Quantitative motor unit action potential analysis in 2 paraspinal neck muscles in adult Royal Dutch Sport horses

BACKGROUND: Reference values for quantitative electromyography (QEMG) in neck muscles of Royal Dutch Sport horses are lacking. OBJECTIVE: Determine normative data on quantitative motor unit action potential (QMUP) analysis of serratus ventralis cervicis (SV) and brachiocephalicus (BC) muscle. ANIMALS: Seven adult normal horses (mean age 9.5 standard deviation [SD] +/- 2.3 years, mean height 1.64 SD +/- 4.5 cm, and mean rectal temperature 37.6 SD +/- 0.3 degrees C). METHODS: An observational study on QMUP analysis in 6 segments of each muscle was performed with commercial electromyography equipment. Measurements were made according to formerly published methods. Natural logarithm transformed data were tested with ANOVA and posthoc testing according to Bonferroni. RESULTS: Mean duration, amplitude, phases, turns, area, and size index (SI) did not differ significantly among the 6 segments in each muscle. Mean amplitude, number of phases, and SI were significantly (P < .002) higher in SV than BC, 520 versus 448 muV, 3.0 versus 2.8 muV, and 0.48 versus 0.30 muV, respectively. In SV 95% confidence intervals (CI) for amplitude, duration, number of phases, turns, polyphasia area, and SI were 488-551 muV, 4.3-4.6 ms, 2.9-3.0, 2.4-2.6, 7-12%, 382-448, and 0.26-0.70, respectively; in BC this was 412-483 muV, 4.3-4.7 ms, 2.7-2.8, 2.4-2.6, 4-7%, 393-469, and 0.27-0.34, respectively. Maximal voluntary activity expressed by turns/second did not differ significantly between SV and BC with a 95% CI of 132-173 and 137-198, respectively. CONCLUSIONS AND CLINICAL IMPORTANCE: The establishment of normative data makes objective QEMG of paraspinal muscles in horses suspected of cervical neurogenic disorders possible. Differences between muscles should be taken into account.

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.

Point mutations in the stem region and the fourth AAA domain of cytoplasmic dynein heavy chain partially suppress the phenotype of NUDF/LIS1 loss in Aspergillus nidulans

Cytoplasmic dynein performs multiple cellular tasks but its regulation remains unclear. The dynein heavy chain has a N-terminal stem that binds to other subunits and a C-terminal motor unit that contains six AAA (ATPase associated with cellular activities) domains and a microtubule-binding site located between AAA4 and AAA5. In Aspergillus nidulans, NUDF (a LIS1 homolog) functions in the dynein pathway, and two nudF6 partial suppressors were mapped to the nudA dynein heavy chain locus. Here we identified these two mutations. The nudAL1098F mutation resides in the stem region, and nudAR3086C is in the end of AAA4. These mutations partially suppress the phenotype of nudF deletion but do not suppress the phenotype exhibited by mutants of dynein intermediate chain and Arp1. Surprisingly, the stronger DeltanudF suppressor, nudAR3086C, causes an obvious decrease in the basal level of dynein's ATPase activity and an increase in dynein's distribution along microtubules. Thus, suppression of the DeltanudF phenotype may result from mechanisms other than simply the enhancement of dynein's ATPase activity. The fact that a mutation in the end of AAA4 negatively regulates dynein's ATPase activity but partially compensates for NUDF loss indicates the importance of the AAA4 domain in dynein regulation in vivo.

A large animal model of spinal muscular atrophy and correction of phenotype.

