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1.  Meta-analysis of 41 Functional Neuroimaging Studies of Executive Function in Schizophrenia 
Archives of general psychiatry  2009;66(8):811-822.
Context:
Prefrontal cortical dysfunction is frequently reported in schizophrenia. It remains unclear whether this represents the coincidence of several prefrontal region- and process-specific impairments or a more unitary dysfunction in a superordinate cognitive control network. Whether these impairments are properly considered reflective of hypofrontality vs hyperfrontality remains unresolved.
Objectives:
To test whether common nodes of the cognitive control network exhibit altered activity across functional neuroimaging studies of executive cognition in schizophrenia and to evaluate the direction of these effects.
Data Sources:
PubMed database.
Study Selection:
Forty-one English-language, peer-reviewed articles published prior to February 2007 were included. All reports used functional neuroimaging during executive function performance by adult patients with schizophrenia and reported whole-brain analyses in standard stereotactic space. Tasks primarily included the delayed match-to-sample, N-back, AX-CPT, and Stroop tasks.
Data Extraction:
Activation likelihood estimation modeling reported activation maxima as the center of a 3-dimensional gaussian function in the meta-analysis, with statistical thresholding and correction for multiple comparisons.
Data Synthesis:
In within-group analyses, healthy controls and patients activated a similarly distributed cortical-subcortical network, prominently including the dorsolateral prefrontal cortex (PFC), ventrolateral PFC, anterior cingulate cortex (ACC), and thalamus. In between-group analyses, patients showed reduced activation in the left dorsolateral PFC, rostral/dorsal ACC, left thalamus (with significant co-occurrence of these areas), and inferior/ posterior cortical areas. Increased activation was observed in several midline cortical areas. Activation within groups varied modestly by task.
Conclusions:
Healthy adults and schizophrenic patients activate a qualitatively similar neural network during executive task performance, consistent with the engagement of a general-purpose cognitive control network, with critical nodes in the dorsolateral PFC and ACC. Nevertheless, patients with schizophrenia show altered activity with deficits in the dorsolateral PFC, ACC, and mediodorsal nucleus of the thalamus. Increases in activity are evident in other PFC areas, which could be compensatory in nature.
doi:10.1001/archgenpsychiatry.2009.91
PMCID: PMC2888482  PMID: 19652121
2.  Variability in Post-Error Behavioral Adjustment Is Associated with Functional Abnormalities in the Temporal Cortex in Children with ADHD 
Background
Error processing is reflected, behaviorally, by slower reaction times (RT) on trials immediately following an error (post-error). Children with Attention-Deficit Hyperactivity Disorder (ADHD) fail to show RT slowing and demonstrate increased intra-subject variability (ISV) on post-error trials. The neural correlates of these behavioral deficits remain unclear. The dorsal anterior cingulate cortex (ACC) and lateral prefrontal cortex (PFC) are key regions implicated in error processing and subsequent behavioral adjustment. We hypothesized that children with ADHD, compared to typically developing (TD) controls, would exhibit reduced PFC activation during post-error (versus post-correct inhibition) trials and reduced dACC activation during error (versus correct inhibition) trials.
Methods
Using fMRI and a Go/No-Go task, we analyzed the neural correlates of error processing in 13 children with ADHD and 17 TD children.
Results
Behaviorally, children with ADHD showed similar RT slowing but increased ISV compared to controls. The post-error contrast revealed a relative increase in BOLD signal in the middle/inferior temporal cortex (TempC), the ACC/supplementary motor area (SMA) and the somatosensory/auditory cortex (AudC) in children with ADHD compared to controls. Importantly, in the ADHD group, increased post-error temporal cortex activity was associated with lower ISV. During error (versus correct inhibition) trials, no between group differences were detected. However, in children with ADHD lower ISV was associated with decreased insula and increased precentral gyrus activity.
Conclusions
In children with ADHD, post-error neural activity suggests first, a shift of attention towards task-irrelevant stimuli (AudC) and second, a recruitment of compensatory regions that resolve stimulus conflict (TempC) and improve response selection/execution (ACC/SMA). ADHD children with higher temporal cortex activation showed lower ISV, suggesting that functional abnormalities in the compensatory temporal regions contribute to increased variability. Moreover, increased ISV may be related to an over-sensitivity to negative outcomes during error trials in ADHD (insula correlation).
doi:10.1111/j.1469-7610.2010.02356.x
PMCID: PMC3110592  PMID: 21175614
error processing; variability; temporal cortex; medial frontal cortex; ADHD; children; fMRI
3.  Insula’s functional connectivity with ventromedial prefrontal cortex mediates the impact of trait alexithymia on state tobacco craving 
Psychopharmacology  2013;228(1):10.1007/s00213-013-3018-8.
Rationale
Alexithymia is a personality trait characterized by difficulty indentifying and describing subjective emotional experiences. Decreased aptitude in the perception, evaluation, and communication of affectively laden mental states has been associated with reduced emotion regulation, more severe drug craving in addicts, and structural/functional alterations in insula and anterior cingulate cortex (ACC). The insula and ACC represent sites of convergence between the putative neural substrates of alexithymia and those perpetuating cigarette smoking.
Objectives
We examined the interrelations between alexithymia, tobacco craving, and insula/ACC neurocircuitry using resting-state functional connectivity (rsFC).
Methods
Overnight-deprived smokers (n=24) and non-smokers (n=20) completed six neuroimaging assessments on different days both in the absence of, and following, varenicline and/or nicotine administration. In this secondary analysis of data from a larger study, we assessed trait alexithymia and state tobacco craving using self-reports and examined the rsFC of bilateral insular subregions (anterior, middle, posterior) and dorsal ACC.
Results
Higher alexithymia in smokers predicted reduced rsFC strength between the right anterior insula (aI) and ventromedial prefrontal cortex (vmPFC). Higher alexithymia also predicted more severe tobacco craving during nicotine withdrawal. Critically, the identified aI–vmPFC circuit fully mediated this alexithymia–craving relation. That is, elevated alexithymia predicted decreased aI–vmPFC rsFC and, in turn, decreased aI–vmPFC rsFC predicted increased craving during withdrawal. A moderated mediation analysis indicated that this aI–vmPFC mediational effect was not observed following drug administration.
