Valuating other people's emotional face expression: a combined functional magnetic resonance imaging and electroencephalography study.

Reading the facial expression of other people is a fundamental skill for social interaction. Human facial expressions of emotions are readily recognized but may also evoke the same experiential emotional state in the observer. We used event-related functional magnetic resonance imaging and multi-channel electroencephalography to determine in 14 right-handed healthy volunteers (29+/-6 years) which brain structures mediate the perception of such a shared experiential emotional state. Statistical parametric mapping showed that an area in the dorsal medial frontal cortex was specifically activated during the perception of emotions that reflected the seen happy and sad emotional face expressions. This area mapped to the pre-supplementary motor area which plays a central role in control of behavior. Low resolution brain electromagnetic tomography-based analysis of the encephalographic data revealed that the activation was detected 100 ms after face presentation onset lasting until 740 ms. Our observation substantiates recently emerging evidence suggesting that the subjective perception of an experiential emotional state-empathy-is mediated by the involvement of the dorsal medial frontal cortex.

Neural correlates of religious experience.

The commonsense view of religious experience is that it is a preconceptual, immediate affective event. Work in philosophy and psychology, however, suggest that religious experience is an attributional cognitive phenomenon. Here the neural correlates of a religious experience are investigated using functional neuroimaging. During religious recitation, self-identified religious subjects activated a frontal-parietal circuit, composed of the dorsolateral prefrontal, dorsomedial frontal and medial parietal cortex. Prior studies indicate that these areas play a profound role in sustaining reflexive evaluation of thought. Thus, religious experience may be a cognitive process which, nonetheless, feels immediate.

Cerebral networks in sensorimotor disturbances.

Increasing evidence suggests that the human brain employs multiple, interconnected brain areas for information processing and control of behavior, including the performance of laboratory tasks. Brain diseases are expected to affect these networks directly by interference and indirectly as a consequence of deficit compensation. Covariance analyses applied to functional brain imaging data open the opportunity to study neural networks and their disease-related changes in the human brain. Here, we review our analytic approach based on principal component analysis (PCA) to address such questions. We will discuss its methodological foundations and applications in patients with sensorimotor disorders. We will show that PCA in combination with, both, hypothesis-driven testing and correlation statistics provides a powerful tool for elucidating disease-related abnormalities and postlesional reorganization of neural networks in the human brain.

Disturbed functional brain interactions underlying deficient tactile object discrimination in Parkinson's disease.

Somatosensory discrimination of cuboid objects was studied in a group of healthy volunteers and patients with Parkinson's disease using regional cerebral blood flow (rCBF) measurements obtained with positron emission tomography (PET) and 15O labeled water [H2 15O]. A 6-[18F]-fluoro-L-dopa (FDOPA) PET scan demonstrated that the patients may be grouped into those with normal and those with abnormally lowA FDOPA uptake in the caudate nucleus. The categorical group comparisons revealed that task-induced rCBF increases were deficient in bilateral motor and sensory cortical areas in the Parkinson patients. Moreover, deficient rCBF increases were evident in the mesial and right dorsolateral prefrontal cortex for patients in a more advanced disease state, who showed low FDOPA uptake in the caudate nucleus. A principal component analysis (PCA), performed on the rCBF data, identified three patterns (principal components, PCs) that differentiated patients from normals. The first PC represented a right-hemisphere dominant, bilateral group of brain areas known to be involved in tactile exploration. A second PC reflected a cortical-subcortical pattern of functional interactions, comprising cortical areas important for working memory processes. The third group-differentiating PC revealed a pattern of functional interactions involving bilateral temporo-parieto-occipital association cortices, which was consistent with a hypothesized supramodal network necessary for object discrimination. In an additional subgroup analysis, greater expression of the third PC pattern predicted greater caudate FDOPA uptake in patients. Our neuroimaging data revealed a disturbance of distinct patterns of brain functional interactions related to the sensorimotor deficit in Parkinson's disease and to deficits of cognitive information processing deficits in the more advanced stage of Parkinson's disease.

