Understanding Challenging Behaviors in Autism Spectrum Disorder: A Multi-Component, Interdisciplinary Model.

A multi-component, interdisciplinary model is described which explains the presence of, and in other cases the lack of, many challenging behaviors associated with autism spectrum disorder (ASD). More specifically, the model expands the operant behavioral conditioning paradigm by taking into account medical comorbidities and interoceptive processing.

Evidence from Characteristics and Comorbidities Suggesting That Asperger Syndrome Is a Subtype of Autism Spectrum Disorder.

The current version of the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM-V) does not consider Asperger syndrome a diagnostic category. This study was undertaken to see if there is evidence that this diagnosis should be reinstated. An online survey was conducted to examine symptoms and behaviors associated with the current diagnostic criteria of autism spectrum disorders (ASD) (DSM-V), and those associated with Asperger syndrome based on the previous version (DSM-IV-TR). The study also examined other characteristics historically associated with autism, as well as impairments often reported in infancy/young childhood and medical comorbidities frequently associated with autism. The sample included 251 individuals who had received a diagnosis of Asperger syndrome and 1888 who were diagnosed with autism or ASD. Numerous similarities and differences were found between the two groups. The findings are discussed in relation to reestablishing Asperger syndrome as a valid diagnostic category as well as a subtype of ASD.

Comparison of Autistic Individuals Who Engage in Self-Injurious Behavior, Aggression, and Both Behaviors.

BACKGROUND: Two of the most challenging behaviors exhibited by individuals on the autism spectrum are self-injurious behavior (SIB) and aggression. The aim of this study was to identify co-occurring symptoms, behaviors, and medical comorbidities that may provide insight into understanding and treating these behaviors. METHOD: A large-scale online survey was used to collect data on symptoms, behaviors, and medically related comorbidities commonly reported in individuals with autism spectrum disorders (ASD). Based on responses from 2327 participants, individuals with ASD were divided into four categories: individuals who engaged in SIB only, individuals who engaged in aggression only, individuals who engaged in both behaviors, and individuals who engaged in neither behavior. RESULTS: There were several characteristics and comorbidities associated with those who engaged in SIB only and in aggression only, in addition to those who engaged in both behaviors. CONCLUSION: The findings in this study provide evidence to support at least two underlying causes of these behaviors (insensitivity to pain and reactions to food) as well as implications for treating them. Furthermore, several behaviors often observed during early childhood may be considered early predictors of these challenging behaviors.

Strategies for Research, Practice, and Policy for Autism in Later Life: A Report from a Think Tank on Aging and Autism.

Over the past decade, there has been a growing interest in adults on the autistic spectrum, and more recently, the challenges related to aging in this population. A two-day Think Tank meeting, focused on aging in autism, was convened amongst international leaders in the field of autism research and practice. This meeting included a series of presentations addressing the current status of aging research, followed by discussions regarding priorities going forward. Attendees shared their thoughts and concerns regarding community services, government policies, societal perspectives and physical and mental health. The goal of these discussions was to consider systematic approaches aimed at providing meaningful supports that can ensure a quality of life for seniors on the autism spectrum.

Novel Prefrontal Synthesis Intervention Improves Language in Children with Autism.

Prefrontal synthesis (PFS) is defined as the ability to juxtapose mental visuospatial objects at will. Paralysis of PFS may be responsible for the lack of comprehension of spatial prepositions, semantically-reversible sentences, and recursive sentences observed in 30 to 40% of individuals with autism spectrum disorder (ASD). In this report we present data from a three-year-long clinical trial of 6454 ASD children age 2 to 12 years, which were administered a PFS-targeting intervention. Tablet-based verbal and nonverbal exercises emphasizing mental-juxtaposition-of-objects were organized into an application called Mental Imagery Therapy for Autism (MITA). The test group included participants who completed more than one thousand exercises and made no more than one error per exercise. The control group was selected from the rest of participants by a matching procedure. Each test group participant was matched to the control group participant by age, gender, expressive language, receptive language, sociability, cognitive awareness, and health score at first evaluation using propensity score analysis. The test group showed a 2.2-fold improvement in receptive language score vs. control group (p < 0.0001) and a 1.4-fold improvement in expressive language (p = 0.0144). No statistically significant change was detected in other subscales not targeted by the exercises. These findings show that language acquisition improves after training PFS and that a further investigation of the PFS-targeting intervention in a randomized controlled study is warranted.

Longitudinal Epidemiological Study of Autism Subgroups Using Autism Treatment Evaluation Checklist (ATEC) Score.

