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Profiling circulating lipids and metabolites in Parkinson's disease (PD) patients could be useful not only to highlight new pathways affected in PD condition but also to identify sensitive and effective biomarkers for early disease detection and potentially effective therapeutic interventions. In this study we adopted an untargeted omics approach in three groups of patients (No L-Dopa, L-Dopa and DBS) to disclose whether long-term levodopa treatment with or without deep brain stimulation (DBS) could reflect a characteristic lipidomic and metabolomic signature at circulating level. Our findings disclosed a wide up regulation of the majority of differentially regulated lipid species that increase with disease progression and severity. We found a relevant modulation of triacylglycerols and acyl-carnitines, together with an altered profile in adiponectin and leptin, that can differentiate the DBS treated group from the others PD patients. We found a highly significant increase of exosyl ceramides (Hex2Cer) and sphingoid bases (SPB) in PD patients mainly in DBS group (p < 0.0001), which also resulted in a highly accurate diagnostic performance. At metabolomic level, we found a wide dysregulation of pathways involved in the biosynthesis and metabolism of several amino acids. The most interesting finding was the identification of a specific modulation of L-glutamic acid in the three groups of patients. L-glutamate levels increased slightly in No L-Dopa and highly in L-Dopa patients while decreased in DBS, suggesting that DBS therapy might have a beneficial effect on the glutamatergic cascade. All together, these data provide novel insights into the molecular and metabolic alterations underlying PD therapy and might be relevant for PD prediction, diagnosis and treatment., 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 © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The objective of this study was to encompass current knowledge about pathophysiological mechanisms of those specific hand postures or deformities caused by central nervous system disorders. In the era of high-resolution neuroimaging and molecular biology, clinicians are progressively losing confidence with neurological examination. Careful hand observation is of key importance in order to differentiate neurological from non-neurological conditions, central from peripheral aetiologies, and organic from functional disorders. Localizing the potential anatomical site is essential to properly conduct subsequent exams. We provided a practical guide for clinicians to recognize hand patterns caused by central nervous system disorders, avoiding mimicking conditions, thus optimizing and prompting the diagnostic pathway., (© 2024. The Author(s).)

In this work, the authors proposed a novel and interesting animal model for studying human neurodegenerative diseases, Botryllus schlosseri , a small invertebrate inhabiting temperate seas worldwide, which shares remarkable similarities with mammals in the expression of genes involved in pathological aging., Competing Interests: The authors report no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Although deep brain stimulation of the subthalamic nucleus (STN-DBS) induces motor benefits in people with Parkinson's disease (PwPD), the size and duration of the effects of STN-DBS on motor axial (e.g., postural instability, trunk posture alterations) and gait impairments (e.g., freezing of gait - FOG) are still ambiguous. Physical therapy (PT) effectively complements pharmacological treatment to improve postural stability, gait performance, and other dopamine-resistant symptoms (e.g. festination, hesitation, axial motor dysfunctions, and FOG) in PwPD who are non-surgically treated. Despite the potential for positive adjuvant effects of PT following STN-DBS surgery, there is a paucity of science available on the topic. In such a scenario, gathering the opinion and expertise of leading investigators worldwide was pursued to study motor rehabilitation in PwPD following STN-DBS. After summarizing the few available findings through a systematic review, we identified clinical and academically experienced DBS clinicians (n=21) to discuss the challenges related to PT following STN-DBS. A 5-point Likert scale questionnaire was used and based on the results of the systematic review along with a Delphi method. Thirty-nine questions were submitted to the panel - half related to general considerations on PT following STN-DBS, half related to PT treatments. Despite the low-to-moderate quality, the few available rehabilitative studies suggested that PT could improve dynamic and static balance, gait performance and posture. Similarly, panellists strongly agreed that PT might help in improving motor symptoms and quality of life, and it may be possibly prescribed to maximize the effects of the stimulation. The experts agreed that physical therapists could be part of the multidisciplinary team taking care of the patients. Also, they agreed on prescribing of conventional PT, but not massage or manual therapy. Our results will inform the rehabilitation and the DBS community to engage, publish and deepen this area of research. Such efforts may spark guidelines for PT following STN-DBS., Competing Interests: A.F. has received payments as consultant and/or speaker from Abbott, Boston Scientific, Ceregate, Inbrain Neuroelectronics, Medtronic, Iota and has received research support from Boston Scientific, Medtronic. K.D.F. reports receiving research support and fellowship support from Medtronic and Boston Scientific and research support from Functional Neuromodulation. CRB has received support from the NIH (UH3 NS119844) and has served as a consultant for NeuraModix. J.K.K. is a consultant to Medtronic, Boston Scientific, aleva and Inomed. A.A.K. is a consultant to Medtronic, Boston Scientific and Teva. A.M.L. is a consultant to Abbott, Boston Scientific, Insightec, Medtronic and Functional Neuromodulation (Scientific Director). EM has received an educational grant from Boston Scientific and honoraria from Medtronic and Newronika. M.S.O. serves as Medical Advisor in the Parkinson’s Foundation, and has received research grants from NIH, Parkinson’s Foundation, the Michael J. Fox Foundation, the Parkinson Alliance, Smallwood Foundation, the Bachmann-Strauss Foundation, the Tourette Syndrome Association, and the UF Foundation. M.S.O. ‘s research is supported by: R01 NS131342 NIH R01 NR014852, R01NS096008, UH3NS119844, U01NS119562. M.S.O. is PI of the NIH R25NS108939 Training Grant. M.S.O. has received royalties for publications with Hachette Book Group, Demos, Manson, Amazon, Smashwords, Books4Patients, Perseus, Robert Rose, Oxford and Cambridge (movement disorders books). M.S.O. is an associate editor for New England Journal of Medicine Journal Watch Neurology and JAMA Neurology. M.S.O. has participated in CME and educational activities (past 12–24 months) on movement disorders sponsored by WebMD/Medscape, RMEI Medical Education, American Academy of Neurology, Movement Disorders Society, Mediflix and by Vanderbilt University. The institution and not M.S.O. receives grants from industry. M.S.O. has participated as a site PI and/or co-PI for several NIH, foundation, and industry sponsored trials over the years but has not received honoraria. Research projects at the University of Florida receive device and drug donations. A.S. received consulting fees from Abbott, Zambon, and Abbvie, and speaker honoraria from bsh medical communication, Abbott, Kyowa Kirin, Novartis, Abbvie, and Alexion, GE Healtcare. The institution of AS, not AS personally, received funding by the Deutsche Forschungsgemeinschaft, the Brunhilde Moll Foundation, and Abbott. L.T. received occasional payments as a consultant for Boston Scientific, L.T. received honoraria as a speaker on symposia sponsored by Boston Scientific, AbbVIE, Novartis, Neuraxpharm, Teva, the Movement Disorders Society und DIAPLAN. The institution of L.T., not L.T. personally, received funding by Boston Scientific, the German Research Foundation, the German Ministry of Education and Research, the Otto-Loewi-Foundation and the Deutsche Parkinson Vereinigung. Neither L.T. nor any member of his family holds stocks, stock options, patents or financial interests in any of the above-mentioned companies or their competitors. L.T. serves as the president of the German Neurological Society without any payment or any income. V.V.V. received occasional payments as a consultant or speaker on symposia from Boston Scientific and Medtronic. J.V. reports grants and personal fees from Medtronic, grants and personal fees from Boston Scientific, personal fees from Abbott outside the submitted work. J.V. was supported by the German Research Foundation (DFG, Project-ID424778381, TRR 295) – J.V. received consulting and lecture fees from Boston Scientific, Medtronic and Newronika, research grants from the German Research Foundation, the German Ministry of Research and Education, Boston Scientific and Medtronic, lecture Honoraria from UCB, Zambon, Abbott. A.P. and S.M. are founders and shareholders of Newronika Spa, Italy. All other authors declare no competing interests.

