EEG functional connectivity as a Riemannian mediator: An application to malnutrition and cognition.

Mediation analysis assesses whether an exposure directly produces changes in cognitive behavior or is influenced by intermediate "mediators". Electroencephalographic (EEG) spectral measurements have been previously used as effective mediators representing diverse aspects of brain function. However, it has been necessary to collapse EEG measures onto a single scalar using standard mediation methods. In this article, we overcome this limitation and examine EEG frequency-resolved functional connectivity measures as a mediator using the full EEG cross-spectral tensor (CST). Since CST samples do not exist in Euclidean space but in the Riemannian manifold of positive-definite tensors, we transform the problem, allowing for the use of classic multivariate statistics. Toward this end, we map the data from the original manifold space to the Euclidean tangent space, eliminating redundant information to conform to a "compressed CST." The resulting object is a matrix with rows corresponding to frequencies and columns to cross spectra between channels. We have developed a novel matrix mediation approach that leverages a nuclear norm regularization to determine the matrix-valued regression parameters. Furthermore, we introduced a global test for the overall CST mediation and a test to determine specific channels and frequencies driving the mediation. We validated the method through simulations and applied it to our well-studied 50+-year Barbados Nutrition Study dataset by comparing EEGs collected in school-age children (5-11 years) who were malnourished in the first year of life with those of healthy classmate controls. We hypothesized that the CST mediates the effect of malnutrition on cognitive performance. We can now explicitly pinpoint the frequencies (delta, theta, alpha, and beta bands) and regions (frontal, central, and occipital) in which functional connectivity was altered in previously malnourished children, an improvement to prior studies. Understanding the specific networks impacted by a history of postnatal malnutrition could pave the way for developing more targeted and personalized therapeutic interventions. Our methods offer a versatile framework applicable to mediation studies encompassing matrix and Hermitian 3D tensor mediators alongside scalar exposures and outcomes, facilitating comprehensive analyses across diverse research domains.

Early protein energy malnutrition impacts life-long developmental trajectories of the sources of EEG rhythmic activity.

Protein Energy Malnutrition (PEM) has lifelong consequences on brain development and cognitive function. We studied the lifelong developmental trajectories of resting-state EEG source activity in 66 individuals with histories of Protein Energy Malnutrition (PEM) limited to the first year of life and in 83 matched classmate controls (CON) who are all participants of the 49 years longitudinal Barbados Nutrition Study (BNS). qEEGt source z-spectra measured deviation from normative values of EEG rhythmic activity sources at 5-11 years of age and 40 years later at 45-51 years of age. The PEM group showed qEEGt abnormalities in childhood, including a developmental delay in alpha rhythm maturation and an insufficient decrease in beta activity. These profiles may be correlated with accelerated cognitive decline.

Harmonized-Multinational qEEG norms (HarMNqEEG).

This paper extends frequency domain quantitative electroencephalography (qEEG) methods pursuing higher sensitivity to detect Brain Developmental Disorders. Prior qEEG work lacked integration of cross-spectral information omitting important functional connectivity descriptors. Lack of geographical diversity precluded accounting for site-specific variance, increasing qEEG nuisance variance. We ameliorate these weaknesses. (i) Create lifespan Riemannian multinational qEEG norms for cross-spectral tensors. These norms result from the HarMNqEEG project fostered by the Global Brain Consortium. We calculate the norms with data from 9 countries, 12 devices, and 14 studies, including 1564 subjects. Instead of raw data, only anonymized metadata and EEG cross-spectral tensors were shared. After visual and automatic quality control, developmental equations for the mean and standard deviation of qEEG traditional and Riemannian DPs were calculated using additive mixed-effects models. We demonstrate qEEG "batch effects" and provide methods to calculate harmonized z-scores. (ii) We also show that harmonized Riemannian norms produce z-scores with increased diagnostic accuracy predicting brain dysfunction produced by malnutrition in the first year of life and detecting COVID induced brain dysfunction. (iii) We offer open code and data to calculate different individual z-scores from the HarMNqEEG dataset. These results contribute to developing bias-free, low-cost neuroimaging technologies applicable in various health settings.

Neurodevelopmental effects of childhood malnutrition: A neuroimaging perspective.

