The effect of carbamazepine on human corticomuscular coherence
Introduction
Oscillatory activity is common within the nervous system. In the visual cortex, synchronous oscillations may be important in ‘binding’ disparate streams of neural information to form a complete visual image (Singer and Gray, 1995). However, it has proved more difficult to find analogous functions for oscillations in other cortical regions. In the sensorimotor cortex, oscillatory activity is commonly observed in two main frequency bands. Oscillations at approximately 10 Hz are thought to arise mainly from somatosensory cortex (Salmelin and Hari, 1994), whilst those in the beta range of approximately 15–30 Hz are attributed to primary motor cortex Baker et al., 1997, Donoghue et al., 1998, Kilner et al., 1999, Murthy and Fetz, 1996. They are seen not only in invasive recordings in monkeys, but also in human electroencephalogram (EEG) and magnetoencephalogram (MEG) Brown et al., 1998, Halliday et al., 1998, Kilner et al., 2000, Mima and Hallett, 1999, Salenius et al., 1997, Stancak and Pfurtscheller, 1996.
The function of sensorimotor cortical oscillations is controversial. Both approximately 10 Hz and 15–30 Hz frequency bands exhibit task-dependent modulations. They are abolished during movement Baker et al., 1997, Kilner et al., 1999, Pfurtscheller and Neuper, 1992, Stancak and Pfurtscheller, 1996, thus arguing against a role in direct programming of motor output. Oscillation power is maximal during a steady contraction, particularly if this follows a movement Baker et al., 1997, Kilner et al., 1999, Pfurtscheller et al., 1996.
Oscillations are also observed in the electromyogram (EMG) of contracting muscles; these can show coherence with activity of the contralateral motor cortex Baker et al., 1997, Conway et al., 1995, Hari and Salenius, 1999, Kilner et al., 1999, Salenius et al., 1997. The phase of corticomuscular coherence is controversial. Some authors have reported a linear phase–frequency relationship, indicating a constant delay between cortex and muscle Brown et al., 1998, Brown et al., 1999, Mima et al., 2000. The slope of the best-fit line was consistent with conduction over fast corticospinal pathways. However, Halliday et al. (1998) and Marsden et al. (1999) reported zero-phase locking between cortex and muscle over a range of frequencies. Important differences in coherence phase result from different recording methods (Mima and Hallett, 1999).
Although oscillations in motor cortical activity are seen around 10 Hz and 15–30 Hz, only the latter band is normally reported to show coherence with muscle activity Baker et al., 1997, Baker et al., 2003, Conway et al., 1995, Kilner et al., 2000, Salenius et al., 1997. Activity around 10 Hz is carried down the corticospinal tract (Baker et al., 2003), and theoretical modelling shows that if anything, it should produce stronger phase locking of motoneurone discharge than the higher frequencies (Baker et al., 2003). The failure to observe 10 Hz corticomuscular coherence is therefore something of an enigma. It is difficult to reconcile with a model, which sees corticomuscular coherence simply as a product of monosynaptic transmission from cortex to spinal motoneurone via the corticospinal tract. Baker et al. (2003) rather suggested that some active system may be involved which specifically prevents 10 Hz coherence; this could be important in the reduction of physiological tremor, which has a component in this range (Elble and Randall, 1976).
In contrast to most authors, Raethjen et al. (2002) found significant approximately 10 Hz coherence in a group of epileptic patients. In addition to the unusual frequency band, coherence values were high (c. 0.6), compared with around 0.1 in normal subjects. The differences may have resulted from the underlying epileptic pathology. However, a further difference from other studies was that all the patients were taking the antiepileptic drug carbamazepine (CBZ). CBZ crosses the blood–brain barrier, allowing it to bind to and stabilise the inactivated state of voltage-gated sodium channels in cortical neurons. This prevents propagation of high-frequency action potentials and reduces seizure activity Elphick, 1988, Schwarz and Grigat, 1989, Willow et al., 1985, Worley and Baraban, 1987. CBZ also has inhibitory actions on L-type calcium channels (Ambrósio et al., 1999), adenosine A1 receptors Biber et al., 1996, Van Calker et al., 1991 and adenylyl cyclase (Chen et al., 1996). In the periphery, CBZ depresses muscle spindle activity (Hershkowitz and Raines, 1978). Given these many actions, the drug could possibly act to reduce the efficacy of the suggested active system for prevention of 10 Hz coherence.
In this study, we assessed the effect of CBZ on corticomuscular coherence in healthy volunteer subjects who performed the same motor task as in Kilner et al. (2000). We found that CBZ produced a significant increase in approximately 20 Hz coherence without changing the negligible level of its approximately 10 Hz counterpart. The drug produced no change in EEG power. Taken together with similar recent pharmacological work, these data suggest an important role for corticomuscular coherence in motor control.
Section snippets
Methods
Experiments were performed on eight young, healthy, male volunteer subjects, right-handed by self report. All gave informed written consent in accordance with the Declaration of Helsinki; procedures were approved by the Human Biology Research Ethics Committee of the University of Cambridge. Carbamazepine was prescribed and administered by one of the authors who is a qualified physician (MRB). To avoid potential adverse effects, doses were kept at the lower end of the range normally used in
Results
Fig. 1 shows the effect of CBZ and placebo upon EEG and EMG power. There were strong EEG power peaks at approximately 10 and 20 Hz in both control and test data (Figs. 1A and 1B)—these represent the dominant oscillatory activity present in the motor cortical region underlying the electrodes. The low frequency (approximately 3 Hz) peak probably results artifactually from the high pass filter setting of the amplifier (3 Hz). Although it appears from Figs. 1A and 1B that there was a small rise in
Discussion
In this study, we have shown that the antiepileptic drug carbamazepine produces a significant increase in human corticomuscular coherence at approximately 20 Hz, whilst leaving the strength of cortical oscillations measured by EEG power unchanged. Paralleling the coherence increase was a rise in EMG power at approximately 20 Hz. Coherence phase was unaffected by the drug. CBZ did not lead to significant coherence at approximately 10 Hz. These effects all occurred with 100 mg CBZ, a dose
Acknowledgements
We wish to thank the volunteer subjects who gave their time to this study. Supported by The Wellcome Trust.
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