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OBJECTIVE To develop and test wearable monitoring of surface electromyography and motion for detection and quantification of positive and negative myoclonus in patients with progressive myoclonic epilepsy type 1 (EPM1). METHODS Surface electromyography and three-dimensional acceleration were measured from 23 EPM1 patients from the biceps brachii (BB) of the dominant and the extensor digitorum communis (EDC) of the non-dominant arm for 48 hours. The patients self-reported the degree of myoclonus in a diary once an hour. Severity of myoclonus with action was evaluated by using video-recorded Unified Myoclonus Rating Scale (UMRS). Correlations of monitored parameters were quantified with the UMRS scores and the self-reported degrees of myoclonus. RESULTS The monitoring-based myoclonus index correlated significantly (p

Progressive myoclonic epilepsy type 1 (EPM1) is caused by biallelic alterations in the CSTB gene, most commonly dodecamer repeat expansions. Although transcranial magnetic stimulation (TMS)-induced long-interval intracortical inhibition (LICI) was previously reported to be normal in EPM1, short-interval intracortical inhibition (SICI) was reduced. We explored the association between these measures and the clinical and genetic features in a separate group of patients with EPM1.TMS combined with electromyography was performed under neuronavigation. LICI was induced with an inter-stimulus interval (ISI) of 100 ms, and SICI with ISIs of 2 and 3 ms, and their means (mSICIs) were expressed as the ratio of conditioned to unconditioned stimuli. LICI and mSICI were compared between patients and controls. Nonparametric correlation was used to study the association between inhibition and parameters of clinical severity, including the Unified Myoclonus Rating Scale (UMRS); among patients with EPM1 due to biallelic expansion repeats, also the association with the number of repeats was assessed.The study protocol was completed in 19 patients (15 with biallelic expansion repeats and 4 compound heterozygotes), and 7 healthy, age- and sex-matched control participants. Compared to controls, patients demonstrated significantly less SICI (median mSICI ratio 1.18 vs 0.38; p .001). Neither LICI nor SICI was associated with parameters of clinical severity. In participants with biallelic repeat expansions, the number of repeats in the more affected allele (greater repeat number [GRN]) correlated with LICI (rho = 0.872; p .001) and SICI (rho = 0.689; p = .006).Our results strengthen the finding of deranged γ-aminobutyric acid (GABA)ergic inhibition in EPM1. LICI and SICI may have use as markers of GABAergic impairment in future trials of disease-modifying treatment in this condition. Whether a higher number of expansion repeats leads to greater GABAergic impairment warrants further study.

Background Idiopathic normal pressure hydrocephalus (iNPH) is a neurodegenerative disease with a characteristic symptom triad of gait disturbance, cognitive decline, and incontinence. Recently, also dysfunctions in upper limbs have been described in iNPH and reported to improve after shunt surgery. We aim to describe the role of upper limb motor function in the clinical assessment of iNPH patients and its influence on activities of daily living (ADL). Methods Seventy-five consecutive patients with probable iNPH were studied pre-operatively and at 3 and 12 months after shunt surgery. The pre-operative evaluation included lumbar drainage of cerebrospinal fluid (tap test). Motor functions were assessed in upper and lower limbs with Grooved Pegboard Test (GPT), Box & Block Test (BBT), Total Score of Gait (TSG), and balance test. ADL was assessed with Barthel’s index and cognition in accordance with the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Results Patients showed improvement in all motor tests and ADL at 3 months after shunt surgery. The improvement remained stable during the 12-month post-operative follow-up. The motor function tests correlated with each other and with ADL. Conclusions A 3-month follow-up period after shunt surgery is adequate to show improvement in motor tasks, and a positive outcome will last for at least 12 months. A shunt-responsive dysfunction of upper limb motor performance plays a major role in ADL of iNPH patients. Therefore, we suggest an evaluation of upper limb motor performance to be included in routine evaluation of iNPH patients.

