Bryan H. King

Consensus Paper: Pathological Role of the Cerebellum in Autism

There has been significant advancement in various aspects of scientific knowledge concerning the role of cerebellum in the etiopathogenesis of autism. In the current consensus paper, we will observe the diversity of opinions regarding the involvement of this important site in the pathology of autism. Recent emergent findings in literature related to cerebellar involvement in autism are discussed, including: cerebellar pathology, cerebellar imaging and symptom expression in autism, cerebellar genetics, cerebellar immune function, oxidative stress and mitochondrial dysfunction, GABAergic and glutamatergic systems, cholinergic, dopaminergic, serotonergic, and oxytocin-related changes in autism, motor control and cognitive deficits, cerebellar coordination of movements and cognition, gene–environment interactions, therapeutics in autism, and relevant animal models of autism. Points of consensus include presence of abnormal cerebellar anatomy, abnormal neurotransmitter systems, oxidative stress, cerebellar motor and cognitive deficits, and neuroinflammation in subjects with autism. Undefined areas or areas requiring further investigation include lack of treatment options for core symptoms of autism, vermal hypoplasia, and other vermal abnormalities as a consistent feature of autism, mechanisms underlying cerebellar contributions to cognition, and unknown mechanisms underlying neuroinflammation.

Lack of efficacy of citalopram in children with autism spectrum disorders and high levels of repetitive behavior: citalopram ineffective in children with autism.

CONTEXT Selective serotonin reuptake inhibitors are widely prescribed for children with autism spectrum disorders. OBJECTIVES To determine the efficacy and safety of citalopram hydrobromide therapy for repetitive behavior in children with autism spectrum disorders. DESIGN National Institutes of Health-sponsored randomized controlled trial. SETTING Six academic centers, including Mount Sinai School of Medicine, North Shore-Long Island Jewish Health System, University of North Carolina at Chapel Hill, University of California at Los Angeles, Yale University, and Dartmouth Medical School. PARTICIPANTS One hundred forty-nine volunteers 5 to 17 years old (mean [SD] age, 9.4 [3.1] years) were randomized to receive citalopram (n = 73) or placebo (n = 76). Participants had autistic spectrum disorders, Asperger disorder, or pervasive developmental disorder, not otherwise specified; had illness severity ratings of at least moderate on the Clinical Global Impressions, Severity of Illness Scale; and scored at least moderate on compulsive behaviors measured with the Childrens Yale-Brown Obsessive Compulsive Scales modified for pervasive developmental disorders. INTERVENTIONS Twelve weeks of citalopram hydrobromide (10 mg/5 mL) or placebo. The mean (SD) maximum dosage of citalopram hydrobromide was 16.5 (6.5) mg/d by mouth (maximum, 20 mg/d). MAIN OUTCOME MEASURES Positive response was defined by a score of much improved or very much improved on the Clinical Global Impressions, Improvement subscale. An important secondary outcome was the score on the Childrens Yale-Brown Obsessive Compulsive Scales modified for pervasive developmental disorders. Adverse events were systematically elicited using the Safety Monitoring Uniform Report Form. RESULTS There was no significant difference in the rate of positive response on the Clinical Global Impressions, Improvement subscale between the citalopram-treated group (32.9%) and the placebo group (34.2%) (relative risk, 0.96; 95% confidence interval, 0.61-1.51; P > .99). There was no difference in score reduction on the Childrens Yale-Brown Obsessive Compulsive Scales modified for pervasive developmental disorders from baseline (mean [SD], -2.0 [3.4] points for the citalopram-treated group and -1.9 [2.5] points for the placebo group; P = .81). Citalopram use was significantly more likely to be associated with adverse events, particularly increased energy level, impulsiveness, decreased concentration, hyperactivity, stereotypy, diarrhea, insomnia, and dry skin or pruritus. CONCLUSION Results of this trial do not support the use of citalopram for the treatment of repetitive behavior in children and adolescents with autism spectrum disorders. Trial Registration clinicaltrials.gov Identifier: NCT00086645.

