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1.  Effect of Predictive Cuing on Response Inhibition in Children with Heavy Prenatal Alcohol Exposure 
Background
Heavy prenatal exposure to alcohol leads to widespread cognitive deficits, including problems with attention and response inhibition. This study examined blood oxygen level-dependent (BOLD) response in children with and without histories of heavy prenatal alcohol exposure during a task of response inhibition consisting of cued and non-cued trials.
Methods
Children and adolescents (ages 8-18y) with (AE=20) and without (CON=15) histories of heavy prenatal exposure to alcohol underwent functional magnetic resonance imaging (fMRI) while performing a go/no-go task. Unbeknownst to subjects, a predictive cue preceded the no-go stimulus in 87% of trials.
Results
Groups were matched on demographic variables and did not differ on most measures of task performance. However, following cued stimuli, the AE group demonstrated a lower hit rate to go stimuli and more conservative response bias than the CON group. Alcohol-exposed participants demonstrated more activation during no-go trials (inhibition) relative to go trials in the left precuneus, cingulate gyrus, anterior cingulate, and right medial frontal gyrus. During cue-dependent response inhibition, the AE group demonstrated less activation in the left pre-central and post-central gyrus compared to the CON group.
Conclusion
Consistent with previous studies of response inhibition, alcohol-exposed children demonstrated greater frontal and parietal activation when attempting to inhibit prepotent responses than controls, despite similar rates of commission errors. This study further demonstrated that alcohol-exposed children had impaired behavioral performance on cued trials and demonstrated less activation in pre-central and post-central gyri relative to controls on these trials. This investigation provides evidence of impaired behavioral and neural processing of sequential information in FASD, which can help improve inhibition in typical populations.
doi:10.1111/acer.12017
PMCID: PMC3771541  PMID: 23094678
Fetal alcohol spectrum disorders (FASD); fetal alcohol syndrome (FAS); response inhibition; cognitive control; functional neuroimaging
2.  Imaging The Anxious Brain - Promise Or Hubris? 
Depression and anxiety  2011;28(3):183-185.
doi:10.1002/da.20796
PMCID: PMC3957362  PMID: 21394850
3.  Treatment Approaches for Interoceptive Dysfunctions in Drug Addiction 
There is emerging evidence that individuals with drug addiction have dysfunctions in brain systems that are important for interoceptive processing, which include, among others, the insular and the anterior cingulate cortices. These individuals may not be expending sufficient neural resources to process perturbations of the interoceptive state but may exert over-activation of these systems when processing drug-related stimuli. As a consequence, insufficient detection and processing of interoceptive state changes may result in inadequate anticipation and preparation to adapt to environmental challenges, e.g., adapt to abstinence in the presence of withdrawal symptoms. Here, we integrate interoceptive dysfunction in drug-addicted individuals, with the neural basis for meditation and exercise to develop a heuristic to target the interoceptive system as potential treatments for drug addiction. First, it is suggested that mindfulness-based approaches can modulate both interoceptive function and insular activation patterns. Second, there is an emerging literature showing that the regulation of physical exercise in the brain involves the insula and anterior cingulate cortex and that intense physical exercise is associated with a insula changes that may provide a window to attenuate the increased interoceptive response to drug-related stimuli. It is concluded that the conceptual framework of interoceptive dysfunctions in drug addiction and the experimental findings in meditation and exercise provide a useful approach to develop new interventions for drug addiction.
doi:10.3389/fpsyt.2013.00137
PMCID: PMC3798869  PMID: 24151471
addiction; interoception; exercise; meditation; insula
4.  Neural functional and structural correlates of childhood maltreatment in women with intimate-partner violence-related posttraumatic stress disorder 
Psychiatry research  2012;211(2):93-103.
Childhood maltreatment (CM) is a strong risk factor for development of posttraumatic stress disorder (PTSD) upon adult exposure to extreme adverse events. However, the neural underpinnings of this relationship are not well understood. Here, we test the hypothesis that severity of CM history is positively correlated with emotion-processing limbic and prefrontal brain activation/connectivity and negatively correlated with prefrontal gray matter volumes in women with PTSD due to intimate-partner violence (IPV-PTSD). Thirty-three women with IPV-PTSD underwent structural and functional magnetic resonance imaging while completing a facial emotion processing task. Multivariate regressions examined the relationship of CM to patterns of activation, connectivity, and gray matter volumes. CM severity was: a) positively correlated with ventral ACC activation while processing angry faces; b) negatively correlated with dorsal ACC and insula activation while processing fear and angry faces, arising from positive correlations with the shape-matching baseline; c) positively correlated with limbic-prefrontal connectivity while processing fear faces but negatively correlated with amygdalo-insular connectivity while processing fear and angry; and d) negatively correlated with prefrontal gray matter volumes. These results suggest CM exposure may account for variability in limbic/prefrontal brain function and prefrontal structure in adulthood PTSD and offer one potential mechanism through which CM confers risk to future development of PTSD.
