• Impact of Tic Disorders on ADHD Outcome Across the Life Cycle: Findings From a Large Group of Adults With and Without ADHD

      Spencer, Thomas J.; Biederman, Joseph; Faraone, Stephen V.; Mick, Eric; Coffey, Barbara; Geller, Daniel; Kagan, Jake; Bearman, Sarah Kate; Wilens, Timothy (American Psychiatric Association Publishing, 2001-04)
      Objective: The impact of tic disorders on the outcome of attention deficit hyperactivity disorder (ADHD) remains a subject of high scientific and clinical interest. To evaluate the impact of comorbid ADHD and tic disorders from a lifespan perspective, the authors systematically examined data from adults with and without ADHD. Method: They comprehensively evaluated 312 consecutively referred adults with ADHD and 252 comparison subjects without ADHD. Tic disorders were characterized along with a wide range of neuropsychiatric correlates, including other comorbid disorders as well as indexes of function in the domains of school, cognition, and interpersonal functioning. Results: A significantly greater proportion of adults with ADHD (12%) than those without ADHD (4%) had tic disorders. Tic disorders followed a mostly remitting course and had little impact on functional capacities. In addition, tic disorders were not associated with stimulant use. Conclusions: These findings in adults with ADHD confirm and extend previous findings in young subjects with ADHD, documenting that although individuals with ADHD are at greater risk for tic disorders, the presence of tic disorders has a limited impact on ADHD outcome.
    • Influence of Gender on Attention Deficit Hyperactivity Disorder in Children Referred to a Psychiatric Clinic

      Biederman, Joseph; Mick, Eric; Faraone, Stephen V.; Braaten, Ellen; Doyle, Alysa; Spencer, Thomas; Wilens, Timothy E.; Frazier, Elizabeth; Johnson, Mary Ann (American Psychiatric Association Publishing, 2002-01)
      Objective: The substantial discrepancy in the male-to-female ratio between clinic-referred (10 to 1) and community (3 to 1) samples of children with attention deficit hyperactivity disorder (ADHD) suggests that gender differences may be operant in the phenotypic expression of ADHD. In this study the authors systematically examined the impact of gender on the clinical features of ADHD in a group of children referred to a clinic. Method: The study included 140 boys and 140 girls with ADHD and 120 boys and 122 girls without ADHD as comparison subjects. All subjects were systematically assessed with structured diagnostic interviews and neuropsychological batteries for subtypes of ADHD as well as emotional, school, intellectual, interpersonal, and family functioning. Results: Girls with ADHD were more likely than boys to have the predominantly inattentive type of ADHD, less likely to have a learning disability, and less likely to manifest problems in school or in their spare time. In addition, girls with ADHD were at less risk for comorbid major depression, conduct disorder, and oppositional defiant disorder than boys with ADHD. A statistically significant gender-by-ADHD interaction was identified for comorbid substance use disorders as well. Conclusions: The lower likelihood for girls to manifest psychiatric, cognitive, and functional impairment than boys could result in gender-based referral bias unfavorable to girls with ADHD
    • The influence of genes on “positive valence systems” constructs: A systematic review

      Hess, Jonathan L.; Kawaguchi, Daniel M.; Wagner, Kayla E.; Faraone, Stephen V.; Glatt, Stephen J. (Wiley, 2015-09-14)
      The Research Domain Criteria (RDoC) address three types of aggression: frustrative non-reward, defensive aggression and offensive/proactive aggression. This review sought to present the evidence for genetic underpinnings of aggression and to determine to what degree prior studies have examined phenotypes that fit into the RDoC framework. Although the constructs of defensive and offensive aggression have been widely used in the animal genetics literature, the human literature is mostly agnostic with regard to all the RDoC constructs. We know from twin studies that about half the variance in behavior may be explained by genetic risk factors. This is true for both dimensional, trait-like, measures of aggression and categorical definitions of psychopathology. The non-shared environment seems to have a moderate influence with the effects of shared environment being unclear. Human molecular genetic studies of aggression are in an early stage. The most promising candidates are in the dopaminergic and serotonergic systems along with hormonal regulators. Genome-wide association studies have not yet achieved genome-wide significance, but current samples are too small to detect variants having the small effects one would expect for a complex disorder. The strongest molecular evidence for a genetic basis for aggression comes from animal models comparing aggressive and non-aggressive strains or documenting the effects of gene knockouts. Although we have learned much from these prior studies, future studies should improve the measurement of aggression by using a systematic method of measurement such as that proposed by the RDoC initiative. © 2015 Wiley Periodicals, Inc.
    • Influence of Parental SUD and ADHD on ADHD in their Offspring: Preliminary Results from a Pilot-controlled Family Study

