A Feasibility Study of Quantitative Motor Assessments in Children Using the Q-Motor Suite

INTRODUCTION

Following current criteria, motor symptoms are key in determining the clinical diagnosis of adult-onset Huntington’s disease (HD), requiring reliable assessments of motor abilities. The Unified Huntington’s Disease Rating Scale Total Motor Score (UHDRS-TMS) is a categorical scale based on expert clinical experience, and is considered the gold standard for determining onset of motor symptoms in HD [1], although there are known limitations [2, 3]. In the past decade, various research efforts were launched to study the natural history of adult-onset HD during the pre-manifest phases in gene-expansion carriers, e.g., PREDICT-HD [4], TRACK-HD [5], and REGISTRY [6]. These efforts highlighted the need for sub-clinical, standardized, quantitative motor assessments, such as Q-Motor [2, 7].

Using force transducers, the Q-Motor suite provides measures of tapping speed and regularity for index fingers (digitomotography), hands (dysdiadochomotography), and feet (pedomotography). Grasping and lifting (manumotography), and involuntary choreiform movements (choreomotography), are also quantified with the additional use of 3-D position sensors [2]. Finally, tongue protrusion force (glossomotography) can be used as a surrogate for the HD clinical sign of the “chameleon tongue” [2]. The TRACK-HD study established that Q-Motor digitomotography tapping assessments were most sensitive in detecting subtle motor manifestations of HD up to two decades before predicted motor onset in adults, both in cross-sectional [8, 9] and longitudinal analyses [5, 8–10]. Variability in tapping performance has been shown to be associated with cortical thinning, and gray- and white matter atrophy in individuals with pre-manifest, and manifest HD [9]. Additionally, Q-Motor performance was significantly correlated with UHDRS-TMS and the disease burden score based on the individual’s age and CAG repeat length [9]. Aspects of Q-Motor have been implemented as an endpoint in clinical trials assessing the efficacy of treatments for reducing motor manifestations in HD and provided higher sensitivity than the UHDRS-TMS [11, 12].

The Kids-HD study was developed to evaluate brain and cognitive developmental changes in youth carriers of the HD mutation, who will develop HD in adulthood [13]. Since these children are typically approximately three decades from disease onset, any potential changes in motor functioning are expected to be subtle, highlighting a need for early, sensitive, objective assessments of motor function, such as Q-Motor speeded tapping. It is possible that the Q-Motor assessments used in TRACK-HD are potentially suitable to detect variation in motor function in at-risk populations. However, the only Q-Motor study conducted in children to date is limited to glossomotography [14]. The following questions need to be addressed before embarking on Q-Motor studies in at-risk youth: [1] can children complete the core Q-Motor assessments currently used in HD clinical trials?; and [2] are Q-Motor measures sensitive to known age-related variation in performance due to developmental maturation? [15]. To address these questions, we administered the core Q-Motor assessments in a sample of children and adolescents recruited from the community.

MATERIALS AND METHODS

Children and adolescents were recruited via advertisement posted at the University of Iowa Hospital and Clinics. Consent was obtained from parents and/or caregivers of the participants and participants provided assent. To be eligible, participants had to be between the ages of 6 and 17 years old and be able to follow simple directions in English. All study procedures were approved by the University of Iowa Hospital & Clinics Institutional Review Board.

Q-Motor assessments are based on pre-calibrated force transducers and 3-D position sensors described in detail elsewhere [2]. Participants completed finger tapping, pronate/supinate tapping hands, foot tapping, grasping and lifting, and assessment of involuntary movements. De-identified data were transferred to the Q-Motor team at the George-Huntington-Institute and processed to extract outcome variables for each participant across all paradigms. Statistical analyses were conducted at the Iowa site.

The following tapping parameters were assessed: [a] Inter-Onset-Interval (IOI), referring to the time between the beginnings of consecutive taps; [b] Inter-Peak-Interval (IPI), referring to the time between peaks of consecutive taps; [c] Inter-Tap-Interval (ITI), which is the time between the end of a tap and the beginning of the next tap; [d] Tap Duration, referring to the time between the beginning of a tap and the end of a tap; [e] Tap Force, which is the maximal tap force applied for a tap; and [f] Tap Speed. Tapping performance was evaluated with standard deviations (SD) and means.

