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Objectives: To investigate the plastic effects of parieto-motor (PAR-MOT) cortico-cortical paired associative paired stimulation (cc-PAS) in patients with two forms of focal dystonia, writer's cramp and cervical dystonia, compared to healthy volunteers (HVs)., Methods: We used cc-PAS to induce associative plasticity using repeated time-locked paired transcranial magnetic stimulation (TMS) pulses over the parietal and motor cortices in 16 patients with writer's cramp (WC), 13 patients with cervical dystonia (CD), and 23 healthy volunteers. We measured parieto-motor corticocortical connectivity using posterior parietal cortex (PPC) to primary motor cortex (M1) facilitation and input-output curves (IOC) of the motor-evoked potential (MEP) before and after PAR-MOT cc-PAS. The PAR-MOT cc-PAS consisted of 100 pairs of TMS pulses every 5 s, with the conditioning pulse applied to the left angular gyrus in the intraparietal sulcus and the test pulse applied to the M1 hotspot of the first dorsal interosseous muscle., Results: The cc-PAS increased the area under the IOC by increasing its maximum level in patients with WC but not in patients with CD or healthy volunteers. The cc-PAS had no significant effect on other IOC parameters. There were no significant differences in PPC to M1 facilitation changes after PAR-MOT cc-PAS among all groups., Conclusions: This study suggests that PAR-MOT cc-PAS abnormally increases M1 excitability in patients with WC but not in those with CD. Additionally, this increased plastic response in patients with WC does not appear to be directly linked to PPC to M1 corticocortical connectivity., Competing Interests: Declaration of competing interest All authors report no conflicts of interest., (Copyright © 2024. Published by Elsevier Inc.)

Aim: Acromegaly is a rare chronic disease, caused by the over-secretion of growth hormone (GH), that creates a pro-inflammatory state, but the exact mechanisms by which GH or insulin-like growth factor 1 (IGF-I) act on inflammatory cells are not fully understood. Aim of the study was to evaluate Interleukin-33 (IL33) and D-series resolvins 1 (RvD1) and the skin perfusion of hands in patients with acromegaly (AP) and healthy controls (HC)., Methods: IL33 and RvD1 have been assessed in 20 AP and 20 HC. Nailfold videocapillaroscopy (NVC) was performed and skin perfusion of hands was assessed by laser speckle contrast analysis (LASCA) in both populations., Results: IL33 was significantly higher in AP compared to HC [73.08 pg/ml (IQR 47.11-100.80 pg/ml) vs 41.5 4 pg/ml (IQR 20.16-55.49 pg/ml), p < 0.05] and RvD1 was significantly lower in AP than HC [36.1 pg/ml (IQR 27.88-66.21 pg/ml) vs 60.01 pg/ml (IQR 46.88-74.69 pg/ml), p < 0.05]. At LASCA, peripheral blood perfusion (PBP) was significantly lower in AP compared to HC [56.66 pU (IQR 46.29-65.44 pU) vs 87 pU (IQR 80-98 pU), p < 0.001]. The median values of ROI1 and ROI3 were significantly lower in AP compared to HC [112.81 pU (IQR 83.36-121.69 pU) vs 131 pU (IQR 108-135 pU), p < 0.05] and [59.78 pU (IQR 46.84-79.75 pU) vs 85 pU (IQR 78-98 pU), p < 0.05], respectively. The proximal-distal gradient (PDG) was observed in 8 of 20 (40 %) AP., Conclusion: Serum IL33 is higher in AP compared to HC; conversely, RvD1 is lower in AP compared to HC. Reduction of PBP of hands was present in AP compared to HC, probably due to endothelial dysfunction., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Motor fatigue is one of the most common symptoms in multiple sclerosis (MS) patients. Previous studies suggested that increased motor fatigue in MS may arise at the central nervous system level. However, the mechanisms underlying central motor fatigue in MS are still unclear. This paper investigated whether central motor fatigue in MS reflects impaired corticospinal transmission or suboptimal primary motor cortex (M1) output (supraspinal fatigue). Furthermore, we sought to identify whether central motor fatigue is associated with abnormal M1 excitability and connectivity within the sensorimotor network. Twenty-two patients affected by relapsing-remitting MS and 15 healthy controls (HCs) performed repeated blocks of contraction at different percentages of maximal voluntary contraction with the right first dorsal interosseus muscle until exhaustion. Peripheral, central, and supraspinal components of motor fatigue were quantified by a neuromuscular assessment based on the superimposed twitch evoked by peripheral nerve and transcranial magnetic stimulation (TMS). Corticospinal transmission, excitability and inhibition during the task were tested by measurement of motor evoked potential (MEP) latency, amplitude, and cortical silent period (CSP). M1 excitability and connectivity was measured by TMS-evoked electroencephalography (EEG) potentials (TEPs) elicited by M1 stimulation before and after the task. Patients completed fewer blocks of contraction and showed higher values of central and supraspinal fatigue than HCs. We found no MEP or CSP differences between MS patients and HCs. Patients showed a post-fatigue increase in TEPs propagation from M1 to the rest of the cortex and in source-reconstructed activity within the sensorimotor network, in contrast to the reduction observed in HCs. Post-fatigue increase in source-reconstructed TEPs correlated with supraspinal fatigue values. To conclude, MS-related motor fatigue is caused by central mechanisms related explicitly to suboptimal M1 output rather than impaired corticospinal transmission. Furthermore, by adopting a TMS-EEG approach, we proved that suboptimal M1 output in MS patients is associated with abnormal task-related modulation of M1 connectivity within the sensorimotor network. Our findings shed new light on the central mechanisms of motor fatigue in MS by highlighting a possible role of abnormal sensorimotor network dynamics. These novel results may point to new therapeutical targets for fatigue in MS., Competing Interests: Declaration of Competing Interest The authors report no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Over the past 30 years, Botulinum toxin (BoNT) has emerged as an effective and safe therapeutic tool for a number of neurological conditions, including dystonia. To date, the exact mechanism of action of BoNT in dystonia is not fully understood. Although it is well known that BoNT mainly acts on the neuromuscular junction, a growing body of evidence suggests that the therapeutic effect of BoNT in dystonia may also depend on its ability to modulate peripheral sensory feedback from muscle spindles. Animal models also suggest a retrograde and anterograde BoNT transportation from the site of injection to central nervous system structures. In humans, however, BoNT central effects seem to depend on the modulation of afferent input rather than on BoNT transportation. In this chapter, we aimed to report and discuss research evidence providing information on the possible mechanisms of action of BoNT in relation to treatment of dystonia., (Copyright © 2023. Published by Elsevier Inc.)

