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1.  Open label smoking cessation with varenicline is associated with decreased glutamate levels and functional changes in anterior cingulate cortex: preliminary findings 
Rationale: Varenicline, the most effective single agent for smoking cessation, is a partial agonist at α4β2 nicotinic acetylcholine receptors. Increasing evidence implicates glutamate in the pathophysiology of addiction and one of the benefits of treatment for smoking cessation is the ability to regain cognitive control.
Objective: To evaluate the effects of 12-week varenicline administration on glutamate levels in the dorsal anterior cingulate cortex (dACC) and functional changes within the cognitive control network.
Methods: We used single-voxel proton magnetic resonance spectroscopy (1H-MRS) in the dACC and functional MRI (fMRI) during performance of a Stroop color-naming task before and after smoking cessation with varenicline in 11 healthy smokers (open label design). Using the dACC as a seed region, we evaluated functional connectivity changes using a psychophysiological interaction (PPI) analysis.
Results: We observed a significant decrease in dACC glutamate + glutamine (Glx)/Cr levels as well as significant blood oxygen level-dependent signal (BOLD) decreases in the rostral ACC/medial orbitofrontal cortex and precuneus/posterior cingulate cortex. These BOLD changes are suggestive of alterations in default mode network (DMN) function and are further supported by the results of the PPI analysis that revealed changes in connectivity between the dACC and regions of the DMN. Baseline measures of nicotine dependence and craving positively correlated with baseline Glx/Cr levels.
Conclusions: These results suggest possible mechanisms of action for varenicline such as reduction in Glx levels in dACC and shifts in BOLD connectivity between large scale brain networks. They also suggest a role for ACC Glx in the modulation of behavior. Due to the preliminary nature of this study (lack of control group and small sample size), future studies are needed to replicate these findings.
PMCID: PMC4085720  PMID: 25071576
addiction; smoking; varenicline; fMRI; MRS; PPI; connectivity; nicotine
2.  Individual Differences in Reinforcement Learning: Behavioral, Electrophysiological, and Neuroimaging Correlates 
NeuroImage  2008;42(2):807-816.
During reinforcement learning, phasic modulations of activity in midbrain dopamine neurons are conveyed to the dorsal anterior cingulate cortex (dACC) and basal ganglia and serve to guide adaptive responding. While the animal literature supports a role for the dACC in integrating reward history over time, most human electrophysiological studies of dACC function have focused on responses to single positive and negative outcomes. The present electrophysiological study investigated the role of the dACC in probabilistic reward learning in healthy subjects using a task that required integration of reinforcement history over time. We recorded the feedback-related negativity (FRN) to reward feedback in subjects who developed a response bias toward a more frequently rewarded (“rich”) stimulus (“learners”) versus subjects who did not (“non-learners”). Compared to non-learners, learners showed more positive (i.e., smaller) FRNs and greater dACC activation upon receiving reward for correct identification of the rich stimulus. In addition, dACC activation and a bias to select the rich stimulus were positively correlated. The same participants also completed a monetary incentive delay (MID) task administered during functional magnetic resonance imaging. Compared to non-learners, learners displayed stronger basal ganglia responses to reward in the MID task. These findings raise the possibility that learners in the probabilistic reinforcement task were characterized by stronger dACC and basal ganglia responses to rewarding outcomes. Furthermore, these results highlight the importance of the dACC to probabilistic reward learning in humans.
PMCID: PMC2548326  PMID: 18595740
Reinforcement Learning; Anterior Cingulate Cortex; Basal Ganglia; Reward; Feedback-related Negativity; Probabilistic Learning
3.  Preparatory Activity and Connectivity in Dorsal Anterior Cingulate Cortex for Cognitive Control 
NeuroImage  2011;57(1):242-250.
Dorsal anterior cingulate cortex (dACC) is composed of functionally distinct subregions that may contribute to the top-down control of response selection and preparation. Multiple motor areas have been identified in dACC, including an anterior zone implicated in conflict monitoring and a caudal zone involved in movement execution. This study tested the involvement of a third cingulate area, the posterior zone of dACC, in the top-down control of response selection and preparation. Sixteen healthy young adults were scanned with event-related functional magnetic resonance imaging while performing a cued go/no-go task that was designed to minimize response conflicts. The activation and functional connectivity of dACC were tested with standard convolution models and psychophysiological interaction analyses, respectively. Ready cues that informed the direction of the impending response triggered preparatory neural activity in the posterior zone of dACC and strengthened functional connectivity with the anterior and caudal zones of dACC, as well as perigenual anterior cingulate cortex, frontal operculum, dorsolateral prefrontal cortex, sensory association cortices, and extra-pyramidal motor areas. The preparatory cues activated dACC above and beyond the general arousing effects common to cues despite negligible conflict in the go/no-go task. The integration of cognitive, sensorimotor, and incentive signals in dACC places the region in an ideal position to select and prepare appropriate behavioral responses to achieve higher-level goals.
PMCID: PMC3101271  PMID: 21515388
4.  Frontal Hyperconnectivity Related to Discounting and Reversal Learning in Cocaine Subjects 
Biological psychiatry  2011;69(11):1117-1123.
