Pain and the emotional brain: pain-related cortical processes are better reflected by affective evaluation than by cognitive evaluation.

The experience of pain has been dissociated into two interwoven aspects: a sensory-discriminative aspect and an affective-motivational aspect. We aimed to explore which of the pain descriptors is more deeply rooted in the human brain. Participants were asked to evaluate applied cold pain. The majority of the trials showed distinct ratings: some were rated higher for unpleasantness and others for intensity. We compared the relationship between functional data recorded from 7 T MRI with unpleasantness and intensity ratings and revealed a stronger relationship between cortical data and unpleasantness ratings. The present study underlines the importance of the emotional-affective aspects of pain-related cortical processes in the brain. The findings corroborate previous studies showing a higher sensitivity to pain unpleasantness compared to ratings of pain intensity. For the processing of pain in healthy subjects, this effect may reflect the more direct and intuitive evaluation of emotional aspects of the pain system, which is to prevent harm and to preserve the physical integrity of the body.

Interindividual variability and individual stability of pain- and touch-related neuronal gamma oscillations.

Brief painful laser and innocuous tactile stimuli have been associated with an increase of neuronal oscillations in the gamma range. Although it is indicated that event-related gamma oscillations may be highly variable across individuals, to date no study has systematically investigated interindividual variability and individual stability of induced gamma synchronization. Here, we addressed this question using two EEG datasets. The first dataset contains two repeated sessions of tactile and painful stimulation from 22 participants. The second dataset contains a single session of painful stimulation from 48 participants. In the first dataset, we observed gamma responses in the majority of the included participants. We found a broad interindividual variety of gamma magnitudes, time-frequency (TF) response patterns, and scalp topographies. Some participants showed a gamma response with individually unique time-frequency patterns, others did not exhibit any gamma response. This was reproducible and therefore stable; subjects with a large gamma magnitude in the first session showed a large gamma magnitude and a similar response pattern in the follow-up session. The second dataset confirmed the large between-subject variability, but only a fraction of the included participants exhibited laser-induced gamma synchronization. Our results indicate that current EEG measures do not reflect the complex reality of the diverse individual response patterns to brief pain and touch experiences. The present findings question whether a similar phenomenon would be observed in other neuroscience domains. Group results may be replicable, but could be driven by a subgroup of the sample.NEW & NOTEWORTHY The interpretation of gamma activity in response to noxious and innocuous somatosensory stimuli has sparked controversy. Here, we show that participants' gamma oscillations measured through electroencephalography vary. Although some participants do not show a distinct gamma response, others exhibit stable and reliable response patterns in terms of time, frequency, and magnitude.

Intrinsic network connectivity reflects the cyclic trajectory of migraine attacks.

BACKGROUND: Episodic migraine is considered to be cyclic in nature, triggered by the hypothalamus. To assess the natural trajectory of intrinsic networks over an entire migraine cycle, we designed a longitudinal intra-individual study using functional magnetic resonance imaging (fMRI). METHODS: Intrinsic network connectivity was assessed for 12 migraineurs in 82 sessions including spontaneous, untriggered headache attacks and follow-up recordings towards the next attack. RESULTS: We found cyclic changes in the visual, auditory, and somatosensory networks, in limbic networks (e.g. thalamo-insular, parahippocampal), and in the salience network (anterior insula and dorsal anterior cingulate cortex). Connectivity changes also extended to further cortical networks, such as the central executive network, the default mode network, as well as subcortical networks. Almost all of these network connectivity changes followed the trajectory of a linear increase over the pain-free interval that peaked immediately prior to the headache, and "dropped" to the baseline level during the headache. These network alterations are associated with a number of cortical functions that may explain the variety of ictal and pre-ictal physiological and psychological migraine symptoms. CONCLUSION: Our results suggest that migraine disease is associated with widespread cyclic alterations of intrinsic networks that develop before the headache is initiated, i.e. during the interictal and premonitory phase. The increasing magnitude of connectivity within these networks towards the next attack may reflect an increasing effort to maintain network integrity.

