Mrc Soundmaster 210 Manual Dexterity
1,2., 3, Sarah Cumming 2, Bob Ballantyne 1, Josephine McGhie 2, Ravi Jampana 3, Cheryl Longman 1, Jonathan J. IntroductionMyotonic dystrophy type 1 (DM1) is a dominantly inherited, multisystem condition resulting from the abnormal expansion of a CTG trinucleotide repeat.
Instructions For Mrc Soundmaster 210
The clinical phenotype is highly variable, with larger CTG repeats broadly associated with earlier onset and more severe symptoms. Although the phenotype presents as a clinical continuum, DM1 may be sub-categorized according to age at onset of symptoms from congenital-onset, through infantile-onset (childhood before age 10 years), juvenile-onset (childhood after 10 years), to adult- and late-onset forms.Symptoms arising from central nervous system (CNS) involvement in DM1 are common , and vary in their impact across this clinical spectrum. In congenital-onset DM1, intellectual disability is a consistent finding, and is frequently accompanied by additional neurodevelopmental diagnoses including autism spectrum disorders (–). In infantile- and juvenile-onset forms, learning difficulties are often present, but are typically milder than those seen in congenital-onset DM1. Educational attainment in these groups may however be further compromised by concomitant attention deficit, autism spectrum or anxiety disorders (, ).The CNS phenotype in adult-onset DM1 is characterized by more subtle deficits of cognition. In this group, global cognitive function is usually found to be normal when measured by standard tools such as the Mini Mental State Examination (–), although distribution may be shifted toward the lower end of the general population range. Case-control studies however have demonstrated impaired performance in a range of targeted neuropsychological assessments, consistent with deficits of visual perception and construction, social cognition, psychomotor speed, executive functioning, visual memory and attention, with smaller effect sizes observed in language and verbal memory domains reviewed in.
Deficits are typically present in several domains in an affected individual , and longitudinal studies confirm progression of cognitive symptoms with time (–).Changes in personality are also described in DM1. Distinctive traits include a tendency toward apathy, and avoidant behaviors such as reluctance to seek new experiences, make new friends or form intimate relationships (–). Furthermore, excessive daytime somnolence is commonly reported, and may occur in the absence of sleep disordered breathing , suggesting a central contribution to this symptom. Imaging studies confirm structural brain changes in DM1, characterized on MRI scanning by progressive, widespread atrophy and the presence of white matter lesions (–). Further, diffusion tensor imaging (DTI) reveals the presence of diffuse, microstructural disruption even in apparently normal-looking white matter.
Tolerability of the ProtocolStroop data were incomplete for four DM1-affected participants; one because the tool was not available, one male could not complete the color tasks due to red-green color blindness, and a third became frustrated and disengaged during the color-word task. Data from the fourth was excluded as she had a diagnosis of visual stress (Mears-Irlen syndrome), and obtained exceptionally low scores in Stroop despite above-average performance in other cognitive domains. Two DM1-affected participants declined to answer items within MDHI, as they felt these were offensive or intrusive (questions related to personality and sexual function, respectively). One DM1-affected participant declined to nominate a relative to complete the informant-DEX questionnaire, and another was unable to identify a suitable contact due to social isolation. All participants who commenced MRI scanning were able to tolerate the full imaging protocol. Deficits in the DM1-Affected Group Compared With ControlsComparison of neuropsychology scores from DM1-affected participants with control participants are summarized in Table.
The DM1-affected group had lower scores on average in all elements of the Stroop, D-KEFS™ Trail Making, Block Design and FAS oral word association tests. The mean total score for ECAS was also lower in the DM1-affected group ( p = 0.004), though subscores for verbal fluency and memory only approached statistical significance ( p = 0.112, 0.085). Visuospatial and language subscores of ECAS showed a significant ceiling effect in DM1-affected participants, with 24 (53%) and 15 (33%), respectively gaining the maximum possible score in these subsections (Supplementary File ). Correction of performance in the Stroop color-word test for basic reading speed attenuated the Cohen's d effect size from a large 1.266 to a smaller, though still significant 0.619 compared with controls. Performance on the D-KEFS™ Trail Making number-letter switching task was no longer significantly different after controlling for basic motor speed (Motor contrast score; p = 0.221).
