Program & Abstract Book - EPFL Latsis Symposium 2009

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EPFL Latsis Symposium 2009: Understanding Violence S-2 26 February 11-13 2009 th e n e u r o b i o l o g y o f impulsivity a n D a g g r e ss i o n in aDhD Lesch, Klaus-Peter Department of Psychiatry, Psychsomatics, and Psychotherapy, University of Würzburg, Germany Attention-deficit/hyperactivity disorder (ADHD; MIM #143465) is defined as a clinically heterogeneous neurodevelopmental syndrome comprising the triad of inattention, hyperactivity and increased impulsivity. It is the most common behavioral disorder in children with persistence into adulthood which profoundly compromises functioning in multiple areas throughout the life span and can significantly contribute to a variety of health, social, and economic problems. Affected individuals are at increased risk for poor educational and occupational achievement despite normal cognitive and intellectual abilities, low income, underemployment, impaired social skills and relationships, family dysfunction, legal difficulties, and delinquency. On the other hand, high IQ and a highly supportive, wellstructured family environment are protective factors against ADHD-related behavioral limitations. While an age-dependent fading may render symptoms not prominent enough to justify diagnosis of ADHD in adulthood, they are frequently associated with clinically significant impairment of cognitive and executive functions as well as stress coping and emotion regulation. As a result, adult ADHD is characterized by high co-morbidity with depression, anxiety disorders, alcohol/drug dependence, and antisocial personality disorders. Twin, adoption, and molecular genetic studies revealed that ADHD is a highly heritable disorder (h2: 70–80%) with a multifactorial pattern of inheritance, likely due to several genes of small or moderate effect size. Genom-wide linkage and microarray-based association and copy number variation analyses identified several susceptibility loci and risk genes. Frequency and ancestry of the susceptibility variants are consistent with the concept that traits associated with the ADHD phenotype have been subject to positive selection and that ADHD is the extreme of a normal variation exacerbated by adverse environmental circumstances. With focus on relevance to pathophysiological and pharmacotherapeutic mechanisms, the candidate gene approach has also been utilized in case-control or family-based studies. Investigations concentrated on genes which modulate synaptic transmission and association with ADHD was detected for genes encoding key modulators of the dopaminergic and serotonergic signalling pathways. Moreover, gene targeting approaches, e.g. generation of knockout mice, provide informative insight into pathophysiological mechanisms of locomotor hyperactivity and effects of psychostimulant drugs, such as methylphenidate or cocaine. Finally, complex interactions are to be expected between environmental factors and multiple genes each with a small to moderate influence on different traits. Perinatal complications, low socio-economic status, disruptive family environment and other psychosocial adversity have been identified
EPFL Latsis Symposium 2009: Understanding Violence S-2 Abstracts for Speakers th e n e u r o b i o l o g y o f impulsivity a n D a g g r e ss i o n in aDhD (co n t i n u e D ) Lesch, Klaus-Peter Department of Psychiatry, Psychsomatics, and Psychotherapy, University of Würzburg, Germany as predisposing environmental risk factors. While prenatal and parental risk factors may be critical mediators of influences on the risk, the association between these variables and ADHD is generally indirect. Converging evidence from animal and human studies including structural and functional neuroimaging implicates dysregulation of prefrontal–striatal– thalamic– cerebellar excitatory and inhibitory circuits with broadening to a multi-pathway framework in the pathophysiology of ADHD. It is widely accepted that ADHD is the common final behavioral consequence of an array of dysfunctions in each of several independent systems, such as cognitive, motivational, and executive pathways, as well as circuitries of stress adaptation and emotion regulation. Executive functions, which consist of a set of higher order thought processes required for adaptive and future-oriented behavior (e.g. deliberate suppression of a response to achieve a later, internally represented goal) and are controlled by frontal-subcortical circuits, include behavioral inhibition, working memory, attention setshifting, interference control, planning, and sustained attention. Impairment of executive functions with failure of inhibitory control; dysregulation of brain systems mediating reward and response cost; and deficits in arousal, activation, and effortful control, are central to the pattern of neuropsychological deficits. Deficits in arousal and effort lead to state-dependent cognitive deficits and underscore the view of an impairment in regulating cognitive functions rather than core deficits in any single function. Inattention but not hyperactivity/impulsivity is associated with deficits in executive functioning and poor academic achievement, whereas hyperactivity/impulsivity appears to be more closely related to dysfunctions of reward mechanisms. Functional neuroimaging studies have assessed the degree of brain activation associated with neuropsychological tasks of attention and disinhibition. The findings are consistent with the structural studies indicating delays in brain maturation processes and locating abnormalities of brain activation in patients with ADHD in fronto–subcortical–cerebellar circuits. Since the spectrum of ADHD features is not explained by a single neuropsychological deficit, disorder-associated impairments are heterogeneous and this complexity corresponds with causal heterogeneity. Despite recognition of ADHD as a neurodevelopmental condition, only few causal explanations have considered the two-way interactions between pre-existing abnormal functioning and biological, cognitive, emotional, motor and social developmental processes, and their contribution to the expression of the clinical phenotype. 27
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