A model of cell surface receptor aggregation.

In this paper we construct and analyze a model of cell receptor aggregation. Experiments have shown that receptors in an aggregated state have greatly reduced mobility. We model the effects of this reduced mobility with a density dependent diffusion and study the impact of density dependent diffusion on aggregate formation in a one-dimensional domain. Critical values of receptor diffusivity and receptor activation are found and compared with numerical simulations. We find that the role of density dependant diffusion is quite limited in the formation of aggregate structures. In the case of receptor activation, the analytical results agree very well with the numerical calculations. Finally, we consider our model in higher dimensional domains. In this case our analysis is primarily numerical.

Stability of asymmetric spike solutions to the Gierer-Meinhardt system.

In this paper, we study the spectra of asymmetric spike solutions to the Gierer-Meinhardt system. It has previously been shown that the spectra of such solutions may be determined by finding the generalized eigenvalues of matrices, which are determined by the positions of the spikes and various parameters from the system. We will examine the spectra of asymmetric solutions near the point at which they bifurcate off of a symmetric branch. We will confirm that all such solutions are unstable in a neighborhood of the bifurcation point and we derive an explicit expression for the leading order terms of the critical eigenvalues.

Embryonic motoneuron-skeletal muscle co-culture in a defined system.

This paper describes a significant biotechnological advancement by creating a minimalist serum-free defined system to co-culture rat mammalian nerve and muscle cells in order to form functional neuromuscular junctions. To date, all the known in vitro nerve and muscle co-culture models use serum containing media; and while functional neuromuscular junctions (NMJ) are described, they failed to detail or quantify the minimum factors needed to recreate the NMJ in vitro. In this work, we demonstrate the development of a defined motoneuron and muscle co-culture system resulting in the formation of NMJs including: 1) a new culture technique, 2) a novel serum-free medium formulation and 3) a synthetic self-assembled monolayer (SAM) substrate N-1 [3-(trimethoxysilyl) propyl] diethylenetriamine (DETA). We characterized the culture by morphology, immunocytochemistry, electrophysiology and videography. This model system provides a better understanding of the minimal growth factor and substrate interactions necessary for NMJ formation and provides a basic system that can be utilized for nerve-muscle tissue engineering, regenerative medicine and development of limb prosthetics.

Infusion of the metabotropic receptor agonist, DCG-IV, into the main olfactory bulb induces olfactory preference learning in rat pups.

DCG-IV, a type 2 metabotropic glutamate receptor (mGluR2) agonist, was infused into the main olfactory bulb of 1-week-old pups exposed to peppermint odor. A preference for peppermint was demonstrated 24 h later. The data support the proposal that disinhibition at dendrodendritic synapses between granule cells and mitral cells is a critical component of olfactory memory formation in the rat pup olfactory bulb as well as in the accessory olfactory bulb of adult rodents.

Preliminary evidence of widespread morphological variations of the brain in dyslexia.

The MR images of 16 men with dyslexia and 14 control subjects were compared using a voxel-based analysis. Evidence of decreases in gray matter in dyslexic subjects, most notably in the left temporal lobe and bilaterally in the temporoparietooccipital juncture, but also in the frontal lobe, caudate, thalamus, and cerebellum, was found. Widely distributed morphologic differences affecting several brain regions may contribute to the deficits associated with dyslexia.

Functional neuroimaging in child psychiatry.

Functional neuroimaging in child psychiatry presents unique scientific, ethical, and technical challenges. The study of childhood disorders presupposes knowledge of neurodevelopment and brain maturation. However, much of human brain science is based on inferences from animal work and indirect neurochemical measures from body fluids. Neuroimaging can examine brain development directly in humans. The benefits can be enormous for learning how and when to intervene to prevent or treat a disorder. These unprecedented potential gains are countered by complex and difficult ethical issues. Technical advances can reduce ethical concerns by minimizing risks. They also promise to enhance the sensitivity and specificity of the measures (eg, by improving spatial and temporal resolution). Judiciously designed investigations will permit the testing of a priori hypotheses built on rational models of neuropathology. Finally, it is the integration of scientific knowledge across the various fields of neuroscience and clinical research that will push the limits of our understanding of health and disease.

Functional neuroimaging of autistic disorders.

