Introduction: Brain stimulation is increasingly used to treat neuropsychiatric disorders. However, the fundamental principles underlying how, when and where plasticity is induced in the human brain are largely unknown. In this study, we examined the neuroplasticity effects of repetitive stimulation by pairing direct electrical stimulation with recordings from the cortical surface.
Methods: Direct intracranial electrical stimulation of 10Hz and 1Hz were applied to 4 human subjects undergoing intracranial monitoring. Brain excitability measurements were quantified using the pre/post stimulation cortico-cortical evoked potential (CCEP), which provide direct measurements of oligosynaptic connections in the human brain (1).
Results: In each subject, 10Hz repetitive stimulation elicited CCEP changes that outlasted the stimulation protocol in a small proportion of regions probed. These were primarily seen in short-range connections, and with equal distribution of potentiation and depression. Findings were primarily evident within 50ms of the CCEP response. 1Hz and 10Hz stimulation protocols demonstrated opposing plasticity effects. For each patient, regions showing plasticity were anatomically closer to the stimulation site and functionally elicited higher amplitude and shorter latency CCEPs compared to non-modulated regions. Classifier built using pre-stimulation amplitude, latency or distance correctly identified region of modulation with >80% accuracy. Combining these pre-stimulation features achieved a classifier sensitivity of >97%, while using distance alone provided a specificity >95%. Finally, we demonstrate the induction phase, captured from intratrain-recordings, partially reflect plasticity effects observed in pre/post CCEPs. Interestingly, several regions not affected in pre/post CCEPs were modulated during the induction phase.
Conclusions: Repetitive stimulation induces predictable changes that outlast stimulation in regions anatomically and functionally connected to the stimulation target. These plasticity effects are partially captured by excitability changes that occur during the stimulation period. This work provides avenues for optimization of stimulation site and the development of novel closed-loop brain stimulation strategies.
Patient Care: Brain stimulation such as deep brain stimulation (DBS) or transcranial magnetic stimulation (TMS) is increasingly used to treat neuropsychiatric disorders by inducing plasticity at specific brain regions. However, our understanding of how, when, and where plasticity is induced in the human brain is critically lacking. Our results provide principles for optimizing electrical stimulation therapies that can be targeted to the region of interest and begin to fill basic gaps in our understanding of stimulation-induced plasticity in humans.
Learning Objectives: 1) Describe the characteristics of cortical response following focal repetitive electrical stimulation
2) Identify the anatomical and functional predictors for plasticity change following electrical stimulation
References: 1) Keller CJ, Honey CJ, Entz L, Bickel S, Groppe DM, Toth E, Ulbert I, Lado FA, Mehta AD (2014) Corticocortical evoked potentials reveal projectors and integrators in human brain networks. J Neurosci 34:9152-9163.