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1.  Reduced Behavioral and Neural Activation in Stimulant Users To Different Error Rates During Decision-Making 
Biological psychiatry  2007;63(11):1054-1060.
Background
Behavioral processes and neural systems dysfunctions that put individuals at risk for drug use in general—and stimulant use in particular—are poorly understood. Here, the hypothesis is examined that stimulant-using subjects adjust their decision-making less as a function of errors as evidenced by attenuated behavioral and neural substrate activation patterns.
Methods
Twelve young adults who had used stimulants were compared with 12 education-matched stimulant-naïve comparison subjects. Subjects completed the two-choice prediction task with three fixed error-rate conditions (20%, 50%, or 80% errors) during functional magnetic resonance imaging.
Results
Stimulant users relative to comparison subjects showed less strategy adjustment to different error rates, e.g., they were less likely to stay with winning responses (win-stay) and to shift away from losing responses (lose-shift). These subjects also showed different activation patterns as a function of error rate in left insular and bilateral dorsolateral prefrontal cortex, but not anterior cingulate. The degree to which individuals adjusted switching rate, or win-stay/lose-shift consistent responses, as a function of errors was correlated with the difference in insular cortex activation differences between high and low error rates.
Conclusions
The behavior of stimulant users is less adaptive to the frequency of errors made and fewer brain processing resources are deployed during decision-making to anticipate erroneous performance. These findings could be markers for the predisposition of drug taking; however, their relevance for development of drug dependence needs further study.
doi:10.1016/j.biopsych.2007.09.007
PMCID: PMC4286246  PMID: 17949691
fMRI; stimulants; decision-making; error processing; insula
2.  Interoception and Drug Addiction 
Neuropharmacology  2013;76(0 0):10.1016/j.neuropharm.2013.07.002.
The role of interoception and its neural basis with relevance to drug addiction is reviewed. Interoception consists of the receiving, processing, and integrating body-relevant signals with external stimuli to affect ongoing motivated behavior. The insular cortex is the central nervous system hub to process and integrate these signals. Interoception is an important component of several addiction relevant constructs including arousal, attention, stress, reward, and conditioning. Imaging studies with drug-addicted individuals show that the insular cortex is hypo-active during cognitive control processes but hyperactive during cue reactivity and drug-specific, reward-related processes. It is proposed that interoception contributes to drug addiction by incorporating an “embodied” experience of drug uses together with the individual’s predicted versus actual internal state to modulate approach or avoidance behavior, i.e. whether to take or not to take drugs. This opens the possibility of two types of interventions. First, one may be able to modulate the embodied experience by enhancing insula reactivity where necessary, e.g. when engaging in drug seeking behavior, or attenuating insula when exposed to drug-relevant cues. Second, one may be able to reduce the urge to act by increasing the frontal control network, i.e. inhibiting the urge to use by employing cognitive training.
doi:10.1016/j.neuropharm.2013.07.002
PMCID: PMC3858461  PMID: 23855999
Interoception; insula; embodiment; relapse; cue reactivity
3.  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
4.  Prefrontal Dysfunction during Emotion Regulation in Generalized Anxiety and Panic Disorder 
Psychological medicine  2012;43(7):1475-1486.
Background
The mechanisms that contribute to emotion dysregulation in anxiety disorders are not well understood. Two common disorders, Generalized Anxiety Disorder (GAD) and Panic Disorder (PD), were examined to test the hypothesis that both disorders are characterized by hypo-activation in prefrontal cortex (PFC) during emotion regulation. A competing hypothesis that GAD in particular is characterized by PFC hyper-activation during emotion regulation (reflecting overactive top-down control) also was evaluated.
Methods
Twenty-two medication-free Healthy Control (HC), 23 GAD, and 18 PD participants underwent functional magnetic resonance imaging (fMRI) during a task that required them to reappraise (i.e., reduce) or maintain emotional responses to negative images.
