RESUMEN
Sensorimotor issues are present in the majority of individuals with autism spectrum disorder (ASD) and are associated with core symptoms. The neural systems associated with these impairments remain unclear. Using a visually guided precision gripping task during functional magnetic resonance imaging, we characterized task-based connectivity and activation of cortical, subcortical, and cerebellar visuomotor networks. Participants with ASD (n = 19; ages 10-33) and age- and sex-matched neurotypical controls (n = 18) completed a visuomotor task at low and high force levels. Relative to controls, individuals with ASD showed reduced functional connectivity of right primary motor-anterior cingulate cortex and left anterior intraparietal lobule (aIPL)-right Crus I at high force only. At low force, increased caudate, and cerebellar activation each were associated with sensorimotor behavior in controls, but not in ASD. Reduced left aIPL-right Crus I connectivity was associated with more severe clinically rated ASD symptoms. These findings suggest that sensorimotor problems in ASD, particularly at high force levels, involve deficits in the integration of multimodal sensory feedback and reduced reliance on error-monitoring processes. Adding to literature positing that cerebellar dysfunction contributes to multiple developmental issues in ASD, our data implicate parietal-cerebellar connectivity as a key neural marker underlying both core and comorbid features of ASD.
Asunto(s)
Trastorno del Espectro Autista , Corteza Motora , Humanos , Mapeo Encefálico/métodos , Cerebelo , Imagen por Resonancia Magnética/métodos , Vías NerviosasRESUMEN
Sensorimotor abnormalities are common in autism spectrum disorder (ASD) and predictive of functional outcomes, though their neural underpinnings remain poorly understood. Using functional magnetic resonance imaging, we examined both brain activation and functional connectivity during visuomotor behavior in 27 individuals with ASD and 30 typically developing (TD) controls (ages 9-35 years). Participants maintained a constant grip force while receiving visual feedback at three different visual gain levels. Relative to controls, ASD participants showed increased force variability, especially at high gain, and reduced entropy. Brain activation was greater in individuals with ASD than controls in supplementary motor area, bilateral superior parietal lobules, and contralateral middle frontal gyrus at high gain. During motor action, functional connectivity was reduced between parietal-premotor and parietal-putamen in individuals with ASD compared to controls. Individuals with ASD also showed greater age-associated increases in functional connectivity between cerebellum and visual, motor, and prefrontal cortical areas relative to controls. These results indicate that visuomotor deficits in ASD are associated with atypical activation and functional connectivity of posterior parietal, premotor, and striatal circuits involved in translating sensory feedback information into precision motor behaviors, and that functional connectivity of cerebellar-cortical sensorimotor and nonsensorimotor networks show delayed maturation.
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Trastorno del Espectro Autista/fisiopatología , Encéfalo/fisiopatología , Conectoma , Red Nerviosa/fisiopatología , Desempeño Psicomotor/fisiología , Adolescente , Adulto , Trastorno del Espectro Autista/diagnóstico por imagen , Encéfalo/diagnóstico por imagen , Niño , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Red Nerviosa/diagnóstico por imagen , Adulto JovenRESUMEN
The 15q11.2 BP1-BP2 deletion (Burnside-Butler) syndrome is emerging as the most common cytogenetic finding in patients with neurodevelopmental or autism spectrum disorders (ASD) presenting for microarray genetic testing. Clinical findings in Burnside-Butler syndrome include developmental and motor delays, congenital abnormalities, learning and behavioral problems, and abnormal brain findings. To better define symptom presentation, we performed comprehensive cognitive and behavioral testing, collected medical and family histories, and conducted clinical genetic evaluations. The 15q11.2 BP1-BP2 region includes the TUBGCP5, CYFIP1, NIPA1, and NIPA2 genes. To determine if additional genomic variation outside of the 15q11.2 region influences expression of symptoms in Burnside-Butler syndrome, whole-exome sequencing was performed on the parents and affected children for the first time in five families with at least one parent and child with the 15q1l.2 BP1-BP2 deletion. In total, there were 453 genes with possibly damaging variants identified across all of the affected children. Of these, 99 genes had exclusively de novo variants and 107 had variants inherited exclusively from the parent without the deletion. There were three genes (APBB1, GOLGA2, and MEOX1) with de novo variants that encode proteins evidenced to interact with CYFIP1. In addition, one other gene of interest (FAT3) had variants inherited from the parent without the deletion and encoded a protein interacting with CYFIP1. The affected individuals commonly displayed a neurodevelopmental phenotype including ASD, speech delay, abnormal reflexes, and coordination issues along with craniofacial findings and orthopedic-related connective tissue problems. Of the 453 genes with variants, 35 were associated with ASD. On average, each affected child had variants in 6 distinct ASD-associated genes (x¯ = 6.33, sd = 3.01). In addition, 32 genes with variants were included on clinical testing panels from Clinical Laboratory Improvement Amendments (CLIA) approved and accredited commercial laboratories reflecting other observed phenotypes. Notably, the dataset analyzed in this study was small and reported results will require validation in larger samples as well as functional follow-up. Regardless, we anticipate that results from our study will inform future research into the genetic factors influencing diverse symptoms in patients with Burnside-Butler syndrome, an emerging disorder with a neurodevelopmental behavioral phenotype.
