Pain: A Distributed Brain Information Network?

Understanding how pain is processed in the brain has been an enduring puzzle, because there doesn''t appear to be a single “pain cortex” that directly codes the subjective perception of pain. An emerging concept is that, instead, pain might emerge from the coordinated activity of an integrated brain network. In support of this view, Woo and colleagues present evidence that distinct brain networks support the subjective changes in pain that result from nociceptive input and self-directed cognitive modulation. This evidence for the sensitivity of distinct neural subsystems to different aspects of pain opens up the way to more formal computational network theories of pain.On the surface, pain should have been one of the easier brain systems to understand. Its fundamental importance in organism defence means that its anatomy should be well conserved across species, unlike systems for language, for instance. And its relatively simple scalar signal (from less pain to more pain) should not require extensive computational processing, unlike sound or vision. However, since Penfield''s failure to convincingly locate a “pain cortex” during his classic awake brain stimulation studies in the 1950s [1], trying to piece together the pain system in the brain has been a story of frustration and debate.     

Mechanism of gain modulation at single neuron and network levels

Gain modulation, in which the sensitivity of a neural response to one input is modified by a second input, is studied at single-neuron and network levels. At the single neuron level, gain modulation can arise if the two inputs are subject to a direct multiplicative interaction. Alternatively, these inputs can be summed in a linear manner by the neuron and gain modulation can arise, instead, from a nonlinear input–output relationship. We derive a mathematical constraint that can distinguish these two mechanisms even though they can look very similar, provided sufficient data of the appropriate type are available. Previously, it has been shown in coordinate transformation studies that artificial neurons with sigmoid transfer functions can acquire a nonlinear additive form of gain modulation through learning-driven adjustment of synaptic weights. We use the constraint derived for single-neuron studies to compare responses in this network with those of another network model based on a biologically inspired transfer function that can support approximately multiplicative interactions.     

Magnetic resonance imaging for chronic pain: diagnosis,manipulation, and biomarkers

Pain is a multidimensional subjective experience with biological, psychological, and social factors. Whereas acute pain can be a warning signal for the body to avoid excessive injury, long-term and ongoing pain may be developed as chronic pain. There are more than 100 million people in China living with chronic pain, which has raised a huge socioeconomic burden. Studying the mechanisms of pain and developing effective analgesia approaches are important for basic and clinical research. Recently, with the development of brain imaging and data analytical approaches, the neural mechanisms of chronic pain have been widely studied. In the first part of this review, we briefly introduced the magnetic resonance imaging and conventional analytical approaches for brain imaging data. Then, we reviewed brain alterations caused by several chronic pain disorders, including localized and widespread primary pain, primary headaches and orofacial pain, musculoskeletal pain, and neuropathic pain, and present meta-analytical results to show brain regions associated with the pathophysiology of chronic pain. Next, we reviewed brain changes induced by pain interventions, such as pharmacotherapy, neuromodulation, and acupuncture. Lastly, we reviewed emerging studies that combined advanced machine learning and neuroimaging techniques to identify diagnostic, prognostic, and predictive biomarkers in chronic pain patients.     

Peripheral Nerve Injury Is Associated with Chronic,Reversible Changes in Global DNA Methylation in the Mouse Prefrontal Cortex

Changes in brain structure and cortical function are associated with many chronic pain conditions including low back pain and fibromyalgia. The magnitude of these changes correlates with the duration and/or the intensity of chronic pain. Most studies report changes in common areas involved in pain modulation, including the prefrontal cortex (PFC), and pain-related pathological changes in the PFC can be reversed with effective treatment. While the mechanisms underlying these changes are unknown, they must be dynamically regulated. Epigenetic modulation of gene expression in response to experience and environment is reversible and dynamic. Epigenetic modulation by DNA methylation is associated with abnormal behavior and pathological gene expression in the central nervous system. DNA methylation might also be involved in mediating the pathologies associated with chronic pain in the brain. We therefore tested a) whether alterations in DNA methylation are found in the brain long after chronic neuropathic pain is induced in the periphery using the spared nerve injury modal and b) whether these injury-associated changes are reversible by interventions that reverse the pathologies associated with chronic pain. Six months following peripheral nerve injury, abnormal sensory thresholds and increased anxiety were accompanied by decreased global methylation in the PFC and the amygdala but not in the visual cortex or the thalamus. Environmental enrichment attenuated nerve injury-induced hypersensitivity and reversed the changes in global PFC methylation. Furthermore, global PFC methylation correlated with mechanical and thermal sensitivity in neuropathic mice. In summary, induction of chronic pain by peripheral nerve injury is associated with epigenetic changes in the brain. These changes are detected long after the original injury, at a long distance from the site of injury and are reversible with environmental manipulation. Changes in brain structure and cortical function that are associated with chronic pain conditions may therefore be mediated by epigenetic mechanisms.     

