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The effect of artifacts on dependence measurement in fMRI.

The study of effective connectivity by means of neuroimaging depends on the measurement of similarity between activity patterns at different locations in the brain, without necessarily presupposing a particular model for this dependence. When these interactions are measured using functional magnetic resonance imaging (fMRI) techniques, however, imaging and physiological artifacts create patterns of dependence that may be unrelated to cortical activity. We demonstrate some of these effects through the measurement of short-range dependencies present in fMRI scans of the primary visual cortex (V1) in the anaesthetized macaque monkey. High-field (4.7 T) fMRI scans were conducted to measure responses based on the blood oxygen level-dependent contrast mechanism, during periods of no sensory stimulation and of visual stimulation with rotating polar-transformed checkerboard gratings. Dependence between the haemodynamic activity at different spatial locations (i.e., different voxels) was measured using correlation, mutual information and functional covariance. Particular attention was paid to understanding the sources of spurious dependence that may be observed during such investigations. Two main effects were detected: (a) short-range correlations introduced by the process of image reconstruction and (b) perturbations in the haemodynamic response caused by breathing. The image reconstruction artifacts were shown to create an artificially high short-range dependence in the readout direction of the scan, and the breathing artifacts caused enhanced short-range dependence in both the readout and phase-encode directions. Additional dependence in the phase-encode direction due to image-ghosting is also possible but will not be discussed in this report, as it can be alleviated by fine adjustment of preemphasis (elimination of eddy currents). A technique is described for removing breathing artifacts, and the effect of breathing on the apparent dependence between voxels is illustrated. The correlation of haemodynamic activity with the stimulus was found to be affected by breathing, although this effect can be neutralised by averaging the haemodynamic responses over many repetitions of the stimulus. Nonetheless, patterns of dependent activity between voxels may be lost in this averaging process, which makes the removal of breathing artifacts necessary if statistical dependence and the study of effective connectivity is the primary aim of an investigation.

Animals↗

Prenatal and postnatal development of GABA-accumulating cells in the occipital neocortex of rat.

The development of the 3H-GABA-accumulating cells in the neocortex has been followed by light microscopical autoradiography, and after resectioning of the original autoradiograms, by electron microscopy. The validity of the methods used are discussed. The study has been limited to the primary visual cortex and its precursors of rat, from embryonic day (E) 15 to adult. GABA-accumulating cells were found from E 16 onwards in the occipital cortex, which is one to two days after cells arrive in the pallial anlage and one day before the first synapses have been found. Until E 18, the prevalent positions of labeled cells were in lamina I and below the cortical plate. Later, labeled cells also occurred as strands within the cortical plate. During the perinatal period, more and more GABA-accumulating neurons and glial cells began to differentiate and show a characteristic distribution at the periphery of unlabeled cell clusters. From postnatal day 11, no apparent change in density or position of labeled neurons took place. At prenatal stages, two main types of labeled cells were found: 1) Comparatively large cells with rounded nuclei and rough endoplasmic reticulum consisting of narrow, electron-lucent cisterns. These cells were tentatively identified as preneurons. 2) Smaller, polymorphous cells with irregular nuclei and rough endoplasmic reticulum with wide cisterns filled with a dense matrix. These cells are probably precursors of glial cells. Both labeled neurons and glial cells were identified at postnatal stages. In young and adult rats, only neurons to be characterized as nonpyramidal neurons were labeled. Synapses were not found on the perikarya of labeled cells until E 21. Also, in postnatal preparations, labeled neurons showed few axo-somatic synapses. These data were correlated with other events of the structural and functional development of the neocortex. The delay between the appearance of GABA accumulating cells and synaptogenesis indicates that apart from being an inhibitory neurotransmitter, GABA might play a specific morphogenetic role in synaptogenesis. This could even be its primary function during early developmental stages.

Animals↗

Reversal of vision metamorphopsia: clinical and anatomical characteristics.

