Wakefulness and loss of awareness: brain and brainstem interaction in the vegetative state.

OBJECTIVE: The ascending reticular activating system (ARAS) modulates circadian wakefulness, which is preserved in a persistent vegetative state (PVS). Its metabolism is preserved. Impairment of metabolism in the polymodal associative cortices (i.e., precuneus) is characteristic of PVS where awareness is abolished. Because the interaction of these 2 structures allows conscious sensory perception, our hypothesis was that an impaired functional connectivity between them participates in the loss of conscious perception. METHODS: (15)O-radiolabeled water PET measurement of regional cerebral blood flow (rCBF) was performed at rest and during a proprioceptive stimulation. Ten patients in PVS and 10 controls were compared in a cross-sectional study. The functional connectivity from the primary sensorimotor cortex (S1M1) and the ARAS in both groups was also investigated. RESULTS: Compared with controls, patients showed significantly less rCBF in posterior medial cortices (precuneus) and higher rCBF in ARAS at rest. During stimulation, bilateral Brodmann area 40 was less activated and not functionally correlated to S1M1 in PVS as it was in controls. Precuneus showed a lesser degree of deactivation in patients. Finally, ARAS whose activity was functionally correlated to that of the precuneus in controls was not in PVS. CONCLUSIONS: Global neuronal workspace theory predicts that damage to long-distance white matter tracts should impair access to conscious perception. During persistent vegetative state, we identified a hypermetabolism in the ascending reticular activating system (ARAS) and impaired functional connectivity between the ARAS and the precuneus. This result emphasizes the functional link between cortices and brainstem in the genesis of perceptual awareness and strengthens the hypothesis that consciousness is based on a widespread neural network.

Nitrous oxide inhalation as a cause of cervical myelopathy.

Current evidence suggests that the incidence of recreational nitrous oxide inhalation is on the rise. Due to the possibility of clinically significant myelopathy, as well as potential response to treatment, it is important to consider this diagnosis when appropriate. We present a case of acquired ataxia and myelopathy due to nitrous oxide abuse and discuss diagnosis, pathophysiology, and response to treatment.

Neural mechanisms underlying the processing of Chinese words: an fMRI study.

The present study employed functional magnetic resonance imaging (fMRI) to investigate the neural mechanisms underlying orthographic, phonological and semantic processing of single character Chinese words. Twelve right-handed native Chinese speakers participated in the study. Three fundamental linguistic tasks including orthographic judgment, phonological matching and semantic association task were used. Our results demonstrated robust activation in the left posterior inferior temporal cortex (BA 37) for all three tasks. While the phonological matching task produced left-lateralized activation in the inferior frontal and parietal regions, semantic association task showed considerable bilateral activation in the inferior frontal and occipito-parietal regions. Direct comparison between phonological matching and semantic association task yielded semantic related activation in the anterior portion of the left inferior frontal gyrus (BA 47) and the right inferior frontal region (Broca's homology; BA 45). Behaviorally, there was no difference in response time between phonological matching and semantic association task. Our findings suggested that differential neural pathways were involved in the processing of meaning and sound of single-character Chinese words. The present study provided systemic information of the neural substrates underlying the processing of different components of Chinese language.

Supraphysiological doses of levothyroxine alter regional cerebral metabolism and improve mood in bipolar depression.

