The Role of MER Processing Pipelines for STN Functional Identification During DBS Surgery: A Feature-Based Machine Learning Approach Vincenzo Levi, Stefania Coelli, Chiara Gorlini, Federica Forzanini, Sara Rinaldo, Nico Golfrè Andreasi, Luigi Romito, Roberto Eleopra, Anna Maria Bianchi Bioengineering, 2025 Microelectrode recording (MER) is commonly used to validate preoperative targeting during subthalamic nucleus (STN) deep brain stimulation (DBS) surgery for Parkinson’s Disease (PD). Although machine learning (ML) has been used to improve STN localization using MER data, the impact of preprocessing steps on the accuracy of classifiers has received little attention. We evaluated 24 distinct preprocessing pipelines combining four artifact removal strategies, three outlier handling methods, and optional feature normalization. The effect of each data processing procedure’s component of interest was evaluated in function of the performance obtained using three ML models. Artifact rejection methods (i.e., unsupervised variance-based algorithm (COV) and background noise estimation (BCK)), combined with optimized outlier management (i.e., statistical outlier identification per hemisphere (ORH)) consistently improved classification performance. In contrast, applying hemisphere-specific feature normalization prior to classification led to performance degradation across all metrics. SHAP (SHapley Additive exPlanations) analysis, performed to determine feature importance across pipelines, revealed stable agreement with regard to influential features across diverse preprocessing configurations. In conclusion, optimal artifact rejection and outlier treatment are essential in preprocessing MER for STN identification in DBS, whereas preliminary feature normalization strategies may impair model performance. Overall, the best classification performance was obtained by applying the Random Forest model to the dataset treated using COV artifact rejection and ORH outlier management (accuracy = 0.945). SHAP-based interpretability offers valuable guidance for refining ML pipelines. These insights can inform robust protocol development for MER-guided DBS targeting.
Simultaneous MEG-LFP Recordings to Assess In Vivo Dystonic Neurophysiological Networks: A Feasibility Study Elisa Visani, Lorenzo Bergamini, Chiara Gorlini, Dunja Duran, Nico Golfrè Andreasi, Giovanna Zorzi, Eleonora Minacapilli, Davide Rossi Sebastiano, Paola Lanteri, Daniele Cazzato, Roberto Eleopra, Vincenzo Levi Brain Sciences, 2025 Background/Objectives: Subcortical local field potentials (LFPs) provide a valuable in vivo window into the neurophysiology of the dystonia network. These signals can be recorded through Deep Brain Stimulation (DBS) devices and combined with whole-head techniques such as magnetoencephalography (MEG) to study cortical–subcortical interactions. However, simultaneous LFP-MEG acquisition poses challenges, including interference from the DBS device and synchronization issues. We present preliminary data on the feasibility and signal quality of concurrent LFP and MEG recordings in dystonia patients. Methods: We assessed simultaneous MEG-LFP recordings in 11 patients with inherited or idiopathic dystonia who underwent bilateral DBS lead implantation in the Globus Pallidus Internus (GPi). Two synchronization strategies were tested: (1) the Tapping method, using an accelerometer placed on the DBS device, and (2) the Stimulation method, which generated detectable artifacts during sham stimulation. Results: Both methods successfully aligned MEG and LFP signals with a mean temporal delay of 91 ± 22 ms for the Tapping method and 288 ± 166 ms for the Stimulation method. Post-implantation signal-to-noise ratio analysis revealed slight degradation but no significant impact on MEG quality (gradiometers: −0.12 ± 1.85 dB; magnetometers: −0.47 ± 2.03 dB). Conclusions: Simultaneous MEG-LFP recordings in dystonic patients are feasible, yielding high-quality signals, and reliable synchronization. Temporal alignment improved with practice, suggesting a short learning curve. This method opens new opportunities to study cortical-subcortical dynamics and strengthens the potential of combining MEG-LFP approaches for investigating dystonia.
