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1.  Childhood Maltreatment, Altered Limbic Neurobiology, and Substance Use Relapse Severity via Trauma-Specific Reductions in Limbic Gray Matter Volume 
JAMA psychiatry  2014;71(8):917-925.
Substance use disorders (SUDs) are among the most common sequelae of childhood maltreatment, yet the independent contributions of SUDs and childhood maltreatment to neurobiological changes and the effect of the latter on relapse risk (a critical variable in addiction treatment) are relatively unknown.
To identify structural neural characteristics independently associated with childhood maltreatment (CM; a common type of childhood adversity), comparing a sample with SUD with a demographically comparable control sample, and to examine the relationship between CM-related structural brain changes and subsequent relapse.
Structural magnetic resonance imaging study comparing 79 treatment-engaged participants with SUD in acute remission in inpatient treatment at a community mental health center vs 98 healthy control participants at an outpatient research center at an academic medical center. Both groups included individuals with a range of CM experiences. Participants with SUD were followed up prospectively for 90 days to assess relapse and relapse severity.
Standard 12-step, recovery-based, inpatient addiction treatment for all participants with SUD.
Gray matter volume (GMV), subsequent substance use relapse, days to relapse, and severity of relapse.
Controlling for SUD and psychiatric comorbidity, CM (dichotomously classified) was uniquely associated with lower GMV across all participants in the left hippocampus (cornu ammonis 1-3, dentate gyrus), parahippocampus (presubiculum, parasubiculum, prosubiculum, subiculum, and entorhinal cortex), and anterior fusiform gyrus (corrected P < .05; uncorrected P = .001). Among the sample with SUD, CM prospectively predicted a shorter relapse to use of any drug (P = .048), while CM-related GMV reductions predicted severity of substance use relapse (P = .04).
Findings indicate that CM was related to decreased GMV in limbic regions, which in turn predicted increased risk of relapse in SUD. These results suggest that CM may significantly affect the course of SUD treatment outcomes and that SUD treatment planning may benefit from identifying and addressing CM.
PMCID: PMC4437819  PMID: 24920451
2.  Effects of acute progesterone administration upon responses to acute psychosocial stress in men 
Animal studies suggest that neuroactive steroids, in particular progesterone and its metabolites, have stress-dampening effects. However, few studies have explored these effects in humans. In this study, we investigated the effects of acute progesterone administration upon responses to the Trier Social Stress Test (TSST).
Healthy men participated in the TSST 3.5h after intramuscular injection of 0, 50 or 100mg progesterone (N=16, 14 and 14). We measured cardiovascular (heart rate, blood pressure), hormonal (plasma adrenocorticotrophic hormone, cortisol and noradrenaline) and subjective (e.g. anxiety, arousal) responses to stress in the three groups.
Before the TSST, progesterone injections increased plasma levels without altering physiological or subjective states. Stress produced its expected physiological and subjective effects among placebo-treated individuals. Progesterone 50mg attenuated peak increases in plasma cortisol and reduced changes in negative mood and alertness after stress, yet it increased plasma noradrenaline and systolic blood pressure. Progesterone 100mg also attenuated stress-induced increases in alertness and arousal yet it potentiated stress-induced increases in diastolic pressure. Thus, progesterone dampened some of the psychological effects of stress but produced inconsistent effects upon physiological stress responses.
PMCID: PMC4351805  PMID: 20158297
progesterone; allopregnanolone; stress; TSST
3.  Abnormal autonomic and associated brain activities during rest in autism spectrum disorder 
Brain  2014;137(1):153-171.
Autism spectrum disorders are associated with social and emotional deficits, the aetiology of which are not well understood. A growing consensus is that the autonomic nervous system serves a key role in emotional processes, by providing physiological signals essential to subjective states. We hypothesized that altered autonomic processing is related to the socio-emotional deficits in autism spectrum disorders. Here, we investigated the relationship between non-specific skin conductance response, an objective index of sympathetic neural activity, and brain fluctuations during rest in high-functioning adults with autism spectrum disorder relative to neurotypical controls. Compared with control participants, individuals with autism spectrum disorder showed less skin conductance responses overall. They also showed weaker correlations between skin conductance responses and frontal brain regions, including the anterior cingulate and anterior insular cortices. Additionally, skin conductance responses were found to have less contribution to default mode network connectivity in individuals with autism spectrum disorders relative to controls. These results suggest that autonomic processing is altered in autism spectrum disorders, which may be related to the abnormal socio-emotional behaviours that characterize this condition.
PMCID: PMC3891443  PMID: 24424916
autism; autonomic nervous system; emotion; skin conductance; resting state
4.  Cognitive Control and Attentional Functions 
Brain and cognition  2013;82(3):301-312.
Cognitive control is essential to flexible, goal-directed behavior under uncertainty, yet its underlying mechanisms are not clearly understood. Because attentional functions are known to allocate mental resources and prioritize the information to be processed by the brain, we propose that the attentional functions of alerting, orienting, and executive control and the interactions among them contribute to cognitive control in the service of uncertainty reduction. To test this hypothesis, we examined the relationship between cognitive control and attentional functions. We used the Majority Function Task (MFT) to manipulate uncertainty in order to evoke cognitive control along with the Revised Attention Network Test (ANT-R) to measure the efficiency and the interactions of attentional functions. A backwards, stepwise regression model revealed that performance on the MFT could be significantly predicted by attentional functions and their interactions as measured by the ANT-R. These results provide preliminary support for our theory that the attentional functions may be involved in the implementation of cognitive control as required to reduce uncertainty, though further investigation is needed.
PMCID: PMC3722267  PMID: 23792472
attention; cognitive control; executive control; uncertainty
5.  Neural Basis of Emotional Decision Making in Trait Anxiety 
The Journal of Neuroscience  2013;33(47):18641-18653.
