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This article reviews the utility of neurophysiological recordings and quantitative sensory testing (QST) in providing sensitive, quantitative, and objective tests for the diagnosis and localization of damage to the trigeminal nerve. Electromyography and recordings of the masseter reflex and compound muscle action potential evoked by transcranial magnetic stimulation or direct electrical stimulation of the masseteric nerve can be of value in evaluating the function of a motor neurons supplying the muscles of mastication. Orthodromic recording of the sensory action potential and trigeminal somatosensory-evoked potential recording with the near-nerve stimulation technique are sensitive tools for the investigation of trigeminal sensory Abeta afferents, whereas recordings of polysynaptic trigeminal brainstem reflexes and tactile QST are less sensitive. At late stages of recovery, the blink reflex and masseter inhibitory reflex are often normal, but at earlier stages, the blink reflex recording has good prognostic value, and the presence of a reflex response may confirm continuity of the nerve trunk after partial laceration. Trigeminal small-fiber function (Adelta and C) can be studied with thermal QST of the cool, warm, heat pain, and cold pain detection thresholds or with laser-evoked potential recording. Thermal QST may remain abnormal years after axonal damage and aids in the diagnosis of late sequelae of trigeminal nerve injury. In a study of the diagnostic value of neurography, blink reflex and thermal QST, and various commonly used clinical sensory tests, neurophysiologic tests and thermal QST had better sensitivity (50% to 88% vs 40% to 59%) and negative predictive values (78% to 100% vs 70% to 74%) compared to clinical examination, whereas the specificity (55% to 100%) and positive predictive values (48% to 73%) were similar. At 1 year after trigeminal nerve injury, the risk of a false negative finding with clinical sensory testing was 94%, whereas the combination of nerve conduction recordings and thermal QST increased the diagnostic yield to 100% in patients with long-standing postsurgical sensory alteration. In conclusion, clinical neurophysiological recordings and QST improve the diagnostic accuracy for trigeminal neuropathy. [ABSTRACT FROM AUTHOR]

Chronic orofacial pain represents a diagnostic and treatment challenge for the clinician. Some conditions, such as atypical facial pain, still lack proper diagnostic criteria, and their etiology is not known. The recent development of neurophysiological methods and quantitative sensory testing for the examination of the trigeminal somatosensory system offers several tools for diagnostic and etiological investigation of orofacial pain. This review presents some of these techniques and the results of their application in studies on orofacial pain and sensory dysfunction. Clinical neurophysiological investigation has greater diagnostic accuracy and sensitivity than clinical examination in the detection of the neurogenic abnormalities of either peripheral or central origin that may underlie symptoms of orofacial pain and sensory dysfunction. Neurophysiological testing may also reveal trigeminal pathology when magnetic resonance imaging has failed to detect it, so these methods should be considered complementary to each other in the investigation of orofacial pain patients. The blink reflex, corneal reflex, jaw jerk, sensory neurography of the inferior alveolar nerve, and the recording of trigeminal somatosensory-evoked potentials with near-nerve stimulation have all proved to be sensitive and reliable in the detection of dysfunction of the myelinated sensory fibers of the trigeminal nerve or its central connections within the brainstem. With appropriately small thermodes, thermal quantitative sensory testing is useful for the detection of trigeminal small-fiber dysfunction (Adelta and C). In neuropathic conditions, it is most sensitive to lesions causing axonal injury. By combining different techniques for investigation of the trigeminal system, an accurate topographical diagnosis and profile of sensory fiber pathology can be determined. Neurophysiological and quantitative sensory tests have already highlighted some similarities among various orofacial pain conditions and have shown heterogeneity within clinical diagnostic categories. With the aid of neurophysiological recordings and quantitative sensory testing, it is possible to approach a mechanism-based classification of orofacial pain. [ABSTRACT FROM AUTHOR]

The blink reflex (BR) is integrated at the brainstem; however, it is modulated by inputs from various structures such as the striatum, globus pallidus, substantia nigra, and nucleus raphe magnus but also from afferent input from the peripheral nervous system. Therefore, it provides information about the pathophysiology of numerous peripheral and central nervous system disorders. The BR is a valuable tool for studying the integrity of the trigemino-facial system, the relevant brainstem nuclei, and circuits. At the same time, some neurophysiological techniques applying the BR may indicate abnormalities involving structures rostral to the brainstem that modulate or control the BR circuits. This is a state-of-the-art review of the clinical application of BR modulation; physiology is reviewed in part 1. In this review, we aim to present the role of the BR and techniques related to its modulation in understanding pathophysiological mechanisms of motor control and pain disorders, in which these techniques are diagnostically helpful. Furthermore, some BR techniques may have a predictive value or serve as a basis for follow-up evaluation. BR testing may benefit in the diagnosis of hemifacial spasm, dystonia, functional movement disorders, migraine, orofacial pain, and psychiatric disorders. Although the abnormalities in the integrity of the BR pathway itself may provide information about trigeminal or facial nerve disorders, alterations in BR excitability are found in several disease conditions. BR excitability studies are suitable for understanding the common pathophysiological mechanisms behind various clinical entities, elucidating alterations in top-down inhibitory systems, and allowing for follow-up and quantitation of many neurological syndromes., (Copyright © 2024 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Abstract: Adults with chronic low back pain, disability, moderate-to-severe pain, and high fear of movement and reinjury were recruited into a trial of a novel, automated, digital therapeutics, virtual reality, psychological intervention for pain (DTxP). We conducted a 3-arm, prospective, double-blind, pilot, randomized, controlled trial comparing DTxP with a sham placebo comparator and an open-label standard care. Participants were enrolled for 6 to 8 weeks, after which, the standard care control arm were rerandomized to receive either the DTxP or sham placebo. Forty-two participants completed assessments at baseline, immediately posttreatment (6-8 weeks), 9-week, and 5-month follow-up. We found that participants in the DTxP group reported greater reductions in fear of movement and better global impression of change when compared with sham placebo and standard care post treatment. No other group differences were noted at posttreatment or follow-up. When compared with baseline, participants in the DTxP group reported lower disability at 5-month follow-up, lower pain interference and fear of movement post treatment and follow-up, and lower pain intensity at posttreatment. The sham placebo group also reported lower disability and fear of movement at 5-month follow-up compared with baseline. Standard care did not report any significant changes. There were a number of adverse events, with one participant reporting a serious adverse event in the sham placebo, which was not related to treatment. No substantial changes in medications were noted, and participants in the DTxP group reported positive gaming experiences., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