Objective: We conducted an open-label cross-over study assessing the global effect of two high-frequency protocols of electric-field navigated repetitive transcranial magnetic stimulation (rTMS) targeted to functional facial motor cortex and comparing their efficacy and tolerability in patients with chronic facial pain. Outcome predictors were also assessed. Methods: We randomized twenty consecutive patients with chronic facial pain (post-traumatic trigeminal neuropathic pain, n=14; persistent idiopathic facial pain, n=4; secondary trigeminal neuralgia, n=2) to receive two distinct 5-day rTMS interventions (10Hz, 2400 pulses and 20Hz, 3600 pulses) separated by six weeks. The target area was assessed by mapping of lower face representation. The primary endpoint was the change in weekly mean of pain intensity (numeric rating scale, NRS) between the baseline and therapy week (1st week), and follow-up weeks (2nd and 3rd weeks) for each rTMS intervention. Response was defined using a combination scale including the patient’s global impression of change and continuance with maintenance treatment. Results: Overall, pain intensity NRS decreased from 7.4 at baseline to 5.9 ten weeks later, after the second rTMS intervention (p=0.009). The repetition of the treatment had a significant effect (F=4.983, p=0.043) indicating that the NRS scores are lower during the second four weeks period. Eight (40%) patients were responders, 4 (20%) exhibited a modest effect, 4 (20%) displayed no effect, and 4 (20%) experienced worsening of pain. High disability and high pain intensity (>7) predicted a better outcome (p=0.043 and p=0.045). Female gender, shorter duration of pain and low Beck Anxiety Inventory scores showed a trend towards a better outcome (p=0.052, 0.060 and 0.055, respectively). Conclusions: High-frequency rTMS targeted to face M1 alleviates treatment resistant chronic facial pain. Repeated treatment improves the analgesic effect. A protocol with higher frequency (above 10Hz), longer session duration (more than 20 minutes) and higher number of pulses (above 2400 pulses/session) did not improve the outcome. The results support early consideration of rTMS.

Repetition suppression (RS) is the adaptation of the neural activity in response to a repeated external stimulus. It has been proposed that RS occurs at the thalamo-cortical level, hence activating a feedback loop to the cortex in order to counteract with the repeated motor cortical activation. In this study, to elucidate the common modulators between the RS and the inhibitory/facilitatory cortical networks, two TMS paradigms were applied, i.e. the characteristic long-interval intracortical inhibition (LICI) and the I1-wave timed short-interval intracortical facilitation (SICF). Since LICI is a local intracortical inhibitory phenomenon affecting cortical excitation over a long interval like the RS, the interaction between RS and LICI was tested. As the I1-wave timed SICF is likely not affected by inhibitory modulation, the appearance of the RS with respect to SICF was investigated. Non-linear interaction between LICI and RS was observed, while I1-wave timed SICF facilitated all MEP responses of RS by a common offset still preserving the RS. These findings implicate that the underlying mechanism for the observed interaction is likely contributed to the activation of the negative thalamo-cortical feedback loop represented by the RS, most likely at the cortical level.

Navigated transcranial magnetic stimulation (nTMS) has developed into a reliable non-invasive clinical and scientific tool over the past decade. Specifically, it has undergone several validating clinical trials that demonstrated high agreement with intraoperative direct electrical stimulation (DES), which paved the way for increasing application for the purpose of motor mapping in patients harboring motor-eloquent intracranial neoplasms. Based on this clinical use case of the technique, in this article we review the evidence for the feasibility of motor mapping and derived models (risk stratification and prediction, nTMS-based fiber tracking, improvement of clinical outcome, and assessment of functional plasticity), and provide collected sets of evidence for the applicability of quantitative mapping with nTMS. In addition, we provide evidence-based demonstrations on factors that ensure methodological feasibility and accuracy of the motor mapping procedure. We demonstrate that selection of the stimulation intensity (SI) for nTMS and spatial density of stimuli are crucial factors for applying motor mapping accurately, while also demonstrating the effect on the motor maps. We conclude that while the application of nTMS motor mapping has been impressively spread over the past decade, there are still variations in the applied protocols and parameters, which could be optimized for the purpose of reliable quantitative mapping.

