David Jose Pedrosa

While nigrostriatal dopaminergic cell loss is the pathological hallmark of Parkinson’s disease, it is well-known that dopamine deficiency cannot fully explain the clinical severity or disease progression. Emerging data suggest that resilience, i.e. the brain’s capacity to maintain function despite pathology, plays a key role in shaping clinical variability of both motor and non-motor symptoms. However, different contributing terms have been proposed, including brain compensation and reserve, and it remains unclear how these terms can be delineated both conceptually and mechanistically. Therefore, here we provide a synthesis of recent neuroimaging evidence on resilience mechanisms in Parkinson’s disease, with the following aims: (i) clarify the terminology; (ii) define the mechanisms; and (iii) relate resilience mechanisms to treatments, including dopamine replacement therapy and deep brain stimulation. We distinguish between compensation and reserve. We define compensation as adaptive neural activity that stabilizes task performance in the presence of pathology, particularly under increased demands, and is inversely related to clinical deficits. By contrast, reserve (cognitive or motor) refers to the capacity of neural resources that is built up across the lifetime, shaped by factors of an individual’s exposome. Compensation has been localized to the parieto-premotor network alongside the relatively preserved anterior striatum. Higher motor reserve has been linked to somatomotor network tolerance, preserved structural integrity and higher striatal functional network connectivity. Cognitive reserve relates to network robustness and structural integrity within the fronto-parietal network. Whether resilience mechanisms drive interindividual variability in long-term treatment response remains unresolved. Lower motor reserve predicts accelerated levodopa dose escalation and increased risk of dyskinesias, while cognitive reserve modulates both cognitive and motor outcomes after deep brain stimulation, highlighting cross-domain interactions. Brain compensation and reserve are two key components of resilience that together shape clinical heterogeneity in Parkinson’s disease across motor and cognitive domains. Although they operate at different timescales and through distinct mechanisms, they remain intrinsically related. Our framework suggests that biomarkers of resilience could complement biological definitions of Parkinson’s disease and shift therapeutic strategies from merely slowing degeneration towards strengthening adaptive capacity. Key priorities for future work are to define the longitudinal relationship between resilience failure and subcortical neurodegeneration using concurrent measures of nigrostriatal decline, multimodal datasets or controlled interventions, and to determine how symptom domain-specific resilience mechanisms shape treatment outcomes to enable targeted modulation and better capture disease heterogeneity.

We are in an era in which increasing numbers of potentially disease-modifying treatments for Parkinson's disease are being tested in clinical development. Current definitions of disease modification have inherent limitations; hence there is a need to establish a clear, unified definition. This unified definition of disease modification should be applicable to both idiopathic and genetic forms of Parkinson's disease. In addition to motor function, it must address important milestones (e.g., cognition, autonomic dysfunction) across all disease stages. This review examines existing definitions and highlights the need for a more holistic approach that integrates the perspectives of patients, healthcare professionals, and researchers.

Cross-frequency coupling has been proposed to facilitate neural information transfer across spatial and temporal scales. Phase–amplitude coupling (PAC), a type of cross-frequency coupling 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 altered pathologically in neurological and psychiatric disease. In Parkinson’s disease, 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. 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, because 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 used high-density EEG with source-localization techniques for patients with Parkinson’s disease at rest. We highlight three key findings: (i) a frequency-specific increase in high β (23–35 Hz)–γ PAC within and between sources of the cortical motor network; (ii) a link between elevated high β–γ PAC and bradykinesia and rigidity when OFF medication, but not tremor; and (iii) a medication-induced reduction in high β–γ PAC in the supplementary motor area correlating with clinical improvement. Altogether, this study provides new insights into the pathophysiology of Parkinson’s disease as an oscillopathy and identifies high β–γ PAC as a potential marker of parkinsonian symptoms and treatment effects. This has important implications for both invasive and non-invasive therapeutic strategies, because high β–γ PAC targeting might hold greater promise than targeting β–γ PAC per se.

Die Parkinson-Krankheit (PK) gehört zu den häufigsten neurodegenerativen Erkrankungen. Der demografische Wandel lässt einen starken Anstieg der Inzidenzen erwarten, was die Dringlichkeit verdeutlicht, sowohl etablierte symptomatische Therapien zu optimieren als auch neue, krankheitsmodifizierende Therapieansätze zu entwickeln. Article published online: 16 March 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