BACKGROUND: Metamorphopsia is a visual illusion that distorts the size, shape, or inclination of objects. Reversal of vision metamorphopsia (RVM) is a rare transient form of metamorphopsia described as an upside-down, 180 degrees rotation of the visual field in the coronal plane. The pathophysiological characteristics of RVM remain unclear. DESIGN: Patients with RVM had a complete neurologic examination during or shortly after an episode of metamorphopsia, with particular emphasis on gaze disorders, visual fields, visually guided hand movements, and perceptual or cognitive deficits. Workup included imaging studies, visual field examinations, and brainstem auditory and visual evoked response. SETTING: Department of Neurology, Hadassah University Hospital, Hebrew University-Hadassah Medical School, Jerusalem, Israel. PATIENTS: Six consecutive patients were evaluated from 1991 to 1996. RESULTS: Five patients had parieto-occipital brain insult sparing the primary visual cortex, and 3 also had evidence of a concomitant brainstem or cerebellar syndrome. One patient had pure brainstem syndrome underlying the RVM. Three patients had complete RVM as well as oblique RVM of less than 180 degrees. CONCLUSIONS: These cases imply a possible anatomical localization of the central integrator of visual extrapersonal orientation. Our observations suggest that a separate central mechanism of visual orientation might exist in each cerebral hemisphere and that occipital and parietal lesions that spare the optic radiations may account for the oblique and complete RVM. We postulate that failure to perceive space in an allocentric coordinate frame, particularly in the coronal roll plane, is potentially the critical event underlying RVM.

Aged↗

Visual hallucinations in posterior cortical atrophy.

BACKGROUND: Visual hallucinations have been reported to occur in up to 25% of patients who meet the criteria for posterior cortical atrophy (PCA). It is not known, however, whether patients who meet the criteria for PCA and have hallucinations are different from those who meet the criteria and do not have hallucinations. OBJECTIVE: To compare the clinical and imaging features of patients with PCA with and without well-formed visual hallucinations. DESIGN: Case-control study. SETTING: Tertiary care medical center. PATIENTS: Fifty-nine patients fulfilling the criteria for PCA were retrospectively identified and divided into 2 groups based on the presence (n = 13) or absence (n = 46) of visual hallucinations. MAIN OUTCOME MEASURES: Statistically significant clinical differences and imaging differences using voxel-based morphometry between the 2 groups. RESULTS: In patients with PCA and hallucinations, parkinsonism and rapid eye movement sleep behavior disorder occurred more frequently, as did myoclonic jerks (P<.001 for both). Voxel-based morphometry showed greater atrophy in a network of structures, including the primary visual cortex, lentiform nuclei, thalamus, basal forebrain, and midbrain, in patients with hallucinations. CONCLUSIONS: Hallucinations in patients with PCA are associated with parkinsonism, rapid eye movement sleep behavior disorder, and myoclonic jerks. The voxel-based morphometry results suggest that hallucinations in PCA cannot be exclusively attributed to atrophy of the posterior association cortices and may involve a circuit of thalamocortical connections.

Age of Onset↗

Plasticity of geniculocortical afferents following brief or prolonged monocular occlusion in the cat.

During a critical period in early life, physiological studies reveal that either prolonged or brief periods of monocular occlusion induce similar plastic changes in the primary visual cortex (area 17) of the cat, leading to a nearly complete loss of visual responses from the deprived eye (Hubel and Wiesel [1970], J. Physiol. (London) 160: 106-154). However, the recovery of function is markedly different in the two conditions, being complete and thorough only after a brief period of monocular occlusion (Movshon [1976] J. Physiol. (London) 261: 125-174). In search for anatomical correlates that distinguish between these two experimental conditions, we compared the geniculocortical connectivity in normal kittens with that following brief (4 days and 6-7 days) or prolonged (> 5 weeks) periods of occlusion of vision in one eye. Transneuronal labeling of the geniculocortical pathway revealed changes in both cases, and single afferent arbors reconstructed in serial sections were similarly shrunken after short or long periods of deprivation. However, a significant expansion of the geniculocortical afferents serving the nondeprived eye was evident mainly after prolonged deprivation. These findings provide further evidence for rapid, activity-dependent remodeling of afferents during development.