Supplementation of standard treatment with high-dose levothyroxine (L-T(4)) is a novel approach for treatment-refractory bipolar disorders. This study tested for effects on brain function associated with mood alterations in bipolar depressed patients receiving high-dose L-T(4) treatment adjunctive to ongoing medication (antidepressants and mood stabilizers). Regional activity and whole-brain analyses were assessed with positron emission tomography and [(18)F]fluorodeoxyglucose in 10 euthyroid depressed women with bipolar disorder, before and after 7 weeks of open-label adjunctive treatment with supraphysiological doses of L-T(4) (mean dose 320 microg/day). Corresponding measurements were acquired in an age-matched comparison group of 10 healthy women without L-T(4) treatment. The primary biological measures were relative regional activity (with relative brain radioactivity taken as a surrogate index of glucose metabolism) in preselected brain regions and neuroendocrine markers of thyroid function. Treatment-associated changes in regional activity (relative to global activity) were tested against clinical response. Before L-T(4) treatment, the patients exhibited significantly higher activity in the right subgenual cingulate cortex, left thalamus, medial temporal lobe (right amygdala, right hippocampus), right ventral striatum, and cerebellar vermis; and had lower relative activity in the middle frontal gyri bilaterally. Significant behavioral and cerebral metabolic effects accompanied changes in thyroid hormone status. L-T(4) improved mood (remission in seven patients; partial response in three); and decreased relative activity in the right subgenual cingulate cortex, left thalamus, right amygdala, right hippocampus, right dorsal and ventral striatum, and cerebellar vermis. The decrease in relative activity of the left thalamus, left amygdala, left hippocampus, and left ventral striatum was significantly correlated with reduction in depression scores. Results of the whole-brain analyses were generally consistent with the volume of interest results. We conclude that bipolar depressed patients have abnormal function in prefrontal and limbic brain areas. L-T(4) may improve mood by affecting circuits involving these areas, which have been previously implicated in affective disorders.

Relationships between sulcal asymmetries and corpus callosum size: gender and handedness effects.

Magnetic resonance imaging was used to establish the presence and nature of relationships between sulcal asymmetries and mid-sagittal callosal size in neurologically intact subjects, and to determine the influences of sex and handedness. Against a background of long-standing disputes, effects of gender and handedness on callosal size, shape, and variability were additionally examined. Both positive and negative correlations between sulcal asymmetry and callosal size were observed, with effects influenced by sex and handedness. The direction of relationships, however, were dependent on the regional asymmetry measured and on whether real or absolute values were used to quantify sulcal asymmetries. Callosal measurements showed no significant effects of sex or handedness, although subtle differences in callosal shape were observed in anterior and posterior regions between males and females and surface variability was increased in males. Individual variations in callosal size appear to outrange any detectable divergences in size between groups. Relationships between sulcal asymmetries and callosal size, however, are influenced by both sex and handedness. Whether magnitudes of asymmetry are related to increases or decreases in callosal size appears dependent on the chosen indicators of asymmetry. It is an oversimplification, therefore, to assume a single relationship exists between cerebral asymmetries and callosal connections.

Localized morphological brain differences between English-speaking Caucasians and Chinese-speaking Asians: new evidence of anatomical plasticity.

Deformation field morphometry was applied to magnetic resonance images to detect differences in brain shape between English-speaking Caucasians and Chinese-speaking Asians. Anatomical differences between these two groups were limited to gyri in the frontal, temporal and parietal lobes, which are known (through functional imaging studies) to differentiate Chinese speakers from English speakers. We interpret these anatomical differences as evidence of neural plasticity shaped by the process of language acquisition during childhood. While anatomical plasticity due to manual skill acquisition (e.g. in musicians) has been established, to our knowledge this is the first report of a brain anatomical difference attributable to a learned cognitive strategy.

A compensatory mirror cortical mechanism for facial affect processing in schizophrenia.

When primates passively observe other subjects perform specific gestures or actions, premotor and motor cortical areas involved in the internal representation and actual execution of those actions exhibit neuronal activation. This mirror mechanism matches observation, representation, and execution, facilitating internal motor rehearsal, imitation, recognition of actions by others and their meanings, and social learning. Schizophrenic patients have deficits in processing affect displayed by other people's faces, which likely relates to the poor social adaptation and functioning seen in the condition. We hypothesized that, when correctly performing working-memory tasks requiring facial affect processing, schizophrenic patients would show relative increased activity in brain areas involved in social learning and in the internal representation of facial expressions when compared to controls. We used functional magnetic resonance imaging in schizophrenic patients and normal controls to detect relative changes of blood flow in cortical areas related to the representation of facial expressions while the subjects performed simple working-memory tasks with facial emotion diagrams or color circles as cues. We found that, when the task cues were facial expressions in contrast to color circles, the schizophrenic group exhibited increased activation of the face movement areas in motor and pre-motor cortex.

Reafferent copies of imitated actions in the right superior temporal cortex.