Grasping/lifting was characterized with mean grip force and variability was assessed with the coefficient of variation, defined as the SD divided by the mean. Involuntary movements were assessed using means of the orientation-index and position index.

Except for tapping speed measures, outcome variables were log transformed to limit impact of skewness. Linear regression models included the (log-transformed) outcome variables as the dependent variable, and age and sex as the independent variables. To reduce the number of tests, estimates for participants’ dominant hand/foot were considered only. Results were considered significant at a False Discovery Rate (FDR) of 5% (q < 0.05).

RESULTS

The sample was comprised of 29 individuals between the ages of 6 and 17 years old (mean age = 11.5 years; SD = 3.2 years), including 12 girls (41%) and 17 boys (59%; Fig. 1). All children in the sample were able to follow the instructions to complete Q-Motor tasks that were assessed in the study.

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Fig.1

Sample characteristics. Age in years (y-axis) is depicted for across sex (x-axis) for each individual in the sample (circles).

Age effects on Q-Motor measures are summarized in Fig. 2. Two general trends emerged for tapping performance: younger children exhibited more irregularity than did older children (negative coefficients in Fig. 2A); and younger children were slower tappers than older children (positive coefficients in Fig. 2A), except for pronate/supinate tapping hands. Likewise, younger children exhibited more variability in grip force during grasping and lifting, and more involuntary activity in the orientation and position-index than did older children (Fig. 2B).

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Fig.2

Impact of age across Q-Motor measures. Panel A depicts the scaled beta coefficients for age (x-axis) for 10 tap variables (y-axis) across three extremities shown in the facets (finger, hand, and foot). Scaled betas are shown in circles, along with 95% confidence limits of the betas. Black marks coefficients that were significantly different from 0 (vertical black line) at an FDR < 5%, and gray marks betas that were not statistically different from 0. Panel B depicts the age coefficients (x-axis) for grip force during lifting and involuntary movements (y-axis). Panels C and D illustrate positive- and negative betas, respectively. Note that due to errors in task administration, 12 observations were missing for the lifting measures (Position-Index and Orientation-Index). Results for these variables were based on 7 girls and 9 boys, with a mean age of 11.2 years old (SD = 3.5). IOI, Inter-Onset-Interval; IPI, Inter-Peak-Interval; ITI, Inter-Tap-Interval; SD, variation; CV, coefficient of variation.

Across all variables assessed, two showed some impact of sex, including finger tap duration (t = 2.4, p < 0.05), and lift grip force (t = 2.2, p < 0.05); however, these effects did not reach significance when FDR was applied (both q > 0.7).

DISCUSSION

This study had two goals: (1) establish feasibility of administering the Q-Motor tasks in children and adolescents; and (2) determine if Q-Motor assessments are sensitive to age-related changes in motor functioning. Complementing prior work assessing tongue force assessment [14], our study demonstrates that children between the ages of 6 and 17 years old reliably completed the various tapping tasks and grasping and lifting measures. We also demonstrated evidence of age-related changes in Q-Motor performance.

Age was a prominent determinant of performance in this study, but not sex. Our sample was relatively small, yet age-related trends in motor performance were generally robust enough to survive corrections for multiple comparisons. In line with prior work [16, 17], the general trends that emerged from the Q-Motor tapping tasks showed that younger children tapped at a slower pace than did older children (with the exception of pronate/supinate hand tapping), and that younger children exhibited more variable motor performance than older children. Likewise, a recent study in preschool children (ages 3 - 6 years old) using a finger tapping paradigm, showed that older children were faster than younger children [16]. As with our study, sex was not associated with performance. In addition to increased speed, age-related improvements in fine motor skills also manifest as increased regularity of movements [17]. In line with this notion, we showed that younger children exhibited more variation in fine motor control than did older children.

