Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration.

A set of glutamylases and deglutamylases controls levels of tubulin polyglutamylation, a prominent post-translational modification of neuronal microtubules. Defective tubulin polyglutamylation was first linked to neurodegeneration in the Purkinje cell degeneration (pcd) mouse, which lacks deglutamylase CCP1, displays massive cerebellar atrophy, and accumulates abnormally glutamylated tubulin in degenerating neurons. We found biallelic rare and damaging variants in the gene encoding CCP1 in 13 individuals with infantile-onset neurodegeneration and confirmed the absence of functional CCP1 along with dysregulated tubulin polyglutamylation. The human disease mainly affected the cerebellum, spinal motor neurons, and peripheral nerves. We also demonstrate previously unrecognized peripheral nerve and spinal motor neuron degeneration in pcd mice, which thus recapitulated key features of the human disease. Our findings link human neurodegeneration to tubulin polyglutamylation, entailing this post-translational modification as a potential target for drug development for neurodegenerative disorders.

Sural nerve conduction studies using ultrasound-guided needle positioning: Influence of age and recording location.

INTRODUCTION: The aim of this study was to compare results of orthodromic sural nerve conduction studies (NCS) using ultrasound-guided needle positioning (USNP) to those of surface electrode recordings. METHODS: Fifty-one healthy subjects, aged 24-80 years, divided into 5 age groups, were examined. Electrical stimuli were applied behind the lateral malleolus. Sensory nerve action potentials (SNAPs) were recorded 8 and 15 cm proximally with surface and needle electrodes. RESULTS: Mean SNAP amplitudes (surface / needle electrodes) averaged 12.7 (SD 7.6) µV / 40.6 (SD 20.8) µV (P < 0.001) for subjects aged 20-29 years, and 5.0 (SD 2.4) µV / 19.8 (SD 9.8) µV (P < 0.01) for subjects >60 years of age. SNAP amplitudes were smaller at the proximal recording location. CONCLUSIONS: NCS using USNP yield higher amplitude responses than surface electrodes in all age groups at all recording sites. SNAP amplitudes are smaller at proximal recording locations due to sural nerve branching. Muscle Nerve 54: 879-882, 2016.

Guidelines on dermatomyositis--excerpt from the interdisciplinary S2k guidelines on myositis syndromes by the German Society of Neurology.

The present guidelines on dermatomyositis (DM) represent an excerpt from the interdisciplinary S2k guidelines on myositis syndromes of the German Society of Neurology (available at www.awmf.org). The cardinal symptom of myositis in DM is symmetrical proximal muscle weakness. Elevated creatine kinase, CRP or ESR as well as electromyography and muscle biopsy also provide important diagnostic clues. Pharyngeal, respiratory, cardiac, and neck muscles may also be affected. Given that approximately 30% of patients also develop interstitial lung disease, pulmonary function tests should be part of the diagnostic workup. Although the cutaneous manifestations in DM are variable, taken together, they represent a characteristic and crucial diagnostic criterion for DM. Approximately 5-20% of individuals exhibit typical skin lesions without any clinically manifest muscle involvement (amyopathic DM). About 30% of adult DM cases are associated with a malignancy. This fact, however, should not delay the treatment of severe myositis. Corticosteroids are the therapy of choice in myositis (1-2 mg/kg). Additional immunosuppressive therapy is frequently required (azathioprine, for children methotrexate). In case of insufficient therapeutic response, the use of intravenous immunoglobulins is justified. The benefit of rituximab has not been conclusively ascertained yet. Acute therapeutic management is usually followed by low-dose maintenance therapy for one to three years. Skin lesions do not always respond sufficiently to myositis therapy. Effective treatment for such cases consists of topical corticosteroids and sometimes also calcineurin inhibitors. Systemic therapies shown to be effective include antimalarial agents (also in combination), methotrexate, and corticosteroids. Intravenous immunoglobulins or rituximab may also be helpful. UV protection is an important prophylactic measure.

Effects of high resistance muscle training on corticospinal output during motor fatigue assessed by transcranial magnetic stimulation.

