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ABSTRACT BACKGROUND AND OBJECTIVES: Conventional electrodiagnostic studies (EDX) are frequently used to support the diagnosis of peripheral neuropathic pain. However, routine EDX has poor diagnostic yield for identifying small fiber neuropathy, which may be cause of neuropathic pain in some patients. This study aimed to assess the gain in diagnostic yield brought by adding pain-related evoked potentials with concentric electrode (CN-PREP) and nociceptive withdrawal reflex (NWR) assessments to EDX. METHODS: Transversal observational accuracy study which included patients referred to routine EDX in a tertiary-care hospital who reported chronic neuropathic pain in their lower limbs. Besides routine EDX, subjects underwent CN-PREP and NWR assessments. Diagnostic yield and tolerability were examined and compared between test studies. RESULTS: The study enrolled 100 patients (54% female), with 57 ± 12 years. EDX was altered in 47% of all patients. The addition of CN-PREP alone, and NWR combined with CN-PREP increased diagnostic yield to 69% and 72%, respectively. CN-PREP proved to be well tolerable, while NWR was associated with higher test-related pain intensity and discontinuation rate (9% vs. 0%). Considering EDX as the reference test, CN-PREP sensitivity was 85.1% and specificity 58.5%. CONCLUSION: Combining CN-PREP with the routine EDX for patients with neuropathic pain is feasible and results in increased diagnostic yield. Conversely, the addition of NWR to the aforementioned tests provides little improvement to this yield and is less tolerable to the patient. Further studies are needed to determine the actual sensitivity and specificity of CN-PREP when compared to the gold-standard for small fiber neuropathy diagnosis, i.e. intraepidermal nerve fiber density assessment.

RESUMO JUSTIFICATIVA E OBJETIVOS: Estudos convencionais de eletrodiagnóstico (EDX) são frequentemente usados para apoiar o diagnóstico de dor neuropática periférica. No entanto, o EDX de rotina tem baixo rendimento diagnóstico para identificar neuropatia de pequenas fibras. O objetivo deste estudo foi avaliar o ganho no rendimento diagnóstico pela adição de avaliações de potenciais evocados relacionados à dor com eletrodo concêntrico (CN-PREP) e reflexo de retirada nociceptiva (NWR) ao EDX. MÉTODOS: Estudo de precisão observacional transversal que incluiu pacientes encaminhados para EDX de rotina com dor neuropática crônica em membros inferiores. Além do EDX de rotina, os indivíduos foram submetidos às avaliações CN-PREP e NWR. O rendimento diagnóstico e a tolerabilidade foram examinados e comparados entre os estudos de teste. RESULTADOS: O estudo envolveu 100 pacientes (54% mulheres), com 57 ± 12 anos. O EDX estava alterado em 47%. A adição de CN-PREP sozinho e NWR combinado com CN-PREP aumentou o rendimento diagnóstico para 69% e 72%, respectivamente. O CN-PREP provou ser bem tolerável, enquanto o NWR foi associado a maior intensidade de dor relacionada ao teste e taxa de descontinuação (9% vs. 0%). Considerando o EDX como teste de referência, a sensibilidade do CN-PREP foi de 85,1% e a especificidade de 58,5%. CONCLUSÃO: A combinação do CN-PREP com o EDX de rotina para pacientes com dor neuropática é viável e resulta em maior rendimento diagnóstico. Já a adição de NWR aos testes mencionados fornece pouca melhora nesse rendimento e é menos tolerável para o paciente. Mais estudos são necessários para determinar a real sensibilidade e especificidade do CN-PREP quando comparado ao padrão-ouro para diagnóstico de neuropatia de pequenas fibras, ou seja, a avaliação da densidade de fibras nervosas intraepidérmicas.

