Effects of methamphetamine abuse and serotonin transporter gene variants on aggression and emotion-processing neurocircuitry.

Individuals who abuse methamphetamine (MA) exhibit heightened aggression, but the neurobiological underpinnings are poorly understood. As variability in the serotonin transporter (SERT) gene can influence aggression, this study assessed possible contributions of this gene to MA-related aggression. In all, 53 MA-dependent and 47 control participants provided self-reports of aggression, and underwent functional magnetic resonance imaging while viewing pictures of faces. Participants were genotyped at two functional polymorphic loci in the SERT gene: the SERT-linked polymorphic region (SERT-LPR) and the intron 2 variable number tandem repeat polymorphism (STin2 VNTR); participants were then classified as having high or low risk for aggression according to individual SERT risk allele combinations. Comparison of SERT risk allele loads between groups showed no difference between MA-dependent and control participants. Comparison of self-report scores showed greater aggression in MA-dependent than control participants, and in high genetic risk than low-risk participants. Signal change in the amygdala was lower in high genetic risk than low-risk participants, but showed no main effect of MA abuse; however, signal change correlated negatively with MA use measures. Whole-brain differences in activation were observed between MA-dependent and control groups in the occipital and prefrontal cortex, and between genetic high- and low-risk groups in the occipital, fusiform, supramarginal and prefrontal cortex, with effects overlapping in a small region in the right ventrolateral prefrontal cortex. The findings suggest that the investigated SERT risk allele loads are comparable between MA-dependent and healthy individuals, and that MA and genetic risk influence aggression independently, with minimal overlap in associated neural substrates

Does the catechol-O-methyltransferase (COMT) Val158Met human polymorphism in influence procrastination?

Genetic studies are enlightening how the expression of several genes influences neuronal activity and all facets of human normal and abnormal behaviour. Among these, a growing body of information shows that a few key genes regulating activity of central neurotransmitters have specific roles in cognitive and/or emotional processes, as ‘procrastination’. We investigated the association of the 5-HTTLPR and COMT Val158Met polymorphisms with students’ procrastination in an academic writing task. Results: showed no relationship between procrastination and the 5-HTT polymorphism but they revealed an association with the COMT Val158Met one. Particularly, the presence of the Met158 allele was found to be significantly associated with the tendency to initiate and complete the assigned task. We hypothesize that the role of central monoamines and of dopamine already identified in impulsive behaviour, extends to procrastination. Since the 158Met allele provides neurons with significantly higher basal dopamine levels when compared to the 158Val allele, our observation suggests that under normal conditions the 158Met allele provides carriers with increased inhibitory control, resulting in an increased tendency to adhere to a planned schedule and therefore reducing procrastination. On the other hand, the Val158 allele may result more effective in increasing carriers’ performances under stress conditions, namely when the schedule deadline is approaching, and dopamine release is increased. This would result in a higher tendency to procrastinate. This hypothesis can readily be tested by applying the experimental approach here employed to various samples of subjects belonging to different categories and extending the analysis to other putative neuron-expressed gene

Developmental imaging genetics: challenges and promises for translational research

Advances in molecular biology, neuroimaging, genetic epidemiology, and developmental psychopathology have provided a unique opportunity to explore the interplay of genes, brain, and behavior within a translational research framework. Herein, we begin by outlining an experimental strategy by which genetic effects on brain function can be explored using neuroimaging, namely, imaging genetics. We next describe some major findings in imaging genetics to highlight the effectiveness of this strategy for delineating biological pathways and mechanisms by which individual differences in brain function emerge and potentially bias behavior and risk for psychiatric illness. We then discuss the importance of applying imaging genetics to the study of psychopathology within a developmental framework. By beginning to move toward a systems-level approach to understanding pathways to behavioral outcomes as they are expressed across development, it is anticipated that we will move closer to understanding the complexities of the specific mechanisms involved in the etiology of psychiatric disease. Despite the numerous challenges that lie ahead, we believe that developmental imaging genetics has potential to yield highly informative results that will ultimately translate into public health benefits. We attempt to set out guidelines and provide exemplars that may help in designing fruitful translational research applications that incorporate a developmental imaging genetics strategy

