Trigeminal neuralgia (TN) is the most common neuropathic pain that occurs in the oral and maxillofacial region. TN is defined as a recurrent facial pain that occurs in one or more branches of the trigeminal nerve; unilateral onset, not extending beyond the distribution of the trigeminal nerve, pain with the following characteristics such as pain lasting from a few seconds to two minutes; severe pain; pain with electric shock, shooting, knife-cutting, or sharp features; pain is evoked by innocuous stimuli within the affected trigeminal distribution and no other better diagnostic method exists (Katusic et al., 1990; MacDonald et al., 2000; Mueller et al., 2011; Headache Classification Committee of the International Headache Society (IHS), 2018; Cruccu et al., 2020). The International Classification of Headache Disorders, 3rd Editon (ICHD-3) in 2018 divides trigeminal neuralgia into three types: idiopathic, classic, and secondary TN. The idiopathic and classic TN were primary trigeminal neuralgia (PTN) in ICHD-2. Classic TN refers to trigeminal neuralgia caused by neurovascular compression (NVC) in cerebellopontine angle in MRI; idiopathic TN refers to trigeminal neuralgia with no obvious abnormality in electrophysiological tests and MRI without NVC. PTN patients have the characteristic clinical manifestations in the above definition (Maarbjerg et al., 2017; Headache Classification Committee of the International Headache Society (IHS), 2018).

The pathogenesis of PTN is still unclear and controversial. The main etiology theories for PTN patients including peripheral etiology, central etiology, allergic reaction, viral infection, comprehensive etiology and so on. It is traditionally believed that PTN is caused by the injury of the peripheral trigeminal nerve. The neurovascular compression (NVC) theory, as a kind of peripheral etiology theory, is the mainstream etiology theory of PTN that is widely accepted. The nerve fiber in root entry/exit zone (REZ) of trigeminal nerve is a bare area that is several millimeters long and is not surrounded by myelin sheaths, so the nerves in this area are more likely to be contacted or compressed by pulsatile blood vessels, resulting in pain (Gardner, 1962; Gubian and Rosahl, 2017).

At present, the diagnosis of PTN still relies on the patients’ subjective symptom description. There is no obvious abnormality in the basic examination of the nervous system of PTN patients (Sjaastad and Bakketeig, 2007; Cruccu et al., 2016). Magnetic resonance tomography angiography (MRTA) is widely used to show whether there is obvious vascular compression of the trigeminal nerve in the cerebellopontine angle area. However, MRTA can just show structure changes – NVC, and the functional changes were not developed. As a result, some confusion arises: the presence of NVC does not necessarily result in PTN; about 24% of the normal population also has NVC of the cerebellopontine angle without pain is that it only shows structure changes but without functional changes (Leal et al., 2010, 2011).

In recent years, with the continuous development of imaging technology, diffusion tensor imaging technology (DTI) has greatly promoted the understanding of brain structure and functional cognition with central nervous diseases. DTI is the only non-invasive method currently used to determine the direction of living biological nerve fibers. It uses the different diffusion characteristics of water molecules in the body to provide more details of brain tissue, especially white matter (Lummel et al., 2015). According to the data information in the DTI image, it can provide the microstructure and information of the local tissue. At present, DTI has been widely used in the study of various neuropsychiatric diseases and can also be used as a navigation technology in brain surgery. The DTI research on PTN is currently mainly based on the whole brain research, and there are few studies on the local microstructural changes of the trigeminal nerve root.

This study intends to quantitatively analyze the local DTI diffusion values in the REZ of the trigeminal nerve in PTN patients and healthy control volunteers, and to find the specific microstructural changes. Subgroup analysis of patients were performed to evaluate the correlation between clinical data and DTI parameters.

This trial recruited a total of 17 patients (12 females and 5 males, with an average age of 59.3 years) who were diagnosed with primary trigeminal neuralgia (PTN) from August 2018 to August 2020 in the Department of Oral Surgery of the Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine. The diagnosis of PTN was made by two senior oral surgeons with extensive experience in the diagnosis of trigeminal neuralgia.