Results
GAD participants reported the least reappraisal use in daily life, and reappraisal use was inversely associated with anxiety severity and functional impairment in these participants. During fMRI, HC demonstrated greater activation during both reappraisal and maintenance than either GAD or PD (who did not differ) in brain areas important for emotion regulation (e.g., dorsolateral and dorsomedial PFC). Furthermore, across all anxious participants, activation during reappraisal in dorsolateral and dorsomedial PFC was inversely associated with anxiety severity and functional impairment.
Conclusions
Emotion dysregulation in GAD and PD may be the consequence of PFC hypo-activation during emotion regulation, consistent with insufficient top-down control. The relationship between PFC hypo-activation and functional impairment suggests that the failure to engage PFC during emotion regulation may be part of the critical transition from dispositionally high anxiety to an anxiety disorder.
doi:10.1017/S0033291712002383
PMCID: PMC4308620  PMID: 23111120
5.  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
6.  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
7.  Resting-State Functional Connectivity of Subgenual Anterior Cingulate Cortex in Depressed Adolescents 
Biological psychiatry  2013;74(12):898-907.
Background
Very few studies have been performed to understand the underlying neural substrates of adolescent major depressive disorder (MDD). Studies in depressed adults have demonstrated that the subgenual anterior cingulate cortex (sgACC) plays a pivotal role in depression and have revealed aberrant patterns of resting-state functional connectivity (RSFC). Here, we examine the RSFC of the sgACC in medication-naïve first-episode adolescents with MDD.
Methods
Twenty-three adolescents with MDD and 36 well-matched control subjects underwent functional magnetic resonance imaging to assess the RSFC of the sgACC.
Results
We observed elevated connectivity between the sgACC and the insula and between the sgACC and the amygdala in the MDD group compared with the control subjects. Decreased connectivity between the sgACC and the precuneus was also found in the MDD group relative to the control subjects. Within the MDD group, higher levels of depression significantly correlated with decreased connectivity between the sgACC and left precuneus. Increased rumination was significantly associated with reduced connectivity between sgACC and the middle and inferior frontal gyri in the MDD group.
Conclusions
Our study is the first to examine sgACC connectivity in medication-naïve first-episode adolescents with MDD compared with well-matched control participants. Our results suggest aberrant functional connectivity among the brain networks responsible for salience attribution, executive control, and the resting-state in the MDD group compared with the control participants. Our findings raise the possibility that therapeutic interventions that can restore the functional connectivity among these networks to that typical of healthy adolescents might be a fruitful avenue for future research.
doi:10.1016/j.biopsych.2013.05.036
PMCID: PMC4103629  PMID: 23910949
Adolescent major depression; amygdala; default mode network; insula; resting-state; subgenual anterior cingulate
8.  What do you feel? Adolescent Drug and Alcohol Users Show Altered Brain Response to Pleasant Interoceptive Stimuli* 
Drug and alcohol dependence  2013;133(2):10.1016/j.drugalcdep.2013.08.015.
Background
Altered interoception, i.e., processing of stimuli from inside the body, has been considered an important component of drug-taking behavior. However, approaches to examine interoceptive sensitivity in humans have been limited. This study examined the hypothesis that adolescents with substance use disorder show altered interoceptive processing, measured by stimulating mechanoreceptive C-fibers (MR-CF) via soft touch.
Methods
Adolescents with substance use disorders (SUD, n=15) and comparison youth (CON, n=17) underwent functional magnetic resonance imaging (fMRI) during anticipation or reception of a positively valenced “Soft Touch” consisting of MR-CF stimulation to the palm or forearm. Visual analog scales (VAS) indexed subjective interoceptive experience (e.g., pleasantness, intensity).
Results
Across all conditions, SUD displayed attenuated left posterior insula activation compared to CON . Greater left anterior insula and right lentiform nucleus activation was evident during the application of soft touch for SUD but not for CON. Whereas for CON, greater left anterior insula activation was associated with higher pleasantness ratings, pleasantness was linked to less anterior insula activation in SUD. Finally, within SUD, attenuated posterior insula activation was related to more recent cannabis use.
