Jump to content

Mechanism of autism

From Wikipedia, the free encyclopedia

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,[1][2] reduced synaptic plasticity,[3] disrupted neural circuit function, gut–brain axis dyshomeostasis,[4][5][6] neuroinflammation,[7] and altered brain structure or connectivity.[8][9][10][11] Autism symptoms stem from maturation-related changes in brain systems.[9] The mechanisms of autism are divided into two main areas: pathophysiology of brain structures and processes, and neuropsychological linkages between brain structures and behaviors, with multiple pathophysiologies linked to various autism behaviors.[10]

Evidence suggests gut–brain axis abnormalities may contribute to autism.[6][4] Studies propose that immune, gastrointestinal inflammation, autonomic nervous system dysfunction, gut microbiota alterations, and dietary metabolites may contribute to brain neuroinflammation and dysfunction.[5] Additionally, enteric nervous system abnormalities could play a role in neurological disorders by allowing disease pathways from the gut to impact the brain.[5]

Synaptic dysfunction also appears to be implicated in autism, with some mutations disrupting synaptic pathways involving cell adhesion.[2] Evidence points to teratogens affecting the early developmental stages, suggesting autism arises very early, possibly within the first eight weeks after conception.[12]

Neuroanatomical studies support that autism may involve abnormal neuronal growth and pruning, leading to brain enlargement in some areas and reduction in others.[13] Functional neuroimaging studies show reduced activation in somatosensory cortices during theory of mind tasks in autistic individuals and highlight potential imbalances in neurotransmitters like glutamate and Γ-aminobutyric acid that may underlie autism's behavioral manifestations.[14]

Pathophysiology

[edit]
Two diagrams of major brain structures implicated in autism. The upper diagram shows the cerebral cortex near the top and the basal ganglia in the center, just above the amygdala and hippocampus. The lower diagram shows the corpus callosum near the center, the cerebellum in the lower rear, and the brain stem in the lower center.
The amygdala, cerebellum, and many other brain regions have been implicated in autism.[15]

Unlike some brain disorders which have clear molecular hallmarks that can be observed in every affected individual, such as Alzheimer's disease or Parkinson's disease, autism does not have a unifying mechanism at the molecular, cellular, or systems level. The autism spectrum may comprise a small set of disorders that converge on a few common molecular pathways, or it may be a large set of disorders with diverse mechanisms.[16] Autism appears to result from developmental factors that affect many or all functional brain systems.[17] Some factors may disturb the timing of brain development rather than the final product.[15]

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.[18]
  • Fewer and smaller Purkinje neurons in the cerebellum. New research suggest a role of the cerebellum in emotional processing and language.[18]
  • 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.[18]
  • 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.[18]
  • 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.[18]
  • Loss of function (LoF) mutations in genes relating to the function and development of the synapse.[19] Some of those implicated include SHANK3, SCN2A, and PTEN.[19]

Brain growth

[edit]

Neuroanatomical studies and the association between autism and teratogens strongly suggest that autism affects brain development soon after conception.[12] This anomaly appears to start a cascade of pathological events in the brain that are significantly influenced by environmental factors.[20] Just after birth, the brains of children with autism tend to grow faster than usual, followed by normal or relatively slower growth in childhood.[21] It is unknown whether early brain overgrowth occurs in all children with autism. It appears to be most prominent in the frontal and temporal lobes, which are associated with higher cognitive specializations such as social cognition, and language development.[22] Hypotheses for the cellular and molecular bases of pathological early overgrowth include an excess of neurons that causes local overconnectivity in key brain regions,[21] and disturbed neuronal migration during early gestation.[23][24]

Synapse dysfunction

[edit]

Synapse and dendritic spine growth may be disrupted in autism due to impaired neurexin–neuroligin cell-adhesion signaling[25] or dysregulated synthesis of synaptic proteins.[26][27] Disrupted synaptic development may also contribute to epilepsy, which may explain why the two conditions are associated.[28]Studies have suggested that excitatory–inhibitory networks may be imbalanced in autism.[24]

Neurotransmitters such as serotonin, dopamine, and glutamate have been implicated in autism.[1] Fragile X, the most common genetic cause of autism, is linked to dysfunction of group I metabotropic glutamate receptors (mGluR), leading some to consider their potential role in autism.[29]

