Altered pain processing in children with migraine: An evoked potential study

In adults, evidence is accumulating that migraine is associated with altered central processing of pain stimuli and, possibly, changes in the allocation of attentional resources to such stimuli. In pediatric migraine, however, little is known about altered pain processing. We examined 15 children with migraine and 15 controls (age 10–15) in an oddball standards task. Children had to respond to rare targets (tones) and ignore frequent painful (pain threshold) or non‐painful mechanical standard stimuli while evoked potentials were obtained. Painful as compared to non‐painful stimuli elicited significantly larger N150, P260 and P300 components of the somatosensory evoked potential in all children. The pain‐evoked N150 and P260 components did not differ significantly between groups. However, in children with migraine, both painful and non‐painful standard stimuli were associated with significantly larger P300 amplitudes at significantly shorter latencies. Perceived intensity of the painful and non‐painful stimuli was comparable in both groups. The evoked potentials and reaction times to the target tones did not differ significantly between groups. Habituation across trials was similar in both groups. Hence, children with migraine may display an automatic attentional bias towards painful and potentially painful somatosensory stimuli. Consistent with the psychobiological perspective of chronic pain, such an attentional bias could constitute an important mechanism for migraine becoming a chronic problem.     

Differences in early sensory-perceptual processing in synesthesia: a visual evoked potential study

Synesthesia is a condition where stimulation of a single sensory modality or processing stream elicits an idiosyncratic, yet reliable perception in one or more other modalities or streams. Various models have been proposed to explain synesthesia, which have in common aberrant cross-activation of one cortical area by another. This has been observed directly in cases of linguistic-color synesthesia as cross-activation of the 'color area', V4, by stimulation of the grapheme area. The underlying neural substrates that mediate cross-activations in synesthesia are not well understood, however. In addition, the overall integrity of the visual system has never been assessed and it is not known whether wider differences in sensory-perceptual processing are associated with the condition. To assess whether fundamental differences in perceptual processing exist in synesthesia, we utilised high-density 128-channel electroencephalography (EEG) to measure sensory-perceptual processing using stimuli that differentially bias activation of the magnocellular and parvocellular pathways of the visual system. High and low spatial frequency gratings and luminance-contrast squares were presented to 15 synesthetes and 15 controls. We report, for the first time, early sensory-perceptual differences in synesthetes relative to non-synesthete controls in response to simple stimuli that do not elicit synesthetic color experiences. The differences are manifested in the early sensory components of the visual evoked potential (VEP) to stimuli that bias both magnocellular and parvocellular responses, but are opposite in direction, suggesting a differential effect on these two pathways. We discuss our results with reference to widespread connectivity differences as a broader phenotype of synesthesia.     

Hierarchical Bayesian inference for the EEG inverse problem using realistic FE head models: depth localization and source separation for focal primary currents

The estimation of the activity-related ion currents by measuring the induced electromagnetic fields at the head surface is a challenging and severely ill-posed inverse problem. This is especially true in the recovery of brain networks involving deep-lying sources by means of EEG/MEG recordings which is still a challenging task for any inverse method. Recently, hierarchical Bayesian modeling (HBM) emerged as a unifying framework for current density reconstruction (CDR) approaches comprising most established methods as well as offering promising new methods. Our work examines the performance of fully-Bayesian inference methods for HBM for source configurations consisting of few, focal sources when used with realistic, high-resolution finite element (FE) head models. The main foci of interest are the correct depth localization, a well-known source of systematic error of many CDR methods, and the separation of single sources in multiple-source scenarios. Both aspects are very important in the analysis of neurophysiological data and in clinical applications. For these tasks, HBM provides a promising framework and is able to improve upon established CDR methods such as minimum norm estimation (MNE) or sLORETA in many aspects. For challenging multiple-source scenarios where the established methods show crucial errors, promising results are attained. Additionally, we introduce Wasserstein distances as performance measures for the validation of inverse methods in complex source scenarios.     

