The feasibility and technical aspects of trigemino-cervical reflex elicitation in humans under general anesthesia.

OBJECTIVE: To analyze the feasibility, neurophysiological aspects, stimulation patterns, and topographic distribution of trigemino-cervical reflex (TCR) components in humans under general anesthesia. METHODS: This prospective observational study enrolled 20 participants who underwent posterior fossa surgery, surgical proceduresin thecraniovertebral junction,or spinal cord surgery. TCR responses were simultaneously recorded in the sternocleidomastoid (SCM) and trapezius muscles after electrical stimulation of the supraorbital and infraorbital nerves. TCR responses were recorded preoperatively and intraoperatively using single-pulse and multipulse (trains of 2-7 electrical stimuli) stimulation, respectively. Two stimulus duration patterns were evaluated: 0.2-0.5 ms and 0.5-1.0 ms. RESULTS: Intraoperatively, short- and long-latency TCR components were obtained in the SCM ipsilateral to the stimulation with variable recordability. Short-latency responses were the most commonly recorded components. A longer stimulus duration (0.5-1.0 ms) seems to favor the elicitation of TCR responses under general anesthesia. CONCLUSIONS: Short-latency components recorded in the SCM ipsilateral to the stimulation could be regularly elicited under general anesthesia when a larger stimulus duration (0.5-1.0 ms) was applied. SIGNIFICANCE: This is the first study to demonstrate the elicitation of TCR components in humans under general anesthesia. This neurophysiological technique can potentially optimize intraoperative neurophysiological monitoring during brainstem surgery.

Mesencephalic trigeminal nucleus neurons with collaterals to both eyelid and masseter muscles shown by fluorescent double-labeling, revealing a potential mechanism for Marcus Gunn Syndrome.

Poking palpebral conjunctiva evoked upper-eyelid retraction during ophthalmic surgery. Iatrogenic eyelid ptosis occurred if eyelid branch of lachrymal nerve was sectioned. Mesencephalic trigeminal nucleus (Vme) neurons were labeled when tracer injected into lachrymal nerve innervating eyelid Mueller's muscle. Masseter afferent Vme neurons projecting to oculomotor nucleus (III) was observed in toad and rat, which helps amphibians to stare prey when they open mouth widely to prey. We hypothesized single Vme neurons may have peripheral collaterals to both eyelid and masseter muscles. WGA-594 was injected into upper eyelid, and WGA-488 was simultaneously delivered into ipsilateral masseter muscle in the same rat. Then, double labeled Vme neurons were found under both conventional and confocal microscope. Meanwhile, contact of WGA-594 positive eyelid afferent Vme neurons with WGA-488 labeled masseter afferent ones were observed sometimes. Combined with our previous observation of oculomotor projection Vme neurons, we thought WGA-594/488 double labeled Vme cells, at least some of them, are oculomotor projecting ones. Contact between eyelid and masseter afferent Vme neurons are supposed to be electrotonically coupled, based on a line of previous studies. If exogenous or genetic factors make these Vme neurons misinterpret masseter input as eyelid afferent signals, these Vme neurons might feedforward massages to eyelid retractor motoneurons in the III. Besides, oculomotor projecting Vme neurons might be co-fired by adjacent masseter afferent Vme neurons through electrotonic coupling once the masseter muscle is activated. In these cases, Marcus Gunn Syndrome might occur. This finding leads to a new hypothesis for the Syndrome.

Intranasal trigeminal sensitivity to mechanical stimuli is associated with the perception of nasal patency.