Asunto(s)
Cromosomas Humanos Par 15/genética , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Discapacidad Intelectual/genética , Discapacidad Intelectual/psicología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Aberraciones Cromosómicas , Cognición , Familia , Femenino , Humanos , Discapacidad Intelectual/patología , Masculino , Persona de Mediana Edad , Equilibrio Postural , Secuenciación del Exoma , Adulto JovenRESUMEN
Nuclear receptor subfamily 2 group F member 1 (NR2F1) is an orphan receptor and transcriptional regulator that is involved in neurogenesis, visual processing and development, and cortical patterning. Alterations in NR2F1 cause Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS), a recently described autosomal dominant disorder characterized by intellectual and developmental disabilities and optic atrophy. This study describes the clinical and neurocognitive features of an individual with a de novo nonsense variant in NR2F1 (NM_005654.5:c.82C > T, p.Gln28*), identified by whole exome sequencing. The patient was diagnosed with autism spectrum disorder (ASD) and unlike most previously reported cases, he had no developmental delay, superior verbal abilities (verbal IQ = 141), and high educational attainment despite reduced nonverbal abilities (nonverbal IQ = 63). He had optic nerve hypoplasia with minimal visual impairment as well as mild dysmorphic features. Compared to both age-matched individuals with ASD and healthy controls, the patient showed reductions in manual motor speed, accuracy of saccadic eye movements, and rates of successful behavioral response inhibition. Although the majority of previously reported cases of BBSOAS have been associated with more global intellectual dysfunction, we report on a patient with selective disruption of nonverbal abilities and superior verbal abilities.
Asunto(s)
Factor de Transcripción COUP I/genética , Discapacidades del Desarrollo/genética , Discapacidad Intelectual/genética , Atrofia Óptica/genética , Adulto , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/fisiopatología , Codón sin Sentido/genética , Discapacidades del Desarrollo/fisiopatología , Femenino , Predisposición Genética a la Enfermedad , Humanos , Discapacidad Intelectual/fisiopatología , Masculino , Atrofia Óptica/fisiopatología , Fenotipo , Secuenciación del Exoma , Adulto JovenRESUMEN
Anxiety disorders are common in autism spectrum disorder (ASD) and associated with social-communication impairment and repetitive behavior symptoms. The neurobiology of anxiety in ASD is unknown, but amygdala dysfunction has been implicated in both ASD and anxiety disorders. Using resting-state functional magnetic resonance imaging, we compared amygdala-prefrontal and amygdala-striatal connections across three demographically matched groups studied in the Autism Brain Imaging Data Exchange (ABIDE): ASD with a comorbid anxiety disorder (N = 25; ASD + Anxiety), ASD without a comorbid disorder (N = 68; ASD-NoAnx), and typically developing controls (N = 139; TD). Relative to ASD-NoAnx and TD controls, ASD + Anxiety individuals had decreased connectivity between the amygdala and dorsal/rostral anterior cingulate cortex (dACC/rACC). The functional connectivity of these connections was not affected in ASD-NoAnx, and amygdala connectivity with ventral ACC/medial prefrontal cortex (mPFC) circuits was not different in ASD + Anxiety or ASD-NoAnx relative to TD. Decreased amygdala-dorsomedial prefrontal cortex (dmPFC)/rACC connectivity was associated with more severe social impairment in ASD + Anxiety; amygdala-striatal connectivity was associated with restricted, repetitive behavior (RRB) symptom severity in ASD-NoAnx individuals. These findings suggest comorbid anxiety in ASD is associated with disrupted emotion-monitoring processes supported by amygdala-dACC/mPFC pathways, whereas emotion regulation systems involving amygdala-ventromedial prefrontal cortex (vmPFC) are relatively spared. Our results highlight the importance of accounting for comorbid anxiety for parsing ASD neurobiological heterogeneity.
