Boys with serious conduct and substance problems (“Antisocial Substance Dependence” (ASD)) repeatedly make impulsive and risky decisions in spite of possible negative consequences. Because prefrontal cortex (PFC) is involved in planning behavior in accord with prior rewards and punishments, structural abnormalities in PFC could contribute to a person's propensity to make risky decisions.

Methods

We acquired high-resolution structural images of 25 male ASD patients (ages 14–18 years) and 19 controls of similar ages using a 3T MR system. We conducted whole-brain voxel-based morphometric analysis (p<0.05, corrected for multiple comparisons at whole-brain cluster-level) using Statistical Parametric Mapping version-5 and tested group differences in regional gray matter (GM) volume with analyses of covariance, adjusting for total GM volume, age, and IQ; we further adjusted between-group analyses for ADHD and depression. As secondary analyses, we tested for negative associations between GM volume and impulsivity within groups and separately, GM volume and symptom severity within patients using whole-brain regression analyses.

Results

ASD boys had significantly lower GM volume than controls in left dorsolateral PFC (DLPFC), right lingual gyrus and bilateral cerebellum, and significantly higher GM volume in right precuneus. Left DLPFC GM volume showed negative association with impulsivity within controls and negative association with substance dependence severity within patients.

Conclusions

ASD boys show reduced GM volumes in several regions including DLPFC, a region highly relevant to impulsivity, disinhibition, and decision-making, and cerebellum, a region important for behavioral regulation, while they showed increased GM in precuneus, a region associated with self-referential and self-centered thinking.

Inhibiting unwanted thoughts, actions and emotions figures centrally in daily life, and the prefrontal cortex is widely viewed as a source of this inhibitory control. We argue that the function of the prefrontal cortex is best understood in terms of representing and actively maintaining abstract information such as goals, which produces two types of inhibitory effects on other brain regions. Inhibition of some subcortical regions takes a directed, global form, with prefrontal regions providing contextual information relevant to when to inhibit all processing in a region. Inhibition within neocortical (and some subcortical) regions takes an indirect, competitive form, with prefrontal regions providing excitation of goal-relevant options. These distinctions are critical for understanding the mechanisms of inhibition and how they can be impaired or improved.

The present research examined the hypothesis that cognitive processes are modulated differentially by trait and state negative affect (NA). Brain activation associated with trait and state NA was measured by fMRI during an attentional control task, the emotion-word Stroop. Performance on the task was disrupted only by state NA. Trait NA was associated with reduced activity in several regions, including a prefrontal area that has been shown to be involved in top-down, goal-directed attentional control. In contrast, state NA was associated with increased activity in several regions, including a prefrontal region that has been shown to be involved in stimulus-driven aspects of attentional control. Results suggest that NA has a significant impact on cognition, and that state and trait NA disrupt attentional control in distinct ways.

The ability to engage in goal-directed behavior despite exposure to stress is critical to resilience. Questions of how stress can impair or improve behavioral functioning are important in diverse settings, from athletic competitions to academic testing. Previous research suggests that controllability is a key factor in the impact of stress on behavior: learning how to control stressors buffers people from the negative effects of stress on subsequent cognitively demanding tasks. In addition, research suggests that the impact of stress on cognitive functioning depends on an individual’s response to stressors: moderate responses to stress can lead to improved performance while extreme (high or low) responses can lead to impaired performance. The present studies tested the hypothesis that (1) learning to behaviorally control stressors leads to improved performance on a test of general executive functioning, the color-word Stroop, and that (2) this improvement emerges specifically for people who report moderate (subjective) responses to stress. Experiment 1: Stroop performance, measured before and after a stress manipulation, was compared across groups of undergraduate participants (n = 109). People who learned to control a noise stressor and received accurate performance feedback demonstrated reduced Stroop interference compared with people exposed to uncontrollable noise stress and feedback indicating an exaggerated rate of failure. In the group who learned behavioral control, those who reported moderate levels of stress showed the greatest reduction in Stroop interference. In contrast, in the group exposed to uncontrollable events, self-reported stress failed to predict performance. Experiment 2: In a second sample (n = 90), we specifically investigated the role of controllability by keeping the rate of failure feedback constant across groups. In the group who learned behavioral control, those who reported moderate levels of stress showed the greatest Stroop improvement. Once again, this pattern was not demonstrated in the group exposed to uncontrollable events. These results suggest that stress controllability and subjective response interact to affect high-level cognitive abilities. Specifically, exposure to moderate, controllable stress benefits performance, but exposure to uncontrollable stress or having a more extreme response to stress tends to harm performance. These findings may provide insights on how to leverage the beneficial effects of stress in a range of settings.

