuncture in the right orbitofrontal cortex and fMRI decreases during verum acupuncture in the left insula and bilateral brainstem. The PET study showed greater [11C]diprenorphine binding decreases during verum acupuncture in the right orbitofrontal cortex, left medial PFC, right thalamus, and right insula and greater [11C]diprenorphine increases during verum acupuncture in the bilateral insula, right medial PFC/ACC, left OFC, and right brainstem. Our results showed involvement of some brain regions only in fMRI results and the involvement of other brain regions only in [11C]diprenorphine PET results. For these two modalities, there was convergence only in the right medial OFC.
Despite acupuncture having been used for more than 2000 years to relieve pain, scientific validation is incomplete and the underlying mechanisms of the therapy are only partly understood. It is now widely held that a critical component of acupuncture analgesia is its mediation by endogenous opioids [4
]. Yet, directly linking the specific brain regions with endogenous opioid release during acupuncture needle stimulation in human beings remains to be experimentally undertaken.
Recently, functional magnetic resonance imaging (fMRI) has been used to investigate the neurobiological mechanisms underlying acupuncture needle manipulation [11
]. It is commonly reported that manual acupuncture needle manipulation induces fMRI signal change in widespread neuronal networks. Many of the brain regions affected by acupuncture needle manipulation are known to contain high concentrations of opioid peptides or opioid peptide receptors. However, the exact brain regions that are involved in the endogenous opioid release remain unclear. In the current study, as expected, some brain regions had significant fMRI signal changes without corresponding changes in [11C]diprenorphine BP and vice versa. While these findings are informative (and will be discussed below), the goal of the current multimodal study was to look for regions of overlap. We would posit that overlapping changes may represent a relationship between fMRI signal and [11C]diprenorphine BP changes in these brain regions. In the current study, the only brain region that exhibited such an overlap between modalities was the right medial OFC. These results suggest that right medial OFC may be an important brain region involved in endogenous opioid modulation during acupuncture analgesia. Other fMRI signal changes may be mediated by other neurotransmitters or, given the small sample size, there may not have been enough statistical power to detect an overlap. Conversely, there are also [11C]diprenorpine BP changes without a corresponding change in fMRI signal in some brain regions. Again, this may be attributable to the small sample size. While the common finding of changes in fMRI signal and [11C]diprenorphine BP in the right medial OFC are intriguing, further studies should be conducted.
Previous studies suggest that the orbital prefrontal cortex can be roughly divided into two interacting networks: the orbital prefrontal network and medial prefrontal network [30
]. The first consists of the agranular insular areas and orbital areas 13b, 13l, 13m, 11l, 12r, 12m and 12l. This network receives signals related to sensory inputs and seems to play an important role in sensory integration. Another network, the medial prefrontal network, consists of all areas on the medial wall including 25, 32, 14r, 14c, 24a, 24b, 11m, 13a, Iai and 12o. Studies suggest these brain regions constitute the origin of the descending projections to the hypothalamus and periaqueductal gray (PAG). The medial orbital prefrontal cortex observed in our study is located near area 11m and thus would project into the medial PAG and hypothalamus.
It is well known that the PAG plays a crucial role in the descending pain inhibition system. For instance, studies suggest that stimulation of specific regions of the midbrain, PAG and surrounding areas could inhibit pain responses to noxious stimulation in both animal studies [27
] and patients suffering from pain disorders [1
]. It has been hypothesized that acupuncture may somehow trigger this descending inhibition system to produce an analgesic effect. This hypothesis has been supported by experiments performed on animals, where it has been found that PAG lesions abolish acupuncture analgesia [39
]. Thus, we speculate that fMRI and PET activation in the medial OFC may indicate the activation of the descending pain inhibition system.
Previous studies in healthy control subjects have demonstrated high uptake of [11C]diprenorphine in diffuse cortical areas known from postmortem studies to have high concentrations of opioid receptors [36
], particularly in subcortical (thalamus) and cortical (insula, prefrontal, and ACC) components of the affective pain network [12
]. Chronic pain studies have demonstrated decreased [11C]diprenorphine binding potential (BP: the ratio of receptor occupancy [Bmax
] to affinity [KD
]) in brain regions associated with the affective pain network (insula, ACC and frontal lobe) during pain states when compared to non-pain states [13
]. Decreased [11C]diprenorphine BP is hypothesized to represent increased binding of opioid receptors by endogenous opioids. Conversely, [11C]diprenorphine BP in components of the affective pain network was significantly increased in a cohort of patients after surgical relief of trigeminal neuralgia pain [14
], consistent with the hypothesis that relief of pain is associated with decreased endogenous opioid release. Recent studies using a high affinity mu-selective opiate agonist, [11C]carfentanil, and PET have demonstrated decreased mu opioid receptor BP in the thalamus and amygdala following administration of acute experimental noxious stimuli consistent with the hypothesis of pain-induced release of endogenous opioid peptides [2
One limitation in our study is the small sample size. Although we found convergence with our two modalities of brain imaging tools only in the right medial OFC , there is no doubt that a whole network is involved in acupuncture analgesia. Thus, we speculate that if the sample size was dramatically increased, additional brain regions may show up as convergences. In any case, this pilot study suggests the potential power of using multiple imaging tools in acupuncture mechanism studies. It must additionally be noted that in order to maximize effective use of expensive neuroimaging resources, we only scanned subjects who responded to acupuncture in earlier sessions. This may limit how fully our data sample represents the general public. Further study is needed at this point.
In this experiment, given the unknown duration of acupuncture treatment effects, the first PET scan was always a baseline test and second PET scan was either a sham or active treatment, depending on a subject’s group randomization. Since our study only compared the difference between verum and placebo acupuncture, the order effect should not have significantly influenced our result.
In summary, common fMRI and PET signal changes may represent a specific marker for endogenous opioid driven changes in neural activity, a pharmacologically specific marker for fMRI signal change. Such studies may increase our understanding of which BOLD signal changes are associated with endogenous opioid release and which BOLD signal changes may be mediated by other neurotransmitter systems. Overall, these preliminary results suggest that integrative multimodal imaging studies have the potential to help elucidate the neural mechanisms of acupuncture.