PURPOSE: The aim of this prospective study was to examine the characteristics of a clinical test for the assessment of nasal trigeminal sensitivity to mechanical stimuli and its association with the perception of nasal patency. METHODS: Thirty-two normosmic healthy subjects participated (17 women and 15 men; age = 26 ± 3 years). Precisely defined air puffs were used with a flow rate of 2L/min for mechanical stimulation. They were presented to the nasal vestibule, nasal septum, and inferior turbinate with various stimulus durations. Thresholds were measured by single-staircase stimuli with changes in stimulus duration in steps of 10 ms. Trigeminal suprathreshold intensity was rated by subjects for stimulus durations of 200, 300, 400, and 500 ms. Test-retest reliability was examined by intraclass correlations (ICCs) and Bland-Altman plot with limits of agreement. Pearson's correlations were calculated between self-rated nasal patency and nasal trigeminal sensitivity. RESULTS: As indicated by trigeminal threshold and suprathreshold intensities, the nasal vestibule is the most sensitive area among the three locations, followed by the nasal septum and the inferior turbinate (p < 0.001). Coefficients of correlations between test and retest were 0.76 for thresholds, and 0.56 suprathreshold intensities (p < 0.001). The Bland-Altman analysis showed a good agreement between test-retest values. In addition, significant positive associations between trigeminal suprathreshold intensities and self-rated nasal obstruction were found at the inferior turbinate (r = 0.4, p < 0.05). CONCLUSION: Reliable assessment of nasal trigeminal sensitivity for air puffs appears to be possible. Nasal trigeminal suprathreshold sensitivity to mechanical stimuli is associated with the perception of nasal patency at the inferior turbinate. This opens a window into the assessment of the perception of nasal airflow in various clinical purposes, especially for patients with sinonasal diseases.

The Effectiveness of Trigeminal Nerve Stimulation on Traumatic Brain Injury.

OBJECTIVES: Trigeminal nerve stimulation (TNS) is a promising strategy in treating diseases of the nervous system. In this study, the effects of TNS on traumatic brain injury (TBI) were investigated in a mouse model. MATERIALS AND METHODS: TBI was induced using a weight-drop device, and TNS treatment was delivered in the first hour after the TBI. Twenty-four hours later, the mice's behavior, brain edema, and expression of inflammatory factors were tested. Functional magnetic resonance imaging also was used to explore the possible effects of TNS on brain activity. RESULTS: TNS alleviates TBI-induced neurological dysfunction in animal behavior tests, besides protecting the blood-brain barrier and reducing the level of brain edema. TNS also effectively reduces the level of tumor necrosis factor-α and interleukin 6 and downregulates the cleaved caspase-3 signaling pathway. A series of brain areas was found to be possibly regulated by TNS, thus affecting the neural functions of animals. CONCLUSION: This study elucidates the role of TNS as an effective treatment for TBI by inhibiting the occurrence of a secondary brain injury.

Intraoperative Sneezing Secondary to Indirect Olfactory Nerve Stimulation.

Sneezing is a poorly understood, protective reflex response. It's characterized by the following sequence: eye closure, inspiration, glottic closure, forced expiration with sudden glottic opening, and release of an elevated intrathoracic pressure creating a flow of explosive air through the nose.1 Studies have indicated an anatomic sneezing area of the brainstem corresponding to the central recipient zone of the nasal sensory neurons in the lateral medulla.2 The traditional pathophysiology of the sneeze is thought to begin by stimulation of the distal branches of the trigeminal nerve within the nasal mucosa. Afferent neural stimuli are transmitted to the trigeminal ganglion and then the lateral medulla. The efferent phase then begins, giving rise to the sneezing sequence described earlier.1 In addition to direct nasal irritation, sneezing has been shown to be triggered by several other causes (Table 1). This suggests that alternative mechanisms of sneeze induction other than direct nasal stimulation exist. We report a case of a 34-year-old man undergoing an awake craniotomy for a recurrent World Health Organization grade 2 oligodendroglioma (IDH-mutant, 1p19q-codeleted, ATRX preserved). During the operation we elicited a sneeze response on 3 occasions on stimulation of the olfactory nerve (Video 1). Although we cannot completely exclude costimulation of the sensory trigeminal terminations in the anterior fossa floor, the actual sneezing occurred during tumor peeling away from the arachnoid surface overlaying the olfactory nerve. This suggests a potential accessory route of sneeze stimulation involving the olfactory nerve distinct from the previously described trigemino-related, autonomic (sympathetic and parasympathetic systems) and psychogenic etiologies.

