2026 ECNP Congress

PS02-2195

What does auditory oddball electroencephalography (not) reveal about arbaclofen treatment response in a clinical trial of autism?

Eleonora Broggi — T. Del Bianco, R. Haartsen, A. San Jose Caceres, L. Colomar, B. Oakley, E. Loth, T. Charman, M. Parellada, C. Arango, E. Jones, D. Murphy, L. Mason · King's College London- Institute of Psychiatry- Psychology and Neuroscience, Department of Forensic & Neurodevelopmental Sciences, London, United Kingdom

2026 ECNP Congress

Background

There are currently no licensed treatments for the core symptoms of autism, and clinical trials are constrained by the absence of mechanistically informed biomarkers [1]. Electroencephalography (EEG) offers a promising solution through time-resolved measures of neural activity more proximal to underlying neurobiology than behavioural endpoints [2]. The EEG auditory oddball paradigm is a well-established probe of sensory processing, presenting repeated standard sounds interspersed with rare deviants. This yields event-related potentials (ERPs) and event-related spectral perturbations (ERSPs), indexing both deviance detection via mismatch negativity (MMN) and repetition suppression (RS) to standards via P1/N1 attenuation [3]. These indices have been linked to cortical excitation/inhibition (E/I) balance—a central framework in autism involving GABAergic inhibition—though their role as proxies of E/I remains to be established. Arbaclofen, a GABA-B receptor agonist, is hypothesised to enhance GABAergic inhibition and restore E/I balance [4], providing a biologically relevant test of whether these putative EEG biomarkers capture treatment-relevant variation in autistic children and adolescents.

Objectives

We aim to explore: (1) the effects of arbaclofen on putative EEG biomarkers—MMN (ERP/ERSP) and RS (ERP/ERSP)—derived from the auditory oddball paradigm; (2) the predictive value of these putative EEG biomarkers for treatment‑related clinical change in autistic children and adolescents.

Methods

In this phase II, randomised, double‑blind, placebo‑controlled trial, 123 autistic children and adolescents (aged 5–17) were administered arbaclofen or placebo for 16 weeks [5]. EEG data were recorded as exploratory measures at week 1 (baseline) and week 16 (post‑treatment), while participants completed an auditory oddball paradigm. We filtered, segmented, cleaned, and averaged EEG data at Fz to extract ERPs and ERSPs at canonical frequency bands for both MMN and RS. Treatment‑related clinical change was assessed using the Vineland Adaptive Behavior Scales, Third Edition (VABS‑3) Socialization domain, Autism Impact Measure (AIM) Total score, and Social Responsiveness Scale, Second Edition (SRS‑2) Total score. Hypotheses were preregistered on the Open Science Framework (OSF) and tested using linear mixed models.

Results

Arbaclofen did not modulate ERPs or ERSPs for either MMN or RS relative to placebo. Low-frequency MMN power, which increased from baseline to post-treatment across both groups (p=0.0196), was not moderated by treatment (p=0.391). Baseline EEG measures also did not predict treatment-related clinical change.

Conclusions

Auditory oddball EEG measures were not modulated by arbaclofen and did not predict treatment response in this trial. Our results neither rule out biologically meaningful effects of arbaclofen on E/I balance, nor establish these scalp-level measures as reliable E/I proxies. More broadly, these findings challenge current translational models in autism, which may oversimplify the relationship between GABA-B mechanisms and standard EEG readouts. Nevertheless, EEG remains one of the most accessible non-invasive methods to probe the living human brain, and future studies in autism should validate these EEG measures in conjunction with direct arbaclofen target engagement.

References

  1. Loth, E., 2023. Does the current state of biomarker discovery in autism reflect the limits of reductionism in precision medicine? Suggestions for an integrative approach that considers dynamic mechanisms between brain, body, and the social environment. Front. Psychiatry 14 (4), 1085445.
  2. Ahmad, J., Ellis, C., Leech, R., Voytek, B., Garces, P., Jones, E., Buitelaar, J., Loth, E., Páscoa Dos Santos, F., Amil, A.F., Verschure, P.F.M.J., Murphy, D., McAlonan, G., 2022. From mechanisms to markers: novel noninvasive EEG proxy markers of the neural excitation and inhibition system in humans. Transl. Psychiatry 12 (1), 467.
  3. Bartha-Doering, L., Deuster, D., Giordano, V., am Zehnhoff-Dinnesen, A., Dobel, C., 2015. A systematic review of the mismatch negativity as an index for auditory sensory memory: From basic research to clinical and developmental perspectives. Psychophysiology 52 (9), 1115-1130. http://dx.doi.org/10.1111/psyp.12459http://dx.doi.org/10.1111/psyp.12459
  4. Ellis, C.L., Ahmad, J., Zoumpoulaki, A., Dimitrov, M., Velthuis, H.E., Pereira, A.C., et al., 2023. The dynamically neurodiverse human brain: Measuring excitatory-inhibitory dynamics and identifying homeostatic differences in autistic and non-autistic people. bioRxivbioRxiv. http://dx.doi.org/10.1101/2023.06.19.23291507http://dx.doi.org/10.1101/2023.06.19.23291507
  5. Parellada, M., San José Cáceres, A., Delorme, R., Moscoso, A., Moreno, C., Calvo, R., et al., 2026. Efficacy, safety, and tolerability of arbaclofen in Autistic children and adolescents, the AIMS-2-TRIALS-CT1: a randomized, double-blind, placebo-controlled phase II trial. EClinicalMedicineEClinicalMedicine 92, 103760. http://dx.doi.org/10.1016/j.eclinm.2026.103760http://dx.doi.org/10.1016/j.eclinm.2026.103760