Interhemispheric and Corticothalamic White-Matter Dysfunction Underlies Affective Morbidity and Impaired Pain Modulation in Chronic Pain.

BACKGROUND: Although patients with chronic pain show behavioral signs of impaired endogenous pain modulation, responsible cerebral networks have yet to be anatomically delineated. We used diffusion tensor imaging (DTI) to examine the white-matter alterations in patients with chronic pain compared with healthy subjects. We further measured thermal pain modulatory responses using the offset analgesia (OA) paradigm. We tested whether the white-matter indices be associated with psychophysical parameters reflecting morbidity and modulatory responses of pain in patients, and whether they could serve as diagnostic biomarkers of chronic pain. METHODS: Twenty-six patients with chronic pain and 18 age- and gender-matched healthy controls were enrolled. After completing psychophysical questionnaires, they underwent OA measurement and whole-brain DTI in a 3 Tesla magnetic resonance imaging scanner. Fractional anisotropy (FA) and radial diffusivity (RD) of the white-matter were computed and compared between the groups with tract-based spatial statistics using the FMRIB Software Library (FSL) software. Correlations were sought among white-matter indices, thermal pain responses, and psychophysical parameters. The white-matter indices and OA-related parameters were tested whether they distinguish patients from controls by receiver operating characteristic analysis. RESULTS: During OA, patients showed a shorter latency to the maximum (maximum visual analog scale [VAS] latency, 16.0 ± 3.7 vs 18.9 ± 3.1 second [mean ± standard deviation, SD]; P = .032) but a longer latency to the minimum pain (OA latency, 15.6 ± 3.5 vs 11.1 ± 4.2 seconds; P = .004) than controls. They showed a smaller mean FA (0.44 ± 0.12 vs 0.45 ± 0.11; P = .012) and a larger mean RD of the global white-matter (0.00057 ± 0.00002 vs 0.00056 ± 0.00002; P = .038) than controls, at specific areas including the corpus callosum, anterior thalamic radiation, and forceps major. FA of the splenium of the corpus callosum was associated with maximum VAS latency (r = 0.493) and OA latency (r = -0.552). The Pain Catastrophizing Scale scores showed strong negative correlations with FA across those specific areas (r = -0.405). Those latencies during OA and white-matter metrics distinguished patients from controls (P < .05). CONCLUSIONS: Patients with chronic pain showed dysfunction of the white matter concerned with interhemispheric communication of sensorimotor information as well as descending corticothalamic modulation of pain in association with affective morbidity and altered temporal dynamics of pain perception. We suggest that an impaired interhemispheric modulation of pain, through the corpus callosum, might be a novel cerebral mechanism in chronification of pain.

The influence of intolerance of uncertainty on the correlation between the severity of symptoms and satisfaction with oral state in patients with burning mouth syndrome.

OBJECTIVE: Intolerance of uncertainty (IU) is thought to be involved with the psychological factors that influence the symptoms in patients with burning mouth syndrome (BMS) and affect their limited satisfaction with the treatments provided. However, the influence of IU on satisfaction has not been explored in detail. Therefore, the purpose of this study was to investigate whether IU can affect the satisfaction of patients with BMS. METHODS: A total of 34 patients with BMS and 100 patients without the disease who visited the general dental clinic were included in the study. They were required to complete a questionnaire measuring the subjective severity of their symptoms and satisfaction with their oral state, and a short IU scale. The BMS patients were separated from the control patients based on the IU score. The coefficients between the severity of symptoms and satisfaction were calculated to examine the influence of IU on the relationship between the two variables. RESULTS: The relationship between satisfaction and severity of symptoms was significant in BMS patients with high IU, but not in control patients with low IU. CONCLUSION: This study demonstrated that IU in BMS patients influences the relationship between the severity of symptoms and the satisfaction, thus indicating that the dissatisfaction in BMS patients with high IU might be prevented by decreasing the IU. CLINICAL RELEVANCE: Limited satisfaction experienced by BMS patients can influence the patient-doctor relationship. This study provides suggestions for building a good patient-doctor relationship.

Differences in the Clinical Characteristics of Persistent Idiopathic Facial Pain (Atypical Odontalgia) Patients with or Without Neurovascular Compression of the Trigeminal Nerve.