Conclusions
These results suggest that a weakened right aI–vmPFC functional circuit confers increased liability for tobacco craving during smoking abstinence. Individual differences in alexithymia and/or aI–vmPFC functional coupling may be relevant factors for smoking cessation success.
doi:10.1007/s00213-013-3018-8
PMCID: PMC3873099  PMID: 23455594
Alexithymia; Craving; Nicotine; Varenicline; Resting-state functional connectivity; Insula; Ventromedial prefrontal cortex; fMRI
4.  Functional Gene Polymorphisms in the Serotonin System and Traumatic Life Events Modulate the Neural Basis of Fear Acquisition and Extinction 
PLoS ONE  2012;7(9):e44352.
Fear acquisition and extinction are crucial mechanisms in the etiology and maintenance of anxiety disorders. Moreover, they might play a pivotal role in conveying the influence of genetic and environmental factors on the development of a (more or less) stronger proneness for, or resilience against psychopathology. There are only few insights in the neurobiology of genetically and environmentally based individual differences in fear learning and extinction. In this functional magnetic resonance imaging study, 74 healthy subjects were investigated. These were invited according to 5-HTTLPR/rs25531 (S+ vs. LALA; triallelic classification) and TPH2 (G(-703)T) (T+ vs. T-) genotype. The aim was to investigate the influence of genetic factors and traumatic life events on skin conductance responses (SCRs) and neural responses (amygdala, insula, dorsal anterior cingulate cortex (dACC) and ventromedial prefrontal cortex (vmPFC)) during acquisition and extinction learning in a differential fear conditioning paradigm. Fear acquisition was characterized by stronger late conditioned and unconditioned responses in the right insula in 5-HTTLPR S-allele carriers. During extinction traumatic life events were associated with reduced amygdala activation in S-allele carriers vs. non-carriers. Beyond that, T-allele carriers of the TPH2 (G(−703)T) polymorphism with a higher number of traumatic life events showed enhanced responsiveness in the amygdala during acquisition and in the vmPFC during extinction learning compared with non-carriers. Finally, a combined effect of the two polymorphisms with higher responses in S- and T-allele carriers was found in the dACC during extinction. The results indicate an increased expression of conditioned, but also unconditioned fear responses in the insula in 5-HTTLPR S-allele carriers. A combined effect of the two polymorphisms on dACC activation during extinction might be associated with prolonged fear expression. Gene-by-environment interactions in amygdala and vmPFC activation may reflect a neural endophenotype translating genetic and adverse environmental influences into vulnerability for or resilience against developing affective psychopathology.
doi:10.1371/journal.pone.0044352
PMCID: PMC3434167  PMID: 22957066
5.  Parsing dimensional versus diagnostic category-related patterns of reward circuitry function in behaviorally and emotionally dysregulated youth in the Longitudinal Assessment of Manic Symptoms (LAMS) study 
JAMA psychiatry  2014;71(1):71-80.
Context
Pediatric disorders characterized by behavioral and emotional dysregulation pose diagnostic and treatment challenges because of high comorbidity, suggesting that they may be better conceptualized dimensionally rather than categorically. Identifying neuroimaging measures associated with behavioral and emotional dysregulation in youth may inform understanding of underlying dimensional vs. disorder-specific pathophysiology.
Objective
Identify, in a large cohort of behaviorally and emotionally dysregulated youth, neuroimaging measures that: 1) are associated with behavioral and emotional dysregulation pathological dimensions (behavioral and emotional dysregulation measured with the Parent General Behavior Inventory 10 Item Mania Scale [PGBI-10M], mania, depression, anxiety); or 2) differentiate diagnostic categories(BPSD, ADHD, anxiety, disruptive behavior disorders (DBD)).
Design
Multi-site neuroimaging study(February 2011–April 2012).
Setting
Academic medical centers: Case Western Reserve University, Cincinnati Children’s Hospital, University of Pittsburgh.
Patients
Referred sample of behaviorally and emotionally dysregulated youth(n=85) from the Longitudinal Assessment of Manic Symptoms study and healthy youth (n=20).
Main Outcome Measures
Region-of-interest analyses examined relationships among prefrontal-ventral striatal reward circuitry during a reward paradigm (Win, Loss, control conditions), symptom dimensions, and diagnostic categories.
Results
Regardless of diagnosis, higher PGBI-10M scores were associated with greater left middle prefrontal cortical (mPFC; r=0.28), and greater levels of anxiety with greater right dorsal anterior cingulate cortical (dACC; r=0.27), activity to Win. The 20 highest (t=2.75) and 20 lowest (t=2.42) PGBI-10M scoring youth showed significantly greater left mPFC activity to Win than 20 healthy youth. DBD were associated with lower left ventrolateral prefrontal cortex(VLPFC) activity to Win (t=2.68) (all ps<0.05, corrected).
Conclusions
Greater PGBI-10M-related left mPFC activity, and greater anxiety-related right dACC activity, to Win may reflect heightened reward sensitivity and greater attention to reward in behaviorally and emotionally dysregulated youth, regardless of diagnosis. Reduced left VLPFC activity to Win may reflect reward insensitivity in youth with DBD. Despite a distinct reward-related neurophysiology in DBD, findings generally support a dimensional approach to studying neural mechanisms in behaviorally and emotionally dysregulated youth.
