Removing the effect of response time on brain activity reveals developmental differences in conflict processing in the posterior medial prefrontal cortex.

In functional magnetic resonance imaging (fMRI) studies, researchers often attempt to ensure that group differences in brain activity are not confounded with group differences in mean reaction time (RT). However, even when groups are matched for performance, they may differ in terms of the RT-BOLD relationship: the degree to which brain activity varies with RT on a trial-by-trial basis. Group activation differences might therefore be influenced by group differences in the relationship between brain activity and time on task. Here, we investigated whether correcting for this potential confound alters group differences in brain activity. Specifically, we reanalyzed data from a functional MRI study of response conflict in children and adults, in which conventional analyses indicated that conflict-related activity did not differ between groups. We found that the RT-BOLD relationship was weaker in children than in adults. Consequently, after removing the effect of RT on brain activity, children exhibited greater conflict-related activity than adults in both the posterior medial prefrontal cortex and the right dorsolateral prefrontal cortex. These results identify the RT-BOLD relationship as an important potential confound in fMRI studies of group differences. They also suggest that the magnitude of the RT-BOLD relationship may be a useful biomarker of brain maturity.

The development of performance-monitoring function in the posterior medial frontal cortex.

BACKGROUND: Despite its critical role in performance-monitoring, the development of posterior medial prefrontal cortex (pMFC) in goal-directed behaviors remains poorly understood. Performance monitoring depends on distinct, but related functions that may differentially activate the pMFC, such as monitoring response conflict and detecting errors. Developmental differences in conflict- and error-related activations, coupled with age-related changes in behavioral performance, may confound attempts to map the maturation of pMFC functions. To characterize the development of pMFC-based performance monitoring functions, we segregated interference and error-processing, while statistically controlling for performance. METHODS: Twenty-one adults and 23 youth performed an event-related version of the Multi-Source Interference Task during functional magnetic resonance imaging (fMRI). Linear modeling of interference and error contrast estimates derived from the pMFC were regressed on age, while covarying for performance. RESULTS: Interference- and error-processing were associated with robust activation of the pMFC in both youth and adults. Among youth, interference- and error-related activation of the pMFC increased with age, independent of performance. Greater accuracy associated with greater pMFC activity during error commission in both groups. DISCUSSION: Increasing pMFC response to interference and errors occurs with age, likely contributing to the improvement of performance monitoring capacity during development.

Pilot study of response inhibition and error processing in the posterior medial prefrontal cortex in healthy youth.

BACKGROUND: Recent neuroimaging work suggests that inhibitory and error processing in healthy adults share overlapping, but functionally distinct neural circuitries within the posterior medial frontal cortex (pMFC); however, it remains unknown whether the pMFC is differentially engaged by response inhibition compared to error commission in the developing brain. Developmental neuroimaging studies of response inhibition have found pMFC activation, but the possible contribution of error-related activation during inhibitory processing has not been well studied in youth. METHOD: To examine the processing of correct response inhibition compared to errors in the developing brain, we performed functional magnetic resonance imaging scans in 11 healthy subjects, ages 8-14 years, during an antisaccade task while performance was monitored. RESULTS: Successful antisaccades activated the pre-supplementary motor area. In contrast, errors on the antisaccade task activated the dorsal anterior cingulate cortex. CONCLUSION: The findings suggest the functional sub-specialization of inhibitory and error processing within the pMFC in this pilot sample of children and adolescents. Future neuroimaging studies of developing inhibitory control should examine both between correct and error trials.

Development of Posterior Medial Frontal Cortex Function in Pediatric Obsessive-Compulsive Disorder.

