Background: Thymoma is strongly associated with paraneoplastic syndromes, notably myasthenia gravis, and more rarely with autoimmune myositis. Among these, contracture-dominant presentations have been only rarely reported and remain poorly characterized. Case Presentation: We describe a 77-year-old woman who developed progressive distal tendon contractures thirteen months after resection of a B1 thymoma. She tested positive for anti-acetylcholine receptor, anti-titin, and anti-ryanodine receptor antibodies. Electrophysiology initially suggested a neurogenic pattern, later revealed myopathic features. Magnetic resonance imaging showed diffuse muscle edema and fibrosis, while muscle biopsy revealed neurogenic changes with secondary myopathic features. Corticosteroids and intravenous immunoglobulin yielded no clinical improvement. Discussion and Conclusions: This case expands the spectrum of thymoma-associated paraneoplastic neuromuscular syndromes and suggests that, in some patients, progressive structural remodeling rather than active inflammation may predominate. Recognition of atypical contracture-predominant presentations may facilitate earlier diagnostic evaluation in patients with thymoma-associated autoantibodies, although therapeutic responsiveness may be variable and likely dependent on disease stage.

Motor side effects may emerge after deep brain stimulation (DBS) of the subthalamic nucleus (STN) in Parkinson’s disease (PD) patients. Out of 60 PD patients, we observed 16 patients displaying de novo dystonic symptoms after the implantation and 11 dystonic PD patients without benefit from the stimulation. We hypothesized that a common neural pathway may cause dystonia in both conditions. Our study aims to investigate the clinical and connectivity substrates of dystonia after STN-DBS. We divided our cohort into four groups: 16 patients displaying dystonia after STN-DBS, 11 patients with previously known dystonia not improving after surgery, 14 patients with dystonic symptoms relieved by the stimulation and 19 controls who never experienced dystonia. MANOVA was used to compare clinical data and the distance of the active contact center from the STN border among the four groups. Finally, we reconstructed the “sour” spots for dystonic symptoms and the associated structural and functional connectivity using a Parkinsonian normative connectome. De novo dystonic and not-improved dystonic patients had a statistically significant longer PD duration before surgery (p = 0.001) and a greater active contact-STN distance (p < 0.001). Moreover, the “sour” spots were similar in both groups and structural and functional connectivity profiles were associated with brain areas correlated with dystonia pathophysiology (cerebellum, midbrain, parietal and temporal cortices). We formulated a two-hit model for dystonia after STN-DBS: a clinical feature of Parkinsonian patients causes predisposing altered plasticity contributing to dystonic symptoms development when coupled with the stimulation of dystonia-related subcortical and cortical structures.

Adaptive deep brain stimulation (aDBS) is a closed-loop system that adjusts stimulation based on patient biomarkers. This study evaluated the cognitive safety of aDBS in Parkinson’s disease (PD). Sixteen PD patients with bilateral subthalamic DBS underwent cognitive assessments (attention, language, memory) 6 days post-surgery during an 8 h protocol. Testing occurred at five time points: T1 (aDBS, medication “off”), T2/T4 (aDBS, medication “on”), and T3/T5 (aDBS “on”, medication “off”). Four patients followed the same protocol with continuousDBS (cDBS). Results showed no cognitive fluctuations in aDBS patients (p ≥ 0.110). However, cDBS patients exhibited significant reaction time (RT) variations (p = 0.019), with RTs lower at T1 than T3 (p = 0.011) and T5 (p = 0.021), and at T4 compared to T2 (p = 0.002). These findings suggest that 8 h aDBS may not adversely affect cognitive performance, providing preliminary evidence of its cognitive safety and stability in PD.

BACKGROUND:Dystonia is common in Parkinson disease patients, affecting about 30% of them. Bilateral subthalamic nucleus deep brain stimulation (DBS) can sometimes lead to dystonia, but this relationship is not well understood. Our aim was to provide a better understanding of dystonia's causes and its connection to DBS. METHODS:We conducted a retrospective analysis of clinical data from 80 Parkinson disease patients who underwent bilateral subthalamic nucleus stimulation, focusing on dystonia before and after surgery and its relation to medication state (on-dystonia/off-dystonia). RESULTS:After DBS, off-dystonia had a higher recovery rate than on-dystonia (43.5% vs. 9.1%). Among patients suffering for on-dystonia, 74.4% had it for the first time after surgery; these patients assumed higher doses of levodopa before DBS. CONCLUSIONS:Patients with off-dystonia before surgery tend to improve after DBS. Otherwise, DBS could have the role of "additive boost" in the process of sensitization of striato-pallidal pathways and lead to on-dystonia in particular patients.

