Idiopathic trigeminal neuralgia (TN) is classically associated with neurovascular compression (NVC) of the trigeminal nerve at the root entry zone (REZ), but NVC-induced structural alterations are not always apparent on conventional imaging. Previous studies report lower fractional anisotropy (FA) in the affected trigeminal nerves of TN patients using diffusion tensor imaging (DTI). However, it is not known if TN patients have trigeminal nerve abnormalities of mean, radial, or axial diffusivity (MD, RD, AD - metrics linked to neuroinflammation and edema) or brain white matter (WM) abnormalities. DTI scans in 18 right-sided TN patients and 18 healthy controls were retrospectively analyzed to extract FA, RD, AD, and MD from the trigeminal nerve REZ, and Tract-Based Spatial Statistics (TBSS) was used to assess brain WM. In patients, the affected trigeminal nerve had lower FA, and higher RD, AD, and MD was found bilaterally compared to controls. Group TBSS (P<0.05, corrected) showed patients had lower FA and increased RD, MD, and AD in brain WM connecting areas involved in the sensory and cognitive-affective dimensions of pain, attention, and motor functions, including the corpus callosum, cingulum, posterior corona radiata, and superior longitudinal fasciculus. These data indicate that TN patients have abnormal tissue microstructure in their affected trigeminal nerves, and as a possible consequence, WM microstructural alterations in the brain. These findings suggest that trigeminal nerve structural abnormalities occur in TN, even if not apparent on gross imaging. Furthermore, MD and RD findings suggest that neuroinflammation and edema may contribute to TN pathophysiology.

Trigeminal neuralgia (TN) is a classic neuralgic pain condition with distinct clinical characteristics. Modeling TN in rodents is challenging. Recently, we found that a foramen in the rodent skull base, the foramen lacerum, provides direct access to the trigeminal nerve root. Using this access, we developed a foramen lacerum impingement of trigeminal nerve root (FLIT) model and observed distinct pain-like behaviors in rodents, including paroxysmal asymmetric facial grimaces, head tilt when eating, avoidance of solid chow, and lack of wood chewing. The FLIT model recapitulated key clinical features of TN, including lancinating pain-like behavior and dental pain-like behavior. Importantly, when compared with a trigeminal neuropathic pain model (infraorbital nerve chronic constriction injury [IoN-CCI]), the FLIT model was associated with significantly higher numbers of c-Fos-positive cells in the primary somatosensory cortex (S1), unraveling robust cortical activation in the FLIT model. On intravital 2-photon calcium imaging, synchronized S1 neural dynamics were present in the FLIT but not the IoN-CCI model, revealing differential implication of cortical activation in different pain models. Taken together, our results indicate that FLIT is a clinically relevant rodent model of TN that could facilitate pain research and therapeutics development.

Focal radiosurgery is a common treatment modality for trigeminal neuralgia (TN), a neuropathic facial pain condition. Assessment of treatment effectiveness is primarily clinical, given the paucity of investigational tools to assess trigeminal nerve changes. Since diffusion tensor imaging (DTI) provides information on white matter microstructure, we explored the feasibility of trigeminal nerve tractography and assessment of DTI parameters to study microstructural changes after treatment. We hypothesized that trigeminal tractography provides more information than 2D-MR imaging, allowing detection of unique, focal changes in the target area after radiosurgery. Changes in specific diffusivities may provide insight into the mechanism of action of radiosurgery on the trigeminal nerve.

