The impact of deep brain stimulation of the ventrointermediate nucleus of the thalamus on the motor learning network and the implications for deep brain electrode location in essential tremor

• Applicant: Privatdozentin Catherine Sweeney-Reed, Ph.D.
• Subject Area: Clinical Neurology; Neurosurgery and Neuroradiology
• Term: from 2020 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 441062426

Motor sequence learning, a type of procedural memory, is fundamental to daily living, enabling automation of frequently repeated activities, such as typing and riding a bike, and is crucial to rehabilitation following loss of function. Procedural memory depends on different brain circuitry to declarative memory, with anatomical and imaging studies revealing a cerebellum–ventral-intermediate nucleus of the thalamus (VIM)–motor cortex network. These same structures also comprise the network that mediates tremor. Deep brain stimulation (DBS) is an established treatment for essential tremor (ET). Given the overlapping circuitry, brain stimulation for tremor could disrupt motor sequence learning. Studies of the effects of VIM-DBS on motor learning have yielded mixed results, however, likely partly due to the diverse study designs and stimulation parameters. We postulate that the precise DBS electrode location may also play a role, based on evidence for a kinaesthetic zone in the VIM. We propose a multi-modal approach to establishing the role of the VIM in the motor learning/tremor network, using the serial reaction time test (SRTT), which is a well-established motor learning paradigm. Participants press buttons corresponding to a series of locations on a screen, comprising random and repeated sequences, which are learned without the participant’s awareness. Patients with ET will perform the SRTT with VIM-DBS on and off, with scalp electroencephalogram (EEG) recording. We also have the rare opportunity to record intracranial electrophysiological data from the VIM during the SRTT. The data analysis will build on our previous work identifying a critical role for the anterior nucleus of the thalamus in episodic memory encoding, in which cross-frequency coupling (CFC) between slow and fast brain electrical activity and brain oscillatory phase alignment suggested local thalamic processing. Electrophysiological markers of motor learning in the motor cortex that are modulated by VIM activity will be sought in the motor cortical EEG recordings following VIM-DBS to identify the effects of modulation of VIM firing, through DBS, on motor cortical activity. We will use high resolution functional magnetic resonance imaging (fMRI) to establish whether a particular subregion of the VIM is engaged in motor learning in healthy participants, comparing the findings with the electrode locations in patients with ET at which motor learning and tremor were most affected by VIM-DBS. An enhanced understanding of the role of the VIM in motor learning is crucial to developing treatment for tremor that takes account of the potential for disruption of motor learning.

• DFG Programme: Research Grants