Disrupted functional connectivity of the pain network in fibromyalgia

Objective: To investigate the impact of chronic pain on brain dynamics at rest. Methods: Functional connectivity was examined in patients with fibromyalgia (FM) (n = 9) and healthy controls (n = 11) by calculating partial correlations between low-frequency blood oxygen levelYdependent fluctuations extracted from 15 brain regions. Results: Patients with FM had more positive and negative correlations within the pain network than healthy controls. Patients with FM displayed enhanced functional connectivity of the anterior cingulate cortex (ACC) with the insula (INS) and basal ganglia ( p values between .01 and .05), the secondary somatosensory area with the caudate (CAU) (p = .012), the primary motor cortex with the supplementary motor area (p = .007), the globus pallidus with the amygdala and superior temporal sulcus (both p values G .05), and the medial prefrontal cortex with the posterior cingulate cortex (PCC) and CAU (both p values G .05). Functional connectivity of the ACC with the amygdala and periaqueductal gray (PAG) matter (p values between .001 and .05), the thalamus with the INS and PAG (both p values G .01), the INS with the putamen (p = .038), the PAG with the CAU (p = .038), the secondary somatosensory area with the motor cortex and PCC (both p values G .05), and the PCC with the superior temporal sulcus (p = .002) was also reduced in FM. In addition, significant negative correlations were observed between depression and PAG connectivity strength with the thalamus (r = j0.64, p = .003) and ACC (r = j0.60, p = .004). Conclusions: These findings demonstrate that patients with FM display a substantial imbalance of the connectivity within the pain network during rest, suggest- ing that chronic pain may also lead to changes in brain activity during internally generated thought processes such as occur at rest. Key words: fibromyalgia, chronic pain, resting state, functional connectivity, partial correlation analysis.Fil: Cifre, Ignacio. No especifíca;Fil: Sitges, Carolina. No especifíca;Fil: Fraiman, Daniel. Universidad de San Andrés; ArgentinaFil: Muñoz, Miguel Ángel. No especifíca;Fil: Balenzuela, Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires; ArgentinaFil: González Roldán, Ana. No especifíca;Fil: Martínez Jauand, Mercedes. No especifíca;Fil: Birbaumer, Niels. No especifíca;Fil: Chialvo, Dante Renato. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Montoya, Pedro. No especifíca

Factores genéticos y psicosociales implicados en la modulación del dolor

La La sensibilidad al dolor y el riesgo sufrir dolor crónico representan fenómenos complejos de naturaleza multidimensional, con una importante variabilidad interindividual. El objetivo de esta tesis doctoral se centró en explorar los factores genéticos y psicosociales implicados en la modulación del dolor y el riesgo a sufrir dolor crónico mediante seis estudios. Los dos primeros exploraron el efecto de factores genéticos y de la edad de inicio de la menopausia en la sensibilidad al dolor en pacientes con fibromialgia en comparación con voluntarias sanas. El primer estudio reveló un incremento de la frecuencia de alelos asociados a una reducida actividad de la enzima COMT en pacientes con síndrome de fibromialgia, junto con una elevada sensibilidad al dolor en estos grupos. El segundo estudio mostró que las pacientes con fibromialgia presentaron una edad de inicio de la menopausia más temprana que las controles. Asimismo, se encontró que las pacientes con menopausia temprana mostraban mayor sensibilidad al dolor que las pacientes con aparición tardía de la menopausia. Los dos siguientes examinaron el papel de factores genéticos en la actividad metabólica cerebral asociada al dolor, la respuesta de analgesia por placebo y en una tarea de funciones ejecutivas. El tercer estudio reveló que el alelo met66 del polimorfismo Val66Met en el gen BDNF se asociaba a un fenotipo de vulnerabilidad, resistencia a la analgesia por placebo, incrementos en la actividad dopaminérgica durante el procesamiento de dolor y reducciones durante la condición placebo. Asimismo, se observó que estos efectos eran dependientes del género del sujeto, con una mayor exacerbación en mujeres y con efectos nulos en hombres. El cuarto estudio mostró aumentos en la actividad del sistema opioide asociados a la respuesta de analgesia por placebo en portadores del alelo C del polimorfismo funcional C385A del gen FAAH. Por otro lado, no se encontraron diferencias significativas debidas a este polimorfismo en la respuesta al dolor en ausencia de placebo, ni en la activación del sistema dopaminérgico. Finalmente, los dos últimos estudios exploraron la modulación social analizando cambios en la actividad eléctrica cerebral como consecuencia de la observación de dolor y tacto en otros. El quinto estudio mostró diferencias en los potenciales evocados visuales en función de la percepción de expresiones faciales de dolor y enfado. El sexto estudio reveló que la observación de experiencias somatosensoriales dolorosas y no dolorosas en otras personas modulaba la amplitud de los potenciales somatosensoriales. Todos estos datos subrayan la naturaleza multidimensional de la respuesta al dolor y resaltan el papel de los factores genéticos y psicosociales en la persistencia del dolor a lo largo del tiempo.Pain sensitivity and risk for chronic pain constitute complex multidimensional phenomena that vary significantly among individuals. The objective of the present Doctoral Thesis was focused on exploring genetic and psychosocial factors involved in the modulation of pain and chronic pain risk throughout six studies. The first two studies explored the effect of genetic factors and age-of-onset of menopause in pain sensitivity in fibromyalgia patients as compared to healthy volunteers. The first study showed an increased frequency of alleles associated with a reduced activity of COMT enzyme in patients with fibromyalgia syndrome, coupled with high sensitivity to pain in these groups. The second study showed that patients with fibromyalgia had an ageof- onset of menopause earlier than controls. We also found that patients with early menopause showed higher pain sensitivity than patients with late age-of-onset of menopause. The next two studies explored brain metabolic activity in response to pain and placebo analgesia and during an executive function task. The third study revealed that met66 allele of the Val66Met polymorphism in the BDNF gene was associated with a phenotype of vulnerability, strength, placebo analgesia, increases in dopaminergic activity during the processing of pain and reductions during the placebo condition. It was also noted that these effects were dependent on gender, being exacerbated in women as compared to men. The fourth study showed increases in placebo analgesia and in placebo-induced opioid activity in the C385 allele of the functional polymorphism C385A of the FAAH gene. Furthermore, there were no significant differences due to this polymorphism in the pain response in absence of placebo, or in dopaminergic system activation. Finally, the latter two studies explored the social modulation of brain electrical activity during observation of pain and somatosensory experiences in other´s. The fifth study showed differences in visual evoked potentials during the sight of pain and anger faces. The sixth study showed that observation of painful and non-painful experiences in others modulated the amplitude of somatosensory evoked potentials in the onlooker. These data underscore the multidimensional nature of pain response and highlight the role of genetic and psychosocial factors in the persistence of pain