Functional neuroimaging methods hold promise for elucidating the neurobiology of autistic disorders, yet they present difficult practical and scientific challenges when applied to these complex and heterogeneous syndromes. Single-state studies of brain metabolism and blood flow thus far have failed to yield consistent findings, but suggest considerable variability in regional patterns of cerebral synaptic activity. Patients with idiopathic autism are less likely to show abnormalities than are patients with comorbid illness or epilepsy. Activation studies have begun to suggest alterations in brain organization for language and cognition. Neurotransmitter studies using positron emission tomography (PET) suggest abnormalities of serotonergic and dopaminergic function. Studies using magnetic resonance spectroscopy (MRS) have begun to document metabolic deficits in the frontal cortex and cerebellum. A single study using magnetoencephalography suggests a high incidence of epileptiform activity in children with autistic regression. Research needs include well-controlled developmental studies, particularly of young subjects and relatively homogeneous subgroups, which balance scientific rigor with ethical constraints. Investigations of the serotonergic and dopaminergic systems, limbic-based memory and emotional systems, and the role of epileptiform activity in autism represent priorities for future research.

Morphological alteration of temporal lobe gray matter in dyslexia: an MRI study.

Functional imaging studies of developmental dyslexia have reported reduced task-related neural activity in the temporal and inferior parietal cortices. To examine the possible contribution of subtle anatomic deviations to these reductions, volumes were measured for the major lobes of the brain, the subcortical nuclei, cerebellum, and lateral ventricles on magnetic resonance imaging (MRI) scans from 16 right-handed dyslexic men, ages 18 to 40, and 14 matched controls, most of whom had previously undergone PET imaging. A specific decrease in tissue volume was localized to the temporal lobes and was particularly prominent on the left (p < .01). An analysis of tissue composition revealed that this reduction was primarily attributable to decreased gray matter within the left temporal lobe (p < .002). Further segmentation of the temporal lobe showed that this reduction was not confined to the superior temporal gyrus, the primary location of primary auditory cortex. Reductions of temporal lobe gray matter may reflect a regional decrease in neuronal number or neuropil, which in turn may result in reading impairment.

ZD1611, an orally active endothelin-A receptor antagonist, prevents chronic hypoxia-induced pulmonary hypertension in the rat.

Endothelin-1 (ET-1) is a potent vasoconstrictor and comitogen implicated in the pathogenesis of pulmonary hypertension (PH). We evaluated the effects of an ET(A)receptor-selective antagonist, ZD1611, on hypoxia-induced PH in rats. <> and <> paradigms were established in which rats were administered placebo or ZD1611 (1-3 mg/kg, q.i.dpo) concomitant with hypoxic exposure (10% O(2)1 ATM) for 14 days or beginning after 7-day hypoxic exposure for 21 days. Compared with normoxic controls, hypoxic exposure plus placebo increased (P<0.05) hematocrit, mass ratio of right ventricle over left ventricle plus septum (RV/LV+S), and right intraventricular peak systolic pressure (RVSP). These latter two effects were decreased (P<0.05) by ZD1611 in both experimental paradigms [RV/LV+S(%)::RVSP(%); prophylactic, 14::32; therapeutic, 28::37]. Hypoxic exposure did not change mean systemic arterial pressure (MSAP). ZD1611 did not affect MSAP, plasma ET-1 concentrations, or blood gases measured when rats respired room air. In mechanistic studies, ZD1611 decreased (P<0.01) smooth muscle hypertrophy of small pulmonary arteries and abolished hypoxia-induced decreases in sensitivity and maximum contraction to ET-1 in isolated extralobar branch pulmonary artery. In conclusion, the ET(A)receptor-selective antagonist, ZD1611, attenuates hypoxia-induced PH in the rat.

A functional lesion in developmental dyslexia: left angular gyral blood flow predicts severity.

Functional imaging studies have shown reduced regional cerebral blood flow (rCBF) in temporal and inferior parietal regions in dyslexia. To relate such abnormalities to the severity of dyslexia, correlations between reading skill and rCBF during a series of reading tasks and visual fixation were mapped for 17 right-handed dyslexic men, ages 18-40, and 14 matched controls. These correlations uniquely identified the left angular gyrus as the most probable site of a functional lesion in dyslexia: Here, higher rCBF was associated with better reading skill in controls (p <.01), but with worse reading skill in dyslexia (p <.01). This suggests that greater reliance on this region normally facilitates reading, but impairs reading in dyslexia. Thus, developmental dyslexia may share a common localization with alexia.

Functional connectivity of the angular gyrus in normal reading and dyslexia.

