The relationship between implicit and explicit processes during motor learning, and for visuomotor adaptation in particular, is poorly understood. We set up a conflict between implicit and explicit processes by instructing subjects to counter a visuomotor rotation using a cognitive strategy in a pointing task. Specifically, they were told the exact nature of the directional perturbation, a rotation that directed them 45°counterclockwise from the desired target, and they were instructed to counter it by aiming for the neighboring clockwise target, 45°away. Subjects were initially successful in completely negating the rotation with this strategy. Surprisingly, however, they were unable to sustain explicit control and made increasingly large errors to the desired target. The cognitive strategy failed because subjects simultaneously adapted unconsciously to the rotation to the neighboring target. Notably, the rate of implicit adaptation to the neighboring target was not significantly different from rotation adaptation in the absence of an opposing explicit strategy. These results indicate that explicit strategies cannot substitute for implicit adaptation to a visuomotor rotation and are in fact overridden by the motor planning system. This suggests that the motor system requires that planned and executed trajectories remain congruous in visual space, and enforces this correspondence even at the expense of an opposing explicit task goal.

Although motor learning is likely to involve multiple processes, phenomena observed in error-based motor learning paradigms tend to be conceptualized in terms of only a single process – adaptation, which occurs through updating an internal model. Here we argue that fundamental phenomena like movement direction biases, savings (faster relearning) and interference do not relate to adaptation but instead are attributable to two additional learning processes that can be characterized as model-free: use-dependent plasticity and operant reinforcement. Although usually “hidden” behind adaptation, we demonstrate, with modified visuomotor rotation paradigms, that these distinct model-based and model-free processes combine to learn an error-based motor task: (1) Adaptation of an internal model channels movements toward successful error reduction in visual space. (2) Repetition of the newly adapted movement induces directional biases towards the repeated movement. (3) Operant reinforcement through association of the adapted movement with successful error reduction is responsible for savings.

People generally select a similar speed for a given motor task, such as reaching for a cup. One well established determinant of movement time is the speed-accuracy trade-off: movement time increases with the accuracy requirement. A second possible determinant is the energetic cost of making a movement. Parkinson's disease (PD), a condition characterized by generalized movement slowing (bradykinesia), provides the opportunity to directly explore this second possibility. We compared reaching movements of patients with PD with those of control subjects in a speed-accuracy trade-off task comprising conditions of increasing difficulty. Subjects completed as many trials as necessary to make 20 movements within a required speed range (trials to criterion, N c ). Difficulty was reflected in endpoint accuracy and N c . Patients were as accurate as control subjects in all conditions (i.e., PD did not affect the speed-accuracy trade-off). However, N c was consistently higher in patients, indicating reluctance to move fast although accuracy was not compromised. Specifically, the dependence of N c on movement energy cost (slope S N ) was steeper in patients than in control subjects. This difference in S N suggests that bradykinesia represents an implicit decision not to move fast because of a shift in the cost/benefit ratio of the energy expenditure needed to move at normal speed. S N was less steep, but statistically significant, in control subjects, which demonstrates a role for energetic cost in the normal control of movement speed. We propose that, analogous to the established role of dopamine in explicit reward-seeking behavior, the dopaminergic projection to the striatum provides a signal for implicit "motor motivation."

Glucocerebrosidase (GBA) mutations have been associated with Parkinson's disease in numerous studies. However, it is unknown whether the increased risk of Parkinson's disease in GBA carriers is due to a loss of glucocerebrosidase enzymatic activity. We measured glucocerebrosidase enzymatic activity in dried blood spots in patients with Parkinson's disease (n = 517) and controls (n = 252) with and without GBA mutations. Participants were recruited from Columbia University, New York, and fully sequenced for GBA mutations and genotyped for the LRRK2 G2019S mutation, the most common autosomal dominant mutation in the Ashkenazi Jewish population. Glucocerebrosidase enzymatic activity in dried blood spots was measured by a mass spectrometry-based assay and compared among participants categorized by GBA mutation status and Parkinson's disease diagnosis. Parkinson's disease patients were more likely than controls to carry the LRRK2 G2019S mutation (n = 39, 7.5% versus n = 2, 0.8%, P < 0.001) and GBA mutations or variants (seven homozygotes and compound heterozygotes and 81 heterozygotes, 17.0% versus 17 heterozygotes, 6.7%, P < 0.001). GBA homozygotes/compound heterozygotes had lower enzymatic activity than GBA heterozygotes (0.85 µmol/l/h versus 7.88 µmol/l/h, P < 0.001), and GBA heterozygotes had lower enzymatic activity than GBA and LRRK2 non-carriers (7.88 µmol/l/h versus 11.93 µmol/l/h, P < 0.001). Glucocerebrosidase activity was reduced in heterozygotes compared to non-carriers when each mutation was compared independently (N370S, P < 0.001; L444P, P < 0.001; 84GG, P = 0.003; R496H, P = 0.018) and also reduced in GBA variants associated with Parkinson's risk but not with Gaucher disease (E326K, P = 0.009; T369M, P < 0.001). When all patients with Parkinson's disease were considered, they had lower mean glucocerebrosidase enzymatic activity than controls (11.14 µmol/l/h versus 11.85 µmol/l/h, P = 0.011). Difference compared to controls persisted in patients with idiopathic Parkinson's disease (after exclusion of all GBA and LRRK2 carriers; 11.53 µmol/l/h, versus 12.11 µmol/l/h, P = 0.036) and after adjustment for age and gender (P = 0.012). Interestingly, LRRK2 G2019S carriers (n = 36), most of whom had Parkinson's disease, had higher enzymatic activity than non-carriers (13.69 µmol/l/h versus 11.93 µmol/l/h, P = 0.002). In patients with idiopathic Parkinson's, higher glucocerebrosidase enzymatic activity was associated with longer disease duration (P = 0.002) in adjusted models, suggesting a milder disease course. We conclude that lower glucocerebrosidase enzymatic activity is strongly associated with GBA mutations, and modestly with idiopathic Parkinson's disease. The association of lower glucocerebrosidase activity in both GBA mutation carriers and Parkinson's patients without GBA mutations suggests that loss of glucocerebrosidase function contributes to the pathogenesis of Parkinson's disease. High glucocerebrosidase enzymatic activity in LRRK2 G2019S carriers may reflect a distinct pathogenic mechanism. Taken t...

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