The review included patients diagnosed with fibromyalgia by local rheumatology associations or other formal institutions. Most studies excluded individuals receiving additional medication to prevent a potential impact on trial results. To ensure study homogeneity, female subjects were predominantly included, given the higher prevalence of fibromyalgia in women. Additionally, certain studies specified a minimum 6-month duration of chronic pain among participants to investigate its effects on individuals with prolonged pain experiences.

Most studies aimed to explore the impact of tDCS stimulation on pain, disability, and quality of life in fibromyalgia patients. The primary brain regions stimulated were M1 and DLPFC, typically with an intensity of 1–2 mA and a duration of 20 min. Randomized controlled trials commonly employed sham tDCS as controls, while only one study compared the effects of repetitive transcranial magnetic stimulation (rTMS) and tDCS on pain and quality of life in fibromyalgia patients (Forogh et al., 2021).

Most of the studies were randomized controlled trials, with five studies using a double-blind approach (Riberto et al., 2011; Villamar et al., 2013; Khedr et al., 2017; Caumo et al., 2022; Ramasawmy et al., 2022), two studies using a cross-over design (Valle et al., 2009; Villamar et al., 2013), and two studies exploring the long-term efficacy of tDCS (Cummiford et al., 2016; Silva et al., 2017).

This study primarily investigated the impact of tDCS stimulation on pain relief in fibromyalgia patients, focusing on pain outcome measures. Visual Analogue Scale (VAS), Numeric Rating Scale (NRS), and Pain Pressure Threshold (PPT) were chosen as the primary pain indicators. Most studies observed that applying 2 mA anodic tDCS to the M1 and DLPFC regions effectively alleviated pain (Roizenblatt et al., 2007; Valle et al., 2009; Villamar et al., 2013; Cummiford et al., 2016; Khedr et al., 2017; Silva et al., 2017; Kang et al., 2020; Forogh et al., 2021; Caumo et al., 2022).

The majority of literature in this study adopts quantitative research methods, primarily comparing the impacts of genuine and sham tDCS stimulation on pain and other functions in patients. While some studies reported no significant changes in pain with sham tDCS, one interesting finding contradicted this trend, suggesting that sham tDCS could exhibit similar analgesic effects, possibly linked to the placebo analgesic effect (Caumo et al., 2022).

“Transcranial Direct Current Stimulation” and “Fibromyalgia” served as MeSH Terms. On November 7, 2022, 75 pertinent studies were retrieved from the PubMed database, underwent manual screening, and ultimately, 18 relevant studies were included (Figure 1). The detailed search strategy is available in the Supplementary material. Research indicates that 10 sessions of anodal tDCS in the M1 region can decrease pain levels in fibromyalgia patients. The development of this condition may be linked to alterations in serum endorphin levels (Khedr et al., 2017). Whether applied singly or periodically, tDCS mitigates pain perception, and stimulating the DLPFC region proves beneficial for relieving fatigue (To et al., 2017). A single 2 mA, 20-min session of tDCS stimulation in the M1 and Supra-orbital area (SO) can yield positive clinical effects (To et al., 2017). Moreover, limited research has addressed enhancing functional connectivity in pain-related brain regions through tDCS. Future studies should employ multiple imaging techniques to observe changes in the brain mechanisms of tDCS analgesia (Caumo et al., 2022). Table 1 provides details on tDCS stimulus parameters and the results of the included studies.

With aberrant central nervous system excitability (Thabit et al., 2021), pain-processing brain regions in FMS sufferers are more hypersensitive to pressure stimuli than healthy people (Truini et al., 2015).

An abnormal mix of enhanced and reduced Functional Connectivity (FC) patterns across the pain matrix was found in individuals with FMS (Cifre et al., 2012), indicating the neural networks involved in pain perception and processing are functioning abnormally.

Anodal tDCS increases while cathodal decreases neural excitability in targeted areas (Pellicciari et al., 2013). A study (Auvichayapat et al., 2018) found that anodal tDCS on M1 increased neuronal activity in that area and decreased neuropathic SCI pain, implying that pain relief occurs by increasing M1 excitability, which is related to pain process (Zortea et al., 2019). Another study discovered that anodal tDCS targeting DLPFC increased DLPFC neural excitability, emotion, and pain relief in participants (Maeoka et al., 2012). Since the DLPFC regulates emotional pain perception, the change may affect how people perceive painful sensations. These synchronous changes suggest tDCS may be helpful to regulate abnormal pain processing and perception in FMS.

Patients with FMS displayed decreased FC between key pain-modulating regions (Jensen et al., 2012) and altered FC among pain process regions and sensorimotor areas (Flodin et al., 2014) relative to healthy individuals. Pain intensity correlates with FC sensory integration disturbances (Pujol et al., 2014). Polanía et al. (2012) found that anodal tDCS on M1 improved the FC between the left thalamus and ipsilateral M1 in healthy persons. Cummiford et al. (2016) found that anodal tDCS on the left M1 and cathodal tDCS on the right supraorbital cortex in FMS sufferers reduced FC between the left ventral posterolateral thalamus seed and left inferior parietal lobule, and FC between periaqueductal gray seed and posterior cingulate, followed by decreased pain. TDCS appears able to modulate disrupted FC in FMS, which may underlie its pain-relieving effects in these patients.