OBJECTIVES:Deep brain stimulation (DBS) is an effective surgical procedure for the treatment of Parkinson disease (PD) and other movement disorders. Immediate and delayed complications after DBS surgery have been described. Perilead edema (PLE) is a DBS-related complication for which the etiology remains unknown. Moreover, PLE frequency and long-term effects are subjects of ongoing debate. Our study aims to elucidate the long-term clinical and neuropsychologic effects of PLE and to find possible etiologic correlates. MATERIALS AND METHODS:We retrospectively collected clinical and neuropsychologic data from 51 patients with PD before and 1 year after DBS. PLE visualized on fluid attenuated inversion recovery magnetic resonance imaging (MRI) sequence was manually segmented. Using appropriate statistical tests, continuous and categorical variables were compared in patients with and those without PLE. A multivariate regression model was used to analyze the contribution of clinical variables to edema volume changes. RESULTS:Overall, 68.62% of patients presented with PLE at the immediate postoperative MRI. Patients with PLE were significantly older (p < 0.001) and had more frequent postoperative confusion episodes (p = 0.025). Furthermore, more microelectrode recording (MER) tracks (p < 0.001) were used in patients with PLE. Multiple MER tracks were directly correlated with edema volume and were the only significant predictors of edema volume changes in a multivariate regression model. No differences were found in other clinical and neuropsychologic variables. CONCLUSIONS:PLE is a frequent postsurgical event and may cause transient postoperative confusion. It seems linked to older age and multiple MER tracks. Although it does not influence global motor and neuropsychologic outcomes, PLE contributes to postoperative confusion episodes. To avoid PLE sequelae, using multiple MER tracks in older patients should be discouraged.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an established treatment for advanced Parkinson’s disease (PD), often leading to positive motor and non-motor outcomes. While objective motor improvements after DBS are well documented, less is known about how patients and all those involved in their care perceive these benefits on a subjective level. The primary aim of the study was to investigate the perception gap between patients, caregivers, and treating neurologists regarding DBS physical and psychological benefits in PD and their correlates. 25 PD patients (age 58.9 ± 8.0 years; 9 women) who underwent bilateral STN-DBS, along with their caregivers and neurologists, rated perceived psychological and physical improvements 6 months after surgery using a two-item Visual Analogue Scales (VAS, 0–10). Intraclass correlation coefficients (ICC [95

