Joseph Gonzalez-Heydrich
Boston Children's Hospital
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Featured researches published by Joseph Gonzalez-Heydrich.
Science Translational Medicine | 2012
Elizabeth Berry-Kravis; David Hessl; Barbara Rathmell; Peter Zarevics; Maryann Cherubini; Karen Walton-Bowen; Yi Mu; Danh V. Nguyen; Joseph Gonzalez-Heydrich; Paul P. Wang; Randall L. Carpenter; Mark F. Bear; Randi J. Hagerman
Administration of a selective GABAB agonist to individuals with fragile X syndrome improves their deficits in social avoidance, a core symptom of the disease. A Fragile Balancing Act A wide array of symptoms—including intellectual disability, anxiety, seizures, and autistic behavior—are associated with fragile X syndrome (FXS). Although some symptoms can be managed (or masked) with drugs or other therapies, treatments that target the fundamental impairments are not available. Henderson et al. and Berry-Kravis et al. now provide evidence that activation of a particular neuronal receptor can improve symptoms in both mice and humans. FXS is caused by silencing of the FMR1 gene, which encodes FMRP, an RNA binding protein that inhibits protein synthesis. In a mouse model of FXS, dendritic protein synthesis is abnormally high; FMRP is believed to regulate mRNAs important for neuronal development. Furthermore, these mice—and some humans with FXS—have an increased density of dendritic spines, which are dynamic structures that make neuronal connections. Dendritic spine plasticity is linked to learning and memory. Normally, FMRP may balance mRNA translation that is stimulated by activation of synaptic receptors that respond to glutamate, an excitatory neurotransmitter. Indeed, inhibitors of these receptors rescue many irregular phenotypes in the animal models but are not yet approved for human use. These mice also exhibit deficient signaling through a different set of receptors, which respond to the inhibitory neurotransmitter GABA—and for which clinically approved agonists already exist. Henderson et al. tested one such GABAB receptor agonist, STX209, in the mouse model and found that it decreased mRNA translation in the cortex and corrected the increased dendritic spine density. Berry-Kravis et al. studied the effects of STX209 in a double-blind, placebo-controlled crossover trial, in which 63 FXS patients received placebo or drug for 4 weeks and then switched to the other treatment. Although a measure of irritability and aggression was unchanged, social avoidance improved; the drug was well tolerated. Thus, this targeted approach, which may help restore the balance between excitatory and inhibitory neurotransmission, has promise for improving social function in FXS. Research on animal models of fragile X syndrome suggests that STX209, a γ-aminobutyric acid type B (GABAB) agonist, might improve neurobehavioral function in affected patients. We evaluated whether STX209 improves behavioral symptoms of fragile X syndrome in a randomized, double-blind, placebo-controlled crossover study in 63 subjects (55 male), ages 6 to 39 years, with a full mutation in the FMR1 gene (>200 CGG triplet repeats). We found no difference from placebo on the primary endpoint, the Aberrant Behavior Checklist—Irritability (ABC-I) subscale. In the other analyses specified in the protocol, improvement was seen on the visual analog scale ratings of parent-nominated problem behaviors, with positive trends on multiple global measures. Post hoc analysis with the ABC—Social Avoidance scale, a newly validated scale for the assessment of fragile X syndrome, showed a significant beneficial treatment effect in the full study population. A post hoc subgroup of 27 subjects with more severe social impairment showed improvements on the Vineland II–Socialization raw score, on the ABC—Social Avoidance scale, and on all global measures. STX209 was well tolerated, with 8% incidences of sedation and of headache as the most frequent side effects. In this exploratory study, STX209 did not show a benefit on irritability in fragile X syndrome. Nonetheless, our results suggest that GABAB agonists have potential to improve social function and behavior in patients with fragile X syndrome.
