Oxidative pathways as a drug target for the treatment of autism

Importance of the field: Autism is a severe, pervasive developmental disorder, the aetiology of which is poorly understood. Current pharmacological treatment options for autism are often focused on addressing comorbid behavioural problems, rather than core features of the disorder. Investigation of a new treatment approach is needed.

Areas covered in this review: Recent research has indicated a possible role of abnormalities in oxidative homeostasis in the pathophysiology of autism, based on reports that a range of oxidative biomarkers are significantly altered in people with autism. This article reviews the current findings on oxidative stress in autism, including genetic links to oxidative pathways, changes in antioxidant levels and other oxidative stress markers. We conducted a search of the literature up to June 2010, using Medline, Pubmed, PsycINFO, CINAHL PLUS and BIOSIS Previews.

What the reader will gain: This review provides an overview of the current understanding of the role of oxidative stress in autism. This will assist in highlighting areas of future therapeutic targets and potential underlying pathophysiology of this disorder.

Take home message: Abnormalities in oxidative homeostasis may play a role in the pathophysiology of autism. Antioxidant treatment may form a potential therapeutic pathway for this complex disorder.

TOBY play-pad application to teach children with ASD – a pilot trial

 Purpose: To investigate use patterns and learning outcomes associated with the use of Therapy Outcomes By You (TOBY. Playpad, an early intervention iPad application. Methods: Participants were 33 families with a child with an autism spectrum disorder (ASD) aged 16 years or less, and with a diagnosis of autism or pervasive developmental disorder - not otherwise specified, and no secondary diagnoses. Families were provided with TOBY and asked to use it for 4-6 weeks, without further prompting or coaching. Dependent variables included participant use patterns and initial indicators of child progress. Results: Twenty-three participants engaged extensively with TOBY, being exposed to at least 100 complete learn units and completing between 17% and 100% of the curriculum. Conclusions: TOBY may make a useful contribution to early intervention programming for children with ASD delivering high rates of appropriate learning opportunities. Further research evaluating the efficacy of TOBY in relation to independent indicators of functioning is warranted.

Targeting the mitochondrial electron transport chain in autism, a systematic review and synthesis of a novel therapeutic approach

Autism is a complex developmental disorder with an unknown etiology and without any curative treatment. The mitochondrial electron transfer chains play a major role in the production of ATP, and the generation and management of reactive oxidative stress (ROS). This paper is a systematic review of the role of the mitochondrial electron transport chain in autism, and a consequent hypothesis for treating autism is synthesized.

An electronic search with pre-specified inclusion criteria was conducted in order to retrieve all the published articles about the mitochondrial electron transport chain in autism. The two databases of PUBMED and Google Scholar were searched.

Osmoregulatory fluid intake but not hypovolemic thirst is intact in mice lacking angiotensin

Water intakes in response to hypertonic, hypovolemic, and dehydrational stimuli were investigated in mice lacking angiotensin II as a result of deletion of the angiotensinogen gene (Agt-/- mice), and in C57BL6 wild-type (WT) mice. Baseline daily water intake in Agt-/- mice was approximately threefold that of WT mice because of a renal developmental disorder of the urinary concentrating mechanisms in Agt-/- mice. Intraperitoneal injection of hypertonic saline (0.4 and 0.8 mol/l NaCl) caused a similar dose-dependent increase in water intake in both Agt-/- and WT mice during the hour following injection. As well, Agt-/- mice drank appropriate volumes of water following water deprivation for 7 h. However, Agt-/- mice did not increase water or 0.3 mol/l NaCl intake in the 8 h following administration of a hypovolemic stimulus (30% polyethylene glycol sc), whereas WT mice increased intakes of both solutions during this time. Osmoregulatory regions of the brain [hypothalamic paraventricular and supraoptic nuclei, median preoptic nucleus, organum vasculosum of the lamina terminalis (OVLT), and subfornical organ] showed an increased number of neurons exhibiting Fos-immunoreactivity in response to intraperitoneal hypertonic NaCl in both Agt-/- mice and WT mice. Polyethylene glycol treatment increased Fos-immunoreactivity in the subfornical organ, OVLT, and supraoptic nuclei in WT mice but only increased Fos-immunoreactivity in the supraoptic nucleus in Agt-/- mice. These data show that brain angiotensin is not essential for the adequate functioning of neural pathways mediating osmoregulatory thirst. However, angiotensin II of either peripheral or central origin is probably necessary for thirst and salt appetite that results from hypovolemia

The effects of a course of intranasal oxytocin on social behaviors in youth diagnosed with autism spectrum disorders: A randomized controlled trial

Background There is increasing interest in oxytocin as a therapeutic to treat social deficits in autism spectrum disorders (ASD). The aim of this study was to investigate the efficacy of a course of oxytocin nasal spray to improve social behavior in youth with ASD. Methods In a double-blind, placebo-controlled trial across two Australian university sites between February 2009 and January 2012, 50 male participants aged between 12 and 18 years, with Autistic or Asperger's Disorder, were randomized to receive either oxytocin (n = 26) or placebo (n = 24) nasal sprays (either 18 or 24 International Units), administered twice-daily for 8 weeks. Participants were assessed at baseline, after 4- and 8-weeks of treatment, and at 3-month follow-up. Primary outcomes were change in total scores on the caregiver-completed Social Responsiveness Scale and clinician-ratings on the Clinical Global Impressions-Improvement scale. Secondary assessments included caregiver reports of repetitive and other developmental behaviors and social cognition. Clinical trial registration: Australian New Zealand Clinical Trials Registry www.anzctr.org.au ACTRN12609000513213. Results Participants who received oxytocin showed no benefit following treatment on primary or secondary outcomes. However, caregivers who believed their children received oxytocin reported greater improvements compared to caregivers who believed their child received placebo. Nasal sprays were well tolerated and there was no evidence of increased side effects resulting from oxytocin administration. Conclusions This is the first evaluation of the efficacy for a course of oxytocin treatment for youth with ASD. Although results did not suggest clinical efficacy, further research is needed to explore alternative delivery methods, earlier age of intervention, and the influence of caregiver expectation on treatment response.

