Dietary tyrosine/phenylalanine depletion effects on behavioral and brain signatures of human motivational processing

Abstract

Dopamine (DA) neurotransmission is critical for motivational processing. We assessed whether disruption of DA synthesis in healthy controls using an amino-acid beverage devoid of catecholamine precursors (tyrosine-phenylalanine depletion (TPD)) would blunt recruitment of the nucleus accumbens (NAcc) by rewards. Sixteen controls ingested each of a tyr/phe-depleting beverage (DEP) or a tyr/phe-balanced (BAL) control beverage in two laboratory visits. Five hours after consumption of each drink, subjects underwent functional magnetic resonance imaging while they viewed anticipatory cues to respond to a target to either win money or avoid losing money. TPD did not exert main effects on mood or on task behavior, but affected brain activation. In right NAcc, TPD blunted activation by anticipation of high rewards. In left NAcc, recruitment anticipating high rewards was modulated by individual differences in mood change across the DEP drink day, where subjects whose mood worsened following TPD (relative to within-day mood change under BAL conditions) also showed lower activation under DEP conditions relative to BAL conditions. Exploratory analysis indicated that TPD qualitatively blunted the voxel-wise spatial extent of suprathreshold activation by reward anticipation. Finally, loss outcomes activated anterior insula under DEP conditions but not under BAL conditions. These data indicate that: (1) dietary depletion of catacholamine precursors will blunt dopaminergic mesolimbic activity, and (2) in controls, synthetic pathways of this neurocircuitry maintain sufficient buffering capacity to resist an effect on motivated behavior. Additional studies are needed to determine if clinical populations would show similar resistance to behavioral effects of TPD.

Figure 1

Monetary incentive delay (MID) task. In each trial, subjects were initially presented with one of four anticipatory cues followed by a fixation crosshair for 1.75–6 s, and a target followed by a post-target fixation crosshair for ∼2–6 s. Subjects were required to respond during target presentation (‘hit') to either win money, avoid losing money, or for no consequence. In single-response trials, subjects next viewed notification of whether or not the target was hit, followed by a 2–6 s intertrial interval with fixation crosshair. In double-response trials (one-third of each of win $0, win 50¢, and win $5 magnitudes), trial outcome notifications were pseudorandomly replaced with the word ‘Again!' This notified the subject that he or she must repeat the trial to obtain its outcome. The ‘Again!' notification was followed by: a 2–6 s fixation crosshair, re-presentation of the same incentive cue, jittered (1.75–6 s) postcue fixation, target presentation of the same duration as the trial's initial target, followed by ∼2–6 s fixation crosshair, and final outcome notification. In double-response trials, hits on both targets were required for trial success.

Figure 2

Effects of tyrosine–phenylalanine depletion (TPD) on free plasma amino-acid concentrations, mood, and task behavior. Acute TPD (tyr/phe-depleting beverage (DEP) beverage), but not the balanced-concentration (BAL) beverage resulted in a substantial reduction in the ratio of catecholamine precursor Tyr relative to competing large neutral amino acids (LNAA) in the plasma obtained 5 h after amino-acid beverage consumption (a). TPD had no effect, however, on Total Mood Disturbance as self-reported on the Profile of Mood States (POMS) (b). Target hit rates on the monetary incentive delay (MID) task (excluding second responses of double-response trials) varied as a function of the incentive at stake in the trial (c), where these differences in hit rates resulted from significant differences in reaction times to targets under different incentive conditions (d). *** denotes mixture × time interaction effect at P<0.0001.

Figure 3

Anticipation cue-elicited signal change in the nucleus accumbens (NAcc) volume of interest (VOI). In a VOI drawn in the NAcc bilaterally (Talairach±10+10−4; inset) modeled peak anticipatory blood oxygen level-dependent (BOLD) signal change reflected the prospective incentive value of hitting the target in both right (a) and left (b) Nacc. Notably, a significant attempt × magnitude interaction effect indicated that this magnitude sensitivity of the NAcc responses was specific to initial/only attempt to hit the target, but not in second (repeat) responses to hit in the double-response trials. Across both sides of the NAcc, a significant mixture × magnitude interaction effect suggested reduced reward-magnitude sensitivity under tyr/phe-depleting beverage (DEP) conditions compared with balanced (BAL) conditions. The net change (increase) in total mood disturbance across the day following tyrosine/phenylalanine depletion (TPD) relative to change under BAL conditions correlated with the net blunting of activation by high reward anticipation under DEP conditions relative to BAL conditions in left NAcc (d) but not right NAcc (c). * denotes mixture-wise P<0.10, **P<0.05.

Figure 4

Statistical maps of activation by anticipation of potential rewards and losses. Anticipation of responding for rewards (50¢, $5) contrasted with anticipation of responding for no incentive activated bilateral ventral striatum under balanced (BAL) (a) and tyr/phe-depleting beverage (DEP) (b) amino-acid conditions. Anticipation of responding to avoid losses ($5) contrasted with anticipation of responding for no incentive also activated bilateral dorsal striatum in both BAL (c) and DEP (d) conditions. There were no voxel-wise amino-acid mixture differences in anticipatory activation for either potential rewards or losses. Statistical maps are right–left reversed per radiological convention, and anatomical underlays are derived from a T1-wieghted scan of a representative subject at the planar Talairach coordinate shown. Color overlays depict uncorrected voxel-wise P statistics, where illuminated voxels or voxel clusters survive false discovery rate correction.

Figure 5

Statistical maps of activation by notification of rewards, by demands to repeat trial, and by notification of losses. Notification of rewards (50¢, $5) contrasted with notification of failure to win reward activated a focal region of vmFC under both balanced (BAL) (a) and tyr/phe-depleting beverage (DEP) (b) conditions. Notification of losses ($5) contrasted with notification of avoided losses did not activate any region above threshold under BAL conditions (c), but activated left anterior insula in under DEP conditions (d). Replacement of outcome notification with the demand to repeat the trial effort (‘Again!') in reward trials (50¢, $5) contrasted with notification of non-wins in single-response reward trials activated inferior occipital and middle frontal cortex under both BAL (e) and DEP (f) conditions, with an additional suprathreshold deactivation of left ventral striatum (VS) under BAL conditions. vmFC, ventromesial frontal cortex.