Brain morphology predicts individual sensitivity to pain: a multicenter machine learning approach.

ABSTRACT: Sensitivity to pain shows a remarkable interindividual variance that has been reported to both forecast and accompany various clinical pain conditions. Although pain thresholds have been reported to be associated to brain morphology, it is still unclear how well these findings replicate in independent data and whether they are powerful enough to provide reliable pain sensitivity predictions on the individual level. In this study, we constructed a predictive model of pain sensitivity (as measured with pain thresholds) using structural magnetic resonance imaging-based cortical thickness data from a multicentre data set (3 centres and 131 healthy participants). Cross-validated estimates revealed a statistically significant and clinically relevant predictive performance (Pearson r = 0.36, P < 0.0002, R2 = 0.13). The predictions were found to be specific to physical pain thresholds and not biased towards potential confounding effects (eg, anxiety, stress, depression, centre effects, and pain self-evaluation). Analysis of model coefficients suggests that the most robust cortical thickness predictors of pain sensitivity are the right rostral anterior cingulate gyrus, left parahippocampal gyrus, and left temporal pole. Cortical thickness in these regions was negatively correlated to pain sensitivity. Our results can be considered as a proof-of-concept for the capacity of brain morphology to predict pain sensitivity, paving the way towards future multimodal brain-based biomarkers of pain.

Savor the flavor: A randomized double-blind study assessing taste-enhanced placebo analgesia in healthy volunteers.

Placebo effects substantially contribute to analgesic treatment outcomes and might be leveraged to enhance gold-standard treatments. The taste of oral medications has been proposed to boost placebo effects. Here, we aimed at estimating how far the taste of an oral medication enhances placebo analgesia. We conducted a randomized, double-blind, between-group, single-visit study, with pre-treatment baseline. Over the course of three substudies, 318 healthy volunteers (297 included) were tested in a clinical trial setting. Participants were subjected to experimental tonic cold water pain (cold pressor test) before and after receiving taste-neutral (water), or bitter (quinine), or sweet (saccharin), or no placebo drops. Pre- versus post-treatment changes in area under the pain rating curve, the main outcome, indicated that placebo treatment showed a small analgesic effect versus no treatment. Added taste induced placebo enhancement in the very small effect size range, but accounted for a substantial portion of the overall placebo effect. No noteworthy advantage of sweet over bitter placebo was observed. An exploration of heart rate (HR) recordings indicated that placebo treatments were associated with an increase in peak HR-response to cold water, but these were not associated with placebo analgesia at an individual level. Placebo treatments were associated with minimal side effects. These results indicate that added taste may be an easy-to-implement, cost-effective, and safe way to optimize treatment outcomes and that taste-neutral preparations may reduce placebo-related outcome variance in clinical trials. Further studies are needed to test if these findings can be translated into clinical scenarios.

Influence on study outcomes of an inpatient study by the behavior of the study staff (PINgPOng): study protocol for a randomized clinical trial.

BACKGROUND: The placebo effect as the symptom improvement following inert treatments is a fixed component of RCTs to differentiate between specific effects of the tested pharmacological substance from other unspecific effects. The PINgPOng study was set up to analyze the influence of a study team trained to either minimize the placebo response and optimize drug-placebo differences or to maximize the placebo response to increase drug efficacy by unspecific factors on the study results of a RCT in a classical early clinical trial setting. METHODS/DESIGN: PINgPOng is a single-center, prospective, randomized, double-blind, placebo-controlled study in a 3-group, 2-sequence, 2-period cross-over design. The study is conducted according to the principles of ICH-GCP and the Declaration of Helsinki on the Phase I-Unit of the University Hospital Bonn. The primary endpoint is the pain intensity in the cold pressor test before and after the administration of 15 mg oxycodone or placebo. The pain intensity is compared between three study conditions: 32 healthy volunteers in each study arm will be treated either by an untrained study team (arm A), by a study team trained to maximize (arm B), or to minimize placebo responses (arm C). Neuroendocrine factors (alpha-amylase activity, salivary cortisol), characteristic traits (anxiety, depression, stress), and somatic reactions are analyzed as covariates of the pain perception. DISCUSSION: The PINgPOng study will allow to answer the question whether and to what extent the behavior of a trained study team (neutral vs. maximize vs. minimize placebo responses) will differentially affect placebo responses in a setting of a highly standardized early clinical trial. The results will help to control the placebo effects by education of the clinical study team and to avoid unnecessary high placebo effects in clinical development. TRIAL REGISTRATION: German Clinical Trials Register DRKS00013586 . Registered on December 22, 2017.

