Raimi L. Quiton

Zona Incerta: A Role in Central Pain

Central pain syndrome (CPS) is a debilitating condition that affects a large number of patients with a primary lesion or dysfunction in the CNS. Despite its discovery over a century ago, the pathophysiological processes underlying the development and maintenance of CPS are poorly understood. We recently demonstrated that activity in the posterior thalamus (PO) is tightly regulated by inhibitory inputs from zona incerta (ZI). Here we test the hypothesis that CPS is associated with abnormal inhibitory regulation of PO by ZI. We recorded single units from ZI and PO in animals with CPS resulting from spinal cord lesions. Consistent with our hypothesis, the spontaneous firing rate and somatosensory evoked responses of ZI neurons were lower in lesioned animals compared with sham-operated controls. In PO, neurons recorded from lesioned rats exhibited significantly higher spontaneous firing rates and greater responses to noxious and innocuous stimuli applied to the hindpaw and to the face. These changes were not associated with increased afferent drive from the spinal trigeminal nucleus or changes in the ventroposterior thalamus. Thus CPS can result from suppressed inputs from the inhibitory nucleus zona incerta to the posterior thalamus.

Sex differences in endogenous pain modulation by distracting and painful conditioning stimulation.

Abstract Sex differences in endogenous pain modulation were tested in healthy volunteers (32 men, 30 women). Painful contact heat stimuli were delivered to the right leg alone, and then in combination with various electrical conditioning stimuli delivered to the left forearm. Four conditioning protocols were applied to each subject in separate sessions: mild, non‐painful (control); distracting; stressful‐yet‐non‐painful; strongly painful. Thermal stimuli were rated on visual analog scales for pain intensity (INT) and unpleasantness (UNP). Distracting and painful conditioning stimuli significantly reduced heat pain INT and UNP ratings for both sexes, with significantly larger distraction effects on INT ratings for men than women (p = 0.004). No sex differences in pain‐evoked hypoalgesia were detected (p > 0.05). The stress protocol did not consistently reduce heat pain ratings, possibly because the protocol was not sufficiently stressful to activate endogenous modulatory systems. Regression analysis revealed that the magnitude of pain‐evoked hypoalgesia was predicted by the perceived distraction (p = 0.003) and stress (p = 0.04) produced by the painful conditioning stimulation, providing evidence that distraction and stress contribute to pain‐evoked hypoalgesia. However, the contribution of stress to pain‐evoked hypoalgesia differed by sex (p = 0.02), with greater perceived stress associated with greater hypoalgesia in men and the opposite trend in women, suggesting sex differences in the mechanisms underlying pain‐evoked hypoalgesia. This study provides indirect evidence that multiple neural mechanisms are involved in endogenous pain modulation and suggests that sex‐specific aspects of these systems may contribute to greater pain sensitivity and higher prevalence of many chronic pain conditions among women.

Conditioned Place Preference Reveals Tonic Pain in an Animal Model of Central Pain

UNLABELLED A limitation of animal models of central pain is their inability to recapitulate all clinical characteristics of the human condition. Specifically, many animal models rely on reflexive measures of hypersensitivity and ignore, or cannot assess, spontaneous pain, the hallmark characteristic of central pain in humans. Here, we adopt a conditioned place preference paradigm to test if animals with lesions in the anterolateral quadrant of the spinal cord develop signs consistent with spontaneous pain. This paradigm relies on the fact that pain relief is rewarding to animals, and has been used previously to show that animals with peripheral nerve injury develop tonic pain. With the use of 2 analgesic treatments commonly used to treat patients with central pain (clonidine infusion and motor cortex stimulation), we demonstrate that analgesic treatments are rewarding to animals with spinal cord lesions but not sham-operated controls. These findings are consistent with the conclusion that animals with spinal cord injury suffer from tonic pain. PERSPECTIVE The hallmark characteristic of central pain in humans is spontaneous pain. Animal models of central pain rely on reflexive measures of hypersensitivity and do not assess spontaneous pain. Demonstrating that animals with spinal cord injury suffer from tonic pain is important to study the etiology of central pain.

Across- and within-session variability of ratings of painful contact heat stimuli.

