通过结合神经成像的激光诱发电位源建模了解人类疼痛的大脑加工(II)

Andrew C.N. Chen , Lars Arendt-Nielsen , Leon Plaghki
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Chen ,&nbsp;Lars Arendt-Nielsen ,&nbsp;Leon Plaghki","doi":"10.1016/S1082-3174(98)80009-3","DOIUrl":null,"url":null,"abstract":"<div><p>Our current positions (Focus articles I and II) regarding the cerebral processing of human pain in the research of LEPs are the following:</p><ul><li><span>1.</span><span><p>Discrete, repeated sensory stimulation in evoked potential research, including laser stimulation in LEPs, is not a usual, natural experience, but an artificial convenience for probing into the window of human brain function.</p></span></li><li><span>2.</span><span><p>LEP methodology requires fundamental standardization.</p></span></li><li><span>3.</span><span><p>LEPs largely reflected neural pathways associated with some aspects of nociceptive processing (the LEPs focused on are those arising from activation of A-δ fibers).</p></span></li><li><span>4.</span><span><p>LEPs, in some circumstances, may dissociate from pain perception.</p></span></li><li><span>5.</span><span><p>Absence of evidence is not evidence of absence. Some neural events (eg, silent generators) and other biophysical constraints (eg, scalp smearing of cortical potentials) can occur. Consequently, no detectable trace of neural activity as ensured in the cortex or at the scalp. Thus, LEPs can never be used to validate the absence of nociception/pain in a person.</p></span></li><li><span>6.</span><span><p>Conversely, non-nociceptive events can influence some aspects of LEPs. Thus, interpretation of LEPs demands full control and understanding of the experimental conditions.</p></span></li><li><span>7.</span><span><p>LEPs attributes are likely to reflect the sensory—discriminatory dimension, but are not sufficient for equating the full multidimensional aspects of human pain.</p></span></li><li><span>8.</span><span><p>The pain experience can be correlated with changes of the amplitudes/latencies in LEPs; but it is not true to state that pain can be inversely inferred from the parameters of the LEPs since other nonpain-related factors can also, simultaneously, affect the LEPs.</p></span></li><li><span>9.</span><span><p>Exploration of the nociceptive processing using LEPs requires quantification of the temporospatial dynamics of the topographic brain activities.</p></span></li><li><span>10.</span><span><p>The precision of measuring the brain topography associated with human pain requires high-resolution EEG (&gt;64 channel), based on the spatial sampling principle (the shallow generators and refined small focal activation demand higher density of electrode arrays than the deep generators; detection of tangent generators demand different assumptions than the radial generators).</p></span></li><li><span>11.</span><span><p>Equivalent current dipole modeling is useful, it can be approximated by the spherical model, but requires the realistic epilloid head model coregistered with MRI for concise analysis.</p></span></li><li><span>12.</span><span><p>Without proper MRI coregistration, the isolated dipole parameters should be reported in the coordinate terms only, and not anatomic attribution.</p></span></li><li><span>13.</span><span><p>Source localization in the individual can be modeled by coregistration of the individual's MRI brain.</p></span></li><li><span>14.</span><span><p>For scientific generality, the group results can be coregistered with the MRI of Talairach-normalized standard brain.</p></span></li><li><span>15.</span><span><p>Final validation of the source model lies on the direct intracranial recording in association with the study of scalp topography.</p></span></li><li><span>16.</span><span><p>Inference of the intracranial recorded activities in LEPs requires strict rules.</p></span></li><li><span>17.</span><span><p>Understanding of the biophysical basis in cerebral processing of LEPs comparing to hemodynamic neuroimaging in PET/fMRI is essential for interpretation of their functional relationship.</p></span></li><li><span>18.</span><span><p>EEG/MEG brain mapping (high temporal, but low spatial resolution) reflects the primary neuronal activation, which is followed (&gt;2 sec to a few min) by PET/fMRI neuroimaging (low temporal, but high spatial resolution) as the secondary hemodynamic responses. However, these neural and hemodynamic activities can exert a mutual influence on one and other.</p></span></li><li><span>19.</span><span><p>3D–4D quantification is needed for measurement and analysis of both the neurophysiological and hemodynamic processing of human function in the brain.</p></span></li><li><span>20.</span><span><p>Pain can never be directly measured in the brain but can be inferred from brain activation under stringent logical constraints.</p></span></li></ul><p>From the clinical perspective, LEPs can be summarized in the following:</p><ul><li><span>1.