In the Block Design subtest, the large effect size remained when weighting for speed was eliminated (standard score vs. Non-adjusted score, Cohen's d = 1.592 vs. 1.459, respectively).DM1-affected participants reported greater fatigue, lower mood and greater pain on FDSS, BDI II, and McGill visual analog scales, respectively (Table ). There was a trend toward greater everyday executive dysfunction as measured by the self-DEX questionnaire, and greater pain reported by SF-36, though these differences did not reach statistical significance ( p = 0.102, 0.061). Levels of low mood, fatigue and pain that could be considered clinically significant were reported frequently in DM1-affected participants. Thirteen (29%) had a BDI II score greater than 13, 27 (60%) had an FDSS score greater than two SDs above the mean score of controls, and 16 (36%) rated bodily pain as “moderate” or greater on SF-36. Comparison of ECAS With Other Cognitive AssessmentsPerformance in the Stroop color-word task did not significantly correlate with ECAS total executive subscore, or score in the sentence completion/cognitive inhibition task alone.
The same was true for Stroop Interference score. Performance in the D-KEFS™ number-letter switching trail did not correlate with the number-letter alternation task of ECAS alone, but had a relatively weak positive correlation with total ECAS executive subscore ( p = 0.006, Adj R 2 = 0.141). The D-KEFS™ motor contrast score did not correlate with the ECAS number-letter alternation task or the total executive subscore.Block Design standard score was positively correlated with both the ECAS visuospatial subscore ( p = 0.008, Adj R 2 = 0.134) and the ECAS executive subscore ( p = 0.011, Adj R 2 = 0.122). Similarly, the Block Design non-adjusted score correlated weakly with the ECAS visuospatial subscore ( p = 0.024, Adj R 2 = 0.092) and with the executive subscore ( p = 0.009, Adj R 2 = 0.127). Only the relationship between the Block Design standard score and ECAS visuospatial subscore remained significant after Benjamini-Hochberg correction. Of note, correlations with the ECAS visuospatial score were likely hampered by the ceiling effect previously described, in that 53% of DM1-affected subjects gained the maximum possible points for this subsection. Relationships Between Self-reported SymptomsIn the DM1-affected group, significant co-linearity was observed between self-reported scales of fatigue, pain and low mood.
BDI II score correlated positively with FDSS score ( p. A highly significant relationship was also observed between mood (BDI II score) and self-reported CNS symptoms. Patients with more symptoms of depression tended to report more cognitive problems (MHDI cognitive impairment subscale; p. To further explore the relative effect of GMV and muscle impairment on cognitive performance, while controlling for other factors, DM1-ActivC© score was then added to this multivariate model, to give: score age + sex + GMV + DM1-ActivC© (Table ). Addition of DM1-ActivC© improved the fit of the model, reflected by an increase in Adj R 2, for the Stroop color and word tasks, Trails 1–5 of the D-KEFS Trail Making Tests and both the Block Design standard and non-adjusted scores. The contribution of DM1-ActivC© score to the model reached statistical significance (at p. There was a trend toward greater depression and self-reported cognitive impairment scores in patients with lower VWML (Figures ).
Higher score in the informant-DEX was significantly associated with greater VWML ( p = 0.001, Adj R 2 = 0.278) (Figure ). DiscussionIn this study, a range of CNS outcome measures currently recommended for use in clinical trials were applied to a moderate-sized cohort of adults with DM1, and compared against age-matched controls.
Correlations were explored with CTG repeat length and MRI evidence of global DM1-related brain changes. The results highlight several important considerations for CNS outcome measure selection in the context of DM1 clinical trials.The feasibility of any protocol for DM1 clinical trials must be considered in the context of the physical limitations, fatigability and behavioral traits present in such cohorts , since these factors could result in a lower threshold for poor compliance or withdrawal compared with other groups.
Despite this, the test protocol we describe was not significantly compromised by disengagement or inability to complete tasks. Furthermore, the neuropsychology test battery was apparently sensitive to impairment in DM1, detecting effect sizes of −0.5 to −1.5 standard deviations compared with controls, with smaller effects in verbal and memory domains, consistent with the profile described in DM1. These findings therefore support the feasibility and sensitivity of the neuropsychology assessments and self-reported questionnaires described for use in clinical studies.Specificity of the neuropsychology battery for central vs.
