**1. Introduction**

Tension-type headache is the most frequent form of headache and a hard-to-treat disease with an estimated prevalence of between 30% and 78% throughout the lifetime of the people who suffer it [1], with an estimated incidence of chronic tension-type headache (CTTH) of between 2% and 3% in the general population [2] that causes considerable functional limitations and have significant personal and economic repercussions [3,4].

The pathophysiological mechanisms of CTTH have yet to be fully defined but are thought to be due both to hypersensitivity in pericranial structures and local nerve receptors [5–8] and deregulation or hypersensitization in central nervous system (CNS) pain modulation pathways [6–10]. These alterations may be interlinked in a self-activating loop that perpetuates cranial pain [11–13] (Figure 1).

**Citation:** Romero-Godoy, R.; Romero-Godoy, S.R.; Romero-Acebal, M.; Gutiérrez-Bedmar, M. Sensory Thresholds and Peripheral Nerve Responses in Chronic Tension-Type Headache and Neuropsychological Correlation. *J. Clin. Med.* **2022**, *11*, 1905. https://doi.org/10.3390/ jcm11071905

Academic Editors: Markus W. Hollmann, Casandra I. Montoro Aguilar and Carmen María Galvez Sánchez

Received: 12 March 2022 Accepted: 27 March 2022 Published: 29 March 2022

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**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

**Figure 1.** Diagram showing the physiology of craniofacial sensitivity, sensory perception of pain, and pain modulation.

As show in Figure 1, sensory perception is a central nervous system process that can be activated by (A) a stimulus that activates receptors or peripheral nerves (peripheral generator) or (B) a nerve impulse initiated in central nerve system circuits (central generator).

(A) A peripheral stimulus (PS) activates external (skin) or internal (fascia, muscles, viscera) neuroreceptors that stimulate nerve fibers. Large-diameter, myelinated nerve fibers (Aα and Aβ) are more easily excitable than small nerve fibers (Aδ and C).

The nerve fibers carry the stimulus to the CNS. Large-diameter, myelinated nerve fibers (Aβ) conduct signals more rapidly than small nerve fibers (Aδ and C).

The first stimuli to reach the spinal cord come from large-diameter, myelinated nerve fibers, which then control the input from the remaining fibers in the dorsal horn of the spinal cord ("gate control").

If signals from the small fibers are particularly intense (intense stimulus) and/or selective, they will override the gate-control mechanism.

Once in the spinal cord (CNS), the nerve impulses travel along the lemniscal pathways or posterior funiculi to suprasegmental structures.

In the head and neck, sensory stimuli travel directly to the trigeminal sensory nucleus in the brain stem.

The impulses reach subcortical structures (thalamus, subcortical nuclei) and then the amygdala and hypothalamus, triggering the emotional reaction and its vegetative response, which in turn is a sensory modulation mechanism.

From the thalamus, impulses travel to cortical structures, such as the limbic cortex, insula cortex, and somatosensory association cortex, generating the sensory cognitive response that perceives the sensation. The sensation is in turn appraised and linked to a prior experience, and this may generate a conditioned response

All these CNS structures are interrelated and constitute the central neuromodulation mechanism.

(B) The circuit can be reversed: an impulse (central stimulus, CS) can be generated primarily in sensory-related CNS structures (central sensory nuclei, psycho-emotional regulation circuits, sensory cortex, etc.), which will trigger perception.

Central hyperstimulation due to functional alterations in pain perception circuits would lead not only to an abnormal, exaggerated perception of pain but also to peripheral tissue hypersensitivity. This stimulates nerve fibers (peripheral hypersensitization), which in turn feed back to the CNS to generate secondary central hypersensitization.

Both mechanisms can be found in chronic pain processes, making it difficult to define the origin of the self-activation loop [13–15].

Stimuli can reach the peripheral nervous system (PNS) from outside (exteroception) or inside (interoception) the body. Excitability is the physiological capacity of the membrane of a nerve fiber to generate an action potential when stimulated. Large-diameter, myelinated nerve fibers (Aα and Aβ) are more excitable and transmit nerve impulses more rapidly than small and unmyelinated fibers (Aδ and C) [16,17]. The excitability of the membrane of a nerve fiber can depend on the intensity and frequency of the stimuli it receives so that a preceding stimulus can cause a transient state of initial hypoexcitability that transitions to hyperexcitability. This peripheral modulation of axonal membrane excitability is more accentuated in large-diameter, myelinated nerve fibers [14,18].

The CNS may be stimulated extrinsically from peripheral nerves or intrinsically by stimuli generated in the CNS itself. Depending on the quality of the stimulus and the type of synapse involved, this will either activate or inhibit the nerve pathways, circuits, and neural networks and modulate CNS activity. The processing of nerve impulses travelling along the spinal cord, brain stem, and brain leads to the perception and evaluation of sensation, setting in motion certain responses that can be reflexive, automatic, or voluntary and are either conditioned or unconditioned or unconscious or conscious [19,20] (Figure 1).

During processing, the sensory impulse leaves an "imprint" or sensory memory that can be accompanied by an emotional component [5,21]. Responses to successive exposure to the same stimulus will be influenced by this sensory and emotional imprint and can facilitate or inhibit the stimulus. This is the process of central sensitization, in which hypersensitization is determined by facilitation and hyposensitization by inhibition. This process is not limited to physical and/or biochemical functional changes in the CNS but can also modulate excitability in peripheral nerve fibers [5,6,15,22–25].

Sensitization, therefore, can be generated from external or internal sensory impulses in the neural circuits involved in the sensory and/or emotional regulation of pain, thus activating a sensation or feeling with a sensitive sensory response that is the same or similar to the response that would have been elicited by an external stimulus [5,6,21,26]. This is consistent with the notion of pain as a sensory and emotional experience "associated with actual or potential tissue damage" [27].

We hypothesized that CTTH may involve primary functional alterations in the central pain modulation circuits that facilitate the perception of pain, promoting in turn peripheral hypersensitivity that causes changes in neuronal excitability and leads to and enhances central hypersensitization. To test this hypothesis, we applied electrical stimulation to healthy volunteers and patients with CTTH to elicit subjective non-nociceptive pain responses and objective responses related to neuronal excitability. We correlated these with various psychological parameters, including anxiety, depression, and emotional regulation, in order to identify probable differences and associations with psychopathological comorbidity.
