Utilising TMS-EEG to Assess the Response to Cerebellar-Brain Inhibition.

Cerebellar-brain inhibition (CBI) is a transcranial magnetic stimulation (TMS) paradigm indexing excitability of cerebellar projections to motor cortex (M1). Stimulation involved with CBI is often considered to be uncomfortable, and alternative ways to index connectivity between cerebellum and the cortex would be valuable. We therefore sought to assess the utility of electroencephalography in conjunction with TMS (combined TMS-EEG) to record the response to CBI. A total of 33 volunteers (25.7 ± 4.9 years, 20 females) participated across three experiments. These investigated EEG responses to CBI induced with a figure-of-eight (F8; experiment 1) or double cone (DC; experiment 2) conditioning coil over cerebellum, in addition to multisensory sham stimulation (experiment 3). Both F8 and DC coils suppressed early TMS-evoked EEG potentials (TEPs) produced by TMS to M1 (P < 0.05). Furthermore, the TEP produced by CBI stimulation was related to the motor inhibitory response to CBI recorded in a hand muscle (P < 0.05), but only when using the DC coil. Multisensory sham stimulation failed to modify the M1 TEP. Cerebellar conditioning produced changes in the M1 TEP that were not apparent following sham stimulation, and that were related to the motor inhibitory effects of CBI. Our findings therefore suggest that it is possible to index the response to CBI using TMS-EEG. In addition, while both F8 and DC coils appear to recruit cerebellar projections, the nature of these may be different.

Cardiac function in gestational diabetes mellitus: A longitudinal study from fetal life to infancy.

OBJECTIVE: To determine whether cardiac functional and structural changes in fetuses of mothers with gestational diabetes mellitus (GDM) persist in the offspring beyond the neonatal period. DESIGN: Longitudinal study. SETTING: Fetal Medicine Unit in a UK teaching hospital. METHODS: 73 women with GDM and 73 women with uncomplicated pregnancy were recruited and fetal cardiac scans were performed at 35-36 weeks' gestation. Repeat echocardiogram was performed in their offspring during infancy. MAIN OUTCOME MEASURES: Fetal and infant cardiac functional and structural changes. RESULTS: Fetuses of mothers with GDM, compared with controls, had more globular right ventricles (sphericity index 0.7, interquartile range [IQR] 0.6/0.7 versus 0.6, IQR 0.5/0.6, P < 0.001) and reduced right global longitudinal systolic strain (-16.4, IQR -18.9/-15.3 versus -18.5, IQR -20.6/-16.8, P = 0.001) and left global longitudinal systolic strain (-20.1, IQR -22.5/-16.9 versus -21.3, IQR -23.5/-19.5), P = 0.021). In the GDM group, compared with controls, in infancy there was higher left ventricular E/e' (8.7, IQR 7.3/9.7 versus 7.9 IQR, 6.8/8.9 P = 0.011) and lower left ventricular global longitudinal systolic strain (-21.0, IQR -22.5/-19.4 versus -22.3, IQR -23.5/-20.7, P = 0.001) and tricuspid annular plane systolic excursion (13.8, IQR 12.7/16.1 versus 15.2, IQR 13.8/16.8, P = 0.003). These differences remained following multivariable analysis. CONCLUSION: Gestational diabetes mellitus is associated with alterations in fetal cardiac function and structure compared with controls and persistent cardiac changes in infancy. TWEETABLE ABSTRACT: Gestational diabetes mellitus, even when well controlled, is associated with fetal cardiac changes and these persist in infancy.

Fetal cardiac function at 35-37 weeks' gestation in pregnancies that subsequently develop pre-eclampsia.

