Madadi Asl, M. | bioRxiv Science

bioRxiv2024

Rhythmic modulation of subthalamo-pallidal interactions depends on synaptic rewiring through inhibitory plasticity

Rhythmic stimulation offers a paradigm to modulate brain oscillations and, therefore, influence brain function. A growing body of evidence indicates that reciprocal interactions between the neurons of the subthalamic nucleus (STN) and globus pallidus externus (GPe) play a central role in the emergence of abnormal synchronous beta (15-30 Hz) oscillations in Parkinsons disease (PD). The proliferation of inhibitory GPe-to-STN synapses following dopamine loss exacerbates this pathological activity. Rhythmic modulation of the STN and/or GPe, for example, by deep brain stimulation (DBS), can restore physiological patterns of activity and connectivity. Here, we tested whether dual targeting of STN-GPe by rhythmic stimulation can modulate pathologically strong GPe-to-STN synapses through inhibitory spike-timing-dependent plasticity (iSTDP). More specifically, we examined how time-shifted paired stimuli delivered to the STN and GPe can lead to inter-population synaptic rewiring. To that end, we first theoretically analysed the optimal range of stimulation time shift and frequency for effective synaptic rewiring. Then, as a minimal model for generating subthalamo-pallidal oscillations in healthy and PD conditions, we considered a biologically inspired STN-GPe loop comprised of conductance-based spiking neurons. Consistent with the theoretical predictions, rhythmic stimulation with appropriate time shift and frequency modified GPe-to-STN interactions through iSTDP, i.e., by long-lasting rewiring of pathologically strong synaptic connectivity. This ultimately caused desynchronising after-effects within each population such that excessively synchronous beta activity in the PD state was suppressed, resulting in a decoupling of the STN-GPe network and restoration of healthy dynamics in the model. Decoupling effects of the dual STN-GPe stimulation can be realised by time-shifted continuous and intermittent stimuli, as well as monopolar and bipolar simulation waveforms. Our findings demonstrate the critical role of neuroplasticity in shaping long-lasting stimulation effects and may contribute to the optimisation of a variety of multi-site stimulation paradigms aimed at reshaping dysfunctional brain networks by targeting plasticity.

neuroscience↗

bioRxiv2022

Decoupling of interacting neuronal populations by time-shifted stimulation through spike-timing-dependent plasticity

The synaptic organization of the brain is constantly modified by activity-dependent synaptic plasticity. In several neurological disorders, abnormal neuronal activity and pathological synaptic connectivity may significantly impair normal brain function. Reorganization of neuronal circuits by therapeutic stimulation has the potential to restore normal brain dynamics. Increasing evidence suggests that the temporal stimulation pattern crucially determines the long-lasting therapeutic effects of stimulation. Here, we tested whether a specific pattern of brain stimulations can enable the suppression of pathologically strong inter-population synaptic connectivity through spike-timing-dependent plasticity (STDP). More specifically, we tested how introducing a time shift between stimuli delivered to two interacting populations of neurons can effectively decouple them. To that end, we first used a tractable model, i.e., two bidirectionally coupled leaky integrate-and-fire (LIF) neurons, to theoretically analyze the optimal range of stimulation frequency and time shift for decoupling. We then extended our results to two reciprocally connected neuronal populations (modules) where inter-population delayed connections were modified by STDP. As predicted by the theoretical results, appropriately time-shifted stimulation causes a decoupling of the two-module system through STDP, i.e., by unlearning pathologically strong synaptic interactions between the two populations. Based on the overall topology of the connections, the decoupling of the two modules, in turn, causes a desynchronization of the populations that outlasts the cessation of stimulation. Decoupling effects of the time-shifted stimulation can be realized by time-shifted burst stimulation as well as time-shifted continuous simulation. Our results provide insight into the further optimization of a variety of multichannel stimulation protocols aiming at a therapeutic reshaping of diseased brain networks.

neuroscience↗