Publications

BACKGROUND: Anterior cruciate ligament (ACL) rupture is a common knee injury among athletes and physically active adults. Despite surgical reconstruction and extensive rehabilitation, reinjuries are common and disability levels are high, even years after therapy and return to activity. Prolonged knee dysfunction may result in part from unresolved neuromuscular deficits of the surrounding joint musculature in response to injury. Indeed, "upstream" neurological adaptations occurring after injury may explain these persistent functional deficits. Despite evidence for injury consequences extending beyond the joint to the nervous system, the link between neurophysiological impairments and patient-reported measures of knee function remains unclear. HYPOTHESIS: Patterns of brain activation for knee control are related to measures of patient-reported knee function in individuals after ACL reconstruction (ACL-R). STUDY DESIGN: Cross-sectional study. LEVEL OF EVIDENCE: Level 3. METHODS: In this multicenter, cross-sectional study, participants with unilateral ACL-R (n = 25; 10 men, 15 women) underwent task-based functional magnetic resonance imaging testing. Participants performed repeated cycles of open-chain knee flexion/extension. Neural activation patterns during the movement task were quantified using blood oxygen level-dependent (BOLD) signals. Regions of interest were generated using the Juelich Histological Brain Atlas. Pearson product-moment correlations were used to determine the relationship between mean BOLD signal within each brain region and self-reported knee function level, as measured by the International Knee Documentation Committee index. Partial correlations were also calculated after controlling for time from surgery and sex. RESULTS: Patient-reported knee function was positively and moderately correlated with the ipsilateral secondary somatosensory cortex (r = 0.57, P = 0.005) and the ipsilateral supplementary motor area (r = 0.51, P = 0.01). CONCLUSION: Increased ipsilateral secondary sensorimotor cortical activity is related to higher perceived knee function. CLINICAL RELEVANCE: Central nervous system mechanisms for knee control are related to subjective levels of knee function after ACL-R. Increased neural activity may reflect central neuroplastic strategies to preserve knee functionality after traumatic injury.

BACKGROUND: This article discusses the putative neural mechanisms of age-related muscle weakness within the broader context of the development of function-promoting therapies for sarcopenia and age-related mobility limitations. We discuss here the evolving definition of sarcopenia and its primary defining characteristic, weakness. METHODS: This review explores the premise that impairments in the nervous system's ability to generate maximal force or power contribute to sarcopenia. RESULTS: Impairments in neural activation are responsible for a substantial amount of age-related weakness. The neurophysiological mechanisms of weakness are multifactorial. The roles of supraspinal descending command mechanisms, spinal motor neuron firing responsivity, and neuromuscular junction transmission failure in sarcopenia are discussed. Research/clinical gaps and recommendations for future work are highlighted. CONCLUSION: Further research is needed to map putative neural mechanisms, determine the clinical relevance of age-related changes in neural activation to sarcopenia, and evaluate the effectiveness of various neurotherapeutic approaches to enhancing physical function.

Changes in old age that contribute to the complex issue of an increased metabolic cost of walking (mass-specific energy cost per unit distance traveled) in older adults appear to center at least in part on changes in gait biomechanics. However, age-related changes in energy metabolism, neuromuscular function and connective tissue properties also likely contribute to this problem, of which the consequences are poor mobility and increased risk of inactivity-related disease and disability. The U.S. National Institute on Aging convened a workshop in September 2021 with an interdisciplinary group of scientists to address the gaps in research related to the mechanisms and consequences of changes in mobility in old age. The goal of the workshop was to identify promising ways to move the field forward toward improving gait performance, decreasing energy cost, and enhancing mobility for older adults. This report summarizes the workshop and brings multidisciplinary insight into the known and potential causes and consequences of age-related changes in gait biomechanics. We highlight how gait mechanics and energy cost change with aging, the potential neuromuscular mechanisms and role of connective tissue in these changes, and cutting-edge interventions and technologies that may be used to measure and improve gait and mobility in older adults. Key gaps in the literature that warrant targeted research in the future are identified and discussed.

Sarcopenia, or age-related decline in muscle form and function, exerts high personal, societal, and economic burdens when untreated. Integrity and function of the neuromuscular junction (NMJ), as the nexus between the nervous and muscular systems, is critical for input and dependable neural control of muscle force generation. As such, the NMJ has long been a site of keen interest in the context of skeletal muscle function deficits during aging and in the context of sarcopenia. Historically, changes of NMJ morphology during aging have been investigated extensively but primarily in aged rodent models. Aged rodents have consistently shown features of NMJ endplate fragmentation and denervation. Yet, the presence of NMJ changes in older humans remains controversial, and conflicting findings have been reported. This review article describes the physiological processes involved in NMJ transmission, discusses the evidence that supports NMJ transmission failure as a possible contributor to sarcopenia, and speculates on the potential of targeting these defects for therapeutic development. The technical approaches that are available for assessment of NMJ transmission, whether each approach has been applied in the context of aging and sarcopenia, and the associated findings are summarized. Like morphological studies, age-related NMJ transmission deficits have primarily been studied in rodents. In preclinical studies, isolated synaptic electrophysiology recordings of endplate currents or potentials have been mostly used, and paradoxically, have shown enhancement, rather than failure, with aging. Yet, in vivo assessment of single muscle fiber action potential generation using single fiber electromyography and nerve-stimulated muscle force measurements show evidence of NMJ failure in aged mice and rats. Together these findings suggest that endplate response enhancement may be a compensatory response to post-synaptic mechanisms of NMJ transmission failure in aged rodents. Possible, but underexplored, mechanisms of this failure are discussed including the simplification of post-synaptic folding and altered voltage-gated sodium channel clustering or function. In humans, there is limited clinical data that has selectively investigated single synaptic function in the context of aging. If sarcopenic older adults turn out to exhibit notable impairments in NMJ transmission (this has yet to be examined but based on available evidence appears to be plausible) then these NMJ transmission defects present a well-defined biological mechanism and offer a well-defined pathway for clinical implementation. Investigation of small molecules that are currently available clinically or being testing clinically in other disorders may provide a rapid route for development of interventions for older adults impacted by sarcopenia.