Long-Term Motor and Cognitive Outcome of Deep Brain Stimulation in Patients With Parkinson Disease With a GBA1 Pathogenic Variant Micol Avenali, Carlo Alberto Artusi, Roberto Cilia, Giulia Giannini, Giada Cuconato, Alberto Albanese, Nico Golfrè Andreasi, Pietro Antenucci, Angelo Antonini, Laura Avanzino, Luca Baldelli, Anna Rita Bentivoglio, Francesco Bove, Marco Bozzali, Giovanna Calandra-Buonaura, Ilaria Cani, Valerio Carelli, Francesco Cavallieri, Antoniangela Cocco, Filippo Cogiamanian, Fabiana Colucci, Pietro Cortelli, Alesssandro De Biase, Francesca Di Biasio, Alessio Di Fonzo, Valentina D'Onofrio, Roberto Eleopra, Antonio Emanuele Elia, Valentina Fioravanti, Danilo Genovese, Andrea Guerra, Alberto Imarisio, Claudia Ledda, Marco Liccari, Chiara Longo, Leonardo Lopiano, Maria Chiara Malaguti, Rachele Malito, Francesca Mameli, Silvia Marino, Raffaella Minardi, Pierfrancesco Mitrotti, Edoardo Monfrini, Claudio Pacchetti, Carla Piano, Vittorio Rispoli, Mario Giorgio Rizzone, Luigi Michele Romito, Luisa Sambati, Mariachiara Sensi, Chiara Sorbera, Francesca Spagnolo, Cristina Tassorelli, Francesca Valentino, Franco Valzania, Roberta Zangaglia, Maurizio Zibetti, , Enza Maria Valente, Valentina Leta, Sylvie Piacentini, Ilaria Palmieri, Marta Picascia, Stefania Lalli, Paola Polverino, Paola Mandich, Roberta Marchese, Giuseppe Di Lorenzo, Amelia Brigandi, Giulia Di Lazzaro, Martina Petracca, Ilaria Trezzi, Emanuele Frattini, Alessia Fiorentino, Pietro Guaraldi Neurology, 2025 BACKGROUND AND OBJECTIVES: genotype and DBS on long-term motor and nonmotor outcomes. METHODS: variant class and DBS target. RESULTS: -between <0.001 and 0.02, respectively), regardless of DBS. No relevant differences emerged on stratification for variant classes or DBS targets, up to 3 years postsurgery. DISCUSSION: Despite its retrospective design, this study supports DBS as a valid therapeutic option for GBA-PD, providing prolonged benefits on motor symptoms and quality of life. The accelerated cognitive decline observed in GBA-PD, compared with non-mutated participants, was similarly present in both operated and non-operated groups, suggesting it is driven by the genotype rather than DBS itself. CLASSIFICATION OF EVIDENCE: -associated PD.
Deep Brain Stimulation for VPS16-Related Dystonia: A Multicenter Study Tatiana Svorenova, Luigi M. Romito, Ahmet Kaymak, Eoin Mulroy, Laura Cif, Elena Moro, Kirsten E. Zeuner, Simone Zittel, Jan Niklas Petry‐Schmelzer, Doreen Gruber, Liesanne Centen, Alberto Albanese, Miriama Ostrozovicova, Vladimir Han, Veronika Magocova, Kamil Knorovsky, Aurelia Kollova, Barbara Garavaglia, Nico Golfrè‐Andreasi, Chiara Reale, Alberto Mazzoni, Giovanna Zorzi, Roberto Eleopra, Vincenzo Levi, Thomas Foltynie, Patricia Limousin, Harith Akram, Ludvic Zrinzo, Francesca Magrinelli, David Murphy, Henry Houlden, Manju A. Kurian, Claudio Baiata, Steffen Paschen, Katja Lohmann, Jens Volkmann, Wolfgang Hamel, Michael T. Barbe, Martje E. van Egmond, MAJ Tijssen, Lubos Ambro, Veronika Jurkova, Robert Jech, Petra Havrankova, Juliane Winkelmann, Michael Zech, Matej Skorvanek Annals of Neurology, 2025 ObjectiveThe objective was to evaluate the effects of deep brain stimulation (DBS) in an international cohort of patients with VPS16‐related dystonia.MethodsThis observational study collected preoperative and postoperative demographic, clinical, stimulation, genetic, neuroimaging, and neurophysiological data of medically refractory DYT‐VPS16 patients with implanted DBS in 10 international centers. Motor symptoms and disability outcomes were assessed using the Burke‐Fahn‐Marsden Dystonia Rating Scale Motor (BFMDRS‐M) and Disability (BFMDRS‐D) scales. A cut‐off threshold for considering response