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Although studying is considered a legitimate scientific nowadays, it is still a very young one. In the early 1970s, a psychologist named J. Guilford was one of the first academic researchers who dared to conduct a study of creativity. One of Guilford’s most famous studies was the nine-dot puzzle. He challenged research subjects to connect all nine dots using just four straight lines without lifting their pencils from the page.
Today many people are familiar with this puzzle and its solution. In the 1970s, however, very few were even aware of its existence, even though it had been around for almost a century. If you have tried solving this puzzle, you can confirm that your first attempts usually involve sketching lines inside the imaginary square. The correct solution, however, requires you to draw lines that extend beyond the area defined by the dots.
At the first stages, all the participants in Guilford’s original study censored their own thinking by limiting the possible solutions to those within the imaginary square (even those who eventually solved the puzzle). Even though they weren’t instructed to restrain themselves from considering such a solution, they were unable to “see” the white space beyond the square’s boundaries.
Only 20 percent managed to break out of the illusory confinement and continue their lines in the white space surrounding the dots. The symmetry, the beautiful simplicity of the solution, and the fact that 80 percent of the participants were effectively blinded by the boundaries of the square led Guilford and the readers of his books to leap to the sweeping conclusion that creativity requires you to go outside the box.
The idea went viral (via 1970s-era media and word of mouth, of course). Overnight, it seemed that creativity gurus everywhere were teaching managers how to think outside the box.
Consultants in the 1970s and 1980s even used this puzzle when making sales pitches to prospective clients. Because the solution is, in hindsight, deceptively simple, clients tended to admit they should have thought of it themselves. Because they hadn’t, they were obviously not as creative or smart as they had previously thought, and needed to call in creative experts.
Or so their consultants would have them believe. The nine-dot puzzle and the phrase “thinking outside the box” became metaphors for creativity and spread like wildfire in, management, psychology, the creative arts, engineering, and personal improvement circles. There seemed to be no end to the insights that could be offered under the banner of thinking outside the box. Speakers, trainers, training program developers, organizational consultants, and university professors all had much to say about the vast benefits of outside-the-box thinking. It was an appealing and apparently convincing message.
Indeed, the concept enjoyed such strong popularity and intuitive appeal that no one bothered to check the facts. No one, that is, before two different research —Clarke Burnham with Kenneth Davis, and Joseph Alba with Robert Weisberg—ran another experiment using the same puzzle but a different research procedure.
Both teams followed the same protocol of dividing participants into two groups. The first group was given the same instructions as the participants in Guilford’s experiment.
The second group was told that the solution required the lines to be drawn outside the imaginary box bordering the dot array. In other words, the “trick” was revealed in advance. Would you like to guess the percentage of the participants in the second group who solved the puzzle correctly? Most people assume that 60 percent to 90 percent of the group given the clue would solve the puzzle easily.
In fact, only a meager 25 percent did. What’s more, in statistical terms, this 5 percent improvement over the subjects of Guilford’s original study is insignificant. In other words, the difference could easily be due to what statisticians call sampling error. Let’s look a little more closely at these surprising results.
Solving this problem requires people to literally think outside the box. Yet participants’ performance was not improved even when they were given specific instructions to do so. That is, direct and explicit instructions to think outside the box did not help. That this advice is useless when actually trying to solve a problem involving a real box should effectively have killed off the much widely disseminated—and therefore, much more dangerous—metaphor that out-of-the-box thinking spurs creativity. After all, with one simple yet brilliant experiment, researchers had proven that the conceptual link between thinking outside the box and creativity was a myth. Of course, in real life you won’t find boxes. But you will find numerous situations where a creative breakthrough is staring you in the face.
They are much more common than you probably think. *From Copyright 2014 Drew Boyd. There are many theories of creativity. What the latest experiment proves is not that creativity lacks any association to thinking outside-the-box, but that such is not conditioned by acquired knowledge, i.e., environmental concerns. For example, there have been some theories such as those of Schopenhauer (see his remarks about Genius) and Freud (see his remarks about Sublimation) that propose creativity is something more like a capacity provided by nature rather than one acquired or learned from the environment.
Rather than disproving the myth, in other words, the experiment might instead offer evidence that creativity is an ability that one is born with, or born lacking, hence why information from the environment didn't impact the results at all. It's an interesting experiment, but the author's conclusion cannot possibly follow from the results of it. I conduct soft skills training and outbound training for Corporates and individuals. To enhance creativity we motivate the participants to approach the problems from variety of vantage points.
Even repeatedly checking the boundary conditions we are able to come up with variety of ways of solving the problem. This is akin to checking the walls of the box. Looking inside the box for additional information, additional resources also helps. Looking at the box from bird's eye view triggers some different creative solutions. Let us not get tied down to the mechanics but free ourselves to find the solution. I will give an example.
You are playing football with family and friends at a distant ground and someone gets bruised badly. No first aid kit is available.
