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Cited by 483Autism Spectrum Disorder ResearchFunctional Brain Connectivity StudiesGenetics and Neurodevelopmental Disorders

Aberrant Striatal Functional Connectivity in Children with Autism

Open access
Di Martino, Adriana, Kelly, Clare, Grzadzinski, Rebecca, Zuo, Xi-Nian, Mennes, Maarten, Mairena, Maria Angeles, Lord, Catherine, Castellanos, F. Xavier +1 more·2011·Biological Psychiatry
DOI 10.1016/j.biopsych.2010.10.029PMC PMC3091619
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Abstract

Background Models of Autism Spectrum Disorders (ASD) as neural dysconnection syndromes have been predominantly supported by examinations of abnormalities in cortico-cortical networks in adults with autism. A broader body of research implicates subcortical structures, particularly the striatum, in the physiopathology of autism. Resting state fMRI has revealed detailed maps of striatal circuitry in healthy and psychiatric populations, and vividly captured maturational changes in striatal circuitry during typical development. Methods Using resting state fMRI, we examined striatal functional connectivity in 20 children with ASD and 20 typically developing children (TDC) between the age of 7.6 and 13.5 years. Whole-brain voxel-wise statistical maps quantified within-group striatal FC and between-group differences for three caudate and three putamen seeds, for each hemisphere. Results Children with ASD mostly exhibited prominent patterns of ectopic striatal functional connectivity (i.e., functional connectivity present in ASD but not in TDC), with increased functional connectivity between nearly all striatal subregions and heteromodal associative and limbic cortex previously implicated in the physiopathology of ASD (e.g., insular and right superior temporal gyrus). Additionally, we found striatal functional hyperconnectivity with the pons, thus expanding the scope of functional alterations implicated in ASD. Secondary analyses revealed ASD-related hyperconnectivity between the pons and insular cortex. Conclusions Examination of functional connectivity of striatal networks in children with ASD revealed abnormalities in circuits involving early developing areas such as the brainstem and insula, with a pattern of increased functional connectivity in ectopic circuits that likely reflects developmental derangement rather than immaturity of functional circuits.

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Written from the paper’s full text.

TL;DR

In 20 children with ASD and 20 typically developing children (TDC) aged 7.6–13.5 years, resting-state fMRI showed predominantly ectopic striatal functional connectivity in ASD, with increased connectivity between nearly all striatal subregions and heteromodal associative/limbic cortex plus striatal hyperconnectivity with the pons. Secondary analyses found ASD-related pons–insula hyperconnectivity, and symptom correlations with restrictive repetitive behavior scores were tentative and did not survive Bonferroni correction.

Key findings

  • Children with ASD showed stronger and more diffuse striatal FC with heteromodal associative and limbic cortex; examples included right VSi–right STG/right mid-insula, left VSs–left central operculum, and right vrP–right STG/planum temporale. Left VSi–left supramarginal gyrus was positively connected in TDC but negatively connected in ASD.
  • Dorsal caudate findings included ASD-related positive FC with regions negatively correlated with DC in TDC: right DC–left temporal fusiform gyrus and left DC–bilateral supramarginal gyrus.
  • Putamen/brainstem findings included strong correlation between both right dorsal putamen seeds and the pons in ASD; right dcP also extended to right parahippocampal gyrus and hippocampus, and left dcP was more correlated with right temporal-occipital fusiform gyrus. Right vrP showed the one ASD-related hypoconnectivity finding, with left lateral occipital cortex.
  • In 17 children with research-reliable ADOS scores, RRB scores correlated with right vrP/right STG FC (partial r(13)=0.69, p=0.005) and right dcP/right pons FC (partial r(13)=−0.64, p=0.011), but these did not survive Bonferroni correction (p<0.004). Age-sensitive analyses suggested ectopic FC rather than delayed development for nearly all aberrant circuits except right VSi.

Methods

  • Twenty children with ASD (after excluding 6 of 26 for excessive movement) and 20 TDC, aged 7.6–13.5 years, were group-matched for age, sex, estimated IQ, and handedness; diagnoses were supported by ADI-R/ADOS and DSM-IV-TR. Secondary analyses included 35 adults (mean age 28.4±8.5 years) from a previous study.
  • Resting-state fMRI acquisition was 6 min 38 s, 197 EPI volumes, 3.0 Tesla, TR=2000 ms, TE=25 ms, 39 slices, 3 mm³ voxels; preprocessing used AFNI and FSL, with displacement <2.5 mm/2.5°, nuisance regression, and MNI152 normalization.
  • Seed-based FC used six striatal seeds (VSi, VSs, DC, dcP, drP, vrP) per hemisphere (12 seeds total), whole-brain voxel-wise correlations, Fisher r-to-z transformation, and group-level ordinary least squares covarying age and full-scale IQ; cluster correction used min Z>2.3, p<0.05 corrected. Secondary TDC vs. typical adult comparisons covaried age and sex.