Aim: Nasal continuous positive airway pressure (CPAP) devices generate loud noise, which might harm auditory function and maturation. The function of auditory pathways can be examined by using brainstem auditory evoked potential (BAEP) and brainstem audiometry (BA) recordings. Our objective was to study whether CPAP treatment during the neonatal period is associated with abnormalities in BAEP and BA recordings., Methods: Included in this retrospective study were preterm infants (birth weight ≤1500 g and/or gestational age ≤32 weeks) born between 2002 and 2006 with a comprehensive clinical background and follow-up data, including the duration of CPAP treatment (n = 162). BAEP and BA were recorded near the mean corrected age of one month. The following variables from BAEP and BA examinations were analysed: latencies of BAEP components I, III, V, interpeak intervals (IPI) I-V, I-III, III-V (ms), amplitude I and V (µV), amplitude ratio I/V and BA thresholds., Results: In the adjusted analysis, a longer CPAP treatment leads to longer latencies of BAEP component III (p = 0.01) and V (p = 0.02) in the right ear., Conclusion: CPAP treatment may impair the auditory maturation and processing mediated via the dominant right ear. The hearing and neurodevelopment of the children who are treated with CPAP should be followed., (© 2021 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Objective: To develop a beta version of a preliminary set of empirically derived research diagnostic criteria (RDC) for burning mouth syndrome (BMS) through expert consensus, which can then be taken into a test period before publication of a final RDC/BMS., Design: A 6 round Delphi process with twelve experts in the field of BMS was used. The first round formed a focus group during which the purpose of the RDC and the definition of BMS was agreed upon, as well as the structure and contents. The remaining rounds were carried out virtually via email to achieve a consensus of the beta version of the RDC/BMS., Results: The definition of BMS was agreed to be 'an intraoral burning or dysaesthetic sensation, recurring daily for more than 2 hours per day over more than 3 months, without evident causative lesions on clinical examination and investigation'. The RDC was based upon the already developed and validated RDC/TMD and formed three main parts: patient self-report; examination; and psychosocial self-report. A fourth additional part was also developed listing aspirational biomarkers which could be used as part of the BMS diagnosis where available, or to inform future research., Conclusion: This Delphi process has created a beta version of an RDC for use with BMS. This will allow future clinical research within BMS to be carried out to a higher standard, ensuring only patients with true BMS are included. Further validation studies will be required alongside refinement of the RDC as trialling progresses., (© 2020 John Wiley & Sons Ltd.)

Background and Purpose: It is well established that patient-related constitutional features predispose to focal peripheral neuropathies. Some of these risk factors were investigated in common focal neuropathies encountered in patients referred for electromyography., Methods: Gender, age, height and body mass index (BMI) were analysed retrospectively as risk factors for 11 focal neuropathies. In all, 9686 patients (age range 18-96 years; 58% women) were included from three different centres, with identical methods and equipment., Results: High BMI was related to carpal tunnel syndrome (CTS), ulnar neuropathy at the elbow (UNE), combined CTS and UNE, meralgia paraesthetica and lumbar radiculopathy. In women, CTS and Morton's metatarsalgia were more common, whilst long thoracic neuropathies, suprascapular neuropathies and UNE were more common in men. Older age increased the risk for CTS, UNE, Morton's metatarsalgia and radiculopathies., Conclusions: Age, gender and BMI are important risk factors for many common focal neuropathies., (© 2019 European Academy of Neurology.)

A group of European experts reappraised the guidelines on the therapeutic efficacy of repetitive transcranial magnetic stimulation (rTMS) previously published in 2014 [Lefaucheur et al., Clin Neurophysiol 2014;125:2150-206]. These updated recommendations take into account all rTMS publications, including data prior to 2014, as well as currently reviewed literature until the end of 2018. Level A evidence (definite efficacy) was reached for: high-frequency (HF) rTMS of the primary motor cortex (M1) contralateral to the painful side for neuropathic pain; HF-rTMS of the left dorsolateral prefrontal cortex (DLPFC) using a figure-of-8 or a H1-coil for depression; low-frequency (LF) rTMS of contralesional M1 for hand motor recovery in the post-acute stage of stroke. Level B evidence (probable efficacy) was reached for: HF-rTMS of the left M1 or DLPFC for improving quality of life or pain, respectively, in fibromyalgia; HF-rTMS of bilateral M1 regions or the left DLPFC for improving motor impairment or depression, respectively, in Parkinson's disease; HF-rTMS of ipsilesional M1 for promoting motor recovery at the post-acute stage of stroke; intermittent theta burst stimulation targeted to the leg motor cortex for lower limb spasticity in multiple sclerosis; HF-rTMS of the right DLPFC in posttraumatic stress disorder; LF-rTMS of the right inferior frontal gyrus in chronic post-stroke non-fluent aphasia; LF-rTMS of the right DLPFC in depression; and bihemispheric stimulation of the DLPFC combining right-sided LF-rTMS (or continuous theta burst stimulation) and left-sided HF-rTMS (or intermittent theta burst stimulation) in depression. Level A/B evidence is not reached concerning efficacy of rTMS in any other condition. The current recommendations are based on the differences reached in therapeutic efficacy of real vs. sham rTMS protocols, replicated in a sufficient number of independent studies. This does not mean that the benefit produced by rTMS inevitably reaches a level of clinical relevance., (Copyright © 2019 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Orofacial pain syndromes encompass several clinically defined and classified entities. The focus here is on the role of clinical neurophysiologic and psychophysical tests in the diagnosis, differential diagnosis, and pathophysiological mechanisms of definite trigeminal neuropathic pain and other chronic orofacial pain conditions (excluding headache and temporomandibular disorders). The International Classification of Headache Disorders 2018 classifies these facial pain disorders under the heading Painful cranial neuropathies and other facial pains. In addition to unambiguous painful posttraumatic or postherpetic trigeminal neuropathies, burning mouth syndrome, persistent idiopathic facial and dental pain, and trigeminal neuralgia have also been identified with neurophysiologic and quantitative sensory testing to involve the nervous system. Despite normal clinical examination, these all include clusters of patients with evidence for either peripheral or central nervous system pathology compatible with the subclinical end of a continuum of trigeminal neuropathic pain conditions. Useful tests in the diagnostic process include electroneuromyography with specific needle, neurography techniques for the inferior alveolar and infraorbital nerves, brain stem reflex recordings (blink reflex with stimulation of the supraorbital, infraorbital, mental, and lingual nerves; jaw jerk; masseter silent period), evoked potential recordings, and quantitative sensory testing. Habituation of the blink reflex and evoked potential responses to repeated stimuli evaluate top-down inhibition, and navigated transcranial magnetic stimulation allows the mapping of reorganization within the motor cortex in chronic neuropathic pain. With systematic use of neurophysiologic and quantitative sensory testing, many of the current ambiguities in the diagnosis, classification, and understanding of chronic orofacial syndromes can be clarified for clinical practice and future research.

