Objective: To examine the independent contributions of prenatal methamphetamine exposure (PME) and prenatal tobacco exposure (PTE) on brain morphology among a sample of nonalcohol-exposed 3- to 5-year-old children followed prospectively since birth. Study Design: The sample included 20 children with PME (19 with PTE) and 15 comparison children (7 with PTE), matched on race, birth weight, maternal education and type of insurance. Subcortical and cortical volumes and cortical thickness measures were derived through an automated segmentation procedure from T1-weighted structural magnetic resonance images obtained on unsedated children. Attention was assessed using the computerized Conners’ Kiddie Continuous Performance Test Version 5 (K-CPT™ V.5). PME effects on subcortical and cortical brain volumes and cortical thickness were tested by general linear model with type III sum of squares, adjusting for PTE, prenatal marijuana exposure, age at time of scan, gender, handedness, pulse sequence and total intracranial volume (for volumetric outcomes). A similar analysis was done for PTE effects on subcortical and cortical brain volumes and thickness, adjusting for PME and the above covariates. Results: Children with PME had significantly reduced caudate nucleus volumes and cortical thickness increases in perisylvian and orbital-frontal cortices. In contrast, children with PTE showed cortical thinning in perisylvian and lateral occipital cortices and volumetric increases in frontal regions and decreases in anterior cingulate. PME was positively related and caudate volume was inversely related to K-CPT reaction time by inter-stimulus interval, a measure of the ability to adjust to changing task demands, suggesting that children with PME may have subtle attentional deficits mediated by caudate volume reductions. Conclusions: Our results suggest that PME and PTE may have distinct differential cortical effects on the developing central nervous system. Additionally, PME may be associated with subtle deficits in attention mediated by caudate volume reductions.

Arria A, Derauf C, LaGasse L, Grant P, Shah R, Smith L, Haning W, Huestis M, Strauss A, Della Grotta S, Liu J, Lester B: Methamphetamine and other substance use during pregnancy: preliminary estimates from the Infant Development, Environment, and Lifestyle (IDEAL) Study. Matern Child Health J 2006;10:293–302.
Thompson BL, Levitt P, Stanwood GD: Prenatal exposure to drugs: effects on brain development and implications for policy and education. Nat Rev Neurosci 2009;10:303–312.
Salisbury AL, Ponder KL, Padbury JF, Lester BM: Fetal effects of psychoactive drugs. Clin Perinatol 2009;36:595–619.
Frost DO, Cadet JL: Effects of methamphetamine-induced neurotoxicity on the development of neural circuitry: a hypothesis. Brain Res Brain Res Rev 2000;34:103–118.
Lester BM, Padbury JF: Third pathophysiology of prenatal cocaine exposure. Dev Neurosci 2009;31:23–35.
Tata DA, Yamamoto BK: Interactions between methamphetamine and environmental stress: role of oxidative stress, glutamate and mitochondrial dysfunction. Addiction 2007;102(suppl 1):49–60.
Nguyen D, Smith LM, Lagasse LL, Derauf C, Grant P, Shah R, Arria A, Huestis MA, Haning W, Strauss A, Della Grotta S, Liu J, Lester BM: Intrauterine growth of infants exposed to prenatal methamphetamine: results from the infant development, environment, and lifestyle study. J Pediatr 2010;157:337–339.
Lagasse LL, Wouldes T, Newman E, Smith LM, Shah RZ, Derauf C, Huestis MA, Arria AM, Grotta SD, Wilcox T, Lester BM: Prenatal methamphetamine exposure and neonatal neurobehavioral outcome in the USA and New Zealand. Neurotoxicol Teratol 2011;33:166–175.
Smith LM, LaGasse L, Derauf C, Grant P, Shah R, Arria A, Huestis M, Haning W, Strauss A, Della Grotta S, Fallone M, Liu J, Lester BM: Prenatal methamphetamine use and neonatal neurobehavioral outcome. Neurotoxicol Teratol 2008;30:20–28.
LaGasse LL, Derauf C, Smith LM, Newman E, Shah R, Neal C, Arria A, Huestis MA, Della Grotta S, Lin H, Dansereau LM, Lester BM: Prenatal methamphetamine exposure and childhood behavior problems at ages 3 and 5. Pediatrics 2012;129:681–688.
