Alexander Neumeister

Johns Hopkins University, Baltimore, Maryland, United States

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Publications (193)797.47 Total impact

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    ABSTRACT: Cognitive theories implicate information-processing biases in the etiology of anxiety disorders. Results of attention-bias studies in posttraumatic stress disorder (PTSD) have been inconsistent, suggesting biases towards and away from threat. Within-subject variability of attention biases in posttraumatic patients may be a useful marker for attentional control impairment and the development of posttrauma symptoms. This study reports 2 experiments investigating threat-related attention biases, mood and anxiety symptoms, and attention-bias variability following trauma. Experiment 1 included 3 groups in a cross-sectional design: (a) PTSD, (b) trauma-exposed without PTSD, and (c) healthy controls with no trauma or Axis I diagnoses. Greater attention-bias variability was found in the PTSD group compared to the other 2 groups ; attention-bias variability was significantly and positively correlated (r = .37) with PTSD symptoms. Experiment 2 evaluated combat-exposed and nonexposed soldiers before and during deployment. Attention-bias variability did not differentiate groups before deployment, but did differentiate groups during deployment ; increased variability was observed in groups with acute posttraumatic stress symptoms and acute depression symptoms only. Attention-bias variability could be a useful marker for attentional impairment related to threat cues associated with mood and anxiety symptoms after trauma exposure.
    Journal of Traumatic Stress 03/2014; · 2.72 Impact Factor
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    ABSTRACT: Background Posttraumatic stress disorder (PTSD) is characterized by heterogeneous clusters of re-experiencing, avoidance, numbing, and hyperarousal symptoms. However, data are lacking regarding the predominant, population-based typologies of this disorder, and how they are linked to trauma-related characteristics, psychiatric comorbidities, and health-related quality of life. Methods We used latent class analyses (LCAs) to evaluate predominant typologies of PTSD in a nationally representative sample of 2463 U.S. adults with PTSD. Multinomial logistic regression analyses were then conducted to evaluate trauma-related characteristics, psychiatric comorbidities, and health-related quality of life variables associated with these typologies. Results LCAs revealed three predominant typologies of PTSD—Anxious-Re-experiencing (weighted prevalence=32.2%), Dysphoric (32.8%), and High Symptom (35.0%). Compared to the Dysphoric class, the Anxious-Re-experiencing and High Symptom classes were more likely to report sexual assault, physical assault, and military combat as their worst traumatic events; had an earlier age of onset and longer duration of PTSD; and were more likely to be diagnosed with nicotine dependence and borderline personality disorder, to have attempted suicide, and had poorer physical health-related quality of life (HRQoL). The High Symptom class had increased odds of all disorders, suicide attempts, and the poorest HRQoL. Limitations Diagnoses were based on DSM-IV criteria and cross-sectional analyses preclude examination of how PTSD typologies are temporally related to other variables. Conclusion PTSD in the general U.S. adult population is characterized by three predominant typologies, which are differentially linked to trauma and clinical characteristics. These findings underscore the importance of personalized approaches to the assessment, monitoring, and treatment of PTSD that take into consideration the heterogeneous manifestations of this disorder.
    Journal of Affective Disorders 01/2014; 162:102-106. · 3.30 Impact Factor
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    ABSTRACT: Introduction Recent confirmatory factor analytic studies of the dimensional structure of posttraumatic stress disorder (PTSD) suggest that this disorder may be best characterized by five symptom dimensions—re-experiencing, avoidance, numbing, dysphoric arousal, and anxious arousal. Hypothalamic-pituitary-adrenal (HPA) axis dysregulation in PTSD and has been attributed to enhanced glucocorticoid responsiveness. However, little is known about how altered HPA-axis function is related to this contemporary phenotypic model of PTSD. Methods We compared morning plasma cortisol levels of drug-free civilian adults with PTSD (N = 29) to trauma-exposed (TC; N = 12) and non-trauma-exposed healthy controls (HC; N = 23). We then examined the relation between cortisol levels and a contemporary 5-factor ‘dysphoric arousal’ model of PTSD symptoms among individuals with PTSD. Results After adjustment for white race/ethnicity, education, lifetime alcohol use disorder, and current smoking status, the PTSD (Cohen's d = 1.1) and TC (Cohen's d = 1.3) groups had significantly lower cortisol levels than the HC group; cortisol levels did not differ between the TC and PTSD groups. Except for age (r = −.46), none of the other demographic, trauma-related, or clinical variables, including lifetime mood/anxiety disorder and severity of current depressive and anxiety symptoms, were associated with cortisol levels. In a stepwise linear regression analysis, age (β = −.44) and severity of emotional numbing symptoms (β = −.35) were independently associated with cortisol levels in the PTSD group; none of the other PTSD symptom clusters or depression symptoms were significant. Post hoc analyses revealed that severity of the emotional numbing symptom of restricted range of affect (i.e., unable to have loving feelings) was independently related to cortisol levels (β = −.35). Conclusion These results suggest that trauma-exposed civilian adults with and without PTSD have significantly lower cortisol levels compared to healthy, non-trauma-exposed adults. They further suggest that low cortisol levels among adults with PTSD may be specifically linked to emotional numbing symptomatology that is unique to the PTSD phenotype and unrelated to depressive symptoms.