CBF oscillations induced by trigeminal nerve stimulation protect the pericontusional penumbra in traumatic brain injury complicated by hemorrhagic shock.

Traumatic peri-contusional penumbra represents crucial targets for therapeutic interventions after traumatic brain injury (TBI). Current resuscitative approaches may not adequately alleviate impaired cerebral microcirculation and, hence, compromise oxygen delivery to peri-contusional areas. Low-frequency oscillations in cerebral blood flow (CBF) may improve cerebral oxygenation in the setting of oxygen deprivation. However, no method has been reported to induce controllable oscillations in CBF and it hasn't been applied as a therapeutic strategy. Electrical stimulation of the trigeminal nerve (TNS) plays a pivotal role in modulating cerebrovascular tone and cerebral perfusion. We hypothesized that TNS can modulate CBF at the targeted frequency band via the trigemino-cerebrovascular network, and TNS-induced CBF oscillations would improve cerebral oxygenation in peri-contusional areas. In a rat model of TBI complicated by hemorrhagic shock, TNS-induced CBF oscillations conferred significant preservation of peri-contusional tissues leading to reduced lesion volume, attenuated hypoxic injury and neuroinflammation, increased eNOS expression, improved neurological recovery and better 10-day survival rate, despite not significantly increasing CBF as compared with those in immediate and delayed resuscitation animals. Our findings indicate that low-frequency CBF oscillations enhance cerebral oxygenation in peri-contusional areas, and play a more significant protective role than improvements in non-oscillatory cerebral perfusion or volume expansion alone.

Neurotization Preferences in Smile Reanimation: A Discrete Choice Experiment.

BACKGROUND: Common donor nerve options in smile reanimation include ipsilateral trigeminal motor or contralateral facial nerve branches. Neurotization preference may be influenced by multiple factors, whose relative importance remains poorly understood. In this article, decision-making in smile reanimation is assessed using a stated preference model. METHODS: Qualitative interviews with facial palsy patients identified five relevant attributes for study: smile type ("smile when biting" versus "smile spontaneously" as proxies for trigeminal versus cross-facial neurotization), number of operations, success rates, complication rates, and side effects. Community volunteers (n = 250) completed a discrete-choice experiment relevant to free muscle transfer for smile reanimation. Preoperative and postoperative states were demonstrated through video vignettes, together with explanation of surgical risks, consequences, and benefits. Attribute importance was modeled using hierarchical Bayes estimation. RESULTS: Two hundred forty-one responses met quality controls. Attribute importance ranked as follows: chance of success, 37.3 percent; smile type, 21.4 percent; side effects, 13.9 percent; complication rates, 13.8; and number of operations, 13.6 percent. All attributes significantly correlated with decision making (p < 0.0001). An aggregate response model revealed most participants (67.6 percent; standard error, 3.0 percent) preferred smile reanimation by cross-facial (assuming a success rate of 80 percent) as opposed to ipsilateral trigeminal motor branch neurotization. When the success rate for cross-facial neurotization was reduced below 67 percent, trigeminal neurotization was preferred. CONCLUSIONS: Despite a higher risk of failure, most respondents preferred a cross-facial as opposed to trigeminal neurotization strategy for smile reanimation. These findings highlight the complexity of decision-making and need for individualized risk tolerance assessment in the field of facial reanimation.

Anatomy of Trigeminal Neuromodulation Targets: From Periphery to the Brain.

