title: Interleaved transcranial magnetic stimulation/functional MRI confirms that lamotrigine inhibits cortical excitability in healthy young men.
abstract: 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.
authors.affiliation: Brain Stimulation Laboratory, Center for Advanced Imaging Research (CAIR), Medical University of South Carolina (MUSC), Charleston, SC 29425, USA. lixi@musc.edu
authors.forename: Xingbao
authors.initials: X
authors.lastname: Li
authors.forename: Charlotte C
authors.initials: CC
authors.lastname: Tenebäck
authors.forename: Ziad
authors.initials: Z
authors.lastname: Nahas
authors.forename: F Andrew
authors.initials: FA
authors.lastname: Kozel
authors.forename: Charles
authors.initials: C
authors.lastname: Large
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Cohn
authors.forename: Daryl E
authors.initials: DE
authors.lastname: Bohning
authors.forename: Mark S
authors.initials: MS
authors.lastname: George
mesh_terms: D000293:Adolescent; D000328:Adult; D001931:Brain Mapping; D002121:Calcium Channel Blockers / Q000097:blood / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000033:anatomy & histology / Q000098:blood supply / Q000187:drug effects* / Q000528:radiation effects*; D002560:Cerebrovascular Circulation; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004558:Electric Stimulation / Q000379:methods; D006801:Humans; D000077213:Lamotrigine; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D009433:Neural Inhibition / Q000187:drug effects / Q000528:radiation effects; D010100:Oxygen / Q000097:blood; D050781:Transcranial Magnetic Stimulation; D014227:Triazines / Q000097:blood / Q000494:pharmacology*
chemical_list: D002121:Calcium Channel Blockers; D014227:Triazines; D010100:Oxygen; D000077213:Lamotrigine