Johannes L. Busch’s research while affiliated with Charité Universitätsmedizin Berlin and other places

Subthalamic deep brain stimulation (STN-DBS) provides unprecedented spatiotemporal precision for the treatment of Parkinson's disease (PD), allowing for direct real-time state-specific adjustments. Inspired by findings from optogenetic stimulation in mice, we hypothesized that STN-DBS effects on movement speed depend on ongoing movement kinematics that patients exhibit during stimulation. To investigate this hypothesis, we implemented a motor state-dependent closed-loop neurostimulation algorithm, adapting DBS burst delivery to ongoing movement speed in 24 PD patients. We found a stronger anti-bradykinetic effect, raising movement speed to the level of healthy controls, when STN-DBS was applied during fast but not slow movements, while only stimulating 5% of overall movement time. To study underlying brain circuits and neurophysiological mechanisms, we investigated the behavioral effects with MRI connectomics and motor cortex electrocorticography. Finally, we demonstrate that machine learning-based brain signal decoding can be used to predict continuous movement speed for fully embedded state-dependent closed-loop algorithms. Our findings provide novel insights into the state-dependency of invasive neuromodulation, which could inspire advanced state-dependent neurostimulation algorithms for brain disorders.

Background Subthalamic beta oscillations are a biomarker for bradykinesia and rigidity in Parkinson's disease (PD), incorporated as a feedback signal in adaptive deep brain stimulation with potential for guiding electrode contact selection. Understanding their longitudinal stability is essential for successful clinical implementation. Objectives We aimed to analyze the long‐term dynamics of beta peak parameters and beta power distribution along electrodes. Methods We recorded local field potentials from 12 channels per hemisphere of 33 PD patients at rest, in a therapy‐off state at two to four sessions (0, 3, 12, 18–44 months) post‐surgery. We analyzed bipolar beta power (13–35 Hz) and estimated monopolar beta power in subgroups with consistent recordings. Results During the initial 3 months, beta peak power increased ( P < 0.0001). While detection of high‐beta peaks was more consistent, low‐ and high‐beta peak frequencies shifted substantially in some hemispheres during all periods. Spatial distribution of beta power correlated over time. Maximal beta power across segmented contact levels and directions was significantly stable compared with chance and increased in stability over time. Active contacts for therapeutic stimulation showed consistently higher normalized beta power than inactive contacts ( P < 0.0001). Conclusions Our findings indicate that beta power is a stable chronic biomarker usable for beta‐guided programming. For adaptive stimulation, high‐beta peaks might be more reliable over time. Greater stability of beta power, center frequency, and spatial distribution beyond an initial stabilization period suggests that the microlesional effect significantly impacts neuronal oscillations, which should be considered in routine clinical practice when using beta activity for automated programming algorithms. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The ability to initiate volitional action is fundamental to human behaviour. Loss of dopaminergic neurons in Parkinson's disease is associated with impaired action initiation, also termed akinesia. Both dopamine and subthalamic deep brain stimulation (DBS) can alleviate akinesia, but the underlying mechanisms are unknown. An important question is whether dopamine and DBS facilitate de novo build-up of neural dynamics for motor execution or accelerate existing cortical movement initiation signals through shared modulatory circuit effects. Answering these questions can provide the foundation for new closed-loop neurotherapies with adaptive DBS, but the objectification of neural processing delays prior to performance of volitional action remains a significant challenge. To overcome this challenge, we studied readiness potentials and trained brain signal decoders on invasive neurophysiology signals in 25 DBS patients (12 female) with Parkinson’s disease during performance of self-initiated movements. Combined sensorimotor cortex electrocorticography (ECoG) and subthalamic local field potential (LFP) recordings were performed OFF therapy (N = 22), ON dopaminergic medication (N = 18) and ON subthalamic deep brain stimulation (N = 8). This allowed us to compare their therapeutic effects on neural latencies between the earliest cortical representation of movement intention as decoded by linear discriminant analysis classifiers and onset of muscle activation recorded with electromyography (EMG). In the hypodopaminergic OFF state, we observed long latencies between motor intention and motor execution for readiness potentials and machine learning classifications. Both, dopamine and DBS significantly shortened these latencies, hinting towards a shared therapeutic mechanism for alleviation of akinesia. To investigate this further, we analysed directional cortico-subthalamic oscillatory communication with multivariate granger causality. Strikingly, we found that both therapies independently shifted cortico-subthalamic oscillatory information flow from antikinetic beta (13-35 Hz) to prokinetic theta (4-10 Hz) rhythms, which was correlated with latencies in motor execution. Our study reveals a shared brain network modulation pattern of dopamine and DBS that may underlie the acceleration of neural dynamics for augmentation of movement initiation in Parkinson’s disease. Instead of producing or increasing preparatory brain signals, both therapies modulate oscillatory communication. These insights provide a link between the pathophysiology of akinesia and its’ therapeutic alleviation with oscillatory network changes in other non-motor and motor domains, e.g. related to hyperkinesia or effort and reward perception. In the future, our study may inspire the development of clinical brain computer interfaces based on brain signal decoders to provide temporally precise support for action initiation in patients with brain disorders.