Conclusions
SUD adolescents exhibit blunted somatovisceral processing of pleasant stimulation, heightened sensitivity in regions responsible for processing reward value, and altered relationships between interoceptive processing and subjective experience.
doi:10.1016/j.drugalcdep.2013.08.015
PMCID: PMC3880189  PMID: 24071571
alcohol; cannabis; interoception; reward; fMRI
9.  Altered Functional Response to Risky Choice in HIV Infection 
PLoS ONE  2014;9(10):e111583.
Background
Risky decision-making is commonly observed in persons at risk for and infected with HIV and is associated with executive dysfunction. Yet it is currently unknown whether HIV alters brain processing of risk-taking decision-making.
Methods
This study examined the neural substrate of a risky decision-making task in 21 HIV seropositive (HIV+) and 19 seronegative (HIV-) comparison participants. Functional magnetic resonance imaging was conducted while participants performed the risky-gains task, which involves choosing among safe (20 cents) and risky (40/80 cent win or loss) choices. Linear mixed effects analyses examining group and decision type were conducted. Robust regressions were performed to examine the relationship between nadir CD4 count and Kalichman sexual compulsivity and brain activation in the HIV+ group. The overlap between the task effects and robust regressions was explored.
Results
Although there were no serostatus effects in behavioral performance on the risky-gains task, HIV+ individuals exhibited greater activation for risky choices in the basal ganglia, i.e. the caudate nucleus, but also in the anterior cingulate, dorsolateral prefrontal cortex, and insula relative to the HIV- group. The HIV+ group also demonstrated reduced functional responses to safe choices in the anterior cingulate and dorsolateral prefrontal cortex relative to the HIV- group. HIV+ individuals with higher nadir CD4 count and greater sexual compulsivity displayed lower differential responses to safe versus risky choices in many of these regions.
Conclusions
This study demonstrated fronto-striatal loop dysfunction associated with HIV infection during risky decision-making. Combined with similar between-group task behavior, this suggests an adaptive functional response in regions critical to reward and behavioral control in the HIV+ group. HIV-infected individuals with higher CD4 nadirs demonstrated activation patterns more similar to seronegative individuals. This suggests that the severity of past immunosuppression (CD4 nadir) may exert a legacy effect on processing of risky choices in the HIV-infected brain.
doi:10.1371/journal.pone.0111583
PMCID: PMC4210250  PMID: 25347679
10.  Altered Cerebral Perfusion in Executive, Affective, and Motor Networks During Adolescent Depression 
Objective
While substantial literature has reported regional cerebral blood flow (rCBF) abnormalities in adults with depression, these studies commonly necessitated the injection of radioisotopes into subjects. The recent development of arterial spin labeling (ASL), however, allows for noninvasive measurements of rCBF. Currently, no published ASL studies have examined cerebral perfusion in adolescents with depression. Thus, the aim of the present study was to examine baseline cerebral perfusion in adolescent depression using a newly developed ASL technique: pseudocontinuous arterial spin labeling (PCASL).
Method
25 medication-naive adolescents (ages 13–17 years) diagnosed with major depressive disorder (MDD) and 26 well-matched controls underwent functional magnetic resonance imaging. Baseline rCBF was measured via a novel PCASL method that optimizes tagging efficiency.
Results
Voxel-based whole brain analyses revealed significant frontal, limbic, paralimbic, and cingulate hypoperfusion in the group with depression (p<0.05, corrected). Hyperperfusion was also observed within the subcallosal cingulate, putamen, and fusiform gyrus (p<0.05, corrected). Similarly, region-of-interest analyses revealed amygdalar and insular hypoperfusion in the group with depression, as well as hyperperfusion in the putamen and superior insula (p<0.05, corrected).
