Ulf Ziemann

The effect of lorazepam on the motor cortical excitability in man

The effect of the short-acting benzodiazepine lorazepam on motor cortex excitability was investigated in 11 healthy volunteers using the technique of focal transcranial magnetic stimulation. The threshold intensity for evoking an electromyographic response in the resting and active abductor digiti minimi muscle, the size of the motor evoked potential, the duration of the cortical and peripheral silent periods, the corticocortical inhibition and facilitation after paired magnetic stimuli, and the transcallosal inhibition were used as parameters to assess various aspects of motor system excitability. Baseline values were compared with data obtained 2, 5 and 24 h after a single oral dose of 2.5 mg lorazepam. Resting and active motor thresholds and the size of the motor evoked potential remained unchanged. The duration of the cortical silent period was prolonged with a maximum effect 5 h after drug intake, while the peripheral silent period did not show any lengthening at that time. The corticocortical inhibition showed a tendency toward more inhibition, while the corticocortical facilitation was almost completely suppressed. The transcallosal inhibition showed an inconsistent trend to less inhibition. In parallel to the pharmacokinetics of lorazepam, all effects peaked at 2 h and 5 h, and were (partially) reversible after 24 h. It is hypothesized that most of these findings are due to the reinforcement of GABA action by lorazepam at the level of the motor cortex. The lack of effect on motor threshold and on the size of the motor evoked potential may indicate that these parameters are physiologically distinct from corticocortical excitability and the cortical silent period. The relevance of the present data in clinical epileptology is discussed.

Changes in human motor cortex excitability induced by dopaminergic and anti-dopaminergic drugs

Transcranial magnetic stimulation was used to probe the acute effect of a single oral dose of various dopaminergic (levodopa, selegiline, bromocriptine) and antidopaminergic drugs (sulpiride, haloperidol) on motor cortex excitability in healthy volunteers. Motor threshold, intracortical inhibition and intracortical facilitation were tested in the abductor digiti minimi muscle. The latter two parameters were studied in a conditioning-test paired stimulus paradigm. The principal findings were an increase in intracortical inhibition by bromocriptine, and, conversely, a decrease in intracortical inhibition and an increase in intracortical facilitation by haloperidol. Effects peaked at delays consistent with the pharmacokinetics of the two drugs and were fully reversible. In conclusion, dopamine receptor agonists and antagonists can be considered inverse modulators of motor cortex excitability: the former enhance inhibition while the latter reduce it. The relation of the present findings to current models of motor excitability abnormalities in movement disorders will be discussed.

Dissociation of the pathways mediating ipsilateral and contralateral motor‐evoked potentials in human hand and arm muscles

1 Growing evidence points toward involvement of the human motor cortex in the control of the ipsilateral hand. We used focal transcranial magnetic stimulation (TMS) to examine the pathways of these ipsilateral motor effects. 2 Ipsilateral motor‐evoked potentials (MEPs) were obtained in hand and arm muscles of all 10 healthy adult subjects tested. They occurred in the finger and wrist extensors and the biceps, but no response or inhibitory responses were observed in the opponens pollicis, finger and wrist flexors and the triceps. 3 The production of ipsilateral MEPs required contraction of the target muscle. The threshold TMS intensity for ipsilateral MEPs was on average 1.8 times higher, and the onset was 5.7 ms later (in the wrist extensor muscles) compared with size‐matched contralateral MEPs. 4 The corticofugal pathways of ipsilateral and contralateral MEPs could be dissociated through differences in cortical map location and preferred stimulating current direction. 5 Both ipsi‐ and contralateral MEPs in the wrist extensors increased with lateral head rotation toward, and decreased with head rotation away from, the side of the TMS, suggesting a privileged input of the asymmetrical tonic neck reflex to the pathway of the ipsilateral MEP. 6 Large ipsilateral MEPs were obtained in a patient with complete agenesis of the corpus callosum. 7 The dissociation of the pathways for ipsilateral and contralateral MEPs indicates that corticofugal motor fibres other than the fast‐conducting crossed corticomotoneuronal system can be activated by TMS. Our data suggest an ipsilateral oligosynaptic pathway, such as a corticoreticulospinal or a corticopropriospinal projection as the route for the ipsilateral MEP. Other pathways, such as branching of corticomotoneuronal axons, a transcallosal projection or a slow‐conducting monosynaptic ipsilateral pathway are very unlikely or can be excluded.

