Elsevier

Drug and Alcohol Dependence

Volume 149, 1 April 2015, Pages 40-48
Drug and Alcohol Dependence

Resting-state regional cerebral blood flow during adolescence: Associations with initiation of substance use and prediction of future use disorders

https://doi.org/10.1016/j.drugalcdep.2015.01.012Get rights and content

Highlights

  • Adolescents who are using or will use alcohol have decreased blood flow to parietal cortex and increased blood flow to mesolimbic cortex, even 3 years prior to beginning to use.

  • Regional cerebral blood flow (rCBF) to mesolimbic and parietal cortex predicted these adolescents’ future drinking patterns and future onset of alcohol and substance use disorders.

  • Variation in resting rCBF to reward and control networks represent trait markers for future risk to use alcohol and to develop use disorders.

Abstract

Background

Adolescence is a period of developmental flux when brain systems are vulnerable to influences of early substance use, which in turn relays increased risk for substance use disorders. Our study intent was to assess adolescent regional cerebral blood flow (rCBF) as it relates to current and future alcohol use. The aim was to identify brain-based predictors for initiation of alcohol use and onset of future substance use disorders.

Methods

Quantitative rCBF was assessed in 100 adolescents (age 12–15). Prospective behavioral assessments were conducted annually over a three-year follow-up period to characterize onset of alcohol initiation, future drinking patterns and use disorders. Comparisons amongst use groups (i.e., current-, future-, and non-alcohol using adolescents) identified rCBF associated with initiation of alcohol use. Regression by future drinking patterns identified rCBF predictive of heavier drinking. Survival analysis determined whether or not baseline rCBF predicted later development of use disorders.

Results

Baseline rCBF was decreased to the parietal cortex and increased to mesolimbic regions in adolescents currently using alcohol as well as those who would use alcohol in the future. Higher baseline rCBF to the left fusiform gyrus and lower rCBF to the right inferior parietal cortex and left cerebellum was associated with future drinking patterns as well as predicted the onset of alcohol and substance use disorders in this cohort.

Conclusions

Variations in resting rCBF to regions within reward and default mode or control networks appear to represent trait markers of alcohol use initiation and are predictive of future development of use disorders.

Introduction

Adolescence is a period of developmental change marked by significant brain maturation and vulnerability of the brain to influences of environmental factors and exposure to substances (Grant et al., 2005). The latter is particularly relevant for adolescents with 9–15% meeting criteria for substance abuse and 5% for substance dependence (period prevalence, National Survey on Drug Use and Health for 2002–2008). These data underscore this adolescent public health problem given the potentially toxic effects of substances on brain development (Guerri and Pascual, 2010).

Most neuroimaging studies have investigated brain function in chronic use among adults (Bjork et al., 2008). The few studies focusing on younger populations have involved adolescents already using substances (Jacobus et al., 2012, Squeglia et al., 2014b). Imaging studies of familial risk for alcoholism in adolescents have focused on brain structure (e.g., Squeglia et al., 2015) and function (Cservenka et al., 2013, Wetherill et al., 2012) in fronto-parietal networks and reward circuitry. These studies indicate susceptibility to ethanol-related brain damage, largely localized in the gray matter of the hippocampus and prefrontal cortex (Squeglia et al., 2014b), as well as reduction in white matter integrity (cf., De Bellis et al., 2008, Squeglia et al., 2014a). However, because these differences co-occurred with use, they cannot clarify whether effects are present prior to use disorder onset, or are the result of use. Recent prospective studies have identified smaller gray matter volume in left paralimbic cingulate, inferior frontal and right cerebellum (Cheetham et al., 2014, Squeglia et al., 2014c) and differences in task-related fronto-parietal activity (Squeglia et al., 2012), proposing these as brain-based risk markers for future substance use.

Neuroimaging metrics that track resting-state, regional cerebral blood flow (rCBF) can provide unique information about the developing brain. rCBF measured with Arterial Spin Labeled (ASL) MRI is useful in characterizing tonic neural activity, allowing for inference to maturation given the need for blood flow to support processes like neuronal proliferation and pruning (Uhlhaas et al., 2010). Until the fairly recent advent of ASL MRI methods, rCBF has not been readily assessed in adolescents because previous methods required radioactive exposure; therefore there is a dearth of information about rCBF in adolescence.

There are few ASL MRI prospective studies of brain development (e.g., De Vis et al., 2013 in neonates), but rCBF can be inferred via studies using functional MRI (fMRI), which assesses blood flow fluctuations and their coherence amongst functionally related regions (i.e., functional connectivity). The correlation between blood flow measured with ASL MRI or as functional connectivity is spatially heterogeneous (Khalili-Mahani et al., 2014), but the following fMRI studies are presented as a proxy to understanding rCBF in adolescence. For example, functional connectivity is altered (Gordon et al., 2010, Lorenz et al., 2014, Sherman et al., 2014) and more diffuse (Jolles et al., 2011, Sherman et al., 2014) in adolescents than in young adults. Development of functional connectivity tends to follow a short-to-long distance trajectory (Fair et al., 2008) and the relationships between different networks (e.g., default mode and cognitive control) become distinct (Bray et al., 2015, Sherman et al., 2014). Maturation of connectivity patterns occurs throughout adolescence (Dosenbach et al., 2008) and into young adulthood, changing again in late adulthood (Lorenz et al., 2014), highlighting the sensitivity of blood flow and functional connectivity to age-related changes in brain structure and function. Importantly, functional connectivity patterns in adolescence can predict impulsivity scores (Shannon et al., 2011), working memory performance (Lorenz et al., 2014), and intelligence (Sherman et al., 2014) suggesting that maturation, supported by alterations in blood flow, can mark personality, mood, and other individualistic pieces of an adolescent's adult brain.

