N-methyl-d-aspartic acid receptor antagonist-induced frequency oscillations in mice recreate pattern of electrophysiological deficits in schizophrenia.

INTRODUCTION: Electrophysiological responses to auditory stimuli have provided a useful means of elucidating mechanisms and evaluating treatments in psychiatric disorders. Deficits in gating during paired-click tasks and lack of mismatch negativity following deviant stimuli have been well characterized in patients with schizophrenia. Recently, analyses of basal, induced, and evoked frequency oscillations have gained support as additional measures of cognitive processing in patients and animal models. The purpose of this study is to examine frequency oscillations in mice across the theta (4-7.5 Hz) and gamma (31-61 Hz) bands in the context of N-methyl-d-aspartic acid receptor (NMDAR) hypofunction and dopaminergic hyperactivity, both of which are thought to serve as pharmacological models of schizophrenia. EXPERIMENTAL PROCEDURES: Electroencephalograms (EEG) were recorded from mice in five treatment groups that consisted of haloperidol, risperidone, amphetamine, ketamine, or ketamine plus haloperidol during an auditory task. Basal, induced and evoked powers in both frequencies were calculated. RESULTS: Ketamine increased basal power in the gamma band and decreased the evoked power in the theta band. The increase in basal gamma was not blocked by treatment with a conventional antipsychotic. No other treatment group was able to fully reproduce this pattern in the mice. CONCLUSIONS: Ketamine-induced alterations in EEG power spectra are consistent with abnormalities in the theta and gamma frequency ranges reported in patients with schizophrenia. Our findings support the hypothesis that NMDAR hypofunction contributes to the deficits in schizophrenia and that the dopaminergic pathways alone may not account for these changes.

High-frequency oscillations (>200 Hz) in the human non-parkinsonian subthalamic nucleus.

The human basal ganglia, and in particular the subthalamic nucleus (STN), can oscillate at surprisingly high frequencies, around 300 Hz [G. Foffani, A. Priori, M. Egidi, P. Rampini, F. Tamma, E. Caputo, K.A. Moxon, S. Cerutti, S. Barbieri, 300-Hz subthalamic oscillations in Parkinson's disease, Brain 126 (2003) 2153-2163]. It has been proposed that these oscillations could contribute to the mechanisms of action of deep brain stimulation (DBS) [G. Foffani, A. Priori, Deep brain stimulation in Parkinson's disease can mimic the 300 Hz subthalamic rhythm, Brain 129 (2006) E59]. However, the physiological role of high-frequency STN oscillations is questionable, because they have been observed only in patients with advanced Parkinson's disease and could therefore be secondary to the dopamine-depleted parkinsonian state. Here, we report high-frequency STN oscillations in the range of the 300-Hz rhythm during intraoperative microrecordings for DBS in an awake patient with focal dystonia as well as in a patient with essential tremor (ET). High-frequency STN oscillations are therefore not exclusively related to parkinsonian pathophysiology, but may represent a broader feature of human STN function.

Nicotinic receptor modulation: advantages for successful Alzheimer's disease therapy.

Galantamine is a modest acetylcholinesterase inhibitor (AChEI) that is also an allosteric potentiating ligand (APL) of nicotinic acetylcholine receptors (nAChRs). In this report, these two effects are shown to be dependent upon each other using a realistic computer model of the cholinergic synaptic cleft. The model is based upon realistic estimates of the anatomy of a neuronal synapse, the kinetic states of pre- and postsynaptic nAChRs, and the acetylcholinesterase enzyme. The number of open postsynaptic nAChRs per action potential is a measure of cholinergic neurotransmission. Using mathematical equations and published data, the effect of the AChEI and APL actions of galantamine is quantitatively described and compared to the effects of pure AChEIs. The model shows that galantamine--compared to similar concentrations of pure AChEIs--is able to compensate for its somewhat modest effect on the cholinesterase enzyme with its allosteric modulatory effects that include the additional benefit of a lower degree of receptor desensitization.