doi:10.1001/jamapsychiatry.2013.2870
PMCID: PMC4238412  PMID: 24285346
6.  What are the Odds? The Neural Correlates of Active Choice during Gambling 
Gambling is a widespread recreational activity and requires pitting the values of potential wins and losses against their probability of occurrence. Neuropsychological research showed that betting behavior on laboratory gambling tasks is highly sensitive to focal lesions to the ventromedial prefrontal cortex (vmPFC) and insula. In the current study, we assessed the neural basis of betting choices in healthy participants, using functional magnetic resonance imaging of the Roulette Betting Task. In half of the trials, participants actively chose their bets; in the other half, the computer dictated the bet size. Our results highlight the impact of volitional choice upon gambling-related brain activity: Neural activity in a distributed network – including key structures of the reward circuitry (midbrain, striatum) – was higher during active compared to computer-dictated bet selection. In line with neuropsychological data, the anterior insula and vmPFC were more activated during self-directed bet selection, and responses in these areas were differentially modulated by the odds of winning in the two choice conditions. In addition, responses in the vmPFC and ventral striatum were modulated by the bet size. Convergent with electrophysiological research in macaques, our results further implicate the inferior parietal cortex (IPC) in the processing of the likelihood of potential outcomes: Neural responses in the IPC bilaterally reflected the probability of winning during bet selection. Moreover, the IPC was particularly sensitive to the odds of winning in the active-choice condition, when the processing of this information was required to guide bet selection. Our results indicate an important role of the IPC in human decision-making under risk and help to integrate neuropsychological data of risk-taking following vmPFC and insula damage with models of choice derived from human neuroimaging and monkey electrophysiology.
doi:10.3389/fnins.2012.00046
PMCID: PMC3328778  PMID: 22529770
betting; choice; fMRI; inferior parietal cortex; ventromedial prefrontal cortex; reward
7.  An fMRI study of the interface between affective and cognitive neural circuitry in pediatric bipolar disorder 
Psychiatry research  2008;162(3):244-255.
The pathophysiology of pediatric bipolar disorder impacts both affective and cognitive brain systems. Understanding disturbances in the neural circuits subserving these abilities is critical for characterizing developmental aberrations associated with the disorder and developing improved treatments. Our objective is to use functional neuroimaging with pediatric bipolar disorder patients employing a task that probes the functional integrity of attentional control and affect processing. Ten euthymic unmedicated pediatric bipolar patients and healthy controls matched for age, sex, race, socioeconomic status, and IQ were scanned using functional magnetic resonance imaging. In a pediatric color word matching paradigm, subjects were asked to match the color of a word with one of two colored circles below. Words had either a positive, negative or neutral emotional valence, and were presented in 30 second blocks. In the negative affect condition, relative to the neutral condition, patients with bipolar disorder demonstrated greater activation of bilateral pregenual anterior cingulate cortex and left amygdala, and less activation in right rostral ventrolateral prefrontal cortex (PFC) and dorsolateral PFC at the junction of the middle frontal and inferior frontal gyri. In the positive affect condition, there was no reduced activation of PFC or increased amygdala activation. The pattern of reduced activation of ventrolateral PFC and greater amygdala activation in bipolar children in response to negative stimuli suggests both disinhibition of emotional reactivity in the limbic system and reduced function in PFC systems that regulate those responses. Higher cortical cognitive areas such as the dorsolateral PFC may also be adversely affected by exaggerated emotional responsivity to negative emotions. This pattern of functional alteration in affective and cognitive circuitry may contribute to the reduced capacity for affect regulation and behavioral self-control in pediatric bipolar disorder.
doi:10.1016/j.pscychresns.2007.10.003
PMCID: PMC2323905  PMID: 18294820
Functional magnetic resonance imaging (fMRI); attention; emotion; affect; cognition; child; adolescent
8.  Anatomical differences and network characteristics underlying smoking cue reactivity 
NeuroImage  2010;54(1):131-141.
A distributed network of brain regions is linked to drug-related cue responding. However, the relationships between smoking cue-induced phasic activity and possible underlying differences in brain structure, tonic neuronal activity and connectivity between these brain areas are as yet unclear. Twenty-two smokers and 22 controls viewed smoking-related and neutral pictures during a functional arterial spin labeling scanning session. T1, resting functional, and diffusion tensor imaging data were also collected. Six brain areas, dorsal lateral prefrontal cortex (dlPFC), dorsal medial prefrontal cortex (dmPFC), dorsal anterior cingulate cortex/cingulate cortex, rostral anterior cingulate cortex (rACC), occipital cortex, and insula/operculum, showed significant smoking cue-elicited activity in smokers when compared with controls and were subjected to secondary analysis for resting state functional connectivity (rsFC), structural, and tonic neuronal activity. rsFC strength between rACC and dlPFC was positively correlated with the cue-elicited activity in dlPFC. Similarly, rsFC strength between dlPFC and dmPFC was positively correlated with the cue-elicited activity in dmPFC while rsFC strength between dmPFC and insula/operculum was negatively correlated with the cue-elicited activity in both dmPFC and insula/operculum, suggesting these brain circuits may facilitate the response to the salient smoking cues. Further, the gray matter density in dlPFC was decreased in smokers and correlated with cue-elicited activity in the same brain area, suggesting a neurobiological mechanism for the impaired cognitive control associated with drug use. Taken together, these results begin to address the underlying neurobiology of smoking cue salience, and may speak to novel treatment strategies and targets for therapeutic interventions.