The Serotonin Transporter Gene Alters Sensitivity to Attention Bias Modification: Evidence for a Plasticity Gene

Background - Attention bias modification (ABM) procedures have been shown to modify biased attention with important implications for emotional vulnerability and resilience. The use of ABM to reduce potentially toxic biases, for instance, is a newly emerging therapy for anxiety disorders. A separate line of gene-by-environment interaction research proposes that many so-called vulnerability genes or risk alleles are better seen as plasticity genes, as they seem to make individuals more susceptible to environmental influences for better and for worse. Methods - A standard ABM procedure was used with a sample of 116 healthy adults. Participants were randomly assigned to one of two training groups. One received an ABM procedure designed to induce a bias in attention toward negative material, while the other was trained toward positive pictures. Individuals with low- and high-expressing forms of the serotonin transporter gene (5-HTTLPR) were compared. Results - Those with a low-expression form (S/S, S/Lg, or Lg/Lg) of the 5-HTTLPR gene developed stronger biases for both negative and positive affective pictures relative to those with the high-expression (La/La) form of the gene. Conclusions - Here, we report the first evidence that allelic variation in the promotor region of the 5-HTTLPR gene predicts different degrees of sensitivity to ABM. These results suggest a potential cognitive mechanism for the gene-by-environment interactions that have been found in relation to the serotonin transporter gene. Variation on this genotype may therefore determine who will benefit most (and least) from therapeutic interventions, adversity, and supportive environments

From genes to behavior: placing cognitive models in the context of biological pathways.

Connecting neural mechanisms of behavior to their underlying molecular and genetic substrates has important scientific and clinical implications. However, despite rapid growth in our knowledge of the functions and computational properties of neural circuitry underlying behavior in a number of important domains, there has been much less progress in extending this understanding to their molecular and genetic substrates, even in an age marked by exploding availability of genomic data. Here we describe recent advances in analytical strategies that aim to overcome two important challenges associated with studying the complex relationship between genes and behavior: (i) reducing distal behavioral phenotypes to a set of molecular, physiological, and neural processes that render them closer to the actions of genetic forces, and (ii) striking a balance between the competing demands of discovery and interpretability when dealing with genomic data containing up to millions of markers. Our proposed approach involves linking, on one hand, models of neural computations and circuits hypothesized to underlie behavior, and on the other hand, the set of the genes carrying out biochemical processes related to the functioning of these neural systems. In particular, we focus on the specific example of value-based decision-making, and discuss how such a combination allows researchers to leverage existing biological knowledge at both neural and genetic levels to advance our understanding of the neurogenetic mechanisms underlying behavior

MAO-A and the EEG Recognition Memory Signal in Left Parietal Cortex

A key part of episodic memory, or memory for the events of our lives, is recognition memory. Recognition memory is the ability to remember previously encountered stimuli. Studies have linked recognition memory to the old/new effect, an EEG indicator of stimulus familiarity. Monoamine oxidase A (MAO-A) is an enzyme that catalyzes monoamines, leading to the depletion of norepinephrine, epinephrine, serotonin, and dopamine. MAO-A is more efficiently transcribed in individuals with a 4 repeating sequence variation (4R) of the MAO-A gene leading to less monoamine availability. As many of these monoamines have been linked to episodic memory, we hypothesized that individuals homozygous for the 4R MAO-A polymorphism would show differences in mean EEG signal amplitudes during recognition memory. EEG data was recorded as participants viewed both new words and words that had been previously presented. Our results show that mean peak amplitudes over the left parietal cortex 500-800 ms post-stimulus presentation for hits were greater than those for correct rejections, indicating the old/new effect. Critically, our results revealed an interaction between mean hit and correct rejection amplitude over the left parietal cortex and MAO-A group. Individuals homozygous for the 4R variation (the High MAO-A group) do not show an old/new effect due to increased correct rejection amplitudes. These results suggest that less monoamine availability leads to new stimuli being identified as old by the left parietal cortex

