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PubMed2002

Cognitive and physiologic correlates of subclinical structural brain disease in elderly healthy control subjects.

CONTEXT: Healthy elderly persons commonly show 4 types of change in brain structure-cortical atrophy, central atrophy, deep white-matter hyperintensities, and periventricular hyperintensities-as forms of subclinical structural brain disease (SSBD). OBJECTIVES: To characterize the volumes of SSBD present with aging and to determine the associations of SSBD, physiology, and cognitive function. DESIGN: Cross-sectional study. SETTING: University of California, Los Angeles, Neuropsychiatric Institute. SUBJECTS: Forty-three community-dwelling healthy control subjects, aged 60 through 93 years. MAIN OUTCOME MEASURES: Volumetric magnetic resonance imaging, neuropsychological testing, and quantitative electroencephalographic coherence (functional connectivity) between brain regions. RESULTS: Regression models demonstrated significant relationships between SSBD volumes, age, cognitive performance, and connectivity. Cortical and central atrophy and periventricular hyperintensities had significant associations with age while deep white-matter hyperintensities did not. Posterior atrophy showed stronger associations with age than did anterior atrophy. Only a subset of subjects at older ages showed large SSBD volumes; older subjects primarily showed increasing variance of SSBD. Although all subjects scored within the normal range on cognitive testing, SSBD volume was inversely related to performance, most notably on the Trail-Making Test part B and the Shipley-Hartford Abstract Reasoning test. Coherence had significant associations with SSBD. Path analysis supported mediation of the effects of deep white-matter hyperintensities and periventricular hyperintensities on cognition by altered connectivity. For several measures, cognitive performance was best explained by coherence, and only secondarily by SSBD. CONCLUSIONS: Modest volumes of SSBD were associated with decrements in cognitive performance within the normal range in healthy subjects. Lower coherence was associated with greater volumes of SSBD and increasing age. Path analysis models suggest that brain functional connectivity mediates some effects of SSBD on cognition.

Aged↗
PubMed1976

[The polymorphism of collagen. New viewpoints on the structure and function of connective tissue].

Recent studies have established that connective tissue contains several chemically and genetically distinct collagens. Here we discuss the nature of these proteins, their occurrence in different tissues and their involvement in disease processes. Types I, II and II collagens show some similarities indicating a common origin. Morphological studies using antibodies against the various collagens indicate that the different collagens occur in different anatomical structures. Alterations in the distribution of these collagens are seen in tissues in certain disease states and may cause the loss of normal tissue function.

Age Factors↗
PubMed2007

Detecting functional nodes in large-scale cortical networks with functional magnetic resonance imaging: a principal component analysis of the human visual system.

This study aimed to demonstrate how a regional variant of principal component analysis (PCA) can be used to delineate the known functional subdivisions of the human visual system. Unlike conventional eigenimage analysis, PCA was carried out as a second-level analysis subsequent to model-based General Linear Model (GLM)-type functional activation mapping. Functional homogeneity of the functional magnetic resonance imaging (fMRI) time series within and between clusters was examined on several levels of the visual network, starting from the level of individual clusters up to the network level comprising two or more distinct visual regions. On each level, the number of significant components was identified and compared with the number of clusters in the data set. Eigenimages were used to examine the regional distribution of the extracted components. It was shown that voxels within individual clusters and voxels located in bilateral homologue visual regions can be represented by a single component, constituting the characteristic functional specialization of the cluster(s). If, however, PCA was applied to time series of voxels located in functionally distinct visual regions, more than one component was observed with each component being dominated by voxels in one of the investigated regions. The model of functional connections derived by PCA was in accordance with the well-known functional anatomy and anatomical connectivity of the visual system. PCA in combination with conventional activation mapping might therefore be used to identify the number of functionally distinct nodes in an fMRI data set in order to generate a model of functional connectivity within a neuroanatomical network.

Adult↗
PubMed2006

The left intraparietal sulcus and verbal short-term memory: focus of attention or serial order?

