Figure 3.

Mismatch negativity data and modeling analysis. (A) Mismatch difference waves (i.e., deviant–standard, mean ± SEM) for control subjects (Con) (n = 94; blue), people with schizophrenia diagnoses (PScz) (n = 96; red), and first-degree relatives (Rel) (n = 42; green) at electrode Fz. Group differences are computed using t tests (uncorrected [unc]) at each time point and are marked with red (PScz vs. Con) and green (Rel vs. Con) bars above the difference waves. There were no significant PScz vs. Rel differences. (B) The lower plot shows the location of the mismatch effect (i.e., deviants—standard) at sensor level across all Con and PScz, displayed at p < .05 (familywise error [FWE]). Fz is shown in white. The peak effect is shown in green (p < .001 [FWE], t₃₇₆ = 11.23). The upper plot shows sensors vs. time; the peak effect occurs at 198 ms. (C) These plots show the interaction of condition and group for the Con > PScz contrast (left) and Con > Rel contrast (right) in the same format as Figure 2B, at the lower threshold of p < .005 (unc) for display purposes. Both groups demonstrate similar differences from Con in the mismatch contrast in frontocentral sensors just before 200 ms. (D) Microcircuit models were compared, differing only in which parameters were allowed to change from their priors (estimated G connectivity parameters are shown, as in Figure 2C). These models’ free G parameters included various combinations of superficial pyramidal and/or deep pyramidal cell (blue) connections to or from inhibitory interneurons (red) and self-inhibition of superficial pyramidal and inhibitory interneuron cells. Note that each parameter within each microcircuit could differ between subjects but was constrained to be the same in every cortical area within subjects, except for superficial pyramidal self-inhibition, which could differ throughout. The final model also estimated delay (D) and time constant (T) parameters (these were fixed in the other five models). (E) Model comparison and evaluation. Left: the protected exceedance probability is the probability a particular model is more likely than any other tested model, above and beyond chance, given the group data. The model with most free parameters is at the far right; it comes second to the 6G model with fixed delays and time constants and 6 microcircuit connectivity parameters estimated. Right: a histogram of R² values for all participants for the winning model; it fits most participants well. (F) A parametric empirical Bayes (PEB) analysis of mismatch negativity model parameters (i.e., connections) that contribute to the PScz > Con mismatch effect. The results are plotted on the left (with 95% Bayesian confidence intervals) and shown in schematic form on the right; parameters with posterior probabilities of p > .95 or p > .99 of contributing to the group difference effect are indicated with 1 (∗) or 2 asterisks (∗∗), respectively. On the plot, self-inhibitory connections are shaded gray, forward (fwd) connections shaded yellow, and backward (bkwd) connections shaded purple (matching the colors in the schematic). The y-axis denotes log-scaling of the effect size; changes of exp (±0.2) are of roughly ±20%. Some parameters have been eliminated during Bayesian model reduction (see Supplement). The analysis indicates that PScz showed greater self-inhibition (or reduction in synaptic gain) in bilateral inferior frontal gyrus (IFG) in the mismatch contrast. The Rel > Con contrast did not show significant effects. (G) PEB analysis of mismatch negativity mismatch effect model parameters that correlate with current (state) abnormal auditory percepts within PScz only, plotted in the same format as Figure 3F. Within PScz, abnormal auditory percepts relate to reduced self-inhibition in right (R) IFG but disinhibition in left (L) IFG (in Broca area). All effects shown in (F) and (G) are also present without the addition of age, sex, and smoking covariates (p > .95). Inclusion of a chlorpromazine dose equivalent covariate renders the analysis in (F) nonsignificant (p > .75), but it makes the overall effect of PScz on L and R IFG self-inhibition become significant (Figure S4C). STG, superior temporal gyrus.