The inclusion criteria for patients were as follows: ①according to the diagnostic criteria of the International Classification of Headache Disorders (ICHD-3) (Headache Classification Committee of the International Headache Society (IHS), 2018); ②unilateral disease; ③right-handed; ④disease duration longer than 6 months; ⑤no previous history of cranial and maxillofacial surgery or radiotherapy and chemotherapy; ⑥disease-related drugs (such as carbamazepine tablets, etc.) were discontinued for more than 48 h.

The exclusion criteria for patients were as follows: ①patients with other chronic pain besides PTN; ②blood pressure over than 180/100 mmHg; ③fasting blood glucose over than 8 mmol/L; ④history of brain trauma or craniocerebral surgery, etc.; ⑤metal implants in the body; ⑥other mental or neurological diseases and claustrophobia.

The study also recruited 34 healthy subjects as the health control group (HC) (24 females and 10 males, with an average age of 57.7 years), matched with the PTN group in terms of average age, gender, handedness, etc. The exclusion criteria for HC were as same as those for PTN group.

The content of this trial complies with the Declaration of Helsinki (as revised in 2013), and all subjects voluntarily participated in this trial and signed the consent form. This trial was approved by the Ethics Committee of the Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine.

The trigeminal nerve is the fifth cranial nerves. PTN refers to the recurrent sudden, severe, lightning-like tingling pain in the distribution area of the trigeminal nerve. Secondary neuralgia symptoms due to various other central nervous system diseases must also be excluded, such as multiple sclerosis and intracranial space-occupying lesions. At present, little is known about the etiology of trigeminal neuralgia. The current world-wide theory is vascular compression proximal to the REZ of the trigeminal nerve – NVC (Jannetta, 1967). The distance between the REZ area and the brain stem is about 2–6 mm (Maarbjerg et al., 2015). REZ area is the transition zone between the central nervous system and the myelin sheath of the peripheral nervous system, which is considered to be most susceptible to vascular compression (Woolfall and Coulthard, 2001). The NVC leads to local microstructural changes in the REZ area, and secondary demyelination of the trigeminal nerve root (Liu et al., 2013). Abnormal remyelination of the demyelinating zone and formation of ectopic synapses due to repeated minimally invasive trauma, possibly related to vascular pulsation, allow sensory transmission through ectopic pacemaker and tactile cross-linking and cross-discharge between axons to make sensory input extremely excited (Devor et al., 2002). Ordinary trigeminal nerve-related magnetic resonance scanning technology can generally only show the approximate running direction of the trigeminal nerve in the cerebellopontine angle and whether there is vascular compression around. The extent to which the fiber bundles were deviated, and the nerve was compressed or deformed was not quantified.

DTI technology has been used since 1996 and has been widely used in recent years. It can be analyzed from different angles through the scanning of multiple gradient fields, and the data of the diffused signals in all directions can be quantified (Fujiwara et al., 2011; Neetu et al., 2016). As a non-invasive MRI method, DTI is increasingly used in the study of neurological or brain diseases. After peripheral nerve injury or sustaining chronic pain, abnormalities in the white matter of the brain will occur (Rappaport and Devor, 1994; Davis et al., 2011). DTI not only has certain reference value and significance for the course of white matter fibers, but also evaluates the integrity of the tissue structure (Leal et al., 2011). This technique has been applied to PTN research (Herweh et al., 2007; Upadhyay et al., 2008; Hodaie et al., 2012). Microstructural abnormalities in the REZ region in PTN patients with NVC has been verified (Van Der Molen, 2018). There are four main diffusion values of DTI, including FA (providing information on the integrity of fiber bundles), MD (reflecting the level of diffusion and diffusion resistance), MD (reflecting the level of diffusion and diffusion resistance), AD (reflecting the local integrity of axons; radial diffusion ratio, and RD (reflecting pathological changes such as demyelinating changes, neuroinflammation and edema of nerves) (Aung et al., 2013).

