Biomedical subjects

A R McIntosh

Publications and source records attributed to A R McIntosh.

At least 55 records · Page 3Linked to original sources

PubMed1998

Functional brain imaging of episodic and semantic memory with positron emission tomography.

Human memory is composed of several independent but interacting systems. These include a system for remembering general knowledge, semantic memory, and a system for recollection of personal events, episodic memory. The results of positron emission tomography (PET) studies of regional cerebral blood flow indicate that networks of distributed brain regions subserve episodic and semantic memory. Some networks seem to be generally engaged in memory processes whereas the involvement of others is specific to factors such as the type of information to be remembered or the level of retrieval success. The PET findings help to understand memory dysfunction (a) by showing that multiple brain regions are involved in different memory processes and (b) by sharpening the interpretation of the functional role of different brain regions.

Brain↗

PubMed1998

Networks of domain-specific and general regions involved in episodic memory for spatial location and object identity.

Positron emission tomography (PET) was used to investigate human episodic memory for spatial location and object identity. We measured regional cerebral bloodflow (rCBF) while subjects engaged in perceptual matching of the location or the identity of line drawings of objects. Perceptual matching also involved incidental encoding of the presented information. Subsequently, rCBF was measured when subjects retrieved the location or the identity of these objects from memory. Using the multivariate partial least squares image analysis, we identified three patterns of activity across the brain that allowed us to distinguish structures that are differentially involved in processing spatial location and object identity from structures that are differentially involved in encoding and retrieval but operate across both domains. Domain-specificity was evident by increased rCBF during the processing of spatial location in the right middle occipital gyrus, supramarginal gyrus, and superior temporal sulcus, and by increased rCBF during the processing of object identity in portions of bilateral lingual and fusiform gyri. There was a nearly complete overlap between domain-specific dorsal and ventral extrastriate cortex activations during perceptual matching and memory retrieval. Evidence of domain-specificity was also found in the prefrontal cortex and the left hippocampus, but the effect interacted with encoding and retrieval. Domain-general structures included bilateral superior temporal cortex regions, which were preferentially activated during encoding, and portions of bilateral middle and inferior frontal gyri, which were preferentially activated during retrieval. Together, our data suggest that encoding and retrieval in episodic memory depend on the interplay between domain-specific structures, most of which are involved in memory as well as perception, and domain-general structures, some of which operate more at encoding and others more at retrieval.

Adult↗

PubMed1998

Analysis of neural interactions explains the activation of occipital cortex by an auditory stimulus.

Analysis of neural interactions explains the activation of occipital cortex by an auditory stimulus. J. Neurophysiol. 80: 2790-2796, 1998. Large-scale neural interactions were characterized in human subjects as they learned that an auditory stimulus signaled a visual event. Once learned, activation of left dorsal occipital cortex (increased regional cerebral blood flow) was observed when the auditory stimulus was presented alone. Partial least-squares analysis of the interregional correlations (functional connectivity) between the occipital area and the rest of the brain identified a pattern of covariation with four dominant brain areas that could have mediated this activation: prefrontal cortex (near Brodmann area 10, A10), premotor cortex (A6), superior temporal cortex (A41/42), and contralateral occipital cortex (A18). Interactions among these regions and the occipital area were quantified with structural equation modeling to identify the strongest sources of the effect on left occipital activity (effective connectivity). Learning-related changes in feedback effects from A10 and A41/42 appeared to account for this change in occipital activity. Influences from these areas on the occipital area were initially suppressive, or negative, becoming facilitory, or positive, as the association between the auditory and visual stimuli was acquired. Evaluating the total effects within the functional models showed positive influences throughout the network, suggesting enhanced interactions may have primed the system for the now-expected visual discrimination. By characterizing both changes in activity and the interactions underlying sensory associative learning, we demonstrated how parts of the nervous system operate as a cohesive network in learning about and responding to the environment.

Acoustic Stimulation↗

PubMed1997

Age-related differences in effective neural connectivity during encoding and recall.

Age-related differences in brain activity may reflect local neural changes in the regions involved or they may reflect a more global transformation of brain function. To investigate this issue, we applied structural equation modeling to the results of a positron emission tomography (PET) study in which young and old adults encoded and recalled word pairs. In the young group there was a shift from positive interactions involving the left prefrontal cortex during encoding to positive interactions involving the right prefrontal cortex during recall, whereas in the old group frontal interactions were mixed during encoding and bilaterally positive during recall. The present results suggest that age-related changes in neural activation are partly due to age-related changes in effective connectivity in the neural network underlying the task.

