Bioinspired closed-loop deep brain stimulation for disorders of decision-making: Using non-invasive methods for predictive neurosurgery

Parkinson's disease (PD) is characterised by slow movement, rigidity, and tremor. PD is caused by reduced dopamine production and first-line treatment is therefore dopamine replacement therapy. This medication becomes less effective over time and deep brain stimulation (DBS) may be considered to treat motor symptoms. The most common brain target is the subthalamic nucleus (STN). Up to 16% of patients with PD also develop impulse control disorders such as compulsive gambling and medication abuse which are devastating for the patient and their family.

Previous studies have identified the critical role of the STN in decision-making, especially in the presence of conflicting information. The STN is thought to exert control on decision-making through low-frequency electrical signals (oscillations) that carry information to and from the prefrontal cortex. After STN-DBS, some patients develop new impulse control disorders whilst others may get better.

The aim of this project is to understand why and translate this understanding into new treatments for disorders of decision-making through three experimental phases.

In experiment 1, these low-frequency oscillations will be replicated through DBS in an attempt to reproduce the observed effects on decision-making seen in previous experiments. Patients who have had an operation to implant DBS electrodes into the STN will be recruited and separated into two groups. One group will have high preoperative impulsivity scores and the other group will have low scores. These two groups will then undertake two computerised cognitive tasks under different experimental conditions. During these tasks, the electrical signals of the brain will be recorded using non-invasive methods (electroencephalography (EEG) and magnetoencephalography (MEG)) to correlate brain signatures with task performance and self-reported impulsive behaviour. Informed by previous studies, these tasks will be done under three experimental conditions (1) no stimulation (2) high-frequency stimulation (clinically routine) and (3) low-frequency stimulation.

In experiment 2, two similar groups (described in experiment 1 but before surgery) will be recruited in addition to age-matched controls. These participants will receive non-invasive transcranial focused ultrasound (FUS) stimulation to particular brain regions known to be involved within a recently identified decision network. Stimulation effects on the brain will then be recorded using functional MRI scans and the effect on decision-making will be assessed using the same cognitive tasks as experiment 1. This experiment will identify the effects of these specific brain regions on decision-making by stimulating them individually. This will allow us to predict the behavioural response of decision network modulation using non-invasive stimulation.

In experiment 3, PD patients with implanted DBS electrodes that have telemetric recording capabilities will be recruited. The aim will be to translate the results of experiment 1 and 2 into a proof-of-concept closed loop system. To achieve this, a subset of brain regions will be stimulated with FUS during a cognitive task. Oscillations will then be recorded from the implanted electrodes to characterise the correlates of this behavioural change deep in the brain. In a second experimental session, DBS will be delivered at a frequency that replicates these brain signals to test the hypothesis that the effect on decision-making will be the same as when stimulating non-invasively with FUS. The final step of this experiment is to demonstrate, in proof-of-concept study, that non-invasive brain stimulation can be used to predict response to invasive DBS and inform a closed-loop stimulation program that delivers stimulation at the correct frequency and time without the need for additional invasive electrode placement.

These experiments will lead to a clinical trial of closed-loop DBS for impulse control disorders in PD.

Experiment 1:
To test the hypothesis that electrophysiological correlates of behaviour (local field potentials (LFPs)) can inform stimulation paradigms, a study of theta-frequency subthalamic nucleus deep brain stimulation (STN-DBS) will be conducted.
PD patients with and without ICBs who have internalised STN-DBS implants will be recruited into a trial of theta-frequency DBS during a high-conflict decision-making task. Behavioural outcomes will be compared against therapeutic-frequency DBS and DBS off. Simultaneous MEG/EEG recordings will quantify mPFC theta-coherence.

Experiment 2:
Transcranial focussed ultrasound stimulation (FUS) has demonstrated reproducible effects on a decision-making network in non-human primates, but this has not yet been tested in humans.
To test the hypothesis that FUS of network nodes in this decision-making network can lead to reproducible and reversible behavioural change in humans, FUS will be applied to targets within this network in PD patients and healthy controls. Participants will complete high-conflict decision-making tasks during FUS and will undergo fMRI imaging to detect network modulation.

Experiment 3:
To test the hypothesis that these network effects are bidirectional and correlate with task performance, PD patients with DBS devices will be recruited into a FUS/DBS study. This will utilise the capacity of modern DBS devices to telemetrically readout LFPs after internalisation:
Phase 1: LFP signals of decision-making will be recorded during FUS of key network nodes. These LFP recordings will be correlated with behavioural outcomes.
Phase 2: Correlated LFP signatures will be used to define stimulation settings. Implanted DBS devices will be programmed to these settings and participants will repeat the decision-making tasks without FUS. Behavioural outcomes will be compared to those during FUS.
Phase 3: These LFP signatures of decision-making will be used in a proof-of-concept closed-loop stimulation paradigm.