BACKGROUND: Approximately 35% of individuals over age 70 report difficulty with mobility. Muscle weakness has been demonstrated to be one contributor to mobility limitations in older adults. The purpose of this study was to examine the moderating effect of brain-predicted age difference (an index of biological brain age/health derived from structural neuroimaging) on the relationship between leg strength and mobility. METHODS: In community dwelling older adults (N = 57, 74.7 +/- 6.93 years; 68% women), we assessed the relationship between isokinetic leg extensor strength and a composite measure of mobility [mobility battery assessment (MBA)] using partial Pearson correlations and multifactorial regression modeling. Brain predicted age (BPA) was calculated from T1 MR-images using a validated machine learning Gaussian Process regression model to explore the moderating effect of BPA difference (BPAD; BPA minus chronological age). RESULTS: Leg strength was significantly correlated with BPAD (r = -0.317, p 0.05) and MBA score (r = 0.541, p 0.001). Chronological age, sex, leg strength, and BPAD explained 63% of the variance in MBA performance (p 0.001). BPAD was a significant moderator of the relationship between strength and MBA, accounting for 7.0% of MBA score variance [ big up tri, openR (2) = 0.044, F(1,51) = 6.83, p = 0.01]. Conditional moderation effects of BPAD indicate strength was a stronger predictor of mobility in those with a great BPAD. CONCLUSION: The relationship between strength and mobility appears to be influenced by brain aging, with strength serving as a possible compensation for decline in neural integrity.

BACKGROUND: Approximately 35% of individuals over age 70 report difficulty with mobility. Muscle weakness has been demonstrated to be one contributor to mobility limitations in older adults. The purpose of this study was to examine the moderating effect of brain-predicted age difference (an index of biological brain age/health derived from structural neuroimaging) on the relationship between leg strength and mobility. METHODS: In community dwelling older adults (N = 57, 74.7 +/- 6.93 years; 68% women), we assessed the relationship between isokinetic leg extensor strength and a composite measure of mobility [mobility battery assessment (MBA)] using partial Pearson correlations and multifactorial regression modeling. Brain predicted age (BPA) was calculated from T1 MR-images using a validated machine learning Gaussian Process regression model to explore the moderating effect of BPA difference (BPAD; BPA minus chronological age). RESULTS: Leg strength was significantly correlated with BPAD (r = -0.317, p 0.05) and MBA score (r = 0.541, p 0.001). Chronological age, sex, leg strength, and BPAD explained 63% of the variance in MBA performance (p 0.001). BPAD was a significant moderator of the relationship between strength and MBA, accounting for 7.0% of MBA score variance [ big up tri, openR (2) = 0.044, F(1,51) = 6.83, p = 0.01]. Conditional moderation effects of BPAD indicate strength was a stronger predictor of mobility in those with a great BPAD. CONCLUSION: The relationship between strength and mobility appears to be influenced by brain aging, with strength serving as a possible compensation for decline in neural integrity.

There is increasing interest in using motor function tests to identify risk of cognitive impairment in older adults (OA). This study examined associations among grip strength, with and without adjustment for muscle mass, manual dexterity and Trail Making Test (TMT) A and B in 77 OA (73.4 +/- 5.2 years) with globally intact cognition. A subset of OA who exhibited mismatched motor function (e.g., in the highest strength and lowest dexterity tertiles, or vice versa) was identified and analyzed. Dexterity showed stronger associations with TMT-A and -B than grip strength (absolute or adjusted). OA with mismatched motor function scored worse on tests of TMT-B, but not -A than those with matched motor function. Dexterity may have more promise than grip strength for identifying increased risk of cognitive impairment. Intriguing, though limited, data suggest that mismatched motor function (strength vs. dexterity) in OAs might be an even more robust marker of such risk.

BACKGROUND: Weakness is a common clinical symptom reported in individuals with chronic alcohol use disorder. However, it remains unclear whether low strength in these individuals is directly related to excessive ethanol intake, other deleterious factors (lifestyle, environment, genetics, etc.), or a combination of both. Therefore, we examined whether (and how) ethanol reduces the muscle's force-producing capacity using a controlled in vivo preclinical mouse model of excessive ethanol intake. METHODS: To establish whether chronic ethanol consumption causes weakness, C57BL/6 female mice consumed 20% ethanol for 40 weeks (following a 2-week ethanol ramping period), and various measures of muscular force were quantified. Functional measures included all-limb grip strength and in vivo contractility of the left ankle dorsiflexors and plantarflexors. Once confirmed that mice consuming ethanol were weaker than age-matched controls, we sought to determine the potential neuromuscular mechanisms of muscle dysfunction by assessing neuromuscular excitation, muscle quantity, and muscle quality. RESULTS: Mice consuming chronic ethanol were 13 to 16% weaker (p /= 0.268). No significant changes were observed between groups for indices of neuromuscular excitation at the level of the motor unit, neuromuscular junction, or plasmalemma (p >/= 0.259, n(2) /= 0.695, n(2)