Pathophysiology of autism

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

Contents

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. [1] 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. [4] 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. [5]

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]

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:

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: [19]

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. As of 2012, 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] [ verification needed ]

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. [23]

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. [16] 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. [16]

Related Research Articles

<span class="mw-page-title-main">Asperger syndrome</span> Neurodevelopmental diagnosis now categorized under Autism Spectrum Disorder

Asperger syndrome (AS), also known as Asperger's syndrome, formerly described a neurodevelopmental disorder characterized by significant difficulties in social interaction and nonverbal communication, along with restricted and repetitive patterns of behavior, interests, and activities. The syndrome has been merged with other disorders into autism spectrum disorder (ASD) and is no longer considered a stand-alone diagnosis. It was considered milder than other diagnoses that were merged into ASD by relatively unimpaired spoken language and intelligence.

<span class="mw-page-title-main">Histamine</span> Organic compound involved in immune responses

Histamine is an organic nitrogenous compound involved in local immune responses communication, as well as regulating physiological functions in the gut and acting as a neurotransmitter for the brain, spinal cord, and uterus. Since histamine was discovered in 1910, it has been considered a local hormone (autocoid) because it lacks the classic endocrine glands to secrete it; however, in recent years, histamine has been recognized as a central neurotransmitter. Histamine is involved in the inflammatory response and has a central role as a mediator of itching. As part of an immune response to foreign pathogens, histamine is produced by basophils and by mast cells found in nearby connective tissues. Histamine increases the permeability of the capillaries to white blood cells and some proteins, to allow them to engage pathogens in the infected tissues. It consists of an imidazole ring attached to an ethylamine chain; under physiological conditions, the amino group of the side-chain is protonated.

<span class="mw-page-title-main">Controversies in autism</span> Controversies about both the cause of autism and the nature of the diagnoses themselves

Diagnoses of autism have become more frequent since the 1980s, which has led to various controversies about both the cause of autism and the nature of the diagnoses themselves. Whether autism has mainly a genetic or developmental cause, and the degree of coincidence between autism and intellectual disability, are all matters of current scientific controversy as well as inquiry. There is also more sociopolitical debate as to whether autism should be considered a disability on its own.

<span class="mw-page-title-main">Conditions comorbid to autism spectrum disorders</span> Medical conditions more common in autistic people

Autism spectrum disorders (ASD) are neurodevelopmental disorders that begin in early childhood, persist throughout adulthood, and affect three crucial areas of development: communication, social interaction and restricted patterns of behavior. There are many conditions comorbid to autism spectrum disorders such as attention-deficit hyperactivity disorder and epilepsy.

<span class="mw-page-title-main">Heritability of autism</span>

The heritability of autism is the proportion of differences in expression of autism that can be explained by genetic variation; if the heritability of a condition is high, then the condition is considered to be primarily genetic. Autism has a strong genetic basis. Although the genetics of autism are complex, autism spectrum disorder (ASD) is explained more by multigene effects than by rare mutations with large effects.

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<span class="mw-page-title-main">Causes of autism</span> Proposed causes of autism

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Autism, formally called autism spectrum disorder (ASD) or autism spectrum condition (ASC), is a neurodevelopmental disorder marked by deficits in reciprocal social communication and the presence of restricted and repetitive patterns of behavior. Other common signs include difficulty with social interaction, verbal and nonverbal communication, along with perseverative interests, stereotypic body movements, rigid routines, and hyper- or hyporeactivity to sensory input. Autism is clinically regarded as a spectrum disorder, meaning that it can manifest very differently in each person. For example, some are nonspeaking, while others have proficient spoken language. Because of this, there is wide variation in the support needs of people across the autism spectrum.

