Alain Kaelin-Lang

A practical guide to diagnostic transcranial magnetic stimulation: Report of an IFCN committee

Transcranial magnetic stimulation (TMS) is an established neurophysiological tool to examine the integrity of the fast-conducting corticomotor pathways in a wide range of diseases associated with motor dysfunction. This includes but is not limited to patients with multiple sclerosis, amyotrophic lateral sclerosis, stroke, movement disorders, disorders affecting the spinal cord, facial and other cranial nerves. These guidelines cover practical aspects of TMS in a clinical setting. We first discuss the technical and physiological aspects of TMS that are relevant for the diagnostic use of TMS. We then lay out the general principles that apply to a standardized clinical examination of the fast-conducting corticomotor pathways with single-pulse TMS. This is followed by a detailed description of how to examine corticomotor conduction to the hand, leg, trunk and facial muscles in patients. Additional sections cover safety issues, the triple stimulation technique, and neuropediatric aspects of TMS.

Modulation of human corticomotor excitability by somatosensory input

In humans, somatosensory stimulation results in increased corticomotoneuronal excitability to the stimulated body parts. The purpose of this study was to investigate the underlying mechanisms. We recorded motor evoked potentials (MEPs) to transcranial magnetic stimulation (TMS) from abductor pollicis brevis (APB), first dorsal interosseous (FDI), and abductor digiti minimi (ADM) muscles. MEP amplitudes, recruitment curves (RC), intracortical inhibition (ICI), intracortical facilitation (ICF), resting (rMT) and active motor thresholds (aMT) were recorded before and after a 2‐h period of ulnar nerve electrical stimulation at the wrist. Somatosensory input was monitored by recording somatosensory evoked potentials. To differentiate excitability changes at cortical vs. subcortical sites, we recorded supramaximal peripheral M‐responses and MEPs to brainstem electrical stimulation (BES). In order to investigate the involvement of GABAergic mechanisms, we studied the influence of lorazepam (LZ) (a GABAA receptor agonist) relative to that of dextromethorphan (DM) (an NMDA receptor antagonist) and placebo in a double‐blind design. We found that somatosensory stimulation increased MEP amplitudes to TMS only in the ADM, confirming a previous report. This effect was blocked by LZ but not by either DM or placebo and lasted between 8 and 20 min in the absence of (i) changes in MEPs elicited by BES, (ii) amplitudes of early somatosensory‐evoked potentials or (iii) M‐responses. We conclude that somatosensory stimulation elicited a focal increase in corticomotoneuronal excitability that outlasts the stimulation period and probably occurs at cortical sites. The antagonistic effect of LZ supports the hypothesis of GABAergic involvement as an operating mechanism.

Directional deep brain stimulation: an intraoperative double-blind pilot study

Deep brain stimulation of different targets has been shown to drastically improve symptoms of a variety of neurological conditions. However, the occurrence of disabling side effects may limit the ability to deliver adequate amounts of current necessary to reach the maximal benefit. Computed models have suggested that reduction in electrode size and the ability to provide directional stimulation could increase the efficacy of such therapies. This has never been demonstrated in humans. In the present study, we assess the effect of directional stimulation compared to omnidirectional stimulation. Three different directions of stimulation as well as omnidirectional stimulation were tested intraoperatively in the subthalamic nucleus of 11 patients with Parkinsons disease and in the nucleus ventralis intermedius of two other subjects with essential tremor. At the trajectory chosen for implantation of the definitive electrode, we assessed the current threshold window between positive and side effects, defined as the therapeutic window. A computed finite element model was used to compare the volume of tissue activated when one directional electrode was stimulated, or in case of omnidirectional stimulation. All but one patient showed a benefit of directional stimulation compared to omnidirectional. A best direction of stimulation was observed in all the patients. The therapeutic window in the best direction was wider than the second best direction (P = 0.003) and wider than the third best direction (P = 0.002). Compared to omnidirectional direction, the therapeutic window in the best direction was 41.3% wider (P = 0.037). The current threshold producing meaningful therapeutic effect in the best direction was 0.67 mA (0.3-1.0 mA) and was 43% lower than in omnidirectional stimulation (P = 0.002). No complication as a result of insertion of the directional electrode or during testing was encountered. The computed model revealed a volume of tissue activated of 10.5 mm(3) in omnidirectional mode, compared with 4.2 mm(3) when only one electrode was used. Directional deep brain stimulation with a reduced electrode size applied intraoperatively in the subthalamic nucleus as well as in the nucleus ventralis intermedius of the thalamus significantly widened the therapeutic window and lowered the current needed for beneficial effects, compared to omnidirectional stimulation. The observed side effects related to direction of stimulation were consistent with the anatomical location of surrounding structures. This new approach opens the door to an improved deep brain stimulation therapy. Chronic implantation is further needed to confirm these findings.

