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Item Alcohol Use and Prefrontal Cortex Volume Trajectories in Young Adults with Mood Disorders and Associated Clinical Outcomes(MDPI, 2022-02-22) Kirsch, Dylan E.; Tretyak, Valeria; Le, Vanessa; Huffman, Ansley; Fromme, Kim; Strakowski, Stephen M.; Lippard, Elizabeth T. C.; Psychiatry, School of MedicineBackground: Alcohol use in the course of mood disorders is associated with worse clinical outcomes. The mechanisms by which alcohol use alters the course of illness are unclear but may relate to prefrontal cortical (PFC) sensitivity to alcohol. We investigated associations between alcohol use and PFC structural trajectories in young adults with a mood disorder compared to typically developing peers. Methods: 41 young adults (24 with a mood disorder, agemean = 21 ± 2 years) completed clinical evaluations, assessment of alcohol use, and two structural MRI scans approximately one year apart. Freesurfer was used to segment PFC regions of interest (ROIs) (anterior cingulate, orbitofrontal cortex, and frontal pole). Effects of group, alcohol use, time, and interactions among these variables on PFC ROIs at baseline and follow-up were modeled. Associations were examined between alcohol use and longitudinal changes in PFC ROIs with prospective mood. Results: Greater alcohol use was prospectively associated with decreased frontal pole volume in participants with a mood disorder, but not typically developing comparison participants (time-by-group-by-alcohol interaction; p = 0.007); however, this interaction became a statistical trend in a sensitivity analysis excluding one outlier in terms of alcohol use. Greater alcohol use and a decrease in frontal pole volume related to longer duration of major depression during follow-up (p’s < 0.05). Conclusion: Preliminary findings support more research on alcohol use, PFC trajectories, and depression recurrence in young adults with a mood disorder including individuals with heavier drinking patterns.Item APPlications of amyloid-β precursor protein metabolites in macrocephaly and autism spectrum disorder(Frontiers Media, 2023-09-20) Sokol, Deborah K.; Lahiri, Debomoy K.; Neurology, School of MedicineMetabolites of the Amyloid-β precursor protein (APP) proteolysis may underlie brain overgrowth in Autism Spectrum Disorder (ASD). We have found elevated APP metabolites (total APP, secreted (s) APPα, and α-secretase adamalysins in the plasma and brain tissue of children with ASD). In this review, we highlight several lines of evidence supporting APP metabolites’ potential contribution to macrocephaly in ASD. First, APP appears early in corticogenesis, placing APP in a prime position to accelerate growth in neurons and glia. APP metabolites are upregulated in neuroinflammation, another potential contributor to excessive brain growth in ASD. APP metabolites appear to directly affect translational signaling pathways, which have been linked to single gene forms of syndromic ASD (Fragile X Syndrome, PTEN, Tuberous Sclerosis Complex). Finally, APP metabolites, and microRNA, which regulates APP expression, may contribute to ASD brain overgrowth, particularly increased white matter, through ERK receptor activation on the PI3K/Akt/mTOR/Rho GTPase pathway, favoring myelination.Item Brain structural connectome in neonates with prenatal opioid exposure(Frontiers Media, 2022-09-16) Vishnubhotla, Ramana V.; Zhao, Yi; Wen, Qiuting; Dietrich, Jonathan; Sokol, Gregory M.; Sadhasivam, Senthilkumar; Radhakrishnan, Rupa; Radiology and Imaging Sciences, School of MedicineIntroduction: Infants with prenatal opioid exposure (POE) are shown to be at risk for poor long-term neurobehavioral and cognitive outcomes. Early detection of brain developmental alterations on neuroimaging could help in understanding the effect of opioids on the developing brain. Recent studies have shown altered brain functional network connectivity through the application of graph theoretical modeling, in infants with POE. In this study, we assess global brain structural connectivity through diffusion tensor imaging (DTI) metrics and apply graph theoretical modeling to brain structural connectivity in infants with POE. Methods: In this prospective observational study in infants with POE and control infants, brain MRI including DTI was performed before completion of 3 months corrected postmenstrual age. Tractography was performed on the whole brain using a deterministic fiber tracking algorithm. Pairwise connectivity and network measure were calculated based on fiber count and fractional anisotropy (FA) values. Graph theoretical metrics were also derived. Results: There were 11 POE and 18 unexposed infants included in the analysis. Pairwise connectivity based on fiber count showed alterations in 32 connections. Pairwise connectivity based on FA values showed alterations in 24 connections. Connections between the right superior frontal gyrus and right paracentral lobule and between the right superior occipital gyrus and right fusiform gyrus were significantly different after adjusting for multiple comparisons between POE infants and unexposed controls. Additionally, alterations in graph theoretical network