Abstract Background Deep brain stimulation (DBS) of the ventral intermediate nucleus and posterior subthalamic area (VIM/PSA) in Essential Tremor (ET) and the subthalamic nucleus (STN) in Parkinson’s disease (PD) are established treatment for tremor. To achieve maximum tremor control, increasing stimulation frequency beyond 130 Hz is part of clinical practice, but lacks scientific evidence. Objective To compare tremor suppression under total electrical energy delivered (TEED)-equivalent stimulation at 130 Hz versus 185 Hz in STN-DBS for PD and VIM/PSA-DBS for ET. Methods In this prospective, double-blind study, acute DBS effects were assessed in 18 people with ET (n = 29 hemispheres), and 25 people with PD (n = 30 hemispheres). Tremor-suppressive effects, evaluated by accelerometry, were compared with TEED-equivalent stimulation at 130 Hz and 185 Hz using linear mixed-effects models, explorative pairwise comparisons, and equivalency testing. Results Linear mixed-effects models revealed no significant effect of stimulation frequency on tremor improvement in both cohorts. Pairwise comparisons showed no consistent differences in total tremor improvement with TEED-equivalent 130 Hz vs 185 Hz DBS. Post-hoc equivalence testing confirmed equivalence of stimulation frequencies under TEED-equivalent conditions within a ± 20% margin of relative tremor improvement. Conclusion This study provides Level II evidence that a higher stimulation frequency of 185 Hz does not offer additional benefit in deep brain stimulation for tremor and supports 130 Hz as the standard stimulation frequency for tremor suppression in ET and PD.

AIMS:To determine how lesion size and location shape longitudinal functional connectivity (FC) changes after stroke. METHODS:Adult male mice underwent atlas-based resting-state fMRI at baseline and 1, 2, and 4 weeks after either a small photothrombotic cortical stroke (N = 25) or a larger transient cortico-striatal MCAO stroke (N = 6). FC was quantified across 98 atlas regions, focusing on sensorimotor cortex, striatum, and thalamus, including intra- and inter-hemispheric connectivity matrices and regional seed strength. RESULTS:Cortical stroke caused widespread hyperconnectivity at Weeks 1-2, with about 90% of connections increased, followed by partial normalization by Week 4. This effect declined most strongly in the ischemic hemisphere and remained more sustained contralesionally. In contrast, cortico-striatal stroke induced global hypoconnectivity at Week 1, with more than 90% of connections decreased, a modest and heterogeneous shift toward baseline at Week 2, and widespread decreases persisting at Week 4. A subset of sensorimotor connections showing opposite changes in the two models robustly separated groups at all post-stroke time points. Regional lesion involvement scaled with the magnitude of baseline-referenced FC alterations. CONCLUSION:Lesion topography drives distinct longitudinal FC trajectories after stroke and may help define network biomarkers and optimal windows for targeted interventions.

Abstract Objective and scalable approaches for detecting subtle motor impairment in isolated REM sleep behavior disorder (iRBD), a prodromal stage of Parkinson’s disease, remain limited. We investigated whether markerless motion capture from single RGB-camera videos can identify gait abnormalities in people living with iRBD and provide interpretable digital biomarkers. We retrospectively analyzed 93 standardized walking videos from three clinical sites. Human pose estimation extracted 12 body markers and 14 kinematic time series. Thirty-five machine learning approaches classified healthy controls (HC) and people with iRBD. The Movement Disorder Society Unified Parkinson’s Disease Rating Scale Part 3 (MDS-UPDRS III) served as the clinical baseline. The best-performing model (tsfresh+XGBoost) achieved an AUROC of 0.739, significantly outperforming the MDS-UPDRS III sum score when trained on data from all three sites. Harmonized multi-site training improved performance. SHAP identified hip-related temporal features as key contributors, which differed between groups and showed stronger associations with regional dopaminergic deficits than clinical scores. Single-camera gait analysis may provide scalable digital biomarkers for low-cost screening and monitoring of prodromal PD. Plain Language Summary People with isolated REM sleep behavior disorder (iRBD) often show subtle changes in their walking that can be difficult to detect during routine clinical examinations. In this study, we used artificial intelligence to analyze videos of a simple walking task without requiring wearable sensors or body markers. The computer-based analysis distinguished people with iRBD from healthy individuals more accurately than standard clinician-rated motor scores. While further validation in larger studies is needed, these findings suggest that video-based movement analysis could become a useful objective tool to support the assessment of people at increased risk of Parkinson’s disease and related disorders.

