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 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.

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.

Prefrontal Gamma Oscillations Encode Tonic Pain in Humans.

Under physiological conditions, momentary pain serves vital protective functions. Ongoing pain in chronic pain states, on the other hand, is a pathological condition that causes widespread suffering and whose treatment remains unsatisfactory. The brain mechanisms of ongoing pain are largely unknown. In this study, we applied tonic painful heat stimuli of varying degree to healthy human subjects, obtained continuous pain ratings, and recorded electroencephalograms to relate ongoing pain to brain activity. Our results reveal that the subjective perception of tonic pain is selectively encoded by gamma oscillations in the medial prefrontal cortex. We further observed that the encoding of subjective pain intensity experienced by the participants differs fundamentally from that of objective stimulus intensity and from that of brief pain stimuli. These observations point to a role for gamma oscillations in the medial prefrontal cortex in ongoing, tonic pain and thereby extend current concepts of the brain mechanisms of pain to the clinically relevant state of ongoing pain. Furthermore, our approach might help to identify a brain marker of ongoing pain, which may prove useful for the diagnosis and therapy of chronic pain.

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.

Endoscopic discectomy of the herniated intervertebral disc and changes in quality-of-life EQ-5D-5L analysis.

Herniated lumbar discs are a common cause of low back pain, which can negatively impact the quality of life of working-age individuals. This study aimed to evaluate changes in the quality of life in patients with sciatica who underwent endoscopic discectomy, a minimally invasive surgical procedure. The study (ClinicalTrials.gov NCT02742311) included 470 patients who underwent transforaminal, interlaminar, or translaminar endoscopic discectomy. Quality of life and pain perception were evaluated by comparing statistically weighted values of EQ-5D-5L, EQ-VAS, Oswestry disability index, and numerical pain scales for lower limb and back pain before and 12 months after the endoscopic procedure. After the procedure, there was a significant improvement in the reduction of back and lower limb pain, as well as in all monitored questionnaires (P < .001), which persisted 12 months after the endoscopy. All evaluated dimensions of the EQ-5D-5L questionnaire indicated a significant improvement in the assessed quality of life (P < .001). The study showed that percutaneous endoscopic lumbar discectomy is an effective pain-treating intervention that can improve the quality of life. There was no observed difference in the percentage of complications or re-herniations when comparing the transforaminal and interlaminar, approaches.

γ Oscillations are involved in the sensorimotor transformation of pain.

Pain signals threat and initiates motor responses to avoid harm. The transformation of pain into a motor response is thus an essential part of pain. Here, we investigated the neural mechanisms subserving the sensorimotor transformation of pain at the cortical level by using electroencephalography. In a simple reaction time experiment, brief painful stimuli were delivered to the left hand of healthy human subjects who responded with button presses of the right hand. The results show that the simple reaction time task was associated with neuronal responses at delta/theta, alpha/beta, and gamma frequencies. The analysis of the relationship between neuronal activity and response speed revealed that gamma oscillations, which were temporally coupled to the painful stimuli, but not temporally coupled to the motor response, predicted reaction times. Lateralization of gamma oscillations indicates that they originate from motor areas rather than from sensory areas. We conclude that gamma oscillations are involved in the sensorimotor transformation of pain whose efficiency they reflect. We hypothesize that the relationship between stimulus-locked gamma oscillations and reaction times reflects a direct thalamo-motor route of nociceptive information that is central to the biological function of pain.

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.

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.

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.

Computing the exact distribution of the Bartlett's test statistic by numerical inversion of its characteristic function.

Application of the exact statistical inference frequently leads to non-standard probability distributions of the considered estimators or test statistics. The exact distributions of many estimators and test statistics can be specified by their characteristic functions, as is the case for the null distribution of the Bartlett's test statistic. However, analytical inversion of the characteristic function, if possible, frequently leads to complicated expressions for computing the distribution function and the corresponding quantiles. An efficient alternative is the well-known method based on numerical inversion of the characteristic functions, which is, however, ignored in popular statistical software packages. In this paper, we present the explicit characteristic function of the corrected Bartlett's test statistic together with the computationally fast and efficient implementation of the approach based on numerical inversion of this characteristic function, suggested for evaluating the exact null distribution used for testing homogeneity of variances in several normal populations, with possibly unequal sample sizes.