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BACKGROUND: Dystonia is associated with disabling nonmotor symptoms like chronic pain (CP), which is prevalent in dystonia and significantly impacts the quality of life (QoL). There is no validated tool for assessing CP in dystonia, which substantially hampers pain management. OBJECTIVE: The aim was to develop a CP classification and scoring system for dystonia. METHODS: A multidisciplinary group was established to develop the Dystonia-Pain Classification System (Dystonia-PCS). The classification of CP as related or unrelated to dystonia was followed by the assessment of pain severity score, encompassing pain intensity, frequency, and impact on daily living. Then, consecutive patients with inherited/idiopathic dystonia of different spatial distribution were recruited in a cross-sectional multicenter validation study. Dystonia-PCS was compared to validated pain, mood, QoL, and dystonia scales (Brief Pain Inventory, Douleur Neuropathique-4 questionnaire, European QoL-5 Dimensions-3 Level Version, and Burke-Fahn-Marsden Dystonia Rating Scale). RESULTS: CP was present in 81 of 123 recruited patients, being directly related to dystonia in 82.7%, aggravated by dystonia in 8.8%, and nonrelated to dystonia in 7.5%. Dystonia-PCS had excellent intra-rater (Intraclass Correlation Coefficient - ICC: 0.941) and inter-rater (ICC: 0.867) reliability. In addition, pain severity score correlated with European QoL-5 Dimensions-3 Level Version's pain subscore (r = 0.635, P < 0.001) and the Brief Pain Inventory's severity and interference scores (r = 0.553, P < 0.001 and r = 0.609, P < 0.001, respectively). CONCLUSIONS: Dystonia-PCS is a reliable tool to categorize and quantify CP impact in dystonia and will help improve clinical trial design and management of CP in patients affected by this disorder. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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OBJECTIVES: It is not known whether cortical plastic changes reported in low-back pain (LBP) are present in all etiologies of LBP. Here we report on the assessment of patients with three LBP conditions: non-specific-LBP (ns-LBP), failed back surgery syndrome (FBSS), and sciatica (Sc). METHODS: Patients underwent a standardized assessment of clinical pain, conditioned pain modulation (CPM), and measures of motor evoked potential (MEPs)-based motor corticospinal excitability (CE) by transcranial magnetic stimulation, including short interval intracortical inhibition (SICI), and intracortical facilitation (ICF). Comparisons were also made with normative data from sex- and age-matched healthy volunteers. RESULTS: 60 patients (42 women, 55.1±9.1 years old) with LBP were included (20 in each group). Pain intensity was higher in patients with neuropathic pain [FBSS (6.8±1.3), and Sc (6.4±1.4)] than in those with ns-LBP (4.7±1.0, P<0.001). The same was shown for pain interference (5.9±2.0, 5.9±1.8, 3.2±1.9, P<0.001), disability (16.4±3.3, 16.3±4.3, 10.4±4.3, P<0.001), and catastrophism (31.1±12.3, 33.0±10.4, 17.4±10.7, P<0.001) scores for FBSS, Sc, and ns-LBP groups, respectively. Patients with neuropathic pain (FBSS, Sc) had lower CPM (-14.8±1.9, -14.1±16.7, respectively) compared to ns-LBP (-25.4±16.6; P<0.02). 80.0% of the FBSS group had defective ICF compared to the other two groups (52.5% for ns-LBP, P=0.025 and 52.5% for Sc, P=0.046). MEPs (140%-rest motor threshold) were low in 50.0% of patients in the FBSS group compared to 20.0% of ns-LBP (P=0.018) and 15.0% of Sc (P=0.001) groups. Higher MEPs were correlated with mood scores (r=0.489), and with lower neuropathic pain symptom scores(r=-0.415) in FBSS. CONCLUSIONS: Different types of LBP were associated with different clinical, CPM and CE profiles, which were not uniquely related to the presence of neuropathic pain. These results highlight the need to further characterize patients with LBP in psychophysics and cortical neurophysiology studies.