Peripheral effects of DM1 was less clear, however. The Stroop and Trail Making Tests are commonly used in clinical and research contexts, and are broadly considered measures of higher, executive cognitive functions. The color-word task of the Stroop requires the subject to suppress a habitual impulse (to say the written word), and instead perform an unfamiliar task (saying the color of ink), while the number-letter switching task of the Trail Making test demands cognitive flexibility to switch repeatedly between two unrelated sequences. In reality however, both are complex tasks, and performance depends on additional domains including attention and basic processing speed (, ). In both tests, comparison with controls showed a similar, large effect size for a simplified version of the task (the color and word cards of the Stroop test, and motor task of the Trail Making Tests) as for the key executive component (the color-word card and number-letter switching trail). Correction of the Stroop color-word score for basic reading speed reduced this large effect size to a moderate Cohen's d value, closer to that of the executive subscore of ECAS.
In the D-KEFS Trail Making Tests, correction of the number-letter switching score for basic motor speed eliminated any significant difference compared to controls, suggesting that a more basic speed limitation is the major contributor to poorer performance in the DM1-affected group.A speed limitation affecting the simpler conditions of the Stroop or Trail Making Tests has been observed in some previous DM1 studies (, ). The nature of this limitation has not been specifically explored, though it has generally been held to reflect a more global cognitive impairment, or deficit in basic processing.
Slowing of basic processing is a key feature of cognitive aging in the general population , and has been linked to reduced integrity of white matter and loss of gray matter volume in older adults (, ), including reduced integrity of fronto-striatal white matter tracts, and volume of subcortical structures. These structural changes are likely to be accelerated as part of the global brain changes seen in DM1, hence an exaggeration of the normal decline in basic speed might be predicted. The fact that we detected a basic speed limitation affecting both manual and vocal modalities could be consistent with a central, domain-general cause. A central slowing of information processing could further be speculated to underlie features of adynamia or apparent apathy that are frequently described in in DM1.On the other hand, some authors have questioned whether physical limitations due to DM1 might significantly contribute to the impairment detected by complex cognitive tests such as the Stroop. Recent data have highlighted similar concerns in studies of cognitive aging, noting that manual dexterity significantly contributes to performance in traditional paper-and-pencil assessments of cognitive processing speed in older adults. Interference from peripheral weakness would undermine use of such tools as CNS outcome measures in DM1 drug trials, since a therapy that successfully improves peripheral weakness or myotonia, and so increases reading aloud speed or manual dexterity, could erroneously give the impression of having impacted cognition. Our data demonstrate significant correlations of performance in key components of the Stroop, Trail Making Tests, and Block Design subtest with GMV after accounting for age and sex, suggesting structural brain changes are major modifiers of performance.
However, inclusion of DM1-ActivC© score in a multivariate model supports the hypothesis that muscle impairment accounts for some of the residual variation in performance in the Stroop Color and Word tasks, as well as all elements of the Trail Making Tests. Perhaps unsurprisingly, the effects of muscle were most pronounced in the number scanning and motor components of the Trail Making Tests.The Block Design test is also a common cognitive assessment, used primarily to assess visuospatial skills. Standard scoring systems are again heavily weighted to reward rapid completion of the designs, hence we hypothesized that distal muscle weakness in DM1 might account for a major portion of the deficit detected compared with controls. In this test however, we observed that the large effect size persisted despite elimination of weighting for speed in the non-adjusted score. Further, scores showed some positive correlation with the visuospatial and executive subscores of ECAS. These findings suggest the Block Design test is indeed sensitive for impairment of visuospatial cognition in DM1 patients. Although the non-adjusted score improved correlations with ePAL and GMV compared with the standard score, this should be interpreted with caution since this value could not be age-adjusted due to a lack of normative data.Overall, our neuropsychology data suggest that there would be value in further work to determine the nature of the basic speed limitation detected in DM1 by the Stroop and Trail Making Tests, and in particular to distinguish whether this is related to peripheral muscle impairment or other central factors.
Furthermore, development and validation of assessments that are not excessively influenced by manual dexterity or dysarthria, perhaps utilizing assistive technology, would also be a useful step toward clinical trial readiness.In self-reported symptom questionnaires, we observed strong mutual correlations between symptoms of fatigue, pain and low mood, consistent with the model of inter-relatedness between mental wellbeing and physical symptoms in DM1 that has driven recent research into cognitive behavioral therapy-based interventions. Patients with lower mood reported more somatic symptoms in general, particularly relating to cognition and social performance. This self-reported impairment was not generally reflected in poorer performance in neuropsychological assessments and, similar to the observations of previous authors (, ), we found a trend toward greater reporting of depression and central symptoms in those with milder white matter change on MRI. It is unclear whether this trend reflects increasing acceptance of symptoms over time, or reduced awareness as has been previously described. In contrast, executive symptoms rated by a relative or carer showed a positive relationship with the severity of MRI changes. These data therefore suggest that self-reported symptoms alone are not an effective means to quantify the severity of the primary disease process in brain in DM1 study cohorts, and highlight a possible role for proxy measures as part of a global CNS assessment.Since study visits for future clinical trials are likely to include additional effort-intensive measures of muscle symptoms as well as a CNS assessment protocol, it remains desirable to minimize redundant or duplicate outcome measures. It is therefore useful to note that, consistent with previous data , subscores within the MDHI correlated well with other measures of similar themes.