Your priority is to get the person to a hospital ( at a distance of 2 hours ). The wound is bleeding and needs to be kept clean and bacteria free till the person reaches the hospital. What will you do? Think of a solution. It is quite close to you.
With all due respect, Professor Boyd, your argument is not at all compelling. It seems that you are taking the 'thinking outside the box' (TOTB) metaphor much more literally than it is intended (or, at least, as I and may others infer). Let me point out a few false and/or negligent statements that you make: 1. To refer to TOTB as 'dangerous' is naive, at best. I, personally, have seen the positive, tranformative effects of not only the 9-dots exercise, but also the occasional use of the term to remind individuals after-the-fact about the value of thinking differently.
The experiment you refer to doesn't even come close to proving what you suggest that it does. To use the term 'proving' in an argument like this is laughable. In real life, you absolutely WILL find boxes.that is, if you understand what the term 'box' refers to. Here, the term is not literal; rather, it refers to a mindset, a perspective, a belief, or an assumption. It is precisely how the human mind works. We all think in boxes all the time. The 'sin,' if you will, is not in thinking inside of a box.but the neglect to readily switch from one box to another, nimbly (see Alan Iny's new book, 'Thinking in New Boxes').
A different -- and very healthy, positive, and productive -- way to think about TOTB is to understand that it merely represents an insight that can remind an individual to consciously become aware of limiting assumptions. And, upon such awareness, to open ones mind and imagination to actively explore new possibilities beyond the obvious or initial answer. If you don't regard this as valid contribution to creativity, then I suggest you consider spending a bit more time outside of that 'box' that you've presented here. I couldn't have said it any better. TOTB is a beautiful skill to have. We are born into multiple boxes that are created upon social agreements (e.g. Illustrated by the hermeneutic circle) but the ones who dare to think outside of what is considered as social or scientific correct (all the boxes together) are the minds whom are absolute free and open towards new moralities, paradigms, innovations and creativity in general.
Saying that TOTB is a negative thing is a very conservative statement and someone who has such a belief is scared of change, scared of diversity and scared of anything that is abstract and out of order. I'm all about TOTB and the best way to TOTB is to fully understand the box in the first place and why some people are scared of TOTB hence also lacking the ability to do so. Fold the paper so all the dots ovelap. Use four lines to connect four dots. Hold the folded paper up to the light.all dots connected; Thinking outside The Box. For that matter, you could fold the paper until all the dots overlapped and you would not need to waste any pencil lead; Thinking outside The Box. Use a very wide pencil lead or charcoal block for that matter, connect all the dots in one fell swoop; Thinking outside The Box.
Forego a pencil altogether and use a bucket of paint to create a huge blot over all the dots; Thinking outside The Box. Question the dots and why they need to be connected in the first place; Thinking outside The Box. Erase the dots; they are a distraction to Thinking outside The Box. Create your own dots and lines in any fashion you desire; Thinking outside The Box. People that say, it's a misguided idea,, do not know how to think outside the box, I can look /listen/ at anything an tell you how to fix it. I play chess with my pc, an beat it all the time, and the reasoning is I do not think logically, like the pc does. It has a set of rules that it was programed with an you were in college, I do not play by the rules, I can play without the queen.Also when you go the a school that teaches how to think about something, that is all you know how to do.I have had engineers come to my deck, hand me a set of blueprints, because that was the way they were taught.
They are never taught to look at it, in there mind to see it working. What I do is show them how wrong they are, an ask them what tool in the world can cut a square hole inside the middle of two long tubes. They can not think outside the box, that they were taught to do. If was going to tell you about an airplane the TR-3B, it travels a little bit under light speed, an it uses nuclear fusion, which turns into plasma an powers the craft, that was built outside the box. An if you do not believe me type it into your search engine, you can also look it up at the library of congress under new patients. You my brother, do not have the inkling of understanding to think outside the box. That's why you are a psychologist an nothing more.
Considering Risk Factors Environmental risk factors must be viewed in context with genetic risks and host characteristics. Environmental factors are also potentially modified by genetics, and may act to increase or decrease risk of disease. It is often said that “age is the greatest risk factor for AD and dementia.” While in one sense the statement is true, because the incidence of AD and dementia increase essentially exponentially with age, the increase is likely not due to age itself, but to the cellular effects of aging coupled with the age-related penetrance of genetic factors. Age itself is not a modifiable risk factor, unless an age limit were to be placed on lifespan by the government—and that is only the stuff of draconian science fiction. Examining factors that could modify the molecular and cellular effects of aging is a more laudable and researchable goal.
Historically, most early studies on environmental risk factors for AD were of rather rudimentary case–control design. AD cases with dementia formed the case groups and cognitively intact persons, usually of similar age and gender, constituted the control group. Exposure histories, prior to onset of the disease (or a similar time for controls), were then obtained in some way from each subject, and the exposure frequencies between groups were compared. While this sounds simple and straightforward, it was fraught with pitfalls. Potential biases from case or control selection methods, and whether selection might in some way be associated with exposure, often caused great and unrecognized difficulties. The differential recollection of past exposures by cases and controls led to recall bias in the measures of effects.
