Improving emotional face perception in ASD with bumetamide: behavioral and fMRI data Nouchine Hadjikhani, MD, PhD Martinos Center for Biomedical Imaging.

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Improving emotional face perception in ASD with bumetamide: behavioral and fMRI data Nouchine Hadjikhani, MD, PhD Martinos Center for Biomedical Imaging Massachusetts General Hospital Harvard Medical School Gillberg Centrum

Autism Spectrum Disorders ASD are neurodevelopmental disorders characterized by social communication impairment repetitive/restricted behaviors ASD affects more than 1% of the population (1:68, CDC 2014) ASD individuals seem to lack social instinct It is known that early intervention can considerably improve their level of functioning and quality of life There is no biomarker for autism, it is a behavioral diagnosis

Evidence for neuronal excitability dysfunction in ASD – high prevalence of epilepsy (~30%) and abnormal EEG in about 60% Anecdotal reports of paradoxical effect of GABA agonist Valium on ASD GABA – excitatory role during pregnancy, but becomes inhibitory at birth Switch from excitatory to inhibitory linked to decrease in the amount of intracellular chlorine Switch also linked to oxytocin Ben Ari 2002

Question: Are neurons in ASD reacting as immature neurons? What will happen if we ‘force them to behave as mature’ by removing intracellular chlorine, with a diuretic?

2010: pilot open-label study on 5 patients, behavioral improvement with very little side effects ( Lemonnier & Ben-Ari, Acta Perdiatrica 2010) 2012: double blind cross over study on 60 participants: significant improvement in autistic symptomatology (Lemonnier et al., Tranlat Psy 2012) 2013: proof of concept pilot behavioral and imaging study on 9 (7+2) adolescents before and after 10 months of treatment (Hadjikhani et al, Autism 2014) 2014: Rodent model of autism : Oxytocin-mediated GABA inhibition during delivery attenuates autism pathogenesis in rodent offspring. Tyzio et al, Science 2014Oxytocin-mediated GABA inhibition during delivery attenuates autism pathogenesis in rodent offspring. Improving autism symptomatology with a bumetanide

Zimmerman and Connors, Science 2014 Bumetanide in the rodent model FraX and VPA Zimmerman and Connors, Science 2014

Proof of concept pilot study 9 participants with ASD, 7 with treatment and 2 without Age at first exam: 19.3±4.6 Second exam after 10 months of bumetamide treatment (1mg/day) Behavioral and fMRI testing at each exam

Behavioral study – RT and accuracy Non verbal emotion matching, morph at 40% intensity

Bumetamide – functional data N=7

Superior temporal cortex (social processing) Hadjikhani et al, Autism 2013 Nucleus accumbens (reward) [EMO>NEU] POST bumet > [EMO>NEU] PRE bumet TP (emotion)

Conclusions Treatment with a diuretic restoring GABA function seems to significantly improve behavior and function in teenagers and young adults with ASD More studies, with a double-blind placebo cross-over design are needed to confirm our observations 7: Hadjikhani et al, Translational Psychiatry 2014; 8: Lemonnier et al, Translational Psychiatry 2012; Hadjikhani et al, Autism 2014