The negative appendicectomy rate at Charlotte Maxeke Johannesburg Academic Hospital - a 10-year review.

BACKGROUND: The negative appendicectomy rate (NAR) is defined as the proportion of surgically removed appendices that are pathologically normal. The acceptable NAR has been a debated issue. Previously, a higher rate was accepted, whilst newer thinking favours a lower rate. Diagnosing appendicitis is often a clinical challenge and may require crosssectional imaging to assist in the diagnosis. METHODS: A retrospective review was conducted at the Charlotte Maxeke Johannesburg Academic Hospital. Appendix histopathological reports were retrieved for patients older than 18 years over a 10-year period. Reports of ultrasound (US) and/or computed tomography (CT) scans were analysed in the last 18 months. RESULTS: One thousand two hundred and seventeen appendicectomy specimens were included. The overall NAR was 19%. This demonstrated a significant downward trend over the period (p < 0.003). Per gender, the female NAR showed a significant decline (p = 0.002) while the male decline was not significant (p = 0.517). Reproductive-age females were found to have significantly higher NAR as compared to other age groups. The overall perforation rate was 17% which demonstrated a significant increase over the study period (p = 0.012). In the last 18 months, 240 appendicectomies were performed. One hundred and eleven patients underwent imaging (46%), of which 78 underwent ultrasound (70%), 14 CT (13%) and 19 US and CT (17%). CONCLUSION: The overall NAR declined significantly over the period. Females under the age of 45 were found to have significantly higher NARs. Further prospective studies are needed to determine the benefit and feasibility of preoperative CT in resource-limited settings, particularly in reproductive-age females to reduce the NAR.

Use of the OVESCO OTSC® Proctology Clip for closure of fistula-in-ano at Wits Donald Gordon Medical Centre - a single centre experience.

BACKGROUND: Definitive closure of fistula-in-ano poses an ongoing surgical challenge. The OVESCO OTSC® Proctology Clip (proctology clip) purports to offer improved preservation of the anal sphincter whilst at the same time curing the fistula by closure. METHODS: A retrospective record review was conducted for patients who received the proctology clip as part of the management of fistula-in-ano in the Colorectal Unit at Wits Donald Gordon Medical Centre (WDGMC). RESULTS: There were 19 cases of fistula-in-ano treated with the proctology clip. All were cryptoglandular in origin. The median age was 50 years (IQR 44-56 years) and post-procedure, the median follow-up duration was 145 days (IQR 63-298 days). Overall, 9 procedures were successful (47%). Success rates were higher for simple (66.7%) as opposed to complex (38.5%) fistula-in-ano. For patients who underwent placement of the proctology clip as a primary procedure, the success rate (50%) was slightly better than those who received the clip as a secondary procedure (44.4%). CONCLUSION: This preliminary data presents our initial experience using the proctology clip. While these data may serve as a "proof of concept", a multi-centre controlled trial comparing this method to the rectal mucosal advancement flap (RMAF) is needed to determine the role of the proctology clip in the management of fistula-in-ano.

Immunogenicity of an interferon-beta1a product.

In order to determine whether Blastoferon®, a biosimilar interferon (IFN)- beta 1a formulation, shares epitopes with other known IFN-beta products, a series of neutralization bioassays were performed with a set of well-characterized anti-IFN- beta monoclonal antibodies and human sera (World Health Organization Reference Reagents). The bioassay was the interferon-induced inhibition of virus cytopathic effect on human cells in culture (EMC virus and A-549 cells). Computer-calculated results were reported as Tenfold Reduction Units (TRU)/ml. To further assess Blastoferon® immunogenicity, in vivo production of anti-IFN beta antibodies was determined in sera of patients included in the pharmacovigilance plan of Blastoferon® by the level of IFN- beta 1a binding antibodies (by enzyme immunoassay -EIA) and neutralizing antibodies (in the Wish-VSV system). The highly characterized neutralizing monoclonal antibodies A1 and A5 that bind to specific regions of the IFN- beta molecule reacted positively with the three beta 1a IFNs: Blastoferon®, Rebif®, and the IFN- beta WHO Second International Standard 00/572. As expected, the non-neutralizing monoclonal antibodies B4 and B7 did not neutralize any of the IFN- beta preparations. The commercially available monoclonal antibody B-02 reacted essentially equally with Rebif® and Blastoferon®. The WHO Reference Reagent human serum anti-IFN- beta polyclonal antibody neutralized all the IFN- beta products, whereas the WHO Reference Reagent human serum anti-IFN-alpha polyclonal antibody G037-501-572 appropriately failed to react with any of the IFN- beta products. On the basis of in vitro reactivity with known, well-characterized monoclonal and polyclonal antibody preparations, Blastoferon® shares immunological determinants with other human interferon- beta products, especially IFN- beta 1a. In vivo antibodies were detected by EIA in 72.9% of 37 chronically treated multiple sclerosis patients, whereas neutralizing antibodies were found in 8.1% of them. Blastoferon® appears to have immunological characteristics comparable to other IFN- beta 1a products.

