Does deep TMS really works for smoking cessation? A prospective, double blind, randomized, sham controlled study.

INTRODUCTION: A substantial proportion of smokers wishing to quit do not stop smoking when using current therapies to aid cessation. Magnetic pulses to specific brain areas designated as transcranial magnetic stimulation may modulate brain activity and thereby change chemical dependencies. Deep transcranial magnetic stimulation (dTMS) with the H4 coil stimulates neuronal pathways in the lateral prefrontal cortex and insula bilaterally, areas involved in tobacco addiction. OBJECTIVE: To evaluate the efficacy and safety of dTMS with T4 coil in smoking cessation. METHODS: In a double blind, controlled clinical trial, adult smokers of at least 10 cigarettes/day were randomized to active (n = 50) versus sham dTMS (n = 50). The protocol involved up to 21 sessions administered over up to 12 weeks. Tobacco use was monitored by self-report and confirmed by expired air monoximetry (at each dTMS visit) and blood cotinine (at the screening visit and at the end of sessions). Participants completed abstinence, mood and cognition scales at determined timepoints during follow-up. RESULTS: In the intention to-treat-analysis, the cessation rate of the intervention and control groups was 14.0%. The reported side effects were as expected for this procedure. Although there were no serious adverse events, three participants were withdrawn according to safety criteria. CONCLUSION: Active treatment with dTMS H4 coil was safe but not effective for smoking cessation.

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.

Pain paths among post-COVID-19 condition subjects: A prospective cross-sectional study with in-person evaluation.

BACKGROUND: New-onset chronic pain has been acknowledged as part of the post-COVID-19 condition. However, available fine-grained data about its clinical phenotype, trajectories and main associated characteristics remain scarce. We described the distinct temporal evolutions of post-COVID-19 pain and their epidemiological and phenotypical features. METHODS: A prospective cross-sectional study enrolled post-COVID-19 condition patients (i.e. who had persisting COVID-19-related symptoms over 30 days since their first positive laboratory test), whose COVID-19 diagnosis had been supported by RT-PCR of oral/nasopharyngeal swab or serology. They underwent in-person evaluations with a structured interview, pain and quality-of-life-related questionnaires and thorough physical examination. Chronic pain (CP) and probable neuropathic pain (NP) were defined according to IASP criteria. RESULTS: The present study included 226 individuals, 177 (78.3%) of whom presented over 3 months since their first COVID-19 symptom. New-onset pain occurred in 170 (75.2%) participants and was chronic in 116 (68.2%). A chronic course was associated with COVID-19-related hospitalization, new-onset fatigue, lower cognitive performance, motor and thermal sensory deficits, mood and sleep impairments and overall lower quality-of-life levels. Probable NP occurred in only 7.6% new-onset pain patients, and was associated with pain chronification, new-onset fatigue, motor and thermal sensory deficits, mechanical allodynia and lower rates of SARS-CoV-2 vaccination. Previous CP was reported by 86 (38.1%) individuals and had aggravated after the infection in 66 (76.7%) of them, which was associated with orthostatic hypotension. CONCLUSIONS: Post-COVID pain phenomena follow different paths, which are associated with specific clinical and epidemiological features, and possibly distinct underlying mechanisms, prognostic and therapeutic implications. SIGNIFICANCE: COVID-19-related pain usually follows a chronic course and is non-neuropathic. Its possible courses and phenotypes are associated with distinct clinical and epidemiological features. This suggests differing underlying mechanisms, which may have significant prognostic and therapeutic implications.

Unraveling the peripheral and local role of inflammatory cytokines in glioblastoma survival.

