These findings highlight that in the EO condition, the FM presented decreased spectral power density in delta and alpha-2 bands placed over BA06 and BA30, respectively. In contrast, the beta-2 and beta-3 frequencies in FM have more power spectra than the BA40 and BA02, respectively. In the EC condition, the FM group exhibits decreased spectral power in the delta frequency on the BA30. Besides, in the difference between EO and EC conditions, there is more activity in brain areas that deal with hearing and seeing above BA21, in the beta-1 band, and in the alpha-1 and alpha-2 bands at BA39 and BA09, respectively. In the difference between EO and EC conditions, FM presented higher connectivity in the beta-2 and beta-3 bands between the insula and the mPFC and thalamus, respectively.
Furthermore, FM showed less connection between the insula and the mPFC under EC conditions. These results point out that the insula, mPFC, and thalamus are related to the integration of sensory, emotional, and cognitive components of the FM and that the beta band is involved in the multisensory processing of pain. We also found that the link between the ACC, insula, S1 and thalamus is linked to pain catastrophizing, the effect of FM symptoms on quality of life, depressive symptoms, and serum BDNF levels.
We found decreased delta waves in the premotor and supplementary motor cortex (BA06). These areas contribute to planning complex and coordinated motor movements and the cingulate gyrus (BA30) that composes the retrosplenial cortex (RSC). It connects to the hippocampus, thalamus, and prefrontal cortex [33]. It is an essential part of the brain's core network involved in many functions, such as episodic memory, navigation, creativity, and planning [34]. This measure backs up the fact that people with FM have problems with their working memory, attention, and executive function [35].
Additionally, previous studies using resting-state fMRI and EEG in healthy subjects found higher delta activity over central-parietal areas of the somatomotor network (SMN). At the same time, the alpha and beta bands showed decreases over central-parietal areas extending to frontal regions. Thus, these findings suggest an inverse relationship between low (delta, theta) and high (alpha, beta) EEG frequencies. High rhythms involve cognitive processes such as self-referential attention or memory, while low frequencies involve sensory processing [36]. From this point of view, our results suggest that the FM group is less aroused at the start of the resting state assessment than the HC. Even though we do not have a clear hypothesis so far to accommodate all the differences between FM and HC found across the different frequency bands, it seems reasonable to derive some conclusions based on the neurophysiopathology of FM. Earlier studies that used other methods, like the EEG spectral density [16], the BOLD signal [13], and the transcranial magnetic stimulation (TMS) parameter [37], support this idea. Ultimately, this set of findings aligns with the notion that cortical hypoactivation may be a marker of cortical dysfunction in FM. It is important to note that they have been linked to the severity of pain disability, the worse symptoms of central sensitization [13], the use of opioids [16], and the severity of the dysfunction of the descending pain modulatory system [37]. Even though the current results add a lot to this field of knowledge, the study design makes it hard to establish cause and effect. On the other hand, these findings are essential for research and clinical settings. They mostly make it possible to use electrophysiological measurements in a controlled experiment, which makes it less likely that assessment biases will affect the results and makes it possible to understand how cortical dysfunction works in nociplastic chronic pain.
The lower activation in the alpha-2 frequency band over areas involved in emotional regulation, sensing, and action (BA30) suggests that precarious emotional regulation of the posterior cingulate cortex (PCC) may come after a prior painful activation of the somatosensory cortex. This finding might explain the catastrophic behavior usually found in FM [38] since the cortical alpha rhythms modulate physiological mechanisms that precede painful motor integration [39]. In contrast to hypoactivation in the cortical areas, the FM group showed increased cross-spectral power in the beta-2 and beta-3 bands over the supramarginal gyrus (BA40) and in the somatosensory cortex (BA02). These areas are involved in preceding visual and tactile stimulation. A previous study found that the higher beta-band power is linked to these regions' functioning to process information from more than one sense [40]. Despite these results' extent of evidence that FM displays a deteriorated function of cortical, indexed by hypoactivation compared to HC, one needs to consider that they may be explained by the sample characteristics related to the severity of disorders, the medication used, disability, comorbidities, etc.
The linear analysis shows that when taking the differences between EO and EC conditions into play, the left insula and right thalamus are more connected in the beta-3 frequency band in the FM group. An fMRI study found that the thalamus is connected to S1, S2, and the insula. It suggests that more activity in the thalamocortical area could cause more activity in the insula, which relates to the long-lasting feeling of pain [41]. It showed that beta- and theta-wave overactivation is linked to thalamocortical dysrhythmia (TCD) in some pain-related areas. For example, when the thalamus function is compromised, these thalamocortical oscillations happen at low theta frequencies and high beta and gamma frequencies. This is how TCD works in pain matrix areas, and it has been suggested that this could lead to chronic pain [42]. These results suggest how people feel, think, and act in response to pain is shaped by how well the different parts of the pain matrix work together. Ong, Stohler, and Herr (2019) [12] found that the pain level during a migraine attack is linked to how well the left insula and the mPFC work together.
On the other hand, in FM, the right insula and left mPFC are more connected in terms of phase synchronization in the beta-2 frequency band. This result is backed up by previous studies showing that the insular cortex integrates sensory information from the corticothalamic ipsi- and contralateral projections. Besides, an earlier study found that the insular cortex combines this information with input from the prefrontal cortex involved in cognitive, emotional, and executive functions. This integrated work among different brain areas defines voluntary responses to pain [43].