    Psychoneuroendocrinology 01/2014; 39:88–93. · 5.14 Impact Factor
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    ABSTRACT: Preclinical evidence implicates the serotonin receptor 5-hydroxytryptamine 1B (5-HT1B) in the effects of cocaine. This study explores 5-HT1B in humans by examining receptor availability in vivo in subjects whose primary addiction is cocaine dependence (CD) using positron emission tomography. Study participants included 14 medically healthy subjects with CD (mean age = 41 ± 6 years) who were compared with 14 age-matched healthy control subjects (mean age = 41 ± 8 years) with no past or current history of cocaine or other illicit substance abuse. Participants underwent magnetic resonance imaging followed by positron emission tomography with the highly selective 5-HT1B tracer, [(11)C]P943, for purposes of quantifying regional binding potential. Voxel-based morphometry and gray matter masking also were employed to control for potential partial volume effects. The [(11)C]P943 positron emission tomography imaging data in nine candidate regions (amygdala, anterior cingulate cortex, caudate, frontal cortex, hypothalamus, pallidum, putamen, thalamus, and ventral striatum) showed significant or nearly significant reductions of regional binding potential in subjects with CD in three regions: anterior cingulate (-16%, p < .01), hypothalamus (-16%, p = .03), and frontal cortex (-7%, p = .08). Voxel-based morphometry showed significant gray matter reductions in the frontal cortex of subjects with CD. After gray matter masking, statistically significant reductions in the [(11)C]P943 regional binding potential were either retained (anterior cingulate, -14%, p = .01; hypothalamus, -20%, p < .01) or achieved (frontal cortex, -14%, p < .01). Whole-brain voxel-wise parameter estimation confirmed these results. Secondary analyses were also significant in some regions for years of cocaine and daily tobacco use. The reductions found in this study suggest that 5-HT1B receptors may contribute to the etiology or expression of CD and potentially represent a target for medication development.
    Biological psychiatry 11/2013; · 8.93 Impact Factor
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    ABSTRACT: Noradrenergic dysfunction is implicated in obesity. The norepinephrine transporter (NET) regulates the synaptic availability of norepinephrine. However, NET availability has not been previously characterized in vivo in obese people using Positron Emission Tomography (PET) imaging. Here we report findings evaluating NET availability in individuals with obesity and matched lean (i.e., normal weight) comparison subjects. Seventeen obese but otherwise healthy individuals with a mean±SD body mass index (BMI) of 34.7±2.6 and 17 lean individuals with a mean±SD BMI of 23.1±1.4 were studied using a High-Resolution Research Tomograph (HRRT) and (S,S)-[(11)C]O-methylreboxetine ([(11)C]-MRB), a radioligand selective for the NET. The regional brain NET binding potential (BPND) was estimated by the multilinear reference tissue model 2 (MRTM2) with the occipital cortex as a reference region. BPND for regions of interest were obtained with the Automated Anatomic Labeling (AAL) template registered to individual's structural MR scans. Obese individuals had lower NET BPND values in the thalamus (p<0.038, 27% reduction) including within the pulvinar (p<0.083, 30% reduction), but not in the hypothalamus, locus coeruleus or the raphe nuclei, compared to lean individuals. When age was included as a covariate, the difference in NET BPND values remained significant in the thalamus (p<0.025) and pulvinar (p<0.042). These results indicate that NET availability is decreased in the thalamus, including the pulvinar, in obese individuals. These findings further support data indicating noradrenergic dysfunction in obesity and suggest impaired NE clearance in obesity.
