Karen D. Davis

Cortical responses to pain in healthy individuals depends on pain catastrophizing

Abstract The personal experience of pain is complex and depends on physiological and psychological factors. From this latter category, pain catastrophizing plays an important role in pain behavior and response. We aimed to determine the effect of pain catastrophizing on central nociceptive processing in healthy individuals. Functional MRI was performed during two pain intensity levels evoked by electrical median nerve stimulation in 22 healthy individuals. Pain catastrophizing scores were determined for all subjects. Pain catastrophizing was not related to activity in regions associated with sensory‐discriminative aspects of pain, such as the primary or secondary somatosensory cortex. Instead, during mild pain, there was a relationship between catastrophizing and activity in cortical regions associated with affective, attention, and motor aspects of pain, including dorsolateral prefrontal, insula, rostral anterior cingulate, premotor, and parietal cortices. During more intense pain, prefrontal cortical regions implicated in the top‐down modulation of pain were negatively correlated with catastrophizing. These findings can be viewed from the framework of an attention model of pain catastrophizing, whereby a cortical vigilance network is engaged during mild pain, but diminished prefrontal cortical modulation impedes disengaging from and suppressing pain during more intense pain. These findings may also implicate catastrophizing in the progression to or persistence of chronic pain.

A neurocognitive model of attention to pain: Behavioral and neuroimaging evidence

READ – Unite de Readaptation et de Medecine physique, Universite catholique de Louvain, Louvain-la-Neuve & Brussels, 1200 Brussels, Belgium Department of Experimental-Clinical and Health Psychology, Universiteit Gent, Ghent, Belgium Centre for Pain Research, University of Bath, UK Division of Brain, Imaging and Behaviour, Toronto Western Research Institute, University Health Network & Department of Surgery and Institute of Medical Science, University of Toronto, Canada Alan Edwards Centre for Research on Pain, Faculty of Dentistry, McGill University, Montreal, Canada

An fMRI study of the anterior cingulate cortex and surrounding medial wall activations evoked by noxious cutaneous heat and cold stimuli

&NA; The anterior cingulate cortex (ACC) and adjacent regions in the medial wall have been implicated in sensory, motor and cognitive processes, including pain. Our previous functional magnetic resonance imaging (fMRI) studies have demonstrated pain‐related activation of the posterior portion of the ACC during transcutaneous electrical nerve stimulation (TENS) and variable patterns of cortical activation with innocuous and noxious thermal stimuli in individual subjects. The present study represents the companion paper to our recent study of pain‐ and thermal‐related cortical activations with the aim to use fMRI to delineate the activations in the ACC and surrounding regions of the medial wall during application of innocuous and noxious thermal stimuli as well as during performance of a motor task in individual subjects. Ten normal subjects were imaged on a conventional 1.5 T GE ‘echospeed’ system. Functional images were obtained from sagittal sections through each hemisphere centered at approximately 3–5 and 7–9 mm from midline. Each subject was imaged during innocuous (cool, warm) and noxious thermal (cold, hot) stimulation of the thenar eminence, and execution of a motor (sequential finger‐thumb opposition) task. Task‐related activations were mostly confined to contralateral and medial ipsilateral images. Although the present results demonstrate intersubject variability in the task‐related activations, some general modality‐specific patterns were apparent: (i) innocuous thermal‐related activations were located mainly in the anterior ACC; (ii) noxious thermal‐related activations were primarily located in the anterior ACC, the ventral portion of the posterior ACC, and the supplementary motor area (SMA); (iii) motor‐related activations were primarily located in the SMA and dorsal portion of the posterior ACC. These results indicate that specific spatial patterns of activation exist within the ACC and surrounding regions of the medial wall for innocuous and noxious thermal stimuli, and that noxious thermal‐ and motor‐related activations appear to be segregated within the ACC. Therefore, we propose a segregation of the ACC into an anterior non‐specific attention/arousal system and a posterior pain system.

