Sex similarities and differences in pain-related periaqueductal gray connectivity

P.A.I.N. Group, McLean Hospital, Belmont, MA, USA.
Pain (Impact Factor: 5.21). 12/2011; 153(2):444-54. DOI: 10.1016/j.pain.2011.11.006
Source: PubMed


This study investigated sex similarities and differences in pain-related functional connectivity in 60 healthy subjects. We used functional magnetic resonance imaging and psychophysiological interaction analysis to investigate how exposure to low vs high experimental pain modulates the functional connectivity of the periaqueductal gray (PAG). We found no sex differences in pain thresholds, and in both men and women, the PAG was more functionally connected with the somatosensory cortex, the supplemental motor area, cerebellum, and thalamus during high pain, consistent with anatomic predictions. Twenty-six men displayed a pain-induced increase in PAG functional connectivity with the amygdala caudate and putamen that was not observed in women. In an extensive literature search, we found that female animals have been largely overlooked when the connections between the PAG and the amygdala have been described, and that women are systematically understudied with regard to endogenous pain inhibition. Our results emphasize the importance of including both male and female subjects when studying basic mechanisms of pain processing, and point toward a possible sex difference in endogenous pain inhibition.

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    • "Fear, anxiety, and pain are all conditions of negative affect that afflict women to a higher degree than men (Bartley and Fillingim, 2013; McLean and Anderson, 2009). The neural substrates of these conditions, which include the amygdala, anterior cingulate cortex (ACC), insula, periaqueductal grey, and prefrontal cortex (Linnman et al., 2012; May, 2007; Shin and Liberzon, 2010; Simons et al., 2014), overlap with and subserve extinction of conditioned fear (Milad and Quirk, 2012). These regions also demonstrate sex differences related to negative affect (Donner and Lowry, 2013; Lebron-Milad and Milad, 2012; Stevens and Hamann, 2012), and we have reported sex differences in the task-related functional activation of parts of this network during acute pain (Linnman et al., 2012), fear conditioning, and fear extinction (Lebron-Milad et al., 2012). "
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    ABSTRACT: The amygdala is a hub in emotional processing, including that of negative affect. Healthy men and women have distinct differences in amygdala responses, potentially setting the stage for the observed sex differences in the prevalence of fear, anxiety, and pain disorders. Here, we examined how amygdala subnuclei resting-state functional connectivity is affected by sex, as well as explored how the functional connectivity is related to estrogen levels. Resting-state functional connectivity was measured using functional magnetic resonance imaging (fMRI) with seeds placed in the left and right laterobasal (LB) and centromedial (CM) amygdala. Sex differences were studied in 48 healthy men and 48 healthy women, matched for age, while the association with estrogen was analyzed in a subsample of 24 women, for whom hormone levels had been assessed. For the hormone analyses, the subsample was further divided into a lower and higher estrogen levels group based on a median split. We found distinct sex differences in the LB and CM amygdala resting-state functional connectivity, as well as preliminary evidence for an association between estrogen levels and connectivity patterns. These results are potentially valuable in explaining why women are more afflicted by conditions of negative affect than are men, and could imply a mechanistic role for estrogen in modulating emotion.
    No preview · Article · Sep 2015 · Psychoneuroendocrinology
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    • "We chose to create this functionally rather than an anatomically defined mask, as PAG is involved in a number of functions not related to pain. This functionally defined mask covers the coordinates reported for pain, acupuncture and placebo, as identified in a recent meta-analysis (Linnman et al., 2012b), as well as a number of other studies (Kucyi et al., 2013; Zyloney et al., 2010). Connectivity of PAG seed with the anatomically defined bilateral Hpc (combined volume 38,189 mm 3 ) and MFC (volume 30,833 mm 3 ) (based on the Harvard–Oxford cortical and subcortical structural atlases, implemented in CONN) was examined. "
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    ABSTRACT: Acupuncture, an ancient East Asian therapy, is aimed at rectifying the imbalance within the body caused by disease. Studies evaluating the efficacy of acupuncture with neuroimaging tend to concentrate on brain regions within the pain matrix, associated with acute pain. We, however, focused on the effect of repeated acupuncture treatment specifically on brain regions known to support functions dysregulated in chronic pain disorders. Transition to chronic pain is associated with increased attention to pain, emotional rumination, nociceptive memory and avoidance learning, resulting in brain connectivity changes, specifically affecting the periaqueductal gray (PAG), medial frontal cortex (MFC) and bilateral hippocampus (Hpc). We demonstrate that the PAG-MFC and PAG-Hpc connectivity in patients with chronic pain due to knee osteoarthritis indeed correlates with clinical severity scores and further show that verum acupuncture-induced improvement in pain scores (compared to sham) is related to the modulation of PAG-MFC and PAG-Hpc connectivity in the predicted direction. This study shows that repeated verum acupuncture might act by restoring the balance in the connectivity of the key pain brain regions, altering pain-related attention and memory.
    Full-text · Article · Sep 2015 · Clinical neuroimaging
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    • "Chronic pain is a complex experience that involves several neural networks tied to sensation, motor activity, cognition, and emotion . Brain regions often associated with the pain experience include the primary and secondary somatosensory cortex (S1 and S2), spinal cord, thalamus, insula, anterior cingulate cortex, prefrontal cortex [3] [60] [78], midbrain areas including the periaqueductal gray [44] and cerebellum [52], and subcortical structures including the hippocampus, basal ganglia, and amygdala [9] [48] [65] [72]. There is a growing interest in the cognitive and emotional aspects of pain [10] with the amygdala emerging as a key region of interest [72]. "
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    ABSTRACT: The amygdala is a key brain region with efferent and afferent neural connections that involve complex behaviors such as pain, reward, fear and anxiety. This study evaluated resting state functional connectivity of the amygdala with cortical and subcortical regions in a group of chronic pain patients (pediatric complex regional pain syndrome) with age-gender matched controls before and after intensive physical-biobehavioral pain treatment. Our main findings include (1) enhanced functional connectivity from the amygdala to multiple cortical, subcortical, and cerebellar regions in patients compared to controls, with differences predominantly in the left amygdala in the pre-treated condition (disease state); (2) dampened hyperconnectivity from the left amygdala to the motor cortex, parietal lobe, and cingulate cortex after intensive pain rehabilitation treatment within patients with nominal differences observed among healthy controls from Time 1 to Time 2 (treatment effects); (4) functional connectivity to several regions key to fear circuitry (prefrontal cortex, bilateral middle temporal lobe, bilateral cingulate, hippocampus) correlated with higher pain-related scores and (5) decreases in pain-related fear associated with decreased connectivity between the amygdala and the motor and somatosensory cortex, cingulate, and frontal areas. Our data suggest that there are rapid changes in amygdala connectivity following an aggressive treatment program in children with chronic pain and intrinsic amygdala functional connectivity activity serving as a potential indicator of treatment response.
    Full-text · Article · May 2014 · Pain
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