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PURPOSE OF REVIEW: Chronic pain is the most prevalent symptomatic disease worldwide. Nonpharmacological interventions, such as noninvasive neuromodulation (NIN), have gained scientific evidence to support their use as an add-on strategy to pharmacological pain management. The most studied NIN technique is repetitive transcranial magnetic stimulation (rTMS). This review aims to identify the current indications for rTMS in the treatment of chronic pain and its new perspectives. RECENT FINDINGS: High-frequency rTMS delivered to the primary motor cortex (M1) is currently a treatment strategy with the most literature support for decreased pain intensity and alleviation of associated symptoms in peripheral neuropathic pain, fibromyalgia and migraine. It has been shown that stimulation sessions are well tolerated and tolerable, and the effects of daily stimulation sessions can be prolonged by spaced maintenance stimulation sessions. Despite its efficacy, some individuals will not respond to rTMS targeted to M1. Lines of research are currently being developed to improve rTMS efficacy either by exploring new therapeutic targets, using novel stimulation parameters or more comprehensively profiling patients who are likely to respond to this treatment modality. SUMMARY: Noninvasive brain stimulation for chronic TMS pain is a well tolerated and reasonable add-on treatment approach for pain syndromes such as neuropathic pain, migraine and fibromyalgia. Strategies to improve its efficacy are an active field of research.

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OBJECTIVES: The posterior-superior insula (PSI) has been shown to be a safe and potentially effective target for neuromodulation in peripheral neuropathic pain (PNP) in humans and animal models. However, it remains unknown whether there is a measurable responder profile to PSI stimulation. Two factors were hypothesized to influence the response of repetitive transcranial magnetic stimulation (rTMS) of the PSI: differences in rTMS target (discrete subregions of the PSI) or PNP phenotype. METHODS: This is a secondary analysis from a randomized, double-blind, sham-controlled, cross-over trial assessing PSI-rTMS in PNP (N = 31, 5 days rTMS) (10.1016/j.neucli.2021.06.003). Active PSI-rTMS true responders (>50% pain reduction from baseline after active but not after sham series of treatment) were compared with not true responders, to determine whether they differed with respect to 1) rTMS neuro-navigational target coordinates, and/or 2) specific neuropathic pain symptom inventory (NPSI) clusters (pinpointed pain, evoked pain, and deep pain) at baseline. RESULTS: Mean rTMS target coordinates did not differ between true (n = 45.1%) and not true responders (p = 0.436 for X, p = 0.120 for Y, and p = 0.116 for Z). The Euclidian distance between true and not true responders was 4.04 mm. When comparing differences in responders between NPSI clusters, no participant within the evoked pain cluster was a true responder (p = 0.024). CONCLUSION: Response to PSI-rTMS may depend on pain cluster subtype rather than on differences in targeting within the PSI.

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OBJECTIVES: Peripheral neuropathic pain (pNeP) is prevalent, and current treatments, including drugs and motor cortex repetitive transcranial magnetic stimulation (rTMS) leave a substantial proportion of patients with suboptimal pain relief. METHODS: We explored the intensity and short-term duration of the analgesic effects produced in pNeP patients by 5 days of neuronavigated deep rTMS targeting the posterior superior insula (PSI) with a double-cone coil in a sham-controlled randomized cross-over trial. RESULTS: Thirty-one pNeP patients received induction series of five active or sham consecutive sessions of daily deep-rTMS to the PSI in a randomized sequence, with a washout period of at least 21 days between series. The primary outcome [number of responders (>50% pain intensity reduction from baseline in a numerical rating scale ranging from 0 to 10)] was significantly higher after real (58.1%) compared to sham (19.4%) stimulation (p = 0.002). The number needed to treat was 2.6, and the effect size was 0.97 [95% CI (0.6; 1.3)]. One week after the 5th stimulation day, pain scores were no longer different between groups, and no difference in neuropathic pain characteristics and interference with daily living were present. No major side effects occurred, and milder adverse events (i.e., short-lived headaches after stimulation) were reported in both groups. Blinding was effective, and analgesic effects were not affected by sequence of the stimulation series (active-first or sham-first), age, sex or pain duration of participants. DISCUSSION: PSI deep-rTMS was safe in refractory pNeP and was able to provide significant pain intensity reduction after a five-day induction series of treatments. Post-hoc assessment of neuronavigation targeting confirmed deep-rTMS was delivered within the boundaries of the PSI in all participants. CONCLUSION: PSI deep-rTMS provided significant pain relief during 5-day induction sessions compared to sham stimulation.