The trigeminal circuit relays somatosensory input from the face into the central nervous system. In central nuclei, the spatial arrangement of neurons reproduces the physical distribution of peripheral receptors, thus generating a somatotopic facial map during development. In mice, the ophthalmic, maxillary, and mandibular trigeminal nerve branches maintain a somatotopic segregation and generate spatially organized patterns of connectivity within hindbrain target nuclei. To investigate conservation of somatotopic organization, we compared trigeminal nerve organization in turtle, chick, and mouse embryos. We found that, in the turtle, mandibular and maxillary ganglion neuron rostrocaudal segregation and trigeminal tract somatotopy are similar to mouse. In contrast, chick mandibular ganglion neurons are located rostrally to maxillary neurons, with some intermingling, supporting previous observations (Noden [1980], J Comp Neurol 190:429-444). This organization results in an inversion of the relative positions and less precise axonal sorting of the maxillary and mandibular branches within the trigeminal tract, as compared to mouse and turtle. Moreover, using the turtle and chick orthologs of Drg11 in combination with Hoxa2 expression and axonal tracings from the periphery, we mapped the chick PrV nucleus position to rhombomere 1, confirming previous studies (Marin and Puelles [1995], Eur J Neurosci 7:1714-1738) and in contrast to mouse PrV, which mainly maps to rhombomere 2-3 (Oury et al. [2006], Science 313:1408-1413). Thus, somatotopy of trigeminal ganglion and nerve organization is only partially conserved through amniote evolution, possibly in relation to the modification of facial somatosensory structures and morphologies.

To determine the anatomical characteristics of the petrous ridge and trigeminal nerve in trigeminal neuralgia (TN) without neurovascular compression (NVC).

Accumulating evidence shows that consciousness is linked to neural oscillations in the thalamocortical system, suggesting that deficits in these oscillations may underlie disorders of consciousness (DOC). However, patient-friendly non-invasive treatments targeting this functional anomaly are still missing and the therapeutic value of oscillation restoration has remained unclear. We propose a novel approach that aims to restore DOC patients' thalamocortical oscillations by combining rhythmic trigeminal-nerve stimulation with comodulated musical stimulation ("musical-electrical TNS"). In a double-blind, placebo-controlled, parallel-group study, we recruited 63 patients with DOC and randomly assigned them to groups receiving gamma, beta, or sham musical-electrical TNS. The stimulation was applied for 40 min on five consecutive days. We measured patients' consciousness before and after the stimulation using behavioral indicators and neural responses to rhythmic auditory speech. We further assessed their outcomes one year later. We found that musical-electrical TNS reliably lead to improvements in consciousness and oscillatory brain activity at the stimulation frequency: 43.5 % of patients in the gamma group and 25 % of patients in the beta group showed an improvement of their diagnosis after being treated with the stimulation. This group of benefitting patients still showed more positive outcomes one year later. Moreover, patients with stronger behavioral benefits showed stronger improvements in oscillatory brain activity. These findings suggest that brain oscillations contribute to consciousness and that musical-electrical TNS may serve as a promising approach to improve consciousness and predict long-term outcomes in patients with DOC.

Nerve injury may induce neuropathic pain. In studying the mechanisms of orofacial neuropathic pain, attention has been paid to the plastic changes that occur in the trigeminal ganglia (TGs) and nucleus in response to an injury of the trigeminal nerve branches. Previous studies have explored the impact of sciatic nerve injury on dorsal root ganglia (DRGs) and it has shown dramatic changes in the expression of multiple biomarkers. In large, the changes in biomarker expression in TGs after trigeminal nerve injury are similar to that in DRGs after sciatic nerve injury. However, important differences exist. Therefore, there is a need to study the plasticity of biomarkers in TGs after nerve injury in the context of the development of neuropathic pain-like behaviors.

Nearly 5 decades ago, the effect of trigeminal nerve stimulation (TNS) on cerebral blood flow was observed for the first time. This implication directly led to further investigations and TNS' success as a therapeutic intervention. Possessing unique connections with key brain and brainstem regions, TNS has been observed to modulate cerebral vasodilation, brain metabolism, cerebral autoregulation, cerebral and systemic inflammation, and the autonomic nervous system. The unique range of effects make it a prime therapeutic modality and have led to its clinical usage in chronic conditions such as migraine, prolonged disorders of consciousness, and depression. This review aims to present a comprehensive overview of TNS research and its broader therapeutic potentialities. For the purpose of this review, PubMed and Google Scholar were searched from inception to August 28, 2023 to identify a total of 89 relevant studies, both clinical and pre-clinical. TNS harnesses the release of vasoactive neuropeptides, modulation of neurotransmission, and direct action upon the autonomic nervous system to generate a suite of powerful multitarget therapeutic effects. While TNS has been applied clinically to chronic pathological conditions, these powerful effects have recently shown great potential in a number of acute/traumatic pathologies. However, there are still key mechanistic and methodologic knowledge gaps to be solved to make TNS a viable therapeutic option in wider clinical settings. These include bimodal or paradoxical effects and mechanisms, questions regarding its safety in acute/traumatic conditions, the development of more selective stimulation methods to avoid potential maladaptive effects, and its connection to the diving reflex, a trigeminally-mediated protective endogenous reflex. The address of these questions could overcome the current limitations and allow TNS to be applied therapeutically to an innumerable number of pathologies, such that it now stands at the precipice of becoming a ground-breaking therapeutic modality.

