Autism spectrum disorder (ASD) is exceptionally heterogeneous in both clinical and physiopathological presentations. Clinical variability applies to ASD-specific symptoms and frequent comorbid psychopathology such as emotional lability (EL). To date, the physiopathological underpinnings of the co-occurrence of EL and ASD are unknown. As a first step, we examined within-ASD inter-individual variability of EL and its neuronal correlates using resting-state functional magnetic resonance imaging (R-fMRI). We analyzed R-fMRI data from 58 children diagnosed with ASD (5–12 years) in relation to the Conners' Parent Rating Scale EL index. We performed both an a priori amygdala region-of-interest (ROI) analysis, and a multivariate unbiased whole-brain data-driven approach. While no significant brain-behavior relationships were identified regarding amygdala intrinsic functional connectivity (iFC), multivariate whole-brain analyses revealed an extended functional circuitry centered on two regions: middle frontal gyrus (MFG) and posterior insula (PI). Follow-up parametric and nonparametric ROI-analyses of these regions revealed relationships between EL and MFG- and PI-iFC with default, salience, and visual networks suggesting that higher-order cognitive and somatosensory processes are critical for emotion regulation in ASD. We did not detect evidence of amygdala iFC underpinning EL in ASD. However, exploratory whole-brain analyses identified large-scale networks that have been previously reported abnormal in ASD. Future studies should consider EL as a potential source of neuronal heterogeneity in ASD and focus on multinetwork interactions.
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References
1.
AbramSV, WisnerKM, GraziopleneRG, KruegerRF, MacDonaldAW, DeYoungCG. 2015. Functional coherence of insula networks is associated with externalizing behavior. J Abnorm Psychol, 124:1079–1091.
2.
AdinoffB, DevousMDSr., BestSE, ChandlerP, AlexanderD, PayneK, et al.2003. Gender differences in limbic responsiveness, by SPECT, following a pharmacologic challenge in healthy subjects. Neuroimage, 18:697–706.
3.
AdolphsR, TranelD, HamannS, YoungAW, CalderAJ, PhelpsEA, et al.1999. Recognition of facial emotion in nine individuals with bilateral amygdala damage. Neuropsychologia, 37:1111–1117.
4.
AhmedSP, Bittencourt-HewittA, SebastianCL. 2015. Neurocognitive bases of emotion regulation development in adolescence. Dev Cogn Neurosci, 15:11–25.
5.
AokiY, CorteseS, TansellaM. 2015. Neural bases of atypical emotional face processing in autism: a meta-analysis of fMRI studies. World J Biol Psychiatry, 16:291–300.
6.
AvantsBB, TustisonNJ, SongG, CookPA, KleinA, GeeJC. 2011. A reproducible evaluation of ANTs similarity metric performance in brain image registration. Neuroimage, 54:2033–2044.
7.
BachevalierJ, LovelandKA. 2006. The orbitofrontal-amygdala circuit and self-regulation of social-emotional behavior in autism. Neurosci Biobehav Rev, 30:97–117.
8.
BehzadiY, RestomK, LiauJ, LiuTT. 2007. A component based noise correction method (CompCor) for BOLD and perfusion based fMRI. Neuroimage, 37:90–101.
9.
BetancurC. 2011. Etiological heterogeneity in autism spectrum disorders: more than 100 genetic and genomic disorders and still counting. Brain Res, 1380:42–77.
10.
BrotmanMA, RichBA, GuyerAE, LunsfordJR, HorseySE, ReisingMM, et al.2010. Amygdala activation during emotion processing of neutral faces in children with severe mood dysregulation versus ADHD or bipolar disorder. Am J Psychiatry, 167:61–69.
11.
ChangLJ, YarkoniT, KhawMW, SanfeyAG. 2013. Decoding the role of the insula in human cognition: functional parcellation and large-scale reverse inference. Cereb Cortex, 23:739–749.
12.
ChenCP, KeownCL, JahediA, NairA, PfliegerME, BaileyBA, MullerRA. 2015. Diagnostic classification of intrinsic functional connectivity highlights somatosensory, default mode, and visual regions in autism. Neuroimage Clin, 8:238–245.
13.
