Trigeminal Fibers Research Articles

Migraine Causality in Alpha-1 Antitrypsin Deficiency

Alpha1-antitrypsin (A1AT) is an anti-inflammatory mediator with antiprotease activity associated with anti-inflammatory and immunomodulatory effects in various inflammatory conditions. A1AT deficiency (A1ATD) has been associated with various hyperinflammatory diseases, such as lung disease (emphysema and bronchiectasis), liver disease (chronic hepatitis, cirrhosis, and hepatoma), and skin diseases (panniculitis). Migraine with aura is one of the common migraine subtypes associated with neuroimmunologic activation and neuroinflammation which is associated with cortical spreading depression and glial hyperinflammation in etioradiopathogenesis, and the main mechanisms explained so far are hyperinflammation of pro-inflammatory mediators, sensitivity of trigeminal nerve fibers and pain-conjugated glial cells activation. In this case report, a causative perspective of migraine with aura and A1ATD was presented through etioradiopathogenetics mechanisms that show the central reflections of systemic hyperinflammatory processes, and the importance of peripheral hyperinflammatory conditions in migraine etiology was examined.

Histochemical Evidence for Reduced Immune Response in Nasal Mucosa of Patients with COVID-19.

The primary entry point of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the nasal mucosa, where viral-induced inflammation occurs. When the immune response fails against SARS-CoV-2, understanding the altered response becomes crucial. This study aimed to compare SARS-CoV-2 immunological responses in the olfactory and respiratory mucosa by focusing on epithelia and nerves. Between 2020 and 2022, we obtained post mortem tissues from the olfactory cleft from 10 patients with histologically intact olfactory epithelia (OE) who died with or from COVID-19, along with four age-matched controls. These tissues were subjected to immunohistochemical reactions using antibodies against T cell antigens CD3, CD8, CD68, and SARS spike protein for viral evidence. Deceased patients with COVID-19 exhibited peripheral lymphopenia accompanied by a local decrease in CD3+ cells in the OE. However, SARS-CoV-2 spike protein was sparsely detectable in the OE. With regard to the involvement of nerve fibers, the present analysis suggested that SARS-CoV-2 did not significantly alter the immune response in olfactory or trigeminal fibers. On the other hand, SARS spike protein was detectable in both nerves. In summary, the post mortem investigation demonstrated a decreased T cell response in patients with COVID-19 and signs of SARS-CoV-2 presence in olfactory and trigeminal fibers.

A novel method of neurophysiological brainstem mapping in neurosurgery

BackgroundBrainstem mapping with electrical stimulation allows functional identification of neural structures during resection of deep lesions. Single pulses or train of pulses are delivered to map cranial nerves and corticospinal tracts, respectively. New methodWe introduce a hybrid stimulation technique for mapping the brainstem. The stimulus consists of an electrical single pulse followed by a short train of 3–5 pulses at 500 Hz, at an interval of 60-75 ms. The responses to this stimulation pattern are recorded from appropriate cranial and limb muscles. ResultsBoth the single pulse and the short train elicit electromyographic responses when motor fibers or motor nuclei of the cranial nerves are stimulated. Responses to the train but not to the preceding single pulse indicate activation of the descending motor tracts, in the mesencephalon and the pons. Conversely, in the medulla, limb responses to stimulation of the corticospinal tracts are elicited by a single pulse. Identification of the extra and intra-axial courses of the trigeminal motor and sensory fibers is possible by recording responses from the masseter and the tongue muscles. Comparison with existing method(s)To date, either a pulse or a train is delivered during brainstem mapping, switching from one to the other modality according to the expected target structure. This procedure can be time-consuming and may even lead to false negative responses to the stimulation, eventually leading to inaccurate neurosurgical procedures. ConclusionsThe novel hybrid pulse-train technique enhances the advantage of brainstem mapping procedure, minimizing pitfalls and improving patient safety.

Internal Neurolysis for Trigeminal Neuralgia: A Preliminary Single-institution Experience in Japan.