Approximately one in five children worldwide suffers from childhood malnutrition and its complications, including increased susceptibility to inflammation and infectious diseases. Due to improved early interventions, most of these children now survive early malnutrition, even in low-resource settings (LRS). However, many continue to exhibit neurodevelopmental deficits, including low IQ, poor school performance, and behavioral problems over their lifetimes. Most studies have relied on neuropsychological tests, school performance, and mental health and behavioral measures. Few studies, in contrast, have assessed brain structure and function, and to date, these have mainly relied on low-cost techniques, including electroencephalography (EEG) and evoked potentials (ERP). The use of more advanced methods of neuroimaging, including magnetic resonance imaging (MRI) and functional near-infrared spectroscopy (fNIRS), has been limited by cost factors and lack of availability of these technologies in developing countries, where malnutrition is nearly ubiquitous. This report summarizes the current state of knowledge and evidence gaps regarding childhood malnutrition and the study of its impact on neurodevelopment. It may help to inform the development of new strategies to improve the identification, classification, and treatment of neurodevelopmental disabilities in underserved populations at the highest risk for childhood malnutrition.

Parental history of moderate to severe infantile malnutrition is associated with cognitive deficits in their adult offspring.

OBJECTIVES: We compared the IQ and academic achievement of the young adult offspring of parents malnourished in infancy and those of a healthy control group in order to test the hypothesis that the offspring of previously malnourished individuals would show IQ and academic deficits that could be related to reduced parental socioeconomic status. METHODS: We conducted a group comparison study based on a community sample in Barbados (Barbados Nutrition Study). Participants were adult children ≥16 years of age whose parents had been malnourished during the first year of life (n = 64; Mean age 19.3 years; 42% male) or whose parents were healthy community controls (n = 50; Mean age 19.7 years; 48% male). The primary outcome was estimated IQ (Wechsler Abbreviated Scale of Intelligence); a secondary outcome was academic achievement (Wide Range Achievement Test - Third Edition). Data were analyzed using PROC MIXED with and without adjusting for parental socioeconomic status (Hollingshead Index of Social Position). RESULTS: IQ was reduced in the offspring of previously malnourished parents relative to the offspring of controls (9.8 point deficit; P < 0.01), but this difference was not explained by parental socioeconomic status or parental IQ. The magnitude of the group difference was smaller for basic academic skills and did not meet criteria for statistical significance. DISCUSSION: The deleterious impact of infant malnutrition on cognitive function may be transmitted to the next generation; however, this intergenerational effect does not appear to be explained by the reduced socioeconomic status or IQ of the parent generation.

Prenatal malnutrition leads to deficits in attentional set shifting and decreases metabolic activity in prefrontal subregions that control executive function.

Globally, over 25% of all children under the age of 5 years experience malnutrition leading to cognitive and emotional impairments that can persist into adulthood and beyond. We use a rodent model to determine the impact of prenatal protein malnutrition on executive functions in an attentional set-shifting task and metabolic activity in prefrontal cortex (PFC) subregions critical to these behaviors. Long-Evans dams were provided with a low (6% casein) or adequate (25% casein) protein diet 5 weeks before mating and during pregnancy. At birth, the litters were culled to 8 pups and fostered to control dams on the 25% casein diet. At postnatal day 90, prenatally malnourished rats were less able to shift attentional set and reverse reward contingencies than controls, demonstrating cognitive rigidity. Naive same-sexed littermates were assessed for regional brain activity using the metabolic marker (14)C-2-deoxyglucose (2DG). The prenatally malnourished rats had lower metabolic activity than controls in prelimbic, infralimbic, anterior cingulate, and orbitofrontal cortices, but had comparable activity in the nearby piriform cortex and superior colliculus. This study demonstrates that prenatal protein malnutrition in a well-described animal model produces cognitive deficits in tests of attentional set shifting and reversal learning, similar to findings of cognitive inflexibility reported in humans exposed to early childhood malnutrition.

Impaired IQ and academic skills in adults who experienced moderate to severe infantile malnutrition: a 40-year study.

