Pain perception and its genesis in the human brain · PDF file678 Acta Physiologica Sinica, October 25, 2008, 60 (5): 677-685 pain[9]. Treede (1999): Pain-related evoked potentials

677Acta Physiologica Sinica, October 25, 2008, 60 (5): 677-685http://www.actaps.com.cn

This work was supported by grants from the National Natural Science Foundation of China (No. 30770691), Beijing MunicipalGovernment for Advancement of Sciences, and Capital Medical University for Innovation Awards.

*Corresponding author. Tel: +86-10-83911514; E-mail: [email protected]

Pain perception and its genesis in the human brainAndrew CN CHEN*

Center for Higher Brain Functions, Capital Medical University, Beijing 100069, China

Abstract: In the past two decades, pain perception in the human brain has been studied with EEG/MEG brain topography and PET/fMRI neuroimaging techniques. A host of cortical and subcortical loci can be activated by various nociceptive conditions. The activationin pain perception can be induced by physical (electrical, thermal, mechanical), chemical (capsacin, ascoric acid), psychological(anxiety, stress, nocebo) means, and pathological (e.g. migraine, neuropathic) diseases. This article deals mainly on the activation, butnot modulation, of human pain in the brain. The brain areas identified are named pain representation, matrix, neuraxis, or signature. Thesites are not uniformly isolated across various studies, but largely include a set of cores sites: thalamus and primary somatic area (SI),second somatic area (SII), insular cortex (IC), prefrontal cortex (PFC), cingulate, and parietal cortices. Other areas less reported andconsidered important in pain perception include brainstem, hippocampus, amygdala and supplementary motor area (SMA). The issuesof pain perception basically encompass both the site and the mode of brain function. Although the site issue is delineared to a largedegree, the mode issue has been much less explored. From the temporal dynamics, IC can be considered as the initial stage in genesis ofpain perception as conscious suffering, the unique aversion in the human brain.

Key words: human pain perception; brain measures; nociceptive pain; pathological pain; anatomy-physiology; genesis

1 Histological perspectives

Since the dawn of evolution, pain has been inflicted in ani-mals and humans. Originally, pain serves a crucial surviv-ing function for warning of bodily injuries in acute painand/or persistent pain. Nevertheless, it becomes maladaptedthat pathological dynamics may modify neural organiza-tion and pain becomes a disease condition in chronic pain.Therefore, perception of pain in the human brain has to beexamined in this dynamic context. So far, A large majorityof research has touched mainly on the experimental acti-vation of the nociception system in acute condition, largelyon the healthy subjects and some on the patients inflictedwith pain suffering. Our knowledge of pain perception canbe summarized as: (1) Large amount comes from nocice-ptive pain in healthy subjects; (2) Some amount comesfrom nociceptive pain modulated by the pathologicalconditions; (3) Few amount comes from the pathologicalpain in pain patients per se. It seems we are advanced withresearch on “sensitivity” of experimental pain over “valid-ity” of pathological pain. Certainly, ease of study dictatesour priority of scientific knowledge.

To begin with, it is worthwhile to list the milestones of

review papers published in the past 15 years regarding painperception in the human brain, on a chronological clarity.This chronological order is often related to technical prow-ess in defining the scientific knowledge. Non-invasive EEG/MEG topography (measuring electric/magnetic and sourceof brain activity) and PET/fMRI tomography (measuringreceptors in PET, metabolite-blood flow in both) are themain techniques in studying pain perception in the humanbrain. Three periods can be divided to characterize thescientific progress. Only those pertinent to the activation,but not modulation, of human pain perception in the brainare cited here.

