Mapping of neural activity produced by thermal pain in the healthy human spinal cord and brain stem: a functional magnetic resonance imaging study

Abstract

Functional magnetic resonance imaging (fMRI) has greatly advanced our current understanding of pain, although most studies to date have focused on imaging of cortical structures. In the present study, we have used fMRI at 3 T to investigate the neural activity evoked by thermal sensation and pain (42°C and 46°C) throughout the entire lower neuroaxis from the first synapse in the spinal cord rostral to the thalamus in healthy subjects. The results demonstrate that noxious thermal stimulation (46°C) produces consistent activity within various structures known to be involved in the pain matrix including the dorsal spinal cord, reticular formation, periaqueductal gray and rostral ventral medulla. However, additional areas of activity were evident that are not considered to be part of the pain matrix, including the olivary nucleus. Thermal stimulation (42°C) reported as either not painful or mildly painful produced quantitative, but not qualitative, differences in neuronal activity depending on the order of experiments. Activity was greater in the spinal cord and brain stem in earlier experiments, compared with repeated experiments after the more noxious (46°C) stimulus had been applied. This study provides significant insight into how the lower neuroaxis integrates and responds to pain in humans.

Introduction

Pain is described as an unpleasant sensory or emotional experience associated with actual or potential tissue damage, or described in terms of such damage (International Association for the Study of Pain). It is an evolutionary adaptive mechanism that functions to warn of impending danger in the environment and is a fundamental component of many disease and injury states. In addition to the somatosensory pain experience that provides information of location and intensity of the pain, danger signals incur psychological, emotional and autonomic responses, which serve to deter dangerous behavior and promote avoidance of harmful stimuli. Hence, pain is a multidimensional and highly subjective experience that is absolutely necessary for survival of the organism. Considering the complex nature of pain, it is not surprising that our understanding of how this complex interplay of sensory, emotional and cognitive processes integrates remains elusive.

The development of neuroimaging techniques, such as functional magnetic resonance imaging (fMRI), has dramatically progressed our understanding of not only the structures important in processing acute and chronic pain but also how the brain is altered by pain (reviewed in [1], [2]). Owing to the high spatial resolution provided by fMRI, and by demonstrating only changes in neural activity between contrasted conditions, fMRI has enabled characterization and dissociation of individual components of the pain matrix in humans. Indeed, within the last decade, fMRI studies have provided invaluable insight by demonstrating how pain is a complex, multidimensional phenomenon that influences a wide variety of nervous system functions. We now know that parallel processing systems consisting of sensory–discriminative, affective–emotional, and cognitive–evaluative dimensions integrate to contribute to the subjective experience of pain (for review, see [3]). Various studies have now reported how factors such as empathy, arousal, anxiety, depression, attention and expectation influence pain and neural activity within the central nervous system (CNS) [4], [5]. Indeed, a variety of pain modulatory systems exist including contextual and/or cognitive manipulation (for review, see [6]).

In contrast to higher brain structures, less is known about the pain matrix in human midbrain, brain stem and spinal cord. Although excellent histological and anatomical atlases of the human CNS exist detailing nociceptive pathways (which are commonly used for CNS mapping), functional studies are required to understand how CNS neural activity is altered in various disease states, including chronic pain conditions. Recent fMRI studies have identified some brain stem structures (periaqueductal gray [PAG], reticular formation) in both central sensitization produced by capsaicin-induced secondary hyperalgesia [7] and in anticipatory neural response to noxious thermal stimulation [8]. To date, though, relatively few studies have mapped functional activity that extends into the spinal cord. This paucity is most likely, in part, due to considerable challenges of acquiring MR images of the spinal cord, in addition to the usual challenges of obtaining high-quality fMRI data [9]. These challenges include the small physical dimensions of the spinal cord, poor magnetic field homogeneity in the cord due to magnetic susceptibility differences and motion of the spinal cord and cerebral spinal fluid motion. However, such challenges have now been overcome or reduced, with the development of novel techniques by our laboratory and others [9], [10], [11], [12], [13], [14], [15].

In the present study, the neuronal activity corresponding to nonnoxious and noxious thermal stimulation of the hand was mapped in caudal brain structures and the spinal cord of healthy subjects spanning from the cervical spinal cord to the thalamus by means of fMRI with a 3T MRI system. The results obtained demonstrated highly sensitive maps of activity, indicating specific regions known to be involved with the “pain matrix” and differences in the responses in these regions with different stimulus intensities, and with the order of experiments. The uniqueness of this study is the ability to correlate regions of activity associated with acute transient pain throughout the entire lower neuroaxis and provides a foundation for comparison and interpretation of future studies aimed at understanding chronic, persistent pain.