Cortical mechanisms of visual hypersensitivity in women at risk for chronic pelvic pain

Abstract

Increased sensory sensitivity across non-nociceptive modalities is a common symptom of chronic pain conditions and is associated with chronic pain development. Providing a better understanding of the brain-behavior relationships that underlie multimodal hypersensitivity (MMH) may clarify the role of MMH in the development of chronic pain. We studied sensory hypersensitivity in a cohort of women (n = 147) who had diary confirmation of menstrual status and were enriched with risk factors for chronic pelvic pain, such as dysmenorrhea and increased bladder sensitivity. We administered 2 experimental tasks to evaluate the cross-modal relationship between visual and visceral sensitivity. Visual sensitivity was probed by presenting participants with a periodic pattern-reversal checkerboard stimulus presented across 5 brightness intensities during electroencephalography recording. Self-reported visual unpleasantness ratings for each brightness intensity were simultaneously assessed. Visceral sensitivity was evaluated with an experimental bladder-filling task associated with early clinical symptoms of chronic pelvic pain. Visually evoked cortical activity increased with brightness intensity across the entire scalp, especially at occipital electrode sites. Visual stimulation-induced unpleasantness was associated with provoked bladder pain and evoked primary visual cortex activity. However, the relationship between unpleasantness and cortical activity was moderated by provoked bladder pain. These results demonstrate that activity in the primary visual cortex is not greater in individuals with greater visceral sensitivity. We hypothesize that downstream interpretation or integration of this signal is amplified in individuals with visceral hypersensitivity. Future studies aimed at reducing MMH in chronic pain conditions should prioritize targeting of cortical mechanisms responsible for aberrant downstream sensory integration.

Figure 1.. Visual stimulation task presented during EEG recording and designed to elicit an SSVEP.

a) Participants viewed an alternating blue-yellow checkerboard pattern with positive and negative reversals across five different brightness intensities modulated with monotonically increasing lux. b) Checkerboards alternated at 25Hz and were presented for 20 seconds before an unpleasantness rating for each brightness intensity. Block order was randomized across participants. c) Participants’ unpleasantness ratings were measured using the Gracely Box Scale with textual descriptors.

Figure 2.. Multilevel modeling allows for comprehensive analysis of brain-behavior relationships accounting menstrual pain, somatic symptoms, provoked bladder pain.

In level 1, participant unpleasantness ratings (U) from visual stimulation were modeled as a function of brightness intensity and cortical activity from 25Hz power spectral density (PSD) estimates. Each participant and electrode were modeled individually, allowing for random intercepts and slopes. Ellipses indicate all participants are included in this model. Intercepts, brightness slopes, and PSD slopes were modeled separately in level 2 as a function of participants’ prior menstrual pain, somatic symptoms, and provoked bladder pain. This was modeled separately for each electrode but across participants. Moderating effects are demonstrated with arrows depicting high vs. low reported pain/symptoms. Therefore, level 2 brightness and PSD slopes depict positive moderating effects; however, negative moderating effects are also possible (not shown). Data presented are fictional and shown for illustrative purposes.

Figure 3.. The unpleasant checkerboard stimuli presented at 25Hz evoked widespread robust SSVEPs focused at Oz.

Left. Broadband PSD averaged across the five presented brightness intensities for all participants shows a clear peak at the 25Hz SSVEP alternating checkerboard frequency at Oz. Grey shading denotes 95% confidence interval. Middle. Topographically plotted intercepts demonstrated elevated PSD estimates toward occipital electrode sites. Right. Topographically plotted regression slopes show scalp-wide positive slopes, especially at occipital sites and Oz, demonstrating an increase in SSVEP PSD estimates with increasing brightness intensities. All topographic sites for intercept and slope effects were significant after correcting for multiple comparisons (p_FDR < .001).

Figure 4.. The relationships between visual unpleasantness and brightness intensity/cortical activity were moderated by menstrual pain, somatic symptoms and provoked bladder pain.

a) Partial regression scatter plots depict the positive relationship between provoked bladder pain and participants’ mean unpleasantness ratings averaged across brightness intensities accounting for menstrual pain and somatic symptoms. b) Topographic plots of regression slopes testing the intercepts from the brightness and PSD models. Oz was our a priori electrode of interest. Raw (grey) and averaged (red) slopes across all participants plotted below demonstrate that increases in brightness intensity and 25Hz PSD resulted in concomitant increases in participant unpleasantness ratings when accounting for one another. c) Scalp topographies of moderating slopes from second level multilevel modeling results. Given that positive relationships were observed between unpleasantness ratings and brightness/PSD in b, positive slopes here depict an increasing positive relationship between moderating variables, while negative slopes depict an increasing negative relationship. Menstrual pain ratings moderated the positive relationship between unpleasantness ratings and brightness, but not 25 Hz PSD at Oz (a priori chosen) and several other exploratory electrode sites. Somatic symptoms did not moderate these relationships at Oz; however, somatic symptoms moderated brightness and PSD slopes at a right posterior site (CP6; p_FDR < .05 corrected), despite conflicting directions of moderation. In contrast, provoked bladder pain moderated the positive relationship between unpleasantness and PSD, but not brightness. Level two regression parameter notation n denotes both the brightness (n=1) and PSD (n=2) slope models. PSD = power spectral density; FDR = false discovery rate.

Figure 5.. At equivalent amounts of primary visual cortex activity, individuals with greater provoked bladder pain experience greater visual discomfort.

Conceptual line plots demonstrate the moderating effect of provoked bladder pain on the relationship between unpleasantness ratings and cortical activity measured via 25Hz power spectral density (PSD) estimates electrode Oz. This moderating effect implies that when stimulus driven oscillatory activity in visual cortex is low, high and low provoked bladder pain individuals experience similar discomfort. However, individuals with greater provoked bladder pain report more unpleasantness when activity increases. Activity in primary visual cortex is therefore not greater in individuals with visceral hypersensitivity; rather, downstream interpretation of this signal is likely amplified in women with comorbid visceral hypersensitivity.