Abnormal processing of the nociceptive input in Parkinson's disease: a study with CO2 laser evoked potentials

Since a number of patients with Parkinson’s Disease (PD) complain of painful sensations, we studied whether the central processing of nociceptive inputs is abnormal in PD. To test this hypothesis, we recorded scalp CO₂ laser evoked potentials (LEPs) to hand skin stimulation in 18 pain-free PD patients with unilateral bradykinetic-rigid syndrome (hemiparkinson) during the off state and in 18 healthy subjects. This technique allows us to explore non-invasively the functional status of some cerebral structures involved in nociceptive input processing. In both PD patients and control subjects, CO₂ laser stimulation gave rise to a main negative N2 potential followed by a positive P2 response at vertex peaking at a latency of about 200 and 300 ms, respectively. These potentials are thought to originate from several brain structures devoted to nociceptive input processing, including the cingulate gyrus and insula. PD patients and normal subjects showed comparable N2 and P2 latencies, whereas the N2/P2 peak-to-peak amplitude was significantly lower in PD patients (regardless of the clinically affected body side) than in controls. LEPs were even recorded after acute L-dopa administration in 7 additional PD patients. L-dopa administration yielded no significant change in N2/P2 amplitude as compared to the off state. These results suggest an abnormal nociceptive input processing in pain-free PD patients which appears to be independent of clinical expression of parkinsonian motor signs and is not affected by dopaminergic stimulation.     

Syntactic and auditory spatial processing in the human temporal cortex: an MEG study

Processing syntax is believed to be a higher cognitive function involving cortical regions outside sensory cortices. In particular, previous studies revealed that early syntactic processes at around 100-200 ms affect brain activations in anterior regions of the superior temporal gyrus (STG), while independent studies showed that pure auditory perceptual processing is related to sensory cortex activations. However, syntax-related modulations of sensory cortices were reported recently, thereby adding diverging findings to the previous studies. The goal of the present magnetoencephalography study was to localize the cortical regions underlying early syntactic processes and those underlying perceptual processes using a within-subject design. Sentences varying the factors syntax (correct vs. incorrect) and auditory space (standard vs. change of interaural time difference (ITD)) were auditorily presented. Both syntactic and auditory spatial anomalies led to very early activations (40-90 ms) in the STG. Around 135 ms after violation onset, differential effects were observed for syntax and auditory space, with syntactically incorrect sentences leading to activations in the anterior STG, whereas ITD changes elicited activations more posterior in the STG. Furthermore, our observations strongly indicate that the anterior and the posterior STG are activated simultaneously when a double violation is encountered. Thus, the present findings provide evidence of a dissociation of speech-related processes in the anterior STG and the processing of auditory spatial information in the posterior STG, compatible with the view of different processing streams in the temporal cortex.     

Modulation of somatosensory evoked magnetic fields by intensity of interfering stimuli in human somatosensory cortex: an MEG study

Somatosensory evoked responses are known to be modulated by previous interfering stimuli. Here, we first investigated the modulatory effects of interfering stimuli with different intensities on somatosensory evoked magnetic field in human primary (S1) and secondary (S2) somatosensory cortices. In the control condition of the study, test stimulus, set to strong intensity, was delivered to the left median nerve. Interfering stimuli with three different levels of intensity from weak (WI) through moderate (MI) and finally to strong (SI) were interspersed to the left median nerve between the test stimuli in each interfering condition. The cortical responses to the test stimulus were modeled with equivalent current dipoles in the contralateral S1 and bilateral S2 cortices from 17 subjects. The amplitude of the N20m deflection from the S1 was not changed by any interfering stimuli, whereas the amplitude of later P35m deflection was reduced by MI stimulus. The amplitude of P60m deflection was reduced by MI and SI stimuli. The extent of amplitude reduction of the bilateral S2 response was markedly increased as intensity of interfering stimuli increased from weak to moderate, but further reduction by the SI stimuli compared to MI stimuli was not observed. Those results indicated that somatosensory cortical activation in the S1 (P35m and P60m) and S2 were modulated by intensity of interfering stimuli. Our findings of a greater gating effect on the bilateral S2 compared to the contralateral S1 indicate that S2 may play an important role in temporal integration of different intensity levels of somatosensory inputs.     