Transcranial magnetic stimulation: its current role in epilepsy research

This paper reviews the current role of transcranial magnetic stimulation (TMS) in epilepsy research. After a brief introduction to the technical principles, the physiology and the safety aspects of TMS, emphasis is put on how human cortex excitability can be assessed by TMS and how this may improve our understanding of pathophysiological mechanisms in epilepsy and the mode of action of antiepileptic drugs (AEDs). Also, potential therapeutical applications of TMS are reviewed. For all aspects of this paper, a clear distinction was made between single-/paired-pulse TMS and repetitive TMS, since these two techniques have fundamentally different scopes and applications.

Pharmacological control of facilitatory I-wave interaction in the human motor cortex. A paired transcranial magnetic stimulation study

A novel paired transcranial magnetic stimulation (TMS) paradigm with a suprathreshold first and a subthreshold second stimulus was used in healthy volunteers to investigate the acute effects of a single oral dose of various CNS-active drugs on short-interval motor evoked potential (MEP) facilitation. MEPs were recorded from the relaxed abductor digiti muscle. Three peaks of MEP facilitation were consistently observed at interstimulus intervals of 1.1-1.5 ms, 2.3-2.7 ms, and 3.9-4.5 ms. The size of these MEP peaks was transiently suppressed by drugs which enhance gamma-aminobutyric acid (GABA) function in the neocortex (lorazepam, vigabatrin, phenobarbital, ethanol), while the GABA-B receptor agonist baclofen, anti-glutamate drugs (gabapentin, memantine), and sodium channel blockers (carbamazepine, lamotrigine) had no effect. The interstimulus intervals effective for the production of the MEP peaks remained unaffected by all drugs. The MEP peaks are thought to be due to a facilitatory interaction of I-(indirect) waves in the motor cortex. Therefore, the present results indicate that the production of I-waves is primarily controlled by GABA related neuronal circuits. The potential relevance of this non-invasive paired TMS protocol for the investigation of I-waves in patients with neurological disease will be discussed.

Enhancement of human motor cortex inhibition by the dopamine receptor agonist pergolide: evidence from transcranial magnetic stimulation

Focal transcranial magnetic stimulation was used to evaluate the effect a single oral dose (0.125 mg) of the dopamine agonist pergolide on the excitability of the motor cortex in five healthy subjects. Resting and active motor thresholds of the abductor digiti minimi muscle were unaffected. The mean duration of the cortical silent period was significantly lengthened by up to 22 ms. The cortico-cortical inhibition as studied by a paired conditioning-test stimulation (interstimulus intervals of 1-5 ms) was enhanced significantly while the cortico-cortical facilitation at longer intervals (6-15 ms) showed only an insignificant trend towards less facilitation. All effects peaked at 3 h after drug intake and were reversible after 24 h. Peripheral motor excitability as tested by the duration of the peripheral silent period and the size of the maximum M wave remained unchanged. The present data support the view that pergolide is capable of enhancing motor cortex inhibition which is known to be deficient in idiopathic Parkinsons disease.

Transient visual field defects induced by transcranial magnetic stimulation over human occipital pole.

Abstract Transient visual field defects (VFDs) and phosphenes were induced in normal volunteers by means of transcranial magnetic stimulation (TMS) using a circular magnetic coil of 12.5 cm diameter placed with its lower rim 2–4 cm above the inion in the midline. Subjects had to detect small, bright dots presented randomly for 14 ms in one of 60 locations on a computer screen resulting in a plot of the central 9° of the visual field. In 8 of 17 subjects, transient VFDs were inducible at peak magnetic field strenghts of 1.1–1.4 T. In the central 1–3°, detection of targets was impaired in both the upper and lower visual field, whereas at 4–9° large parts of only the lower visual field were affected with a sharp cut-off along the horizontal meridian. Targets at 1° in the lower field were affected with lower TMS intensities than corresponding locations in the upper or peripheral locations in the lower field. Detection of central targets was affected at more caudal stimulation sites than detection of peripheral targets. Phosphenes were elicitable in 14 of 17 subjects at clearly lower field strengths of 0.6–1.0 T. Many subjects perceived chromatophosphenes. From a discussion of the literature on patients with VFDs and the known topography of the human visual system, it is concluded that the transient VFDs at 1–3° are probably due to stimulation of both striate cortex (V1) and extrastriate areas (V2/V3), while VFDs in the lower visual field at eccentricities 4–9° are due to stimulation of V2/V3 but not V1.