Limitations

  • Stated in the paper: sample size was on par with ASD functional imaging studies but larger samples are needed for ASD heterogeneity; failure to detect robust FC–symptom relationships may reflect not sampling symptoms beyond cardinal diagnostic domains; too few females were included to examine group-by-sex interactions; incomplete cerebellar coverage in some participants prevented full striatal-cerebellar analyses; the thalamus was not examined directly due to limitations on thalamic functional parcellation; and the ectopic FC model remains speculative until validated by cross-sectional and longitudinal studies beginning in early development.
  • Stated in the paper: the symptom correlations did not survive Bonferroni correction for multiple comparisons.
  • Evident from the text: the design is cross-sectional, so it cannot establish developmental trajectories; medication status was mixed (10 medication-naïve, 7 off psychoactive medications for varying periods, 2 on psychostimulants discontinued 24 hours before scanning, 1 on melatonin), which may affect FC; and only school-age children were studied, so findings may not generalize to younger or older ASD groups.

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Registry

Crossref · 10.1016/j.biopsych.2010.10.029

Cites

99 of 99 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

0 of 96 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    In children with ASD, for the right dcP, significant FC extended to the right parahippocampal gyrus and hippocampus.

    “for the right dcP, significant FC also extended to the right parahippocampal gyrus and hippocampus.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Resting-state fMRI functional connectivity provides a valid measure of functional brain connectivity.
  • Findingown data

    Children with ASD showed more extended and significantly stronger FC between the right vrP and the right STG and planum temporale.

    “Children with ASD showed more extended and significantly stronger FC between right vrP and right STG and planum temporale”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Resting-state fMRI functional connectivity provides a valid measure of functional brain connectivity.
  • Findingown data

    In 17 children with research-reliable ADOS scores, RRB scores negatively correlated with right dcP/right pons FC (partial r(13)= -0.64, p= 0.011).

    “and a negative correlation for the right dcP/right pons FC (partial r(13)= -0.64, p= 0.011)”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Resting-state fMRI functional connectivity provides a valid measure of functional brain connectivity.
  • Findingown data

    Children with ASD showed striatal functional hyperconnectivity with the pons.

    “Additionally, we found striatal functional hyperconnectivity with the pons, thus expanding the scope of functional alterations implicated in ASD.”
    • Also stated in: § Discussion · plain
      “We also found evidence of striatal functional hyperconnectivity with the pons, thus expanding the scope of functional alterations implicated in ASD.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Resting-state fMRI functional connectivity provides a valid measure of functional brain connectivity.
  • Findingown data

    Secondary analyses revealed ASD-related hyperconnectivity between the pons and insular cortex.

    “Secondary analyses revealed ASD-related hyperconnectivity between the pons and insular cortex.”
    • Also stated in: § Iterative FC Brainstem Analyses · plain
      “Massive FC was observed between the pons and insula, involving the posterior and middle insula divisions bilaterally, and the anterior insula in the right hemisphere only”
    • Also stated in: § Discussion · plain
      “Secondary FC analyses focusing on this brainstem area revealed broad patterns of ASD-related hyperconnectivity with bilateral insular cortices.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Resting-state fMRI functional connectivity provides a valid measure of functional brain connectivity.
  • May combine two claims. 16
  • Classified as probably not a substantial claim. 42

  • May combine two claims.

    Findingown data

    In children with ASD, the left VSi and left supramarginal gyrus were negatively connected, whereas in TDC these two regions were positively connected.

    “while the left VSi showed positive FC with the left supramarginal gyrus in TDC, these two regions were negatively connected in the ASD group”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Resting-state fMRI functional connectivity provides a valid measure of functional brain connectivity.

  • May combine two claims.

    Findingown data

    For nearly all aberrant circuits, significantly positive FC was observed in the ASD group, but FC was either absent or negative in each of the other two groups (TDC, TA).

    “For nearly all of the aberrant circuits, significantly positive FC was observed in the ASD group, but FC was either absent or negative in each of the other two groups (TDC, TA).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Resting-state fMRI functional connectivity provides a valid measure of functional brain connectivity.
    • Rests on an assumption: Cross-sectional differences between children and adults reflect developmental maturational changes.

  • May combine two claims.

    Findingcitation

    Patterns of striatal FC obtained for TDC were grossly similar to those previously obtained with TA, though with notably more diffuse and stronger local positive FC.

