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.

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.

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.

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.

Effects of neuromodulation on executive functions and food desires in individuals with obesity: a systematic review / Efectos de la neuromodulación sobre las funciones ejecutivas y los deseos alimentarios en pacientes con obesidad: revisión sistemática

Objective: to describe the effects of neuromodulation on the performance of executive functions in overweight and/or individuals with obesity. Methods: articles published in PubMed, ScienceDirect, BIREME, and Web of Science databases were selected using the following combination of descriptors: (“problem solving” OR “executive function” OR memory) AND (tDCS OR TMS) AND obesity. After applying the selection criteria, 08 articles were included for analysis. Results: the articles included had an average of 30.1 participants per study, with a minimum of 12 and a maximum of 76. The overall nutritional status ranged from underweight to grade 3 obesity, and the general mean body mass index was 28,1 kg/m2. Regarding the instruments used to assess executive functions, the most frequent were: the flanker paradigm; binocular rivalry for Continuous Flash Suppression (bCFS/NoCFS); Stroop task; Go/No-Go task; and N-back task. The primary outcomes were dependent on the neuromodulation target site. Reduced food craving and improved performance in the active group were observed from decreased response time and increased precision in cognitive tasks. Conclusion: neuromodulation can generate changes in executive functions, reducing food cravings in overweight and individuals with obesity. (AU)

Objetivo: describir los efectos de la neuromodulación en el desempeño de funciones ejecutivas en pacientes con sobrepeso y/o obesidad. Métodos: se seleccionaron artículos publicados en las bases de datos PubMed, ScienceDirect, BIREME y Web of Science utilizando la siguiente combinación de descriptores: (“resolución de problemas” O “función ejecutiva” O memoria) Y (tDCS O TMS) Y obesidad. Después de aplicar los criterios de selección, 08 artículos fueron incluidos para el análisis. Resultados: los artículos incluidos tuvieron un promedio de 30,1 participantes por estudio, con un mínimo de 12 y un máximo de 76. El estado nutricional general osciló entre bajo peso y obesidad grado 3, y el índice de masa corporal promedio general fue de 28,1 kg/m2. En cuanto a los instrumentos utilizados para evaluar las funciones ejecutivas, los más frecuentes fueron: paradigma del flanqueador; rivalidad binocular para la supresión continua de flash (bCFS/NoCFS); tarea de Stroop; Tarea Go/No-Go; y tarea N-back. Los resultados primarios dependieron del sitio objetivo de la neuromodulación. Se observó una reducción del antojo de alimentos y un mejor rendimiento en el grupo activo debido a la disminución del tiempo de respuesta y al aumento de la precisión en las tareas cognitivas.Conclusión: la neuromodulación puede generar cambios en las funciones ejecutivas, reduciendo el antojo de alimentos en personas con sobrepeso y obesidad. (AU)

Mirror peripheral neuropathy and unilateral chronic neuropathic pain: insights from asymmetric neurological patterns in leprosy.

ABSTRACT: Leprosy-related multiple mononeuropathy offers a pattern of impairment where neuropathy with and without neuropathic pain (NeP) are present in the same individual, thus allowing to investigate peripheral sensory and innervation in both conditions. This cross-sectional study collected data on clinical and neurological examination, pain assessment questionnaires, quantitative sensory test, and intraepidermal nerve fiber density of patients with leprosy and divided the cohort into 2 groups: with NeP (P+) and without NeP (P-). Furthermore, we assessed mirror body areas in the same NeP individuals with bilateral neuropathy also presenting unilateral NeP. Pain-free patients having unilateral neuropathy were controls. A total of 37 P+ and 22 P- patients were evaluated. Limb areas with NeP had signs of C-fiber dysfunction and hyperesthesia on quantitative sensory testing compared with limb areas having neuropathy without NeP. Skin denervation was found in all patients with leprosy. Comparisons of limbs with and without neuropathy and with and without NeP revealed that higher heat pain thresholds (HPTs) were associated with neuropathic pain areas, whereas less altered HPT was correlated with higher fiber density. Furthermore, a relationship was found between time of leprosy treatment termination and more intense neuropathy, expressed by HPT increasing 0.03°C each month. As expected, interindividual comparisons failed to show differences in intraepidermal nerve fiber density and subepidermal plexus areas between P+ and P- patients ( P = 0.2980, P = 0.9044; respectively). Higher HPT and lower mechanical detection threshold were related to NeP. This study pointed out the relevance of intraindividual comparisons including mirror areas when assessing local changes in peripheral NeP.