doi:10.1016/j.pscychresns.2012.08.006
PMCID: PMC3570713  PMID: 23154098
early life stress; anxiety; imaging; trauma; abuse; neglect
5.  Anterior Insular Cortex Anticipates Impending Stimulus Significance 
NeuroImage  2009;45(3):976-983.
Touch is a fundamental, but complex, element of everyday interaction that impacts one’s sensory and affective experience via interoceptive processing. The insular cortex is an integral component of the neural processes involved in interoception, i.e. the generation of an “emotional moment in time” through the sensing of the internal body state (Craig, 2002). Here, we examine the contribution of different parts of the insular cortex in the representation of both affective and sensory aspects of touch. To that end, subjects were administered a cued application of touch during functional MRI. We find that stimulus-related activation occurs in the mid-to-posterior insula, whereas anticipatory related activation is seen mostly in anterior insula. Moreover, the degree of activation in anterior insula during anticipation is correlated with the degree of activation in the posterior insula and caudate during stimulus processing. Finally, the degree of activation in the anterior insula during anticipation is also correlated with experienced intensity of the touch. Taken together, these results are consistent with the hypothesis that the anterior insula is preparing for the sensory and affective impact of touch. This preparatory function has important implications for the understanding of both anxiety and addictive disorders because dysfunctions in anticipatory processing are a fundamental part of the psychopathology.
PMCID: PMC3758834  PMID: 19280711
6.  Young Adults at Risk for Stimulant Dependence show Reward Dysfunction during Reinforcement-Based Decision Making 
Biological psychiatry  2012;73(3):235-241.
Background
While stimulant dependent individuals continue to make risky decisions in spite of poor outcomes, much less is known about decision-making characteristics of occasional stimulant users (OSU) at risk for developing stimulant dependence. This study examines whether OSU exhibit inefficient learning and execution of reinforced decision-outcome contingencies.
Methods
OSU (n=161) and stimulant-naïve comparison subjects (CTL; n=48) performed a Paper Scissors Rock task during functional magnetic resonance imaging. Selecting a particular option was associated with a pre-determined probability of winning, which was altered repeatedly to examine neural and behavioral characteristics of reinforced contingencies.
Results
OSU displayed greater anterior insula, inferior frontal gyrus (IFG), and dorsal striatum activation than CTL during late trials when contingencies were familiar (as opposed to being learned) in the presence of comparable behavioral performance in both groups. Follow-up analyses demonstrated that during late trials: (1) OSU with high cannabis use displayed greater activation in these brain regions than CTL, whereas OSU with low cannabis use did not differ from the other two groups; and (2) OSU preferring cocaine exhibited greater anterior insula, IFG, and dorsal striatum activation than CTL and also displayed higher activation in the former two regions than OSU who preferred prescription stimulants.
Conclusions
OSU exhibit inefficient resource allocation during the execution of reinforced contingencies that may be a result of additive effects of cocaine and cannabis use. A critical next step is to establish whether this inefficiency predicts transition to stimulant dependence.
doi:10.1016/j.biopsych.2012.08.018
PMCID: PMC3674030  PMID: 23021534
stimulants; amphetamine; decision making; reward; dorsal striatum; fMRI
7.  The effect of age on neural processing of pleasant soft touch stimuli 
Tactile interactions with our environment stimulate afferent fibers within the skin, which deliver information about sensations of pain, texture, itch and other feelings to the brain as a comprehensive sense of self. These tactile interactions can stimulate brain regions involved in interoception and reward processing. This study examined subjective, behavioral, and neural processing as a function of age during stimulation of A-beta (Aβ) and C tactile (CT) afferents using a soft brush stroke task. 16 adolescents (ages 15–17), 22 young adults (ages 20–28), and 20 mature adults (ages 29–55) underwent a simple continuous performance task while periodically anticipating and experiencing a soft touch to the palm or forearm, during functional magnetic resonance imaging (fMRI). fMRI results showed that adolescents displayed greater bilateral posterior insula activation than young and mature adults across all conditions and stimulus types. Adolescents also demonstrated greater bilateral posterior insula activation than young and mature adults specifically in response to the soft touch condition. Adolescents also exhibited greater activation than mature adults in bilateral inferior frontal gyrus and striatum during the soft touch condition. However, mature adults showed greater striatum activation than adolescents and young adults during anticipation. In the left anterior cingulate cortex, mature adults exhibited greater activation than adolescents and young adults when anticipating the upcoming touch. These results support the hypothesis that adolescents show an exaggerated neural response to pleasant stimulation of afferents, which may have profound effects on how they approach or avoid social and risky situations. In particular, heightened interoceptive reactivity to pleasant stimuli might cause adolescents to seek experiences that are associated with pleasant stimulation.