While reinforcement has repeatedly been shown to impact motor adaptation, previous inconsistent findings hinder our mechanistic understanding. To conciliate contradictory views, we used two distinct motor tasks to investigate whether reinforcement differentially modulates two core motor learning processes: between-trial learning resulting from motor planning and within-trial learning supported by the online correction of ongoing movements. We observed successful adaptation, retention and highly similar temporal profiles of adaptation for both tasks, in line with the notion that motor adaptation of upper limb movements is likely to result from updates in both motor planning and online correction. Reinforcement enhanced performance in the task allowing for within-trial adaptation. Conversely, higher degrees of early motor variability were associated with faster between-trial but not within-trial adaptation. These results highlight a dissociation of factors affecting motor adaptation: Reinforcement seems to primarily impact within-trial learning linked to the online correction of ongoing movements. In contrast, early motor variability might benefit between-trial learning by informing motor planning potentially via an exploration of the motor output space. Our results help explain previous inconsistent findings and add to our theoretical understanding by demonstrating that the effects of reinforcement and motor variability may depend on whether adaptation is driven by within- or between-trial learning.

Objective Microstates derived from EEG amplitude and connectivity states from EEG phase examine distinct aspects of the brain's dynamic organization. However, it is unclear how sensitive they are to changes in functional connectivity in Alzheimer's disease (AD). We examined pre- and post-task alterations of brain activity in AD patients to compare the ability of microstates and connectivity states to capture disease-related network dysfunction. Methods Resting-state EEG (RS-EEG) was recorded before and after a memory task in fifteen patients with AD and fifteen healthy controls. During the memory task, either low-intensity repetitive transcranial magnetic stimulation (rTMS) over the parieto-occipital region or sham stimulation was applied. We quantified microstates and phase-based connectivity states in the alpha frequency range from the RS-EEG. Results While microstates showed task-related alterations in healthy controls only, connectivity states were more sensitive to alterations in the AD group. rTMS appeared to reduce these task-related alterations in connectivity states. Connectivity states indicated a shift towards lower, more diffuse connectivity in AD patients. Connectivity states were correlated with memory task performance and amyloid-beta levels in the AD group. Conclusions Connectivity states indicated decreased task-related network stability in AD patients, which correlated with memory task performance. The findings support the neural efficiency hypothesis, which states that more efficient brain network optimization during tasks is linked to better performance. Significance Given the progressive decline of alpha power in AD patients, phase-based connectivity states provide valuable complementary information to microstates and may serve as a biomarker for assessing large-scale network alterations in relation to disease progression.

Beyond immediate neuronal damage,functional and structural connectivity is altered brain-wide with implications for functional deficits and recovery in stroke.It remains unclear,however,if the level of axonal damage,as well as compensatory plasticity,i.e.,axonal sprouting and remyelination,depend on the lesion size and topology.This study compared two different stroke models in adult male mice,with the aim of uncovering the dynamics in white matter changes.Repetitive diffusion magnetic resonance imaging was acquired over 4 weeks post photothrombotic cortical(1.41％±0.92％of brain volume)and middle cerebral artery occlusion cortico-striatal(11.53％±2.8％of brain volume)strokes.Structural connectivity changes were mapped over time at the whole-brain level.We quantified inter-and intra-hemispheric seed strength changes over time,with seed strength reflecting how strongly each region was connected to the rest of the brain.Differences between groups and time points were assessed using a mixed model corrected for multiple comparisons.The results showed that large cortico-striatal lesions led to increased structural connectivity in sensorimotor regions,whereas small cortical lesions induced asymmetric connectivity changes:an increase extending globally from the ischemic hemisphere and a decrease expanding globally from the healthy hemisphere.These findings highlight that stroke severity and lesion size significantly affect the temporal dynamics and spatial distribution of connectivity disruptions,emphasizing the need for targeted monitoring of neural changes post-stroke.

