tDCS for fibromyalgia treatment

Although several studies have supported the efficacy of transcranial direct current stimulation (tDCS) for pain relief in fibromyalgia patients, recent review studies conclude that the effects reported are low or non-significant. The main limitations of the field are:

  • The lack of controlled studies, with sham conditions and long-term follow-ups, and with an adequate selection and assessment of the main symptoms of fibromyalgia in the pre-and post-treatment.
  • The use of unspecific brain targets (i.e. primary motor cortex, M1, or dorsolateral prefrontal cortex, DLPFC), with no previous attempt to apply tDCS in regions specifically involved in pain, as the operculo insular cortex (OIC).

 

The main objective of this project was to test the efficacy of tDCS on cognitive functioning and core symptoms of fibromyalgia, comparing three cortical targets (M1, DLPFC, and OIC) and a sham stimulation group. Also, we analysed the long-term tDCS effects, with follow-ups after 6 and 12 months.

RESULTS & CONCLUSIONS

  • Both active and sham tDCS produced an alleviation of the main symptoms of fibromyalgia: clinical and experimental pain, fatigue, cognitive problems, and sleep disorders. This improvement was maintained for at least 6 months.

Active tDCS appears to be more effective than placebo sham stimulation in relieving depressive symptomatology in patients with fibromyalgia. However, the evidence for this effect was not sufficiently robust.

 

  • Throughout the 15 tDCS sessions, a reduction in pain was observed. However, this evolution fluctuated, precluding the estimation of a minimum number of sessions necessary to alleviate this symptom.
  • tDCS is a safe technique and was well tolerated by patients with fibromyalgia; after the sessions, the patients showed no adverse effects.
  • After the 15 tDCS sessions (active and placebo), patients with fibromyalgia showed an improvement in their quality of life and a reduction in the impact of the disease in their lives. These effects were clinically significant and were maintained for at least 6 months.
  • tDCS (active and placebo) caused an improvement in the cognitive performance of patients with fibromyalgia and facilitated a larger allocation of attentional neural resources to stimulus processing during cognitive task execution.
  • There was no difference in the effects of tDCS between the cortical targets selected for the stimulation (M1, CPFDL, and COI) in any of the variables analysed.
  • Our results cast doubt on the efficacy of tDCS as a treatment for fibromyalgia and highlight the importance of the placebo effect.

 

ensayo clinico bap

Publications

 

  • Fernandez-Feijoo, F., Samartin-Veiga, N., & Carrillo-de-la-Peña, M. T. (2022). Quality of life in patients with fibromyalgia: Contributions of disease symptoms, lifestyle and multi-medication. Frontiers in Psychology, 13, 924405. Doi: 10.3389/fpsyg.2022.924405
  • Samartin-Veiga, N., González-Villar, A. J., Pidal-Miranda, M., Vázquez-Millán, A., & Carrillo-de-la-Peña, M. T. (2022). Active and sham transcranial direct current stimulation (tDCS) improved quality of life in female patients with fibromyalgia. Quality of Life Research, 31, 2519-2534. Doi: 10.1007/s11136-022-03106-1
  • Samartin-Veiga, N., Pidal-Miranda, M., González-Villar, A. J., Bradley, C., Garcia-Larrea, L., O’Brien, A. T., & Carrillo-de-la-Peña, M. T. (2021). Transcranial direct current stimulation of 3 cortical targets is no more effective than placebo as treatment for fibromyalgia: a double-blind sham-controlled clinical trial. Pain, 163(7), e850-e861. Doi: 10.1097/j.pain.0000000000002493
  • Gil-Ugidos, A., Rodriguez-Salgado, D., Pidal-Miranda, M., Samartin-Veiga, N., Fernández-Prieto, M., & Carrillo-de-la-Peña, M. T. (2021) Working memory performance, pain and associated clinical variables in women with fibromyalgia. Frontiers in Psychology, 12. Doi: 10.3389/fpsyg.2021.747533

Detection of genetic biomarkers of fibromyalgia

In this project, we aimed to identify genetic biomarkers of fibromyalgia (FM), mainly in the GABAergic and glutamatergic neurotransmission pathways, using a Discordant Sib Pair (DSP) approach, a particular design of the Family Based Association Tests (FBAT). We recruited 556 FM patients and 395 of their relatives from the nuclear family. Besides blood extractions, a complete assessment (including ACR 2010 criteria, clinical history interview, and scales to evaluate the core symptoms of FM) was performed for both patients and relatives.

dolor-cronico

RESULTS & CONCLUSIONS

The genetic association study analysing 41 SNPs identified a genetic biomarker (SNP rs6454674 in the cannabinoid receptor one gene, CNR1) associated with co-occurring depression in FM patients. No significant associations were evidenced comparing FM patients and their healthy relatives. Other SNPs were identified in subgroups of FM patients characterised by depression and sleep disturbance. The data related to rs4680 (COMT gene) were not available in this first analysis and are currently being analysed.