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BACKGROUND: We assessed whether COVID-19 is associated with de novo pain and de novo chronic pain (CP). METHODS: This controlled cross-sectional study was based on phone interviews of patients discharged from hospital after COVID-19 compared to the control group composed of individuals hospitalized during the same period due to non-COVID-19 causes. Patients were classified as having previous CP based on the ICD-11/IASP criteria, de novo pain (i.e. any new type of pain, irrespective of the pain status before hospital stay), and de novo CP (i.e. persistent or recurring de novo pain, lasting more than 3 months) after COVID-19. We assessed pain prevalence and its characteristics, including headache profile, pain location, intensity, interference, and its relationship with fatigue, and persistent anosmia. Forty-six COVID-19 and 73 control patients were included. Both groups had similar sociodemographic characteristics and past medical history. RESULTS: Length of in-hospital-stay and ICU admission rates were significantly higher amongst COVID-19 survivours, while mechanical ventilation requirement was similar between groups. Pre-hospitalisation pain was lower in COVID-19 compared to control group (10.9% vs. 42.5%; p = 0.001). However, the COVID-19 group had a significantly higher prevalence of de novo pain (65.2% vs. 11.0%, p = 0.001), as well as more de novo headache (39.1%) compared to controls (2.7%, p = 0.001). New-onset CP was 19.6% in COVID-19 patients and 1.4% (p = 0.002) in controls. These differences remained significant (p = 0.001) even after analysing exclusively (COVID: n = 40; controls: n = 34) patients who did not report previous pain before the hospital stay. No statistically significant differences were found for mean new-onset pain intensity and interference with daily activities between both groups. COVID-19 pain was more frequently located in the head/neck and lower limbs (p < 0.05). New-onset fatigue was more common in COVID-19 survivours necessitating inpatient hospital care (66.8%) compared to controls (2.5%, p = 0.001). COVID-19 patients who reported anosmia had more new-onset pain (83.3%) compared to those who did not (48.0%, p = 0.024). CONCLUSION: COVID-19 was associated with a significantly higher prevalence of de novo CP, chronic daily headache, and new-onset pain in general, which was associated with persistent anosmia. SIGNIFICANCE: There exists de novo pain in a substantial number of COVID-19 survivours, and some develop chronic pain. New-onset pain after the infection was more common in patients who reported anosmia after hospital discharge.

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Background: Novel coronavirus disease (COVID-19) morbidity is not restricted to the respiratory system, but also affects the nervous system. Non-invasive neuromodulation may be useful in the treatment of the disorders associated with COVID-19. Objective: To describe the rationale and empirical basis of the use of non-invasive neuromodulation in the management of patients with COVID-10 and related disorders. Methods: We summarize COVID-19 pathophysiology with emphasis of direct neuroinvasiveness, neuroimmune response and inflammation, autonomic balance and neurological, musculoskeletal and neuropsychiatric sequela. This supports the development of a framework for advancing applications of non-invasive neuromodulation in the management COVID-19 and related disorders. Results: Non-invasive neuromodulation may manage disorders associated with COVID-19 through four pathways: (1) Direct infection mitigation through the stimulation of regions involved in the regulation of systemic anti-inflammatory responses and/or autonomic responses and prevention of neuroinflammation and recovery of respiration; (2) Amelioration of COVID-19 symptoms of musculoskeletal pain and systemic fatigue; (3) Augmenting cognitive and physical rehabilitation following critical illness; and (4) Treating outbreak-related mental distress including neurological and psychiatric disorders exacerbated by surrounding psychosocial stressors related to COVID-19. The selection of the appropriate techniques will depend on the identified target treatment pathway. Conclusion: COVID-19 infection results in a myriad of acute and chronic symptoms, both directly associated with respiratory distress (e.g., rehabilitation) or of yet-to-be-determined etiology (e.g., fatigue). Non-invasive neuromodulation is a toolbox of techniques that based on targeted pathways and empirical evidence (largely in non-COVID-19 patients) can be investigated in the management of patients with COVID-19.

