Several brain areas show signal decreases during many different cognitive tasks in functional imaging studies, including the posterior cingulate cortex (PCC) and a medial frontal region incorporating portions of the medial frontal gyrus and ventral anterior cingulate cortex (MFG/vACC). It has been suggested that these areas are components in a default mode network that is engaged during rest and disengaged during cognitive tasks. This study investigated the functional connectivity between the PCC and MFG/vACC during a working memory task and at rest by examining temporal correlations in magnetic resonance signal levels between the regions. The two regions were functionally connected in both conditions. In addition, performance on the working memory task was positively correlated with the strength of this functional connection not only during the working memory task, but also at rest. Thus, it appears these regions are components of a network that may facilitate or monitor cognitive performance, rather than becoming disengaged during cognitive tasks. In addition, these data raise the possibility that the individual differences in coupling strength between these two regions at rest predict differences in cognitive abilities important for this working memory task.

Functional brain imaging studies have identified a set of brain areas typically activated during cognitive tasks (task-positive brain areas) and another set of brain areas typically deactivated during cognitive tasks (task-negative brain areas). Negative correlations, or anticorrelations, between taskpositive and task-negative brain areas have been reported at rest. Furthermore, the strength of these anticorrelations appears to be related to cognitive function. However, studies examining anticorrelations have typically employed global regression or similar analysis steps that force anticorrelated relationships to exist between brain areas. Therefore the validity of these findings has been questioned. Here we examine anticorrelations between a task-negative region in the medial frontal gyrus/anterior cingulate cortex and dorsolateral prefrontal cortex, a classic task-positive area, using an analysis that does not include global regression. Instead, we control for whole-brain correlations in the group-level analysis. Using this approach, we demonstrate that the strength of the functional connection between the medial frontal cortex and the dorsolateral prefrontal cortex is related to cognitive function and that this relationship is not an artifact of global regression.

Glutamatergic neurotransmission mediated by N-methyl-D-aspartate (NMDA) receptors is vital for the cortical computations underlying cognition and might be disrupted in severe neuropsychiatric illnesses such as schizophrenia. Studies on this topic have been limited to processes in local circuits; however, cognition involves large-scale brain systems with multiple interacting regions. A prominent feature of the human brain's global architecture is the anticorrelation of default-mode vs. task-positive systems. Here, we show that administration of an NMDA glutamate receptor antagonist, ketamine, disrupted the reciprocal relationship between these systems in terms of task-dependent activation and connectivity during performance of delayed working memory. Furthermore, the degree of this disruption predicted task performance and transiently evoked symptoms characteristic of schizophrenia. We offer a parsimonious hypothesis for this disruption via biophysically realistic computational modeling, namely cortical disinhibition. Together, the present findings establish links between glutamate's role in the organization of large-scale anticorrelated neural systems, cognition, and symptoms associated with schizophrenia in humans.default-mode network | task-based activation | task-based deactivation | pharmacological manipulation | fMRI D rug treatments for serious mental illnesses and investigations of the neurochemical bases of healthy cognition have, for the most part, targeted the slow neuromodulatory neurotransmitters, dopamine and serotonin (1). However, rapid excitatory glutamatergic and inhibitory γ-aminobutyric acid (GABA) signals mediate local and long-range cortical computations (2) and play a critical role in cognition and severe psychiatric illnesses such as schizophrenia (3-5). We investigated how disrupting the N-methyl-D-aspartate (NMDA) receptor component of fast glutamatergic neurotransmission via the administration of the NMDA receptor antagonist ketamine altered cognitive performance and systemslevel neural activity and connectivity in healthy volunteers. Furthermore, we related these system-level neural changes to behavior and transiently evoked psychotic symptoms associated with schizophrenia.Studies investigating glutamate's role in cognition have largely focused on local circuits (5-7); however, cognition involves largescale brain systems with multiple interacting regions. Recent neuroimaging work highlights the competitive relationships between two large-scale neural systems: a set of brain regions preferentially engaged during tasks that require goal-directed cognition and attention (task-positive) and the regions associated with resting conditions [default-mode network (DMN)] (8-10). The neurotransmitter mechanisms behind this inverse relationship remain unexplored, as does the role of this phenomenon in serious mental illness (11). Thus far, functional neuroimaging (fMRI) investigations of these large-scale neural systems have mostly been correlational (12), and the synaptic mechanisms for these eff...