Background Adaptive deep brain stimulation (aDBS) is becoming a real therapeutic option for patients candidate to DBS, and implantable devices are now commercially available. Here we present the results of a blinded randomized cross-over pilot trial aimed at comparing aDBS with conventional DBS (cDBS). Methods Fifteen patients were implanted with the AlphaDBS device (Newronika SpA, Milan, Italy, [NCT04681534][1]). In 11 patients, the device replaced a previous Medtronic Activa PC at battery depletion, while the others were four first-time implant patients. Patients underwent two study phases, a short-term follow up (ST-FUP) in the hospital in which the patient received aDBS and cDBS for one day each (in random order), and a 1-month long-term follow-up phase (LT-FUP), with the patient at home treated for two weeks in each DBS mode. The primary endpoint was safety, measured as the occurrence of stimulation-related adverse events. Secondary outcomes regarded effectiveness measured through the UPDRS-III and the UDysRS scales used in clinical setting, and a 3-day diary used for home assessment to estimate good on time (GOT, ON time without troublesome dyskinesia). At the end of the study period, patients blindly decided their preferred stimulation mode and whether or not to keep the investigational device thus entering an open label extension phase. Findings No aDBS-related adverse events were reported. The AlphaDBS device reliably recorded deep brain signals and applied a linear algorithm that changed the stimulation current every minute based on the average local field potential amplitude calculated in a patient-specific beta frequency range. In the ST-FUP, aDBS improved patients as much as cDBS, with lower UDysRS scores. In the LT-FUP, considering intra-patient individual difference, aDBS provided greater benefit than cDBS in 80% of patients. The same percentage of patients preferred and continued with aDBS to date. Interpretation These results suggest that aDBS is safe and effective and can be applied in a large population of parkinsonian patients who are candidate for DBS. aDBS improves more than cDBS the majority of patients and it is also subjectively preferred by them in the long term. Further research is needed to better understand the profile of the best responders and the scheduling of aDBS. ### Competing Interest Statement SM, AP, LR, ML, FC, SB, FT, GF are founders and shareholders of Newronika SpA. II, E.M. is member of the scientific advisory board of Newronika SpA, J.V. is member of the scientific advisory board of Newronika SpA and works as a consultant to Boston Scientific and Medtronic, and has received honoraria for lectures from Boston Scientific and Medtronic as well as research grants from Boston Scientific and Medtronic, A.M.L. is member of the scientific advisory board of Newronika SpA, has served as a consultant for Boston Scientific, Medtronic, Aleva, and Abbott and is a co-founder of Functional Neuromodulation. ### Clinical Trial [NCT04681534][1] ### Clinical Protocols ### Funding Statement The study was sponsored by Newronika SpA ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Bioethics Committee at National Oncology Institute of Maria Skłodowska-Curie, National Research Institute in Warsaw; Comitato Etico Milano Area 2; Comitato Etico IRCCS Istituto Neurologico C. Besta; Comitato Etico interaziendale AOUC Citta della Salute e della Scienza, AO Ordine Mauriziano di Torino, ASL Citta di Torino gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04681534&atom=%2Fmedrxiv%2Fearly%2F2025%2F02%2F24%2F2025.02.20.25322374.atom

Introduction Deep brain stimulation (DBS) of the subthalamic nucleus (STN) improves motor functions in patients with Parkinson’s disease (PD) but may cause a decline in specific cognitive domains including executive processes and language.The aim of this study was to derive standardized regression-based (SRB) reliable change indices (RCIs) in an Italian cohort of Parkinson's patients undergoing STN-DBS to detect clinically meaningful variations in verbal fluency (VF) one year after surgery define. Methods Before (T0) and 12 months after (T1) surgery, 36 PD patients who underwent bilateral STN-DBS were evaluated with the Alternate Verbal Fluency Battery (AVFB), including phonemic (PVF), semantic (SVF) and alternate VF tests (AVF) and a composite shifting index (CSI). At T0, motor status was assessed using the Unified Parkinson's Disease Rating Scale-III (UPDRS-III) and L-dopa equivalent daily dose was recorded. Results Group-level declines were limited to PVF and SVF scores. Applications of these RCIs revealed idiosyncratic patterns of longitudinal trends that differed from those at the group level. Indeed, when looking at individual performances, no clustered pattern of decline or improvement could be visibly detected. The UPDRS-III predicted T1 AVF and CSI scores. Conclusion Our study provides Italian practitioners and researchers with SRB-RCIs to detect meaningful differences in the VF performance of PD patients undergoing STN-DBS one year after surgery. Variables associated with postoperative cognitive changes can be used in future studies to develop multivariable predictive models to support clinical decision making and patient counselling.