Color-opponent receptive fields derived from independent component analysis of natural images.

Independent Component Analysis (ICA) of images of natural scenes has been shown to generate basis functions, or filters, which resemble spatial [Bell & Sejnowski (1997). Vision Research, 37, 3327-3338; van Hateren & van der Schaaf (1998). Proceedings of the Royal Society of London B, 265, 359-366] and spatiotemporal [van Hateren & Ruderman (1998) Proceedings of the Royal Society of London B, 265, 2315-2320] receptive fields of simple cells of the striate cortex. ICA yields statistically independent components which provide for a redundancy-reduced representation of the data. Using one of several published algorithms [Lee (1998). Independent component analysis: theory and applications. Boston; Kluwer Academic], we applied linear ICA to color images of natural scenes. The resulting independent component filters (ICFs) separate into either luminance or color filters. The luminance filters are localized and oriented edge detectors as reported previously. The color filters resemble either blue-yellow or red-green double-opponent receptive fields with various orientations. An equal number of each type of filter (luminance, red-green, and blue-yellow) is obtained. Thus, ICA predicts that spatiochromatic information is coded in statistically independent luminance, blue-yellow, and red-green opponent pathways with a relatively equal representation and specific spatial profiles at the cortical level.

Neuroengineering models of brain disease.

The techniques of computational simulation have begun to be applied to modeling neurological disease and mental illness. Such neuroengineering models provide a conceptual bridge between molecular/cellular pathology and cognitive performance. We consider models of Alzheimer's disease, Parkinson's disease, and schizophrenia. Each of these diseases involves a disorder of neuromodulation coupled with underlying neuronal pathology. Parallels arising between these models suggests that a common set of computational mechanisms may account for functional loss across a spectrum of brain diseases. In particular, we focus on attractor-based network dynamics and how they arise from neural architectures, on mechanisms for linking sequences of attractor states and their role in cognition, and on the role of neuromodulation in controlling these processes. These studies suggest new approaches to understanding the forebrain circuits underlying cognition, and point toward a new tool for dissecting the pathophysiology of brain disease.

Neuromodulatory control of hippocampal function: towards a model of Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder of cognitive function whose cellular pathology and molecular etiology have been increasingly and dramatically unraveled over the last several years. Despite this substantial knowledge base, the disease remains poorly understood due to a basic lack of understanding of how memories are stored and recalled in the brain. We describe a preliminary attempt at constructing a detailed model of these basic neural mechanisms; in particular, the natural dynamics of neuronal activity in hippocampal region CA3 and the modulation and control of these dynamics by subcortical cholinergic and GABAergic input to the hippocampus. We view the construction of such a model, with sufficient detail at the cellular and subcellular level, to be a necessary first step in understanding the effect of AD pathology on the functional behavior of the underlying neural circuitry. The network is based on the 66-compartment hippocampal pyramidal cell model of Traub and colleagues and their 51-compartment interneuron interconnected with realistic AMPA-, NMDA-, and GABA(A)-mediated synapses. Traub and others have shown that a network composed of these modeled cells is capable of synchronization in the gamma frequency range. We demonstrate here that this synchronization mechanism can implement an attractor-based autoassociative memory. A new input pattern arrives at the beginning of each theta cycle (comprised of 5-10 gamma cycles), and the pattern of activity across the network converges, over several gamma cycles, to a stable attractor that represents the stored memory. In this model, cholinergic deprivation, one of the hallmarks of AD, leads to a slowing of the gamma frequency which reduces the number of "cycles" available to reach an attractor state. We suggest that this may be one mechanism underlying the memory loss and cognitive slowing seen in AD. Our results also support the idea that acetylcholine acts on individual neurons to induce and maintain a transition from intrinsic bursting to spiking in pyramidal cells. These results are consistent with the hypothesis that spiking and bursting in CA3 pyramidal cells mediate separate behavioral functions, and that cholinergic input is required for the transition to and support of behavioral states associated with the online processing and recall of information.