doi:10.3389/fnbeh.2014.00052
PMCID: PMC3930859  PMID: 24600366
interoception; fMRI; development; CT afferents; reward; touch; adolescence; insular cortex
8.  Sex Differences in the Neural Processing of Aversive Interoceptive Events: The Benefit of Relief 
PLoS ONE  2013;8(12):e84044.
Do men and women process and experience unpleasant bodily states differently? We used fMRI to determine brain processing before, during and after an aversive respiratory stimulation. No sex difference emerged during anticipation or stimulation. However, after the offset of the stimulation, men but not women showed enhanced activation of brain regions that are important for interoception and reward processing. Moreover, this activation was highest in those males who rated the preceding stimulation as most unpleasant. These results indicate that men are particularly sensitive to reward associated with the termination of an aversive event, which may signal relief.
doi:10.1371/journal.pone.0084044
PMCID: PMC3875519  PMID: 24386327
9.  High versus Low Level of Response to Alcohol: Evidence of Differential Reactivity to Emotional Stimuli 
Biological psychiatry  2012;72(10):848-855.
Background
The low level of response (LR) or sensitivity to alcohol is genetically influenced and predicts heavy drinking and alcohol problems. Functional magnetic resonance imaging (fMRI) studies using cognitive tasks suggest that subjects with a low LR process cognitive information differently after placebo and alcohol than those with a high LR, but no studies have evaluated if similar LR group differences are seen during an emotional processing task.
Methods
fMRI data were gathered from 116 non-alcoholic subjects (60 women) following oral placebo or ~0.7 ml/kg of ethanol while performing a modified emotional faces processing task. These included 58 low- and high-LR pairs matched on demography and aspects of substance use.
Results
Blood alcohol levels and task performance were similar across LR groups, but low LR subjects consumed ~ 0.8 drinks more per occasion. Thirteen brain regions (mostly the middle and inferior frontal gyri, cingulate, and insula) showed significant LR group or LR by placebo/alcohol condition interactions for emotional (mostly happy) faces relative to non-face trials. Low LR subjects generally showed decreasing BOLD response contrasts across placebo to alcohol, while high LR showed increasing contrasts from placebo to alcohol, even after controlling for drinking quantities and alcohol-related changes in cerebral blood flow.
Conclusions
Thus, LR group fMRI differences are as prominent during an emotional face task as during cognitive paradigms. Low LR individuals processed both types of information in a manner that might contribute to an impaired ability to recognize modest levels of alcohol intoxication in a range of life situations.
doi:10.1016/j.biopsych.2012.04.016
PMCID: PMC3433640  PMID: 22608014
fMRI; alcohol sensitivity; emotional stimuli; fear; Hariri; alcoholism
10.  Decision-Making Dysfunctions of Counterfactuals in Depression: Who Might I have Been? 
Cognitive neuroscience enables us now to decompose major depressive disorder into dysfunctional component processes and relate these processes to specific neural substrates. This approach can be used to illuminate the biological basis of altered psychological processes in depression, including abnormal decision-making. One important decision-related process is counterfactual thinking, or the comparison of reality to hypothetical alternatives. Evidence suggests that individuals with depression experience exaggerated emotional responses due to focusing on counterfactual decision outcomes in general and regret, i.e., the emotion associated with focus on an alternative superior outcome, in particular. Regret is linked to self-esteem in that it involves the evaluation of an individual’s own decisions. Alterations of self-esteem, in turn, are a hallmark of depression. The literature on the behavioral and neural processes underlying counterfactual thinking, self-esteem, and depression is selectively reviewed. A model is proposed in which unstable self-representation in depression is more strongly perturbed when a different choice would have produced a better outcome, leading to increased feelings of regret. This approach may help unify diverse aspects of depression, can generate testable predictions, and may suggest new treatment avenues targeting distorted counterfactual cognitions, attentional biases toward superior counterfactual outcomes, or increased affective response to regretted outcomes.
doi:10.3389/fpsyt.2013.00143
PMCID: PMC3820979  PMID: 24265620
major depressive disorder; decision-making; emotions; neurosciences; self concept; neostriatum; cognition; affect
11.  The breathing conundrum – interoceptive sensitivity and anxiety 
Depression and anxiety  2013;30(4):315-320.