Autism spectrum disorder (ASD) refers to a variety of conditions typically identified by challenges with social skills, communication, speech, and repetitive sensory-motor behaviors. The 11th International Classification of Diseases (ICD-11), released in January 2021, characterizes ASD by the associated deficits in the ability to initiate and sustain two-way social communication and restricted or repetitive behavior unusual for the individual's age or situation. Although linked with early childhood, the symptoms can appear later as well. Symptoms can be detected before the age of two and experienced practitioners can give a reliable diagnosis by that age. However, official diagnosis may not occur until much older, even well into adulthood. There is a large degree of variation in how much support a person with ASD needs in day-to-day life. This can be classified by a further diagnosis of ASD level 1, level 2, or level 3. Of these, ASD level 3 describes people requiring very substantial support and who experience more severe symptoms. ASD-related deficits in nonverbal and verbal social skills can result in impediments in personal, family, social, educational, and occupational situations. This disorder tends to have a strong correlation with genetics along with other factors. More research is identifying ways in which epigenetics is linked to autism. Epigenetics generally refers to the ways in which chromatin structure is altered to affect gene expression. Mechanisms such as cytosine regulation and post-translational modifications of histones. Of the 215 genes contributing, to some extent in ASD, 42 have been found to be involved in epigenetic modification of gene expression. Some examples of ASD signs are specific or repeated behaviors, enhanced sensitivity to materials, being upset by changes in routine, appearing to show reduced interest in others, avoiding eye contact and limitations in social situations, as well as verbal communication. When social interaction becomes more important, some whose condition might have been overlooked suffer social and other exclusion and are more likely to have coexisting mental and physical conditions. Long-term problems include difficulties in daily living such as managing schedules, hypersensitivities, initiating and sustaining relationships, and maintaining jobs.

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The mechanisms of autism are the molecular and cellular processes believed to cause or contribute to the symptoms of autism. Multiple processes are hypothesized to explain different autism spectrum features. These hypotheses include defects in synapse structure and function, reduced synaptic plasticity, disrupted neural circuit function, gut–brain axis dyshomeostasis, neuroinflammation, and altered brain structure or connectivity.