Introduction: Central fatigue refers to a reduced drive of motor cortical output during exercise, and performance can be enhanced after training. However, the effects of training on central fatigue remain unclear. Changes in cortical output can be addressed non-invasively using transcranial magnetic stimulation (TMS). The aim of the study was to compare responses to TMS during a fatiguing exercise before and after a 3 weeks lasting resistance training, in healthy subjects. Methods: The triple stimulation technique (TST) was used to quantify a central conduction index (CCI = amplitude ratio of central conduction response and peripheral nerve response) to the abductor digiti minimi muscle (ADM) in 15 subjects. The training consisted of repetitive isometric maximal voluntary contractions (MVC) of ADM for 2 min twice a day. Before and after this training, TST recordings were obtained every 15 s during an 2 min exercise of MVC of the ADM, where subjects performed repetitive contractions of the ADM, and repeatedly during a recovery period of 7 min. Results: There was a consistent decrease of force to approximately 40% of MVC in all experiments and in all subjects, both before and after training. In all subjects, CCI decreased during exercise. While before training, theCCI decreased to 49% (SD 23.7%) after 2 min of exercise, it decreased after training onlyto 79% (SD 26.4%) after exercise (p < 0.01). Discussion: The training regimen increased the proportion of target motor units that could be activated by TMS during a fatiguing exercise. The results point to a reduced intracortical inhibition, which may be a transient physiological response to facilitate the motor task. Possible underlying mechanisms at spinal and supraspinal sites are discussed.

Reproducibility of sensory nerve conduction studies of the sural nerve using ultrasound-guided needle positioning.

INTRODUCTION: In this study we sought to evaluate the reproducibility of sensory nerve conduction studies (NCS) using ultrasound-guided needle positioning (USNP). METHODS: Orthodromic NCS of the sural nerve using needle electrodes with USNP as well as surface electrodes were conducted twice in 20 healthy volunteers. RESULTS: The mean sensory nerve action potential (SNAP) amplitude in the initial examination was 39.5 µV using needle electrodes with USNP, and 12.5 µV using surface electrodes (P < 0.0001). The mean SNAP amplitude in the follow-up examination was 39.2 µV using needle electrodes with USNP, and 12.4 µV using surface electrodes (P < 0.0001). The mean intraindividual change in SNAP amplitude (test-retest) was 21.2% using needle electrodes with USNP, and 24.8% using surface electrodes (P = 0.6). CONCLUSIONS: Sensory NCS of the sural nerve using needle electrodes with USNP have reliable test-retest reproducibility and yield greater SNAP amplitudes than sensory NCS using surface electrodes.

Corticospinal output and loss of force during motor fatigue.

The objective of this study was to analyze central motor output changes in relation to contraction force during motor fatigue. The triple stimulation technique (TST, Magistris et al. in Brain 121(Pt 3):437-450, 1998) was used to quantify a central conduction index (CCI = amplitude ratio of central conduction response and peripheral nerve response, obtained simultaneously by the TST). The CCI removes effects of peripheral fatigue from the quantification. It allows a quantification of the percentage of the entire target muscle motor unit pool driven to discharge by a transcranial magnetic stimulus. Subjects (n = 23) performed repetitive maximal voluntary contractions (MVC) of abductor digiti minimi (duration 1 s, frequency 0.5 Hz) during 2 min. TST recordings were obtained every 15 s, using stimulation intensities sufficient to stimulate all cortical motor neurons (MNs) leading to the target muscle, and during voluntary contractions of 20% of the MVC to facilitate the responses. TST was also repetitively recorded during recovery. This basic exercise protocol was modified in a number of experiments to further characterize influences on CCI of motor fatigue (4 min exercise at 50% MVC; delayed fatigue recovery during local hemostasis, "stimulated exercise" by 20 Hz trains of 1 s duration at 0.5 Hz during 2 min). In addition, the cortical silent period was measured during the basic exercise protocol. Force fatigued to approximately 40% of MVC in all experiments and in all subjects. In all subjects, CCI decreased during exercise, but this decrease varied markedly between subjects. On average, CCI reductions preceded force reductions during exercise, and CCI recovery preceded force recovery. Exercising at 50% for 4 min reduced muscle force more markedly than CCI. Hemostasis induced by a cuff delayed muscle force recovery, but not CCI recovery. Stimulated exercise reduced force markedly, but CCI decreased only marginally. Summarized, force reduction and reduction of the CCI related poorly quantitatively and in time, and voluntary drive was particularly critical to reduce the CCI. The fatigue induced reduction of CCI may result from a central inhibitory phenomenon. Voluntary muscle activation is critical for the CCI reduction, suggesting a primarily supraspinal mechanism.

