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Close Figure Viewer. Browse All Figures Return to Figure. Table 1. Brain functioning during the effortful regulation of emotion was elicited using an emotional faces n -back task, which is a modified version of the standard working memory n -back task including 0-back and 2-back working memory conditions An n -back task is one that asks participants to respond when they view a stimulus e.

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In addition to the working memory conditions 0-back and 2-back , four emotional valence distracter conditions no faces, happy faces, fearful faces, and neutral faces were presented to participants. Faces were flanked on each side of the n -back letter stimuli Figure 1. The faces were from the NimStim dataset in grayscale 35 , were normalized for size and luminance, and balanced by gender.

Both working memory and emotional valence conditions were presented in randomized blocks of 12 trials each. Each block started with instructions indicating the working memory condition 0-back or 2-back presented on the screen for ms, which was followed by the target stimulus letters presented flanked by the different emotional valence distracter conditions happy, fearful, neutral, or no face for ms, with an interstimulus interval jittered at an average of ms.

The total task time was 6 min and 56 s with each emotional valence distracter condition presented once for both the 0-back and 2-back conditions. All the participants completed two runs of the emotional faces n -back paradigm, with the exception of one TAU participant that completed one run. Since the focus of this research was on emotion regulation during effortful cognitive processing, only data from the effortful 2-back condition were analyzed. Figure 1. Example of a 2-back happy face distracter condition from the emotional faces n -back task.

A 3-T Siemens Verio whole-body scanner with a channel head coil was used to collect structural and functional neuroimaging data at the Scientific Imaging and Brain Research Center at Carnegie Mellon University. The images were normalized to a common Montreal Neurological Institute MNI coordinate space using an indirect normalization pipeline, with parameters obtained from a high-resolution T1 structural image. Images were smoothed with an 8-mm full-width at half maximum Gaussian kernel.

In addition to assessing brain functioning during effortful emotion regulation measured by the emotional faces n -back task outlined above, behavioral measures of emotion processing were also utilized in the parent study 18 to examine behavioral emotion processing skills at pre- and posttreatment. Noteworthy, brain regions important for emotion processing, which includes emotion regulation, such as limbic areas, have been shown to be associated with performance on both these measures 40 , The ER is also a frequently utilized measure of emotion processing in schizophrenia, as it has good psychometric properties 45 and is able to discriminate between healthy controls and individuals with schizophrenia The ER is a forced-choice, computer-administered assessment of the ability to accurately recognize different emotions.

The task involves a series of 40 happy, sad, angry, fearful, or neutral non-emotional faces. Scores represent number of correct responses, with a higher score indicating better performance. All participants were maintained on antipsychotic medications approved for the treatment of schizophrenia or schizoaffective disorder as prescribed by their treating psychiatrist. Table 1 lists antipsychotic medication characteristics of the participants. Cognitive enhancement therapy is a performance-based, comprehensive, developmental approach to the remediation of social-cognitive and neurocognitive deficits in participants with schizophrenia CET consists of 60 h of weekly computer-based neurocognitive training to in attention, memory and problem-solving and 45 small-group sessions to address social-cognitive deficits that limit functional recovery from schizophrenia.

To encourage socialization, neurocognitive training is implemented in patient pairs and conducted with coaching from a CET therapist. The 1. Key theoretically driven components of the social-cognitive groups include perspective-taking, social gist abstraction, non-verbal communication, emotion management, and foresightfulness. The social-cognitive group curriculum encourages participants to engage in activities that include responding to unrehearsed social exchanges, presenting homework, participating in social-cognitive exercises, providing feedback to others, and leading homework review.

Neurocognitive training in memory and problem-solving using PSSCogReHab 47 software proceeds concurrently with the social-cognitive groups after the conclusion of attention training. A complete description of CET has been provided elsewhere Treatment as usual served as the comparison treatment condition in this randomized feasibility trial of CET for schizophrenia participants who misuse substances. TAU consisted of traditional social services and mental health programs, which included psychiatric services, case management, individual supportive therapy, vocational rehabilitation, dual diagnosis treatment programs, and other community-based treatments for substance use.