Effects of neuromodulation on executive functions and food desires in individuals with obesity: a systematic review.

Introduction: Objective: to describe the effects of neuromodulation on the performance of executive functions in overweight and/or individuals with obesity. Methods: articles published in PubMed, ScienceDirect, BIREME, and Web of Science databases were selected using the following combination of descriptors: ("problem solving" OR "executive function" OR memory) AND (tDCS OR TMS) AND obesity. After applying the selection criteria, 08 articles were included for analysis. Results: the articles included had an average of 30.1 participants per study, with a minimum of 12 and a maximum of 76. The overall nutritional status ranged from underweight to grade 3 obesity, and the general mean body mass index was 28,1 kg/m2. Regarding the instruments used to assess executive functions, the most frequent were: the flanker paradigm; binocular rivalry for Continuous Flash Suppression (bCFS/NoCFS); Stroop task; Go/No-Go task; and N-back task. The primary outcomes were dependent on the neuromodulation target site. Reduced food craving and improved performance in the active group were observed from decreased response time and increased precision in cognitive tasks. Conclusion: neuromodulation can generate changes in executive functions, reducing food cravings in overweight and individuals with obesity.

Introducción: Objetivo: describir los efectos de la neuromodulación en el desempeño de funciones ejecutivas en pacientes con sobrepeso y/o obesidad. Métodos: se seleccionaron artículos publicados en las bases de datos PubMed, ScienceDirect, BIREME y Web of Science utilizando la siguiente combinación de descriptores: ("resolución de problemas" O "función ejecutiva" O memoria) Y (tDCS O TMS) Y obesidad. Después de aplicar los criterios de selección, 08 artículos fueron incluidos para el análisis. Resultados: los artículos incluidos tuvieron un promedio de 30,1 participantes por estudio, con un mínimo de 12 y un máximo de 76. El estado nutricional general osciló entre bajo peso y obesidad grado 3, y el índice de masa corporal promedio general fue de 28,1 kg/m2. En cuanto a los instrumentos utilizados para evaluar las funciones ejecutivas, los más frecuentes fueron: paradigma del flanqueador; rivalidad binocular para la supresión continua de flash (bCFS/NoCFS); tarea de Stroop; Tarea Go/No-Go; y tarea N-back. Los resultados primarios dependieron del sitio objetivo de la neuromodulación. Se observó una reducción del antojo de alimentos y un mejor rendimiento en el grupo activo debido a la disminución del tiempo de respuesta y al aumento de la precisión en las tareas cognitivas. Conclusión: la neuromodulación puede generar cambios en las funciones ejecutivas, reduciendo el antojo de alimentos en personas con sobrepeso y obesidad.

Preoperative Predictors for Acute Pain After Photorefractive Keratectomy.

PURPOSE: The aim of this study was to identify preoperative predictors for the occurrence of early severe postoperative pain in patients undergoing photorefractive keratectomy (PRK). The implementation of preoperative screening methods may facilitate more specific or aggressive pain therapies specifically targeted to individuals at a high risk of experiencing severe postoperative pain. METHODS: This was exploratory research that included patients who underwent PRK. Before PRK, patients were administered a sociodemographic questionnaire, the Pain Catastrophizing Scale, and the State-Trait Anxiety Inventory and underwent corneal sensitivity and conditioned pain modulation (CPM) tests. Post-PRK pain was assessed using a pain intensity visual analog scale (VAS), and the short-form McGill Pain Questionnaire (SF-MPQ) was completed 21 days before PRK and 1, 24, 48, and 72 hours after PRK. Spearman correlations were calculated for pain scores and preoperative predictors. RESULTS: This research included 34 eyes of 34 patients. Preoperative corneal sensitivity was positively correlated with post-PRK pain scores as assessed by VAS and SF-MPQ (rho = 0.39 and rho = 0.41, respectively, P < 0.05). No correlations were found between Pain Catastrophizing Scale, State-Trait Anxiety Inventory, and CPM scores and post-PRK pain scores ( P > 0.05). CONCLUSIONS: Abnormal presurgical corneal sensitivity was a protective marker for severe pain after PRK, while scores as assessed by VAS and SF-MPQ and CPM were not related to postoperative pain.