Exposure history was often inadequately or incompletely determined. Poor assessment of temporality between risk factors and disease onset—for example, failure to account for whether putative risk factors could be actual effects of the disease syndrome (e.g., depression)—often led to so-called “reverse causation.” Figure 15.1 shows clearly the difficulty in determining correctly the temporality of exposure relative to the inception of disease pathology when the case definition rests on dementia diagnosis while the initiation of pathology may have begun 20 years earlier—causing the etiologic exposure window to include only exposures prior to that time. Because of these and other methodological flaws, most of the case–control studies of environmental risk factors occurring between 1975 and 1990 should be viewed through the prism of skepticism, even though investigators of the time were attempting to conduct state-of-the-art investigations. By about 1990, researchers realized that more valid answers to risk factor questions could be obtained using “cohort” study designs; that is, enrolling cognitively normal persons and examining them periodically over time to determine whether their cognition had worsened, or worsened to the point of dementia [52–54]. These designs eliminated much of the potential selection bias seen in case–control studies and also had the advantage of obtaining exposure histories directly from cognitively intact subjects, since despite imperfect recall the subjects did not know if they would later develop symptomatic disease. The results of environmental risk factor studies based on cohort designs are generally more likely to be valid than those previously obtained from case–control studies.
Still, case–control studies that are very well done can provide valid estimates. Thus, it is the reader’s task to examine each such study critically in order to make a judgment about the potential value and validity of its results. Etiology and Pathogenesis Environmental risk factors. JDM is thought to be the result of environmental triggers in genetically susceptible individuals, leading to immune dysfunction and specific tissue responses. The potential role of environmental factors in myositis etiology is supported by reports of geographical and seasonal clustering of cases. 21,22,54,63,67,68 Seasonality in the birth distributions of JDM patients who are Hispanic, those with the human leukocyte antigen (HLA) risk factor DRB1 ∗0301 allele, and those with the p155 autoantibody suggests that perinatal or early life exposures may be implicated in these subgroups.
69 Evidence for the participation of infectious agents is for the most part indirect. 70 In two large cohorts, an antecedent upper respiratory infection or gastrointestinal illness frequently preceded onset of JDM symptoms within 3 months, 65,68 and in a case-control study, children with JDM more frequently reported symptoms of an antecedent illness than healthy control children.
63 Cases of infections with coxsackievirus, influenza, Group A Streptococcus, Toxoplasmosis, parvovirus, hepatitis B, Borrelia, and Leishmania preceding the onset of JDM have been documented. 37,72 Although acute muscle inflammation may result from viral illness, there are no unequivocal data supporting a viral cause for JDM.
73,74 Serological evidence of coxsackievirus B infection was first reported in 83% of children with early JDM, compared with 25% of control subjects, 75 but a second case-control study failed to confirm this association, and enteroviral, herpes virus, and Toxoplasma titers were also not elevated. 63 A search for the presence of viral genome in affected muscle from patients with JDM using the polymerase chain reaction was negative. 76 Acute transitory myositis may occur after influenza infection. 77-84 A case-controlled study suggests elevated titers of influenza A and parainfluenza virus in affected juvenile myositis patients compared to matched controls. 85 Children with JDM have been reported to express IgG antibodies against viral non–syncytium-inducing protein, perhaps induced by persistent parvovirus B19 infection, 86 although a case-controlled study failed to reveal elevation in titers or persistent B19 viral genome in the peripheral blood or muscle of JDM patients compared to matched healthy control children. 87 Group A Streptococcus may be more frequent in juvenile polymyositis patients compared to healthy controls. 88 Relapse with β-hemolytic streptococcal disease may be related to molecular mimicry between the M5 protein and skeletal muscle myosin and immune responses to homologous peptide regions.
89-91 Toxoplasma gondii was demonstrated in muscle in one patient with JDM. 92 Elevated antibody titers to Toxoplasma have been reported in some studies, 93,94 but appropriate controls were lacking. A dermatomyositislike disease has been described in a few children with agammaglobulinemia in association with echovirus infection 95,96 and occasionally in patients with selective immunoglobulin A (IgA) deficiency 97,98 or deficiency of the second component of complement (C2), all children in whom an inordinate susceptibility to infection might be anticipated 99 (see Chapter 37). Electron microscopic examination of muscle has demonstrated tubuloreticular structures within endothelial cells that resembled the myxoviruslike particles identified in patients with systemic lupus erythematosus (SLE). These cytoplasmic tubular array structures are thought to indicate a type I interferon response, which could be induced by viral infections.
64,100,101 This finding, however, may be artefactual and reflect degenerative or regenerative alterations in cytoplasmic constituents of endothelial cells ( Fig. 102,103 Less information is available on noninfectious environmental exposures related to the onset of JDM.
