CoChat
Sign Up
Cited by 723Autism Spectrum Disorder ResearchGenetics and Neurodevelopmental DisordersChild Nutrition and Feeding Issues

Consensus Paper: Pathological Role of the Cerebellum in Autism

Open access
Fatemi, S. Hossein, Aldinger, Kimberly A., Ashwood, Paul, Bauman, Margaret L., Blaha, Charles D., Blatt, Gene J., Chauhan, Abha, Chauhan, Ved +15 more·2012·The Cerebellum
DOI 10.1007/s12311-012-0355-9PMC PMC3677555
Open this paper in CoChat — free accountOpen PDF

Abstract

There has been significant advancement in various aspects of scientific knowledge concerning the role of cerebellum in the etiopathogenesis of autism. In the current consensus paper, we will observe the diversity of opinions regarding the involvement of this important site in the pathology of autism. Recent emergent findings in literature related to cerebellar involvement in autism are discussed, including: cerebellar pathology, cerebellar imaging and symptom expression in autism, cerebellar genetics, cerebellar immune function, oxidative stress and mitochondrial dysfunction, GABAergic and glutamatergic systems, cholinergic, dopaminergic, serotonergic, and oxytocin-related changes in autism, motor control and cognitive deficits, cerebellar coordination of movements and cognition, gene-environment interactions, therapeutics in autism, and relevant animal models of autism. Points of consensus include presence of abnormal cerebellar anatomy, abnormal neurotransmitter systems, oxidative stress, cerebellar motor and cognitive deficits, and neuroinflammation in subjects with autism. Undefined areas or areas requiring further investigation include lack of treatment options for core symptoms of autism, vermal hypoplasia, and other vermal abnormalities as a consistent feature of autism, mechanisms underlying cerebellar contributions to cognition, and unknown mechanisms underlying neuroinflammation.

Integrity signals

Registry

Crossref · 10.1007/s12311-012-0355-9

Cites

313 of 313 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 285 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    No relationship was observed between Purkinje cell number and performance on a sustained attention task.

    “No relationship was observed between Purkinje cell number and performance on a sustained attention task [286].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [286] Martin LA, Goldowitz D, Mittleman G. Sustained attention in the mouse: a study of the relationship with the cerebellum. Behav Neurosci. 2006;120(2):477–81. source

      Not checked in the free run.

  • Findingown data

    Lurcher mice with a total absence of Purkinje cells showed marked attenuations in cerebellar stimulation-evoked dopamine transmission in the medial prefrontal cortex.

    “Lurcher mice with a total absence of Purkinje cells showed marked attenuations in cerebellar stimulation-evoked dopamine transmission in the medial PFC (Figure 9, bottom)”
    Quote in the paperSubstantial claim
  • Findingown data

    There was a negative relationship between Purkinje cell number and investigatory nose poking in a hole-board exploration task.

    “(3) investigatory nose poking in a hole-board exploration task [287].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [287] Martin LA, Goldowitz D, Mittleman G. Repetitive behavior and increased activity in mice with Purkinje cell loss: a model for understanding the role of cerebellar pathology in autism. Eur J Neurosci. 2010;31:544–55. source

      Not checked in the free run.

  • Findingown data

    Developmental loss of cerebellar Purkinje cells affected performance on some but not all executive functions in the chimera model.

    “First, the developmental loss of cerebellar Purkinje cells affected performance on some, but not all executive functions.”
    Quote in the paperSubstantial claim
  • Findingcitation

    There was a negative relationship between Purkinje cell number and activity in an open field.

    “(2) activity in an open field,”
    Quote in the paperSubstantial claim
  • May combine two claims. 108
  • Classified as probably not a substantial claim. 28

  • May combine two claims.

    Findingown data

    In the vermis, no abnormalities of Purkinje cell size or number were identified in autistic individuals, so no microscopic cellular explanation for vermal hypoplasia was found.

    “Despite several detailed analyses of the vermis, our studies have been unable to identify any abnormalities of PC size or number in this region, thus failing to provide any microscopic cellular explanation for vermal hypoplasia as reported by cranial imaging studies [8].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] Courchesne E, Saitoh O, Yeung-Courchesne R, Press GA, Lincoln AJ, et al. Abnormality of cerebellar vermian lobules VI and VII in patients with infantile autism: identification of hypoplastic and hyperplastic subgroups by MR imaging. AJR. 1994;162:123–30. source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    In children with autism, there is a brain region-specific deficit in levels of electron transport chain complexes: reduced complexes III and V in the cerebellum, complex I in the frontal cortex, and complexes II, III, and V in the temporal cortex compared to age-matched controls.

    “Reduced levels of complexes III and V in the cerebellum, of complex I in the frontal cortex, and of complexes II, III, and V in the temporal cortex were observed in children with autism as compared to age-matched control subjects [103].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [103] Chauhan A, Gu F, Essa MM, Wegiel J, Kaur K, Brown WT, et al. Brain region-specific deficit in mitochondrial electron transport chain complexes in children with autism. J Neurochem. 2011;117:209–20. source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Oxidative stress differentially affects selective brain regions in autism: increased oxidative stress and mitochondrial abnormalities were observed in cerebellum, temporal cortex, and frontal cortex, but not in parietal and occipital cortices.

    “Our studies of different brain regions showed that oxidative stress differentially affects selective brain regions, i.e., cerebellum, temporal and frontal cortices, in autism [103–105, 107]. Increased oxidative stress and mitochondrial abnormalities were not observed in the parietal and occipital cortices in autism [103–105, 107].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [103] Chauhan A, Gu F, Essa MM, Wegiel J, Kaur K, Brown WT, et al. Brain region-specific deficit in mitochondrial electron transport chain complexes in children with autism. J Neurochem. 2011;117:209–20. source

      Not checked in the free run.

    • cites [104] Muthaiyah B, Essa MM, Chauhan V, Brown WT, Wegiel J, Chauhan A. Increased lipid peroxidation in cerebellum and temporal cortex of brain in autism. J Neurochem. 2009;108 Suppl 1:73.

      Not checked in the free run.

    • cites [105] Chauhan A, Audhya T, Chauhan V. Increased DNA oxidation in the cerebellum, frontal and temporal cortex of brain in autism. Transactions of the American Society for Neurochemistry. Windermere: American Society for Neurochemistry; 2011. p. 81.

      Not checked in the free run.

    • cites [107] Chauhan A, Essa MM, Muthaiyah B, Brown WT,Wegiel J, Chauhan V. Increased protein oxidation in cerebellum, frontal and temporal cortex in autism. International Meeting for Autism Research (Abstract), May 2010.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Reduced Purkinje cell numbers may not be present in all autistic cases; in three of six autistic brains, Purkinje cell numbers approximated controls.

    “Whitney et al. [6] has suggested that the presence of reduced numbers of PCs in the brains of autistic individuals may not be present in all cases. In three of the six brains of autistic individuals, the number of PCs closely approximated that of the controls.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] Whitney ER, Kemper TL, Bauman ML, Rosene DL, Blatt GJ. Cerebellar Purkinje cells are reduced in a subpopulation of autistic brains: a stereological experiment using calbindin-D28k. Cerebellum. 2008;7(3):406–16. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Autism is a clinically heterogeneous condition whose core features include delayed and disordered language, impaired social interaction, restricted interests, and insistence on sameness.

    “Autism is a clinically complex and heterogeneous disorder. The core features include delayed and disordered language, impaired social interaction, isolated areas of interest, and an insistence on sameness [1].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th ed (DSM-4). Washington, DC: APA; 1994.

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The cause of autism remains poorly defined, with both genetic and environmental factors implicated.

    “Currently, the cause of autism remains poorly defined but both genetic and environmental factors have been implicated [2].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2] Wassink TH, Brzustowicz LM, Bartlett CW, Szatmari P. The search for autism disease genes. Ment Retard Dev Disabil Res Rev. 2004;10:272–83. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Gaze linked to cerebellar function is characteristically atypical in individuals with autistic disorder, and subtle oculomotor alterations suggest abnormalities in cortico-cerebellar connectivity.

    “Gaze linked to cerebellar function [23] is characteristically atypical in individuals with AD and the observation of subtle oculomotor alterations suggests abnormalities in cortico-cerebellar connectivity [24, 25].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [23] Brettler SC, Fuchs AF, Ling L. Discharge patterns of cerebellar output neurons in the caudal fastigial nucleus during head-free gaze shifts in primates. Ann NY Acad Sci. 2003;1004:61–8. source

      Not checked in the free run.

    • cites [24] Takarae Y, Minshew NJ, Luna B, Sweeney JA. Oculomotor abnormalities parallel cerebellar histopathology in autism. J Neurol Neurosurg Psychiatry. 2004;75(9):1359–61. source

      Not checked in the free run.

    • cites [25] Nowinski CV, Minshew NJ, Luna B, Takarae Y, Sweeney JA. Oculomotor studies of cerebellar function in autism. Psychiatry Res. 2005;137(1–2):11–9. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The cerebellum connects with many cortical and subcortical structures and modulates cognitive, language, motor, sensory, and emotional functions associated with these regions.

    “It is known that the cerebellum connects with many cortical and subcortical structures in the cerebral hemispheres and acts as a modulator for many of the cognitive, language, motor, sensory and emotional functions associated with these regions [18].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] Schmahmann J. The cerebellum and cognition. International review of neurobiology, vol. 41. San Diego: Academic; 1997.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In autistic individuals, neurons of the deep cerebellar nuclei differ in size according to age: cases over 21 show small pale neurons significantly decreased in number, while childhood cases ages 5-13 show unusually large and plentiful neurons.

    “All of the autistic cases over the age of 21 years showed small pale neurons that were significantly decreased in number, whereas in all of the childhood cases, ages 5–13 years, the neurons in these same nuclear groups were unusually large and plentiful in numbers [14].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14] Kemper TL, Bauman ML. Neuropathology of infantile autism. J Neuropath Exp Neurol. 1998;57:645–52. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Autism is a disorder of prenatal onset with neurobiological processes extending into the postnatal period.

    “These findings support the concept that autism is a disorder of prenatal onset with neurobiological processes that extend into the postnatal period.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The neuropathology of autism may involve an ongoing postnatal process, based on deep cerebellar nuclei findings, similar findings in other nuclei, early brain overgrowth, and reduced cortical thickness with age.

    “These observations, in conjunction with similar findings in the nucleus of the Diagonal Band of Broca in the septum and in the inferior olivary nuclei, combined with observations of overgrowth of brain volume early in life [15, 16] and a more recent report of reduced cortical thickness with age [17], suggests that the underlying neuropathology of autism may be associated with an ongoing postnatal”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [15] Hazlett HC, Poe M, Gerig G, Smith RG, Provenzale J, Ross A, et al. Magnetic resonance imaging and head circumference study of brain size in autism: birth through age 2 years. Arch Gen Psychiatry. 2005;62:11366–76. source

      Not checked in the free run.

