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Recently developed optogenetic technology, which allows high-fidelity control of neuronal activity, has been applied to investigate the neural circuits underlying sensory processing and behavior. The nasal cavity is innervated by the olfactory nerve and trigeminal nerve, which are closely related to common symptoms of rhinitis, such as impairment of smell, itching, and sneezing. The olfactory system has an amazing ability to distinguish thousands of odorant molecules at trace levels. However, there are many issues in olfactory sensing mechanisms that need to be addressed. Optogenetics offers a novel technical approach to solve this dilemma. Therefore, we review the recent advances in olfactory optogenetics to clarify the mechanisms of chemical sensing, which may help identify the mechanism of dysfunction and suggest possible treatments for impaired smell. Additionally, in rhinitis patients, alterations in the other nerve (trigeminal nerve) that innervates the nasal cavity can lead to hyperresponsiveness to various nociceptive stimuli and central sensitization, causing frequent and persistent itching and sneezing. In the last several years, the application of optogenetics in regulating nociceptive receptors, which are distributed in sensory nerve endings, and amino acid receptors, which are distributed in vital brain regions, to alleviate overreaction to nociceptive stimuli, has gained significant attention. Therefore, we focus on the progress in optogenetics and its application in neuromodulation of nociceptive stimuli and discuss the potential clinical translation for treating rhinitis in the future., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Feng Xiang et al.)

Background: This study aimed to determine how nasal airflow measures and trigeminal function vary among patients with chronic rhinosinusitis (CRS) versus healthy controls and whether these measures are correlated with subjective nasal obstruction (SNO), olfactory function, and CRS control., Methodology: Participants included CRS patients and healthy controls. After a structured medical history, nasal airflow (peak nasal inspiratory flow [PNIF]; active anterior rhinomanometry [AAR]), trigeminal function (trigeminal lateralization test, CO2 sensitivity), and olfactory "Sniffin's Sticks" odor identification test) tests were performed. SNO ratings were also obtained., Results: Sixty-nine participants were included (37 men, 32 women, mean age 51 years). There was no significant difference for objective nasal airflow between patients and controls, but CRS patients had worse SNO, trigeminal function, and olfaction compared to controls. SNO, but not objective nasal airflow tests, was negatively correlated with CO2 sensitivity and odor identification., Conclusion: The perception of nasal obstruction does not only depend on nasal airflow, but may also be modulated by trigeminal function and other factors. Thus, the role of objective nasal airflow measures as a sole method of functional nasal obstruction assessment in CRS remains limited.

Objective: The trigemino-cervical complex (TCC) seems under dopaminergic inhibitory control and the abnormalities of trigemino-cervical reflex (TCR) have been reported in disorders associated with the dopaminergic system and various pain disorders. If the inhibitory response in TCC is likely dopaminergic, we hypothesized that TCR, which has never been evaluated in restless legs syndrome (RLS) patients before, would be also abnormal., Methods: TCR was recorded from bilateral sternocleidomastoid and splenius capitis muscles in consecutive 15 drug-naive RLS patients and 16 age- and sex-matched healthy subjects. The right and left infraorbital branches of the trigeminal nerve were stimulated by percutaneous electrical stimulation separately. The presence rates, onset latencies, amplitudes, and durations of responses were measured and compared between patients with RLS and controls., Results: The presence rates, onset latencies and amplitudes of TCR responses were similar between RLS patients and controls, however, the durations of responses were bilaterally longer in RLS patients compared to healthy volunteers., Conclusions: Hyperexcitability of TCR suggests defective sensory processing in the brainstem probably due to impairment of descending inhibitory dopaminergic system in RLS. The sensitization of TCC in RLS patients may also be a possible factor that might explain the association of RLS and pain disorders.

Background: Central and peripheral sensitization are characterized by widespread hyperalgesia that is manifested by larger pain extent area and reduction in pressure pain threshold (PPT). PPT decreases in patients with migraine not only over the trigeminal cervical complex but also throughout the body., Methods: A cross-sectional study was adopted to assess the local and widespread hyperalgesia in chronic and episodic migraine patients respect to healthy controls. The guidelines of Andersen's were used to evaluate the PPT bilaterally over 3 muscles in the trigemino-cervical complex (temporalis, sub-occipitalis, trapezius) and over 1 muscle far from this area (tensor fasciae latae)., Results: Thirty subjects with episodic migraine (35.8 ± 2.82 years), 30 with chronic migraine (53.03 ± 19.79 years), and 30 healthy controls (29.06 ± 14.03 years) were enrolled. The interaction effect was present for the trapezius muscle with a significant difference between the right and the left side in episodic group (p = 0.003). A group effect was highlighted in all four muscles analyzed such as suboccipital (p < 0.001), temporalis (p > 0.001), trapezius (p < 0.001), and TFL (p < 0.001). PPT was usually higher in the control group than in the episodic group which in turn was characterized by higher PPT values than the chronic group., Conclusions: People with chronic and episodic migraine presented lower PPT than healthy controls both in the trigeminal and in the extra-trigeminal area. People with chronic migraine presented lower PPT than episodic migraine only in the trigeminal area. Temporalis and sub-occipitalis are the most sensitive muscles in people with chronic and episodic migraine., (© 2024. The Author(s).)

Background: Nerve fibers related to pain and temperature sensation in the trigeminal nerve territory converge with the upper cervical spinal nerves from the level of the lower medulla oblongata to the upper cervical cord. This structure is called the trigemino-cervical complex and may cause referred pain in the territory of the trigeminal or upper cervical spinal nerves., Case Series: Here, we report three cases of paroxysmal neuralgia in the occipital region with mild conjunctivitis or a few reddish spots in the ipsilateral trigeminal nerve territory. The patients exhibited gradual progression of these reddish spots evolving into vesicles over the course of several days, despite the absence of a rash in the occipital region. The patients were diagnosed with trigeminal herpes zoster and subsequently received antiherpetic therapy. Remarkably, the neuralgia in the occipital region showed gradual amelioration or complete resolution before the treatment, with no sequelae reported in the occipital region., Discussion: The trigemino-cervical complex has the potential to cause neuralgia in the occipital region, as referred pain, caused by trigeminal herpes zoster. These cases suggest that, even if conjunctivitis or reddish spots appear to be trivial in the trigeminal nerve territory, trigeminal herpes zoster should be considered when neuralgia occurs in the ipsilateral occipital region., (© 2024 The Authors. Headache: The Journal of Head and Face Pain published by Wiley Periodicals LLC on behalf of American Headache Society.)