I. Early period (1990-1999):Chen (1993): EEG/MEG mapping of human pain[1].Chen (1993): PET/fMRI neuroimaging of human pain[2].Casey (1996): Neuronal determinants of pain[3].Jones(1996): Inflammatory pain[4].Kramer (1997): EEG and headache[5].Frishberg (1997): Neuroimaging in headache disorders[6].Bromm (1998): Neurophysiological evaluation of pain[7].Ingvar (1999): Pain and functional imaging[8].Casey (1999): Forebrain mechanisms of nociception and

Review

Acta Physiologica Sinica, October 25, 2008, 60 (5): 677-685678

pain[9].Treede (1999): Pain-related evoked potentials from

parasylvian cortex[10].Treede (1999): Cortical representation of pain[11].

II. Middle period (2000-2004):Schnitzler (2000): Neurophysiology/neuroanatomy of

pain perception[12].Treede (2000): Cortical representation of pain near lat-

eral sulcus[13].Kakigi (2000): Pain-related SEP[14].Derbyshire (2000): Pain neuromatrix[15].Casey (2000): Concept of pain mechanisms[16].Wiech (2000): Neuroimaing of chronic pain[17].Aziz (2000): Neuroimaging of visceral sensation[18].Cutrer (2000): Functional neuroimaging of migraine

pathophysiology[19].Bradley (2000): Neuroimaging in fibromyalgia[20].Chen (2001): New perspective of EEG/MEG brain map-

ping and PET/fMRI neuroimaging of human pain[21].Bromm (2001): Brain images of pain[22].Goadsby (2001): Neuroimaging in headache[23].Rainville (2001): Representation of acute and persistent

pain[24].Price (2002): Pain and consciousness[25]

Rainville (2002): pain affect and pain modulation[26].Kakigi (2003): C-fiber in human pain[27].Garcia-Larrea (2003): Laser evoked potentials[28].Lorenz (2003): Attentional and cognitive factors in LEP[29].May (2003): Neuroimaging and headache[30].Derbyshire (2003): Visceral afferent pathways and brain

imaging[31].Mackey (2004): Functional imaging of chronic pain[32].Mechtler (2004): Pathogenesis of primary headache[33].Sánchez del Rio (2004): Functional neuroimaging of head-

aches[34].Chiapparini(2004): Neuroradiological findings of head-

ache[35].May (2004): Neuroimaging in primary headache[36].Davis (2004): Neuroimaging of pain[37].

III. Recent period (2005-2008):Kakigi (2005): Electrophysiological studies on human pain

perception[38].Lorenz (2005): Imaging acute vs pathological pain[39].Apkarian (2005): Human brain mechanisms of pain per-

ception and regulation in health and disease[40].Cohen (2005): Functional neuroimaging of primary head-

ache disorders[41].

May (2005): Imaging in the pathophysiology and diag-nosis of headache[42].

Tracey (2005): Nociceptive processing in the humanbrain[43].

de Leeuw (2005): Neuroimaging techniques for orofacialpain[44].

Favier (2005): Chronic cluster headache[45].Rossi (2005): Central pain modulation in chronic head-

aches[46].Treede (2006): Nociceptive network of the human brain[47].Aurora (2006): Brain dysfuncion in migraine[48].May (2006): Functional anatomy of headache [49].Mee (2006): Psychological pain[50].Cohen (2006): Primary headache disorders[51].May (2006): Functional imaging in headache[49].Derbyshire (2006): Brain in pain[52].Anderson (2006): Plasticity of pain-related neuronal ac-

tivity in the human thalamus[53].Schweinhardt (2006): Imaging pain in patients[54].Borsook (2006): Migraine pathophysiology[55].Detsky (2006): Migraine neuroimaging[56].Williams (2006): FMRI findings in fibromyalgia[57].Jackson (2006): Pain empathy[58].Mayer (2006): Brain-gut axis[59].Duquette (2007): Pain and emotion[60].DaSilva (2007): Neuroimaging findings in cluster head-

ache[61].May (2007): Functional and structural imaging in mi-

graine[62].Cook (2007): Imaging pain of fibromyalgia[63].May (2007): Visualising the brain in pain[64].Leone (2007): Functional neuroimaging and headache

pathophysiology[65].Moisset (2007): Brain imaging of neuropathic pain[66].Tracey (2007): The cerebral signature for pain percep-

tion and its modulation[67].Linder (2007): Post-traumatic headache[68].Veldhuijzen (2007): Imaging central pain syndromes[69].Derbyshire (2007): Modeling pain circuits[70].Derbyshire (2007): Imaging visceral pain[71].Wood (2008): Central dopamine in pain and analgesia[72].Tracey (2008): Imaging pain[73].

