Pharmacologic attenuation of cross-modal sensory augmentation within the chronic pain insula

Abstract

Pain can be elicited through all mammalian sensory pathways yet cross-modal sensory integration, and its relationship to clinical pain, is largely unexplored. Centralized chronic pain conditions such as fibromyalgia are often associated with symptoms of multisensory hypersensitivity. In the present study, female fibromyalgia patients demonstrated cross-modal hypersensitivity to visual and pressure stimuli compared to age- and sex-matched healthy controls. Functional magnetic resonance imaging (fMRI) revealed that insular activity evoked by an aversive level of visual stimulation was associated with the intensity of fibromyalgia pain. Moreover attenuation of this insular activity by the analgesic pregabalin was accompanied by concomitant reductions in clinical pain. A multivariate classification method using support vector machines (SVM) applied to visual evoked brain activity distinguished fibromyalgia patients from healthy controls with 82% accuracy. A separate SVM classification of treatment effects on visual evoked activity reliably identified when patients were administered pregabalin as compared to placebo. Both SVM analyses identified significant weights within the insular cortex during aversive visual stimulation. These data suggest that abnormal integration of multisensory and pain pathways within the insula may represent a pathophysiological mechanism in some chronic pain conditions, and that insular response to aversive visual stimulation may have utility as a marker for analgesic drug development.

Towards a neurophysiological signature for fibromyalgia

“…Central processing of non-painful sensory signals may be of particular importance in maintaining clinical pain in FM, in agreement with previous work [29; 42; 58]. Consistently, Harte and colleagues very recently showed that fMRI data during a visual task could discriminate FM patients vs. healthy controls with 82% accuracy[29]. The Multisensory pattern shows early sensory cortical processing attenuation, which is consistent with reduced processing of fine sensory/discriminative properties of stimulus[1; 18; 46; 53], accompanied by amplification of sensory integration (in agreement with [29]) and self-referential aspects of the response, including potential threat of harm[17].…”

“…Central processing of non-painful sensory signals may be of particular importance in maintaining clinical pain in FM, in agreement with previous work [29; 42; 58]. Consistently, Harte and colleagues very recently showed that fMRI data during a visual task could discriminate FM patients vs. healthy controls with 82% accuracy[29].…”

Multivariate classification of pain-evoked brain activity in temporomandibular disorder

“…Here, BOLD responses to a flashing checkerboard (perceived to be unpleasant by many) were able to differentiate patients from controls with 82% accuracy using SVM [22]. Furthermore, in a smaller subset of patients who underwent a crossover pregabalin/placebo treatment, degree of right insula activation by the visual stimulus was positively correlated with responsiveness to pregabalin, and classified drug versus placebo with 82% accuracy.…”

The Potential Role of Sensory Testing, Skin Biopsy, and Functional Brain Imaging as Biomarkers in Chronic Pain Clinical Trials: IMMPACT Considerations

“…In addition, analyses of pooled fMRI data from studies utilizing different imaging equipment and analysis procedures have produced informative and consistent inferences about brain structure and function in chronic pain disorders [86, 93, 99]. Emerging approaches to imaging analysis, such as support vector machines, may also prove useful in addressing concerns about replication [77, 123, 196]. These statistical approaches typically divide participant data into 2 groups: (1) ‘training’ groups, used to estimate a distributed pattern that serves as a provisional brain marker, and (2) ‘test’ groups, used to evaluate its predictive accuracy.…”