The neurodevelopmental frontostriatal disorders: evolutionary adaptiveness and anomalous lateralization

The frontostriatal system (dorsolateral prefrontal cortex, lateral orbitofrontal cortex, anterior cingulate, supplementary motor area, and associated basal-ganglia structures) is subject to a range of neurodevelopmental disorders: Tourette's syndrome (TS), obsessive compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), schizophrenia (SCZ), autism, and probably depression. The system is responsible for our adaptive responses (initiation, execution, or withholding) to environmental situations, and the above disorders, involving effectively excessive release or withholding of various types of response, are all a consequence of changes in specific frontostriatal regions. The disorders all have a genetic component, and their persistence in the genome indicates that their clinical manifestations may also be associated, perhaps in low levels in close relatives, with certain adaptive advantages in given situations. Thus autism is associated with computational careers, depression with literary creativity, SCZ with lateral thinking and the Odyssean personality, ADHD with an Ice-Age readiness to respond, OCD with a focused range of interests, and TS with competitive sports and jazz improvisation. The disorders are all highly comorbid, and which one predominantly manifests may depend on how the frontostriatal system happens to be compromised as a result of inherited genetic predispositions and environmental contingency. We review the adaptive nature of the various subclinical manifestations and the evidence for concomitant phenomena (possibly epiphenomena): alterations in structural, functional, and behavioral lateralization in each syndrome. Indeed it is not clear that altered lateralization in frontostriatal disorders of a neurodevelopmental origin generally has any adaptive significance; it may often simply serve as a marker for altered regulatory function of the frontostriatal system, alterations which in low genetic dosage or penetrance continue to play an adaptive role in clinically unaffected close relatives of probands, but which, in high dosage or penetrance in the probands themselves, are generally deleterious.     

Brain imaging in neurogenetic conditions: realizing the potential of behavioral neurogenetics research

Behavioral neurogenetics research is a new method of scientific inquiry that focuses on investigation of neurodevelopmental dysfunction associated with specific genetic conditions. This research method provides a powerful tool for scientific inquiry into human gene-brain-behavior linkages that complements more traditional research approaches. In particular, the use of specific genetic conditions as models of common behavioral and cognitive disorders occurring in the general population can reveal insights into neurodevelopmental pathways that might otherwise be obscured or diluted when investigating more heterogeneous, behaviorally defined subject groups. In this paper, we review five genetic conditions that commonly give rise to identifiable neurodevelopmental and neuropsychiatric disability in children: fragile X syndrome, velo-cardio-facial syndrome, Williams syndrome, Turner syndrome, and Klinefelter syndrome. While emphasis is placed on describing the brain morphology associated with these conditions as revealed by neuroimaging studies, we also include information pertaining to molecular genetic, postmortem, and neurobehavioral investigations to illustrate how behavioral neurogenetics research can contribute to an improved understanding of brain disorders in childhood.     

Tangled webs: tracing the connections between genes and cognition

The rise of molecular genetics is having a pervasive influence in a wide variety of fields, including research into neurodevelopmental disorders like dyslexia, speech and language impairments, and autism. There are many studies underway which are attempting to determine the roles of genetic factors in the aetiology of these disorders. Beyond the obvious implications for diagnosis, treatment and understanding, success in these efforts promises to shed light on the links between genes and aspects of cognition and behaviour. However, the deceptive simplicity of finding correlations between genetic and phenotypic variation has led to a common misconception that there exist straightforward linear relationships between specific genes and particular behavioural and/or cognitive outputs. The problem is exacerbated by the adoption of an abstract view of the nature of the gene, without consideration of molecular, developmental or ontogenetic frameworks. To illustrate the limitations of this perspective, I select two cases from recent research into the genetic underpinnings of neurodevelopmental disorders. First, I discuss the proposal that dyslexia can be dissected into distinct components specified by different genes. Second, I review the story of the FOXP2 gene and its role in human speech and language. In both cases, adoption of an abstract concept of the gene can lead to erroneous conclusions, which are incompatible with current knowledge of molecular and developmental systems. Genes do not specify behaviours or cognitive processes; they make regulatory factors, signalling molecules, receptors, enzymes, and so on, that interact in highly complex networks, modulated by environmental influences, in order to build and maintain the brain. I propose that it is necessary for us to fully embrace the complexity of biological systems, if we are ever to untangle the webs that link genes to cognition.     