Quantification of neutralizing antibodies to human type I interferons using division-arrested frozen cells carrying an interferon-regulated reporter-gene.

Development of neutralizing antibodies (NAbs) to interferons (IFNs) can reduce the clinical response to IFN therapy. As current cell-based assays for quantifying NAbs have limitations, a highly sensitive and reproducible assay was developed, using division-arrested frozen human U937 cells transfected with the luciferase reportergene controlled by an IFN-responsive chimeric promoter, which allows IFN activity to be determined with precision within hours. Assay-ready PIL5 cells can be stored frozen for >3 years without loss of IFN sensitivity or the need for cell propagation. The assay is highly IFN sensitive (detecting <1.0 IU/mL), reproducible (SE +/- 15%) over concentrations from <1.0 to 100 IU/mL and able to measure different IFN subtypes and their pegylated variants. The use of this assay has shown that NAbs from patients treated with IFN-alpha2 exhibited markedly lower titers against 10 LU/mL of low specific activity IFNs, namely, IFN-alpha1, PEG-Intron(TM) (Schering-Plough, Levallois-Perret,France), or Pegasys(TM) (Hoffmann-La Roche, Neuilly-sur-Seine, France, than against 10 LU/mL IFN-alpha2. Similarly, NAbs from patients treated with IFN-beta1a exhibit lower titers against 10 LU/mL of low specific activity IFN-beta1b than against IFN-beta1a. The combination of the use of division-arrested, IFN-responsive human cells transfected with the luciferase reporter-gene makes the rapid PIL5 assay for NAbs highly advantageous.

Reduced effectiveness of long-term interferon-beta treatment on relapses in neutralizing antibody-positive multiple sclerosis patients: a Canadian multiple sclerosis clinic-based study.

Multiple sclerosis (MS) patients treated with interferon-beta (IFN-beta) often form anti-IFN-beta antibodies accompanied by a reduction in IFN-beta bioavailability. The clinical effect of these antibodies remains controversial. MS patients in British Columbia, Canada, must be diagnosed and evaluated annually by neurologists in an MS clinic in order to be reimbursed for their IFN-beta prescriptions. We have identified at the UBC MS clinic a cohort of 262 patients, each having been treated with a single IFN-beta preparation more than three years, some for nearly a decade. Of 119 patients treated with Betaseron (IFN-beta1b), 18 (15.1%) were neutralizing antibody positive (NAb+) at the time of the study, whereas of 131 treated with subcutaneous Rebif (IFN-beta1a SC), 16 (12.2%) were NAb+, but none of 12 treated with intramuscular Avonex (IFN-beta1a) had detectable neutralizing antibodies. During the first two years of treatment, the relapse rate was significantly reduced from pre-treatment rates (P<0.001) and appeared to be unaffected by the subsequent NAb status. However, the relapse rates in the NAb+ patients were significantly greater than in the NAb- patients during years 3 (P<0.010) and 4 (P<0.027). Betaseron-treated NAb+ patients tended to have more relapses than NAb- patients during year 3 and this almost reached significance (P=0.056) but their relapse rate did not differ in year 4 and later. In contrast, Rebif-treated NAb+ patients tended to have more relapses in year 3 than Rebif-treated NAb- patients (P=0.074), but in year 4 they clearly (P=0.009) had more relapses than Rebif-treated NAb- patients. There was no convincing effect on progression of disability in any group.