BACKGROUND: Persistent idiopathic facial pain (PIFP) is the unexplained pain along the territory of the trigeminal nerve, including nonorganic tooth pain called atypical odontalgia (AO). Though PIFP is debilitating to patients' livelihood and well-being, its pathophysiology remains poorly understood. Although neurovascular compression (NVC) of the trigeminal nerve is known to be associated with trigeminal neuralgia (TN), the relationship between NVC and other orofacial pains has not been fully elucidated. METHODS: In this study, we investigated the differences in the characteristics of PIFP (primarily AO) patients in the presence or absence of NVC. A retrospective analysis was performed on data from 121 consecutive patients who had been diagnosed with unilateral PIFP according to the criteria of the International Classification of Headache Disorders (ICHD)-3 and underwent magnetic resonance imaging scans of the head. RESULTS: In the group without NVC, characteristic findings were significant for psychiatric morbidity, somatization, and pain disability, when compared with the group with NVC. Furthermore, the group without NVC exhibited significant headache, noncardiac chest pain, shortness of breath, and pain catastrophizing. CONCLUSIONS: These results suggest that PIFP patients can be divided into two groups: one consistent with a neuropathic pain phenotype when NVC is present and a functional somatic symptom phenotype when presenting without NVC. Our findings may enable a more precise understanding of pathophysiology of PIFP and lead to better treatment strategies.

Pharmacotherapy in relieving the symptoms of burning mouth syndrome: A 1-year follow-up study.

OBJECTIVE: Burning mouth syndrome (BMS) is a chronic intraoral burning sensation with no identifiable causes. In this study, we aim to demonstrate the effectiveness of treatment strategy using ethyl loflazepate monotherapy or in combination with milnacipran or amitriptyline. METHOD: A hospital-based, retrospective study was conducted in 86 patients. The patients were divided into remission group and non-remission group. The remission group comprised patients who were satisfied with their pain relief within a year of treatment initiation and did not require any follow-up treatment. The treatment was considered effective if the patient got remission within 1 year or was able to reduce the visual analogue scale (VAS) score to <20, in the absence of remission. RESULTS: The treatment strategy was effective in 76.7% of the patients. Significant reductions (p < .05) in VAS scores from 73.5 ± 14.2 at first visit to 14.7 ± 8.7 at last visit in the remission group, and from 79.7 ± 14.3 at first visit to 33.4 ± 23.7 after 1 year of treatment in the non-remission group were noted. CONCLUSION: The treatment strategy using ethyl loflazepate monotherapy or in combination with milnacipran or amitriptyline can be very effective in reducing pain in BMS patients.

Comorbid depressive disorders and left-side dominant occlusal discomfort in patients with phantom bite syndrome.

BACKGROUND: Phantom bite syndrome (PBS) is characterised by occlusal discomfort without corresponding dental abnormalities. Despite repeated, failed dental treatments, patients with PBS persist in seeking bite correction. PBS has been regarded as a mental disorder. However, we have reported that PBS patients with a dental trigger tend to have less psychiatric history than those without. Hence, the symptoms of PBS cannot be explained by a mental disorder alone, and it is unclear if mental disorders affect occlusal sensation. OBJECTIVE: To elucidate the pathophysiology of PBS, we analysed the dental history, PBS symptom laterality and psychiatric history of patients. METHODS: In this retrospective study, we reviewed outpatients with PBS who presented at our clinic between April 2012 and March 2017. Their medical records were reviewed for demographic data, medical history and laterality of occlusal discomfort. RESULTS: Approximately half of the 199 enrolled patients had bilateral occlusal discomfort. In the others, the side with occlusal discomfort generally tended to be the one that had received dental treatment. There was no significant relationship between the side chiefly affected by occlusal discomfort and whether dental treatment had been received; however, the affected side differed depending on whether the patient had comorbid psychiatric disorders (P = .041). CONCLUSIONS: The distributions of the side with symptoms of PBS were different between those with and without comorbid psychiatric disorders, suggesting that psychiatric disorders might affect occlusal sensation due to a subtle dysfunction in brain areas central to sensory integration. Central dysfunction might play an important role in PBS.

