Should trigeminal neuralgia be considered a clinically isolated syndrome?

The association between trigeminal neuralgia (TN) and multiple sclerosis (MS) is well established. Many MS patients with TN have magnetic resonance imaging (MRI) evidence of a symptomatic demyelinating lesion. Although infratentorial presentations are included in the diagnostic criteria for MS, there remains confusion in clinical practice as to whether TN should be considered a clinically isolated syndrome for the application of McDonald criteria. In this case series, we discuss this diagnostic quandary in patients presenting with TN and additional MRI findings suggestive of MS and highlight the unmet need for data in such patients to optimally guide their care.

Trigeminal neuralgia associated with multiple sclerosis: A multimodal assessment of brainstem plaques and response to Gamma Knife radiosurgery.

BACKGROUND: Gamma Knife radiosurgery (GKRS) is a minimally invasive procedure for trigeminal neuralgia secondary to multiple sclerosis (MS-TN). Patients with MS-TN experience suboptimal response rates to treatment, and the relationship between trigeminal microstructure and treatment outcome is poorly understood. OBJECTIVE: To characterize imaging features of MS-TN pain and GKRS response. METHODS: 3 T diffusion-weighted imaging (DWI), T1-w, T2-w, and fluid-attenuated inversion recovery (FLAIR) sequences were acquired for 18 MS-TN patients undergoing GKRS. Brainstem plaques were standardized into a common space to determine plaque distribution. Ratio of T1-w/T2-w or "myelin maps (MM)" was generated. Multi-tensor tractography was used to delineate the radiosurgical target (RT), root entry zone (REZ), and proximal pontine segment (PPS) of the trigeminal nerves. RESULTS: Laterality of MS-TN is associated with increased axial diffusivity at the PPS, whereas decreased MM at the PPS correlated with poor GKRS response. Preoperatively, GKRS responders have higher fractional anisotropy at the RT, higher axial diffusivity at the REZ, and higher MM intensities at the PPS. CONCLUSION: This study demonstrates that diffusivities and MM intensities are important correlates of pain and treatment response, respectively. Overall, preoperative multimodal assessment of the central trigeminal pathway is a better indicator of GKRS response than postoperative assessment of the reduction in fractional anisotropy peripherally.

Social propinquity in rodents as measured by tube cooccupancy differs between inbred and outbred genotypes.

Existing assays of social interaction are suboptimal, and none measures propinquity, the tendency of rodents to maintain close physical proximity. These assays are ubiquitously performed using inbred mouse strains and mutations placed on inbred genetic backgrounds. We developed the automatable tube cooccupancy test (TCOT) based on propinquity, the tendency of freely mobile rodents to maintain close physical proximity, and assessed TCOT behavior on a variety of genotypes and social and environmental conditions. In outbred mice and rats, familiarity determined willingness to cooccupy the tube, with siblings and/or cagemates of both sexes exhibiting higher cooccupancy behavior than strangers. Subsequent testing using multiple genotypes revealed that inbred strain siblings do not cooccupy at higher rates than strangers, in marked contrast to both outbred and rederived wild mice. Mutant mouse strains with "autistic-like" phenotypes (Fmr1-/y and Eif4e Ser209Ala) displayed significantly decreased cooccupancy.

The Utility of Diffusion Tensor Imaging in Neuromodulation: Moving Beyond Conventional Magnetic Resonance Imaging.

