The neural network that contributes to the suffering which accompanies persistent pain states involves a number of brain regions. Of primary interest is the contribution of the cingulate cortex in processing the affective component of pain. The purpose of this review is to summarize recent data obtained using novel behavioral paradigms in animals based on measuring escape and/or avoidance of a noxious stimulus. These paradigms have successfully been used to study the nature of the neuroanatomical and neurochemical contributions of the anterior cingulate cortex (ACC) to higher order pain processing in rodents.

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The anterior cingulate cortex and pain processing

The insula, a “cortical hub” buried within the lateral sulcus, is involved in a number of processes including goal-directed cognition, conscious awareness, autonomic regulation, interoception, and somatosensation. While some of these processes are well known in the clinical presentation of migraine (i.e., autonomic and somatosensory alterations), other more complex behaviors in migraine, such as conscious awareness and error detection, are less well described. Since the insula processes and relays afferent inputs from brain areas involved in these functions to areas involved in higher cortical function such as frontal, temporal, and parietal regions, it may be implicated as a brain region that translates the signals of altered internal milieu in migraine, along with other chronic pain conditions, through the insula into complex behaviors. Here we review how the insula function and structure is altered in migraine. As a brain region of a number of brain functions, it may serve as a model to study new poten...

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The Insula A “Hub of Activity” in Migraine

Classic trigeminal neuralgia (CTN) is a chronic neuropathic pain state characterized by intense, piercing spasms of the orofacial region, and may be attributable to abnormal pain processing in the central nervous system Our study investigated neuronal alterations using voxel-based morphometry (VBM), diffuse tensor imaging (DTI), and resting-state functional connectivity in 38 patients with CTN and 38 matched healthy controls For voxel-based morphometry analyses, patients with CTN displayed gray matter volume (GMV) reductions in the anterior-cingulate cortex (ACC) and mid-cingulate cortex, insula, secondary somatosensory cortex (S2), primary motor cortex (M1), premotor area, and several regions in the temporal lobe For DTI analysis, patients compared with controls had increased mean diffusivity (MD) and decreased fractional anisotropy (FA) in the corpus callosum and the bilateral corona radiata, and increased mean diffusivity with no fractional anisotropy changes across the bilateral superior longitudinal fasciculus, the internal and external capsule, the thalamus and brainstem Additionally, patients with CTN had enhanced functional connectivity between the right insula/S2 and ACC, medial prefrontal cortex, posterior cingulate cortex, and bilateral dorsolateral prefrontal cortex Furthermore, gray matter volume of left inferior temporal gyrus negatively correlated with current pain intensity and disease duration in patients, and connectivity of the right insula/S2-ACC was negatively correlated with pain intensity, depression, and anxiety ratings This study provides multiple lines of evidence supporting aberrant structural and functional patterns that are observed in patients with CTN, which may help us better understand the pathophysiology of CTN and facilitate the development of new therapies for this disease

Altered brain structure and function associated with sensory and affective components of classic trigeminal neuralgia.

Human experimental pain models are widely used to study drug effects under controlled conditions. However, efforts to improve both animal and human experimental model selection, on the basis of increased understanding of the underlying pathophysiological pain mechanisms, have been disappointing, with poor translation of results to clinical analgesia. We have developed an alternative approach to the selection of suitable pain models that can correctly predict drug efficacy in particular clinical settings. This is based on the analysis of successful or unsuccessful empirical prediction of clinical analgesia using experimental pain models. We analyzed statistically the distribution of published mutual agreements or disagreements between drug efficacy in experimental and clinical pain settings. Significance limits were derived by random permutations of agreements. We found that a limited subset of pain models predicts a large number of clinically relevant pain settings, including efficacy against neuropathic pain for which novel analgesics are particularly needed. Thus, based on empirical evidence of agreement between drugs for their efficacy in experimental and clinical pain settings, it is possible to identify pain models that reliably predict clinical analgesic drug efficacy in cost-effective experimental settings.

Human models of pain for the prediction of clinical analgesia.

Pain Assessment in 21st-Century Neuropsychiatry. Introducing Plural, Perspective, Situated Epistemic Frames for the Epidiagnostic Characterisation of Pain Experiences

Sumatriptan, a drug widely used to alleviate migraine headaches, has several somatosensory adverse effects, including tactile allodynia. To understand whether sumatriptan affects sensory and affective circuitries simultaneously, we investigated the responses of 12 healthy volunteers to electrical stimuli after infusion with either sumatriptan or saline. Using a double-blind crossover study design, we used functional magnetic resonance imaging (fMRI) to measure brain activation in different areas during electrical stimulation. The visual analog scale (VAS) and short-form McGill pain questionnaire (SF-MPQ) were used to rate stimulation-evoked sensations and affections after drug administration. VAS rating, SF-MPQ, and block fMRI were all performed in each subject during sumatriptan and saline injection. Echo-planar imaging sequences were used to determine the whole-brain blood oxygenation level-dependent signal of the entire brain. Our results showed that sumatriptan predominantly activated regions in the medial pain system and smaller regions in the lateral pain system. These regions included the secondary somatosensory cortex (SII), anterior insular cortex, orbitofrontal cortex, medial thalamus, cerebellar supravermis, dentate nucleus, and the majority of the anterior cingulate cortex (ACC). In contrast, activation following saline administration was observed primarily in the lateral pain system, including the primary sensory cortex, lateral SII, posterior insular cortex, anterior ACC, and lateral thalamus. Importantly, we found that VAS ratings and MPQ scores were increased after sumatriptan infusion, but not after saline administration. Our fMRI, VAS, and SF-MPQ findings suggest that sumatriptan plays a significant role in the affective dimension of pain and a minor role related to sensory discrimination.

A pharmaco-fMRI study on pain networks induced by electrical stimulation after sumatriptan injection.

Background: Pain-related studies have mainly been performed through traditional methods, which lack the rigorous analysis of anatomical locations. Functional magnetic resonance imaging (fMRI) is a noninvasive method detecting neural activity, and has the ability to precisely locate related activations in vivo. Moreover, few studies have used painful stimulation of changed intensity to investigate relevant functioning nuclei in the human brain. Aim: This study mainly focused on the pain-related activations induced by electrical stimulation with different intensities using fMRI. Furthermore, the electrophysiological characteristics of different pain-susceptible-neurons were analyzed to construct the pain modulatory network, which was corresponding to painful stimulus of changed intensity. Materials and Methods: Twelve volunteers underwent functional scanning receiving different electrical stimulation. The data were collected and analyzed to generate the corresponding functional activation maps and response time curves related to pain. Results: The common activations were mainly located in several specific regions, including the secondary somatosensory cortex (SII), insula, anterior cingulate cortex (ACC), thalamus, and other cerebral regions. Moreover, innocuous electrical stimulation primarily activated the lateral portions of SII and thalamus, as well as the posterior insula, anterior ACC, whereas noxious electrical stimulation primarily activated the medial portions of SII and thalamus, as well as the anterior insula, the posterior ACC, with larger extensions and greater intensities. Conclusion: Several specified cerebral regions displayed different response patterns during electrical stimulation by means of fMRI, which implied that the corresponding pain-susceptible-neurons might process specific aspects of pain. Elucidation of functions on pain-related regions will help to understand the delicate pain modulation of human brain.

Wang Yuan

Papers

A pharmaco-fMRI study on pain networks induced by electrical stimulation after sumatriptan injection.

A functional magnetic resonance imaging study of human brain in pain-related areas induced by electrical stimulation with different intensities.