dc.description.abstracteng | The lack of effective treatments for managing pain and associated symptoms in
fibromyalgia (FM) poses both a clinical challenge and an economic burden on the health
sector. Typical FM therapies include an array of pharmacological and non-pharmacological
interventions. Commonly used drugs have demonstrated only mild improvements in FM while
benefitting only a minority of patients. In this scenario, repeated anodal transcranial direct
current stimulation (tDCS) and mindfulness-based interventions have emerged as two promising
non-pharmacological treatments for pain relief and improvement of FM-associated symptoms.
However, the strength and durability of the therapeutic benefits of these methods vary across
studies. The combination of non-pharmacological therapies has been proposed as a way to
optimise and bolster the therapeutic effects of monomodal interventions. Although the
combination of tDCS and mindfulness meditation (MM) has shown synergistic effects in both
healthy individuals and patients with neuropsychiatric disorders and some chronic pain
conditions, it has not yet been investigated in patients with FM. The rationale behind exploring
this combination was to modulate the brain state via MM, with the goal of boosting the
neuroplastic effects of currently recommended conventional tDCS protocols for chronic pain.
In this dissertation, the current state of the literature on combining these two methods was
reviewed. A sham-controlled randomised pilot clinical study was conducted to test the
preliminary therapeutic efficacy and safety of a ten-day intervention concurrently applying
anodal tDCS targeting the left primary motor cortex (M1) and MM, administered as a clinicbased treatment, in patients with FM. Prior to the combined therapy, participants received a fiveday training in MM. Patients in the active tDCS group reported a larger clinically meaningful
improvement in quality of life following the combined intervention, compared to those receiving
sham tDCS paired with MM or treatment-as-usual. No differences in pain reduction and
improvements in sleep quality or psychological well-being were observed among the groups.
Building on these findings and addressing the limitations of the pilot study, we investigated the
therapeutic and mechanistic impact of a ten-day treatment combining anodal tDCS over the left
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M1 and MM on pain relief, quality of life, and associated symptoms in individuals with FM
trained in mindfulness. Participants in this trial completed a four-week brief mindfulness
intervention tailored for FM (BMIF) prior to randomisation. The combined treatment was
administered as an at-home intervention under remote supervision. To investigate the possible
underlying mechanisms, we measured changes in cortical excitability using transcranial
magnetic stimulation (TMS) of the left M1. Finally, we implemented a responder analysis
approach to decipher the effects of the BMIF and the add-on combination of tDCS and MM
with regard to emotion regulation (ER), which is one of the primary targets mediating
improvement in symptom burden and management in FM. Although patients showed
improvements in clinical symptoms, no superior therapeutic benefits were observed when
pairing MM with anodal tDCS, compared to the combination of MM with sham tDCS. Both
groups demonstrated substantial and acute pain relief and improvements in quality of life, sleep
quality, affect, and psychological well-being following the combined intervention. The lack of
group differences in TMS metrics failed to provide meaningful insights into the potential
synergistic mechanisms of tDCS and MM. Interestingly, clinical responders to the combined
intervention in the active tDCS group exhibited impaired ER compared to the sham group, even
suggesting potential antagonistic effects of pairing M1-tDCS with MM for ER. Moreover, the
reduction of the cortical excitability of the left M1, likely mediated by daily MM practice, might
block the mechanistic consequences of anodal tDCS of the left M1. On the other hand, the nonspecific main effect of time in clinical outcomes, alongside a large significant increase in
mindfulness over time, hints at a potential ‘mindfulness effect’, in line with previous studies
showing that longer MM practice results in greater therapeutic benefits in FM.
The introduction of the Medical Device Regulation in 2021 and the recent reclassification of
some of the non-invasive brain stimulation (NIBS) devices (for example, tDCS and TMS) to
the same risk level as invasive deep brain stimulation in the European Union have imposed a
considerable hindrance to the research and further development of tDCS. A multinational
participatory study including different stakeholders involved in the consumption, use,
manufacturing, and regulation of NIBS was conducted to address the clinical, academic, legal,
ethical, and social concerns surrounding NIBS. The different stakeholders’ perspectives were
analysed and compiled to draft a set of recommendations for the use and regulation of NIBS,
including tDCS in the European subcontinent. To improve the accessibility of tDCS to patients,
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the optimisation of currently available NIBS treatments via broader administration and further
development of home-based tDCS as well as personalisation of therapy have been suggested by
the stakeholders. Stricter regulation of tDCS for non-medical reasons and research focused on
higher effectiveness of tDCS, underlying mechanisms, and development of responders were
also proposed, among others.
Taken together, our work challenges the combination of M1-tDCS and MM as a strategy to
optimise tDCS treatment for pain relief and symptom improvement in patients with FM.
However, this dissertation highlights the pivotal role of clinical research regarding combined
interventions, whereby two therapies beneficial on their own might not necessarily be more
effective when combined. Future research should explore the additional effect of combining
MM and tDCS compared to tDCS and MM alone and delve deeper into the workings of the
combined intervention using more sophisticated neuroimaging tools, with the goal of
developing novel and individualised methods to optimise the currently available NIBS
technologies for the treatment of FM. | de |