Quantitative sensory testing (QST) is applied to evaluate somatosensory nerve fiber function in the spinal system. This study uses QST in patients with sensory dysfunctions after oral and maxillofacial surgery.

In the spinal nervous system, the expression of galanin (GAL) and galanin receptors (GALRs) that play important roles in the transmission and modulation of nociceptive information can be affected by nerve injury. However, in the trigeminal nervous system, the effects of trigeminal nerve injury on the expression of GAL are controversy in the previous studies. Besides, little is known about the effects of trigeminal nerve injury on the expression of GALRs. In the present study, the effects of trigeminal nerve injury on the expression of GAL and GALRs in the rat trigeminal ganglion (TG) were investigated by using quantitative real-time reverse transcription-polymerase chain reaction and immunohistochemistry. To identify the nerve-injured and nerve-uninjured TG neurons, activating transcription factor 3 (ATF3, the nerve-injured neuron marker) was stained by immunofluorescence. The levels of GAL mRNA in the rostral half and caudal half of the TG dramatically increased after transection of infraorbital nerve (ION) and inferior alveolar nerve (IAN), respectively. Immunohistochemical labeling of GAL and ATF3 revealed that GAL level was elevated in both injured and adjacent uninjured small and medium-sized TG neurons after ION/IAN transection. In addition, the levels of GAL2R-like immunoreactivity were reduced in both injured and adjacent uninjured TG neurons after ION/IAN transection, while levels of GAL1R and GAL3R-like immunoreactivity remained unchanged. Furthermore, the number of small to medium-sized TG neurons co-expressing GAL- and GAL1R/GAL2R/GAL3R-like immunoreactivity was significantly increased after ION/IAN transection. In line with previous studies in other spinal neuron systems, these results suggest that GAL and GALRs play functional roles in orofacial neuropathic pain and trigeminal nerve regeneration after trigeminal nerve injury.

The effect of topical glycerol injection into the rat trigeminal nerves was investigated histologically and immunohistochemically. Anhydrous glycerol was injected into the preganglionic portion of the trigeminal nerves via a ventral approach. Extensive myelin swelling and axonolysis were observed in the rats killed 1 and 2 weeks after glycerol injection. Numerous inflammatory cells were seen especially in the animals sacrificed 1 week after surgery. Myelin disintegration continued up to 4 weeks after glycerol injection. In normal and saline injected sham operated nerves, calcitonin gene-related peptide (CGRP)- and substance P(SP)-like immunoreactivities were densely localized in the nerve fibers. A marked decrease in both CGRP- and SP-like immunofluorescence was seen in the nerves after glycerol injection. The remaining nerve fibers often had blunt endings with increased fluorescence. Swollen and winding structures were also found. These immunohistochemical changes were observed in the rats killed 1 and 2 weeks following surgery. A similar change but of lesser degree was seen in the 4-week-animal. The present study suggests that topical glycerol injection into the trigeminal nerve induces degeneration of the nerves immunoreactive to CGRP and SP. These changes emphasize the putative functional implications of the peptides in relieving the pain of trigeminal neuralgia after topical glycerol injection.