Intrinsic network activity reflects the fluctuating experience of tonic pain.

Although we know sensation is continuous, research on long-lasting and continuously changing stimuli is scarce and the dynamic nature of ongoing cortical processing is largely neglected. In a longitudinal study, 38 participants across four sessions were asked to continuously rate the intensity of an applied tonic heat pain for 20 min. Using group-independent component analysis and dual regression, we extracted the subjects' time courses of intrinsic network activity. The relationship between the dynamic fluctuation of network activity with the varying time courses of three pain processing entities was computed: pain intensity, the direction of pain intensity changes, and temperature. We were able to dissociate the spatio-temporal patterns of objective (temperature) and subjective (pain intensity/changes of pain intensity) aspects of pain processing in the human brain. We found two somatosensory networks with distinct functions: one network that encodes the small fluctuations in temperature and consists mainly of bilateral primary somatosensory cortex (SI), and a second right-lateralized network that encodes the intensity of the subjective experience of pain consisting of SI, secondary somatosensory cortex, the posterior cingulate cortex, and the thalamus. We revealed the somatosensory dynamics that build up toward a current subjective percept of pain. The timing suggests a cascade of subsequent processing steps toward the current pain percept.

Individually unique dynamics of cortical connectivity reflect the ongoing intensity of chronic pain.

ABSTRACT: Chronic pain diseases are characterised by an ongoing and fluctuating endogenous pain, yet it remains to be elucidated how this is reflected by the dynamics of ongoing functional cortical connections. In this study, we investigated the cortical encoding of 20 patients with chronic back pain and 20 chronic migraineurs in 4 repeated fMRI sessions. A brain parcellation approach subdivided the whole brain into 408 regions. Linear mixed-effects models were fitted for each pair of brain regions to explore the relationship between the dynamic cortical connectivity and the observed trajectory of the patients' ratings of fluctuating endogenous pain. Overall, we found that periods of high and increasing pain were predominantly related to low cortical connectivity. The change of pain intensity in chronic back pain was subserved by connections in left parietal opercular regions, right insular regions, as well as large parts of the parietal, cingular, and motor cortices. The change of pain intensity direction in chronic migraine was reflected by decreasing connectivity between the anterior insular cortex and orbitofrontal areas, as well as between the PCC and frontal and anterior cingulate cortex regions. Of interest, the group results were not mirrored by the individual patterns of pain-related connectivity, which rejects the idea of a common neuronal core problem for chronic pain diseases. The diversity of the individual cortical signatures of chronic pain encoding results adds to the understanding of chronic pain as a complex and multifaceted disease. The present findings support recent developments for more personalised medicine.

Patients with chronic pain exhibit individually unique cortical signatures of pain encoding.

Chronic pain is characterised by an ongoing and fluctuating intensity over time. Here, we investigated how the trajectory of the patients' endogenous pain is encoded in the brain. In repeated functional MRI (fMRI) sessions, 20 patients with chronic back pain and 20 patients with chronic migraine were asked to continuously rate the intensity of their endogenous pain. Linear mixed effects models were used to disentangle cortical processes related to pain intensity and to pain intensity changes. At group level, we found that the intensity of pain in patients with chronic back pain is encoded in the anterior insular cortex, the frontal operculum, and the pons; the change of pain in chronic back pain and chronic migraine patients is mainly encoded in the anterior insular cortex. At the individual level, we identified a more complex picture where each patient exhibited their own signature of endogenous pain encoding. The diversity of the individual cortical signatures of chronic pain encoding results bridge between clinical observations and neuroimaging; they add to the understanding of chronic pain as a complex and multifaceted disease.

Intrinsic network activity reflects the ongoing experience of chronic pain.

