Husseini K Manji

National Institute of Mental Health (NIMH), 베서스다, Maryland, United States

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Publications (335)2335.89 Total impact

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    ABSTRACT: Background Genetic contributions to major depressive disorder (MDD) are thought to result from multiple genes interacting with each other. Different procedures have been proposed to detect such interactions. Which approach is best for explaining the risk of developing disease is unclear. This study sought to elucidate the genetic interaction landscape in candidate genes for MDD by conducting a SNP-SNP interaction analysis using an exhaustive search through 3,704 SNP-markers in 1,732 cases and 1,783 controls provided from the GAIN MDD study. We used three different methods to detect interactions, two logistic regressions models (multiplicative and additive) and one data mining and machine learning (MDR) approach. Results Although none of the interaction survived correction for multiple comparisons, the results provide important information for future genetic interaction studies in complex disorders. Among the 0.5% most significant observations, none had been reported previously for risk to MDD. Within this group of interactions, less than 0.03% would have been detectable based on main effect approach or an a priori algorithm. We evaluated correlations among the three different models and conclude that all three algorithms detected the same interactions to a low degree. Although the top interactions had a surprisingly large effect size for MDD (e.g. additive dominant model Puncorrected = 9.10E-9 with attributable proportion (AP) value = 0.58 and multiplicative recessive model with Puncorrected = 6.95E-5 with odds ratio (OR estimated from β3) value = 4.99) the area under the curve (AUC) estimates were low (< 0.54). Moreover, the population attributable fraction (PAF) estimates were also low (< 0.15). Conclusions We conclude that the top interactions on their own did not explain much of the genetic variance of MDD. The different statistical interaction methods we used in the present study did not identify the same pairs of interacting markers. Genetic interaction studies may uncover previously unsuspected effects that could provide novel insights into MDD risk, but much larger sample sizes are needed before this strategy can be powerfully applied.
    BioData Mining 09/2014; 7:19. DOI:10.1186/1756-0381-7-19 · 1.54 Impact Factor
  • Husseini K Manji, Thomas W Insel, Vaibhav A Narayan
    dressNature Reviews Drug Discovery 08/2014; 13(8):561-2. DOI:10.1038/nrd4395 · 37.23 Impact Factor
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    ABSTRACT: Introduction: Bipolar disorder (BPD) is a severe illness with few treatments available. Understanding BPD pathophysiology and identifying potential relevant targets could prove useful for developing new treatments. Remarkably, subtle impairments of mitochondrial function may play an important role in BPD pathophysiology. Areas covered: This article focuses on human studies and reviews evidence of mitochondrial dysfunction in BPD as a promising target for the development of new, improved treatments. Mitochondria are crucial for energy production, generated mainly through the electron transport chain (ETC) and play an important role in regulating apoptosis and calcium (Ca(2+)) signaling as well as synaptic plasticity. Mitochondria move throughout the neurons to provide energy for intracellular signaling. Studies showed polymorphisms of mitochondria-related genes as risk factors for BPD. Postmortem studies in BPD also show decreased ETC activity/expression and increased nitrosative and oxidative stress (OxS) in patient brains. BPD has been also associated with increased OxS, Ca(2+) dysregulation and increased proapoptotic signaling in peripheral blood. Neuroimaging studies consistently show decreased energy levels and pH in brains of BPD patients. Expert opinion: Targeting mitochondrial function, and their role in energy metabolism, synaptic plasticity and cell survival, may be an important avenue for development of new mood-stabilizing agents.
