Chapter 2, PART 6. AUTISM: UNDERSTANDING, DIAGNOSIS, AND TREATMENT

I do not claim that my work pioneered the biological understanding of autism. For decades, researchers worldwide—at institutions such as Johns Hopkins, Harvard, Karolinska, Columbia, UC San Diego, and Baylor—have published rigorous studies that challenge the view of autism as purely genetic or behavioral. My contribution is to clarify how these diverse biological discoveries come together in actual clinical cases, supporting a view of autism as a complex biological condition.

As medicine shifted from behavioral description to laboratory and immunological analysis, the traditional definition of autism changed. This transition led to a clear argument: autism, rather than being a mysterious disorder, is now defined as a chronic, multisystem, infectious-inflammatory condition with neurological effects.

When a Behavioral Model of Autism Replaced Biological Medicine

Autism spectrum disorder (ASD) is currently defined through behavioral criteria: impairments in social communication, restricted interests, and repetitive behaviors. These features form the basis of diagnostic frameworks such as the Diagnostic and Statistical Manual of Mental Disorders, which has guided clinical practice for decades.

Over the past twenty years, research has documented neuroinflammation, immune dysregulation, microbiome disturbances, and metabolic dysfunction in many individuals with autism. These findings raise a fundamental question:

How did a condition with increasing biological evidence become conceptualized primarily as a behavioral disorder?

To understand this disconnect, it is essential to examine the historical trajectory of autism research, in which early scientific limitations shaped a conceptual framework that later became institutionalized. This context helps explain how the current perspective came to hold sway.

The Origins of a Behavioral Syndrome

Autism was first systematically described in the early 1940s by two physicians working independently: Leo Kanner and Hans Asperger.

Kanner identified a group of children characterized by profound social withdrawal, repetitive behaviors, and unusual language development. Asperger described children with preserved language but distinctive cognitive and social characteristics.

Both physicians relied entirely on clinical observation. At the time, the scientific tools necessary to investigate the biological basis of neurodevelopmental disorders did not yet exist. Immunology was still developing as a discipline, neuroimaging technologies were decades away, and molecular genetics had not yet emerged.

As a result, autism entered medicine as a syndrome defined by behavior rather than by biological mechanism. This circumstance would profoundly shape the direction of autism research for the next eighty years.

The Rise of the Behavioral Paradigm

In the absence of biological explanations, autism became interpreted primarily as a disorder of behavior.

The rise of behavioral psychology in the mid-twentieth century reinforced this view. The theoretical foundation originated in the work of B. F. Skinner was later adapted for autism therapy by Ole Ivar Lovaas.

This approach evolved into Applied Behavior Analysis (ABA), a method focused on reinforcing desirable behaviors and discouraging undesirable ones through structured training.

At the time, the approach appeared reasonable. Medicine lacked a mechanistic understanding of autism, and behavioral interventions offered measurable changes in observable functioning.

However, an important historical detail is often overlooked:

ABA became the dominant therapeutic model before modern biological sciences began investigating autism mechanisms.

Institutionalization of the Behavioral Model

Once established, the behavioral paradigm became deeply embedded in medical and educational systems.

Diagnostic criteria developed by the American Psychiatric Association through the DSM defined autism entirely through behavioral symptoms. Educational systems adopted behavioral therapy as the primary intervention, and insurance reimbursement programs increasingly supported ABA therapy.

Over time, the ABA sector evolved into a large healthcare industry across North America and Europe.

When clinical systems, reimbursement structures, and professional training programs align around a particular disease model, it becomes difficult to reassess the scientific foundations of that model.

Biological Evidence Emerges

Beginning in the late twentieth century, advances in neuroscience, immunology, and molecular biology began challenging the purely behavioral model of autism.

One of the most influential findings came from neuropathological research demonstrating chronic neuroinflammation in the autistic brain.

In a landmark study published in Annals of Neurology, Vargas and colleagues reported widespread microglial activation and astrocytic inflammation in the brains of individuals with autism. These findings suggested that autism might involve ongoing inflammatory processes affecting neural development.

Subsequent studies have documented elevated inflammatory cytokines in both brain tissue and cerebrospinal fluid of autistic individuals. Meta-analyses have confirmed consistent increases in pro-inflammatory cytokines, including interleukin-6, tumor necrosis factor-α, and interferon-γ.

These findings suggest that the autistic brain may often be in a state of chronic immune activation.

Immune Dysregulation

Evidence for immune abnormalities in autism has accumulated over the past two decades.

Meta-analyses and large cohort studies have documented:

• altered T-cell responses

• abnormal natural killer cell activity

• increased pro-inflammatory cytokines

• autoantibodies targeting neural proteins

• maternal immune activation during pregnancy

Several epidemiological studies have also linked maternal infection during pregnancy with increased autism risk.

A large population-based study published in JAMA Psychiatry reported that maternal infection requiring hospitalization during pregnancy was associated with a significantly increased likelihood of autism in offspring.

Experimental animal models have further demonstrated that maternal immune activation can alter fetal brain development and produce behavioral abnormalities resembling autism.

Together, these findings suggest that immune dysfunction may play a central role in autism pathogenesis.

Neuroinflammation

Evidence of neuroinflammation has become one of the most consistent biological findings in autism research.

Post-mortem studies and neuroimaging investigations have demonstrated:

• microglial activation across multiple brain regions

• increased inflammatory cytokines in cerebrospinal fluid

• astrocyte dysfunction

• oxidative stress within neural tissue

These processes can disrupt synaptic development, neuronal connectivity, and neuroplasticity during critical periods of brain development.

