Biomedical subjects

M L Crawford

Publications and source records attributed to M L Crawford.

At least 19 recordsLinked to original sources

PubMed2001

Experimental glaucoma in primates: changes in cytochrome oxidase blobs in V1 cortex.

PURPOSE: To evaluate the effects of ganglion cell depletion from experimental glaucoma on the relative metabolic activities of neurons in the cytochrome oxidase blobs of V1 cortex in the macaque visual system. METHODS: Monocular experimental glaucoma was induced in adult monkeys (Macaca mulatta and Macaca fascicularis) by laser application to the trabecular meshwork, increasing the intraocular pressure. After other experiments, the primary visual cortices were analyzed for functional excitation from surviving ganglion cells, as indicated by cytochrome oxidase histochemistry. RESULTS: Cytochrome oxidase reactivity was uniformly reduced in blobs with input from the glaucomatous eye in a manner consistent with loss of known afferent inputs. The average size of glaucomatous blobs in layers 2 and 3 of V1 cortex was reduced by half. CONCLUSIONS: Experimental glaucoma in monkeys reduces retinal input to the central nervous system, thereby reducing the metabolic drive to downstream targets, as indicated by the reduction in the size of cytochrome oxidase blobs in layers 2 and 3 of V1 cortex. The pattern of cytochrome oxidase loss within the blob was uniform, suggesting that all sources of afferent input to the blobs were affected by experimental glaucoma.

Afferent Pathways↗

PubMed2000

Glaucoma in primates: cytochrome oxidase reactivity in parvo- and magnocellular pathways.

PURPOSE: To evaluate the differential effects of ganglion cell depletion from experimental glaucoma on the relative metabolic activities of neurons in the parvo (P)- and magno (M)-cellular visual pathways of the macaque visual system. METHODS: Monocular experimental glaucoma was induced in monkeys (Macaca mulatta and M. fascicularis) by applying a laser to the trabecular meshwork to increase intraocular pressure (IOP). After other behavioral and electrophysiological studies, the lateral geniculate nuclei (LGNs) and the primary visual cortices were analyzed for functional afference from surviving ganglion cells, indicated by cytochrome oxidase (CO) histochemistry. RESULTS: CO reactivity (COR) indicated a general reduction in neural metabolism with increasing severity of glaucoma. COR in the LGNs was reduced to the same degree in both the P- and M-cellular layers. In layer 4Cbeta of the V1 cortex, the reactivity was always reduced more than in the layer 4Calpha division. CONCLUSIONS: Experimental glaucoma in monkeys reduces visual afference to the central nervous system, thereby reducing the metabolic drive as indicated by COR. The detrimental effect of glaucoma did not appear to be any greater for the M-cell, rather than the P-cell pathway in the LGN or in the visual cortex. Both are affected by the duration and severity of the experimental glaucoma. Overall, the alterations in metabolism of neurons in the parallel visual pathways supplied by the Palpha and Pbeta ganglion cells do not suggest that tests based on the functional properties of one or the other would provide optimal assessment of glaucoma.

Animals↗

PubMed1999

Cellular immune response to phogrin in the NOD mouse: cloned T-cells cause destruction of islet transplants.

The ability of nonobese diabetic (NOD) mice to mount a cellular immune response to the secretory granule protein tyrosine phosphatase (PTP), phogrin was evaluated by immunization of 8- to 12-week-old animals with recombinant phogrin in complete Freund's adjuvant. Draining lymph nodes displayed a robust proliferative response to the protein, as did derived T-cell lines and clones. Ten clones obtained by limiting dilution were all CD4+ and of a T-helper-1-like phenotype, but showed variation in their Vbeta usage. Of the 10 clones, 3 responded to endogenous antigens in rat islets. Two of these caused the destruction of rat islets that had been transplanted under the kidney capsule of streptozotocin-treated NOD scid mice without affecting adjacent thyroid implants. The results demonstrate the feasibility of generating antigen-specific diabetes-inducing CD4+ cells by direct immunization of NOD mice and their potential use for further studies of the antigenic epitopes in the PTP family members. The conclusion, based on serological studies, that PTP members do not play a role in the pathogenesis of type 1 diabetes in rodent models needs reevaluation in light of these findings.