Cognitive and affective processing has been the central focus of brain-related functions in psychology and psychiatry for many years. Much less attention has been paid to, what could be considered the primary function of the brain, to regulate the function of the body. Recent developments, which include the conceptualization of interoception as a process consisting of integrating the information coming from the inside of the body in the central nervous system (CNS) and the appreciation that complex emotional processes are fundamentally affected by the processing and regulation of somatic states, have profoundly changed the view of the function and dysfunction of the brain. This review focuses on the relationship between breathing and anxiety. Several anxiety disorders have been associated with altered breathing, perception of breathing and response to manipulations of breathing. Both clinical and experimental research studies are reviewed that relate breathing dysfunctions to anxiety. Altered breathing may be useful as a physiological marker of anxiety as well as a treatment target using interoceptive interventions.
doi:10.1002/da.22076
PMCID: PMC3805119  PMID: 23468141
12.  Posttraumatic Stress Disorder Increases Sensitivity to Long Term Losses among Patients with Major Depressive Disorder 
PLoS ONE  2013;8(10):e78292.
Background
Decisions under risk and with outcomes that are delayed in time are ubiquitous in real life and can have a significant impact on the health and wealth of the decision-maker. Despite its potential relevance for real-world choices, the degree of aberrant risky and intertemporal decision-making in patients suffering from major depressive disorder (MDD) and posttraumatic stress disorder (PTSD) has received little attention to date.
Method
We used a case-control design to compare decision-making in healthy control subjects (N=16) versus untreated depressed subjects in a current major depressive episode (N=20). In order to examine how major depressive disorder (MDD) may impact decision-making, subjects made decisions over (1) risky outcomes and (2) delayed outcomes in the domain of gains and losses using choice paradigms from neuroeconomics. In a pre-planned analysis, depressed subjects were subdivided into those with primary PTSD along with comorbid MDD (MDD+PTSD) versus those with primary MDD without PTSD (MDD-only). Choice behavior was modeled via a standard econometric model of intertemporal choice, a quasi-hyperbolic temporal discounting function, which was estimated for each subject group separately.
Results
Under conditions of potential gain, depressed subjects demonstrated greater discounting for gains across all time frames compared to controls. In the realm of losses, both subgroups of depressed subjects discounted more steeply than controls for short time frames. However, for delayed losses ranging from >1-10 years, MDD+PTSD subjects showed shallower discounting rates relative to MDD-only subjects, who continued to discount future losses steeply. Risk attitudes did not contribute to differences in intertemporal choice.
Conclusions
Depressed patients make choices that minimize current pain and maximize current reward, despite severe later consequences or lost opportunities. Anxiety associated with PTSD may serve as a partially protective factor in decision-making about long-term potential losses compared to MDD patients without PTSD.
doi:10.1371/journal.pone.0078292
PMCID: PMC3792061  PMID: 24116235
13.  Deployment and Post-Deployment Experiences in OEF/OIF Veterans: Relationship to Gray Matter Volume 
PLoS ONE  2013;8(9):e75880.
Background
Combat-related PTSD has been associated with reduced gray matter volume in regions of the prefrontal and temporal cortex, hippocampus, insula, and amygdala. However, the relationship between gray matter volume and specific deployment and post-deployment experiences has not been investigated. The aim of this study was to delineate how such experiences may contribute to structural brain changes for combat veterans.
Methods
Operation Iraqi Freedom/Operation Enduring Freedom veterans (N = 32) completed magnetic resonance imaging, the Deployment Risk and Resilience Inventory, Alcohol Use Disorders Identification Test, and Clinical Administered PTSD Scale. Voxel-wise Huber robust multiple regressions were used to quantify the relationship between gray matter volume and deployment experiences (combat experiences, military social support) and post-deployment symptoms (PTSD, alcohol use).
