*3.1. Differences in Subjective and Objective Electrophysiological Responses between Subjects with Chronic Tension-Type Headache and Healthy Controls*

Table 1 and Figures 3 and 4 compare the stimulus intensity values for the defined response thresholds and the intensity values between the IDTs analyzed. Significant differences were observed between groups (HC and CTTH) in the subjective SPT response (*p* < 0.001) and the electrophysiological ISR (*p* < 0.001) and SMR (*p* < 0.001) responses, all of which were higher in the CTTH group vs. HCs. No differences were found between groups with respect to the subjective PPT response (*p* = 0.372). The only IDT in which a significant difference was observed was ISR-SMR (*p* < 0.001), which was greater in CTTH subjects. The SPT-PPT IDT (*p* = 0.090) and the SMR-PPT IDT (*p* = 0.302) did not differ between groups, and there were no significant differences in the electrophysiological SNCV parameters (*p* = 0.526) or SNAP amplitude (*p* = 0.613).

Table 2 shows the correlations between subjective SPT and PPT responses, electrophysiological ISR and SMR responses, and IDTs between the CTTH patients and HCs.

The logistic regression study showed that the statistically significant differences observed between groups in SPT, ISR, and SMR are independent of the age and gender effect (X2 = 10.276, *p* = 0.246), thus proving the goodness-of-fit null hypothesis and showing that the model is capable of correctly classifying 80% of the subjects.

**Table 1.** Electrical stimuli intensity response thresholds and intensity difference between thresholds in CTTH (*n* = 40) and healthy controls (*n* = 40).


Quantitative variables are expressed as mean ± standard deviation and median. CTTH, chronic tension-type headache; IDT, intensity difference between thresholds; ISR, initial sensory response; PPT, pain perception threshold; SMR, supramaximal response; SPT, sensory perception threshold. <sup>a</sup> *t*-test, <sup>b</sup> Mann–Whitney U-test. \*\* *p* < 0.01.

**Figure 3.** Comparison of sensory responses to electrical stimuli in CTTH patients and healthy controls. CTTH, chronic tension-type headache; HC, healthy control; IDT, intensity difference between thresholds; ISR, initial sensory response; PPT, pain perception threshold; S, stimulus; SMR, supramaximal response; SPT, sensory perception threshold.

**Figure 4.** Box plots comparing subjective and objective electrophysiological responses and IDTs between healthy controls and CTTH patients. IDT, intensity difference between thresholds; ISR, initial sensory response; PPT, pain perception threshold; SMR, supramaximal response; SPT, sensory perception threshold.

**Table 2.** Correlation between subjective and objective electrophysiological responses and IDTs in healthy controls and CTTH.


Data expressed as the Pearson correlation coefficient. CTTH, chronic tension-type headache; HC, healthy controls; IDT, intensity difference between thresholds; ISR, initial sensory response; PPT, pain perception threshold; SMR, supramaximal response; SPT, sensory perception threshold. \* *p* < 0.05, \*\* *p* < 0.01.

The ROC curve showed that the SPT (90% sensitivity and 63% specificity), ISR (82.5% sensitivity and 58% specificity), and SMR (70% sensitivity and 72.5% specificity) responses were diagnostically accurate (Figure 5).

**Figure 5.** ROC curve of subjects with or without CTTH.

*3.2. Psychological Differences between Subjects with Chronic Tension-Type Headache and Healthy Controls*

Table 3 shows the differences in psychological questionnaire scores between the CTTH group and HCs. In HCs, these scores were within reference limits for the healthy population. Scores for state anxiety (*p* < 0.001), trait anxiety (*p* < 0.001), depression (*p* < 0.001), and state negative affect (*p* < 0.001) were significantly higher in the CTTH group vs. HCs, while score for state positive affect (*p* < 0.001) and trait positive affect (*p* = 0.020) and cognitive reappraisal (*p* < 0.005) were significantly lower in the CTTH group vs. HCs.

**Table 3.** Psychological differences between subjects with CTTH and healthy controls according to their questionnaire scores.


Quantitative variables are expressed as mean ± standard deviation. The data express the numerical score obtained on the questionnaires. CTTH, chronic tension-type headache. <sup>a</sup> *t*-test, \* *p* < 0.05, \*\* *p* < 0.01.

#### *3.3. Correlations between Electrophysiological and Psychological Variables*

In the control group, a positive correlation was observed between trait positive affect and PPT (r = 0.338, *p* = 0.033) and also between PPT-related intervals: SPT-PPT (r = 0.344, *p* = 0.030) and SMR-PPT (r = 0.379, *p* = 0.016).

In the CTTH group, a positive correlation was observed between PPT and the psychological variable trait positive affect (r = 0.306, *p* = 0.055) and a negative correlation between the SMR-PPT interval and the psychological variables trait negative affect (r = −0.315, *p* = 0.047), state anxiety (r = −0.360, *p* = 0.022), trait anxiety (r = −0.431, *p* = 0.005), and depression (r = −0.368, *p* = 0.019). The SMR-PPT interval only presented a significant positive correlation with respect to cognitive reappraisal (r = 0.324, *p* = 0.042) (Figure 6).

