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Kathryn B Holroyd,1 Lisa Fosdick,2 Gwenn S Smith,1 Jeannie-Marie Leoutsakos,1 Cynthia A Munro,1 Esther S Oh,1 Kristen E Drake,2 Paul B Rosenberg,1 William S Anderson,1 Stephen Salloway,3–5 J Cara Pendergrass,6 Anna D Burke,7 David A Wolk,8 David F Tang-Wai,9–11 Francisco A Ponce,12 Wael F Asaad,13,14 Marwan N Sabbagh,15 Michael S Okun,16 Gordon Baltuch,17 Kelly D Foote,18 Steven D Targum,2,6 Andres M Lozano,10,11 Constantine G Lyketsos1 1Johns Hopkins University Memory and Alzheimer's Treatment Center, Baltimore, MD, 2Functional Neuromodulation Ltd, Minneapolis, MN, 3Department of Neurology, Butler Hospital, 4Department of Neurology, Rhode Island Hospital, 5Department of Neurology, Warren Alpert Medical School of Brown University, Providence, RI, 6Clintara LLC, Boston, MA, 7Banner Alzheimer's Institute, Phoenix, AZ, 8Penn Memory Center, Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA; 9Department of Neurology, 10Department of Neurosurgery, University of Toronto, 11Division of Neurology, University Health Network Memory Clinic, Toronto, ON, Canada; 12Division of Neurological Surgery, Barrow Neurological Institute, St Joseph's Hospital and Medical Center, Phoenix, AZ, 13Department of Neurosurgery, Rhode Island Hospital, 14Department of Neurosurgery, Warren Alpert Medical School of Brown University, Providence, RI, 15Banner Sun Health Research Institute, Sun City, AZ, 16Center for Movement Disorders and Neurorestoration, Department of Neurology, University of Florida – Gainsville, Gainsville, FL, 17Center for Functional and Restorative Neurosurgery, University of Pennsylvania, Philadelphia, PA, 18Department of Neurosurgery, Center for Movement Disorders and Neurorestoration, University of Florida, Gainsville, FL, USA Background: There are currently few available treatments and no cure for Alzheimer disease (AD), a growing public health burden. Animal models and an open-label human trial have indicated that deep brain stimulation (DBS) of memory circuits may improve symptoms and possibly slow disease progression. The ADvance trial was designed to examine DBS of the fornix as a treatment for mild AD. Methods: ADvance is a randomized, double-blind, placebo-controlled, delayed-start, multicenter clinical trial conducted at six sites in the US and one site in Canada. Eighty-five subjects initially consented to be screened for the trial. Of these, 42 subjects who met inclusion and exclusion criteria were implanted with DBS leads anterior to the columns of the fornix bilaterally. They were randomized 1:1 to DBS “off” or DBS “on” groups for the initial 12 months of follow-up. After 1 year, all subjects will have their devices turned “on” for the remainder of the study. Postimplantation, subjects will return for 13 follow-up visits over 48 months for cognitive and psychiatric assessments, brain imaging (up to 12 months), and safety monitoring. The primary outcome measures include Alzheimer's Disease Assessment Scale – cognitive component (ADAS-cog-13), Clinical Dementia Rating sum of boxes (CDR-SB), and cerebral glucose metabolism measured with positron emission tomography. This report details the study methods, baseline subject characteristics of screened and implanted participants, and screen-to-baseline test–retest reliability of the cognitive outcomes. Results: Implanted subjects had a mean age of 68.2 years, were mostly male (55%), and had baseline mean ADAS-cog-13 and CDR-SB scores of 28.9 (SD, 5.2) and 3.9 (SD, 1.6), respectively. There were no significant differences between screened and implanted or nonimplanted subjects on most demographic or clinical assessments. Implanted subjects had significantly lower (better) ADAS-cog-11 (17.5 vs 21.1) scores, but did not differ on CDR-SB. Scores on the major outcome measures for the trial were consistent at screening and baseline. Conclusion: ADvance was successful in enrolling a substantial group of patients for this novel application of DBS, and the study design is strengthened by rigorous subject selection from seven sites, a double-blind placebo-controlled design, and extensive open-label follow-up. Keywords: deep brain stimulation, Alzheimer disease, fornix, methods, clinical trials

