Neural underpinnings of implicit motor sequence learning: effects of non-invasive brain stimulation in healthy adults and Parkinson's disease

Nearly all our daily motor activities, from getting out of bed to driving, walking and
typing, involve executing movements in a specific order. Our ability to incidentally learn
such sequential motor actions is termed implicit motor sequence learning (IMSL) and is
thought to be mediated by two interconnected sets of brain circuits: the basal ganglia
network and the cerebellar network. However, their exact contributions to IMSL across
different stages of learning remain unclear.
This dissertation aimed to explore the neural underpinnings of IMSL, using
transcranial direct-current stimulation (tDCS), a non-invasive brain stimulation technique.
To this end, the effects of tDCS were assessed across the acquisition, short-term and long-
term consolidation phases of IMSL, in healthy adults, and in individuals with Parkinson’s
disease (PD), where IMSL is impaired. In PD, basal ganglia dysfunction leads to alterations
in cerebellar brain activity as well, making it a prime neural model to study the contributions
of these networks to IMSL. Given the importance of IMSL in our daily motor activities,
impairments in this skill not only affect the daily lives of people with PD, but also impede
their successful motor rehabilitation. Therefore, an additional goal of this dissertation was
to determine the potential of tDCS to enhance IMSL in PD.
This dissertation showed a beneficial effect of tDCS applied to the primary motor
cortex (M1) and cerebellum on the acquisition of IMSL in healthy young adults. It also
revealed for the first time that tDCS can enhance sequential knowledge acquisition in
individuals with PD. Based on the overall result pattern, and in particular, comparing
acquisition and consolidation stages, we propose the expectancy hypothesis: tDCS
enhances the acquisition of IMSL by increasing susceptibility to sequence disruptions in
early learning, leading to heightened awareness of potential disruptions, which ultimately
induces more flexible responding during consolidation. With regard to stimulation site, the
positive effects of M1 stimulation seem to stem from co-stimulation of M1 and the motor
association cortex (MAC), rather than focal stimulation of M1 alone. This suggests that the
MAC’s importance during early IMSL was previously underestimated. Cerebellar tDCS
similarly enhanced IMSL during acquisition, supporting the sequence detection hypothesis,
which posits that the cerebellum serves a sequence-specific role in IMSL. This challenges
previous claims and the traditional view of IMSL that the cerebellum exclusively supports
non-sequence-specific motor adaptation processes.
Finally, our clinical studies showed that, in particular, PD patients with mild cognitive
impairments benefitted from the positive effects of tDCS on IMSL. These results show that
it is important to take the cognitive status of patients into account when considering
neurostimulation.
Overall, our findings provide valuable insights into the neural underpinnings of
IMSL, and identify several important implications for both research and clinical practice in
this domain.