Browsing by Subject "Hyperactivity"

Now showing 1 - 4 of 4
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    Guanabenz Reduces Hyperactivity and Neuroinflammation Caused by Latent Toxoplasmosis in Mice
    (2020-02) Martynowicz, Jennifer Marie; Sullivan, William J., Jr.; Arrizabalaga, Gustavo; Boehm II, Stephen L.; Gilk, Stacey D.; Spinola, Stanley M.
    Toxoplasma gondii is an intracellular parasite that causes persistent, lifelong infection in one-third of humans worldwide. The parasite converts from a lytic, actively replicating form (tachyzoite) into a latent tissue cyst form (bradyzoite) that evades host immunity and is impervious to current drugs. While acute infection can be life threatening to immunosuppressed individuals, chronic infection has been linked to behavioral changes in rodents and neurological disease in humans. Notably, chronic infection in mice leads to hyperactivity in an open field. Whether these behavioral changes are due to parasite manipulation of the host or the host response to infection remains an outstanding question. We have previously shown that the anti-hypertensive drug guanabenz reduces Toxoplasma cyst burden in the brains of BALB/c mice, providing a means to examine whether brain cyst depletion reverses behavioral changes. We used two mouse strains (BALB/c and C57BL/6) differing in their susceptibility to infection. Following drug treatment of chronically infected mice, locomotor activity in an open field was assessed. In both mouse strains, the increased hyperactivity seen during chronic infection returned to normal levels following guanabenz treatment. Guanabenz reduced brain cyst burden ~70% in BALB/c mice as expected, but it increased cyst burden 49% in C57BL/6 mice. Examination of the brains showed that guanabenz decreased inflammation and perivascular cuffing in both infected mouse strains. Our study shows for the first time that it is possible to reverse a key behavioral change associated with chronic Toxoplasma infection. Surprisingly, the rescue from parasite-induced hyperactivity correlates with a decrease in neuroinflammation instead of cyst counts, suggesting that some behavioral changes arise from host responses to infection rather than a parasite-driven process.
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    Guanfacine treatment improves ADHD phenotypes of impulsivity and hyperactivity in a neurofibromatosis type 1 mouse model
    (BMC, 2020-01-15) Lukkes, J. L.; Drozd, H. P.; Fitz, S. D.; Molosh, A. I.; Clapp, D. W.; Shekhar, A.; Psychiatry, School of Medicine
    BACKGROUND: Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder with a mutation in one copy of the neurofibromin gene (NF1+/-). Even though approximately 40-60% of children with NF1 meet the criteria for attention deficit hyperactivity disorder (ADHD), very few preclinical studies, if any, have investigated alterations in impulsivity and risk-taking behavior. Mice with deletion of a single NF1 gene (Nf1+/-) recapitulate many of the phenotypes of NF1 patients. METHODS: We compared wild-type (WT) and Nf1+/- mouse strains to investigate differences in impulsivity and hyperactivity using the delay discounting task (DDT), cliff avoidance reaction (CAR) test, and open field. We also investigated whether treatment with the clinically effective alpha-2A adrenergic receptor agonist, guanfacine (0.3 mg/kg, i.p.), would reverse deficits observed in behavioral inhibition. RESULTS: Nf1+/- mice chose a higher percentage of smaller rewards when both 10- and 20-s delays were administered compared to WT mice, suggesting Nf1+/- mice are more impulsive. When treated with guanfacine (0.3 mg/kg, i.p.), Nf1+/- mice exhibited decreased impulsive choice by waiting for the larger, delayed reward. Nf1+/- mice also exhibited deficits in behavioral inhibition compared to WT mice in the CAR test by repetitively entering the outer edge of the platform where they risk falling. Treatment with guanfacine ameliorated these deficits. In addition, Nf1+/- mice exhibited hyperactivity as increased distance was traveled compared to WT controls in the open field. This hyperactivity in Nf1+/- mice was reduced with guanfacine pre-treatment. CONCLUSIONS: Overall, our study confirms that Nf1+/- mice exhibit deficits in behavioral inhibition in multiple contexts, a key feature of ADHD, and can be used as a model system to identify alterations in neural circuitry associated with symptoms of ADHD in children with NF1.