OBJECTIVES: Conventional targeting methods for neuromodulation therapies are insufficient for visualizing targets along white matter pathways and localizing targets in patient-specific space. Diffusion tensor imaging (DTI) holds promise for enhancing neuromodulation targeting by allowing detailed visualization of white matter tracts and their connections on an individual level. MATERIAL AND METHODS: We review the literature on DTI and neuromodulation, focusing on clinical studies that have utilized DTI tractography for surgical neuromodulation planning. This primarily includes the growing number of studies on tractography-guided targeting in deep brain stimulation as well as magnetic resonance-guided focused ultrasound. RESULTS: In this review, we discuss three main topics: 1) an overview of the basic principles of DTI, its metrics, and tractography, 2) the evolution and utility of DTI to better guide neuromodulation targets, and 3) the ability of DTI to investigate structural connectivity and brain networks, and how such a network perspective may be an integral part of identifying new or optimal neuromodulation targets. CONCLUSION: There is increasing evidence that DTI is superior to conventional targeting methods with respect to improving brain stimulation therapies. DTI has the ability to better define anatomical targets by allowing detailed visualization of white matter tracts and localizing targets based on individual anatomy. Network analyses can lead to the identification of new or optimal stimulation targets based on understanding how target regions are connected. The integration of DTI as part of routine MRI and surgical planning offers a more personalized approach to therapy and may be an important path for the future of neuromodulation.

Brain imaging signatures of neuropathic facial pain derived by artificial intelligence.

Advances in neuroimaging have permitted the non-invasive examination of the human brain in pain. However, a persisting challenge is in the objective differentiation of neuropathic facial pain subtypes, as diagnosis is based on patients' symptom descriptions. We use artificial intelligence (AI) models with neuroimaging data to distinguish subtypes of neuropathic facial pain and differentiate them from healthy controls. We conducted a retrospective analysis of diffusion tensor and T1-weighted imaging data using random forest and logistic regression AI models on 371 adults with trigeminal pain (265 classical trigeminal neuralgia (CTN), 106 trigeminal neuropathic pain (TNP)) and 108 healthy controls (HC). These models distinguished CTN from HC with up to 95% accuracy, and TNP from HC with up to 91% accuracy. Both classifiers identified gray and white matter-based predictive metrics (gray matter thickness, surface area, and volume; white matter diffusivity metrics) that significantly differed across groups. Classification of TNP and CTN did not show significant accuracy (51%) but highlighted two structures that differed between pain groups-the insula and orbitofrontal cortex. Our work demonstrates that AI models with brain imaging data alone can differentiate neuropathic facial pain subtypes from healthy data and identify regional structural indicates of pain.

Brainstem trigeminal fiber microstructural abnormalities are associated with treatment response across subtypes of trigeminal neuralgia.

ABSTRACT: Neurosurgical treatments for trigeminal neuralgia (TN) can provide long-lasting pain relief; however, some patients fail to respond and undergo multiple, repeat procedures. Surgical outcomes can vary depending on the type of TN, but the reasons for this are not well understood. Neuroimaging studies of TN point to abnormalities in the brainstem trigeminal fibers; however, whether this is a common characteristic of treatment nonresponse across different subtypes of TN is unknown. Here, we used diffusion tensor imaging (DTI) to determine whether the brainstem trigeminal fiber microstructure is a common biomarker of surgical response in TN and whether the extent of these abnormalities is associated with the likelihood of response across subtypes of TN. We studied 98 patients with TN (61 classical TN, 26 TN secondary to multiple sclerosis, and 11 TN associated with a solitary pontine lesion) who underwent neurosurgical treatment and 50 healthy controls. We assessed treatment response using pain intensity measures and examined microstructural features by extracting pretreatment DTI metrics from the proximal pontine segment of the trigeminal nerves. We found that microstructural abnormalities in the affected pontine trigeminal fibers (notably, lower fractional anisotropy and higher radial diffusivity) highlight treatment nonresponders (n = 47) compared with responders (n = 51) and controls, and that the degree of abnormalities is associated with the likelihood of surgical response across subtypes of TN. These novel findings demonstrate the value of DTI as an objective, noninvasive tool for the prediction of treatment response and elucidate the features that distinguish treatment responders from nonresponders in the TN population.

Regional brain morphology predicts pain relief in trigeminal neuralgia.