      Wilens, Timothy E.; Hahesy, Amy L.; Biederman, Joseph; Bredin, Elizabeth; Tanguay, Sarah; Kwon, Anne; Faraone, Stephen V. (Wiley, 2005-03)
      As part of a pilot-controlled family-based study of the children of parents with and without substance use disorders (SUD), the influence of parental SUD and ADHD on the risk for ADHD in offspring was evaluated. Using structured psychiatric interviews, 96 families (183 youth; mean age 11.6 years) were assessed. To evaluate the effect of parental ADHD and SUD, the offspring were stratified into four groups based on parental status: children of parents with neither ADHD nor SUD, children of parents with SUD only, children of parents with ADHD only, and children of parents with both ADHD and SUD. Using generalized estimating equation models, parental SUD and ADHD were used to predict ADHD in the offspring. The rate of children with ADHD increased among children of parents with neither disorder (3%), children of parents with SUD (13%), children of parents with ADHD (25%), and children of parents with both ADHD and SUD (50%) (p ¼ :001). Children of parents with ADHD or ADHD plus SUD were more likely to have ADHD in comparison to children of parents with neither diagnosis (p < 0:05). Children of parents with ADHD plus SUD were at greater risk of ADHD in comparison to children of parents with SUD only (p ¼ 0:01). Despite the small sample size, the results of this study seem to suggest that the offspring of SUD or ADHD parents are at elevated risk for ADHD compared to controls. The offspring of parents with both ADHD and SUD appear to be at the highest risk for ADHD, highlighting the need for careful screening of this group of youth for ADHD. Replication studies clarifying the nature and strength of the association are necessary.
    • Informativeness of Self-Reports of ADHD Symptoms in Monitoring Response to Stimulant Treatment in Clinically Referred Adults With ADHD

      Biederman, Joseph; Fitzgerald, Maura; Spencer, Thomas J.; Adler, Lenard A.; Abrams, Jessica; Biederman, Itai; Faraone, Stephen V. (SAGE Publications, 2018-05-26)
      To investigate the informativeness of self-reports of ADHD symptoms in adults with ADHD in the clinical setting. Method: Subjects were clinically referred adults aged 19 years to 67 years of age of both sexes (N = 54). All subjects were on stable doses of stimulant and were considered responders to treatment. ADHD symptoms were assessed using the ADHD Investigator Symptom Rating Scale (AISRS) and the ADHD Self-Report Scale (ASRS). Spearman’s rank correlations were used to assess the correlations between clinician-assessed ADHD and patients’ self-reports. Results: Spearman’s rank correlation analysis found evidence of a strong, positive association between total scores on the AISRS and the ASRS (rs = .65, df = 52, p < .001). Conclusion: Results have important implications for the management and monitoring of treatment response in the clinical setting through patients’ self-report.(J. of Att. Dis. 2020; 24(3) 420-424)
    • Investigating the Role of Paxillin in Mammary Gland Morphogenesis and Breast Cancer Progression

      Turner, Christopher; Xu, Weiyi (2020)
      Breast cancer is one of the most invasive cancers among women. Understanding the mechanisms contributing to breast cancer progression may identify potential ways to prevent and cure the disease. Meanwhile, mammary gland morphogenesis shares similar mechanisms to allow the ducts to invade and occupy the fat pad. Thus, it is equally important to investigate the normal mammary gland development as breast tumor progression. Paxillin, as a focal adhesion scaffold protein, has previously been implicated in multiple types of cancer cell migration and invasion through its role in cell- ECM signaling. Herein, I utilized a novel paxillin conditional knockout mouse model and paxillin knockout mouse crossed with PyMT breast tumor mouse model to show that paxillin is critical for both mammary gland morphogenesis and breast tumor progression. In Chapter 2, by evaluating the developing mammary gland morphology with immunohistochemistry and the three-dimensional cultured mammary organoids and acini, a critical role of paxillin was shown in facilitating apical-basal polarity formation in the luminal epithelial cells in part, through its control of HDAC6 activity and associated microtubule acetylation. Correct polarization and columnar shape of the epithelial cells potentially contributes to lumen formation and branching of the ducts. Investigation in Chapter 3 highlights a crucial role of paxillin in breast cancer invasion and distant organ metastasis, but did not affect the primary tumor growth rate. Further analysis revealed that paxillin is required for the endocytosis and recycling of E- cadherin, which is important for the maintenance of Adherens junction equilibrium during cancer cell collective migration. This thesis characterizes the roles for paxillin in mammary gland morphogenesis and breast cancer progression and reveals the importance of paxillin-dependent apical trafficking in normal epithelial cells, and E-cadherin trafficking in collective migrating tumor cells. Together, this work highlights a trafficking-dependent mechanism for paxillin during both physiologic and pathologic processes in the mammary gland.
    • Investigation of parent-of-origin effects in ADHD candidate genes