Background and Aims: Neuropathic mechanisms are involved in burning mouth syndrome (BMS), and variation of the dopamine D2 receptor (DRD2) gene contributes to experimental pain perception. We investigated whether neurophysiologic findings differ in BMS patients compared to healthy controls, and whether 957C>T polymorphism of the DRD2 gene influences thermal sensitivity or pain experience in BMS., Methods: Forty-five BMS patients (43 women), mean age 62.5 years, and 32 healthy controls (30 women), mean age 64.8 years, participated. Patients estimated pain intensity, interference, suffering and sleep with Numeric Rating Scale. Blink reflex tests of the supraorbital (SON), mental (MN) and lingual (LN) nerves, and thermal quantitative sensory testing were done. The results were analysed with ANOVA. DRD2 gene 957C>T polymorphism was determined in 31 patients, and its effects on neurophysiologic and clinical variables were analysed., Results: Cool (p = 0.0090) and warm detection thresholds (p = 0.0229) of the tongue were higher in BMS patients than controls. The stimulation threshold for SON BR was higher in patients than in controls (p = 0.0056). The latencies of R2 component were longer in BMS patients than in controls (p = 0.0005) at the SON distribution. Habituation of SON BR did not differ between the groups. The heat pain thresholds were highest (p = 0.0312) in homozygous patients with 957TT, who also reported most interference (p = 0.0352) and greatest suffering (p = 0.0341). Genotype 957CC associated with sleep disturbances (p = 0.0254)., Conclusions: Burning mouth syndrome patients showed thermal hypoesthesia within LN distribution compatible with small fibre neuropathy. The DRD2 957C>T genotype influences perception and experience of BMS pain., Significance: The results confirm earlier findings of neuropathic pain in BMS. The DRD2 957 C>T genotype influences perception and experience of clinical pain in BMS., (© 2019 European Pain Federation - EFIC®.)

Introduction: We evaluated diagnostic value of sensory tests during recovery from iatrogenic sensory neuropathy using intraoperatively verified nerve injury with subjective symptoms as gold standard., Methods: Inferior alveolar nerves were monitored neurophysiologically throughout mandibular osteotomy in 19 patients. Sensory disturbance was registered and sensation tested using clinical and quantitative sensory (QST) and neurophysiologic tests postoperatively at 1, 3, 6, and 12 months. Sensitivity, specificity, and predictive values were calculated for all tests., Results: The sensitivity of clinical tests was at best 37%, with 100% specificity, but they lost diagnostic value at chronic stages. Best diagnostic accuracy (highest combination of sensitivity and specificity) at different time points was achieved by combining neurophysiologic and thermal QST or tactile and thermal QST. The single most accurate test was sensory neurography., Conclusions: Neurography or combinations of neurophysiologic and quantitative tests enables most reliable early and late diagnosis. Clinical sensory examination is inadequate for accurate diagnosis. Muscle Nerve 59:342-347, 2019., (© 2018 Wiley Periodicals, Inc.)

Background and Objective: We investigated the associations of maternal diet and serum fatty acids during pregnancy and in early infancy on infantile neurodevelopment., Methods: Pattern-reversal visual evoked potentials (pVEP) as depictors of central nervous system maturation were recorded from 56 children when they were 2 years old. Maternal nutrient intakes were calculated from food diaries and fish consumption from questionnaires collected during pregnancy. Serum phospholipid fatty acids were determined by gas chromatography in late pregnancy and from infants at 1 month of age., Results: The children of the women who consumed fish three or more times per week during the last trimester of pregnancy had a higher pVEP component P100 amplitude for 60' (mean 23.4, SD 8.1) and 30' (mean 20.4, SD 6.7) of arcminute check sizes compared to those who consumed fish 0-2 times per week (mean 15.0, SD 4.8, p = 0.023, adjusted for birth weight and gender p = 0.058 and mean 13.4, SD 2.0, respectively, p = 0.028, adjusted p = 0.072). Maternal and child serum phospholipid fatty acids correlated with child pVEP measurements., Conclusion: The results of this small-scale study suggest that fish consumption during pregnancy and perinatal serum fatty acid status may associate with neurodevelopment within visual system during infancy.