Quantitative measures of rCBF show alcohol-related shifts providing a basis for understanding the physiology of regions affected by alcohol exposure. For example, increased global perfusion is seen with acute alcohol administration, is greater in females than males (Marxen et al., 2014), and is particularly elevated in the cingulate, frontal and parietal cortex and the hippocampi (Khalili-Mahani et al., 2011, Strang et al., 2014, Tolentino et al., 2011). Among chronic alcohol abusers, there is persistent reduced blood flow and atrophy in these same regions (Suzuki et al., 2010). These data demonstrate sensitivity of certain regions to alcohol, but it is unclear how they are affected in early experimentation or continued use in adolescence.

Early initiation of alcohol use is associated with higher risk to develop alcohol use disorders (Behrendt et al., 2009, Grant et al., 2005), suggesting that traits may exist that predispose one to substance experimentation or sensitivity to exposure. This population is of particular interest because, although alcohol abuse and dependence is rare in adolescence, the population prevalence of these disorders jumps to 6% by late adolescence (Cohen et al., 1993, Rohde et al., 1996), particularly when they are comorbid with mood, stress-related or behavioral disorders (Aseltine et al., 1998, Clark et al., 1998), which also increase in prevalence during adolescence (Birmaher et al., 1996). Alcohol tends to be the substance most available and used by adolescents (Kirby and Barry, 2012), and its initiation is often followed by experimentation with other substances.

The hypotheses underlying this study are driven by fMRI findings of altered frontal and parietal function in substance-naïve offspring of alcoholics (Hanson et al., 2011, Wetherill et al., 2012) and altered reward network activity with chronic alcohol use and addiction (Haber and Knutson, 2010, Suzuki et al., 2010). Our primary hypothesis is that the developing brain will show altered rCBF to frontal, parietal and mesolimbic regions associated with initiation of alcohol use in adolescents who are currently using, or will initiate use, relative to those who remain alcohol naïve. A related hypothesis is that these findings will relate to future drinking patterns as neural predictors of heavier drinking. A secondary hypothesis is that baseline rCBF to some, if not all of these regions, will have prognostic significance to predict alcohol initiation and future alcohol use disorders in a cohort of adolescents who are just beginning to initiate alcohol use.

Section snippets

Subjects

Three hundred thirty-two adolescents were recruited into the Teen Alcohol Outcomes Study (TAOS; Williamson: R01AA016274) via commercial phone lists containing families living within a 30-mile radius of the University of Texas Health Science Center at San Antonio (UTHSCA). Healthy adolescents, without dental appliances, and their parent/guardian completed self-report assessments and diagnostic interviews. All subjects assented to participate and their parent/guardian provided informed consent

Demographic and behavioral correlates of alcohol use

One hundred TAOS participants met criteria for study and had ASL MRI images at baseline. This nested cohort was slightly older (TAOS: 14.3 years of age, nested cohort: 13.7 years of age; t[329] = −3.52, p < 0.0001), but demonstrated the same gender and ethnicity distributions (gender: χ2df = 1 = 0.47, p = 0.49; ethnicity: χ2df = 3 = 1.82, p = 0.61) as the larger group.

The use groups did not differ for demographic or behavioral measures. Current Users demonstrated more self-reported depressive symptoms and

Discussion

We sought to determine: (1) whether adolescents who are, or will be, drinking alcohol demonstrate altered rCBF in fronto-parietal or reward centers of the brain, (2) whether baseline rCBF marks heavier rates of future drinking, and (3) whether these rCBF markers associated with early drinking behavior predict future alcohol or substance use disorders. The analyses to address these goals were controlled for the effects of mood, stress and behavior, factors also associated with onset of substance

Author disclosures

Role of funding source

This work was funded in part by grants from the National Institute on Alcohol Abuse and Alcoholism to Drs. Williamson (R01AA016274) and Ramage (R03AA020823-01).

Contributors

All authors were involved in the drafting and editing of this manuscript. Drs. Williamson and Olvera oversaw data collection and quality assurance. Drs. Williamson and Ramage were involved in the conception of this study and the analysis of the behavioral/questionnaire and imaging data. Dr. Lin conducted the conversion of raw ASL MRI data to quantitative blood flow counts. Dr. Ramage oversaw all aspects of this study and is responsible for the drafting and editing of the majority of the

Conflict of interest

Drs. Ramage, Lin, Olvera and Williamson have no financial disclosures. Dr. Fox has received funding from the following sources over the past two years: equity interest in Cerebral Magnetics, LLC and msMRI, LLC. In addition, he receives royalties from Wiley-Blackwell for serving as the Editor-in-Chief of Human Brain Mapping.

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