By measuring diffusion values, previous studies (Song et al., 2003; Leal et al., 2011) found that FA decreased in the REZ of the trigeminal nerve while MD increased in the REZ. Leal et al. (2011) studied the DTI parameters of TGN in 10 TN patients with NVC and found that compared with the control group, the FA value of the affected side of TGN was significantly lower and the AD value was significantly higher. However, other parameters have not been studied. In most of DTI related research in PTN, there was few correlations analysis between the values with clinical manifestations.

The FA value is usually used to describe the integrity of nerve fibers, and the MD value reflects the diffusion resistance and the molecular weight of water in the tissue. Long-term NVC will lead to axonal demyelination and degeneration at first, and FA value decreased. The loss of tissue structure in the REZ, in turn, leads to a decrease in diffusion barriers and an increase in MD values, so a decrease in the FA value on the affected side is negatively correlated with an increase in the MD value (Leal et al., 2011). Nerve atrophy is considered a late consequence of chronic physiological stress after demyelination (Gizewski et al., 2014). Low FA and high MD suggested pathological features of axonal demyelination, neuroinflammation and edema, and so on. These results are consistent with the pathological manifestations of axonal loss, axonopathy, demyelination, abnormal demyelination, residual myelin debris, and collagen deposition in nerve specimens from PTN patients.

Among the 17 patients included in this study, 12/17 had NVC manifestations of the affected side on MRTA, and 8/17 had NVC manifestations on the patients’ healthy side. The results of diffusion values analysis showed that, regardless of whether there was vascular compression, the overall mean of the patients’ healthy side of PTN group was not significantly different from that of the HC group; the DTI parameters of the patients’ affected side were significantly different from those of the healthy side of PTN group and the HC group; the DTI parameters have no statistical difference between the NVC group and None-NVC group. These results indicate that there is no correlation between the occurrence of microstructural changes in the REZ of the trigeminal nerve in PTN patients and NVC, which needs to be further verified by expanding the sample size.

The results of this study showed that the increase of the duration of PTN was related to the decrease of the FA value and the increase of the MD and RD values of the patients, which suggesting that the duration of pain was an important factor affecting the microstructure changes of the trigeminal nerve. The correlation analysis between the patients’ DTI parameters and the VAS pain score showed that the FA value was negatively correlated with the VAS, indicating that the more severe the microstructure change of the trigeminal nerve fiber, the more severe the pain. At the same time, it was observed that there was no significant difference between the medication history and the changes of DTI parameters in the REZ. In this study, the PCoA between the PTN group and the HC group was carried out for all indicators, and there were significant differences between the affected side of the PTN group and the HC group.

Among the 17 patients, 11 patients underwent surgical treatment, of which 9 patients underwent MVD surgery, and 2 patients underwent RFT. The symptoms of all patients were relieved after surgery, and 7 patients participated in DTI 6 months after surgery. The follow-up data showed that among the DTI diffusion values of the 7 patients, the FA value showed an upward trend after surgery, and the MD, AD and RD values all showed a downward trend. Postoperative DTI-related diffusion values of patients tended to change to healthy controls. It is suggested that the relief of symptoms in patients with PTN contributes to the improvement of microstructural abnormalities in the REZ of the trigeminal nerve.

There are still some shortcomings in this trial. For example, the sample size is not large enough, which leads to some problems such as inconsistency between some negative conclusions and positive results reported in the literature. It needs to be supplemented with relevant data in the future to improve. The connection and changes of the peripheral structure and the central structure of the trigeminal nerve in the pathogenesis of PTN need to be further confirmed by follow-up studies.

The original contributions presented in this study are included in the article/Supplementary material, further inquiries can be directed to the corresponding authors.

The studies involving human participants were reviewed and approved by the Ethics Committee of the Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine. The patients/participants provided their written informed consent to participate in this study.

YWa designed the study, collected the data, and wrote the manuscript. DW performed the imaging data. YWu coordinated issues related to imaging tests. CZ provided guidance and assistance to statistics. WW and LL collected the clinical data of all subjects. YL adjusted imaging parameters and guided image processing. MC and WC provided test and manuscript writing ideas and subsequent revision.