Repetitive transcranial magnetic stimulation (rTMS) has shown variable effect on tinnitus. A prospective, randomized 6-month follow-up study on parallel groups was conducted to compare the effects of neuronavigated rTMS to non-navigated rTMS in chronic tinnitus. Forty patients (20 men, 20 women), mean age of 52.9 years (standard deviation [ SD] = 11.7), with a mean tinnitus duration of 5.8 years ( SD = 3.2) and a mean tinnitus intensity of 62.2/100 ( SD = 12.8) on Visual Analog Scale (VAS 0-100) participated. Patients received 10 sessions of 1-Hz rTMS to the left temporal area overlying auditory cortex with or without neuronavigation. The main outcome measures were VAS scores for tinnitus intensity, annoyance, and distress, and Tinnitus Handicap Inventory (THI) immediately and at 1, 3, and 6 months after treatment. The mean tinnitus intensity (hierarchical linear mixed model: F 3  = 7.34, p = .0006), annoyance ( F 3  = 4.45, p = .0093), distress ( F 3  = 5.04, p = .0051), and THI scores ( F 4  = 17.30, p < .0001) decreased in both groups with non-significant differences between the groups, except for tinnitus intensity ( F 3  = 2.96, p = .0451) favoring the non-navigated rTMS. Reduction in THI scores persisted for up to 6 months in both groups. Cohen's d for tinnitus intensity ranged between 0.33 and 0.47 in navigated rTMS and between 0.55 and 1.07 in non-navigated rTMS. The responder rates for VAS or THI ranged between 35% and 85% with no differences between groups ( p = .054-1.0). In conclusion, rTMS was effective for chronic tinnitus, but the method of coil localization was not a critical factor for the treatment outcome.

Here we review the literature assessing the roles of the brain dopaminergic and serotonergic systems in the modulation of pain as revealed by in vivo human studies using positron emission tomography. In healthy subjects, dopamine D 2 /D 3 receptor availability particularly in the striatum and serotonin 5-HT 1A and 5-HT 2A receptor availabilities in the cortex predict the subject's response to tonic experimental pain. High availability of dopamine D 2 /D 3 or serotonin 5-HT 2A receptors is associated with high pain intensity, whereas high availability of 5-HT 1A receptors associates with low pain intensity. Chronic neuropathic pain is associated with high striatal dopamine D 2 /D 3 receptor availability, for which low endogenous dopamine tone is a plausible explanation, although a compensatory increase in striatal dopamine D 2 /D 3 receptor density may also contribute. In contrast, chronic musculoskeletal pain is associated with low baseline availability of striatal dopamine D 2 /D 3 receptors. In healthy subjects, brain serotonin 5-HT 1A as well as dopamine D 2 /D 3 receptor availabilities associate with the subject's response criterion rather than the capacity to discriminate painful thermal stimuli suggesting that these neurotransmitter systems act mainly on non-sensory rather than sensory factors of thermally induced pain experience. Additionally, 5-HT 1A receptor availability predicts the subject's discriminative ability but not response criterion for non-painful tactile test stimuli, while no such correlation is observed with dopamine D 2 /D 3 receptors. These findings suggest that dopamine acting on striatal dopamine D 2 /D 3 receptors and serotonin acting on cortical 5-HT 1A and 5-HT 2A receptors contribute to top-down pain regulation in humans., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Introduction: We describe a new nerve conduction study technique with reference values for the 3 branches of the supraclavicular nerve (SCN) in young healthy subjects and application of it in 2 patients., Methods: The recording electrode was placed on the posterior border of the sternocleidomastoid muscle, 6-7 cm from the sternoclavicular joint. SCN branches were stimulated below the clavicle, 2.5, 7, and 10.5 cm lateral to the sternoclavicular joint., Results: Twenty healthy volunteers (10 men), 19-38 years, mean 25.9 years (SD 6.3), and 2 patients with SCN lesions were studied. The mean conduction velocities of the SCN branches were 70-78 m/s (SD 8-10 m/s), and amplitudes 3-4 µV (SD 0.9-2.0 µV). There were no side-to-side or gender differences., Discussion: The 3 SCN branches could be studied in all subjects. We provide reference values for young subjects. This new method was useful in verifying SCN lesions in 2 patients. Muscle Nerve 58: 300-303, 2018., (© 2018 Wiley Periodicals, Inc.)

Objective: Chronic tinnitus has been associated with several psychiatric disorders. Only few studies have investigated these disorders using validated diagnostic interviews. The aims were to diagnose psychiatric and personality disorders with structured interviews, to assess self-rated psychiatric symptoms and elucidate temporal relations between psychiatric disorders and tinnitus., Design: Current and lifetime DSM-IV diagnoses of axis-I (psychiatric disorders) and axis-II (personality disorders) were assessed using structured clinical interviews (SCID-I and -II). Current subjective psychiatric symptoms were evaluated via self-rating instruments: the Symptom Check List-90 (SCL-90), the Beck Depression Inventory, and the Dissociative Experiences Scale (DES)., Study Sample: 83 patients (mean age 51.7, 59% men) with chronic, disturbing tinnitus and a median Tinnitus Handicap Inventory score of 32., Results: The rates of lifetime and current major depression were 26.5% and 2.4%. The lifetime rate of obsessive-compulsive personality disorder (type C) was 8.4%. None of the patients had cluster B personality disorder or psychotic symptoms. The SCL-90 subscales did not differ from the general population, and median DES score was low, 2.4., Conclusions: Tinnitus patients are prone to episodes of major depression and often also have obsessive-compulsive personality features. Psychiatric disorders seem to be comorbid or predisposing conditions rather than consequences of tinnitus. Clinical trial reference: ClinicalTrials.gov (ID NCT 01929837).

Primary burning mouth syndrome (BMS) is defined as an "intraoral burning or dysaesthetic sensation, recurring daily… more than 3 months, without clinically evident causative lesions" (IHS 2013). In addition to pain, taste alterations are frequent (dysgeusia, xerostomia). Although lacking clinical signs of neuropathy, more accurate diagnostic methods have shown neuropathic involvement at various levels of the neuraxis in BMS: peripheral small fiber damage (thermal quantitative sensory testing, electrogustatometry, epithelial nerve fiber density), trigeminal system lesions in the periphery or the brainstem (brainstem reflex recordings, trigeminal neurography, evoked potentials), or signs of decreased inhibition within the central nervous system (deficient brainstem reflex habituation, positive signs in quantitative sensory testing, neurotransmitter-positron emission tomography findings indicative of deficient striatal dopamine function). Abnormalities in electrogustatometry indicate the involvement of the small Aδ taste afferents, in addition to somatosensory small fibers. According to these findings, the clinical entity of BMS can be divided into 2 main subtypes compatible with either peripheral or central neuropathic pain, which may overlap in individual patients. The central type does not respond to local treatments and associates often with psychiatric comorbidity (depression or anxiety), whereas the peripheral type responds to peripheral lidocaine blocks and topical clonazepam. Burning mouth syndrome is most prevalent in postmenopausal women, having led to a hypothesis that BMS is triggered as a consequence of nervous system damage caused by neurotoxic factors affecting especially vulnerable small fibers and basal ganglia in a setting of decrease in neuroprotective gonadal hormones and increase in stress hormone levels, typical for menopause.