OBJECTIVES: To evaluate IQ and academic skills in adults who experienced an episode of moderate-to-severe infantile malnutrition and a healthy control group, all followed since childhood in the Barbados Nutrition Study. METHODS: IQ and academic skills were assessed in 77 previously malnourished adults (mean age = 38.4 years; 53% male) and 59 controls (mean age = 38.1 years; 54% male). Group comparisons were carried out by multiple regression and logistic regression, adjusted for childhood socioeconomic factors. RESULTS: The previously malnourished group showed substantial deficits on all outcomes relative to healthy controls (P < 0.0001). IQ scores in the intellectual disability range (< 70) were nine times more prevalent in the previously malnourished group (odds ratio = 9.18; 95% confidence interval = 3.50-24.13). Group differences in IQ of approximately one standard deviation were stable from adolescence through mid-life. DISCUSSION: Moderate-to-severe malnutrition during infancy is associated with a significantly elevated incidence of impaired IQ in adulthood, even when physical growth is completely rehabilitated. An episode of malnutrition during the first year of life carries risk for significant lifelong functional morbidity.

Malnutrition in the first year of life and personality at age 40.

BACKGROUND: Early childhood malnutrition is associated with cognitive and behavioral impairment during childhood and adolescence, but studies in adulthood are limited. METHODS: Using the NEO-PI-R personality inventory, we compared personality profiles at 37-43 years of age (M 40.3 years, SD 1.9) of Barbadian adults who had experienced moderate-to-severe protein-energy malnutrition (PEM) in the first year of life (n = 77) with healthy controls, who were former classmates of the index cases and were matched for age, gender, and handedness in childhood (n = 57). The previously malnourished participants had been rehabilitated, with good health and nutrition documented up to 12 years of age, and study participants were followed longitudinally from childhood to 40 years. Group comparisons were adjusted for childhood and adolescent standard of living, with and without correcting for IQ. RESULTS: At the broad domain or factor level, previously malnourished participants had higher scores on Neuroticism and lower scores on Extraversion, Openness, Agreeableness, and Conscientiousness than did the healthy controls. At the subdomain or facet level, previously malnourished participants reported more anxiety, vulnerability, shyness and lowered sociability, less intellectual curiosity, greater suspiciousness of others, a more egocentric than altruistic orientation, and a lowered sense of efficacy or competence. CONCLUSIONS: Malnutrition limited to the first year of life with good health and nutrition documented up to 12 years of age is associated with a significant overrepresentation of adult personality trait scores outside of the average range. This outcome has important implications for a variety of important life and mental health outcomes.

Early childhood malnutrition impairs adult resting brain function using near-infrared spectroscopy.

Introduction: Early childhood malnutrition affects 200+ million children under 5 years of age worldwide and is associated with persistent cognitive, behavioral and psychiatric impairments in adulthood. However, very few studies have investigated the long-term effects of childhood protein-energy malnutrition (PEM) on brain function using a functional hemodynamic brain imaging technique. Objective and methods: This study aims to investigate functional brain network alterations using near infrared spectroscopy (NIRS) in adults, aged 45-51 years, from the Barbados Nutrition Study (BNS) who suffered from a single episode of malnutrition restricted to their first year of life (n = 26) and controls (n = 29). A total of 55 individuals from the BNS cohort underwent NIRS recording at rest. Results and discussion: Using functional connectivity and permutation analysis, we found patterns of increased Pearson's correlation with a specific vulnerability of the frontal cortex in the PEM group (ps < 0.05). Using a graph theoretical approach, mixed ANCOVAs showed increased segregation (ps = 0.0303 and 0.0441) and decreased integration (p = 0.0498) in previously malnourished participants compared to healthy controls. These results can be interpreted as a compensatory mechanism to preserve cognitive functions, that could also be related to premature or pathological brain aging. To our knowledge, this study is the first NIRS neuroimaging study revealing brain function alterations in middle adulthood following early childhood malnutrition limited to the first year of life.

Spectral quantitative and semi-quantitative EEG provide complementary information on the life-long effects of early childhood malnutrition on cognitive decline.

