The deep and the deeper: Spinal cord and deep brain stimulation for neuropathic pain.

Neuropathic pain occurs in people experiencing lesion or disease affecting the somatosensorial system. It is present in 7 % of the general population and may not fully respond to first- and second-line treatments in up to 40 % of cases. Neuromodulation approaches are often proposed for those not tolerating or not responding to usual pharmacological management. These approaches can be delivered surgically (invasively) or non-invasively. Invasive neuromodulation techniques were the first to be employed in neuropathic pain. Among them is spinal cord stimulation (SCS), which consists of the implantation of epidural electrodes over the spinal cord. It is recommended in some guidelines for peripheral neuropathic pain. While recent studies have called into question its efficacy, others have provided promising data, driven by advances in techniques, battery capabilities, programming algorithms and software developments. Deep brain stimulation (DBS) is another well-stablished neuromodulation therapy routinely used for movement disorders; however, its role in pain management remains limited to specific research centers. This is not only due to variable results in the literature contesting its efficacy, but also because several different brain targets have been explored in small trials, compromising comparisons between these studies. Structures such as the periaqueductal grey, posterior thalamus, anterior cingulate cortex, ventral striatum/anterior limb of the internal capsule and the insula are the main targets described to date in literature. SCS and DBS present diverse rationales for use, mechanistic backgrounds, and varying levels of support from experimental studies. The present review aims to present their methodological details, main mechanisms of action for analgesia and their place in the current body of evidence in the management of patients with neuropathic pain, as well their particularities, effectiveness, safety and limitations.

ASSESSMENT OF HUMAN FETUSES UNDERGOING ACUTE PAIN: VALIDATION OF THE FETAL-7 SCALE.

Improvements in fetal ultrasound have allowed for the diagnosis and treatment of fetal diseases in the uterus, often though surgery. However, little attention has been drawn to the assessment of fetal pain. To address this gap, a fetal pain scoring system, known as the Fetal-7 scale, was developed. The present study is a full validation of the Fetal-7 scale. The validation involved two steps: i. four fetuses with indication of surgery were evaluated in three conditions perioperatively: acute pain, rest, and under loud sound stimulation. Facial expressions were assessed by 30 raters using screenshots from 4D high-definition ultrasound films; ii., assessment of sensitivity and specificity of the Fetal-7 scale in 54 healthy fetuses and two fetuses undergoing acute pain after preoperative anesthetic intramuscular injection. There was high internal consistency with Cronbach's alpha (α) of 0.99. Intra-rater reliability of the Fetal-7 scale (test-retest) calculated by intraclass correlation coefficient (ICC) was 0.95, and inter-rater reliability was 0.99. The scale accurately differentiated between healthy fetuses at rest and those experiencing acute pain (sensitivity of 100% and specificity of 94.4%). The Fetal-7 scale is a valid tool for assessing acute pain-related behavior in third trimester fetuses and may be of value in guiding analgesic procedures efficacy in these patients. Further research is warranted to explore the presence of post-operative pain in fetuses and its effects afterbirth. PERSPECTIVE: Recordings with three-dimension ultrasound of human fetuses undergoing pre-operative anesthetic injections revealed complex facial expressions during acute pain, similar to those collected in newborns. This study presented the validation process and cut-off value of the Fetal-7 scale, paving the way for the study of pain before birth in humans.

Evoked oscillatory cortical activity during acute pain: Probing brain in pain by transcranial magnetic stimulation combined with electroencephalogram.

