Auditory System Target Engagement During Plasticity-Based Interventions in Schizophrenia: A Focus on Modulation of N-Methyl-D-Aspartate-Type Glutamate Receptor Function

Abstract

Cognitive deficits are predictive of long-term social and occupational functional deficits in schizophrenia but are currently without gold-standard treatments. In particular, augmentation of auditory cortical neuroplasticity may represent a rate-limiting first step before addressing higher-order cognitive deficits. We review the rationale for N-methyl-d-aspartate-type glutamate receptor (NMDAR) modulators as treatments for auditory plasticity deficits in schizophrenia, along with potential serum and electroencephalographic target engagement biomarkers for NMDAR function. Several recently published NMDAR-modulating treatment studies are covered, involving D-serine, memantine, and transcranial direct current stimulation. While all three interventions appear to modulate auditory plasticity, direct agonists (D-serine) appear to have the largest and most consistent effects on plasticity, at least acutely. We hypothesize that there may be synergistic effects of combining procognitive NMDAR-modulating approaches with auditory cortical neuroplasticity cognitive training interventions. Future studies should assess biomarkers for target engagement and patient stratification, along with head-to-head studies comparing putative interventions and potential long-term versus acute effects.

Keywords: Biomarker; Cognition; MMN; NMDA; Plasticity; Schizophrenia; Treatment.

Figure 1

A. Voltage topography maps for d-serine (top), bitopertin (middle) and placebo (bottom) subjects for MMN, shown at peak latencies. Analyzed electrode noted by blue circle (Fz). B. Line graph of % change in behavioral plasticity on the adaptive tone-matching task across sessions for the indicated treatment orders. C. Scatter plot for % change in behavioral plasticity on the adaptive tone-matching task vs. change in MMN amplitude to the trained tone. E. Modified from (8, 89). Error bars indicate standard error of the mean; ***p<0.001

Figure 2

Effects of memantine on A: PPI; B: MMN; C, D: ASSR in healthy subjects or schizophrenia patients. Patients and HS (n’s=42 & 42) were tested after placebo or memantine (10 or 20 mg p.m.; 20 mg shown here). Compared to healthy subjects, patients had deficits in MMN and ASSR. Memantine (20 mg) significantly enhanced PPI (A; p<0.04 for 10–120 ms; p<0.01 for 60 ms), MMN (B; p<0.014; Duration; Pitch; Combined) and ASSR (C: evoked power, 40 Hz *p<0.025; D: gamma phase locking, *p<0.002). E. Distributions of “memantine effect” (memantine (20 mg) minus placebo) on early auditory processing performance, for (left to right): PPI (60 ms), MMN, gamma power and gamma coherence, in healthy subjects or schizophrenia patients (pooled, since there were no group differences in memantine effects) Modified from (97, 98).