</span><span><p>Appearance of an evoked cerebral potential gives evidence that a peripheral sensory impulse pattern has been transmitted to the brain via activation of a given afferent system. The specificity of the evoked response is mainly conditioned by the specificity of the stimulus for the afferent system under investigation.</p></span></li><li><span>2.</span><span><p>The specificity of the CO<sub>2</sub> laser-induced responses for the thermo-algesic pathways under normal conditions has been well documented.</p></span></li><li><span>3.</span><span><p>Thus, there are several reasons for obtaining LEPs in patients with suspected lesions of thermo-algesic pathways: (a) to confirm objectively the presence of a sensory dysfunction or deficit, (b) to find the underlying mechanism of the dysfunction, (c) to detect subclinical abnormalities, (d) to monitor the evolution of them, and (e) to evaluate the effect of therapeutic intervention.</p></span></li><li><span>4.</span><span><p>LEPs have been utilized with success in a variety of neuropathological conditions in which conventional electrical evoked potentials were proven to be noncontributive or inappropriate such as in small-fiber neuropathies, radiculopathies, myelopathies, brainstem lesions, central pain syndromes, and states of hyperalgesia.</p></span></li><li><span>5.</span><span><p>A great amount of work remains to be done as to establish a normative database which would define the various aspects of the late and especially the ultralate LEPs possibly altered in nervous diseases, the investigation of which has only be started.</p></span></li></ul><p>In the near future, we anticipate the following developments:</p><ul><li><span>1.</span><span><p>Differential activation of the peripheral nerve fibers to examine the specificity of nociception in both psychophysics and brain topography.</p></span></li><li><span>2.</span><span><p>Characterization of the brain topography and isolation/identification of the generators for the ultralate LEPs in studying the cerebral processing of C-fibertype human pain.</p></span></li><li><span>3.</span><span><p>Application of high-resolution EEG for quantifying the temporospatial activation of LEPs.</p></span></li><li><span>4.</span><span><p>Cortical imaging, based on sound individual brain biophysics, which can be used to delineate the scalp topography in LEPs; the projected scalp activation on the cortex proper requires little assumption than the source modeling does.</p></span></li><li><span>5.</span><span><p>Source modeling based on the realistic head and brain in both individuals and groups of controlled subjects.</p></span></li><li><span>6.</span><span><p>Close inspection and study with simultaneous recordings of LEPs and fast neuroimaging techniques in EPI—fMRI.</p></span></li><li><span>7.</span><span><p>Cross-validation of the different functional brain mappings/neuroimagings in LEPs.</p></span></li><li><span>8.</span><span><p>Further systematic works in the intracranial recordings of LEPs to noxious and non-noxious stimulations for getting more specific information.</p></span></li><li><span>9.</span><span><p>Modeling of the cerebral processing of LEPs in human pain on the principles of both modular segregation and functional integration.</p></span></li><li><span>10.</span><span><p>Examination of “the binding problem” in pain, that is, how unified experience is achieved by binding of fragmentary neural events at multiple locations.</p></span></li><li><span>11.</span><span><p>Generalization of LEPs to other pain-inducing modalities, such as thermal/mechanical/chemical stimuli, inflicted on different body tissues (eg, muscle or viscera).</p></span></li><li><span>12.</span><span><p>Elucidation of nociceptive/pain substrates (areas, systems) and their hierarchical organization in the brain.</p></span></li><li><span>13.</span><span><p>Complex experimental design to integrate the major pain attributes (sensory—affect—cognition) for examination of their deterministic effects on the brain activation.</p></span></li><li><span>14.</span><span><p>Theoretical neural network analysis on how pain perception/consciousness can be accomplished within the frame of 300 msec in the brain.</p></span></li><li><span>15.</span><span><p>Increase the clinical use of LEPs in conjunction with the quantitative sensory test, in patients with characterized brain lesions, spinal cord affections, or peripheral nerve damages.</p></span></li><li><span>16.</span><span><p>Better understanding of the pain-related pathophysiology by studying the physiological processing of LEPs and anatomic/functional source imaging of LEPs.</p></span></li></ul></div>","PeriodicalId":101001,"journal":{"name":"Pain Forum","volume":"7 4","pages":"Pages 221-230"},"PeriodicalIF":0.0000,"publicationDate":"1998-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S1082-3174(98)80009-3","citationCount":"1","resultStr":"{\"title\":\"Understanding of cerebral processing of human pain (II) by source modeling of laser-evoked potentials in conjunction with neuroimaging\",\"authors\":\"Andrew C.N. Chen ,&nbsp;Lars Arendt-Nielsen ,&nbsp;Leon Plaghki\",\"doi\":\"10.1016/S1082-3174(98)80009-3\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>Our current positions (Focus articles I and II) regarding the cerebral processing of human pain in the research of LEPs are the following:</p><ul><li><span>1.