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M M Mesulam

Publications and source records attributed to M M Mesulam.

At least 37 records · Page 2Linked to original sources
PubMed1999

The large-scale neural network for spatial attention displays multifunctional overlap but differential asymmetry.

Functional magnetic resonance imaging (fMRI) was used to determine the brain regions activated by two types of covert visuospatial attentional shifts: one based on exogenous spatial priming and the other on foveally presented cues which endogenously regulated the direction of spatial expectancy. Activations were seen in the cortical and subcortical components of a previously characterized attentional network, namely, the frontal eye fields, posterior parietal cortex, the cingulate gyrus, the putamen, and the thalamus. Additional activations occurred in the anterior insula, dorsolateral prefrontal cortex, temporo-occipital cortex in the middle and inferior temporal gyri, the supplementary motor area, and the cerebellum. Direct comparisons showed a nearly complete overlap in the location of activations resulting from the two tasks. However, the spatial priming task displayed a more pronounced rightward asymmetry of parietal activation, and a conjunction analysis showed that the area of posterior parietal cortex jointly activated by both tasks was more extensive in the right hemisphere. Furthermore, the posterior parietal and temporo-occipital activations were more pronounced in the task of endogenous attentional shifts. The results show that both exogenous (based on spatial priming) and endogenous (based on expectancy cueing) shifts of attention are subserved by a common network of cortical and subcortical regions. However, the differences between the two tasks, especially in the degree of rightward asymmetry, suggests that the pattern of activation within this network may show variations that reflect the specific attributes of the attentional task.

Adult↗
PubMed1999

Cholinergic neurons of the nucleus basalis of Meynert receive cholinergic, catecholaminergic and GABAergic synapses: an electron microscopic investigation in the monkey.

An electron microscopic analysis of the nucleus basalis in the macaque monkey was carried out following the immunohistochemical labeling of choline acetyltransferase, either by itself or in conjunction with glutamate decarboxylase or tyrosine hydroxylase. Cholinergic axon varicosities were frequently encountered, and formed large, usually asymmetric, synapses on both choline acetyltransferase-immunopositive and -immunonegative dendrites of nucleus basalis neurons. Catecholaminergic (tyrosine hydroxylase-immunoreactive) axon varicosities formed synapses which in most cases were classified as asymmetric, and glutamate decarboxylase-immunoreactive (GABAergic) axons formed clearly symmetric synapses, each on to choline acetyltransferase-immunopositive or -immunonegative dendrites. These findings indicate that cholinergic cells in the nucleus basalis of the monkey, also known as Ch4 neurons, receive numerous synaptic inputs from cholinergic, catecholaminergic and GABAergic axons.

Animals↗
PubMed1999

m2 muscarinic receptor immunolocalization in cholinergic cells of the monkey basal forebrain and striatum.

Pharmacological studies have suggested that the m2 muscarinic receptor functions as an autoreceptor in the cholinergic axons which innervate the cerebral cortex and striatum. To test this hypothesis in the macaque monkey, we used a subtype-specific antibody to the m2 muscarinic receptor. Immunoreactive cells were well visualized in the nucleus basalis, where some of these cells displayed dense m2 immunoreactivity, while others were lightly labeled. This heterogeneity of labeling intensity was not based on peculiarities of the methodology, because cholinergic cells of the striatum expressed uniformly dense m2 immunoreactivity. Concurrent labeling with choline acetyltransferase immunoreactivity proved that most of the heavily m2-labeled cells in the nucleus basalis were also choline acetyl-transferase positive. The findings demonstrate that at least 10-25% of the cholinergic neurons in the nucleus basalis of the monkey are densely m2 immunoreactive. In the striatum, concurrent labeling demonstrated that the majority, if not all, choline acetyltransferase-positive cells also contained m2 immunoreactivity. In addition, these experiments identified a population of smaller striatal cells which were m2 immunoreactive and choline acetyltransferase negative. Consecutive labeling with m2 immunoreactivity and NADPH-diaphorase histochemistry demonstrated that many of these m2-immunoreactive non-cholinergic neurons belonged to the population of nitric oxide-synthesizing medium aspiny neurons. The findings indicate that the m2 muscarinic receptor may be expressed at high levels in only a subset of cholinergic basal forebrain neurons. In contrast, m2 receptors appear to be expressed by all cholinergic cells of the striatum.

