Pathophysiology of autism explained

The pathophysiology of autism is the study of the physiological processes that cause or are otherwise associated with autism spectrum disorders.

Autism's symptoms result from maturation-related changes in various systems of the brain.^[1] How autism occurs is not yet well understood. Its mechanism can be divided into two areas: the pathophysiology of brain structures and processes associated with autism, and the neuropsychological linkages between brain structures and behaviors. The behaviors appear to have multiple pathophysiologies.^[2]

There is evidence that gut–brain axis abnormalities may be involved.^{[3] [4] [5]} A 2015 review proposed that immune, gastrointestinal inflammation, malfunction of the autonomic nervous system, gut flora alterations, and food metabolites may cause brain neuroinflammation and dysfunction. A 2016 review concludes that enteric nervous system abnormalities might play a role in neurological disorders such as autism. Neural connections and the immune system are a pathway that may allow diseases originated in the intestine spread to the brain.

Several lines of evidence point to synaptic dysfunction as a cause of autism.^[6] Some rare mutations may lead to autism by disrupting some synaptic pathways, such as those involved with cell adhesion.^[7] All known teratogens (agents that cause birth defects) related to the risk of autism appear to act during the first eight weeks from conception, and though this does not exclude the possibility that autism can be initiated or affected later, there is strong evidence that autism arises very early in development.^[8]

In general, neuroanatomical studies support the concept that autism may involve a combination of brain enlargement in some areas and reduction in others.^[9] These studies suggest that autism may be caused by abnormal neuronal growth and pruning during the early stages of prenatal and postnatal brain development, leaving some areas of the brain with too many neurons and other areas with too few neurons.^[10] Some research has reported an overall brain enlargement in autism, while others suggest abnormalities in several areas of the brain, including the frontal lobe, the mirror neuron system, the limbic system, the temporal lobe, and the corpus callosum.^{[11] [12]}

In functional neuroimaging studies, when performing theory of mind and facial emotion response tasks, the median person on the autism spectrum exhibits less activation in the primary and secondary somatosensory cortices of the brain than the median member of a properly sampled control population. This finding coincides with reports demonstrating abnormal patterns of cortical thickness and grey matter volume in those regions of autistic peoples' brains.^[13]

The imbalance in excitatory and inhibitory neurotransmission, particularly involving neurotransmitters such as glutamate and gamma-aminobutyric acid, has also been proposed as a potential mechanism underlying the behavioral and cognitive manifestations observed in individuals with ASD.^[14]

Brain connectivity

Brains of autistic individuals have been observed to have abnormal connectivity and the degree of these abnormalities directly correlates with the severity of autism. Following are some observed abnormal connectivity patterns in autistic individuals:^{[15] [16]}

• Decreased connectivity between different specialized regions of the brain (e.g. lower neuron density in corpus callosum) and relative over-connectivity within specialized regions of the brain by adulthood. Connectivity between different regions of the brain ('long-range' connectivity) is important for integration and global processing of information and comparing incoming sensory information with the existing model of the world within the brain. Connections within each specialized regions ('short-range' connections) are important for processing individual details and modifying the existing model of the world within the brain to more closely reflect incoming sensory information. In infancy, children at high risk for autism that were later diagnosed with autism were observed to have abnormally high long-range connectivity which then decreased through childhood to eventual long-range under-connectivity by adulthood.
• Abnormal preferential processing of information by the left hemisphere of the brain vs. preferential processing of information by right hemisphere in neurotypical individuals. The left hemisphere is associated with processing information related to details whereas the right hemisphere is associated with processing information in a more global and integrated sense that is essential for pattern recognition. For example, visual information like face recognition is normally processed by the right hemisphere which tends to integrate all information from an incoming sensory signal, whereas an ASD brain preferentially processes visual information in the left hemisphere where information tends to be processed for local details of the face rather than the overall configuration of the face. This left lateralization negatively impacts both facial recognition and spatial skills.^[17]
• Increased functional connectivity within the left hemisphere which directly correlates with severity of autism. This observation also supports preferential processing of details of individual components of sensory information over global processing of sensory information in an ASD brain.
• Prominent abnormal connectivity in the frontal and occipital regions. In autistic individuals low connectivity in the frontal cortex was observed from infancy through adulthood. This is in contrast to long-range connectivity which is high in infancy and low in adulthood in ASD. Abnormal neural organization is also observed in the Broca's area which is important for speech production.