BACKGROUND: Trigeminal neuralgia, a severe chronic neuropathic pain disorder, is widely believed to be amenable to surgical treatments. Nearly 20% of patients, however, do not have adequate pain relief after surgery. Objective tools for personalized pre-treatment prognostication of pain relief following surgical interventions can minimize unnecessary surgeries and thus are of substantial benefit for patients and clinicians. PURPOSE: To determine if pre-treatment regional brain morphology-based machine learning models can prognosticate 1 year response to Gamma Knife radiosurgery for trigeminal neuralgia. METHODS: We used a data-driven approach that combined retrospective structural neuroimaging data and support vector machine-based machine learning to produce robust multivariate prediction models of pain relief following Gamma Knife radiosurgery for trigeminal neuralgia. Surgical response was defined as ≥ 75% pain relief 1 year post-treatment. We created two prediction models using pre-treatment regional brain gray matter morphology (cortical thickness or surface area) to distinguish responders from non-responders to radiosurgery. Feature selection was performed through sequential backwards selection algorithm. Model out-of-sample generalizability was estimated via stratified 10-fold cross-validation procedure and permutation testing. RESULTS: In 51 trigeminal neuralgia patients (35 responders, 16 non-responders), machine learning models based on pre-treatment regional brain gray matter morphology (14 regional surface areas or 13 regional cortical thicknesses) provided robust a priori prediction of surgical response. Cross-validation revealed the regional surface area model was 96.7% accurate, 100.0% sensitive, and 89.1% specific while the regional cortical thickness model was 90.5% accurate, 93.5% sensitive, and 83.7% specific. Permutation testing revealed that both models performed beyond pure chance (p < 0.001). The best predictor for regional surface area model and regional cortical thickness model was contralateral superior frontal gyrus and contralateral isthmus cingulate gyrus, respectively. CONCLUSIONS: Our findings support the use of machine learning techniques in subsequent investigations of chronic neuropathic pain. Furthermore, our multivariate framework provides foundation for future development of generalizable, artificial intelligence-driven tools for chronic neuropathic pain treatments.

Trigeminal neuralgia associated with a solitary pontine lesion: clinical and neuroimaging definition of a new syndrome.

Conventional magnetic resonance imaging of patients with trigeminal neuralgia (TN) does not typically reveal associated brain lesions. Here, we identify a unique group of TN patients who present with a single brainstem lesion, who do not fulfill diagnostic criteria for multiple sclerosis (MS). We aim to define this new clinical syndrome, which we term TN associated with solitary pontine lesion (SPL-TN), using a clinical and neuroimaging approach. We identified 24 cases of SPL-TN, 18 of which had clinical follow-up for assessment of treatment response. Lesion mapping was performed to determine the exact location of the lesions and site of maximum overlap across patients. Diffusion tensor imaging was used to assess the white-matter microstructural properties of the lesions. Diffusivity metrics were extracted from the (1) SPL-TN lesions, (2) contralateral, unaffected side, (3) MS brainstem plaques from 17 patients with TN secondary to MS, (4) and healthy controls. We found that 17/18 patients were nonresponders to surgical treatment. The lesions were uniformly located along the affected trigeminal pontine pathway, where the site of maximum overlap across patients was in the area of the trigeminal nucleus. The lesions demonstrated abnormal white-matter microstructure, characterized by lower fractional anisotropy, and higher mean, radial, and axial diffusivities compared with the unaffected side. The brainstem trigeminal fiber microstructure within a lesion highlighted the difference between SPL-TN lesions and MS plaques. In conclusion, SPL-TN patients have identical clinical features to TN but have a single pontine lesion not in keeping with MS and are refractory to surgical management.

Temporal disconnection between pain relief and trigeminal nerve microstructural changes after Gamma Knife radiosurgery for trigeminal neuralgia.

