Baclofen-associated neurophysiologic target engagement across species in fragile X syndrome / Carrie R. JONAK in Journal of Neurodevelopmental Disorders, 14 (2022)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 14 (2022) Titre : Baclofen-associated neurophysiologic target engagement across species in fragile X syndrome Type de document : texte imprimé Auteurs : Carrie R. JONAK, Auteur ; Ernest V. PEDAPATI, Auteur ; Lauren M. SCHMITT, Auteur ; Samantha A. ASSAD, Auteur ; Manbir S. SANDHU, Auteur ; Lisa DESTEFANO, Auteur ; Lauren ETHRIDGE, Auteur ; Khaleel A. RAZAK, Auteur ; John A. SWEENEY, Auteur ; Devin K. BINDER, Auteur ; Craig A. ERICKSON, Auteur Langues : Anglais (eng) Mots-clés : Animals  Baclofen/pharmacology  Disease Models, Animal  Fragile X Mental Retardation Protein/genetics  Fragile X Syndrome/complications/drug therapy  Humans  Male  Mice  Mice, Knockout  Autism  Baclofen  Biomarker  Electroencephalography  Fragile X syndrome  Multielectrode array  in fragile X syndrome held by the Cincinnati Children’s Research Foundation  (CCRF) and licensed out at the discretion of CCRF. CAE is a current consultant to  Impel, Stalicla, and Scioto Bioscience. Index. décimale : PER Périodiques Résumé : BACKGROUND: Fragile X syndrome (FXS) is the most common inherited form of neurodevelopmental disability. It is often characterized, especially in males, by intellectual disability, anxiety, repetitive behavior, social communication deficits, delayed language development, and abnormal sensory processing. Recently, we identified electroencephalographic (EEG) biomarkers that are conserved between the mouse model of FXS (Fmr1 KO mice) and humans with FXS. METHODS: In this report, we evaluate small molecule target engagement utilizing multielectrode array electrophysiology in the Fmr1 KO mouse and in humans with FXS. Neurophysiologic target engagement was evaluated using single doses of the GABA(B) selective agonist racemic baclofen (RBAC). RESULTS: In Fmr1 KO mice and in humans with FXS, baclofen use was associated with suppression of elevated gamma power and increase in low-frequency power at rest. In the Fmr1 KO mice, a baclofen-associated improvement in auditory chirp synchronization was also noted. CONCLUSIONS: Overall, we noted synchronized target engagement of RBAC on resting state electrophysiology, in particular the reduction of aberrant high frequency gamma activity, across species in FXS. This finding holds promise for translational medicine approaches to drug development for FXS, synchronizing treatment study across species using well-established EEG biological markers in this field. TRIAL REGISTRATION: The human experiments are registered under NCT02998151. En ligne : https://dx.doi.org/10.1186/s11689-022-09455-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=574 [article] Baclofen-associated neurophysiologic target engagement across species in fragile X syndrome [texte imprimé] / Carrie R. JONAK, Auteur ; Ernest V. PEDAPATI, Auteur ; Lauren M. SCHMITT, Auteur ; Samantha A. ASSAD, Auteur ; Manbir S. SANDHU, Auteur ; Lisa DESTEFANO, Auteur ; Lauren ETHRIDGE, Auteur ; Khaleel A. RAZAK, Auteur ; John A. SWEENEY, Auteur ; Devin K. BINDER, Auteur ; Craig A. ERICKSON, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 14 (2022) Mots-clés : Animals  Baclofen/pharmacology  Disease Models, Animal  Fragile X Mental Retardation Protein/genetics  Fragile X Syndrome/complications/drug therapy  Humans  Male  Mice  Mice, Knockout  Autism  Baclofen  Biomarker  Electroencephalography  Fragile X syndrome  Multielectrode array  in fragile X syndrome held by the Cincinnati Children’s Research Foundation  (CCRF) and licensed out at the discretion of CCRF. CAE is a current consultant to  Impel, Stalicla, and Scioto Bioscience. Index. décimale : PER Périodiques Résumé : BACKGROUND: Fragile X syndrome (FXS) is the most common inherited form of neurodevelopmental disability. It is often characterized, especially in males, by intellectual disability, anxiety, repetitive behavior, social communication deficits, delayed language development, and abnormal sensory processing. Recently, we identified electroencephalographic (EEG) biomarkers that are conserved between the mouse model of FXS (Fmr1 KO mice) and humans with FXS. METHODS: In this report, we evaluate small molecule target engagement utilizing multielectrode array electrophysiology in the Fmr1 KO mouse and in humans with FXS. Neurophysiologic target engagement was evaluated using single doses of the GABA(B) selective agonist racemic