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    Positive effects of methylphenidate on hyperactivity are moderated by monoaminergic gene variants in children with autism spectrum disorders
    (Springer Nature, 2014) McCracken, J. T.; Badashova, K. K.; Posey, D. J.; Aman, M. G.; Scahill, L; Tierney, E.; Arnold, L. E.; Vitiello, B.; Whelan, F.; Chuang, S. Z.; Davies, M.; Shah, B.; McDougle, C. J.; Nurmi, E. L.; Psychiatry, School of Medicine
    Methylphenidate (MPH) reduces hyperactive-impulsive symptoms common in children with autism spectrum disorders (ASDs), however, response and tolerability varies widely. We hypothesized monoaminergic gene variants may moderate MPH effects in ASD, as in typically developing children with attention-deficit/hyperactivity disorder. Genotype data were available for 64 children with ASD and hyperactivity who were exposed to MPH during a 1-week safety/tolerability lead-in phase and 58 who went on to be randomized to placebo and three doses of MPH during a 4-week blinded, crossover study. Outcome measures included the Clinical Global Impression-Improvement (CGI-I) scale and the Aberrant Behavior Checklist (ABC-hyperactivity index). A total of 14 subjects discontinued the study because of MPH side effects. Subjects were genotyped for variants in DRD1-DRD5, ADRA2A, SLC6A3, SLC6A4, MAOA and MAOB, and COMT. Forty-nine percent of the sample met positive responder criteria. In this modest but relatively homogeneous sample, significant differences by DRD1 (P=0.006), ADRA2A (P<0.02), COMT (P<0.04), DRD3 (P<0.05), DRD4 (P<0.05), SLC6A3 (P<0.05) and SLC6A4 (P<0.05) genotypes were found for responders versus non-responders. Variants in DRD2 (P<0.001) and DRD3 (P<0.04) were associated with tolerability in the 14 subjects who discontinued the trial. For this first MPH pharmacogenetic study in children with ASD, multiple monoaminergic gene variants may help explain individual differences in MPH's efficacy and tolerability.
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    Trajectory Analysis for Identifying Classes of Attention Deficit Hyperactivity Disorder (ADHD) in Children of the United States
    (Bentham Open, 2024-05-21) Lee, Yu-Sheng; Sprong, Matthew Evan; Shrestha, Junu; Smeltzer, Matthew P.; Hollender, Heaven; Health Sciences, School of Health and Human Sciences
    Background: Attention Deficit Hyperactivity Disorder (ADHD) is a mental health disorder that affects attention and behavior. People with ADHD frequently encounter challenges in social interactions, facing issues, like social rejection and difficulties in interpersonal relationships, due to their inattention, impulsivity, and hyperactivity. Methods: A National Longitudinal Survey of Youth (NLSY) database was employed to identify patterns of ADHD symptoms. The children who were born to women in the NLSY study between 1986 and 2014 were included. A total of 1,847 children in the NLSY 1979 cohort whose hyperactivity/inattention score was calculated when they were four years old were eligible for this study. A trajectory modeling method was used to evaluate the trajectory classes. Sex, baseline antisocial score, baseline anxiety score, and baseline depression score were adjusted to build the trajectory model. We used stepwise multivariate logistic regression models to select the risk factors for the identified trajectories. Results: The trajectory analysis identified six classes for ADHD, including (1) no sign class, (2) few signs since preschool being persistent class, (3) few signs in preschool but no signs later class, (4) few signs in preschool that magnified in elementary school class, (5) few signs in preschool that diminished later class, and (6) many signs since preschool being persistent class. The sensitivity analysis resulted in a similar trajectory pattern, except for the few signs since preschool that magnified later class. Children's race, breastfeeding status, headstrong score, immature dependent score, peer conflict score, educational level of the mother, baseline antisocial score, baseline anxious/depressed score, and smoking status 12 months prior to the birth of the child were found to be risk factors in the ADHD trajectory classes. Conclusion: The trajectory classes findings obtained in the current study can (a) assist a researcher in evaluating an intervention (or combination of interventions) that best decreases the long-term impact of ADHD symptoms and (b) allow clinicians to better assess as to which class a child with ADHD belongs so that appropriate intervention can be employed.