Animals↗

PubMed1999

Ganglion cell losses underlying visual field defects from experimental glaucoma.

PURPOSE: To investigate the relationship between ganglion cell losses and visual field defects caused by glaucoma. METHODS: Behavioral perimetry and histology data were obtained from 10 rhesus monkeys with unilateral experimental glaucoma that was induced by argon laser treatments to their trabecular meshwork. After significant visual field defects had developed, the retinas were collected for histologic analysis. The ganglion cells were counted by light microscopy in cresyl violet-stained retina sections, and the percentage of ganglion cell loss (treated to control eye counts) was compared with the depth of visual field defect (treated to control eye thresholds) at corresponding retinal and perimetry test locations. Sensitivity losses as a function of ganglion cell losses were analyzed for Goldmann III, white and Goldmann V, and short- and long-wavelength perimetry test stimuli. RESULTS: The relationship between the proportional losses of ganglion cells and visual sensitivity, measured with either white or colored stimuli, was nonlinear. With white stimuli, the visual sensitivity losses were relatively constant (approximately 6 dB) for ganglion cell losses of less than 30% to 50%, and then with greater amounts of cell loss the visual defects were more systematically related to ganglion cell loss (approximately 0.42 dB/percent cell loss). The forms of the neural-sensitivity relationships for visual defects measured with short- or long-wavelength perimetry stimuli were similar when the visual thresholds were normalized to compensate for differences in expected normal thresholds for white and colored perimetry stimuli. CONCLUSIONS: Current perimetry regimens with either white or monochromatic stimuli do not provide a useful estimate of ganglion cell loss until a substantial proportion have died. The variance in ganglion cell loss is large for mild defects that would be diagnostic of early glaucoma and for visual field locations near the fovea where sensitivity losses occur relatively late in the disease process. The neural-sensitivity relationships were essentially identical for both white and monochromatic test stimuli, and it therefore seems unlikely that the higher sensitivity for detecting glaucoma with monochromatic stimuli is based on the size-dependent susceptibility of ganglion cells to injury from glaucoma.

Animals↗

PubMed1998

Glutamine immunoreactivity in Müller cells of monkey eyes with experimental glaucoma.

The action of glutamate in retina is largely terminated through rapid uptake by Müller cells and subsequent conversion primarily to glutamine. Glutamine, transferred from Müller cells to neurons, serves as a precursor for the formation of glutamate in neurons completing the glutamate-glutamine cycle. In a monkey model of high-tension glaucoma, we have examined glutamine immunoreactivity in the Müller cell as well as the number of Müller cells to determine whether the activity of these cells in the glutamate-glutamine cycle is affected, particularly since high vitreal glutamate has been reported in glaucoma. Unilateral glaucoma was induced in three monkeys by argon laser application to the trabecular meshwork. LR White sections of retina from the temporal mid-periphery (about 23 degrees) and the parafovea (central 3 degrees) were immunolabeled for glutamine using immunogold and silver intensification. The percentage difference in labeling intensity (darkness) in the glaucomatous retina was determined relative to the labeling found in the control retina by image analysis. Ganglion cell density was estimated from radial sections in the parafovea and from retinal whole mounts in the mid-periphery. The number of Müller cells was estimated from vibratome sections immunolabeled by vimentin antibodies in the temporal mid-periphery (about 30 degrees). Glutamine immunoreactivity was localized predominately in ganglion cells and Müller cells. However, the intensity of glutamine immunolabeling was greater in Müller cells of glaucomatous eyes than in control eyes. This increase in glutamine immunolabeling was 25-32% in the temporal mid-periphery and 27-48% in the parafovea. Müller cell number in the glaucomatous eye was similar to that of the control in the temporal mid-periphery. The data in this study indicate that the increase in glutamine in Müller cells is not a consequence of their loss and that Müller cell function in the glutamate-glutamine cycle continues in glaucomatous eyes. These findings are consistent with a previous report that extracellular/vitreal glutamate concentration is elevated in high-tension glaucoma.