Derauf C, LaGasse LL, Smith LM, Newman E, Shah R, Neal C, Arria A, Huestis MA, Della Grotta S, Dansereau LM, Lin H, Lester BM: Prenatal methamphetamine exposure and inhibitory control among young school-age children. J Pediatr 2012, E-pub ahead of print.
Chang L, Smith LM, LoPresti C, Yonekura ML, Kuo J, Walot I, Ernst T: Smaller subcortical volumes and cognitive deficits in children with prenatal methamphetamine exposure. Psychiatry Res 2004;132:95–106.
Sowell ER, Leow AD, Bookheimer SY, Smith LM, O’Connor MJ, Kan E, Rosso C, Houston S, Dinov ID, Thompson PM: Differentiating prenatal exposure to methamphetamine and alcohol versus alcohol and not methamphetamine using tensor-based brain morphometry and discriminant analysis. J Neurosci 2010;30:3876–3885.
Frank DA, Augustyn M, Knight WG, Pell T, Zuckerman B: Growth, development, and behavior in early childhood following prenatal cocaine exposure: a systematic review. JAMA 2001;285:1613–1625.
Bauer CR, Langer JC, Shankaran S, Bada HS, Lester B, Wright LL, Krause-Steinrauf H, Smeriglio VL, Finnegan LP, Maza PL, Verter J: Acute neonatal effects of cocaine exposure during pregnancy. Arch Pediatr Adolesc Med 2005;159:824–834.
Norman AL, Crocker N, Mattson SN, Riley EP: Neuroimaging and fetal alcohol spectrum disorders. Dev Disabil Res Rev 2009;15:209–217.
Zhou D, Lebel C, Lepage C, Rasmussen C, Evans A, Wyper K, Pei J, Andrew G, Massey A, Massey D, Beaulieu C: Developmental cortical thinning in fetal alcohol spectrum disorders. Neuroimage 2011;58:16–25.
Yang Y, Roussotte F, Kan E, Sulik KK, Mattson SN, Riley EP, Jones KL, Adnams CM, May PA, O’Connor MJ, Narr KL, Sowell ER: Abnormal cortical thickness alterations in fetal alcohol spectrum disorders and their relationships with facial dysmorphology. Cereb Cortex 2011 2012;22:1170–1179.
Toro R, Leonard G, Lerner JV, Lerner RM, Perron M, Pike GB, Richer L, Veillette S, Pausova Z, Paus T: Prenatal exposure to maternal cigarette smoking and the adolescent cerebral cortex. Neuropsychopharmacology 2008;33:1019–1027.
Quinn B, Shienkopf S, Kennedy D, Fischl B, Kosofsky B: Assessment of validity of probabilistic atlases for automated subcortical brain structures in pediatric population (abstract No. 464). Abstracts of the 12th Annual Meeting of the Organization for Human Brain Mapping. Neuroimage 2006;31;(suppl 1):e1.
Smith LM, LaGasse LL, Derauf C, Grant P, Shah R, Arria A, Huestis M, Haning W, Strauss A, Della Grotta S, Liu J, Lester BM: The infant development, environment, and lifestyle study: effects of prenatal methamphetamine exposure, polydrug exposure, and poverty on intrauterine growth. Pediatrics 2006;118:1149–1156.
Dale AM, Fischl B, Sereno MI: Cortical surface-based analysis. I. Segmentation and surface reconstruction. Neuroimage 1999;9:179–194.
Fischl B, Sereno MI, Tootell RB, Dale AM: High-resolution intersubject averaging and a coordinate system for the cortical surface. Hum Brain Map 1999;8:272–284.
Fischl B, Dale AM: Measuring the thickness of the human cerebral cortex from magnetic resonance images. Proc Natl Acad Sci USA 2000;97:11050–11055.
Walhovd KB, Fjell AM, Reinvang I, Lundervold A, Dale AM, Eilertsen DE, Quinn BT, Salat D, Makris N, Fischl B: Effects of age on volumes of cortex, white matter and subcortical structures. Neurobiol Aging 2005;26:1261–1270.
Fischl B, Liu A, Dale AM: Automated manifold surgery: constructing geometrically accurate and topologically correct models of the human cerebral cortex. IEEE Trans Med Imaging 2001;20:70–80.
Desikan RS, Ségonne F, Fischl B, Quinn BT, Dickerson BC, Blacker D, Buckner RL, Dale AM, Maguire RP, Hyman BT, Albert MS, Killiany RJ: An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest. Neuroimage 2006;31:968–980.
