(no abstract)
Human Origins: Lessons from Autism Spectrum Disorders
Friday, October 05, 2012Abstracts
Abstracts
The Autism Spectrum is a diverse group of neurodevelopmental disorders that share a common set of characteristics, which includes restricted interests, repetitive behaviors and difficulties with social interaction and communication. The biggest known risk factors for autism are genes. However, the mutations that have been firmly implicated in autism are unlike the genetic variants that explain common late-onset diseases such as heart disease and diabetes. Most of the genes or genomic regions that are known to contribute to autism are “mutation hotspots”. Disease-causing variants confer significant risk. Such variants segregate in families over a few generations or can be observed as spontaneous mutations (DNMs) in an affected child. From the perspective of genetics, the characteristic of humans that is most clearly reflected in autism is the intrinsic mutability of our genome.
Although the neurobiology of autism has been studied for more than two decades, the majority of studies have examined brain anatomy 10 or more years after the onset of clinical symptoms. The early neural defects that cause autism remain unknown, but their signature is likely to most evident during the first years of life when clinical symptoms are emerging. This lecture highlights several new findings about the neural and genomic abnormalities in autism at young ages. It contrasts brain pathology at young ages versus adult ages in autism. Evidence supports three phases of brain development pathology in autism: a phase of early brain overgrowth in some percentage of toddlers, then arrest of growth and finally degeneration in some percentage of cases. Early brain overgrowth, which is present in a large percentage of cases, may be a key to discovering the neural bases for emergence of autistic behavior as well as its genetic and non-genetic causes. We discovered that excess neuron number is one cause of early brain overgrowth, and abnormal cortical patterning. Gene expression results also point to abnormal cortical patterning during development. Such abnormalities in cortical patterning and wiring may lead to exuberant local and short distance cortical interactions impeding the function of long-distance interactions between brain regions. Since large-scale networks underlie socio-emotional and communication functions, such alterations in brain architecture could relate to the early clinical manifestations in autism. As such, autism may additionally provide unique insight into genetic and developmental processes that shape early neural wiring patterns and make possible higher-order social, emotional and communication functions that epitomize humans.
This talk describes new research on the origins of ‘social cognition’—the mechanisms by which infants come to understand other people and interpret their actions and intentions before language. Typically developing children learn quickly and easily from observing the actions performed by others. This is supported by two key building blocks—imitation and gaze following—that are operative in early infancy, rare in the animal kingdom, and impaired in children with autism spectrum disorders. I unite imitation and gaze following under a theoretical ‘Like-Me’ developmental framework (Meltzoff, 2007). This framework holds that infants at first recognize that other people are ‘like me’ in behavioral actions and from this foundation gradually develop the idea that others are ‘like me’ in their internal mental states (theory of mind). I will show how this developmental framework helps illuminate the origins of one of the most treasured aspects of our mental life—our powerful ability and motivation to learn from other people—and will discuss implications for understanding children with autism spectrum disorders.
Autism is a developmental disorder impacting one out of every 100 children born today. It is a disorder that affects how the brain grows and works, yet the functional brain characteristics of autism during the time when symptoms first appear, namely 12-36 months, is almost completely unknown. This is because autism remains behaviorally defined and diagnosed, thus limiting the ages that it can be studied. New early identification approaches, however, such as the 1-Year Well-Baby Check-Up Approach, will help push the age of first diagnosis much lower and allow for the study and treatment of autism as young as 12-months or younger. This lecture will consider how early screening at the 1st birthday can positively impact the search for biomarkers and lead to new discoveries. This lecture will also emphasize patterns of eye gaze as a potent early marker of autism and consider how fMRI can be used to examine neural functional organization in response to language in ASD toddlers. This research is supported by NIMH Autism Center of Excellence (P50) and R01 grants.