Neuropathology

Listed below are some characteristic findings in ASD brains on molecular and cellular levels regardless of the specific genetic variation or mutation contributing to autism in a particular individual:

• Limbic system with smaller neurons that are more densely packed together. Given that the limbic system is the main center of emotions and memory in the human brain, this observation may explain social impairment in ASD.
• Fewer and smaller Purkinje neurons in the cerebellum. New research suggest a role of the cerebellum in emotional processing and language.
• Increased number of astrocytes and microglia in the cerebral cortex. These cells provide metabolic and functional support to neurons and act as immune cells in the nervous system, respectively.
• Increased brain size in early childhood causing macrocephaly in 15–20% of ASD individuals. The brain size however normalizes by mid-childhood. This variation in brain size in not uniform in the ASD brain with some parts like the frontal and temporal lobes being larger, some like the parietal and occipital lobes being normal sized, and some like cerebellar vermis, corpus callosum, and basal ganglia being smaller than neurotypical individuals.
• Cell adhesion molecules that are essential to formation and maintenance of connections between neurons, neuroligins found on postsynaptic neurons that bind presynaptic cell adhesion molecules, and proteins that anchor cell adhesion molecules to neurons are all found to be mutated in ASD.

Gut-immune-brain axis

46% to 84% of autistic individuals have GI-related problems like reflux, diarrhea, constipation, inflammatory bowel disease, and food allergies.^[18] It has been observed that the makeup of gut bacteria in autistic people is different than that of neurotypical individuals which has raised the question of influence of gut bacteria on ASD development via inducing an inflammatory state.^[19] Listed below are some research findings on the influence of gut bacteria and abnormal immune responses on brain development:

• Some studies on rodents have shown gut bacteria influencing emotional functions and neurotransmitter balance in the brain, both of which are impacted in ASD.
• The immune system is thought to be the intermediary that modulates the influence of gut bacteria on the brain. Some ASD individuals have a dysfunctional immune system with higher numbers of some types of immune cells, biochemical messengers and modulators, and autoimmune antibodies. Increased inflammatory biomarkers correlate with increased severity of ASD symptoms and there is some evidence to support a state of chronic brain inflammation in ASD.
• More pronounced inflammatory responses to bacteria were found in ASD individuals with an abnormal gut microbiota. Additionally, immunoglobulin A antibodies that are central to gut immunity were also found in elevated levels in ASD populations. Some of these antibodies may attack proteins that support myelination of the brain, a process that is important for robust transmission of neural signal in many nerves.
• Activation of the maternal immune system during pregnancy (by gut bacteria, bacterial toxins, an infection, or non-infectious causes) and gut bacteria in the mother that induce increased levels of Th17, a pro-inflammatory immune cell, have been associated with an increased risk of autism. Some maternal IgG antibodies that cross the placenta to provide passive immunity to the fetus can also attack the fetal brain.
• It is proposed that inflammation within the brain promoted by inflammatory responses to harmful gut microbiome impacts brain development.
• Pro-inflammatory cytokines IFN-γ, IFN-α, TNF-α, IL-6 and IL-17 have been shown to promote autistic behaviors in animal models. Giving anti-IL-6 and anti-IL-17 along with IL-6 and IL-17, respectively, have been shown to negate this effect in the same animal models.
• Some gut proteins and microbial products can cross the blood–brain barrier and activate mast cells in the brain. Mast cells release pro-inflammatory factors and histamine which further increase blood–brain barrier permeability and help set up a cycle of chronic inflammation.

Social brain interconnectivity

A number of discrete brain regions and networks among regions that are involved in dealing with other people have been discussed together under the rubric of the social brain., there is a consensus that autism spectrum is likely related to problems with interconnectivity among these regions and networks, rather than problems with any specific region or network.^[20]

Temporal lobe

Functions of the temporal lobe are related to many of the deficits observed in individuals with ASDs, such as receptive language, social cognition, joint attention, action observation, and empathy. The temporal lobe also contains the superior temporal sulcus and the fusiform face area, which may mediate facial processing. It has been argued that dysfunction in the superior temporal sulcus underlies the social deficits that characterize autism. Compared to neurotypical individuals, one study found that individuals with high-functioning autism had reduced activity in the fusiform face area when viewing pictures of faces.^[21]

Mitochondria

ASD could be linked to mitochondrial disease, a basic cellular abnormality with the potential to cause disturbances in a wide range of body systems.^[22] A 2012 meta-analysis study, as well as other population studies show that approximately 5% of autistic children meet the criteria for classical mitochondrial dysfunction.^[23] It is unclear why this mitochondrial disease occurs, considering that only 23% of children with both ASD and mitochondrial disease present with mitochondrial DNA abnormalities.