Oral dysesthesia associated with autistic traits: a retrospective chart review.

Oral dysesthesia denotes a condition characterized by abnormal sensations in oral regions without a somatic basis, and is often seen in people with autistic traits, including those with autism spectrum disorder. This study aimed to examine the association between the symptoms of oral dysesthesia and the degree of autistic traits. A retrospective chart review was performed on 44 patients with oral dysesthesia, and associations among the subscales of the Oral Dysesthesia Rating Scale (Oral DRS), Autism Spectrum Quotient (AQ), and Glasgow Sensory Questionnaire (GSQ) were investigated. A Pearson correlation analysis revealed a significant, positive correlation between AQ scores and the A3 (squeezing or pulling) subscale of the Oral DRS (r = 0.37), but there were no significant correlations between the AQ and other subscale scores. There was a significant correlation between the AQ and GSQ score, but no correlation was detected between the GSQ and A3 scores or any other Oral DRS subscale scores. In conclusion, an abnormal squeezing or pulling sensation in oral regions without a somatic basis was associated with autistic traits and could be highlighted as a specific abnormality in sensory processing in autism spectrum disorder.

Increase in IGF-1 Expression in the Injured Infraorbital Nerve and Possible Implications for Orofacial Neuropathic Pain.

Insulin-like growth factor-1 (IGF-1) is upregulated in the injured peripheral nerve bundle and controls nociceptive neuronal excitability associated with peripheral nerve injury. Here, we examined the involvement of IGF-1 signaling in orofacial neuropathic pain following infraorbital nerve injury (IONI) in rats. IONI promoted macrophage accumulation in the injured ION, as well as in the ipsilateral trigeminal ganglion (TG), and induced mechanical allodynia of the whisker pad skin together with the enhancement of neuronal activities in the subnucleus caudalis of the spinal trigeminal nucleus and in the upper cervical spinal cord. The levels of IGF-1 released by infiltrating macrophages into the injured ION and the TG were significantly increased. The IONI-induced the number of transient receptor potential vanilloid (TRPV) subfamily type 4 (TRPV4) upregulation in TRPV subfamily type 2 (TRPV2)-positive small-sized, and medium-sized TG neurons were inhibited by peripheral TRPV2 antagonism. Furthermore, the IONI-induced mechanical allodynia was suppressed by TRPV4 antagonism in the whisker pad skin. These results suggest that IGF-1 released by macrophages accumulating in the injured ION binds to TRPV2, which increases TRPV4 expression in TG neurons innervating the whisker pad skin, ultimately resulting in mechanical allodynia of the whisker pad skin.

Evaluating Burning Mouth Syndrome as a Comorbidity of Atypical Odontalgia: The Impact on Pain Experiences.

OBJECTIVE: This study aimed (1) to investigate the differences in clinical characteristics of patients between 2 groups, those who have atypical odontalgia (AO) only and those who have AO with burning mouth syndrome (BMS), and (2) to assess the influence of psychiatric comorbidity factors on patients' experiences. METHOD: Medical records and psychiatric referral forms of patients visiting the Psychosomatic Dentistry Clinic of Tokyo Medical and Dental University between 2013 and 2016 were reviewed. The final sample included 2 groups of 355 patients: those who have AO only (n = 272) and those who have AO with BMS (AO-BMS; n = 83). Clinicodemographic variables (gender, age, comorbid psychiatric disorders, and history of headache or sleep disturbances) and pain variables (duration of illness, pain intensity, and severity of accompanying depression) were collected. Initial pain assessment was done using the Short-Form McGill Pain Questionnaire, and depressive state was determined using the Zung Self-Rating Depression Scale. RESULTS: The average age, female ratio, and sleep disturbance prevalence in the AO-only group were significantly lower than those in AO-BMS group. AO-BMS patients rated overall pain score and present pain intensity significantly higher than did the AO-only patients (P = 0.033 and P = 0.034, respectively), emphasizing sharp (P = 0.049), hot-burning (P = 0.000), and splitting (P = 0.003) characteristics of pain. Patients having comorbid psychiatric disorders had a higher proportion of sleep disturbance in both groups and a higher proportion of depressive state in the AO-only group. CONCLUSIONS: AO-BMS patients have different epidemiological characteristics, sleep quality, and pain experiences compared to AO-only patients. The presence of psychiatric comorbidities in both groups may exacerbate sleep quality. We suggest that BMS as a comorbid oral disorder in AO patients contributes to a more intensively painful experience.