In a large North American registry of JDM patients, 38% of patients reported two or more exposures within 6 months prior to diagnosis, generally a combination of infectious and noninfectious exposures, with variation in the exposures in clinical and serological subgroups of patients. Noninfectious exposures included medications (18%), a number of which were potentially photosensitizing or myopathic, immunizations (11%), stressful life events (11%), unusual sun exposure (7%), and others including chemicals, animal contact, weight training, and dietary supplement use (. SUSCEPTIBILITY GENES IN NEURODEGENERATION Environmental risk factors alone cannot be responsible for the majority of sporadic forms of neurodegenerative diseases, whose etiology is most likely due to the contribution of several susceptibility genes at multiple loci and interaction between them and/or environmental factors. Late onset Alzheimer's disease represents the vast majority of all AD cases with an age at onset of 65 years or older.
Studies on both twins and first-degree relatives indicate the existence of a contribution of genetic factors in LOAD ( 52, 53), however the most highly replicated genetic risk factor for LOAD is the apolipoprotein E ( APOE) gene on chromosome 19q13. The APOE-ɛ4 allele imposes a 2.3–3 fold increased risk of AD for chromosome copy carried by an individual, compared to the common APOE-ɛ 3 allele, while the APOE-ɛ 2 allele decreases the risk ( 54, 55). Thus the effect of the APOE-ɛ 4 variant is dose related with a lower estimated risk in heterozygous carriers, compared to homozygous APOE-ɛ 4 individuals, moreover the effect of APOE-ɛ 4 on the risk of AD decreases with increasing human age ( 54). APOE-ɛ 4 variant is associated with higher plasma cholesterol levels, and is supposed to enhance Aβ deposition and the formation of neuritic plaques ( 44); however APOE-ɛ 4 is not a causative gene, meaning that the presence of this variant is neither necessary nor sufficient to develop the disease. More than 50% of the genetic variance of AD is not due to mutations in APP, PS1, PS2, and APOE-ɛ4, suggesting the existence of additional susceptibility and perhaps causative AD loci ( 56). Several genes have been associated, over the years, with the risk of AD, but none of them has been repeated and confirmed as an AD susceptibility factor with the same consistency as APOE-ɛ 4; in addition wide-genome linkage studies suggest the existence of multiple putative AD loci, with evidence for chromosomes 12, 10, 9, and 6 ( 57). Because of the strong association between APOE-ɛ 4 and the risk of AD, several genes involved in cholesterol metabolism and transport have been studied as potential susceptibility factors: polymorphisms of the genes encoding cholesterol 24-hydroxylase ( CYP46A1), the ATP-binding cassette A1 ( ABCA1), and the low-density lipoprotein-receptor-related protein ( LRP1), have been considered in association studies with the risk of AD; despite some associations being reported, results are almost conflicting, not repeated, and are inconclusive ( 44).
At present among promising gene candidates identified by positional cloning on chromosome 10 there are CTNNA3, PLAU, and mainly IDE. Indeed it is considered that there might be as many as four additional genes with similar effect size to APOE yet to be discovered ( 55). APOE variants have also been studied for their possible role in other neurodegenerative conditions: the APOE-ɛ 2 allele, which is protective in AD, is an emerging risk factor for sporadic PD and frontotemporal dementia; while no consistent associations have been observed for the APOE-ɛ 4 variant ( 58, 59). There is virtually no evidence for an association between APOE genotype and the risk of ALS; however some evidence indicates an effect of the APOE genotype on the age of onset and clinical presentation of sporadic ALS, with a protective role for both the APOE-ɛ 2 and APOE-ɛ 3 variants respect to the APOE-ɛ4 one ( 18); inconclusive results have been obtained in association studies between APOE-ɛ 4 and the risk or progression of CJD ( 60). Epidemiological studies suggest that elevated plasma homocysteine levels play an important role in the pathogenesis of AD, and folate and homocysteine-metabolizing gene polymorphisms, mainly in the methylenetetrahydrofolate reductase gene ( MTHFR), have been tested as risk factors for the occurrence of AD; however, despite some associations and interactions with the APOE genotype being observed ( 61), results are still controversial ( 62). Long-term inflammation is a risk factor for AD, and associations between genes encoding for members of the interleukin (IL) family, particularly IL-1α, and AD have been observed ( 63). Several chemicals require metabolic activation to exert their toxic effect, so that polymorphisms in genes encoding for enzymes involved either in the phase I or in the phase II of the metabolic processes, have been extensively tested as possible susceptibility factors in neurodegenerative disorders.