Journal of Child and Adolescent Psychopharmacology | 2001
Jean A. Frazier; Joseph Biederman; Mauricio Tohen; Peter D. Feldman; T. Jacobs; V. Toma; Michael Rater; Reem Tarazi; Grace S. Kim; Stacey B. Garfield; Mari Sohma; Joseph Gonzalez-Heydrich; Richard C. Risser; Zachary M. Nowlin
OBJECTIVE The goal of this study was to assess the effectiveness and tolerability of olanzapine in the treatment of acute mania in children and adolescents. METHODS This was an 8-week, open-label, prospective study of olanzapine monotherapy (dose range 2.5-20 mg/day) involving 23 bipolar youths (manic, mixed, or hypomanic; 5-14 years old). Weekly assessments were made using the Young Mania Rating Scale (YMRS), Clinical Global Impressions Severity Scale (CGI-S), Brief Psychiatric Rating Scale, and Childrens Depression Rating Scale. Adverse events were assessed through self-reports, vital sign and weight monitoring, laboratory analytes, and extrapyramidal symptom rating scales (Barnes Akathisia Scale, Simpson-Angus Scale, and Abnormal Involuntary Movement Scale). RESULTS Twenty-two of the 23 youths (96%) completed the study. Olanzapine treatment was associated with significant improvement in mean YMRS score (-19.0 +/- 9.2, p < 0.001). Using predefined criteria for improvement of > or = 30% decline in the YMRS and a CGI-S Mania score of < or = 3 at endpoint, the overall response rate was 61%. Overall, olanzapine was well tolerated, and extrapyramidal symptom measures were not significantly different from baseline. Body weight increased significantly over the study (5.0 +/- 2.3 kg, p < 0.001). CONCLUSIONS Open-label olanzapine treatment was efficacious and well tolerated in the treatment of acute mania in youths with bipolar disorder. Future placebo-controlled, double-blind studies are warranted.
Epilepsy & Behavior | 2008
Alcy Torres; Jane Whitney; Joseph Gonzalez-Heydrich
Attention-deficit/hyperactivity disorder (ADHD) in children with epilepsy is a common source of impairment. Based on review of Medline indexed articles, meeting abstracts, and data requested from drug manufacturers, a summary of evidence that might guide treatment and research is presented. Methylphenidate (MPH) has shown high response rates and no increase in seizures in small trials. However, low baseline seizure rates, small numbers of subjects, and short observation periods limit the power of these studies to detect increases in seizure risk. Although longer-term effects of MPH and its effects in children with frequent seizures need to be studied, the evidence available at this time best supports use of MPH for the treatment of ADHD not amenable to changes in antiepileptic drugs or improvements in seizure control. This treatment should be part of a biopsychosocial approach. Other agents show promise. Preclinical, retrospective and open-label studies on amphetamines and atomoxetine support undertaking randomized controlled studies of these agents in patients with ADHD plus epilepsy. In contrast, additional data on guanfacine and modafinil should be gathered before undertaking randomized controlled studies with these agents.
Frontiers in Synaptic Neuroscience | 2010
Lindsay M. Oberman; Frederick Ifert-Miller; Umer Najib; Shahid Bashir; Ione O.C. Woollacott; Joseph Gonzalez-Heydrich; Jonathan Picker; Alexander Rotenberg; Alvaro Pascual-Leone
Fragile X Syndrome (FXS) is the most common heritable cause of intellectual disability. In vitro electrophysiologic data from mouse models of FXS suggest that loss of fragile X mental retardation protein affects intracortical excitability and synaptic plasticity. Specifically, the cortex appears hyperexcitable, and use-dependent long-term potentiation (LTP) and long-term depression (LTD) of synaptic strength are abnormal. Though animal models provide important information, FXS and other neurodevelopmental disorders are human diseases and as such translational research to evaluate cortical excitability and plasticity must be applied in the human. Transcranial magnetic stimulation paradigms have recently been developed to non-invasively investigate cortical excitability using paired pulse stimulation, as well as LTP- and LTD-like synaptic plasticity in response to theta burst stimulation (TBS) in vivo in the human. TBS applied on consecutive days can be used to measure metaplasticity (the ability of the synapse to undergo a second plastic change following a recent induction of plasticity). The current study investigated intracortical inhibition, plasticity and metaplasticity in full mutation females with FXS, participants with autism spectrum disorders (ASD), and neurotypical controls. Results suggest that intracortical inhibition is normal in participants with FXS, while plasticity and metaplasticity appear abnormal. ASD participants showed abnormalities in plasticity and metaplasticity, as well as heterogeneity in intracortical inhibition. Our findings highlight the utility of non-invasive neurophysiological measures to translate insights from animal models to humans with neurodevelopmental disorders, and thus provide direct confirmation of cortical dysfunction in patients with FXS and ASD.