The trigeminal nerve complex is a very important and somewhat unique component of the nervous system. It is responsible for the sensory signals that arise from the most part of the face, mouth, nose, meninges, and facial muscles, and also for the motor commands carried to the masticatory muscles. These signals travel through a very complex set of structures: dermal receptors, trigeminal branches, Gasserian ganglion, central nuclei, and thalamus, finally reaching the cerebral cortex. Other neural structures participate, directly or indirectly, in the transmission and modulation of the signals, especially the nociceptive ones; these include vagus nerve, sphenopalatine ganglion, occipital nerves, cervical spinal cord, periaqueductal gray matter, hypothalamus, and motor cortex. But not all stimuli transmitted through the trigeminal system are perceivable. There is a constant selection and modulation of the signals, with either suppression or potentiation of the impulses. As a result, either normal sensory perceptions are elicited or erratic painful sensations are created. Electrical neuromodulation refers to adjustable manipulation of the central or peripheral pain pathways using electrical current for the purpose of reversible modification of the function of the nociceptive system through the use of implantable devices. Here, we discuss not only the distal components, the nerve itself, but also the sensory receptors and the main central connections of the brain, paying attention to the possible neuromodulation targets.

External trigeminal nerve stimulation for drug resistant epilepsy: A randomized controlled trial.

BACKGROUND: External trigeminal nerve stimulation (ETNS) is an emergent, non-invasive neurostimulation therapy delivered bilaterally with adhesive skin electrodes. In previous studies, ETNS was associated to a decrease in seizure frequency in patients with focal drug-resistant epilepsy (DRE). OBJECTIVE: To determine the long-term efficacy and tolerability of ETNS in patients with focal DRE. Moreover, to explore whether its efficacy depends on the epileptogenic zone (frontal or temporal), and its impact on mood, cognitive function, quality of life, and trigeminal nerve excitability. METHODS: Forty consecutive patients with frontal or temporal DRE, unsuitable for surgery, were randomized to ETNS or usual medical treatment. Participants were evaluated at 3, 6 and 12 months for efficacy, side effects, mood scales, neuropsychological tests and trigeminal nerve excitability. RESULTS: Subjects had a median of 15 seizures per month and had tried a median of 12.5 antiepileptic drugs. At 12 months, percentage of responders was 50% in ETNS group and 0% in control group. Seizure frequency in ETNS group decreased by -43.5% from baseline. Temporal epilepsy subgroup responded better than frontal epilepsy subgroup (55.56% vs. 45.45%, respectively). Median stimulation intensity was 6.2 mA. ETNS improved quality of life, but not anxiety or depression. Long-term ETNS affected neither neuropsychological function, nor trigeminal nerve excitability. No relevant adverse events were observed. CONCLUSIONS: ETNS is an effective and well-tolerated therapy for focal DRE. Patients with temporal epilepsy showed a better response than those with frontal epilepsy. Future studies with larger populations may define its role compared to other neurostimulation techniques. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that ETNS reduces seizure frequency in patients with focal DRE.

Leucine-rich α-2-glycoprotein-1 promotes diabetic corneal epithelial wound healing and nerve regeneration via regulation of matrix metalloproteinases.

Leucine-rich α-2-glycoprotein-1 (LRG1) is involved in several pathophysiological processes, including angiogenesis, cutaneous wound repair and cancer metastasis. In this study, we investigated the potential role and mechanism of LRG1 in corneal re-epithelialisation and nerve regeneration in streptozotocin-induced diabetic mice. We found decreased levels of LRG1 in the corneal epithelium after wounding in diabetic mice compared to normal controls. Hyperglycaemia downregulated the LRG1 expression in the corneal epithelium in vivo, as well as in vitro in a cultured mouse corneal epithelial stem/progenitor cell line (TKE2 cells) exposed to high glucose (HG; 30 mM) in the culture medium. Exogenous application of LRG1 accelerated corneal re-epithelialisation and nerve regeneration in normal mice and diabetic mice. LRG1 also overcame the suppression of wound healing in TKE2 cells by HG conditions, and it activated repair-related signalling by JAK2/STAT3, AKT, epidermal growth factor receptor (EGFR) and transforming growth factor (TGF)-ß3. We also found that LRG1 treatment overcame the hyperglycaemia-suppressed expression of matrix metalloproteinase 3 (MMP3) and metalloproteinase 13 (MMP13) in the regenerated corneal epithelium. The promoted effects of LRG1 on corneal re-epithelialisation and nerve regeneration were blocked by inhibitors of MMP3 and MMP13. Subconjunctival injection of 0.5 µg MMP inhibitors did not cause any obvious toxic damage in corneal epithelial cells. Immunoprecipitation and proximity ligation assay experiments confirmed that endogenous LRG1 coprecipitated with MMP3 and MMP13 in TKE2 cells. These results indicate that LRG1 promoted wound repair and nerve regeneration in the diabetic corneal epithelium by regulation of MMPs. Our findings reveal a new function and mechanism for LRG1 in the cornea, and they provide new insights for a better understanding of diabetic keratopathy.