Family Factors in the Development, Treatment, and Prevention of Childhood Anxiety Disorders

It is now widely accepted that anxiety disorders run in families, and current etiological models have proposed both genetic and environmental pathways to anxiety development. In this paper, the familial role in the development, treatment, and prevention of anxiety disorders in children is reviewed. We focus on three anxiety disorders in youth, namely, generalized, separation, and social anxiety as they often co-occur both at the symptom and disorder level and respond to similar treatments. We begin by presenting an overview of a broad range of family factors associated with anxiety disorders. Findings from these studies have informed intervention and prevention strategies that are discussed next. Throughout the paper we shed light on the challenges that plague this research and look toward the future by proposing directions for much needed study and discussing factors that may improve clinical practice and outcomes for affected youth and their families.     

Verhaltensgenetik

Behavioural genetics has provided ample evidence for the influence of genes on personality traits and psychological disorders. In this review, the methodological strategies of behavioural genetics are described and study results with special relevance for psychotherapists are highlighted.Moreover, some traditional myths and misunderstandings are discussed. In particular, two findings are underscored: While genetic factors substantially contribute to the development of personality traits, environmental influences shared by the members of a family appear to be virtually absent. In contrast, environmental factor specific to an individual seem to play an important role.Second, genes do not only have a direct impact on the development of psychological disorders, but also act in an indirect way by increasing the probability of exposure to stressful life events which in turn function as risk factors for psychological disorders. It is concluded that research should incorporate both genetic and environmental factors to be able to evaluate their relative impact and elucidate the interaction of nature and nurture.     

Genes,Fears, Phobias,and Phobic Disorders

It has become widely accepted that we may be biologically “prepared” to associate fear more easily with some stimuli (e.g., heights) than with other stimuli (e.g., electric outlets). The current literature on the topic of the genetics of fears and phobias is surveyed with an eye toward answering the question “What might be heritable?” For ordinary fears among the general population, heredity appears to contribute mainly to a trait of general fearfulness and may be a major reason for the strong intercorrelation among different fears. Surprisingly, the available evidence suggests little environmental transmission from parent to offspring, although adoption data have yet to be reported on this issue. Although the results of two small twin series are consistent with some genetic influence on clinically significant phobias, it is still not clear what might be genetically transmitted in these disorders. There is a strong possibility that phobic disorders may be genetically heterogeneous.     

Soziales Trauma

Social traumatization is targeted at entire victim groups and occurs in a societal context. The classification of posttraumatic stress disorders in DSM-5, which intentionally fails to differentiate between different types of traumatic events, ignores the social factors of traumatogenic pathologies. Whereas clinical practice unanimously embraces the thorough exploration of patients’ individual life experiences and history of suffering, taking the relevant social and environmental factors into account, in the classification systems (DSM-5 and ICD-10) it has been decided to address posttraumatic disorders as individual pathologies and not as social phenomena. Even equating social trauma with a disease may foster this partial exclusion, which in turn can contribute to perpetuation of the posttraumatic condition.     

Autism and 15q11-q13 disorders: behavioral, genetic, and pathophysiological issues

New insights into biological factors that underlie autism may be gained by comparing autism to other neurodevelopmental disorders that have autistic features and relatively well-delineated genetic etiologies or neurobiological findings. This review moves beyond global diagnoses of autism and instead uses an endophenotypic approach to compare specific clusters of autistic symptomatology to features of chromosome 15q11-q13 disorders. Paternally or maternally derived deficiencies of 15q11-q13 result in Prader-Willi or Angelman syndromes, and we first use a global approach to review potential autism susceptibility genes in the 15q11-q13 region. We then use a more trait-based approach to suggest possible ties between specific phenotypic characteristics of autism and Prader-Willi syndrome, namely savant-like skills. We conclude with insights from pathophysiological studies that implicate altered development of specific neuron types and circuits in the cerebral cortex as part of the pathophysiological processes associated with autism and mental retardation.     

