Non-invasive induction of long-term potentiation in human sensory cortex

Abstract

Long-term potentiation (LTP) is a candidate synaptic mechanism underlying learning and memory that has been studied extensively at the cellular and molecular level in laboratory animals. To date, LTP has only been directly demonstrated in humans in isolated cortical tissue obtained from patients undergoing surgery, where it displays properties identical to those seen in non-human preparations. Inquiry into the functional significance of LTP has been hindered by the absence of a human model. The experiments in this thesis attempted to create a human model to study LTP. The first direct demonstration of LTP in human sensory cortex was induced by rapid repetitive presentation of a visual checkerboard (a photic ‘tetanus’) which leads to a persistent enhancement of one of the early components of the visual evoked potential (Nib) in normal humans that lasts over 1 hour. This photic tetanus was also found to induce a long-lasting enhanced alpha desynchronization suggesting increased neuronal output. This finding was extended into the auditory modality, where rapidly presented tone pips induced a long-lasting enhancement of the main component of the auditory evoked potential (Nl) and was found to be independent of alterations in the state of arousal. Using fMRI, hemodynamic responses in the extrastriate visual cortex were significantly increased to checkerboards presented at a low frequency after the administration of the photic tetanus, again suggesting the photic tetanus induced a long-lasting increase in neuronal output. This photic tetanus was found to cause an immediate lowering of visual detection thresholds, suggesting that LTP, a neural mechanism which alters synaptic strength in mnemonic networks, underlies behaviour. Finally LTP was induced by a photic tetanus in fully anaesthetized rats. This potentiation was found to be NMDA receptor dependent and, through testing of the thalamo-cortical pathway, most likely generated in the cortex. While LTP is known to exist in the human brain, the ability to directly elicit LTP from non-surgical patients will provide a human model system allowing the detailed examination of synaptic plasticity in normal subjects and may have future clinical applications in the diagnosis and assessment of cognitive disorders and possible use in rehabilitation.