</span><span><p>Discrete, repeated sensory stimulation in evoked potential research, including laser stimulation in LEPs, is not a usual, natural experience, but an artificial convenience for probing into the window of human brain function.</p></span></li><li><span>2.</span><span><p>LEP methodology requires fundamental standardization.</p></span></li><li><span>3.</span><span><p>LEPs largely reflected neural pathways associated with some aspects of nociceptive processing (the LEPs focused on are those arising from activation of A-δ fibers).</p></span></li><li><span>4.</span><span><p>LEPs, in some circumstances, may dissociate from pain perception.</p></span></li><li><span>5.</span><span><p>Absence of evidence is not evidence of absence. Some neural events (eg, silent generators) and other biophysical constraints (eg, scalp smearing of cortical potentials) can occur. Consequently, no detectable trace of neural activity as ensured in the cortex or at the scalp. Thus, LEPs can never be used to validate the absence of nociception/pain in a person.</p></span></li><li><span>6.</span><span><p>Conversely, non-nociceptive events can influence some aspects of LEPs. Thus, interpretation of LEPs demands full control and understanding of the experimental conditions.</p></span></li><li><span>7.</span><span><p>LEPs attributes are likely to reflect the sensory—discriminatory dimension, but are not sufficient for equating the full multidimensional aspects of human pain.</p></span></li><li><span>8.</span><span><p>The pain experience can be correlated with changes of the amplitudes/latencies in LEPs; but it is not true to state that pain can be inversely inferred from the parameters of the LEPs since other nonpain-related factors can also, simultaneously, affect the LEPs.</p></span></li><li><span>9.</span><span><p>Exploration of the nociceptive processing using LEPs requires quantification of the temporospatial dynamics of the topographic brain activities.</p></span></li><li><span>10.</span><span><p>The precision of measuring the brain topography associated with human pain requires high-resolution EEG (&gt;64 channel), based on the spatial sampling principle (the shallow generators and refined small focal activation demand higher density of electrode arrays than the deep generators; detection of tangent generators demand different assumptions than the radial generators).</p></span></li><li><span>11.</span><span><p>Equivalent current dipole modeling is useful, it can be approximated by the spherical model, but requires the realistic epilloid head model coregistered with MRI for concise analysis.</p></span></li><li><span>12.</span><span><p>Without proper MRI coregistration, the isolated dipole parameters should be reported in the coordinate terms only, and not anatomic attribution.</p></span></li><li><span>13.</span><span><p>Source localization in the individual can be modeled by coregistration of the individual's MRI brain.</p></span></li><li><span>14.</span><span><p>For scientific generality, the group results can be coregistered with the MRI of Talairach-normalized standard brain.</p></span></li><li><span>15.</span><span><p>Final validation of the source model lies on the direct intracranial recording in association with the study of scalp topography.</p></span></li><li><span>16.</span><span><p>Inference of the intracranial recorded activities in LEPs requires strict rules.</p></span></li><li><span>17.</span><span><p>Understanding of the biophysical basis in cerebral processing of LEPs comparing to hemodynamic neuroimaging in PET/fMRI is essential for interpretation of their functional relationship.</p></span></li><li><span>18.</span><span><p>EEG/MEG brain mapping (high temporal, but low spatial resolution) reflects the primary neuronal activation, which is followed (&gt;2 sec to a few min) by PET/fMRI neuroimaging (low temporal, but high spatial resolution) as the secondary hemodynamic responses. However, these neural and hemodynamic activities can exert a mutual influence on one and other.</p></span></li><li><span>19.</span><span><p>3D–4D quantification is needed for measurement and analysis of both the neurophysiological and hemodynamic processing of human function in the brain.</p></span></li><li><span>20.</span><span><p>Pain can never be directly measured in the brain but can be inferred from brain activation under stringent logical constraints.</p></span></li></ul><p>From the clinical perspective, LEPs can be summarized in the following:</p><ul><li><span>1.</span><span><p>Appearance of an evoked cerebral potential gives evidence that a peripheral sensory impulse pattern has been transmitted to the brain via activation of a given afferent system. The specificity of the evoked response is mainly conditioned by the specificity of the stimulus for the afferent system under investigation.