Comparison of recent pivotal recommendations for the diagnosis and treatment of late-onset Pompe disease using diagnostic nodes-the Pompe disease burden scale.

Pompe disease is a rare autosomal-recessive disorder characterised by limb-girdle myopathy and respiratory weakness in the late-onset form (LOPD). Various mutations in the acid alpha-glucosidase gene lead to toxic lysosomal and extra-lysosomal glycogen accumulation in all organs due to ineffective glycogen clearance by the encoded enzyme. Only one randomized trial demonstrated beneficial effects of respiratory function and meters walked in the 6-min walking test with enzyme replacement therapy (ERT). These results were confirmed in several retrospective and prospective observations and in meta-analyses. Due to a potential lifelong therapy, moderate efficacy and high treatment costs time of ERT initiation and cessation is an ongoing matter of debate. So far, several national and international recommendations have been published with different criteria concerning diagnosis, initiation and cessation of ERT in LOPD. We therefore formally analysed recent published recommendations and consensus statements of LOPD using diagnostic nodes (DODES) as a special software tool. With DODES, an objective analysis becomes possible if the content of the recommendations is represented as algorithms using cross-compatible elements. This analysis formally disclosed both, areas of great heterogeneity and concordance for the diagnosis and management of LOPD and paved the way for a Pompe disease burden scale focussing on ERT initiation. According to this investigation further clinical research should concentrate on ERT in pre-symptomatic and severely affected LOPD patients and on cessation criteria for ERT as these issues are areas of international uncertainty and discordance.

Extent, impact, and predictors of diagnostic delay in Pompe disease: A combined survey approach to unveil the diagnostic odyssey.

BACKGROUND: Early diagnosis is of substantial benefit for patients with Pompe disease. Yet underdiagnosing and substantial diagnostic delay are still frequent and the determinants of this are unknown. This study is the first to systematically investigate the diagnostic odyssey in Pompe disease from patients', parents', and physicians' perspectives. METHODS: Patients with infantile or late onset Pompe disease, their parents as well as their metabolic experts were invited to fill in respective surveys. The survey addressed perceived disease symptoms at onset and during the course of the disease, specialties of involved physicians, activities of patient-initiated search for diagnosis and the perceived impact of time to diagnosis on outcome. Results of experts' and patients'/parents' surveys were compared and expressed by descriptive statistics. RESULTS AND DISCUSSION: We collected data on 15 males and 17 females including 9 infantile and 23 late onset Pompe patients. All received the correct diagnosis at a metabolic or musculoskeletal expert center. Patients with direct referral to the expert center had the lowest diagnostic delay, while patients who were seen by several physicians, received the correct diagnosis after 44%-200% longer delay. The proportion of direct referral varied strongly between pediatricians (57%) and other disciplines (18%-36%). CONCLUSION: Our study highlights a substantially larger diagnostic delay in Pompe patients that are not directly referred to expert centers for diagnostic work. Our findings may be used to develop more successful strategies for early diagnosis. SYNOPSIS: Diagnostic delay in Pompe disease is substantial particularly in patients that are not directly referred to expert centers for diagnostic workup, so facilitating direct referral may be a new strategy for early diagnosis.

Nutrient pattern analysis in critically ill patients using Omics technology (NAChO) - Study protocol for a prospective observational study.

INTRODUCTION: Intensive care unit-acquired weakness (ICU-AW) is often observed in critically ill patients with prolonged intensive care unit (ICU) stay. We hypothesized that evolving metabolic abnormalities during prolonged ICU stay are reflected by changing nutrient patterns in blood, urine and skeletal muscle, and that these patterns differ in patients with/without ICU-AW and between patients with/without sepsis. METHODS: In a prospective single-center observational trial, we aim to recruit 100 critically ill patients (ICU length of stay ≥ 5 days) with severe sepsis/septic shock ("sepsis group", n = 50) or severe head trauma/intracerebral hemorrhage ("CNS group", n = 50). Patients will be sub-grouped for presence or absence of ICU-AW as determined by the Medical Research Council sum score. Blood and urine samples will be collected and subjected to comprehensive nutrient analysis at different time points by targeted quantitative mass spectrometric methods. In addition, changes in muscular tissue (biopsy, when available), muscular architecture (ultrasound), electrophysiology, body composition analyses (bioimpedance, cerebral magnetic resonance imaging), along with clinical status will be assessed. Patients will be followed-up for 180 and 360 days including assessment of quality of life. DISCUSSION: Key objective of this trial is to assess changes in nutrient pattern in blood and urine over time in critically ill patients with/without ICU-AW by using quantitative nutrient analysis techniques. Peer-reviewed published NAChO data will allow for a better understanding of metabolic changes in critically ill patients on standard liquid enteral nutrition and will likely open up new avenues for future therapeutic and nutritional interventions.

