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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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Groups were equivalent with regard to age, race, IQ and receipt of public assistance; however, groups differed slightly with regard to family income. Specifically, HC were more likely to have a higher family income than CP PSY- youth (t(35)=2.08, p.05) and CP PSY+ youth (t(50)=2.30, p.05). As expected, both CP groups had significantly higher levels of CP, CU, ADHD and internalizing symptoms relative to HC. However, CP PSY- and CP PSY+ youth only differed on levels of psychopathic features (CU: t(35)=-3.59, p.005; narcissism: t(35)=-5.80, p.001; impulsivity: t(35)=-3.40, p.005; APSD total score: t(35)=8.24, p.001) and demonstrated equivalent levels of CP, ADHD and internalizing problems. Task performance was also examined and there were no group differences with regard to mean reaction time or number of non-responses.

General Task Activation to Reward and Punishment Prior to examining potential group differences, preliminary analyses were conducted to examine task-specific, whole-brain activation to the receipt of 1) reward and 2) punishment to

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response to reward (i.e., big and small combined) across all participants indicated that the task produced robust activation throughout expected reward-related circuitry (Figure 5, Table 5).

Clusters of significant positive BOLD response were observed in the bilateral striatum (including VS and DS), extending laterally to inferior frontal gyrus and OFC (BA47), caudally to the ventral portion of the posterior cingulate gyrus and rostrally to the insula; bilateral middle and inferior frontal gyri, extending to the mPFC (BA10) and OFC (BA11); bilateral dorsal ACC, extending to superior frontal gyrus; superior and inferior parietal lobe; and bilateral occipital lobe.

The average BOLD response to punishment (i.e., big and small combined) across all participants indicated that the task produced BOLD response patterns throughout the expected punishment-related circuitry (Figure 6, Table 6). While overlap with reward-related circuitry was considerable, BOLD response to punishment was notably less robust. Clusters of significant positive BOLD response were found in the bilateral ACC, extending to superior frontal gyrus;

bilateral thalamus, extending to parts of the caudate body and tail; bilateral inferior frontal gyrus, extending to insula and OFC (BA47); bilateral middle frontal gyrus extending to the mPFC (BA10); superior and inferior parietal lobule; and bilateral occipital lobe.

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Note. Sx=symptoms; ADHD=attention deficit hyperactivity disorder; CU=callous-unemotional traits; APSD=Antisocial Process Screening Device; * Correlation significant at p.05; ** Correlation significant at p.01.

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Note. ADHD=Attention Deficit Hyperactivity Disorder; APSD=Antisocial Process Screening Device; CU=Callous-Unemotional Traits; HC=Healthy Controls. Means designated with different subscript letters are significantly different from each other (p.05) based on post-hoc independent sample t-tests.

┼ Group differences on the aggressive behaviors subscale, rule breaking subscale and externalizing composite were also examined. CPCU- and CPCU+ were equivalent on each (p.50) and both groups evidenced significantly greater scores than HC (p.05).

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Note. ADHD=Attention Deficit Hyperactivity Disorder; APSD=Antisocial Process Screening Device; CU=Callous-Unemotional Traits; HC=Healthy Controls. Means designated with different subscript letters are significantly different from each other (p.05) based on post-hoc independent sample t-tests.

┼ Group differences on the aggressive behaviors subscale, rule breaking subscale and externalizing composite were also examined. CP PSY- and CP PSY+ were equivalent on each (p.50) and both groups evidenced significantly greater scores than HC (p.05).

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Overall task-related activation associated with large and small reward compared with implicit baseline, collapsed across group, with whole-brain family-wise error (FWE) correction of p 0.05, 20 voxel extent threshold. a) Slices shown at x = 8, y = 16, z = -1; b) Transverse slices shown every 4 units on the y-axis.

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b.