**Figure 6.** Correlation between pain facilitation and neuropsychological variables.

## **4. Discussion**

The SPT indicates the degree of subjective non-nociceptive sensory discrimination. Physiologically, it is determined by the activation of large-diameter, myelinated nerve fibers (Aα and Aβ) that are more susceptible to excitation and that rapidly transmit the impulse to the CNS, where it is initially recognized (Figure 1) [10,12,15].

In our study, the SPT was significantly higher in patients with CTTH compared to healthy controls (Figures 3 and 4). In patients with CTTH, this has been previously observed in both trigger points [42,43] and other body areas [44–46] and could be due to a lower capacity for subjective sensory discrimination due to an alertness/attention deficit in the CNS (central dysmodulation) or hypoexcitability in Aα and Aβ nerve fibers, which are more excitable and conduct nerve impulse more rapidly (peripheral dysmodulation) [40].

The ISR and SMR are objective parameters related to nerve excitability. Both responses are recorded by stimulating Aβ fibers. The ISR objectively indicates the activation of a sufficient number Aβ sensory nerve fibers to evoke a sensory potential capable of being detected in the electrophysiological study, while the SMR indicates the activation of all the sensory fibers in the nerve. Although small nerve fibers (Aδ and C), which are associated with thermal and pain sensitivity, can be activated at the SMR intensity, they do not contribute to the SNAP observed in conventional electrophysiology [47].

The stimulus intensity required to reach the ISR and SMR was higher in subjects with CTTH compared to HCs, which suggests that Aβ nerve fibers in subjects with CTTH are less susceptible to excitability compared to healthy individuals (Figures 3 and 4). Studies have shown that hyperstimulation of a nerve can determine the hypoexcitability of its fibers, with the larger, myelinated Aβ nerves being the most easily modulated [5,14,18,40].

We were unable to observe the degree of excitability of Aδ and C fibers since they are not expressed in SNAPs. However, we, like other authors, have assumed that they are either not hypoexcited or less hypoexcited than large-diameter fibers [14,18,40].

The hypoexcitability of Aβ fibers was observed at a point distant from trigger points that are potentially hypersensitive in patients with CTTH, suggesting that it may be a diffuse event. We evaluated this finding in the median sensitive nerve because of its higher sensibility and stability response recording; the evaluation of this sensitive response in other sensitive nerve in lower limbs may be of interest in other new studies.

When the intensity of the electrical stimulus is increased, a PPT is reached, in which the sensory interpretation changes from non-nociceptive to painful. The PPT is an indicator of the capacity to recognize and modulate pain perception on a psychosensorial level and is determined by activation of the Aδ and C fibers (already achieved by delivering the intensity needed to achieve an SMR) and by the successive steps, connections, and regulations that occur from the time the painful sensory impulse enters the CNS until it reaches the somatosensory perceptive and associative cortex (Figure 1).

Other authors [46,48] have also failed to observe any differences in PPT between subjects with CTTH and healthy controls, and this has also been reported in other types of patients with idiopathic pain symptoms, such as fibromyalgia or local regional pain syndrome [49–51]. This, however, is a controversial finding since other authors contend that patients with CTTH have a lower PPT [52–56].

We attempted to resolve this issue by evaluating the SMR-PPT IDT. This interval indicates the intensity increase required from excitation of all the sensory fibers of the nerve until pain is perceived; we have therefore called it the "pain permeability interval". Although the differences observed were not significant, this interval is shorter in subjects with CTTH compared to healthy controls (Figures 3 and 4), leading us to believe that an alteration in central pain regulation circuits facilitates central pain perception.

If there is indeed a central, generalized pain facilitation mechanism, we need to consider why cranial pain in patients with CTTH is localized instead of generalized as it is in fibromyalgia. Although this is a questionable assumption, one possible explanation is that the frontotemporal cranial structures, which receive their sensory innervation from the trigeminal nerve, have more direct access to the CNS and less input modulation than in body areas where access is through the spinal cord gate-control filter [13,42,43,57,58].

According to the central sensitization theory of chronic pain, competent nociceptive stimuli can trigger neuroplasticity processes in the central circuits that transmit, modulate, and perceive pain; thus, the perception of a particular pain is either facilitated and perpetuated permanently or elicited with a far lower intensity pain stimulus [5,6]. This theory is based on the hypothesis that external nociceptive stimuli are the primary drivers of these changes due to myofascial contraction or alteration and local biochemical and inflammatory changes. This leads to secondary hypersensitization in central circuits, which in turn triggers peripheral adaptation responses in sensory receptors and local pericranial myofascial territories (trigger points) that cause and perpetuate the situation [5,6,22,52,56,59–61]. In our study, we found that subjects with CTTH presented a significantly lower permeability for pain, so we believe that the primary cause for hypersensitization is central dysmodulation.

