Publications by authors named "Seward B Rutkove"

175 Publications

On the measurement of skeletal muscle anisotropic permittivity property with a single cross-shaped needle insertion.

Sci Rep 2022 May 19;12(1):8494. Epub 2022 May 19.

Department of Electrical and Computer Engineering, University of Utah, Salt Lake City, UT, 84112, USA.

Application of minimally invasive methods to enable the measurement of tissue permittivity in the neuromuscular clinic remain elusive. This paper provides a theoretical and modeling study on the measurement of the permittivity of two-dimensional anisotropic tissues such as skeletal muscle with a multi-electrode cross-shaped needle. For this, we design a novel cross-shaped needle with multiple-electrodes and analyse apparent impedance corresponding to the measured impedance. In addition, we propose three methods of estimate anisotropic muscle permittivity. Compared to existing electrical impedance-based needle methods that we have developed, the new needle design and numerical methods associated enable estimating in vivo muscle permittivity values with only a single needle insertion. Being able to measure muscle permittivity directly with a single needle insertion could open up an entirely new area of research with direct clinical application, including using these values to assist in neuromuscular diagnosis and to assess subtle effects of therapeutic intervention on muscle health.
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http://dx.doi.org/10.1038/s41598-022-12289-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9120124PMC
May 2022

Design and pilot testing of a 26-gauge impedance-electromyography needle in wild-type and ALS mice.

Muscle Nerve 2022 Jun 14;65(6):702-708. Epub 2022 Apr 14.

Department of Electrical and Computer Engineering, University of Utah, Salt Lake City, Utah, USA.

Introduction/aims: Needle impedance-electromyography (iEMG) is a diagnostic modality currently under development that combines intramuscular electrical impedance with concentric electromyography (EMG) in a single needle. We designed, manufactured, and tested a prototype iEMG needle in a cohort of wild-type (WT) and SOD1G93A amyotrophic lateral sclerosis (ALS) mice to assess its ability to record impedance and EMG data.

Methods: A new six-electrode, 26-gauge, iEMG needle was designed, manufactured and tested. Quantitative impedance and qualitative "gestalt" EMG were performed sequentially on bilateral quadriceps of 16-wk-old SOD1G93A ALS (N = 6) and WT (N = 6) mice by connecting the needle first to an impedance analyzer (with the animal at rest) and then to a standard EMG system (with the animal fully under anesthesia to measure spontaneous activity and briefly during awakening to measure voluntary activity). The needle remained in the muscle throughout the measurement period.

Results: EMG data were qualitatively similar to that observed with a commercially available concentric EMG needle; fibrillation potentials were observed in 84% of the ALS mice and none of the WT mice; motor unit potentials were also readily identified. Impedance data revealed significant differences in resistance, reactance, and phase values between the two groups, with ALS animals having reduced reactance and resistance values.

Discussion: This work demonstrates the feasibility of a single iEMG needle conforming to standard dimensions of size and function. Further progress of iEMG technology for enhanced neuromuscular diagnosis and quantification of disease status is currently in development.
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http://dx.doi.org/10.1002/mus.27551DOI Listing
June 2022

Altered electrical properties in skeletal muscle of mice with glycogen storage disease type II.

Sci Rep 2022 03 29;12(1):5327. Epub 2022 Mar 29.

Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.

Electrical impedance methods, including electrical impedance myography, are increasingly being used as biomarkers of muscle health since they measure passive electrical properties of muscle that alter in disease. One disorder, Pompe Disease (Glycogen storage disease type II (GSDII)), remains relatively unstudied. This disease is marked by dramatic accumulation of intracellular myofiber glycogen. Here we assessed the electrical properties of skeletal muscle in a model of GSDII, the Pompe (Pompe) mouse. Ex vivo impedance measurements of gastrocnemius (GA) were obtained using a dielectric measuring cell in 30-week-old female Pompe (N = 10) and WT (N = 10) mice. Longitudinal and transverse conductivity, σ, and the relative permittivity, ε, and Cole-Cole complex resistivity parameters at 0 Hz and infinite frequency, ρ and ρ, respectively, and the intracellular resistivity, ρ were determined from the impedance data. Glycogen content (GC) was visualized histologically and quantified biochemically. At frequencies > 1 MHz, Pompe mice demonstrated significantly decreased longitudinal and transverse conductivity, increased Cole-Cole parameters, ρ and ρ-ρ, and decreased ρ. Changes in longitudinal conductivity and ρ correlated with increased GC in Pompe animals. Ex vivo high frequency impedance measures are sensitive to alterations in intracellular myofiber features considered characteristic of GSDII, making them potentially useful measures of disease status.
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http://dx.doi.org/10.1038/s41598-022-09328-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8964715PMC
March 2022

Impact of the KL2/Catalyst Medical Research Investigator Training (CMeRIT) Program on the careers of early-stage clinical and translational investigators.

J Clin Transl Sci 2022 24;6(1):e16. Epub 2022 Jan 24.

Harvard Catalyst, The Harvard Clinical and Translational Science Center, Harvard Medical School, Boston, Massachusetts, USA.