doi:10.1016/j.neuroimage.2010.07.063
PMCID: PMC2962771  PMID: 20688176
Smoking cue; anatomical; ASL; DTI; VBM; resting state functional connectivity
9.  Amygdala and Dorsal Anterior Cingulate Connectivity during an Emotional Working Memory Task in Borderline Personality Disorder Patients with Interpersonal Trauma History 
Working memory is critically involved in ignoring emotional distraction while maintaining goal-directed behavior. Antagonistic interactions between brain regions implicated in emotion processing, e.g., amygdala, and brain regions involved in cognitive control, e.g., dorsolateral and dorsomedial prefrontal cortex (dlPFC, dmPFC), may play an important role in coping with emotional distraction. We previously reported prolonged reaction times associated with amygdala hyperreactivity during emotional distraction in interpersonally traumatized borderline personality disorder (BPD) patients compared to healthy controls (HC): Participants performed a working memory task, while neutral versus negative distractors (interpersonal scenes from the International Affective Picture System) were presented. Here, we re-analyzed data from this study using psychophysiological interaction analysis. The bilateral amygdala and bilateral dorsal anterior cingulate cortex (dACC) were defined as seed regions of interest. Whole-brain regression analyses with reaction times and self-reported increase of dissociation were performed. During emotional distraction, reduced amygdala connectivity with clusters in the left dorsolateral and ventrolateral PFC was observed in the whole group. Compared to HC, BPD patients showed a stronger coupling of both seeds with a cluster in the right dmPFC and stronger positive amygdala connectivity with bilateral (para)hippocampus. Patients further demonstrated stronger positive dACC connectivity with left posterior cingulate, insula, and frontoparietal regions during emotional distraction. Reaction times positively predicted amygdala connectivity with right dmPFC and (para)hippocampus, while dissociation positively predicted amygdala connectivity with right ACC during emotional distraction in patients. Our findings suggest increased attention to task-irrelevant (emotional) social information during a working memory task in interpersonally traumatized patients with BPD.
doi:10.3389/fnhum.2014.00848
PMCID: PMC4211399  PMID: 25389397
amygdala; anterior cingulate cortex; borderline personality disorder; emotional distraction; emotional working memory; functional connectivity; interpersonal trauma; psychophysiological interactions
10.  Anterior cingulate neurons represent errors and preparatory attention within the same behavioral sequence 
The anterior cingulate cortex (ACC) has been implicated in both preparatory attention (i.e., selecting behaviorally relevant stimuli) and in detecting errors. We recorded from the rat ACC and medial prefrontal cortex (mPFC), which is functionally homologous with the primate dorsolateral PFC, during an attention task. The 3-choice serial reaction time task requires a rat to orient toward and divide attention between 3 brief (300 msec duration) light stimuli presented in random order across nose poke holes in an operant chamber. In both the ACC and mPFC, we found that neural activity was related to the level of preparatory (pre-cue) attention and subsequent correct or incorrect choice, in that the magnitude of the single units' response to the cue was lower on incorrect trials and was not different from baseline on unattended trials. This preparatory neural activity consisted of both excitatory and inhibitory phasic responses. The number of units responding to the cue was similarly graded, in that fewer units exhibited phasic responses to the cue on incorrect and unattended trials, compared to correct trials. Although preparatory activity was found in both the ACC and mPFC, activity after incorrect nose pokes, which may be related to error detection, were only observed in the ACC. Thus, during the same behavioral sequence, the ACC encodes both error-related events and preparatory attention, whereas the mPFC only participates in preparatory attention. The finding of substantial inhibitory activity during the preparatory period suggests a critical role for inhibition of pyramidal cells in PFC-mediated cognitive functions.
doi:10.1523/JNEUROSCI.1142-09.2009
PMCID: PMC2730728  PMID: 19458213
attention-deficit hyperactivity disorder; dopamine; prefrontal cortex; schizophrenia; single unit; rat
11.  Anterior cingulate cortex and cognitive control: Neuropsychological and electrophysiological findings in two patients with lesions to dorsomedial prefrontal cortex 
Brain and cognition  2012;80(2):237-249.
Whereas neuroimaging studies of healthy subjects have demonstrated an association between the anterior cingulate cortex (ACC) and cognitive control functions, including response monitoring and error detection, lesion studies are sparse and have produced mixed results. Due to largely normal behavioral test results in two patients with medial prefrontal lesions, a hypothesis has been advanced claiming that the ACC is not involved in cognitive operations. In the current study, two comparably rare patients with unilateral lesions to dorsal medial prefrontal cortex (MPFC) encompassing the ACC were assessed with neuropsychological tests as well as Event-Related Potentials in two experimental paradigms known to engage prefrontal cortex (PFC). These included an auditory Novelty Oddball task and a visual Stop-signal task. Both patients performed normally on the Stroop test but showed reduced performance on tests of learning and memory. Moreover, altered attentional control was reflected in a diminished Novelty P3, whereas the posterior P3b to target stimuli was present in both patients. The error-related negativity, which has been hypothesized to be generated in the ACC, was present in both patients, but alterations of inhibitory behavior were observed. Although interpretative caution is generally called for in single case studies, and the fact that the lesions extended outside the ACC, the findings nevertheless suggest a role for MPFC in cognitive control that is not restricted to error monitoring.
doi:10.1016/j.bandc.2012.07.008
PMCID: PMC4067454  PMID: 22935543
Anterior cingulate cortex; Prefrontal cortex; Executive function; Event-related potentials; Cognitive control; Novelty P3
12.  Neural Correlates of Attention Bias to Threat in Post-traumatic Stress Disorder 
Biological psychology  2012;90(2):134-142.
Attentional biases have been proposed to contribute to symptom maintenance in Posttraumatic Stress Disorder (PTSD), although the neural correlates of these processes have not been well defined; this was the goal of the present study. We administered an attention bias task, the dot probe, to a sample of 37 (19 control, 18 PTSD+) traumatized African-American adults during fMRI. Compared to controls, PTSD+ participants demonstrated increased activation in the dorsolateral prefrontal cortex (dlPFC) in response to threat cue trials. In addition, attentional avoidance of threat corresponded with increased ventrolateral prefrontal cortex (vlPFC) and dorsal anterior cingulate cortex (dACC) activation in the PTSD group, a pattern that was not observed in controls. These data provide evidence to suggest that relative increases in dlPFC, dACC and vlPFC activation represent neural markers of attentional bias for threat in individuals with PTSD, reflecting selective disruptions in attentional control and emotion processing networks in this disorder.