The development of the organization of the motor representation areas in children and adolescents is not well-known. This cross-sectional study aimed to provide an understanding for the development of the functional motor areas of the upper extremity muscles by studying healthy right-handed children (6–9 years, n = 10), preadolescents (10–12 years, n = 13), adolescents (15–17 years, n = 12), and adults (22–34 years, n = 12). The optimal representation site and resting motor threshold (rMT) for the abductor pollicis brevis (APB) were assessed in both hemispheres using navigated transcranial magnetic stimulation (nTMS). Motor mapping was performed at 110% of the rMT while recording the EMG of six upper limb muscles in the hand and forearm. The association between the motor map and manual dexterity (box and block test, BBT) was examined. The mapping was well-tolerated and feasible in all but the youngest participant whose rMT exceeded the maximum stimulator output. The centers-of-gravity (CoG) for individual muscles were scattered to the greatest extent in the group of preadolescents and centered and became more focused with age. In preadolescents, the CoGs in the left hemisphere were located more laterally, and they shifted medially with age. The proportion of hand compared to arm representation increased with age (p = 0.001); in the right hemisphere, this was associated with greater fine motor ability. Similarly, there was less overlap between hand and forearm muscles representations in children compared to adults (p

Motor functions improve during childhood and adolescence, but little is still known about the development of cortical motor circuits during early life. To elucidate the neurophysiological hallmarks of motor cortex development, we investigated the differences in motor cortical excitability and connectivity between healthy children, adolescents, and adults by means of navigated suprathreshold motor cortex transcranial magnetic stimulation (TMS) combined with high-density electroencephalography (EEG). We demonstrated that with development, the excitability of the motor system increases, the TMS-evoked EEG waveform increases in complexity, the magnitude of induced activation decreases, and signal spreading increases. Furthermore, the phase of the oscillatory response to TMS becomes less consistent with age. These changes parallel an improvement in manual dexterity and may reflect developmental changes in functional connectivity. Hum Brain Mapp 38:2599-2615, 2017. © 2017 Wiley Periodicals, Inc.

The combination of transcranial magnetic stimulation with simultaneous electroencephalography (TMS–EEG) offers direct neurophysiological insight into excitability and connectivity within neural circuits. However, there have been few developmental TMS–EEG studies to date, and they all have focused on primary motor cortex stimulation. In the present study, we used navigated high‐density TMS–EEG to investigate the maturation of the superior frontal cortex (dorsal premotor cortex [PMd]), which is involved in a broad range of motor and cognitive functions known to develop with age. We demonstrated that reactivity to frontal cortex TMS decreases with development. We also showed that although frontal cortex TMS elicits an equally complex TEP waveform in all age groups, the statistically significant between‐group differences in the topography of the TMS‐evoked peaks and differences in current density maps suggest changes in effective connectivity of the right PMd with maturation. More generally, our results indicate that direct study of the brain's excitability and effective connectivity via TMS–EEG co‐registration can also be applied to pediatric populations outside the primary motor cortex, and may provide useful information for developmental studies and studies on developmental neuropsychiatric disorders. peerReviewed

Motor functions are frequently impaired in Asperger syndrome (AS). In this study, we examined the motor cortex structure and function using navigated transcranial magnetic stimulation (nTMS) and voxel-based morphometry (VBM) and correlated the results with the box and block test (BBT) of manual dexterity and physical activity in eight boys with AS, aged 8–11 years, and their matched controls. With nTMS, we found less focused cortical representation areas of distinct hand muscles in AS. There was hemispheric asymmetry in the motor maps, silent period duration and active MEP latency in the AS group, but not in controls. Exploratory VBM analysis revealed less gray matter in the left postcentral gyrus, especially in the face area, and less white matter in the precentral area in AS as compared to controls. On the contrary, in the right leg area, subjects with AS displayed an increased density of gray matter. The structural findings of the left hemisphere correlated negatively with BBT score in controls, whereas the structure of the right hemisphere in the AS group correlated positively with motor function as assessed by BBT. These preliminary functional (neurophysiological and behavioral) findings are indicative of asymmetry, and co-existing structural alterations may reflect the motor impairments causing the deteriorations in manual dexterity and other motor functions commonly encountered in children with AS. Electronic supplementary material The online version of this article (10.1007/s10548-019-00704-0) contains supplementary material, which is available to authorized users.

