Memantine Effects on Electroencephalographic Measures of Putative Excitatory/Inhibitory Balance in Schizophrenia

Abstract

Background: Abnormalities in cortical excitation and inhibition (E/I) balance are thought to underlie sensory and information processing deficits in schizophrenia. Deficits in early auditory information processing mediate both neurocognitive and functional impairment and appear to be normalized by acute pharmacologic challenge with the NMDA antagonist memantine (MEM).

Methods: Thirty-six subjects with a diagnosis of schizophrenia and 31 healthy control subjects underwent electroencephalographic recordings. Subjects ingested either placebo or MEM (10 or 20 mg) in a double-blind, within-subject, crossover, randomized design. The aperiodic, 1/f-like scaling property of the neural power spectra, which is thought to index relative E/I balance, was estimated using a robust linear regression algorithm.

Results: Patients with schizophrenia had greater aperiodic components compared with healthy control subjects (p < .01, d = 0.64), which was normalized after 20 mg MEM. Analysis revealed a significant dose × diagnosis interaction (p < .0001, d = 0.82). Furthermore, the MEM effect (change in aperiodic component in MEM vs. placebo conditions) was associated with baseline attention and vigilance (r = .54, p < .05) and MEM-induced enhancements in gamma power (r = -.60, p < .01).

Conclusions: Findings confirmed E/I balance abnormalities in schizophrenia that were normalized with acute MEM administration and suggest that neurocognitive profiles may predict treatment response based on E/I sensitivity. These data provide proof-of-concept evidence for the utility of E/I balance indices as metrics of acute pharmacologic sensitivity for central nervous system therapeutics.

Trial registration: ClinicalTrials.gov NCT03860597.

Keywords: Cognition; Early auditory information processing; Electroencephalography; Excitation/inhibition balance; Memantine; Schizophrenia.

Copyright © 2020 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1.

Aperiodic and periodic features – effects of acute MEM. SZ is characterized by steeper aperiodic slopes relative to NCS, indicative of greater power at lower frequencies. PSD are presented in log-log space; color-coded region represent canonical frequency bands as follows: theta (dark grey, 4–8 Hz), alpha (blue, 8–12 Hz), beta (light blue, 12–30 Hz), gamma (light grey, 30–50 Hz) (a). Acute dose of MEM 20 mg had a “normalizing” effect on aperiodic slopes (b). The “memantine effect” was more pronounced at gamma frequencies (c). Data are presented as mean ± SEM. Note: **p < .01, *p < .05.

Figure 2.

Baseline Attention and Vigilance predicts MEM effect of aperiodic slopes. MEM had greater “normalizing” effects (slope reduction) in individuals with lower vs. higher baseline attention (r= .54;p< .05).