Background and Purpose: Boxing is associated with a high risk of head injuries and increases the likelihood of chronic traumatic encephalopathy. This study explores the effects of sub-concussive impacts on boxers by applying both linear and nonlinear analysis methods to electroencephalogram (EEG) data., Methods: Twenty-one boxers were selected (mean ± SD, age 28.38 ± 5.5 years; weight 67.55 ± 8.90 kg; years of activity 6.76 ± 5.45; education 14.19 ± 3.08 years) and divided into 'beginner' and 'advanced' groups. The Montreal Cognitive Assessment and the Frontal Assessment Battery were administered; EEG data were collected in both eyes-open (EO) and eyes-closed (EC) conditions during resting states. Analyses of EEG data included normalized power spectral density (nPSD), power law exponent (PLE), detrended fluctuation analysis and multiscale entropy. Statistical analyses were used to compare the groups., Results: Significant differences in nPSD and PLE were observed between the beginner and advanced boxers, with advanced boxers showing decreased mean nPSD and PLE (nPSD 4-7 Hz, p = 0.013; 8-13 Hz, p = 0.003; PLE frontal lobe F3 EC, p = 0.010). Multiscale entropy analysis indicated increased entropy at lower frequencies and decreased entropy at higher frequencies in advanced boxers (F3 EC, p = 0.024; occipital lobe O1 EO, p = 0.029; occipital lobe O2 EO, p = 0.036). These changes are similar to those seen in Alzheimer's disease., Conclusion: Nonlinear analysis of EEG data shows potential as a neurophysiological biomarker for detecting the asymptomatic phase of chronic traumatic encephalopathy in boxers. This methodology could help monitor athletes' health and reduce the risk of future neurological injuries in sports., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Importance: If history teaches, as cardiac pacing moved from fixed-rate to on-demand delivery in in 80s of the last century, there are high probabilities that closed-loop and adaptive approaches will become, in the next decade, the natural evolution of conventional Deep Brain Stimulation (cDBS). However, while devices for aDBS are already available for clinical use, few data on their clinical application and technological limitations are available so far. In such scenario, gathering the opinion and expertise of leading investigators worldwide would boost and guide practice and research, thus grounding the clinical development of aDBS., Observations: We identified clinical and academically experienced DBS clinicians (n=21) to discuss the challenges related to aDBS. A 5-point Likert scale questionnaire along with a Delphi method was employed. 42 questions were submitted to the panel, half of them being related to technical aspects while the other half to clinical aspects of aDBS. Experts agreed that aDBS will become clinical practice in 10 years. In the present scenario, although the panel agreed that aDBS applications require skilled clinicians and that algorithms need to be further optimized to manage complex PD symptoms, consensus was reached on aDBS safety and its ability to provide a faster and more stable treatment response than cDBS, also for tremor-dominant Parkinson's disease patients and for those with motor fluctuations and dyskinesias., Conclusions and Relevance: Despite the need of further research, the panel concluded that aDBS is safe, promises to be maximally effective in PD patients with motor fluctuation and dyskinesias and therefore will enter into the clinical practice in the next years, with further research focused on algorithms and markers for complex symptoms., Competing Interests: Declaration of interest M.G., N.V.M., S.O., T.B., E.S., Y.T., C.H., P.L. declare no conflict of interest. M.A.P is a consultant for Boston Scientific, Insightec, Medtronic and Abbott. She has received reimbursement of travel expenses to attend scientific meetings by Palex, Boston Scientific and Medtronic. She has received speaker honoraria from Palex. G. Deuschl G.D. has served as a consultant for Boston Scientific and Cavion and as DSMB member for Functional Neuromodulation. He has received royalties from Thieme Publishers and funding from the German Research Council (SFB 1261, T1). A.F. has received payments as consultant and/or speaker from Abbott, Boston Scientific, Ceregate, Inbrain Neuroelectronics, Medtronic, Iota and has received research support from Boston Scientific, Medtronic. R.M.F. has received speaker honoraria from the Spanish Neurological Society research foundation, Insightec, Palex, Bial and Zambon; has a consulting agreement with Treefrog Therapeutics; has received Reimbursement of travel expenses to attend scientific meetings by Palex, Zambon, the International Parkinson and Movement Disorder Society, the IAPDRD and the World Parkinson Congress; and has received research funding from Instituto de Salud Carlos III, Madrid, Spain for health research projects (PI21 Proyectos de investigacion en salud, AES 2021). C.G.S. has received lecture honoraria from Exeltis, Zambon, Palex, Insightec, Fundacion ACE, Societa Italiana Parkinson e Disordini del Movimento and Asociacion Madrilena de Neurologia, and reimbursement of travel expenses to attend scientific conferences from Boston Scientific and Esteve. J.K.K. is a consultant to Medtronic, Boston Scientific, aleva and Inomed A.A.K. is a consultant to Medtronic, Boston Scientific and Teva. S.L. is a consultant for Iota Biosciences and has previously received honorarium from Medtronic. S. L. research is support by NINDS NIH grants R01NS131405, K23NS120037 and Wellcome discovery award 226645/Z/22/Z A.M.L. is a consultant to Abbott, Boston Scientific, Insightec, Medtronic and Functional Neuromodulation (Scientific Director). M.S.O. serves as Medical Advisor in the Parkinson Foundation, and has received research grants from NIH, Parkinson Foundation, the Michael J. Fox Foundation, the Parkinson Alliance, Smallwood Foundation, the Bachmann-Strauss Foundation, the Tourette Syndrome Association, and the UF Foundation. M.S.O. ‘s research is supported by: R01 NS131342 NIH R01 NR014852, R01NS096008, UH3NS119844, U01NS119562. M.S.O. is PI of the NIH R25NS108939 Training Grant. M.S.O. has received royalties for publications with Hachette Book Group, Demos, Manson, Amazon, Smashwords, Books4Patients, Perseus, Robert Rose, Oxford and Cambridge (movement disorders books). M.S.O. is an associate editor for New England Journal of Medicine Journal Watch Neurology and JAMA Neurology. M.S.O. has participated in CME and educational activities (past 12–24 months) on movement disorders sponsored by WebMD/Medscape, RMEI Medical Education, American Academy of Neurology, Movement Disorders Society, Mediflix and by Vanderbilt University. The institution and not M.S.O. receives grants from industry. M.S.O. has participated as a site PI and/or co-I for several NIH, foundation, and industry sponsored trials over the years but has not received honoraria. Research projects at the University of Florida receive device and drug donations. J.L.O. received consulting payments from Abbott, Acorda, Jazz, Adamas, AcureX and Aspen as well as research or training grants from Biogen, Boston scientific, Medtronic, Neuroderm, Runelabs, Abbvie, Merz, Amneal and Acadia. A.S. received consulting fees from Abbott, Zambon, and Abbvie, and speaker honoraria from bsh medical communication, Abbott, Kyowa Kirin, Novartis, Abbvie, and Alexion, GE Healtcare. The institution of AS, not AS personally, received funding by the Deutsche Forschungsgemeinschaft, the Brunhilde Moll Foundation, and Abbott. P.A.S. is compensated for time spent on the data safety and monitoring board for Neuralink, Inc. L.T. received occasional payments as a consultant for Boston Scientific, L.T. received honoraria as a speaker on symposia sponsored by Boston Scientific, AbbVIE, Novartis, Neuraxpharm, Teva, the Movement Disorders Society und DIAPLAN. The institution of L.T., not L.T. personally received funding by Boston Scientific, the German Research Foundation, the German Ministry of Education and Research, the Otto-Loewi-Foundation and the Deutsche Parkinson Vereinigung. Neither L.T. nor any member of his family holds stocks, stock options, patents or financial interests in any of the above-mentioned companies or their competitors. Lars Timmermann serves as the president of the German Neurological Society without any payment or any income. G.T. received financial support from Boston Scientific and Medtronic; Research agreement with RuneLabs and Medtronic not related to the present work V.V.V. received occasional payments as a consultant or speaker on symposia from Boston Scientific and Medtronic. J. Volkmann JV reports grants and personal fees from Medtronic, grants and personal fees from Boston Scientific, personal fees from Abbott outside the submitted work. JV was supported by the German Research Foundation (DFG, Project-ID424778381, TRR 295) - JV received consulting and lecture fees from Boston Scientific, Medtronic and Newronika. Research grants from the German Research Foundation, the German Ministry of Research and Education, Boston Scientific and Medtronic. Lecture Honoraria from UCB, Zambon, Abbott. A.P. and S.M. are founders and shareholders of Newronika Spa, Italy.

