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Background: There are currently no intraoperative neurophysiological tools to assess the effectiveness of trigeminal nerve decompression during microvascular decompression surgery for drug-resistant trigeminal neuralgia. In microvascular decompression surgery for hemifacial spasm, an abnormal electromyographic activation of facial muscles after stimulation of the offending vessel was identified and named 'Z-L response'., Methods: We adapted a neurophysiological protocol to elicit a Z-L response during microvascular decompression surgery for trigeminal neuralgia and applied it to a prospective series of 18 surgical patients., Results: Patients had suffered from trigeminal neuralgia for a median 9-year timeframe, and median preoperative Barrow Neurological Institute pain score was 4.5. Through monopolar stimulation, using rising amplitudes starting from 0.1 mA, we confirmed intraoperatively the true culprit vessel before decompression. In 4/18 cases, multiple offending vessels were identified (22 conflicts overall). After decompression, a significant increase in activation threshold (p < 0.0001) confirmed the effectiveness of the maneuver; in 10 cases, Z-L response was abolished. Using this technique, we obtained excellent or good outcome (Barrow Neurological Institute 1-3) in all patients, with a significant reduction in postoperative Barrow Neurological Institute score as compared with preoperative one (median Barrow Neurological Institute 1; p = 0.0002)., Conclusion: we provide the first evidence on the applicability and clinical usefulness of Z-L response during microvascular decompression surgery for trigeminal neuralgia., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Microvascular decompression (MVD) has proven efficacy in trigeminal neuralgia (TN) and hemifacial spasm (HFS). This study utilized computational fluid dynamics (CFD) to investigate the impact of MVD on wall shear stress (WSS) of responsible arteries (RAs) at the neurovascular contact (NVC). A total of 21 cases (10 TN, 11 HFS) were analyzed, involving RAs at NVC validated through intraoperative photographs. Hemodynamic parameters (WSS, vessel diameter, flow rate, pressure drop) was calculated using CFD for the RAs based on 3D silent-magnetic resonance angiograms. The NVC was segmented into NVC-proximal, NVC-site, and NVC-distal portions using simulated 3D CFD images that correlated with surgical observations. WSS ratios of NVC-site to NVC-proximal (NVC-site/proximal) was calculated both before and after MVD. Prior to MVD, WSS in the RA at the NVC displayed a peaked curve with a maximum at NVC-site; however, post MVD, it presented a smooth curve without peaks. The WSS ratio exhibited a significant decrease after MVD. The impact of MVD on WSS of RAs at NVC was evaluated in both TN and HFS cases. Analyzing the hemodynamics of RAs through CFD and identifying WSS peaks at NVC portions before MVD provided a more detailed and localized understanding of the morphologically depicted NVC., (© 2024. The Author(s).)

Objective: Chronic constriction injury (CCI) of the infraorbital nerve induces neuropathic pain, such as allodynia and hyperalgesia, in the orofacial area. However, the changes in the local circuits of the central nervous system following CCI remain unclear. This study aimed to identify the changes following CCI in Thy1-GCaMP6s transgenic mice., Methods: Neural activity in the primary somatosensory cortex (S1) and motor cortex (M1) following whisker stimulation was assessed using in vivo Ca 2+ imaging. CCI-induced changes in responses were analyzed., Results: Before CCI, whisker stimulation induced a greater Ca 2+ response in the contralateral S1 than in the ipsilateral S1 and contralateral M1. The peak Ca 2+ response amplitude in the bilateral S1 and contralateral M1 decreased two days after CCI compared to before CCI. Decreased Ca 2+ response amplitude in these regions was observed until four days after CCI. Seven days after CCI, the Ca 2+ response amplitude in the contralateral S1 decreased, whereas that in the ipsilateral S1 and contralateral M1 recovered to control levels., Conclusion: These results suggest that neural activity in regions receiving excitatory inputs via corticocortical pathways recovers earlier than in regions receiving thalamocortical inputs. (185/250 words)., Competing Interests: Declaration of competing interest The authors declare no potential conflicts of interest with respect to the authorship and/or publication of this article., (Copyright © 2024 Japanese Association for Oral Biology. Published by Elsevier B.V. All rights reserved.)

Background: Widespread neuropathic pain usually affects a wide range of body areas and inflicts huge suffering on patients. However, little is known about how it happens and effective therapeutic interventions are lacking., Methods: Widespread neuropathic pain was induced by partial infraorbital nerve transection (p-IONX) and evaluated by measuring nociceptive thresholds. In vivo/vitro electrophysiology were used to evaluate neuronal activity. Virus tracing strategies, combined with optogenetics and chemogenetics, were used to clarify the role of remodeling circuit in widespread neuropathic pain., Results: We found that in mice receiving p-IONX, along with pain sensitization spreading from the orofacial area to distal body parts, glutamatergic neurons in the ventral posteromedial nucleus of the thalamus (VPM Glu ) were hyperactive and more responsive to stimulations applied to the hind paw or tail. Tracing experiments revealed that a remodeling was induced by p-IONX in the afferent circuitry of VPM Glu , notably evidenced by more projections from glutamatergic neurons in the dorsal column nuclei (DCN Glu ). Moreover, VPM Glu receiving afferents from the DCN extended projections further to glutamatergic neurons in the posterior insular cortex (pIC). Selective inhibition of the terminals of DCN Glu in the VPM, the soma of VPM Glu or the terminals of VPM Glu in the pIC all alleviated trigeminal and widespread neuropathic pain., Conclusion: These results demonstrate that hyperactive VPM Glu recruit new afferents from the DCN and relay the extra-cephalic input to the pIC after p-IONX, thus hold a key position in trigeminal neuropathic pain and its spreading. This study provides novel insights into the circuit mechanism and preclinical evidence for potential therapeutic targets of widespread neuropathic pain., (© 2024. The Author(s).)

Background: The association between paroxysmal hemicrania (PH) and trigeminal neuralgia-the so-called PH-tic syndrome-has rarely been described. However, a correct diagnosis is crucial since both disorders require specific treatments. Little is known about pathophysiological mechanisms, and, to date, there are no electrophysiological studies in patients with PH-tic syndrome., Case: We describe the case of a 52-year-old man with a PH-tic syndrome successfully treated with an association of carbamazepine (1200 mg/day) and indomethacin (150 mg/die). Patient underwent trigeminal reflex testing, including blink and masseter inhibitory reflex, and laser-evoked potential (LEP) recording after supraorbital region stimulation in the affected and unaffected side. Both neurophysiological investigations resulted normal; LEPs failed to detect any latency asymmetry between both sides., Conclusions: Neurophysiological findings demonstrate for the first time the integrity of somatosensory system in a primary PH-tic syndrome case. Central pathophysiological mechanisms and hypothalamic dysregulation may contribute to the development of this rare syndrome., (© 2024. Fondazione Società Italiana di Neurologia.)