DNA methylation was also analysed through bisulfite sequencing in candidate regions in a restricted group of FM patients and controls. The analysis brought the focus on the GCSAML gene, pointing out the connection with potential immune system dysfunction in FM patients.

The results suggest the need to approach FM using clinical subgroups of patients defined by specific sub-phenotypes or comorbidities. Replication of these contributors could be essential for understanding FM molecular pathophysiology and possible differentiated interventions.

Publications

  •  Gerra, M. C., Carnevali, D., Pedersen, I. S., Donnini, C., Manfredini, M., González-Villar, A., … & Carrillo-De-La-Peña, M. T. (2021). DNA methylation changes in genes involved in inflammation and depression in fibromyalgia: a pilot study. Scandinavian Journal of Pain, 21(2), 372-383. Doi: 10.1515/sjpain-2020-0124
  • Gerra, M. C., González-Villar, A., Arendt-Nielsen, L., Pedersen, I. S., Triñanes, Y., Donnini, C., … & Carrillo-de-la-Peña, M. T. (2021). A family-based study to identify genetic biomarkers of fibromyalgia: consideration of patients’ subgroups. Clin Exp Rheumatol, 39(130), S144-S152. Doi: 10.55563/clinexprheumatol/bq7x9n
  • Trinanes, Y., González‐Villar, A., Gómez‐Perretta, C., & Carrillo‐de‐la‐Peña, M. T. (2015). Suicidality in chronic pain: predictors of suicidal ideation in fibromyalgia. Pain Practice, 15(4), 323-332. Doi: 10.1111/papr.12186

EEG Biomarkers of Fibromyalgia

Although considerable progress has been made in the last decades in the understanding of fibromyalgia (FM), its aetiology and pathophysiology are still not fully understood. It has been proposed that the hypersensitivity shown by patients with FM could be a consequence of a dysfunctional perceptual (generalised hypervigilance) and attentional (biases) pattern, which would contribute to both the development and maintenance of the disease; however, the existing evidence is inconclusive.

 

The main aim of this project was to explore the presence of possible dysfunctions in cortical inhibition mechanisms, increases in brain response to non-painful stimuli, and attentional biases towards disease-related stimuli in women with FM. For this purpose, electroencephalographic (EEG) activity has been studied in 63 patients with FM and 60 healthy controls, during the execution of widely researched and validated tasks (P50 paradigm, tasks using intense stimulation, emotional Stroop). The results obtained do not confirm deficits in sensory modulation at the pre-attentional level, nor a greater brain response to stimuli of increasing intensity, nor an attentional bias towards negative words and words related to the disease different to that of healthy people. In some tasks, a significant effect of medication was found, which could have affected the pattern of results. In addition, EEG indices suggest that FM patients devote less attentional resources during task performance. In spontaneous EEG activity, patients with FM showed increased beta band connectivity between different brain networks and alterations in some microstates parameters. These alterations, that are related to the dominance of endogenous top-down influences, can explain the limited processing of novel external events and the deterioration of flexible behavior and cognition frequently reported for FM.

 

Overall, the results did not support the hypothesis of generalised hypervigilance or the presence of attentional biases. Nevertheless, the study showed the need to consider subgroups of patients

