Basal ganglia theta power indexes trait anxiety in people with Parkinson's disease

Neuropsychiatric symptoms are common and disabling in Parkinson's disease, with troublesome anxiety occurring in one-third of patients. Management of anxiety in Parkinson's disease 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 patients with Parkinson's disease 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 from subthalamic nucleus or globus pallidus pars interna DBS implants in three Parkinson's disease cohorts: (i) patients with recordings (subthalamic nucleus) performed in hospital at rest via perioperatively externalized leads, without active stimulation, both ON and OFF dopaminergic medication; (ii) patients with recordings (subthalamic nucleus or globus pallidus pars interna) performed at home while resting, via a chronically implanted commercially available sensing-enabled neurostimulator (Medtronic Percept™ device), ON dopaminergic medication, with stimulation both on and off; and (iii) patients with recordings performed at home while engaging in a behavioural task via subthalamic nucleus and globus pallidus pars interna leads and electrocorticography paddles over the premotor cortex connected to an investigational sensing-enabled neurostimulator, ON dopaminergic medication, with stimulation both on and 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 was extracted from the local field potential recordings, and its relationship with anxiety ratings was assessed using linear mixed-effects models. In total, 33 patients with Parkinson's disease (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 Parkinson's disease. Our data suggest that theta could be a possible physiomarker of neuropsychiatric symptoms and specifically of anxiety in Parkinson's disease, potentially suitable for guiding advanced DBS treatment tailored to the needs of the individual patient, including non-motor symptoms.