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References

  1. 1 2 Penn HE (February 2006). "Neurobiological correlates of autism: a review of recent research". Child Neuropsychology. 12 (1): 57–79. doi:10.1080/09297040500253546. PMID   16484102. S2CID   46119993.
  2. ↑ London E (October 2007). "The role of the neurobiologist in redefining the diagnosis of autism". Brain Pathology. 17 (4): 408–411. doi:10.1111/j.1750-3639.2007.00103.x. PMC   8095627 . PMID   17919126. S2CID   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. doi:10.1016/j.phrs.2018.03.020. PMC   6368356 . PMID   29614380.
  4. 1 2 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. doi: 10.2147/PHMT.S85717 . PMC   5683266 . PMID   29388597.
  5. 1 2 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. doi:10.1038/nrgastro.2016.107. PMC   5005185 . PMID   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. doi:10.1016/S0140-6736(09)61376-3. PMC   2863325 . PMID   19819542. (Erratum:  doi:10.1016/S0140-6736(11)61666-8, [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)61666-8/fulltext ])
  7. ↑ Betancur C, Sakurai T, Buxbaum JD (July 2009). "The emerging role of synaptic cell-adhesion pathways in the pathogenesis of autism spectrum disorders" (PDF). Trends in Neurosciences. 32 (7): 402–412. doi:10.1016/j.tins.2009.04.003. PMC   10354373 . PMID   19541375. S2CID   8644511.
  8. ↑ Arndt TL, Stodgell CJ, Rodier PM (2005). "The teratology of autism". International Journal of Developmental Neuroscience. 23 (2–3): 189–199. doi:10.1016/j.ijdevneu.2004.11.001. PMID   15749245. S2CID   17797266.
  9. ↑ Koenig K, Tsatsanis KD, Volkmar FR (2001). "Neurobiology and Genetics of Autism: A Developmental Perspective". In Burack JA, Charman T, Yirmiya N, Zelazo PR (eds.). The development of autism: perspectives from theory and research. Mahwah, N.J.: L. Erlbaum. pp. 73–92. ISBN   9780805832457. OCLC   806185029.
  10. ↑ Minshew NJ (April 1996). "Brief report: brain mechanisms in autism: functional and structural abnormalities". Journal of Autism and Developmental Disorders. 26 (2): 205–9. doi:10.1007/BF02172013. PMID   8744486. S2CID   8134205.
  11. ↑ Stanfield AC, McIntosh AM, Spencer MD, Philip R, Gaur S, Lawrie SM (June 2008). "Towards a neuroanatomy of autism: a systematic review and meta-analysis of structural magnetic resonance imaging studies". European Psychiatry. 23 (4): 289–99. doi:10.1016/j.eurpsy.2007.05.006. PMID   17765485. S2CID   29070618.
  12. ↑ Lefebvre A, Beggiato A, Bourgeron T, Toro R (July 2015). "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. doi: 10.1016/j.biopsych.2015.02.010 . PMID   25850620. S2CID   8794474.
  13. ↑ Sugranyes G, Kyriakopoulos M, Corrigall R, Taylor E, Frangou S (2011). "Autism spectrum disorders and schizophrenia: meta-analysis of the neural correlates of social cognition". PLOS ONE. 6 (10): e25322. Bibcode:2011PLoSO...625322S. doi: 10.1371/journal.pone.0025322 . PMC   3187762 . PMID   21998649.
  14. ↑ Estes, Myka L.; McAllister, A. Kimberley (2016-08-19). "Maternal immune activation: Implications for neuropsychiatric disorders". Science. 353 (6301): 772–777. Bibcode:2016Sci...353..772E. doi:10.1126/science.aag3194. ISSN   0036-8075. PMC   5650490 . PMID   27540164.
  15. 1 2 3 4 5 O'Reilly C, Lewis JD, Elsabbagh M (2017). "Is functional brain connectivity atypical in autism? A systematic review of EEG and MEG studies". PLOS ONE (Review). 12 (5): e0175870. Bibcode:2017PLoSO..1275870O. doi: 10.1371/journal.pone.0175870 . PMC   5414938 . PMID   28467487.
  16. 1 2 3 4 5 6 7 8 9 10 Chen JA, Peñagarikano O, Belgard TG, Swarup V, Geschwind DH (2015). "The emerging picture of autism spectrum disorder: genetics and pathology". Annual Review of Pathology (Review). 10: 111–44. doi: 10.1146/annurev-pathol-012414-040405 . PMID   25621659.
  17. ↑ "Autism spectrum disorder - Symptoms and causes". Mayo Clinic. Retrieved 2024-01-26.
  18. ↑ Al-Beltagi M (May 2021). "Autism medical comorbidities". World Journal of Clinical Pediatrics. 10 (3): 15–28. doi: 10.5409/wjcp.v10.i3.15 . PMC   8085719 . PMID   33972922. Gastrointestinal (GI) disorders are significantly more common in children with ASD; they occur in 46% to 84% of them.
  19. 1 2 3 4 5 6 7 8 Azhari A, Azizan F, Esposito G (July 2019). "A systematic review of gut-immune-brain mechanisms in Autism Spectrum Disorder". Developmental Psychobiology. 61 (5): 752–771. doi:10.1002/dev.21803. hdl: 10220/49107 . PMID   30523646. S2CID   54523742.
  20. ↑ Kennedy DP, Adolphs R (November 2012). "The social brain in psychiatric and neurological disorders". Trends in Cognitive Sciences. 16 (11): 559–72. doi:10.1016/j.tics.2012.09.006. PMC   3606817 . PMID   23047070.
  21. ↑ Schultz RT (2005). "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. doi:10.1016/j.ijdevneu.2004.12.012. PMID   15749240. S2CID   17078137.
  22. ↑ Haas RH, Parikh S, Falk MJ, Saneto RP, Wolf NI, Darin N, Cohen BH (December 2007). "Mitochondrial disease: a practical approach for primary care physicians". Pediatrics. 120 (6): 1326–1333. doi:10.1542/peds.2007-0391. PMID   18055683. S2CID   4939996.
  23. 1 2 Rossignol DA, Frye RE (March 2012). "Mitochondrial dysfunction in autism spectrum disorders: a systematic review and meta-analysis". Molecular Psychiatry. 17 (3): 290–314. doi:10.1038/mp.2010.136. PMC   3285768 . PMID   21263444.
  24. ↑ "Autism". www.who.int. Retrieved 2024-01-26.
  25. ↑ Gentile S (August 2015). "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. doi:10.1016/j.jad.2015.04.048. PMID   25985383.
  26. ↑ Dragioti E, Solmi M, Favaro A, Fusar-Poli P, Dazzan P, Thompson T, et al. (October 2019). "Association of Antidepressant Use With Adverse Health Outcomes: A Systematic Umbrella Review". JAMA Psychiatry. 76 (12): 1241–1255. doi:10.1001/jamapsychiatry.2019.2859. PMC   6777224 . PMID   31577342.
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