One of the most consistently activated regions during verbal short-term memory (STM) tasks is the left intraparietal sulcus (IPS). However, its precise role remains a matter of debate. While some authors consider the IPS to be a specific store for serial order information, other data suggest that it serves a more general function of attentional focalization. In the current fMRI experiment, we investigated these two hypotheses by presenting different verbal STM conditions that probed recognition for word identity or word order and by assessing functional connectivity of the left IPS with distant brain areas. If the IPS has a role of attentional focalization, then it should be involved in both order and item conditions, but it should be connected to different brain regions, depending on the neural substrates involved in processing the different types of information (order versus phonological/orthographic) to be remembered in the item and order STM conditions. We observed that the left IPS was activated in both order and item STM conditions but for different reasons: during order STM, the left IPS was functionally connected to serial/temporal order processing areas in the right IPS, premotor and cerebellar cortices, while during item STM, the left IPS was connected to phonological and orthographic processing areas in the superior temporal and fusiform gyri. Our data support a position considering that the left IPS acts as an attentional modulator of distant neural networks which themselves are specialized in processing order or language representations. More generally, they strengthen attention-based accounts of verbal STM.

Adult↗
PubMed1999

Reciprocal interdependence between pineal gland and avian immune system. NEL Review.

The immune system of mammals and birds exhibits the same basic anatomical and functional organization, including dichotomy into the cellular and humoral immune response. Specificities of avian immune system may be, however, very useful for understanding numerous phylogenetic and evolutionary mysteries. Similarities and differences between mammals and birds in terms of several pineal gland functions are well known, and they seem to include the immunomodulatory activity of melatonin (MEL) as well. Embryonic pinealectomy of the chicken demonstrated functional interrelationships between the development of the pineal gland, immune system and/or neuroendocrine network, and embryonic bursectomy influenced the diurnal rhythm of the pineal gland function and abolished the effect of immunization on serum MEL level. Also immunization with a thymo-dependent antigen (SRBC) evoked some changes in the chicken nocturnal pineal NAT activity. We have found that the pineal gland and MEL control the diurnal rhythm of immunity in the chicken, but we were not able to demonstrate any immunostimulatory and anti-glucocorticoid MEL effects, regardless of the chicken's age, sex, season, and hormone dose used. The existence of functional connections between the pineal gland and the immune system in chickens was, however, confirmed in other experimental approaches. Specific and reversible binding of 2-[125I]iodoMEL to the membrane preparations from lymphoid glands was demonstrated in several avian species. In vitro MEL diminished lymphocyte proliferation stimulated by the common T-cell mitogens, while alone failed to influence the blast formation. Reciprocal functional connections between the avian immune system and the pineal gland seem to be well documented, but the mechanism(s) involved have to be elucidated.

Journal Article↗
PubMed1996

Alterations in functional neuroanatomical connectivity in Alzheimer's disease. Positron emission tomography of auditory verbal short-term memory.

Conscious recall of past events which have specific temporal and spatial contexts, termed episodic memory, is mediated by a system of interrelated brain regions. In Alzheimer's disease (AD) this system breaks down, resulting in an inability to recall events from the immediate past. Studies of normal human auditory-verbal short-term memory suggest that the brain system underlying these processes has distinct components, and the present study utilized the methods of functional brain mapping to determine the nature and extent of the breakdown that occurs in AD. Using subtraction techniques of PET-acquired images of regional cerebral blood flow we demonstrate that AD patients show a compensatory hyperactivation of various regions of cerebral cortex normally involved in these tasks, as well as activation of cortical areas not activated by normal elderly subjects. These results provide clear evidence of functional plasticity in the AD patient's brain even if those changes do not result in normal memory function.

Aged↗
PubMed1990

Effects of advancing age on the central response of rat facial neurons to axotomy: light microscope morphometry.