The inhibition of unwanted behaviors is considered an effortful and controlled ability. However, inhibition also requires the detection of contexts indicating that old behaviors may be inappropriate – in other words, inhibition requires the ability to monitor context in the service of goals, which we refer to as context-monitoring. Using behavioral, neuroimaging, electrophysiological and computational approaches, we tested whether motoric stopping per se is the cognitively-controlled process supporting response inhibition, or whether context-monitoring may fill this role. Our results demonstrate that inhibition does not require control mechanisms beyond those involved in context-monitoring, and that such control mechanisms are the same regardless of stopping demands. These results challenge dominant accounts of inhibitory control, which posit that motoric stopping is the cognitively-controlled process of response inhibition, and clarify emerging debates on the frontal substrates of response inhibition by replacing the centrality of controlled mechanisms for motoric stopping with context-monitoring.

When we speak, we constantly retrieve and select words for production in the face of multiple possible alternatives. Our ability to respond in such underdetermined situations is supported by left ventrolateral prefrontal cortical (VLPFC) regions, but there is active debate about whether these regions support: (1) selection between competing alternatives, (2) controlled retrieval from semantic memory, or (3) selection and controlled retrieval in distinct subregions of VLPFC (selection in mid-VLPFC and controlled retrieval in anterior-VLPFC). Each of these theories has been supported by some prior evidence, but challenged by other findings, leaving the debate unresolved. We propose that these discrepancies in the previous literature reflect problems in the way that selection and controlled retrieval processes have been operationalized and measured. Using improved measures, we find that shared neural substrates in left VLPFC support both selection and controlled retrieval, with no dissociation between mid and anterior regions. Moreover, selection and retrieval demands interact in left VLPFC, such that selection effects are greatest when retrieval demands are low, consistent with prior behavioral findings. These findings enable a synthesis and reinterpretation of prior evidence, and suggest that the ability to respond in underdetermined situations is affected by both selection and retrieval mechanisms for verbal material subserved by left VLPFC, and these processes interact in meaningful ways.

Motivation and executive function are both necessary for the completion of goal-directed behavior. Research investigating the manner in which these processes interact is beginning to emerge and has implicated middle frontal gyrus (MFG) as a site of interaction for relevant neural mechanisms. However, this research has focused on state motivation, and it has not examined functional lateralization. The present study examined the impact of trait levels of approach and avoidance motivation on neural processes associated with executive function. Functional magnetic resonance imaging was conducted while participants performed a color-word Stroop task. Analyses identified brain regions in which trait approach and avoidance motivation (measured by questionnaires) moderated activation associated with executive control. Approach was hypothesized to be associated with left-lateralized MFG activation, whereas avoidance was hypothesized to be associated with right-lateralized MFG activation. Results supported both hypotheses. Present findings implicate areas of middle frontal gyrus in top-down control to guide behavior in accordance with motivational goals.

Studies of inhibitory control have focused on inhibition of motor responses. Individuals with ADHD consistently show reductions in inhibitory control and exhibit reduced activity of rLPFC activity compared to controls when performing such tasks. Recently these same brain regions have been implicated in the inhibition of memory retrieval. The degree to which inhibition of motor responses and inhibition of memory retrieval might involve overlapping systems has been relatively unexplored. The current study examined whether inhibitory difficulties in ADHD extend to inhibitory control over memory retrieval. During fMRI 16 individuals with ADHD and 16 controls performed the Think/No-Think (TNT) task. Behaviorally, the Stop Signal Reaction Time task (SSRT) was used to assess inhibitory control over motor responses. To link both of these measures to behavior, the severity of inattentive and hyperactive symptomatology was also assessed. Behaviorally, ADHD individuals had specific difficulty in inhibiting, but not in elaborating/increasing memory retrieval, which was correlated with symptom severity and longer SSRT. Additionally, ADHD individuals showed reduced activity in rLPFC during the TNT, as compared to control individuals. Moreover, unlike controls, in whom the correlation between activity of the rMFG and hippocampus predicts inhibitory success, no such correlation was observed for ADHD individuals. Moreover, decreased activity in rIFG in individuals with ADHD predicted a decrease in the ability to inhibit motor responses. These results suggest that inhibitory functions of rLPFC include control over both memory and motoric processes. They also suggest that inhibitory deficits in individuals with ADHD extend to the memory domain.