    • cites [16] Lainhart JE, Bigler ED, Bocian M, Coon H, Dinh E, Dawson G, et al. Head circumference and height in autism: a study by the collaborative program of excellence in autism. Am J Med Genet A. 2006;140:2257–74. source

      Not checked in the free run.

    • cites [17] Hardan AY, Libove RA, Keshavan MS, Melhem NM, Minshew NJ. A preliminary longitudinal magnetic resonance imaging study of brain volume and cortical thickness in autism. Biol Psychiatry. 2009;66:313–5. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The posterior vermis may have an important role in facilitating language function, which is a core impairment in autistic disorder.

    “For instance, the posterior vermis may have an important role in facilitating language function [27] which, although heterogeneous in AD, is a core impairment [28].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [27] Ackermann H, Wildgruber D, Daum I, Grodd W. Does the cerebellum contribute to cognitive aspects of speech production? A functional magnetic resonance imaging (fMRI) study in humans. Neurosci Lett. 1998;247(2–3):187–90. source

      Not checked in the free run.

    • cites [28] Tager-Flusberg H, Caronna E. Language disorders: autism and other pervasive developmental disorders. Pediatr Clin North Am. 2007;54(3):469–81. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Autistic disorder genetic architecture is complex, with variants of any individual locus present in only 1-2% of patients, and collectively all known genetic causes accounting for just 15% of cases.

    “AD genetic architecture is complex, with variants of any individual locus present in only 1–2% of patients, and collectively all known genetic causes accounting for just 15% of cases [55].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [55] Schaaf CP, Zoghbi HY. Solving the autism puzzle a few pieces at a time. Neuron. 2011;70(5):806–8. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    About 30% of patients with Fragile X Syndrome are also diagnosed with autistic disorder, and more than 2% of autistic disorder patients are co-diagnosed with Fragile X Syndrome.

    “For example, ~30% of patients with Fragile X Syndrome (FXS), the most common inherited cause of intellectual disability, are also diagnosed with AD. FXS is also one of the most common genetic causes of AD with >2% of AD patients co-diagnosed with FXS (http://www.fragilex.org).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites http://www.fragilex.org

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Vermal hypoplasia, particularly lobules VI-VII, may be associated with autistic disorder, but the specificity of this relationship is not well established and there is heterogeneity within autistic disorder.

    “Thus, vermal hypoplasia, particularly lobules VI-VII, may be associated with AD but the specificity of this relationship is not well established and there is heterogeneity within AD.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [32] Scott JA, Schumann CM, Goodlin-Jones BL, Amaral DG. A comprehensive volumetric analysis of the cerebellum in children and adolescents with autism spectrum disorder. Autism Res. 2009;2(5):246–57. source

      Not checked in the free run.

    • cites [34] Courchesne E, Saitoh O, Townsend J, Yeung-Courchesne R, Press G, Lincoln A, et al. Cerebellar hypoplasia and hyperplasia in infantile autism. Lancet. 1994;343:63–4. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Acquired cerebellar lesions involving the posterior lobe of the vermis, part of a reciprocal network with the anterior limbic system, are associated with mild cognitive impairment, executive function deficits, expressive language impairment, and affective blunting or disinhibition, behaviors recognized in autistic disorder.

    “Acquired cerebellar lesions involving the posterior lobe of the vermis, part of a reciprocal anatomical network with the anterior limbic system, have been associated with mild cognitive impairment, deficits of executive function, expressive language impairment, and affective blunting or disinhibition [31], all behaviors recognized in AD.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31] Schmahmann JD, Sherman JC. The cerebellar cognitive affective syndrome. Brain. 1998;121(4):561–79. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Approximately 40% of Tuberous Sclerosis patients are co-diagnosed with autistic disorder, and those with cerebellar lesions have more severe autistic disorder features than those with lesions restricted to other brain regions.

    “Approximately 40% of TS patients are co-diagnosed with AD, and those with cerebellar lesions have more severe AD features than those with lesions restricted to other brain regions [60].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [60] Eluvathingal TJ, Behen ME, Chugani HT, Janisse J, Bernardi B, Chakraborty P, et al. Cerebellar lesions in tuberous sclerosis complex: neurobehavioral and neuroimaging correlates. J Child Neurol. 2006;21(10):846–51. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Cerebellar vermis hypoplasia has been noted in seven patients with 22q13 deletion syndrome, suggesting that SHANK3 may be involved in cerebellar development.

    “Cerebellar vermis hypoplasia has been noted in seven patients with 22q13DS, suggesting that SHANK3 may be involved in cerebellar development [61, 62].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [61] Moessner R, Marshall CR, Sutcliffe JS, Skaug J, Pinto D, Vincent J, et al. Contribution of SHANK3 mutations to autism spectrum disorder. Am J Hum Genet. 2007;81(6):1289–97. source

      Not checked in the free run.

    • cites [62] Philippe A, Boddaert N, Vaivre-Douret L, Robel L, Danon-Boileau L, Malan V, et al. Neurobehavioral profile and brain imaging study of the 22q13.3 deletion syndrome in childhood. Pediatrics. 2008;122(2):e376–82. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Homozygous mutations in AHI1 were the first identified Joubert Syndrome cause, and common genetic variation in AHI1 has been associated with non-syndromic autistic disorder.

    “Homozygous mutations in AHI1 were the first identified JS cause and common genetic variation in AHI1, represented by single nucleotide polymorphisms (SNPs), was subsequently found to be associated with non-syndromic AD [64].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [64] Alvarez Retuerto AI, Cantor RM, Gleeson JG, Ustaszewska A, Schackwitz WS, Pennacchio LA, et al. Association of common variants in the Joubert syndrome gene (AHI1) with autism. Hum Mol Genet. 2008;17(24):3887–96. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Elevated plasma cytokine levels (IL-1β, IL-6, IL-12p40, TNFα), altered immunoglobulin levels, elevated complement proteins, and increased chemokine levels (CCL2, CCL5, CCL11) are reported in the plasma of young children with autistic disorder compared with matched typically developing children.

    “Elevated plasma cytokine levels (IL-1β, IL-6, IL-12p40 and TNFα) [82–84], altered immunoglobulin levels [85, 86], elevated levels of complement proteins [87], and increased chemokine levels (CCL2, CCL5 and CCL11) [88] are reported in the plasma of young children with AD compared with matched typically developing children.”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [82] Ashwood P, Krakowiak P, Hertz-Picciotto I, Hansen R, Pessah I, Van de Water J. Elevated plasma cytokines in autism spectrum disorders provide evidence of immune dysfunction and are associated with impaired behavioral outcome. Brain Behav Immun. 2011;25:40–5. source

      Not checked in the free run.

    • cites [83] Ashwood P, Anthony A, Torrente F, Wakefield AJ. Spontaneous mucosal lymphocyte cytokine profiles in children with autism and gastrointestinal symptoms: mucosal immune activation and reduced counter regulatory interleukin-10. J Clin Immunol. 2004;24:664–73. source

      Not checked in the free run.

    • cites [84] Ashwood P, Wakefield AJ. Immune activation of peripheral blood and mucosal CD3+ lymphocyte cytokine profiles in children with autism and gastrointestinal symptoms. J Neuroimmunol. 2006;173:126–34. source

      Not checked in the free run.

    • cites [85] Heuer L, Ashwood P, Goines P, Krakowiak P, Hertz-Picciotto I, Hansen R, et al. Reduced levels of immunoglobulin in children with autism correlates with behavioral symptoms. Autism Research. 2008;1:275–83. source

      Not checked in the free run.

    • cites [86] Enstrom A, Krakowiak P, Onore C, Pessah IN, Hertz-Picciotto I, Hansen RL, et al. Increased IgG4 levels in children with autism disorder. Brain Behav Immun. 2009;23:389–95. source

      Not checked in the free run.

    • cites [87] Corbett BA, Kantor AB, Schulman H, Walker WL, Lit L, Ashwood P, et al. A proteomic study of serum from children with autism showing differential expression of apolipoproteins and complement proteins. Mol Psychiatry. 2007;12:292–306. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The consistent finding of patients with both autistic disorder and cerebellar malformations implicates the cerebellum in autism pathogenesis and suggests that individuals with cerebellar malformations represent an important subgroup of autistic disorder patients.

    “Thus, although the number of individuals diagnosed with both ADs and cerebellar malformations is small, the consistent finding of patients with both phenotypes implicates the cerebellum in autism pathogenesis and suggests that individuals with cerebellar malformations represent an important subgroup of AD patients.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Autistic disorder is diagnosed in up to 40% of children with Joubert Syndrome, which is defined by significant cerebellar vermis hypoplasia and a distinctive brainstem malformation.

    “AD is diagnosed in up to 40% of children with Joubert Syndrome (JS), which is defined by significant cerebellar vermis hypoplasia and a distinctive brainstem malformation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Compared with controls, brain tissue specimens from cerebellum, midfrontal, and cingulate gyrus in autistic disorder show marked activation of microglia and astrocytes with up-regulation of HLA-DR and glial fibrillary acidic protein, respectively; prominent monocyte and macrophage accumulation in the cerebellum is also detected.

    “Compared with controls, brain tissue specimens from cerebellum, midfrontal and cingulate gyrus in AD show marked activation of microglia and astrocytes with the up-regulation of the cell surface major histocompatibility complex (MHC) molecule HLA-DR and, glial fibrillary acidic protein, respectively. Prominent monocyte and macrophage accumulation in the cerebellum is also detected.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [73] Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol. 2005;57(1):67–81. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A decrease in glutathione, an increase in its oxidized disulfide form, and a decrease in the GSH/GSSG redox ratio are observed in the cerebellum and temporal cortex of individuals with autism, suggesting a glutathione redox imbalance.

    “A decrease in GSH, an increase in its oxidized disulfide form (GSSG) and a decrease in the redox ratio of GSH/GSSG were observed in the cerebellum and temporal cortex of individuals with autism, suggesting a glutathione redox imbalance in autism [111].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [111] Chauhan A, Audhya T, Chauhan V. Brain region-specific glutathione redox imbalance and increased DNA oxidation in autism. J Neurochem. 2011;118(suppl 1):217.

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Accumulating evidence suggests that a common feature in autism cases may be oxidative stress, the mechanism through which environmental factors exert deleterious effects, which may be exacerbated by interaction of genetically susceptible alleles.

    “Accumulating evidence suggests that a common feature in autism cases may be oxidative stress, the mechanism through which environmental factors exert their deleterious effects, which may be further exacerbated by the interaction of genetically susceptible alleles [96–100].”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [96] Chauhan A, Chauhan V, Brown WT, editors. Autism: oxidative stress, inflammation and immune abnormalities. Boca Raton: CRC Press; 2009.

      Not checked in the free run.

    • cites [97] Deth R, Muratore C, Benzecry J, Power-Charnitsky VA, Waly M. How environmental and genetic factors combine to cause autism: a redox/methylation hypothesis. Neurotoxicology. 2008;29:190–201. source

      Not checked in the free run.

    • cites [98] Chauhan A, Chauhan V. Oxidative stress in autism. Pathophysiology. 2006;13:171–81. source

      Not checked in the free run.

