Sex similarities and differences in pain-related periaqueductal gray connectivity

P.A.I.N. Group, McLean Hospital, Belmont, MA, USA.
Pain (Impact Factor: 5.84). 12/2011; 153(2):444-54. DOI: 10.1016/j.pain.2011.11.006
Source: PubMed

ABSTRACT 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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    • "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.
    Pain 05/2014; 155(9). DOI:10.1016/j.pain.2014.05.023 · 5.84 Impact Factor
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    • "Neuroimaging research of pain processing is growing tremendously, with the primary and secondary somatosensory cortex (S1 and S2), spinal cord, thalamus, insula, anterior cingulate cortex, and prefrontal cortex consistently identified (Apkarian et al., 2005; Peyron et al., 2000; Tracey, 2008). Emerging imaging research also implicates midbrain areas (e.g., periaqueductal gray) (Linnman et al., 2011), the cerebellum (Moulton et al., 2010), and subcortical structures including the hippocampus, basal ganglia, and amygdala (Borsook et al., 2010; Schweinhardt and Bushnell, 2010). While a number of studies show amygdala activation, few have focused on the area in human imaging as it relates to pain and analgesia (Upadhyay et al., 2010). "
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    ABSTRACT: The amygdala, a small deep brain structure involved in behavioral processing through interactions with other brain regions, has garnered increased attention in recent years in relation to pain processing. As pain is a multidimensional experience that encompasses physical sensation, affect, and cognition, the amygdala is well suited to play a part in this process. Multiple neuroimaging studies of pain in humans have reported activation in the amygdala. Here, we summarize these studies by performing a coordinate-based meta-analysis within experimentally induced and clinical pain studies using an activation likelihood estimate analysis. The results are presented in relation to locations of peak activation within and outside of amygdala subregions. The majority of studies identified coordinates consistent with human amygdala cytoarchitecture indicating reproducibility in neuroanatomical labeling across labs, analysis methods, and imaging modalities. Differences were noted between healthy and clinical pain studies: in clinical pain studies, peak activation was located in the laterobasal region, suggestive of the cognitive-affective overlay present among individuals suffering from chronic pain; while the less understood superficial region of the amygdala was prominent among experimental pain studies. Taken together, these findings suggest several important directions for further research exploring the amygdala's role in pain processing. Hum Brain Mapp, 2012. © 2012 Wiley Periodicals, Inc.
    Human Brain Mapping 02/2014; 35(2). DOI:10.1002/hbm.22199 · 6.92 Impact Factor
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    • "PPI analyses compute whole-brain connectivity maps for a given seed region (Stephan, 2004) and identify areas in which the connectivity with the seed significantly changes due to an experimental factor, that is, the psychological context (Friston et al., 1997). In healthy individuals, PPIs have been applied to study amygdala–prefrontal interactions in the context of fear (Banks et al., 2007; Das et al., 2005; Williams et al., 2006), and periaqueductal gray connectivity during pain (Linnman et al., 2012) and defensive fear (Mobbs et al., 2009). Despite the simplicity of PPI, testing for task-specific connectivity changes of one single region in the absence of particular model assumptions , its applications in the context of group comparisons involving neuropsychiatric populations have been relatively rare. "
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    ABSTRACT: Abstract Neurobiological models of obsessive-compulsive disorder (OCD) assume abnormalities in corticostriatal networks involving cingulate and orbitofrontal cortices, but the connectivity within these systems is rarely addressed in experimental imaging studies in this patient group. Using an established monetary reinforcement paradigm known to involve the cingulate cortex and the ventral striatum, the present study sought to test for altered corticostriatal coupling in OCD patients anticipating potential punishment. The anterior midcingulate cortex (aMCC), a region integrating negative emotion, pain, and cognitive control, was chosen as a seed region due to its particular relevance in OCD, representing the neurosurgical target for cingulotomy, and showing increased responses to errors in OCD patients. Results from psychophysiological interaction analyses revealed that significantly altered, inverse coupling occurs between the aMCC and the ventral striatum when OCD patients anticipate potential punishment. This abnormality links the two major contemporary neurosurgical OCD target sites, and provides direct experimental evidence of altered corticostriatal connectivity in OCD. Noteworthy, an abnormal aMCC coupling with cortical areas outside of traditional corticostriatal circuitry was identified besides the alteration in the cingulostriatal pathway. In conclusion, these findings support the importance of applying connectivity methods to study corticostriatal networks in OCD, and favor the application of effective connectivity methods to study corticostriatal abnormalities in OCD patients performing tasks that involve symptom provocation and reinforcement learning.
    07/2012; 2(4):191-202. DOI:10.1089/brain.2012.0078
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