Altered circuit connectivity

[edit]
A human brain viewed from above. About 10% is highlighted in yellow and 10% in blue. There is a tiny green region (~0.5%) where they overlap.
Autistic individuals tend to use different brain areas (yellow) for a movement task compared to a control group (blue).[30]

The underconnectivity theory of autism posits that autistic people tend to have fewer high-level neural connections and less global synchronization, along with an excess of low-level processes.[31] Functional connectivity studies have found both hypo- and hyperconnectivity in brains of autistic people.[32] Hypoconnectivity is commonly observed for interhemispheric (e.g. lower neuron density in corpus callosum)[33] and cortico-cortical functional connectivity.[34] Some studies have found local overconnectivity in the cerebral cortex and weak functional connections between the frontal lobe and the rest of the cortex.[35] Abnormal default mode network (task-negative) connectivity is often observed. Toggling between task-negative network activation and task-positive network activation (consisting of the dorsal attention network and salience network) may be less efficient, possibly reflecting a disturbance of self-referential thought.[36] Such patterns of low function and aberrant activation in the brain may depend on whether the brain is performing social or nonsocial tasks. [37]

Some studies have suggested that autism is a disorder of the association cortex.[38] Event-related potentials with respect to attention, orientation to auditory and visual stimuli, novelty detection, language and face processing, and information storage are altered in autistic individuals; several studies have found a preference for nonsocial stimuli.[39] Magnetoencephalography studies have observed delayed processing of auditory signals in autistic children.[40]

The mirror neuron system (MNS) theory of autism hypothesizes that disrupted development of the MNS impairs autistic people's ability to imitate others, leading to core autistic features of social impairment and communication difficulties. In animals, the MNS activates when an animal performs an action or observes another animal perform the same action. The MNS may contribute to an individual's understanding of other people by enabling the modeling of their behavior via embodied simulation of their actions, intentions, and emotions.[41][42] Several studies have tested this hypothesis by demonstrating structural abnormalities in MNS regions of individuals with ASD, delay in the activation in the core circuit for imitation in individuals with ASD, and a correlation between reduced MNS activity and severity of the syndrome in children with ASD.[43] However, individuals with autism also have abnormal brain activation in many circuits outside the MNS[44] and the MNS theory does not explain the normal performance of children with autism on imitation tasks that involve a goal or object.[45]

Common copy number variation associations have suggested similarities between the mechanisms of autism and schizophrenia. For loci such as 16p11.2, 16p13.1, 22p11, and 22q13, deletion is associated with autism whereas duplication is associated with schizophrenia. Conversely, 1q21.1 and 22p11.2 duplication is associated with autism and deletion with schizophrenia.[46]

It has been observed that people with ASD tend to have preferential processing of information on the left hemisphere compared to the right. 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.[33][47]

Inflammation

[edit]

The immune system is thought to play an important role in autism. Children with autism have been found by researchers to have inflammation of both the peripheral and central immune systems as indicated by increased levels of pro-inflammatory cytokines and significant activation of microglia.[48][49][7] Biomarkers of abnormal immune function have also been associated with increased impairments in behaviors that are characteristic of the core features of autism such as, deficits in social interactions and communication.[49] Interactions between the immune system and the nervous system begin early during the embryonic stage of life, and successful neurodevelopment depends on a balanced immune response. It is thought that activation of a pregnant mother's immune system such as from environmental toxicants or infection can contribute to causing autism through causing a disruption of brain development.[50][51][52] This is supported by recent studies that have found that infection during pregnancy is associated with an increased risk of autism.[53][54]

Some evidence suggests that gut–brain axis abnormalities may be involved by means of impaired serotonin signaling and inflammation.[6] A 2015 review proposed that immune dysregulation, gastrointestinal inflammation, autonomic nervous system malfunction, gut microbiota alterations, and food metabolites may cause brain neuroinflammation and dysfunction.[4] A 2016 review concluded that enteric nervous system abnormalities might play a role in neurological disorders such as autism.[5]

Metabolism

[edit]

Some data suggests neuronal overgrowth observed in autism may be caused by an increase in several growth hormones[55] or impaired regulation of growth factor receptors. Some inborn errors of metabolism are associated with autism, but probably account for less than 5% of cases.[56]

Brain connectivity

[edit]

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:[33][18]

  • 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.[33]
  • 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.[33][57]
  • 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.[33]
  • 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.[33] Abnormal neural organization is also observed in the Broca's area which is important for speech production.[18]

