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1.  A Brain Network Instantiating Approach and Avoidance Motivation 
Psychophysiology  2012;49(9):1200-1214.
Research indicates that dorsolateral prefrontal cortex (DLPFC) is important for pursuing goals, and areas of DLPFC are differentially involved in approach and avoidance motivation. Given the complexity of the processes involved in goal pursuit, DLPFC is likely part of a network that includes orbitofrontal cortex (OFC), cingulate, amygdala, and basal ganglia. This hypothesis was tested with regard to one component of goal pursuit, the maintenance of goals in the face of distraction. Examination of connectivity with motivation-related areas of DLPFC supported the network hypothesis. Differential patterns of connectivity suggest a distinct role for DLPFC areas, with one involved in selecting approach goals, one in selecting avoidance goals, and one in selecting goal pursuit strategies. Finally, differences in trait motivation moderated connectivity between DLPFC and OFC, suggesting that this connectivity is important for instantiating motivation.
PMCID: PMC4559331  PMID: 22845892
2.  Adolescents' Neural Processing of Risky Decisions: Effects of Sex and Behavioral Disinhibition 
PLoS ONE  2015;10(7):e0132322.
Accidental injury and homicide, relatively common among adolescents, often follow risky behaviors; those are done more by boys and by adolescents with greater behavioral disinhibition (BD).
Neural processing during adolescents' risky decision-making will differ in youths with greater BD severity, and in males vs. females, both before cautious behaviors and before risky behaviors.
Methodology/Principal Findings
81 adolescents (Patients with substance and conduct problems, and comparison youths (Comparisons)), assessed in a 2 x 2 design (Patients:Comparisons x Male:Female) repeatedly decided between doing a cautious behavior that earned 1 cent, or a risky one that either won 5 or lost 10 cents. Odds of winning after risky responses gradually decreased. Functional magnetic resonance imaging captured brain activity during 4-sec deliberation periods preceding responses. Most neural activation appeared in known decision-making structures. Patients, who had more severe BD scores and clinical problems than Comparisons, also had extensive neural hypoactivity. Comparisons' greater activation before cautious responses included frontal pole, medial prefrontal cortex, striatum, and other regions; and before risky responses, insula, temporal, and parietal regions. Males made more risky and fewer cautious responses than females, but before cautious responses males activated numerous regions more than females. Before risky behaviors female-greater activation was more posterior, and male-greater more anterior.
Neural processing differences during risky-cautious decision-making may underlie group differences in adolescents' substance-related and antisocial risk-taking. Patients reported harmful real-life decisions and showed extensive neural hypoactivity during risky-or-cautious decision-making. Males made more risky responses than females; apparently biased toward risky decisions, males (compared with females) utilized many more neural resources to make and maintain cautious decisions, indicating an important risk-related brain sexual dimorphism. The results suggest new possibilities for prevention and management of excessive, dangerous adolescent risk-taking.
PMCID: PMC4503769  PMID: 26176860
3.  Female Adolescents with Severe Substance and Conduct Problems Have Substantially Less Brain Gray Matter Volume 
PLoS ONE  2015;10(5):e0126368.
Structural neuroimaging studies have demonstrated lower regional gray matter volume in adolescents with severe substance and conduct problems. These research studies, including ours, have generally focused on male-only or mixed-sex samples of adolescents with conduct and/or substance problems. Here we compare gray matter volume between female adolescents with severe substance and conduct problems and female healthy controls of similar ages. Hypotheses: Female adolescents with severe substance and conduct problems will show significantly less gray matter volume in frontal regions critical to inhibition (i.e. dorsolateral prefrontal cortex and ventrolateral prefrontal cortex), conflict processing (i.e., anterior cingulate), valuation of expected outcomes (i.e., medial orbitofrontal cortex) and the dopamine reward system (i.e. striatum).
We conducted whole-brain voxel-based morphometric comparison of structural MR images of 22 patients (14-18 years) with severe substance and conduct problems and 21 controls of similar age using statistical parametric mapping (SPM) and voxel-based morphometric (VBM8) toolbox. We tested group differences in regional gray matter volume with analyses of covariance, adjusting for age and IQ at p<0.05, corrected for multiple comparisons at whole-brain cluster-level threshold.
