Dextromethorphan decreases the excitability of the human motor cortex

The activation of N-methyl-D-aspartate (NMDA) receptors has been implicated in several forms of neocortical synaptic plasticity such as long-term potentiation and long-term depression,^1-4 but also in excitotoxicity-mediated neuronal death in various neurodegenerative diseases⁵ or under ischemic conditions.⁶ Blockade of NMDA receptors was effective in preventing deafferentation-induced plasticity of sensory maps in the somatosensory cortex of nonhuman primates.^7,8 Dextromethorphan (DM), a noncompetitive blocker of the NMDA receptor, showed neuroprotective properties in ischemia-induced neuronal damage in rats.⁹ However, DM appeared ineffective in therapeutic trials in human neurodegenerative disease such as PD¹⁰ or ALS.¹¹ In the current study we employed transcranial magnetic stimulation (TMS) in healthy volunteers before and after a single oral dose of DM to learn whether this NMDA receptor antagonist is capable of reducing the activity of excitatory circuits in the normal human motor cortex.

Methods. Subjects. Eight healthy volunteers (mean age, 31.8 ± 11.3 years; range, 18 to 54 years; three women and five men) participated in the study. All gave written informed consent. Experiments were approved by the institutional review board.

Measures of motor excitability. Details of the experimental protocol have been described elsewhere.¹² In short, motor evoked potentials (MEPs) were recorded with surface electromyography (EMG) from the left abductor digiti minimi (ADM) muscle. The amplified and bandpass-filtered (0.1 to 2 kHz) EMG raw signal was digitized (analog/digital rate, 5 kHz) and fed into a laboratory computer (486 DX, IBM PC/AT, American Megatrends, Inc., Norcross, GA). TMS was delivered through a focal figure-of-eight shaped coil (each loop measured 70 mm in diameter) connected to two magnetic stimulators via a BiStim module (Magstim, Whitland, Dyfed, UK), and placed flat on the skull over the right motor cortex at the site optimal for left ADM activation. The induced current in the brain beneath the junction of the coil flowed from posterior to anterior, approximately perpendicular to the assumed line of the central sulcus.

Resting motor threshold (RMT) was determined to the nearest 1% of maximal stimulator output and was defined as the minimum stimulus intensity that produced MEPs ≥50 µV in at least 5 of 10 trials. Active motor threshold (AMT) was determined in the moderately active ADM (approximately 10% of the maximum voluntary contraction, monitored by an auditory feedback of the EMG signal) and was defined as the minimum intensity that produced an MEP ≥100 µV in an average of five consecutive trials. It is currently thought that the motor threshold reflects primarily the excitability of neuronal membranes because voltage-gated sodium or calcium channel blockers increase motor threshold.^12-14

Peak-to-peak MEP amplitudes were measured in the resting ADM at stimulus intensities of 100, 110, 130, and 150% RMT (MEP recruitment curve). Conditional averages (10 trials per stimulus intensity) of MEP amplitudes were calculated and related to the size of the maximum M wave (M_max). The slope of the MEP recruitment curve is related to the number of corticospinal neurons that can be activated at a given stimulus intensity, mainly indirectly through corticocortical connections.¹⁵

Intracortical inhibition (ICI) and intracortical facilitation (ICF) were obtained in the resting ADM according to a previously described paired TMS protocol^16,17 using a sub-threshold (90% AMT) conditioning stimulus followed by a suprathreshold test stimulus (adjusted to produce control MEPs of approximately 1 mV in peak-to-peak amplitude) at 12 different interstimulus intervals (ISIs) from 1 to 30 msec. Four blocks of 40 trials were run. Each consisted of 10 control trials (test stimulus alone) and 30 paired stimulation trials (three ISIs per block) in a random order. For each ISI, the amplitude ratio of the mean conditioned MEP to the control MEP was calculated.^16,17 ICI and ICF were defined as the averages of the MEP ratios obtained at inhibitory ISIs of 1 to 5 msec, and facilitatory ISIs of 7 to 20 msec respectively. Several lines of evidence have accumulated that imply that ICI and ICF reflect primarily the excitability of separate inhibitory and excitatory interneuronal circuits within the motor cortex, which in turn regulate the activity of motor cortical output cells.^16-19

The cortical silent period (CSP) was measured in 10 trials each at stimulus intensities of 125, 150, and 200% AMT in the moderately active ADM. CSP duration was defined in the rectified single trials from the time of the magnetic stimulus to the first reoccurrence of voluntary EMG activity. For each stimulus intensity the average was calculated. Many authors (for review see Hallett²⁰) suggested that the CSP duration is related to long-lasting inhibitory mechanisms at the level of the motor cortex. However, other mechanisms such as the accessibility of voluntary motor drive to the primary motor cortex may also play a role (e.g., see Classen et al.²¹ and Ziemann et al.²²).

Supramaximal electrical stimulation (0.2-msec square-wave constant current pulses) of the ulnar nerve at the wrist was used to assess spinal and peripheral motor excitability. While the ADM was active, the duration of the peripheral silent period (PSP; measured from the time of the electrical stimulus to the first recurrence of voluntary EMG activity), the peak-to-peak amplitudes of F waves, and M_max were determined (average, 10 trials). All parameters of motor excitability were measured before and 1.5, 4, 6.5, and 24 hours after a single oral dose of 150 mg DM was administered in five 30-mg capsules. Adverse side effects were generally slight (lightheadedness in five subjects, sedation in four subjects, and nausea in three subjects) and did not interfere with the subjects' ability to comply fully with the requirements of the experimental protocol.