Structural covariance networks and causal effects within can provide critical information on gray matter reorganization and disease-related hierarchical changes. Based on the T1WI data of 43 classical trigeminal neuralgia patients and 45 controls, we constructed morphological similarity networks of cortical thickness, sulcal depth, fractal dimension, and gyrification index. Moreover, causal structural covariance network analyses were conducted in regions with morphological abnormalities or altered nodal properties, respectively. We found that patients showed reduced sulcal depth, gyrification index, and fractal dimension, especially in the salience network and the default mode network. Additionally, the integration of the fractal dimension and sulcal depth networks was significantly reduced, accompanied by decreased nodal efficiency of the bilateral temporal poles, and right pericalcarine cortex within the sulcal depth network. Negative causal effects existed from the left insula to the right caudal anterior cingulate cortex in the gyrification index map, also from bilateral temporal poles to right pericalcarine cortex within the sulcal depth network. Collectively, patients exhibited impaired integrity of the covariance networks in addition to the abnormal gray matter morphology in the salience network and default mode network. Furthermore, the patients may experience progressive impairment in the salience network and from the limbic system to the sensory system in network topology, respectively., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Chronic neuropathic pain can result from nervous system injury and can persist in the absence of external stimuli. Although ongoing pain characterizes the disorder, in many individuals, the intensity of this ongoing pain fluctuates dramatically. Previously, it was identified that functional magnetic resonance imaging signal covariations between the midbrain periaqueductal gray (PAG) matter, rostral ventromedial medulla (RVM), and spinal trigeminal nucleus are associated with moment-to-moment fluctuations in pain intensity in individuals with painful trigeminal neuropathy (PTN). Since this brainstem circuit is modulated by higher brain input, we sought to determine which cortical sites might be influencing this brainstem network during spontaneous fluctuations in pain intensity. Over 12 min, we recorded the ongoing pain intensity in 24 PTN participants and classified them as fluctuating ( n  = 13) or stable ( n  = 11). Using a PAG seed, we identified connections between the PAG and emotional-affective sites such as the hippocampal and posterior cingulate cortices, the sensory-discriminative posterior insula, and cognitive-affective sites such as the dorsolateral prefrontal (dlPFC) and subgenual anterior cingulate cortices that were altered dependent on spontaneous high and low pain intensity. Additionally, sliding-window functional connectivity analysis revealed that the dlPFC-PAG connection anticorrelated with perceived pain intensity over the entire 12 min period. These findings reveal cortical systems underlying moment-to-moment changes in perceived pain in PTN, which likely cause dysregulation in the brainstem circuits previously identified, and consequently alter the appraisal of pain across time., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 Meylakh et al.)

Trigeminal neuralgia (TN) is a highly debilitating facial pain condition. Magnetic resonance imaging (MRI) is the main method for generating insights into the central mechanisms of TN pain in humans. Studies have found both structural and functional abnormalities in various brain structures in TN patients as compared with healthy controls. Whereas studies have also examined aberrations in brain networks in TN, no studies have to date investigated causal interactions in these brain networks and related these causal interactions to the levels of TN pain. We recorded fMRI data from 39 TN patients who either rested comfortably in the scanner during the resting state session or tracked their pain levels during the pain tracking session. Applying Granger causality to analyze the data and requiring consistent findings across the two scanning sessions, we found 5 causal interactions, including: (1) Thalamus → dACC, (2) Caudate → Inferior temporal gyrus, (3) Precentral gyrus → Inferior temporal gyrus, (4) Supramarginal gyrus → Inferior temporal gyrus, and (5) Bankssts → Inferior temporal gyrus, that were consistently associated with the levels of pain experienced by the patients. Utilizing these 5 causal interactions as predictor variables and the pain score as the predicted variable in a linear multiple regression model, we found that in both pain tracking and resting state sessions, the model was able to explain ∼36 % of the variance in pain levels, and importantly, the model trained on the 5 causal interaction values from one session was able to predict pain levels using the 5 causal interaction values from the other session, thereby cross-validating the models. These results, obtained by applying novel analytical methods to neuroimaging data, provide important insights into the pathophysiology of TN and could inform future studies aimed at developing innovative therapies for treating TN., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Neuropathic pain (NP) conditions involve lesions to the somatosensory nervous system leading to chronic and debilitating pain. Many patients suffering from NP utilize pharmacological treatments with various drugs that seek to reduce pathologic neuronal states. However, many of these drugs show poor efficacy as well as cause significant adverse effects. Because of this, there is a major need for the development of safer and more efficacious drugs to treat NP., Areas Covered: In this review, we analyzed current treatments being developed for a variety of NP conditions. Specifically, we sought drugs in phase II/III clinical trials with indications for NP conditions. Various databases were searched including Google Scholar, PubMed, and clinicaltrials.gov., Expert Opinion: All the mentioned targets for treatments of NP seem to be promising alternatives for existing treatments that often possess poor side effect profiles for patients. However, gene therapy potentially offers the unique ability to inject a plasmid containing growth factors leading to nerve growth and repair. Because of this, gene therapy appears to be the most intriguing new treatment for NP.

Trigeminal neuralgia (TN) is a facial pain disorder characterized by intense and paroxysmal pain that profoundly affects quality of life and presents complex challenges in diagnosis and treatment. TN can be categorized as classical, secondary and idiopathic. Epidemiological studies show variable incidence rates and an increased prevalence in women and in the elderly, with familial cases suggesting genetic factors. The pathophysiology of TN is multifactorial and involves genetic predisposition, anatomical changes, and neurophysiological factors, leading to hyperexcitable neuronal states, central sensitization and widespread neural plasticity changes. Neurovascular compression of the trigeminal root, which undergoes major morphological changes, and focal demyelination of primary trigeminal afferents are key aetiological factors in TN. Structural and functional brain imaging studies in patients with TN demonstrated abnormalities in brain regions responsible for pain modulation and emotional processing of pain. Treatment of TN involves a multifaceted approach that considers patient-specific factors, including the type of TN, with initial pharmacotherapy followed by surgical options if necessary. First-line pharmacological treatments include carbamazepine and oxcarbazepine. Surgical interventions, including microvascular decompression and percutaneous neuroablative procedures, can be considered at an early stage if pharmacotherapy is not sufficient for pain control or has intolerable adverse effects or contraindications., (© 2024. Springer Nature Limited.)

Trigeminal neuropathic pain (TNP) is a major concern in both dentistry and medicine. The progression from normal to chronic TNP through activation of the insular cortex (IC) is thought to involve several neuroplastic changes in multiple brain regions, resulting in distorted pain perception and associated comorbidities. While the functional changes in the insula are recognized contributors to TNP, the intricate mechanisms underlying the involvement of the insula in TNP processing remain subjects of ongoing investigation. Here, we have overviewed the most recent advancements regarding the functional role of IC in regulating TNP alongside insights into the IC's connectivity with other brain regions implicated in trigeminal pain pathways. In addition, the review examines diverse modulation strategies that target the different parts of the IC, thereby suggesting novel diagnostic and therapeutic management of chronic TNP in the future., (© 2024. The Author(s).)