</p></span></li><li><span>2.</span><span><p>The specificity of the CO<sub>2</sub> laser-induced responses for the thermo-algesic pathways under normal conditions has been well documented.</p></span></li><li><span>3.</span><span><p>Thus, there are several reasons for obtaining LEPs in patients with suspected lesions of thermo-algesic pathways: (a) to confirm objectively the presence of a sensory dysfunction or deficit, (b) to find the underlying mechanism of the dysfunction, (c) to detect subclinical abnormalities, (d) to monitor the evolution of them, and (e) to evaluate the effect of therapeutic intervention.</p></span></li><li><span>4.</span><span><p>LEPs have been utilized with success in a variety of neuropathological conditions in which conventional electrical evoked potentials were proven to be noncontributive or inappropriate such as in small-fiber neuropathies, radiculopathies, myelopathies, brainstem lesions, central pain syndromes, and states of hyperalgesia.</p></span></li><li><span>5.</span><span><p>A great amount of work remains to be done as to establish a normative database which would define the various aspects of the late and especially the ultralate LEPs possibly altered in nervous diseases, the investigation of which has only be started.</p></span></li></ul><p>In the near future, we anticipate the following developments:</p><ul><li><span>1.</span><span><p>Differential activation of the peripheral nerve fibers to examine the specificity of nociception in both psychophysics and brain topography.</p></span></li><li><span>2.</span><span><p>Characterization of the brain topography and isolation/identification of the generators for the ultralate LEPs in studying the cerebral processing of C-fibertype human pain.</p></span></li><li><span>3.</span><span><p>Application of high-resolution EEG for quantifying the temporospatial activation of LEPs.</p></span></li><li><span>4.</span><span><p>Cortical imaging, based on sound individual brain biophysics, which can be used to delineate the scalp topography in LEPs; the projected scalp activation on the cortex proper requires little assumption than the source modeling does.</p></span></li><li><span>5.</span><span><p>Source modeling based on the realistic head and brain in both individuals and groups of controlled subjects.</p></span></li><li><span>6.</span><span><p>Close inspection and study with simultaneous recordings of LEPs and fast neuroimaging techniques in EPI—fMRI.</p></span></li><li><span>7.</span><span><p>Cross-validation of the different functional brain mappings/neuroimagings in LEPs.</p></span></li><li><span>8.</span><span><p>Further systematic works in the intracranial recordings of LEPs to noxious and non-noxious stimulations for getting more specific information.</p></span></li><li><span>9.</span><span><p>Modeling of the cerebral processing of LEPs in human pain on the principles of both modular segregation and functional integration.</p></span></li><li><span>10.</span><span><p>Examination of “the binding problem” in pain, that is, how unified experience is achieved by binding of fragmentary neural events at multiple locations.</p></span></li><li><span>11.</span><span><p>Generalization of LEPs to other pain-inducing modalities, such as thermal/mechanical/chemical stimuli, inflicted on different body tissues (eg, muscle or viscera).</p></span></li><li><span>12.</span><span><p>Elucidation of nociceptive/pain substrates (areas, systems) and their hierarchical organization in the brain.</p></span></li><li><span>13.</span><span><p>Complex experimental design to integrate the major pain attributes (sensory—affect—cognition) for examination of their deterministic effects on the brain activation.</p></span></li><li><span>14.</span><span><p>Theoretical neural network analysis on how pain perception/consciousness can be accomplished within the frame of 300 msec in the brain.</p></span></li><li><span>15.</span><span><p>Increase the clinical use of LEPs in conjunction with the quantitative sensory test, in patients with characterized brain lesions, spinal cord affections, or peripheral nerve damages.</p></span></li><li><span>16.</span><span><p>Better understanding of the pain-related pathophysiology by studying the physiological processing of LEPs and anatomic/functional source imaging of LEPs.</p></span></li></ul></div>\",\"PeriodicalId\":101001,\"journal\":{\"name\":\"Pain Forum\",\"volume\":\"7 4\",\"pages\":\"Pages 221-230\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"1998-12-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://sci-hub-pdf.com/10.1016/S1082-3174(98)80009-3\",\"citationCount\":\"1\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Pain Forum\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S1082317498800093\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Pain Forum","FirstCategoryId":"1085","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1082317498800093","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 1

