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1.  Separate neural representations for physical pain and social rejection 
Nature communications  2014;5:5380.
Current theories suggest that physical pain and social rejection share common neural mechanisms, largely by virtue of overlapping functional magnetic resonance imaging (fMRI) activity. Here we challenge this notion by identifying distinct multivariate fMRI patterns unique to pain and rejection. Sixty participants experience painful heat and warmth and view photos of ex-partners and friends on separate trials. FMRI pattern classifiers discriminate pain and rejection from their respective control conditions in out-of-sample individuals with 92% and 80% accuracy. The rejection classifier performs at chance on pain, and vice versa. Pain-and rejection-related representations are uncorrelated within regions thought to encode pain affect (for example, dorsal anterior cingulate) and show distinct functional connectivity with other regions in a separate resting-state data set (N = 91). These findings demonstrate that separate representations underlie pain and rejection despite common fMRI activity at the gross anatomical level. Rather than co-opting pain circuitry, rejection involves distinct affective representations in humans.
doi:10.1038/ncomms6380
PMCID: PMC4285151  PMID: 25400102
2.  The Neural Mechanisms Underlying Internally and Externally Guided Task Selection 
NeuroImage  2013;84:10.1016/j.neuroimage.2013.08.047.
While some prior work suggests that medial prefrontal cortex (MFC) regions mediate freely chosen actions, other work suggests that the lateral frontal pole (LFP) is responsible for control of abstract, internal goals. The present study uses fMRI to determine whether the voluntary selection of a task in pursuit of an overall goal relies on MFC regions or the LFP. To do so, we used a modified voluntary task switching (VTS) paradigm, in which participants choose an individual task to perform on each trial (i.e., a subgoal), under instructions to perform the tasks equally often and in a random order (i.e. the overall goal). In conjunction, we examined patterns of activation in the face of irrelevant, but task-related external stimuli that might nonetheless influence task selection. While there was some evidence that the MFC was involved in voluntary task selection, we found that the LFP and anterior insula (AI) were crucial to task selection in the pursuit of an overall goal. In addition, activation of the LFP and AI increased in the face of environmental stimuli that might serve as an interfering or conflicting external bias on voluntary task choice. These findings suggest that the LFP supports task selection according to abstract, internal goals, and leaves open the possibility that MFC may guide action selection in situations lacking in such top-down biases. As such, the current study represents a critical step towards understanding the neural underpinnings of how tasks are selected voluntarily to enable an overarching goal.
doi:10.1016/j.neuroimage.2013.08.047
PMCID: PMC3849139  PMID: 23994316
executive function; cognitive flexibility; goal maintenance; volition; fMRI
3.  Default mode network activity in male adolescents with conduct and substance use disorder* 
Drug and alcohol dependence  2013;134:242-250.
Background
Adolescents with conduct disorder (CD) and substance use disorders (SUD) experience difficulty evaluating and regulating their behavior in anticipation of future consequences. Given the role of the brain's default mode network (DMN) in self-reflection and future thought, this study investigates whether DMN is altered in adolescents with CD and SUD, relative to controls.
Methods
Twenty adolescent males with CD and SUD and 20 male controls of similar ages underwent functional magnetic resonance imaging as they completed a risk-taking decision task. We used independent component analysis as a data-driven approach to identify the DMN spatial component in individual subjects. DMN activity was then compared between groups.
Results
Compared to controls, patients showed reduced activity in superior, medial and middle frontal gyrus (Brodmann area (BA) 10), retrosplenial cortex (BA 30) and lingual gyrus (BA 18), and bilateral middle temporal gryus (BA 21/22) - DMN regions thought to support self-referential evaluation, memory, foresight, and perspective taking. Furthermore, this pattern of reduced activity in patients remained robust after adjusting for the effects of depression and attention-deficit hyperactivity disorder (ADHD). Conversely, when not adjusting for effects of depression and ADHD, patients demonstrated greater DMN activity than controls solely in the cuneus (BA 19).
Conclusions
Collectively, these results suggest that comorbid CD and SUD in adolescents is characterized by atypical activity in brain regions thought to play an important role in introspective processing. These functional imbalances in brain networks may provide further insight into the neural underpinnings of conduct and substance use disorders.
doi:10.1016/j.drugalcdep.2013.10.009
PMCID: PMC3895766  PMID: 24210423
Default Mode Network; Conduct Disorder; Substance Use Disorder; Independent Component Analysis; Functional MRI
4.  Individual Differences in the Balance of GABA to Glutamate in pFC Predict the Ability to Select among Competing Options 
Journal of cognitive neuroscience  2014;26(11):2490-2502.