Data on the state of sense of smell in patients who had a new coronavirus infection caused by the SARS-CoV-2 virus are currently reduced because of the impairment of the olfactory nerve system. There are practically no results in studies of disorders in the trigeminal nerve system., Objective: Qualitative assessment of olfactory disorders after COVID-19 according to the system of olfactory and trigeminal nerves with a targeted assessment of the functional component of olfactory disorders., Material and Methods: We examined 40 patients aged 19 to 66 who had a coronavirus infection. All patients underwent neurological, otorhinolaryngological examinations, olfactometry, filled out the hospital anxiety and depression scale., Results: Anosmia was diagnosed in 5 (12.5%) patients, hyposmia in 21 (52.5%) patients, and normosmia in 14 (35%) patients. Formed: the 1st group - 14 patients (35%) with normogram according to olfactometry; the 2nd group - 26 patients (65%) with anosmia/hyposmia. In the 1st group, disorders of the anxiety-depressive spectrum were significantly more common. In the 2nd group, a low identification of odors was found, lying in the spectrum of fresh, sharp, unpleasant, irritating, compared with sweet and pleasant or neutral, which indicates a predominant lesion of the trigeminal system., Conclusion: In patients with complaints of impaired sense of smell after undergoing COVID-19, the possible functional nature of anosmia/hyposmia should be taken into account, which requires the referral of such patients to psychotherapeutic specialists, and the possible entry of olfactory disorders into the 'trigeminal' spectrum.

Objective: Next to olfactory function, the nose can also perceive chemestetic sensations mediated by the trigeminal nerve. While olfactory dysfunction as a symptom of COVID-19 is well described, there has been little research on the limitation of other nasal sensory inputs due to SARS-CoV-2 infection. The aim of this study was to determine possible limitations of nasal chemesthesis after COVID-19 infection by a psychophysiological diagnostic tool., Methods: In 65 patients with a PCR-confirmed, former COVID-19 disease, olfaction was tested by means of a sniffin' sticks test, tasting by taste sprays and chemesthesis with a menthol dilution series. The subjective self-assessment of the patients was recorded via a questionnaire., Results: We found a restriction of nasal chemesthesis and the extent correlated with the loss of smell, as well as with the values of the taste score, but not with subjective self-assessment., Conclusion: Not only the ability to smell and taste, but also nasal chemesthesis is affected by COVID-19., Competing Interests: Declaration of Competing interest The authors received no external funding for this work and declare no conflicts of interest or competing interests., (Copyright © 2021 Japanese Society of Otorhinolaryngology-Head and Neck Surgery, Inc. Published by Elsevier B.V. All rights reserved.)

Purpose of Review: Headache is a common symptom of COVID-19 with emerging literature being published on the subject. Although it may seem unspecific, scientific evidence has allowed a better definition of this headache type, revealing relevant associations with other COVID-19 symptoms and prognoses. We therefore sought to highlight the most remarkable findings concerning headache secondary to COVID-19, specifically focusing on epidemiology, characteristics, pathophysiology, and treatments., Recent Findings: The real prevalence of headache as a symptom of COVID-19 is still unclear ranging from 10 to 70%. Headache mainly has a tension-type-like phenotype, although 25% of individuals present with migraine-like features that also occur in patients without personal migraine history. This finding suggests that a likely pathophysiological mechanism is the activation of the trigeminovascular system. SARS-CoV-2 neurotropism can occur by trans-synaptic invasion through the olfactory route from the nasal cavity, leading to anosmia which has been associated with headache. SARS-CoV-2 protein has been found not only in olfactory mucosa and bulbs but also in trigeminal branches and the trigeminal ganglion, supporting this hypothesis. However, other mechanisms such as brain vessels inflammation due to SARS-CoV-2 damage to the endothelium or systemic inflammation in the context of cytokine storm cannot be ruled out. Interestingly, headache has been associated with lower COVID-19 mortality. No specific treatment for COVID-19 headache is available at present. Studies show that investigating COVID-19 headache represents an opportunity not only to better understand COVID-19 in general but also to advance in the knowledge of both secondary and primary headaches. Future research is therefore warranted., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Competing Interests: The authors report no conflicts of interest.

Objective: To explore the cortical areas targeted by acute transcutaneous trigeminal nerve stimulation (TNS) in patients with drug-resistant epilepsy (DRE) using single photon emission computed tomography (SPECT)., Methods: Ten patients with DRE underwent brain SPECT at baseline and immediately after a 20-minute TNS (0.25 ms; 120 Hz; 30 s ON and 30 s OFF) applied bilaterally to the infraorbital nerve. The French Color Standard International Scale was used for qualitative analyses and z-scores were used to calculate the Odds Ratio (OR)., Results: At baseline global hypoperfusion (mainly in temporo-mesial, temporo-parietal and fronto-temporal and temporo-occipital areas) was detected in all patients. Following TNS, a global increase in cortical tracer uptake and a significant decrease in median hypoperfusion score were observed. A significant effect favoring a general TNS-induced increase in cortical perfusion (OR = 4.96; p = 0.0005) was detected in 70% of cases, with significant effects in the limbic (p = 0.003) and temporal (p = 0.003) lobes. Quantitative analyses of z-scores confirmed significant TNS-induced increases in perfusion in the temporal (+0.59 SDs; p = 0.001), and limbic (+0.43 SDs; p = 0.03) lobes., Conclusion: Short-term TNS is followed a global increase in cortical perfusion, namely in the temporal and limbic lobes., Significance: The TNS-induced perfusion increase may reflect neurons' activity changes in cortical areas implicated in the epilepsy network., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Background: Photophobia is a potentially debilitating symptom often found in dry eye disease (DE), migraine and traumatic brain injury (TBI)., Methods: We conducted a review of the literature via a PubMed search of English language articles with a focus on how photophobia may relate to a shared pathophysiology across DE, migraine and TBI., Results: DE, migraine and TBI are common conditions in the general population, are often comorbid, and share photophobia as a symptom. Across the three conditions, neural dysregulation of peripheral and central nervous system components is implicated in photophobia in various animal models and in humans. Enhanced activity of the neuropeptide calcitonin gene-related peptide (CGRP) is closely linked to photophobia. Current therapies for photophobia include glasses which shield the eyes from specific wavelengths, botulinum toxin, and inhibition of CGRP and its receptor. Many individuals have persistent photophobia despite the use of these therapies, and thus, development of new therapies is needed., Conclusions: The presence of photophobia in DE, migraine and TBI suggests shared trigeminothalamic pathophysiologic mechanisms, as explained by central neuroplasticity and hypersensitivity mediated by neuropeptide CGRP. Treatment strategies which target neural pathways (ie, oral neuromodulators, transcutaneous nerve stimulation) should be considered in patients with persistent photophobia, specifically in individuals with DE whose symptoms are not controlled with traditional therapies., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The trigeminal nerve directly innervates key vascular structures both centrally and peripherally. Centrally, it is known to innervate the brainstem and cavernous sinus, whereas peripherally the trigemino-cerebrovascular network innervates the majority of the cerebral vasculature. Upon stimulation, it permits direct modulation of cerebral blood flow (CBF), making the trigeminal nerve a promising target for the management of cerebral vasospasm. However, trigeminally mediated cerebral vasodilation has not been applied to the treatment of vasospasm., Objective: To determine the effect of percutaneous electrical stimulation of the infraorbital branch of the trigeminal nerve (pTNS) on the cerebral vasculature., Methods: In order to determine the stimulus-response function of pTNS on cerebral vasodilation, CBF, arterial blood pressure, cerebrovascular resistance, intracranial pressure, cerebral perfusion pressure, cerebrospinal fluid calcitonin gene-related peptide (CGRP) concentrations, and the diameter of cerebral vessels were measured in healthy and subarachnoid hemorrhage (SAH) rats., Results: The present study demonstrates, for the first time, that pTNS increases brain CGRP concentrations in a dose-dependent manner, thereby producing controllable cerebral vasodilation. This vasodilatory response appears to be independent of the pressor response induced by pTNS, as it is maintained even after transection of the spinal cord at the C5-C6 level and shown to be confined to the infraorbital nerve by administration of lidocaine or destroying it. Furthermore, such pTNS-induced vasodilatory response of cerebral vessels is retained after SAH-induced vasospasm., Conclusion: Our study demonstrates that pTNS is a promising vasodilator and increases CBF, cerebral perfusion, and CGRP concentration both in normal and vasoconstrictive conditions., (© Congress of Neurological Surgeons 2021.)

