Neurophysiological mechanisms of cortical plasticity impairments in schizophrenia and modulation by the NMDA receptor agonist D-serine

Joshua T. Kantrowitz*, Michael L. Epstein, Odeta Beggel, Stephanie Rohrig, Jonathan M. Lehrfeld, Nadine Revheim, Nayla P. Lehrfeld, Jacob Reep, Emily Parker, Gail Silipo, Merav Ahissar, Daniel C. Javitt

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

76 Scopus citations

Abstract

Schizophrenia is associated with deficits in cortical plasticity that affect sensory brain regions and lead to impaired cognitive performance. Here we examined underlying neural mechanisms of auditory plasticity deficits using combined behavioural and neurophysiological assessment, along with neuropharmacological manipulation targeted at the N-methyl-D-aspartate type glutamate receptor (NMDAR). Cortical plasticity was assessed in a cohort of 40 schizophrenia/schizoaffective patients relative to 42 healthy control subjects using a fixed reference tone auditory plasticity task. In a second cohort (n = 21 schizophrenia/schizoaffective patients, n = 13 healthy controls), event-related potential and event-related time-frequency measures of auditory dysfunction were assessed during administration of the NMDAR agonist D-serine. Mismatch negativity was used as a functional read-out of auditory-level function. Clinical trials registration numbers were NCT01474395/NCT02156908. Schizophrenia/schizoaffective patients showed significantly reduced auditory plasticity versus healthy controls (P = 0.001) that correlated with measures of cognitive, occupational and social dysfunction. In event-related potential/time-frequency analyses, patients showed highly significant reductions in sensory N1 that reflected underlying impairments in θ responses (P < 0.001), along with reduced θ and β-power modulation during retention and motor-preparation intervals. Repeated administration of D-serine led to intercorrelated improvements in (i) auditory plasticity (P < 0.001); (ii) θ-frequency response (P < 0.05); and (iii) mismatch negativity generation to trained versus untrained tones (P = 0.02). Schizophrenia/schizoaffective patients show highly significant deficits in auditory plasticity that contribute to cognitive, occupational and social dysfunction. D-serine studies suggest first that NMDAR dysfunction may contribute to underlying cortical plasticity deficits and, second, that repeated NMDAR agonist administration may enhance cortical plasticity in schizophrenia.

Original languageAmerican English
Pages (from-to)3281-3295
Number of pages15
JournalBrain
Volume139
Issue number12
DOIs
StatePublished - Dec 2016

Bibliographical note

Publisher Copyright:
© The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.

Keywords

  • Clinical trials
  • Cortical plasticity
  • Imaging
  • Schizophrenia
  • Social cognition

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