    • cites [99] Kern JK, Jones AM. Evidence of toxicity, oxidative stress, and neuronal insult in autism. J Toxicol Environ Health B Crit Rev. 2006;9:485–99. source

      Not checked in the free run.

    • cites [100] Wells PG, McCallum GP, Chen CS, Henderson JT, Lee CJ, Perstin J, et al. Oxidative stress in developmental origins of disease: teratogenesis, neurodevelopmental deficits, and cancer. Toxicol Sci. 2009;108:4–18. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Reeler heterozygous mice with reduced reelin show decreased GAD67 and fewer GABAA and GABAB receptors in whole brain and hippocampus.

    “Reeler heterozygous mice, which are haploinsufficient for reelin, exhibit decreased GAD 67 [138] and reduced GABAA and GABAB receptors in the whole brain and hippocampus, respectively [139].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [138] Nullmeier S, Panther P, Dobrowolny H, Frotscher M, Zhao S, Schwegler H, et al. Region-specific alteration of GABAergic markers in the brain of heterozygous reeler mice. Eur J Neurosci. 2011;33:689–98. source

      Not checked in the free run.

    • cites [139] Cremer CM, Lubke JH, Palomero-Gallagher N, Zilles K. Laminar distribution of neurotransmitter receptors in different reeler mouse brain regions. Brain Struct Funct. 2011;216:201–18. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Reelin regulates neuronal lamination during embryonic development and supports neuronal migration and synaptic plasticity throughout life.

    “As a serine protease of the extracellular matrix, Reelin regulates proper lamination of neurons during embryonic development and helps in migration of neurons and maintenance of synaptic plasticity throughout life [135–137].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [135] Quattrocchi CC, Wannenes F, Persico AM, Ciafré SA, D’Arcangelo G, Farace MG, et al. Reelin is a serine protease of the extracellular matrix. J Biol Chem. 2002;277:303–9. source

      Not checked in the free run.

    • cites [136] Weeber EJ, Beffert U, Jones C, Christian JM, Forster E, Sweatt JD, et al. Reelin and ApoE receptors cooperate to enhance hippocampal synaptic plasticity and learning. J Biol Chem. 2002;277:39944–52. source

      Not checked in the free run.

    • cites [137] Forster E, Tielsch A, Saum B, Weiss KH, Johanssen C, Graus-Porta D, et al. Reelin, Disabled 1, and beta 1 integrins are required for the formation of the radial glial scaffold in the hippocampus. Proc Natl Acad Sci. 2002;99:13178–83. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    FMRP is an RNA-binding protein that regulates target RNAs post-transcriptionally and binds about 4% of brain mRNA.

    “FMRP, translated from the Fragile X mental retardation-1 (FMR1) gene, is an RNA-binding protein involved in post-transcriptional regulation of target RNAs [157] and binds approximately 4% of the mRNA expressed in the brain [158].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [157] De Rubeis S, Bagni C. Fragile X mental retardation protein control of neuronal mRNA metabolism: insights into mRNA stability. Mol Cell Neurosci. 2010;43:43–50. source

      Not checked in the free run.

    • cites [158] Bassell GJ, Warren ST. Fragile X Syndrome: loss of local mRNA regulation alters synaptic development and function. Neuron. 2008;60:201–14. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Glutamate is important for emotional behavior acquisition, and NMDA receptors mediate long-term potentiation underlying learning and memory, processes impaired in autism.

    “Glutamate is important in the acquisition of emotional behavior [149] and N-methyl-aspartic acid (NMDA)-glutamate receptors are responsible for long term potentiation [150], underlying learning and memory; two processes impaired in subjects with autism.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [149] Hoehn-Saric R, McLeod DR, Glowa JR. The effects NMDA receptor blockade on the acquisition of a conditioned emotional response. Biol Psychiatry. 1991;30:170–6. source

      Not checked in the free run.

    • cites [150] Lisman J. Long-term potentiation: outstanding questions and attempted synthesis. Philos Trans R Soc Lond B Biol Sci. 2003;358:829–42. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Glutamate is the main excitatory neurotransmitter and regulates neurogenesis, neuronal outgrowth, survival, and synaptogenesis during brain development.

    “Glutamate is the main excitatory neurotransmitter in the brain and it plays a key role during brain development by regulating multiple processes including neurogenesis, neuronal outgrowth, neuron survival, and synaptogenesis [148].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [148] Mattson MP. Glutamate and neurotrophic factors in neuronal plasticity and disease. Ann N Y Acad Sci. 2008;1144:97–112. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Reelin binds to VLDLR, apolipoprotein E receptor 2, and α3β1 integrin.

    “Reelin binds to several protein receptors, including very low density lipoprotein receptor (VLDLR), apolipoprotein E receptor 2 and α3β1 integrin [144–146].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [144] D’Arcangelo G, Homayouni R, Keshvara L, Rice DS, Sheldon M, Curran T. Reelin is a ligand for lipoprotein receptors. Neuron. 1999;24:471–9. source

      Not checked in the free run.

    • cites [145] Hiesberger T, Trommsdorff M, Howell BW, Goffinet A, Mumby MC, Cooper JA, et al. Direct binding of Reelin to VLDL receptor and ApoE receptor 2 induces tyrosine phosphorylation of disabled-1 and modulates tau phosphorylation. Neuron. 1999;24:481–9. source

      Not checked in the free run.

    • cites [146] Dulabon L, Olson EC, Taglienti MG, Eisenhuth S, McGrath B, Walsh CA, et al. Reelin binds alpha3beta1 integrin and inhibits neuronal migration. Neuron. 2000;27:33–44. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Multiple studies have replicated abnormal reelin expression in autism, including RELN polymorphisms, decreased Reelin mRNA in superior frontal cortex and cerebellum, and reduced Reelin in blood.

    “Several studies have demonstrated abnormal reelin expression in autism and replicated these results; notably, polymorphisms of the RELN gene [140, 141], decreased Reelin mRNA in superior frontal cortex and cerebellum [89], and reduced Reelin expression in blood analyses [143].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [140] Kelemenova S, Schmidtova E, Ficek A, Celec P, Kubranska A, Ostatnikova D. Polymorphisms of candidate genes in Slovak autistic patients. Psychiatr Genet. 2010;20:137–9. source

      Not checked in the free run.

    • cites [141] Persico AM, D’Agruma L, Maiorano N, Totaro A, Militerni R, Bravaccio C, et al. Reelin gene alleles and haplotypes as a factor predisposing to autistic disorder. Mol Psychiatry. 2001;6:150–9. source

      Not checked in the free run.

    • cites [89] Enstrom AM, Lit L, Onore CE, Gregg JP, Hansen R, Pessah IN, et al. Altered gene expression and function of peripheral blood natural killer cells in children with autism. Brain Behav Immun. 2009;23:124–33. source

      Not checked in the free run.

    • cites [143] Fatemi SH, Stary JM, Egan EA. Reduced blood levels of reelin as a vulnerability factor in pathophysiology of autistic disorder. Cell Mol Neurobiol. 2002;22:139–52. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    In adult autism, VLDLR is upregulated and Dab-1 is significantly reduced in superior frontal cortex and cerebellum, suggesting impaired Reelin pathway signaling.

    “VLDLR is upregulated in the superior frontal cortex and cerebellum in adult patients with autism, while Dab-1 is significantly reduced in these areas [89], suggesting impaired signaling in the Reelin pathway.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [89] Enstrom AM, Lit L, Onore CE, Gregg JP, Hansen R, Pessah IN, et al. Altered gene expression and function of peripheral blood natural killer cells in children with autism. Brain Behav Immun. 2009;23:124–33. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mutations in FMRP cause Fragile X syndrome, and individuals with FXS and autism often have overlapping diagnoses.

    “Mutations involving the fragile X mental retardation protein (FMRP) lead to Fragile X syndrome (FXS). Individuals with FXS and autism often share overlapping diagnoses [156].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [156] Demark JL, Feldman MA, Holden JJ. Behavioral relationship between autism and fragile X syndrome. Am J Ment Retard. 2003;108:314–26. source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    FMRP is significantly reduced in cerebellum and frontal cortex of autistic subjects, while mGluR5 is elevated in brains of children with autism.

    “In addition, FMRP has been demonstrated to be significantly reduced in the cerebellum and frontal cortex of autistic subjects, while mGluR5 is elevated in the brains of children with autism.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    OTR knockout mice show social recognition deficits that can be remediated by oxytocin injections in medial amygdala.

    “OTR mouse knockouts show social recognition deficits that can be remediated by oxytocin injections in the medial amygdala [163].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [163] Ferguson JN, Aldag JM, Insel TR, Young LJ. Oxytocin in the medial amygdala is essential for social recognition in the mouse. J Neurosci. 2001;21:8278–85. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Low oxytocin concentrations are measured in rat cerebellum, but high densities of oxytocin receptors are localized in amygdala and also found in hippocampus, hypothalamus, thalamus, mesencephalon, and brainstem.

    “Low concentrations of oxytocin have been measured in the cerebellum in rats [161] but high densities of oxytocin receptors (OTR) are localized in the amygdala and are also found in parts of the hippocampus, hypothalamus, thalamus, mesencephalon and brainstem.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [161] Hashimoto H, Fukui K, Noto T, Nakajima T, Kato N. Distribution of vasopressin and oxytocin in rat brain. Endocrinol Jpn. 1985;32(1):89–97. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Reductions in FMRP co-occur with elevated mGluR5 and decreased GABAA β3 receptors, indicating a link between these molecular systems and potential therapeutic targets.

    “Additionally, reductions in FMRP occurred in association with elevations in mGluR5 and decreases in GABAA β3 receptors indicating a linkage between these divergent molecular systems and pointing to potential therapeutic targets in autism.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The findings highlight roles for the GABAergic system, GAD enzymes, Reelin, glutamate receptors/transporters, mGluR5, and FMRP in autism.

    “In conclusion, the above findings highlight the role of the GABAergic system, GAD enzymes, Reelin, glutamate receptors/transporters, mGluR5, and FMRP in autism.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Significant reductions in GABAA and GABAB receptors and decreased GAD65 and GAD67 enzymes in autism suggest impaired conversion of glutamate to GABA.

    “While significant reductions in GABAA and GABAB receptors have been observed in subjects with autism, decreased GAD 65 and 67 enzymes have also been found, suggesting impaired conversion of glutamate to GABA in these patients.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Animal studies show the MAO projects to anterior lobe, caudal vermis, flocculus, and deep cerebellar nuclei, most of which show pathological abnormalities in autism.

    “From animal studies, the MAO projects to the anterior lobe, caudal vermis and the flocculus in cerebellar cortex and to the globose, emboliform and fastigial deep cerebellar nuclei, most of which show pathological abnormalities in autism [3].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] Bauman ML, Kemper TL. Histoanatomic observations of the brain in early infantile autism. Neurology. 1985;35:866–74. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Oxytocin infusion improves repetitive behaviors in adults with autism and has positive effects on social behaviors and cognition.

