Superconditioning TMS for examining upper motor neuron function in MND.

The dying forward hypothesis of motor neuron disease (MND) suggests that corticomotoneurons induce excitotoxic anterior horn cell death, with involvement of the glutamatergic neurotransmitter system. The aim of the present study was to apply novel threshold tracking transcranial magnetic stimulation (TMS) techniques in conjunction with peripheral nerve excitability studies in MND patients to further investigate the dying forward hypothesis and possibly determine the site of disease onset. Studies were undertaken in 23 MND patients using a 90-mm circular coil connected to a BiStim magnetic stimulator for cortical studies and electrical stimulation for peripheral nerve excitability studies. Motor-evoked potentials and compound muscle action potentials (CMAPs) were recorded from the right abductor pollicis brevis in the same setting. Measures of cortical and peripheral nerve excitability were correlated with clinical and neurophysiological parameters of disease severity. Short-interval intracortical inhibition (SICI) was significantly reduced in MND patients compared with controls (MND group = 3.6 +/- 0.8%; controls = 8.5 +/- 1.0%, P < 0.001), most prominently in MND patients with limb-onset disease. Changes in intracortical inhibition were accompanied by alterations in the magnetic stimulus-response curve, cortical silent period duration and resting motor threshold, all indicative of cortical hyperexcitability. Although the reduction in SICI was more pronounced in MND patients with less severe disease, as assessed by the CMAP amplitude, it remained evident even in MND patients with advanced disease. Measures of peripheral disease burden, namely the CMAP amplitude (r = -0.6) and neurophysiological index (r = -0.6), correlated with cortical hyperexcitability changes, as did the strength-duration time constant (r = -0.6), a peripheral marker of axonal excitability. Simultaneous assessment of central and peripheral nerve excitability has established the presence of co-existent upper and lower motor neuron dysfunction, with cortical hyperexcitability an early feature in MND.

To investigate whether the early effects of voluntary teeth clenching (VTC) among the first dorsal interosseous (FDI), abductor digiti minimi (ADM), and abductor pollicis brevis (APB) muscles are differently modulated depending on their muscle properties, we examined the responses of motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation with selected current directions and by brainstem magnetic stimulation (BMS). Although MEP responses with anterior-medially current direction (preferentially elicited I1-waves) were facilitated in all three muscles, those responses with posterior-laterally current direction (preferentially elicited I3-waves) were different among FDI, ADM, and APB muscles. That is, MEP responses in FDI and APB muscles were significantly reduced, whereas those responses in ADM muscle were not significantly reduced. Further, inhibitory effects of VTC in FDI muscle were more potent than those in ADM or APB muscles. On the other hand, the responses to BMS were unchanged by VTC in all three muscles, suggesting that the modulations of MEP were attributed to the cortical origin. On the basis of our previous findings that the inhibitory connections in FDI muscle are more potent than those in ADM muscle (Takahashi et al. in Clin Neurophysiol 116:2757-2764, 2005), the cortical effects of VTC among three hand muscles are differently modulated, depending on muscle properties, presumably the extents of inhibitory connections to corticospinal tract neurons. Considering that the functional capacity in FDI muscle is higher than that in ADM or APB muscles, the cortical inhibitory effect of VTC might contribute to the sophisticated regulation of the motor outputs even during VTC.

New Forms of ALS/MND Defined by Mutations in New Genes

Previously, we showed that a three-pulse train of weak transcranial magnetic stimulation (TMS) pulses-a superconditioning (SC) train-when followed by a stronger TMS pulse could enhance the inhibition or facilitation of the resultant motor evoked potential (MEP) compared with that seen with traditional dual-pulse inputs. The purpose of the present study was to establish the relative minimum intensity of SC pulses needed to influence MEP output and whether this differed for upper- versus lower-limb muscles. We examined 33 older adult subjects, targeting abductor pollicis brevis and tibialis anterior muscles. Older subjects were included in the anticipation of using findings from this study to guide further studies in persons with amyotrophic lateral sclerosis. Three-pulse trains of SC inputs of different intensities were delivered either 1 millisecond before (for inhibition) or 10 millisecond before (for facilitation) a stronger TMS test pulse. Motor evoked potential magnitudes for SC +test sets were normalized to test input responses and were compared within and between subjects. For inhibition, the minimum intensity of SC pulses needed to influence the follow-on MEP was found to be 60% of the target muscle's resting three-pulse MEP threshold for most abductor pollicis brevis and tibialis anterior muscles (2-millisecond interpulse intervals). For facilitation, somewhat higher intensities (70%) were typically needed to cause facilitation. Both values of SC pulses for inhibition/facilitation are considerably lower than the intensity of the conditioning pulse-often reported as 80% of the single-pulse threshold-typically used in dual-pulse TMS paradigms. This approach may allow testing of upper motor neuron function using weaker stimulus pulse intensities than are typically employed, improving testing compliance in persons whose thresholds are elevated because of injury or disease.