baclofen (RBAC). RESULTS: In Fmr1 KO mice and in humans with FXS, baclofen use was associated with suppression of elevated gamma power and increase in low-frequency power at rest. In the Fmr1 KO mice, a baclofen-associated improvement in auditory chirp synchronization was also noted. CONCLUSIONS: Overall, we noted synchronized target engagement of RBAC on resting state electrophysiology, in particular the reduction of aberrant high frequency gamma activity, across species in FXS. This finding holds promise for translational medicine approaches to drug development for FXS, synchronizing treatment study across species using well-established EEG biological markers in this field. TRIAL REGISTRATION: The human experiments are registered under NCT02998151. En ligne : https://dx.doi.org/10.1186/s11689-022-09455-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=574

Developmental milestones and daily living skills in individuals with Angelman syndrome / Anjali SADHWANI in Journal of Neurodevelopmental Disorders, 16 (2024)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 16 (2024) Titre : Developmental milestones and daily living skills in individuals with Angelman syndrome Type de document : texte imprimé Auteurs : Anjali SADHWANI, Auteur ; Sonya POWERS, Auteur ; Anne WHEELER, Auteur ; Hillary MILLER, Auteur ; Sarah Nelson POTTER, Auteur ; Sarika U. PETERS, Auteur ; Carlos A. BACINO, Auteur ; Steven A. SKINNER, Auteur ; Logan K. WINK, Auteur ; Craig A. ERICKSON, Auteur ; Lynne M. BIRD, Auteur ; Wen-Hann TAN, Auteur Langues : Anglais (eng) Mots-clés : Humans  Angelman Syndrome/physiopathology/genetics/complications  Activities of Daily Living  Female  Child, Preschool  Male  Child  Adolescent  Infant  Child Development/physiology  Longitudinal Studies  Motor Skills/physiology  Developmental Disabilities/etiology  Adult  Young Adult  Activities of Daily Living  Child development  Developmental disabilities  Intellectual disability Index. décimale : PER Périodiques Résumé : BACKGROUND: Angelman syndrome (AS) is a neurodevelopmental disorder associated with severe global developmental delay. However, the ages at which different developmental skills are achieved in these individuals remain unclear. We seek to determine the probability and the age of acquisition of specific developmental milestones and daily living skills in individuals with AS across the different molecular subtypes, viz. class I deletion, class II deletion, uniparental disomy, imprinting defect, and UBE3A variants. METHODS: Caregivers participating in a longitudinal multicenter Angelman Syndrome Natural History Study completed a questionnaire regarding the age at which their children achieved specific developmental milestones and daily living skills. The Cox Proportional Hazard model was applied to analyze differences in the probability of achievement of skills at various ages among five molecular subtypes of AS. RESULTS: Almost all individuals, regardless of molecular subtype, were able to walk with support by five years of age. By age 15, those with a deletion had at least a 50% probability of acquiring 17 out of 30 skills compared to 25 out of 30 skills among those without a deletion. Overall, fine and gross motor skills such as holding and reaching for small objects, sitting, and walking with support were achieved within a fairly narrow range of ages, while toileting, feeding, and hygiene skills tend to have greater variability in the ages at which these skills were achieved. Those without a deletion had a higher probability (25-92%) of achieving daily living skills such as independently toileting and dressing compared to those with a deletion (0-13%). Across all molecular subtypes, there was a low probability of achieving independence in bathing and brushing teeth. CONCLUSION: Individuals with AS without a deletion are more likely to achieve developmental milestones and daily living skills at an earlier age than those with a deletion. Many individuals with AS are unable to achieve daily living skills necessary for independent self-care. En ligne : https://dx.doi.org/10.1186/s11689-024-09548-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=575 [article] Developmental milestones and daily living skills in individuals with Angelman syndrome [texte imprimé] / Anjali SADHWANI, Auteur ; Sonya POWERS, Auteur ; Anne WHEELER, Auteur ; Hillary MILLER, Auteur ; Sarah Nelson POTTER, Auteur ; Sarika U. PETERS, Auteur ; Carlos A. BACINO, Auteur ; Steven A. SKINNER, Auteur ; Logan K. WINK, Auteur ; Craig A. ERICKSON, Auteur ; Lynne M. BIRD, Auteur ; Wen-Hann TAN, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 16 (2024) Mots-clés : Humans  Angelman Syndrome/physiopathology/genetics/complications  Activities of Daily Living  Female  Child, Preschool  Male  Child  Adolescent  Infant  Child Development/physiology  Longitudinal Studies  Motor Skills/physiology  Developmental Disabilities/etiology  Adult  Young Adult  Activities of Daily Living  Child development  Developmental disabilities  Intellectual disability Index. décimale : PER Périodiques Résumé : BACKGROUND: Angelman syndrome (AS) is a neurodevelopmental disorder associated with severe global developmental delay. However, the ages at which different developmental skills are achieved in these individuals remain unclear. We seek to determine the probability and the age of acquisition of specific developmental milestones and daily living skills in individuals with AS across the different molecular subtypes, viz. class I deletion, class II deletion, uniparental disomy, imprinting defect, and UBE3A variants. METHODS: Caregivers participating in a longitudinal multicenter Angelman Syndrome Natural History Study completed a questionnaire regarding the age at which their children achieved specific developmental milestones and daily living skills. The Cox Proportional Hazard model was applied to analyze differences in the probability of achievement of skills at various ages among five molecular subtypes of AS. RESULTS: Almost all individuals, regardless of molecular subtype, were able to walk with support by five years of age. By age 15, those with a deletion had at least a 50% probability of acquiring 17 out of 30 skills compared to 25 out of 30 skills among those without a deletion. Overall, fine and gross motor skills such as holding and reaching for small objects, sitting, and walking with support were achieved within a fairly narrow range of ages, while toileting, feeding, and hygiene skills tend to have greater variability in the ages at which these skills were achieved. Those without a deletion had a higher probability (25-92%) of achieving daily living skills such as independently toileting and dressing compared to those with a deletion (0-13%). Across all molecular subtypes, there was a low probability of achieving independence in bathing and brushing teeth. CONCLUSION: Individuals with AS without a deletion are more likely to achieve developmental milestones and daily living skills at an earlier age than those with a deletion. Many individuals with AS are unable to achieve daily living skills necessary for independent self-care. En ligne : https://dx.doi.org/10.1186/s11689-024-09548-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=575

Developmental studies in fragile X syndrome / Khaleel A. RAZAK in Journal of Neurodevelopmental Disorders, 12 (2020)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 12 (2020) Titre : Developmental studies in fragile X syndrome Type de document : texte imprimé Auteurs : Khaleel A. RAZAK, Auteur ; Kelli C. DOMINICK, Auteur ; Craig A. ERICKSON, Auteur Langues : Anglais (eng) Mots-clés : Adolescent  Animals  Child  Child, Preschool  Disease Models, Animal  Female  Fragile X Mental Retardation Protein/genetics  Fragile X Syndrome/genetics  Humans  Infant  Male  Mice  Mice, Knockout  Young Adult Index. décimale : PER Périodiques Résumé : Fragile X syndrome (FXS) is the most common single gene cause of autism and intellectual disabilities. Humans with FXS exhibit increased anxiety, sensory hypersensitivity, seizures, repetitive behaviors, cognitive inflexibility, and social behavioral impairments. The main purpose of this review is to summarize developmental studies of FXS in humans and in the mouse model, the Fmr1 knockout mouse. The literature presents considerable evidence that a number of early developmental deficits can be identified and that these early deficits chart a course of altered developmental experience leading to symptoms well characterized in adolescents and adults. Nevertheless, a number of critical issues remain unclear or untested regarding the development of symptomology and underlying mechanisms. First, what is the role of FMRP, the protein product of Fmr1 gene, during different developmental ages? Does the absence of FMRP during early development lead to irreversible changes, or could reintroduction of FMRP or therapeutics aimed at FMRP-interacting proteins/pathways hold promise when provided in adults? These questions have implications for clinical trial designs in