Does pain modality play a role in the interruptive function of acute visceral compared with somatic pain?

ABSTRACT: Acute pain captures attentional resources and interferes with ongoing cognitive processes, including memory encoding. Despite broad clinical implications of this interruptive function of pain for the pathophysiology and treatment of chronic pain conditions, existing knowledge exclusively relies on studies using somatic pain models. Visceral pain is highly prevalent and seems to be more salient and threatening, suggesting that the interruptive function of pain may be higher in acute visceral compared with somatic pain. Implementing rectal distensions as a clinically relevant experimental model of visceral pain along with thermal cutaneous pain for the somatic modality, we herein examined the impact of pain modality on visual processing and memory performance in a visual encoding and recognition task and explored the modulatory role of pain-related fear and expectation in 30 healthy participants. Despite careful and dynamically adjusted matching of stimulus intensities to perceived pain unpleasantness over the course of trials, we observed greater impairment of cognition performance for the visceral modality with a medium effect size. Task performance was not modulated by expectations or by pain-related fear. Hence, even at matched unpleasantness levels, acute visceral pain is capable of interfering with memory encoding, and this impact seems to be relatively independent of pain-related cognitions or emotions, at least in healthy individuals. These results likely underestimate the detrimental effect of chronic pain on cognitive performance, which may be particularly pronounced in acute and chronic visceral pain.

Resting-state functional heterogeneity of the right insula contributes to pain sensitivity.

Previous studies have described the structure and function of the insular cortex in terms of spatially continuous gradients. Here we assess how spatial features of insular resting state functional organization correspond to individual pain sensitivity. From a previous multicenter study, we included 107 healthy participants, who underwent resting state functional MRI scans, T1-weighted scans and quantitative sensory testing on the left forearm. Thermal and mechanical pain thresholds were determined. Connectopic mapping, a technique using non-linear representations of functional organization was employed to describe functional connectivity gradients in both insulae. Partial coefficients of determination were calculated between trend surface model parameters summarizing spatial features of gradients, modal and modality-independent pain sensitivity. The dominant connectopy captured the previously reported posteroanterior shift in connectivity profiles. Spatial features of dominant connectopies in the right insula explained significant amounts of variance in thermal (R2 = 0.076; p < 0.001 and R2 = 0.031; p < 0.029) and composite pain sensitivity (R2 = 0.072; p < 0.002). The left insular gradient was not significantly associated with pain thresholds. Our results highlight the functional relevance of gradient-like insular organization in pain processing. Considering individual variations in insular connectopy might contribute to understanding neural mechanisms behind pain and improve objective brain-based characterization of individual pain sensitivity.

Network properties and regional brain morphology of the insular cortex correlate with individual pain thresholds.

Pain thresholds vary considerably across individuals and are influenced by a number of behavioral, genetic and neurobiological factors. However, the neurobiological underpinnings that account for individual differences remain to be fully elucidated. In this study, we used voxel-based morphometry (VBM) and graph theory, specifically the local clustering coefficient (CC) based on resting-state connectivity, to identify brain regions, where regional gray matter volume and network properties predicted individual pain thresholds. As a main finding, we identified a cluster in the left posterior insular cortex (IC) reaching into the left parietal operculum, including the secondary somatosensory cortex, where both regional gray matter volume and the local CC correlated with individual pain thresholds. We also performed a resting-state functional connectivity analysis using the left posterior IC as seed region, demonstrating that connectivity to the pre- as well as postcentral gyrus bilaterally; that is, to the motor and primary sensory cortices were correlated with individual pain thresholds. To our knowledge, this is the first study that applied VBM in combination with voxel-based graph theory in the context of pain thresholds. The co-location of the VBM and the local CC cluster provide first evidence that both structure and function map to the same brain region while being correlated with the same behavioral measure; that is, pain thresholds. The study highlights the importance of the posterior IC, not only for pain perception in general, but also for the determination of individual pain thresholds.