Background: Deep brain stimulation (DBS) is an effective surgical procedure for the treatment of Parkinson disease (PD) and other movement disorders. Immediate and delayed complications after DBS surgery have been described. Peri-lead edema (PLE) is a DBS-related complication whose etiology is still unknown. Moreover, PLE frequency and long-term effects are subjects of ongoing debate. Objectives: To elucidate the long-term clinical and neuropsychological effects of PLE and to find possible etiological correlates. Methods: We retrospectively collected clinical and neuropsychological data from 51 PD patients before and one year after DBS. PLE visualized on FLAIR MRI sequence was manually segmented. Using appropriate statistical tests, continuous and categorical variables were compared between patients with and without PLE. A multivariate regression model was employed to analyze the contribution of clinical variables to edema volume changes. Results: 68.62% of patients presented PLE at the immediate postoperative MRI. Patients with PLE were significantly older (p<0.001) and had more frequent postoperative confusion episodes (p=0.025). Furthermore, more MER (microelectrode recording) tracks (p<0.001) were used in patients with PLE. Multiple MER tracks were directly correlated with edema volume and were the only significant predictors of edema volume changes in a multivariate regression model. No differences were found in other clinical and neuropsychological variables. Conclusions: PLE is a frequent post-surgical event and may cause transient postoperative confusion. It seems linked to older age and multiple MER tracks. Although it does not influence global motor and neuropsychological outcomes, PLE contributes to postoperative confusion episodes. To avoid PLE sequelae, using multiple MER tracks in older patients should be discouraged. ### Competing Interest Statement Dr. Luigi Gianmaria Remore reports a relationship with Newronika that includes: travel reimbursement. Dr. Elena Pirola reports a relationship with Medtronic that includes: travel reimbursement. Dr. Antonella Maria Ampollini reports a relationship with Boston Scientific Corporation that includes: travel reimbursement. Dr. Marco Locatelli reports a relationship with Newronika that includes: equity or stocks. Dr. Ioannis U. Isaias reports a relationship with Newronika that includes: equity or stocks. Dr. Filippo Cogiamanian reports a relationship with Newronika that includes: equity or stocks. Dr. Francesca Mameli reports a relationship with Newronika that includes: equity or stocks. Dr. Roberta Ferrucci reports a relationship with Newronika that includes: equity or stocks. The other 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. ### Funding Statement This study was funded by the following grants: RC2023-235, RC2024-400 (Italian Ministry of Health). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee of Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico waived ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors

Gait disturbance is a common and severe symptom of Parkinson’s disease that severely impairs quality of life. Current treatments provide only partial benefits with wide variability in outcomes. Also, deep brain stimulation of the subthalamic nucleus (STN-DBS), a mainstay treatment for bradykinetic-rigid symptoms and parkinsonian tremor, is poorly effective on gait. We applied a novel DBS paradigm, adjusting the current amplitude linearly with respect to subthalamic beta power (adaptive DBS), in one parkinsonian patient with gait impairment and chronically stimulated with conventional DBS. We studied the kinematics of gait and gait initiation (anticipatory postural adjustments) as well as subthalamic beta oscillations with both conventional and adaptive DBS. With adaptive DBS, the patient showed a consistent and long-lasting improvement in walking while retaining benefits on other disease-related symptoms. We suggest that adaptive DBS can benefit gait in Parkinson’s disease possibly by avoiding overstimulation and dysfunctional entrainment of the supraspinal locomotor network.

Background/Objectives: High cognitive reserve (CR) has been shown to have beneficial effects on global cognition, cognitive decline, and risk of dementia in Parkinson’s disease (PD). We evaluated the influence of CR on the long-term cognitive outcomes of patients with PD who underwent subthalamic nucleus deep brain stimulation (STN-DBS). Methods: Twenty-five patients with PD underwent neuropsychological screening using the Montreal Cognitive Assessment (MoCA) at baseline, 1 year, and 5 years after bilateral STN-DBS. CR was assessed using the Cognitive Reserve Index questionnaire. According to CR score, patients were assigned to two different groups (LowCR group ≤ 130, HighCR group > 130). Results: Our data showed that patients in the HighCR group obtained a better performance with the MoCA total score at long-term follow-up compared to those in the LowCR group ([mean ± SE] LowCR group: 21.4 ± 1.2 vs. HighCR group: 24.5 ± 1.3, p = 0.05). The cognitive profile of the HighCR group remained unchanged over time. Conversely, the LowCR group had worse global cognition 5 years after surgery (T0: 25.3 ± 0.6 vs. T2: 21.4 ± 1.2, p = 0.02). Cognitive decline was not associated with mood, demographics, or clinical variables. Conclusions: These preliminary findings suggest that higher CR may be protective in PD cognition after STN-DBS. Specifically, a high CR may help cope with long-term decline in the context of surgical treatment. Quantifying a patient’s CR could lead to more personalized medical care, tailoring postoperative support and monitoring for those at higher risk of cognitive decline.