Aim: Little is known about short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA). We present our experience with SUNCT/SUNA patients to aid identification and management of these disorders., Methods: A retrospective review of patient records of one orofacial pain clinic was performed. Inclusion criteria was a diagnosis of SUNCT/SUNA confirmed with at least one follow-up visit., Results: Six of the 2464 new patients seen between 2015-2018 met the selection criteria (SUNCT n = 2, SUNA n = 4). Gender distribution was one male to one female and average age of diagnosis was 52 years (range 26-62). Attacks were located in the V1/V2 trigeminal distributions, and five patients reported associated intraoral pain. Pain quality was sharp, shooting, and burning with two patients reporting "numbness". Pain was moderate-severe in intensity, with daily episodes that typically lasted for seconds. Common autonomic features were lacrimation, conjunctival injection, rhinorrhea, and flushing. Frequent triggers were touching the nose or a specific intraoral area. Lamotrigine and gabapentin were commonly used as initial therapy., Conclusions: Differentiating between SUNCT/SUNA does not appear to be clinically relevant. Presenting symptoms were consistent with those published, except 5/6 patients describing intraoral pain and two patients describing paresthesia.

Background: 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., Methods: Consciousness behavioral analysis, Electroencephalogram (EEG) recording, Chemogenetics, Microarray analysis, Milliplex MAP rat peptide assay, Chromatin immune-precipitation (ChIP), Dual-luciferase reporter experiment, Western blot, PCR and Fluorescence in situ hybridization (FISH)., Results: TNS can markedly activate the neuronal activities of the lateral hypothalamus (LH) and the spinal trigeminal nucleus (Sp5), as well as improve rat consciousness level and EEG activities. Then we proved that LH activation and upregulated neuropeptide hypocretin are beneficial for promotion of consciousness recovery. We then applied gene microarray experiment and found hypocretin might be mediated by a well-known transcription factor Early growth response gene 1 (EGR1), and the results were confirmed by ChIP and Dual-luciferase reporter experiment., Conclusion: This study illustrates that TNS is an effective arousal strategy Treatment for LOC state via the activation of Sp5 and LH neurons and upregulation of hypocretin expression., (Copyright © 2021. Published by Elsevier Inc.)

Background: Trigeminal-cardiac reflex (TCR) is a brainstem vagus reflex that occurs when any center or peripheral branch of the trigeminal nerve was stimulated or operated on. The typical clinical manifestation is sudden bradycardia with or without blood pressure decline. The rhino-cardiac reflex which is one type of TCR is rare in clinical practice. As the rhino-cardiac reflex caused by disinfection of the nasal cavity is very rare, we report these two cases to remind other anesthesiologists to be vigilant to this situation., Case Presentation: This case report describes two cases of cardiac arrest caused by rhino-cardiac reflex while disinfecting nasal cavity before endoscopic transsphenoidal removal of pituitary adenomas. Their heart rate all dropped suddenly at the very moment of nasal stimulation and recovered quickly after stimulation was stopped and the administration of drugs or cardiac support., Conclusion: Although the occurrence of rhino-cardiac reflex is rare, we should pay attention to it in clinical anesthesia. It is necessary to know the risk factors for preventing it. Once it occurs, we should take active and effective rescue measures to avoid serious complications.

Objective: To determine whether erenumab, a new monoclonal antibody to the calcitonin gene-related peptide (CGRP) receptor, exerts functional central effects in migraineurs by performing functional imaging scans on patients treated with erenumab., Methods: We conducted an fMRI study on 27 patients with migraine using a well-established trigeminal nociceptive paradigm, examining patients before and 2 weeks after administration of the CGRP receptor antibody erenumab 70 mg., Results: Comparing both visit days in all patients (n = 27) revealed that erenumab leads to a decrease in activation in the right thalamus (i.e., contralateral to the stimulated side), right middle temporal gyrus, right lingual gyrus, left operculum, and several clusters on both sides of the cerebellum. Furthermore, when responders (n = 9) and nonresponders (n = 8) of the respective same headache state were compared, we found a significant reduction of hypothalamic activation after the administration of erenumab in responders only ( t = 4.78; contrast estimate 29.79 [90% confidence interval 19.53-40.05]). This finding of reduced hypothalamic activation was confirmed when absolute headache days was used as a regressor., Interpretation: These findings suggest that erenumab may not be an exclusively peripheral migraine treatment but has additional central effects. Whether this is due to secondary changes after peripheral modulation of sensory input or indeed represents a direct central mode of action is discussed., (© 2020 American Academy of Neurology.)

The trigeminovagal reflex is a phenomenon that occurs rarely during maxillofacial surgery. Previously described as the oculocardiac reflex, this reflex can occur during ocular and periocular surgery. To be more anatomically precise, it was renamed the trigeminocardiac or trigeminovagal reflex, since stimulation of any part of the trigeminal nerve can elicit this reflex arc. We describe a case of asystole during mobilization of a maxilla following a Le Fort 1 osteotomy.

