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A significant body of experimental evidence has demonstrated that it is possible to induce the illusion of ownership of a fake limb or even an entire fake body using multisensory correlations. Recently, immersive virtual reality has allowed users to experience the same sensations of ownership over a virtual body inside an immersive virtual environment, which in turn allows virtual reality users to have the feeling of being “embodied” in a virtual body. Using such virtual embodiment to manipulate body perception is starting to be extensively investigated and may have clinical implications for conditions that involve altered body image such as chronic pain. Here, we review experimental and clinical studies that have explored the manipulation of an embodied virtual body in immersive virtual reality for both experimental and clinical pain relief. We discuss the current state of the art, as well as the challenges faced by, and ideas for, future research. Finally, we explore the potentialities of using an embodied virtual body in immersive virtual reality in the field of neurorehabilitation, specifically in the field of pain.

Antagonism of transient receptor potential ankyrin type-1 (TRPA1) channels counteracts the experimentally induced trigeminal neuralgia (TN) pain. TRPA1 channels activated/sensitized by inflammatory stimuli can modulate glial cell activity, a driving force for pathological pain. Additionally, the evidence of a link between TRPA1 and the inflammatory-related Toll-like receptors 4 (TLR4) and 7 (TLR7) highlights the potential of the TRPA1-blocking strategy to reduce pain and inflammation in TN. In this study, we aimed to further investigate the putative involvement of TRPA1 channels in the inflammatory pathways following the development of TN. We focused on the possible modulation of glial activity after TRPA1 blockade and the crosstalk of TRPA1 with TLR7 and TLR4. In a rat model of TN, based on chronic constriction injury of the infraorbital nerve, the impact of TRPA1 antagonism through ADM_12 treatment was assessed following the onset of mechanical allodynia (26 days post-surgery). The evaluation of central and peripheral inflammatory mediators (by rt-PCR and ELISA) and immunofluorescence staining of glial expression in the trigeminal nucleus caudalis was investigated using plasma samples and areas related to the trigeminal system (trigeminal ganglion and areas containing the trigeminal nucleus caudalis). Compared to sham-operated rats, the TN-like animals showed significant increases in the number of microglial and astroglial cells in the trigeminal nucleus caudalis, with higher and lower protein plasma levels of pro-inflammatory and anti-inflammatory cytokines, respectively. Additionally, in the trigeminal-related areas, TN-like animals showed significantly higher gene expression levels of TLR4, TLR7, miR-let-7b, and high-mobility group box-1. TRPA1 antagonism reverted all the observed alterations in TN-like rats in the trigeminal-related areas and plasma except microglial cell number in the trigeminal nucleus caudalis. The findings suggest that, in addition to their known involvement in the nociceptive pathway, TRPA1 channels may also play a direct or indirect role in pain-related inflammation, through the activation of TLR4- and TLR7-mediated pathways at the neuronal and glial levels.

The aim of this study was to determine which supervised machine learning (ML) algorithm can most accurately classify people with Parkinson’s disease (pwPD) from speed-matched healthy subjects (HS) based on a selected minimum set of IMU-derived gait features. Twenty-two gait features were extrapolated from the trunk acceleration patterns of 81 pwPD and 80 HS, including spatiotemporal, pelvic kinematics, and acceleration-derived gait stability indexes. After a three-level feature selection procedure, seven gait features were considered for implementing five ML algorithms: support vector machine (SVM), artificial neural network, decision trees (DT), random forest (RF), and K-nearest neighbors. Accuracy, precision, recall, and F1 score were calculated. SVM, DT, and RF showed the best classification performances, with prediction accuracy higher than 80% on the test set. The conceptual model of approaching ML that we proposed could reduce the risk of overrepresenting multicollinear gait features in the model, reducing the risk of overfitting in the test performances while fostering the explainability of the results.

BackgroundMonoclonal antibodies (mABs) targeting the calcitonin gene-related peptide (CGRP) pathway represent the first disease-specific preventive migraine therapy. Growing evidence suggests that they are effective in the preventive treatment of difficult-to-treat patients. In this study, we evaluated the psychological predictors of the outcome of treatment with the anti-CGRP monoclonal antibody erenumab in patients with chronic migraine (CM).MethodsSeventy-five patients with CM who had already failed at least 3 preventive therapies received erenumab every 28 days for a period of 12 months. Before the first administration, patients received a full psychological evaluation using The Structured Clinical Interview for DSM-5 Clinician Version (SCID-5-CV) to assess personality disturbances (primary outcome), mood and anxiety disorders, and as well specific questionnaires to evaluate alexithymia traits, childhood traumas, and current stressors (secondary outcomes).ResultsAfter 12 months of treatment, 53 patients reported a reduction of at least 50% in headache days/per month (Responders), whereas 22 did not (Non Responders). When compared to Responders, Non Responders were characterized by a higher prevalence of personality disorders belonging to Cluster C (avoidant, dependent, and obsessive-compulsive) (77% vs 37%, p = .001). Non Responders were also characterized by a higher prevalence of anxiety disorders (90% vs 60%, p = 0.007), showed more alexithymic traits (51.7 ± 13.7 vs 42.9 ± 14.3, p = 0.017), and reported a higher number of 'at least serious' current stressors (3.2 ± 4.0 vs 0.8 ± 1.4, p < .0001) than Responders. At the multivariate analysis, higher prevalence of Cluster C personality disorders (OR 3.697; p = 0.05) and higher number of ‘at least serious’ life events (OR 1.382; p = 0.017) arose as prognostic factors of erenumab failure.ConclusionsErenumab confirmed its effectiveness in a population of difficult-to-treat migraine. The presence of “anxious-fearful” personality together with current stressors and anxiety represent negative predictors of treatment outcome.Trial registrationThe study protocol was registered at clinicaltrials.gov (NCT04361721).