Dissecting central post-stroke pain: a controlled symptom-psychophysical characterization.

Central post-stroke pain affects up to 12% of stroke survivors and is notoriously refractory to treatment. However, stroke patients often suffer from other types of pain of non-neuropathic nature (musculoskeletal, inflammatory, complex regional) and no head-to-head comparison of their respective clinical and somatosensory profiles has been performed so far. We compared 39 patients with definite central neuropathic post-stroke pain with two matched control groups: 32 patients with exclusively non-neuropathic pain developed after stroke and 31 stroke patients not complaining of pain. Patients underwent deep phenotyping via a comprehensive assessment including clinical exam, questionnaires and quantitative sensory testing to dissect central post-stroke pain from chronic pain in general and stroke. While central post-stroke pain was mostly located in the face and limbs, non-neuropathic pain was predominantly axial and located in neck, shoulders and knees (P < 0.05). Neuropathic Pain Symptom Inventory clusters burning (82.1%, n = 32, P < 0.001), tingling (66.7%, n = 26, P < 0.001) and evoked by cold (64.1%, n = 25, P < 0.001) occurred more frequently in central post-stroke pain. Hyperpathia, thermal and mechanical allodynia also occurred more commonly in this group (P < 0.001), which also presented higher levels of deafferentation (P < 0.012) with more asymmetric cold and warm detection thresholds compared with controls. In particular, cold hypoesthesia (considered when the threshold of the affected side was <41% of the contralateral threshold) odds ratio (OR) was 12 (95% CI: 3.8-41.6) for neuropathic pain. Additionally, cold detection threshold/warm detection threshold ratio correlated with the presence of neuropathic pain (ρ = -0.4, P < 0.001). Correlations were found between specific neuropathic pain symptom clusters and quantitative sensory testing: paroxysmal pain with cold (ρ = -0.4; P = 0.008) and heat pain thresholds (ρ = 0.5; P = 0.003), burning pain with mechanical detection (ρ = -0.4; P = 0.015) and mechanical pain thresholds (ρ = -0.4, P < 0.013), evoked pain with mechanical pain threshold (ρ = -0.3; P = 0.047). Logistic regression showed that the combination of cold hypoesthesia on quantitative sensory testing, the Neuropathic Pain Symptom Inventory, and the allodynia intensity on bedside examination explained 77% of the occurrence of neuropathic pain. These findings provide insights into the clinical-psychophysics relationships in central post-stroke pain and may assist more precise distinction of neuropathic from non-neuropathic post-stroke pain in clinical practice and in future trials.

Dissecting neuropathic from poststroke pain: the white matter within.

ABSTRACT: Poststroke pain (PSP) is a heterogeneous term encompassing both central neuropathic (ie, central poststroke pain [CPSP]) and nonneuropathic poststroke pain (CNNP) syndromes. Central poststroke pain is classically related to damage in the lateral brainstem, posterior thalamus, and parietoinsular areas, whereas the role of white matter connecting these structures is frequently ignored. In addition, the relationship between stroke topography and CNNP is not completely understood. In this study, we address these issues comparing stroke location in a CPSP group of 35 patients with 2 control groups: 27 patients with CNNP and 27 patients with stroke without pain. Brain MRI images were analyzed by 2 complementary approaches: an exploratory analysis using voxel-wise lesion symptom mapping, to detect significant voxels damaged in CPSP across the whole brain, and a hypothesis-driven, region of interest-based analysis, to replicate previously reported sites involved in CPSP. Odds ratio maps were also calculated to demonstrate the risk for CPSP in each damaged voxel. Our exploratory analysis showed that, besides known thalamic and parietoinsular areas, significant voxels carrying a high risk for CPSP were located in the white matter encompassing thalamoinsular connections (one-tailed threshold Z > 3.96, corrected P value <0.05, odds ratio = 39.7). These results show that the interruption of thalamocortical white matter connections is an important component of CPSP, which is in contrast with findings from nonneuropathic PSP and from strokes without pain. These data can aid in the selection of patients at risk to develop CPSP who could be candidates to pre-emptive or therapeutic interventions.

