Effects of lithium and fampridine on electroencephalography profiles in healthy volunteers

Lithium is the first line treatment for bipolar disorder (BD), a disorder characterised by cyclic perturbations in mood, correlated with aberrant patterns of brain connectivity and rhythmicity in distributed brain networks. These patterns of activity, reflecting the intrinsic electrophysiological properties of constituent neurons, are dependent upon membrane ion channel function. BD is strongly associated with disturbances in genes responsible for ion channel expression, localisation and structure and can be treated with some antiepileptic drugs, acting directly on ion channels. Thus, ion channel dysfunction is strongly implicated in BD, however, lithium has had no known effect on ion channels. Recently, we found that lithium selectively blocks a specific K+ current, the delay current (ID), found in several types of brain neuron. ID can influence action potential threshold and output timing, how inputs from different synaptic sources are integrated, and network synchrony and rhythmicity. Output timing (gating) and synchrony are important variables in brain network function, contributing to the formation and dissolution of functional brain networks over time. Modulation of ID, including by lithium, may influence patterns of connectivity and rhythmicity in the brain and could explain the effectiveness of lithium in BD. We have found, additionally, that Fampridine (4AP), a prescription treatment for multiple sclerosis, blocks ID in cortical projection neurons in vitro. We therefore hypothesise, that Fampridine may act as an adjunctive or replacement therapy for lithium in BD. In order to assess this hypothesis, we aim to examine activity and functional connectivity changes in EEG recordings of healthy volunteers in the presence of lithium, Fampridine and placebo control. The specific objectives of the study are: • To examine the early and late effects of dose (Fampridine) and dose timing of lithium and Fampridine on EEG changes in healthy volunteers. • To evaluate the magnitude and duration of affective changes following administration of lithium, Fampridine or placebo in healthy volunteers. Blood testing will also show any associations of cognitive changes with levels of Li+ / Fampridine and its metabolites in the participant’s bloodstream.