Afferent Pathways↗

Development of connections within and between areas V1 and V2 of macaque monkeys.

We have investigated the development of intrinsic and interareal connections in areas V1 and V2 of the macaque monkey using postmortem transport of the lipophilic fluorescent tracer diI, applied to brains fixed at different pre- and postnatal ages. Intrinsic connections in the deep layers of V1 are evident on embryonic day 108 (E108), but are not robust in the superficial layers until around E118, when migration is largely complete. Both intrinsic horizontal projections and extrinsic projections to V2 initially have a continuous distribution. Patchy projections are first evident in V1 around E145, the same age at which cytochrome oxidase blobs appear, presumably signaling the differentiation of the blob-dominated and interblob-dominated streams in the primary visual cortex. The magnocellular-dominated stream becomes distinct at earlier stages (by E122), as judged by connectional and histochemical criteria. In area V2, intrinsic connections initially (at E108) involve only deep layer cells and do not have a clustered organization. By E130, superficial layer cells are involved and the V2 intrinsic connections have a patchy distribution; by E145, an adult-like pattern is present. The projection from V2 to V1 passes through an early stage (up to E133) of originating principally from deep layer cells, and thereafter originating from superficial as well as deep layers. We found evidence for changes in dendritic morphology during development. Most notably, at E118, many neurons in layer 6 which are involved in intrinsic or interareal connections have dendrites that extend well into the superficial layers, even into layer 1, a characteristic not reported in the adult.

Animals↗

Does the visual system of the flying fox resemble that of primates? The distribution of calcium-binding proteins in the primary visual pathway of Pteropus poliocephalus.

It has been proposed that flying foxes and echolocating bats evolved independently from early mammalian ancestors in such a way that flying foxes form one of the suborders most closely related to primates. A major piece of evidence offered in support of a flying fox-primate link is the highly developed visual system of flying foxes, which is theorized to be primate-like in several different ways. Because the calcium-binding proteins parvalbumin (PV) and calbindin (CB) show distinct and consistent distributions in the primate visual system, the distribution of these same proteins was examined in the flying fox (Pteropus poliocephalus) visual system. Standard immunocytochemical techniques reveal that PV labeling within the lateral geniculate nucleus (LGN) of the flying fox is sparse, with clearly labeled cells located only within layer 1, adjacent to the optic tract. CB labeling in the LGN is profuse, with cells labeled in all layers throughout the nucleus. Double labeling reveals that all PV+ cells also contain CB, and that these cells are among the largest in the LGN. In primary visual cortex (V1) PV and CB label different classes of non-pyramidal neurons. PV+ cells are found in all cortical layers, although labeled cells are found only rarely in layer I. CB+ cells are found primarily in layers II and III. The density of PV+ neuropil correlates with the density of cytochrome oxidase staining; however, no CO+ or PV+ or CB+ patches or blobs are found in V1. These results show that the distribution of calcium-binding proteins in the flying fox LGN is unlike that found in primates, in which antibodies for PV and CB label specific separate populations of relay cells that exist in different layers. Indeed, the pattern of calcium-binding protein distribution in the flying fox LGN is different from that reported in any other terrestrial mammal. Within V1 no PV+ patches, CO blobs, or patchy distribution of CB+ neuropil that might reveal interblobs characteristic of primate V1 are found; however, PV and CB are found in separate populations of non-pyramidal neurons. The types of V1 cells labeled with antibodies to PV and CB in all mammals examined including the flying fox suggest that the similarities in the cellular distribution of these proteins in cortex reflect the fact that this feature is common to all mammals.

Animals↗

Numbers of meynert and layer IVB cells in area V1: a stereologic analysis in young and aged macaque monkeys.