Following axotomy, the regrowth of peripheral axons takes longer in older individuals than in young ones. The present study compares central responses of facial motor neurons to a crush injury of the facial nerve in 3-month-old and 15-month-old male rats sampled through 28 days post-crush (dpc). Neuronal somata, nuclei, and nucleoli were measured in 30 microns brain stem sections within subdivisions of the facial nucleus that contain the cell bodies responsible for the movement of the vibrissae. The temporal patterns of change in the size of the three structures were interpreted with reference to the re-establishment of functional connections, i.e., the return of voluntary vibrissae activity, which is delayed by 4 days in the older animals relative to the younger ones. There was no age-related difference in the pattern of somal swelling and recovery, nor was there an age-related difference in the response of nuclei and nucleoli to axotomy through 4 dpc. Both nuclei and nucleoli increased in size in animals of both age groups, but after 4 dpc in the older animals nuclear enlargement was prolonged and the nucleolar increases were less robust compared to the younger animals. The greatest age difference appeared with the re-establishment of functional connections. In the 3-month-old animals, the resumption of whisker activity coincided with vigorous transient increases in the sizes of nuclei and nucleoli; in the 15-month-old animals, there was little nuclear response to functional recovery and a comparatively small increase in nuclear sizes.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMedDate not supplied

[Interrelationship between differently spaced neurons in the auditory and motor zones of the cerebral cortex in cats].

Multineuronal activity was studied in unrestrained cats with bundles of seven electrodes (tips dia. 50 mcm) chronically implanted in the auditory and motor cortex. Spikes of the highest and lowest amplitude were isolated from each neurogram by an amplitude discriminator. Functional connections between neurones located under different electrodes at a distance of up 540 mcm were defined by statistical dependence of the isolated spike series. In the auditory cortex, the distance at which it was possible to detect connections between high amplitude neurones (H-H) did not exceed 450 mcm, while between low amplitude neurones (L-L) it was 270 mcm. In the motor cortex, dependent relations for similar pairs of neurones (H-H) and (L-L) were found at all the studied distances up to 540 mcm. For mixed neuronal pairs (H-L and L-H) functional connections at different distances were differently expressed at various distances.

Animals↗
PubMed2004

Imagery in sentence comprehension: an fMRI study.

This study examined brain activation while participants read or listened to high-imagery sentences like The number eight when rotated 90 degrees looks like a pair of spectacles or low-imagery sentences, and judged them as true or false. The sentence imagery manipulation affected the activation in regions (particularly, the intraparietal sulcus) that activate in other mental imagery tasks, such as mental rotation. Both the auditory and visual presentation experiments indicated activation of the intraparietal sulcus area in the high-imagery condition, suggesting a common neural substrate for language-evoked imagery that is independent of the input modality. In addition to exhibiting greater activation levels during the processing of high-imagery sentences, the left intraparietal sulcus also showed greater functional connectivity in this condition with other cortical regions, particularly language processing regions, regardless of the input modality. The comprehension of abstract, nonimaginal information in low-imagery sentences was accompanied by additional activation in regions in the left superior and middle temporal areas associated with the retrieval and processing of semantic and world knowledge. In addition to exhibiting greater activation levels during the processing of low-imagery sentences, this left temporal region also revealed greater functional connectivity in this condition with other left hemisphere language processing regions and with prefrontal regions, regardless of the input modality. The findings indicate that sentence comprehension can activate additional cortical regions that process information that is not specifically linguistic but varies with the information content of the sentence (such as visual or abstract information). In particular, the left intraparietal sulcus area appears to be centrally involved in processing the visual imagery that a sentence can evoke, while activating in synchrony with some core language processing regions.

Adolescent↗
PubMedDate not supplied

Rat hepatic microsomal aldehyde dehydrogenase. Identification of 3- and 4-substituted aromatic aldehydes as substrates of the enzyme.

The rat hepatic microsomal aldehyde dehydrogenase (mALDH) metabolizes aliphatic and aromatic aldehydes to the corresponding acids with NAD as the optimal cofactor. However, dehydrogenation of the aliphatic compounds is substantially more efficient. In the present study, a series of aromatic aldehydes was evaluated as substrates of the purified mALDH so that the physicochemical factors that contribute to substrate affinity could be evaluated. Substitution of the aromatic system in the 3- and 4-positions produced relatively good substrates, but 2-substituted congeners did not undergo dehydrogenation. However, aldehydes with hydrophilic substituents in the 3- or 4-positions and those with extremely bulky substituents at both positions (e.g., 3,4-dibenzyloxy) were also poor substrates for the enzyme and dehydrogenation was undetectable. A quantitative structure-activity relationship was determined that related the logarithm of the Michaelis constants for 27 substituted aromatic aldehydes with the zero-order connectivity function of the molecule (0 chi), the shapes of the 3- and 4-substituents (kappa), and the electronic nature of the 4-substituent (sigma). In this equation, 81% of the data variance was explained. From a consideration of the dimensions of 3-phenoxybenzaldehyde, which was a relatively good substrate, the mALDH possesses a narrow cleft within the active site that is at least 7.5 angstroms wide and extends at least 12 angstroms from the catalytic residue (probably cysteine). Previously established relationships between connectivity functions and molecular polarizability suggest that dipolar interactions within the active site, as well as dispersion forces, may play a role in substrate specificity. Although optimal shapes for carbocyclic substituents were not provided by the analysis, the unfavorable effect on dehydrogenation from hydrophilic and large substituents suggests that the active site of the mALDH is relatively rigid and that the orientation of the substrate in relation to the catalytic cysteine and the cofactor binding site is critical.