The neurology of empty categories aphasics' failure to detect ungrammaticality.

A direct investigation into the grammatical abilities of Broca's and Wernicke's aphasics sought to obtain critical evidence for a revised model of the functional neuroanatomy of language. We examined aphasics' ability to make grammaticality judgments on a set of theoretically selected, highly complex syntactic structures that involve, most prominently, fine violations of constraints on syntactic movement. Although both groups have been thought to possess intact abilities in this domain, we discovered severe deficits; Broca's and Wernicke's aphasics (whose performances differed) exhibited clear, delineated, and grammatically characterizable deficits - they follow from the Trace-Deletion Hypothesis, which is motivated by independent comprehension results. These conclusions have both linguistic and neurological implications; Linguistically, they show that the aphasic deficit interacts with more than one module of the grammar. Namely, it manifests not only when the thematic module is called for in interpretive tasks but also when constraints on syntactic movement are tapped in a study of judgment. Neurologically, the results support a view of receptive grammatical mechanisms in the left cortex, which is functionally more restrictive than currently assumed; neuroanatomically, however, it is more distributed.

Extraction of perceptually salient contours by striate cortical networks.

We present a cortical-based model for computing the perceptual salience of contours embedded in noisy images. It has been suggested that horizontal intra-cortical connections in primary visual cortex may modulate contrast detection thresholds and pre-attentive "pop-out". In our model, horizontal connections mediate context-dependent facilitatory and inhibitory interactions among oriented cells. Strongly facilitated cells undergo temporal synchronization; and perceptual salience is determined by the level of synchronized activity. The model accounts for a range of reported psychophysical and physiological effects of contour salience. In particular, the model proposes that intrinsic properties of synchronization account for the increased salience of smooth, closed contours. Application of the model to real images is demonstrated.

Gap-filling and end-of-sentence effects in real-time language processing: implications for modeling sentence comprehension in aphasia.

We present an on-line study showing different sources of lexical activation during sentence comprehension, distinguishing in this respect between reflexive syntactic and less temporarily constrained nonsyntactic sources. Specifically, we show that both the syntactic process of gap filling and a nonsyntactic end-of-sentence effect can be measurable in real time and can be temporally separated. The distinction between activation sources provides a new perspective on real-time sentence comprehension in aphasia and accounts for the disparate results reported in the literature.

Coarse-grain parallel computing for very large scale neural simulations in the NEXUS simulation environment.

We describe a neural simulator designed for simulating very large scale models of cortical architectures. This simulator, NEXUS, uses coarse-grain parallel computing by distributing computation and data onto multiple conventional workstations connected via a local area network. Coarse-grain parallel computing offers natural advantages in simulating functionally segregated neural processes. We partition a complete model into modules with locally dense connections--a module may represent a cortical area, column, layer, or functional entity. Asynchronous data communications among workstations are established through the Network File System, which, together with the implicit modularity, decreases communications overhead, and increases overall performance. Coarse-grain parallelism also benefits from the standardization of conventional workstations and LAN, including portability between generations and vendors.

Concurrent application of tretinoin (retinoic acid) partially protects against corticosteroid-induced epidermal atrophy.

