Nils Danner

Motor potentials evoked by navigated transcranial magnetic stimulation in healthy subjects.

Summary: Navigated transcranial magnetic stimulation (TMS) is a tool for targeted, noninvasive stimulation of cerebral cortex. Transcranial stimuli can depolarize neurons and evoke measurable effects which are unique in two ways: the effects are caused directly and without a consciousness of the subject, and, the responses from peripheral muscles provide a direct measure for the integrity of the whole motor pathway. The clinical relevance of the method has not always been fully exposed because localizing the optimal stimulation site and determining the optimal stimulation strength have been dependent on time-consuming experimentation and skill. Moreover, in many disorders it has been uncertain, whether the lack of motor responses is the result of true pathophysiological changes or merely because of unoptimal stimulation. We characterized the muscle responses from human primary motor cortex system by navigated TMS to provide normative values for the clinically relevant TMS parameters on 65 healthy volunteers aged 22 to 81 years. We delivered focal TMS pulses on the primary motor area (M1) and recorded muscle responses on thenar and anterior tibial muscles. Motor threshold, latencies and amplitudes of motor-evoked potentials, and silent period duration were measured. The correction of the motor-evoked potential latency for subjects’ height is provided. In conclusion, we provide a modified baseline of TMS-related parameters for healthy subjects. Earlier such large-scale baseline material has not been available.

Navigated transcranial magnetic stimulation and computed electric field strength reduce stimulator-dependent differences in the motor threshold

The motor threshold (MT) is a fundamental parameter for evaluating cortical excitability in transcranial magnetic stimulation (TMS) despite remarkable variation, both within, and between subjects. We intended to test whether the variation could be reduced by targeting the stimulation on-line and modeling the TMS-induced electric field on individual MR images. Navigated TMS was used to map the primary motor cortex for the representation area of the thenar muscles (abductor pollicis brevis) and to determine the MT. Thirteen healthy subjects participated in the study. To determine the between-subject variation, the MTs of nine subjects were measured with two different stimulators (comparison study). To study the individual variation, the MT measurement was repeated 20 times in four subjects always using the same stimulator (longitudinal study). In the comparison study, the MTs differed significantly between the two stimulators over all subjects (p<0.001), whereas the electric field strengths did not exhibit significant difference between the stimulators. Both, the MTs, and the electric field strengths showed similar variations, which were greater between subjects (comparison study) than within subjects (longitudinal study). In the comparison study, the distance between the locations of the two different coils on the scalp was significantly greater than the distance between the induced electric field maxima in the brain (p<0.001). We conclude that on-line navigation can be used to reduce the variation caused by different stimulator types and individual subject anatomy. In addition, cortical excitability can be evaluated by using computed electric field strength as well as stimulator-dependent MT.

Altered cortical inhibition in Unverricht—Lundborg type progressive myoclonus epilepsy (EPM1)

PURPOSE Progressive myoclonus epilepsies (PMEs) comprise a heterogeneous group of conditions characterized by an imbalance between excitatory and inhibitory neuronal mechanisms. The aim of this study was to assess the function of the motor cortex in Unverricht-Lundborg disease (ULD), progressive myoclonus epilepsy type 1 (EPM1). METHODS Genetically verified EPM1 patients (n=24) were studied and compared with healthy subjects (n=24). MRI-navigated transcranial magnetic stimulation (TMS) was used to study the function of the motor cortex. Motor threshold (MT) and cortical silent period (SP) were used as parameters to evaluate cortical excitability. Peripheral muscle responses were recorded at the thenar and hypothenar using on-line electromyography (EMG). RESULTS The normal shortening of SP duration with age was not evident in EPM1. Thus, older patients exhibited significantly prolonged SPs in comparison to healthy control subjects (p<0.05). The MTs, measured as both stimulator output percentage and induced electric field strength (EF), were significantly higher in EPM1 patients than in control subjects (p<0.001). The stimulation of the thenar caused a co-activation in the hypothenar with significantly higher amplitudes as compared to controls (p<0.05). CONCLUSIONS The prolongation of the SPs with age in EPM1 patients suggests a prevailing inhibitory tonus of the primary motor cortex (M1) as possible reactive mechanism to the disease. Antiepileptic drugs may contribute to the increased MT but do not affect the SP. The results and methodology of this study can lead to a better understanding of the pathophysiology and progression of EPM1.