Asunto(s)
Trastorno del Espectro Autista , Amígdala del Cerebelo/diagnóstico por imagen , Ansiedad/diagnóstico por imagen , Trastornos de Ansiedad/diagnóstico por imagen , Trastorno del Espectro Autista/diagnóstico por imagen , Encéfalo/diagnóstico por imagen , Mapeo Encefálico , Humanos , Imagen por Resonancia Magnética , Vías Nerviosas/diagnóstico por imagenRESUMEN
In addition to core deficits in social-communication abilities and repetitive behaviors and interests, many patients with autism spectrum disorder (ASD) experience developmental comorbidities, including sensorimotor issues. Sensorimotor issues are common in ASD and associated with more severe clinical symptoms. Importantly, sensorimotor behaviors are precisely quantifiable and highly translational, offering promising targets for neurophysiological studies of ASD. We used functional MRI to identify brain regions associated with sensorimotor behavior using a visually guided precision gripping task in individuals with ASD (n = 20) and age-, IQ-, and handedness-matched controls (n = 18). During visuomotor behavior, individuals with ASD showed greater force variability than controls. The blood oxygen level-dependent signal for multiple cortical and subcortical regions was associated with force variability, including motor and premotor cortex, posterior parietal cortex, extrastriate cortex, putamen, and cerebellum. Activation in the right premotor cortex scaled with sensorimotor variability in controls but not in ASD. Individuals with ASD showed greater activation than controls in left putamen and left cerebellar lobule VIIb, and activation in these regions was associated with more severe clinically rated symptoms of ASD. Together, these results suggest that greater sensorimotor variability in ASD is associated with altered cortical-striatal processes supporting action selection and cortical-cerebellar circuits involved in feedback-guided reactive adjustments of motor output. Our findings also indicate that atypical organization of visuomotor cortical circuits may result in heightened reliance on subcortical circuits typically dedicated to motor skill acquisition. Overall, these results provide new evidence that sensorimotor alterations in ASD involve aberrant cortical and subcortical organization that may contribute to key clinical issues in patients.NEW & NOTEWORTHY This is the first known study to examine functional brain activation during precision visuomotor behavior in autism spectrum disorder (ASD). We replicate previous findings of elevated force variability in ASD and find these deficits are associated with atypical function of ventral premotor cortex, putamen, and posterolateral cerebellum, indicating cortical-striatal processes supporting action selection and cortical-cerebellar circuits involved in feedback-guided reactive adjustments of motor output may be key targets for understanding the neurobiology of ASD.
Asunto(s)
Trastorno del Espectro Autista/fisiopatología , Trastorno del Espectro Autista/psicología , Encéfalo/fisiopatología , Desempeño Psicomotor/fisiología , Adolescente , Adulto , Mapeo Encefálico , Cerebelo/fisiopatología , Femenino , Fuerza de la Mano , Humanos , Imagen por Resonancia Magnética , Masculino , Corteza Motora/fisiopatología , Putamen/fisiopatología , Adulto JovenRESUMEN
Individuals with fragile X mental retardation 1 (FMR1) gene premutations are at increased risk for fragile X-associated tremor/ataxia syndrome (FXTAS) during aging. However, it is unknown whether older FMR1 premutation carriers, with or without FXTAS, exhibit functional motor control deficits compared with healthy individuals. The purpose of this study, therefore, was to determine whether older FMR1 premutation carriers exhibit impaired ability to perform functional motor tasks. Eight FMR1 premutation carriers (age: 58.88 ± 8.36 years) and eight age- and sex-matched healthy individuals (60.13 ± 9.25 years) performed (1) a steady isometric force control task with the index finger at 20% of their maximum voluntary contraction (MVC) and; (2) a single-step task. During the finger abduction task, firing rate of multiple motor units of the first dorsal interosseous (FDI) muscle was recorded. Compared with healthy controls, FMR1 premutation carriers exhibited (1) greater force variability (coefficient of variation of force) during isometric force (1.48 ± 1.02 vs. 0.63 ± 0.37%; P = 0.04); (2) reduced firing rate of multiple motor units during steady force, and; (3) reduced velocity of their weight transfer during stepping (156.62 ± 26.24 vs. 191.86 ± 18.83 cm/s; P = 0.01). These findings suggest that older FMR1 premutation carriers exhibit functional motor control deficits that reflect either subclinical issues associated with premutations independent of FXTAS, or prodromal markers of the development of FXTAS.