Male life-course persistent antisocial behavior: A review of neurodevelopmental factors

Life-course-persistent antisocial behavior, which is almost exclusively male, is arguably the single most important child clinical problem. The neurodevelopmental factors which contribute to this markedly male predominance stem from the greater male vulnerability to inherited and acquired neurodevelopmental impairments which increase the risk for antisocial behavior. The factors that contribute to this greater male vulnerability are discussed, and implications for prevention are presented.     

Neurodevelopmental and psychosocial risk factors in serial killers and mass murderers

Multiple and serial murders are rare events that have a very profound societal impact. We have conducted a systematic review, following PRISMA guidelines, of both the peer reviewed literature and of journalistic and legal sources regarding mass and serial killings. Our findings tentatively indicate that these extreme forms of violence may be a result of a highly complex interaction of biological, psychological and sociological factors and that, potentially, a significant proportion of mass or serial killers may have had neurodevelopmental disorders such as autism spectrum disorder or head injury. Research into multiple and serial murders is in its infancy: there is a lack of rigorous studies and most of the literature is anecdotal and speculative. Specific future study of the potential role of neurodevelopmental disorders in multiple and serial murders is warranted and, due to the rarity of these events, innovative research techniques may be required.     

Genetics in eating disorders: state of the science

Eating disorders have been viewed as psychiatric illnesses that are strongly influenced by societal pressures towards thinness and attractiveness. Although the environmental context of these disorders must not be neglected, recent research in the area of genetic epidemiology suggests a substantial influence of genetic factors on liability to eating disorders. This review presents a synthesis of current knowledge about genetic factors implicated in the etiology of eating disorders.     

Sources of covariation among attention-deficit/hyperactivity disorder, oppositional defiant disorder, and conduct disorder: the importance of shared environment.

Research has documented high levels of covariation among childhood externalizing disorders, but the etiology of this covariation is unclear. To unravel the sources of covariation among attention-deficit/hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), and conduct disorder (CD), the authors studied 11-year-old twins (N = 1,506) from the Minnesota Twin Family Study. Symptom counts for each of these disorders were obtained from interviews administered to the twins and their mothers. A model was fit that allowed the parsing of genetic, shared environmental (factors that make family members similar to each other), and nonshared environmental (factors that make family members different from each other) contributions to covariation. The results revealed that although each disorder was influenced by genetic and environmental factors, a single shared environmental factor made the largest contribution to the covariation among ADHD, ODD, and CD.     

Interpreting Behavioral Genetic Results: Suggestions for Counselors and Clients

Treatment strategies often are premised on modifying either environmental factors or clients' interpretations of the interpersonal environment, which are assumed to be causing problem behaviors or emotional distress. A more complete analysis would take into account the role played by genetic transmission in an individual's personality, for example, intraversion- extraversion and sense of personal control, and in the occurrence of psychopathological disorders, such as depression. When developing interventions, both counselors and clients may be helped by behavioral genetic information (a) indicating the heritability of propensities or disorders as well as (b) confirming the importance of environmental influences that hold out the possibility of change.     

Factors Influencing Clinical Correlates of Chronic Traumatic Encephalopathy (CTE): a Review

Chronic traumatic encephalopathy (CTE) is a neuropathologically defined disease reportedly linked to a history of repetitive brain trauma. As such, retired collision sport athletes are likely at heightened risk for developing CTE. Researchers have described distinct pathological features of CTE as well a wide range of clinical symptom presentations, recently termed traumatic encephalopathy syndrome (TES). These clinical symptoms are highly variable, non-specific to individuals described as having CTE pathology in case reports, and are often associated with many other factors. This review describes the cognitive, emotional, and behavioral changes associated with 1) developmental and demographic factors, 2) neurodevelopmental disorders, 3) normal aging, 4) adjusting to retirement, 5) drug and alcohol abuse, 6) surgeries and anesthesia, and 7) sleep difficulties, as well as the relationship between these factors and risk for developing dementia-related neurodegenerative disease. We discuss why some professional athletes may be particularly susceptible to many of these effects and the importance of choosing appropriate controls groups when designing research protocols. We conclude that these factors should be considered as modifiers predominantly of the clinical outcomes associated with repetitive brain trauma within a broader biopsychosocial framework when interpreting and attributing symptom development, though also note potential effects on neuropathological outcomes. Importantly, this could have significant treatment implications for improving quality of life.     