The role of brain asymmetries of dopaminergic neurons in motor symptoms of Parkinson's disease is still undefined. Local field recordings from the subthalamic nucleus revealed some neurophysiological biomarkers of the disease: increased beta activity, increased low-frequency activity and high-frequency oscillations. Phase-amplitude coupling coordinates the timing of neuronal activity and allows determining the mechanism for communication within distinct regions of the brain. In this study, we discuss the use of phase-amplitude coupling to assess the differences between the two hemispheres in a cohort of 24 patients with Parkinson's disease before and after levodopa administration. Subthalamic low- (12-20 Hz) and high-beta (20-30 Hz) oscillations were compared with low- (30-45 Hz), medium- (70-100 Hz) and high-frequency (260-360 Hz) bands. We found a significant beta-phase-amplitude coupling asymmetry between left and right and an opposite-side-dependent effect of the pharmacological treatment, which is associated with the reduction of motor symptoms. In particular, high coupling between high frequencies and high-beta oscillations was found during the OFF condition ( P < 0.01) and a low coupling during the ON state ( P < 0.0001) when the right subthalamus was assessed; exactly the opposite happened when the left subthalamus was considered in the analysis, showing a lower coupling between high frequencies and high-beta oscillations during the OFF condition ( P < 0.01), followed by a higher one during the ON state ( P < 0.01). Interestingly, these asymmetries are independent of the motor onset side, either left or right. These findings have important implications for neural signals that may be used to trigger adaptive deep brain stimulation in Parkinson's and could provide more exhaustive insights into subthalamic dynamics., Competing Interests: T.B., R.F., T.A., A.A., and M.G. reported no conflicts of interest. S.M. and A.P. are founders and shareholders of Newronika Spa., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Elderly patients who undergo major surgery (not-neurosurgical) under general anaesthesia frequently complain about cognitive difficulties, especially during the first weeks after surgical "trauma". Although recovery usually occurs within a month, about one out of four patients develops full-blown postoperative Neurocognitive disorders (NCD) which compromise quality of life or daily autonomy. Mild/Major NCD affect approximately 10% of patients from three months to one year after major surgery. Neuroinflammation has emerged to have a critical role in the postoperative NCDs pathogenesis, through microglial activation and the release of pro-inflammatory cytokines which increase blood-brain-barrier permeability, enhance movement of leukocytes into the central nervous system (CNS) and favour the neuronal damage. Moreover, pre-existing Mild Cognitive Impairment, alcohol or drugs consumption, depression and other factors, together with several intraoperative and post-operative sequelae, can exacerbate the severity and duration of NCDs. In this context it is crucial rely on current progresses in serum and CSF biomarker analysis to frame neuroinflammation levels, along with establishing standard protocol for neuropsychological assessment (with specific set of tools) and to apply cognitive training or neuromodulation techniques to reduce the incidence of postoperative NCDs when required. It is recommended to identify those patients who would need such preventive intervention early, by including them in pre-operative and post-operative comprehensive evaluation and prevent the development of a full-blown dementia after surgery. This contribution reports all the recent progresses in the NCDs diagnostic classification, pathogenesis discoveries and possible treatments, with the aim to systematize current evidences and provide guidelines for multidisciplinary care., 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 © 2024 Elsevier Inc. All rights reserved.)

Objective: To assess whether monopolar multi-electrode transcranial direct current stimulation (tDCS) montages might selectively affect deep brain structures through computational predictions and neurophysiological assessment., Methods: Electric field distribution in deep brain structures (i.e., thalamus and midbrain) were estimated through computational models simulating tDCS with two monopolar and two monopolar multi-electrode montages. Monopolar multi-electrode tDCS was then applied to healthy subject, and effects on pontine and medullary circuitries was evaluated studying changes in blink reflex (BR) and masseter inhibitory reflex (MIR)., Results: Computational results suggest that tDCS with monopolar multi-electrode montages might induce electric field intensities in deep brain structure comparable to those in grey matter, while neurophysiological results disclosed that BR and MIR were selectively modulated by tDCS only when cathode was placed over the right deltoid., Conclusions: Multi-electrode tDCS (anodes over motor cortices, cathode over right deltoid) could induce significant electric fields in the thalamus and midbrain, and selectively affect brainstem neural circuits., Significance: Multi-electrode tDCS (anodes over motor cortices, cathode over right deltoid) might be further explored to affect brainstem activity, also in the context of non-invasive deep brain stimulation., Competing Interests: Conflict of Interest Statement M.G., A.M.B., M.P., N.M., M.B., Ros.F., G.L., K.M. and T.B. declare no conflict of interest. R.F. and A.P. are founders and shareholders of Newronika Spa. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines., (Copyright © 2023 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

This scientific commentary refers to 'Long-term analgesic effect of trans-spinal direct current stimulation compared to non-invasive motor cortex stimulation in complex regional pain syndrome, by Hodaj et al . (https://doi.org/10.1093/braincomms/fcad191)., Competing Interests: The authors have no conflicts of interest to declare., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Long COVID syndrome has emerged as a long-lasting consequence of acute SARS-CoV-2 infection in adults. In addition, children may be affected by Long COVID, with potential clinical issues in different fields, including problems in school performance and daily activities. Yet, the pathophysiologic bases of Long COVID in children are largely unknown, and it is difficult to predict who will develop the syndrome. In this multidisciplinary clinical review, we summarise the latest scientific data regarding Long COVID and its impact on children. Special attention is given to diagnostic tests, in order to help the physicians to find potential disease markers and quantify impairment. Specifically, we assess the respiratory, upper airways, cardiac, neurologic and motor and psychological aspects. Finally, we also propose a multidisciplinary clinical approach.