Understanding vulnerability for depression from a cognitive neuroscience perspective: a reappraisal of attentional factors and a new conceptual framework

We propose a framework to understand increases in vulnerability for depression after recurrent episodes that links attention processes and schema activation to negative mood states, by integrating cognitive and neurobiological findings. Depression is characterized by a mood-congruent attentional bias at later stages of information processing. The basic idea of our framework is that decreased activity in prefrontal areas, mediated by the serotonin metabolism which the HPA axis controls, is associated with an impaired attenuation of subcortical regions, resulting in prolonged activation of the amygdala in response to stressors in the environment. Reduced prefrontal control in interaction with depressogenic schemas leads to impaired ability to exert attentional inhibitory control over negative elaborative processes such as rumination, leading in turn to sustained negative affect. These elaborative processes are triggered by the activation of negative schemas after confrontation with stressors. In our framework, attentional impairments are postulated as a crucial process in explaining the increasing vulnerability after depressive episodes, linking cognitive and biological vulnerability factors. We review the empirical data on the biological factors associated with the attentional impairments and detail how they are associated with rumination and mood regulation. The aim of our framework is to stimulate translational research

Genes of the serotonergic and dopaminergic pathways and their interaction affect the expression of Behavioural and Psychological Symptoms in Dementia (BPSD).

Although there is evidence for the involvement of genes of serotonergic and dopaminergic systems in the manifestation of the Behavioural and Psychological Symptoms in Dementia (BPSD), genetic association studies are contradictory. We used 1008 probable AD patients from the UK and applied a Multiple Indicators Multiple Causes (MIMIC) approach to investigate the effect of 11 polymorphisms in the serotonergic and dopaminergic systems, on four behavioural sub-phenotypes, namely "psychosis"," moods", "agitation" and "behavioural dyscontrol", as well as on 12 NPI items. Significant findings included the association of DRD1 A48G with "psychosis" (p=0.037), the association of DAT1 VNTR with "agitation" (p=0.006) and the association of DRD4 with "moods" sub-phenotype (p=0.008). In addition, associations were identified between DRD1 A48G and DAT1 VNTR with aberrant motor behaviour (AMB) symptoms (p=0.001 and p=0.015 respectively), between DRD4 and sleep disturbances (p=0.018) and between 5HTTLPR and apathy (p=0.033). Finally, significant interactions were observed between COMT Val158Met and 5HTTLPR with "psychosis" (p=0.026), between HTTLPR and STin2 with "psychosis" (p=0.005), between DAT1 3'UTR VNTR and COMT Val158Met with "agitation" (p=0.0001) and between DAT1 3'UTR VNTR and 5HTTLPR with the "moods" factor (p=0.0027). The complexity of the interrelations between genetic variation, behavioural symptoms and clinical variables was efficiently captured by this MIMIC model

Using Biomedical Technologies to Inform Economic Modeling: Challenges and Opportunities for Improving Analysis of Environmental Policies

Advances in biomedical technology have irrevocably jarred open the black box of human decision making, offering social scientists the potential to validate, reject, refine and redefine the individual models of resource allocation that form the foundation of modern economics. In this paper we (1) provide a comprehensive overview of the biomedical methods that may be harnessed by economists and other social scientists to better understand the economic decision making process; (2) review research that utilizes these biomedical methods to illuminate fundamental aspects of the decision making process; and (3) summarize evidence from this literature concerning the basic tenants of neoclassical utility that are often invoked for positive welfare analysis of environmental policies. We conclude by raising questions about the future path of policy related research and the role biomedical technologies will play in defining that path.neuroeconomics, neuroscience, brain imaging, genetics, welfare economics, utility theory, biology, decision making, preferences, Institutional and Behavioral Economics, Research Methods/ Statistical Methods, D01, D03, D6, D87,