Coordinated Reset Stimulation of Plastic Neural Networks with Spatially Dependent Synaptic Connections Provisionally Accepted

Justus A. Kromer^1* Peter A. Tass¹

• ¹Stanford University, United States

Background: Abnormal neuronal synchrony is associated with several neurological disorders,
including Parkinson’s disease (PD), essential tremor, dystonia, and epilepsy. Coordinated
reset (CR) stimulation was developed computationally to counteract abnormal neuronal
synchrony. During CR stimulation, phase-shifted stimuli are delivered to multiple stimulation sites.
Computational studies in plastic neural networks reported that CR stimulation drove the networks
into an attractor of a stable desynchronized state by down-regulating synaptic connections, which
led to long-lasting desynchronization effects that outlasted stimulation. Later, corresponding
long-lasting desynchronization and therapeutic effects were found in animal models of PD and PD
patients. To date, it is unclear how spatially dependent synaptic connections, as typically observed
in the brain, shape CR-induced synaptic down-regulation and long-lasting effects. Methods: We
performed numerical simulations of networks of leaky integrate-and-fire neurons with spike-timing-
dependent plasticity and spatially dependent synaptic connections to study and further improve
acute and long-term responses to CR stimulation. Results: The characteristic length scale of
synaptic connections relative to the distance between stimulation sites plays a key role in CR
parameter adjustment. In networks with short synaptic length scales, a substantial synaptic
down-regulation can be achieved by selecting appropriate stimulus-related parameters, such as
the stimulus amplitude and shape, regardless of the employed spatiotemporal pattern of stimulus
deliveries. Complex stimulus shapes can induce local connectivity patterns in the vicinity of the
stimulation sites. In contrast, in networks with longer synaptic length scales, the spatiotemporal
sequence of stimulus deliveries is of major importance for synaptic down-regulation. In particular,
rapid shuffling of the stimulus sequence is advantageous for synaptic down-regulation. Conclusion:
Our results suggest that CR stimulation parameters can be adjusted to synaptic connectivity to
further improve the long-lasting effects. Furthermore, shuffling of CR sequences is advantageous
for long-lasting desynchronization effects. Our work provides important hypotheses on CR
parameter selection for future preclinical and clinical studies.