Effects of Somatosensory Stimulation on Use-Dependent Plasticity in Chronic Stroke

Background and Purpose— There is a need to develop strategies to enhance the beneficial effects of motor training, including use-dependent plasticity (UDP), in neurorehabilitation. Peripheral nerve stimulation (PNS) modulates motor cortical excitability in healthy humans and could influence training effects in stroke patients. Methods— We compared the ability of PNS applied to the (1) arm, (2) leg, and (3) idle time to influence training effects in the paretic hand in 7 chronic stroke patients. The end point measure was the magnitude of UDP. Results— UDP was more prominent with arm stimulation (increased by 22.8%) than with idle time (by 2.9%) or leg stimulation (by 6.4%). Conclusions— PNS applied to the paretic limb paired with motor training enhances training effects on cortical plasticity in stroke patients.

Enhancing the quality of studies using transcranial magnetic and electrical stimulation with a new computer-controlled system.

Transcranial magnetic (TMS) and electrical (TES) stimulation of the human brain have become useful tools in neurophysiological and neuropsychological research. Here we describe an integrated system that allows experimental control, data recording and analysis of neurophysiological and neuropsychological TMS and TES procedures (including motor thresholds, recruitment curves, intracortical inhibition and facilitation with paired pulses). The system uses a multifunction input/output board and a set of virtual instruments (VI) programmed with the Labview graphical programming language. It also includes online curve fitting of recruitment curves using the Boltzmann sigmoid function and monitoring of the preinnervation grade of the target muscle. Modules for neuropsychological stimulus presentation or faster repetitive stimulation can be easily added. This system yields more accurate data recording and analysis in a user friendly and unified environment.

Effect of levetiracetam on human corticospinal excitability

Objective: To investigate whether levetiracetam (LTC) alters corticospinal excitability in humans. Background: Although the antiepileptic activity of LTC is well recognized, its mechanism of action has yet to be determined. Transcranial magnetic stimulation (TMS) has been used to investigate the pharmacologic effects of various antiepileptic drugs on human corticospinal excitability. Methods: The authors performed TMS before and after double-blind administration of 3000 mg LTC or placebo in six healthy volunteers. TMS measurements included resting and active motor threshold (MT), recruitment curve of motor-evoked potential amplitudes, intracortical inhibition, and facilitation using the paired-pulse technique and silent period. F-wave and compound muscle action potential (CMAP) were also measured. Results: In recruitment curve measurements, motor-evoked potential amplitude was reduced for LTC with high stimulation intensity (130% and 140% of resting MT) compared with placebo (p < 0.05 and p < 0.01), but not with relatively low stimulation intensity (110% and 120%). The changes in other TMS measurements as well as F-wave and CMAP after LTC did not differ significantly from those observed after placebo administration. Conclusion: These results suggest that LTC reduces the corticospinal neuronal response to magnetic stimulation, preferentially affecting less excitable neurons. The lack of change in F-wave and CMAP suggests that this effect is mainly derived from the motor cortex.