Internal neurolysis (IN) is a surgical procedure in which the trigeminal fibers are separated between the pons and porus trigeminus to relieve trigeminal neuralgia (TN). Recent investigations revealed that the number of nerve bundles made by IN varies, and immediate postoperative hypesthesia exceeded 90% and pain control rate at 1 year was 77%-93.5%. We present the preliminary experience of 18 patients who underwent IN for TN between June 2020 and June 2022. The Barrow Neurological Institute pain scale (BNI-PS) was recorded preoperatively and in June 2023, and the Barrow Neurological Institute hypesthesia scale (BNI-HS) was recorded preoperatively, immediate postoperatively and in June 2023. Intraoperatively, the number of bundles made by IN was reviewed. Preoperative BNI-PS ranged between VI and V. Two patients experienced BNI-HS II due to percutaneous procedure prior to IN. Intraoperatively, 3 bundles were made by IN in 7 patients, 4 bundles in 5, and 5 bundles in 6. Immediate postoperative BNI-HS I was recorded in 6 patients and II in 12 (66.7%). The last follow-up revealed that BNI-PS I and II were recorded in 13 patients (72.2%) and BNI-HS I and II in 6 patients, respectively. Our results demonstrated that the rates of immediate postoperative hypesthesia (66.7%) and pain control (72.2%) at 1 year or later were below those of previous reports. Therefore, we are currently combing to make at least 6 bundles. Detailed surgical technique and cardiac reflex alerts during the procedure are described.

Endoscopic far-lateral supracerebellar infratentorial approach for resection of dumbbell-shaped trigeminal schwannoma: surgical techniques and preliminary results.

Trigeminal schwannomas (TSs) are mostly benign tumors. However, dumbbell-shaped TSs are most challenging for surgeons and pose a high surgical risk. We describe the technique of the purely endoscopic far-lateral supracerebellar infratentorial approach (EFL-SCITA) for removing dumbbell-shaped TSs and further discuss the feasibility of this approach and our experience. EFL-SCITA was performed for resection of 5 TSs between January 2020 and March 2023. The entire procedure was performed endoscopically with the goal of total tumor resection. During the operation, the tumor was exposed in close proximity and multiple angles under the endoscope, and the peri-tumor nerves were carefully identified and protected, especially the normal trigeminal fiber bundles around the tumor. All the tumors of 5 patients involved the middle and posterior cranial fossa, of which total removal was achieved in 2 patients and near-total removal in 3 patients. The most common preoperative symptoms were relieved after surgery. Two patients had postoperative mild facial paralysis (House-Brackmann grade II), and 1 patient had abducens palsy; both recovered during the follow-up period. Two patients experienced new postoperative facial hypesthesia, and 1 experienced mastication weakness, which did not recover. There was no tumor recurrence or residual tumor growth during the follow-up period in any of the patients. EFL-SCITA is a new and effective alternative for the surgical treatment of TSs. For dumbbell-shaped TSs, this approach provides sufficient surgical field exposure and freedom of operation.

Lipopolysaccharide-induced Trigeminal Ganglion Nerve Fiber Damage is Associated with Autophagy Inhibition.

This study aimed to determine whether lipopolysaccharide (LPS) induces the loss of corneal nerve fibers in cultured trigeminal ganglion (TG) cells, and the underlying mechanism of LPS-induced TG neurite damage. TG neurons were isolated from C57BL/6 mice, and the cell viability and purity were maintained for up to 7 days. Then, they were treated with LPS (1 µg/mL) or the autophagy regulator (autophibib and rapamycin) alone or in combination for 48 h, and the length of neurites in TG cells was examined by the immunofluorescence staining of the neuron-specific protein β3-tubulin. Afterwards, the molecular mechanisms by which LPS induces TG neuron damage were explored. The immunofluorescence staining revealed that the average length of neurites in TG cells significantly decreased after LPS treatment. Importantly, LPS induced the impairment of autophagic flux in TG cells, which was evidenced by the increase in the accumulation of LC3 and p62 proteins. The pharmacological inhibition of autophagy by autophinib dramatically reduced the length of TG neurites. However, the rapamycin-induced activation of autophagy significantly lessened the effect of LPS on the degeneration of TG neurites. LPS-induced autophagy inhibition contributes to the loss of TG neurites.