Cytochrome P450 iso-enzymes (CYPs) are involved in phase I, they add a molecule of oxygen to the parent molecule leading to the formation of an intermediate, which can then react with phase II enzymes such as glutathione S-transferases (GSTs) or N-acetyltransferases (NATs). A polymorphism of CYP2D6, encoding for a cytochrome P450 enzyme which metabolizes MPTP, has been associated with PD in some studies, but not in others, and the relevance of this polymorphism in sporadic PD remains controversial ( 64). Bobby Bland Two Steps From The Blues Rapidshare. Association studies between CYP2D6 polymorphisms and ALS are still inconclusive ( 18). Conflicting results have been obtained also when polymorphisms in the CYP1A1 gene, responsible for the metabolisms of chemicals present in cigarette smoke, have been tested for their possible association with PD ( 64). GSTs are a family of dimeric proteins whose primary function is to detoxify electrophiles capable of binding to DNA, and the toxic effects of pesticides can be attenuated through a GST-mediated metabolism. An association between GSTP1 polymorphisms and PD was described in a pesticide exposed population ( 65). Moreover GSTP1 polymorphisms have been recently proposed as candidate susceptibility variants for AD ( 66, 67).
Studies on Drosophila models of PD with mutations in the parkin gene indicate that overexpression of glutathione S-transferase S1 gene in dopaminergic neurons suppresses neurodegeneration ( 68); moreover a recent role in modulating age at onset of both AD and PD has been observed for polymorphisms in the GSTO1 and GSTO2 genes ( 69, 70), however others did not find association with the age at onset of AD ( 71). No association between GSTO1 and GSTO2 variants and age at onset of HD has been found ( 72).
N-acetyltransferase 2 (NAT2) participates in drug and xenobiotic metabolism and more than 25 mutant alleles have been observed for the NAT2 gene, several of them leading to a slow acetylator phenotype. The NAT2 slow acetylator phenotype has been associated with an increased risk of early-onset PD ( 73); moreover NAT2 has been suggested to be a potential low-penetrance gene in AD pathogenesis ( 74); however results are still inconclusive and require further clarification ( 75). Monoamine oxidase B (MAO-B) plays a key role in the metabolism of dopamine and MPTP, and is a generator of free radicals leading to oxidative damage; for all these reasons an active role of this enzyme in the pathogenesis of PD and other neurodegenerative disorders has been supposed and tested: controversial results have been obtained in association studies between MAO-B polymorphisms and PD ( 64), however a MAO-B variant has been associated with age at onset of ALS, supporting a role for oxidative stress in ALS ( 18).
Among other candidate susceptibility genes for PD, polymorphisms of the genes encoding for the dopamine receptors D2 and D4 and for the dopamine trasporter yielded conflicting results in association studies, or still require confirmation ( 64). Concerning neurotransmitters and AD, a polymorphism of the gene encoding the serotonin receptor (5-HT2A) has been associated with neuropsychiatric symptoms in AD ( 76, 77). Abnormal accumulation of neurofilaments in the cell body and proximal axons of motor neurons is a common pathological hallmark of ALS, suggesting a role for neurofilaments in motor neuron pathology. Coding sequences of neurofilaments are polymorphic, and these variants are among putative susceptibility factors in sporadic ALS ( 78). Excitotoxicity genes and DNA-repair genes are among other candidate risk factors for ALS ( 18). In contrast with the other neurodegenerative diseases discussed in this chapter, HD is caused by mutations in a single gene; for this reason other genes are likely to affect the age at onset or the progression of the disease, rather than the risk. The most convincing example is given by the gene encoding the glutamate kainate ionotropic receptor R6 ( GluR6), which has been associated with age at onset ( 79).
Different mutations in the same locus ( PRNP) can either be causative of familial prion diseases or result in susceptibility variants for the sporadic forms. A common polymorphism at codon 129 of PRNP, leading to a methionine to valine substitution, has been observed to interact with causative mutations in familial CJD, affecting both clinical presentation and progression; moreover this polymorphism has been also associated with the risk of sporadic forms of CJD ( 60). Susceptibility factors for neurodegeneration are listed in Table 3. Risk factors for glioma Environmental Risk Factors Many environmental and behavioral risk factors have been investigated as causative for glioma. The only well-validated factors are an increased risk associated with exposure to ionizing radiation 4 (the type of radiation generated by atomic bombs, therapeutic radiation treatment, CT scans, MRI scans, and x-rays) and a decreased risk in persons with history of allergy or other atopic disease 5 (including eczema, psoriasis, and asthma).
Recent review articles have further elaborated on the current state of risk factor research in malignant brain tumors. 6 Heritable Genetic Risk Factors Several inherited, monogenic mendelian cancer syndromes are associated with increased incidence of glioblastoma, including Lynch syndrome (glioblastoma and other gliomas), Li-Fraumeni syndrome (glioblastoma and other gliomas), melanoma–neural system tumor syndrome (all gliomas), and Ollier disease/Maffucci syndrome (all gliomas). 6,7 However, these monogenic disorders account for only a small proportion of glioma cases (. Maternal environmental exposures and immune maturation Most environmental risk factors implicated in the allergy epidemic have demonstrated effects on early immune development, beginning in utero. This includes microbial exposure, early nutritional patterns, smoking, and other environmental pollutants, with demonstrated effects on both animal models and human observational and/or intervention studies.