Animals↗
PubMed1999

Monoaminergic-cholinergic interactions in the primate basal forebrain.

Anatomical studies in the rat have shown that the cholinergic cells of the nucleus basalis receive synapses from monoamine axons, but similar evidence is lacking in primates. We used single- and double-labeling immunocytochemistry to visualize monoamine axons and their relationship with the cholinergic cells of the basal forebrain of the monkey. Norepinephrine axons, labeled with dopamine-beta-hydroxylase antibodies, formed a bed of fine varicose axons that co-distributed with the cholinergic cells. Tyrosine hydroxylase-immunoreactive axons, presumed to be mainly dopaminergic, were 10-20 times more abundant than dopamine-beta-hydroxylase axons throughout the basal forebrain, except in the medial septal area, where their density was lower. Serotonin-immunoreactive axons formed a dense axon plexus throughout the basal forebrain. Double-labeling light microscopy demonstrated that each of the three types of monoamine axons formed frequent direct contacts with the cholinergic cells. Electron microscopy showed that the noradrenergic and the putative dopaminergic axons synapsed on the cholinergic cells. In the human brain, immunolabeling with antibodies to dopamine-beta-hydroxylase, tyrosine hydroxylase and tryptophan hydroxylase (for serotonin axons) showed axon densities in the nucleus basalis comparable to those of the monkey brain. The data demonstrate that all three of these monoamine systems innervate the cholinergic and possibly also the non-cholinergic cells of the nucleus basalis, and therefore affect the release of acetylcholine in the cerebral cortex.

Animals↗
PubMed1999

Mechanisms underlying diminished novelty-seeking behavior in patients with probable Alzheimer's disease.

OBJECTIVE: To better understand apathy and disengagement in patients with Alzheimer's disease (AD), the authors investigated possible behavioral mechanisms underlying diminished novelty-seeking activity in patients with probable AD. BACKGROUND: Apathy and disengagement have been shown to be the most common behavioral changes associated with AD. METHOD: Patients and age-matched normal controls had their eye movements recorded while pairs of line drawings pitting an incongruous figure against a congruous figure were shown on a screen for 12 seconds. Characteristics of a subset of AD patients who were indifferent to novel visual stimuli as measured by exploratory eye movements were compared to those of a subset of AD patients who were attracted to novel stimuli to a degree similar to that of normal controls. RESULTS: The indifferent patients were judged by informants, who completed a personality questionnaire, to exhibit a greater degree of apathy. The two AD groups did not differ in overall dementia severity or performance on a Saccade-to-Target Task that required shifts of attention and gaze. In a separate task, the indifferent patients were able to accurately identify the more novel stimuli in 97.5% of trials. Normal control subjects exhibited a strong bias toward processing novel stimuli, directing a higher proportion of their first fixations and dwell time to the incongruous stimuli whether the analysis was run for 3, 6, or 12 seconds of viewing. Indifferent patients did not direct their initial fixation toward novel stimuli and distributed their looking time evenly between incongruous and congruous stimuli throughout all measured intervals. CONCLUSIONS: The results suggest that the indifference to novelty observed in some patients with probable AD cannot simply be attributed to global cognitive decline, more elementary attentional deficits, more rapid habituation of response to novel stimuli, or an inability to discriminate upon demand between stimuli of varying degrees of novelty. It is more likely that their behavior reflects a disruption, by AD pathology, of neural systems that modulate behavioral engagement and maintain attentional bias toward novel events in the environment.

Aged↗
PubMed1998

Regulation of attention to novel stimuli by frontal lobes: an event-related potential study.

