A trial of spinal cord stimulation (SCS) was performed in people with gait-impaired Parkinson’s (ClinicalTrials.gov: NCT05110053). Fourteen patients underwent gait assessments and [18F]-FDG and [18F]-FEOBV PET at baseline, six, and twelve months after SCS. Twelve participants were randomised to six-month MicroBurst or sham, followed by six-month extension with stimulation. The primary outcomes were feasibility and safety, as captured by the trial process measures and nature and frequency of adverse events, respectively, and the Postural Instability and Gait Disorder (PIGD) score as a clinical outcome. Secondary outcomes included assessments of balance and gait at home and at visits, including the Lower Body and Gait (LBG) score, imaging, and patient-reported outcomes of changes in gait, balance and quality of life. Seventeen patients (12

Focused ultrasound is rapidly emerging as a novel technology for the development of symptomatic therapies and supporting disease-modifying treatments for Parkinson's disease (PD). At the forefront of this development is thermoablation using high-intensity focused ultrasound, an incisionless treatment that has been extensively tested in clinical trials and so far has received clinical approval for the treatment of essential tremor and PD patients. At the other end of the spectrum, low-intensity focused ultrasound has been demonstrated in both neuromodulation and blood-brain barrier opening to allow the entry of therapeutic molecules into the central nervous system. The aim of this review is both to provide an overview of the current and future roles of focused ultrasound in disease-modifying treatments for PD with a special focus on outlining the full complexity of the disease beyond dopaminergic cell loss and to bridge clinical and preclinical research. First, we establish PD as a disease including both circuit dysfunctions and molecular pathology. Second, we discuss focused ultrasound state-of-the-art clinically and when relevant in relation to other similar treatment strategies (ie, deep brain stimulation). Third, we highlight preclinical advances and the potential of focused ultrasound to become a disease-modifying treatment. Understanding the therapeutic effects of focused ultrasound in a complex disease like PD is necessary to harness the full potential of the technology. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

BackgroundEssential tremor is a common movement disorder, characterized by kinetic tremor, most commonly of the upper extremities. The Quality of Life in Essential Tremor (QUEST) scale is an oft-used subjective rating scale of tremor severity and quality of life (QoL) in these patients, including for monitoring subjective improvement after advanced treatment. It contains subdomains concerned with overall and health-related QoL, a self-assessment of tremor severity and of the functional impact of tremor on activities of daily living. The questionnaire has not been validated in Danish. This study was aimed at translating and validating the QUEST and piloting it among Danish ET patients.MethodsThe translation and cultural adaptation of the QUEST was carried out per the guidelines of the World Health Organization (WHO) and the International Society of Pharmacoeconomics and Outcomes Research (ISPOR) task force for translation and cultural adaptation. It was subsequently disseminated among a cohort of ET patients.ResultsThe QUEST was successfully translated and piloted among 112 ET patients. Respondents found the QUEST to be understandable (75/77; 97.4%). For categorical items, there was a high degree of agreement in responses at retest (60.0%-94.0%). According to Cohen ' s kappa, agreement was mostly strong. Continuous outcomes were more variable, particularly the subdomains of the functional self-assessment. The mean score for each subdomain ranged from 19.46 (SD 21.87) for work and finance, 24.13 (SD 25.31) for communication, 32.49 (SD 23.21) for psychosocial, 40.21 (SD 34.11) for hobby and leisure, and 42.77 (SD 27.08) for physical. In general, subdomains were weakly to moderately correlated with overall health and QoL.ConclusionWe have successfully translated and validated the QUEST questionnaire for use among Danish ET patients. The questionnaire is now available for Danish clinicians and researchers treating ET patients. The results indicate some unmet needs in the Danish cohort of tremor patients.

