A Meta-Analysis for Understanding the Role of the COMT Val158Met Variant in the Susceptibility to Alcoholism

The hypothesis of association between 158Met allele of catechol-o-methyltransferase (COMT) gene and poor dopamine catabolism, dopamine remains prolonged for their half-time in the prefrontal cortex and gets more reward from alcohol than COMT Val158 allele, has generated much interest, research and controversy. Hence, a meta-analysis to explore possible role of COMT Val158Met variant and alcoholism has been performed. Twenty-two case-control data sets containing 3602 alcoholism patients and 5183 healthy subjects genotyped for COMT Val158Met variant has been included and assessed for their association with alcoholism. Meta-analyses were conducted with the use of MetaGenyo web tool. The results of this study confirmed that the COMT Val158Met variant is not contributing to the risk of alcoholism (Dominant model: OR = 1.10 (95% CI = 0.92-1.30), I2 = 49%). Subgroup analysis by ethnicity also found no association of this allele with alcoholism risk in both Asian (Dominant model: OR = 1.15 (95% CI = 0.83-1.60), I2 = 43%) and Caucasian (Dominant model: OR = 1.07 (95% CI = 0.87-1.32), I2 = 54%) populations. The meta-analysis results of this study suggest no significant correlation between COMT Val158Met variant and alcoholism

INTERNET ADDICTION AMONG UNDERGRADUATE STUDENTS IN SOUTH KOREA: ASSOCIATION WITH COMT (VAL158MET) GENOTYPE AND PSYCHOLOGICAL FACTORS

With the recent diversification and universalization of the Internet, the Internet use rate has increased rapidly. A growing body of research suggests that Internet addiction, defined as pathologically preoccupied Internet use, which results in physical, psychological, social, and/or financial distress, has become a serious health and social problem worldwide. The catechol-o-methyltransferase (COMT) (Val158Met) is one of the candidate genes that have been studied to understand the various illnesses related to dopaminergic neurotransmission, including substance-related and addictive disorders (SRADs). However, little research has been conducted to examine the association between the COMT genotype and Internet addiction. This dissertation is composed of three papers. The first paper is a systematized review of the literature, which aims to synthesize the findings regarding the psychosocial risk factors of Internet addiction among undergraduate students. The second paper is also a systematized review of the literature, which aims to investigate the relationship between the COMT genotype and SRADs. The third paper is a cross-sectional descriptive study that aims to (a) identify issues related to the feasibility of conducting a study that involves the collection of saliva samples and web-based survey data with participants who are undergraduate students in South Korea and (b) describe the relationships among Internet addiction, the COMT genotype, and psychological variables (depressive symptoms, social anxiety, self-esteem, self-efficacy, stress, and coping strategy). The PI recruited 250 Korean undergraduate students from university campuses in Seoul and the Seoul metropolitan area. The study procedure, including the collection of saliva samples and the web-based survey, was found to be feasible. 54.8% of the participants were categorized as having Internet addiction. COMT (Val158Met) was not significantly associated with Internet addiction. However, Internet addiction was significantly associated with all investigated psychological variables. Studies should not be limited to only one genotype, but should include analysis of the multi-locus genetic profile that may be related to Internet addiction. Research that focuses on gene-gene interactions and gene-environmental interactions in terms of Internet addiction is needed. Future research is needed to continue the development of standardized assessment tools and feasible and effective interventions and treatments for Internet addiction.Doctor of Philosoph

Aripiprazole for the treatment of psychotic symptoms in patients with dementia with Lewy bodies: a case series

Yuka Sugawara Kikuchi, Tetsuo ShimizuDepartment of Neuropsychiatry, Akita University Graduate School of Medicine, Akita 010-8543, JapanPurpose: The core features of dementia with Lewy bodies (DLB) are cognitive fluctuations, visual hallucinations, and parkinsonian symptoms. Although there have been several reports on the efficacy of treatments for psychotic symptoms in patients with DLB, little is known regarding the treatment effects of aripiprazole. The aim of this study was to evaluate the efficacy and safety of aripiprazole for the treatment of psychotic symptoms in patients with DLB.Patients and methods: We employed a 10-week, open-label study design with 11 patients who met the criteria for DLB. The patients had previously experienced persistent or intermittent delusions, hallucinations, or both for at least 1 month. Aripiprazole was initiated at a low dose (3 or 6 mg/day) and titrated to higher doses at 2-week intervals or more rapidly, as needed. The Neuropsychiatric Inventory (NPI), Brief Psychiatric Rating Scale (BPRS), and Clinical Global Impression-Severity (CGI-S) were administered at baseline and 1, 2, 4, 8, and 10 weeks later. The Simpson–Angus Scale (SAS), Clinical Dementia Rating (CDR), and Mini-Mental State Examination (MMSE) Scale were evaluated at baseline and at week 10. The NPI, CGI-S, and BPRS scores were compared between the baseline and each assessment point and between each assessment point and the one before assessment point. The SAS, CDR, and MMSE scores were compared between the baseline and the end point.Results: The mean NPI and BPRS scores improved until the fourth week; they significantly decreased at each assessment point compared to the previous one. Afterward, improvements slowed and continued without significant decrease. The median SAS scores significantly decreased at the end point compared to the baseline (P<0.05). The median MMSE score was higher at the end point than at the baseline (P<0.05).Conclusion: This study showed that aripiprazole may be effective and well tolerated for the treatment of psychotic symptoms in patients with DLB. Keywords: aripiprazole, Lewy bodies, dementia, psychotic symptom

