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1.  Exogenous Glucocorticoids Decrease Subgenual Cingulate Activity Evoked by Sadness 
Neuropsychopharmacology  2013;38(5):826-845.
The glucocorticoid hormone cortisol is known to have wide-ranging effects on a variety of physiological systems, including the morphology and physiology of the amygdala and hippocampus. Disruptions of cortisol regulation and signaling are also linked with psychiatric disorders involving emotional disturbances. Although there is much evidence to suggest a relationship between cortisol signaling and the brain physiology underlying emotion, few studies have attempted to test for direct effects of cortisol on the neurophysiology of emotion. We administered exogenous synthetic cortisol (hydrocortisone, HCT) using two different dosing regimens (25 mg/day over 4 days, 100 mg single dose), in a double-blind placebo-controlled functional magnetic resonance imaging (fMRI) study. During fMRI scanning, healthy subjects viewed images designed to induce happy, sad, and neutral emotional states. Subjective emotional reactions were collected for each experimental stimulus after fMRI scanning. Mood ratings were also collected throughout the 4 days of the study. Both dose regimens of HCT resulted in decreased subgenual cingulate activation during sadness conditions. The 25 mg/day regimen also resulted in higher arousal ratings of sad stimuli. No effects of HCT were observed on any mood ratings. Few reliable effects of HCT were observed on brain activity patterns or subjective emotional responses to stimuli that were not sad. The inhibitory effects of cortisol on sadness-induced subgenual cingulate activity may have critical relevance to the pathophysiology of major depression, as both subgenual hyperactivity and decreased sensitivity to cortisol signaling have been documented in patients with depression.
PMCID: PMC3599059  PMID: 23303057
cortisol; emotion; fMRI; glucocorticoids; corticosteroids; subgenual; Imaging; Clinical or Preclinical; Neuroendocrinology; Psychopharmacology; Neurophysiology; Cortisol; Emotion; fMRI; Glucocorticoids; Corticosteroids
2.  Chronic medication does not affect hyperactive error responses in obsessive-compulsive disorder 
Psychophysiology  2010;47(5):913-920.
Patients with obsessive-compulsive disorder (OCD) show an increased error-related negativity (ERN), yet previous studies have not controlled for medication use, which may be important given evidence linking performance monitoring to neurotransmitter systems targeted by treatment, such as serotonin. In an examination of 19 unmedicated OCD patients, 19 medicated OCD patients, 19 medicated patient controls without OCD, and 21 unmedicated healthy controls, we found greater ERNs in OCD patients than in controls, irrespective of medication use. Severity of generalized anxiety and depression was associated with ERN amplitude in controls but not patients. These data confirm previous findings of an exaggerated error response in OCD, further showing that it cannot be attributed to medication. The absence in patients of a relationship between ERN amplitude and anxiety/depression, as was found in controls, suggests that elevated error signals in OCD may be disorder-specific.
PMCID: PMC3928597  PMID: 20230510
Error-related negativity (ERN); Event-related potentials (ERPs); Anxiety; Anterior cingulate cortex (ACC)
3.  Cannabinoid facilitation of fear extinction memory recall in humans 
Neuropharmacology  2012;64(1):396-402.
A first-line approach to treat anxiety disorders is exposure-based therapy, which relies on extinction processes such as repeatedly exposing the patient to stimuli (conditioned stimuli; CS) associated with the traumatic, fear-related memory. However, a significant number of patients fail to maintain their gains, partly attributed to the fact that this inhibitory learning and its maintenance is temporary and conditioned fear responses can return. Animal studies have shown that activation of the cannabinoid system during extinction learning enhances fear extinction and its retention. Specifically, CB1 receptor agonists, such as Δ9-tetrahydrocannibinol (THC), can facilitate extinction recall by preventing recovery of extinguished fear in rats. However, this phenomenon has not been investigated in humans. We conducted a study using a randomized, double-blind, placebo-controlled, between-subjects design, coupling a standard Pavlovian fear extinction paradigm and simultaneous skin conductance response (SCR) recording with an acute pharmacological challenge with oral dronabinol (synthetic THC) or placebo (PBO) 2 hours prior to extinction learning in 29 healthy adult volunteers (THC = 14; PBO = 15) and tested extinction retention 24 hours after extinction learning. Compared to subjects that received PBO, subjects that received THC showed low SCR to a previously extinguished CS when extinction memory recall was tested 24 hours after extinction learning, suggesting that THC prevented the recovery of fear. These results provide the first evidence that pharmacological enhancement of extinction learning is feasible in humans using cannabinoid system modulators, which may thus warrant further development and clinical testing.
