Influencia del polimorfismo Val158Met del gen de la catecol O-metiltransferasa (COMT) sobre la disfunción cognitiva y la percepción de fatiga en pacientes con fibromialgia

Introduction and aim of investigation. Pain is defined as an unpleasant sensation caused by actual or potential harm. In some cases, pain can be sustained over time, leading chronic pain disorders that have not only health but also economic, social and emotional consequences. Among chronic pain disorders, fibromyalgia syndrome is one of the most prevalent. Fibromyalgia has been defined as a chronic, with no standardised treatment and an unknown aetiology. Among the factors that have been reported as predisposing to this disease genetics factor has become one of the most interesting, although the influence of other social or environmental factors has not been ruled out. Specifically, the rs4680/Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene has been consistently associated with severity of pain, anxiety or depression in fibromyalgia. Despite this evidence, studies that have investigated the relationship between different COMT genotypes and other physical and affective symptoms, such as fatigue or fear of pain, has so far been less explored. Similarly, the relationship between genetic factors and cognitive dysfunction related to working memory in fibromyalgia has not been explored to date. Thus, the aim of this Doctoral Thesis was to explore the relationship between these genetic factors (specifically COMT genotypes) and physical, affective and cognitive symptoms (working memory) using various methodologies such as psychological and neuropsychological tests, as well as techniques for recording electrical brain activity (ERP).

Methods. To explore the relationship between genotypes of the Val158Met/rs4680 polymorphism of the COMT and the different symptoms that are prevalent in fibromyalgia syndrome (physical, affective and cognitive symptoms), three studies were carried out. In the first one, a total of 185 women took part, 108 women diagnosed with fibromyalgia and 77 women without chronic pain. Several psychological tests and visual-analogue scales were administered to assess physical and affective symptoms. Specifically, the Beck Depression Inventory (BDI) was used to assess the level of depression, while the State-Trait Anxiety Inventory (STAI-R/STAI-E) was administered to assess anxiety. Pain catastrophizing was assessed with the Pain Catastrophizing Scale (PCS), the fear of pain with the Fear of Pain Questionnaire (FPQ-III) and fear of movement using the Tampa Scale of Kinesiophobia (TSK). Finally, physical symptoms such as pain and fatigue were assessed with visual-analogue scales (VAS for pain and VAS for fatigue). In the second study, several neuropsychological tests were used to explore the spatial and verbal working memory performance of patients with fibromyalgia and healthy controls. Specifically, 167 women took part in this study (86 had a diagnosis of fibromyalgia and 81 healthy women matched on educational level and age) and completed the working memory tasks of the Weschler Memory Scale III (WMS-II): Letters and Numbers and Spatial Span Test. Finally, in the third and last study comprising the present Doctoral Thesis, the spatio-temporal neural dynamics associated with working memory processing were explored using a spatial N-back paradigm using event-related potentials (ERPs). A saliva sample was collected to genotype the COMT gene in all participants in the studies (patients and controls), allowing us to explore the relationship between these genotypes and the physical, affective and cognitive symptoms reported in the different studies.

Results. In the first study, results showed that patients with fibromyalgia carrying the Met/Met genotype reported higher levels of fatigue than patients bearing the Met/Val genotype. However, no statistical differences in self-reported fatigue levels were observed between patients carrying the Met/Met and Val/Val genotypes. The most relevant results of this study showed that medical fear of pain was able to modulate, only, the relationship between fibromyalgia patients carrying the methionine allele (Met/Met or Met/Val) and reported fatigue. In the second study, we observed that our results converge with previous literature, confirming the presence of cognitive dysfunction in working memory in fibromyalgia patients. More interestingly, our results showed a significant influence of the COMT gene (Val158Met polymorphism) on the working memory performance of patients. Thus, fibromyalgia patients carrying the Val/Val genotype showed significantly worse scores than those participants in the control group carrying the same genotype. This effect was obtained for the Span of Spatial Span Test backward, Spatial Span Test backward score, Spatial Span Test total score (sum of Spatial Span Test forward and backward) and the Working Memory Index of the WMS-III. In addition, patients with fibromyalgia who were homozygous for valine (Val/Val) scored significantly worse on Spatial Span Test backward score and Spatial Span Test total than patients who were heterozygous (Met/Val). Regarding the last study, patients with fibromyalgia showed longer reaction times and higher error rates than healthy control participants. Furthermore, the genotypes of the Val158Met/rs4680 polymorphism of the COMT gene were able to modulate electrophysiological activity during the spatial N-back task. Thus, fibromyalgia patients carrying the Val/Val genotype exhibited a greater amplitude of the frontocentral P2 component compared to carriers of the same genotype in the control group. Unexpectedly, our data do not confirm the relationship between COMT gene genotypes and modulation of amplitudes of the P3 component in any scalp region.