Human secondary somatosensory cortex is involved in the processing of somatosensory rare stimuli: an fMRI study

In the human somatosensory system, the contralateral primary somatosensory cortex (SI) is presumed to process and encode type and intensity of the sensory inputs, whereas the bilateral secondary somatosensory cortex (SII) is believed to perform higher order functions including sensorimotor integration, integration of information from the two body halves, attention, learning and memory. In this fMRI study we investigated the effect of attention on the activation of SI and SII, as induced by nonpainful and painful rare deviant electric stimuli during somatosensory oddball tasks. The working hypothesis is of stronger effects of attention on SII with respect to SI. Four runs were acquired according to an oddball scheme. Frequent nonpainful electrical stimuli were delivered to the ulnar nerve at motor threshold, whereas rare/deviant stimuli were delivered to median nerve in four conditions (one condition per run): nonpainful, painful, counting nonpainful, and counting painful. Results showed a statistically significant fMRI activation in bilateral SII but not in contralateral SI when the rare/deviant median nerve stimuli were delivered at nonpainful and painful levels as well as at the two levels of attention considered (i.e., associated with counting and non-counting tasks). Furthermore, fMRI activation in SII did not differ across the different levels of stimulus intensity (nonpainful, painful) and attention (non-counting, counting). These results corroborate the notion that SII is the target of independent pathways for the processing and integration of nonpainful and painful somatosensory stimuli salient for further high-order elaborations.     

The role of the prefrontal cortex in recognition memory and memory for source: an fMRI study.

We employed fMRI to index neural activity in prefrontal cortex during tests of recognition and source memory. At study, subjects were presented with words displayed either to the left or right of fixation, and, depending on the side, performed one of two orienting tasks. The test phase consisted of a sequence of three 10-word blocks, displayed in central vision. For one block, subjects performed recognition judgements on a mixture of two old and eight new words (low density recognition). For another block, recognition judgements were performed on a mixture of eight old and two new words (high density recognition). In the remaining block, also consisting of eight old and two new items, the requirement was to judge whether each word had been presented at study on the left or the right. Relative to the low density condition, high density recognition was associated with increased activity in right and, to a lesser extent, left, anterior prefrontal cortex (BA 10), replicating the findings of two previous PET studies. Right anterior prefrontal activity did not show any further increase during the source task. Instead, greater activity was found, relative to high density recognition, in left BA 10, left inferior frontal gyrus (BA 45/47), and bilateral opercular cortices (BA 45/47). The findings are inconsistent with the proposal that activation of right anterior prefrontal cortex during memory retrieval reflects "postretrieval" processing demands, such demands being considerably greater for judgments of source than recognition. The findings provide further evidence that the left prefrontal cortex plays a role in episodic memory retrieval when the task explicitly requires recovery of contextual as well as item information.     

Somatotopic organization of the processing of muscle and cutaneous pain in the left and right insula cortex: a single-trial fMRI study

The insula is involved in processing noxious information. It is consistently activated by acute noxious stimuli, can elicit pain on stimulation, and lesions encompassing the insula can alter pain perception. Anatomical tracing, electrophysiological and functional brain imaging investigations have suggested that the insula is somatotopically organized with respect to noxious cutaneous inputs. It has also recently been revealed that the anterior insula displays differential activation during cutaneous compared with muscle pain. Given this difference, it is important to determine if an insula somatotopy also exists for muscle pain. Using high-resolution functional magnetic resonance imaging (fMRI) we compared insula activation patterns in 23 subjects during muscle and cutaneous pain induced in the right leg and forearm. Group and frequency analyses revealed somatotopically organized signal increases in the posterior contralateral (left) and ipsilateral (right) anterior insula. Within the posterior contralateral insula, signal increases during both cutaneous and muscle forearm pain were located lateral and anterior to those evoked by leg pain, whereas in the ipsilateral anterior insula the pattern was reversed. Furthermore, within the ipsilateral anterior insula, muscle pain activated a region anterior to that activated by cutaneous pain. This somatotopic organization may be crucial for pain localization or other aspects of the pain experience that differ depending on both stimulation site and type of tissue activated. This study reveals that the insula is organized somatopically with respect to muscle and cutaneous pain and that this organization is further separated according to the tissue in which the pain originates.     