Background: We evaluated clinical against psychophysical (tactile and thermal quantitative sensory test [QST]), neurophysiologic (somatosensory evoked potential [SEP]), and epithelial nerve fiber density (ENFD) examinations in detection and follow-up of sensory alterations after breast reconstruction done with or without nerve anastomoses., Patients and Methods: In a prospective 2-year follow-up design, 56 breast cancer patients underwent innervated and 20 patients noninnervated free rectus abdominis muscle-sparing flap (ms-TRAM) breast reconstruction. Healthy contralateral breasts (36 patients) and 20 healthy volunteer women served as control participants. The diagnostic values of clinical examination, QST, SEP, and ENFD tests were assessed at baseline, and 1 and 2 years postoperatively., Results: Sensation of mastectomized thoracic skin was impaired before reconstruction surgery, confirmed with QST (P < .001 for tactile, warm and cool detection; others not significant). All tests were further impaired at 1 year (P < .012-.0001), but mostly showed improvement during subsequent follow-up (P < .001-.0001), except for vibration and 2-point discrimination, ENFD, and SEP. QST improved diagnostic accuracy for large as well as small fiber function performing best in assessing sensory recovery at 2 years. Of clinical tests, sharp-blunt discrimination was modestly useful (sensitivity, 0.85; poor specificity, 0.17). Two-point and vibration discrimination tests had poor diagnostic values. SEP recording was modestly sensitive (0.50), but not specific (0.25). Because of sparse epithelial innervation already at baseline, ENFD performed poorly., Conclusion: Most tests could identify sensory nerve damage postoperatively. Tactile and thermal QST were most reliable, and sensitive also in confirming sensory recovery. SEP recording was useful especially in differentiating surgical techniques, whereas ENFD and clinical examination performed poorly, with the exception of sharp-blunt discrimination., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Repetitive transcranial magnetic stimulation (rTMS) at M1/S1 cortex has been shown to alleviate neuropathic pain., Objectives: To investigate the possible neurobiological correlates of cortical neurostimulation for the pain relief., Methods: We studied the effects of M1/S1 rTMS on nociception, brain dopamine D2 and μ-opioid receptors using a randomized, sham-controlled, double-blinded crossover study design and 3D-positron emission tomography (PET). Ten healthy subjects underwent active and sham rTMS treatments to the right M1/S1 cortex with E-field navigated device. Dopamine D2 and μ-receptor availabilities were assessed with PET radiotracers [ 11 C]raclopride and [ 11 C]carfentanil after each rTMS treatment. Thermal quantitative sensory testing (QST), contact heat evoked potential (CHEP) and blink reflex (BR) recordings were performed between the PET scans., Results: μ-Opioid receptor availability was lower after active than sham rTMS (P ≤ 0.0001) suggested release of endogenous opioids in the right ventral striatum, medial orbitofrontal, prefrontal and anterior cingulate cortices, and left insula, superior temporal gyrus, dorsolateral prefrontal cortex and precentral gyrus. There were no differences in striatal dopamine D2 receptor availability between active and sham rTMS, consistent with lack of long-lasting measurable dopamine release. Active rTMS potentiated the dopamine-regulated habituation of the BR compared to sham (P = 0.02). Thermal QST and CHEP remained unchanged after active rTMS., Conclusions: rTMS given to M1/S1 activates the endogenous opioid system in a wide brain network associated with processing of pain and other salient stimuli. Direct enhancement of top-down opioid-mediated inhibition may partly explain the clinical analgesic effects of rTMS., Significance: Neurobiological correlates of rTMS for the pain relief are unclear. rTMS on M1/S1 with 11 C-carfentanyl-PET activates endogenous opioids. Thermal and heat pain thresholds remain unchanged. rTMS induces top-down opioid-mediated inhibition but not change the sensory discrimination of painful stimuli., (© 2017 European Pain Federation - EFIC®.)

Objective: Repetitive transcranial magnetic stimulation (rTMS) may alleviate tinnitus. We evaluated effects of electric field (E-field) navigated rTMS targeted according to tinnitus pitch. No controlled studies have investigated anatomically accurate E-field-rTMS for tinnitus., Design: Effects of E-field-rTMS were evaluated in a prospective randomised placebo-controlled 6-month follow-up study on parallel groups. Patients received 10 sessions of 1 Hz rTMS or placebo targeted to the left auditory cortex corresponding to tonotopic representation of tinnitus pitch. Effects were evaluated immediately after treatment and at 1, 3 and 6 months. Primary outcome measures were visual analogue scores (VAS 0-100) for tinnitus intensity, annoyance and distress, and the Tinnitus Handicap Inventory (THI)., Study Sample: Thirty-nine patients (mean age 50.3 years)., Results: The mean tinnitus intensity (F 3  = 15.7, p < 0.0001), annoyance (F 3  = 8.8, p = 0.0002), distress (F 3  = 9.1, p = 0.0002) and THI scores (F 4  = 13.8, p < 0.0001) decreased in both groups over time with non-significant differences between the groups. After active rTMS, 42% and 37% of the patients showed excellent response at 1 and 3 months against 15% and 10% in the placebo group (p = 0.082 and p = 0.065)., Conclusions: Despite the significant effects of rTMS on tinnitus, differences between active and placebo groups remained non-significant, due to large placebo-effect and wide inter-individual variation.