Analyses of intrinsic network activity have been instrumental in revealing cortical processes that are altered in chronic pain patients. In a novel approach, we aimed to elucidate how intrinsic functional networks evolve in regard to the fluctuating intensity of the experience of chronic pain. In a longitudinal study with 156 fMRI sessions, 20 chronic back pain patients and 20 chronic migraine patients were asked to continuously rate the intensity of their endogenous pain. We investigated the relationship between the fluctuation of intrinsic network activity with the time course of subjective pain ratings. For chronic back pain, we found increased cortical network activity for the salience network and a local pontine network, as well as decreased network activity in the anterior and posterior default mode network for higher pain intensities. Higher pain intensities in chronic migraine were accompanied with lower activity in a prefrontal cortical network. By taking the perspective of the individual, we focused on the variability of the subjective perception of pain, which include phases of relatively low pain and phases of relatively high pain. The present design of the assessment of ongoing endogenous pain can be a powerful and promising tool to assess the signature of a patient's endogenous pain encoding.

Migraine attacks as a result of hypothalamic loss of control.

Migraine is a complex neurological disorder affecting approximately 12% of the population. The pathophysiology is not yet fully understood, however the clinical features of the disease, such as the cyclic behaviour of attacks and vegetative symptoms, suggest a prominent role of the hypothalamus. Previous research has observed neuronal alterations at different time points during the migraine interval, specifically just before the headache is initiated. We therefore aimed to assess the trajectory of migraineurs' brain activity over an entire migraine cycle. Using functional magnetic resonance imaging (fMRI) with pseudo-continuous arterial spin labelling (ASL), we designed a longitudinal intra-individual study to detect the rhythmicity of (1) the cerebral perfusion and (2) the hypothalamic connectivity over an entire migraine cycle. Twelve episodic migraine patients were examined in 82 sessions during spontaneous headache attacks with follow-up recordings towards the next attack. We detected cyclic changes of brain perfusion in the limbic circuit (insula and nucleus accumbens), with the highest perfusion during the headache attack. In addition, we found an increase of hypothalamic connectivity to the limbic system over the interictal interval towards the attack, then collapsing during the headache phase. The present data provide strong evidence for the predominant role of the hypothalamus in generating migraine attacks. Due to a genetically-determined cortical hyperexcitability, migraineurs are most likely characterised by an increased susceptibility of limbic neurons to the known migraine trigger. The hypothalamus as a metronome of internal processes is suggested to control these limbic circuits: migraine attacks may occur as a result of the hypothalamus losing control over the limbic system. Repetitive psychosocial stress, one of the leading trigger factors reported by patients, might make the limbic system even more vulnerable and lead to a premature triggering of a migraine attack. Potential therapeutic interventions are therefore suggested to strengthen limbic circuits with dedicated medication or psychological approaches.

A novel tool for the removal of muscle artefacts from EEG: Improving data quality in the gamma frequency range.

BACKGROUND: The past two decades have seen a particular focus towards high-frequency neural activity in the gamma band (>30 Hz). However, gamma band activity shares frequency range with unwanted artefacts from muscular activity. NEW METHOD: We developed a novel approach to remove muscle artefacts from neurophysiological data. We re-analysed existing EEG data that were decomposed by a blind source separation method (independent component analysis, ICA), which helped to better spatially and temporally separate single muscle spikes. We then applied an adapting algorithm that detects these singled-out muscle spikes. RESULTS: We obtained data almost free from muscle artefacts; we needed to remove significantly fewer artefact components from the ICA and we included more trials for the statistical analysis compared to standard ICA artefact removal. All pain-related cortical effects in the gamma band have been preserved, which underlines the high efficacy and precision of this algorithm. CONCLUSIONS: Our results show a significant improvement of data quality by preserving task-relevant gamma oscillations of presumed cortical origin. We were able to precisely detect, gauge, and carve out single muscle spikes from the time course of neurophysiological measures without perturbing cortical gamma. We advocate the application of the tool for studies investigating gamma activity that contain a rather low number of trials, as well as for data that are highly contaminated with muscle artefacts. This validation of our tool allows for the application on event-free continuous EEG, for which the artefact removal is more challenging.

