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The transmembrane 6 superfamily member 2 (TM6SF2) loss-of-function variant rs58542926 is a genetic risk factor for nonalcoholic fatty liver disease and progression to fibrosis but is paradoxically associated with lower levels of hepatically derived triglyceride-rich lipoproteins. TM6SF2 is expressed predominantly in liver and small intestine, sites for triglyceride-rich lipoprotein biogenesis and export. In light of this, we hypothesized that TM6SF2 may exhibit analogous effects on both liver and intestine lipid homeostasis. To test this, we genotyped rs58542926 in 983 bariatric surgery patients from the Geisinger Medical Center for Nutrition and Weight Management, Geisinger Health System, in Pennsylvania and from 3,556 study participants enrolled in the Amish Complex Disease Research Program. Although these two cohorts have different metabolic profiles, carriers in both cohorts had improved fasting lipid profiles. Importantly, following a high-fat challenge, carriers in the Amish Complex Disease Research Program cohort exhibited significantly lower postprandial serum triglycerides, suggestive of a role for TM6SF2 in the small intestine. To gain further insight into this putative role, effects of TM6SF2 deficiency were studied in a zebrafish model and in cultured human Caco-2 enterocytes. In both systems TM6SF2 deficiency resulted in defects in small intestine metabolism in response to dietary lipids, including significantly increased lipid accumulation, decreased lipid clearance, and increased endoplasmic reticulum stress. CONCLUSIONS These data strongly support a role of TM6SF2 in the regulation of postprandial lipemia, potentially through a similar function for TM6SF2 in the lipidation and/or export of both hepatically and intestinally derived triglyceride-rich lipoproteins. (Hepatology 2017;65:1526-1542).

This study evaluated the neural basis of verbal working memory (WM) function in a group of 20 children and adolescents with fetal alcohol spectrum disorders (FASDs) and 20 typically developing comparison participants using functional magnetic resonance imaging (fMRI). Both groups showed prominent activation in the frontal-parietal-cerebellar network known to be important for verbal WM. Despite equivalent behavioral performance between groups, alcohol-exposed individuals showed increased activation relative to typically developing individuals in left dorsal frontal and left inferior parietal cortices, and bilateral posterior temporal regions during verbal WM. These effects remained even when group differences on IQ were statistically controlled. This pattern of increased activation coupled with equivalent behavioral performance between groups suggests that individuals with FASD recruit a more extensive network of brain regions during verbal WM relative to typically developing individuals. These findings may suggest that frontal-parietal processing during verbal WM is less efficient in alcohol-exposed individuals.

Down syndrome is characterized by disproportionately severe impairments of speech and language, yet little is known about the neural underpinnings of these deficits. We compared fMRI activation patterns during passive story listening in 9 young adults with Down syndrome and 9 approximately age-matched, typically developing controls. The typically developing group exhibited greater activation than did the Down syndrome group in classical receptive language areas (superior and middle temporal gyri) for forward > backward speech; the Down syndrome group exhibited greater activation in cingulate gyrus, superior and inferior parietal lobules, and precuneus for both forward speech > rest and backward speech > rest. The Down syndrome group showed almost no difference in activation patterns between the language (forward speech) and nonlanguage (backward speech) conditions.