Objective To review the clinical entity of primary burning mouth syndrome (BMS), its pathophysiological mechanisms, accurate new diagnostic methods and evidence-based treatment options, and to describe novel lines for future research regarding aetiology, pathophysiology, and new therapeutic strategies. Description Primary BMS is a chronic neuropathic intraoral pain condition that despite typical symptoms lacks clear clinical signs of neuropathic involvement. With advanced diagnostic methods, such as quantitative sensory testing of small somatosensory and taste afferents, neurophysiological recordings of the trigeminal system, and peripheral nerve blocks, most BMS patients can be classified into the peripheral or central type of neuropathic pain. These two types differ regarding pathophysiological mechanisms, efficacy of available treatments, and psychiatric comorbidity. The two types may overlap in individual patients. BMS is most frequent in postmenopausal women, with general population prevalence of around 1%. Treatment of BMS is difficult; best evidence exists for efficacy of topical and systemic clonazepam. Hormonal substitution, dopaminergic medications, and therapeutic non-invasive neuromodulation may provide efficient mechanism-based treatments for BMS in the future. Conclusion We present a novel comprehensive hypothesis of primary BMS, gathering the hormonal, neuropathic, and genetic factors presumably required in the genesis of the condition. This will aid in future research on pathophysiology and risk factors of BMS, and boost treatment trials taking into account individual mechanism profiles and subgroup-clusters.

Background: We describe a new dual neurorrhaphy method for a free abdominal-based flap and compare sensory recovery with this novel technique to that with conventional neurorrhaphy technique for breast reconstruction., Methods: 70 breast cancer patients underwent muscle sparing innervated transversal rectus abdominis myocutaneous flap (neuro ms-TRAM) breast reconstruction with either a novel dual neurorrhaphy technique (N = 41) or single (N = 29) neurorrhaphy only. Dual neurorrhaphy was performed on both sides and single neurorrhaphy on one side of the flap, using the end-to-end or end-to-side technique. Two years postoperatively, quantitative sensory testing (QST) was performed for tactile, and thermal sensory modalities, and other tests included sharp-blunt, vibration, and two-point discrimination. Sensory modalities were scored either zero (abnormal) or one point (normal) at each test site against normal reference values (five sites for most tests). The total sensory scores (TSC) were calculated on the basis of the sums of the individual test scores, and all data are presented as the median (interquartile range, IQR)., Results: The median of TSC in the breast reconstruction with the dual neurorrhaphy was higher (15.3, IQR 11.8-19.4), than that with the single neurorrhaphy (11.5, IQR 9.1-17.4) (P = 0.037). Regarding the different sensory modalities, the dual technique especially enhanced the tactile (P = 0.005) and cool detection (P = 0.021) recovery compared to the single neurorrhaphy., Conclusions: Dual neurorrhaphy improved the sensory recovery of the reconstructed breast, and may therefore be recommended for clinical practice. © 2014 Wiley Periodicals, Inc. Microsurgery 37:21-28, 2017., (© 2016 Wiley Periodicals, Inc.)

There is limited data on electromyography (EMG) findings in other motor neuron disorders than amyotrophic lateral sclerosis (ALS). We assessed whether the distribution of active denervation detected by EMG, i.e. fibrillations and fasciculations, differs between ALS and slowly progressive motor neuron disorders. We compared the initial EMG findings of 43 clinically confirmed, consecutive ALS patients with those of 41 genetically confirmed Late-onset Spinal Motor Neuronopathy and 14 Spinal and Bulbar Muscular Atrophy patients. Spontaneous activity was more frequently detected in the first dorsal interosseus and deltoid muscles of ALS patients than in patients with the slowly progressive motor neuron diseases. The most important observation was that absent fibrillations in the first dorsal interosseus muscle identified the benign forms with sensitivities of 66%-77% and a specificity of 93%. The distribution of active denervation may help to separate ALS from mimicking disorders at an early stage., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Although electroencephalogram reactivity (i.e. transient changes in electrical brain activity following external stimulus) might be useful in depth-of-anaesthesia monitoring, it has not been systematically examined with different anaesthetics at doses titrated to unresponsiveness. Three 10-subject groups of healthy volunteers received dexmedetomidine, propofol or sevoflurane in escalating pseudo-steady-state concentrations at 10-min intervals until they did not open their eyes to command. The electroencephalogram was continuously recorded and spectral variables were calculated with short-time Fourier transform and time-varying autoregressive modelling. Electroencephalogram reactivity was most prominent in the midfrontal derivations (termed F3 and F4). During drug-induced unresponsiveness, electroencephalogram reactivity was still present in all drug groups. Dexmedetomidine, propofol and sevoflurane induced distinct suppression patterns on the electroencephalogram reactivity at the same clinical endpoint (unresponsiveness). Reactivity was best maintained with propofol, while only minimally preserved with dexmedetomidine and sevoflurane. Thus, it may be difficult to harness reactivity for depth-of-anaesthesia monitoring., (© 2014 The Association of Anaesthetists of Great Britain and Ireland.)

Objective: Repetitive transcranial magnetic stimulation (rTMS) has shown potential in reducing tinnitus symptoms. We evaluated effects of electric field (E-field) navigated rTMS targeted neuroanatomically according to tinnitus pitch., Design: In this open methodological pilot study, the patients received E-field navigated 1-Hz rTMS in daily treatment sessions to the left superior temporal gyrus, targeted according to tonotopic representation of their individual tinnitus pitch. Patients rated their tinnitus intensity and annoyance with a numeric rating scale (NRS) from 0 to 10 at the baseline and after each rTMS session. They also rated their global impression of change (scale - 3 to + 3) after the treatment., Study Sample: Thirteen patients (mean age 53 years; 10 men, 3 women) with chronic, intractable tinnitus., Results: The mean intensity was 7.1 (SD 1.8) at the baseline, decreasing to 4.5 (SD 2.2) after the rTMS (p < 0.0001). The mean annoyance 7.0 (SD 1.8) at the baseline decreased to 4.0 (SD 2.4) after the treatment (p < 0.0001). Intensity diminished at least 30% in 8/13 patients and annoyance in 9/13 patients. A total of 10/13 patients felt subjective benefit from the treatment., Conclusions: These preliminary observations suggest that E-field-rTMS may improve the current treatment options for intractable tinnitus.

