Physiological recruitment of motor units by high-frequency electrical stimulation of afferent pathways

Neuromuscular electrical stimulation (NMES) is commonly used in rehabilitation, but\ua0electrically evoked muscle activation is in several ways different from\ua0voluntary muscle contractions. These differences lead to challenges in\ua0the use of NMES for restoring muscle function. We investigated the\ua0use of low-current, high-frequency nerve stimulation to activate the\ua0muscle via the spinal motoneuron (MN) pool to achieve more natural\ua0activation patterns. Using a novel stimulation protocol, the H-reflex\ua0responses to individual stimuli in a train of stimulation pulses at 100\ua0Hz were reliably estimated with surface EMG during low-level\ua0contractions. Furthermore, single motor unit recruitment by afferent\ua0stimulation was analyzed with intramuscular EMG. The results\ua0showed that substantially elevated H-reflex responses were obtained\ua0during 100-Hz stimulation with respect to a lower stimulation frequency. Furthermore, motor unit recruitment using 100-Hz stimulation was not fully synchronized, as it occurs in classic NMES, and the\ua0discharge rates differed among motor units because each unit was\ua0activated only after a specific number of stimuli. The most likely\ua0mechanism behind these observations is the temporal summation of\ua0subthreshold excitatory postsynaptic potentials from Ia fibers to the\ua0MNs. These findings and their interpretation were also verified by a\ua0realistic simulation model of afferent stimulation of a MN population.\ua0These results suggest that the proposed stimulation strategy may allowgeneration of considerable levels of muscle activation b

Electrical Stimulation of Afferent Pathways for the Suppression of Pathological Tremor

Pathological tremors are involuntary oscillatory movements which cannot be fully attenuated using conventional treatments. For this reason, several studies have investigated the use of neuromuscular electrical stimulation for tremor suppression. In a recent study, however, we found that electrical stimulation below the motor threshold also suppressed tremor, indicating involvement of afferent pathways. In this study, we further explored this possibility by systematically investigating how tremor suppression by afferent stimulation depends on the stimulation settings. In this way, we aimed at identifying the optimal stimulation strategy, as well as to elucidate the underlying physiological mechanisms of tremor suppression. Stimulation strategies varying the stimulation intensity and pulse timing were tested in nine tremor patients using either intramuscular or surface stimulation. Significant tremor suppression was observed in six patients (tremor suppression > 75% was observed in three patients) and the average optimal suppression level observed across all subjects was 52%. The efficiency for each stimulation setting, however, varied substantially across patients and it was not possible to identify a single set of stimulation parameters that yielded positive results in all patients. For example, tremor suppression was achieved both with stimulation delivered in an out-of-phase pattern with respect to the tremor, and with random timing of the stimulation. Overall, these results indicate that low-current stimulation of afferent fibers is a promising approach for tremor suppression, but that further research is required to identify how the effect can be maximized in the individual patient.This work has been supported by the Commission of the European Union through the grant ICT-2011-287739 (NeuroTREMOR).Peer reviewedPeer Reviewe

Evaluation of optical flow algorithms for tracking endocardial surfaces on three-dimensional ultrasound data

With relatively high frame rates and the ability to acquire volume data sets with a stationary transducer, 3D ultrasound systems, based on matrix phased array transducers, provide valuable three-dimensional information, from which quantitative measures of cardiac function can be extracted. Such analyses require segmentation and visual tracking of the left ventricular endocardial border. Due to the large size of the volumetric data sets, manual tracing of the endocardial border is tedious and impractical for clinical applications. Therefore the development of automatic methods for tracking three-dimensional endocardial motion is essential. In this study, we evaluate a four-dimensional optical flow motion tracking algorithm to determine its capability to follow the endocardial border in three dimensional ultrasound data through time. The four-dimensional optical flow method was implemented using three-dimensional correlation. We tested the algorithm on an experimental open-chest dog data set and a clinical data set acquired with a Philips' iE33 three-dimensional ultrasound machine. Initialized with left ventricular endocardial data points obtained from manual tracing at end-diastole, the algorithm automatically tracked these points frame by frame through the whole cardiac cycle.A finite element surface was fitted through the data points obtained by both optical flow tracking and manual tracing by an experienced observer for quantitative comparison of the results. Parameterization of the finite element surfaces was performed and maps displaying relative differences between the manual and semi-automatic methods were compared.The results showed good consistency between manual tracing and optical flow estimation on 73% of the entire surface with fewer than 10% difference. In addition, the optical flow motion tracking algorithm greatly reduced processing time (about 94% reduction compared to human involvement per cardiac cycle) for analyzing cardiac function in three-dimensional ultrasound data sets

Nanoscopic insights into seeding mechanisms and toxicity of α-synuclein species in neurons.