Conclusions
Adolescents with depression and healthy adolescents appear to differ on rCBF in executive, affective, and motor networks. Dysfunction in these regions may contribute to the cognitive, emotional, and psychomotor symptoms commonly present in adolescent depression. These findings point to possible biomarkers for adolescent depression that could inform early interventions and treatments and establishes a methodology for using PCASL to noninvasively measure rCBF in clinical and healthy adolescent populations.
doi:10.1016/j.jaac.2013.07.008
PMCID: PMC3825460  PMID: 24074474
cerebral blood flow; functional magnetic resonance imaging (fMRI); major depressive disorder (MDD); pseudocontinuous arterial spin labeling (PCASL)
11.  Altered Neural Processing of the Need to Stop in Young Adults at Risk for Stimulant Dependence 
The Journal of Neuroscience  2014;34(13):4567-4580.
Identification of neurocognitive predictors of substance dependence is an important step in developing approaches to prevent addiction. Given evidence of inhibitory control deficits in substance abusers (Monterosso et al., 2005; Fu et al., 2008; Lawrence et al., 2009; Tabibnia et al., 2011), we examined neural processing characteristics in human occasional stimulant users (OSU), a population at risk for dependence. A total of 158 nondependent OSU and 47 stimulant-naive control subjects (CS) were recruited and completed a stop signal task while undergoing functional magnetic resonance imaging (fMRI). A Bayesian ideal observer model was used to predict probabilistic expectations of inhibitory demand, P(stop), on a trial-to-trial basis, based on experienced trial history. Compared with CS, OSU showed attenuated neural activation related to P(stop) magnitude in several areas, including left prefrontal cortex and left caudate. OSU also showed reduced neural activation in the dorsal anterior cingulate cortex (dACC) and right insula in response to an unsigned Bayesian prediction error representing the discrepancy between stimulus outcome and the predicted probability of a stop trial. These results indicate that, despite minimal overt behavioral manifestations, OSU use fewer brain processing resources to predict and update the need for response inhibition, processes that are critical for adjusting and optimizing behavioral performance, which may provide a biomarker for the development of substance dependence.
doi:10.1523/JNEUROSCI.2297-13.2014
PMCID: PMC3965782  PMID: 24672002
Bayesian model; cognitive control; ideal observer model; inhibitory control; stimulants
12.  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
13.  Altered Risk-Related Processing in Substance Users: Imbalance of Pain and Gain 
Drug and alcohol dependence  2013;132(0):13-21.
Background
Substance use disorders (SUDs) can be conceptualized as a form of risk-taking behavior with the potential for highly aversive outcomes such as health or legal problems. Risky decision-making likely draws upon several related brain processes involved in estimations of value and risk, executive control, and emotional processing. SUDs may result from a dysfunction in one or more of these cognitive processes.
Methods
We performed a systematic literature review of functional neuroimaging studies examining risk-related decision making in individuals with SUDs. A quantitative meta-analysis tool (GingerALE) and qualitative approach was used to summarize the imaging results.
Results
Meta-analysis findings indicate that individuals with SUDs exhibit differences in neural activity relative to healthy controls during risk-taking in the anterior cingulate cortex, orbitofrontal cortex, dorsolateral prefrontal cortex, striatum, insula, and somatosensory cortex. In addition, a qualitative review of the literature suggests that individuals with SUDs may have altered function in the amygdala and ventromedial prefrontal cortex.
Conclusions
The neuroimaging literature reveals that several neural substrates involved in the computation of risk may function suboptimally in SUDs. Future research is warranted to elucidate which computational processes are affected, whether dysfunctional risk-related processing recovers with sobriety, and whether different drugs of abuse have specific effects on risk-taking.
doi:10.1016/j.drugalcdep.2013.03.019
PMCID: PMC3748224  PMID: 23623507
Risk-taking; Drug Abuse; Addiction; Neuroimaging; Decision-making
14.  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
15.  Methamphetamine Dependent Individuals show Attenuated Brain Response to Pleasant Interoceptive Stimuli* 
Drug and alcohol dependence  2013;131(3):238-246.
