Adolescent substance use and functional connectivity between the ventral striatum and hippocampus

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Highlights

  • Connections between the ventral striatum (VS) and hippocampus guide reward behavior.

  • VS-hippocampal connectivity has been shown to be higher in adolescents vs. adults.

  • Higher VS-hippocampal connectivity predicts greater substance use in adolescents.

  • Longitudinal results confirmed in a large publicly available dataset (NCANDA).

  • Adolescent substance use may relate to stronger reinforcement learning-memory link.

Abstract

Neurodevelopmental explanations for adolescent substance use have focused on heightened sensitivity of mesolimbic circuitry, centered on the ventral striatum (VS). Recent evidence suggests that, relative to adults, adolescents show a stronger link between reinforcement learning and episodic memory for rewarding outcomes and greater functional connectivity between the VS and hippocampus, which may reflect a heightened reward modulation of memory. However, a link between VS-hippocampal circuitry and adolescent substance use has yet to be established. Two separate studies were conducted to evaluate whether variation in VS-hippocampal resting-state functional connectivity (rs-FC) predicts subsequent adolescent substance use exposure. A pilot study (Study 1) was conducted in 19 youth recruited from a high sociodemographic risk population (N = 19; mean age = 13.3 SD = 1.4; 14 females; 47% Black Non-Hispanic, 32% White Non-Hispanic). To replicate results of Study 1, Study 2 utilized data from the National Consortium on Adolescent Neurodevelopment and Alcohol (N = 644; mean age = 16.3 SD = 2.5; 339 females; 11% Black Non-Hispanic, 11% Hispanic/Latino, 66% White Non-Hispanic). Resting-state fMRI data were collected at a baseline time point and lifetime and past year self-reported substance use was collected at a follow up visit. Regression models tested whether baseline VS-hippocampal rs-FC predicted substance use exposure at follow up, as measured by an index score reflecting the number of substance classes (e.g., alcohol, marijuana) tried and overall frequency of use. Across both studies, higher VS-hippocampal rs-FC at baseline predicted greater substance use exposure at follow up (pFWE < 0.05). These data provide the first evidence linking increased VS-hippocampal connectivity with greater adolescent substance use exposure. Results fit with the emerging idea that variation in adolescent substance use may relate to not only individual differences in mesolimbic sensitivity to reward, but also to an individuals’ memory sensitivity to reward as measured by connectivity between canonical memory and reward regions.

Introduction

Experimentation with alcohol, marijuana, and other substances is common among adolescents [1,2]. However, adolescent substance use is associated with increased risk of substance use disorders in adulthood, which have a lifetime prevalence of approximately 10% in the US [3]. Adolescent substance use has also been linked to later cognitive problems (e.g., learning, memory, attention), which may relate to changes in adolescent brain structure and function [4,5]. Adolescent substance use tends to co-occur with engagement in other health risk behaviors, including sexual activity, violent behavior, and reckless driving [6]. Together, the consequences of substance use for a substantial number of adolescents are severe, including lifelong health problems and accidents and unintentional injuries, which represent the leading cause of death among young people ages 10–24 in the US [7]. The enormous public health costs of adolescent substance use [8,9] have motivated research into the underlying neurobiological mechanisms, and to identifying early patterns that predict subsequent engagement or escalation of use.

A propensity for substance use and other risk-taking behavior during adolescence is thought to arise from heightened sensitivity of mesolimbic reward circuitry [10,11]. Prior neuroimaging studies indicate that key areas of mesolimbic circuitry, particularly the ventral striatum (VS), are more responsive to incentive-based stimuli (e.g., peer approval) in adolescents relative to both adults and children [12,13]. The VS plays a central role in reward-seeking behavior and learning, and is a key target of dopaminergic projections from midbrain regions such as the ventral tegmental area (VTA) [14]. Given that mesolimbic dopaminergic systems are involved in reward-seeking and incentive motivation [15,16], heightened VS reactivity during adolescence is thought to convey an increased sensitivity to positive outcomes, even if the behavior is risky [17]. In line with this notion, higher VS reactivity has been shown to correspond with more risky decisions during risk taking paradigms [18,19] and with adolescent substance use [20].

Recent evidence suggests that it is not only a heightened neural sensitivity to rewarding outcomes that drives risk-taking behavior during adolescence, but also an increased ability for reward to modulate long-term memory [21]. Indeed, Davidow and colleagues [22] demonstrated that, relative to adults, adolescents show better reinforcement learning and a stronger link between reinforcement learning and episodic memory for rewarding outcomes. This behavioral effect was associated with increased prediction error-related activity in the hippocampus and stronger functional connectivity (FC) between the striatum and the hippocampus during reward learning, which may reflect enhanced reward modulation of long-term memory [22]. Together, the VS, hippocampus, and VTA form a critical reward-memory loop that signals the motivational significance of events and modulates episodic memory formation in the hippocampus [23,24]. Recent studies suggest that connections between the VS and hippocampus, in particular, are critical for predicting individual differences in reward modulation of memory [25]. A recent functional magnetic resonance imaging (fMRI) and lesion study suggests that, alongside the VS, the hippocampus is required for value-based learning [26]. VS-hippocampal circuitry has also been implicated in context-dependent decision making [27] and the formation and retrieval of drug-environment associations, in particular [28,29]. Therefore, during adolescence, a developmental period associated with an increase in substance experimentation and use, individual differences in mesolimbic circuitry may relate to a propensity for further exploration or escalation of use.