Conclusions. The results obtained in the present investigation provide evidence about the influence of the genotypes of the rs4680/Val158Met polymorphism of the COMT gene on different symptomatology of fibromyalgia syndrome. Briefly, the Met/Met genotype of the COMT gene has been shown to be associated with more severe presentation of physical symptoms, such as fatigue. In addition, affective symptoms (fear of pain) may modulate the presentation of fatigue in genetically predisposed fibromyalgia patients (carriers of the Met allele). On the other hand, the influence of COMT gene genotypes on cognitive symptoms follows a different pattern. In this case, the Val/Val genotype in fibromyalgia patients seems to be associated with worse cognitive symptoms, as shown by our data on spatial working memory tasks. This different pattern could be explained by the wide and varied pathophysiological effect associated with the genotypes of the COMT gene, which would affect differently the most prevalent symptoms of the disease.

Furthermore, the Val/Val genotype is not only associated with poorer behavioural performance in working memory tasks, but also with an electrophysiological pattern reflected by higher amplitudes of the P2 component in patients with fibromyalgia bearing Val/Val genotype. This genotype influence seems to be more evident in working memory sub-processes associated with executive attention, linked to P2 amplitude modulation. However, the implementation of switch and updating sub-processes in working memory do not seem to be sensitive to the effect of the different genotypes of the COMT gene. Taken together, these data could partly explain the extent and variability in the severity of symptoms presented by fibromyalgia patients and could help to establish subgroups or patient profiles in order to establish interventions more tailored to the characteristics of the patients. Furthermore, the findings suggest the importance of cognitive aspects in the disease and the need for further knowledge on the extent and nature of these symptoms.

Studies described below have been developed thanks to various research projects funded by both national and regional public institutions: “Brain mechanisms related to attentional biases towards negative information in fibromyalgia: treatment by neurofeedback with fMRI” (PSI2017-85241-R), “The study of human emotion and its application to populations with difficulties of adaptation in the personal and social spheres (S2015/HUM-3327 EMO-CM)” and “Sapientia Project: In search of General Knowledge in Global Culture” (SAPIENTIA-CMH2019/HUM-5705)”.

This Doctoral Thesis begins with a general introduction to the relevant issues of the present research, describing the basic aspects of pain, as well as its perception. Subsequently, the characteristics of fibromyalgia syndrome, the definition of the disease, diagnostic criteria, prevalence, as well as its most relevant clinical aspects are presented in detail. Then, a section is reserved for the cognitive dysfunction of the disease and, specifically, working memory, as a key element in the presentation of the disease. Next, working memory is defined, some models are described and the relationship of this cognitive process with neural activity in both patients and the general population are explained. To conclude the first section, the relationship between the COMT gene fibromyalgia syndrome, working memory and the event-related potentials is presented. Subsequently, the three experiments that make up the current thesis are presented following the same structure. After a brief introduction, the methodology and results are presented in a more extended way, ending with a discussion of the relevant aspects of each research. To conclude this Doctoral Thesis, a section of general discussion and conclusions on the results reported in the three studies is included. The two publications derived from studies 1 and 2 that have been accepted at the time of finalising the manuscript are attached as Annex 1 and Annex 2.