Introduction: A practical solution to the incidental unreliability of intraoperative neuromonitoring (IONM) may be the simultaneous neurophysiological recording and control of the surgical field through a camera (the concept of “Real-time” IONM). During “Real-time” IONM, the surgeon is immediately warned about the possibility of damage to the neural structures during, but not after, standard idiopathic scoliosis (IS) corrective surgery procedures (the concept of “Surgeon–neurophysiologist” interactive, verbal IONM). This study aimed to compare the advantages, utilities, reliabilities, and time consumption of the two IONM scenarios. Methods: Studies were performed in two similar groups of patients undergoing surgery primarily due to Lenke 2 idiopathic scoliosis (N = 120), when both IONM approaches were applied. Neurophysiological evaluations of the spinal transmission were performed pre- (T0), intra- (before (T1) and after (T2) surgery), and postoperatively (T3), as well as once in healthy volunteers (control, N = 60). Non-invasive and innovative recordings of the motor evoked potentials (MEPs) bilaterally from the peroneal (PER) nerve and tibialis anterior (TA) muscle were performed with surface electrodes as a result of transcranial magnetic stimulation (TMS) or electrical stimulation (TES) at T0–T3. Results: In both groups, the MEP amplitudes and latencies recorded from the PER nerve were approximately 67% lower and 3.1 ms shorter than those recorded from the TA muscle. The MEP recording parameters differed similarly at T0–T3 compared to the control group. In all patients, the MEP parameters induced by TMS (T0) and TES (T1) did not differ. The MEP amplitude parameters recorded from the TA and PER at T1 and T2 indicated a bilateral improvement in the neural spinal conduction due to the surgical intervention. The TMS-induced MEP amplitude at T3 further increased bilaterally. In both IONM groups, an average 51.8 BIS level of anesthesia did not affect the variability in the MEP amplitude, especially in the PER recordings when the applied TES strength was 98.2 mA. The number of fluctuations in the MEP parameters was closely related to the number of warnings from the neurophysiologist during the transpedicular screw implantation, corrective rod implantation, and distraction, derotation, and compression procedures, and it was higher in the “Surgeon–neurophysiologist” IONM group. The average duration of surgery was shorter by approximately one hour in the “Real-time” IONM group. The number of two-way communications between the surgeon and the neurophysiologist and vice versa in the “Real-time” IONM group decreased by approximately half. Conclusions: This study proves the superiority of using “Real-time” IONM over the standard “Surgeon–neurophysiologist” IONM procedure in increasing the safety and non-invasiveness, shortening the time, and lowering the costs of the surgical treatment of IS patients. The modifications of the MEP nerve-conduction-recording technology with surface electrodes from nerves enable precise and reliable information on the pediatric patient’s neurological condition at every stage of the applied surgical procedures, even under conditions of slight fluctuations in anesthesia.

The neural mechanisms underlying unintended mirror movements (MMs) of one hand during unimanual movements of the other hand in patients with Parkinson's disease (PD) are largely unexplored. Here we used surface electromyographic (EMG) analysis and focal transcranial magnetic stimulation (TMS) to investigate the pathophysiological substrate of MMs in four PD patients. Surface EMG was recorded from both abductor pollicis brevis (APB) and first dorsal interosseous (FDI) muscles. Cross-correlation EMG analysis revealed no common motor drive to the two APBs during intended unimanual tasks. Focal TMS of either primary motor cortex (M1) elicited normal motor-evoked potentials (MEPs) in the contralateral APB, whereas MEPs were not seen in the ipsilateral hand. During either mirror or voluntary APB contraction, focal TMS of the contralateral M1 produced a long-lasting silent period (SP), whereas stimulation of the ipsilateral M1 produced a short-lasting SP. During either mirror or voluntary finger tapping, 5 Hz repetitive TMS (rTMS) of the contralateral M1 disrupted EMG activity in the target FDI, whereas the effects of rTMS of the ipsilateral M1 were by far slighter. During either mirror or voluntary APB contraction, paired-pulse TMS showed a reduction of short-interval intracortical inhibition in the contralateral M1. These findings provide converging evidence that, in PD, MMs do not depend on unmasking of ipsilateral projections but are explained by motor output along the crossed corticospinal projection from the mirror M1.

