Bologna, M

Merola, A

Ricciardi, L

English

St George's Online Research Archive

EDITORIALpublished: 10 January 2020doi: 10.3389/fneur.2019.01350Frontiers in Neurology | www.frontiersin.org 1 January 2020 | Volume 10 | Article 1350Edited and reviewed by:Alberto Albanese,Catholic University of the SacredHeart, Italy*Correspondence:Matteo Bolognamatteo.bologna@uniroma1.itSpecialty section:This article was submitted toMovement Disorders,a section of the journalFrontiers in NeurologyReceived: 21 October 2019Accepted: 09 December 2019Published: 10 January 2020Citation:Bologna M, Merola A and Ricciardi L(2020) Editorial: InnovativeTechnologies and Clinical Applicationsfor Invasive and Non-invasiveNeuromodulation: From theWorkbench to the Bedside.Front. Neurol. 10:1350.doi: 10.3389/fneur.2019.01350Editorial: Innovative Technologiesand Clinical Applications for Invasiveand Non-invasive Neuromodulation:From the Workbench to the BedsideMatteo Bologna 1,2*, Aristide Merola 3 and Lucia Ricciardi 41Department of Human Neurosciences, Sapienza University of Rome, Rome, Italy, 2 IRCCS Neuromed, Pozzilli, Italy,3Department of Neurology, Wexner Medical Center, The Ohio State University, Columbus, OH, United States,4Neurosciences Research Centre, Molecular and Clinical Sciences Research Institute, St. George’s University of London,London, United KingdomKeywords: deep brain stimulation (DBS), Non-invasive focal mechanical vibrations (NIFMV), Parkinson’s disease(PD), spinal cord stimulation (SCS), transcranial magnetic stimulation (TMS), transcranial ultrasound stimulation(tUS)Editorial on the Research TopicInnovative Technologies and Clinical Applications for Invasive and Non-invasiveNeuromodulation: From theWorkbench to the BedsideInvasive and non-invasive brain stimulation represent one of the most promising scientificadvances of the last decades (1). This special issue was designed to highlight and critically discussinnovative neurostimulation procedures for Parkinson’s disease (PD) and other neurologicalconditions. Of the 17 papers initially submitted to the journal by international researchers, 13were considered suitable for publication after a thorough peer-review process. These included fiveoriginal researches, five reviews, one systematic review, one brief research report, and one casereport. The following is a short summary of the main results of each of these manuscripts.Deep Brain Stimulation (DBS) of the subthalamic nucleus (STN), the ventral-intermediatenucleus (VIM), and the globus pallidus pars interna (GPi) are well-established therapeutic optionsfor medically refractory PD, essential tremor, and dystonia (2, 3). However, several aspects relatedto DBS programming and post-surgical management of medications still remain to be clarified. Intheir manuscript, Koeglsperger et al. provide a concise review of strategies for DBS programmingand dopaminergic medications adjustments following DBS. In another review from the samegroup, by Hell et al., summarizes and carefully discusses future perspectives for DBS, includingtarget identification, adaptive closed-loop stimulation, and associated feedback signals.Although STN- and GPi-DBS are both considered effective in reducing levodopa-induceddyskinesia (LID), the comparative efficacy of the two targets on dyskinesia remains unclear. Liuet al. conducted a meta-analysis of studies reporting data on STN- and GPi-DBS efficacy on LID.The authors found that GPi-DBS may reduce dyskinesia to a higher extent than STN-DBS at12 months. This observation implies that mechanisms for dyskinesia reduction may be differentbetween STN- and GPi-DBS. Future studies are needed to clarify the complex biological interactionwith different systems of fibers involved in the modulation of motor symptoms in the two mostcommon targets for DBS in the basal ganglia.STN-DBS may also have a beneficial effect on balance and gait in PD. However, publishedresults yielded variable conclusions. In their prospective controlled study, Szlufik et al. evaluatedthe impact of STN-DBS on balance disorders in PD. The authors found a beneficial effect ofSTN-DBS on static and dynamic instability in the short-term follow-up, while long-term dataremain controversial. Zhang et al., report the case of a PD patient implanted with STN-DBSand complaining of severe speech problems. Tremor and speech problems were both effectivelyBologna et al. Non-invasive Neuromodulation in Movement Disorderstreated by a novel stimulation procedure, i.e., variable-frequency stimulation (VFS) consisting of a combination of highfrequencies. This