Pairing transcranial direct current stimulation and mindfulness meditation in the treatment of fibromyalgia
by Perianen Ramasawmy
Date of Examination:2024-08-15
Date of issue:2024-08-22
Advisor:Prof. Dr. Andrea Antal
Referee:Prof. Dr. Melanie Wilke
Referee:Prof. Dr. Frank Petzke
Referee:PD Dr. Peter Dechent
Referee:Prof. Dr. Christine Stadelmann-Nessler
Referee:Dr. Nicola Strenzke
Persistent Address:
http://dx.doi.org/10.53846/goediss-10684
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Abstract
English
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 8 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, 9 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.
Keywords: transcranial direct current stimulation; mindfulness; meditation; non-invasive brain stimulation; fibromyalgia