Following traumatic brain injury (TBI), ischemia and hypoxia play a major role in further worsening of the damage, a process referred to as 'secondary injury'. Protecting neurons from causative factors of secondary injury has been the guiding principle of modern TBI management. Stimulation of trigeminal nerve induces pressor response and improves cerebral blood flow (CBF) by activating the rostral ventrolateral medulla. Moreover, it causes cerebrovasodilation through the trigemino-cerebrovascular system and trigemino-parasympathetic reflex. These effects are capable of increasing cerebral perfusion, making trigeminal nerve stimulation (TNS) a promising strategy for TBI management. Here, we investigated the use of electrical TNS for improving CBF and brain oxygen tension (PbrO2), with the goal of decreasing secondary injury. Severe TBI was produced using controlled cortical impact (CCI) in a rat model, and TNS treatment was delivered for the first hour after CCI. In comparison to TBI group, TBI animals with TNS treatment demonstrated significantly increased systemic blood pressure, CBF and PbrO2 at the hyperacute phase of TBI. Furthermore, rats in TNS-treatment group showed significantly reduced brain edema, blood-brain barrier disruption, lesion volume, and brain cortical levels of TNF-α and IL-6. These data provide strong early evidence that TNS could be an effective neuroprotective strategy.

In the brain, insulin acts as a growth factor, regulates energy homeostasis, and is involved in learning and memory acquisition. Many central nervous system (CNS) diseases are characterized by deficits in insulin signaling. Pre-clinical studies have shown that intranasal insulin is neuroprotective in models of Alzheimer's disease, Parkinson's disease, and traumatic brain injury. Clinical trials have also shown that intranasal insulin elicits beneficial cognitive effects in patients with Alzheimer's disease. It is known that insulin can be detected in the CNS within minutes following intranasal administration. Despite these advances, the anatomical pathways that insulin utilizes to reach the CNS and the cellular CNS targets after intranasal administration are not fully understood. Here, we intranasally administered fluorescently labeled insulin and imaged its localization within the brain and trigeminal nerves. Our data indicates that intranasal insulin can reach cellular CNS targets along extracellular components of the trigeminal nerve. Upon CNS entry, we found insulin significantly increased levels of an activated form of the insulin receptor. These findings suggest that the intranasal route of administration is able to effectively deliver insulin to CNS targets in a biologically active form.

Trigeminal sensorimotor activity stimulates arousal and cognitive performance, likely through activation of the locus coeruleus (LC). In this study we investigated, in normal subjects, the effects of bilateral trigeminal nerve stimulation (TNS) on the LC-dependent P300 wave, elicited by an acoustic oddball paradigm. Pupil size, a proxy of LC activity, and electroencephalographic power changes were also investigated. Before TNS/sham-TNS, pupil size did not correlate with P300 amplitude across subjects. After TNS but not sham-TNS, a positive correlation emerged between P300 amplitude and pupil size within frontal and median cortical regions. TNS also reduced P300 amplitude in several cortical areas. In both groups, before and after TNS/sham-TNS, subjects correctly indicated all the target stimuli. We propose that TNS activates LC, increasing the cortical norepinephrine release and the dependence of the P300 upon basal LC activity. Enhancing the signal-to-noise ratio of cortical neurons, norepinephrine may improve the sensory processing, allowing the subject to reach the best discriminative performance with a lower level of neural activation (i.e., a lower P300 amplitude). The study suggests that TNS could be used for improving cognitive performance in patients affected by cognitive disorders or arousal dysfunctions.

To determine if trigeminal nerve electrical stimulation (TNS) would be an effective arousal treatment for loss of consciousness (LOC), we applied neuroscientific methods to investigate the role of potential brain circuit and neuropeptide pathway in regulating level of consciousness.