Corticospinal excitability (CSE) is modulated by stroke-induced lesions affecting the brain. This modulation is known to be dependent on the timing of the evaluation, and strongest abnormalities are often found in the acute stage. Our study aimed to characterize changes in CSE asymmetry between the affected and the unaffected hemisphere (AH and UH) during the first month after stroke onset and at 6 month follow-up. Neuronavigated transcranial magnetic stimulation (nTMS) was used to assess the CSE of the abductor pollicis brevis (APB) muscle of the hand and tibialis anterior (TA) muscle of the leg in 16 patients over 5 time-points. AH excitability recovered significantly during 6 months, whereas interhemispheric asymmetry remained significant up to 1 month post-stroke in the APB muscle. Greater initial CSE was associated with good motor function at 6 months. The motor cortical excitatory recovery initiated within week of the stroke and was most prominent within 1 month after stroke onset. Lesion size correlated with CSE of the UH at 10 days, while overall severity of the symptoms correlated inversely with CSE of the AH. This study demonstrates the quick improvement in the CSE via estimation of interhemispheric asymmetry; however, the recovery in the asymmetry continues to normalize even after reaching the threshold for normal values in CSE. peerReviewed

Objective To assess the inter-hemispheric differences in neuronal function and structure of the motor cortex in a small group of chronic stroke patients having suffered a restricted ischemic lesion affecting hand motor representation. GABAergic intracortical inhibition, known to be affected by stroke lesion, was also investigated. Methods Eight patients exhibiting little or no motor impairment were studied using transcranial magnetic stimulation (TMS) and diffusion weighted imaging (DWI) >15months from diagnosis. Resting motor threshold (MT) for 50μV and 2mV motor evoked potentials, and short-interval intracortical inhibition (SICI) were measured from hand muscles. Apparent diffusion coefficients (ADCs) were analyzed from the DWI for the primary motor cortex (M1), the supplementary motor area (SMA) and thalamus for reflecting changes in neuronal organization. Results The MTs did not differ between the affected (AH) and unaffected hemisphere (UH) in 50μV responses, while the MTs for 2mV responses were higher ( p =0.018) in AH. SICI was weakened in AH ( p =0.008). ADCs were higher in the affected M1 compared to the unaffected M1 ( p =0.018) while there were no inter-hemispheric differences in SMA or thalamus. Conclusions Inter-hemispheric asymmetry and neuronal organization demonstrated abnormalities in the M1. However, no confident inference can be made whether the observed alterations in neurophysiological and imaging measures have causal role for motor rehabilitation in these patients. Significance Neurophysiological changes persist and are detectable using TMS years after stroke even though clinical symptoms have normalized.

Background Transcranial magnetic stimulation (TMS) can evaluate cortical excitability and integrity of motor pathways via TMS-induced responses. The responses are affected by the orientation of the stimulated neurons with respect to the direction of the TMS-induced electric field. Therefore, besides being a functional imaging tool, TMS may potentially assess the local structural properties. Yet, TMS has not been used for this purpose. New method A novel principle to evaluate the relation between function and structure of the motor cortex is presented. This functional anisotropy is evaluated by an anisotropy index (AI), based on motor evoked potential amplitudes induced with different TMS coil orientations, i.e. different electric field directions at a cortical target. To compare the AI with anatomical anisotropy in an explorative manner, diffusion tensor imaging-derived fractional anisotropy (FA) was estimated at different depths near the stimulation site. Results AI correlated inversely with cortical excitability through the TMS-induced electric field at motor threshold level. Further, there was a trend of negative correlation between AI and FA. Comparison with existing methods None of the existing methods alone can detect the relationship between direct motor cortex activation and local neuronal structure. Conclusions The AI appears to provide information on the functional neuronal anisotropy of the motor cortex by coupling neurophysiology and neuroanatomy within the stimulated cortical region. The AI could prove useful in the evaluation of neurological disorders and traumas involving concurrent structural and functional changes in the motor cortex. Further studies on patients are needed to confirm the usability of AI.

