Sudarshan Dayanidhi

DEFINITION AND CLASSIFICATION OF HYPERKINETIC MOVEMENTS IN CHILDHOOD

Hyperkinetic movements are unwanted or excess movements that are frequently seen in children with neurologic disorders. They are an important clinical finding with significant implications for diagnosis and treatment. However, the lack of agreement on standard terminology and definitions interferes with clinical treatment and research. We describe definitions of dystonia, chorea, athetosis, myoclonus, tremor, tics, and stereotypies that arose from a consensus meeting in June 2008 of specialists from different clinical and basic science fields. Dystonia is a movement disorder in which involuntary sustained or intermittent muscle contractions cause twisting and repetitive movements, abnormal postures, or both. Chorea is an ongoing random‐appearing sequence of one or more discrete involuntary movements or movement fragments. Athetosis is a slow, continuous, involuntary writhing movement that prevents maintenance of a stable posture. Myoclonus is a sequence of repeated, often nonrhythmic, brief shock‐like jerks due to sudden involuntary contraction or relaxation of one or more muscles. Tremor is a rhythmic back‐and‐forth or oscillating involuntary movement about a joint axis. Tics are repeated, individually recognizable, intermittent movements or movement fragments that are almost always briefly suppressible and are usually associated with awareness of an urge to perform the movement. Stereotypies are repetitive, simple movements that can be voluntarily suppressed. We provide recommended techniques for clinical examination and suggestions for differentiating between the different types of hyperkinetic movements, noting that there may be overlap between conditions. These definitions and the diagnostic recommendations are intended to be reliable and useful for clinical practice, communication between clinicians and researchers, and for the design of quantitative tests that will guide and assess the outcome of future clinical trials.

Dexterous Manipulation Is Poorer at Older Ages and Is Dissociated From Decline of Hand Strength

BACKGROUND The ability to dynamically control fingertip force vector magnitude and direction is critical for dexterous manipulation. We quantified the dynamic control of fingertip forces to examine how dexterous manipulation declines with age. METHODS The strength-dexterity (SD) test measures fingertip forces during compression of a slender spring prone to instability and buckling. The greatest sustained compression (designed to be under 3 N), and force dynamics therein, have been shown to be simple and quick measures of dynamic dexterous manipulation ability. We measured pinch strength and strength-dexterity test in a cross-sectional population of 98 people from 18 to 89 years of age. RESULTS Dexterous manipulation ability is poorer at older ages, beginning in middle age (p < .001), with greater decline past 65 years of age. Fingertip force dynamics during spring compression and stabilization show a deterioration of neuromuscular control with age. Importantly, this novel detection of decline in dynamic manipulation ability is not correlated with, and thus cannot be entirely explained by, the known decline in pinch strength. We also measured standardized tests of dexterity in participants older than 45, and discuss how the strength-dexterity test uniquely captures features of sensorimotor capabilities for dexterous manipulation in this adult population. CONCLUSIONS Starting in middle age, changes in the functional interactions among sensory, motor, and neural capabilities result in measurably poorer dynamic dexterous manipulation. This deterioration of neuromuscular control motivates and enables future studies to understand the physiological bases for this functional decline so critical to activities of daily living and quality of life.

Skeletal muscle satellite cells: mediators of muscle growth during development and implications for developmental disorders.

Satellite cells (SCs) are the muscle stem cells responsible for longitudinal and cross‐sectional postnatal growth and repair after injury and which provide new myonuclei when needed. We review their morphology and contribution to development and their role in sarcomere and myonuclear addition. SCs, similar to other tissue stem cells, cycle through different states, such as quiescence, activation, and self‐renewal, and thus we consider the signaling mechanisms involved in maintenance of these states. The role of the SC niche and their interactions with other cells, such as fibroblasts and the extracellular matrix, are all emerging as major factors that affect aging and disease. Interestingly, children with cerebral palsy appear to have a reduced SC number, which could play a role in their reduced muscular development and even in muscular contracture formation. Finally, we review the current information on SC dysfunction in children with muscular dystrophy and emerging therapies that target promotion of myogenesis and reduction of fibrosis. Muscle Nerve 50: 723–732, 2014

Developmental improvements in dynamic control of fingertip forces last throughout childhood and into adolescence

