The blink reflex and its modulation - Part 2: Pathophysiology and clinical utility.

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.

A prospective, double-blind, pilot, randomized, controlled trial of an "embodied" virtual reality intervention for adults with low back pain.

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.

Successful suppression of musical hallucinations with low-frequency rTMS of the left temporo-parietal junction: A case report.

BACKGROUND: Inhibitory low frequency repetitive transcranial magnetic stimulation (rTMS) of the temporo-parietal area has been applied to treat both auditory verbal hallucinations as well as tinnitus. OBJECTIVE: We hypothesized that 1 Hz rTMS to the left temporoparietal junction (TPJ) may be beneficial in alleviating musical hallucinations (MH), another condition with auditory experiences in the absence of an external source. METHODS: Here we describe a patient with almost insufferable life-long MH with comorbid depression, who received inhibitory rTMS to the left TPJ as well as the right dorsolateral prefrontal cortex (DLPFC). RESULTS: The intrusiveness and frequency of her MH as well as her depressive symptoms alleviated quickly and substantially, and once-a-week maintenance therapy with rTMS seemed to preserve this amelioration. Future studies will hopefully reveal whether this is a viable treatment approach for other patients suffering from MH with or without comorbid depression.

Continuous positive airway pressure treatment may negatively affect auditory maturation in preterm infants.

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.

Developing a research diagnostic criteria for burning mouth syndrome: Results from an international Delphi process.

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.

Non-invasive therapeutic brain stimulation for treatment of resistant focal epilepsy in a teenager.

AIMS: A 13-year-old boy with symptomatic focal epilepsy due to a right parietal dysembryoplastic neuroepithelial tumor (DNET) presented pre- and post-operatively fluctuating tinnitus and sensory symptoms which became persistent after incomplete tumor resection. He received low-frequency rTMS treatment and cathodal tDCS treatment. METHODS: Case report with clinical details and pictures from rTMS and tDCS stimulation targets. RESULTS: The patient became symptom free with an initial low-frequency rTMS treatment series targeted to the EEG-verified epileptic zone followed by maintenance therapy at the same region with cathodal tDCS at home. CONCLUSIONS: Both rTMS and tDCS could be more often used in adolescents when drug treatment and surgery do not cease focal epilepsy, here with fluctuating tinnitus.

Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS): An update (2014-2018).

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.

Differential Diagnosis of Chronic Neuropathic Orofacial Pain: Role of Clinical Neurophysiology.

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.

Neuronavigated Versus Non-navigated Repetitive Transcranial Magnetic Stimulation for Chronic Tinnitus: A Randomized Study.

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: F3 = 7.34, p = .0006), annoyance ( F3 = 4.45, p = .0093), distress ( F3 = 5.04, p = .0051), and THI scores ( F4 = 17.30, p < .0001) decreased in both groups with non-significant differences between the groups, except for tinnitus intensity ( F3 = 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.

Neurophysiology and genetics of burning mouth syndrome.

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.

Perinatal nutrition impacts on the functional development of the visual tract in infants.

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.

Validation of diagnostic methods for traumatic sensory neuropathy and neuropathic pain.

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.

Dopaminergic and serotonergic mechanisms in the modulation of pain: In vivo studies in human brain.

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 D2/D3 receptor availability particularly in the striatum and serotonin 5-HT1A and 5-HT2A receptor availabilities in the cortex predict the subject's response to tonic experimental pain. High availability of dopamine D2/D3 or serotonin 5-HT2A receptors is associated with high pain intensity, whereas high availability of 5-HT1A receptors associates with low pain intensity. Chronic neuropathic pain is associated with high striatal dopamine D2/D3 receptor availability, for which low endogenous dopamine tone is a plausible explanation, although a compensatory increase in striatal dopamine D2/D3 receptor density may also contribute. In contrast, chronic musculoskeletal pain is associated with low baseline availability of striatal dopamine D2/D3 receptors. In healthy subjects, brain serotonin 5-HT1A as well as dopamine D2/D3 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-HT1A 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 D2/D3 receptors. These findings suggest that dopamine acting on striatal dopamine D2/D3 receptors and serotonin acting on cortical 5-HT1A and 5-HT2A receptors contribute to top-down pain regulation in humans.

Nerve conduction study of the three supraclavicular nerve branches.

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.

Psychiatric (Axis I) and personality (Axis II) disorders and subjective psychiatric symptoms in chronic tinnitus.

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).

Is burning mouth syndrome a neuropathic pain condition?

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.