Evaluating movement disorders in pediatric patients receiving risperidone: a comparison of spontaneous reports and research criteria for TD

<p>Abstract</p> <p>Background</p> <p>Movement disorders (MD) in children are relatively common and may be associated with medication use. Objective methods (ie rating scales) and specific research criteria may be helpful in identifying MD-related adverse events that would otherwise not be apparent from spontaneous reports. We assessed whether more stringent and rigorous criteria would provide MD rates similar to those derived subjectively from spontaneous reports.</p> <p>Methods</p> <p>MDs were assessed in children with disruptive behavior disorders (DBDs) and subaverage intelligence receiving risperidone. Data were from three 1-year, open-label studies in subjects 4–14 years old. Dyskinesia severity was rated by the Extrapyramidal Symptom Rating Scale (ESRS) dyskinesia subscale. Tardive dyskinesia (TD) was defined: mild dyskinesia (scores 2, 3) in two anatomical areas; or moderate dyskinesia (score ≥ 4) in one area for ≥ 4 weeks in subjects without dyskinesia at baseline (scores 0, 1).</p> <p>Results</p> <p>The mean (± SD) age of subjects was 9.4 ± 2.4 years, the mean (± SD) risperidone dose was 1.6 ± 0.7 mg/day, and the mean (± SD) exposure was 317.8 ± 104.5 days. ESRS data were available for 668 subjects. Mean ESRS scores were low throughout the study. At baseline, 655 subjects had no dyskinetic symptoms. One subject met predefined TD criteria after a risperidone dose reduction. Symptoms persisted for 4 weeks, resolving with continued treatment and no dosage change. Two different subjects had TD by spontaneous adverse-event reports, with dyskinetic symptoms at 1–2 visits, and symptoms that resolved after treatment discontinuation. Thirteen subjects had dyskinesia at baseline; their mean ESRS dyskinesia scores decreased at endpoint.</p> <p>Conclusion</p> <p>Using objective rating scales and research criteria, low-dose risperidone was associated with low risk of TD and other MDs in children with DBDs in three large 1-year studies. Careful, objective evaluation of emergent MDs during all stages of treatment is essential for identifying treatment-emergent TD.</p

Decorrelation and efficient coding by retinal ganglion cells

An influential theory of visual processing asserts that retinal center-surround receptive fields remove spatial correlations in the visual world, producing ganglion cell spike trains that are less redundant than the corresponding image pixels. For bright, high-contrast images, this decorrelation would enhance coding efficiency in optic nerve fibers of limited capacity. We tested the central prediction of the theory and found that the spike trains of retinal ganglion cells were indeed decorrelated compared with the visual input. However, most of the decorrelation was accomplished not by the receptive fields, but by nonlinear processing in the retina. We found that a steep response threshold enhanced efficient coding by noisy spike trains and that the effect of this nonlinearity was near optimal in both salamander and macaque retina. These results offer an explanation for the sparseness of retinal spike trains and highlight the importance of treating the full nonlinear character of neural codes

Dendritic Spikes Amplify the Synaptic Signal to Enhance Detection of Motion in a Simulation of the Direction-Selective Ganglion Cell

The On-Off direction-selective ganglion cell (DSGC) in mammalian retinas responds most strongly to a stimulus moving in a specific direction. The DSGC initiates spikes in its dendritic tree, which are thought to propagate to the soma with high probability. Both dendritic and somatic spikes in the DSGC display strong directional tuning, whereas somatic PSPs (postsynaptic potentials) are only weakly directional, indicating that spike generation includes marked enhancement of the directional signal. We used a realistic computational model based on anatomical and physiological measurements to determine the source of the enhancement. Our results indicate that the DSGC dendritic tree is partitioned into separate electrotonic regions, each summing its local excitatory and inhibitory synaptic inputs to initiate spikes. Within each local region the local spike threshold nonlinearly amplifies the preferred response over the null response on the basis of PSP amplitude. Using inhibitory conductances previously measured in DSGCs, the simulation results showed that inhibition is only sufficient to prevent spike initiation and cannot affect spike propagation. Therefore, inhibition will only act locally within the dendritic arbor. We identified the role of three mechanisms that generate directional selectivity (DS) in the local dendritic regions. First, a mechanism for DS intrinsic to the dendritic structure of the DSGC enhances DS on the null side of the cell's dendritic tree and weakens it on the preferred side. Second, spatially offset postsynaptic inhibition generates robust DS in the isolated dendritic tips but weak DS near the soma. Third, presynaptic DS is apparently necessary because it is more robust across the dendritic tree. The pre- and postsynaptic mechanisms together can overcome the local intrinsic DS. These local dendritic mechanisms can perform independent nonlinear computations to make a decision, and there could be analogous mechanisms within cortical circuitry

Adaptation-Dependent Synchronous Activity Contributes to Receptive Field Size Change of Bullfrog Retinal Ganglion Cell

