The COMT Val108/158Met polymorphism and medial temporal lobe volumetry in patients with schizophrenia and healthy adults.

Abnormalities of the medial temporal lobe have been consistently demonstrated in schizophrenia. A common functional polymorphism, Val108/158Met, in the putative schizophrenia susceptibility gene, catechol-O-methyltransferase (COMT), has been shown to influence medial temporal lobe function. However, the effects of this polymorphism on volumes of medial temporal lobe structures, particularly in patients with schizophrenia, are less clear. Here we measured the effects of COMT Val108/158Met genotype on the volume of two regions within the medial temporal lobe, the amygdala and hippocampus, in patients with schizophrenia and healthy control subjects. We obtained MRI and genotype data for 98 schizophrenic patients and 114 matched controls. An automated atlas-based segmentation algorithm was used to generate volumetric measures of the amygdala and hippocampus. Regression analyses included COMT met allele load as an additive effect, and also controlled for age, intracranial volume, gender and acquisition site. Across patients and controls, each copy of the COMT met allele was associated on average with a 2.6% increase in right amygdala volume, a 3.8% increase in left amygdala volume and a 2.2% increase in right hippocampus volume. There were no effects of COMT genotype on volumes of the whole brain and prefrontal regions. Thus, the COMT Val108/158Met polymorphism was shown to influence medial temporal lobe volumes in a linear-additive manner, mirroring its effect on dopamine catabolism. Taken together with previous work, our data support a model in which lower COMT activity, and a resulting elevation in extracellular dopamine levels, stimulates growth of medial temporal lobe structures.

Smoking status as a potential confounder in the study of brain structure in schizophrenia.

Several but not all MRI studies have reported volume reductions in the hippocampus and dorsolateral prefrontal cortex (DLPFC) in patients with schizophrenia. Given the high prevalence of smoking among schizophrenia patients and the fact that smoking has also been associated with alterations in brain morphology, this study evaluated whether a proportion of the known gray matter reductions in key brain regions may be attributed to smoking rather than to schizophrenia alone. We examined structural MRI data of 112 schizophrenia patients (53 smokers and 59 non-smokers) and 77 healthy non-smoker controls collected by the MCIC study of schizophrenia. An automated atlas based probabilistic method was used to generate volumetric measures of the hippocampus and DLPFC. The two patient groups were matched with respect to demographic and clinical variables. Smoker schizophrenia patients showed significantly lower hippocampal and DLPFC volumes than non-smoker schizophrenia patients. Gray matter volume reductions associated with smoking status ranged between 2.2% and 2.8%. Furthermore, we found significant volume differences between smoker patients and healthy controls in the hippocampus and DLPFC, but not between non-smoker patients and healthy controls. Our data suggest that a proportion of the volume reduction seen in the hippocampus and DLPFC in schizophrenia is associated with smoking rather than with the diagnosis of schizophrenia. These results may have important implications for brain imaging studies comparing schizophrenia patients and other groups with a lower smoking prevalence.

Structural differences in adult orbital and ventromedial prefrontal cortex predicted by infant temperament at 4 months of age.

CONTEXT: The term temperament refers to a biologically based predilection for a distinctive pattern of emotions, cognitions, and behaviors first observed in infancy or early childhood. High-reactive infants are characterized at age 4 months by vigorous motor activity and crying in response to unfamiliar visual, auditory, and olfactory stimuli, whereas low-reactive infants show low motor activity and low vocal distress to the same stimuli. High-reactive infants are biased to become behaviorally inhibited in the second year of life, defined by timidity with unfamiliar people, objects, and situations. In contrast, low-reactive infants are biased to develop into uninhibited children who spontaneously approach novel situations. OBJECTIVE: To examine whether differences in the structure of the ventromedial or orbitofrontal cerebral cortex at age 18 years are associated with high or low reactivity at 4 months of age. DESIGN: Structural magnetic resonance imaging in a cohort of 18-year-olds enrolled in a longitudinal study. Temperament was determined at 4 months of age by direct observation in the laboratory. SETTING: Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital. PARTICIPANTS: Seventy-six subjects who were high-reactive or low-reactive infants at 4 months of age. MAIN OUTCOME MEASURE: Cortical thickness. RESULTS: Adults with a low-reactive infant temperament, compared with those categorized as high reactive, showed greater thickness in the left orbitofrontal cortex. Subjects categorized as high reactive in infancy, compared with those previously categorized as low reactive, showed greater thickness in the right ventromedial prefrontal cortex. CONCLUSIONS: To our knowledge, this is the first demonstration that temperamental differences measured at 4 months of age have implications for the architecture of human cerebral cortex lasting into adulthood. Understanding the developmental mechanisms that shape these differences may offer new ways to understand mood and anxiety disorders as well as the formation of adult personality.