A Developmental Model of Infantile Nystagmus

The possibility that infantile nystagmus (IN) may reflect a failure in early sensorimotor integration has been proposed for more than a century, but is only recently being borne out in animal studies. The underlying neural and genetic substrate for this plasticity is complex. We propose that, in most cases, IN develops as a developmental response to reduced contrast sensitivity to high-spatial frequencies in an early "critical period," however caused, whether by structural malformations (e.g. foveal hypoplasia) or poor optics (e.g. cataract). As shown by psychophysics, contrast sensitivity to low spatial frequencies is enhanced by motion of the image across the retina. Based on our previous theoretical study (Harris & Berry, Nonlinear Dynamics, 2006), we argue that the best compromise between moving the image and maintaining the image near the fovea (or its remnant) is to oscillate the eyes with jerk nystagmus with increasing velocity waveforms, as seen empirically. The generation of jerk waveforms relies heavily on the saccadic system, which is immature in infancy. Pendular waveforms may therefore provide an alternative to jerk waveforms, and may explain why they are seen more often in young infants. We discuss the implications of this developmental model for the need to synchronize sensory and motor developments in normal development. Failure of this synchronization may also explain some idiopathic cases

A Distal Model of Congenital Nystagmus as Nonlinear Adaptive Oscillations

Congenital nystagmus (CN) is an incurable pathological spontaneous oscillation of the eyes with an onset in the first few months of life. The pathophysiology of CN is mysterious. There is no consistent neurological abnormality, but the majority of patients have a wide range of unrelated congenital visual abnormalities affecting either the cornea, lens, retina or optic nerve. In this theoretical study, we show that these eye oscillations could develop as an adaptive response to maximize visual contrast with poor foveal function in the infant visuomotor system, at a time of peak neural plasticity. We argue that in a visual system with abnormally poor high spatial frequency sensitivity, image contrast is not only maintained by keeping the image on the fovea (or its remnant) but also by some degree of image motion. Using the calculus of variations, we show that the optimal trade-off between these conflicting goals is to generate oscillatory eye movements with increasing velocity waveforms, as seen in real CN. When we include a stochastic component to the start of each epoch (quick-phase inaccuracy) various observed waveforms (including pseudo-cycloid) emerge as optimal strategies. Using the delay embedding technique, we find a low fractional dimension as reported in real data. We further show that, if a velocity command-based pre-motor circuitry (neural integrator) is harnessed to generate these waveforms, the emergence of a null region is inevitable. We conclude that CN could emerge paradoxically as an ‘optimal’ adaptive response in the infant visual system during an early critical period. This can explain why CN does not emerge later in life and why CN is so refractory to treatment. It also implies that any therapeutic intervention would need to be very early in life

Congenital Nystagmus as Non-Linear Adaptive Oscillations

Congenital Nystagmus (CN) is a pathological involuntary oscillation of the eyes with an onset within the first few months of life, with an incidence of about 1:3000. It is a life-long oculomotor disorder that cannot be explained by any underlying neurological abnormality which might compromise adaptive mechanisms. There is no cure, and CN has so far defied explanation in spite of numerous attempts to model the disorder. In this theoretical study we show that these eye oscillations could develop as an adaptive response to maximise visual contrast with poor foveal function in the infant visuomotor system, at a time of peak neural plasticity. We propose that CN is a normal developmental adaptive response to an abnormal congenital sensory input. This can explain why CN does not emerge later in life and why CN is so refractory to treatment. It also implies that any therapeutic intervention would need to be very early in life