Adult↗

PubMed1997

Induction of free radicals in hepatocytes, mitochondria and microsomes of rats by ochratoxin A and its analogs.

Oxidative damage may be one of the manifestations of cellular damage in the toxicity of ochratoxin A (OA). OA; its three natural analogs, OB, OC and O alpha; and three synthetic analogs, the ethyl amide of OA (OE-OA), O-methylated OA (OM-OA), and the lactone-opened OA (OP-OA) were used to study free radical generation in hepatocytes, mitochondria and microsomes from rats. Electron paramagnetic resonance spectroscopy (EPR) using alpha-(4-pyridyl-1-oxide)-N-tert-butyl nitrone (4-POBN) as a spin trapping agent showed an enhanced free radical generation due to the addition of NADPH to the microsomes. An EPR signal was not observed in the mitochondria and hepatocyte samples when they were treated with a variety of agents. Addition of OM-OA together with NADPH and Fe3+ to the microsomes resulted in a strong EPR signal compared with the other analogs, whereas the signal could be quenched by the addition of catalase. OM-OA does not have a dissociable phenolate group and does not chelate Fe3+. The spin adduct hyperfine splitting constants indicated the presence of alpha-hydroxyethyl radicals resulting from generated hydroxyl radicals, which were trapped by 4-POBN. The results also suggested that the production of hydroxyl radicals by OA does not require a dissociable phenolate group or the prior formation of an OA-Fe complex.

Animals↗

PubMed1997

Age-related differences in neural activity during memory encoding and retrieval: a positron emission tomography study.

Positron emission tomography (PET) was used to compare regional cerebral blood flow (rCBF) in young (mean 26 years) and old (mean 70 years) subjects while they were encoding, recognizing, and recalling word pairs. A multivariate partial-least-squares (PLS) analysis of the data was used to identify age-related neural changes associated with (1) encoding versus retrieval and (2) recognition versus recall. Young subjects showed higher activation than old subjects (1) in left prefrontal and occipito-temporal regions during encoding and (2) in right prefrontal and parietal regions during retrieval. Old subjects showed relatively higher activation than young subjects in several regions, including insular regions during encoding, cuneus/precuneus regions during recognition, and left prefrontal regions during recall. Frontal activity in young subjects was left-lateralized during encoding and right-lateralized during recall [hemispheric encoding/retrieval asymmetry (HERA)], whereas old adults showed little frontal activity during encoding and a more bilateral pattern of frontal activation during retrieval. In young subjects, activation in recall was higher than that in recognition in cerebellar and cingulate regions, whereas recognition showed higher activity in right temporal and parietal regions. In old subjects, the differences in blood flow between recall and recognition were smaller in these regions, yet more pronounced in other regions. Taken together, the results indicate that advanced age is associated with neural changes in the brain systems underlying encoding, recognition, and recall. These changes take two forms: (1) age-related decreases in local regional activity, which may signal less efficient processing by the old, and (2) age-related increases in activity, which may signal functional compensation.

Adult↗

PubMed1997

Cognitive subtractions may not add up: the interaction between semantic processing and response mode.

Determining the areas of brain activity associated with cognitive processing has typically relied on the use of a subtraction paradigm, which is based on the premise that the neural processes underlying behavior are additive. If the additivity assumption is valid then brain regions associated with a semantic processing task should be the same regardless of how participants make a response. To investigate this proposition, participants underwent six PET scans, in which they made semantic or letter word judgments, responding "yes" or "no" in three different modes: mouse-clicking, spoken response, or silent thought. Analyses showed an increase in regional cerebral blood flow associated with semantic processing in the left inferior frontal cortex, anterior cingulate, and right cerebellum for all three response conditions. However, there was a significant interaction: the greatest increase was observed in the mouse-click condition and the weakest change seen with silent thought. Moreover, other areas of the brain were uniquely activated for each response mode. The results indicate that different areas of the brain were recruited for semantic processing depending on how participants had to organize their responses. Implications for the additivity assumption and methods of analysis to be used in conjunction with the subtraction technique are discussed.