Results
There was an interaction between severity of combat experiences and military social support for orbitofrontal gyrus gray matter volume. Specifically, individuals with more orbitofrontal gyrus gray matter volume reported less combat experiences and higher unit support. Individuals with more severe PTSD symptoms showed reduced gray matter volume within a large temporal region (inferior temporal and parahippocampal gyrus).
Conclusions
The identified association between unit support and orbitofrontal gyrus volume supports two potential resilience mechanisms to be delineated with future longitudinal studies. First, individuals with larger orbitofrontal gyrus may engage in greater quality of social interactions and thus experience combat as less stressful. Second, individuals who experience greater unit support may preserve a larger orbitofrontal gyrus, serving to “protect” them from aversive consequences of combat.
doi:10.1371/journal.pone.0075880
PMCID: PMC3776771  PMID: 24058706
14.  Acute Ethanol Effects on Brain Activation in Low- and High-Level Responders to Alcohol 
Background
A low level of response (LR) to alcohol is an important endophenotype associated with an increased risk for alcoholism. However, little is known about how neural functioning may differ between individuals with low and high LRs to alcohol. This study examined whether LR group effects on neural activity varied as a function of acute alcohol consumption.
Methods
30 matched high- and low-LR pairs (N=60 healthy young adults) were recruited from the University of California, San Diego and administered a structured diagnostic interview and laboratory alcohol challenge followed by two fMRI sessions under placebo and alcohol conditions, in randomized order. Task performance and BOLD response contrast to high relative to low working memory load in an event-related visual working memory (VWM) task was examined across 120 fMRI sessions.
Results
Both LR groups performed similarly on the VWM task across conditions. A significant LR group by condition interaction effect was observed in inferior frontal and cingulate regions, such that alcohol attenuated the LR group differences found under placebo (p<.05). The LR group by condition effect remained even after controlling for cerebral blood flow, age, and typical drinking quantity.
Conclusions
Alcohol had differential effects on brain activation for low and high LR individuals within frontal and cingulate regions. These findings represent an additional step in the search for physiological correlates of a low LR, and identify brain regions that may be associated with the low LR response.
doi:10.1111/j.1530-0277.2010.01193.x
PMCID: PMC3774836  PMID: 20477775
Level of response; fMRI; visual working memory; cerebral blood flow
15.  Evidence for Subtle Verbal Fluency Deficits in Occasional Stimulant Users: Quick to Play Loose with Verbal Rules 
Journal of psychiatric research  2010;45(3):361-368.
Psychostimulants like cocaine and amphetamine are commonly abused by young adults who often state that they take these drugs to increase social or cognitive performance. The current study tested the hypothesis that individuals at early stages of occasional stimulant use show subtle executive dysfunctions such as verbal fluency deficits. 155 young (age 18-25), non-dependent occasional users of stimulants and 49 stimulant naïve comparison subjects performed the Delis-Kaplan Verbal Fluency test. Correlation and median split analyses were conducted to account for stimulant history and co-drug use. Compared to stimulant naïve subjects, occasional stimulant users generated significantly more responses on an over-learned verbal fluency task (Category Fluency), but at the expense of increased error rates (Set Loss and Repetition Errors). These performance differences were not related to lifetime uses of stimulants or marijuana. Taken together, these results support the hypothesis that individuals who are using stimulants occasionally exhibit subtle executive dysfunctions when required to generate verbal sets under time pressure. In particular, occasional stimulant users apply quickly but inaccurately verbal rules, which may represent a mix of diminished cognitive flexibility along with increased rigidity and impulsivity. This specific executive dysfunction may help to identify individuals at risk for stimulant use or dependence.
doi:10.1016/j.jpsychires.2010.07.005
PMCID: PMC3424267  PMID: 20673916
stimulant; cocaine; amphetamine; executive function; verbal fluency
16.  Emotion and decision-making: affect-driven belief systems in anxiety and depression 
Trends in cognitive sciences  2012;16(9):476-483.
Emotion processing and decision-making are integral aspects of daily life. However, our understanding of the interaction between these constructs is limited. In this review, we summarize theoretical approaches to the link between emotion and decision-making, and focus on research with anxious or depressed individuals that reveals how emotions can interfere with decision-making. We integrate the emotional framework based on valence and arousal with a Bayesian approach to decision-making in terms of probability and value processing. We then discuss how studies of individuals with emotional dysfunctions provide evidence that alterations of decision-making can be viewed in terms of altered probability and value computation. We argue that the probabilistic representation of belief states in the context of partially observable Markov decision processes provides a useful approach to examine alterations in probability and value representation in individuals with anxiety and depression and outline the broader implications of this approach.
doi:10.1016/j.tics.2012.07.009
PMCID: PMC3446252  PMID: 22898207
17.  The effect of pregabalin on sensorimotor gating in ‘low’ gating humans and mice 
Neuropharmacology  2012;63(3):480-485.