Complete suppression of voluntary motor drive during the silent period after transcranial magnetic stimulation.

Abstract To evaluate changes in the motor system during the silent period (SP) induced by transcranial magnetic stimulation (TMS) of the motor cortex, we investigated motor thresholds as parameters of the excitability of the cortico-muscular pathway after a suprathreshold conditioning stimulus in the abductor digiti minimi muscle (ADM) of normal humans. Since the unconditioned motor threshold was lower during voluntary tonic contraction than at rest (31.9±5.4% vs. 45.6±7.5%), it is suggested that the difference between active and resting motor threshold indicates the magnitude of the voluntary drive on the cortico-muscular pathway. Therefore, we compared conditioned resting and active motor threshold (cRMT and cAMT) during the SP. cRMT showed an intensity-dependent period of elevation of more than 200 ms in duration and approximately 17% of the maximum stimulator output above the unconditioned threshold, due to decreased excitability of the cortico-muscular pathway after the conditioning stimulus. Some 30–40 ms after the conditioning stimulus, cAMT approximated cRMT, indicating complete suppression of the voluntary motor drive. This suppression did not start directly after the conditioning stimulus since cAMT was still significantly lower than the cRMT within the first 30–40 ms. Threshold elevation was significantly longer than the SP (220±41 vs. 151±28 ms). Recovery of the voluntary motor drive started late in the SP and was nearly complete at the end of the SP, although thresholds were still significantly elevated. We conclude that the SP is largely due to a suppression of voluntary motor drive, while the threshold elevation is a different inhibitory phenomenon that is of less importance for the generation of the SP, at least in its late part. It is argued that the pathway of fast cortico-spinal fibers activated by TMS is partially different from the pathway involved in the maintenance of tonic voluntary muscle activation.

Changes in 5-HT1A and NMDA binding sites by a single rapid transcranial magnetic stimulation procedure in rats

The effects of a single rapid-rate transcranial magnetic stimulation (rTMS) exposure on neurotransmitter binding sites in the rat brain 24 h after the stimulation were examined. Quantification by in vitro-autoradiography showed no differences for 3H-paroxetine binding (5-HT uptake sites) between rTMS-treated, sham and control animals. In contrast, the number of 5-HT1A binding sites (labeled with 3H-8-OH-DPAT) were selectively increased in the rTMS-group with significantly higher BMAX values in the frontal cortex, the cingulate cortex, and the anterior olfactory nucleus. A non-specific increase in NMDA binding sites (labeled with 125I-MK-801) in rTMS and sham animals was observed in the hippocampal formation. A selective increase of these binding sites after rTMS was detected in the ventromedial hypothalamus, the basolateral amygdala and layers 5-6 of the parietal cortex. These findings imply that a single rTMS exposure can result in persistent effects on NMDA and 5-HT1A binding sites even 24 h after stimulation and therefore may be of relevance with respect to the therapeutic action of rTMS reported from clinical studies.

Delay in simple reaction time after focal transcranial magnetic stimulation of the human brain occurs at the final motor output stage

It is known that the execution of the motor response in a simple reaction time (RT) task can be delayed by transcranial magnetic stimulation (TMS). This paper is aimed at determining the site of action where the delay in RT occurs. A delay in RT was obtained only at those TMS sites over the motor cortex contralateral to the responding hand, which produced also a muscle twitch in the responding hand. The delay in RT covaried with the TMS intensity and increased the closer the time of TMS approached the expected time of reaction onset. Visual and auditory go-signals yielded similar delays in RT, but only when TMS was applied about 40 ms later for the visual go-signal, corresponding to the modality specific difference in RT control values. TMS of the supplementary motor area (SMA) immediately prior to the expected time of reaction onset produced no delay in RT. Spinal excitability as tested by F waves showed a pre-movement facilitation in the control trials which continued seemingly undisturbed during the period of RT delay after TMS. It can be concluded that the delay in RT is not due to SMA stimulation or spinal inhibition but depends on effective stimulation of neural elements in the motor cortex which are active very late in the process of movement release from the final motor output stage.