Species-specific distributions of tyrosine hydroxylase-immunoreactive neurons in the prefrontal cortex of anthropoid primates.

In this study, we assessed the distribution of cortical neurons immunoreactive for tyrosine hydroxylase (TH) in prefrontal cortical regions of humans and nonhuman primate species. Immunohistochemical methods were used to visualize TH-immunoreactive (TH-ir) neurons in areas 9 (dorsolateral prefrontal cortex) and 32 (anterior paracingulate cortex). The study sample included humans, great apes (chimpanzee, bonobo, gorilla, orangutan), one lesser ape (siamang), and Old World monkeys (golden guenon, patas monkey, olive baboon, moor macaque, black and white colobus, and François' langur). The percentage of neurons within the cortex expressing TH was quantified using computer-assisted stereology. TH-ir neurons were present in layers V and VI and the subjacent white matter in each of the Old World monkey species, the siamang, and in humans. TH-ir cells were also occasionally observed in layer III of human, siamang, baboon, colobus, and François' langur cortex. Cortical cells expressing TH were notably absent in each of the great ape species. Quantitative analyses did not reveal a phylogenetic trend for percentage of TH-ir neurons in these cortical areas among species. Interestingly, humans and monkey species exhibited a bilaminar pattern of TH-ir axon distributions within prefrontal regions, with layers I-II and layers V-VI having the densest contingent of axons. In contrast, the great apes had a different pattern of laminar innervation, with a remarkably denser distribution of TH-ir axons within layer III. It is possible that the catecholaminergic afferent input to layer III in chimpanzees and other great apes covaries with loss of TH-ir cells within the cortical mantle.

Dendritic architecture of the von Economo neurons.

The von Economo neurons are one of the few known specializations to hominoid cortical microcircuitry. Here, using a Golgi preparation of a human postmortem brain, we describe the dendritic architecture of this unique population of neurons. We have found that, in contrast to layer 5 pyramidal neurons, the von Economo neurons have sparse dendritic trees and symmetric apical and basal components. This result provides the first detailed anatomical description of a neuron type unique to great apes and humans.

The anterior cingulate cortex. The evolution of an interface between emotion and cognition.

We propose that the anterior cingulate cortex is a specialization of neocortex rather than a more primitive stage of cortical evolution. Functions central to intelligent behavior, that is, emotional self-control, focused problem solving, error recognition, and adaptive response to changing conditions, are juxtaposed with the emotions in this structure. Evidence of an important role for the anterior cingulate cortex in these functions has accumulated through single-neuron recording, electrical stimulation, EEG, PET, fMRI, and lesion studies. The anterior cingulate cortex contains a class of spindle-shaped neurons that are found only in humans and the great apes, and thus are a recent evolutionary specialization probably related to these functions. The spindle cells appear to be widely connected with diverse parts of the brain and may have a role in the coordination that would be essential in developing the capacity to focus on difficult problems. Furthermore, they emerge postnatally and their survival may be enhanced or reduced by environmental conditions of enrichment or stress, thus potentially influencing adult competence or dysfunction in emotional self-control and problem-solving capacity.

Magnetic resonance microscopy of iron in the basal forebrain cholinergic structures of the aged mouse lemur.

Increased non-heme iron levels in the brain of Alzheimer's disease (AD) patients are higher than the levels observed in age matched normal subjects. Iron level in structures that are highly relevant for AD, such as the basal forebrain, can be detected post mortem with histochemistry. Because of the small size of these structures, in vivo MR detection is very difficult at conventional field magnets (1.5 and 4 T). In this study, we observed iron deposits with histochemistry and MR microscopy at 11.7 T in the brain of the mouse lemur, a strepsirhine primate which is the only known animal model of aging presenting both senile plaques and neurofibrillary degeneration. We also examined a related species, the dwarf lemur. Iron distribution in aged animals (8 to 15 years old) agrees with previous findings in humans. In addition, the high iron levels of the globus pallidus is paralleled by a comparable contrast in basal forebrain cholinergic structures. Because of the enhancement of iron-dependent contrast with increasing field strength, microscopic magnetic resonance imaging of the mouse lemur appears to be an ideal model system for studying in vivo iron changes in the basal forebrain in relation to aging and neurodegeneration.

Topographical localization of lipofuscin pigment in the brain of the aged fat-tailed dwarf lemur (Cheirogaleus medius) and grey lesser mouse lemur (Microcebus murinus): comparison to iron localization.

