On “neurodivergence". 2. Autism spectrum disorder (ASD)

In an earlier article I discussed the idea of neurodivergence. This term denotes the some difference in one’s brain construction such that one’s behavior is different from that of most other people, those deemed to be “neurotypical”. The behavioral differences presumably reflect emotional and often cognitive differences that the altered brain neural construction gives rise to. Though everyone is different from everyone else in some details of brain construction, certain patterns of difference occur. Such recognizable patterns of difference constitute the major recognized (and named) forms of neurodivergence.

On “neurodivergence”. 1. What does it mean and why does it matter?

In this piece, I focus on one of the commonest categories and, in its range of manifestations, one of the most puzzling. This is so called “autistic spectrum disorder”, abbreviated ASD, described briefly in the earlier piece. Unlike certain classical psychological conditions, which were first named in the 18^th and 19^th centuries (psychosis, schizophrenia, “hysteria”, hypochondria), ASD acquired its moniker in the early 21^st century. Its precursor term was “autism”, which was first described in the scientific literature in 1943.

Autism was first seen and described as manifesting in infants. These young children were clearly different from other infants in several key traits. First, they seemed incapable of normal responses to other people, including their mothers. Indeed, there was a kind of unresponsiveness to normal human contact and speech that most infants begin to show from an earlier age. The unusual infants were also slow to develop language capacity and indeed many never achieved anything like normal speaking ability or seeming ability to understand what was being said. They also showed repetitive movements of their arms, legs or heads that normal children do not show. Finally, and not least, as they grew older, it became clear that they seemed to lack normal empathic capacity; they had a hard time understanding the feelings of others to a degree that was abnormal. (Today, it is understood that people with autistic characteristics often have empathy but some difficulties, nevertheless, in relating to other individuals and problems in expressing their feelings.)

Unsurprisingly in terms of the language deficits of these children, there were usually big cognitive deficits. Some of this learning disability was connected to the language problems but it seemed even more fundamental. Those who reached adulthood retained these traits. Autism was an early developing trait but essentially a lifetime condition. Its basic elements were connected to each other but precisely how was a mystery.

This was autism as it was originally conceived of and described in the 1940s and 1950s. Yet, as the 20^th century proceeded, it became clear that there were many individuals who had autistic characteristics to various degrees but not always the complete set. One group, in particular, seemed autistic in several key respects – in particular, the lack of emotional connection to others, the socialization deficits that can result from that, and often repetitive behaviors– while exhibiting the reverse cognitive characteristic – specifically, high cognitive ability instead of deficits. . These were the “high-functioning autistics”, people who have much higher intelligence than average while having the emotional-empathic gaps typical of autism. This particular condition had its own label for several decades, Asperger’s syndrome, after the psychiatrist who first identified it as a distinct psychological state. ¹

This variability indicates that autism is really a family of related conditions rather than a strictly defined unitary one, though there were some shared commonalities. To denote this variety, the term “autistic spectrum disorder” was coined, in the first decade of our new century, and widely adapted.

This marked an advance in understanding but also ultimately provoked more questions. The word “spectrum”, at least in physics, implies a continuum of states, such as that denoting the wavelengths of light. Was ASD really a continuum or a set of discrete and distinguishable states, albeit with some variability in the severity of the individual treats? If so, how many such different states are there?

At a fundamental cellular level, what does ASD signify in terms of changes in brain neural circuitry? Again, if there are separable, quasi-discrete kinds of ASD, how do their neural circuitries differ from each other?

At an even more fundamental biological level, was there a large element of genetic causation? From the patterns of ASD within families, it was soon clear that that there was a genetic element involved, some large degree of “heritability”, though it clearly was not a simple Mendelian (single gene) inheritance pattern. (For the kinds of influences that shape human traits, see Time to move on from Nature vs. Nurture). If so, roughly how many gene differences might be involved in triggering development of the condition? Whatever the number might be, that would not mean that all or even most had to be genetically altered, just that some fraction would have to be to instigate the ASD state. Nevertheless, the greater the number of genes involved, the greater the puzzle of the genetic basis, in terms of what specific genes, or more accurately their genetic variants (alleles) were doing in contributing to the ASD state.

A different, though related, question concerned external environmental influences and when they acted in development of the individual child. Were the mother’s nutritional status or her smoking or drinking habits relevant? What about other factors, such as infections? Were there particularly sensitive stages in the child’s developmental trajectory, such as the embryonic or fetal stage or the neonatal period? And again, if there are different types of ASD, are there different risk factors and/or different sensitive periods for the different varieties?

This is a lot of questions to pose, and it is not the complete set possible, but they are all relevant to understanding ASD. None have been completely answered and the answers to most are still largely unknown. Even a long scholarly review article could not do justice to all of the relevant material; here I will just briefly discuss two areas: environmental and genetic risk factors for ASD.

Risk Factors

The question of whether there are environmental risk factors is important for most health conditions or states that deviate from the norm; there usually is an environmental component. This matter has become especially important for ASD because in recent decades the apparent incidence has increased dramatically. In the first big survey, in the year 2000, the frequency was about 1 per 150 people, which was already higher than expected. Today, it is about 1 per 36 people. This is a huge increase. Furthermore, it is found across all demographic groups, which indicates that the method of scoring is probably valid and that the frequency does not reflect socio-economic peculiarities of any specific group.