    “Improvements in repetitive behaviors in adults with autism following oxytocin infusion have been demonstrated [169] as well as positive effects on social behaviors and cognition [170].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [169] Hollander E, Novotny S, Hanratty M, Yaffe R, DeCaria CM, Aronowitz BR, et al. Oxytocin infusion reduces repetitive behaviors in adults with autistic and Asperger’s disorders. Neuropsychopharm. 2003;28:193–8. source

      Not checked in the free run.

    • cites [170] Hollander E, Bartz J, Chaplin W, Phillips A, Sumner J, Soorya L, et al. Oxytocin increases retention of social cognition in autism. Biol Psychiatry. 2007;61:498–503. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A follow-up study found increased α4 mRNA expression in cerebellum but decreased subunit protein levels and binding.

    “A follow up study [173] found increased α4 mRNA expression in cerebellum but subunit protein levels and binding decreased.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [173] Martin-Ruiz CM, Lee M, Perry RH, Baumann M, Court JA, Perry EK. Molecular analysis of nicotinic receptor expression in autism. Brain Res Mol Brain Res. 2004;123(1–2):81–90. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Intranasal oxytocin may reduce repetitive behaviors and increase performance on social recognition tasks.

    “Intranasal administration of oxytocin may reduce repetitive behaviors, and increase performance on tasks of social recognition [171].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [171] Bartz JA, Hollander E. Oxytocin and experimental therapeutics in autism spectrum disorders. Prog Brain Res. 2008;170:451–62. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Nicotinic cholinergic antagonists, including some antidepressants, have ameliorated some autistic symptoms and are being explored as novel therapeutic agents.

    “On the other hand, nicotinic cholinergic antagonists including some anti-depressants have helped ameliorate some autistic symptoms and are being explored as novel therapeutic agents [175].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [175] Lippiello PM. Nicotinic cholinergic antagonists: a novel approach for the treatment of autism. Med Hypotheses. 2006;66(5):985–90. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Increased M2 cholinergic receptor expression in MAO in normal developing infants compared to fetal binding suggests muscarinic receptors may act as early growth factors in infant development.

    “In contrast, increased M2 cholinergic receptor expression in the MAO in normal developing infants compared to fetal binding has been reported [177], suggesting a possible role of muscarinic receptors as an early growth factor in infant development.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [177] Armstrong DD, Assman S, Kinney HC. Early developmental changes in the chemoarchitecture of the human inferior olive: a review. J Neuropathol Exp Neurol. 1999;58:1–11. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Oxytocin may interact with dopamine to modulate socio-affiliative behaviors, and central oxytocin pathways may serve as therapeutic targets to improve mood and social behaviors.

    “Oxytocin may also interact with dopamine to modulate socio-affiliative behaviors and central oxytocin pathways may serve as therapeutic targets to improve mood and social behaviors [168].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [168] Baskerville TA, Douglas AJ. Dopamine and oxytocin interactions underlying behaviors: potential contributions to behavioral disorders. CNS Neurosci Ther. 2010;16(3):e92–e123. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    α7 nicotinic receptors are located on GABA inhibitory neurons; selective stimulation would cause GABA release and help restore inhibitory tone.

    “In this regard, nicotinic cholinergic receptor type α7 is located on the surface of GABA inhibitory neurons and selective stimulation of this receptor subtype would cause GABA release and play a role in restoring inhibitory tone [174].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [174] Deutsch SI, Urbano MR, Neumann SA, Burket JA, Katz E. Cholinergic abnormalities in autism: is there a rationale for selective nicotinic agonist interventions? Clin Neuropharmacol. 2010;33(3):114–20. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    Nicotinic agonists are thought to enhance attention, cognition, and memory and may be useful therapeutic tools.

    “Nicotinic agonists are thought to enhance attentional processes, cognition and memory and thus may be useful as a therapeutic tool.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In development, the balance of dopamine D1 and D2 receptor activation is critical for GABA neuron migration from basal forebrain to cerebral cortex and may contribute to developmental disorders such as autism.

    “In development, the physiological balance of dopamine D1 and D2 receptor activation is critical for GABA neuron migration from the basal forebrain to the cerebral cortex and may contribute to developmental disorders such as autism [181].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [181] Crandall JE, McCarthy DM, Araki KY, Sims JR, Ren J-Q, Bhide PG. Dopamine receptor activation modulates GABA neuron migration from the basal forebrain to the cerebral cortex. J Neurosci. 2007;27(14):3813–22. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Increased numbers of 5-HT axons and terminals were reported in various brain regions via immunocytochemical labeling of 5-HT transporter in post-mortem autism subjects aged 2-29, questioning wide use of SSRIs as therapeutic agents.

    “An increased number of 5-HT axons and terminals were reported in a variety of brain regions via immunocytochemical labeling of 5-HT transporter in post-mortem autism subjects aged 2–29 years old bringing into question the wide use of SSRIs as therapeutic agents [187].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [187] Azmitia EC, Singh JS, Whitaker-Azmitia PM. Increased serotonin axons (immunoreactive to 5-HT transporter) in postmortem brains from young autism donors. Neuropharm. 2011;60:1347–54. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Williams et al. tested four SSRIs and concluded no evidence of effect in autistic children, emerging evidence of harm, and limited evidence of effectiveness in autistic adults.

    “In fact, Williams et al. [188] tested four SSRIs and concluded that there is no evidence of effect in autistic children and emerging evidence of harm, and limited evidence of effectiveness in autistic adults.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [188] Williams K, Wheeler DM, Silove N, Hazell P. Selective serotonin reuptake inhibitors (SSRIs) for autism spectrum disorders (ASD). Cochrane Database Syst Rev. 2010;4(8):CD004677.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Dentato-thalamo-cortical neurons are thought to be glutamatergic, implicating glutamate as a modulator of mPFC dopaminergic activity.

    “The dentato-thalamo-cortical neurons are thought to be glutamatergic and thus implicate glutamate as a modulator of mPFC dopaminergic activity [179].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [179] Rogers TD, Dickson PE, Heck DH, Goldowitz D, Mittleman G, Blaha CD. Connecting the dots of the cerebro-cerebellar role in cognitive function: neuronal pathways for cerebellar modulation of dopamine release in the prefrontal cortex. Synapse. 2011;65(11):1204–12. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In normal post-mortem human cerebellum, SERT concentration is relatively low compared to other brain regions except white matter, allowing its use as a reference region in binding studies.

    “In normal post-mortem human cerebellum, there is a relatively low concentration of 5-HT transporters (SERT) compared to other brain regions except in the white matter and can be used as a reference region in binding studies looking at other brain regions with higher binding densities [184].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [184] Kish SJ, Furukawa Y, Chang L-J, Tong J, Ginovart N, Wilson A, et al. Regional distribution of serotonin transporter protein in post-mortem human brain: is the cerebellum a SERT-free brain region? Nucl Med Biol. 2005;32(2):123–8. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    SSRIs targeting 5-HTT and 5-HTR may also target some dopamine receptor types.

    “It is noteworthy that some selective serotonin reuptake inhibitors (SSRIs) that target 5-HTT and 5-HTR may also target some dopamine receptor types.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    A PET study found reduced serotonin transporter binding in anterior and posterior cingulate cortex in high functioning autistic subjects, associated with impaired social cognition, and in thalamus associated with repetitive/obsessive behavior.

    “In a PET imaging study, serotonin transporter binding was reduced in the anterior and posterior cingulate cortex in high functioning autistic subjects associated with impaired social cognition and, in the thalamus associated with repetitive and /or obsessive behavior and interests [182].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [182] Nakamura K, Sekine Y, Ouchi Y, Tsujii M, Yoshikawa E, Futatsubashi M, et al. Brain serotonin and dopamine transporter bindings in adults with high-functioning autism. Arch Gen Psychiatry. 2010;67(1):58–68. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    High 5-HT5A mRNA expression is found in cerebellum, especially in Purkinje cells, granule cells, and dentate nucleus, and may contribute to emotional, cognitive, and motor functions associated with autism.

    “In contrast, a high level of 5-HT5A mRNA expression was found in the cerebellum especially localized to Purkinje cells and in the granule cells and dentate nucleus in both hemispheres and the vermis and may contribute to emotional, cognitive and motor functions associated with autism [185].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [185] Marazziti D. A further support to the hypothesis of a link between serotonin, autism, and the cerebellum. Biol Psychiatry. 2002;52(2):143. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    Cerebellar pathology in autism and other cognitive disorders could result from functional loss of cerebellar-mPFC circuitry due to abnormal dopaminergic activity in mPFC.

    “It has been recently reported that cerebellar pathology in autism and other cognitive disorders could result from the functional loss of cerebellar-mPFC circuitry due to abnormal dopaminergic activity in the mPFC [179].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [179] Rogers TD, Dickson PE, Heck DH, Goldowitz D, Mittleman G, Blaha CD. Connecting the dots of the cerebro-cerebellar role in cognitive function: neuronal pathways for cerebellar modulation of dopamine release in the prefrontal cortex. Synapse. 2011;65(11):1204–12. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    SSRIs and/or atypical antipsychotics that block both 5-HT2R and dopamine D1/D2 receptors are especially attractive for possible clinical benefits.

    “For example, SSRIs and/or atypical antipsychotics that block both 5-HT2R and dopamine D1 and D2 receptors are especially attractive for possible clinical benefits [183].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [183] Buitelaar JK, Willemsen-Swinkels SH. Medication treatment in subjects with autistic spectrum disorders. Eur Child Adolesc Psychiatry. 2000;9(1):185–97.

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Peripheral 5-HT effects in autism are well documented, but central 5-HT differences are still emerging.

    “Peripheral 5-HT effects in autism are well documented but central 5-HT differences are still emerging.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Freitag et al. found gross and fine motor impairments are associated with severity of autistic symptoms, suggesting possible common pathophysiological mechanisms.

    “Freitag et al. [198] found that gross and fine motor impairments are associated with the severity of autistic symptoms suggesting possible common pathophysiological mechanisms.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [198] Freitag CM, Kleser C, Schneider M, von Gontard A. Quantitative assessment of neuromotor function in adolescents with high functioning autism and Asperger Syndrome. J Autism Dev Disord. 2007;37(5):948–59. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Recent studies document impaired vestibular control and gross and fine motor abnormalities similar to those in patients with established cerebellar disease.

    “Recent studies have documented impaired vestibular control [197], and gross and fine motor abnormalities similar to those demonstrated by patients with established cerebellar disease [198].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [197] Molloy CA, Dietrich KN, Bhattacharya A. Postural stability in children with autism spectrum disorder. J Autism Dev Disord. 2003;33(6):643–52. source

      Not checked in the free run.

    • cites [198] Freitag CM, Kleser C, Schneider M, von Gontard A. Quantitative assessment of neuromotor function in adolescents with high functioning autism and Asperger Syndrome. J Autism Dev Disord. 2007;37(5):948–59. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The majority of single-gene disorders associated with AD also feature cerebellar pathology, suggesting that linking cerebellar structural abnormalities to core neurobehavioral features may provide insights into AD etiology.

