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2.  Resting-State Functional Connectivity of Subgenual Anterior Cingulate Cortex in Depressed Adolescents 
Biological psychiatry  2013;74(12):898-907.
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.
Twenty-three adolescents with MDD and 36 well-matched control subjects underwent functional magnetic resonance imaging to assess the RSFC of the sgACC.
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.
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.
PMCID: PMC4103629  PMID: 23910949
Adolescent major depression; amygdala; default mode network; insula; resting-state; subgenual anterior cingulate
3.  Altered Cerebral Perfusion in Executive, Affective, and Motor Networks During Adolescent Depression 
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).
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.
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).
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.
PMCID: PMC3825460  PMID: 24074474
cerebral blood flow; functional magnetic resonance imaging (fMRI); major depressive disorder (MDD); pseudocontinuous arterial spin labeling (PCASL)
4.  Whole Brain Expression of Bipolar Disorder Associated Genes: Structural and Genetic Analyses 
PLoS ONE  2014;9(6):e100204.
Studies of bipolar disorder (BD) suggest a genetic basis of the illness that alters brain function and morphology. In recent years, a number of genetic variants associated with BD have been identified. However, little is known about the associated genes, or brain circuits that rely upon their function. Using an anatomically comprehensive survey of the human transcriptome (The Allen Brain Atlas), we mapped the expression of 58 genes with suspected involvement in BD based upon their relationship to SNPs identified in genome wide association studies (GWAS). We then conducted a meta-analysis of structural MRI studies to identify brain regions that are abnormal in BD. Of 58 BD associated genes, 22 had anatomically distinct expression patterns that could be categorized into one of three clusters (C1–C3). Brain regions with the highest and lowest expression of these genes did not overlap strongly with anatomical sites identified as abnormal by structural MRI except in the parahippocampal gyrus, the inferior/superior temporal gyrus and the cerebellar vermis, regions where overlap was significant. Using the 22 genes in C1–C3 as reference points, additional genes with correlated expression patterns were identified and organized into sets based on similarity. Further analysis revealed that five of these gene sets were significantly associated with BD, suggesting that anatomical expression profile is correlated with genetic susceptibility to BD, particularly for genes in C2. Our data suggest that expression profiles of BD-associated genes do not explain the majority of structural abnormalities observed in BD, but may be useful in identifying new candidate genes. Our results highlight the complex neuroanatomical basis of BD, and reinforce illness models that emphasize impaired brain connectivity.
PMCID: PMC4062532  PMID: 24941232
5.  Combat-Exposed War Veterans at Risk for Suicide Show Hyperactivation of Prefrontal Cortex and Anterior Cingulate During Error Processing 
Psychosomatic medicine  2012;74(5):471-475.
Suicide is a significant public health problem. Suicidal ideation (SI) increases the risk for completed suicide. However, the brain basis of SI is unknown. The objective of this study was to examine the neural correlates of self-monitoring in individuals at risk for suicide. We hypothesized that combat veterans with a history of SI relative to those without such a history would show altered activation in the anterior cingulate cortex and related circuitry during self-monitoring.
Two groups of combat-exposed war veterans (13 men with and 13 men without history of SI) were studied. Both the SI and non-SI participants had two or more of the following: a) current major depressive disorder, b) current posttraumatic stress disorder, and c) history of mild traumatic brain injury, and each subject performed a validated stop task during functional magnetic resonance imaging. Error-related activation was compared between the SI and non-SI groups.
The SI group demonstrated more error-related activation of the anterior cingulate (8256 mm3, t = 2.51) and prefrontal cortex (i.e., clusters >2048 mm3, voxelwise p < .05). The SI and non-SI participants showed similar behavioral task performance (i.e., mean error rate, F values < 0.63, p values > .43; and mean reaction times, F = 0.27, p = .61).
These findings suggest neural correlates of altered self individuals with a history of SI and may further suggest that functional magnetic resonance imaging could be used to identify individuals at risk for suicide before they engage in suicidal behavior.
PMCID: PMC4018224  PMID: 22511726
6.  Does a shared neurobiology for foods and drugs of abuse contribute to extremes of food ingestion in anorexia and bulimia nervosa? 
Biological psychiatry  2013;73(9):836-842.