Addressing the maturation of higher-order cognitive functions relevant to psychiatric disorders in mice

Psychiatric disorders are a large class of debilitating mental illnesses that affect everyday life of patients and people around them. In fact, they result in alteration of thinking, moods, behavior and increased risk of disability, pain, death, or loss of freedom. Nevertheless, the exact mechanisms behind these diseases are still unknown. Over the last few years, researchers focused on the study of abnormalities in brain neurodevelopment genetic mutations, impact of traumatic events and the interaction between these factors. In particular, both genetic and environmental factors may influence brain developmental process throughout childhood, adolescence and adulthood. Previous studies investigated how genetic and environmental risk factors act during sensitive brain developmental periods whereby altering adult behavior and possibly causing vulnerability to neuropsychiatric disorders. Different brain systems have been involved in the development of psychiatric disorders. However, for disorders such as attentional deficit hyperactivity disorder (ADHD), schizophrenia, and post-traumatic stress disorder (PTSD) there are consistent evidence of a major implication of the dopaminergic and endocannabinoid systems. Dopamine (DA) plays an important role acting as a trophic factor, in the development of neuronal cyto-architecture and also modulating neurodevelopmental processes during the embryonic and postnatal period. In particular, dopaminergic alterations within the prefrontal cortex (PFC) or Striatum, two brain area involved in cognition, learning and emotion, have been previously correlated to the etiology of neuropsychiatric disorders like schizophrenia, autism and ADHD. On the other hand, several studies have related dysfunctions of endocannabinoid system to psychiatric disorders. In fact, the relationship between cannabis consumption, especially during critical period of brain development, and schizophrenia onset has been demonstrated

Different Types of Decision Making Impairments in Anorexia Nervosa

Research on neurocognitive aspects in Anorexia Nervosa (AN) has outlined a cognitive profile characterized by deficiency in the ability to set-shifting (cognitive flexibility) and weak central coherence. A smaller agreement emerges in relation to the compromission of decisional profiles frequently observed in patients with AN since both the complexity of the pathology and the executive function itself make it unclear the nature of these alterations and its relationships with specific or independent clinical and enviornmental variables. The aim of this study was: to investigate different types of decision-making (DM) ability, veridical and adaptive, in a sample of patients with AN using the Iowa Gambling Task and the Cognitive Bias Task; to analyze test performance using a specific cognitive model for the Iowa Gambling Task (Expectancy Valence Learning Model), and to study the relationship with clinical features, focusing on their relationship with neuropsychological profiles and clinical variables; to explore the neural correlations of the two tasks with functional connectivity; to observe the the impact of the genetic profile on different types of DM. Materials and Methods: The sample, consisting of 310 female subjects with AN lifetime and 301 female subjects without diagnosis of lifetime eating disorders, was tested in relation to DM abilities through the Iowa Gambling Task and cognitive Bias Task. All of the participants completed a baseline assessment including the Structured Clinical Interview (SCID) for the DSM-IV, section for eating disorders, and neuropsychological tests including the Wisconsin Card Sorting Test, and Trail Making Test for assessing abilities of abstraction and cognitive flexibility; 10 "and 30" interference memory test for evaluation of working memory, Stop Signal Task for evaluation of inibitory control. The Expectancy Valence Model (EVM) was used to analyze the results obtained in IGT. A genotyping was performed to evaluate the impact of the major polymorphisms implicated in decision-making (158 Val → Met) of the COMT gene and single nucleotide A / G polymorphism (SNP rs25531) of the serotonin carrier gene 5 - HTTLPR. In a smaller subgroup of 35 AN and 34 Healthy control seed based resting state Functional connectivity was explored. Compared to the group of healthy subjects, the decision-making profile of patients suffering from AN was worse in both Iowa Gambling Task (IGT), which evaluates veridical DM, and Cognitive Bias Task (Cbias), which evaluates adaptive DM, regardless of the diagnostic subtype (restrictive vs. binging/purging), psychopathology severity, scholarity, manual 3 dominance or outcome specific treatment. However in IGT the affective decision-making seems to be independent of IMC, conversely in Cbias the adaptive decisional profile was influenced by underweight. Both types of decision-making in patients were not affected by neurocognitive or clinical variables considered. The unfavorable geotype in AN resulted the homozygous for the met allele of the Comt gene and for the short variant of the serotonin transporter gene. The resting functional connectivity explored on the seeds of interest (executive network, orbitofrontal cortex, accumbens and amygdala) in a subgroup of patients and controls showed significantly different patterns of correlation with the scores of IGt and Cbias. In addition, different resting neural patterns appear to be involved in the two different tasks considered. Only in the AN group a positive correlation between the scores on IGT and the activity of the amygdala resulted. In AN group an higher coactivation within the executive, accumbens and orbitofrontal networks was linked to higher context-independency decisional style assessed with CBias, whereas for the executive network the opposite was true for healthy women. In summary our results confirm an impairment of different types of decision making in AN and highlitght the importance of assessing decisional processes with different specific tasks in clinical sample. In particular different maladaptative strategies are associated with ineffective decisional profiles in AN, consisting in a “myopia for the future” and “anxiety inhibition” in veridical situations and in a difficulty to update/review one’s own mindset according to new environmental stimuli (context indipendent reasoning strategies) in adaptive decisional framework. The severity of malnurishment seems to influence adaptive decisional style conferring a bias toward a context indipent reasoning, suggesting the need of metacognitive approach to help patients to be more aware of their tendency to automatically use selection bias in DM contexts. Genetic polimorphysms may in part account for the impaired decision making observed in AN patients, with a negative impact of met Comt allele and the short variant of 5HTTLPR polymorphism. Functional connectivity suggests the presence of different dysfunctional decision making networks in AN patients in the two decisional framework, confirming the importance of emotion and anxiety on decisional performance in AN. Since the cross sectional design of our study, further and longitudinal studies with recovered and at risk subjects are necessary to confirm our results