BACKGROUND:Motor asymmetry is a hallmark of Parkinson's disease (PD), but ~20% of patients present with symmetric motor signs, which are associated with faster disease progression and poorer dopaminergic response. The impact of motor symmetry on activities of daily living (ADL) outcomes following subthalamic deep brain stimulation (STN-DBS) remains unclear. We hypothesised that patients with symmetric PD experience less ADL improvement post-STN-DBS than asymmetric PD patients. METHODS:This was a prospective, quasi-experimental, non-randomised, controlled, international multicentre study with a 6-month follow-up. The primary outcome was the Scales for Outcomes in Parkinson's Disease-Motor ADL scale. Secondary outcomes included Unified Parkinson's Disease Rating Scale motor examination and Parkinson's Disease Questionnaire-8 (PDQ-8). We defined symmetric PD as a right-to-left hemibody motor score equalling 1. We analysed within-group longitudinal changes, between-group outcome differences, effect size and correlations between PDQ-8 and motor changes. We confirmed results in a propensity-score matched subcohort with well-balanced demographic and clinical parameters. RESULTS:We included 200 patients with asymmetric and 54 with symmetric PD. In symmetric PD, ADL remained stable, which was not associated with the observed PDQ-8 improvement. In contrast, in asymmetric PD, ADL improved with a moderate effect size, which correlated moderately with PDQ-8 improvement. In symmetric PD, the absolute risk of experiencing no clinically relevant postoperative ADL improvement was 23.8% higher. CONCLUSIONS:This study provides class IIb evidence of worse ADL outcome of STN-DBS in patients with symmetric compared with asymmetric PD. Clinicians should counsel patients with symmetric PD on their elevated risk of ADL non-response when discussing STN-DBS as a treatment option.

STUDY OBJECTIVES:Sleep disorders are common non-motor symptoms of Parkinson's disease (PD) that significantly impact patients' quality of life. Specifically, alterations in sleep microstructure - such as reduced slow-wave activity and sleep spindles - are prevalent in PD. The locus coeruleus (LC), the brain's primary source of noradrenaline, plays a pivotal role in regulating sleep and wakefulness and is highly vulnerable to neurodegeneration in PD. This study explores whether disruptions in sleep microarchitecture in PD are linked to LC degeneration. METHODS:We assessed polysomnography for sleep macroarchitecture, EEG spectral power, and spindle density in 32 PD patients and 24 age- and sex-matched controls. In a sample subset (n = 42), neuromelanin-sensitive MRI was performed, and LC neuromelanin contrast was correlated to sleep metrics. RESULTS:PD patients exhibited reduced slow-wave activity (p < 0.01), slow-to-fast frequency ratio (p < 0.01), and spindle density (p < 0.05) compared to HC subjects. LC neuromelanin contrast was diminished in PD patients (p < 0.05). Even though group differences were detected for slow-wave activity, a positive correlation between LC contrast and spindle density but not slow-wave activity was observed in the entire sample. CONCLUSIONS:The findings indicate that spindle density, but not slow-wave activity, is associated with LC degeneration. Further research is needed to determine whether, besides this association, noradrenergic dysfunction is causal for impaired sleep microarchitecture and whether this connection also contributes to cognitive decline in PD and other neurodegenerative diseases, such as Alzheimer's disease.