Deep brain stimulation is an effective therapy for tremor in Parkinson’s disease, yet clinical outcomes vary substantially across individuals. This variability highlights the need for continuous and quantitative measures that more accurately capture symptom severity and treatment response. Although precise subthalamic targeting remains fundamental to effective therapy, accounting for network-level modulation of disrupted motor circuits underlying core symptoms may further enhance clinical benefit. Nevertheless, the relative contributions of local and network-level effects to tremor suppression remain unclear, limiting our understanding of the mechanisms driving clinical improvement. In this study, we identified a patient-specific connectivity fingerprint associated with effective tremor suppression following subthalamic deep brain stimulation. Twenty patients with Parkinson’s disease underwent objective tremor quantification using accelerometry during systematic monopolar reviews. For each stimulation setting, the corresponding volume of tissue activated served as a seed for probabilistic tractography, informed by individual diffusion-weighted imaging and subject-specific parcellation of grey and white matter structures. Subsequently, partial least squares regression was employed to analyse over 1,500 stimulation conditions, aiming to identify brain regions whose connectivity patterns predicted tremor outcomes. Ultimately, the resulting network model was compared with a local-effects model to assess whether network mapping provided superior predictive capability for motor improvement compared to traditional local targeting methods. Our results demonstrate that (1) modulation of the basal ganglia and the cerebello-thalamo-cortical circuit at the network level predicts clinical improvement more accurately than local stimulation alone ( P < 0.001); and (2) optimal stimulation sites for tremor relief are located in white-matter regions adjacent to the subthalamic nucleus. Model significance was confirmed through permutation testing ( P < 0.001). Based on these findings, we propose a framework that combines sensor-based measurements with monopolar mapping to investigate the effects of symptom-specific neuromodulation and to guide the selection of connectomic parameters for personalised treatment of motor symptoms.

Background: Despite the widespread adoption of deep brain stimulation (DBS) for treating Parkinson's disease (PD) over the last few decades, standardized post-operative care protocols remain lacking. Objective: This study aimed to establish expert consensus on managing post-operative subthalamic nucleus (STN-DBS). Methods: A three-round online Delphi study was conducted involving an international panel of DBS experts actively engaged in all facets of post-operative care. In the initial round, the panel generated ideas regarding essential components of a post-operative care protocol. In rounds two and three, numerical ratings and rankings were employed to achieve consensus on the formulated statements. This iterative process culminated in a refined STN-DBS care protocol. Results: The study included 76 international participants who, over three survey rounds, reached consensus on 129 components of a care protocol for managing post-operative STN-DBS. The final protocol encompassed eleven essential domains: hospital discharge, rehabilitation referral, imaging and lead review, monopolar testing, local field potential sensing, troubleshooting, medication management, multiprofessional care, follow-up, empowerment of patients and caregivers, and quality control of management procedures. Conclusions: This Delphi-based, expert-driven process resulted in a comprehensive care protocol for patients undergoing STN-DBS. The findings offer a valuable resource for healthcare professionals, providing a structured, consensus-based framework aimed at optimizing post-operative outcomes. In addition to supporting clinical practice, these recommendations may help inform policy development and drive systematic improvements in care delivery. Further research and validation in diverse clinical settings will be essential to assess the generalizability and real-world impact of the proposed procedures.

The impact of Deep Brain Stimulation (DBS) on emotion processing remains debated. The aim of this study was to investigate whether the localisation of stimulation within the subthalamic nucleus (STN) differentially influences emotion processing in sixteen patients with Parkinson’s disease. An emotion recognition task was employed before and three months after STN-DBS surgery in off-medication state. Volumes of activated tissue (VATs) were mapped to STN subregions and correlated with task performance changes. Larger right ventrolateral non-motor STN VATs were associated with improved recognition of positive emotions (ρ = 0.54, p = 0.04). This association was right-lateralised, involving fibres connecting the STN to the prefrontal cortex, suggesting a lateralised network basis for emotion processing in PD. Larger VATs in left dorsolateral STN were linked to perceiving emotions more positively. Our findings highlight the role of stimulation site in non-motor STN-DBS outcomes which may explain previous inconsistent findings regarding DBS-effects on emotion processing.