Cutaneous atrophy arising from prolonged use of potent topical corticosteroids has long been a concern. Thus, it would be advantageous to find an agent which protects against atrophy produced by corticosteroids but at the same time does not impair their anti-inflammatory effects. Recent work shows that topical all-trans retinoic acid (tretinoin) prevents skin atrophy in mice treated with topical corticosteroids, but such studies have not been performed in humans. We performed an 8-week clinical, histological and biochemical study to test the ability of tretinoin to enhance efficacy and inhibit atrophogenicity of topical corticosteroids, when used in the treatment of psoriasis. In each of 20 psoriasis patients, one plaque, and its perilesional skin, was treated once daily with betamethasone dipropionate and tretinoin 0.1%, and one plaque, and its perilesional skin, treated with once daily betamethasone dipropionate and tretinoin vehicle. There was no difference in the speed or degree of improvement in plaques treated with either the topical corticosteroid/tretinoin combination or with corticosteroid alone. Light microscopy revealed a 19% reduction in epidermal thickness, in corticosteroid-treated perilesional skin, as compared with a slight (1%) increase in corticosteroid/tretinoin-treated perilesional areas (P = 0.067). Western blot analysis showed a 55% reduction in procollagen I aminopropeptide in perilesional skin treated corticosteroid alone, as compared with a 45% reduction in corticosteroid/tretinoin-treated perilesional skin. These data indicate that the addition of tretinoin does not impair the efficacy of a topical corticosteroid, in the treatment of psoriasis, and partially ameliorates epidermal atrophy produced by the topical corticosteroid.

Two concentrations of topical tretinoin (retinoic acid) cause similar improvement of photoaging but different degrees of irritation. A double-blind, vehicle-controlled comparison of 0.1% and 0.025% tretinoin creams.

BACKGROUND AND DESIGN: The efficacy of topical tretinoin (all-trans-retinoic acid) in treating photoaging is well established. Questions that remain are (1) whether irritation causes all or part of the improvement; (2) the concentration of tretinoin that maximizes clinical response with minimal side effects; and (3) the effects of long-term treatment on components of the cutaneous immune system. To address these issues, 99 photoaged patients completed a 48-week study using 0.1% tretinoin cream (n = 32), 0.025% tretinoin (n = 35), or vehicle (n = 32) once daily in a double-blind manner. Before and after treatment, we assessed histologic features, keratinocyte expression of HLA-DR and intercellular adhesion molecule-1, numbers of epidermal Langerhans' cells and epidermal and dermal T lymphocytes, and vascularity as measured by dermal endothelial cell area. RESULTS: Both 0.1% and 0.025% tretinoin produced statistically significant overall improvement in photoaging of the face compared with vehicle; there were no clinically or statistically significant differences in efficacy between the two concentrations of tretinoin. After 48 weeks, 0.1% and 0.025% tretinoin produced similar statistically significant epidermal thickening (by 30% and 28%, respectively) compared with vehicle (11% decrease) and increased vascularity (by 100% and 89%, respectively) compared with vehicle (9% decrease). By various analyses, irritant side effects (erythema and scaling) were statistically significantly greater with 0.1% tretinoin than with 0.025% tretinoin. No significant changes occurred in any immunologic markers when tretinoin and vehicle treatments were compared. CONCLUSIONS: Tretinoin 0.1% and 0.025% produce similar clinical and histologic changes in patients with photoaging, despite significantly greater incidence of irritation with the higher concentration. The separation between clinical improvement and irritation suggests that mechanisms other than irritation dominate tretinoin-induced repair of photoaging in humans.

Characterization of the spatial-frequency spectrum in the perception of shape from texture.

The major cue to shape from texture is the compression of texture as a function of surface curvature [J. Exp. Psychol. 13, 242 (1987); Vision Res. 33, 827 (1993)]. A number of computational models have been proposed in which compression is measured by detection of changes in the spatial-frequency spectrum [Comput. Graphics Image Process. 5, (1976)]. We propose that the visual system uses a strategy of characterizing the frequency spectrum by a simple set of measures and of tracking the changes in this characterization rather than determining changes in the shape of the actual spectra. Our evidence is based on a number of psychophysical demonstrations that use stimuli with specifically tailored frequency spectra, constructed from white noise filtered in the frequency domain. Our evidence suggests that the visual system determines the average peak frequency of the spectrum and uses this measure as its characterization. Changes in fp are strongly correlated with the degree of surface curvature, and, over a range of stimuli, fp takes account of the variance in local estimates of the frequency spectrum. One computes fp by determining the peak frequency at each spatial location and then averaging these frequency values over a local spatial region. We show that fp is related to the second-order moment but is more biologically plausible and shows superior ability to function in the presence of noise. As a test of this model, we have constructed a neural network architecture for computing shape from texture. Our model is limited to orthographically projected, homogeneous textures without in-surface rotation. The early stages of the model consist of multiple simple-cell units tuned to different orientations and spatial frequencies. We show that these simple cells are inadequate for the determination of compression but that the outputs of complex-cell-like units after normalization generate estimates of surface slant and tilt. The network shows qualitative agreement with human perception of shape from texture over a wide range of real and artificial stimuli.

