Archival Report| Volume 8, ISSUE 3, P311-319, March 2023

Aberrant Neural Response During Face Processing in Girls With Fragile X Syndrome: Defining Potential Brain Biomarkers for Treatment Studies

Published:September 20, 2021DOI:



      Children and adolescents with fragile X syndrome (FXS) manifest significant symptoms of anxiety, particularly in response to face-to-face social interaction. In this study, we used functional near-infrared spectroscopy to reveal a specific pattern of brain activation and habituation in response to face stimuli in young girls with FXS, an important but understudied clinical population.


      Participants were 32 girls with FXS (age: 11.8 ± 2.9 years) and a control group of 28 girls without FXS (age: 10.5 ± 2.3 years) matched for age, general cognitive function, and autism symptoms. Functional near-infrared spectroscopy was used to assess brain activation during a face habituation task including repeated upright/inverted faces and greeble (nonface) objects.


      Compared with the control group, girls with FXS showed significant hyperactivation in the frontopolar and dorsal lateral prefrontal cortices in response to all face stimuli (upright + inverted). Lack of neural habituation (and significant sensitization) was also observed in the FXS group in the frontopolar cortex in response to upright face stimuli. Finally, aberrant frontopolar sensitization in response to upright faces in girls with FXS was significantly correlated with notable cognitive-behavioral and social-emotional outcomes relevant to this condition, including executive function, autism symptoms, depression, and anxiety.


      These findings strongly support a hypothesis of neural hyperactivation and accentuated sensitization during face processing in FXS, a phenomenon that could be developed as a biomarker end point for improving treatment trial evaluation in girls with this condition.