Gut-immune-brain axis

[edit]

46% to 84% of autistic individuals have GI-related problems like reflux, diarrhea, constipation, inflammatory bowel disease, and food allergies.[58] 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.[59] Listed below are some research findings on the influence of gut bacteria and abnormal immune responses on brain development:[59]

  • Some studies on rodents have shown gut bacteria influencing emotional functions and neurotransmitter balance in the brain, both of which are impacted in ASD.[18]
  • 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.[59]
  • 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.[59]
  • 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.[59]
  • It is proposed that inflammation within the brain promoted by inflammatory responses to harmful gut microbiome impacts brain development.[59]
  • 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.[59]
  • 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.[59]

Social brain interconnectivity

[edit]

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.[60]

Temporal lobe

[edit]

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.[61][verification needed]

Mitochondria

[edit]

ASD could be linked to mitochondrial disease, a basic cellular abnormality with the potential to cause disturbances in a wide range of body systems.[62] 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.[63] 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.[63]

Serotonin

[edit]

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.[18] 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.[64]

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.[65] Confounding by indication has since then been shown to be likely.[66] However, it is also hypothesized that SSRIs may help reduce symptoms of ASD and even positively affect brain development in some ASD patients.[18]

Neuropsychology

[edit]

Two major categories of cognitive theories have been proposed to explain links between autistic brains and behavior.

Social cognition

[edit]

The first category focuses on deficits in social cognition. Simon Baron-Cohen's empathizing–systemizing theory postulates that autistic individuals can systemize—that is, they can develop internal rules of operation to handle events inside the brain—but are less effective at empathizing by handling events generated by other agents. An extension, the extreme male brain theory, hypothesizes that autism is an extreme case of the male brain, defined psychometrically as individuals in whom systemizing is better than empathizing.[67] These theories are somewhat related to Baron-Cohen's earlier theory of mind approach, which hypothesizes that autistic behavior arises from an inability to ascribe mental states to oneself and others. The theory of mind hypothesis is supported by the atypical responses of children with autism to the Sally–Anne test for reasoning about others' motivations,[67] and the mirror neuron system theory of autism described in Pathophysiology maps well to the hypothesis.[43] However, most studies have found no evidence of impairment in autistic individuals' ability to understand other people's basic intentions or goals; instead, data suggests that impairments are found in understanding more complex social emotions or in considering others' viewpoints.[68]

Nonsocial cognition

[edit]

The second category focuses on nonsocial or general processing: the executive functions such as working memory, planning, inhibition. In his review, Kenworthy states that "the claim of executive dysfunction as a causal factor in autism is controversial", however, "it is clear that executive dysfunction plays a role in the social and cognitive deficits observed in individuals with autism".[69] Tests of core executive processes such as eye movement tasks indicate improvement from late childhood to adolescence, but performance never reaches typical adult levels.[70] A strength of the theory is predicting stereotyped behavior and narrow interests;[71] two weaknesses are that executive function is hard to measure[69] and that executive function deficits have not been found in young children with autism.[72]

Weak central coherence theory

[edit]

Weak central coherence theory hypothesizes that a limited ability to see the big picture underlies the central disturbance in autism. One strength of this theory is predicting special talents and peaks in performance in autistic people.[73] A related theory—enhanced perceptual functioning—focuses more on the superiority of locally oriented and perceptual operations in autistic individuals.[74] Yet another, monotropism, posits that autism stems from a different cognitive style, tending to focus attention (or processing resources) intensely, to the exclusion of other stimuli.[75] These theories map well from the underconnectivity theory of autism.

Issues with categories

[edit]

Neither category is satisfactory on its own; social cognition theories poorly address autism's rigid and repetitive behaviors, while most of the nonsocial theories have difficulty explaining social impairment and communication difficulties.[76] A combined theory based on multiple deficits may prove to be more useful.[77]

