Hypothetical novel simulations to explain the evolutionary survival of the hypo-reproductive extreme tail in the complex human diversity.

Hierarchical structures which lie hidden between human complex conditions and reproductivity cannot be simple, and trends of each population component does not necessarily pertain to evolutionary theories. As an illustration, the fitness of individuals with heritable extreme conditions can be low across continuing generations in observational data. Autism and schizophrenia are characterized by such evolutionary paradox of survival and hypo-reproductivity in the complex human diversity. Theoretical mechanisms for the observational fact were evaluated using a simple formula which was established to simulate stochastic epistasis-mediated phenotypic diversity. The survival of the hypo-reproductive extreme tail could be imitated just by the predominant presence of stochastic epistasis mechanism, suggesting that stochastic epistasis might be a genetic prerequisite for the evolutionary paradox. As supplemental cofactors of stochastic epistasis, a random link of the extreme tail to both un- and hyper-reproductivity and group assortative mating were shown to be effective for the paradox. Especially, the mixed localization of un- and hyper-reproductivity in the tail of a generational population evidently induced the continuous survival of outliers and extremes. These hypothetical considerations and mathematical simulations may suggest the significance of stochastic epistasis as the essential genetic background of complex human diversity.

Developmental social vulnerability as the intrinsic origin of psychopathology: A paradigm shift from disease entities to psychiatric derivatives within human diversity.

How a social episode is perceived by a person and how the experience affects her/his subsequent behaviors will inevitably and sometimes accidentally vary in each case on the developmental trajectory from the birth of consciousness to death. Both the preceding developmental conditions and the social impact of the episode become a starting point for the following states of human complex conditions, creating the extraordinary diversity that characterizes our complex society. In this evolutionarily carved landscape, genetic factors including stochastic epistasis, environmental modification, and gene-environment interactions are all active. In these processes, interactions between developmental social vulnerability and environmental influences can lead to the emergence and persistence of some derivative states with social maladaptation. In our model, every psychiatric condition including aberrant paranoid-hallucinatory states is classified as a derivative state. The probability distribution curve for these derivative states has a non-linear relationship with the liability in the population, and there is none with probability 1.0 or zero. Individuals with trivial social vulnerability or high resilience may develop the derivative states in tremendously stressful circumstances, and individuals with huge social vulnerability may not necessarily develop the derivative states in the presence of adequate social supports. Social skillfulness/unskillfulness and behavioral flexibility/inflexibility form the core of the vulnerability-related dimensions. The clinical picture of a derivative manifestation is profiled depending on the individual trait levels in the derivative-related dimensions. Each derivative state has a requisite lineup of dimensions and each dimension can contribute to multiple psychiatric conditions. For example, aberrant paranoid-hallucinatory states and bipolar condition may share some developmental conditions as the derivative-related dimensions. Therefore, multiple derivative states can co-occur or be sequentially comorbid. Although the 'learned strategies' can ostensibly mask the clinical manifestation of developmental deviations, the change of the true dimensional position to the socially skillful direction is efficiently obtained through social experiences in a supportive environment. The liability-probability model makes it impossible to discriminate individuals with psychiatric diagnosis from individuals without the diagnosis and allows all of us to reside in the same human complex diversity.

The origin of complex human diversity: Stochastic epistatic modules and the intrinsic compatibility between distributional robustness and phenotypic changeability

The continuing prevalence of a highly heritable and hypo-reproductive extreme tail of a human neurobehavioral quantitative diversity suggests the reproductive majority retains the genetic mechanisms for extremes. From the perspective of stochastic epistasis, the effect of an epistatic modifier variant can randomly vary in both phenotypic value and effect direction among carriers depending on the genetic identity and the modifier carriers are ubiquitous in the population. The neutrality of the mean genetic effect in carriers ensures the survival of the variant under selection pressures. Functionally or metabolically related modifier variants make an epistatic network module and dozens of modules may be involved in the phenotype. To assess the significance of stochastic epistasis, a simplified module-based model was simulated. The individual repertoire of the modifier variants in a module also contributes in genetic identity, which determines the genetic contribution of each carrier modifier. Because the entire contribution of a module to phenotypic outcome is unpredictable in the model, the module effect represents the total contribution of related modifiers as a stochastic unit in simulations. As a result, the intrinsic compatibility between distributional robustness and quantitative changeability could mathematically be simulated using the model. The artificial normal distribution shape in large-sized simulations was preserved in each generation even if the lowest fitness tail was non-reproductive. The robustness of normality across generations is analogous to the real situation of complex human diversity, including neurodevelopmental conditions. The repeated regeneration of a non-reproductive extreme tail may be essential for survival and change of the reproductive majority, implying extremes for others. Further simulation to illustrate how the fitness of extreme individuals can be low across generations may be necessary to increase the plausibility of this stochastic epistasis model.

Quantitative Nature of Social Vulnerability and Autism: An Important Paradigm Shift in the DSM-5 for Autism Spectrum Disorder.

In the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV), autistic characteristics in social interaction and communication are described as qualitative impairments. However, the difference between autistics and nonautistics in the draft of the 5th edition (DSM-5 draft) is quantitative rather than qualitative. The word "qualitative" is deleted in the draft text, and it is specified that the relation between social demands and individual limited capacities is critical for symptom manifestation (criterion C). Because the proposed levels of support requirement in the draft are mere observable outcomes of social vulnerability, the boundary between level 1 and nonautistic condition is determined by the relation between social demands and individual capacities. In addition to the introduction of the single category (autism spectrum disorder (ASD)) to cover the entire case spectrum, the DSM-5 draft is clearly based on a conviction that ASD is indistinguishable from the normal behavioral range. This concise review provides an explanation for this implicit paradigm shift from qualitative to quantitative. Importantly, the conditional role of social demands for symptom manifestation in the draft can be plausibly interpreted using a unique liability-probability model.