Temporal dynamics of local cortical rhythms during acute pain remain largely unknown. The current study used a novel approach based on transcranial magnetic stimulation combined with electroencephalogram (TMS-EEG) to investigate evoked-oscillatory cortical activity during acute pain. Motor (M1) and dorsolateral prefrontal cortex (DLPFC) were probed by TMS, respectively, to record oscillatory power (event-related spectral perturbation and relative spectral power) and phase synchronization (inter-trial coherence) by 63 EEG channels during experimentally induced acute heat pain in 24 healthy participants. TMS-EEG was recorded before, during, and after noxious heat (acute pain condition) and non-noxious warm (Control condition), delivered in a randomized sequence. The main frequency bands (α, ß1, and ß2) of TMS-evoked potentials after M1 and DLPFC stimulation were recorded close to the TMS coil and remotely. Cold and heat pain thresholds were measured before TMS-EEG. Over M1, acute pain decreased α-band oscillatory power locally and α-band phase synchronization remotely in parietal-occipital clusters compared with non-noxious warm (all p < .05). The remote (parietal-occipital) decrease in α-band phase synchronization during acute pain correlated with the cold (p = .001) and heat pain thresholds (p = .023) and to local (M1) α-band oscillatory power decrease (p = .024). Over DLPFC, acute pain only decreased ß1-band power locally compared with non-noxious warm (p = .015). Thus, evoked-oscillatory cortical activity to M1 stimulation is reduced by acute pain in central and parietal-occipital regions and correlated with pain sensitivity, in contrast to DLPFC, which had only local effects. This finding expands the significance of α and ß band oscillations and may have relevance for pain therapies.

Trans-Spinal Theta Burst Magnetic Stimulation in Parkinson's Disease and Gait Disorders.

BACKGROUND: Gait disorders in patients with Parkinson's disease (PD) can become disabling with disease progression without effective treatment. OBJECTIVES: To investigate the efficacy of intermittent θ burst trans-spinal magnetic stimulation (TsMS) in PD patients with gait and balance disorders. METHODS: This was a randomized, parallel, double-blind, controlled trial. Active or sham TsMS was applied at third thoracic vertebra with 100% of the trans-spinal motor threshold, during 5 consecutive days. Participants were evaluated at baseline, immediately after last session, 1 and 4 weeks after last session. Primary outcome was Total Timed Up and Go (TUG) values comparing active versus sham phases 1 week after intervention. The secondary outcome measurements consisted of motor, gait and balance scales, and questionnaires for quality of life and cognition. RESULTS: Thirty-three patients were included, average age 68.5 (6.4) years in active group and 70.3 (6.3) years in sham group. In active group, Total TUG mean baseline was 107.18 (95% CI, 52.1-116.1), and 1 week after stimulation was 93.0 (95% CI, 50.7-135.3); sham group, Total TUG mean baseline was 101.2 (95% CI, 47.1-155.3) and 1 week after stimulation 75.2 (95% CI 34.0-116.4), P = 0.54. Similarly, intervention had no significant effects on secondary outcome measurements. During stimulation period, five patients presented with mild side effects (three in active group and two in sham group). DISCUSSION: TsMS did not significantly improve gait or balance analysis in patients with PD and gait disorders. The protocol was safe and well tolerated. © 2024 International Parkinson and Movement Disorder Society.

Phenotypical characterization of exteroceptive sensation and pain symptoms on diabetic patients.

BACKGROUD: Diabetic neuropathy (DN) is one of the most common complications of diabetes, affecting about half of individuals with the disease. Among the various symptoms of DN, the development of chronic pain stands out and manifests as exacerbated responses to sensorial stimuli. The conventional clinical treatments used for general neuropathy and associated painful symptoms, still brings uncomplete and unsatisfactory pain relief. Patients with neuropathic pain syndromes are heterogeneous. They present with a variety of sensory symptoms and pain qualities which difficult the correct diagnosis of sensory comorbidities and consequently, the appropriate chronic pain management. AIMS: Herein, we aimed to demonstrate the existence of different sensory profiles on diabetic patients by investigating epidemiological and clinical data on the symptomatology of a group of patients with DN. METHODS: This is a longitudinal and observational study, with a sample of 57 volunteers diagnosed with diabetes from outpatient day clinic of Hospital Universitário of the University of São Paulo-Brazil. After being invited and signed the Informed Consent Form (ICF), patients were submitted to clinical evaluation and filled out pain and quality of life questionnaires. They also performed quantitative sensory test (QST) and underwent skin biopsy for correlation with cutaneous neuropathology. RESULTS: Data demonstrate that 70% of the studied sample presented some type of pain, manifesting in a neuropathic or nociceptive way, what has a negative impact on the life of patients with DM. We also demonstrated a positive association between pain and anxiety and depression, in addition to pain catastrophic thoughts. Three distinct profiles were identified in the sample, separated according to the symptoms of pain: (i) subjects without pain; (ii) with mild or moderate pain; (iii) subjects with severe pain. We also identified through skin biopsy that diabetic patients presented advanced sensory impairment, as a consequence of the degeneration of the myelinated and unmyelinated peripheral fibers. This study characterized the painful symptoms and exteroceptive sensation profile in these diabetic patients, associated to a considerable level of sensory degeneration, indicating, and reinforcing the importance of the long-term clinical monitoring of individuals diagnosed with DM, regarding their symptom profiles and exteroceptive sensitivity.