2 Sites of pain activation in the HUMAN brain

2.1 Research in healthy subjects: nociceptive painCasey[3] has early stated that the principle “Multipleperipheral, segmental, and supraspinal neuronal activitiescontrol nociceptive processing at all levels of the neuraxis”,

679Andrew CN CHEN: Pain Perception and its Genesis in the Human Brain

and later emphasized the complexity mechanisms in per-ception also involved pain-inhibitory and pain-facilitatingpathways linked to cognitive, emotional, and stress-responsesystems[9]. Among the complexities, the forebrain mecha-nisms act in all levels of neuraxis[9]. The major determi-nant factors can be empirically examined: gender, the typeof noxious stimuli, and origin of nociceptive input. Thebrain structures invoked by noxious stimulatoin across thevarious factors emerged are: the bilateral thalamus, thecontralateral insula and anterior cingulate cortex (ACC),premotor cortex, and the cerebellar vermis. The corticalrepresentation of pain was early summarized by Treede etal.[11]: primary somatosensory cortex (SI), secondary so-matosensory cortex (SII) and its vicinity in the parietaloperculum, insular cortex (IC), ACC and prefrontal cortex(PFC).

In first set of meta-analysis of pain perception in thehuman brain[15, 74], Derbyshire[15] has emphasized theneuromatrix of pain activation invoked by a noxious eventcan involve the sensory, affective, cognitive, motor,inhibitory, and autonomic responses, while there is scantevidence that any particular region or circuit exclusivelyacts in pain perception. Also, the responses in patients areless clear in a whole, but a reduction in cerebral responseshas been noted. Peyron et al.[74] have made the followingpoints: (1) Cerebral blood flow (CBF) increases to noxiousstimuli are almost constantly observed in SII and insularregions, and in ACC. (2) The responses are slightly lessconsistent in the contralateral thalamus and SI. (3) Activa-tion of the lateral thalamus. SI, SII and insula are thoughtto be related to the sensory-discriminative aspects of painprocessing. (4) The thalamic response is bilateral, prob-ably reflecting generalized arousal in reaction to pain. (5)ACC appears to participate in both the affective andattentional concomitants of pain sensation, as well as inresponse selection. (6) Increased blood flow in the poste-rior parietal and prefrontal cortices is thought to reflectattentional and memory networks activated by noxiousstimulation. (7) Less noted but frequent activation con-cerns motor-related areas such as the striatum, cerebellumand supplementary motor area (SMA), as well as regionsinvolved in pain control such as the periaqueductal grey atbrainstem.

The affective dimension of pain perception was articu-lated by Price[75], and delineated the central network con-sisting of (1) a direct spinal pathways to limbic structuresand medial thalamic nuclei provide direct inputs to brainareas involved in affect, (2) an indirect spinal pathways tosomatosensory thalamic and cortical areas and then through

a cortico-limbic pathway integrates nociceptive input withcontextual information and memory to provide cognitivemediation of pain affect, and (3) both direct and cortico-limbic pathways converge on the same anterior cingulatecortical and subcortical structures whose function may beto establish emotional valence and response priorities.

