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1.  Anxiety positive subjects show altered processing in the anterior insula during anticipation of negative stimuli 
Human brain mapping  2010;32(11):1836-1846.
Prior neuroimaging studies support the hypothesis that anticipation, an important component of anxiety, may be mediated by activation within the insular and medial prefrontal cortices including the anterior cingulate cortex. However, there is an insufficient understanding of how affective anticipation differs across anxiety groups in emotional brain loci and networks. We examined 14 anxiety positive (AP) and 14 anxiety normative (AN) individuals completing an affective picture anticipation task during functional magnetic resonance imaging (fMRI). Brain activation was examined across groups for cued anticipation (to aversive or pleasant stimuli). Both groups showed greater activation in the bilateral anterior insula during cued differential anticipation (i.e., aversive vs. pleasant) and activation on the right was significantly higher in AP compared to AN subjects. Functional connectivity showed that the left anterior insula was involved in a similar network during pleasant anticipation in both groups. The left anterior insula during aversive and the right anterior insula during all anticipation conditions co-activated with a cortical network consisting of frontal and parietal lobes in the AP group to a greater degree. These results are consistent with the hypothesis that anxiety is related to greater anticipatory reactivity in the brain and that there may be functional asymmetries in the brain that interact with psychiatric traits.
PMCID: PMC3215249  PMID: 21181800
2.  Escitalopram attenuates posterior cingulate activity during self evaluation in healthy volunteers 
Psychiatry research  2010;182(2):81-87.
Medial cortex is critically involved in self-referential processing. Little is known about how SSRIs affect medial cortical activity during self-assessment. We hypothesized that 3 week oral administration of escitalopram 10mg per day would alter activity related to self-referential processing in medial cortex. Fifteen healthy females performed a self-assessment task during fMRI on two occasions – once after 3 weeks of placebo and once at the end of 3 weeks of escitalopram. Task conditions involved responding “yes” or “no” to whether various positive and negative adjectives described the subject (i.e., “self” evaluation trials) or the subject’s best friend (i.e., “other” evaluation trials), whereas the comparison condition involved responding whether the valence of various adjectives was positive or negative (i.e., “word” evaluation trials). Behaviorally after escitalopram, subjects less frequently endorsed that negative adjectives described themselves. Three main neuroimaging results were observed: (1) increased activation in medial prefrontal cortex and posterior cingulate related to self minus word evaluation trials, (2) increased activation in posterior cingulate related to escitalopram minus placebo for self and word evaluation trials, (3) drug by task interactions in the insula, cerebellum and prefrontal cortex. These results show that SSRIs change medial cortical activity and may alter self-evaluation.
PMCID: PMC2882791  PMID: 20418072
SSRI; medial cortex; fMRI; self; cingulate; emotion processing
3.  Association between Individual Differences in Self-Reported Emotional Resilience and the Affective Perception of Neutral Faces 
Journal of affective disorders  2008;114(1-3):286-293.
Resilience, i.e., the ability to cope with stress and adversity, relies heavily on judging adaptively complex situations. Judging facial emotions is a complex process of daily living that is important for evaluating the affective context of uncertain situations, which could be related to the individual's level of resilience. We used a novel experimental paradigm to test the hypothesis that highly resilient individuals show a judgment bias towards positive emotions.
65 non-treatment seeking subjects completed a forced emotional choice task when presented with neutral faces and faces morphed to display a range of emotional intensities across sadness, fear, and happiness.
Overall, neutral faces were judged more often to be sad or fearful than happy. Furthermore, high compared to low resilient individuals showed a bias towards happiness, particularly when judging neutral faces.
This is a cross-sectional study with a non-clinical sample.
These results support the hypothesis that resilient individuals show a bias towards positive emotions when faced with uncertain emotional expressions. This capacity may contribute to their ability to better cope with certain types of difficult situations, perhaps especially those that are interpersonal in nature.
PMCID: PMC2691748  PMID: 18957273
Emotion perception; Resilience; Facial expressions; Neutral faces
4.  Subchronic SSRI administration attenuates insula response during affective anticipation 
The anterior cingulate cortex (ACC) and insula are important neural substrates for the integration of cognitive, emotional, and physiological information, as well as the coordination of responses to anticipated stimuli. Increased neural activation within these structures has been observed in individuals with anxiety and depressive disorders. Selective serotonin reuptake inhibitors (SSRIs) are among the most effective and frequently prescribed anxiolytic agents, yet it is not known whether ACC or insula underlie the effects of these drugs. We examined whether subchronic administration of an SSRI to healthy volunteers attenuate activation in ACC or insula during anticipation, an important emotional process underlying anxiety. Support for this hypothesis would help to understand where and by what process SSRIs may exert beneficial effects as anxiolytics and would provide further mechanistic evidence for functional magnetic resonance imaging (fMRI) as a biomarker for the development of anxiolytics.
Participants and Design
15 volunteers participated in a double-blind, placebo-controlled, randomized cross-over study. Participants completed a pleasant and aversive picture cued anticipation task during fMRI after taking either escitalopram (10 mg) or placebo for 21 days.
Main Outcome Measure
Percent BOLD signal change during SSRI administration.
Escitalopram significantly decreased activation in bilateral posterior and middle insula during the anticipation condition irrespective of stimulus valence and in medial prefrontal and ACC during anticipation of aversive versus pleasant images.
Reduced insular and ACC activation during anticipation may be integral to the therapeutic efficacy of SSRIs and provide a mechanistic approach for the use of pharmacofMRI in the identification of novel pharmacotherapeutic agents.
PMCID: PMC2846821  PMID: 19545475
SSRI; escitalopram; insula; fMRI; anticipation
5.  Escitalopram effects on insula and amygdala BOLD activation during emotional processing 
Psychopharmacology  2007;196(4):661-672.
