Relationship of resting brain hyperconnectivity and schizophrenia-like symptoms produced by the NMDA receptor antagonist ketamine in humans.

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 the 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 22 subjects and to an additional, partially overlapping, sample of 12 subjects. Symptoms before and after the experimental session were rated with the Positive and Negative Syndrome 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 min 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.

Selective neuroanatomic abnormalities in Down's syndrome and their cognitive correlates: evidence from MRI morphometry.

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.

Individual differences in neurobehavioral disruption during mild and moderate hypoglycemia in adults with IDDM.

This study investigated the neurobehavioral effects of mild and moderate hypoglycemia in adults with insulin-dependent diabetes mellitus (IDDM). On 2 consecutive days, 26 subjects were tested in a counterbalanced, randomized, single-blind, crossover design. On the experimental day, subjects performed tests at 6.4, 3.6, and 2.6 mmol/l and again after glycemic recovery to 6.3 mmol/l. On the control day, subjects performed tests four times at euglycemia. Three months after testing, 15 subjects repeated the experimental day protocol. Results demonstrated that both mild and moderate hypoglycemia significantly disrupted performance. However, performance deterioration varied substantially across individual subjects. Men exhibited significantly more deterioration than women at mild hypoglycemia, and subjects with a history of unconsciousness due to hypoglycemia exhibited more deterioration than subjects with no such history. Individual deterioration scores during repeat testing significantly correlated with performance during original testing. Recovery from hypoglycemia-related impairment varied across individuals and was correlated with degree of impairment during hypoglycemia. These results suggest that the glycemic threshold for onset and recovery from neurobehavioral deterioration with hypoglycemia, as well as degree of impairment experienced, varies across individuals. Furthermore, these individual differences are stable across time.