Introduction: The incidence of Creutzfeldt-Jakob disease (CJD) in Finland in 1974-1989 was reported to be 0.6/1 000 000. Our aim was to compare the current incidence of CJD in Finland with the earlier incidence and also study the diagnostics of the disease., Methods: Register study of the Finnish CJD cases from 1997 to 2012 and the clinical data of CJD patients within the Hospital District of Southwest Finland from 2007 to 2013., Results: There were 119 cases. The average yearly incidence was 1.36-1.44/1 000 000., Conclusions: Compared with the previous study, the incidence in Finland appears to have increased. The change is propably due to increased awareness and improved diagnostic methods.

A group of European experts was commissioned to establish guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS) from evidence published up until March 2014, regarding pain, movement disorders, stroke, amyotrophic lateral sclerosis, multiple sclerosis, epilepsy, consciousness disorders, tinnitus, depression, anxiety disorders, obsessive-compulsive disorder, schizophrenia, craving/addiction, and conversion. Despite unavoidable inhomogeneities, there is a sufficient body of evidence to accept with level A (definite efficacy) the analgesic effect of high-frequency (HF) rTMS of the primary motor cortex (M1) contralateral to the pain and the antidepressant effect of HF-rTMS of the left dorsolateral prefrontal cortex (DLPFC). A Level B recommendation (probable efficacy) is proposed for the antidepressant effect of low-frequency (LF) rTMS of the right DLPFC, HF-rTMS of the left DLPFC for the negative symptoms of schizophrenia, and LF-rTMS of contralesional M1 in chronic motor stroke. The effects of rTMS in a number of indications reach level C (possible efficacy), including LF-rTMS of the left temporoparietal cortex in tinnitus and auditory hallucinations. It remains to determine how to optimize rTMS protocols and techniques to give them relevance in routine clinical practice. In addition, professionals carrying out rTMS protocols should undergo rigorous training to ensure the quality of the technical realization, guarantee the proper care of patients, and maximize the chances of success. Under these conditions, the therapeutic use of rTMS should be able to develop in the coming years., (Copyright © 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

We tested whether variation of the dopamine D2 receptor (DRD2) gene contributes to individual differences in thermal pain sensitivity and analgesic efficacy of repetitive transcranial magnetic stimulation (rTMS) in healthy subjects (n=29) or susceptibility to neuropathic pain in patients with neurophysiologically confirmed diagnosis (n=16). Thermal sensitivity of healthy subjects was assessed before and after navigated rTMS provided to the S1/M1 cortex. All subjects were genotyped for the DRD2 gene 957C>T and catechol-O-methyltransferase (COMT) protein Val158Met polymorphisms. In healthy subjects, 957C>T influenced both innocuous and noxious thermal detection thresholds that were lowest in 957TT homozygotes (P values from .0277 to .0462). rTMS to S1 cortex had analgesic effect only in 957TT homozygote genotype (P=.0086). In patients, prevalence of 957TT homozygote genotype was higher than in a healthy Finnish population (50% vs 27%; P=.0191). Patients with 957TT genotype reported more severe pain than patients with other genotypes (P=.0351). COMT Val158Met polymorphism was not independently associated with the studied variables. Genetic regulation of DRD2 function by 957C>T polymorphism thus seems to influence thermal and pain sensitivity, its modulation by rTMS, and susceptibility to neuropathic pain. This indicates a central role for the dopamine system and DRD2 in pain and analgesia. This may have clinical implications regarding individualized selection of patients for rTMS treatment and assessment of risks for neuropathic pain., (Copyright © 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Background: Classic abdominoplasty for a transverse rectus abdominis musculocutaneous (TRAM) flap breast reconstruction impairs abdominal somatosensory function at the donor site. The aim of this study was to investigate whether the type of surgical procedure has an effect on somatosensory alterations of abdominal skin after TRAM flap breast reconstruction., Methods: Sixty patients (mean ± SD age, 50 ± 6.0 years) who underwent microvascular TRAM flap breast reconstruction and 20 healthy subjects (control group; mean age, 46 ± 6.7 years) participated in the study. Twenty patients had bilateral-nerve anastomosis, 20 had single-nerve anastomosis, and 20 underwent no nerve dissection for the TRAM flap. Clinical sensory examination and tactile and thermal quantitative sensory testing were performed and a patient questionnaire was administered at a mean of 2 to 4.5 years after surgery., Results: All surgical techniques produced significant sensory impairment below the umbilicus, but there were no significant differences in total sensibility scores between the groups with single-nerve (mean sensibility score, 21.98 ± 2.7) and double-nerve (mean sensibility score, 20.71 ± 3.6) anastomosis of the TRAM flap. The best sensibility scores were found in the group with single-nerve dissection. Fifteen percent of patients complained of mild pain, and 13 percent felt occasional tactile hyperesthesia in their abdominal skin, mostly around the umbilicus and scars., Conclusions: In this study, unilateral or bilateral nerve dissection when preparing and lifting a TRAM flap did not seem to increase sensory alterations or postoperative pain in the abdominal donor site after breast reconstruction surgery. Cautious microneurovascular dissection techniques may even improve sensory recovery of the abdominal skin after TRAM flap breast reconstruction surgery.

One of the greatest challenges of modern neuroscience is to discover the neural mechanisms of consciousness and to explain how they produce the conscious state. We sought the underlying neural substrate of human consciousness by manipulating the level of consciousness in volunteers with anesthetic agents and visualizing the resultant changes in brain activity using regional cerebral blood flow imaging with positron emission tomography. Study design and methodology were chosen to dissociate the state-related changes in consciousness from the effects of the anesthetic drugs. We found the emergence of consciousness, as assessed with a motor response to a spoken command, to be associated with the activation of a core network involving subcortical and limbic regions that become functionally coupled with parts of frontal and inferior parietal cortices upon awakening from unconsciousness. The neural core of consciousness thus involves forebrain arousal acting to link motor intentions originating in posterior sensory integration regions with motor action control arising in more anterior brain regions. These findings reveal the clearest picture yet of the minimal neural correlates required for a conscious state to emerge.

