Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia

Abnormalities of prefrontal cortical function are prominent features of schizophrenia and have been associated with genetic risk, suggesting that susceptibility genes for schizophrenia may impact on the molecular mechanisms of prefrontal function. A potential susceptibility mechanism involves regulation of prefrontal dopamine, which modulates the response of prefrontal neurons during working memory. We examined the relationship of a common functional polymorphism (Val108/158 Met) in the catechol-O-methyltransferase (COMT) gene, which accounts for a 4-fold variation in enzyme activity and dopamine catabolism, with both prefrontally mediated cognition and prefrontal cortical physiology. In 175 patients with schizophrenia, 219 unaffected siblings, and 55 controls, COMT genotype was related in allele dosage fashion to performance on the Wisconsin Card Sorting Test of executive cognition and explained 4% of variance (P = 0.001) in frequency of perseverative errors. Consistent with other evidence that dopamine enhances prefrontal neuronal function, the load of the low-activity Met allele predicted enhanced cognitive performance. We then examined the effect of COMT genotype on prefrontal physiology during a working memory task in three separate subgroups (n = 11–16) assayed with functional MRI. Met allele load consistently predicted a more efficient physiological response in prefrontal cortex. Finally, in a family-based association analysis of 104 trios, we found a significant increase in transmission of the Val allele to the schizophrenic offspring. These data suggest that the COMT Val allele, because it increases prefrontal dopamine catabolism, impairs prefrontal cognition and physiology, and by this mechanism slightly increases risk for schizophrenia.

Functional activation of the human ventrolateral frontal cortex during mnemonic retrieval of verbal information.

Regional cerebral blood flow was measured with positron emission tomography during the performance of a verbal free recall task, a verbal paired associate task, and tasks that required the production of verbal responses either by speaking or writing. Examination of the differences in regional cerebral blood flow between these conditions demonstrated that the left ventrolateral frontal cortical area 45 is involved in the recall of verbal information from long-term memory, in addition to its contribution to speech. The act of writing activated a network of areas involving posterior parietal cortex and sensorimotor areas but not ventrolateral frontal cortex.

Inhibitory influence of frontal cortex on locus coeruleus neurons.

The functional influence of the frontal cortex (FC) on the noradrenergic nucleus locus coeruleus (LC) was studied in the rat under ketamine anesthesia. The FC was inactivated by local infusion of lidocaine or ice-cold Ringer's solution while recording neuronal activity simultaneously in FC and LC. Lidocaine produced a transient increase in activity in FC, accompanied by a decrease in LC unit and multiunit activity. This was followed by a total inactivation of FC and a sustained increase in firing rate of LC neurons. Subsequent experiments revealed antidromic responses in the FC when stimulation was applied to the LC region. The antidromic responses in FC were found in a population of neurons (about 8%) restricted to the dorsomedial area, FR2. The results indicate that there is a strong inhibitory influence of FC on the tonic activity of LC neurons. The antidromic responses in FC to stimulation of the LC region suggest that this influence is locally mediated, perhaps through interneurons within the nucleus or neighboring the LC.

Tab. 1: Rates of advance of the frontal push-moraines of 19 lobes in front of an approx. 4.5 km long margin of the Kötlujökull

In the last years masses of ice, about 5 km long, have been protruding from the lowest part of an advancing glacier margin of the Kötlujökull in Southern Iceland. In the summer of 1983, they appeared as sediment-covered lobes, 10-60 m long, bordering the glacier rnargin like agarland. 1 to 3 push-rnoraines without ice core, rnostly sickle-shaped, occured first in the frontal parts of the lobes: behind thern came several ice-cored moraines with heights of up to several metres. The active ice in front of the precipice of the glacier is called the "glacier-foot" in this paper. The digging out of 9 lobes and the measuring of the advance of 19 lobes showed that in most cases this glacierfoot had split up at its distal end into several plate- or stem-shaped pieces of ice which were situated one upon the other, separated by moraine deposits and proceeding irregularly into the foreland at the rate of several mm/h, The sometimes different rate of advance in the same lobe and different rates of advanee in adjoining lobes (some being entirely inactive) point to a type of rnovement which is independent of the general advance of the glacier. Research in the winter of 1983/84 showed less activity in 3 examined lobes, but the activity had not ceased. The advancement of the lower parts of the glacier-foot into and across the sands of the foreland implies the following genesis of pushmoraines: Shoving off a plate of sand, folding it and pushing it over the foreland at average rates of up to 7,2 mm/h, according to the investigations in thc summer of 1983. At a certain stage of the folding process, new folds begin to develop in front of the old, and the old folds are shifted onto the backslope of thc folds in front of them until they are completely unired. In this way, "püe-moraines" arise, which become higher and higher. They include two or more folds declining towards the glacier. Systems of small moraines presumably of the same genesis occur on old moraine areas in front of the Kötlujökull. The possible cause of formation of a glacier-foot is discussed, and the moraines of the Kötlujökull are compared with certain pleistocene push-moraines.

A 1995 Solectria 4-door sedan into flat frontal barrier at 48.1 kph. Final report.

National Highway Traffic Safety Administration, Office of Vehicle Safety Compliance, Washington, D.C.

Final report of a Renaissance Cars Tropica Roadster into flat frontal barrier at 47.6 kph.

National Highway Traffic Safety Administration, Washington, D.C.

Research MIV (modified integrated vehicle). Volume II/1 - frontal impact. Final report.

National Highway Traffic Safety Administration, Washington, D.C.

A 1995 Solectria E-10 pickup into flat frontal barrier. Final report.

National Highway Traffic Safety Administration, Washington, D.C.

A 1993 Solectria Force into a flat frontal barrier. Final report.

National Highway Traffic Safety Administration, Washington, D.C.

A 1993 Sebring Zev into flat frontal barrier. Final report.

National Highway Traffic Safety Administration, Washington, D.C.

Minicars Research Safety Vehicle to 1979 Dodge Challenger crash test report - frontal aligned impact at 86.52 mph closing speed.

National Highway Traffic Safety Administration, Office of Vehicle Safety Compliance, Washington, D.C.

Research safety vehicle (RSV) crash test report: test no. 3054-1 - 41 mph flat barrier frontal impact. Final report.

National Highway Traffic Safety Administration, Washington, D.C.

Final report of a 1993 Solectria Force into flat frontal barrier.

National Highway Traffic Safety Administration, Washington, D.C.