The functional role of dorso-lateral premotor cortex during mental rotation: an event-related fMRI study separating cognitive processing steps using a novel task paradigm

Subjects deciding whether two objects presented at angular disparity are identical or mirror versions of each other usually show response times that linearly increase with the angle between objects. This phenomenon has been termed mental rotation. While there is widespread agreement that parietal cortex plays a dominant role in mental rotation, reports concerning the involvement of motor areas are less consistent. From a theoretical point of view, activation in motor areas suggests that mental rotation relies upon visuo-motor rather than visuo-spatial processing alone. However, the type of information that is processed by motor areas during mental rotation remains unclear. In this study we used event-related fMRI to assess whether activation in parietal and dorsolateral premotor areas (dPM) during mental rotation is distinctively related to processing spatial orientation information. Using a newly developed task paradigm we explicitly separated the processing steps (encoding, mental rotation proper and object matching) required by mental rotation tasks and additionally modulated the amount of spatial orientation information that had to be processed. Our results show that activation in dPM during mental rotation is not strongly modulated by the processing of spatial orientation information, and that activation in dPM areas is strongest during mental rotation proper. The latter finding suggests that dPM is involved in more generalized processes such as visuo-spatial attention and movement anticipation. We propose that solving mental rotation tasks is heavily dependent upon visuo-motor processes and evokes neural processing that may be considered as an implicit simulation of actual object rotation.     

Corticotropin-releasing-hormone lacks analgesic properties: an experimental study in humans, using non-inflammatory pain.

The antinociceptive potency of corticotropin-releasing-hormone (CRH) has been established in several animal studies in which both central and peripheral sites of action were considered. However, there have not yet been any experimental trials, besides one attempt using clinical dental pain demonstrating the potential analgesic properties of CRH in humans. For this reason, we studied the effect of CRH on experimental heat pain sensitivity in 18 healthy men, using a double-blind, cross-over and placebo-controlled design. A dose of 100 microg (i.v.) was chosen because of its well-known neuroendocrine effects in humans. The pain parameters assessed were, visual analog scale (VAS) ratings for pain intensity and pain unpleasantness, pain thresholds and scores for discrimination ability. To differentiate between a direct analgesic effect of CRH and indirect effects via evoked hormonal responses in the hypothalamic-pituitary-adrenocortical (HPA) system (beta-endorphin, ACTH, cortisol), CRH was applied with and without a pre-treatment with dexamethasone. In neither of the two conditions was there any systematic change in our pain parameters. This failure to find any evidence suggesting an analgesic action of CRH or of the subsequent hormones of the HPA system was obtained despite the fact that CRH produced clear neuroendocrine responses such as increases in the plasma concentration of beta-endorphin and cortisol. It is unclear whether the lack of analgesic action of CRH is due to its non-existence in humans, due to the use of a pain model which does not assess minute changes in pain sensitivity and does not trigger substantial inflammatory responses, or due to an insufficient dose of CRH.     

Nociceptive and non-nociceptive sub-regions in the human secondary somatosensory cortex: an MEG study using fMRI constraints

Previous evidence from functional magnetic resonance imaging (fMRI) has shown that a painful galvanic stimulation mainly activates a posterior sub-region in the secondary somatosensory cortex (SII), whereas a non-painful sensory stimulation mainly activates an anterior sub-region of SII [Ferretti, A., Babiloni, C., Del Gratta, C., Caulo, M., Tartaro, A., Bonomo, L., Rossini, P.M., Romani, G.L., 2003. Functional topography of the secondary somatosensory cortex for non-painful and painful stimuli: an fMRI study. Neuroimage 20 (3), 1625-1638.]. The present study, combining fMRI with magnetoencephalographic (MEG) findings, assessed the working hypothesis that the activity of such a posterior SII sub-region is characterized by an amplitude and temporal evolution in line with the bilateral functional organization of nociceptive systems. Somatosensory evoked magnetic fields (SEFs) recordings after alvanic median nerve stimulation were obtained from the same sample of subjects previously examined with fMRI [Ferretti, A., Babiloni, C., Del Gratta, C., Caulo, M., Tartaro, A., Bonomo, L., Rossini, P.M., Romani, G.L., 2003. Functional topography of the secondary somatosensory cortex for non-painful and painful stimuli: an fMRI study. Neuroimage 20 (3), 1625-1638.]. Constraints for dipole source localizations obtained from MEG recordings were applied according to fMRI activations, namely, at the posterior and the anterior SII sub-regions. It was shown that, after painful stimulation, the two posterior SII sub-regions of the contralateral and ipsilateral hemispheres were characterized by dipole sources with similar amplitudes and latencies. In contrast, the activity of anterior SII sub-regions showed statistically significant differences in amplitude and latency during both non-painful and painful stimulation conditions. In the contralateral hemisphere, the source activity was greater in amplitude and shorter in latency with respect to the ipsilateral. Finally, painful stimuli evoked a response from the posterior sub-regions peaking significantly earlier than from the anterior sub-regions. These results suggested that both ipsi and contra posterior SII sub-regions process painful stimuli in parallel, while the anterior SII sub-regions might play an integrative role in the processing of somatosensory stimuli.     