Female adolescents with severe substance and conduct problems compared to controls showed significantly less gray matter volume in right dorsolateral prefrontal cortex, left ventrolateral prefrontal cortex, medial orbitofrontal cortex, anterior cingulate, bilateral somatosensory cortex, left supramarginal gyrus, and bilateral angular gyrus. Considering the entire brain, patients had 9.5% less overall gray matter volume compared to controls.
Female adolescents with severe substance and conduct problems in comparison to similarly aged female healthy controls showed substantially lower gray matter volume in brain regions involved in inhibition, conflict processing, valuation of outcomes, decision-making, reward, risk-taking, and rule-breaking antisocial behavior.
PMCID: PMC4441424  PMID: 26000879
4.  Reduced Neural Tracking of Prediction Error in Substance-Dependent Individuals 
The American journal of psychiatry  2013;170(11):1356-1363.
Substance-dependent individuals make poor decisions on the Iowa Gambling Task, a reward-related decision-making task that involves risk and uncertainty. Task performance depends on several factors, including how sensitive individuals are to feedback and how well they learn based on such feedback. A physiological signal that guides decision making based on feedback is prediction error. The authors investigated whether disruptions in the neural systems underlying prediction error processing in substance-dependent individuals could account for decision-making performance on a modified Iowa Gambling Task.
Thirty-two substance-dependent individuals and 30 healthy comparison subjects played a modified version of the Iowa Gambling Task during MR scanning. Trial-to-trial behavior and functional MRI (fMRI) blood-oxygen-level-dependent (BOLD) signal were analyzed using a computational model of prediction error based on internal expectancies. The authors investigated how well BOLD signal tracked prediction error in the striatum and the orbitofrontal cortex as well as over the whole brain in patients relative to comparison subjects.
Compared with healthy subjects, substance-dependent patients were less sensitive to loss compared with gain, made less consistent choices, and performed worse on the modified Iowa Gambling Task. The ventral striatum and medial orbitofrontal cortex did not track prediction error as strongly in patients as in healthy subjects.
Weaker tracking of prediction error in substance-dependent relative to healthy individuals suggests that altered frontal-striatal error learning signals may underlie decision-making impairments in drug abusers. Computational fMRI may help bridge the knowledge gap between physiology and behavior to inform research aimed at substance abuse treatment.
PMCID: PMC4426095  PMID: 23897123
5.  Organization of the Human Frontal Pole Revealed by Large-Scale DTI-Based Connectivity: Implications for Control of Behavior 
PLoS ONE  2015;10(5):e0124797.
The goal of the current study was to examine the pattern of anatomical connectivity of the human frontal pole so as to inform theories of function of the frontal pole, perhaps one of the least understood region of the human brain. Rather than simply parcellating the frontal pole into subregions, we focused on examining the brain regions to which the frontal pole is anatomically and functionally connected. While the current findings provided support for previous work suggesting the frontal pole is connected to higher-order sensory association cortex, we found novel evidence suggesting that the frontal pole in humans is connected to posterior visual cortex. Furthermore, we propose a functional framework that incorporates these anatomical connections with existing cognitive theories of the functional organization of the frontal pole. In addition to a previously discussed medial-lateral distinction, we propose a dorsal-ventral gradient based on the information the frontal pole uses to guide behavior. We propose that dorsal regions are connected to other prefrontal regions that process goals and action plans, medial regions are connected to other brain regions that monitor action outcomes and motivate behaviors, and ventral regions connect to regions that process information about stimuli, values, and emotion. By incorporating information across these different levels of information, the frontal pole can effectively guide goal-directed behavior.
PMCID: PMC4422440  PMID: 25945925
Depression and anxiety  2014;31(10):805-813.