&NA; This study examined within‐ and across‐session consistency of visual analog scale (VAS) pain intensity and unpleasantness ratings of contact heat stimuli in 64 subjects (32 male). Subjects participated in four sessions over 14 days, with three stimulus series per session. Two levels of painful heat (pain‐lo: rated 40, and pain‐hi: rated 70 on a 0–100 VAS) were delivered in randomized order during each series, with temperatures selected on an individual subject basis to equalize pain perception across subjects. Across‐session ratings declined by the fourth session for both pain levels (p = 0.01). Within‐session ratings declined by the third series for both pain levels (p < 0.001). While significant, changes in across‐ and within‐session ratings were of small magnitude. Comparison of coefficients of variation (CVs) for across‐ and within‐session ratings revealed that pain‐lo ratings were more variable than pain‐hi ratings (p < 0.001). Across‐ and within‐session CVs were highly correlated for each pain level (pain‐lo p < 0.001; pain‐hi p = 0.001), suggesting that variability of VAS ratings is a characteristic of individual subjects over both short and long time scales. Across‐ and within‐session CVs were significantly negatively correlated with individual ratings of the stimuli, but were not correlated with demographic or psychosocial factors. Furthermore, sex did not impact consistency of ratings, demonstrating that neither sex is more variable in ratings than the other over time. Taken together, these findings suggest that VAS ratings of painful contact heat are relatively stable over time but the variability of these ratings is significantly impacted by the perceived intensity of the stimulus.

Abnormal activity of primary somatosensory cortex in central pain syndrome.

Central pain syndrome (CPS) is a debilitating and chronic pain condition that results from a lesion or dysfunction in the CNS. The pathophysiological mechanisms underlying CPS are poorly understood. We recently demonstrated that CPS is associated with suppressed inputs from the inhibitory nucleus zona incerta to the posterior thalamus (PO). As a consequence, activity in PO is abnormally increased in CPS. Because the perception of pain requires activity in the cerebral cortex, CPS must also involve abnormal cortical activity. Here we test the hypothesis that CPS is associated with increased activity in the primary somatosensory cortex (SI), a major projection target of PO that plays an important role in processing sensory-discriminative aspects of pain. We recorded activity of single units in SI in rats with CPS resulting from spinal cord lesions. Consistent with our hypothesis, SI neurons recorded from lesioned rats exhibited significantly higher spontaneous firing rates and greater responses evoked by innocuous and noxious mechanical stimulation of the hindpaw compared with control rats. Neurons from lesioned rats also showed a greater tendency than controls to fire bursts of action potentials in response to noxious stimuli. Thus, the excruciatingly painful symptoms of CPS may result, at least in part, from abnormally increased activity in SI.

Age-related changes in nociceptive processing in the human brain.

Abstract:  Functional magnetic resonance imaging (fMRI) was used to compare cortical nociceptive responses to painful contact heat in healthy young (ages 22–30, n= 7) and older (ages 56–75, n= 7) subjects. Compared to young subjects, older subjects had significantly smaller pain‐related fMRI responses in anterior insula (aINS) (P < 0.04), primary somatosensory cortex (S1) (P= 0.03), and supplementary motor area (P= 0.02). Gray matter volumes in S1 and aINS were significantly smaller for the older group (P= 0.02 and 0.0001, respectively), suggesting reduced processing capacity in these regions that might account for smaller pain‐related fMRI responses.

Intersession reliability of fMRI activation for heat pain and motor tasks

As the practice of conducting longitudinal fMRI studies to assess mechanisms of pain-reducing interventions becomes more common, there is a great need to assess the test–retest reliability of the pain-related BOLD fMRI signal across repeated sessions. This study quantitatively evaluated the reliability of heat pain-related BOLD fMRI brain responses in healthy volunteers across 3 sessions conducted on separate days using two measures: (1) intraclass correlation coefficients (ICC) calculated based on signal amplitude and (2) spatial overlap. The ICC analysis of pain-related BOLD fMRI responses showed fair-to-moderate intersession reliability in brain areas regarded as part of the cortical pain network. Areas with the highest intersession reliability based on the ICC analysis included the anterior midcingulate cortex, anterior insula, and second somatosensory cortex. Areas with the lowest intersession reliability based on the ICC analysis also showed low spatial reliability; these regions included pregenual anterior cingulate cortex, primary somatosensory cortex, and posterior insula. Thus, this study found regional differences in pain-related BOLD fMRI response reliability, which may provide useful information to guide longitudinal pain studies. A simple motor task (finger-thumb opposition) was performed by the same subjects in the same sessions as the painful heat stimuli were delivered. Intersession reliability of fMRI activation in cortical motor areas was comparable to previously published findings for both spatial overlap and ICC measures, providing support for the validity of the analytical approach used to assess intersession reliability of pain-related fMRI activation. A secondary finding of this study is that the use of standard ICC alone as a measure of reliability may not be sufficient, as the underlying variance structure of an fMRI dataset can result in inappropriately high ICC values; a method to eliminate these false positive results was used in this study and is recommended for future studies of test–retest reliability.