Protective effect inhibiting the expression of miR-181a on the diabetic corneal nerve in a mouse model.

To investigate the protective effect of inhibiting miR-181a on diabetic corneal nerve in mice, we chose male C57BL/6 mice with streptozotocin (STZ) -induced diabetes as animal models. The expression of miR-181a in trigeminal ganglion tissue (TG) of diabetic mice was detected by real-time PCR. In vitro, we cultured mouse trigeminal ganglion neurons and measured the neuronal axon growth when treated under miR-181a antagomir and negative conditions (NTC). Immunofluorescence showed a significant increase in neuronal axon length in trigeminal ganglion cells treated with miR-181a antagomir. In animal models, we performed epithelial scraping and subconjunctival injection of the miR-181a antagomir and miRNA antagomir NTC to observe the corneal nerve repair by corneal nerve staining. miR-181a antagomir subconjunctival injection significantly increased the corneal epithelium healing of diabetic mice compared with that of the NTC group. Meanwhile, corneal nerve staining showed that the repair of corneal nerve endings was significantly promoted. As the targets of the 181a, ATG5 and BCL-2 were previously identified. The results of Western blot showed that the expression of autophagy associated protein ATG5 and LC3B-II and the expression of anti-apoptotic protein Bcl-2 were decreased in the high-glucose cell culture environment and the diabetic TG tissue. The expression of ATG5, LC3B-II and Bcl-2 were significantly increased after miR-181a antagomir treatment compared with negative control group. This study showed that inhibition of miR-181a expression in diabetic mice could increase ATG5-mediated autophagic activation, BCL-2-mediated inhibition of apoptosis, and promote the growth of trigeminal sensory neurons and the regeneration of corneal nerve fibers. It has a protective effect on diabetic corneal neuropathy.

Neuroprotective Effect of Citicoline Eye Drops on Corneal Sensitivity After LASIK.

PURPOSE: To evaluate the accelerator role of a topically administered neuroprotective eye drop (citicoline) on the recovery of corneal sensitivity after laser in situ keratomileusis (LASIK). METHODS: In this prospective, controlled study, 78 eyes of 78 patients (mean age: 26.8 ± 7.6 years) were enrolled in the study group and their eyes were treated with topical citicoline three times a day for 1 month postoperatively. Seventy-eight eyes of 78 patients (mean age: 26.1 ± 7.4 years) were randomly selected as the control group and their eyes were treated with lubricant hyaluronic acid (0.15%) eye drops three times a day for 1 month. Corneal sensitivity was assessed in both groups using a Cochet-Bonnet esthesiometer at baseline and 1, 2, 3, 4, 6, 8, and 12 weeks after the LASIK procedure. RESULTS: Corneal sensitivity at 1, 2, 3, 4, and 6 weeks after LASIK was significantly better in the citicoline group than the control group (P < .05 for all). Differences between the groups at 8 and 12 weeks after LASIK were not significant (P > .05). CONCLUSIONS: Topically administered citicoline eye drops had beneficial effects in the early recovery of corneal sensitivity during the first 6 weeks after LASIK, suggesting that citicoline may play a significant role in accelerating corneal reinnervation. [J Refract Surg. 2019;35(12):764-770.].

