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Using deep brain stimulation to treat parkinson2019s disease

Research by Oxford Professors John Stein and Tipu Aziz has had a significant impact on advanced Parkinson's disease patients affected by freezing of gait and loss of balance.

Millions of people worldwide suffer from Parkinson’s disease (PD) and the numbers are set to rise dramatically over the next decades, owing to an increase in life expectancy.

Symptoms of PD are both physical (tremor, rigidity, freezing of movement, falls, speech problems, bladder and bowel problems) and mental (depression, anxiety, hallucinations, insomnia). PD has been treated with dopaminergic drugs since the discovery of levodopa in the 1960s. Although patients with PD often initially respond well to this these drugs, long-term drug treatment can exacerbate the original problems and leave patients with severe drug-resistant symptoms. Of these, the symptoms affecting movement are probably the most distressing; dyskinesia can cause patients to writhe uncontrollably, while akinesia means they can suddenly ‘freeze’ and be unable to move at all, rendering them prone to loss of balance and falling.

A new target for the alleviation of Parkinsonism the subthalamic nucleus was developed by Tipu Aziz, from the Nuffield Department of Clinical Neurosciences, as a means to alleviate uncontrollable movement in advanced PD patients. This treatment has proved very successful and has transformed the lives of over 100,000 patients. However, it does not benefit around 10% of PD patients who suffer most from the opposite problem ‘freezing’.

Working with John Stein and his colleagues, from the Department of Physiology Anatomy and Genetics, Tipu investigated whether stimulation of other brain regions could help patients with gait freezing and related problems.

The pedunculopontine nucleus (PPN), an area in the brainstem much deeper than the subthalamic nucleus, was already known to play an important part in motor control.  Their experiments revealed that stimulation of the PPN could lead to an increase in activity and that this worked, at least in part, by a non-dopaminergic pathway. Subsequent experiments established the connections between the PPN, subthalamic nucleus and other areas of the brain.  This enabled the researchers to determine the ideal locations in the PPN for deep brain stimulation (DBS).

This work was swiftly taken up clinically by other researchers and applied to humans with the result that PPN stimulation as a treatment for severe akinesia in PD (either in isolation, or in

combination with other forms of DBS or drug therapy) is now becoming more widely available. Since 2008, around 200 PD patients have been successfully treated using PPN DBS, experiencing great improvements in their symptoms and quality of life. Before surgery, people are often unable to get up from a chair unaided; walk with a slow, shuffling, stiff gait, (often needing help with balance to avoid falling); freezing completely and losing balance. After surgery, patients are often transformed, able to get up from a chair, walk and turn with virtually normal movements. In addition to surgery carried out by Tipu Aziz, PPN DBS has been successfully performed by a number of other neurosurgeons worldwide, for example in France. The numbers undergoing PPN DBS are expected to grow rapidly in line with those for other forms of DBS already established, eventually extending the treatment to thousands of suitable advanced PD patients. The success of this technique in PD has led to PPN DBS also being investigated as a treatment for progressive supranuclear palsy, another difficult-to treat condition in which patients suffer movement disorders.

As well as alleviating severe gait problems, there is mounting evidence that PPN stimulation also improves sleep in PD patients. Chronic sleep disturbance is a major cause of distress in PD; insomnia, excessive daytime sleepiness, nightmares, sleep attacks (sudden involuntary episodes of sleep) and REM sleep behaviour disorder are all common.

The effectiveness of PPN stimulation has been described in neuroscience and neurosurgical

journals, at international meetings, through the Parkinson’s Disease Society and through the PPN task force, a group set up by the Movement Disorders Society, upon which both Professors Aziz and Stein serve.

Funding:  This project received over £2,000,000 from The Medical Research Council, The Norman Collisson Foundation and the Charles Wolfson Charitable Trust.