Queratopatía neurotrófica severa en paciente con compromiso bilateral del reflejo palpebral con diferente sustrato neurológico pos-TEC: reporte de un caso

Se presenta el caso de un paciente que experimentó un TEC severo, asociado a fracturas de huesos craneales y lesión de pares craneales: II par izquierdo, ramas sensitivas corneales y oculares de la primera rama del trigémino derecho, y VII par izquierdo. Secundario a lo anterior, en el paciente se alteró el reflejo palpebral de manera bilateral, pero con un sustrato neurológico diferente. Con el paso del tiempo, ya en fase crónica pos-TEC, el paciente desarrolló una queratopatía neurotrófica severa. Es un caso llamativo por la correlación neuroanatómica que exige y el papel trófico epitelial que representa el nervio trigémino a nivel corneal y porque otorga información al personal médico en neurociencias clínicas para predecir la aparición de una complicación compleja de tratar como lo es la queratopatía neurotrófica. Son escasos los reportes en la literatura de esta temática, asociada a TEC y lesión de diferentes pares craneanos.

The Nasal Solitary Chemosensory Cell Signaling Pathway Triggers Mouse Avoidance Behavior to Inhaled Nebulized Irritants.

The nasal epithelium houses a population of solitary chemosensory cells (SCCs). SCCs express bitter taste receptors and taste transduction signaling components and are innervated by peptidergic trigeminal polymodal nociceptive nerve fibers. Thus, nasal SCCs respond to bitter compounds, including bacterial metabolites, and these reactions evoke protective respiratory reflexes and innate immune and inflammatory responses. We tested whether SCCs are implicated in aversive behavior to specific inhaled nebulized irritants using a custom-built dual-chamber forced-choice device. The behavior of mice was recorded and analyzed for the time spent in each chamber. Wild-type (WT) mice exhibited an aversion to 10 mm denatonium benzoate (Den) or cycloheximide and spent more time in the control (saline) chamber. The SCC-pathway knock-out (KO) mice did not exhibit such an aversion response. The bitter avoidance behavior of WT mice was positively correlated with the concentration increase of Den and the number of exposures. Bitter-ageusic P2X2/3 double KO mice similarly showed an avoidance response to nebulized Den, excluding the taste system's involvement and pointing to an SCC-mediated major contributor to the aversive response. Interestingly, SCC-pathway KO mice showed an attraction to higher Den concentrations; however, chemical ablation of the olfactory epithelium eliminated this attraction attributed to the smell of Den. These results demonstrate that activation of SCCs leads to a rapid aversive response to certain classes of irritants with olfaction, but not gustation, contributing to the avoidance behavior during subsequent irritant exposures. This SCC-mediated avoidance behavior represents an important defense mechanism against the inhalation of noxious chemicals.

OnabotulinumtoxinA: Still the Present for Chronic Migraine.

OnabotulinumtoxinA (BT-A) is one of the few drugs approved for the preventive treatment of chronic migraine (CM). Despite this, some aspects of its mechanism of action are still a matter of debate, and the precise magnitude of BT-A effects needs to be completely elucidated. BT-A acts primarily upon trigeminal and cervical nerve endings, by inhibiting the release of inflammatory mediators such as calcitonin gene-related peptide, as well as reducing the insertion of ionotropic and metabotropic receptors into the neuronal membrane. These actions increase the depolarization threshold of trigeminal and cervical nerve fibers, thus reducing their activation. The central actions of BT-A are still a matter of debate: a retrograde axonal transport has been postulated, but not clearly assessed in humans. Clinically, the efficacy of BT-A in CM has been assessed by large, randomized placebo-controlled trials, such as the Phase 3 REsearch Evaluating Migraine Prophylaxis Therapy (PREEMPT) trials. Those results were also confirmed in a wide range of open-label studies, even for long-term periods. Recently, novel findings have led to a better understanding of its pharmacological actions and clinical usefulness in migraine prevention. This narrative review summarizes, updates and critically revises the available data on BT-A and its possible implementation in chronic migraine. Moreover, the current role of BT-A in CM treatment has been discussed.

Objectively-captured Changes in Trigeminal Fibers before and after Microvascular Decompression Using 3D T2-SPACE MRI Might Relate to Eventual Residual Symptoms.