metrics were identified with fiber count and FA value derived tracts. Conclusion: Comparisons show significant differences in fiber count in two structural connections. The long-term clinical outcomes related to these findings may be assessed in longitudinal follow-up studies.Item Effects of stress-dependent growth on evolution of sulcal direction and curvature in models of cortical folding(Elsevier, 2023) Balouchzadeh, Ramin; Bayly, Philip V.; Garcia, Kara E.; Radiology and Imaging Sciences, School of MedicineThe majority of human brain folding occurs during the third trimester of gestation. Although many studies have investigated the physical mechanisms of brain folding, a comprehensive understanding of this complex process has not yet been achieved. In mechanical terms, the "differential growth hypothesis" suggests that the formation of folds results from a difference in expansion rates between cortical and subcortical layers, which eventually leads to mechanical instability akin to buckling. It has also been observed that axons, a substantial component of subcortical tissue, can elongate or shrink under tensile or compressive stress, respectively. Previous work has proposed that this cell-scale behavior in aggregate can produce stress-dependent growth in the subcortical layers. The current study investigates the potential role of stress-dependent growth on cortical surface morphology, in particular the variations in folding direction and curvature over the course of development. Evolution of sulcal direction and mid-cortical surface curvature were calculated from finite element simulations of three-dimensional folding in four different initial geometries: (i) sphere; (ii) axisymmetric oblate spheroid; (iii) axisymmetric prolate spheroid; and (iv) triaxial spheroid. The results were compared to mid-cortical surface reconstructions from four preterm human infants, imaged and analyzed at four time points during the period of brain folding. Results indicate that models incorporating subcortical stress-dependent growth predict folding patterns that more closely resemble those in the developing human brain. Statement of significance: Cortical folding is a critical process in human brain development. Aberrant folding is associated with disorders such as autism and schizophrenia, yet our understanding of the physical mechanism of folding remains limited. Ultimately mechanical forces must shape the brain. An important question is whether mechanical forces simply deform tissue elastically, or whether stresses in the tissue modulate growth. Evidence from this paper, consisting of quantitative comparisons between patterns of folding in the developing human brain and corresponding patterns in simulations, supports a key role for stress-dependent growth in cortical folding.Item Efficacy of a 4-part program on brain development(Cambridge University Press, 2018-06) Silver, Emily; Michael, Nancy; Medicine, School of MedicineOBJECTIVES/SPECIFIC AIMS: (1) Provide basic brain knowledge about development and resiliency. (2) Develop an understanding of how a mother can impact a child’s brain development. (3) Foster a sense of agency to increase the likelihood that a mother will enact positive changes. (4) Develop the ability to recognize a connection between one’s own behaviors and a child’s development and behaviors. METHODS/STUDY POPULATION: Tested the efficacy of a 4-week intervention program on neurodevelopment for homeless mothers. Mothers (n=4) residing at the Center for the Homeless in South Bend, IN were recruited. Used community partner feedback, weekly surveys, and pre/post tests to look at changes in basic content knowledge, behavioral change, and self-efficacy. RESULTS/ANTICIPATED RESULTS: Preliminary results indicate an increase in knowledge about neurodevelopment, although results on behavioral changes are inconclusive. The program is anticipated to run a second time with a new group of parents residing in the Center for the Homeless to increase sample size. DISCUSSION/SIGNIFICANCE OF IMPACT: Anticipated that the results will add to the existing literature concerning effective interventions in strengthening parenting and neuroscience knowledge in vulnerable populations.Item Genetic associations with childhood brain growth, defined in two longitudinal cohorts(Wiley, 2018-06) Szekely, Eszter; Schwantes-An, Tae-Hwi Linus; Justice, Cristina M.; Sabourin, Jeremy A.; Jansen, Philip R.; Muetzel, Ryan L.; Sharp, Wendy; Tiemeier, Henning; Sung, Heejong; White, Tonya J.; Wilson, Alexander F.; Shaw, Philip; Medical and Molecular Genetics, School of MedicineGenome-wide association studies (GWASs) are unraveling the genetics of adult brain neuroanatomy as measured by cross-sectional anatomic magnetic resonance imaging (aMRI). However, the genetic mechanisms that shape childhood brain development are, as yet, largely unexplored. In this study we identify common genetic variants associated with childhood brain development as defined by longitudinal aMRI. Genome-wide single nucleotide polymorphism (SNP) data were determined in two cohorts: one enriched for attention-deficit/hyperactivity disorder (ADHD) (LONG cohort: 458 participants; 119 with