New strategies for visualizing self-assembly processes at the nanoscale give deep insights into the molecular origins of disease. An example is the self-assembly of misfolded proteins into amyloid fibrils, which is related to a range of neurodegenerative disorders, such as Parkinson's and Alzheimer's diseases. Here, we probe the links between the mechanism of α-synuclein (AS) aggregation and its associated toxicity by using optical nanoscopy directly in a neuronal cell culture model of Parkinson's disease. Using superresolution microscopy, we show that protein fibrils are taken up by neuronal cells and act as prion-like seeds for elongation reactions that both consume endogenous AS and suppress its de novo aggregation. When AS is internalized in its monomeric form, however, it nucleates and triggers the aggregation of endogenous AS, leading to apoptosis, although there are no detectable cross-reactions between externally added and endogenous protein species. Monomer-induced apoptosis can be reduced by pretreatment with seed fibrils, suggesting that partial consumption of the externally added or excess soluble AS can be significantly neuroprotective.We thank Dr Q. Jeng and Dr A. Stephens for technical assistance and Dr J. Skepper for TEM imaging. This work was funded by grants from the U.K. Medical Research Council (MR/K015850/1 and MR/K02292X/1), Alzheimer’s Research UK (ARUK-EG2012A-1), U.K. Engineering and Physical Sciences Research Council (EPSRC) (EP/H018301/1) and the Wellcome Trust (089703/Z/09/Z). D.P. wishes to acknowledge support from the Swiss National Science Foundation and the Wellcome Trust through personal fellowships. A.K.B thanks Magdalene College, Cambridge and the Leverhulme Trust for support.This is the author accepted manuscript. The final version is available from the National Academy of Sciences via http://dx.doi.org/10.1073/pnas.1516546113

Bar Evolution Over the Last Eight Billion Years: A Constant Fraction of Strong Bars in GEMS

One third of present-day spirals host optically visible strong bars that drive their dynamical evolution. However, the fundamental question of how bars evolve over cosmological times has yet to be addressed, and even the frequency of bars at intermediate redshifts remains controversial. We investigate the frequency of bars out to z~1.0 drawing on a sample of 1590 galaxies from the GEMS survey, which provides morphologies from HST ACS two-color images, and highly accurate redshifts from the COMBO-17 survey. We identify spiral galaxies using the Sersic index, concentration parameter, and rest-frame color. We characterize bars and disks by fitting ellipses to F606W and F850LP images, taking advantage of the two bands to minimize bandpass shifting. We exclude highly inclined (i>60 deg) galaxies to ensure reliable morphological classifications, and apply completeness cuts of M_v <= -19.3 and -20.6. More than 40% of the bars that we detect have semi major axes a<0.5" and would be easily missed in earlier surveys without the small PSF of ACS. The bars that we can reliably detect are fairly strong (with ellipticities e>=0.4) and have a in the range ~1.2-13 kpc. We find that the optical fraction of such strong bars remains at ~(30% +- 6%) from the present-day out to look-back times of 2-6 Gyr (z~0.2-0.7) and 6-8 Gyr (z~0.7-1.0); it certainly shows no sign of a drastic decline at z>0.7. Our findings of a large and similar bar fraction at these three epochs favor scenarios in which cold gravitationally unstable disks are already in place by z~1, and where on average bars have a long lifetime (well above 2 Gyr). The distributions of structural bar properties in the two slices are, however, not statistically identical and therefore allow for the possibility that the bar strengths and sizes may evolve over time.Comment: Accepted by ApJ Letters, to appear in Nov 2004 issue. Minor revisions,updated reference

Fast Fluorescence Lifetime Imaging Reveals the Aggregation Processes of α-Synuclein and Polyglutamine in Aging Caenorhabditis elegans.