The aim of this study was to determine the effects of unilateral deep brain stimulation (DBS) on the control and coordination of grasping forces produced by Parkinson's disease (PD) patients. Ten advanced PD patients with unilateral DBS in the globus pallidus (GPi) or the subthalamic nucleus (STN) (5 patients in each group) performed a functional bimanual dexterous manipulation task. Experiments were performed in the "Off" medication state with DBS "On" and "Off. " DBS resulted in (a) significant clinical improvements, (b) greater maximum grip force for both limbs, (c) reduced movement time, and (d) bilateral coupling of grasping forces. There were no significant differences between the GPi and STN groups for any clinical or kinematic measures. DBS of the GPi and STN leads to an improvement in the motor functioning of advanced PD patients. Improvement in force-timing specification during DBS might allow PD patients to employ a feedforward method of force control. [ABSTRACT FROM AUTHOR]

In recent years, studies of essential tremor (ET) have demonstrated that the disease is associated with functionally-relevant cognitive abnormalities, a mood disturbance and other psychiatric co-morbidities, a functionally significant gait disorder, hearing deficits, and a variety of types of tremor. The tremor has been shown to be progressive in nature and quite disabling for a large number of sufferers. Also, recent clinical-epidemiological studies have linked prevalent ET to other neurodegenerative diseases and at least one study has demonstrated an increased risk of mortality in an ET cohort. While many of these studies are derived from clinic-based samples, population-based studies have also substantiated these findings, suggesting that even in the general population, the disease is associated with disability and with co-morbidity. Based on these available studies, it would seem inaccurate to append the word "benign" to ET. Not unlike the word "essential" itself, the word "benign" is an antiquated and outdated term that reflects an era where little was understood about ET. Historically, the general doctors who frequently encountered the disorder would educate patients that it was a benign, non-progressive condition not associated with any co-morbidity or risk of long-term worry. This notion, conceived by prior generations of physicians, is now known to be inaccurate. It is therefore our recommendation that the medical community open the dialog to consider formally discontinuing this nosology ("benign essential tremor") and to adopt the use of the term "essential tremor." Use of the word "benign" is a mischaracterization of the disease course, and could be prove misleading especially in the evolving doctor-patient relationship. In those cases with currently-mild tremor, the nosology "mild essential tremor" would be a more accurate reflection of disease. [ABSTRACT FROM AUTHOR]

Background: Recently, anterior limb of the internal capsule and nucleus accumbens deep brain stimulation (DBS) has been used in the treatment of medication-refractory obsessive-compulsive disorder (OCD). This region has been previously explored with lesion therapy, but with the advent of DBS there exists the possibility of monitoring the acute and chronic effects of electrical stimulation. The stimulation-induced benefits and side effects can be reversibly and blindly applied to a variety of locations in this region.Objective: To explore the acute effects of DBS in the anterior limb of the internal capsule and nucleus accumbens region.Methods: Ten total DBS leads in five patients with chronic and severe treatment-refractory OCD were tested. Patients were examined 30 days after DBS placement and received either "sham" testing or actual testing of the acute effects of DBS (the alternative condition tested 30 days later).Results: Pooled responses were reviewed for comparability of distribution using standard descriptive methods, and relationships between the variables of interest were sought using chi2 analysis. A total of 845 stimulation trials across the five patients were recorded and pooled. Of these 16% were elicited from sham stimulation and 17% from placebo (0 V stimulation). A comparison of active to sham trials showed that sham stimulation was not associated with significant side effects or responses from patients. Non-mood-related responses were found to be significantly associated with the ventral lead contacts (0 and 1) (p = 0.001). Responses such as taste, smell and smile were strongly associated with the most ventral lead positions. Similarly, physiological responses--for example, autonomic changes, increased breathing rate, sweating, nausea, cold sensation, heat sensation, fear, panic and panic episodes--were significantly associated with ventral stimulation (p = 0.001). Fear and panic responses appeared clustered around the most ventral electrode (0). Acute stimulation resulted in either improved or worsened mood responses in both the dorsal and ventral regions of the anterior limb of the internal capsule.Conclusion: The acute effects of DBS in the region of the anterior limb of the internal capsule and nucleus accumbens, particularly when obtained in a blinded fashion, provide a unique opportunity to localise brain regions and explore circuitry. [ABSTRACT FROM AUTHOR]