Although microvascular decompression (MVD) is a reliable treatment for trigeminal neuralgia (TN), neurosurgeons sometimes encounter patients whose symptoms do not improve postoperatively or who experience good treatment efficacy but develop other sensory disturbances. This study aims to objectively identify changes in nerve fibers before and after surgery by MRI and to clarify the relationship between the changes and residual postoperative symptoms. We retrospectively analyzed data from 36 consecutive patients who underwent MVD for classical TN at our hospital between November 2019 and November 2020. Cases that fulfilled the diagnostic criteria for multiple sclerosis were excluded. We confirmed the changes on the brainstem side of the trigeminal nerve preoperatively and at seven days postoperatively using 3D T2-SPACE MRI, in which the patients were divided into three groups: preoperative T2 high intensity positive (A), postoperative T2 high intensity positive (B), and no T2 high-intensity region (C). The primary outcome measures were therapeutic efficacy and frequency of postoperative numbness. The results of MVD surgery were evaluated one year postoperatively. The percentage of cases in which treatment outcomes were rated as excellent or good at one year: group A: 0 (0%), group B: 6 (100%), and group C: 25 (96.2%) (p < 0.05); the frequency of numbness: 2 (50%) in group A, 3 (50%) in group B, and 1 (3.8%) in group C, indicating significant differences between the three groups (p < 0.05). 3D T2-SPACE MRI sequences can be used to identify changes in trigeminal nerve fibers before and after MVD, which might correlate with eventual residual symptoms.

Symptoms: Sudden Hearing Loss and Aural Fullness

Symptoms: Sudden Hearing Loss and Aural Fullness

Electrophysiological evidence of subclinical trigeminal dysfunction in patients with COVID-19 and smell impairment: A pilot study.

BackgroundSmell and taste disturbances are among the most frequent neurological symptoms in patients with COVID-19. A concomitant impairment of the trigeminal nerve has been suggested in subjects with olfactory dysfunction, although it has not been confirmed with objective measurement techniques. In this study, we explored the trigeminal function and its correlations with clinical features in COVID-19 patients with impaired smell perception using electrophysiological testing.MethodsWe enrolled 16 consecutive patients with mild COVID-19 and smell impairment and 14 healthy controls (HCs). Olfactory and gustatory symptoms were assessed with self-reported questionnaires. Electrophysiological evaluation of the masseter inhibitory reflex (MIR) and blink reflex (BR) was carried out to test the trigeminal function and its connections within the brainstem.ResultsMasseter inhibitory reflex (MIR) analysis revealed higher latency of ipsilateral and contralateral early silent period in patients when compared with HCs. No significant differences between groups were detected as regards the duration of the early and late silent period. However, several patients showed a prolonged duration of the early silent period. BR evaluation disclosed only an increased amplitude of early components in patients.ConclusionsPatients with COVID-19 and smell impairment show a subclinical trigeminal nerve impairment. Trigeminal alterations mainly involve the oligosynaptic pathway, as a result of either direct viral damage or secondary neuroinflammation of the peripheral trigeminal fibers, whereas the polysynaptic ponto-medullary circuits seem to be spared. The prolonged duration of the early silent period and the increased amplitude of early BR response might reflect a compensatory upregulation of the trigeminal function as a consequence of the olfactory dysfunction.

Neurosensory development of the four brainstem-projecting sensory systems and their integration in the telencephalon.

Somatosensory, taste, vestibular, and auditory information is first processed in the brainstem. From the brainstem, the respective information is relayed to specific regions within the cortex, where these inputs are further processed and integrated with other sensory systems to provide a comprehensive sensory experience. We provide the organization, genetics, and various neuronal connections of four sensory systems: trigeminal, taste, vestibular, and auditory systems. The development of trigeminal fibers is comparable to many sensory systems, for they project mostly contralaterally from the brainstem or spinal cord to the telencephalon. Taste bud information is primarily projected ipsilaterally through the thalamus to reach the insula. The vestibular fibers develop bilateral connections that eventually reach multiple areas of the cortex to provide a complex map. The auditory fibers project in a tonotopic contour to the auditory cortex. The spatial and tonotopic organization of trigeminal and auditory neuron projections are distinct from the taste and vestibular systems. The individual sensory projections within the cortex provide multi-sensory integration in the telencephalon that depends on context-dependent tertiary connections to integrate other cortical sensory systems across the four modalities.