Network simulations of retinal and cortical contributions to color constancy.

A biologically-based neural network simulation is used to analyze the contributions to color perception of each of several processing steps in the visual system from the retina to cortical area V4. We consider the effects on color constancy and color induction of adaptation, spectral opponency, non-linearities including saturation and rectification, and spectrally-specific long-range inhibition. This last stage is a novel mechanism based on cells which have been described in V4. The model has been tested with simulations of several well known psychophysical color constancy and color induction experiments. We conclude from these simulations the following: (1) a simple push-pull spectrally specific contrast mechanism, using large surrounds analogous to those found in V4, is very effective in producing general color constancy and color induction behavior; (2) given some spatio-temporal averaging, receptor adaptation can also produce a degree of color constancy; (3) spectrally opponent processes have spatial frequency dependent responses to color and brightness contrast which affect the contribution of the V4 mechanism to color constancy in images with nonuniform backgrounds; and (4) the effect of the V4 mechanism depends on the difference between center and surround while the effect of adaptation depends on the total sum of inputs from both center and surround and therefore the two stages cooperate to increase the range of stimulus conditions under which color constancy can be achieved.

A multistage neural network for color constancy and color induction.

A biologically-based multistage neural network is presented which produces color constant responses to a variety of color stimuli. The network takes advantage of several mechanisms in the human visual system, including retinal adaptation, spectral opponency, and spectrally-specific long-range inhibition. This last stage is a novel mechanism based on cells which have been described in cortical area V4. All stages include nonlinear response functions. The model emulates human performance in several psychophysical paradigms designed to test color constancy and color induction. We measured the amount of constancy achieved with both natural and artificial simulated illuminants, using homogeneous grey backgrounds and more complex backgrounds, such as Mondrians. On average, the model performs as well or better than the average human color constancy performance under similar conditions. The network simulation also displays color induction and assimilation behavior consistent with human perceptual data.

Intermediate-level visual representations and the construction of surface perception.

Abstract Visual processing has often been divided into three stages-early, intermediate, and high level vision, which roughly correspond to the sensation, perception, and cognition of the visual world. In this paper, we present a network-based model of intermediate-level vision that focuses on how surfaces might be represented in visual cortex. We propose a mechanism for representing surfaces through the establishment of "ownership"-a selective binding of contours and regions. The representation of ownership provides a central locus for visual integration. Our simulations show the ability to segment real and illusory images in a manner consistent with human perception. In addition, through ownership, other processes such as depth, transparency, and surface completion can interact with one another to organize an image into a perceptual scene.

Topical retinoic acid (tretinoin) for melasma in black patients. A vehicle-controlled clinical trial.

