Serial neuroimaging of brain growth and development in very preterm infants receiving tailored neuropromotive support in the NICU. Protocol for a prospective cohort study

IntroductionChildren born very preterm (VP) remain at risk for long-term neurodevelopmental impairment. Patterns of brain growth and injury, and how early neuropromotive therapies might mitigate developmental risk in VP infants remain insufficiently understood.MethodsThis is a prospective cohort study of VP infants born at/before 32 weeks gestation. The study will enroll n = 75 consecutively-born VP infants in a level-III NICU. Exposed infants will be categorized into two groups (group 1: low-risk, n = 25 or group 2: high-risk, n = 25) based on the degree of neurological injury on early brain magnetic resonance imaging (MRI) at enrollment. Infants in the low-risk group (i.e., without significant injury defined as intraventricular hemorrhage with dilation, moderate or severe white matter injury, or cerebellar hemorrhage) will receive neurodevelopmental support utilizing the Supporting and Enhancing NICU Sensory Experiences (SENSE) program, while infants in the high-risk group (with neurological injury) will receive more intensive neurorehabilitative support (SENSE-plus). Age-specific, tailored sensory experiences will be facilitated contingently, preferentially by the infant's family with coaching from NICU staff. VP infants in exposure groups will undergo a brain MRI approximately every 2 weeks from enrollment until term-equivalent to monitor brain growth and evolution of injury. Exposed infants will be compared with a reference group (group 3: n = 25), i.e. VP infants whose families decline initial enrollment in SENSE, and subsequently undergo a term-equivalent brain MRI for other purposes. The primary aim of this study is characterization of term-equivalent brain growth and development among VP infants receiving NICU-based neuropromotive interventions compared to VP infants receiving the standard of care. Secondary aims include defining the timing and factors associated with total and regional brain growth on serial brain MRI among VP infants, (Aim 2), and using early imaging to tailor developmental intervention in the NICU while exploring associations with outcomes in VP infants at discharge and at two years corrected age (Aim 3).DiscussionThis study will address gaps in understanding patterns of brain growth and injury drawing on serial MRI of hospitalized VP infants. These data will also explore the impact of intensive, tailored neuropromotive support delivered prior to term-equivalent on child and family outcomes

Maternal pomegranate juice intake and brain structure and function in infants with intrauterine growth restriction: A randomized controlled pilot study.

Polyphenol-rich pomegranate juice has been shown to have benefit as a neuroprotectant in animal models of neonatal hypoxic-ischemia. No published studies have investigated maternal polyphenol administration as a potential neuroprotectant in at-risk newborns, such as those with intrauterine growth restriction (IUGR). This was a randomized, placebo-controlled, double-blind pilot study to investigate the impact of maternal pomegranate juice intake in pregnancies with IUGR, on newborn brain structure and function at term-equivalent age (TEA). Mothers with IUGR at 24-34 weeks\u27 gestation were recruited from Barnes-Jewish Hospital obstetrical clinic. Consented mothers were randomized to treatment (8 oz. pomegranate juice) or placebo (8 oz. polyphenol-free juice) and continued to take juice daily from enrollment until delivery (mean 20.1 and 27.1 days, respectively). Infants underwent brain MRI at TEA (36-41 weeks\u27 gestation). Brain measures were compared between groups including: brain injury score, brain metrics, brain volumes, diffusion tensor imaging and resting state functional connectivity. Statistical analyses were undertaken as modified intention-to-treat (including randomized participants who received their allocated intervention and whose infants received brain MRI) and per-protocol (including participants who strictly adhered to the protocol, based on metabolite status). Seventy-seven mothers were randomized to treatment (n = 40) or placebo (n = 37). Of these, 28 and 27 infants, respectively, underwent term-equivalent MRI. There were no group differences in brain injury, metrics or volumes. However, treatment subjects displayed reduced diffusivity within the anterior and posterior limbs of the internal capsule compared with placebo. Resting state functional connectivity demonstrated increased correlation and covariance within several networks in treatment subjects, with alterations most apparent in the visual network in per-protocol analyses. Direct effects on health were not found. In conclusion, maternal pomegranate juice intake in pregnancies with known IUGR was associated with altered white matter organization and functional connectivity in the infant brain, suggesting differences in brain structure and function following in utero pomegranate juice exposure, warranting continued investigation. Clinical trial registration. NCT00788866, registered November 11, 2008, initial participant enrollment August 21, 2012

Maternal Milk Provision in the Neonatal Intensive Care Unit and Mother–Infant Emotional Connection for Preterm Infants

Maternal milk (MM) intake during neonatal intensive care unit (NICU) hospitalization is associated with improved neurodevelopment in preterm infants. Underlying mechanisms may include stronger mother–infant emotional connection. This paper examines associations between MM provision in the NICU with maternal connection to her infant using three factors validated in our sample: maternal sensitivity, emotional concern, and positive interaction/engagement. We studied 70 mothers of infants born <1500 g and/or <32 weeks’ gestation. Associations between MM provision and mother–infant connection were modeled using median regression adjusted for clustering. Mothers who provided exclusive MM (i.e., 100% MM, no other milk) reported higher levels of maternal sensitivity by a median score of 2 units (β = 2.00, 95% CI: 0.76, 3.24, p = 0.002) than the mixed group (i.e., MM < 100% days, other milk ≥1 days), as well as greater emotional concern (β = 3.00, 95% CI: −0.002, 6.00, p = 0.05). Among mothers of very preterm infants, greater milk provision was associated with greater maternal sensitivity, but also with greater emotional concern about meeting the infant’s needs. These findings highlight the importance of supporting MM provision and early infant care as an integrated part of lactation support. The findings may also provide insight into links between MM provision in the NICU and infant neurodevelopment

Impact of adrenal hormones, reproductive aging, and major depression on memory circuitry decline in early midlife.