to DBS was set at 25% of BFMDRS‐M improvement at the last follow‐up (FU) compared to baseline.ResultsThe cohort consisted of 26 participants (17 men, 65.4%). Age at dystonia onset and surgery was 17.8 ± 10.9 and 35.3 ± 14.8 years, respectively. At the last FU, 102.5 ± 57.3 months (range, 2–216), the mean BFMDRS‐M improvement was 41.6 ± 37.3% (26/26 patients) and 34.8 ± 42.6% for the BFMDRS‐D (23/26 patients). Most patients (19/26, 73%) were considered responders. Higher motor improvement was associated with stimulation of the ventroposterior portion of the internal globus pallidus. A significant inverse relationship was observed between improvement in BFMDRS‐M at last FU, and the presence of spasticity (p = 0.027) and fixed skeletal deformities (p = 0.001) before surgery. Non‐responders had a younger age at disease onset and at implantation, shorter disease duration at DBS surgery, and higher baseline BFMDRS scores.InterpretationDBS was an effective treatment for three‐quarters of patients with pathogenic VPS16 variants in our cohort. Mean motor improvement was most pronounced at the 1‐year FU, but persisted at the last FU despite disease progression. ANN NEUROL 2025
Quantitative Tractography-Based Evaluations in Essential Tremor Patients after MRgFUS Thalamotomy Francesco Ghielmetti, Domenico Aquino, Nico Golfrè Andreasi, Federica Mazzi, Elena Greco, Roberto Cilia, Elena De Martin, Sara Rinaldo, Mario Stanziano, Vincenzo Levi, Arianna Braccia, Marcello Marchetti, Maria L. Fumagalli, Greta Demichelis, Fabiana Colucci, Luigi Michele Romito, Grazia Devigili, Antonio E. Elia, Valentina Caldiera, Mattia Verri, Elisa Francesca Ciceri, Francesco Di Meco, Marina Grisoli, Maria Grazia Bruzzone, Roberto Eleopra Movement Disorders Clinical Practice, 2024 BackgroundMagnetic resonance‐guided focused ultrasound (MRgFUS) targeting the thalamic ventral intermediate nucleus (VIM) is an innovative treatment for drug‐refractory essential tremor (ET). The relationship between lesion characteristics, dentate‐rubro‐thalamic‐tract (DRTT) involvement and clinical benefit remains unclear.ObjectivesTo investigate whether clinical outcome is related to lesion volume and/or its overlap with the DRTT. To compare the reliability of probabilistic versus deterministic tractography in reconstructing the DRTT and improving VIM targeting.MethodsForty ET patients who underwent MRgFUS thalamotomy between 2019 and 2022 were retrospectively analyzed. Clinical outcomes and adverse effects were recorded at 1/6/12 months after the procedure. The DRTT was generated using deterministic and probabilistic tractography on preoperative diffusion‐tensor 3 T‐images and location and volume of the lesion were calculated.ResultsProbabilistic tractography identified both decussating (d‐DRTT) and non‐decussating (nd‐DRTT) components of the DRTT, whereas the deterministic approach only identified one component overlapping with the nd‐DRTT. Despite the lesions predominantly intersecting the medial portion of the d‐DRTT, with a significantly greater overlap in responder patients, we observed only a non‐significant correlation between tremor improvement and increased d‐DRTT‐lesion overlap (r = 0.22, P = 0.20). The lesion volume demonstrated a significant positive correlation with clinical improvement at 1‐day MRI (r = 0.42, P < 0.01).ConclusionVariability in the reconstructed DRTT position relative to the lesion center of mass, even among good responders, suggests that this fiber bundle is unlikely to be considered the sole target for a successful MRgFUS thalamotomy in ET. Indirect individualized targeting allows for more precise and reproducible identification of actual treatment coordinates than the direct method.