The observed age-related changes in fine motor function are likely a manifestation of maturation of central nervous system structures involved in motor control which continue to mature throughout childhood and adolescence, including the motor cortex, basal ganglia, and cerebellum [18–21]. For instance, a functional imaging study showed that compared with adults, children exhibited differential activation of these areas when completing a finger tapping task [22]. Our results imply that various motor functions covered by Q-Motor are sensitive to developmental changes in childhood, making it a suitable measure for studying subtle motor manifestations of HD in at-risk youth. Nevertheless, we acknowledge that it will be important to follow up on our results to determine if the findings of our study can be applied to other participants, most notably young children and those with Juvenile Onset HD.

The HD community is embarking on clinical trials evaluating the efficacy of huntington lowering therapies for the treatment of patients in the early phases of disease [23]. The ultimate goal for the HD community is to implement preventative treatments that ensure that disease manifestations in gene-expansion carriers can be delayed, or that affected individuals can live their lives free of HD [24]. Preventative therapies may potentially have to be administered very early to child and adolescent carriers of the HD mutation, highlighting a need for reliable endpoints for trials in pre-manifest, prodromal, and symptomatic children and adolescents. While quantitative measures such as Q-Motor are not yet validated and accepted by regulatory agencies, these measures detect cross-sectional and longitudinal signals in pre-manifest gene-expansion carriers and could be used for proof-of-concept studies and regulatory acceptance may be sought as more data become available [23, 25]. Q-Motor measures are already applied as an exploratory endpoint in the ongoing SIGNAL study conducted by Vaccinex in conjunction with the Huntington Study Group with two thirds of subjects recruited in prodromal stages of HD [23].

Our results demonstrate that Q-Motor assessments provide non-invasive, easy to administer measures to assess motor function during development in children and adolescents. Therefore, the application of Q-Motor measures in clinical development programs with children is potentially feasible. The global network of HD clinics already equipped with Q-Motor devices due to its use in multiple global multi-center HD trials further supports this strategy and reduces costs [2]. Future studies should investigate thecross-sectional and longitudinal characteristics of Q-Motor measures in at-risk children and adolescents with HD to explore their use in future clinical trials in these subjects.

CONFLICT OF INTEREST

EvdP and NP have no conflict of interest to report. RS is employee of the George-Huntington-Institute, a private research institute focused on clinical and preclinical research in Huntington’s disease, and QuantiMedis, a clinical research organization providing Q-Motor (quantitative motor) services in clinical trials and research. RR is founding director and owner of the George-Huntington-Institute, a private research institute focused on clinical and preclinical research in Huntington’s disease, and QuantiMedis, a clinical research organization providing Q-Motor (quantitative motor) services in clinical trials and research. He holds appointments at the Dept. of Radiology of the University of Muenster and at the Department of Neurodegenerative Diseases and Hertie-Institute for Clinical Brain Research, University of Tuebingen. Dr. Reilmann serves as elected member of the Steering Committees of the European Huntington Disease Network (EHDN) and the Huntington Study Group (HSG), co-chair of the Task Force on Huntington’s disease and member of the Task Force on Technology of the International Parkinson and Movement Disorder Society (IPMDS). He has provided consulting services, advisory board functions, clinical trial services, quantitative motor analyses, and/or lectures for Actelion Pharmaceuticals, Amarin Neuroscience, AOP Orphan Pharmaceuticals, Cure Huntington Disease Initiative Foundation (CHDI), Desitin, Hoffmann-La Roche, IONIS Pharmaceuticals, Ipsen, Lundbeck, Link Medicine, MEDA Pharma, Medivation, Mitoconix, Neurocrine, Neurosearch, Novartis AG, Omeros, Pfizer, Prana Biotechnology, Prilenia, Raptor Pharmaceuticals, Siena Biotech, Temmler Pharma, Teva Pharmaceuticals, uniQure, Vaccinex, Wave Life Sciences, and Wyeth Pharmaceuticals. He has received grant support from the Bundesministerium für Bildung und Forschung (BMBF), the Cure Huntington Disease Initiative Foundation(CHDI), the Deutsche Forschungsgemeinschaft (DFG), the Deutsches Zentrum für Neurodegeneration und Entzündung (DZNE), the European Union 7th Framework Program (EU-FP7), the European Huntington Disease Network (EHDN), the High-Q-Foundation, and the National Science Foundation (NSF).