Animals↗

PubMed1998

Column spacing in normal and visually deprived monkeys.

A recent model for the development of the pattern of eye-dominance domains in primary visual cortex predicts that stimulus conditions during early visual life determine the spacing (or periodicity) of ocular dominance columns (ODC). The model predicts that normal binocular visual experience consists of highly correlated binocular stimulation and leads to relatively narrow ODC spacing, while abnormal binocular visual stimulation attendant with strabismus consists of non-correlated, incoherent, and asynchronous stimulation and leads to wider than normal ODC spacing. Evidence in support of the model has been presented for strabismus in the kitten. We tested the predictions of the model in normal monkeys and others subjected to various forms of abnormal visual experience during infancy. We identified and measured the inter-column spacing (or periodicity) in the V1 cortex of 19 adult monkeys (M. mulatta) using the cytochrome-oxidase (CO) histochemical method. There were no significant differences in the V1 inter-column spacing between normal adult monkeys (n=5) and other adult monkeys having had monocular-form deprivation (n=5), experimental anisometropia (n=5), or experimental strabismus (n=4) early in life. The quality of early binocular visual experience is not a significant determinant of the inter-column spacing in primate V1 cortex. Therefore, the model predicting an increase in the ODC periodicity with strabismus is not supported.

Analysis of Variance↗

PubMed1997

Stereopsis and disparity vergence in monkeys with subnormal binocular vision.

The surgical treatment for strabismus in infants generally results in microtropia or subnormal binocular vision. Although the clinical characteristics of these conditions are well established, there are important questions about the mechanisms of binocular vision in these patients that can best be investigated in an appropriate animal model. In the present psychophysical investigations, spatial frequency response functions for disparity-induced fusional vergence and for local stereopsis were studied in macaque monkeys, who demonstrated many of the major visual characteristics of patients whose eyes were surgically aligned during infancy. In six rhesus monkeys, unilateral esotropia was surgically induced at various ages (30-184 days of age). However, over the next 12 months, all of the monkeys recovered normal eye alignment. Behavioral measurements at 4-6 years of age showed that the monkeys' prism-induced fusional vergence responses were indistinguishable from those of control monkeys or humans with normal binocular vision. Investigations of stereo-depth discrimination demonstrated that each of the experimental monkeys also had stereoscopic vision, but their stereoacuities varied from being essentially normal to severely stereo-deficient. The degree of stereo-deficiency was not related to the age at which surgical esotropia was induced, or to the presence or absence of amblyopia, and was not dependent on the spatial frequency of the test stimulus. Altogether, these experiments demonstrate that a temporary, early esotropia can affect the binocular disparity responses of motor and sensory components of binocular vision differently, probably because of different sensitive periods of development for the two components.

Amblyopia↗

PubMed1997

Severe cystitis associated with tiaprofenic acid.

OBJECTIVE: To review the UK spontaneous reports of urinary disorders associated with tiaprofenic acid and other non-steroidal anti-inflammatory drugs (NSAIDs) and put them into context of the usage of these preparations in the UK. METHODS: Suspected adverse drug reaction (ADR) reports of urinary disorders associated with tiaprofenic acid and other NSAIDs received by the UKs spontaneous ADR reporting scheme were analysed. RESULTS: Between 1982, when tiaprofenic acid was introduced in the UK, and August 1994, 69 cases of cystitis were reported, with a further 32 reports describing related urinary symptoms including frequency, dysuria and haematuria. Only eight cases of cystitis were reported for all other NSAIDs. The duration of treatment with tiaprofenic acid before the onset of urinary symptoms varied markedly (range 2 days to > 3 years). In patients in whom a drug-induced cause was suspected and the drug was stopped promptly, recovery usually occurred within weeks. However, many patients continued on long-term treatment with tiaprofenic acid and underwent extensive investigations to determine the cause of their urinary symptoms. On cystoscopy and biopsy, the findings were similar to interstitial cystitis. Most patients with chronic cystitis recovered after withdrawal of tiaprofenic acid, but some patients had surgery before the drug was stopped. CONCLUSION: Tiaprofenic acid can cause severe cystitis. These reports highlight the importance of taking a full drug history in patients with unexplained chronic cystitis. Tiaprofenic acid should be stopped immediately in all patients developing urinary symptoms.