The present study was undertaken to explore the distribution of lipofuscin in the brain of cheirogaleids by autofluorescence and compare it to other studies of iron distribution. Aged dwarf (Cheirogaleus medius) and mouse (Microcebus murinus) lemurs provide a reliable model for the study of normal and pathological cerebral aging. Accumulation of lipofuscin, an age pigment derived by lipid peroxidation, constitutes the most reliable cytological change correlated with neuronal aging. Brain sections of four aged (8-15 year old) and 3 young (2-3 year old) animals were examined. Lipofuscin accumulation was observed in the aged animals but not in the young ones. Affected regions include the hippocampus (granular and pyramidal cells), where no iron accumulation was observed, the olfactory nucleus and the olfactory bulb (mitral cells), the basal forebrain, the hypothalamus, the cerebellum (Purkinje cells), the neocortex (essentially in the pyramidal cells), and the brainstem. Even though iron is known to catalyse lipid oxidation, our data indicate that iron deposits and lipofuscin accumulation are not coincident. Different biochemical and morphological cellular compartments might be involved in iron and lipofuscin deposition. The nonuniform distribution of lipofuscin indicates that brain structures are not equally sensitive to the factors causing lipofuscin accumulation. The small size, the rapid maturity, and the relatively short life expectancy of the cheirogaleids make them a good model system in which to investigate the mechanisms of lipofuscinogenesis in primates.

A neuronal morphologic type unique to humans and great apes.

We report the existence and distribution of an unusual type of projection neuron, a large, spindle-shaped cell, in layer Vb of the anterior cingulate cortex of pongids and hominids. These spindle cells were not observed in any other primate species or any other mammalian taxa, and their volume was correlated with brain volume residuals, a measure of encephalization in higher primates. These observations are of particular interest when considering primate neocortical evolution, as they reveal possible adaptive changes and functional modifications over the last 15-20 million years in the anterior cingulate cortex, a region that plays a major role in the regulation of many aspects of autonomic function and of certain cognitive processes. That in humans these unique neurons have been shown previously to be severely affected in the degenerative process of Alzheimer's disease suggests that some of the differential neuronal susceptibility that occurs in the human brain in the course of age-related dementing illnesses may have appeared only recently during primate evolution.

Topographical localization of iron in brains of the aged fat-tailed dwarf lemur (Cheirogaleus medius) and gray lesser mouse lemur (Microcebus murinus).

Iron deposits in the human brain are characteristic of normal aging but have also been implicated in various neurodegenerative diseases. Among nonhuman primates, strepsirhines are of particular interest because hemosiderosis has been consistently observed in captive aged animals. In particular, the cheirogaleids, because of their small size, rapid maturity, fecundity, and relatively short life expectancy, are a useful model system for the study of normal and pathological cerebral aging. This study was therefore undertaken to explore iron localization in the brain of aged cheirogaleids (mouse and dwarf lemurs) with histochemistry and magnetic resonance microscopy. Results obtained with both techniques were comparable. There was no difference between old animals in the two species. The young animals (3 years old) showed no iron deposits. In the old animals (8-15 years old), iron pigments were mainly localized in the globus pallidus, the substantia nigra, the neocortical and cerebellar white matter, and anterior forebrain structures, including the nucleus basalis of Meynert. This distribution agrees with previous findings in monkeys and humans. In addition, we observed iron in the thalamus of these aged non-human primates. Microscopic NMR images clearly reveal many features seen with the histochemical procedure, and magnetic resonance microscopy is a powerful method for visualizing age-related changes in brain iron.

Distance modulation of neural activity in the visual cortex.

Humans use distance information to scale the size of objects. Earlier studies demonstrated changes in neural response as a function of gaze direction and gaze distance in the dorsal visual cortical pathway to parietal cortex. These findings have been interpreted as evidence of the parietal pathway's role in spatial representation. Here, distance-dependent changes in neural response were also found to be common in neurons in the ventral pathway leading to inferotemporal cortex of monkeys. This result implies that the information necessary for object and spatial scaling is common to all visual cortical areas.

Analysis of retinotopic maps in extrastriate cortex.

