Intrinsic excitation-inhibition imbalance affects medial prefrontal cortex differently in autistic men versus women

Abstract

Excitation-inhibition (E:I) imbalance is theorized as an important pathophysiological mechanism in autism. Autism affects males more frequently than females and sex-related mechanisms (e.g., X-linked genes, androgen hormones) can influence E:I balance. This suggests that E:I imbalance may affect autism differently in males versus females. With a combination of in-silico modeling and in-vivo chemogenetic manipulations in mice, we first show that a time-series metric estimated from fMRI BOLD signal, the Hurst exponent (H), can be an index for underlying change in the synaptic E:I ratio. In autism we find that H is reduced, indicating increased excitation, in the medial prefrontal cortex (MPFC) of autistic males but not females. Increasingly intact MPFC H is also associated with heightened ability to behaviorally camouflage social-communicative difficulties, but only in autistic females. This work suggests that H in BOLD can index synaptic E:I ratio and that E:I imbalance affects autistic males and females differently.

References 113

1. 1.

   Alcauter S, Lin W, Smith JK, Goldman BD, Reznick JS, Gilmore JH, Gao W. Frequency of spontaneous BOLD signal shifts during infancy and correlates with cognitive performance. Developmental Cognitive Neuroscience. 2015;12:40-50.

   Not in our library10.1016/j.dcn.2014.10.004

2. 2.

   Alexander GM, Rogan SC, Abbas AI, Armbruster BN, Pei Y, Allen JA, Nonneman RJ, Hartmann J, Moy SS, Nicolelis MA, McNamara JO, Roth BL. Remote control of neuronal activity in transgenic mice expressing evolved G protein-coupled receptors. Neuron. 2009;63:27-39.

   Not in our library10.1016/j.neuron.2009.06.014

3. 3.

   Allen EA, Erhardt EB, Damaraju E, Gruner W, Segall JM, Silva RF, Havlicek M, Rachakonda S, Fries J, Kalyanam R, Michael AM, Caprihan A, Turner JA, Eichele T, Adelsheim S, Bryan AD, Bustillo J, Clark VP, Feldstein Ewing SW, Filbey F, Ford CC, Hutchison K, Jung RE, Kiehl KA, Kodituwakku P, Komesu YM, Mayer AR, Pearlson GD, Phillips JP, Sadek JR, Stevens M, Teuscher U, Thoma RJ, Calhoun VD. A baseline for the multivariate comparison of resting-state networks. Frontiers in Systems Neuroscience. 2011;5:2.

   Not in our library10.3389/fnsys.2011.00002

4. 4.

   Balsters JH, Zerbi V, Sallet J, Wenderoth N, Mars RB. Primate homologs of mouse cortico-striatal circuits. eLife. 2020;9:e53680.

   Not in our library10.7554/elife.53680

5. 5.

   Barbieri F, Mazzoni A, Logothetis NK, Panzeri S, Brunel N. Stimulus dependence of local field potential spectra: experiment versus theory. Journal of Neuroscience. 2014;34:14589-14605.

   Not in our library10.1523/jneurosci.5365-13.2014

6. 6.
   The Experiences of Late-diagnosed Women with Autism Spectrum Conditions: An Investigation of the Female Autism Phenotype · 2016

   No notice
7. 7.

   Baron-Cohen S, Wheelwright S, Skinner R, Martin J, Clubley E. The autism-spectrum quotient (AQ): evidence from asperger syndrome/high-functioning autism, males and females, scientists and mathematicians. Journal of Autism and Developmental Disorders. 2001a;31:5-17.

   Not in our library10.1023/a:1005653411471

8. 8.

   Baron-Cohen S, Wheelwright S, Hill J, Raste Y, Plumb I. The "Reading the Mind in the Eyes" Test revised version: a study with normal adults, and adults with Asperger syndrome or high-functioning autism. Journal of Child Psychology and Psychiatry. 2001b;42:241-251.

   Not in our library10.1111/1469-7610.00715

9. 9.