This supports the MDHI as a good stand-alone measure of self-reported symptoms. This is with the caveat that, as outlined above, self-reported symptom scales may be influenced by mood or insight issues, and hence should be supported by objective measures of the relevant disease process where possible in the context of a clinical trial.Correlations of CTG repeat length with neuropsychology assessments were comparatively poor. Several factors likely contribute to this observation, including relatively small cohort size, which may be subject to selection bias, and selection for adult onset DM1 only (excluding severe phenotypes and thus large repeat sizes). Because the cognitive phenotype in DM1 is generally one of mild impairment within the general population range, (in contrast to muscle weakness, which may be affected well outwith the range of normal variation), it may be that the effect of CTG repeat length on the multifactorial trait of cognition is too subtle to detect within the sample tested. A more marked effect of repeat length on muscle strength compared with central phenotypes is supported by the observation that the strongest genetic correlation observed in our cohort was with the MDHI mobility score.With regard to genotype-phenotype correlations, it is also noteworthy that the three individuals identified with variant repeats reported particularly mild muscle impairment in DM1-ActivC ©.
This adds to growing evidence that individuals with DM1 due to variant repeats may be statistical outliers in terms of disease severity , and so reinforces a role for robust genotyping, including screening for variant repeats, in DM1 clinical trials.Although this study was not intended primarily to evaluate MRI biomarkers, it was interesting to note an apparent sex effect on GMV in this cohort. Inclusion of sex in a multivariate model improved both correlations of GMV with age, and with performance in several neuropsychology assessments, although stringent correction for multiple comparisons meant some could not be considered significant. To our knowledge, sex-specific differences in gray matter atrophy have not specifically been explored in DM1, but in the general population, a marginally greater rate of gray matter atrophy in males is observed. Therefore, given that several features of DM1 show a sex bias in penetrance , it is plausible that a sex effect on gray matter atrophy might exist in DM1. This finding highlights sex as an important cofactor to consider in future studies aiming to identify imaging biomarkers. Unlike global GMV, VWML did not correlate well with cognitive impairment measured by neuropsychology assessments, nor with CTG repeat length in this study. Given that white matter lesions in the general population may be influenced by vascular risk factors , it is probable that additional environmental and/or genetic factors also influence the severity of VWMLs in DM1, which may limit their potential for use as a disease-specific biomarker.
Further studies in larger cohorts, using a variety of imaging modalities and regional structural measures as well as a longitudinal design are warranted to identify clinically meaningful imaging markers in DM1. ConclusionsThis case control study applied a range of CNS measures with potential for use in clinical trials to 45 adults with DM1. Our data highlight muscle impairment and possible deficits in simple information processing as potential confounders of performance in complex neuropsychology assessments, particularly Trail Making and Stroop tests. We demonstrated that low mood is associated with greater self-reporting of central symptoms in general, and that significant depression appears to be more common in those with milder CNS involvement. An apparent sex effect was observed in volumetric analysis of global gray matter, which shows promise as a potential outcome measure, although further longitudinal studies in a larger population using a range of MRI modalities are indicated to identify and validate imaging biomarkers.
Author ContributionsMH, JMcL, CL, RJ, JE, DM, and MF contributed to the conception and design of the study. SC and JMcG generated and curated genetic data. BB contributed to identification of participants and interpretation of clinical data. JMcL and RJ undertook MRI planning and analysis. MH undertook clinical data collection, primary data analysis, and prepared the first manuscript draft, with guidance from SC, JE, MF, and DM. All authors contributed intellectually to subsequent redrafting of the manuscript. FundingThis study was funded by grants from Muscular Dystrophy UK (Ref: MC3/1073) and Chief Scientist Office Scotland (Ref: CAF/MD/15/01).
