Defining and manipulating the neural basis of hypoactive and hyperactive behaviours in Parkinson's disease.

Parkinson's disease (PD) is a very common degenerative disease of the brain, affecting 1% of the population over the age of 60. PD compromises the control of voluntary movement and causes symptoms such as tremor, slowness of movements and stiffness. Beside these well-known movement symptoms, people with PD commonly experience a number of "non-motor" symptoms including changes in mood and behavior such as depression, anxiety, lack of motivation (apathy) and impulsive behaviour. In recent years these symptoms have emerged as an important focus for clinical assessment and research since they are very disabling for people with PD and their families. We still do not understand enough about the mechanism of these symptoms, and treatment options are very limited.

Deep brain stimulation (DBS) is a common therapy for treating motor symptoms in PD. This treatment involves inserting electrodes into a specific part of the brain (most often the subthalamic nucleus). Recording from these electrodes provides a unique opportunity to study the neural activity of various brain structures. Previous research studies using this technique have led to major advances in understanding how motor symptoms are caused and have led directly to developments in therapy.

In our study, we aim to identify brain networks that underlie mood and behavioural disturbance in people with PD. We will then see if we can modulate these networks using particular patterns of deep brain stimulation.

People with PD newly implanted with deep brain stimulation electrodes will be included in the study. The data gathered will include performance at computer tasks probing apathy and impulsive behavior and recordings from the brain electrodes. We hope that this work will help us understand how these disabling symptoms arise and might help us develop better treatments.

People with Parkinson's disease (PD) often experience neuropsychiatric symptoms ranging from hypoactive behaviours such as apathy and depression to hyperactive behaviours such as impulsive compulsive behaviours. Although these symptoms are common and disabling, their physiopathology is unclear and there is a lack of effective treatment. It has been suggested that behavioural hypo- and hyper-activation might be linked to hypo and hyper motoric states in PD and that the subthalamic nucleus (STN) might play a key role in their pathophysiology, as for motor symptoms. Deep Brain Stimulation (DBS) of STN is a powerful treatment for PD motor complications but its role in behavioural disorders is unclear.
Our study aims to record the local field potential (LFP) in PD patients with STN-DBS and to identify common neural biomarkers of hypo and hyperactive behaviours. We have 3 specific hypotheses that we will test: 1. Different spatio-spectral patterns of STN LFP activity and of LFP coupling with frontal EEG are associated with different aspects of hypo- and hyperactive behaviours in PD. We will record STN LFP with high spatial resolution using directional electrodes, simultaneously with EEG, during tasks challenging key aspects of behavioural control e.g. the Stop-Signal Reaction Time task, Temporal Binding task and Effort-based decision-making task.
2: Different spatio-spectral patterns of LFP activity are causally important in aspects of hypo-and hyperactive behaviours in PD. We will steer electrical currents to target the topography of relevant relevant LFP patterns in the STN to manipulate task performance with DBS.
3: The amplitude of spatio-spectral patterns relates to the severity of hypo- and hyperactive behaviours in PD. We will contrast task performance during random bursts of DBS with bursts triggered by activity changes in the STN. Our findings will help clarify the pathophysiology of hypo and hyperactive behaviours and help us adapt DBS for the their treatment

Neuropsychiatric symptoms such as depression, apathy and impulsive behaviour have a major impact on people with Parkinson and their families. To date there is only limited knowledge about the causes of these symptoms and treatment is often ineffective. Our study aims to fill this knowledge gap by clarifying the mechanisms behind these symptoms and to use this to help identify novel treatment strategies.

There are a number of potential beneficiaries from our study. First, the academic audience will benefit from our results, which will shed light on a poorly understood but very disabling set of symptoms for people with PD. We will ensure that we inform as wide an audience as possible about our progress and results by presenting them in local, national and international conferences and meetings. We will also report our findings in scientific journals, ensuring free access to the papers.

Second, people with PD and their families will benefit from our study. By understanding the mechanisms of these symptoms we hope to provide opportunities for new treatment strategies such as adaptive Deep Brain Stimulation. Improved treatment of the neuropsychiatric symptoms will directly improve quality of life for people with PD and their families which is currently strongly negatively impacted by these disabling disorders.

Third, clinicians will benefit from this study since the results should provide means of better controlling neuropsychiatric symptoms in people with PD with DBS.

Finally, our study will produce health and economic benefits since developing an effective treatment for neuropsychiatric symptoms will reduce the number of medical consultations and admission in the hospital that are often required to manage these neuropsychiatric comorbidities.