A growing body of literature now suggests that neuroimmune interactions play a significant role in neurodevelopmental disorders, including autism.

Infection as a Biological Trigger

Another line of research has examined the role of infections in neurodevelopmental disorders.

Congenital infections such as cytomegalovirus, rubella, and toxoplasmosis are well-established causes of neurological damage and developmental delay.

Beyond congenital infections, persistent or latent infections have also been proposed as potential contributors to chronic neuroinflammation.

Several studies have reported increased prevalence of herpesviruses and other pathogens in subsets of autistic individuals. Although these findings remain heterogeneous, they suggest that chronic infections may contribute to sustained immune activation in some cases.

Persistent immune stimulation from chronic infection could, in theory, influence neural development via inflammatory pathways.

The Microbiome and the Brain

In recent years, research has increasingly focused on the gut–brain axis.

Studies have documented significant differences in the intestinal microbiome of individuals with autism, including reduced microbial diversity and increased prevalence of certain bacterial species.

A landmark study published in Nature demonstrated that alterations in gut microbiota could influence behavior and brain chemistry in animal models.

Microbial metabolites produced in the intestine can enter systemic circulation and interact with immune and neural signaling pathways.

These findings suggest that disturbances of microbiomes may influence neurodevelopment through metabolic and immune mechanisms.

Clinical Observations

Clinical observations often reveal patterns that precede mechanistic explanations.

In clinical practice, many autistic individuals have systemic abnormalities beyond behavioral symptoms, including inflammatory markers, immune dysregulation, gastrointestinal disturbances, and metabolic alterations.

These findings suggest that autism symptoms may sometimes reflect broader biological processes affecting multiple physiological systems.

Although clinical responses vary, addressing biological abnormalities—such as inflammation, immune dysregulation, or metabolic imbalance—has occasionally been associated with functional improvements in subsets of patients.

Such observations underscore the central argument of this section: to truly understand autism, it is essential to investigate its biological mechanisms rather than rely solely on behavioral descriptions.

The Genetic Turn

Despite emerging biological evidence from immunology and neuroinflammation research, autism research in the early twenty-first century shifted strongly toward genetics.

Large genomic studies identified numerous rare mutations associated with autism. A landmark analysis published in Nature identified dozens of genes involved in synaptic development and neuronal signaling.

Subsequent studies expanded this list to hundreds of genes statistically associated with autism spectrum disorder.

However, most identified mutations account for only a small proportion of autism cases, and few genetic discoveries have yet been translated into effective therapeutic strategies.

Epigenetics and Gene Regulation

Another branch of biology—epigenetics—has produced findings that challenge purely genetic explanations.

Epigenetic mechanisms regulate gene expression without altering the DNA sequence itself. Environmental factors such as inflammation, infection, toxins, and metabolic stress can influence gene activity through epigenetic modifications.

Research suggests that many genes associated with autism may be dysregulated rather than permanently mutated.

From this perspective, autism may involve disturbances in gene regulation and developmental signaling pathways rather than fixed genetic defects.

The Ade Hypothesis of Regressive Autism

One of the most puzzling phenomena in autism research is regressive autism, in which children lose previously acquired developmental skills.

A possible mechanism worth exploring is antibody-dependent enhancement (ADE), a process in which non-neutralizing antibodies facilitate viral entry into immune cells and amplify inflammatory responses.

ADE is well documented in viral infections such as dengue and certain coronavirus diseases.

If similar immune mechanisms occur during persistent viral infections in early childhood, they could, in theory, trigger episodes of intense immune activation affecting the developing brain.

Although this hypothesis remains speculative, it may offer a framework linking infection, immune dysregulation, neuroinflammation, and developmental regression.

Further research is required to evaluate this possibility.

A Broader Problem in Neurology

Autism also illustrates a broader challenge within neurology and psychiatry.

Many neurological disorders are classified primarily by symptoms rather than by biological mechanisms.

In most areas of medicine, diseases are categorized according to etiology and pathogenesis. Symptom-based classifications can group conditions arising from fundamentally different biological processes.

As biological research advances, many neurological disorders—including autism—may ultimately require reclassification according to their underlying mechanisms.

Returning to Biological Medicine

Progress in autism research may require a shift toward integrative biological models.

Understanding autism will likely require combining insights from multiple disciplines:

• immunology

• neuroinflammation research

• microbiology

• genetics and epigenetics

• metabolism

• environmental biology

Such integration may help transform autism from a purely behavioral diagnosis into a condition understood through its biological mechanisms.

This transition may ultimately open new avenues for prevention and treatment.

For Doctors: Selected References

Atladóttir H.O. et al. Maternal infection requiring hospitalization during pregnancy and autism spectrum disorders. JAMA Psychiatry.

Sanders S.J. et al. Insights into autism spectrum disorder genomic architecture. Nature.

Hsiao E.Y. et al. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Nature.

Knuesel I. et al. Maternal immune activation and neurodevelopmental disorders. Nature Reviews Neuroscience.

De Rubeis S. et al. Synaptic, transcriptional, and chromatin genes disrupted in autism. Nature.

Modabbernia A. et al. Cytokine alterations in autism spectrum disorder: systematic review and meta-analysis. Molecular Psychiatry.

Estes M.L., McAllister A.K. Maternal immune activation: implications for neuropsychiatric disorders. Nature Reviews Neuroscience.

Zerbo O. et al. Maternal infection during pregnancy and autism risk. JAMA Psychiatry.

Hsiao E.Y. Microbiota and neurodevelopmental disorders. Nature.