Objective: To investigate whether the changes in the corticospinal excitability contribute to the anticipatory postural adjustments (APAs) in the lower limb muscles when performing the ballistic upper limb movement of the dart throwing.Methods: We examined the primary motor cortex (M1) excitability of the lower limb muscles [tibialis anterior (TA) and soleus (SOL) muscles] during the APA phase by using transcranial magnetic stimulation (TMS) in the healthy volunteers. The surface electromyography (EMG) of anterior deltoid, triceps brachii, biceps brachii, TA, and SOL muscles was recorded and the motor evoked potential (MEP) to TMS was recorded in the TA muscle along with the SOL muscle. TMS at the hotspot of the TA muscle was applied at the timings immediately prior to the TA onset. The kinematic parameters including the three-dimensional motion analysis and center of pressure (COP) during the dart throwing were also assessed.Results: The changes in COP and EMG of the TA muscle occurred preceding the dart throwing, which involved a slight elbow flexion followed by an extension. The correlation analysis revealed that the onset of the TA muscle was related to the COP change and the elbow joint flexion. The MEP amplitude in the TA muscle, but not that in the SOL muscle, significantly increased immediately prior to the EMG burst (100, 50, and 0 ms prior to the TA onset).Conclusion: Our findings demonstrate that the corticospinal excitability of the TA muscle increases prior to the ballistic upper limb movement of the dart throwing, suggesting that the corticospinal pathway contributes to the APA in the lower limb in a muscle-specific manner.

Aim and Objective: Motor-evoked responses using transcranial magnetic stimulation (TMS) have been studied in India in various diseases. However, no normative data are available for young healthy Indian adults. The aim was to generate normative data for young healthy Indian adults in our laboratory so that it can be used as normative data for comparison in various disorders. Materials and Methods: Motor-evoked responses using TMS in 15 young healthy Indian adults (mean age 32.8 years, mean height 166 cm) was studied using circular flat coil capable of delivering 1.5 tesla magnetic energy. Various parameters such as cortical threshold (CT), cortical latency (CL), central conduction time (CCT), root latency (RL), and amplitude of motor-evoked potentials (MEP) were studied. Results: The mean CT was 830 standard deviation (SD) 45 mv (55%) for abductor pollicis brevis (APB), 930 SD 65 mv (62%) for biceps brachii, and 1260 SD 52 mv (84%) for extensor digitorum brevis (EDB). The mean CL was 21.2 SD 1.14 ms for APB, 11.5 SD 0.1 ms for biceps, and 37.6 SD 0.75 ms for EDB. The mean RL was 14.7 SD 0.96 ms in APB, 6.12 SD 0.78 ms in biceps, and 21.33 SD 1.30 ms in EDB. The mean CCT was 6.53 SD 1.02 ms in APB, 5.6 SD 1.1 ms in biceps, and 16.7 SD 0.92 ms in EDB. The mean MEP amplitude was 4.20 SD 2.14 mv in APB, 3.21 SD 1.37 mv in biceps, and 1.10 SD 0.38 mv in EDB. The mean normal value of MEP/MAP ratio for APB was 0.29 SD 0.09, for EDB 0.12 SD 0.03. Conclusion: Various studies have been done using TMS to study motor-evoked responses. However, there has been a slight difference in values among them due to the type of coil used, energy delivered, and interobserver difference. Every electrophysiology laboratory should have its own value to act as a baseline for comparison with that in disorders of nervous system. No data for normal values in Indian population is available.