Poststroke cognitive impairment (PSCI) is a severe sequela of stroke. There are no effective therapeutic options for it. In this study, we evaluated whether electroacupuncture (EA) on the trigeminal nerve-innervated acupoints could alleviate PSCI and identified the mechanisms in an animal model. The male Sprague-Dawley rat middle cerebral artery occlusion (MCAO) model was used in our study. EA was conducted on the two scalp acupoints, EX-HN3 ( Yintang ) and GV20 ( Baihui ), innervated by the trigeminal nerve, for 14 sessions, daily. Morris water maze and novel object recognition were used to evaluate the animal's cognitive performance. Neuroprotection and synaptic plasticity biomarkers were analyzed in brain tissues. Ischemia-reperfusion (I/R) injury significantly impaired spatial and cognition memory, while EA obviously reversed cognitive deterioration to the control level in the two cognitive paradigms. Moreover, EA reversed the I/R injury-induced decrease of brain-derived neurotrophic factor, tyrosine kinase B, N-methyl-D-aspartic acid receptor 1, α -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor, γ -aminobutyric acid type A receptors, Ca 2+ /calmodulin-dependent protein kinase II, neuronal nuclei, and postsynaptic density protein 95 expression in the prefrontal cortex and hippocampus. These results suggest that EA on the trigeminal nerve-innervated acupoints is an effective therapy for PSCI, in association with mediating neuroprotection and synaptic plasticity in related brain regions in the MCAO rat model., Competing Interests: The authors declare that they have no competing interest., (Copyright © 2020 Yu Zheng et al.)

Background: Stimulation of the occipital or trigeminal nerves has been successfully used to treat chronic refractory neurovascular headaches such as migraine or cluster headache, and painful neuropathies. Convergence of trigeminal and occipital sensory afferents in the 'trigeminocervical complex' (TCC) from cutaneous, muscular, dural, and visceral sources is a key mechanism for the input-induced central sensitization that may underlie the altered nociception. Both excitatory (glutamatergic) and inhibitory (GABAergic and glycinergic) mechanisms are involved in modulating nociception in the spinal and medullary dorsal horn neurons, but the mechanisms by which nerve stimulation effects occur are unclear. This study was aimed at investigating the acute effects of electrical stimulation of the greater occipital nerve (GON) on the responses of neurons in the TCC to the mechanical stimulation of the vibrissal pad., Methods: Adult male Wistar rats were used. Neuronal recordings were obtained in laminae II-IV in the TCC in control, sham and infraorbital chronic constriction injury (CCI-IoN) animals. The GON was isolated and electrically stimulated. Responses to the stimulation of vibrissae by brief air pulses were analyzed before and after GON stimulation. In order to understand the role of the neurotransmitters involved, specific receptor blockers of NMDA (AP-5), GABA A (bicuculline, Bic) and Glycine (strychnine, Str) were applied locally., Results: GON stimulation produced a facilitation of the response to light facial mechanical stimuli in controls, and an inhibition in CCI-IoN cases. AP-5 reduced responses to GON and vibrissal stimulation and blocked the facilitation of GON on vibrissal responses found in controls. The application of Bic or Str significantly reduced the facilitatory effect of GON stimulation on the response to vibrissal stimulation in controls. However, the opposite effect was found when GABAergic or Glycinergic transmission was prevented in CCI-IoN cases., Conclusions: GON stimulation modulates the responses of TCC neurons to light mechanical input from the face in opposite directions in controls and under CCI-IoN. This modulation is mediated by GABAergic and Glycinergic mechanisms. These results will help to elucidate the neural mechanisms underlying the effectiveness of nerve stimulation in controlling painful craniofacial disorders, and may be instrumental in identifying new therapeutic targets for their prevention and treatment.

Objective: The study aimed at investigating the sensitivity to noise and chemosensory environmental stressors as well as the relation to perceived stress, depression and anxiety in subjects with chronic tinnitus as compared to subjects without tinnitus., Methods: We included 75 subjects with chronic tinnitus and 75 age and sex-matched subjects without tinnitus. Standardized questionnaires assessing the level of distress and impairment of quality of life caused by tinnitus, perceived level of stress, anxiety and depression, environmental noise and chemosensory sensitivity were used. A subgroup of 27 subjects with chronic tinnitus and 20 age-matched subjects without tinnitus underwent testing of olfactory function with the Sniffin' Sticks test and testing of intranasal trigeminal function using CO2 thresholds., Results: Our data confirmed the increased environmental noise sensitivity (NSS) in patients with tinnitus. Furthermore, we observed an increased environmental chemosensory sensitivity (CSS), but no difference in measured chemosensory function. Subjects with tinnitus showed also significant higher levels of perceived stress, anxiety and depression and those symptoms partially correlated to CSS and NSS. Predictors of both NSS and CSS results were the presence / absence of tinnitus and high anxiety levels while neither stress nor depression were found as predicting variables., Conclusions: The results suggest that chronic tinnitus is related to a multisensory environmental hypersensitivity. Anxiety seems to be a predictor of this environmental vulnerability., (Copyright © 2020 Elsevier Inc. All rights reserved.)

An epileptic seizure can trigger a headache during (ictal) or after (postictal) the termination of the event. Little is known about the pathophysiology of seizure-induced headaches. In the current study, we determined whether a seizure can activate nociceptive pathways that carry pain signals from the meninges to the spinal cord, and if so, to what extent and through which classes of peripheral and central neurons. To achieve these goals, we used single-unit recording techniques and an established animal model of seizure (picrotoxin) to determine the effects of epileptic seizure on the activity of trigeminovascular Aδ-, C-, wide-dynamic range, and high-threshold neurons in male and female rats. Occurrence of seizure activated 54%, 50%, 68%, and 39% of the Aδ-, C-, wide-dynamic range, and high-threshold neurons, respectively. Regardless of their class, activated neurons exhibited a twofold to fourfold increase in their firing, which started immediately (1 min) or up to 90 min after seizure initiation, and lasted as short as 10 min or as long as 120 min. Administration of lidocaine to the dura prevented activation of all neuronal classes but not the initiation or maintenance of the seizure. These findings suggest that all neuronal classes may be involved in the initiation and maintenance of seizure-induced headache, and that their activation patterns can provide a neural substrate for explaining the timing and duration of ictal and possibly postictal headaches. By using seizure, which is evident in humans, this study bypasses controversies associated with cortical spreading depression, which is less readily observed in humans. SIGNIFICANCE STATEMENT This preclinical study provides a neural substrate for ictal and postictal headache. By studying seizure effects on the activity of peripheral (C and Aδ) and central (wide dynamic range and high-threshold) trigeminovascular neurons in intact and anesthetized dura, the findings help resolve two outstanding questions about the pathophysiology of headaches of intracranial origin. The first is that abnormal brain activity (i.e., seizure) that is evident in human (unlike cortical spreading depression) gives rise to specific and selective activation of the different components of the trigeminovascular system, and the second is that the activation of all components of the trigeminovascular pathway (i.e., peripheral and central neurons) depends on activation of the meningeal nociceptors from their receptors in the dura., (Copyright © 2020 the authors.)