Is starvation in anorexia nervosa (AN) or overeating in bulimia nervosa (BN) a form of addiction? Alternatively, why are individuals with BN more vulnerable and AN protected from substance abuse? Such questions have been generated by recent studies that suggest that there are overlapping neural circuits for foods and drugs of abuse.
In order to determine whether a shared neurobiology contributes to eating disorders (EDs) and substance abuse, this review focused on imaging studies that investigated response to tastes of food and tasks designed to characterize reward and behavioral inhibition in AN and BN.
BN and those with substance abuse disorders may share dopamine D2 receptor related vulnerabilities, and opposite findings may contribute to “protection” from substance abuse in AN. Moreover, imaging studies provide insights into executive cortico-striatal processes related to extraordinary inhibition and self-control in AN and diminished inhibitory self-control in BN that may influence the rewarding aspect of palatable foods and likely other consummatory behaviors.
AN and BN tend to have premorbid traits, such as perfectionism and anxiety that make them vulnerable to employing extremes of food ingestion which serve to reduce negative mood states. Dysregulation within and/or between limbic and executive cortio-striatal circuits contributes to such symptoms. Limited data support the hypothesis that reward and inhibitory processes may contribute to symptoms in ED and addictive disorders, but little is known about the molecular biology of such mechanisms in terms of shared or independent processes.
PMCID: PMC3755487  PMID: 23380716
imaging; eating disorders; anorexia nervosa; bulimia nervosa; PET; fMRI; addictive Disorders
7.  Altered insula response to sweet taste processing after recovery from anorexia and bulimia nervosa 
The American journal of psychiatry  2013;170(10):1143-1151.
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.
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.
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).
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.
PMCID: PMC3971875  PMID: 23732817
8.  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.
PMCID: PMC3570713  PMID: 23154098
early life stress; anxiety; imaging; trauma; abuse; neglect
9.  Young Adults at Risk for Stimulant Dependence show Reward Dysfunction during Reinforcement-Based Decision Making 
Biological psychiatry  2012;73(3):235-241.
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.
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.
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.
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.
PMCID: PMC3674030  PMID: 23021534
stimulants; amphetamine; decision making; reward; dorsal striatum; fMRI
10.  Nothing Tastes as Good as Skinny Feels: The Neurobiology of Anorexia Nervosa 
Trends in neurosciences  2013;36(2):10.1016/j.tins.2013.01.003.
Individuals with anorexia nervosa (AN) engage in relentless, restrictive eating and often become severely emaciated. Because there are no proven treatments, AN has high rates of relapse, chronicity, and death. Those with AN tend to have childhood temperament and personality traits, such as anxiety, obsessions, and perfectionism, which may reflect neurobiological risk factors for developing AN. Restricted eating may be a means of reducing negative mood caused by skewed interactions between serotonin aversive or inhibitory and dopamine reward systems. Brain imaging studies suggest altered eating is a consequence of dysregulated reward, and/or awareness of homeostatic needs, perhaps related to enhanced executive ability to inhibit incentive motivational drives. Understanding the neurobiology of this disorder is likely to be important for developing more effective treatments.
PMCID: PMC3880159  PMID: 23333342
anorexia nervosa; eating disorders; dopamine; serotonin; fMRI; PET brain imaging
Recent evidence raises the possibility that symptoms of anorexia nervosa (AN) could be related to impaired interoception. Pain is an interoceptive process with well-characterized neuroanatomical pathways that may overlap to a large degree with neural systems that may be dysregulated in AN individuals, such as the insula.
Functional Magnetic Resonance Imaging (fMRI) was used to assess neural substrates of pain anticipation and processing in ten healthy control women (CW) and 12 individuals recovered from AN (REC AN) in order to avoid the confounding effects of malnutrition. Painful heat stimuli were applied while different colors signaled the intensity of the upcoming stimuli.
REC AN compared to CW showed greater activation within right anterior insula (rAI), dorsolateral prefrontal cortex (dlPFC) and cingulate during pain anticipation, and greater activation within dlPFC and decreased activation within posterior insula during painful stimulation. Greater anticipatory rAI activation correlated positively with alexithymic feelings in REC AN subjects.