doi:10.1016/j.biopsycho.2012.03.001
PMCID: PMC3340884  PMID: 22414937
Attention bias; PTSD; Threat; fMRI; Prefrontal cortex; Neuroimaging; Posttraumatic Stress Disorder; Anterior cingulate cortex; Dorsolateral prefrontal cortex; Cognition
13.  Distinct Regions of Prefrontal Cortex Mediate Resistance and Vulnerability to Depression 
The neuroanatomical correlates of depression remain unclear. Functional imaging data have associated depression with abnormal patterns of activity in prefrontal cortex (PFC), including the ventromedial (vmPFC) and dorsolateral (dlPFC) sectors. If vmPFC and dlPFC are critical neural substrates for the pathogenesis of depression, then damage to either area should affect the expression of depressive symptoms. Using patients with brain lesions we show that, relative to nonfrontal lesions, bilateral vmPFC lesions are associated with markedly low levels of depression, whereas bilateral dorsal PFC lesions (involving dorsomedial and dorsolateral areas in both hemispheres) are associated with substantially higher levels of depression. These findings demonstrate that vmPFC and dorsal PFC are critically and causally involved in depression, although with very different roles: vmPFC damage confers resistance to depression, whereas dorsal PFC damage confers vulnerability.
doi:10.1523/JNEUROSCI.2324-08.2008
PMCID: PMC2644261  PMID: 19020027
depression; emotion; prefrontal cortex; ventromedial; dorsolateral; neuropathology
14.  A Meta-Analysis of Functional Neuroimaging Studies of Self and Other Judgments Reveals a Spatial Gradient for Mentalizing in Medial Prefrontal Cortex 
Journal of cognitive neuroscience  2012;24(8):1742-1752.
The distinction between processes used to perceive and understand the self and others has received considerable attention in psychology and neuroscience. Brain findings highlight a role for various regions, in particular the medial prefrontal cortex (mPFC), in supporting judgments about both the self and others. We performed a meta-analysis of 107 neuroimaging studies of self- and other-related judgments using Multilevel Kernel Density Analysis (MKDA; Kober & Wager, 2010). We sought to determine what brain regions are reliably involved in each judgment type, and in particular, what the spatial and functional organization of mPFC is with respect to them. Relative to non-mentalizing judgments, both self and other judgments were associated with activity in mPFC, ranging from ventral to dorsal extents, as well as common activation of the left temporoparietal junction (TPJ) and posterior cingulate. A direct comparison between self and other judgments revealed that ventral mPFC (vmPFC), as well as left ventrolateral PFC and left insula, were more frequently activated by self-related judgments, whereas dorsal mPFC (dmPFC), in addition to bilateral TPJ and cuneus, were more frequently activated by other-related judgments. Logistic regression analyses revealed that ventral and dorsal mPFC lay at opposite ends of a functional gradient: the z-coordinates reported in individual studies predicted whether the study involved self- or other-related judgments, which were associated with increasingly ventral or dorsal portions of mPFC, respectively. These results argue for a distributed rather than localizationist account of mPFC organization and support an emerging view on the functional heterogeneity of mPFC.
doi:10.1162/jocn_a_00233
PMCID: PMC3806720  PMID: 22452556
15.  Functioning of Neural Systems Supporting Emotion Regulation in Anxiety-Prone Individuals 
NeuroImage  2010;54(1):689-696.
Previous neuroimaging studies suggest that prefrontal cortex (PFC) modulation of the amygdala and related limbic structures is an underlying neural substrate of effortful emotion regulation. Anxiety-prone individuals experience excessive negative emotions, signaling potential dysfunction of systems supporting down-regulation of negative emotions. We examined the hypothesis that anxious individuals require increased recruitment of lateral and medial PFC to decrease negative emotions. An emotion regulation task that involved viewing moderately negative images was presented during functional magnetic resonance imaging (fMRI). Participants with elevated trait anxiety scores (n = 13) and normal trait anxiety scores (n = 13) were trained to reduce negative emotions using cognitive reappraisal. Blood oxygenation level-dependent (BOLD) changes were contrasted for periods when participants were reducing emotions versus when they were maintaining emotions. Compared to healthy controls, anxious participants showed greater activation of brain regions implicated in effortful (lateral PFC) and automatic (subgenual anterior cingulate cortex) control of emotions during down-regulation of negative emotions. Left ventrolateral PFC activity was associated with greater self-reported reduction of distress in anxious participants, but not in healthy controls. These findings provide evidence of altered functioning of neural substrates of emotion regulation in anxiety-prone individuals. Anxious participants required greater engagement of lateral and medial PFC in order to successfully reduce negative emotions.
doi:10.1016/j.neuroimage.2010.07.041
PMCID: PMC2962684  PMID: 20673804
Emotion; Emotion Regulation; fMRI; Anxiety; Prefrontal Cortex; Anterior Cingulate Cortex
16.  Cortical activation during delay discounting in abstinent methamphetamine dependent individuals 
Psychopharmacology  2008;201(2):183-193.
Background
Methamphetamine (MA)-dependent individuals prefer smaller immediate over larger delayed rewards in delay discounting (DD) tasks. Human and animal data implicate ventral (amygdala, ventral striatum, ventrolateral prefrontal cortex insula) and dorsal (dorsolateral prefrontal cortex, dorsal anterior cingulate cortex and posterior parietal cortex) systems in DD decisions. The ventral system is hypothesized to respond to the salience and immediacy of rewards while the dorsal system is implicated in the process of comparison and choice.
Methods
We used functional Magnetic Resonance Imaging to probe the neural correlates of DD in 19 recently abstinent MA-dependent patients and 17 age- and gender-matched controls.
Results
Hard DD choices were associated with greatest activation in bilateral middle cingulate, posterior parietal cortex (PPC), and the right rostral insula. Control subjects showed more activation than MA patients bilaterally in the precuneus and in the right caudate nucleus, anterior cingulate cortex (ACC), and dorsolateral prefrontal cortex (DLPFC). Magnitude of discounting was correlated with activity in the amygdala, DLPFC, posterior cingulate cortex and PPC.
