PMID- 32746967 OWN - NLM STAT- MEDLINE DCOM- 20210212 LR - 20240329 IS - 2050-084X (Electronic) IS - 2050-084X (Linking) VI - 9 DP - 2020 Aug 4 TI - Intrinsic excitation-inhibition imbalance affects medial prefrontal cortex differently in autistic men versus women. LID - 10.7554/eLife.55684 [doi] LID - e55684 AB - 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. CI - (c) 2020, Trakoshis et al. FAU - Trakoshis, Stavros AU - Trakoshis S AD - Laboratory for Autism and Neurodevelopmental Disorders, Center for Neuroscience and Cognitive Systems @UniTn, Istituto Italiano di Tecnologia, Rovereto, Italy. AD - Department of Psychology, University of Cyprus, Nicosia, Cyprus. FAU - Martinez-Canada, Pablo AU - Martinez-Canada P AD - Neural Computation Laboratory, Center for Neuroscience and Cognitive Systems @UniTn, Istituto Italiano di Tecnologia, Rovereto, Italy. AD - Optical Approaches to Brain Function Laboratory, Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genova, Italy. FAU - Rocchi, Federico AU - Rocchi F AD - Functional Neuroimaging Laboratory, Center for Neuroscience and Cognitive Systems @UniTn, Istituto Italiano di Tecnologia, Rovereto, Italy. FAU - Canella, Carola AU - Canella C AD - Functional Neuroimaging Laboratory, Center for Neuroscience and Cognitive Systems @UniTn, Istituto Italiano di Tecnologia, Rovereto, Italy. FAU - You, Wonsang AU - You W AD - Artificial Intelligence and Image Processing Laboratory, Department of Information and Communications Engineering, Sun Moon University, Asan, Republic of Korea. FAU - Chakrabarti, Bhismadev AU - Chakrabarti B AD - Autism Research Centre, Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom. AD - Centre for Integrative Neuroscience and Neurodynamics, School of Psychology and Clinical Language Sciences, University of Reading, Reading, United Kingdom. FAU - Ruigrok, Amber Nv AU - Ruigrok AN AD - Autism Research Centre, Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom. FAU - Bullmore, Edward T AU - Bullmore ET AD - Cambridgeshire and Peterborough National Health Service Foundation Trust, Cambridge, United Kingdom. AD - Brain Mapping Unit, Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom. FAU - Suckling, John AU - Suckling J AD - Brain Mapping Unit, Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom. FAU - Markicevic, Marija AU - Markicevic M AD - Neural Control of Movement Lab, D-HEST, ETH Zurich, Zurich, Switzerland. AD - Neuroscience Center Zurich, University and ETH Zurich, Zurich, Switzerland. FAU - Zerbi, Valerio AU - Zerbi V AUID- ORCID: 0000-0001-7984-9565 AD - Neural Control of Movement Lab, D-HEST, ETH Zurich, Zurich, Switzerland. AD - Neuroscience Center Zurich, University and ETH Zurich, Zurich, Switzerland. CN - MRC AIMS Consortium FAU - Baron-Cohen, Simon AU - Baron-Cohen S AD - Autism Research Centre, Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom. AD - Cambridgeshire and Peterborough National Health Service Foundation Trust, Cambridge, United Kingdom. FAU - Gozzi, Alessandro AU - Gozzi A AUID- ORCID: 0000-0002-5731-4137 AD - Functional Neuroimaging Laboratory, Center for Neuroscience and Cognitive Systems @UniTn, Istituto Italiano di Tecnologia, Rovereto, Italy. FAU - Lai, Meng-Chuan AU - Lai MC AD - Autism Research Centre, Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom. AD - The Margaret and Wallace McCain Centre for Child, Youth & Family Mental Health, Azrieli Adult Neurodevelopmental Centre, and Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Canada. AD - Department of Psychiatry and Autism Research Unit, The Hospital for Sick Children, Toronto, Canada. AD - Department of Psychiatry, Faculty of Medicine, University of Toronto, Toronto, Canada. AD - Department of Psychiatry, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan. FAU - Panzeri, Stefano AU - Panzeri S AUID- ORCID: 0000-0003-1700-8909 AD - Neural Computation Laboratory, Center for Neuroscience and Cognitive Systems @UniTn, Istituto Italiano di Tecnologia, Rovereto, Italy. FAU - Lombardo, Michael V AU - Lombardo MV AUID- ORCID: 0000-0001-6780-8619 AD - Laboratory for Autism and Neurodevelopmental Disorders, Center for Neuroscience and Cognitive Systems @UniTn, Istituto Italiano di Tecnologia, Rovereto, Italy. AD - Autism Research Centre, Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom. LA - eng SI - GEO/GSE86457 GR - 400061/MRC_/Medical Research Council/United Kingdom GR - MR/N026063/1/MRC_/Medical Research Council/United Kingdom GR - MC_G0802534/MRC_/Medical Research Council/United Kingdom GR - 602849/Simons Foundation/International GR - 755816/H2020 European Research Council/International GR - 802371/H2020 European Research Council/International PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200804 PL - England TA - Elife JT - eLife JID - 101579614 SB - IM CIN - Elife. 