Asunto(s)
Ataxia/fisiopatología , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Síndrome del Cromosoma X Frágil/fisiopatología , Actividad Motora/fisiología , Contracción Muscular/fisiología , Reclutamiento Neurofisiológico/fisiología , Temblor/fisiopatología , Anciano , Fenómenos Biomecánicos , Femenino , Dedos/fisiopatología , Pie/fisiopatología , Heterocigoto , Humanos , Contracción Isométrica/fisiología , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Inhibitory control deficits are common in autism spectrum disorder (ASD) and associated with more severe repetitive behaviors. Inhibitory control deficits may reflect slower execution of stopping processes, or a reduced ability to delay the onset of behavioral responses in contexts of uncertainty. Previous studies have documented relatively spared stopping processes in ASD, but whether inhibitory control deficits in ASD reflect failures to delay response onset has not been systematically assessed. Further, while improvements in stopping abilities and response slowing are seen through adolescence/early adulthood in health, their development in ASD is less clear. METHODS: A stop-signal test (SST) was administered to 121 individuals with ASD and 76 age and IQ-matched healthy controls (ages 5-28). This test included 'GO trials' in which participants pressed a button when a peripheral target appeared and interleaved 'STOP trials' in which they were cued to inhibit button-presses when a stop-signal appeared at variable times following the GO cue. STOP trial accuracy, RT of the stopping process (SSRT), and reaction time (RT) slowing during GO trials were examined. RESULTS: Relative to controls, individuals with ASD had reduced accuracy on STOP trials. SSRTs were similar across control and ASD participants, but RT slowing was reduced in patients compared to controls. Age-related increases in stopping ability and RT slowing were attenuated in ASD. Reduced stopping accuracy and RT slowing were associated with more severe repetitive behaviors in ASD. DISCUSSION: Our findings show that inhibitory control deficits in ASD involve failures to strategically delay behavioral response onset. These results suggest that reduced preparatory behavioral control may underpin inhibitory control deficits as well as repetitive behaviors in ASD. Typical age-related improvements in inhibitory control during late childhood/early adolescence are reduced in ASD, highlighting an important developmental window during which treatments may mitigate cognitive alterations contributing to repetitive behaviors.
Asunto(s)
Trastorno del Espectro Autista/fisiopatología , Función Ejecutiva/fisiología , Inhibición Psicológica , Desempeño Psicomotor/fisiología , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Masculino , Adulto JovenRESUMEN
Force control deficits have been repeatedly documented in autism spectrum disorder (ASD). They are associated with worse social and daily living skill impairments in patients suggesting that developing a more mechanistic understanding of the central and peripheral processes that cause them may help guide the development of treatments that improve multiple outcomes in ASD. The neuromuscular mechanisms underlying force control deficits are not yet understood. Seventeen individuals with ASD and 14 matched healthy controls completed an isometric index finger abduction test at 60% of their maximum voluntary contraction (MVC) during recording of the first dorsal interosseous (FDI) muscle to determine the neuromuscular processes associated with sustained force variability. Central modulation of the motorneuron pool activation of the FDI muscle was evaluated at delta (0-4 Hz), alpha (4-10 Hz), beta (10-35 Hz) and gamma (35-60 Hz) frequency bands. ASD patients showed greater force variability than controls when attempting to maintain a constant force. Relative to controls, patients also showed increased central modulation of the motorneuron pool at beta and gamma bands. For controls, reduced force variability was associated with reduced delta frequency modulation of the motorneuron pool activity of the FDI muscle and increased modulation at beta and gamma bands. In contrast, delta, beta, and gamma frequency oscillations were not associated with force variability in ASD. These findings suggest that alterations of central mechanisms that control motorneuron pool firing may underlie the common and often impairing symptoms of ASD.
Asunto(s)
Trastorno del Espectro Autista/fisiopatología , Contracción Isométrica , Neuronas Motoras/fisiología , Adolescente , Adulto , Ondas Encefálicas , Estudios de Casos y Controles , Potenciales Evocados Motores , Femenino , Dedos/fisiología , Humanos , Masculino , Músculo Esquelético/fisiologíaRESUMEN
Sensorimotor abnormalities are common in autism spectrum disorder (ASD) and among the earliest manifestations of the disorder. They have been studied far less than the social-communication and cognitive deficits that define ASD, but a mechanistic understanding of sensorimotor abnormalities in ASD may provide key insights into the neural underpinnings of the disorder. In this human study, we examined rapid, precision grip force contractions to determine whether feedforward mechanisms supporting initial motor output before sensory feedback can be processed are disrupted in ASD. Sustained force contractions also were examined to determine whether reactive adjustments to ongoing motor behavior based on visual feedback are altered. Sustained force was studied across multiple force levels and visual gains to assess motor and visuomotor mechanisms, respectively. Primary force contractions of individuals with ASD showed greater peak rate of force increases and large transient overshoots. Individuals with ASD also showed increased sustained force variability that scaled with force level and was more severe when visual gain was highly amplified or highly degraded. When sustaining a constant force level, their reactive adjustments were more periodic than controls, and they showed increased reliance on slower feedback mechanisms. Feedforward and feedback mechanism alterations each were associated with more severe social-communication impairments in ASD. These findings implicate anterior cerebellar circuits involved in feedforward motor control and posterior cerebellar circuits involved in transforming visual feedback into precise motor adjustments in ASD.