OBJECTIVE: Gamma Knife radiosurgery (GKRS) is a noninvasive surgical treatment option for patients with medically refractive classic trigeminal neuralgia (TN). The long-term microstructural consequences of radiosurgery and their association with pain relief remain unclear. To better understand this topic, the authors used diffusion tensor imaging (DTI) to characterize the effects of GKRS on trigeminal nerve microstructure over multiple posttreatment time points. METHODS: Ninety-two sets of 3-T anatomical and diffusion-weighted MR images from 55 patients with TN treated by GKRS were divided within 6-, 12-, and 24-month posttreatment time points into responder and nonresponder subgroups (≥ 75% and < 75% reduction in posttreatment pain intensity, respectively). Within each subgroup, posttreatment pain intensity was then assessed against pretreatment levels and followed by DTI metric analyses, contrasting treated and contralateral control nerves to identify specific biomarkers of successful pain relief. RESULTS: GKRS resulted in successful pain relief that was accompanied by asynchronous reductions in fractional anisotropy (FA), which maximized 24 months after treatment. While GKRS responders demonstrated significantly reduced FA within the radiosurgery target 12 and 24 months posttreatment (p < 0.05 and p < 0.01, respectively), nonresponders had statistically indistinguishable DTI metrics between nerve types at each time point. CONCLUSIONS: Ultimately, this study serves as the first step toward an improved understanding of the long-term microstructural effect of radiosurgery on TN. Given that FA reductions remained specific to responders and were absent in nonresponders up to 24 months posttreatment, FA changes have the potential of serving as temporally consistent biomarkers of optimal pain relief following radiosurgical treatment for classic TN.

Increased pain sensitivity and decreased opioid analgesia in T-cell-deficient mice and implications for sex differences.

The processing of pain in the central nervous system is now known to have an important immune component, including T cells of the adaptive immune system. T cells have been shown to release endogenous opioids, and although it is well known that opioids have effects on T-cell populations, very little attention has been given to the converse: how T cells may affect opioid regulation. We find here that, in addition to displaying significantly increased baseline pain sensitivity across various pain modalities, T-cell-deficient mice (CD-1 nude, Rag1 null mutant, and Cd4 null mutant) exhibit pronounced deficiencies in morphine inhibition of thermal or inflammatory pain. Nude mice are also deficient in endogenous opioid-mediated analgesia, exhibiting no stress-induced analgesia from restraint. The relevant T-cell subpopulation seems to be CD4 T cells because adoptive transfer of them but not CD8 cells into nude mice rescues both the pain and morphine analgesia phenotypes. As previously reported, we also observe a sex difference in CD-1 mice, with females requiring 2- to 3-fold more morphine than males to produce equal analgesia. Nude mice display no sex differences in morphine analgesia, and the sex difference is restored in nude mice of either sex receiving CD4 T cells from CD-1 donor male or female mice. These results suggest that CD4 T cells play an as yet unappreciated role in opioid analgesia and may be a driver of sex differences therein.

Modulation of social behavior and dominance status by chronic pain in mice.

The potential influence of pain on social behavior in laboratory animals has rarely been evaluated. Using a new assay of social behavior, the tube co-occupancy test (TCOT), we assess propinquity-the tendency to maintain close physical proximity-in mice exposed to pain using subcutaneous zymosan or spared nerve injury as noxious stimuli. Our previous experience with the TCOT showed that outbred mouse sibling dyads show higher levels of tube co-occupancy than stranger dyads. We find here that long-lasting pain from spared nerve injury given to both mice in the dyad abolishes this effect of familiarity, such that strangers also display high levels of propinquity. We performed a separate experiment to assess the effect on dominance behavior of nerve injury to one or both mice of a dyad in which relative dominance status had been previously established via the confrontation tube test. We find that neuropathic pain given only to the dominant mouse reverses the relationship in male but not female mice, such that the previously subordinate mouse becomes dominant. These observations bolster the scant but growing evidence that pain can robustly affect social behavior in animals.

Male-Specific Conditioned Pain Hypersensitivity in Mice and Humans.