Pregabalin, an anticonvulsant and anxiolytic compound that binds to α2-δ auxiliary subunit Types 1 and 2 of voltage-gated calcium channels, has been shown to reduce excitatory neurotransmission partially through modulation of glutamatergic signaling. Prepulse inhibition (PPI) of startle is an operational measure of sensorimotor gating impacted by disruption of the glutamatergic system and is reduced in schizophrenia patients. Dysregulation of the glutamatergic system has also been implicated in the pathophysiology of schizophrenia. Here we tested the hypothesis that pregabalin may ameliorate PPI in a model of deficient gating in humans and mice. In study 1, 14 healthy human subjects participated in a within subjects, cross-over study with placebo, 50 mg or 200 mg pregabalin treatment prior to undergoing a PPI task. In study 2, 24 C57BL/6 mice underwent a similar procedure with vehicle, 30 and 100 mg/kg dose treatments. In both studies, subjects were assigned to a “Low” or “High” gating group using a median split procedure based on their PPI performance during placebo/vehicle. Drug effects were then examined across these groups. In humans, pregabalin treatment significantly increased PPI performance in the “low gating” group. In mice, pregabalin treatment significantly increased PPI in the low gating group but reduced PPI in the high gating group. Across species, pregabalin treatment improves PPI in subjects with low gating. These data support further exploration of pregabalin as a potential treatment for disorders characterized by sensorimotor gating deficits and glutamatergic hypersignaling, such as schizophrenia.
doi:10.1016/j.neuropharm.2012.04.018
PMCID: PMC3572212  PMID: 22575075
Schizophrenia; Pre-pulse inhibition; Glutamate; Pregabalin; Startle; Sensorimotor gating
18.  Amygdala Response and Functional Connectivity During Emotion Regulation: A Study of 14 Depressed Adolescents 
Journal of Affective Disorders  2012;139(1):75-84.
Background
Ineffective emotion regulation and abnormal amygdala activation have each been found in adolescent-onset major depressive disorder. However, amygdala activation during emotion regulation has not been studied in adolescent-onset major depressive disorder.
Method
Fourteen unmedicated adolescents diagnosed with current depression without comorbid psychiatric disorders and fourteen well-matched controls ages 13 to 17 years underwent an emotional regulation task during functional magnetic resonance imaging. During this task, participants viewed negatively-valence images and were asked to notice how they were feeling without trying to change it and maintain their emotional reaction (“Maintain”) or to interpret the image in such a way as minimize their emotional response (“Reduce”).
Results
Imaging analyses demonstrated that adolescents with depression showed: (1) greater right amygdala activation during the maintain condition relative to controls, (2) less connectivity during the maintain condition between the amygdala and both the insula and medial prefrontal cortex than controls, and (3) a significant positive correlation between amygdala-seeded connectivity during maintenance of emotion and psychosocial functioning.
Limitations
The current study is cross-sectional comparison and longitudinal investigations with larger sample sizes are needed to examine the association between amygdala reactivity and emotion regulation over time in adolescent MDD.
Conclusions
During the maintain condition, adolescents with depression showed a heightened amygdala response and less reciprocal activation in brain regions that may modulate the amygdala. A poorly modulated, overreactive amygdala may contribute to poor emotion regulation.
doi:10.1016/j.jad.2012.01.044
PMCID: PMC3340443  PMID: 22401827
Major Depression; Functional MRI; Insula; Reappraisal; Prefrontal Cortex
19.  Non-Dependent Stimulant Users of Cocaine and Prescription Amphetamines Show Verbal Learning and Memory Deficits 
Biological psychiatry  2010;68(8):762-769.
Background
Stimulants are used increasingly to enhance social (cocaine) or cognitive performance (stimulants normally prescribed, prescription stimulants, e.g. methylphenidate, amphetamines). Chronic use, on the other hand, has been associated with significant verbal memory and learning deficits. This study sought to determine whether subtle learning and memory problems characterize individuals who exhibit occasional but not chronic use of stimulants.
Methods
154 young (age 18–25) occasional, non-dependent stimulant users and 48 stimulant naïve comparison subjects performed the California Verbal Learning test (CVLT-II). Lifetime uses of stimulants and co-use of marijuana were considered in correlation and median split analyses.