Advancing research on the etiology, prevention, and treatment of psychopathology requires the field to move beyond modular conceptualizations of neural dysfunction toward understanding disturbance in key brain networks. Although some studies of anxiety and depression have begun doing so, they typically suffer from several drawbacks, including: (1) a categorical approach ignoring transdiagnostic processes, (2) failure to account for substantial anxiety and depression comorbidity, (3) examination of networks at rest, which overlooks disruption manifesting only when networks are challenged. Accordingly, the present study examined relationships between transdiagnostic dimensions of anxiety/depression and patterns of functional connectivity while goal maintenance was challenged.
Participants (n = 179, unselected community members and undergraduates selected to be high/low on anxiety/depression) performed a task in which goal maintenance was challenged (color-word Stroop) while fMRI data were collected. Analyses examined moderation by anxiety/depression of condition-dependent coupling between regions of dorsolateral prefrontal cortex (dlPFC) previously associated with approach and avoidance motivation and amygdala/orbitofrontal cortex (OFC).
Anxious arousal was positively associated with amygdala↔right dlPFC coupling. Depression was positively associated with OFC↔right dlPFC coupling and negatively associated with OFC↔left dlPFC coupling.
Findings advance the field toward an integrative model of the neural instantiation of anxiety/depression by identifying specific, distinct dysfunctions associated with anxiety and depression in networks important for maintaining approach and avoidance goals. Specifically, findings shed light on potential neural mechanisms involved in attentional biases in anxiety and valuation biases in depression and underscore the importance of examining transdiagnostic dimensions of anxiety/depression while networks are challenged.
PMCID: PMC4418555  PMID: 24753242
amygdale; anxiety; depression; dorsolateral prefrontal cortex; orbitofrontal cortex, network; transdiagnostic
7.  Depression and Anxious Apprehension Distinguish Frontocingulate Cortical Activity during Top-Down Attentional Control 
Journal of abnormal psychology  2011;120(2):272-285.
A network consisting of left dorsal lateral prefrontal cortex (LDLPFC) and dorsal anterior cingulate cortex (dACC) has been implicated in top-down attentional control. Few studies have systematically investigated how this network is altered in psychopathology, despite evidence that depression and anxiety are associated with attentional control impairments. fMRI and dense-array ERP data were collected in separate sessions from 100 participants during a color-word Stroop task. fMRI results guided ERP source modeling to characterize the time course of activity in LDLPFC (300-440 ms) and dACC (520-680 ms). At low levels of depression, LDLPFC activity was indirectly related to Stroop interference and only via dACC activity. In contrast, at high levels of depression, dACC did not play an intervening role, and increased LDLPFC activity was directly related to decreased Stroop interference. Specific to high levels of anxious apprehension, higher dACC activity was related to more Stroop interference. Results indicate that depression and anxious apprehension modulate temporally and functionally distinct aspects of the frontocingulate network involved in top-down attention control.
PMCID: PMC4406398  PMID: 21553941
depression; anxious apprehension; dACC; LDLPFC; attention; color-word Stroop
8.  Co-occurring Anxiety Influences Patterns of Brain Activity in Depression 
Brain activation associated with anhedonic depression and co-occurring anxious arousal and anxious apprehension was measured by fMRI during performance of an emotion-word Stroop task. Consistent with EEG findings, depression was associated with rightward frontal lateralization in dorsolateral prefrontal cortex (DLPFC), but only when anxious arousal was elevated and anxious apprehension was low. Activity in right inferior frontal gyrus (IFG) was also reduced for depression under the same conditions. In contrast, depression was associated with more activity in anterior cingulate cortex (dACC and rACC) and bilateral amygdala. Results imply that depression, particularly when accompanied by anxious arousal, may result in a failure to implement top-down processing by appropriate brain regions (left DLPFC, right IFG) due to increased activation in regions associated with responding to emotionally salient information (right DLPFC, amygdala).
PMCID: PMC4403735  PMID: 20233962
9.  Temporal profile of fronto-striatal-limbic activity during implicit decisions in drug dependence 
Drug and alcohol dependence  2014;136:108-114.
