Stein Research
Movement Disorders, Pain and Dyslexia
Movement disorders are the commonest problem in neurology, and most movements are visually guided. Studying visually guided movements and the responsiveness of brain motor networks in trained monkeys has therefore enabled important advances in both neurophysiology and neurology. It has led Prof Stein to develop a world-leading predictive model of cerebellar function and has also elucidated how the basal ganglia and the brainstem control locomotion and whole limb movements.
These insights have enabled Prof. Stein in collaboration with neurosurgeon Prof. Tipu Aziz to develop new techniques of deep brain stimulation in conditions such as Parkinson’s disease; these techniques are rescuing patients previously confined to a wheelchair to return to a fully mobile life. Likewise, they can now successfully alleviate intractable pains, such as those suffered in a phantom limb after amputation, using deep brain stimulation (DBS). They are now also developing DBS techniques for the control of blood pressure and for the treatment of depression.
Prof Stein’s research into the visual guidance of attention and movements in monkeys has also helped to elucidate why children with developmental dyslexia often suffer visual letter confusions. This has led to techniques to help children stabilise their visual perceptions when reading and hence make much better reading progress. These insights have also begun to explain how particular nutritional deficiencies may contribute to dyslexic problems and to antisocial behaviour. Studies of the families with dyslexia that are under investigation have additionally contributed to recent exciting advances in our understanding of how genetic susceptibility may lead to the neurodevelopmental abnormalities that underlie dyslexia.
Visual guidance of movement
John Stein has been studying the visual guidance of movement since he gave up clinical neurology in the mid-1970s. With Mitch Glickstein (Brown University and then UCL) he first showed that there is a dense projection to the cerebellum via the pontine nuclei from the visual dorsal ‘where’ stream that is dominated by visual ‘magnocellular’, motion-sensitive,, input. He then began studying the visual responsiveness of cells in the posterior parietal cortex, cerebellum and basal ganglia (the latter are the two most important subcortical motor centres) during visually guided movements in trained monkeys. With Chris Miall and Dan Wolpert, he then developed the predictive model of cerebellar function that now dominates the field.
Studying monkey movements, initially with Mitch Glickstein and Alan Gibson (Barrow Neurological Centre, Phoenix, Arizona) and latterly with Prof. Tipu Aziz (Nuffield Dept of Surgery, Oxford), has led to a new theory of how the Basal Ganglia (BG) and upper brainstem control locomotor and whole limb movements. By recording field potentials from electrodes inserted for DBS in patients with movement disorders, they have shown that DBS alleviates these by entraining and controlling previously uncontrolled spontaneous oscillations in BG/upper brainstem motor networks. In particular, they have shown in monkeys that the brainstem pedunculopontine nucleus (PPN) is overinhibited in MPTP induced Parkinsonism, and that this inhibition can be overcome by electrically stimulating this nucleus. This has now been carried out in several severely akinetic patients unresponsive to any other treatment; stimulating the PPN can return them to a fully mobile life.
Developmental Dyslexia
Studying the role of the posterior parietal cortex (PPC) in the visual guidance of attention and eye movements in monkeys helped to explain how this area integrates eye position, head and retinal signals to compute where targets are located with respect to the observer. This turned out not only to illuminate the phenomena of neglect that follow PPC strokes in adults, but suggested that mild impairments of its development in children might explain some of their problems with learning to read. Many dyslexics complain that words and letters seem to move around, change places and blur, which explains why they have trouble working out what order the letters should be in. Understanding how these problems arise has helped to develop techniques to stabilise their visual perceptions when reading and greatly improve their progress.
Current Research Programme
Movement disorders
John Stein’s research with Tipu Aziz studying Parkinsonian monkeys has been transferred directly to improvements in deep brain stimulation techniques in patients with movement disorders. They are continuing to analyse the oscillatory behaviour of the basal ganglia and related circuits in order to identify field potential ‘signatures’ of the different kinds of movement disorders (e.g. Parkinson’s dyskinesias, akinesia, dystonia, etc) that can then be used to determine the best DBS target for each.
They are also collaborating with Prof. Kevin Warwick (Engineering, Reading University) to improve the design of deep brain stimulators to detect growth of uncontrolled oscillations and deliver an optimum pattern of stimuli to eliminate them.