Mapping the localization of the functional brain regions in trigeminal neuralgia (TN) patients is still lacking. The study aimed to explore the functional brain alterations and influencing factors in TN patients using functional brain imaging techniques. All participants underwent functional brain imaging to collect resting-state brain activity. The significant differences in regional homogeneity (ReHo) and amplitude of low frequency (ALFF) between the TN and control groups were calculated. After familywise error (FWE) correction, the differential brain regions in ReHo values between the two groups were mainly located in bilateral middle frontal gyrus, bilateral inferior cerebellum, right superior orbital frontal gyrus, right postcentral gyrus, left inferior temporal gyrus, left middle temporal gyrus, and left gyrus rectus. The differential brain regions in ALFF values between the two groups were mainly located in the left triangular inferior frontal gyrus, left supplementary motor area, right supramarginal gyrus, and right middle frontal gyrus. With the functional impairment of the central pain area, the active areas controlling memory and emotion also change during the progression of TN. There may be different central mechanisms in TN patients of different sexes, affected sides, and degrees of nerve damage. The exact central mechanisms remain to be elucidated., (© 2024. The Author(s).)

Background: The trigeminocardiac reflex (TCR) is a brainstem reflex commonly elicited during percutaneous balloon compression (PBC) for the treatment of trigeminal neuralgia (TN), which is characterized by drastic hemodynamic disturbances, such as bradycardia, arrhythmias and even cardiac arrest. In order to prevent catastrophic consequences, it is vital to screen the risk factors of TCR during perioperative period. The primary purpose of this study was to identify potential risk factors associated with TCR in patients with TN undergoing PBC, and to summarize the enlightenment of clinical anesthesia management., Methods: The clinical data of 165 patients diagnosed with TN undergoing PBC from January 2021 to December 2021 were retrospectively analyzed. TCR was defined as a sudden decrease in heart rate of 20% or more compared with baseline, and / or cardiac arrest, coinciding with the stimulus of any branch of the trigeminal nerve. And a clear cause-effect relationship between heart rate reduction and PBC-related intervention was required. All demographic characteristics as well as surgical and anesthetic data were compared between TCR group and TCR-free group. Univariate and multivariate logistic regression analysis were used to further analyze TCR-related risk factors., Results: Of the 165 patients enrolled in this study, 73 (44.2%) were male and 92 (55.8%) were female, and the average age was 64.22 ± 9.72 years. The incidence of TCR in the patients with TN during PBC was 54.5%. The results of multivariate regression analysis indicated that the risk factor for TCR was heart rate < 60 beats/min immediately before foramen ovale puncture (OR: 4.622; 95%CI: 1.470-14.531; P < 0.05)., Conclusion: Heart rate < 60 beats/min immediately before foramen ovale puncture was independently associated with TCR. Therefore, it is necessary for anesthesiologists to raise heart rate appropriately to prevent TCR during PBC., Competing Interests: Declaration of Competing Interest The authors declared no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Trigeminal neuralgia (TN) is a disease characterized by recurring, short-lived, electric shock-like pain experienced on one side of the face. Microvascular decompression (MVD) is one of the most effective surgical interventions for resolving TN caused by neurovascular compression. This study aimed to determine the predictive and prognostic factors of surgical outcomes., Methods: This retrospective cohort study enrolled patients diagnosed with TN who underwent MVD at our hospital during 2013-2019. The demographic information, pain character, peri-operative Barrow Neurological Institute (BNI) scale, medication, operative finding were recorded. And the outcome was Outcomes were divided into drug-free and drug-dependent group. Predisposing factors for each outcome were analyzed by one-way analysis of variance, followed by a Mann-Whitney U test or Kruskal-Wallis test., Results: A total of 104 consecutive patients received MVD to treat TN, and 88 patients were enrolled in this study. The overall postoperative drug-free outcome was 72.7%. A significant difference in drug-free outcomes was observed for patients with typical TN (80.8%) compared with patients with atypical TN (33.33%, p = 0001). When severe venous compression was encountered during MVD, the drug-free outcome fell to 50% (10/20, p = 0.009). The Mann-Whitney U test indicated typical TN as a positive predictive factor of a drug-free outcome, whereas severe venous compression was a negative predictive factor. The patients with preoperative BNI score of 4 had better improvement than others (p = 0.045). Age, onset duration, and arterial loop had no specific difference in this study., Conclusion: In our study, atypical TN and severe venous compression were associated with poor outcomes. Regrouping atypical TN into precise diagnosis represents an immediate priority according to our result. The preoperative BNI score could be used as an effective predictive tool for the outcome of MVD surgery., Competing Interests: Conflicts of interest: The authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2021, the Chinese Medical Association.)

Depression symptoms are often found in patients suffering from chronic pain, a phenomenon that is yet to be understood mechanistically. Here, we systematically investigate the cellular mechanisms and circuits underlying the chronic-pain-induced depression behavior. We show that the development of chronic pain is accompanied by depressive-like behaviors in a mouse model of trigeminal neuralgia. In parallel, we observe increased activity of the dopaminergic (DA) neuron in the midbrain ventral tegmental area (VTA), and inhibition of this elevated VTA DA neuron activity reverses the behavioral manifestations of depression. Further studies establish a pathway of glutamatergic projections from the spinal trigeminal subnucleus caudalis (Sp5C) to the lateral parabrachial nucleus (LPBN) and then to the VTA. These glutamatergic projections form a direct circuit that controls the development of the depression-like behavior under the state of the chronic neuropathic pain., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: Neurophysiological investigation of nociceptive pathway has so far been limited to late cortical responses. We sought to detect early components of the cortical evoked potentials possibly reflecting primary sensory activity., Methods: The 150 IDE micropatterned electrode was used to selectively activate Aδ intraepidermic fibres of the right hand dorsum in 25 healthy subjects and 3 patients suffering from trigeminal neuralgia. Neurographic recordings were performed to assess type of stimulated fibres and check selectivity. Cortical evoked potentials were recorded from C3'-Fz and Cz-Au1., Results: Neurographic recordings confirmed selective activation of Aδ fibres. Early components were detected after repetitive stimulation (0.83/s rate and 250-500 averages); the first negative component occured at 40 ms (N40) on the contralateral scalp., Conclusions: The provided data support the hypothesis that N40 could be the cortical primary response conducted by fast Aδ fibres., Significance: This is the first report of early, possibly primary, cortical responses in humans by nociceptive peripheral stimulation. Although not perfected yet to allow widespread diagnostic use, this is probably the only method to allow fully objective evaluation of the nociceptive system, with important future implications in experimental and clinical neurophysiology., Competing Interests: Declaration of Competing Interest The micropatterned 150 IDE is the object of a patent registration, joint property of the University of Genova and the Italian National Research Council (CNR). The author M. Leandri, as one of the inventors, may receive a share of profits in case of commercialisation and he declares a potential conflict of interest. All other authors have no conflict of interest., (Copyright © 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Objective: This study aimed to characterize key features, and to assess the clinical development of common nondental facial pain syndromes such as persistent idiopathic facial pain (PIFP), trigeminal neuralgia (TN), and neuropathic facial pain (NEUROP)., Methods: This is a longitudinal study in which prospective questionnaire data of patients presenting to a specialized outpatient clinic were collected from 2009 to 2019. A telephone interview was conducted with the same patients in 2020 to assess the natural disease history., Results: n = 411 data sets of patients with chronic facial pain were compiled. Among these were n = 150 patients with PIFP, n = 111 patients with TN, and n = 86 patients with NEUROP. Guideline therapy had not been initiated in 38.7% (58/150; PIFP), 19.8% (22/111; TN), and 33.7% (29/86; NEUROP) patients. Of the patients with PIFP, 99.3% (149/150) had primarily consulted a dentist due to their pain syndrome. The additional telephone interview was completed by 236 out of the 411 patients (57.4%). Dental interventions in healthy teeth had been performed with the intention to treat the pain in many patients (78/94 [83.0%] PIFP; 34/62 [54.8%] TN; 19/43 [44.2%] NEUROP), including dental extractions. 11.3% (7/43) of the patients with TN had never profited from any therapy. In contrast, 29.8% (28/94) of the patients with PIFP had never profited from any therapy. Furthermore, the primary pharmaceutical therapy options suggested by national guidelines were, depending on the substance class, only considered to be effective by 13.8% (13/94; antidepressants) and 14.9% (14/94; anticonvulsants) of the patients with PIFP., Conclusions: Facial pain syndromes pose a considerable disease burden. Although treatment of TN seems to be effective in most patients, patients with PIFP and NEUROP report poor effectiveness even when following guideline therapy suggestions. In addition, unwarranted dental interventions are common in facial pain syndromes., (© 2021 The Authors. Headache: The Journal of Head and Face Pain published by Wiley Periodicals LLC on behalf of American Headache Society.)