Ultra-high-field imaging reveals increased whole brain connectivity underpins cognitive strategies that attenuate pain.

We investigated how the attenuation of pain with cognitive interventions affects brain connectivity using neuroimaging and a whole brain novel analysis approach. While receiving tonic cold pain, 20 healthy participants performed three different pain attenuation strategies during simultaneous collection of functional imaging data at seven tesla. Participants were asked to rate their pain after each trial. We related the trial-by-trial variability of the attenuation performance to the trial-by-trial functional connectivity strength change of brain data. Across all conditions, we found that a higher performance of pain attenuation was predominantly associated with higher functional connectivity. Of note, we observed an association between low pain and high connectivity for regions that belong to brain regions long associated with pain processing, the insular and cingulate cortices. For one of the cognitive strategies (safe place), the performance of pain attenuation was explained by diffusion tensor imaging metrics of increased white matter integrity.

Strategy-dependent modulation of cortical pain circuits for the attenuation of pain.

The effectiveness of cognitive strategies to attenuate pain has been reported in various behavioural studies, however the underlying neuronal mechanisms are only now beginning to be understood. Using a 7 T fMRI, we investigated three different pain attenuation strategies in 20 healthy subjects via: (a) non-imaginal distraction by counting backwards in steps of seven; (b) imaginal distraction by imagining a safe place; and (c) reinterpretation of the pain valence (reappraisal). Although we found considerable variability in the performances, all strategies exhibited a significant relief of pain compared to an unmodulated pain condition. Our finding argues against a subject's potential predisposition for a certain attenuation approach, as some of the subjects performed well on all attenuation tasks yet others performed low on all attenuation tasks. We further investigated the variability of performance within-subjects and explored the cortical regions that contribute to successful single attempts of pain attenuation at trial level. For each of the three tasks, we found a different pattern of brain activity that reflects the performance of pain attenuation. The more successful trials are related to reduced activity of different parts of the insular cortex. Behavioural data suggest that distraction is the preferable cognitive strategy to modulate pain perception. For three different cognitive strategies we revealed brain regions that are suggested to reliably modulate the perception of pain. The findings could be of utmost benefit for future attempts to integrate neuroscientific techniques into the treatment of pain. Further studies are necessary to investigate whether the present results are transferable to patients as an essential part of the multimodal therapy for chronic pain. These patients may also benefit from additional neurofeedback techniques by combining the strategies with the cortical feedback in order to modulate pain-related brain activity.

Cortical abnormalities in episodic migraine: A multi-center 3T MRI study.

BACKGROUND: Several previous studies have investigated cortical abnormalities, specifically cortical thickness, in patients with migraine, with variable results. The relatively small sample sizes of most previous studies may partially explain these inconsistencies. OBJECTIVE: To investigate differences of cortical thickness between control subjects and migraineurs in a large cohort. METHODS: Three Tesla MRI data of 131 patients (38 with and 93 without aura) and 115 control subjects were analysed. A vertex-wise linear model was applied controlling for age, gender and MRI scanner to investigate differences between groups and determine the impact of clinical factors on cortical thickness measures. RESULTS: Migraineurs showed areas of thinned cortex compared with controls bilaterally in the central sulcus, in the left middle-frontal gyrus, in left visual cortices and the right occipito-temporal gyrus. Frequency of migraine attacks and the duration of the disorder had a significant impact on cortical thickness in the sensorimotor cortex and middle-frontal gyrus. Patients without aura showed thinner cortex than controls bilaterally in the central sulcus and in the middle frontal gyrus, in the left primary visual cortices, in the left supramarginal gyrus and in the right cuneus. Patients with aura showed clusters of thinner cortex bilaterally in the subparietal sulcus (between the precuneus and posterior cingulate cortex), in the left intraparietal sulcus and in the right anterior cingulate. CONCLUSION: These results indicate cortical abnormalities in specific brain regions in migraineurs. Some of the observed abnormalities may reflect a genetic susceptibility towards developing migraine attacks, while others are probably a consequence of repeated head pain attacks.