In the past few years the scientific community has witnessed a prodigious surge in research activity, publication of data and progress in understanding the mechanistic components of migraine. This renaissance is the result of efforts initiated decades ago that are finally being translated into benefits for individuals affected by this disease.Key advancesTrials have demonstrated that monoclonal antibodies that target calcitonin gene-related peptide 1 induce marked improvements (>75%) among a small but meaningful proportion of patients with chronic migraine1 or episodic migraine2.Noninvasive vagal nerve stimulation delivered with two short-duration stimulations at the neck level has proved effective in the treatment of migraine attacks: one-third of patients achieved pain-free status at 2 h (ref.4).Preclinical data support the idea that pituitary adenylate cyclase-activating polypeptide and its G-protein-coupled receptors are viable targets for new migraine treatments8.Intriguing findings obtained in a migraine-specific animal model point to another potential pathway implicated in migraine pain: inhibition of acid-sensing ion channels prevents cephalic allodynia10.

Purpose To evaluate secondary outcomes including changes in functioning and disability associated with galcanezumab, a humanized monoclonal antibody to calcitonin gene-related peptide, in patients with chronic migraine. Methods Patients randomly received galcanezumab (120 mg n  = 278, 240 mg n  = 277) or placebo ( n  = 558) during 3 months of double-blind treatment, followed by a 9-month open-label extension. The Migraine-Specific Quality-of-Life Questionnaire v2.1 (MSQv2.1) measured the impact of migraine on patient functioning. The Migraine Disability Assessment (MIDAS) quantified headache-related disability. Changes from baseline were analyzed with mixed model repeated measures or analysis of covariance. Results Total MSQ score at baseline was 44.88 ± 18.02 (mean ± SD), indicating significant functional impairment. At Month 3, least squares (LS) mean change ± SE in total MSQ for galcanezumab-treated patients were 20.51 ± 1.49 (120 mg) and 20.49 ± 1.49 (240 mg), both statistically significantly greater vs placebo-treated patients (14.55 ± 1.21; both P  < 0.001). Total MIDAS score at baseline was 67.24 ± 57.31 (mean ± SD). At Month 3, LS mean change ± SE from baseline in total MIDAS for galcanezumab-treated patients was statistically significantly greater than placebo for 120 mg group (placebo: − 11.53 ± 3.38 vs 120 mg: − 20.27 ± 4.07; P  < 0.05) but not for 240 mg group (− 17.02 ± 4.05). At Month 12, within-group mean changes from baseline for total MSQ (28.56 ± 1.19 previous placebo; 29.53 ± 1.51 previous 120 mg; 25.83 ± 1.49 previous 240 mg) and MIDAS scores (− 28.47 ± 2.95 previous placebo; − 31.47 ± 3.69 previous 120 mg; − 31.13 ± 3.62 previous 240 mg) were statistically significant ( P  < 0.001) for the open-label treatment population regardless of previous double-blind treatment assignment. Conclusions Galcanezumab-treated patients with chronic migraine reported statistically significant improvements in functioning and disability, representing a clinically significant change. Trial registration ClinicalTrials.gov registry: NCT02614261. Registered 25 November 2015.

BackgroundIn Parkinson’s disease (PD), physical activity may represent a possible non-pharmacological intervention not only for improving motor symptoms but also for modulating cognitive impairment.AimsTo evaluate the efficacy of an intensive physical program on cognitive functions in mid-stage PD patients with mild cognitive impairment (PD-MCI) over a 6-month follow-up.MethodsThis is a 6-month randomized controlled follow-up study. 40 PD-MCI patients were randomized to receive physical therapy (PT) or no specific intervention beside drug treatment (CT). Cognitive and motor assessments were performed at baseline (T0), 4 weeks after baseline (T1) and 6 months after T0. In a previous study, we reported a significant improvement in global cognitive functioning and attention/working-memory at T1. Here, we evaluated the residual effect of the training intervention at 6 months on both cognitive and motor performances.ResultsIntra-group analysis showed that at T2 most of cognitive and motor performances remained stable in the PT when compared to T0, while a significant worsening was observed in the CT. Between-group comparison at T2 showed significantly better results in PT than CT as regards MoCA and motor scales. The percentage change of cognitive and motor performances between T1 and T2 confirmed the benefit of physical therapy on global cognitive functioning scores (MMSE and MoCA).ConclusionsIn this follow-up extension of a longitudinal randomized controlled study, we demonstrated that physical therapy has a positive effect on cognitive functions, which extends beyond the duration of the treatment itself to, at least temporarily, reducing cognitive decline.Trial registrationTrial registration number (ClinicalTrials.gov): NCT04012086 (9th July 2019).