The role of diaschisis in stroke recovery.

BACKGROUND AND PURPOSE: Recovery from hemiparesis after stroke has been shown to involve reorganization in motor and premotor cortical areas. However, whether poststroke recovery also depends on changes in remote brain structures, ie, diaschisis, is as yet unresolved. To address this question, we studied regional cerebral blood flow in 7 patients (mean+/-SD age, 54+/-8 years) after their first hemiparetic stroke. METHODS: We analyzed imaging data voxel by voxel using a principal component analysis by which coherent changes in functional networks could be disclosed. Performance was assessed by a motor score and by the finger movement rate during the regional cerebral blood flow measurements. RESULTS: The patients had recovered (P<0. 001) from severe hemiparesis after on average 6 months and were able to perform sequential finger movements with the recovered hand. Regional cerebral blood flow at rest differentiated patients and controls (P<0.05) by a network that was affected by the stroke lesion. During blindfolded performance of sequential finger movements, patients were differentiated from controls (P<0.05) by a recovery-related network and a movement-control network. These networks were spatially incongruent, involving motor, sensory, and visual cortex of both cerebral hemispheres, the basal ganglia, thalamus, and cerebellum. The lesion-affected and recovery-related networks overlapped in the contralesional thalamus and extrastriate occipital cortex. CONCLUSIONS: Motor recovery after hemiparetic brain infarction is subserved by brain structures in locations remote from the stroke lesion. The topographic overlap of the lesion-affected and recovery-related networks suggests that diaschisis may play a critical role in stroke recovery.

Reorganized cerebral metabolic interactions in temporal lobe epilepsy.

Patients with left temporal lobe epilepsy demonstrate language impairments that are not well understood. To explore abnormal patterns of brain functional connections with respect to language processing, we applied a principal component analysis to resting regional cerebral metabolic data obtained with positron emission tomography in patients with right- and left-sided temporal lobe epilepsy and controls. Two principal components were expressed differentially among the groups. One principal component comprised a pattern of metabolic interactions involving left inferior frontal and left superior temporal regions-corresponding to Broca's and Wernicke's areas, respectively-and right mesial temporal cortex and right thalamus. Functional couplings between these brain regions were abnormally enhanced in the left-sided epilepsy patients. The right thalamic left superior temporal coupling was also abnormally enhanced in the right-sided epilepsy patients, but differentially from that in the left-sided patients. The other principal component was characterized by a pattern of metabolic interactions involving right and left mid prefrontal and right superior temporal cortex. Although both the right- and left-sided epilepsy patients showed decreased functional couplings between left mid prefrontal and the other brain regions, a weaker right-left mid prefrontal coupling in the left-sided epilepsy patients best distinguished them from the right-sided patients. The two mutually independent, abnormal metabolic patterns each predicted verbal intelligence deficits in the patients. The findings suggest a site-dependent reorganization of two independent, language-subserving pathways in temporal lobe epilepsy.

PET reveals occipitotemporal pathway activation during elementary form perception in humans.

To define brain regions involved in feature extraction or elementary form perception, regional cerebral blood flow (rCBF) was measured using positron emission tomography (PET) in subjects viewing two classes of achromatic textures. Textures composed of local features (e.g. extended contours and rectangular blocks) produced activation or increased rCBF along the occipitotemporal pathway relative to textures with the same mean luminance, contrast, and spatial-frequency content but lacking organized form elements or local features. Significant activation was observed in striate, extrastriate, lingual, and fusiform cortices as well as the hippocampus and brain stem. On a scan-by-scan basis, increases in rCBF shifted from the occipitotemporal visual cortices to medial temporal (hippocampus) and frontal lobes with increased exposure to only those textures containing local features. These results suggest that local feature extraction occurs throughout the occipitotemporal (ventral) pathway during extended exposure to visually salient stimuli, and may indicate the presence of similar receptive-field mechanisms in both occipital and temporal visual areas of the human brain.

