Although the sensory function is roughly normal in patients with TN, subtle tactile and thermal sensory deficits may occur at the trigeminal territory as detected by sophisticated quantitative sensory testing [
21]. A delayed conduction in large afferent fibres has been detected in 50% of TN patients even in the absence of any clinical hypoesthesia [
22]. A conduction delay and a nociceptive laser-evoked potential amplitude reduction have been demonstrated ipsilaterally in 51% of TN subjects [
23], indicating a dysfunction in Aδ and C fibres. The present study sought to detect these trifling changes - expectantly reflecting axonal lesions, demyelination and/or conduction block - as assessed by tactile and painful threshold in order to correlate them with possible WM diffusional and GM morphological changes. No significant differences in tactile and pain thresholds between the symptomatic and non-symptomatic sides or in tactile threshold between patients and controls were noticed. However, the pain threshold in patients was slightly and significantly increased (p ≤ 0.001). Bilateral activation of the descending diffuse noxious inhibitory controls (DNIC) with release of endorphins, due to the repetition of painful paroxysms of TN [
24] could explain this finding, but this seems unlikely since during pain threshold determination no neuralgic pain putatively activating the inhibitory control has been triggered. A second possibility would be the antinociceptive effect of CBZ, which has been described in rats [
25,
26] and TN patients after noxious laser stimulation [
23].
TN and white matter abnormalities
The results of this investigation suggest that the brain white matter tracts microstructure is spared in TN, as shown by the absence of DTI abnormalities.
Subtle abnormalities reveled by FA decrease have been detected in the trigemino-thalamic and thalamocortical tracts in migraine patients [
10]. Subsequent studies using TBSS analysis in other pain conditions (fibromyalgia [
12], complex regional pain [
11], cluster headache [
9], temporomandibular disorders [
8]) have reported abnormalities in white matter tracts involved in sensory, modulatory and cognitive functions.
The present results could be interpreted in two different ways. First, changes in diffusion could be too subtle or restricted to be identified by TBSS analysis. The sample size seems adequate as abnormalities have been detected in about seven cluster headache patients using the same technique [
9]. Second, there are really no changes in diffusion in TN differently to migraine. Perhaps because TN is a paroxysmal pain, unlike the complex regional pain, TDM or fibromyalgia and/or does not involve in principle a genetic predisposition as in migraine. It seems that the diffusional abnormalities in the trigeminal root on the symptomatic side which would correspond to a focal demyelination and/or axonal loss [
27] have no impact in the intracranial white matter tracts.
Nevertheless, we found a significant volume reduction (p = 0.04) of the mid-anterior corpus callosum that connects the motor areas of hemispheres. Clinical and experimental studies suggest an inhibitory effect of pain on the motor cortex [
28‐
30]. Da Silva reported on reduced thickness of the primary motor cortex contralaterally to a trigeminal neuropathic pain, which could be hypothetically explained by inhibition of facial and cervical muscles to avoid pain triggering [
31]. As patients with TN also limit talking, chewing and facial movements to avoid pain triggering [
32,
33], this could be also justify our findings.
TN and grey matter abnormalities
We found changes in cortical thickness in TN patients as compared with controls. Cortical thickness changes, either increase or reduction, involve supraspinal nociceptive processing areas, such the orbitofrontal cortex, the insula and motor cortex, the anterior cingulate gyrus and temporal lobe, similarly to the other in pain syndromes . However, after the correction for multiple comparisons only the inferior temporal/fusiform cortex and cuneus/pre-cuneus regions remained significanty thinner (p = 0,05). In addition, the inferior temporal gyrus/fusiform cortex thickness showed a negative correlation with CBZ dose, the larger the cortical thickness, the lower the medication usage.
Pain-related grey matter changes have been reported in several pain conditions. A meta-analysis of 30 published VBM studies in 15 chronic pain conditions has shown that cortical changes (increase or decrease of grey matter) vary among different pain syndromes but overlap in areas such as cingulate and insular cortex, temporal lobe, frontal and prefrontal cortex, thalamus and basal ganglia, motor cortex, brainstem and dorsolateral prefrontal cortex, all brain areas involved in supraspinal nociceptive processing [
34]. In an heterogeneous group including both TN and trigeminal neuropathy, Gustin et al. [
13] found grey matter reduction in the primary somatosensory cortex, anterior insula, putamen and nucleus acumbens. The thalamic volume decrease was only seen in patients with trigeminal neuropathy but not TN. An specific study of morphometric changes in TN [
14] revealed brain matter volume reduction in the primary somatosensory and orbitofrontal cortices as well as anterior cingulate, cortex insula, secondary somatosensory cortex, thalamus, putamen, caudate nucleus, dorsolateral prefrontal cortex, precuneus and cerebellum. With these results Oberman et al. [
14] concluded that the GMV reduction areas were nonspecific and would reflect only the chronic pain.