Background. In order to improve management, the files and tissue sections of 28 cases of malignant peripheral nerve sheath tumors (MPNST) diagnosed at the University of Virginia Health Sciences Center between 1960 and 1990 were reviewed. Methods. Clinical data tabulated included age, sex, race, the presence or absence of von Recklinghausen neurofibromatosis type 1 (NF‐1), tumor size, tumor location, type of treatment, and status of surgical margins. Pathologic study included assessment of mitotic rate, divergent differentiation, cellular atypia, necrosis, and vascular reaction. Results. The median disease‐free survival time was 11 months, and the median overall survival time was 44 months. Overall survival and disease‐free survival were significantly influenced by patient age, tumor location, tumor size, extent of surgery, and quality of margins. Patients with a family history of neurofibromatosis also had better disease‐free survival. None of the other clinical variables correlated with survival. Conclusions. The authors recommended that patients with NF‐1 be followed closely for MPNST development. For most cases, treatment should include aggressive surgery with wide surgical margins combined with adjuvant radiation therapy. Chemotherapy may have a role for treatment failures.

N-methyl-D-aspartate glutamate receptor (NMDA-R) antagonists produce schizophrenia-like positive and negative symptoms in healthy human subjects. Preclinical research suggests that NMDA-R antagonists interfere with the function of gamma-aminobutyric acid (GABA) neurons and alter brain oscillations. These changes have been hypothesized to contribute to psychosis. In this investigation, we evaluated the hypothesis that the NMDA-R antagonist ketamine produces alterations in cortical functional connectivity during rest that are related to symptoms. We administered ketamine to a primary sample of twenty-two subjects and to an additional, partially overlapping, sample of twelve subjects. Symptoms before and after the experimental session were rated with the Positive and Negative Symptom Scale (PANSS). In the primary sample, functional connectivity was measured via functional magnetic resonance imaging almost immediately after infusion began. In the additional sample, this assessment was repeated after 45 minutes of continuous ketamine infusion. Global, enhanced functional connectivity was observed at both timepoints and this hyperconnectivity was related to symptoms in a region-specific manner. This study supports the hypothesis that pathological increases in resting brain functional connectivity contribute to the emergence of positive and negative symptoms associated with schizophrenia.

We examined the pattern of neuroanatomic abnormalities in adults with Down's syndrome (DS) and the cognitive correlates of these abnormalities. Specifically, we compared this pattern with what would be predicted by the hypotheses attributing DS pathology to either premature aging or Alzheimer's disease. We measured a number of brain regions on MRIs of 25 subjects: 13 persons with the DS phenotype and 12 age- and sex-matched healthy volunteers. Study participants had no history of cardiovascular disease, diabetes, thyroid dysfunction, or seizure disorder. After statistical adjustment for differences in body size, we found that, in comparison with controls, DS subjects had substantially smaller cerebral and cerebellar hemispheres, ventral pons, mammillary bodies, and hippocampal formations. In the cerebellar vermis of DS subjects, we observed smaller lobules VI to VIII without appreciable differences in other regions. In addition, we noted trends for shrinkage of the dorsolateral prefrontal cortex, anterior cingulate gyrus, inferior temporal and parietal cortices, parietal white matter, and pericalcarine cortex in DS subjects compared with normal controls. The parahippocampal gyrus was larger in DS subjects. We found no significant group differences in the volumes of the prefrontal white matter, the orbitofrontal cortex, the pre- and postcentral gyri, or the basal ganglia. We conclude that the pattern of selective cerebral damage in DS does not clearly fit the predictions of the premature aging or Alzheimer's disease hypotheses. To examine the relationship between brain abnormalities and cognitive deficits observed in DS, we correlated the size of brain regions that were significantly reduced in DS with performance on tests of intelligence and language. The correlation analysis suggested age-related decline in the DS subjects in general intelligence and basic linguistic skills. General intelligence and mastery of linguistic concepts correlated negatively with the volume of the parahippocampal gyrus. There was no relationship between total brain size and the cognitive variables.

Individuals who develop schizophrenia often suffer long standing deficits. All too often available treatments remain palliative and do not improve the long-term course of illness. The neurobiological deficits associated with the onset of schizophrenia may be most active and damaging in the early stages of this life long illness, a fact which has shifted the focus of research and clinical work toward the early or prodromal stages of this disorder. Results from limited studies suggest that early intervention may lead to a better prognosis. Early interventions that could delay or prevent the onset of psychotic illnesses have obvious public health implications and rely on being able to identify true prodromal patients. The Structured Interview for Prodromal Symptoms and the Scale of Prodromal Symptoms are assessment instruments developed for operationally defining diagnosis and for quantitatively rating symptom severity for patients prodromal for psychosis.

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