REC AN showed a mismatch between anticipation and objective responses, suggesting altered integration and, possibly, disconnection between reported and actual interoceptive state. Alexithymia assessment provided additional evidence of an altered ability to accurately perceive bodily signals in women recovered from anorexia nervosa.
PMCID: PMC3507323  PMID: 22836447
Anorexia; insula; pain; anticipation; homeostasis; fmri; interoception; alexithymia; eating disorders; dorsolateral prefrontal
12.  Are Extremes of Consumption in Eating Disorders Related to an Altered Balance between Reward and Inhibition? 
The primary defining characteristic of a diagnosis of an eating disorder (ED) is the “disturbance of eating or eating-related behavior that results in the altered consumption or absorption of food” (DSM V; American Psychiatric Association, 2013). There is a spectrum, ranging from those who severely restrict eating and become emaciated on one end to those who binge and overconsume, usually accompanied by some form of compensatory behaviors, on the other. How can we understand reasons for such extremes of food consummatory behaviors? Recent work on obesity and substance use disorders has identified behaviors and neural pathways that play a powerful role in human consummatory behaviors. That is, corticostriatal limbic and dorsal cognitive neural circuitry can make drugs and food rewarding, but also engage self-control mechanisms that may inhibit their use. Importantly, there is considerable evidence that alterations of these systems also occur in ED. This paper explores the hypothesis that an altered balance of reward and inhibition contributes to altered extremes of response to salient stimuli, such as food. We will review recent studies that show altered sensitivity to reward and punishment in ED, with evidence of altered activity in corticostriatal and insula processes with respect to monetary gains or losses, and tastes of palatable foods. We will also discuss evidence for a spectrum of extremes of inhibition and dysregulation behaviors in ED supported by studies suggesting that this is related to top-down self-control mechanisms. The lack of a mechanistic understanding of ED has thwarted efforts for evidence-based approaches to develop interventions. Understanding how ED behavior is encoded in neural circuits would provide a foundation for developing more specific and effective treatment approaches.
PMCID: PMC4260511  PMID: 25538579
anorexia nervosa; bulimia nervosa; eating disorders; reward processing; inhibition; cognitive control; gustatory processing
13.  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.
PMCID: PMC3875519  PMID: 24386327
15.  Further Evidence of Emotional Allodynia in Unmedicated Young Adults with Major Depressive Disorder 
PLoS ONE  2013;8(11):e80507.
Recent evidence suggests that sensitivity to the emotional sequela of experimental thermal pain(measured by emotional unpleasantness) is heightened in individuals with major depressive disorder(MDD), a phenomenon we termed “emotional allodynia”. The aim of this study was to examine whether acute happy and sad mood induction alters emotional allodynia in MDD. We hypothesized that emotional allodynia will be a robust characteristic of individuals with MDD compared to healthy controls. Thus, it would remain following acute mood induction, independent of valence.
Twenty-one subjects with current MDD and 21 well-matched healthy subjects(HC) received graded brief temperature stimuli following happy and sad mood inductions procedures(MIP). All subjects rated the intensity and affect(pleasantness/unpleasantness) of each stimulus. Sensory(pain intensity) and affective(pain unpleasantness) thresholds were determined by methods of constant stimuli.
The MIPs reliably induced happy and sad mood and the resulting induced mood and subjective arousal were not different between the groups at the time of temperature stimulation. Compared to HC, MDD individuals demonstrated emotional allodynia. We found significantly decreased affective pain thresholds whereby significantly lower temperatures became unpleasant in the MDD compared to the HC group. This was not observed for the sensory pain thresholds. Within the MDD, the affective pain thresholds were significantly lower than the corresponding pain intensity thresholds, whereby non-painful temperatures were already unpleasant for the MDD irrespective of the induced mood. This was not observed for the HC groups where the affective and pain intensity thresholds were comparable.
These findings suggest that emotional allodynia may be a chronic characteristic of current MDD. Future studies should determine if emotional allodynia persists after psychological or pharmacological interventions. Finally, longitudinal work should examine whether emotional allodynia is a result of or vulnerability for depression and the role it plays in the increased susceptibility for pain complaints in this disorder.
PMCID: PMC3842925  PMID: 24312229
16.  High versus Low Level of Response to Alcohol: Evidence of Differential Reactivity to Emotional Stimuli 
Biological psychiatry  2012;72(10):848-855.
