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Human Brain Mapping 35:5877–5887 (2014)

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Combining Diffusion Tensor Imaging and Magnetic Resonance Spectroscopy to Study Reduced Frontal White Matter Integrity in Youths With Family Histories of Substance Use Disorders Ashley Acheson,1,2* S. Andrea Wijtenburg,3 Laura M. Rowland,3,4 Bethany C. Bray,5 Frank Gaston,3 Charles W. Mathias,1 Peter T. Fox,2 William R. Lovallo,6 Susan N. Wright,3 L. Elliot Hong,3 Stephen McGuire,7 Peter Kochunov,3 and Donald M. Dougherty1 1

Department of Psychiatry, University of Texas Health Science Center at San Antonio, San Antonio, Texas 2 Research Imaging Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas 3 Department of Psychiatry, Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, Maryland 4 Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, Maryland 5 The Methodology Center, The Pennsylvania State University, University Park, Pennsylvania 6 Behavioral Sciences Laboratories, Veterans Affairs Medical Center and University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 7 Department of Neurology, University of Texas Health Science Center at San Antonio, San Antonio, Texas r

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Abstract: Individuals with a family history of substance use disorder (FH1) show impaired frontal white matter as indicated by diffusion tensor imaging (DTI). This impairment may be due to impaired or delayed development of myelin in frontal regions, potentially contributing to this population’s increased risk for developing substance use disorders. In this study, we examined high angular resolution DTI and proton magnetic resonance spectroscopy data from the anterior corona radiata were collected in 80 FH1 and 34 FH2 youths (12.9 6 1.0 years old). White matter integrity indices included fractional anisotropy (FA), N-acetylaspartate (NAA), and total choline (tCho). Lower FA suggests decreased myelination. Decreased NAA coupled with higher tCho suggests impaired build-up and maintenance of cerebral myelin and consequently greater breakdown of cellular membranes. We found FH1 youths had lower FA (P < 0.0001) and NAA (P 5 0.017) and higher tCho (P 5 0.04). FH density

Additional Supporting Information may be found in the online version of this article. Contract grant sponsor(s): NIDA, NIBIB, and NIMH of the National Institutes of Health; Contract grant number(s): R01DA026868, R01-DA033997, R01-EB015611, R01-MH094520, and T32-MH067533. *Correspondence to: Ashley Acheson; Department of Psychiatry and Research Imaging Institute, The University of Texas Health C 2014 Wiley Periodicals, Inc. V

Science Center at San Antonio, 7703 Floyd Curl Drive, MC 6240, San Antonio, TX 78229. E-mail: [email protected] Received for publication 24 March 2014; Revised 3 June 2014; Accepted 14 July 2014. DOI: 10.1002/hbm.22591 Published online 20 July 2014 in Wiley Online Library (wileyonlinelibrary.com).

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Acheson et al.

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(number of parents and grandparents with substance use disorders) was negatively correlated with FA (P < 0.0001) and NAA (P 5 0.011) and positively correlated with tCho (P 5 0.001). FA was independently predicted by both FH density (P 50.006) and NAA (P5 0.002), and NAA and tCho were both independent predictors of FH density (P < 0.001). Our finding of lower frontal FA in FH1 youths corresponding to lower NAA and increased tCho is consistent with delayed or impaired development of frontal white matter in FH1 youths. Longitudinal studies are needed to determine how these differences relate to substance use outcomes. Hum Brain Mapp 35:5877–5887, 2014. VC 2014 Wiley Periodicals, Inc. Key words: frontal white matter integrity; family history; risk; diffusion tensor imaging; proton magnetic resonance spectroscopy; substance use r

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INTRODUCTION Persons with a family history of alcohol or other substance use disorders (FH1) are at a greater risk for developing these disorders than those with no such histories (FH2), and this risk increases with greater FH densities (number of affected biological relatives) [Cloninger et al., 1981; Finn et al., 1990; Lieb et al., 2002; McCaul et al., 1990; Merikangas, 1990a; Merikangas et al., 1998; Reich et al., 1998; Slutske et al., 2002]. This risk for developing substance use disorder in FH1 individuals peaks during adolescence and early adulthood, similar to trends observed in general population that are thought to be at least partially by the relatively slow maturation of frontocortical and frontostriatal tracts resulting in poor inhibition of reward-seeking and risk-taking behavior [Blakemore and Robbins, 2012; Ernst and Fudge, 2009; Somerville and Casey, 2010]. Plausibly therefore, FH1 individuals may be expected to have relatively poorer development of these tracts compared to their peers, contributing to their increased risk. Consistent with this, we recently found evidence for delayed/impaired myelination of frontal white matter in FH1 youths and young adults that may at least partially resolve with age [Acheson et al., in press]. Specifically, we used diffusion tensor imaging (DTI) to index white matter integrity in all major brain tracts in FH1 and FH2 youths and adults. FH1 youths had decreased white matter integrity in frontocortical and frontostriatal tracts as well as some parietocortical tracts. In contrast, FH1 adults had decreased white matter integrity only in frontocortical tracts. Collectively, these results suggest that some white matter deficits in FH1 youths may recover, but deficits in frontal white matter integrity may persist at least into early adulthood. These deficits may relate to altered concentrations of biologically important metabolites in white matter as has been demonstrated in normal aging and schizophrenia [Kochunov et al., 2010c; Tang et al., 2007; Wijtenburg et al., 2012]. A better understanding of the biological mechanisms that underlie the impaired frontal white matter integrity in FH1 individuals may provide important insight into potential neurobiological mechanisms contributing to their elevated risk for developing substance use disorders. In this study, we investigated the physiological and metabolic factors contributing to compromised integrity of