The incidence, characteristics, impact and risk factors of post-COVID chronic pain in Thailand: A single-center cross-sectional study.

The COVID-19 pandemic has affected millions of individuals worldwide. Pain has emerged as a significant post-COVID-19 symptom. This study investigated the incidence, characteristics, and risk factors of post-COVID chronic pain (PCCP) in Thailand. A cross-sectional study was conducted in participants who had been infected, including those hospitalized and monitored at home by SARS-CoV-2 from August to September 2021. Data were collected for screening from medical records, and phone interviews were done between 3 to 6 months post-infection. Participants were classified into 1) no-pain, 2) PCCP, 3) chronic pain that has been aggravated by COVID-19, or 4) chronic pain that has not been aggravated by COVID-19. Pain interference and quality of life were evaluated with the Brief Pain Inventory and EuroQol Five Dimensions Five Levels Questionnaire. From 1,019 participants, 90% of the participants had mild infection, assessed by WHO progression scale. The overall incidence of PCCP was 3.2% (95% CI 2.3-4.5), with 2.8% (95% CI 2.0-4.1) in mild infection, 5.2% (95% CI 1.2-14.1) in moderate infection and 8.5% (95% CI 3.4-19.9) in severe infection. Most participants (83.3%) reported pain in the back and lower extremities and were classified as musculoskeletal pain and headache (8.3%). Risk factors associated with PCCP, included female sex (relative risk [RR] 2.2, 95% CI 1.0-4.9) and greater COVID-19 severity (RR 3.5, 95% CI 1.1-11.7). Participants with COVID-19-related exacerbated chronic pain displayed higher pain interferences and lower utility scores than other groups. In conclusion, this study highlights the incidence, features, and risk factors of post-COVID chronic pain (PCCP) in Thailand. It emphasizes the need to monitor and address PCCP, especially in severe cases, among females, and individuals with a history of chronic pain to improve their quality of life in the context of the ongoing COVID-19 pandemic.

Deep Brain Stimulation Improves Parkinson's Disease-Associated Pain by Decreasing Spinal Nociception.

Dopamine exerts antinociceptive effects on pain in PD at cortical and spinal levels, whereas only cortical effects have been described for DBS, so far. By assessing the nociceptive flexion reflex (NFR) threshold at medication on, and DBS ON and OFF in two patients, we showed that DBS additionally decreases spinal nociception.

Vagal electrostimulation in postoperative thoracic surgery reduces the systemic inflammatory response and cardiopulmonary complications: an experimental study in pigs.