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.
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.
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.
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.
PMCID: PMC3433640  PMID: 22608014
fMRI; alcohol sensitivity; emotional stimuli; fear; Hariri; alcoholism
17.  A factor analysis of different temperament domains in a border region in rural Southern California 
Journal of affective disorders  2010;126(0):46-48.
Temperament has been described as an oligogenic model that confers attributes to individuals in their daily functioning. Understanding of these temperaments can help understanding psychiatric status and therapeutic needs of a patient population. As the Latino population grows providers need to become more familiar with their psychiatric status.
To describe how the characteristics of different temperament domains in a community vs a private practice clinic of patients being treated for a mood disorder.
Retrospective record review was conducted in 117 patients with mood disorders who received the Temperament Scale (TEMPS). Forty nine were from a community clinic (CM) and 68 from a private practice (PP).
The following temperament domains were found. In PP: depressed 17/69 (25%); cyclothymic 18/69 (26%); hyperthymic 16/69 (23%); anxious 14/68 (20%); irritable 4/69 (5%). Among CM: depressed 10/49 (20%); cyclothymic 14/49 (28%); hyperthymic 8/49 (16%); anxious 15/49 (30%); irritable 2/49 (5%). Using factor analysis to determine the significant domains among clinics, cyclothima (0.82) and irritability (0.81) were the most relevant, regardless of psychosocial background and language differences.
Cross-sectional retrospective study without longitudinal follow up.
This study elucidates how temperament domains could be considered a valuable tool in evaluating patients in mood disorders clinic. The tool elucidates valuable characteristics that could be applied for guidance in diagnosis and treatment without being biased by different socio-cultural background or language differences. The factor analysis helps elucidate the pertinence of TEMPS scores that may not be the focus of clinical intervention although they contribute significantly to the structure of an individual's temperament, specifically emotional labiality (i.e., cyclothima and irritability).
PMCID: PMC3782388  PMID: 20392499
Temperament; Rural; Cyclothymia
18.  Acute Ethanol Effects on Brain Activation in Low- and High-Level Responders to Alcohol 
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.
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.
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.
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.
PMCID: PMC3774836  PMID: 20477775
Level of response; fMRI; visual working memory; cerebral blood flow
19.  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
20.  Amygdala Response and Functional Connectivity During Emotion Regulation: A Study of 14 Depressed Adolescents 
Journal of Affective Disorders  2012;139(1):75-84.
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.
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”).
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.
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.
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.
PMCID: PMC3340443  PMID: 22401827
Major Depression; Functional MRI; Insula; Reappraisal; Prefrontal Cortex
21.  Red Brain, Blue Brain: Evaluative Processes Differ in Democrats and Republicans 
PLoS ONE  2013;8(2):e52970.
Liberals and conservatives exhibit different cognitive styles and converging lines of evidence suggest that biology influences differences in their political attitudes and beliefs. In particular, a recent study of young adults suggests that liberals and conservatives have significantly different brain structure, with liberals showing increased gray matter volume in the anterior cingulate cortex, and conservatives showing increased gray matter volume in the in the amygdala. Here, we explore differences in brain function in liberals and conservatives by matching publicly-available voter records to 82 subjects who performed a risk-taking task during functional imaging. Although the risk-taking behavior of Democrats (liberals) and Republicans (conservatives) did not differ, their brain activity did. Democrats showed significantly greater activity in the left insula, while Republicans showed significantly greater activity in the right amygdala. In fact, a two parameter model of partisanship based on amygdala and insula activations yields a better fitting model of partisanship than a well-established model based on parental socialization of party identification long thought to be one of the core findings of political science. These results suggest that liberals and conservatives engage different cognitive processes when they think about risk, and they support recent evidence that conservatives show greater sensitivity to threatening stimuli.
PMCID: PMC3572122  PMID: 23418419
22.  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.
