The study explores the impact of malnutrition at enrollment on executive function (EF) and emotional regulation (ER) in malnourished 1-year-old children and whether specially designed brain directed therapeutic feeds improve EF/ER outcomes at three years of age. The study will detect changes in EF and ER related to nutritional rehabilitation using specially designed ready to use therapeutic feeds (E-RUSF Nutriset) during the repletion phase and maintained for two years until age 3 with enhanced E-SQLNS (small quantity lipid based nutrient supplement) also modified to provide adequate brain directed micro and macronutrients. The investigators hypothesize that standard Bangladeshi designed B-RUSF and SQLNS (Nutriset) do not provide adequate nutrients to supply the brain during the rapid catch-up growth and subsequent early childhood growth phases of rehabilitation from Moderate Acute Malnutrition (MAM). The investigators predict that the children with moderately severe malnutrition treated with E-RUSF followed by 2 years of E-SQLNS will show an exuberance of connections (higher functional connectivity) than children receiving standard Bangladeshi rehabilitation feeds B-RUSF and SQLNS. This prediction is based on past work using EEG to examine the BEAN sample in Bangladesh, and differs from the sample in Boston, where the investigators anticipate that among healthy, normally nourished children, greater connectivity will be associated with better cognitive outcomes. The Core Toolkit will be deployed to the Bangladesh site to define its utility in prediction of executive dysfunction and emotional dysregulation in the context of low-income status, malnutrition and nutritional intervention. All nutritional intervention groups of malnourished children will also receive a set psychosocial stimulation curriculum that has been shown to be effective on severely malnourished children with therapeutic feedings.

Malnutrition affects around 47 million children under 5 years of age annually and underlies 45% of the mortality in low- and middle-income countries where around 2 billion survivors suffer long term cognitive and behavioural sequelae. Acute malnutrition, comprising both MAM (Moderate Acute Malnutrition) and SAM (Severe Acute Malnutrition) causes 14.6% of all deaths of children under 5 years of age globally. It is a significant problem in Bangladesh where > 40% of under-fives have chronic or moderately acute malnutrition. The long-term consequences of malnutrition for the 5.5 million children under 5 years that suffer from chronic malnutrition (stunting or low height-for-age) and the 14% are acutely malnourished (wasting or low weight-for-height) include poor brain development with resultant impairment of the development of cognitive, motor, and socio-emotional skills throughout childhood and adulthood. Malnutrition during early childhood negatively affects cognition, behaviour, school performance and productivity in later life. Further, current rehabilitation feeding regimes do not reverse the impairment in brain development as these are designed with rapid catch-up growth as the principal goal.

Malnourished children have an abnormal assembly of the early gut microbiota which may impair brain function by disturbing the bidirectional neural and immune interactions between gut and brain by altered production of signal molecules by the microbiota such as short-chain fatty acids, and neurotransmitters. Nutritionally wasted children notably have marked brain atrophy on MRI and while re-feeding reverses brain atrophy, significant deficits remain in function and microstructure. It is likely that the anatomic reconstitution of the brain with feeds designed principally for corporal rapid catch-up growth results in brain structure which is unable to provide substrate for normal cognitive and emotional performance. Fixing this must depend at least in part on provision of the appropriate nutrients in amounts that meet demands during rapid catch-up growth of the body and brain.

The investigators propose that nutrient deficiencies, and gut microbiome dysbiosis both induce structural and functional abnormalities of the brain in malnutrition that lead to neuropsychological sequelae in childhood and later life. The human brain develops during intrauterine life as well as early childhood, especially in the developmental window between birth and 3 years of age. Better recovery of brain architecture and function in children suffering malnutrition will result from augmenting feeds with key nutrients with targeted functionality in the brain during rapid brain regrowth. The supplements are E-RUSF (Ready to Use Therapeutic Feed-enhanced manufactured by Nutriset) and E-SQLNS (standard/enhanced small quantity lipid based nutrient supplements) all containing key nutrients for rehabilitating wasted brains: 24 micronutrients (vitamins and minerals) provided at recommended daily allowance levels, functional lipids (Long Chain Polyunsaturated Fatty Acids DHA and EPA), sialylated milk oligosaccharides, neural specific antioxidants (zeaxanthine, lutein; crypto-xanthine) and microbiome modulating dietary soluble fibre mix (inulin + FOS), 6 g per 26g daily dose of E-SQLNS, as well as within a daily 100g ration of E-RUSF. The comparator group will receive standard of care therapeutic feeds in Bangladesh. These feeds are an energy dense chickpea-based RUSF with a targeted calorie delivery of 250 kcal/50 g (per serving) with caloric distribution 45-50 percent from fat and 8-10 percent from protein.