terms of optimal treatment windows, but few studies have systematically addressed these issues in preclinical and clinical work. Published studies also point to complex trajectories of symptom development, leading to the conclusion that single developmental time point studies are unlikely to disambiguate effects of genetic mutation from effects of altered developmental experience and compensatory plasticity. We conclude by suggesting a number of experiments needed to address these major gaps in the field. En ligne : https://dx.doi.org/10.1186/s11689-020-09310-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=573 [article] Developmental studies in fragile X syndrome [texte imprimé] / Khaleel A. RAZAK, Auteur ; Kelli C. DOMINICK, Auteur ; Craig A. ERICKSON, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 12 (2020) Mots-clés : Adolescent  Animals  Child  Child, Preschool  Disease Models, Animal  Female  Fragile X Mental Retardation Protein/genetics  Fragile X Syndrome/genetics  Humans  Infant  Male  Mice  Mice, Knockout  Young Adult Index. décimale : PER Périodiques Résumé : Fragile X syndrome (FXS) is the most common single gene cause of autism and intellectual disabilities. Humans with FXS exhibit increased anxiety, sensory hypersensitivity, seizures, repetitive behaviors, cognitive inflexibility, and social behavioral impairments. The main purpose of this review is to summarize developmental studies of FXS in humans and in the mouse model, the Fmr1 knockout mouse. The literature presents considerable evidence that a number of early developmental deficits can be identified and that these early deficits chart a course of altered developmental experience leading to symptoms well characterized in adolescents and adults. Nevertheless, a number of critical issues remain unclear or untested regarding the development of symptomology and underlying mechanisms. First, what is the role of FMRP, the protein product of Fmr1 gene, during different developmental ages? Does the absence of FMRP during early development lead to irreversible changes, or could reintroduction of FMRP or therapeutics aimed at FMRP-interacting proteins/pathways hold promise when provided in adults? These questions have implications for clinical trial designs in terms of optimal treatment windows, but few studies have systematically addressed these issues in preclinical and clinical work. Published studies also point to complex trajectories of symptom development, leading to the conclusion that single developmental time point studies are unlikely to disambiguate effects of genetic mutation from effects of altered developmental experience and compensatory plasticity. We conclude by suggesting a number of experiments needed to address these major gaps in the field. En ligne : https://dx.doi.org/10.1186/s11689-020-09310-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=573

Specialization of the brain for language in children with Fragile X Syndrome: a functional Near Infrared Spectroscopy study / Elizabeth SMITH in Journal of Neurodevelopmental Disorders, 16 (2024)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 16 (2024) Titre : Specialization of the brain for language in children with Fragile X Syndrome: a functional Near Infrared Spectroscopy study Type de document : texte imprimé Auteurs : Elizabeth SMITH, Auteur ; Kelli C. DOMINICK, Auteur ; Lauren M. SCHMITT, Auteur ; Ernest V. PEDAPATI, Auteur ; Craig A. ERICKSON, Auteur Langues : Anglais (eng) Mots-clés : Humans  Spectroscopy, Near-Infrared  Male  Female  Fragile X Syndrome/physiopathology/complications  Child  Child, Preschool  Auditory Cortex/physiopathology  Speech Perception/physiology  Language  Acoustic Stimulation  Brain/physiopathology  Functional Laterality/physiology  Auditory cortex  Fragile X syndrome  Functional near infrared spectroscopy  Speech perception  Review Board at Cincinnati Children’s Hospital Medical Center (CCHMC) and was  performed in accordance with the protections set forth in the Declaration of  Helsinki. Participant’s parents or legal guardians provided written informed  consent for participation. Consent for publication: Participant’s parents or  legal guardians provided written informed consent for publication of deidentified  data. Competing interests: The authors declare no competing interests. Index. décimale : PER Périodiques Résumé : Specialization of the brain for language is early emerging and essential for language learning in young children. Fragile X Syndrome (FXS) is a neurogenetic disorder marked by