Sensory characteristics and chronic facial pain conditions: Cross-sectional study.

OBJECTIVES: This study investigated patients with neuropathic, myofascial and other orofacial pain conditions according to the differences and similarities of the sensory profile, and the association between sensory findings and neuropathic or non-neuropathic conditions. DESIGN: 132 healthy controls were compared with 174 orofacial pain patients that were classified into three groups (neuropathic, masticatory myofascial and other orofacial pain condition) and evaluated with a systematized protocol of sensory testing. Data were analyzed with chi-quare and Bonferroni correction (categorical data), Student´s t test, oneway ANOVA, Tukey (quantitative features), Pearson´s coefficient for correlations and logistic regression. RESULTS: Cold, olfactory and superficial pain thresholds were higher in the group of neuropathic facial pain compared with the other groups, and the highest vibratory thresholds were observed in the group of other orofacial pain conditions. Deep pain thresholds were statistically lower in the group with masticatory myofascial pain. CONCLUSIONS: Positive sensory findings (eg. hyperalgesia) were more common in the group of patients with masticatory myofascial pain, supporting inflammatory systemic mechanisms, and negative sensory findings not restricted to the trigeminal nerve (eg. hypoesthesia, hyposmia) were more frequent in patients with neuropathic conditions. Non-classical neuropathic orofacial pains also showed sensory impairment from pain chronification and from the overlap with functional disorders.

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.

Improvement of Non-motor Symptoms and Quality of Life After Deep Brain Stimulation for Refractory Dystonia: A 1-Year Follow-Up.

Introduction: Deep brain stimulation (DBS) is a treatment option for refractory dystonia's motor symptoms, while its non-motor symptoms (NMS) have been less systematically assessed. We aimed to describe the effects of DBS on NMS in refractory generalized inherited/idiopathic dystonia prospectively. Methods: We evaluated patients before and 1 year after DBS surgery and applied the following scales: Burke-Fahn-Marsden Rating Scale (BFMRS), NMS Scale for Parkinson's Disease (NMSS-PD), Parkinson's Disease Questionnaire-8, short-form Brief Pain Inventory (BPI), Neuropathic Pain Symptom Inventory (NPSI), and short-form McGill Pain Questionnaire (MPQ). Results: Eleven patients (38.35 ± 11.30 years) underwent surgery, all with generalized dystonia. Motor BFMRS subscore was 64.36 ± 22.94 at baseline and 33.55 ± 17.44 1 year after DBS surgery (47.9% improvement, p = 0.003). NMSS-PD had a significant change 12 months after DBS, from 70.91 ± 59.07 to 37.18 ± 55.05 (47.5% improvement, p = 0.013). NMS changes were mainly driven by changes in the gastrointestinal (p = 0.041) and miscellaneous domains (p = 0.012). Seven patients reported chronic pain before DBS and four after it. BPI's severity and interference scores were 4.61 ± 2.84 and 4.12 ± 2.67, respectively, before surgery, and 2.79 ± 2.31 (0.00-6.25) and 1.12 ± 1.32 (0.00-3.00) after, reflecting a significant improvement (p = 0.043 and p = 0.028, respectively). NPSI score was 15.29 ± 13.94 before, while it was reduced to 2.29 ± 2.98 afterward (p = 0.028). MPQ's total score was 9.00 ± 3.32 before DBS, achieving 2.71 ± 2.93 after (p = 0.028). Conclusions: DBS improves NMS in generalized inherited/idiopathic dystonia, including chronic pain.