Substance dependence is associated with impaired decision-making and altered fronto-striatal-limbic activity. Both greater and lesser brain activity have been reported in drug users compared to controls during decision-making. Inconsistent results might be explained by group differences in the temporal profile of the functional magnetic resonance imaging (fMRI) response. While most previous studies model a canonical hemodynamic response, a finite impulse response (FIR) model measures fMRI signal at discrete time points without assuming a temporal profile. We compared brain activity during decision-making and feedback in substance users and controls using two models: a canonical hemodynamic response function (HRF) and a FIR model.
37 substance-dependent individuals (SDI) and 43 controls performed event-related decision-making during fMRI scanning. Brain activity was compared across group using canonical HRF and FIR models.
Compared to controls, SDI were impaired at decision-making. The canonical HRF model showed that SDI had significantly greater fronto-striatal-limbic activity during decisions and less activity during feedback than controls. The FIR model confirmed greater activity in SDI during decisions. However, lower activity in SDI during feedback corresponded to a lower post-stimulus undershoot of the hemodynamic response.
Greater activity in fronto-striatal-limbic pathways in SDI compared to controls is consistent with prior work, further supporting the hypothesis that abnormalities in these circuits underlie impaired decision-making. We demonstrate for the first time using FIR analysis that lower activity during feedback may simply reflect the tail end of the hemodynamic response to decision, the post-stimulus undershoot, rather than an actual difference in feedback response.
PMCID: PMC4041284  PMID: 24491458
Substance dependence; fronto-striatal-limbic system; Iowa Gambling Task; decision-making; finite impulse response (FIR); canonical hemodynamic response function
10.  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.
PMCID: PMC4285151  PMID: 25400102
11.  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.
PMCID: PMC3849139  PMID: 23994316
executive function; cognitive flexibility; goal maintenance; volition; fMRI
12.  Default mode network activity in male adolescents with conduct and substance use disorder* 
Drug and alcohol dependence  2013;134:242-250.
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.
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.
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).
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.
PMCID: PMC3895766  PMID: 24210423
Default Mode Network; Conduct Disorder; Substance Use Disorder; Independent Component Analysis; Functional MRI
13.  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.
PMCID: PMC4182145  PMID: 24742191
14.  Sex modulates approach systems and impulsivity in substance dependence 
Drug and alcohol dependence  2013;133(1):222-227.
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.
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.
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].
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.
PMCID: PMC3786050  PMID: 23725607
Substance dependence; sex; impulsivity; approach systems; affect
15.  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.
PMCID: PMC4113425  PMID: 19091966
Interhemispheric; Synchrony; fMRI; Connectivity; Lateralization; Hemisphere; Coordination
16.  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.
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.
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.
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.
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.
PMCID: PMC3618865  PMID: 23428318
Substance Dependence; Approach; Avoidance; Resting-State; Executive Control Network; Laterality; BIS/BAS
17.  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.
PMCID: PMC3843223  PMID: 24376427
mind-wandering; autobiographical; rumination; depression; mindfulness
18.  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.
PMCID: PMC3703501  PMID: 19619566
19.  Negative reinforcement learning is affected in substance dependence 
Drug and Alcohol Dependence  2011;123(1-3):84-90.
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.
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.
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.
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.
PMCID: PMC3292654  PMID: 22079143
Substance dependence; decision making; negative reinforcement
20.  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.
PMCID: PMC3680711  PMID: 23781192
inhibition; anxiety; depression; DLPFC; attentional control
21.  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.
PMCID: PMC3701233  PMID: 23847500
5-HTTLPR; Stroop; fMRI; prefrontal cortex (PFC); eye-gaze; anxiety; positive affect
22.  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.
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.
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.
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.
PMCID: PMC3170449  PMID: 21592680
Antisocial; DLPFC; Inhibition; Dependence; Precuneus; Self-referential
23.  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.
PMCID: PMC3189388  PMID: 21889391
24.  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.
PMCID: PMC3424055  PMID: 22934089
negative affect; attentional control; prefrontal cortex; emotion; fMRI
25.  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.
PMCID: PMC3369195  PMID: 22701442
stress; executive function; controllability; contingency

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