Laminar cortical dynamics of visual form and motion interactions during coherent object motion perception.

How do visual form and motion processes cooperate to compute object motion when each process separately is insufficient? Consider, for example, a deer moving behind a bush. Here the partially occluded fragments of motion signals available to an observer must be coherently grouped into the motion of a single object. A 3D FORMOTION model comprises five important functional interactions involving the brain's form and motion systems that address such situations. Because the model's stages are analogous to areas of the primate visual system, we refer to the stages by corresponding anatomical names. In one of these functional interactions, 3D boundary representations, in which figures are separated from their backgrounds, are formed in cortical area V2. These depth-selective V2 boundaries select motion signals at the appropriate depths in MT via V2-to-MT signals. In another, motion signals in MT disambiguate locally incomplete or ambiguous boundary signals in V2 via MT-to-V1-to-V2 feedback. The third functional property concerns resolution of the aperture problem along straight moving contours by propagating the influence of unambiguous motion signals generated at contour terminators or corners. Here, sparse 'feature tracking signals' from, for example, line ends are amplified to overwhelm numerically superior ambiguous motion signals along line segment interiors. In the fourth, a spatially anisotropic motion grouping process takes place across perceptual space via MT-MST feedback to integrate veridical feature-tracking and ambiguous motion signals to determine a global object motion percept. The fifth property uses the MT-MST feedback loop to convey an attentional priming signal from higher brain areas back to V1 and V2. The model's use of mechanisms such as divisive normalization, endstopping, cross-orientation inhibition, and long-range cooperation is described. Simulated data include: the degree of motion coherence of rotating shapes observed through apertures, the coherent vs. element motion percepts separated in depth during the chopsticks illusion, and the rigid vs. nonrigid appearance of rotating ellipses.

A quantitative evaluation of the AVITEWRITE model of handwriting learning.

Much sensory-motor behavior develops through imitation, as during the learning of handwriting by children. Such complex sequential acts are broken down into distinct motor control synergies, or muscle groups, whose activities overlap in time to generate continuous, curved movements that obey an inverse relation between curvature and speed. The adaptive vector integration to endpoint handwriting (AVITEWRITE) model of Grossberg and Paine (2000) [A neural model of corticocerebellar interactions during attentive imitation and predictive learning of sequential handwriting movements. Neural Networks, 13, 999-1046] addressed how such complex movements may be learned through attentive imitation. The model suggested how parietal and motor cortical mechanisms, such as difference vector encoding, interact with adaptively-timed, predictive cerebellar learning during movement imitation and predictive performance. Key psychophysical and neural data about learning to make curved movements were simulated, including a decrease in writing time as learning progresses; generation of unimodal, bell-shaped velocity profiles for each movement synergy; size scaling with isochrony, and speed scaling with preservation of the letter shape and the shapes of the velocity profiles; an inverse relation between curvature and tangential velocity; and a two-thirds power law relation between angular velocity and curvature. However, the model learned from letter trajectories of only one subject, and only qualitative kinematic comparisons were made with previously published human data. The present work describes a quantitative test of AVITEWRITE through direct comparison of a corpus of human handwriting data with the model's performance when it learns by tracing the human trajectories. The results show that model performance was variable across the subjects, with an average correlation between the model and human data of 0.89+/-0.10. The present data from simulations using the AVITEWRITE model highlight some of its strengths while focusing attention on areas, such as novel shape learning in children, where all models of handwriting and the learning of other complex sensory-motor skills would benefit from further research.

Mapping of IFN-beta epitopes important for receptor binding and biologic activation: comparison of results achieved using antibody-based methods and alanine substitution mutagenesis.