Objective: This study compares the complementary information from semi-quantitative EEG (sqEEG) and spectral quantitative EEG (spectral-qEEG) to detect the life-long effects of early childhood malnutrition on the brain. Methods: Resting-state EEGs (N = 202) from the Barbados Nutrition Study (BNS) were used to examine the effects of protein-energy malnutrition (PEM) on childhood and middle adulthood outcomes. sqEEG analysis was performed on Grand Total EEG (GTE) protocol, and a single latent variable, the semi-quantitative Neurophysiological State (sqNPS) was extracted. A univariate linear mixed-effects (LME) model tested the dependence of sqNPS and nutritional group. sqEEG was compared with scores on the Montreal Cognitive Assessment (MoCA). Stable sparse classifiers (SSC) also measured the predictive power of sqEEG, spectral-qEEG, and a combination of both. Multivariate LME was applied to assess each EEG modality separately and combined under longitudinal settings. Results: The univariate LME showed highly significant differences between previously malnourished and control groups (p < 0.001); age (p = 0.01) was also significant, with no interaction between group and age detected. Childhood sqNPS (p = 0.02) and adulthood sqNPS (p = 0.003) predicted MoCA scores in adulthood. The SSC demonstrated that spectral-qEEG combined with sqEEG had the highest predictive power (mean AUC 0.92 ± 0.005). Finally, multivariate LME showed that the combined spectral-qEEG+sqEEG models had the highest log-likelihood (-479.7). Conclusion: This research has extended our prior work with spectral-qEEG and the long-term impact of early childhood malnutrition on the brain. Our findings showed that sqNPS was significantly linked to accelerated cognitive aging at 45-51 years of age. While sqNPS and spectral-qEEG produced comparable results, our study indicated that combining sqNPS and spectral-qEEG yielded better performance than either method alone, suggesting that a multimodal approach could be advantageous for future investigations. Significance: Based on our findings, a semi-quantitative approach utilizing GTE could be a valuable diagnostic tool for detecting the lasting impacts of childhood malnutrition. Notably, sqEEG has not been previously explored or reported as a biomarker for assessing the longitudinal effects of malnutrition. Furthermore, our observations suggest that sqEEG offers unique features and information not captured by spectral quantitative EEG analysis and could lead to its improvement.

Infant malnutrition is associated with persisting attention deficits in middle adulthood.

Infantile malnutrition is known to be associated with cognitive and behavioral impairment during childhood and adolescence. Data pertaining to longer-term effects on behavioral outcomes in adulthood are limited. In this study, we report associations between infantile malnutrition and attention problems in adults at midlife. Attention problems were assessed by the Conners Adult ADHD Rating Scales (CAARS) and the Conners Continuous Performance Test (CPT) in 145 Barbadian adults (aged 37-43 y) who had been followed longitudinally since childhood. Previously malnourished participants (n = 80) had experienced moderate to severe protein-energy malnutrition in the first year of life and were successfully rehabilitated thereafter. They were compared with healthy adults (n = 65) who were former classmates of the index cases and who had been matched for age, sex, and handedness in childhood. Multiple regression analyses showed persisting effects of childhood malnutrition on both the CAARS and the CPT, independent of effects of household standard of living assessed in childhood. The malnutrition effect on the CAARS ratings was independent of IQ, whereas this effect was attenuated for the CPT after adjustment for IQ. Teacher-reported attention problems in childhood predicted attention problems in adulthood, indicating continuity over the life span. Infantile malnutrition may have long-term effects on attentional processes nearly 40 y after the episode, even with excellent long-term nutritional rehabilitation and independent of socioeconomic conditions in childhood and adolescence. This finding has major public health implications for populations exposed to early childhood malnutrition.

Infant malnutrition predicts conduct problems in adolescents.

OBJECTIVES: The purpose of this study was to compare the prevalence of conduct problems in a well-documented sample of Barbadian adolescents malnourished as infants and a demographic comparison group and to determine the extent to which cognitive impairment and environmental factors account for this association. METHODS: Behavioral symptoms were assessed using a 76-item self-report scale in 56 Barbadian youth (11-17 years of age) with histories of protein-energy malnutrition (PEM) limited to the first year of life and 60 healthy classmates. Group comparisons were carried out by longitudinal and cross-sectional multiple regression analyses at 3 time points in childhood and adolescence. RESULTS: Self-reported conduct problems were more prevalent among previously malnourished youth (P < 0.01). Childhood IQ and home environmental circumstances partially mediated the association with malnutrition. Teacher-reported classroom behaviors at earlier ages were significantly correlated with youth conduct problems, confirming the continuity of conduct problems through childhood and adolescence. DISCUSSION: Self-reported conduct problems are elevated in children and adolescents with histories of early childhood malnutrition. Later vulnerability to increased conduct problems appears to be mediated by the more proximal neurobehavioral effects of the malnutrition on cognitive function and by adverse conditions in the early home environment.