The clinical diagnostic utility of transcranial magnetic stimulation: report of an IFCN committee.

The review focuses on the clinical diagnostic utility of transcranial magnetic stimulation (TMS). The central motor conduction time (CMCT) is a sensitive method to detect myelopathy and abnormalities may be detected in the absence of radiological changes. CMCT may also detect upper motor neuron involvement in amyotrophic lateral sclerosis. The diagnostic sensitivity may be increased by using the triple stimulation technique (TST), by combining several parameters such as CMCT, motor threshold and silent period, or by studying multiple muscles. In peripheral facial nerve palsies, TMS may be used to localize the site of nerve dysfunction and clarify the etiology. TMS measures also have high sensitivity in detecting lesions in multiple sclerosis and abnormalities in CMCT or TST may correlate with motor impairment and disability. Cerebellar stimulation may detect lesions in the cerebellum or the cerebellar output pathway. TMS may detect upper motor neuron involvement in patients with atypical parkinsonism and equivocal signs. The ipsilateral silent period that measures transcallosal inhibition is a potential method to distinguish between different parkinsonian syndromes. Short latency afferent inhibition (SAI), which is related to central cholinergic transmission, is reduced in Alzheimer's disease. Changes in SAI following administration of cholinesterase inhibitor may be related to the long-term efficacy of this treatment. The results of MEP measurement in the first week after stroke correlate with functional outcome. We conclude that TMS measures have demonstrated diagnostic utility in myelopathy, amyotrophic lateral sclerosis and multiple sclerosis. TMS measures have potential clinical utility in cerebellar disease, dementia, facial nerve disorders, movement disorders, stroke, epilepsy, migraine and chronic pain.

Trial-to-trial size variability of motor-evoked potentials. A study using the triple stimulation technique.

Motor-evoked potentials (MEPs) vary in size from one stimulus to the next. The objective of this study was to determine the cause and source of trial-to-trial MEP size variability. In two experiments involving 10 and 14 subjects, the variability of MEPs to cortical stimulation (cortical-MEPs) in abductor digiti minimi (ADM) and abductor hallucis (AH) was compared to those responses obtained using the triple stimulation technique (cortical-TST). The TST eliminates the effects of motor neuron (MN) response desynchronization and of repetitive MN discharges. Submaximal stimuli were used in both techniques. In six subjects, cortical-MEP variability was compared to that of brainstem-MEP and brainstem-TST. Variability was greater for MEPs than that for TST responses, by approximately one-third. The variability was the same for cortical- and brainstem-MEPs and was similar in ADM and AH. Variability concerned at least 10-15% of the MN pool innervating the target muscle. With the stimulation parameters used, repetitive MN discharges did not influence variability. For submaximal stimuli, approximately two-third of the observed MEP size variability is caused by the variable number of recruited alpha-MNs and approximately one-third by changing synchronization of MN discharges. The source of variability is most likely localized at the spinal segmental level.

Estimation of voluntary elicited motor neuron discharge using a peripheral nerve collision technique at different contraction strengths.

OBJECTIVE: To estimate non-invasively the amount, recruitment pattern and discharge frequency of spinal motor neurons (MN) at contraction strength >20% of maximal voluntary contraction (MVC) of small hand muscles. METHODS: A peripheral collision technique was used and consisted of supramaximal electrical stimuli at Erb's point and at the wrist, synchronizing descending volleys of action potential during voluntary isometric contractions of the abductor digiti minimi muscle at 20-80% of MVC strength and 1-8 s of contraction duration. Responses of 13 healthy volunteers were quantified and analysed using a recently described model of MN behaviour. RESULTS: A linear relationship between MN discharge and force generation was noticed with R2 = 0.996, and was confirmed using the simulation results (R2 = 0.997) for contraction durations up to 8 s. For each investigated force level, discharge frequency and recruitment pattern were calculated for individual MN. CONCLUSIONS: Using this method, MN discharge properties during voluntary activity can be estimated non-invasively. SIGNIFICANCE: This method provides new opportunities for the non-invasive study of MN behaviour, and could be expanded to patients with conduction failure and during fatigue.