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        • Hagerman R.
        • Hoem G.
        • Hagerman P.
        Fragile X and autism: Intertwined at the molecular level leading to targeted treatments.
        Mol Autism. 2010; 1: 12
        • Crawford D.C.
        • Acuña J.M.
        • Sherman S.L.
        FMR1 and the fragile X syndrome: Human genome epidemiology review.
        Genet Med. 2001; 3: 359-371
        • Garrett A.S.
        • Menon V.
        • MacKenzie K.
        • Reiss A.L.
        Here’s looking at you, kid: Neural systems underlying face and gaze processing in fragile X syndrome.
        Arch Gen Psychiatry. 2004; 61: 281-288
        • Bartholomay K.L.
        • Lee C.H.
        • Bruno J.L.
        • Lightbody A.A.
        • Reiss A.L.
        Closing the gender gap in fragile X syndrome: Review on females with FXS and preliminary research findings.
        Brain Sci. 2019; 9: 11
        • Hartley S.L.
        • Seltzer M.M.
        • Raspa M.
        • Olmstead M.
        • Bishop E.
        • Bailey D.B.
        Exploring the adult life of men and women with fragile X syndrome: Results from a national survey.
        Am J Intellect Dev Disabil. 2011; 116: 16-35
        • Lachiewicz A.M.
        Abnormal behaviors of young girls with fragile X syndrome.
        Am J Med Genet. 1992; 43: 72-77
        • Watson C.
        • Hoeft F.
        • Garrett A.S.
        • Hall S.S.
        • Reiss A.L.
        Aberrant brain activation during gaze processing in boys with fragile X syndrome.
        Arch Gen Psychiatry. 2008; 65: 1315-1323
        • Hoeft F.
        • Carter J.C.
        • Lightbody A.A.
        • Cody Hazlett H.
        • Piven J.
        • Reiss A.L.
        Region-specific alterations in brain development in one- to three-year-old boys with fragile X syndrome.
        Proc Natl Acad Sci U S A. 2010; 107: 9335-9339
        • Bruno J.L.
        • Garrett A.S.
        • Quintin E.M.
        • Mazaika P.K.
        • Reiss A.L.
        Aberrant face and gaze habituation in fragile X syndrome.
        Am J Psychiatry. 2014; 171: 1099-1106
        • Cui X.
        • Bray S.
        • Bryant D.M.
        • Glover G.H.
        • Reiss A.L.
        A quantitative comparison of NIRS and fMRI across multiple cognitive tasks.
        Neuroimage. 2011; 54: 2808-2821
        • Li R.
        • Potter T.
        • Wang J.
        • Shi Z.
        • Wang C.
        • Yang L.
        • et al.
        Cortical hemodynamic response and connectivity modulated by sub-threshold high-frequency repetitive transcranial magnetic stimulation.
        Front Hum Neurosci. 2019; 13: 90
        • Li R.
        • Rui G.
        • Chen W.
        • Li S.
        • Schulz P.E.
        • Zhang Y.
        Early detection of Alzheimer’s disease using non-invasive near-infrared spectroscopy.
        Front Aging Neurosci. 2018; 10: 366
        • Li R.
        • Nguyen T.
        • Potter T.
        • Zhang Y.
        Dynamic cortical connectivity alterations associated with Alzheimer’s disease: An EEG and fNIRS integration study.
        Neuroimage Clin. 2019; 21: 101622
        • Li R.
        • Rui G.
        • Zhao C.
        • Wang C.
        • Fang F.
        • Zhang Y.
        Functional network alterations in patients with amnestic mild cognitive impairment characterized using functional near-infrared spectroscopy.
        IEEE Trans Neural Syst Rehabil Eng. 2020; 28: 123-132
        • Li Y.
        • Yu D.
        Variations of the functional brain network efficiency in a young clinical sample within the autism spectrum: A fNIRS investigation.
        Front Physiol. 2018; 9: 67
        • Li R.
        • Potter T.
        • Huang W.
        • Zhang Y.
        Enhancing performance of a hybrid EEG-fNIRS system using channel selection and early temporal features.
        Front Hum Neurosci. 2017; 11: 462
        • Mayseless N.
        • Hawthorne G.
        • Reiss A.L.
        Real-life creative problem solving in teams: fNIRS based hyperscanning study.
        Neuroimage. 2019; 203: 116161
        • Elliott C.D.
        • Salerno J.D.
        • Dumont R.
        • Willis J.O.
        Differential Ability Scales.
        2nd ed. The Psychological Corporation, San Antonio2007
        • Gioia G.A.
        • Isquith P.K.
        • Guy S.C.
        • Kenworthy L.
        BRIEF-2: Behavior Rating Inventory of Executive Function.
        Lutz: Psychological Assessment Resources, 2015
        • Constantino J.N.
        • Gruber C.P.
        Social Responsiveness Scale: SRS-2.
        2nd ed. Western Psychological Services, Los Angeles2012
        • Esbensen A.J.
        • Rojahn J.
        • Aman M.G.
        • Ruedrich S.