All efforts were made to link both CET and TAU participants with necessary mental health and substance abuse services while participating in the study. Individuals were then assessed every 6 months using the aforementioned behavioral emotion processing measures. See Eack et al. The study protocol was approved by the University of Pittsburgh Institutional Review Board, was reviewed annually, and was registered in the national clinical trials database NCT Functional neuroimaging data are inherently hierarchical in nature, with brain images collected every 2 s nested within individuals in a time series.

Analysis proceeds by first estimating the effects of task condition on brain activity for each individual first-level analysis and then subjecting those contrasts to group second-level analyses SPM8 was utilized for first- and second-level voxel-based analyses to examine the differential posttreatment effects of CET compared to TAU on emotion regulation-related brain functioning.

First-level analyses consisted of modeling neural responses during each condition of the emotional faces n -back task with general linear models in each of the participants. First-level models also included the signal and motion outliers identified by the Artifact Detection Tool as covariates First-level contrasts happy face vs. To control the effect of general visual stimulation, the second-level contrasts compared emotional faces to neutral faces [e. As mentioned above, second-level models included age and race as confounding covariates.

A single region of interest mask was created in the Wake Forest University PickAtlas toolbox 50 with anatomical definitions provided by Tzourio-Mazoyer, Landeau Regions of interest included frontolimbic and striatal areas, which were the bilateral amygdala, insula, dorsolateral prefrontal cortex DLPFC , ventromedial prefrontal cortex, orbitofrontal cortex, striatum, nucleus accumbens, and the anterior cingulate cortex.

These regions have been repeatedly implicated in the regulation of emotion 22 , 24 , 36 , Due to the conservativeness of voxel-wise multiple comparison corrections in small samples 53 , Type I error was controlled using a cluster-extent thresholding method.

Cluster-level correction with a small sample may provide the best balance between type I and type II error Associations between differential posttreatment effects during emotion regulation-related brain functioning and changes in behavioral emotion regulation performance from pre- to posttreatment were analyzed with bivariate correlations and mediator models executed in R 3. It was determined that age, race, and antipsychotic medication dose were not significantly related to emotion processing behavioral performance and emotion regulation-related brain functioning.

Therefore, these variables were not included as covariates to retain statistical power in correlations and mediator models. Average magnitude estimates per region of interest per participant were extracted using MarsBar, version 0. A path analysis approach was used for the mediation analysis 58 , which was based on the mediator-analytic framework presented by Kraemer et al. Mediator models were constructed with a series of linear models 60 that analyzed the indirect effects of treatment assignment predictor on longitudinal changes in emotion processing behavioral performance outcome through posttreatment emotion regulation-related brain functioning mediator.

This was accomplished by computing the association between 1 treatment assignment and emotion regulation-related brain functioning, 2 emotion regulation-related brain function and longitudinal changes in emotion processing behavioral performance, and 3 treatment assignment and longitudinal changes in emotion processing behavioral performance. Based on MacKinnon et al. Logarithmic transformations were used to correct any variables with significantly skewed distributions prior to analysis, which included the left inferior orbital frontal cortex, right DLPFC BA 46 , and reaction time from the emotional faces n -back.

Missing data were handled with an expectation-maximization approach Reaction time and accuracy performance on the emotional faces n -back task was also analyzed in R with mixed-effects models examining group CET vs. TAU , working memory loading 0-back vs. One TAU participant had accuracy data available but did not have recorded reaction time data due to technical issues.

Such results are confirmatory that participants were paying attention to the task and any differences in brain functioning elicited during the task are not due to differential inability to complete the task. Region-of-interest voxel-based analyses were conducted using a 2 CET vs. No significant interaction effects were observed with regard to the emotional distracter conditions, and thus the main effects of treatment group were examined.

Compared to the TAU group, CET participants displayed significantly greater activation during the emotion regulation task in a large cluster involving the left inferior orbital frontal, insula, and ventromedial prefrontal cortices Table 2 ; Figure 2. Participants treated with CET, compared to TAU, also had significantly greater emotion regulation-related activation in the right DLPFC, right anterior cingulate cortex, right putamen, bilateral caudate, and in a moderately sized cluster in the right orbital frontal and right ventromedial prefrontal cortices Table 2 ; Figure 2.

