Jul 2026· Journal of Neural Engineering· 0 citations
Medicine
TL;DR
These findings demonstrate that STN motor representations are context-dependent, anatomically organized, and temporally distinct, reinforcing the STN's dynamic engagement during motor execution.
Abstract
Objective
Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an established therapy for Parkinson's disease (PD), yet optimizing outcomes remains challenging due to the complexity of STN functional architecture and the subjectivity of intraoperative assessments. Furthermore, the encoding of fine versus gross movements across STN dorsoventral subregions remains poorly understood. This study aimed to characterize region- and movement-specific modulation of STN neuronal activity using synchronized electrophysiology and markerless motion tracking-derived kinematics.
APPROACH
We recorded intraoperative electrophysiological and videographic data from 11 subjects with PD (15 hemispheres) undergoing awake STN-DBS implantation surgery. Microelectrode recordings were synchronized with high-resolution kinematics during repeated trials of continuous upper-limb motor tasks involving both distal and proximal muscle groups. Instantaneous firing rate (IFR) and neuronal responsiveness metrics were quantified using a parameter-free Zenith of Event-based Time-locked Anomalies (ZETA) statistical framework and analyzed with linear mixed-effects models.
MAIN
Results
STN single-unit activity (SUA) and multi-unit activity (MUA) features exhibited robust region- and movement-specific modulation. Firing rates for both SUA and MUA were significantly higher in the dorsal STN during active movements, particularly distal fine motor tasks, compared to ventral STN and baseline activity. ZETA-test analyses revealed significant movement-specific responsiveness across STN subregions, with more dextrous, distal movements eliciting stronger responses than more coordinated, proximal movements. Temporal dynamics of neuronal responsiveness also varied with STN depth and movement type, indicating hierarchical recruitment of STN subregions in the encoding of movement-specific temporal motifs.
Significance
These findings demonstrate that STN motor representations are context-dependent, anatomically organized, and temporally distinct, reinforcing the STN's dynamic engagement during motor execution. By identifying objective electrophysiological features linked to movement context and STN region, this work provides a quantitative foundation for reducing reliance on subjective assessments to inform data-driven DBS targeting, programming, and closed-loop control strategies.
INTRODUCTION
Apathy is a common and disabling non-motor symptom in Parkinson's disease (PD) that can diminish the therapeutic benefit of subthalamic nucleus deep brain stimulation (STN-DBS). We previously demonstrated that co-stimulation of the left ventromedial prefrontal cortex (vmPFC) can alleviate apathy following levodopa withdrawal in PD patients treated with STN-DBS. Building on these findings, we investigated whether presurgical white matter integrity of the vmPFC-STN pathway constitutes a structural correlate of clinically significant apathy prior to DBS.
METHODS
Preoperative T1-weighted and diffusion MRI data from 119 PD patients undergoing STN-DBS were analyzed. Based on Starkstein Apathy Scale (SAS) scores, patients were classified as apathetic (SAS ≥ 14; n = 67) or non-apathetic (n = 52). Fractional anisotropy (FA) maps were processed using FSL's Tract-Based Spatial Statistics pipeline. Voxel-wise group comparisons were performed with threshold-free cluster enhancement (5,000 permutations), restricted to a bilateral vmPFC-STN mask derived from probabilistic tractography from the previously published cohort.
RESULTS
A significant cluster (74 voxels) within the left vmPFC-STN ROI showed reduced FA in apathetic patients (TFCE-corrected p = 0.0294). Post-hoc analyses revealed higher mean diffusivity (p = 0.0206) and radial diffusivity (p = 0.001) in the apathetic group, while axial diffusivity did not differ. Exploratory subset analysis suggested baseline vmPFC-STN integrity may influence apathy response to vmPFC DBS.
CONCLUSION
Clinically significant apathy in PD prior to STN-DBS is associated with reduced white matter integrity in the left internal capsule involving the broader left-sided vmPFC projection system. Identifying this structural substrate may contribute to future optimization of apathy management with STN-DBS.
Jip de Bruin, B. Kopell, Helen S. Mayberg et al.· Brain Stimulation· 0 citations
Psychiatric symptoms in Parkinson's disease (PD) are highly prevalent and challenging to treat. This study maps oscillatory neural activity to diverse psychiatric symptoms in PD, using resting-state subthalamic nucleus (STN) local field potentials (LFPs) and frontal EEG in 55 PD patients undergoing deep brain stimulation (DBS). We tested whether 1) distinct psychiatric symptoms are associated with frequency-specific neural signatures using power spectral analyses and machine learning, across both eyes-open and eyes-closed sensory-attentional states. 2) symptom encoding is spatially segregated within the STN, with electrophysiological (defined by peak spectral power) and anatomical (defined by STN boundaries) mappings providing complementary information. 3) these regions exhibit distinct structural connectivity profiles, assessed using STN-seeded tractography from the UK Biobank normative connectome. Our analysis revealed spectral, spatial, and connectivity segregation. Depression was associated with increased alpha power, primarily detected by anatomical mapping, whereas apathy (increased high beta) and trait impulsivity (reduced low gamma) were detected with both anatomical and electrophysiological STN mapping. UK Biobank analyses further showed that STN-based alpha clusters (depression-related) preferentially connected with prefrontal, orbitofrontal, and cingulate cortices, while peak low-beta clusters (motor-related) connected with SMA and premotor areas. High-beta and low-gamma bands showed convergent connectivity across peak and STN-based clusters despite ventral-dorsal differences. These findings disentangle neurophysiological substrates of PD psychiatry, identifying symptom-specific biomarkers and informing targeted neuromodulation strategies.
