Our results support the hypothesis of a correlation between serum BDNF and S100B in FM patients and their association with PPT. This is the first report of serum S100B levels in a human FM sample and its association with another mediator of CS, serum BDNF. Furthermore, we observed that both serum BDNF and S100B were higher in FM patients with lower PPT.
To the best of our knowledge, this is the first study to assess serum S100B in a human sample with FM. In animal models of hyperalgesia induced by chronic restraint and with unpredictable stress, serum S100B was found to be consistently elevated, although its concentration was not related to brain tissue levels [22, 23]. Nevertheless, in healthy female humans, serum S100B has been correlated with its concentration in oligodendrocytes, particularly in the frontal, parietal, corpus callosum, dorsolateral prefrontal, and temporal white matter [24, 25], and, to a lesser degree, in the dorsolateral prefrontal and temporal cortices . Thus, the serum levels of S100B may represent white matter structural changes, which, at the cellular level, indicate that this serum mediator might be a proxy of neuroglia changes. Thus, the indirect assessment of CS is valuable because it would demonstrate the role of neuroglia in this pathological phenomenon . Although astrocytic S100B has been correlated with serotonergic drug activity [19, 26], our study did not assess neither adjust for serotonergic parameters or psychotropic drugs to address this possible correlation in the present sample.
BDNF had previously been studied in FM, and although its serum [27, 28], plasma  and cerebrospinal fluid  levels have been consistently found to be elevated compared with controls, its association with PPT has not been previously reported in FM. A relationship between BDNF and the PPT has been previously described in healthy volunteers, and its direction is dependent on gender, where females exhibit proportional PPT and BDNF, while males demonstrate an inverse relationship . Although our female FM sample had a response that contrasted to that found in healthy females and was similar to the samples of healthy males, we cannot exclude the possibility that menopause could be involved in the observed effect, due to the mean age of our sample and the lack of control for hormonal levels in our study . The serum BDNF relationship with PPT may be tracked at different levels, because BDNF is widely distributed in the CNS and its binding to its high-affinity trkB receptor enhances C fiber-evoked responses, thereby activating signaling pathways in the spinothalamic track and subsequently strengthening excitatory synapses while promoting disinhibition of descending pathways .
Using different neuroimaging approaches (i.e., magnetoencephalograpy (MEG) , functional magnetic resonance imaging (fMRI) , proton magnetic resonance spectroscopy (H-MRS) ), it has been shown that lower PPT is correlated with higher brain activation in FM compared to controls. Lower PPT has also been associated with higher concentrations of glutamate within the posterior insula, which supports the finding of enhanced excitatory neurotransmission in FM . Furthermore, single nucleotide polymorphisms (SNPs) in the gene encoding the catechol-O-methyltransferase (COMT) (i.e., met/met genotype Val158Met SNP), which has also been postulated to contribute to the pathogenesis of FM, have been correlated with lower PPT . Taken together, these findings support the validity of using PPT in FM as a proxy for these hypothesized pathophysiological mechanisms. Our results further suggest that the PPT might also represent the CS mechanisms involved in FM, because lower PPT is correlated with higher BDNF and S100B, which are mediators involved in CS. Also, the WPI was inversely correlated with the PPT, indicating that those with lower threshold tend to present greater number of painful areas.
Other clinical characteristics were also correlated with serum BDNF and S100B. The inverse correlation of age with BDNF has been previously described in healthy subjects  but not in FM patients. As a component of the regression modeling, the effect of other confounders on the association between PPT and serum mediators was adjusted. In more than half of our sample, a major depression disorder in the MINI was identified, thereby representing a higher prevalence than previously reported in a Canadian representative survey . Nevertheless, these differences may be attributed to different diagnostic and sampling methods employed by the study. Importantly, chronic pain is strongly associated with depressive symptoms [37, 38], which limits the extent to which this potential confounding factor may be controlled, because it is a component of chronic pain syndromes. Psychiatric disorders are expected to affect the association of the PPT and serum mediators studied; however, only the obsessive compulsive disorder, which is a component of the spectrum of anxiety disorders, showed an effect on serum BDNF. Although other studies have failed to demonstrate that serum BDNF levels differ between FM and controls with comparable anxiety levels , we cannot conclude that anxiety itself  or the associated antidepressant drugs  used had an effect on both BDNF and S100B levels. Because we only recruited females in our sample, care should be taken when extrapolating for the male population because the association of BDNF with PPT is correlated with gender in healthy subjects  and male FM patients present lower PPT compared to females .
Because CS is conceptualized as a continuum phenomenon in which FM lies at one of its extremes  and PPT is proportionally associated with alterations in genetic and cortical activation in the FM, our findings suggest that the serum assessment of BDNF and S100B may also be considered as a proxy of the CS spectrum in FM. A serum test related to CS and available for clinicians would provide patients and caregivers with an additional tool to improve their understanding of FM, and would help to alleviate the burden of suffering or accompanying a condition that is unfortunately socially perceived as occurring “all in the head” of patients. The cross-sectional nature of our study design does not allow for the inference of causality, and thus, future studies are required to determine how these mediators may be responsible of the reduction in PPT in FM patients, and if they may represent biomarkers for this condition. Besides that, because our study did not include healthy controls, care must be taken regarding generalization out of the FM population. Also, it is worth noting that as expected for the characteristics of the disease, plenty of patients in our sample used psychotropic drugs including antidepressants, which have been associated with modulation of the BDNF . Taken together, these findings may be applicable for clinical use to define therapeutic approaches, particularly considering that PPT is a quantitative clinical tool to assess tenderness and sensitization in FM with good reproducibility and discrimination ability [22–24]. Because genetic  and neuroimaging studies [26–28] have consistently shown its association with changes attributed to the CS, PPT may also be considered as a powerful tool for translational purposes in FM research.