    NeuroImage 10/2013; · 6.25 Impact Factor
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    ABSTRACT: IMPORTANCE Animal data suggest that chronic stress is associated with a reduction in norepinephrine transporter (NET) availability in the locus coeruleus. However, it is unclear whether such models are relevant to posttraumatic stress disorder (PTSD), which has been linked to noradrenergic dysfunction in humans. OBJECTIVES To use positron emission tomography and the radioligand [11C]methylreboxetine to examine in vivo NET availability in the locus coeruleus in the following 3 groups of individuals: healthy adults (HC group), adults exposed to trauma who did not develop PTSD (TC group), and adults exposed to trauma who developed PTSD (PTSD group) and to evaluate the relationship between NET availability in the locus coeruleus and a contemporary phenotypic model of PTSD symptoms. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional positron emission tomography study under resting conditions at academic and Veterans Affairs medical centers among 56 individuals in the following 3 study groups: HC (n = 18), TC (n = 16), and PTSD (n = 22). MAIN OUTCOMES AND MEASURES The [11C]methylreboxetine-binding potential of NET availability in the locus coeruleus and the severity of PTSD symptoms assessed using the Clinician-Administered PTSD Scale. RESULTS The PTSD group had significantly lower NET availability than the HC group (41% lower, Cohen d = 1.07). NET availability did not differ significantly between the TC and HC groups (31% difference, Cohen d = 0.79) or between the TC and PTSD groups (15% difference, Cohen d = 0.28). In the PTSD group, NET availability in the locus coeruleus was independently positively associated with the severity of anxious arousal (ie, hypervigilance) symptoms (r = 0.52) but not with any of the other PTSD symptom clusters. CONCLUSIONS AND RELEVANCE These results suggest that PTSD is associated with significantly reduced NET availability in the locus coeruleus and that greater NET availability in this brain region is associated with increased severity of anxious arousal symptoms in individuals with PTSD.
    JAMA Psychiatry 09/2013; · 12.01 Impact Factor
  • Molecular psychiatry 09/2013; 18(9):953. · 15.05 Impact Factor
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    ABSTRACT: [(11)C]AFM, or [(11)C]2-[2-(dimethylaminomethyl)phenylthio]-5-fluoromethylphenylamine, is a new positron emission tomography (PET) radioligand with high affinity and selectivity for the serotonin transporter (SERT). The purpose of this study was to determine the most appropriate kinetic model to quantify [(11)C]AFM binding in the healthy human brain. Positron emission tomography data and arterial input functions were acquired from 10 subjects. Compartmental modeling and the multilinear analysis-1(MA1) method were tested using the arterial input functions. The one-tissue model showed a lack of fit in low-binding regions, and the two-tissue model failed to estimate parameters reliably. Regional time-activity curves were well described by MA1. The rank order of [(11)C]AFM binding potential (BPND) matched well with the known regional SERT densities. For routine use of [(11)C]AFM, several noninvasive methods for quantification of regional binding were evaluated, including simplified reference tissue models (SRTM and SRTM2), and multilinear reference tissue models (MRTM and MRTM2). The best methods for region of interest (ROI) analysis were MA1, MRTM2, and SRTM2, with fixed population kinetic values ( or b') for the reference methods. The MA1 and MRTM2 methods were best for parametric imaging. These results showed that [(11)C]AFM is a suitable PET radioligand to image and quantify SERT in humans.Journal of Cerebral Blood Flow & Metabolism advance online publication, 7 August 2013; doi:10.1038/jcbfm.2013.134.
    Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 08/2013; · 5.46 Impact Factor
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    ABSTRACT: Endocannabinoids and their attending cannabinoid type 1 (CB1) receptor have been implicated in animal models of post-traumatic stress disorder (PTSD). However, their specific role has not been studied in people with PTSD. Herein, we present an in vivo imaging study using positron emission tomography (PET) and the CB1-selective radioligand [(11)C]OMAR in individuals with PTSD, and healthy controls with lifetime histories of trauma (trauma-exposed controls (TC)) and those without such histories (healthy controls (HC)). Untreated individuals with PTSD (N=25) with non-combat trauma histories, and TC (N=12) and HC (N=23) participated in a magnetic resonance imaging scan and a resting PET scan with the CB1 receptor antagonist radiotracer [(11)C]OMAR, which measures the volume of distribution (VT) linearly related to CB1 receptor availability. Peripheral levels of anandamide, 2-arachidonoylglycerol, oleoylethanolamide, palmitoylethanolamide and cortisol were also assessed. In the PTSD group, relative to the HC and TC groups, we found elevated brain-wide [(11)C]OMAR VT values (F(2,53)=7.96, P=0.001; 19.5% and 14.5% higher, respectively), which were most pronounced in women (F(1,53)=5.52, P=0.023). Anandamide concentrations were reduced in the PTSD relative to the TC (53.1% lower) and HC (58.2% lower) groups. Cortisol levels were lower in the PTSD and TC groups relative to the HC group. Three biomarkers examined collectively-OMAR VT, anandamide and cortisol-correctly classified nearly 85% of PTSD cases. These results suggest that abnormal CB1 receptor-mediated anandamide signaling is implicated in the etiology of PTSD, and provide a promising neurobiological model to develop novel, evidence-based pharmacotherapies for this disorder.Molecular Psychiatry advance online publication, 14 May 2013; doi:10.1038/mp.2013.61.
    Molecular psychiatry 05/2013; · 15.05 Impact Factor
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    ABSTRACT: Post-traumatic stress disorder (PTSD) is a common and chronic anxiety disorder that can result after exposure to a traumatic event. Though our understanding of the aetiology of PTSD is incomplete, several neurobiological systems have been implicated in the pathophysiology and vulnerability towards developing PTSD after trauma exposure. We aimed to provide a concise review of benchmark findings in important neurobiological systems related to the aetiology and maintenance of PTSD symptomology. Specifically, we discuss functional aetiologies in the noradrenergic, serotonergic, endogenous cannabinoid and opioid systems as well as the hypothalamic-pituitary adrenal (HPA) axis. This article provides a succinct framework to appreciate the current understanding of neurobiological mechanisms related to the pathophysiology of PTSD and how these findings may impact the development of future, targeted pharmacological treatments for this debilitating disorder.
    CNS Drugs 03/2013; · 4.83 Impact Factor
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    ABSTRACT: Multiple lines of evidence suggest that serotonin type 1A (5-HT(1A)) receptor dysfunction is involved in the pathophysiology of mood disorders, and that alterations in 5-HT(1A) receptor function play a role in the mechanisms of antidepressant and mood stabilizer treatment. The literature is in disagreement, however, as to whether 5-HT(1A) receptor binding abnormalities exist in bipolar disorder (BD). We acquired PET images of 5-HT(1A) receptor binding in 26 unmedicated BD subjects and 37 healthy controls using [(18)F]FCWAY, a highly selective 5-HT(1A) receptor radio-ligand. The mean 5-HT(1A) receptor binding potential (BP(P)) was significantly lower in BD subjects compared to controls in cortical regions where 5-HT(1A) receptors are expressed post-synaptically, most prominently in the mesiotemporal cortex. Post-hoc assessments involving other receptor specific binding parameters suggested that this difference particularly affected the females with BD. The mean BP(P) did not differ between groups in the raphe nucleus, however, where 5-HT(1A) receptors are predominantly expressed pre-synaptically. Across subjects the BP(P) in the mesiotemporal cortex was inversely correlated with trough plasma cortisol levels, consistent with preclinical literature indicating that hippocampal 5-HT(1A) receptor expression is inhibited by glucocorticoid receptor stimulation. These findings suggest that 5-HT(1A) receptor binding is abnormally reduced in BD, and this abnormality may particularly involve the postsynaptic 5-HT(1A) receptor system of individuals with a tendency toward cortisol hypersecretion.
    European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 02/2013; · 3.68 Impact Factor
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    ABSTRACT: Brain-derived neurotrophic factor (BDNF) has been implicated in the pathophysiology of psychiatric and neurological disorders and in the mechanisms of antidepressant pharmacotherapy. Psychiatric and neurological conditions have also been associated with reduced brain levels of N-acetyl-aspartate (NAA), which has been used as a putative marker of neural integrity. However, few studies have explored the relationship between BDNF polymorphisms and NAA levels directly. Here, we present data from a single-voxel proton magnetic resonance spectroscopy study of 64 individuals and explore the relationship between BDNF polymorphisms and prefrontal NAA level. Our results indicate an association between a single nucleotide polymorphism (SNP) within BDNF, known as rs1519480, and reduced NAA level (p = 0.023). NAA levels were further predicted by age and Asian ancestry. There was a significant rs1519480 × age interaction on NAA level (p = 0.031). Specifically, the effect of rs1519480 on NAA level became significant at age ⩾34.17 yr. NAA level decreased with advancing age for genotype TT (p = 0.001) but not for genotype CT (p = 0.82) or CC (p = 0.34). Additional in silico analysis of 142 post-mortem brain samples revealed an association between the same SNP and reduced BDNF mRNA expression in the prefrontal cortex. The rs1519480 SNP influences BDNF mRNA expression and has an impact on prefrontal NAA level over time. This genetic mechanism may contribute to inter-individual variation in cognitive performance seen during normal ageing, as well as contributing to the risk for developing psychiatric and neurological conditions.