This study examined the relationship between orienting responses to novel events and subsequent exploratory behavior. The N2-P3 electrophysiologic component of the orienting response was found to be larger for novel than repetitive background stimuli. Across subjects, the amplitude of this N2-P3 response in frontal regions strongly predicted the proportional increase in the duration of viewing directed toward novel compared to background stimuli. Within subjects, larger N2-P3 amplitudes in response to novel stimuli were associated with longer viewing durations on those stimuli. These results suggest that the N2-P3 component of the orienting response reflects the activity of a neural system involving frontal networks that dynamically regulates the subsequent allocation of attentional resources to novel stimuli.

Adult↗
PubMed1998

Infracortical interstitial cells concurrently expressing m2-muscarinic receptors, acetylcholinesterase and nicotinamide adenine dinucleotide phosphate-diaphorase in the human and monkey cerebral cortex.

Intense immunoreactivity for the m2-muscarinic receptor was found in a population of interstitial polymorphic neurons embedded within the infracortical white matter and the adjacent deep layers of the cerebral cortex. These infracortical neurons were evenly distributed throughout architectonic subdivisions of the monkey cortex except for parts of primary visual cortex where they were less numerous. A similar set of m2-immunoreactive interstitial cells was also detected in the human lateral temporal neocortex obtained at surgery. Upon electron microscopic examination, they were found to receive unlabelled synaptic inputs and displayed abundant rough endoplasmic reticulum, a prominent nucleolus, and invaginations of the nuclear membrane. Double labelling of m2 immunoreactivity and acetylcholinesterase histochemistry demonstrated that approximately 90% of the m2-positive infracortical cells were acetylcholinesterase-rich in the monkey and human brains. Conversely, the proportion of acetylcholinesterase-rich infracortical neurons that were m2-immunoreactive was over 90% in the monkey and at least 50% in the human. The concurrent visualization of nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) enzyme activity with m2 immunoreactivity in the monkey and human brain showed that 85-95% of m2-immunoreactive infracortical cells were NADPH-d positive. Conversely, about 70% of NADPH-d cells contained m2 immunoreactivity. These observations provide the most convincing information to date that many of the acetylcholinesterase-rich neurons located in the infracortical white matter of the cerebral cortex are likely to be cholinoceptive. The expression of NADPH-d by these neurons suggests that they may also provide a relay through which cholinergic innervation, originating predominantly from the nucleus basalis of Meynert, could regulate the release of nitric oxide in the cerebral cortex and subjacent white matter. The degeneration of these neurons may account for at least some of the depletion of m2 receptors that has been reported in Alzheimer's disease.

Acetylcholinesterase↗
PubMed1998

Trajectories of cholinergic pathways within the cerebral hemispheres of the human brain.

All sectors of the human cerebral cortex receive dense cholinergic input. The origin of this projection is located in the Ch4 cell group of the nucleus basalis of Meynert. However, very little is known about the location of the pathways which link the cholinergic neurons of the nucleus basalis to the human cerebral cortex. This question was addressed in whole-hemisphere sections processed for the visualization of multiple cholinergic markers. Two highly organized and discrete bundles of cholinergic fibres extended from the nucleus basalis to the cerebral cortex and amygdala and were designated as the medial and lateral cholinergic pathways. These bundles contained acetylcholinesterase, choline acetyltransferase and nerve growth factor receptors, confirming their cholinergic nature and origin within the basal forebrain. The medial pathway joined the white matter of the gyrus rectus, curved around the rostrum of the corpus callosum to enter the cingulum and merged with fibres of the lateral pathway within the occipital lobe. It supplied the parolfactory, cingulate, pericingulate and retrosplenial cortices. The lateral pathway was subdivided into a capsular division travelling in the white matter of the external capsule and uncinate fasciculus and a perisylvian division travelling within the claustrum. Branches of the perisylvian division supplied the frontoparietal operculum, insula and superior temporal gyrus. Branches of the capsular division innervated the remaining parts of the frontal, parietal and temporal neocortex. Representation of these cholinergic pathways within a 3D MRI volume helped to identify white matter lesion sites that could interfere with the corticopetal flow of cholinergic pathways.