Conclusions
Our findings were consistent with a model wherein dorsal cognitive systems modulate the neural response of ventral regions. Patients addicted to MA, who strongly prefer smaller immediate over larger delayed rewards, activate the dorsal cognitive control system in order to overcome their preference. Activation of the amygdala during choice of delayed rewards was associated with a greater degree of discounting, suggesting that heavily discounting MA-dependent individuals may be more responsive to the negative salience of delayed rewards than controls.
doi:10.1007/s00213-008-1261-1
PMCID: PMC2835463  PMID: 18685833
Methamphetamine; Delay discounting; Brain imaging
17.  Normal amygdala activation but deficient ventrolateral prefrontal activation in adults with bipolar disorder during euthymia 
NeuroImage  2011;59(1):738-744.
Functional neuroimaging studies have implicated the involvement of the amygdala and ventrolateral prefrontal cortex (vlPFC) in the pathophysiology of bipolar disorder. Hyperactivity in the amygdala and hypoactivity in the vlPFC have been reported in manic bipolar patients scanned during the performance of an affective faces task. Whether this pattern of dysfunction persists during euthymia is unclear. Using functional magnetic resonance imaging (fMRI), 24 euthymic bipolar and 26 demographically matched healthy control subjects were scanned while performing an affective task paradigm involving the matching and labeling of emotional facial expressions. Neuroimaging results showed that, while amygdala activation did not differ significantly between groups, euthymic patients showed a significant decrease in activation of the right vlPFC (BA47) compared to healthy controls during emotion labeling. Additionally, significant decreases in activation of the right insula, putamen, thalamus and lingual gyrus were observed in euthymic bipolar relative to healthy control subjects during the emotion labeling condition. These data, taken in context with prior studies of bipolar mania using the same emotion recognition task, could suggest that amygdala dysfunction may be a state-related abnormality in bipolar disorder, whereas vlPFC dysfunction may represent a trait-related abnormality of the illness. Characterizing these patterns of activation is likely to help in understanding the neural changes related to the different mood states in bipolar disorder, as well as changes that represent more sustained abnormalities. Future studies that assess mood-state related changes in brain activation in longitudinal bipolar samples would be of interest.
doi:10.1016/j.neuroimage.2011.07.054
PMCID: PMC3216485  PMID: 21854858
bipolar disorder; amygdala; prefrontal cortex; fmri; emotion
18.  Compensation or inhibitory failure? Testing hypotheses of age-related right frontal lobe involvement in verbal memory ability using structural and diffusion MRI 
Functional neuroimaging studies report increased right prefrontal cortex (PFC) involvement during verbal memory tasks amongst low-scoring older individuals, compared to younger controls and their higher-scoring contemporaries. Some propose that this reflects inefficient use of neural resources through failure of the left PFC to inhibit non-task-related right PFC activity, via the anterior corpus callosum (CC). For others, it indicates partial compensation – that is, the right PFC cannot completely supplement the failing neural network, but contributes positively to performance. We propose that combining structural and diffusion brain MRI can be used to test predictions from these theories which have arisen from fMRI studies. We test these hypotheses in immediate and delayed verbal memory ability amongst 90 healthy older adults of mean age 73 years. Right hippocampus and left dorsolateral prefrontal cortex (DLPFC) volumes, and fractional anisotropy (FA) in the splenium made unique contributions to verbal memory ability in the whole group. There was no significant effect of anterior callosal white matter integrity on performance. Rather, segmented linear regression indicated that right DLPFC volume was a significantly stronger positive predictor of verbal memory for lower-scorers than higher-scorers, supporting a compensatory explanation for the differential involvement of the right frontal lobe in verbal memory tasks in older age.
doi:10.1016/j.cortex.2014.08.001
PMCID: PMC4317301  PMID: 25241394
Verbal memory; Cognitive ageing; Compensation; MRI; Frontal lobe; Corpus callosum
19.  The Contributions of Prefrontal Cortex and Executive Control to Deception: Evidence from Activation Likelihood Estimate Meta-analyses 
Cerebral Cortex (New York, NY)  2008;19(7):1557-1566.
Previous neuroimaging studies have implicated the prefrontal cortex (PFC) and nearby brain regions in deception. This is consistent with the hypothesis that lying involves the executive control system. To date, the nature of the contribution of different aspects of executive control to deception, however, remains unclear. In the present study, we utilized an activation likelihood estimate (ALE) method of meta-analysis to quantitatively identify brain regions that are consistently more active for deceptive responses relative to truthful responses across past studies. We then contrasted the results with additional ALE maps generated for 3 different aspects of executive control: working memory, inhibitory control, and task switching. Deception-related regions in dorsolateral PFC and posterior parietal cortex were selectively associated with working memory. Additional deception regions in ventrolateral PFC, anterior insula, and anterior cingulate cortex were associated with multiple aspects of executive control. In contrast, deception-related regions in bilateral inferior parietal lobule were not associated with any of the 3 executive control constructs. Our findings support the notion that executive control processes, particularly working memory, and their associated neural substrates play an integral role in deception. This work provides a foundation for future research on the neurocognitive basis of deception.
doi:10.1093/cercor/bhn189
PMCID: PMC2693617  PMID: 18980948
anterior cingulate; fMRI; lie detection; lying; neuroimaging; prefrontal cortex
20.  Stress-Induced Impairment of a Working Memory Task: Role of Spiking Rate and Spiking History Predicted Discharge 
PLoS Computational Biology  2012;8(9):e1002681.