Neural correlates of the prolonged salience of painful stimulation.

Pain is a unique class of sensory experience from the perspective of salience. Nonpainful somatosensory stimuli usually require behavioral relevance or voluntary attention to maintain salience. In contrast, painful stimuli tend to have sustained salience even without explicit behavioral relevance or voluntary attention. We have previously identified a frontal-parietal-cingulate network of regions responding transiently to nonpainful sensory events. This network is sensitive to the task relevance and novelty of sensory events and likely represents the salience of events in the sensory environment. Since pain can remain salient for a prolonged period, we hypothesized that this network should show transient responses to the onset or offset of a nonpainful stimulus, but sustained responses throughout the duration of a painful stimulus. To test this hypothesis, we used functional MRI to examine the response of these regions to sustained (60-s) periods of painful and nonpainful transcutaneous electrical nerve stimulation. As predicted, the temporoparietal, inferior frontal, and anterior cingulate cortex showed only transient responses to the onset or offset of nonpainful stimulation, but a sustained response throughout the duration of painful stimulation. These regions therefore show tonic responses to stimuli with tonic salience, supporting a general role for these areas in representing stimulus salience. The thalamus and putamen also responded tonically throughout painful but not nonpainful stimulation. Previous studies have implicated the basal ganglia in supporting voluntary sustained attention. Our findings suggest that the basal ganglia may play a more general role in supporting sustained salience, whether through voluntary or involuntary mechanisms.

Altered Brain Structure in Irritable Bowel Syndrome: Potential Contributions of Pre-Existing and Disease-Driven Factors

BACKGROUND & AIMS Brain imaging studies have identified abnormal rectal-evoked responses and cortical thinning in patients with irritable bowel syndrome (IBS). However, it is not known whether these abnormalities are pre-existing or develop as result of long-term IBS. Therefore, we tested whether abnormal structural gray matter integrity in IBS correlates with individual disease symptoms, duration of the IBS, or the personality characteristic of pain catastrophizing. METHODS Eleven IBS patients and 16 age-matched healthy subjects underwent structural magnetic resonance imaging. Voxel-based morphometry and cortical thickness analysis were used to identify abnormalities in subcortical and cortical regions, respectively, and their correlation to individual characteristics. RESULTS The IBS group showed increased hypothalamic gray matter and cortical thinning in the anterior midcingulate cortex compared with controls, a strong negative correlation between dorsolateral prefrontal cortex thickness and pain catastrophizing, and a positive correlation between anterior insula thickness and pain duration. In the insula, there was cortical thinning in patients with short-term IBS, but long-term IBS pain was associated with a more normal insula thickness. CONCLUSIONS Our findings provide new insight into IBS and chronic pain through evidence for structural changes that could fit with functional abnormalities. We report that patients with IBS have increased hypothalamic gray matter, which may be related to the association among IBS, stress, and the hypothalamic-pituitary-adrenal axis. Furthermore, we have identified some supraspinal abnormalities that may be pre-existing and contribute to vulnerability, and others that may develop over time, possibly because of chronic abnormal inputs.

Human anterior cingulate cortex neurons encode cognitive and emotional demands.

The cortical mechanisms and substrates of cognitive and emotional demands are poorly understood. Lesion studies and functional imaging implicate the anterior cingulate cortex (ACC). The caudal ACC (cACC) has been implicated in cognitive processes such as attention, salience, interference, and response competition, mostly on the basis of neuroimaging results. To test the hypothesis that individual cACC neurons subserve these functions, we monitored neuronal activity from single cells in the cACC while subjects were engaged in a mental arithmetic task, the cognitively demanding counting Stroop task, and/or the emotional Stroop interference task. We now report the first direct measures of single neurons in humans identifying a population of cACC neurons that respond differentially or in a graded manner to cognitively demanding high- and low-conflict Stroop tasks, including those with emotional valence. These data indicate that cACC neurons may be acting as salience detectors when faced with conflict and difficult or emotional stimuli, consistent with neuroimaging results of cACC responses to abrupt sensory, novel, task-relevant, or painful stimuli.

