Sensory system abnormalities in childhood dystonia / dystonic cerebral palsy - are sensory networks modulated by Deep Brain Stimulation?

Dystonia is a severely disabling and painful motor disorder in which people suffer involuntary muscle contractions causing twisting movements, abnormal postures and painful spasms. It affects at least 70 000 people in the UK (similar to Multiple Sclerosis). There are many causes but we don't yet fully understand what happens within the brain to produce these abnormal movements. Adult-onset dystonia usually involves a single part of the body, whereas childhood-onset dystonia is often widespread and so severe that people find it impossible to control their bodies. This can prevent children with relatively normal intellect from achieving adult independence. The long-term care needs of these individuals are hugely expensive to the National Health Service and society.

Dystonia has no cure but symptoms can be improved by a technique called Deep Brain Stimulation (DBS). This involves using fine wires, called electrodes, to deliver electrical pulses to a specific group of nerve cells deep within the brain, called the Globus Pallidus interna (GPi). The electrodes are implanted in the brain during an operation performed by a neurosurgeon. During the surgery, we can record the activity of nerve cells in the GPi using special recording electrodes.

DBS is more effective in some types of dystonia than others but we do not know why because a) we don't yet know how DBS works and b) we don't yet understand the mechanisms responsible for different types of dystonia, especially dystonia resulting from brain injury during infancy (dystonic cerebral palsy). This gap in our knowledge limits our ability to develop and apply effective therapies.

Most studies investigating the mechanisms of dystonia have been in adults with genetic forms of dystonia. These studies have shown that "inhibition", the mechanism by which the body "damps down" activity within the nervous system, is reduced in people with dystonia. There is also evidence of abnormalities in the way the brain processes sensory information. Thus one possible mechanism of dystonia is that abnormal perception of sensory inputs leads to distorted or excessive movements. However, none of these mechanisms have been investigated in dystonic cerebral palsy.

Studying which mechanisms are common and which differ between different types of dystonia is key to understanding the causes and improving our ability to treat this disabling condition. My own work has identified differences in the activity of GPi nerve cells between different types of dystonia and has shown that the activity of these cells is related to outcome from DBS surgery. I have also found evidence of abnormal sensory pathways in some children with dystonia, particularly in dystonic cerebral palsy. My data suggest that such sensory deficits may be linked to outcome from DBS, but more powerful markers of outcome are still needed. I plan to take this forward by investigating whether measures of sensory processing within the brain are abnormal in different types of dystonia and whether these measures relate to outcome from DBS.

To investigate sensory processing I will use frequency analysis methods to detect changes in EEG (brainwave) activity in relation to a sensory stimulus and a motor task. I will compare these measures in children with different types of dystonia and in children with good and poor outcome following DBS. I will also analyse the activity of GPi cells recorded at the time of DBS surgery and compare these across different types of dystonia. Finally I will assess the pathway linking the GPi and the cortex (the outer layer of the brain) by using the implanted stimulator to evoke activity in the cortex. These data will determine whether sensory processing is abnormal in dystonic cerebral palsy and whether measures of sensory processing relate to outcome from DBS. This has important implications for predicting outcome, selecting the most appropriate candidates for surgery and in counselling patients and families.