Asunto(s)
Cerebelo/fisiopatología , Trastornos Generalizados del Desarrollo Infantil/fisiopatología , Retroalimentación Fisiológica , Fuerza de la Mano , Desempeño Psicomotor , Adolescente , Adulto , Estudios de Casos y Controles , Niño , Femenino , Humanos , MasculinoRESUMEN
Atypical age-dependent changes of white matter (WM) microstructure play a central role in abnormal brain maturation of the children with autism spectrum disorder (ASD), but their early manifestations have not been systematically characterized. The entire brain core WM voxels were surveyed to detect differences in WM microstructural development between 31 children with ASD of 2-7 years and 19 age-matched children with typical development (TD), using measurements of fractional anisotropy (FA) and radial diffusivity (RD) from diffusion tensor imaging (DTI). The anatomical locations, distribution, and extent of the core WM voxels with atypical age-dependent changes in a specific tract or tract group were delineated and evaluated by integrating the skeletonized WM with a digital atlas. Exclusively, unidirectional FA increases and RD decreases in widespread WM tracts were revealed in children with ASD before 4 years, with bi-directional changes found for children with ASD of 2-7 years. Compared to progressive development that raised FA and lowered RD during 2-7 years in the TD group, flattened curves of WM maturation were found in multiple major WM tracts of all five tract groups, particularly associational and limbic tracts, in the ASD group with trend lines of ASD and TD crossed around 4 years. We found atypical age-dependent changes of FA and RD widely and heterogeneously distributed in WM tracts of children with ASD. The early higher WM microstructural integrity before 4 years reflects abnormal neural patterning, connectivity, and pruning that may contribute to aberrant behavioral and cognitive development in ASD. Hum Brain Mapp 37:819-832, 2016. © 2015 Wiley Periodicals, Inc.
Asunto(s)
Trastorno del Espectro Autista/patología , Encéfalo/crecimiento & desarrollo , Encéfalo/patología , Sustancia Blanca/crecimiento & desarrollo , Sustancia Blanca/patología , Niño , Preescolar , Análisis por Conglomerados , Imagen de Difusión Tensora , Humanos , Procesamiento de Imagen Asistido por Computador , Modelos Lineales , Masculino , Vías Nerviosas/crecimiento & desarrollo , Vías Nerviosas/patología , Índice de Severidad de la EnfermedadRESUMEN
Adolescence represents a period of vulnerability to psychiatric problems due to a range of factors, including advances in social and cognitive abilities, increased levels of autonomy in decision-making and behavioral governance, and greater exposure to opportunities for risk-taking behavior. Adding to these psychological and social challenges, adolescence also is marked by robust maturational changes affecting both the microcircuitry and connectivity between widely distributed brain systems. These changes alter the communication among parallel, distributed brain networks, have implications for one's vulnerability to engage in risk behavior and make the brain particularly susceptible to external perturbations, such as exposure to neurotoxic substances.
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Conducta del Adolescente/psicología , Asunción de Riesgos , Adolescente , Encéfalo , Toma de Decisiones , Humanos , Trastornos Relacionados con Sustancias/psicologíaRESUMEN
Sensorimotor impairments are common in autism spectrum disorder (ASD), but they are not well understood. Here we examined force control during initial pulses and the subsequent rise, sustained, and relaxation phases of precision gripping in 34 individuals with ASD and 25 healthy control subjects. Participants pressed on opposing load cells with their thumb and index finger while receiving visual feedback regarding their performance. They completed 2- and 8-s trials during which they pressed at 15%, 45%, or 85% of their maximum force. Initial pulses guided by feedforward control mechanisms, sustained force output controlled by visual feedback processes, and force relaxation rates all were examined. Control subjects favored an initial pulse strategy characterized by a rapid increase in and then relaxation of force when the target force was low (Type 1). When the target force level or duration of trials was increased, control subjects transitioned to a strategy in which they more gradually increased their force, paused, and then increased their force again. Individuals with ASD showed a more persistent bias toward the Type 1 strategy at higher force levels and during longer trials, and their initial force output was less accurate than that of control subjects. Patients showed increased force variability compared with control subjects when attempting to sustain a constant force level. During the relaxation phase, they showed reduced rates of force decrease. These findings suggest that both feedforward and feedback motor control mechanisms are compromised in ASD and these deficits may contribute to the dyspraxia and sensorimotor abnormalities often seen in this disorder.