This study examined changes in corticomotor excitability and plasticity after a thumb abduction training task in young and old adults. Electromyographic (EMG) recordings were obtained from right abductor pollicis brevis (APB, target muscle) and abductor digiti minimi (ADM, control muscle) in 14 young (18-24 yr) and 14 old (61-82 yr) adults. The training task consisted of 300 ballistic abductions of the right thumb to maximize peak thumb abduction acceleration (TAAcc). Transcranial magnetic stimulation (TMS) of the left primary motor cortex was used to assess changes in APB and ADM motor evoked potentials (MEPs) and short-interval intracortical inhibition (SICI) before, immediately after, and 30 min after training. No differences in corticomotor excitability (resting and active TMS thresholds, MEP input-output curves) or SICI were observed in young and old adults before training. Motor training resulted in improvements in peak TAAcc in young (177% improvement, P < 0.001) and old (124%, P = 0.005) subjects, with greater improvements in young subjects (P = 0.002). Different thumb kinematics were observed during task performance, with increases in APB EMG related to improvements in peak TAAcc in young (r(2) = 0.46, P = 0.008) but not old (r(2) = 0.09, P = 0.3) adults. After training, APB MEPs were 50% larger (P < 0.001 compared with before) in young subjects, with no change after training in old subjects (P = 0.49), suggesting reduced use-dependent corticomotor plasticity with advancing age. These changes were specific to APB, because no training-related change in MEP amplitude was observed in ADM. No significant association was observed between change in APB MEP and improvement in TAAcc with training in individual young and old subjects. SICI remained unchanged after training in both groups, suggesting that it was not responsible for the diminished use-dependent corticomotor plasticity for this task in older adults.

F137. Effects of repetitive transcranial magnetic stimulation on short-latency afferent inhibition: A study in treatment-resistant depression

The identification of the chromosome 9 open reading frame 72 (c9orf72) gene hexanucleotide repeat expansion represents a major advance in the understanding of amyotrophic lateral sclerosis (ALS) pathogenesis. The pathophysiological mechanism by which the c9orf72 gene expansion leads to neurodegeneration is not yet elucidated. Cortical hyperexcitability is potentially an important pathophysiological process in sporadic ALS and familial ALS (FALS). To investigate whether cortical hyperexcitability forms the pathophysiological basis of c9orf72 FALS using the threshold-tracking transcranial magnetic stimulation technique. Prospective case-control single-center study that took place at hospitals and outpatient clinics from January 1, 2013, to January 1, 2015. Clinical and functional assessments along with transcranial magnetic stimulation studies were taken on 15 patients with c9orf72 FALS and 11 asymptomatic expansion carriers of c9orf72 who were longitudinally followed up for 3 years. Results were compared with 73 patients with sporadic ALS and 74 healthy control participants. Cortical excitability variables, including short-interval intracortical inhibition, were measured in patients with c9orf72 FALS and results were compared with asymptomatic c9orf72 carriers, patients with sporadic ALS, and healthy control participants. Mean (SD) short-interval intracortical inhibition was significantly reduced in patients with c9orf72 FALS (1.2% [1.8%]) and sporadic ALS (1.6% [1.2%]) compared with asymptomatic c9orf72 expansion carriers (10.2% [1.8%]; F = 16.1; P < .001) and healthy control participants (11.8% [1.0%]; F = 16.1; P < .001). The reduction of short-interval intracortical inhibition was accompanied by an increase in intracortical facilitation (P < .01) and motor-evoked potential amplitude (P < .05) as well as a reduction in the resting motor threshold (P < .05) and cortical silent period duration (P < .001). This study establishes cortical hyperexcitability as an intrinsic feature of symptomatic c9orf72 expansion-related ALS but not asymptomatic expansion carriers.

Motor evoked potentials (MEPs) induced through transcranial magnetic stimulation (TMS) are susceptible to several sources of variability including gender, hand dominance, and upper extremity length. Conflicting evidence on the relationship between MEPs and subject characteristics has been reported. The purposes of this study were to determine if MEPs are different between genders and between right- and left-hand dominant subjects, and to determine if MEPs are correlated with upper extremity length. Using a case-control design, we recorded MEPs from 45 healthy subjects (age 21.6 ± 2.0 years; 24 females, 21 males) with a MagStim200 stimulating coil positioned over the primary motor cortex. Evoked responses were recorded by surface EMG electrodes from the abductor pollicis brevis, abductor digiti minimi and first dorsal interosseous muscles contralateral to the site of TMS. Evoked responses were analyzed to determine motor thresholds, latencies and amplitudes. Central motor conduction time (CMCT) was estimated from MEP, M response, and F wave latencies. Gender and hand dominance did not significantly influence thresholds, MEP amplitudes, or CMCT (P > .05). MEP latencies were moderately correlated with upper extremity length (R = .62 right median, R = .50 left median, R = .45 right ulnar, R = .51 left ulnar MEP latency, P < .01). An ANCOVA using upper extremity length as the covariate demonstrated no significant differences between genders (Wilk's λ = .89, F = 2.45, P = .10). After adjusting MEP latencies to upper limb length, no significant differences were observed between dominant and non-dominant limbs (F = .002, P = .97 median, and F = .03, P = .56 ulnar) nor between genders (F = 2.7, P = .11 median; F = .05, P = .82 ulnar). Variability in MEP latencies between genders was due to differences in upper extremity length. Adjusting MEP latencies to upper limb length is recommended for more accurate comparison and meaningful interpretation between subjects. Hand dominance and gender do not significantly influence motor thresholds, MEP amplitude, or CMCT.