The classic neurologic model for reading, based on studies of patients with acquired alexia, hypothesizes functional linkages between the angular gyrus in the left hemisphere and visual association areas in the occipital and temporal lobes. The angular gyrus also is thought to have functional links with posterior language areas (e.g., Wernicke's area), because it is presumed to be involved in mapping visually presented inputs onto linguistic representations. Using positron emission tomography , we demonstrate in normal men that regional cerebral blood flow in the left angular gyrus shows strong within-task, across-subjects correlations (i.e., functional connectivity) with regional cerebral blood flow in extrastriate occipital and temporal lobe regions during single word reading. In contrast, the left angular gyrus is functionally disconnected from these regions in men with persistent developmental dyslexia, suggesting that the anatomical disconnection of the left angular gyrus from other brain regions that are part of the "normal" brain reading network in many cases of acquired alexia is mirrored by its functional disconnection in developmental dyslexia.

A magnetic resonance imaging study of planum temporale asymmetry in men with developmental dyslexia.

BACKGROUND: Imaging studies have suggested anomalous anatomical asymmetries in language-related regions of the temporal and parietal lobes in individuals with developmental dyslexia. Autopsy studies have reported unusual symmetry of the planum temporale (PT) in patients with dyslexia. Methodological limitations characterize much of this literature, however. OBJECTIVE: To examine the size and asymmetry of the PT and its extension into the parietal lobe (planum parietale [PP]) in men with well-characterized, persistent dyslexia by using magnetic resonance imaging and 3-dimensional surface rendering techniques. METHODS: The brains of 16 right-handed dyslexic men aged 18 to 40 years and 14 matched control subjects were studied with magnetic resonance imaging. Most of these subjects were previously studied with positron emission tomography, which demonstrated functional abnormalities in temporal and parietal brain regions in the dyslexic group. The area of the PT was determined with the aid of 3-dimensional surface-rendering techniques. The size of the PP was estimated by measuring the length of the posterior ascending ramus on 3 parasagittal slices. RESULTS: Approximately 70% to 80% of both groups showed equivalent leftward (left > right) asymmetries of the PT; approximately 50% to 60% showed equivalent rightward (right > left) asymmetries of the PP. These asymmetries showed equivalent moderate inverse correlations with each other in both groups. CONCLUSIONS: These results challenge the notion that anomalous asymmetry of the PT is strongly associated with developmental dyslexia. Given the heterogeneity of the dyslexic population, some subgroup of dyslexic individuals (i.e., those with developmental language disorders) may show unusual symmetry or reversed asymmetry in this region. However, anomalous asymmetry of the planum did not contribute to functional abnormalities demonstrated in these patients by positron emission tomography.

Phonological and orthographic components of word recognition. A PET-rCBF study.

Pronunciation (of irregular/inconsistent words and of pseudowords) and lexical decision-making tasks were used with 15O PET to examine the neural correlates of phonological and orthographic processing in 14 healthy right-handed men (aged 18-40 years). Relative to a visual-fixation control task, all four experimental tasks elicited a left-lateralized stream of activation involving the lingual and fusiform gyri, perirolandic cortex, thalamus and anterior cingulate. Both pronunciation tasks activated the left superior temporal gyrus, with significantly greater activation seen there during phonological (pseudoword) than during orthographic (real word) pronunciation. The left inferior frontal cortex was activated by both decision-making tasks; more intense and widespread activation was seen there during phonological, than during orthographic, decision making, with the activation during phonological decision-making extending into the left insula. Correlations of reference voxels in the left superior temporal gyrus and left inferior frontal region with the rest of the brain were highly similar for the phonological and orthographic versions of each task type. These results are consistent with connectionist models of reading, which hypothesize that both real words and pseudowords are processed within a common neural network.

Three-dimensional cortical morphometry of the planum temporale in childhood-onset schizophrenia.

OBJECTIVE: Anomalous planum temporale asymmetry has been linked to both schizophrenia and dyslexia. The authors examined the planum temporale of adolescents with childhood-onset schizophrenia who had a high rate of prepsychotic language disorders. METHOD: Planum temporale area and asymmetry were measured in 16 right-handed adolescent patients with schizophrenia who had experienced onset of psychosis by age 12. The same measures were made in 16 healthy adolescents matched for age, sex, and handedness. RESULTS: No differences between the healthy adolescents and those with schizophrenia in planum temporale area or asymmetry were observed. Prepsychotic language disorder predicted abnormal planum temporale asymmetry in the adolescents with schizophrenia. CONCLUSIONS: These findings do not support anomalous planum temporale asymmetry as a basis for psychopathology in childhood-onset schizophrenia.

A positron emission tomographic study of impaired word recognition and phonological processing in dyslexic men.