Dehydroepiandrosterone-sulfate (DHEAS) is an adrenal androgen that is, in part, aromatized to estradiol. It continues to be produced after menopause and provides estrogenicity after depletion of ovarian hormones. Estradiol depletion contributes to memory circuitry changes over menopause, including changes in hippocampal (HIPP) and dorsolateral- and ventrolateral-prefrontal cortex (DLPFC; VLPFC) function. Further, major depressive disorder (MDD) patients have, in general, lower levels of estradiol and lower DHEAS than healthy controls, thus potentially a higher risk of adverse menopausal outcomes. We investigated whether higher DHEAS levels after menopause is associated with better memory circuitry function, especially in women with MDD. 212 adults (ages 45-55, 50% women) underwent clinical and fMRI testing. Participants performed a working memory (WM) N-back task and an episodic memory verbal encoding (VE) task during fMRI scanning. DHEAS levels were significantly associated with memory circuitry function, specifically in MDD postmenopausal women. On the WM task, lower DHEAS levels were associated with increased HIPP activity. On the VE task, lower DHEAS levels were associated with decreased activity in the HIPP and VLPFC. In contrast, there was no association between DHEAS levels and memory circuitry function in MDD pre/perimenopausal women, men, and non-MDD participants regardless of sex and reproductive status. In fact, MDD postmenopausal women with higher levels of DHEAS were similar to MDD pre/perimenopausal women and men. Thus, memory circuitry deficits associated with MDD and a lower ability of the adrenal gland to produce DHEAS after menopause may contribute to a lower ability to maintain intact memory function with age

Impact of adrenal hormones, reproductive aging, and major depression on memory circuitry decline in early midlife.

Dehydroepiandrosterone-sulfate (DHEAS) is an adrenal androgen that is, in part, aromatized to estradiol. It continues to be produced after menopause and provides estrogenicity after depletion of ovarian hormones. Estradiol depletion contributes to memory circuitry changes over menopause, including changes in hippocampal (HIPP) and dorsolateral- and ventrolateral-prefrontal cortex (DLPFC; VLPFC) function. Further, major depressive disorder (MDD) patients have, in general, lower levels of estradiol and lower DHEAS than healthy controls, thus potentially a higher risk of adverse menopausal outcomes. We investigated whether higher DHEAS levels after menopause is associated with better memory circuitry function, especially in women with MDD. 212 adults (ages 45-55, 50% women) underwent clinical and fMRI testing. Participants performed a working memory (WM) N-back task and an episodic memory verbal encoding (VE) task during fMRI scanning. DHEAS levels were significantly associated with memory circuitry function, specifically in MDD postmenopausal women. On the WM task, lower DHEAS levels were associated with increased HIPP activity. On the VE task, lower DHEAS levels were associated with decreased activity in the HIPP and VLPFC. In contrast, there was no association between DHEAS levels and memory circuitry function in MDD pre/perimenopausal women, men, and non-MDD participants regardless of sex and reproductive status. In fact, MDD postmenopausal women with higher levels of DHEAS were similar to MDD pre/perimenopausal women and men. Thus, memory circuitry deficits associated with MDD and a lower ability of the adrenal gland to produce DHEAS after menopause may contribute to a lower ability to maintain intact memory function with age

Associations of Macronutrient Intake Determined by Point-of-Care Human Milk Analysis with Brain Development among very Preterm Infants

Point-of-care human milk analysis is now feasible in the neonatal intensive care unit (NICU) and allows accurate measurement of macronutrient delivery. Higher macronutrient intakes over this period may promote brain growth and development. In a prospective, observational study of 55 infants born at <32 weeks’ gestation, we used a mid-infrared spectroscopy-based human milk analyzer to measure the macronutrient content in repeated samples of human milk over the NICU hospitalization. We calculated daily nutrient intakes from unfortified milk and assigned infants to quintiles based on median intakes over the hospitalization. Infants underwent brain magnetic resonance imaging at term equivalent age to quantify total and regional brain volumes and fractional anisotropy of white matter tracts. Infants in the highest quintile of energy intake from milk, as compared with the lower four quintiles, had larger total brain volume (31 cc, 95% confidence interval [CI]: 5, 56), cortical gray matter (15 cc, 95%CI: 1, 30), and white matter volume (23 cc, 95%CI: 12, 33). Higher protein intake was associated with larger total brain (36 cc, 95%CI: 7, 65), cortical gray matter (22 cc, 95%CI: 6, 38) and deep gray matter (1 cc, 95%CI: 0.1, 3) volumes. These findings suggest innovative strategies to close nutrient delivery gaps in the NICU may promote brain growth for preterm infants