First discovered in the macaque, mirror neurons – neurons that fire when executing a goal-directed action as well as when observing the same action being performed by others – are thought to provide a neural mechanism whereby others’ actions and intentions can be readily understood. More recent findings, including single cell recordings in humans, suggest that mirroring is not a peculiar property of the motor system but a more common phenomenon whereby vicarious neural activity may also be used to read others’ mental states and perhaps empathize with how they feel as well. Importantly, mirror neurons may also provide a neural substrate for imitation, a critical means for cultural learning in humans. In this talk, I will first describe the relevance of mirror neurons for social functioning. I will then discuss the empirical evidence suggesting that the so-called ‘mirror neuron system’ may be hyporesponsive in autism. Lastly, I will conclude by highlighting critical questions for future research in these areas.
Our laboratory has been working to identify autism risk genes and understand how these might lead to autism spectrum disorders (ASD). Many genes with distinct functions have been identified as ASD susceptibility genes. Our efforts using systems biology approaches demonstrate that pathways necessary for normal brain development and function are altered in ASD. Identification of these pathways has allowed us to begin to understand what these tell us about autisms etiology and aid in the development of treatments. Although ASD affects what are often thought to be human-related features of social cognition, the human specificity of these effects is still not well understood.
I describe a simple model, based in evolutionary biology, neurodevelopment, and genetics, for understanding how the primary features of autism are related to the major neuroanatomical and cognitive traits that are highly-developed or unique to the human lineage. By this model, human-specific adaptations, especially brain size and brain structures that subserve social interactions, are explicitly connected with their alterations in autism spectrum conditions. This evolutionary-medical perspective has several important implications for understanding and analyzing autism and other psychological variation in humans. First, autism can be conceived as a relative extreme of natural, evolved variation, which involves reduced development of some traits, enhancements of other traits, and trade-offs between different abilities. This means that genes ‘for’ autism represent genes underlying the bases and facets of social cognition, and genes mediating trade-offs between social and other skills. Genetic studies and studies of 'autism gene' functions may be guided by this inference. Second, by this model, psychotic-affective conditions (including schizophrenia, bipolar disorder, depression, and borderline personality) represent diametric opposites to autism spectrum conditions, with neurotypical development and cognition at the centre. This bidirectional spectrum of psychological variation leads to reciprocal illumination of research findings across autism and psychotic-affective conditions, with practical implications regarding such issues as the increases in autism diagnoses and the development of treatments. I present data salient to these points, from the literature and from my laboratory, with a focus on rigorous application of evolutionary concepts and tools to understanding the causes of autism.
Autism affects males much more often than females. The explanation for this must either lie in diagnostic practice (e.g., there may be under-diagnosis of females due to their better surface social skills), hormones (e.g., the sex steroid hormones such as testosterone, which is converted into estradiol/estrogen, both of which affect brain function and brain development), genetics (e.g., X-linked genes, or genes regulating sex steroid hormones) or (most likely) a mix of all three factors. In this talk I summarize work from our lab from 5 lines of investigation:
(1) The role of testosterone produced by the fetus (henceforth fetal testosterone or FT) in the development of individual differences in typical language and social skills, and in typical attention to detail and narrow interests;
(2) The role of FT in the development of typical brain structure and function;
(3) The role of FT in the development of autism and autistic traits.
(4) The evidence for sex steroid hormone dysregulation in autism and their family relatives.
(5) The association between genes that regulate testosterone, and autism.
These lines of research suggest a baby’s sex steroid hormones are a key part of the puzzle of autism.
My interest in Autism Spectrum Disorders (ASD) stems from an earlier, and broader, interest in mirror neurons and their dysfunction (and restitution of function) in neurology. We begin with a brief survey of the mirror neuron system (MNS) seen from an evolutionary perspective and deal with some criticisms (mainly by psychologists and philosophers). We then make specific predictions of what to expect from their dysfunction in neurological populations with stroke or phantom limbs (and current evidence of mirror feedback therapy which taps into the MNS) as well as neurotypical populations who overlap with ASD. We also report a tangentially related, but astonishing, preliminary observation that paralysis and pain in the right hand (and fingers) can lead to retrograde brain changes causing dyscalculia and finger agnosia. Can this be reversed with mirror feedback?