Neural oscillations can be modulated by non-invasive brain stimulation techniques, including transcranial alternating current stimulation (tACS). However, direct evidence of tACS effects at the cortical level in humans is still limited. In a tACS-electroencephalography co-registration setup, we investigated the ability of tACS to modulate cortical somatosensory information processing as assessed by somatosensory-evoked potentials (SEPs). To better elucidate the neural substrates of possible tACS effects we also recorded peripheral and spinal SEPs components, high-frequency oscillations (HFOs), and long-latency reflexes (LLRs). Finally, we studied whether changes were limited to the stimulation period or persisted thereafter. SEPs, HFOs, and LLRs were recorded during tACS applied at individual mu and beta frequencies and at the theta frequency over the primary somatosensory cortex (S1). Sham-tACS was used as a control condition. In a separate experiment, we assessed the time course of mu-tACS effects by recording SEPs before (T0), during (T1), and 1 min (T2) and 10 min (T3) after stimulation. Mu-tACS increased the amplitude of the N20 component of SEPs compared to both sham and theta-tACS. No differences were found between sham, beta-, and theta-tACS conditions. Also, peripheral and spinal SEPs, P25, HFOs, and LLRs did not change during tACS. Finally, mu-tACS-induced modulation of N20 amplitude specifically occurred during stimulation (T1) and vanished afterwards (i.e., at T2 and T3). Our findings suggest that TACS applied at the individual mu frequency is able to modulate early somatosensory information processing at the S1 level and the effect is limited to the stimulation period., Competing Interests: Declarations of Competing Interest None., (Copyright © 2022. Published by Elsevier Inc.)

Background: The aim of this study was to evaluate the role of Color Doppler Ultrasonography (CDUS) of proper palmar digital arteries (PPDA) as predictive marker of new digital ulcers (DUs) in systemic sclerosis (SSc) patients during 5 years follow-up., Methods: 36 SSc patients were examined using nailfold videocapillaroscopy (NVC) and CDUS of PPDA., Results: Fourteen (38.9%) patients had chronic or acute occlusions (C and D pattern) on CDUS evaluation. Using a cut-off of 0.70, 21 (58.3%) patients had a Resistive Index (RI) ≥0.70. Nineteen (52.8%) patients developed new DUs during the follow-up. The median value of RI was higher in SSc patients with DUs than in SSc patients without DUs [0.73 (IQR 0.70-0.81) vs 0.67 (IQR 0.57-0.70), p < 0.0001]. The Kaplan-Meier analysis showed a free survival from new DUs higher (p < 0.01) in SSc patients with Pattern A and B than SSc patients with Pattern C and D. The Kaplan-Meier curves showed that free survival from new DUs is lower (p < 0.001) in SSc patients with increased RI (≥0.70) than in SSc patients with normal RI. In multivariate analysis with two co-variates, RI ≥ 0.70 [HR 5.197 (1.471-18.359), p < 0.01] and NVC late scleroderma pattern [HR 7.087 (1.989-25.246), p < 0.01] were predictive markers of new DUs., Conclusions: RI of PPDA in association with NVC could be used to evaluate SSc patients with increased risk of new DUs development., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives: To evaluate expansion of CD21 low B cells and their role in B cell homeostasis, apoptosis, clinical manifestations and serum vascular endothelial growth factor (VEGF) in systemic sclerosis (SSc)., Materials and Methods: B-cells subpopulations and apoptosis have been assessed in 74 SSc patients and 20 healthy donors. Renal Doppler ultrasound, echocardiography, pulmonary function test and VEGF were performed., Results: SSc patients with expanded CD21 low B cells (SSc-CD21 low ) show a distinct B cell profile with increased memory B cells compared to patients without CD21 low B cells (SSc-CD21 + ). Renal resistive index, systolic pulmonary arterial pressure and FVC/DLCO ratio were significantly higher in SSc-CD21 low group than SSc-CD21 + , DLCO was lower in SSc-CD21 low group than SSc-CD21 + . We found a positive linear correlation between CD21 low and sPAP, RI and FVC/DLCO ratio whereas a negative correlation was observed between CD21 low and DLCO and VEGF levels., Conclusions: CD21 low B cells are increased in SSc patients with visceral vascular manifestations., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)