Glutamatergic Response to Heat Pain Stress in Schizophrenia

Regulation of stress response involves top-down mechanisms of the frontal-limbic glutamatergic system. As schizophrenia is associated with glutamatergic abnormalities, we hypothesized that schizophrenia patients may have abnormal glutamatergic reactivity within the dorsal anterior cingulate cortex (dACC), a key region involved in perception of and reaction to stress. To test this, we developed a somatic stress paradigm involving pseudorandom application of safe but painfully hot stimuli to the forearm of participants while they were undergoing serial proton magnetic resonance spectroscopy to measure changes in glutamate and glutamine levels in the dACC. This paradigm was tested in a sample of 21 healthy controls and 23 patients with schizophrenia. Across groups, glutamate levels significantly decreased following exposure to thermal pain, while ratio of glutamine to glutamate significantly increased. However, schizophrenia patients exhibited an initial increase in glutamate levels during challenge that was significantly different from controls, after controlling for heat pain tolerance. Furthermore, in patients, the acute glutamate response was positively correlated with childhood trauma (r = .41, P = .050) and inversely correlated with working memory (r = -.49, P = .023). These results provide preliminary evidence for abnormal glutamatergic response to stress in schizophrenia patients, which may point toward novel approaches to understanding how stress contributes to the illness.

Alcohol-triggered signs of migraine: An animal model.

Abstract We describe an animal model where characteristics of migraine can be triggered by alcohol administration. In rats chronically implanted with a cannula overlying the transverse sinus, we applied potassium chloride (KCl) (or saline) to the meninges to sensitize trigeminovascular afferents. We assessed effects of repeated KCl application on animal behavior using conditioned place avoidance paradigm. In KCl-treated rats we discovered that alcohol injections (0.2 mg/kg), but not saline, resulted in the development of extracephalic allodynia and signs of ongoing pain.

Higher Dispositional Optimism Predicts Lower Pain Reduction During Conditioned Pain Modulation

Optimism is associated with lower pain sensitivity, positive adjustment to chronic pain, and greater reduction of pain thresholds in a conditioned pain modulation (CPM) paradigm. We hypothesized that participants with higher levels of optimism would experience greater inhibition of suprathreshold pain during CPM. Seventy-seven healthy adults completed a test of optimism, the Life Orientation Test-Revised, as well as measures of depression, pain catastrophizing, and neuroticism. Participants also underwent psychophysical tests of heat pain tolerance, heat pain threshold, and CPM. CPM magnitude was calculated as the change in heat pain ratings when applied alone and simultaneously with painful pressure. Greater optimism was significantly correlated with reduced CPM magnitude (P = .013). Regression analysis was performed using optimism as a predictor of CPM magnitude while controlling for pain catastrophizing, neuroticism, depression, and age. The overall model was significant (P = .003). Significant positive coefficients were found for depression (P = .014) and optimism (P < .001) scores. These results suggest that greater optimism predicts less inhibition of suprathreshold pain, the opposite of our hypothesis. This unexpected finding may be due to factors such as perceived stress and coping differences, and suggests that modulation of threshold-level and suprathreshold pain involves different underlying mechanisms. PERSPECTIVE: This article reports that greater optimism predicts less inhibition of suprathreshold pain, in contrast with previous work showing that optimism correlates positively with pain threshold reductions. These findings suggest that the association between optimism and the function of endogenous pain modulatory systems is complex and differs for threshold-level and suprathreshold pain.