Imitation is a complex phenomenon, the neural mechanisms of which are still largely unknown. When individuals imitate an action that already is present in their motor repertoire, a mechanism matching the observed action onto an internal motor representation of that action should suffice for the purpose. When one has to copy a new action, however, or to adjust an action present in one's motor repertoire to a different observed action, an additional mechanism is needed that allows the observer to compare the action made by another individual with the sensory consequences of the same action made by himself. Previous experiments have shown that a mechanism that directly matches observed actions on their motor counterparts exists in the premotor cortex of monkeys and humans. Here we report the results of functional magnetic resonance experiments, suggesting that in the superior temporal sulcus, a higher order visual region, there is a sector that becomes active both during hand action observation and during imitation even in the absence of direct vision of the imitator's hand. The motor-related activity is greater during imitation than during control motor tasks. This newly identified region has all the requisites for being the region at which the observed actions, and the reafferent motor-related copies of actions made by the imitator, interact.

Regional spatial normalization: toward an optimal target.

PURPOSE: The purpose of this work was to develop methods for defining, constructing, and evaluating a "minimal deformation target" (MDT) brain for multisubject studies based on analysis of the entire group. The goal is to provide a procedure that will create a standard, reproducible target brain image based on common features of a group of three-dimensional MR brain images. METHOD: The average deformation and dispersion distance, derived from discrete three-dimensional deformation fields (DFs), are used to identify the best individual target (BIT) brain. This brain is assumed to be the one with the minimal deformation bias within a group of MR brain images. The BIT brain is determined as the one with the minimal target quality score, our cost function based on the deformation displacement and dispersion distance. The BIT brain is then transformed to the MDT brain using an average DF to create an optimized target brain. This analysis requires the calculation of a large number of DFs. To overcome this limitation, we developed an analysis method (the fast method) that reduces the task from order N2 complexity to one of order N, a tremendous advantage for large-N studies. RESULTS: Multiscale correlation analysis in a group of 20 subjects demonstrated the superiority of warping using the MDT target brain, made from the BIT brain, over several individual and MDT-transformed target brains also from the group. CONCLUSION: Analysis of three-dimensional DF provides a means to quickly create a reproducible MDT target brain for any set of subjects. Warping to the MDT target was shown by an independent multiscale correlation method to produce superior results.

Brain mapping: its use in patients with neurological disorders.

Using imaging to study disorders of the brain is a process that is now almost a century old. The most rapid advances and the greatest number of new techniques have been developed in the last thirty years. These methods provide previously unavailable insights into the mechanism of disease, diagnostic information for patients as well as an objective and noninvasive way of planning and monitoring therapy. The overall strategy for using these methods is discussed in this review along with illustrative highlights of three techniques: diffusion and perfusion magnetic resonance imaging, helical X-ray computed tomography and optical intrinsic signal imaging. While new techniques provide different perspectives about brain physiology and pathophysiology, advanced analytic methods for all techniques, new and old, have demonstrated their ability to extract more information from these methods than simple qualitative analysis can provide. Strategies for developing large population, probabilistically-based references and atlases are discussed along with disease-specific atlases of use in studying the natural history of a disorders, therapeutic interventions and strategies for monitoring clinical trials of new therapeutic agents. The integration of information across modalities, spatial and temporal scales, subjects and clinical trials should provide an effective way of providing more comprehensive insights into the mechanisms of disorders that effect the human nervous system, both improving diagnostics and the planning and monitoring of therapeutics.

A probabilistic atlas and reference system for the human brain: International Consortium for Brain Mapping (ICBM).

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 first 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 first 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.

Experience-dependent modulation of motor corticospinal excitability during action observation.

The primate premotor cortex is endowed with an "action observation/execution matching system", that is, the same premotor neurons discharge when actions are performed and when actions are observed. Hence, this system predicts a strong visual input to the motor system. Whether this input is dependent on visual experience or not has not been previously investigated. To address this issue we compared corticospinal excitability while subjects viewed frequently observed and less frequently observed hand actions of others and of themselves. Motor corticospinal excitability was larger when the action orientations were as they are frequently observed (Self-away, subject's own hand facing out from the subject, or Other-toward, an unknown hand facing toward the subject) compared with less frequently observed actions (Self-toward, subject's own hand facing "toward" the subject, or Other-away, an unknown hand facing out from the subject). This finding suggests that the modulation of motor corticospinal excitability during action observation and hence the "action observation/execution matching system" is largely dependent upon visual experience.