Appraising the effectiveness of electrical and magnetic brain stimulation techniques in acute major depressive episodes: an umbrella review of meta-analyses of randomized controlled trials

Electrical and magnetic brain stimulation techniques present distinct mechanisms and efficacy in the acute treatment of depression. This was an umbrella review of meta-analyses of randomized controlled trials of brain stimulation techniques for managing acute major depressive episodes. A systematic review was performed in the PubMed/MEDLINE databases from inception until March 2020. We included the English language meta-analysis with the most randomized controlled trials on the effects of any brain stimulation technique vs. control in adults with an acute depressive episode. Continuous and dichotomous outcomes were assessed. A Measurement Tool to Assess Systematic Reviews-2 was applied and the credibility of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation framework. Seven meta-analyses were included (5,615 patients), providing evidence for different modalities of brain stimulation techniques. Three meta-analyses were evaluated as having high methodological quality, three as moderate, and one as low. The highest quality of evidence was found for high frequency-repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation, and bilateral rTMS. There is strong clinical research evidence to guide future clinical use of some techniques. Our results confirm the heterogeneity of the effects across these techniques, indicating that different mechanisms of action lead to different efficacy profiles.

Motor cortex stimulation for chronic neuropathic pain: results of a double-blind randomized study.

Motor cortex stimulation via surgically implanted electrodes has been used as an off-label treatment for chronic neuropathic pain, but its efficacy has not been fully established. We aimed to objectively study the efficacy of motor cortex stimulation and characterize potential predictors of response. In this randomized, double-blind, sham-controlled, single centre trial, we recruited 18 patients with chronic neuropathic pain who did not adequately respond to conventional treatment and had a numerical pain rating scale (NRS) score ≥6. Patients were initially assigned to receive 3 months of active ('on') or sham ('off') stimulation in a double-blind cross-over phase. This was followed by a 3-month single-blind phase, and 6 months of open-label follow-up. A meaningful response in our trial was defined as a ≥30% or 2-point reduction in NRS scores during active stimulation. Using Bayesian statistics, we found a 41.4% probability of response towards on versus off motor cortex stimulation. The probability of improvement during active stimulation (double-blind, single-blind and open-label phases) compared to baseline was 47.2-68.5%. Thirty nine per cent of the patients were considered long-term responders, 71.4% of whom had facial pain, phantom limb pain or complex regional pain syndrome. In contrast, 72.7% of non-responders had either post-stroke pain or pain associated with brachial plexus avulsion. Thirty-nine per cent of patients had a substantial postoperative analgesic effect after electrode insertion in the absence of stimulation. Individuals with diagnoses associated with a good postoperative outcome or those who developed an insertional effect had a near 100% probability of response to motor cortex stimulation. In summary, we found that ∼40% of patients responded to motor cortex stimulation, particularly those who developed an insertional effect or had specific clinical conditions that seemed to predict an appropriate postoperative response.

Dry needling has lasting analgesic effect in shoulder pain: a double-blind, sham-controlled trial.

INTRODUCTION: Myofascial pain syndrome (MPS) affects most patients with chronic shoulder pain. Dry needling (DN) is a common treatment for MPS, but its temporal pattern and sensory effects remain unknown. OBJECTIVES: We evaluated in a randomized, sham-controlled study the pattern of analgesic efficacy and local sensory changes of a single session of DN for MPS in patients with chronic shoulder pain. METHODS: Patients with chronic shoulder pain were randomized into active (n = 20) or sham (n = 21) groups. A single DN was performed by a researcher blinded to group assignment and pain outcomes. Pain intensity was assessed by the numeric rating score, and sensory thresholds were evaluated with a quantitative sensory testing protocol, including the area of tactile sensory abnormalities 7 days before needling, right before, and 7 days after the intervention. RESULTS: Dry needling led to significant larger pain intensity reduction (from 6.30 ± 2.05 to 2.40 ± 2.45 in the active group; P = 0.02, effect size = -1.3 (95% CI [-2.0 to -0.68]); (number necessary to treat = 2.1). Pain reduction scores were significantly different on the second day after needling and persisted so until the seventh day and were accompanied by improvement in other dimensions of pain and a decrease in the area of mechanical hyperalgesia in the active DN group alone (P < 0.05). CONCLUSION: Active trigger points DN provided analgesic effects compared with sham and decreased the area of local mechanical hyperalgesia. These findings have practical clinical implications and may provide mechanistic insights behind MPS.