Individuals vary greatly in their ability to select one item or response when presented with a multitude of options. Here we investigate the neural underpinnings of these individual differences. Using magnetic resonance spectroscopy, we found that the balance of inhibitory versus excitatory neurotransmitters in pFC predicts the ability to select among task-relevant options in two language production tasks. The greater an individual’s concentration of GABA relative to glutamate in the lateral pFC, the more quickly he or she could select a relevant word from among competing options. This outcome is consistent with our computational modeling of this task [Snyder, H. R., Hutchison, N., Nyhus, E., Curran, T., Banich, M. T., O’Reilly, R. C., et al. Neural inhibition enables selection during language processing. Proceedings of the National Academy of Sciences, U.S.A., 107, 16483–16488, 2010], which predicts that greater net inhibition in pFC increases the efficiency of resolving competition among task-relevant options. Moreover, the association with the GABA/glutamate ratio was specific to selection and was not observed for executive function ability in general. These findings are the first to link the balance of excitatory and inhibitory neural transmission in pFC to specific aspects of executive function.
doi:10.1162/jocn_a_00655
PMCID: PMC4182145  PMID: 24742191
5.  Sex modulates approach systems and impulsivity in substance dependence 
Drug and alcohol dependence  2013;133(1):222-227.
Background
Personality traits such as pathological engagement in approach behaviors, high levels of impulsivity and heightened negative affect are consistently observed in substance dependent individuals (SDI). The clinical course of addiction has been shown to differ between sexes. For example, women increase their rates of consumption of some drugs of abuse more quickly than men. Despite the potential influence of personality and sex on features of addiction, few studies have investigated the interaction of these factors in substance dependence.
Methods
Fifty-one SDI (26 male, 25 female) and 66 controls (41 male, 25 female) completed the Behavioral Inhibition/Behavioral Activation System (BIS/BAS) Scales, the Barratt Impulsiveness Scale, and the Positive and Negative Affect Schedule (PANAS-X). Data were analyzed with 2×2 ANCOVAs testing for main effects of group, sex and group by sex interactions, adjusting for education level.
Results
Significant group by sex interactions were observed for BAS scores [F(1,116)=7.03, p<.01] and Barratt Motor Impulsiveness [F(1,116)=6.11, p<.02] with female SDI showing the highest approach tendencies and impulsivity followed by male SDI, male controls, and finally female controls. SDI scored higher on negative affect [F(1,116)=25.23, p<.001] than controls. Behavioral Inhibition System scores were higher in women than men [F(1,116)=14.03, p< .001].
Conclusion
Higher BAS and motor impulsivity in SDI women relative to SDI men and control women suggest that personality traits that have been previously associated with drug use may be modulated by sex. These factors may contribute to differences in the disease course observed in male compared to female drug users.
doi:10.1016/j.drugalcdep.2013.04.032
PMCID: PMC3786050  PMID: 23725607
Substance dependence; sex; impulsivity; approach systems; affect
6.  Regional Variation in Interhemispheric Coordination of Intrinsic Hemodynamic Fluctuations 
Electrophysiological studies have long demonstrated a high degree of correlated activity between the left and right hemispheres, however little is known about regional variation in this interhemispheric coordination. While cognitive models and neuroanatomical evidence suggest differences in coordination across primary sensory-motor cortices versus higher-order association areas, these have not been characterized. Here, we used resting-state functional magnetic resonance imaging data acquired from 62 healthy volunteers to examine interregional correlation in spontaneous low-frequency hemodynamic fluctuations. Using a probabilistic atlas, we correlated probability-weighted time series from 112 regions comprising the entire cerebrum. We then examined regional variation in correlated activity between homotopic regions, contrasting primary sensory-motor cortices, unimodal association areas, and heteromodal association areas. Consistent with previous studies, robustly correlated spontaneous activity was noted between all homotopic regions, which was significantly higher than that between nonhomotopic (heterotopic and intrahemispheric) regions. We further demonstrated substantial regional variation in homotopic interhemispheric correlations that was highly consistent across subjects. Specifically, there was a gradient of interhemispheric correlation, with highest correlations across primary sensory-motor cortices (0.758,sd=0.152), significantly lower correlations across unimodal association areas (0.597,sd=0.230) and still lower correlations across heteromodal association areas (0.517,sd=0.226). These results demonstrate functional differences in interhemispheric coordination related to the brain’s hierarchical subdivisions. Synchrony across primary cortices may reflect networks engaged in bilateral sensory integration and motor coordination while lower coordination across heteromodal association areas is consistent with functional lateralization of these regions. This novel method of examining interhemispheric coordination may yield insights regarding diverse disease processes as well as healthy development.
doi:10.1523/JNEUROSCI.4544-08.2008
PMCID: PMC4113425  PMID: 19091966
Interhemispheric; Synchrony; fMRI; Connectivity; Lateralization; Hemisphere; Coordination
7.  Resting-state activity in the left executive control network is associated with behavioral approach and is increased in substance dependence 
Drug and alcohol dependence  2013;129(0):1-7.