Adult↗
PubMed1998

From sensation to cognition.

Sensory information undergoes extensive associative elaboration and attentional modulation as it becomes incorporated into the texture of cognition. This process occurs along a core synaptic hierarchy which includes the primary sensory, upstream unimodal, downstream unimodal, heteromodal, paralimbic and limbic zones of the cerebral cortex. Connections from one zone to another are reciprocal and allow higher synaptic levels to exert a feedback (top-down) influence upon earlier levels of processing. Each cortical area provides a nexus for the convergence of afferents and divergence of efferents. The resultant synaptic organization supports parallel as well as serial processing, and allows each sensory event to initiate multiple cognitive and behavioural outcomes. Upstream sectors of unimodal association areas encode basic features of sensation such as colour, motion, form and pitch. More complex contents of sensory experience such as objects, faces, word-forms, spatial locations and sound sequences become encoded within downstream sectors of unimodal areas by groups of coarsely tuned neurons. The highest synaptic levels of sensory-fugal processing are occupied by heteromodal, paralimbic and limbic cortices, collectively known as transmodal areas. The unique role of these areas is to bind multiple unimodal and other transmodal areas into distributed but integrated multimodal representations. Transmodal areas in the midtemporal cortex, Wernicke's area, the hippocampal-entorhinal complex and the posterior parietal cortex provide critical gateways for transforming perception into recognition, word-forms into meaning, scenes and events into experiences, and spatial locations into targets for exploration. All cognitive processes arise from analogous associative transformations of similar sets of sensory inputs. The differences in the resultant cognitive operation are determined by the anatomical and physiological properties of the transmodal node that acts as the critical gateway for the dominant transformation. Interconnected sets of transmodal nodes provide anatomical and computational epicentres for large-scale neurocognitive networks. In keeping with the principles of selectively distributed processing, each epicentre of a large-scale network displays a relative specialization for a specific behavioural component of its principal neurospychological domain. The destruction of transmodal epicentres causes global impairments such as multimodal anomia, neglect and amnesia, whereas their selective disconnection from relevant unimodal areas elicits modality-specific impairments such as prosopagnosia, pure word blindness and category-specific anomias. The human brain contains at least five anatomically distinct networks. The network for spatial awareness is based on transmodal epicentres in the posterior parietal cortex and the frontal eye fields; the language network on epicentres in Wernicke's and Broca's areas; the explicit memory/emotion network on epicentres in the hippocampal-entorhinal complex and the amygdala; the face-object recognition network on epicentres in the midtemporal and temporopolar cortices; and the working memory-executive function network on epicentres in the lateral prefrontal cortex and perhaps the posterior parietal cortex. Individual sensory modalities give rise to streams of processing directed to transmodal nodes belonging to each of these networks. The fidelity of sensory channels is actively protected through approximately four synaptic levels of sensory-fugal processing. The modality-specific cortices at these four synaptic levels encode the most veridical representations of experience. Attentional, motivational and emotional modulations, including those related to working memory, novelty-seeking and mental imagery, become increasingly more pronounced within downstream components of unimodal areas, where they help to create a highly edited subjective version of the world. (ABSTRACT TRUNCATED)

Attention↗
PubMed1998

Relationship between plaques, tangles, and loss of cortical cholinergic fibers in Alzheimer disease.

