{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T11:52:23Z","timestamp":1768564343620,"version":"3.49.0"},"posted":{"date-parts":[[2024,1,26]]},"group-title":"Neurology","reference-count":68,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,1,26]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>In the search for objective tools to quantify neural function in Rett Syndrome (RTT), which are crucial in the evaluation of therapeutic efficacy in clinical trials, recordings of sensory-perceptual functioning using event-related potential (ERP) approaches have emerged as potentially powerful tools. Considerable work points to highly anomalous auditory evoked potentials (AEPs) in RTT. However, an assumption of the typical signal-averaging method used to derive these measures is \u201cstationarity\u201d of the underlying responses \u2013 i.e. neural responses to each input are highly stereotyped. An alternate possibility is that responses to repeated stimuli are highly variable in RTT. If so, this will significantly impact the validity of assumptions about underlying neural dysfunction, and likely lead to overestimation of underlying neuropathology. To assess this possibility, analyses at the single-trial level assessing signal-to-noise ratios (SNR), inter-trial variability (ITV) and inter-trial phase coherence (ITPC) are necessary.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>AEPs were recorded to simple 100Hz tones from 18 RTT and 27 age-matched controls (Ages: 6-22 years). We applied standard AEP averaging, as well as measures of neuronal reliability at the single-trial level (i.e. SNR, ITV, ITPC). To separate signal-carrying components from non-neural noise sources, we also applied a denoising source separation (DSS) algorithm and then repeated the reliability measures.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Substantially increased ITV, lower SNRs, and reduced ITPC were observed in auditory responses of RTT participants, supporting a \u201cneural unreliability\u201d account. Application of the DSS technique made it clear that non-neural noise sources contribute to overestimation of the extent of processing deficits in RTT. Post-DSS, ITV measures were substantially reduced, so much so that pre-DSS ITV differences between RTT and TD populations were no longer detected. In the case of SNR and ITPC, DSS substantially improved these estimates in the RTT population, but robust differences between RTT and TD were still fully evident.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>To accurately represent the degree of neural dysfunction in RTT using the ERP technique, a consideration of response reliability at the single-trial level is highly advised. Non-neural sources of noise lead to overestimation of the degree of pathological processing in RTT, and denoising source separation techniques during signal processing substantially ameliorate this issue.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2024.01.25.24301723","type":"posted-content","created":{"date-parts":[[2024,1,26]],"date-time":"2024-01-26T18:55:10Z","timestamp":1706295310000},"source":"Crossref","is-referenced-by-count":2,"title":["Probing a neural unreliability account of auditory sensory processing atypicalities in Rett Syndrome"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3116-226X","authenticated-orcid":false,"given":"Tufikameni","family":"Brima","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6947-6811","authenticated-orcid":false,"given":"Shlomit","family":"Beker","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3682-9171","authenticated-orcid":false,"given":"Kevin D.","family":"Prinsloo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John S.","family":"Butler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aleksandra","family":"Djukic","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8570-6325","authenticated-orcid":false,"given":"Edward G.","family":"Freedman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0094-4015","authenticated-orcid":false,"given":"Sophie","family":"Molholm","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4300-3098","authenticated-orcid":false,"given":"John J.","family":"Foxe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2024012921050816000_2024.01.25.24301723v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/13810"},{"issue":"2","key":"2024012921050816000_2024.01.25.24301723v1.2","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/S0387-7604(89)80078-6","article-title":"Neurophysiological findings in the Rett syndrome, II: Visual and auditory brainstem, middle and late evoked responses","volume":"11","year":"1989","journal-title":"Brain