Background: Conventional thoracotomy (CT) often leads to systemic inflammatory response syndrome (SIRS), which induces several clinical complications. CT remains widely used in low-income institutions. Although minimally invasive surgical procedures, such as robotic surgery (RS), have been used to prevent many of the complications inherit from the surgical procedure. Here, we investigated the protective effect of vagus nerve stimulation (VNS) in a pre-clinical model during CT or RS and postoperative period (POP) relative to clinical complications and inflammatory control. The objective was to compare hemodynamic features and cytokine levels in the blood, lung, and bronchoalveolar lavage (BAL) fluids of animals subjected to CT or RS with or without VNS. Methods: Twenty-four minipigs were subjected to 12 animals CT and 12 animals RS, with or without VNS, and accompanied 24 h later by pulmonary lobectomy. Blood samples for evaluating the hemodynamic parameters were collected before the surgical preparation, immediately after the beginning of VNS, and every 4 h until 24 h after the lobectomy. BAL fluid and lung tissue were collected at the end of the experiment. Cytokine levels were evaluated in the blood, BAL fluid, and lung tissues. Results: VNS maintained a more stable heart rate during POP and decreased the incidence of overall cardiac complications while preventing increase in IL-6 levels 12 h after lobectomy, compared to sham animals. No differences were found in cytokine expression in the BAL fluid and lung tissue in any of the studied groups. Conclusions: Taken together, our data suggested that VNS should be considered a non-pharmacological tool in the prevention of the exacerbated inflammatory response responsible for severe clinical complications, especially in more aggressive surgical procedures.

Parkinson's Disease-related Pains are Not Equal: Clinical, Somatosensory and Cortical Excitability Findings in Individuals With Nociceptive Pain.

Chronic pain is a frequent and burdensome nonmotor symptom of Parkinson's disease (PD). PD-related chronic pain can be classified as nociceptive, neuropathic, or nociplastic, the former being the most frequent subtype. However, differences in neurophysiologic profiles between these pain subtypes, and their potential prognostic and therapeutic implications have not been explored yet. This is a cross-sectional study on patients with PD (PwP)-related chronic pain (ie, started with or was aggravated by PD). Subjects were assessed for clinical and pain characteristics through questionnaires and underwent quantitative sensory tests and motor corticospinal excitability (CE) evaluations. Data were then compared between individuals with nociceptive and non-nociceptive (ie, neuropathic or nociplastic) pains. Thirty-five patients were included (51.4% male, 55.7 ± 11.0 years old), 20 of which had nociceptive pain. Patients with nociceptive PD-related pain had lower warm detection threshold (WDT, 33.34 ± 1.39 vs 34.34 ± 1.72, P = .019) and mechanical detection threshold (MDT, 2.55 ± 1.54 vs 3.86 ± .97, P = .007) compared to those with non-nociceptive pains. They also presented a higher proportion of low rest motor threshold values than the non-nociceptive pain ones (64.7% vs 26.6%, P = .048). In non-nociceptive pain patients, there was a negative correlation between WDT and non-motor symptoms scores (r = -.612, P = .045) and a positive correlation between MDT and average pain intensity (r = .629, P = .038), along with neuropathic pain symptom scores (r = .604, P = .049). It is possible to conclude that PD-related chronic pain subtypes have distinctive somatosensory and CE profiles. These preliminary data may help better frame previous contradictory findings in PwP and may have implications for future trial designs aiming at developing individually-tailored therapies. PERSPECTIVE: This work showed that PwP-related nociceptive chronic pain may have distinctive somatosensory and CE profiles than those with non-nociceptive pain subtypes. These data may help shed light on previous contradictory findings in PwP and guide future trials aiming at developing individually-tailored management strategies.

Pain in Parkinson disease: mechanistic substrates, main classification systems, and how to make sense out of them.