    Expert Opinion on Therapeutic Targets 07/2014; 18(10):1-17. DOI:10.1517/14728222.2014.940893 · 4.90 Impact Factor
  • Guang Chen, Ioline D Henter, Husseini K Manji
    Biological Psychiatry 07/2014; 76(2):86-8. DOI:10.1016/j.biopsych.2014.05.005 · 9.47 Impact Factor
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    ABSTRACT: The brain encodes information about past experience in specific populations of neurons that communicate with one another by firing action potentials. Studies of experience-dependent neural plasticity have largely focused on individual synaptic changes in response to neuronal input. Indicative of the neuronal output transmitted to downstream neurons, persistent firing patterns are affected by prior experience in selective neuronal populations. However, little is known about the molecular and cellular mechanisms by which experience-related persistent firing patterns are regulated in specific neuronal populations. Using frontal cortical slices prepared from transgenic mice carrying a fluorescent reporter of Arc gene expression, this study investigates how behavioral experience and the activity-regulated Arc gene affect patterns of neuronal firing. We found that motor training increases Arc expression in subsets of excitatory neurons. Those neurons exhibit persistent firing in contrast to Arc-negative neurons from the same mice or neurons from the untrained mice. Furthermore, in mice carrying genetic deletion of Arc, the frontal cortical circuitry is still in place to initiate experience-dependent gene expression, but the level of persistent firing thereafter is diminished. Finally, our results showed that the emergence of persistent activity is associated with Arc-dependent changes in the function of NMDA-type glutamate receptors, rather than changes in AMPA-type receptors or membrane excitability. Our findings therefore reveal an Arc-dependent molecular pathway by which gene-experience interaction regulates the emergence of persistent firing patterns in specific neuronal populations.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 05/2014; 34(19):6583-95. DOI:10.1523/JNEUROSCI.0167-14.2014 · 6.75 Impact Factor
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    ABSTRACT: The prediction of treatment response in many neuropsychiatric disorders would be facilitated by easily accessible biomarkers. Using flow cytometry, we herein demonstrate correlations between early reductions of p11 levels in Natural Killer (NK) cells and monocytes and antidepressant response to citalopram in patients with major depressive disorder (MDD).
    Molecular Psychiatry 03/2014; 19(9). DOI:10.1038/mp.2014.13 · 15.15 Impact Factor
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    ABSTRACT: Abnormal serotonin type 1A (5-HT1A) receptor function and binding have been implicated in the pathophysiology of mood disorders. Preclinical studies have consistently shown that stress decreases the gene expression of 5-HT1A receptors in experimental animals, and that the associated increase in hormone secretion plays a crucial role in mediating this effect. Chronic administration of the mood stabilizers lithium and divalproex (valproate semisodium) reduces glucocorticoid signaling and function in the hippocampus. Lithium has further been shown to enhance 5-HT1A receptor function. To assess whether these effects translate to human subject with bipolar disorder (BD), positron emission tomography (PET) and [18F]trans-4-fluoro-N-(2-[4-(2-methoxyphenyl) piperazino]-ethyl)-N-(2-pyridyl) cyclohexanecarboxamide ([(18)F]FCWAY) were used to acquire PET images of 5-HT1A receptor binding in 10 subjects with BD, before and after treatment with lithium or divalproex. Mean 5-HT1A binding potential (BPP) significantly increased following mood stabilizer treatment, most prominently in the mesiotemporal cortex (hippocampus plus amygdala). When mood state was also controlled for, treatment was associated with increases in BPP in widespread cortical areas. These preliminary findings are consistent with the hypothesis that these mood stabilizers enhance 5-HT1A receptor expression in BD, which may underscore an important component of these agents' mechanism of action.
    Journal of Psychopharmacology 08/2013; DOI:10.1177/0269881113499204 · 2.81 Impact Factor
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    ABSTRACT: Available treatments for depression have significant limitations, including low response rates and substantial lag times for response. Reports of rapid antidepressant effects of a number of compounds, including the glutamate N-methyl-D-aspartate receptor antagonist ketamine, have spurred renewed translational neuroscience efforts aimed at elucidating the molecular and cellular mechanisms of action that result in rapid therapeutic response. This perspective provides an overview of recent advances utilizing compounds with rapid-acting antidepressant effects, discusses potential mechanism of action and provides a framework for future research directions aimed at developing safe, efficacious antidepressants that achieve satisfactory remission not only by working rapidly but also by providing a sustained response.Molecular Psychiatry advance online publication, 21 May 2013; doi:10.1038/mp.2013.55.
    Molecular Psychiatry 05/2013; DOI:10.1038/mp.2013.55 · 15.15 Impact Factor
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    ABSTRACT: BACKGROUND: Multiple lines of evidence support a role for the glutamatergic system in the pathophysiology of major depressive disorder (MDD). Ketamine, an N-methyl-D-aspartate antagonist, rapidly improves depressive symptoms in individuals with treatment-resistant depression. The neural mechanisms underlying this effect remain unknown. METHODS: In this preliminary study, 20 unmedicated participants with treatment-resistant MDD underwent positron emission tomography to measure regional cerebral glucose metabolism at baseline and following ketamine infusion (single dose of .5mg/kg intravenous over 40minutes). Metabolic data were compared between conditions using a combination of region-of-interest and voxelwise analyses, and differences were correlated with the associated antidepressant response. RESULTS: Whole-brain metabolism did not change significantly following ketamine. Regional metabolism decreased significantly under ketamine in the habenula, insula, and ventrolateral and dorsolateral prefrontal cortices of the right hemisphere. Metabolism increased postketamine in bilateral occipital, right sensorimotor, left parahippocampal, and left inferior parietal cortices. Improvement in depression ratings correlated directly with change in metabolism in right superior and middle temporal gyri. Conversely, clinical improvement correlated inversely with metabolic changes in right parahippocampal gyrus and temporoparietal cortex. CONCLUSIONS: Although preliminary, these results indicate that treatment-resistant MDD subjects showed decreased metabolism in the right habenula and the extended medial and orbital prefrontal networks in association with rapid antidepressant response to ketamine. Conversely, metabolism increased in sensory association cortices, conceivably related to the illusory phenomena sometimes experienced with ketamine. Further studies are needed to elucidate how these functional anatomical changes relate to the molecular mechanisms underlying ketamine's rapid antidepressant effects.