Resting-state functional magnetic resonance imaging (fMRI) has provided a novel approach for examining interhemispheric interaction, demonstrating a high degree of functional connectivity between homotopic regions in opposite hemispheres. However, heterotopic resting state functional connectivity (RSFC) remains relatively uncharacterized. In the present study, we examine non-homotopic regions, characterizing heterotopic RSFC and comparing it to intrahemispheric RSFC, to examine the impact of hemispheric separation on the integration and segregation of processing in the brain. Resting-state fMRI scans were acquired from 59 healthy participants to examine interregional correlations in spontaneous low frequency fluctuations in BOLD signal. Using a probabilistic atlas, we correlated probability-weighted time series from 112 regions (56 per hemisphere) distributed throughout the entire cerebrum. We compared RSFC for pairings of non-homologous regions located in different hemispheres (heterotopic connectivity) to RSFC for the same pairings when located within hemisphere (intrahemispheric connectivity). For positive connections, connectivity strength was greater within each hemisphere, consistent with integrated intrahemispheric processing. However, for negative connections, RSFC strength was greater between the hemispheres, consistent with segregated interhemispheric processing. These patterns were particularly notable for connections involving frontal and heteromodal regions. The distribution of positive and negative connectivity was nearly identical within and between the hemispheres, though we demonstrated detailed regional variation in distribution. We discuss implications for leading models of interhemispheric interaction. The future application of our analyses may provide important insight into impaired interhemispheric processing in clinical and aging populations.

Background

Adolescence is commonly characterized by impulsivity, poor decision-making, and lack of foresight. However, the developmental neural underpinnings of these characteristics are not well established.

Methodology/Principal Findings

To test the hypothesis that these adolescent behaviors are linked to under-developed proactive control mechanisms, the present study employed a hybrid block/event-related functional Magnetic Resonance Imaging (fMRI) Stroop paradigm combined with self-report questionnaires in a large sample of adolescents and adults, ranging in age from 14 to 25. Compared to adults, adolescents under-activated a set of brain regions implicated in proactive top-down control across task blocks comprised of difficult and easy trials. Moreover, the magnitude of lateral prefrontal activity in adolescents predicted self-report measures of impulse control, foresight, and resistance to peer pressure. Consistent with reactive compensatory mechanisms to reduced proactive control, older adolescents exhibited elevated transient activity in regions implicated in response-related interference resolution.

Conclusions/Significance

Collectively, these results suggest that maturation of cognitive control may be partly mediated by earlier development of neural systems supporting reactive control and delayed development of systems supporting proactive control. Importantly, the development of these mechanisms is associated with cognitive control in real-life behaviors.

Although numerous EEG studies have shown that depression is associated with abnormal functional asymmetries in frontal cortex, fMRI and PET studies have largely failed to identify specific brain areas showing this effect. The present study tested the hypothesis that emotion processes are related to asymmetric patterns of fMRI activity, particularly within dorsolateral prefrontal cortex (DLPFC). Eleven depressed and 18 control participants identified the color in which pleasant, neutral, and unpleasant words were printed. Both groups showed a leftward lateralization for pleasant words in DLPFC. In a neighboring DLPFC area, the depression group showed more right-lateralized activation than controls, replicating EEG findings. These data confirm that emotional stimulus processing and trait depression are associated with asymmetric brain functions in distinct subregions of the DLPFC that may go undetected unless appropriate analytic procedures are used.

Background

Attentional control difficulties in individuals with attention-deficit/ hyperactivity disorder (ADHD) might reflect poor working memory (WM) ability, especially as WM ability and attentional control rely on similar brain regions. The current study examined whether WM ability might explain group differences in brain activation between adults with ADHD and normal controls during attentional demand.

Methods

Participants were 20 adults with ADHD combined subtype with no comorbid psychiatric or learning disorders, and 23 controls similar in age, IQ, and gender. WM measures were obtained from the WAIS-III and WMS-R. Brain activation was assessed with functional magnetic resonance imaging (fMRI) while performing a Color-Word Stroop task.

Results

Group differences in WM ability explained a portion of the activation in left dorsolateral prefrontal cortex (DLPFC), which has been related to the creation and maintenance of an attentional set for task-relevant information. In addition, greater WM ability predicted increased activation of brain regions related to stimulus-driven attention and response selection processes in the ADHD group, but not in the control group.

Conclusions

The inability to maintain an appropriate task set in young adults with combined type ADHD, associated with decreased activity in left DLPFC, may in part be due to poor WM ability. Furthermore, in individuals with ADHD, higher WM ability may relate to increased recruitment of stimulus-driven attention and response selection processes, perhaps as a compensatory strategy.