OBJECTIVE: To compare fetal cardiac morphology and function between pregnancies that subsequently developed pre-eclampsia (PE) and those that remained normotensive. METHODS: This was a prospective observational study in 1574 pregnancies at 35-37 weeks' gestation, including 76 that subsequently developed PE. We carried out comprehensive assessment of fetal cardiac morphology and function including novel imaging modalities, such as speckle-tracking echocardiography, and measured uterine artery pulsatility index, mean arterial pressure (MAP), serum placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1) and cerebroplacental ratio (CPR). The findings in the group that subsequently developed PE were compared to those in pregnancies that remained normotensive. RESULTS: In fetuses of mothers who subsequently developed PE, compared to those from normotensive pregnancies, there was a more globular right ventricle, as shown by reduced right ventricular sphericity index, reduced right ventricular systolic contractility, as shown by reduced global longitudinal strain, and reduced left ventricular diastolic function, as shown by increased E/A ratio. On multivariable regression analysis, these indices demonstrated an association with PE, independent of maternal characteristics and fetal size. In pregnancies that subsequently developed PE, compared to those that remained normotensive, MAP, sFlt-1 and the incidence of low birth weight were higher, whereas serum PlGF, CPR and the interval between assessment and delivery were lower. These findings demonstrate that, in pregnancies that develop PE, there is evidence of impaired placentation, reflected in low PlGF and reduced birth weight, placental ischemia, evidenced by increased sFlt-1 which becomes apparent in the interval of 2-4 weeks preceding the clinical onset of PE, and consequent fetal hypoxia-induced redistribution in the fetal circulation, reflected in the low CPR. CONCLUSION: Although the etiology of the observed fetal cardiac changes in pregnancies that subsequently develop PE remains unclear, it is possible that the reduction in right-heart systolic function is the consequence of high afterload due to increased placental resistance, whilst the early left ventricular diastolic changes could be due to fetal hypoxia-induced redistribution in the fetal circulation. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Influence of birth weight on fetal cardiac indices at 35-37 weeks' gestation.

OBJECTIVE: Echocardiographic studies have reported that fetuses with low birth weight, compared to those with normal birth weight, have globular hearts and reduced cardiac function. Dichotomizing continuous variables, such as birth weight, may be helpful in describing pathology in small studies but can prevent us from identifying physiological responses in relation to change in size. The aim of this study was to explore associations between fetal cardiac morphology and function and birth weight, as a continuous variable, as well as uterine artery (UtA) pulsatility index (PI), as an indirect measure of placental perfusion, and the cerebroplacental ratio (CPR), as an indirect measure of fetal oxygenation. METHODS: This was a prospective study of 1498 women with singleton pregnancy undergoing routine ultrasound examination at 35 + 0 to 36 + 6 weeks' gestation. Pregnancies complicated by pregestational or gestational diabetes mellitus, chronic hypertension, pregnancy-induced hypertension or pre-eclampsia were excluded from the analysis. Conventional and more advanced echocardiographic modalities, such as speckle tracking, were used to assess fetal cardiac function in the right and left ventricles. The morphology of the fetal heart was assessed by calculating the right and left sphericity indices. In addition, the PI of the UtA, umbilical artery (UA) and fetal middle cerebral artery (MCA) was determined and the CPR was calculated by dividing MCA-PI by UA-PI. Multiple linear regression models were used to assess determinants of fetal echocardiographic parameters. RESULTS: The study population included 146 (9.7%) small-for-gestational-age (SGA) fetuses with birth weight < 10th percentile and 68 (4.5%) with fetal growth restriction (FGR). In the SGA and FGR groups, compared to the non-SGA and non-FGR fetuses, respectively, there was a more globular right ventricle and reduced left and right ventricular systolic function, and, from the left ventricular diastolic functional indices, the E/A ratio was increased. There was a linear association of right ventricular sphericity index, indices of left and right ventricular systolic function and E/A ratio with birth-weight Z-score. There were no significant associations between cardiac morphological and functional indices and UtA-PI Z-score or CPR Z-score. CONCLUSIONS: This screening study at 35-37 weeks' gestation has demonstrated that birth weight is a determinant of fetal cardiac morphology and function but UtA-PI and CPR, as indirect measures of placental perfusion and fetal oxygenation, are not. This suggests that the differences in fetal cardiac indices between small and appropriately grown fetuses may be part of a normal physiological response to change in fetal size rather than part of a pathological adaptation to abnormal placental perfusion and fetal oxygenation. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Insight into the incidence of acute aortic dissection in the German region of Berlin and Brandenburg.