Gait problems in people with Parkinson's disease are increasingly common as disease progresses. Symptoms include freezing of gait (FoG) and a predisposition to falls. The causative pathophysiology is not completely understood. In this study, PET with 18F-fluoroethoxybenzovesamicol (18F-FEOBV), a presynaptic marker of cholinergic terminal density, and 18F-fluorodeoxyglucose (18F-FDG) was performed in a cohort of people with Parkinson's disease and gait disorder to derive spatial covariance networks of cholinergic and metabolic activity and to evaluate the correlation of such networks against the frequency of FoG and other gait measures. Fourteen patients with Parkinson's disease and FoG in the ON motor state underwent PET using 18F-FEOBV and 18F-FDG on two separated days. Following spatial normalization, functional networks were derived by principal component analysis. The individual expression of linear combinations of principal components was subsequently correlated with measures of FoG in the ON motor state (ON-FoG) and a lower body and gait subsection of the Unified Parkinson's Disease Rating Scale part III. Gait measures were derived from home-worn measures using a triaxial accelerometer. We found a derived pattern of 18F-FEOBV binding that was correlated with ON-FoG (R2 = 0.46975, P = 0.045) and with other lower body and gait signs (R2 = 0.78591, P = 0.0077). Lower levels of cholinergic activity in the thalamus, hippocampus, striatum, anterior cingulate and areas of the brainstem consistent with the mesencephalic locomotor region were associated with worse ON-FoG and gait disturbances. The derived pattern was not associated with overall disease duration or progression as assessed by standard motor scores. There was no correlation between 18F-FEOBV and OFF-FoG. For 18F-FDG, no correlation between covariance patterns and gait assessments could be found. However, a statistically significant correlation was found for a subset of lower body and gait symptoms (R2 = 0.78306, P = 0.002). These results exhibit a correlation between lower levels of cholinergic function in locomotor-related areas of the brainstem and objective measures of dopamine medication ON-FoG, potentially indicating a causative link between the two. No association was found with OFF-FoG. Taken together, our results provide support for the role of the cholinergic system in the occurrence of dopamine medication ON-FoG.

BACKGROUND:Essential tremor is the most common hyperkinetic movement disorder. Magnetic resonance imaging-guided focused ultrasound (MRgFUS) has emerged as second-line therapy. OBJECTIVE:The aim was to obtain the results of the first 108 patients treated with MRgFUS in Denmark. METHODS:Data were entered in a quality assurance database at baseline and 3, 6, and 12 months. Clinician- and patient-rated treatment efficacy was evaluated using the Fahn-Marin-Tolosa (FMT) scale and the Patient Global Impression of Change. RESULTS:A total of 108 persons have currently been treated. Tremor improved by a total mean 6.39 points (95% confidence interval [CI]: 5.01;7.76, P < 0.00001) and 9.63 points (95% CI: 7.60;11.66, P < 0.00001), 10.42 (95% CI: 9.06;11.79, P < 0.00001), and 26.45 (95% CI: 22.46;30.43, P < 0.00001) for FMT parts A, B, and C, respectively, at 3 months. Side effects occurred in 65.7% of patients at 3 months and 33.7% at 12 months. CONCLUSION:Our findings are in line with existing evidence. Questions regarding persistence of gait- and balance-related side effects remain.

Background:Patients with multiple comorbidities can present as a diagnostic challenge as overlapping symptomatology complicates the discovery of emergent pathology. Symptoms of alcohol misuse or orthostatic hypotension may especially cloud the diagnosis of insidious neurological disease, such as posterior circulation infarct. With a growing elderly population, it is expected that the complex multimorbid patient will represent a growing challenge to prompt stroke detection and treatment. Case Description:Herein, we present a 69-year-old male with a history of alcohol abuse, chronic obstructive pulmonary disease, type 2 diabetes mellitus, paroxysmal atrial fibrillation, and congestive heart disease. The patient arrived at our emergency department with dizziness, ataxia, and diplopia. His symptoms had a sudden onset and gradual exacerbation over a span of 2 days, notably aggravated by standing and walking, but relieved when seated or supine. Notably, a month before admission, the patient had been treated with anti-congestive medications for severe congestive heart failure leading to a weight loss of 55 lbs over period of 2 weeks. The initial differential diagnoses were orthostatism, Wernicke's encephalopathy (WE), and ischemic stroke. Magnetic resonance imaging (MRI) revealed a subacute infarct in the medial longitudinal fasciculus (MLF). Conclusions:The case underscores the challenge in diagnosing neurological conditions in multimorbid individuals. The combination of various underlying conditions may drastically complicate the diagnosis. Successful diagnosis and treatment necessitates meticulous evaluation of clinical observations, medical history, current medications, and pertinent diagnostic evaluations to effectively narrow down the potential differential diagnoses.

