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 14.979.6% (mean7SD) increase in rMT 3 h after the drug, compared with a 0.6710.9% increase 3 h after placebo (t ¼ 3.41, df ¼ 11, po0.01). 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.

Investigating the neural basis for functional and effective connectivity. Application to fMRI

“…TMS has been used in conjunction with PET as a tool for investigating functional connectivity (Fox et al 1997;Paus et al 1998;Mottaghy et al 2000). Recently, studies combining TMS and fMRI have been reported (Bohning et al 2000;Siebner et al 2003;Li et al 2004). The model, whose construction was based on experimental neuroanatomical and neurophysiological measurements, generates simulated neuronal data that agree with experimental data obtained from mammalian studies, and also generates simulated PET/fMRI data that are in accord with experimental findings from human studies.…”

Does neuroimaging research examining the pathophysiology of posttraumatic stress disorder require medication-free patients?

“…43 The effects of lamotrigine on BOLD signal changes induced by transcranial magnetic stimulation (TMS) have also been examined in healthy participants. 44 Lamotrigine at clinically relevant serum concentrations diffusely inhibited cortical activation induced by TMS applied over the motor cortex. In contrast, when TMS was applied over the prefrontal cortex, lamotrigine increased the TMS-induced activation of limbic regions such as the orbitofrontal cortex and hippocampus.…”

Mobilization of Medial and Lateral Frontal-Striatal Circuits in Cocaine Users and Controls: An Interleaved TMS/BOLD Functional Connectivity Study

“…The stimulator was located outside of the scanning room. The pulses were delivered through a 8 m cable that first attached to the bottom of an RF filter, and then passed through the waveguide into the MR scanning room where it was led through the bore of the MRI and terminated in a custom nonferromagnetic figure-of-eight TMS coil (Bohning et al, 2003;George et al, 2003;Li et al, 2004;Nahas et al, 2001). …”