Purpose: Corticospinal silent period (SP) may be interrupted by a burst of muscle activity followed by a second (late) SP, generally assumed to be a continuation from the primary SP. Our objective was to characterize the input–output behavior of the late SP. Methods: Transcranial magnetic stimulation was applied on the cortical representation area of the right-hand muscles of 12 healthy subjects. Single-pulse transcranial magnetic stimulation was given with varying stimulation intensities normalized to the individual resting motor threshold (60% to 130% of the resting motor threshold) during voluntary muscle contraction. Electromyogram was recorded from first dorsal interosseous and abductor pollicis brevis muscles. Primary and late SPs were analyzed as absolute SPs, and input–output characteristics were assessed. Results: The late SP exhibited fundamentally different input–output characteristics from that of the primary SP. The late SP most likely presented itself at stimulation intensities of 90% to 100% of the resting motor threshold. Conclusions: Different input–output characteristics of the late SP compared with the primary SP indicate that the late SP possess mechanisms different from the primary SP. The exact origin of the late SP remains unclear. Understanding the origins of the late SP could provide valuable insight on corticospinal inhibitory processes.

Article, Cortical motor mapping in pre-surgical applications can be performed using motor evoked potential (MEP) amplitudes evoked with neuronavigated transcranial magnetic stimulation. The MEP latency, which is a more stable parameter than the MEP amplitude, has not so far been utilized in motor mapping. The latency, however, may provide information about the stress in damaged motor pathways, e.g. compression by tumors, which cannot be observed from the MEP amplitudes. Thus, inclusion of this parameter could add valuable information to the presently used technique of MEP amplitude mapping. In this study, the functional cortical representations of first dorsal interosseous (FDI), abductor pollicis brevis (APB) and abductor digiti minimi (ADM) muscles were mapped in both hemispheres of ten healthy righthanded volunteers. The cortical muscle representations were evaluated by the area and centre of gravity (CoG) by using MEP amplitudes and latencies. As expected, the latency and amplitude CoGs were congruent and were located in the centre of the maps but in a few subjects, instead of a single centre, several loci with short latencies were observed. In conclusion, MEP latencies may be useful in distinguishing the cortical representation areas with the most direct pathways from those pathways with prolonged latencies. However, the potential of latency mapping to identify stressed motor tract connections at the subcortical level will need to be verified in future studies with patients., published version, http://purl.org/eprint/status/PeerReviewed

We characterized the maturation of the excitability of the motor cortex and corticospinal tract from childhood to adulthood using electric field (EF) navigated TMS and correlated the results with manual dexterity.Both hemispheres of healthy right-handed children (6-9 years, n=10), preadolescents (10-12 years, n=13), adolescents (14-17 years, n=12) and young adults (22-34 years, n=12) of both genders were examined. The optimal cortical representation site and resting motor threshold (rMT) were determined for the abductor pollicis brevis muscle. Motor-evoked potential (MEP) latencies and amplitudes in relaxed and active states, input-output curves and silent period (SP) durations were determined. Manual dexterity was assessed with the Box and Block Test.rMT (in terms of maximal stimulator output or EF strength) decreased with age (P0.001) and stabilized when reaching adolescence. The MEP amplitude (P=0.037) and latency increased (P0.001) with age. Input-output curves showed age-dependent changes in several parameters. SP duration decreased with age (P0.001), and demonstrated hemispheric asymmetry in the children (P=0.030). Manual dexterity correlated negatively with rMT (P0.001).The excitation/inhibition balance develops with age and correlates with manual dexterity. Strong corticospinal inhibition was observed in the children and this was found to decrease with age. Interhemispheric asymmetry was only observed for SP duration in the children. Knowledge of normal development is crucial for the understanding of developmental disabilities and using estimates of effective EF may be advantageous in future pediatric studies.

Navigated transcranial magnetic stimulation (nTMS) is used for mapping muscle representations in the primary motor cortex. We used sulcus-aligned mapping and electric field (E-field) modeling to investigate the excitability of the motor hand area for further understanding the methodological limitations of nTMS.We studied 10 healthy volunteers to locate the cortical target eliciting the largest responses (the hotspot) in the first dorsal interosseous (FDI) muscle. Six additional targets were placed along the central sulcus at 5-mm distances. Resting motor thresholds (rMTs) and optimal coil orientations were determined at all targets, and a conventional motor mapping was conducted. The cortical E-fields, induced by stimulating the targets with rMT intensities and optimal coil orientations, were modeled in a realistic head geometry to estimate the activated cortical sites.The rMTs increased with increasing distance from the hotspot (p 0.001). The greatest motor-evoked potential (MEP) amplitudes occurred with the coil perpendicular to the sulcus and with the coil pointing towards the hotspot or the center of gravity of the motor map. The E-field strengths at the hotspot (99±26 V/m) remained above previously estimated thresholds for activation.Depending on the target location, optimal coil orientations may deviate significantly from the conventional perpendicular-to-sulcus angle, which is often assumed optimal. These orientations seem to maintain the E-field stable in the hand knob, regardless of the sulcal shape near the stimulated target.The coil orientation is crucial for the accuracy of motor mapping, and the apparent motor map may extend due to remote hotspot activation.