Scopolamine into the anterior cingulate cortex diminishes nociception in a neuropathic pain model in the rat: an interruption of ‘nociception‐related memory acquisition’?

The cingulate cortex plays a key role in the affective component related to pain perception. This structure receives cholinergic projections and also plays a role in memory processing. Therefore, we propose that the cholinergic system in the anterior cingulate cortex is involved in the nociceptive memory process. We used scopolamine (10 microg in 0.25 mircrol/saline) microinjected into the anterior cingulate cortex, either before thermonociception followed by a sciatic denervation, between thermonociception and denervation or after both procedures (n=10 each). The vehicle group (saline solution 0.9%, n=14) was microinjected before thermonociception. Chronic nociception was measured by the autotomy score, which onset and incidence were also determined. Group scopolamine-thermonociception-denervation (STD) presented the lowest autotomy score as compared to vehicle and group thermonociception-denervation-scopolamine (TDS) (vehicle vs. STD, p=0.002, STD vs. TDS, p=0.001). Group thermonociception-scopolamine-denervation (TSD) showed a diminished autotomy score when compared to TDS (p=0.053). STD group showed a delay in the onset of AB as compared to the rest of the groups. Group TSD presented a significative delay (p=0.048) in AB onset when compared to group TDS. There were no differences in the incidence between groups. The results show that nociception-related memory processed in the anterior cingulate cortex is susceptible of being modified by the cholinergic transmission blockade. When scopolamine is microinjected prior to the nociceptive stimuli, nociception-related memory acquisition is prevented. The evidence obtained in this study shows the role of the anterior cingulate cortex in the acquisition of nociception-related memory.     

Influence of tissue conductivity anisotropy on EEG/MEG field and return current computation in a realistic head model: a simulation and visualization study using high-resolution finite element modeling

To achieve a deeper understanding of the brain, scientists, and clinicians use electroencephalography (EEG) and magnetoencephalography (MEG) inverse methods to reconstruct sources in the cortical sheet of the human brain. The influence of structural and electrical anisotropy in both the skull and the white matter on the EEG and MEG source reconstruction is not well understood. In this paper, we report on a study of the sensitivity to tissue anisotropy of the EEG/MEG forward problem for deep and superficial neocortical sources with differing orientation components in an anatomically accurate model of the human head. The goal of the study was to gain insight into the effect of anisotropy of skull and white matter conductivity through the visualization of field distributions, isopotential surfaces, and return current flow and through statistical error measures. One implicit premise of the study is that factors that affect the accuracy of the forward solution will have at least as strong an influence over solutions to the associated inverse problem. Major findings of the study include (1) anisotropic white matter conductivity causes return currents to flow in directions parallel to the white matter fiber tracts; (2) skull anisotropy has a smearing effect on the forward potential computation; and (3) the deeper a source lies and the more it is surrounded by anisotropic tissue, the larger the influence of this anisotropy on the resulting electric and magnetic fields. Therefore, for the EEG, the presence of tissue anisotropy both for the skull and white matter compartment substantially compromises the forward potential computation and as a consequence, the inverse source reconstruction. In contrast, for the MEG, only the anisotropy of the white matter compartment has a significant effect. Finally, return currents with high amplitudes were found in the highly conducting cerebrospinal fluid compartment, underscoring the need for accurate modeling of this space.     