Background: Parkinson’s disease (PD) multimodal complex treatment (PD-MCT) is an inpatient therapeutic programme specifically designed for patients exhibiting parkinsonian symptoms. Established in Germany, this comprehensive approach addresses the multifaceted challenges associated with the management of PD, particularly in advanced stages or when complications such as motor fluctuations, dyskinesia, or non-motor symptoms become pronounced. The programme integrates pharmacological optimization, physiotherapy, occupational therapy, speech therapy, and psychological support, among other complementary therapies, to enhance patient outcomes holistically. Despite its availability for seventeen years, only seven studies evaluating the effectiveness of PD-MCT have been conducted. In this study we evaluated the effects of PD-MCT with a special focus on gait, hypothesizing an improvement after the treatment. Methods: In this single-centre cohort study at a German university hospital we included patients with PD diagnosed by the Movement Disorder Society (MDS) criteria, aged 18–85 years, legal capacity to consent and admitted for treatment with PD-MCT. We assessed changes in motor and non-motor symptoms using Wilcoxon’s signed rank test on pre/post measurements of part III of the motor part of the MDS Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), the Parkinson’s Disease Questionnaire (PDQ-39) and the Timed Up and Go Test (TUG). As a particular emphasis was placed on gait analysis we objectively measured gait throughout the treatment period using advanced mobile sensor technology and analysed gait speed, stride length and lift height using linear mixed effects models. Results: In our sample of 43 PD patients we found significant improvements in MDS-UPRDRS part III (V = 679, p = 0.001), PDQ-39 (V = 770, p < 0.001) and TUG (V = 753.5, p < 0.001) values. as well as in the assessed gait parameters gait speed (t = 66.44, p < 0.001), stride length (t = 62.67, p < 0.001) and lift height (t = 28.16, p < 0.001). Conclusions: Our results underscore the added value of a multimodal inpatient approach, thereby supporting its role as a justified investment in the management of complex PD cases. This work contributes to the expanding body of evidence advocating for integrated, multidisciplinary care models in the treatment of neurodegenerative disorders. Trial registration: This study has not been registered.

Zittern gehört zu den häufigsten neurologischen Symptomen und beeinträchtigt die Lebensqualität der Patienten häufig in starkem Maße. Gerade in der Primär-Versorgung älterer Menschen ist es entscheidend, einen Tremor im Rahmen einer Parkinson-Krankheit von anderen möglichen Tremores abzugrenzen, um eine gezielte Therapie zu ermöglichen. Dieser Beitrag bietet einen kompakten Überblick zum Thema und soll bei der Früherkennung des Parkinson-Tremors unterstützen. Tremor is the most common movement disorder in clinical neurology and it significantly impacts patients’ quality of life. In primary care, particularly among older adults, differentiating between tremor types is essential for early diagnosis and appropriate management, especially when Parkinson’s disease is suspected. This review provides a concise overview of tremor classification and diagnostic strategies, with a focus on distinguishing Parkinsonian tremor from other common tremor syndromes such as essential, dystonic, functional, orthostatic, and secondary tremors. Key clinical characteristics, including tremor type (rest, postural, kinetic, re-emergent), frequency, distribution, and associated neurological signs, are discussed in detail. The hallmark of Parkinsonian tremor, an asymmetric resting tremor with a “pill-rolling” quality and possible re-emergence after postural, is highlighted as a critical diagnostic clue, particularly when accompanied by bradykinesia and non-motor prodromal symptoms such as REM sleep behaviour disorder, constipation, or hyposmia. The article outlines a pragmatic diagnostic pathway, including clinical examination, structured anamnesis, medication review, and the use of neuro-imaging or DAT-SPECT when indicated. Therapeutic options are also discussed, ranging from dopaminergic medication to advanced interventions like deep brain stimulation or focused ultrasound for refractory tremor. The review aims to support non-expert clinicians in making accurate early diagnoses and initiating therapy. Article published online: 29 August 2025 © 2025. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

Background: Processing of emotion plays a critical role in social interaction. People with Parkinson’s Disease (PwPD) may experience impaired facial emotion recognition for negative emotions. Previous evidence regarding the effects of deep brain stimulation in the subthalamic nucleus (STN-DBS) is inconclusive. Objective: To investigate the impact of STN-DBS on emotion processing in PwPD controlling for effects of disease progression and DBS-induced changes in cognitive ability. The secondary aim was to explore the effect of post-DBS adjustments of dopamine replacement therapy. Methods: 32 cognitively intact PwPD (16 DBS, 16 non-DBS) and 22 healthy controls performed tasks assessing recognition and discrimination of emotions and an emotional Go/No-Go paradigm, complemented by task versions using non-emotional stimuli. Baseline assessments were conducted two months before DBS surgery and followed up three months postoperatively. Mixed-effects models analysed group-by-time interactions on task performance measured as accuracy and reaction time. Associations of longitudinal changes in non-motor symptoms and medication dosages with task performance were assessed using bootstrapped Pearson’s correlations. Results: A significant DBS-associated increase in reaction times was found specifically in the emotional conditions, while there was no evidence for a DBS-effect on the accuracy of emotion recognition or discrimination. Post-DBS dose reduction of dopamine agonists was associated with improvement in emotion recognition. Conclusion: STN-DBS does not lead to a generalized decline in emotional processing when controlling for important confounders. Instead, changes in response speed suggest altered processing dynamics. Adjustments in pharmacological treatment regimens contribute to altered FER after DBS surgery.