Background: Mood, cognitive, and behavioural changes have been reported with deep brain stimulation (DBS) in the thalamus, globus pallidus interna, and anterior limb of the internal capsule/nucleus accumbens region.Objective: To investigate panic and fear resulting from DBS.Methods: Intraoperative DBS in the region of the right and then left anterior limb of the internal capsule and nucleus accumbens region was undertaken to treat a 52 year old man with treatment refractory obsessive-compulsive disorder (OCD). Mood, anxiety, OCD, alertness, heart rate, and subjective feelings were recorded during intraoperative test stimulation and at follow up programming sessions.Results: DBS at the distal (0) contact (cathode 0-, anode 2+, pulse width 210 ms, rate 135 Hz, at 6 volts) elicited a panic attack (only seen at the (0) contact). The patient felt flushed, hot, fearful, and described himself as having a "panic attack." His heart rate increased from 53 to 111. The effect (present with either device) was witnessed immediately after turning the device on, and abruptly ceased in the off conditionConclusions: DBS of the anterior limb of the internal capsule and nucleus accumbens region caused severe "panic." This response may result from activation of limbic and autonomic networks. [ABSTRACT FROM AUTHOR]

Research in movement disorders in 2012 has improved our understanding of the pathogenic mechanisms of disease and led to development of potential novel therapeutic approaches. Key advances were linked to mechanisms underlying spread of neurodegenerative pathology, immunotherapy, stem cells, genetics and deep brain stimulation in parkinsonism and related disorders. [ABSTRACT FROM AUTHOR]

Purpose: Researchers have consistently observed in right-handed individuals across normal and disease states that the 'dominant' left hemisphere has greater ipsilateral control of the left side than the right hemisphere has over the right. We sought to determine whether this ipsilateral influence of the dominant hemisphere reported in Parkinson's disease extends to treatments such as deep brain stimulation (DBS) and whether it affects outcome. We hypothesised that among Parkinson right-handers, unilateral left DBS would provide greater ipsilateral motor improvement compared with the ipsilateral motor improvement experienced on the right side.Scope: A total of 73 Parkinson patients who underwent unilateral DBS of the subthalamic nucleus (STN) or globus palidus internus (GPi) participated. Left and right 'composite scores', were computed by separately adding all items on the left and right side from the motor section of the Unified Parkinson Disease Rating Scale. The change in the pre- and 4-month post-implantation score was the primary outcome measure. The mean motor scores improved by 4.96 ± 11.79 points (p < 0.001) post-surgery on the ipsilateral side of the DBS implantation. Regression analyses revealed that the side (left vs. right) and target (STN vs. GPi) did not significantly contribute in the effect of ipsilateral motor improvement (p = 0.3557).Conclusion: While DBS on the 'dominant' left side failed to exert a greater ipsilateral influence compared with DBS on the non-dominant right side, significant ipsilateral motor improvements were observed after unilateral stimulation regardless of site of implantation and laterality. [ABSTRACT FROM AUTHOR]

Background: Deep Brain Stimulation (DBS) surgery can effectively treat many debilitating motor symptoms of Parkinson's disease (PD), but axial symptom improvement is variable. Predictors for post-DBS axial symptom performance have yet to be identified. Pre-surgery ventricle volume may be one predictor, for increasing ventricular size has been associated with worsening gait disturbance. In PD, ventricle size may also increase with the advancement of motor symptoms.Objective: To examine the hypotheses that 1) lateral ventricular volumes would predict motor and axial motor symptom change from pre to four months post unilateral DBS, and 2) PD patients have larger ventricle volumes contralateral to side of symptom onset.Methods: Idiopathic PD patients (n = 37) completed pre-surgery volumetric brain scans and UPDRS motor testing (off-medication), unilateral DBS (Globus Pallidus interna, n = 11; subthalamic nucleus, n = 26), and 4-month follow-up motor assessments (on-stimulation). Ventricle volumes were normalized using total intracranial volume.Results: Total ventricular volume as well as measurements of contralateral/ipsilateral volumes to side of symptom onset or DBS lead placement did not predict outcome motor measures or correlate to axial motor change. Patients improving at least 2 standard errors of measurement (n = 6) did not have smaller ventricles relative to those without significant change. Post-operative hemorrhage (n = 1) had ventricle volumes similar to the group average. There was no asymmetry in ventricular volume by side of onset or side of lead placement.Conclusion: Ventricular volume was a poor predictor of acute motor change following DBS. Asymmetrical ventricles may not be a consistent imaging marker for PD motor dysfunction. [ABSTRACT FROM AUTHOR]