Recent observations in our laboratory have indicated substantial and systematic regional variations in the loss of cortical cholinergic fibers in Alzheimer disease (AD). Previous attempts to study the relationship between cortical cholinergic loss and the density of cortical pathological lesions have resulted in conflicting findings. Furthermore, most reports have correlated density of plaques and tangles with the residual level of cholinergic innervation rather than its loss. The purpose of the present study was to determine the relationship between loss of cholinergic axons and density of tangles and beta-amyloid (Abeta) deposits in various cortical areas of AD brains. Abeta deposits and tangles were observed throughout the cerebral cortex. Quantitative analysis revealed almost no correlation between loss of cholinergic fibers and the density of Abeta deposits. Qualitative observations revealed similar results when cored and neuritic plaques were considered separately. By contrast, cholinergic fiber loss displayed a significant correlation with the density of tangles (r = 0.52-0.79). However, in a few areas, such as the cingulate cortex, tangle density appeared to be unrelated to the loss of cholinergic fibers. These results indicate that cortical cholinergic denervation in AD is related to cytoskeletal pathology. However, the lack of a perfect relationship with cytoskeletal pathology implicates additional factors in the cholinergic pathology of AD.

Aged↗
PubMed1998

Dopamine agonists reorient visual exploration away from the neglected hemispace.

OBJECTIVE: To study the effects of bromocriptine, a dopamine agonist, on visual search. BACKGROUND: The anatomic substrate of spatial attention takes the form of a distributed network with interconnected cortical (frontal, parietal, and cingulate) and subcortical (striatal and thalamic) components. Dopamine appears to exert a modulatory effect on the function of this network. METHODS: Seven consecutive right-handed subjects with right-sided cerebral lesions were studied using a computerized target search paradigm. Eye movements were recorded. RESULTS: Bromocriptine caused the subjects to spend more time exploring the ipsilesional hemispace and therefore increased the relative neglect of the contralesional left hemispace. However, target detection accuracy did not change. Bromocriptine thus had a differential impact on the exploratory-motor versus sensory-perceptual components of directed attention. CONCLUSIONS: Our results show that bromocriptine may worsen some aspects of hemispatial neglect in patients with lesions that include the postsynaptic components of ascending dopaminergic pathways.

Adult↗
PubMed1997

Age-related loss of calbindin from human basal forebrain cholinergic neurons.

Loss of basal forebrain cholinergic neurons (BFCN) occurs in many age-related neurological diseases. Although age is the common risk factor in these disorders, no consistent age-related changes have been reported in the human BFCN. We investigated age-related alterations in choline acetyltransferase (ChAT), low-affinity nerve growth factor receptor (p75LNGFR) and calbindin-D28k (CalBP) immunoreactivity in the human BFCN. No significant age-related changes were observed in ChAT or p75LNGFR immunoreactivity. By contrast, normal aging was accompanied by a selective, substantial and significant loss of CalBP immunoreactivity from the BFCN. Other CalBP-positive neurons were unchanged. Loss of the calcium buffering capacity conferred by CalBP may leave the BFCN vulnerable to damage in neurodegenerative disorders.

Adult↗
PubMed1997

Butyrylcholinesterase in the life cycle of amyloid plaques.

Deposits of diffuse beta-amyloid (Abeta) may exist in the brain for many years before leading to neuritic degeneration and dementia. The factors that contribute to the putative transformation of the Abeta amyloid from a relatively inert to a pathogenic state remain unknown and may involve interactions with additional plaque constituents. Matching brain sections from 2 demented and 4 nondemented subjects were processed for the demonstration of Abeta immunoreactivity, butyrylcholinesterase (BChE) enzyme activity, and thioflavine S binding. Additional sections were processed for the concurrent demonstration of two or three of these markers. A comparative analysis of multiple cytoarchitectonic areas processed with each of these markers indicated that Abeta plaque deposits are likely to undergo three stages of maturation, ie, a "diffuse" thioflavine S-negative stage, a thioflavine S-positive (ie, compact) but nonneuritic stage, and a compact neuritic stage. A multiregional analysis showed that BChE-positive plaques were not found in cytoarchitectonic areas or cortical layers that contained only the thioflavine S-negative, diffuse type of Abeta plaques. The BChE-positive plaques were found only in areas containing thioflavine S-positive compact plaques, both neuritic and nonneuritic. Within such areas, almost all (>98%) BChE-containing plaques bound thioflavine S, and almost all (93%) thioflavine S plaques contained BChE. These results suggest that BChE becomes associated with amyloid plaques at approximately the same time that the Abeta deposit assumes a compact beta-pleated conformation. BChE may therefore participate in the transformation of Abeta from an initially benign form to an eventually malignant form associated with neuritic tissue degeneration and clinical dementia.