Dynamic scanning of 15O-butanol with positron emission tomography can identify regional cerebral activations.

To determine task-specific activations of the human brain in individual subjects, we applied pixel-by-pixel t-map statistics to the regional cerebral perfusion data obtained sequentially by dynamic scanning of [15O]-butanol with positron emission tomography (PET). The listmode data were binned into frames of 2 sec, and multiple corresponding pixel-by-pixel activation-minus-control subtractions were used for t-map calculation. The subtraction frames covering 10-40 sec after tracer arrival in the brain showed the activation-related increase of regional cerebral perfusion. A mismatch of the activation and control data by 2 sec resulted in a mean error of <5% of the integrated activity increase. To validate these results, we simulated images with a spatial resolution and signal-to-noise ratio equivalent to that of the [15O]-butanol subtraction images. By means of these simulated images, we determined the minimal data requirements for t-map analysis, the degree of spatial correlations in the image matrix, and the distribution of noise in the t-maps. The simulation results provided a measure to estimate the significance of regional cerebral perfusion changes recorded with [15O]-butanol. The location and spatial extent of regional cerebral activations obtained from dynamic data corresponded closely to those obtained with quantitative measurements of regional cerebral blood flow (rCBF). Our results show that statistical parametric mapping of [15O]-butanol scanning data allows the detection of significant, task-specific brain activations in single activation-control comparisons in individual subjects.

Enhanced regional cerebral metabolic interactions in thalamic circuitry predicts motor recovery in hemiparetic stroke.

We applied a multiple regression/discriminant analysis to resting metabolic data from patients with first hemiparetic suprathalamic infarctions to determine if metabolic interdependencies, which may separate recovered (N=12) from nonrecovered (N=9) patients, suggest important motor-recovery pathways. Recovered, vs. nonrecovered, patients showed an enhanced ipsilesional thalamic-contralesional cerebellar metabolic interdependency. This pattern correctly classified 91% of recovered and 88% of nonrecovered patients. Metabolic interactions involving bilateral supplementary motor area, ipsilesional thalamus, and contralesional cerebellum distinguished all recovered patients from age/sex-matched controls (N=12). These results suggest that altered functional interactions in thalamic circuitry may reflect plastic reorganization associated with motor recovery from hemiparesis.

Adult fragile X syndrome: neuropsychology, brain anatomy, and metabolism.

To understand the implications of suboptimal gene expression in fragile X syndrome -fra(X)-, we sought to define the central nervous abnormalities in fra(X) syndrome to determine if abnormalities in specific brain regions or networks might explain the cognitive and behavioral abnormalities in this syndrome. Cranial and ventricular volumes were measured with quantitative computed tomography (CT), regional cerebral metabolic rates for glucose (rCMRglc) were measured with [18-F]-2-fluoro-2-deoxy-D-glucose (18FDG), and patterns of cognition were determined with neuropsychological testing in ten healthy, male patients with karyotypically proven fra(X) syndrome (age range 20-30 yr). Controls for the CT studies were 20 healthy males (age range 21-37 yr), controls for the PET studies were 9 healthy males (age range 22-31 yr), and controls for the neuropsychological tests were 10 young adult, male Down syndrome (DS) subjects (age range 22-31 yr). The mean mental age of the fra(X) syndrome group was 5.3 yr (range 3.5-7.5 yr; Stanford-Binet Intelligence Scale). Despite comparable levels of mental retardation, the fra(X) subjects showed poorer attention/short term memory in comparison to the DS group. Further, the fra(X) subjects showed a relative strength in verbal compared to visuospatial attention/short term memory. As measured with quantitative CT, 8 fra(X) subjects had a significant (P < 0.05) 12% greater intracranial volume (1,410 +/- 86 cm3) as compared to controls (1,254 +/- 122 cm3). Volumes of the right and left lateral ventricles and the third ventricle did not differ between groups. Seven of eight patients had greater right lateral ventricle volumes than left, as opposed to 9 out of 20 controls (P < 0.05). Global gray matter CMR-glc in nine fra(X) patients was 9.79 +/- 1.28 mg/100 g/minute and did not differ from 8.84 +/- 1.31 mg/100 g/minute in the controls. R/L asymmetry in metabolism of the superior parietal lobe was significantly higher in the patients than controls. A preliminary principal component analysis of metabolic data showed that the fra(X) subjects tended to form a separate subgroup that is characterized by relative elevation of normalized metabolism in the lenticular nucleus, thalamus, and premotor regions. Further, a discriminant function, that reflected rCMRglc interactions of the right lenticular and left premotor regions, distinguished the fra(X) subjects from controls. These regions are part of a major group of functionally and anatomically related brain regions and appear disturbed as well in autism with which fra(X) has distinct behavioral similarities. These results show a cognitive profile in fra(X) syndrome that is distinct from that of Down syndrome, that the larger brains in fragile X syndrome are not accompanied by generalized cerebral cortical atrophy or hypoplasia, and that distinctive alterations in resting regional glucose metabolism, measured with 18 FDG and PET, occur in fra(X) syndrome.

