Attenuated Neural Processing of Risk in Young Adults at Risk for Stimulant Dependence

Abstract

Objective: Approximately 10% of young adults report non-medical use of stimulants (cocaine, amphetamine, methylphenidate), which puts them at risk for the development of dependence. This fMRI study investigates whether subjects at early stages of stimulant use show altered decision making processing.

Methods: 158 occasional stimulants users (OSU) and 50 comparison subjects (CS) performed a "risky gains" decision making task during which they could select safe options (cash in 20 cents) or gamble them for double or nothing in two consecutive gambles (win or lose 40 or 80 cents, "risky decisions"). The primary analysis focused on risky versus safe decisions. Three secondary analyses were conducted: First, a robust regression examined the effect of lifetime exposure to stimulants and marijuana; second, subgroups of OSU with >1000 (n = 42), or <50 lifetime marijuana uses (n = 32), were compared to CS with <50 lifetime uses (n = 46) to examine potential marijuana effects; third, brain activation associated with behavioral adjustment following monetary losses was probed.

Results: There were no behavioral differences between groups. OSU showed attenuated activation across risky and safe decisions in prefrontal cortex, insula, and dorsal striatum, exhibited lower anterior cingulate cortex (ACC) and dorsal striatum activation for risky decisions and greater inferior frontal gyrus activation for safe decisions. Those OSU with relatively more stimulant use showed greater dorsal ACC and posterior insula attenuation. In comparison, greater lifetime marijuana use was associated with less neural differentiation between risky and safe decisions. OSU who chose more safe responses after losses exhibited similarities with CS relative to those preferring risky options.

Discussion: Individuals at risk for the development of stimulant use disorders presented less differentiated neural processing of risky and safe options. Specifically, OSU show attenuated brain response in regions critical for performance monitoring, reward processing and interoceptive awareness. Marijuana had additive effects by diminishing neural risk differentiation.

Fig 1. Risky Gains Task.

In two subsequent gambles on 96 trials, subjects could gamble the safe option (cash in 20 cents) for double or nothing, to gain 40 or, in the potential second gamble, 80 cents (“risky” decisions). Positive values needed to be collected within their respective 1sec presentation window. 54 trials were predefined as rewarded (+20, +40, +80), 24 as punished 40 trials (-40) and 18 as punished 80 (-80) trials. Overall totals were displayed on top after a given trial, so that subjects could monitor their performance and monetary wins and losses. Decision phase regressors for fMRI analysis were defined as lasting from the onset of the trial until the subject had made a response, or, in the case of a response latency greater than 1sec, until the subject was presented with a negative value. The baseline regressor encompassed the time to initiation of the trial and the time after presenting the outcome, and also included the null trials that are interspersed.

Fig 2. Occasional stimulant users (OSU) show an attenuated left anterior insula and right dorsolateral prefrontal (DLPFC) activation during risky and safe decision making.

LME analysis results, group main effect (n = 208). Cluster significance of p < .05 corrected for multiple comparisons (voxel-wise probability: p < .05). R indicates right; error bars represent standard errors; CS = comparison subjects.

Fig 3. Occasional stimulant users (OSU) present lower subgenual anterior cingulate cortex (sgACC) recruitment during risky decisions and less deactivation of inferior frontal gyrus to safe decisions than comparison subjects (CS).

LME analysis results, group by decision (risky vs. safe) interaction (n = 208). Cluster significance of p < .05 corrected for multiple comparisons (voxel-wise probability: p < .05). R indicates right, error bars represent standard errors, asterisk = sign. at p = 0.05.

Fig 4. Huber robust regression with lifetime substance use in occasional stimulant users (n = 158).

Stimulant users with relatively greater lifetime stimulant uses show a diminished recruitment of anterior cingulate. Risky vs. safe decisions, cluster significance of p < .05 corrected for multiple comparisons (voxel-wise probability: p < .05).

Fig 5. Effects of co-use of marijuana.

Occasional stimulant users with relatively high numbers of lifetime co-use of marijuana (High THC OSU) are characterized by (A) a weaker relative deactivation of the right anterior insula to risky and safe decisions (main effect of subgroup,) and (B) a weaker neural differentiation of risky and safe decisions in the dorsal striatum compared to Low THC OSU driven by an absent relative decrease of activation during safe decisions (interaction subgroup by decision), n = 120. Cluster significance of p < .05 corrected for multiple comparisons (voxel-wise probability: p < .05). R indicates right, error bars represent standard errors, asterisk = sign. at p = 0.05.