    “Patterns of striatal FC obtained for TDC were grossly similar to those previously obtained with TA (42;44;45) though with notably more diffuse and stronger local positive FC”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [42] Postuma, 2006, Basal ganglia functional connectivity based on a meta-analysis of 126 positron emission tomography and functional magnetic resonance imaging publications, Cereb Cortex source

      Not checked in the free run.

    • cites [44] Kelly, 2009, L-dopa modulates functional connectivity in striatal cognitive and motor networks: A double-blind placebo-controlled study, J Neurosci source

      Not checked in the free run.

    • cites [45] Hazlett, 2005, Magnetic resonance imaging and head circumference study of brain size in autism: Birth through age 2 years, Arch Gen Psychiatry source

      Not checked in the free run.

    • Rests on an assumption: Resting-state fMRI functional connectivity provides a valid measure of functional brain connectivity.

  • May combine two claims.

    Findingown data

    In the ASD group, nearly all striatal seeds showed significantly stronger and more diffuse FC with both regions typically included in striatal networks, as well as with ectopic areas, which are not functionally connected with the striatum in TDC.

    “However, in the ASD group, nearly all striatal seeds showed significantly stronger and more diffuse FC with both regions typically included in striatal networks, as well as with ectopic areas, which are not functionally connected with the striatum in TDC.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Resting-state fMRI functional connectivity provides a valid measure of functional brain connectivity.

  • May combine two claims.

    Findingown data

    Both child groups showed positive FC with anterior and posterior insula, as well as with superior and middle temporal gyri bilaterally, areas not typically observed in DC circuitry in TA.

    “Both child groups also showed positive FC with anterior and posterior insula, as well as with superior and middle temporal gyri bilaterally, areas not typically observed in DC circuitry in TA.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Resting-state fMRI functional connectivity provides a valid measure of functional brain connectivity.

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

    Study design and conductcitation

    Research-reliable scores were obtained for 17 (85%) children using the new diagnostic ADOS algorithm.

    “Research-reliable scores were obtained for 17 (85%) children using the new diagnostic ADOS algorithm (53).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [53] Kaufman, 1997, Schedule for Affective Disorders and Schizophrenia for School-Age Children Present and Lifetime version (K-SADS-PL): Initial reliability and validity data, J Am Acad Child Adolesc Psychiatry source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    We employed six previously validated striatal regions of interest (seeds).

    “We employed six previously validated (42) striatal regions of interest (“seeds”).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [42] Postuma, 2006, Basal ganglia functional connectivity based on a meta-analysis of 126 positron emission tomography and functional magnetic resonance imaging publications, Cereb Cortex source

      Not checked in the free run.

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

    Premisecitation

    Caudate hyperactivation was evident in a study of sensorimotor processes in ASD.

    “caudate hyperactivation was evident in a study of sensorimotor processes in ASD (41).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [41] Di Martino, 2008, Functional connectivity of human striatum: A resting state FMRI study, Cereb Cortex source

      Not checked in the free run.

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

    Study design and conductown data

    Partial correlations controlling for age and IQ were computed for symptom severity analyses.

    “Consistent with our primary analyses we computed partial correlations, controlling for age and IQ.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    A task-based fMRI study reported increased striatal FC with frontal, parietal, and occipital lobes in adults with ASD during a sensorimotor task, relative to TA.

    “in a task-based fMRI study, increased striatal FC with frontal, parietal, and occipital lobes was reported in adults with ASD during a sensorimotor task, relative to TA (35).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] Qiu, 2010, Basal ganglia shapes predict social, communication, and motor dysfunctions in boys with autism spectrum disorder, J Am Acad Child Adolesc Psychiatry

      Not checked in the free run.

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

    Study design and conductown data

    FC analyses in data registered to a local template yielded substantially similar results.

    “FC analyses in data registered to a local template yielded substantially similar results (Figure S3 in Supplement 1).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Resting-state fMRI functional connectivity provides a valid measure of functional brain connectivity.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Gaussian Random Field theory was used for cluster-level multiple comparisons correction (min Z > 2.3; p < 0.05, corrected).

    “Gaussian Random Field theory was used for cluster-level multiple comparisons correction (min Z > 2.3; p < 0.05, corrected).”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    We excluded six children with ASD due to excessive movement.

    “We enrolled 26 children with ASD and excluded six children due to excessive movement.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    The ASD and TDC groups did not differ in ethnicity.

    “Caucasian (11 and 8, in the TDC and ASD groups, respectively) and African American (4 and 3 for the TDC and the ASD groups, respectively) predominated (groups did not differ).”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    The ASD and TDC groups did not differ in handedness.