While it is clear that the development of dexterous manipulation in children exhibits dramatic improvements over an extended period, it is difficult to separate musculoskeletal from neural contributors to these important functional gains. This is in part due to the inability of current methods to disambiguate improvements in hand strength from gains in finger dexterity (i.e., the dynamic control of fingertip force vectors at low magnitudes). We adapted our novel instrumentation to evaluate finger dexterity in 130 typically developing children between the ages of 4 and 16 yr. We find that finger dexterity continues to develop well into late adolescence and musculoskeletal growth and strength are poorly correlated with the improvements in dexterity. Importantly, because these behavioral results seem to mirror the known timelines of neuroanatomical development up to adolescence, we speculate that they reflect the functional benefits of such continual neural maturation. This novel perspective now enables the systematic study of the functional roles of specific neuroanatomical structures and their connectivity, maturity, and plasticity. Moreover, the temporal dynamics of the fingertip force vectors shows improvements in stability that provide a novel way to look at the maturation of finger control. From a clinical perspective, our results provide a practical means to chart functional development of dexterous manipulation in typically developing children and could be adapted for clinical use and for use in children with developmental disorders.

Outcome measures for hand function naturally reveal three latent domains in older adults: strength, coordinated upper extremity function, and sensorimotor processing

Understanding the mapping between individual outcome measures and the latent functional domains of interest is critical to a quantitative evaluation and rehabilitation of hand function. We examined whether and how the associations among six hand-specific outcome measures reveal latent functional domains in elderly individuals. We asked 66 healthy older adult participants (38F, 28M, 66.1 ± 11.6 years, range: 45–88 years) and 33 older adults (65.8 ± 9.7 years, 44–81 years, 51 hands) diagnosed with osteoarthritis (OA) of the carpometacarpal (CMC) joint, to complete six functional assessments: hand strength (Grip, Key and Precision Pinch), Box and Block, Nine Hole Pegboard, and Strength-Dexterity tests. The first three principal components suffice to explain 86% of variance among the six outcome measures in healthy older adults, and 84% of variance in older adults with CMC OA. The composition of these dominant associations revealed three distinct latent functional domains: strength, coordinated upper extremity function, and sensorimotor processing. Furthermore, in participants with thumb CMC OA we found a blurring of the associations between the latent functional domains of strength and coordinated upper extremity function. This motivates future work to understand how the physiological effects of thumb CMC OA lead upper extremity coordination to become strongly associated with strength, while dynamic sensorimotor ability remains an independent functional domain. Thus, when assessing the level of hand function in our growing older adult populations, it is particularly important to acknowledge its multidimensional nature—and explicitly consider how each outcome measure maps to these three latent and fundamental domains of function. Moreover, this ability to distinguish among latent functional domains may facilitate the design of treatment modalities to target the rehabilitation of each of them.

Decrease in muscle contraction time complements neural maturation in the development of dynamic manipulation

Developmental improvements in dynamic manipulation abilities are typically attributed to neural maturation, such as myelination of corticospinal pathways, neuronal pruning, and synaptogenesis. However the contributions from changes in the peripheral motor system are less well understood. Here we investigated whether there are developmental changes in muscle activation-contraction dynamics and whether these changes contribute to improvements in dynamic manipulation in humans. We compared pinch strength, dynamic manipulation ability, and contraction time of the first dorsal interosseous muscle in typically developing preadolescent, adolescent, and young adults. Both strength and dynamic manipulation ability increased with age (p < 0.0001 and p < 0.00001, respectively). Surprisingly, adults had a 33% lower muscle contraction time compared with preadolescents (p < 0.01), and contraction time showed a significant (p < 0.005) association with dynamic manipulation abilities. Whereas decreases in muscle contraction time during development have been reported in the animal literature, our finding, to our knowledge, is the first report of this phenomenon in humans and the first finding of its association with manipulation. Consequently, the changes in the muscle contractile properties could be an important complement to neural maturation in the development of dynamic manipulation. These findings have important implications for understanding central and peripheral contributors to deficits in manipulation in atypical development, such as in children with cerebral palsy.

