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

Abstract

Individuals with a family history of substance use disorder (FH+) 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 FH+ and 34 FH− youths (12.9 ±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 FH+ youths had lower FA (P <0.0001) and NAA (P =0.017) and higher tCho (P =0.04). FH density (number of parents and grandparents with substance use disorders) was negatively correlated with FA (P <0.0001) and NAA (P =0.011) and positively correlated with tCho (P =0.001). FA was independently predicted by both FH density (P =0.006) and NAA (P= 0.002), and NAA and tCho were both independent predictors of FH density (P <0.001). Our finding of lower frontal FA in FH+ youths corresponding to lower NAA and increased tCho is consistent with delayed or impaired development of frontal white matter in FH+ youths. Longitudinal studies are needed to determine how these differences relate to substance use outcomes.

Increased Forebrain Activations in Youths with Family Histories of Alcohol and Other Substance Use Disorders Performing a Go/NoGo Task

“…Overall, our findings suggest that global activation increases in FH+ youths are modulated by FH density and not specific to the inhibitory components of the task. This pattern of increased activations in FH+ youths may be at least partially due to impaired forebrain white matter development (Herting et al, 2010, Acheson et al, 2014b, Acheson et al, 2014a) leading to greater activations as a result of less efficient neural communication during task performance.…”

“…The increased forebrain activations in FH+ youths may be due at least in part to their impaired forebrain white matter integrity (Herting et al, 2010, Acheson et al, 2014b, Acheson et al, 2014a) as decreased forebrain white matter integrity has previously been associated with increased forebrain activations during task performance and is thought to indicate increased energy required due to poorer insulation of axonal tracts resulting in decreased neural efficiency (Burzynska et al, 2013, Zhu et al, 2013). Specifically, improved white matter integrity increases the efficiency of neuronal firing by reducing ion leak through axonal membranes and shifting some of the metabolic burden of action potential propagation from neurons to oligodendrocytes and other glial cells by facilitating saltatory conduction.…”

“…We have previously reported that these FH+ youths have impaired white matter integrity (Acheson et al, 2014a, Acheson et al, 2014b). We used a block design go/no go task and examined effects of FH status on activations in blocks with only go trials, blocks with 50% go and 50% no go trials, and a contrast of those 2 conditions.…”

“…This risk is thought to be driven by behavioral and cognitive characteristics of “behavioral undercontrol” or “neurobehavioral disinhibition” consisting of increased sensation seeking and antisocial behaviors as well as deficits in executive functioning, impulse control, decision making, and attention (e.g., Stevens et al, 2003, Deckel, 1999, Corral et al, 2003, Acheson et al, 2011a, Acheson et al, 2011b, Lovallo et al, 2006, Tarter et al, 2003, Sher et al, 2004, Sher and Trull, 1994). Further, this increased risk may be at least partially driven by impaired or altered development of forebrain circuitry as FH+ youths and young adults appear to have impaired frontal white matter development (Herting et al, 2010, Acheson et al, 2014b, Acheson et al, 2014a) and show evidence of altered forebrain activity at both rest and while performing cognitive tasks (e.g., Schweinsburg et al, 2004, Acheson et al, 2009, Silveri et al, 2011, Heitzeg et al, 2010, Cservenka et al, 2012, Spadoni et al, 2008). However, it is not fully understood how forebrain activity is altered in FH+ individuals and ultimately how these alterations may contribute to substance use disorder risk.…”

“…While interesting and important, these studies did not compare overall activations in FH+ and FH− individuals across all task conditions while performing the task. Given that reduced cerebral myelination is associated with increased BOLD activations (Burzynska et al, 2013, Zhu et al, 2013), FH+ youths may be expected to show increased forebrain activations generally while performing go/no go tasks since they appear to have forebrain white matter impairments (Herting et al, 2010, Acheson et al, 2014b, Acheson et al, 2014a). This is an important distinction as it would suggest more basic differences in FH+ individuals such as more globally decreased forebrain neural efficiency in FH+ individuals rather than differences limited to inhibitory circuitry functioning.…”