PMCID: PMC3445738  PMID: 22796109
4.  CRH-stimulated cortisol release and food intake in healthy, non-obese adults 
Psychoneuroendocrinology  2009;35(4):607-612.
There is considerable anecdotal and some scientific evidence that stress triggers eating behavior, but underlying physiological mechanisms remain uncertain. The hypothalamic-pituitary-adrenal (HPA) axis is a key mediator of physiological stress responses and may play a role in the link between stress and food intake. Cortisol responses to laboratory stressors predict consumption but it is unclear whether such responses mark a vulnerability to stress-related eating or whether cortisol directly stimulates eating in humans.
We infused healthy adults with corticotropin-releasing hormone (CRH) at a dose that is subjectively undetectable but elicits a robust endogenous cortisol response, and measured subsequent intake of snack foods, allowing analysis of HPA reactivity effects on food intake without the complex psychological effects of a stress paradigm.
CRH elevated cortisol levels relative to placebo but did not impact subjective anxious distress. Subjects ate more following CRH than following placebo and peak cortisol response to CRH was strongly related to both caloric intake and total consumption.
These data show that HPA axis reactivity to pharmacological stimulation predicts subsequent food intake and suggest that cortisol itself may directly stimulate food consumption in humans. Understanding the physiological mechanisms that underlie stress-related eating may prove useful in efforts to attack the public health crises created by obesity.
PMCID: PMC2843773  PMID: 19828258
stress; cortisol; CRH; appetite; HPA
5.  Cognitive modulation of endocrine responses to CRH stimulation in healthy subjects 
Psychoneuroendocrinology  2009;35(3):451-459.
The hypothalamic-pituitary adrenal (HPA) axis is critical for biobehavioral adaptation to challenge and appears dysregulated in a range of psychiatric disorders. Its precise role in psychopathology remains unclear and discrepant and difficult to explain findings abound in the clinical literature. Basic research suggests this system is sensitive to psychosocial cues, but psychosocial milieu factors are rarely controlled or examined in psychiatric studies using biological probes of the HPA axis. To test the hypothesis that psychological factors might complicate HPA study results even in direct, pharmacological challenge paradigms, endocrine responses to corticotropin-releasing hormone (CRH) were examined under two different cognitive preparation conditions.
Healthy subjects (n=32) received standard instructions or a cognitive intervention (CI) prior to injection with CRH and placebo, given on separate days in random order. The CI combined access to control over drug exposure with novelty reduction and coping enhancement. Blood samples were obtained via intravenous catheter before and after CRH.
Cognitive intervention reduced corticotropin (ACTH) levels, but only when CRH was given first (intervention by order interaction). It did not reduce cortisol response. The CI and visit (1st or 2nd) both impacted cortisol levels on placebo day.
Modifiable psychological factors may amplify or inhibit HPA axis activity in pharmacological activation paradigms, including CRH stimulation tests. The factors manipulated by the CI (novelty/familiarity, control and coping) may have particular salience to the HPA axis. Differential sensitivity to such factors could impact results in studies applying biological HPA probes to psychiatric populations.
PMCID: PMC2824051  PMID: 19758763
stress; cortisol; ACTH, corticotropin-releasing hormone; control; coping
6.  Effects of perceived control and cognitive coping on endocrine stress responses to pharmacological activation 
Biological psychiatry  2008;64(8):701-707.
The hypothalamic-pituitary adrenal (HPA) axis may mediate negative health effects of stress. It is sensitive to cognitive/emotional factors like novelty, perceived control and coping. Psychological intervention that reduces novelty, and enhances cognitive coping and sense of control can reduce cortisol responses to pentagastrin, a pharmacological HPA activator. This study attempted to identify the core factors that modulate HPA axis activity in this model.
Varying instructions were administered prior to drug exposure in a two-visit (placebo first) pentagastrin infusion paradigm. Healthy subjects (n=40) were randomly assigned to 1 of 4 instruction groups: (1) Standard instruction (SI); (2) Full cognitive intervention (CI); (3) The CI control component alone; or (4) The CI novelty reduction/coping components alone. Blood samples were obtained via intravenous catheter before and after pentagastrin.