OBJECTIVE: Abnormal engagement of the posterior medial frontal cortex (pMFC) occurs during performance monitoring in obsessive-compulsive disorder (OCD), including in pediatric patients. Yet, the development of pMFC function in OCD-affected youth remains poorly understood. METHOD: A total of 69 patients with pediatric OCD and 72 healthy controls (HC), 8 to 19 years of age, were scanned during the Multisource Interference Task (MSIT). The effects of group, age, performance, and interactions on pMFC response to errors and interference were tested in the region of interest [ROI]) and whole-brain analyses. Secondary analyses considered bilateral anterior insula/frontal operculum (aI/fO), given the contribution of these regions with pMFC to a cingulo-opercular network (CON) for task control (e.g., error and interference processing). RESULTS: Error-related pMFC activity was greater for OCD patients than for HC, increased with age in OCD patients, but decreased with age in HC. Greater pMFC activation associated with better performance in HC but not OCD patients. In the patients, greater pMFC activation to errors was associated with lower OCD severity. Altered error-related activation and performance associations were also observed in the right aI/fO in OCD patients, whereas the left aI/fO response to interference was associated with lower OCD severity. CONCLUSION: Atypical increase in error-related pMFC activation with age in pediatric OCD suggests altered development of pMFC function during the early course of illness. Greater pMFC activation with better performance in HC, and with age and lower symptom severity in OCD patients, suggests an adaptive function of heightened pMFC response to errors that could be further enhanced (e.g., via cognitive training) to improve outcomes in OCD from the early course of illness.

Error-related hyperactivity of the anterior cingulate cortex in obsessive-compulsive disorder.

BACKGROUND: Hyperactivity of the anterior cingulate cortex (ACC) in patients with obsessive-compulsive disorder (OCD) has been shown to increase with symptom provocation and to normalize with treatment-induced symptom reduction. Although the functional significance of anterior cingulate involvement in OCD remains unknown, electrophysiological evidence has linked this region to error-processing abnormalities in patients with OCD. In this functional magnetic resonance imaging (fMRI) study, we sought to further localize error-processing differences within the ACC of OCD patients compared with healthy subjects. METHODS: Event-related fMRI data were collected for eight OCD patients and seven healthy subjects during the performance of a simple cognitive task designed to elicit errors but not OCD symptoms. RESULTS: Both OCD patients and healthy subjects demonstrated dorsal ACC activation during error commission. The OCD patients exhibited significantly greater error-related activation of the rostral ACC than comparison subjects. Activity in this region was positively correlated with symptom severity in the patients. CONCLUSIONS: Error-processing abnormalities within the rostral anterior cingulate occur in the absence of symptom expression in patients with OCD.

Trial-by-Trial Adjustments of Cognitive Control Following Errors and Response Conflict are Altered in Pediatric Obsessive Compulsive Disorder.

BACKGROUND: Impairments of cognitive control have been theorized to drive the repetitive thoughts and behaviors of obsessive compulsive disorder (OCD) from early in the course of illness. However, it remains unclear whether altered trial-by-trial adjustments of cognitive control characterize young patients. To test this hypothesis, we determined whether trial-by-trial adjustments of cognitive control are altered in children with OCD, relative to healthy controls. METHODS: Forty-eight patients with pediatric OCD and 48 healthy youth performed the Multi-Source Interference Task. Two types of trial-by-trial adjustments of cognitive control were examined: post-error slowing (i.e., slower responses after errors than after correct trials) and post-conflict adaptation (i.e., faster responses in high-conflict incongruent trials that are preceded by other high-conflict incongruent trials, relative to low-conflict congruent trials). RESULTS: While healthy youth exhibited both post-error slowing and post-conflict adaptation, patients with pediatric OCD failed to exhibit either of these effects. Further analyses revealed that patients with low symptom severity showed a reversal of the post-conflict adaptation effect, whereas patients with high symptom severity did not show any post-conflict adaptation. CONCLUSION: Two types of trial-by-trial adjustments of cognitive control are altered in pediatric OCD. These abnormalities may serve as early markers of the illness.

Developmental alterations of frontal-striatal-thalamic connectivity in obsessive-compulsive disorder.