    “18 of the 20 children with ASD were right-handed (groups did not differ).”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    We did not covary sex because there were few females (3 ASD, 6 TDC).

    “We did not covary sex given the few females (3 ASD, 6 TDC).”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Models of ASD as a brain dysconnection syndrome have emerged from analyses of abnormalities in cortico-cortical connections.

    “Models of ASD as a brain dysconnection syndrome (8-13) have emerged from analyses of abnormalities in cortico-cortical connections.”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [8] Frith, 2004, Is autism a disconnection disorder?, Lancet Neurol source

      Not checked in the free run.

    • cites [9] Belmonte, 2004, Autism as a disorder of neural information processing: Directions for research and targets for therapy, Mol Psychiatry source

      Not checked in the free run.

    • cites [10] Just, 2004, Cortical activation and synchronization during sentence comprehension in high-functioning autism: Evidence of underconnectivity, Brain source

      Not checked in the free run.

    • cites [11] Minshew, 2007, The new neurobiology of autism: Cortex, connectivity, and neuronal organization, Arch Neurol source

      Not checked in the free run.

    • cites [12] Geschwind, 2007, Autism spectrum disorders: Developmental disconnection syndromes, Curr Opin Neurobiol source

      Not checked in the free run.

    • cites [13] Hughes, 2007, Autism: The first firm finding = underconnectivity?, Epilepsy Behav source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    The strength of FC between cortical and subcortical regions progressively decreases with age.

    “Concurrently, the strength of FC between cortical and subcortical regions progressively decreases (6), suggesting decreased subcortical influence over cortical functioning with age.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [6] Supekar, 2009, Development of large-scale functional brain networks in children, PLoS Biol source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Diffuse patterns of local FC are gradually replaced by a distributed architecture, dominated by focal long-range connections.

    “diffuse patterns of local FC are gradually replaced by a distributed architecture, dominated by focal long-range connections (3-6).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [3] Fair, 2007, Development of distinct control networks through segregation and integration, Proc Natl Acad Sci U S A source

      Not checked in the free run.

    • cites [4] Fair, 2008, The maturing architecture of the brain's default network, Proc Natl Acad Sci U S A source

      Not checked in the free run.

    • cites [5] Kelly, 2009, Development of anterior cingulate functional connectivity from late childhood to early adulthood, Cereb Cortex source

      Not checked in the free run.

    • cites [6] Supekar, 2009, Development of large-scale functional brain networks in children, PLoS Biol source

      Not checked in the free run.

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

    Premisecitation

    Morphological studies have generally reported increased caudate volume in ASD.

    “Morphological studies have generally reported increased caudate volume in ASD (37;38).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [37] Stanfield, 2008, Towards a neuroanatomy of autism: A systematic review and meta-analysis of structural magnetic resonance imaging studies, Eur Psychiatry source

      Not checked in the free run.

    • cites [38] Dapretto, 2006, Understanding emotions in others: mirror neuron dysfunction in children with autism spectrum disorders, Nat Neurosci source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Overall, the literature suggests abnormal striatal-cortical circuits in ASD and highlights the need for their direct investigation in this population.

    “Overall, this literature suggests abnormal striatal-cortical circuits in ASD and highlights the need for their direct investigation in this population.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    Secondary analyses comparing TDC to TA were conducted covarying age and sex.

    “Secondary analyses comparing TDC to TA, were conducted covarying age and sex.”
    Quote in the paperNot a substantial claim

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

    Study design and conductreasoning

    We covaried age and full-scale IQ in group-level FC analyses.

    “However, given their wide ranges (Table 1), we covaried age and full-scale IQ.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    The ASD and TDC groups did not differ significantly with respect to IQ, age, sex, or SES.

    “The ASD and the TDC groups did not differ significantly with respect to IQ, age, sex, or SES.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Disturbances in these maturational processes are increasingly implicated in neurodevelopmental conditions such as autism spectrum disorders (ASD).

    “Disturbances in these maturational processes are increasingly implicated in neurodevelopmental conditions such as autism spectrum disorders (ASD) (7).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [7] Courchesne, 2007, Mapping early brain development in autism, Neuron source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Studies of FC in ASD have found evidence of reduced long-range FC in various cortical circuits.

    “Studies of FC in ASD have found evidence of reduced long-range FC in various cortical circuits (14-24).”
    Quote in the paperSubstantial claim0 of 10 sources checked
    • cites [14] Jones, 2010, Sources of group differences in functional connectivity: An investigation applied to autism spectrum disorder, Neuroimage source

      Not checked in the free run.

    • cites [15] Kennedy, 2006, Failing to deactivate: Resting functional abnormalities in autism, Proc Natl Acad Sci U S A source

      Not checked in the free run.