摘要

关于LEPs研究中人类疼痛的大脑加工,我们目前的立场(焦点文章I和II)如下:1。诱发电位研究中离散的、重复的感觉刺激,包括对lep的激光刺激,并不是一种通常的、自然的体验,而是一种人为的便利,以探索人类大脑功能的窗口。LEP方法需要基本的标准化。lep在很大程度上反映了与伤害性加工的某些方面相关的神经通路(重点关注的lep是由A-δ纤维激活引起的)。在某些情况下,lep可能与疼痛感知分离。没有证据不等于没有证据。可能发生一些神经事件(如无声发生器)和其他生物物理限制(如头皮皮层电位的涂抹)。因此,在皮层或头皮上没有可检测到的神经活动痕迹。因此,lep永远不能被用来证实一个人没有伤害感觉/疼痛。相反,非伤害性事件可以影响lep的某些方面。因此,解释lep需要完全控制和理解实验条件。lep的属性可能反映了感觉上的区别,但不足以等同于人类疼痛的全部多维方面。疼痛体验可与lep振幅/潜伏期的变化相关;但是说疼痛可以从LEPs的参数反向推断是不正确的,因为其他与疼痛无关的因素也可以同时影响LEPs。利用lep探索伤害性加工需要对地形脑活动的时空动态进行量化。测量与人类疼痛相关的大脑地形的精度需要基于空间采样原理的高分辨率EEG (&gt;64通道)(浅层发生器和精细的小焦点激活比深层发生器需要更高的电极阵列密度;正切发生器的检测需要与径向发生器不同的假设)。等效电流偶极子模型是有用的,它可以用球形模型近似,但需要与MRI共同注册的真实的epilloid头部模型进行简明分析。如果没有正确的MRI共配准,孤立的偶极子参数只能在坐标项中报告,而不能在解剖归因中报告。个体的源定位可以通过个体MRI大脑的共配准来建模。为了科学的通用性,该组结果可与talairach归一化标准脑的MRI共同登记。源模型的最终验证依赖于与头皮地形研究相结合的直接颅内记录。对lep颅内记录活动的推断需要严格的规则。与PET/fMRI的血流动力学神经成像相比,了解lep脑处理的生物物理基础对于解释它们的功能关系至关重要。脑电/脑磁图(高时间分辨率,但低空间分辨率)反映了初级神经元的激活,随后(2秒到几分钟)通过PET/fMRI神经成像(低时间分辨率,但高空间分辨率)作为次级血流动力学反应。然而,这些神经和血流动力学活动可以相互影响,19.3 - 4d量化是测量和分析人脑功能的神经生理和血流动力学过程所必需的。疼痛永远无法在大脑中直接测量,但可以在严格的逻辑约束下从大脑活动中推断出来。从临床角度来看,lep可归纳为以下几个方面:1。诱发脑电位的出现表明,外围感觉冲动模式已通过特定传入系统的激活传递到大脑。诱发反应的特异性主要取决于所研究传入系统的刺激的特异性。在正常条件下,CO2激光诱导的热痛觉通路的特异性已经得到了很好的证明。因此,在疑似热痛觉通路病变的患者中获得lep有以下几个原因:(a)客观地确认感觉功能障碍或缺陷的存在,(b)寻找功能障碍的潜在机制,(c)检测亚临床异常,(d)监测其演变,(e)评估治疗干预的效果。lep已被成功地应用于各种神经病理条件,其中传统的电诱发电位被证明是无效的或不合适的,如小纤维神经病、神经根病、脊髓病、脑干病变、中枢性疼痛综合征和痛觉过敏状态。
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Understanding of cerebral processing of human pain (II) by source modeling of laser-evoked potentials in conjunction with neuroimaging

