Cortical Pain Processing in the Rat Anterior Cingulate Cortex and Primary Somatosensory Cortex

Zhengdong Xiao,David Rosenberg,Leor Shalot,Erik Martinez,Jing Wang,Zhe Sage Chen,Qiaosheng Zhang,Robert Talay,Prathamesh M Kulkarni,Haocheng Zhou,Qianning Hou

doi:10.3389/fncel.2019.00165

Abstract

Pain is a complex multidimensional experience encompassing sensory-discriminative, affective-motivational and cognitive-emotional components mediated by different neural mechanisms. Investigations of neurophysiological signals from simultaneous recordings of two or more cortical circuits may reveal important circuit mechanisms on cortical pain processing. The anterior cingulate cortex (ACC) and primary somatosensory cortex (S1) represent two most important cortical circuits related to sensory and affective processing of pain. Here, we recorded in vivo extracellular activity of the ACC and S1 simultaneously from male adult Sprague-Dale rats (n = 5), while repetitive noxious laser stimulations were delivered to animalÕs hindpaw during pain experiments. We identified spontaneous pain-like events based on stereotyped pain behaviors in rats. We further conducted systematic analyses of spike and local field potential (LFP) recordings from both ACC and S1 during evoked and spontaneous pain episodes. From LFP recordings, we found stronger phase-amplitude coupling (theta phase vs. gamma amplitude) in the S1 than the ACC (n = 10 sessions), in both evoked (p = 0.058) and spontaneous pain-like behaviors (p = 0.017, paired signed rank test). In addition, pain-modulated ACC and S1 neuronal firing correlated with the amplitude of stimulus-induced event-related potentials (ERPs) during evoked pain episodes. We further designed statistical and machine learning methods to detect pain signals by integrating ACC and S1 ensemble spikes and LFPs. Together, these results reveal differential coding roles between the ACC and S1 in cortical pain processing, as well as point to distinct neural mechanisms between evoked and putative spontaneous pain at both LFP and cellular levels.

Highlights

Pain is a complex sensory experience involving multidimensional components, encoded by distributed cortical pain circuits
All experimental studies were performed in accordance with the National Institutes of Health (NIH) Guide for the Care and Use of Laboratory Animals to ensure minimal animal use and discomfort, and were approved by the New York University School of Medicine (NYUSOM) Institutional Animal Care and Use Committee (IACUC)
Evoked pain episodes are uniquely associated with the noxious stimulus presentation and quantitative pain behaviors (Cheppudira, 2006); whereas spontaneous pain-like behaviors often involve frequent aberrant movement such as flinching, shaking, paw lifting and paw licking (Kawasaki et al, 2012; Whittaker and Howarth, 2014; Murai et al, 2016)

Summary

Introduction

Pain is a complex sensory experience involving multidimensional components, encoded by distributed cortical pain circuits. The primary somatosensory cortex (S1) is known to represent the sensory-discriminative component of pain (Vierck et al, 2013), whereas the anterior cingulate cortex (ACC) is known to represent the affective-motivational component of pain (Bushnell et al, 2013). Human neuroimaging experiments have suggested that many other neocortical regions, such as the insular, secondary somatosensory cortex, prefrontal cortex, and orbitofrontal cortex, play important roles in pain processing (Davis et al, 2017). Stimulus-evoked pain is induced by a noxious stimulus, whereas spontaneous pain is detached from an overt external stimulus. It is known that repeated noxious stimulations can elicit spontaneous pain behaviors (Bennett, 2012); identification of spontaneous pain remains challenging in animal studies (Tappe-Theodor and Kuner, 2014)

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Conclusion