Demographic, Clinical, and Behavioral Measures
There was a trend for the effect of Group in age (F = 2.44, df = 2,56, p = .10); TAU-alone patients were slightly older than HC (t = 1.96, df = 35, p = .06). There were Group effects in education (F = 3.53, df = 2,56, p = .04) and IQ (F = 4.70, df = 2,55, p = .01); TAU+ alone patients, relative to HC, had fewer years in education (t = 1.79, df = 35, p = .01) and lower IQ (t = 3.30, df = 34, p = .002). CBT+TAU patients did not differ from TAU-alone patients in age, education, IQ, baseline symptoms, age at illness onset, illness duration, and antipsychotic dose or from HC in demographic characteristics ().
CBT+TAU, but not TAU-alone, patients showed changes in symptoms from baseline to follow-up (Group × Time: total PANSS scores, F = 6.74, df = 1,34, p = .014; positive symptoms, F = 4.42, p = .043; negative symptoms, F = 4.47, p = .042; general psychopathology: F = 4.49, p = .041; ). Only the CBT+TAU group showed reduced symptoms at follow-up (total PANSS scores: t = 3.43, df = 18, p = .003; positive symptoms: t = 3.48, p = .003; negative symptoms: t = 1.88, p = .07; general psychopathology: t = 3.02, p = .007). Baseline symptom severity did not correlate with CBT responsiveness (change in total symptoms, r = .17, p = .48). Covarying for baseline symptoms, there was significant symptom improvement (change scores) in the CBT+TAU, relative to TAU-alone, group (total PANSS scores: F = 8.16, df = 1,36, p = .007; positive symptoms: F = 7.01, p = .012; negative symptoms: F = 8.27, p = .007; general psychopathology: F = 5.98, p = .02). As can be expected given earlier noted independence between baseline symptoms and symptom improvement in CBT+TAU patients, residual symptom change score correlated highly positively with the absolute symptom change scores (total PANSS; r = .962, p < .001). Illness duration, education, and IQ were not associated with CBT responsiveness (p values > .40).
For performance accuracy, there was a main effect of Load (F = 91.85, df = 4,106, p < .001; lower accuracy with increasing load); Group (F = 1.86, df = 2,53, p = .17) and Group × Load (F = 1.66, df = 2,53, p = .20) effects were nonsignificant. For latency, there were significant Group (F = 4.24, df = 2,53, p = .02; covarying for age, F = 4.02, df = 2,52, p = .024) and Group × Load (F = 4.24, df = 2,53, p = .02; covarying for age, F = 4.02, df = 2,52, p = .024) effects indicating longer latencies in both patient groups compared to HC, especially at 1-back and 2-back (p values < .05); there was no difference between the CBT+TAU and TAU-alone groups (p values > .40). The relationships between CBT responsiveness and performance (accuracy: 1-back, r = .33, 2-back, r = .21; latency: r = −.08, r = −.25), although in the expected direction (better performance with positive CBT response), failed to reach significance.
Pretherapy Brain Activity and CBT Responsiveness
Task-Related Activity Changes
Expected associations emerged between pretherapy task-related activity at 2-back (> 0-back) and CBT responsiveness (, ); these relationships were absent in the TAU-alone group (). Specifically, a reduction in total PANSS scores was associated with greater activity bilaterally in the inferior-middle frontal gyrus, mainly the DLPFC (BA 46). A medial PFC–anterior cingulate cluster (uncorrected p = .012) failed to survive SVC. A reduction in positive symptoms was associated with greater left inferior-middle frontal gyrus, most consistently Brodmann's area [BA] 9-46, activity. A reduction in negative symptoms was associated with greater pretherapy activity in a large left-sided cluster including the caudate, dorsomedial PFC, and DLPFC (BA 9-46). A reduction in general psychopathology was associated with greater activity bilaterally in the inferior-middle frontal gyrus, primarily BA 46.
Figure 2 Brain activity associated with response to cognitive–behavioral therapy in patients with schizophrenia during the 2-back > 0-back contrast. The top row shows positive associations and the bottom row negative associations (maps thresholded (more ...)
Brain Areas Showing Positive and Negative Associations with CBT Responsiveness in Patients
Figure 3 Scatterplots of task-load-related activity (2-back > 0-back) in the left (x= −54, y = 12, z = 26) and right (x = 52, y = 24, z = 22) frontal lobes against the change in symptoms (reduction from baseline) separately for the cognitive–behavioral (more ...)
No other activation was positively associated with a change in total or subscale symptom scores at any task load. Activity in several regions, mainly those found to be deactivated during memory load relative to no memory load (0-back/rest) conditions (Supplement 1
), was associated negatively with CBT responsiveness during 1-back and 2-back (> 0-back) conditions (, ). These relationships are due to relatively stronger deactivations during memory load conditions in patients with the strongest CBT response.
The CBT+TAU and HC groups did not differ in activity of the regions positively or negatively associated with CBT responsiveness (p values > .20).
Within the left DLPFC connectivity maps (2-back > 0-back), CBT responsiveness associated positively with covarying increases in activity in a lingual gyrus-cerebellum cluster (peak: −4[x], −70[y], −4[z], T = 5.20; subpeaks: 8,−70, 0, T = 4.84 and −2,−70,−14; T = 4.30; 874 contiguous voxels; cluster-corrected p = .04), and negatively with activity in the insula extending to thalamus/brainstem and middle/superior temporal gyrus (peak: −38,6,−6; T = 5.04; subpeaks: −4,−14,−4; T = 4.74 and −40,−12,0, T = 4.67; 4187 contiguous voxels, cluster-corrected p < .001) (). Within the right DLPFC connectivity maps (2-back > 0-back), CBT responsiveness associated negatively with activity in the thalamus extending to parahippocampal and posterior cingulate gyri (peak: −12,−24,6; T = 4.96; subpeaks: 14,−46,4; T = 4.83 and −4,−64,12; T = 4.65; 7841 contiguous voxels, cluster-corrected p < .001).
Figure 4 Left dorsolateral prefrontal cortex (DLPFC) connectivity association with response to cognitive–behavioral therapy (CBT) in patients with schizophrenia during the 2-back > 0-back contrast. The top row shows positive associations, and the (more ...) DLPFC Connectivity
In HC, the areas of significantly covarying increases with the left and right PFC activity during 2-back (> 0-back) included a large area surrounding the seed voxel and extending to the contralateral PFC and anterior cingulate, and a much smaller area in the left inferior parietal cortex (BA 40) (Table 2 in Supplement 1
). Similar coactivations occurred in CBT+TAU patients, although the parietal cluster extended to a much smaller area for left DLPFC and was absent for right PFC. Posterior cingulate activity showed significantly covarying decreases with the left and right PFC activity in HC; this was present weakly for left PFC and nonsignificant for right PFC in CBT+TAU group.