The diagnostic criteria for MAM in children 6 to 59 months of age are weight-for-height z-score <-2 and ≥-3 z-score of WHO child growth standards and/or MUAC <12.5 and ≥11.5 cm. This definition is also supported by USAID. There are about 1.8 million children under 5 years of age in Bangladesh with MAM. The study will be conducted in the Mirpur area within the Dhaka city. The Mirpur study/surveillance area is well known to all staff working in the Mirpur field clinic as they have been working in this area on existing studies for the last 10 years. The investigators have established a field clinic/lab located within ward 5 where staff have been working for the BEAN project (PR-14110 and PR-18036) for the last 7 years. Existing staff will therefore recruit the children and mothers from the study area. The Mirpur area is a densely populated area and is located around 8 km from the main campus of icddr, b at Mohakhali, Dhaka. Mirpur was selected as the study site because it is inhabited by poor and middle-class families, residential and sanitary conditions are typical of any congested urban settlements, and there have been ongoing research activities in this area for the last 30 years.

This study design will adequately assess the capabilities of the EF/ER Toolkit in the control group allowing comparisons to high-income country data. Through the two interventional arms, and the comparison to 3y old untreated children, there will be high quality pilot data on the EF/ER response to interventions to power a definitive trial. The enrolled children will have follow-up visits at 2 years and 3 years of age with EF/ER for developmental assessment.

Inclusion criteria:

Inclusion criteria for malnourished (MAM) children at 1 and 3 years of age: All of the following criteria must be met for a subject to be eligible to participate in the study

• Mother willing to sign consent form
• Child age 12-15 months or 36-39 months of age
• WHZ <-2 and ≥-3 z-score, and/or MUAC <12.5 and ≥11.5 cm and free from any acute illness
• Mother agrees to feed their children a study diet at home.
• Mother willing to bring the child to the clinic for assessment (morbidity, nutrition history, adherence to treatment, anthropometry and advice to mother on parenting) and clinical examination.
• Mother will agree to provide her biological samples
• Mother willing to have a child undergo biological sample collection and neuropsychological assessment at baseline (1-year-old) and at ages 2 years and 3 years at the clinic.
• Family has no plan to move from the study area in the next three years.

Inclusion criteria for Control group with normal health (normal Z score):

• Mother willing to sign consent form
• Child age 12-15 months
• WHZ score > -1 and free from any acute illness
• Mother willing to bring the child to the clinic for assessment (morbidity, nutrition history, adherence to treatment, anthropometry and advice to mother on parenting) and clinical examination.
• Mother will agree to provide her biological samples (see below).
• Mother willing to have a child undergo biological sample collection and neuropsychological assessment at baseline at 1 year old and again at 2 years and 3 years at the clinic.
• Family has no plan to move from the study area in the next two years.

Exclusion Criteria:

Exclusion criteria for malnourished (MAM) children: Meeting any of the following criteria will exclude a subject from study participation

• Mother who is not willing to sign a consent form.
• Congenital anomaly.
• Mother who is not willing to feed the rehabilitation feed or the small quantity supplement to her child.
• Family will not stay 3 years in the study area.

Exclusion criteria for Control group with normal health (normal Z score): Meeting any of the following criteria will exclude a subject from study participation -

• Mother who is not willing to sign a consent form.
• Child age >15 months or < 12m.
• Mother who is not willing to feed the rehabilitation feed or the small quantity supplement to her child.
• Family will not stay 3 years in the study area.
• Any congenital anomaly.

Participants will sign a form, to give us permission to release participant data information to authorized researchers and the safety committees, icddr,b Ethical Review Committee, regulatory authorities (both in Bangladesh and the United States), the study sponsor, Synapse (a research data sharing and collaboration platform) designees, and other research organizations.

At the end of the study, all of the specimens will be stored at icddr,b for 5 years.

We will keep all information collected from you and your child confidential and locked in a secure place under the responsibility of the study investigators. Data will be saved in secure servers at icddr,b and Boston Children's Hospital. Biological samples will be stored securely without identifying information at icddr,b. Neuro imaging testing will be done in private rooms, and subjects will be coded by a de-identified number. In addition, staff and researchers have completed the Course in The Protection of Human Research Subjects.