Linbin Wang, Ying Zhao, Peng Huang et al.· Brain : a journal of neurolo...· 0 citations
Postural and locomotor dysfunction represent axial symptoms of Parkinson’s disease (PD), which remain poorly treated by medication and deep brain stimulation. Whilst non-invasive neuromodulation of the vestibular system via the vestibular nucleus complex (VNC) offers a novel therapeutic avenue, the underlying circuits are still poorly characterized. Here we show that the mouse VNC feeds extensive Vglut2-defined projections into striato-thalamo-subthalamic and caudal medulla motor hubs and receives substantial input from the sensorimotor cortex. Optogenetic activation of excitatory VNC neurons at sub-symptomatic intensities increased cFos-based activity in basal ganglia-associated and brainstem motor targets. Unbiased pose dynamics and motion analysis respectively showed enhancement of behavioural modularity and locomotion with threshold-level stimulation. In a mouse model of PD, the latter further favored naturalistic gait patterns through improved motor coordination. Our data identify excitatory VNC processes as candidates for therapeutic targeting of axial motor dysfunction in the context of PD. In this work by Hartig et al., inspired by non-invasive stimulation of the vestibular system in humans, the authors use a thresholded optical stimulation paradigm to alleviate symptoms of locomotor dysfunction in a Parkinson’s disease mouse model.
J. Hartig, M. Friedrich, J. Signoret-Genest et al.· Nature Communications· 0 citations
Parkinson’s disease (PD) is diagnosed after motor symptoms appear, although non-motor symptoms emerge years earlier. Following years of pharmacological treatment, high-frequency stimulation (HFS) of the subthalamic nucleus (STN), a key hub in goal-directed behaviors, can be proposed. While HFS-STN reliably improves motor symptoms, it does not specifically address non-motor symptoms. Clarifying how STN dysfunction contributes to these symptoms could improve stimulation strategies. Here, we longitudinally recorded STN local field potentials in two macaques performing a demanding task during chronic low-dose MPTP treatment. This progressive model, evolving from an asymptomatic stage to motivational, cognitive, and motor deficits, enabled detailed characterization of non-motor stages preceding motor impairment. Each stage was associated with distinct electrophysiological alterations, including early loss of reward-related theta activity, followed by disappearance of decision-related theta oscillations and later reduction of movement-related beta rebound. In the stable parkinsonian stage, stimulation of different STN territories produced complementary behavioral effects: dorsal HFS improved motor performance, whereas ventral low-frequency stimulation alleviated motivational deficits. These findings reveal a temporal relationship between STN dysfunction and symptom onset and support site- and frequency-specific stimulation strategies to address motor and non-motor symptoms in PD.
Mathilde Bertrand, S. Chabardès, Jessy Hugues Dit Ciles et al.· npj Parkinson's Disease· 0 citations
In Parkinson’s Disease, subthalamic deep brain stimulation improves movement initiation but can induce impulsivity. The origin of these effects remains unclear. Here, we test the hypothesis that modulation of automatic response inhibition, an underrecognized process that governs the ability to refrain from reacting, accounts for both effects.
Nineteen Parkinson’s disease patients were assessed for: I) behavioral changes in a simple Go/NoGo task, ON vs. OFF deep brain stimulation, II) structural connectivity between the stimulated subthalamic region and the supplementary motor complex, and III) a previously established electroencephalographic marker of automatic response inhibition (the DMF170).
Under stimulation, patients exhibited faster reaction times and increased commission errors. These changes were accompanied by an increase in DMF170 amplitude, which correlated with reaction times. Finally, behavioral changes were associated with stimulation volume overlap with fibers connecting the subthalamic nucleus to the supplementary motor complex.
Our findings link improved movement initiation and increased impulsivity under stimulation of the subthalamic nucleus to a shared anatomical and functional substrate, namely the subthalamic nucleus-supplementary motor cortex loop supporting automatic response inhibition.
Garance M. Meyer, Marion Albares, Guillaume Lio et al.· Brain Communications· 0 citations