Internal representation of movement in children with developmental coordination disorder : a mental rotation task

Recent studies show that children with developmental coordination disorder (DCD) have difficulties in generating an accurate visuospatial representation of an intended action, which are shown by deficits in motor imagery. This study sought to test this hypothesis further using a mental rotation paradigm. It was predicted that children with DCD would not conform to the typical pattern of responding when required to imagine movement of their limbs. Participants included 16 children with DCD and 18 control children; mean age for the DCD group was 10 years 4 months, and for controls 10 years. The task required children to judge the handedness of single-hand images that were presented at angles between 0° and 180° at 45° intervals in either direction. Results were broadly consistent with the hypothesis above. Responses of the control children conformed to the typical pattern of mental rotation: a moderate trade-off between response time and angle of rotation. The response pattern for the DCD group was less typical, with a small trade-off function. Response accuracy did not differ between groups. It was suggested that children with DCD, unlike controls, do not automatically enlist motor imagery when performing mental rotation, but rely on an alternative object-based strategy that preserves speed and accuracy. This occurs because these children manifest a reduced ability to make imagined transformations from an egocentric or first-person perspective.

Procedural learning in children with developmental coordination disorder

Despite the fact that developmental coordination disorder (DCD) is characterised by a deficit in the ability to learn or automate motor skills, few studies have examined motor learning over repeated trials. In this study we examined procedural learning in a group of 10 children with DCD (aged 8–12 years) and age-matched controls without DCD. The learning task was modelled on that of Nissen and Bullemer [Cognitive Psychology 19 (1987) 1]. Children performed a serial reaction time (SRT) task in which they were required to learn a spatial sequence that repeated itself every 10 trials. Children were not aware of the repetition. Spatial targets were four (horizontal) locations presented on a computer monitor. Children responded using four response keys with the same horizontal mapping as the stimulus. They were tested over five blocks of 100 trials each. The first four blocks presented the same repeating sequence, while the fifth block was randomised. Procedural learning was indexed by the slope of the regression of RT on blocks 1–4. Results showed that most children displayed strong procedural learning of the sequence, despite having no explicit knowledge about it. Overall, there was no group difference in the magnitude of learning over blocks of trials – most children performed within the normal range. Procedural learning for simple sequential movements appears to be intact in children with DCD. This suggests that cortico-striatal circuits that are strongly implicated in the sequencing of simple movements appear to be function normally in DCD.

Screening children with developmental coordination disorder : the development of the caregiver assessment of movement participation

This study investigated the psychometric properties of the Caregiver Assessment of Movement Participation (CAMP), which was developed to measure and identify children with movement participation problems in home contexts. The test-retest reliability, as well as the concurrent and contrast-group validity of the 35-item parent-proxy CAMP, was examined on 312 children aged 5 to 8 years using intraclass correlation, factor analysis, and the Rasch model. Initial findings on the CAMP appeared to support its validity. Testing on other properties from a practical perspective, such as finding the best rating scale structure and cutpoints, are recommended before using the instrument for child health surveillance screening.

Metacognitive, cognitive and developmental predictors of generalised anxiety disorder symptoms

Generalised anxiety disorder (GAD) is the most significant and common of the anxiety disorders. Intolerance of uncertainty (IU) and negative metacognitive beliefs are two prominent cognitive factors in models of GAD, however only one study to date has examined the relative contribution of these factors. Therefore, this study aimed to investigate and compare these cognitive factors in their prediction of GAD symptoms, and also to examine possible developmental influences on GAD by examining the link between symptoms and the parentification style of childrearing. In this analogue study, 119 non-clinical participants (M age 22.90 years; 95 females, 24 males) completed measures of these constructs. Results indicated that both IU and negative beliefs about worry significantly related to GAD symptoms, however, the degree to which they predicted GAD symptoms did not significantly differ. Although a weak but significant relationship was found between parentification and GAD, this relationship did not remain significant after controlling for depression. Implications and limitations are discussed.

Impaired online control in children with developmental coordination disorder reflects development immaturity

The present study aimed to clarify whether a reduced ability to correct movements in-flight observed in children with developmental coordination disorder (DCD) reflects a developmental immaturity or deviance from the typical trajectory. Eighteen children with DCD (8–12 years), 18 age-matched controls, and 12 younger controls (5–7 years) completed a double-step reaching task. Compared to older controls, children with DCD and younger controls showed similarly prolonged reaching when the target unexpectedly shifted at movement onset and were equally slow to correct their reaching trajectory. These results suggest that impaired online control in DCD reflects developmental immaturity, possibly implicating the parietal-cerebellar cortices.