Background: Central sensitization (CS) is a form of neuroplasticity characterized by changes in the neural sensitivity, responsiveness, and/or output that are not contingent on peripheral input nor activity-dependent. CS is characterized by activation of unmyelinated C-fibers resulting in a cascade of events at molecular and cellular levels which eventuate into generation of synaptic currents at rest. CS, therefore, contributes to heightened generalized pain sensitivity, further complicates the process of reaching a diagnosis, and increases the possibility of treatment failure. BODY: Trigeminal nerve is the main sensory supplier of the anterior part of the head, including the intraoral structures. Primary afferent nociceptors of the trigeminal nerve and low threshold mechanoreceptors synapse with wide dynamic range (WDR) neurons in the pons. This multifaceted network of nerve interactions which is further complicated by the modulatory circuits that can suppress or heighten the activity of WDR neurons is one of the main contributors to CS. The importance of CS in orofacial pain disorders is emphasized in the context of chronic pain development. As for all chronic pain conditions, it is crucial to consider the biopsychosocial aspects of chronic orofacial pain in managing this diverse group of conditions. This review highlights current understanding of the biopsychosocial model and central mechanisms contributing to the pathogenesis of chronic orofacial pain., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The fifth cranial nerve is the common denominator for many headaches and facial pain pathologies currently known. Projecting from the trigeminal ganglion, in a bipolar manner, it connects to the brainstem and supplies various parts of the head and face with sensory innervation. In this review, we describe the neuroanatomical structures and pathways implicated in the sensation of the trigeminal system. Furthermore, we present the current understanding of several primary headaches, painful neuropathies and their pharmacological treatments. We hope that this overview can elucidate the complex field of headache pathologies, and their link to the trigeminal nerve, to a broader field of young scientists.

Olfactory dysfunction (OD) in Parkinson's disease (PD) appears several years before the presence of motor disturbance. Olfactory testing has the potential to serve as a tool for early detection of PD, but OD is not specific to PD as it affects up to 20% of the general population. Olfaction includes an orthonasal and a retronasal components; in some forms of OD, retronasal olfactory function is preserved. We aimed to evaluate whether combined testing components allows for discriminating between PD-related OD and non-Parkinsonian OD (NPOD). The objective of this study is to orthonasal and retronasal olfactory function in PD patients and compare them to a NPOD group and to healthy controls. We hypothesized that this combined testing allows to distinguish PD patients from both other groups. We included 32 PD patients, 25 NPOD patients, and 15 healthy controls. Both olfactory components were impaired in PD and NPOD patients, compared with controls; however, NPOD patients had significantly better orthonasal scores than PD patients. Furthermore, the ratio of retronasal/orthonasal score was higher in PD than in both other groups. In the NPOD group, orthonasal and retronasal scores were significantly correlated; no such correlation could be observed in PD patients. In summary, PD patients seem to rely on compensatory mechanisms for flavor perception. Combined orthonasal and retronasal olfactory testing may contribute to differentiate PD patients from patients with NPOD., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Ameloblastomas are locally invasive and aggressive odontogenic tumors treated via surgical resection, which results in facial deformity and significant morbidity. Few studies have addressed the cellular and molecular events of ameloblastoma onset and progression, thus hampering the development of non-invasive therapeutic approaches. Tumorigenesis is driven by a plethora of factors, among which innervation has been long neglected. Recent findings have shown that innervation directly promotes tumor progression. On this basis, we investigated the molecular characteristics and neurotrophic properties of human ameloblastomas. Our results showed that ameloblastomas express dental epithelial stem cell markers, as well as components of the Notch signaling pathway, indicating persistence of stemness. We demonstrated that ameloblastomas express classical stem cell markers, exhibit stem cell potential, and form spheres. These tumors express also molecules of the Notch signaling pathway, fundamental for stem cells and their fate. Additionally, we showed that ameloblastomas express the neurotrophic factors NGF and BDNF, as well as their receptors TRKA, TRKB, and P75/NGFR, which are responsible for their innervation by trigeminal axons in vivo. In vitro studies using microfluidic devices showed that ameloblastoma cells attract and form connections with these nerves. Innervation of ameloblastomas might play a key role in the onset of this malignancy and might represent a promising target for non-invasive pharmacological interventions.

Trigeminal neuralgia is defined by its clinical characteristics of paroxysmal unilateral facial pain in a well-defined territory. Distribution of the pain may be in one or several of the cutaneous and/or mucous territories of the three divisions with V2 pain being the most frequent territory followed by V3 and V1. Factors determining the distribution of pain have not yet been systematically investigated. It is now well recognized that vascular compression factor is a predominant aetiology of classical trigeminal neuralgia. In this study we aimed to find whether there is a relation between the location of the vascular compression and the peripheral distribution of the pain. Patients with classical trigeminal neuralgia in whom microvascular decompression was performed were included. Data recorded pertained to the nature of the conflict, its degree and, most importantly, location around the root: supero-median, supero-lateral or inferior. Equally, clinical data for the distribution of pain were recorded. Most of the patients 318 (89.3%) had the compression coming from above, i.e. 220 (61.7%) had compression from a supero-medial direction and 98 (27.5%) from a supero-lateral direction; inferior compression was present in 38 patients (10.7%). Distribution of the pain was significantly different according to the location of the conflict (P = 0.0005, Fisher Exact test). Odds ratios were computed for each location of compression and painful territory involved. According to the overall distribution of pain, patients with supero-medial compression had an odds ratio of 2.7 [95% confidence interval (CI) 1.66-4.41] of manifesting with V1 pain. Conversely V3 pain was less likely to occur with supero-median compression than the other types of pain (odds ratio 0.53, 95% CI 0.34-0.83). Inferior compression on the other hand was more likely to manifest with V3 pain with an odds ratio of 2.56 (95% CI 1.21-5.45). Overall V2 pain had an odds ratio close to 1 regardless of the type of compression. These findings suggest an association between the location of the neurovascular conflict with its resulting insult and the distribution of pain supporting a somatotopic view of the organization of the trigeminal root and a role of the conflict in the clinical manifestation of trigeminal neuralgia., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Activation of peripheral and/or central trigeminovascular pain pathways are implicated in the pathogenesis of migraine. Small fibers mediate pain, thermal sensation, and autonomic functions. Axon flare response is correlated with local C-fiber activation and calcitonin gene-related peptide release. Laser speckle contrast analysis (LASCA) detects very subtle microcirculatory changes that are not visible to the naked eye., Case: Axon flare response was elicited by 0.01 mL intradermal (i.d.) histamine introduced to the left forehead, trigeminal nerve ophthalmic branch (V1) skin area. Skin microvascular blood flow data were recorded using a LASCA real-time microcirculation imaging system. In the healthy control, prick stimulus slightly elevated focal skin microcirculation only at the stimulated focal area. However, in our patient with chronic migraine, the unilateral prick stimulation transiently (over 10 to 12 seconds) increased ipsilateral skin microcirculation at all 3 branches of the trigeminal nerve, with a slight expansion across the midline. Left V1 stimulation by i.d. histamine induced not only prominent but also long-lasting (10 to 15 minutes of recording time) axon flare response at the ipsilateral V1, V2, and V3 areas, with an expansion to the contralateral V1 area and without any report of allodynia or hyperalgesia. The treatment decreased axon flare characteristics probably by inhibiting neurogenic inflammation., Discussion: The clinical characteristics and individual response to treatment vary widely across patients with pain. Here, we demonstrated the presence of transient spread of increased microcirculation at the ipsilateral trigeminal nerve, and also across the midline after prick stimulus, whereas a more prominent, widespread, and long-lasting histamine-induced axon flare response occurred in a rare subclass of patient who had chronic migraine with autonomic symptoms. The modulatory effect of the pharmacological intervention has also been objectively quantified by LASCA., (© 2019 World Institute of Pain.)