   Bédard C, Kröger H, Destexhe A. Does the 1/f frequency scaling of brain signals reflect self-organized critical states? Physical Review Letters. 2006;97:118102.

   Not in our library10.1103/physrevlett.97.118102

10. 10.

    Bedford SA, Park MTM, Devenyi GA, Tullo S, Germann J, Patel R, Anagnostou E, Baron-Cohen S, Bullmore ET, Chura LR, Craig MC, Ecker C, Floris DL, Holt RJ, Lenroot R, Lerch JP, Lombardo MV, Murphy DGM, Raznahan A, Ruigrok ANV, Smith E, Spencer MD, Suckling J, Taylor MJ, Thurm A, Lai MC, Chakravarty MM, MRC AIMS Consortium. Large-scale analyses of the relationship between sex, age and intelligence quotient heterogeneity and cortical morphometry in autism spectrum disorder. Molecular Psychiatry. 2020;25:614-628.

    Not in our library10.1038/s41380-019-0420-6

11. 11.

    Bejerot S, Eriksson JM, Bonde S, Carlström K, Humble MB, Eriksson E. The extreme male brain revisited: gender coherence in adults with autism spectrum disorder. British Journal of Psychiatry. 2012;201:116-123.

    Not in our library10.1192/bjp.bp.111.097899

12. 12.

    Bertero A, Liska A, Pagani M, Parolisi R, Masferrer ME, Gritti M, Pedrazzoli M, Galbusera A, Sarica A, Cerasa A, Buffelli M, Tonini R, Buffo A, Gross C, Pasqualetti M, Gozzi A. Autism-associated 16p11.2 microdeletion impairs prefrontal functional connectivity in mouse and human. Brain. 2018;141:2055-2065.

    Not in our library10.1093/brain/awy111

13. 13.

    Bethlehem RA, Seidlitz J. Normative age modelling of cortical thickness in autistic males. bioRxiv. 2018.

    Not in our library10.1101/252593

14. 14.

    Bozzi Y, Provenzano G, Casarosa S. Neurobiological bases of autism-epilepsy comorbidity: a focus on excitation/inhibition imbalance. European Journal of Neuroscience. 2018;47:534-548.

    Not in our library10.1111/ejn.13595

15. 15.

    Brunel N, Wang XJ. What determines the frequency of fast network oscillations with irregular neural discharges? I. synaptic dynamics and excitation-inhibition balance. Journal of Neurophysiology. 2003;90:415-430.

    Not in our library10.1152/jn.01095.2002

16. 16.

    Buckner RL, DiNicola LM. The brain's default network: updated anatomy, physiology and evolving insights. Nature Reviews Neuroscience. 2019;20:593-608.

    Not in our library10.1038/s41583-019-0212-7

17. 17.

    Bullmore E, Long C, Suckling J, Fadili J, Calvert G, Zelaya F, Carpenter TA, Brammer M. Colored noise and computational inference in neurophysiological (fMRI) time series analysis: resampling methods in time and wavelet domains. Human Brain Mapping. 2001;12:61-78.

    Not in our library10.1002/1097-0193(200102)12:2<61::aid-hbm1004>3.0.co;2-w

18. 18.

    Buss AT, Wifall T, Hazeltine E, Spencer JP. Integrating the behavioral and neural dynamics of response selection in a dual-task paradigm: a dynamic neural field model of dux et al. (2009). Journal of Cognitive Neuroscience. 2014;26:334-351.

    Not in our library10.1162/jocn_a_00496

19. 19.
    Comparison of the dynamics of neural interactions in integrate-and-fire networks with current-based and conductance-based synapses · 2014

    Not checked
20. 20.

    Chantiluke K, Barrett N, Giampietro V, Santosh P, Brammer M, Simmons A, Murphy DG, Rubia K. Inverse fluoxetine effects on inhibitory brain activation in non-comorbid boys with ADHD and with ASD. Psychopharmacology. 2015;232:2071-2082.

    Not in our library10.1007/s00213-014-3837-2

21. 21.