Stress, pervasive in society, contributes to over half of all work place accidents a year and over time can contribute to a variety of psychiatric disorders including depression, schizophrenia, and post-traumatic stress disorder. Stress impairs higher cognitive processes, dependent on the prefrontal cortex (PFC) and that involve maintenance and integration of information over extended periods, including working memory and attention. Substantial evidence has demonstrated a relationship between patterns of PFC neuron spiking activity (action-potential discharge) and components of delayed-response tasks used to probe PFC-dependent cognitive function in rats and monkeys. During delay periods of these tasks, persistent spiking activity is posited to be essential for the maintenance of information for working memory and attention. However, the degree to which stress-induced impairment in PFC-dependent cognition involves changes in task-related spiking rates or the ability for PFC neurons to retain information over time remains unknown. In the current study, spiking activity was recorded from the medial PFC of rats performing a delayed-response task of working memory during acute noise stress (93 db). Spike history-predicted discharge (SHPD) for PFC neurons was quantified as a measure of the degree to which ongoing neuronal discharge can be predicted by past spiking activity and reflects the degree to which past information is retained by these neurons over time. We found that PFC neuron discharge is predicted by their past spiking patterns for nearly one second. Acute stress impaired SHPD, selectively during delay intervals of the task, and simultaneously impaired task performance. Despite the reduction in delay-related SHPD, stress increased delay-related spiking rates. These findings suggest that neural codes utilizing SHPD within PFC networks likely reflects an additional important neurophysiological mechanism for maintenance of past information over time. Stress-related impairment of this mechanism is posited to contribute to the cognition-impairing actions of stress.
Author Summary
When faced with stressful situations, normal thought processes can be impaired including the ability to focus attention or make decisions requiring deep thought. These effects can result in accidents at the workplace and in combat, jeopardizing the lives of others. To date, the effect of stress on the way neurons communicate and represent cognitive functions is poorly understood. Differing theories have provided opposing predictions regarding the effects of stress-related chemical changes in the brain on neuronal activity of the prefrontal cortex (PFC). In this study, we show that stress increases the discharge rate of PFC neurons during planning and assessment phases of a task requiring the PFC. Additionally, using a point process model of neuronal activity we show that stress, nonetheless, impairs the ability of PFC neurons to retain representations of past events over time. Together these findings suggest that stress-related impairment of cognitive function may involve deficits in the ability of PFC neurons to retain information about past events beyond changes in neuronal firing rates. We believe that this advancement provides new insight into the neural codes of higher cognitive function that may lead to the development of novel treatments for stress-related diseases and conditions involving PFC-dependent cognitive impairment.
doi:10.1371/journal.pcbi.1002681
PMCID: PMC3441423  PMID: 23028279
21.  Spatio-temporal Dynamics of Error Processing Dysfunctions in Major Depressive Disorder 
Archives of general psychiatry  2008;65(2):179-188.
Context
Depression is characterized by executive dysfunctions and abnormal reactions to errors; however, little is known about the brain mechanisms that underlie these deficits.
Objective
To examine whether abnormal reactions to errors in patients with major depressive disorder (MDD) are associated with exaggerated paralimbic activation and/or a failure to recruit subsequent cognitive control to account for mistakes in performance.
Design
Between February 15, 2005, and January 19, 2006, we recorded 128-channel event-related potentials while study participants performed a Stroop task, modified to incorporate performance feedback.
Setting
Patients with MDD and healthy comparison subjects were recruited from the general community.
Participants
Study participants were 20 unmedicated patients with MDD and 20 demographically matched comparison subjects.
Main Outcome Measures
The error-related negativity and error positivity were analyzed through scalp and source localization analyses. Functional connectivity analyses were conducted to investigate group differences in the spatiotemporal dynamics of brain mechanisms that underlie error processing.
Results
Relative to comparison subjects, patients with MDD displayed significantly lower accuracy after incorrect responses, larger error-related negativity, and higher current density in the rostral anterior cingulate cortex (ACC) and medial prefrontal cortex (PFC) (Brodmann area 10/32) 80 milliseconds after committing an error. Functional connectivity analyses revealed that for the comparison subjects, but not the patients with MDD, rostral ACC and medial PFC activation 80 milliseconds after committing an error predicted left dorsolateral PFC (Brodmann area 8/9) activation 472 milliseconds after committing an error.
Conclusions
Unmedicated patients with MDD showed reduced accuracy and potentiated error-related negativity immediately after committing errors, highlighting dysfunctions in the automatic detection of unfavorable performance outcomes. New analytic procedures allowed us to show that abnormal reaction to committing errors was accompanied by hyperactivation in rostral ACC and medial PFC regions 80 milliseconds after committing errors and a failure to recruit dorsolateral PFC-based cognitive control. Future studies are warranted to investigate whether these dysfunctions might foster the emergence and maintenance of negative processing biases and thus increase vulnerability to depression.
doi:10.1001/archgenpsychiatry.2007.19
PMCID: PMC2587280  PMID: 18250256
22.  PTSD symptom severity is associated with increased recruitment of top-down attentional control in a trauma-exposed sample☆ 
NeuroImage : Clinical  2014;7:19-27.
Background
Recent neuroimaging work suggests that increased amygdala responses to emotional stimuli and dysfunction within regions mediating top down attentional control (dorsomedial frontal, lateral frontal and parietal cortices) may be associated with the emergence of anxiety disorders, including posttraumatic stress disorder (PTSD). This report examines amygdala responsiveness to emotional stimuli and the recruitment of top down attention systems as a function of task demands in a population of U.S. military service members who had recently returned from combat deployment in Afghanistan/Iraq. Given current interest in dimensional aspects of pathophysiology, it is worthwhile examining patients who, while not meeting full PTSD criteria, show clinically significant functional impairment.
Methods
Fifty-seven participants with sub-threshold levels of PTSD symptoms completed the affective Stroop task while undergoing fMRI. Participants with PTSD or depression at baseline were excluded.
Results
Greater PTSD symptom severity scores were associated with increased amygdala activation to emotional, particularly positive, stimuli relative to neutral stimuli. Furthermore, greater PTSD symptom severity was associated with increased superior/middle frontal cortex response during task conditions relative to passive viewing conditions. In addition, greater PTSD symptom severity scores were associated with: (i) increased activation in the dorsolateral prefrontal, lateral frontal, inferior parietal cortices and dorsomedial frontal cortex/dorsal anterior cingulate cortex (dmFC/dACC) in response to emotional relative to neutral stimuli; and (ii) increased functional connectivity during emotional trials, particularly positive trials, relative to neutral trials between the right amygdala and dmFC/dACC, left caudate/anterior insula cortex, right lentiform nucleus/caudate, bilateral inferior parietal cortex and left middle temporal cortex.