Within-subject effect of coil-to-cortex distance on cortical electric field threshold and motor evoked potentials in transcranial magnetic stimulation

Motor threshold (MT) is a global measure of corticospinal excitability in transcranial magnetic stimulation determined over the primary motor cortex. It is commonly quantified as stimulation intensity (SI(MT)) able to induce a muscle response over certain threshold amplitude after 5/10 consecutive stimuli. SI(MT) is known to be dependent on coil-to-cortex distance (CCD). Hypothetically, the effect of CCD on SI(MT) could be removed by using a computed estimate for the stimulus-induced maximum cortical electric field at MT level (EF(MT)). The CCDs of six volunteers were artificially increased by a maximum of 16.3±3.5mm in 5-7 steps. At each CCD, the MT was estimated for the first dorsal interosseous muscle of the right hand as SI(MT) and EF(MT) as well as threshold curves. We found that SI(MT) correlated with CCD while EF(MT) did not. CCD had a significant effect on the within-subject variation in SI(MT) (F(6,28)=80.16, p<0.0001), but not in EF(MT) (F(6,28)=0.69, p=0.656) (analysis of variance). Furthermore, CCD had a minor, but significant within-subject effect on single-trial motor evoked potentials induced at different stimulation intensities, whereas the obvious major effect was caused by stimulation intensity. In conclusion, EF(MT) can be used as a measure of corticospinal excitability instead of SI(MT) to reduce the effect of within-subject variation in CCD.

Effect of individual anatomy on resting motor threshold – Computed electric field as a measure of cortical excitability

INTRODUCTION Transcranial magnetic stimulation (TMS) is used for assessing the excitability of cortical neurons and corticospinal pathways by determining the subject-specific motor threshold (MT). However, the MT is dependent on the TMS instrumentation and exhibits large variation. We hypothesized that between-subject differences in scalp-to-cortex distance could account for the variation in the MT. Computational electric field (EF) estimation could theoretically be applied to reduce the effect of anatomical differences, since it provides a more direct measure of corticospinal excitability. METHODS The resting MT of the thenar musculature of 50 healthy subjects (24 male and 26 female, 22-69 years) was determined bilaterally at the primary motor cortex with MRI-navigated TMS using monophasic and biphasic stimulation. The TMS-induced maximum EF was computed at a depth of 25 mm from the scalp (EF(25 mm)) and at the individual depth of the motor cortex (EF(cortex)) determined from MRI-scans. RESULTS All excitability parameters (MT, EF(25 mm) and EF(cortex)) correlated significantly with each other (p<0.001). EF(cortex) at MT intensity was 95±20 V/m for biphasic and 120±24 V/m for monophasic stimulation. The MT did not correlate with the anatomical scalp-to-cortex distance, whereas the coil-to-cortex distance was found to correlate positively with the MT and negatively with EF(cortex) (p<0.05). DISCUSSION In healthy subjects, the scalp-to-cortex distance is not a significant determinant of the MT, and thus the use of EF(cortex) does not offer substantial advantages. However, it provides a purposeful and promising tool for studying non-motor cortical areas or patient groups with possible disease-related anatomical alterations.

Motor cortical plasticity is impaired in Unverricht-Lundborg disease.