Our current positions (Focus articles I and II) regarding the cerebral processing of human pain in the research of LEPs are the following:

  • 1.

    Discrete, repeated sensory stimulation in evoked potential research, including laser stimulation in LEPs, is not a usual, natural experience, but an artificial convenience for probing into the window of human brain function.

  • 2.

    LEP methodology requires fundamental standardization.

  • 3.

    LEPs largely reflected neural pathways associated with some aspects of nociceptive processing (the LEPs focused on are those arising from activation of A-δ fibers).

  • 4.

    LEPs, in some circumstances, may dissociate from pain perception.

  • 5.

    Absence of evidence is not evidence of absence. Some neural events (eg, silent generators) and other biophysical constraints (eg, scalp smearing of cortical potentials) can occur. Consequently, no detectable trace of neural activity as ensured in the cortex or at the scalp. Thus, LEPs can never be used to validate the absence of nociception/pain in a person.

  • 6.

    Conversely, non-nociceptive events can influence some aspects of LEPs. Thus, interpretation of LEPs demands full control and understanding of the experimental conditions.

  • 7.

    LEPs attributes are likely to reflect the sensory—discriminatory dimension, but are not sufficient for equating the full multidimensional aspects of human pain.

  • 8.

    The pain experience can be correlated with changes of the amplitudes/latencies in LEPs; but it is not true to state that pain can be inversely inferred from the parameters of the LEPs since other nonpain-related factors can also, simultaneously, affect the LEPs.

  • 9.

    Exploration of the nociceptive processing using LEPs requires quantification of the temporospatial dynamics of the topographic brain activities.

  • 10.

    The precision of measuring the brain topography associated with human pain requires high-resolution EEG (>64 channel), based on the spatial sampling principle (the shallow generators and refined small focal activation demand higher density of electrode arrays than the deep generators; detection of tangent generators demand different assumptions than the radial generators).

  • 11.

    Equivalent current dipole modeling is useful, it can be approximated by the spherical model, but requires the realistic epilloid head model coregistered with MRI for concise analysis.

  • 12.

    Without proper MRI coregistration, the isolated dipole parameters should be reported in the coordinate terms only, and not anatomic attribution.

  • 13.

    Source localization in the individual can be modeled by coregistration of the individual's MRI brain.

  • 14.

    For scientific generality, the group results can be coregistered with the MRI of Talairach-normalized standard brain.

  • 15.

    Final validation of the source model lies on the direct intracranial recording in association with the study of scalp topography.

  • 16.

    Inference of the intracranial recorded activities in LEPs requires strict rules.

  • 17.

    Understanding of the biophysical basis in cerebral processing of LEPs comparing to hemodynamic neuroimaging in PET/fMRI is essential for interpretation of their functional relationship.

  • 18.

