Background: Deep brain stimulation is an established therapy for several neurological disorders; however, its effects on neuronal activity vary across brain regions and depend on stimulation settings. Understanding these variable responses can aid in the development of physiologically-informed stimulation paradigms in existing or prospective indications. Objective: Provide experimental and computational insights into the brain-region-specific and frequency-dependent effects of extracellular stimulation on neuronal activity. Methods: In patients with movement disorders, single-neuron recordings were acquired from the subthalamic nucleus, substantia nigra pars reticulata, ventral intermediate nucleus, or reticular thalamus during microstimulation across various frequencies (1e100 Hz) to assess single-pulse and frequencyresponse functions. Moreover, a biophysically-realistic computational framework was developed which generated postsynaptic responses under the assumption that electrical stimuli simultaneously activated all convergent presynaptic inputs to stimulation target neurons. The framework took into consideration the relative distributions of excitatory/inhibitory afferent inputs to model site-specific responses, which were in turn embedded within a model of short-term synaptic plasticity to account for stimulation frequency-dependence. Results: We demonstrated microstimulation-evoked excitatory neuronal responses in thalamic structures (which have predominantly excitatory inputs) and inhibitory responses in basal ganglia structures (predominantly inhibitory inputs); however, higher stimulation frequencies led to a loss of site-specificity and convergence towards neuronal suppression. The model confirmed that site-specific responses could be simulated by accounting for local neuroanatomical/microcircuit properties, while suppression of neuronal activity during high-frequency stimulation was mediated by short-term synaptic depression. Conclusions: Brain-region-specific and frequency-dependant neuronal responses could be simulated by considering neuroanatomical (local microcircuitry) and neurophysiological (short-term plasticity) properties.

Ventral intermediate thalamic stimulation is effective in treating essential tremor and tremor-dominant Parkinson’s disease, but its precise mechanism of action is unclear. Milosevic et al. show that thalamic inhibition of neuronal firing is necessary for tremor reduction, suggesting that the thalamus acts as a filter for uncoupling central and peripheral tremor networks.

The mechanisms underlying the therapeutic benefits of deep-brain stimulation (DBS) are complex and varied. Milosevic et al. examine frequency-dependent effects of DBS on cell firing and synaptic plasticity in the basal ganglia of patients with Parkinson’s disease. Enhanced inhibitory synaptic plasticity, and frequency-dependent potentiation and depression may underlie the observed therapeutic effects.

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Background Beta‐frequency oscillations (13–30 Hz) are a subthalamic hallmark in patients with Parkinson's disease, and there is increased interest in their utility as an intraoperative marker. Objectives The objectives of this study were to assess whether beta activity measured directly from macrocontacts of deep brain stimulation leads could be used (a) as an intraoperative electrophysiological approach for guiding lead placements and (b) for physiologically informed stimulation delivery. Methods Every millimeter along the surgical trajectory, local field‐potential data were collected from each macrocontact, and power spectral densities were calculated and visualized (n = 39 patients). This was done for online intraoperative functional mapping and post hoc statistical analyses using 2 methods: generating distributions of spectral activity along surgical trajectories and direct delineation (presence versus lack) of beta peaks. In a subset of patients, this approach was corroborated by microelectrode recordings. Furthermore, the match rate between beta peaks at the final target position and the clinically determined best stimulation site were assessed. Results Subthalamic recording sites were delineated by both methods of reconstructing functional topographies of spectral activity along surgical trajectories at the group level (P < 0.0001). Beta peaks were detected when any portion of the 1.5 mm macrocontact was within the microelectrode‐defined subthalamic border. The highest beta peak at the final implantation site corresponded to the site of active stimulation in 73.3% of hemispheres (P < 0.0001). In 93.3% of hemispheres, active stimulation corresponded to the first‐highest or second‐highest beta peak. Conclusions Online measures of beta activity with the deep brain stimulation macroelectrode can be used to inform surgical lead placement and contribute to optimization of stimulation programming procedures. © 2020 International Parkinson and Movement Disorder Society

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IntroductionSubthalamic deep brain stimulation (DBS) is beneficial when delivered at a high frequency. However, the effects of current amplitude and pulse width on subthalamic neuronal activity during high-frequency stimulation have not been investigated.MethodsIn 20 patients with Parkinson’s disease each undergoing subthalamic DBS, we recorded single-unit subthalamic activity using one microelectrode, while a separate microelectrode was used to deliver 5–10 s trains of stimulation at 100 Hz using varying current amplitudes and pulse widths (44 neurons investigated).ResultsAnalysis of variance tests confirmed significant (p<0.001) main effects of both current amplitude and pulse width on subthalamic neuronal firing during stimulation and on poststimulus inhibitory silent periods. Prolonged silent periods were often followed by postinhibitory rebound burst excitations. Additionally, a significant (p<0.0001) correlation was found between neuronal firing and total electrical energy delivered (TEED). With TEED values≤31.2 µJ/s (associated with DBS parameters of ≤2.0 mA, 130 Hz stimulation frequency and 60 µs pulse width, assuming 1 kΩ impedance), neuronal firing was sustained at a rate of 32.4%±3.3% (mean±SE), while with values>31.2 µJ/s, neurons fired at only 4.3%±1.2%.ConclusionsNeuronal suppression is likely an important mechanism of action of therapeutically beneficial subthalamic DBS, which may underlie clinically relevant behavioural changes.