        Reliability and validity of an assessment instrument for anxiety, depression, and mood among individuals with mental retardation.
        J Autism Dev Disord. 2003; 33: 617-629
        • Achenbach T.M.
        • Rescorla L.
        Manual for the ASEBA School-Age Forms & Profiles: An Integrated System of Multi-Informant Assessment.
        ASEBA, Burlington2001: 238
        • Wig G.S.
        • Grafton S.T.
        • Demos K.E.
        • Kelley W.M.
        Reductions in neural activity underlie behavioral components of repetition priming.
        Nat Neurosci. 2005; 8: 1228-1233
        • Burgess P.W.
        • Dumontheil I.
        • Gilbert S.J.
        The gateway hypothesis of rostral prefrontal cortex (area 10) function.
        Trends Cogn Sci. 2007; 11: 290-298
        • Gilbert S.J.
        • Gonen-Yaacovi G.
        • Benoit R.G.
        • Volle E.
        • Burgess P.W.
        Distinct functional connectivity associated with lateral versus medial rostral prefrontal cortex: A meta-analysis.
        Neuroimage. 2010; 53: 1359-1367
        • Heekeren H.R.
        • Marrett S.
        • Ruff D.A.
        • Bandettini P.A.
        • Ungerleider L.G.
        Involvement of human left dorsolateral prefrontal cortex in perceptual decision making is independent of response modality.
        Proc Natl Acad Sci U S A. 2006; 103: 10023-10028
        • Eippert F.
        • Veit R.
        • Weiskopf N.
        • Erb M.
        • Birbaumer N.
        • Anders S.
        Regulation of emotional responses elicited by threat-related stimuli.
        Hum Brain Mapp. 2007; 28: 409-423
        • MacDonald 3rd, A.W.
        • Cohen J.D.
        • Stenger V.A.
        • Carter C.S.
        Dissociating the role of the dorsolateral prefrontal and anterior cingulate cortex in cognitive control.
        Science. 2000; 288: 1835-1838
        • Lee Y.
        • Kim C.
        The role of frontopolar cortex in the individual differences in conflict adaptation.
        Neurosci Lett. 2019; 705: 212-218
        • Gauthier I.
        • Behrmann M.
        • Tarr M.J.
        Are greebles like faces? Using the neuropsychological exception to test the rule.
        Neuropsychologia. 2004; 42: 1961-1970
        • Scherf K.S.
        • Behrmann M.
        • Minshew N.
        • Luna B.
        Atypical development of face and greeble recognition in autism.
        J Child Psychol Psychiatry. 2008; 49: 838-847
        • McPartland J.C.
        • Webb S.J.
        • Keehn B.
        • Dawson G.
        Patterns of visual attention to faces and objects in autism spectrum disorder.
        J Autism Dev Disord. 2011; 41: 148-157
        • Berry-Kravis E.
        • Des Portes V.
        • Hagerman R.
        • Jacquemont S.
        • Charles P.
        • Visootsak J.
        • et al.
        Mavoglurant in fragile X syndrome: Results of two randomized, double-blind, placebo-controlled trials.
        Sci Transl Med. 2016; 8: 321ra5
        • Youssef E.A.
        • Berry-Kravis E.
        • Czech C.
        • Hagerman R.J.
        • Hessl D.
        • Wong C.Y.
        • et al.
        Effect of the mGluR5-NAM basimglurant on behavior in adolescents and adults with fragile X syndrome in a randomized, double-blind, placebo-controlled trial: FragXis phase 2 results.
        Neuropsychopharmacology. 2018; 43: 503-512
        • Budimirovic D.B.
        • Berry-Kravis E.
        • Erickson C.A.
        • Hall S.S.
        • Hessl D.
        • Reiss A.L.
        • et al.
        Updated report on tools to measure outcomes of clinical trials in fragile X syndrome.
        J Neurodev Disord. 2017; 9: 14
        • Berry-Kravis E.M.
        • Harnett M.D.
        • Reines S.A.
        • Reese M.A.
        • Ethridge L.E.
        • Outterson A.H.
        • et al.
        Inhibition of phosphodiesterase-4D in adults with fragile X syndrome: A randomized, placebo-controlled, phase 2 clinical trial.
        Nat Med. 2021; 27: 862-870
        • Duy P.Q.
        • Budimirovic D.B.
        Fragile X syndrome: Lessons learned from the most translated neurodevelopmental disorder in clinical trials.
        Transl Neurosci. 2017; 8: 7-8
        • Bruno J.L.
        • Hosseini S.H.
        • Lightbody A.A.
        • Manchanda M.K.
        • Reiss A.L.
        Brain circuitry, behavior, and cognition: A randomized placebo-controlled trial of donepezil in fragile X syndrome.
        J Psychopharmacol. 2019; 33: 975-985
        • Mazzocco M.M.
        • Sonna N.L.
        • Teisl J.T.
        • Pinit A.
        • Shapiro B.K.
        • Shah N.
        • Reiss A.L.
        The FMR1 and FMR2 mutations are not common etiologies of academic difficulty among school-age children.
        J Dev Behav Pediatr. 1997; 18: 392-398