The aim of this study is to investigate the effect of olfactory dysfunction (OD) on the two other chemical senses, namely gustation and the intranasal trigeminal system. Taste and trigeminal function were analyzed in a retrospective cross-sectional study of 178 participants with OD (n = 78 posttraumatic, n = 42 idiopathic, n = 27 post-infectious and n = 31 chronic rhinosinusitis (CRS) OD). All patients had been investigated for OD at our smell and taste outpatient clinic. Evaluation of olfaction was performed by means of the Sniffin' Sticks test (odor threshold, odor discrimination and odor identification), whereas gustatory function was assessed with the Taste Strips test and the intranasal trigeminal sensitivity by means of the lateralization task. The degree of olfactory impairment was found to depend on the cause of OD, but not on patients' age. Patients with posttraumatic OD showed lower olfactory function than patients with idiopathic, post-infectious and CRS OD (p = 0.01). Gustatory and trigeminal sensitivity in turn depended on age rather than the cause of olfactory dysfunction. Partial correlations between olfactory, gustatory, and trigeminal scores, with age as covariate, were significant, showing a decrease of taste and trigeminal function proportional to the OD (p < 0.05). The present data suggest that the three chemical senses are closely connected for humans underlining that in case of OD the remaining chemical senses (taste, trigeminal function) tend to decrease rather than compensate as this is seen for sensory loss in other modalities. This finding has direct clinical implications and importance when dealing with smell and taste disorders.

Migraine is a complex brain disorder, characterized by attacks of unilateral headache and global dysfunction in multisensory information processing, whose underlying cellular and circuit mechanisms remain unknown. The finding of enhanced excitatory, but unaltered inhibitory, neurotransmission at intracortical synapses in mouse models of familial hemiplegic migraine (FHM) suggested the hypothesis that dysregulation of the excitatory-inhibitory balance in specific circuits is a key pathogenic mechanism. Here, we investigated the thalamocortical (TC) feedforward inhibitory microcircuit in FHM1 mice of both sexes carrying a gain-of-function mutation in Ca V 2.1. We show that TC synaptic transmission in somatosensory cortex is enhanced in FHM1 mice. Due to similar gain of function of TC excitation of layer 4 excitatory and fast-spiking inhibitory neurons elicited by single thalamic stimulations, neither the excitatory-inhibitory balance nor the integration time window set by the TC feedforward inhibitory microcircuit was altered in FHM1 mice. However, during repetitive thalamic stimulation, the typical shift of the excitatory-inhibitory balance toward excitation and the widening of the integration time window were both smaller in FHM1 compared with WT mice, revealing a dysregulation of the excitatory-inhibitory balance, whereby the balance is relatively skewed toward inhibition. This is due to an unexpected differential effect of the FHM1 mutation on short-term synaptic plasticity at TC synapses on cortical excitatory and fast-spiking inhibitory neurons. Our findings point to enhanced transmission of sensory, including trigeminovascular nociceptive, signals from thalamic nuclei to cortex and TC excitatory-inhibitory imbalance as mechanisms that may contribute to headache, increased sensory gain, and sensory processing dysfunctions in migraine. SIGNIFICANCE STATEMENT Migraine is a complex brain disorder, characterized by attacks of unilateral headache and by global dysfunction in multisensory information processing, whose underlying cellular and circuit mechanisms remain unknown. Here we provide insights into these mechanisms by investigating thalamocortical (TC) synaptic transmission and the function of the TC feedforward inhibitory microcircuit in a mouse model of a rare monogenic migraine. This microcircuit is critical for gating information flow to cortex and for sensory processing. We reveal increased TC transmission and dysregulation of the cortical excitatory-inhibitory balance set by the TC feedforward inhibitory microcircuit, whereby the balance is relatively skewed toward inhibition during repetitive thalamic activity. These alterations may contribute to headache, increased sensory gain, and sensory processing dysfunctions in migraine., (Copyright © 2019 the authors.)

Olfactory dysfunction is a frequent early non-motor symptom of Parkinson's disease (PD). There is evidence that with regard to trigeminal perception, PD-related olfactory dysfunction is different from other olfactory disorders. More specifically, trigeminal sensitivity, when measured behaviorally, was unimpaired in PD patients as opposed to patients with non-Parkinsonian olfactory dysfunction (NPOD). We sought to investigate the trigeminal pathway by measuring electrophysiological recordings from the nasal epithelium and EEG-derived event-related potentials in response to a specific trigeminal stimulus in 21 PD patients and compare them to 23 patients with NPOD and 25 controls (C). The peripheral trigeminal response, as measured by the negative-mucosa potential, showed no difference between patients with PD and controls whereas PD patients showed faster responses than patients with NPOD, the latter having shown slower and larger responses than controls (18 PD, 14 NPOD, 20 C). The central trigeminal response, as measured by event-related potentials, revealed larger early component response in PD patients compared to patients with NPOD (15 PD, 21 NPOD, 23 C). As expected, psychophysical olfactory testing showed impaired olfactory function in both groups of patients as opposed to controls. Discriminant analysis revealed a model that could predict group membership for 80% of participants based on the negative-mucosa potential latency, olfactory threshold and discrimination tests. These results provide novel insights into the pattern of trigeminal activation in PD which will help to differentiate PD-related olfactory loss from NPOD, a crucial step towards establishing early screening batteries for PD including smell tests.

