ANeustart Builds on the Science of Brain Development

Brain Development in Autism

Autism is a developmental disorder affecting 1 in 100 children worldwide. While much of the etiology of autism is still unknown, either genetic, environmental, or both can impact prenatal brain development. Altered brain connectivity occurs when too few connections are made or when an abundance of inefficient brain connections is not eliminated, leading to inefficient communication. Efficient communication between cells is the basis of a child’s ability to learn, play, and socialize.  

Nutrient needs in brain development 

At certain stages of development, one million brain connections are made every second, leaving the process of brain development particularly vulnerable to deficiencies or imbalances. Brain development requires protein, minerals such as iron, zinc, selenium, iodine, and vitamins such as folate, vitamin A, choline, and long-chain polyunsaturated fatty acids, and more as the precursors for the metabolic process needed to build synapses. Different brain areas maturate at different times, and any imbalance can leave specific brain areas with the inability to cultivate efficient synapses3.

 

Nutrient Imbalances in Autism 

Alterations in brain connectivity in development and functional differences observed postnatally as mentioned above (as reduced synaptic pruning, neuroinflammation, comorbid immune conditions, microbiome dysbiosis, mitochondrial dysfunction, and increases in oxidative stress) all deplete resources or divert resources for use by other systems that are needed metabolically for brain function. Indeed, children with autism show various imbalances in vitamins, minerals, and important biological compounds. Adams et al. 201116 specifically showed reduced levels of biotin, magnesium, calcium, and sulfate and dysregulation in glutathione pathways, and ATP was lower than in control children. In contrast, iron, copper, phosphorus, and choline levels were higher in ASD children with high variability. In a large cohort of 274 children in China, Gau M et al. 2020, found that vitamin D, folate, calcium, magnesium, iron, and zinc were lower in ASD children. Interestingly, no differences were found in vitamin A levels between groups. However, stratifying according to vitamin A status reveals worse symptoms in children with vitamin A deficiency. 

Dietary Interventions

Adams LB et al. 201819 used a 12-month random controlled trial with comprehensive nutritional intervention including vitamins, minerals, amino acid combination, and a gluten-free casein-free diet. The participants were ages 3-58. The results were highly variable, but several improvements have been reported, specifically changes in the Autism Treatment Evaluation Checklist (ATEC).

A meta-analysis performed on gluten-free casein-free diets for 297 patients who had received the diet by Quan et al. 2022 showed overall improvements in repetitive behaviors and cognition in children on the diet. In a review by Whiteley et al. 201521, the authors conclude that the diet may benefit certain groups of children specifically due to heterogeneity reported in intervention studies. Finally, in a study comparing the outcomes of a ketogenic intervention vs. gluten-free casein-free children 3-8 years old, El-Rahidy et al. 201722 showed that both types of dietary interventions improve Children's Autism Rating Scale (CARS) and ATEC scores. The ketogenic diet intervention led to a more significant improvement in sociability and cognition subscales in the ATEC. In contrast, gluten-free casein-free diets showed more significant changes in the health and behavior subscale of the ATEC questionnaire. 

 

Evidence for nutrient-based therapy in autism. 

Single Vitamin Interventions

In a review of vitamin supplementation in ASD children, Robea et al. 202023 review the positive impacts of supplementation individually of B1, B6, B12, vitamin D, and vitamin A on autism symptoms. Vitamin D helped improve hyperactivity, while supplementation of B6 and magnesium improved both core one and core two symptoms of autism. Both vitamin B6 and B12 independently were also able to improve ATP and glutathione levels (reported to be low in ASD). Weekly supplementation with Vitamin A in general and specifically, a 6-month intervention with vitamin A to ASD children with vitamin A deficiency showed that vitamin A improves vitamin A status and social responsiveness. The effect was found to act through oxytocin receptors, and possibly increasing Bacteroidetes in the gut helped to improve social behavior24. 

 

Several papers have also focused on supplementing folinic acid, a form of folate that more readily crosses the blood-brain barrier. It was shown that a subset of children with autism has autoantibodies to the folate transporter, which is responsible for carrying folate into the brain, effectively blocking its transport to the brain. In Frye R.E et al. 202025, a review of studies using d,l-leucovorin (folinic acid) showed a slight improvement in verbal communication as measured by changes in standard deviation in children with autism who were supplemented. Children who were positive for antibodies showed better improvement in verbal communication. 

Amino Acid Interventions

A double-blind, randomized clinical trial of levocarnitine by Geier et al. 26 or L-carnitine therapy (50 mg/kilogram-body weight/day) administered for three months significantly improved CARS and ATEC symptom scales. Specifically, in the ATEC, there were significant improvements in the cognition subscale. Another study by Farid et al. 201327 using (100 mg/kg body weight/day) for six months showed significant improvement in CARS scores and significant differences in free and total carnitine levels. Improvements due to carnitine intervention presumably improve mitochondrial function since carnitine facilitates the transport of long-chain fatty acids from the cytosol into the mitochondrial matrix, where fatty-acid oxidation occurs. 

Bioactive compound interventions 

In Bent et al. 201828, children with ASD gave urine samples and then started a 12-week open-label supplementation of sulforaphane (extracted from broccoli seeds). Urinary metabolites that were correlated with changes in symptoms and additionally mild improvements were seen in hyperactivity behaviors in the classroom setting. 

A follow-up to the study was a 15-week randomized parallel, double-blind placebo-controlled clinical trial with 15-week open-label treatment and 6-week no-treatment extensions29. The children showed more than 20% improvement in the aberrant behavior checklist (ABC), numerous physiological changes from reduced immune markers, improvement in mitochondrial function, and specifically increases in ATP-linked respiration that correlated with improvement in the ABC checklist. However, there were no changes in their primary outcome measured by the Ohio Autism Clinical Impressions Scale, so they considered the study results mild or ineffective at changing overall autism symptoms. 

 

Microbiome-based interventions

Several interventions have been tested to increase the healthy flora in children with autism. Among them are antibiotics, prebiotics, probiotics, and fecal microbial transplants. Studies using antibiotics or probiotics that affect Clostridium have shown at least some benefit in symptoms related to communication and behavior. Lactobacillus acidophilus improved behavioral symptoms and reduced the ratio of candida markers of d-arabinitol and l-arabinitol30. In rodent models, the L. reuterii strain increased pro-social oxytocin levels and social behavior31. In Grimaldi R et al. 201832, prebiotic B-GOS intervention improved gastrointestinal symptoms in a child on an unrestricted diet and showed accompanying changes in urine metabolites. Fecal transplant has also shown changes in the Clostridium population and accompanying behavioral improvements. However, choosing the right donors and correct timelines for therapy have yet to be fully understood7.

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