Background
Individuals with drug addictions report increased willingness to approach rewards. Approach behaviors are thought to involve executive control processes and are more strongly represented in the left compared to right prefrontal cortex. A direct link between approach tendencies and left hemisphere activity has not been shown in the resting brain. We hypothesized that compared to controls, substance dependent individuals (SDI) would have greater left hemisphere activity in the left executive control network (ECN) at rest.
Methods
Twenty-five SDI and 25 controls completed a Behavioral Inhibition System/Behavioral Activation System (BIS/BAS) questionnaire and underwent a resting-state fMRI scan. Group independent component analysis was performed. We used template matching to identify the left and right ECN separately and compared the corresponding components across groups. Across group, BAS scores were correlated with signal fluctuations in the left ECN and BIS scores with right ECN.
Results
BAS scores were higher in SDI compared to controls (p<.003) and correlated with signal fluctuation in the left ECN. SDI showed significantly more activity than controls in the left prefrontal cortex of the left ECN. Conversely, SDI showed less activity than controls in the right prefrontal cortex of the right ECN.
Conclusions
Results from this study suggest that approach tendencies are related to the left ECN, even during rest. Higher resting-state signal in the left ECN may play a role in heightened approach tendencies that contribute to drug-seeking behavior.
doi:10.1016/j.drugalcdep.2013.01.021
PMCID: PMC3618865  PMID: 23428318
Substance Dependence; Approach; Avoidance; Resting-State; Executive Control Network; Laterality; BIS/BAS
8.  A penny for your thoughts: dimensions of self-generated thought content and relationships with individual differences in emotional wellbeing 
A core aspect of human cognition involves overcoming the constraints of the present environment by mentally simulating another time, place, or perspective. Although these self-generated processes confer many benefits, they can come at an important cost, and this cost is greater for some individuals than for others. Here we explore the possibility that the costs and benefits of self-generated thought depend, in part, upon its phenomenological content. To test these hypotheses, we first developed a novel thought sampling paradigm in which a large sample of young adults recalled several recurring thoughts and rated each thought on multiple content variables (i.e., valence, specificity, self-relevance, etc.). Next, we examined multi-level relationships among these content variables and used a hierarchical clustering approach to partition self-generated thought into distinct dimensions. Finally, we investigated whether these content dimensions predicted individual differences in the costs and benefits of the experience, assessed with questionnaires measuring emotional health and wellbeing. Individuals who characterized their thoughts as more negative and more personally significant scored higher on constructs associated with Depression and Trait Negative Affect, whereas those who characterized their thoughts as less specific scored higher on constructs linked to Rumination. In contrast, individuals who characterized their thoughts as more positive, less personally significant, and more specific scored higher on constructs linked to improved wellbeing (Mindfulness). Collectively, these findings suggest that the content of people’s inner thoughts can (1) be productively examined, (2) be distilled into several major dimensions, and (3) account for a large portion of variability in their functional outcomes.
doi:10.3389/fpsyg.2013.00900
PMCID: PMC3843223  PMID: 24376427
mind-wandering; autobiographical; rumination; depression; mindfulness
9.  The Neural Basis of Sustained and Transient Attentional Control in Young Adults with ADHD 
Neuropsychologia  2009;47(14):3095-3104.
Differences in neural activation during performance on an attentionally demanding Stroop task were examined between 23 young adults with ADHD carefully selected to not be co-morbid for other psychiatric disorders and 23 matched controls. A hybrid blocked/single-trial design allowed for examination of more sustained vs. more transient aspects of attentional control. Our results indicated neural dysregulation across a wide range of brain regions including those involved in overall arousal, top-down attentional control, late-stage and response selection and inhibition. Furthermore, this dysregulation was most notable in lateral regions of DLPFC for sustained attentional control and in medial areas for transient aspects of attentional control. Because of the careful selection and matching of our two groups, these results provide strong evidence that the neural systems of attentional control are dysregulated in young adults with ADHD and are similar to dysregulations seen in children and adolescents with ADHD.
doi:10.1016/j.neuropsychologia.2009.07.005
PMCID: PMC3703501  PMID: 19619566
10.  Negative reinforcement learning is affected in substance dependence 
Drug and Alcohol Dependence  2011;123(1-3):84-90.