The epitopes important for receptor binding and activation of human interferon-beta1a (IFN-beta1a) were mapped with monoclonal antibodies (mAb), grouped on the basis of their specificity and ability to neutralize biologic activity, and alanine scanning mutagenesis (ASM). The binding properties of nine mAb were defined, using ASM-IFN-beta mutants having alanine substituted at targeted, surface-exposed residues. The results were correlated with the mAb neutralizing potency. Of six mAb that bound either at or adjacent to the IFNAR-2 receptor chain binding site defined by the ASM epitopes, only three had measurable neutralizing activity. Two of these inhibited IFN-beta/IFNAR-2 complex formation, suggesting that steric hindrance of receptor binding constitutes their mechanism of neutralization. However, two mAb that bound to sites remote from the IFNAR-2 binding site on IFN-beta also inhibited IFN-beta/IFNAR-2 complex formation and demonstrated potent neutralizing activity. Thus, neutralizing mAb may employ mechanisms other than steric blockade to inhibit directly the binding of receptor by cytokine, limiting their usefulness as tools to define precise receptor-ligand interaction sites.

A model of movement coordinates in the motor cortex: posture-dependent changes in the gain and direction of single cell tuning curves.

This article outlines a methodology for investigating the coordinate systems by which movement variables are encoded in the firing rates of individual motor cortical neurons. Recent neurophysiological experiments have probed the issue of underlying coordinates by examining how cellular preferred directions (as determined by the center-out task) change with posture. Several key experimental findings have resulted that constrain hypotheses about how motor cortical cells encode movement information. But while the significance of shifts in preferred direction is well known and widely accepted, posture-dependent changes in the depth of modulation of a cell's tuning curve--that is, gain changes--have not been similarly identified as a means of coordinate inference. This article develops a vector field framework in which the preferred direction and the gain of a cell's tuning curve are viewed as dual components of a unitary response vector. The formalism can be used to compute how each aspect of cell response covaries with posture as a function of the coordinate system in which a given cell is hypothesized to encode its movement information. Such an integrated approach leads to a model of motor cortical cell activity that codifies the following four observations: (i) cell activity correlates with hand movement direction; (ii) cell activity correlates with hand movement speed; (iii) preferred directions vary with posture; and (iv) the modulation depth of tuning curves varies with posture. Finally, the model suggests general methods for testing coordinate hypotheses at the single-cell level and simulates an example protocol for three possible coordinate systems: Cartesian spatial, shoulder-centered, and joint angle.

Linking the laminar circuits of visual cortex to visual perception: development, grouping, and attention.

How do the laminar circuits of visual cortical areas V1 and V2 implement context-sensitive binding processes such as perceptual grouping and attention, and how do these circuits develop and learn in a stable way? Recent neural models clarify how preattentive and attentive perceptual mechanisms are intimately linked within the laminar circuits of visual cortex, notably how bottom-up, top-down, and horizontal cortical connections interact within the cortical layers. These laminar circuits allow the responses of visual cortical neurons to be influenced, not only by the stimuli within their classical receptive fields, but also by stimuli in the extra-classical surround. Such context-sensitive visual processing can greatly enhance the analysis of visual scenes, especially those containing targets that are low contrast, partially occluded, or crowded by distractors. Attentional enhancement can selectively propagate along groupings of both real and illusory contours, thereby showing how attention can selectively enhance object representations. Recent models explain how attention may have a stronger facilitatory effect on low contrast than on high contrast stimuli, and how pop-out from orientation contrast may occur. The specific functional roles which the model proposes for the cortical layers allow several testable neurophysiological predictions to be made. Model mechanisms clarify how intracortical and intercortical feedback help to stabilize cortical development and learning. Although feedback plays a key role, fast feedforward processing is possible in response to unambiguous information. Model circuits are capable of synchronizing quickly, but context-sensitive persistence of previous events can influence how synchrony develops.

The neutralization of interferons by antibody. I. Quantitative and theoretical analyses of the neutralization reaction in different bioassay systems.