The Harvard Catalyst KL2/CMeRIT program is a 2-year mentored institutional career award that includes KL2 grants funded by National Institutes of Health (NIH) and CMeRIT grants funded by Harvard Catalyst nonfederal funds. The purpose of this study was to compare outcomes for early-stage investigators funded by the KL2/CMeRIT program to a group of applicants who were not chosen for support to assess the potential impact of the program on early career outcomes. Career data, including academic promotions, subsequent grant funding, and publication rates, from both successful and unsuccessful 2008-2018 KL2/CMeRIT applicants were compiled throughout the year 2020. Data were obtained directly through outreach to both groups and through assessment of online resources. The cohort comprised 487 individuals, 109 awardees, and 378 nonawardees. Awardees were more likely to be subsequently involved in clinical and translational research than nonawardees (92% vs 75%, < 0.001). A higher proportion of awardees also had achieved academic promotion (81% vs 69%, = 0.016) and subsequent NIH funding (72% vs 58%, = 0.047), while there was no difference in publication rates ( = 0.555). Participants in the Harvard Catalyst KL2/CMeRIT program demonstrate greater early career success than nonparticipants though the nonparticipants also fared relatively well.
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http://dx.doi.org/10.1017/cts.2022.7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8889229PMC
January 2022

Nonhomogeneous volume conduction effects affecting needle electromyography: an analytical and simulation study.

Physiol Meas 2021 12 28;42(11). Epub 2021 Dec 28.

Sanchez Research Lab, Department of Electrical and Computer Engineering, University of Utah, Salt Lake City, UT 84112-9206, United States of America.

Needle electromyography (EMG) is used to study the electrical behavior of myofiber properties in patients with neuromuscular disorders. However, due to the complexity of electrical potential spatial propagation in nonhomogeneous diseased muscle, a comprehensive understanding of volume conduction effects remains elusive. Here, we develop a framework to study the conduction effect of extracellular abnormalities and electrode positioning on extracellular local field potential (LFP) recordings.The framework describes the macroscopic conduction of electrical potential in an isotropic, nonhomogeneous (i.e. two tissue) model. Numerical and finite element model simulations are provided to study the conduction effect in prototypical monopolar EMG measurements.LFPs recorded are influenced in amplitude, phase and duration by the electrode position in regards to the vicinity of tissue with different electrical properties.The framework reveals the influence of multiple mechanisms affecting LFPs including changes in the distance between the source-electrode and tissue electrical properties.Our modeled predictions may lead to new ways for interpreting volume conduction effects on recorded EMG activity, for example in neuromuscular diseases that cause structural and compositional changes in muscle tissue. These change will manifest itself by changing the electric properties of the conductor media and will impact recorded potentials in the area of affected tissue.
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http://dx.doi.org/10.1088/1361-6579/ac38c0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8744488PMC
December 2021

Relationships between in vivo surface and ex vivo electrical impedance myography measurements in three different neuromuscular disorder mouse models.

PLoS One 2021 29;16(10):e0259071. Epub 2021 Oct 29.

Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States of America.

Electrical impedance myography (EIM) using surface techniques has shown promise as a means of diagnosing and tracking disorders affecting muscle and assessing treatment efficacy. However, the relationship between such surface-obtained impedance values and pure muscle impedance values has not been established. Here we studied three groups of diseased and wild-type (WT) animals, including a Duchenne muscular dystrophy model (the D2-mdx mouse), an amyotrophic lateral sclerosis (ALS) model (the SOD1 G93A mouse), and a model of fat-related atrophy (the db/db diabetic obese mouse), performing hind limb measurements using a standard surface array and ex vivo measurements on freshly excised gastrocnemius muscle. A total of 101 animals (23 D2-mdx, 43 ALS mice, 12 db/db mice, and corresponding 30 WT mice) were studied with EIM across a frequency range of 8 kHz to 1 MHz. For both D2-mdx and ALS models, moderate strength correlations (Spearman rho values generally ranging from 0.3-0.7, depending on the impedance parameter (i.e., resistance, reactance and phase) were obtained. In these groups of animals, there was an offset in frequency with impedance values obtained at higher surface frequencies correlating more strongly to impedance values obtained at lower ex vivo frequencies. For the db/db model, correlations were comparatively weaker and strongest at very high and very low frequencies. When combining impedance data from all three disease models together, moderate correlations persisted (with maximal Spearman rho values of 0.45). These data support that surface EIM data reflect ex vivo muscle tissue EIM values to a moderate degree across several different diseases, with the highest correlations occurring in the 10-200 kHz frequency range. Understanding these relationships will prove useful for future applications of the technique of EIM in the assessment of neuromuscular disorders.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0259071PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8555802PMC
December 2021

Correction to: Profiling age-related muscle weakness and wasting: neuromuscular junction transmission as a driver of age-related physical decline.

Geroscience 2021 Dec;43(6):2835-2836

Division of Neuromuscular Diseases, Department of Neurology, The Ohio State University Wexner Medical Center, 1060 Carmack Road, Room 207, Columbus, OH, 43210, USA.

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http://dx.doi.org/10.1007/s11357-021-00464-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8602468PMC
December 2021

Hindlimb suspension in Wistar rats: Sex-based differences in muscle response.

Physiol Rep 2021 10;9(19):e15042

Department of Neurology, Harvard Medical School - Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.