Objective: To review the literature and to identify practice gaps in the management of the hospitalized Parkinson's disease (PD) patient.Background: Patients with PD are admitted to hospitals at higher rates, and frequently have longer hospital stays than the general population. Little is known about outpatient interventions that might reduce the need for hospitalization and also reduce hospital-related complications.Methods: A literature review was performed on PubMed about hospitalization and PD between 1970 and 2010. In addition, in press peer-reviewed papers or published abstracts known to the authors were included. Information was reviewed by a National Parkinson Foundation workgroup and a narrative review article was generated.Results: Motor disturbances in PD are believed to be a causal factor in the higher rates of admissions and complications. However, other conditions are commonly recorded as the primary reason for hospitalization including motor complications, reduced mobility, lack of compliance, inappropriate use of neuroleptics, falls, fractures, pneumonia, and other important medical problems. There are many relevant issues related to hospitalization in PD. Medications, dosages and specific dosage schedules are critical. Staff training regarding medications and medication management may help to avoid complications, particularly those related to reduced mobility, and aspiration pneumonia. Treatment of infections and a return to early mobility is also critical to management.Conclusions: Educational programs, recommendations, and guidelines are needed to better train interdisciplinary teams in the management of the PD patient. These initiatives have the potential for both cost savings and improved outcomes from a preventative and a hospital management standpoint. [ABSTRACT FROM AUTHOR]

Deep brain stimulation (DBS) has been associated with increased apathy in patients with PD, yet studies lack longitudinal data and have not assessed differences between sites of implantation (i.e. STN versus GPi). We assessed apathy prior to surgery and 6 months post-surgery using a longitudinal design-latent growth curve modeling. We hypothesized that apathy would increase post-surgery, and be related to subthalamic nucleus (versus globus pallidus interna) implantation. Forty-eight PD patients underwent unilateral surgery to either GPi or STN and completed the Apathy Scale prior to surgery and 2, 4, and 6 months post-surgery. Forty-eight matched PD controls completed the Apathy Scale at a 6-month interval. Results indicated apathy increased linearly from pre- to 6-months post-DBS by .66 points bi-monthly, while apathy in the control group did not change. There was no relationship between apathy and DBS site. Higher baseline depression was associated with higher baseline apathy, but not with change in apathy. Middle-aged adults (<65) had a steeper trajectory of apathy than older adults (≥ 65). Apathy trajectory was not related to motor severity, laterality of DBS, levodopa medication reduction, or motor changes after surgery. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease (PD) impacts several domains of functioning, some of which may be neglected when designing treatment or evaluating outcome using current clinical standards. We therefore argue that taking the patients' perspectives of their condition may allow for a more in-depth assessment of patient goals and subsequent tailoring of care.Methods: One hundred and forty-eight patients with idiopathic PD completed a modified version of the Patient-Centered Outcomes Questionnaire (PCOQ-PD), to evaluate treatment success and expectations from the patient's perspective across 10 motor and non-motor functional domains. We also examined patient subgroups based on importance of improvement in various domains.Results: Patients' ratings suggested there was substantial variation in functional interference that was generally unrelated to demographic variables. On average, across all domains, patients indicated a 50.32% reduction in symptoms would be successful (range = 40.63-58.23%), regardless of treatment experience. Change scores between patients' usual levels of symptom interference and their treatment success levels suggested a greater degree of change was desired in motor versus non-motor domains (p < 0.05). Finally, cluster analyses revealed two patient subgroups based on overall importance of improvement (High vs. Low Importance Endorsement). Notably, the two groups differed in self-reported usual symptom levels despite having similar clinical severity.Conclusions: We empirically examined treatment success from the PD patient's view as opposed to clinician judgment alone, thereby broadening the set of criteria by which to evaluate outcome. Findings from this exploratory study may guide future treatment emphases and guide patient-provider communication via clarification of patient-defined success. [ABSTRACT FROM AUTHOR]

A substantial number of individuals with Parkinson's disease who display impaired postural stability experience accelerated cognitive decline and an increased prevalence of dementia. To date, studies suggest that this relationship, believed to be due to involvement of nondopaminergic circuitry, occurs later in the disease process. Research has yet to adequately investigate this cognitive-posturomotor relationship especially when examining earlier disease states. To gain greater understanding of the relationship between postural stability and cognitive function/dysfunction we evaluated a more stringent, objective measure of postural stability (center of pressure displacement), and also more specific measures of cognition in twenty-two patients with early to moderate stage Parkinson's disease. The magnitude of the center of pressure displacement in this cohort was negatively correlated with performance on tests known to activate dorsolateral frontal regions. Additionally, the postural stability item of the UPDRS exhibited poor correlation with the more objective measure of center of pressure displacement and all specific measures of cognition. These results may serve as rationale for a more thorough evaluation of postural stability and cognition especially in individuals with mild Parkinson's disease. Greater understanding of the relationship between motor and cognitive processes in Parkinson's disease will be critical for understanding the disease process and its potential therapeutic possibilities. [ABSTRACT FROM AUTHOR]

