Matthis Synofzik

Bio: Matthis Synofzik is an academic researcher from University of Tübingen. The author has contributed to research in topics: Ataxia & Medicine. The author has an hindex of 49, co-authored 318 publications receiving 9031 citations. Previous affiliations of Matthis Synofzik include University of Antwerp & Montreal Children's Hospital.

Targeted next generation sequencing as a diagnostic tool in epileptic disorders

Abstract: SUMMARY Purpose: Epilepsies have a highly heterogeneous background with a strong genetic contribution. The variety of unspecific and overlapping syndromic and nonsyndromic phenotypes often hampers a clear clinical diagnosis and prevents straightforward genetic testing. Knowing the genetic basis of a patient’s epilepsy can be valuable not only for diagnosis but also for guiding treatment and estimating recurrence risks. Methods: To overcome these diagnostic restrictions, we composed a panel of genes for Next Generation Sequencing containing the most relevant epilepsy genes and covering the most relevant epilepsy phenotypes known so far. With this method, 265 genes were analyzed per patient in a single step. We evaluated this panel on a pilot cohort of 33 index patients with concise epilepsy phenotypes or with a severe but unspecific seizure disorder covering

A Pan‐European Study of the C9orf72 Repeat Associated with FTLD: Geographic Prevalence, Genomic Instability, and Intermediate Repeats

Abstract: We assessed the geographical distribution of C9orf72 G(4) C(2) expansions in a pan-European frontotemporal lobar degeneration (FTLD) cohort (n = 1,205), ascertained by the European Early-Onset Dementia (EOD) consortium. Next, we performed a meta-analysis of our data and that of other European studies, together 2,668 patients from 15 Western European countries. The frequency of the C9orf72 expansions in Western Europe was 9.98% in overall FTLD, with 18.52% in familial, and 6.26% in sporadic FTLD patients. Outliers were Finland and Sweden with overall frequencies of respectively 29.33% and 20.73%, but also Spain with 25.49%. In contrast, prevalence in Germany was limited to 4.82%. In addition, we studied the role of intermediate repeats (7-24 repeat units), which are strongly correlated with the risk haplotype, on disease and C9orf72 expression. In vitro reporter gene expression studies demonstrated significantly decreased transcriptional activity of C9orf72 with increasing number of normal repeat units, indicating that intermediate repeats might act as predisposing alleles and in favor of the loss-of-function disease mechanism. Further, we observed a significantly increased frequency of short indels in the GC-rich low complexity sequence adjacent to the G(4) C(2) repeat in C9orf72 expansion carriers (P < 0.001) with the most common indel creating one long contiguous imperfect G(4) C(2) repeat, which is likely more prone to replication slippage and pathological expansion.

Misattributions of agency in schizophrenia are based on imprecise predictions about the sensory consequences of one's actions

Abstract: The experience of being the initiator of one's own actions seems to be infallible at first glance. Misattributions of agency of one's actions in certain neurological or psychiatric patients reveal, however, that the central mechanisms underlying this experience can go astray. In particular, delusions of influence in schizophrenia might result from deficits in an inferential mechanism that allows distinguishing whether or not a sensory event has been self-produced. This distinction is made by comparing the actual sensory information with the consequences of one's action as predicted on the basis of internal action-related signals such as efference copies. If this internal prediction matches the actual sensory event, an action is registered as self-caused; in case of a mismatch, the difference is interpreted as externally produced. We tested the hypothesis that delusions of influence are based on deficits in this comparator mechanism. In particular, we tested whether patients' impairments in action attribution tasks are caused by imprecise predictions about the sensory consequences of self-action. Schizophrenia patients and matched controls performed pointing movements in a virtual-reality setup in which the visual consequences of movements could be rotated with respect to the actual movement. Experiment 1 revealed higher thresholds for detecting experimental feedback rotations in the patient group. The size of these thresholds correlated positively with patients' delusions of influence. Experiment 2 required subjects to estimate their direction of pointing visually in the presence of constantly rotated visual feedback. When compared to controls, patients' estimates were significantly better adapted to the feedback rotation and exhibited an increased variability. In interleaved trials without visual feedback, i.e. when pointing estimates relied solely on internal action-related signals, this variability was likewise increased and correlated with both delusions of influence and the size of patients' detection thresholds as assessed in the first experiment. These findings support the notion that delusions of influence are based on imprecise internal predictions about the sensory consequences of one's actions. Moreover, we suggest that such imprecise predictions prompt patients to rely more strongly on (and thus adapt to) external agency cues, in this case vision. Such context-dependent weighted integration of imprecise internal predictions and alternative agency cues might thus reflect the common basis for the various misattributions of agency in schizophrenia patients.