    • cites [16] Cherkassky, 2006, Functional connectivity in a baseline resting-state network in autism, Neuroreport source

      Not checked in the free run.

    • cites [17] Paakki, 2010, Alterations in regional homogeneity of resting-state brain activity in autism spectrum disorders, Brain Res source

      Not checked in the free run.

    • cites [18] Just, 2007, Functional and anatomical cortical underconnectivity in autism: Evidence from an FMRI study of an executive function task and corpus callosum morphometry, Cereb Cortex source

      Not checked in the free run.

    • cites [19] Kana, 2006, Sentence comprehension in autism: Thinking in pictures with decreased functional connectivity, Brain source

      Not checked in the free run.

    • cites [20] Koshino, 2008, fMRI investigation of working memory for faces in autism: Visual coding and underconnectivity with frontal areas, Cereb Cortex source

      Not checked in the free run.

    • cites [21] Castelli, 2002, Autism, Asperger syndrome and brain mechanisms for the attribution of mental states to animated shapes, Brain source

      Not checked in the free run.

    • cites [22] Villalobos, 2005, Reduced functional connectivity between V1 and inferior frontal cortex associated with visuomotor performance in autism, Neuroimage source

      Not checked in the free run.

    • cites [23] Welchew, 2005, Functional disconnectivity of the medial temporal lobe in Asperger's syndrome, Biol Psychiatry source

      Not checked in the free run.

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

    Premisecitation

    The four functionally distinct insular areas are ventral and dorsal AI areas associated with empathy and cognitive functions, a posterior region associated with sensorimotor processes, and an intermediate region involved in olfactory-gustatory functions.

    “These are ventral and dorsal AI areas, associated with empathy and cognitive functions respectively, a posterior region associated with sensorimotor processes, and an intermediate region involved in olfactory-gustatory functions (76).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [76] Silani, 2008, Levels of emotional awareness and autism: An fMRI study, Soc Neurosci source

      Not checked in the free run.

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

    Study design and conductnone given

    Our sample size is on-par with functional imaging studies of ASD.

    “Although our sample size is on-par with functional imaging studies of ASD, larger samples are needed to account for the marked heterogeneity characteristic of ASD.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Initial R-fMRI work has revealed ASD-related increases in FC between STG and PCC.

    “For example, initial R-fMRI work has revealed ASD-related increases in FC between STG and PCC (28) and increased regional homogeneity of temporal cortices including STG (92).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] Monk, 2009, Abnormalities of intrinsic functional connectivity in autism spectrum disorders, Neuroimage source

      Not checked in the free run.

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

    Premisecitation

    A recent meta-analysis of functional imaging studies of autism highlighted ASD-related insula hypoactivation in studies examining social processing.

    “a recent meta-analysis of functional imaging studies of autism highlighted ASD-related insula hypoactivation in studies examining social processing (30)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Di Martino, 2009, Relationship between cingulo-insular functional connectivity and autistic traits in neurotypical adults, Am J Psychiatry source

      Not checked in the free run.

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

    Premisecitation

    Initial R-fMRI work has revealed increased regional homogeneity of temporal cortices including STG in ASD.

    “For example, initial R-fMRI work has revealed ASD-related increases in FC between STG and PCC (28) and increased regional homogeneity of temporal cortices including STG (92).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [92] Fernandez-Gil, 2010, Anatomy of the brainstem: A gaze into the stem of life, Semin Ultrasound CT MRI source

      Not checked in the free run.

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

    Premisecitation

    Posterior divisions of the right STG are implicated in perception of intentional movements such as eye gaze, salience of acoustic cues, prediction of reward based on other agents' strategies, and live face-to-face interactions.

    “Posterior divisions of the right STG (pSTG) have been implicated in perception of intentional movements such as eye gaze (81), salience of acoustic cues (82;83), prediction of reward based on other agents’ strategies (84), and live face-to-face interactions (85).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [81] Redcay, 2008, The superior temporal sulcus performs a common function for social and speech perception: Implications for the emergence of autism, Neurosci Biobehav Rev source

      Not checked in the free run.

    • cites [82] Haruno, 2009, Activity in the superior temporal sulcus highlights learning competence in an interaction game, J Neurosci source

      Not checked in the free run.

    • cites [83] Redcay, 2010, Live face-to-face interaction during fMRI: A new tool for social cognitive neuroscience, Neuroimage source

      Not checked in the free run.

    • cites [84] Frith, 2001, Mind blindness and the brain in autism, Neuron source

      Not checked in the free run.

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

    Study design and conductreasoning

    We did not examine the thalamus directly because of current limitations on thalamic functional parcellation.