Ground-based animal models have been used extensively to understand the effects of microgravity on various physiological systems. Among them, hindlimb suspension (HLS), developed in 1979 in rats, remains the gold-standard and allows researchers to study the consequences of total unloading of the hind limbs while inducing a cephalic fluid shift. While this model has already brought valuable insights to space biology, few studies have directly compared functional decrements in the muscles of males and females during HLS. We exposed 28 adult Wistar rats (14 males and 14 females) to 14 days of HLS or normal loading (NL) to better assess how sex impacts disuse-induced muscle deconditioning. Females better maintained muscle function during HLS than males, as shown by a more moderate reduction in grip strength at 7 days (males: -37.5 ± 3.1%, females: -22.4 ± 6.5%, compared to baseline), that remains stable during the second week of unloading (males: -53.3 ± 5.7%, females: -22.4 ± 5.5%, compared to day 0) while the males exhibit a steady decrease over time (effect of sex × loading p = 0.0002, effect of sex × time × loading p = 0.0099). This was further supported by analyzing the force production in response to a tetanic stimulus. Further functional analyses using force production were also shown to correspond to sex differences in relative loss of muscle mass and CSA. Moreover, our functional data were supported by histomorphometric analyzes, and we highlighted differences in relative muscle loss and CSA. Specifically, female rats seem to experience a lesser muscle deconditioning during disuse than males thus emphasizing the need for more studies that will assess male and female animals concomitantly to develop tailored, effective countermeasures for all astronauts.
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http://dx.doi.org/10.14814/phy2.15042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8493566PMC
October 2021

The oestrous cycle and skeletal muscle atrophy: Investigations in rodent models of muscle loss.

Exp Physiol 2021 12 18;106(12):2472-2488. Epub 2021 Oct 18.

Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.

New Findings: What is the central question of this study? Is the oestrous cycle affected during disuse atrophies and, if so, how are oestrous cycle changes related to musculoskeletal outcomes? What is the main finding and its importance? Rodent oestrous cycles were altered during disuse atrophy, which was correlated with musculoskeletal outcomes. However, the oestrous cycle did not appear to be changed by Lewis lung carcinoma, which resulted in no differences in muscle size in comparison to healthy control animals. These findings suggest a relationship between the oestrous cycle and muscle size during atrophic pathologies.

Abstract: Recent efforts have focused on improving our understanding of female muscle physiology during exposure to muscle atrophic stimuli. A key feature of female rodent physiology is the oestrous cycle. However, it is not known how such stimuli interact with the oestrous cycle to influence muscle health. In this study, we investigated the impact of muscle atrophic stimuli on the oestrous cycle and how these alterations are correlated with musculoskeletal outcomes. A series of experiments were performed in female rodents, including hindlimb unloading (HU), HU followed by 24 h of reloading, HU combined with dexamethasone treatment, and Lewis lung carcinoma. The oestrous cycle phase was assessed throughout each intervention and correlated with musculoskeletal outcomes. Seven or 14 days of HU increased the duration in dioestrus or metoestrus (D/M; low hormones) and was negatively correlated with gastrocnemius mass. Time spent in D/M was also negatively correlated with changes in grip strength and bone density after HU, and with muscle recovery 24 h after the cessation of HU. The addition of dexamethasone strengthened these relationships between time in D/M and reduced musculoskeletal outcomes. However, in animals with Lewis lung carcinoma, oestrous cyclicity did not differ from that of control animals, and time spent in D/M was not correlated with either gastrocnemius mass or tumour burden. In vitro experiments suggested that enhanced protein synthesis induced by estrogen might protect against muscle atrophy. In conclusion, muscle atrophic insults are correlated with changes in the oestrous cycle, which are associated with deterioration in musculoskeletal outcomes. The magnitude of oestrous cycle alterations depends on the atrophic stimuli.
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http://dx.doi.org/10.1113/EP089962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8639792PMC
December 2021

Estimation of forced vital capacity using speech acoustics in patients with ALS.

Amyotroph Lateral Scler Frontotemporal Degener 2021 ;22(sup1):14-21

Department of Speech Pathology, Arizona State University, Phoenix, AZ, USA.

In this study, we present and provide validation data for a tool that predicts forced vital capacity (FVC) from speech acoustics collected remotely via a mobile app without the need for any additional equipment (e.g. a spirometer). We trained a machine learning model on a sample of healthy participants and participants with amyotrophic lateral sclerosis (ALS) to learn a mapping from speech acoustics to FVC and used this model to predict FVC values in a new sample from a different study of participants with ALS. We further evaluated the cross-sectional accuracy of the model and its sensitivity to within-subject change in FVC. We found that the predicted and observed FVC values in the test sample had a correlation coefficient of .80 and mean absolute error between .54 L and .58 L (18.5% to 19.5%). In addition, we found that the model was able to detect longitudinal decline in FVC in the test sample, although to a lesser extent than the observed FVC values measured using a spirometer, and was highly repeatable (ICC = 0.92-0.94), although to a lesser extent than the actual FVC (ICC = .97). These results suggest that sustained phonation may be a useful surrogate for VC in both research and clinical environments.
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http://dx.doi.org/10.1080/21678421.2020.1866013DOI Listing
September 2021

No, it's not 1976 all over again.

Ann Neurol 2021 08 23;90(2):189-190. Epub 2021 Jun 23.

New York University School of Global Public Health, New York, NY.

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http://dx.doi.org/10.1002/ana.26142DOI Listing
August 2021

Putting the patient first: The validity and value of surface-based electrical impedance myography techniques.

Clin Neurophysiol 2021 07 20;132(7):1752-1753. Epub 2021 Apr 20.

