DS0407 -

LOsing COntrol of MOTor Inhibition : a different View of parkinsonian akinesia – LOCOMOTIV

Submission summary

Adaptive behavior is composed of planning, initiating and executing actions. A crucial component of adaptive behavior is response inhibition, the capacity to refrain from reacting to external events or internal urges, which underlies the ability to deliberately select one plan of action from amongst potentially many. Recent conceptual and methodological insights have significantly challenged our understanding of response inhibition, including the discovery of distinct types of response inhibition that are easily confounded with each other as well as with ancillary cognitive processes. The neural processes underlying these different types of response inhibition have not yet been unraveled, and are the focus of our proposal.

The dominant view of response inhibition is that it is initiated when specific stimuli are identified, which applies for example when observing a stop sign at an intersection. This selective and reactive inhibition can be distinguished from an inhibitory process that applies to stimuli non-selectively, which might be reflected in slowing for any sign on the road when driving in an unfamiliar city for the first time. Inhibition can also be applied proactively in the absence of explicit stimuli, acting to gate actions in contexts where fast or erroneous actions are undesirable. Ecologically relevant response inhibition likely includes mixtures of proactive and reactive inhibition. Our first goal is to determine how cortical networks in healthy individuals are modulated during distinct types of response inhibition using electrophysiological methods with sufficient temporal resolution to characterize changes in neural activity that must occur in the brief span of time required to inhibit actions (hundreds of milliseconds).

Identifying the neural bases of response inhibition is also a pressing clinical issue. Indeed, while impulsivity is usually viewed as the unique outcome of disorders of response inhibition, excessive inhibitory control may actually lead to difficulty initiating actions. This is manifest in Parkinson’s disease (PD), where akinesia is particularly disabling and can be partially alleviated by dopaminergic therapy or deep brain stimulation (DBS). Interestingly, dopaminergic therapy or DBS can also induce impulsivity, indicating that PD is an excellent model for understanding changes in response inhibition. Recent neuroimaging investigations from our group show that akinesia and impulsivity are respectively associated with hyper- and hypoactivation within cortical networks supporting response inhibition, suggesting that akinesia and impulsivity might be two sides of the same coin. These observations constitute solid grounds that motivate our second goal, which is to investigate the cortico-basal ganglia mechanisms of response inhibition in PD patients, who provide an unprecedented view of intracranial neural activity during response inhibition.

New conceptual and technical developments place our consortium in a unique position to elucidate the mechanisms of inhibitory control in the normal state, and its breakdown in disease states. Our project consists of coordinated experiments in healthy humans, PD patients, non-human primates, and a non-human primate model of PD that aim to pinpoint the cellular and network patterns of neural activity underlying response inhibition and related disorders associated with both the effects of the disease and the effects of DBS. We propose a common set of experiments combining psychological modeling with high-resolution human/monkey electrophysiology and novel methods to localize relevant neural activity in space, time and frequency. The new data obtained in the course of this research promises to offer insight into a wide range of neurological diseases, and will be useful for developing novel therapeutic options such as identifying new DBS targets and closed-loop/neurofeedback approaches in order to treat akinesia or impulsivity.

Project coordination

Brian LAU (Institut National de la Santé et de la Recherche Médicale - INSERM)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

INSERM - UMRS 1127 - Eq Neurochirurgie Expérimentale Institut National de la Santé et de la Recherche Médicale - INSERM
INSERM - UMRS 1127 - Thérapeutiques Expérimentale de la Neurodégénérescence Institut National de la Santé et de la Recherche Médicale
UCB Lyon 1 - CRNL Université Claude Bernard Lyon 1 - Centre de Recherche en Neurosciences de Lyon

Help of the ANR 771,033 euros
Beginning and duration of the scientific project: December 2016 - 48 Months

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