Intensive coordinative training improves motor performance in degenerative cerebellar disease.

Abstract: Objectives: The cerebellum is known to play a strong functional role in both motor control and motor learning. Hence, the benefit of physiotherapeutic training remains controversial for patients with cerebellar degeneration. In this study, we examined the effectiveness of a 4-week intensive coordinative training for 16 patients with progressive ataxia due to cerebellar degeneration (n = 10) or degeneration of afferent pathways (n = 6). Methods: Effects were assessed by clinical ataxia rating scales, individual goal attainment scores, and quantitative movement analysis. Four assessments were performed: 8 weeks before, immediately before, directly after, and 8 weeks after training. To control for variability in disease progression, we used an intraindividual control design, where performance changes with and without training were compared. Results: Significant improvements in motor performance and reduction of ataxia symptoms were observed in clinical scores after training and were sustained at follow-up assessment. Patients with predominant cerebellar ataxia revealed more distinct improvement than patients with afferent ataxia in several aspects of gait like velocity, lateral sway, and intralimb coordination. Consistently, in patients with cerebellar but without afferent ataxia, the regulation of balance in static and dynamic balance tasks improved significantly. Conclusion: In patients with cerebellar ataxia, coordinative training improves motor performance and reduces ataxia symptoms, enabling them to achieve personally meaningful goals in everyday life. Training effects were more distinct for patients whose afferent pathways were not affected. For both groups, continuous training seems crucial for stabilizing improvements and should become standard of care. Level of evidence: This study provides Class III evidence that coordinative training improves motor performance and reduces ataxia symptoms in patients with progressive cerebellar ataxia.

I and i

Abstract: There is, I think, something ethereal about i —the square root of minus one. I remember first hearing about it at school. It seemed an odd beast at that time—an intruder hovering on the edge of reality. Usually familiarity dulls this sense of the bizarre, but in the case of i it was the reverse: over the years the sense of its surreal nature intensified. It seemed that it was impossible to write mathematics that described the real world in …

Using Multivariate Statistics

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Whatever next? Predictive brains, situated agents, and the future of cognitive science

Abstract: Brains, it has recently been argued, are essentially prediction machines. They are bundles of cells that support perception and action by constantly attempting to match incoming sensory inputs with top-down expectations or predictions. This is achieved using a hierarchical generative model that aims to minimize prediction error within a bidirectional cascade of cortical processing. Such accounts offer a unifying model of perception and action, illuminate the functional role of attention, and may neatly capture the special contribution of cortical processing to adaptive success. This target article critically examines this "hierarchical prediction machine" approach, concluding that it offers the best clue yet to the shape of a unified science of mind and action. Sections 1 and 2 lay out the key elements and implications of the approach. Section 3 explores a variety of pitfalls and challenges, spanning the evidential, the methodological, and the more properly conceptual. The paper ends (sections 4 and 5) by asking how such approaches might impact our more general vision of mind, experience, and agency.

Systematic review of levodopa dose equivalency reporting in Parkinson's disease

Abstract: Interpretation of clinical trials comparing different drug regimens for Parkinson's disease (PD) is complicated by the different dose intensities used: higher doses of levodopa and, possibly, other drugs produce better symptomatic control but more late complications. To address this problem, conversion factors have been calculated for antiparkinsonian drugs that yield a total daily levodopa equivalent dose (LED). LED estimates vary, so we undertook a systematic review of studies reporting LEDs to provide standardized formulae. Electronic database and hand searching of references identified 56 primary reports of LED estimates. Data were extracted and the mean and modal LEDs calculated. This yielded a standardized LED for each drug, providing a useful tool to express dose intensity of different antiparkinsonian drug regimens on a single scale. Using these conversion formulae to report LEDs would improve the consistency of reporting and assist the interpretation of clinical trials comparing different PD medications.