Department of Neurology, Barrow Neurological Institute, Phoenix, AZ, USA.

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http://dx.doi.org/10.1016/j.clinph.2021.03.020DOI Listing
July 2021

Profiling age-related muscle weakness and wasting: neuromuscular junction transmission as a driver of age-related physical decline.

Geroscience 2021 06 24;43(3):1265-1281. Epub 2021 Apr 24.

Division of Neuromuscular Diseases, Department of Neurology, The Ohio State University Wexner Medical Center, 1060 Carmack Road, Room 207, Columbus, OH, 43210, USA.

Pathological age-related loss of skeletal muscle strength and mass contribute to impaired physical function in older adults. Factors that promote the development of these conditions remain incompletely understood, impeding development of effective and specific diagnostic and therapeutic approaches. Inconclusive evidence across species suggests disruption of action potential signal transmission at the neuromuscular junction (NMJ), the crucial connection between the nervous and muscular systems, as a possible contributor to age-related muscle dysfunction. Here we investigated age-related loss of NMJ function using clinically relevant, electrophysiological measures (single-fiber electromyography (SFEMG) and repetitive nerve stimulation (RNS)) in aged (26 months) versus young (6 months) F344 rats. Measures of muscle function (e.g., grip strength, peak plantarflexion contractility torque) and mass were assessed for correlations with physiological measures (e.g., indices of NMJ transmission). Other outcomes also included plantarflexion muscle contractility tetanic torque fade during 1-s trains of stimulation as well as gastrocnemius motor unit size and number. Profiling NMJ function in aged rats identified significant declines in NMJ transmission stability and reliability. Further, NMJ deficits were tightly correlated with hindlimb grip strength, gastrocnemius muscle weight, loss of peak contractility torque, degree of tetanic fade, and motor unit loss. Thus, these findings provide direct evidence for NMJ dysfunction as a potential mechanism of age-related muscle dysfunction pathogenesis and severity. These findings also suggest that NMJ transmission modulation may serve as a target for therapeutic development for age-related loss of physical function.
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http://dx.doi.org/10.1007/s11357-021-00369-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190265PMC
June 2021

A novel method for estimating the fractional Cole impedance model using single-frequency DC-biased sinusoidal excitation.

Circuits Syst Signal Process 2021 Feb 13;40(2):543-558. Epub 2020 Aug 13.

Department of Electrical and Computer Engineering, Sorenson Molecular Biotechnology Building, Office 3721, 36 South Wasatch Drive, University of Utah, Salt Lake City, UT 84112, USA.

Objective: The Cole model is a widely used fractional circuit model in electrical bioimpedance applications for evaluating the content and status of biological tissues and fluids. Existing methods for estimating the Cole impedance parameters are often based on -frequency data obtained from stepped-sine measurements fitted using a complex non-linear least square (CNLS) algorithm. Newly emerged numerical methods from the magnitude of electrical bio-impedance data-only do not need CNLS fitting, but they still require -frequency stepped-sine data. This study proposes a novel approach to estimating the Cole impedance parameters that combines a numerical and time-domain fitting method based on a -frequency DC-biased sinusoidal current excitation.

Approach: First, the transient and steady-state voltage response along with the current excitation are acquired in electrical bio-impedance measurement. From the sampled data, a numerical method is applied to provide the initial estimation of the Cole impedance parameters, which are then used in a time-domain iterative fitting algorithm.

Results: The accuracy of the algorithm proposed is tested with noisy electrical bio-impedance simulations. The maximum relative error of the estimated Cole impedance parameters is 1% considering 2% (34 dB) additive Gaussian noise. Experimental measurements performed on a 2R-1C circuit and some fruit samples show a mean difference less than 1% and 5% respectively compared to the Cole impedance parameters estimated from a commercial electrical bio-impedance analyzer performing stepped-sine measurements and CNLS fitting.

Significance: This is the first method that allows estimating the Cole impedance parameters from -frequency electrical bio-impedance data. The approach presented could find broad use in many applications, including -frequency body impedance analysis.
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http://dx.doi.org/10.1007/s00034-020-01512-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987131PMC
February 2021

Estimating myofiber cross-sectional area and connective tissue deposition with electrical impedance myography: A study in D2-mdx mice.

Muscle Nerve 2021 06 7;63(6):941-950. Epub 2021 Apr 7.

Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.

Introduction: Surface electrical impedance myography (sEIM) has the potential for providing information on muscle composition and structure noninvasively. We sought to evaluate its use to predict myofiber size and connective tissue deposition in the D2-mdx model of Duchenne muscular dystrophy (DMD).

Methods: We applied a prediction algorithm, the least absolute shrinkage and selection operator, to select specific EIM measurements obtained with surface and ex vivo EIM data from D2-mdx and wild-type (WT) mice (analyzed together or separately). We assessed myofiber cross-sectional area histologically and hydroxyproline (HP), a surrogate measure for connective tissue content, biochemically.

Results: Using WT and D2-mdx impedance values together in the algorithm, sEIM gave average root-mean-square errors (RMSEs) of 26.6% for CSA and 45.8% for HP, which translate into mean errors of ±363 μm for a mean CSA of 1365 μm and of ±1.44 μg HP/mg muscle for a mean HP content of 3.15 μg HP/mg muscle. Stronger predictions were obtained by analyzing sEIM data from D2-mdx animals alone (RMSEs of 15.3% for CSA and 34.1% for HP content). Predictions made using ex vivo EIM data from D2-mdx animals alone were nearly equivalent to those obtained with sEIM data (RMSE of 16.59% for CSA), and slightly more accurate for HP (RMSE of 26.7%).