Background and Purpose: Core clinical manifestations of COVID-19 include influenza-like and respiratory symptoms. However, it is now evident that neurological involvement may occur during SARS-CoV-2 infection, covering an extensive spectrum of phenotypical manifestations. A major challenge arising from this pandemic is represented by detecting emerging neurological complications following recovery from SARS-CoV-2 infection. To date, a few post-COVID-19-infected subjects diagnosed with Parkinson disease (PD) have been described, raising the possibility of a connection between the infection and neurodegenerative processes. Here, we describe a case series of six subjects who developed PD after COVID-19., Methods: Patients were observed at Scientific Institute for Research and Health Care Mondino Foundation Hospital, Pavia (Italy), and San Paolo University Hospital of Milan (Italy) between March 2021 and June 2022. In all subjects, SARS-CoV-2 infection was confirmed by means of reverse transcriptase polymerase chain reaction from a nasopharyngeal swab. Subjects underwent an accurate neurological evaluation, and neuroimaging studies were performed., Results: We describe six subjects who developed PD with an average time window after SARS-CoV-2 infection of 4-7 weeks. Apparently, no relationship with COVID-19 severity emerged, and no overt structural brain abnormalities were found. All subjects experienced unilateral resting tremor at onset and showed a satisfactory response to dopaminergic treatment., Conclusions: Immune responses to SARS-CoV-2 infection have been shown to shape the individual susceptibility to develop long-term consequences. We hypothesize that, in these subjects, COVID-19 has unmasked a latent neurodegenerative process. Characterization of the neuroinflammatory signatures in larger cohorts is warranted, which might provide novel insights into the pathogenesis of PD., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Clinical findings suggest that transcutaneous spinal direct current stimulation (tsDCS) can modulate ascending sensitive, descending corticospinal, and segmental pathways in the spinal cord (SC). However, several aspects of the stimulation have not been completely understood, and realistic computational models based on MRI are the gold standard to predict the interaction between tsDCS-induced electric fields and anatomy. Here, we review the electric fields distribution in the SC during tsDCS as predicted by MRI-based realistic models, compare such knowledge with clinical findings, and define the role of computational knowledge in optimizing tsDCS protocols. tsDCS-induced electric fields are predicted to be safe and induce both transient and neuroplastic changes. This could support the possibility to explore new clinical applications, such as spinal cord injury. For the most applied protocol (2-3 mA for 20-30 min, active electrode over T10-T12 and the reference on the right shoulder), similar electric field intensities are generated in both ventral and dorsal horns of the SC at the same height. This was confirmed by human studies, in which both motor and sensitive effects were found. Lastly, electric fields are strongly dependent on anatomy and electrodes' placement. Regardless of the montage, inter-individual hotspots of higher values of electric fields were predicted, which could change when the subjects move from a position to another (e.g., from the supine to the lateral position). These characteristics underlines the need for individualized and patient-tailored MRI-based computational models to optimize the stimulation protocol. A detailed modeling approach of the electric field distribution might contribute to optimizing stimulation protocols, tailoring electrodes' configuration, intensities, and duration to the clinical outcome.

Introduction: Neurological sequelae following SARS-CoV-2 infection still represent a serious concern both for neurologists and neuroscientists. In our paper, we investigated pain, myalgia, and fatigue as symptoms in long-COVID patients with an electrophysiological approach, comprising the evaluation of sympathetic skin responses (SSRs) and quantitative electromyography (qEMG)., Materials and Methods: Twelve patients were enrolled (mean age, 47.7 ± 11.6 years), referred to our attention because of myalgia, pain, or muscle cramps, which persisted about 6 months after the diagnosis of SARS-CoV-2 infection. They underwent conventional electroneurography (ENG), needle electromyography (EMG), and SSRs; moreover, qEMG was performed by sampling at least 20 motor unit potentials (20-30 MUPs) during weak voluntary contraction in deltoid and tibialis anterior muscles. The mean duration, amplitude, and percentage of polyphasic potentials were assessed and compared with healthy and age-matched volunteers., Results: ENG did not disclose significant changes compared to healthy subjects; needle EMG did not reveal denervation activity. In addition, qEMG showed MUPs similar to those recorded in healthy volunteers in terms of polyphasia (deltoid: p = 0.24; TA: p = 0.35), MUP area (deltoid: p = 0.45; TA: p = 0.44), mean duration (deltoid: p = 0.06; TA: p = 0.45), and amplitude (deltoid: p = 0.27; TA: p = 0.63). SSRs were not recordable from lower limbs in seven patients (58%) and from the upper ones in three of them (25%)., Conclusion: Our data suggest an involvement of the autonomic system, with a focus on cholinergic efferent sympathetic activity, without any evidence of myopathic changes., (© 2023. The Author(s).)

Human neuronal loss occurs through different cellular mechanisms, mainly studied in vitro. Here, we characterized neuronal death in B. schlosseri , a marine colonial tunicate that shares substantial genomic homology with mammals and has a life history in which controlled neurodegeneration happens simultaneously in the brains of adult zooids during a cyclical phase named takeover. Using an ultrastructural and transcriptomic approach, we described neuronal death forms in adult zooids before and during the takeover phase while comparing adult zooids in takeover with their buds where brains are refining their structure. At takeover, we found in neurons clear morphologic signs of apoptosis (i.e., chromatin condensation, lobed nuclei), necrosis (swollen cytoplasm) and autophagy (autophagosomes, autolysosomes and degradative multilamellar bodies). These results were confirmed by transcriptomic analyses that highlighted the specific genes involved in these cell death pathways. Moreover, the presence of tubulovesicular structures in the brain medulla alongside the over-expression of prion disease genes in late cycle suggested a cell-to-cell, prion-like propagation recalling the conformational disorders typical of some human neurodegenerative diseases. We suggest that improved understanding of how neuronal alterations are regulated in the repeated degeneration-regeneration program of B. schlosseri may yield mechanistic insights relevant to the study of human neurodegenerative diseases.

Background: Focal extracorporeal shock wave therapy (fESWT) is a physical therapy vastly studied and used for various musculoskeletal disorders. However, the effect of fESWT on central nervous system is still to be determined., Objective: To elucidate spinal and supra-spinal mechanisms of fESWT in healthy subjects, in order to widen the spectrum of its clinical applications., Methods: In this quasi-experimental, unblinded, proof-of-concept clinical study, 10 voluntary healthy subjects underwent fESWT and were assessed immediately before (T0), immediately after (T1) and seven days after (T2) the intervention. As neurophysiological outcomes, motor evoked potentials (resting motor threshold, maximal motor evoked potential and maximal compound muscle action potential ratio, cortical silent period, total conduction motor time, direct and indirect central motor conduction time), F-waves (minimal and mean latency, persistence and temporal dispersion) and H-reflex (threshold, amplitude, maximal H reflex and maximal compound muscle action potential ratio, latency) were considered., Results: Resting motor threshold and F-waves temporal dispersion significantly decreased, respectively, from T1 and T2 and from T0 and T2 (for both, p <  0.05). H-reflex threshold increase between T0 and T1. Analysis disclosed a strong negative correlation between Δ3 cortical silent period (i.e., T2 -T1 recordings) and Δ1 Hr threshold (i.e., T1 -T0 recordings) (r = -0.66, p <  0.05), and a positive strong relationship between Δ3 cortical silent period and Δ3 Hr threshold (r = 0.63, p <  0.05)., Conclusions: fESWT modulates corticospinal tract excitability in healthy volunteers, possibly inducing an early inhibition followed by a later facilitation after one week.