ADHD) and the other from a population-based cohort (Generation R: 257 participants). The growth of the brain's major regions (cerebral cortex, white matter, basal ganglia, and cerebellum) and one region of interest (the right lateral prefrontal cortex) were defined on all individuals from two aMRIs, and a GWAS and a pathway analysis were performed. In addition, association between polygenic risk for ADHD and brain growth was determined for the LONG cohort. For white matter growth, GWAS meta-analysis identified a genome-wide significant intergenic SNP (rs12386571, P = 9.09 × 10-9 ), near AKR1B10. This gene is part of the aldo-keto reductase superfamily and shows neural expression. No enrichment of neural pathways was detected and polygenic risk for ADHD was not associated with the brain growth phenotypes in the LONG cohort that was enriched for the diagnosis of ADHD. The study illustrates the use of a novel brain growth phenotype defined in vivo for further study.Item Pilot Study of Fetal Brain Development and Morphometry in Prenatal Opioid Exposure and Smoking on Fetal MRI(Elsevier, 2022) Radhakrishnan, Rupa; Brown, Brandon P.; Haas, David M.; Zang, Yong; Sparks, Christina; Sadhasivam, Senthilkumar; Radiology and Imaging Sciences, School of MedicinePurpose: The purpose of this study was to assess for any differences in brain maturation, structure and morphometry in fetuses exposed to opioids in utero, compared to non-opioid exposed fetuses on fetal MRI. Methods: We performed a prospective study in pregnant women using opioids and healthy pregnant women without prenatal opioid use. We evaluated brain maturation, structure, and morphometry on second or third trimester fetal MRI and assessed group differences. Results: 28 pregnant women were enrolled, 12 with opioid exposure (average gestational age 33.67, range 28-39 w), 9 of whom also smoked, and 16 without opioid exposure (average gestational age 32.53, range 27-38 w). There was a significant difference in the anteroposterior diameter of the fetal cerebellar vermis in the opioid exposed fetuses compared to non-opioid exposed fetuses (p = 0.004). There were no significant differences in brain biparietal diameter, fronto-occipital diameter, transverse cerebellar diameter and anteroposterior dimension of the pons in opioid exposed fetuses compared to non-opioid exposed fetuses. There were no abnormalities in brain maturation and no major brain structural abnormalities in the opioid exposed fetuses. Conclusion: Smaller fetal anteroposterior cerebellar vermian dimension was associated with in utero opioid exposure. There were no abnormalities in brain maturation or major structural abnormalities in fetuses exposed to opioids.Item Sexually dimorphic DYRK1A overexpression on postnatal day 15 in the Ts65Dn mouse model of Down syndrome: Effects of pharmacological targeting on behavioral phenotypes(Elsevier, 2022) Hawley, Laura E.; Prochaska, Faith; Stringer, Megan; Goodlett, Charles R.; Roper, Randall J.; Biology, School of ScienceThe neurotypical spatiotemporal patterns of gene expression are disrupted in Down syndrome (DS) by trisomy of human chromosome 21 (Hsa21), resulting in altered behavioral development and brain circuitry. The Ts65Dn DS mouse model exhibits similar phenotypes to individuals with DS due to three copies of approximately one-half of the genes found on Hsa21. Dual-specificity Tyrosine Phosphorylation-regulated Kinase 1a (Dyrk1a), one of these triplicated genes, is an attractive target to normalize brain development due to its influence in cellular brain deficits seen in DS. We hypothesized that postnatal development of DYRK1A expression is dysregulated in trisomic animals, and found significant overexpression of DYRK1A in the hippocampus, cerebral cortex, and cerebellum at postnatal day (P) 15 in male—but not female—Ts65Dn mice. We then hypothesized the existence of sex-dependent effects of trisomy on neurobehavioral attributes during P16-17, and that administration of a DYRK1A inhibitor (CX-4945, ∼75mg/kg) beginning on P14 would normalize aberrant behavior in trisomic animals. Both male and female trisomic mice given control injections of phosphate buffered saline (PBS) displayed sustained levels of locomotor activity over a 10-minute test in contrast to the PBS-treated euploid animals that showed significant within-session habituation. Trisomic animals were more persistent in choosing to remain in home shavings in a preference test. Treatment with CX-4945 failed to confirm therapeutic effects. CX-4945 prevented growth, and both CX-4945 and its 10% dimethyl sulfoxide vehicle affected locomotor activity in trisomic and euploid groups, indicating a non-specific disruption of behavior. Despite the negative outcomes for CX-4945, the novel demonstration of sexually dimorphic DYRK1A expression in trisomic animals at P15 supports the broader hypothesis that overexpression of trisomic genes in DS can vary with age, sex, and brain region. Identifying the developmental timing of periods of dysregulated DYRK1A may be important for understanding individual differences in neurodevelopmental trajectories in DS and for developing effective therapeutic interventions targeting DYRK1A.