Rebecca C. Shaffer

Drug-refractory aggression, self-injurious behavior, and severe tantrums in autism spectrum disorders: A chart review study

Aggression, self-injurious behavior, and severe tantrums are impairing symptoms frequently experienced by individuals with autism spectrum disorders. Despite US Food and Drug Administration approval of two atypical antipsychotics targeting these symptoms in youth with autistic disorder, they remain frequently drug refractory. We define drug-refractory aggression, self-injurious behavior, and severe tantrums in people with autism spectrum disorders as behavioral symptoms requiring medication adjustment despite previous trials of risperidone and aripiprazole or previous trials of three psychotropic drugs targeting the symptom cluster, one of which was risperidone or aripiprazole. We reviewed the medical records of individuals of all ages referred to our clinic for autism spectrum disorder diagnostic evaluation, as well as pharmacotherapy follow-up notes for all people meeting autism spectrum disorder criteria, for drug-refractory symptoms. Among 250 consecutively referred individuals, 135 met autism spectrum disorder and enrollment criteria, and 53 of these individuals met drug-refractory symptom criteria. Factors associated with drug-refractory symptoms included age 12 years or older (p < 0.0001), diagnosis of autistic disorder (p = 0.0139), and presence of intellectual disability (p = 0.0273). This pilot report underscores the significance of drug-refractory aggression, self-injurious behavior, and severe tantrums; suggests the need for future study clarifying factors related to symptom development; and identifies the need for focused treatment study of this impairing symptom domain.

The neurobehavioral and molecular phenotype of Angelman Syndrome.

Angelman Syndrome (AS) is a rare neurodevelopmental disorder associated with developmental delay, speech impairment, gait ataxia, and a unique behavioral profile. AS is caused by loss of maternal expression of the paternally imprinted UBE3A gene. In this study we aim to contribute to understanding of the neurobehavioral phenotype of AS with particular focus on the neuropsychiatric presentation of the disorder. We also undertake initial exploration of brain‐derived neurotrophic factor (BDNF) plasma levels in AS. Twelve individuals ages 3 years or older with a confirmed genetic diagnosis of AS underwent detailed medical history, phenotypic characterization, and BDNF plasma sampling. The results of this study demonstrate that individuals with AS suffer from significant developmental delay, impaired adaptive behavior, and sleep disruption. Additionally, hyperactivity/impulsivity appears to be the primary behavioral domain noted in these individuals. The majority of individuals in this project met criteria for autism spectrum disorder on the Autism Diagnostic Observation Schedule (ADOS); however, a negative correlation was noted between ADOS score and developmental age. BDNF plasma levels in AS individuals were significantly elevated compared to neurotypical controls. This is the first report of abnormal BDNF levels in AS, and one that necessitates larger future studies. The results provide a clue to understanding abnormal neuronal development in AS and may help guide future AS research.

Abnormal Cortical Plasticity in Youth with Autism Spectrum Disorder: A Transcranial Magnetic Stimulation Case–Control Pilot Study

Abstract Objective: This case–control study investigated the use of a low-intensity repetitive transcranial magnetic stimulation (rTMS) protocol to measure motor cortex (M1) plasticity in youth with autism spectrum disorder (ASD) compared with typically developing children (TDC). We hypothesized that impairments in long-term potentiation-like properties represent a neurophysiological biomarker of abnormal cortical function in ASD. Methods: We studied youth with ASD aged 11–18 years and matched controls (TDC). Intermittent theta burst stimulation (iTBS) was delivered to the dominant M1 at an intensity of 70% of resting motor threshold. Suprathreshold single-pulse TMS was performed to compare amplitudes of motor-evoked potentials (MEP) measured from surface electromyography electrodes on a target muscle before (20 pulses) and after (10 pulses/time point) iTBS at predefined timepoints (up to 30 minutes) to measure any potentiation effects. A linear mixed model was used to examine group differences in MEP amplitudes over time following iTBS. Results: Nine youth with ASD (mean age 15.6; 7 males; 6 right-hand dominant) and 9 TDC (mean age 14.5; 5 males; 9 right-hand dominant) participated. All subjects tolerated the procedure well. Both groups had a mean increase in excitability after iTBS for 30 minutes; however, the time course of excitability changes differed (F9,144 = 2.05; p = 0.038). Post-hoc testing identified a significant decrease in amplitude of the ASD group at 20 minutes following iTBS compared with the TDC after correcting for multiple comparisons. Conclusion: In this study, we demonstrate early evidence for a potential physiological biomarker of cortical plasticity in youth with ASD using a rapid low-intensity rTMS protocol with a discriminate measure at 20 minutes following stimulation. The procedure was well tolerated by all 18 participants. Future work will include modification of the protocol to improve the ability to distinguish subtypes of ASD based on behavioral and cognitive testing.