The cerebellum is involved in multiple closed-loops circuitry which connect the cerebellar modules with the motor cortex, prefrontal, temporal, and parietal cortical areas, and contribute to motor control, cognitive processes, emotional processing, and behavior. Among them, the cerebello-thalamo-cortical pathway represents the anatomical substratum of cerebellum-motor cortex inhibition (CBI). However, the cerebellum is also connected with basal ganglia by disynaptic pathways, and cerebellar involvement in disorders commonly associated with basal ganglia dysfunction (e.g., Parkinson's disease and dystonia) has been suggested. Lately, cerebellar activity has been targeted by non-invasive brain stimulation (NIBS) techniques including transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) to indirectly affect and tune dysfunctional circuitry in the brain. Although the results are promising, several questions remain still unsolved. Here, a panel of experts from different specialties (neurophysiology, neurology, neurosurgery, neuropsychology) reviews the current results on cerebellar NIBS with the aim to derive the future steps and directions needed. We discuss the effects of TMS in the field of cerebellar neurophysiology, the potentials of cerebellar tDCS, the role of animal models in cerebellar NIBS applications, and the possible application of cerebellar NIBS in motor learning, stroke recovery, speech and language functions, neuropsychiatric and movement disorders., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Non-Invasive Brain Stimulation (NIBS) techniques, such as transcranial Direct Current Stimulation (tDCS) and repetitive Magnetic Transcranial Stimulation (rTMS), are well-known non-pharmacological approaches to improve both motor and non-motor symptoms in patients with neurodegenerative disorders. Their use is of particular interest especially for the treatment of cognitive impairment in Alzheimer's Disease (AD), as well as axial disturbances in Parkinson's (PD), where conventional pharmacological therapies show very mild and short-lasting effects. However, their ability to interfere with disease progression over time is not well understood; recent evidence suggests that NIBS may have a neuroprotective effect, thus slowing disease progression and modulating the aggregation state of pathological proteins. In this narrative review, we gather current knowledge about neuroprotection and NIBS in neurodegenerative diseases (i.e., PD and AD), just mentioning the few results related to stroke. As further matter of debate, we discuss similarities and differences with Deep Brain Stimulation (DBS)-induced neuroprotective effects, and highlight possible future directions for ongoing clinical studies.

Transcranial electrical stimulation (tES) techniques, such as direct current stimulation (tDCS) and transcranial alternating current stimulation (tACS), cause neurophysiological and behavioral modifications as responses to the electric field are induced in the brain. Estimations of such electric fields are based mainly on computational studies, and in vivo measurements have been used to expand the current knowledge. Here, we review the current tDCS- and tACS-induced electric fields estimations as they are recorded in humans and non-human primates using intracerebral electrodes. Direct currents and alternating currents were applied with heterogeneous protocols, and the recording procedures were characterized by a tentative methodology. However, for the clinical stimulation protocols, an injected current seems to reach the brain, even at deep structures. The stimulation parameters (e.g., intensity, frequency and phase), the electrodes' positions and personal anatomy determine whether the intensities might be high enough to affect both neuronal and non-neuronal cell activity, also deep brain structures.

Implanting deep brain stimulation (DBS) electrodes in patients with Parkinson's disease often results in the appearance of a non-infectious, delayed-onset edema that disappears over time. However, the time window between the DBS electrode and DBS stimulating device implant is often used to record local field potentials (LFPs) which are used both to better understand basal ganglia pathophysiology and to improve DBS therapy. In this work, we investigated whether the presence of post-surgery edema correlates with the quality of LFP recordings in eight patients with advanced Parkinson's disease implanted with subthalamic DBS electrodes. The magnetic resonance scans of the brain after 8.5 ± 1.5 days from the implantation surgery were segmented and the peri-electrode edema volume was calculated for both brain hemispheres. We found a correlation ( ρ = -0.81, p < 0.0218, Spearman's correlation coefficient) between left side local field potentials of the low beta band (11-20 Hz) and the edema volume of the same side. No other significant differences between the hemispheres were found. Despite the limited sample size, our results suggest that the effect on LFPs may be related to the edema localization, thus indicating a mechanism involving brain networks instead of a simple change in the electrode-tissue interface., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Prenassi, Borellini, Bocci, Scola, Barbieri, Priori, Ferrucci, Cogiamanian, Locatelli, Rampini, Vergari, Pastore, Datola and Marceglia.)

Background and Rationale: Hyperkinetic movement disorders represent a heterogeneous group of diseases, different from a genetic and clinical perspective. In the past, neurophysiological approaches provided different, sometimes contradictory findings, pointing to an impaired cortical inhibition as a common electrophysiological marker. Our aim was to evaluate changes in interhemispheric communication in patients with idiopathic cervical dystonia (ICD) and spinocerebellar ataxias (SCAs)., Materials and Methods: Eleven patients with ICD, 7 with genetically confirmed SCA2 or SCA3, and 10 healthy volunteers were enrolled. The onset latency and duration of the ipsilateral silent period (iSPOL and iSPD, respectively), as well as the so-called transcallosal conduction time (TCT), were then recorded from the abductor pollicis brevis of the right side using an 8-shaped focal coil with wing diameters of 70 mm; all these parameters were evaluated and compared among groups. In SCAs, changes in neurophysiological measures were also correlated to the mutational load., Results: iSPD was significantly shorter in patients with SCA2 and SCA3, when compared both to control and ICD ( P < .0001); iSPOL and TCT were prolonged in SCAs patients ( P < .001). Changes in iSPD, iSPOL, and TCT in SCAs are significantly correlated with the mutational load ( P = .01, P = .02, and P = .002, respectively)., Discussion: This is the first study to assess changes in interhemispheric communication in patients with SCAs and ICD, using a transcranial magnetic stimulation protocol. Together with previous data in Huntington's disease, we suggest that these changes may underlie, at least in part, a common disease mechanism of polyglutamine disorders.