    Biological psychiatry 03/2013; DOI:10.1016/j.biopsych.2013.02.008 · 9.47 Impact Factor
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    ABSTRACT: Following their birth in the adult hippocampal dentate gyrus, newborn progenitor cells migrate into the granule cell layer where they differentiate, mature, and functionally integrate into existing circuitry. The hypothesis that adult hippocampal neurogenesis is physiologically important has gained traction, but the precise role of newborn neurons in hippocampal function remains unclear. We investigated whether loss of new neurons impacts dendrite morphology and glutamate levels in area CA3 of the hippocampus by utilizing a human GFAP promoter-driven thymidine kinase genetic mouse model to conditionally suppress adult neurogenesis. We found that chronic ablation of new neurons induces remodeling in CA3 pyramidal cells and increases stress-induced release of the neurotransmitter glutamate. The ability of persistent impairment of adult neurogenesis to influence hippocampal dendrite morphology and excitatory amino acid neurotransmission has important implications for elucidating newborn neuron function, and in particular, understanding the role of these cells in stress-related excitoxicity.
    Brain Structure and Function 03/2013; DOI:10.1007/s00429-013-0532-8 · 4.57 Impact Factor
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    Dataset: JCP,2010b
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    ABSTRACT: The time has come to move beyond product-focused 'magic bullet' therapeutic development strategies towards models that can also incorporate devices, tools and services to provide integrated health-care solutions.
    dressNature Reviews Drug Discovery 02/2013; 12(2):85-86. DOI:10.1038/nrd3944 · 37.23 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). DOI:10.1038/srep00667 · 5.58 Impact Factor
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    ABSTRACT: A public-private partnership to establish biomarkers of dementia in Down's syndrome could aid the development of preventive therapies for the dementia associated with both Down's syndrome and Alzheimer's disease, based on the apparent common pathogenic role of amyloid precursor protein in the two conditions.
    dressNature Reviews Drug Discovery 08/2012; 11(9):655-6. DOI:10.1038/nrd3822 · 37.23 Impact Factor
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    ABSTRACT: The N-methyl-d-aspartate (NMDA) receptor antagonist ketamine has rapid antidepressant effects in treatment-resistant major depressive disorder (MDD). In rats, ketamine selectively increased electroencephalogram (EEG) slow wave activity (SWA) during non-rapid eye movement (REM) sleep and altered central brain-derived neurotrophic factor (BDNF) expression. Taken together, these findings suggest that higher SWA and BDNF levels may respectively represent electrophysiological and molecular correlates of mood improvement following ketamine treatment. This study investigated the acute effects of a single ketamine infusion on depressive symptoms, EEG SWA, individual slow wave parameters (surrogate markers of central synaptic plasticity) and plasma BDNF (a peripheral marker of plasticity) in 30 patients with treatment-resistant MDD. Montgomery-Åsberg Depression Rating Scale scores rapidly decreased following ketamine. Compared to baseline, BDNF levels and early sleep SWA (during the first non-REM episode) increased after ketamine. The occurrence of high amplitude waves increased during early sleep, accompanied by an increase in slow wave slope, consistent with increased synaptic strength. Changes in BDNF levels were proportional to changes in EEG parameters. Intriguingly, this link was present only in patients who responded to ketamine treatment, suggesting that enhanced synaptic plasticity - as reflected by increased SWA, individual slow wave parameters and plasma BDNF - is part of the physiological mechanism underlying the rapid antidepressant effects of NMDA antagonists. Further studies are required to confirm the link found here between behavioural and synaptic changes, as well as to test the reliability of these central and peripheral biomarkers of rapid antidepressant response.