References

[edit]
  1. ^ a b 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.
  2. ^ a b 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. doi:10.1016/j.tins.2009.04.003. PMC 10354373. PMID 19541375. S2CID 8644511.
  3. ^ Walsh CA, Morrow EM, Rubenstein JL (October 2008). "Autism and brain development". Cell. 135 (3): 396–400. doi:10.1016/j.cell.2008.10.015. PMC 2701104. PMID 18984148.
  4. ^ a b c 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. ^ a b c d 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.
  6. ^ a b c 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.
  7. ^ a b Rossignol DA, Frye RE (2014). "Evidence linking oxidative stress, mitochondrial dysfunction, and inflammation in the brain of individuals with autism". Frontiers in Physiology. 5: 150. doi:10.3389/fphys.2014.00150. PMC 4001006. PMID 24795645.
  8. ^ Sarovic D (November 2021). "A Unifying Theory for Autism: The Pathogenetic Triad as a Theoretical Framework". Frontiers in Psychiatry (Review). 12: 767075. doi:10.3389/fpsyt.2021.767075. PMC 8637925. PMID 34867553. S2CID 244119594.
  9. ^ a b 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.
  10. ^ a b 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.
  11. ^ Baird G, Cass H, Slonims V (August 2003). "Diagnosis of autism". BMJ. 327 (7413): 488–493. doi:10.1136/bmj.327.7413.488. PMC 188387. PMID 12946972.
  12. ^ a b 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.
  13. ^ 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.
  14. ^ Estes ML, McAllister AK (August 2016). "Maternal immune activation: Implications for neuropsychiatric disorders". Science. 353 (6301): 772–777. doi:10.1126/science.aag3194. PMC 5650490. PMID 27540164.
  15. ^ a b Amaral DG, Schumann CM, Nordahl CW (March 2008). "Neuroanatomy of autism". Trends in Neurosciences. 31 (3): 137–145. doi:10.1016/j.tins.2007.12.005. PMID 18258309. S2CID 18648870.
  16. ^ Geschwind DH (October 2008). "Autism: many genes, common pathways?". Cell. 135 (3): 391–395. doi:10.1016/j.cell.2008.10.016. PMC 2756410. PMID 18984147.
  17. ^ Müller RA (2007). "The study of autism as a distributed disorder". Mental Retardation and Developmental Disabilities Research Reviews. 13 (1): 85–95. doi:10.1002/mrdd.20141. PMC 3315379. PMID 17326118.
  18. ^ a b c d e f g h i j 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: 111–144. doi:10.1146/annurev-pathol-012414-040405. PMID 25621659.
  19. ^ a b De Rubeis S, He X, Goldberg AP, Poultney CS, Samocha K, Cicek AE, et al. (November 2014). "Synaptic, transcriptional and chromatin genes disrupted in autism". Nature. 515 (7526): 209–215. Bibcode:2014Natur.515..209.. doi:10.1038/nature13772. PMC 4402723. PMID 25363760.
  20. ^ Casanova MF (October 2007). "The neuropathology of autism". Brain Pathology. 17 (4): 422–433. doi:10.1111/j.1750-3639.2007.00100.x. PMC 8095561. PMID 17919128. S2CID 6959302.
  21. ^ a b Courchesne E, Pierce K, Schumann CM, Redcay E, Buckwalter JA, Kennedy DP, et al. (October 2007). "Mapping early brain development in autism". Neuron. 56 (2): 399–413. doi:10.1016/j.neuron.2007.10.016. PMID 17964254. S2CID 10662307.
  22. ^ Geschwind DH (2009). "Advances in autism". Annual Review of Medicine. 60: 367–380. doi:10.1146/annurev.med.60.053107.121225. PMC 3645857. PMID 19630577.
  23. ^ Schmitz C, Rezaie P (February 2008). "The neuropathology of autism: where do we stand?". Neuropathology and Applied Neurobiology. 34 (1): 4–11. doi:10.1111/j.1365-2990.2007.00872.x. PMID 17971078. S2CID 23551620.
  24. ^ a b Persico AM, Bourgeron T (July 2006). "Searching for ways out of the autism maze: genetic, epigenetic and environmental clues". Trends in Neurosciences. 29 (7): 349–358. doi:10.1016/j.tins.2006.05.010. PMID 16808981. S2CID 26722022.