Movement disorders as well as peripheral neuropathies are extremely frequent in the general population; therefore, it is not uncommon to encounter patients with both these conditions. Often, the coexistence is coincidental, due to the high incidence of common causes of peripheral neuropathy, such as diabetes and other age-related disorders, as well as of Parkinson disease (PD), which has a typical late onset. Nonetheless, there is broad evidence that PD patients may commonly develop a sensory and/or autonomic polyneuropathy, triggered by intrinsic and/or extrinsic mechanisms. Similarly, some peripheral neuropathies may develop some movement disorders in the long run, such as tremor, and rarely dystonia and myoclonus, suggesting that central mechanisms may ensue in the pathogenesis of these diseases. Although rare, several acquired or hereditary causes may be responsible for the combination of movement and peripheral nerve disorders as a unique entity, some of which are potentially treatable, including paraneoplastic, autoimmune and nutritional aetiologies. Finally, genetic causes should be pursued in case of positive family history, young onset or multisystemic involvement, and examined for neuroacanthocytosis, spinocerebellar ataxias, mitochondrial disorders and less common causes of adult-onset cerebellar ataxias and spastic paraparesis. Deep phenotyping in terms of neurological and general examination, as well as laboratory tests, neuroimaging, neurophysiology, and next-generation genetic analysis, may guide the clinician toward the correct diagnosis and management., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Introduction: Clinical neurophysiology deals with nervous system functions assessed with electrophysiological and ultrasound-based imaging techniques. Even though the need for highly specialized neurophysiologists has increased, residency training rarely takes today's requirements into account. This study aimed to snapshot the neurophysiological training provided by Italian specialization schools in neurology., Methods: A single-page web-based survey comprising 13 multiple-choice categorical and interval scale questions was sent via e-mail to neurology specialization school directors. The survey addressed the programs' structural neurophysiology organization, time dedicated to each clinical neurophysiology subspecialty, and descriptors assessing the discipline's importance (e.g., residents who attempted residential courses, gained certifications, or awards gained)., Results: The most studied neurophysiological techniques were electroencephalography (EEG) and electromyography (EMG). Most specialization schools devoted less than 3 months each to multimodal evoked potentials (EPs), ultrasound sonography (US), and intra-operative monitoring. Of the 35 specialization schools surveyed, 77.1% reported that four students, or fewer, participated in the Italian Society of Clinical Neurophysiology Examination in Neurophysiology. Of the 35 specialization centers surveyed, 11.4% declared that the final evaluation required students to discuss a neurophysiological test., Discussion: Our survey underlined the poorly standardized technical requirements in postgraduate neurology specialization schools, wide variability among training programs, and limited training on multi-modal evoked potentials, intraoperative monitoring, and sonography. These findings underline the need to reappraise and improve educational and training standards for clinical neurophysiology during postgraduate specialization schools in neurology with an international perspective., (© 2021. The Author(s).)

The emergence of SARS-CoV-2 and its related disease caused by coronavirus (COVID-19) has posed a huge threat to the global population, with millions of deaths and the creation of enormous social and healthcare pressure. Several studies have shown that besides respiratory illness, other organs may be damaged as well, including the heart, kidneys, and brain. Current evidence reports a high frequency of neurological manifestations in COVID-19, with significant prognostic implications. Importantly, emerging literature is showing that the virus may spread to the central nervous system through neuronal routes, hitting the brainstem and cardiorespiratory centers, potentially exacerbating the respiratory illness. In this systematic review, we searched public databases for all available evidence and discuss current clinical and pre-clinical data on the relationship between the lung and brain during COVID-19. Acknowledging the involvement of these primordial brain areas in the pathogenesis of the disease may fuel research on the topic and allow the development of new therapeutic strategies.

Objectives: To evaluate spectra and their correlations with clinical symptoms of local field potentials (LFP) acquired from wide- and close-spaced contacts (i.e. between contacts 0-3 or LFP03, and contacts 1-2 or LFP12 respectively) on the same DBS electrode within the subthalamus (STN) in Parkinson's disease (PD), before and after levodopa administration., Methods: LFP12 and LFP03 were recorded from 20 PD patients. We evaluated oscillatory power, local and switched phase-amplitude coupling (l- and Sw-PAC) and correlation with motor symptoms (UPDRSIII)., Results: Before levodopa, both LFP03 and LFP12 power in the α band inversely correlated with UPDRSIII. Differences between contacts were found in the low-frequency bands power. After levodopa, differences in UPDRSIII were associated to changes in LFP03 low-β and LFP12 HFO (high frequency oscillations, 250-350 Hz) power, while a modulation of the low-β power and an increased β-LFO (low frequency oscillations, 15-45 Hz) PAC was found only for LFP12., Conclusion: This study reveals differences in spectral pattern between LFP12 and LFP03 before and after levodopa administration, as well as different correlations with PD motor symptoms., Significance: Differences between LFP12 and LFP03 may offer an opportunity for optimizing adaptive deep brain stimulation (aDBS) protocols for PD. LFP12 can be used to detect β-HFO coupling and β power (i.e. bradykinesia), while LFP03 are optimal for low frequency oscillations (dyskinesias)., 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 © 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Background and Rationale: Histopathological studies revealed degeneration of the dorsal motor nucleus of the vagus nerve (VN) early in the course of idiopathic Parkinson's disease (IPD). Degeneration of VN axons should be detectable by high-resolution ultrasound (HRUS) as a thinning of the nerve trunk. In order to establish if the VN exhibits sonographic signs of atrophy in IPD, we examined patients with IPD compared with age-matched controls., Material and Methods: We measured the caliber (cross-sectional area, CSA) and perimeter of the VN in 20 outpatients with IPD (8 females and 12 males; mean age 73.0 + 8.6 years) and in age-matched controls using HRUS. Evaluation was performed by blinded raters using an Esaote MyLab Gamma device in conventional B-Mode with an 8-19 MHz probe., Results: In both sides, the VN CSA was significantly smaller in IPD outpatients than in controls (right 2.37 + 0.91, left 1.87 + 1.35 mm 2 versus 6.0 + 1.33, 5.6 + 1.26 mm 2 ; p <0.001), as well as the perimeter (right 5.06 + 0.85, left 4.78 + 1.74 mm versus 8.87 + 0.86, 8.58 + 0.97 mm; p <0.001). There were no significant correlations between VN CSA and age, the Hoehn and Yahr scale, L-dopa therapy, and disease duration., Conclusion: Our findings provide evidence of atrophy of the VNs in IPD patients by HRUS. Moreover, HRUS of the VN represent a non-invasive easy imaging modality of screening in IPD patients independent of disease stage and duration and an interesting possible additional index of disease., (© 2021. The Author(s).)

Introduction: Neurological complications of SARS-CoV-2 disease have received growing attention, but only few studies have described to date clinical and neurophysiological findings in COVID patients during their stay in intensive care units (ICUs). Here, we neurophysiologically assessed the presence of either critical illness neuropathy (CIP) or myopathy (CIM) in ICU patients., Materials and Methods: Patients underwent a neurophysiological assessment, including bilateral examination of the median, ulnar, deep peroneal and tibial motor nerves and of the median, ulnar, radial and sural sensory nerves. Needle electromyography (EMG) was performed for both distal and proximal muscles of the lower and upper limbs. In order to differentiate CIP from CIM, Direct Muscle Stimulation (DMS) was applied either to the deltoid or tibialis anterior muscles. Peak to peak amplitudes and onset latencies of the responses evoked by DMS (DMS amp , DMS lat ) or by motor nerve stimulation (MNS amp , MNS lat ) were compared. The ratio MNS amp to DMS amp (NMR) and the MNS lat to DMS lat difference (NMD: MNS lat  - DMS lat ) were also evaluated., Results: Nerve conduction studies showed a sensory-motor polyneuropathy with axonal neurogenic pattern, as confirmed by needle EMG. Both MNS amp and NMR were significantly reduced when compared to controls (p < 0.0001), whereas MNS lat and NMD were markedly increased (p = 0.0049)., Conclusions: We have described COVID patients in the ICU with critical illness neuropathy (CIP). COVID-related CIP could have implications for the functional recovery and rehabilitation strategies., (© 2021. Fondazione Società Italiana di Neurologia.)