Adverse Drug Reaction Reporting Systems↗

PubMed1997

Binocular spatial phase tuning characteristics of neurons in the macaque striate cortex.

We employed microelectrode recording techniques to study the sensitivity of individual neurons in the striate cortex of anesthetized and paralyzed monkeys to relative interocular image disparities and to determine the effects of basic stimulus parameters on these cortical binocular interactions. The visual stimuli were drifting sine wave gratings. After the optimal stimulus orientation, spatial frequency, and direction of stimulus movement were found, the cells' disparity tuning characteristics were determined by measuring responses as a function of the relative interocular spatial phase of dichoptic grating pairs. No attempts were made to assess absolute position disparities or horizontal disparities relative to the horopter. The majority (approximately 70%) of simple cells were highly sensitive to interocular spatial phase disparities, particularly neurons with balanced ocular dominances. Simple cells typically demonstrated binocular facilitation at the optimal phase disparity and binocular suppression for disparities 180 degrees away. Fewer complex cells were phase selective (approximately 40%); however, the range of disparity selectivity in phase-sensitive complex cells was comparable with that for simple cells. Binocular interactions in non-phase-sensitive complex cells were evidenced by binocular response amplitudes that differed from responses to monocular stimulation. The degree of disparity tuning was independent of a cell's optimal orientation or the degree of direction tuning. However, disparity-sensitive cells tended to have narrow orientation tuning functions and the degree of disparity tuning was greatest for the optimal stimulus orientations. Rotating the stimulus for one eye 90 degrees from the optimal orientation usually eliminated binocular interactions. The effects of phase disparities on the binocular response amplitude were also greatest at the optimal spatial frequency. Thus a cell's sensitivity to absolute position disparities reflects its spatial tuning characteristics, with cells sensitive to high spatial frequencies being capable of signaling very small changes in image disparity. On the other hand, stimulus contrast had relatively little effect on a cell's disparity tuning, because response saturation occurred at the same contrast level for all relative interocular phase disparities. Thus, as with orientation tuning, a cell's optimal disparity and the degree of disparity selectivity were invariant with contrast. Overall, the results show that sensitivity to interocular spatial phase disparities is a common property of striate neurons. A cell's disparity tuning characteristics appear to largely reflect its monocular receptive field properties and the interocular balance between excitatory and inhibitory inputs. However, distinct functional classes of cortical neurons could not be discriminated on the basis of disparity sensitivity alone.

Action Potentials↗

PubMed1997

Residual binocular interactions in the striate cortex of monkeys reared with abnormal binocular vision.