      Kim, Jang Woo; Waldman, Irwin D.; Faraone, Stephen V.; Biederman, Joseph; Doyle, Alysa E.; Purcell, Shaun; Arbeitman, Lori; Fagerness, Jesen; Sklar, Pamela; Smoller, Jordan W. (Wiley, 2007)
    • JUNCTIONAL ARMADILLO (β-CATENIN) MAINTAINS PROPER TISSUE ARCHITECTURE DURINGDROSOPHILAEYE DEVELOPMENT

      Pignoni, Francesca; DeSantis, Dana F (2020)
      Formation of thecompoundeye of Drosophilarequires carefully orchestrated developmental events that occur in its progenitor epithelium, the eye imaginal disc.This tissue is composed of two continuous, apposed epithelia: the disc proper epithelium (DpE), which forms the retina, and the peripodial epithelium (PE), which ultimately forms head cuticle. In this work, I describe an armadillo (b-catenin)loss-of-function condition in which the developing DpEis disrupted and displays a phenotype that I call“retinalshift”. This developmental phenotype ultimately results in abnormal fly eye morphology that is incompatible with compound eye vision.I uncover a role for the PE in maintaining proper retinal epithelium morphology during eye formation and trace the molecular mechanism to the regulation of Hippo-Yki pathway in PE cells by the function of Armadillo at the adherens junctions.
    • Laboratory-Observed Behavioral Disinhibition in the Young Offspring of Parents With Bipolar Disorder: A High-Risk Pilot Study

      Hirshfeld-Becker, Dina R.; Biederman, Joseph; Henin, Aude; Faraone, Stephen V.; Cayton, Gabrielle A.; Rosenbaum, Jerrold F. (American Psychiatric Association Publishing, 2006-02)
      Objective: This study tested whether behavioral disinhibition is more prevalent among offspring of parents with bipolar disorder than among offspring of parents without bipolar disorder. Method: The authors conducted a secondary analysis of data from a preexisting high-risk study of offspring at risk for panic disorder and depression (N=278) that had included some children with parents who had bipolar disorder (N=34). Children (ages 2–6) had been classified as behaviorally inhibited, disinhibited, or neither in laboratory assessments. Results: Offspring of bipolar parents had significantly higher rates of behavioral disinhibition than offspring of parents without bipolar disorder. Behavioral inhibition did not differ between groups. Differences were not accounted for by parental panic disorder or major depression or by parental history of attention deficit hyperactivity disorder, conduct disorder, antisocial personality, or substance use disorders. Conclusions: Results suggest a familial link between bipolar disorder in parents and behavioral disinhibition in their offspring. Behavioral disinhibition may be a familially transmitted predisposing factor for dysregulatory distress later in life.
    • Lack of Association Between Behavioral Inhibition and Psychosocial Adversity Factors in Children at Risk for Anxiety Disorders

      Hirshfeld-Becker, Dina R.; Biederman, Joseph; Faraone, Stephen V.; Segool, Natasha; Buchwald, Jennifer; Rosenbaum, Jerrold F. (American Psychiatric Association Publishing, 2004-03)
      Objective: In a previous controlled study of offspring at risk for anxiety disorders, the authors found that parental panic disorder with comorbid major depression was associated with child behavioral inhibition, the temperamental tendency to be quiet and restrained in unfamiliar situations. To explore whether this association was mediated by environmental factors, the authors examined associations between psychosocial adversity variables and behavioral inhibition in this group of children. Method: Subjects included 200 offspring of parents with panic disorder and/or major depression and 84 comparison children of parents without mood or anxiety disorders. Behavioral inhibition was assessed through laboratory observations. The associations between behavioral inhibition and the following psychosocial factors were examined: socioeconomic status; an index of adversity factors found in previous studies to be additively associated with child psychopathology; family intactness, conflict, expressiveness, and cohesiveness; exposure to parental psychopathology; sibship size; birth order; and gender. Results: The results showed no associations between behavioral inhibition and any of the psychosocial factors in the study group as a whole, despite adequate power to detect medium effect sizes. Among low-risk comparison children only, some definitions of behavioral inhibition were associated with low socioeconomic status, low family cohesion, and female gender. Conclusions: The results suggest that the psychosocial adversity factors examined in this study do not explain the previous finding that offspring of parents with panic disorder are at high risk for behavioral inhibition.
    • Lack of Association Between Parental Alcohol or Drug Addiction and Behavioral Inhibition in Children