Tilidine and dipyrone (metamizole) in cold pressor pain: A pooled analysis of efficacy, tolerability, and safety in healthy volunteers.

The cold pressor test (CPT) is widely implemented and offers a simple, experimental acute pain model utilizing cold pain. Previous trials have frequently paired the CPT with opioids in order to investigate the mechanisms underlying pharmacological analgesia, due to their known analgesic efficacy. However, opioid side effects may lead to unblinding and raise concerns about the safety of the experimental setting. Despite the established clinical efficacy of dipyrone (metamizole), its efficacy, tolerability, and safety in cold pressor pain has not been systematically addressed to date. This pooled analysis included data of 260 healthy volunteers from three randomized, placebo-controlled, double-blind substudies using the CPT following a pre-test-post-test-design. These substudies allow for comparing a single dose of 800 mg dipyrone with two different doses of the opioid tilidine/naloxone (50/4 mg and 100/8 mg, respectively). Outcomes included pain intensity ratings, pain tolerance, medication-attributed side effects, as well as changes of blood pressure and heart rate. We demonstrate that both opioid doses and dipyrone had a comparable, significant analgesic effect on cold pressor pain. However, dipyrone was associated with significantly less self-reported adverse effects and these were not significantly different from those under placebo. These results indicate that the combination of dipyrone and the CPT provides a safe, tolerable, and effective experimental model for the study of pharmacological analgesia. In combination with a CPT, dipyrone may be useful as a positive control, or baseline medication for the study of analgesic modulation.

Meta-analysis of neural systems underlying placebo analgesia from individual participant fMRI data.

The brain systems underlying placebo analgesia are insufficiently understood. Here we performed a systematic, participant-level meta-analysis of experimental functional neuroimaging studies of evoked pain under stimulus-intensity-matched placebo and control conditions, encompassing 603 healthy participants from 20 (out of 28 eligible) studies. We find that placebo vs. control treatments induce small, widespread reductions in pain-related activity, particularly in regions belonging to ventral attention (including mid-insula) and somatomotor networks (including posterior insula). Behavioral placebo analgesia correlates with reduced pain-related activity in these networks and the thalamus, habenula, mid-cingulate, and supplementary motor area. Placebo-associated activity increases occur mainly in frontoparietal regions, with high between-study heterogeneity. We conclude that placebo treatments affect pain-related activity in multiple brain areas, which may reflect changes in nociception and/or other affective and decision-making processes surrounding pain. Between-study heterogeneity suggests that placebo analgesia is a multi-faceted phenomenon involving multiple cerebral mechanisms that differ across studies.

Pain-free resting-state functional brain connectivity predicts individual pain sensitivity.

Individual differences in pain perception are of interest in basic and clinical research as altered pain sensitivity is both a characteristic and a risk factor for many pain conditions. It is, however, unclear how individual sensitivity to pain is reflected in the pain-free resting-state brain activity and functional connectivity. Here, we identify and validate a network pattern in the pain-free resting-state functional brain connectome that is predictive of interindividual differences in pain sensitivity. Our predictive network signature allows assessing the individual sensitivity to pain without applying any painful stimulation, as might be valuable in patients where reliable behavioural pain reports cannot be obtained. Additionally, as a direct, non-invasive readout of the supraspinal neural contribution to pain sensitivity, it may have implications for translational research and the development and assessment of analgesic treatment strategies.

Probabilistic TFCE: A generalized combination of cluster size and voxel intensity to increase statistical power.

The threshold-free cluster enhancement (TFCE) approach integrates cluster information into voxel-wise statistical inference to enhance detectability of neuroimaging signal. Despite the significantly increased sensitivity, the application of TFCE is limited by several factors: (i) generalisation to data structures, like brain network connectivity data is not trivial, (ii) TFCE values are in an arbitrary unit, therefore, P-values can only be obtained by a computationally demanding permutation-test. Here, we introduce a probabilistic approach for TFCE (pTFCE), that gives a simple general framework for topology-based belief boosting. The core of pTFCE is a conditional probability, calculated based on Bayes' rule, from the probability of voxel intensity and the threshold-wise likelihood function of the measured cluster size. In this paper, we provide an estimation of these distributions based on Gaussian Random Field theory. The conditional probabilities are then aggregated across cluster-forming thresholds by a novel incremental aggregation method. pTFCE is validated on simulated and real fMRI data. The results suggest that pTFCE is more robust to various ground truth shapes and provides a stricter control over cluster "leaking" than TFCE and, in many realistic cases, further improves its sensitivity. Correction for multiple comparisons can be trivially performed on the enhanced P-values, without the need for permutation testing, thus pTFCE is well-suitable for the improvement of statistical inference in any neuroimaging workflow. Implementation of pTFCE is available at https://spisakt.github.io/pTFCE.