Discussion: Surface EIM combined with a predictive algorithm can provide estimates of muscle pathology comparable to values obtained using ex vivo EIM, and can be used as a surrogate measure of disease severity and progression and response to therapy.
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http://dx.doi.org/10.1002/mus.27240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8883327PMC
June 2021

To Zoom or Not to Zoom: The Should I Travel Index Revisited during the Coronavirus Disease Pandemic.

Ann Neurol 2021 06 15;89(6):1057-1058. Epub 2021 Feb 15.

Department of Neurology, University of Miami, Miller School of Medicine, Miami, FL, USA.

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http://dx.doi.org/10.1002/ana.26038DOI Listing
June 2021

Antisense oligonucleotide and adjuvant exercise therapy reverse fatigue in old mice with myotonic dystrophy.

Mol Ther Nucleic Acids 2021 Mar 26;23:393-405. Epub 2020 Nov 26.

Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA.

Patients with myotonic dystrophy type 1 (DM1) identify chronic fatigue as the most debilitating symptom, which manifests in part as prolonged recovery after exercise. Clinical features of DM1 result from pathogenic gain-of-function activity of transcripts containing an expanded microsatellite CUG repeat (CUG). In DM1 mice, therapies targeting the CUG transcripts correct the molecular phenotype, reverse myotonia, and improve muscle pathology. However, the effect of targeted molecular therapies on fatigue in DM1 is unknown. Here, we use two mouse models of DM1, age-matched wild-type controls, an exercise-activity assay, electrical impedance myography, and therapeutic antisense oligonucleotides (ASOs) to show that exaggerated exercise-induced fatigue progresses with age, is unrelated to muscle fiber size, and persists despite correction of the molecular phenotype for 3 months. In old DM1 mice, ASO treatment combined with an exercise training regimen consisting of treadmill walking 30 min per day 6 days per week for 3 months reverse all measures of fatigue. Exercise training without ASO therapy improves some measures of fatigue without correction of the molecular pathology. Our results highlight a key limitation of ASO monotherapy for this clinically important feature and support the development of moderate-intensity exercise as an adjuvant for targeted molecular therapies of DM1.
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http://dx.doi.org/10.1016/j.omtn.2020.11.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787993PMC
March 2021

Repeatability of Commonly Used Speech and Language Features for Clinical Applications.

Digit Biomark 2020 Sep-Dec;4(3):109-122. Epub 2020 Dec 2.

Arizona State University, Phoenix, Arizona, USA.

Introduction: Changes in speech have the potential to provide important information on the diagnosis and progression of various neurological diseases. Many researchers have relied on open-source speech features to develop algorithms for measuring speech changes in clinical populations as they are convenient and easy to use. However, the repeatability of open-source features in the context of neurological diseases has not been studied.

Methods: We used a longitudinal sample of healthy controls, individuals with amyotrophic lateral sclerosis, and individuals with suspected frontotemporal dementia, and we evaluated the repeatability of acoustic and language features separately on these 3 data sets.

Results: Repeatability was evaluated using intraclass correlation (ICC) and the within-subjects coefficient of variation (WSCV). In 3 sets of tasks, the median ICC were between 0.02 and 0.55, and the median WSCV were between 29 and 79%.

Conclusion: Our results demonstrate that the repeatability of speech features extracted using open-source tool kits is low. Researchers should exercise caution when developing digital health models with open-source speech features. We provide a detailed summary of feature-by-feature repeatability results (ICC, WSCV, SE of measurement, limits of agreement for WSCV, and minimal detectable change) in the online supplementary material so that researchers may incorporate repeatability information into the models they develop.
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http://dx.doi.org/10.1159/000511671DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772887PMC
December 2020

Effects of mexiletine on hyperexcitability in sporadic amyotrophic lateral sclerosis: Preliminary findings from a small phase II randomized controlled trial.

Muscle Nerve 2021 03 31;63(3):371-383. Epub 2020 Dec 31.

Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA.

Background: To collect preliminary data on the effects of mexiletine on cortical and axonal hyperexcitability in sporadic amyotrophic lateral sclerosis (ALS) in a phase 2 double-blind randomized controlled trial.

Methods: Twenty ALS subjects were randomized to placebo and mexiletine 300 or 600 mg daily for 4 wk and assessed by transcranial magnetic stimulation and axonal excitability studies. The primary endpoint was change in resting motor threshold (RMT).

Results: RMT was unchanged with 4 wk of mexiletine (combined active therapies) as compared to placebo, which showed a significant increase (P = .039). Reductions of motor evoked potential (MEP) amplitude (P = .013) and accommodation half-time (P = .002), secondary outcome measures of cortical and axonal excitability, respectively, were also evident at 4 wk on mexiletine.

Conclusions: The relative stabilization of RMT in the treated subjects was unexpected and could be attributed to unaccounted sources of error or chance. However, a possible alternative cause is neuromodulation preventing an increase. The change in MEP amplitude and accommodation half-time supports the reduction of cortical and axonal hyperexcitability with mexiletine.
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http://dx.doi.org/10.1002/mus.27146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8513796PMC
March 2021

Effect of Ezogabine on Cortical and Spinal Motor Neuron Excitability in Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial.