Here we report the results of the subgroup analyses of an observational cohort of children whose parents completed the Autism Treatment Evaluation Checklist (ATEC) over the period of several years. A linear mixed effects model was used to evaluate longitudinal changes in ATEC scores within different patient subgroups. All groups decreased their mean ATEC score over time indicating improvement of symptoms, however there were significant differences between the groups. Younger children improved more than the older children. Children with milder ASD improved more than children with more severe ASD in the Communication subscale. There was no difference in improvement between females vs. males. One surprising finding was that children from developed English-speaking countries improved less than children from non-English-speaking countries.

A Cohort Study Comparing Women with Autism Spectrum Disorder with and without Generalized Joint Hypermobility.

Reports suggest comorbidity between autism spectrum disorder (ASD) and the connective tissue disorder, Ehlers-Danlos syndrome (EDS). People with EDS and the broader spectrum of Generalized Joint Hypermobility (GJH) often present with immune- and endocrine-mediated conditions. Meanwhile, immune/endocrine dysregulation is a popular theme in autism research. We surveyed a group of ASD women with/without GJH to determine differences in immune/endocrine exophenotypes. ASD women 25 years or older were invited to participate in an online survey. Respondents completed a questionnaire concerning diagnoses, immune/endocrine symptom history, experiences with pain, and seizure history. ASD women with GJH (ASD/GJH) reported more immune- and endocrine-mediated conditions than their non-GJH counterparts (p = 0.001). Autoimmune conditions were especially prominent in the ASD/GJH group (p = 0.027). Presence of immune-mediated symptoms often co-occurred with one another (p < 0.001-0.020), as did endocrine-mediated symptoms (p < 0.001-0.045), irrespective of the group. Finally, the numbers of immune- and endocrine-mediated symptoms shared a strong inter-relationship (p < 0.001), suggesting potential system crosstalk. While our results cannot estimate comorbidity, they reinforce concepts of an etiological relationship between ASD and GJH. Meanwhile, women with ASD/GJH have complex immune/endocrine exophenotypes compared to their non-GJH counterparts. Further, we discuss how connective tissue regulates the immune system and how the immune/endocrine systems in turn may modulate collagen synthesis, potentially leading to higher rates of GJH in this subpopulation.

Autism Treatment Evaluation Checklist (ATEC) Norms: A "Growth Chart" for ATEC Score Changes as a Function of Age.

Most early-intervention Autism Spectrum Disorder (ASD) clinical trials are limited by the availability of psychometric technicians who assess each child's abilities before and after therapeutic intervention. If parents could administer regular psychometric evaluations of their children, then the cost of clinical trials will be reduced, enabling longer clinical trials with the larger number of participants. The Autism Treatment Evaluation Checklist (ATEC) was designed nearly two decades ago to provide such a tool, but the norms on the longitudinal changes in ATEC in the "treatment as usual" population were lacking. Here we report the norms of the observational cohort who voluntarily completed ATEC evaluations over the period of four years from 2013 to 2017.

Neuropathological Mechanisms of Seizures in Autism Spectrum Disorder.

This manuscript reviews biological abnormalities shared by autism spectrum disorder (ASD) and epilepsy. Two neuropathological findings are shared by ASD and epilepsy: abnormalities in minicolumn architecture and γ-aminobutyric acid (GABA) neurotransmission. The peripheral neuropil, which is the region that contains the inhibition circuits of the minicolumns, has been found to be decreased in the post-mortem ASD brain. ASD and epilepsy are associated with inhibitory GABA neurotransmission abnormalities including reduced GABAA and GABAB subunit expression. These abnormalities can elevate the excitation-to-inhibition balance, resulting in hyperexcitablity of the cortex and, in turn, increase the risk of seizures. Medical abnormalities associated with both epilepsy and ASD are discussed. These include specific genetic syndromes, specific metabolic disorders including disorders of energy metabolism and GABA and glutamate neurotransmission, mineral and vitamin deficiencies, heavy metal exposures and immune dysfunction. Many of these medical abnormalities can result in an elevation of the excitatory-to-inhibitory balance. Fragile X is linked to dysfunction of the mGluR5 receptor and Fragile X, Angelman and Rett syndromes are linked to a reduction in GABAA receptor expression. Defects in energy metabolism can reduce GABA interneuron function. Both pyridoxine dependent seizures and succinic semialdehyde dehydrogenase deficiency cause GABA deficiencies while urea cycle defects and phenylketonuria cause abnormalities in glutamate neurotransmission. Mineral deficiencies can cause glutamate and GABA neurotransmission abnormalities and heavy metals can cause mitochondrial dysfunction which disrupts GABA metabolism. Thus, both ASD and epilepsy are associated with similar abnormalities that may alter the excitatory-to-inhibitory balance of the cortex. These parallels may explain the high prevalence of epilepsy in ASD and the elevated prevalence of ASD features in individuals with epilepsy.

A review of traditional and novel treatments for seizures in autism spectrum disorder: findings from a systematic review and expert panel.