Primary burning mouth syndrome (BMS) is severe, disabling and chronic intraoral pain condition for which no local or systemic cause can be found and clinical examination is normal. It mostly affects elderly citizens, especially postmenopausal women with prevalence up to 12-18%. In addition to spontaneous burning pain, patients may complain of taste alterations. Recent neurophysiologic, psychophysical, neuropathological, and functional imaging studies have elucidated that several neuropathic mechanisms, mostly subclinical, act at different levels of the neuraxis and contribute to the pathophysiology of primary BMS. Demonstration of loss of small diameter nerve fibres in the tongue epithelium explains thermal hypoesthesia and increase in taste detection thresholds found in quantitative sensory testing. As in neuropathic pain, decreased brain activation to heat stimuli has been demonstrated with fMRI in BMS patients. However, it seems that the clinical diagnosis of primary BMS encompasses at least three distinct, subclinical neuropathic pain states that may overlap in individual patients. The first subgroup (50-65%) is characterized by peripheral small diameter fibre neuropathy of intraoral mucosa. The second subgroup (20-25%) consists of patients with subclinical lingual, mandibular, or trigeminal system pathology that can be dissected with careful neurophysiologic examination but is clinically indistinguishable from the other two subgroups. The third subgroup (20-40%) fits the concept of central pain that may be related to hypofunction of dopaminergic neurons in the basal ganglia. The neurogenic factors acting in these subgroups differ, and will require different treatment strategies. In the future, with proper use of diagnostic tests, BMS patients may benefit from interventions specifically targeted at the underlying pathophysiological mechanisms., (Copyright © 2011 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Purpose: The effect of the type of nerve injury on subjective sensory disturbances and recovery has not been addressed in orthognathic surgery. Using neurophysiologic monitoring during 19 bilateral sagittal split osteotomy operations, we were able to classify intraoperative inferior alveolar nerve injuries as either axonal or demyelinating. This study aimed to analyze the quality and extent of the subjective sensations experienced by the patients after these 2 injury types at different time points up to 12 months., Materials and Methods: Of the 36 injured nerves, 21 showed signs of demyelinating injury and 15 showed signs of axonal damage. The quality of subjective sensory symptoms was asked about at 2 weeks and 1, 3, 6, and 12 months postoperatively and classified into 4 categories: normal, negative, positive (including pain), and mixed sensations. In addition, the extent of the sensory alteration was determined by measuring the affected skin regions from symptom charts., Results: The quantity, quality, and evolution of experienced subjective sensations differed between the injury types during follow-up: Subjective sensations normalized more rapidly after demyelinating-type injuries than after axonal-type injuries. Persistence of mixed sensation patterns at 3 months and appearance instead of disappearance of positive sensory phenomena after 3 months indicated axonal damage. Painful sensations at 1 month or later after surgery indicated axonal damage and predicted poor recovery and more long-term sequelae., Conclusions: Postoperative pain at 1 month and type of nerve injury are important prognostic factors for the persistence of subjective symptoms and development of neuropathic pain., (Copyright © 2011 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: The aims of the present study were to investigate whether microneurovascular breast reconstruction with a free transverse rectus abdominis musculocutaneous (TRAM) flap and nerve repair with nerves other than ThIV and ThXI improve sensory recovery of the breast compared to traditional free TRAM flap without nerve repair, and which nerve is optimal for the neural anastomosis of the flap., Methods: Twenty breast cancer patients underwent breast reconstruction with a free TRAM flap and nerve repair (neuro-TRAM) with the best available nerve from the axillary area and 20 control patients had traditional free TRAM flap without nerve repair (standard-TRAM). Neurorrhaphy was done by end-to-end or end-to-side techniques. Sensory and quantitative sensory testings (QST) were performed. Patient satisfaction was evaluated by a clinical questionnaire. The results were analysed by Mann-Whitney tests., Results: Mean follow-up was 32 months for the neuro-TRAM, and 54 months for the standard-TRAM group. Sensory outcome was better in the neuro-TRAM group (sensory score 45% of that of the contralateral breast) than in the standard-TRAM group (26% of the contralateral side). The median (quartiles) of total scores in the operated breasts was 12.9 (9.5-19.2) in neuro-TRAM group and 8.1 (3.5-10.7) in standard-TRAM group (Mann-Whitney Test (p=0.006)). All nerves available in the thoracic and axillary areas and both of the anastomosis techniques were successful in the reinnervation procedure. Nerve repair did not influence overall patient satisfaction., Conclusions: This study indicates that any nerve repair results in improved sensory recovery after TRAM flap breast reconstruction. Any nerve available for anastomosis in the recipient site is potentially able to provide moderately good cutaneous sensibility to the TRAM-breast., (Copyright © 2010 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

This case report elucidates pitfalls of clinical and radiologic investigations of neuropathic pain due to trigeminal pathology, and utility of neurophysiologic examination when diagnosing facial pain. Our patient was a 63-year-old woman who developed acute, severe facial pain, first located behind the left eye. Neuralgic exacerbations, paresthesia within lower face on the left and restricted mouth opening occurred during the course of the disease with gradual progression. Brain MRI and CT scans were interpreted as normal at 4 and 10 months after symptom onset. At 9 months, detailed neurophysiologic examination showed severe chronic mandibular neuropathy at the left oval foramen with more prominent disturbance of the thick myelinated nerve fibers than the small fibers suggesting compressive etiology. Guided by the neurophysiologic findings, 11 months after the onset of the symptoms, a new brain MRI with contrast enhancement revealed metastatic adenocarcinoma of the left temporal bone along the mandibular nerve, exactly matching the site indicated by the neurophysiologic examination. Neurophysiologic tests offer cost-effective, sensitive tools for screening and accurate level diagnostics of neuropathy and neuropathic pain, which can be utilized also in the diagnosis of facial pain. In addition, whenever there are progressing neurologic deficits or neurophysiologic signs indicating expansive lesion, despite initially normal findings in the brain imaging studies, repeated MRI examinations are warranted, preferably focusing to the 'neurophysiologic region of interest' to avoid radiologic sampling errors. As no isolated technique achieves 100% diagnostic accuracy, only rational combinations of different methods will result in correct diagnosis of facial pain without unnecessary delays. Treatment of neuropathic pain is often delayed because of difficulties in reaching the correct diagnosis. During the work-up, many differential diagnostic alternatives have to be considered, also in patients with chronic orofacial pain. Table 1 shows the most important differential diagnoses of orofacial pain.