The necessity of animal models in pain research.

&NA; There exists currently a fair degree of introspection in the pain research community about the value of animal research. This review represents a defense of animal research in pain. We discuss the inherent advantage of animal models over human research as well as the crucial complementary roles animal studies play vis‐à‐vis human imaging and genetic studies. Finally, we discuss recent developments in animal models of pain that should improve the relevance and translatability of findings using laboratory animals. We believe that pain research using animal models is a continuing necessity–to understand fundamental mechanisms, identify new analgesic targets, and inform, guide and follow up human studies–if novel analgesics are to be developed for the treatment of chronic pain.

fMRI of human somatosensory and cingulate cortex during painful electrical nerve stimulation

Functional MRI (fMRI) can detect changes from resting levels of blood flow and oxygenation during task performance (i.e. activation). We used a simple electrical nerve stimulation technique together with fMRI to study pain processes in the human cortex. Images of the primary somatosensory (SI) and cingulate cortex (Cg) were obtained from subjects during stimulation at painful and non-painful intensities. Stimuli that evoked non-painful tingling sensations activated the contralateral SI but not Cg. Stimuli that evoked painful sensations activated both the contralateral SI and Cg. These data indicate that fMRI can detect pain-related changes in SI and Cg evoked by electrical stimulation of peripheral nerves. These findings add to the evidence for a role of SI and Cg in human pain processes and provide a simple method of stimulus delivery for its study.

Activation of trigeminal brain-stem nociceptive neurons by dural artery stimulation

Vascular head pain is thought to result from activation of trigeminal sensory nerve fibers innervating cranial blood vessels. Support for this hypothesis was sought by searching in the trigeminal brain-stem subnucleus caudalis (SNC) for neuronal responses evoked by electrical stimulation of the middle meningeal artery (MMA). Seventy-eight SNC neurons were found which could be excited by MMA stimulation of the facial skin. These results provide the first report of the existence and functional properties of brain-stem neurons likely to be involved in mediating vascular head pain.

A comparison of the burst activity of lateral thalamic neurons in chronic pain and non-pain patients

Thalamic neurons are known to switch their firing from a tonic pattern during wakefulness to a bursting pattern during sleep. Several studies have described the existence of bursting activity in awake chronic pain patients and have suggested that this activity is abnormal and may be related to their pain. However, we have frequently observed bursting activity in awake non-pain patients suggesting that there may not be a causal relationship between thalamic bursting activity and chronic pain. To examine this issue more rigorously we compared the incidence and pattern of bursting activity of lateral thalamic neurons of both pain and non-pain patients in a state of wakefulness. Recordings were obtained from lateral thalamic areas of different groups of patients (n = 91) suffering from pain disorders (e.g. anaesthesia dolorosa, phantom limb pain, trigeminal neuralgia, post-stroke pain) and motor disorders (e.g. Parkinsons disease, essential tremor) during stereotactic surgical procedures for the treatment of pain and movement disorders. Burst indices (the number of bursting cells per electrode track) were computed for all the explorations in the two groups. The burst indices in the pain and non-pain groups (1.73 +/- 0.28 and 1.14 +/- 0.16, respectively) were not significantly different from each other. The bursts were analyzed to see if they fulfilled the criteria of low-threshold calcium spike (LTS)-evoked bursts characterized by (i) a shortening of the first interspike interval with an increase in the number of interspike intervals in the burst and also (ii) a progressive prolongation of successive interspike intervals. LTS-evoked bursts were identified in 27/47 (57%) bursting cells in pain patients and 15/32 (47%) cells in non-pain patients. These data demonstrate that the occurrence of bursting activity and of LTS-evoked bursts in the human thalamus is prevalent in both pain and non-pain patients. This suggests that the bursting activity of thalamic neurons in pain patients is not necessarily related to the occurrence of their pain.