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«by Amy Lynn Byrd, Ph.D. B.S. in Psychology, College of Charleston, 2006 M.S. in Clinical Psychology, University of Pittsburgh, 2010 Submitted to the ...»

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a) Region in BA10 significant at p 0.005, corrected using 3DclusterSim threshold for contiguous voxels (F(2, 244)=7.63, 8 voxels). Slices shown at x= -5, y=50, z =9 (MNI peak voxel); b) Bar graph depicts extracted mean blood oxygen level-dependent (BOLD) response for each group across all conditions within the cluster along with standard errors; c) For descriptive purposes, mean level activation, along with standard errors, within the significant cluster by group and condition are also presented.

** = p 0.01. The p-values are based on Games-Howell pairwise comparisons for extracted mean BOLD response.

80 Figure 8. Activation in the left amygdala is association with CPCU group X task condition interaction

a) Region in the amygdala significant at p 0.05, corrected using 3DclusterSim threshold for contiguous voxels (F(6,244) = 9.41, 22 voxels). Slices shown at x = -22, y = -6, z = -19 (MNI peak voxel); b) Bar graphs depict extracted mean blood oxygen level-dependent (BOLD) response across all voxels within the cluster along with standard errors.

* = p 0.05; ** = p 0.01. The p-values are based on Games-Howell pairwise comparisons for extracted mean BOLD response. NS=non-significant.

81 Figure 9. Activation in the left caudate is associated with CPCU group X task condition interaction

a) Region in the caudate significant at p 0.005, corrected using 3DclusterSim threshold for contiguous voxels (F(6,244) = 4.37, 14 voxels). Slices shown at x = -12, y =3, z =15 (MNI peak voxel); b) Bar graphs depict extracted mean blood oxygen level-dependent (BOLD) response across all voxels within the cluster along with standard errors.

* = p 0.05. The p-values are based on Games-Howell pairwise comparisons for extracted mean BOLD response. NS=non-significant.

82 Figure 10. Exploratory whole brain analyses revealed CPCU group X task condition interaction within the bilateral cingulate gyrus and left postcentral gyrus

a) Region in the bilateral cingulated gyrus significant at a threshold of p.001 with 20 contiguous voxels, uncorrected for multiple comparisons (F(6,244)= 4.37, 25 voxels). Slices shown at x =5, y =9, z =31; b) Bar graphs depict extracted mean blood oxygen level-dependent (BOLD) response across all voxels within the cingulate gyrus cluster along with standard errors;

c) Region in the left postcentral gyrus significant at a threshold of p.001 with 20 contiguous voxels, uncorrected for multiple comparisons (F(6,244)= 4.37, 27 voxels). Slices shown at x=-53 y=-9, z=21; d) Bar graphs depict extracted mean blood oxygen level-dependent (BOLD) response across all voxels within the postcentral gyrus cluster along with standard errors.

* = p 0.05; **= p 0.01. The p-values are based on Games-Howell pairwise comparisons for extracted mean BOLD response. NS=non-significant.

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a) Region in the bilateral amygdala significant at p 0.05, corrected using 3DclusterSim threshold for contiguous voxels (Right amygdala: 33 voxels, z = 3.06; Left amygdala: 29 voxels, z = 2.77). Slice shown at x = 28, y =0, z =-28; b) Scatter plot depicts association between baseline levels of conduct problems (x-axis) and mean BOLD change in the amygdala (y-axis) after controlling for co-occurring CU traits (r=-.42).

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The following set of secondary analyses examined potential group differences in reward and punishment processing using alternative classification criteria (i.e., total level of psychopathic features) that more closely mirrors past research in this area. Analyses were conducted identically to those described above. Main effects of condition are described above and are not reiterated here (see Table 7).

Main effect of group within a priori ROIs No significant main effects of group were detected for any of the ROIs.

Group X condition interaction with a priori ROIs Brain regions exhibiting a significant group by condition interaction are displayed in Table 9. A significant interaction emerged in the bilateral amygdala (Figure 12) and follow-up analysis indicated that groups differed in their responsivity to big punishment. Youth with CP PSY+ demonstrated significantly lower activation following the receipt of punishment relative to HC and this finding remained significant after accounting for potential confounds. However, CP PSY- did not differ in their level of BOLD response to punishment when compared to CP PSY+ youth or HC.

