Cholinergic enhancement and increased selectivity of perceptual processing during working memory.

Using functional magnetic resonance imaging, we investigated the mechanism by which cholinergic enhancement improves working memory. We studied the effect of the cholinesterase inhibitor physostigmine on subcomponents of this complex function. Cholinergic enhancement increased the selectivity of neural responses in extrastriate cortices during visual working memory, particularly during encoding. It also increased the participation of ventral extrastriate cortex during memory maintenance and decreased the participation of anterior prefrontal cortex. These results indicate that cholinergic enhancement improves memory performance by augmenting the selectivity of perceptual processing during encoding, thereby simplifying processing demands during memory maintenance and reducing the need for prefrontal participation.

Complementary neural mechanisms for tracking items in human working memory.

Recognition of a specific visual target among equally familiar distracters requires neural mechanisms for tracking items in working memory. Event-related functional magnetic resonance imaging revealed evidence for two such mechanisms: (i) Enhanced neural responses, primarily in the frontal cortex, were associated with the target and were maintained across repetitions of the target. (ii) Reduced responses, primarily in the extrastriate visual cortex, were associated with stimulus repetition, regardless of whether the stimulus was a target or a distracter. These complementary neural mechanisms track the status of familiar items in working memory, allowing for the efficient recognition of a currently relevant object and rejection of irrelevant distracters.

Discrete cortical regions associated with knowledge of color and knowledge of action.

The areas of the brain that mediate knowledge about objects were investigated by measuring changes in regional cerebral blood flow (rCBF) using positron emission tomography (PET). Subjects generated words denoting colors and actions associated with static, achromatic line drawings of objects in one experiment, and with the written names of objects in a second experiment. In both studies, generation of color words selectively activated a region in the ventral temporal lobe just anterior to the area involved in the perception of color, whereas generation of action words activated a region in the middle temporal gyrus just anterior to the area involved in the perception of motion. These data suggest that object knowledge is organized as a distributed system in which the attributes of an object are stored close to the regions of the cortex that mediate perception of those attributes.

An area specialized for spatial working memory in human frontal cortex.

Working memory is the process of maintaining an active representation of information so that it is available for use. In monkeys, a prefrontal cortical region important for spatial working memory lies in and around the principal sulcus, but in humans the location, and even the existence, of a region for spatial working memory is in dispute. By using functional magnetic resonance imaging in humans, an area in the superior frontal sulcus was identified that is specialized for spatial working memory. This area is located more superiorly and posteriorly in the human than in the monkey brain, which may explain why it was not recognized previously.

Distributed and overlapping representations of faces and objects in ventral temporal cortex.

The functional architecture of the object vision pathway in the human brain was investigated using functional magnetic resonance imaging to measure patterns of response in ventral temporal cortex while subjects viewed faces, cats, five categories of man-made objects, and nonsense pictures. A distinct pattern of response was found for each stimulus category. The distinctiveness of the response to a given category was not due simply to the regions that responded maximally to that category, because the category being viewed also could be identified on the basis of the pattern of response when those regions were excluded from the analysis. Patterns of response that discriminated among all categories were found even within cortical regions that responded maximally to only one category. These results indicate that the representations of faces and objects in ventral temporal cortex are widely distributed and overlapping.

Age-related reductions in human recognition memory due to impaired encoding.

The participation of the medial temporal cortex and other cerebral structures in the memory impairment that accompanies aging was examined by means of positron emission tomography. Cerebral blood flow (rCBF) was measured during encoding and recognition of faces. Young people showed increased rCBF in the right hippocampus and the left prefrontal and temporal cortices during encoding and in the right prefrontal and parietal cortex during recognition. Old people showed no significant activation in areas activated during encoding in young people but did show right prefrontal activation during recognition. Age-related impairments of memory may be due to a failure to encode the stimuli adequately, which is reflected in the lack of cortical and hippocampal activation during encoding.

Distributed neural systems for the generation of visual images.

