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From mechanisms to markers: novel noninvasive EEG proxy markers of the neural excitation and inhibition system in humans

Research output: Contribution to journalReview articlepeer-review

Jumana Ahmad, Claire Ellis, Robert Leech, Bradley Voytek, Pilar Garces, Emily Jones, Jan Buitelaar, Eva Loth, Francisco Pascoa dos Santos, Adrian Amil, Paul Verschure, Declan Murphy, Grainne McAlonan

Original languageEnglish
Article number467
JournalTranslational psychiatry
Issue number1
Accepted/In press6 Oct 2022
Published8 Nov 2022

Bibliographical note

Funding Information: This work was supported by the EU-AIMS (European Autism Interventions) and AIMS-2-TRIALS programmes which receive support from Innovative Medicines Initiative Joint Undertaking Grant No. 115300 and 777394, the resources of which are composed of financial contributions from the European Union’s FP7 and Horizon2020 Programmes, and the European Federation of Pharmaceutical Industries and Associations (EFPIA) companies’ in-kind contributions, and AUTISM SPEAKS, Autistica and SFARI. There was further support from the Horizon2020 programme CANDY (Grant No. 847818). CE PhD funding is provided by the Sackler Institute for Translational Neurodevelopment. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. Any views expressed are those of the author(s) and not necessarily those of the funders. Funding Information: JB has been for the past 3 years a consultant to/member of the advisory board of/and/or speaker for Janssen Cilag BV, Takeda/Shire, Roche, Medicine, Angelini and Servier. He is not an employee of any of these companies, and not a stock shareholder of any of these companies. He has no other financial or material support, including expert testimony, patents, and royalties. DM has received consultancy fees from F. Hoffmann-La Roche and Servier. GM has received consultancy fees from Greenwich Biosciences. GM and DM are supported by the Sackler Institute for Translational Neurodevelopment, the MRC Centre for Neurodevelopmental Disorders, and the NIHR-Maudsley Biomedical Research Center. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care. PG is an employee of F. Hoffmann-La Roche Ltd. The remaining authors declare no competing interests. Publisher Copyright: © 2022, The Author(s).

King's Authors


Brain function is a product of the balance between excitatory and inhibitory (E/I) brain activity. Variation in the regulation of this activity is thought to give rise to normal variation in human traits, and disruptions are thought to potentially underlie a spectrum of neuropsychiatric conditions (e.g., Autism, Schizophrenia, Downs’ Syndrome, intellectual disability). Hypotheses related to E/I dysfunction have the potential to provide cross-diagnostic explanations and to combine genetic and neurological evidence that exists within and between psychiatric conditions. However, the hypothesis has been difficult to test because: (1) it lacks specificity —an E/I dysfunction could pertain to any level in the neural system- neurotransmitters, single neurons/receptors, local networks of neurons, or global brain balance - most researchers do not define the level at which they are examining E/I function; (2) We lack validated methods for assessing E/I function at any of these neural levels in humans. As a result, it has not been possible to reliably or robustly test the E/I hypothesis of psychiatric disorders in a large cohort or longitudinal patient studies. Currently available, in vivo markers of E/I in humans either carry significant risks (e.g., deep brain electrode recordings or using Positron Emission Tomography (PET) with radioactive tracers) and/or are highly restrictive (e.g., limited spatial extent for Transcranial Magnetic Stimulation (TMS) and Magnetic Resonance Spectroscopy (MRS). More recently, a range of novel Electroencephalography (EEG) features has been described, which could serve as proxy markers for E/I at a given level of inference. Thus, in this perspective review, we survey the theories and experimental evidence underlying 6 novel EEG markers and their biological underpinnings at a specific neural level. These cheap-to-record and scalable proxy markers may offer clinical utility for identifying subgroups within and between diagnostic categories, thus directing more tailored sub-grouping and, therefore, treatment strategies. However, we argue that studies in clinical populations are premature. To maximize the potential of prospective EEG markers, we first need to understand the link between underlying E/I mechanisms and measurement techniques.

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