Background: Dystonia can be treated with Deep Brain Stimulation (DBS) of the Globus pallidus interna but outcomes vary widely. My work shows clear differences in neurophysiological parameters between different types of dystonia and suggests these measures may relate to outcome.
Aims/Objectives: To compare changes in sensorimotor cortex EEG activity in relation to a sensory or sensorimotor task in children with different types of dystonia and to investigate whether such changes relate to DBS outcome.
Subjects: 24 children with primary dystonia, 24 with dystonic cerebral palsy and 24 typically developing children.
Methods: Spectral EEG changes will be assessed in relation to a) electrical stimulation of the median nerve as per standard clinical Somatosensory Evoked Potentials, b) a passive wrist flexion/extension task, c) where possible, an active wrist flexion/extension task. Scalp EEG will be recorded using Ag/AgCl electrodes positioned according to the 10-20 system. EEG will be band-pass filtered (1-100Hz), EEG spectral power will be calculated using the Fast Fourier transform or Wavelets, and changes in spectral power, EEG-EEG coherence and EEG-EMG coherence will be measured in four frequency bands (theta 4-7Hz, alpha 8-12Hz, beta 13-30Hz, gamma 31-85Hz). Spectral changes will be compared across aetiological groups and in relation to DBS outcome. In children who have had DBS, neural connections between the Globus Pallidus and sensorimotor cortex will be analysed using Deep Brain Stimulation Evoked Potentials. Firing patterns of pallidal neurons will also be assessed using micro-electrode data recorded from the Globus Pallidus at the time of surgery.
Scientific and medical opportunities: This work has important implications a) for increasing our scientific understanding of the mechanisms of dystonia and b) for clinical decision-making, by using neurophysiological parameters to predict outcome, thus improving patient selection and counselling of families.

Dystonia is a severely disabling motor disorder. Patients find it impossible to control their bodies due to involuntary muscle contractions, twisting movements, abnormal postures and painful muscle spasms. This project addresses important clinical and scientific questions regarding the underlying mechanisms and the treatment of this group of disorders. The potential impacts of this research are broad, primarily for health, society and the advancement of knowledge but also with benefits for the economy, industry and individuals.

Knowledge
Unfortunately the pathophysiological mechanisms causing different types of dystonia are still not understood. This limits both the development of new therapies and the effective use of current ones, such as Deep Brain Stimulation (DBS). This project will advance fundamental scientific knowledge about the role of abnormal sensory pathways and processing in children with different types of dystonia. This impact will be of benefit to other groups studying motor neuroscience and the mechanisms of neurological disease. By comparing the findings pre- and post-DBS and by relating the findings to outcome I hope to increase understanding of how DBS works and which patients are most likely to benefit.
This knowledge will also have an impact by informing the direction of future studies in this area, both for my own research and that of other groups.

Health - Improving life for Patients
The knowledge gained from this project will have direct application to medical practice, with clear potential to inform clinical decision-making and to guide neuromodulation therapy to benefit patients. Our findings could help to improve the efficacy of DBS by guiding the selection of alternative stimulation targets and may also help to improve the cost-effectiveness of technologies, by enhancing the prediction of benefit from DBS.
The sensory system is also amenable to other, non-invasive therapies, so a broader understanding of how these processes are disrupted in dystonia will facilitate the targeted application of such therapies to individual patients. This knowledge may also guide the development of new therapies to treat patients with movement disorders.

Society and Economy
Dystonia affects approximately 70 000 people in the United Kingdom (probably underestimated) and may arise from various aetiologies, including dystonic-dyskinetic cerebral palsy arising from perinatal Hypoxic Ischaemic Encephalopathy (HIE) due to birth asphyxia. The NHS spends £482 million per year (20% of the obstetric budget) on maternity compensation claims, primarily for payments to cover the lifelong care needs of these individuals. Whilst preventive measures must also be researched, it is vital that we find ways to treat this disabling motor condition. Ameliorating the motor disability will not only relieve suffering for the children themselves but will have economic benefit by reducing their care costs. Improving the effectiveness of existing technologies such as DBS, as outlined above, will contribute to this.

Industry
There are also potential benefits to industry since we anticipate that our findings will increase scientific understanding of how DBS works. This has potential impact for the development of neuromodulation technology, including facilitating the use of real-time feedback of brain activity to neurostimulation devices to improve their performance and enable a more individualized approach to treatment. This in turn will improve the efficacy of DBS, bringing benefit for patients.

People
This fellowship will enhance the development and progression of my career. In the longer term, I hope the outputs of this project will facilitate me developing and educating my own team of researchers.