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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.
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.
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.
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.
PMCID: PMC2888482  PMID: 19652121
2.  Crack cocaine use impairs anterior cingulate and prefrontal cortex function in women with HIV infection 
Journal of neurovirology  2014;20(4):352-361.
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.
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.
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.
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.
PMCID: PMC4090256  PMID: 24760360
HIV; crack cocaine; African American; verbal memory; fMRI; prefrontal cortex
3.  Variability in Post-Error Behavioral Adjustment Is Associated with Functional Abnormalities in the Temporal Cortex in Children with ADHD 
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.
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.
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.
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).
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.
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.
We examined the interrelations between alexithymia, tobacco craving, and insula/ACC neurocircuitry using resting-state functional connectivity (rsFC).
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.
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.
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.
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.
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.
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.
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.
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.
•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.
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.
PMCID: PMC3434167  PMID: 22957066
7.  Neural substrates of approach-avoidance conflict decision-making 
Human brain mapping  2014;36(2):449-462.
Animal approach-avoidance conflict paradigms have been used extensively to operationalize anxiety, quantify the effects of anxiolytic agents, and probe the neural basis of fear and anxiety. Results from human neuroimaging studies support that a frontal-striatal-amygdala neural circuitry is important for approach-avoidance learning. However, the neural basis of decision-making is much less clear in this context. Thus, we combined a recently developed human approach-avoidance paradigm with functional magnetic resonance imaging (fMRI) to identify neural substrates underlying approach-avoidance conflict decision-making. Fifteen healthy adults completed the approach-avoidance conflict (AAC) paradigm during fMRI. Analyses of variance were used to compare conflict to non-conflict (avoid-threat and approach-reward) conditions and to compare level of reward points offered during the decision phase. Trial-by-trial amplitude modulation analyses were used to delineate brain areas underlying decision-making in the context of approach/avoidance behavior. Conflict trials as compared to the non-conflict trials elicited greater activation within bilateral anterior cingulate cortex (ACC), anterior insula, and caudate, as well as right dorsolateral prefrontal cortex. Right caudate and lateral PFC activation was modulated by level of reward offered. Individuals who showed greater caudate activation exhibited less approach behavior. On a trial-by-trial basis, greater right lateral PFC activation related to less approach behavior. Taken together, results suggest that the degree of activation within prefrontal-striatal-insula circuitry determines the degree of approach versus avoidance decision-making. Moreover, the degree of caudate and lateral PFC activation is related to individual differences in approach-avoidance decision-making. Therefore, the AAC paradigm is ideally suited to probe anxiety-related processing differences during approach-avoidance decision-making.
PMCID: PMC4300249  PMID: 25224633
prefrontal cortex; anterior cingulate cortex; insula; caudate; striatum; emotion; reward; punishment
8.  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.
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.
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)).
Multi-site neuroimaging study(February 2011–April 2012).
Academic medical centers: Case Western Reserve University, Cincinnati Children’s Hospital, University of Pittsburgh.
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.
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).
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.
PMCID: PMC4238412  PMID: 24285346
9.  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.
PMCID: PMC3328778  PMID: 22529770
betting; choice; fMRI; inferior parietal cortex; ventromedial prefrontal cortex; reward
10.  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.
PMCID: PMC2323905  PMID: 18294820
Functional magnetic resonance imaging (fMRI); attention; emotion; affect; cognition; child; adolescent
11.  Neural Circuitry of Impaired Emotion Regulation in Substance Use Disorders 
The American journal of psychiatry  2016;173(4):344-361.
Impaired emotion regulation contributes to the development and severity of substance use disorders (substance disorders). This review summarizes the literature on alterations in emotion regulation neural circuitry in substance disorders, particularly in relation to disorders of negative affect (without substance disorder), and it presents promising areas of future research. Emotion regulation paradigms during functional magnetic resonance imaging are conceptualized into four dimensions: affect intensity and reactivity, affective modulation, cognitive modulation, and behavioral control. The neural circuitry associated with impaired emotion regulation is compared in individuals with and without substance disorders, with a focus on amygdala, insula, and prefrontal cortex activation and their functional and structural connectivity. Hypoactivation of the rostral anterior cingulate cortex/ventromedial prefrontal cortex (rACC/vmPFC) is the most consistent finding across studies, dimensions, and clinical populations (individuals with and without substance disorders). The same pattern is evident for regions in the cognitive control network (anterior cingulate and dorsal and ventrolateral prefrontal cortices) during cognitive modulation and behavioral control. These congruent findings are possibly related to attenuated functional and/or structural connectivity between the amygdala and insula and between the rACC/vmPFC and cognitive control network. Although increased amygdala and insula activation is associated with impaired emotion regulation in individuals without substance disorders, it is not consistently observed in substance disorders. Emotion regulation disturbances in substance disorders may therefore stem from impairments in prefrontal functioning, rather than excessive reactivity to emotional stimuli. Treatments for emotion regulation in individuals without substance disorders that normalize prefrontal functioning may offer greater efficacy for substance disorders than treatments that dampen reactivity.