Developmental plasticity and circuit mechanisms of dopamine-modulated aggression

Aggression and violence pose a significant public health concern to society. Aggression is a highly conserved behavior that shares common biological correlates across species. While aggression developed as an evolutionary adaptation to competition, its untimely and uncontrolled expression is maladaptive and presents itself in a number of neuropsychiatric disorders. A mechanistic hypothesis for pathological aggression links aberrant behavior with heightened dopamine function. However, while dopamine hyper-activity is a neural correlate of aggression, the developmental aspects and circuit level contributions of dopaminergic signaling have not been elucidated. In this dissertation, I aim to address these questions regarding the specifics of dopamine function in a murine model of aggressive behavior. In chapter I, I provide a review of the literature that describes the current state of research on aggression. I describe the background elements that lay the foundation for experimental questions and original data presented in later chapters. I introduce, in detail, published studies that describe the clinical manifestation and epidemiological spread, the dominant categories, the anatomy and physiology, and the pharmacology of aggression, with a particular emphasis on the dopaminergic system. Finally, I describe instances of genetic and environmental risk factors impacting aggression, concluding with studies revealing an important role for interactions among genetics, environmental factors, and age in the development of aggression. In chapter II, I investigate the developmental origins of aggression by examining sensitive periods during which perturbations to the dopaminergic system impact adult aggressive behavior. Previous work in our laboratory has concluded that periadolescent (postnatal days 22-41) elevation in dopamine, via transient dopamine transporter blockade, leads to increased adult aggression and heightened response to amphetamine. I expanded on these findings by temporally refining the opening and closing of this window of sensitivity, specifically to postnatal days 32 to 41, during which increases in dopaminergic tone increase adult aggression and behavioral sensitivity to psychostimulants. The potentiated response to amphetamine indicated to us a state of altered dopaminergic physiology. We next validated this hypothesis and found increased firing rate (in vitro), and increased bursting and population activity (in vivo) at baseline. These data indicate that elevated periadolescent dopamine impacts maturation of the dopamine system, leading to a hyper-active dopaminergic and aggressive predisposition. In conclusion, this chapter introduces a developmental component to the hyper-dopaminergic model of aggression. In chapter III, I report a series of experiments exploring the direct and causal involvement of dopamine in driving aggression. While dopamine hyper-activity is a neural correlate of aggression, the precise brain circuits involved have not been elucidated. Using optogenetics, I established a causal role for the ventral tegmental area (a key source of dopamine) in aggression modulation. I further advanced this finding by demonstrating that the modulatory role of dopamine, is population- and projection-specific. I found that activity of ventral tegmental area, but not substantia nigra, dopamine neurons promotes aggression. Furthermore, controlled stimulation of ventral tegmental area dopaminergic terminals in the lateral septum, but not the nucleus accumbens, mediates increased aggression. I selectively traced connectivity between the lateral septum and the ventral tegmental area using a Cre-driven, population-specific viral vector. I used this virus to show that anatomically distinct clusters of ventral tegmental area dopamine cells send projections to the lateral septum and the nucleus accumbens, thereby dissociating the two target sites both behaviorally and anatomically. Furthermore, I found that while local dopamine release in the lateral septum increases aggression, it has no bearing on reward behaviors thus indicating a stronger association with impulsive, and not motivated, aggression. In conclusion, this chapter offers causal evidence for dopamine’s role in modulating impulsive aggression by identifying a distinct pathway from the ventral tegmental area to the lateral septum that controls aggression. In the work described in chapter IV, my aim was to determine the mechanism underlying ventral tegmental area to lateral septum dopamine-mediated aggression. I first characterized the expression of dopamine receptors in the lateral septum and found that D2 receptors heavily colocalize with the dominant population of neurons in the lateral septum, i.e. GABAergic cells. Moreover, the D2 receptors are perfectly aligned with incoming dopamine afferents. Next we investigated, in acute brain slices, how D2 signaling affects lateral septum function. We revealed that activating D2 receptors hyperpolarizes D2-expressing lateral septum neurons. This effect was abolished with bath application of the D2 receptor antagonist, sulpiride. We validated the functional involvement of post-synaptic D2 signaling in a behavioral test, and found that the aggression induced by direct terminal release of dopamine at the lateral septum is reversed by acutely blocking local D2 receptor signaling. In conclusion, this chapter demonstrates that the ventral tegmental area to lateral septum dopamine pathway, via D2-mediated inhibition of GABAergic lateral septum neurons, is necessary to drive ventral tegmental area-triggered aggression. In chapter V, I engage in a general discussion addressing how the findings from each chapter can be linked to provide a more comprehensive outlook on environmental and genetic risk factors that can modulate ventral tegmental area-triggered aggression. I discuss possible pre- and post-synaptic mechanisms that could impact the functionality of the identified dopaminergic ventral tegmental area to lateral septum pathway. Moreover, in distinguishing this specific dopamine circuit and lateral septum D2 signaling as an underlying correlate of violent pathology, this dissertation aims to evoke deeper understanding of the mechanism of current antipsychotics used to manage aggression. I end this dissertation by proposing new empirical questions, techniques and lines of research that could further develop my findings as well strengthen the links between dominant models of aggression that exist in the field today