Functional neuroimaging studies suggest that chronic cocaine use is associated with frontal lobe abnormalities. Functional connectivity (FC) alterations of cocaine dependent individuals (CD), however, are not yet clear. This is the first study to our knowledge that examines resting FC of anterior cingulate cortex (ACC) in CD. Because ACC is known to integrate inputs from different brain regions to regulate behavior, we hypothesize that CD will have connectivity abnormalities in ACC networks. In addition, we hypothesized that abnormalities would be associated with poor performance in delayed discounting and reversal learning tasks.
Resting functional magnetic resonance imaging data were collected to look for FC differences between twenty-seven cocaine dependent individuals (CD) (5 females, age: M=39.73, SD=6.14) and twenty-four controls (5 females, age: M=39.76, SD = 7.09). Participants were assessed with delayed discounting and reversal learning tasks. Using seed-based FC measures, we examined FC in CD and controls within five ACC connectivity networks with seeds in subgenual, caudal, dorsal, rostral, and perigenual ACC.
CD showed increased FC within the perigenual ACC network in left middle frontal gyrus, ACC and middle temporal gyrus when compared to controls. FC abnormalities were significantly positively correlated with task performance in delayed discounting and reversal learning tasks in CD.
The present study shows that participants with chronic cocaine-dependency have hyperconnectivity within an ACC network known to be involved in social processing and mentalizing. In addition, FC abnormalities found in CD were associated with difficulties with delay rewards and slower adaptive learning.
PMCID: PMC3090521  PMID: 21371689
cocaine; functional connectivity; anterior cingulate; delayed discount; reversal learning; frontal
5.  Altered salience network connectivity predicts macronutrient intake after sleep deprivation 
Scientific Reports  2015;5:8215.
Although insufficient sleep is a well-recognized risk factor for overeating and weight gain, the neural mechanisms underlying increased caloric (particularly fat) intake after sleep deprivation remain unclear. Here we used resting-state functional magnetic resonance imaging and examined brain connectivity changes associated with macronutrient intake after one night of total sleep deprivation (TSD). Compared to the day following baseline sleep, healthy adults consumed a greater percentage of calories from fat and a lower percentage of calories from carbohydrates during the day following TSD. Subjects also exhibited increased brain connectivity in the salience network from the dorsal anterior cingulate cortex (dACC) to bilateral putamen and bilateral anterior insula (aINS) after TSD. Moreover, dACC-putamen and dACC-aINS connectivity correlated with increased fat and decreased carbohydrate intake during the day following TSD, but not during the day following baseline sleep. These findings provide a potential neural mechanism by which sleep loss leads to increased fat intake.
PMCID: PMC4314629  PMID: 25645575
6.  Insular and Anterior Cingulate Circuits in Smokers with Schizophrenia 
Schizophrenia research  2012;142(1-3):223-229.
Schizophrenia (SZ) is associated with high rates of smoking. We previously found that dorsal anterior cingulate (dACC) – striatum resting state functional connectivity (rsFC) is independently associated with nicotine addiction and psychiatric illness. Since the insula is implicated in nicotine dependence, we hypothesized that SZ smokers will have greater dysfunction in smoking-related insular and dACC circuits than normal control smokers (NC) independent of smoking severity, consistent with an inherent disease-related weakening of smoking-related circuits. Nicotine challenge was used to demonstrate that decreased rsFC in identified circuits reflects addiction trait and is not affected by pharmacological state. Twenty-four NC smokers and 20 smokers with SZ matched on nicotine addiction severity participated in a resting state fMRI study and were scanned during two separate sessions while receiving a placebo or nicotine patch, in a randomized, cross-over design. Using individualized, anatomically defined anterior and posterior insula and dACC as regions of interest (ROI), whole brain rsFC was performed using each ROI as a seed. Significant negative correlations between smoking severity and rsFC between insula, dACC and striatum were found for both groups. Furthermore, smokers with SZ demonstrated additive reductions in circuit strength between the dACC and insula compared to NC smokers independent of smoking severity. Nicotine challenge did not significantly alter rsFC in insula-dACC-striatal circuits. Reduced rsFC strength between the insula, dACC and striatum is associated with nicotine addiction severity in both non-psychiatrically ill and in SZ smokers. Decreased insula-dACC rsFC may index overlapping circuitry associated with smoking and SZ.
PMCID: PMC3502674  PMID: 23021898
resting state functional connectivity; schizophrenia; smoking; nicotine; insula; anterior cingulate
7.  Resting-state functional connectivity in anterior cingulate cortex in normal aging 
Growing evidence suggests that normal aging is associated with cognitive decline and well-maintained emotional well-being. The anterior cingulate cortex (ACC) is an important brain region involved in emotional and cognitive processing. We investigated resting-state functional connectivity (FC) of two ACC subregions in 30 healthy older adults vs. 33 healthy younger adults, by parcellating into rostral (rACC) and dorsal (dACC) ACC based on clustering of FC profiles. Compared with younger adults, older adults demonstrated greater connection between rACC and anterior insula, suggesting that older adults recruit more proximal dACC brain regions connected with insula to maintain a salient response. Older adults also demonstrated increased FC between rACC and superior temporal gyrus and inferior frontal gyrus, decreased integration between rACC and default mode, and decreased dACC-hippocampal and dACC-thalamic connectivity. These altered FCs reflected rACC and dACC reorganization, and might be related to well emotion regulation and cognitive decline in older adults. Our findings provide further insight into potential functional substrates of emotional and cognitive alterations in the aging brain.