    The International Journal of Neuropsychopharmacology 12/2012; · 5.64 Impact Factor
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    ABSTRACT: Targeted metabolomics provides an approach to quantify metabolites involved in specific molecular pathways. We applied an electrochemistry-based, targeted metabolomics platform to define changes in tryptophan, tyrosine, purine and related pathways in the depressed and remitted phases of major depressive disorder (MDD). Biochemical profiles in the cerebrospinal fluid of unmedicated depressed (n514; dMDD) or remitted MDD subjects (n514; rMDD) were compared against those in healthy controls (n518; HC). The rMDD group showed differences in tryptophan and tyrosine metabolism relative to the other groups. The rMDD group also had higher methionine levels and larger methionine-to-glutathione ratios than the other groups, implicating methylation and oxidative stress pathways. The dMDD sample showed nonsignificant differences in the same direction in several of the metabolic branches assessed. The reductions in metabolites associated with tryptophan and tyrosine pathways in rMDD may relate to the vulnerability this population shows for developing depressive symptoms under tryptophan or catecholamine depletion.
    Scientific Reports 09/2012; 2(667). · 2.93 Impact Factor
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    ABSTRACT: Previous imaging studies have suggested that there is an age-related decline in brain serotonin (5-hydroxytryptamine) measures in healthy subjects. This paper addresses whether the availability of 5-hydroxytryptamine receptor 1B (5-HT(1B)) is seen to decrease with aging via PET imaging. Forty-eight healthy control subjects (mean age ± SD, 30 ± 10 y; age range, 18-61 y; 33 men, 15 women) underwent (11)C-P943 scanning on a high-resolution PET tomograph. Regions were examined with and without gray matter masking, the latter in an attempt to control for age-related gray matter atrophy on nondisplaceable binding potential (BP(ND)) as determined by a validated multilinear reference tissue model. 5-HT(1B) BP(ND) decreased in the cortex at an average rate of 8% per decade without and 9% with gray matter masking. A negative association with age was also observed in all individual cortical regions. Differences in the putamen and pallidum (positive association) were significant after adjustment for multiple comparisons. No sex- or race-related effects on 5-HT(1B) BP(ND) were found in any regions. These findings indicate that age is a relevant factor for 5-HT(1B) in the cortex of healthy adults.
    Journal of Nuclear Medicine 07/2012; 53(9):1411-4. · 5.77 Impact Factor
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    ABSTRACT: The highly diverse serotonergic system with at least 16 different receptor subtypes is implicated in the pathophysiology of most neuropsychiatric disorders including affective and anxiety disorders, obsessive compulsive disorder, post-traumatic stress disorder, eating disorders, sleep disturbance, attention deficit/hyperactivity disorder, drug addiction, suicidal behavior, schizophrenia, Alzheimer, etc. Alterations of the interplay between various pre- and postsynaptic receptor subtypes might be involved in the pathogenesis of these disorders. However, there is a lack of comprehensive in vivo values using standardized procedures. In the current PET study we quantified 3 receptor subtypes, including the major inhibitory (5-HT(1A) and 5-HT(1B)) and excitatory (5-HT(2A)) receptors, and the transporter (5-HTT) in the brain of healthy human subjects to provide a database of standard values. PET scans were performed on 95 healthy subjects (age=28.0 ± 6.9 years; 59% males) using the selective radioligands [carbonyl-(11)C]WAY-100635, [(11)C]P943, [(18)F]altanserin and [(11)C]DASB, respectively. A standard template in MNI stereotactic space served for region of interest delineation. This template follows two anatomical parcellation schemes: 1) Brodmann areas including 41 regions and 2) AAL (automated anatomical labeling) including 52 regions. Standard values (mean, SD, and range) for each receptor and region are presented. Mean cortical and subcortical binding potential (BP) values were in good agreement with previously published human in vivo and post-mortem data. By means of linear equations, PET binding potentials were translated to post-mortem binding (provided in pmol/g), yielding 5.89 pmol/g (5-HT(1A)), 23.5 pmol/g (5-HT(1B)), 31.44 pmol/g (5-HT(2A)), and 11.33 pmol/g (5-HTT) being equivalent to the BP of 1, respectively. Furthermore, we computed individual voxel-wise maps with BP values and generated average tracer-specific whole-brain binding maps. This knowledge might improve our interpretation of the alterations taking place in the serotonergic system during neuropsychiatric disorders.
