[58] Among those functional connections that differed between CM and controls, rs-fc of anterior insula with mediodorsal thalamus and anterior insula with periaqueductal gray correlated with number of years that subjects had CM. Correlations with a marker of disease burden (ie, number of CM years) serve as evidence that these

rs-fc differences between CM and controls directly relate to having migraine. Furthermore, the mediodorsal thalamus likely has a role in headache because: (1) it participates in long-term pain memory; (2) it plays a role in sensory-discriminative pain, encoding the intensity of noxious heat; (3) it is involved in striatal and limbic system arousal; (4) animal Dinaciclib order studies have identified trigeminal projections to the medial thalamus.[61-63] The periaqueductal gray is a key region of the brainstem descending pain-modulating system, a system which modulates trigeminal nociceptive transmission. The descending pain-modulating system is predominantly pain inhibiting, although it is also capable of pain facilitation.[64-67] There is substantial interest in the role of the periaqueductal gray in migraine because of the prior identification of atypical periaqueductal gray structure and atypical periaqueductal

gray function in migraineurs.[26, 48] In this study, CM had atypical rs-fc of anterior insula to periaqueductal gray. Prior structural and functional connectivity studies show that the periaqueductal gray is connected to anterior insula.[68-70] Furthermore, Torin 1 nmr prestimulus functional connectivity between the anterior insula and periaqueductal gray determines if a future stimulus is perceived as painful.[57] Thus, atypical rs-fc between anterior

insula and periaqueductal gray in CM subjects might relate to the enhanced susceptibility to pain that is characteristic of CM. We hypothesize that atypical rs-fc between anterior insula and periaqueductal gray identified in CM could relate to inappropriate control of the PAG via the anterior insula, a “higher order” pain-processing region. Although correlations between rs-fc of strength and number of CM years suggest a direct relationship between these two parameters, conclusions cannot be drawn regarding the causality or the direction of these potential associations (eg, greater number of migraine years leads to greater aberrations in rs-fc vs more atypical rs-fc leads to earlier onset or longer duration of migraine). Longitudinal studies are needed to draw strict conclusions. The identification of atypical rs-fc in CM involving brain regions participating in multiple aspects of the pain experience is consistent with expectations based upon the knowledge of the migraine phenotype. CM is a disorder with wide-ranging effects because of frequent pain, negative effects on mood, and impairment of cognition.