Introduction The reactivity to transcranial magnetic stimulation (TMS) changes with development. For example, motor cortex TMS-evoked EEG response decreases significantly with age. Structurally, the grey matter of the motor cortex reaches maturity by the age of 10 years, whereas the maturation of superficial white matter continues until early adulthood. The relationship between these concurrent structural and functional changes remains unclear. Methods We studied 10 healthy children (mean age 10.5), 10 adolescents (mean age 16.0 years) and 7 adults (mean age 26.5 years). Fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) were defined from diffusion weighted MRI data obtained from the left hand knob area on motor cortex. Cortical thickness (grey matter, GM) of the same area was assessed from T1-weighted MRI. TMS was focused on the left hand knob with a stimulation intensity of 110% of the resting motor threshold. EEG was recorded with a 60-channel TMS-compatible amplifier. The total EEG activity was assessed using the global mean field power (GMFP) calculated across all electrodes and the local activation as a local mean field power (LMFPleft) computed across the electrodes surrounding the left hand knob. GMFP and LMFPleft areas in the 15–500 ms post stimulus interval were used for statistical analyses. Between-group differences in TMS-EEG, GM and DTI metrics were analyzed with one-way ANOVA, and Pearson’s correlation was used to analyze correlations between functional and structural data. Results GMFP area (F = 12.65, p p p p > 0.8). GMFP and LMFPleft showed a significant correlation with MD (r = 0.421, p p p p p p Conclusion Previously, it has been suggested that smaller EEG responses in adults compared with those in children may be associated with GM loss in the pre- and peripubescent period. In this study, a developmental decline of TMS evoked global and local EEG responses correlated with the maturation of local short-range microstructural changes revealed by DTI rather than GM in the motor cortex. These results indicate that the development profile of TMS-evoked EEG activity may associate with maturation of the microstructure of underlying short range white matter connections.

Background Sex is known to influence brain development. However, sex differences in cortical excitability and their relationship to motor functions is unclear. Aim We examined the sex related differences in the degree of handedness, left and right motor cortex excitability and manual dexterity. Methods 28 healthy adolescents (age 16–19 years,19 girls) were studied. The degree of right-handedness was determined by the Waterloo Handedness Questionnaire. Motor threshold (MT) of the abductor pollicis brevis was measured on both hemispheres. Box and block test (BBT) was used for manual dexterity. Independent samples t-test was used in statistical analysis. Results There were no differences between sexes in handedness (mean score 27 for girls, 24 for boys) or manual dexterity (78 in girls, 74 in boys for right hand; 75 in girls, 72 in boys for left hand). MT of the right hemisphere was significantly higher in boys (46%) compared with girls (39%) (p = 0.012). The MT of the left hemisphere was also higher in boys (44%) compared with girls (39%) but this did not reach significance (p = 0.077). Discussion Although the handedness or the manual dexterity did not differ between the sexes, the cortical excitability was lower (as indicated by higher MT) in the right (non-dominant) hemisphere in boys. There is a well-established developmental decrease in MT from childhood to adolescence, and the higher MT in the right hemisphere may indicate that cortical development of the boys lags behind the girls. These preliminary results need more power to confirm the findings of sex differences.

