A. Kriplani

Brain monoamine oxidase A activity predicts trait aggression

The genetic deletion of monoamine oxidase A (MAO A), an enzyme that breaks down the monoamine neurotransmitters norepinephrine, serotonin, and dopamine, produces aggressive phenotypes across species. Therefore, a common polymorphism in the MAO A gene (MAOA, Mendelian Inheritance in Men database number 309850, referred to as high or low based on transcription in non-neuronal cells) has been investigated in a number of externalizing behavioral and clinical phenotypes. These studies provide evidence linking the low MAOA genotype and violent behavior but only through interaction with severe environmental stressors during childhood. Here, we hypothesized that in healthy adult males the gene product of MAO A in the brain, rather than the gene per se, would be associated with regulating the concentration of brain amines involved in trait aggression. Brain MAO A activity was measured in vivo in healthy nonsmoking men with positron emission tomography using a radioligand specific for MAO A (clorgyline labeled with carbon 11). Trait aggression was measured with the multidimensional personality questionnaire (MPQ). Here we report for the first time that brain MAO A correlates inversely with the MPQ trait measure of aggression (but not with other personality traits) such that the lower the MAO A activity in cortical and subcortical brain regions, the higher the self-reported aggression (in both MAOA genotype groups) contributing to more than one-third of the variability. Because trait aggression is a measure used to predict antisocial behavior, these results underscore the relevance of MAO A as a neurochemical substrate of aberrant aggression.

Evidence That Brain MAO A Activity Does Not Correspond to MAO A Genotype in Healthy Male Subjects

BACKGROUND A functional polymorphism in the promoter region of the monoamine oxidase A (MAO A) gene has two common alleles that are referred to as the high and low MAO A genotypes. We report the first in vivo human study to determine whether there is an association between MAO A genotype and brain MAO A activity in healthy male subjects. METHODS Brain MAO A activity was measured with positron emission tomography and [(11)C]clorgyline in 38 healthy adult male nonsmokers genotyped for MAO A polymorphism. RESULTS There was no significant difference in brain MAO A activity between the high (n = 26) and low (n = 12) MAO A genotypes. CONCLUSIONS The lack of an association between the high and low MAO A genotype and brain MAO A activity suggests that this polymorphism by itself does not contribute to differences in brain MAO A activity in healthy adult male subjects.

Fast Uptake and Long-Lasting Binding of Methamphetamine in the Human Brain: Comparison with Cocaine

Methamphetamine is one of the most addictive and neurotoxic drugs of abuse. It produces large elevations in extracellular dopamine in the striatum through vesicular release and inhibition of the dopamine transporter. In the U.S. abuse prevalence varies by ethnicity with very low abuse among African Americans relative to Caucasians, differentiating it from cocaine where abuse rates are similar for the two groups. Here we report the first comparison of methamphetamine and cocaine pharmacokinetics in brain between Caucasians and African Americans along with the measurement of dopamine transporter availability in striatum. Methamphetamines uptake in brain was fast (peak uptake at 9 min) with accumulation in cortical and subcortical brain regions and in white matter. Its clearance from brain was slow (except for white matter which did not clear over the 90 min) and there was no difference in pharmacokinetics between Caucasians and African Americans. In contrast cocaines brain uptake and clearance were both fast, distribution was predominantly in striatum and uptake was higher in African Americans. Among individuals, those with the highest striatal (but not cerebellar) methamphetamine accumulation also had the highest dopamine transporter availability suggesting a relationship between METH exposure and DAT availability. Methamphetamines fast brain uptake is consistent with its highly reinforcing effects, its slow clearance with its long-lasting behavioral effects and its widespread distribution with its neurotoxic effects that affect not only striatal but also cortical and white matter regions. The absence of significant differences between Caucasians and African Americans suggests that variables other than methamphetamine pharmacokinetics and bioavailability account for the lower abuse prevalence in African Americans.

A Simultaneous PET/MRI scanner based on RatCAP in small animals

The ability to acquire high resolution anatomical data as well as quantitative functional information in vivo is becoming an increasingly important factor in the diagnosis of disease. Simultaneous acquisition of PET and MRI data would provide essentially perfect co-registration between the two images which is particularly important for tissues whose position and shape can change between sequential scans. RatCAP is a complete 3D tomograph that is designed to image the brain of an awake rat. A special MRI coil composed of 2 saddle elements working in quadrature mode was mounted on a Delrin cylinder specifically designed to fit inside the RatCAP but allowing the rats head to be placed inside as well. Simultaneous PET/MRI images of the rat brain have been acquired in a 4 T MRI scanner using the RatCAP detector, with minimal effect on MRI images.