    “The majority of single-gene disorders associated with AD also are characterized by cerebellar pathology, suggesting that linking cerebellar structural abnormalities to core neurobehavioral features in AD may provide important insights into the etiology of these disorder(s) [190].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [190] Abrahams BS, Geschwind DH. Connecting genes to brain in the autism spectrum disorders. Arch Neurol. 2010;67(4):395–9. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cerebellar involvement in coordinated movements is well described, and recent work indicates the cerebellum also plays an important role in non-motor functions.

    “Cerebellar involvement in coordinated movements has been well described [310], and recent work indicates that the cerebellum plays an important role in non-motor functions as well [191] (Table 2).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [310] Manni E, Petrosini L. A century of cerebellar somatotopy: a debated representation. Nat Rev Neurosci. 2004;5(3):241–9. source

      Not checked in the free run.

    • cites [191] Leiner HC, Leiner AL, Dow RS. Does the cerebellum contribute to mental skills? Behav Neurosci. 1986;100(4):443–54. source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    There is considerable anatomical basis for distinguishing motor and cognitive cerebellar systems, but the extent of functional impairment of each in AD remains poorly understood.

    “There is thus a considerable anatomical basis for distinguishing motor and cognitive cerebellar systems, but the extent to which each of these systems is functionally impaired in AD remains poorly understood.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Sensorimotor pathways are identified throughout the cerebellum, with preferential involvement of anterior lobules I-V and lobule VIII.

    “Sensorimotor pathways have been identified throughout the cerebellum, and preferential involvement of anterior lobules I–V and lobule VIII has been documented (Figure 5).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    AD is defined by three core symptom categories: social impairment, communication abnormalities, and restricted/repetitive behaviors.

    “AD is defined by three core symptom categories: social impairment, communication abnormalities, and restricted and repetitive behaviors.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    During gross motor movements, individuals with AD show reduced ipsilateral anterior cerebellar activation and more diffuse activation across lobules VI-VII.

    “When performing gross motor movements during fMRI studies, individuals with AD show reduced ipsilateral anterior cerebellar activation [199] and more diffuse activation across lobules VI-VII [200].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [199] Mostofsky SH, Powell SK, Simmonds DJ, Goldberg MC, Caffo B, Pekar JJ. Decreased connectivity and cerebellar activity in autism during motor task performance. Brain. 2009;132(9):2413–25. source

      Not checked in the free run.

    • cites [200] Allen G, Courchesne E. Differential effects of developmental cerebellar abnormality on cognitive and motor functions in the cerebellum: an fMRI study of autism. Am J Psychiatry. 2003;160(2):262–73. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Recent findings that oculomotor deficits in AD are also present in unaffected family members suggest dysfunctions within oculomotor vermis may be familial and could serve as intermediate phenotypes for gene discovery.

    “Our recent findings that oculomotor deficits observed in individuals with AD also are present in unaffected family members suggest that dysfunctions within the oculomotor vermis may be familial and could serve as intermediate phenotypes for gene discovery [204].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [204] Mosconi MW, Kay M, D’Cruz AM, Guter S, Kapur K, Macmillan C, et al. Neurobehavioral abnormalities in first-degree relatives of individuals with autism. Arch Gen Psychiatry. 2010;67(8):830–40. source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Executive dysfunctions and attention deficits are well characterized in AD, but few studies have linked these impairments to cerebellar abnormalities.

    “Executive dysfunctions and attention deficits are well characterized in AD, but few studies have linked these impairments to cerebellar abnormalities.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Verbal and spatial working memory deficits are consistently documented in AD, but no known studies report an association with cerebellar abnormalities.

    “Verbal and spatial working memory deficits have been consistently documented in AD, but no known studies have reported an association with functional or structural abnormalities within the cerebellum.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    The primacy of the cerebellum to cognitive dysfunctions in AD remains unclear.

    “But, the primacy of the cerebellum to cognitive dysfunctions in AD remains unclear.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Some memory functions are compromised in AD, and the extent of impairment is strongly associated with task complexity.

    “Some memory functions are compromised in AD, although there is evidence that the extent to which subjects are impaired is strongly associated with the complexity of the task [205].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [205] Williams DL, Goldstein G, Minshew NJ. The profile of memory function in children with autism. Neuropsychology. 2006;20(1):21–9. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    FMRI studies of saccades and smooth pursuit document reduced activation within posterior vermis and increased involvement of association cortices and dentate nuclei in AD.

    “FMRI studies of saccades and smooth pursuit document reduced activation within the posterior vermis, and increased involvement of association cortices and dentate nuclei in AD [203].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [203] Takarae Y, Minshew NJ, Luna B, Sweeney JA. Atypical involvement of frontostriatal systems during sensorimotor control in autism. Psychiatry Res. 2007;156(2):117–27. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Individuals with AD show impairments in executive function, memory, and language abilities.

    “Individuals with AD show impairments in executive function, memory and language abilities [205].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [205] Williams DL, Goldstein G, Minshew NJ. The profile of memory function in children with autism. Neuropsychology. 2006;20(1):21–9. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Pattern generators play major life supporting roles in all vertebrate nervous systems today.

    “Pattern generators still play major life supporting roles (breathing, swallowing, chewing, walking and running etc.) in all vertebrate nervous systems today.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Cerebellar abnormalities are established in AD and may contribute to neurobehavioral deficits.

    “In conclusion, cerebellar abnormalities are established in AD, and they may contribute to neurobehavioral deficits.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    The cerebellum's crystalline network architecture is highly homogeneous throughout the structure, suggesting one principle neuronal operation is performed in all parts.

    “The cerebellum’s crystalline network architecture is highly homogeneous throughout the entire structure, suggesting that one principle neuronal operation is performed in all parts of the cerebellum.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Post-mortem anatomical studies of autistic brains reveal loss of Purkinje cells in posterior vermis and intermediate cerebellar cortex as the most consistent neuropathology, suggesting a key role of the cerebellum in autism.

    “Post-mortem anatomical studies of brains from autistic individuals thus far revealed loss of Purkinje cells in the posterior vermis and intermediate cerebellar cortex as the most consistent neuropathology, suggesting a key role of the cerebellum in autism [213].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [213] Courchesne E. Brainstem, cerebellar and limbic neuroanatomical abnormalities in autism. Curr Opin Neurobiol. 1997;7:269–78. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Rhythmic stereotypic movements controlled by central pattern generator circuits are among the evolutionarily oldest and most important motor patterns.

    “Rhythmic stereotypic movements controlled by central pattern generator circuits are among the evolutionarily oldest and most important motor patterns.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Yuste and colleagues suggested the wiring diagram of the neocortical network is analogous to pattern generator circuits.

    “Yuste and colleagues recently suggested that the wiring diagram of the neocortical network is analogous to pattern generator circuits [218]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [218] Yuste R, MacLean JN, Smith J, Lansner A. The cortex as a central pattern generator. Nat Rev Neurosci. 2005;6:477–83. source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Movements require precise spatiotemporal coordination of dozens of muscles, and the cerebellum is believed to coordinate the precise timing of muscle activities.

    “Movements, even simple ones, require precise spatiotemporal coordination of dozens of muscles and it is believed that the cerebellum is involved in coordinating the precise timing of muscle activities [215–217].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [215] Sasaki K, Gemba H. Cerebro-cerebellar interactions: for fast and stable timing of voluntary movement. In: Mano N, Hamada I, DeLong MR, editors. Role of the cerebellum and basal ganglia in voluntary movement. Amsterdam: Elsevier; 1993. p. 41–50.

      Not checked in the free run.

    • cites [216] Ivry RB, Keele SW, Diener HC. Dissociation of the lateral and medial cerebellum in movement timing and movement execution. Exp Brain Res. 1988;73:167–80. source

      Not checked in the free run.

    • cites [217] Braitenberg V. Is the cerebellar cortex a biological clock in the millisecond range? In: Fox CA, Snider RS, editors. Progress in Brain Research. Vol.25. The Cerebellum. Amsterdam: Elsevier; 1967. p. 334–46.

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Reciprocal connections between neocortical motor and non-motor association areas and the cerebellum have been carefully mapped out.

    “Reciprocal connections between neocortical motor and non-motor association areas and the cerebellum have also been carefully mapped out [211, 212].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [211] Kelly RM, Strick PL. Cerebellar loops with motor cortex and prefrontal cortex of a nonhuman primate. J Neurosci. 2003;23:8432–44. source

      Not checked in the free run.

    • cites [212] Middleton FA, Strick PL. Cerebellar projections to the prefrontal cortex of the primate. J Neurosci. 2001;21:700–12. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Molinari and colleagues suggested the cerebellum is crucially involved in analyzing sequential events in the behavioral domain.

    “Molinari and colleagues also suggested that the cerebellum is crucially involved in analyzing sequential events, albeit in the behavioral domain, i.e. at a considerably slower time scale than the neuronal sequences discussed here [226].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [226] Molinari M, Chiricozzi FR, Clausi S, Tedesco AM, De Lisa M, Leggio MG. Cerebellum and detection of sequences, from perception to cognition. Cerebellum. 2008;7:611–5. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    The hypothesis presented offers a possible answer to how the cerebellum could contribute to motor and cognitive processes under the constraint that the same neuronal mechanism applies to both functions.

    “The hypothesis presented here offers a possible answer to the question of how the cerebellum could contribute to motor and cognitive processes under the constraint that the same neuronal mechanism should apply to both functions.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Recent studies report cerebellar control of dopamine release in prefrontal cortex, a mechanism that might be triggered by spatiotemporal cortical activity patterns.

    “Important new clues, however, come from recent studies reporting cerebellar control of dopamine release in the prefrontal cortex [179, 180], a mechanism that might be triggered by spatiotemporal cortical activity patterns, as proposed here.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [179] Rogers TD, Dickson PE, Heck DH, Goldowitz D, Mittleman G, Blaha CD. Connecting the dots of the cerebro-cerebellar role in cognitive function: neuronal pathways for cerebellar modulation of dopamine release in the prefrontal cortex. Synapse. 2011;65(11):1204–12. source

      Not checked in the free run.

    • cites [180] Mittleman G, Goldowitz D, Heck DH, Blaha CD. Cerebellar modulation of frontal cortex dopamine efflux in mice: relevance to autism and schizophrenia. Synapse. 2008;62(7):544–50. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Other researchers suggested terms 'cognitive dysmetria' or 'dysmetria of thought' to describe the effect of loss of cerebellar function on cognition, implying strong similarities between motor and cognitive cerebellar function.

    “It is interesting, that other researchers, based on clinical observations alone, suggested the terms “cognitive dysmetria” [227] or “dysmetria of thought” [31] to describe the effect of loss of cerebellar function on cognition, implying strong similarities between motor and cognitive cerebellar function.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [227] Andreasen NC, Paradiso S, O’Leary DS. “Cognitive dysmetria” as an integrative theory of schizophrenia: a dysfunction in cortical-subcortical-cerebellar circuitry? Schizophr. Bull. 1998;24:203–18.

      Not checked in the free run.