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forebrain white matter in FH1 youths using a novel combination of diffusion tensor imagine (DTI) and proton magnetic resonance spectroscopy (1H-MRS). We used DTI to measure fractional anisotropy (FA), an estimate cerebral myelin levels that describes directional selectivity of the random diffusion of water molecules observed along major white matter tracts [Basser, 1994; Conturo et al., 1996; Pierpaoli and Basser, 1996; Song et al., 2005; Ulug et al., 1995]. We used 1H-MRS to quantify concentrations of N-acetylaspartate (NAA), total choline (tCho), and total creatine (tCr), which are neurochemicals that reflect axonal health, cellar membrane breakdown, and energy metabolism, respectively [Balestrino et al., 2002; Munoz Maniega et al., 2008; Venkatesh et al., 2001]. Variability in these neurochemicals can explain a large proportion of the variability in FA values [Hao et al., 2013; Kochunov et al., 2010c; Wijtenburg et al., 2012]. Specifically, NAA has an important role in the development and maintenance of myelin [Moffett et al., 2007]. Related, elevated tCho concentrations can be interpreted as evidence for elevated breakdown of cellular membranes [Klein, 2000]. During normal adolescent development, NAA levels rise and tCho levels fall due to suppressed membrane turnover, leading to increased myelin levels [Cecil and Jones, 2001]. Finally, tCr level is an index of cellular energy metabolism activity, that is, known to decline with advanced age and neurological diseases but can be used as reference measure in more healthy populations [Chang et al., 1996, 2009]. By combining DTI and 1H-MRS measures in FH1 youth, we can gain unique insights into deficits in white matter integrity occurring in this population, prior to onset of substance use disorders. We studied the correspondence between anterior corona radiata (ACR) FA values and concentrations of NAA, tCho, and tCr in the ACR region in a large cohort of FH1 and FH2 youths. We focused our analyses on the ACR because it is the largest forebrain white matter bundle, allowing for measuring both DTI and 1H-MRS in pure frontal white matter [Wijtenburg et al., 2012] and because this region showed reduced FA values in independent cohorts of FH1 youths and young adults [Acheson et al., in press; Herting et al., 2010]. We used regression analyses to estimate the proportion of individual variability in FA values that can be explained by concentrations of NAA,

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Frontal White Matter and Family History

tCho, and tCr and the ability of these neurochemicals to predict FH density. We hypothesized that the impaired ACR FA in FH1 youths would be related to both decreased NAA and elevated tCho, consistent with impaired or delayed frontal myelination in these individuals.

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ents meeting criteria for substance use disorders. Scores ranged from 0 (FH– participants) to a possible 6 (FH1 participants with both parents and all grandparents affected).

Collection and Processing of Magnetic Resonance Imaging and Spectroscopy

METHODS Participants Thirty-four FH2 and 80 FH1 youths (10 to 14 years old, average age 5 12.9 6 1.0) were recruited from a cohort of 386 volunteers in an ongoing longitudinal study on adolescent development and substance use involvement [Ryan et al., Submitted]. FH1 youths were deliberately oversampled to ensure a range in substance outcomes in the longitudinal portion of the study. Estimated intelligence was assessed using the Wechsler Abbreviated Scale of Intelligence [WASI; Psychological Corporation, 1999]. Family socioeconomic status was measured using the Four Factor Index of Socioeconomic Status [FFISS; Hollingshead, 1975]. Psychiatric symptoms and diagnoses were assessed using the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version [K-SADS-PL; Kaufman et al., 1997] administered by trained research assistants and reviewed by a staff psychiatrist board-certified in child and adolescent psychiatry. Externalizing and internalizing symptoms for all participants were assessed from parent or guardian reports on the Child Behavior Checklist [Achenbach, 2001]. Exclusion criteria included: regular substance use [defined as substance use at least once per month for 6 consecutive months; Clark et al., 2005], positive breath alcohol or urine drug test at time of screening, low IQ (

Combining diffusion tensor imaging and magnetic resonance spectroscopy to study reduced frontal white matter integrity in youths with family histories of substance use disorders.

Individuals with a family history of substance use disorder (FH+) show impaired frontal white matter as indicated by diffusion tensor imaging (DTI). T...
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