    The International Journal of Neuropsychopharmacology 06/2012; 16(2):1-11. DOI:10.1017/S1461145712000545 · 5.26 Impact Factor
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    ABSTRACT: The N-methyl-d-aspartate (NMDA) receptor antagonist ketamine has rapid antidepressant effects in treatment-resistant major depressive disorder (MDD). In rats, ketamine selectively increased electroencephalogram (EEG) slow wave activity (SWA) during non-rapid eye movement (REM) sleep and altered central brain-derived neurotrophic factor (BDNF) expression. Taken together, these findings suggest that higher SWA and BDNF levels may respectively represent electrophysiological and molecular correlates of mood improvement following ketamine treatment. This study investigated the acute effects of a single ketamine infusion on depressive symptoms, EEG SWA, individual slow wave parameters (surrogate markers of central synaptic plasticity) and plasma BDNF (a peripheral marker of plasticity) in 30 patients with treatment-resistant MDD. Montgomery-Åsberg Depression Rating Scale scores rapidly decreased following ketamine. Compared to baseline, BDNF levels and early sleep SWA (during the first non-REM episode) increased after ketamine. The occurrence of high amplitude waves increased during early sleep, accompanied by an increase in slow wave slope, consistent with increased synaptic strength. Changes in BDNF levels were proportional to changes in EEG parameters. Intriguingly, this link was present only in patients who responded to ketamine treatment, suggesting that enhanced synaptic plasticity - as reflected by increased SWA, individual slow wave parameters and plasma BDNF - is part of the physiological mechanism underlying the rapid antidepressant effects of NMDA antagonists. Further studies are required to confirm the link found here between behavioural and synaptic changes, as well as to test the reliability of these central and peripheral biomarkers of rapid antidepressant response.
    The International Journal of Neuropsychopharmacology 06/2012; · 5.26 Impact Factor
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    ABSTRACT: Borderline personality disorder (BPD) is a prevalent and difficult to treat psychiatric condition characterized by abrupt mood swings, intense anger and depression, unstable interpersonal relationships, impulsive self-destructive behavior and a suicide rate of approximately 10%. Possible underlying molecular dysregulations in BPD have not been well explored. Protein kinase C (PKC) and brain-derived neurotrophic factor (BDNF) have both been implicated in affective disorders, but their role in BPD has not been examined. Platelets were isolated from blood obtained from 24 medication-free BPD patients and 18 healthy control subjects. PKC-α, phosphorylated-PKC-α (p-PKCα), PKC-βII, and BDNF were measured in platelet homogenates by immunoblotting. In the males, platelet BDNF and PKC-α levels were lower in patients than controls. p-PKC-α and PKC-βII were lower at trend levels. In the entire sample, platelet p-PKCα and PKC-α activity were lower, at a trend level, in patients compared to controls. This is the first report to our knowledge of PKC and BDNF activity in BPD and calls for replication. These findings are consistent with altered PKC and BDNF activity in a range of neuropsychiatric conditions including bipolar disorder, depression and suicide.
    Psychiatry Research 05/2012; DOI:10.1016/j.psychres.2012.04.026 · 2.68 Impact Factor
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    ABSTRACT: Major psychiatric illnesses such as mood disorders and schizophrenia are chronic, recurrent mental illnesses that affect the lives of millions of individuals. Although these disorders have traditionally been viewed as 'neurochemical diseases', it is now clear that they are associated with impairments of synaptic plasticity and cellular resilience. Although most patients with these disorders do not have classic mitochondrial disorders, there is a growing body of evidence to suggest that impaired mitochondrial function may affect key cellular processes, thereby altering synaptic functioning and contributing to the atrophic changes that underlie the deteriorating long-term course of these illnesses. Enhancing mitochondrial function could represent an important avenue for the development of novel therapeutics and also presents an opportunity for a potentially more efficient drug-development process.
    Nature Reviews Neuroscience 04/2012; 13(5):293-307. DOI:10.1038/nrn3229 · 31.38 Impact Factor
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    ABSTRACT: Apathy is frequently observed in numerous neurological disorders, including Alzheimer's and Parkinson's, as well as neuropsychiatric disorders including schizophrenia. Apathy is defined as a lack of motivation characterized by diminished goal-oriented behavior and self-initiated activity. This study evaluated a chronic restraint stress (CRS) protocol in modeling apathetic behavior, and determined whether administration of an anticholinesterase had utility in attenuating CRS-induced phenotypes. We assessed behavior as well as regional neuronal activity patterns using FosB immunohistochemistry after exposure to CRS for 6 h/d for a minimum of 21 d. Based on our FosB findings and recent clinical trials, we administered an anticholinesterase to evaluate attenuation of CRS-induced phenotypes. CRS resulted in behaviors that reflect motivational loss and diminished emotional responsiveness. CRS-exposed mice showed differences in FosB accumulation, including changes in the cholinergic basal forebrain system. Facilitating cholinergic signaling ameliorated CRS-induced deficits in initiation and motivational drive and rescued immediate early gene activation in the medial septum and nucleus accumbens. Some CRS protocols may be useful for studying deficits in motivation and apathetic behavior. Amelioration of CRS-induced behaviors with an anticholinesterase supports a role for the cholinergic system in remediation of deficits in motivational drive.