    • cites [31] Schmahmann JD, Sherman JC. The cerebellar cognitive affective syndrome. Brain. 1998;121(4):561–79. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Precisely timed spatiotemporal cortical activity patterns, transmitted through pontine nuclei, would be detected by the cerebellum and trigger specific and precisely timed responses in cerebellar output activity, which via thalamus would contribute to coordination of neocortical network activity involved in cognitive or motor processes.

    “Thus precisely timed spatiotemporal cortical activity patterns, transmitted through-and potentially transformed in-the pontine nuclei would be detected by the cerebellum and trigger specific and precisely timed responses in cerebellar output activity which would–via the thalamus-contribute to the coordination of neocortical network activity involved in cognitive or motor processes (Figure 6).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    In addition to broader diagnostic criteria and greater awareness, a real increase in incidence is also likely.

    “in addition to broader diagnostic criteria and greater awareness, a real increase in incidence is also likely [230, 233].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [230] Persico AM, Bourgeron T. Searching for ways out of the autism maze: genetic, epigenetic and environmental clues. Trends Neurosci. 2006;29:349–58. source

      Not checked in the free run.

    • cites [233] Landrigan PJ. What causes autism? Exploring the environmental contribution. Curr Opin Pediatr. 2010;22:219–25. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The incidence of autism has dramatically risen during the last two decades from 2-5/10,000 to approximately 1-2/1,000 children.

    “The incidence of autism has dramatically risen during the last two decades from 2–5/10,000 to approximately 1–2/1,000 children [232];”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [232] Fombonne E. Epidemiology of autistic disorder and other pervasive developmental disorders. J Clin Psychiatry. 2005;66 Suppl 10:3–8.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The most frequently reported cerebellar anomalies in autism include smaller vermis volume, Purkinje cell numbers reduced by up to 50%, ectopic neurons in white matter, and patchy cytoarchitectonic ectopias in cerebellar cortex.

    “The anomalies most frequently reported include a smaller vermis volume, Purkinje cell numbers reduced by up to 50%, ectopic neurons in the white matter, and patchy cytoarchitectonic ectopias in the cerebellar cortex [32, 33, 118, 228, 229].”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [32] Scott JA, Schumann CM, Goodlin-Jones BL, Amaral DG. A comprehensive volumetric analysis of the cerebellum in children and adolescents with autism spectrum disorder. Autism Res. 2009;2(5):246–57. source

      Not checked in the free run.

    • cites [33] Ritvo ER, Freeman BJ, Scheibel AB, Duong T, Robinson H, Guthrie D, et al. Lower Purkinje cell counts in the cerebella of four autistic subjects: initial findings of the UCLA–NSAC autopsy research project. Am J Psychiatry. 1986;143(7):862–6. source

      Not checked in the free run.

    • cites [118] Bauman ML, Kemper TL. Neuroanatomic observations of the brain in autism: a review and future directions. Int J Dev Neurosci. 2005;23:183–7. source

      Not checked in the free run.

    • cites [228] Courchesne E, Yeung-Courchesne R, Press GA, Hesselink JR, Jernigan TL. Hypoplasia of cerebellar vermal lobules VI and VII in autism. N Engl J Med. 1988;318:1349–54. source

      Not checked in the free run.

    • cites [229] Bauman ML. Microscopic neuroanatomic abnormalities in autism. Pediatrics. 1991;87:791–6. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Genetics strongly contributes to the pathogenesis of AD, but many patients reveal no obviously pathogenic mutations or copy number variants, and initial heritability estimates as high as >90% have been challenged by more recent twin studies.

    “Secondly, genetics strongly contributes to the pathogenesis of AD, but many patients reveal no obviously pathogenic mutations or copy number variants, and initial heritability estimates as high as >90% [234] have been challenged by more recent twin studies [235].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [234] Bailey A, Le Couteur A, Gottesman I, Bolton P, Simonoff E, Yuzda E, et al. Autism as a strongly genetic disorder: evidence from a British twin study. Psychol Med. 1995;25:63–77. source

      Not checked in the free run.

    • cites [235] Hallmayer J, Cleveland S, Torres A, Phillips J, Cohen B, Torigoe T, et al. Genetic heritability and shared environmental factors among twin pairs with autism. Arch Gen Psychiatry. 2011;68(11):1095–102. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The significant decrease in serum arylesterase, but not diazoxonase PON1 activity, recorded in AD samples points toward excessive oxidative stress as perhaps playing a more prominent role than acetylcholinesterase inhibition.

    “However, the significant decrease in serum arylesterase, but not in diazoxonase PON1 activity recorded in our AD samples points toward excessive oxidative stress, previously documented in AD patients and boosted by OPs, as perhaps playing a more prominent role than acetylcholinesterase inhibition [236].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [236] Gaita L, Manzi B, Sacco R, Lintas C, Altieri L, Lombardi F, et al. Decreased serum arylesterase activity in autism spectrum disorders. Psychiatry Res. 2010;180:105–13. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Autism is associated with RELN gene variants yielding reduced Reelin expression in vitro and in vivo, and with PON1 gene variants responsible for lower gene expression and reduced detoxification of some OP compounds.

    “At the same time, autism is associated with RELN gene variants yielding reduced Reelin gene expression both in vitro and in vivo, and with PON1 gene variants responsible for lower gene expression and reduced detoxification of some OP compounds [140, 239, 240].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [140] Kelemenova S, Schmidtova E, Ficek A, Celec P, Kubranska A, Ostatnikova D. Polymorphisms of candidate genes in Slovak autistic patients. Psychiatr Genet. 2010;20:137–9. source

      Not checked in the free run.

    • cites [239] D’Amelio M, Ricci I, Sacco R, Liu X, D'Agruma L, Muscarella LA, et al. Paraoxonase gene variants are associated with autism in North America, but not in Italy: possible regional specificity in gene-environment interactions. Mol Psychiatry. 2005;10:1006–16. source

      Not checked in the free run.

    • cites [240] Persico AM, Levitt P, Pimenta AF. Polymorphic GGC repeat differentially regulates human reelin gene expression levels. J Neural Transm. 2006;113:1373–82. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The PON1 gene encodes a calcium-dependent enzyme paraoxonase that inactivates OPs, degrades lipid peroxides, breaks down bacterial endotoxins, and prevents protein lactonation.

    “The PON1 gene encodes for a calcium-dependent enzyme frequently defined “paraoxonase”, which exerts several enzymatic activities including the inactivation of OPs, the degradation of lipid peroxides preventing atherosclerosis and vascular disease, the breakdown of bacterial endotoxins, and the prevention of protein lactonation [236].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [236] Gaita L, Manzi B, Sacco R, Lintas C, Altieri L, Lombardi F, et al. Decreased serum arylesterase activity in autism spectrum disorders. Psychiatry Res. 2010;180:105–13. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ca2+ is rapidly removed from cytoplasm into extracellular space by plasma membrane calcium ATPases; ATP2B2 encodes PMCA2, whose kinetics and Ca2+ affinity make it critical to synaptic function and plasticity especially in Purkinje cell dendritic spines and parvalbumin-positive GABAergic interneurons.

    “Ca2+ is rapidly removed from the cytoplasm into the extracellular space by plasma membrane calcium ATPases (PMCAs); the ATP2B2 gene encodes for PMCA2, whose faster kinetic and broader Ca2+ affinity range makes this PMCA critical to synaptic function and plasticity especially in the dendritic spines of Purkinje cells and in parvalbumin-positive gabaergic interneurons [244–246].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [244] Empson RM, Garside ML, Knöpfel T. Plasma membrane Ca2+ ATPase 2 contributes to short-term synapse plasticity at the parallel fiber to Purkinje neuron synapse. J Neurosci. 2007;27:3753–8. source

      Not checked in the free run.

    • cites [245] Burette AC, Strehler EE, Weinberg RJ. “Fast” plasma membrane calcium pump PMCA2a concentrates in GABAergic terminals in the adult rat brain. J Comp Neurol. 2009;512:500–13. source

      Not checked in the free run.

    • cites [246] Garside ML, Turner PR, Austen B, Strehler EE, Beesley PW, Empson RM. Molecular interactions of the plasma membrane calcium ATPase 2 at pre- and post-synaptic sites in rat cerebellum. Neuroscience. 2009;162:383–95. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Both Reelin protein levels and PON1 enzymatic activity are significantly reduced in AD individuals compared to controls.

    “Both Reelin protein levels and PON1 enzymatic activity (measured as “arylesterase” in these studies) are significantly reduced in AD individuals compared to controls [89, 236–238].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [89] Enstrom AM, Lit L, Onore CE, Gregg JP, Hansen R, Pessah IN, et al. Altered gene expression and function of peripheral blood natural killer cells in children with autism. Brain Behav Immun. 2009;23:124–33. source

      Not checked in the free run.

    • cites [236] Gaita L, Manzi B, Sacco R, Lintas C, Altieri L, Lombardi F, et al. Decreased serum arylesterase activity in autism spectrum disorders. Psychiatry Res. 2010;180:105–13. source

      Not checked in the free run.

    • cites [237] Paşca SP, Nemeş B, Vlase L, Gagyi CE, Dronca E, Miu AC, et al. High levels of homocysteine and low serum paraoxonase 1 arylesterase activity in children with autism. Life Sci. 2006;78:2244–8. source

      Not checked in the free run.

    • cites [238] Lugli G, Krueger JM, Davis JM, Persico AM, Keller F, Smalheiser NR. Methodological factors influencing measurement and processing of plasma reelin in humans. BMC Biochem. 2003;4:9. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Abnormal CNS lamination including discontinuities in cerebellar Purkinje cell layer and behavioral abnormalities occur in heterozygous reeler mice prenatally exposed to chlorpyrifos.

    “as well as (b) abnormal CNS lamination including discontinuities in the cerebellar Purkinje cell layer and behavioral abnormalities in heterozygous reeler mice (expressing 50% lower amounts of reelin compared to wild-type mice) prenatally exposed to the OP chlorpyrifos [242].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [242] Mullen B, Khialeeva E, Carpenter EM. Dab1-lacZ reporter reveals CNS lamination defects in a mouse model for autism. Program no. 147.12, 2010 Neuroscience Meeting Planner. Society for Neuroscience, San Diego CA. online.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mice prenatally exposed to the PAH benzo(a)pyrene display blunted MET gene expression and behavioral deficits in a novelty test.

    “Mice prenatally exposed to the PAH benzo(a)pyrene display blunted MET gene expression and behavioral deficits in a novelty test [253].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [253] Sheng L, Ding X, Ferguson M, McCallister M, Rhoades R, Maguire M, et al. Prenatal polycyclic aromatic hydrocarbon exposure leads to behavioral deficits and downregulation of receptor tyrosine kinase, MET. Toxicol Sci. 2010;118:625–34. source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    The cerebellum has been identified as a potential region of interest for autism and other neurobehavioral syndromes, but it has received very little direct attention as a therapeutic target.