    “Finally, even though cortico-striatal circuits are mediated by the thalamus, we did not examine the thalamus directly because of current limitations on thalamic functional parcellation.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    We included too few females to examine group by sex interactions.

    “Additionally, we included too few females to examine group by sex interactions.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Morphometric studies of individuals with ASD have revealed reduced grey and white matter in the pons and brainstem more broadly.

    “Evidence from neuropathology (96) and electrophysiology (97) also implicate the brainstem in ASD; morphometric studies of individuals with ASD have revealed reduced grey and white matter in the pons, and brainstem more broadly (90;e.g., 98).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [90] Shukla, 2010, Regional homogeneity of fMRI time series in autism spectrum disorders, Neurosci Lett source

      Not checked in the free run.

    • cites [98] Zhang, 2008, Intrinsic functional relations between human cerebral cortex and thalamus, J Neurophysiol source

      Not checked in the free run.

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

    Interpretationreasoning

    Failure to detect robust relationships between FC and symptom severity may reflect our failure to sample symptoms beyond the cardinal diagnostic domains.

    “Along with sample size, failure to detect robust relationships between FC and symptom severity may reflect our failure to sample symptoms beyond the cardinal diagnostic domains.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    ASD-related abnormalities in temporal gyri gray matter have been noted.

    “ASD-related abnormalities in temporal gyri gray matter have also been noted (90).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [90] Shukla, 2010, Regional homogeneity of fMRI time series in autism spectrum disorders, Neurosci Lett source

      Not checked in the free run.

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

    Premisecitation

    Increased FC between STG and frontal cortex in ASD emerged from a study of language processes.

    “Increased FC between STG and frontal cortex in ASD emerged from a study of language processes (91), while R-fMRI studies of ASD are beginning to reveal STG abnormalities.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [91] Dawson, 2005, Neurocognitive and electrophysiological evidence of altered face processing in parents of children with autism: Implications for a model of abnormal development of social brain circuitry in autism, Dev Psychopathol source

      Not checked in the free run.

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

    Premisecitation

    fMRI studies of ASD have demonstrated abnormal activation of the pSTG during tasks involving perception of intentional movements, particularly in the right hemisphere.

    “Consistent with a role of pSTG in these processes, fMRI studies of ASD have demonstrated abnormal activation of the pSTG during tasks involving perception of intentional movements, particularly in the right hemisphere (86-88).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [86] Wang, 2007, Reading affect in the face and voice: Neural correlates of interpreting communicative intent in children and adolescents with autism spectrum disorders, Arch Gen Psychiatry source

      Not checked in the free run.

    • cites [87] von dem Hagen, 2010, Autism spectrum traits in the typical population predict structure and function in the posterior superior temporal sulcus [published online ahead of print May 3], Cereb Cortex

      Not checked in the free run.

    • cites [88] Toal, 2010, Clinical and anatomical heterogeneity in autistic spectrum disorder: A structural MRI study, Psychol Med source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    This resembles TDC functional architecture rather than that of TA, suggesting developmental immaturity in ASD.

    “This resembles TDC functional architecture rather than that of TA (3;5;25), suggesting developmental immaturity in ASD.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [3] Fair, 2007, Development of distinct control networks through segregation and integration, Proc Natl Acad Sci U S A source

      Not checked in the free run.

    • cites [5] Kelly, 2009, Development of anterior cingulate functional connectivity from late childhood to early adulthood, Cereb Cortex source

      Not checked in the free run.

    • cites [25] Uddin, 2010, Typical and atypical development of functional human brain networks: insights from resting-state FMRI, Front Syst Neurosci source

      Not checked in the free run.

    • Rests on an assumption: Cross-sectional differences between children and adults reflect developmental maturational changes.

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

    Premisecitation

    Increased local and reduced long-range FC characteristic of immature development has been reported to be widespread in Tourette's disorder and was also found in ADHD.

    “increased local and reduced long-range FC- characteristic of immature development- has been reported to be widespread in Tourette’s disorder (along with two anomalous circuits) (67) and was also found in ADHD (68).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [67] Castellanos, 2008, Cingulate-precuneus interactions: A new locus of dysfunction in adult attention-deficit/hyperactivity disorder, Biol Psychiatry source

      Not checked in the free run.

    • cites [68] Mizuno, 2006, Partially enhanced thalamocortical functional connectivity in autism, Brain Res source

      Not checked in the free run.

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

    Interpretationown data

    Our results support broadening the focus of examination in ASD to regions involved in early stages of brain development, such as the brainstem, insula, and striatum.