Figure 6. Combined effects of large and small punishment reveal task-related activation throughout punishment-related circuitry Overall task-related activation associated with large and small punishment compared with implicit baseline, collapsed across groups, with whole-brain family-wise error (FWE) correction of p 0.

05, 20 voxel extent threshold. a) Slices shown at x = 3 y =1, z = -1; b) Transverse slices shown every 4 units on the y-axis.

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RECEIPT OF REWARD AND PUNISHMENT AMONG BOYS WITH CP AND CU?

The first primary analysis of interest examined potential group differences in reward and punishment processing using a 3x4 ANOVA. While the focus was on the main effect of group and the interaction between group and condition, the main effect of condition was also examined and significant results are presented. All significant group differences were re-examined accounting for potential confounds (i.e., family income, IQ, clinically significant ADHD and internalizing symptoms). Lastly, CP and CU constructs were examined continuously as predictors of BOLD response to reward and punishment within a regression framework.





Main effect of condition within a priori ROIs A significant main effect of condition was found for each of the ROIs examined indicating differential BOLD response to reward and punishment conditions across all participants (Table 7). In line with the whole-brain analyses described above, there was greater activation to reward relative to punishment within the bilateral amygdala, striatum, ACC, bilateral mPFC and bilateral OFC. Pairwise t-tests corrected for multiple comparisons indicated that within each of these regions BOLD response to big and little reward was significantly greater than BOLD response to big punishment (ps.005, ps.05, respectively); additionally responsivity to big reward was greater relative to little punishment (ps.001).

Main effect of group within a priori ROIs Significant between-group differences for BOLD response collapsed across all reward and punishment conditions were only evident in the mPFC (BA10; Table 7). Figure 7 presents the mean BOLD response for the cluster that significantly differed between groups. Results indicated that across all conditions both groups of CP youth exhibited lower BOLD response;

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However, this finding was reduced to trend level significance after controlling for potential confounds (p=.09).

Group X condition interaction with a priori ROIs Brain regions exhibiting a significant group by condition interaction are displayed in Table 7. A significant interaction emerged for a cluster of voxels in the left amygdala and probing revealed significant differences in response to big reward and big punishment (Figure 8).

Follow-up group comparisons with extracted mean BOLD values from this cluster indicated that both CP groups exhibited significantly lower activation following the receipt of punishment relative to HC, who evidenced significant activation within this cluster. Importantly, these differences remained significant after accounting for potential confounds; however, there was no significant difference between CPCU- and CPCU+ youth in terms of their BOLD response to big punishment within this region. Additionally, CPCU- also exhibited a significantly lower BOLD response to big reward in the amygdala relative to HC. However, this was reduced to nonsignificance after accounting for potential confounds and clinically significant internalizing problems emerged as a significant predictor (p=.02).

Another significant group by condition interaction emerged within the left striatum, specifically within the caudate body (Table 7). Further probing of the interaction revealed significant group differences in BOLD response to big reward and big punishment (Figure 9).

While CPCU+ youth demonstrated the increased reactivity to big reward, BOLD activation was equivalent to that of HC. Significant differences emerged only for CPCU- youth who exhibited a significantly lower BOLD response to the receipt of a big reward relative to HC and CPCU+ youth. Within this region, the CPCU- group also exhibited a significantly lower BOLD response

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youth and HC. All group differences were reduced to non-significance after accounting for potential confounds, though none of the control variables emerged as significant predictors.

Whole Brain Analyses: Exploratory Exploratory whole brain analyses failed to identify any areas of activation associated with the overall main effect of group. However, two clusters of activation emerged related to the group X condition interaction and they included the bilateral cingulate gyrus (BA24/BA32) and the left postcentral gyrus (Figure 10). Consistent with analyses described above, post-hoc analyses revealed that groups differed in their responsivity to big reward and big punishment. In the cingulate gyrus, CPCU+ youth demonstrated a significantly greater BOLD response to reward relative to CPCU- youth, though neither group differed from HC. Within this same cluster, both CP groups had lower activation following punishment relative to HC, however, only CPCU- youth significantly differed from HC. In the postcentral gyrus, CPCU+ youth evidenced a significantly greater BOLD response to the receipt of reward relative to CPCU- youth and HC.