The present study was designed to test the hypothesis that increased FC between the VS and hippocampus predicts greater subsequent substance use exposure in adolescence. This hypothesis is based on the notion that youth who show greater VS-hippocampal FC may be sensitized to better learn from rewarding experiences and may therefore be more likely to subsequently apply this learning to new situations or contexts and engage in substance use [21,22]. We focus on VS-hippocampal FC in particular, given the fMRI study in adults linking VS-hippocampal (but not VTA-hippocampal) connectivity to individual differences in reward modulation of memory [25], and given that, relative to adults, adolescents show better reinforcement learning which is associated with higher VS-hippocampal FC [22]. However, we also test VTA-VS and VTA-hippocampal connectivity in follow up analyses. We examined mesolimbic interactions using resting-state FC (rs-FC), given that patterns of intrinsic connectivity derived using rs-FC have been shown to be relatively stable over time and tasks, and predict individual differences in cognition [30,31]. For example, rs-FC among the hippocampus, VS, and midbrain has been shown to vary across individuals [23], and VS-hippocampal rs-FC tracks variation in memory modulation by reward [25]. Our hypothesis was first tested using a pilot imaging study (Study 1) performed in a sample of youth at high sociodemographic risk for substance use and associated negative outcomes [32] (Detroit, Michigan, USA). We then performed an independent replication study using data collected in n = 644 US adolescents and young adults (Study 2) from a large, publicly available longitudinal dataset (National Consortium on Adolescent Neurodevelopment and Alcohol, NCANDA).

Section snippets

Material and methods

This report leverages two completely independent studies (Studies 1 and 2) to examine individual differences in mesolimbic rs-FC that predict subsequent substance use exposure during adolescence. All included participants had resting-state fMRI scans at time point 1 (T1) and returned for a subsequent substance use assessment during adolescence (time point 2, T2). Given that additional data were available for Study 2 (e.g., substance use exposure at T1), we performed several follow up analyses.

Substance use exposure is common across Study 1 and 2 samples

42% and 48% of participants in Study 1 and Study 2, respectively, endorsed lifetime exposure to at least one substance at T2, with alcohol, marijuana, and cigarettes being the most common (see Table 2 for summary of lifetime and past year use). Lifetime and past year substance use was highly interrelated across both studies (rs >0.9, ps < 0.001). Across both studies, older youth reported more substance use than younger youth (Study 1: r = 0.5, p = 0.03; Study 2: r = 0.45, p < 0.001; see Fig. 1B

Conclusions

A wealth of research indicates that reward can augment episodic memories and that variation in mesolimbic connectivity, particularly VS-hippocampal connectivity, tracks individual differences in reward modulation of memory [25]. Important recent work by Davidow and colleagues [22] demonstrated increased VS-hippocampal connectivity in adolescents relative to adults, which corresponded with stronger integration of reward-related reinforcement learning into long-term memory. These results provide

Funding

Research reported in this publication was supported, in part, by the Departments of Pharmacy Practice and Pediatrics, and the Merrill Palmer Skillman Institute of WSU. Dr. Rabinak is supported by NIH National Institute of Mental Health Grant R61 MH111935. Dr. Marusak is supported by NIH National Institute of Mental Health Grant K01 MH119241. Drs. Huntley and Keating are supported by the NIH Eunice Kennedy Shriver National Institute of Child and Human Development (R01 HD075806).

Declaration of competing interest

None.

CRediT authorship contribution statement

Edward D. Huntley: Conceptualization, Methodology, Validation, Formal analysis, Writing - original draft. Hilary A. Marusak: Conceptualization, Methodology, Validation, Formal analysis, Writing - original draft. Sarah E. Berman: Data curation, Writing - review & editing. Clara G. Zundel: Data curation, Writing - review & editing. Joshua R.B. Hatfield: Data curation, Writing - review & editing. Daniel P. Keating: Resources, Writing - review & editing. Christine A. Rabinak: Writing - review &

Acknowledgments

The authors would like to thank Craig Peters, Shelley Paulisin, Sajah Fakhoury, Allesandra Iadipaolo, Limi Sharif, Xhenis Brahimi, Farah Sheikh, Suzanne Brown, Ph.D., Laura M. Crespo, Ph.D., Kelsey Sala-Hamrick, Ph.D., Klaramari Gellci, Maria Tocco, Andrea Bedway, M.D., Angela Vila, Yashwanth Katkuri, M.S., Richard Genik, Ph.D., and Pavan Jella, M.S., of Wayne State University (WSU) for assistance in participant recruitment and data collection. Thank you also to the adolescents and families who

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