Impact of Early Childhood Malnutrition on Adult Brain Function: An Evoked-Related Potentials Study.

More than 200 million children under the age of 5 years are affected by malnutrition worldwide according to the World Health Organization. The Barbados Nutrition Study (BNS) is a 55-year longitudinal study on a Barbadian cohort with histories of moderate to severe protein-energy malnutrition (PEM) limited to the first year of life and a healthy comparison group. Using quantitative electroencephalography (EEG), differences in brain function during childhood (lower alpha1 activity and higher theta, alpha2 and beta activity) have previously been highlighted between participants who suffered from early PEM and controls. In order to determine whether similar differences persisted into adulthood, our current study used recordings obtained during a Go-No-Go task in a subsample of the original BNS cohort [population size (N) = 53] at ages 45-51 years. We found that previously malnourished adults [sample size (n) = 24] had a higher rate of omission errors on the task relative to controls (n = 29). Evoked-Related Potentials (ERP) were significantly different in participants with histories of early PEM, who presented with lower N2 amplitudes. These findings are typically associated with impaired conflict monitoring and/or attention deficits and may therefore be linked to the attentional and executive function deficits that have been previously reported in this cohort in childhood and again in middle adulthood.

Early malnutrition predicts parent reports of externalizing behaviors at ages 9-17.

OBJECTIVE: To determine whether externalizing behaviors are more prevalent in youth who have experienced an episode of malnutrition in the first year of life than in healthy comparison youth. METHOD: Parents of previously malnourished youth and a matched healthy comparison group completed a behavior rating scale when the youth were 9-15 years of age and again, 2 years later, when they were 11-17 years of age. Longitudinal multiple regression analysis was applied to evaluate group differences adjusted for baseline age, sex, household standard of living, and maternal depressive symptoms. RESULTS: Early childhood malnutrition was associated with problems in executive functioning at both occasions. Malnutrition also predicted discernibly higher parent-reported levels of aggression toward peers at 9-15 years than at 11-17 years. These findings were independent of baseline age, sex, household standard of living, and maternal depressive symptoms. Problem behaviors in general decreased during follow-up. CONCLUSION: Parents report persisting problems with executive functioning through adolescence in youth who suffered an episode of moderate-to-severe protein-energy malnutrition in the first year of life, while reports of aggression, although more common when this cohort were younger, did not persist at follow-up.

Prenatal protein malnutrition alters the proportion but not numbers of parvalbumin-immunoreactive interneurons in the hippocampus of the adult Sprague-Dawley rat.

Prenatal protein malnutrition alters the structure and function of the adult rat hippocampal formation. The current study examines the effect of prenatal protein malnutrition on numbers of parvalbumin-immunoreactive (PV-IR) GABAergic interneurons, which are important for perisomatic inhibition of hippocampal pyramidal neurons. Brain sections from prenatally protein malnourished and normally nourished rats were stained for parvalbumin and PV-IR neurons were quantified using stereology in the dentate gyrus, CA3/2 and CA1 subfields, and the subiculum for both cerebral hemispheres. Results demonstrated that prenatal malnutrition did not affect the number of PV-IR interneurons in the hippocampus. Since prenatal protein malnutrition reduces total neuron numbers in the CA1 subfield (1), this results in an altered ratio of PV-IR interneurons to total neuronal numbers (from 1:22.9 in controls to 1:20.5 in malnourished rats). Additionally, there was no hemispheric asymmetry of either PV-IR neuron numbers or ratio of PV-IR:total neuron numbers.

In vivo microdialysis shows differential effects of prenatal protein malnutrition and stress on norepinephrine, dopamine, and serotonin levels in rat orbital frontal cortex.