    NeuroImage 07/2012; 63(1):447-59. · 6.25 Impact Factor
  • Molecular psychiatry 05/2012; · 15.05 Impact Factor
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    ABSTRACT: Patents with major depression have evidence of a proinflammatory state with consistent elevations in acute phase proteins and in the levels of inflammatory mediators such as interleukin-6 and tumor necrosis factor-α. We report here a study of the serum levels of immunoglobulin A (IgA) in medication-free patients with major depression in the remitted state (ruMDD). Selective IgA deficiency is the most common form of immunoglobulin abnormality, and is often associated with a higher than expected incidence of proinflammatory and autoimmune phenomena. We measured serum IgG, IgM, and IgA in 28 ruMDD patients and 27 healthy subjects (Ctrl) at 0 (pretreatment), 7, and 24h following sham depletion and tryptophan (TrpD) depletion conducted at least 8 days apart under balanced, randomized, blinded conditions. Immunoglobulins were measured by automated immunonephelometry. Data were analyzed by repeated measures ANOVA with diagnosis as a fixed effect and drug (TrpD vs. sham), and time as repeated measures factors. Serum IgA was consistently lower in ruMDD patients vs. Ctrl at all time points examined (p<0.04 for main effect of diagnosis). Serum IgG and IgM levels did not show significant differences by diagnosis. Medication-free patients with major depression in the remitted state have a significant reduction in serum IgA levels measured on multiple occasions. In the light of the fact that IgA serves many immunomodulatory, anti-inflammatory roles, this finding supports the concept that major depressive illness represents a proinflammatory state.
    Neuroscience Letters 05/2012; 520(1):1-5. · 2.03 Impact Factor
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    ABSTRACT: BACKGROUND: Several lines of evidence link cannabinoid (CB) type 1 (CB (1) ) receptor-mediated endogenous CB (eCB) signaling to the etiology of alcohol dependence (AD). However, to date, only peripheral measures of eCB function have been collected in living humans with AD and no human in vivo data on the potentially critical role of the brain CB (1) receptor in AD have been published. This is an important gap in the literature, because recent therapeutic developments suggest that these receptors could be targeted for the treatment for AD. METHODS: Medication-free participants were scanned during early abstinence 4 weeks after their last drink. Using positron emission tomography (PET) with a high-resolution research tomograph and the CB (1) receptor selective radiotracer [(11) C]OMAR, we determined [(11) C]OMAR volume of distribution ( V (T) ) values, a measure of CB (1) receptor density, in a priori selected brain regions in men with AD (n = 8, age 37.4 ± 7.9 years; 5 smokers) and healthy control (HC) men (n = 8, age 32.5 ± 6.9 years; all nonsmokers). PET images reconstructed using the MOLAR algorithm with hardware motion correction were rigidly aligned to the subject-specific magnetic resonance (MR) image, which in turn was warped to an MR template. Time-activity curves (TACs) were extracted from the dynamic PET data using a priori selected regions of interest delineated in the MR template space. RESULTS: In AD relative to HC, [(11) C]OMAR V (T) values were elevated by approximately 20% (p = 0.023) in a circuit, including the amygdala, hippocampus, putamen, insula, anterior and posterior cingulate cortices, and orbitofrontal cortex. Age, body mass index, or smoking status did not influence the outcome. CONCLUSIONS: These findings agree with preclinical evidence and provide the first, albeit still preliminary in vivo evidence suggesting a role for brain CB (1) receptors in AD. The current study design does not answer the important question of whether elevated CB (1) receptors are a preexisting vulnerability factor for AD or whether elevations develop as a consequence of AD.