    EEG/MEG brain mapping (high temporal, but low spatial resolution) reflects the primary neuronal activation, which is followed (>2 sec to a few min) by PET/fMRI neuroimaging (low temporal, but high spatial resolution) as the secondary hemodynamic responses. However, these neural and hemodynamic activities can exert a mutual influence on one and other.

  • 19.

    3D–4D quantification is needed for measurement and analysis of both the neurophysiological and hemodynamic processing of human function in the brain.

  • 20.

    Pain can never be directly measured in the brain but can be inferred from brain activation under stringent logical constraints.

From the clinical perspective, LEPs can be summarized in the following:

  • 1.

    Appearance of an evoked cerebral potential gives evidence that a peripheral sensory impulse pattern has been transmitted to the brain via activation of a given afferent system. The specificity of the evoked response is mainly conditioned by the specificity of the stimulus for the afferent system under investigation.

  • 2.

    The specificity of the CO2 laser-induced responses for the thermo-algesic pathways under normal conditions has been well documented.

  • 3.

    Thus, there are several reasons for obtaining LEPs in patients with suspected lesions of thermo-algesic pathways: (a) to confirm objectively the presence of a sensory dysfunction or deficit, (b) to find the underlying mechanism of the dysfunction, (c) to detect subclinical abnormalities, (d) to monitor the evolution of them, and (e) to evaluate the effect of therapeutic intervention.

  • 4.

    LEPs have been utilized with success in a variety of neuropathological conditions in which conventional electrical evoked potentials were proven to be noncontributive or inappropriate such as in small-fiber neuropathies, radiculopathies, myelopathies, brainstem lesions, central pain syndromes, and states of hyperalgesia.

  • 5.

    A great amount of work remains to be done as to establish a normative database which would define the various aspects of the late and especially the ultralate LEPs possibly altered in nervous diseases, the investigation of which has only be started.

In the near future, we anticipate the following developments:

  • 1.

    Differential activation of the peripheral nerve fibers to examine the specificity of nociception in both psychophysics and brain topography.

  • 2.

    Characterization of the brain topography and isolation/identification of the generators for the ultralate LEPs in studying the cerebral processing of C-fibertype human pain.

  • 3.

    Application of high-resolution EEG for quantifying the temporospatial activation of LEPs.

  • 4.

    Cortical imaging, based on sound individual brain biophysics, which can be used to delineate the scalp topography in LEPs; the projected scalp activation on the cortex proper requires little assumption than the source modeling does.

  • 5.

    Source modeling based on the realistic head and brain in both individuals and groups of controlled subjects.

  • 6.

    Close inspection and study with simultaneous recordings of LEPs and fast neuroimaging techniques in EPI—fMRI.

  • 7.

    Cross-validation of the different functional brain mappings/neuroimagings in LEPs.

  • 8.

    Further systematic works in the intracranial recordings of LEPs to noxious and non-noxious stimulations for getting more specific information.

  • 9.

    Modeling of the cerebral processing of LEPs in human pain on the principles of both modular segregation and functional integration.

  • 10.

    Examination of “the binding problem” in pain, that is, how unified experience is achieved by binding of fragmentary neural events at multiple locations.

  • 11.

    Generalization of LEPs to other pain-inducing modalities, such as thermal/mechanical/chemical stimuli, inflicted on different body tissues (eg, muscle or viscera).

  • 12.

    Elucidation of nociceptive/pain substrates (areas, systems) and their hierarchical organization in the brain.

  • 13.

    Complex experimental design to integrate the major pain attributes (sensory—affect—cognition) for examination of their deterministic effects on the brain activation.

  • 14.

    Theoretical neural network analysis on how pain perception/consciousness can be accomplished within the frame of 300 msec in the brain.

  • 15.

    Increase the clinical use of LEPs in conjunction with the quantitative sensory test, in patients with characterized brain lesions, spinal cord affections, or peripheral nerve damages.

  • 16.

    Better understanding of the pain-related pathophysiology by studying the physiological processing of LEPs and anatomic/functional source imaging of LEPs.

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Author index Subject index The fallacy of using a solitary outcome measure as the standard for satisfactory pain treatment outcome Measuring the impact of pain Old dogs, new tricks
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