We investigated the nature of residual binocular interactions in the striate cortex (V1) of monkey models for the two most common causes of visual dysfunction in young children, specifically anisometropia and strabismus. Infant rhesus monkeys were raised wearing either anisometropic spectacle lenses that optically defocused one eye or ophthalmic prisms that optically produced diplopia and binocular confusion. Earlier psychophysical investigations had demonstrated that all subjects exhibited permanent binocular vision deficits and, in some cases, amblyopia. When the monkeys were adults, the responses of individual V1 neurons were studied with the use of microelectrode recording techniques while the animals were anesthetized and paralyzed. The manner in which the signals from the two eyes were combined in individual cells was investigated by dichoptically stimulating both eyes simultaneously with drifting sine wave gratings. In both lens- and prism-reared monkeys, fewer neurons had balanced ocular dominances and greater numbers of neurons were excited by only one eye. However, many neurons that appeared to be monocular exhibited clear binocular interactions during dichoptic stimulation. For the surviving binocular neurons, the maximum binocular response amplitudes were lower than normal; fewer neurons, particularly complex cells, were sensitive to relative interocular spatial phase disparities; and the remaining disparity-sensitive neurons exhibited lower degrees of binocular interaction. In prism-reared monkeys, an unusually high proportion of complex cells exhibited binocular suppression during dichoptic stimulation. Binocular contrast summation experiments showed that for both cooperative and antagonistic binocular interactions, contrast signals from the two eyes were combined by individual neurons in a normal linear fashion in both lens- and prism-reared monkeys. The observed binocular deficits appear to reflect a reduction in functional inputs from one eye and/or spatial imprecision in the monocular receptive fields rather than an aberrant form of binocular interaction. In the prism-reared monkeys, the predominance of suppression suggests that inhibitory connections were, however, less susceptible to diplopia and confusion than excitatory connections. Overall, there were many parallels between V1 physiology in our monkey models and the residual vision of humans with anisometropia or strabismus.

Animals↗

PubMed1996

Loss of stereopsis in monkeys following prismatic binocular dissociation during infancy.

Prismatic binocular dissociation was used during infancy to mimic conditions of strabismus in macaque infants. Prisms worn continuously produce a diplopia unfavorable for the maintenance and development of the binocular visual system. Prism-reared monkeys were tested as young adults and found to be permanently stereoblind for dynamic random dot stereograms. Control monkeys did comparably to humans on such tests. It is concluded that short periods of diplopia attendant with strabismus are sufficient to produce permanent stereoblindness.

Age of Onset↗

PubMed1996

Optical control of early visual experience in monkeys.

Experimental control of the early visual experience of primates has employed a variety of surgical manipulations such as suturing the eyelids or cutting the extraocular muscles in order to mimic infantile visual disorders of children. For several years, we have successfully used optical means for these experimental simulations and the methods are described here.

Amblyopia↗

PubMed1996

Excitatory binocular neurons are lost following prismatic binocular dissociation in infant monkeys.

Four infant rhesus monkeys had prismatic dissociation of binocular vision by viewing the world through prisms. Those monkeys tested previously for ability to utilize horizontal disparity cues in detection of dynamic random dot stereograms, were found here to have few excitatory binocular neurons in visual cortex (V1). Each eye was well represented in the monocular ability to drive cortical neurons, whilst stimulus orientation tuning appeared normal in the monocular neurons, but somewhat less sensitive in the remaining binocular neurons. Binocular dissociation early in life constitutes conditions unfavorable for the maintenance of neural connections delivering binocular excitation to the visual cortex.

Aging↗

PubMed1996

Judgments by monkeys of apparent depth in dynamic random-dot stereograms.

Young macaques discriminated apparent depths of targets embedded in dynamic random dot stereograms; a test of stereopsis. In a 'same/different' paradigm, the discrimination took longer if the pair of stimuli appeared to be in same depth plane, than when they appeared to be located in a different depth plane. The decision time was an inverse function of the disparity difference. Apparent depth discrimination performance decreased as a function of disparity, with no differences in judgments regarding crossed or uncrossed disparities.

Animals↗

PubMed1996

Shrinkage and recovery of cells of the lateral geniculate nuclei with prism-rearing in macaques.

Infant macaque monkeys (Macaca mulatta) were subjected to optical dissociation of binocular vision by wearing prisms before their eyes for 30 days, beginning about 30 days of age. Such treatment mimicked strabismus during infancy and resulted in a dramatic loss of cortical binocular neurons. A concurrent shrinkage of 21% was found in the cells of the lateral geniculate nuclei (LGN) at the end of a terminal electrophysiological study at 60 days of age. A group of monkeys surviving for 5 years showed recovery of normal cell size, even though they did not recover functional binocular neurons in visual cortex.