Background: The exact mechanisms underlying the onset of a migraine attack are not completely understood. It is, however, now well accepted that the onset of the excruciating throbbing headache of migraine is mediated by the activation and increased mechanosensitivity (i.e. sensitization) of trigeminal nociceptive afferents that innervate the cranial meninges and their related large blood vessels., Objectives: To provide a critical summary of current understanding of the role that the cranial meninges, their associated vasculature, and immune cells play in meningeal nociception and the ensuing migraine headache., Methods: We discuss the anatomy of the cranial meninges, their associated vasculature, innervation and immune cell population. We then debate the meningeal neurogenic inflammation hypothesis of migraine and its putative contribution to migraine pain. Finally, we provide insights into potential sources of meningeal inflammation and nociception beyond neurogenic inflammation, and their potential contribution to migraine headache.

Objective: To review and discuss the literature relevant to the role of brainstem structure and function in headache., Background: Primary headache disorders, such as migraine and cluster headache, are considered disorders of the brain. As well as head-related pain, these headache disorders are also associated with other neurological symptoms, such as those related to sensory, homeostatic, autonomic, cognitive and affective processing that can all occur before, during or even after headache has ceased. Many imaging studies demonstrate activation in brainstem areas that appear specifically associated with headache disorders, especially migraine, which may be related to the mechanisms of many of these symptoms. This is further supported by preclinical studies, which demonstrate that modulation of specific brainstem nuclei alters sensory processing relevant to these symptoms, including headache, cranial autonomic responses and homeostatic mechanisms., Review Focus: This review will specifically focus on the role of brainstem structures relevant to primary headaches, including medullary, pontine, and midbrain, and describe their functional role and how they relate to mechanisms of primary headaches, especially migraine.

Background: Stroke is the most frequent reason of neurological dysphagia Electrophysiological studies can be used to evaluate oral, pharyngeal and initial phase of esophageal phase., Aims: This study aims to noninvasively evaluate mastication, mimic, and tongue muscles of stroke patients, which play an important role in the oral phase of swallowing process and compare them with healthy individuals., Setting and Design: This study was conducted at the Physical Medicine and Rehabilitation Clinic of our hospital between January 2014 and December 2016., Materials and Methods: Fifty-one patients who were admitted to our clinic with stroke and 51 healthy individuals were evaluated for the study. Demographic features of individuals were recorded. The swallowing intervals and motor action potentials (MAPs) of trigeminal, facial and hypoglossal nerves were measured. After four weeks of treatment schedule, patients were re-evaluated., Statistical Analysis: The Wilcoxon Signed Rank test, the Mann-Whitney U test and Fisher exact test were used in this study., Results: The all swallowing intervals were found prolonged compared to the healthy controls (P < 0.05). The MAPs of the masseter, orbicularis oculi, and intrinsic tongue muscles were significantly lower in patient group (P < 0.05). After treatment, we found significant improvement for all parameters in patient group, but the swallowing intervals were still significantly prolonged, and MAPs of these muscles were still lower (P < 0.05)., Conclusion: Although swallowing is examined as different phases, the process is complicated and should be evaluated totally. In post-stroke dysphagia, oral phase of swallowing process is as important as phayngeal phase and perioral, mastication, and tongue muscles are influenced even in an early period as a month., Competing Interests: None

Trigeminal-targeted treatments (TTTs), the most specific and selective therapeutic migraine approach to date, are effective in approximately 60% of patients regardless of treatment type or mechanism, at least if used alone. Sixty percent is also the proportion of migraineurs who develop migraine-like episodes following experimental intravenous administration of trigeminal neuropeptides and roughly 60% is the percentage of patients with a unilateral migraine tracing the area of cutaneous distribution of the trigeminal ophthalmic branch. Hence, mechanisms other than the trigeminovascular activation are probably involved in the 40% of migraineurs who do not respond to TTTs. A closer cooperation between clinical and basic neuroscientists is needed to explore migraine models because only a careful appraisal of migraine endophenotypes may help to unravel their underlying multifaceted pathophysiological machinery., (© 2019 American Headache Society.)

To evaluate the effect of triple puncture on primary trigeminal neuralgia (pTN), 64 patients with pTN were randomly assigned to two groups: treatment group and control group. The participants in the treatment group received triple puncture treatment of 6 times per week for 4 weeks, and those in control group were given carbamazepine (300-600 mg per day) for at least 1 month. Before and after treatment, the primary outcomes including the total efficiency rate and the VAS pain scores, and the secondary outcomes including the frequency of pain attack and adverse events were observed. Sixty-two participants finished the study (33 in treatment group and 29 in control group individually). After treatment, the symptoms (mainly pain) of the two groups were alleviated. The total efficiency rate in the treatment group and control group was 90.9% and 75.9% respectively. The VAS pain scores and frequency of pain attack were significantly reduced in the treatment group as compared with the control group (P<0.05). The incidence of adverse events in the treatment group and control group was 9.1% and 24.1% respectively. It can be inferred that triple puncture can effectively improve the quality of life of patients with pTN and has less side effects.

Objective: To assess conditioned pain modulation efficiency in persons with and without migraine headaches., Design: Cross-sectional assessment of experimental pain., Setting: University campus and surrounding community in a large Midwestern US city., Subjects: Twenty-three adults with and 32 without a history of migraine headaches participated in the study. Participants were mostly female (N = 40) with an average age of 23 years., Methods: Four electrocutaneous stimulations of the supraorbital branch of the left trigeminal nerve were delivered at 150% of an individually determined pain threshold. Conditioned pain modulation was assessed by applying a noxious counterstimulus (forearm ischemia) and delivering four more electrocutaneous stimulations. After each stimulation, pain and the nociceptive blink reflex were assessed. Depression and pain catastrophizing were assessed to control for the potential influence of these variables on pain modulation., Results: Participants with and without migraine headaches had similar baseline pain responsivity, without significant differences in pain report or nociceptive blink reflexes. Pain report was inhibited by conditioned pain modulation in both the migraine and control groups. However, unlike nonmigraine controls, participants with migraines did not exhibit an inhibition of nociceptive blink reflexes during the ischemia task. This pattern persisted after controlling for level of pain catastrophizing and depression., Conclusions: Migraine sufferers exhibited impaired conditioned pain modulation of the nociceptive blink reflex, suggesting a deficiency in inhibition of trigeminal nociception, which may contribute to the development of migraine headaches., (© 2019 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Horses with trigeminal mediated headshaking (TMHS) have a decreased activation threshold of the trigeminal nerve and clinical signs are suspected to be a manifestation of trigeminal neuralgia. Electrical nerve stimulation (ENS) is used for management of neuralgia in humans and appears to work via gate control theory. Use of an equine specific percutaneous ENS program in over 130 TMHS horses has resulted in approximately 50% success return to previous work. Electroacupuncture may also be useful in the management TMHS. Optimization of ENS procedures for TMHS is likely to require a greater understanding of the etiopathogenesis of the aberrant neurophysiology., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The trigeminal root entry zone (TREZ) is the transitional zone of central and peripheral tissue compartments in the trigeminal root. Microvascular compression on the TREZ is the main etiology of most idiopathic trigeminal neuralgia (TN) patients. However, the pathogenesis of TN is still uncertain. To investigate the glial plasticity changes in oligodendrocytes, Schwann cells, astrocytes and microglia/macrophages in the TREZ in TN, immunohistochemical staining and Western blot methods were performed in rats with TN induced by compression injury. The results showed that mechanical compression injury in the trigeminal nerve of the TN rats induced glial plasticity in the TREZ, which dynamically changed the glial interface of the CNS-PNS transitional zone. Additionally, glial fibrillary acidic protein (GFAP)-immunoreactive astrocyte processes significantly proliferated and extended distally from the central region to the peripheral side of the TREZ after nerve compression injury in the TN group. Moreover, the expression of p75 in Schwann cells was upregulated on the peripheral side of the TREZ, and activated Iba-1-immunoreactive microglia/macrophages were observed on both sides of the TREZ. A significantly higher number of Schwann cells, astrocytes and microglia/macrophages were found in the TN group than in the sham operation group (p < 0.05). In conclusion, mechanical compression injury in the TN rats activated various glial cells, including oligodendrocytes, astrocytes, Schwann cells and microglia/macrophages, in the CNS-PNS transitional zone of TREZ. Changes in glial cell plasticity in the TREZ after compression injury might be involved in TN pathogenesis.