Adult↗

PubMed1997

Brain regions differentially involved in remembering what and when: a PET study.

Recollecting a past episode involves remembering not only what happened but also when it happened. We used positron emission tomography (PET) to directly contrast the neural correlates of item and temporalorder memory. Subjects studied a list of words and were then scanned while retrieving information about what words were in the list or when they occurred within the list. Item retrieval was related to increased neural activity in medial temporal and basal forebrain regions, whereas temporal-order retrieval was associated with activations in dorsal prefrontal, cuneus/precuneus, and right posterior parietal regions. The dissociation between temporal and frontal lobe regions confirms and extends previous lesion data. The results show that temporal-order retrieval involves a network of frontal and posterior brain regions.

Adult↗

PubMed1997

Lateralization and behavioral correlation of changes in regional cerebral blood flow with classical conditioning of the human eyeblink response.

Laterality of changes in regional cerebral blood flow (rCBF) during classical conditioning of the human eyeblink response was studied and changes in rCBF were correlated with conditioned responses. In 10 normal volunteers, rCBF was mapped with positron emission tomography and H2(15)O during pairings of a binaural tone conditioned stimulus and an air puff unconditioned stimulus to the left eye. Control conditions consisted of explicitly unpaired presentations of the tone and air puff before (control) and after (extinction) pairings. During pairings, rCBF increased significantly in right primary auditory cortex (contralateral to air puff) and decreased significantly in left and right cerebellar cortex. There were also increases in rCBF in right auditory association cortex and left temporoccipital cortex. Decreases in rCBF were noted bilaterally in the temporal poles and in the left prefrontal cortex. Positive correlations between changes in rCBF and percent conditioned responses were located in middle cerebellum, right superior temporal cortex, left dorsal premotor cortex, right middle cingulate, and right superior temporal cortex. There were negative correlations in left inferior prefrontal cortex, left middle prefrontal cortex, and right inferior parietal cortex. The data replicate our previous findings of lateralized changes in rCBF following presentations of a binaural tone and air puff to the right eye and indicate that there are pairing-specific changes in primary auditory cortex and cerebellum that are not unique to the left or right hemisphere but are a function of the side of training. The commonalities as well as differences in regional involvement in our present and previous experiment as well as in other eyeblink studies illustrate the advantage of functional neuroimaging to quantify different strategies used by the brain to perform seemingly similar functions. Indeed, the data support the notion that learning-related changes can be detected in a number of specific, but not necessarily invariant, brain regions, and that the involvement of any one region is dependent on the characteristics of the particular learning situation.

Acoustic Stimulation↗

PubMed1996

Brain cognition and metabolism in Down syndrome adults in association with development of dementia.

To identify changes in brain functions associated with the development of dementia, brain metabolism and cognition were assessed repeatedly in 12 adults with Down syndrome (DS) using positron emission tomography and neuropsychological tests. Ten subjects remained non-demented (ND) and showed no significant changes over time in cognitive measures or in cerebral metabolism. Two subjects developed dementia after 7 years. Brain functions were relatively stable prior to the onset of dementia; after the onset of dementia, both cognitive function and glucose metabolism in parietal and temporal brain regions known to be vulnerable to Alzheimer disease (AD) showed a rapid linear decline. These findings support the concept that brain functions are stable over time in ND individuals with DS and that decline of brain functions in DS subjects with dementia follows two distinct phases that correspond to the clinical progression of AD. This may have implications for timing of new therapeutic strategies.

Adult↗

PubMed1996

Free radical generation as induced by ochratoxin A and its analogs in bacteria (Bacillus brevis).

Lipid peroxidation is considered as one of the manifestations of cellular damage in the toxicity of ochratoxin A (OA). OA; its three natural analogs, OB, OC, and Oalpha; and four synthetic analogs, d-OA, the ethylamide of OA (OE-OA), O-methylated OA (OM-OA), and the lactone-opened OA (OP-OA) were used to study free radical generation in bacteria with Bacillus brevis as a model system. The uptake of the different ochratoxins by B. brevis varied substantially depending on the molecular structures. Electron paramagnetic resonance spectroscopy using alpha-(4-pyridyl-1-oxide)-N-tert-butyl nitrone as a spin trapping agent showed an enhanced free radical generation due to the addition of OA and most of the analogs. The EPR signals could be further enhanced by the addition of Ca2+, a calcium ionophore and an ATPase uncoupler, whereas they were eliminated by incubating the growing cells with vitamin E. The spin adduct hyperfine splitting constants indicate the presence of alpha-hydroxyethyl radicals resulting from generated hydroxyl radicals, which are trapped by alpha-(4-pyridyl-1-oxide)-N-tert-butyl nitrone. The results further suggest that OA induces free radical production in this model system by enhancing the permeability of the cellular membrane to Ca2+.

