NIMH Intramural Research Program

Bethesda, MD, United States

NIMH Intramural Research Program

Bethesda, MD, United States
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Murphy D.L.,NIMH Intramural Research Program | Moya P.R.,NIMH Intramural Research Program
Current Opinion in Pharmacology | Year: 2011

Recent major findings from studies of SLC6A4 and its corresponding protein, the serotonin (5-HT) transporter (SERT) in humans, rodents and non-human primates indicate that combinations of SLC6A4 non-coding 5′, 3′ UTRs and intronic regions plus coding variants acting together can change 5HT transport as much as 40-fold in vitro. In vivo, SLC6A4 variants in humans and other species lead to marked physiological changes, despite mitigating neurodevelopmental adaptations in 5-HT receptors plus compensatory alterations in 5-HT synthesis and metabolism. Polymorphisms in SLC6A4 are associated with differences in emotional, endocrine, and personality characteristics as well as many diseases. This gene, in combinations with gene × gene (G × G) and gene × environment (G × E) interactions nonetheless remains incompletely understood, with some association findings remaining controversial. Considering its primary importance in the regulation and function of the entire serotonergic system (as evidenced by the consequences of SERT-mediated reuptake inhibition by SRIs like fluoxetine in humans and of genetically engineered changes in mice and rats), it seems likely that SLC6A4 and SERT will remain areas of high interest in our field's attempts to better understand and treat 5-HT-related disorders. © 2011 Elsevier Ltd. All rights reserved.

Denayer E.,Catholic University of Leuven | Stewart D.R.,U.S. National Cancer Institute | Keymolen K.,University Hospital Brussels | Plasschaert E.,Catholic University of Leuven | And 6 more authors.
American Journal of Medical Genetics, Part C: Seminars in Medical Genetics | Year: 2011

Legius syndrome is a RAS-MAPK syndrome characterized by pigmentary findings similar to neurofibromatosis type 1 (NF1), but without tumor complications. Learning difficulties and behavioral problems have been reported to be associated with Legius syndrome, but have not been studied systematically. We investigated intelligence and behavior in 15 patients with Legius syndrome and 7 unaffected family members. We report a mean full-scale IQ of 101.57 in patients with Legius syndrome, which does not differ from the control group. We find a significantly lower Performance IQ in children with Legius syndrome compared to their unaffected family members. Few behavioral problems are present as assessed by the Child Behavior Checklist (CBCL) questionnaire. Our observations suggest that, akin to the milder somatic phenotype, the cognitive phenotype in Legius syndrome is less severe than that of NF1. © 2011 Wiley-Liss, Inc.

Murphy D.L.,NIMH Intramural Research Program | Timpano K.R.,Massachusetts General Hospital | Wheaton M.G.,University of North Carolina at Chapel Hill | Greenberg B.D.,Butler University | Miguel E.C.,University of Sao Paulo
Dialogues in Clinical Neuroscience | Year: 2010

Obsessive-compulsive disorder (OCD) is a clinical syndrome whose hallmarks are excessive, anxiety-evoking thoughts and compulsive behaviors that are generally recognized as unreasonable, but which cause significant distress and impairment. When these are the exclusive symptoms, they constitute uncomplicated OCD. OCD may also occur in the context of other neuropsychiatric disorders, most commonly other anxiety and mood disorders. The question remains as to whether these combinations of disorders should be regarded as independent, cooccurring disorders or as different manifestations of an incompletely understood constellation of OCD spectrum disorders with a common etiology. Additional considerations are given here to two potential etiology-based subgroups: (i) an environmentally based group in which OCD occurs following apparent causal events such as streptococcal infections, brain injury, or atypical neuroleptic treatment; and (ii) a genomically based group in which OCD is related to chromosomal anomalies or specific genes. Considering the status of current research, the concept of OCD and OCD-related spectrum conditions seems fluid in 2010, and in need of ongoing reappraisal. © 2010, LLS SAS. All rights reserved.

Correia S.,Brown University | Hubbard E.,Oregon Health And Science University | Hassenstab J.,Brown University | Yip A.,Brown University | And 5 more authors.
Brain Imaging and Behavior | Year: 2010

Dysfunction in circuits linking frontal cortex and basal ganglia (BG) is strongly implicated in obsessive-compulsive disorder (OCD). On MRI studies, neuropsychiatric disorders with known BG pathology have abnormally short T2 relaxation values (a putative biomarker of elevated iron) in this region. We asked if BG T2 values are abnormal in OCD. We measured volume and T2 and T1 relaxation rates in BG of 32 adults with OCD and 33 matched controls. There were no group differences in volume or T1 values in caudate, putamen, or globus pallidus (GP). The OCD group had lower T2 values (suggesting higher iron content) in the right GP, with a trend in the same direction for the left GP. This effect was driven by patients whose OCD symptoms began from around adolescence to early adulthood. The results suggest a possible relationship between age of OCD onset and iron deposition in the basal ganglia. © 2009 Springer Science+Business Media, LLC.