Fischl B, Salat DH, Busa E, Albert M, Dieterich M, Haselgrove C, van der Kouwe A, Killiany R, Kennedy D, Klaveness S, Montillo A, Makris N, Rosen B, Dale AM: Whole brain segmentation: automated labeling of neuroanatomical structures in the human brain. Neuron 2002;33:341–355.
Fjell AM, Walhovd KB, Reinvang I, Lundervold A, Dale AM, Quinn BT, Makris N, Fischl B: Age does not increase rate of forgetting over weeks – neuro anatomical volumes and visual memory across the adult life-span. J Int Neuropsychol Soc 2005;11:2–15.
Bayley N: Bayley Scales of Infant Development, ed 2. New York, Psychological Corporation, 1993.
Achenbach TM, Rescorla LA: Manual for the ASEBA Preschool Forms and Profiles. Burlington, University of Vermont, Research Center for Children, Youth, and Families, 2000.
Conners C (ed): Conners’ Kiddie Continuous Performance Test (K-CPT™): Version 5 for Windows® – Technical Guide and Software Manual. North Tonawanda, Multi-Health Systems, 2006.
Good CD, Johnsrude IS, Ashburner J, Henson RN, Friston KJ, Frackowiak RS: Cerebral asymmetry and the effects of sex and handedness on brain structure: a voxel-based morphometric analysis of 465 normal adult human brains. Neuroimage 2001;14:685–700.
Rivkin MJ, Davis PE, Lemaster JL, Cabral HJ, Warfield SK, Mulkern RV, Robson CD, Rose-Jacobs R, Frank DA: Volumetric MRI study of brain in children with intrauterine exposure to cocaine, alcohol, tobacco, and marijuana. Pediatrics 2008;121:741–50.
Gallinat J, Meisenzahl E, Jacobsen LK, Kalus P, Bierbrauer J, Kienast T, Witthaus H, Leopold K, Seifert F, Schubert F, Staedtgen M: Smoking and structural brain deficits: a volumetric MR investigation. Eur J Neurosci 2006;24:1744–1750.
Jacobsen LK, Slotkin TA, Mencl WE, Frost SJ, Pugh KR: Gender-specific effects of prenatal and adolescent exposure to tobacco smoke on auditory and visual attention. Neuropsychopharmacology 2007;32:2453–2464.
Batty MJ, Liddle EB, Pitiot A, Toro R, Groom MJ, Scerif G, Liotti M, Liddle PF, Paus T, Hollis C: Cortical gray matter in attention-deficit/hyperactivity disorder: a structural magnetic resonance imaging study. J Am Acad Child Adolesc Psychiatry 2010;49:229–238.
Makris N, Biederman J, Valera EM, Bush G, Kaiser J, Kennedy DN, Caviness VS, Faraone SV, Seidman LJ: Cortical thinning of the attention and executive function networks in adults with attention-deficit/hyperactivity disorder. Cereb Cortex 2007;17:1364–1375.
Casey BJ, Epstein JN, Buhle J, Liston C, Davidson MC, Tonev ST, Spicer J, Niogi S, Millner AJ, Reiss A, Garrett A, Hinshaw SP, Greenhill LL, Shafritz KM, Vitolo A, Kotler LA, Jarrett MA, Glover G: Frontostriatal connectivity and its role in cognitive control in parent-child dyads with ADHD. Am J Psychiatry 2007;164:1729–1736.
Derauf C, Kekatpure M, Neyzi N, Lester B, Kosofsky B: Neuroimaging of children following prenatal drug exposure. Semin Cell Dev Biol 2009;20:441–454.
Froehlich TE, Lanphear BP, Auinger P, Hornung R, Epstein JN, Braun J, Kahn RS: Association of tobacco and lead exposures with attention-deficit/hyperactivity disorder. Pediatrics 2009;124:e1054–e1063.
Kikinis Z, Fallon JH, Niznikiewicz M, Nestor P, Davidson C, Bobrow L, Pelavin PE, Fischl B, Yendiki A, McCarley RW, Kikinis R, Kubicki M, Shenton ME: Gray matter volume reduction in rostral middle frontal gyrus in patients with chronic schizophrenia. Schizophr Res 2010;123:153–159.
Smith LM, LaGasse LL, Derauf C, Newman E, Shaw R, Haning W, Arria A, Huestis M, Strauss A, Della Grotta S, Dansereau LM, Lin H, Lester BM: Motor and cognitive outcomes through three years of age in children exposed to prenatal methamphetamine. Neurotox Teratol 2011;33:176–184.