preliminary observation should be confirmedin future controlled studies. Again, concerning the possibledetrimental effects of DBS, the review paper titled: “A Reviewof Cognitive Outcomes Across Movement Disorder PatientsUndergoing Deep Brain Stimulation,” by Cernera et al. discussthe issue of DBS-associated cognitive declines and adverseeffects on quality of life in PD and other movement disorders.Pathophysiological mechanisms for cognitive changes occurringafter DBS are also discussed.Non-invasive neuromodulation, including TranscranialMagnetic Stimulation (TMS), in movement disorders is achallenging issue for both clinical and research purposes (4–6).Various non-invasive brain stimulation protocols have beenstudied in different conditions and settings. Hence, the reliabilityand validity of non-invasive neuromodulation techniques arestill to be elucidated. In this regard, various methodologicalfactors, possibly influencing the outcome measure, need tobe better investigated. Fricke et al. developed an associativedual-site rTMS (1Hz) targeting the premotor and primarymotor cortex. The protocol aimed to activate different cortico-basal ganglia projections and, therefore, to target pathogenicoscillations at distinct STN subregions. The study resultsdemonstrate that the stimulation was tolerated well, but didnot improve motor symptoms in PD. Even though resultswere negative, this study raises interest toward non-invasivetreatment options for PD symptoms. Furthermore, negativetherapeutic results should not discourage the use of non-invasivestimulation techniques as a tool to investigate pathophysiologicalmechanisms underlying movement disorders. For example,dystonia is a relatively frequent movement disorder with unclearpathophysiology. However, the cerebellum is now considered akey area in the generation of dystonic symptoms. Odorfer et al.combined non-invasive cerebellar stimulation, i.e., continuoustheta-burst stimulation and functional magnetic resonanceimaging techniques, and investigated simple finger tappingin patients with cervical dystonia. Results indicate that fingermovements, although clinically normal, are associated withaltered cerebellar activity, further supporting the hypothesisof a prominent cerebellar involvement in dystonia. Finally, itshould be considered that non-invasive stimulation techniquesalso allow to investigate physiological aspects not necessarilyinvolved in the motor control. For example, mesial corticalareas in the frontal lobe and the ventral striatum are key nodesinvolved in decision-making and executive functions. In theiroriginal research study, including neuroimaging techniques,Popa et al. demonstrate how deep inhibitory rTMS can influencethe underlying network functional connectivity of the targetedmesio-prefrontal-cingulo-striatal circuits regions. The studyemphasizes that the modulation of resting neural activity inmesial prefrontal-striatal circuits by non-invasive techniques asAbbreviations: DBS, Deep Brain Stimulation; GPi, Globus Pallidus internus;LID, levodopa-induced dyskinesia; NIFMV, Non-Invasive Focal MechanicalVibrations; PD, Parkinson’s disease; SCS, Spinal Cord Stimulation; STN,Subthalamic Nucleus; TMS, Transcranial Magnetic Stimulation; tUS, TranscranialUltrasound Stimulation.a potential therapeutic tool for a wide range of psychiatric andneurologic disorders, particularly drug-cue reactivity processesrelevant to addiction.An increasing number of studies on animals and humanssuggest that both the peripheral and the central nervoussystem can be targeted and potentially modulated by ultrasoundstimulation techniques (7). An important aspect concerns thepossibility to suppress or facilitate ongoing neural activity(during stimulation), as well as to induce long-lasting effectsor even tissue ablation. In their review paper, di Biase et al.summarize mechanisms of actions, stimulation parameters, andtherapeutic application of Transcranial Ultrasound Stimulation(tUS) in healthy humans and various disease states. In theiroriginal research article, Gibson et al. demonstrate that tUSdelivered via a commercially available diagnostic imagingultrasound system transiently increases excitability in the motorcortex. The results raise the intriguing possibility of new clinicalapplications for this technology, mainly as a diagnostic imagingfor neuroplasticity induction not only in the motor cortex, butalso in other brain areas. This initial but promising resultsencourage further research studies.Alternative non-invasive stimulation techniques, like SpinalCord Stimulation (SCS) and Non-Invasive Focal MechanicalVibrations (NIFMV), may also improve motor control indifferent neurological diseases (8, 9). The review paper byFonoff et al. summarizes the most relevant advances fromexperimental and clinical studies, including anecdotal reports,on SCS for gait disorders. The author discusses the potentialmechanisms of action, neural substrates, and clinical outcomesof SCS, suggesting that gait abnormalities in parkinsoniansyndromes, particularly freezing of gait, can improve withSCS. However, the authors acknowledge that future well-designed trials are needed to delineate the possible therapeuticapplications for SCS. The results of the pilot open-label trialby Schirinzi et al. indicate that NIFMV represents a feasible,safe, and effective option of supportive therapy for patientswith cerebellar ataxia. More extensive controlled studies arenecessary to confirm these preliminary observations and todefine other critical methodological aspects related to treatmentand eligibility criteria.In conclusion, the editors wish to thank all the authors, thereviewers, and the editorial board members for contributing tothis special issue. We hope that this special issue might inspirefuture and novel research approaches in the field of invasive andnon-invasive neuromodulation in Parkinson’s disease and othermovement disorders.AUTHOR CONTRIBUTIONSAll authors listed have made a substantial, direct and intellectualcontribution to the work, and approved it for publication.FUNDINGAM was supported by NIH (KL2 TR001426). He has receivedspeaker honoraria from Abbott Laboratories and Medtronic.LR was funded by the UK’s Medical Research Council (MRC)Clinical Academic Research Partnerships grant.Frontiers in Neurology | www.frontiersin.org 2 January 2020 | Volume 10 | Article 1350Bologna et al. Non-invasive Neuromodulation in Movement DisordersREFERENCES1. Hallett M, Rothwell J. Milestones in clinical neurophysiology. Mov Disord.(2011) 26:958–67. doi: 10.1002/mds.235722. Eisenstein M. Electrotherapy: shock value. Nature. (2016) 538:S10–2.doi: 10.1038/538S10a3. Kühn AA, Volkmann J. Innovations in deep brain stimulation methodology.Mov Disord. (2017) 32:11–9. doi: 10.1002/mds.267034. Dayan E, Censor N, Buch ER, Sandrini M, Cohen LG. Noninvasive brainstimulation: from physiology to network dynamics and back. Nat Neurosci.(2013) 16:838–44. doi: 10.1038/nn.34225. BolognaM, Suppa A, Conte A, Latorre A, Rothwell JC, Berardelli A. Are studiesof motor cortex plasticity relevant in human patients with Parkinson’s disease?Clin Neurophysiol. (2016) 127:50–9. doi: 10.1016/j.clinph.2015.02.0096. Hallett M, Di Iorio R, Rossini PM, Park JE, Chen R, Celnik P,et al. Contribution of transcranial magnetic stimulation to assessment ofbrain connectivity and networks. Clin Neurophysiol. (2017) 128:2125–39.doi: 10.1016/j.clinph.2017.08.0077. Krishna V, Sammartino F, Rezai A. A review of the current therapies,challenges, and future directions of transcranial focused ultrasound technology:advances in diagnosis and treatment. JAMA Neurol. (2018) 75:246–54.doi: 10.1001/jamaneurol.2017.31298. Murillo N, Valls-Sole J, Vidal J, Opisso E, Medina J, Kumru H. Focalvibration in neurorehabilitation. Eur J Phys Rehabil Med. (2014)50:231–42.9. Yadav AP, Nicolelis MAL. Electrical stimulation of the dorsal columns ofthe spinal cord for Parkinson’s disease. Mov Disord. (2017) 32:820–32.doi: 10.1002/mds.27033Conflict of Interest: The authors declare that the research was conducted in theabsence of any commercial or financial relationships that could be construed as apotential conflict of interest.Copyright © 2020 Bologna, Merola and Ricciardi. This is an open-access articledistributed under the terms of the Creative Commons Attribution License (CC BY).The use, distribution or reproduction in other forums is permitted, provided theoriginal author(s) and the copyright owner(s) are credited and that the originalpublication in this journal is cited, in accordance with accepted academic practice.No use, distribution or reproduction is permitted which does not comply with theseterms.Frontiers in Neurology | www.frontiersin.org 3 January 2020 | Volume 10 | Article 1350

Editorial: Innovative Technologies and Clinical Applications for Invasive and Non-invasive Neuromodulation: From the Workbench to the Bedside.

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Editorial: Innovative Technologies and Clinical Applications for Invasive and Non-invasive Neuromodulation: From the Workbench to the Bedside.

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