PMCID: PMC4979988  PMID: 26771738
12.  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.
PMCID: PMC2962771  PMID: 20688176
Smoking cue; anatomical; ASL; DTI; VBM; resting state functional connectivity
13.  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.
PMCID: PMC4211399  PMID: 25389397
amygdala; anterior cingulate cortex; borderline personality disorder; emotional distraction; emotional working memory; functional connectivity; interpersonal trauma; psychophysiological interactions
14.  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.
PMCID: PMC2730728  PMID: 19458213
attention-deficit hyperactivity disorder; dopamine; prefrontal cortex; schizophrenia; single unit; rat
15.  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.
PMCID: PMC4067454  PMID: 22935543
Anterior cingulate cortex; Prefrontal cortex; Executive function; Event-related potentials; Cognitive control; Novelty P3
16.  Temporal Dynamics of Stress-Induced Alternations of Intrinsic Amygdala Connectivity and Neuroendocrine Levels 
PLoS ONE  2015;10(5):e0124141.
Stress-induced changes in functional brain connectivity have been linked to the etiology of stress-related disorders. Resting state functional connectivity (rsFC) is especially informative in characterizing the temporal trajectory of glucocorticoids during stress adaptation. Using the imaging Maastricht Acute Stress Test (iMAST), we induced acute stress in 39 healthy volunteers and monitored the neuroendocrine stress levels during three runs of resting state functional magnetic resonance imaging (rs-fMRI): before (run 1), immediately following (run 2), and 30min after acute stress (run 3). The iMAST resulted in strong increases in cortisol levels. Whole-brain analysis revealed that acute stress (run 2 - 1) was characterized by changes in connectivity of the amygdala with the ventrolateral prefrontal cortex (vlPFC), ventral posterior cingulate cortex (PCC), cuneus, parahippocampal gyrus, and culmen. Additionally, cortisol responders were characterized by enhanced amygdala - medial prefrontal cortex (mPFC) connectivity. Stress recovery (run 3 - 2) was characterized by altered amygdala connectivity with the dorsolateral prefrontal cortex (dlPFC), ventral and dorsal anterior cingulate cortex (ACC), anterior hippocampal complex, cuneus, and presupplementary motor area (preSMA). Opposite to non-responders, cortisol responders were characterized by enhanced amygdala connectivity with the anterior hippocampal complex and parahippocampal gyrus, and reduced connectivity with left dlPFC, dACC, and culmen during early recovery. Acute stress responding and recovery are thus associated with changes in the functional connectivity of the amygdala network. Our findings show that these changes may be regulated via stress-induced neuroendocrine levels. Defining stress-induced neuronal network changes is pertinent to developing treatments that target abnormal neuronal activity.
PMCID: PMC4422669  PMID: 25946334
17.  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.
PMCID: PMC3340884  PMID: 22414937
Attention bias; PTSD; Threat; fMRI; Prefrontal cortex; Neuroimaging; Posttraumatic Stress Disorder; Anterior cingulate cortex; Dorsolateral prefrontal cortex; Cognition
18.  Neurobiological impact of nicotinic acetylcholine receptor agonists: An ALE meta-analysis of pharmacological neuroimaging studies 
Biological psychiatry  2015;78(10):711-720.
Nicotinic acetylcholine receptor (nAChR) agonists augment cognition among cigarette smokers and nonsmokers, yet the systems-level neurobiological mechanisms underlying such improvements are not fully understood. Aggregating neuroimaging results regarding nAChR agonists provides a means to identify common functional brain changes that may be related to pro-cognitive drug effects.
We conducted a meta-analysis of pharmacological neuroimaging studies within the activation likelihood estimation framework. We identified published studies contrasting a nAChR drug condition versus a baseline and coded each contrast by activity change direction (decrease or increase), participant characteristics (smokers or nonsmokers), and drug manipulation employed (pharmacological administration or cigarette smoking).
When considering all studies, nAChR agonist administration was associated with activity decreases in multiple regions, including the ventromedial prefrontal cortex (vmPFC), posterior cingulate cortex (PCC), parahippocampus, insula, and the parietal and precentral cortices. Conversely, activity increases were observed in lateral frontoparietal cortices, the anterior cingulate cortex (ACC), thalamus, and cuneus. Exploratory analyses indicated that both smokers and nonsmokers showed activity decreases in the vmPFC and PCC, and increases in lateral frontoparietal regions. Among smokers, both pharmacological administration and cigarette smoking were associated with activity decreases in the vmPFC, PCC, and insula, and increases in the lateral PFC, dorsal ACC, thalamus, and cuneus.
These results provide support for the systems-level perspective that nAChR agonists suppress activity in default-mode network regions and enhance activity in executive control network regions in addition to reducing activation of some task-related regions. We speculate these are potential mechanisms by which nAChR agonists enhance cognition.