    “Although the cerebellum has been identified as a potential region of interest for autism and also for a variety of other neurobehavioral syndromes and symptoms that overlap with autism, it has received very little direct attention from the standpoint of being a therapeutic target.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationreasoning

    The three scenarios exemplify the heuristic potential of investigating gene-environment interactions in neurodevelopmental disorders.

    “The three scenarios briefly outlined above exemplify the heuristic potential of investigating gene-environment interactions in neurodevelopmental disorders.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Interactions with PAHs may involve loci encoding other proteins of the MET pathway, as these show secondary changes in gene expression, SERPINE1 and PLAUR gene variants are also associated with autism, and significant gene-gene interactions have been shown between MET and PLAUR.

    “Furthermore, interactions with PAHs may involve loci encoding other proteins of the MET pathway, as these show secondary changes in gene expression [252], SERPINE1 and PLAUR gene variants are also associated with autism [254], and significant gene-gene interactions have been shown between MET and PLAUR [254].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [252] Campbell DB, Sutcliffe JS, Ebert PJ, Militerni R, Bravaccio C, Trillo S, et al. A genetic variant that disrupts MET transcription is associated with autism. Proc Natl Acad Sci USA. 2006;103:16834–9. source

      Not checked in the free run.

    • cites [254] Campbell DB, Li C, Sutcliffe JS, Persico AM, Levitt P. Genetic evidence implicating multiple genes in the MET receptor tyrosine kinase pathway in autism spectrum disorder. Autism Res. 2008;1:159–68. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The C allele at rs1858830 in the MET gene promoter is significantly associated with autism and decreases MET transcription in vitro and in postmortem brains.

    “Furthermore, the C allele at rs1858830, located in the MET gene promoter, is significantly associated with autism and decreases MET transcription both in vitro and in postmortem brains [251, 252].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [251] Campbell DB, D’Oronzio R, Garbett K, Ebert PJ, Mirnics K, Levitt P, et al. Disruption of cerebral cortex MET signaling in autism spectrum disorder. Ann Neurol. 2007;62:243–50. source

      Not checked in the free run.

    • cites [252] Campbell DB, Sutcliffe JS, Ebert PJ, Militerni R, Bravaccio C, Trillo S, et al. A genetic variant that disrupts MET transcription is associated with autism. Proc Natl Acad Sci USA. 2006;103:16834–9. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Individuals carrying ATP2B2 gene variants possibly associated with reduced gene expression, if prenatally exposed to PCBs, can be predicted to develop intracellular Ca2+ spikes of greater duration and/or amplitude, likely interfering with neuronal migration, dendritic spine formation, and synaptogenesis, especially in the parallel fiber-to-Purkinje cell synapse.

    “Hence, individuals carrying ATP2B2 gene variants possibly associated with reduced gene expression, if prenatally exposed to PCBs, can be predicted to develop intracellular Ca2+ spikes of greater duration and/or amplitude, likely interfering with neuronal migration, dendritic spine formation and synaptogenesis, especially in the parallel fiber-to-Purkinje cell synapse.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    The cerebellum is central in a wide range of functions sometimes impaired in autism, including timing and coordination of movement, motor learning, evaluation of match between intention and action, predictive learning, environmental exploration, behavioral inhibition, attention, and visual orienting.

    “Nevertheless, the cerebellum is central in a wide range of functions sometimes found to be impaired in autism, including timing and coordination of movement, motor learning, evaluation of the match between intention and action, predictive learning, environmental exploration, behavioral inhibition, attention, and visual orienting.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Moderate and high doses of methylphenidate modified T2 relaxation time in the vermis in boys with ADHD: for the most hyperactive boys T2 increased; for nonhyperactive boys T2 was lower.

    “For example, moderate and high doses of methylphenidate modified T2 relaxation time (a measure of relative blood volume or flow) in the vermis in boys with ADHD: for boys with ADHD who were the most hyperactive T2 relaxation time increased; for boys with ADHD who were nonhyperactive, T2 relaxation time was lower [259].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [259] Anderson CM, Polcari A, Lowen SB, Renshaw PF, Teicher MH. Effects of methylphenidate on functional magnetic resonance relaxometry of the cerebellar vermis in boys with ADHD. Am J Psychiatry. 2002;159:1322–8. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    The cerebellar vermis is associated with modulation of limbic functions including emotion, sensory reactivity, and salience detection.

    “In particular, the cerebellar vermis is associated with modulation of limbic functions including emotion, sensory reactivity, and salience detection.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Serotonergic drugs are among the most widely prescribed medications for individuals with autism, and while not specifically studied in autism for cerebellar effects, fluoxetine rescues some aspects of the consequences of neuronal cell death in the cerebellum in the Weaver mouse via effects on GIRK2 channels.

    “Serotonergic drugs are among the most widely prescribed medications for individuals with autism, and while not specifically studied in autism for their cerebellar effects, it is interesting that the SSRI, fluoxetine, rescues some aspects of the consequences of neuronal cell death in the cerebellum in the Weaver mouse via its effects on GIRK2 channels [260].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [260] Takahashi T, Kobayashi T, Ozaki M, Takamatsu Y, Ogai Y, Ohta M, et al. G protein-activated inwardly rectifying K+ channel inhibition and rescue of weaver mouse motor functions by antidepressants. Neurosci Res. 2006;54:104–11. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Motor planning and performance deficits have been demonstrated in association with cerebellar abnormality in some children with autism, and restricted/repetitive behaviors in others, so some current behavioral targets may actually be proxies for the cerebellum.

    “In as much as motor planning and performance deficits have been demonstrated in association with cerebellar abnormality in some children with autism [e.g., 199], and restricted and repetitive behaviors in others [e.g., 257], some current behavioral targets may actually be proxies for the cerebellum.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [199] Mostofsky SH, Powell SK, Simmonds DJ, Goldberg MC, Caffo B, Pekar JJ. Decreased connectivity and cerebellar activity in autism during motor task performance. Brain. 2009;132(9):2413–25. source

      Not checked in the free run.

    • cites [257] Rojas DC, Peterson E, Winterrowd E, Reite ML, Rogers SJ, Tregellas JR. Regional gray matter volumetric changes in autism associated with social and repetitive behavior symptoms. BMC Psychiatry. 2006;6:56. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    The cerebellum is one of the busiest intersections in the brain, receiving signals from and sending signals back to nearly every major neural system.

    “Moreover, the cerebellum is one of the busiest intersections in the brain--receiving signals from and sending signals back to nearly every major neural system.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    A pharmacological approach not studied in autism but which may deserve consideration based on cerebellar findings of Ji et al. may be calcium channel modulating agents.

    “Thus, a pharmacological approach that has not been studied in autism, but which may deserve consideration based upon cerebellar findings of Ji and colleagues [112] may be calcium channel modulating agents.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [112] Ji L, Chauhan A, Brown WT, Chauhan V. Increased activities of Na+/K+-ATPase and Ca2+/Mg2+-ATPase in the frontal cortex and cerebellum of autistic individuals. Life Sci. 2009;85:788–93. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Calcium channelopathies have been identified as a drug development target in autism and may deserve prioritization.

    “Calcium channelopathies have been identified as a drug development target in autism [265], and may deserve to be prioritized.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [265] Lory P, Mezghrani A. Calcium channelopathies in inherited neurological disorders: relevance to drug screening for acquired channel disorders. IDrugs. 2010;13:467–71.

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Drugs with more direct cerebellar effects may deserve particular consideration in autism and related conditions based on historical weight of evidence implicating this structure.

    “Drugs that are known to have more direct cerebellar effects may deserve particular consideration in autism and related conditions based on the historical weight of evidence implicating this structure.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Benzodiazepine use in autism is relatively uncommon due to concerns of behavioral disinhibition; some anticonvulsants likely exert GABAergic effects and are used for mood stabilization; there is ongoing interest in GABAergic treatments for catatonia in autism.

    “While benzodiazepine use in autism is relatively uncommon, owing to concerns of behavioral disinhibition, some anticonvulsants that likely exert GABAergic effects are used for mood stabilization [262], and there is ongoing interest in the potential role of GABAergic treatments for catatonia in autism [263].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [262] Johannessen Landmark C. Antiepileptic drugs in non-epilepsy disorders: relations between mechanisms of action and clinical efficacy. CNS Drugs. 2008;22:27–47. source

      Not checked in the free run.

    • cites [263] Fink M, Taylor MA, Ghaziuddin N. Catatonia in autistic spectrum disorders: a medical treatment algorithm. Int Rev Neurobiol. 2006;72:233–44. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Another approach for autism therapeutics may be to address the cerebellum transynaptically.

    “Another approach for autism therapeutics may be to address the cerebellum transynaptically.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The GABA B receptor agonist arbaclofen has been reported helpful in preliminary trials for irritability and social withdrawal in autism and is moving forward in clinical trials.

    “Additionally, the GABA B receptor agonist, arbaclofen, has been reported to be helpful in preliminary trials for irritability and social withdrawal in autism and is moving forward in clinical trials [264].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [264] Wang P, Erickson CA, Ginsberg G, Rathmell B, Cerubini M, Zarevics P, et al. Effects of STX209 (arbaclofen) on social and communicative function in ASD: results of an 8 week open label trial. International Meeting for Autism Research. 2011 May. San Diego, CA.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Serotonin and NMDA receptors within the IO can potently modulate cerebellar output, either by changing HCN and Cav3.1 channel activity after 5-HT2A receptor activation to modulate pacemaking, or by changing spatial patterns of electrotonic coupling after NMDA receptor activation to regulate synchronous spiking in the cerebellum.

    “Serotonin and NMDA receptors within the IO can potently modulate cerebellar output, either by changing HCN and Cav3.1 channel activity after 5-HT2A receptor activation to modulate pacemaking [266, 267], or by changing spatial patterns of electrotonic coupling after NMDA receptor activation to regulate synchronous spiking in the cerebellum [268].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [266] Placantonakis DG, Schwarz C, Welsh JP. Serotonin suppresses subthreshold and suprathreshold oscillatory activity of rat inferior olive neurons in vitro. J Physiol (Lond). 2000;524:833–51. source

      Not checked in the free run.

    • cites [267] Placantonakis DG, Welsh JP. Two distinct oscillatory states determined by the NMDA receptor in rat inferior olive. J Physiol (Lond). 2001;534:123–40. source

      Not checked in the free run.

    • cites [268] Welsh JP, Han VZ. The NMDA receptor potentiates electrotonic coupling between inferior olive neurons. Society for Neuroscience Abstracts. 2010; 525–5.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ji et al. found brain-region specific increases in activities of Na+/K+-ATPase and Ca2+/Mg2+-ATPase in autism and suggested increased activity in cerebellum may be due to compensatory responses to increased intracellular calcium concentration.

    “Ji and colleagues found brain-region specific increases in the activities of Na(+)/K(+)-ATPase and Ca(2+)/Mg(2+)-ATPase in autism and suggested that increased activity of these enzymes in the cerebellum may be due to compensatory responses to increased intracellular calcium concentration.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [112] Ji L, Chauhan A, Brown WT, Chauhan V. Increased activities of Na+/K+-ATPase and Ca2+/Mg2+-ATPase in the frontal cortex and cerebellum of autistic individuals. Life Sci. 2009;85:788–93. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    These calcium channels are an increasingly recognized target for investigational therapeutics and are abundantly expressed in the primate IO.