Abstract Background Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a well-established treatment for Parkinson’s disease (PD). Beyond basic omnidirectional, monopolar stimulation, advanced stimulation settings (AS), such as directional or vertical current steering, variation of pulse width and frequency, bipolar and interleaving stimulation are increasingly available. Our aim was to summarize current evidence on AS in STN-DBS in PD and systemically report their application and potential benefits in clinical routine. Methods In this retrospective single-center observational study, we analyzed stimulation settings of 145 patients with bilateral STN-DBS 3, 6, and 12 months postoperatively. Secondary outcomes included preoperative levodopa response, lead positions, and postoperative reduction of levodopa-equivalent daily dose (LEDD) in patients staying with basic stimulation settings (BS) compared to those initially with AS at 3-months follow-up and those with a change from BS to AS. Results AS were applied in 40.7%, 55.9%, and 73.8% of patients at 3, 6, and 12 months respectively. LEDD reduction after three months was higher in patients remaining with BS or initially AS than in patients with a switch to AS after three months, while there was no difference at 12 months. Median distance of leads to the center of gravity of the motor-STN was slightly larger when AS were applied. Conclusions AS are frequently employed in clinical routine at a specialized DBS center. They may compensate for deviant lead placement in terms of stimulation efficacy measured by postoperative LEDD reduction. Prospective studies are warranted, focusing on specific AS indications in chronic DBS to optimize individual patient outcomes.

Previous studies emphasize phase synchronization as a fundamental mechanism for integrating local features into coherent percepts. We employed a novel paradigm and dynamic graph analysis based on EEG to track neural dynamics associated with perceiving a face (or not) while keeping the stimuli identical. Thirty participants underwent a pretest to establish perceptual thresholds for detecting faces within images overlaid with visual noise. These thresholds were then applied in an EEG experiment with the same task, focusing on images with 50% and 75% detection probabilities. In the high-alpha band, we observed increased coupling (100-275 msec after stimulus onset) between the left and right occipitotemporal electrodes when an ambiguous stimulus was perceived as a face, indicating conscious face perception. The failure to perceive a face resulted in enhanced theta band phase synchronization between bilateral occipitotemporal electrodes and increased high-alpha-band coupling between the left frontal and right occipitotemporal electrodes, which showed face-selective responses. These synchronizations are likely to reflect the continuous gathering of individual bits of facial information rather than signaling the presence or absence of a face percept. Additionally, we identified frontal-occipitotemporal theta-band couplings related to the stimulus's informational content, irrespective of whether the inherent face was perceived. Our findings reveal distinct temporal dynamics in phase synchronization at specific frequencies, indicating a specialized system for face perception during integrated information processing across the frontal and visual cortex, resolving ambiguities.

ABSTRACT Background Corticospinal tract (CST) damage is a major cause of post-stroke motor deficits. However, it remains unclear which estimates of CST damage best predict motor recovery, especially regarding different aspects of motor control. While conventional CST-lesion metrics offer superior feasibility, data-driven machine learning (ML) approaches may better capture patients’ propensity for task-specific recovery with important implication for their use as future clinical biomarkers. Methods Providing the first direct longitudinal comparison of these approaches based exclusively on CST-lesion patterns, we evaluated six conventional CST-lesion metrics and a voxel-wise ML approach using clinical MRI data from 127 acute ischemic stroke patients. Acute impairment and outcome (>3 months post-stroke) were assessed for basal and complex motor functions. Conventional CST-lesion metrics and ML were used to predict task-specific motor impairment and outcome. Results All conventional CST-lesion metrics correlated significantly with both acute impairment and motor outcome across motor domains, with metrics weighted for CST narrowing and tract probability performing best. However, predictive performance for unseen patients was low. ML outperformed conventional markers in predicting acute impairment across motor domains and basal motor outcome, but failed to predict complex motor outcome. Topographically, predictive voxels clustered within and above the posterior limb of the internal capsule, with distinct CST subregions associated with basal versus complex motor impairment, consistent with a task-specific somatotopic organization. Conclusions The predictive utility of CST biomarkers was task- and timepoint-dependent. While ML may improve predictive performance, complex motor outcome remained difficult to predict, likely reflecting greater reliance on distributed cortical reorganization beyond the CST. By revealing task-specific CST subregions, voxel-wise ML provides an anatomically informed foundation for future predictive models. Such future models should combine CST biomarkers with measures of broader motor network integrity to enable individualized prognosis tailored to specific motor domains and recovery stages.

Zusammenfassung Die Alzheimer-Krankheit ist ein langjähriger biologischer Prozess, dessen neuropathologischen Veränderungen bereits Jahrzehnte vor der klinischen Manifestation beginnen. Fortschritte in der Biomarkerdiagnostik ermöglichen eine frühzeitige Identifikation pathologischer Veränderungen und eine präzisere Einordnung verschiedener Krankheitsstadien. Da therapeutische Optionen bislang nur begrenzte Effekte zeigen, rücken modifizierbare Risikofaktoren und präventive Lebensstilinterventionen zunehmend in den Fokus.