JAMA Neurol 2021 02;78(2):186-196

Department of Neurology, University of California Irvine, Irvine.

Importance: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of the motor nervous system. Clinical studies have demonstrated cortical and spinal motor neuron hyperexcitability using transcranial magnetic stimulation and threshold tracking nerve conduction studies, respectively, although metrics of excitability have not been used as pharmacodynamic biomarkers in multi-site clinical trials.

Objective: To ascertain whether ezogabine decreases cortical and spinal motor neuron excitability in ALS.

Design, Setting, And Participants: This double-blind, placebo-controlled phase 2 randomized clinical trial sought consent from eligible participants from November 3, 2015, to November 9, 2017, and was conducted at 12 US sites within the Northeast ALS Consortium. Participants were randomized in equal numbers to a higher or lower dose of ezogabine or to an identical matched placebo, and they completed in-person visits at screening, baseline, week 6, and week 8 for clinical assessment and neurophysiological measurements.

Interventions: Participants were randomized to receive 600 mg/d or 900 mg/d of ezogabine or a matched placebo for 10 weeks.

Main Outcomes And Measures: The primary outcome was change in short-interval intracortical inhibition (SICI; SICI-1 was used in analysis to reflect stronger inhibition from an increase in amplitude) from pretreatment mean at screening and baseline to the full-dose treatment mean at weeks 6 and 8. The secondary outcomes included levels of cortical motor neuron excitability (including resting motor threshold) measured by transcranial magnetic stimulation and spinal motor neuron excitability (including strength-duration time constant) measured by threshold tracking nerve conduction studies.

Results: A total of 65 participants were randomized to placebo (23), 600 mg/d of ezogabine (23), and 900 mg/d of ezogabine (19 participants); 45 were men (69.2%) and the mean (SD) age was 58.3 (8.8) years. The SICI-1 increased by 53% (mean ratio, 1.53; 95% CI, 1.12-2.09; P = .009) in the 900-mg/d ezogabine group vs placebo group. The SICI-1 did not change in the 600-mg/d ezogabine group vs placebo group (mean ratio, 1.15; 95% CI, 0.87-1.52; P = .31). The resting motor threshold increased in the 600-mg/d ezogabine group vs placebo group (mean ratio, 4.61; 95% CI, 0.21-9.01; P = .04) but not in the 900-mg/d ezogabine group vs placebo group (mean ratio, 1.95; 95% CI, -2.64 to 6.54; P = .40). Ezogabine caused a dose-dependent decrease in excitability by several other metrics, including strength-duration time constant in the 900-mg/d ezogabine group vs placebo group (mean ratio, 0.73; 95% CI, 0.60 to 0.87; P < .001).

Conclusions And Relevance: Ezogabine decreased cortical and spinal motor neuron excitability in participants with ALS, suggesting that such neurophysiological metrics may be used as pharmacodynamic biomarkers in multisite clinical trials.

Trial Registration: ClinicalTrials.gov Identifier: NCT02450552.
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http://dx.doi.org/10.1001/jamaneurol.2020.4300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7684515PMC
February 2021

Predicting myofiber cross-sectional area and triglyceride content with electrical impedance myography: A study in db/db mice.

Muscle Nerve 2021 01 28;63(1):127-140. Epub 2020 Oct 28.

Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.

Background: Electrical impedance myography (EIM) provides insight into muscle composition and structure. We sought to evaluate its use in a mouse obesity model characterized by myofiber atrophy.

Methods: We applied a prediction algorithm, ie, the least absolute shrinkage and selection operator (LASSO), to surface, needle array, and ex vivo EIM data from db/db and wild-type mice and assessed myofiber cross-sectional area (CSA) histologically and triglyceride (TG) content biochemically.

Results: EIM data from all three modalities provided acceptable predictions of myofiber CSA with average root mean square error (RMSE) of 15% in CSA (ie, ±209 μm for a mean CSA of 1439 μm ) and TG content with RMSE of 30% in TG content (ie, ±7.3 nmol TG/mg muscle for a mean TG content of 25.4 nmol TG/mg muscle).

Conclusions: EIM combined with a predictive algorithm provides reasonable estimates of myofiber CSA and TG content without the need for biopsy.
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http://dx.doi.org/10.1002/mus.27095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8891989PMC
January 2021

Using Electrical Impedance Myography as a Biomarker of Muscle Deconditioning in Rats Exposed to Micro- and Partial-Gravity Analogs.

Front Physiol 2020 15;11:557796. Epub 2020 Sep 15.

Department of Neurology, Harvard Medical School - Beth Israel Deaconess Medical Center, Boston, MA, United States.