Glioblastoma (GBM) is a life-threatening disease that presents high morbidity and mortality. The standardized treatment protocol results in a global survival of less than three years in the majority of cases. Immunotherapies have gained wide recognition in cancer treatment; however, GBM has an immunosuppressive microenvironment diminishing the possible effectiveness of this therapy. In this sense, investigating the inflammatory settings and the tumoral nature of GBM patients are an important goal to create an individual plan of treatment to improve overall survival rate and quality of life of these patients. Thirty-two patients who underwent surgical resection of GBM were included in this study. Tumor samples and 10 mL of peripheral blood were collected and immediately frozen. TNF-a, IL-1a and IL-4 were evaluated in the tumor and TNF-a, IL-1a and TGF-b in the plasma by Luminex assay. Immunohistochemistry analysis to determine immune celular profile was done, including immunohistochemistry for CD20, CD68 and CD3. Three cases were excluded. Tumor topography, tumor nature, and tumor volume reconstructions were accurately analyzed by T1-weighted, T2-weighted, and FLAIR magnetic resonance imaging. We found that GBM patients with below median peripheral levels of TNF-a and IL-1a had a decreased survival rate when compared to above median patients. On the other hand, patients with below median peripheral levels of TGF-b increased overall survival rate. Intratumoral IL-1a above median was associated with higher number of macrophages and fewer with B cells. Furthermore, plasmatic TNF-a levels were correlated with intratumoral TNF-a levels, suggesting that peripheral cytokines are related to the tumoral microenvironment. Even though tumor size has no difference regarding survival rate, we found a negative correlation between intratumoral IL-4 and tumor size, where larger tumors have less IL-4 expression. Nevertheless, the tumoral nature had a significant effect in overall survival rate, considering that infiltrative tumors showed decreased survival rate and intratumoral TNF-a. Moreover, expansive tumors revealed fewer macrophages and higher T cells. In multiple variation analyzes, we demonstrated that infiltrative tumors and below median peripheral IL-1a expression represent 3 times and 5 times hazard ratio, respectively, demonstrating a poor prognosis. Here we found that peripheral cytokines had a critical role as prognostic tools in a small cohort of GBM patients.

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.

Contribution of intracranial pressure to human dynamic cerebral autoregulation after acute brain injury.

Cerebral perfusion pressure (CPP) is normally expressed by the difference between mean arterial blood pressure (MAP) and intracranial pressure (ICP) but comparison of the separate contributions of MAP and ICP to human cerebral blood flow autoregulation has not been reported. In patients with acute brain injury (ABI), internal jugular vein compression (IJVC) was performed for 60 s. Dynamic cerebral autoregulation (dCA) was assessed in recordings of middle cerebral artery blood velocity (MCAv, transcranial Doppler), and invasive measurements of MAP and ICP. Patients were separated according to injury severity as having whole/undamaged skull, large fractures, or craniotomies, or following decompressive craniectomy. Glasgow coma score was not different for the three groups. IJVC induced changes in MCAv, MAP, ICP, and CPP in all three groups. The MCAv response to step changes in MAP and ICP expressed the dCA response to these two inputs and was quantified with the autoregulation index (ARI). In 85 patients, ARI was lower for the ICP input as compared with the MAP input (2.25 ± 2.46 vs. 3.39 ± 2.28; P < 0.0001), and particularly depressed in the decompressive craniectomy (DC) group (n = 24, 0.35 ± 0.62 vs. 2.21 ± 1.96; P < 0.0005). In patients with ABI, the dCA response to changes in ICP is less efficient than corresponding responses to MAP changes. These results should be taken into consideration in studies aimed to optimize dCA by manipulation of CPP in neurocritical patients.

Trayectorias del dolor en sujetos con afección post-COVID-19: estudio prospectivo y transversal con evaluación presencial / Pain paths among post-COVID-19 condition subjects: a prospective cross-sectional study with in-person evaluation

Antecedentes: El dolor crónico de nueva aparición se considera que forma parte de la condición o afección post-COVID-19. Sin embargo, los datos detallados existentes sobre el fenotipo clínico, las trayectorias y las principales características asociadas siguen siendo escasos. Describimos las distintas evoluciones temporales del dolor post-COVID-19 y sus rasgos epidemiológicos y fenotípicos. Métodos: Estudio prospectivo y transversal de pacientes con afección post-COVID-19 (es decir, con síntomas persistentes relacionados con la COVID-19 durante 30 días desde la primera prueba positiva de laboratorio) cuyo diagnóstico de COVID-19 estuviera basado en la RT-PCR de un frotis oral/nasofaríngeo o una serología. Se sometieron a evaluaciones presenciales mediante una entrevista estructurada, cuestionarios de dolor y calidad de vida y una exploración física exhaustiva. El dolor crónico (DC) y el dolor neuropático (DN) probablemente se definieron conforme a los criterios IASP.Resultados: El presente estudio incluyó 226 individuos, 177 (78,3 %) de los cuales se presentaron pasados más de 3 meses desde el primer síntoma de COVID-19. Tenían dolor de nueva aparición 170 (75,2 %) de los participantes y dolor crónico 116 (68,2 %). El curso crónico se asociaba a hospitalización por COVID-19, fatiga de nueva aparición, menor rendimiento cognitivo, déficits motores y sensitivos térmicos, alteraciones del ánimo y el sueño, y niveles generalmente inferiores de calidad de vida. El DN probable afectaba a solo el 7,6 % de los pacientes con dolor de nueva aparición y se asociaba a cronificación del dolor, fatiga de nueva aparición, déficits motores y de sensación térmica, alodinia mecánica y tasas menores de vacunación frente al SARS-CoV-2. Referían DC previo 86 (38,1 %) individuos, y este había empeorado tras la infección en 66 (76,7 %) de ellos, lo que se asociaba a hipotensión ortostática...(AU)