Background The subgenual gyrus is a promising target for deep brain stimulation (DBS) against depression. However, to optimize this treatment modality, we need translational animal models. Aim To describe the anatomy and connectivity of the Göttingen minipig subgenual area (sgC). Materials and methods The frontal pole of 5 minipigs was cryosectioned into 40 µm coronal and horizontal sections and stained with Nissl and NeuN-immunohistochemistry to visualize cytoarchitecture and cortical lamination. Eight animals were unilaterally stereotaxically injected in the sgC with anterograde (BDA) and retrograde (FluroGold) tracers to reveal the sgC connectivity. Results In homology with human nomenclature (Brodmann 1909), it can be subdivided into three distinct areas named area 25 (BA25), area 33 (BA33), and indusium griseum (IG). BA25 is a narrow agranular cortex, approximately 1 mm thick. It has a poor laminar differentiation in the deeper layers due to a similar appearance of layer III and V neurons. Perpendicular to the surface cell, poor columns of white matter stretch deep into layers II and III, thereby segregating small groups of closely arranged neurons in the superficial layers. BA33 is less differentiated than BA25. Accordingly, the cortex is narrower and displays a complete lack of laminar differentiation due to diffusely arranged small, lightly stained neurons. It abuts the indusium griseum, which is a neuron-dense band of heavily stained small neurons separating BA33 directly from the corpus callosum and the posteriorly located septum. Conclusion The minipig sgC displays a cytoarchitectonic pattern and connectivity like the human and may be well suited for further translational studies on BA25-DBS against depression.

Cell replacement therapies for Parkinson's disease (PD) based on transplantation of pluripotent stem cell derived dopaminergic neurons are now entering clinical trials. Here, we present quality, safety, and efficacy data supporting the first-in-human STEM-PD phase I/IIa clinical trial along with the trial design. The STEM-PD product was manufactured under GMP and quality tested in vitro and in vivo to meet regulatory requirements. Importantly, no adverse effects were observed upon testing of the product in a 39-week rat GLP safety study for toxicity, tumorigenicity, and biodistribution, and a non-GLP efficacy study confirmed that the transplanted cells mediated full functional recovery in a pre-clinical rat model of PD. We further observed highly comparable efficacy results between two different GMP batches, verifying that the product can be serially manufactured. A fully in vivo-tested batch of STEM-PD is now being used in a clinical trial of 8 patients with moderate PD, initiated in 2022.

The human brain contains billions of neurons that flexibly interconnect to support local and global computational spans. As neuronal activity propagates through the neural medium, it approaches a critical state hedged between ordered and disordered system regimes. Recent work demonstrates that this criticality coincides with the small-world topology, a network arrangement that accommodates both local (subcritical) and global (supercritical) system properties. On one hand, operating near criticality is thought to offer several neurocomputational advantages, e.g., high-dynamic range, efficient information capacity, and information transfer fidelity. On the other hand, aberrations from the critical state have been linked to diverse pathologies of the brain, such as post-traumatic epileptiform seizures and disorders of consciousness. Modulation of brain activity, through neuromodulation, presents an attractive mode of treatment to alleviate such neurological disorders, but a tractable neural framework is needed to facilitate clinical progress. Using a variation on the generative small-world model of Watts and Strogatz and Kuramoto's model of coupled oscillators, we show that the topological and dynamical properties of the small-world network are divided into two functional domains based on the range of connectivity, and that these domains play distinct roles in shaping the behavior of the critical state. We demonstrate that short-range network connections shape the dynamics of the system, e.g., its volatility and metastability, whereas long-range connections drive the system state, e.g., a seizure. Together, these findings lend support to combinatorial neuromodulation approaches that synergistically normalize the system dynamic while mobilizing the system state.