BACKGROUND: Stanford acute type A aortic dissection (ATAAD) is a potentially lethal condition. Epidemiology studies show a statistical incidence in Europe of approximately 2-16 cases/100,000 inhabitants/year. In Germany, the estimated incidence (here subsumed under "thoracic aortic dissection" with 4.63 cases/100,000 inhabitants/year) is mainly extracted from medical death certificates by the German Federal Statistical Office. The prehospital incidence of ATAAD deaths is largely unknown. Since patients often die in the pre-hospital setting, the incidence of ATAAD is therefore likely to be higher than current estimates. MATERIAL AND METHODS: For the period from 2010 to 2014, we retrospectively analyzed all in-hospital ATAAD data from two of the largest cardiac surgical centers that treat ATAAD in the Berlin-Brandenburg region. In addition, autopsy reports of all forensic medicine institutes and of one large pathological provider in the region were analyzed to identify additional non-hospitalized ATAAD patients. Based on these findings, the regional incidence of ATAAD was calculated. RESULTS: In addition to in-hospital ATAAD patients (n=405), we identified additional 145 lethal ATAAD cases among 14,201 autopsy reports. The total of 550 ATAAD cases led to an estimated incidence of 11.9 cases/100,000 inhabitants/year for the whole Berlin-Brandenburg region. Arterial hypertension, pre-existing aortic dilatation, and hereditary connective tissue disorder were found in, respectively, 62.7%, 10%, and 1.8% of patients. CONCLUSION: ATAAD is more frequent than previously reported. Our results show that when patients who die outside of cardiac surgery centers are included, the incidence of ATAAD significantly exceeds the rate reported by the Federal Statistical Office.

Medium-chain fatty acids modulate myocardial function via a cardiac odorant receptor.

Several studies have demonstrated the expression of odorant receptors (OR) in various human tissues and their involvement in different physiological and pathophysiological processes. However, the functional role of ORs in the human heart is still unclear. Here, we firstly report the functional characterization of an OR in the human heart. Initial next-generation sequencing analysis revealed the OR expression pattern in the adult and fetal human heart and identified the fatty acid-sensing OR51E1 as the most highly expressed OR in both cardiac development stages. An extensive characterization of the OR51E1 ligand profile by luciferase reporter gene activation assay identified 2-ethylhexanoic acid as a receptor antagonist and various structurally related fatty acids as novel OR51E1 ligands, some of which were detected at receptor-activating concentrations in plasma and epicardial adipose tissue. Functional investigation of the endogenous receptor was carried out by Ca2+ imaging of human stem cell-derived cardiomyocytes. Application of OR51E1 ligands induced negative chronotropic effects that depended on activation of the OR. OR51E1 activation also provoked a negative inotropic action in cardiac trabeculae and slice preparations of human explanted ventricles. These findings indicate that OR51E1 may play a role as metabolic regulator of cardiac function.

Inter- and intra-subject variability of motor cortex plasticity following continuous theta-burst stimulation.