Visual impairments that are not related to optical changes are not uncommon during aging, and a number of psychophysical investigations have documented deficits in motion detection as well as in spatiotemporal contrast sensitivity in elderly people. However, little is known about the extent and nature of age-related changes in neural structure and how they may affect visual function in aging. To address this question, the authors analyzed the effect of aging on two well-characterized neuronal populations in the primary visual cortex (area V1) of macaque monkeys. Four young adult (ages, 7-11 years) and four aged (ages, 26-32 years) rhesus monkeys were analyzed. The animals were perfused, and their brains were prepared for immunohistochemistry with an antibody to neurofilament protein. Unbiased stereologic estimates of the total numbers of neurofilament protein-containing layer IVB cells and Meynert cells were obtained by using the optical fractionator method for the calcarine cortex and the opercular cortex separately. Stereologic estimates of the volume of these parts of area V1 also were calculated by using the Cavalieri principle. A considerable degree of interindividual variability in neuron numbers and cortical volume was observed among animals of both groups. However, there were no differences in either Meynert cell numbers or layer IVB cell numbers between the aged group and the young group. It is noteworthy that the oldest animal in the sample had the lowest numbers of Meynert cells, indicating that, despite the small size of the available sample, it is possible that some animals have a certain degree of neuronal loss in area V1 during aging. No change in the volume of area V1 was observed as a function of aging. These data suggest that the deficits that occur during aging in the visual system are not due to the loss of highly specific neocortical neuronal populations, such as those analyzed in this study. Rather, it is possible that more subtle alterations in the neurochemical characteristics or synaptic organization of the functional pathways subserving the different visual modalities are responsible for these deficits.

Age Factors↗

Visual form discrimination from texture cues: a PET study.

With the purpose of localising the cerebral cortical areas participating in the discrimination of visual form generated exclusively by texture cues, we measured changes in regional cerebral blood flow (rCBF) with positron emissions tomography (PET) and 15O-butanol as the tracer. The subjects performed two odd-one-out discrimination tasks: a form-from-texture discrimination task (in which a visual form was defined by differences in texture) and its reference task, the discrimination of texture. During task performance, activated fields were present bilaterally in the primary visual cortex and its immediate extrastriate cortex, the right lateral occipital gyrus, bilaterally in the fusiform and superior temporal gyri and posterior parts of the superior parietal lobules, along the medial bank of the right intraparietal sulcus, and in the right supramarginal gyrus. Other fields were found in the cingulate and prefrontal cortex. The findings demonstrate that the discrimination of visual form as defined by texture engages cortical fields that are widely distributed ion the human brain. In the visual cortex, the activated fields are present in both the occipito-temporal and occipito-parietal visual areas. These results suggest that the perception and discrimination of forms in the visual system requires the joint-activation of neuronal populations in the visual cortex.

Adult↗

Application of double voxel functional spectroscopy to event-related cognitive experiments.

The hemodynamic response to functional activation can be regarded as the convolution of the neuronal response with an unknown kernel. As such, it introduces an intrinsic blurring that limits the attainable temporal resolution of functional magnetic resonance (fMR) techniques. This study demonstrates that by measurement of displacements in activation onsets between different types of trial, it is nevertheless possible to obtain a subsecond temporal accuracy in fMR. A single trial stimulation paradigm was adopted: a simple search task embedded in a longer period of visual flicker stimulation that produced reliable activations in the primary visual cortex and supplementary motor area. Data were acquired from both of these regions using double voxel functional spectroscopy.

Evoked Potentials, Visual↗

Investigation of BOLD signal dependence on cerebral blood flow and oxygen consumption: the deoxyhemoglobin dilution model.

The relationship between blood oxygenation level-dependent (BOLD) MRI signals, cerebral blood flow (CBF), and oxygen consumption (CMR(O2)) in the physiological steady state was investigated. A quantitative model, based on flow-dependent dilution of metabolically generated deoxyhemoglobin, was validated by measuring BOLD signals and relative CBF simultaneously in the primary visual cortex (V1) of human subjects (N = 12) during graded hypercapnia at different levels of visual stimulation. BOLD and CBF responses to specific conditions were averaged across subjects and plotted as points in the BOLD-CBF plane, tracing out lines of constant CMR(O2). The quantitative deoxyhemoglobin dilution model could be fit to these measured iso-CMR(O2) contours without significant (P </= 0.05) residual error and yielded MRI-based CMR(O2) measurements that were in agreement with PET results for equivalent stimuli. BOLD and CBF data acquired during graded visual stimulation were then substituted into the model with constant parameters varied over plausible ranges. Relative changes in CBF and CMR(O2) appeared to be coupled in an approximate ratio of approximately 2:1 for all realistic parameter settings. Magn Reson Med 42:849-863, 1999.