The effects of prenatal exposure to methamphetamine on neurocognitive skills are not well understood. Chang and colleagues documented lower scores on measures of verbal memory, spatial memory, attention, and visual motor integration in methamphetamine-exposed children compared to unexposed participants (1). However, the largest reported sample of prenatal MA exposure reported that 49% of participating methamphetamine users also used alcohol during pregnancy, and only 10% used methamphetamine alone (2). These high rates of co-exposure to alcohol during pregnancy render it difficult to separate effects of methamphetamine exposure from alcohol exposure. Heavy prenatal alcohol exposure is known to detrimentally affect verbal memory (3). Verbal memory encompasses learning and recall of verbal information from long-term storage. Verbal learning is an important cognitive skill because it underlies basic academic skills such as vocabulary acquisition. The verbal nature of classroom instruction implicates that deficits in verbal learning may detrimentally influence achievement in other areas such as math and science. Three independent research groups have shown that children with prenatal exposure to alcohol perform more poorly on both immediate and delayed recall of verbal information compared to unexposed participants (4-6). All three studies concluded that problems of verbal memory were specific to encoding or learning of new information, and retention of information was not different between exposed and unexposed groups after accounting for initial encoding differences (4-6). Consistent with these behavioral findings, we have recently shown that unexposed control subjects activate left medial temporal structures important for verbal memory more than children with prenatal alcohol exposure during a verbal memory task using functional magnetic resonance imaging (fMRI) (7). Examination of prenatal methamphetamine exposure presents significant challenges given that a significant number of individuals with methamphetamine exposure have concomitant alcohol exposure. For this reason, we have recently attempted to address the specificity of methamphetamine exposure on neurocognitive performance by comparing a methamphetamine plus alcohol-exposed group of children to an alcohol-exposed only group and an unexposed control group. Both exposed groups performed more poorly than the unexposed control group on measures of verbal memory; however, there was no difference between our methamphetamine plus alcohol-exposed and our alcohol exposure only groups (8). These behavioral data suggested that decreased verbal memory performance in children exposed to both methamphetamine and alcohol may be due to the effects of alcohol rather than to the effects of methamphetamine. A limitation with behavioral performance data is that they cannot reveal whether neurocognitive systems engaged to achieve task completion are similar in children with different exposure histories. A similar level of performance can be achieved via engagement of different neurocognitive systems. For example, Brown and colleagues showed that children and adults engage different brain regions on word generation tasks despite equivalent levels of performance (9). Among atypically developing populations (e.g., dyslexia), different patterns of activation between the studied population and normally developing controls have been interpreted as effortful compensatory mechanisms and/or functional disruptions in the studied population (10, 11). To date, no studies have evaluated the effects of prenatal methamphetamine exposure on brain activation patterns. In the present exploratory study, we asked whether children with histories of prenatal exposure to methamphetamine plus alcohol engaged different neurocognitive systems during a verbal memory task in comparison to unexposed controls and children with exposure to alcohol only. The alcohol-exposed group is a necessary control given that the majority of our methamphetamine-exposed participants also have concomitant alcohol exposure. The term Fetal Alcohol Spectrum Disorders (FASD) has been proposed to capture the continuum of effects attributable to prenatal alcohol exposure (12, 13). We followed the Washington diagnostic system (12), under which the FASD umbrella term includes Fetal Alcohol Syndrome (FAS) and Partial Fetal Alcohol Syndrome (PFAS) on the more severe end of the spectrum where facial dysmorphology is prominent. Those who do not meet criteria for FAS or PFAS have less prominent facial dysmorphology and physical evidence of brain damage, and have been referred to as Alcohol-Related Neurobehavioral Disorder (ARND). Individuals in the ARND category also show impaired cognitive performance across multiple domains, suggesting that alcohol teratogenesis on brain development exists in the absence of facial dysmorphology (14). In order to minimize the possibility that heavy alcohol exposure effects may mask more subtle effects of methamphetamine exposure, we excluded from both the methamphetamine-exposed and the alcohol-exposed only groups those who met criteria for FAS and PFAS, the most severe manifestations of prenatal alcohol exposure. If methamphetamine has a specific effect on the development of the verbal memory system or interacts with alcohol in influencing the development of this system, then the methamphetamine-exposed children are expected to show a different pattern of activation during our verbal memory task compared to both the unexposed and the alcohol-exposed only groups.

Dynamic changes in brain structure, activation, and cognitive abilities co-occur during development, but little is known about how changes in brain structure relate to changes in cognitive function or brain activity. By using cortical pattern matching techniques to correlate cortical gray matter thickness and functional brain activity over the entire brain surface in 24 typically developing children, we integrated structural and functional magnetic resonance imaging data with cognitive test scores to identify correlates of mature performance during orthographic processing. Fast-naming individuals activated the right fronto-parietal attention network in response to novel fonts more than slow-naming individuals, and increased activation of this network was correlated with more mature brain morphology in the same fronto-parietal region. These relationships remained even after effects of age or general cognitive ability were statistically controlled. These results localized cortical regions where mature morphology corresponds to mature patterns of activation, and may suggest a role for experience in mediating brain structure-activation relationships.

Development of working memory (WM) aptitude parallels structural changes in the frontal-parietal association cortices important for performance within this cognitive domain. The cerebellum has been proposed to function in support of the postulated phonological loop component of verbal WM, and along with frontal and parietal cortices, has been shown to exhibit linear WM load-dependent activation in adults. It is not known if these kinds of WM load-dependent relationships exist for cerebro-cerebellar networks in developmental populations, and whether there are age-related changes in the nature of load-dependency between childhood, adolescence, and adulthood. The present study used fMRI and a verbal Sternberg WM task with three load levels to investigate developmental changes in WM load-dependent cerebro-cerebellar activation in a sample of 30 children, adolescents, and young adults between the ages of 7 and 28. The neural substrates of linear load-dependency were found to change with age. Among adolescents and adults, frontal, parietal and cerebellar regions showed linear load-dependency, or increasing activation under conditions of increasing WM load. In contrast, children recruited only left ventral prefrontal cortex in response to increasing WM load. These results demonstrate that, while children, adolescents, and young adults activate similar cerebro-cerebellar verbal working memory networks, the extent to which they rely on parietal and cerebellar regions in response to increasing task difficulty changes significantly between childhood and adolescence.