Two new techniques for analyzing retinotopic maps--arrow diagrams and visual field sign maps--are demonstrated with a large electrophysiological mapping data set from owl monkey extrastriate visual cortex. An arrow diagram (vectors indicating receptive field centers placed at cortical coordinates) provides a more compact and understandable representation of retinotopy than does a standard receptive field chart (accompanied by a penetration map) or a double contour map (e.g., isoeccentricity and isopolar angle as a function of cortical x, y-coordinates). None of these three representational techniques, however, make separate areas easily visible, especially in data sets containing numerous areas with partial, distorted representations of the visual hemifield. Therefore, we computed visual field sign maps (non-mirror-image vs mirror-image visual field representation) from the angle between the direction of the cortical gradient in receptive field eccentricity and the cortical gradient in receptive field angle for each small region of the cortex. Visual field sign is a local measure invariant to cortical map orientation and distortion but also to choice of receptive field coordinate system. To estimate the gradients, we first interpolated the eccentricity and polar angle data onto regular grids using a distance-weighted smoothing algorithm. The visual field sign technique provides a more objective method for using retinotopy to outline multiple visual areas. In order to relate these arrow and visual field sign maps accurately to architectonic features visualized in the stained, flattened cortex, we also developed a deformable template algorithm for warping the photograph-derived penetration map using the final observed location of a set of marking lesions.

Laminar organization of acetylcholinesterase and cytochrome oxidase in the lateral geniculate nucleus of prosimians.

Hess and Rockland [Hess and Rockland (1983) Brain Res. 289, 322-325] proposed that the distribution of acetylcholinesterase within the lateral geniculate nucleus might correlate with the daily activity patterns shown by primates. In diurnal primates, the magnocellular laminae show a greater acetylcholinesterase reaction product. In nocturnal primates, the parvocellular laminae are more heavily stained. We have examined the laminar distribution of acetylcholinesterase and cytochrome oxidase in the lateral geniculate nucleus of a series of rare prosimian primates. In all prosimians examined, the most dense acetylcholinesterase reaction product is seen in the parvocellular layers of the lateral geniculate nucleus. Heavy cytochrome oxidase activity is seen in both the magnocellular and parvocellular layers, but not the koniocellular layers of the prosimian lateral geniculate nucleus. We have also employed a polyclonal antibody to choline acetyltransferase to examine the laminar organization or cholinergic activity in the Galago (Bushbaby) lateral geniculate nucleus. We report that choline acetyltransferase immunoreactivity does not correlate with acetylcholinesterase activity in the prosimian lateral geniculate nucleus. Although the lateral geniculate nucleus is more immunoreactive than most other thalamic structures and although the intercalated koniocellular laminae demonstrate somewhat lighter choline acetyltransferase immunoreactivity, no great difference in staining intensity is seen between the parvocellular and magnocellular laminae. In addition, we examined the phenotype of known inputs to assess the laminar specificity of cholinergic projections to the bushbaby lateral geniculate nucleus. Layer VI of primary visual cortex, which is known to be a source of acetylcholinesterase in the parvocellular layers, does not contain cholinergic cells, nor does the pretectal nucleus, which projects mainly to the parvocellular layers. The parabigeminal nucleus is cholinergic; however, this nucleus is known to project to the koniocellular layers, along with the non-cholinergic superior colliculus. Finally, the pedunculopontine tegmental nucleus, which provides a strong input to many regions of the thalamus, including the lateral geniculate nucleus, is cholinergic. The laminar organization of its input to the lateral geniculate nucleus is not known. Increased acetylcholinesterase reaction product within the parvocellular layers of the lateral geniculate nucleus is common to all strepsirhine primates. The pattern is also seen in the only two nocturnal haplorhine primates, Tarsius and Aotus (owl monkey). The relation of this increased acetylcholinesterase activity to cholinergic function remains unclear.(ABSTRACT TRUNCATED AT 400 WORDS)

Brain structures and life-span in primate species.

In haplorhine primates, when the effect of body weight is removed, brain weight is correlated with maximum recorded life-span. In this paper we have analyzed the relationships between volumes of specific brain structures and life-span. When the effect of body weight is removed, the volumes of many brain structures are significantly, positively correlated with maximum recorded life-span. However, the volumes of the medulla and most first-order sensory structures do not correlate with life-span. The cerebellum is the brain structure that best correlates with life-span. Parts of the cerebellum are particularly vulnerable to age-related loss of mass in humans. For another measure of the life cycle, female reproductive age, a similar set of brain structures is significantly, positively correlated (again with the exceptions of the medulla and most first-order sensory structures). There are some differences between the structures correlated for life-span and female reproductive age. For example, the hippocampus and lateral geniculate nucleus correlate with female reproductive age but do not correlate with life-span. In strepsirhine primates, when the effect of body weight is removed, total brain weight does not significantly correlate with either life-span or female reproductive age. However, the volumes of some brain structures in strepsirhines do correlate with these life-cycle parameters. The centromedial complex of the amygdala is the only structure to correlate with life-span in both strepsirhine and haplorhine primates. This structure participates in the regulation of blood pressure and in the stress response, which may be key factors governing life-span.