      Biederman, Joseph; Hirshfeld-Becker, Dina R.; Rosenbaum, Jerrold F.; Perenick, Sarah G.; Wood, Julia; Faraone, Stephen V. (American Psychiatric Association Publishing, 2001-10)
      Objective: “Behavioral inhibition to the unfamiliar” has been proposed as a precursor to anxiety. A recent study proposed that it may also be a precursor to alcoholism. The authors sought to replicate the latter finding through a secondary analysis of data from a large study of young children (age 2–6 years)—offspring of parents with panic and depressive disorders—who had been assessed for behavioral inhibition through laboratory-based observations. Method: The offspring were stratified on the basis of presence or absence of parental lifetime history of DSM-III-R alcohol dependence (N=115 versus N=166, respectively) or drug dependence (N=78 versus N=203). The rates of behavioral inhibition were then compared between groups. Results: Despite adequate power to detect associations, neither parental alcohol dependence nor drug dependence was associated with a higher risk for behavioral inhibition in the offspring. Conclusions: These results are not consistent with the hypothesis linking behavioral inhibition to addictions
    • Laminins regulate retinal angiogenesis

      Brunken, William J.; Biswas,Saptarshi (2017)
      Vascular pathologies are the leading causes of acquired blindness in the developed world. While many studies sought to unravel cell-intrinsic and growth factor-mediated regulations of angiogenesis, it is only recently that the role of the basement membrane (BM) components in angiogenesis began to be explored. Several diseases with ocular manifestations are known to alter vascular BM compositions. Therefore, a detailed knowledge of the BM-mediated signals that regulate angiogenesis is of great importance. Laminins, a critical component of the BM, have been shown to regulate several aspects of angiogenesis in the retina. Our laboratory previously demonstrated that the laminin composition of the inner limiting membrane (ILM) regulates astrocyte migration, and consequently vascular expansion along the retinal surface. Here, I examined the role of γ3- and β2-containing laminins in two specific aspects of angiogenesis: 1) vascular branching and endothelial cell proliferation in the nascent vascular plexus, and 2) arterial morphogenesis in the remodeling zone. Results presented in Chapter 2 and Appendix 1 demonstrate that laminin composition of the BM is a critical regulator of microglial recruitment to the growing nascent plexus, where microglia facilitate vascular branching. Furthermore, microglia interact with the astrocyte-derived layer of the vascular BM, and that this interaction regulates iii microglial activation. The activation state of microglia, in turn, regulates endothelial cell proliferation. Results presented in Chapter 3 and Appendix 2 demonstrate that vascular BM laminins are critical regulators of arterial morphogenesis. Specifically, my results reveal a novel mechanism where γ3- containing laminins signal through dystroglycan to induce Dll4/Notch signaling in arterial endothelial cells, regulating proper arterial morphogenesis. Finally, in Appendix 3, I examined the coordinated expression of different laminin chains in the vascular BM. My preliminary results suggest that expressions of laminin α2-, α5- and γ3-chains in the retinal vascular BM are coordinately regulated with the expression of laminin β2-chain. In conclusion, this study sheds light on hitherto unexplored mechanisms by which BM laminins regulate retinal vascular development.
    • Linkage of chromosome 13q32 to schizophrenia in a large veterans affairs cooperative study sample