Background: Gamma Knife radiosurgery (GKRS) is a safe and effective treatment option for trigeminal neuralgia (TN). However, there is no objective, noninvasive tool to identify nonresponders or late responders to GKRS and to facilitate longitudinal patient management. We hypothesized that diffusivity metrics obtained 3 months after GKRS may correlate with response to treatment., Methods: Sixteen patients with TN treated with GKRS underwent preprocedural and 3-month postprocedural 3-T magnetic resonance imaging of the brain. Diffusion tensor metrics of axial diffusivity, radial diffusivity, and fractional anisotropy were extracted from the pontine segments, the root entry zones, and the distal cisternal segments of both trigeminal nerves. Diffusivity metrics at the 3-month post-GKRS time point were compared with pain relief at last follow-up. Favorable response to GKRS was defined as pain intensity of I-III on the Barrow Neurological Institute scale., Results: The median clinical follow-up was 11 months (range 3-18 months). Patients with favorable response to GKRS at last follow-up had lower mean fractional anisotropy values at the pontine segment (P = 0.04) and increased mean radial diffusivity values at the root entry zones (P = 0.032) of the treated trigeminal nerve on the 3-month diffusion tensor imaging sequences as compared with the nonresponders., Conclusions: Diffusivity metrics changes on the treated trigeminal nerve at the 3-month time point after GKRS for TN correlated with pain relief at last follow-up. Further, well-designed studies are warranted to establish the clinical application of diffusion tensor imaging as a noninvasive, prognostic tool in patients with TN managed with GKRS., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Neuroimaging studies have documented brain structural alterations induced by chronic pain, particularly in gray matter volume. However, the effects of trigeminal neuralgia (TN), a severe paroxysmal pain disorder, on cortical morphology are not yet known. In this study, we recruited 30 TN patients and 30 age-, and gender-matched healthy controls (HCs). Using Computational Anatomy Toolbox (CAT12), we calculated and compared group differences in cortical thickness, gyrification, and sulcal depth with two-sample t tests (p < 0.05, multiple comparison corrected). Relationships between altered cortical characteristics and pain intensity were investigated with correlation analysis. Compared to HCs, TN patients exhibited significantly decreased cortical thickness in the left inferior frontal, and left medial orbitofrontal cortex; decreased gyrification in the left superior frontal cortex; and decreased sulcal depth in the bilateral superior frontal (extending to anterior cingulate) cortex. In addition, we found significantly negative correlations between the mean cortical thickness in left medial orbitofrontal cortex and pain intensity, and between the mean gyrification in left superior frontal cortex and pain intensity. Chronic pain may be associated with abnormal cortical thickness, gyrification and sulcal depth in trigeminal neuralgia. These morphological changes might contribute to understand the underlying neurobiological mechanism of trigeminal neuralgia., (© 2021. The Author(s).)

The nucleus accumbens core (NAcc) is an important component of brain reward circuitry, but studies have revealed its involvement in pain circuitry also. However, its effect on trigeminal neuralgia (TN) and the mechanism underlying it are yet to be fully understood. Therefore, this study aimed to examine the outcomes of optogenetic stimulation of NAcc GABAergic neurons in an animal model of TN. Animals were allocated into TN, sham, and control groups. TN was generated by infraorbital nerve constriction and the optogenetic virus was injected into the NAcc. In vivo extracellular recordings were acquired from the ventral posteromedial nucleus of the thalamus. Alterations of behavioral responses during stimulation "ON" and "OFF" conditions were evaluated. In vivo microdialysis was performed in the NAcc of TN and sham animals. During optogenetic stimulation, electrophysiological recordings revealed a reduction of both tonic and burst firing activity in TN animals, and significantly improved behavioral responses were observed as well. Microdialysis coupled with liquid chromatography/tandem mass spectrometry analysis revealed significant alterations in extracellular concentration levels of GABA, glutamate, acetylcholine, dopamine, and citrulline in NAcc upon optic stimulation. In fine, our results suggested that NAcc stimulation could modulate the transmission of trigeminal pain signals in the TN animal model.

Microvascular decompression is the first choice for treating the primary trigeminal neuralgia to provide the most extended duration of pain freedom. However, in microvascular decompression, we found that this kind of operation is only suitable for some patients. It is of great value to objectively judge the function and abnormality of the trigeminal pain conduction pathway in guiding the operation process. This brief report investigates the value of pain evoked potential by electrical stimulation and noceciptive blink reflex in trigeminal neuralgia. We detected the pain evoked potential in 34 patients with trigeminal neuralgia and 48 healthy controls treated by electrical stimulation and blink reflex. We demonstrated no significant differences in the latencies of V 1 , V 2 , V 3 , and R 2 of the affected side and the contralateral side in patients with trigeminal neuralgia. The latencies of those four indicators of the affected side in patients with trigeminal neuralgia were notably decreased compared to those on the same side in healthy controls. The receiver operating characteristic curve analysis showed that the area under curve, sensitivity and specificity of the combined diagnosis of latency and amplitude were significantly higher than the single diagnosis. The latency and amplitude of V 1 were highly sensitive, while those of V 2 was highly specific. Trigeminal neuralgia can be effectively diagnosed by combining pain evoked potential by electrical stimulation and noceciptive blink reflex. The pathogenesis of trigeminal neuralgia should be combined with peripheral pathogenicity and the theory of central pathogenicity., Competing Interests: The authors declare no conflict of interest., (© 2021 The Author(s). Published by IMR Press.)

