Ignore the glitch but mind the switch: Positive effects of methylphenidate on cognition in attention deficit hyperactivity disorder are related to prediction gain.

Neuropsychological symptoms such as inattention and distractibility constitute a core characteristic of attention deficit hyperactivity disorder (ADHD). Here, we tested the hypothesis that attentional dysfunctions result from a deficit in neural gain modulation, which translates into difficulty in predictively weighting relevant sensory input while ignoring distraction. We compared thirty-seven hitherto untreated adults diagnosed with ADHD and thirty-eight healthy participants with a serial switch-drift task that requires internal models of predictable digit sequences to be either updated or stabilized. Switches between sequences that had to be indicated by key presses and digit omissions within a sequence (drifts) that should be ignored varied by stimulus-bound surprise quantified as Shannon information. To investigate whether catecholaminergic modulation by increasing extracellular norepinephrine and dopamine levels leads to an amelioration in prediction gain, participants were tested twice, with patients receiving a single dose of methylphenidate, a norepinephrine/dopamine reuptake inhibitor, in the second session. Patients and controls differed in both updating and stabilizing, depending on the respective event surprise. Specifically, patients showed difficulty in detecting expectable switches, while having greater difficulty to ignore surprising distractions. Thus, underconfident prior beliefs in ADHD may fail to appropriately weight expected relevant input, whereas the gain of neural responses to unexpected irrelevant distractors is increased. Methylphenidate improved both flexibility and stability of prediction and had a positive effect on selective responding over time. Our results suggest that ADHD is associated with an impairment in the use of prior expectations to optimally weight sensory inputs, which is improved by increasing catecholaminergic neurotransmission.