Failure of Neural Responses to Safety Cues in Schizophrenia

Figure 1. The 2-day experimental paradigm. In this example, the blue light is the conditioned stimulus (CS) that was paired during fear conditioning with the electrical stimulation and was later presented during the extinction learning phase (CS+E). The fear learning context here is the office, whereas the extinction learning context is the library.

Figure 2. Skin conductance responses (SCR) on day 1 of the experiment. Mean SCRs for the fear conditioning (A) and extinction learning (B) phases are plotted. Means for each phase (early and late conditioning and end of extinction learning) are calculated using 4 CS+ and 4 CS− trials. Because it is only possible to measure levels of fear extinction and delayed fear extinction memory in participants who show some fear conditioning, participants who did not have 2 or more trials with a response magnitude of 0.3 μS or greater during the fear conditioning phase were excluded from the SCR analyses for all of the phases that followed (2 control subjects and 3 schizophrenic patients).¹⁷ One additional control subject was excluded from the extinction learning analysis because of poor electrode contact during data collection. Thus, the fear conditioning SCR analyses include data of 17 control subjects and 20 schizophrenic patients, and the extinction learning SCR analysis includes data of 14 control subjects and 17 schizophrenic patients. Both the control and schizophrenia groups acquired differential conditioned fear responses (CS+ > CS) during early conditioning. Although there was a trend toward a difference between the 2 groups in differential early fear conditioning (P = .07), there were no significant differences between the 2 groups in SCRs to the CS+ and CS− alone. * P < .05; † P < .0005, for the results of the within-group paired t tests.

Figure 3. Neural responses during fear conditioning. Voxelwise maps (A, C, and E) and bar plots (B, D, and F) showing responses of regions with significantly greater activation for the CS+ minus CS− contrast in the control subjects (n = 17) compared with the schizophrenic patients (n = 18) during fear conditioning: the left posterior cingulate gyrus (A and B), left hippocampus and amygdala (C and D) during early fear conditioning, and the right hippocampus and thalamus (E and F) during late fear conditioning. Percent signal change values, relative to a low-level baseline condition, were extracted using 3-mm radius spheres centered on the coordinate of the voxel showing the peak between-group difference (see Table 2 for coordinates and P values). The low-level baseline condition consisted of the average signal intensity over the functional magnetic resonance imaging run. * P < .05; † P < .005; ‡ P < .0005. Symbols that are closest to the bar plots represent P values for the within-group paired t tests, while those that are further from the plots represent P values for between-group comparisons. The P values of the between-group comparison at each voxel in A, C, and E are indicated by the colored bar (values less than .0001 are represented by the same color).

Figure 4. Skin conductance and neural responses during retrieval of extinction and fear memories. A, Bar plots showing mean Extinction Retention Index values for the control (n = 13) and schizophrenia (n = 13) groups (an additional 2 control subjects and 4 schizophrenic patients were excluded from the day 2 skin conductance response (SCR) analyses because of poor electrode contact during data collection). B, Bar plots showing the expected pattern of context dependence of SCRs during day 2 to the CS+ presented during extinction learning (CS+E) in the control group (n = 13): lower SCRs (ie, less fear) to the CS+E in the extinction compared with the fear context. In contrast, the schizophrenic patients (n = 13) showed an aberrant pattern of responses on day 2, showing lower SCRs to the CS+E in the fear compared with the extinction context. C, A voxel-wise map of the results of the comparison between the mean activation levels (for the CS+E minus CS+U contrast) during extinction recall in the control (n = 17) and schizophrenia (n = 15) groups showed that the ventromedial prefrontal cortex (vmPFC) exhibited significantly greater activation in the control subjects compared with the schizophrenic patients. The P values of the between-group comparison at each voxel in C are indicated by the colored bar (values less than .005 are represented by the same color). D, Bar plots showing the expected context gating of vmPFC responses in the control group: greater responses to CS+E (vs CS+U) in the extinction compared with the fear context. In contrast, the schizophrenic patients failed to recruit the vmPFC in either context. Percent signal change data were extracted using a 3-mm radius sphere centered on the voxel showing the peak between-group difference in the vmPFC during extinction recall. Five schizophrenic patients were excluded from the day 2 functional magnetic resonance imaging analyses because of excessive head motion. Light blue bars indicate skin conductance (B) or blood oxygen level–dependent (D) responses during extinction recall; dark blue bars, skin conductance (B) or blood oxygen level–dependent (D) responses during fear renewal. CON indicates control group; SCZ, schizophrenia group. * P = .03.

Figure 5. Correlations between skin conductance and neural responses during fear conditioning and negative symptom levels. A, Scatterplot illustrating the relationship between negative symptom severity, as measured by the Positive and Negative Syndrome Scale (PANSS) negative symptom subscale score, and early differential fear conditioning (CS+ minus CS− skin conductance responses [SCRs]). Values for antipsychotic-treated (n = 12) and antipsychotic-free (n = 8) schizophrenic patients are presented as blue and orange diamonds, respectively. B, A map of the clusters of voxels that showed less differential activation during early fear conditioning in patients with greater levels of negative symptoms (inverse correlations between CS+ minus CS− activation and negative symptom severity; n = 18) is shown (cluster corrected for the whole brain; P < .005). The Talairach coordinates and location of the voxel with the lowest P value for this correlation are 2, -41, -20 (Brodmann are [BA] 23), z = 3.98, P = 7 × 10⁻⁵ (white arrow). Also, the location and lowest P value for the more dorsal and anterior peak found in the posterior cingulate gyrus for this correlation are 0, -11, 33 (BA 23/24); z = 3.54, P = 4 × 10⁻⁴. The P values of the Pearson correlation at each voxel in B are indicated by the colored bar (values less than .0003 are represented by the same color). Because during early fear conditioning, the control subjects and schizophrenic patients showed opposite patterns of responses within the posterior cingulate gyrus (Figure 3B), this correlation suggested that the between-group difference in activation during this phase was driven largely by abnormal (reversed) responses of the schizophrenic patients with high levels of negative symptoms. When the contributions of the individual items of the PANSS negative symptom subscale to these 2 correlations were examined, it was found that all of the items, except social withdrawal (r = -0.16; P = .51) and emotional withdrawal, which showed only a trend (r = −0.40; P = .08), showed significant inverse correlations (P < .05) with SCR during early fear conditioning. Also, significant inverse correlations were found between blunted affect (r = −0.60; P = .008), poor rapport (r = −0.47; P = .05), and stereotyped thinking (r = −0.58; P = .01), and posterior cingulate gyrus responses during early fear conditioning.