    “Our results support broadening the focus of examination in ASD to regions involved in early stages of brain development, such as the brainstem, insula, and striatum.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    In a study of autistic traits in typical adults, the severity of autistic traits was directly related to the extent to which FC between mid-insula and pregenual ACC resembled that of the ventral AI (low autistic traits) as opposed to posterior insular regions (high autistic traits).

    “In that study, the severity of autistic traits was directly related to the extent to which FC between mid-insula and pregenual ACC resembled that of the ventral AI (low autistic traits) as opposed to posterior insular regions (high autistic traits; 30).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Di Martino, 2009, Relationship between cingulo-insular functional connectivity and autistic traits in neurotypical adults, Am J Psychiatry source

      Not checked in the free run.

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

    Premisecitation

    Reductions in white matter volume and hypoactivation of the pSTG during a Stroop task positively correlated with levels of autistic traits in typical adults.

    “Recent work showed that reductions in white matter volume and hypoactivation of the pSTG during a Stroop task positively correlated with levels of autistic traits in TA (89).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [89] Shih, 2010, Atypical network connectivity for imitation in autism spectrum disorder, Neuropsychologia source

      Not checked in the free run.

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

    Premisecitation

    Functional hyperconnectivity in clinical populations is increasingly interpreted as reflecting delayed or stunted maturational processes.

    “Functional hyperconnectivity in clinical populations is increasingly interpreted as reflecting delayed or stunted maturational processes.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [67] Castellanos, 2008, Cingulate-precuneus interactions: A new locus of dysfunction in adult attention-deficit/hyperactivity disorder, Biol Psychiatry source

      Not checked in the free run.

    • cites [68] Mizuno, 2006, Partially enhanced thalamocortical functional connectivity in autism, Brain Res source

      Not checked in the free run.

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

    Premisecitation

    Models of autism have posited brainstem abnormalities, based on early ontogeny of brainstem development and evidence of increased prevalence of putative ASD cases associated with early exposure to teratogens affecting brainstem development.

    “Noting the early ontogeny of brainstem development and evidence of increased prevalence of putative ASD cases associated with early exposure to teratogens affecting brainstem development (95), models of autism have posited brainstem abnormalities (66).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [95] Russo, 2008, Deficient brainstem encoding of pitch in children with autism spectrum disorders, Clin Neurophysiol source

      Not checked in the free run.

    • cites [66] Church, 2009, Control networks in paediatric Tourette syndrome show immature and anomalous patterns of functional connectivity, Brain source

      Not checked in the free run.

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

    Premisecitation

    Recent work suggests that AI function may be more directly related to alexithymia, a phenomenon associated with, but distinct from, impaired empathy.

    “recent work suggests that AI function may be more directly related to alexithymia, a phenomenon that is associated with, but distinct from, impaired empathy (77;78).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [77] Craig, 2003, Interoception: The sense of the physiological condition of the body, Curr Opin Neurobiol source

      Not checked in the free run.

    • cites [78] 2000

      Not checked in the free run.

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

    Premisecitation

    The anterior insula is implicated in empathy, task-control, and in the ability to integrate visceral, autonomic processes to guide behavior.

    “the anterior insula (AI) which is implicated in empathy (72), task-control (73), and more broadly, in the ability to integrate visceral, autonomic processes to guide behavior (74-76).”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [72] Craig, 2009, How do you feel—now?, Nat Rev Neurosci source

      Not checked in the free run.

    • cites [73] Seeley, 2007, Dissociable intrinsic connectivity networks for salience processing and executive control, J Neurosci source

      Not checked in the free run.

    • cites [74] Kurth, 2010, A link between the systems: Functional differentiation and integration within the human insula revealed by meta-analysis, Brain Struct Funct source

      Not checked in the free run.

    • cites [75] Bird, 2010, Empathic brain responses in insula are modulated by levels of alexithymia but not autism, Brain source

      Not checked in the free run.

    • cites [76] Silani, 2008, Levels of emotional awareness and autism: An fMRI study, Soc Neurosci source

      Not checked in the free run.

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

    Premisecitation

    A meta-analysis of 1768 task-based functional imaging studies found that insular cortex is heterogeneous and comprises four functionally distinct areas.

    “A meta-analysis of 1768 task-based functional imaging studies highlighted the heterogeneity of insular cortex and identified four functionally distinct areas (76).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [76] Silani, 2008, Levels of emotional awareness and autism: An fMRI study, Soc Neurosci source

      Not checked in the free run.

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

    Study design and conductown data

    Incomplete coverage of the cerebellum in some participants prevented full analyses of striatal-cerebellar functional interactions.

    “Incomplete coverage of the cerebellum in some participants prevented full analyses of striatal-cerebellar functional interactions.”
    Quote in the paperNot a substantial claim
50 of 50

  • The paper relies on this without support.