Our research shows changes in how the brain works linked to pain catastrophizing and the effect of FM symptoms on the quality of life (see Table 4 and Fig. 6A). We found that in EO, the beta-3 band is conversely correlated with the linear connectivity between the right ACC, the right insula, and the left S1. According to these results, pain catastrophizing might be related to enhanced functional connectivity (FC) among areas playing a role in pain perception (S1, anterior insula, and thalamus) [44]. They are also linked to an increase in connectivity within the DMN (mPFC-posterior cingulate cortex (PCC)/precuneus) or between the DMN and the periaqueductal gray (PAG)/periventricular gray (PVG) [45]. The DLPFC is one of the most critical parts of the descending pain modulatory system [44]. In the same way, the connectivity between the DMN and the medial thalamus was also related to pain catastrophizing [45]. Neuroimaging studies found that pain catastrophizing leads to changes in the structure and function of the brain. Besides, a cognitive-behavioral therapy study found that pain catastrophizing is associated with more gray matter in the PFC, parietal, and somatosensory cortex [46]. Another study found that chronic pain is related to alterations in gray matter (GM) and FC [47].
In contrast, in the EC condition, connectivity has a negative correlation with the impact of pain on quality of life as measured by FIQ. Our results showed that the connectivity of the beta-3 frequency band in the left hemisphere had an inverse correlation with the connection between ACC and S1 and the impact of fibromyalgia on quality of life (see Table 4 and Fig. 6C). The ACC is involved in several cognitive and emotional processing tasks as a critical part of the limbic system. A previous study found less intrinsic connectivity between the DMN and the insula [10]. Studies found that a higher level of connectivity among cortical areas involved with pain processing is linked to less pain. The ACC has been linked to affective pain because the excitatory activity of its neurons is needed for negative emotions related to pain [48, 49]. However, it has been unclear whether and how the ACC decodes and tells the difference between sensory pain and affective pain.
In the difference between EO and EC conditions, the connection between the left insula and the right thalamus in the beta-1 band was negatively correlated with depression. This finding fits with other evidence suggesting that cortical thickness lateralization may also be linked to depressive symptoms. In a previous study, adolescent girls who later became clinically depressed were found to have thicker gray matter in the left insula than those who did not become depressed [49]. People with depressive symptoms seem to have abnormally lateralized activation in the insula and limbic structures when their emotions are stimulated [50]. In line with these results, a meta-analysis found that the left insula was more active when people were angry, sad, or scared in response to unpleasant stimuli [51]. Previous studies have shown that the insula is involved in processing multidimensional pain aspects, which include sensory, affective, and cognitive dimensions.
In neuroimaging studies of acute experimental pain, the insula is one of the most active parts of the brain [4]. Several studies in EO or EC conditions discovered that low beta band power (13–20 Hz) in chronic neuropathic pain could be a potential brain GABAergic signaling marker [52]. Based on this information, it seems reasonable to think that the severity of FM symptoms like pain, depression, and central sensitization may be linked to an imbalance in the GABAergic and glutamatergic concentrations in different structures, such as the insula [53]. However, the insula does more than just process pain signals. It has been linked to several unpleasant interoceptive and exteroceptive experiences [54]. So, more research is needed to figure out how left insula thickness and insula asymmetry are related to depressive symptoms and widespread pain.
In the EO condition, the delta band positively correlates with the connectivity between the left insula, the right mPFC, and serum BDNF (see Table 4 and Fig. 6B). This is important because the BDNF protein consistently promotes synaptic plasticity. Even though there is no clear explanation for these results, one needs parsimony to translate them into the clinical setting. According to the literature, delta waves are related to neural plasticity processes. At the same time, people with chronic pain, especially those with nociplastic pain, have higher serum levels of BDNF [55, 56]. Serum BDNF was conversely correlated with the function of the DPMS [57]. Whereas in the spinal cord, the increase of BDNF is allied with a reduction in the GABA inhibitory activity and increased excitability of the spinothalamic tract [58]. In another study with FM, we found that a standard pain stimulus led to more functional connections between the motor areas and the PFC [15]. Roy et al. (2020) [59] found that the right frontal-parietal regions are more likely to have more delta waves in the Met/Met homozygous genotype of BDNF than in the heterozygous genotype.
Several methodological aspects must be addressed in the interpretation of these results: First, this study was cross-sectional, so we could not determine whether long-term chronic pain or a more severe disease was responsible for the electrophysiological changes. Second, the source localization has a low resolution due to the small number of EEG sensors (18 electrodes). This is enough for source reconstruction, but it makes anatomical accuracy less accurate. Third, groups were not matched up and had different years in school or ages. Fourth, only women were included because FM is more common in women and because men and women have different ways of dealing with pain, brain activity, and connections [60]. Fifth, it is not possible to control all possible confounding factors. Antidepressants, painkillers, mood stabilizers, and antipsychotic medications are a few of these factors that affect people with FM. Lastly, because this is a cross-sectional study, more longitudinal research is needed to figure out the role of pain matrix connectivity as a predictor of how chronic pain will change over time.
These results mainly indicate the insula's role in the connectivity integration of different pain processing circuits in FM and point out the beta band activity taking part in this process. So, these results suggest that the insula functional connectivity at rest could be an objective biomarker of how pain is processed and related to the severity of clinical symptoms in people with FM.