Pain related to MRgFUS: a merely minor transient adverse event? Paolo Amami, Sara Prioni, Marco Fusar Poli, Riccardo Pascuzzo, Elisa Bocchi, Nico Golfrè Andreasi, Grazia Devigili, Roberto Cilia, Sara Rinaldo, Vincenzo Levi, Francesco Ghielmetti, Marina Grisoli, Marco Gemma, Francesco DiMeco, Roberto Eleopra, Sylvie Piacentini Journal of Neurology Neurosurgery and Psychiatry, 2024
Aceruloplasminemia: Unique Clinical and MRI Findings in a Patient with a Novel Frameshift Mutation Fabiana Colucci, Silvia Barca, Roberto Cilia, Valentino De Franco, Antonio E. Elia, Nico Golfrè Andreasi, Luigi Romito, Roberta Telese, Arianna Braccia, Valentina Leta, Marina Grisoli, Celeste Panteghini, Barbara Garavaglia, Grazia Devigili, Roberto Eleopra Movement Disorders Clinical Practice, 2024 Aceruloplasminemia (ACP; OMIM #604290) is a rare disorder caused by biallelic mutations of the ceruloplasmin (CP) gene, resulting in the absence of serum CP.1 CP inactivation leads to iron metabolism abnormalities with subsequent cellular iron accumulation. ACP may present with systemic symptoms (eg, anemia, liver disease, diabetes mellitus, and retinopathy) several years before the onset of progressive movement disorders and dementia.2 Although genetic testing and biochemical analysis are mandatory to confirm the diagnosis, brain MRI is considered useful for distinguishing neurodegeneration with brain iron accumulation (NBIA) subtypes.3 Here, we report an ACP patient with cystic basal ganglia cavitations on MRI, a feature considered typical of neuroferritinopathy.3, 4 A 61-year-old Caucasian female, born to nonconsanguineous parents, presented with a 25-year history of gait impairment. Symptoms began at the age of 36 with lower limb pain and weakness followed by trunk and limb involuntary movements. In her 50s, she became dependent due to progressive motor disability and cognitive impairment. Non-motor symptoms included constipation, urinary urgency and incontinence, and mood deflection. Neurological examination revealed: saccadic pursuit and slow vertical saccades; cerebellar-dystonic dysarthria; tetraparesis with brisk osteotendinous reflexes; dysmetria at finger-nose maneuver; global akinesia associated with irregular choreic movements involving her face, trunk, upper and lower limbs (Video 1, Segment A). Her gait was possible only with bilateral aid, wide-based and associated with dystonia of the trunk and lower limbs (Video 1, Segment B). Cognitive evaluation showed deficit of attention, visual constructive abilities, and long-term memory (MoCA 21.1/30); right arm apraxia; depression. Headache and iron deficiency anemia (refractory to iron supplementation) were reported since childhood. Her mother and her maternal uncle presented similar clinical findings (iron-deficiency anemia, progressive gait impairment and cognitive decline) since their 30s (Fig. 1, panel A). Biological analysis in serum proved low iron (40 μg/dl; normal values (n.v.) 40–145) and copper levels (3 μg/dl; n.v. 65–165), absence of ceruloplasmin (2 mg/dl; n.v.20–60). Ferritin levels were increased in serum (730 ng/mL; n.v. 10–150) and CSF (137 mg/mL; n.v. <17 mg/mL). Albeit liver function was normal, abdomen ultrasonography showed steatosis. Laboratory tests and ophthalmologic evaluation excluded diabetes mellitus and retinal involvement. Cardiovascular autonomic function testing showed baroreflex failure: delayed orthostatic hypotension at head up tilt test and impaired adrenergic sympathetic function at the Valsalva maneuver, with relatively preserved muscle sympathetic function. Plasma epinephrine levels were reduced both supine and after 3-minute standing, whereas norepinephrine levels were normal in both conditions. 