Asunto(s)
Trastorno del Espectro Autista/diagnóstico , Trastorno del Espectro Autista/fisiopatología , Fuerza de la Mano , Desempeño Psicomotor , Adolescente , Niño , Preescolar , Femenino , Fuerza de la Mano/fisiología , Humanos , Masculino , Estimulación Luminosa/métodos , Desempeño Psicomotor/fisiología , Factores de TiempoRESUMEN
BACKGROUND AND AIM: Selective serotonin reuptake inhibitors such as escitalopram are commonly used to treat patients with autism spectrum disorder (ASD), but there are individual differences in treatment response and tolerability. CYP2C19 encodes the primary enzyme responsible for escitalopram metabolism and we investigated whether polymorphisms in CYP2C19 were related to symptoms and dosing in a pharmacogenetic study of ASD. PARTICIPANTS AND METHODS: Participants completed the Aberrant Behavior Checklist--Community Version (ABC-CV) weekly for 6 weeks. Escitalopram was initiated at a dose of 2.5 mg per day, with weekly increases to 20 mg unless intolerable side-effects occurred. Three CYP2C19 metabolizer groups, including ultrarapid, extensive, and reduced metabolizers, were examined in relation to symptom improvement and tolerated dose. RESULTS: ABC-CV scores improved over the course of treatment (P<0.0001). No differences were identified in the rate of improvement across metabolizer groups for the ABC-CV irritability subscale, which was the primary outcome for clinical symptoms. There was a trend for a metabolizer group by time interaction with respect to dose (P=0.10). This interaction was driven by the linear rate of change from week 1 to study endpoint between the reduced metabolizers and ultrarapid metabolizer groups (P=0.05). Post-hoc analyses identified significant differences in the rate of dose escalation between ultrarapid metabolizers and extensive metabolizers and for ultrarapid metabolizers compared with reduced metabolizers (P's<0.04), whereby ultrarapid metabolizers showed a slower rate of change in dose over time. CONCLUSION: CYP2C19 ultrarapid metabolizers were associated with reduced tolerance to a fixed titration schedule of open-label escitalopram in this ASD study sample. Possible explanations may involve the altered kinetics of faster metabolizers or previously unknown activities of escitalopram metabolites.
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Trastorno del Espectro Autista/tratamiento farmacológico , Trastorno del Espectro Autista/metabolismo , Citalopram/administración & dosificación , Citalopram/farmacocinética , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C19/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/administración & dosificación , Inhibidores Selectivos de la Recaptación de Serotonina/farmacocinética , Adolescente , Adulto , Trastorno del Espectro Autista/genética , Niño , Preescolar , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Resultado del TratamientoRESUMEN
Autism spectrum disorder (ASD) is associated with a diverse range of etiological processes, including both genetic and non-genetic causes. For a plurality of individuals with ASD, it is likely that the primary causes involve multiple common inherited variants that individually account for only small levels of variation in phenotypic outcomes. This genetic landscape creates a major challenge for detecting small but important pathogenic effects associated with ASD. To address similar challenges, separate fields of medicine have identified endophenotypes, or discrete, quantitative traits that reflect genetic likelihood for a particular clinical condition and leveraged the study of these traits to map polygenic mechanisms and advance more personalized therapeutic strategies for complex diseases. Endophenotypes represent a distinct class of biomarkers useful for understanding genetic contributions to psychiatric and developmental disorders because they are embedded within the causal chain between genotype and clinical phenotype, and they are more proximal to the action of the gene(s) than behavioral traits. Despite their demonstrated power for guiding new understanding of complex genetic structures of clinical conditions, few endophenotypes associated with ASD have been identified and integrated into family genetic studies. In this review, we argue that advancing knowledge of the complex pathogenic processes that contribute to ASD can be accelerated by refocusing attention toward identifying endophenotypic traits reflective of inherited mechanisms. This pivot requires renewed emphasis on study designs with measurement of familial co-variation including infant sibling studies, family trio and quad designs, and analysis of monozygotic and dizygotic twin concordance for select trait dimensions. We also emphasize that clarification of endophenotypic traits necessarily will involve integration of transdiagnostic approaches as candidate traits likely reflect liability for multiple clinical conditions and often are agnostic to diagnostic boundaries. Multiple candidate endophenotypes associated with ASD likelihood are described, and we propose a new focus on the analysis of "endophenotype trait domains" (ETDs), or traits measured across multiple levels (e.g., molecular, cellular, neural system, neuropsychological) along the causal pathway from genes to behavior. To inform our central argument for research efforts toward ETD discovery, we first provide a brief review of the concept of endophenotypes and their application to psychiatry. Next, we highlight key criteria for determining the value of candidate endophenotypes, including unique considerations for the study of ASD. Descriptions of different study designs for assessing endophenotypes in ASD research then are offered, including analysis of how select patterns of results may help prioritize candidate traits in future research. We also present multiple candidate ETDs that collectively cover a breadth of clinical phenomena associated with ASD, including social, language/communication, cognitive control, and sensorimotor processes. These ETDs are described because they represent promising targets for gene discovery related to clinical autistic traits, and they serve as models for analysis of separate candidate domains that may inform understanding of inherited etiological processes associated with ASD as well as overlapping neurodevelopmental disorders.
