“Inflammatory Soup” Mediators of inflammation in CRPS

Complex Regional Pain Syndrome type 1 (CRPS1) is a disease of the extremity that usually occurs as a complication after surgery or trauma, although spontaneous occurrence has also been described. The clinical features include pain/sensory abnormalities, vasomotor dysfunction, edema/sudomotor dysfunction, and motor/trophic changes. The diagnosis of CRPS is based on findings during the history and physical examination. Several diagnostic criteria sets have been developed, and the most used are the Veldman criteria, the IASP criteria (the International Association for the Study of Pain), and the Bruehl criteria. There is a distinction between CRPS types 1 and 2. Type 1 occurs without any peripheral nerve lesion, whereas in type 2 there is definite peripheral nerve damage. In the Netherlands, the incidence of CRPS is estimated to be approximately 26.2 per 100,000 person years, with a median age of onset of 52.7 years. CRPS occurs more often in females than in males, with a ratio of approximately 3.4:1. The upper extremity is more often affected than the lower extremity, and the right and the left sides of the body are affected with the same frequency. A fracture is the most common precipitating event (44%) for CRPS, followed by a contusion/sprain in 17% of the population

Regulation of peripheral blood flow in Complex Regional Pain Syndrome: clinical implication for symptomatic relief and pain management

Background. During the chronic stage of Complex Regional Pain Syndrome (CRPS), impaired microcirculation is related to increased vasoconstriction, tissue hypoxia, and metabolic tissue acidosis in the affected limb. Several mechanisms may be responsible for the ischemia and pain in chronic cold CPRS. Discussion. The diminished blood flow may be caused by either sympathetic dysfunction, hypersensitivity to circulating catecholamines, or endothelial dysfunction. The pain may be of neuropathic, inflammatory, nociceptive, or functional nature, or of mixed origin. Summary. The origin of the pain should be the basis of the symptomatic therapy. Since the difference in temperature between both hands fluctuates over time in cold CRPS, when in doubt, the clinician should prioritize the patient's report of a persistent cold extremity over clinical tests that show no difference. Future research should focus on developing easily applied methods for clinical use to differentiate between central and peripheral blood flow regulation disorders in individual patients

Perception of Thermal Pain and the Thermal Grill Illusion Is Associated with Polymorphisms in the Serotonin Transporter Gene

AIM: The main aim of this study was to assess if the perception of thermal pain thresholds is associated with genetically inferred levels of expression of the 5-HT transporter (5-HTT). Additionally, the perception of the so-called thermal grill illusion (TGI) was assessed. Forty-four healthy individuals (27 females, 17 males) were selected a-priori based on their 5-HTTLPR/rs25531 ('tri-allelic 5-HTTLPR') genotype, with inferred high or low 5-HTT expression. Thresholds for heat- and cold-pain were determined along with the sensory and affective dimensions of the TGI. RESULTS: Thresholds to heat- and cold-pain correlated strongly (rho  = -0.58, p<0.001). Individuals in the low 5-HTT-expressing group were significantly less sensitive to heat-pain (p = 0.02) and cold-pain (p = 0.03), compared to the high-expressing group. A significant gender-by-genotype interaction also emerged for cold-pain perception (p = 0.02); low 5-HTT-expressing females were less sensitive. The TGI was rated as significantly more unpleasant (affective-motivational dimension) than painful (sensory-discriminatory dimension), (p<0.001). Females in the low 5-HTT expressing group rated the TGI as significantly less unpleasant than high 5-HTT expressing females (p<0.05), with no such differences among men. CONCLUSION/SIGNIFICANCE: We demonstrate an association between inferred low 5-HTT expression and elevated thresholds to thermal pain in healthy non-depressed individuals. Despite the fact that reduced 5-HTT expression is a risk factor for chronic pain we found it to be related to hypoalgesia for threshold thermal pain. Low 5-HTT expression is, however, also a risk factor for depression where thermal insensitivity is often seen. Our results may thus contribute to a better understanding of the molecular underpinnings of such paradoxical hypoalgesia. The results point to a differential regulation of thermoafferent-information along the neuraxis on the basis of 5-HTT expression and gender. The TGI, suggested to rely on the central integration of thermoafferent-information, may prove a valuable tool in probing the affective-motivational dimension of these putative mechanisms

5-HT modulation of pain perception in humans

© 2017, The Author(s). Introduction: Although there is clear evidence for the serotonergic regulation of descending control of pain in animals, little direct evidence exists in humans. The majority of our knowledge comes from the use of serotonin (5-HT)-modulating antidepressants as analgesics in the clinical management of chronic pain. Objectives: Here, we have used an acute tryptophan depletion (ATD) to manipulate 5-HT function and examine its effects of ATD on heat pain threshold and tolerance, attentional manipulation of nociceptive processing and mood in human volunteers. Methods: Fifteen healthy participants received both ATD and balanced amino acid (BAL) drinks on two separate sessions in a double-blind cross-over design. Pain threshold and tolerance were determined 4 h post-drink via a heat thermode. Additional attention, distraction and temperature discrimination paradigms were completed using a laser-induced heat pain stimulus. Mood was assessed prior and throughout each session. Results: Our investigation reported that the ATD lowered plasma TRP levels by 65.05 ± 7.29% and significantly reduced pain threshold and tolerance in response to the heat thermode. There was a direct correlation between the reduction in total plasma TRP levels and reduction in thermode temperature. In contrast, ATD showed no effect on laser-induced pain nor significant impact of the distraction-induced analgesia on pain perception but did reduce performance of the painful temperature discrimination task. Importantly, all findings were independent of any effects of ATD on mood. Conclusion: As far as we are aware, it is the first demonstration of 5-HT effects on pain perception which are not confounded by mood changes