Results
Compared to stimulant naïve subjects, occasional stimulant users showed significant performance deficits, most pronounced in the verbal recall and recognition domains. Lifetime uses of stimulants and marijuana did not affect CVLT-II performance. The type of stimulant used, however, was of major relevance: users of cocaine only were less impaired, while cumulative use of prescription stimulants was associated with impaired verbal learning and memory capacities.
Conclusions
These results support the hypothesis of subtle and possibly pre-existing neurocognitive deficiencies in occasional users of stimulants, which may be related to the motivation of using these drugs. More importantly, despite beneficial short-term effects, cumulative use, particularly of prescription amphetamines and methylphenidate, intensifies these deficits.
doi:10.1016/j.biopsych.2010.04.021
PMCID: PMC2949490  PMID: 20605137
Stimulant; cocaine; amphetamine; executive function; verbal learning; verbal memory
20.  The Role of Interoception and Alliesthesia in Addiction 
This review presents a novel conceptualization of addiction, integrating the concepts of interoception (i.e., the CNS representation of visceral feelings) and alliesthesia (i.e., that rewarding properties of stimuli are dependent on the internal state of the individual) with existing theories. It is argued that the body state, as defined by the integration of interoceptive information, is a crucial arbiter of the risk for initiation of and transition to compulsive use of addictive compounds. Overall, individuals at risk for drug dependence are characterized by an altered internal bodily state that leads to a change in hedonic and incentive motivational properties of addictive drugs. Specifically, drug dependent individuals experience alliesthesia of interoceptive processing, leading to increased incentive motivational properties of the drug over time and thereby increasing the probability of subsequent use. This extension of previous theories of addiction to include interoception and alliesthesia is based upon a clearly delineated set of neural substrates mediating interoception, key elements of which also recently have been implicated in drug addiction. The model thereby provides new potential targets for interventions that are aimed at changing the internal state that puts the individual at risk for continued substance use.
doi:10.1016/j.pbb.2009.08.005
PMCID: PMC2753707  PMID: 19698739
Addiction; Insula; Interoception; Alliesthesia; Reward
21.  Nothing to lose: Processing blindness to potential losses drives thrill and adventure seekers 
Neuroimage  2011;59(3):2850-2859.
Sensation seeking has been linked to increased risk taking and is therefore crucial in influencing behavioral outcomes of risk-taking behavior. Using functional magnetic resonance imaging (fMRI), the neural underpinnings of risk appraisal were studied in a large subject sample (n=188), stratified according to thrill and adventure seeking (TAS) ratings. As defined by a median split of the sample, low and high TAS groups were compared on a simple decision-making task completed during fMRI. The task was designed such that risk (i.e., magnitude of outcome) and gains (i.e., direction of outcome) could be mapped independently. Behavioral analysis indicated that high TAS individuals are more sensitive to rewards but less discriminating between risk with and without punishment and that low TAS individuals are less sensitive to rewards but quite sensitive to receiving punishments in risky situations. Imaging results on the group differences for the interaction between level of risk and level of gain showed differences in the right superior frontal gyrus (BA6), left insula (BA21), right nucleus accumbens, left lentiform nucleus, and left precuneus (BA7). The presented data suggest a neural model of risk processing in sensation seeking individuals such that the positive response to reward outweighs the impact of equivalent loss. This imbalance in approach/avoidance is evident in differences in the underlying neural substrates in TAS individuals and leads to greater risk behavior in the face of potential loss.
doi:10.1016/j.neuroimage.2011.09.048
PMCID: PMC3256346  PMID: 21982930
sensation seeking; fMRI; SFG; neural correlates; decision making; risk taking
22.  Role of functional magnetic resonance imaging in drug discovery 
Neuropsychology review  2007;17(2):179-188.
In this review, we survey the state of the field of functional magnetic resonance imaging (fMRI) as it relates to drug discovery and drug development. We highlight the advantages and limitations of fMRI for this purpose and suggest ways to improve the use of fMRI for developing new therapeutics, with emphasis on treatments for anxiety disorders. Fundamentally, pharmacological studies with standard psychiatric treatments using standardized behavioral probes during fMRI will need to be carried out to determine characteristic brain signatures that could be used to predict whether novel compounds are likely to have specific therapeutic effects.
doi:10.1007/s11065-007-9023-0
PMCID: PMC2841045  PMID: 17436113
23.  fMRI Differences between Subjects with Low and High Responses to Alcohol during a Stop Signal Task 
Background
A low level of response (i.e., a low LR) to alcohol is a genetically influenced phenotype that predicts later alcoholism. While the low LR reflects, at least in part, a low brain response to alcohol, the physiological underpinnings of the low LR have only recently been addressed.