神经递质和调质参与导水管周围灰质痛觉调控的研究进展

导水管周围灰质(periaqueductal gray,PAG)在疼痛的调控过程中处于一个不可或缺的位置.其不仅是痛觉信息上行传递的重要部位,还是疼痛抑制系统的重要组成部分.在PAG,包括γ-氨基丁酸(γ-aminobutyric acid,GABA)、5-羟色胺(5-hydroxytryptamine,5-HT)和谷氨酸(glutamate,Glu)在内的神经递质以及内源性阿片肽(endogenous opioid peptides,EOP)和内源性大麻素(endocannabinoid,e CB)为代表的神经调质都参与了PAG对疼痛的信息传递以及调节.本文重点综述GABA、5-HT、Glu、EOP和eCB在PAG参与疼痛生理调控机制的研究进展,以期为中枢神经系统的镇痛研究提供一定的理论基础.     

臂丛神经撕脱伤后慢性疼痛患者脑区葡萄糖代谢的研究

臂丛神经撕脱伤后慢性疼痛是一种临床上顽固性神经病理性疼痛.然而,对于其潜在的中枢机制还知之甚少.为了进一步探讨臂丛神经撕脱伤后慢性疼痛的相关脑区活动,利用18F-脱氧葡萄糖(FDG)正电子断层扫描(PET)技术观察臂丛神经撕脱后慢性疼痛患者的脑葡萄糖代谢.选择左侧臂丛神经撕脱伤后慢性疼痛行脊髓后根入髓区(DREZ)切开术后疼痛减轻>75%的患者,共5例,分别在术前和术后14天行PET扫描采集数据,同时行视觉模拟评分(VAS),汉密尔顿(Hamilton)抑郁和焦虑评分.用统计参数图(SPM2)软件分析数据.与术前疼痛状态下相比,术后葡萄糖代谢明显减低的脑区有双侧尾状核,眶额回(OFC)(BA11),对侧扣带下回(BA25)和同侧前额叶背外侧区域(DLPFC)(BA46/47).葡萄糖代谢明显增高的脑区有对侧丘脑,枕核和同侧项叶(BA7).研究结果提示,涉及情绪、注意和疼痛内在调节的脑区在臂丛神经撕脱伤后慢性疼痛的调制中发挥重要作用.     

Effects of the removal of the orbito-frontal cortex on the development of reflex analgesia

The authors studied the effect of electric acupuncture stimulation (EAP) on the changes in pain thresholds prior to and after removal of the orbito-frontal cortex (OFC) of the brain in behavioral experiments on adult cats. Removal of OFC increased the thresholds of pain response at the 4th and the 5th levels of the conventional scale, reflecting emotionally-affective manifestations of pain, and intensified the effect of antinociceptive EAP. The results obtained are analysed in relation to the inhibitory tonic effect of OFC on antinociceptive structures of the brain. Different effects of OFC and somatosensory cortex on the antinociceptive structures of the brain are discussed.     

Indispensable role of quantum theory in the brain dynamics

Recently, Tegmark pointed out that the superposition of ion states involved in the superposition of firing and resting states of a neuron quickly decohere. It undoubtedly indicates that neural networks cannot work as quantum computers, or computers taking advantage of coherent states. Does it also mean that the brain can be modeled as a neural network obeying classical physics? Here we show that it does not mean that the brain can be modeled as a neural network obeying classical physics. A brand new perspective in research of neural networks from quantum theoretical aspect is presented.     

大鼠鞘内注射多巴胺受体激动剂与拮抗剂对痛及针刺镇痛的影响

在大鼠电刺激甩测痛模型上,应用鞘内注射（ｉｔ）多巴胺（ＤＡ）受体选择性激动剂与拮抗剂,分析大鼠脊髓ＤＡ受体亚型Ｄ１和Ｄ２在痛及针刺镇痛（ＡＡ）中的作用。结果显示,在正常清醒大鼠,ｉｔ Ｄ２受体选择性激动剂,Ｙ１７１５５５（ＬＹ）或Ｄ１／Ｄ２受体激动剂阿朴吗啡（ＡＰＯ）有镇痛作用（呈剂量依赖式增加）,并加强ＡＡ,而ｉｔ Ｄ１受体选择性激动剂ＳＫＦ３８３９３（ＳＫＦ）对痛及ＡＡ均无影响;ｉｔ Ｄ１受体     

Impact of gamma-oscillatory inhibition on the signal transmission of a cortical pyramidal neuron