Another significant group by condition interaction emerged within the left striatum and this was specific to the putamen (Table 9). Further probing of the interaction revealed significant groups differences in BOLD response to big punishment (Figure 13). Similar to activation patterns seen within the amygdala, CP PSY+ evidenced significantly lower activation to punishment relative to HC, while youth in the CP PSY- group did not differ significantly from

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for potential confounds.

Whole Brain Analyses: Exploratory Exploratory whole brain analyses failed to identify any areas of activation associated with the overall main effect of group or the group X condition interaction.

Continuous Analyses within a priori ROIs: Associations with CP and PSY As described above, analyses were re-run using continuous CP and PSY scores to BOLD response to each of the reward and punishment outcomes within the targeted ROIs using all participants (Table 10). First, the bivariate associations between PSY and individual differences in BOLD responding were examined (see Table for bivariate associations with CP). Next, multivariate analyses examined the unique association between CP and PSY and the BOLD response after controlling for their co-occurrence.





Bivariate Associations Consistent with group-based analyses, PSY was unrelated to responsivity to reward in all of the ROIs examined. Higher levels of PSY were associated with reduced BOLD response to big punishment in the bilateral amygdala, bilateral dorsal striatum (i.e., caudate and putamen), and left OFC.

Unique Associations When CP and PSY were entered simultaneously into a multivariate regression, significant results emerged only within the bilateral amygdala and only to the receipt of punishment (Table 10). Specifically, increased CP was negatively associated with BOLD response to punishment in the amygdala after accounting for the co-occurrence of PSY. All other bivariate associations were reduced to non-significance.

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When CP groups were differentiated based on the presence of psychopathic features, fewer group differences emerged. Contrary to hypotheses, there was no variation seen in responsivity to reward and group differences surfaced only in responsiveness to big punishment.

In line with prediction, both CP groups evidenced lower reactivity to punishment within the amygdala; however, contrary to hypotheses, only CP PSY+ significantly differed from HC and there were no differences between CP PSY+ and CP PSY- youth. These findings were echoed in regression analyses that demonstrated significant negative associations between amygdala reactivity to punishment and CP severity, even after accounting for co-occurring psychopathic features. This same pattern of group differences emerged in response to punishment within the putamen, though the direction of activation was contrary to prediction. Specifically, CP PSY+ youth demonstrated significantly lower activation within this region relative to HC though differences between subgroups of CP youth failed to reach significance.

In sum, results reiterate a reduced sensitivity to punishment that is most consistently evidenced in the amygdala. Importantly, these findings remained significant after controlling for potential confounds. Moreover, there was no evidence that reduced reactivity to punishment was specific to a subgroup of CP youth psychopathic features.

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a) Region in the bilateral amygdala significant at p 0.05, corrected using 3DclusterSim threshold for contiguous voxels (Left amygdala: 39 voxels, F(6,244) = 5.01; Right amygdala: 29 voxels, F(6,244) = 3.90). Slice shown at x = -21, y =-3, z =-18; b) Bar graphs depict extracted mean blood oxygen level-dependent (BOLD) response across all voxels within the cluster along with standard errors.

** = p 0.01. The p-values are based on Games-Howell pairwise comparisons for extracted mean BOLD response. NS=non-significant.

90 Figure 13. Activation in the left putamen is associated with CP PSY group X task condition interaction

a) Region in the putamen significant at p 0.005, corrected using 3DclusterSim threshold for contiguous voxels (F(6,244) = 4.28, 62 voxels). Slices shown at x = -12, y =3, z =15 (MNI peak voxel); b) Bar graphs depict extracted mean blood oxygen level-dependent (BOLD) response across all voxels within the cluster along with standard errors.

* = p 0.05. The p-values are based on Games-Howell pairwise comparisons for extracted mean BOLD response. NS=non-significant.

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PROCESSING ASSOCIATED WITH RESPONSIVENESS TO TREATMENT?

