We have identified a preliminary brain classifier associated with CPP. This GM classifier distinguishes individuals with CPP from matched healthy controls with an accuracy of 73%. On the basis of our findings, several brain regions were revealed to have positive weights contributing to the SVM classification of CPPs vs healthy controls. These regions included bilateral primary somatosensory cortex (S1), left pre-SMA, bilateral hippocampus, and left amygdala. The nature of positive weights of these regions suggests that patients with CPP may have increased GM density within these regions.
Previous morphological studies of chronic pain have revealed altered (typically decreased) GM density across numerous brain regions implicated in pain processing and perception (reviewed in ).
Increased GM density in S1 was observed in another chronic visceral pain syndrome (irritable bowel syndrome), both in terms of GM volume  and cortical thickness . A region we identified within the primary somatosensory cortex (S1) was highly similar in location to a VBM study of women with CPP also collected through the MAPP Research Network . Somatotopically, 2 regions that we observed in S1 were within a region activated during electrical stimulation of the human clitoris . Our results of another S1 region (MNI: 44, −24, 56) closely corresponded to a region of S1 activity related to spontaneous pain ratings observed in a previous VBM study of males with CPP (MNI: 36, −28, 58) . Importantly, patients included in our study had symptoms characteristic of interstitial cystitis, with pain in the lower abdomen accompanied by urinary symptoms (eg, increased urgency, increased frequency of urination, painful filling of the bladder). Also, the majority (85%) of participants with CPP also showed signs of pelvic floor dysfunction, which typically involves a hypertonic state of the pelvic floor musculature [12,39].
The differences in symptoms between our CPP patient population and those of previous morphological studies of CPP may account for differences in GM density findings. Specifically, one previous CPP study observed decreased GM density within the left middle frontal gyrus, right putamen, bilateral midcingulate cortex, right insular cortex, and left thalamus in a patient population with endometriosis and pain. However, these findings of regional decreased GM density may contrast with our present findings because they defined CPP as moderate to severe pelvic pain of 4 or more (on a 10-point scale) and excluded patients with interstitial cystitis . Further, our patient population included only 9 individuals with endometriosis. In contrast to our present findings, and possibly due to sex-related differences in CPP, male CPP patients previously demonstrated decreased GM volume within the left anterior cingulate cortex . Another VBM study of CPP in male subjects, revealed through a region of interest correlation analysis, showed a positive correlation of right insular cortex GM density with pain severity and a positive correlation of anterior cingulate cortex GM density with duration of pain (ie, pain chronicity) .
Positive weights within bilateral parahippocampal/hippocampal gyri and amygdala also significantly contributed to our classification of CPP. Complementary to our findings, greater GM density within the left amygdala was previously observed in a patient population of CPP and endometriosis . However, decreased amygdala GM volume has been observed in irritable bowel syndrome  and in healthy individuals with increased visceral sensitivity . Increased GM density within the parahippocampal gyrus and basal ganglia has also been observed in participants with provoked vestibulodynia . Increased GM volume has also been observed in patients with primary dysmenorrhea in the right posterior hippocampus among several other brain regions of altered GM volume . In contrast, other studies using VBM have shown less GM in the hippocampus in posttraumatic stress disorder [10,21,54] and chronic fatigue syndrome . The amygdala and hippocampus, in addition to processes of emotion and memory, play direct roles in pain modulation and processing of anxiety, fear and aversive contents of pain [16,29,37,41,43,47]. Together, our and others’ observations of altered GM density within the hippocampus and amygdala in chronic pain states may reflect an altered state of pain modulation and emotional-regulatory aspects of chronic pain.
The range of symptom durations included in each study population could account for inconsistent findings of GM density change. In support of this concept, we observed that the degree of patients’ positive SVM weight within regions of our significance map was related to symptom duration, but only at certain stages of chronic pain. This suggests that the relationship between GM density and symptom duration may not be linear over time. Additionally, this relationship differs for distinct brain regions. For example, our results suggest that in S1, GM density may increase in the first few years of chronic pain; but as pain persists past the first initial years, the GM density may decrease—the longer the pain, the less the GM density. In contrast, in the left hippocampus we observed a negative correlation of GM density and symptom duration during the first 10years of pain but not after (potential decreases in GM density over time up to 10years), similar to a previous investigation . In other chronic pain conditions, less GM density is observed in insular cortex, S1 and motor cortex; these differences are significantly correlated with pain duration, but only when the duration is greater than 5years . However, importantly, these observations are not based on longitudinal studies, but rather on correlation results at a single time point. While it currently remains unclear whether chronic pain causes nonlinear morphological changes over time, emerging data from longitudinal studies indicate that this might be the case [22,45].
Brain morphological changes in chronic pain typically show decreases in GM density in brain regions related to aspects of pain processing (reviewed in ). In contrast, our observations of positive SVM weights indicate increased GM density within regions of S1, hippocampus and amygdala in CPP. Thus, changes in brain morphology may vary between different types of chronic pain, as noted previously . For example, less total GM volume is observed in chronic low back pain and fibromyalgia , but not in participants with complex regional pain syndrome or knee osteoarthritis. However, regions of increased GM density are not entirely rare. For example, increased GM density has also been observed in striatal regions in fibromyalgia [46,52]. Differences in directionality of GM change across studies of chronic pain could be attributed to the differences in the various populations being studied, presence or absence of comorbidities, and medication usage.
We here describe a preliminary structural MRI classifier of CPP. Future characterization of a true brain classifier for CPP will require larger sample sizes, refined models and extensive model validation (eg, prospective testing and/or inclusion of independent training and test sets). Future analyses could also use more optimal analysis methods of modeled correction for nuisance features such as age [17,25]. Further, it is currently unknown whether these regions of greater GM density may be a specific feature of CPP and or generalizable to other chronic pain conditions.
We have identified a preliminary structural brain based classifier representative of CPP. The classifier was comprised of several distributed regions of positive SVM weight that contributed to our SVM algorithm including S1, pre-SMA, the hippocampus, and amygdala. While previous studies have typically observed decreased GM density in chronic pain, the regions we identified suggest regional increased GM density in CPP. Ultimately, the good classification accuracy observed in our study suggests the significance of these regions in distinguishing participants with CPP from healthy controls and serve as a preliminary potential biomarker for CPP. While a structural brain classifier of CPP as a definitive marker of disease would have significant ethical and legal implications, our results are preliminary and further investigation is warranted. Through the combination of SVM analyses of brain structure and function with additional genotype and phenotype biomarkers, we may ultimately define strong predictors of treatment response, define subgroups of chronic pain syndromes and develop tailored and systematic therapy for the individual patient.
The authors report no conflict of interest.
Thanks to Cody Ashe-McNally for his technical expertise in coordinating and running the cross-site quality control of all MAPP Research Network neuroimaging data. Special thanks to Jeff Alger for his expertise as a physicist at UCLA in oversight and coordination of the multisite collection of neuroimaging data. Funding for the MAPP Research Network was obtained under a cooperative agreement from National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH) (DK82370, DK82342, DK82315, DK082344, DK082325, DK082345, DK082333, and DK082316). This study was also supported by an additional NIH grant (K24 DA029262) and the Redlich Pain Research Endowment. The authors declare no competing financial interests.
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