Corneal Denervation Causes Epithelial Apoptosis Through Inhibiting NAD+ Biosynthesis.

Purpose: To determine if trigeminal innervations of the corneal epithelium maintains its integrity and homeostasis through controlling the nicotinamide adenine dinucleotide (NAD) content of this tissue. Methods: Corneal denervation of C57BL/6 mice was induced by squeezing the nerve bundles that derive from the trigeminal ganglion and was confirmed by whole-mount corneal nerve staining and the sensation test. The apoptosis of the corneal epithelium was examined by TUNEL assay and annexin V/propidium iodide staining. NAD biosynthesis-related enzymes were analyzed by quantitative PCR, immunofluorescence staining, and Western blotting. FK866, an inhibitor of nicotinamide phosphoribosyltransferase (NAMPT), exogenous nicotinamide mononucleotide (NMN), and NAD+ were used to evaluate the effect of NAD+ on the apoptosis of cultured corneal epithelial cells and epithelial detachment in denervated mice. Protein expression that related to apoptosis and phosphorylation were analyzed by Western blotting. Results: The denervated mice showed spontaneous corneal epithelial detachment and cell apoptosis accompanied with impaired epithelial NAD+ contents due to low levels of NAMPT. Similarly, inhibition of NAMPT recapitulated epithelial detachment as in denervated mice and induced apoptosis in cultured corneal epithelial cells. The replenishment of NMN or NAD+ partially slowed down corneal nerve fiber degeneration, reduced the epithelial defect in denervated mice, and improved apoptosis induction in FK866-treated cells by restoring the activation levels of SIRT1, AKT, and CREB. Conclusions: Corneal denervation lowered epithelial NAD+ contents through reducing the expression of NAMPT and caused cell apoptosis and epithelial defects, suggesting that corneal innervations contribute to epithelial homeostasis by regulating NAD+ biosynthesis.

Characterization and Transcriptional Activation of the Immediate Early Gene ARC During a Neural Correlate of Classical Conditioning.

Plasticity and learning genes require regulatory mechanisms that have the flexibility to respond to a variety of sensory stimuli to generate adaptive behavioral responses. The immediate early gene (IEG) activity-regulated cytoskeleton-associated protein (ARC) is rapidly induced not only by neuronal stimulation but also during a variety of learning tasks. How ARC is regulated in response to complex stimuli during associative learning remains to be fully detailed. Here, we characterized the structure of the ARC gene in the pond turtle and mechanisms of its transcriptional activation during a neural correlate of eyeblink classical conditioning. The tARC gene is regulated in part by the presence of paused polymerase (RNAPII) that is poised at the promoter for rapid gene induction. Conditioning induces permissive chromatin modifications in the tARC promoter that allows binding by the transcription factor cAMP response element-binding protein (CREB) within 5 min of training. During learning acquisition, the pausing factor negative elongation factor (NELF) dissociates from the promoter thereby releasing RNAPII for active transcription. Data additionally suggest that the DNA insulator protein CCCTC-binding factor (CTCF) is required for transcription by mediating a learning-induced interaction of the ARC promoter with an enhancer element. Our study suggests that the learning-inducible IEG tARC utilizes both paused RNAPII and rapid chromatin modifications that allow for dynamic gene responsiveness required when an organism is presented with a variety of environmental stimuli.

F wave, A wave, H reflex, and blink reflex.