  25. ^ Südhof TC (October 2008). "Neuroligins and neurexins link synaptic function to cognitive disease". Nature. 455 (7215): 903–911. Bibcode:2008Natur.455..903S. doi:10.1038/nature07456. PMC 2673233. PMID 18923512.
  26. ^ Kelleher RJ, Bear MF (October 2008). "The autistic neuron: troubled translation?". Cell. 135 (3): 401–406. doi:10.1016/j.cell.2008.10.017. PMID 18984149. S2CID 619383.
  27. ^ Bear MF, Dölen G, Osterweil E, Nagarajan N (January 2008). "Fragile X: translation in action". Neuropsychopharmacology. 33 (1): 84–87. doi:10.1038/sj.npp.1301610. PMC 4327813. PMID 17940551.
  28. ^ Tuchman R, Moshé SL, Rapin I (February 2009). "Convulsing toward the pathophysiology of autism". Brain & Development. 31 (2): 95–103. doi:10.1016/j.braindev.2008.09.009. PMC 2734903. PMID 19006654.
  29. ^ Dölen G, Osterweil E, Rao BS, Smith GB, Auerbach BD, Chattarji S, et al. (December 2007). "Correction of fragile X syndrome in mice". Neuron. 56 (6): 955–962. doi:10.1016/j.neuron.2007.12.001. PMC 2199268. PMID 18093519.
  30. ^ Powell K (August 2004). "Opening a window to the autistic brain". PLoS Biology. 2 (8): E267. doi:10.1371/journal.pbio.0020267. PMC 509312. PMID 15314667.
  31. ^ Just MA, Cherkassky VL, Keller TA, Kana RK, Minshew NJ (April 2007). "Functional and anatomical cortical underconnectivity in autism: evidence from an FMRI study of an executive function task and corpus callosum morphometry". Cerebral Cortex. 17 (4): 951–961. doi:10.1093/cercor/bhl006. PMC 4500121. PMID 16772313.
  32. ^ Williams DL, Goldstein G, Minshew NJ (August 2006). "Neuropsychologic functioning in children with autism: further evidence for disordered complex information-processing". Child Neuropsychology. 12 (4–5): 279–298. doi:10.1080/09297040600681190. PMC 1803025. PMID 16911973.
  33. ^ a b c d e f g 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.
  34. ^ Ha S, Sohn IJ, Kim N, Sim HJ, Cheon KA (December 2015). "Characteristics of Brains in Autism Spectrum Disorder: Structure, Function and Connectivity across the Lifespan". Experimental Neurobiology (Review). 24 (4): 273–284. doi:10.5607/en.2015.24.4.273. PMC 4688328. PMID 26713076.
  35. ^ Murias M, Webb SJ, Greenson J, Dawson G (August 2007). "Resting state cortical connectivity reflected in EEG coherence in individuals with autism". Biological Psychiatry. 62 (3): 270–273. doi:10.1016/j.biopsych.2006.11.012. PMC 2001237. PMID 17336944.
  36. ^ Broyd SJ, Demanuele C, Debener S, Helps SK, James CJ, Sonuga-Barke EJ (March 2009). "Default-mode brain dysfunction in mental disorders: a systematic review". Neuroscience and Biobehavioral Reviews. 33 (3): 279–296. doi:10.1016/j.neubiorev.2008.09.002. PMID 18824195. S2CID 7175805.
  37. ^ Di Martino A, Ross K, Uddin LQ, Sklar AB, Castellanos FX, Milham MP (January 2009). "Functional brain correlates of social and nonsocial processes in autism spectrum disorders: an activation likelihood estimation meta-analysis". Biological Psychiatry. 65 (1): 63–74. doi:10.1016/j.biopsych.2008.09.022. PMC 2993772. PMID 18996505.
  38. ^ Minshew NJ, Williams DL (July 2007). "The new neurobiology of autism: cortex, connectivity, and neuronal organization". Archives of Neurology. 64 (7): 945–950. doi:10.1001/archneur.64.7.945. PMC 2597785. PMID 17620483.
  39. ^ Jeste SS, Nelson CA (March 2009). "Event related potentials in the understanding of autism spectrum disorders: an analytical review". Journal of Autism and Developmental Disorders. 39 (3): 495–510. doi:10.1007/s10803-008-0652-9. PMC 4422389. PMID 18850262.
  40. ^ Roberts TP, Schmidt GL, Egeth M, Blaskey L, Rey MM, Edgar JC, et al. (May 2008). "Electrophysiological signatures: magnetoencephalographic studies of the neural correlates of language impairment in autism spectrum disorders". International Journal of Psychophysiology. 68 (2): 149–160. doi:10.1016/j.ijpsycho.2008.01.012. PMC 2397446. PMID 18336941.