Background

Adolescents with conduct and substance problems (“Antisocial Substance Disorder” (ASD)) repeatedly engage in risky antisocial and drug-using behaviors. We hypothesized that, during processing of risky decisions and resulting rewards and punishments, brain activation would differ between abstinent ASD boys and comparison boys.

Methodology/Principal Findings

We compared 20 abstinent adolescent male patients in treatment for ASD with 20 community controls, examining rapid event-related blood-oxygen-level-dependent (BOLD) responses during functional magnetic resonance imaging. In 90 decision trials participants chose to make either a cautious response that earned one cent, or a risky response that would either gain 5 cents or lose 10 cents; odds of losing increased as the game progressed. We also examined those times when subjects experienced wins, or separately losses, from their risky choices. We contrasted decision trials against very similar comparison trials requiring no decisions, using whole-brain BOLD-response analyses of group differences, corrected for multiple comparisons. During decision-making ASD boys showed hypoactivation in numerous brain regions robustly activated by controls, including orbitofrontal and dorsolateral prefrontal cortices, anterior cingulate, basal ganglia, insula, amygdala, hippocampus, and cerebellum. While experiencing wins, ASD boys had significantly less activity than controls in anterior cingulate, temporal regions, and cerebellum, with more activity nowhere. During losses ASD boys had significantly more activity than controls in orbitofrontal cortex, dorsolateral prefrontal cortex, brain stem, and cerebellum, with less activity nowhere.

Conclusions/Significance

Adolescent boys with ASD had extensive neural hypoactivity during risky decision-making, coupled with decreased activity during reward and increased activity during loss. These neural patterns may underlie the dangerous, excessive, sustained risk-taking of such boys. The findings suggest that the dysphoria, reward insensitivity, and suppressed neural activity observed among older addicted persons also characterize youths early in the development of substance use disorders.

Attention Deficit Hyperactivity Disorder (ADHD) is a widely diagnosed psychiatric disorder of childhood that may continue to manifest itself during adulthood. Across adults and children, inattention appears to be the most developmentally stable symptomatology of ADHD. To determine the neural systems that may be linked to such symptoms, the association between brain activation in a group of young adults in the face of an attentional challenge (the Stroop task) and inattentive symptoms was examined with functional magnetic resonance imaging. The results implicated a broad array of brain regions that are linked to behaviors compromised in ADHD, including executive function/cognitive control (prefrontal cortex, dorsal striatum), reward and motivational circuitry (ventral striatum), and stimulus representation and timing (posterior cortex and cerebellum). Also implicating these regions as being important for the manifestation of ADHD symptoms, the variability in the size of the BOLD signal across individuals was significantly higher for the ADHD group than for the control group, and variability across the time series in individuals with ADHD was linked to symptom severity and behavioral performance. The results suggest that a diverse set of brain structures is linked to ADHD symptoms and that the variability of activation within these regions may contribute to compromised attentional control.

Two experiments utilized a think/no-think paradigm to examine whether cognitive control of memories differs depending on whether they contain information with negative or neutral emotional content. During a training phase, participants learned face-word pairs (Experiment 1) or face-picture pairs (Experiment 2). In a subsequent experimental phase, participants were shown faces and told to think of the items paired with some of the faces and to try not to think of the items paired with other faces. Finally, in a test phase, participants were again shown each face and asked to recall the item with which it had been paired previously. Results for both verbal (Experiment 1) and nonverbal (Experiment 2) items indicated that the facilitatory and inhibitory influences of cognitive control were larger for negative than neutral items.

In this paper we provide a focused review of the literature examining neural mechanisms involved in cognitive control over memory processes that can influence, and in turn are influenced, by emotional processes. The review is divided into two parts, the first focusing on working memory and the second on long-term memory. With regard to working memory, we discuss the neural bases of 1) control mechanisms that can select against distracting emotional information, 2) mechanisms that can regulate emotional reactions or responses, 3) how mood state influences cognitive control, and 4) individual differences in control mechanisms. For long-term memory, we briefly review 1) the neural substrates of emotional memory, 2) the cognitive and neural mechanisms that are involved in controlling emotional memories and 3) how these systems are altered in post-traumatic stress disorder. Finally, we consider tentative generalizations that can be drawn from this relatively unexplored conjunction of research endeavors.