Brain Mapping↗

Developmental and sensory-dependent changes of group II metabotropic glutamate receptors.

Metabotropic glutamate receptors (mGluRs) are potential participants of sensory-dependent modification of neural connections. Here, we examined the involvement of cAMP-linked mGluRs (mGluR2/3) in sensory-dependent plasticity by studying the correlation of mGluR2/3 changes with the critical period of ocular dominance plasticity, a form of sensory-dependent plasticity, and exploring the effects of dark rearing on mGluR2/3 in the primary visual cortex of cats. Immunohistochemistry showed that the laminar distribution of mGluR2/3 changed with the critical period and was sensitive to dark rearing. The mGluR2/3 immunostaining became most intense in layer IV at the beginning of the critical period and was reduced in layer IV but became intense in layers I-III at the peak of the period, then was concentrated primarily in layers I-upper III at the end of the critical period. Dark rearing delayed these pattern changes for weeks and elevated the normally declining mGluR2/3 quantity shortly after the peak of the critical period. The effects of dark rearing and the correlation of early mGluR2/3 laminar changes with geniculocortical afferent segregation indicate that mGluR2/3 circuitry in the visual cortex is influenced by visual inputs. Our data suggest that mGluR2/3 together with another sensory-influenced mGluR, mGluR5, may participate in the sensory-dependent modification of neural connections in the visual cortex.

Animals↗

fMRI of visual system activation in the conscious rabbit.

A conscious rabbit preparation developed for fMRI, and the results from visual stimulation studies at a 4.7T magnetic field are described. The rabbit is ideal for these experiments because of its natural tolerance for restraint. High spatial and temporal resolution magnetic resonance images, without movement artifacts, were obtained during long periods of restraint. Functional activation in primary visual cortex and lateral geniculate nucleus (LGN) were reproducibly observed in response to light stimulus. In comparison to existing anesthetized animal models, a functional response free of the anesthetic modulation can be recorded with the new approach. The conscious animal model can be applied to functional studies of sensory systems, learning and memory, and drug-induced cerebral activation.

Animals↗

Postnatal development of the monkey's visual system.

The sudden increase of nervous activity after birth may influence the development of many parts of the brain. The visual system provides a particularly striking example of the crucial significance of birth itself in the maturation of the nervous system, for visual experience is obviously unlikely in utero. The role of the activity of afferent neurons in maintaining, even guiding, the formation of functional connections in the visual pathways has been extensively studied in a variety of species: such work in primates might give insight into the same process in man and into the aetiology of certain developmental disorders of vision. We have performed anatomical and physiological experiments on the monkey's lateral geniculate nucleus (LGN), which receives input from the optic nerves, and the primary visual cortex, to which the LGN sends its axons. In both structures there are enormous functional changes after birth, but those in the LGN seem not to depend on normal visual stimulation while those in the cortex seem crucially dependent on visual input.

Animals↗

Stripe selection: an intrinsic property of some pattern-forming models with nonlinear dynamics.

In two-dimensional pattern formation, the genesis of stripped rather than spotted patterns may involve preexisting spatial asymmetries, such as unidirectional gradients or asymmetric shape of the pattern-forming domain. In the absence of such asymmetries, some kinds of nonlinear dynamics still lead to striped rather than spotted patterns. We have studied the latter effect both by extensive computer experiments on a range of nonlinear models and by mathematical analysis. We conclude that, when the dynamic equations are written in terms of departure from the unpatterned state, the presence of nonlinearities which are odd functions of these departures (e.g., cubic terms) together with absence of even nonlinearities (e.g., quadratic terms) ensures stripe formation. In computer experiments, we have studied the dynamics of two-morphogen reaction-diffusion models. The mathematical analysis presented in the Appendix shows that the same property exists in more generalized models for pattern formation in the primary visual cortex.