The highly specific ability of antibodies to inhibit the biologic activity of cytokines or other therapeutic proteins is widely used in research and a subject of increasing clinical importance. The need exists for a standardized approach to the reporting of neutralizing antibody potency soundly based on theoretical and practical considerations and tested by experimental data. Pursuant to the original studies of Kawade on the theoretical and functional aspects of neutralization of interferons (IFN), experimental data were obtained by different laboratories employing varied methodology to address two hypotheses concerning the nature of IFN neutralization reactions, based on a derived formula that allows expression of neutralizing power as the reduction of 10 laboratory units (LU)/ml to 1 LU/ml, the end point of most bioassays. Two hypotheses are posed: (1) antibody acts to neutralize a fixed amount of biologically active IFN molecules, or (2) antibody reduces IFN activity in a set ratio of added/residual biologically active IFN. The first, or fixed amount, hypothesis relates to the reactivity of high-affinity antibodies neutralizing equimolar amounts of antigen, whereas the second, or constant proportion, hypothesis postulates a reduction in the ratio of total added IFN to residual active IFN molecules, such as a low-affinity antibody might exhibit. Analyses of data of the neutralization of IFN-alpha and IFN-beta are presented, employing human polyclonal antibodies and murine monoclonal antibodies (mAb). The theoretical constructs of Kawade are extended in the Appendix and correlated with new experimental data in the text. The data clearly indicate that the low-antibody affinity, constant proportion hypothesis, rather than the high-antibody affinity, fixed amount hypothesis, is applicable, if the bioassay is sensitive to IFN. The findings presented here and in the following paper (pp. 743-755, this issue) taken together provide the basis for a standardized method of expression of neutralizing potency and substantiate the earlier operational 10/1 LU/ml approach recommended by the World Health Organization. The accompanying paper relates neutralization results to the sensitivity of the bioassay to IFN and describes the rationale for a recommended unit of antibody neutralization.

The neutralization of interferons by antibody. II. Neutralizing antibody unitage and its relationship to bioassay sensitivity: the tenfold reduction unit.

The importance of establishing a common method of reporting neutralizing antibody levels is emphasized by the fact that patients injected repeatedly with a human interferon (HuIFN) may develop such antibodies that can abrogate the beneficial effects of the treatment. The earlier experimental and theoretical constructs of Kawade led to certain recommendations by the World Health Organization (WHO) concerning the methodology of neutralization tests and how to report the resultant data. A WHO international collaborative study on two human sera with antibodies against HuIFN-alpha and HuIFN-beta provided the opportunity not only to test the theoretical concepts concerning the neutralization reaction with data obtained in different bioassay systems in different laboratories but also to obtain enough data points for statistical evaluation with bioassays having a great range of sensitivity to IFN. The analyses substantiate and extend the original conclusions of Kawade that the neutralization follows the reaction mode of low-affinity antibody, in accord with the constant proportion hypothesis by which antibody reduces IFN activity in a set ratio of added/residual biologically active IFN, a consequence of the low molar concentration of free IFN at the neutralization end point. The present results support the recommendation that the preferred way to state the index of neutralization of antibodies is a titer (t), calculated by the formula t = f(n - 1)/9, where f is the reciprocal of the antibody dilution achieving the end point, and n is the IFN concentration measured in that day's titration. The tenfold reduction unit (TRU) of neutralization is proposed for use in expressing the quantity, or unitage, of IFN neutralizing antibody. The utility of its application is explained. The use of the index of neutralization described and the proposed derivative term of antibody unitage, TRU, should help make the results from different laboratories employing different bioassay systems more readily comparable and interpretable, provided the bioassays are sufficiently sensitive to IFN.

Neural dynamics of motion integration and segmentation within and across apertures.

A neural model is developed of how motion integration and segmentation processes, both within and across apertures, compute global motion percepts. Figure-ground properties, such as occlusion, influence which motion signals determine the percept. For visible apertures, a line's terminators do not specify true line motion. For invisible apertures, a line's intrinsic terminators create veridical feature-tracking signals. Sparse feature-tracking signals can be amplified before they propagate across position and are integrated with ambiguous motion signals within line interiors. This integration process determines the global percept. It is the result of several processing stages: directional transient cells respond to image transients and input to a directional short-range filter that selectively boosts feature-tracking signals with the help of competitive signals. Then, a long-range filter inputs to directional cells that pool signals over multiple orientations, opposite contrast polarities, and depths. This all happens no later than cortical area MT. The directional cells activate a directional grouping network, proposed to occur within cortical area MST, within which directions compete to determine a local winner. Enhanced feature-tracking signals typically win over ambiguous motion signals. Model MST cells that encode the winning direction feed back to model MT cells, where they boost directionally consistent cell activities and suppress inconsistent activities over the spatial region to which they project. This feedback accomplishes directional and depthful motion capture within that region. Model simulations include the barberpole illusion, motion capture, the spotted barberpole, the triple barberpole, the occluded translating square illusion, motion transparency and the chopsticks illusion. Qualitative explanations of illusory contours from translating terminators and plaid adaptation are also given.