Orofacial pain, including temporomandibular joint disorders pain, trigeminal neuralgia, dental pain, and debilitating headaches, affects millions of Americans each year with significant population health impact. Despite the existence of a large body of information on the subject, the molecular underpinnings of orofacial pain remain elusive. Two decades of research has identified that transient receptor potential (TRP) ion channels play a crucial role in pathological pain. A number of TRP ion channels are clearly expressed in the trigeminal sensory system and have critical functions in the transduction and pathogenesis of orofacial pain. Although there are many similarities, the orofacial sensory system shows some distinct peripheral and central pain processing and different sensitivities from the spinal sensory system. Relative to the extensive review on TRPs in spinally-mediated pain, the summary of TRPs in trigeminally-mediated pain has not been well-documented. This review focuses on the current experimental evidence involving TRP ion channels, particularly TRPV1, TRPA1, TRPV4, and TRPM8 in orofacial pain, and discusses their possible cellular and molecular mechanisms.

Objective: This narrative review aims to update the reader on the new classification of trigeminal neuralgia (TN), clinical signs, pathophysiologic evidence, and their implications on management. This review is based on the authors' collective experience and knowledge of the literature in addition to a literature search., Background: In recent years, the phenotype of TN has been intensively studied leading to discrete groups of patients. These include patients with TN with additional continuous pain, and patients with and without neurovascular compression of the trigeminal dorsal root entry zone. A number of associated clinical signs such as tearing and sensory changes need further research., Methods: The literature on TN was searched in PubMed with the aims of providing evidence for the recently published third edition of the International Classification of Headache Disorders (ICHD) and update the clinical phenotype and management of the TN subcategories., Results: The ICHD's new classification for TN is based on reliable clinical data, imaging, and neurophysiologic studies. The TN classification reflects current knowledge and has improved the possibility for clinicians to choose adequate management options. However, there is a lack of effective, safe drugs for the management of TN and sparse, robust data on neurosurgical options., Conclusion: Research into all aspects of TN-diagnosis, pharmacotherapy, surgery, long-term management prognosis, and natural history-is needed. Research should adhere to the ICHD's schema for TN. Improved drugs are needed along with rigorous research into surgical options and their efficacy for different subtypes of TN., (© 2021 American Headache Society.)

We proposed to perform a comparative analysis of growth factors, cytokines, and chemokine receptors on the salivary cells in the saliva obtained from trigeminal neuralgia (TN) and normal subjects. Saliva was collected from TN and healthy subjects. Salivary cells were isolated by centrifugation. The expression of the cell surface marker was analyzed by flow cytometry. A cytometric bead array was done to measure the levels of cytokines and growth factors on the flow cytometer. Saliva from TN subjects showed lower growth factor levels of Angiopoietin-2, bFGF, HGF, SCF, TGF-α, and VEGF and higher cytokine levels of IL-1β, TNF-α, CCL2, IL-17A, IL-6, and CXCL8, as well as higher expression levels of chemokine receptors CCR1 (CD191), CR3 (CD11b), CCR2 (CD192), CXCR5 (CD185), and CCR5 (CD196) in the cells from TN saliva. A certain set of cytokines and growth factors in the saliva, as well as chemokine receptors on salivary cells, could be a useful tool in the diagnostics and prognostics of trigeminal neuralgia. Trigeminal neuralgia is one of the significant pathological conditions in the class of chronic diseases around the world. Many targeted approaches are being tried by various research groups to utilize the information of the inflammatory microenvironment to resolve the pathology of chronic TN.

The nature of trigeminal neuropathic pain (TN) attacks is regarded as the ignition of ectopic action potentials from the trigeminal root following vascular compression, which seemed to be related to transmembrane proteins and inflammation factors. This study focused on the mechanosensitive channel Piezo2 and cytokine IL-6. The chronic constriction injury of infraorbital nerve in SD rats was used to establish the TN model. The trigeminal ganglion was then achieved to perform immunocytochemistry studies. A significant upregulation of Piezo2 and IL-6 was showed in the TN model rats. The Piezo2 positive accounted for 72.3±9.5% in those IL-6 positive neurons. The Piezo2 co-localized with CGRP, IB4 and NF-200 but not with GFAP, which implied that it was expressed in both the C-type and the A-type neurons. After administration of GsMTx4 or anti-rat IL-6 antibody in the TN model, the dynamic allodynia and pinprick hyperalgesia scores as well as the mechanical threshold changed significantly. In the sham-operation rates, with local administration of IL-6, an upregulation of Piezo2 was also exhibited. Our study demonstrated that the up-regulation of Piezo2 in the pain afferent neurons following trigeminal nerve injury may play a role in the development of the neuralgia. Meanwhile, the expression of Piezo2 may be modulated by inflammatory cytokines, such as IL-6.

Objectives: To describe the characteristics and treatment of trigeminal neuralgia in children attending a dedicated pediatric headache clinic., Background: Data on trigeminal neuralgia as a cause of headache are largely derived from adult studies. Little is known about the etiology, symptoms, treatment, and outcome of the disorder in children and adolescents., Methods: A case series study was undertaken. The database of a headache clinic within a tertiary, university-affiliated, pediatric medical center was searched for all patients aged 3-18 years presenting with clinical and epidemiological features of trigeminal neuralgia or trigeminal neuropathy from January 2015 to December 2019. The diagnosis was revised for the present study according to the criteria of the International Classification of Headache Disorders, third edition. Data on demographic parameters, clinical symptoms, treatment, and outcome were collected from the medical files., Results: Of the 1040 patients who presented to our clinic during the study period, five (0.5%) were diagnosed with trigeminal neuralgia. Mean patient age was 15.1 ± 3.0 years (range 9.5-17.5; 95% CI 10.8-18.9). All had idiopathic type: purely paroxysmal in one and with concomitant continuous pain in four. Findings on herpes serology in all five and magnetic resonance imaging were normal in four patients. In the fifth, a vascular ring was noted from the superior cerebellar artery around the right trigeminal nerve without radiologic evidence of vascular nerve compression. All patients were initially treated with carbamazepine: one reported partial relief, two did not respond, and two had severe adverse effects. Three patients were switched to gabapentin but only one responded well. Three patients were treated with nerve block., Conclusion: Trigeminal neuralgia accounted for only a small proportion of patients seeking treatment for headache in pediatric headache clinic over a 5-year period. Unlike findings in adults, vascular compression was not the underlying mechanism in any of our patients. The response to pharmacologic treatment was poor. Nerve block may serve as an alternative when pharmacologic treatment fails., (© 2020 American Headache Society.)