Acetaldehyde↗
PubMed2006

Functional and anatomical cortical underconnectivity in autism: evidence from an FMRI study of an executive function task and corpus callosum morphometry.

The brain activation of a group of high-functioning autistic participants was measured using functional magnetic resonance imaging during the performance of a Tower of London task, in comparison with a control group matched with respect to intelligent quotient, age, and gender. The 2 groups generally activated the same cortical areas to similar degrees. However, there were 3 indications of underconnectivity in the group with autism. First, the degree of synchronization (i.e., the functional connectivity or the correlation of the time series of the activation) between the frontal and parietal areas of activation was lower for the autistic than the control participants. Second, relevant parts of the corpus callosum, through which many of the bilaterally activated cortical areas communicate, were smaller in cross-sectional area in the autistic participants. Third, within the autism group but not within the control group, the size of the genu of the corpus callosum was correlated with frontal-parietal functional connectivity. These findings suggest that the neural basis of altered cognition in autism entails a lower degree of integration of information across certain cortical areas resulting from reduced intracortical connectivity. The results add support to a new theory of cortical underconnectivity in autism, which posits a deficit in integration of information at the neural and cognitive levels.

Adult↗
PubMed2006

Changes in hippocampal connectivity in the early stages of Alzheimer's disease: evidence from resting state fMRI.

A selective distribution of Alzheimer's disease (AD) pathological lesions in specific cortical layers isolates the hippocampus from the rest of the brain. However, functional connectivity between the hippocampus and other brain regions remains unclear in AD. Here, we employ a resting state functional MRI (fMRI) to examine changes in hippocampal connectivity comparing 13 patients with mild AD versus 13 healthy age-matched controls. Hippocampal connectivity was investigated by examination of the correlation between low frequency fMRI signal fluctuations in the hippocampus and those in all other brain regions. We found that functional connectivity between the right hippocampus and a set of regions was disrupted in AD; these regions are: medial prefrontal cortex (MPFC), ventral anterior cingulate cortex (vACC), right inferotemporal cortex, right cuneus extending into precuneus, left cuneus, right superior and middle temporal gyrus and posterior cingulate cortex (PCC). We also found increased functional connectivity between the left hippocampus and the right lateral prefrontal cortex in AD. In addition, rightward asymmetry of hippocampal connectivity observed in elderly controls was diminished in AD patients. The disrupted hippocampal connectivity to the MPFC, vACC and PCC provides further support for decreased activity in "default mode network" previously shown in AD. The decreased connectivity between the hippocampus and the visual cortices might indicate reduced integrity of hippocampus-related cortical networks in AD. Moreover, these findings suggest that resting-state fMRI might be an appropriate approach for studying pathophysiological changes in early AD.

Aged↗
PubMed1989

Discharge patterns of rostrolateral medullary expiratory neurons in the cat: regulation by concurrent network processes.