Despite the fact that seizures are commonly associated with autism spectrum disorder (ASD), the effectiveness of treatments for seizures has not been well studied in individuals with ASD. This manuscript reviews both traditional and novel treatments for seizures associated with ASD. Studies were selected by systematically searching major electronic databases and by a panel of experts that treat ASD individuals. Only a few anti-epileptic drugs (AEDs) have undergone carefully controlled trials in ASD, but these trials examined outcomes other than seizures. Several lines of evidence point to valproate, lamotrigine, and levetiracetam as the most effective and tolerable AEDs for individuals with ASD. Limited evidence supports the use of traditional non-AED treatments, such as the ketogenic and modified Atkins diet, multiple subpial transections, immunomodulation, and neurofeedback treatments. Although specific treatments may be more appropriate for specific genetic and metabolic syndromes associated with ASD and seizures, there are few studies which have documented the effectiveness of treatments for seizures for specific syndromes. Limited evidence supports l-carnitine, multivitamins, and N-acetyl-l-cysteine in mitochondrial disease and dysfunction, folinic acid in cerebral folate abnormalities and early treatment with vigabatrin in tuberous sclerosis complex. Finally, there is limited evidence for a number of novel treatments, particularly magnesium with pyridoxine, omega-3 fatty acids, the gluten-free casein-free diet, and low-frequency repetitive transcranial magnetic simulation. Zinc and l-carnosine are potential novel treatments supported by basic research but not clinical studies. This review demonstrates the wide variety of treatments used to treat seizures in individuals with ASD as well as the striking lack of clinical trials performed to support the use of these treatments. Additional studies concerning these treatments for controlling seizures in individuals with ASD are warranted.

Proposed toxic and hypoxic impairment of a brainstem locus in autism.

Electrophysiological findings implicate site-specific impairment of the nucleus tractus solitarius (NTS) in autism. This invites hypothetical consideration of a large role for this small brainstem structure as the basis for seemingly disjointed behavioral and somatic features of autism. The NTS is the brain's point of entry for visceral afference, its relay for vagal reflexes, and its integration center for autonomic control of circulatory, immunological, gastrointestinal, and laryngeal function. The NTS facilitates normal cerebrovascular perfusion, and is the seminal point for an ascending noradrenergic system that modulates many complex behaviors. Microvascular configuration predisposes the NTS to focal hypoxia. A subregion--the "pNTS"--permits exposure to all blood-borne neurotoxins, including those that do not readily transit the blood-brain barrier. Impairment of acetylcholinesterase (mercury and cadmium cations, nitrates/nitrites, organophosphates, monosodium glutamate), competition for hemoglobin (carbon monoxide, nitrates/nitrites), and higher blood viscosity (net systemic oxidative stress) are suggested to potentiate microcirculatory insufficiency of the NTS, and thus autism.

Effect of pioglitazone treatment on behavioral symptoms in autistic children.

INTRODUCTION: Autism is complex neuro-developmental disorder which has a symptomatic diagnosis in patients characterized by disorders in language/communication, behavior, and social interactions. The exact causes for autism are largely unknown, but is has been speculated that immune and inflammatory responses, particularly those of Th2 type, may be involved. Thiazolidinediones (TZDs) are agonists of the peroxisome proliferator activated receptor gamma (PPARgamma), a nuclear hormone receptor which modulates insulin sensitivity, and have been shown to induce apoptosis in activated T-lymphocytes and exert anti-inflammatory effects in glial cells. The TZD pioglitazone (Actos) is an FDA-approved PPARgamma agonist used to treat type 2 diabetes, with a good safety profile, currently being tested in clinical trials of other neurological diseases including AD and MS. We therefore tested the safety and therapeutic potential of oral pioglitazone in a small cohort of children with diagnosed autism. CASE DESCRIPTION: The rationale and risks of taking pioglitazone were explained to the parents, consent was obtained, and treatment was initiated at either 30 or 60 mg per day p.o. A total of 25 children (average age 7.9 +/- 0.7 year old) were enrolled. Safety was assessed by measurements of metabolic profiles and blood pressure; effects on behavioral symptoms were assessed by the Aberrant Behavior Checklist (ABC), which measures hyperactivity, inappropriate speech, irritability, lethargy, and stereotypy, done at baseline and after 3-4 months of treatment. DISCUSSION AND EVALUATION: In a small cohort of autistic children, daily treatment with 30 or 60 mg p.o. pioglitazone for 3-4 months induced apparent clinical improvement without adverse events. There were no adverse effects noted and behavioral measurements revealed a significant decrease in 4 out of 5 subcategories (irritability, lethargy, stereotypy, and hyperactivity). Improved behaviors were inversely correlated with patient age, indicating stronger effects on the younger patients. CONCLUSION: Pioglitazone should be considered for further testing of therapeutic potential in autistic patients.