Objective: Cognitive changes are heterogeneous in Parkinson's disease (PD). This study compared whether anticholinergic burden drives differences in cognitive domain performance and empirically-derived PD-cognitive phenotypes., Method: A retrospective chart review contained participants (n = 493) who had idiopathic PD without dementia. Participants' medications were scored (0-3) and summed based on the anticholinergic cognitive burden scale (ACBS). We examined the ACBS' relationship to five cognitive domain composites (normative z-scores) and three (K-means clustering based) cognitive phenotypes: cognitively intact, low executive function (EF), and predominately impaired EF/memory. Analyses included Spearman correlations, analysis of covariance, and Pearson chi-squared test., Results: Overall, phenotypes did not differ in anticholinergic burden, and (after false-discovery-rate corrections) no cognitive domains related. When comparing those above and below the clinically relevant ACBS cutoff (i.e., score ≥3), no significant phenotype or domain differences were found., Conclusions: Anticholinergic medication usage did not drive cognitive performance in a large clinical sample of idiopathic PD without dementia., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Previous studies have suggested that glucagon-like peptide-1 receptor agonists (GLP-1RAs) may have a disease-modifying effect in the development of Parkinson's disease (PD), but population studies yielded inconsistent results., Objective: The aim was to compare the risk of PD associated with GLP-1RAs compared to dipeptidyl peptidase 4 inhibitors (DPP4i) among older adults with type 2 diabetes (T2D)., Methods: Using U.S. Medicare administrative data from 2016 to 2020, we conducted a population-based cohort study comparing the new use of GLP-1RA with the new use of DPP4i among adults aged ≥66 years with T2D. The primary endpoint was a new diagnosis of PD. A stabilized inverse probability of treatment weighting (sIPTW)-adjusted Cox proportional hazards regression model was employed to estimate the hazard ratio (HR) and 95% confidence intervals (CI) for PD between GLP-1RA and DPP4i users., Results: This study included 89,074 Medicare beneficiaries who initiated either GLP-1RA (n = 30,091) or DPP4i (n = 58,983). The crude incidence rate of PD was lower among GLP-1RA users than DPP4i users (2.85 vs. 3.92 patients per 1000 person-years). An sIPTW-adjusted Cox model showed that GLP-1RA users were associated with a 23% lower risk of PD than DPP4i users (HR, 0.77; 95% CI, 0.63-0.95). Our findings were largely consistent across different subgroup analyses such as sex, race, and molecular structure of GLP-1RA., Conclusion: Among Medicare beneficiaries with T2D, the new use of GLP-1RAs was significantly associated with a decreased risk of PD compared to the new use of DPP4i. © 2024 International Parkinson and Movement Disorder Society., (© 2024 International Parkinson and Movement Disorder Society.)

Objective: To determine if the co-occurrence of apathy and impulse control disorders (ICDs) in Parkinson disease is dependent on instrument selection and assess the concurrent validity of three motivation measures by examining interrelationships between them., Method: Ninety-seven cognitively normal individuals with idiopathic Parkinson disease (PD) completed the Questionnaire for Impulsive-Compulsive Disorders in Parkinson Disease-Rating Scale (QUIP-RS) and three apathy measures: the Apathy Scale, Lille Apathy Rating Scale, and Item 4 of the Movement Disorder Society-Unified Parkinson Disease Rating Scale., Results: Fifty (51.5%) participants were classified as apathetic on at least one measure, and only four individuals (4.3%) obtained clinically elevated scores on all three measures. The co-occurrence of apathy and ICD varied across measures., Conclusions: We observed a co-occurrence of apathy and ICDs in PD patients with each apathy instrument; however, limited concurrent validity exists across measures. This is important for future investigations into shared pathophysiology and the design of future clinical trials aimed at improving the early detection and treatment of these debilitating syndromes., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

In this review, we summarize preclinical and clinical trials investigating innovative neuromodulatory approaches for Parkinson disease (PD) motor symptom management. We highlight the following technologies: temporal interference, nanoparticles for drug delivery, blood-brain barrier opening, gene therapy, optogenetics, upconversion nanoparticles, magnetothermal nanoparticles, magnetoelectric nanoparticles, ultrasound-responsive nanoparticles, and designer receptors exclusively activated by designer drugs. These studies establish the basis for novel and promising neuromodulatory treatments for PD motor symptoms., (© 2024. The Author(s).)