Asunto(s)
Trastorno del Espectro Autista , Trastornos del Neurodesarrollo , Lactante , Humanos , Trastorno del Espectro Autista/genética , Endofenotipos , Lenguaje , Estudios de Asociación GenéticaRESUMEN
Aging FMR1 premutation carriers are at risk of developing neurodegenerative disorders, including fragile X-associated tremor/ataxia syndrome (FXTAS), and there is a need to identify biomarkers that can aid in identification and treatment of these disorders. While FXTAS is more common in males than females, females can develop the disease, and some evidence suggests that patterns of impairment may differ across sexes. Few studies include females with symptoms of FXTAS, and as a result, little information is available on key phenotypes for tracking disease risk and progression in female premutation carriers. Our aim was to examine quantitative motor and cognitive traits in aging premutation carriers. We administered oculomotor tests of visually guided/reactive saccades (motor) and antisaccades (cognitive control) in 22 premutation carriers (73% female) and 32 age- and sex-matched healthy controls. Neither reactive saccade latency nor accuracy differed between groups. FMR1 premutation carriers showed increased antisaccade latencies relative to controls, both when considering males and females together and when analyzing females separately. Reduced saccade accuracy and increased antisaccade latency each were associated with more severe clinically rated neuromotor impairments. Findings indicate that together male and female premutation carriers show a reduced ability to rapidly exert volitional control over prepotent responses and that quantitative differences in oculomotor behavior, including control of visually guided and antisaccades, may track with FXTAS - related degeneration in male and female premutation carriers.
RESUMEN
Background: Sensorimotor impairments are common in autism spectrum disorder (ASD) and evident in unaffected first-degree relatives, suggesting that they may serve as important endophenotypes associated with inherited risk. We tested the familiality of sensorimotor impairments in ASD across multiple motor behaviors and effector systems and in relation to parental broader autism phenotypic (BAP) characteristics. Methods: Fifty-eight autistic individuals (probands), 109 parents, and 89 control participants completed tests of manual motor and oculomotor control. Sensorimotor tests varied in their involvement of rapid, feedforward control and sustained, sensory feedback control processes. Subgroup analyses compared families with at least one parent showing BAP traits (BAP+) and those in which neither parent showed BAP traits (BAP-). Results: Probands with BAP- parents (BAP- probands) showed rapid manual motor and oculomotor deficits, while BAP+ probands showed sustained motor impairments compared to controls. BAP- parents showed impaired rapid oculomotor and sustained manual motor abilities relative to BAP+ parents and controls. Atypical rapid oculomotor impairments also were familial. Limitations: Larger samples of ASD families including greater samples of probands with BAP+ parents are needed. Genetic studies also are needed to link sensorimotor endophenotype findings directly to genes. Conclusions: Results indicate rapid sensorimotor behaviors are selectively impacted in BAP- probands and their parents and may reflect familial liabilities for ASD that are independent of familial autistic traits. Sustained sensorimotor behaviors were affected in BAP+ probands and BAP- parents re ecting familial traits that may only confer risk when combined with parental autistic trait liabilities. These findings provide new evidence that rapid and sustained sensorimotor alterations represent strong but separate familial pathways of ASD risk that demonstrate unique interactions with mechanisms related to parental autistic traits.