Serotonin

Serotonin is a major neurotransmitter in the nervous system and contributes to formation of new neurons (neurogenesis), formation of new connections between neurons (synaptogenesis), remodeling of synapses, and survival and migration of neurons, processes that are necessary for a developing brain and some also necessary for learning in the adult brain. 45% of ASD individuals have been found to have increased blood serotonin levels. Abnormalities in the serotonin transporter have also been found in ASD individuals. It has been hypothesized that increased activity of serotonin in the developing brain may facilitate the onset of ASD, with an association found in six out of eight studies between the use of selective serotonin reuptake inhibitors (SSRIs) by the pregnant mother and the development of ASD in the child exposed to SSRI in the antenatal environment.^[24]

The study could not definitively conclude SSRIs caused the increased risk for ASD due to the biases found in those studies, and the authors called for more definitive, better conducted studies.^[25] Confounding by indication has since then been shown to be likely.^[26] However, it is also hypothesized that SSRIs may help reduce symptoms of ASD and even positively affect brain development in some ASD patients.

References

1. Penn HE . February 2006 . Neurobiological correlates of autism: a review of recent research . Child Neuropsychology . 12 . 1 . 57–79 . 10.1080/09297040500253546 . 16484102 . 46119993.
2. London E . October 2007 . The role of the neurobiologist in redefining the diagnosis of autism . Brain Pathology . 17 . 4 . 408–411 . 10.1111/j.1750-3639.2007.00103.x . 8095627 . 17919126 . 24860348.
3. Israelyan N, Margolis KG . June 2018 . Serotonin as a link between the gut-brain-microbiome axis in autism spectrum disorders . Pharmacological Research . Review . 132 . 1–6 . 10.1016/j.phrs.2018.03.020 . 6368356 . 29614380.
4. Wasilewska J, Klukowski M . 2015 . Gastrointestinal symptoms and autism spectrum disorder: links and risks - a possible new overlap syndrome . Pediatric Health, Medicine and Therapeutics . Review . 6 . 153–166 . 10.2147/PHMT.S85717 . 5683266 . 29388597 . free .
5. Rao M, Gershon MD . September 2016 . The bowel and beyond: the enteric nervous system in neurological disorders . Nature Reviews. Gastroenterology & Hepatology . Review . 13 . 9 . 517–528 . 10.1038/nrgastro.2016.107 . 5005185 . 27435372 . immune dysregulation, GI inflammation, malfunction of the ANS, genetic and metabolic activity of the microbiome, and dietary metabolites may contribute to brain dysfunction and neuroinflammation depending upon individual genetic vulnerability.
6. Levy SE, Mandell DS, Schultz RT . November 2009 . Autism . Lancet . 374 . 9701 . 1627–1638 . 10.1016/S0140-6736(09)61376-3 . 2863325 . 19819542.
7. Betancur C, Sakurai T, Buxbaum JD . July 2009 . The emerging role of synaptic cell-adhesion pathways in the pathogenesis of autism spectrum disorders . Trends in Neurosciences . 32 . 7 . 402–412 . 10.1016/j.tins.2009.04.003 . 19541375 . 10354373 . 8644511.
8. Arndt TL, Stodgell CJ, Rodier PM . 2005 . The teratology of autism . International Journal of Developmental Neuroscience . 23 . 2–3 . 189–199 . 10.1016/j.ijdevneu.2004.11.001 . 15749245 . 17797266.
9. Book: The development of autism: perspectives from theory and research. Koenig K, Tsatsanis KD, Volkmar FR. L. Erlbaum. 2001. 9780805832457. Burack JA, Charman T, Yirmiya N, Zelazo PR. Mahwah, N.J.. 73–92. Neurobiology and Genetics of Autism: A Developmental Perspective. 806185029.
10. Minshew NJ . 8134205 . Brief report: brain mechanisms in autism: functional and structural abnormalities . Journal of Autism and Developmental Disorders . 26 . 2 . 205–9 . April 1996 . 8744486 . 10.1007/BF02172013 .