36-Months follow-up assessment after cessation and resuming of enzyme replacement therapy in late onset Pompe disease: data from the Swiss Pompe Registry.

INTRODUCTION: Although not curative, enzyme replacement therapy (ERT) with recombinant human acid alpha-glucosidase enzyme has shown to be effective in the treatment of late-onset Pompe disease (LOPD). For this potentially life-long treatment, little is known on the clinical effect of cessation and resuming ERT. Due to a Swiss supreme court decision on ERT reimbursement, a temporary stop of ERT occurred in our study population. The aim of this study was to report the 36-months follow-up assessments after resuming ERT. METHODS: After resuming ERT, seven patients suffering from genetically and enzymatically confirmed LOPD had periodic, mandatory, prospective assessments of pulmonary function tests, muscle strength summary scores, distances walked in timed walking tests, and patient-reported questionnaires. Data were statistically analyzed for significant differences between time points at ERT cessation, at ERT resuming, and 36 months thereafter. RESULTS: After resuming ERT forced vital capacity (p = 0.007) and distance walked in the 6 min walk test (6-MWT, p = 0.011) significantly increased at 36 months. Compared to before ERT cessation, distance walked in 6-MWT at 36 months still remained significantly lower (p = 0.005). Self-reported scores in the fatigue severity scale significantly declined at 36 months after resuming ERT (p = 0.019). No other functional or reported parameter significantly changed at 36 months after resuming ERT. CONCLUSIONS: Our data suggests that long-term interruption of ERT in LOPD may lead to deterioration of clinical meaningful parameters and quality of life. In addition, a clinical restoration after ERT cessation is possible for most of the LOPD patients within a 36 months follow-up.

Neuromonitoring During Robotic Cochlear Implantation: Initial Clinical Experience.

During robotic cochlear implantation a drill trajectory often passes at submillimeter distances from the facial nerve due to close lying critical anatomy of the temporal bone. Additional intraoperative safety mechanisms are thus required to ensure preservation of this vital structure in case of unexpected navigation system error. Electromyography based nerve monitoring is widely used to aid surgeons in localizing vital nerve structures at risk of injury during surgery. However, state of the art neuromonitoring systems, are unable to discriminate facial nerve proximity within submillimeter ranges. Previous work demonstrated the feasibility of utilizing combinations of monopolar and bipolar stimulation threshold measurements to discretize facial nerve proximity with greater sensitivity and specificity, enabling discrimination between safe (> 0.4 mm) and unsafe (< 0.1 mm) trajectories during robotic cochlear implantation (in vivo animal model). Herein, initial clinical validation of the determined stimulation protocol and nerve proximity analysis integrated into an image guided system for safety measurement is presented. Stimulation thresholds and corresponding nerve proximity values previously determined from an animal model have been validated in a first-in-man clinical trial of robotic cochlear implantation. Measurements performed automatically at preoperatively defined distances from the facial nerve were used to determine safety of the drill trajectory intraoperatively. The presented system and automated analysis correctly determined sufficient safety distance margins (> 0.4 mm) to the facial nerve in all cases.

Ultrasound-Guided Electrodes for Conduction Studies of the Saphenous Nerve.

PURPOSE: Saphenous nerve conduction studies are difficult, because the nerve is hard to localize and evoked responses are small. Ultrasound imaging may assist in the accurate localization and optimal positioning of surface (SE) and needle electrodes (NE). METHODS: The study population included 39 subjects and was divided into two groups. Group A consisted of 20 healthy subjects, whereas group B of 19 patients with polyneuropathies. Orthodromic conduction was measured by distal supramaximal nerve stimulation. Surface electrode and NE recordings were compared. RESULTS: In the control group, SEs recorded responses in 17 of 20 healthy subjects, whereas NEs in 19. In the patients' group, SEs recorded responses in 7 of 19 patients, whereas NEs in 16. In all healthy subjects and patients, sensory nerve action potentials recorded by NEs were significantly larger than those obtained by SEs (healthy subjects: 5.85 ± 3.01 µV vs. 1.98 ± 1.37 µV, P < 0.0001; patients 3.05 ± 2.35 µV vs. 0.71 ± 1.14 µV, t-test P < 0.0001). CONCLUSIONS: Ultrasound guidance allows precise electrode positioning for saphenous nerve electrophysiological testing. Amplitudes of the recorded sensory nerve action potentials are clearly higher with ultrasound-guided needle than with surface recordings.