A Developmental Model of Congenital Nystagmus

Purpose: Congenital nystagmus (CN) is a spontaneous oscillation of the eyes with an onset in the first few months of life. In 90% of affected children there is an associated underlying sensory defect (foveal hypoplasia, cone dysfunction, cataracts, etc.). In 10% no underlying visual defect can be found, and the nystagmus is labelled as ‘idiopathic’. CN appears to be a developmental anomaly of sensorimotor integration, as it is not have an onset later in infancy or beyond, but why such a wide variety of early onset visual defects should lead to life-long oscillation of the eyes is a mystery. Previous models have focussed on a systems level approach to explain how CN might be generated by known oculomotor circuits. We ask, instead, why CN might occur. Model: Our basic tenet is that infant visuomotor development is highly plastic during some early ‘critical’ period. A defect of foveal vision occurring during (and only during) this period leads to an anomalous connectivity in the oculomotor circuitry, which becomes permanent thereafter. We propose that circuitry normally used for precise foveal registration of a visual object (gaze holding, fixation, and smooth pursuit) develops to maintain some degree of image motion, as this would maximise contrast for a low spatial frequency system. However, this motion is in conflict with maintaining the image on the fovea (or its remnant). We explore the best oculomotor strategy to cope with this conflict. Results: The optimal strategy (in the least squares sense) is to oscillate the eyes in one meridian with alternating slow and quick (saccade) phases. Remarkably, the optimal waveform profile has an increasing-velocity profile. Many of the unique waveforms seen empirically in CN are also optimal strategies given realistic uncertainty in the initial position of a slow phase. Using non-linear dynamical systems analysis, we show that these ‘optimal’ oscillations have similar fractional correlation dimensions to observed data. We also show that a ‘null region’, as commonly observed in CN, would be an inevitable consequence of a velocity driven oculomotor system. Conclusions: We have developed a new approach to understanding oculomotor development, in which we examine the best strategy to maximise visual contrast. In a normal foveate visual system with fine oculomotor control, the best strategy is to develop good foveal registration, which we call ‘fixation’, and ‘smooth pursuit’. If, however, the fovea is absent or not being stimulated (eg. cataracts), the best strategy would be to develop oscillations of the type seen in CN. It implies that the chaotic oscillations are the result of a physiological developmental adaptive process. This is in contrast to the prevailing view that CN is a disease that can be ‘cured’. It is not surprising that CN has proven remarkably refractory to therapeutic intervention with only minimal (if any) long-term successes using drugs, surgery, or even biofeedback. We argue that CN is as adaptive and permanent as normal eye movements are in a normally sighted individual

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No abstract available

Optimal Probabilistic Forecasts for Counts

Optimal probabilistic forecasts of integer-valued random variables are derived. The optimality is achieved by estimating the forecast distribution nonparametrically over a given broad model class and proving asymptotic efficiency in that setting. The ideas are demonstrated within the context of the integer autoregressive class of models, which is a suitable class for any count data that can be interpreted as a queue, stock, birth and death process or branching process. The theoretical proofs of asymptotic optimality are supplemented by simulation results which demonstrate the overall superiority of the nonparametric method relative to a misspecified parametric maximum likelihood estimator, in large but .nite samples. The method is applied to counts of wage claim benefits, stock market iceberg orders and civilian deaths in Iraq, with bootstrap methods used to quantify sampling variation in the estimated forecast distributions.Nonparametric Inference; Asymptotic Efficiency; Count Time Series; INAR Model Class; Bootstrap Distributions; Iceberg Stock Market Orders.

Visualization of the distribution of autophosphorylated calcium/calmodulin-dependent protein kinase II after tetanic stimulation in the CA1 area of the hippocampus