2020 Aug 04;9:. PMID: 32746964 MH - Adult MH - Animals MH - Autistic Disorder/*physiopathology MH - *Communication MH - England MH - Female MH - Humans MH - Inhibition, Psychological MH - Language MH - Magnetic Resonance Imaging MH - Male MH - Mice MH - Mice, Inbred C57BL/*physiology MH - Middle Aged MH - Prefrontal Cortex/*physiopathology MH - Sex Factors MH - Young Adult PMC - PMC7402681 OAB - Autism is a condition that is usually diagnosed early in life that affects how a person communicates and socializes, and is often characterized by repetitive behaviors. One key theory of autism is that it reflects an imbalance in levels of excitation and inhibition in the brain. Excitatory signals are those that make other brain cells more likely to become active; inhibitory signals have the opposite effect. In non-autistic individuals, inhibitory activity outweighs excitatory activity. In people with autism, by contrast, an increase in excitatory activity is believed to produce an imbalance in excitation and inhibition. Most of the evidence to support this excitation-inhibition imbalance theory has come from studies of rare mutations that cause autism. Many of these mutations occur on the sex chromosomes or are influenced by androgen hormones (hormones that usually play a role on typically male traits). However, most people with autism do not possess these particular mutations. It was thus unclear whether the theory could apply to everyone with autism or, for example, whether it may better apply to specific groups of individuals based on their sex or gender. This is especially important given that about four times as many men and boys compared to women and girls are diagnosed with autism. Trakoshis, Martinez-Canada et al. have now found a way to ask whether any imbalance in excitation and inhibition in the brain occurs differently in men and women. Using computer modeling, they identified a signal in brain scans that corresponds to an imbalance of excitation and inhibition. After showing that the technique works to identify real increases in excitation in the brain scans of mice, Trakoshis, Martinez-Canada et al. looked for this signal, or biomarker, in brain scans of people with and without autism. All the people in the study identified with the gender that matched the sex they were assigned at birth. The results revealed differences between the men and women with autism. Men with autism showed an imbalance in excitation and inhibition in specific 'social brain' regions including the medial prefrontal cortex, but women with autism did not. Notably, many of these brain regions are strongly affected by androgen hormones. Previous studies have found that women with autism are sometimes better at hiding or 'camouflaging' their difficulties when socializing or communicating than men with autism. Trakoshis, Martinez-Canada et al. showed that the better a woman was at camouflaging her autism, the more her brain activity in this region resembled that of non-autistic women. Excitation-inhibition imbalance may thus affect specific brain regions involved in socializing and communication more in men who have autism than in women with the condition. Balanced excitation and inhibition in these brain areas may enable some women with autism to camouflage their difficulties socializing or communicating. Being able to detect imbalances in activity using standard brain imaging could be useful for clinical trials. Future studies could use this biomarker to monitor responses to drug treatments that aim to adjust the balance between excitation and inhibition. OABL- eng OTO - NOTNLM OT - autism OT - excitation OT - fMRI OT - heterogeneity OT - human OT - human biology OT - inhibition OT - medicine OT - mouse OT - neuroscience OT - sex/gender COIS- ST, PM, FR, CC, WY, BC, AR, JS, MM, VZ, SB, AG, ML, SP, ML No competing interests declared, EB is employed half-time by the University of Cambridge and half-time at GlaxoSmithKline plc (GSK); he holds stock in GSK. All other authors have no conflict of interests to declare. EDAT- 2020/08/05 06:00 MHDA- 2021/02/13 06:00 PMCR- 2020/08/04 CRDT- 2020/08/05 06:00 PHST- 2020/02/02 00:00 [received] PHST- 2020/06/29 00:00 [accepted] PHST- 2020/08/05 06:00 [entrez] PHST- 2020/08/05 06:00 [pubmed] PHST- 2021/02/13 06:00 [medline] PHST- 2020/08/04 00:00 [pmc-release] AID - 55684 [pii] AID - 10.7554/eLife.55684 [doi] PST - epublish SO - Elife. 2020 Aug 4;9:e55684. doi: 10.7554/eLife.55684.