Statistical procedures. The different measures of motor excitability were analyzed separately. The effect of DM was evaluated in an analysis of variance model of repeated measures, with time as the intrasubject effect. Conditional on significance of the F value, the measures obtained at the four delays after drug intake were compared individually with the baseline data in post hoc two-tailed paired Student's t-tests. In general, significance was accepted at p < 0.05. However, for the paired t-tests the level of significance was adjusted by dividing it by the number of comparisons (0.05 ÷ 4 = 0.0125) to approximate the conservativeness of post hoc statistics corrected for multiple comparisons, which are not appropriate in repeated-measure statistics.

Results. A single oral dose of 150 mg DM resulted in a temporary increase in ICI and a decrease in ICF (see figure, table). These effects peaked at 1.5 hours after drug intake but were no longer statistically significant after 4 hours. Furthermore, DM produced an overall lengthening effect on CSP₂₀₀, which was only a nonsignificant trend at 1.5 and 4 hours in the post hoc pairwise comparisons (see the table). All other measures of motor excitability (RMT, AMT, MEP recruitment, CSP₁₂₅, CSP₁₅₀, PSP, F wave, and M_max) were not affected by DM (see the table).

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Figure. Intracortical inhibition (A) and intracortical facilitation (B) are pooled across inhibitory interstimulus intervals of 1 to 5 msec and facilitatory intervals of 7 to 20 msec respectively, and are expressed as the ratio of conditioned motor evoked potential (MEP) versus control MEP amplitudes (ordinates). Data are plotted against the delay (abscissa) after intake of a single oral dose of 150 mg dextromethorphan. The individual data of the eight subjects are shown by gray lines and different symbols. Mean data and standard errors are denoted by the heavy black lines and error bars. Asterisks at 1.5 hours after drug intake indicate a significant drug-induced deepening of intracortical inhibition and a suppression of intracortical facilitation. *p < 0.05. **p < 0.005.

Discussion. The principal new finding of the current study was that a single oral dose of an NMDA receptor antagonist induced a temporary deepening of ICI and a suppression of ICF in the normal human brain. ICI and ICF reflect the excitability of respectively inhibitory and excitatory interneuronal circuits at the level of the motor cortex.^16,17 Both measures are regulated in part by γ-aminobutyric acid (GABA)^12,23,24-the major inhibitory neurotransmitter in the mammalian cerebral cortex. The current findings demonstrate that DM is also capable of increasing inhibition and decreasing excitation in the motor cortex as defined by these TMS measures. Very likely, these effects are produced by a noncompetitive NMDA receptor blockade that is thought to be the responsible mechanism for the neuroprotective and anticonvulsant properties of this drug (for review see Netzer et al.²⁵). At high concentrations, DM is also a blocker of voltage-dependent Ca²⁺ and Na⁺ channels,²⁵ but it is unlikely that these modes of action were relevant to the current results, because classic ion channel-blocking antiepileptic drugs like carbamazepine and phenytoin have no effect on ICI or ICF.^12,14 Furthermore, DM had no effect on motor threshold, which is elevated by ion channel blockers.^12-14

The duration of the CSP is thought to reflect the activity of inhibitory mechanisms in the motor cortex,²⁰ but its physiology is not completely understood and its relation to GABA is less clear than for ICI or ICF.^12,26,27 The current findings indicate that a suppression of the excitatory motor cortical drive through a blockade of NMDA receptors can lead to a slight lengthening of the CSP.

DM is metabolized rapidly and extensively to dextrorphan, which has a high affinity for the phencyclidine binding site of the NMDA receptor, and has potent neuroprotective and anticonvulsant properties similar to DM.²⁸ Both DM and dextrorphan have short plasma peak times of 1.2 to 2.2 hours in extensive metabolizers.²⁹ Therefore, the peaking of DM effects on motor excitability at 1.5 hours in the current experiments is compatible with the pharmacokinetics of this compound. Whether DM, dextrorphan, or both were responsible for the observed results is uncertain.

To our knowledge, the effects of the major excitatory neurotransmitter in the CNS glutamate on motor excitability have not been studied with TMS, except in one other study using riluzole rather than DM.³⁰ This is surprising because glutamate is considered of crucial importance in the regulation of cortical excitability, in excitotoxicity-mediated neurodegeneration, and in various forms of neuroplasticity. Previous TMS studies (for review see Ziemann et al.³¹) showed that the excitability of the motor cortex is increased in various forms of epilepsy and in some neurodegenerative diseases such as ALS.^32,33 The latter studies related their findings to the hypothesis that glutamatergic excitotoxicity plays an important role in the pathogenesis of this disease. The current TMS experiments support this view by showing that a single oral dose of the NMDA receptor antagonist DM can shift the balance toward less excitation and more inhibition even in the normal human brain.

Acknowledgment

The authors thank J. Dambrosia for help with the statistical analysis.