    Resting-state fMRI functional connectivity provides a valid measure of functional brain connectivity.

    “For each subject, we derived whole-brain voxel-wise correlations associated with the mean time-series for each of the 12 seeds (six per hemisphere) using 3dfim+ (AFNI).”

  • The paper relies on this without support.

    Cross-sectional differences between children and adults reflect developmental maturational changes.

    “Thirty-five adults (mean age: 28.4±8.5 years) described in our previous study (42) were included for secondary analyses of striatal age-related changes.”

  • The paper relies on this without support.

    The 20 children with ASD and 20 TDC are representative of children with ASD and typically developing children, respectively.

    “Twenty TDC selected from a larger pool of children participating in ongoing studies were group-matched for age, sex, estimated IQ, and handedness.”

  • The paper relies on this without support.

    Brainstem dysfunction has been rarely considered in imaging studies of ASD.

    “Despite these convergent lines of evidence, brainstem dysfunction has been rarely considered in imaging studies of ASD.”

  • The paper relies on this without support.

    The ventral striatum (VSi) plays a role in reward mechanisms.

    “Given the role of the VSi in reward mechanisms, abnormal FC between these regions may underlie the hypothesized deficiency of social rewards in ASD (93).”
5 of 5

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?

  • Several recent imaging studies on resting-state functional connectivity and DTI confirm disruptive neural activation dynamics in ASD within the vmPFC-VS-amygdala circuitry.

    “In fact, several recent imaging studies on resting-state functional connectivity and DTI confirm disruptive neural activation dynamics in ASD within the vmPFC–VS–amygdala circuitry [78-81].”

    From Social “wanting” dysfunction in autism: neurobiological underpinnings and treatment implications (2012) · cites this paper as [79]

Statistics recomputed

Every reported test result, recomputed from its test statistic and degrees of freedom. A result shows as not adding up only once an independent check has confirmed it.

  • Consistentr(13) = 0.69reported p = .005 · recomputed p = .004

    “r(13)=0.69, p = .005”

  • Consistentr(13) = -0.64reported p = .011 · recomputed p = .010

    “r(13)= -0.64, p = .011”

2 of 2

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.

  • Left VSi finding reverses the stated direction of group difference

    Major

    The paragraph says that children with ASD had significantly increased FC in areas negatively connected in TDC. Its specific example instead reports positive left VSi-supramarginal gyrus FC in TDC and negative FC in ASD-the opposite direction.

1 of 1

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Related

Authors
Di Martino, A., Kelly, C., Grzadzinski, R., Zuo, X.-N., Mennes, M., Mairena, M. A., Lord, C., Castellanos, F. X., & Milham, M. P.
Affiliations
  • NYU Langone Health (US)
  • Chinese Academy of Sciences (CN)
  • University of Michigan (US)
  • Nathan Kline Institute for Psychiatric Research (US)
ORCID
Venue
Biological Psychiatry
Publisher
Elsevier BV
Published
2011-05
Volume
69
Issue
9
Pages
847-856
ISSN
0006-3223 (ISSN-L)
DOI
10.1016/j.biopsych.2010.10.029
PMC
PMC3091619
OpenAlex
W2076683771
Semantic Scholar
28fc058221872486311ea70dad98cc53b6d5ad08
Cited by
483
References
100
Citations by year
2026: 20 · 2025: 19 · 2024: 28 · 2023: 25 · 2022: 20 · 2021: 40 · 2020: 48 · 2019: 33 · 2018: 34 · 2017: 31 · 2016: 32 · 2015: 50 · 2014: 27 · 2013: 42 · 2012: 27
FWCI
16.72
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Biological Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Institutional Repository of Institute of Psychology, Chinese Academy of Sciences (Institute of Psychology, Chinese Academy of Sciences) (submittedVersion)
  • UNICA IRIS Institutional Research Information System (University of Cagliari) (submittedVersion)
Funders
  • National Alliance for Research on Schizophrenia and Depression
  • National Institute of Mental Health (K23MH087770)
  • National Institute of Child Health and Human Development (R01HD065282)
  • Autism Speaks
  • Stavros Niarchos Foundation
  • Alicia Koplowitz Foundation
  • Leon Levy Foundation
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Functional Brain Connectivity Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Keywords
autism spectrum disorder, striatum, functional connectivity, children, caudate nucleus, putamen, insula, passive optical networks, brainstem, resting-state functional connectivity
MeSH terms
Adolescent, Autistic Disorder, Brain Mapping, Cerebral Cortex, Child, Corpus Striatum, Female, Humans, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Male, Nerve Net, Neural Pathways

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 2026-10-10.

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

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.

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