Finely tuned gamma oscillations have been recorded from the subthalamic nucleus and cortex in Parkinson's disease patients undergoing deep brain stimulation and are often associated with dyskinesia. More recently, it was shown that deep brain stimulation entrains finely tuned gamma to 1/2 of the stimulation frequency; however, the functional role of this signal is not yet fully understood. We recorded local field potentials from the subthalamic nucleus in 19 chronically implanted Parkinson's disease patients under effective dopaminergic medication and during deep brain stimulation with increasing stimulation amplitude, while they were at rest and during repetitive hand movements. We analyzed the effect of stimulation intensity on gamma band 1:2 entrainment and compared the entrained signal during rest and during repetitive movement. Spontaneous finely tuned gamma was present in eight out of 19 patients (peak frequency μ = 78.4 ±4.3 Hz). High-frequency deep brain stimulation induced 1:2 gamma entrainment in 15 out of 19 patients. Entrainment occurred at a mean stimulation amplitude of 2.2 ±0.75 mA and disappeared or decreased in power during higher stimulation amplitude in three patients. In patients with spontaneous finely tuned gamma, increasing the stimulation amplitude induced a progressive frequency shift of spontaneous finely tuned gamma until it locked to 1:2 entrainment. Only five out of 15 patients with entrained gamma activity showed dyskinesia during stimulation. Further, there was a significant increase in the power of 1:2 entrained gamma activity during movement in comparison to rest. Finally, patients with entrained gamma activity had faster movements as compared to those without gamma entrainment. These findings argue for a functional relevance of the stimulation-induced 1:2 gamma entrainment in Parkinson's disease patients as a prokinetic activity that, however, is not necessarily promoting dyskinesia. Previously published electrophysiological models of entrainment fit well to our results and support our findings that stimulation-induced entrainment can be a promising real-life biomarker for closed-loop deep brain stimulation.

Deep brain stimulation (DBS) is a brain circuit intervention that can modulate distinct neural pathways for the alleviation of neurological symptoms in patients with brain disorders. In Parkinson's disease, subthalamic DBS clinically mimics the effect of dopaminergic drug treatment, but the shared pathway mechanisms on cortex-basal ganglia networks are unknown. To address this critical knowledge gap, we combined fully-invasive neural multisite recordings in patients undergoing DBS surgery with MRI-based whole-brain connectomics. Our findings demonstrate that dopamine and DBS exert distinct mesoscale effects through modulation of local neural population synchrony. In contrast, at the macroscale, DBS mimics dopamine in its suppression of excessive interregional network synchrony associated with indirect and hyperdirect cortex-basal ganglia pathways. Our results provide a better understanding of the circuit mechanisms of dopamine and DBS, laying the foundation for advanced closed-loop neurostimulation therapies.

The ability to initiate movement is fundamental to human behavior. Loss of dopaminergic neurons in Parkinson’s disease (PD) is associated with impaired movement initiation, also termed akinesia. Dopamine and subthalamic deep brain stimulation (DBS) can alleviate akinesia, but the underlying mechanisms are unknown. We recorded invasive neural activity from both sensorimotor cortex and subthalamic nucleus (STN) in 25 PD patients performing self-initiated movements. Readiness potentials and brain signal decoding revealed long latencies between the neural representation of motor intention and execution. Dopamine and STN-DBS shortened these latencies, while shifting directional cortico-subthalamic oscillatory coupling from antikinetic beta (13-35 Hz) to prokinetic theta (4-10 Hz) rhythms. Our study highlights a key role for dopamine and basal ganglia in the evolution of preparatory brain signals and encoding of motor intention. It further reveals a therapeutic mechanism for acceleration of action initiation through modulation of pathological synchrony that may be leveraged with closed-loop neurostimulation. Highlights Investigation of invasive neural activity during self-initiated movement in Parkinson’s disease Loss of dopamine is associated with long latencies between motor cortex activity and motor onset Dopamine and subthalamic deep brain stimulation can shorten these latencies Both therapies shift cortex-basal ganglia coupling from beta to theta rhythms

Background Deep brain stimulation ( DBS ) is an effective treatment option for patients with Parkinson's disease ( PD ). However, clinical programming remains challenging with segmented electrodes. Objective Using novel sensing‐enabled neurostimulators, we investigated local field potentials ( LFPs ) and their modulation by DBS to assess whether electrophysiological biomarkers may facilitate clinical programming in chronically implanted patients. Methods Sixteen patients (31 hemispheres) with PD implanted with segmented electrodes in the subthalamic nucleus and a sensing‐enabled neurostimulator were included in this study. Recordings were conducted 3 months after DBS surgery following overnight withdrawal of dopaminergic medication. LFPs were acquired while stimulation was turned OFF and during a monopolar review of both directional and ring contacts. Directional beta power and stimulation‐induced beta power suppression were computed. Motor performance, as assessed by a pronation‐supination task, clinical programming and electrode placement were correlated to directional beta power and stimulation‐induced beta power suppression. Results Better motor performance was associated with stronger beta power suppression at higher stimulation amplitudes. Across directional contacts, differences in directional beta power and the extent of stimulation‐induced beta power suppression predicted motor performance. However, within individual hemispheres, beta power suppression was superior to directional beta power in selecting the contact with the best motor performance. Contacts clinically activated for chronic stimulation were associated with stronger beta power suppression than non‐activated contacts. Conclusions Our results suggest that stimulation‐induced β power suppression is superior to directional β power in selecting the clinically most effective contact. In sum, electrophysiological biomarkers may guide programming of directional DBS systems in PD patients. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.