1. The identification of numerous functional connections among medullary respiratory related neurons led us to postulate specific short time scale correlations among neuronal spike trains consistent with 1) inhibition of rostrolateral medullary augmenting expiratory (E-AUG) neurons by other E-AUG cells, and 2) inhibitory control of the postulated E-AUG neural network by decrementing expiratory (E-DEC) neurons. Recent observations of reduced rostrolateral E-AUG cell activity following stimulation of sensory afferents raised the additional question of whether reflex control mechanisms use the identified functional connections to mediate their effects. 2. Experiments were conducted on 42 anesthetized, paralyzed, bilaterally vagotomized, artificially ventilated cats. Impulse trains of two or more respiratory related neurons of the lateral medulla, including at least one rostrolateral medullary E-AUG neuron, were simultaneously recorded together with phrenic nerve efferent activity. Most neurons were tested for spinal axonal projections with antidromic stimulation methods. In some experiments, the central cut end of the right vagus nerve was electrically stimulated during the expiratory interval. Data were analyzed using cycle-triggered histograms, auto- and cross-correlograms, logical cross-correlograms, snowflake scatter diagrams, and peristimulus time histograms. 3. Seven of 73 pairs (9.6%) of ipsilateral E-AUG neurons exhibited short time scale correlations in firing probability. Two rostral pairs had coincident increases in activity. Five pairs were characterized by a reduction in activity in a rostral neuron following spikes in the other cell; concurrent serial inhibition among one set of three E-AUG neurons was indicated. These five pairs, together with three other similarly correlated pairs described previously, were studied further: spikes recorded during the first and second halves of the expiratory (E) phase were analyzed separately. This phase segmentation unmasked multiple correlations implying reciprocal inhibition between one pair of E-AUG neurons. Short time scale troughs in correlograms generated from late E-phase spike trains had significantly (P less than 0.05) greater detectability indices than troughs in early E-phase correlograms. Multineuron correlations revealed two cases in which the firing probability of the target E-AUG neuron was reduced less when only reference E-AUG cell spikes coincident with spikes in a third, E-DEC, neuron were used as trigger events. 4. Enhanced rostral E-AUG neuron firing probabilities coincident with or following impulses in ipsilateral E-DEC neurons were detected in 6 of 94 (6.4%) rostral pairs.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗
PubMed1991

Regeneration of functional synaptic connections between widely separated neurons in the adult mammalian central nervous system.

The responses to light of retinal ganglion cells with regenerated axons can be recorded from axons teased from peripheral nerve grafts replacing the optic nerve of the adult rat or hamster. These responses resemble those of normal retinal ganglion cells but can no longer be observed several months after grafting, concomitant with ongoing loss of the population of axotomized retinal ganglion cells. Synapses formed with neurons in the superior colliculus by retinal ganglion cell axons regenerated through peripheral nerve grafts mediate both excitatory and inhibitory responses. These experiments demonstrate that when provided with an appropriate milieu for elongation, neurons indigenous to the adult mammalian central nervous system can make functional reconnections with distant targets within the nervous system.

Animals↗
PubMed1999

Formation of functional synaptic connections between cultured cortical neurons from agrin-deficient mice.

Numerous studies suggest that the extracellular matrix protein agrin directs the formation of the postsynaptic apparatus at the neuromuscular junction (NMJ). Strong support for this hypothesis comes from the observation that the high density of acetylcholine receptors (AChR) normally present at the neuromuscular junction fails to form in muscle of embryonic agrin mutant mice. Agrin is expressed by many populations of neurons in the central nervous system (CNS), suggesting that this molecule may also play a role in neuron-neuron synapse formation. To test this hypothesis, we examined synapse formation between cultured cortical neurons isolated from agrin-deficient mouse embryos. Our data show that glutamate receptors accumulate at synaptic sites on agrin-deficient neurons. Moreover, electrophysiological analysis demonstrates that functional glutamatergic and gamma-aminobutyric acid (GABA)ergic synapses form between mutant neurons. The frequency and amplitude of miniature postsynaptic glutamatergic and GABAergic currents are similar in mutant and age-matched wild-type neurons during the first 3 weeks in culture. These results demonstrate that neuron-specific agrin is not required for formation and early development of functional synaptic contacts between CNS neurons, and suggest that mechanisms of interneuronal synaptogenesis are distinct from those regulating synapse formation at the neuromuscular junction.

2-Amino-5-phosphonovalerate↗
PubMed2001

Dynamic imaging of coherent sources: Studying neural interactions in the human brain.

