Female and male brains are similar in many aspects but different in others, which could lead to similar but also sex different neural responses depending on environmental stimuli (Witelson, 1991; Cahill, 2006). Pain shows gender variations that might influence acupuncture treatment (Lund and Lundeberg, 2008
). This study revealed gender differences in the level of response and the preferential spatial distribution in each task-negative or task-positive network during needle manipulation of acupuncture (; , and ) despite the similarity in the general pattern of hemodynamic response (Hui et al., 2005; Bai et al., 2007; Fang et al., 2008). Brain activities induced by needle stimulation during acupuncture shown in this study can be interpreted as deactivation/activation during an attention demanding task, e.g. a sensory stimulation relevant to the resting state. Interestingly, needle manipulation during acupuncture had effects with gender differences not only on the brain regions related to sensation but also on the networks related to cognition and emotion.
Needle manipulation during acupuncture induced significantly stronger deactivation of the LPNN/DMN system especially at the posterior cingulate (BA31), precuneus and angular gyrus in females but stronger activation at the sensorimotor network (SII) in males (, and ). The brain shows gender differences early in development (Joseph, 2000
; Cosgrove et al., 2007), and the differences continue to be subtle but significant as the brain matures (Kovalev et al., 2003
; Cahill, 2006). Gender differences are observed in endogenous opioids (Dahan et al., 2008
), dopaminergic, serotonergic, and gamma-aminobutyrinergic markers (Kovalev et al., 2003
) indicate that male and female brains are neurochemically distinct, and all these neurotransmitters are shown to be modulated by acupuncture (Han et al., 1980; Chen et al., 2008; Yang et al., 2008). Therefore, the gender different patterns induced by needle manipulation during acupuncture are likely to reveal the sex dimorphisms of brain, which is also observed in the cognitive or emotional tasks.
Acupuncture induced deactivation of core structures at the three hubs of the DMN: 1) the medial prefrontal lobe; 2) the amygdala, hippocampus and parahippocampus at the medial temporal lobe and 3) the posterior cingulated (BA31), precuneus and retrosplenial cortex at the medial parietal cortex (). Greater deactivation in females than in males was especially significant at BA31 and precuneus (). At LV3 acupoint, the average responses were deactivations in females vs. activations in males at the DMN regions (). The functional connectivities between BA31 and the pregenual cingulate (PCG) or hippocampus were much stronger in females than males ( and ). All these brain structures influenced by the needle manipulation mediate cognitive and emotional tasks with gender differences. For example, BA31 and precuneus are the brain structures involved in cognitive decline and the development of Alzheimer's disease (AD) (Miller et al., 2008
), and being a female is a risk factor to develop AD (Sotiropoulos et al., 2008
). In the resting state, women have relatively higher glucose metabolism than men at the posterior cingulate (BA31) of the DMN (Gur et al., 1995
). Animal studies demonstrate that sex influences the role of the hippocampus in memory and learning (Shors et al., 2001
), and in responding to chronic stress (McEwen, 2002
). Women exhibit greater activation in the middle, inferior, and orbito-frontal cortices than men shown by fMRI when conducting tasks of auditory verbal working memory (Goldstein et al., 2005
). Men and women have different activated patterns in the frontal, mid-temporal and occipitoparietal cortex when performing phonological or spatial or verbal fluency tasks (Gur et al., 2000; Halari et al., 2006
The angular gyrus, a limbic-associated structure, revealed substantial gender differences during acupuncture, a new finding with potential significance. The angular gyrus was deactivated and had positive correlation with the posterior cingulate (BA31) in females; however, it was activated and had anticorrelation with BA31 in males ( and ). Traditionally female social activities such as child rearing may have contributed to the functional evolution of the angular gyrus (Joseph, 2000
). Imaging studies show that gender differences for antisocial, violent, and psychopathic behavior may in part be attributable to differences in the dorsal and ventral prefrontal cortex, amygdala, and angular gyrus (Raine et al., 1997; Miczek et al., 2007; Proverbio et al., 2008
). When mediating cognitive tasks, the angular gyrus is activated in men but not so in women (Halari et al., 2006
). The angular gyrus is functionally connected with amygdala when responding to emotional face expression (Iidaka et al., 2001
). Gender differences also exist in the size and activities of amygdala (Goldstein et al., 2001; Seifritz et al., 2003; Hamann et al., 2004; Cahill et al., 2004). The amygdala and hypothalamus demonstrated deactivation during acupuncture, but did not show significant gender differences in this study ().
, induced by needle manipulation, is essential for clinical efficacy of acupuncture according to traditional Chinese medicine, there is no universally agreed metric for deqi
). While it is possible that the anticorrelated areas were artificially introduced by global signal regression in the seed-based correlation analyses (Murphy et al., 2009
), it is noteworthy that the severity of soreness in deqi
was not correlated with the activation of the somatosensory cortex but rather with the deactivation of the brain networks controlling emotion and cognition, further suggesting another major pathway for the mediation of acupuncture action. Additionally, the scores of soreness, a major component of deqi
sensations, were correlated with deactivation at the angular gyrus and visual cortex (BA18/19) only in females; but no such correlations were observed in males (). One possibility is that females and males process pain or other sensations by acupuncture differently in the brain, thus women seek acupuncture treatment more frequently than men (Ben-Arye et al., 2009
). Another possibility is that deqi
during acupuncture is not completely parallel with the brain activities. Women and men have different activation at the brain regions including BA31 when viewing painful stimuli (Proverbio et al., 2009
). Gender differences in the brain activities when conducting cognitive or emotional tasks were observed at the DMN and limbic regions even when the behavioral outcomes of the tasks between females and males do not show differences in the scores of cognitive tasks (Grabowski et al., 2003; Piefke and Fink, 2005).
Since this study was not originally designed for gender differences in acupuncture, there are limitations. Considering the effects of circulating sex hormones accounting for partly sex difference, one limitation was the lack of information on the menstrual circle phase of the females. Although potential subjects with known depression or anxiety were excluded from the study, we did not conduct a formal psychiatric examination to evaluate any unreported psychiatric disorder. Psychological tests are probably needed to examine the baseline mental status of the subjects and to correlate with the brain function. We cannot completely rule out the possibility that men might have been less likely than women to report sharp pain during acupuncture, which would enhance activation and attenuate deactivation of the brain systems in males (Hui et al., 2007
). However, women and men did not show differences on reporting dull pain and aching (), arguing against that men only underreported sharp pain in our study. This study was to examine the sex differences of brain responding to a part of the acupuncture procedure, e.g. sensory stimulation by needle manipulation. Since needle manipulation evoking deqi
sensation is an important factor for the efficacy of acupuncture, this study suggests that the gender effect probably exists in acupuncture treatment and needs to be considered when conducting an acupuncture study.