A four-dimensional probabilistic atlas of the human brain.

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.

Mapping therapeutic response in a patient with malignant glioma.

Short-interval scanning of patients offers a detailed understanding of the natural progression of tumor tissue, as revealed through imaging markers such as contrast enhancement and edema, prior to therapy. Following treatment, short-interval scanning can also provide evidence of attenuation of growth rates. We present a longitudinal imaging study of a patient with glioblastoma multiforme (GBM) scanned 15 times in 104 days on a 3 T MR scanner. Images were analyzed independently by two automated algorithms capable of creating detailed maps of tumor changes as well as volumetric analysis. The algorithms, a nearest-neighbor-based tissue segmentation and a surface-modeling algorithm, tracked the patient's response to temozolomide, showing an attenuation of growth. The need for surrogate imaging end-points, of which growth rates are an example, is discussed. Further, the strengths of these algorithms, the insight gained by short-interval scanning, and the need for a better understanding of imaging markers are also described.

Language switching and language representation in Spanish-English bilinguals: an fMRI study.

The current experiment was designed to investigate the nature of cognitive control in within- and between-language switching in bilingual participants. To examine the neural substrate of language switching we used functional magnetic resonance imaging (fMRI) as subjects named pictures in one language only or switched between languages. Participants were also asked to name (only in English) a separate set of pictures as either the actions or the objects depicted or to switch between these two types of responses on each subsequent picture. Picture naming compared to rest revealed activation in the dorsolateral prefrontal cortex, which extended down into Broca's area in the left hemisphere. There were no differences in the activation pattern for each language. English and Spanish both activated overlapping areas of the brain. Similarly, there was no difference in activation for naming actions or objects in English. However, there was increased intensity of activation in the dorsolateral prefrontal cortex for switching between languages relative to no-switching, an effect which was not observed for naming of actions or objects in English. We suggest that the dorsolateral prefrontal cortex serves to attenuate interference that results from having to actively enhance and suppress two languages in alternation. These results are consistent with the view that switching between languages involves increased general executive processing. Finally, our results are consistent with the view that different languages are represented in overlapping areas of the brain in early bilinguals.

Qualitative and quantitative evaluation of six algorithms for correcting intensity nonuniformity effects.

The desire to correct intensity nonuniformity in magnetic resonance images has led to the proliferation of nonuniformity-correction (NUC) algorithms with different theoretical underpinnings. In order to provide end users with a rational basis for selecting a given algorithm for a specific neuroscientific application, we evaluated the performance of six NUC algorithms. We used simulated and real MRI data volumes, including six repeat scans of the same subject, in order to rank the accuracy, precision, and stability of the nonuniformity corrections. We also compared algorithms using data volumes from different subjects and different (1.5T and 3.0T) MRI scanners in order to relate differences in algorithmic performance to intersubject variability and/or differences in scanner performance. In phantom studies, the correlation of the extracted with the applied nonuniformity was highest in the transaxial (left-to-right) direction and lowest in the axial (top-to-bottom) direction. Two of the six algorithms demonstrated a high degree of stability, as measured by the iterative application of the algorithm to its corrected output. While none of the algorithms performed ideally under all circumstances, locally adaptive methods generally outperformed nonadaptive methods.

Imaging: window on the brain.

Given the rapid advances in neuroimaging and brain mapping, it is no surprise that a whole host of new and burgeoning techniques are on the horizon as we enter the 21st century. This brief review focuses on methods that are just entering the clinical experience or are now being explored in a research setting but have the imminent potential for clinical use. A number of brain mapping techniques now allow the clinician to monitor disease progression and therapeutic effects in either the routine clinical setting or experimental clinical trials. A battery of methods are now available for the preoperative and intraoperative evaluation of patients with lesions in or near critical cortical areas or for targeting purposes when deep nuclei of the brain are potential sites of therapeutic ablation or electrophysiologic stimulation. The development of probabilistic atlases will soon provide a means of understanding normal variants of human brain structure and function and studying brain disorders and their treatment in an objective and quantifiable fashion. Techniques that are now on the horizon for imaging gene expression, neuronal excitivity, and connectivity are presented in their current stage of development. It is clear that brain mapping and neuroimaging will continue to be ever more important parts of clinical neuroscience and may ultimately serve as the bridge between the molecular and clinical domains of this field. Arch Neurol. 2000;57:1413-1421

Patterns of brain activation in people at risk for Alzheimer's disease.

