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Pain demands attention, yet pain can be reduced by focusing attention elsewhere. The neural processes involved in this robust psychophysical phenomenon, attentional analgesia, are still being defined. Our previous fMRI study linked activity in the brainstem triad of locus coeruleus (LC), rostral ventromedial medulla (RVM) and periaqueductal grey (PAG) with attentional analgesia. Here we identify and model the functional interactions between these regions and the cortex in healthy human subjects (n = 57), who received painful thermal stimuli whilst simultaneously performing a visual attention task. RVM activity encoded pain intensity while contralateral LC activity correlated with attentional analgesia. Psycho-Physiological Interaction analysis and Dynamic Causal Modelling identified two parallel paths between forebrain and brainstem. These connections are modulated by attentional demand: a bidirectional anterior cingulate cortex (ACC) - right-LC loop, and a top-down influence of task on ACC-PAG-RVM. By recruiting discrete brainstem circuits, the ACC is able to modulate nociceptive input to reduce pain in situations of conflicting attentional demand., (Copyright © 2020. Published by Elsevier Inc.)

Chronic pain is thought to arise because of maladaptive changes occurring within the peripheral nervous system and CNS. The transition from acute to chronic pain is known to involve the spinal cord (Woolf and Salter, 2000). Therefore, to investigate altered human spinal cord function and translate results obtained from other species, a noninvasive neuroimaging technique is desirable. We have investigated the functional response in the cervical spinal cord of 18 healthy human subjects (aged 22-40 years) to noxious thermal and non-noxious tactile stimulation of the left and right forearms. Physiological noise, which is a significant source of signal variability in the spinal cord, was accounted for in the general linear model. Group analysis, performed using a mixed-effects model, revealed distinct regions of activity that were dependent on both the side and the type of stimulation. In particular, thermal stimulation on the medial aspect of the wrist produced activity within the C6/C5 segment ipsilateral to the side of stimulation. Similar to data recorded in animals (Fitzgerald, 1982), painful thermal stimuli produced increased ipsilateral and decreased contralateral blood flow, which may reflect, respectively, excitatory and inhibitory processes. Nonpainful punctate stimulation of the thenar eminence provoked more diffuse activity but was still ipsilateral to the side of stimulation. These results present the first noninvasive evidence for a lateralized response to noxious and non-noxious stimuli in the human spinal cord. The development of these techniques opens the path to understanding, at a subject-specific level, central sensitization processes that contribute to chronic pain states.

Relief from pain in humans is frequently measured by computing the reduction on an 11-point pain intensity scale. However, this definition of relief may be insufficient to capture the utility of pain relief for the individual. Based on pain literature and evidence from studies examining relief and reward, it is clear that pain relief is a broad concept comprising several factors, only one of which is pain intensity reduction. According to opponent process theory, all sensations consist of a primary process and a slow 'opponent process' of opposite valence, the purpose of which is to reduce the deviation from homeostatic balance. Here, opponent process theory provided a framework to explore the interaction between pain, relief and reward. We devised three psychophysical studies examining the temporal (Experiment I) and magnitude (Experiments I and II) relationships between pain severity and its subsequent relief. In Experiment III, we further manipulated the magnitude and pleasantness of relief experienced by applying innocuous cooling following noxious heat stimulation of capsaicin-sensitized skin. Results confirmed predictions from opponent process theory and showed that pain intensity reduction was significantly stronger than relief intensity ratings. Furthermore, continuous relief ratings appeared to reflect the speed of pain intensity reduction. Varying pain intensity parametrically confirmed that relief increases with pain intensity. That innocuous cooling following primary hyperalgesia intervention significantly increased the intensity, pleasantness and duration of relief provides further evidence that pain relief encapsulates more than a reduction in pain intensity. Importantly, the high relief pleasantness ratings confirmed the hypothesized link between relief and reward.

Previous human imaging studies have revealed a network of brain regions involved in the processing of allodynic pain; this includes prefrontal areas, insula, cingulate cortex, primary and secondary somatosensory cortices and parietal association areas. In this study, the neural correlates of the perceived intensity of allodynic pain in neuropathic pain patients were investigated. In eight patients, dynamic mechanical allodynia was provoked and brain responses recorded using functional magnetic resonance imaging (fMRI). Voxels in which the magnitude of fMRI signal correlated linearly with the ratings of allodynic pain across the group were determined in a whole brain analysis using a general linear model. To ensure that activation reflected only allodynic pain ratings, a nuisance variable containing ratings of ongoing pain was included in the analysis. We found that the magnitude of activation in the caudal anterior insula (cAI) correlates with the perceived intensity of allodynic pain across subjects, independent of the level of ongoing pain. However, the peak of activation in the allodynic condition was located in the rostral portion (rAI). This matches the representation of other clinical pain syndromes, confirmed by a literature review. In contrast, experimental pain in healthy volunteers resides predominantly in the cAI, as shown by the same literature review. Taken together, our data and the literature review suggest a functional segregation of anterior insular cortex.