A what-and-where fusion neural network for recognition and tracking of multiple radar emitters.

A neural network recognition and tracking system is proposed for classification of radar pulses in autonomous Electronic Support Measure systems. Radar type information is considered with position-specific information from active emitters in a scene. Type-specific parameters of the input pulse stream are fed to a neural network classifier trained on samples of data collected in the field. Meanwhile, a clustering algorithm is used to separate pulses from different emitters according to position-specific parameters of the input pulse stream. Classifier responses corresponding to different emitters are separated into tracks, or trajectories, one per active emitter, allowing for more accurate identification of radar types based on multiple views of emitter data along each emitter trajectory. Such a What-and-Where fusion strategy is motivated by a similar subdivision of labor in the brain. The fuzzy ARTMAP neural network is used to classify streams of pulses according to radar type using their functional parameters. Simulation results obtained with a radar pulse data set indicate that fuzzy ARTMAP compares favorably to several other approaches when performance is measured in terms of accuracy and computational complexity. Incorporation into fuzzy ARTMAP of negative match tracking (from ARTMAP-IC) facilitated convergence during training with this data set. Other modifications improved classification of data that include missing input pattern components and missing training classes. Fuzzy ARTMAP was combined with a bank of Kalman filters to group pulses transmitted from different emitters based on their position-specific parameters, and with a module to accumulate evidence from fuzzy ARTMAP responses corresponding to the track defined for each emitter. Simulation results demonstrate that the system provides a high level of performance on complex, incomplete and overlapping radar data.

A neural model of smooth pursuit control and motion perception by cortical area MST.

Smooth pursuit eye movements (SPEMs) are eye rotations that are used to maintain fixation on a moving target. Such rotations complicate the interpretation of the retinal image, because they nullify the retinal motion of the target, while generating retinal motion of stationary objects in the background. This poses a problem for the oculomotor system, which must track the stabilized target image while suppressing the optokinetic reflex, which would move the eye in the direction of the retinal background motion (opposite to the direction in which the target is moving). Similarly, the perceptual system must estimate the actual direction and speed of moving objects in spite of the confounding effects of the eye rotation. This paper proposes a neural model to account for the ability of primates to accomplish these tasks. The model simulates the neurophysiological properties of cell types found in the superior temporal sulcus of the macaque monkey, specifically the medial superior temporal (MST) region. These cells process signals related to target motion, background motion, and receive an efference copy of eye velocity during pursuit movements. The model focuses on the interactions between cells in the ventral and dorsal subdivisions of MST, which are hypothesized to process target velocity and background motion, respectively. The model explains how these signals can be combined to explain behavioral data about pursuit maintenance and perceptual data from human studies, including the Aubert--Fleischl phenomenon and the Filehne Illusion, thereby clarifying the functional significance of neurophysiological data about these MST cell properties. It is suggested that the connectivity used in the model may represent a general strategy used by the brain in analyzing the visual world.

A neural model of how horizontal and interlaminar connections of visual cortex develop into adult circuits that carry out perceptual grouping and learning.

