Advanced Parkinson’s disease is characterized by periods of poor mobility, dyskinesia and progressive decline in functional independence of the affected person despite the manipulation of levodopa doses and the introduction of supplemental therapies such as catechol-O-methyl transferase inhibitors, monoamine oxidase-B inhibitors and dopamine agonists. The implementation of drug delivery systems allows to bypass problems related to irregular and often unpredictable intestinal absorption of oral levodopa, which significantly affects its bioavailability and contributes to the development and persistence of motor complications. Subcutaneous apomorphine and levodopa/carbidopa jejunal infusion systems have been available for many years and their efficacy is confirmed by randomized studies and long-term experience in many centers worldwide. Recently, a new formulation of levodopa/carbidopa infusion gel that includes the catechol-O-methyl transferase inhibitor Entacapone has been introduced to the market. The use of entacapone allows to reduce total daily dose of administered levodopa. Two different soluble formulations of levodopa/carbidopa (ND0612 and ABBV-951) have completed clinical development, and both can ensure subcutaneous delivery by a portable pump infusion system. ABBV-951 uses a foslevodopa/foscarbidopa formulation, both prodrugs to improve absorption and tolerability. Both systems provide effective improvement of motor complications and are likely to expand the therapeutic options in advanced patients. Future efforts should focus on the earlier detection of patients who are candidates for device-aided therapies, increasing appropriate referral and broadening the availability of these treatments globally.

Deep brain stimulation (DBS) has emerged as an invasive neuromodulation technique for the treatment of several neurological disorders, but the mechanisms underlying its effects remain partially elusive. In this context, the application of Transcranial Magnetic Stimulation (TMS) in patients treated with DBS represents an intriguing approach to investigate the neurophysiology of cortico-basal networks. Experimental studies combining TMS and DBS that have been performed so far have mainly aimed to evaluate the effects of DBS on the cerebral cortex and thus to provide insights into DBS’s mechanisms of action. The modulation of cortical excitability and plasticity by DBS is emerging as a potential contributor to its therapeutic effects. Moreover, pairing DBS and TMS stimuli could represent a method to induce cortical synaptic plasticity, the therapeutic potential of which is still unexplored. Furthermore, the advent of new DBS technologies and novel treatment targets will present new research opportunities and prospects to investigate brain networks. However, the application of the combined TMS-DBS approach is currently limited by safety concerns. In this review, we sought to present an overview of studies performed by combining TMS and DBS in neurological disorders, as well as available evidence and recommendations on the safety of their combination. Additionally, we outline perspectives for future research by highlighting knowledge gaps and possible novel applications of this approach.

With the introduction of sensing-enabled deep brain stimulation devices, characterization of long-term biomarker dynamics is of growing importance for treatment optimization. The microlesion effect is a well-known phenomenon of transient clinical improvement in the acute post-operative phase. While beta band activity is confirmed as a reliable biomarker for bradykinesia using chronic recordings, little is known about the ideal time point for initial electrophysiology-based programming. To investigate the microlesion effect impact in chronic biomarker recordings. Subthalamic peak biomarker power was continuously recorded during the first 40 post-operative days in 12 Parkinson's disease patients implanted with a sensing-enabled neurostimulator. Daily change in mean peak power and complexity was analyzed. Additionally, power spectral density at rest was compared between immediate postoperative period and three-months-follow-up. We additionally present continuous pallidal recordings in 2 dystonia patients. Mean peak power increased postoperatively, and the rate of change stabilized at 22-29 days. Peak power complexity showed a decrease in the number of recurrence states and laminarity, stabilizing around the same time point. Biomarker activity showed a significant increase at 3-month-follow up compared to the early post-operative phase. The microlesion effect was clinically reflected as a decrease in pre-vs. postoperative medication before setting of chronic stimulation parameters. The transient postoperative microlesional effect is characterized by reduced beta band power and reduced neural signal complexity that gradually stabilize towards the end of the first month after surgery and most likely reflect local neuronal adaptation. These findings are important for the timing of electrophysiology-supported DBS programming, such as contact selection or adaptive algorithms.

Objective: Parkinson's disease (PD) is increasingly conceptualized as a disorder of large‐scale brain networks, yet whether and how frequency‐specific functional connectivity reorganizes across stages remains poorly understood. In this study, we used high‐density electroencephalography (EEG) to characterize cortico‐cortical functional connectivity across the clinical spectrum of PD. Methods: We performed high‐density EEG in a cross‐sectional cohort of 140 PD patients spanning early, intermediate, and advanced stages and 57 healthy controls. Cortico‐cortical functional connectivity was reconstructed in source space across multiple frequency bands and analyzed using network‐based statistics combined with machine‐learning models to identify stage‐dependent network alterations and evaluate their diagnostic and prognostic relevance. Results: We detected 3 distinct large‐scale networks showing divergent trajectories across disease stages. An α‐band network involving prefrontal and parieto‐temporal regions exhibited progressive hypoconnectivity and was associated with cognitive and axial impairment. A β‐band sensorimotor network showed progressive hyperconnectivity, paralleling bradykinesia severity. A high‐γ network demonstrated increased connectivity in early PD, followed by a progressive connectivity breakdown, and was inversely associated with motor complications. Multiband integration achieved near‐perfect discrimination between early PD and healthy controls and robust stratification across disease stages. Band‐specific networks also predicted clinical milestones of disease progression, with preserved α connectivity identifying patients at lower risk for cognitive and axial impairment, and stronger high‐ γ connectivity indicating reduced vulnerability to motor complications. Interpretation: Together, these results identify frequency‐specific cortical networks as markers of disease stage and clinical vulnerability and support high‐density EEG connectivity as a scalable systems‐level biomarker for diagnosis, staging, and risk stratification in PD. ANN NEUROL 2026

Plain language summary: Detecting the source of abnormal beta oscillations in Parkinson's Disease: evidence from a case of impaired connection between cerebral cortex and basal ganglia. In Parkinson's Disease, a key feature is an exaggerated, oscillatory activity in the brain called the “beta rhythm”, which occurs in the circuit, particularly relevant for motor functions, connecting the cortex (the outer brain layer) and the basal ganglia (the deeper structures). Scientists have long debated whether the exact source of this pathological activity was located in the cortex or in the basal ganglia. This report describes a critical clue from an unexpected event: a person with Parkinson's disease developed temporary swelling (edema) that affected both the sensorimotor cortex and the basal ganglia. Notably, this event was limited to one side of the brain and occurred in a subject who carried a medical device that enables recordings of the beta rhythm from inside the basal ganglia. In this peculiar case, the excessive beta rhythm on the affected side was completely suppressed and only returned once the swelling in the overlying sensorimotor cortex had resolved, even though the edema in the basal ganglia itself had recovered earlier. This unique observation suggests that the integrity of the cortex is essential for the pathological beta rhythm to occur in Parkinson's Disease, lending strong support to the theory that this disruptive electrical rhythm is generated in the cortex before spreading to deeper brain structures such as the basal ganglia.