Effect of pregnancy and birth on the course of myasthenia gravis before or after transsternal radical thymectomy.

OBJECTIVE: Myasthenia gravis (MG) affects women at childbearing age. Therefore, the question arises if these patients should become pregnant and if thymectomy has a positive effect on the course of MG in pregnant patients. METHODS: Fifteen pregnancies had been followed retrospectively. All patients underwent transsternal radical thymectomy for MG. The course of MG in the period before, during, and after the pregnancy was scored according to Ossermann's classification. The effect of thymectomy on delivery and on the newborns was evaluated. RESULTS: Patients were divided in two groups: pregnancies before (group I, n=8) and after (group II, n=7) thymectomy. During pregnancy, in group I, one deterioration was observed and in seven patients the disease was unchanged. In group II, one deterioration, five unchanged courses, and one improvement were observed. In the postpartum period, in group I, seven patients did not change and one improved. In group II, two deteriorations, three unchanged courses, and two improvements were observed. Before pregnancy, group II patients were in a better Ossermann stage in comparison with those in group I. Eight of the 12 deliveries were spontaneous (three abortus). Myasthenic symptoms were observed in two newborns in group I. CONCLUSION: Our data suggest that MG is not prohibitive to have children. The course of MG after transsternal radical thymectomy is often ameliorated. A better MG-stage, reached after thymectomy, before pregnancy seems to be correlated with a better course during pregnancy.

A Neuromonitoring Approach to Facial Nerve Preservation During Image-guided Robotic Cochlear Implantation.

HYPOTHESIS: A multielectrode probe in combination with an optimized stimulation protocol could provide sufficient sensitivity and specificity to act as an effective safety mechanism for preservation of the facial nerve in case of an unsafe drill distance during image-guided cochlear implantation. BACKGROUND: A minimally invasive cochlear implantation is enabled by image-guided and robotic-assisted drilling of an access tunnel to the middle ear cavity. The approach requires the drill to pass at distances below 1  mm from the facial nerve and thus safety mechanisms for protecting this critical structure are required. Neuromonitoring is currently used to determine facial nerve proximity in mastoidectomy but lacks sensitivity and specificity necessaries to effectively distinguish the close distance ranges experienced in the minimally invasive approach, possibly because of current shunting of uninsulated stimulating drilling tools in the drill tunnel and because of nonoptimized stimulation parameters. To this end, we propose an advanced neuromonitoring approach using varying levels of stimulation parameters together with an integrated bipolar and monopolar stimulating probe. MATERIALS AND METHODS: An in vivo study (sheep model) was conducted in which measurements at specifically planned and navigated lateral distances from the facial nerve were performed to determine if specific sets of stimulation parameters in combination with the proposed neuromonitoring system could reliably detect an imminent collision with the facial nerve. For the accurate positioning of the neuromonitoring probe, a dedicated robotic system for image-guided cochlear implantation was used and drilling accuracy was corrected on postoperative microcomputed tomographic images. RESULTS: From 29 trajectories analyzed in five different subjects, a correlation between stimulus threshold and drill-to-facial nerve distance was found in trajectories colliding with the facial nerve (distance <0.1  mm). The shortest pulse duration that provided the highest linear correlation between stimulation intensity and drill-to-facial nerve distance was 250  µs. Only at low stimulus intensity values (≤0.3  mA) and with the bipolar configurations of the probe did the neuromonitoring system enable sufficient lateral specificity (>95%) at distances to the facial nerve below 0.5  mm. However, reduction in stimulus threshold to 0.3  mA or lower resulted in a decrease of facial nerve distance detection range below 0.1  mm (>95% sensitivity). Subsequent histopathology follow-up of three representative cases where the neuromonitoring system could reliably detect a collision with the facial nerve (distance <0.1  mm) revealed either mild or inexistent damage to the nerve fascicles. CONCLUSION: Our findings suggest that although no general correlation between facial nerve distance and stimulation threshold existed, possibly because of variances in patient-specific anatomy, correlations at very close distances to the facial nerve and high levels of specificity would enable a binary response warning system to be developed using the proposed probe at low stimulation currents.