BACKGROUND: Developmental dyslexia is characterized by impaired word recognition, which is thought to result from deficits in phonological processing. Improvements during the course of development are thought to disproportionately involve orthographic components of reading; phonological deficits persist into adulthood. OBJECTIVE: To localize the neural correlates of impaired word recognition and phonological processing in men with developmental dyslexia. METHODS: Regional cerebral blood flow was measured with oxygen 15 positron emission tomography in 17 men with dyslexia and in 14 matched controls during the performance of phonological and orthographic tasks--pronunciation (reading aloud) and lexical decision making--designed to activate posterior and anterior perisylvian cortices, respectively. RESULTS: Altered patterns of activation (reduced activation, unusual deactivation) were seen in dyslexic men in mid- to posterior temporal cortex bilaterally and in inferior parietal cortex, predominantly on the left, during both pronunciation and decision making. In contrast, dyslexic men demonstrated essentially normal activation of left inferior frontal cortex during both phonological and orthographic decision making. CONCLUSION: These, along with prior findings, are compatible with a hypothesis of bilateral involvement of posterior temporal and parietal cortices in dyslexia.

The visual deficit theory of developmental dyslexia.

Dyslexia is an impairment in reading that can result from an abnormal developmental process in the case of developmental dyslexia or cerebral insult in the case of acquired dyslexia. It has long been known that the clinical manifestations of developmental dyslexia are varied. In addition to their reading difficulties, individuals with developmental dyslexia exhibit impairments in their ability to process the phonological features of written or spoken language. Recently, it has been demonstrated with a variety of experimental approaches that these individuals are also impaired on a number of visual tasks involving visuomotor, visuospatial, and visual motion processing. The results of these studies, as well as the anatomical and physiological anomalies seen in the brains of individuals with dyslexia, suggest that the pathophysiology of developmental dyslexia is more complex than originally thought, extending beyond the classically defined language areas of the brain. Functional neuroimaging is a useful tool to more precisely delineate the pathophysiology of this reading disorder.

Regional MRI measurements of the corpus callosum: a methodological and developmental study.

A technique for quantifying the midsagittal size and shape of the corpus callosum (CC) from magnetic resonance brain scans is presented. The technique utilizes the distances to the ventral and dorsal boundaries of small sectors of the CC from a reference point to compute the size and shape parameters of the CC and its subdivisions. Intrarater and interrater interclass correlation coefficients for the area measurements ranged from 0.88 to 0.99. Correlations between these automated measures and those obtained by pixel counting were equally high. The corpus callosa of 104 (57 male and 47 female) right-handed healthy children and adolescents, ages 4-18, were examined in relation to age and sex. Corpus callosum growth was most striking for the splenium and isthmus with some changes in the midbody regions. The area and perimeter of these regions increased, shapes became more compact, and the boundaries became more regular with age. The length and curvature at the anterior and posterior regions of the CC increased more rapidly in males than in females. These significant and consistent results indicate that the method is reliable and sensitive to developmental changes of the CC.

Abnormal processing of visual motion in dyslexia revealed by functional brain imaging.

It is widely accepted that dyslexics have deficits in reading and phonological awareness, but there is increasing evidence that they also exhibit visual processing abnormalities that may be confined to particular portions of the visual system. In primate visual pathways, inputs from parvocellular or magnocellular layers of the lateral geniculate nucleus remain partly segregated in projections to extrastriate cortical areas specialized for processing colour and form versus motion. In studies of dyslexia, psychophysical and anatomical evidence indicate an anomaly in the magnocellular visual subsystem. To investigate the pathophysiology of dyslexia, we used functional magnetic resonance imaging (fMRI) to study visual motion processing in normal and dyslexic men. In all dyslexics, presentation of moving stimuli failed to produce the same task-related functional activation in area V5/MT (part of the magnocellular visual subsystem) observed in controls. In contrast, presentation of stationary patterns resulted in equivalent activations in V1/V2 and extrastriate cortex in both groups. Although previous studies have emphasized language deficits, our data reveal differences in the regional functional organization of the cortical visual system in dyslexia.

Corpus callosum morphology, as measured with MRI, in dyslexic men.

To test the hypothesis of anomalous anatomy in posterior brain regions associated with language and reading, the corpus callosum was imaged in the midsagittal plane with magnetic resonance. The areas of the anterior, middle, and posterior segments were measured in 21 dyslexic men (mean age 27 yrs, SD 6) and in 19 matched controls. As predicted, the area of the posterior third of the corpus callosum, roughly equivalent to the isthmus and splenium, was larger in dyslexic men than in controls. No differences were seen in the anterior or middle corpus callosum. The increased area of the posterior corpus callosum may reflect anatomical variation associated with deficient lateralization of function in posterior language regions of the cortex and their right-sided homologues, hypothesized to differ in patients with dyslexia.