As astronauts prepare to undertake new extra-terrestrial missions, innovative diagnostic tools are needed to better assess muscle deconditioning during periods of weightlessness and partial gravity. Electrical impedance myography (EIM) has been used to detect muscle deconditioning in rodents exposed to microgravity during spaceflight or using the standard ground-based model of hindlimb unloading via tail suspension (HU). Here, we used EIM to assess muscle changes in animals exposed to two new models: hindlimb suspension using a pelvic harness (HLS) and a partial weight-bearing (PWB) model that mimics partial gravity (including Lunar and Martian gravities). We also used a simple needle array electrode in lieu of surface or EIM approaches previously employed. Our HLS results confirmed earlier findings obtained after spaceflight and tail suspension. Indeed, one EIM measure (i.e., phase-slope) that was previously reported as highly sensitive, was significantly decreased after HLS (day 0: 14.60 ± 0.97, day 7: 11.03 ± 0.81, and day 14: 10.13 ± 0.55 | Deg/MHz|, < 0.0001), and was associated with a significant decrease in muscle grip force. Although EIM parameters such as 50 kHz phase, reactance, and resistance remained variable over 14 days in PWB animals, we identified major PWB-dependent effects at 7 days. Moreover, the data at both 7 and 14 days correlated to previously observed changes in rear paw grip force using the same PWB model. In conclusion, our data suggest that EIM has the potential to serve as biomarker of muscle deconditioning during exposure to both micro- and partial- gravity during future human space exploration.
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http://dx.doi.org/10.3389/fphys.2020.557796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7522465PMC
September 2020

Corrigendum: Partial Weight-Bearing in Female Rats: Proof of Concept in a Martian-Gravity Analog.

Front Physiol 2020 3;11:672. Epub 2020 Jul 3.

Harvard Medical School - Beth Israel Deaconess Medical Center, Department of Neurology, Boston, MA, United States.

[This corrects the article DOI: 10.3389/fphys.2020.00302.].
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http://dx.doi.org/10.3389/fphys.2020.00672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7350894PMC
July 2020

Improved ALS clinical trials through frequent at-home self-assessment: a proof of concept study.

Ann Clin Transl Neurol 2020 07 9;7(7):1148-1157. Epub 2020 Jun 9.

Barrow Neurological Clinic, Phoenix, AZ, USA.

Objective: To determine the potential for improving amyotrophic lateral sclerosis (ALS) clinical trials by having patients or caregivers perform frequent self-assessments at home.

Methods And Participants: We enrolled ALS patients into a nonblinded, longitudinal 9-month study in which patients and caregivers obtained daily data using several different instruments, including a slow-vital capacity device, a hand grip dynamometer, an electrical impedance myography-based fitness device, an activity tracker, a speech app, and the ALS functional rating scale-revised. Questions as to acceptability were asked at two time points.

Results: A total of 113 individuals enrolled, with 61 (43 men, 18 women, mean age 60.1 ± 9.9 years) collecting a minimum of 7 days data and being included in the analysis. Daily measurements resulted in more accurate assessments of the slope of progression of the disease, resulting in smaller sample size estimates for a hypothetical clinical trial. For example, by performing daily slow-vital capacity measurements, calculated sample size was reduced to 182 subjects/study arm from 882/arm for monthly measurements. Similarly, performing the ALS functional rating scale weekly rather than monthly led to a calculated sample size of 73/arm as compared to 274/arm. Participants generally found the procedures acceptable and, for many, improved their sense of control of their disease.

Interpretation: Frequent at-home measurements using standard tools holds the prospect of tracking progression and reducing sample size requirements for clinical trials in ALS while also being acceptable to the patients. Future studies in this and other neurological disorders should consider adopting this approach to data collection.
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http://dx.doi.org/10.1002/acn3.51096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359124PMC
July 2020

Teleneurology during the COVID-19 pandemic: A step forward in modernizing medical care.

J Neurol Sci 2020 07 21;414:116930. Epub 2020 May 21.

Beth Israel Deaconess Medical Center, Department of Neurology, 330 Brookline Ave, Boston 02215, MA, USA.

Background: The COVID-19 pandemic mandated rapid transition from face-to-face encounters to teleneurology visits. While teleneurology is regularly used in acute stroke care, its application in other branches of neurology was limited. Here we review how the recent pandemic has created a paradigm shift in caring for patients with chronic neurological disorders and how academic institutions have responded to the present need.

Method: Literature review was performed to examine the recent changes in health policies. Number of outpatient visits and televisits in the Department of Neurology was reviewed from Yale University School of Medicine and Johns Hopkins School of Medicine to examine the road to transition to televisit.

Results: The federal government and the insurance providers extended their supports during the COVID-19 pandemic. Several rules and regulations regarding teleneurology were revised and relaxed to address the current need. New technologies for video conferencing were incorporated. The transition to televisits went smoothly in both the institutions and number of face-to-face encounters decreased dramatically along with a rapid rise in televisits within 2 weeks of the declaration of national emergency.

Conclusion And Relevance: The need for "social distancing" during the COVID-19 pandemic has created a major surge in the number of teleneurology visits, which will probably continue for the next few months. It may have initiated a more permanent transition to virtual technology incorporated medical care.
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http://dx.doi.org/10.1016/j.jns.2020.116930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7241381PMC
July 2020

Dose-dependent skeletal deficits due to varied reductions in mechanical loading in rats.

NPJ Microgravity 2020 18;6:15. Epub 2020 May 18.

1Center for Advanced Orthopaedic Studies, Beth Israel Deaconess Medical Center, Boston, MA USA.