Patients with Unverricht–Lundborg disease, also referred to as progressive myoclonus epilepsy type 1, exhibit widespread motor symptoms and signs in addition to epileptic seizures, which suggest abnormal excitability of the primary motor pathways. To explore the plasticity of the sensory–motor cortex, we employed a modern neurophysiological method, the paired associative stimulation protocol, which resembles the concept of long‐term potentiation of experimental studies. Seven patients with genetically verified Unverricht–Lundborg disease and 13 healthy control subjects were enrolled in the study to characterize cortical sensory–motor plasticity. In the study protocol, peripheral electric median nerve stimulation preceded navigated transcranial magnetic stimulation targeted to the representation area of thenar musculature on the contralateral primary motor cortex. The protocol consisted of 132 transcranial magnetic stimulation trials at 0.2 Hz, preceded by peripheral sensory stimulation at 25 ms. Motor‐evoked potential amplitudes were analyzed at baseline and after the paired associative stimulation protocol at an intensity of 130% of the individual motor threshold. The patients with Unverricht–Lundborg disease exhibited an average decrease of 15% in motor‐evoked potential amplitudes 30 minutes after paired associative stimulation, whereas in the control subjects, a significant increase (101%) was observed (P < .05), as expected. The results indicate a lack of normal cortical plasticity in Unverricht–Lundborg disease, which stresses the role of abnormal motor cortical functions or sensorimotor integration as possible pathophysiological contributors to the motor symptoms. The impaired cortical plasticity may be associated with the previously reported structural and physiological abnormalities of the primary motor cortex.

Refining the phenotype of Unverricht-Lundborg disease (EPM1): A population-wide Finnish study

Objective: This Finnish nationwide study aimed to refine the clinical phenotype variability and to identify factors that could explain the extensive variability in the clinical severity of the symptoms observed among patients with Unverricht-Lundborg disease (progressive myoclonus epilepsy type 1 [EPM1]) homozygous for the dodecamer expansion mutation in the cystatin B (CSTB) gene. Methods: The study population consisted of 66 (33 men and 33 women) patients with genetically confirmed EPM1 homozygous for the CSTB expansion mutation for whom the sizes of the expanded alleles were determined. The clinical evaluation included videorecorded Unified Myoclonus Rating Scale and retrospectively collected medical history. The navigated transcranial magnetic stimulation test was used to determine motor threshold (MT) and silent period (SP) of the motor cortex. Results: An earlier age at onset for EPM1 and longer disease duration were associated with more severe action myoclonus, lower performance IQ, increased MT, and prolonged SP. The number of dodecamer repeats in CSTB alleles varied between 38 and 77. On average, the size of the longer expanded alleles of patients was independently associated with MT, but exerted only a modulating effect on age at onset, myoclonus severity, and SP. Conclusions: As a group, earlier disease onset and longer duration are associated with more severe phenotype. Even though the vast majority of patients with EPM1 have a uniform genetic mutation, the actual size of the longer CSTB expansion mutation allele is likely to have a modulating effect on the age at disease onset, myoclonus severity, and cortical neurophysiology.

Alterations of motor cortical excitability and anatomy in Unverricht‐Lundborg disease

Unverricht‐Lundborg disease is the most common form of progressive myoclonus epilepsies. In addition to generalized seizures, it is characterized by myoclonus, which usually is the most disabling feature of the disease. Classically, the myoclonus has been attributed to increased excitability of the primary motor cortex. However, inhibitory cortical phenomena have also been described along with anatomical alterations. We aimed to characterize the relationship between the excitability and anatomy of the motor cortex and their association with the severity of the clinical symptoms. Seventy genetically verified patients were compared with forty healthy controls. The symptoms were evaluated with the Unified Myoclonus Rating Scale. Navigated transcranial magnetic stimulation was applied to characterize the excitability of the primary motor cortex by determining the motor thresholds and cortical silent periods. In addition, the induced cortical electric fields were estimated using individual scalp‐to‐cortex distances measured from MRIs. A cortical thickness analysis was performed to elucidate possible disease‐related anatomical alterations. The motor thresholds, cortical electric fields, and silent periods were significantly increased in the patients (P < 0.01). The silent periods correlated with the myoclonus scores (r = 0.48 to r = 0.49, P < 0.001). The scalp‐to‐cortex distance increased significantly with disease duration (r = 0.56, P < 0.001) and correlated inversely with cortical thickness. The results may reflect the refractory nature of the myoclonus and indicate a possible reactive cortical inhibitory mechanism to the underlying disease process. This is the largest clinical series on Unverricht‐Lundborg disease and the first study describing parallel pathophysiological and structural alterations associated with the severity of the symptoms.

