Jamie Horder, Mendez MA, Spain D, Faulkner J, De La Harpe Golden D, Murphy DGM

1. A Visual Perceptual Task Provides Evidence for an Excitatory:Inhibitory Imbalance in Adults with Autism Jamie Horder, Mendez MA, Spain D, Faulkner J, De La Harpe Golden D, Murphy DGM Department of Forensic and Neurodevelopmental Sciences Institute of Psychiatry, King’s College London United Kingdom

2. Background - general • Converging evidence implicates excitatory neurotransmitter glutamate and inhibitory GABA in ASD. • Altered excitatory:inhibitory (“E:I”) balance may be key

3. Background: elusive GABA? • We have observed alterations in glutamate using [1H]MRS (Horder et al 2013; Horder et al in prep), and have preliminary evidence of GABA receptors abnormalities (Mendez et al 2013), • But we found no differences in GABA itself in adults with ASD (Horder et al in prep). For more on these results… “Abnormalities in Subcortical Glutamate/Glutamine, but Not GABA, in Adults with an ASD: A [1H]MRS Study” Saturday 10:42 AM Marquis A Room

4. Background: a selective deficit? • However it’s possible that GABA deficits in ASD are limited to a subset of inhibitory interneurons: • If so, changes might be hard to detect with MRS, yet of functional importance. • A hypothesis:

5. Background - probing GABA • GABAergic inhibition has numerous well-defined roles in sensory pathways. • Perceptual tasks could probe cortical GABA. • We chose the paradoxical motion perception (PMP) visual task.

6. Paradoxical Motion Perception In the visual cortex, contrast-coding neurons inhibit motion-coding cells via lateral GABA firing. With large stimuli, it is harder to see motion in higher-contrast images compared to low contrast ones. GABA drives this. ‘Paradoxical’: large, high-contrast stimuli are usually easier to see! If there is a GABA deficit, the paradoxical effect should be lower in ASD i.e. high contrast performance should be better. It has been used as a probe of GABA in healthy volunteers (Glasser et al 2010) and in depression (Golomb et al 2009) etc.

7. Participants • Adult males with a diagnosis of ASD, IQ>70 and control males matched on age and full-scale IQ (t-test, all p>0.4). N = 30 (12 + 18). • Ages: 18-56 years (mean 30.6). Full scale IQ: 95-139 (mean 119). • ASD diagnosis by expert clinical judgement using ICD-10-R criteria based on ADOS Module IV and, except where caregivers were unavailable, ADI-R. • No history of epilepsy, genetic disorder, psychosis, drug and alcohol abuse. Depression and anxiety were not exclusion criteria. • Participants were not on any psychoactive medication at the time of scanning, and for at least six weeks previously.

8. Results In the ASD group, the degree of the paradoxical effect was reduced (p=0.022) implying reduced GABA signalling within the visual cortex. As expected, a paradoxical effect was observed over all participants taken as a whole (higher sensory threshold for large, bright stimuli, compared to small bright)

9. Discussion • This is the first study to use the paradoxical motion perception task in adults with ASD. • In children, Foss-Feig et al (2013) showed a slightly different pattern of results - no difference in paradoxical spatial suppression, but, improved performance at high contrast overall. • Further work should extend these results to larger samples including more diverse patients

10. Conclusions • We found perceptual performance consistent with reduced GABAergic inhibition in visual cortex in unmedicated adult males with an ASD • Data are consistent with an excitatory-inhibitory balance theory of autism and we hypothesise that GABA abnormalities may be better measured at a functional rather than a molecular level. • Some questions: • Do ‘objectively’ measured perceptual abnormalities relate to the subjective sensory symptoms common in ASD? • Could electrophysiology (EEG/MEG) probe perceptual hyperexcitability? • Useful as an outcome measure for pharmacology?

11. Acknowledgements • Laura Ajram • Ellie Wilson • Eileen Daly • EU-AIMS Consortium • MRC • NIHR • Wellcome Trust