Background: Modulation of pathological neural circuit activity in the brain with a minimum of com-plications is an area of intense interest. Objective: The goal of the study was to alter neurons' physiological states without apparent damage of cellular integrity using stereotactic radiosurgery (SRS). Methods: We treated a 7.5 mm-diameter target on the visual cortex of Goeurottingen minipigs with doses of 40, 60, 80, and 100 Gy. Six months post-irradiation, the pigs were implanted with a 9 mm-wide, eight-shank multi-electrode probe, which spanned the radiation focus as well as the low-exposure neighboring areas. Results: Doses of 40 Gy led to an increase of spontaneous firing rate, six months post-irradiation, while doses of 60 Gy and greater were associated with a decrease. Subjecting the animals to visual stimuli resulted in typical visual evoked potentials (VEP). At 40 Gy, a significant reduction of the P1 peak time, indicative of higher network excitability was observed. At 80 Gy, P1 peak time was not affected, while a minor reduction at 60 Gy was seen. No distance-dependent effects on spontaneous firing rate, or on VEP were observed. Post-mortem histology revealed no evidence of necrosis at doses below 60 Gy. In an in vitro assay comprising of iPS-derived human neuron-astrocyte co-cultures, we found a higher vulnerability of inhibitory neurons than excitatory neurons with respect to radiation, which might provide the cellular mechanism of the disinhibitory effect observed in vivo. Conclusion: We provide initial evidence for a rather circuit-wide, long-lasting disinhibitory effect of low sub-ablative doses of SRS. (c) 2022 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Disabling gait symptoms, especially freezing of gait (FoG), represents a milestone in the progression of Parkinson’s disease (PD). This systematic review and network meta-analysis assessed and ranked interventions according to their effectiveness in treating gait symptoms in people with PD across four different groups of gait measures. A systematic search was carried out across PubMed, EMBASE, PubMed Central (PMC), and Cochrane Central Library from January 2000 to April 2021. All interventions, or combinations, were included. The primary outcome was changes in objective gait measures, before and after intervention. Outcome measures in the included studies were stratified into four different types of gait outcome measures; dynamic gait, fitness, balance, and freezing of gait. For the statistical analysis, five direct head-to-head comparisons of interventions, as well as indirect comparisons were performed. Corresponding forest plots ranking the interventions were generated. The search returned 6288 articles. From these, 148 articles could be included. Of the four different groups of measurement, three were consistent, meaning that there was agreement between direct and indirect evidence. The groups with consistent evidence were dynamic gait, fitness, and freezing of gait. For dynamic gait measures, treatments with the largest observed effect were Aquatic Therapy with dual task exercising (SMD 1.99 [− 1.00; 4.98]) and strength and balance training (SMD 1.95 [− 0.20; 4.11]). For measures of fitness, treatments with the largest observed effects were aquatic therapy (SMD 3.41 [2.11; 4.71] and high-frequency repetitive transcranial magnetic stimulation (SMD 2.51 [1.48; 3.55]). For FoG measures, none of the included interventions yielded significant results. Some interventions can ameliorate gait impairment in people with PD. No recommendations on a superior intervention can be made. None of the studied interventions proved to be efficacious in the treatment of FoG. PROSPERO (registration ID CRD42021264076).

Introduction:Gait difficulties are common in Parkinson's disease (PD) and cause significant disability. These symptoms are often resistant to treatment. Spinal cord stimulation (SCS) has been found to improve gait, including freezing of gait, in a small number of patients with PD. The mechanism of action is unclear, and some patients are non-responders. With this double-blind, placebo-controlled efficacy and feasibility clinical and imaging study, we aim to shed light on the mechanism of action of SCS and collect data to inform development of a scientifically sound clinical trial protocol. We also aim to identify clinical and imaging biomarkers at baseline that could be predictive of a favourable or a negative outcome of SCS and improve patient selection. Methods and analysis:A total of 14 patients will be assessed with clinical rating scales and gait evaluations at baseline, and at 6 and 12 months after SCS implantation. They will also receive serial 18F-deoxyglucose and 18FEOBV PET scans to assess the effects of SCS on cortical/subcortical activity and brain cholinergic function. The first two patients will be included in an open pilot study while the rest will be randomised to receive active treatment or placebo (no stimulation) for 6 months. From this point, the entire cohort will enter an open label active treatment phase for a subsequent 6 months. Ethics and dissemination:This study was reviewed and approved by the Committee on Health Research Ethics, Central Denmark RM. It is funded by the Danish Council for Independent Research. Independent of outcome, the results will be published in peer-reviewed journals and presented at national and international conferences. Trial registration number:NCT05110053; ClinicalTrials.gov Identifier.

BACKGROUND:Neuromodulation is a rapidly expanding therapeutic option considered within neuropsychiatry, pain and rehabilitation therapy. Combining electrostimulation with feedback from fMRI can provide information about the mechanisms underlying the therapeutic effects, but so far, such studies have been hampered by the lack of technology to conduct safe and accurate experiments. Here we present a system for fMRI compatible electrical stimulation, and the first proof-of-concept neuroimaging data with deep brain stimulation (DBS) in pigs obtained with the device.NEW METHOD:The system consists of two modules, placed in the control and scanner room, connected by optical fiber. The system also connects to the MRI scanner to timely initiate the stimulation sequence at start of scan. We evaluated the system in four pigs with DBS in the subthalamic nucleus (STN) while we acquired BOLD responses in the STN and neocortex.RESULTS:We found that the system delivered robust electrical stimuli to the implanted electrode in sync with the preprogrammed fMRI sequence. All pigs displayed a DBS-STN induced neocortical BOLD response, but none in the STN.COMPARISONS WITH EXISTING METHOD:The system solves three major problems related to electric stimuli and fMRI examinations, namely preventing distortion of the fMRI signal, enabling communication that synchronize the experimental conditions, and surmounting the safety hazards caused by interference with the MRI scanner.CONCLUSIONS:The fMRI compatible electrical stimulator circumvents previous problems related to electroceuticals and fMRI. The system allows flexible modifications for fMRI designs and stimulation parameters, and can be customized to electroceutical applications beyond DBS.