Re-Wiring the Human Brain - PROJECT SUMMARY / ABSTRACT Behaviors and mental functions are emergent properties of large-scale neuronal networks where connectivity strengths between nodes define the network. Correspondingly, many neurological and psychiatric symptoms arise from network-level imbalances where structural and/or functional connectivity between specific brain areas has been altered (e.g., sub-cortical stroke, traumatic brain injury TBI). For structural injury, while the adult brain has little capacity to re-grow damaged long-range axons, it may be possible to restore connectivity by training the brain to use alternate routes reconnecting the areas and/or counteracting maladaptive connectivity changes, with the goal of improving motor/behavioral/cognitive function. This also applies to disorders without structural injury but with acquired pathological connectivity changes (e.g., addictions, depression). To restore the network in a controlled fashion, there is a critical need to develop techniques that can selectively engage the targeted connection and increase or reduce its effective connectivity strength. Moreover, the techniques should be appli- cable to the human brain and ideally be non-invasive. To this aim, cortico-cortical paired associative stimulation (ccPAS) protocols have been proposed, presumably engaging spike timing-dependent plasticity (STDP) mech- anisms. However, progress in applying ccPAS in humans has been limited. This is because millisecond-precision intracranial conduction delays, which are a prerequisite for choosing ccPAS parameters that would have the desired effect, are not known. Further, neurophysiological outcome measures to capture intracranial ccPAS ef- fects are lacking, which makes it difficult to assess if the stimulation achieved its goals – in fact, it has not even been convincingly shown if ccPAS engages STDP. The overall goal of the proposal, therefore, is to overcome these barriers by (a) crafting novel techniques that can measure the required fast intracranial conduction delays, (b) developing outcome measures that capture ccPAS neurophysiological effects accurately, and (c) proving ccPAS mechanisms. Specifically, inspired by previous animal and human studies, as well as our own preliminary ccPAS data, we will stimulate two interconnected cortical regions with millisecond-level asynchronies with two independent transcranial magnetic stimulator (TMS) coils. Our preliminary data show source-space cortico-cor- tical evoked potentials (ccEP) that capture both the required conduction delays and serve as outcomes of ccPAS effects at the physiologically relevant fast (<10 ms) timescales. Further, our preliminary data that parametrically manipulates ccPAS asynchronies are in accord with that the mechanism is indeed STDP. If successful, this study will transform our capability to non-invasively manipulate brain interregional effective connectivity in the human brain, therefore laying the foundation for a new class of robust network-level therapies in disorders that involve brain connectivity changes in a broad range of neurological and psychiatric disorders.
