Cortical Electrophysiology of Response Inhibition in Parkinson's Disease

Patients with Parkinson's disease (PD) commonly develop difficulties with executive function due to neurodegeneration in neuronal networks that involve the prefrontal cortex and associative territories of the basal ganglia, even in early stages of the disease. Executive cognitive functions serve to direct behavior toward a goal and modify actions to accommodate changing demands. One of the key components of executive control is the ability to cancel or inhibit habitual responses. Motor response inhibition is critical in everyday life, for example, to stop crossing the street when a speeding car appears. In patients with PD, the failure of these inhibitory control mechanisms may manifest, for example, as an inability to stop festinating gait or as impulsively jumping out of a chair and losing balance. Beyond the failure of stopping or inhibiting motor responses, patients with PD are also prone to impulsivity and compulsions, leading to behaviors such as overeating or gambling. Approximately 15-20% of PD patients are diagnosed with impulse control disorders which can be exacerbated by dopaminergic medications. Furthermore, PD patients with deep brain stimulation (DBS) may develop additional impairments in executive function. Given the prevalence of executive dysfunction, the everyday-importance of this issue, and the connection with PD therapies, disease- or therapy-induced alterations in inhibitory control are an important area of research in PD.

The primary clinical objective for DBS therapy in PD has been to optimize motor function. The effect of stimulation on cognition and behavior, particularly in the subthalamic nucleus (STN), has been controversial. Behavioral side effects have been supported by reports of worsened cognition, increased impulsivity and even suicidal behavior. While large, randomized trials do not show significant detrimental changes in global cognition with DBS, meta-analyses and systematic reviews have shown adverse effects on executive functions, particularly response inhibition. Based on animal studies, the STN can be divided into a sensorimotor (dorsolateral), cognitive-associative (ventromedial) and limbic (medial) parts. Most DBS leads implanted into the STN contain four ring-shaped contacts, spaced over a total distance of 7.5-10.5mm. While surgeons generally target the dorsolateral sensorimotor region of the STN, the most ventral DBS contacts almost inevitably end up in the ventral associative or limbic regions of the nucleus. There are anecdotal observations of abrupt mood and behavioral changes (impulsivity, hypomania, depression) with STN DBS, perhaps due to spread of stimulation to the ventral STN regions. However, the effect of stimulation location on cognitive function is poorly understood and unaccounted for in clinical programming which may lead to suboptimal gains in quality of life.

Electrophysiology and imaging studies have demonstrated that the STN is a key node in the inhibitory network, although other basal ganglia nuclei are involved. The STN receives input from prefrontal cortical areas (via the prefrontal hyperdirect pathway) and is thought to provide a global inhibitory signal to the basal ganglia and thalamus to halt habitual responses and allow additional processing time in situations of conflict and uncertainty. STN DBS might (antidromically) disrupt the inhibitory signal from the cortex, leading to impulsive responses and inability to inhibit actions. However, it remains unclear whether stimulation in the STN worsens or improves motor response inhibition. It is also possible that some aspects of inhibitory control (proactive vs. reactive) can worsen during stimulation while others improve suggesting that the effects may be mediated by different pathways or mechanisms. Proactive inhibition refers to preparatory mechanisms that facilitate action inhibition (i.e. enables a person to act with restraint), while reactive inhibition is a sudden stopping process triggered by an external stimulus.

This study will address the following knowledge gaps:

1. Which cortical mechanisms (on the level of population-based electrophysiologic activity) are engaged in different aspects of inhibitory control (proactive control vs reactive; discrete movements vs continuous) in PD patients compared to healthy controls? 2. Does the effect of STN DBS on motor response inhibition depend on activation of the prefrontal hyperdirect pathway?

Successful completion of the proposed studies will provide substantial new knowledge about the frontal brain areas involved in inhibitory control, their topographic representation within the STN and means of cortico-subcortical communication. The results may inform future DBS targeting and programming strategies, aiming to avoid cognitive side effects of STN DBS. Recent engineering upgrades to clinical devices (e.g. segmented leads) allow more precise fine tuning of the stimulation field which can serve to design stimulation strategies that maximize motor benefit and minimize cognitive and behavioral side effects.

This study will enroll patients with Parkinson's Disease as well as health controls. Participation in this trial does not affect patient's clinical management. Patients' medication (levodopa) dosages and decision to undergo deep brain stimulation surgery are based on clinical needs.

There are 3 study aims:

Aim 1: To determine the effect of the PD disease process, levodopa treatment, and cognitive status on performance and cortical electrophysiology during motor response inhibition tasks. Participants with PD prior to surgery to implant the DBS leads and healthy controls are examined in Aim 1.

Aim 2: To characterize cortico-subthalamic connectivity during proactive motor response inhibition during surgery to implant clinically-indicated DBS leads in participants with PD.

Aim 3: To determine if activation of the prefrontal cortico-STN hyperdirect pathway impairs response inhibition in participants with PD from Aim 1 after implantation of DBS leads.

The experimental interventions considered in this study are: 1) medication state (PD patients are tested in levodopa-off and levodopa-on state), and 2) DBS stimulation settings (PD patients are tested under 4 stimulation settings: clinical, sham, maximizing prefrontal activation, and minimizing prefrontal activation). Healthy controls will attend two study visits, while patients with PD will be in the study for up to 18 months.

• Electroencephalogram (EEG) Signals During GNG for Participants in Aim 1 [Time frame: Day 1 (before and after levodopa dosage for persons with PD)]
• Electroencephalogram (EEG) Signals During MSS for Participants in Aim 1 [Time frame: Day 1 (before and after levodopa dosage for persons with PD)]
• Electrocorticography (ECoG) Signals During GNG for Participants in Aim 2 [Time frame: During surgical procedure to implant clinically-indicated DBS leads (approximately 15 minutes on the single day of surgery)]
• Electroencephalogram (EEG) Signals During GNG for Participants in Aim 3 [Time frame: Up to 12 months post-implantation of DBS leads]
• Electroencephalogram (EEG) Signals During MSS for Participants in Aim 3 [Time frame: Up to 12 months post-implantation of DBS leads]