Placebo Effects on the Neurologic Pain Signature: A Meta-analysis of Individual Participant Functional Magnetic Resonance Imaging Data.

Importance: Placebo effects reduce pain and contribute to clinical analgesia, but after decades of research, it remains unclear whether placebo treatments mainly affect nociceptive processes or other processes associated with pain evaluation. Objective: We conducted a systematic, participant-level meta-analysis to test the effect of placebo treatments on pain-associated functional neuroimaging responses in the neurologic pain signature (NPS), a multivariate brain pattern tracking nociceptive pain. Data Sources: Medline (PubMed) was searched from inception to May 2015; the search was augmented with results from previous meta-analyses and expert recommendations. Study Selection: Eligible studies were original investigations that were published in English in peer-reviewed journals and that involved functional neuroimaging of the human brain with evoked pain delivered under stimulus intensity-matched placebo and control conditions. The authors of all eligible studies were contacted and asked to provide single-participant data. Data Extraction and Synthesis: Data were collected between December 2015 and November 2017 following the Preferred Reporting Items for Systematic Review and Meta-Analyses of individual participant data guidelines. Results were summarized across participants and studies in a random-effects model. Main Outcomes and Measures: The main, a priori outcome was NPS response; pain reports were assessed as a secondary outcome. Results: We obtained data from 20 of 28 identified eligible studies, resulting in a total sample size of 603 healthy individuals. The NPS responses to painful stimulation compared with baseline conditions were positive in 575 participants (95.4%), with a very large effect size (g = 2.30 [95% CI, 1.92 to 2.69]), confirming its sensitivity to nociceptive pain in this sample. Placebo treatments showed significant behavioral outcomes on pain ratings in 17 of 20 studies (85%) and in the combined sample (g = -0.66 [95% CI, -0.80 to -0.53]). However, placebo effects on the NPS response were significant in only 3 of 20 studies (15%) and were very small in the combined sample (g = -0.08 [95% CI, -0.15 to -0.01]). Similarly, analyses restricted to studies with low risk of bias (g = -0.07 [95% CI, -0.15 to 0.00]) indicated very small effects, and analyses of just placebo responders (g = -0.22 [95% CI, -0.34 to -0.11]) indicated small effects, as well. Conclusions and Relevance: Placebo treatments have moderate analgesic effects on pain reports. The very small effects on NPS, a validated measure that tracks levels of nociceptive pain, indicate that placebo treatments affect pain via brain mechanisms largely independent of effects on bottom-up nociceptive processing.

The effect of dopamine on conditioned placebo analgesia in healthy individuals: a double-blind randomized trial.

RATIONALE: Better means to control placebo effects are key to optimizing treatment outcomes. Dopamine-based reward and learning mechanisms have been hypothesized to drive placebo effects. Here, we tested whether dopamine augmentation can modulate learned placebo effects. METHODS: We performed a randomized, double-blind parallel group study with 70 healthy adult participants to test whether a single oral dose of the dopamine precursor levodopa/carbidopa (100/25 mg) administered before the acquisition of conditioned placebo analgesia enhances the placebo response in an established experimental placebo model using heat pain. RESULTS: Overall, the observed levels of placebo analgesia in our sample were low and not statistically significant. Levodopa, compared to placebo, only led to a marginal increase in placebo analgesia. Female participants tended to show larger placebo responses than male participants. Within the female subgroup, levodopa showed small-to-moderate effects on placebo analgesia; however, this effect was not statistically significant. CONCLUSIONS: In summary, the present study could not provide evidence for a placebo augmenting effect of levodopa-enhanced dopamine levels in healthy subjects. Further studies are needed to elucidate whether placebo enhancement can be achieved through dopamine augmentation.