ColePM, MartinSE, DennisTA. 2004. Emotion regulation as a scientific construct: methodological challenges and directions for child development research. Child Dev, 75:317–333.
ConstantinoJN, ToddRD. 2003. Autistic traits in the general population: a twin study. Arch Gen Psychiatry, 60:524–530.
16.
CraigAD. 2009. How do you feel—now? The anterior insula and human awareness. Nat Rev Neurosci, 10:59–70.
17.
DaltonKM, NacewiczBM, JohnstoneT, SchaeferHS, GernsbacherMA, GoldsmithHH, et al.2005. Gaze fixation and the neural circuitry of face processing in autism. Nat Neurosci, 8:519–526.
18.
DepueBE, OrrJM, SmolkerHR, NaazF, BanichMT. 2016. The organization of right prefrontal networks reveals common mechanisms of inhibitory regulation across cognitive, emotional, and motor processes. Cereb Cortex, 26:1634–1646.
19.
Di MartinoA, YanCG, LiQ, DenioE, CastellanosFX, AlaertsK, et al.2014. The autism brain imaging data exchange: towards a large-scale evaluation of the intrinsic brain architecture in autism. Mol Psychiatry, 19:659–667.
20.
EbischSJ, GalleseV, WillemsRM, MantiniD, GroenWB, RomaniGL, et al.2011. Altered intrinsic functional connectivity of anterior and posterior insula regions in high-functioning participants with autism spectrum disorder. Hum Brain Mapp, 32:1013–1028.
21.
EklundA, NicholsTE, KnutssonH. 2016. Cluster failure: why fMRI inferences for spatial extent have inflated false-positive rates. Proc Natl Acad Sci U S A, 113:7900–7905.
GeeDG, HumphreysKL, FlanneryJ, GoffB, TelzerEH, ShapiroM, et al.2013. A developmental shift from positive to negative connectivity in human amygdala-prefrontal circuitry. J Neurosci, 33:4584–4593.
GrecucciA, GiorgettaC, BoniniN, SanfeyAG. 2013. Reappraising social emotions: the role of inferior frontal gyrus, temporo-parietal junction and insula in interpersonal emotion regulation. Front Hum Neurosci, 7:523.
28.
GreenSA, RudieJD, ColichNL, WoodJJ, ShirinyanD, HernandezL, et al.2013. Overreactive brain responses to sensory stimuli in youth with autism spectrum disorders. J Am Acad Child Adolesc Psychiatry, 52:1158–1172.
29.
GrzadzinskiR, HuertaM, LordC. 2013. DSM-5 and autism spectrum disorders (ASDs): an opportunity for identifying ASD subtypes. Mol Autism, 4:12.
30.
HuertaM, BishopSL, DuncanA, HusV, LordC. 2012. Application of DSM-5 criteria for autism spectrum disorder to three samples of children with DSM-IV diagnoses of pervasive developmental disorders. Am J Psychiatry, 169:1056–1064.
31.
HulvershornLA, MennesM, CastellanosFX, Di MartinoA, MilhamMP, HummerTA, RoyAK. 2014. Abnormal amygdala functional connectivity associated with emotional lability in children with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry, 53:351–361.e351.
32.
JenkinsonM, BannisterP, BradyM, SmithS. 2002. Improved optimization for the robust and accurate linear registration and motion correction of brain images. Neuroimage, 17:825–841.
33.
JiangYV, CapistranoCG, PalmBE. 2014. Spatial working memory in children with high-functioning autism: intact configural processing but impaired capacity. J Abnorm Psychol, 123:248–257.
34.
KaufmanJ, BirmaherB, BrentD, RaoU, FlynnC, MoreciP, et al.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, 36:980–988.
35.
KellyC, BiswalBB, CraddockRC, CastellanosFX, MilhamMP. 2012. Characterizing variation in the functional connectome: promise and pitfalls. Trends Cogn Sci, 16:181–188.
36.
KoppCB. 2009. Emotion-focused coping in young children: self and self-regulatory processes. New Dir Child Adolesc Dev, 2009:33–46.
LecavalierL. 2006. Behavioral and emotional problems in young people with pervasive developmental disorders: relative prevalence, effects of subject characteristics, and empirical classification. J Autism Dev Disord, 36:1101–1114.