Massey S.H.,Northwestern University | Estabrook R.,Northwestern University | O'Brien T.C.,Illinois College | Pine D.S.,NIMH Intramural Research Program | And 4 more authors.
Neuroscience Letters | Year: 2015

Prenatal smoking cessation has been described as an empathic action "for the baby," but this has not been empirically demonstrated. We capitalized on a genetically-characterized extant dataset with outstanding measurement of prenatal smoking patterns and maternal face processing data (as an indicator of empathy) to test this hypothesis, and explore how empathy and smoking patterns may be moderated by a genetic substrate of empathy, the oxytocin receptor gene (OXTR). Participants were 143Caucasian women from the East Boston family study with repeated prospective reports of smoking level, adjusted based on repeated cotinine bioassays. Salivary DNA and face processing (Diagnostic Analysis of Nonverbal Accuracy-2) were assessed 14 years later at an adolescent follow-up of offspring. Two-thirds of participants reported smoking prior to pregnancy recognition. Of these, 21% quit during pregnancy; 56% reduced smoking, and 22% smoked persistently at the same level. A significant interaction between face processing and OXTR variants previously associated with increased sensitivity to social context, rs53576GG and rs2254298A, was found ( β= -181; p=015); greater ability to identify distress in others was associated with lower levels of smoking during pregnancy for rs53576(GG)/rs2254298(A) individuals ( p=013), but not for other genotypes ( p=892). Testing this "empathy hypothesis of prenatal smoking cessation" in larger studies designed to examine this question can elucidate whether interventions to enhance empathy can improve prenatal smoking cessation rates. © 2014 Elsevier Ireland Ltd.

Jenewein J.,University of Zürich | Moergeli H.,University of Zürich | Sprott H.,University of Zürich | Honegger D.,University of Zürich | And 9 more authors.
European Journal of Pain (United Kingdom) | Year: 2013

Background: Fibromyalgia syndrome (FMS) is frequently associated with psychiatric conditions, particularly anxiety. Deficits in contingency learning during fear conditioning have been hypothesized to increase anxiety and, consequently, pain sensation in susceptible individuals. The goal of this study was to examine the relationship between contingency learning and pain experience in subjects with FMS and rheumatoid arthritis (RA). Methods: Fourteen female FMS subjects, 14 age-matched female RA subjects and 14 age-matched female healthy controls (HCs) were included in a fear-conditioning experiment. The conditioned stimulus (CS) consisted of visual signs, the unconditioned stimulus (US) of thermal stimuli. CS- predicted low-temperature exposure (US), while CS+ was followed by low or high temperature. Results: In the FMS group, only 50% of the subjects were aware of the US-CS contingency, whereas 86% of the RA subjects and all of the HCs were aware of the contingency. CS+ induced more anxiety than CS- in RA subjects and HCs. As expected, low-temperature exposure was experienced as less painful after CS- than after CS+ in these subjects. FMS subjects did not show such adaptive conditioning. The effects of the type of CS on heart rate changes were significant in the HCs and the aware FMS subjects, but not in the unaware FMS subjects. Conclusions: Contingency learning deficits represent a potentially promising and specific, but largely unstudied, psychopathological factor in FMS. Deficits in contingency learning may increase anxiety and, consequently, pain sensation. These findings have the potential to contribute to the development of novel therapeutic approaches for FMS. © 2013 European Federation of International Association for the Study of Pain Chapters.

Thapar A.,University of Cardiff | Collishaw S.,University of Cardiff | Pine D.S.,NIMH Intramural Research Program | Thapar A.K.,University of Cardiff
The Lancet | Year: 2012

Unipolar depressive disorder in adolescence is common worldwide but often unrecognised. The incidence, notably in girls, rises sharply after puberty and, by the end of adolescence, the 1 year prevalence rate exceeds 4. The burden is highest in low-income and middle-income countries. Depression is associated with substantial present and future morbidity, and heightens suicide risk. The strongest risk factors for depression in adolescents are a family history of depression and exposure to psychosocial stress. Inherited risks, developmental factors, sex hormones, and psychosocial adversity interact to increase risk through hormonal factors and associated perturbed neural pathways. Although many similarities between depression in adolescence and depression in adulthood exist, in adolescents the use of antidepressants is of concern and opinions about clinical management are divided. Effective treatments are available, but choices are dependent on depression severity and available resources. Prevention strategies targeted at high-risk groups are promising. © 2012 Elsevier Ltd.