Fronto-Insular Connectivity during Pain Distraction Is Impaired in Patients with Somatoform Pain.

BACKGROUND AND PURPOSE: Somatoform pain disorder is characterized by chronic pain and various psychological symptoms including increased attention to mental and physical processes. Given that the medial prefrontal cortex (mPFC) of the default mode network (DMN) and the anterior insula of the salience network are critically involved in intrinsic and attentional processes, we investigated the involvement of these networks during the distraction from physical pain in somatoform pain patients. METHODS: During painful and nonpainful heat stimulation, attentional distraction from physical processes was modulated with a Stroop task. Thirteen patients were investigated with functional magnetic resonance imaging (fMRI) and compared to 13 controls. Main outcomes were spatial maps of coherent fMRI activity based on independent component analysis and functional connectivity (FC) resulting from psychophysiological interaction analysis. RESULTS: Behavioral pain intensity ratings were reduced during the distraction task in both groups. At brain level, we found deviant network activities in the DMN (particularly in the mPFC) and in the salience network (bilaterally in the anterior insula) in patients. During pain stimulation, Stroop-induced distraction decreased the FC between the mPFC and anterior insula in controls but not in patients. CONCLUSIONS: Modulating the FC between the mPFC and the insula may be highly relevant for shifting the attention away from external stimuli, including nociceptive input. The observed alterations in somatoform pain patients may foster new strategies in cognitive behavioral training tools for these patients.

Neuronal Oscillations in Various Frequency Bands Differ between Pain and Touch.

Although humans are generally capable of distinguishing single events of pain or touch, recent research suggested that both modalities activate a network of similar brain regions. By contrast, less attention has been paid to which processes uniquely contribute to each modality. The present study investigated the neuronal oscillations that enable a subject to process pain and touch as well as to evaluate the intensity of both modalities by means of Electroencephalography. Nineteen healthy subjects were asked to rate the intensity of each stimulus at single trial level. By computing Linear mixed effects models (LME) encoding of both modalities was explored by relating stimulus intensities to brain responses. While the intensity of single touch trials is encoded only by theta activity, pain perception is encoded by theta, alpha and gamma activity. Beta activity in the tactile domain shows an on/off like characteristic in response to touch which was not observed in the pain domain. Our results enhance recent findings pointing to the contribution of different neuronal oscillations to the processing of nociceptive and tactile stimuli.

Morphological Abnormalities of Thalamic Subnuclei in Migraine: A Multicenter MRI Study at 3 Tesla.

The thalamus contains third-order relay neurons of the trigeminal system, and animal models as well as preliminary imaging studies in small cohorts of migraine patients have suggested a role of the thalamus in headache pathophysiology. However, larger studies using advanced imaging techniques in substantial patient populations are lacking. In the present study, we investigated changes of thalamic volume and shape in a large multicenter cohort of patients with migraine. High-resolution T1-weighted MRI data acquired at 3 tesla in 131 patients with migraine (38 with aura; 30.8 ± 9 years old; 109 women; monthly attack frequency: 3.2 ± 2.5; disease duration: 14 ± 8.4 years) and 115 matched healthy subjects (29 ± 7 years old; 81 women) from four international tertiary headache centers were analyzed. The thalamus and thalamic subnuclei, striatum, and globus pallidus were segmented using a fully automated multiatlas approach. Deformation-based shape analysis was performed to localize surface abnormalities. Differences between patients with migraine and healthy subjects were assessed using an ANCOVA model. After correction for multiple comparisons, performed using the false discovery rate approach (p < 0.05 corrected), significant volume reductions of the following thalamic nuclei were observed in migraineurs: central nuclear complex (F(1,233) = 6.79), anterior nucleus (F(1,237) = 7.38), and lateral dorsal nucleus (F(1,238) = 6.79). Moreover, reduced striatal volume (F(1,238) = 6.9) was observed in patients. This large-scale study indicates structural thalamic abnormalities in patients with migraine. The thalamic nuclei with abnormal volumes are densely connected to the limbic system. The data hence lend support to the view that higher-order integration systems are altered in migraine. SIGNIFICANCE STATEMENT: This multicenter imaging study shows morphological thalamic abnormalities in a large cohort of patients with episodic migraine compared with healthy subjects using state-of-the-art MRI and advanced, fully automated multiatlas segmentation techniques. The results stress that migraine is a disorder of the CNS in which not only is brain function abnormal, but also brain structure is undergoing significant remodeling.