Sex differences in patterns of hemispheric cerebral metabolism: a multiple regression/discriminant analysis of positron emission tomographic data.

Sex differences in brain hemispheric structure and function have been reported, and sex-related differences in hemispheric interregional correlations were reported in a prior analysis of resting PET glucose metabolic (rCMRglc) data. To explore further the effect of sex on patterns of hemispheric brain functional interactions, we applied a multiple regression/discriminant analysis to resting rCMRglc PET data from young normal men and women to test two hypotheses: (1) women have stronger between-hemisphere functional interactions; (2) men have stronger within-hemisphere functional interactions. Two separate discriminant functions based on these hypotheses distinguished men and women: the first reflected rCMRglc interdependencies between hemispheres and correctly classified all women and 94% of the men; the second reflected rCMRglc interdependencies within the left hemisphere and correctly classified 82% of the women and 88% of the men. Because the discriminant functions successfully distinguished men and women, these results provide support for both hypotheses.

Detection of an Alzheimer disease pattern of cerebral metabolism in Down syndrome.

Correlational analysis of cerebral metabolic (rCMRglc) data obtained with positron emission tomography (PET) assesses group differences and has demonstrated reduced frontal-parietal rCMRglc interdependencies in Alzheimer's disease (AD). A multivariate analysis of rCMRglc data assesses individual differences. We recently identified discriminant functions, reflecting frontal-parietal rCMRglc interdependencies, that separated AD from control subjects. To test if the functions would identify an AD rCMRglc pattern in older Down syndrome (DS) adults with (DS DAT+) or without (DS DAT-) dementia, we applied the functions to longitudinal rCMRglc data in: young DS (n = 15), DS DAT- (n = 10), DS DAT+ (n = 4), and young controls (n = 15). All DS DAT+ and some of the later DS DAT- scans were classified as AD. The results provide additional validation of the functions and suggest their utility for the early detection of AD.

Abnormal pattern of cerebral glucose metabolic rates involving language areas in young adults with Down syndrome.

Correlational and discriminant analyses were applied to "resting" state (eyes covered, ears plugged) regional cerebral glucose metabolic data, obtained with positron emission tomography (PET) and [18F] fluorodeoxyglucose in 14 retarded adults with Down syndrome (10 men, 4 women; age 26-38 years) and 17 age- and sex-matched controls. Down and control subjects showed no differences in the pattern of correlations. However, a discriminant function, reflecting regional interactions involving primary language areas, successfully classified the Down (100%) and control (88%) subjects. The results are consistent with a disruption of brain regional interactions involving language areas in adults with Down syndrome.