Clinical Vignette: A 23-year-old woman with pantothenate kinase-associated neurodegeneration (PKAN) presented with medication-refractory generalized dystonia and an associated gait impairment., Clinical Dilemma: Bilateral globus pallidus internus (GPi) deep brain stimulation (DBS) can be an effective treatment for dystonia. However, outcomes for PKAN DBS have been variable and there are no standardized criteria for patient selection., Clinical Solution: Bilateral GPi DBS implantation resulted in improvement in dystonia and gait. The benefit has persisted over one year after implantation., Gap in Knowledge: PKAN is a rare neurodegenerative disorder and evidence supporting the use of PKAN DBS has been largely limited to case reports and case series. Consequently, there is a paucity of long-term data, especially on gait-related outcomes., Expert Commentary: The clinical characteristics of dystonia that respond to DBS tend to respond in PKAN. Clinicians counselling patients about the effects of DBS for PKAN should thoughtfully discuss gait and postural instability as important aspects to consider, especially as the disease will progress post-DBS., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2024 The Author(s).)

The term "catatonia" was introduced by German psychiatrist Karl Kahlbaum in 1874. Although historically tied to schizophrenia, catatonia exhibits a diverse range of phenotypes and has been observed in various medical and neuropsychiatric conditions. Its intrinsic movement characteristics and association with hypokinetic and hyperkinetic phenomenologies place catatonia within the purview of movement disorders. Despite the presence of catatonia in psychiatry literature for over 150 years, many gaps and controversies persist regarding its etiopathogenesis, phenomenology, diagnostic criteria, and treatment. The current versions of the International Classification of Diseases (ICD-11) and the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) require clinicians to identify any three signs of 15 (ICD-11) or 12 (DSM-5) for the diagnosis of catatonia. Catalepsy and waxy flexibility are the only motor features with high specificity for the diagnosis. We highlight the gaps and controversies in catatonia as a movement disorder, emphasize the lack of a clear definition, and discuss the inconsistencies in the description of various catatonic signs. We propose the exploration of a bi-axial classification framework similar to that used for dystonia and tremor to encourage the evaluation of underlying etiologies and to guide therapeutic decisions to improve the outcome of these patients. © 2024 International Parkinson and Movement Disorder Society., (© 2024 International Parkinson and Movement Disorder Society.)

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.

Deep brain stimulation of the subthalamic nucleus and globus pallidus internus is approved by the Food and Drug Administration for treating dystonia. Both targets have shown effectiveness in improving symptoms, but post-operative outcomes can vary significantly among patients. This variability has led researchers to explore alternative neuromodulation targets that might offer more consistent results. Emerging research has highlighted several promising new targets for DBS in dystonia. This review examines pre-clinical and clinical data on novel DBS targets for dystonia and explores non-invasive neuromodulation studies that shed light on the disease's underlying pathological circuitry., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2024 The Author(s).)

Background: Responsive deep brain stimulation (rDBS) uses physiological signals to deliver stimulation when needed. rDBS is hypothesized to reduce stimulation-induced speech effects associated with continuous DBS (cDBS) in patients with essential tremor (ET)., Objective: To determine if rDBS reduces cDBS speech-related side effects while maintaining tremor suppression., Methods: Eight ET participants with thalamic DBS underwent unilateral rDBS. Both speech evaluations and tremor severity were assessed across three conditions (DBS OFF, cDBS ON, and rDBS ON). Speech was analyzed using intelligibility ratings. Tremor severity was scored using the Fahn-Tolosa-Marin Tremor Rating Scale (TRS)., Results: During unilateral cDBS, participants experienced reduced speech intelligibility (P = 0.025) compared to DBS OFF. rDBS was not associated with a deterioration of intelligibility. Both rDBS (P = 0.026) and cDBS (P = 0.038) improved the contralateral TRS score compared to DBS OFF., Conclusions: rDBS maintained speech intelligibility without loss of tremor suppression. A larger prospective chronic study of rDBS in ET is justified. © 2024 International Parkinson and Movement Disorder Society., (© 2024 International Parkinson and Movement Disorder Society.)

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.