Maladaptive behavior differences in Prader-Willi syndrome due to paternal deletion versus maternal uniparental disomy

Maladaptive behavior was compared across 23 people with Prader-Willi syndrome due to paternal deletion to 23 age- and gender-matched subjects with maternal uniparental disomy. Controlling for the higher IQs of the uniparental disomy group, deleted cases showed significantly higher maladaptive ratings on the Child Behavior Checklists Internalizing, Externalizing, and Total domains as well as more symptom-related distress on the Yale-Brown Obsessive-Compulsive Scale. Across both measures, deleted cases were more apt to skin-pick, bite their nails, hoard, overeat, sulk, and withdraw. A dampening of symptom severity is suggested in Prader-Willi syndrome cases due to maternal uniparental disomy. Findings are compared to Angelman syndrome, and possible genetic mechanisms are discussed, as are implications for Prader-Willi syndrome and obsessive-compulsive behaviors.

Double-blind, placebo-controlled study of amantadine hydrochloride in the treatment of children with autistic disorder

OBJECTIVE To test the hypothesis that amantadine hydrochloride is a safe and effective treatment for behavioral disturbances--for example, hyperactivity and irritability--in children with autism. METHOD Thirty-nine subjects (intent to treat; 5-19 years old; IQ > 35) had autism diagnosed according to DSM-IV and ICD-10 criteria using the Autism Diagnostic Interview-Revised and the Autism Diagnostic Observation Schedule-Generic. The Aberrant Behavior Checklist-Community Version (ABC-CV) and Clinical Global Impressions (CGI) scale were used as outcome variables. After a 1-week, single-blind placebo run-in, patients received a single daily dose of amantadine (2.5 mg/kg per day) or placebo for the next week, and then bid dosing (5.0 mg/kg per day) for the subsequent 3 weeks. RESULTS When assessed on the basis of parent-rated ABC-CV ratings of irritability and hyperactivity, the mean placebo response rate was 37% versus amantadine at 47% (not significant). However, in the amantadine-treated group there were statistically significant improvements in absolute changes in clinician-rated ABC-CVs for hyperactivity (amantadine -6.4 versus placebo -2.1; p = .046) and inappropriate speech (-1.9 versus 0.4; p = .008). CGI scale ratings were higher in the amantadine group: 53% improved versus 25% (p = .076). Amantadine was well tolerated. CONCLUSIONS Parents did not report statistically significant behavioral change with amantadine. However, clinician-rated improvements in behavioral ratings following treatment with amantadine suggest that further studies with this or other drugs acting on the glutamatergic system are warranted. The design of these and similar drug trials in children with autistic disorder must take into account the possibility of a large placebo response.

Is schizophrenia on the autism spectrum

With the ongoing consideration of the diagnostic criteria for mental disorders that is active in the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) and International Classification of Diseases (ICD-11) revision processes, it is timely to review the phenomenological overlap between autism and schizophrenia. These disorders have at various times been regarded alternatively as closely related and as non-overlapping and incompatible. Nevertheless, there are several reports in the literature that have described individuals with both autism and schizophrenia, and the broader phenotypes of these disorders clearly intersect. Recent studies reveal theory of mind deficits in both disorders, and mirror neuron impairments also appear to be shared. There also may be similar connectivity deficits emerging in functional imaging studies, and both disorders share several genetic signals that are being identified through detection of copy number variants. Taken together, these data suggest that it may be time to revisit the possibility that these disorders are related.