Background
Mechano-receptive C-fiber (MR-CF) stimulation via slow stroking of C-fiber rich skin areas can be used to probe the relationship between reward and interoception. Individuals with substance use disorders show impaired reward processing, and dysfunctional interoceptive processing of MR-CF may contribute to this dysfunction. This study predicted that methamphetamine dependent (MD) individuals would exhibit altered responses to MR-CF stimulation in brain regions important for interoception.
Methods
Recently abstinent MD (n=25) and comparison (CTL, n=17) subjects received a pleasant interoceptive stimulus (“Soft Touch” consisting of a slow brush stroke) to the palm or forearm during functional magnetic resonance imaging. Subjects were provided with cues signaling stimulation to examine anticipatory and stimulus-related processing. Subjective responses were measured using visual analog scales (VAS).
Results
Groups were similar on behavioral performance and ratings of the interoceptive stimuli, yet MD exhibited lower anterior insula, dorsal striatum, and thalamus activation than CTL, across anticipation and soft touch conditions. The lower the anterior insula activation, the faster the reaction time across conditions in MD, whereas the opposite pattern was evident in CTL. Striatal activation in MD was greater than CTL during anticipation, but lower during soft touch. Greater striatal attenuation was associated with higher VAS pleasantness ratings of soft touch.
Conclusions
MD expend fewer brain processing resources during soft touch, a form of positively-valenced interoceptive stimuli, in brain areas that are important for both interoception and reward. Future studies will ascertain if sustained abstinence from methamphetamine use can normalize aberrant neural interoceptive processing.
doi:10.1016/j.drugalcdep.2013.05.029
PMCID: PMC3760794  PMID: 23806873
methamphetamine; interoception; reward; fMRI
17.  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
18.  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
19.  Altered insula response to sweet taste processing after recovery from anorexia and bulimia nervosa 
The American journal of psychiatry  2013;170(10):1143-1151.
Objective
Recent studies suggest that altered function of higher-order appetitive neural circuitry may contribute to restricted eating in anorexia nervosa and overeating in bulimia nervosa. This study used sweet tastes to interrogate gustatory neurocircuitry involving the anterior insula and related regions that modulate sensory-interoceptive-reward signals in response to palatable foods.
Method
Subjects recovered from anorexia and bulimia were studied to avoid confounding effects of altered nutritional state. Functional magnetic resonance imaging measured brain response to repeated tastes of sucrose and sucralose to disentangle neural processing of caloric and non-caloric sweet tastes. Whole-brain functional analysis was constrained to anatomical regions of interest.
Results
Compared to matched control women (n=14), women recovered from anorexia (n=14) had diminished (F(1,27)=7.79, p=0.01) and women recovered from bulimia (n=14) had exaggerated (F(1,27)=6.12, p=0.02) right anterior insula hemodynamic response to tastes of sucrose. Furthermore, anterior insula responses to sucrose compared to sucralose was exaggerated in recovered subjects (lower in women recovered from anorexia and higher in women recovered from bulimia).
Conclusions
The anterior insula integrates sensory/reward aspects of taste in the service of nutritional homeostasis. For example, one possibility is that restricted eating and weight loss occur in anorexia nervosa because of a failure to accurately recognize hunger signals, whereas overeating in bulimia nervosa could represent an exaggerated perception of hunger signals. This response may reflect the altered calibration of signals related to sweet taste and the caloric content of food and may offer a pathway to novel and more effective treatments.
doi:10.1176/appi.ajp.2013.11111745
PMCID: PMC3971875  PMID: 23732817
20.  Imaging The Anxious Brain - Promise Or Hubris? 
Depression and anxiety  2011;28(3):183-185.
doi:10.1002/da.20796
PMCID: PMC3957362  PMID: 21394850
21.  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
22.  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
23.  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
24.  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
25.  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

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