In vivo functional localization of the human visual cortex using positron emission tomography and magnetic resonance imaging.

Positron emission tomography (PET) and magnetic resonance imaging (MRI) are two recently developed methods for imaging the human brain in vivo. One application of PET measures stimulus-evoked changes in cerebral blood flow while MRI provides a detailed anatomical map of the brain. Here we report the combined application of these two techniques in the same human subject. Subtracted PET scans of a brain receiving visual stimulation were superimposed upon MRI images of the same brain. The PET scans were converted into the MRI coordinate space before superposition, which allowed for a more precise correlation between MRI anatomical data and PET physiological data. Responses were localized in striate and extrastriate visual areas as well as in the posterior thalamus.

Transient and sustained responses in four extrastriate visual areas of the owl monkey.

Single neuron responses to stationary flashed bars were recorded from four extrastriate visual areas in the owl monkey: the middle temporal area (MT), the dorsal lateral area (DL), the dorsal medial area (DM), and the medial area (M). Data were collected at the optimum bar size and orientation for each cell. Each post-stimulus histogram was normalized to its maximum bin height. A cumulative histogram was produced for each area by adding together all the corresponding cell histograms. The cumulative histograms reveal a short latency, transient component and a longer latency, sustained component to the response for each of the areas. In all four areas there was a strong response, but the sustained component was much larger in DL and DM than in MT or M. The transient response in DL had a much longer latency than in the other areas. The dichotomy between areas which are slow-sustained responding and areas which are fast-transient responding is similar to the differences found between the magnocellular and parvocellular pathways.

Retinotopic organization of human visual cortex mapped with positron-emission tomography.

The retinotopic organization of primary visual cortex was mapped in normal human volunteers. Positron-emission tomographic measurements of regional cerebral blood flow were employed to detect focal functional brain activation. Oxygen-15-labeled water, delivered by intravenous bolus, was used as the blood flow tracer to allow multiple stimulated-state (n = 5) and control-state (n = 3) measurements to be acquired for each of 7 subjects. Responses were identified by applying a maximum-detection algorithm to subtraction-format images of the stimulus-induced change in cerebral blood flow. Response locales were described using a standardized system of stereotactic coordinates. Changes in stimulus location (macular, perimacular, peripheral, upper-field, lower-field) caused systematic, highly significant changes in response locale within visual cortex. Discrete extrastriate visual responses were also observed.

Mapping human visual cortex with positron emission tomography.

Positron-emission tomography (PET) can localize functions of the human brain by imaging regional cerebral blood flow (CBF) during voluntary behaviour. Functional brain mapping with PET, however, has been hindered by PET's poor spatial resolution (typically greater than 1 cm). We have developed an image-analysis strategy that can map functional zones not resolved by conventional PET images. Brain areas selectively activated by a behavioural task can be isolated by subtracting a paired control-state image from the task-state image, thereby removing areas not recruited by the task. When imaged in isolation the centre of an activated area can be located very precisely. This allows subtle shifts in response locale due to changes in task to be detected readily despite poor spatial resolution. As an initial application of this strategy we mapped the retinal projection topography of human primary visual cortex. Functional zones separated by less than 3 mm (centre-to-centre) were differentiated using PET CBF images with a spatial resolution of 18 mm. This technique is not limited to a particular brain area or type of behaviour but does require that the increase in CBF produced by the task be both intense and focal.

Direction-specific adaptation in area MT of the owl monkey.

Single neurons were recorded in owl monkey middle temporal visual cortex (MT). Directional neurons showed direction-selective adaptation to pattern motion: responses to motion in the preferred direction were reduced by adaptation to motion in the preferred direction and enhanced by adaptation in the opposite direction. Non-directional neurons did not show significant adaptation.

Visual response properties of neurons in four extrastriate visual areas of the owl monkey (Aotus trivirgatus): a quantitative comparison of medial, dorsomedial, dorsolateral, and middle temporal areas.