41,42 Microbial exposure is arguably the strongest environmental stimulus for immune maturation, particular of regulatory and Th1 adaptive responses. Whereas most studies investigating the early immunomodulatory mechanisms have focused on postnatal microbial exposure, it is increasingly clear that the maternal microbial environment during pregnancy is also important in early immune programming. 43–46 In normal healthy pregnancies, microbes can be detected in amniotic fluid, 47,48 placental 48 and fetal membranes, 48,49 cord blood, 50 and meconium. 51–53 This reveals that the womb is not sterile after all, and that antenatal microbial exposure provides an important initial source of immune stimulation for the fetus.
Experimental models confirm that exposure to bacterial endotoxin, probiotic bacteria, or other apathogenic bacteria has immunomodulatory effects and protects the offspring against an allergic phenotype. 54–56 These effects appeared to be mediated by activation of maternal innate (TLR) pathways, 56 with associated epigenetic effects on the regulation of Th1 gene expression in the newborn offspring. 57 Bavarian farmhouses provide one of the best natural experiments to see the effects of microbial exposure on humans. 43,58,59 Children growing up in this setting have a reduced risk of allergic disease, 60 and antenatal exposure affords greater protection from allergy than postnatal exposure alone. 58,59 Biological data collected from cord blood samples also support this antenatal effect.
At birth, newborns from farming families have increased numbers and function of regulatory cells (T reg) and lower type 2 immune responses. 19 At age 4, T reg function is still more efficient in farm milk–exposed children, which points to a strong persisting effect during immune maturation. 20 They also show higher Th1 responses, which are likely to be important for suppressing the development of allergy in the critical period after birth. 61 Most of these protective effects, most particularly against asthma, appear to result from contact with cows and straw and consumption of unpasteurized farm milk 62—all major indicators of the high microbial diversity that characterizes the farm environment.
Furthermore, prenatal farm exposure was associated with a distinct epigenetic methylation pattern of asthma- and allergy-related genes such as genes from the ORMDL family, RAD50, IL13, and IL4. 63 Thus, part of the farm effect may be mediated by epigenetic regulation. Maternal nutrition has another significant influence on immune development and allergy risk.
64–66 Both specific nutrients and common dietary patterns have major effects on all aspects of fetal development, including immune function. A particular dietary pattern that has shown protection from allergy and other NCDs is the Mediterranean diet. Protection against childhood wheezing and other allergic manifestations 67–69 may be related to higher levels of fiber, omega-3 polyunsaturated fatty acids (n-3-PUFA), and antioxidants in fresh fruits and vegetables (vitamins A, C, and E) and prebiotics, 66 all of which may have direct effects on immune function and anti-inflammatory effects on tissues. In particular, we have shown how increasing n-3-PUFA levels of diets in both pregnancy 70 and infancy 71 can have favorable effects on infant immune function (increasing Th1 responses and reducing Th2 responses).
Adverse exposures in pregnancy may also influence fetal immune development, the most obvious and well-studied of which is maternal smoking, with toxic effects on placental function and many aspects of fetal growth and development. This includes specific effects on lung growth and asthma risk 72 and on immune function. 73,74 Oxidative stress produced by cigarette smoking and air pollution can have significant epigenetic effects including remodeling of proinflammatory genes. 42 Mice exposed to diesel exhaust particles show an increased production of IgE with associated underlying epigenetic effects.
75 In humans, exposure to traffic particles in pregnancy has also been associated with epigenetic changes and has increased risk of developing asthma symptoms in children. 76 The many thousands of modern chemicals and pollutants that contaminate modern homes, food, clothing, and water sources, accumulating in human tissue with age, also may have adverse effects on human immune development, 77,78 although this is still ill-defined.
Notably, many of these and other contaminants have been associated with epigenetic effects 79,80 including effects on global deoxyribonucleic acid methylation patterns at the low-dose exposure found in the ambient environment. 81 A number of other exposures in pregnancy are also likely to influence immune function (reviewed elsewhere 65), including maternal stress and hypothalamic–pituitary–adrenal activation, which are closely linked to placental and immune function. Medications commonly used in pregnancy, such as antacids, reflux medications, paracetamol, and antibiotics, 82–84 may carry an increased risk of some allergic diseases. Finally, there are emerging possible risk factors for allergy that are of uncertain significance, including higher risk of asthma in children conceived by in vitro fertilization. 85 Although this can be partly explained by the higher risk of neonatal complications, lower parental fertility appears to be a factor. 85 This could implicate a range of other modern environmental factors contributing to changes in reproductive health.
All of these relationships serve to highlight the importance of the in utero environment in early immune programming as an essential prelude to environmental encounter after birth, shaping many other aspects of development and future health. Environmental factors The major environmental risk factor is HBV infection, which has been firmly associated with PAN for 40 years. In areas endemic for HBV infection, up to 95% of cases are associated with it. In France, falling HBV infection rates have correlated with a decrease in HBV-associated PAN. 12 In Alaska, HBV-associated PAN has disappeared from the population following the introduction of a vaccination program. In this population, infection was associated with D genotype HBV. 13 Other viruses such as human immunodeficiency virus (HIV), parvovirus B19, and hepatitis C virus (HCV) have also been associated with PAN.