Reduced skeletal loading leads to marked bone loss. Animal models of hindlimb suspension are widely used to assess alterations in skeleton during the course of complete unloading. More recently, the effects of partial unloading on the musculoskeletal system have been interrogated in mice and rats, revealing dose-dependent effects of partial weight bearing (PWB) on the skeleton and skeletal muscle. Here, we extended these studies to determine the structural and functional skeletal alterations in 14-week-old male Wister rats exposed to 20%, 40%, 70%, or 100% of body weight for 1, 2, or 4 weeks ( = 11-12/group). Using in vivo pQCT, we found that trabecular bone density at the proximal tibia declined in proportion to the degree of unloading and continued progressively with time, without evidence of a plateau by 4 weeks. Ex vivo measurements of trabecular microarchitecture in the distal femur by microcomputed tomography revealed deficits in bone volume fraction, 2 and 4 weeks after unloading. Histologic analyses of trabecular bone in the distal femur revealed the decreased osteoblast number and mineralizing surface in unloaded rats. Three-point bending of the femoral diaphysis indicated modest or no reductions in femoral stiffness and estimated modulus due to PWB. Our results suggest that this rat model of PWB leads to trabecular bone deterioration that is progressive and generally proportional to the degree of PWB, with minimal effects on cortical bone.
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http://dx.doi.org/10.1038/s41526-020-0105-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235020PMC
May 2020

Partial Weight-Bearing in Female Rats: Proof of Concept in a Martian-Gravity Analog.

Front Physiol 2020 3;11:302. Epub 2020 Apr 3.

Harvard Medical School - Beth Israel Deaconess Medical Center, Department of Neurology, Boston, MA, United States.

Many studies have investigated the physiological response to microgravity in both astronauts and animals. However, while space agencies have sought to deploy more women on their missions; animal models rarely include females studies or comparisons between males and females. Therefore, we exposed adult female rats to 2 weeks of partial weight-bearing at either 100% of their normal loading (PWB100) or 40% of their normal loading (PWB40), corresponding to Martian gravity-analog, and assess muscle function, force and histomorphometry. Females exposed to PWB showed an 11.62% decline in hindlimb grip force associated with an 11.84% decrease in soleus myofiber size after 14 days of exposure, while maintaining normal blood oxygenation and stress levels. This pilot study represents the first experiment designed to understand the muscular disuse associated with a partial reduction in mechanical loading in female rats, and the first step needed to develop successful mitigating strategies.

New And Noteworthy: This research article describes the first use of quadrupedal partial weight-bearing in female rats. This study demonstrates the feasibility of partial gravity analogs in females and allows for future investigations about the impact of sex on muscle deconditioning due to reduced mechanical loading.
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http://dx.doi.org/10.3389/fphys.2020.00302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7145975PMC
April 2020

A robust and novel electrical impedance metric of pulmonary function in ALS patients.

Physiol Meas 2020 05 7;41(4):044005. Epub 2020 May 7.

Department of Neurology, Beth Israel Deaconess Medical Center (BIDMC), Boston, MA 02215, United States of America. Harvard Medical School, Boston, MA 02115, United States of America.

Objective: Pulmonary function tests (PFTs) are important for assessing respiratory function in amyotrophic lateral sclerosis (ALS) patients. However, weakness of oral and glottal closure, due to concomitant bulbar dysfunction, may result in unreliable PFT values stemming from leakage of air around the breathing tube and through the glottis. In this study, we assessed whether standard thoracic electrical impedance tomography (EIT) could serve as a surrogate measure for PFTs.

Approach: Thoracic EIT was performed simultaneously with standard PFTs on seven ALS patients without clinical bulbar weakness (six men and one woman, mean age of 63 years) and ten healthy volunteers (seven men and three women, mean age of 57 years). A raw impedance metric along with more standard EIT measures were computed and correlated with the normalized forced vital capacity (FVC). Additionally, test/re-test metrics and EIT images were analyzed.

Main Results: The impedance metric was found to be robust and sensitive to lung activity. We also identified qualitative EIT differences between healthy volunteers and ALS patients, with the ALS images showing greater heterogeneity. Significant correlations with FVC were found for both impedance and EIT metrics in ALS patients (r = 0.89) and for the impedance metric only in healthy volunteers (r = 0.49).

Significance: This suggests that EIT, using our novel impedance metric, has the potential to serve as an alternative technology to standard PFTs for assessing pulmonary function in patients with ALS, offering new metrics of disease status for those with bulbar weakness.
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http://dx.doi.org/10.1088/1361-6579/ab85cfDOI Listing
May 2020

Conference report on contractures in musculoskeletal and neurological conditions.

Muscle Nerve 2020 06 7;61(6):740-744. Epub 2020 Mar 7.

The Shirley Ryan AbilityLab, Chicago, Illinois.

Limb contractures are debilitating complications associated with various muscle and nervous system disorders. This report summarizes presentations at a conference at the Shirley Ryan AbilityLab in Chicago, Illinois, on April 19-20, 2018, involving researchers and physicians from diverse disciplines who convened to discuss current clinical and preclinical understanding of contractures in Duchenne muscular dystrophy, stroke, cerebral palsy, and other conditions. Presenters described changes in muscle architecture, activation, extracellular matrix, satellite cells, and muscle fiber sarcomeric structure that accompany or predispose muscles to contracture. Participants identified ongoing and future research directions that may lead to understanding of the intersecting factors that trigger contractures. These include additional studies of changes in muscle, tendon, joint, and neuronal tissues during contracture development with imaging, molecular, and physiologic approaches. Participants identified the requirement for improved biomarkers and outcome measures to identify patients likely to develop contractures and to accurately measure efficacy of treatments currently available and under development.
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http://dx.doi.org/10.1002/mus.26845DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229996PMC
June 2020
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