ABSTRACT: Parkinson disease (PD) affects up to 2% of the general population older than 65 years and is a major cause of functional loss. Chronic pain is a common nonmotor symptom that affects up to 80% of patients with (Pw) PD both in prodromal phases and during the subsequent stages of the disease, negatively affecting patient's quality of life and function. Pain in PwPD is rather heterogeneous and may occur because of different mechanisms. Targeting motor symptoms by dopamine replacement or with neuromodulatory approaches may only partially control PD-related pain. Pain in general has been classified in PwPD according to the motor signs, pain dimensions, or pain subtypes. Recently, a new classification framework focusing on chronic pain was introduced to group different types of PD pains according to mechanistic descriptors: nociceptive, neuropathic, or neither nociceptive nor neuropathic. This is also in line with the International Classification of Disease-11 , which acknowledges the possibility of chronic secondary musculoskeletal or nociceptive pain due to disease of the CNS. In this narrative review and opinion article, a group of basic and clinical scientists revise the mechanism of pain in PD and the challenges faced when classifying it as a stepping stone to discuss an integrative view of the current classification approaches and how clinical practice can be influenced by them. Knowledge gaps to be tackled by coming classification and therapeutic efforts are presented, as well as a potential framework to address them in a patient-oriented manner.

Development and Validation of the Dystonia-Pain Classification System: A Multicenter Study.

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.

Motor corticospinal excitability abnormalities differ between distinct chronic low back pain syndromes.

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.

Site matters: Central neuropathic pain characteristics and somatosensory findings after brain and spinal cord lesions.

BACKGROUND: It is unknown if different etiologies or lesion topographies influence central neuropathic pain (CNP) clinical manifestation. METHODS: We explored the symptom-somatosensory profile relationships in CNP patients with different types of lesions to the central nervous system to gain insight into CNP mechanisms. We compared the CNP profile through pain descriptors, standardized bedside examination, and quantitative sensory test in two different etiologies with segregated lesion locations: the brain, central poststroke pain (CPSP, n = 39), and the spinal cord central pain due to spinal cord injury (CPSCI, n = 40) in neuromyelitis optica. RESULTS: Results are expressed as median (25th to 75th percentiles). CPSP presented higher evoked and paroxysmal pain scores compared to CPSCI (p < 0.001), and lower cold thermal limen (5.6°C [0.0-12.9]) compared to CPSCI (20.0°C [4.2-22.9]; p = 0.004). CPSCI also had higher mechanical pain thresholds (784.5 mN [255.0-1078.0]) compared to CPSP (235.2 mN [81.4-1078.0], p = 0.006) and higher mechanical detection threshold compared to control areas (2.7 [1.5-6.2] vs. 1.0 [1.0-3.3], p = 0.007). Evoked pain scores negatively correlated with mechanical pain thresholds (r = -0.38, p < 0.001) and wind-up ratio (r = -0.57, p < 0.001). CONCLUSIONS: CNP of different etiologies may present different pain descriptors and somatosensory profiles, which is likely due to injury site differences within the neuroaxis. This information may help better design phenotype mechanism correlations and impact trial designs for the main etiologies of CNP, namely stroke and spinal cord lesions. This study provides evidence that topography may influence pain symptoms and sensory profile. The findings suggest that CNP mechanisms might vary according to pain etiology or lesion topography, impacting future mechanism-based treatment choices.

Corticomotor excitability is altered in central neuropathic pain compared with non-neuropathic pain or pain-free patients.

OBJECTIVES: Central neuropathic pain (CNP) is associated with altered corticomotor excitability (CE), which can potentially provide insights into its mechanisms. The objective of this study is to describe the CE changes that are specifically related to CNP. METHODS: We evaluated CNP associated with brain injury after stroke or spinal cord injury (SCI) due to neuromyelitis optica through a battery of CE measurements and comprehensive pain, neurological, functional, and quality of life assessments. CNP was compared to two groups of patients with the same disease: i. with non-neuropathic pain and ii. without chronic pain, matched by sex and lesion location. RESULTS: We included 163 patients (stroke=93; SCI=70: 74 had CNP, 43 had non-neuropathic pain, and 46 were pain-free). Stroke patients with CNP had lower motor evoked potential (MEP) in both affected and unaffected hemispheres compared to non- neuropathic pain and no-pain patients. Patients with CNP had lower amplitudes of MEPs (366 µV ±464 µV) than non-neuropathic (478 ±489) and no-pain (765 µV ± 880 µV) patients, p < 0.001. Short-interval intracortical inhibition (SICI) was defective (less inhibited) in patients with CNP (2.6±11.6) compared to no-pain (0.8±0.7), p = 0.021. MEPs negatively correlated with mechanical and cold-induced allodynia. Furthermore, classifying patients' results according to normative data revealed that at least 75% of patients had abnormalities in some CE parameters and confirmed MEP findings based on group analyses. DISCUSSION: CNP is associated with decreased MEPs and SICI compared to non-neuropathic pain and no-pain patients. Corticomotor excitability changes may be helpful as neurophysiological markers of the development and persistence of pain after CNS injury, as they are likely to provide insights into global CE plasticity changes occurring after CNS lesions associated with CNP.