Nature, Nurture, and Attention Deficit Hyperactivity Disorder

This commentary shows that Joseph's (this issue) review of the genetics of attention deficit hyperactivity disorder (ADHD) contains errors of scientific logic and ignores much relevant research. Thus, we reject his conclusions. We also reject Joseph's approach of pitting nature against nurture as if these two facets of human life are at odds with one another. Instead, most scientists who study the genetics of psychiatric disorders embrace the idea that these disorders are influenced by both genes and environmental factors. In fact, the twin studies criticized by Joseph provide the strongest evidence that environmental risk factors play a substantial role in the etiology of ADHD. They do so by showing that when one identical twin has ADHD the risk to the co-twin is much less than 100%, a fact which can only be explained by environmental risk factors. We also reject the idea that genetic studies have hindered psychosocial research, stigmatized patients, or promoted psychopharmacologic treatments. Genetic studies have aimed at solving one part of the puzzle of ADHD. By testing a parsimonious theory, they have set the stage for gene discovery and the delineation of how genes and environment combine to cause this impairing disorder.     

Understanding the Covariation Among Childhood Externalizing Symptoms: Genetic and Environmental Influences on Conduct Disorder,Attention Deficit Hyperactivity Disorder,and Oppositional Defiant Disorder Symptoms

Conduct disorder (CD), attention deficit hyperactivity disorder (ADHD), and oppositional defiant disorder (ODD) are common childhood externalizing disorders that frequently co-occur. However, the causes of their comorbidity are not well understood. To address that question, we analyzed data from > 600 Finnish twin pairs, who completed standardized interviews at age 14. Behavior genetic methods were used to examine how genetic/environmental factors contribute to each disorders symptoms and to their covariation. We found significant genetic effects on each disorder with only modest evidence of shared environmental influences. Our data suggest the comorbidity among CD, ADHD, and ODD is primarily explained by shared genetic influences; however, each disorder was also under unique genetic influence, supporting the distinction of each disorder.     

Anorexia Nervosa,Major Depression,and Suicide Attempts: Shared Genetic Factors

The extent to which genetic and environmental factors influenced anorexia nervosa (AN), major depressive disorder (MDD), and suicide attempts (SA) were evaluated. Participants were 6,899 women from the Swedish Twin Study of Adults: Genes and Environment. A Cholesky decomposition assessed independent and overlapping genetic and environmental contributions to AN, MDD, and SA. Genetic factors accounted for a substantial amount of liability to all three traits; unique environmental factors accounted for most of the remaining liability. Shared genetic factors may underlie the coexpression of these traits. Results underscore the importance of assessing for signs of suicide among individuals with AN.     

Genes and family environment in familial clustering of cancer

Familial clustering of a disease is defined as the occurrence of the disease within some families in excess of what would be expected from the occurrence in the population. It has been demonstrated for several cancer types, ranging from rare cancers as the adenomatosis-coli-associated colon cancer or the Li-Fraumeni syndrome to more common cancers as breast cancer and colon cancer. Familial clustering, however, is merely an epidemiological pattern, and it does not tell whether genetic or environmental causes or both in combination are responsible for the familial clustering. Familial clustering may be due to genetic predisposition to the disease, but exposure to environmental factors — shared by members of some families, but not by members of other families — may also cause familial clustering and hence mimic genetic inheritance in the study of nuclear families. Based on assumptions regarding the individual steps in the biological process starting with exposure to carcinogens and ending with death from disseminated cancer we suggest that genetic and environmental factors may both be involved in most of these steps. The present paper focuses on research methodologies necessary to discriminate between the effect of genes and family environment in the development of cancer.