123I-MIBG SPECT showed reduced density of postganglionic sympathetic myocardial nerve terminals. Dopamine transporter SPECT imaging was normal. T 2 * $$ {\mathrm{T}}_2^{\ast } $$ and susceptibility-weighted brain MR showed hypointensity of bilateral striata (caudate nuclei and putamina), thalami, red nuclei, dentate nuclei, coupled with hyperintensity (cavitation) of anterior putamina (Fig. 1, Panel B–F). T1-weighted images showed cortical and cerebellar atrophy. CT scan excluded basal ganglia calcification (Fig. 1, Panel F,G). Prior to brain MRI, genetic testing for Huntington's disease, Huntington-like forms (prion protein gene, JHP3, SCA17, ACDY5), C9Orf72, SCA2, SCA3, and α-tocopherol-transfer-protein gene were negative. Subsequent next-generation sequencing panel for NBIA genes revealed a homozygous variant in exon 4 of CP gene (c.650 T > C with p.Phe217Ser). This variant is not present in the ExAc database and it is predicted to be pathogenic by in silico analysis. Iron chelating therapy (deferoxamine) did not change clinical and MRI abnormalities. Tetrabenazine 25 mg t.i.d. partially improved choreic movements. Fewer than 60 ACP cases have been reported so far. The natural course of ACP is variable and the phenotypic spectrum may include ataxia, involuntary movements (facial and neck dystonia, tremor, and chorea), parkinsonism, depression, and cognitive impairment.2, 5 Genotype–phenotype correlation is still unclear.5 This patient showed unique clinical and MRI features. Clinically, our case had young-onset chorea-dystonia combined with parkinsonism and ataxia, complicated by anemia refractory to iron treatment and elevated ferritin in serum and CSF. A novel clinical finding worth underlining is cardiovascular autonomic dysfunction with abnormal response of plasma epinephrine and norepinephrine. Although iron accumulation may be toxic to sympathetic neurons and cause adrenergic cardiovascular impairment,6, 7 the relationship between iron overload and dysautonomia in ACP needs further investigation. We recommend investigating orthostatic hypotension in ACP as a potential cause of falls. Concerning MRI, ACP typically shows a unique pattern: a simultaneous iron deposition in all basal ganglia, thalami, dentate nuclei, and cortex.8, 9 MRI findings had been claimed to differentiate ACP from neuroferritinopathy, the latter typically showing hyperintensities of the globus pallidus and putamen, due to cystic degeneration (cavitations).8, 10 This case represents the first description of striatal cavitations in ACP, suggesting that cystic degeneration are not specific and develop as a function of time in different NBIA subtypes. Longitudinal MRI studies may shed light on the pathophysiology of cavitations due to iron accumulation in basal ganglia. Iron chelation therapy is usually beneficial for ACP, as early treatment leads to decreased iron accumulation and subsequent disability.11 Unfortunately, deferoxamine was unsuccessful due to delayed diagnosis. We thank Dr. Luigi Santilio, MD, for his help in video recording. Open access funding provided by BIBLIOSAN. (1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the first draft, B. Review and Critique; F.C.: 1A, 1B, 1C, 3A S.B.: 1A, 1B, 1C, 3A R.C.: 1A, 1B, 1C, 3A, 3B V.D.F.: 1C, 3A A.E.E.: 1B, 1C, 3B N.G.A.: 1B, 1C, 3B L.R.: 1B, 1C R.T.: 1B, 1C A.B.: 1B, 1C V.L.: 1B, 1C, 3B M.G.: 1B, 3B C.P.: 1C B.G.: 1C G.D.: 1A, 1B, 1C, 3B RE: 1A, 1B, 1C, 3B Ethical compliance statement: The authors confirm that the approval of an institutional review board was not required for this work. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. The manuscript submitted for publication has been performed in accordance with ethical standards stated in the 1964 Declaration of Helsinki and its later amendments. Written informed consent was obtained from the patient for the publication of this case report and for the publication of all iconographic and video materials. Funding Sources and Conflicts of Interest: The authors declare that there are no conflicts of interest relevant to this work. Financial Disclosures for the previous 12 months: All authors have nothing to disclose.