Publications

  • Samartin-Veiga, N., González-Villar, A. J., Triñanes, Y., Gómez-Perretta, C., & Carrillo-de-la-Peña, M. T. (2020). Effects of intensity, attention and medication on auditory-evoked potentials in patients with fibromyalgia. Scientific Reports, 10(1), 1-12. Doi: 10.1038/s41598-020-78377-0
  • González-Villar, A. J., Triñanes, Y., Gómez-Perretta, C., & Carrillo-de-la-Peña, M. T. (2020). Patients with fibromyalgia show increased beta connectivity across distant networks and microstates alterations in resting-state electroencephalogram. Neuroimage, 223, 117266.
  • Gómez-Perretta, C., Triñanes, Y., González-Villar, A. J., & Carrillo-de-la-Peña, M. T. (2016). Evaluation of the accuracy of several symptoms and domains in distinguishing patients diagnosed with fibromyalgia from healthy controls. Clinical and Experimental Rheumatology, 34(2 Suppl 96), S14-25. PMID: 26812139.
  • Carrillo-de-la-Peña, M. T., Triñanes, Y., González-Villar, A., Romero-Yuste, S., Gómez-Perretta, C., Arias, M., & Wolfe, F. (2015). Convergence between the 1990 and 2010 ACR diagnostic criteria and validation of the Spanish version of the Fibromyalgia Survey Questionnaire (FSQ). Rheumatology International, 35(1), 141-151. Doi: 10.1007/s00296-014-3074-3
  • Carrillo‐de‐la‐Peña, M. T., Triñanes, Y., González‐Villar, A., Gómez‐Perretta, C., & García‐Larrea, L. (2015). Filtering out repetitive auditory stimuli in fibromyalgia: A study of P50 sensory gating. European Journal of Pain, 19(4), 576-584. Doi: 10.1002/ejp.627
  • Trinanes, Y., González‐Villar, A., Gómez‐Perretta, C., & Carrillo‐de‐la‐Peña, M. T. (2015). Suicidality in chronic pain: predictors of suicidal ideation in fibromyalgia. Pain Practice, 15(4), 323-332. Doi: https://doi.org/10.1111/papr.12186
  • Triñanes, Y., González-Villar, A., Gómez-Perretta, C., & Carrillo-de-la-Peña, M. T. (2014). Profiles in fibromyalgia: algometry, auditory evoked potentials and clinical characterization of different subtypes. Rheumatology International, 34(11), 1571-1580. Doi: 10.1007/s00296-014-3007-1
  • González-Villar, A. J., Triñanes, Y., Zurrón, M., & Carrillo-de-la-Peña, M. T. (2014). Brain processing of task-relevant and task-irrelevant emotional words: An ERP study. Cognitive, Affective, & Behavioral Neuroscience, 14(3), 939-950. Doi: 10.3758/s13415-013-0247-6

Cognitive dysfunction in FM

Cognitive dysfunction is very frequent in chronic pain syndromes, such as fibromyalgia (FM), and encompasses both objective difficulties, measured through neuropsychological tests, and self-reported complaints. Previous studies do not show consistent results on the specific cognitive domains impaired nor on their relationship with subjective complaints or clinical symptoms. In this project, we delved into the study of subjective dyscognition, finding that 95% of FM patients report moderate to severe memory problems, which appear to be associated with depression and fatigue, having a significant functional impact on the patients’ daily lives. Also, we explored the neuropsychological performance of the patients in executive processes (inhibitory control, working memory) and found no significant difference from healthy controls in their overall performance. Our results also suggested a disconnection between neuropsychological performance and subjective complaints.

 

Despite the absence of impairments at the behavioral level, patients showed alterations in electroencephalographic markers, with reduced modulation of posterior alpha and midfrontal theta power during working memory and motor inhibition tasks. The FM patients also showed lower functional connectivity between midfrontal scalp locations and rest of the areas in the theta band, suggesting greater difficulty in mobilizing and maintaining cognitive resources.

Publications

 

  • Gil-Ugidos, A., Rodriguez-Salgado, D., Pidal-Miranda, M., Samartin-Veiga, N., Fernández-Prieto, M., & Carrillo-de-la-Peña, M. T. (2021). Working memory performance, pain and associated clinical variables in women with fibromyalgia. Frontiers in Psychology, 12. Doi: 10.3389/fpsyg.2021.747533 
  • Pidal-Miranda, M., González-Villar, A. J., & Carrillo-de-la-Peña, M. T. (2019). Pain expressions and inhibitory control in patients with fibromyalgia: behavioural and neural correlates. Frontiers in Behavioral Neuroscience, 12, 323.Doi: 10.3389/fnbeh.2018.00323.
  • González-Villar, A. J., Arias, M., & Carrillo-de-la-Peña, M. T. (2019). Brain electrical activity associated with visual attention and reactive motor inhibition in patients with fibromyalgia. Psychosomatic medicine, 81(4), 380-388.
  • Pidal-Miranda, M., González-Villar, A. J., Carrillo-de-la-Peña, M. T., Andrade, E., & Rodríguez-Salgado, D. (2018). Broad cognitive complaints but subtle objective working memory impairment in fibromyalgia patients. PeerJ, 6, e5907. https://doi.org/10.7717/peerj.5907
  • González‐Villar, A. J., & Carrillo‐de‐la‐Peña, M. T. (2017). Brain electrical activity signatures during performance of the Multisource Interference Task. Psychophysiology, 54(6), 874-881.
  • González-Villar, A. J., Pidal-Miranda, M., Arias, M., Rodríguez-Salgado, D., & Carrillo-de-la-Peña, M. T. (2017). Electroencephalographic evidence of altered top–down attentional modulation in fibromyalgia patients during a working memory task. Brain Topography, 30(4), 539-547. Doi: 10.1007/s10548-017-0561-3