Uncrossed cortico-muscular projections in humans are abundant to facial muscles of the upper and lower face, but may differ between sexes.

It is a popular concept in clinical neurology that muscles of the lower face receive predominantly crossed cortico-bulbar motor input, whereas muscles of the upper face receive additional ipsilateral, uncrossed input. To test this notion, we used focal transcranial magnetic brain stimulation to quantify crossed and uncrossed cortico-muscular projections to 6 different facial muscles (right and left Mm. frontalis, nasalis, and orbicularis oris) in 36 healthy right-handed volunteers (15 men, 21 women, mean age 25 years). Uncrossed input was present in 78% to 92% of the 6 examined muscles. The mean uncrossed: crossed response amplitude ratios were 0.74/0.65 in right/left frontalis, 0.73/0.59 in nasalis, and 0.54/0.71 in orbicularis oris; ANOVA p>0.05). Judged by the sizes of motor evoked potentials, the cortical representation of the 3 muscles was similar. The amount of uncrossed projections was different between men and women, since men had stronger left-to-left projections and women stronger right-to-right projections. We conclude that the amount of uncrossed pyramidal projections is not different for muscles of the upper from those of the lower face. The clinical observation that frontal muscles are often spared in central facial palsies must, therefore, be explained differently. Moreover, gender specific lateralization phenomena may not only be present for higher level behavioural functions, but may also affect simple systems on a lower level of motor hierarchy.

Impact of coil position and electrophysiological monitoring on determination of motor thresholds to transcranial magnetic stimulation.

OBJECTIVE: We compared motor and movement thresholds to transcranial magnetic stimulation (TMS) in healthy subjects and investigated the effect of different coil positions on thresholds and MEP (motor-evoked potential) amplitudes. METHODS: The abductor pollicis brevis (APB) 'hot spot' and a standard scalp position were stimulated. APB resting motor threshold (APB MEP-MT) defined by the '5/10' electrophysiological method was compared with movement threshold (MOV-MT), defined by visualization of movements. Additionally, APB MEP-MTs were evaluated with the '3/6 method,' and MEPs were recorded at a stimulation intensity of 120% APB MEP-MT at each position. RESULTS: APB MEP-MTs were significantly lower by stimulation of the 'hot spot' than of the standard position, and significantly lower than MOV-MTs (n=15). There were no significant differences between the '3/6' and the '5/10' methods, or between APB MEP amplitudes by stimulating each position at 120% APB MEP-MT. CONCLUSIONS: Coil position and electrophysiological monitoring influenced motor threshold determinations. Performing 6 instead of 10 trials did not produce different threshold measurements. Adjustment of intensity according to APB MEP-MT at the stimulated position did not influence APB MEP amplitudes. SIGNIFICANCE: Standardization of stimulation positions, nomenclature and criteria for threshold measurements should be considered in design and comparison of TMS protocols.

Significance of coil orientation for motor evoked potentials from nasalis muscle elicited by transcranial magnetic stimulation.

OBJECTIVE: In transcranial magnetic stimulation (TMS) of the motor cortex, the optimal orientation of the coil on the scalp is dependent on the muscle under investigation, but not yet known for facial muscles. METHODS: Using a figure-of-eight coil, we compared TMS induced motor evoked potentials (MEPs) from eight different coil orientations when recording from ipsi- and contralateral nasalis muscle. RESULTS: The MEPs from nasalis muscle revealed three components: The major ipsi- and contra-lateral middle latency responses of approximately 10 ms onset latency proved entirely dependent on voluntary pre-innervation. They were most easily obtained from a coil orientation with posterior inducing current direction, and in this respect resembled the intrinsic hand rather than the masseter muscles. Early short duration responses of around 6 ms onset latency were best elicited with an antero-lateral current direction and not pre-innervation dependent, and therefore most probably due to stimulation of the nerve roots. Late responses (>18 ms) could inconsistently be elicited with posterior coil orientations in pre-innervated condition. CONCLUSIONS: By using the appropriate coil orientation and both conditions relaxed and pre-innervated, cortically evoked MEP responses from nasalis muscle can reliably be separated from peripheral and reflex components and also from cross talk of masseter muscle activation.