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1.  Crack cocaine use impairs anterior cingulate and prefrontal cortex function in women with HIV infection 
Journal of neurovirology  2014;20(4):352-361.
Objective
Crack cocaine use is associated with impaired verbal memory in HIV-infected women more than -uninfected women. To understand the neural basis for this impairment, this study examined the effects of crack cocaine use on activation of the prefrontal cortex (PFC) and strategic encoding during a verbal memory task in HIV-infected women.
Methods
Three groups of HIV-infected women from the Chicago Consortium of the Women’s Interagency HIV Study were compared: current users of crack cocaine (n=10), former users of cocaine (n=11), and women who had never used cocaine (n=9). Participants underwent functional magnetic resonance imaging during a verbal memory task and completed a neuropsychological test of verbal memory.
Results
On the neuropsychological test, current crack users performed significantly worse than other groups on semantic clustering, a measure of strategic encoding, p < .05. During encoding, activation in left anterior cingulate cortex (ACC) was lower in current and former cocaine users compared to never users. During recognition, activation in bilateral PFC, specifically left dorsal medial PFC and bilateral dorsolateral PFC, was lower in current and former users compared to women who had never used cocaine. Lower activation in left dorsolateral PFC was correlated with worse performance on the recognition task, p < .05.
Conclusion
The verbal learning and memory deficits associated with cocaine use in women with HIV may be partially accounted for by alterations in ACC and PFC function.
doi:10.1007/s13365-014-0250-x
PMCID: PMC4090256  PMID: 24760360
HIV; crack cocaine; African American; verbal memory; fMRI; prefrontal cortex
2.  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
3.  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
4.  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
5.  Increases in frontostriatal connectivity are associated with response to dorsomedial repetitive transcranial magnetic stimulation in refractory binge/purge behaviors 
NeuroImage : Clinical  2015;8:611-618.
Background
Conventional treatments for eating disorders are associated with poor response rates and frequent relapse. Novel treatments are needed, in combination with markers to characterize and predict treatment response. Here, resting-state functional magnetic resonance imaging (rs-fMRI) was used to identify predictors and correlates of response to repetitive transcranial magnetic stimulation (rTMS) of the dorsomedial prefrontal cortex (dmPFC) at 10 Hz for eating disorders with refractory binge/purge symptomatology.
Methods
28 subjects with anorexia nervosa, binge−purge subtype or bulimia nervosa underwent 20–30 sessions of 10 Hz dmPFC rTMS. rs-fMRI data were collected before and after rTMS. Subjects were stratified into responder and nonresponder groups using a criterion of ≥50% reduction in weekly binge/purge frequency. Neural predictors and correlates of response were identified using seed-based functional connectivity (FC), using the dmPFC and adjacent dorsal anterior cingulate cortex (dACC) as regions of interest.
Results
16 of 28 subjects met response criteria. Treatment responders had lower baseline FC from dmPFC to lateral orbitofrontal cortex and right posterior insula, and from dACC to right posterior insula and hippocampus. Responders had low baseline FC from the dACC to the ventral striatum and anterior insula; this connectivity increased over treatment. However, in nonresponders, frontostriatal FC was high at baseline, and dmPFC-rTMS suppressed FC in association with symptomatic worsening.
Conclusions
Enhanced frontostriatal connectivity was associated with responders to dmPFC-rTMS for binge/purge behavior. rTMS caused paradoxical suppression of frontostriatal connectivity in nonresponders. rs-fMRI could prove critical for optimizing stimulation parameters in a future sham-controlled trial of rTMS in disordered eating.
Highlights
•dmPFC-rTMS was performed on patients with treatment-refractory AN and BN.•Resting-state fMRI was collected to identify predictors and correlates of response.•dmPFC-rTMS achieves robust improvement on bingeing and purging in AN and BN.•Responders have lower baseline corticostriatal connectivity compared to nonresponders.•Increased corticostriatal connectivity is associated with treatment response.
doi:10.1016/j.nicl.2015.06.008
PMCID: PMC4506986  PMID: 26199873
6.  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
7.  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
8.  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
9.  Neural Correlates of Emotional Interference in Social Anxiety Disorder 
PLoS ONE  2015;10(6):e0128608.
