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Interleaved transcranial magnetic stimulation and fMRI suggests that lamotrigine and valproic acid have different effects on corticolimbic activity

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Abstract

Rationale

Combined transcranial magnetic stimulation (TMS) and functional magnetic resonance imaging (fMRI) can be used to study anticonvulsant drugs. A previous study showed that lamotrigine (LTG) inhibited brain activation induced when TMS was applied over motor cortex, whereas it increased activation induced by TMS applied over prefrontal cortex.

Objectives

The present double-blind, placebo-controlled, crossover study in 30 healthy subjects again combined TMS and fMRI to test whether the effects seen previously with LTG would be confirmed and to compare these with a second anticonvulsant drug, valproic acid (VPA).

Results

Statistical parametric mapping analysis showed that both LTG and VPA, compared to placebo, inhibited TMS-induced activation of the motor cortex. In contrast, when TMS was applied over prefrontal cortex, LTG increased the activation of limbic regions, confirming previous results; VPA had no effect.

Conclusion

We conclude that LTG and VPA have similar inhibitory effects on motor circuits, but differing effects on the prefrontal corticolimbic system. The study demonstrates that a combination of TMS and fMRI techniques may be useful in the study of the effects of neuroactive drugs on specific brain circuits.

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Acknowledgments

This study was funded primarily by an unrestricted research grant from GlaxoSmithKline to Dr. George, as well as from Center for Advanced Imaging Research and Brain Stimulation Laboratory infrastructure and resources. CHL is a full-time employee of GlaxoSmithKline S.p.A. None of the other authors has equity or financial conflicts. Drs. Li and George had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

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Authors and Affiliations

  1. Brain Stimulation Laboratory, Department of Psychiatry, Medical University of South Carolina, 502N, 67 President St, Charleston, SC, 29425, USA

    Xingbao Li, Raffaella Ricci, Berry Anderson, Ziad Nahas & Mark S. George

  2. The Center for Advanced Imaging Research, Medical University of South Carolina, Charleston, SC, USA

    Xingbao Li, Daryl E. Bohning & Mark S. George

  3. Medicines Research Centre, GlaxoSmithKline S.p.A., Verona, Italy

    Charles H. Large

  4. Ralph H. Johnson VA Medical Center, Charleston, SC, USA

    Mark S. George

Authors
  1. Xingbao Li
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  2. Raffaella Ricci
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  3. Charles H. Large
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  4. Berry Anderson
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  5. Ziad Nahas
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  6. Daryl E. Bohning
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  7. Mark S. George
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Corresponding author

Correspondence to Xingbao Li.

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Table S1

Comparisons of drugs of TMS in active regions during 100% MT-TMS and voluntary movement over motor cortex. Voluntary movement of the thumb caused a BOLD response in primary motor cortex (M1), premotor cortex (PMd), supplemental motor area (SMA), nucleus caudatus, and thalamus. Analyzing the effects of drug treatment compared to placebo on the BOLD response induced by voluntary thumb movement, a significantly smaller response was observed in the caudate nucleus after treatment with either LTG or VPA. However, comparing LTG and VPA, the BOLD response to voluntary thumb movement in inferior parietal, putamen, and caudate was reduced to a greater extent by VPA, whereas LTG reduced the response in SMA to a greater extent. A two-way ANOVA within SPM showed a significant main effect of TMS intensity (F = 11.29, df = 1, 144). TMS intensity-related changes were observed in paracentral lobule, postcentral gyrus/precentral gyrus, and SMA. Considering stimulus intensity, on the placebo day, motor cortex TMS at 120% RMT caused more activation than 100% RMT in M1 and SMA. However, following treatment with either LTG or VPA, no significant difference in motor cortex TMS-induced BOLD response was observed comparing 100% RMT with 120% RMT in any brain region (XLS 26 kb)

Table S2

Comparisons of drugs of TMS in active regions during 100% MT-TMS and voluntary movement over prefrontal cortex. A two-way ANOVA indicated a significant main effect of TMS intensity (F = 11.38; df = 1, 120). TMS intensity-related changes were observed in anterior cingulate cortex and superior medial frontal cortex. With respect to stimulus intensity, on the placebo day, TMS at 120% RMT over prefrontal cortex caused more activation than TMS at 100% RMT in anterior cingulate cortex. Following treatment with LTG, TMS at 120% RMT caused more activation than 100% RMT in superior medial frontal cortex. Finally, following treatment with VPA, there was no significant difference in activation caused by TMS at 100% RMT and TMS at 120% RMT in any brain region (XLS 25 kb)

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Li, X., Ricci, R., Large, C.H. et al. Interleaved transcranial magnetic stimulation and fMRI suggests that lamotrigine and valproic acid have different effects on corticolimbic activity. Psychopharmacology 209, 233–244 (2010). https://doi.org/10.1007/s00213-010-1786-y

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