A theoretical framework for the site-specific and frequency-dependent neuronal effects of deep brain stimulation

• Published in: Brain stimulation 2021-07, Vol.14 (4), p.807-821
• Main Authors: Milosevic, Luka, Kalia, Suneil K., Hodaie, Mojgan, Lozano, Andres M., Popovic, Milos R., Hutchison, William D., Lankarany, Milad
• Format: Article
• Language: English
• Subjects: Basal ganglia; Deep brain stimulation; Synapse; Synaptic depression; Thalamus
• ISSN: 1935-861X; 1876-4754
• DOI: 10.1016/j.brs.2021.04.022

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. Provide experimental and computational insights into the brain-region-specific and frequency-dependent effects of extracellular stimulation on neuronal activity. 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 (1–100 Hz) to assess single-pulse and frequency-response 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. 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. Brain-region-specific and frequency-dependant neuronal responses could be simulated by considering neuroanatomical (local microcircuitry) and neurophysiological (short-term plasticity) properties. •Extracellular stimulation is brain-region-specific and frequency-dependent.•Neuronal stimulus responses were excitatory in thalamus & inhibitory in basal ganglia.•High-frequency stimulation led to neuronal suppression/a loss of site-specificity.•Responses to single stimuli could be predicted based on anatomy/local microcircuitry.•Frequency-dependant neuronal suppressi