Nearby retinal ganglion cells of similar functional subtype have a tendency to discharge spikes in synchrony. The synchronized activity is involved in encoding some aspects of visual input. On the other hand, neurons always continuously adjust their activities in adaptation to some features of visual stimulation, including mean ambient light, contrast level, etc. Previous studies on adaptation were primarily focused on single neuronal activity, however, it is also intriguing to investigate the adaptation process in population neuronal activities. In the present study, by using multi-electrode recording system, we simultaneously recorded spike discharges from a group of dimming detectors (OFF-sustained type ganglion cells) in bullfrog retina. The changes in receptive field properties and synchronization strength during contrast adaptation were analyzed. It was found that, when perfused using normal Ringer's solution, single neuronal receptive field size was reduced during contrast adaptation, which was accompanied by weakening in synchronization strength between adjacent neurons' activities. When dopamine (1 µM) was applied, the adaptation-related receptive field area shrinkage and synchronization weakening were both eliminated. The activation of D1 receptor was involved in the adaptation-related modulation of synchronization and receptive field. Our results thus suggest that the size of single neuron's receptive field is positively related to the strength of its synchronized activity with its neighboring neurons, and the dopaminergic pathway is responsible for the modulation of receptive field property and synchronous activity of the ganglion cells during the adaptation process

Expression of SPIG1 Reveals Development of a Retinal Ganglion Cell Subtype Projecting to the Medial Terminal Nucleus in the Mouse

Visual information is transmitted to the brain by roughly a dozen distinct types of retinal ganglion cells (RGCs) defined by a characteristic morphology, physiology, and central projections. However, our understanding about how these parallel pathways develop is still in its infancy, because few molecular markers corresponding to individual RGC types are available. Previously, we reported a secretory protein, SPIG1 (clone name; D/Bsp120I #1), preferentially expressed in the dorsal region in the developing chick retina. Here, we generated knock-in mice to visualize SPIG1-expressing cells with green fluorescent protein. We found that the mouse retina is subdivided into two distinct domains for SPIG1 expression and SPIG1 effectively marks a unique subtype of the retinal ganglion cells during the neonatal period. SPIG1-positive RGCs in the dorsotemporal domain project to the dorsal lateral geniculate nucleus (dLGN), superior colliculus, and accessory optic system (AOS). In contrast, in the remaining region, here named the pan-ventronasal domain, SPIG1-positive cells form a regular mosaic and project exclusively to the medial terminal nucleus (MTN) of the AOS that mediates the optokinetic nystagmus as early as P1. Their dendrites costratify with ON cholinergic amacrine strata in the inner plexiform layer as early as P3. These findings suggest that these SPIG1-positive cells are the ON direction selective ganglion cells (DSGCs). Moreover, the MTN-projecting cells in the pan-ventronasal domain are apparently composed of two distinct but interdependent regular mosaics depending on the presence or absence of SPIG1, indicating that they comprise two functionally distinct subtypes of the ON DSGCs. The formation of the regular mosaic appears to be commenced at the end of the prenatal stage and completed through the peak period of the cell death at P6. SPIG1 will thus serve as a useful molecular marker for future studies on the development and function of ON DSGCs

Anxiety Disorders in Children and Adolescents with Autistic Spectrum Disorders: A Meta-Analysis

There is considerable evidence that children and adolescents with autistic spectrum disorders (ASD) are at increased risk of anxiety and anxiety disorders. However, it is less clear which of the specific DSM-IV anxiety disorders occur most in this population. The present study used meta-analytic techniques to help clarify this issue. A systematic review of the literature identified 31 studies involving 2,121 young people (aged <18 years) with ASD, and where the presence of anxiety disorder was assessed using standardized questionnaires or diagnostic interviews. Across studies, 39.6% of young people with ASD had at least one comorbid DSM-IV anxiety disorder, the most frequent being specific phobia (29.8%) followed by OCD (17.4%) and social anxiety disorder (16.6%). Associations were found between the specific anxiety disorders and ASD subtype, age, IQ, and assessment method (questionnaire versus interview). Implications for the identification and treatment of anxiety in young people with ASD are discussed

Molecular identification of a retinal cell type that responds to upward motion

The retina contains complex circuits of neurons that extract salient information from visual inputs. Signals from photoreceptors are processed by retinal interneurons, integrated by retinal ganglion cells (RGCs) and sent to the brain by RGC axons. Distinct types of RGC respond to different visual features, such as increases or decreases in light intensity (ON and OFF cells, respectively), colour or moving objects1, 2, 3, 4, 5. Thus, RGCs comprise a set of parallel pathways from the eye to the brain. The identification of molecular markers for RGC subsets will facilitate attempts to correlate their structure with their function, assess their synaptic inputs and targets, and study their diversification. Here we show, by means of a transgenic marking method, that junctional adhesion molecule B (JAM-B) marks a previously unrecognized class of OFF RGCs in mice. These cells have asymmetric dendritic arbors aligned in a dorsal-to-ventral direction across the retina. Their receptive fields are also asymmetric and respond selectively to stimuli moving in a soma-to-dendrite direction; because the lens reverses the image of the world on the retina, these cells detect upward motion in the visual field. Thus, JAM-B identifies a unique population of RGCs in which structure corresponds remarkably to function

Understanding the retinal basis of vision across species

The vertebrate retina first evolved some 500 million years ago in ancestral marine chordates. Since then, the eyes of different species have been tuned to best support their unique visuoecological lifestyles. Visual specializations in eye designs, large-scale inhomogeneities across the retinal surface and local circuit motifs mean that all species' retinas are unique. Computational theories, such as the efficient coding hypothesis, have come a long way towards an explanation of the basic features of retinal organization and function; however, they cannot explain the full extent of retinal diversity within and across species. To build a truly general understanding of vertebrate vision and the retina's computational purpose, it is therefore important to more quantitatively relate different species' retinal functions to their specific natural environments and behavioural requirements. Ultimately, the goal of such efforts should be to build up to a more general theory of vision