Networks of synchronized fast-spiking interneurons are thought to be key elements in the generation of gamma (γ) oscillations (30–80 Hz) in the brain. We examined how such γ-oscillatory inhibition regulates the output of a cortical pyramidal cell. Specifically, we modeled a situation where a pyramidal cell receives inputs from γ-synchronized fast-spiking inhibitory interneurons. This model successfully reproduced several important aspects of a recent experimental result regarding the γ-inhibitory regulation of pyramidal cellular firing that is presumably associated with the sensation of whisker stimuli. Through an in-depth analysis of this model system, we show that there is an obvious rhythmic gating effect of the γ-oscillated interneuron networks on the pyramidal neuron’s signal transmission. This effect is further illustrated by the interactions of this interneuron network and the pyramidal neuron. Prominent power in the γ frequency range can emerge provided that there are appropriate delays on the excitatory connections and inhibitory synaptic conductance between interneurons. These results indicate that interactions between excitation and inhibition are critical for the modulation of coherence and oscillation frequency of network activities.     

WLPVG approach to the analysis of EEG-based functional brain network under manual acupuncture

Functional brain network, one of the main methods for brain functional studies, can provide the connectivity information among brain regions. In this research, EEG-based functional brain network is built and analyzed through a new wavelet limited penetrable visibility graph (WLPVG) approach. This approach first decompose EEG into δ, θ, α, β sub-bands, then extracting nonlinear features from single channel signal, in addition forming a functional brain network for each sub-band. Manual acupuncture (MA) as a stimulation to the human nerve system, may evoke varied modulating effects in brain activities. To investigating whether and how this happens, WLPVG approach is used to analyze the EEGs of 15 healthy subjects with MA at acupoint ST36 on the right leg. It is found that MA can influence the complexity of EEG sub-bands in different ways and lead the functional brain networks to obtain higher efficiency and stronger small-world property compared with pre-acupuncture control state.     

Emotional regulation of pain: the role of noradrenaline in the amygdala

The perception of pain involves the activation of the spinal pathway as well as the supra-spinal pathway,which targets brain regions involved in affective and cognitive processes.Pain and emotions have the capacity to influence each other reciprocally;negative emotions,such as depression and anxiety,increase the risk for chronic pain,which may lead to anxiety and depression.The amygdala is a key-player in the expression of emotions,receives direct nociceptive information from the parabrachial nucleus,and is densely innervated by noradrenergic brain centers.In recent years,the amygdala has attracted increasing interest for its role in pain perception and modulation.In this review,we will give a short overview of structures involved in the pain pathway,zoom in to afferent and efferent connections to and from the amygdala,with emphasis on the direct parabrachio-amygdaloid pathway and discuss the evidence for amygdala’s role in pain processing and modulation.In addition to the involvement of the amygdala in negative emotions during the perception of pain,this brain structure is also a target site for many neuromodulators to regulate the perception of pain.We will end this article with a short review on the effects of noradrenaline and its role in hypoalgesia and analgesia.     

Pain research in China

In addition to investigating the anatomy,neurochemistry and neurophysiology of pain pathways,Chinese researchers have extended their work into the molecular and cellular mechanisms of sensory afferent transmission at the spinal cord level as well as cognitive processing in the brain.The mechanism underlying acupuncture analgesia remains a subject of special interest for Chinese pain researchers,with the aim of combining clinical practice with the understanding of pain transmission and analgesic mechanism.     

Endocannabinoids and related fatty acid derivatives in pain modulation

The brain produces at least five compounds that possess sub-micromolar affinity for cannabinoid receptors: anandamide, 2-arachidonoylglycerol, noladin ether, virodhamine, and N-arachidonoyldopamine (NADA). One function of these and/or related compounds is to suppress pain sensitivity. Much evidence supports a role of endocannabinoids in pain modulation in general, and some evidence points to the role of particular endocannabinoids. Related endogenous fatty acid derivatives such as oleamide, palmitoylethanolamide, 2-lineoylglycerol, 2-palmitoylglycerol, and a family of arachidonoyl amino acids may interact with endocannabinoids in the modulation of pain sensitivity.     

