Elsevier

Clinical Neurophysiology

Volume 123, Issue 2, February 2012, Pages 351-357
Clinical Neurophysiology

Carbamazepine reduces short-interval interhemispheric inhibition in healthy humans

https://doi.org/10.1016/j.clinph.2011.07.027Get rights and content

Abstract

Objective

We sought to elucidate the influence of centrally active drugs on interhemispheric inhibition (IHI) between primary motor cortices in healthy humans.

Methods

We therefore studied IHI before and 2 h after intake of a single oral dose of carbamazepine, dextrometorphane, lorazepam, or placebo and compared it with the well known results for short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF). Drugs were tested in separate sessions and in random order.

Results

While SICI and ICF were not altered by carbamazepine, IHI was reduced at the interstimulus interval of 8 ms. Dextrometorphane tended to enhance SICI and to reduce ICF and had no effect on IHI. Lorazepam reduced ICF as expected and enhanced IHI at the long intervals of 50 and 80 ms. A moderate trend for interhemispheric facilitation was inconsistently observed at the interval 2 ms and blocked by carbamazepine. In addition, carbamazepine increased the motor threshold.

Conclusions

We conclude that circuits mediating short interstimulus intervals of IHI are susceptible to sodium channel blockade.

Significance

The results increase our knowledge of interhemispheric transmission.

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.

References (46)

  • R. Chen et al.

    Organization of ipsilateral excitatory and inhibitory pathways in the human motor cortex

    J Neurophysiol

    (2003)
  • Z.J. Daskalakis et al.

    Effect of antipsychotics on cortical inhibition using transcranial magnetic stimulation

    Psychopharmacol (Berl)

    (2003)
  • V. Di Lazzaro et al.

    Direct demonstration of interhemispheric inhibition of the human motor cortex produced by transcranial magnetic stimulation

    Exp Brain Res

    (1999)
  • T. Elbert et al.

    Increased cortical representation of the fingers of the left hand in string players

    Science

    (1995)
  • A. Ferbert et al.

    Interhemispheric inhibition of the human motor cortex

    J Physiol (Lond)

    (1992)
  • P.T. Fox et al.

    A PET study of the neural systems of stuttering

    Nature

    (1996)
  • A.P. Geradin et al.

    Pharmacokinetics of carbamazepine in normal humans after single and repeated oral doses

    J Pharmacokinet Biopharm

    (1976)
  • C. Gerloff et al.

    Inhibitory influence of the ipsilateral motor cortex on responses to stimulation of the human cortex and pyramidal tract

    J Physiol (Lond)

    (1998)
  • R. Hanajima et al.

    Interhemispheric facilitation of the hand motor area in humans

    J Physiol

    (2001)
  • F. Heinen et al.

    Absence of transcallosal inhibition following focal magnetic stimulation in preschool children

    Ann Neurol

    (1998)
  • S. Hutchinson et al.

    Cerebellar volume of musicians

    Cereb Cortex

    (2003)
  • M. Inghilleri et al.

    Antiepileptic drugs and cortical excitability: a study with repetitive transcranial stimulation

    Exp Brain Res

    (2004)
  • T. Kujirai et al.

    Corticocortical inhibition in human motor cortex

    J Physiol

    (1993)
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