Our results are similar to the previous studies in pain syndromes only in a single-binary comparison (p < 0.01), which could be explained by a lack of statistical power in this group of patients or most likely by methodological differences. Surface-based analyses provides a more precise measure of cortical thickness as VBM analysis reflects a mixed measure of grey matter, including cortical surface area or cortical folding, as well as cortical thickness [
35].
After multiple comparisons only cuneus/precuneus and inferior temporal/fusiform cortex remained significantly thinner in the TN group. Although cuneus and precuneus areas are classically related to visual information processing, they are limited by the parieto-occipital sulcus, a multisensory integration area [
36]. One of the cuneus function seems to be to integrate the somato-sensory information with other sensory stimuli and cognitive processes such as attention, learning and memory [
37]. These areas are activated together with sensory/motor areas and structures related to pain in response to pricking sensation generated by a thermal painful stimulus in trigeminal and extra-trigeminal territory [
38,
39] and after selective stimulation of Aδ fibers [
40]. An EEG-MEG study in neurogenic pain patients showed precuneus and cuneus hyperactivation in patients with TN but not with lower limb pain [
41]. In line with the present study, Oberman et al. [
14] found a reduction in GMV in the left precuneus in TN patients not related to the pain duration, attack frequency or VRS. On the contrary, cluster headache patients have an increase in the cuneus GMV [
42]. Pain is very intense in both TN and cluster headache, indicating that the opposite results in this respect cannot be explained by differences in pain severity. The pain location, mostly to the lower face in TN as opposed to retro-ocular, fronto-temporal areas in cluster headache; together with the clear pathophysiological differences, central/hypothalamic cantered in cluster headache versus peripheral in TN, could explain the contrast in GMV findings among these disorders.
A significant reduction in cortical thickness was noticed in the left fusiform cortex, an area involved with body and face recognition [
43]. It is also activated during postoperative pain [
44] and by stimulation of Aδ fibers as well as the cuneus [
40].
The perception of painful electrical shock seems activate a number of cerebral areas, namely left fusiform cortex, hippocampus, primary and associative visual cortex extending to the cuneus and precuneus as well as a more anterior network all belonging to dopaminergic pathways [
45]. The activity of this areas was negatively correlated to pain intensity rating, especially at the left fusiform gyrus [
45]. This posterior network, activated during electric shock stimulation, may be involved in a mental imagery process related to the retrieval of shock perception [
45]. The pain in TN is shock-like in nature and could activate similar regions.
Volumetric changes of the left fusiform gyrus have been found in patients with migraine. Compared to controls, this region was significantly atrophied in migraine without aura, while in migraine with aura it was increased. In the most of patients the migraine was bilateral [
46]. Pain anticipation and perception have been associated with the left fusiform gyrus, where the activity was negatively correlated with the pain rating [
45]. It is possible that the left fusiforme cortex reduction may not depend on the side where the pain occurs.
The role of CBZ on the present results cannot be overlooked as the inferior temporal/fusiform cortex thickness reduction was negatively correlated with the CBZ dose, which had a positive correlation with the illness duration. Chronic CBZ was shown to change cellular signaling in rats, which could interfere with the functional and structural responses of various brain areas [
47]. It remains to be determined whether CBZ affects grey matter thickness or not.
The cornerstone of TN is the electric shock-like pain evoked at trigger zones by light touch. It seems related to the ephaptic cross-talk between Aβ fibres mediating light touch and small-myelinated Aδ fibres close to the trigeminal nerve root entry zone, where there a focal demyelination is caused by neurovascular compression. Our study showed a thickness reduction of the fusiform cortex and cuneus, structures that can be activated by Aδ fibres stimulation and would be involved in a mental imagery process related to the retrieval of shock. These data strongly suggest that such cortical areas are involved in TN pathogenesis. However, our results do not elucidate whether these changes reflect plastic changes of the brain as a consequence of multiple, daily shock-like pain conveyed by Aδ fibres or a causal factor in the development of TN. Although a partial reversal of morphologic changes of the brain after pain treatment has been reported Rodriguez-Raecke [
48], the four patients re-scaned 6 months after successful microvascular decompression showed no evolutive changes. It is possible that either the follow-up was too short or TN actualy requires an interplay between peripheral vascular compression and GM structural predisposition in order to develop, which is supported by the occasional presence of asymptomatic neurovascular compressions. Future studies may address this issue with longer follow-up.