This study compares the effects on motor symptoms between conventional deep brain stimulation (cDBS) and closed-loop adaptive deep brain stimulation (aDBS) in patients with Parkinson's Disease. The aDBS stimulation is controlled by the power in the beta band (12-35 Hz) of local field potentials recorded directly by subthalamic nucleus electrodes. Eight subjects were assessed in two 8-h stimulation sessions (first day, cDBS; second day, aDBS) with regular levodopa intake and during normal daily activities. The Unified Parkinson's Disease Rating Scale (UPDRS) part III scores, the Rush scale for dyskinesias, and the total electrical energy delivered to the tissues per second (TEEDs) were significantly lower in the aDBS session (relative UPDRS mean, cDBS: 0.46 ± 0.05, aDBS: 0.33 ± 0.04, p = 0.015; UPDRS part III rigidity subset mean, cDBS: 2.9143 ± 0.6551 and aDBS: 2.1429 ± 0.5010, p = 0.034; UPDRS part III standard deviation cDBS: 2.95, aDBS: 2.68; p = 0.047; Rush scale, cDBS 2.79 ± 0.39 versus aDBS 1.57 ± 0.23, p = 0.037; cDBS TEEDs mean: 28.75 ± 3.36 µj s -1 , aDBS TEEDs mean: 16.47 ± 3.33, p = 0.032 Wilcoxon's sign rank test). This work further supports the safety and effectiveness of aDBS stimulation compared to cDBS in a daily session, both in terms of motor performance and TEED to the patient., (© 2021. The Author(s).)

Background and Aims: Chronic pain is a complex clinical condition, often devastating for patients and unmanageable with pharmacological treatments. Converging evidence suggests that transcutaneous spinal Direct Current Stimulation (tsDCS) might represent a complementary therapy in managing chronic pain. In this randomized, double-blind and sham-controlled crossover study, we assessed tsDCS effects in chronic pain patients. Methods: Sixteen patients (aged 65.06 ± 16.16 years, eight women) with chronic pain of different etiology underwent sham and anodal tsDCS (anode over the tenth thoracic vertebra, cathode over the somatosensory cortical area: 2.5 mA, 20 min, 5 days for 1 week). As outcomes, we considered the Visual Analog Scale (VAS), the Neuropathic Pain Symptom Inventory (NPSI), and the components of the lower limb flexion reflex (LLFR), i.e., RIII threshold, RII latency and area, RIII latency and area, and flexion reflex (FR) total area. Assessments were conducted before (T0), immediately at the end of the treatment (T1), after 1 week (T2) and 1 month (T3). Results: Compared to sham, anodal tsDCS reduced RIII area at T2 ( p = 0.0043) and T3 ( p = 0.0012); similarly, FR total area was reduced at T3 ( p = 0.03). Clinically, anodal tsDCS dampened VAS at T3 ( p = 0.015), and NPSI scores at T1 ( p = 0.0012), and T3 ( p = 0.0015), whereas sham condition left them unchanged. Changes in VAS and NPSI scores linearly correlated with the reduction in LLFR areas ( p = 0.0004). Conclusions: Our findings suggest that tsDCS could modulate nociceptive processing and pain perception in chronic pain syndromes., Competing Interests: RF, MV, SB, and AP are founders and shareholders of Newronika Spa. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Guidetti, Ferrucci, Vergari, Aglieco, Naci, Versace, Pacheco-Barrios, Giannoni-Luza, Barbieri, Priori and Bocci.)

Parkinson's disease (PD) is a proteinopathy associated with the aggregation of α-synuclein and the formation of lipid-protein cellular inclusions, named Lewy bodies (LBs). LB formation results in impaired neurotransmitter release and uptake, which involve membrane traffic and require lipid synthesis and metabolism. Lipids, particularly ceramides, are accumulated in postmortem PD brains and altered in the plasma of PD patients. Autophagy is impaired in PD, reducing the ability of neurons to clear protein aggregates, thus worsening stress conditions and inducing neuronal death. The inhibition of ceramide synthesis by myriocin (Myr) in SH-SY5Y neuronal cells treated with preformed α-synuclein fibrils reduced intracellular aggregates, favoring their sequestration into lysosomes. This was associated with TFEB activation, increased expression of TFEB and LAMP2, and the cytosolic accumulation of LC3II, indicating that Myr promotes autophagy. Myr significantly reduces the fibril-related production of inflammatory mediators and lipid peroxidation and activates NRF2, which is downregulated in PD. Finally, Myr enhances the expression of genes that control neurotransmitter transport (SNARE complex, VMAT2, and DAT), whose progressive deficiency occurs in PD neurodegeneration. The present study suggests that counteracting the accumulation of inflammatory lipids could represent a possible therapeutic strategy for PD.

Background: Adaptive Deep Brain Stimulation (aDBS) is now considered as a new feasible and effective paradigm to deliver DBS to patients with Parkinson's disease (PD) in such a way that not only stimulation is personalized and finely tuned to the instantaneous patient's state, but also motor improvement is obtained with a lower amount of energy transferred to the tissue. Amplitude-controlled aDBS was shown to significantly decrease the amplitude-driven total electrical energy delivered to the tissue (aTEED), an objective measure of the amount of energy transferred by DBS amplitude to the patient's brain. However, there is no direct evidence of a relationship between aTEED and the occurrence of DBS-related adverse events in humans. Objective: In this work, we investigated the correlation of aTEED with the occurrence of levodopa-induced dyskinesias pooling all the data available from our previous experiments using aDBS and cDBS. Methods: We retrospectively analyzed data coming from 19 patients with PD undergoing surgery for STN-DBS electrode positioning and participating to experiments involving cDBS and aDBS delivery. Patients were all studied some days after the surgery (acute setting). The aTEED and dyskinesia assessments (Rush Dyskinesia Rating Scale, RDRS) considered in the Med ON-Stim ON condition. Results: We confirmed both that aTEED values and RDRS were significantly lower in the aDBS than in cDBS sessions (aTEED mean value, cDBS: 0.0278 ± 0.0011 j, vs. aDBS: 0.0071 ± 0.0003 j, p < 0.0001 Wilcoxon's rank sum; normalized RDRS mean score, cDBS: 0.66 ± 0.017 vs. aDBS: 0.45 ± 0.01, p = 0.025, Wilcoxon's rank sum test). In addition, we found a direct significant correlation between aTEED and RDRS (ρ = 0.44, p = 0.0032, Spearman's correlation). Conclusions: Our results provide a first piece of evidence that aTEED is correlated to the amount of levodopa-induced dyskinesias in patients with PD undergoing STN-DBS, thus supporting the role of aDBS as feasible and safe alternative to cDBS., Competing Interests: SM, AP, SB, FC, PR, and ML are founder and shareholder of Newronika SpA, a spin-off company of the Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico and of the University of Milan. MA was employed by the company Newronika SpA. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Prenassi, Arlotti, Borellini, Bocci, Cogiamanian, Locatelli, Rampini, Barbieri, Priori and Marceglia.)