The effects of treatment failure generalize across different routes of drug administration.

Failure of medical treatments can hamper responses to subsequent treatments. It has been suggested that changing the route of drug administration could reduce such negative carry-over effects, but direct evidence for this approach is lacking. We therefore investigated in 211 healthy volunteers whether changes in drug administration route reduce such carry-over effects. A positive or negative treatment history with topical analgesic treatments was induced experimentally in a mock clinical trial setting. Subsequently, a different inert drug was introduced via the same (topical) or another (oral) route of administration and its analgesic efficacy was tested. Changing the route of drug administration induced expectations of positive treatment effects in the subjects but did not actually counteract the negative carry-over effects on treatment efficacy. These findings indicate that learned carry-over effects generalize over time and across routes of drug administration-independent of conscious expectations. Other strategies are needed to prevent negative carry-over effects of treatment failure from influencing the results of subsequent treatment attempts.

Combined glutamate and glutamine levels in pain-processing brain regions are associated with individual pain sensitivity.

The relationship between glutamate and γ-aminobutyric acid (GABA) levels in the living human brain and pain sensitivity is unknown. Combined glutamine/glutamate (Glx), as well as GABA levels can be measured in vivo with single-voxel proton magnetic resonance spectroscopy. In this cross-sectional study, we aimed at determining whether Glx and/or GABA levels in pain-related brain regions are associated with individual differences in pain sensitivity. Experimental heat, cold, and mechanical pain thresholds were obtained from 39 healthy, drug-free individuals (25 men) according to the quantitative sensory testing protocol and summarized into 1 composite measure of pain sensitivity. The Glx levels were measured using point-resolved spectroscopy at 3 T, within a network of pain-associated brain regions comprising the insula, the anterior cingulate cortex, the mid-cingulate cortex, the dorsolateral prefrontal cortex, and the thalamus. GABA levels were measured using GABA-edited spectroscopy (Mescher-Garwood point-resolved spectroscopy) within the insula, the anterior cingulate cortex, and the mid-cingulate cortex. Glx and/or GABA levels correlated positively across all brain regions. Gender, weekly alcohol consumption, and depressive symptoms were significantly associated with Glx and/or GABA levels. A linear regression analysis including all these factors indicated that Glx levels pooled across pain-related brain regions were positively associated with pain sensitivity, whereas no appreciable relationship with GABA was found. In sum, we show that the levels of the excitatory neurotransmitter glutamate and its precursor glutamine across pain-related brain regions are positively correlated with individual pain sensitivity. Future studies will have to determine whether our findings also apply to clinical populations.

Pain modulation by intranasal oxytocin and emotional picture viewing - a randomized double-blind fMRI study.

The hormone oxytocin has been hypothesized to influence the emotional dimension of pain. This randomized, placebo-controlled, double-blind, crossover study explored whether intranasal oxytocin and emotional context can affect heat pain perception in 30 healthy male volunteers. After receiving 36 IU oxytocin or placebo, participants underwent functional Magnetic Resonance Imaging (fMRI) during which noxious and non-noxious thermode heat stimuli were applied. Simultaneously, scenes from the International Affective Pictures System (IAPS) with positive, neutral, and negative emotional valence were shown. Heat intensity and unpleasantness ratings were obtained. The activity of whole-brain correlates of heat processing was quantified via multi-voxel pattern analysis. We observed no appreciable main effects of oxytocin on ratings or neural pain correlates. Effects of emotional picture valence on ratings were smaller than reported in previous studies. Nevertheless, oxytocin was found to significantly enhance the influence of picture valence on unpleasantness ratings at noxious heat levels. No corresponding changes in whole-brain correlates of heat intensity processing were found. Our study provides evidence that intranasal oxytocin increases the effects of emotional context on the subjective unpleasantness of experimental heat pain. Future studies are needed to determine whether this effect can be utilized in clinical settings.

Theory of Mind and Emotional Awareness in Chronic Somatoform Pain Patients.