Clinical Outcome of Partial Sensory Rhizotomy in Negative-Exploration Trigeminal Neuralgia and Technical Nuances

Background: Microvascular decompression is considered to be a potential treatment for most trigeminal neuralgia cases with obvious neurovascular conflict. Partial sensory rhizotomy (PSR) is an alternate option in cases of negative investigation for neurovascular conflict, although its effectiveness and technical complexity are still being debated. Objective: To evaluate the therapeutic efficacy of PSR following negative-exploration trigeminal neuralgia (NETN) in terms of pain control, adverse effects from sensory fiber destruction, and patient satisfaction in the short-term or after 1 month, and in the long-term or after 12 months. In addition, technical nuances were highlighted to mitigate the negative effects of PSR. Materials and Methods: The present study enrolled 27 NETN patients, and all were operated by the same neurosurgeon. The patients underwent surgery via a keyhole retromastoid technique, with extensive exploration for any possible intraoperative neurovascular conflict. A modified PSR approach was used to operate on these negative exploration cases, and this entailed cutting fewer than 1/5 of the trigeminal sensory fibers. The short-term or within one month, and long-term or after one-year intervals were used to track all instances. The therapeutic efficacy of employing pain score and subjective sensation in terms of pain control, adverse consequences from sensory fiber destruction, and patient satisfaction were investigated. Results: Eighty-five point two percent of patients reported excellent pain control following PSR, in terms of both pain score and total pain alleviation. Despite having their trigeminal nerve fibers severed, not all of the patients experienced numbness, and 45% of patients recovered to some extent on their own within a year. Only 13% of patients had Anesthesia Dolorosa in the present trial, which could be attributable because only 1/5 of the trigeminal nerve fibers were severed. There was no relationship between pain distribution and pain alleviation efficacy before and after PSR. When PSR was effective, most patients should notice an improvement within a month of the surgery. Conclusion: For patients with negative exploration following keyhole suboccipital craniectomy, PSR proved to be therapeutic and effective in alleviating trigeminal neuralgic pain. The majority of the patients can tolerate the minor side effects from minute nerve destruction well, particularly numbness, which partially resolves on its own with time. Keywords: Negative exploration; Trigeminal neuralgia; Microvascular decompression; Partial sensory rhizotomy; Efficacy

Unravelling the role of unmyelinated nerve fibres in trigeminal neuralgia with concomitant continuous pain

ObjectiveIn this clinical and neurophysiological study, we aimed to test trigeminal nerve fibre function in patients with trigeminal neuralgia, with and without concomitant continuous pain. MethodsWe enrolled 65 patients with a definite diagnosis of primary trigeminal neuralgia. Patients were grouped according to whether they experienced purely paroxysmal pain (36) or also had concomitant continuous pain (29). All participants underwent trigeminal reflex testing to assess the function of large non-nociceptive myelinated fibres and laser-evoked potentials to assess the function of small myelinated Aδ and unmyelinated C fibres. Neurophysiological examiners were blinded to the affected side. ResultsThe only neurophysiological abnormality distinguishing the two groups of patients was the side asymmetry of C fibre-related laser-evoked potential amplitude (p = 0.005), which was higher in patients with concomitant continuous pain than in patients with purely paroxysmal pain (indicative of a reduced C fibre-related laser-evoked potential amplitude in the affected side of patients with concomitant continuous pain). ConclusionsOur clinical and neurophysiological study indicates that in patients with trigeminal neuralgia concomitant continuous pain is associated with unmyelinated C fibre damage as assessed with laser-evoked potentials. SignificanceOur findings suggest that concomitant continuous pain is related to unmyelinated C fibre loss, possibly triggering abnormal activity in denervated trigeminal second-order neurons.