The nematode worm Caenorhabditis elegans has emerged as an important model organism in the study of the molecular mechanisms of protein misfolding diseases associated with amyloid formation because of its small size, ease of genetic manipulation, and optical transparency. Obtaining a reliable and quantitative read-out of protein aggregation in this system, however, remains a challenge. To address this problem, we here present a fast time-gated fluorescence lifetime imaging (TG-FLIM) method and show that it provides functional insights into the process of protein aggregation in living animals by enabling the rapid characterization of different types of aggregates. Specifically, in longitudinal studies of C. elegans models of Parkinson's and Huntington's diseases, we observed marked differences in the aggregation kinetics and the nature of the protein inclusions formed by α-synuclein and polyglutamine. In particular, we found that α-synuclein inclusions do not display amyloid-like features until late in the life of the worms, whereas polyglutamine forms amyloid characteristics rapidly in early adulthood. Furthermore, we show that the TG-FLIM method is capable of imaging live and non-anaesthetized worms moving in specially designed agarose microchambers. Taken together, our results show that the TG-FLIM method enables high-throughput functional imaging of living C. elegans that can be used to study in vivo mechanisms of protein aggregation and that has the potential to aid the search for therapeutic modifiers of protein aggregation and toxicity

Hubble Space Telescope/WFPC2 Investigation of the Nuclear Morphology in the Toomre Sequence of Merging Galaxies

We report on the properties of nuclear regions in the Toomre Sequence of merging galaxies, based on imaging data gathered with the Hubble Space Telescope WFPC2 camera. We have imaged the 11 systems in the proposed evolutionary merger sequence in the F555W and F814W broad-band filters, and in H-alpha+[NII] narrow-band filters. The broad-band morphology of the nuclear regions varies from non-nucleated starburst clumps through dust-covered nuclei to a nucleated morphology. There is no unambiguous trend in the morphology with merger stage. The emission-line morphology is extended beyond the nucleus in most cases, but centrally concentrated (within 1 kpc) emission-line gas can be seen in the four latest-stage merger systems. We have quantified the intrinsic luminosity densities and colors within the inner 100 pc and 1 kpc of each identified nucleus. We find little evidence for a clear trend in nuclear properties along the merger sequence, other than a suggestive rise in the nuclear luminosity density in the most evolved members of the sequence. The lack of clear trends in nuclear properties is likely due both to the effects of obscuration and geometry, as well as the physical variety of galaxies included in the Toomre Sequence.Comment: LaTeX, 24 pages, 21 figures, 2 tables, accepted for publication in The Astronomical Journal, paper with high resolution figures can be accessed at http://www.stsci.edu/~marel/psgzdir/toomreWFPC2.ps.g

Hubble Space Telescope Imaging of Brightest Cluster Galaxies

We used the HST WFPC2 to obtain I-band images of the centers of 81 brightest cluster galaxies (BCGs), drawn from a volume-limited sample of nearby BCGs. The images show a rich variety of morphological features, including multiple or double nuclei, dust, stellar disks, point source nuclei, and central surface brightness depressions. High resolution surface brightness profiles could be inferred for 60 galaxies. Of those, 88% have well-resolved cores. Twelve percent of the BCG sample lacks a well-resolved core; all but one of these BCGs have ``power-law'' profiles. Some of these galaxies have higher luminosities than any power-law galaxy identified by Faber et al. (1997), and have physical upper limits on the break radius well below the values observed for core galaxies of the same luminosity. These results support the idea that the central structure of early-type galaxies is bimodal in its physical properties, but also suggest that there exist high luminosity galaxies with power-law profiles (or unusually small cores). The BCGs in the latter category tend to fall at the low end of the BCG luminosity function and tend to have low values of the quantity alpha (the logarithmic slope of the metric luminosity as a function of radius, at 10 kpc). Since theoretical calculations have shown that the luminosities and alpha values of BCGs grow with time as a result of accretion, this suggests a scenario in which elliptical galaxies evolve from power-law profiles to core profiles through accretion and merging. This is consistent with theoretical scenarios that invoke the formation of massive black hole binaries during merger events (Abridged).Comment: Accepted for publication in AJ. Postscript file with high resolution figures (1 and 3) is available at http://spider.ipac.caltech.edu/staff/seppo/bcgfig