Although there is a documented association between plasma nicotine levels and smoking behavior, recent studies indicate that denicotinized cigarettes reduced craving and symptoms of tobacco withdrawal. Denicotinized cigarettes (that deliver tar but insignificant amounts of nicotine) and conventional cigarettes were compared in a within-subject spaced smoking study. In six sessions, subjects (n=10) smoked denicotinized cigarettes or conventional cigarettes every 30, 60 or 240 min (8, 4 or 1 cigarette(s)). EEG effects of the last cigarette of each session were deduced by comparisons with EEG recordings collected before smoking. Conventional cigarettes increased spectral edge EEG frequency, decreased θ power and increased β1 power. Denicotinized cigarettes decreased spectral frequency. The EEG effects of both cigarettes depended upon the recentness of smoking. The results indicate that nicotine delivery, recentness and the process of smoking importantly influence the EEG; other, non-nicotine components of tobacco smoke may also exert EEG effects.

Relational reasoning, or the ability to identify and consider relationships between multiple mental representations, is a fundamental component of high-level cognition (Robin and Holyoak, 1995). The capacity to reason with relations enables abstract thought and may be at the core of what makes human cognition unique (Penn et al., 2008). This capacity improves throughout childhood and adolescence (Ferrer et al., 2009). Here, we sought to better understand the neural mechanisms that support its emergence. We have hypothesized previously, based on fMRI research in adults, that (1) inferior parietal lobe (IPL) plays a central role in representing relationships between mental representations (first-order relations) and (2) rostrolateral prefrontal cortex (RLPFC) integrates inputs from IPL to build second-order relational structures (i.e., relations between relations). In the present study, we examined fMRI and cortical thickness data from 85 children and adolescents (ages 6–18 years). Participants performed a relational matching task in which they viewed arrays of four visual stimuli and determined whether two stimuli shared a particular feature (a first-order relational judgment) or whether two pairs of stimuli matched according to the same feature (a second-order relational judgment). fMRI results provide evidence for increased functional selectivity across ages 6–18 years in RLPFC and IPL. Specifically, young children engaged RLPFC and IPL indiscriminately for first-order and second-order relational judgments, and activation for first-order relations diminished with age whereas activation for second-order relations stayed elevated. Examination of cortical thickness revealed that increased functional selectivity in RLPFC could be partly accounted for by cortical thinning in IPL.

We examined functional MRI activation patterns corresponding to verbal paired associate learning in a group of 11 children with heavy prenatal alcohol exposure compared with 16 typically developing children. Among the typically developing children, prominent activation was observed in the left medial temporal lobe, left dorsal frontal lobe and bilateral posterior temporal cortices during learning and recall. Analyses revealed significantly less activation in left medial and posterior temporal regions and significantly more activation in right dorsal frontal cortex in the alcohol-exposed children relative to controls, even when group differences in memory test performance were statistically controlled. These results may indicate an increased reliance on frontal memory systems in the children with heavy prenatal alcohol exposure, perhaps compensating for dysfunctional medial temporal memory systems. Our findings are consistent with neuropsychological and structural imaging studies, and provide the first evidence for brain activation abnormalities, independent of group performance differences, during verbal learning and recall in children with heavy prenatal alcohol exposure.

Prenatal exposure to alcohol can result in neuroanatomical and neurocognitive deficits. High-resolution magnetic resonance imaging, surface-based image analytic methods, and neuropsychological measures were used to characterize the cerebellar vermis and to evaluate potential cognitive correlates of vermal morphology in 21 children and adolescents with prenatal alcohol exposure and 21 normally developing individuals. Alcohol-exposed individuals showed statistically significant reductions in the midline sagittal areas of the anterior vermis and posterior-inferior vermis, and significant displacement of the anterior and posterior-inferior vermal regions. Anterior vermal dysmorphology was negatively correlated with verbal learning and memory performance within the alcohol-exposed group. These observations expand on previous reports of cerebellar abnormalities in prenatal alcohol exposure, in that they localize the specific pattern of cerebellar vermal dysmorphology.