Trigeminal Nerve Affection in Patients with Neuro-Sjögren Detected by Corneal Confocal Microscopy

Background: Patients with Sjögren’s syndrome and polyneuropathy more frequently develop cranial nerve affection when compared to patients with chronic inflammatory demyelinating polyneuropathy (CIDP). We therefore aimed to analyze trigeminal corneal nerve fibre characteristics in both patient groups. Methods: A total of 26 patients with Sjögren’s syndrome associated neuropathy and 29 patients with CIDP were recruited at our university hospital and compared to 6 healthy controls. Dry eye symptoms and signs were assessed via clinical examination and the Ocular Disease Surface Index questionnaire. Trigeminal corneal nerve fibres were analyzed via corneal confocal microscopy (CCM) as a non-invasive in vivo microscopy. Results: CCM revealed significantly reduced corneal nerve fibre density and corneal nerve fibre main branch density in the Neuro-Sjögren group when compared with healthy controls. There were no significant group differences between the Neuro-Sjögren and the CIDP group for any of the microscopic parameters. Dry eye assessment showed similarly reduced scores for both patient groups, while healthy controls showed better results for objective dry eye signs. There was no correlation between microscopic parameters of the corneal confocal microscopy and parameters of dry eye assessment. Conclusions: Our data revealed trigeminal corneal nerve affection in patients with neuropathy associated with Sjögren’s syndrome and patients with CIDP detected by CCM. No difference was found between both neuropathy groups indicating that CCM is not able to distinguish between both entities.

Distribution of TRPM8-expressing trigeminal nerve fibers in the pons and medulla oblongata of the mouse brain

Transient receptor potential melastatin 8 (TRPM8), a cold-mediated ion channel, is well known to be expressed in primary sensory neurons; however, limited information is currently available on the distribution of TRPM8-expressing trigeminal nerve fibers in the brainstem. The present study showed the distribution of TRPM8-expressing fibers in the pons and medulla oblongata of the TRPM8 KO mice engineered by knocking in EGFP at the frame of the start codon of TRPM8. In addition, TRPM8-expressing fibers were also observed in the brachium pontis, middle cerebellar peduncle, the sensory root of the trigeminal nerve, and spinal trigeminal tract (sp5). Furthermore, TRPM8-expressing nerve fibers surrounded the somata of HuC/D-positive neurons in the sp5. Moreover, the distribution of TRPM8-expressing fibers from rostral to caudal was visualized in sagittal sections of the mouse brain. The present results also revealed that a high number of TRPM8-expressing fibers colocalized with CTB-labeled fibers in the sp5 following an injection of CTB into the whisker compared to mice's eye and ear. These results show the distribution pathway of TRPM8-expressing fibers in the pons and medulla oblongata and possible involvement in peripheral signaling from the trigeminal nerve.

Long latency responses in tongue muscle elicited by various stimulation sites in anesthetized humans – New insights into tongue-related brainstem reflexes

BackgroundLong Latency Responses (LLR) in tongue muscles are a scarcely described phenomenon, the physiology of which is uncertain. ObjectivesThe aim of this exploratory, observational study was to describe tongue-LLR elicited by direct trigeminal nerve (DTNS), dorsal column (DoColS), transcranial electric (TES) and peripheral median nerve (MNS) stimulation in a total of 93 patients undergoing neurosurgical procedures under general anesthesia. MethodsBilateral tongue responses were derived concurrently after each of the following stimulations: (1) DTNS applied with single monophasic or train-of-three pulses, ≤5 mA; (2) DoColS applied with a train-of-three pulses, ≤10 mA; (3) TES consisting of an anodal train-of-five stimulation, ≤250 mA; (4) MNS at wrist consisting of single or train-of-three monophasic pulses, ≤50 mA. Polyphasic tongue muscle responses exceeding the latencies of tongue compound muscle action potentials or motor evoked potentials were classified as LLR. ResultsTongue-LLR were evoked from all stimulation sites, with latencies as follows: (1) DTNS: solely ipsilateral 20.2 ± 3.3 msec; (2) DoColS: ipsilateral 25.9 ± 1.6 msec, contralateral 25.1 ± 4.2 msec; (3) TES: contralateral 55.3 ± 10.2 msec, ipsilateral 54.9 ± 12.0 msec; (4) MNS: ipsilateral 37.8 ± 4.7 msec and contralateral 40.3 ± 3.5 msec. ConclusionThe tongue muscles are a common efferent in brainstem pathways targeted by trigeminal and cervical sensory fibers. DTNS can elicit the “trigemino-hypoglossal-reflex”. For the MNS elicited tongue-LLR, we propose the term “somatosensory-evoked tongue-reflex”. Although the origin of the TES related tongue-LLR remains unclear, these data will help to interpret intraoperative tongue recordings.