Functional imaging techniques have allowed researchers to look within the brain, and revealed the cortical representation of pain. Initial experiments, performed in the early 1990s, revolutionized pain research, as they demonstrated that pain was not processed in a single cortical area, but in several distributed brain regions. Over the last decade, the roles of these pain centres have been investigated and a clearer picture has emerged of the medial and lateral pain system. In this brief article, we review the imaging literature to date that has allowed these advances to be made, and examine the new frontiers for pain imaging research: imaging the brainstem and other structures involved in the descending control of pain; functional and anatomical connectivity studies of pain processing brain regions; imaging models of neuropathic pain-like states; and going beyond the brain to image spinal function. The ultimate goal of such research is to take these new techniques into the clinic, to investigate and provide new remedies for chronic pain sufferers.

Brain activity was studied by fMRI in 18 healthy subjects during stimulation of the thenar eminence of the hand with either warm (non-painful, 40 degrees C) or hot (painful, 46-49 degrees C) stimuli using a contact thermode. Experiments were performed on the right and left hand independently and with two attentional contexts: subjects either attended to pain or attended to a visual global motion discrimination task (to distract them from pain). Group analysis demonstrated that attended warm stimulation of the right hand did not produce any significantly activated clusters. Painful thermal stimulation of either hand elicited significant activity over a large network of brain regions, including insula, inferior frontal gyrus, cingulate gyrus, secondary somatosensory cortex, cerebellum, and medial frontal gyrus (corrected P < 0.05). Insula activity was distributed along its anterior-posterior axis and depended on the hand stimulated and attentional context. In particular, activity within the posterior insula was contralateral to the site of stimulation, tested using regions of interest (ROI) analysis: significant side x site interaction (P = 0.001). With attention diverted from the painful stimulus bilateral anterior insula activity moved posteriorly to midinsula and decreased in extent (ROI analysis: significant main effect of attention (P = 0.03)). The role of the insula in thermosensation and attention is discussed.

Four subjects with small restricted cerebral cortical infarcts have been examined. One had a lesion confined to the parietal operculum (SII), while in the second the SII lesion also encroached on the posterior insula; in the third subject, both banks of the sylvian fissure and the dorsal insula were involved, while in the fourth the lesion involved the upper bank of the sylvian fissure. In all cases, the postcentral gyrus (SI) was intact. Subjects 1 and 2 had mild spontaneous pain, but subjects 3 and 4 had never had spontaneous pain. In the affected areas, none could feel mechanical (skinfold pinch) pain. The 2 subjects with spontaneous pain could not discriminate sharpness (pinprick), but this was unimpaired in the third and fourth subjects. Warmth, cold, and heat pain were impaired in the 2 subjects with spontaneous pain, but not in those without; however warm-cold difference was greater in the affected regions of all subjects. The possibility must nevertheless be considered that the presence of central pain in some way alters the cortical mechanisms for the perception of thermal stimuli. Certainly, as we had earlier observed, spontaneous pain only occurs when there is interference with thermal sensation. Functional MRI (fMRI) studies following thermal stimulation in subjects 1 and 2 showed these areas, particularly SII, to be concerned with the reception of innocuous and noxious thermal stimuli, mechanical (skinfold pinch) pain and sharpness (pinprick), implying that SI is principally concerned with the reception of low-intensity mechanical stimuli, although it was activated in 1 of our fMRI-studied subjects by innocuous cooling. Copyright © 2004 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: Fibromyalgia is a prevalent pain condition that is associated with cognitive impairments including in attention, memory, and executive processing. It has been proposed that fibromyalgia may be caused by altered central pain processing characterised by a loss of endogenous pain modulation. We tested whether attentional analgesia, where cognitive engagement diminishes pain percept, was attenuated in patients with fibromyalgia (n = 20) compared with matched healthy controls (n = 20). An individually calibrated, attentional analgesia paradigm with a 2 × 2 factorial design was used with brain and brainstem-focussed functional magnetic resonance imaging. Patients with fibromyalgia had both lower heat pain thresholds and speeds in a visual attention task. When this was taken into account for both attentional task and thermal stimulation, both groups exhibited an equivalent degree of attentional analgesia. Functional magnetic resonance imaging analysis showed similar patterns of activation in the main effects of pain and attention in the brain and brainstem (with the sole exceptions of increased activation in the control group in the frontopolar cortex and the ipsilateral locus coeruleus). The attentional analgesic effect correlated with activity in the periaqueductal gray and rostral ventromedial medulla. These findings indicate that patients with fibromyalgia can engage the descending pain modulatory system if the attentional task and noxious stimulus intensity are appropriately titrated. [ABSTRACT FROM AUTHOR]