This study investigated the clinical usefulness of motor-evoked potentials (MEPs) produced by transcranial magnetic stimulation of the brain for cervical myelopathy patients. The purpose of this study was to determine the usefulness of MEPs for the assessment of the severity of myelopathy and prediction of the outcome of laminoplasty. Magnetic stimulation has been widely used for examination of the descending excitatory motor pathways in the central nervous system, but little attention has been paid to cervical myelopathy. We measured the MEPs of 56 patients who underwent surgery for cervical myelopathy. The MEPs from the abductor pollicis brevis, abductor digiti minimi, tibialis anterior, and abductor hallucis muscle were evoked by transcranial magnetic brain stimulation. The latency from the anterior horn cell of the spinal cord to the hand or foot muscles was also measured, with the F-value [(F + M - 1)/2] calculated. This was followed by estimation of the central motor conduction time (CMCT). Severity of clinical disability was scored on the basis of symptoms according to a modified ADL scale for cervical myelopathy of the Japanese Orthopedic Association (JOA) score. The average CMCT of the symptomatic side significantly correlated with the preoperative JOA score. The average CMCT of the symptomatic side significantly correlated with the 1-year postoperative JOA score. The average CMCT for patients with poor outcome was significantly longer than that for patients with good outcome. CMCT of 15 milliseconds or more in the upper extremities or that of 22 milliseconds or more in the lower extremities indicated poor prognosis. In patients with cervical myelopathy, the CMCT significantly correlated with the results of clinical assessment. These findings regarding the duration of CMCT may be useful parameters in spinal pathology for prediction of the outcome of surgical treatment.

Intracortical inhibition in the human trigeminal motor system

Low amplitude muscle vibration (0.5 ms; 80 Hz; duration 1.5 s) was applied in turn to each of three different intrinsic hand muscles (first dorsal interosseus, FDI; abductor pollicis brevis, APB; and abductor digiti minimi, ADM) in order to test its effect on the EMG responses evoked by transcranial magnetic stimulation (TMS). Recordings were also taken from flexor and extensor carpi radialis (FCR and ECR, respectively). We evaluated the amplitude of motor evoked potentials (MEPs) produced by a single TMS pulse, short interval intracortical inhibition and facilitation (SICI and ICF) and long interval intracortical inhibition (LICI). TMS pulses were applied 1 s after the start of vibration with subjects relaxed throughout. Vibration increased the amplitude of MEPs evoked in the vibrated muscle (162 +/- 6 % of MEP with no vibration; mean +/- S.E.M.), but suppressed MEPs in the two non-vibrated hand muscles (72 +/- 9 %). Compared with no vibration (test response reduced to 51 +/- 5 % of control), there was less SICI in the vibrated muscle (test response reduced to 92 +/- 28 % of control) and more in the non-vibrated hand muscles (test response reduced to 27 +/- 5 % of control). The opposite occurred for LICI: compared with the no vibration condition (test response reduced to 33 +/- 6 % control), there was more LICI in the vibrated muscle (test response reduced to 17 +/- 3 % control) than in the non-vibrated hand muscles (test response reduced to 80 +/- 11 % control) even when the intensity of the test stimulus was adjusted to compensate for the changes in baseline MEP. There was no effect on ICF. Cutaneous stimulation of the index finger (80 Hz, 1.5 s duration, twice sensory threshold) had no consistent differential effect on any of the parameters. We conclude that vibratory input from muscle can differentially modulate excitability in motor cortical circuits.