BACKGROUND AND DESIGN: Melasma is an acquired, masklike, facial hyperpigmentation. The pathogenesis and treatment of melasma in black (African-American) patients is poorly understood. We investigated the efficacy of topical 0.1% all-trans-retinoic acid (tretinoin) in the treatment of melasma in black patients. Twenty-eight of 30 black patients with melasma completed a 10-month, randomized, vehicle-controlled clinical trial in which they applied either 0.1% tretinoin or vehicle cream daily to the entire face. They were evaluated clinically (using our Melasma Area and Severity Index), colorimetrically, and histologically. RESULTS: After 40 weeks, there was a 32% improvement in the Melasma Area and Severity Index score in the tretinoin treatment group compared with a 10% improvement in the vehicle group. Colorimetric measurements showed lightening of melasma after 40 weeks of tretinoin treatment vs vehicle. Lightening of melasma, as determined clinically, correlated well with colorimetric measurements. Histologic examination of involved skin revealed a significant decrease in epidermal pigmentation in the tretinoin group compared with the vehicle group. Side effects were limited to a mild "retinoid dermatitis" occurring in 67% of tretinoin-treated patients. Among the patients in this study in comparison with comparably recruited white patients, melasma was reported to have begun at a later age and was more likely to be in a malar distribution. CONCLUSIONS: This controlled study demonstrates that topical 0.1% tretinoin lightens melasma in black patients, with only mild side effects.

Topical tretinoin (retinoic acid) treatment of hyperpigmented lesions associated with photoaging in Chinese and Japanese patients: a vehicle-controlled trial.

BACKGROUND: Hyperpigmented lesions are a predominant component of photoaging in Chinese and Japanese persons. Topical 0.1% tretinoin cream improves the hyperpigmentation associated with photoaging in Caucasian persons. OBJECTIVE: Our purpose was to assess the efficacy of 0.1% tretinoin cream treatment of hyperpigmented lesions associated with photoaging in Chinese and Japanese patients. METHODS: Forty-five photoaged patients (23 Chinese, 22 Japanese) completed a double-blind, randomized study in which 21 applied 0.1% tretinoin cream and 24 applied vehicle cream once daily to face and/or hands for 40 weeks. Patients' hyperpigmented lesions were evaluated clinically and by colorimetry throughout the study and by histologic analysis of skin biopsy specimens taken before therapy and at the end of treatment. RESULTS: At the end of treatment, hyperpigmented lesions of the face and hands were lighter or much lighter in 90% of patients receiving tretinoin compared with 33% receiving vehicle (p < 0.0001). Colorimetry demonstrated significant lightening of lesions after tretinoin compared with vehicle (p < 0.05). Histologic analysis of hyperpigmented lesions demonstrated a statistically significant 41% decrease in epidermal pigmentation with tretinoin therapy as compared with a 37% increase in the vehicle group (p = 0.0004). No patient withdrew for adverse effects. CONCLUSION: By clinical, colorimetric, and histologic evaluation, 0.1% tretinoin cream significantly lightens the hyperpigmentation of photoaging in Chinese and Japanese patients.

An in vivo experimental model for effects of topical retinoic acid in human skin.

An occlusive patch-test assay has been developed for assessment of topical retinoid action in human epidermis. Previous work with this assay has demonstrated marked epidermal hyperplasia in skin treated with topical all-trans-retinoic acid for 4 days and similar effects with the local irritant, sodium lauryl sulphate. To investigate the capabilities of this assay further, a time-course and dose-response were performed with all-trans-retinoic acid, and a comparison made with sodium lauryl sulphate. At no time, between 1 and 4 days, could the clinical or histological effects of 0.1% and 0.025% cream formulations of all-trans-retinoic acid be distinguished from each other. Epidermal hyperplasia was used to generate a 4-day dose-response for all-trans-retinoic acid at concentrations from 0.001 to 0.025% dissolved in a 70% ethanol/30% propylene glycol vehicle. All-trans-retinoic acid could be successfully differentiated from sodium lauryl sulphate at 2 days by virtue of its greater ability to increase epidermal thickness, spongiosis and glycosaminoglycan deposition. It appears that although all-trans-retinoic acid and sodium lauryl sulphate produce similar epidermal histological changes at 4 days, significant differences at earlier time-points suggest differing mechanisms of action. In addition, this in vivo human assay is able to provide potency ranking for doses of all-trans-retinoic acid, and may predict clinical efficacy of retinoids in improvement of acne and/or photodamage.