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

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

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

Effects of nasally applied oxytocin on pain perception and processing

This placebo-controlled, double blind, cross-over trial performed with 36 healthy volunteers has been published as: Zunhammer M, Geis S, Busch V, Greenlee MW, Eichhammer P (2014) Effects of intranasal oxytocin on thermal pain in healthy men: a randomized functional magnetic resonance imaging study. Psychosom Med 77: 156–166. doi:10.1097/PSY.0000000000000142. The trial has been registered as a Phase I trial in the EU Clinical Trials Register under EUDRA-CT: 2009-015115-40. However, since the EU Clinical Trials Register does not publish Phase I trials, this re-registration was necessary to make the original trial protocol publicly available

Original Study Protocol

Original Study Protocol as approved with the Ethics Committee and the BfArM. The telefone numbers of the investigators have been removed for publication

Central modulators of human pain: Effects of oxytocin, exam stress, breathing exercises and transcranial magnetic stimulation

The available means to control human pain are insufficient, novel mechanisms of pain modulation must be explored and understood. This cumulative dissertation comprises four studies, which explored potential means to modulate pain in the central nervous system. An overview on the current understanding of pain, its basic mechanisms, and its known modulators is provided. Study 1 tested if a high intranasal dose of the neuro-hypophyseal hormone oxytocin affected perception and processing of thermal pain in 36 healthy male volunteers. Experimental pain thresholds were obtained and a functional Magnetic Resonance Imaging experiment with ratings of noxious heat was conducted. Oxytocin was found to reduce ratings of perceived heat intensity and amygdala activity. Both effects were small and independent of temperature. Although the hypothesis of an antinociceptive effect of oxytocin could not be confirmed, the study provides first evidence for effects of oxytocin on thermal stimulus processing. Study 2, a longitudinal questionnaire study, examined the effects of a period of academic exam stress on bodily symptoms in 150 students. Various symptoms of pain, as well as gastro-intestinal and autonomic complaints were found to increase during exam stress. Neuroticism, but not alexithymia, trait anxiety, or depression explained symptom increases under exam stress. Study two offers the first comprehensive, quantitative description of bodily symptoms under exam stress. Neuroticism was identified as a potential predisposing personality factor for the occurrence of bodily symptoms under stress. Study 3 aimed at elucidating physiological mechanisms behind the proposed antinociceptive effects of slow breathing exercises in 20 healthy participants. Breathing frequency, heart rate variability, and hyperventilation were not found to predict changes in experimental pain thresholds or heat pain ratings. A correlation between heart rate at baseline and pain ratings could be observed, confirming that autonomic nervous system function and pain are intertwined. Study 4 explored and tested if and how repetitive transcranial magnetic stimulation (rTMS) over the cerebellum affected thermal pain thresholds in two separate experiments. Although pain-relieving effects of cerebellar rTMS could be found in a first experiment, the second experiment showed that these effects were driven by peripheral mechanisms and/or the placebo effect. The study highlights the importance of proper experimental control conditions when investigating central modulators of pain. In a concluding discussion, the current methodology of pain research is reviewed. The methods used for this dissertation are discussed and limitations are identified; findings are summarized and further directions of research are highlighted

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

Somatic symptoms evoked by exam stress in university students: the role of alexithymia, neuroticism, anxiety and depression.

OBJECTIVE:The etiology of somatization is incompletely understood, but could be elucidated by models of psychosocial stress. Academic exam stress has effectively been applied as a naturalistic stress model, however its effect on somatization symptoms according to ICD-10 and DSM-IV criteria has not been reported so far. Baseline associations between somatization and personality traits, such as alexithymia, have been studied exhaustively. Nevertheless, it is largely unknown if personality traits have an explanatory value for stress induced somatization. METHODS:This longitudinal, quasi-experimental study assessed the effects of university exams on somatization - and the reversal of effects after an exam-free period. Repeated-observations were obtained within 150 students, measuring symptom intensity before, during and after an exam period, according to the Screening for Somatoform Symptoms 7-day (SOMS-7d). Additionally, self-reports on health status were used to differentiate between medically explained and medically unexplained symptoms. Alexithymia, neuroticism, trait-anxiety and baseline depression were surveyed using the Toronto-Alexithymia Scale (TAS-20), the Big-Five Personality Interview (NEO-FFI), the State Trait Anxiety Inventory (STAI) and Beck's Depression Inventory (BDI-II). These traits were competitively tested for their ability to explain somatization increases under exam stress. RESULTS:Somatization significantly increased across a wide range of symptoms under exam stress, while health reports pointed towards a reduction in acute infections and injuries. Neuroticism, alexithymia, trait anxiety and depression explained variance in somatization at baseline, but only neuroticism was associated with symptom increases under exam stress. CONCLUSION:Exam stress is an effective psychosocial stress model inducing somatization. A comprehensive quantitative description of bodily symptoms under exam stress is supplied. The results do not support the stress-alexithymia hypothesis, but favor neuroticism as a personality trait of importance for somatization

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

Mixed model results: predictors of sleep quality.

<p>Estimated unstandardized coefficients (<b><i>β</i></b>) of the mixed model, with corresponding t-tests against the null-hypothesis of no effect. The mixed model included a random intercept term for each participant. Positive beta values indicate an increase in PSQI score and therefore a decrease in sleep quality. All co-variates were mean-centered. †Value represents effect size of factor time.</p><p>Mixed model results: predictors of sleep quality.</p