Pain memories are hypothesized to be critically involved in the transition of pain from an acute to a chronic state. To help elucidate the underlying neurobiological mechanisms of pain memory, we developed novel paradigms to study context-dependent pain hypersensitivity in mouse and human subjects, respectively. We find that both mice and people become hypersensitive to acute, thermal nociception when tested in an environment previously associated with an aversive tonic pain experience. This sensitization persisted for at least 24 hr and was only present in males of both species. In mice, context-dependent pain hypersensitivity was abolished by castrating male mice, pharmacological blockade of the hypothalamic-pituitary-adrenal axis, or intracerebral or intrathecal injections of zeta inhibitory peptide (ZIP) known to block atypical protein kinase C (including the protein kinase Mζ isoform). In humans, men, but not women, self-reported higher levels of stress when tested in a room previously associated with tonic pain. These models provide a new, completely translatable means for studying the relationship between memory, pain, and stress.

Early postsurgical diffusivity metrics for prognostication of long-term pain relief after Gamma Knife radiosurgery for trigeminal neuralgia.

OBJECTIVE: Gamma Knife radiosurgery (GKRS) is an important treatment modality for trigeminal neuralgia (TN). Current longitudinal assessment after GKRS relies primarily on clinical diagnostic measures, which are highly limited in the prediction of long-term clinical benefit. An objective, noninvasive, predictive tool would be of great utility to advance the clinical management of patients. Using diffusion tensor imaging (DTI), the authors' aim was to determine whether early (6 months post-GKRS) target diffusivity metrics can be used to prognosticate long-term pain relief in patients with TN. METHODS: Thirty-seven patients with TN treated with GKRS underwent 3T MRI scans at 6 months posttreatment. Diffusivity metrics of fractional anisotropy, axial diffusivity, radial diffusivity, and mean diffusivity were extracted bilaterally from the radiosurgical target of the affected trigeminal nerve and its contralateral, unaffected nerve. Early (6 months post-GKRS) diffusivity metrics were compared with long-term clinical outcome. Patients were identified as long-term responders if they achieved at least 75% reduction in preoperative pain for 12 months or longer following GKRS. RESULTS: Trigeminal nerve diffusivity at 6 months post-GKRS was predictive of long-term clinical effectiveness, where long-term responders (n = 19) showed significantly lower fractional anisotropy at the radiosurgical target of their affected nerve compared to their contralateral, unaffected nerve and to nonresponders. Radial diffusivity and mean diffusivity, correlates of myelin alterations and inflammation, were also significantly higher in the affected nerve of long-term responders compared to their unaffected nerve. Nonresponders (n = 18) did not exhibit any characteristic diffusivity changes after GKRS. CONCLUSIONS: The authors demonstrate that early postsurgical target diffusivity metrics have a translational, clinical value and permit prediction of long-term pain relief in patients with TN treated with GKRS. Importantly, an association was found between the footprint of radiation and clinical effectiveness, where a sufficient level of microstructural change at the radiosurgical target is necessary for long-lasting pain relief. DTI can provide prognostic information that supplements clinical measures, and thus may better guide the postoperative assessment and clinical decision-making for patients with TN.

Epiregulin and EGFR interactions are involved in pain processing.

The EGFR belongs to the well-studied ErbB family of receptor tyrosine kinases. EGFR is activated by numerous endogenous ligands that promote cellular growth, proliferation, and tissue regeneration. In the present study, we have demonstrated a role for EGFR and its natural ligand, epiregulin (EREG), in pain processing. We show that inhibition of EGFR with clinically available compounds strongly reduced nocifensive behavior in mouse models of inflammatory and chronic pain. EREG-mediated activation of EGFR enhanced nociception through a mechanism involving the PI3K/AKT/mTOR pathway and matrix metalloproteinase-9. Moreover, EREG application potentiated capsaicin-induced calcium influx in a subset of sensory neurons. Both the EGFR and EREG genes displayed a genetic association with the development of chronic pain in several clinical cohorts of temporomandibular disorder. Thus, EGFR and EREG may be suitable therapeutic targets for persistent pain conditions.