The Optimal Targeting for Focused Ultrasound Thalamotomy Differs between Dystonic and Essential Tremor: A 12-Month Prospective Pilot Study Nico Golfrè Andreasi, Arianna Braccia, Vincenzo Levi, Sara Rinaldo, Francesco Ghielmetti, Roberto Cilia, Luigi Michele Romito, Salvatore Bonvegna, Antonio Emanuele Elia, Grazia Devigili, Roberta Telese, Fabiana Colucci, Maria Grazia Bruzzone, Giuseppe Messina, Marta Corradi, Mario Stanziano, Valentina Caldiera, Sara Prioni, Paolo Amami, Marco Fusar Poli, Sylvie Hélène Marie Jeanne Piacentini, Marina Grisoli, Elisa Francesca Maria Ciceri, Francesco DiMeco, Roberto Eleopra Movement Disorders Clinical Practice, 2024
Ambroxol as a disease-modifying treatment to reduce the risk of cognitive impairment in GBA -associated Parkinson's disease: A multicentre, randomised, double-blind, placebo-controlled, phase II trial. The AMBITIOUS study protocol Fabiana Colucci, Micol Avenali, Rosita De Micco, Marco Fusar Poli, Silvia Cerri, Mario Stanziano, Ana Bacila, Giada Cuconato, Valentina Franco, Diego Franciotta, Cristina Ghezzi, Matteo Gastaldi, Antonio Emanuele Elia, Luigi Romito, Grazia Devigili, Valentina Leta, Barbara Garavaglia, Nico Golfrè Andreasi, Federico Cazzaniga, Chiara Reale, Caterina Galandra, Giancarlo Germani, Pierfrancesco Mitrotti, Gerardo Ongari, Ilaria Palmieri, Marta Picascia, Anna Pichiecchio, Mattia Verri, Fabrizio Esposito, Mario Cirillo, Federica Di Nardo, Simone Aloisio, Mattia Siciliano, Sara Prioni, Paolo Amami, Sylvie Piacentini, Maria Grazia Bruzzone, Marina Grisoli, Fabio Moda, Roberto Eleopra, Alessandro Tessitore, Enza Maria Valente, Roberto Cilia BMJ Neurology Open, 2023
Levodopa Equivalent Dose of Safinamide: A Multicenter, Longitudinal, Case–Control Study Roberto Cilia, Emanuele Cereda, Marco Piatti, Andrea Pilotto, Luca Magistrelli, Nico Golfrè Andreasi, Salvatore Bonvegna, Elena Contaldi, Francesca Mancini, Gabriele Imbalzano, Rosa De Micco, Fabiana Colucci, Arianna Braccia, Gabriele Bellini, Francesco Brovelli, Roberta Zangaglia, Giulia Lazzeri, Maria Claudia Russillo, Enrica Olivola, Chiara Sorbera, Viviana Cereda, Patrizia Pinto, Patrizia Sucapane, Giorgio Gelosa, Mario Meloni, Francesca Pistoia, Maria Sessa, Margherita Canesi, Nicola Modugno, Claudio Pacchetti, Laura Brighina, Maria Teresa Pellecchia, Roberto Ceravolo, Mariachiara Sensi, Maurizio Zibetti, Cristoforo Comi, Alessandro Padovani, Anna L. Zecchinelli, Alessio Di Fonzo, Alessandro Tessitore, Francesca Morgante, Roberto Eleopra Movement Disorders Clinical Practice, 2023
Magnetic Resonance–Guided Focused Ultrasound Thalamotomy May Spare Dopaminergic Therapy in Early-Stage Tremor-Dominant Parkinson's Disease: A Pilot Study Nico Golfrè Andreasi, Roberto Cilia, Luigi Michele Romito, Salvatore Bonvegna, Giulia Straccia, Antonio Emanuele Elia, Alessio Novelli, Giuseppe Messina, Giovanni Tringali, Vincenzo Levi, Grazia Devigili, Sara Rinaldo, Valentina Gasparini, Marina Grisoli, Mario Stanziano, Francesco Ghielmetti, Sara Prioni, Elisa Bocchi, Paolo Amami, Sylvie Hélène Marie Jeanne Piacentini, Elisa Francesca Maria Ciceri, Maria Grazia Bruzzone, Roberto Eleopra Movement Disorders, 2022