OBJECTIVE: Pediatric obsessive-compulsive disorder is characterized by abnormalities of frontal-striatal-thalamic circuitry that appear near illness onset and persist over its course. Distinct frontal-striatal-thalamic loops through cortical centers for cognitive control (anterior cingulate cortex) and emotion processing (ventral medial frontal cortex) follow unique maturational trajectories, and altered connectivity within distinct loops may be differentially associated with OCD at specific stages of development. METHOD: Altered development of striatal and thalamic connectivity to medial frontal cortex was tested in 60 OCD patients compared with 61 healthy control subjects at child, adolescent, and adult stages of development, using resting-state functional connectivity MRI. RESULTS: OCD in the youngest patients was associated with reduced connectivity of dorsal striatum and medial dorsal thalamus to rostral and dorsal anterior cingulate cortex, respectively. Increased connectivity of dorsal striatum to ventral medial frontal cortex was observed in patients at all developmental stages. In child patients, reduced connectivity between dorsal striatum and rostral anterior cingulate cortex correlated with OCD severity. CONCLUSIONS: Frontal-striatal-thalamic loops involved in cognitive control are hypoconnected in young patients near illness onset, whereas loops implicated in emotion processing are hyperconnected throughout the illness.

Conditional Differences in Mean Reaction Time Explain Effects of Response Congruency, but not Accuracy, on Posterior Medial Frontal Cortex Activity.

According to the conflict-monitoring model of cognitive control, the posterior medial frontal cortex (pMFC) plays an important role in detecting conflict between competing motor responses. Consistent with this view, pMFC activity is greater in high-conflict trials (e.g., incongruent trials and errors) than in low-conflict trials (e.g., congruent trials and correct responses) of distractor interference tasks. However, in both low- and high-conflict trials, pMFC activity increases linearly with reaction time (RT). Thus, heightened pMFC activity in high-conflict trials may simply reflect the fact that mean RT is longer in high-conflict than in low-conflict trials. To investigate this hypothesis, we reanalyzed data from a previously published fMRI study in which participants performed an event-related version of the multi-source interference task. Critically, after controlling for conditional differences in mean RT, effects of response congruency on pMFC activity were eliminated; in contrast, effects of response accuracy on pMFC activity remained robust. These findings indicate that effects of response congruency on pMFC activity may index any of several processes whose recruitment increases with time on task (e.g., sustained attention). However, effects of response accuracy reflect processes unique to error trials. We conclude that effects of response accuracy on pMFC activity provide stronger support for the conflict-monitoring model than effects of response congruency.

Altered function and connectivity of the medial frontal cortex in pediatric obsessive-compulsive disorder.

BACKGROUND: Exaggerated concern for correct performance has been linked to hyperactivity of the medial frontal cortex (MFC) in adult obsessive-compulsive disorder (OCD), but the role of the MFC during the early course of illness remains poorly understood. We tested whether hyperactive MFC-based performance monitoring function relates to altered MFC connectivity within task control and default mode networks in pediatric patients. METHODS: Eighteen pairs of OCD and matched healthy youth underwent functional magnetic resonance imaging during performance monitoring and at rest. Task-related hyperactivations in the posterior and ventral MFC were used as seeds for connectivity analyses during task and resting state. RESULTS: In posterior MFC, patients showed greater activation of dorsal anterior cingulate cortex (dACC) than control subjects, with greater activation predicting worse performance. In ventral MFC, control subjects exhibited deactivation, whereas patients activated this region. Compared with control subjects, patients showed increased dACC-ventral MFC connectivity during task and decreased dACC-right anterior operculum and ventral MFC-posterior cingulate connectivity during rest. CONCLUSIONS: Excessive activation and increased interactions of posterior and ventral MFC during performance monitoring may combine with reduced resting state connectivity of these regions within networks for task control and default mode to reflect early markers of OCD. Alteration of reciprocal interactions between these networks could potentiate the intrusion of ventral MFC-based affectively laden, self-referential thoughts, while disrupting posterior MFC-based performance-monitoring function in young patients.