New updates on transcranial magnetic stimulation in chronic pain.

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.

Non-invasive insular stimulation for peripheral neuropathic pain: Influence of target or symptom?

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.

Assessing the burden of osteoarthritis in Latin America: a rapid evidence assessment.

This rapid evidence assessment (REA) was conducted to explore the burden of weight-bearing joint osteoarthritis in the developing countries of Latin America. REA methodology used a standardized search strategy to identify observational studies published from 2010 to 23 April 2020 that reported outcomes pertaining to the epidemiology and humanistic or economic burden of weight-bearing osteoarthritis. Relevant data from each included study were used to populate bespoke data extraction tables and qualitatively analyzed. Thirteen publications were identified that reported on knee and hip osteoarthritis in the Latin American region. Overall prevalence of physician-diagnosed symptomatic knee osteoarthritis in adults ranged from 1.55% in Peru to 7.4% in Ecuador. Total prevalence of grade ≥ 2 radiographic knee osteoarthritis was 22% among those ≥ 39 years of age in Brazil and 25.5% among those ≥ 40 years of age in Mexico. The prevalence of symptomatic/radiographic knee osteoarthritis was 7.1% in people ≥ 18 years of age in Mexico and 17.6% among those ≥ 40 years of age. Prevalence of hip osteoarthritis was similar to or slightly lower than knee osteoarthritis. The limited data available indicates weight-bearing osteoarthritis negatively affects quality of life and that the economic burden may vary between countries with different healthcare systems. The limited evidence found in the published literature suggests the burden of osteoarthritis in Latin America is substantial. Our analysis identified several evidence gaps, particularly for health-related quality of life and socioeconomic outcomes. Further research is of particular importance in areas where government-subsidized healthcare and resources are scarce.

Safety and Outcomes of Dentate Nucleus Deep Brain Stimulation for Cerebellar Ataxia.

Cerebellar symptoms remain orphan of treatment options despite being prevalent and incapacitating. Investigate whether dentate nucleus deep brain stimulation (DN DBS) is safe and leads to improvements in cerebellar symptoms when compared to sham stimulation. This randomized double-blind crossover pilot trial enrolled five patients with spinocerebellar ataxia type 3 or post-lesion ataxia. Active or sham phases were randomly performed three months apart. The primary outcome was ataxia improvement as measured by the Scale for the Assessment and Rating of Ataxia (SARA) after the active compared to the sham period. Secondary outcome measures included safety and tolerability, the Fahn-Tolosa-Marin Tremor Rating Scale (FTMRS), quality of life measurements, and patients' global impression of change. The effects on ataxia were numerically better in four out of five patients after active versus sham stimulation. The composite SARA score did not change after comparing active to sham stimulation (8.6 ± 3.6 versus 10.1 ± 4.1; p = 0.223). The FTMRS showed significant improvement after active stimulation versus sham (18.0 ± 17.2 versus 22.2 ± 19.5; p = 0.039) as did patients' global impression of change (p = 0.038). The quality of life was not modified by stimulation (p = 0.337). DN DBS was well tolerated without serious adverse events. One patient had the electrode repositioned. DN DBS is a safe and well tolerated procedure that is effective in alleviating cerebellar tremor. In this small cohort of ataxic patients, DN DBS did not achieve statistical significance for ataxia improvement.