Abstract
I aimed to investigate the therapeutic mechanism of action of lithium as a mood stabiliser and first line treatment of bipolar disorder, as well as the aetiology of the disorder. I hypothesised that the debilitating behavioural extremes of bipolar disorder are a consequence of hyperstable default mode network and central executive network configurations, brought on by aberrant salience network weighting of extero- and interoceptive stimuli. I further hypothesised that successful lithium treatment restores the salience weighting deficits and thus flexibility of the other core networks, resulting in affective stabilisation in responsive patients. I investigated the electrophysiological effects of lithium at the cellular / molecular scale using an ex vivo rodent projection neuron model. Using extracellular recording, I found that lithium blockade of a delay-like current acutely increases excitability and decreases the variability of response to synaptic input, potentially contributing to more reliable signal transmission and network stability. I further found differential effects of lithium on the spontaneously generated and sensory-evoked activity of the circuit, suggesting that the self-organised activity of the microcircuit is affected differently to the information transferring functions of the circuit. This could have implications for understanding the macro-level (network) effects of lithium. Additionally, I investigated lithium induced and bipolar disorder related differences at the functional brain network level using wide-band EEG recordings in patients and healthy volunteers. I found decreases in infraslow current source density in regions associated with the regulation of emotional homeostasis, perhaps suggesting dysregulation of the underlying networks. I additionally found non-homogenous differences in functional and effective connectivity between the three intrinsic networks in patients and healthy volunteers, suggesting the way in which these networks form, dissolve and communicate may be implicated in the manifestations of BD and its treatment with lithium. These findings may facilitate the development of novel pharmaceutical or non-invasive neuromodulation therapies.