Trigeminal neuralgia commonly results in pain behaviors and cognitive impairment. Convincing evidence suggests that TWIK-related spinal cord K+ (TRESK) exerts antinociceptive and neuroprotective effects. However, its possible potentials in trigeminal neuralgia remain unclear. Trigeminal neuralgia model was established in rats by generating an infraorbital nerve chronic constriction injury, and rats received intrathecal injections of TRESK-overexpressing lentivirus and siRNA expression vector-targeted against TRESK (si-TRESK) into the trigeminal ganglions. Mechanical allodynia was evaluated by mechanical withdrawal threshold. Cognitive capacity was tested using Morris water maze. The TRESK expression was determined by quantitative real-time polymerase chain reaction and Western blotting. Results showed that the mRNA and protein levels of TRESK were significantly downregulated in trigeminal ganglions in injured rats. Intrathecal treatment with TRESK reduced mechanical allodynia and relieved learning and memory deficits in trigeminal neuralgia rats, while si-TRESK injection caused neuropathic pain and cognitive deficits. In summary, the present study concluded that TRESK ameliorated pain-associated behaviors and cognitive deficits, which was useful as an alternative approach in management of trigeminal neuralgia.

Trigeminal Neuralgia (TN) is a chronic neurological disease that is strongly associated with neurovascular compression (NVC) of the trigeminal nerve near its root entry zone. The trigeminal nerve at the site of NVC has been extensively studied but limbic structures that are potentially involved in TN have not been adequately characterized. Specifically, the hippocampus is a stress-sensitive region which may be structurally impacted by chronic TN pain. As the center of the emotion-related network, the amygdala is closely related to stress regulation and may be associated with TN pain as well. The thalamus, which is involved in the trigeminal sensory pathway and nociception, may play a role in pain processing of TN. The objective of this study was to assess structural alterations in the trigeminal nerve and subregions of the hippocampus, amygdala, and thalamus in TN patients using ultra-high field MRI and examine quantitative differences in these structures compared with healthy controls.

Background and aim A recent sham-controlled trial showed that external trigeminal nerve stimulation (eTNS) is effective in episodic migraine (MO) prevention. However, its mechanism of action remains unknown. We performed 18-fluorodeoxyglucose positron emission tomography (FDG-PET) to evaluate brain metabolic changes before and after eTNS in episodic migraineurs. Methods Twenty-eight individuals were recruited: 14 with MO and 20 healthy volunteers (HVs). HVs underwent a single FDG-PET, whereas patients were scanned at baseline, directly after a first prolonged session of eTNS (Cefaly®) and after three months of treatment (uncontrolled study). Results The frequency of migraine attacks significantly decreased in compliant patients ( N = 10). Baseline FDG-PET revealed a significant hypometabolism in fronto-temporal areas, especially in the orbitofrontal (OFC) and rostral anterior cingulate cortices (rACC) in MO patients. This hypometabolism was reduced after three months of eTNS treatment. Conclusion Our study shows that metabolic activity of OFC and rACC, which are pivotal areas in central pain and behaviour control, is decreased in migraine. This hypometabolism is reduced after three months of eTNS. eTNS might thus exert its beneficial effects via slow neuromodulation of central pain-controlling areas, a mechanism also previously reported in chronic migraine and cluster headache after percutaneous occipital nerve stimulation. However, this finding needs to be confirmed by further studies using a sham condition.

Injury of the trigeminal nerve in oral and maxillofacial surgery can occur. Schwann cell mitochondria are regulators in the development, maintenance and regeneration of peripheral nerve axons. Evidence shows that after the nerve injury, mitochondrial bioenergetic dysfunction occurs and is associated with pain, neuropathy and nerve regeneration deficit. A challenge for research is to individuate new therapies able to normalise mitochondrial and energetic metabolism to aid nerve recovery after damage. Photobiomodulation therapy can be an interesting candidate, because it is a technique involving cell manipulation through the photonic energy of a non-ionising light source (visible and NIR light), which produces a nonthermal therapeutic effect on the stressed tissue.

The neurotrophin Nerve Growth factor (NGF) is known to influence the phenotype of mature nociceptors, for example by altering synthesis of neuropeptides, and changes in NGF levels have been implicated in the pathophysiology of chronic pain conditions such as neuropathic pain. We have tested the hypothesis that after partial nerve injury, NGF accumulates within the skin and causes 'pro-nociceptive' phenotypic changes in the remaining population of sensory nerve fibres, which could underpin the development of neuropathic pain.