PMCID: PMC4212807  PMID: 25400578
aging; fMRI; resting state; functional connectivity; anterior cingulate cortex
8.  Common and Distinct Neural Mechanisms of Attentional Switching and Response Conflict 
Brain research  2012;1469:92-102.
The human capacities for overcoming prepotent actions and flexibly switching between tasks represent cornerstones of cognitive control. Functional neuroimaging has implicated a diverse set of brain regions contributing to each of these cognitive control processes. However, the extent to which attentional switching and response conflict draw on shared or distinct neural mechanisms remains unclear. The current study examined the neural correlates of response conflict and attentional switching using event-related functional magnetic resonance imaging (fMRI) and a fully randomized 2×2 design. We manipulated an arrow-word version of the Stroop task to measure conflict and switching in the context of a single task decision, in response to a common set of stimuli. Under these common conditions, both behavioral and imaging data showed significant main effects of conflict and switching but no interaction. However, conjunction analyses identified frontal regions involved in both switching and response conflict, including the dorsal anterior cingulate cortex (dACC) and left inferior frontal junction. In addition, connectivity analyses demonstrated task-dependent functional connectivity patterns between dACC and inferior temporal cortex for attentional switching and between dACC and posterior parietal cortex for response conflict. These results suggest that the brain makes use of shared frontal regions, but can dynamically modulate the connectivity patterns of some of those regions, to deal with attentional switching and response conflict.
PMCID: PMC3411858  PMID: 22750124
Cognitive control; Attentional switching; Response conflict; Prefrontal cortex; fMRI; functional connectivity
9.  Brain Circuits That Link Schizophrenia to High Risk of Cigarette Smoking 
Schizophrenia Bulletin  2012;39(6):1373-1381.
Schizophrenia is associated with a high prevalence of smoking. Functional connectivity between the dorsal anterior cingulate (dACC) and limbic regions including the ventral striatum, extended amygdala and parahippocampal areas has been previously implicated in the genetics and clinical severity of smoking. In this study, we test the hypothesis that dACC functional circuits are key paths for the high risk of smoking comorbidity in schizophrenia. Resting state functional magnetic resonance imaging (fMRI) was performed using the dACC as a seed region in smoking and nonsmoking patients with schizophrenia (n = 54), matched controls (n = 65), and nonpsychotic first-degree relatives (n = 24). Multiple regions had decreased connectivity with the dACC in schizophrenia patients when compared with matched controls (n = 65). Several of these functional circuits were also associated with nicotine addiction severity; the largest cluster included limbic areas such as the parahippocampal, extended amygdala, ventral striatal, and posterior insula regions, indicating an overlap of schizophrenia and nicotine addiction on to this circuit. These same functional connectivity–defined circuits were also significantly impaired in schizophrenia nonsmokers compared with control nonsmokers and in nonpsychotic first-degree relatives. Functional connectivity between the dACC and limbic regions is inherently abnormal in schizophrenia, related to its genetic liability regardless of smoking, and overlaps with a nicotine addiction–related circuit. Our findings establish a biologically defined brain circuit mechanism that contributes to the high prevalence of smoking.
PMCID: PMC3796082  PMID: 23236076
nicotine; anterior cingulate; functional connectivity; limbic
10.  Altered function and connectivity of the medial frontal cortex in pediatric obsessive compulsive disorder 
Biological psychiatry  2010;68(11):1039-1047.
Exaggerated concern for correct performance has been linked to hyperactivity of the medial frontal cortex (MFC) in adult obsessive compulsive disorder (OCD), but the role of the MFC during the early course of illness remains poorly understood. We tested whether hyperactive MFC-based performance monitoring function relates to altered MFC connectivity within task control and default mode networks in pediatric patients.
Eighteen pairs of OCD and matched healthy youth underwent functional magnetic resonance imaging during performance monitoring and at rest. Task-related hyperactivations in the posterior and ventral MFC were used as seeds for connectivity analyses during task and resting state.
In posterior MFC, patients showed greater activation of dorsal anterior cingulate cortex (dACC) than controls, with greater activation predicting worse performance. In ventral MFC, controls exhibited deactivation, whereas patients activated this region. Compared to controls, patients showed increased dACC - ventral MFC connectivity during task, and decreased dACC - right anterior operculum and ventral MFC- posterior cingulate connectivity during rest.
Excessive activation and increased interactions of posterior and ventral MFC during performance monitoring may combine with reduced resting state connectivity of these regions within networks for task control and default mode to reflect early markers of OCD. Alteration of reciprocal interactions between these networks could potentiate the intrusion of vMFC-based affectively laden, self-referential thoughts while disrupting pMFC-based performance-monitoring function in young patients.
PMCID: PMC2988474  PMID: 20947065
pediatric obsessive compulsive disorder; medial frontal cortex; performance monitoring; resting state connectivity; default mode network; task control network
11.  Neurons in Dorsal Anterior Cingulate Cortex Signal Postdecisional Variables in a Foraging Task 
The Journal of Neuroscience  2014;34(2):646-655.