Primary motor cortex alterations in a compound heterozygous form of Unverricht–Lundborg disease (EPM1)

PURPOSE Unverricht-Lundborg disease (EPM1) is the most common form of progressive myoclonus epilepsies. The genetic background is a homozygous dodecamer repeat extension mutation in the cystatin B (CSTB) gene. However, mutations occurring in a compound heterozygous form with the expansion mutation have also been reported. In Finland, we have found five EPM1 patients compound heterozygous for the dodecamer repeat expansion and the c.202C>T mutation in the CSTB gene (chEPM1). There are no previous clinical or neurophysiological studies on these patients. Thus, we aimed to characterize possible functional alterations in primary motor cortical areas. METHODS Five chEPM1 patients were compared with homozygous patients and healthy controls. All patients underwent a clinical evaluation to characterize the severity of the symptoms. Navigated transcranial magnetic stimulation (TMS) was used to study cortical excitability by determining the motor thresholds (MT), silent periods (SP) and motor evoked potential (MEP) characteristics. Continuous electroencephalography (EEG) was recorded during the measurements. Voxel-based MRI morphometry (VBM) was used to study differences in gray matter volume. RESULTS The chEPM1 patients exhibited an inhibitory cortical tonus reflected as elevated MTs and prolonged SPs. EEG showed spontaneous focal epileptiform activity in centro-temporal and parietal areas in addition to more widespread and generalized discharges. VBM revealed loss of gray matter volume in primary motor cortical areas and thalami. DISCUSSION The chEPM1 patients exhibited functional and structural changes in primary motor cortical areas. The functional changes are more profound as compared to homozygous patients, suggesting a neurophysiological background for the more severe clinical symptoms.

Locating and Outlining the Cortical Motor Representation Areas of Facial Muscles With Navigated Transcranial Magnetic Stimulation.

BACKGROUND Navigated transcranial magnetic stimulation (nTMS) has become established as an accurate noninvasive technique for mapping the functional motor cortex for the representation areas of upper and lower limb muscles but not yet for facial musculature. OBJECTIVE To characterize the applicability and clinical impact of using nTMS to map cortical motor areas of facial muscles in healthy volunteers and neurosurgical tumor patients. METHODS Eight healthy volunteers and 12 patients with tumor were studied. The motor threshold (MT) was determined for the abductor pollicis brevis and mentalis muscles. The lateral part of the motor cortex was mapped with suprathreshold stimulation intensity, and motor evoked potentials were recorded from several facial muscles. The patient protocol was modified according to the clinical indication. RESULTS In all healthy subjects, motor evoked potentials were elicited in the mentalis (mean latency, 13.4 milliseconds) and orbicularis oris (mean latency, 12.6 milliseconds) muscles. At 110% of MT of the mentalis, the motor evoked potentials of facial muscles were elicited mainly in the precentral gyrus but also from one gyrus anterior and posterior to it. The cortical areas applicable for mapping were limited by an artifact attributable to direct peripheral nerve stimulation. The mapping protocol was successful in 10 of 12 tumor patients at locating the representation area of the lower facial muscles. The MT of the facial muscles was significantly higher than that of the abductor pollicis brevis. CONCLUSION nTMS is an applicable and clinically beneficial noninvasive method to preoperatively map the cortical representation areas of the facial muscles in the lower part of the face. Instead of using the MT of the abductor pollicis brevis, the stimulus intensity during mapping should be proportioned to the MT of a facial muscle.