The amygdala and insular cortex are integral to the processing of emotionally salient stimuli. We have shown in healthy volunteers that an anxiolytic agent, lorazepam, dose-dependently attenuates activation of limbic structures.
The current study investigated whether administration of a selective serotonin reuptake inhibitor (SSRI), escitalopram, alters the activation of limbic structures. We hypothesized that subchronic (21 days) SSRI treatment attenuates the activation of the amygdala and insula during processing of emotional faces.
Thirteen healthy volunteers participated in a double-blind, placebo-controlled, cross-over, randomized study. After 21 days of treatment with either escitalopram or placebo, participants underwent functional magnetic resonance imaging (fMRI) during which all subjects completed an emotion face assessment task, which has been shown to elicit amygdala and insula activation.
Subjects activated the bilateral insula and amygdala following treatment with both escitalopram and placebo. In subjects who were adherent to the protocol (as evidenced by sufficiently high urine concentrations of escitalopram), a reduction in amygdala activation was seen in the escitalopram condition compared to placebo.
The current investigation provides further evidence for the mechanism of action of SSRIs through the attenuation of activation in brain regions responsible for emotion processing and provides support for the use of BOLD-fMRI with pharmacological probes to help identify the specific therapeutic effect of these agents in patients with anxiety and mood disorders.
PMCID: PMC2839135  PMID: 18058090
SSRI; escitalopram; insula; amygdala; fMRI; emotion processing
6.  Lorazepam Dose-dependently Decreases Risk-taking Related Activation in Limbic Areas 
Psychopharmacology  2006;189(1):105-116.
Several studies have examined the role of different neurotransmitter systems in modulating risk-taking behavior.
This investigation was aimed to determine whether the benzodiazepine lorazepam dose-dependently alters risk-taking behavior and underlying neural substrates.
Fifteen healthy, non-smoking, individuals (6 females, 9 males), aged 18–39 years (mean 27.6 +/− 1.4 years) with 12–18 years of education (mean 15.6 +/− 0.3 years) underwent functional magnetic resonance imaging while performing a risk-taking decision-making task.
Our results show that lorazepam did not affect risky behavior at 0.25 and 1mg, but dose-dependently attenuated activation in (a) the amygdala and medial prefrontal cortex during the response selection phase, and in (b) the bilateral insular cortex and amygdala during the outcome (i.e., rewarded or punished) phase. Furthermore, a lorazepam-induced increase in insular cortex activation was associated with less risky responses.
Taken together, our findings support the idea that GABAergic modulation in limbic and paralimbic structures is important during both the response selection and outcome phase of risk-taking decision-making.
PMCID: PMC2839080  PMID: 17016713
Risk-taking; decision-making; fMRI; insula; amygdala; medial prefrontal cortex; GABAergic; lorazepam
7.  Increased Amygdala Activation is Related to Heart Rate During Emotion Processing in Adolescent Subjects 
Neuroscience letters  2007;428(2-3):109-114.
Emotions have been conceptualized as representations of bodily responses to a stimulus that critically involves the autonomic nervous system (ANS). An association between amygdala activation and ANS activity has been shown in adults. However, to date, no studies have demonstrated this association in adolescents. Examining the interaction between the ANS and amygdala in healthy adolescents may provide information about age-related changes in the association between amygdala activation and ANS measures. Therefore, the aim of this study was to examine the relationship between amygdala activation and heart rate in normal adolescents. Eighteen 12- to 17-year old adolescents participated. Heart rate data was collected during functional magnetic resonance imaging while subjects performed a facial expression matching task that reliably activates the amygdala. Adolescents showed significant amygdala activation for all facial expressions relative to the shape-matching, control task. Moreover, the degree of activation in the right amygdala for Fearful faces was significantly correlated with heart rate (Spearman’s rho = 0.55, p = 0.018, two-tailed). This study shows that amygdala activity is related to heart rate in healthy adolescents. Thus, similar to adults, adolescents show a coupling between processing emotional events and adjusting the ANS accordingly. Furthermore, this study confirms previous adolescent studies showing amygdala activation to Fearful, Angry, and Happy faces. Finally, the results of the present study lay the foundation for future research to investigate whether adolescents with mood or anxiety disorders show an altered coupling between processing emotionally salient events and ANS activity.
PMCID: PMC2171034  PMID: 18029095
8.  Young adult stimulant users' increased striatal activation during uncertainty is related to impulsivity 
NeuroImage  2006;33(2):725-731.
Young adults who use stimulants (e.g., cocaine, amphetamines) are at particular risk of transitioning to dependence. Previously, we demonstrated increased risk-taking in young adults who had used stimulants (Leland and Paulus, 2005). Since outcome uncertainty is a critical element of risk, we investigated whether such individuals have different neural responses to uncertainty than their stimulant-naïve peers.
Eleven young adults (age 18–25) who had used stimulants were compared with 11 age- and education-matched stimulant-naïve controls using functional magnetic resonance imaging and a card prediction task with relatively certain/uncertain outcome conditions.
The caudate, an area involved in processing salient events, was among those regions more active in users than controls in response to uncertainty. Personality measures revealed that users were more impulsive than controls, and that neural response to uncertainty in a number of areas including the thalamus/caudate was positively correlated with impulsivity.
These results are consistent with the idea that young adults who have used stimulant find uncertainty particularly salient, due in part to preexisting differences in impulsivity, and may be subject to more “action pressure” when making decisions under uncertainty. This neural and personality profile may constitute a marker for increased risk of stimulant use.
PMCID: PMC1668709  PMID: 16959497
fMRI; stimulants; uncertainty; striatum; impulsivity; salience

Results 1-8 (8)