Background
Negative reinforcement results in behavior to escape or avoid an aversive outcome. Withdrawal symptoms are purported to be negative reinforcers in perpetuating substance dependence, but little is known about negative reinforcement learning in this population. The purpose of this study was to examine reinforcement learning in substance dependent individuals (SDI), with an emphasis on assessing negative reinforcement learning. We modified the Iowa Gambling Task to separately assess positive and negative reinforcement. We hypothesized that SDI would show differences in negative reinforcement learning compared to controls and we investigated whether learning differed as a function of the relative magnitude or frequency of the reinforcer.
Methods
Thirty subjects dependent on psychostimulants were compared with 28 community controls on a decision making task that manipulated outcome frequencies and magnitudes and required an action to avoid a negative outcome.
Results
SDI did not learn to avoid negative outcomes to the same degree as controls. This difference was driven by the magnitude, not the frequency, of negative feedback. In contrast, approach behaviors in response to positive reinforcement were similar in both groups.
Conclusions
Our findings are consistent with a specific deficit in negative reinforcement learning in SDI. SDI were relatively insensitive to the magnitude, not frequency, of loss. If this generalizes to drug-related stimuli, it suggests that repeated episodes of withdrawal may drive relapse more than the severity of a single episode.
doi:10.1016/j.drugalcdep.2011.10.017
PMCID: PMC3292654  PMID: 22079143
Substance dependence; decision making; negative reinforcement
11.  Cortical organization of inhibition-related functions and modulation by psychopathology 
Individual differences in inhibition-related functions have been implicated as risk factors for a broad range of psychopathology, including anxiety and depression. Delineating neural mechanisms of distinct inhibition-related functions may clarify their role in the development and maintenance of psychopathology. The present study tested the hypothesis that activity in common and distinct brain regions would be associated with an ecologically sensitive, self-report measure of inhibition and a laboratory performance measure of prepotent response inhibition. Results indicated that sub-regions of DLPFC distinguished measures of inhibition, whereas left inferior frontal gyrus and bilateral inferior parietal cortex were associated with both types of inhibition. Additionally, co-occurring anxiety and depression modulated neural activity in select brain regions associated with response inhibition. Results imply that specific combinations of anxiety and depression dimensions are associated with failure to implement top-down attentional control as reflected in inefficient recruitment of posterior DLPFC and increased activation in regions associated with threat (MTG) and worry (BA10). Present findings elucidate possible neural mechanisms of interference that could help explain executive control deficits in psychopathology.
doi:10.3389/fnhum.2013.00271
PMCID: PMC3680711  PMID: 23781192
inhibition; anxiety; depression; DLPFC; attentional control
12.  Individual differences in emotion-cognition interactions: emotional valence interacts with serotonin transporter genotype to influence brain systems involved in emotional reactivity and cognitive control 
The serotonin transporter gene (5-HTTLPR) influences emotional reactivity and attentional bias toward or away from emotional stimuli, and has been implicated in psychopathological states, such as depression and anxiety disorder. The short allele is associated with increased reactivity and attention toward negatively-valenced emotional information, whereas the long allele is associated with increased reactivity and attention toward positively-valenced emotional information. The neural basis for individual differences in the ability to exert cognitive control over these bottom-up biases in emotional reactivity and attention is unknown, an issue investigated in the present study. Healthy adult participants were divided into two groups, either homozygous carriers of the 5-HTTLPR long allele or homozygous carriers of the short allele, and underwent functional magnetic resonance imaging (fMRI) while completing an Emotional Stroop-like task that varied in the congruency of task-relevant and task-irrelevant information and the emotional valence of the task-irrelevant information. Behaviorally, participants demonstrated the classic “Stroop effect” (responses were slower for incongruent than congruent trials), which did not differ by 5-HTTLPR genotype. However, fMRI results revealed that genotype influenced the degree to which neural systems were engaged depending on the valence of the conflicting task-irrelevant information. While the “Long” group recruited prefrontal control regions and superior temporal sulcus during conflict when the task-irrelevant information was positively-valenced, the “Short” group recruited these regions during conflict when the task-irrelevant information was negatively-valenced. Thus, participants successfully engaged cognitive control to overcome conflict in an emotional context using similar neural circuitry, but the engagement of this circuitry depended on emotional valence and 5-HTTLPR status. These results suggest that the interplay between emotion and cognition is modulated, in part, by a genetic polymorphism that influences serotonin neurotransmission.
doi:10.3389/fnhum.2013.00327
PMCID: PMC3701233  PMID: 23847500
5-HTTLPR; Stroop; fMRI; prefrontal cortex (PFC); eye-gaze; anxiety; positive affect
13.  Reduced Cortical Gray Matter Volume In Male Adolescents With Substance And Conduct Problems 
Drug and alcohol dependence  2011;118(2-3):295-305.