A growing number of imaging studies suggest that alcohol cues, mainly visual, elicit activation in mesocorticolimbic structures. Such findings are consistent with the growing recognition that these structures play an important role in the attribution of incentive salience and the pathophysiology of addiction. The present study investigated whether the presentation of alcohol taste cues can activate brain regions putatively involved in the acquisition and expression of incentive salience. Using functional magnetic resonance imaging, we recorded BOLD activity while delivering alcoholic tastes to 37 heavy drinking but otherwise healthy volunteers. The results yielded a pattern of BOLD activity in mesocorticolimbic structures (ie prefrontal cortex, striatum, ventral tegmental area/substantia nigra) relative to an appetitive control. Further analyses suggested strong connectivity between these structures during cue-elicited urge and demonstrated significant positive correlations with a measure of alcohol use problems (ie the Alcohol Use Disorders Identification Test). Thus, repeated exposure to the taste alcohol in the scanner elicits activation in mesocorticolimbic structures, and this activation is related to measures of urge and severity of alcohol problems.

Background

Although many neuroimaging studies have examined changes in brain function in adults with substance use disorders, far fewer have examined adolescents. This study investigated patterns of brain activation in adolescents with severe substance and conduct problems (SCP) compared to controls.

Methods

Functional magnetic resonance imaging (fMRI) at 1.5 Tesla assessed brain activation in 12 adolescent males with SCP, ranging in age from 14 to 18, and 12 controls similar in age, gender, and neighborhood while performing the attentionally-demanding Stroop task.

Results

Even though the adolescents with SCP performed as well as the controls, they activated a more extensive set of brain structures for incongruent (e.g., “red” in blue ink) versus congruent (e.g. “red” in red ink) trials. These regions included parahippocampal regions bilaterally, posterior regions involved in language-related processing, right-sided medial prefrontal areas, and subcortical regions including the the thalamus and caudate.

Conclusion

These preliminary results suggest that the neural mechanisms of attentional control in youth with SCP differ from youth without such problems. This difficulty may prevent SCP youth from ignoring salient but distracting information in the environment, such as drug-related information.

Background

Chronic exposure to drugs of addiction induces cellular adaptations in orbitofrontal cortex (OFC) and associated limbic-prefrontal pathways that may underlie abuse-related behavior. A propensity to make risky decisions in spite of substantial negative consequences may be mediated by medial OFC dysfunction in substance dependent individuals (SDI). We tested the hypothesis that medial OFC gray matter (GM) volume would be lower in SDI compared to controls.

Methods

Nineteen SDI and 20 controls participated. SDI were dependent on 2 or more substances, most often cocaine, amphetamine, and alcohol with mean duration of abstinence 4.7, 2.4, and 3.2 years, respectively. High resolution T1 weighted Images were acquired on a 3T MR system. Image processing and analyses was conducted using voxel-based morphometry (VBM) implemented in SPM5. Differences in regional GM volume were tested using an analysis of covariance model, co-varying for global GM and age. Statistical maps were set at p<.05, corrected for multiple comparisons. Medial OFC GM volume was correlated with behavioral performance on a modified gambling task.

Results

There was lower GM volume specifically in bilateral medial OFC in SDI compared to controls. There was a small but significant correlation between medial OFC GM and persistence of playing high risk decks on a modified gambling task.

Conclusions

This is the first paper to use VBM with whole brain correction for multiple comparisons in SDI after prolonged abstinence. Reduced medial OFC GM may reflect long-term adaptations within the reward-learning circuit underlying pathological decision making in substance dependence.

Background

We examined whether individual differences in hemispheric utilization can interact with the intrinsic attentional biases of the cerebral hemispheres. Evidence suggests that the hemispheres have competing biases to direct attention contralaterally, with the left hemisphere (LH) having a stronger bias than the right hemisphere. There is also evidence that individuals have characteristic biases to utilize one hemisphere more than the other for processing information, which can induce a bias to direct attention to contralateral space. We predicted that LH-biased individuals would display a strong rightward attentional bias, which would create difficulty in selectively attending to target stimuli in the left visual field (LVF) as compared to right in the performance of a bilateral flanker task.

Results

Consistent with our hypothesis, flanker interference effects were found on the N2c event-related brain potential and error rate for LH-biased individuals in the Attend-LVF condition. The error rate effect was correlated with the degree of hemispheric utilization bias for the LH-Bias group.

Conclusion

We conclude that hemispheric utilization bias can enhance a hemisphere's contralateral attentional bias, at least for individuals with a LH utilization bias. Hemispheric utilization bias may play an important and largely unrecognized role in visuospatial attention.