Practice Parameters For The Assessment And Treatment Of Children, Adolescents, And Adults With Mental Retardation And Comorbid Mental Disorders

Mental retardation (MR) is a heterogeneous condition defined by significantly subaverage intellectual and adaptive functioning and onset before age 18 years. With an approach underscored by principles of normalization and the availability of appropriate education and habilitation, persons with MR generally live, are educated, and work in the community. Mental disorders occur more commonly in persons with MR than in the general population. However, the disorders themselves are essentially the same. Clinical presentations can be modified by poor language skills and by life circumstances, so a diagnosis might hinge more heavily on observable behavioral symptoms. The diagnostic assessment considers and synthesizes the biological, psychological, and psychosocial context of mental disorders. Comprehensive treatment integrating various approaches, including family counseling, pharmacological, educational, habilitative, and milieu interventions is the rule.

Treatment of Pain in Acutely Burned Children

The child with burns suffers severe pain at the time of the burn and during subsequent treatment and rehabilitation. Pain has adverse physiological and emotional effects, and research suggests that pain management is an important factor in better outcomes. There is increasing understanding of the private experience of pain, and how children benefit from honest preparation for procedures. Developmentally appropriate and culturally sensitive pain assessment, pain relief, and reevaluation have improved, becoming essential in treatment. Pharmacological treatment is primary, strengthened by new concepts from neurobiology, clinical science, and the introduction of more effective drugs with fewer adverse side effects and less toxicity. Empirical evaluation of various hypnotic, cognitive, behavioral, and sensory treatment methods is advancing. Multidisciplinary assessment helps to integrate psychological and pharmacological pain-relieving interventions to reduce emotional and mental stress, and family stress as well. Optimal care encourages burn teams to integrate pain guidelines into protocols and critical pathways for improved care.

JunB protects against myeloid malignancies by limiting hematopoietic stem cell proliferation and differentiation without affecting self-renewal.

Loss of the JunB/AP-1 transcription factor induces a myeloproliferative disease (MPD) arising from the hematopoietic stem cell (HSC) compartment. Here, we show that junB inactivation deregulates the cell-cycle machinery and increases the proliferation of long-term repopulating HSCs (LT-HSCs) without impairing their self-renewal or regenerative potential in vivo. We found that JunB loss destabilizes a complex network of genes and pathways that normally limit myeloid differentiation, leading to impaired responsiveness to both Notch and TGF-beta signaling due in part to transcriptional deregulation of the Hes1 gene. These results demonstrate that LT-HSC proliferation and differentiation are uncoupled from self-renewal and establish some of the mechanisms by which JunB normally limits the production of myeloid progenitors, hence preventing initiation of myeloid malignancies.

Exploring the Manifestations of Anxiety in Children with Autism Spectrum Disorders.

This study explores the manifestation and measurement of anxiety symptoms in 415 children with ASDs on a 20-item, parent-rated, DSM-IV referenced anxiety scale. In both high and low-functioning children (IQ above vs. below 70), commonly endorsed items assessed restlessness, tension and sleep difficulties. Items requiring verbal expression of worry by the child were rarely endorsed. Higher anxiety was associated with functional language, IQ above 70 and higher scores on several other behavioral measures. Four underlying factors emerged: Generalized Anxiety, Separation Anxiety, Social Anxiety and Over-arousal. Our findings extend our understanding of anxiety across IQ in ASD and provide guidance for improving anxiety outcome measurement.

Measuring Anxiety as a Treatment Endpoint in Youth with Autism Spectrum Disorder

Despite the high rate of anxiety in individuals with autism spectrum disorder (ASD), measuring anxiety in ASD is fraught with uncertainty. This is due, in part, to incomplete consensus on the manifestations of anxiety in this population. Autism Speaks assembled a panel of experts to conduct a systematic review of available measures for anxiety in youth with ASD. To complete the review, the panel held monthly conference calls and two face-to-face meetings over a fourteen-month period. Thirty eight published studies were reviewed and ten assessment measures were examined: four were deemed appropriate for use in clinical trials, although with conditions; three were judged to be potentially appropriate, while three were considered not useful for clinical trials assessing anxiety. Despite recent advances, additional relevant, reliable and valid outcome measures are needed to evaluate treatments for anxiety in ASD.