Abstract: Cannabis is reported to be remarkably effective for the relief of otherwise intractable pain. However, the bases for pain relief afforded by this psychotropic agent are debatable. Nonetheless, the frontal-limbic distribution of cannabinoid receptors in the brain suggests that cannabis may target preferentially the affective qualities of pain. This central mechanism of action may be relevant to cannabinoid analgesia in humans, but has yet to be demonstrated. Here, we employed functional magnetic resonance imaging to investigate the effects of delta-9-tetrahydrocannabinol (THC), a naturally occurring cannabinoid, on brain activity related to cutaneous ongoing pain and hyperalgesia that were temporarily induced by capsaicin in healthy volunteers. On average, THC reduced the reported unpleasantness, but not the intensity of ongoing pain and hyperalgesia: the specific analgesic effect on hyperalgesia was substantiated by diminished activity in the anterior mid cingulate cortex. In individuals, the drug-induced reduction in the unpleasantness of hyperalgesia was positively correlated with right amygdala activity. THC also reduced functional connectivity between the amygdala and primary sensorimotor areas during the ongoing-pain state. Critically, the reduction in sensory-limbic functional connectivity was positively correlated with the difference in drug effects on the unpleasantness and the intensity of ongoing pain. Peripheral mechanisms alone cannot account for the dissociative effects of THC on the pain that was observed. Instead, the data reveal that amygdala activity contributes to interindividual response to cannabinoid analgesia, and suggest that dissociative effects of THC in the brain are relevant to pain relief in humans. [Copyright &y& Elsevier]

Abstract: The spinal cord is the main pathway for information between the central and the peripheral nervous systems. Non-invasive functional MRI offers the possibility of studying spinal cord function and central sensitisation processes. However, imaging neural activity in the spinal cord is more difficult than in the brain. A significant challenge when dealing with such data is the influence of physiological noise (primarily cardiac and respiratory), and currently there is no standard approach to account for these effects. We have previously studied the various sources of physiological noise for spinal cord fMRI at 1.5T and proposed a physiological noise model (PNM) (). An alternative de-noising strategy, selective averaging filter (SAF), was proposed by . In this study we reviewed and implemented published physiological noise correction methods at higher field (3T) and aimed to find the optimal models for gradient-echo-based BOLD acquisitions. Two general techniques were compared: physiological noise model (PNM) and selective averaging filter (SAF), along with regressors designed to account for specific signal compartments and physiological processes: cerebrospinal fluid (CSF), motion correction (MC) parameters, heart rate (HR), respiration volume per time (RVT), and the associated cardiac and respiratory response functions. Functional responses were recorded from the cervical spinal cord of 18 healthy subjects in response to noxious thermal and non-noxious punctate stimulation. The various combinations of models and regressors were compared in three ways: the model fit residuals, regression model F-tests and the number of activated voxels. The PNM was found to outperform SAF in all three tests. Furthermore, inclusion of the CSF regressor was crucial as it explained a significant amount of signal variance in the cord and increased the number of active cord voxels. Whilst HR, RVT and MC explained additional signal (noise) variance, they were also found (in particular HR and RVT) to have a negative impact on the parameter estimates (of interest) — as they may be correlated with task conditions e.g. noxious thermal stimuli. Convolution with previously published cardiac and respiratory impulse response functions was not found to be beneficial. The other novel aspect of current study is the investigation of the influence of pre-whitening together with PNM regressors on spinal fMRI data. Pre-whitening was found to reduce non-white noise, which was not accounted for by physiological noise correction, and decrease false positive detection rates. [Copyright &y& Elsevier]