Based on the knowledge up to 2000, Chen[21] introduceda general model of pain perception in the human brain (seeFig. 1 in the section on mode of pain perception). The painimpulse transmission at brain stem, thalamus, SI and SIIfor ascending activation in sensory-discriminative func-tion and descending regulation. The transaction of aver-sion and affect memory in perception take place at insular,hippocampus, and amygdale nuclei. The translation of cog-nitive attention and execution in pain perception resides atACC for attention/autonomic regulation and posterior cin-gulate cortex (PCC) for pain memory, at the parietal cor-tex for spatial vigilance and PFC for executive function ofcognitive-evaluative function. This model is fairly consis-tent with that articulated by Apkarian et al.[40] from a meta-analysis taking into account of variation in noxious stimuli(electrical, thermal, mechanical), measurement techniques(EEG, PET, fMRI), and sample categories (healthyvolunteers, patients). Acute pain network is shown to in-clude thalamus, SI, SII, ACC, IC and PFC.

In addition to the above brain responses by physical ac-tivation of pain perception, chemical activation in the healthysubjects by ascorbic acid is worthy notice[76]. The tonicnoxious chemical stimulation by ascorbic acid activatesthe cingulate cortex and the putative foot representationarea of SI. Pain-related activation in the majority of sub-jects is shown in SI, cingulate, motor, and premotor cortex,while negative correlations can be found in medial parietal,perigenual cingulate, and medial prefrontal regions.Furthermore, anticipation to pain per se activates distrib-uted cortical parietal, cingulate and frontal regions, prob-ably reflecting the dynamic anxiety in pain activation.

Finally, pain perception in the human brain can be in-voked by psychological activation. Anticipation of chemi-cal nociception[77] enhanced the putative representation areaof the contralateral SI but decreased during anticipation inother portions of the contralateral and ipsilateral SI, and inthe anteroventral cingulate cortex. A top-down process byanticipation seems to modulate cortical systems involvedin sensory and affective components of pain even in theabsence of actual noxious input. It suggests that cognitivefactors can directly influence the activity of cortical noci-ceptive networks.

Another controlled type of psychological activation is

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studied by imaged pain[78]. Imaged pain by hypnoticsuggestion, without actual painful stimulation, revealed sig-nificant changes during hypnotically induced pain experi-ence within the thalamus, ACC, IC, and PFC. The findingscompare well with the activation patterns during pain fromknown experimental nociceptive activations.

As an antidote to placebo, nocebo[79, 80] by negative ver-bal suggestions or subjective thoughts can induce antici-patory anxiety about the impending pain increase, whichmay trigger the activation of cholecystokinin (CCK). Inturn, CCK facilitates pain transmission. And CCK-antago-nists have been found to block this anxiety-inducedhyperalgesia.2.2 Experimental activation in patients with pain:pathological sensitizationMost experimental stimuli conducted on the pain patientsinvolve physical activation, some chemical activation, andfew psychological activation. The study goals are simu-lated to probe pathological condition in alteration of experi-mental pain in the patient brain. Thus, it allows isolationand identification of brain of pathological changes in patients.

To begin with, the brain of pain patients may be some-times maladaptive to the persist or even chronic pain con-ditions in response to peripheral and central nervous sys-tem injury, as in allodynia behavior. Abnormal pain evokedby innocuous stimuli in allodynia has been associated withincrease of the thalamic, insular and SII responses, but aparadoxical CBF decrease in ACC[39]. Allodynia is usualphysiological effect, and can induce hyperalgesia in re-sponse to non-noxiously tactile or thermal stimulation inhealthy subjects. Brain responses in allodynia by tactilemechanical stimulation differ slightly from those by ther-mal stimulation. Both of them excite SI, SII, IC and frontalcortices, but add cingulate and somatosensory cortices inthermal hyperalgesia.