Objective: Microvascular decompression (MVD) has remained the first-line surgical treatment of trigeminal neuralgia when an offending vessel can be identified that is causing neurovascular compression. However, patients without neurovascular compression can either develop trigeminal neuralgia or recurrence after MVD. In addition, patients with venous and less severe arterial compression have been shown to have reduced efficacy after MVD. Internal neurolysis is a surgical technique used to separate the fascicles of the trigeminal nerve and might be a good option for patients with trigeminal neuralgia but without vascular compression., Methods: A retrospective, institutional review board-approved medical record review was performed of adult patients with trigeminal neuralgia who had undergone internal neurolysis. The search resulted in 32 patients who had been treated from 2016 to 2019. The Barrow Neurological Institute (BNI) pain intensity scale and hypesthesia scale (HS) were used to determine the outcomes., Results: The average follow-up was 20 months (range, 3-40 months). The postoperative outcomes showed a BNI pain intensity scale score of I for 50%, with excellent control in 56%, successful control in 78%, adequate control in 94%, and poor control in 6%. Significantly more patients without previous treatment had had successful pain control (95% vs. 54%). Six patients (19%) experienced pain recurrence and were significantly more likely to experience pain recurrence compared with patients without a previous procedure (39% vs. 5%). The overall BNI-HS score postoperatively was I for 28%, II for 69%, and III for 3%., Conclusions: Internal neurolysis with and without MVD has shown efficacy in treating trigeminal neuralgia in carefully selected patients., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Percutaneous compression of the trigeminal ganglion (PCTG) has been used to treat trigeminal neuralgia since 1983. A PCTG-related trigeminocardiac reflex (TCR) can induce dramatic hemodynamic disturbances. This study investigates the effects of depth of propofol anesthesia on hemodynamic changes during PCTG., Materials and Methods: A total of 120 patients who underwent PTCG for trigeminal neuralgia were randomly assigned to control group-intravenous saline pretreatment before PCTG puncture and anesthesia targeted to bispectral index (BIS) 40 to 60 throughout, and study group-intravenous propofol 1 to 2 mg/kg pretreatment to deepen anesthesia to BIS<40 before PCTG. Mean arterial pressure, heart rate (HR), cardiac output, system vascular resistance, and BIS were measured at 9 time points during the procedure, and the incidence of the TCR was observed at T5 and T6., Results: BIS was lower in the study group compared with the control after pretreatment with propofol or saline, respectively. Compared with the control group, mean arterial pressure was lower in the study group at several points during the procedure, but there was no difference in HR between the 2 groups at any point. Cardiac output was higher and system vascular resistance lower in the study compared with the control group. In the control group, 42 (70.0%) and 52 (86.7%) of patients developed a TCR at the 2 points, and 37 (67.1%) and 45 (75.0%) in the study group. There was no difference in the incidence of TCR between the 2 groups., Conclusion: Increasing the depth of propofol anesthesia partially attenuated PTCG-related elevation of blood pressure but did not modify the abrupt reduction in HR.

Trigeminal neuralgia is a pain condition that is frequently misdiagnosed and challenging to manage. We present the case of a patient with trigeminal neuralgia with multiple misdiagnoses and poorly managed pain. Despite the presence of trigger zones both inside and outside her mouth, complete symptom resolution was ultimately achieved through onabotulinumtoxinA injections, delivered solely intraorally.

Trigeminal neuralgia is a very painful neurological condition with severe, stimulus-evoked, short-lasting stabbing pain attacks in the face. The past decade has offered new insights into trigeminal neuralgia symptomatology, pathophysiology, and treatment, leading to a change in the classification of the condition. An accurate diagnosis is crucial because neuroimaging interpretation and clinical management differ among the various forms of facial pain. MRI using specific sequences should be a part of the diagnostic workup to detect a possible neurovascular contact and exclude secondary causes. Demonstration of a neurovascular contact should not be used to confirm a diagnosis but rather to facilitate surgical decision making. Carbamazepine and oxcarbazepine are drugs of first choice for long-term treatment, whereas microvascular decompression is the first-line surgery in medically refractory patients. Advances in neuroimaging techniques and animal models will provide further insight into the causes of trigeminal neuralgia and its pathophysiology. Development of more efficacious treatment options is highly warranted., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Previous studies have reported that electrical stimulation of the motor cortex is effective in reducing trigeminal neuropathic pain; however, the effects of optical motor cortex stimulation remain unclear., Objective: The present study aimed to investigate whether optical stimulation of the primary motor cortex can modulate chronic neuropathic pain in rats with infraorbital nerve constriction injury., Methods: Animals were randomly divided into a trigeminal neuralgia group, a sham group, and a control group. Trigeminal neuropathic pain was generated via constriction of the infraorbital nerve and animals were treated via selective inhibition of calcitonin gene-related peptide in the trigeminal ganglion. We assessed alterations in behavioral responses in the pre-stimulation, stimulation, and post-stimulation conditions. In vivo extracellular recordings were obtained from the ventral posteromedial nucleus of the thalamus, and viral and α-CGRP expression were investigated in the primary motor cortex and trigeminal ganglion, respectively., Results: We found that optogenetic stimulation significantly improved pain behaviors in the trigeminal neuralgia animals and it provided more significant improvement with inhibited α-CGRP state than active α-CGRP state. Electrophysiological recordings revealed decreases in abnormal thalamic firing during the stimulation-on condition., Conclusion: Our findings suggest that optical motor cortex stimulation can alleviate pain behaviors in a rat model of trigeminal neuropathic pain. Transmission of trigeminal pain signals can be modulated via knock-down of α-CGRP and optical motor cortex stimulation.

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.

Background: Trigeminal neuralgia (TN) is an orofacial condition defined by reoccurring, spontaneous, short-lived but excruciating stabbing pain. Pharmacological interventions constitute the first-line treatment for TN, with antiepileptic drugs commonly prescribed. People treated for TN pain with antiepileptic drugs describe cognitive and motor difficulties affecting activities of daily living, and report poorer quality of life. We undertook the first comprehensive objective evaluation of sensorimotor and cognitive performance in participants being treated for TN pain with antiepileptic drugs relative to age-matched controls., Methods: Participants (43 TN, 41 control) completed a battery of sensorimotor (steering, aiming and tracking) and cognitive (working memory, processing speed, inhibition) tasks., Results: The TN group performed significantly worse than controls on the sensorimotor tracking and aiming tasks and across all cognitive measures., Conclusions: The data explain why patients treated with antiepileptic drugs report impairment when conducting activities of daily living (given the need for cognitive and motor capability within most of these). The study is an important first step in: (i) ensuring there is adequate information on the impact of pharmacological treatment; (ii) identifying measures to determine optimal medication dosage and track change over time; (iii) creating an evidence base that could allow scientific justification of alternative pain treatment options for TN (e.g. the costs/benefits of surgery).

Introduction: Changes in blood pressure during trigeminal combing have been discussed in recent years. In this study, a retrospective analysis of patients with trigeminal neuralgia (TN) requiring microvascular decompression (MVD) with nerve combing was carried out to investigate fluctuation in arterial blood pressure during trigeminal nerve combing and its surgical effect and corresponding pathogenesis., Methods: A total of 70 cases of MVD with nerve combing performed during the treatment of primary TN patients were selected between January 2017 and January 2018 at Peking University People's Hospital. The degree of pain and prognosis of the patients were evaluated according to the visual analog scale. Postoperative facial numbness of the 2 groups were assessed by the Barrow Neurological Institute facial numbness score. Arterial blood pressure changes before and while combing the trigeminal nerve during MVD were dynamically monitored, and the patients were divided into responders and nonresponders. Total adrenaline (AD), norepinephrine (NE), and dopamine values were measured before and during trigeminal nerve combing., Results: Increased arterial blood pressure during the combing of the trigeminal nerve in MVD had a significant correlation with the prognosis of patients, with patients with higher arterial blood pressure having a better prognosis (P < 0.05). In the increased arterial blood pressure patients, precombing total AD and NE means were dramatically improved (P < 0.05)., Conclusions: This study shows that changes in arterial blood pressure during trigeminal nerve combing in MVD were correlated with the prognosis of patients. Further research is necessary to clarify the mechanism of increased arterial blood pressure., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Invasive motor Cortex Stimulation (iMCS) was introduced in the 1990's for the treatment of chronic neuropathic orofacial pain (CNOP), although its effectiveness remains doubtful. However, CNOP is known to be a heterogeneous group of orofacial pain disorders, which can lead to different responses to iMCS. Therefore, this paper investigated (1) whether the effectiveness of iMCS is significantly different among different CNOP disorders and (2) whether other confounding factors can be impacting iMCS results in CNOP. A systematic review and meta-analysis using a linear mixed-model was performed. Twenty-three papers were included, totaling 140 CNOP patients. Heterogeneity of the studies showed to be 55.8%. A visual analogue scale (VAS) measured median pain relief of 66.5% (ranging from 0-100%) was found. Linear mixed-model analysis showed that patients suffering from trigeminal neuralgia responded significantly more favorable to iMCS than patients suffering from dysfunctional pain syndromes (p = 0.030). Also, patients suffering from CNOP caused by (supra)nuclear lesions responded marginally significantly better to iMCS than patients suffering from CNOP due to trigeminal nerve lesions (p = 0.049). No other confounding factors were elucidated. This meta-analysis showed that patients suffering from trigeminal neuralgia and patients suffering from (supra)nuclear lesions causing CNOP responded significantly more favorable than others on iMCS. No other confounding factors were found relevant.