    Behavioral and Brain Functions 03/2012; 8:15. DOI:10.1186/1744-9081-8-15 · 2.00 Impact Factor
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    ABSTRACT: The N-methyl-D-aspartate antagonist ketamine has rapid antidepressant effects in patients with treatment-resistant major depression (TRD); these effects have been reported to last for 1 week in some patients. However, the extent and duration of this antidepressant effect over longer periods has not been well characterized under controlled conditions. Riluzole, a glutamatergic modulator with antidepressant and synaptic plasticity-enhancing effects, could conceivably be used to promote the antidepressant effects of ketamine. This study sought to determine the extent and time course of antidepressant improvement to a single-ketamine infusion over 4 weeks, comparing the addition of riluzole vs placebo after the infusion. Forty-two subjects (18-65) with TRD and a Montgomery-Asberg Depression Rating Scale (MADRS) score of ≥ 22 received a single intravenous infusion of ketamine (0.5 mg/kg). Four to six hours post-infusion, subjects were randomized to double-blind treatment with either riluzole (100-200 mg/day; n=21) or placebo (n=21) for 4 weeks. Depressive symptoms were rated daily. A significant improvement (P<0.001) in MADRS scores from baseline was found. The effect size of improvement with ketamine was initially large and remained moderate throughout the 28-day trial. Overall, 27% of ketamine responders had not relapsed by 4 weeks following a single ketamine infusion. The average time to relapse was 13.2 days (SE=2.2). However, the difference between the riluzole and placebo treatment groups was not significant, suggesting that the combination of riluzole with ketamine treatment did not significantly alter the course of antidepressant response to ketamine alone.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 02/2012; 37(6):1526-33. DOI:10.1038/npp.2011.338 · 7.83 Impact Factor

Publication Stats

22k Citations
2,335.89 Total Impact Points

Institutions

  • 1990–2014
    • National Institute of Mental Health (NIMH)
      • • Experimental Therapeutics and Pathophysiology
      • • Laboratory of Molecular Pathophysiology
      • • Section on Pharmacology
      베서스다, Maryland, United States
  • 2013
    • University of Utah
      • Department of Psychiatry
      Salt Lake City, Utah, United States
  • 2012–2013
    • Janssen Research & Development, LLC
      Raritan, New Jersey, United States
  • 2009–2012
    • Johnson & Johnson
      Нью-Брансуик, New Jersey, United States
    • University of Zurich
      Zürich, Zurich, Switzerland
    • University of Wuerzburg
      Würzburg, Bavaria, Germany
    • Penn State Hershey Medical Center and Penn State College of Medicine
      Hershey, Pennsylvania, United States
  • 2010
    • La Jolla Pharmaceutical
      San Diego, California, United States
  • 2002–2009
    • National Institutes of Health
      • • National Institute of Mental Health (NIMH): National Institute of Health
      • • Laboratory of Molecular Physiology
      Maryland, United States
  • 2008
    • Missouri Institute of Mental Heath
      Maryland, United States
    • Karolinska Institutet
      • Department of Neuroscience
      Solna, Stockholm, Sweden
  • 2007
    • University of Pittsburgh
      Pittsburgh, Pennsylvania, United States
    • University of Minnesota Duluth
      • College of Pharmacy
      Duluth, Minnesota, United States
    • University of Texas at Dallas
      Richardson, Texas, United States
    • University of Tartu
      • Department of Psychiatry (ARPS)
      Dorpat, Tartu, Estonia
    • U.S. Department of Health and Human Services
      Washington, Washington, D.C., United States
  • 2006
    • University of Patras
      Rhion, West Greece, Greece
  • 2004–2006
    • Northern Inyo Hospital
      BIH, California, United States
    • Dokuz Eylul University
      • Department of Psychiatry
      İzmir, Izmir, Turkey
  • 2005
    • Yale University
      • Department of Psychiatry
      New Haven, Connecticut, United States
  • 2003
    • National Heart, Lung, and Blood Institute
      Maryland, United States
  • 1996–2003
    • Wayne State University
      • Department of Psychiatry and Behavioral Neurosciences
      Detroit, Michigan, United States