Although trait anxiety has been associated with risk decision making, whether it is related to risk per se or to the feeling of the risk, as well as the underlying neurocognitive mechanisms, remains unclear. Using a decision-making task with a manipulation of frame (i.e., written description of options as a potential gain or loss) and functional magnetic resonance imaging, we investigated the neurocognitive relationship between trait anxiety and decision making. The classic framing effect was observed: participants chose the safe option when it was described as a potential gain, but they avoided the same option when it was described as a potential loss. Most importantly, trait anxiety was positively correlated with this behavioral bias. Trait anxiety was also positively correlated with amygdala-based “emotional” system activation and its coupling with the ventromedial prefrontal cortex (vmPFC) when decisions were consistent with the framing effect, but negatively correlated with the dorsal anterior cingulate cortex (dACC)-based “analytic” system activation and its connectivity to the vmPFC when decisions ran counter to the framing effect. Our findings suggest that trait anxiety is not associated with subjective risk preference but an evaluative bias of emotional information in decision making, underpinned by a hyperactive emotional system and a hypoactive analytic system in the brain.
PMCID: PMC3834062  PMID: 24259585
6.  Cognition–Emotion Integration in the Anterior Insular Cortex 
Cerebral Cortex (New York, NY)  2012;23(1):20-27.
Both cognitive and affective processes require mental resources. However, it remains unclear whether these 2 processes work in parallel or in an integrated fashion. In this functional magnetic resonance imaging study, we investigated their interaction using an empathy-for-pain paradigm, with simultaneous manipulation of cognitive demand of the tasks and emotional valence of the stimuli. Eighteen healthy adult participants viewed photographs showing other people's hands and feet in painful or nonpainful situations while performing tasks of low (body part judgment) and high (laterality judgment) cognitive demand. Behavioral data showed increased reaction times and error rates for painful compared with nonpainful stimuli under laterality judgment relative to body part judgment, indicating an interaction between cognitive demand and stimulus valence. Imaging analyses showed activity in bilateral anterior insula (AI) and primary somatosensory cortex (SI), but not posterior insula, for main effects of cognitive demand and stimulus valence. Importantly, cognitive demand and stimulus valence showed a significant interaction in AI, SI, and regions of the frontoparietal network. These results suggest that cognitive and emotional processes at least partially share common brain networks and that AI might serve as a key node in a brain network subserving cognition–emotion integration.
PMCID: PMC3513949  PMID: 22275476
cognition; emotion; empathy; fMRI; insula
7.  Spontaneous brain activity relates to autonomic arousal 
Although possible sources and functions of the resting state networks (RSN) of the brain have been proposed, most evidence relies on circular logic and reverse inference. We propose that autonomic arousal provides an objective index of psychophysiological states during rest that may also function as a driving source of the activity and connectivity of RSN. Recording blood oxygenation level-dependent (BOLD) signal using functional magnetic resonance imaging and skin conductance simultaneously during rest in human subjects, we found that the spontaneous fluctuations of BOLD signals in key nodes of RSN are associated with changes in non-specific skin conductance response, a sensitive psychophysiological index of autonomic arousal. Our findings provide evidence of an important role for the autonomic nervous system to the spontaneous activity of the brain during ‘rest’.
PMCID: PMC3435430  PMID: 22895703
resting-state functional connectivity MRI; autonomic arousal; skin conductance response; interoception; consciousness
8.  Functional Neural Correlates of Attentional Deficits in Amnestic Mild Cognitive Impairment 
PLoS ONE  2013;8(1):e54035.
Although amnestic mild cognitive impairment (aMCI; often considered a prodromal phase of Alzheimer’s disease, AD) is most recognized by its implications for decline in memory function, research suggests that deficits in attention are present early in aMCI and may be predictive of progression to AD. The present study used functional magnetic resonance imaging to examine differences in the brain during the attention network test between 8 individuals with aMCI and 8 neurologically healthy, demographically matched controls. While there were no significant behavioral differences between groups for the alerting and orienting functions, patients with aMCI showed more activity in neural regions typically associated with the networks subserving these functions (e.g., temporoparietal junction and posterior parietal regions, respectively). More importantly, there were both behavioral (i.e., greater conflict effect) and corresponding neural deficits in executive control (e.g., less activation in the prefrontal and anterior cingulate cortices). Although based on a small number of patients, our findings suggest that deficits of attention, especially the executive control of attention, may significantly contribute to the behavioral and cognitive deficits of aMCI.
PMCID: PMC3543395  PMID: 23326568
9.  Functional deficits of the attentional networks in autism 
Brain and Behavior  2012;2(5):647-660.
Attentional dysfunction is among the most consistent observations of autism spectrum disorders (ASD). However, the neural nature of this deficit in ASD is still unclear. In this study, we aimed to identify the neurobehavioral correlates of attentional dysfunction in ASD. We used the Attention Network Test-Revised and functional magnetic resonance imaging to examine alerting, orienting, and executive control functions, as well as the neural substrates underlying these attentional functions in unmedicated, high-functioning adults with ASD (n = 12) and matched healthy controls (HC, n = 12). Compared with HC, individuals with ASD showed increased error rates in alerting and executive control, accompanied by lower activity in the mid-frontal gyrus and the caudate nucleus for alerting, and by the absence of significant functional activation in the anterior cingulate cortex (ACC) for executive control. In addition, greater behavioral deficiency in executive control in ASD was correlated with less functional activation of the ACC. These findings of behavioral and neural abnormalities in alerting and executive control of attention in ASD may suggest core attentional deficits, which require further investigation.
PMCID: PMC3489817  PMID: 23139910
Alerting; anterior cingulate cortex; attentional networks; autism; executive control

Results 1-9 (9)