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.
doi:10.1016/j.drugalcdep.2011.04.006
PMCID: PMC3170449  PMID: 21592680
Antisocial; DLPFC; Inhibition; Dependence; Precuneus; Self-referential
14.  A unified framework for inhibitory control 
Trends in cognitive sciences  2011;15(10):453-459.
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.
doi:10.1016/j.tics.2011.07.011
PMCID: PMC3189388  PMID: 21889391
15.  Neural Mechanisms of Attentional Control Differentiate Trait and State Negative Affect 
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.
doi:10.3389/fpsyg.2012.00298
PMCID: PMC3424055  PMID: 22934089
negative affect; attentional control; prefrontal cortex; emotion; fMRI
16.  When Does Stress Help or Harm? The Effects of Stress Controllability and Subjective Stress Response on Stroop Performance 
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.
doi:10.3389/fpsyg.2012.00179
PMCID: PMC3369195  PMID: 22701442
stress; executive function; controllability; contingency
17.  Cognitive Control Reflects Context Monitoring, Not Motoric Stopping, in Response Inhibition 
PLoS ONE  2012;7(2):e31546.
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.
doi:10.1371/journal.pone.0031546
PMCID: PMC3288048  PMID: 22384038
18.  Choosing our words: Retrieval and selection processes recruit shared neural substrates in left ventrolateral prefrontal cortex 
Journal of cognitive neuroscience  2011;23(11):3470-3482.
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.
doi:10.1162/jocn_a_00023
PMCID: PMC3168706  PMID: 21452939
19.  Trait Approach and Avoidance Motivation: Lateralized Neural Activity Associated with Executive Function 
NeuroImage  2010;54(1):661-670.
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.
doi:10.1016/j.neuroimage.2010.08.037
PMCID: PMC2962704  PMID: 20728552
Approach; Avoidance; Motivation; Executive Function; Laterality; fMRI
20.  Inhibitory Control of Memory Retrieval and Motor Processing Associated with the Right Lateral Prefrontal Cortex: Evidence from Deficits in Individuals with ADHD 
Neuropsychologia  2010;48(13):3909-3917.
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.
doi:10.1016/j.neuropsychologia.2010.09.013
PMCID: PMC2979319  PMID: 20863843
ADHD; Inhibition; fMRI; Memory; Symptom; Emotion
21.  Low Frequency Fluctuations Reveal Integrated and Segregated Processing among the Cerebral Hemispheres 
NeuroImage  2010;54(1):517-527.
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.
doi:10.1016/j.neuroimage.2010.05.073
PMCID: PMC3134281  PMID: 20570737
22.  Behavioral performance predicts grey matter reductions in the right inferior frontal gyrus in young adults with combined type ADHD 
Psychiatry research  2010;182(3):231-237.
doi:10.1016/j.pscychresns.2010.01.012
PMCID: PMC2914826  PMID: 20493669
anatomy; imaging; VBM; ADHD; adult; morphology
23.  Cognitive Control in Adolescence: Neural Underpinnings and Relation to Self-Report Behaviors 
PLoS ONE  2011;6(6):e21598.
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.
doi:10.1371/journal.pone.0021598
PMCID: PMC3125248  PMID: 21738725
24.  Localization of Asymmetric Brain Function in Emotion and Depression 
Psychophysiology  2010;47(3):442-454.
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.
doi:10.1111/j.1469-8986.2009.00958.x
PMCID: PMC3086589  PMID: 20070577
25.  Attentional Control Activation Relates to Working Memory in Attention-Deficit/Hyperactivity Disorder 
Biological psychiatry  2010;67(7):632-640.
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.
doi:10.1016/j.biopsych.2009.10.036
PMCID: PMC2953472  PMID: 20060961
attention-deficit/hyperactivity disorder; ADHD; working memory; attentional control; Stroop task; functional magnetic resonance imaging; fMRI; adults

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