The trigeminal pathways.

The role of the trigeminal system in facial and dural sensitivity has been recognized for a long time. More recently, the trigeminal system has also been considered a prominent actor in brain nociceptive innervation. It is the anatomical substrate of several frequent conditions, such as primary or secondary headaches, trigeminal neuralgia, and other orofacial pains. Appreciation of the delicate anatomical arrangement of the trigeminal pathway is one of the keys to understanding these conditions' pathophysiology and to proposing innovative treatments. This review provides a structured presentation of existing knowledge about the trigeminal system, from classical anatomical data to the most recent literature. First, we present the organization of the trigeminal pathway from the trigeminal divisions, nerve, and nuclei to the thalamus and somatosensory cortex. We describe the neurons and fibers' repartition at each level, depending on the location (somatotopic organization) and the type of receptors (modal organization). Such a dual somatotopic-modal arrangement of the trigeminal fibers is especially clear for the juxtapontine segment of the trigeminal nerve and the trigeminal nuclei of the brainstem. It has significant clinical consequences both for diagnosis and treatment. Second, we explore how the trigeminal system is modulated and involved in reflexes, for instance the trigemino-cardiac and the trigemino-autonomic reflexes, which could play an essential role in the autonomic symptoms observed in cluster headache. Finally, we present how to interact with this complex system to relieve pain mediated by the trigeminal system. This section covers both neuromodulatory and lesional approaches.

Tgfbr2 in Dental Pulp Cells Guides Neurite Outgrowth in Developing Teeth.

Transforming growth factor β (TGFβ) plays an important role in tooth morphogenesis and mineralization. During postnatal development, the dental pulp (DP) mesenchyme secretes neurotrophic factors that guide trigeminal nerve fibers into and throughout the DP. This process is tightly linked with dentin formation and mineralization. Our laboratory established a mouse model in which Tgfbr2 was conditionally deleted in DP mesenchyme using an Osterix promoter-driven Cre recombinase (Tgfbr2 cko ). These mice survived postnatally with significant defects in bones and teeth, including reduced mineralization and short roots. Hematoxylin and eosin staining revealed reduced axon-like structures in the mutant mice. Reporter imaging demonstrated that Osterix-Cre activity within the tooth was active in the DP and derivatives, but not in neuronal afferents. Immunofluorescence staining for β3 tubulin (neuronal marker) was performed on serial cryosections from control and mutant molars on postnatal days 7 and 24 (P7, P24). Confocal imaging and pixel quantification demonstrated reduced innervation in Tgfbr2 cko first molars at both stages compared to controls, indicating that signals necessary to promote neurite outgrowth were disrupted by Tgfbr2 deletion. We performed mRNA-Sequence (RNA-Seq) and gene onotology analyses using RNA from the DP of P7 control and mutant mice to investigate the pathways involved in Tgfbr2-mediated tooth development. These analyses identified downregulation of several mineralization-related and neuronal genes in the Tgfbr2 cko DP compared to controls. Select gene expression patterns were confirmed by quantitative real-time PCR and immunofluorescence imaging. Lastly, trigeminal neurons were co-cultured atop Transwell filters overlying primary Tgfbr2 f/f DP cells. Tgfbr2 in the DP was deleted via Adenovirus-expressed Cre recombinase. Confocal imaging of axons through the filter pores showed increased axonal sprouting from neurons cultured with Tgfbr2-positive DP cells compared to neurons cultured alone. Axon sprouting was reduced when Tgfbr2 was knocked down in the DP cells. Immunofluorescence of dentin sialophosphoprotein in co-cultured DP cells confirmed reduced mineralization potential in cells with Tgfbr2 deletion. Both our proteomics and RNA-Seq analyses indicate that axonal guidance cues, particularly semaphorin signaling, were disrupted by Tgfbr2 deletion. Thus, Tgfbr2 in the DP mesenchyme appears to regulate differentiation and the cells’ ability to guide neurite outgrowth during tooth mineralization and innervation.