11. Stanfield AC, McIntosh AM, Spencer MD, Philip R, Gaur S, Lawrie SM . Towards a neuroanatomy of autism: a systematic review and meta-analysis of structural magnetic resonance imaging studies . European Psychiatry . 23 . 4 . 289–99 . June 2008 . 17765485 . 10.1016/j.eurpsy.2007.05.006 . 29070618 .
12. Lefebvre A, Beggiato A, Bourgeron T, Toro R . 8794474 . Neuroanatomical Diversity of Corpus Callosum and Brain Volume in Autism: Meta-analysis, Analysis of the Autism Brain Imaging Data Exchange Project, and Simulation . Biological Psychiatry . 78 . 2 . 126–34 . July 2015 . 25850620 . 10.1016/j.biopsych.2015.02.010 . free .
13. Sugranyes G, Kyriakopoulos M, Corrigall R, Taylor E, Frangou S . Autism spectrum disorders and schizophrenia: meta-analysis of the neural correlates of social cognition . PLOS ONE . 6 . 10 . e25322 . 2011 . 21998649 . 3187762 . 10.1371/journal.pone.0025322 . 2011PLoSO...625322S . free .
14. Estes . Myka L. . McAllister . A. Kimberley . 2016-08-19 . Maternal immune activation: Implications for neuropsychiatric disorders . Science . en . 353 . 6301 . 772–777 . 2016Sci...353..772E . 10.1126/science.aag3194 . 0036-8075 . 5650490 . 27540164.
15. O'Reilly C, Lewis JD, Elsabbagh M . Is functional brain connectivity atypical in autism? A systematic review of EEG and MEG studies . PLOS ONE . 12 . 5 . e0175870 . 2017 . 28467487 . 5414938 . 10.1371/journal.pone.0175870 . 2017PLoSO..1275870O . Review. free .
16. Chen JA, Peñagarikano O, Belgard TG, Swarup V, Geschwind DH . The emerging picture of autism spectrum disorder: genetics and pathology . Annual Review of Pathology . 10 . 111–44 . 2015 . 25621659 . 10.1146/annurev-pathol-012414-040405 . Review. free .
17. Web site: Autism spectrum disorder - Symptoms and causes . 2024-01-26 . Mayo Clinic . en.
18. Al-Beltagi M . Autism medical comorbidities . English . World Journal of Clinical Pediatrics . 10 . 3 . 15–28 . May 2021 . 33972922 . 8085719 . 10.5409/wjcp.v10.i3.15 . Gastrointestinal (GI) disorders are significantly more common in children with ASD; they occur in 46% to 84% of them. . free .
19. Azhari A, Azizan F, Esposito G . A systematic review of gut-immune-brain mechanisms in Autism Spectrum Disorder . Developmental Psychobiology . 61 . 5 . 752–771 . July 2019 . 30523646 . 10.1002/dev.21803 . 54523742 . 10220/49107 . free .
20. Kennedy DP, Adolphs R . The social brain in psychiatric and neurological disorders . Trends in Cognitive Sciences . 16 . 11 . 559–72 . November 2012 . 23047070 . 3606817 . 10.1016/j.tics.2012.09.006 .
21. Schultz RT . Developmental deficits in social perception in autism: the role of the amygdala and fusiform face area . International Journal of Developmental Neuroscience . 23 . 2–3 . 125–41 . 2005 . 15749240 . 10.1016/j.ijdevneu.2004.12.012 . 17078137 .
22. Haas RH, Parikh S, Falk MJ, Saneto RP, Wolf NI, Darin N, Cohen BH . Mitochondrial disease: a practical approach for primary care physicians . Pediatrics . 120 . 6 . 1326–1333 . December 2007 . 18055683 . 10.1542/peds.2007-0391 . 4939996 .
23. Rossignol DA, Frye RE . Mitochondrial dysfunction in autism spectrum disorders: a systematic review and meta-analysis . Molecular Psychiatry . 17 . 3 . 290–314 . March 2012 . 21263444 . 3285768 . 10.1038/mp.2010.136 .
24. Web site: Autism . 2024-01-26 . www.who.int . en.
25. Gentile S . Prenatal antidepressant exposure and the risk of autism spectrum disorders in children. Are we looking at the fall of Gods? . Journal of Affective Disorders . 182 . 132–7 . August 2015 . 25985383 . 10.1016/j.jad.2015.04.048 .
26. Dragioti E, Solmi M, Favaro A, Fusar-Poli P, Dazzan P, Thompson T, Stubbs B, Firth J, Fornaro M, Tsartsalis D, Carvalho AF, Vieta E, McGuire P, Young AH, Shin JI, Correll CU, Evangelou E . 6 . Association of Antidepressant Use With Adverse Health Outcomes: A Systematic Umbrella Review . JAMA Psychiatry . 76 . 12 . 1241–1255 . October 2019 . 31577342 . 6777224 . 10.1001/jamapsychiatry.2019.2859 .