The dorsal anterior cingulate cortex (dACC) is a key hub of the brain's executive control system. Although a great deal is known about its role in outcome monitoring and behavioral adjustment, whether and how it contributes to the decision process remain unclear. Some theories suggest that dACC neurons track decision variables (e.g., option values) that feed into choice processes and is thus “predecisional.” Other theories suggest that dACC activity patterns differ qualitatively depending on the choice that is made and is thus “postdecisional.” To compare these hypotheses, we examined responses of 124 dACC neurons in a simple foraging task in which monkeys accepted or rejected offers of delayed rewards. In this task, options that vary in benefit (reward size) and cost (delay) appear for 1 s; accepting the option provides the cued reward after the cued delay. To get at dACC neurons' contributions to decisions, we focused on responses around the time of choice, several seconds before the reward and the end of the trial. We found that dACC neurons signal the foregone value of the rejected option, a postdecisional variable. Neurons also signal the profitability (that is, the relative value) of the offer, but even these signals are qualitatively different on accept and reject decisions, meaning that they are also postdecisional. These results suggest that dACC can be placed late in the decision process and also support models that give it a regulatory role in decision, rather than serving as a site of comparison.
PMCID: PMC3870941  PMID: 24403162
12.  GABA Levels in The Dorsal Anterior Cingulate Cortex Associated with Difficulty Ignoring Smoking-Related Cues in Tobacco-Dependent Volunteers 
Neuropsychopharmacology  2013;38(6):1113-1120.
Substance abusers have difficulty ignoring drug-related cues, which is associated with relapse vulnerability. This ‘attentional bias' towards drug cues translates into an inability to ignore drug-related stimuli and may reflect deficits in the brain regions, such as the dorsal anterior cingulate cortex (dACC)—a key region in cognitive control and adaptive decision making. Quantifying relationships between attentional biases to drug cues and dACC neurochemistry could aid in identifying neurobiological mechanisms associated with increased relapse vulnerability precipitated by drug cues. As gamma-aminobutyric acid (GABA) deficits have been linked to impaired cognition and addictive disorders, we hypothesized that reduced GABA in the dACC would be associated with increased attentional biases towards smoking-related cues. We confirmed this hypothesis among nicotine-dependent tobacco smokers by combining an offline behavioral measure of attentional bias with magnetic resonance spectroscopy. Smokers with the greatest attentional bias also experienced more negative affect during early nicotine withdrawal. Findings revealed a relationship between heightened reactivity to drug cues, and both decreasing dACC GABA and early withdrawal symptoms. Because reduced GABA function in frontal brain regions disrupt cognitive function, our findings suggest that smokers with diminished dACC GABA may lack the cognitive resources to successfully ignore highly salient distractors such as tobacco-related stimuli and therefore might be more prone to cue-induced relapse. This newly discovered relationship between dACC GABA and attentional bias provides evidence for a neurochemical target, which may aid smoking cessation in highly cue-reactive individuals.
PMCID: PMC3629395  PMID: 23306182
addiction & substance abuse; attentional bias; dACC; GABA; imaging; clinical or preclinical; negative affect; neurochemistry; nicotine dependence; tobacco; GABA; dACC; negative affect; attentional bias; tobacco; nicotine dependence
13.  Cortical activation during delay discounting in abstinent methamphetamine dependent individuals 
Psychopharmacology  2008;201(2):183-193.
Methamphetamine (MA)-dependent individuals prefer smaller immediate over larger delayed rewards in delay discounting (DD) tasks. Human and animal data implicate ventral (amygdala, ventral striatum, ventrolateral prefrontal cortex insula) and dorsal (dorsolateral prefrontal cortex, dorsal anterior cingulate cortex and posterior parietal cortex) systems in DD decisions. The ventral system is hypothesized to respond to the salience and immediacy of rewards while the dorsal system is implicated in the process of comparison and choice.
We used functional Magnetic Resonance Imaging to probe the neural correlates of DD in 19 recently abstinent MA-dependent patients and 17 age- and gender-matched controls.
Hard DD choices were associated with greatest activation in bilateral middle cingulate, posterior parietal cortex (PPC), and the right rostral insula. Control subjects showed more activation than MA patients bilaterally in the precuneus and in the right caudate nucleus, anterior cingulate cortex (ACC), and dorsolateral prefrontal cortex (DLPFC). Magnitude of discounting was correlated with activity in the amygdala, DLPFC, posterior cingulate cortex and PPC.
Our findings were consistent with a model wherein dorsal cognitive systems modulate the neural response of ventral regions. Patients addicted to MA, who strongly prefer smaller immediate over larger delayed rewards, activate the dorsal cognitive control system in order to overcome their preference. Activation of the amygdala during choice of delayed rewards was associated with a greater degree of discounting, suggesting that heavily discounting MA-dependent individuals may be more responsive to the negative salience of delayed rewards than controls.