Phenotypic change in trigeminal ganglion neurons associated with satellite cell activation via extracellular signal-regulated kinase phosphorylation is involved in lingual neuropathic pain.

Iatrogenic trigeminal nerve injuries remain a common and complex clinical problem. Satellite glial cell (SGC) activation, associated phosphorylation of extracellular signal-regulated kinase (ERK), and neuropeptide expression in the trigeminal ganglion (TG) are known to be involved in trigeminal neuropathic pain related to trigeminal nerve injury. However, the involvement of these molecules in orofacial neuropathic pain mechanisms is still unknown. Phosphorylation of ERK1/2 in lingual nerve crush (LNC) rats was observed in SGCs. To evaluate the role of neuron-SGC interactions under neuropathic pain, calcitonin gene-related peptide (CGRP)-immunoreactive (IR), phosphorylated ERK1/2 (pERK1/2)-IR and glial fibrillary acidic protein (GFAP)-IR cells in the TG were studied in LNC rats. The number of CGRP-IR neurons and neurons encircled with pERK1/2-IR SGCs was significantly larger in LNC rats compared with sham rats. The percentage of large-sized CGRP-IR neurons was significantly higher in LNC rats. The number of CGRP-IR neurons, neurons encircled with pERK1/2-IR SGCs, and neurons encircled with GFAP-IR SGCs was decreased following CGRP receptor blocker CGRP8-37 or mitogen-activated protein kinase/ERK kinase 1 inhibitor PD98059 administration into the TG after LNC. Reduced thresholds to mechanical and heat stimulation to the tongue in LNC rats were also significantly recovered following CGRP8-37 or PD98059 administration. The present findings suggest that CGRP released from TG neurons activates SGCs through ERK1/2 phosphorylation and TG neuronal activity is enhanced, resulting in the tongue hypersensitivity associated with lingual nerve injury. The phenotypic switching of large myelinated TG neurons expressing CGRP may account for the pathogenesis of tongue neuropathic pain.

Interaction between calcitonin gene-related peptide-immunoreactive neurons and satellite cells via P2Y12 R in the trigeminal ganglion is involved in neuropathic tongue pain in rats.

The P2Y12 receptor expressed in satellite cells of the trigeminal ganglion is thought to contribute to neuropathic pain. The functional interaction between neurons and satellite cells via P2Y12 receptors and phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2) underlying neuropathic pain in the tongue was evaluated in this study. Expression of P2Y12 receptor was enhanced in pERK1/2-immunoreactive cells encircling trigeminal ganglion neurons after lingual nerve crush. The administration to lingual nerve crush rats of a selective P2Y12 receptor antagonist, MRS2395, attenuated tongue hypersensitivity to mechanical and heat stimulation and suppressed the increase in the relative numbers of calcitonin gene-related peptide (CGRP)-immunoreactive neurons and neurons encircled by pERK1/2-immunoreactive cells. Administration of the P2Y1,12,13 receptor agonist, 2-(methylthio)adenosine 5'-diphosphate trisodium salt hydrate (2-MeSADP), to naïve rats induced neuropathic pain in the tongue, as in lingual nerve crush rats. Co-administration of 2-MeSADP + MRS2395 to naïve rats did not result in hypersensitivity of the tongue. The relative number of CGRP-immunoreactive neurons increased following this co-administration, but to a lesser degree than observed in 2-MeSADP-administrated naïve rats, and the relative number of neurons encircled by pERK1/2-immunoreactive cells did not change. These results suggest that the interaction between activated satellite cells and CGRP-immunoreactive neurons via P2Y12 receptors contributes to neuropathic pain in the tongue associated with lingual nerve injury.

Comparison of cerebral blood flow in oral somatic delusion in patients with and without a history of depression: a comparative case series.