This is not a public health crisis, as it would be if these were figures for an infectious disease. After all, many individuals with ASD are functioning members of society, have families, etc. It is, however, of concern since people with ASD can have problems of social adjustment and difficulties of social interaction with “neurotypical” people. It often therefore creates problems.

The question about the current figure of ASD frequency is: is it real? Has there actually been this tremendous increase in human populations in the past few decades? Has there, for instance, been some environmental change that has caused a genuine increase in the number of people who experience ASD? ²

Or is it an artifact of ascertainment bias in ASD detection? Has there been in some change in the way the studies are done that makes it more likely that there will be a positive diagnosis of ASD than earlier?

The answer is not known but my guess is that both elements contribute. Being judged “autistic” used to be associated with a great stigma and that is much less true, hence the tests for ASD may well include a loosening of the criteria for what constitutes autism. On the other hand, there is more information about environmental factors that might play a part in triggering development along the ASD pathway and a number have been discovered. These include influenza infections late in pregnancy and various other immune system reactions, especially those involving inflammatory responses in the brain. Others include various heavy metal ions in the mother’s blood and some nutritional factors. The evidence is correlational and statistical but much is quite strong. There is clearly a major role that environmental factors can and do play in many individual instances of ASD. ³

This fact also pertains to some hopeful possibilities in therapies for ameliorating cases of ASD. Much information indicates that the infant’s environment, as they are developing into a child, can affect that development, for good or ill effect. Studies are beginning to point the way toward how certain play and learning exercises, cognitive behavioral therapies, with infants can reduce the severity of an ASD case if it is diagnosed early and the therapy begun then.

The search for genetic risk factors in autism has been proceeding for more than three decades and the amount, and reliability, of the work has increased in parallel with the advancement of the genetic techniques. The aggregate findings show a strong role for genetic factors; they may contribute 50% to the heritability of ASD. Mutations in hundreds of different genes have been found to be involved in increasing the probability of ASD developing. ⁴

One might wonder whether there is something surprising about the sheer numbers of genes whose genetic variants can contribute to ASD. These large numbers must have caused some initial distress in the researchers doing this work. Genetic causation is easier to explore when the number of genes involved is small. Smaller numbers make it easier develop hypotheses about the roles of genetic variants in specific genes than when there are 100s of candidates. However, I would argue that there is nothing at all surprising about it.

Recall that the particular traits altered in autism (apart from the repetitive behaviours) are amongst the most complex in human psychology: cognition, language ability, social interactions. Generally, the more complex the trait, the more genes there will be whose products are likely to be involved in the normal development of the trait. Correspondingly, the greater the number of genes involved, the greater the number of genes whose genetic variants might interfere, however slightly but nevertheless significantly, with the normal development of the trait.

Neural circuitry is a particularly complex property. Since most mutations that have an effect are loss-of-function mutations, one can readily see how slight loss-of-function genetic variants in genes whose products help build neural circuitry could cause deviations from the optimal neural circuitry.

On genes and personality

Nevertheless, despite this too-great number of candidate genes whose variants might be important in ASD, analysis of the aggregate results is pointing to about a dozen genes that may be particularly important. ⁵ These in turn, with other information, are beginning to give hints as to which neural circuits are affected in ASD and how they are altered in this condition. In turn, this gives new hope that this most serious and often deeply disruptive psychological condition, which for so long was seen as untreatable, is moving toward being better understood. We will return to the genetics of ASD in a later article.a

1. Hans Asperger (1906-1980) was an Austrian pediatrician and a pioneer in the study of autistic behaviors. Much controversy, however, surrounds the degree to which he agreed with Nazi ideology in the 1930s and ‘40s and participated in activities consistent with it, e.g. the euthanasia of children with disabilities. The dropping of Asperger’s syndrome as one named subtype of ASD was probably influenced, in part, by these questions surrounding his professional practice.

2. One long standing suspicion from the 1990s was that vaccination against measles predisposed to ASD. The original paper claiming this was long ago discredited and withdrawn by the journal that published it but lives on in certain conspiracy-minded groups. The reality is that vaccination is not a risk factor for ASD.

3. A good review is Chaste,P., Leboyer, M. (2012). Autism risk factors: genes, environment, and gene-environment interactions. Dialogues Clin Neurosci. 14:281-292. A more recent perspective, treating autism as a developmental problem is that of Green, J. (2022). Autism as emergent and transactional. Frontiers in Psychiatry doi 10.3389/fpsyt.2022.988755

4. For one comprehensive review of the studies of the genetics of ASD, see Qui, S. et al. (2022). Genetics of autism spectrum disorder: an umbrella review of systematic reviews and meta-analyses. Translational Psychiatry 12:249 doi.org/10.1038/s41 398-022. This article also homes in on a dozen genes that might be particularly important in the condition.

5. Same source as above, see Qui, S. et al. (2022).