Methods
Forty-nine drinking but not yet alcoholic matched pairs of 18-25-year-old subjects (N = 98; 53% female) with low and high LRs as established in separate alcohol challenges were evaluated in two event-related functional magnetic resonance imaging (fMRI) sessions (placebo and ~ 0.7 ml/kg of alcohol) while performing a validated stop signal task. The high and low LR groups had identical blood alcohol levels during the alcohol session.
Results
Significant high versus low LR group and LR group × condition effects were observed in blood oxygen level dependent (BOLD) signal during error and inhibitory processing, despite similar LR-group performance on the task. In most clusters with significant (corrected p<.05, clusters >1344 μl) LR group × alcohol/placebo condition interactions, the low LR group demonstrated relatively less, whereas the high LR group demonstrated more, error and inhibition-related activation after alcohol compared to placebo.
Conclusions
This is one of the first fMRI studies to demonstrate significant differences between healthy groups with different risks for a future life threatening disorder. The results may suggest a brain mechanism that contributes to how a low LR might enhance the risk for future heavy drinking and alcohol dependence.
doi:10.1111/j.1530-0277.2011.01590.x
PMCID: PMC3253183  PMID: 22003983
alcohol; reaction; risk; fMRI
24.  The influence of emotions on cognitive control: feelings and beliefs—where do they meet? 
The influence of emotion on higher-order cognitive functions, such as attention allocation, planning, and decision-making, is a growing area of research with important clinical applications. In this review, we provide a computational framework to conceptualize emotional influences on inhibitory control, an important building block of executive functioning. We first summarize current neuro-cognitive models of inhibitory control and show how Bayesian ideal observer models can help reframe inhibitory control as a dynamic decision-making process. Finally, we propose a Bayesian framework to study emotional influences on inhibitory control, providing several hypotheses that may be useful to conceptualize inhibitory control biases in mental illness such as depression and anxiety. To do so, we consider the neurocognitive literature pertaining to how affective states can bias inhibitory control, with particular attention to how valence and arousal may independently impact inhibitory control by biasing probabilistic representations of information (i.e., beliefs) and valuation processes (e.g., speed-error tradeoffs).
doi:10.3389/fnhum.2013.00508
PMCID: PMC3776943  PMID: 24065901
emotion; inhibitory control; Bayesian modeling; ideal observer model
25.  Altered frontocingulate activation during aversive interoceptive processing in young adults transitioning to problem stimulant use 
Problems associated with stimulant use have been linked to frontocingulate, insular, and thalamic dysfunction during decision making and alterations in interoceptive processing. However, little is known about how interoception and decision making interact and contribute to dysfunctions that promote the transition from recreational drug use to abuse or dependence. Here, we investigate brain activation in response to reward, punishment, and uncertainty during an aversive interoceptive challenge in current and former stimulant (cocaine and amphetamine) users using functional magnetic resonance imaging (fMRI). Young adults previously identified as recreational users (n = 184) were followed up 3 years later. Of these, 18 individuals progressed to problem stimulant use (PSU), whereas 15 desisted stimulant use (DSU). PSU, DSU, and 14 healthy comparison subjects (CTL) performed a two-choice prediction task at three fixed error rates (20% = reward, 50% = uncertainty, 80% = punishment) during which they anticipated and experienced episodes of inspiratory breathing load. Although groups did not differ in insula activation or subjective breathing load ratings, PSU exhibited lower right inferior frontal gyrus (IFG) and bilateral anterior cingulate (ACC) activation than DSU and CTL during aversive interoceptive processing as well as lower right IFG in response to decision making involving uncertainty. However, PSU exhibited greater bilateral IFG activation than DSU and CTL while making choices within the context of punishing feedback, and both PSU and DSU showed lower thalamic activation during breathing load than CTL. Findings suggest that frontocingulate attenuation, reflecting reduced resources devoted to goal maintenance and action selection in the presence of uncertainty and interoceptive perturbations, may be a biomarker for susceptibility to PSU.
doi:10.3389/fnsys.2013.00089
PMCID: PMC3828508  PMID: 24298242
functional magnetic resonance imaging (fMRI); stimulants; decision making; error processing; interoception; breathing load

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