      Faraone, Stephen V.; Skol, Andrew D.; Tsuang, Debby W.; Bingham, Stephen; Young, Keith A.; Prabhudesai, Sarita; Haverstock, Susan L.; Mena, Felicitas; Menon, Aerath Sri Kumar; Bisset, Darren; et al. (Wiley, 2002-07-29)
      Several prior reports have suggested that chromosomal region 13q32 may harbor a schizophrenia susceptibility gene. In an attempt to replicate this finding, we assessed linkage between chromosome 13 markers and schizophrenia in 166 families, each with two or more affected members. The families, assembled from multiple centers by the Department of Veterans Affairs Cooperative Studies Program, included 392 sampled affected subjects and 216 affected sib pairs. By DSM-III-R criteria, 360 subjects (91.8%) had a diagnosis of schizophrenia and 32 (8.2%) were classified as schizoaffective disorder, depressed. The families had mixed ethnic backgrounds. The majority were northern European-American families (n = 62, 37%), but a substantial proportion were African-American kindreds (n = 60, 36%). Chromosome 13 markers, spaced at intervals of approximately 10 cM over the entire chromosome and 2-5 cM for the 13q32 region were genotyped and the data analyzed using semi-parametric affected only linkage analysis. For the combined sample (with race broadly defined and schizophrenia narrowly defined) the maximum LOD score was 1.43 (Z-score of 2.57; P = 0.01) at 79.0 cM between markers D13S1241 (76.3 cM) and D13S159 (79.5 cM). Both ethnic groups showed a peak in this region. The peak is within 3 cM of the peak reported by Brzustowicz et al.
    • Liver-specific glucocorticoid action in alcoholic liver disease

      Lu, Hong; Wang, Yazheng (2021)
      The number of deaths due to alcoholic liver disease is increasing every year. Glucocorticoids (GCs) are the only first-line drugs for alcoholic hepatitis (AH) treatment but have limited efficacy. Long-term high-dose GC use can cause various side effects on extrahepatic tissues, such as immunosuppression and neuromuscular side effects, which may be a limiting factor for GC treatment of AH. Therefore, liver-specific GC-targeted therapy may have multiple advantages compared with systemic GC for AH. This research explored the role of liver-specific deficiency of glucocorticoid receptor (GR) in AH induced by a high-fat diet (HFD) plus ethanol binge. Females are less prone to AH induced by HFD plus acute binge drinking, likely due to sex differences in estrogen (E2) signaling. We found that hepatic GR deficiency worsened steatosis in both genders of AH mice but only aggravated the liver injury in male AH mice. Multiple signaling pathways were dysregulated in GR knockout AH mice. Interestingly, hepatic expression of estrogen receptor (ERα) was induced, and the E2-inactivating enzyme was markedly down-regulated in GR knockout AH mice, suggesting enhanced E2 signaling in these mice. Our data mining found marked dysregulation of many GR-target genes important for lipid catabolism, cytoprotection, and inflammation in patients with severe AH. These key GR-target genes were similarly induced or down-regulated by our liver-targeting GC prodrugs and the parent drug at 1μM in primary human hepatocytes. In contrast, GC prodrugs had much weaker inhibitory effects than the parent drug on LPS-induction of IL-1B in mouse macrophages, suggesting a good liver selectivity of our liver-targeting GC prodrugs. The ultimate goal of this study is to determine the mechanistic role of GR in alcoholic fatty liver disease and develop targeted drug therapies to treat alcoholic hepatitis.
    • Localization of sarcomeric proteins during muscle assembly in mouse cardiomyocytes and skeletal myotubes

      Sanger, Jean; Sanger, Joseph; Welchons, Matthew J (2017)
      This study seeks to investigate the role of contractions in myofibrillogenesis, and structure of nascent myofibrils. The model system employed in these experiments was cultured quail myotubes. In order to determine the role of contractions in myofibrillogensis, contractions were indirectly inhibited with elevated KCl, and directly inhibited with 2,3 butanedione monoxime (BDM), a small cell-permeable inhibitor of actin & muscle myosin interactions. Myotubes were treated with contraction inhibitors at 2½days –soon after the main fusion event. On the 6thculture day, there was significant delay in myofibrillogensis in myotubes exposed to elevated KCl. This delay was characterized by the expansion of nascent myofibrils at the spreading edges of myotubes. This delay in myofibrillogenesis was not accompanied by diminished accumulations of muscle myosin. On the 4thculture day, there was complete arrest of myofibrillogenesis at the nascent step with the treatment of BDM. As a result, it is concluded that contractions are necessary for the progression of nascent myofibrils to mature myofibrils. The structure of nascent myofibrils was further investigated with super resolution microscopy. Structured illumination microscopy (SIM) and stimulated emission depletion (STED) microscopy revealed mini-A-bands –shorter than 1.5 μmin length –associated with nascent myofibrils. These structures were spaced at varying intervals, and oriented at angles deviating the from the actin superstructure of the nascent myofibril. Mini-A-bands were also observed to progressively in expand in length distal to the spreading edges of myotubes. STED imaging indicates that some mini-A-band are adjacent to, and not integrated within, the actin superstructure of nascent myofibrils.