Downloaded from http://journals.lww.com/pain by HNLkrTPcQw931HROR/H/oK2p4ZAyc+/Im98zersB/Z7ni9qJ5M3sXu/BbHdDr5hOngZmkWJdTFbpZacvXLyZNKZvZzfl1nJz+LxHFLmqk7Y= on 02/17/2021 Research Paper Pain sensitivity and the primary sensorimotor cortices: a multimodal neuroimaging study David M. Niddam a,b, *, Shuu-Jiun Wang a,c,d , Shang-Yueh Tsai e,f Abstract The primary somatosensory cortex (SI) is a critical part of the neural substrate underlying interindividual differences in pain sensitivity. Here, we investigated whether resting-state functional connectivity, gray matter density (GMD), and GABA and Glx (glutamate and glutamine) levels of the sensorimotor cortices were related to pain thresholds and whether such imaging measures could predict high and low pain sensitivity. Functional, structural, and spectroscopic magnetic resonance data were obtained from 48 healthy participants together with pain thresholds of the right index finger. Left and right sensorimotor networks (SMN) were extracted by means of independent component analysis, and GMD was measured within the combined SMN by means of voxel-based morphometry. Spectroscopic data were acquired from the bilateral sensorimotor cortices. Within the left SMN, functional connectivity to the right SI correlated positively with pain thresholds. In addition, GMD in the left SI and the GABA laterality index correlated positively with pain thresholds. A positive correlation was also found between the GABA laterality index and the left SMN connectivity to the right SI. Finally, the above mentioned functional connectivity and GMD measures could correctly predict high and low pain sensitivity in 83.7% of the study population. In summary, we showed that interindividual differences in pain sensitivity were related to the resting-state functional connectivity, interhemispheric GABA tone, and GMD of the sensorimotor cortices. Furthermore, high and low pain sensitivity could be predicted with high accuracy using imaging measures from the primary sensorimotor cortices. Keywords: Functional connectivity, GABA, Gray matter density, Sensorimotor network, Resting-state, Classification 1. Introduction Pain is a multidimensional subjective experience that is influenced by a wide range of biological, psychological, and social factors. These give rise to a substantial interindividual variability in pain sensitivity. High and low pain sensitive individuals have been shown to differ in their response to the same physical stimulus in the contralateral primary somatosensory cortex (SI), anterior cingulate cortex (ACC), and prefrontal cortex, regions involved in discriminative, affective, and cognitive aspects of pain process- ing. 8 Furthermore, variation in pain sensitivity has also been associated with structural measures such as cortical thickness and gray matter density (GMD), particularly in SI. 11,12 Thus, SI seems to be a critical part of the neural substrate underlying interindividual differences in pain sensitivity, at least with respect to experimentally induced acute pain. A bilateral sensorimotor network (SMN) has been identified using resting-state functional magnetic resonance imaging (rs-fMRI). 5 The SMN can be identified, among others, by means of independent component analysis, a method widely used to separate the rs-fMRI data into independent functional brain networks. Using a small number of components (20-25), the SMN occurs as a single bilateral network. 33 However, with a larger number of components (;40), the SMN splits into 2 lateralized subnetworks, largely confined to opposite hemispheres and each containing the hand representation of SI. Although the function of the SMN remains unclear, connectivity changes within the SMN has been found to be related to functional properties of the motor system such as for example,handedness, 28 motor weakness, 27 and motor learning. 2 By contrast, little is known about how the SMN, and in particular the lateralized SMNs, relates to somatosensory or pain sensitivity. The neurochemical basis of the SMN has only recently started to be explored. The major excitatory and inhibitory neurotransmitters of the brain, that is, glutamate and GABA, can be measured by magnetic resonance spectroscopy (MRS). An inverse relationship has been found between GABA levels of the left (dominant) sensorimotor cortex and the functional connectivity strength of the entire SMN as well as the functional connectivity between left and right sensorimotor cortices. 33 It is, thus, conceivable that if functional connectivity of the SMN is related to interindividual differences in pain sensitivity, then GABA or glutamate levels in these areas may also contribute. Here, we sought to determine whether functional connectivity of the lateralized SMNs, GMD, as well as GABA and glutamate levels of the bilateral sensorimotor cortices were associated with pain Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. D.M. Niddam and S.-Y. Tsai are co-corresponding authors. a Brain Research Center, National Yang-Ming University, Taipei, Taiwan, b Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan, c Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan, d Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, e Graduate Institute of Applied Physics, National Chengchi University, Taipei, Taiwan, f Research Center for Mind, Brain and Learning, National Chengchi University, Taipei, Taiwan *Corresponding author. Address: Brain Research Center and Institute of Brain Science, National Yang-Ming University, No. 155, Sec. 2, LiNong St, Taipei 11221, Taiwan. Tel.: 1886-2-2826-7000 ext 6151; fax: 1886-2-2822-3970. E-mail address: niddam@ym.edu.tw (D.M. Niddam). PAIN 162 (2021) 846–855 © 2020 International Association for the Study of Pain http://dx.doi.org/10.1097/j.pain.0000000000002074 846 D.M. Niddam et al. · 162 (2021) 846–855 PAIN ® Copyright © 2020 by the International Association for the Study of Pain. Unauthorized reproduction of this article is prohibited.