Maternal Bacterial Infection During Pregnancy and Offspring Risk of Psychotic Disorders: Variation by Severity of Infection and Offspring Sex

ObjectivePrevious studies suggest that prenatal immune challenges may elevate the risk of schizophrenia and related psychoses in offspring, yet there has been limited research focused on maternal bacterial infection. The authors hypothesized that maternal bacterial infection during pregnancy increases offspring risk of psychotic disorders in adulthood, and that the magnitude of this association varies as a function of severity of infectious exposure and offspring sex.MethodsThe authors analyzed prospectively collected data from 15,421 pregnancies among women enrolled between 1959 and 1966 at two study sites through the Collaborative Perinatal Project. The sample included 116 offspring with confirmed psychotic disorders. The authors estimated associations between maternal bacterial infection during pregnancy and psychosis risk over the subsequent 40 years, stratified by offspring sex and presence of reported parental mental illness, with adjustment for covariates.ResultsMaternal bacterial infection during pregnancy was strongly associated with psychosis in offspring (adjusted odds ratio=1.8, 95% CI=1.2-2.7) and varied by severity of infection and offspring sex. The effect of multisystemic bacterial infection (adjusted odds ratio=2.9, 95% CI=1.3-5.9) was nearly twice that of less severe localized bacterial infection (adjusted odds ratio=1.6, 95% CI=1.1-2.3). Males were significantly more likely than females to develop psychosis after maternal exposure to any bacterial infection during pregnancy.ConclusionsThe study findings suggest that maternal bacterial infection during pregnancy is associated with an elevated risk for psychotic disorders in offspring and that the association varies by infection severity and offspring sex. These findings call for additional investigation and, if the findings are replicated, public health and clinical efforts that focus on preventing and managing bacterial infection in pregnant women

Gestational cytokine concentrations and neurocognitive development at 7 years

Gestational inflammation may contribute to brain abnormalities associated with childhood neuropsychiatric disorders. Limited knowledge exists regarding the associations of maternal cytokine levels during pregnancy with offspring neurocognitive development. We assayed the concentrations of five cytokines (interleukin (IL)-6, IL-1β, IL-8, tumor necrosis factor alpha (TNF-α), and IL-10) up to four times in the 2nd and 3rd trimesters of pregnancy using stored prenatal sera from 1366 participants in the New England Family Study (enrollment 1959–1966). Intelligence (IQ), academic achievement, and neuropsychological functioning of singleton offspring were assessed at age 7 years using standardized tests. We used linear mixed models with random effects to estimate the cumulative exposure to each cytokine during 2nd and 3rd trimesters, and then related cumulative cytokine exposure to a wide range of offspring neurocognitive outcomes. We found that children of women with higher levels of the pro-inflammatory cytokine, TNF-α, in the 2nd and 3rd trimesters had lower IQ (B = −2.51, 99% CI: −4.84,−0.18), higher problem scores in visual-motor maturity (B = 0.12, 99% CI: 0.001,0.24), and lower Draw-a-Person test scores (B = −1.28, 99% CI: −2.49,−0.07). Higher gestational levels of IL-8, another pro-inflammatory molecule, were associated with better Draw-a-Person test scores and tactile finger recognition scores. Other cytokines were not associated with our outcome of interest. The opposing directions of associations observed between TNF-α and IL-8 with childhood outcomes suggest pleiotropic effects of gestational inflammation across the domains of neurocognitive functioning. Although the path to psychopathological disturbances in children is no doubt multifactorial, our findings point to a potential role for immune processes in the neurocognitive development of children

Sex differences, hormones, and fMRI stress response circuitry deficits in psychoses

Response to stress is dysregulated in psychosis (PSY). fMRI studies showed hyperactivity in hypothalamus (HYPO), hippocampus (HIPP), amygdala (AMYG), anterior cingulate (ACC), orbital and medial prefrontal (OFC; mPFC) cortices, with some studies reporting sex differences. We predicted abnormal steroid hormone levels in PSY would be associated with sex differences in hyperactivity in HYPO, AMYG, and HIPP, and hypoactivity in PFC and ACC, with more severe deficits in men. We studied 32 PSY cases (50.0% women) and 39 controls (43.6% women) using a novel visual stress challenge while collecting blood. PSY males showed BOLD hyperactivity across all hypothesized regions, including HYPO and ACC by FWE-correction. Females showed hyperactivity in HIPP and AMYG and hypoactivity in OFC and mPFC, the latter FWE-corrected. Interaction of group by sex was significant in mPFC (F = 7.00, p = 0.01), with PSY females exhibiting the lowest activity. Male hyperactivity in HYPO and ACC was significantly associated with hypercortisolemia post-stress challenge, and mPFC with low androgens. Steroid hormones and neural activity were dissociated in PSY women. Findings suggest disruptions in neural circuitry-hormone associations in response to stress are sex-dependent in psychosis, particularly in prefrontal cortex