American Journal of Medical Genetics | 2008
Stephen V. Faraone; Alysa E. Doyle; Jessica Lasky-Su; Pamela Sklar; Eugene J. D'Angelo; Joseph Gonzalez-Heydrich; Christopher J. Kratochvil; Eric Mick; Kristy L. Klein; Amy J. Rezac; Joseph Biederman
Results of behavioral genetic and molecular genetic studies have converged to suggest that both genes contribute to the development of ADHD. Although prior linkage studies have produced intriguing results, their results have been inconsistent, with no clear pattern of results emerging across studies. We genotyped 5,980 SNPs across the genome in 1,187 individuals from families with children diagnosed with ADHD. We then performed two nonparametric linkage analyses on ADHD families: (1) an affected sibling pair linkage analysis on 217 families with 601 siblings diagnosed with ADHD and (2) a variance components linkage analysis using the number of ADHD symptoms as the phenotype on 260 families with 1,100 phenotyped siblings. The affection status linkage analysis had a maximum LOD score of 1.85 on chromosome 8 at 54.2 cM. The maximum LOD score in the variance components linkage analysis was 0.8 on chromosome 8 at 93.4 cM. The absence of regions of significant or suggestive linkage in these data suggest that there are no genes of large effect contributing to the ADHD phenotype.
Epilepsy & Behavior | 2007
Joseph Gonzalez-Heydrich; Alice Dodds; Jane Whitney; Carlene MacMillan; Deborah P. Waber; Stephen V. Faraone; Katrina Boyer; Christine Mrakotsky; David R. DeMaso; Blaise F. D. Bourgeois; Joseph Biederman
OBJECTIVE Attention-deficit hyperactivity disorder (ADHD) coexisting with epilepsy is poorly understood; thus, we compared the clinical correlates and psychiatric comorbid conditions of 36 children with epilepsy and ADHD aged 6 to 17 years enrolled in an ADHD treatment trial, with those reported in the literature on children with ADHD without epilepsy. METHODS Measures included the Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children (KSADS), the Wechsler Abbreviated Scale of Intelligence (WASI), and the Scales for Independent Behavior-Revised (SIB-R). RESULTS Mean IQ was 86+/-19, and SIB-R Standard Score was 72+/-26. The ADHD-Combined subtype, composed of both inattentive and hyperactive symptoms, was most frequent (58%). Sixty-one percent exhibited a comorbid disorder, including anxiety disorders (36%) and oppositional defiant disorder (31%). CONCLUSIONS Comorbidity in ADHD with epilepsy is similar to that in ADHD without epilepsy reported in the literature. These preliminary data argue that the pathophysiology of ADHD has common components in both populations.