BACKGROUND: The potential of non-invasive brain stimulation (NIBS) for studying, and inducing, functionally relevant neuroplasticity is dependent on protocols that can induce lasting, robust and reliable effects. A current limiting factor is the large inter- and intra-subject variability in NIBS-induced neuroplastic responses. There has been some study of inter-subject response variability and factors that contribute to it; however, intra-subject response variability has, so far, received little investigation. OBJECTIVES: By testing participants on multiple occasions we aimed to (1) compare inter- and intra-subject variability of neuroplastic responses induced by continuous theta-burst stimulation (cTBS); (2) determine whether the transcranial magnetic stimulation (TMS) intensity used to measure cTBS-induced neuroplastic responses contributes to response variability; (3) determine whether assessment of factors known to influence response variability can be used to explain some of the variability in cTBS-induced neuroplastic responses across experimental sessions. METHODS: In three separate experimental sessions, motor-evoked potential (MEP) input-output (IO) curves were obtained before and after cTBS, and questionnaire-based assessments of physical activity and perceived stress were obtained. RESULTS: cTBS-induced MEP suppression was greatest at the upper end of the IO curve (150-180% resting motor threshold; RMT) and most consistent across subjects and across experimental sessions when assessed with a TMS intensity of 150% RMT. The magnitude of cTBS-induced MEP suppression evoked at 150% RMT correlated with self-reported perceived stress, but not with self-reported physical activity. CONCLUSIONS: The most reliable TMS intensity to probe cTBS-induced long-term depression (LTD)-like neuroplastic responses is 150% RMT. This is unlikely to simply be a ceiling effect and, we suggest, may be due to changes in the descending volley evoked at higher stimulus intensities. The perceived stress scale appears to be sufficiently sensitive to measure the influence of subject stress on LTD-like neuroplastic responses.

Re-induction with L-DNR/FLAG improves response after AML relapse, but not long-term survival.

BACKGROUND: According to the results of the international study Relapsed AML 2001/01 response was better after re-induction with L-DNR/FLAG (liposomal daunorubicin, fludarabine, cytarabine, G-CSF) compared to FLAG only but survival rate was not improved. However, the findings might be group-specific. METHOD: Patient characteristics, actual therapy given and long-term course of the disease in 155 pediatric patients (including non-randomized) with first relapse and 10 primary nonresponders treated in Germany were analyzed. RESULTS: Overall 4-year survival rates after relapse were similar in the 2 treatment groups L-DNR/FLAG and FLAG (0.43 ± 0.05 vs. 0.47 ± 0.06, p(log-rank)=0.47). The rate of randomization was low (65%) and 5% of the 101 randomized patients changed the treatment arm. Therefore, induction was based in 40% patients on an individual decision with preference for L-DNR/FLAG. There were less patients with favorable cytogenetics and morphology in the L-DNR/FLAG-group (p<0.04). Response to the first re-induction course at day 28 tended to be more unfavorable with FLAG only. In this patient group protocol intensifications were more frequent as compared to the L-DNR/FLAG-group (p=0.07), and late CR could be achieved after intensification in 9/18 poor responding patients. CONCLUSION: The initial selection bias of relapse patients with unfavorable risk factors to the disadvantage of the L-DNR/FLAG-group and the more drug- and time-intensive treatment after 1(st) re-induction given in the FLAG-group may have nullified the initial beneficial effect of L-DNR containing re-induction therapy and led to similar and relatively favorable survival rates in both treatment groups in Germany.

Motor unit activity after eccentric exercise and muscle damage in humans.

It is well known that unaccustomed eccentric exercise leads to muscle damage and soreness, which can produce long-lasting effects on muscle function. How this muscle damage influences muscle activation is poorly understood. The purpose of this brief review is to highlight the effect of eccentric exercise on the activation of muscle by the nervous system, by examining the change in motor unit activity obtained from surface electromyography (EMG) and intramuscular recordings. Previous research shows that eccentric exercise produces unusual changes in the EMG­force relation that influences motor performance during isometric, shortening and lengthening muscle contractions and during fatiguing tasks. When examining the effect of eccentric exercise at the single motor unit level, there are substantial changes in recruitment thresholds, discharge rates, motor unit conduction velocities and synchronization, which can last for up to 1 week after eccentric exercise. Examining the time course of these changes suggests that the increased submaximal EMG after eccentric exercise most likely occurs through a decrease in motor unit conduction velocity and an increase in motor unit activity related to antagonist muscle coactivation and low-frequency fatigue. Furthermore, there is a commonly held view that eccentric exercise produces preferential damage to high-threshold motor units, but the evidence for this in humans is limited. Further research is needed to establish whether there is preferential damage to high-threshold motor units after eccentric exercise in humans, preferably by linking changes in motor unit activity with estimates of motor unit size using selective intramuscular recording techniques.