Hippocampal damage and affective disorders after treatment of cerebral aneurysms.

Despite good neurological outcome after the treatment of ruptured or incidental cerebral aneurysms, many patients complain about mood disturbances such as anxiety and depression. The present study investigated the nature of these affective disorders, their trigger factors, and corresponding structural brain changes. We assessed 63 patients matched by history of previous subarachnoid hemorrhage (SAH) and treatment modality (clipping vs. coiling) by a test battery including the Hospital Anxiety and Depression Scale (HADS) and beck depression inventory-II (BDI-II). MR imaging for the evaluation of structural changes included H(1)-MR spectroscopy, hippocampal volumetry, and diffusion tensor imaging (DTI). The applied multimodal imaging revealed no significant differences between patients with previous SAH and patients with incidental aneurysms; there were also no substantial differences between patients with and without previous SAH with respect to depression and anxiety. However, we observed significantly higher mean HADS scores in patients treated surgically versus patients treated by coiling (p < 0.01). BDI-II tended to be higher in surgically treated patients, but this difference appeared statistically insignificant. Surgically treated patients displayed substantial hippocampal damage in all imaging techniques: reduction in mean concentrations of N-acetylaspartate (p = 0.04), hippocampal volume reduction (p = 0.012), and diffusion disorder (p = 0.02). The structural alterations correlated significantly with the increased HADS scores. In contrast to endovascular treatment, aneurysm surgery seems to be associated with an increased incidence of mood disorders corresponding to hippocampal neuronal loss, independent of preceding SAH.

Pain sensitisers exhibit grey matter changes after repetitive pain exposure: a longitudinal voxel-based morphometry study.

Previous research in health and disease has shown that exposure to pain changes the density of cortical grey matter (GM). Such structural changes of the brain might, however, depend crucially on how this pain experience is evaluated and processed in the brain. In the present study we aimed to detect pain-rating patterns and underlying GM changes after the application of repetitive painful stimulation using voxel-based morphometry (VBM). Healthy volunteers were investigated (n=27), receiving 8 noxious and 8 innocuous thermal stimuli on the right forearm for 11 consecutive working days. Data were compared with a control group without any intervention (n=18). Behavioural data demonstrated that a subgroup of volunteers (n=14) sensitised, whereas the others (n=13) habituated over the stimulation days. The VBM analysis revealed no increase but a significant reduction of GM density, eg, in the anterior cingulate cortex, the insular cortex and the frontal cortex, exclusively in the group of sensitisers. By contrast, pain habituaters did not show any density changes in the GM. Depending on the individual perception of pain during the time course of stimulation, the repetitive application of painful stimuli changed the GM density in pain-processing brain regions exclusively in those subjects who were characterised by the lack of habituation. Because VBM studies investigating patients experiencing chronic pain observed similar decreases in GM density and increasing pain ratings over time, the sensitisers in our study may have a higher vulnerability to developing chronic pain syndromes in later life.