Visual perception of houses, faces, and chairs evoke differential responses in ventral temporal cortex. Using fMRI, we compared activations evoked by perception and imagery of these object categories. We found content-related activation during imagery in extrastriate cortex, but this activity was restricted to small subsets of the regions that showed category-related activation during perception. Within ventral temporal cortex, activation during imagery evoked stronger responses on the left whereas perception evoked stronger responses on the right. Additionally, visual imagery evoked activity in parietal and frontal cortex, but this activity was not content related. These results suggest that content-related activation during imagery in visual extrastriate cortex may be implemented by "top-down" mechanisms in parietal and frontal cortex that mediate the retrieval of face and object representations from long-term memory and their maintenance through visual imagery.

The effect of face inversion on activity in human neural systems for face and object perception.

The differential effect of stimulus inversion on face and object recognition suggests that inverted faces are processed by mechanisms for the perception of other objects rather than by face perception mechanisms. We investigated the face inversion using functional magnetic resonance imaging (fMRI). The principal effect of face inversion on was an increased response in ventral extrastriate regions that respond preferentially to another class of objects (houses). In contrast, house inversion did not produce a similar change in face-selective regions. Moreover, stimulus inversion had equivalent, minimal effects for faces in in face-selective regions and for houses in house-selective regions. The results suggest that the failure of face perception systems with inverted faces leads to the recruitment of processing resources in object perception systems, but this failure is not reflected by altered activity in face perception systems.

Distinct representations of eye gaze and identity in the distributed human neural system for face perception.

Face perception requires representation of invariant aspects that underlie identity recognition as well as representation of changeable aspects, such as eye gaze and expression, that facilitate social communication. Using functional magnetic resonance imaging (fMRI), we investigated the perception of face identity and eye gaze in the human brain. Perception of face identity was mediated more by regions in the inferior occipital and fusiform gyri, and perception of eye gaze was mediated more by regions in the superior temporal sulci. Eye-gaze perception also seemed to recruit the spatial cognition system in the intraparietal sulcus to encode the direction of another's gaze and to focus attention in that direction.

Attribute-based neural substrates in temporal cortex for perceiving and knowing about objects.

The cognitive and neural mechanisms underlying category-specific knowledge remain controversial. Here we report that, across multiple tasks (viewing, delayed match to sample, naming), pictures of animals and tools were associated with highly consistent, category-related patterns of activation in ventral (fusiform gyrus) and lateral (superior and middle temporal gyri) regions of the posterior temporal lobes. In addition, similar patterns of category-related activity occurred when subjects read the names of, and answered questions about, animals and tools. These findings suggest that semantic object information is represented in distributed networks that include sites for storing information about specific object attributes such as form (ventral temporal cortex) and motion (lateral temporal cortex).

'What' and 'where' in the human brain.

Multiple visual areas in the cortex of nonhuman primates are organized into two hierarchically organized and functionally specialized processing pathways, a 'ventral stream' for object vision and a 'dorsal stream' for spatial vision. Recent findings from positron emission tomography activation studies have localized these pathways within the human brain, yielding insights into cortical hierarchies, specialization of function, and attentional mechanisms.

Brain atrophy in hypertension. A volumetric magnetic resonance imaging study.