Subjects receiving an intervention had smaller cortisol responses than subjects receiving standard instructions. “Coping” alone had as strong an impact as the more complex intervention that combined “coping” and “control.” “Control alone” also reduced cortisol but its HPA impact appeared less robust.
Brief psychological manipulation can significantly reduce HPA activation in challenge paradigms. Cognitive preparation that focused on side effects, reduced potential surprise and enhanced cognitive coping modulated HPA axis activity as effectively as a previously tested intervention that combined coping and control manipulations. A sense of control alone also reduced cortisol release. The results support development of “control” or “coping” techniques to combat negative health effects of stress that are mediated by HPA axis activation.
PMCID: PMC2579765  PMID: 18571624
stress; cortisol; pentagastrin; control; coping; anxiety
7.  Beyond Anxious Predisposition: Do Padecer de Nervios and Ataque de Nervios Add Incremental Validity to Predictions of Current Distress among Mexican Mothers? 
Depression and Anxiety  2011;29(1):23-31.
Nervios (PNRV) and ataque de nervios (ATQ) are culture-bound syndromes with overlapping symptoms of anxiety, depression, and dissociation, shown to have inconsistent associations to psychiatric disorder. Few studies test the basic assumption that PNRV and ATQ are uniformly linked to distress outcomes across Latina/o immigrant groups. This study examined: (a) the extent to which acculturative stress, Latino/U.S. American acculturation, and anxious predisposition were associated with lifetime history of ATQ and PNRV, and (b) the extent to which ATQ and PNRV add incremental validity in explaining acculturative stress and psychological distress beyond measures of anxious predisposition.
Participants (n = 82) included Mexican mothers who completed surveys on acculturation, trait anxiety, anxiety sensitivity, lifetime ATQ/PNRV, psychological distress, and acculturative stress.
Lifetime PNRV, but not lifetime ATQ, was significantly predictive of psychological distress. PNRV was also linked to trait anxiety. Psychometric measures of anxious predisposition (trait anxiety, anxiety sensitivity) were more robust predictors of distress outcomes than lifetime history of ATQ/PNRV.
Inquiry into lifetime history of nervios may be a useful point of entry in talking to Mexican immigrant mothers about stress and distress. However, standard tools for assessing anxiety sensitivity and trait anxiety appear most useful in identifying and explaining presence of psychological distress. Further research is needed to determine the cross-cultural relevance of trait anxiety and anxiety sensitivity, and its implications for the development of anxiety treatments that are effective across cultures.
PMCID: PMC3209491  PMID: 21769996
anxiety sensitivity; culture-bound syndrome; nervios; Latinos; clinical utility
8.  Developmental alterations of frontal-striatal-thalamic connectivity in obsessive compulsive disorder 
Pediatric obsessive-compulsive disorder is characterized by abnormalities of frontal-striatalthalamic circuitry that appear near illness onset and persist over its course. Distinct frontal-striatal-thalamic loops through cortical centers for cognitive control (anterior cingulate cortex) and emotion processing (ventral medial frontal cortex) follow unique maturational trajectories, and altered connectivity within distinct loops may be differentially associated with OCD at specific stages of development.
Altered development of striatal and thalamic connectivity to medial frontal cortex was tested in 60 OCD patients compared to 61 healthy controls at child, adolescent and adult stages of development, using resting state functional connectivity MRI.
OCD in the youngest patients was associated with reduced connectivity of dorsal striatum and medial dorsal thalamus to rostral and dorsal anterior cingulate cortex, respectively. Increased connectivity of dorsal striatum to ventral medial frontal cortex was observed in patients at all developmental stages. In child patients, reduced connectivity between dorsal striatum and rostral anterior cingulate cortex correlated with OCD severity.
Frontal-striatal-thalamic loops involved in cognitive control are hypoconnected in young patients near illness onset, while loops implicated in emotion-processing are hyperconnected throughout the illness.
PMCID: PMC3167379  PMID: 21871375
obsessive compulsive disorder; frontal-striatal-thalamic; medial frontal cortex; resting state connectivity; development
9.  Resting-State Functional Connectivity between Fronto-Parietal and Default Mode Networks in Obsessive-Compulsive Disorder 
PLoS ONE  2012;7(5):e36356.