    Alcoholism Clinical and Experimental Research 05/2012; · 3.42 Impact Factor
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    ABSTRACT: Exploring intermediate phenotypes within the human brain's functional and structural circuitry is a promising approach to explain the relative contributions of genetics, complex behaviors and neural mechanisms in the development of major depressive disorder (MDD). The polymorphic region 5-HTTLPR in the serotonin transporter gene (SLC6A4) has been shown to modulate MDD risk, but the neural underpinnings are incompletely understood. 37 right handed healthy women between 21 and 61 years of age were invited to participate in an fMRI modified n-back study. The functional polymorphism 5-HTTLPR located in the promoter region of the SLC6A4 gene was genotyped using polymerase chain reaction (PCR). Short 5-HTTLPR allele carriers showed more blood-oxygen-level-dependent (BOLD) bilateral prefrontal cortex activation in the right [F(2, 30) = 4.8, η(2) = .25, p = .026] and left [F(2, 30) = 4.1, η(2) = .22, p = .015] inferior frontal gyrus pars triangularis with increasing n-back task difficulty relative to long 5-HTTLPR allele carriers. Short 5-HTTLPR allele carriers had inferior task performance on the most difficult n-back condition [F(2, 30) = 4.9, η(2) = .26, p = .014]. This activation pattern found in healthy at risk individuals resembles an activation pattern that is typically found in patients suffering from acute MDD. Altered function in these areas may reflect intermediate phenotypes and may help explain the increased risk of depression in short 5-HTTLPR allele carriers.
    PLoS ONE 01/2012; 7(1):e30564. · 3.73 Impact Factor
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    ABSTRACT: Studies of populations at genetic risk have the potential to explore the underlying structural and functional mechanisms in the development of psychological disorders. The polymorphic region (5-HTTLPR) in the serotonin transporter gene (SLC6A4) has been associated with major depression (MDD) (Caspi et al., 2003). In healthy women, variation in the human brain white matter microstructure integrity in the uncinate fascicule (UF) has been suggested as an endophenotypes in the development of MDD. Pacheco et al. (2009) found a unique effect of age and 5-HTTLPR within the left frontal UF. The present study examined whether these associations persist along the adult life span. Thirty-seven right-handed healthy women between 21 and 61 years of age were invited for a diffusion MRI study. The functional polymorphism 5-HTTLPR located in the promoter region of the SLC6A4 gene was genotyped using polymerase chain reaction (PCR). Fractional anisotropy (FA) was generated for the UF based on Tract-Based Spatial Statistics (TBSS). Models of emotion regulation circuitry suggest that working memory is important in conscious emotion regulation (Price and Drevets, 2010). To explore if 5-HTTLPR is related to this aspects of emotion processing, a working memory pathway, the superior longitudinal fascicule (SLF) was included. The results demonstrate that age may explain the hypothesized association between 5-HTTLPR and frontal UF white matter integrity in healthy adult women. Both white matter changes associated with the aging process and those associated with growth and development may explain why the earlier reported unique effects of genotype in frontal UF FA do not persist into adulthood.
    Frontiers in Human Neuroscience 01/2012; 6:19. · 2.91 Impact Factor

Publication Stats

3k Citations
797.47 Total Impact Points

Institutions

  • 2013
    • Johns Hopkins University
      Baltimore, Maryland, United States
  • 2004–2013
    • Yale University
      • Department of Psychiatry
      New Haven, CT, United States
  • 1997–2013
    • National Institute of Mental Health (NIMH)
      • Division of Intramural Research Programs
      Maryland, United States
  • 2012
    • Howard University
      Washington, West Virginia, United States
    • CUNY Graduate Center
      New York City, New York, United States
  • 2010–2012
    • Mount Sinai School of Medicine
      • Department of Psychiatry
      Manhattan, NY, United States
  • 2004–2011
    • National Center for PTSD
      Washington, Washington, D.C., United States
  • 2007–2009
    • Yale-New Haven Hospital
      New Haven, Connecticut, United States
  • 1996–2009
    • University of Vienna
      • Neurological Clinic
      Wien, Vienna, Austria
  • 2008
    • University of Zurich
      Zürich, Zurich, Switzerland
    • Hebrew University of Jerusalem
      • Department of Psychiatry
      Jerusalem, Jerusalem District, Israel
  • 1999–2006
    • National Institutes of Health
      • Branch of Mood and Anxiety Disorders
      Bethesda, MD, United States
  • 2005
    • University of Texas Southwestern Medical Center
      • Department of Psychiatry
      Dallas, TX, United States
  • 2001
    • Vienna General Hospital
      Wien, Vienna, Austria