Expression of adenosine A2a receptors gene in the olfactory bulb and spinal cord of rat and mouse

The expression of adenosine A2a receptors (A2aR) in the mammalian striatum is well known. In contrast the exact distribution of A2aR in other regions of the central nervous system remains unclear. The aim of this study was to investigate the A2aR gene expression in the rat olfactory bulb and spinal cord, two regions which are seldom included in mapping studies. Secondly, we compared the A2aR expression in the rat and in the mouse brain. Hybridization histochemistry was performed with an S35-labelled radioactive oligonucleotide probe. The results show strong expression of A2aR in the mouse and rat striatum in accordance with previous reports. In the olfactory bulb a weak but specific expression of A2aR was found in the granular cell layer in both species. In contrast, no significant expression of the A2aR gene was observed in other parts of the brain or the rat spinal cord. The presence of the A2aR in the mammalian olfactory bulb suggests a functional role for this receptor in olfaction.

Localization of DJ-1 mRNA in the mouse brain

DJ-1 is mutated in autosomal recessive, early onset Parkinsons disease but the exact localization of the DJ-1 gene product in the mammalian brain is largely unknown. We aimed to evaluate the DJ-1 mRNA expression pattern in the mouse brain. Serial coronal sections of brains of five male and five female adult mice were investigated by using in situ hybridization with a DJ-1 specific 35S-labeled oligonucleotide probe. Hybridized sections were analyzed after exposure to autoradiography films and after coating with a photographic emulsion. DJ-1 was heterogeneously expressed throughout the mouse central nervous system. A high expression of DJ-1 mRNA was detected in neuronal and non-neuronal populations of several structures of the motor system such as the substantia nigra, the red nucleus, the caudate putamen, the globus pallidus, and the deep nuclei of the cerebellum. Furthermore, DJ-1 mRNA was also highly expressed in non-motor structures including the hippocampus, the olfactory bulb, the reticular nucleus of the thalamus, and the piriform cortex. The high expression of DJ-1 mRNA in brain regions involved in motor control is compatible with the occurrence of parkinsonian symptoms after DJ-1 mutations. However, expression in other regions indicates that a dysfunction of DJ-1 may contribute to additional clinical features in patients with a DJ-1 mutation.

Expression of adenosine A2a receptor gene in rat dorsal root and autonomic ganglia

The adenosine A2a receptors (A2aR) play an important role in the purinergic mediated neuromodulation. The presence of A2aR in the brain is well established. In contrast, little is known about their expression in the periphery. The purpose of this study was to investigate the expression of A2aR gene in the autonomic (otic, sphenopalatine, ciliary, cervical superior ganglia and carotid body) and in the dorsal root ganglia of normal rat. Hybridization histochemistry with S35-labelled radioactive oligonucleotide probes was used. An expression of A2aR gene was found in the large neuronal cells of the rat dorsal root ganglia. The satellite cells showed no expression of A2aR gene. In the superior cervical ganglion, isolated ganglion cells expressed A2aR. In the carotid body clusters of cells with a strong A2aR gene expression were found. In contrast, the ciliary and otic ganglia did not expressed A2aR gene, and only few small sized A2aR expressing cells were demonstrated in the sphenopalatine ganglion. The discrete distribution of A2aR gene expression in the peripheral nervous system speaks for a role of this receptor in the purinergic modulation of sensory information as well as in the sympathetic nervous system.

Motor sequence learning performance in Parkinson's disease patients depends on the stage of disease

It is still unclear, whether patients with Parkinsons disease (PD) are impaired in the incidental learning of different motor sequences in short succession, although such a deficit might greatly impact their daily life. The aim of this study was thus to clarify the relation between disease parameters of PD and incidental motor learning of two different sequences in short succession. Results revealed that the PD patients were able to acquire two sequences in short succession but needed more time than healthy subjects. However, both the severity of axial manifestations, as assessed on a subsection of the Unified Parkinsons Disease Rating Scale III (UPDRS III) and the Hoehn and Yahr score, and the levodopa-equivalent dose (LED) were negatively correlated with the sequence learning performance. These findings indicate that, although PD patients are able to learn two sequences in short succession, they need more time and their overall sequence learning performance is strongly correlated with the stage of disease.