Background The interhemispheric difference in cortical excitability and its relationship to motor functions is unclear. Aim We examined the relationship between handedness, left and right motor cortex excitability and fine and gross motor functions in adolescence. Methods 28 healthy adolescents (age 16–19 years, 19 girls) were studied. Handedness was determined by the Waterloo Handedness Questionnaire. Motor threshold (MT) of the abductor pollicis brevis was measured on both hemispheres using biphasic stimulation, and on the left hemisphere also with monophasic stimulation. Box and block test (BBT) was used for manual dexterity, line run and standing long jump for gross motor tasks. Spearman correlations and paired samples t -test were used. Results All subjects were right-handed; handedness score varied between 16 and 40. MT of the left hemisphere assessed with monophasic stimulation correlated with handedness (−0.516, p = 0.006) and remained a trend with biphasic waveform (−0.353, p = 0.065). MT was not different between hemispheres (40.3 in the left vs. 41.3% in the right hemisphere). BBT result was better with right hand (76.7 vs 73.9, p = 0.008). MT of the right hemisphere correlated with the BBT of the right hand ( r = −0.383, p = 0.044). MTs and gross motor tasks did not correlate. Discussion On the right, non-dominant hemisphere, higher excitability was associated with better ipsilateral performance. Gross motor functions may be more strongly related to muscle force and therefore do not correlate with cortical excitability. Clearly established right-handedness is related to higher excitability in the dominant hemisphere. Interestingly, this seems to partly depend on the stimulation type.

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.

a b s t r a c t Cortical silent period (cSP) is a short interruption in electromyography (EMG) during active muscle contraction induced with transcranial magnetic stimulation (TMS). The cSP is a measure of cortical inhi- bition and is believed to represent inhibitory interneuron effects on excited motor cortical areas. Several pathological conditions and pharmacological manipulations induce changes to cSP duration indicating alterations in intracortical inhibition. At present, it is common to manually analyse the cSP duration from measured EMG. However, to avoid inter-examiner effects on cSP interpretation and detection, as well as to allow for quick measurement online, automated routine would be preferable. In this study, we evaluate the feasibility of a straight-forward cSP detection routine based on analysing the rectified first derivative of the EMG signal following TMS. Previously measured cSPs of 54 healthy subjects were reanalysed manually by two of the authors and using the automated routine. Furthermore, we recruited one subject for whom the cSPs were induced with several stimulation intensities, and those cSPs were analysed manually by two of the authors as well as using the automated routine. We found that cSPs were detected correctly by the automated cSP detection routine, and agreement with manually analysed subject-specific mean cSPs was excellent (ICC = 0.992, p < 0.001). The inter-examiner variability was sim- ilar to the variability between manual and automated analysis. Hence, we believe the introduced cSP detection routine would be feasible for online cSP detection, in such a way that is presently used to detect the motor evoked potentials.

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, p0.0001), 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.

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 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 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.

Objectives Navigated TMS (nTMS) is commonly used to map motor cortex in adults. However, little is known about the development of the motor representations in younger subjects. We did a nTMS mapping study to assess the feasibility of motor cortex mapping in children, and to examine developmental changes in the locations and extents of distal and proximal upper extremity muscles. The relation to manual dexterity was also studied. Methods Both hemispheres of healthy, right-handed children (6–9 years, n = 10), preadolescents (10–12 years, n = 12), adolescents (15–17 years, n = 12) and adults (22–34 years, n = 12) were examined. The optimal site for abductior pollicis brevis (APB) was localized and resting motor threshold (rMT) determined. Motor mapping was performed at 110% of rMT of the APB was performed while recording EMG of three distal (APB, ADM, FDI) and three proximal (extensor carpi radialis, flexor carpi radialis, biceps brachii) muscles. The representation area was calculated with spline-interpolation and the ratio of hand and arm was correlated with a motor skill task (box and block test, BBT). Results The mapping was feasible in all but two of the youngest children whose rMT exceeded the maximum stimulator output. In younger subjects, the muscles of the forearm were occasionally eliciting larger and more frequent MEPs. The optimal sites of APB were found in anatomically expected locations, either in the precentral gyrus or in central suclus. The hand/arm representations ratio was below 1 in children, and increased approximately linearly with age. This ratio also correlated with BBT test score (rho = 0.456, p = 0.002). Discussion nTMS suits well for studying of development of the motor cortex. It may be worth monitoring several upper limb muscles during motor mapping in children as the excitability of the forearm muscles may be lower than that of small hand muscles. The hand/arm representations ratio increases with development and associates with greater fine motor ability in the right hemisphere. Conclusions Our results demonstrate a developmental course in the organization of the cortex and its associations with motor skills. Significance The results of this study contribute to the elucidation of the development of motor skills and the applicability of nTMS in pediatric populations.

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.

