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Additional file 1. SPIRIT checklist.

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. CA Zunhammer - CA Greenlee

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.

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., Die zur Verfügung stehenden Möglichkeiten der Schmerzlinderung beim Menschen sind unzureichend. Die Mechanismen der Schmerzmodulation müssen erforscht und besser verstanden werden. Die folgende Arbeit gibt zunächst einen Überblick über das gegenwärtige Verständnis des Schmerzes, seine zugrunde liegenden Mechanismen und Modulatoren. In Studie 1 dieser Arbeit wurde bei 36 männlichen Probanden untersucht, ob eine hohe intranasale Dosis des Neurohypophysen-Hormons Oxytocin die Wahrnehmung und Verarbeitung thermaler Schmerzreize verändert. Experimentelle Schmerzschwellen wurden bestimmt, sowie die Bewertung und zerebrale Verarbeitung schmerzhafter Hitzereize anhand funktioneller Magnetresonanztomographie untersucht. Im Ergebnis hatte Oxytocin einen signifikanten reduzierenden Effekt auf die Bewertung von Hitze-Intensitäten und die Aktivität der Amygdala. Diese Effekte waren klein und unabhängig von der applizierten Temperatur. Die Studie konnte damit die Hypothese einer anti-nociceptiven Wirkung von Oxytocin nicht bestätigen, aber erste Belege für einen Effekt von Oxytocin auf die zentralnervöse Verarbeitung von Hitzereizen liefern. Studie 2, eine longitudinale Fragebogenstudie, untersuchte die Effekte einer akademischen Prüfungsperiode auf das körperliche Befinden bei 150 Studierenden. Verschiedene Schmerzsymptome, aber auch gastro-intestinale und autonome Beschwerden nahmen unter Prüfungsstress zu. Die Persönlichkeitsdimension Neurotizismus konnte einen signifikanten Anteil der unter Stress auftretenden Symptome vorhersagen, nicht so Alexithymie, Ängstlichkeit und Depressivität. Studie 2 bietet die erste umfassende, quantitative Erfassung körperliche Symptome unter Prüfungsstress mit dem Screeningfragebogen für Somatoforme Störungen (SOMS). Neurotizismus wurde als möglicher prädisponierender Faktor für das Auftreten körperlicher Beschwerden unter Stress identifiziert. Studie 3 zielte darauf ab, mögliche physiologische Mechanismen der analgetischen Wirkung von Atemübungen zu untersuchen. Weder Atemfrequenz, Herzratenvariabilität, noch Hyperventilation zeigten sich als signifikante Prädiktoren experimenteller Hitzeschmerzschwellen und Hitzeschmerz-Ratings bei 20 gesunden Probanden. Eine Korrelation zwischen der Herzrate bei Versuchsbeginn und Hitzeschmerzratings konnte beobachtet werden und damit ein weiterer Beleg für das Zusammenspiel zwischen autonomem Nervensystem und Schmerzwahrnehmung gefunden werden. In Studie 4 wurde anhand zweier Experimente die Möglichkeit einer Beeinflussung thermaler Schmerzschwellen durch repetitive transcranielle Magnetstimulation (rTMS) des Cerebellums erforscht. Obwohl zunächst im ersten Experiment schmerzreduzierende Effekte cerebellärer TMS beobachtet wurden, zeigte das zweite Experiment, dass diese Effekte periphäre Ursachen haben oder dem Placebo-Effekt geschuldet sind. Studie 4 verdeutlicht die Bedeutsamkeit valider Kontrollbedingungen bei der Untersuchung zentralnervöser Schmerzmodulation. Die abschließende Diskussion befasst sich mit der gängigen Methodik in der experimentellen Schmerzforschung. Die Methoden, Ergebnisse und Einschränkungen der vorgestellten Studien werden zusammengefasst und zukünftige Forschungsrichtungen aufgezeigt.

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.

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.