Obsessive-compulsive disorder (OCD) is characterized by an excessive focus on upsetting or disturbing thoughts, feelings, and images that are internally-generated. Internally-focused thought processes are subserved by the “default mode network" (DMN), which has been found to be hyperactive in OCD during cognitive tasks. In healthy individuals, disengagement from internally-focused thought processes may rely on interactions between DMN and a fronto-parietal network (FPN) associated with external attention and task execution. Altered connectivity between FPN and DMN may contribute to the dysfunctional behavior and brain activity found in OCD.
The current study examined interactions between FPN and DMN during rest in 30 patients with OCD (17 unmedicated) and 32 control subjects (17 unmedicated). Timecourses from seven fronto-parietal seeds were correlated across the whole brain and compared between groups.
OCD patients exhibited altered connectivity between FPN seeds (primarily anterior insula) and several regions of DMN including posterior cingulate cortex, medial frontal cortex, posterior inferior parietal lobule, and parahippocampus. These differences were driven largely by a reduction of negative correlations among patients compared to controls. Patients also showed greater positive connectivity between FPN and regions outside DMN, including thalamus, lateral frontal cortex, and somatosensory/motor regions.
OCD is associated with abnormal intrinsic functional connectivity between large-scale brain networks. Alteration of interactions between FPN and DMN at rest may contribute to aspects of the OCD phenotype, such as patients' inability to disengage from internally-generated scenarios and thoughts when performing everyday tasks requiring external attention.
PMCID: PMC3343054  PMID: 22570705
10.  Hyperactive error responses and altered connectivity in ventromedial and fronto-insular cortices in obsessive-compulsive disorder 
Biological psychiatry  2010;69(6):583-591.
Patients with obsessive compulsive disorder (OCD) show abnormal functioning in ventral frontal brain regions involved in emotional/motivational processes, including anterior insula/frontal operculum (aI/fO) and ventromedial frontal cortex (VMPFC). While OCD has been associated with an increased neural response to errors, the influence of motivational factors on this effect remains poorly understood.
To investigate the contribution of motivational factors to error processing in OCD, and to examine functional connectivity between regions involved in the error response, functional magnetic resonance imaging data were measured in 39 OCD patients (20 unmedicated, 19 medicated) and 38 control subjects (20 unmedicated, 18 medicated) during an error-eliciting interference task where motivational context was varied using monetary incentives (null, loss, and gain).
Across all errors, OCD patients showed reduced deactivation of VMPFC and greater activation in left aI/fO as compared to controls. For errors specifically resulting in a loss, patients further hyperactivated VMPFC as well as right aI/fO. Independent of activity associated with task events, OCD patients showed greater functional connectivity between VMPFC and regions of bilateral aI/fO and right thalamus.
OCD patients show greater activation in neural regions associated with emotion and valuation when making errors, which could be related to altered intrinsic functional connectivity between brain networks. These results highlight the importance of emotional/motivational responses to mistakes in OCD, and point to the need for further study of network interactions in the disorder.
PMCID: PMC3059508  PMID: 21144497
fMRI; performance monitoring; anxiety; default mode; salience network; functional coupling
11.  Naturalistic Stress and Cortisol Response to Awakening: Adaptation to Seafaring 
Psychoneuroendocrinology  2008;33(7):1023-1026.
Study of the hypothalmic-pituitary adrenal (HPA) axis has been critical to advancing our understanding of human adaptation to stress. The cortisol response to awakening (CRA) is a potentially useful measure for understanding group and individual differences in HPA axis regulation. In this study, the CRA was examined in the context of a naturalistic stressor – a six-week voyage of work and study aboard an oceangoing ship, including both experienced and novice sailors. Thirty-one subjects provided weekday and weekend baseline CRA data onshore prior to boarding, followed by three CRAs at sea and one shore leave CRA. Subjective measures of sleep, stress and control were also collected. Results suggest that novice sailors' cortisol response to awakening was elevated at sea relative to both a shoreside weekend and a shore leave during the voyage, but the most striking elevation was found during a workday onshore. Inexperienced students' profiles changed differently over the course of the voyage from those of professional crew. CRAs were not affected by sleep variables and were not predicted by subjective ratings. These data support the value of the cortisol response to awakening as a neuroendocrine marker of HPA regulatory responses to a naturalistic stressor, influenced by changes in work and living environment, and perhaps prior experience with the stressor.
PMCID: PMC2562531  PMID: 18657911
cortisol response to awakening; stress; naturalistic stressors; HPA axis

Results 1-11 (11)