The Monckton group (University of Glasgow) also thank the Myotonic Dystrophy Support Group (UK) for their continued support. Conflict of Interest StatementDM has been a paid scientific consultant and/or received honoraria from Biogen Idec, AMO Pharma, Charles River, and Vertex Pharmaceuticals. DM also has a research contract with AMO Pharma.
JE is a co-author of the Behavioral Assessment of the Dysexecutive Syndrome test battery, and as such receives royalties from use of the Dysexecutive (DEX) Questionnaire. MH, JMcL, SC, BB, JMcG, RJ, CL, and MF report no relevant disclosures. AcknowledgmentsThe authors wish to thank the participants and their families for their co-operation with the study.
Authors are also grateful to Tracey Hopkins, Rosemary Woodward, Evonne McLennan, Caroline Crosbie, Laura Dymock, Fiona Savage, Patricia Clarkin, and Margaret Hay of the Glasgow Clinical Research Imaging Facility, Queen Elizabeth University Hospital, who undertook MRI imaging. The authors thank the Scottish Myotonic Dystrophy Consortium for support of this project. The Scottish Myotonic Dystrophy Consortium are: Cheryl Longman, Douglas Wilcox, Alison Wilcox, Richard Petty, Yvonne Robb, Maria Elena Farrugia, Helen Gregory, Alexis Duncan, Catherine McWilliam, John Dean, Anne-Marie Taylor, Lorna MacLeish, Monika Rahman, Anne McKeown, Kirsten Patterson, Mark Hamilton, Bob Ballantyne, Sarah Cumming, and Darren G.
The Scottish Myotonic Dystrophy Consortium is a subgroup of the Scottish Muscle Network; Programme Manager Hugh Kennedy, Programme Support Officer Laura Craig. Raw FDSS and DM1-ActivC© scores were converted to centile scores by Professor Catharina G.
Faber, Maastricht University Medical Center+. The authors thank Professor Hanns Lochmuller for valued input regarding selection of outcome measures.DNA and serum from consenting DM1-affected participants have been stored at the MRC Centre Biobank for Rare and Neuromuscular Diseases, The John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle University.
Supplementary MaterialThe Supplementary Material for this article can be found online at:Supplementary File S1. Raw results data.Supplementary File S2. Linear regression analyses and Benjamini-Hochberg correction. Keywords: myotonic dystrophy, neuropsychology assessment, outcome measures, small pool PCR, voxel based morphometryCitation: Hamilton MJ, McLean J, Cumming S, Ballantyne B, McGhie J, Jampana R, Longman C, Evans JJ, Monckton DG and Farrugia ME (2018) Outcome Measures for Central Nervous System Evaluation in Myotonic Dystrophy Type 1 May Be Confounded by Deficits in Motor Function or Insight. Doi: 10.3389/fneur.2018.00780Received: 04 June 2018; Accepted: 30 August 2018; Published: 02 October 2018.
MRC decoders are widely distributed in most hobby shops that carry many fine MRC products.Unfortunately MRC was very late getting into the DCC market. More specifically, they came to the sound decoder market very late.
With the introduction of these products, they have a lot of bells and whistle so to speak on the outside, but under the hood, there is not much there and what is there sometime does not follow the NMRA DCC standards. Pretty on the outside by limited brains on the inside.Since the first release of MRC sound decoders, many new series of decoder have been released. Unfortunately, they have not caught up to the level of sound decoder performance that MRC competators have offered from the start. Each MRC release of a new sound decoder series is an improvement in catching up. But it begs the question as to WHY can't MRC just focus on catching up 100% first and then build up from there.EXAMPLES OF KNOWN MRC SOUND DECODER PROBLEMSNot all versions of MRC decoder have ALL of these problems. It depends on which generation of MRC decoder you have.
This has lead to confusion in the market place regardind how well the decoder works. Some say I have no problem while other say they do. The problem is the decoder feature playing field is not level or even.
So two people both owning MRC decoders but both are many generations apart will have very different opinions. The other part of the problem is the feature set the do offer is often less the competitor decoder offers. MRC owners may have no idea what they are missing if they never tried the other brands of DCC sound decoders.
Ignorance is bliss sort of thing.Below is a partial list of known MRC decoder problems:1) No programming track support.2) Limited to no CV programmable volume level support.3) Violates NMRA DCC Standards regarding CV assignments and/or value ranges.4) Violates NMRA DCC Standards regarding advanced Function Control Support.5) Stalls on dirty track and forces the train to wait until it runs the 'Start The Engine' sequence.