The COVID-19 pandemic has forced governments to impose quarantines and lockdowns as containment strategy, raising concerns about mental health and low level of physical activity performed by quarantined populations. In this study, we assess the level of physical activity and psychological wellbeing in a sample of the Italian population during lockdown through an online format of International Physical Activity Questionnaire (IPAQ) and Psychological General Well-Being index-Short version (PGWB-S) . Of 317 adult responders considered, most were female (61.2%), young adults (52.4%), living in little-to-medium size cities (80.1%) and with high-level education (62.8%). Most of our sample performed physical activity mostly during leisure time and domestic activities, and 60.9% were highly active. No interactions were found between physical activity and the demographic characteristics considered. Subjects performing high level of physical activity felt more energetic and vital than those with moderate ( p < 0.0001) and low levels ( p < 0.0001) of physical activity. Our participants performed enough activity to satisfy the WHO Guidelines, mainly due to domestic activity and activity performed during leisure time, with an overall moderately positive psychological reaction to lockdown.

Despite transcranial Direct Current Stimulation (DCS) is currently proposed as a symptomatic treatment in Parkinson's disease, the intracellular and molecular mechanisms elicited by this technique are still unknown, and its disease-modifying potential unexplored. Aim of this study was to elucidate the on-line and off-line effects of DCS on the expression, aggregation and degradation of alpha-synuclein (asyn) in a human neuroblastoma cell line under basal conditions and in presence of pharmachologically-induced increased asyn levels. Following DCS, gene and protein expression of asyn and its main autophagic catabolic pathways were assessed by real-time PCR and Western blot, extracellular asyn levels by Dot blot. We found that, under standard conditions, DCS increased monomeric and reduced oligomeric asyn forms, with a concomitant down-regulation of both macroautophagy and chaperone-mediated autophagy. Differently, in presence of rotenone-induced increased asyn, DCS efficiently counteracted asyn accumulation, not acting on its gene transcription, but potentiating its degradation. DCS also reduced intracellular and extracellular asyn levels, increased following lysosomal inhibition, independently from autophagic degradation, suggesting that other mechanisms are also involved. Collectively, these findings suggest that DCS exerts on-line and off-line effects on the expression, aggregation and autophagic degradation of asyn, indicating a till unknown neuroprotective role of tDCS.

Objective : Hereditary spastic paraplegia (HSP) represents a heterogeneous group of neurodegenerative diseases characterized by progressive spasticity and lower limb weakness. We assessed the effects of transcutaneous spinal direct current stimulation (tsDCS) in HSP. Design: A double-blind, randomized, crossover and sham-controlled study. Setting : Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, Milan. Participants : eleven patients with HSP (six men, mean age ± SD: 37.3 ± 8.1 years), eight affected by spastin/SPG4,1 by atlastin1/SPG3a, 1 by paraplegin/SPG7 and 1 by ZFYVE26/SPG15. Interventions : tsDCS (anodal or sham, 2.0 mA, 20', five days) delivered over the thoracic spinal cord (T10-T12). Outcome measures: Motor-evoked potentials (MEPs), the H-reflex (Hr), F-waves, the Ashworth scale for clinical spasticity, the Five Minutes Walking test and the Spastic Paraplegia Rating Scale (SPRS) were assessed. Patients were evaluated before tsDCS ( T 0 ), at the end of the stimulation ( T 1 ), after one week ( T 2 The score of the Ashworth scale improved in the anodal compared with sham group, up to two months following the end of stimulation (T T , P = .0137; T 3 ) and two months ( T 4 ). Results: The score of the Ashworth scale improved in the anodal compared with sham group, up to two months following the end of stimulation (T 1 , P = .0137; T 4 , P = .0244), whereas the Five Minutes Walking test and SPRS did not differ between the two groups. Among neurophysiological measures, both anodal and sham tsDCS left Hr, F-waves and MEPs unchanged over time. Conclusions: Anodal tsDCS significantly decreases spasticity and might be a complementary strategy for the treatment of spasticity in HSP.

The aim of this study was to assess cerebrospinal fluid (CSF) concentrations of specific amino acids using a high-performance liquid chromatography system in a sample of patients with functional movement disorders (FMDs) and in a sample of controls. CSF levels of glutamate were significantly lower in patients with FMD than in controls. This finding argues in favor of glutamatergic dysfunction in the pathophysiology of FMD.

Introduction: In recent years, a growing body of literature has investigated the use of non-invasive brain stimulation (NIBS) techniques as a putative treatment in Huntington's Disease (HD). Our aim was to evaluate the effects of cerebellar transcranial Direct Current Simulation (ctDCS) on the motor outcome in patients affected by HD, encompassing at the same time the current knowledge about the effects of NIBS both on motor and non-motor dysfunctions in HD. Materials and Methods: Four patients (two females) were enrolled and underwent ctDCS (both anodal or sham, elapsed by at least 3 months: 2.0 mA, 20 min per day, 5 days a week). Clinical scores were assessed by using the Unified Huntington's Disease Rating Scale - part I (UHDRS-I), immediately before ctDCS (T 0 ), at the end of the 5-days treatment (T 1 ) and 4 weeks later (T 2 ). Results: Anodal ctDCS improved motor scores compared to baseline ( p = 0.0046), whereas sham stimulation left them unchanged ( p = 0.33, Friedman test). In particular, following anodal ctDCS, UHDRS-I score significantly improved, especially regarding the subitem "dystonia," both at T 1 and T 2 compared to sham condition ( p < 0.05; Wilcoxon matched-pairs signed test). Conclusions: ctDCS improved motor scores in HD, with effects lasting for about 4 weeks after tDCS completion. This is the first study discussing the putative role of cerebellar non-invasive simulation for the treatment of HD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Bocci, Baloscio, Ferrucci, Sartucci and Priori.)

This review focuses on new and/or less standardized event-related potentials methods, in order to improve their knowledge for future clinical applications. The olfactory event-related potentials (OERPs) assess the olfactory functions in time domain, with potential utility in anosmia and degenerative diseases. The transcranial magnetic stimulation-electroencephalography (TMS-EEG) could support the investigation of the intracerebral connections with very high temporal discrimination. Its application in the diagnosis of disorders of consciousness has achieved recent confirmation. Magnetoencephalography (MEG) and event-related fields (ERF) could improve spatial accuracy of scalp signals, with potential large application in pre-surgical study of epileptic patients. Although these techniques have methodological limits, such as high inter- and intraindividual variability and high costs, their diffusion among researchers and clinicians is hopeful, pending their standardization.

Background: Mutations in TGM6 gene, encoding for transglutaminase 6 (TG6), have been implicated in the pathogenesis of spinocerebellar ataxia type 35 (SCA35), a rare autosomal dominant disease marked by cerebellar degeneration and characterized by postural instability, incoordination of gait, features of cerebellar dysfunction and pyramidal signs., Case Presentation: Here we report the case of an Italian patient with late-onset, slowly progressive cerebellar features, including gait ataxia, scanning speech and ocular dysmetria and pyramidal tract signs. Whole exome sequencing revealed the rare heterozygous c.1024C > T (p.R342W) variant of TGM6, located at a highly evolutionary conserved position and predicted as pathogenic by in silico tools. Expression of TG6-R342W mutant in HEK293T cells led to a significant reduction of transamidase activity compared to wild-type TG6., Conclusion: This finding extends SCA35 genetic landscape, highlighting the importance of TGM6 screening in undiagnosed late-onset and slowly progressive cerebellar ataxias.