BACKGROUND:After a motor stroke, brain networks mediating reaching and grasping undergo functional reorganization, particularly in the parietal cortex. Online repetitive transcranial magnetic stimulation (rTMS) can probe the behavioral relevance of stimulated cortical territories. However, anatomical interpretation is limited because the induced electric field is spatially distributed and may not correspond precisely to the nominal stimulation target. OBJECTIVE:To investigate how individual rTMS-induced E-field distributions relate to interference effects of online rTMS over the anterior intraparietal sulcus (IPS) on grasping in stroke patients and healthy controls. METHODS:Eighteen chronic stroke patients and eighteen matched controls performed a reach-grasp-lift task during online rTMS of the IPS. Individual E-fields were modeled and correlated with rTMS-induced changes in 3D kinematic measures. The overlap between E-field maxima and a meta-analytically defined grasping network, as well as cytoarchitectonic parietal regions, was quantified. RESULTS:In both groups, spatial overlap between the induced E-field and the grasping-related network was linked to rTMS effects on movement smoothness. Changes in grip shaping and smoothness were associated with E-field overlap in the IPS in healthy controls. In patients, the analogous association was observed for the inferior parietal lobule (IPL) rather than the IPS, a pattern compatible with reorganization of parietal specialization after stroke. CONCLUSIONS:E-field-based analyses may improve the interpretation of rTMS effects on grasping in healthy and reorganized neural circuits. This can provide a framework for neuromodulation strategies that focus on individually defined functional targets rather than standard landmarks.

Structural cortico-cortical connectivity is essential for motor recovery after stroke, with undamaged fibre tracts potentially serving as structural reserve for functional reorganization. Yet, the mechanisms by which the structural reserve contributes to changes in functional network configurations to improve post-stroke motor control remains unknown. Here, we assessed structural (diffusion spectrum imaging) and effective (fMRI-based Dynamic Causal Modelling) connectivity to examine how the structural reserve may guide motor network reorganization of upper limb motor control. Specific features of cortico-cortical structural reserve were associated with distinct patterns of functional network configurations: limited intrahemispheric structural reserve between ipsilesional primary motor cortex and premotor areas was linked to interhemispheric rerouting of motor commands via the contralesional primary motor cortex, particularly when ipsilesional corticospinal tract integrity was low. In contrast, limited interhemispheric structural reserve between ipsilesional primary motor cortex and contralesional premotor areas was related to intrahemispheric rerouting via the ipsilesional premotor cortex, especially in patients with high residual corticospinal tract integrity. Even though both alternative pathways may allow bypassing damaged corticospinal tract fibres originating from the ipsilesional primary motor cortex, we observed a clear behavioural dissociation: in patients who substantially recovered, enhanced intrahemispheric rerouting was indicative of better hand function, reflecting beneficial reorganization. Conversely, interhemispheric rerouting was associated with pronounced motor impairment of the paretic arm and primarily observed in non-substantially recovered patients, in line with task-specific maladaptive reorganization. Our findings emphasize that the motor network’s available structural reserve critically shapes functional network reorganization by predetermining whether motor commands are primarily rerouted intra- or interhemispherically with distinct implications for motor recovery. Besides helping to reconcile previous conflicting interpretations on the role of contralesional primary motor cortex, our results underscore that the individual level of structural motor network reserve should be considered for future therapeutic approaches aiming at amplifying motor recovery after stroke.

