Neurocognitive Precursors of Substance Misuse Corresponding to Risk, Resistance, and Resilience Pathways: Implications for Prevention Science

Abstract

Studies of substance misuse prevention generally focus on characteristics that typify risk, with the assumption that the prevalence of the problem will be optimally reduced by identifying, targeting, and reducing or eliminating risk factors. However, this risk-centered approach neglects variations in individual-level and environmental characteristics that portend differential pathways that are distinguishable by timing of substance use initiation (e.g., early versus delayed), the likelihood of use escalation versus eventual desistance, and enduring abstinence, despite exposure to significant risk factors. Considering the various underpinnings of these distinct substance use trajectories is critical to a more nuanced understanding of the effects, potency, and malleability of factors that are known to increase risk or confer protection. Here, we discuss three pathways relative to substance use patterns and predictors in the context of adversity, a well-known, highly significant influence on propensity for substance misuse. The first pathway is designated as "high risk" based on early onset of substance use, rapid escalation, and proneness to substance use disorders. Individuals who defy all odds and eventually exhibit adaptive developmental outcomes despite an initial maladaptive reaction to adversity, are referred to as "resilient." However, another categorization that has not been adequately characterized is "resistant." Resistant individuals include those who do not exhibit problematic substance use behaviors (e.g., early onset and escalation) and do not develop substance use disorders or other forms of psychopathology, despite significant exposure to factors that normally increase the propensity for such outcomes (e.g. trauma and/or adversity). In this paper, we apply this conceptualization of risk, resistance, and resilience for substance misuse to a more fine-grained analysis of substance use pathways and their corresponding patterns (e.g., non-use, initiation, escalation, desistance). The significance of the progression of neurocognitive functioning over the course of development is discussed as well as how this knowledge may be translated to make a science-based determination of intervention targets. This more encompassing theoretical model has direct implications for primary prevention and clinical approaches to disrupt risk pathways and to optimize long-term outcomes.

Keywords: neurocognitive; neuroimaging; prevention science; resilience; resistance; risk; substance misuse/abuse.

Figure 1

The Accumulative Risk Model. Shown here are the two main categories of factors that constitute the accumulative developmental context, i.e., genetic and environmental factors. The combined effect of the number, type, and severity of these factors confers risk for substance abuse. Genetic variants are considered as switches, which are either “on” or “off.” This conceptualization reflects the common binary consideration of genetic risk (i.e., individuals are often considered at risk or not depending on the particular variant of a given gene that they happen to carry). To reflect their more continuous nature, environmental factors are presented as dials, turned up or down depending on the magnitude of the experience. The unique combination of genetic switches and environmental dials drives neurodevelopmental trajectories that underlie particular cognitive, behavioral, and affective intermediate phenotypes, which, in turn, can result in an increased liability threshold, beyond which an individual is considered to be at greater likelihood of developing problematic substance use behaviors and eventual SUD. Importantly, the functional relationship between factors is not linear, and some environmental factors may exacerbate or attenuate the effects of the particular genes via epigenetic modifications.

Figure 2

(a) Theoretical neurodevelopmental trajectories corresponding to adaptive and maladaptive outcomes. (1) Resistance: absence of change in the developmental trajectory despite exposure to adversity; (2) Resilience: initial reaction followed by gradual degradation of the response to adversity and eventual restoration of an adaptive developmental trajectory; (3) Delayed risk: apparent early resistance to adversity but eventual decline toward maladaptive outcomes/risk; (4) Risk: initial and continued reaction to adversity, resulting in maladaptive outcomes, and (5) Recovery: a shift in neurodevelopmental trajectory back toward adaptive outcomes, following disease onset/crossing the liability threshold for a disorder, and corresponding to intervention (i.e., treatment) onset. Critical time points in delineating those factors that contribute to risk or resistance and resilience include (A) the initial departure in neurodevelopmental trajectories, perhaps corresponding to adversity or other stressors, (B) the time point at which trajectories may deviate from initial direction (i.e. resilience and delayed risk), (C) the time beyond which specific risk outcomes (e.g., substance abuse) are highly probable and beyond which individuals with high levels of risk are likely to have crossed the liability threshold, and (D) intervention/treatment onset. Note: “outcomes” includes all relevant intermediate phenotypes consisting of or related to neurodevelopment (e.g., brain structure and function, cognition, behavior, affect, etc.). The “accumulative developmental context” refers to the combined genetic and environmental context that drives brain development (as depicted in Figure 1 ), and although this context is critical to neurodevelopment it precedes observable distinctions between neurodevelopmental trajectories; this includes those factors that may be considered to be detrimental or protective. (b) (i) Key stages in the cycle of addiction (after 22) and (ii) brain regions that these key stages map to and putative functions of each region that are relevant to the development of SUD. Included here are critical regions in which functional and structural deficits have been shown to be associated with at least one of the stages in the cycle of addiction. Functional variability in these regions in response to the characteristics of the accumulative developmental context (i.e., key genetic, environmental, and psychosocial influences on neurodevelopment) likely underlie the likelihood of which trajectory (i.e., from 2a.) an individual follows. If so, these same regions and the cognitive, behavioral, and affective functions they support have considerable potential to serve as targets for preventive interventions.