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.

EQ-5D-5L questionnaire as suitable assessment of quality of life after epiduroscopy : Multicenter randomized double-blind pilot study.

BACKGROUND: Epiduroscopy is a well-established diagnostic and to certain level therapeutic tool in complex situations, where conventional methods such as magnetic resonance imaging (MRI) lack power or resolution to detect pathological changes. Such a situation is primarily failed back surgery syndrome (FBSS) but also radicular pain without surgery. The aim of this study was to determine the effectiveness of epiduroscopic treatment in patients with FBSS. METHODS: A total of 79 patients with FBSS were randomized into 2 groups. The first group underwent epiduroscopy and received mechanical lysis of adhesions only, the second group received also medication into the epidural space (methylprednisolone and hyaluronidase). Patients were subsequently followed for 12 months, with evaluation also after 6 months post-epiduroscopy. Patients were checked in terms of mobility, self-care, usual activities, pain/discomfort and anxiety/depression as defined in the 5­dimensional EQ-5D-5L questionnaire and to asses suitability of this questionnaire in chronic pain states. Data were collected using EQ-5D-5L questionnaire and also quality of life (QoL) questionnaire. RESULTS: In the terms of ability to walk (dimension mobility) and also ability to do housework, study or leisure activities (dimension usual activity) patients improved in both groups after 6 and 12 months after epiduroscopy. In pain dimension there was improvement mainly after 6 months which correlated also with self-care dimension and quality of life self-assessment. Results in anxiety/depression dimension were mixed. CONCLUSION: Epiduroscopy appears to be a beneficial procedure for both patient groups, especially after 6 months, with some benefit remaining after 12 months. The EQ-5D-5L questionnaire seems to be a suitable and comprehensive way to assess patient health in chronic pain states.

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.

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.

Variability issues in determining the concentration of isoprene in human breath by PTR-MS.

This paper deals with variability issues connected with the proton transfer reaction-mass spectrometry (PTR-MS) measurements of isoprene concentration. We focus on isoprene as an abundant and widely studied compound in human breath. The variability caused by the measurement process is described by the within-sample distribution. Thus, based on the formula for computing isoprene concentration that reflects the principle of the PTR-MS, a theoretical model for the within-sample distribution of isoprene concentration is suggested. This model, which assumes that the distribution is proportional to a quotient of two independent Poisson-distributed random variables, is then confronted with empirical distributions obtained from 17 breath samples collected from a healthy individual within a month. (In each sample, isoprene concentration was determined 97 times.) The empirical within-sample distributions are also compared to normal and log-normal distributions. While those seem to be satisfactory approximations, the theoretical model is found suitable only in 10 out of 17 breath samples. We also comment on the stability of samples during the measurement process in the PTR-MS instrument and, for the sake of comparison, determine the within-sample and the within-subject variability of isoprene concentrations in our data. The respective geometric standard deviations are 1.01 and 1.29.

Breath isoprene--aspects of normal physiology related to age, gender and cholesterol profile as determined in a proton transfer reaction mass spectrometry study.

BACKGROUND: This study was performed to clarify variations in breath isoprene concentrations with age, gender, body mass index (BMI) and total serum cholesterol. Our cohort consisted of 205 adult volunteers of different smoking background without health complaints. Total cholesterol in blood serum was measured in 79 of these volunteers. METHODS: Mixed expiratory exhaled breath was sampled using Tedlar bags. Concentrations of isoprene were then determined using proton transfer reaction-mass spectrometry. RESULTS: Isoprene concentrations ranged from 5.8 to 274.9 ppb, with an overall geometric mean (GM) of 99.3 ppb. There was no statistically significant difference in mean isoprene in breath between males and females (GM 105.4 and 95.5 ppb, respectively). Ageing led to a decrease in concentration in men, with an estimated slope of the regression line for log-transformed isoprene concentrations of -0.0049, but did not influence isoprene levels in women. We did not observe any significant correlation between isoprene breath content and cholesterol level in blood, even after adjusting for the possible influence of age. Similarly, no correlation was found between isoprene levels and BMI. CONCLUSIONS: Isoprene concentrations in exhaled breath showed gender-specific correlations with respect to age. Further investigations are necessary to clarify the relation between isoprene concentrations in exhaled breath and cholesterol levels and synthesis rates in blood.