PMCID: PMC2835463  PMID: 18685833
Methamphetamine; Delay discounting; Brain imaging
14.  Anterior cingulate proton spectroscopy glutamate levels differ as a function of smoking cessation outcome 
Cigarette smoking is the leading preventable cause of death. Unfortunately, the majority of smokers who attempt to quit smoking relapse within weeks. Abnormal dorsal anterior cingulate cortex (dACC) function may contribute to tobacco smoking relapse vulnerability. Growing evidence suggests that glutamate neurotransmission is involved in mediating nicotine dependence. We hypothesized that prior to a cessation attempt, dACC glutamate levels would be lower in relapse vulnerable smokers.
Proton magnetic resonance spectra (MRS) were obtained from dACC and a control region, the parieto-occipital cortex (POC), using two-dimensional J-resolved MRS at 4 Tesla and analyzed using LCModel. Nine nicotine-dependent women were scanned prior to making a quit attempt. Subjects then were divided into two groups; those able to maintain subsequent abstinence aided by nicotine replacement therapy (NRT) and those who slipped while on NRT (smoked any part of a cigarette after attaining at least 24 hours of abstinence).
Slip subjects exhibited significantly reduced dACC MRS glutamate (Glu/Cr) levels (p<0.03) compared to abstinent subjects. This effect was not observed in the POC control region.
Our preliminary findings suggest that dACC Glu levels as measured with MRS may help identify and/or be a biomarker for relapse vulnerable smokers. Future research following up on these findings may help clarify the role of dACC Glu in smoking dependence that may lead to new treatment strategies.
PMCID: PMC3303218  PMID: 21616118
dorsal anterior cingulate cortex; glutamate; relapse; smoking; spectroscopy; nicotine
15.  Exaggerated and Disconnected Insular-Amygdalar BOLD Response to Threat-Related Emotional Faces in Women with Intimate-Partner Violence PTSD 
Biological psychiatry  2010;68(5):433-441.
Imaging studies of posttraumatic stress disorder (PTSD) have identified functional differences in the amygdala and anterior cingulate (ACC)/medial prefrontal cortex during emotion processing. Recent investigations of the limbic sensory system and its associated neural substrate, the insular cortex, have demonstrated its importance for emotional awareness. Intimate-partner violence (IPV) is one of the most common causes of PTSD among women. This study examined the hypothesis that women with IPV-PTSD show a dysregulation of this limbic sensory system while processing threat-related emotional faces.
12 women with IPV-PTSD and 12 non-traumatized comparison women underwent BOLD functional magnetic resonance imaging while completing an emotional-face matching task.
IPV-PTSD subjects relative to comparison subjects displayed increased activation of the anterior insula and amygdala and decreased connectivity among the anterior insula, amygdalae, and ACC while matching to fearful vs. happy target faces. A similar pattern of activation differences was also observed for angry vs. happy target faces. IPV-PTSD subjects relative to comparison subjects also displayed increased dACC/mPFC activation and decreased vACC activation when matching to a male vs. a female target, and the extent of increased dACC activation correlated positively with hyperarousal symptoms.
Women with IPV-PTSD display hyperactivity and disconnection among affective and limbic sensory systems while processing threat-related emotion. Furthermore, hyperactivity of cognitive-appraisal networks in IPV-PTSD may promote hypervigilant states of awareness through an exaggerated sensitivity to contextual cues, i.e. male gender, which relate to past trauma.
PMCID: PMC2921473  PMID: 20573339
posttraumatic stress; anxiety; emotion; insula; amygdala; anterior cingulate
16.  Human Dorsal Anterior Cingulate Cortex Neurons Mediate Ongoing Behavioral Adaptation 
Nature  2012;488(7410):218-221.
The ability to optimize behavioral performance when confronted with continuously evolving environmental demands is a key element of human cognition. The dorsal anterior cingulate cortex (dACC), which lies on the medial surface of the frontal lobes, plays an important role in regulating cognitive control. Hypotheses regarding its function include guiding reward-based decision making1, monitoring for conflict between competing responses2, and predicting task difficulty3. Precise mechanisms of dACC function remain unknown, however, due to the limited number of human neurophysiological studies. Here we demonstrate with functional imaging and human single-neuron recordings that the firing of individual dACC neurons encodes current and recent cognitive load. We show that the modulation of current dACC activity by previous activity produces a behavioral adaptation that accelerates reactions to cues of similar difficulty as previous ones, and retards reactions to cues of differing difficulty. Furthermore, this conflict adaptation, or Gratton effect2,4, is abolished after surgically targeted dACC ablation. Our results demonstrate that the dACC provides a continuously updated prediction of expected cognitive demand to optimize future behavioral responses. In situations with stable cognitive demands, this signal promotes efficiency by hastening responses, but in situations with changing demands, it engenders accuracy by delaying responses.
PMCID: PMC3416924  PMID: 22722841
17.  N-Acetylcysteine Normalizes Glutamate Levels in Cocaine-Dependent Patients: A Randomized Crossover Magnetic Resonance Spectroscopy Study 
Neuropsychopharmacology  2012;37(9):2143-2152.