Animals↗

PubMed1996

Binocularity in prism-reared monkeys.

Prismatic binocular dissociation in infant monkeys mimicked a concomitant squint. Within 3 weeks, the numbers of binocular neurons in the primary visual cortex were reduced by half and did not recover with up to 5 years of subsequent unrestricted binocular visual experience. The monkeys failed to show binocular summation for spatial contrast sensitivity tasks and were unable to utilise horizontal binocular disparities in random-dot stereograms-two indices of stereoblindness. Electrophysiological analysis of the V1 and V2 cortices showed a dramatic reduction in binocular neurons. Analysis of interocular spatial phase tuning functions showed a conspicuous loss of excitatory binocular drive in V1 neurons which was sufficient to account for many of the defects in binocular function.

Animals↗

PubMed1996

Motor and sensory fusion in monkeys: psychophysical measurements.

Motor and sensory fusion, the basic processes of binocularity, must be present for bifoveal fixation with true fusion and stereopsis during ordinary viewing. The characteristics of motor and sensory fusion have been established for patients with normal and subnormal binocular vision; the present report describes our psychophysical studies of these processes in the macaque monkey. Three recent investigations of motor and sensory fusion in monkeys are described. The studies involved: (1) the comparability of motor and sensory fusion in monkeys and humans with normal binocular vision, (2) the effects of an early period of abnormal binocular vision on motor and sensory fusion in monkeys, and (3) the contrast sensitivity for binocular disparity in monkeys with stereo-deficiencies. The results of these studies demonstrated an excellent homology between the normal binocular vision of monkeys and humans. We also found that a period of esotropia during infancy caused deficiencies in sensory fusion, but not motor fusion. In some monkeys, the sensory deficiency persisted over the entire range of binocular disparities that were compatible with stereopsis, while other subjects demonstrated normal stereo-sensitivity for the largest fusible binocular disparities. The stereo-deficiencies of these monkeys, along with other visual attributes, suggest that their binocular vision is a viable model for the binocularity of patients with subnormal binocular vision or the monofixation syndrome.

Animals↗

PubMed1996

The scotopic electroretinogram of macaque after retinal ganglion cell loss from experimental glaucoma.

PURPOSE: This study describes the dark-adapted electroretinograms (ERGs) of macaque monkeys with severe visual field defects and substantial retinal ganglion cell loss as a consequence of long-standing ocular hypertension. METHODS: Monocular experimental glaucoma was produced by argon laser trabeculoplasty, and visual fields were assessed with behavioral static perimetry. Electroretinographic responses to brief ganzfeld flashes under fully dark-adapted conditions were recorded using DTL fiber electrodes in anesthetized animals. The authors quantified retinal layer thickness and cell loss in 1-micron radial sections and inspected optic nervous under the light microscope. RESULTS: At the lowest intensities, a sensitive negative component of the scotopic ERG, which normally peaks approximately 200 msec after stimulus onset, was present in the control eyes but was reduced greatly or was virtually absent in the experimental eyes of monkeys with severe visual field loss. A previously unreported sensitive positive component of the scotopic ERG remained in both eyes. In the control eyes, the positive component gave rise to a sharp peak approximately 120 msec after stimulus onset, but in the experimental eyes, because of the absence of the more delayed sensitive negative potential, it was sustained, lasting as long as 700 msec. Scotopic a- and b-waves and oscillatory potentials in the experimental eyes were not consistently different from control eyes. Ganglion cell and optic nerve loss in the experimental eyes was substantial, and there was little other obvious retinal damage. CONCLUSIONS: A sensitive negative component is reduced or absent from the dark-adapted ERGs of macaque monkeys with severe visual field defects and substantial retinal ganglion cell loss as a consequence of long-standing ocular hypertension.

Animals↗