In studying neuropathic pain of patients due to periph-eral or central neurological lesions with exhibition ofallodynia, Moisset and Bouhassira[66] from meta-analysisindicate: (1) spontaneous pain is associated with changesof thalamic activity in the medial pain system in relation topain affect, (2) allodynia activation can be varied due toboth intrinsic and extrinsic factors, and (3) there is no uniquepain matrix or allodynia matrix. The brain areas activatedin allodynia of neuropathic pain are seemed well tocicomscribe the general pain matrix: thalamus, and SI, SII,IC, ACC and PFC.2.3 Research in pain patients: fibromyalgesia, head-ache

Recently, the default mode network of brain function[81],i.e. resting brain function devoid of any activation, has beenwell identified in various conditions of brain diseases.Likewise, it becomes necessary to identify the default modenetwork of clinical pain conditions. In this context, thechronic low back pain patients[82] exhibit reduced deactiva-tion in several key default mode network regions, which issuggested to underlie the cognitive and behavioral impair-ments accompanying chronic pain. However, pain per-ception studied in fibromyalgesia patients has been investi-gated to explore probable maladapted brain regions. But,little gross abnormality in brain activities is yet defined[57].

Likewise, studies of patients respectively with severecluster headache, migraine, and headache of persistentnature have come to a general profile[62, 65]. Cluster head-ache is related with the activation of the posterior hypotha-lamic grey matter, migraine with the brainstem area, attime of cortical hyperexcitability and interacts with trigeminalnociceptive system[61].

3 Modes of pain activation in the human brain

It is almost granted that knowledge of the sites of brainactivation is fully necessary, but has to be regarded as notsufficient, in the understanding of pain processing in thehuman brain. After nearly 15 years of intensive pain inves-tigation in neuroimaging, we now have to turn to our spareknowledge in understanding the mechanisms, i.e. mode ofaction, in human pain perception. Perception is singularpsychological construct, with a complex physiologicalphenomenon in the brain, as that of consciousness. Themode of action can involve in several stages: sensory trans-duction and transmission, affective translation, and cogni-tive transaction. The Chen model (Fig. 1) provides a goodspatial and temporal illustration in conception, but is notgood enough to understand how the hierarchy organiza-tion of information processing in parallel function. We havelittle knowledge of the input/output linkage of electrical sig-nals and chemical mediators in this regard at the site ofbrain areas identified for pain processing in the human brain.

The mode of pain perception can be defined in threedistinct conceptual stages and functional neuraxis setsshown in Fig. 1. (1) Sensory transmission at the brainstemarea, also acting in descending regulation, and the thalamicrelay nuclei, while sensory discrimination of spatial/tem-poral features in SI cortex. (2) Affect transaction at theSII, IC, amygdala and hippocampus cortices for aversivelearning, visceral nociception, and autonomic effect. (3)

681Andrew CN CHEN: Pain Perception and its Genesis in the Human Brain

Fig. 1. A general model of pain perception in the human brain. Transmission of sensory nociception is largely considered as serial processingfrom brainstem (BS), thalamus (T), SI and SII. This sensory-perceptual system participates in the cerebral functions of detection, localization,timing, learning, relay, integration, ascending transmission and descending regulation of pain. The transaction of painful emotion is probablyconsidered as parallel processing at sites of insular cortex (IC), amygdala (A), hippocampus (Hip), hypothalamus (H) and cingular cortex (Cg).This affective-motivational system participates in the functions of affective reaction, visceral activation, multi-sensory integration, homeosta-sis regulation, fear and memory. Translation of painful cognition is assumed to be carried out by the integration of several cortical areas inprefrontal cortex (PFC), primary motor cortex (MI), supplementary motor cortex (SMA) and posterior parietal cortex (PPC). This cognitive-evaluation system participates in the functions of executive control, co-ordination of action/intention and spatial/bodily attention. Nevertheless,the biophysical and physiological mechanisms of these pain processings in the brain still remain unknown[7].

Cognitive attention at the ACC, PFC, as well in responseselection or action planning. This extensive network, widelydistributed in the human brain, in pain perception may op-erate in hierarchy or in parallel under both spatial-temporaldynamics. The mode of action in pain perception is con-jectured after empirical verification at present.