Accordingly, the direction of greater activation related to CET during emotion regulation in the above frontolimbic and striatal regions may be indicative that CET is contributing to neurobiological changes in people with schizophrenia and comorbid substance misuse problems.

Table 2. Differential activation during the emotional faces n -back task observed between CET and TAU participants at posttreatment. Figure 2. Regions of significantly greater activation in participants completing 18 months of CET, compared to TAU, during the emotional faces n -back task. Mediation analyses revealed that, when adjusting for treatment assignment, greater differential emotion regulation-related activation, favoring CET, in the cluster involving the left inferior orbital frontal, ventromedial prefrontal, and insula cortices, had a significant direct effect on improved total scores on the MSCEIT, with this cluster significantly mediating the association between treatment assignment and improved performance on this test Table 3.

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No direct or mediation effects were observed with regard to changes scores on the ER Table 3. Relationships between posttreatment emotion regulation brain functioning and longitudinal changes in behavioral emotion processing performance. Substance misuse among people with schizophrenia, especially for alcohol and cannabis 2 , is a common, significant problem as addiction is associated with more severe illness trajectories 11 and worse community functioning 6.

Poor emotion regulation may be a key contributor of elevating the risk for substance misuse in individuals with schizophrenia 3 , 4. Neural correlates of disrupted emotion regulation in individuals with schizophrenia and substance misuse problems 52 have been shown to include frontal, limbic, and striatal regions important for emotional neurocircuitry 22 , 23 , The direct and mediation effects of these neurobiological differences on longitudinal changes in behavioral emotion processing outcomes were also examined.

Compared to participants in TAU, CET participants displayed significantly greater activation in frontal, limbic, and striatal networks involved in the regulation of emotion at posttreatment 22 — 24 , 36 , 63 , including the DLPFC, ventromedial prefrontal cortex, orbital frontal cortex, anterior cingulate, insula, caudate, and putamen.

No significant interactions were observed regarding emotional valence during the emotional faces n -back task. Longitudinal improvements in behavioral emotion processing abilities were correlated with greater activation in the majority of these above regions. Interestingly, a mediating effect was observed in an area including the orbital frontal cortex, ventromedial prefrontal cortex, and the insula such that greater brain activation in these regions mediated longitudinal improvements in behavioral emotion processing abilities.

This is evidenced by research demonstrating that communication of prefrontal and limbic regions modulates cognitive control over emotion regulation abilities 64 — 66 , which has been observed to be dysregulated in individuals with schizophrenia 67 , Meta-analytic evidence has shown that cognitive remediation interventions have a common neural plasticity effect of increasing activation in frontal and limbic regions that are related to improved cognitive and socio-emotional functioning in individuals with schizophrenia The findings from this investigation of increased task-related activation in some overlapping frontolimbic regions are supportive of CET as an effective intervention for supporting functional recovery of this underserved, vulnerable population.

Of course, these findings have many caveats that preclude firm conclusions regarding causality of treatment efficacy. The first limitation is the very small sample size employed in this research, particularly in the TAU condition. This may explain the lack of significant emotional valence interactions with group assignment from the emotional faces n -back task, although sufficient power was available to detect the very large effects observed in frontolimbic brain functioning.

Also related to the small sample size, the groups were not perfectly matched especially with regard to age and race. Although age and race were not significantly different between the groups, we did include them as possible confounders in all analyses examining differential effects of treatment on brain functioning. Noteworthy, CET had a higher, but non-significantly different attrition rate compared to TAU in the larger feasibility trial [for a further description, see Eack et al.

Next, because the imaging component was an opportunistic add-on study funded near the completion of the parent clinical trial, no pretreatment imaging data were available. Posttreatment randomized-controlled trials are common and protect against many threats to internal validity 71 , but in the case of quantitative outcomes with unknown baseline values, they are unable to determine the magnitude of change. Brans, R.

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