Imaging CNS Modulation of Pain in Humans

Department of Neurology, NeuroImage Nord, University Medical Center Hamburg-Eppendorf, Germany.
Physiology (Impact Factor: 4.86). 01/2009; 23(6):371-80. DOI: 10.1152/physiol.00024.2008
Source: PubMed


Pain is a highly complex and subjective experience that is not linearly related to the nociceptive input. What is clear from anecdotal reports over the centuries and more recently from animal and human experimentation is that nociceptive information processing and consequent pain perception is subject to significant pro- and anti-nociceptive modulations. These modulations can be initiated reflexively or by contextual manipulations of the pain experience including cognitive and emotional factors. This provides a necessary survival function since it allows the pain experience to be altered according to the situation rather than having pain always dominate. The so-called descending pain modulatory network involving predominantly medial and frontal cortical areas, in combination with specific subcortical and brain stem nuclei appears to be one key system for the endogenous modulation of pain. Furthermore, recent findings from functional and anatomical neuroimaging support the notion that an altered interaction of pro- and anti-nociceptive mechanisms may contribute to the development or maintenance of chronic pain states. Research on the involved circuitry and implemented mechanisms is a major focus of contemporary neuroscientific research in the field of pain and should provide new insights to prevent and treat chronic pain states.

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    • "Chez le volontaire sain, des situations d'hyperalgésie ontété rapportées en association avec une activité du tronc cérébral supposée refléter la sensibilisation (Zambreanu et al., 2005), mais aussi avec des activités excessives préfrontales (Seifert & Maihofner, 2009). Ces théories n'ontà ce jour pas pû etre vérifiées expérimentalement par imagerie fonctionnelle (Bingel & Tracey, 2008). Il n'est donc possible de livrer ici que quelques pistes, par exemple, une hyperactivité dans le tronc cérébral de patients soumisà une stimulation nociceptive dans la zone cérébrale correspondantà leurs douleurs ostéoathritiques (Gwilym et al., 2009). "
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    ABSTRACT: In this review, we summarize the contribution of functional imaging to the question of nociception in humans. In the beginning of the 90's, brain areas supposed to be involved in physiological pain processes essentially concerned the primary somatosensory area (SI), thalamus, and anterior cingulate cortex. In spite of these a priori hypotheses, the first imaging studies revealed that the main brain areas and those providing the most consistent activations in pain conditions were the insular and the SII cortices, bilaterally. This has been checked with other techniques such as intracerebral recordings of evoked potentials after nociceptive stimulations with laser showing a consistent response in the operculo-insular area whose amplitude correlates with pain intensity. In spite of electrode implantations in other areas of the brain, only rare and inconsistent responses have been found outside the operculo-insular cortices. With electrical stimulation delivered directly in the brain, it has also been shown that stimulation in this area only - and not in other brain areas - was able to elicit a painful sensation. Thus, over the last 15 years, the operculo-insular cortex has been re-discovered as a main area of pain integration, mainly in its sensory and intensity aspects. In neuropathic pain also, these areas have been demonstrated as being abnormally recruited, bilaterally, in response to innocuous stimuli. These results suggest that plastic changes may occur in brain areas that were pre-defined for generating pain sensations. Conversely, when the brain activations concomitant to pain relief were taken in account, a large number of studies pointed out medial prefrontal and rostral cingulate areas as being associated with pain controls. Interestingly, these activations may correlate with the magnitude of pain relief, with the activation of the peri-acqueductal grey (PAG) and, at least in some instances, with the involvement of endogenous opioids.
    Full-text · Article · Jun 2014 · Biologie Aujourd'hui
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    • "This phenomenon has been referred to as habituation. Apart from peripheral mechanisms, like decreased responsiveness of primary afferents, pain processing in the CNS may significantly contribute to the habituation phenomenon (Bingel and Tracey, 2008). In heat pain and laser-evoked pain, this involves parts of the antinociceptive system with the rostral anterior cingulate cortex (ACC) and the periaqueductal grey (PAG) (Bingel et al., 2007; Mobascher et al., 2010). "
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    ABSTRACT: Background Habituation to repetitive noxious stimuli is a well-known phenomenon. We investigated brain correlates of habituation to pain in a transdermal electrical pain model using functional magnetic resonance imaging (fMRI). Methods Electrical painful stimulation with 1Hz was applied to the volar forearm of 48 healthy subjects for 45min. Before and after conditioning stimulation, psychophysical testing and fMRI were performed. During fMRI sessions, the subjects underwent blockwise painful electrical stimulation with a fixed percept-adapted current intensity. After fMRI 1 and fMRI 2 subjects rated the individual pain intensity of the electrical stimulus. ResultsSubstantial habituation occurred during conditioning electrical stimulation. Accordingly, areas typically involved in pain processing showed decreased activity after conditioning stimulation. The blood oxygen level-dependent signal of the subgenual anterior cingulate gyrus, the superior parietal lobule and the supplemental motor area correlated positively with habituation. In contrast, activity in the periaqueductal grey, thalamus and insula correlated negatively. The results of the correlation analyses did not survive correction for multiple comparisons. Conclusions With this study, we identified central components associated with habituation to repetitive painful stimuli. The results suggest that an increase in tonic inhibitory activity in cortical pain processing areas is a major mechanism contributing to habituation to phasic noxious stimuli. Moreover, areas involved in descending pain modulation were differentially modulated. This may hint at a simultaneous activation of facilitating and inhibiting nociceptive systems that are both altered in the transdermal electrical pain model.
    Full-text · Article · Jan 2014 · European journal of pain (London, England)
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    • "Second, an inverse relationship was included, representing a rapid decline in the consecutive ERFIAs, followed by a gradual decline or plateau phase—ie, habituation of the initial trials is more pronounced than that later in the experiment. Third, a quadratic function, representing a sensitization process (or dishabituation) after an initial habituation, was modeled [34]. Thus, habituation was modeled in three ways: linear habituation (trial number), fast habituation (inverse relationship, computed as 1/trial), and dishabituation (parabolic relationship, computed as trial*trial) [26]. "
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    ABSTRACT: In analyzing time-locked event-related potentials (ERPs), many studies have focused on specific peaks and their differences between experimental conditions. In theory, each latency point after a stimulus contains potentially meaningful information, regardless of whether it is peak-related. Based on this assumption, we introduce a new concept which allows for flexible investigation of the whole epoch and does not primarily focus on peaks and their corresponding latencies. For each trial, the entire epoch is partitioned into event-related fixed-interval areas under the curve (ERFIAs). These ERFIAs, obtained at single trial level, act as dependent variables in a multilevel random regression analysis. The ERFIA multilevel method was tested in an existing ERP dataset of 85 healthy subjects, who underwent a rating paradigm of 150 painful and non-painful somatosensory electrical stimuli. We modeled the variability of each consecutive ERFIA with a set of predictor variables among which were stimulus intensity and stimulus number. Furthermore, we corrected for latency variations of the P2 (260 ms). With respect to known relationships between stimulus intensity, habituation, and pain-related somatosensory ERP, the ERFIA method generated highly comparable results to those of commonly used methods. Notably, effects on stimulus intensity and habituation were also observed in non-peak-related latency ranges. Further, cortical processing of actual stimulus intensity depended on the intensity of the previous stimulus, which may reflect pain-memory processing. In conclusion, the ERFIA multilevel method is a promising tool that can be used to study event-related cortical processing.
    Full-text · Article · Nov 2013 · PLoS ONE
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