Eccentric muscle damage increases intermuscular coherence during a fatiguing isometric contraction.

AIM: The purpose of this study was to determine the effect of eccentric muscle damage on muscle activation patterns and intermuscular coherence during a fatiguing isometric contraction involving the elbow flexor muscles. METHODS: Ten young subjects participated in three experimental sessions that involved the performance of maximum voluntary contractions (MVCs), a constant-force task at 30% MVC, and a fatiguing isometric contraction at 30% MVC. The three sessions were performed before, 2 h after and 2 days after eccentric exercise to induce muscle damage in elbow flexor muscles. Task performance was quantified with electromyography (EMG) from the elbow flexor (biceps brachii, brachialis and brachioradialis) and extensor (triceps brachii) muscles, M-wave amplitude of biceps brachii, elbow flexor force fluctuations and endurance time of a fatiguing contraction. Intermuscular coherence during the fatiguing contraction was quantified from the rectified surface EMGs between muscle pairs. RESULTS: Eccentric exercise resulted in several indicators of muscle damage, such as a prolonged decline in muscle strength and an increase in muscle soreness 2 days after exercise. A 29% reduction in endurance time was observed 2 h after eccentric muscle damage, which returned to baseline 2 days later. The reduced endurance time 2 h after muscle damage was accompanied by an increase in EMG-EMG coherence between biceps brachii and brachialis muscles, which was observed at the end of the fatiguing contraction. CONCLUSION: These findings suggest that eccentric muscle damage produces a decrease in endurance time that is accompanied by an increase in intermuscular coherence in the presence of fatigue.

Neural adaptations to strength training: moving beyond transcranial magnetic stimulation and reflex studies.

It has long been believed that training for increased strength not only affects muscle tissue, but also results in adaptive changes in the central nervous system. However, only in the last 10 years has the use of methods to study the neurophysiological details of putative neural adaptations to training become widespread. There are now many published reports that have used single motor unit recordings, electrical stimulation of peripheral nerves, and non-invasive stimulation of the human brain [i.e. transcranial magnetic stimulation (TMS)] to study neural responses to strength training. In this review, we aim to summarize what has been learned from single motor unit, reflex and TMS studies, and identify the most promising avenues to advance our conceptual understanding with these methods. We also consider the few strength training studies that have employed alternative neurophysiological techniques such as functional magnetic resonance imaging and electroencephalography. The nature of the information that these techniques can provide, as well as their major technical and conceptual pitfalls, are briefly described. The overall conclusion of the review is that the current evidence regarding neural adaptations to strength training is inconsistent and incomplete. In order to move forward in our understanding, it will be necessary to design studies that are based on a rigorous consideration of the limitations of the available techniques, and that are specifically targeted to address important conceptual questions.

[Antisense oligonucleotides for therapy of cystic fibrosis. Inhibition of sodium absorption mediated by ENaC in nasal epithelial cells]. / Antisense-Oligonukleotide zur Therapie der Mukoviszidose. Inhibition der ENaC-vermittelten Natriumabsorption in humanen Nasenepithelzellen.

BACKGROUND: The genetic disease cystic fibrosis (CF) is characterised by reduced chloride secretion mediated by the cystic fibrosis transmembrane conductance regulator (CFTR) and Na(+) hyperabsorption through amiloride-sensitive epithelial sodium channels (ENaC). Mutations in CFTR cause the accumulation of thick mucus and dysfunction of mucociliary clearance in the respiratory tract. MATERIAL AND METHODS: In this project it was investigated whether Na(+) hyperabsorption is inhibited by the use of antisense oligonucleotides (AON). For functional analyses monolayers of human non-CF and CF nasal epithelial cells were measured in modified Ussing chambers. To analyse the AON effects on the protein level Western blotting analyses were carried out. RESULTS: AON transfection significantly inhibits Na(+) absorption via ENaC in non-CF and CF cells. Furthermore, Western blot analyses demonstrate a suppression of the ENaC protein in AON transfected human non-CF cells. CONCLUSION: The inhibition of ENaC associated Na(+) absorption by specific AON could offer a new perspective for the regulation of the Na(+) hyperabsorption in CF patients.