To determine whether hypertension, the predominant risk factor for stroke and vascular dementia, is associated with brain atrophy, magnetic resonance imaging (MRI) scans were performed to quantify brain volumes and cerebrospinal fluid spaces. Eighteen otherwise healthy, cognitively normal older hypertensive men (mean +/- SD age, 69 +/- 8 years, duration of hypertension 10-35 years) and 17 age-matched healthy, normotensive male control subjects were studied in a cross-sectional design. Axial proton-density image slices were analyzed using region-of-interest and segmentation analyses. The hypertensive subjects had significantly larger mean volumes of the right and left lateral ventricles (p less than 0.05, both absolute volume and volume normalized to intracranial volume) and a significantly smaller normalized mean left hemisphere brain volume (p less than 0.05) with a trend toward significance for a smaller normalized mean right hemisphere volume (p less than 0.09). Four hypertensive subjects and one healthy control subject were found to have severe periventricular hyperintensities on T2-weighted MRI images. When data for these subjects were removed from the analyses, the normalized lateral ventricle volumes remained significantly larger in the hypertensive group. Lateral ventricle enlargement was not related to age or use of diuretics in the hypertensive group nor to duration of hypertension between 10 and 24 years. Our findings suggest that long-standing hypertension results in structural changes in the brain. Longitudinal studies will determine whether MRI-associated changes are progressive and if such changes identify hypertensive subjects at increased risk for clinically apparent brain dysfunction.

Volumetric magnetic resonance imaging in men with dementia of the Alzheimer type: correlations with disease severity.

Using magnetic resonance imaging (MRI), we measured the volumes of various brain structures and cerebrospinal fluid (CSF) in 19 men with dementia of the Alzheimer type (DAT) and 18 healthy age-matched control men. The mean (+/- S.D) Mini-Mental State exam score (MMSE) of the DAT men was 16 +/- 7; 9 were mildly (MMSE > 20), 5 moderately (MMSE 10-20), and 5 severely (MMSE < 10) demented. Brain and CSF volumes were normalized as a percent of the traced intracranial volume to control for the relation of volumes of cerebral structures to head size, and analyzed statistically. The whole group of DAT subjects had significantly smaller mean cerebral brain matter and temporal lobe volumes (p < 0.05), and significantly larger mean ventricular and temporal lobe peripheral CSF volumes than did controls. Mean volumes of the subcortical nuclei did not differ significantly between groups, and mean volume of temporal lobe brain matter decreased significantly more than whole brain, suggesting regional loss of brain matter in DAT. Mildly demented DAT patients had significantly smaller mean cerebral brain matter and temporal lobe volumes and significantly larger volumes of lateral ventricles, and of temporal lobe peripheral CSF, than did controls. Neuropsychological measures of disease severity in DAT patients were significantly (p < 0.05) and appropriately correlated to volumes of cerebral brain matter and right lateral ventricle. These results suggest that in DAT: (i) significant brain atrophy is present early in the disease process, (ii) brain atrophy correlates with severity of cognitive impairment, and (iii) there is greater involvement of the telencephalic association system than whole brain, and there is relative sparing of the caudate, lenticular and thalamic nuclei.

A PET study of Turner's syndrome: effects of sex steroids and the X chromosome on brain.

Women with Turner's syndrome (TS) allow us to study the neurobiological associates of cognitive and behavioral abnormalities because they lack one/part of one X chromosome, and endogenous estrogen. We studied 13 healthy controls (mean age +/- SD, 28 +/- 6 years) and 16 TS subjects (mean age +/- SD, 26 +/- 6 years). We measured cognitive abilities using neuropsychological tests, and cerebral metabolic rates for glucose with positron emission tomography. Compared to controls, TS subjects had significant absolute hypermetabolism in most brain areas; however, normalized metabolism was significantly lower in TS subjects than controls in the insula and association neocortices bilaterally, and there were significant differences in functional metabolic associations of brain region pairs originating in occipital cortex bilaterally, and within the right hemisphere. There were significant correlations between right-left cognitive and metabolic asymmetries in the TS group. Also, within TS a preliminary analysis demonstrated "X chromosome dosage" effects in language ability and left temporal metabolism, asymmetry of right-left test scores, and parietal metabolism. We hypothesize that within TS: i) generalized brain hypermetabolism reflects global abnormalities in neuron packing; ii) neuronal abnormalities occur in association neocortex that differ in nature or extent from whole brain and are associated with significant differences in normalized metabolism; iii) cognitive deficits are related to brain metabolic abnormalities; and iv) social-behavioral problems may be related to abnormalities of brain metabolism. Moreover, in human brain the X chromosome involved in development of the association neocortices.