    Coghlan S, Horder J, Inkster B, Mendez MA, Murphy DG, Nutt DJ. GABA system dysfunction in autism and related disorders: from synapse to symptoms. Neuroscience & Biobehavioral Reviews. 2012;36:2044-2055.

    Not in our library10.1016/j.neubiorev.2012.07.005

22. 22.
    The ASD Living Biology: from cell proliferation to clinical phenotype · 2018

    No notice
23. 23.

    Cox RW. AFNI: software for analysis and visualization of functional magnetic resonance neuroimages. Computers and Biomedical Research. 1996;29:162-173.

    Not in our library10.1006/cbmr.1996.0014

24. 24.

    Deco G, Rolls ET, Horwitz B. "What" and "where" in visual working memory: a computational neurodynamical perspective for integrating FMRI and single-neuron data. Journal of Cognitive Neuroscience. 2004;16:683-701.

    Not in our library10.1162/089892904323057380

25. 25.

    Dhamala E, Jamison KW, Sabuncu MR, Kuceyeski A. Sex classification using long-range temporal dependence of resting-state functional MRI time series. Human Brain Mapping. 2020;6:25030.

    Not in our library10.1002/hbm.25030

26. 26.

    Di Martino A, Ross K, Uddin LQ, Sklar AB, Castellanos FX, Milham MP. Functional brain correlates of social and nonsocial processes in autism spectrum disorders: an activation likelihood estimation meta-analysis. Biological Psychiatry. 2009;65:63-74.

    Not in our library10.1016/j.biopsych.2008.09.022

27. 27.

    Di Martino A, Yan CG, Li Q, Denio E, Castellanos FX, Alaerts K, Anderson JS, Assaf M, Bookheimer SY, Dapretto M, Deen B, Delmonte S, Dinstein I, Ertl-Wagner B, Fair DA, Gallagher L, Kennedy DP, Keown CL, Keysers C, Lainhart JE, Lord C, Luna B, Menon V, Minshew NJ, Monk CS, Mueller S, Müller RA, Nebel MB, Nigg JT, O'Hearn K, Pelphrey KA, Peltier SJ, Rudie JD, Sunaert S, Thioux M, Tyszka JM, Uddin LQ, Verhoeven JS, Wenderoth N, Wiggins JL, Mostofsky SH, Milham MP. The autism brain imaging data exchange: towards a large-scale evaluation of the intrinsic brain architecture in autism. Molecular Psychiatry. 2014;19:659-667.

    Not in our library10.1038/mp.2013.78

28. 28.

    Ferenczi EA, Zalocusky KA, Liston C, Grosenick L, Warden MR, Amatya D, Katovich K, Mehta H, Patenaude B, Ramakrishnan C, Kalanithi P, Etkin A, Knutson B, Glover GH, Deisseroth K. Prefrontal cortical regulation of brainwide circuit dynamics and reward-related behavior. Science. 2016;351:aac9698.

    Not in our library10.1126/science.aac9698

29. 29.

    Gao R, Peterson EJ, Voytek B. Inferring synaptic excitation/inhibition balance from field potentials. NeuroImage. 2017;158:70-78.

    Not in our library10.1016/j.neuroimage.2017.06.078

30. 30.

    Glasser MF, Coalson TS, Robinson EC, Hacker CD, Harwell J, Yacoub E, Ugurbil K, Andersson J, Beckmann CF, Jenkinson M, Smith SM, Van Essen DC. A multi-modal parcellation of human cerebral cortex. Nature. 2016;536:171-178.

    Not in our library10.1038/nature18933

31. 31.

    Goense JB, Logothetis NK. Neurophysiology of the BOLD fMRI signal in awake monkeys. Current Biology. 2008;18:631-640.

    Not in our library10.1016/j.cub.2008.03.054

32. 32.

    Gozzi A, Ceolin L, Schwarz A, Reese T, Bertani S, Crestan V, Bifone A. A multimodality investigation of cerebral hemodynamics and autoregulation in pharmacological MRI. Magnetic Resonance Imaging. 2007;25:826-833.