Aged↗
PubMed1997

Cholinergic synapses in human cerebral cortex: an ultrastructural study in serial sections.

Cholinergic axons in the human cerebral cortex were analyzed by electron microscopy. Choline acetyltransferase (ChAT) immunoreactivity was used to identify cholinergic axons in samples of anterior temporal lobe removed at surgery. A systematic survey of labeled axon varicosities, visualized in complete serial sections, showed that 67% of all varicosities formed identifiable synaptic specializations. These synapses were usually symmetric and quite small, often present in only one to two serial sections. However, an occasional synapse was asymmetric and larger, seen in five to seven serial sections. The postsynaptic processes at cholinergic synapses were often identified as spiny dendrites or spines. The existence of cholinergic axons in the human cerebral cortex has been demonstrated in numerous studies. Our findings provide the first ultrastructural evidence that these axons make synaptic contact with cortical neurons in the human brain.

Adult↗
PubMed1997

Retrograde degeneration and colchicine protection of basal forebrain cholinergic neurons following hippocampal injections of an immunotoxin against the P75 nerve growth factor receptor.

Intracerebroventricular injection of 192 IgG antibody against the p75LNGFR rat low affinity nerve growth factor receptor conjugated with saporin, a ribosome inactivating protein, has been shown to destroy the p75LNGFR-expressing cholinergic neurons of the basal forebrain. We injected this immunotoxin into the hippocampus and studied its retrograde effect upon the cholinergic neurons of the medial septum and the vertical limb of the diagonal band of Broca. Seven days after injection, there was a nearly total depletion of cholinergic axons within the hippocampus. This depletion was associated with a marked and significant decrease in the number of cholinergic neurons of the ipsilateral medial septum and the vertical limb of the diagonal band of Broca. At longer survival times, these changes were more pronounced. Parvalbumin-positive, GABAergic neurons within the same areas of the basal forebrain were not affected by immunotoxin injections. Injections of saporin alone had no effect upon cholinergic neurons. Simultaneous injection of colchicine with the immunotoxin resulted in a significant reduction of retrograde degeneration of cholinergic neurons and relative preservation of hippocampal cholinergic axons. These observations suggest that 192 IgG-saporin is transported retrogradely from the hippocampus to the cholinergic neurons in the medial septum and the vertical limb of the diagonal band of Broca and provide a model for retrograde degeneration of basal forebrain cholinergic neurons following cortically based toxic-pathologic processes.

Animals↗
PubMed1997

Functional localization of the system for visuospatial attention using positron emission tomography.

PET was used to image the neural system underlying visuospatial attention. Analysis of data at both the group and individual-subject level provided anatomical resolution superior to that described to date. Six right-handed male subjects were selected from a pilot behavioural study in which behavioural responses and eye movements were recorded. The attention tasks involved covert shifts of attention, where peripheral cues indicated the location of subsequent target stimuli to be discriminated. One attention condition emphasized reflexive aspects of spatial orientation, while the other required controlled shifts of attention. PET activations agreed closely with the cortical regions recently proposed to form the core of a neural network for spatial attention. The two attention tasks evoked largely overlapping patterns of neural activation, supporting the existence of a general neural system for visuospatial attention with regional functional specialization. Specifically, neocortical activations were observed in the right anterior cingulate gyrus (Brodmann area 24), in the intraparietal sulcus of right posterior parietal cortex, and in the mesial and lateral premotor cortices (Brodmann area 6).

Attention↗