Parkinson’s disease uncovers an underlying sensitivity of subthalamic nucleus neurons to beta-frequency cortical input

Abstract

Abnormally sustained beta-frequency synchronisation between the motor cortex and subthalamic nucleus (STN) is associated with motor symptoms in Parkinson's disease (PD).It is currently unclear whether STN neurons have a preference for beta-frequency input (12-35Hz), rather than cortical input at other frequencies, and how such a preference would arise following dopamine depletion. To address this question, we combined analysis of cortical and STN recordings from awake PD patients undergoing deep brain stimulation surgery with recordings of identified STN neurons in anaesthetised rats. In PD patients, we demonstrate that a subset of STN neurons are strongly and selectively sensitive to fluctuations of cortical beta oscillations over time, linearly increasing their phase-locking strength with respect to full range of instantaneous amplitude. In rats, we probed the frequency response of STN neurons more precisely, by recording spikes evoked by short bursts of cortical stimulation with variable frequency (4-40Hz) and constant amplitude. In both healthy and dopaminedepleted animals, only beta-frequency stimulation selectively led to a progressive reduction in the variability of spike timing through the stimulation train. We hypothesize, that abnormal activation of the indirect pathway, via dopamine depletion and/or cortical stimulation, could trigger an underlying sensitivity of the STN microcircuit to beta-frequency input. Brown P. 2008. Highfrequency stimulation of the subthalamic nucleus suppresses oscillatory beta activity in patients with Parkinson's disease in parallel with improvement in motor performance. The Journal of neuroscience : the official journal of the Society for Neuroscience. 28:6165-6173. Kuhn AA, Trottenberg T, Kivi A, Kupsch A, Schneider GH, Brown P. 2005. The relationship between local field potential and neuronal discharge in the subthalamic nucleus of patients with Parkinson's disease. Experimental neurology. 194:212-220. Kühn AA, Tsui A, Aziz T, Ray N, Brucke C, Kupsch A, Schneider GH, Brown P. 2009. Pathological synchronisation in the subthalamic nucleus of patients with Parkinson's disease relates to both bradykinesia and rigidity. Exp Neurol. 215:380-387. Lachaux JP, Rodriguez E, Martinerie J, Varela FJ. 1999. Measuring phase synchrony in brain signals. Human brain mapping. 8:194-208. Lalo E, Thobois S, Sharott A, Polo G, Mertens P, Pogosyan A, Brown P. 2008. Patterns of bidirectional communication between cortex and basal ganglia during movement in patients with Parkinson disease. J Neurosci. 28:3008-3016. Levy R, Ashby P, Hutchison WD, Lang AE, Lozano AM, Dostrovsky JO. 2002. Dependence of subthalamic nucleus oscillations on movement and dopamine in Parkinson's disease. Brain : a journal of neurology. 125:1196-1209. Little S, Pogosyan A, Kuhn AA, Brown P. 2012. Beta band stability over time correlates with Parkinsonian rigidity and bradykinesia. Exp Neurol. 236:383-388.