Disorder-relevant but task-unrelated stimuli impair cognitive performance in social anxiety disorder (SAD); however, time course and neural correlates of emotional interference are unknown. The present study investigated time course and neural basis of emotional interference in SAD using event-related functional magnetic resonance imaging (fMRI). Patients with SAD and healthy controls performed an emotional stroop task which allowed examining interference effects on the current and the succeeding trial. Reaction time data showed an emotional interference effect in the current trial, but not the succeeding trial, specifically in SAD. FMRI data showed greater activation in the left amygdala, bilateral insula, medial prefrontal cortex (mPFC), dorsal anterior cingulate cortex (ACC), and left opercular part of the inferior frontal gyrus during emotional interference of the current trial in SAD patients. Furthermore, we found a positive correlation between patients’ interference scores and activation in the mPFC, dorsal ACC and left angular/supramarginal gyrus. Taken together, results indicate a network of brain regions comprising amygdala, insula, mPFC, ACC, and areas strongly involved in language processing during the processing of task-unrelated threat in SAD. However, specifically the activation in mPFC, dorsal ACC, and left angular/supramarginal gyrus is associated with the strength of the interference effect, suggesting a cognitive network model of attentional bias in SAD. This probably comprises exceeded allocation of attentional resources to disorder-related information of the presented stimuli and increased self-referential and semantic processing of threat words in SAD.
doi:10.1371/journal.pone.0128608
PMCID: PMC4456154  PMID: 26042738
10.  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
11.  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
12.  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
13.  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
14.  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
15.  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
16.  Diminished Medial Prefrontal Activity behind Autistic Social Judgments of Incongruent Information 
PLoS ONE  2012;7(6):e39561.
Individuals with autism spectrum disorders (ASD) tend to make inadequate social judgments, particularly when the nonverbal and verbal emotional expressions of other people are incongruent. Although previous behavioral studies have suggested that ASD individuals have difficulty in using nonverbal cues when presented with incongruent verbal-nonverbal information, the neural mechanisms underlying this symptom of ASD remain unclear. In the present functional magnetic resonance imaging study, we compared brain activity in 15 non-medicated adult males with high-functioning ASD to that of 17 age-, parental-background-, socioeconomic-, and intelligence-quotient-matched typically-developed (TD) male participants. Brain activity was measured while each participant made friend or foe judgments of realistic movies in which professional actors spoke with conflicting nonverbal facial expressions and voice prosody. We found that the ASD group made significantly less judgments primarily based on the nonverbal information than the TD group, and they exhibited significantly less brain activity in the right inferior frontal gyrus, bilateral anterior insula, anterior cingulate cortex/ventral medial prefrontal cortex (ACC/vmPFC), and dorsal medial prefrontal cortex (dmPFC) than the TD group. Among these five regions, the ACC/vmPFC and dmPFC were most involved in nonverbal-information-biased judgments in the TD group. Furthermore, the degree of decrease of the brain activity in these two brain regions predicted the severity of autistic communication deficits. The findings indicate that diminished activity in the ACC/vmPFC and dmPFC underlies the impaired abilities of individuals with ASD to use nonverbal content when making judgments regarding other people based on incongruent social information.
doi:10.1371/journal.pone.0039561
PMCID: PMC3382122  PMID: 22745788
17.  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
18.  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
19.  Decreased neural activity and neural connectivity while performing a set-shifting task after inhibiting repetitive transcranial magnetic stimulation on the left dorsal prefrontal cortex 
BMC Neuroscience  2015;16:45.
Background
Sub-optimal functioning of the dorsal prefrontal cortex (PFC) is associated with executive dysfunction, such as set-shifting deficits, in neurological and psychiatric disorders. We tested this hypothesis by investigating the effect of low-frequency ‘inhibiting’ off-line repetitive transcranial magnetic stimulation (rTMS) on the left dorsal prefrontal cortex on behavioural performance, neural activity, and network connectivity during the performance of a set-shifting paradigm in healthy elderly (mean age 50+).
Results
Behaviorally, we found a group-by-session interaction for errors on set-shift trials, although post hoc tests did not yield significant findings. In addition, the verum group, when compared with the sham group, displayed reduced task-related activity in the left temporal gyrus, and reduced task-related connectivity of the left PFC with the left postcentral gyrus and posterior insula.
Conclusion
These results show that low-frequency off-line rTMS on the left dorsal PFC resulted in reduced task-related activity and network connectivity, which was accompanied by a subtle behavioural effect, thereby further corroborating the importance of an optimally functioning PFC in set-shifting.
doi:10.1186/s12868-015-0181-3
PMCID: PMC4511070  PMID: 26199083
Key-words; Set-shifting; Low-frequency repetitive transcranial magnetic stimulation; Functional magnetic resonance imaging; Prefrontal cortex; Connectivity
20.  The Essential Role of Primate Orbitofrontal Cortex in Conflict-Induced Executive Control Adjustment 
The Journal of Neuroscience  2014;34(33):11016-11031.