Posterior-superior insular deep transcranial magnetic stimulation alleviates peripheral neuropathic pain - A pilot double-blind, randomized cross-over study.

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.

Abnormal sensory thresholds of dystonic patients are not affected by deep brain stimulation.

BACKGROUND: Unlike motor symptoms, the effects of deep brain stimulation (DBS) on non-motor symptoms associated with dystonia remain unknown. METHODS: The objective of this study was to assess the effects of DBS on evoked experimental pain and cutaneous sensory thresholds in a crossover, double-blind on/off study and compare these results with those of healthy volunteers (HV). RESULTS: Sixteen patients with idiopathic dystonia (39.9 ± 13 years old, n = 14 generalized) with DBS of the globus pallidus internus underwent a battery of quantitative sensory testing and assessment using a pain top-down modulation system (conditioned pain modulation, CPM). Results for the more and less dystonic body regions were compared in on and off stimulation. The patients' results were compared to age- and sex-matched HV. Descending pain modulation CPM responses in dystonic patients (on-DBS, 11.8 ± 40.7; off-DBS, 1.8 ± 22.1) was abnormally low (defective) compared to HV (-15.6 ± 23.5, respectively p = .006 and p = .042). Cold pain threshold and cold hyperalgesia were 54.8% and 95.7% higher in dystonic patients compared to HV. On-DBS CPM correlated with higher Burke-Fahn-Marsden disability score (r = 0.598; p = .014). While sensory and pain thresholds were not affected by DBS on/off condition, pain modulation was abnormal in dystonic patients and tended to be aggravated by DBS. CONCLUSION: The analgesic effects after DBS do not seem to depend on short-duration changes in cutaneous sensory thresholds in dystonic patients and may be related to changes in the central processing of nociceptive inputs.

Sorting pain out of salience: assessment of pain facial expressions in the human fetus.

INTRODUCTION: The question of whether the human fetus experiences pain has received substantial attention in recent times. With the advent of high-definition 4-dimensional ultrasound (4D-US), it is possible to record fetal body and facial expressions. OBJECTIVE: To determine whether human fetuses demonstrate discriminative acute behavioral responses to nociceptive input. METHODS: This cross-sectional study included 5 fetuses with diaphragmatic hernia with indication of intrauterine surgery (fetoscopic endoluminal tracheal occlusion) and 8 healthy fetuses, who were scanned with 4D-US in 1 of 3 conditions: (1) acute pain group: Fetuses undergoing intrauterine surgery were assessed in the preoperative period during the anesthetic injection into the thigh; (2) control group at rest: Facial expressions at rest were recorded during scheduled ultrasound examinations; and (3) control group acoustic startle: Fetal facial expressions were recorded during acoustic stimulus (500-4000 Hz; 60-115 dB). RESULTS: Raters blinded to the fetuses' groups scored 65 pictures of fetal facial expressions based on the presence of 12 items (facial movements). Analyses of redundancy and usefulness excluded 5 items for being of low discrimination capacity (P>0.2). The final version of the pain assessment tool consisted of a total of 7 items: brow lowering/eyes squeezed shut/deepening of the nasolabial furrow/open lips/horizontal mouth stretch/vertical mouth stretch/neck deflection. Odd ratios for a facial expression to be detected in acute pain compared with control conditions ranged from 11 (neck deflection) to 1,400 (horizontal mouth stretch). Using the seven-item final tool, we showed that 5 is the cutoff value discriminating pain from nonpainful startle and rest. CONCLUSIONS: This study inaugurates the possibility to study pain responses during the intrauterine life, which may have implications for the postoperative management of pain after intrauterine surgical interventions.