Prenatal protein malnutrition (PPM) alters the developing brain including changes in monoaminergic systems and attention. In the present study, we used in vivo microdialysis to examine the relationship between PPM, acute stress, and extracellular serotonin (5HT), dopamine (DA) and norepinephrine (NE) in both hemispheres of lateral orbital frontal cortices (lOFC) in the adult rat. We hypothesized that prenatal protein malnutrition would alter extracellular concentrations of cortical monoamines. The effects of an acute restraint stress were also assessed because PPM alters the brain's response to stress. We used adult male, Long-Evans rats [10 prenatally malnourished (6% casein) and 10 prenatally well-nourished (25% casein)]. Samples were collected from the left and right hemispheres of the lOFC every 20 min for 6 hr total and quantified using high-performance liquid chromatography (HPLC). After 2 hr of sampling, animals were exposed to a 40-min restraint stress. Extracellular levels of NE were significantly higher in PPM animals than in well-nourished controls across both hemispheres at all time-points. In contrast, baseline levels of 5HT and DA levels did not differ between nutritional groups. 5HT levels, but not NE or DA levels, were elevated compared to baseline levels in both nutritional groups and in both hemispheres during the first 20 min of stress exposure. These data highlight the impact of PPM on neuromodulatory systems and the profile of changes in response to acute stress. Additional studies are needed to determine how these basal and stress-related responses impact cognitive performance and whether these differences persist during cognitive testing. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Intergenerational effects of childhood maltreatment and malnutrition on personality maladaptivity in a Barbadian longitudinal cohort.

Childhood adversities are linked with mental health problems throughout the life course, including personality pathology. Less is known about consequences in the next generation, particularly in non-Western populations. In the Barbados Nutrition Study, we assessed associations of two parental (G1) childhood adversities- (1) maltreatment history using the Childhood Trauma Questionnaire-Short Form (CTQ-SF), and (2) clinically ascertained infant malnutrition limited to the first year of life-on PD symptoms in their G2 offspring, using NEO FFM PD prototypes. In linear regression models clustered by family and adjusted for other G1 childhood adversities and family socioeconomic status, we found that G1 parental history of childhood maltreatment was significantly associated with increased G2 offspring Borderline, Histrionic, Narcissistic, and Dependent PD scores. When G1 childhood malnutrition was the exposure of interest, we found a significant association with Schizoid PD scores. When the sample was restricted to offspring of G1 mothers, even more extensive associations with G2 personality pathology were observed. This study supports a link between parental exposure to childhood adversities and increased personality maladaptivity in the next generation, with some specific patterns worthy of further exploration.

Prenatal Protein Malnutrition Produces Resistance to Distraction Similar to Noradrenergic Deafferentation of the Prelimbic Cortex in a Sustained Attention Task.

Exposure to malnutrition early in development increases likelihood of neuropsychiatric disorders, affective processing disorders, and attentional problems later in life. Many of these impairments are hypothesized to arise from impaired development of the prefrontal cortex. The current experiments examine the impact of prenatal malnutrition on the noradrenergic and cholinergic axons in the prefrontal cortex to determine if these changes contribute to the attentional deficits seen in prenatal protein malnourished rats (6% casein vs. 25% casein). Because prenatally malnourished animals had significant decreases in noradrenergic fibers in the prelimbic cortex with spared innervation in the anterior cingulate cortex and showed no changes in acetylcholine innervation of the prefrontal cortex, we compared deficits produced by malnutrition to those produced in adult rats by noradrenergic lesions of the prelimbic cortex. All animals were able to perform the baseline sustained attention task accurately. However, with the addition of visual distractors to the sustained attention task, animals that were prenatally malnourished and those that were noradrenergically lesioned showed cognitive rigidity, i.e., were less distractible than control animals. All groups showed similar changes in behavior when exposed to withholding reinforcement, suggesting specific attentional impairments rather than global difficulties in understanding response rules, bottom-up perceptual problems, or cognitive impairments secondary to dysfunction in sensitivity to reinforcement contingencies. These data suggest that prenatal protein malnutrition leads to deficits in noradrenergic innervation of the prelimbic cortex associated with cognitive rigidity.