Low-frequency common modulation of soleus motor unit discharge is enhanced during postural control in humans.

The maintenance of quiet stance requires the activation of muscles bilaterally. The soleus muscles in each leg share a common function in standing; that is, each muscle acts to control antero-posterior (AP) sway on its own side. We sought to determine the extent to which oscillations in motor unit discharge were related in motor unit pairs of the soleus muscles during postural and voluntary isometric tasks, both within and between legs. Subjects stood quietly for 5 min or performed a voluntary isometric plantarflexion contraction in a seated position. During the postural tasks, the excursions of AP sway between legs were highly correlated (rho = 0.86 +/- 0.06). The strength of common modulation of motor unit discharge rates was assessed using time- and frequency-domain analyses. The time-domain common drive analysis revealed that the strongest correlation in motor unit discharge modulation occurred in the postural task with unilateral pairs (rho = 0.71 +/- 0.13) being more strongly correlated than bilateral pairs (rho = 0.50 +/- 0.16). Common modulation of motor unit discharge was lowest for the voluntary tasks, with rho = 0.38 +/- 0.11 and 0.16 +/- 0.08 for unilateral and bilateral pairs, respectively. Similarly, the frequency-domain coherence analysis demonstrated an identical ordering effect, with the largest maximum pooled coherence occurring during standing posture in unilateral (0.070 at 1.6 Hz) and bilateral (0.055 at 1.6 Hz) recordings, whereas minimal coherence was observed in the voluntary task in both unilateral and bilateral recordings within the 0-5 Hz range. These results indicate that in the soleus muscle, common modulation of motor unit discharge is greater during postural tasks than during voluntary isometric tasks and can be observed in both bilateral and unilateral motor unit pairs. Differences in the extent of co-modulation of motor unit discharge between tasks may be attributed to either differences in the descending control or differences in the proprioceptive input between postural and isometric tasks.

Long-term activity in upper- and lower-limb muscles of humans.

Despite limited data on humans, previous studies suggest that there is an association between the duration of daily muscle activity and the proportion of type I muscle fibers. We quantified the activity of limb muscles in healthy men and women during normal use and compared these measurements with published reports on fiber-type proportions. Seven men (age range = 21-28 yr) and seven women (age range = 18-26 yr) participated in two 10-h recording sessions. Electromyogram (EMG) activity of four muscles in nondominant upper (first dorsal interosseus and biceps brachii) and lower limbs (vastus medialis and vastus lateralis) was recorded with surface electrodes. Hand and arm muscles were active for 18% of the recording time, whereas leg muscles were active for only 10% of the recording time. On average, upper-limb muscles were activated 67% more often than lower-limb muscles. When lower-limb muscles were activated, however, the mean amplitude of each burst was greater in leg muscles [18 and 17% maximum voluntary contraction (MVC)] compared with hand (8% MVC) and arm (6% MVC) muscles. Temporal association in activity between pairs of muscles was high for the two lower-limb muscles (r2 = 0.7) and relatively weak for the two upper-limb muscles (r2 = 0.09). Long-term muscle activity was only different between men and women for the biceps brachii muscle. We found no relation between duration of muscle activity in 10-h recordings and the reported values of type I fibers in men and women.

Gene expression of the key enzymes of melatonin synthesis in extrapineal tissues of the rat.