Reduced satellite cell number in situ in muscular contractures from children with cerebral palsy

Satellite cells (SC) are quiescent adult muscle stem cells critical for postnatal development. Children with cerebral palsy have impaired muscular growth and develop contractures. While flow cytometry previously demonstrated a reduced SC population, extracellular matrix abnormalities may influence the cell isolation methods used, systematically isolating fewer cells from CP muscle and creating a biased result. Consequently, the purpose of this study was to use immunohistochemistry on serial muscle sections to quantify SC in situ. Serial cross‐sections from human gracilis muscle biopsies (n = 11) were labeled with fluorescent antibodies for Pax7 (SC transcriptional marker), laminin (basal lamina), and 4′,6‐diamidino‐2‐phenylindole (nuclei). Fluorescence microscopy under high magnification was used to identify SC based on labeling and location. Mean SC/100 myofibers was reduced by ∼70% (p < 0.001) in children with CP (2.89 ± 0.39) compared to TD children (8.77 ± 0.79). Furthermore, SC distribution across fields was different (p < 0.05) with increased percentage of SC in fields being solitary cells (p < 0.01) in children with CP. Quantification of SC number in situ, without any other tissue manipulation confirms children with spastic CP have a reduced number. This stem cell loss may, in part, explain impaired muscle growth and apparent decreased responsiveness of CP muscle to exercise.

Long term functional outcomes after early childhood pollicization

STUDY DESIGN Retrospective Cohort INTRODUCTION Important outcomes of polliciation to treat thumb hypoplasia/aplasia include strength, function, dexterity, and quality of life. PURPOSE OF THE STUDY To evaluate outcomes and examine predictors of outcome after early childhood pollicization. METHODS 8 children (10 hands) were evaluated 3-15 years after surgery. Physical examination, questionnaires, grip and pinch strength, Box and Blocks, 9-hole pegboard, and strength-dexterity (S-D) tests were performed. RESULTS Pollicized hands had poor strength and performance on functional tests. Six of 10 pollicized hands had normal dexterity scores but less stability in maintaining a steady-state force. Predictors of poorer outcomes included older age at surgery, reduced metacarpophalangeal and interphalangeal range of motion, and radial absence. DISCUSSION Pollicization resulted in poor strength and overall function, but normal dexterity was often achieved using altered control strategies. CONCLUSIONS Most children should obtain adequate dexterity despite weakness after pollicization except older or severely involved children. LEVEL OF EVIDENCE IV.

Reduced skeletal muscle satellite cell number alters muscle morphology after chronic stretch but allows limited serial sarcomere addition

Introduction: Muscles add sarcomeres in response to stretch, presumably to maintain optimal sarcomere length. Clinical evidence from patients with cerebral palsy, who have both decreased serial sarcomere number and reduced satellite cells (SCs), suggests a hypothesis that SCs may be involved in sarcomere addition. Methods: A transgenic Pax7‐DTA mouse model underwent conditional SC depletion, and their soleii were then stretch‐immobilized to assess the capacity for sarcomere addition. Muscle architecture, morphology, and extracellular matrix (ECM) changes were also evaluated. Results: Mice in the SC‐reduced group achieved normal serial sarcomere addition in response to stretch. However, muscle fiber cross‐sectional area was significantly smaller and was associated with hypertrophic ECM changes, consistent with fibrosis. Conclusions: While a reduced SC population does not hinder serial sarcomere addition, SCs play a role in muscle adaptation to chronic stretch that involves maintenance of both fiber cross‐sectional area and ECM structure. Muscle Nerve 55: 384–392, 2017

Quantitative assessment of dynamic control of fingertip forces after pollicization

Dexterity after finger pollicization (reconstruction to thumb) is critical to functional outcomes. While most tests of hand function evaluate a combination of strength, coordination, and motor control, the Strength-Dexterity (S-D) paradigm focuses on the dynamic control of fingertip forces. We evaluated 10 pollicized and 5 non-pollicized hands from 8 participants ages 4-17 years (2 female, 6 male; 10.6 ± 4.5 years). Participants partially compressed and held an instrumented spring prone to buckling between the thumb and first finger to quantify dynamic control over the direction and magnitude of fingertip forces. They also completed traditional functional tests including grip, lateral pinch, and tripod pinch strength, Box and Blocks, and 9-hole peg test. Six of 10 pollicized hands and all non-pollicized hands had S-D scores comparable to typically developing children. However, dynamical analysis showed that pollicized hands exhibit greater variability in compression force, indicating poorer corrective action. Almost all pollicized hands scored below the normal range for the traditional functional tests. The S-D test Z-scores correlated moderately with Z-scores from the other functional tests (r = 0.54-0.61; p = 0.02-0.04) but more weakly than amongst the other functional measures (r = 0.58-0.83; p = 0.0002-0.02), suggesting that the S-D test captures a different domain of function. A higher incidence of radial absence in the hands with poor S-D scores (3/4 vs. 0/6 in hands with normal S-D scores, p = 0.03) was the only clinical characteristic associated with S-D outcome. Overall, these results suggest that while most pollicized hands can control fingertip forces, the nature of that control is altered.