  41. ^ Williams JH (April 2008). "Self-other relations in social development and autism: multiple roles for mirror neurons and other brain bases". Autism Research. 1 (2): 73–90. doi:10.1002/aur.15. PMID 19360654. S2CID 15269399.
  42. ^ Dinstein I, Thomas C, Behrmann M, Heeger DJ (January 2008). "A mirror up to nature". Current Biology. 18 (1): R13–R18. doi:10.1016/j.cub.2007.11.004. PMC 2517574. PMID 18177704.
  43. ^ a b Iacoboni M, Dapretto M (December 2006). "The mirror neuron system and the consequences of its dysfunction". Nature Reviews. Neuroscience. 7 (12): 942–951. doi:10.1038/nrn2024. PMID 17115076. S2CID 9463011.
  44. ^ Frith U, Frith CD (March 2003). "Development and neurophysiology of mentalizing". Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. 358 (1431): 459–473. doi:10.1098/rstb.2002.1218. PMC 1693139. PMID 12689373.
  45. ^ Hamilton AF (January 2008). "Emulation and mimicry for social interaction: a theoretical approach to imitation in autism". Quarterly Journal of Experimental Psychology. 61 (1): 101–115. doi:10.1080/17470210701508798. PMID 18038342. S2CID 14569936.
  46. ^ Crespi B, Stead P, Elliot M (January 2010). "Evolution in health and medicine Sackler colloquium: Comparative genomics of autism and schizophrenia". Proceedings of the National Academy of Sciences of the United States of America. 107 (Suppl 1): 1736–1741. Bibcode:2010PNAS..107.1736C. doi:10.1073/pnas.0906080106. PMC 2868282. PMID 19955444.
  47. ^ "Autism spectrum disorder - Symptoms and causes". Mayo Clinic. Retrieved 2024-01-26.
  48. ^ Hsiao EY (2013). "Immune Dysregulation in Autism Spectrum Disorder". Neurobiology of Autism. International Review of Neurobiology. Vol. 113. pp. 269–302. doi:10.1016/B978-0-12-418700-9.00009-5. ISBN 9780124187009. PMID 24290389.
  49. ^ a b Onore C, Careaga M, Ashwood P (March 2012). "The role of immune dysfunction in the pathophysiology of autism". Brain, Behavior, and Immunity. 26 (3): 383–392. doi:10.1016/j.bbi.2011.08.007. PMC 3418145. PMID 21906670.
  50. ^ Patterson PH (July 2011). "Maternal infection and immune involvement in autism". Trends in Molecular Medicine. 17 (7): 389–394. doi:10.1016/j.molmed.2011.03.001. PMC 3135697. PMID 21482187.
  51. ^ Chaste P, Leboyer M (September 2012). "Autism risk factors: genes, environment, and gene-environment interactions". Dialogues in Clinical Neuroscience. 14 (3): 281–292. doi:10.31887/DCNS.2012.14.3/pchaste. PMC 3513682. PMID 23226953.
  52. ^ Ashwood P, Wills S, Van de Water J (July 2006). "The immune response in autism: a new frontier for autism research". Journal of Leukocyte Biology. 80 (1): 1–15. CiteSeerX 10.1.1.329.777. doi:10.1189/jlb.1205707. PMID 16698940. S2CID 17531542. Archived from the original on 5 October 2006.
  53. ^ Lee BK, Magnusson C, Gardner RM, Blomström Å, Newschaffer CJ, Burstyn I, et al. (February 2015). "Maternal hospitalization with infection during pregnancy and risk of autism spectrum disorders". Brain, Behavior, and Immunity. 44: 100–105. doi:10.1016/j.bbi.2014.09.001. PMC 4418173. PMID 25218900.
  54. ^ Atladóttir HO, Thorsen P, Østergaard L, Schendel DE, Lemcke S, Abdallah M, et al. (December 2010). "Maternal infection requiring hospitalization during pregnancy and autism spectrum disorders". Journal of Autism and Developmental Disorders. 40 (12): 1423–1430. doi:10.1007/s10803-010-1006-y. PMID 20414802. S2CID 23471371.
  55. ^ Hughes JR (December 2009). "Update on autism: a review of 1300 reports published in 2008". Epilepsy & Behavior. 16 (4): 569–589. doi:10.1016/j.yebeh.2009.09.023. PMID 19896907. S2CID 8013774.
  56. ^ Manzi B, Loizzo AL, Giana G, Curatolo P (March 2008). "Autism and metabolic diseases". Journal of Child Neurology. 23 (3): 307–314. doi:10.1177/0883073807308698. PMID 18079313. S2CID 30809774.