OBJECTIVE: The present study aimed at investigating whether chronic pain patients are impaired in Theory of Mind (ToM), or Emotional Awareness. METHODS: Thirty inpatients suffering from chronic somatoform pain, as well as thirty healthy controls matched for age, sex, and education were recruited. ToM abilities were measured using the Frith-Happé animation task, in which participants interpret video-clips depicting moving geometric forms that mimic social interactions. The responses given were scored for appropriateness and the degree of inferred intentionality according to established protocols. Emotional awareness was measured using the Levels of Emotional Awareness Scale (LEAS), for which participants provide written descriptions of feelings in imaginary emotional situations. Standardized scoring was performed to capture the number and quality of emotional terms used. RESULTS: Responses lengths were similar in both groups and for both tasks. Patients attained significantly lower intentionality but not appropriateness scores when interpreting ToM interactions. No significant group differences were found when interpreting goal directed interactions. Emotional awareness scores were significantly lower in patients compared to healthy controls. CONCLUSIONS: Our results suggest that chronic pain patients are impaired in mentalizing and emotional awareness. Future studies are needed to determine whether these ToM and emotional awareness deficits contribute to the etiology of somatoform pain and whether addressing these deficits in therapeutic interventions can improve polymodal pain therapy.

Effects of intranasal oxytocin on thermal pain in healthy men: a randomized functional magnetic resonance imaging study.

OBJECTIVE: Intranasal oxytocin has been shown to affect human social and emotional processing, but its potential to affect pain remains elusive. This randomized, placebo-controlled, double-blind, crossover trial investigated the effect of intranasal oxytocin on the perception and processing of noxious experimental heat in 36 healthy male volunteers. METHODS: Thermal thresholds were determined according to the Quantitative Sensory Testing protocol. A functional magnetic resonance imaging experiment including intensity and unpleasantness ratings of tonic heat was used to investigate the effects of oxytocin within the brain. RESULTS: Thirty men (aged 18-50 years) were included in the study. Intranasal oxytocin had no significant effect on thermal thresholds, but significantly (t = -2.06, p = .046) reduced heat intensity ratings during functional magnetic resonance imaging. The effect on intensity ratings was small (-3.46 points on a 100-point visual analog scale [95% confidence interval {CI} = -6.86 to -0.07] and independent of temperature. No effects of oxytocin on stimulus- or temperature-related processing were found at the whole-brain level at a robust statistical threshold. A region of interest analysis indicated that oxytocin caused small but significant decreases in left (-0.045%, 95% CI = -0.087 to -0.003, t = -2.19, p = .037) and right (-0.051%, 95% CI = -0.088 to -0.014], t = -2.82, p = .008) amygdala activity across all temperatures. CONCLUSIONS: The present study provides evidence for a significant but subtle inhibitory effect of oxytocin on thermal stimulus ratings and concurrent amygdala activity. Neither of the two effects significantly depended of temperature; therefore, the hypothesis of a pain-specific effect of oxytocin could not be confirmed. TRIAL REGISTRATION: EUDRA-CT 2009-015115-40.

Sleep quality during exam stress: the role of alcohol, caffeine and nicotine.

Academic exam stress is known to compromise sleep quality and alter drug consumption in university students. Here we evaluated if sleeping problems and changes in legal drug consumption during exam stress are interrelated. We used the Pittsburgh Sleep Quality Index (PSQI) to survey sleep quality before, during, and after an academic exam period in 150 university students in a longitudinal questionnaire study. Self-reports of alcohol, caffeine, and nicotine consumption were obtained. The Perceived Stress Questionnaire (PSQ-20) was used as a measure of stress. Sleep quality and alcohol consumption significantly decreased, while perceived stress and caffeine consumption significantly increased during the exam period. No significant change in nicotine consumption was observed. In particular, students shortened their time in bed and showed symptoms of insomnia. Mixed model analysis indicated that sex, age, health status, as well as the amounts of alcohol and caffeine consumed had no significant influence on global sleep quality. The amount of nicotine consumed and perceived stress were identified as significant predictors of diminished sleep quality. Nicotine consumption had a small-to-very-small effect on sleep quality; perceived stress had a small-to-moderate effect. In conclusion, diminished sleep quality during exam periods was mainly predicted by perceived stress, while legal drug consumption played a minor role. Exam periods may pose an interesting model for the study of stress-induced sleeping problems and their mechanisms.