Decline in attentional inhibition among migraine patients: an event‐related potential study using the Stroop task

BackgroundAs a disorder of brain dysfunction, migraine has been associated with cognitive decline. However, no consistent results with respect to the attention function in migraineurs have been found, and the relationship between attentional inhibition and migraine is also unclear. In this study, the attentional inhibition function was evaluated using event-related potentials (ERPs) while migraine patients and healthy controls were performing the color–word Stroop task.MethodsIn this study, 75 migraine patients and 41 age-, gender-, and education-matched healthy controls were enrolled. The Stroop task was performed, and both behavioral and ERP data were analyzed.ResultsAs to the behavioral data, the migraine group had a longer reaction time compared to the control group, but no difference in Stroop effect was observed. With respect to ERP components, the amplitudes of both early and late medial frontal negativity (MFN) were decreased in the migraine group. Additionally, obvious differences in the early MFN and sustained potential (SP) amplitudes were found between patients with and without allodynia.ConclusionsAt the behavioral level, migraine patients exhibited decreased executive ability but no obvious decline in inhibition. By contrast, a decline in attentional inhibition during the migraine interictal phase was confirmed by the analysis of ERP components, mainly those associated with changes in the conflict-monitoring stage, independent of confounding factors such as age, education, medication and mood disorders. Migraine patients with allodynia exhibited some significant differences in early MFN and SP compared to those without, supporting the hypothesis that migraine chronification aggravates the decline in attentional inhibition.     

Asian and Siberian ginseng as a potential modulator of immune function: an in vitro cytokine study using mouse macrophages

BACKGROUND: Ginseng is a widely used herbal product in China, other Asian countries, and in the Unites States. There is a traditional belief that ginseng stimulates immune functions. In this study, the innate effects of Asian and Siberian ginsengs on cytokines and chemokines produced by cultured macrophages were examined. MATERIALS AND METHODS: The effects of Asian and Siberian ginseng on cytokines and chemokines produced by cultured macrophages were examined. Mouse macrophages (J774A.1) were incubated with Asian or Siberian ginseng at varying concentrations (1, 10, 100, and 1000 microg/ml) for 24 h and then harvested for RNA isolation. The expression levels of IL-1beta, IL-12, TNF-alpha, MIP-1 alpha, and MIP-2 mRNA were measured by quantitative PCR. RESULTS: Our data showed that Asian ginseng induced a statistically significant increase in IL-12 expression at both mRNA and protein levels. However, the minor twofold increase is probably biologically insignificant. No significant increase of IL-12 by Siberian ginseng was observed at any dose level studied. No significant change in IL-1beta, IL-15, TNF-alpha, or MIP-1alpha mRNA was observed by either Asian or Siberian ginseng treatment. CONCLUSIONS: Our data showed statistically significant differential regulation of IL-12 by Asian ginseng. Siberian ginseng did not show a statistically significant increase. We conclude that both Asian ginseng and Siberian ginseng cannot significantly stimulate innate macrophage immune functions that influence cellular immune responses. Therefore, contrary to the popular belief, Asian and Siberian ginseng may not stimulate immune function.     

Understanding the role of injury/illness sensitivity and anxiety sensitivity in (automatic) pain processing: an examination using the extrinsic affective simon task.

Three fundamental fears are assumed to underlie psychopathology: Anxiety Sensitivity (AS), Injury/illness sensitivity (IS), and Fear of Negative Evaluation (FNE). Both AS and IS may form risk factors for the development and exacerbation of chronic pain. The current research examines the relation between these fears and automatic threat appraisal for pain-related stimuli. Study 1 (n=48) additionally examined content-specific associations of AS and FNE with the automatic threat appraisal of, respectively, panic and social evaluative cues. Study 2 (n=60) additionally focused on the association of IS and AS with the engagement in health protecting behavior, and the use of health care services. Both studies found evidence for an automatic threat appraisal of aversive stimuli. Study 2 demonstrated a positive association between the automatic threat appraisal for pain-related stimuli and individuals' IS levels. IS was found to be the single best predictor of the tendency to engage in health protecting behavior, whereas AS was the single best predictor of the reported use of health care services. PERSPECTIVE: This study contributes to the field of knowledge on putative risk factors for chronic pain. Results demonstrate an automatic threat appraisal toward pain-related stimuli that is related to vulnerability traits for pain. This automatic threat appraisal might initiate relatively spontaneous (nonstrategic) pain-maintaining behavioral responses.