human factors in computing systems | 1998
Marina Umaschi Bers; Edith Ackermann; Justine Cassell; Beth Donegan; Joseph Gonzalez-Heydrich; David R. DeMaso; Carol Strohecker; Sarah Lualdi; Dennis Nathan Bromley; Judith Karlin
This paper describes exploration of uses of a computational storytelling environment on the Car- diology Unit of the ChildrenHospital in Boston, during the summer of 1997. Young cardiac patients ranging from age 7 to 16 used the SAGE environment to tell personal stories and cre- ate interactive characters, as a way of coping with cardiac illness, hospitalizations, and invasive medical procedures. This pilot study is part of a larger collaborative effort between Children ´ Hospital and MERL - A Mitsubishi Electric Research Laboratory, to develop a web-based appli- cation, the Experience Journal, to assist patients and their families in dealing with serious medical illness. The focus of the paper is on young patientsof SAGE, on SAGEaffordances in the context of the hospital, and on design recommendations for the development of future computa- tional play kits for expressing and exchanging feelings and ideas. Preliminary analysis of young patientsindicates that children used different modes of interaction-direct, mediated, and differed-, depending upon what personae the narrator chooses to take on. These modes seem to vary with the mindset and health condition of the child.
Epilepsy & Behavior | 2010
Joseph Gonzalez-Heydrich; Jane Whitney; Deborah P. Waber; Peter W. Forbes; Olivia Hsin; Stephen V. Faraone; Alice Dodds; Sneha Rao; Christine Mrakotsky; Carlene MacMillan; David R. DeMaso; Carl de Moor; Alcy Torres; Blaise F. D. Bourgeois; Joseph Biederman
OBJECTIVE The goal of this study was to pilot a randomized controlled trial of OROS methylphenidate (OROS-MPH) to treat attention deficit hyperactivity disorder (ADHD) plus epilepsy. METHODS Thirty-three patients, 6-18years of age, taking antiepileptic drugs and with a last seizure 1-60months prior were assigned to a maximum daily dose of 18, 36, or 54mg of OROS-MPH in a double-blind placebo-controlled crossover trial. RESULTS There were no serious adverse events and no carryover effects in the crossover trial. OROS-MPH reduced ADHD symptoms more than did placebo treatment. There were too few seizures during the active (5) and placebo arms (3) to confidently assess seizure risk; however, considering exposure time, we observed an increased daily risk of seizures with increasing dose of OROS-MPH, suggesting that potential safety concerns require further study. CONCLUSION A larger study to assess the effect of OROS-MPH on seizure risk is needed. A crossover design including subjects with frequent seizures could maximize power and address high patient heterogeneity and recruitment difficulties.
human factors in computing systems | 2001
Marina Umaschi Bers; Joseph Gonzalez-Heydrich; David R. DeMaso
We describe a five-month pilot project conducted in the dialysis unit at Bostons Childrens Hospital. Pediatric patients with renal disease used the Zora graphical multi-user environment while facing hemodialysis. Zora is an identity construciton environment specifically designed to help young people explore issues of identity, while engaging in a participatory virtual community. This paper presents the experience and evaluates the feasibility and safety of using Zora in a hospital setting. It describes how Zora facilitated explorations of identity and mutual patient support and interaction. Finally it also presents design recommendations for future interventions of this kind. More generally, this paper explores the potential of technology specifically designed with therapeutic purposes to help patients cope with their illness.
Expert Opinion on Investigational Drugs | 2008
Lourival Baptista-Neto; Alice Dodds; Sneha Rao; Jane Whitney; Alcy Torres; Joseph Gonzalez-Heydrich
Methylphenidate (MPH) is one of the most commonly prescribed medications to treat attention deficit hyperactivity disorder (ADHD). Despite the elevated rates of ADHD in children with epilepsy, few studies have examined the use of MPH in this population. Case reports have warned about new-onset seizures in patients treated with MPH, and drug–drug interactions between MPH and antiepileptic drugs (AEDs), as well as antidepressants. However, retrospective chart reviews, open-label trials and controlled trials of MPH in patients with epilepsy and ADHD have noted significant improvements in ADHD symptoms without an exacerbation of seizures or an adverse effect on AED serum levels. This paper reviews the chemistry and mechanisms of action of MPH, as well as preclinical, premarketing clinical trials and postmarketing data relevant to its use in patients with ADHD and epilepsy.