Parkinson's disease uncovers an underlying sensitivity of subthalamic nucleus neurons to beta-frequency cortical input in vivo.

Baaske MK
Kormann E
Holt AB
Gulberti A
McNamara CG
Pötter-Nerger M
Westphal M
Engel AK
Hamel W
Brown P
Moll CK
Sharott A

It is unclear why people with Parkinson's disease have exaggerated rhythmic electrical activity at so-called beta frequency across many brain areas. Using recordings from patients undergoing neurosurgery and a rodent model of the disease, we show that the electrical impulses of single nerve cells in one of these brain areas, the subthalamic nucleus, are more sensitive to beta-frequency input than other rhythms. 

Scientific 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 (12-35 Hz), 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 human PD patients undergoing deep brain stimulation surgery with recordings of identified STN neurons in anaesthetised rats. In these patients, we demonstrate that a subset of putative STN neurons is strongly and selectively sensitive to magnitude fluctuations of cortical beta oscillations over time, linearly increasing their phase-locking strength with respect to the full range of instantaneous amplitude in the beta-frequency range. In rats, we probed the frequency response of STN neurons in the cortico-basal-ganglia-network more precisely, by recording spikes evoked by short bursts of cortical stimulation with variable frequency (4-40 Hz) and constant amplitude. In both healthy and dopamine-depleted rats, only beta-frequency stimulation led to a progressive reduction in the variability of spike timing through the stimulation train. This suggests, that the interval of beta-frequency input provides an optimal window for eliciting the next spike with high fidelity. 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.

The left panel shows analysis of the synchronisation of neurons in the subthalamic nucleus to spontaneous cortical oscillations of different frequencies as a function of the strength of the latter. The right panel shows raster plots demonstrating that pulses at 20 Hz progressively decrease the variance of cortically evoked spiking. The bottom plot shows a version of top raster, but showing only the first 20ms after each stimulus.
In Parkinsonian patients undergoing neurosurgery (left), the activity of neurons in the subthalamic nucleus (STN) becomes increasing synchronised to cortical beta oscillations (12-35Hz, colour scale) as their strength (beta amplitude) increases. This relationship was not observed at other frequencies. Right, in a rodent model of Parkinson’s disease, stimulation of the cortex using bursts of beta frequency pulses (red lines) progressively decreased the variability in evoked spiking. The bottom panel shows only the first 20ms after each of stimuli in the panel above.
2020. Neurobiol. Dis., 146:105119.
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