Conclusions
We suggest that these data may reflect two phenomena associated with increased PTSD symptomatology in combat-exposed, but PTSD negative, armed services members. First, these data indicate increased emotional responsiveness by: (i) the positive relationship between PTSD symptom severity and amygdala responsiveness to emotional relative to neutral stimuli; (ii) greater BOLD response as a function of PTSD symptom severity in regions implicated in emotion (striatum) and representation (occipital and temporal cortices) during emotional relative to neutral conditions; and (iii) increased connectivity between the amygdala and regions implicated in emotion (insula/caudate) and representation (middle temporal cortex) as a function of PTSD symptom severity during emotional relative to neutral trials. Second, these data indicate a greater need for the recruitment of regions implicated in top down attention as indicated by (i) greater BOLD response in superior/middle frontal gyrus as a function of PTSD symptom severity in task relative to view conditions; (ii) greater BOLD response in dmFC/dACC, lateral frontal and inferior parietal cortices as a function of PTSD symptom severity in emotional relative to neutral conditions and (iii) greater functional connectivity between the amygdala and inferior parietal cortex as a function of PTSD symptom severity during emotional relative to neutral conditions.
Highlights
•Greater PTSD symptoms associated with increased amygdala activation to emotional stimuli•PTSD symptoms associated with greater top down attention response in task and emotion conditions•PTSD symptoms were associated with slower reaction times.•Increased top down attention recruitment may compensate for heightened emotional responses.
doi:10.1016/j.nicl.2014.11.012
PMCID: PMC4299952  PMID: 25610763
Post-traumatic stress disorder; Emotion attention; Amygdala; Top down attention
23.  Working Memory for Complex Figures: An fMRI Comparison of Letter and Fractal n-Back Tasks 
Neuropsychology  2002;16(3):370-379.
n -back letter and fractal tasks were administered to 11 participants during functional magnetic resonance imaging to test process specificity theories of prefrontal cortex (PFC) function and assess task validity. Tasks were matched on accuracy, but fractal n-back responses were slower and more conservative. Maintenance (1-back minus 0-back) activated inferior parietal and dorsolateral PFC, with additional activation in right ventrolateral PFC during letter n-back and left lingual gyrus during fractal n-back. Maintenance plus manipulation (2-back minus 0-back) activated inferior parietal, Broca’s area, insula, and dorsolateral and ventral PFC, with greater right dorsolateral PFC activation for letter n-back. Manipulation only (2-back minus 1-back) produced additional and equivalent dorsolateral PFC and anterior cingulate activation in both tasks. Results support fractal n-back validity and indicate substantial overlap in working memory functions of dorsal and ventral PFC.
PMCID: PMC4332798  PMID: 12146684
24.  Neurobiology of Decision-Making in Adolescents 
Behavioural brain research  2010;217(1):67-76.
The study examined the relationship between risk-taking behavior during selection of monetary rewards and activations in the anterior cingulate cortex (ACC), orbitofrontal cortex (OFC) and medial prefrontal cortex (mPFC), brain regions that are associated with decision-making. Thirty-three adolescents with no personal or family history of any psychiatric illness were administered the Wheel of Fortune (WOF) task using a functional magnetic resonance imaging protocol. The WOF is a computerized two-choice, probabilistic monetary reward task. Selection of a reward, particularly a low-probability/high-magnitude reward choice, induced greater activations in dorsal ACC, ventrolateral OFC and mPFC than the control condition. Although similar findings have been reported by earlier studies, the results from this study were not impacted by reaction times and expected values and persisted even after controlling for sociodemographic factors. Post-hoc analysis revealed greater activation of ACC and mPFC in response to selection of rewards of larger magnitude than those of smaller magnitude when the probability of reward was maintained constant. Adolescents with greater frequency of high-risk behavior (defined as low-probability/high magnitude reward choice) had lower activation of ACC, OFC and mPFC than those who engaged in this behavior less frequently. These findings suggest individual differences in prefrontal cortical function with regards to decision-making process in adolescents.
doi:10.1016/j.bbr.2010.09.033
PMCID: PMC3004983  PMID: 20933020
Neurobiology; choice; selection; adolescents; decision-making; rewards
25.  Neural correlates of set-shifting: decomposing executive functions in schizophrenia 
Background
Although there is considerable evidence that patients with schizophrenia have impaired executive functions, the neural mechanisms underlying these deficits are unclear. Generation and selection is one of the basic mechanisms of executive functioning. We investigated the neural correlates of this mechanism by means of functional magnetic resonance imaging (fMRI) in patients with schizophrenia and healthy controls.
Methods
We used the Wisconsin Card Sorting Test (WCST) in an event-related fMRI study to analyze neural activation patterns during the distinct components of the WCST in 36 patients with schizophrenia and 28 controls. We focused our analyses on the process of set-shifting. After participants received negative feedback, they had to generate and decide on a new sorting rule.
Results
A widespread activation pattern encompassing the inferior and middle frontal gyrus, parietal, temporal and occipital cortices, anterior cingulate cortex (ACC), supplementary motor area, insula, caudate, thalamus and brainstem was observed in patients with schizophrenia after negative versus positive feedback, whereas in healthy controls, significant activation clusters were more confined to the cortical areas. Significantly increased activation in the rostral ACC after negative feedback and in the dorsal ACC during matching after negative feedback were observed in schizophrenia patients compared with controls. Controls showed activation in the bilateral dorsolateral prefrontal cortex (Brodmann area 46), whereas schizophrenia patients showed activation in the right dorsolateral pre-frontal cortex only.
Limitations
All patients were taking neuroleptic medication, which has an impact on cognitive function as well as on dopaminergic and serotonergic prefrontal metabolism.
Conclusion
Our data suggest that, in patients with schizophrenia, set-shifting is associated with increased activation in the rostral and dorsal ACC, reflecting higher emotional and cognitive demands, respectively.
doi:10.1503/jpn.090181
PMCID: PMC2928285  PMID: 20731964

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