For others: epistasis and the evolutionary survival of an extreme tail of the quantitative distribution of autistic assets.

The ongoing paradigm shift from the traditional qualitative dichotomy concept to the quantitative framework increases the necessity of an evolutionary implication and interpretation of the presence of a hypo-reproductive behavioral extreme (autism) with strong genetic contribution. As a theoretical challenge to explain the survival of the dimensional distribution of autistic traits, an epistasis-associated oscillation of fitness outcomes is proposed. In this hypothesis, an allele could contribute to the existence of both phenotypic extreme tails and the hypothesized genetic machinery (quantitative trait loci) for autism would necessarily be common in the entire human population. The postulated autism genes would allow autistics to enjoy autistic traits and assets and all of the residual non-autistic individuals could owe their social skills and reproductive advantages to the same autism genes. Importantly, the reported modest correlations between core autistic dimensions can be illustrated using unsynchronized epistatic pleiotropy.

Computerized lifelong mentoring support using robot for autistic individuals.

Developmental diversity in childhood is transformed into personality variation in adulthood. This view is now revalued through an ongoing paradigm shift in the field of developmental conditions, the transition from the qualitative dichotomy perspective to the quantitative concept. In the quantitative concept, autism is not a disease nor a developmental qualitative disorder, but a behavioral extreme in individual variation. Although the traditional qualitative view cannot interpret the recent worldwide prevalence of autism, the increase in the reported number of cases with autism and border cases can be easily explained by a dimensional exploration in which the primary autistic phenotype is regarded as an evolutional superiority. Therefore, the only suitable intervention is mentoring which provides a powerful lifelong support for higher social achievement in individuals with autism. Here, we hypothesize the coming mentoring circumstances for autistic individuals in the near future. Ongoing progress in robot and computer technology might allow the guardians to leave the major part of mentoring support to an individualized robot, and the 'folk physics' tendency in individuals with autism could facilitate the spread of the mentoring support system. The development of the robot mentor software may be simple because of the uniformity and stereotypy of the behavior patterns in individuals with autism. With the help of the robot mentor and under its guidance, autistic people might enjoy their social life and contribute to the prosperity of the human society to the maximum degree. Because the future population ratio of autistics/non-autistics might be reversed according to the current trend of the prevalence, mentoring robot programs for autistic individuals should be developed without delay as a novel preliminary activity in the Jiminy Cricket movement, which is a campaign to reverse the estrangement of the present majority from autism and to increase the number of mentors for autistic individuals. In this article, prerequisites for the mentoring program of the robot mentor are expected and discussed.

The prenatal autistic imprinting hypothesis: developmental maladaptation to the environmental changes between womb and the social world.

Although the importance of biological and genetic aspects of the etiology is well recognized, the pathological process of autism still remains to be elucidated. In contrast to a qualitative dichotomy concept, a dimensional perspective that places the autistic traits as quantitative extremes can easily explain the diversity and subtlety of the clinical features. In a dimensional (quantitative continuum) condition, no single qualitative process can distinguish the extremes from normal variations. In addition, the traditional view, which regards autism as a hypo-reproductive disease with a strong genetic contribution, cannot interpret the recent worldwide prevalence of autism. From a novel viewpoint, we have proposed 'the prenatal autistic imprinting hypothesis' in which autism is regarded as an inevitable consequence of human social evolution in both past and future. Postulated primary phenotypes are closely associated with the autistic savant skills and the autistic adherent temperament, and might increase the chance of specific prenatal experiences, named 'autistic imprinting'. An earlier prenatal brain growth and an earlier establishment of a type of consciousness may be critical for the imprinting process. A postnatal autistic social maladaptation may be a mere outcome of the putative intrauterine behavioral adaptation in individuals with the primary phenotypes. Both an autistic manner of thinking, which is referred to as 'visual thinking', and the prenatal early development of visual cortical architectures may play a key role in the autistic imprinting process.

The scientific establishment of a new therapeutic intervention for developmental conditions: practical and ethical principles.

BACKGROUND: Although the randomized controlled trial (RCT) is a major methodological breakthrough extending the limits of objectivity in clinical medical science, clinical trials of surgery have seldom included placebo surgery as a control, for ethical reasons. Especially in clinical studies intended eventually to establish a new intervention for developmental conditions, it has been recognized that there is huge examiner bias. In addition, the many miraculous cases that have been reported in nonsurgical open trials for developmental conditions and have eventually been evaluated as nonspecific positive outcomes in RCTs suggest that empirically promising interventions must be subjected to scientific scrutiny as soon as possible in the field of developmental conditions. APPLICATION TO PEDIATRIC NEUROSURGERY: Therefore, in childhood neurosurgery, clinical studies to establish a new therapeutic measure for developmental conditions should be designed as rigorously as possible using optimized scientific methods. The worldwide ethical guideline, the Declaration of Helsinki issued by the World Medical Association, can provide principles for the establishment of a new intervention in the treatment of a patient when proven therapeutic methods do not exist or methods used thus far have been ineffective. Physicians' discretion to use unproven or new therapeutic measures for such patients is approved in the presence of efforts of an ethical and scientific approach. Even if the measure is a very promising intervention, the research aspects must completely be demonstrated for informed consent and review by the ethical committee and the trial must be regarded as a clinical research. Especially when an RCT is not possible for ethical reasons, appropriate epidemiological data or animal experiments should suggest that the new measure is effective before a clinical trial. In a clinical setting, where neither epidemiological studies nor animal experimentation can be introduced, if necessary the researcher should collaborate with experts to obtain multidisciplinary justification for clinical testing.