Lesions causing Alice in Wonderland Syndrome map to a common brain network linking body and size perception

Background In Lewis Carroll’s 1865 novel “Alice’s Adventures in Wonderland”, the protagonist experiences distortions in the size of her body and those of others. This fiction becomes reality in neurological patients with Alice in Wonderland Syndrome (AIWS). Brain lesions causing AIWS may offer unique insights into the syndrome’s elusive neuroanatomy. Methods A systematic literature search identified 37 cases of lesion-induced AIWS. Lesion locations were mapped onto a brain atlas and functional connectivity between each lesion location and other brain regions was estimated using resting-state fMRI data from 1000 healthy subjects. Connections common to AIWS lesions were identified and compared to connections from 1073 lesions associated with 25 other neuropsychiatric disorders. Alignment between this lesion-derived AIWS network and neuroimaging findings from patients with AIWS due to other etiologies was assessed. Results Although AIWS lesions occurred in many different brain locations, these lesions fell within a specific, functionally connected brain network. This network was defined by connectivity to the right extrastriate body area, a brain region selectively activated by viewing body parts, and the inferior parietal cortex, a brain region involved in processing of size and scale. This connectivity pattern was specific to AIWS when compared to lesions causing other neuropsychiatric disorders and aligned with neuroimaging findings in patients with AIWS from other etiologies. Conclusion Lesions causing AIWS fall within a specific brain network defined by connectivity to two distinct brain regions, one region involved in body perception and another in processing of size and scale. ### Competing Interest Statement MDF owns patents on using brain connectivity to guide brain stimulation, and has received investigator-initiated research funding from Neuronetics Inc, which is unrelated to the present work. ### Funding Statement This study did not receive any funding. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This retrospective study is based on 37 cases from the medical literature. The table is included in the manuscript. Case IDAIWS\_TypeDOI / Pubmed identifier (PMID)Foundational search AIWS\_01A10.1186/s12883-020-01970-3Y AIWS\_02B10.21203/rs.3.rs-2090631/v1N AIWS\_03B10.21203/rs.3.rs-2090631/v1N AIWS\_04A10.1007/s00415-012-6827-5Y AIWS\_05B10.1371/journal.pone.0079938Y AIWS\_06A10.1016/j.neuropsychologia.2011.11.018N AIWS\_07B10.1007/s00415-007-0671-zN AIWS\_08A10.1097/WNN.0b013e31826b70deY AIWS\_09A10.1097/WNN.0b013e31826b70deY AIWS\_10B10.1590/0004-282X20190094Y AIWS\_11C10.1080/13554794.2019.1656751Y AIWS\_12B10.1080/13554794.2018.1562079Y AIWS\_13B10.5692/clinicalneurol.cn-001081Y AIWS\_14B10.1016/j.nrl.2016.10.011Y AIWS\_15B10.4103/jnrp.jnrp\_449\_17Y AIWS\_16B10.1007/978-981-10-7668-8\_52Y AIWS\_17B10.1007/s11682-015-9355-yY AIWS\_18B10.1155/2014/272084Y AIWS\_19B10.1016/j.nrl.2014.09.009Y AIWS\_20B10.1016/j.nrl.2014.09.009Y AIWS\_21B10.1016/j.ajem.2012.10.029Y AIWS\_22B10.1016/j.nrl.2010.07.029Y AIWS\_23B10.1016/j.jns.2010.05.015Y AIWS\_24B10.1016/j.jns.2010.05.015Y AIWS\_25B10.1136/jnnp.2006.100842Y AIWS\_26B10.1016/s0028-3932(99)00041-xY AIWS\_27B10.1093/brain/122.2.339Y AIWS\_28B10.1016/S0010-9452(08)70742-1NY AIWS\_29B10.1136/jnnp.57.1.73Y AIWS\_30B10.1136/jnnp.57.1.73Y AIWS\_31CKim YD, Ryu SY, Kim JS, Lee KS. Alice in Wonderland Syndrome in a Case with Infarct in the Right Medial Temporal Lobe. J Korean Neurol Assoc. 2006;24(4):364-366.Y AIWS\_32BPMID: 26111290Y AIWS\_33B10.1136/jnnp.54.1.68N AIWS\_34B10.2169/internalmedicine.8295-16N AIWS\_35B10.1136/jnnp.61.4.420-aN AIWS\_36B10.1016/j.cortex.2020.02.012N AIWS_37A10.1093/brain/awz179N I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Lesion masks in MNI space are available upon request to the corresponding author. The code for lesion connectivity analysis is freely distributed via the Lead-DBS toolbox ([www.lead-dbs.org][1]). The fully preprocessed version of the human resting-state fMRI-derived connectome is publicly available on Harvard Dataverse ( doi:10.7910/DVN/ILXIKS and . [1]: http://www.lead-dbs.org