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Reflections on Autism

Autism was once a private matter. It was rare to encounter an individual on the spectrum. If one did, it was usually a family member or neighbor. Treatments were non-existent or based on treating parents to improve their parenting skills. In some regrettable instances, questionable and invasive medical treatments were undertaken in response to the nearly unbearable sense of desperation felt by families. As studies began to include ever larger numbers of recognized cases, autism came to be described in terms of a core set of behaviors, principally arising from a dysfunctional social engagement system. These behaviors served as the basis for diagnosis and for therapies using reward circuits in the nervous system to reinforce positive social behaviors (directed eye gaze, joint attention, purposeful speech) and diminish unwanted ones (self-injury, biting, hair-pulling, scratching, obsessive activity).

Philosopher in Meditation engraved after Rembrandt by Devilliers l’aîné for Joseph Lavallée

Philosopher in Meditation engraved after Rembrandt by Devilliers l’aîné for Joseph Lavallée. Source: CC BY-SA 3.0

But now hardly a day goes by without some news report about the challenges of living with autism, a friend discussing a neighbor, hearing of an unusual achievement of someone on the spectrum, or reading an alarming exposé of an agency running dangerous group homes. And an extremely favorable development is that the pursuit of knowledge about autism now more closely resembles research into cancer and other conditions and autism can be explained in increasingly sophisticated terms of fundamental cellular biology, such as gene transcription, protein structure, and signal processing. This exciting news means that advances in any field of biomedical science can now be used to make discoveries leading to new treatments for autism.

In the early 1990’s the field of autism research was isolated and outside the purview of the medical community, except for a few pioneers, because there was little in the way of remedies that a physician could offer and, indeed, little incentive for doctors to specialize in treating autistic individuals, except for a few physician-scientists whose vision and compassion set the stage for the advances being made across a broad front today. The prospects for a deeper biomedical understanding of autism were heralded by the publication of a seminal book by Dr. Bernard Rimland. The discovery of cerebellar Purkinje cell abnormalities in post-mortem specimens by Drs. Margaret Bauman and Tom Kemper was strong evidence for disturbed neural circuitry as a cause for autism. Dr. Mary Coleman made a strong case for metabolic imbalances, not just in the brain, but in other bodily systems, as a common feature of autism. Dr. Donald Cohen believed that autism arose from a derailment, somewhere along the line, of the normal process of child development. These pioneering observations are reflected in some of the most important advances now being made in a much stronger field of autism research.

Considering the tremendous advances in developmental biology then being made, it was becoming possible to imagine that an ultimate understanding of the fundamental causes of autism might be achieved in the not too distant future. The Decade of the Brain and the Human Genome Project were just getting underway. Seizing the opportunity, the National Institute of Child Health and Human Development (NICHD) hosted a workshop on the future of autism research. Included were some of the most influential and successful scientists of the time, few of whom were working in the field of autism. The hope was to take a fresh look at the baffling and seemingly intractable problem of autism by considering the rapid advances in understanding Parkinson’s disease, cystic fibrosis, and cancer, as well as major advances in molecular and cellular biology. At about the same time, through the impassioned efforts of family advocates and champions within the government, funding for autism research began to accelerate, as evidenced by President Obama’s declaration that autism was to be designated a high priority for the National Institutes of Health.

The conclusion of these early efforts to ignite this field rested on four basic facts about autism, each of which provided important clues for researchers: 1. identical twins with autism have a high concordance rate for the behavioral symptoms of autism (70-90%) compared with fraternal twins, indicating a genetic origin; 2. the prevalence rate for males is at least four times higher than for females, suggesting linkage to the sex chromosomes or an endocrine protective factor in females; 3. autism is highly heterogeneous in its presentation, with large differences in speaking ability, motor disturbances, aggression, eating disorders, numerical ability, and artistic talent; 4. autism appears to be on the increase, either because of as yet unidentified features of modern life (environmental factors, pathogen-human interactions) or possibly because more broadly-defined diagnostic categories have expanded the autism spectrum, resulting in only an apparent increase.

Furthermore, from a behavioral perspective, any discussion of autism must include the near universality of communication impairments, including in some cases complete lack of speech, echolalia, or poor responsiveness to social context. Frustration of this basic human drive itself explains many of the socially maladaptive behaviors associated with autism. It is clear that communication technologies, in many cases developed to help victims of stroke, Parkinson’s disease, cerebral palsy, war injuries, and Amyotrophic Lateral Sclerosis (ALS, or Lou Gehrig’s Disease), will also enable individuals on the spectrum to express their natural intelligence, often underestimated because of difficulty in writing and speaking.

Autistic individuals may also face serious problems with processing the primary inputs from their senses, resulting in overloads and ineffective parsing into ‘chunks’ of motor control instructions to the muscle groups used to generate speech. The latest neuroimaging tools, working at a millisecond time resolution are required to observe these subtle events, and are beginning to reveal where and when a sensory signal becomes distorted or out-of-sync with converging information from other channels. In learning to speak, a young person’s brain must subtly intermix and modulate external sounds with self-generated utterances transmitted through the bones of the skull. Any slight delay or distortion can interfere with learning to speak, even though the person may perfectly well understand language, syntax and grammar.