  57. ^ "Autism spectrum disorder - Symptoms and causes". Mayo Clinic. Retrieved 2024-01-26.
  58. ^ 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.
  59. ^ a b c d e f g h 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.
  60. ^ Kennedy DP, Adolphs R (November 2012). "The social brain in psychiatric and neurological disorders". Trends in Cognitive Sciences. 16 (11): 559–572. doi:10.1016/j.tics.2012.09.006. PMC 3606817. PMID 23047070.
  61. ^ 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): 125–141. doi:10.1016/j.ijdevneu.2004.12.012. PMID 15749240. S2CID 17078137.
  62. ^ Haas RH, Parikh S, Falk MJ, Saneto RP, Wolf NI, Darin N, et al. (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.
  63. ^ a b 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.
  64. ^ "Autism". www.who.int. Retrieved 2024-01-26.
  65. ^ 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: 132–137. doi:10.1016/j.jad.2015.04.048. PMID 25985383.
  66. ^ Dragioti E, Solmi M, Favaro A, Fusar-Poli P, Dazzan P, Thompson T, et al. (December 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.
  67. ^ a b Baron-Cohen S (March 2009). "Autism: the empathizing-systemizing (E-S) theory". Annals of the New York Academy of Sciences. 1156 (1): 68–80. Bibcode:2009NYASA1156...68B. doi:10.1111/j.1749-6632.2009.04467.x. PMID 19338503. S2CID 1440395.
  68. ^ Hamilton AF (August 2009). "Goals, intentions and mental states: challenges for theories of autism". Journal of Child Psychology and Psychiatry, and Allied Disciplines. 50 (8): 881–892. CiteSeerX 10.1.1.621.6275. doi:10.1111/j.1469-7610.2009.02098.x. PMID 19508497.
  69. ^ a b Kenworthy L, Yerys BE, Anthony LG, Wallace GL (December 2008). "Understanding executive control in autism spectrum disorders in the lab and in the real world". Neuropsychology Review. 18 (4): 320–338. doi:10.1007/s11065-008-9077-7. PMC 2856078. PMID 18956239.
  70. ^ O'Hearn K, Asato M, Ordaz S, Luna B (2008). "Neurodevelopment and executive function in autism". Development and Psychopathology. 20 (4): 1103–1132. doi:10.1017/S0954579408000527. PMID 18838033. S2CID 33559397.
  71. ^ Hill EL (January 2004). "Executive dysfunction in autism". Trends in Cognitive Sciences. 8 (1): 26–32. doi:10.1016/j.dr.2004.01.001. PMID 14697400.
  72. ^ Sigman M, Spence SJ, Wang AT (2006). "Autism from developmental and neuropsychological perspectives". Annual Review of Clinical Psychology. 2: 327–355. doi:10.1146/annurev.clinpsy.2.022305.095210. PMID 17716073.
  73. ^ Happé F, Frith U (January 2006). "The weak coherence account: detail-focused cognitive style in autism spectrum disorders". Journal of Autism and Developmental Disorders. 36 (1): 5–25. doi:10.1007/s10803-005-0039-0. PMID 16450045. S2CID 14999943.
  74. ^ Mottron L, Dawson M, Soulières I, Hubert B, Burack J (January 2006). "Enhanced perceptual functioning in autism: an update, and eight principles of autistic perception". Journal of Autism and Developmental Disorders. 36 (1): 27–43. doi:10.1007/s10803-005-0040-7. PMID 16453071. S2CID 327253.
  75. ^ Murray D, Lesser M, Lawson W (May 2005). "Attention, monotropism and the diagnostic criteria for autism" (PDF). Autism. 9 (2): 139–156. doi:10.1177/1362361305051398. PMID 15857859. S2CID 6476917. Archived from the original (PDF) on 19 May 2018. Retrieved 18 March 2018.
  76. ^ Happé F, Ronald A, Plomin R (October 2006). "Time to give up on a single explanation for autism". Nature Neuroscience. 9 (10): 1218–1220. doi:10.1038/nn1770. PMID 17001340. S2CID 18697986.
  77. ^ Rajendran G, Mitchell P (2007). "Cognitive theories of autism" (PDF). Dev Rev. 27 (2): 224–60. doi:10.1016/j.dr.2007.02.001. S2CID 34448439.
Retrieved from "https://wiki.riteme.site/w/index.php?title=Mechanism_of_autism&oldid=1254759946"