Memantine Effects on Sensorimotor Gating and Neurocognition in Schizophrenia

Primary outcomes

1. Prepulse Inhibition (PPI)

   Time frame: 7 and 14 days post baseline

   PPI of the startle reflex is the automatic reduction in startle magnitude (assessed by EMG of orbicularis oculi) when a startling stimulus (40 ms 118 dB(A) noise burst; "PULSE") is preceded (10-120 msec) by a weak stimulus (here a 20 msec burst 16 dB over background "PREPULSE"). A %PPI metric is calculated based on the relative startle magnitude on (PREPULSE + PULSE) trials vs. PULSE alone trials. Possible maximal inhibition is 100%; there is no maximal "negative" value of inhibition. There is no clear "advantage" or "disadvantage" for lower or higher %PPI values, though on average, schizophrenia patients demonstrate lower % values compared to matched healthy subjects. Day 1 was baseline testing: testing occurred, data was collected, but no "intervention" was given. There were two possible "interventions": active (MEM 20 mg po) and placebo. One intervention was given on day 7 post baseline, the other intervention was given on day 14 post baseline, with order of intervention balanced.

2. Mismatch Negativity (MMN); Unit of Measure of MMN is Microvolts.

   Time frame: 7 and 14 days post baseline

   85 dB SPL stimuli were presented via Etymotic ER3-A insert earphones. A 4-tone auditory oddball paradigm with 82% standards & 18% deviant stimuli, differed from standard in pitch, duration, or both. A pseudorandomized sequence produced a minimum of 3 standard tones between each deviant stimulus. All tones had 5-ms rise/fall times presented with a fixed 500-ms stimulus onset asynchrony. Subjects viewed a silent movie & instructed to ignore auditory stimuli. EEG were continuously recorded at a sampling rate of 2048-Hz from 64 channels, using BioSemi ActiveTwo system & downsampled to 512-Hz. Deviant-minus-standard difference waves were generated for each deviant type & low-pass filtered (20-Hz zerophase shift, 24 dB/octave rolloff). MMN was computed as mean amplitude across 135-205 ms range for each deviant type in difference waveforms at electrode Fz. Data were analyzed by RM-ANOVA, with diagnosis as a between-subject factor, & drug condition (placebo vs MEM) as a within-subject factor.

3. Gamma Auditory Steady-state Response (ASSR). The Primary Unit of Measure of Auditory Steady State Response (ASSR) is Gamma Evoked Power (γEP), Expressed as "Microvolts-squared".

   Time frame: 7 and 14 days post baseline

   1 ms, 85 dB clicks were presented in 500 ms trains at a frequency of 40 Hz; 250 click trains were played (inter-train interval=0.5 s). EEG was continuously recorded with 64-channel BioSemi ActiveTwo system (sampling rate=2048 Hz). Data processed offline via Matlab, EEGlab, & BrainVision Analyzer. Continuous data were segmented relative to stimulus onset (-100 ms to 500 ms) & each epoch was baseline-corrected relative to 100 ms pre-stimulus interval. γEP was assessed based on first 100 artifact-free epochs at Fz. Averaged epochs across click trains were transformed into power spectrum via fast Fourier transform using a bin width of 2 Hz. 40 Hz power spectrum was averaged across 4 Hz band from 38-42 Hz. Data were analyzed by RM-ANOVA, with diagnosis as a between- & drug condition (placebo vs MEM) as a within-subject factor. Analyses revealed robust & time bin-independent effects of diagnosis & drug across 200-500 ms window & thus this interval was the focus of all subsequent analyses.