Continuous Analyses within a priori ROIs: Associations with CP and CU To augment the group based findings, analyses were re-run using continuous CP and CU scores for all participants to predict BOLD responding to each of the reward and punishment conditions within the targeted ROIs. First, the bivariate associations between CP and CU and individual differences in BOLD response to reward and punishment were examined. Next, multivariate analyses examined the unique association between CP and CU and the BOLD response to reward and punishment after controlling for their co-occurrence. All bivariate and multivariate results are presented in Table 8.

Bivariate Associations

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and this was specific to the amygdala. Specifically, higher CP was associated with reduced activation in the left amygdala following reward. With regard to punishment, the BOLD response was negatively associated with CP in all of the ROIs examined. Higher levels of CP were correlated with lower BOLD response in the bilateral amygdala, bilateral striatum, bilateral ACC, left mPFC and bilateral OFC. Additionally, CU demonstrated a negative association with BOLD response to punishment in the bilateral amygdala, left dorsal striatum (i.e., caudate and putamen) and left OFC; however, these associations were notably less robust than those with CP.

Unique Associations When CP and CU were entered simultaneously to examine unique associations with BOLD response after accounting for their overlapping variance, significant results emerged only within the bilateral amygdala and only to the receipt of punishment (Table 8). Increased CP was negatively associated with BOLD response to punishment in the amygdala, after accounting for CU (Figure 11); however, CU failed to contribute any unique variance. All other bivariate associations were reduced to non-significance, though one association that approached significance is worth noting. CU demonstrated a positive association with BOLD response in the left caudate after controlling for CP, though this association failed to reach the cluster threshold (voxels=13; z-score: 3.45; p.001; MNI peak coordinate: z=3.45, x=19, y=25).

Summary Several differences emerged between HC and CP groups in terms of BOLD responsivity to reward and punishment. Notably, these differences were specific to receipt of big reward and big punishment. Regarding responsivity to reward, differences within the left caudate, left amygdala and left mPFC were found. In contrast to expectation, CPCU- youth exhibited lower

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youth did not significantly differ from HC in reactivity to big reward in any region. Taken together, CP youth without CU traits appear to exhibit a pattern of hypoactive neural responding to reward across several key brain regions, whereas CPCU+ youth exhibit a more normative neural response to the receipt of reward. Noteworthy, these findings were reduced to trend level significance after accounting for potential confounds, with some suggestion that reduced BOLD response to reward in the amygdala was uniquely associated with clinically significant internalizing problems.

With regard to reactivity to punishment, differential responsiveness was consistently shown within the amygdala and in the predicted direction. As hypothesized, both the CPCU- and CPCU+ youth exhibited reduced neural responsivity in the left amygdala following the receipt of big punishment and this was in direct contrast to HC who demonstrated increased BOLD response to big punishment in this same region. These findings remained significant after controlling for potential confounds and were consistent with regression analyses demonstrating unique associations between reduced reactivity to punishment within the amygdala and CP severity. Additionally, both groups of CP youth demonstrated similar levels of (reduced) responsivity to punishment within the caudate and mPFC. However, when compared to HC, who were characterized by increased BOLD response to punishment in both of these regions, only CPCU- youth demonstrated significantly lower activation.

Overall, while there were several significant differences between groups of children with CP and HC regarding responsivity to both reward and punishment, there was little difference in responsivity within subgroups of children with CP. In fact, the only difference that did emerge was specific to responsivity to big reward within the caudate and this was contradictory to

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among subgroups of CP youth with and without CU traits, results more consistently point to reduced amygdala responsivity to punishment among youth with CP, regardless of the their levels of CU traits, relative to HC.

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