Moreover, tDCS can alter oscillatory activity of brain at a network level (Donaldson et al., 2019). These oscillations integrate and separate brain areas involved in sensory-painful perception and processing (Kim and Davis, 2021). Research found enhanced oscillations in the anterior cingulate and prefrontal cortex of FMS patients correlated with increased pain, fatigue, and stress during rest (Fallon et al., 2018). Another study demonstrated that a high-definition tDCS modulated oscillations and reduced FMS pain (Castillo-Saavedra et al., 2016). These alterations suggest that tDCS may reduce pain by modulating abnormal neural oscillations in FMS.

In all, tDCS may relieve FMS pain by modulating cortical excitability, FC, and neural oscillations.

Neuroinflammation refers to inflammatory processes within the central nervous system that are known to exacerbate pain sensations in FMS (Mendieta et al., 2016). An imbalance between pro- and anti-inflammatory cytokines in cerebrospinal fluid (CSF) is common in FMS. Studies showed increased pro-inflammatory chemokines/cytokines interleukin 1 (IL-1), IL-6, IL-8, and TNF-α, and decreased anti-inflammatory cytokines IL-4 and IL-10 in the CSF of FMS sufferers compared to healthy individuals (Ross et al., 2010; Mendieta et al., 2016). Moreover, microglia and mast cells (MCs) are engaged in FMS, activated to secrete more pro-inflammatory Cytokines (Theoharides et al., 2019). Pro-inflammatory cytokine dysregulation aggravates low-grade inflammation in CNS, activates or even sensitizes nociceptors, causes pain sensitization, and triggers hyperalgesia (Siracusa et al., 2021).

Transcranial direct current stimulation may reduce FMS pain by modulating neuroinflammation, possibly achieved by stimulating brain immune cells, such as MCs and glial cells, to regulate pro-inflammatory cytokines release. Research showed tDCS can reduce the activation of microglia (Walter et al., 2022), a type of essential glial cell in the neuroinflammatory process, thus decreasing the synthesis of TNF and other inflammatory mediators (Guo et al., 2020).

Animal models show that tDCS can change neuroinflammatory mediators. IL-1β (Lopes et al., 2020; Regner et al., 2020) and IL-6 (Guo et al., 2020) were reduced in the CNS structure of animals following tDCS stimulation, while IL-1α (Santos et al., 2020), IL-10 (Santos et al., 2020), and IL-4 (Lopes et al., 2019) were increased. Moreover, animals in these experiments showed analgesic response after tDCS stimulation, which provided a window into the pain relief caused by neuroinflammatory modulation. Human studies also confirmed the analgesic effect of tDCS caused by the regulation of neuroinflammation. A sham-controlled study found plasma IL-8 reduced significantly among bipolar disorder sufferers after using tDCS (Goerigk et al., 2021). In other studies, depressed individuals had a non-significant decrease in plasma IL-6 and TNF-α compared to the sham group after tDCS activation (Brunoni et al., 2014, 2018). These findings suggest tDCS may relieve FMS pain by modulating neuroinflammation through balancing pro- and anti-inflammatory cytokines. Further tDCS studies in FMS patients with a focus on cytokines are needed to confirm the consistency of the changed cytokine and analgesic response, verifying its ability to influence neuroinflammation for pain relief.

Pain in FMS may be associated with an impairment of excitatory and inhibitory neurotransmission (Harris, 2010). Abnormal levels of neurotransmitters were found in the CSF and brain of FMS patients, such as glutamate and substance P, serotonin (5-HT), noradrenaline, dopamine, and gamma-aminobutyric acid (GABA) (Clauw et al., 2011). Changed neurotransmitter levels increased pro-nociceptive transmission and reduced anti-nociceptive transmission. Changed endogenous cerebral opioid activation is another anomaly in FMS (Schrepf et al., 2016).

Transcranial direct current stimulation shows promise for reducing FMS pain by regulating neurotransmitters implicated in its complex pathophysiology. Increased levels of glutamate (excitatory) and reduced levels of GABA (inhibitory) contribute to FMS hyperalgesia (Harris, 2010; Pomares et al., 2020). Studies (Zhao et al., 2020; Lengu et al., 2021) show that tDCS can modulate cortical levels of GABA and glutamate, impacting neuronal signaling. Bifrontal tDCS (anode over left DLPFC and cathode over right DLPFC with a current of 2 mA) increased dopamine in the ventral striatum in healthy participants (Fonteneau et al., 2018). Research found that tDCS with an anode on the left and a cathode on the right DLPFC in healthy subjects enhanced left striatal GABA, correlated with increased right striatal dopamine, and decreased GABA in the left DLPFC (Bunai et al., 2021). Additional research shows tDCS can also affect serotonin (Brunoni et al., 2013) and noradrenaline (Mishima et al., 2019) release. Changes in transmitters induced by tDCS may activate pain inhibitory pathways to cause pain relief in FMS.