Dev"},{"key":"2024012921050816000_2024.01.25.24301723v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/S0387-7604(87)80076-1"},{"key":"2024012921050816000_2024.01.25.24301723v1.4","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-7610.2006.01681.x"},{"issue":"1","key":"2024012921050816000_2024.01.25.24301723v1.5","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1186\/s11689-021-09383-0","article-title":"Looking for consistency in an uncertain world: test-retest reliability of neurophysiological and behavioral readouts in autism","volume":"13","year":"2021","journal-title":"J Neurodev Disord"},{"key":"2024012921050816000_2024.01.25.24301723v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.nlm.2011.05.006"},{"key":"2024012921050816000_2024.01.25.24301723v1.7","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0018993"},{"key":"2024012921050816000_2024.01.25.24301723v1.8","doi-asserted-by":"publisher","DOI":"10.1016\/j.neubiorev.2017.06.016"},{"key":"2024012921050816000_2024.01.25.24301723v1.9","doi-asserted-by":"publisher","DOI":"10.1093\/cercor\/bhs109"},{"key":"2024012921050816000_2024.01.25.24301723v1.10","doi-asserted-by":"publisher","DOI":"10.1093\/cercor\/bhq170"},{"issue":"1","key":"2024012921050816000_2024.01.25.24301723v1.11","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/s11689-023-09515-8","article-title":"Assessing the integrity of auditory sensory memory processing in CLN3 disease (Juvenile Neuronal Ceroid Lipofuscinosis (Batten disease)): an auditory evoked potential study of the duration-evoked mismatch negativity (MMN)","volume":"16","year":"2024","journal-title":"J Neurodev Disord"},{"issue":"1","key":"2024012921050816000_2024.01.25.24301723v1.12","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1038\/s41398-019-0463-0","article-title":"Auditory sensory memory span for duration is severely curtailed in females with Rett syndrome","volume":"9","year":"2019","journal-title":"Transl Psychiatry"},{"key":"2024012921050816000_2024.01.25.24301723v1.13","doi-asserted-by":"publisher","DOI":"10.1093\/cercor\/bhw375"},{"issue":"4","key":"2024012921050816000_2024.01.25.24301723v1.14","first-page":"275","article-title":"[Event-related potentials and language processing]","volume":"24","year":"1994","journal-title":"Neurophysiol Clin"},{"key":"2024012921050816000_2024.01.25.24301723v1.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2014.05.068"},{"key":"2024012921050816000_2024.01.25.24301723v1.16","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneumeth.2008.03.015"},{"key":"2024012921050816000_2024.01.25.24301723v1.17","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneumeth.2003.10.009"},{"key":"2024012921050816000_2024.01.25.24301723v1.18","doi-asserted-by":"publisher","DOI":"10.1007\/s007870070047"},{"key":"2024012921050816000_2024.01.25.24301723v1.19","doi-asserted-by":"crossref","unstructured":"Dwyer, P. , S. Vukusic , Z. J. Williams , C. D. Saron and S. M. Rivera (2022). \u201c\u201cNeural Noise\u201d in Auditory Responses in Young Autistic and Neurotypical Children.\u201d J Autism Dev Disord.","DOI":"10.1007\/s10803-022-05797-4"},{"issue":"1","key":"2024012921050816000_2024.01.25.24301723v1.20","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1186\/s11689-016-9166-5","article-title":"Automatic cortical representation of auditory pitch changes in Rett syndrome","volume":"8","year":"2016","journal-title":"J Neurodev Disord"},{"key":"2024012921050816000_2024.01.25.24301723v1.21","doi-asserted-by":"publisher","DOI":"10.1007\/s00221-001-0906-7"},{"issue":"1","key":"2024012921050816000_2024.01.25.24301723v1.22","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1186\/s13023-021-01818-0","article-title":"Assessing the integrity of auditory processing and sensory memory in adults with cystinosis (CTNS gene mutations)","volume":"16","year":"2021","journal-title":"Orphanet J Rare Dis"},{"issue":"1","key":"2024012921050816000_2024.01.25.24301723v1.23","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1038\/s41398-020-0764-3","article-title":"Assessing auditory processing endophenotypes associated with Schizophrenia in individuals with 22q11.2 deletion syndrome","volume":"10","year":"2020","journal-title":"Transl Psychiatry"},{"key":"2024012921050816000_2024.01.25.24301723v1.24","doi-asserted-by":"crossref","first-page":"102170","DOI":"10.1016\/j.nicl.2020.102170","article-title":"Impaired auditory sensory memory in Cystinosis despite typical sensory processing: A high-density electrical mapping study of the mismatch negativity (MMN)","volume":"25","year":"2020","journal-title":"Neuroimage Clin"},{"key":"2024012921050816000_2024.01.25.24301723v1.25","doi-asserted-by":"publisher","DOI":"10.1016\/S1388-2457(03)00093-2"},{"issue":"11","key":"2024012921050816000_2024.01.25.24301723v1.26","doi-asserted-by":"crossref","first-page":"3688","DOI":"10.1111\/ejn.15219","article-title":"The identification of predominant auditory