Wakschlag L.S.,University of Illinois at Chicago | Kistner E.O.,University of Chicago | Pine D.S.,NIMH Intramural Research Program | Biesecker G.,University of Illinois at Chicago | And 10 more authors.
Molecular Psychiatry | Year: 2010

Genetic susceptibility to antisocial behavior may increase fetal sensitivity to prenatal exposure to cigarette smoke. Testing putative gene × exposure mechanisms requires precise measurement of exposure and outcomes. We tested whether a functional polymorphism in the gene encoding the enzyme monoamine oxidase A (MAOA) interacts with exposure to predict pathways to adolescent antisocial behavior. We assessed both clinical and information-processing outcomes. One hundred seventy-six adolescents and their mothers participated in a follow-up of a pregnancy cohort with well-characterized exposure. A sex-specific pattern of gene × exposure interaction was detected. Exposed boys with the low-activity MAOA 5′ uVNTR (untranslated region variable number of tandem repeats) genotype were at increased risk for conduct disorder (CD) symptoms. In contrast, exposed girls with the high-activity MAOA uVNTR genotype were at increased risk for both CD symptoms and hostile attribution bias on a face-processing task. There was no evidence of a gene-environment correlation (rGE). Findings suggest that the MAOA uVNTR genotype, prenatal exposure to cigarettes and sex interact to predict antisocial behavior and related information-processing patterns. Future research to replicate and extend these findings should focus on elucidating how gene × exposure interactions may shape behavior through associated changes in brain function. © 2010 Macmillan Publishers Limited All rights reserved.

Emery A.C.,National Health Research Institute | Eiden M.V.,NIMH Intramural Research Program | Mustafa T.,National Health Research Institute | Eiden L.E.,National Health Research Institute
Science Signaling | Year: 2013

G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor (GPCR)-mediated increases in the second messenger cyclic adenosine monophosphate (cAMP) activate the mitogenactivated protein kinase (MAPK) extracellular signal-regulated kinase (ERK), and in neuroendocrine cells, this pathway leads to cAMP-dependent neuritogenesis mediated through Rap1 and B-Raf. We found that the Rap guanine nucleotide exchange factor Rapgef2 was enriched from primary bovine neuroendocrine cells by cAMP-agarose affinity chromatography and that it was specifically eluted by cAMP. With loss-offunction experiments in the rat neuronal cell line Neuroscreen-1 (NS-1) and gain-of-function experiments in human embryonic kidney 293T cells, we demonstrated that Rapgef2 connected GPCR-dependent activation of adenylate cyclase and increased cAMP concentration with the activation of ERK in neurons and endocrine cells. Furthermore, knockdown of Rapgef2 blocked cAMP-and ERK-dependent neuritogenesis. Our data are consistent with a pathway involving the cAMP-mediated activation of Rapgef2, which then stimulates Rap1, leading to increases in B-Raf, MEK, and ERK activity. © 2013 American Association for the Advancement of Science. All Rights Reserved.

PubMed | International Psychoanalytic University, University of Zürich, University of Bern and NIMH Intramural Research Program
Type: Journal Article | Journal: The journal of pain : official journal of the American Pain Society | Year: 2016

There is growing evidence that fear-learning abnormalities are involved in the development of posttraumatic stress disorder (PTSD) and chronic pain. More than 50% of PTSD patients suffer from chronic pain. This study aimed to examine the role of fear-learning deficits in the link between pain perception and PTSD. We included 19 subjects with PTSD and 21 age- and sex-matched healthy control subjects in a fear-conditioning experiment. The conditioned stimulus (CS) consisted of visual signs flashed upon a screen in front of each subject. The unconditioned stimulus was either a low or high temperature impulse delivered through a thermal contact thermode on the subjects hand. A designation of CS- was assigned to CS always followed by nonpainful low-temperature stimuli; a designation of CS+ was given to CS that were randomly followed by either a low or a more painful high temperature. Skin conductance was used as a physiological marker of fear. In healthy control subjects, CS+induced more fear than CS-, and a low-temperature stimulus induced less subjective pain after CS- than after CS+. PTSD subjects failed to demonstrate such adaptive conditioning. Fear ratings after CS presentation were significantly higher in the PTSD group than in the control group. There were significant interaction effects between group and the type of CS on fear and pain ratings. Fear-learning deficits are a potentially promising, specific psychopathological factor in altered pain perception associated with PTSD. Deficits in safety learning may increase fear and, consequently, pain sensations. These findings may contribute to elucidating the pathogenesis behind the highly prevalent comorbidity that exists between PTSD and pain disorders, and to developing new treatments.This study provides new insights into the pathogenesis of chronic pain in patients with PTSD. The findings may help to develop new treatment strategies for this highly prevalent comorbidity in PTSD.

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