high rates of delays in both expressive and receptive language, but neural activation patterns during speech and language processing are unknown. We report results of a functional Near Infrared Spectroscopy (fNIRS) study of responses to speech and nonspeech sounds in the auditory cortex in a sample of 2- to 10-year-old children with FXS and typically developing controls (FXS n = 23, TDC n = 15, mean age = 6.44 and 7.07 years, respectively). Specifically, we measured changes in oxygenated and deoxygenated hemoglobin in the auditory cortex during blocks of speech and nonspeech matched noise in children with FXS and sex-and-age-matched controls. Similar to controls, children with FXS showed hemodynamic change consistent with neural activation of the primary auditory regions for speech as well as leftward lateralization for speech sound processing, strength of which was associated with higher verbal abilities in FXS. However, while controls showed neural differentiation of speech and nonspeech in the left auditory cortex, children with FXS did not demonstrate differentiation of the two conditions in this study. In addition, the children with FXS showed a greater neural activation to the nonspeech condition overall. Overall, these results suggest that basic patterns of neural activation for speech are present in FXS in childhood, but neural response to nonspeech sounds may differ in FXS when compared to controls. En ligne : https://dx.doi.org/10.1186/s11689-024-09582-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=576 [article] Specialization of the brain for language in children with Fragile X Syndrome: a functional Near Infrared Spectroscopy study [texte imprimé] / Elizabeth SMITH, Auteur ; Kelli C. DOMINICK, Auteur ; Lauren M. SCHMITT, Auteur ; Ernest V. PEDAPATI, Auteur ; Craig A. ERICKSON, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 16 (2024) Mots-clés : Humans  Spectroscopy, Near-Infrared  Male  Female  Fragile X Syndrome/physiopathology/complications  Child  Child, Preschool  Auditory Cortex/physiopathology  Speech Perception/physiology  Language  Acoustic Stimulation  Brain/physiopathology  Functional Laterality/physiology  Auditory cortex  Fragile X syndrome  Functional near infrared spectroscopy  Speech perception  Review Board at Cincinnati Children’s Hospital Medical Center (CCHMC) and was  performed in accordance with the protections set forth in the Declaration of  Helsinki. Participant’s parents or legal guardians provided written informed  consent for participation. Consent for publication: Participant’s parents or  legal guardians provided written informed consent for publication of deidentified  data. Competing interests: The authors declare no competing interests. Index. décimale : PER Périodiques Résumé : Specialization of the brain for language is early emerging and essential for language learning in young children. Fragile X Syndrome (FXS) is a neurogenetic disorder marked by high rates of delays in both expressive and receptive language, but neural activation patterns during speech and language processing are unknown. We report results of a functional Near Infrared Spectroscopy (fNIRS) study of responses to speech and nonspeech sounds in the auditory cortex in a sample of 2- to 10-year-old children with FXS and typically developing controls (FXS n = 23, TDC n = 15, mean age = 6.44 and 7.07 years, respectively). Specifically, we measured changes in oxygenated and deoxygenated hemoglobin in the auditory cortex during blocks of speech and nonspeech matched noise in children with FXS and sex-and-age-matched controls. Similar to controls, children with FXS showed hemodynamic change consistent with neural activation of the primary auditory regions for speech as well as leftward lateralization for speech sound processing, strength of which was associated with higher verbal abilities in FXS. However, while controls showed neural differentiation of speech and nonspeech in the left auditory cortex, children with FXS did not demonstrate differentiation of the two conditions in this study. In addition, the children with FXS showed a greater neural activation to the nonspeech condition overall. Overall, these results suggest that basic patterns of neural activation for speech are present in FXS in childhood, but neural response to nonspeech sounds may differ in FXS when compared to controls. En ligne : https://dx.doi.org/10.1186/s11689-024-09582-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=576

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