A multistudy analysis reveals that evoked pain intensity representation is distributed across brain systems

Information is coded in the brain at multiple anatomical scales: locally, distributed across regions and networks, and globally. For pain, the scale of representation has not been formally tested, and quantitative comparisons of pain representations across regions and networks are lacking. In this multistudy analysis of 376 participants across 11 studies, we compared multivariate predictive models to investigate the spatial scale and location of evoked heat pain intensity representation. We compared models based on (a) a single most pain-predictive region or resting-state network; (b) pain-associated cortical–subcortical systems developed from prior literature (“multisystem models”); and (c) a model spanning the full brain. We estimated model accuracy using leave-one-study-out cross-validation (CV; 7 studies) and subsequently validated in 4 independent holdout studies. All spatial scales conveyed information about pain intensity, but distributed, multisystem models predicted pain 20% more accurately than any individual region or network and were more generalizable to multimodal pain (thermal, visceral, and mechanical) and specific to pain. Full brain models showed no predictive advantage over multisystem models. These findings show that multiple cortical and subcortical systems are needed to decode pain intensity, especially heat pain, and that representation of pain experience may not be circumscribed by any elementary region or canonical network. Finally, the learner generalization methods we employ provide a blueprint for evaluating the spatial scale of information in other domains.

Is pain represented by a single brain area or network, spanning multiple systems or distributed throughout the brain? fMRI brain decoding in a large multi-study dataset shows that multiple cortical and subcortical systems are needed to decode pain intensity; the approach is novel and can characterize scale of representation across diverse brain processes.     

Functional studies using antibodies against orphanin FQ/nociceptin

Orphanin FQ/nociceptin (OFQ) is a recently discovered endogenous ligand for the novel opioid receptor-like receptor (ORL-1). There are numerous reports in the literature demonstrating paradoxical effects of exogenous OFQ on pain modulation. For example, OFQ produces a pronociceptive effect in the brain and an analgesic effect in the spinal cord. In order to better understand the physiological actions of OFQ, the present study focused on the pain-modulatory effect of endogenously released OFQ measured using antibody microinjection techniques. We found that electroacupuncture analgesia (EA) was increased by intracerebroventricular (i.c.v.) injection of an OFQ-antibody and decreased following intrathecal injection. Furthermore, i.c.v. OFQ-antibody partially reversed tolerance to both chronic morphine and chronic EA. These data suggest that endogenously released OFQ plays an important role in pain modulation, where pain sensitivity in the brain and spinal cord is increased and decreased, respectively.     

Sensorimotor and Pain Modulation Brain Abnormalities in Trigeminal Neuralgia: A Paroxysmal,Sensory-Triggered Neuropathic Pain

Objective

Idiopathic trigeminal neuralgia (TN) is characterized by paroxysms of severe facial pain but without the major sensory loss that commonly accompanies neuropathic pain. Since neurovascular compression of the trigeminal nerve root entry zone does not fully explain the pathogenesis of TN, we determined whether there were brain gray matter abnormalities in a cohort of idiopathic TN patients. We used structural MRI to test the hypothesis that TN is associated with altered gray matter (GM) in brain areas involved in the sensory and affective aspects of pain, pain modulation, and motor function. We further determined the contribution of long-term TN on GM plasticity.

Methods

Cortical thickness and subcortical GM volume were measured from high-resolution 3T T1-weighted MRI scans in 24 patients with right-sided TN and 24 healthy control participants.

Results

TN patients had increased GM volume in the sensory thalamus, amygdala, periaqueductal gray, and basal ganglia (putamen, caudate, nucleus accumbens) compared to healthy controls. The patients also had greater cortical thickness in the contralateral primary somatosensory cortex and frontal pole compared to controls. In contrast, patients had thinner cortex in the pregenual anterior cingulate cortex, the insula and the orbitofrontal cortex. No relationship was observed between GM abnormalities and TN pain duration.

Conclusions

TN is associated with GM abnormalities in areas involved in pain perception, pain modulation and motor function. These findings may reflect increased nociceptive input to the brain, an impaired descending modulation system that does not adequately inhibit pain, and increased motor output to control facial movements to limit pain attacks.     

Effect of intranasal arginine vasopressin on human headache

Arginine vasopressin (AVP), a nonapeptide hormone of posterior pituitary, reaches the central nervous system from systemic blood circulation with a difficulty because of the blood–brain barrier (BBB). The interest has been expressed in the use of the nasal route for delivery of AVP to the brain directly, exploiting the olfactory pathway. Our previous study has demonstrated that AVP in the brain rather than the spinal cord and blood circulation plays an important role in rat pain modulation. For understanding the role of AVP on pain modulation in human, the communication tried to investigate the effect of intranasal AVP on human headache. The results showed that (1) AVP concentration in both plasma and cerebrospinal fluid (CSF) increased significantly in headache patients, who related with the headache level; (2) there was a positive relationship between plasma and CSF AVP concentration in headache patients; and (3) intranasal AVP could relieve the human headache in a dose-dependent manner. The data suggested that intranasal AVP, which was delivered to the brain through olfactory region, could treat human headache and AVP might be a potential drug of pain relief by intranasal administration.