Late responses include F waves, A waves, H reflex, and the blink reflex. These responses help enhance routine nerve conduction studies. Despite the use of F waves in multiple clinical applications, their studies can technically challenge even the most experienced electromyographers. They vary in latency, amplitude, and configuration, whereas A waves show no change in latency or morphology. Electrical stimulation of the supraorbital branch of the trigeminal nerve on one side results in a reflexive activation of the facial nucleus causing contraction of the orbicularis oculi muscle, short latency R1 ipsilaterally, and long latency R2 bilaterally. F waves can help determine the presence of a polyneuropathy. A waves can reflect axonal damage. H reflexes provide nerve conduction measurements along the entire length of the nerve, demonstrating abnormalities in neuropathies and radiculopathies. Abnormalities in the blink reflex can suggest the presence of an acoustic neuroma or a demyelinating polyneuropathy, which can affect the cranial nerves. This reflex, which also needs appropriate technical expertise, helps to assess cranial nerves V and VII along with their connections in the pons and medulla. The blink reflex, the electrical version of the corneal reflex, represents a polysynaptic reflex.

The Second Division of Trigeminal Nerve for Corneal Neurotization: A Novel One-Stage Technique in Combination With Facial Reanimation.

Corneal neurotization represents an effective surgical strategy to restore corneal sensibility in patients affected by neurotrophic keratopathy.Corneal sensibility is essential in preserving structure and function of the eye. Loss of corneal sensibility can lead to a degenerative condition of the cornea known as neurotrophic keratopathy.Moreover, patients suffering from facial palsy show failure of full eyelid closure resulting in chronic corneal exposure and subsequent progressive damage.Reports have shown that the use of the contralateral ophthalmic division of the trigeminal nerve can be effective in restoring corneal sensibility. In the present study the authors expose a new technique by means of which direct neurotization of the anesthetic cornea was achieved using the homolateral second division of the trigeminal nerve. Effectiveness of the technique was evaluated using in vivo confocal microscopy.To the best of authors' knowledge, this is the first report of this technique in literature.

Correlation between olfactory function, trigeminal sensitivity, and nasal anatomy in healthy subjects.

PURPOSE: Few studies have investigated the correlation between chemosensory function (trigeminal and olfactory) and nasal volume in humans, even though nasal anatomy is crucial for the sense of smell. Aim of this study was to evaluate these correlations in normosmic subjects. METHODS: Two hundred and fifty-six healthy volunteers (age range 19-69 years) participated. Olfactory function was investigated for (the rose-like) phenylethyl alcohol odor threshold and odor identification (OI) using the Sniffin' Sticks test, while nasal structure was evaluated by acoustic rhinometry (AR); trigeminal sensitivity was assessed in terms of detection "thresholds" for the odorless carbon dioxide (CO2). RESULTS: There were negative correlations between olfactory sensitivity at threshold level and minimum cross-sectional area (MCSA) in both nostrils. No significant correlations were found between OI and nasal anatomy. Similar to olfactory sensitivity, with regard to the trigeminal stimulus CO2 for the right nostril subjects were the more sensitive the smaller the MCSA. CONCLUSIONS: The current results emphasize the significance of nasal anatomy for trigeminal/olfactory threshold perception. Interestingly, correlations were not found between suprathreshold odor identification and nasal anatomy. Other than odor identification, odor thresholds appear to depend on subtle differences in nasal anatomy.

Treatment of neurotrophic keratopathy with minimally invasive corneal neurotisation: long-term clinical outcomes and evidence of corneal reinnervation.