39.
LeDouxJE. 1996. The Emotional Brain: The Mysterious Underpinnings of Emotional Life. New York, NY: Simon & Schuster.
40.
LeibenluftE. 2011. Severe mood dysregulation, irritability, and the diagnostic boundaries of bipolar disorder in youths. Am J Psychiatry, 168:129–142.
41.
LewisJD, EvansAC, PruettJR, BotteronK, ZwaigenbaumL, EstesA, et al.2014. Network inefficiencies in autism spectrum disorder at 24 months. Transl Psychiatry, 4:e388.
42.
LordC, RisiS, LambrechtL, CookEHJr., LeventhalBL, DiLavorePC, et al.2000. The autism diagnostic observation schedule-generic: a standard measure of social and communication deficits associated with the spectrum of autism. J Autism Dev Disord, 30:205–223.
43.
LordC, RutterM, Le CouteurA. 1994. Autism Diagnostic Interview-Revised: a revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders. J Autism Dev Disord, 24:659–685.
44.
MazefskyCA, HerringtonJ, SiegelM, ScarpaA, MaddoxBB, ScahillL, WhiteSW. 2013. The role of emotion regulation in autism spectrum disorder. J Am Acad Child Adolesc Psychiatry, 52:679–688.
45.
McRaeK, GrossJJ, WeberJ, RobertsonER, Sokol-HessnerP, RayRD, et al. KN. 2012. The development of emotion regulation: an fMRI study of cognitive reappraisal in children, adolescents and young adults. Soc Cogn Affect Neurosci, 7:11–22.
46.
MenonV, UddinLQ. 2010. Saliency, switching, attention and control: a network model of insula function. Brain Struct Funct, 214:655–667.
47.
MinshewNJ, KellerTA. 2010. The nature of brain dysfunction in autism: functional brain imaging studies. Curr Opin Neurol, 23:124–130.
48.
MinshewNJ, WilliamsDL. 2007. The new neurobiology of autism: cortex, connectivity, and neuronal organization. Arch Neurol, 64:945–950.
49.
MonkCS, WengSJ, WigginsJL, KurapatiN, LouroHM, CarrascoM, et al.2010. Neural circuitry of emotional face processing in autism spectrum disorders. J Psychiatry Neurosci, 35:105–114.
50.
MosconiMW, Cody-HazlettH, PoeMD, GerigG, Gimpel-SmithR, PivenJ. 2009. Longitudinal study of amygdala volume and joint attention in 2- to 4-year-old children with autism. Arch Gen Psychiatry, 66:509–516.
51.
MoseleyRL, ShtyrovY, MohrB, LombardoMV, Baron-CohenS, PulvermullerF. 2015. Lost for emotion words: what motor and limbic brain activity reveals about autism and semantic theory. Neuroimage, 104:413–422.
52.
NebelMB, EloyanA, NettlesCA, SweeneyKL, AmentK, WardRE, et al.2016. Intrinsic visual-motor synchrony correlates with social deficits in autism. Biol Psychiatry, 79:633–641.
53.
NguyenVT, BreakspearM, HuX, GuoCC. 2016. The integration of the internal and external milieu in the insula during dynamic emotional experiences. Neuroimage, 124(Pt A):455–463.
54.
NordahlCW, LangeN, LiDD, BarnettLA, LeeA, BuonocoreMH, et al.2011. Brain enlargement is associated with regression in preschool-age boys with autism spectrum disorders. Proc Natl Acad Sci U S A, 108:20195–20200.
55.
PelphreyKA, ShultzS, HudacCM, Vander WykBC. 2011. Research review: constraining heterogeneity: the social brain and its development in autism spectrum disorder. J Child Psychol Psychiatry, 52:631–644.
56.
PerlmanSB, JonesBM, WakschlagLS, AxelsonD, BirmaherB, PhillipsML. 2015. Neural substrates of child irritability in typically developing and psychiatric populations. Dev Cogn Neurosci, 14:71–80.
57.