Bacillus↗

PubMed1996

General and specific brain regions involved in encoding and retrieval of events: what, where, and when.

Remembering an event involves not only what happened, but also where and when it occurred. We measured regional cerebral blood flow by positron emission tomography during initial encoding and subsequent retrieval of item, location, and time information. Multivariate image analysis showed that left frontal brain regions were always activated during encoding, and right superior frontal regions were always activated at retrieval. Pairwise image subtraction analyses revealed information-specific activations at (i) encoding, item information in left hippocampal, location information in right parietal, and time information in left fusiform regions; and (ii) retrieval, item in right inferior frontal and temporal, location in left frontal, and time in anterior cingulate cortices. These results point to the existence of general encoding and retrieval networks of episodic memory whose operations are augmented by unique brain areas recruited for processing specific aspects of remembered events.

Adult↗

PubMed1996

Network analysis of positron emission tomography regional cerebral blood flow data: ensemble inhibition during episodic memory retrieval.

Two important objectives in the neuroscience of memory are (1) identification of neural pathways involved in memory processes; and (2) characterization of the pattern of interactions between these pathways. Functional neuroimaging can contribute to both of these goals. Using image subtraction analysis of regional cerebral blood flow data measured with positron emission tomography, we identified brain regions that changed activity during episodic memory retrieval (visual work recognition). Relative to a baseline reading task, decreased activity was observed in bilateral prefrontal, bilateral anterior and posterior temporal, and posterior cingulate cortices. Brain regions showing increased activity were the right prefrontal (different from deactivated regions), left anterior cingulate, and left occipital cortices, and vermis of cerebellum. We then performed a network analysis with structural equation modeling to test the hypothesis that regional decreases came about through active inhibition by regions showing increased activity during retrieval. This analysis demonstrated that the influence of activated regions on deactivated regions was more negative during retrieval than during reading, confirming the inhibition hypothesis. Such confirmation could not have been made from the subtraction analysis alone because decreases can come about, at the very least, through reduction of functional influences as well as by active inhibition. The concepts of ensemble excitation and inhibition, as defined through network analysis, are introduced. We argue that is is critical to examine the combined pattern of excitatory and inhibitory influences to fully appreciate the neural basis of episodic memory.

Analysis of Variance↗

PubMed1996

Activation of medial temporal structures during episodic memory retrieval.

Medial temporal lobe structures have been implicated in human episodic memory. Patients with medial temporal lesions show memory deficits, and functional neuroimaging studies have revealed activation in this region during episodic encoding and retrieval when data are averaged over a sample of subjects. The relevance of such observations for memory performance has remained unclear, however. Here we have used positron emission tomography (PET) to examine cerebral blood flow related to verbal episodic retrieval. We observed strong positive correlations between retrieval and blood flow in left medial temporal structures in individual normal human subjects. In addition, multivariate analysis showed that regions in the left medial temporal lobe were dominant components of a pattern of brain regions that distinguished a high-retrieval condition from conditions of lower retrieval. These results suggest that medial temporal activity is related to retrieval success rather than retrieval attempt, possibly by reflecting reactivation of stored patterns.

Brain Mapping↗

PubMed1996

Sex differences in human brain morphometry and metabolism: an in vivo quantitative magnetic resonance imaging and positron emission tomography study on the effect of aging.