Deficiencies in an endogenous pain management system may induce widespread pain in FMS (Schrepf et al., 2016). The intrinsic pain-regulating system modulates spinal cord pain signals via the descending brainstem-to-spinal cord pathway. This system appears to be strengthened by TDCS to reduce pain signaling and thus relieve pain (DosSantos et al., 2018). Research also linked pain relief to increased beta-endorphin levels (Chaudhry and Gossman, 2021). A review found that tDCS enhances dysfunctional neuronal circuitries involved in the pain-descending inhibitory system associated with opioids, thereby reducing chronic non-cancer-related pain (Zortea et al., 2019). DosSantos et al. (2012) discovered that tDCS over M1 boosted the endogenous-opioid release and the experimental cold pain threshold in a subject with trigeminal neuropathic pain. Another clinical trial (Khedr et al., 2017) indicated that left M1 tDCS reduced pain, improved mood, and boosted β-endorphin levels in FMS sufferers. To summarize, tDCS affects glutamate, serotonin, noradrenaline, dopamine, GABA, and endogenous brain opioids. These modulations may explain tDCS’ analgesic impact.

People with FMS suffer abnormal rCBF and metabolism in pain-related regions, which may contribute to pain severity. Patients with FMS have lower CBF than controls in different brain regions, including the thalamus, caudate nucleus, pontine tegmentum, and basal ganglia (Kwiatek et al., 2000; Schmidt-Wilcke et al., 2007; Shokouhi et al., 2016). Given that these areas play a crucial role in processing and regulating pain, the reduction in CBF may be a major consideration in the heightened sensitivity to pain and chronic discomfort suffered by patients with FMS. Alterations in metabolism were also found in different regions of the brain in individuals with FMS (Guedj et al., 2008), which were related to how well the disorder would progress (Usui et al., 2017).

A study (Zheng et al., 2011) showed that anodal tDCS significantly raised rCBF (17.1%) during stimulation, which returned to baseline afterward, while cathodal tDCS caused a smaller rCBF increase in participants. La Rocca et al. (2022) found TDCS stimulation on M1 restored basic cortical hypometabolism in patients with FMS. Jales Junior et al. (2015) found that tDCS significantly increased rCBF in basal ganglia, and this alteration correlates with reduced pain in patients with FMS. These regions are critical to pain processing. Negative rCBF and cortical hypometabolism can affect neuronal function and pain processing. These studies collectively suggest that tDCS modulates rCBF and hypometabolism, which may normalize the dysfunctional neural circuits involved in pain perception, thereby reducing the pain experienced by FMS patients.

Transcranial direct current stimulation may reduce FMS pain by altering the brain’s pain response by inducing plasticity. Neuroplastic changes, including long-term potentiation (LTP) and long-term depression (LTD) (Kourosh-Arami et al., 2021), refer to the ability of the brain to reshape itself by generating new neural connections. Because of this adaptability, FMS causes an overactive brain pain processing system and generalized widespread pain (Gerra et al., 2021; Jayakar et al., 2021; Mezhov et al., 2021). Neuroplastic changes are associated with brain-derived neurotrophic factor (BDNF), which affects neuronal growth and synaptic connectivity. Research indicates that the BDNF levels in participants with FMS were lower than those in healthy controls (Iannuccelli et al., 2022).

Evidence shows that tDCS can cause cerebral excitability alterations that can persist longer than the stimulation period (Farnad et al., 2021; Santos et al., 2021), offering compelling insights into its potential impact on neuroplasticity. Further substantiating this view are animal experiments, which have demonstrated that tDCS enhanced LTP, reduced LTD, and increased BDNF concentration in some areas in the brain of rats (Kronberg et al., 2017; Yu et al., 2019). Another investigation suggested that tDCS can decrease BDNF levels and decrease pain in people with knee pain, and it supported an association between change in BDNF and change in clinical pain (Suchting et al., 2021).

Transcranial direct current stimulation can induce neuroplasticity in a manner dependent on N-methyl-D-aspartate receptors (NMDARs) (Liebetanz et al., 2002; Nitsche et al., 2003), which can regulate signaling pathways by allowing positively charged ions, such as calcium, to enter the cell and strengthen the synapse. Research also discovered that tDCS increased the amount of NMDA receptors and subsequently enhanced pain-related responses in animals (Li et al., 2022a,b). This suggests tDCS enhances NMDAR-mediated synaptic plasticity by increasing neuronal membrane NMDAR density, heightening synaptic responsiveness crucial to modulating pain.

Accordingly, tDCS can trigger long-term neuroplastic changes in the brain. These changes are crucial in FMS, as they can lead to a reorganization of the pain processing pathways in the brain. Alterations in plasticity-related pathways may be accomplished by inducing LTP and upregulating BDNF or NMDARs.