Training and Supporting Caregivers in Evidence-Based Practices

Given the increase in prevalence rates of Autism Spectrum Disorders (ASD) and evidence that intensive early intervention is important in prognosis, there is an increased need for services and interventions for children with ASD. However, given the limited resources in many areas, there has been increased emphasis placed on providing evidence-based parent training and parent support to enhance outcomes and quality of life. The purpose of this paper is to review the research supporting parent training programs and the variety of methods currently available. Factors related to parental stress and mental health are discussed, along with parent and family factors to consider when choosing a parent training program. Limitations to the existing research and areas for future consideration are also presented.

Eye gaze and pupillary response in Angelman syndrome

BACKGROUND Angelman syndrome (AS) is a rare neurological disorder characterized by severe developmental disability, communication impairment, elevated seizure risk, and motor system abnormalities. AIMS The aims of this study were to determine the feasibility of social scene eye tracking and pupillometry measures in individuals with AS and to compare the performance of AS participants to individuals with idiopathic Autism Spectrum Disorder (ASD) and typically developing controls (TDC). METHODS AND PROCEDURES Individuals with AS and age- and gender- matched controls completed a social eye tracking paradigm. Neurobehavioral characterization of AS participants was completed via a battery of psychological testing and caregiver behavioral evaluations. OUTCOMES AND RESULTS Eight of seventeen recruited AS participants completed the eye tracking paradigm. Compared to TDC, AS subjects demonstrated significantly less preference for social scenes than geometric shapes. Additionally, AS subjects showed less pupil dilation, compared to TDC, when viewing social scenes versus geometric shapes. There was no statistically significant difference found between AS and ASD subjects in either social eye tracking or pupillometry. CONCLUSIONS AND IMPLICATIONS The use of eye tracking and pupillometry may represent an innovative measure for quantifying AS-associated impairments in social salience.

Challenges in Conducting Clinical Trials for Pharmacotherapies in Fragile X Syndrome: Lessons Learned

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and most common single gene cause of autism spectrum disorder (ASD). Even in the context of a single gene disorder like FXS, characteristic cognitive and behavioral heterogeneity creates challenges in conducting targeted pharmacotherapy trials. Neuroscientific advances have elucidated aspects of the underlying neurobiology in FXS and have guided targeted treatment development in the last decade. However, despite significant preclinical progress, recent clinical trials have failed to consistently demonstrate therapeutic efficacy based on behavioral outcome measures in patients with FXS. One potential explanation for these failures is that many behavioral measures are not capable of quantitively capturing clinically significant change in such short-term trials. Further, the use of parent and clinician report instruments as primary outcome measures creates additional challenges in clinical trials. Future trials may employ more quantitative measures of evaluating the pathophysiology of FXS to avoid placebo-response resulting from rater bias. Quantitative measures of language, eye gaze, molecular dysregulation, and brain function may be used to identify which individuals may best respond to a particular treatment and to capture potential treatment-associated change. Here, we present a thorough review and reconsideration of the challenges encountered in conducting clinical trials in FXS to allow for lessons learned to drive future success in this field.

Brief Report: Diminished Gaze Preference for Dynamic Social Interaction Scenes in Youth with Autism Spectrum Disorders

In this study, we present an eye-tracking paradigm, adapted from previous work with toddlers, for assessing social-interaction looking preferences in youth ages 5–17 with ASD and typically-developing controls (TDC). Videos of children playing together (Social Scenes, SS) were presented side-by-side with animated geometric shapes (GS). Participants with ASD demonstrated reduced SS preferences compared to TDC, results also represented continuously by associations between higher SS preferences and fewer social difficulties across the combined sample. Exploratory analyses identified associations between increased SS preferences and higher Vineland Daily Living Skills in ASD and suggested SS preferences in TDC females might drive ASD versus TDC between-group differences. These findings describe potentially sex-linked couplings between preferences for social information and social functioning in school-aged children.