This oscillatory activity recorded in field potentials is probably associated with increased local blood flow, which can be imaged by functional magnetic resonance imaging (FMRI). They are therefore correlating the changes in oscillatory activity with FMRI. In addition, diffusion tensor imaging (DTI) is being used to investigate changes in neuroanatomical connectivity in these patients. Carrying out similar DTI in monkeys is enabling the validation of DTI techniques by comparing monkey connections revealed by DTI with the connections shown by conventional neuroanatomical tracing methods.
DBS for Pain
Techniques developed for movement disorders are now being applied to the problem of central neuropathic pain – pain that persists despite removal of its original cause. Recording field potentials from the pain matrix has shown that this pain is again associated with spontaneous oscillations in this network, and that stimulating areas within the network, such as the periventricular grey (PVG), can eliminate the oscillations. If this is successful, then the pain goes also.
Blood pressure control
These changes in pain perception are also associated with changes in sympathetic outflow, so that PVG stimulation changes blood pressure mainly by altering myocardial contractility and peripheral resistance. PVG DBS may therefore offer a new treatment for intractable hypertension and its converse, postural hypotension, so they are developing these possibilities as well.
Depression
Preliminary evidence suggests that analogous uncontrolled oscillatory activity in mesolimbic circuits involving the orbitofrontal cortex may also underlie some forms of depression. Profs Stein and Aziz have been able to record abnormal oscillations in the subgenual cingulate cortex that disappear on stimulating there. They have discovered that continuous stimulation is often followed by great improvement in these patients’ intractable depression. However, improvement is not seen in all patients, and they are attempting, as for pain and movement disorders, to determine the field potential waveform ‘signatures’ that will tell us which sites in which patients will improve depression.
Developmental Dyslexia
10% of all children have exceptional difficulties learning to read despite normal or high intelligence (developmental dyslexia). This condition is strongly hereditary. Building on Prof Stein’s research elucidating the visual control of movement in monkeys, his team runs clinics in Reading and Oxford for studying and treating children with visually based reading problems. They investigate why these children have such problems, focussing on Prof Stein’s hypothesis that they have genetically based impaired development of the magnocellular systems of neurones in the brain. The function of these neurones can often be improved using simple visual treatments such as coloured filters or improved nutrition. Magnocellular neurones appear to be particularly vulnerable to lack of dietary omega-3 essential fatty acids (normally derived from oily fish) and, with Dr Alex Richardson (Physiology, Anatomy and Genetics), they have been able to show that supplementing the diets of children with dyslexic, dyspraxic, or attentional problems can greatly improve their concentration and reading .
Antisocial behaviour
Poor control of attention and impulsive behaviour also characterises young offenders. With Bernard Gesch (supported by Natural Justice and the Wellcome Trust), Prof. Stein is repeating on much larger numbers a trial that showed that nutritional supplements could reduce antisocial behaviour in a Young Offender’s Institution by one third – perhaps the largest reduction in criminal behaviour ever shown. In addition, they have been asked by the Home Office to consult on the design of trials of nutritional supplements to determine whether improved nutrition might reduce antisocial behaviour and improve performance in the outside community and in schools.
Dyslexia Genetics
Dyslexia has a strong biological basis. With Prof. Anthony Monaco (Wellcome Trust Centre for Human Genetics, Oxford) Prof Stein has used his group of over 300 Oxford dyslexic families to identify chromosomal sites that link strongly with dyslexia, including one on chromosome 6 that seems to control neuronal migration early in brain development. The EU project NEURODYS has built on this to start a major new European effort to clarify the biological bases of developmental dyslexia. Confirming relations between dyslexia, candidate genes and brain regions requires large samples from diverse cultures and languages – a characteristic European feature. NEURODYS links 15 top research groups and clinics from nine different countries. It also covers the most common European languages of the 2.5 million dyslexic school children. The project combines innovative analyses of how the reading problems relate to genes, environment, brain structure, and brain function. Nearly 4000 children will be assessed in this large coordinated effort.
Further information can be found at: http://www.physiol.ox.ac.uk/Research_Groups/Stein/