Why Is an Early Start of Training Related to Musical Skills in Adulthood? A Genetically Informative Study

Experts in domains such as music or sports often start training early. It has been suggested that this may reflect a sensitive period in childhood for skill acquisition. However, it could be that familial factors (e.g., genetics) contribute to the association. Here, we examined the effect of age of onset of musical training on musical aptitude and achievement in professional musicians (n = 310) and twins (n = 7,786). In line with previous literature, results showed that an earlier age of onset was associated with higher aptitude and achievement in both samples. After we adjusted for lifetime practice hours, age of onset was associated only with aptitude (p .14). Twin analyses showed that the association with aptitude was fully explained by familial factors. Thus, these findings provide little support for a sensitive period for music but highlight that familiar factors play an important role for associations between age of onset of training and skills in adulthood

The effects of playing music on mental health outcomes

The association between active musical engagement (as leisure activity or professionally) and mental health is still unclear, with earlier studies reporting contrasting findings. Here we tested whether musical engagement predicts (1) a diagnosis of depression, anxiety, schizophrenia, bipolar or stress-related disorders based on nationwide patient registers or (2) self-reported depressive, burnout and schizotypal symptoms in 10,776 Swedish twins. Information was available on the years individuals played an instrument, including their start and stop date if applicable, and their level of achievement. Survival analyses were used to test the effect of musical engagement on the incidence of psychiatric disorders. Regression analyses were applied for self-reported psychiatric symptoms. Additionally, we conducted co-twin control analyses to further explore the association while controlling for genetic and shared environmental confounding. Results showed that overall individuals playing a musical instrument (independent of their musical achievement) may have a somewhat increased risk for mental health problems, though only significant for self-reported mental health measures. When controlling for familial liability associations diminished, suggesting that the association is likely not due to a causal negative effect of playing music, but rather to shared underlying environmental or genetic factors influencing both musicianship and mental health problems

A comprehensive investigation into the genetic relationship between music engagement and mental health (in press)

Abstract While music engagement is often regarded as beneficial for mental health, some studies report higher risk for depression and anxiety among musicians. This study investigates whether shared underlying genetic influences (genetic pleiotropy) or gene-environment interaction could be at play in the music-mental health association using measured genotypes. In 5,648 Swedish twins with information on music and sport engagement, creative achievements, self-reported mental health and psychiatric diagnoses based on nationwide patient registries, we derived polygenic scores for major depression, bipolar disorder, schizophrenia, neuroticism, sensitivity to environmental stress, depressive symptoms and general musicality. In line with phenotypic associations, individuals with higher polygenic scores for major depression and bipolar disorder were more likely to play music, practice more music and reach higher levels of general artistic achievements, while a higher genetic propensity for general musicality was marginally associated with a higher risk for a depression diagnosis. Importantly, polygenic scores for major depression and bipolar remained associated with music engagement when excluding individuals who experienced psychiatric symptoms, just as a genetic propensity for general musicality predicted a depression diagnosis regardless of whether and how much individuals played music. In addition, we found no evidence for gene-environment interaction: the phenotypic association between music engagement and mental health outcomes did not differ for individuals with different genetic vulnerability for mental health problems. Altogether, our findings suggest that mental health problems observed in musically active individuals are partly explained by a pre-existing genetic risk for depression and bipolar disorder and likely reflect horizontal pleiotropy (when one gene influences multiple traits), rather than causal influences of mental health on music engagement, or vice versa (referred to as vertical pleiotropy)

Risk factors for parental psychopathology: a study in families with children or adolescents with psychopathology

The parents of children with psychopathology are at increased risk for psychiatric symptoms. To investigate which parents are mostly at risk, we assessed in a clinical sample of families with children with psychopathology, whether parental symptom scores can be predicted by offspring psychiatric diagnoses and other child, parent and family characteristics. Parental depressive, anxiety, avoidant personality, attention-deficit/hyperactivity (ADHD), and antisocial personality symptoms were measured with the Adult Self Report in 1805 mothers and 1361 fathers of 1866 children with a psychiatric diagnosis as assessed in a child and adolescent psychiatric outpatient clinic. In a multivariate model, including all parental symptom scores as outcome variables, all offspring psychiatric diagnoses, offspring comorbidity and age, parental age, parental educational attainment, employment, and relationship status were simultaneously tested as predictors. Both 35.7% of mothers and 32.8% of fathers scored (sub)clinical for at least one symptom domain, mainly depressive symptoms, ADHD symptoms or, only in fathers, avoidant personality symptoms. Parental psychiatric symptoms were predicted by unemployment. Parental depressive and ADHD symptoms were further predicted by offspring depression and offspring ADHD, respectively, as well as by not living together with the other parent. Finally, parental avoidant personality symptoms were also predicted by offspring autism spectrum disorders. In families with children referred to child and adolescent psychiatric outpatient clinics, parental symptom scores are associated with adverse circumstances and with similar psychopathology in their offspring. This signifies, without implying causality, that some families are particularly vulnerable, with multiple family members affected and living in adverse circumstances