Carbamazepine reduces short-interval interhemispheric inhibition in healthy humans
Highlights
► In humans, interhemispheric motor cortex inhibition (IHI) is modulated by different drugs at different intervals. ► Carbamazepine reduces short-interval interhemispheric inhibition, lorazepam enhances long-interval interhemispheric inhibition. ► This suggests an influence of sodium channel dependent mechanisms on short interval IHI and of GABAergic mechanisms on longer-interval IHI.
Introduction
Laterality of human brain function is a long-standing topic in many areas of neuroscience (Friederici, 2006, Travis, 1978). In particular, the interaction of motor cortices has been subject to studies of handedness, early musical training (Ridding et al., 2000), developmental stuttering (Fox et al., 1996) and recovery after stroke (Weiller et al., 1995). Transcranial magnetic stimulation allows studying the interaction of motor cortices non-invasively in the intact human (Ferbert et al., 1992). It allows quantifying interhemispheric inhibition (IHI), i.e. the suppression of the excitability in one motor cortex by activation of the contralateral motor cortex (Boroojerdi et al., 1996, Ferbert et al., 1992, Müller-Dahlhaus et al., 2008). IHI relies primarily (Meyer et al., 1995), but not exclusively (Gerloff et al., 1998), on transcallosal fibers. Modulation of IHI could be meaningful in rehabilitation of stroke or alleviation of stuttering. However, little is known about the pharmacological background of IHI. The relevant transcallosal fibers are probably excitatory and possibly glutamatergic (Meyer et al., 1995, Müller-Dahlhaus et al., 2008) and likely to synapse on inhibitory interneurons in the contralateral motor cortex. Hence, we here set out to explore the sensitivity of IHI to single doses of the NMDA-receptor-antagonist dextrometorphane, and we additionally tested the sodium channel blocker carbamazepine and the GABA-agonist lorazepam.
Section snippets
Methods
We investigated 13 healthy young subjects (four men) with a mean age of 25.1 (standard deviation, SD 1.8) years. They were recruited from the University of Göttingen campus and paid for participation. All were right-handed with a mean Oldfield handedness score of 81.8 (SD 23.6) points. None of the participants showed neurological or medical abnormalities on routine examination or had a history of medical or neurological disease. None of the participants was taking CNS-active drugs at the time
Results
Side effects reported by the subjects included: LOR: fatigue (12 subjects); CBZ: fatigue (5); DMO: dizziness (10), and nausea (10). These side effects reached their maximum within 1–4 h after intake and were fully reversible until the morning after the experiment. None of the subjects dropped out of the study.
The motor threshold and the stimulation intensities necessary to yield baseline MEP amplitudes of test or conditioning pulse MEP amplitudes were all increased by CBZ, whereas LOR left the
Discussion
The results demonstrate that the interhemispheric inhibition is modulated by different drugs at different intervals. CBZ reduced IHI at the interval 8 ms, and LOR enhanced IHI at longer intervals.
Although interhemispheric interaction of motor cortices is a key feature of brain development, particularly for hand function and language, literature on the pharmacological basis of human transcallosal inhibition is surprisingly scarce. With regard to neuroleptics, neither haloperidol nor olanzapine
Interhemispheric facilitation
In their original report, Ferbert and coworkers noted an interhemispheric facilitation at very short interstimulus intervals (2 ms) to be “capricious” and difficult to detect in a reproducible manner (Ferbert et al., 1992). This is confirmed by our set of data, where the pre-drug baselines show a variable degree of facilitation at the interval of 2 ms, with the difference to unconditioned test pulses never reaching significance. This suggests a modest amount and an important intra-individual
Limitations
Limitations of the study comprise the lack of longer interstimulus intervals and the unevenness of millisecond steps in between intervals, which renders a detailed curve function analysis very difficult. Single loading dose studies do not necessarily predict effects after longer periods of drug intake (Liepert et al., 1997, Sommer et al., 1999, Stefan et al., 1998).
Another limitation is the use of only one conditioning pulse intensity. Studying a range of conditioning pulse intensities might
Conclusion
The results demonstrate that the short intervals of interhemispheric inhibition are susceptible to the effect of CBZ. We conclude that short interstimulus intervals of IHI differ from longer intervals by being susceptible to sodium channel blockade. Possible mechanisms are a delayed activation or a reduced firing rate of inhibitory interneurons mediating inhibition.
Acknowledgments
M.S. has been supported by a grant from the DFG (Deutsche Forschungsgemeinschaft, SO 429/2-2), W.P. by the Bernstein Center for Computational Neuroscience (01GQ0432) and the German Ministry for Education and Research (01GQ0782). We thank Dr. Mathias Bohn for preparing the medication.
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