BACKGROUND: There are significant age and sex effects in cognitive ability and brain disease. However, sex differences in aging of human brain areas associated with nonreproductive behavior have not been extensively studied. We hypothesized that there would be significant sex differences in aging of brain areas that subserve speech, visuospatial, and memory function. METHODS: We investigated sex differences in the effect of aging on human brain morphometry by means of volumetric magnetic resonance imaging and on regional cerebral metabolism for glucose by positron emission tomography. In the magnetic resonance imaging study, we examined 69 healthy right-handed subjects (34 women and 35 men), divided into young (age range, 20 to 35 years) and old (60 to 85 years) groups. In the positron emission tomography study, we investigated 120 healthy right-handed subjects (65 women and 55 men) aged 21 to 91 years. RESULTS: In the magnetic resonance imaging study, age-related volume loss was significantly greater in men than women in whole brain and frontal and temporal lobes, whereas it was greater in women than men in hippocampus and parietal lobes. In the positron emission tomography study, significant sex differences existed in the effect of age on regional brain metabolism, and asymmetry of metabolism, in the temporal and parietal lobes, Broca's area, thalamus, and hippocampus. CONCLUSIONS: We found significant sex differences in aging of brain areas that are essential to higher cognitive functioning. Thus, our findings may explain some of the age-sex differences in human cognition and response to brain injury and disease.

Adult↗

PubMed1996

Spatial pattern analysis of functional brain images using partial least squares.

This paper introduces a new tool for functional neuroimage analysis: partial least squares (PLS). It is unique as a multivariate method in its choice of emphasis for analysis, that being the covariance between brain images and exogenous blocks representing either the experiment design or some behavioral measure. What emerges are spatial patterns of brain activity that represent the optimal association between the images and either of the blocks. This process differs substantially from other multivariate methods in that rather than attempting to predict the individual values of the image pixels, PLS attempts to explain the relation between image pixels and task or behavior. Data from a face encoding and recognition PET rCBF study are used to illustrate two types of PLS analysis: an activation analysis of task with images and a brain-behavior analysis. The commonalities across the two analyses are suggestive of a general face memory network differentially engaged during encoding and recognition. PLS thus serves as an important extension by extracting new information from imaging data that is not accessible through other currently used univariate and multivariate image analysis tools.

Algorithms↗

PubMed1996

The neural correlates of intentional learning of verbal materials: a PET study in humans.

The purpose of this study was to identify the brain regions invoked when subjects attempt to learn verbal materials for a subsequent memory test. Twelve healthy subjects undertook two different tasks: reading and encoding of word pairs, while they were being scanned using [15O]H2O positron emission tomography (PET). As expected, the encoding pairs were remembered much better (recall 39% vs. 8%; P < 0.001) than reading pairs in a subsequent memory test. The encoding scans, as compared to reading scans, showed activation of the left prefrontal cortex, the anterior cingulate cortex and the left medial temporal cortex. The left prefrontal activations were in two discrete regions: (i) a left anterior and inferior left prefrontal (Brodmann's areas 45, 46) which we attribute to semantic processing; and (ii) a left posterior mid-frontal region (BA 6, 44) which may reflect rote rehearsal. We interpret the data to suggest that when subjects use cognitive strategies of semantic processing and rote-rehearsal to learn words, they invoke discrete regions of the left prefrontal cortex. And this activation of the left prefrontal cortex along with the medial temporal region leads to a neurophysiological memory trace which can be used to guide subsequent memory retrieval.

Adult↗

PubMed1996

Semiquinone free radical formation by daunorubicin aglycone incorporated into the cellular membranes of intact Chinese hamster ovary cells.

The production of semiquinone free radicals has been measured by electron paramagnetic resonance spectroscopy (EPR) in Chinese hamster ovary cells in which 7-hydroxy daunorubicin aglycone had been incorporated. The highly lipophilic daunorubicin aglycone was incorporated into the cellular membrane by swirling a cell suspension over a thin layer of daunorubicin aglycone. Thus, the observed semiquinone free radical was likely formed directly in the lipophilic environment of the cellular membrane. The linewidth of the observed EPR signal suggested that a neutral protonated semiquinone species was formed. In the presence of the cell-impermeant paramagnetic line broadening agent chromium(III) oxalate, no detectable signal was observed. This result indicates that even though the semiquinone is embedded in the membrane, it is still partly accessible to the external chromium(III) oxalate. Analysis of chloroform extracts of the cells after EPR experiments indicated that daunorubicin aglycone was extensively metabolized. The results of a growth inhibition assay carried out on cells into which daunorubicin aglycone had been incorporated showed almost no effect on cell growth. This result indicates that in spite of significant daunorubicin aglycone-induced radical formation taking place directly in the cell membrane, little cell damage results.

Animals↗