Development of a simultaneous PET/MRI scanner

A combined magnetic resonance imaging (MRI) and positron emission tomography (PET) scanner would be a great benefit to nuclear medicine. The anatomical detail given by MRI and spectroscopy available with magnetic resonance spectroscopy (MRS) complement the quantitative physiological imaging obtained with PET. Such a device has not become a reality because of the incompatibilities of photomultiplier tubes (PMTs) and their associated electronics with MRIs high magnetic fields, as well as significant constraints on PET camera size due to the limited patient port of MR scanners. Recent advances in solid-state electronics have opened the possibility of replacing photomultiplier tubes with avalanche photodiodes (APDs) that are compact and do not share the vulnerabilities of PMTs to magnetic fields. Currently, we are planning to build a miniature PET tomograph using only solid-state electronics to give a combination MRI/PET scanner for small animals. This technology, once developed, can be extended to human scanner designs.

System performance simulations of the RatCAP awake rat brain scanner

The capability to create high quality images from data acquired by the Rat Conscious Animal PET tomograph (RatCAP) has been evaluated using modified versions of the PET Monte Carlo code Simulation System for Emission Tomography (SimSET). The proposed tomograph consists of lutetium oxyorthosilicate (LSO) crystals arranged in 12 4 /spl times/ 8 blocks. The effects of the RatCAPs small ring diameter (/spl sim/40 mm) and its block detector geometry on image quality for small animal studies have been investigated. Since the field of view will be almost as large as the ring diameter, radial elongation artifacts due to parallax error are expected to degrade the spatial resolution and thus the image quality at the edge of the field of view. In addition to Monte Carlo simulations, some preliminary results of experimentally acquired images in both two-dimensional (2-D) and 3-D modes are presented.

The design and performance of the 2 nd -generation RatCAP awake rat brain PET system

The original prototype RatCAP PET scanner for conscious rat brain imaging has undergone a redesign of most major components resulting in a distinct 2nd -generation instrument. While maintaining the same field of view (38 mm diameter, 18 mm axial) and similar overall architecture, the new design allows for longer crystals to provide approximately a factor of 2 increase in coincidence sensitivity with a minimal increase in size and weight. The front-end electronics ASIC has been significantly upgraded, featuring programmable amplifier gains, lower noise, differential digital communication (LVDS), and selectable energy window modes and analog outputs for debugging. The rigid-flex circuit interconnecting the 12 blocks is now more mechanically stable and draws less power which minimizes APD gain shifts. The downstream time-stamp and signal processing module (TSPM) has been modified to be compatible with the new ASICs and further includes DACs for threshold control, twice as many inputs, and a doubling of data throughput capacity. The user interface and data acquisition software is in Labview, and data processing and image reconstruction software is being further developed to maximize imaging accuracy for quantitative neuroscience studies. Finally, a new mechanical support system has been constructed to improve the rats tolerance of the scanner. Preliminary data indicate improved energy and time resolution compared to the 1st-generation prototype and first images of the rat brain while conscious have been obtained.

The RatCAP conscious small animal PET tomography

The RatCAP is a small, head mounted PET tomograph designed and built to image the brain of an awake rat. It allows PET imaging studies to be carried out on laboratory rats without the use of anesthesia, which severely suppresses brain functions and affects many of the neurological activities that one would like to study using PET. The tomograph consists of a 4 cm diameter ring containing 12 block detectors, each of which is comprised of a 4 times 8 array of 2.2 times 2.2 times 5 mm3 LSO crystals read out with a matching APD array. The APDs are read out using a custom designed ASIC and VME readout system. We have successfully performed a system integration test with a partially instrumented tomograph ring. We present the recent progress towards a fully integrated system

The MAO-A genotype does not modulate resting brain metabolism in adults

Variation in the monoamine-oxidase-A (MAO-A) gene has been associated with volumetric changes in corticolimbic regions with differences in their response to relevant emotional tasks. Here we show no changes in baseline regional brain metabolism as a function of genotype indicating that, unchallenged, corticolimbic activity is not modulated by the MAO-A genotype.

Preliminary Studies of a Simultaneous PET/MRI Scanner Based on the RatCAP Small Animal Tomograph

We are developing a scanner that will allow the simultaneous acquisition of high resolution anatomical data using magnetic resonance imaging (MRI) and quantitative physiological data using positron emission tomography (PET). The approach is based on the technology used for the RatCAP conscious small animal PET tomograph which utilizes block detectors consisting of pixelated arrays of LSO crystals read out with matching arrays of avalanche photodiodes (APDs) and a custom-designed ASIC. A version of the detector is being developed that will be constructed out of all nonmagnetic materials that can be operated inside the MRI field. We have demonstrated that the PET detector works inside the MRI field using 511 keV gamma rays, and have obtained MRI images with various detector components that show minimal distortion in the MRI image. We plan to improve on the image quality in the future using completely nonmagnetic components and by tuning the MRI pulse sequences. The combined result will be a highly compact, low mass PET scanner that can operate inside an MRI magnet without distorting the MRI image, and can be retrofitted into existing MRI instruments.