To provide a new protocol for a simple determination of resting motor threshold (MT) and assessment of excitation-inhibition balance in motor cortex and pathways.Navigated TMS was used to map cortical representation area of the FDI muscle bilaterally in ten healthy subjects. Reference MTs were determined using a threshold hunting paradigm. Subsequently, a novel stimulation protocol was applied which included 70 stimuli (7 intensities, sub- and suprathreshold). The "MT-curve" was constructed by computing the MTs with several threshold amplitudes with the novel protocol. The measurements were repeated. Sensitivity of the MT-curve to stimulus location was also tested.The reference MTs agreed with those determined with the novel protocol (R=0.96-0.99, p0.001). Based on coefficient of repeatability derived from non-parametric one-way ANOVA, the repeatability was good (ρ(AO)=0.929, p0.05). Generally, the mean difference between the repeated MT-curves was3% of the maximum stimulator output. Coil movement 10mm medially from the optimal stimulus location increased that difference to7%.The MTs derived using the MT-curve protocol concurred with the reference MTs. The MT-curve is highly reproducible and sensitive to the exact cortical location of stimulation.The MT-curves provide a simple way to assess motor pathway status using a single stimulation train. This may be useful in the follow-up and monitoring of motor pathway recovery e.g. from stroke or trauma.

To characterize the behaviour of primary motor cortex and to determine appropriate measurement parameters for short-interval cortical inhibition (SICI) and intracortical facilitation (ICF) by paired-pulse transcranial magnetic stimulation (TMS) with the aid of MRI-based neuronavigation.Paired-pulse TMS was targeted to the optimal cortical representation sites of the abductor pollicis brevis (APB) muscle in 48 healthy right-handed volunteers. Motor evoked potentials (MEPs) were recorded from the APB and abductor digiti minimi (ADM) muscles. The conditioning stimulus (CS) intensities were 80% and 90% and the test stimulus was 120% of the resting motor threshold (rMT). The interstimulus intervals (ISIs) were 3, 7, 13, 22 and 28 ms.Inhibition was observed at 3 ms with a CS of 80%. Facilitation emerged at ISIs of 7 and 13 ms with both CS intensities, more prominently with 90%. At ISI of 22 ms, facilitation was observed in ADM (p0.01) but not in APB. No uniform amplitude change was observed at ISI of 28 ms. For both muscles, MEP latencies were shortened (p0.01) at ISIs of 3 and 7 ms and prolonged (p0.01) at 28 ms.Inhibition is most prominent at ISI of 3 ms and CS of 80% of rMT, whereas CS of 90% of rMT and ISIs of 7 and 13 ms are preferable for facilitation. Latencies appear to be stable and independent indicators of both phenomena should be taken into account.Both the latency and amplitude of MEPs are important parameters when paired-pulse paradigms are used in clinical studies.

Transcranial magnetic stimulation (TMS) of the superior frontal gyrus in the non-primary motor area (NPMA) can evoke motor-evoked potentials (MEPs) at 20 ms latency range in contralateral distal hand muscles similar to stimulation of M1 and indicating monosynaptic corticospinal tracts. We compared the intracortical inhibitory and excitatory balance in primary motor cortex (M1) and in NPMA by navigated single- and paired-pulse TMS (ppTMS). We also evaluated the spatial stability of muscle representations in M1 and NPMA by remapping 11 healthy subjects one year after the initial mapping. Resting motor threshold (rMT) was higher in NPMA than in M1 as were the MEP amplitudes evoked by 120% rMT stimulation intensity of the local MT. Short-interval intracortical inhibition (SICI) was significantly weaker in NPMA than in M1 at ISI of 2 ms and conditioning stimulus (CS) 80% rMT. Our findings suggest that the cortical hand representations in NPMA 1) are connected to lower motoneurons monosynaptically, 2) are less strictly organized, i.e. motoneuron population representing a discrete hand muscle is sparser and less dense than in M1 and 3) have the capacity to generate powerful, rapid muscle contraction if sufficient number of motoneurones are activated. In NPMA, local intracortical inhibitory and excitatory activity is mainly similar to that in M1. The lower SICI in NPMA at an ISI of 2 ms may reflect less strict topographic organization and readiness to reorganization of neural circuits during motor learning or after motor deficits. Hum Brain Mapp, 2010. © 2010 Wiley-Liss, Inc.