Preclinical data point to the contribution of transient receptor potential ankyrin 1 (TRPA1) channels to the complex mechanisms underlying migraine pain. TRPA1 channels are expressed in primary sensory neurons, as well as in glial cells, and they can be activated/sensitized by inflammatory mediators. The aim of this study was to investigate the relationship between TRPA1 channels and glial activation in the modulation of trigeminal hyperalgesia in preclinical models of migraine based on acute and chronic nitroglycerin challenges. Rats were treated with ADM_12 (TRPA1 antagonist) and then underwent an orofacial formalin test to assess trigeminal hyperalgesia. mRNA levels of pro- and anti-inflammatory cytokines, calcitonin gene-related peptide (CGRP) and glia cell activation were evaluated in the Medulla oblongata and in the trigeminal ganglia. In the nitroglycerin-treated rats, ADM_12 showed an antihyperalgesic effect in both acute and chronic models, and it counteracted the changes in CGRP and cytokine gene expression. In the acute nitroglycerin model, ADM_12 reduced nitroglycerin-induced increase in microglial and astroglial activation in trigeminal nucleus caudalis area. In the chronic model, we detected a nitroglycerin-induced activation of satellite glial cells in the trigeminal ganglia that was inhibited by ADM_12. These findings show that TRPA1 antagonism reverts experimentally induced hyperalgesia in acute and chronic models of migraine and prevents multiple changes in inflammatory pathways by modulating glial activation.

BackgroundThe effectiveness of computer-based cognitive training (CCT) remains controversial, especially in older adults with neurodegenerative diseases.AimsTo evaluate the efficacy of CCT in patients with Parkinson’s disease and mild cognitive impairment (PD-MCI).MethodsIn this randomized controlled trial, 53 patients were randomized to receive CCT delivered by means of CoRe software, traditional paper-and-pencil cognitive training (PCT), or an unstructured activity intervention (CG). In each group, the intervention lasted 3 consecutive weeks (4 individual face-to-face sessions/week). Neuropsychological assessment was administered at baseline (T0) and post-intervention (T1). Outcome measures at T0 and T1 were compared within and between groups. The Montreal Overall Cognitive Assessment (MoCA) was taken as the primary outcome measure.ResultsUnlike the PCT group and the CG, the patients receiving CCT showed significant medium/large effect size improvements in MoCA performance, global cognition, executive functions, and attention/processing speed. No baseline individual/demographic variables were associated with greater gains from the intervention, although a negative correlation with baseline MoCA performance was found.ConclusionCCT proved effective in PD-MCI patients when compared with traditional PCT. Further follow-up assessments are being conducted to verify the retention of the gains and the potential ability of the tool to delay conversion to PD-dementia.Trial registration number (ClinicalTrials.gov): NCT04111640 (30th September 2019).

BackgroundCalcitonin gene related peptide (CGRP) is a key neuropeptide involved in the activation of the trigeminovascular system and it is likely related to migraine chronification. Here, we investigated the role of CGRP in an animal model that mimics the chronic migraine condition via repeated and intermittent nitroglycerin (NTG) administration. We also evaluated the modulatory effect of topiramate on this experimental paradigm. Male Sprague-Dawley rats were injected with NTG (5 mg/kg, i.p.) or vehicle, every 2 days over a 9-day period (5 total injections). A group of animals was injected with topiramate (30 mg/kg, i.p.) or saline every day for 9 days. Twenty-four hours after the last administration of NTG or vehicle, animals underwent tail flick test and orofacial Von Frey test. Rats were subsequently sacrificed to evaluate c-Fos and CGRP gene expression in medulla-pons region, cervical spinal cord and trigeminal ganglia.ResultsNTG administration induced spinal hyperalgesia and orofacial allodynia, together with a significant increase in the expression of CGRP and c-Fos genes in trigeminal ganglia and central areas. Topiramate treatment prevented NTG-induced changes by reversing NTG-induced hyperalgesia and allodynia, and inhibiting CGRP and c-Fos gene expression in all areas evaluated.ConclusionsThese findings point to the role of CGRP in the processes underlying migraine chronification and suggest a possible interaction with gamma-aminobutyrate (GABA) and glutamate transmission to induce/maintain central sensitization and to contribute to the dysregulation of descending pain system involved in chronic migraine.