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 3h after the drug, compared with a 0.6 ± 10.9% increase 3h 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.
Bibliographical noteFunding Information:
This study was funded primarily by an unrestricted research grant from GSK to Dr George as well as from Center for Advanced Imaging Research and Brain Stimulation Laboratory infrastructure and resources. We would like to acknowledge the help of Poya Moghadam (MUSC summer student) as well as helpful past discussions with Barbara Grassi of GSK. The authors and the Brain Stimulation Laboratory are supported in part by research grants from the National Alliance for Research on Schizophrenia and Depression (NARSAD), the Stanley Foundation, NINDS Grant RO1-AG40956, and the Defense Advanced Research Projects Agency (DARPA). The Laboratory has also received grant support from Cyberonics (VNS), Neotonus, and Neuronetics (TMS) for clinical trials. None of the authors have equity or financial conflicts. Drs George, Nahas, and Bohning have filed an invention disclosure for interleaving TMS with fMRI as a tool for examining the brain effects of CNS compounds. This work was presented in abstract form at the Annual Meeting of American College of Neuropsy-chopharmacology, Hawaii, December 14, 2001 and the Annual Meeting of American Psychiatric Association, Philadelphia, PA, May 21, 2002.
- Healthy young men
- Motor cortex
- Prefrontal cortex
- Transcranial magnetic stimulation