steady-state response brain sources in electroencephalography using denoising source separation","volume":"53","year":"2021","journal-title":"Eur J Neurosci"},{"key":"2024012921050816000_2024.01.25.24301723v1.27","doi-asserted-by":"publisher","DOI":"10.1002\/mrdd.10020"},{"key":"2024012921050816000_2024.01.25.24301723v1.28","doi-asserted-by":"crossref","first-page":"844830","DOI":"10.3389\/fpsyt.2022.844830","article-title":"Hyper-Sensitivity to Pitch and Poorer Prosody Processing in Adults With Autism: An ERP Study","volume":"13","year":"2022","journal-title":"Front Psychiatry"},{"issue":"5","key":"2024012921050816000_2024.01.25.24301723v1.29","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.1007\/s10803-014-2276-6","article-title":"Cortical variability in the sensory-evoked response in autism","volume":"45","year":"2015","journal-title":"J Autism Dev Disord"},{"key":"2024012921050816000_2024.01.25.24301723v1.30","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1016\/B978-0-444-64032-1.00036-9","article-title":"Cognitive neurophysiology: Event-related potentials","volume":"160","year":"2019","journal-title":"Handb Clin Neurol"},{"issue":"1","key":"2024012921050816000_2024.01.25.24301723v1.31","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/S0387-7604(12)80181-1","article-title":"Evoked potentials in the Rett syndrome","volume":"12","year":"1990","journal-title":"Brain Dev"},{"key":"2024012921050816000_2024.01.25.24301723v1.32","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2788.2011.01404.x"},{"key":"2024012921050816000_2024.01.25.24301723v1.33","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.ijdevneu.2019.01.001","article-title":"Spoken word processing in Rett syndrome: Evidence from event-related potentials","volume":"73","year":"2019","journal-title":"Int J Dev Neurosci"},{"issue":"2","key":"2024012921050816000_2024.01.25.24301723v1.34","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1097\/00003446-198704000-00008","article-title":"Test-retest variability of auditory event-related potentials","volume":"8","year":"1987","journal-title":"Ear Hear"},{"issue":"12","key":"2024012921050816000_2024.01.25.24301723v1.35","doi-asserted-by":"crossref","first-page":"2058","DOI":"10.1002\/aur.2362","article-title":"Individuals With Autism Have No Detectable Deficit in Neural Markers of Prediction Error When Presented With Auditory Rhythms of Varied Temporal Complexity","volume":"13","year":"2020","journal-title":"Autism Res"},{"issue":"1","key":"2024012921050816000_2024.01.25.24301723v1.36","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1038\/s41398-019-0672-6","article-title":"Reduced visual evoked potential amplitude in autism spectrum disorder, a variability effect?","volume":"9","year":"2019","journal-title":"Transl Psychiatry"},{"key":"2024012921050816000_2024.01.25.24301723v1.37","doi-asserted-by":"publisher","DOI":"10.1177\/1099800404267682"},{"key":"2024012921050816000_2024.01.25.24301723v1.38","doi-asserted-by":"publisher","DOI":"10.1002\/ana.24513"},{"key":"2024012921050816000_2024.01.25.24301723v1.39","unstructured":"Luck, S. J . (2014). An introduction to the event-related potential technique, MIT press."},{"key":"2024012921050816000_2024.01.25.24301723v1.40","doi-asserted-by":"publisher","DOI":"10.3758\/s13428-016-0809-y"},{"key":"2024012921050816000_2024.01.25.24301723v1.41","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2007.06.004"},{"key":"2024012921050816000_2024.01.25.24301723v1.42","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.brainres.2017.05.021","article-title":"Long-term test-retest reliability of event-related potential (ERP) recordings during treadmill walking using the mobile brain\/body imaging (MoBI) approach","volume":"1716","year":"2019","journal-title":"Brain Res"},{"key":"2024012921050816000_2024.01.25.24301723v1.43","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneumeth.2007.03.024"},{"key":"2024012921050816000_2024.01.25.24301723v1.44","doi-asserted-by":"publisher","DOI":"10.1016\/0168-5597(88)90040-8"},{"issue":"10","key":"2024012921050816000_2024.01.25.24301723v1.45","doi-asserted-by":"crossref","first-page":"80","DOI":"10.15844\/pedneurbriefs-29-10-7","article-title":"Visual Evoked Potentials in Rett Syndrome","volume":"29","year":"2015","journal-title":"Pediatr Neurol Briefs"},{"key":"2024012921050816000_2024.01.25.24301723v1.46","doi-asserted-by":"publisher","DOI":"10.3389\/fpsyg.2011.00051"},{"issue":"3","key":"2024012921050816000_2024.01.25.24301723v1.47","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1080\/15622975.2019.1605198","article-title":"EEG\/ERP-based biomarker\/neuroalgorithms in adults with ADHD: Development, reliability, and application in clinical practice","volume":"21","year":"2020","journal-title":"World J Biol