Conflict in information processing evokes trial-by-trial behavioral modulations. Influential models suggest that adaptive tuning of executive control, mediated by mid-dorsal lateral prefrontal cortex (mdlPFC) and anterior cingulate cortex (ACC), underlies these modulations. However, mdlPFC and ACC are parts of distributed brain networks including orbitofrontal cortex (OFC), posterior cingulate cortex (PCC), and superior-dorsal lateral prefrontal cortex (sdlPFC). Contributions of these latter areas in adaptive tuning of executive control are unknown. We trained monkeys to perform a matching task in which they had to resolve the conflict between two behavior-guiding rules. Here, we report that bilateral lesions in OFC, but not in PCC or sdlPFC, impaired selection between these competing rules. In addition, the behavioral adaptation that is normally induced by experiencing conflict disappeared in OFC-lesioned, but remained normal in PCC-lesioned or sdlPFC-lesioned monkeys. Exploring underlying neuronal processes, we found that the activity of neurons in OFC represented the conflict between behavioral options independent from the other aspects of the task. Responses of OFC neurons to rewards also conveyed information of the conflict level that the monkey had experienced along the course to obtain the reward. Our findings indicate dissociable functions for five closely interconnected cortical areas suggesting that OFC and mdlPFC, but not PCC or sdlPFC or ACC, play indispensable roles in conflict-dependent executive control of on-going behavior. Both mdlPFC and OFC support detection of conflict and its integration with the task goal, but in contrast to mdlPFC, OFC does not retain the necessary information for conflict-induced modulation of future decisions.
doi:10.1523/JNEUROSCI.1637-14.2014
PMCID: PMC4131015  PMID: 25122901
conflict; executive control; lesion study; orbitofrontal cortex
21.  Causal Evidence Supporting Functional Dissociation of Verbal and Spatial Working Memory in the Human Dorsolateral Prefrontal Cortex 
The European journal of neuroscience  2014;39(11):1973-1981.
The human dorsolateral prefrontal cortex (dlPFC) is crucial for monitoring and manipulating information in working memory, but whether such contributions are domain-specific remains unsettled. Neuroimaging studies have shown bilateral dlPFC activity associated with working memory independent of stimulus domain, but the causality of this relationship cannot be inferred. Repetitive transcranial magnetic stimulation (rTMS) has the potential to test whether the left and right dlPFC contribute equally to verbal and spatial domains, however this is the first study to investigate the interaction of task domain and hemisphere using offline rTMS to temporarily modulate dlPFC activity. In separate sessions, twenty healthy right-handed adults received 1Hz-rTMS to left dlPFC, right dlPFC, plus the vertex as a control site. Working memory performance was assessed pre- and post-rTMS using both verbal-‘letter’ and spatial-‘location’ versions of the 3-back task. Response times were faster post-rTMS, independent of task domain or stimulation condition, indicating the influence of practice or other nonspecific effects. For accuracy, rTMS of the right dlPFC, but not the left dlPFC or vertex, led to a transient dissociation: reducing spatial, but increasing verbal accuracy. A post-hoc correlation analysis found no relationship between these changes indicating the substrates underlying verbal and spatial domains are functionally independent. Collapsing across time, there was a trend towards a double dissociation, suggesting a potential laterality in functional organization of verbal and spatial working memory. At a minimum, these findings provide human evidence for domain-specific contributions of the dlPFC to working memory and reinforce the potential of rTMS to ameliorate cognition.
doi:10.1111/ejn.12584
PMCID: PMC4043922  PMID: 24713032
rTMS; dlPFC; working memory; functional specialization; functional neuroanatomy
22.  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
23.  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
24.  Event-Related Functional Magnetic Resonance Imaging Investigation of Executive Control in Very Old Individuals with Mild Cognitive Impairment 
Biological psychiatry  2005;57(7):761-767.
Background
Attentional control of executive cognitive function (ECF) decreases in older individuals with Alzheimer Disease (AD). In order to examine early AD-related changes in the neural substrates of ECF attentional control, we measured activation dorsolateral prefrontal (dLPFC), posterior parietal (PPC), and anterior cingulate cortex (ACC) in adults with mild cognitively impairment (MCI) and in cognitively normal (CN) adults.
Methods
Functional magnetic resonance imaging analysis of brain activation in MCI (n = 8, mean age 79.5) and CN (n = 8 mean age 81.5) during increasing loads of attentional demands.
Results
MCI and CN older adults performed with similar accuracy and reaction time. MCI had greater activation than CN in PPC (right p = .03 and left p = .05) and dlPFC areas (right p = .002 and left p = .004), while activation in ACC was similar in the two groups. Response to increasing loads of the task differed by group: MCI selectively engaged bilateral PPC (right p = .03, left p = .04), while CN subjects increased bilateral dlPFC activation (right p = .005 and left p = .02) and ACC activation (p = .04). Among MCI, greater load-related changes in PPC activity were associated with smaller load-related changes in accuracy rates (r = −.85, p = .07) and greater increases in reaction times (r = .97, p = .01). In CN subjects, load-related change in PPC activation was associated with load-related change in reaction time (r = .76, p = .02) but not with changes in accuracy rates.
Conclusions
PPC and dlPFC may show early functional changes associated with MCI.
doi:10.1016/j.biopsych.2004.12.031
PMCID: PMC2848401  PMID: 15820233
Executive cognitive function; dementia; functional MRI
25.  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

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