BACKGROUND: A significant number of patients visit dental clinics because of unusual oral sensations for which no physical cause can be found. Such patients are recognized as having oral somatic delusion (OSD). OSD may be either primary (monosymptomatic) or secondary to another disease, such as depression or cerebral infarction. Although the presenting complaints of patients with primary and secondary OSD are nearly indistinguishable, symptoms in patients with secondary OSD seem to be resistant to treatment compared with those in patients with primary OSD. Moreover, right dominant cerebral blood flow (CBF) has been reported in patients with primary OSD, but the difference in CBF between patients with primary and secondary OSD remains unclear. The aim of this study was to assess the differences in clinical characteristics and CBF distribution between patients with monosymptomatic OSD (non-depression group) and OSD in conjunction with remitted depression (depression group). METHODS: Participants were 27 patients of a psychosomatic dentistry clinic, all diagnosed with OSD. They were categorized into either the non-depression group (17 patients) or the depression group (10 patients) on the basis of assessments by their personal medical providers. CBF was examined using single-photon emission computed tomography. RESULTS: There was no difference in clinical presentation between the two groups. A significant right dominant asymmetry in the temporal and posterior cerebral regions was observed in both groups. In the central region, a right dominance was seen in the non-depression group, while a left dominance was seen in the depression group. Moreover, the mean regional CBF values for patients in the depression group were significantly lower in several regions (including bilateral callosomarginal, precentral, angular, temporal, posterior cerebral, pericallosal, lenticular nucleus, thalamus, and hippocampus; and right central and cerebellum) than for patients in the non-depression group. CONCLUSION: These results suggest that the temporal and posterior cerebral regions are involved in in the pathophysiology of OSD, regardless of depression history, and that widespread CBF reduction is a characteristic of remitted depression.

Oral Dysesthesia Rating Scale: a tool for assessing psychosomatic symptoms in oral regions.

BACKGROUND: The concept of cenesthopathy was first introduced by Dupré and Camus in 1907 to describe clinically unexplainable bodily sensations mainly attributed to psychiatric pathology. If it occurs in oral regions, it is termed oral cenesthopathy and it has been of special interest to psychiatrists and dentists. While there is no independently defined criteria for this condition, which is classified as either a delusional or a somatoform disorder, clinical practice and research require a standard scale to measure and rate its symptoms. In this study, we included any types of psychosomatic symptoms in oral regions as oral dysesthesia, and developed an Oral Dysesthesia Rating Scale (Oral DRS) and evaluated its validity and reliability as an assessment tool. METHODS: The scale was developed based on literature review and extensive clinical experience. Twelve reviewers assessed relevancy of each item to oral dysesthesia symptoms by 1-4 scoring scale and item content validity index was computed. To evaluate the inter-rater reliability of Oral DRS, pairs of raters administered the scale to 40 randomly selected patients with complaints of oral dysesthesia symptoms and Cohen's weighted kappa coefficient was determined for each item. RESULTS: The scale assesses the severity of feelings of foreign body [A1], exudation [A2], squeezing-pulling [A3], movement [A4], misalignment [A5], pain [A6], and spontaneous thermal sensation or tastes [A7], and the degree of impairment in eating [B1], articulation [B2], work [B3], and social activities [B4] on a scale of 0-5. Items A1, A2, A3, A4, B3, and B4 demonstrated acceptable content validity. Inter-rater reliabilities were good or excellent for all items evaluated. CONCLUSION: The Oral DRS can help define the nosography of clinically unexplainable oral dysesthesia through further case evaluation and clinical research and facilitate devising of treatment modalities.

Reappraising the psychosomatic approach in the study of "chronic orofacial pain": looking for the essential nature of these intractable conditions.

As burning mouth syndrome (BMS) and atypical odontalgia (AO) continue to remain complex in terms of pathophysiology and lack explicit treatment protocol, clinicians are left searching for appropriate solutions. Oversimplification solves nothing about what bothers us in clinical situations with BMS or AO. It is important to treat a complicated phenomenon as complex. We should keep careful observations and fact-finding based on a pragmatic approach toward drug selection and prescription with regular follow-up. We also need to assess the long-term prognosis of treatment with a meticulous selection of sample size and characteristics. Further investigation of BMS and AO from a psychosomatic perspective has the potential to provide new insight into the interface between brain function and "chronic orofacial pain."