Background: New-onset chronic pain has been acknowledged as part of the post-COVID-19 condition. However, available fine-grained data about its clinical phenotype, trajectories and main associated characteristics remain scarce. We described the distinct temporal evolutions of post-COVID-19 pain and their epidemiological and phenotypical features.Methods: A prospective cross-sectional study enrolled post-COVID-19 condition patients (i.e. who had persisting COVID-19-related symptoms over 30 days since their first positive laboratory test), whose COVID-19 diagnosis had been supported by RT-PCR of oral/nasopharyngeal swab or serology. They underwent in-person evaluations with a structured interview, pain and quality-of-life-related questionnaires and thorough physical examination. Chronic pain (CP) and probable neuropathic pain (NP) were defined according to IASP criteria.Results: The present study included 226 individuals, 177 (78.3 %) of whom presented over 3 months since their first COVID-19 symptom. Newonset pain occurred in 170 (75.2 %) participants and was chronic in 116 (68.2 %). A chronic course was associated with COVID-19-related hospitalization, new-onset fatigue, lower cognitive performance, motor and thermal sensory deficits, mood and sleep impairments and overall lower quality-of-life levels. Probable NP occurred in only 7.6 % new-onset pain patients, and was associated with pain chronification, new-onset fatigue, motor and thermal sensory deficits, mechanical allodynia and lower rates of SARSCoV-2 vaccination. Previous CP was reported by 86 (38.1 %) individuals and had aggravated after the infection in 66 (76.7 %) of them, which was associated with orthostatic hypotension.Conclusions: Post-COVID pain phenomena follow different paths, which are associated with specific clinical and epidemiological features, and possibly distinct underlying mechanisms, prognostic and therapeutic implications...(AU)

A systematic review and meta-analysis of fusion rate enhancements and bone graft options for spine surgery.

Our study aimed to evaluate differences in outcomes of patients submitted to spinal fusion using different grafts measuring the effectiveness of spinal fusion rates, pseudarthrosis rates, and adverse events. Applying the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, this systematic review and meta-analysis identified 64 eligible articles. The main inclusion criteria were adult patients that were submitted to spinal fusion, autologous iliac crest (AIC), allograft (ALG), alloplastic (ALP; hydroxyapatite, rhBMP-2, rhBMP-7, or the association between them), and local bone (LB), whether in addition to metallic implants or not, was applied. We made a comparison among those groups to evaluate the presence of differences in outcomes, such as fusion rate, hospital stay, follow-up extension (6, 12, 24, and 48 months), pseudarthrosis rate, and adverse events. Sixty-four studies were identified. LB presented significantly higher proportions of fusion rates (95.3% CI 89.7-98.7) compared to the AIC (88.6% CI 84.8-91.9), ALG (87.8% CI 80.8-93.4), and ALP (85.8% CI 75.7-93.5) study groups. Pseudarthrosis presented at a significantly lower pooled proportion of ALG studies (4.8% CI 0.1-15.7) compared to AIC (8.6% CI 4.2-14.2), ALP (7.1% CI 0.9-18.2), and LB (10.3% CI 1.8-24.5). ALP and AIC studies described significantly more cases of adverse events (80 events/404 patients and 860 events/2001 patients, respectively) compared to LB (20 events/311 patients) and ALG (73 events/459 patients). Most studies presented high risk-of-bias scores. Based on fusion rates and adverse events proportions, LB showed a superior trend among the graft cases we analyzed. However, our review revealed highly heterogeneous data and a need for more rigorous studies to better address and assist surgeons' choices of the best spinal grafts.

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.

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.