OBJECTIVES Spinal muscular atrophy (SMA) is caused by reduced levels of survival motor neuron (SMN) protein, which results in motoneuron loss. Therapeutic strategies to increase SMN levels including drug compounds, antisense oligonucleotides, and scAAV9 gene therapy have proved effective in mice. We wished to determine whether reduction of SMN in postnatal motoneurons resulted in SMA in a large animal model, whether SMA could be corrected after development of muscle weakness, and the response of clinically relevant biomarkers. METHODS Using intrathecal delivery of scAAV9 expressing an shRNA targeting pig SMN1, SMN was knocked down in motoneurons postnatally to SMA levels. This resulted in an SMA phenotype representing the first large animal model of SMA. Restoration of SMN was performed at different time points with scAAV9 expressing human SMN (scAAV9-SMN), and electrophysiology measurements and pathology were performed. RESULTS Knockdown of SMN in postnatal motoneurons results in overt proximal weakness, fibrillations on electromyography indicating active denervation, and reduced compound muscle action potential (CMAP) and motor unit number estimation (MUNE), as in human SMA. Neuropathology showed loss of motoneurons and motor axons. Presymptomatic delivery of scAAV9-SMN prevented SMA symptoms, indicating that all changes are SMN dependent. Delivery of scAAV9-SMN after symptom onset had a marked impact on phenotype, electrophysiological measures, and pathology. INTERPRETATION High SMN levels are critical in postnatal motoneurons, and reduction of SMN results in an SMA phenotype that is SMN dependent. Importantly, clinically relevant biomarkers including CMAP and MUNE are responsive to SMN restoration, and abrogation of phenotype can be achieved even after symptom onset.

The use of electromyography interference pattern analysis to determine muscle force of the deep digital flexor muscle in healthy and laminitic horses

BACKGROUND: In equine laminitis, the deep digital flexor muscle (DDFM) appears to have increased muscle force, but evidence-based confirmation is lacking. OBJECTIVES: The purpose of this study was to test if the DDFM of laminitic equines has an increased muscle force detectable by needle electromyography interference pattern analysis (IPA). ANIMALS AND METHODS: The control group included six Royal Dutch Sport horses, three Shetland ponies and one Welsh pony [10 healthy, sound adults weighing 411 ± 217 kg (mean ± SD) and aged 10 ± 5 years]. The laminitic group included three Royal Dutch Sport horses, one Friesian, one Haflinger, one Icelandic horse, one Welsh pony, one miniature Appaloosa and six Shetland ponies (14 adults, weight 310 ± 178 kg, aged 13 ± 6 years) with acute/chronic laminitis. The electromyography IPA measurements included firing rate, turns/second (T), amplitude/turn (M) and M/T ratio. Statistical analysis used a general linear model with outcomes transformed to geometric means. RESULTS: The firing rate of the total laminitic group was higher than the total control group. This difference was smaller for the ponies compared to the horses; in the horses, the geometric mean difference of the laminitic group was 1.73 [geometric 95% confidence interval (CI) 1.29-2.32], and in the ponies this value was 1.09 (geometric 95% CI 0.82-1.45). CONCLUSION AND CLINICAL RELEVANCE: In human medicine, an increased firing rate is characteristic of increased muscle force. Thus, the increased firing rate of the DDFM in the context of laminitis suggests an elevated muscle force. However, this seems to be only a partial effect as in this study, the unchanged turns/second and amplitude/turn failed to prove the recruitment of larger motor units with larger amplitude motor unit potentials in laminitic equids.

Effects of rivastigmine on actigraphically monitored motor activity in severe agitation related to Alzheimer's disease: a placebo-controlled pilot study

Acetylcholinesterase inhibitors (AChEIs) are effective in the treatment of cognitive symptoms in Alzheimer's disease (AD). Because the behavioral and psychological symptoms of dementia (BPSD) have also been attributed to central cholinergic deficits, we examined whether the AChEI rivastigmine can reduce motor activity as measured in a rater-independent manner by wrist actigraphy in agitated AD patients. A total of 20 consecutive AD inpatients (13 females, 7 males, 80.4+/-9.1 years, S.D.) were included from our geriatric psychiatry unit, all of whom were exhibiting agitated behavior not attributable to delirium. Patients were assigned randomly and in a single-blinded fashion to rivastigmine 3mg or placebo for 14 days. Motor activity levels were monitored using an actigraph worn continuously on the wrist of the non-dominant hand. At the beginning and end of the study, patients were assessed using the Neuropsychiatric Inventory (NPI) and Nurses' Observation Scale for Geriatric Patients (NOSGER). Patients in the rivastigmine group exhibited less agitation than placebo recipients on the NPI-agitation subscale, but not on NOSGER. Actigraphic measurements showed a tendency towards reduced motor activity in the rivastigmine group. Because rivastigmine usually exerts its main effects after a longer period of time, the short-term effects seen in our study justify further controlled clinical trials examining the use of rivastigmine in BPSD by means of actigraphy.

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.