BACKGROUND: The epsilon4 allele of the apolipoprotein E gene (APOE) is the chief known genetic risk factor for Alzheimer's disease, the most common cause of dementia late in life. To determine the relation between brain responses to tasks requiring memory and the genetic risk of Alzheimer's disease, we performed APOE genotyping and functional magnetic resonance imaging (MRI) of the brain in older persons with intact cognition. METHODS: We studied 30 subjects (age, 47 to 82 years) who were neurologically normal, of whom 16 were carriers of the APOE epsilon4 allele and 14 were homozygous for the APOE epsilon3 allele. The mean age and level of education were similar in the two groups. Patterns of brain activation during functional MRI scanning were determined while subjects memorized and recalled unrelated pairs of words and while subjects rested between such periods. Memory was reassessed in 14 subjects two years later. RESULTS: Both the magnitude and the extent of brain activation during memory-activation tasks in regions affected by Alzheimer's disease, including the left hippocampal, parietal, and prefrontal regions, were greater among the carriers of the APOE epsilon4 allele than among the carriers of the APOE epsilon3 allele. During periods of recall, the carriers of the APOE epsilon4 allele had a greater average increase in signal intensity in the hippocampal region (1.03 percent vs. 0.62 percent, P<0.001) and a greater mean (+/-SD) number of activated regions throughout the brain (15.9+/-6.2 vs. 9.4+/-5.5, P=0.005) than did carriers of the APOE epsilon3 allele. Longitudinal assessment after two years indicated that the degree of base-line brain activation correlated with degree of decline in memory. CONCLUSIONS: Patterns of brain activation during tasks requiring memory differ depending on the genetic risk of Alzheimer's disease and may predict a subsequent decline in memory.

Cerebral metabolic and cognitive decline in persons at genetic risk for Alzheimer's disease.

The major known genetic risk for Alzheimer's disease (AD), apolipoprotein E-4 (APOE-4), is associated with lowered parietal, temporal, and posterior cingulate cerebral glucose metabolism in patients with a clinical diagnosis of AD. To determine cognitive and metabolic decline patterns according to genetic risk, we investigated cerebral metabolic rates by using positron emission tomography in middle-aged and older nondemented persons with normal memory performance. A single copy of the APOE-4 allele was associated with lowered inferior parietal, lateral temporal, and posterior cingulate metabolism, which predicted cognitive decline after 2 years of longitudinal follow-up. For the 20 nondemented subjects followed longitudinally, memory performance scores did not decline significantly, but cortical metabolic rates did. In APOE-4 carriers, a 4% left posterior cingulate metabolic decline was observed, and inferior parietal and lateral temporal regions demonstrated the greatest magnitude (5%) of metabolic decline after 2 years. These results indicate that the combination of cerebral metabolic rates and genetic risk factors provides a means for preclinical AD detection that will assist in response monitoring during experimental treatments.

Modulating emotional responses: effects of a neocortical network on the limbic system.

Humans share with animals a primitive neural system for processing emotions such as fear and anger. Unlike other animals, humans have the unique ability to control and modulate instinctive emotional reactions through intellectual processes such as reasoning, rationalizing, and labeling our experiences. This study used functional MRI to identify the neural networks underlying this ability. Subjects either matched the affect of one of two faces to that of a simultaneously presented target face (a perceptual task) or identified the affect of a target face by choosing one of two simultaneously presented linguistic labels (an intellectual task). Matching angry or frightened expressions was associated with increased regional cerebral blood flow (rCBF) in the left and right amygdala, the brain's primary fear centers. Labeling these same expressions was associated with a diminished rCBF response in the amygdalae. This decrease correlated with a simultaneous increase in rCBF in the right prefrontal cortex, a neocortical region implicated in regulating emotional responses. These results provide evidence for a network in which higher regions attenuate emotional responses at the most fundamental levels in the brain and suggest a neural basis for modulating emotional experience through interpretation and labeling.