AIM: To report clinical outcomes and evidence of corneal innervation in patients with neurotrophic keratopathy (NK) treated with minimally invasive corneal neurotisation (MICN) using a sural nerve graft and donor sensory nerves from the face. METHODS: Patients undergoing MICN at The Hospital for Sick Children, Toronto, Canada were prospectively recruited. Data on central corneal sensation (CCS, measured with Cochet-Bonnet aesthesiometer), best-corrected visual acuity (BCVA) and corneal epithelial integrity were collected. In four patients who subsequently underwent keratoplasty, immunohistochemical analysis was performed on the corneal explants. One patient underwent magnetoencephalography (MEG) after MICN to characterise the neurophysiological pathways involved. RESULTS: Between November 2012 and February 2017, 19 eyes of 16 patients underwent MICN. Mean follow-up was 24.0±16.1 months (range, 6-53). Mean CCS significantly improved from 0.8±2.5 mm to 49.7±15.5 mm at final follow-up (p<0.001). Mean BCVA remained stable, and the number of episodes of corneal epithelial defects after MICN was significantly reduced compared with the year leading up to the procedure (21% vs 89%, respectively; p<0.0001). In the four eyes that underwent keratoplasties after MICN, all transplants fully re-epithelialised and regained sensation subsequently. Immunohistochemistry of the corneal explants demonstrated evidence of corneal reinnervation. In one patient who was 8 months after MICN, novel neuroactivity was detected on MEG in the ipsilateral somatosensory cortex on mechanical stimulation of the reinnervated cornea. CONCLUSIONS: By providing an alternative source of innervation, MICN improves corneal sensation and stabilises the corneal epithelium, permitting optical keratoplasty for patients with NK-related corneal opacity.

Pain threshold monitoring during chronic constriction injury of the infraorbital nerve in rats.

Background: The chronic constriction injury (CCI) of the infraorbital nerve (ION) has been used to establish an animal mode of trigeminal neuralgia (TN), but key parameters of the model have not been quantified until now. Objective: The aim of the study was to quantify a standard of pain threshold to evaluate a successful TN model in Sprague-Dawley (SD) rats. Methods: Forty-eight adult SD rats (200-220 g) underwent chronic constriction injury of the infraorbital nerve. The pain threshold was tested one day preoperatively (baseline) and day 1, 3, 7, 14, 28 postoperatively using the up-down method. At day 28, all the animals were killed by dislocation of the cervical spine and the trigeminal nerve specimens were removed for electron microscopy. Results: The baseline pain threshold was 14.40 ± 0.87 g. Postoperatively, all the rats presented an initial reduced sensitivity to mechanical stimulation from day 1 (15.63 ± 1.92 g) through 7 (17.39 ± 1.43 g) after the surgery. At day 14, 32 (66.7%) began to show significant mechanical allodynia (0.71 ± 0.43 g) which did not change significantly till day 28 (0.88 ± 0.54 g). These animals were regarded as successful TN models with a 95% confidence interval of the pain threshold of 0.58-1.27 at Day 14. The electron microscopy demonstrated homogeneously demyelinated changes in those successful TN model animals rather than severe or mild epineurial lesions in those unsuccessful model animals. Conclusion: Our study showed that an animal TN model could be established with a two-week chronic constriction injury of the infraorbital nerve. The mechanical allodynia index <1.27 at Day 14 was suggested as a criterion for a successful model.

Mouse strains and sexual divergence in corneal innervation and nerve regeneration.

A variety of mouse strains and sexes are used in studies of corneal wound healing and nerve regeneration. However, there is a gap of knowledge about corneal nerve density and its function in different mouse strains and sexes. In this study, we report a strain divergence of total and substance P (SP) sensory corneal nerves in uninjured mice. The BALB/c mouse showed the highest nerve density, corneal sensitivity, and tear volume followed by CFW and then C57BL/6. No differences were found in total nerves and SP-positive nerves between sexes. After injury damaged the corneal nerves, an important role for mouse strains, biologic sex, and their association to corneal nerve regeneration was identified. All female mice have a faster nerve regeneration rate than males. The molecular mechanism of this sexual divergence involves higher secretion neurotrophic factors in tears, which in turn modulate gene expression in trigeminal ganglion neurons. An important upstream signaling regulator was ß-estradiol, and topical treatment with ß-estradiol confirmed its function in corneal nerve regeneration. In conclusion, our study shows that the strain and sex of laboratory mice significantly affect the different indicators of corneal innervation and nerve regeneration. Researchers investigating corneal diseases should carefully consider these factors.-Pham, T. L., Kakazu, A., He, J., Bazan, H. E. P. Mouse strains and sexual divergence in corneal innervation and nerve regeneration.