DRD2 Variation and Frontostriatal Morphology: Genetic and Volumetric Predictors of Resilience to Substance Use Disorders

Individuals with a family history of alcohol dependence are at increased risk for all substance use disorders (SUDs). Common genetic, morphological, and personality characteristics are thought to contribute to the greater addiction susceptibility among this population. The identification of predictors of resilience to any SUD could improve our understanding of the etiology of addiction and guide future prevention and interventions efforts. Aberrant dopaminergic transmission and frontostriatal circuitry have been identified in substance dependent individuals and their unaffected relatives in association with greater impulsivity. Therefore, the current study sought to evaluate variation in the C957T polymorphism of the dopamine D2 receptor gene (SNP rs6277) and volume of the orbitofrontal cortex (OFC) and caudate nucleus as predictors of resilience to SUD among individuals at high familial risk and normal controls. Families with multiple cases of alcohol dependence, known as multiplex families, are ideal for studying disease-related genotypes and endophenotypes. The present study included offspring from multiplex alcohol dependence families and control families who received annual clinical diagnostic assessments, MRI scans, and provided blood samples for genotyping. Binary logistic mixed model regression analyses were conducted to quantify the relationships between genetic and morphological variation and SUD onset by age 20. The results revealed a significant association between C957T variation and resilience in young adulthood (p = .046). A risk by gene interaction was also observed for OFC volume, such that among HR offspring only, DRD2 genotype was a significant predictor of total OFC volume (p = .034). The identification of mechanisms mediating the association between DRD2 variation and resilience to SUD could contribute to the development of future preventative interventions for high-risk individuals

A transdisciplinary perspective of chronic stress in relation to psychopathology throughout life span development

The allostatic load (AL) model represents an interdisciplinary approach to comprehensively conceptualize and quantify chronic stress in relation to pathologies throughout the life cycle. This article first reviews the AL model, followed by interactions among early adversity, genetics, environmental toxins, as well as distinctions among sex, gender, and sex hormones as integral antecedents of AL. We next explore perspectives on severe mental illness, dementia, and caregiving as unique human models of AL that merit future investigations in the field of developmental psychopathology. A complimenting transdisciplinary perspective is applied throughout, whereby we argue that the AL model goes beyond traditional stress–disease theories toward the advancement of person-centered research and practice that promote not only physical health but also mental healt