PROJECT SUMMARY
Cognitive impairments like over-perserveration, mental rigidity, and cognitive inflexibility accompany
several neurological diseases – most prominently, Parkinson's Disease (PD). PD is the second most common
neurodegenerative disorder in humans. While it is a predominantly motor disorder, many PD patients experience
cognitive symptoms. However, despite the broad incidence of impaired cognitive flexibility in PD and other
disorders, little is known about the mechanistic neural underpinnings of this ability in health and disease. Hence,
there is a critical need for a mechanistic neural theory of cognitive flexibility. In this grant proposal, we propose
to test a working model of this ability, which centers on the role of a fronto-basal ganglia (FBg) brain mechanism
for inhibition. We use a converging evidence approach that includes intracranial recordings from the basal
ganglia, scalp EEG, motor systems measurements, and brain stimulation.
The core hypothesis of the proposed model is that rapid cognitive flexibility depends on a neural
mechanism for inhibitory control. Based on extensive pilot data, we propose that this mechanism allows healthy
individuals to adaptively disengage from ongoing cognitive processes (working memory, task set representations,
attentional focus, etc.). Importantly, the proposed neural mechanism is – until now – largely known as a motor
inhibition mechanism: it can serve to stop already initiated actions by recruiting a network of FBg brain regions
to inhibit motor activity. The circuitry underlying this inhibitory control mechanism is known to be damaged in PD,
which is thought to explain some of its motor symptoms. Our proposal that this mechanism can serve to also
inhibit cognition could explain why PD patients overpersevere on outdated cognitive processes: damage to the
same mechanism whose malfunction impairs motor inhibition in PD may also impair cognitive flexibility.
To test this model, the first of group of studies in this proposal is designed to identify the types of situations
in which the inhibitory FBg mechanism is engaged. Specifically, neural and motor signatures of the inhibitory
FBg mechanism will be measured across different types of situations that require rapid cognitive control (errors,
response-conflict, unexpected perceptual events). The goal is to investigate whether the mechanism is active in
a broad array of scenarios that demand rapid cognitive flexibility. The second group of studies aims to investigate
the potential inhibitory influence of the FBg mechanism on cognitive representations. Specifically, activity of the
FBg mechanism will be measured in a new battery of tasks designed to test how ongoing task set representations
and attentional processes are interrupted when necessary. The goal is to test the core proposition of the model,
namely, that the FBg mechanism's inhibitory capacity extends beyond the motor system, and can affect active
cognitive representations. The final group of studies will test the effects of different types of brain stimulation on
the inhibitory FBg mechanism's ability to inhibit ongoing cognitive representations. These studies aim to provide
causal evidence for the model and translate it into clinical practice.