Yamamoto BK, Moszczynska A, Gudelsky GA: Amphetamine toxicities. Ann NY Acad Sci 2010;1187:101–121.
Zhu JPQ, Xu W, Angulo JA: Methamphetamine-induced cell death: selective vulnerability in neuronal subpopulations of the striatum in mice. Neuroscience 2006;140:607–622.
Avants BB, Hurt H, Giannetta JM, Epstein CL, Shera DM, Rao H, Wang J, Gee JC: Effects of heavy in utero cocaine exposure on adolescent caudate morphology. Pediatr Neurol 2007;37:275–279.
Peterson BS, Vohr B, Staib LH, Cannistraci CJ, Dolberg A, Schneider KC, Katz KH, Westerveld M, Sparrow S, Anderson AW, Duncan CC, Makuch RW, Gore JC, Ment LR: Regional brain volume abnormalities and long-term cognitive outcome in preterm infants. JAMA 2000;284:1939–1947.
Peterson BS, Anderson AW, Ehrenkranz R, Staib LH, Tageldin M, Colson E, Gore JC, Duncan CC, Makuch R, Ment LR: Regional brain volumes and their later neurodevelopmental correlates in term and preterm infants. Pediatrics 2003;111:939–948.
Grahn JA, Parkinson JA, Owen AM: The cognitive functions of the caudate nucleus. Prog Neurobiol 2008;86:141–155.
Casey BJ, Tottenham N, Fossella J: Clinical, imaging, lesion, and genetic approaches toward a model of cognitive control. Dev Psychobiol 2002;40:237–254.
Greenberg LM: Test of variables of attention. J Clin Psychol 1998;54:461–476.
Kiblawi ZN, Smith LM, LaGasse LL, Derauf C, Newman E, Shah R, Arria A, Huestis MA, DellaGrotta S, Dansereau LM, Neal C, Lester BM: The effects of prenatal methamphetamine exposure on attention as assessed by continuous performance tests: results from the Infant, Development, Environment, and Lifestyle (IDEAL) Study. Abstract accepted for poster presentation at 2012 Pediatric Academic Societies meeting.
Raz A, Buhle J: Typologies of attentional networks. Nat Rev Neurosci 2006;7:367–379.
Sowell ER, Thompson PM, Welcome SE, Henkenius AL, Toga AW, Peterson BS: Cortical abnormalities in children and adolescents with attention-deficit hyperactivity disorder. Lancet 2003;362:1699–1707.
Sowell ER, Mattson SN, Kan E, Thompson PM, Riley EP, Toga AW: Abnormal cortical thickness and brain-behavior correlation patterns in individuals with heavy prenatal alcohol exposure. Cereb Cortex 2008;18:136–144.
Fried PA, Watkinson B, Gray R: Differential effects on cognitive functioning in 13- to 16-year-olds prenatally exposed to cigarettes and marijuana. Neurotoxicol Teratol 2003;25:427–436.
Overmeyer S, Bullmore ET, Suckling J, Simmons A, Williams SC, Santosh PJ, Taylor E: Distributed grey and white matter deficits in hyperkinetic disorder: MRI evidence for anatomical abnormality in an attentional network. Psychol Med 2001;31:1425–1435.
Seidman LJ, Valera EM, Makris N, Monuteaux MC, Boriel DL, Kelkar K, Kennedy DN, Caviness VS, Bush G, Aleardi M, Faraone SV, Biederman J: Dorsolateral prefrontal and anterior cingulated cortex volumetric abnormalities in adults with attention-deficit/hyperactivity disorder identified by magnetic resonance imaging. Biol Psychiatry 2006;60:1071–1080.
Cornelius MD, Day NL: Developmental consequences of prenatal tobacco exposure. Curr Opin Neurol 2009;22:121–125.
Hochberg Y: A sharper Bonferroni procedure for multiple tests of significance. Biometrika 1988;75:800–802.
Lebel C, Sowell E: Diffusion tensor imaging studies of prenatal drug exposure: challenges of poly-drug use in pregnant women. J Pediatr 2011;159:709–710.
Peterson BS: Conceptual, methodological, and statistical challenges in brain imaging studies of developmentally based psychopathologies. Dev Psychopathol 2003;15:811–832.
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