Individual differences in cerebral metabolic patterns during pharmacotherapy in obsessive-compulsive disorder: a multiple regression/discriminant analysis of positron emission tomographic data.

A multiple regression/discriminant analysis of positron emission tomographic cerebral metabolic (rCMRglc) data in 10 obsessive-compulsive disorder (OCD) patients before and during pharmacotherapy was carried out to see if rCMRglc interdependencies distinguished OCD patients from controls. Before therapy, a discriminant function reflecting parietal, sensorimotor, and midbrain rCMRglc interdependencies correctly classified eight (80%) of the 10 patients as OCD; after therapy, six (70%) were classified as controls, most of whom were responders. Before therapy, rCMRglc interdependencies involving basal ganglia, thalamus, limbic, and sensory and association cortical regions distinguished 67% of patients who clinically responded to drug (RESP, n = 6) and 75% of patients who did not (NRESP, n = 4) from controls. After therapy, all RESP were classified as controls; classification of NRESP remained unchanged. The results suggest the conjunctive utility of this method to assess individual differences in rCMRglc during pharmacotherapy, and to explore the neurobiology of OCD.

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.

Pattern of cerebral metabolic interactions in a subject with isolated amnesia at risk for Alzheimer's disease: a longitudinal evaluation.

A pattern of reduced cerebral metabolic rate for glucose (rCMRglc) has been shown by positron emission tomography (PET) in patients with dementia of the Alzheimer type. To verify if a similar rCMRglc pattern is present in subjects 'at risk' for Alzheimer's disease (AD), we used high-resolution PET to longitudinally study a subject with isolated memory impairment and a family history for autosomal dominant AD. Initial rCMRglc data did not reveal any consistent abnormality as compared to a group of sex- and age-matched healthy controls. However, 1 year later, a follow-up evaluation did reveal reduced parietal rCMRglc values coinciding with a worsening of cognitive impairment, which suggested that standard analyses of resting rCMRglc data may not be useful in the early diagnosis of AD. In contrast, when a previously determined discriminant function for distinguishing controls from AD patients was applied, the subject was correctly identified as an AD patient on both PET scans.

Interregional correlations of resting cerebral glucose metabolism in old and young women.

A correlational analysis of normalized (regional to whole-brain) regional cerebral metabolic rates for glucose obtained in the 'resting' state (eyes covered, ears plugged) using [18F]fluorodeoxyglucose, demonstrated differences between old and young women in patterns of functional associations. Fifteen healthy young (age less than 40 years) and 17 healthy old women (age greater than 64 years) were scanned with a Scanditronix PC1024-7B tomograph. The brain was divided into 65 regions of interest. The old women had fewer and less positive correlations between pairs of metabolic ratios in the frontal and parietal cortices. The results suggest an age-related reduction in frontal and parietal functional interactions in the 'resting' state that is consistent with a prior correlation analysis using a low resolution ECAT II scanner on young and old men. Reduced functional interactions may reflect age-related cognitive changes.

Gender differences in correlations of cerebral glucose metabolic rates in young normal adults.

Correlational analysis of normalized regional cerebral metabolic data obtained by positron emission tomography, in healthy subjects in the 'resting' state (eyes covered, ears plugged) using [18F]2-fluoro-2-deoxy-D-glucose, demonstrated gender differences in patterns of functional associations. Fifteen women and 18 men (less than 40 yr) were scanned with a Scanditronix PC1024-7B tomograph. The brain was divided into 65 regions of interest (ROIs). There were no differences between men and women in global or regional metabolic rates, or in metabolic right-left asymmetries. Although the total number of significant correlations did not differ between men and women, patterns differed: female correlations rF were most positive than male correlations rM more often than rM greater than rF; and most rF greater than rM cases involved left frontal and sensorimotor ROIs, whereas most rM greater than rF cases involved right sensorimotor and occipital ROIs. The findings demonstrate gender differences in the pattern of functional neocortical interactions at the 'resting' state.