PitskelNB, BollingDZ, KaiserMD, PelphreyKA, CrowleyMJ. 2014. Neural systems for cognitive reappraisal in children and adolescents with autism spectrum disorder. Dev Cogn Neurosci, 10:117–128.
58.
PosnerJ, KassE, HulvershornL. 2014. Using stimulants to treat ADHD-related emotional lability. Curr Psychiatry Rep, 16:478.
59.
PosnerJ, RauhV, GruberA, GatI, WangZ, PetersonBS. 2013. Dissociable attentional and affective circuits in medication-naive children with attention-deficit/hyperactivity disorder. Psychiatry Res, 213:24–30.
60.
RicheyJA, DamianoCR, SabatinoA, RittenbergA, PettyC, BizzellJ, et al.2015. Neural mechanisms of emotion regulation in autism spectrum disorder. J Autism Dev Disord, 45:3409–3423.
61.
RoyAK, KleinRG, AngelosanteA, Bar-HaimY, LeibenluftE, HulvershornL, et al.2013. Clinical features of young children referred for impairing temper outbursts. J Child Adolesc Psychopharmacol, 23:588–596.
62.
SeeleyWW, MenonV, SchatzbergAF, KellerJ, GloverGH, KennaH, et al.2007. Dissociable intrinsic connectivity networks for salience processing and executive control. J Neurosci, 27:2349–2356.
63.
ShawP, StringarisA, NiggJ, LeibenluftE. 2014. Emotion dysregulation in attention deficit hyperactivity disorder. Am J Psychiatry, 171:276–293.
64.
ShehzadZ, KellyC, ReissPT, Cameron CraddockR, EmersonJW, McMahonK, et al.2014. A multivariate distance-based analytic framework for connectome-wide association studies. Neuroimage, 93Pt 1:74–94.
65.
ShenMD, LiDD, KeownCL, LeeA, JohnsonRT, AngkustsiriK, RogersSJ, et al.2016. Functional connectivity of the amygdala is disrupted in preschool-aged children with autism spectrum disorder. J Am Acad Child Adolesc Psychiatry, 55:817–824.
66.
SimonoffE, JonesCR, PicklesA, HappeF, BairdG, CharmanT. 2012. Severe mood problems in adolescents with autism spectrum disorder. J Child Psychol Psychiatry, 53:1157–1166.
67.
SylvesterCY, WagerTD, LaceySC, HernandezL, NicholsTE, SmithEE, JonidesJ. 2003. Switching attention and resolving interference: fMRI measures of executive functions. Neuropsychologia, 41:357–370.
68.
UddinLQ, SupekarK, LynchCJ, KhouzamA, PhillipsJ, FeinsteinC, et al.2013. Salience network-based classification and prediction of symptom severity in children with autism. JAMA Psychiatry, 70:869–879.
69.
VissersME, CohenMX, GeurtsHM. 2012. Brain connectivity and high functioning autism: a promising path of research that needs refined models, methodological convergence, and stronger behavioral links. Neurosci Biobehav Rev, 36:604–625.
70.
von dem HagenEA, StoyanovaRS, RoweJB, Baron-CohenS, CalderAJ. 2014. Direct gaze elicits atypical activation of the theory-of-mind network in autism spectrum conditions. Cereb Cortex, 24:1485–1492.
71.
WickerB, FonluptP, HubertB, TardifC, GepnerB, DeruelleC. 2008. Abnormal cerebral effective connectivity during explicit emotional processing in adults with autism spectrum disorder. Soc Cogn Affect Neurosci, 3:135–143.
72.
WilenskyAE, SchafeGE, KristensenMP, LeDouxJE. 2006. Rethinking the fear circuit: the central nucleus of the amygdala is required for the acquisition, consolidation, and expression of Pavlovian fear conditioning. J Neurosci, 26:12387–12396.
73.
WinklerAM, RidgwayGR, WebsterMA, SmithSM, NicholsTE. 2014. Permutation inference for the general linear model. Neuroimage, 92:381–397.
74.
YeoBT, KrienenFM, SepulcreJ, SabuncuMR, LashkariD, HollinsheadM, et al.2011. The organization of the human cerebral cortex estimated by intrinsic functional connectivity. J Neurophysiol, 106:1125–1165.
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