Motivated by the vast amount of information that is rapidly accumulating about the human brain in digital form, we embarked upon a program in 1992 to develop a four-dimensional probabilistic atlas and reference system for the human brain. Through an International Consortium for Brain Mapping (ICBM) a dataset is being collected that includes 7000 subjects between the ages of eighteen and ninety years and including 342 mono-and dizygotic twins. Data on each subject includes detailed demographic, clinical, behavioural and imaging information. DNA has been collected for genotyping from 5800 subjects. A component of the programme uses post-mortem tissue to determine the probabilistic distribution of microscopic cyto-and chemoarchitectural regions in the human brain. This, combined with macroscopic information about structure and function derived from subjects in vivo, provides the ¢rst large scale opportunity to gain meaningful insights into the concordance or discordance in micro-and macroscopic structure and function. The philosophy, strategy, algorithm development, data acquisition techniques and validation methods are described in this report along with database structures. Examples of results are described for the normal adult human brain as well as examples in patients with Alzheimer's disease and multiple sclerosis. The ability to quantify the variance of the human brain as a function of age in a large population of subjects for whom data is also available about their genetic composition and behaviour will allow for the ¢rst assessment of cerebral genotype^phenotype^behavioural correlations in humans to take place in a population this large. This approach and its application should provide new insights and opportunities for investigators interested in basic neuroscience, clinical diagnostics and the evaluation of neuropsychiatric disorders in patients.

Alpha-band (8-14 Hz) oscillatory EEG activity was examined with high-density scalp electrical recording during the cue-stimulus interval of an endogenous spatial cueing paradigm. In different blocks, cued spatial locations (left or right) were in either the upper or lower visual field, and attended stimuli were either oriented Ts or moving dots. Distractor stimuli were equally likely in the uncued hemifield. Sustained focal increases of alpha-band activity were seen over occipital cortex contralateral to the direction of the to-be-ignored location (ipsilateral to the cued direction of attention) before onset of the to-be-attended stimulus. The focus of alpha-band activity also moved depending on whether cued locations were in the upper or lower field. Results are consistent with active gating of uncued spatial locations.

High-density eeg recordings revealed sensory specific modulation of anticipatory parieto-occipital approximately 10 Hz oscillatory activity when visually presented word cues instructed subjects in an intermodal selective attention paradigm. Cueing attention to the auditory features of imminent compound audio-visual stimuli resulted in significantly higher approximately 10 Hz amplitude in the period preceding onset of this stimulus than when attention was cued to the visual features. We propose that this parieto-occipital approximately 10 Hz activity reflects a disengaged visual attentional system in preparation for anticipated auditory input that is attentionally more relevant. Conversely, lower approximately 10 Hz activity during the attend-visual condition may reflect active engagement of parieto-occipital areas in the anticipatory period. These results support models implicating parieto-occipital areas in the directing and maintenance of visual attention.

SUMMARY Schizophrenia patients suffer from severe cognitive deficits, such as impaired reality monitoring. Reality monitoring is the ability to distinguish the source of internal experiences from outside reality. During reality monitoring tasks, schizophrenia patients make errors identifying “I made it up” items, and even during accurate performance, they show abnormally low activation of the medial prefrontal cortex (mPFC), a region that supports self-referential cognition. We administered 80 hours of computerized training of cognitive processes to schizophrenia patients and found improvement in reality monitoring that correlated with increased mPFC activity. In contrast, patients in a computer games control condition did not show any behavioral or neural improvements. Notably, recovery in mPFC activity after training was associated with improved social functioning six months later. These findings demonstrate that a serious behavioral deficit in schizophrenia, and its underlying neural dysfunction, can be improved by well-designed computerized cognitive training, resulting in better quality of life.

Working memory has been linked to elevated single neuron discharge in monkeys and to oscillatory changes in the human EEG, but the relation between these effects has remained largely unexplored. We addressed this question by measuring local field potentials and single unit activity simultaneously from multiple electrodes placed in extrastriate visual cortex while monkeys were performing a working memory task. We describe a significant enhancement in theta band energy during the delay period. Theta oscillations had a systematic effect on single neuron activity, with neurons emitting more action potentials near their preferred angle of each theta cycle. Sample-selective delay activity was enhanced if only action potentials emitted near the preferred theta angle were considered. Our results suggest that extrastriate visual cortex is involved in short-term maintenance of information and that theta oscillations provide a mechanism for structuring the recurrent interaction between neurons in different brain regions that underlie working memory.

This study provides a time frame for the initial trajectory of activation flow along the dorsal and ventral visual processing streams and for the initial activation of prefrontal cortex in the human. We provide evidence that this widespread system of sensory, parietal, and prefrontal areas is activated in less than 30 ms, which is considerably shorter than typically assumed in the human event-related potential (ERP) literature and is consistent with recent intracranial data from macaques. We find a mean onset latency of activity over occipital cortex (C1(e)) at 56 ms, with dorsolateral frontal cortex subsequently active by just 80 ms. Given that activity in visual sensory areas typically continues for 100-400 ms prior to motor output, this rapid system-wide activation provides a time frame for the initiation of feedback processes onto sensory areas. There is clearly sufficient time for multiple iterations of interactive processing between sensory, parietal, and frontal areas during brief (e.g., 200 ms) periods of information processing preceding motor output. High-density electrical mapping also suggested activation in dorsal stream areas preceding ventral stream areas. Our data suggest that multiple visual generators are active in the latency range of the traditional C1 component of the ERP, which has often been taken to represent V1 activity alone. Based on the temporal pattern of activation shown in primate recordings and the evidence from these human recordings, we propose that only the initial portion of the C1 component (approximately the first 10-15 ms; C1(e)) is likely to represent a response that is predominated by V1 activity. These data strongly suggest that activity represented in the "early" ERP components such as P1 and N1 (and possibly even C1) is likely to reflect relatively late processing, after the initial volley of sensory afference through the visual system and involving top-down influences from parietal and frontal regions.

The authors describe the development of a four-dimensional atlas and reference system that includes both macroscopic and microscopic information on structure and function of the human brain in persons between the ages of 18 and 90 years. Given the presumed large but previously unquantified degree of structural and functional variance among normal persons in the human population, the basis for this atlas and reference system is probabilistic. Through the efforts of the International Consortium for Brain Mapping (ICBM), 7,000 subjects will be included in the initial phase of database and atlas development. For each subject, detailed demographic, clinical, behavioral, and imaging information is being collected. In addition, 5,800 subjects will contribute DNA for the purpose of determining genotype- phenotype-behavioral correlations. The process of developing the strategies, algorithms, data collection methods, validation approaches, database structures, and distribution of results is described in this report. Examples of applications of the approach are described for the normal brain in both adults and children as well as in patients with schizophrenia. This project should provide new insights into the relationship between microscopic and macroscopic structure and function in the human brain and should have important implications in basic neuroscience, clinical diagnostics, and cerebral disorders.

Event-related brain potentials (ERPs) were recorded from young, middle-aged, and older adults to infrequent target and novel stimuli during a version of the oddball paradigm. Analyses of scalp distribution suggested that the shift to a more frontally oriented topography with increasing age was confined to the P3 component (as compared to N1 and P2) elicited by both target and novel stimuli. This first demonstration of an age-related shift in the scalp distribution of the novelty P3 elicited by auditory stimuli was associated with an age-related increase in the false-alarm rate to novel stimuli. These age-associated differences in scalp distribution and false-alarm rate are consistent with a change in frontal lobe activity with increasing age.