In terms of time scale at the initial stage of pain activa-tion in the brain, the bilateral areas are near sylvian featurecommand special attention and considered as the first cor-tical relay station in the central processing of noxious stimuli[13].Using somatosensory evoked potentials (SEPs) in responseto intracutaneous galvanic stimulations, the measured cor-tical topographic maps display clear different activationmaps between non-painful and painful stimuli. At the middlelatency phase (70-140 ms), the anatomical substrates areisolated and identified. In fact, this recent study (Chen andTheuvenet, paper in submission) has identified both tem-poral differentiation and spatial segregation of SII and IC.The contralateral SII source at 93 ms and the N114 IC areseparated by 21 ms in time, and segregated by a Euclidianspace of 23.2 mm in distance. The model of the IC as the

generator of pain perception in the discrete noxious activa-tion in the brain is illustrated in Fig. 2, and the dipole iden-tifications in Fig. 3.

4 Conclusions

In 15 years of pain research of pain perception in the hu-man brain by non-invasive EEG/MEG tomography and PET/fMRI tomography, a network of wide distributed brainareas is identified as sites in processing noxious activation.These core areas include thalamus relay in sensorytransmission, the somatotopic organization of SI serves insensory discrimination of spatial and temporal nociceptiveevent, with SII in recognition, memory, and learning ofpain information. The IC involves in affective-motivationfunction to aversion and autonomic effect. The ACC par-ticipates mainly in attention and response selection. ThePCC consolidates affective memory and emotional displays.The PPC acts in sensory registration and selectedawareness. The PFC commands in executive control overcognitive-evaluative aspect of pain perception. The sites

Acta Physiologica Sinica, October 25, 2008, 60 (5): 677-685682

of pain perception are well replicated in studies of healthysubjects. In patients of fibromyalgesia and neuropathic pain,discrete brain mal-adaption in noxious processing has yetto be specifically identified. Nevertheless, cluster migraineof enhanced activation in the brainstem area and clusterheadache at the posterior hypothalamus grey matter are

considered to be pain-related disease specific. Given themode of function, subscribed than empirically verified ineach brain area for pain perception, much less is reallyknown in the virtual mechanisms of pain processing withinthe nociceptive neural network. By controlled discrete in-tracutaneous galvanic stimulation, we contend that IC at

Fig. 2. Scalp field potentials at three stages (73 ms, 93 ms, 114 ms) in middle latency. At the peak 73 ms in the middle latency period, a maincontralateral centro-medial negativity was focalized. At the peak 93 ms and 114 ms stages, three main focal negativities (contralateral centro-medial site, contralateral left temporal site, ipsilateral right temporal site) were isolated along with the associated medial-frontal positivity atthe forehead. At 114 ms, the somatosensory evoked potentials (SEPs) recorded at the focal electrodes showed the largest activity (note the 2-fold increase in scale bars) and was located at the centro-medial site. While the SEPs at the contralateral site was larger than the ipsilateral site(redlines denote the study time at 114 ms), the ipsilateral peak latency lagged 13 ms compared to the contralateral peak (Chen and Theuvenet,paper in submission).

683Andrew CN CHEN: Pain Perception and its Genesis in the Human Brain

Fig. 3. Correlation of scalp potentials, dipole sites and insular structure.Three main dipoles are depicted as the generators for the respectivetopographic maxima in Fig. 2, and the anatomical substrates identi-fied are respectively the ipsilateral lentiform cortex, vertex SMA andcontralateral main insular generator in response to painful galvanicstimulation. The inlet image displays a real post-mortem brain, withthe lateral cortex dissected to reveal the shape, size, and position ofthe insular cortex (courtesy of Digital Anatomist Project, Universityof Washington, Seattle, USA). The virtual relation of the left insulardipole is indicated by red arrow. This supports the role of the insularcortex in the genesis of pain perception in human (Chen andTheuvenet, paper in submission).

the middle latency stage (70-140 ms) may be a valid can-didate for the generator of pain perception in the humanbrain.

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