INSIGHTS | 20. The Link Between Autism & Inflammation
Neuroimaging allows us to look inside that infinitely complex structure we call the brain. Unfortunately, this isn't routinely done for those with Autism.
Article: Normal Rates of Neuroradiological Findings in Children with High Functioning Autism
Background
In recent years, people have become justifiably skeptical about Big Pharma and vaccines. With recent covid policies, the definition of “anti-vaxxer” has expanded as well.
When I was in school, an anti-vaxxer was characterized as someone who thought the MMR vaccine caused autism. But recently, our regulators have expanded this definition to include anyone opposed to vaccine mandates.
Quite the range of beliefs for one derogatory term.
But, this article is not about vaccines.
This piece is about the role of inflammation in neurological disease, with attention on autism.
What is Autism?
The definition and diagnostic criteria for autism should help illustrate how incomplete and uncertain a condition it really is. Initially, people would refer to those with difficulties in language & social interaction as autistic.
Now, we refer to it as autism spectrum disorder (ASD) because, over time we learned that it wasn’t as simple as we thought.
The most recent Diagnostic and Statistical Manual of Mental Disorders (DSM-5) has very elaborate diagnostic criteria:
Persistent deficits in social communication and interaction
Restricted or repetitive patterns of behavior, interest or activities
Symptoms must be present in early developmental period
Symptoms cause impairment in social, occupational, and life settings
Not better explained by intellectual disability or global developmental delay…
But, intellectual disability frequently co-occurs with ASD (go figure)
The DSM goes on to state that the doctor must specify if there is:
Intellectual impairment
Language impairment
Developmental, mental, or behavioral disorders
Catatonia - abnormal muscle tone
Associated with medical or environmental factors
It’s all a bit complicated.
What is Autism, really?
One of the best descriptions I have come across was from Karl Deisseroth, who was a guest on the Lex Fridman podcast. Karl is best known for his pioneering work on optogenetics, but is also a psychiatrist.
In Karl’s view, autism is an inability to appropriately process new information.
You may be wondering ‘what is the connection between social interactions and processing new information?’
As Karl points out, since autistic people have difficulty processing novel information, the domain within which that would manifest the greatest is social dynamics. There is nothing as unpredictable, chaotic and idiosyncratic as interactions with other humans.
Thus, it would make sense for the most apparent ‘deficiency’ within autism to be social interaction. A natural extension of this would be language fluency and intellectual disability.
What causes Autism?
You can find an extensive list of possible causes for Autism, but fundamentally we do not know. It is almost certain that if ASD represented a unique disease, it would have multiple causes.
If you think about the fundamental problem (as described by Deisseroth), slow processing of novel information, it isn’t difficult to imagine the possible causal or contributory factors.
For example: maternal nutritional status, pre-natal and perinatal factors, complications during birth, immunologic & inflammatory stress during infancy, exposure to toxins, lack of cognitive support & nourishment during early years, poor behavior modelling, and so on.
I believe there are two factors that are often ignored with autism:
Poor behavioral modeling, and its impact across generations - to be written about in a future article.
Overall inflammatory state and the impact this has on anatomy and physiology of the brain - the topic of this article.
The Normal Brain
An MRI is useful because it allows us to look at the brain with exceptional contrast resolution. The stronger the magnetic field, the higher the resolution - generally speaking.
Here we have a T2-weighted image of a normal brain:
Notice a couple of things:
Gray matter is gray (ribbon of cortex along the periphery)
White matter is really dark - especially near the top of the image (which corresponds to the frontal lobes)
Normal cerebrospinal fluid is bright white - in the sulci between the cortical gyri, and within the lateral ventricles at the center of the image.
The problem with a T2-weighted image is that all fluid will be bright, making it difficult to differentiate between normal fluid and pathological fluid.
This is what a FLAIR sequence is for. It suppresses normal fluid, so all that is left is pathologic fluid, if there is any.
Notice in the above normal FLAIR sequence:
Gray and white matter are whitish-gray and dark, respectively - like T2 image
This time, the normal CSF within the sulci and ventricles are suppressed - so they appear dark
The above images were most likely taken with a 1.5 Tesla strength magnet.
Bonus: Look what happens when we crank this up to 7 Tesla - beautiful isn’t it?
The Inflamed Brain
If you are looking for a pathologic lesion, you are most definitely getting a FLAIR sequence. A common location for chronic lesions is the white matter - the connective tracts of the brain.
Rarely is there a pathologic diagnosis of the brain which does not manifest with lesions in the white matter, which are visible on FLAIR.
But, what does it mean for there to be a white matter lesion?
They can result from several things:
Demyelination - like with multiple sclerosis
Gliosis - fancy word for scarring
Infarction - such as from strokes or bleeds
Disease of the veins which alters perfusion and drainage
Inflammation - systemic or focal
Infection
Tumor
As the brain experiences inflammation the person will manifest neurological symptoms. If it is acute and severe, the person may become comatose.
If the inflammation is low-grade and persists chronically, then corresponding regions of the brain will start to develop features like scarring, volume loss (prolonged ischemia), bleeding, demyelination, and swelling.
Exhibit A. FLAIR sequence of a person with multiple sclerosis - a demyelinating disorder:
Look at all those white blotches in locations including: surrounding the ventricles, in the deep white matter, and the subcortical (more specialized regions) white matter.
Imaging Autism
Since genes are a common way to look at illness, outdated perspectives on autism included assumptions about its genetic basis and heritability.
So, the early attempts at characterizing the imaging findings of ASD looked at major heritable anatomic differences. This early research was often done with computed tomography or low resolution MRIs - making finer anatomic differences difficult to distinguish, if not impossible.
Consequently, the American Academy of Neurology, the American Academy of Child and Adolescent Psychiatry, and the American Academy of Pediatrics have independently concluded that imaging is not indicated as part of the routine evaluation of children with autism.
More recent research, which has not made its way into diagnostic or management algorithms within fiat medicine, uses higher resolution imaging.
These studies reveal more interesting pictures.
For example, Boddaert et al look at MRI of 69 children with ASD and 77 normal. In ASD, distinct abnormalities were found including: 27.5% had white matter lesions and 29% subcortical lesions & infarcts within the temporal lobes.
Granted, not all studies show similar frequency of these lesions. The article linked at the top did not find a difference in kids with ASD. But, they also have differences in imaging technique and age-range, which may account for these observations.
Regardless, my assertion is not that these lesions explain all cases of ASD.
I argue that some of the symptoms may be explained by these lesions. They may even point to multiple contributing causes, which manifest in the global picture of ‘autism.’
Why White Matter Lesions?
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