Relations between neuropsychological and cerebral metabolic asymmetries in early Alzheimer's disease.

Regional CMRglc (rCMRglc) values were determined with positron emission tomography (PET) in 10 patients with mild to moderate clinically diagnosed Alzheimer's disease (AD) and in 26 healthy controls. rCMRglc in frontal, parietal, and temporal association cortices were significantly more laterally asymmetrical in AD patients than in controls (p less than 0.05). Furthermore, lateral asymmetry of rCMRglc in AD patients but not in the control subjects correlated significantly with asymmetry of language and visuospatial functions such that lower left than right rCMRglc was associated with relatively greater impairment of language and vice versa. The results demonstrate that discrepancies between language and visuospatial deficits in patients with early AD are related to asymmetrical reductions in cerebral cortical glucose metabolism.

Regional cerebral glucose metabolism is normal in young adults with Down syndrome.

Regional CMRglc (rCMRglc) values were measured with [18F]2-fluoro-2-deoxy-D-glucose (18FDG) and positron emission tomography (PET), using a Scanditronix PC-1024-7B scanner, in 14 healthy, noninstitutionalized subjects with trisomy 21 (Down syndrome; DS) (mean age 30.0 years, range 25-38 years) and in 13 sex-matched, healthy volunteers (mean age 29.5 years, range 22-38 years). In the DS group, mean mental age on the Peabody Picture Vocabulary Test was 7.8 years and dementia was not present. Resting rCMRglc was determined with eyes covered and ears occluded in a quiet, darkened room. Global gray CMRglc equaled 8.76 +/- 0.76 mg/100 g/min (mean +/- SD) in the DS group as compared with 8.74 +/- 1.19 mg/100 g/min in the control group (p greater than 0.05). Gray matter regional measurements also did not differ between groups. The ratio of rCMRglc to global CMRglc, calculated to reduce the variance associated with absolute rCMRglc, and right/left ratios did not show any consistent differences. These results show that healthy young DS adults do not have alterations in regional or global brain glucose metabolism, as measured with 18FDG and PET, prior to an age at which the neuropathological changes in Alzheimer disease are reported to occur.

Early detection of Alzheimer's disease: a statistical approach using positron emission tomographic data.

Correlational analysis of regional cerebral glucose metabolism (rCMRglc) obtained by high-resolution positron emission tomography (PET) has demonstrated reduced neocortical rCMRglc interactions in mildly/moderately demented patients with probable Alzheimer's disease (AD). Thus, identification of individual differences in patterns of rCMRglc interactions may be important for the early detection of AD, particularly among individuals at greater risk for developing AD (e.g., those with a family history of AD). Recently, a statistical procedure, using multiple regression and discriminant analysis, was developed to assess individual differences in patterns of rCMRglc interdependencies. We applied this new statistical procedure to resting rCMRglc PET data from mildly/moderately demented patients with probable AD and age/sex-matched controls. The aims of the study were to identify a discriminant function that would (a) distinguish patients from controls and (b) identify an AD pattern in an individual at risk for AD with isolated memory impairment whose initial PET scan showed minor abnormalities, but whose second scan showed parietal hypometabolism, coincident with further cognitive decline. Two discriminant functions, reflecting interactions involving regions most involved in reduced correlations in probable AD, correctly classified 87% of the patients and controls, and successfully identified the first scan of the at-risk individual as AD (probability > 0.70). The results suggest that this statistical approach may be useful for the early detection of AD.

Nature of mental retardation and dementia in Down syndrome: study with PET, CT, and neuropsychology.