Corrigendum: Behavioral and Neural Correlates of Cognitive Training and Transfer Effects in Stroke Patients.

[This corrects the article DOI: 10.3389/fneur.2020.01048.].

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.

Robotic and standard surgical intervention as adjunct therapies for retroperitoneal ganglioneuroma resection: a case report.

BACKGROUND: Ganglioneuroma (GN) is ranked by the International Neuroblastoma Pathology Classification as a benign tumor. It can occur anywhere along the sympathetic nerve chain and surgical excision is the treatment of choice. CASE PRESENTATION: An 18-year-old female patient sought medical assistance after 6 months of constant dorsal and back pain radiating from the thoracic region to the right abdominal flank. Magnetic resonance imaging revealed a solid nodular lesion with heterogeneous post-contrast enhancement and lobulated contours, centered on the right foramina of D12-L1, with a projection to the intracanal space, which compressed and laterally displaced the dural sac and had a right paravertebral extension between the vertebral bodies of D11 and superior aspect of L2. Ganglioneuroma was diagnosed using immunohistochemical analysis. It was decided to use a surgical approach in two stages: robot assisted for the anterior/retroperitoneal mass and a posterior hemilaminectomy/microsurgical approach to attempt total resection, avoiding the traditional anterior thoracoabdominal surgical incision and optimizing the patient's postoperative outcomes. No postoperative adverse events were noted, and the patient was discharged on postoperative day 5. CONCLUSION: This retroperitoneal GN presentation was peculiar because it originated at the D12 nerve root, which extended to the retroperitoneal space and inside the spinal canal. We hope that our case report can assist future decisions in similar circumstances.

Early tracheostomy in stroke patients: A meta-analysis and comparison with late tracheostomy.

Tracheostomy (TQT) timing and its benefits is a current discussion in medical society. We aimed to compare the outcomes of early (ET) versus late tracheostomy (LT) in stroke patients with systematic review and meta-analysis, according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. Five hundred and nineteen studies were retrieved, whereas three were selected for the systematic review and meta-analysis. There were 5636 patients in the ET group (3151 male, 2470 female, 15 not reported - NR) and 7637 patients in the LT group (4098 male, 3542 female, and 33 NR). ET was significantly associated with fewer days in the hospital (weighted mean difference: -7.73 [95 % CI -8.59-6.86], p < 0.001) and reduced cases of ventilator-associated pneumonia (VAP) (risk difference: 0.71 [95 % CI 0.62-0.81], p < 0.001). There were no between-group statistical differences in intensive care unit stay duration, mechanical ventilation duration, or mortality. The findings from this meta-analysis cannot state that ET in severe stroke patients contributes to better outcomes when compared with LT. Scandalized assessments and randomized trials are encourage for better assessment.

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.

Electrical stimulation of the posterior insula induces mechanical analgesia in a rodent model of neuropathic pain by modulating GABAergic signaling and activity in the pain circuitry.

The insula has emerged as a critical target for electrical stimulation since it influences pathological pain states. We investigated the effects of repetitive electrical stimulation of the insular cortex (ESI) on mechanical nociception, and general locomotor activity in rats subjected to chronic constriction injury (CCI) of the sciatic nerve. We also studied neuroplastic changes in central pain areas and the involvement of GABAergic signaling on ESI effects. CCI rats had electrodes implanted in the left agranular posterior insular cortex (pIC), and mechanical sensitivity was evaluated before and after one or five daily consecutive ESIs (15 min each, 60 Hz, 210 µs, 1 V). Five ESIs (repetitive ESI) induced sustained mechanical antinociception from the first to the last behavioral assessment without interfering with locomotor activity. A marked increase in Fos immunoreactivity in pIC and a decrease in the anterior and mid-cingulate cortex, periaqueductal gray and hippocampus were noticed after five ESIs. The intrathecal administration of the GABAA receptor antagonist bicuculline methiodide reversed the stimulation-induced antinociception after five ESIs. ESI increased GAD65 levels in pIC but did not interfere with GABA, glutamate or glycine levels. No changes in GFAP immunoreactivity were found in this work. Altogether, the results indicate the efficacy of repetitive ESI for the treatment of experimental neuropathic pain and suggest a potential influence of pIC in regulating pain pathways partially through modulating GABAergic signaling.

The Parkinson disease pain classification system: results from an international mechanism-based classification approach.

