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Neuropsychiatric symptoms are common and disabling in Parkinson's disease (PD), with troublesome anxiety occurring in one-third of patients. Management of anxiety in PD is challenging, hampered by insufficient insight into underlying mechanisms, lack of objective anxiety measurements, and largely ineffective treatments. In this study, we assessed the intracranial neurophysiological correlates of anxiety in PD patients treated with deep brain stimulation (DBS) in the laboratory and at home. We hypothesized that low-frequency (theta-alpha) activity would be associated with anxiety. We recorded local field potentials (LFP) from the subthalamic nucleus (STN) or the globus pallidus pars interna (GPi) DBS implants in three PD cohorts: 1) patients with recordings (STN) performed in hospital at rest via perioperatively externalized leads, without active stimulation, both ON or OFF dopaminergic medication; 2) patients with recordings (STN or GPi) performed at home while resting, via a chronically implanted commercially available sensing-enabled neurostimulator (Medtronic PerceptTM device), ON dopaminergic medication, with stimulation both on or off; 3) patients with recordings performed at home while engaging in a behavioral task via STN and GPi leads and electrocorticography paddles over premotor cortex connected to an investigational sensing-enabled neurostimulator, ON dopaminergic medication, with stimulation both on or off. Trait anxiety was measured with validated clinical scales in all participants, and state anxiety was measured with momentary assessment scales at multiple time points in the two at-home cohorts. Power in theta (4-8 Hz) and alpha (8-12 Hz) ranges were extracted from the LFP recordings, and their relation with anxiety ratings was assessed using linear mixed-effects models. In total, 33 PD patients (59 hemispheres) were included. Across three independent cohorts, with stimulation off, basal ganglia theta power was positively related to trait anxiety (all p<0.05). Also in a naturalistic setting, with individuals at home at rest with stimulation and medication ON, basal ganglia theta power was positively related to trait anxiety (p<0.05). This relationship held regardless of the hemisphere and DBS target. There was no correlation between trait anxiety and premotor cortical theta-alpha power. There was no within-patient association between basal ganglia theta-alpha power and state anxiety. We showed that basal ganglia theta activity indexes trait anxiety in PD. Our data suggest that theta could be a possible physiomarker of neuropsychiatric symptoms and specifically of anxiety in PD, potentially suitable for guiding advanced DBS treatment tailored to the individual patient's needs, including non-motor symptoms., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Choosing whether to exert effort to obtain rewards is fundamental to human motivated behavior. However, the neural dynamics underlying the evaluation of reward and effort in humans is poorly understood. Here, we report an exploratory investigation into this with chronic intracranial recordings from the prefrontal cortex (PFC) and basal ganglia (BG; subthalamic nuclei and globus pallidus) in people with Parkinson's disease performing a decision-making task with offers that varied in levels of reward and physical effort required. This revealed dissociable neural signatures of reward and effort, with BG beta (12 to 20 Hz) oscillations tracking effort on a single-trial basis and PFC theta (4 to 7 Hz) signaling previous trial reward, with no effects of net subjective value. Stimulation of PFC increased overall acceptance of offers and sensitivity to reward while decreasing the impact of effort on choices. This work uncovers oscillatory mechanisms that guide fundamental decisions to exert effort for reward across BG and PFC, supports a causal role of PFC for such choices, and seeds hypotheses for future studies., Competing Interests: Competing interests statement:M.H. has received honoraria from Eli Lilley, Otsuka and Sumitomo Pharma for lectures/participation in advisory panels, and is a founding member of the Oxford University spin-out NeuHealth. P.A.S. receives grant support from Medtronic. S.L. has honoraria from Medtronic and is a consultant for Iota Biosciences. All other authors declare no competing interests.

Background: Neuropsychiatric symptoms are common and disabling in Parkinson's disease (PD), with troublesome anxiety occurring in one-third of patients. Management of anxiety in PD is challenging, hampered by insufficient insight into underlying mechanisms, lack of objective anxiety measurements, and largely ineffective treatments.In this study, we assessed the intracranial neurophysiological correlates of anxiety in PD patients treated with deep brain stimulation (DBS) in the laboratory and at home. We hypothesized that low-frequency (theta-alpha) activity would be associated with anxiety., Methods: We recorded local field potentials (LFP) from the subthalamic nucleus (STN) or the globus pallidus pars interna (GPi) DBS implants in three PD cohorts: 1) patients with recordings (STN) performed in hospital at rest via perioperatively externalized leads, without active stimulation, both ON or OFF dopaminergic medication; 2) patients with recordings (STN or GPi) performed at home while resting, via a chronically implanted commercially available sensing-enabled neurostimulator (Medtronic Percept ™ device), ON dopaminergic medication, with stimulation both ON or OFF; 3) patients with recordings performed at home while engaging in a behavioral task via STN and GPi leads and electrocorticography paddles (ECoG) over premotor cortex connected to an investigational sensing-enabled neurostimulator, ON dopaminergic medication, with stimulation both ON or OFF.Trait anxiety was measured with validated clinical scales in all participants, and state anxiety was measured with momentary assessment scales at multiple time points in the two at-home cohorts. Power in theta (4-8 Hz) and alpha (8-12 Hz) ranges were extracted from the LFP recordings, and their relation with anxiety ratings was assessed using linear mixed-effects models., Results: In total, 33 PD patients (59 hemispheres) were included. Across three independent cohorts, with stimulation OFF, basal ganglia theta power was positively related to trait anxiety (all p<0.05). Also in a naturalistic setting, with individuals at home at rest with stimulation and medication ON, basal ganglia theta power was positively related to trait anxiety (p<0.05). This relationship held regardless of the hemisphere and DBS target. There was no correlation between trait anxiety and premotor cortical theta-alpha power. There was no within-patient association between basal ganglia theta-alpha power and state anxiety., Conclusion: We showed that basal ganglia theta activity indexes trait anxiety in PD. Our data suggest that theta could be a possible physiomarker of neuropsychiatric symptoms and specifically of anxiety in PD, potentially suitable for guiding advanced DBS treatment tailored to the individual patient's needs, including non-motor symptoms., Competing Interests: Competing interests SL is a consultant for Iota Biosciences. FM received consultancy fees from Boston Scientific and Medtronic, is a member of advisory boards of Abbvie, Boston Scientific, Merz, Medtronic, and Roche, received speaking Honoraria from Abbvie, Boston Scientific, Merz, Medtronic, and International Parkinson’s Disease and Movement Disorders Society, received royalties from Springer, and received research support from NIHR, Innovate UK, Global Kinetic, and Merz. MGH is a member of the Medicines and Healthcare products Regulatory Agency (MHRA) interim devices working group. The other authors have nothing to declare. There are no other relationships or activities that could appear to have influenced the submitted work.