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.