    “These calcium channels are an increasingly recognized target for investigational therapeutics, and are abundantly expressed in the primate IO [47].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [47] Welsh JP, Han VZ, Rossi D, Mohr C, Odagari M, Daunais J, et al. Bidirectional plasticity in the primate inferior olive induced by chronic ethanol intoxication and sustained abstinence. Proc Natl Acad Sci USA. 2011;108:10314–9. source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    IO neurons project monosynaptically to Purkinje cells, the only output neuron of the cerebellar cortex, and regulate throughput of the mossy fiber/parallel fiber system.

    “IO neurons project monosynaptically to Purkinje cells, the only output neuron of the cerebellar cortex, and regulate the throughput of the mossy fiber/parallel fiber system.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The cerebellum may modulate executive functions, likely through reciprocal connections to cortical regions.

    “Mounting evidence from human neuroimaging and acquired lesion studies suggests that the cerebellum may modulate executive functions [274], likely by means of reciprocal connections to cortical regions [26].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [274] Bellebaum C, Daum I. Cerebellar involvement in executive control. Cerebellum. 2007;6:184–92. source

      Not checked in the free run.

    • cites [26] Strick P, Dum R, Fiez J. Cerebellum and nonmotor function. Ann Rev Neurosci. 2009;32(1):413–34. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Specific deletion of IB2 in mice causes altered Purkinje cell morphology and disrupted cerebellar glutamatergic transmission.

    “Specific deletion of IB2 in mice results in altered Purkinje cell morphology and disruptions in cerebellar glutamatergic transmission [277].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [277] Giza J, Urbanski MJ, Prestori F, Bandyopadhyay B, Yam A, Friedrich V, et al. Behavioral and cerebellar transmission deficits in mice lacking the autism-linked gene islet brain-2. J Neurosci. 2010;30:14805–16. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Therapeutics targeted at precerebellar afferents may present future opportunities to address cerebellar pathophysiology in children with autism.

    “Thus, therapeutics targeted at precerebellar afferents may present future opportunities to address cerebellar pathophysiology in children with autism.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    A better understanding of the cerebellum and its afferents in autism could inform treatment selection and future drug development.

    “and a better understanding of the role of the cerebellum and its afferents in autism could importantly inform treatment selection and future drug development.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    IB2 and Pax6 are linked with syndromes that are co-morbid for autistic disorder: Phelan-McDermid syndrome and WAGR.

    “Of these genes, both IB2 and Pax6 are explicitly linked with syndromes that are co-morbid for AD: Phelan-McDermid syndrome and WAGR (Wilm’s tumor, Aniridia, Genitourinary malformations, and mental Retardation syndrome).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Autistic disorder is a behaviorally defined, multi-causal, developmental disorder associated with various neuropathologies.

    “Autistic disorder is a behaviorally-defined, multi-causal, developmental disorder that is associated with various neuropathologies [273].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [273] Amaral DG, Schumann CM, Nordahl CW. Neuroanatomy of autism. Trends Neurosci. 2008;31:137–45. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The studies outlined support a role for the cerebellum in autistic disorder and provide clues about mechanisms by which cerebellar pathology may contribute to the overall autistic phenotype.

    “Collectively, the studies outlined here support a role for the cerebellum in AD and provide clues to the mechanisms by which cerebellar pathology may contribute to the overall AD phenotype.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductcitation

    Individual chimeric mice showed no signs of motor impairment unless they lost more than 90% of Purkinje cells, in which case they were excluded from analyses.

    “Importantly, individual chimeric mice did not show signs of motor impairment unless they lost greater than 90% of their Purkinje cells in which case they were excluded from the analyses [285].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [285] Martin LA, Escher T, Goldowitz D, Mittleman G. A relationship between cerebellar Purkinje cells and spatial working memory demonstrated in a lurcher/chimera mouse model system. Genes Brain Behav. 2004;3:158–66. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Multiple drug treatment options, such as calcium channel modulating agents, GABAB receptor agonists, and serotonin and NMDA receptor modulating drugs, may be of potential use in treating autism.

    “Multiple drug treatment options, such as calcium channel modulating agents, GABAB receptor agonists, and serotonin and NMDA receptor modulating drugs may be of potential use in treatment of autism;”
    Quote in the paperNot a substantial claim
129 of 129

  • The paper relies on this without support.

    Many autistic individuals have dysfunction in both fine and gross motor skills.

    “Many autistic individuals exhibit dysfunction in both fine and gross motor skills.”

  • The paper relies on this without support.

    The cerebellum normally participates in conditioned reflexes, mental imagery, anticipatory planning, attention, affective behavior, visual spatial organization, and sensory data acquisition.

    “The cerebellum is also known to play a role in classic conditioned reflex responses, mental imagery, anticipatory planning, aspects of attention, affective behavior, visual spatial organization and the control of sensory data acquisition.”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Valproate-exposed rat claim cites an allelic-variant paper

    Minor

    The cited reference [282] is listed as a report on HOXA1 and HOXB1 allelic variants, whereas the text uses it to support a claim about cerebellar pathology in rats exposed to valproic acid.

  • A study attributed to Webb cites Landrigan instead

    Minor

    The text attributes a finding about cerebellar measurements in children to Webb et al. [233], but reference [233] lists Landrigan as its author and concerns environmental contributions to autism.

  • Reelin claim points to a natural-killer-cell reference

    Minor

    The cited reference [89] is listed as a study of peripheral blood natural killer cells, not the reported measurements of Reelin in brain tissue.

3 of 3

Cites

Flagged first, then by citations

Research works printed but not linked: 7

  1. Arin DM, Bauman ML, Kemper TL. The distribution of Purkinje cell loss in the cerebellum in autism. Neurology. 1991;41(Suppl):307.
  2. Oristaglio J, Ghaffari M, Hyman West S, Welsh JP, Malone R. A sensory timing abnormality in autism revealed by classical eyeblink conditioning. Soc Neurosci Abstr. 2012; (in press).
  3. Muthaiyah B, Essa MM, Chauhan V, Brown WT, Wegiel J, Chauhan A. Increased lipid peroxidation in cerebellum and temporal cortex of brain in autism. J Neurochem. 2009;108 Suppl 1:73.
  4. Chauhan A, Audhya T, Chauhan V. Increased DNA oxidation in the cerebellum, frontal and temporal cortex of brain in autism. Transactions of the American Society for Neurochemistry. Windermere: American Society for Neurochemistry; 2011. p. 81.
  5. Blatt GJ, VanSluytman G, Marcon RG. Decreased density of 3[H]AFDX-labeled cholinergic M2 receptors in the medial accessory olive in autism. Soc Neurosci. 2004;34:116.12.
  6. Sasaki K, Gemba H. Cerebro-cerebellar interactions: for fast and stable timing of voluntary movement. In: Mano N, Hamada I, DeLong MR, editors. Role of the cerebellum and basal ganglia in voluntary movement. Amsterdam: Elsevier; 1993. p. 41–50.
  7. Martin LA, Goldowitz D, Mittleman G. Sustained attention in the mouse: a study of the relationship with the cerebellum. Behav Neurosci. 2006;120(2):477–81. · DOI · Paper page

Cited by

Sorted by citations

Related

Authors
Fatemi, S. H., Aldinger, K. A., Ashwood, P., Bauman, M. L., Blaha, C. D., Blatt, G. J., Chauhan, A., Chauhan, V., Dager, S. R., Dickson, P. E., Estes, A. M., Goldowitz, D., Heck, D. H., Kemper, T. L., King, B. H., Martin, L. A., Millen, K. J., Mittleman, G., Mosconi, M. W., Persico, A. M., Sweeney, J. A., Webb, S. J., & Welsh, J. P.
Affiliations
  • University of Minnesota (US)
  • University of Southern California (US)
  • University of California, Davis (US)
  • Harvard University (US)
  • University of Memphis (US)
  • Boston University (US)
  • University of Washington (US)
  • University of British Columbia (CA)
  • University of Tennessee Health Science Center (US)
  • Azusa Pacific University (US)
  • The University of Texas Southwestern Medical Center (US)
  • Università Campus Bio-Medico (IT)
Corresponding author
Fatemi, S. Hossein
ORCID
Venue
The Cerebellum
Publisher
Springer Science and Business Media LLC
Published
2012-02-28
Volume
11
Issue
3
Pages
777-807
ISSN
  • 1473-4222 (ISSN-L)
  • 1473-4230
DOI
10.1007/s12311-012-0355-9
PMC
PMC3677555
OpenAlex
W2020374060
Cited by
723
References
313
Citations by year
2026: 33 · 2025: 48 · 2024: 56 · 2023: 52 · 2022: 61 · 2021: 48 · 2020: 46 · 2019: 59 · 2018: 50 · 2017: 43 · 2016: 61 · 2015: 52 · 2014: 45 · 2013: 49 · 2012: 20
FWCI
27.16
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • The Cerebellum (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion, cc-by)
Funders
  • Autism Speaks (AS3587)
  • Pfizer
  • Autism Research Institute
  • Emch Foundation
  • National Alliance for Research on Schizophrenia and Depression
  • Hussman Foundation
  • Office for People With Developmental Disabilities
  • Ministero della Salute (RFPS-2007-5-640174)
  • National Institutes of Health (UL1TR000130, NICHD‐R01, KL2TR000131)
  • National Institute of Mental Health (HD055741, K23MH092696)
  • National Institute of Neurological Disorders and Stroke (NS31224, R01 NS31224-18, R01NS063009, R01NS038975, R01-NS31224, R01NS072441, R01NS031224, R01NS060887, NS38975-05)
  • National Institute of Child Health and Human Development (HD 055741)
  • National Center for Advancing Translational Sciences
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (P50HD055751, P50HD055782, R01 HD05571, R01HD039459, R01HD065283, P01HD035465, R01HD052074, HD-055741, R21HD065269, R01HD055741, HD35465)
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Health Sciences › Medicine › Psychiatry and Mental health › Child Nutrition and Feeding Issues
Keywords
cerebellum, autism spectrum disorder, cerebellar pathology, cerebellar vermis hypoplasia, neuroinflammation, oxidative stress, mitochondrial dysfunction, GABAergic system, glutamatergic system, neurotransmitter systems, motor control deficits, cognitive impairment, gene-environment interaction, animal models of autism
MeSH terms
Reelin Protein, Animals, Autistic Disorder, Cerebellar Diseases, Cerebellum, Cognition Disorders, Disease Models, Animal, gamma-Aminobutyric Acid, Humans, Magnetic Resonance Imaging, Mitochondria, Movement Disorders, Nerve Tissue Proteins, Serine Endopeptidases, Cell Adhesion Molecules, Neuronal, Extracellular Matrix Proteins, Neurotransmitter Agents, Oxidative Stress, Glutamic Acid, Gene-Environment Interaction

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-05.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-05.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review