Increased limbic and brainstem activity during migraine attacks following olfactory stimulation.

OBJECTIVE: Migraine patients have dysfunctional cortical olfactory processing and very often report hypersensitivity and phobic symptoms to odors during acute headache attacks. However, imaging data of how the brain processes associate migraine symptoms, such as photophobia, phonophobia, or osmophobia, are rare. METHODS: The present study aimed to explore neuronal processing in response to olfactory stimulation (rose odor) in migraine patients in and outside acute headache attacks. Using event-related fMRI we studied 20 migraine patients and compared behavioral and imaging data with sex- and age-matched healthy controls. Additionally, 13 of the 20 patients were scanned within 6 hours after the onset of a spontaneous migraine attack. RESULTS: Imaging data showed that interictal migraineurs did not differ from control subjects. However, during spontaneous and untreated attacks, migraine patients showed significantly higher blood oxygen level-dependent signal intensities in brain areas including limbic structures (amygdala and insular cortices) and, more specifically, in the rostral pons in response to olfactory stimulation. CONCLUSIONS: Increased activity in the rostral part of the pons has previously been specifically linked to the pain of the migraine attack. The present finding suggests that the activity level of this structure can be triggered by olfactory input and thus points to the strong physiologic relationship between the olfactory and the trigemino-nociceptive pathway in the pathophysiology of migraine disease.

Trigeminal nociceptive transmission in migraineurs predicts migraine attacks.

Several lines of evidence suggest a major role of the trigeminovascular system in the pathogenesis of migraine. Using functional magnetic resonance imaging (fMRI), we compared brain responses during trigeminal pain processing in migraine patients with those of healthy control subjects. The main finding is that the activity of the spinal trigeminal nuclei in response to nociceptive stimulation showed a cycling behavior over the migraine interval. Although interictal (i.e., outside of attack) migraine patients revealed lower activations in the spinal trigeminal nuclei compared with controls, preictal (i.e., shortly before attack) patients showed activity similar to controls, which demonstrates that the trigeminal activation level increases over the pain-free migraine interval. Remarkably, the distance to the next headache attack was predictable by the height of the signal intensities in the spinal nuclei. Migraine patients scanned during the acute spontaneous migraine attack showed significantly lower signal intensities in the trigeminal nuclei compared with controls, demonstrating activity levels similar to interictal patients. Additionally we found-for the first time using fMRI-that migraineurs showed a significant increase in activation of dorsal parts of the pons, previously coined "migraine generator." Unlike the dorsal pons activation usually linked to migraine attacks, the gradient-like activity following nociceptive stimulation in the spinal trigeminal neurons likely reflects a raise in susceptibility of the brain to generate the next attack, as these areas increase their activity long before headache starts. This oscillating behavior may be a key player in the generation of migraine headache, whereas attack-specific pons activations are most likely a secondary event.

Insular cortex activity is associated with effects of negative expectation on nociceptive long-term habituation.

It is generally accepted that acute painful experience is influenced by context information shaping expectation and modulating attention, arousal, stress, and mood. However, little is known about the nature, duration, and extent of this effect, particularly regarding the negative expectation. We used a standardized longitudinal pain paradigm and painful heat test stimuli in healthy participants over a time course of 8 consecutive days, inducing nociceptive habituation over time. Thirty-eight healthy volunteers were randomly assigned to two different groups. One group received the information that the investigators expected the pain intensity to increase over time (context group). The other group was not given any information (control group). All participants rated the pain intensity of the daily standardized pain paradigm on a visual analog scale. In agreement with previous studies the pain ratings in the control group habituated over time. However, the context group reported no change of pain ratings over time. Functional imaging data showed a difference between the two groups in the right parietal operculum. These data suggest that a negative context not only has an effect on immediate pain but can modulate perception of pain in the future even without experience/conditioning. Neuronally, this process is mediated by the right opercular region.