On a neuropsychological level, we found significantly higher rates of state anxiety and trait anxiety, significantly higher rates of depression, and a far lower capacity for emotional regulation in patients with CTTH compared to healthy controls (Table 3). These neuropsychological alterations are closely related to their extremely short "pain permeability interval" (Figures 3 and 4), leading us to believe that central dysmodulation mechanisms together with neuropsychological alterations play an important role in the origin of pain perception facilitation in subjects with CTTH.

We did not find any correlation between the higher SPT observed in subjects with CTTH and any particular psychopathological or emotional regulation trait, which suggests to us that this lower discrimination sensitivity to sensory perception is an independent defining trait of the psychological variables found in subjects with CTTH and that this could be related to attention span or sensory avoidance in these subjects, a hypothesis that could be explored in subsequent studies.

Studies have shown that the CNS acts as the primary sensory trigger in circuits that transmit, modulate, perceive and evaluate feelings and that these can precede the functional and structural modifications that occur as an organic expression of such feelings in peripheral areas, where, by a process of sustained activation (such as gestures, postures, muscle, or myofascial tone), they bring about functional and structural modifications that may in turn act as the causal mechanisms of a process of hypersensitization and pain re-entry facilitation [15,20,21,26].

Some authors have observed that people with chronic pain, specifically patients with CTTH, present a greater psychopathological burden in the form of anxiety, depression, or emotional management difficulties [10,15,62–64]. These are frequently linked to other comorbidities that cause chronic pain, such as fibromyalgia, osteoarticular pain, oral and facial pain, abdominal pain, postoperative pain, or neurovegetative alterations, such as irritable bowel syndrome, tachycardia, etc. [5,6,15,63].

Neuropsychological alterations may be secondary to or influenced by a persistent painful life experience although their primary or secondary link to CTTH is controversial and should be explored in future studies. However, it is evident that their presence worsens and/or perpetuates CTTH symptoms [15].

To summarize, CTTH is associated with primary central pain facilitation that can set in motion by a particular painful experience that can then lead to hypersensitivity in peripheral tissue structures. These alterations lead to sensory hyperstimulation that may induce a relative hypoexcitability of Aβ fibers and further facilitates the input of pain sensations in the CNS, mediated peripherally by Aδ and C fibers. This re-entry loop perpetuates the painful experience and reinforces central hypersensitization. The close correlation with psychopathological alterations, such as anxiety, depression, or lack of emotional control, can be an expression of the cause itself or a consequence of the sustained painful life experience, thus helping to perpetuate and reinforce the pain [64–68].

Despite the fact that the diagnosis of CTTH is clinical, it would be necessary to evaluate these patients in both neurophysiological and neuropsychological aspects to better define the profile of each one and adapt the best therapeutic management to avoid the perpetuation and reinforce sensitization.

### **5. Conclusions**

The nervous system is an integrated, dynamic macro-complex in which all functions are interdependent, synchronized, and reciprocal and modulated by plasticity mechanisms. Therefore, chronic processes can be difficult to isolate or disassociate from a physiological perspective. This study helps show that the primary cause of pain perception dysmodulation in patients with CTTH might be a primary predisposition in the CNS, which leads to secondary peripheral hypersensitization and hypoexcitability of Aβ fibers. Greater pain facilitation is closely associated with a greater psychological comorbidity burden of anxiety, depression, and emotional disturbance. We believe that our findings can improve the conceptual understanding of CTTH and help clinicians achieve a more effective and sustained therapeutic response.

**Author Contributions:** Conceptualization, R.R.-G., S.R.R.-G., M.R.-A. and M.G.-B.; methodology, R.R.-G., S.R.R.-G., M.R.-A. and M.G.-B.; validation R.R.-G., S.R.R.-G., M.R.-A. and M.G.-B., formal analysis, R.R.-G. and M.R.-A.; investigation, R.R.-G., S.R.R.-G., M.R.-A. and M.G.-B.; resources, R.R.-G., S.R.R.-G., M.R.-A. and M.G.-B.; data curation, R.R.-G. and M.R.-A.; writing—original draft preparation, R.R.-G., S.R.R.-G., M.R.-A. and M.G.-B.; writing—review and editing, R.R.-G., S.R.R.-G., M.R.-A. and M.G.-B.; visualization, R.R.-G., S.R.R.-G., M.R.-A. and M.G.-B.; supervision, R.R.-G., S.R.R.-G., M.R.-A. and M.G.-B. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** The study was approved by the Ethics Committee of the University of Malaga. All subjects participated voluntarily and signed an informed consent form before inclusion. This study complies with the ethical criteria defined in the Declaration of Helsinki of 2014 and Organic Act March 2018, of 5 December, on the Protection of Personal Data and Guarantee of Digital Rights.

**Informed Consent Statement:** Informed consent was obtained from all subjects involved in the study.

**Data Availability Statement:** Not applicable.

**Conflicts of Interest:** The authors declare no conflict of interest.
