Little is known about how lamotrigine (LTG) works within brain circuits to achieve its clinical effects. We wished to determine whether the new technique of interleaved transcranial magnetic stimulation (TMS)/functional magnetic resonance imaging (fMRI) could be used to assess the effects of LTG on activated motor or prefrontal/limbic circuits. We carried out a randomized, double-blind, crossover trial involving two visits 1 week apart with TMS measures of cortical excitability and blood oxygen level-dependent TMS/fMRI. Subjects received either a single oral dose of 325 mg of LTG or placebo on each visit. In all, 10 subjects provided a complete data set that included interleaved TMS/fMRI measures and resting motor threshold (rMT) determinations under both placebo and LTG conditions. A further two subjects provided only rMT data under the two drug conditions. LTG caused a 14.9+/-9.6% (mean+/-SD) increase in rMT 3 h after the drug, compared with a 0.6+/-10.9% increase 3 h after placebo (t=3.41, df =11, p<0.01). fMRI scans showed that LTG diffusely inhibited cortical activation induced by TMS applied over the motor cortex. In contrast, when TMS was applied over the prefrontal cortex, LTG increased the TMS-induced activation of limbic regions, notably the orbitofrontal cortex and hippocampus. These results suggest that LTG, at clinically relevant serum concentrations, has a general inhibitory effect on cortical neuronal excitability, but may have a more complex effect on limbic circuits. Furthermore, the interleaved TMS/fMRI technique may be a useful tool for investigating regional brain effects of psychoactive compounds.
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