Immune-Related Genetic Risk Factors for Schizophrenia Although several environmental risk factors for schizophrenia seem to converge on immune activation pathways, many immune-related genetic risk factors, including common gene variants, copy number variations, and short nucleotide polymorphisms, are also associated with schizophrenia. The most replicable site is on chromosome 6, which harbors specific haplotypes of immune genes, including those encoding major histocompatibility complex (MHC) proteins.
Consistent with this, several large genome-wide studies have together identified over 450 schizophrenia-associated short nucleotide polymorphisms that map to the MHC locus ( International Schizophrenia et al., 2009; Jia et al., 2012; Lee, Woon, Teo, & Sim, 2012; Michel, Schmidt, & Mirnics, 2012; Shi et al., 2009; Stefansson et al., 2009). In addition, a meta-analysis of data from genome-wide association studies significantly associates a region of linkage disequilibrium on chromosome 6p22.1–6p21.31 with schizophrenia ( Shi et al., 2009). MHC1 is involved in different aspects of immunity, brain development, and synaptic plasticity ( McAllister, 2014).
Short nucleotide polymorphism rs6904-71, located in the MHC region, is associated with delayed episodic memory and decreased hippocampal volume in schizophrenia and healthy subjects ( Walters et al., 2013). Interestingly, two protective HLA alleles, HLA-B ∗08:01 and DRB1 ∗03:01, have been identified ( Irish Schizophrenia Genomics & the Wellcome Trust Case Control, 2012). In searching for schizophrenia susceptibility genes in the class III region of the human MHC, three short nucleotide polymorphisms near the NOTCH4 locus are associated with schizophrenia-rs1009382, rs204887, and rs8283 ( Wei & Hemmings, 2004). Mutations in stimulating factor receptor 2 alpha ( CSF2RA), IL3RA, IL1, and the promoter haplotype for TNFA are also linked to schizophrenia ( Katila, Hanninen, & Hurme, 1999; Lencz et al., 2007; Saviouk, Chow, Bassett, & Brzustowicz, 2005).
Altogether, these findings suggest that genetic predisposition can contribute to the widespread immune dysregulation observed in schizophrenic individuals and further raises the interesting notion of convergent pathways by which immune-related environmental and genetic risk factors contribute to the etiopathology of schizophrenia. Claim Two: Environmental and Genetic Risk Factors for Autism Cause Brain Disruptions that are not Causally Specific to Autism Symptoms Genetic and environmental risk factors yield autism symptoms along with other symptoms and disorders. As Lord and Jones (2012) posited, “the most significant scientific challenge to the concept of autism as one ‘disease’ or even ‘diseases’ is the heterogeneity of the genetic findings” (p.
Fragile X syndrome ( Bray et al., 2011), Rett syndrome ( Goffin et al., 2012), and other genetic risk factors for autism symptoms have been associated with varied brain disruptions and a range of phenotypes. Variant phenotypes have included complete autism phenotypes, partial autism phenotypes, and phenotypes comprised of non-autism symptoms along with or independent of autism symptoms ( Hoeft et al., 2011; Wulffaert, Van Berckelaer-Onnes, & Scholte, 2009). For example, Fernandez et al. (2012) reported evidence for three large de novo (new and unique to the set of individuals studied) chromosomal copy number variants that caused both autism symptoms and tic disorders. Fernandez et al. (2012) argued that their findings supported the idea of shared genetic bases for different clinical diagnoses.
As Addington and Rapoport (2012) noted, the study of mental disorders has “little reason to expect phenotypic specificity from a particular genetic variant” (p. Talkowski et al. (2012) explored balanced chromosomal abnormalities that index single gene disruptions in a large sample of individuals diagnosed with autism and individuals diagnosed with other neurodevelopmental disorders. The researchers found possible causal gene variants previously linked to neurodevelopmental disorders, single gene contributors to microdeletion syndromes, new gene variants, and genes associated with schizophrenia and bipolar disorder. Talkowski et al.
(2012) proposed a polygenic basis for autism, in which differing mutations in the same sets of genes contributed in an overlapping fashion to autism, schizophrenia, psychosis, bipolar disorder, and intellectual disability. State and Levitt (2011) made the essential point about the widespread nature of brain disruptions caused by genetic variants. They stated, “ Complex functions mediated by hierarchically organized circuitries that include sensory and motor, autonomic regulatory, social-emotional, and cognitive domains” ( State & Levitt, 2011, p. 1) are altered in autism by varied disruptions in the “neurodevelopmental processes that are guided by thousands of genes” ( State & Levitt, 2011, p.