The following sets of analyses were conducted to examine the association between individual differences in BOLD response to reward and punishment and treatment responsiveness. As described above, overall treatment effectiveness, effect of brain function and the interaction between treatment group and brain function were examined. For these analyses, brain function was defined as those clusters reaching significance in group level analyses. Prior to examining potential associations between abnormalities in reward/punishment processing and treatment responsiveness, information regarding the success of random assignment and service use is presented.

Random Assignment and Service Use As described above, participants were randomly assigned to one of two treatment conditions (SNAP versus TAU) as a part of a larger treatment study, which demonstrated moderate treatment effects (Burke & Loeber, 2014). To verify that randomization was successful among the current subsample of participants, groups were compared on all study variables of interest. Table 11 presents the means and standard deviations for all study variables at baseline and post-treatment follow-up for youth participating in SNAP and youth participating in TAU.

Both treatment groups were equivalent on all demographic and baseline measures.

Of those enrolled in SNAP, children attended an average of 6.63 (SD=4.73) of the 12 child sessions and parents attended an average of 5.89 (SD=4.57) of the 12 parent sessions; this did not significantly differ from those in the larger treatment sample. While over 50% of children

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attended 8 or more parent sessions, there were 4 children (21%) who attended no child sessions and 4 (21%) parents who attended no parent sessions. As the larger treatment evaluation was implemented with an intent-to-treat design, all participants were retained in the analyses after randomization, regardless of their level of service use.

Of those assigned to TAU, only 2 (13.3%) children were engaged in wrap around services by the 3-month follow-up assessment and this was comparable to percentage of youth engaged in the larger treatment sample (16 out of 122, 13.1%). An additional 5 (33.3%) children engaged in lower intensity mental health services by the 3-month follow-up, including outpatient mental health treatment and other behavioral health services. This was also comparable to the larger treatment sample.

Effects of brain function on treatment outcome Separate repeated measures ANOVAs were conducted for each of the clusters that significantly differentiated groups in the analyses described above (Aim 1) and the effects of interest are shown in Table 12. As predicted, there was an overall effect of intervention as indicated by the interaction between time (CP at baseline, CP at 3-month) and treatment group (Figure 14). Post-hoc paired sample t-tests revealed a significant reduction in CP from baseline to 3-month follow-up for youth participating in SNAP (t(18)=5.14; p.001), whereas youth in the TAU group did not experience any significant change in CP across this same period (t(14)=1.13; p.25). This is in line with hypotheses and indicates that youth participating in SNAP experienced significant reductions in CP over time relative to those youth in TAU.

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there a significant interaction between time, treatment group and brain function, suggesting that brain function did not moderate intervention effects on CP over time.

In a second set of analyses effects of interest were examined using binary logistic regression with treatment responders versus non-responders as the dependent variable.

Expanding on the findings described above, there was a consistent trend level main effect of treatment indicating that relative to youth receiving TAU, youth assigned to SNAP were more likely to respond to treatment as defined by a 5 or more point reduction (0.5 SD) in CP over time as measured by the CBCL. However, consistent with the aforementioned analyses there was no evidence for a main effect of brain function or a treatment group by brain function interaction.

Summary Consistent with hypotheses and findings from the larger treatment study (Burke & Loeber, 2014), results confirm the overall effectiveness of the SNAP intervention. However, contrary to prediction, abnormalities in responsivity to reward/punishment were unassociated with level of CP at follow-up and there was no evidence of moderation. Thus, regardless of individual differences in responsivity to reward/punishment, youth assigned to SNAP were more likely to experience significant reductions in CP over time.

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\Note. TX=treatment; X=interaction; CPCU=conduct problems, callous-unemotional traits; CP PSY=conduct problems, psychopathic features; mPFC=medial prefrontal cortex; R/L=right and left.

* = p 0.05; ** = p 0.01

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Post-hoc paired sample t-tests revealed significant differences between baseline levels of CP and CP at 3-month follow-up for those youth participating in SNAP (t(33)=5.14; p.001). No differences were seen between levels of CP at baseline and 3-month follow-up for those youth in TAU (t(33)=1.13; p.25).

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