PMCID: PMC3256346  PMID: 21982930
sensation seeking; fMRI; SFG; neural correlates; decision making; risk taking
23.  Alcohol Attenuates Activation in the Bilateral Anterior Insula during an Emotional Processing Task: A Pilot Study † 
Aims: Alcohol acutely reduces agitation and is widely used in social situations, but the neural substrates of emotion processing during its intoxication are not well understood. We examine whether alcohol's social stress dampening effect may be via reduced activity in the cortical systems that subserve awareness of bodily sensations, and are associated with affective distress. Methods: Blood oxygen level-dependent activation was measured through 24 functional magnetic resonance imaging sessions in 12 healthy volunteers during an emotional face-processing task following ingestion of a moderate dose of alcohol and a placebo beverage. Results: Results revealed that bilateral anterior insula response to emotional faces was significantly attenuated following consumption of alcohol, when compared with placebo (clusters >1472 μl; corrected P < 0.05). Conclusion: Attenuated response in the anterior insula after alcohol intake may explain some of the decreased interoceptive awareness described during intoxication.
PMCID: PMC3201697  PMID: 21665869
24.  Neural substrates of time perception and impulsivity 
Brain research  2011;1406:43-58.
Several studies provide empirical evidence for the association between impulsivity and time perception. However, little is known about the neural substrates underlying this function. This investigation examined the influence of impulsivity on neural activation patterns during the encoding and reproduction of intervals with durations of 3, 9 and 18 seconds using event-related functional magnetic resonance imaging (fMRI). Twenty-seven subjects participated in this study, including 15 high impulsive subjects that were classified based on their self-rating. FMRI activation during the duration reproduction task was correlated with measures of two self-report questionnaires related to the concept of impulsivity (Barratt Impulsiveness Scale, BIS; Zimbardo Time Perspective Inventory, ZTPI). Behaviorally, those individuals who under-reproduced temporal intervals also showed lower scores on the ZTPI future perspective subscale and higher scores on the BIS. FMRI activation revealed an accumulating pattern of neural activity peaking at the end of the 9- and 18-s interval within right posterior insula. Activations of brain regions during the reproduction phase of the timing task, such as those related to motor execution as well as to the ‘core control network’ – encompassing the inferior frontal and medial frontal cortex, the anterior insula as well as the inferior parietal cortex – were significantly correlated with reproduced duration, as well as with BIS and ZTPI subscales. In particular, the greater activation in these regions the shorter were the reproduced intervals, the more impulsive was an individual and the less pronounced the future perspective. Activation in the core control network, thus, may form a biological marker for cognitive time management and for impulsiveness.
PMCID: PMC3145046  PMID: 21763642
time perception; duration reproduction; impulsivity; time perspective; fMRI
25.  Pregabalin Influences Insula and Amygdala Activation During Anticipation of Emotional Images 
Neuropsychopharmacology  2011;36(7):1466-1477.
Pregabalin (PGB) has shown potential as an anxiolytic for treatment of generalized and social anxiety disorder. PGB binds to voltage-dependent calcium channels, leading to upregulation of GABA inhibitory activity and reduction in the release of various neurotransmitters. Previous functional magnetic resonance imaging (fMRI) studies indicate that selective serotonin reuptake inhibitors and benzodiazepines attenuate amygdala, insula, and medial prefrontal cortex activation during anticipation and emotional processing in healthy controls. The aim of this study was to examine whether acute PGB administration would attenuate activation in these regions during emotional anticipation. In this double-blind, placebo-controlled, randomized crossover study, 16 healthy controls completed a paradigm involving anticipation of negative and positive affective images during fMRI approximately 1 h after administration of placebo, 50, or 200 mg PGB. Linear mixed model analysis revealed that PGB was associated with (1) decreases in left amygdala and anterior insula activation and (2) increases in anterior cingulate (ACC) activation, during anticipation of positive and negative stimuli. There was also a region of the anterior amygdala in which PGB dose was associated with increased activation during anticipation of negative and decreased activation during anticipation of positive stimuli. Attenuation of amygdala and insula activation during anticipatory or emotional processing may represent a common regional brain mechanism for anxiolytics across drug classes. PGB induced increases in ACC activation could be a unique effect related to top–down modulation of affective processing. These results provide further support for the viability of using pharmaco-fMRI to determine the anxiolytic potential of pharmacologic agents.
PMCID: PMC3096815  PMID: 21430645
pregabalin; neuroimaging; insula; amygdala; anticipation; psychopharmacology; neuropharmacology; psychopharmacology; mood/anxiety/stress disorders; imaging; clinical or preclinical; pregabalin; anxiety; insula; prefrontal cortex; amygdala

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