Treatment with N-acetylcysteine (NAC) normalizes glutamate (Glu) homeostasis and prevents relapse in drug-dependent animals. However, the effect of NAC on brain Glu levels in substance-dependent humans has not yet been investigated. Proton magnetic resonance spectroscopy (1H MRS) was used to investigate Glu changes in the dorsal anterior cingulate cortex (dACC) after a single dose of NAC in cocaine-dependent patients and normal controls. In an open-label, randomized, crossover study, 8 cocaine-dependent patients and 14 healthy controls underwent two scan sessions: one group receiving no compound and the other following a single administration of 2400 mg NAC. The Barratt Impulsiveness Scale was administered to examine the relation between dACC Glu levels and impulsivity. In the medication-free condition, Glu levels in the dACC were significantly higher in cocaine-dependent patients compared with healthy controls. After administration of NAC, Glu levels were reduced in the cocaine-dependent group, whereas NAC had no effect in healthy controls. Higher baseline Glu levels were associated with higher impulsivity, and both were predictive of greater NAC-induced Glu reduction. The current findings indicate that NAC can normalize elevated Glu levels in cocaine-dependent patients. These findings may have important implications for treatment, because abnormal Glu levels are related to relapse, and treatment with NAC prevented relapse in animal studies. Furthermore, clinical studies have indicated beneficial effects of NAC in cocaine-dependent patients, and the current study suggests that these beneficial effects might in part be mediated by the ability of NAC to normalize glutamatergic abnormalities.
PMCID: PMC3398721  PMID: 22549117
cocaine dependence; N-acetylcysteine; glutamate; magnetic resonance spectroscopy; impulsivity; cocaine dependence; N-acetylcysteine; glutamate; magnetic resonance spectroscopy; impulsivity
18.  Reward circuit connectivity relates to delay discounting in children with attention-deficit/hyperactivity disorder 
Attention-deficit/hyperactivity disorder (ADHD) is a prevalent psychiatric disorder that has poor long-term outcomes and remains a major public health concern. Recent theories have proposed that ADHD arises from alterations in multiple neural pathways. Alterations in reward circuits are hypothesized as one core dysfunction, leading to altered processing of anticipated rewards. The nucleus accumbens (NAcc) is particularly important for reward processes; task-based fMRI studies have found atypical activation of this region while the participants performed a reward task. Understanding how reward circuits are involved with ADHD may be further enhanced by considering how the NAcc interacts with other brain regions. Here we used the technique of resting-state functional connectivity MRI (rs-fcMRI) to examine the alterations in the NAcc interactions and how they relate to impulsive decision making in ADHD. Using rs-fcMRI, this study: examined differences in functional connectivity of the NAcc between children with ADHD and control children; correlated the functional connectivity of NAcc with impulsivity, as measured by a delay discounting task; and combined these two initial segments to identify the atypical NAcc connections that were associated with impulsive decision making in ADHD. We found that functional connectivity of NAcc was atypical in children with ADHD and the ADHD-related increased connectivity between NAcc and the prefrontal cortex was associated with greater impulsivity (steeper delayed-reward discounting). These findings are consistent with the hypothesis that atypical signaling of the NAcc to the prefrontal cortex in ADHD may lead to excessive approach and failure in estimating future consequences; thus, leading to impulsive behavior.
PMCID: PMC3581744  PMID: 23206930
Attention Deficit Hyperactivity Disorder; reward; nucleus accumbens; fMRI; delay discounting; functional connectivity
19.  Nicotine Addiction and Nicotine's Actions Are Associated with Separate Cingulate Cortex Functional Circuits 
Archives of general psychiatry  2009;66(4):431-441.
Understanding the mechanisms underlying nicotine addiction in order to develop more effective treatment is a public health priority. Research consistently shows that nicotine transiently improves multiple cognitive functions. However, using nicotine replacement to treat nicotine addiction yields generally inconsistent results. While this dichotomy is well known, the reasons are unclear. Imaging studies showed that nicotine challenges almost always involve cingulate cortex, suggesting that this loci may be a key region associated with nicotine addiction and its treatment.
To identify cingulate functional circuits that are associated with the severity of nicotine addiction and to study how nicotine affects them.
Using region-specific resting-state fMRI signals to extract resting-state cingulate functional connectivity, and to study how nicotine addiction and acute nicotine administration modulate these functional pathways, in a double-blind, placebo-controlled design.
Outpatient clinics.
Nineteen healthy smokers.
Single dose (21/35mg) nicotine patch.
Main Outcome Measure(s)
Correlation of nicotine addiction severity and cingulate resting state functional connectivity, and effects of acute nicotine on connectivity strength.
Clearly separated pathways that correlated with nicotine addiction vs. nicotinic action were found. The severity of nicotine addiction was associated with the strength of dorsal anterior cingulate cortex (dACC)-striatal circuits, which were not modified by nicotine patch administration. In contrast, acute nicotine enhanced cingulate-neocortical functional connectivity patterns.
Nicotine addiction was strongly associated with functional circuits interconnecting dACC and the striatum. Acute nicotine administration had no significant effect on these circuits. Rather, nicotine enhanced several cingulate-neocortical functional connectivity circuits that were not associated with the severity of nicotine addiction, but may play a role in nicotine's cognitive enhancing properties. Resting state dACC-striatum functional connectivity may serve as a circuit-level biomarker for nicotine addiction, and the development of new therapeutics aiming to enhance the dACC-striatum functional pathways may be effective for nicotine addiction treatment.