Autophosphorylation of calcium/calmodulin-dependent protein kinase II (CaMKII) at threonine-286 produces Ca2+-independent kinase activity and has been proposed to be involved in induction of long-term potentiation by tetanic stimulation in the hippocampus. We have used an immunocytochemical method to visualize and quantify the pattern of autophosphorylation of CaMKII in hippocampal slices after tetanization of the Schaffer collateral pathway. Thirty minutes after tetanic stimulation, autophosphorylated CaM kinase II (P-CaMKII) is significantly increased in area CA1 both in apical dendrites and in pyramidal cell somas. In apical dendrites, this increase is accompanied by an equally significant increase in staining for nonphosphorylated CaM kinase II. Thus, the increase in P-CaMKII appears to be secondary to an increase in the total amount of CaMKII. In neuronal somas, however, the increase in P-CaMKII is not accompanied by an increase in the total amount of CaMKII. We suggest that tetanic stimulation of the Schaffer collateral pathway may induce new synthesis of CaMKII molecules in the apical dendrites, which contain mRNA encoding its alpha-subunit. In neuronal somas, however, tetanic stimulation appears to result in long-lasting increases in P-CaMKII independent of an increase in the total amount of CaMKII. Our findings are consistent with a role for autophosphorylation of CaMKII in the induction and/or maintenance of long-term potentiation, but they indicate that the effects of tetanus on the kinase and its activity are not confined to synapses and may involve induction of new synthesis of kinase in dendrites as well as increases in the level of autophosphorylated kinase

Testing for a unit root in the presence of a possible break in trend

In this paper we consider the issue of testing a time series for a unit root in the possible presence of a break in a linear deterministic trend at some unknown point in the series. We propose a break fraction estimator which, in the presence of a break in trend, is consistent for the true break fraction at rate Op(T^-1) when there is either a unit root or near-unit root in the stochastic component of the series. In contrast to other estimators available in the literature, when there is no break in trend, our proposed break fraction estimator converges to zero at rate Op(T^-1/2). Used in conjunction with a quasi difference (QD) detrended unit root test that incorporates a trend break regressor in the deterministic component, we show that these rates of convergence ensure that known break fraction null critical values are applicable asymptotically. Unlike available procedures in the literature this holds even if there is no break in trend (the true break fraction is zero), in which case the trend break regressor is dropped from the deterministic component and standard QD detrended unit root test critical values then apply. We also propose a second testing procedure which makes use of a formal pre-test for a trend break in the series, including a trend break regressor only where the pre-test rejects the null of no break. Both procedures ensure that the correctly sized (near-) efficient unit root test that allows (does not allow) for a break in trend is applied in the limit when a trend break does (does not) occur.Unit root test; quasi difference de-trending; trend break; pre-test; asymptotic power

Attempted DNA extraction from a Rancho La Brea Columbian mammoth (Mammuthus columbi): prospects for ancient DNA from asphalt deposits.

Fossil-bearing asphalt deposits are an understudied and potentially significant source of ancient DNA. Previous attempts to extract DNA from skeletons preserved at the Rancho La Brea tar pits in Los Angeles, California, have proven unsuccessful, but it is unclear whether this is due to a lack of endogenous DNA, or if the problem is caused by asphalt-mediated inhibition. In an attempt to test these hypotheses, a recently recovered Columbian mammoth (Mammuthus columbi) skeleton with an unusual pattern of asphalt impregnation was studied. Ultimately, none of the bone samples tested successfully amplified M. columbi DNA. Our work suggests that reagents typically used to remove asphalt from ancient samples also inhibit DNA extraction. Ultimately, we conclude that the probability of recovering ancient DNA from fossils in asphalt deposits is strongly (perhaps fatally) hindered by the organic compounds that permeate the bones and that at the Rancho La Brea tar pits, environmental conditions might not have been ideal for the general preservation of genetic material

Photoacoustic ultrasound sources from diffusion-limited aggregates

Metallic diffusion-limited aggregate (DLA) films are well-known to exhibit near-perfect broadband optical absorption. We demonstrate that such films also manifest a substantial and relatively material-independent photoacoustic response, as a consequence of their random nanostructure. We theoretically and experimentally analyze photoacoustic phenomena in DLA films, and show that they can be used to create broadband air- coupled acoustic sources. These sources are inexpensive and simple to fabricate, and work into the ultrasonic regime. We illustrate the device possibilities by building and testing an optically-addressed acoustic phased array capable of producing virtually arbitrary acoustic intensity patterns in air.Comment: 5 pages, 5 figure