The signaling perspective offers new ways of understanding some of the movement, coordination, and body awareness problems faced by individuals on the spectrum. Similarly, the proprioceptive and endocrine systems are largely outside of our conscious control and, unless new tools are developed to track communications along the mind-body axis, internal problems with these systems will always be simply interpreted in terms of externally observed behavior and given psychological interpretations having no basis in reality. Once autism is seen in these multi-system contexts, some widely used interventions might be fine-tuned to meet specific challenges faced by individuals with autism.

The body itself is a finely-tuned machine. Rhythm, synchrony and feedback control are essential elements in the smooth functioning of its movements and its ability to learn and take on new tasks. An emerging field of research considers how impairments in the circuits involving motor cortex, striatum, and cerebellum known to coordinate sophisticated motor activities, including speech, music and athletic performance may be hallmarks of autism.

But what is autism? Are we any closer to an explanation of how it arises and what influences its progression over the lifespan? If it is genetic, why doesn’t it ‘run in families’? Why does it appear in just one or two generations (except for recessive ‘syndromic’ forms of autism, such as Fragile X or Rett Syndromes)? Why aren’t identical twins 100% concordant for the outward signs of autism? These questions force us to look beyond purely psychosocial or behavioral descriptions of autism and focus on the brain circuits involved in generating speech and behavior. Answers might be found in exploring how genetic networks control the development of these systems and how the full panoply of molecules encountered every day by our bodies in our manufactured surroundings or in our exposures to pathogens rapidly propagated by human travel.

While the original hope was that mutations in one or a few genes might explain all of the cases of autism, genomic studies involving many tens of thousands of autistic individuals are instead finding great complexity in the genetic landscape, involving at least 100 well-documented mutated genes. Although this presents a daunting challenge, there is hope that all of the individual genetic causes of autism may affect just a few crucial checkpoints or control hubs in common neurological systems, providing an explanation for both heterogeneity and the existence of a spectrum. The existence of common molecular targets across the autism spectrum that can be modulated by molecular (drugs and biologics) or by physical (touch, sounds, sights) interventions offers a broad highway of hope.

Another way to imagine the emergence of autism, not only during development, but as an ongoing condition, is that only a few neuronal cell types are struggling to carry out their critical roles, much like those Purkinje cells in the cerebellum observed by Margaret Bauman. Other examples include inhibitory cells that shape electrical signals in the brain, glial cells that nourish brain cells and provide immune surveillance, and singular classes of molecular subunits comprising excitatory cells. A good example is provided by the discovery that common mutations in SHANK3, a synaptic scaffolding protein, seem to affect only one or a few very specific cell types in the striatum, a region in the striatum responsible for ‘chunking’ cortex-generated ‘action plans’ for frequently used neuromuscular activity like speaking particular words or carrying out a fine motor activity like playing the piano. Thus, even though many genes other than SHANK3, perhaps in combination, may influence the development of the striatum, a common final pathway might be found that can be targeted by pharmaceutical interventions or physical modulation of the senses of sound, sight, smell, or touch.

What must be remembered is that autism is not a degenerative disease, but rather a condition, perhaps of metabolic origin, that could be shifted to more efficient states by a wide variety of interventions, not just pharmaceuticals or behavioral protocols, but acting on senses as well.

While autism certainly appears to be of neurodevelopmental origin, appearing early in life, it is often a lifelong condition. Individuals on the spectrum need physicians and other medical support staff that understand how difficult it is to convey where a pain might be or to answer the usual questions in a medical examination. Furthermore, physiological or metabolic causes of outward behavioral indications of autism might have undisclosed effects on other bodily systems such as the gastrointestinal or autonomic nervous systems.

Expectations for a deeper understanding of autism are considerably greater now that new investigators, trained in molecular, cellular, and neurobiology, have been drawn into the field by the opportunity to address the profound and disturbing mystery of autism. It is not just basic science that is providing new insights but also medical doctors, specializing in neurology and physiology, who are treating greater and greater numbers of persons with autism. The insights of the autism research pioneers in the early 1990’s have borne fruit. That simple list of four basic observations remains, but has been considerably refined by genomic and metabolic studies involving thousands of participants. Genes relevant to autism are being used to manipulate high level systems in animal models (flies, mice, rats, zebrafish) in order to investigate mechanisms universal across species. Although complex, the relationships between mind and body, brain and action, language and speech, and neurodevelopment are being analyzed with powerful computer algorithms working on large data sets collected on subjects using powerful new generations of neuroimaging instruments.

The human brain and its astonishing cerebral cortex, using all of the conscious and unconscious signals reaching it from the senses and the body’s internal circuits, creates patterns of association, memory and action that express the unique personalities of all human beings. Autistic individuals create their lives as do the rest of us in response to the challenges of living and a few have broken through to express themselves revealing the same dreams and hopes of the rest of humanity, and some that only they can uniquely experience.


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