PMCID: PMC2774753  PMID: 19349313
20.  Abnormal Brain Connectivity Patterns in Adults with ADHD: A Coherence Study 
PLoS ONE  2012;7(9):e45671.
Studies based on functional magnetic resonance imaging (fMRI) during the resting state have shown decreased functional connectivity between the dorsal anterior cingulate cortex (dACC) and regions of the Default Mode Network (DMN) in adult patients with Attention-Deficit/Hyperactivity Disorder (ADHD) relative to subjects with typical development (TD). Most studies used Pearson correlation coefficients among the BOLD signals from different brain regions to quantify functional connectivity. Since the Pearson correlation analysis only provides a limited description of functional connectivity, we investigated functional connectivity between the dACC and the posterior cingulate cortex (PCC) in three groups (adult patients with ADHD, n = 21; TD age-matched subjects, n = 21; young TD subjects, n = 21) using a more comprehensive analytical approach – unsupervised machine learning using a one-class support vector machine (OC-SVM) that quantifies an abnormality index for each individual. The median abnormality index for patients with ADHD was greater than for TD age-matched subjects (p = 0.014); the ADHD and young TD indices did not differ significantly (p = 0.480); the median abnormality index of young TD was greater than that of TD age-matched subjects (p = 0.016). Low frequencies below 0.05 Hz and around 0.20 Hz were the most relevant for discriminating between ADHD patients and TD age-matched controls and between the older and younger TD subjects. In addition, we validated our approach using the fMRI data of children publicly released by the ADHD-200 Competition, obtaining similar results. Our findings suggest that the abnormal coherence patterns observed in patients with ADHD in this study resemble the patterns observed in young typically developing subjects, which reinforces the hypothesis that ADHD is associated with brain maturation deficits.
PMCID: PMC3458950  PMID: 23049834
21.  Neuroeconomics and Adolescent Substance Abuse: Individual Differences in Neural Networks and Delay Discounting 
Many adolescents with substance use problems show poor response to evidence based treatments. Treatment outcome has been associated with individual differences in impulsive decision making as reflected by delay discounting (DD) rates (preference for immediate rewards). Adolescents with higher rates of DD were expected to show greater neural activation in brain regions mediating impulsive/habitual behavioral choices and less activation in regions that mediate reflective/executive behavioral choices.
Thirty adolescents being treated for substance abuse completed a DD task optimized to balance choices of immediate versus delayed rewards and a control condition accounted for activation during magnitude valuation. A group independent component analysis on functional magnetic resonance imaging (fMRI) time courses identified neural networks engaged during DD. Network activity was correlated with individual differences in discounting rate.
Higher discounting rates were associated with diminished engagement of an executive attention control network involving the dorsolateral prefrontal cortex, dorsomedial prefrontal cortex, inferior parietal cortex, cingulate cortex, and precuneus. Higher discounting rates were also associated with less deactivation in a “bottom up” reward valuation network involving the amygdala, hippocampus, insula, and ventromedial prefrontal cortex. These 2 networks were significantly negatively correlated.
Results support relations between competing executive and reward valuation neural networks and temporal decision making, an important potentially modifiable risk factor relevant for prevention and treatment of adolescent substance abuse.
Clinical trial registration information—The Neuroeconomics of Behavioral Therapies for Adolescent Substance Abuse;; NCT01093898.
PMCID: PMC3712894  PMID: 23800488
adolescent substance abuse; delay discounting; functional magnetic resonance imaging (fMRI); neuroeconomics
22.  Voluntary Modulation of Anterior Cingulate Response to Negative Feedback 
PLoS ONE  2014;9(11):e107322.
Anterior cingulate and medial frontal cortex (dACC/mFC) response to negative feedback represents the actions of a generalized error-monitoring system critical for the management of goal-directed behavior. Magnitude of dACC/mFC response to negative feedback correlates with levels of post-feedback behavioral change, and with proficiency of operant learning processes. With this in mind, it follows that an ability to alter dACC/mFC response to negative feedback may lead to representative changes in operant learning proficiency. To this end, the present study investigated the extent to which healthy individuals would show modulation of their dACC/mFC response when instructed to try to either maximize or minimize their neural response to the presentation of contingent negative feedback. Participants performed multiple runs of a standard time-estimation task, during which they received feedback regarding their ability to accurately estimate a one-second duration. On Watch runs, participants were simply instructed to try to estimate as closely as possible the one second duration. On Increase and Decrease runs, participants performed the same task, but were instructed to “try to increase [decrease] their brain's response every time they received negative feedback”. Results indicated that participants showed changes in dACC/mFC response under these differing instructional conditions: dACC/mFC activity following negative feedback was higher in the Increase condition, and dACC activity trended lower in the Decrease condition, compared to the Watch condition. Moreover, dACC activity correlated with post-feedback performance adjustments, and these adjustments were highest in the Increase condition. Potential implications for neuromodulation and facilitated learning are discussed.
PMCID: PMC4222862  PMID: 25376010
23.  Brain Reactivity to Smoking Cues Prior to Smoking Cessation Predicts Ability to Maintain Tobacco Abstinence 
Biological psychiatry  2010;67(8):722-729.