Besides the pineal gland, melatonin is reported to be produced in a number of extrapineal sites, where it could act as an intracellular mediator or paracrine signal in addition to its endocrine effects. In view of the suggested immunoregulatory role of melatonin, we compared lymphoid organs and several other tissues of the rat for their potential to synthesize melatonin. Using the reverse transcription-polymerase chain reaction (RT-PCR) method, we determined the tissue-specific expression of mRNAs encoding two key enzymes of the melatonin biosynthesis: serotonin-N-acetyltransferase (NAT) and hydroxyindole-O-methyltransferase (HIOMT). The minimal number of PCR cycles required to obtain a positive signal served as a measure for the abundance of a given mRNA. NAT and HIOMT mRNAs were detected in all tested tissues at high numbers of PCR cycles (40 and 45, respectively). At 35 cycles, only gut, testis, spinal cord, raphe nuclei, stomach fundus and striatum yielded positive signals for both enzymes. In conclusion, the presence of NAT and HIOMT mRNAs in a wide range of tissues corroborates and extends the notion of extrapineal melatonin synthesis. Comparatively low levels of the HIOMT messages in lymphoid organs, however, indicate a limited significance of melatonin synthesis within the immune system.

Limb immobilization alters muscle activation patterns during a fatiguing isometric contraction.

The purpose of the study was to determine the role of excitation-contraction coupling in the increased endurance time for low-force contractions after 4 weeks of elbow joint immobilization. Twelve subjects participated in a protocol that required immobilization of the elbow joint in a fiberglass cast for 4 weeks, and 4 subjects acted as controls. Measurements of muscle strength, contractile properties, and fatigability were performed before and after 4 weeks of limb immobilization, and after 4 weeks of recovery. The immobilization intervention produced significant reductions in the daily activity of the elbow flexor muscles, a 21% decline in the maximum voluntary contraction (MVC) force, and a 31% decrease in the maximum load that could be lifted once. Seven of the immobilized subjects exhibited an unusual pattern of muscle activity during the fatiguing contraction after immobilization, which was associated with an increase in the endurance time of the elbow flexor muscles (mean = 220%) in these subjects. The unusual pattern of muscle activity involved lower relative activity of the brachialis muscle, no increase in the amplitude of the electromyogram (EMG) for the elbow flexor muscles, and intermittent rather than continuous EMG. In contrast, the force-frequency relationship of biceps brachii was not altered by immobilization in these subjects, suggesting that adaptations in excitation-contraction coupling were not the primary cause of the prolonged endurance time after immobilization. Rather, the results suggest that the prolonged endurance time exhibited by some subjects after immobilization was largely due to adaptations within the nervous system.

Motor-unit synchronization is not responsible for larger motor-unit forces in old adults.

Motor-unit synchronization, which is a measure of the near simultaneous discharge of action potentials by motor units, has the potential to influence spike-triggered average force and the steadiness of a low-force isometric contraction. The purpose of the study was to estimate the contribution of motor-unit synchronization to the larger spike-triggered average forces and the decreased steadiness exhibited by old adults. Eleven young (age 19-30 yr) and 14 old (age 63-81 yr) adults participated in the study. Motor-unit activity was recorded with two fine-wire intramuscular electrodes in the first dorsal interosseus muscle during isometric contractions that caused the index finger to exert an abduction force. In a separate session, steadiness measurements were obtained during constant-force isometric contractions at target forces of 2.5, 5, 7. 5, and 10% of the maximum voluntary contraction (MVC) force. Mean (+/-SD) motor-unit forces measured by spike-triggered averaging were larger in old (15.5 +/- 12.1 mN) compared with young (7.3 +/- 5.7 mN) adults, and the differences were more pronounced between young (8.7 +/- 6.4 mN) and old (19.9 +/- 12.2 mN) men. Furthermore, the old adults had a reduced ability to maintain a steady force during an isometric contraction, particularly at low target forces (2.5 and 5% MVC). Mean (+/-SD) motor-unit synchronization, expressed as the frequency of extra synchronous discharges above chance in the cross-correlogram, was similar in young [0.66 +/- 0.4 impulses/s (imp/s); range, 0.35-1.51 imp/s; 53 pairs) and old adults (0.72 +/- 0.5 imp/s; range, 0.27-1.38 imp/s; 56 pairs). The duration of synchronous peaks in the cross-correlogram was similar for each group (approximately 16 ms). These data suggest that motor-unit synchronization is not responsible for larger spike-triggered average forces in old adults and that motor-unit synchronization does not contribute to the decreased steadiness of low-force isometric contractions observed in old adults.