Influential theories on error processing assume that when we make errors, adaptive processes are triggered to improve our behaviour. These processes appear to be more effective after participants have detected an error. Therefore, the assessment of error awareness, allowing a differential analysis of detected and undetected errors, and behavioural adjustments have gained increasing attention in the field of cognitive control over the past decades. A common methodological challenge in studies investigating error detection is that the number of undetected errors is usually relatively low. Here, we introduce a new experimental task that pursued the primary goal to generate a high error rate including many detected and undetected errors which is stable over the time on task. Study 1 (n = 21 adults) clearly showed the task was successful in producing those indented error rates. Exploratory analyses of study 1 further suggested that post-error adjustments (measured as post-error slowing and post-error accuracy) are unrelated to error awareness in the current study. Based on findings of study 1, study 2 (n = 20 adults) used the experimental task to test whether error awareness could specifically be manipulated within one experimental session by changing a single task feature. As expected, the modulation affected error detection, but did not affect the total error rate. Potential applications of the Speeded Inference Task (short SIT) are discussed. With this newly developed paradigm, we wish to lay the foundation for future research to better understand (neural) processes associated with error awareness.

Cross-frequency coupling (CFC) has been proposed to facilitate neural information transfer across spatial and temporal scales. Phase-amplitude coupling (PAC), a type of CFC in which the amplitude of a faster brain oscillation is coupled to the phase of a slower brain oscillation, is implicated in various higher-order cognitive functions and was shown to be pathologically altered in neurological and psychiatric disease. In Parkinson's disease (PD), the coupling between gamma amplitude (50-150 Hz) and beta phase (13-35 Hz) is exaggerated. Enhanced β-γ PAC was found in the subthalamic nucleus and various cortical sources and shown to be responsive to dopaminergic therapy and deep brain stimulation (DBS). Therefore, exaggerated β-γ PAC has been proposed to be a disease marker and a potential target for brain circuit interventions. Despite these promising findings, a significant knowledge gap remains, as the spatial and frequency-specific dynamics of β-γ PAC and its association with motor symptoms and therapy remain elusive. To address this knowledge gap, we employed high-density electroencephalography (EEG) with source localisation techniques for patients with PD at rest. We highlight three key findings: (1) a frequency-specific increase in high β (23-35 Hz)-γ PAC within and between sources of the cortical motor network, (2) a link between elevated high β-γ PAC and bradykinesia and rigidity when OFF medication, but not tremor, and (3) a medication-induced reduction in high β-γ PAC in the supplementary motor area correlating with clinical improvement. Altogether, this study provides novel insights into the pathophysiology of PD as an oscillopathy and identifies high β-γ PAC as a potential marker of Parkinsonian symptoms and treatment effects. This has important implications for invasive as well as non-invasive therapeutic strategies as high β-γ PAC targeting might hold greater promise than targeting β-γ PAC per se.

Concussive brain injury (CBI), the pathophysiological substrate underlying clinical concussion, is a frequent yet insufficiently understood condition with potential long-term neurological impairment in a subset of patients. Especially repetitive CBI, i.e., in contact sports, has been associated with lasting cognitive deficits and progressive neurodegeneration (e.g., chronic traumatic encephalopathy, CTE). To address this knowledge gap, a reproducible mouse model of closed-head rotational brain injury that recapitulates key biomechanical and pathological features of CBI was established. A stereotactically guided electromagnetic impactor was used to deliver a standardized strike to the intact skull. To reduce focal strain on the skull and adjacent brain tissue, the impactor tip was fitted with a custom-made silicone cap. This configuration reliably induced head rotation with low inter-animal variability while preventing skull fractures or microscopic tissue injury. To preserve physiological neuronal and vascular activity and to avoid potentially neuromodulatory effects of deep anesthesia, brain injury was induced in conscious mice under light sedation using the α2-agonist medetomidine. The induced impacts caused reproducible rotational head motion with only minor variability attributable to head positioning. Structural brain integrity was assessed using in vivo T2-weighted magnetic resonance imaging and confirmed by ex vivo histological analyses, which revealed no evidence of tissue disruption, contusion, or microbleeds but demonstrated a mild, widespread disruption of the microvascular interface. This novel model of rotational closed-head brain injury provides a robust experimental platform for longitudinal investigations of subtle neurovascular, inflammatory, and blood-brain barrier alterations that occur in the absence of overt structural pathology. Its application enables mechanistic insights into the pathophysiology of clinical concussion and potential neurodegenerative consequences of repetitive injury, thereby facilitating the development of urgently needed clinical biomarkers.