Functional connectivity between cortical areas may appear as correlated time behavior of neural activity. It has been suggested that merging of separate features into a single percept ("binding") is associated with coherent gamma band activity across the cortical areas involved. Therefore, it would be of utmost interest to image cortico-cortical coherence in the working human brain. The frequency specificity and transient nature of these interactions requires time-sensitive tools such as magneto- or electroencephalography (MEG/EEG). Coherence between signals of sensors covering different scalp areas is commonly taken as a measure of functional coupling. However, this approach provides vague information on the actual cortical areas involved, owing to the complex relation between the active brain areas and the sensor recordings. We propose a solution to the crucial issue of proceeding beyond the MEG sensor level to estimate coherences between cortical areas. Dynamic imaging of coherent sources (DICS) uses a spatial filter to localize coherent brain regions and provides the time courses of their activity. Reference points for the computation of neural coupling may be based on brain areas of maximum power or other physiologically meaningful information, or they may be estimated starting from sensor coherences. The performance of DICS is evaluated with simulated data and illustrated with recordings of spontaneous activity in a healthy subject and a parkinsonian patient. Methods for estimating functional connectivities between brain areas will facilitate characterization of cortical networks involved in sensory, motor, or cognitive tasks and will allow investigation of pathological connectivities in neurological disorders.

Algorithms↗
PubMed1988

Structure and function of connective tissue in cardiac muscle: collagen types I and III in endomysial struts and pericellular fibers.

Heart myocytes and capillaries are enmeshed in a complex array of connective tissue structures arranged in several levels of organization: epimysium, the sheath of connective tissue that surrounds muscles; perimysium, which is associated with groups of cells; and endomysium, which surrounds and interconnects individual cells. The present paper is a review of work in this field with an emphasis on new, unpublished findings, including composition of endomysial fibers and disposition of newly described perimysial fibers. The role of scanning electron microscopy in the development of current understanding is also outlined. Biaxially arranged epimysial fibers form a sheath around papillary muscles and trabeculae that becomes increasingly well-oriented with the muscle axis during stretch. Perimysial structures are associated with groups of cells, and include weaves and septa of collagen, tendon-like fibers between weaves, ribbon-like fibers perpendicular to myocytes, and the newly described coiled perimysial fibers, which form an array in parallel with the myocytes and the epimysial net. The endomysium includes struts that bridge cells and pericellular fibers; both contain collagen types I and III. The evidence for the latter is presented in this paper and depends upon the use of antibody localization with fluorescent markers in light microscopy and colloidal gold for scanning electron microscopy. The implications of the composition of collagen fibers for myocardial function are discussed in relation to intra-cellular and other extra-cellular structures.

Animals↗
PubMed1997

An in vitro model of the kitten retinogeniculate pathway.

An organotypic explant coculture method is described for the developing retinogeniculate pathway of the cat. Retinal explants and thalamic slices containing the dorsal lateral geniculate nucleus (LGN), derived from early postnatal kittens, can be grown in serum-free culture medium for several days. In such cultures, retinal ganglion cells (RGCs) and LGN neurons retained their age-specific morphological features and developed functional connections. Labeling of RGCs and their processes with DiI showed that all three major classes of RGCs (alpha/Y, beta/X, gamma/W) were present in cocultured retinal explants. Retinal axons readily regenerated into thalamic slices and, over time, developed arbors within the LGN. Retrograde labeling from the LGN traced the origin of these axons almost exclusively to alpha-cells in the retina. In vitro intracellular recordings indicated that LGN cells maintained their basic electrophysiological properties in coculture. Current injection generated action potentials, and, at hyperpolarized levels, it led to low-threshold Ca2+ spiking. Regenerated retinal axons also formed functional connections with LGN neurons. Electrical stimulation of the retinal explant elicited excitatory postsynaptic responses (EPSPs) in LGN cells. Drop application of specific glutamate antagonists indicated that EPSPs had both N-methyl-D-aspartate (NMDA) and non-NMDA receptor components. The morphology of the LGN neurons was examined after intracellular injections of biocytin during recording. Labeled cells were very similar to those of early postnatal kittens. Although, in general, they had relatively small soma and simple dendritic branching patterns, a few could be recognized as X- or Y-cells. Thus the coculture model can be used to assay the regenerative propensity of different types of RGCs during development.

Action Potentials↗