ABSTRACT: Pain is a common nonmotor symptom in patients with Parkinson disease (PD) but the correct diagnosis of the respective cause remains difficult because suitable tools are lacking, so far. We developed a framework to differentiate PD- from non-PD-related pain and classify PD-related pain into 3 groups based on validated mechanistic pain descriptors (nociceptive, neuropathic, or nociplastic), which encompass all the previously described PD pain types. Severity of PD-related pain syndromes was scored by ratings of intensity, frequency, and interference with daily living activities. The PD-Pain Classification System (PD-PCS) was compared with classic pain measures (ie, brief pain inventory and McGill pain questionnaire [MPQ], PDQ-8 quality of life score, MDS-UPDRS scores, and nonmotor symptoms). 159 nondemented PD patients (disease duration 10.2 ± 7.6 years) and 37 healthy controls were recruited in 4 centers. PD-related pain was present in 122 patients (77%), with 24 (15%) suffering one or more syndromes at the same time. PD-related nociceptive, neuropathic, or nociplastic pain was diagnosed in 87 (55%), 25 (16%), or 35 (22%), respectively. Pain unrelated to PD was present in 35 (22%) patients. Overall, PD-PCS severity score significantly correlated with pain's Brief Pain Inventory and MPQ ratings, presence of dyskinesia and motor fluctuations, PDQ-8 scores, depression, and anxiety measures. Moderate intrarater and interrater reliability was observed. The PD-PCS is a valid and reliable tool for differentiating PD-related pain from PD-unrelated pain. It detects and scores mechanistic pain subtypes in a pragmatic and treatment-oriented approach, unifying previous classifications of PD-pain.

Electrical stimulation of the posterior insula induces mechanical analgesia in a rodent model of neuropathic pain by modulating GABAergic signaling and activity in the pain circuitry

The insula has emerged as a critical target for electrical stimulation since it influences pathological pain states. We investigated the effects of repetitive electrical stimulation of the insular cortex (ESI) on mechanical nociception, and general locomotor activity in rats subjected to chronic constriction injury (CCI) of the sciatic nerve. We also studied neuroplastic changes in central pain areas and the involvement of GABAergic signaling on ESI effects. CCI rats had electrodes implanted in the left agranular posterior insular cortex (pIC), and mechanical sensitivity was evaluated before and after one or five daily consecutive ESIs (15 min each, 60 Hz, 210 μs, 1 V). Five ESIs (repetitive ESI) induced sustained mechanical antinociception from the first to the last behavioral assessment without interfering with locomotor activity. A marked increase in Fos immunoreactivity in pIC and a decrease in the anterior and mid-cingulate cortex, periaqueductal gray and hippocampus were noticed after five ESIs. The intrathecal administration of the GABAA receptor antagonist bicuculline methiodide reversed the stimulation-induced antinociception after five ESIs. ESI increased GAD65 levels in pIC but did not interfere with GABA, glutamate or glycine levels. No changes in GFAP immunoreactivity were found in this work. Altogether, the results indicate the efficacy of repetitive ESI for the treatment of experimental neuropathic pain and suggest a potential influence of pIC in regulating pain pathways partially through modulating GABAergic signaling.

Behavioral and Neural Correlates of Cognitive Training and Transfer Effects in Stroke Patients.

Stroke lesions are frequently followed by cognitive impairments. Cognitive training is a non-pharmacological intervention that can promote neural compensation mechanisms and strategies to remediate cognitive impairments. The aims of this study were: (1) To investigate the cognitive performance, generalization effects, and neural correlates of semantic organization strategy training (SOST) in patients with chronic left frontoparietal stroke and healthy controls (HC); and (2) to compare the behavioral effects and neural correlates of SOST with an active control psychoeducation intervention (PI). In this randomized controlled study, all participants were randomly allocated into two groups, one group received SOST, and the other received PI intervention. Participants underwent two fMRI sessions, one prior and the other, after intervention. In each fMRI session, images were obtained during memory encoding task using a list of semantically related words. We found improved post-intervention memory performance in participants that received SOST (both patients and controls), indicated by number of words recalled, word clustering scores, and performance in a generalization task. The fMRI analysis revealed negative correlation between task performance and regions of the default-mode network. These results suggest that cognitive training using semantic organization strategy can improve episodic memory performance and promote potential functional neuroplasticity in patients with ischemic stroke lesions. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03644290.