RESUMEN
Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder diagnosed based on social impairment, restricted interests, and repetitive behaviors. Contemporary theories posit that cerebellar pathology contributes causally to ASD by disrupting error-based learning (EBL) during infancy. The present study represents the first test of this theory in a prospective infant sample, with potential implications for ASD detection. Methods: Data from the Infant Brain Imaging Study (n = 94, 68 male) were used to examine 6-month cerebellar functional connectivity magnetic resonance imaging in relation to later (12/24-month) ASD-associated behaviors and outcomes. Hypothesis-driven univariate analyses and machine learning-based predictive tests examined cerebellar-frontoparietal network (FPN; subserves error signaling in support of EBL) and cerebellar-default mode network (DMN; broadly implicated in ASD) connections. Cerebellar-FPN functional connectivity was used as a proxy for EBL, and cerebellar-DMN functional connectivity provided a comparative foil. Data-driven functional connectivity magnetic resonance imaging enrichment examined brain-wide behavioral associations, with post hoc tests of cerebellar connections. Results: Cerebellar-FPN and cerebellar-DMN connections did not demonstrate associations with ASD. Functional connectivity magnetic resonance imaging enrichment identified 6-month correlates of later ASD-associated behaviors in networks of a priori interest (FPN, DMN), as well as in cingulo-opercular (also implicated in error signaling) and medial visual networks. Post hoc tests did not suggest a role for cerebellar connections. Conclusions: We failed to identify cerebellar functional connectivity-based contributions to ASD. However, we observed prospective correlates of ASD-associated behaviors in networks that support EBL. Future studies may replicate and extend network-level positive results, and tests of the cerebellum may investigate brain-behavior associations at different developmental stages and/or using different neuroimaging modalities.
RESUMEN
The premutation of the fragile X messenger ribonucleoprotein 1 (FMR1) gene is characterized by an expansion of the CGG trinucleotide repeats (55 to 200 CGGs) in the 5' untranslated region and increased levels of FMR1 mRNA. Molecular mechanisms leading to fragile X-premutation-associated conditions (FXPAC) include cotranscriptional R-loop formations, FMR1 mRNA toxicity through both RNA gelation into nuclear foci and sequestration of various CGG-repeat-binding proteins, and the repeat-associated non-AUG (RAN)-initiated translation of potentially toxic proteins. Such molecular mechanisms contribute to subsequent consequences, including mitochondrial dysfunction and neuronal death. Clinically, premutation carriers may exhibit a wide range of symptoms and phenotypes. Any of the problems associated with the premutation can appropriately be called FXPAC. Fragile X-associated tremor/ataxia syndrome (FXTAS), fragile X-associated primary ovarian insufficiency (FXPOI), and fragile X-associated neuropsychiatric disorders (FXAND) can fall under FXPAC. Understanding the molecular and clinical aspects of the premutation of the FMR1 gene is crucial for the accurate diagnosis, genetic counseling, and appropriate management of affected individuals and families. This paper summarizes all the known problems associated with the premutation and documents the presentations and discussions that occurred at the International Premutation Conference, which took place in New Zealand in 2023.
Asunto(s)
Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil , Síndrome del Cromosoma X Frágil , Humanos , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/metabolismo , Mutación/genética , ARN Mensajero/metabolismo , Expansión de Repetición de Trinucleótido/genética , Síndrome del Cromosoma X Frágil/diagnóstico , Síndrome del Cromosoma X Frágil/genética , Síndrome del Cromosoma X Frágil/terapiaRESUMEN
Brain morphometric studies often incorporate comparative hemispheric asymmetry analyses of segmented brain structures. In this work, we present evidence that common user guided structural segmentation techniques exhibit strong left-right asymmetric biases and thus fundamentally influence any left-right asymmetry analyses. In this study, MRI scans from ten pediatric subjects were employed for studying segmentations of amygdala, globus pallidus, putamen, caudate, and lateral ventricle. Additionally, two pediatric and three adult scans were used for studying hippocampus segmentation. Segmentations of the sub-cortical structures were performed by skilled raters using standard manual and semi-automated methods. The left-right mirrored versions of each image were included in the data and segmented in a random order to assess potential left-right asymmetric bias. Using shape analysis we further assessed whether the asymmetric bias is consistent across subjects and raters with the focus on the hippocampus. The user guided segmentation techniques on the sub-cortical structures exhibited left-right asymmetric volume bias with the hippocampus displaying the most significant asymmetry values (p<<0.01). The hippocampal shape analysis revealed the bias to be strongest on the lateral side of the body and medial side of the head and tail. The origin of this asymmetric bias is considered to be based in laterality of visual perception; therefore segmentations with any degree of user interaction contain an asymmetric bias. The aim of our study is to raise awareness in the neuroimaging community regarding the presence of the asymmetric bias and its influence on any left-right hemispheric analyses. We also recommend reexamining previous research results in the light of this new finding.