Animals↗

Human sensory stimulation and deprivation: positron emission tomographic results and strategies.

Fluorine-18-labeled fluorodeoxyglucose was used to measure local cerebral glucose metabolism by means of positron emission tomography (PET) in patients and in normal subjects. Various states of audiovisual stimulation and deprivation were explored. Our experience in performing neurobehavioral PET studies in over 145 normal right-handed individuals is described. In normal subjects metabolic left-right symmetry was found in states of partial sensory deprivation (eyes patched or ears plugged). Metabolic asymmetries (right less than left) were observed in subjects with more complete sensory deprivation (eyes patched and ears plugged). Auditory stimulation studies in normal subjects demonstrated metabolic evidence of cerebral lateralization. No correlation between site of metabolic response and side of stimulation was observed. Both the site and the side (left versus right) of maximal metabolic response correlated with the type (verbal versus nonverbal) and content of the stimulus as well as with the strategy used by the subject to solve the listening task. Visual stimuli of increasing complexity produced symmetrical increases in metabolic rate for the primary and secondary visual cortices. Focal stimulation of the central portion of the retina produced focal responses limited to the occipital poles, while full-field visual stimulation produced increased metabolic activity throughout the entire extent of the primary visual cortex. Patients with lesions of the visual pathway that spared the visual cortex itself demonstrated abnormalities in visual cortical metabolic rate that correlated with clinical symptoms. The refinement of neurobehavioral PET studies is discussed in terms of the limitations presently induced by spatial resolution, temporal resolution, anatomical localization accuracy, experimental neuropsychological paradigm design, and data analysis techniques. These limitations, as well as future prospects for using PET to study human brain function in both normal and pathological states, are discussed.

Acoustic Stimulation↗

Hemispheric lateralization of spatial contrast sensitivity.

Visuospatial contrast sensitivity was determined by the Arden grating chart in 23 patients with cerebral infarctions involving the primary visual cortex or visual association cortex. Subjects were classified into three groups according to their lesions: I, 6 patients with unilateral medial occipital or occipitotemporal lesions; II, 6 patients with left lateral parieto-occipital lesions; and III, 11 patients with right lateral parieto-occipital lesions. Contrast sensitivity was markedly reduced in Group III, especially in patients having hemispatial agnosia. Group I patients with hemispatial agnosia showed almost normal contrast sensitivity. Spatial contrast sensitivity appears to be more affected when the lesion has an influence on the nondominant lateral parieto-occipital cortex.

Adult↗

Looking for the lunate sulcus: a magnetic resonance imaging study in modern humans.

The position of the lunate sulcus in fossil endocasts (when it can be determined) may serve as a potential marker of cognitive development in extinct hominid species. While the lunate sulcus is reliably present in the brains of great apes and forms the anterolateral boundary of the primary visual cortex, in humans its presentation is much more variable, and even if present, it does not correspond to a functional region. Grafton Elliot Smith, who named the lunate sulcus, claimed that it was homologous in humans and the great apes. Using high-resolution MRI, we assessed the presence/absence and course of the lunate sulcus in 110 adult subjects. We found that in the vast majority of cases, lunate sulci identified on the surface of the occipital lobe are actually composed of smaller sulcal segments that converge into an apparently continuous composite lunate sulcus. We found only 3 examples in 220 hemispheres (1.4%) of continuous lunate sulci that resembled ape lunates in form (albeit in a more posterior position). Composite lunate sulci were found in 32.7% of left hemispheres and 26.4% of right hemispheres. These results, combined with those from histological and functional imaging studies, indicate that human and ape lunate sulci are not homologous structures. We suggest that the extent of functional reorganization of the occipital region during hominid evolution has been underestimated, and that changes in this region were not just passively shaped by expansion of parietal association cortex.

Adult↗