    Not in our library10.1016/j.mri.2007.03.003

33. 33.

    Gutierrez-Barragan D, Basson MA, Panzeri S, Gozzi A. Infraslow state fluctuations govern spontaneous fMRI network dynamics. Current Biology. 2019;29:2295-2306.

    Not in our library10.1016/j.cub.2019.06.017

34. 34.

    Haller M. Parameterizing neural power spectra. bioRxiv. 2018.

    Not in our library10.1101/299859

35. 35.

    Happé F, Ronald A, Plomin R. Time to give up on a single explanation for autism. Nature Neuroscience. 2006;9:1218-1220.

    Not in our library10.1038/nn1770

36. 36.

    Hawrylycz MJ, Lein ES, Guillozet-Bongaarts AL, Shen EH, Ng L, Miller JA, van de Lagemaat LN, Smith KA, Ebbert A, Riley ZL, Abajian C, Beckmann CF, Bernard A, Bertagnolli D, Boe AF, Cartagena PM, Chakravarty MM, Chapin M, Chong J, Dalley RA, David Daly B, Dang C, Datta S, Dee N, Dolbeare TA, Faber V, Feng D, Fowler DR, Goldy J, Gregor BW, Haradon Z, Haynor DR, Hohmann JG, Horvath S, Howard RE, Jeromin A, Jochim JM, Kinnunen M, Lau C, Lazarz ET, Lee C, Lemon TA, Li L, Li Y, Morris JA, Overly CC, Parker PD, Parry SE, Reding M, Royall JJ, Schulkin J, Sequeira PA, Slaughterbeck CR, Smith SC, Sodt AJ, Sunkin SM, Swanson BE, Vawter MP, Williams D, Wohnoutka P, Zielke HR, Geschwind DH, Hof PR, Smith SM, Koch C, Grant SGN, Jones AR. An anatomically comprehensive atlas of the adult human brain transcriptome. Nature. 2012;489:391-399.

    Not in our library10.1038/nature11405

37. 37.

    He BJ. Scale-Free properties of the functional magnetic resonance imaging signal during rest and task. The Journal of Neuroscience. 2011;31:13786-13795.

    Not in our library10.1523/jneurosci.2111-11.2011

38. 38.

    He BJ. Scale-free brain activity: past, present, and future. Trends in Cognitive Sciences. 2014;18:480-487.

    Not in our library10.1016/j.tics.2014.04.003

39. 39.

    Horder J, Andersson M, Mendez MA, Singh N, Tangen Ä, Lundberg J, Gee A, Halldin C, Veronese M, Bölte S, Farde L, Sementa T, Cash D, Higgins K, Spain D, Turkheimer F, Mick I, Selvaraj S, Nutt DJ, Lingford-Hughes A, Howes OD, Murphy DG, Borg J. GABAA receptor availability is not altered in adults with autism spectrum disorder or in mouse models. Science Translational Medicine. 2018;10:eaam8434.

    Not in our library10.1126/scitranslmed.aam8434

40. 40.
    “Putting on My Best Normal”: Social Camouflaging in Adults with Autism Spectrum Conditions · 2017

    No notice

Cited by papers we hold 6

• The aperiodic exponent of subthalamic field potentials reflects excitation/inhibition balance in Parkinsonism · 2023
  No notice
• Globally elevated excitation–inhibition ratio in children with autism spectrum disorder and below-average intelligence · 2022
  Not checked
• Exposure to GABAA Receptor Antagonist Picrotoxin in Pregnant Mice Causes Autism-Like Behaviors and Aberrant Gene Expression in Offspring · 2022
  Not checked
• Neurophysiological and behavioral effects of multisession prefrontal tDCS and concurrent cognitive remediation training in patients with autism spectrum disorder (ASD): A double-blind, randomized controlled fNIRS study · 2022
  Not checked
• An increase of inhibition drives the developmental decorrelation of neural activity · 2022
  No notice
• mTOR-related synaptic pathology causes autism spectrum disorder-associated functional hyperconnectivity · 2021
  No notice

Reads

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.