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Author Notes:

Correspondence: Pediatric Psychology and Feeding Disorders Program, The Marcus Autism Center, 1920 Briarcliff Road, Atlanta, GA 30329, USA. E-mail: wgsharp@emory.edu

We thank Drs Kerry Ressler and Warren Jones for their guidance and Savonya McAllister, Ashley Trumbull, and Emily Maddox for assisting with conducting structured meals and helping with data collection.

WGS has received research support and served as a consultant for Nutricia.

LS has served as a consultant for the following companies: Roche, Coronado, Bracket, Neuren, MedAdvante.

LS also received research support from Shire and Roche.

The remaining authors declare no conflict of interest.

Subjects:

Research Funding:

This work was supported by an award from the Emory/Children’s Pediatric Research Center & Yerkes National Primate Research Center.

The Yerkes National Primate Research Center is supported by the Office of Research Infrastructure Programs/OD P51OD011132.

The Emory Microscopy Core is supported by an NINDS Core Facilities grant, P30NS055077.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Psychiatry
  • CYCLOSERINE FACILITATES EXTINCTION
  • OBSESSIVE-COMPULSIVE DISORDER
  • GOAL-DIRECTED ACTIONS
  • BASOLATERAL AMYGDALA
  • PREFRONTAL CORTEX
  • FEAR EXTINCTION
  • REINFORCER DEVALUATION
  • EXPOSURE THERAPY
  • CONDITIONED FEAR
  • LEARNED FEAR

Successful pharmacotherapy for the treatment of severe feeding aversion with mechanistic insights from cross-species neuronal remodeling

Tools:

Journal Title:

Translational Psychiatry

Volume:

Volume 7, Number 6

Publisher:

, Pages e1157-e1157

Type of Work:

Article | Final Publisher PDF

Abstract:

Pediatric feeding disorders affect up to 5% of children, causing severe food intake problems that can result in serious medical and developmental outcomes. Behavioral intervention (BI) is effective in extinguishing feeding aversions, and also expert-dependent, time/labor-intensive and not well understood at a neurobiological level. Here we first conducted a double-blind, placebo-controlled trial comparing BI with BI plus d-cycloserine (DCS). DCS is a partial N-methyl-d-aspartate (NMDA) receptor agonist shown to augment extinction therapies in multiple anxiety disorders. We examined whether DCS enhanced extinction of feeding aversion in 15 children with avoidant/restrictive food intake disorder (ages 20-58 months). After five treatment days, BI improved feeding by 37%. By contrast, BI+DCS improved feeding by 76%. To gain insight into possible mechanisms of successful intervention, we next tested the neurobiological consequences of DCS in a murine model of feeding aversion and avoidance. In mice with conditioned food aversion, DCS enhanced avoidance extinction across a broad dose range. Confocal fluorescence microscopy and three-dimensional neuronal reconstruction indicated that DCS enlarged dendritic spine heads-the primary sites of excitatory plasticity in the brain-within the orbitofrontal prefrontal cortex, a sensory-cognition integration hub. DCS also increased phosphorylation of the plasticity-associated extracellular signal-regulated kinase 1/2. In summary, DCS successfully augments the extinction of food aversion in children and mice, an effect that may involve plasticity in the orbitofrontal cortex. These results warrant a larger-scale efficacy study of DCS for the treatment of pediatric feeding disorders and further investigations of neural mechanisms.

Copyright information:

© 2017 The Author(s)

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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