In fact, alterations or combinations of alterations in organizing factors, including gene variants, chromosomal number variants, altered epigenetic processes, and untoward gene–environment interactions may impair brain circuits for many behaviors: social, perceptual, motor, cognitive, and others ( Goh & Peterson, 2012; Sivakumaran et al., 2011). Similarly, environmental risk factors for autism symptoms have yielded many varied outcomes including individuals with all diagnostic autism symptoms, with some autism symptoms, and with many other symptom patterns, along with or independent of autism symptoms. These outcomes include intellectual disability, cerebral palsy, motor disorders, and other neurocognitive impairments ( Guinchat et al., 2012b ).
A wide range of environmental insults are possible, and evidence for environmental risk factors suggests that environmental risk factors are unlikely to disrupt only brain circuits that generate social impairment and aberrant motor and sensory behaviors. Mwaniki, Atieno, Lawn, and Newton (2012) reviewed outcomes of intrauterine and neonatal insults. They reported that epilepsy, vision problems, hearing problems, cognitive impairment, motor impairment, and social impairment were all possible outcomes of insults before or during delivery. (2011) stated that an adverse intrauterine environment, including fetal neuroinflammation from any cause, could confer death of gray matter in the cerebellum, hippocampus, and cortex, and cerebral white matter damage causing long-term deficits in neural connectivity.
Lubsen et al. (2011) argued that glial and neuronal cell death in various brain regions occurred for children delivered prematurely. The researchers also found evidence suggesting that there was damage to neurobiological processes directing axonal growth and synaptogenesis. An additional problem is that interconnected networks increase the vulnerability of individual circuits to developmental disruption. The many brain circuits mediating social behavior are woven through the brain’s interconnections ( Akil et al., 2010; Berntson et al., 2012; Koch, 2012; Molenberghs, Cunnington, & Mattingley, 2012; Solari & Stoner, 2011; Van Essen & Ugurbil, 2012).
For example, consider the central autism symptom of social interaction impairment. As outlined in Chapter 3, social neuroscience research has demonstrated that social interaction depends on many different neurochemicals and many brain circuits, including those mediating social motivation, social cognition, behavioral flexibility, perceptual processing, and many others. Evidence suggests there are multi-purpose processing centers, such as the amygdala, that mediate both social and non-social behaviors. Even presumptively dedicated social brain processing centers such as the fusiform face area may serve more general processing functions, such as discrimination and categorizing of objects. A meta-analysis of 125 studies of human mirror neuron system function conducted by Molenberghs et al.
(2012) suggested that, depending on the tasks involved, the mirror system provides comprehension of action or comprehension of the emotions of others. Berntson, Norman, Hawkley, and Cacioppo (2012) argued, “complexities associated with navigating social systems in primates led to the evolutionary development of some of the most complex networks of the brain the complexity of these networks has thus far precluded a clear mapping between social and neurological processes” (p. In sum, there are many circuits mediating social behavior, many of these circuits are multi-purpose, and circuits mediating social behavior are interwoven with the totality of cortical and subcortical circuits, systems, and networks. Therefore, in order for genetic and environmental risk factors to impair social interaction, risk factors must necessarily cause brain disruptions that impair not only social-behavior-mediating brain circuits, but also brain circuits mediating other behaviors. A brain disruption yielding social impairment would therefore be likely to cause varied additional symptoms such as developmental delay, atypical motor behaviors, and language impairment or delay. As noted earlier, neuroscience findings for regional circuits, systems, and networks within the larger connectome do not suggest that there could be an easy mapping of these interwoven, overlapping, and shared circuits to specific symptoms. For example, Wei et al. Kenwood Integrated Dishwasher Handbook 44.
(2011) hypothesized that three major brain development processes were disrupted in autism: neuron migration; the balance of excitatory and inhibitory synapses; and synaptogenesis. All three are global brain development disruptions. Consequently, the brain disruption model outlined by Wei et al.
(2011) effectively predicts that intellectual disability, motor delay, language impairment, attention deficit/hyperactivity disorder symptoms, and other non-diagnostic symptoms would be likely to co-occur with autism symptoms. Of course, there may be rare cases, like the famous HM of memory research, wherein an individual has severe neurodevelopmental social impairment because of a specific lesion. However, there are myriad brain circuits and neurochemicals that determine the many skills needed for typical social interaction behavior. As outlined in Chapter 3, our many social brain circuits reflect the behavioral evidence that human means for social communication are overbuilt. We have many alternate ways of communicating with one another, such as eye gaze, facial expressions, gestures, body movement, voice tone and pattern, and language. Consequently, a specific focal lesion is less likely to be able to cause severe developmental social interaction impairment.
In sum, the totality of evidence demonstrates that developmental brain disruptions caused by genetic and environmental risk factors for autism will not map one-to-one with autism symptoms. Thus, because these brain disruptions will not be causally specific for autism, efforts to validate autism as a single disorder will continue to fail. Moreover, the presence of associated symptoms with autism symptoms suggests that the autism spectrum of symptoms and the broad autism phenotype will also continue to fail to be validated.