Recent evidence suggests that Alzheimer's disease is an etiologically heterogeneous disorder. A human model of Alzheimer's disease exists that avoids such problems of etiologic heterogeneity. Down syndrome (DS), trisomy 21, is a genetic disorder in which an extra portion of chromosome 21 leads to mental retardation, short stature, and phenotypic abnormalities. Prior investigations by others have shown that DS subjects over 40 years of age demonstrate neuropathologic and neurochemical defects postmortem that are virtually indistinguishable from those found in brains of Alzheimer's disease patients and a universal cognitive deterioration more severe in demented than nondemented older DS subjects. In our study, these nondemented older DS subjects show a distinctive pattern of age-related deficits, while a more global pattern is seen in demented older DS subjects. Dementia occurs in 40% of older DS subjects. We find that in older demented DS subjects positron emission tomography (PET) shows identical patterns of abnormal glucose metabolism as those described previously in Alzheimer's disease patients, selectively involving the phylogenetically newer association areas of parietal and temporal neocortices but sparing primary sensory and motor regions. Further, we find in older demented DS patients quantitative computer-assisted tomography (CT) indicates accelerated neuronal loss and brain atrophy, similar to that previously shown in Alzheimer's disease patients. As a potential use of the DS model, we observed a case of DS with dementia but without mental retardation. This case suggests that expression of dementia in DS may involve genes on chromosome 21 other than in the "obligatory" distal segment of the q arm. Alternatively, differential expression of genes on the q arm of chromosome 21 might cause dementia without phenotypic features and mental retardation.

Activation of cerebral blood flow during a visuoperceptual task in patients with Alzheimer-type dementia.

Changes in regional cerebral blood flow (rCBF) associated with a face-matching task were examined using positron emission tomography (PET) and H2(15)O in 7 patients with mild-moderate dementia of the Alzheimer type (DAT) and in 8 healthy age-matched controls. rCBF was normalized to whole brain flow and pixel-by-pixel difference images were computed by contrasting flow during a control task to flow during face matching. Both patients and controls showed bilateral rCBF increases in occipitotemporal extrastriate cortex during face matching. The magnitude of these increases was not significantly different between the groups. In addition, the patients showed greater rCBF activation in regions of occipital and frontal cortex. These results show that early in the course of DAT, patients utilize extrastriate cortex to perform a visuoperceptual task, as do control subjects but also show rCBF increases in additional cortical areas. Activation of these additional areas of cortex in the patients may reflect an increased attentional load during face matching due to their reduced cognitive capacity.

Low glucose metabolism during brain stimulation in older Down's syndrome subjects at risk for Alzheimer's disease prior to dementia.

OBJECTIVE: Down's syndrome is characterized by the genetically programmed accumulation of substantial Alzheimer's disease neuropathology after age 40 and the development of early dementia years later, providing a unique human model to investigate the preclinical phases of Alzheimer's disease. Older nondemented adults with Down's syndrome show normal rates of regional cerebral glucose metabolism at rest before the onset of dementia, indicating that their neurons maintain function at rest. The authors hypothesized that an audiovisual stimulation paradigm, acting as a stress test, would reveal abnormalities in cerebral glucose metabolism before dementia in the neocortical parietal and temporal areas most vulnerable to Alzheimer's disease. METHOD: Regional cerebral glucose metabolism was assessed by means of positron emission tomography (PET) with [18F]fluorodeoxyglucose in eight younger (mean age = 35 years, SD = 2) and eight older (mean age = 50, SD = 7) healthy, nondemented adults with trisomy 21 Down's syndrome. PET scans were performed at rest and during audiovisual stimulation in the same scanning session. Levels of general intellectual functioning and compliance were similar in the two groups. RESULTS: At rest the two groups showed no difference in glucose metabolism in any cerebral region. In contrast, during audiovisual stimulation the older subjects with Down's syndrome had significantly lower glucose metabolic rates in the parietal and temporal cortical areas. CONCLUSIONS: Abnormalities in cerebral metabolism during stimulation appeared in the first cortical regions typically affected in Alzheimer's disease. These results indicate that a stress test paradigm can detect metabolic abnormalities in the preclinical stages of Alzheimer's disease despite normal cerebral metabolism at rest.