A neural model suggests how horizontal and interlaminar connections in visual cortical areas V1 and V2 develop within a laminar cortical architecture and give rise to adult visual percepts. The model suggests how mechanisms that control cortical development in the infant lead to properties of adult cortical anatomy, neurophysiology and visual perception. The model clarifies how excitatory and inhibitory connections can develop stably by maintaining a balance between excitation and inhibition. The growth of long-range excitatory horizontal connections between layer 2/3 pyramidal cells is balanced against that of short-range disynaptic interneuronal connections. The growth of excitatory on-center connections from layer 6-to-4 is balanced against that of inhibitory interneuronal off-surround connections. These balanced connections interact via intracortical and intercortical feedback to realize properties of perceptual grouping, attention and perceptual learning in the adult, and help to explain the observed variability in the number and temporal distribution of spikes emitted by cortical neurons. The model replicates cortical point spread functions and psychophysical data on the strength of real and illusory contours. The on-center, off-surround layer 6-to-4 circuit enables top-down attentional signals from area V2 to modulate, or attentionally prime, layer 4 cells in area V1 without fully activating them. This modulatory circuit also enables adult perceptual learning within cortical area V1 and V2 to proceed in a stable way.

Kinematic coordinates in which motor cortical cells encode movement direction.

During goal-directed reaching in primates, a sensorimotor transformation generates a dynamical pattern of muscle activation. Within the context of this sensorimotor transformation, a fundamental question concerns the coordinate systems in which individual cells in the primary motor cortex (MI) encode movement direction. This article develops a mathematical framework that computes, as a function of the coordinate system in which an individual cell is hypothesized to operate, the spatial preferred direction (pd) of that cell as the arm configuration and hand location vary. Three coordinate systems are explicitly modeled: Cartesian spatial, shoulder-centered, and joint angle. The computed patterns of spatial pds are distinct for each of these three coordinate systems, and experimental approaches are described that can capitalize on these differences to compare the empirical adequacy of each coordinate hypothesis. One particular experiment involving curved motion was analyzed from this perspective. Out of the three coordinate systems tested, the assumption of joint angle coordinates best explained the observed cellular response properties. The mathematical framework developed in this paper can also be used to design new experiments that are capable of disambiguating between a given set of specified coordinate hypotheses.

The resonant dynamics of speech perception: interword integration and duration-dependent backward effects.

How do listeners integrate temporally distributed phonemic information into coherent representations of syllables and words? For example, increasing the silence interval between the words "gray chip" may result in the percept "great chip," whereas increasing the duration of fricative noise in "chip" may alter the percept to "great ship" (B. H. Repp, A. M. Liberman, T. Eccardt, & D. Pesetsky, 1978). The ARTWORD neural model quantitatively simulates such context-sensitive speech data. In ARTWORD, sequentially stored phonemic items in working memory provide bottom-up input to unitized list chunks that group together sequences of items of variable length. The list chunks compete with each other. The winning groupings feed back to establish a resonance which temporarily boosts the activation levels of selected items and chunks, thereby creating an emergent conscious percept whose properties match such data.

Visual cortical mechanisms of perceptual grouping: interacting layers, networks, columns, and maps.

The visual cortex has a laminar organization whose circuits form functional columns in cortical maps. How this laminar architecture supports visual percepts is not well understood. A neural model proposes how the laminar circuits of V1 and V2 generate perceptual groupings that maintain sensitivity to the contrasts and spatial organization of scenic cues. The model can decisively choose which groupings cohere and survive, even while balanced excitatory and inhibitory interactions preserve contrast-sensitive measures of local boundary likelihood or strength. In the model, excitatory inputs from lateral geniculate nucleus (LGN) activate layers 4 and 6 of V1. Layer 6 activates an on-center off-surround network of inputs to layer 4. Together these layer 4 inputs preserve analog sensitivity to LGN input contrasts. Layer 4 cells excite pyramidal cells in layer 2/3, which activate monosynaptic long-range horizontal excitatory connections between layer 2/3 pyramidal cells, and short-range disynaptic inhibitory connections mediated by smooth stellate cells. These interactions support inward perceptual grouping between two or more boundary inducers, but not outward grouping from a single inducer. These boundary signals feed back to layer 4 via the layer 6-to-4 on-center off-surround network. This folded feedback joins cells in different layers into functional columns while selecting winning groupings. Layer 6 in V1 also sends top-down signals to LGN using an on-center off-surround network, which suppresses LGN cells that do not receive feedback, while selecting, enhancing, and synchronizing activity of those that do. The model is used to simulate psychophysical and neurophysiological data about perceptual grouping, including various Gestalt grouping laws.