Trigeminal neuralgia (TN) is debilitating and is usually accompanied by mood disorders. The lateral habenula (LHb) is considered to be involved in the modulation of pain and mood disorders, and the present study aimed to determine if and how the LHb participates in the development of pain and anxiety in TN. To address this issue, a mouse model of partial transection of the infraorbital nerve (pT-ION) was established. pT-ION induced stable and long-lasting primary and secondary orofacial allodynia and anxiety-like behaviors that correlated with the increased excitability of LHb neurons. Adeno-associated virus (AAV)-mediated expression of hM4D(Gi) in glutamatergic neurons of the unilateral LHb followed by clozapine-N-oxide application relieved pT-ION-induced anxiety-like behaviors but not allodynia. Immunofluorescence validated the successful infection of AAV in the LHb, and microarray analysis showed changes in gene expression in the LHb of mice showing allodynia and anxiety-like behaviors after pT-ION. Among these differentially expressed genes was Tacr3, the downregulation of which was validated by RT-qPCR. Rescuing the downregulation of Tacr3 by AAV-mediated Tacr3 overexpression in the unilateral LHb significantly reversed pT-ION-induced anxiety-like behaviors but not allodynia. Whole-cell patch clamp recording showed that Tacr3 overexpression suppressed nerve injury-induced hyperexcitation of LHb neurons, and western blotting showed that the pT-ION-induced upregulation of p-CaMKII was reversed by AAV-mediated Tacr3 overexpression or chemicogenetic inhibition of glutamatergic neurons in the LHb. Moreover, not only anxiety-like behaviors, but also allodynia after pT-ION were significantly alleviated by chemicogenetic inhibition of bilateral LHb neurons or by bilateral Tacr3 overexpression in the LHb. In conclusion, Tacr3 in the LHb plays a protective role in treating trigeminal nerve injury-induced allodynia and anxiety-like behaviors by suppressing the hyperexcitability of LHb neurons. These findings provide a rationale for suppressing unilateral or bilateral LHb activity by targeting Tacr3 in treating the anxiety and pain associated with TN.

Trigeminal neuralgia (TN), a sudden, needle-like pain in the distribution area of the trigeminal nerve, can seriously affect the physical and mental health of patients. In chronic pain conditions including TN, increased levels of brain-derived neurotrophic factor (BDNF) may enhance pain transmission. This study compares the effect of palmatine administration on the expression of BDNF and its receptor TrkB (tropomyosin receptor kinase B) in trigeminal ganglion cells of Sprague-Dawley rats in a sham versus TN model group. Within 14 days of surgery, the mechanical allodynia threshold of the TN group was significantly lower than that of the sham group, while the TN + palmatine group had a higher mechanical pain sensitivity threshold than the TN group (p < 0.05). Real-time quantitative PCR, immunohistochemistry, and immunofluorescence showed that BDNF and TrkB expression in the TN group was higher than that in the sham group, while palmatine treatment could reverse these changes. Western blotting showed that palmatine treatment could reduce the elevated phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2) in TN rats. Thus, the BDNF/TrkB pathway may be involved in the pain transmission process of TN, and palmatine treatment may reduce pain transmission by inhibiting the BDNF/TrkB pathway and suppressing ERK1/2 phosphorylation.

Emotional disorders are common comorbid conditions that further exacerbate the severity and chronicity of chronic pain. However, individuals show considerable vulnerability to the development of chronic pain under similar pain conditions. In this study on male rat and mouse models of chronic neuropathic pain, we identify the histone deacetylase Sirtuin 1 (SIRT1) in central amygdala as a key epigenetic regulator that controls the development of comorbid emotional disorders underlying the individual vulnerability to chronic pain. We found that animals that were vulnerable to developing behaviors of anxiety and depression under the pain condition displayed reduced SIRT1 protein levels in central amygdala, but not those animals resistant to the emotional disorders. Viral overexpression of local SIRT1 reversed this vulnerability, but viral knockdown of local SIRT1 mimicked the pain effect, eliciting the pain vulnerability in pain-free animals. The SIRT1 action was associated with CaMKIIα downregulation and deacetylation of histone H3 lysine 9 at the CaMKII α promoter. These results suggest that, by transcriptional repression of CaMKII α in central amygdala, SIRT1 functions to guard against the emotional pain vulnerability under chronic pain conditions. This study indicates that SIRT1 may serve as a potential therapeutic molecule for individualized treatment of chronic pain with vulnerable emotional disorders. SIGNIFICANCE STATEMENT Chronic pain is a prevalent neurological disease with no effective treatment at present. Pain patients display considerably variable vulnerability to developing chronic pain, indicating individual-based molecular mechanisms underlying the pain vulnerability, which is hardly addressed in current preclinical research. In this study, we have identified the histone deacetylase Sirtuin 1 (SIRT1) as a key regulator that controls this pain vulnerability. This study reveals that the SIRT1-CaMKIIaα pathway in central amygdala acts as an epigenetic mechanism that guards against the development of comorbid emotional disorders under chronic pain, and that its dysfunction causes increased vulnerability to the development of chronic pain. These findings suggest that SIRT1 activators may be used in a novel therapeutic approach for individual-based treatment of chronic pain., (Copyright © 2020 the authors.)

Patients with radicular low back pain (radicular LBP, sciatica) frequently describe their pain as "shooting" or "radiating." The dictionary meaning of these words implies rapid movement, and indeed, many sufferers report feeling pain moving rapidly from the lower back or buttock into the leg. But, others do not. Moreover, the sensation of movement is paradoxical; it is neither predicted nor accounted for by current ideas about the pathophysiology of radicular LBP. We have used a structured questionnaire to evaluate the sensory qualities associated with "shooting" and "radiating" in 155 patients, 98 with radicular LBP and 57 with trigeminal neuralgia, a second chronic pain condition in which shooting/radiating are experienced. Results indicated a spectrum of different sensations in different people. Although many sciatica patients reported rapid downward movement of their pain, even more reported downward expansion of the area of pain, some reported upward movement, and for some, there was no spatial dynamic at all. The velocity of movement or expansion was also variable. By cross-referencing sensations experienced in the sciatica and trigeminal neuralgia cohorts with known signal processing modes in the somatosensory system, we propose testable hypotheses concerning the pathophysiology of the various vectorial sensations reported, their direction and velocity, and the structures in which they are generated. Systematic evaluation of qualitative features of "shooting" and "radiating" pain at the time of diagnosis can shed light on the pain mechanism in the individual patient and perhaps contribute to a better therapeutic outcomes.