Gender differences in the fatigability of human skeletal muscle.

After participating in a 4-wk intervention that reduced normal usage of the elbow flexor muscles, all six women, but only one of six men, experienced a marked increase in the endurance time during a low-force fatiguing contraction. The increase in endurance time was associated with an altered pattern of muscle activation that did not involve the commonly observed progressive increase in muscle activity. Rather, the muscle activity comprised intermittent motor unit activity. In those individuals who exhibited this behavior, the novel pattern of muscle activity was only present immediately after 4 wk of limb immobilization and not before the intervention or after 4 wk of recovery. These findings suggest possible differences between women and men in the adaptations of the neuromuscular system.

A comparison of cross-correlation and surface EMG techniques used to quantify motor unit synchronization in humans.

Two methods used to estimate the strength of motor unit (MU) synchronization in a muscle are the direct cross-correlation of MU discharge times, and averaging of the surface electromyogram (SEMG) with respect to discharge of a reference MU. Although indirect, the latter approach has the advantage that a global estimate of MU synchrony can be obtained quickly and easily. The two methods are generally regarded as providing equivalent information on the extent of MU synchronization in a muscle, but this proposition has not previously been tested quantitatively. In the present study, we used both the SEMG technique (189 MUs) and cross-correlation of MU discharge (498 MU pairs) to estimate MU synchrony in 28 first dorsal interosseus (FDI) muscles from 16 subjects. Despite considerable overlap in the identity of MUs used to quantify synchrony with each method, linear regression revealed no significant correlation between the estimates of MU synchronization in FDI muscles obtained with the two techniques (r2= 0.04, n = 28). This discrepancy was not due to insufficient sampling of the MU population with the cross-correlation method, although we found evidence for a non-uniform tendency for synchronous discharge in two of 13 motor units providing sufficient data for the analysis. The most likely explanation for the discrepancy between the estimates of MU synchrony is that methodological problems with the SEMG technique limit its accuracy. These problems are difficult to avoid under normal experimental conditions, and we conclude that the SEMG method is not reliable for quantitative comparisons of MU synchrony between muscles and subjects.

Voluntary movement after pallidotomy in severe Parkinson's disease.

The mechanisms of improvement in parkinsonian bradykinesia after posteroventral pallidotomy were investigated in 17 patients undergoing unilateral pallidotomy for severe Parkinson's disease. Clinical ratings of 'off' period bradykinesia demonstrated a maximal improvement of 22% 3 months postoperatively. Kinematic assessments of rapid repetitive finger and sequential arm movements were performed after overnight withdrawal of antiparkinsonian medications. There was a bilateral reduction in the inter-onset latency of a two-stage sequential arm movement and a contralateral increase in speed of arm movement after pallidotomy. There was no significant improvement postoperatively in the rhythm, amplitude or speed of repetitive finger movements. The results confirm the clinical impression that pallidotomy improves bradykinesia. This was more evident for complex limb movements, which used attentional strategies and external (visual and auditory) cues, than for repetitive fingertapping movements, which were largely internally generated. Since ablation of the pallidum can only reduce inhibitory pallidal outflow, it is unlikely to restore the normal pallidal influence on thalamocortical motor circuits. Therefore, any improvement in bradykinesia after pallidotomy must be related to mechanisms other than restoration of pallidothalamocortical connectivity. Based on the above observations, we suggest that some of the changes in motor control may be explained by the greater efficacy of external cues in facilitating movement after withdrawal of the abnormal pallidal discharge.