PMCID: PMC4494985  PMID: 25662104
pharmacological functional magnetic resonance imaging (fMRI); activation likelihood estimation (ALE); nicotine; withdrawal; default mode network (DMN); executive control network (ECN)
19.  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.
PMCID: PMC4456154  PMID: 26042738
20.  Relating Intrinsic Low-Frequency BOLD Cortical Oscillations to Cognition in Schizophrenia 
Neuropsychopharmacology  2015;40(12):2705-2714.
The amplitude of low-frequency fluctuations (ALFF) in the blood oxygenation level-dependent (BOLD) signal during resting-state fMRI reflects the magnitude of local low-frequency BOLD oscillations, rather than interregional connectivity. ALFF is of interest to studies of cognition because fluctuations in spontaneous intrinsic brain activity relate to, and possibly even constrain, task-evoked brain responses in healthy people. Lower ALFF has been reported in schizophrenia, but the cognitive correlates of these reductions remain unknown. Here, we assess relationships between ALFF and attention and working memory in order to establish the functional relevance of intrinsic BOLD oscillatory power alterations with respect to specific cognitive impairments in schizophrenia. As part of the multisite FBIRN study, resting-state fMRI data were collected from schizophrenia subjects (SZ; n=168) and healthy controls (HC; n=166). Voxelwise fractional ALFF (fALFF), a normalized ALFF measure, was regressed on neuropsychological measures of sustained attention and working memory in SZ and HC to identify regions showing either common slopes across groups or slope differences between groups (all findings p<0.01 height, p<0.05 family-wise error cluster corrected). Poorer sustained attention was associated with smaller fALFF in the left superior frontal cortex and bilateral temporoparietal junction in both groups, with additional relationships in bilateral posterior parietal, posterior cingulate, dorsal anterior cingulate (ACC), and right dorsolateral prefrontal cortex (DLPFC) evident only in SZ. Poorer working memory was associated with smaller fALFF in bilateral ACC/mPFC, DLPFC, and posterior parietal cortex in both groups. Our findings indicate that smaller amplitudes of low-frequency BOLD oscillations during rest, measured by fALFF, were significantly associated with poorer cognitive performance, sometimes similarly in both groups and sometimes only in SZ, in regions known to subserve sustained attention and working memory. Taken together, these data suggest that the magnitude of resting-state BOLD oscillations shows promise as a biomarker of cognitive function in health and disease.
PMCID: PMC4864646  PMID: 25944410
21.  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.
PMCID: PMC2644261  PMID: 19020027
depression; emotion; prefrontal cortex; ventromedial; dorsolateral; neuropathology
22.  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.
PMCID: PMC3806720  PMID: 22452556
23.  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.
PMCID: PMC2962684  PMID: 20673804
Emotion; Emotion Regulation; fMRI; Anxiety; Prefrontal Cortex; Anterior Cingulate Cortex
24.  Specifically altered brain responses to threat in generalized anxiety disorder relative to social anxiety disorder and panic disorder 
NeuroImage : Clinical  2016;12:698-706.
Despite considerable effort, the neurobiological underpinnings of hyper-responsive threat processing specific to patients suffering from generalized anxiety disorder (GAD) remain poorly understood. The current functional magnetic resonance imaging (fMRI) study aims to delineate GAD-specific brain activity during immediate threat processing by comparing GAD patients to healthy controls (HC), to social anxiety disorder (SAD) and to panic disorder (PD) patients.
Brain activation and functional connectivity patterns to threat vs. neutral pictures were investigated using event-related fMRI. The sample consisted of 21 GAD, 21 PD, 21 SAD and 21 HC.
GAD-specific elevated activity to threat vs. neutral pictures was found in cingulate cortex, dorsal anterior insula/frontal operculum (daI/FO) and posterior dorsolateral prefrontal cortex (dlPFC). Defining these effects as seed regions, we detected GAD-specific increased functional connectivity to threat vs. neutral pictures between posterior dlPFC and ventrolateral prefrontal cortex, between cingulate cortex and amygdala, between cingulate cortex and anterior insula, as well as decreased functional connectivity between daI/FO and mid-dlPFC.
The findings present the first evidence for GAD-specific neural correlates of hyper-responsive threat processing, possibly reflecting exaggerated threat sensitivity, maladaptive appraisal and attention-allocation processes.
•Threat processing investigation across multiple anxiety disorders•First neural evidence of GAD-specific threat-related alterations•GAD-specific alterations primarily located in prefrontal cortex•Alterations are suggestive of exaggerated threat sensitivity
PMCID: PMC5065042  PMID: 27761400
Cingulate cortex; Prefrontal cortex; Anterior insula; Threat processing; RDoC
25.  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.
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+).
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.
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.
PMCID: PMC4511070  PMID: 26199083
Key-words; Set-shifting; Low-frequency repetitive transcranial magnetic stimulation; Functional magnetic resonance imaging; Prefrontal cortex; Connectivity

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