The underlying causes of migraine headache remained enigmatic for most of the 20th century. In 1979, The Lancet published a novel hypothesis proposing an integral role for the neuropeptide-containing trigeminal nerve. This hypothesis led to a transformation in the migraine field and understanding of key concepts surrounding migraine, including the role of neuropeptides and their release from meningeal trigeminal nerve endings in the mechanism of migraine, blockade of neuropeptide release by anti-migraine drugs, and activation and sensitisation of trigeminal afferents by meningeal inflammatory stimuli and upstream role of intense brain activity. The study of neuropeptides provided the first evidence that antisera directed against calcitonin gene-related peptide (CGRP) and substance P could neutralise their actions. Successful therapeutic strategies using humanised monoclonal antibodies directed against CGRP and its receptor followed from these findings. Nowadays, 40 years after the initial proposal, the trigeminovascular system is widely accepted as having a fundamental role in this highly complex neurological disorder and provides a road map for future migraine therapies., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Purpose: Familial dysautonomia (FD) is a rare autosomal recessive disease that affects the development of sensory and autonomic neurons, including those in the cranial nerves. We aimed to determine whether conventional brain magnetic resonance imaging (MRI) could detect morphologic changes in the trigeminal nerves of these patients., Methods: Cross-sectional analysis of brain MRI of patients with genetically confirmed FD and age- and sex-matched controls. High-resolution 3D gradient-echo T1-weighted sequences were used to obtain measurements of the cisternal segment of the trigeminal nerves. Measurements were obtained using a two-reader consensus., Results: Twenty pairs of trigeminal nerves were assessed in ten patients with FD and ten matched controls. The median (interquartile range) cross-sectional area of the trigeminal nerves in patients with FD was 3.5 (2.1) mm 2 , compared to 5.9 (2.0) mm 2 in controls (P < 0.001). No association between trigeminal nerve area and age was found in patients or controls., Conclusions: Using conventional MRI, the caliber of the trigeminal nerves was significantly reduced bilaterally in patients with FD compared to controls, a finding that appears to be highly characteristic of this disorder. The lack of correlation between age and trigeminal nerve size supports arrested neuronal development rather than progressive atrophy.

Inflammation or injuries of the trigeminal nerve are often associated with persistent facial pain and its sequelae. A number of models have been described to study trigeminal pain in rodents, but the long-lasting behavioral consequences are unknown. This study characterizes the impact of a distal infraorbital nerve injury, called DIONI, which consists of ligature and transection of distal fibers of the infraorbital nerve. We assessed nociception using a conflict paradigm and optogenetics, and a set of reward, aversion, spatial, temporal, and competition tasks in the IntelliCage to study multiple aspects of cognition, circadian rhythms, and social interactions in groups of mice in home cage environments. Mice with DIONI developed cold and mechanical allodynia, and hypersensitivity towards blue light stimulation. They maintained a long-lasting memory of aversive stimuli (airpuff from above), but had no difficulty in learning appetitive tasks, which consisted in developing a preference for a rewarding corner in the IntelliCage. Indeed, they were more strongly "addicted" to sugar than sham mice but temporarily failed to relearn the location of rewarding sites after corner switching (reversal learning). They were mildly overactive in some tasks but without disruptions of circadian rhythms or impact on social structure. They adopted a strategy to maintain licking with fewer nosepokes, presumably trying to avoid mechanical stimulation of the snout. The results suggest that mice with DIONI develop strong aversive memories and some cognitive inflexibility, but create adaptive strategies to cope with the persistent trigeminal hypersensitivity.

Background: Migraine is a primary headache disorder involving dysregulation of central and peripheral pain pathways. Medical treatment is often limited by drug side effects, comorbidities and poor compliance. This makes neuromodulation an ideal option for migraine treatment. Cefaly® is a transcutaneous electrical neurostimulator designed specifically for migraine treatment. It results in external trigeminal nerve stimulation of the supraorbital and supratrochlear nerves. External trigeminal nerve stimulation is effective for acute and preventive migraine treatment and may result in normalization of dysregulated pain pathways., Objective: Our objective was to provide a narrative review of the neuroanatomical and pathophysiological basis of external trigeminal nerve stimulation for migraine treatment and to provide the rationale behind the choice of the electrical parameters used for external trigeminal nerve stimulation., Methods: We reviewed external trigeminal nerve stimulation clinical trial publications, basic science neurostimulation literature, publications describing pathophysiological mechanisms in migraine, and documentation used in the application for the Food and Drug Administration approval of external trigeminal nerve stimulation., Results: The electrical parameters used for external trigeminal nerve stimulation were chosen to maximize safety and efficacy. Critical parameters include generator characteristics, pulse shape, pulse duration, pulse frequency and session duration and frequency. We explain the rationale behind determination of each parameter. There is evidence of dysregulated central and peripheral pathways in migraine and evidence that external trigeminal nerve stimulation may normalize function of these pathways., Conclusion: External trigeminal nerve stimulation is a safe and effective Food and Drug Administration-approved option for the acute and preventive treatment of migraine. The electrical parameters were optimized specifically for external stimulation of the trigeminal nerve to maximum safety, comfort and efficacy.