Psychiatry"},{"issue":"Suppl 1","key":"2024012921050816000_2024.01.25.24301723v1.48","first-page":"14","article-title":"Rett syndrome: natural history and underlying disease mechanisms","volume":"6","year":"1997","journal-title":"Eur Child Adolesc Psychiatry"},{"key":"2024012921050816000_2024.01.25.24301723v1.49","doi-asserted-by":"publisher","DOI":"10.1177\/0883073815579707"},{"key":"2024012921050816000_2024.01.25.24301723v1.50","doi-asserted-by":"publisher","DOI":"10.1155\/2011\/156869"},{"issue":"7","key":"2024012921050816000_2024.01.25.24301723v1.51","doi-asserted-by":"crossref","first-page":"2050029","DOI":"10.1142\/S012906572050029X","article-title":"Dyslexia Diagnosis by EEG Temporal and Spectral Descriptors: An Anomaly Detection Approach","volume":"30","year":"2020","journal-title":"Int J Neural Syst"},{"key":"2024012921050816000_2024.01.25.24301723v1.52","doi-asserted-by":"publisher","DOI":"10.1002\/ana.22154"},{"key":"2024012921050816000_2024.01.25.24301723v1.53","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.brainres.2017.08.028","article-title":"Distinguishing response to names in Rett and MECP2 Duplication syndrome: An ERP study of auditory social information processing","volume":"1675","year":"2017","journal-title":"Brain Res"},{"key":"2024012921050816000_2024.01.25.24301723v1.54","doi-asserted-by":"publisher","DOI":"10.1126\/science.164.3877.326"},{"issue":"10","key":"2024012921050816000_2024.01.25.24301723v1.55","doi-asserted-by":"crossref","first-page":"4283","DOI":"10.1111\/ejn.14865","article-title":"Understanding human individuation of unfamiliar faces with oddball fast periodic visual stimulation and electroencephalography","volume":"52","year":"2020","journal-title":"Eur J Neurosci"},{"key":"2024012921050816000_2024.01.25.24301723v1.56","doi-asserted-by":"publisher","DOI":"10.1111\/ejn.13400"},{"issue":"4","key":"2024012921050816000_2024.01.25.24301723v1.57","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1002\/ana.26029","article-title":"Multisite Study of Evoked Potentials in Rett Syndrome","volume":"89","year":"2021","journal-title":"Ann Neurol"},{"key":"2024012921050816000_2024.01.25.24301723v1.58","doi-asserted-by":"crossref","first-page":"30","DOI":"10.3389\/fnint.2020.00030","article-title":"Evoked Potentials and EEG Analysis in Rett Syndrome and Related Developmental Encephalopathies: Towards a Biomarker for Translational Research","volume":"14","year":"2020","journal-title":"Front Integr Neurosci"},{"key":"2024012921050816000_2024.01.25.24301723v1.59","first-page":"3","article-title":"Denoising source separation","volume":"6","year":"2005","journal-title":"Journal of machine learning research"},{"key":"2024012921050816000_2024.01.25.24301723v1.60","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-8749.1995.tb12037.x"},{"key":"2024012921050816000_2024.01.25.24301723v1.61","doi-asserted-by":"crossref","first-page":"128","DOI":"10.3389\/fpsyt.2017.00128","article-title":"A Pilot Study of Possible Easy-to-Use Electrophysiological Index for Early Detection of Antidepressive Treatment Non-Response","volume":"8","year":"2017","journal-title":"Front Psychiatry"},{"key":"2024012921050816000_2024.01.25.24301723v1.62","doi-asserted-by":"publisher","DOI":"10.1097\/00004691-199509010-00003"},{"key":"2024012921050816000_2024.01.25.24301723v1.63","doi-asserted-by":"publisher","DOI":"10.1016\/j.braindev.2006.02.011"},{"issue":"1","key":"2024012921050816000_2024.01.25.24301723v1.64","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1177\/1550059417745933","article-title":"Electrophysiological Markers of Motivation in Psychosis","volume":"49","year":"2018","journal-title":"Clin EEG Neurosci"},{"key":"2024012921050816000_2024.01.25.24301723v1.65","doi-asserted-by":"publisher","DOI":"10.1126\/science.150.3700.1187"},{"key":"2024012921050816000_2024.01.25.24301723v1.66","doi-asserted-by":"publisher","DOI":"10.1126\/science.155.3768.1436"},{"issue":"1","key":"2024012921050816000_2024.01.25.24301723v1.67","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1038\/s41398-020-00877-4","article-title":"Atypical processing of tones and phonemes in Rett Syndrome as biomarkers of disease progression","volume":"10","year":"2020","journal-title":"Transl Psychiatry"},{"key":"2024012921050816000_2024.01.25.24301723v1.68","doi-asserted-by":"publisher","DOI":"10.1002\/dev.20245"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2024.01.25.24301723","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T19:49:40Z","timestamp":1768506580000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.1101\/2024.01.25.24301723"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,26]]},"references-count":68,"URL":"https:\/\/doi.org\/10.1101\/2024.01.25.24301723","relation":{},"subject":[],"published":{"date-parts":[[2024,1,26]]},"subtype":"preprint"}}