The impact of prolonged environmental stress on homeostatic plasticity in the intact human cortex

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The human brain is capable of profound and rapid adaptation in response to environmental change. This ability is integral to learning and memory and is underpinned by a myriad of structural and functional mechanisms, collectively known as synaptic plasticity. Importantly, synaptic plasticity relies on a positive feedback loop that, left unchecked, has the potential to destabilise neural networks through the induction of excessive neural firing (uncontrolled long-term potential [LTP] of synaptic efficacy) or complete neural silencing (uncontrolled long-term depression [LTD] of synaptic efficacy). To prevent destabilisation, a second type of plasticity, termed homeostatic plasticity, maintains neural stability within a physiologically stable range. Despite the importance of homeostatic plasticity to healthy brain function, our understanding of this mechanism has primarily been informed by studies performed in vitro. Human studies probing the functional relevance of homeostatic plasticity are limited. In particular, how the human brain maintains neural stability in the context of prolonged environmental stress remains unclear. Pain is a salient, dynamic and behaviourally relevant source of environmental stress that provides a useful model with which to study the interaction between stress and plasticity in humans. Using human experimental pain models, the short-term objective of this proposal is to develop a detailed theoretical understanding of how homeostatic plasticity maintains neural stability in the human primary motor cortex (M1) in the presence of prolonged pain. Toward this objective, my trainees and I will address five aims: aim 1) to investigate homeostatic plasticity induced by an excitatory priming protocol within intracortical inhibitory and facilitatory networks of the human M1 in response to prolonged pain; aim 2) to investigate homeostatic plasticity induced by an inhibitory priming protocol within intracortical inhibitory and facilitatory networks of the human M1 in response to prolonged pain; aim 3) to examine whether the homeostatic response is restricted to the cortical representation of the muscle in pain; aim 4) to explore the relationship between synaptic and homeostatic plasticity in response to prolonged pain and aim 5) to explore the relationship between pain severity and the homeostatic response. The long-term goal of my research is to understand how synaptic and homeostatic plasticity interact in the service of healthy brain function. The outcomes of the proposed research will advance our fundamental understanding of homeostatic plasticity, providing novel data on how the human brain balances competing demands of neural change and neural stability when the system is exposed to salient, dynamic and prolonged environmental stress. This information is essential for the development of brain-machine interfaces and artificial intelligence applications related to learning and memory.