Objective. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) improves motor outcomes in Parkinson's disease (PD) but may have adverse long-term effects on specific cognitive domains. The aim of this study was to investigate the association between total electrical energy (TEED) delivered by DBS and postoperative changes in verbal fluency. Methods. Seventeen PD patients undergoing bilateral STN-DBS were assessed with the Alternate Verbal Fluency Battery (AVFB), which includes phonemic (PVF), semantic (SVF), and alternate verbal fluency (AVF) tests, before surgery (T0) and after 6 (T1) and 12 months (T2). Bilateral TEED and average TEEDM were recorded at T1 and T2. For each AVFB measurement, changes from T0 to T1 (A-01) and from T0 to T2 (A-02) were calculated. Results. At T1, PVF (p = 0.007) and SVF scores (p = 0.003) decreased significantly. TEED measures at T1 and T2 were unrelated to A-01 and A-02 scores, respectively. However, an inverse, marginally significant association was detected between the TEEDM and A-01 scores for the AVF (p = 0.041, against an a adjusted = 0.025). Conclusions. In conclusion, the present reports provide preliminary evidence that TEED may not be responsible or only slightly responsible for the decline in VF performance after STN-DBS in PD.

Background: While conventional subthalamic (STN) deep brain stimulation (cDBS) provides stimulation with constant parameters, current adaptive paradigms (aDBS) modulate the stimulation amplitude based on subthalamic beta power dynamics. The efficacy of long-term aDBS paradigms is currently under study.

Objectives: Despite the large amount of literature examining the potential influence of subthalamic nucleus deep brain stim-ulation (STN-DBS) on psychiatric symptoms and cognitive disorders, only a few studies have focused on its effect on personality. We investigated the correlation between total electrical energy delivered (TEED) and the occurrence of depressive traits in patients with Parkinson disease (PD) after one year of DBS.Materials and Methods: Our study involved 20 patients with PD (12 women, mean [+/- SD] age 57.60 +/- 7.63 years) who underwent bilateral STN-DBS, whose personality characteristics were assessed using the Minnesota Multiphasic Personality Inventory-2 (MMPI-2), according to the core assessment program for surgical interventional therapies in Parkinson's disease (CAPSIT-PD) procedure.Results: We found that despite a marked improvement in motor functions and quality of life after 12 months, patients showed a significant increase in MMPI-2 subscales for depression (D scale and Depression scale) and in other content component scales (low self-esteem, work interference, and negative treatment indicators). Interestingly, only the TEED on the right side was inversely correlated with the changes in scale D (rs = -0.681, p = 0.007), whereas depressive traits did not correlate with disease duration, levodopa equivalent daily dose (LEDD) reduction, patient's age, or severity of motor symptoms.Conclusions: Our preliminary observations indicate that despite the excellent motor outcome and general improvement in quality of life, DBS treatment can result in patients poorly adjusting to their personal, familiar, and socio-professional life. Different influences and multiple factors (such as TEED, intra/postsurgical procedure, coping mechanisms, and outcome expectations) may affect depressive traits. Further advances are expected to improve stimulation methods.

Developmental and epileptic encephalopathy 45 (DEE45) is a neurogenetic disorder caused by heterozygous pathogenic variants of GABRB1, encoding the beta1 subunit of the GABA type A receptor. Only three infants with DEE45 have been reported so far, and a detailed description of the disease history of these patients is still lacking. We describe the clinical and genetic findings of a 21-year-old woman with DEE45 carrying a novel de novo GABRB1 mutation (c.841A>G, p.T281A). The patient presented at birth with hypotonia and focal apneic seizures evolving in a phenotype of epilepsy of infancy with migrating focal seizures that were refractory to antiseizure medications. Epileptic spasms partially responsive to steroid therapy appeared in the second year of life. Acquired microcephaly, profound mental retardation, and tetraparesis became evident with development. During childhood and adolescence, the epileptic phenotype evolved toward a Lennox-Gastaut Syndrome. Atypical absence status and clusters of tonic seizures occurred, often triggered by respiratory infections. The main strengths of this work are the identification of a novel pathogenic GABRB1 variant localized in the same transmembrane domain of a previously described mutation and the detailed description of the clinical trajectory of GABRB1-related encephalopathy along 21 years of disease history.

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.