Coordinated Human Brainstem and Spinal Cord Networks during the Expectation of Pain Have Elements Unique from Resting-State Effects

Abstract

Functional magnetic resonance imaging (fMRI) research on the human brainstem (BS) and spinal cord (SC) has identified extensive BS/SC resting-state networks (RSNs) by showing spontaneous coordinated blood oxygenation-level dependent (BOLD) signal fluctuations in the absence of a stimulus. Studies have shown that these networks can be influenced by participants’ level of arousal or attention (e.g., watching a video), and linked network function to autonomic homeostatic regulation. Here we explore how the cognitive state of expecting pain can influence connectivity in these networks. Data from two studies (a predictable pain stimulus study, and a resting-state study) were compared to show the effects of expecting pain on BS/SC networks, and how networks differed from networks associated with the resting-state. In each study, BOLD fMRI data were obtained from the cervical SC and brainstem in healthy participants at 3 tesla using a T2-weighted single-shot fast spin-echo imaging method. Functional connectivity was investigated within the entire 3D volume by means of structural equation modeling (SEM) and analyses of covariance (ANCOVA). Results showed extensive connectivity within/across BS and SC regions during the expectation of pain, and ANCOVA analyses showed that connectivity in specific components of these networks varied with individual pain sensitivity. Comparing these results to RSN fluctuations revealed commonalities in coordination between BS and SC regions, and specific BS–BS connectivity fluctuations unique to the expectation of pain. Based on the regions involved, these results provide evidence of brainstem regulation specific to the expectation of pain.

Evidence for Integration of Cognitive, Affective, and Autonomic Influences During the Experience of Acute Pain in Healthy Human Volunteers

“…However, we also found interesting differences in connectivity across the control groups, and evidence of autonomic priming before the onset of pain, with additional autonomic involvement during and after noxious stimulation. These findings are in agreement with recently published investigations from our lab ( Stroman et al, 2018 , 2021 ; Warren et al, 2019 , 2021 ; Ioachim et al, 2020 ).…”

“…As pain is a complex sensory experience involving cognitive, affective, and interoceptive control that is dependent on individual pain history and memory, it is important for these systems to interact in order to create awareness of, and reactions to, pain in an individualized way ( Melzack and Katz, 2013 ). Research in the field continually provides evidence of this multi-sensory and cognitive integration leading to the unique experience of pain ( Becerra et al, 2001 ; Bornhovd et al, 2002 ; Villemure and Bushnell, 2002 ; Godinho et al, 2006 ; Leknes and Tracey, 2008 ; Porreca and Navratilova, 2017 ; Moayedi et al, 2018 ; Thompson and Neugebauer, 2019 ; Yuan et al, 2019 ; Ioachim et al, 2020 ; Tu et al, 2020 ; Stroman et al, 2021 ; Warren et al, 2021 ) ng been implicated in the experience of pain, and complex communication between these regions is just beginning to be investigated in humans. Future studies may focus on expanding these intricate network analyses to include the higher limbic regions such as the amygdala, and other cortical regions including sensory, frontal/executive, and memory areas.…”

Reliability of resting-state functional connectivity in the human spinal cord: assessing the impact of distinct noise sources

“…Over the last decades, the spatiotemporal organization of spontaneous fluctuations of BOLD signals in the brain has been widely investigated and intrinsic resting-state networks have been considered as building blocks of brain function that are relevant for cognition and behavior (Deco et al, 2011; Fox & Raichle, 2007; Petersen & Sporns, 2015; Raichle et al, 2001; Wig, 2017). With a delay of about 20 years and on a much smaller scale, a similar perspective has opened up for spinal cord function, with resting-state fMRI studies demonstrating that spontaneous BOLD fluctuations of the spinal cord are spatiotemporally organized as well (Barry et al, 2014; Barry et al, 2016; Barry et al, 2018; Conrad et al, 2018; Eippert et al, 2017a; Harita & Stroman, 2017; Harita et al, 2018; Hu et al, 2018; Ioachim et al, 2019; Ioachim et al, 2020; Kinany et al, 2020; Kong et al, 2014; Liu et al, 2016a; Liu et al, 2016b; Martucci et al, 2019; Martucci et al, 2021; San Emeterio Nateras et al, 2016; Vahdat et al, 2020; Weber et al, 2018; Wei et al, 2009; for a review see Harrison et al, 2021). More specifically, region-of-interest (ROI) based functional connectivity techniques have revealed statistically significant connectivity between the time-series of bilateral ventral horns as well as between bilateral dorsal horns in humans and similar functional connectivity patterns have been identified in non-human primates and rodents as well (Chen et al, 2015; Wu et al, 2018; Wu et al, 2019).…”

Music to My Senses: Functional Magnetic Resonance Imaging Evidence of Music Analgesia Across Connectivity Networks Spanning the Brain and Brainstem

“…Here, we used SEM as a means to investigate coordination across networks of regions. This method has successfully identified robust networks of connectivity across the brain, brainstem, and spinal cord in our previously published work ( 51 , 58 , 68 , 73 – 75 , 77 , 78 ).…”