The Use of DREADDs to Deconstruct Behavior.

A central goal in understanding brain function is to link specific cell populations to behavioral outputs. In recent years, the selective targeting of specific neural circuits has been made possible with the development of new experimental approaches, including chemogenetics. This technique allows for the control of molecularly defined subsets of cells through engineered G protein-coupled receptors (GPCRs), which have the ability to activate or silence neuronal firing. Through chemogenetics, neural circuits are being linked to behavioral outputs at an unprecedented rate. Further, the coupling of chemogenetics with imaging techniques to monitor neural activity in freely moving animals now makes it possible to deconstruct the complex whole-brain networks that are fundamental to behavioral states. In this review, we highlight a specific chemogenetic application known as DREADDs (designer receptors exclusively activated by designer drugs). DREADDs are used ubiquitously to modulate GPCR activity in vivo and have been widely applied in the basic sciences, particularly in the field of behavioral neuroscience. Here, we focus on the impact and utility of DREADD technology in dissecting the neural circuitry of various behaviors including memory, cognition, reward, feeding, anxiety and pain. By using DREADDs to monitor the electrophysiological, biochemical, and behavioral outputs of specific neuronal types, researchers can better understand the links between brain activity and behavior. Additionally, DREADDs are useful in studying the pathogenesis of disease and may ultimately have therapeutic potential.

Increasing placebo responses over time in U.S. clinical trials of neuropathic pain.

Recent failures of clinical trials of novel analgesics designed to treat neuropathic pain have led to much speculation about the underlying reasons. One often discussed possibility is that the placebo response in these trials has increased in recent years, leading to lower separation between the drug and placebo arms. Whether this has indeed occurred has not yet been adequately addressed. Here, we extracted data from published randomized controlled trials (RCTs) of drugs for the treatment of chronic neuropathic pain over the years 1990 to 2013. We find that placebo responses have increased considerably over this period, but drug responses have remained stable, leading to diminished treatment advantage. This trend has been driven by studies conducted in the United States. Consideration of participant and study characteristics revealed that in the United States but not elsewhere, RCTs have increased in study size and length. These changes are associated with larger placebo response. Analysis of individual RCT time courses showed different kinetics for the treatment vs placebo responses, with the former evolving more quickly than the latter and plateauing, such that maximum treatment advantage was achieved within 4 weeks.

Molecular genetic mechanisms of allelic specific regulation of murine Comt expression.

A functional allele of the mouse catechol-O-methyltransferase (Comt) gene is defined by the insertion of a B2 short interspersed repeat element in its 3'-untranslated region (UTR). This allele has been associated with a number of phenotypes, such as pain and anxiety. In comparison with mice carrying the ancestral allele (Comt+), Comt B2i mice show higher Comt mRNA and enzymatic activity levels. Here, we investigated the molecular genetic mechanisms underlying this allelic specific regulation of Comt expression. Insertion of the B2 element introduces an early polyadenylation signal generating a shorter Comt transcript, in addition to the longer ancestral mRNA. Comparative analysis and in silico prediction of Comt mRNA potential targets within the transcript 3' to the B2 element was performed and allowed choosing microRNA (miRNA) candidates for experimental screening: mmu-miR-3470a, mmu-miR-3470b, and mmu-miR-667. Cell transfection with each miRNA downregulated the expression of the ancestral transcript and COMT enzymatic activity. Our in vivo experiments showed that mmu-miR-667-3p is strongly correlated with decreasing amounts of Comt mRNA in the brain, and lentiviral injections of mmu-miR-3470a, mmu-miR-3470b, and mmu-miR-667 increase hypersensitivity in the mouse formalin model, consistent with reduced COMT activity. In summary, our data demonstrate that the Comt+ transcript contains regulatory miRNA signals in its 3'-untranslated region leading to mRNA degradation; these signals, however, are absent in the shorter transcript, resulting in higher mRNA expression and activity levels.