Developing means to identify smokers at high risk for relapse could advance relapse prevention therapy. We hypothesized that functional magnetic resonance imaging (fMRI) reactivity to smoking-related cues, measured prior to a quit attempt, could identify smokers with heightened relapse vulnerability.
Twenty-one nicotine-dependent women underwent fMRI prior to quitting smoking, during which smoking-related and neutral images were shown. These smokers also were tested for possible attentional biases to smoking-related words using a computerized emotional Stroop (ES) task previously found to predict relapse. Smokers then made a quit attempt and were grouped based on outcomes (abstinence versus slip: smoking 1 cigarette after attaining abstinence). Pre-quit fMRI and ES measurements in these groups were compared.
Slip subjects had heightened fMRI reactivity to smoking-related images in brain regions implicated in emotion, interoceptive awareness, and motor planning and execution. Smoking cue-induced insula and dorsal anterior cingulate cortex (dACC) reactivity correlated with an attentional bias to smoking-related words. A discriminant analysis of ES and fMRI data predicted outcomes with 79% accuracy. Additionally, smokers who slipped had decreased fMRI functional connectivity between an insula-containing network and brain regions involved in cognitive control, including the dACC and dorsal lateral prefrontal cortex, possibly reflecting reduced top-down control of smoking-related cue-induced emotions.
These findings suggest that the insula and dACC are important substrates of smoking relapse vulnerability. The data also suggest that relapse-vulnerable smokers can be identified prior to quit attempts, which could enable personalized treatment, improve tobacco-dependence treatment outcomes, and reduce smoking-related morbidity and mortality.
PMCID: PMC2954596  PMID: 20172508
Insula; Dorsal anterior cingulate cortex; fMRI; emotional Stroop task; tobacco; relapse
24.  Neural Circuitry of Impulsivity in a Cigarette Craving Paradigm 
Impulsivity has been shown to play a pivotal role in the onset, pattern of consumption, relapse and, most notably, craving of illicit and licit drugs such as cigarette smoking. The goal of this study was to examine the neurobiological influence of trait impulsivity during cue-induced cigarette craving. Thirty-one chronic smokers passively viewed appetitive smoking-related and neutral images while being scanned and reported their feelings of craving. They completed the Barratt Impulsiveness Scale, a measure of trait impulsivity. We conducted functional connectivity analyses using the psycho-physiological interaction method. During the processing of smoking stimuli, participants presented increased activations in the cingulate and prefrontal cortices. We observed a significant positive relationship between impulsivity scores and reported craving. A negative correlation was observed between the impulsivity score and activity in the posterior cingulate cortex (PCC). The insula, dorsal anterior cingulate cortex (dACC) as well as the dorsolateral prefrontal cortex (DLPFC) presented a negative connectivity with the PCC. Consistent with the view that the PCC is related to the ability to resist cigarette craving, our results suggest that high impulsive smokers have greater difficulty in controlling their cravings, and that this weakness may be mediated by lower PCC activity. Moreover, we argue that the less PCC activity, the greater the probability of a stronger emotional, physiological, and biased attentional response to smoking cues mediated by insula, dACC, and DLPFC activity. This is the first study on this topic, and so, results will need to be replicated in both licit and illicit drug abusers. Our findings also highlight a need for more emphasis on the PCC in drug addiction research, as it is one of the most consistently activated regions in functional magnetic resonance imaging studies examining the neural correlates of cue-induced alcohol, drug, and tobacco cravings.
PMCID: PMC3712893  PMID: 23874307
craving; impulsivity; cigarette smoking; neural correlates; fMRI
25.  Unstable Prefrontal Response to Emotional Conflict and Activation of Lower Limbic Structures and Brainstem in Remitted Panic Disorder 
PLoS ONE  2009;4(5):e5537.
The neural mechanisms of panic disorder (PD) are only incompletely understood. Higher sensitivity of patients to unspecific fear cues and similarities to conditioned fear suggest involvement of lower limbic and brainstem structures. We investigated if emotion perception is altered in remitted PD as a trait feature.
Methodology/Principal Findings
We used blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) to study neural and behavioural responses of 18 remitted PD patients and 18 healthy subjects to the emotional conflict paradigm that is based on the presentation of emotionally congruent and incongruent face/word pairs. We observed that patients showed stronger behavioural interference and lower adaptation to interference conflict. Overall performance in patients was slower but not less accurate. In the context of preceding congruence, stronger dorsal anterior cingulate cortex (dACC) activation during conflict detection was found in patients. In the context of preceding incongruence, controls expanded dACC activity and succeeded in reducing behavioural interference. In contrast, patients demonstrated a dropout of dACC and dorsomedial prefrontal cortex (dmPFC) recruitment but activation of the lower limbic areas (including right amygdala) and brainstem.
This study provides evidence that stimulus order in the presentation of emotional stimuli has a markedly larger influence on the brain's response in remitted PD than in controls, leading to abnormal responses of the dACC/dmPFC and lower limbic structures (including the amygdala) and brainstem. Processing of non-panic related emotional stimuli is disturbed in PD patients despite clinical remission.
PMCID: PMC2680057  PMID: 19462002

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