1. The response properties of 354 single neurons in the medial (M), dorsomedial (DM), dorsolateral (DL), and middle temporal (MT) visual areas were studied quantitatively with bar, spot, and random-dot stimuli in chronically implanted owl monkeys with fixed gaze. 2. A directionality index was computed to compare the responses to stimuli in the optimal direction with the responses to the opposing direction of movement. The greater the difference between opposing directions, the higher the index. MT cells had much higher direction indices to moving bars than cells in DL, DM, and M. 3. A tuning index was computed for each cell to compare the responses to bars moving in the optimal direction, or flashed in the optimal orientation, with the responses in other directions or orientations within +/- 90 degrees. Cells in all four areas were more sharply tuned to the orientation of stationary flashed bars than to moving bars, although a few cells (9/92( were unresponsive in the absence of movement. DM cells tended to be more sharply tuned to moving bars than cells in the other areas. 4. Directionality in DM, DL, and MT was relatively unaffected by the use of single-spot stimuli instead of bars; tuning in all four areas was broader to spots than bars. 5. Moving arrays of randomly spaced spots were more strongly excitatory than bar stimuli for many neurons in MT (16/31 cells). These random-dot stimuli were also effective in M, but evoked no response or weak responses from most cells in DM and DL. 6. The best velocities of movement were usually in the range of 10-100 degrees/s, although a few cells (22/227), primarily in MT (14/69 cells), preferred higher velocities. 7. Receptive fields of neurons in all four areas were much larger than striate receptive fields. Eccentricity was positively correlated with receptive-field size (r = 0.62), but was not correlated with directionality index, tuning index, or best velocity. 8. The results support the hypothesis that there are specializations of function among the cortical visual areas.

Interhemispheric connections of visual cortex in the owl monkey, Aotus trivirgatus, and the bushbaby, Galago senegalensis.

Anatomical techniques have been used to map within visual cortex th pattern of degenerating axonal terminals produced by surgical section of the splenium of the corpus callosum in the owl monkey, Aotus trivirgatus, and the bushbaby, Galago senegalensis. Previous studies in other species have shown that callosal inputs terminate preferentially in regions where the vertical meridian of the visual field is represented. Such a correspondence can serve as a useful aid for locating the boundaries of visual areas. The goals of this study have been (1) to assess the degree of correspondence between callosal inputs and previously identified vertical meridian representations in the owl monkey and bushbaby, and (2) to gain information from the pattern of callosal inputs concerning the existence and organization of as yet unidentified extrastriate visual areas. In both the owl monkey and the bushbaby, a discrete band of degenerating axonal terminals corresponds precisely to the vertical meridian representation at the V1-V2 border, and a less precise increase in the density of degenerating axonal terminals corresponds to the vertical meridian representation of extrastriate area MT. A well-defined band of degeneration on the ventral surface of the owl monkey's cerebral hemisphere corresponds to a previously unknown vertical meridian representation which is shared by two newly identified extrastriate visual areas. Elsewhere in visual cortex the pattern of callosal connections is more complex. Although this pattern may still reflect visual topography, it is not immediately useful for distinguishing areal boundaries.

Organization of the face representation in macaque motor cortex.

We stimulated with microelectrodes the face representation in precentral motor cortex in macaque monkeys. Responses were very discrete; at threshold current levels the usual response was a small focus of movement in part of a muscle. Facial muscles cluster together in the posterior and anterior portions of the precentral gyrus with tongue movements represented in the intervening region and along the lateral extent. Within each cluster there are multiple representations of individual muscle movements. In long penetrations down the anterior wall of the central sulcus we were able to advance the electrode tangentially through cortex. In these penetrations we encountered a series of discrete zones each of which was related to the movement of a particular muscle or part of a muscle in the face. The lowest threshold points were found in the center of each zone, and as the microelectrode progressed toward the edge, thresholds rose until there was a shift to a new muscle movement. Successive stimulation points separated by as little as 50 micrometer could yield different responses. These zones could be either roughly cylindrical or take the form of narrow curving bands running mediolaterally across cortex. There is a tendency for adjacent muscles to occur together, and the representation may be roughly topographical within the limits set by the morphological structure of the muscles themselves. The most commonly evoked muscle response was in zygomaticus, which retracts the corners of the mouth in expressions of fear and anger.