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A expressão facial de dor pode provocar diferentes reações comportamentais. Todavia, ainda não está claro se a face de dor evoca respostas motoras mais lentas ou mais rápidas, quando comparada à expressão com valência positiva, e sua interação com o sexo da pessoa que demonstra a expressão facial. O objetivo desse trabalho foi avaliar o padrão de resposta motora de mulheres em uma tarefa de reconhecimento de expressões faciais de alegria e dor em faces femininas e masculinas. Na tarefa experimental, 32 estudantes classificaram emoções faciais dinâmicas de homens e mulheres entre as opções de alegria e dor, sendo registradas as respostas de tempo de reação manual (TRM). A ANOVA indicou uma diferença entre faces masculinas e femininas apenas para a identificação da dor (p = 0,001), mas não da alegria (p = 0,064). Neste caso, a dor foi reconhecida mais rapidamente na face masculina (TRM = 625,1 ms) que na face feminina (TRM = 668,0 ms). Considera-se que este padrão de resposta motora pode estar relacionado à detecção de situações potencialmente ameaçadoras no ambiente, com possibilidade de ser estudado em pessoas com dor crônica.

The facial expression of pain can provoke different behavioral reactions. However, it is not clear whether the face of pain evokes slower or faster motor responses when compared with positive valence expression and its interaction with the gender of the person who demonstrates facial expression. The objective of this work was to evaluate the motor response pattern of women in a task of recognizing facial expressions of happiness and pain in female and male faces. In the experimental task, 32 students classified dynamic facial emotions of men and women among the options of happiness and pain, and manual reaction time (MRT) responses were recorded. The ANOVA indicated a difference between male and female faces only for the identification of pain (p = 0.001), but not happiness (p = 0.064). In this case, the pain was recognized more quickly on the male face (TRM = 625.1 ms) compared to the female face (TRM = 668.0 ms). It is considered that this pattern of motor response may be related to the detection of potentially threatening situations in the environment, with the possibility of being studied in people with chronic pain.

La expresión facial del dolor puede provocar diferentes reacciones conductuales. Sin embargo, aún no está claro si el rostro de dolor evoca respuestas motoras más lentas o más rápidas, en comparación con la expresión con valencia positiva, y su interacción con el sexo de la persona que demuestra expresión facial. El objetivo de este trabajo fue evaluar el patrón de respuesta motora de las mujeres en una tarea de reconocimiento de expresiones faciales de alegría y dolor en rostros femeninos y masculinos. En la tarea experimental, 32 estudiantes clasificaron las emociones faciales dinámicas de hombres y mujeres entre las opciones de alegría y dolor, y se registraron las respuestas de tiempo de reacción manual (TRM). El ANOVA indicó una diferencia entre los rostros masculinos y femeninos solo para la identificación del dolor (p = 0.001), pero no alegría (p = 0.064). En este caso, el dolor se reconoció más rápidamente en el rostro masculino (TRM = 625.1 ms) comparado al rostro femenino (TRM = 668.0 ms). Se considera que este patrón de respuesta motora puede estar relacionado con la detección de situaciones potencialmente amenazantes en el entorno, con posibilidad de ser estudiado en personas con dolor crónico.