Jan R. Wessel, PhD - US grants

DESCRIPTION (provided by applicant): Over-valuation of drug-associated stimuli is a central psychological component of substance abuse. Changing these valuation patterns is key for cognitive-behavioral interventions targeted at treating drug abuse. Yet, such interventions focused on stimulus-devaluation have shown limited success, perhaps because no clear-cut mechanism has been established that reliably leads to stimulus devaluation. Our preliminary data show that stopping motor actions towards rewarding stimuli leads to a reduction in stimulus valuation. Here we will investigate the mechanisms underlying this compelling effect and we will also examine if stopping-related devaluation decreases nicotine urges in smokers. To investigate the underlying mechanisms we will perform behavioral experiments with control conditions to examine if the effect is due to stopping per se, or to other factors such as distraction and effort. We hypothesize that the devaluation effects are specific to stopping action, so no devaluation should be found in the control experiments. We further suppose that the way in which stopping action affects devaluation is by means of stopping-induced global suppression. We will index global suppression by using transcranial magnetic stimulation to measure the suppression of task-irrelevant motor effectors when participants stop their action. We hypothesize that the amount of global suppression that occurs when people stop will correspond with the amount of stimulus devaluation that occurs. Finally, we will run a behavioral experiment to determine if this stopping paradigm can be leveraged to try to reduce smoking urges in heavy smokers. Overall, this project could help to determine the exact psychological mechanism underlying stopping-induced devaluation and it could provide proof-of-concept data in smokers of the efficacy of this behavioral intervention.

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.

Abstract Activity in the ?-frequency band (15-29Hz) is a highly prominent feature of neural recordings found across species, recording techniques, and spatial scales. Changes in ?-activity are particularly prominent during motor processes. Movement-related ?-activity can be observed in the cortical areas of the pyramidal motor system, as well as in the subcortical areas of the extrapyramidal motor system. Pathological ?-activity is a hallmark of movement disorders, most prominently of Parkinson's Disease (PD). Indeed, ?-activity is used both as a neurophysiological marker of disease progression in PD and as a target in newly developed, cutting-edge treatment methods such as closed-loop adaptive neurostimulation. However, recent studies in non-human animals have cast a fundamental layer of doubt on the nature of this neural signal and its relationship to behavior. Past studies of ?-activity have focused on averaged changes of signal-power across time (or across trials of a task), as is typical in neurophysiological studies. What recent studies have shown, however, is that unaveraged ?-band activity is not characterized by the type of steady (de)synchronizations of activity that are found in the average. Instead, ? is characterized by short, transient, burst-like `events'. The burst-like nature of this signal, however, is lost in the average ? and along with it, the systematic relationships that can be found between dynamics of these ?-burst events and motor control on individual trials. Therefore, there is a critical need to investigate how burst-like ?-events relate to both normal and pathological motor control in humans. We here propose a detailed, systematic investigation of this relationship. In an extensive pilot investigation, we have found that both human movement initiation and movement cancellation are accompanied by highly specific and systematic patterns of non-invasively recorded ?-bursts. This suggests the overarching hypothesis that ?- bursts are a universal signature that signify inhibitory processes in the motor system. The work in this grant proposal aims to systematically test this guiding hypothesis by linking specific patterns of ?-bursts to established theoretical models of motor inhibition in the human brain, by investigating the origins of movement-related ?- bursts in both cortical and subcortical regions that constitute the human motor system, and by providing causal evidence for the role of ?-bursts in conveying inhibitory motor control commands across the motor system.