Trigeminal neuralgia (TN) is a chronic disorder of the trigeminal nerve characterized by repeated electrical shock-like sensations on one side of the face. It can cause severe pain in the face and disrupt or impair quality of life in patients. Options for the management of TN consist of pharmacological and surgical treatments, including Gamma Knife radiosurgery (GKRS). GKRS has been used for TN for a long time because of its low rate of complications and high success rate. Moreover, GKRS can be of use for drug-resistant TN patients who are poor surgical candidates due to medical comorbidities, patients of older age, or patients who refuse invasive therapy. We reviewed the rationale, effects, safety, and current treatment policies of GKRS for TN in view of our institution's results and a review of the literature to date., Competing Interests: The authors have no potential conflicts of interest to disclose., (© Copyright: Yonsei University College of Medicine 2020.)

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: Olfactory dysfunction (OD) is a frequent symptom of Parkinson's disease (PD) that appears years prior to diagnosis. Previous studies suggest that PD-related OD is different from non-parkinsonian forms of olfactory dysfunction (NPOD) as PD patients maintain trigeminal sensitivity as opposed to patients with NPOD who typically exhibit reduced trigeminal sensitivity. We hypothesize the presence of a specific alteration of functional connectivity between trigeminal and olfactory processing areas in PD., Objective: We aimed to assess potential differences in functional connectivity within the chemosensory network in 15 PD patients and compared them to 15 NPOD patients, and to 15 controls., Methods: Functional MRI scanning session included resting-state and task-related scans where participants carried out an olfactory and a trigeminal task. We compared functional connectivity, using a seed-based correlation approach, and brain network modularity of the chemosensory network., Results: PD patients had impaired functional connectivity within the chemosensory network while no such changes were observed for NPOD patients. No group differences we found in modularity of the identified networks. Both patient groups exhibited impaired connectivity when executing an olfactory task, while network modularity was significantly weaker for PD patients than both other groups. When performing a trigeminal task, no changes were found for PD patients, but NPOD patients exhibited impaired connectivity. Conversely, PD patients exhibited a significantly higher network modularity than both other groups., Conclusion: In summary, the specific pattern of functional connectivity and chemosensory network recruitment in PD-related OD may explain distinct behavioral chemosensory features in PD when compared to NPOD patients and healthy controls.

P2Y purinergic receptors expressed in neurons and satellite glial cells (SGCs) of the trigeminal ganglion (TG) contribute to inflammatory and neuropathic pain. P2Y 14 receptor expression is reported in the spinal cord, dorsal root ganglion (DRG), and TG. In present study, the role of P2Y 14 receptor in the TG in inflammatory orofacial pain of Sprague-Dawley (SD) rats was investigated. Peripheral injection of complete Freund's adjuvant (CFA) induced mechanical hyperalgesia with the rapid upregulation of P2Y 14 receptor, glial fibrillary acidic protein (GFAP), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), C-C chemokine CCL2, phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2), and phosphorylated p38 (p-p38) proteins in the TG. Furthermore, immunofluorescence staining confirmed the CFA-induced upregulation of P2Y 14 receptor. Double immunostaining showed that P2Y 14 receptor colocalized with glutamine synthetase (GS) and neuronal nuclei (NeuN). Finally, trigeminal injection of a selective antagonist (PPTN) of P2Y 14 receptor attenuated CFA-induced mechanical hyperalgesia. PPTN also decreased the upregulation of the GFAP, IL-1β, TNF-α, CCL2, p-ERK1/2, and p-p38 proteins. Our findings showed that P2Y 14 receptor in TG may contribute to orofacial inflammatory pain via regulating SGCs activation, releasing cytokines (IL-1β, TNF-α, and CCL2), and phosphorylating ERK1/2 and p38., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Neuroimaging studies have shown that chronic pain is maladaptive and influences brain function and behavior by altering the flexible cerebral information flow. We utilized power spectral analysis to investigate the impact of classic trigeminal neuralgia (TN) on the oscillation dynamics of intrinsic brain activity in humans. The amplitude of low-frequency fluctuations (ALFF) and fractional ALFF (fALFF) were measured in 29 TN patients and 34 age- and sex-matched healthy controls (HCs) via resting-state functional MRI (R-fMRI). Two different frequency bands (slow-5: 0.01-0.027 Hz; slow-4: 0.027-0.073 Hz) were analyzed. Differences in blood oxygen level-dependent (BOLD) signal fluctuations and related resting-state functional connectivity (rsFC) between the TN patients and HCs were identified. The TN patients had reduced ALFF/fALFF in the posterior cingulate cortex (PCC), left insula, left dorsolateral prefrontal cortex (DLPFC), left putamen and bilateral temporal lobe, exclusively in the frequency of the slow-5 band. Whole brain rsFC analyses with these six different regions as seeds revealed two weaker circuits including the PCC-medial prefrontal cortex (mPFC) and DLPFC-hippocampus circuits, indicating abnormal interactions with the default mode network (DMN) in TN patients. The functional connectivity between the default-mode regions (mPFC and PCC) in the slow-5 band tracked pain intensity. Together, our results provide novel insights into how TN disturbs the cortical rhythms and functional interactions of the brain. These insights may have implications for the understanding and treatment of brain dysfunction in chronic pain patients, including TN patients.

This study aimed to analyze the hemodynamic features of the offending artery at sites of neurovascular compression (NVC) using computational fluid dynamics (CFD). A total of 23 patients who underwent microvascular decompression (MVD) for primary trigeminal neuralgia (TN) between January 2015 and December 2016 were enrolled in this study. The compressing vessel at the NVC site was identified microsurgically in all cases, and patients were divided into two groups based on the intraoperative findings: (1) the arterial NVC group and (2) the non-arterial NVC control group. A 3D surface model of the structures surrounding the NVC was created using preoperative magnetic resonance imaging (MRI), and CFD analysis was performed for the target artery. In addition to standard parameters, such as the wall shear stress (WSS), flow velocity, and pressure, we calculated the WSS ratio (WSSR) by dividing the WSS at the NVC by the mean WSS of the target. Arterial compression was observed intraoperatively in 13 patients. The mean WSSR of the arterial NVC group was significantly higher than that of the control group (2.36 ± 1.00 vs. 1.18 ± 0.73, P <0.05). There were no significant intergroup differences in the other calculated parameters. High WSSR, which indicates elevated WSS at the sites of NVC, was identified as a unique parameter of arterial compression that may contribute to TN. CFD could be a useful clinical tool in determining the target of MVD under preoperative conditions.

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.

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.