In for a penny, in for a pound: methylphenidate reduces the inhibitory effect of high stakes on persistent risky choice

Methylphenidate (MPH) is a stimulant that increases extracellular levels of dopamine and noradrenaline. It can diminish risky decision-making tendencies in certain clinical populations. MPH is also used, without license, by healthy adults, but the impact on their decision-making is not well established. Previous work has found that dopamine receptor activity of healthy adults can modulate the influence of stake magnitude on decisions to persistently gamble after incurring a loss. In this study, we tested for modulation of this effect by MPH in 40 healthy human adults. In a double-blind experiment, 20 subjects received 20 mg of MPH, while 20 matched controls received a placebo. All were provided with 30 rounds of opportunities to accept an incurred loss from their assets or opt for a "double-or-nothing" gamble that would either avoid or double it. Rounds began with a variable loss that would double with every failed gamble until it was accepted, recovered, or reached a specified maximum. Probability of recovery on any gamble was low and ambiguous. Subjects receiving placebo gambled less as the magnitude of the stake was raised and as the magnitude of accumulated loss escalated over the course of the task. In contrast, subjects treated with MPH gambled at a consistent rate, well above chance, across all stakes and trials. Trait reward responsiveness also reduced the impact of high stakes. The findings suggest that elevated catecholamine activity by MPH can disrupt inhibitory influences on persistent risky choice in healthy adults

Modulation of social influence by methylphenidate

The ability to infer value from the reactions of other people is a common and essential ability with a poorly understood neurobiology. Commonly, social learning matches one's values and behavior to what is perceived as normal for one's social group. This is known as conformity. Conformity of value correlates with neural activity shared by cognitions that depend on optimum catecholamine levels, but catecholamine involvement in conformity has not been tested empirically. Methylphenidate (MPH) is an indirect dopamine and noradrenalin agonist, commonly used for the treatment of attention-deficit hyperactivity disorder for which it reduces undesirable behavior as evaluated by peers and authority figures, indicative of increased conformity. We hypothesized that MPH might increase conformity of value. In all, 38 healthy adult females received either a single oral 20 mg dose of MPH or placebo (PL). Each subject rated 153 faces for trustworthiness followed immediately by the face's mean rating from a group of peers. After 30 min and a 2-back continuous-performance working-memory task, subjects were unexpectedly asked to rate all the faces again. Both the groups tended to change their ratings towards the social norm. The MPH group exhibited twice the conformity effect of the PL group following moderate social conflict, but this did not occur following large conflicts. This suggests that MPH might enhance signals that would otherwise be too weak to evoke conformity. MPH did not affect 2-back performance. We provide a new working hypothesis of a neurocognitive mechanism by which MPH reduces socially disruptive behavior. We also provide novel evidence of catecholamine mediation of social learning [corrected]

Imaging acetylcholinesterase density in peripheral organs in Parkinson's disease with ¹¹C-donepezil PET

Parkinson's disease is associated with early parasympathetic dysfunction leading to constipation and gastroparesis. It has been suggested that pathological α-synuclein aggregations originate in the gut and ascend to the brainstem via the vagus. Our understanding of the pathogenesis and time course of parasympathetic denervation in Parkinson's disease is limited and would benefit from a validated imaging technique to visualize the integrity of parasympathetic function. The positron emission tomography tracer 5-[(11)C]-methoxy-donepezil was recently validated for imaging acetylcholinesterase density in the brain and peripheral organs. Donepezil is a high-affinity ligand for acetylcholinesterase—the enzyme that catabolizes acetylcholine in cholinergic synapses. Acetylcholinesterase histology has been used for many years for visualizing cholinergic neurons. Using 5-[(11)C]-methoxy-donepezil positron emission tomography, we studied 12 patients with early-to-moderate Parkinson's disease (three female; age 64 ± 9 years) and 12 age-matched control subjects (three female; age 62 ± 8 years). We collected clinical information about motor severity, constipation, gastroparesis, and other parameters. Heart rate variability measurements and gastric emptying scintigraphies were performed in all subjects to obtain objective measures of parasympathetic function. We detected significantly decreased (11)C-donepezil binding in the small intestine (−35%; P = 0.003) and pancreas (−22%; P = 0.001) of the patients. No correlations were found between the (11)C-donepezil signal and disease duration, severity of constipation, gastric emptying time, and heart rate variability. In Parkinson's disease, the dorsal motor nucleus of the vagus undergoes severe degeneration and pathological α-synuclein aggregations are also seen in nerve fibres innervating the gastro-intestinal tract. In contrast, the enteric nervous system displays little or no loss of cholinergic neurons. Decreases in (11)C-donepezil binding may, therefore, represent a marker of parasympathetic denervation of internal organs, but further validation studies are needed