Investigating the neural substrates of saccadic plasticity and the mechanisms of transcranial direct current stimulation.

To make accurate movements regardless of fatigue, aging and (not least) learning new motor skills, the brain continuously adapts motor output using sensory information; a process known as motor learning or adaptation. The quick eye movements made to move gaze from one point of interest to another are called saccades. These are the most common movements made by man; on average three times a second. We can manipulate these movements in the laboratory to force motor adaptation to take place over a short period of time, a process called saccadic adaptation. At present it is not precisely known how or where the brain process the changes that underlie this adaptation.

Modern techniques in neuroscience allow us to manipulate the excitability of the brain in healthy subjects. The techniques are temporary, harmless and painless. The stimulation is accurate and specific enough to allow us to alter the activity in a small part of the brain to investigate whether that area is involved in saccadic adaptation. We will use two techniques i) transcranial magnetic stimulation (TMS) and ii) transcranial direct-current stimulation (TDCS). TMS can be used to temporarily interfere with a small region of the brain. We will use this technique to probe sites in the brain during saccadic adaptation. At present we think that there are several that are involved in the process, both the cortex and an area at the back of the brain called the cerebellum.

Nerve cells in the cerebellum become more excited when the saccades are adapted to become larger than they originally were, and less excited when saccades are adapted to become smaller. Depending on the polarity of stimulation TDCS can be used to excite or inhibit brain activity. Therefore, using TDCS to excite cells in the cerebellum should facilitate the adaptation of saccades to become larger and hinder the adaption to decrease saccade size. The exact opposite should be the case if we use TDCS to lower excitability of cells of the cerebellum. We will test this idea. The results will not only inform us about the nature of the mechanisms of adaptation but will also affirm the theory of how we think TDCS works, which as a novel technique is not entirely understood.

We will also investigate how the output of the cerebellum changes, as the saccades are adapted. Some patients with tremor have surgery to implant electrodes into a part of the brain called the thalamus. Stimulation of this part of the brain can reduce tremor. The technique is called deep brain stimulation. The procedure is done in two operations, one to implant the electrode, another to implant the stimulator a week later. In the intervening period we can record neural activity from the electrode. The part of the thalamus implanted is the part of the structure that receives input from the cerebellum. We have already recorded eye movement related activity in this part of the thalamus. If the electrophysiological changes that are seen in monkeys during adaptation are replicated in humans, we will see changes in the electrical activity in the cerebellar outflow as recorded in the thalamus when the subjects adapt their saccades.

Finally we will also record local field potentials from the cerebellar thalamus at rest and during eye movements before and after TDCS. An Increase or decrease in cerebellar excitability induced by TDCS we be seen as predictable changes in electrical activity in the thalamus. In this way we will be able to better understand how TDCS influences the excitable properties of the brain. These final two undertakings will be first such recordings in human physiology.

Our plan of work will not only provide invaluable new information on where and how in the brain adaptive mechanisms occur but will also shed light on the mechanisms of the developing technique of TDCS. Such information will be invaluable for assessing plastic and induced plastic strategies for rehabilitative interventions.

Recent studies have demonstrated that reactive and volitional saccades are under the control partially segregated mechanisms and that these mechanisms are to be found in physically separate parts of the brain. The segregation is also seen in the plastic mechanisms that underpin the adaptation of these classes of saccades. We will use a classic double step saccade paradigm to induce adaptation in both reflexive pro-saccades and voluntary scanning saccades. To investigate the functional localisation of plasticity TMS will be used to temporarily interrupt the function of the parietal and frontal eye fields and the cerebellum. The study will investigate whether interruption of these sites has a specific effect on one or other class of saccade.

Cells in the cerebellum change their firing patterns during adaptation of reflexive pro-saccades in a way that could drive the adaptation. It is thought that outward adaptation (saccade size increases) is caused by excitatory, whereas inward adaptation (saccades size decrease) is caused by inhibitory processes. TDCS can be applied in a configuration with inhibitory and excitatory consequences respectively on the underlying neural tissue. We will use TDCS applied to the cerebellum to test the effect of increasing inhibition or excitation on the production of inward and outward reactive saccadic adaptation - we predict a double-dissociation.

We will also record local field potentials from electrodes implanted in the thalamic targets of the cerebellum in patients undergoing deep brain stimulation surgery during inward an outward saccadic adaptation. Recording the electrophysiological output of the cerebellum will inform us of the electrophysiolgical changes in the cerebellum; a first in the human. We will also record local field potentials from the cerebellar thalamus during rest and saccadic eye movements before and after TDCS. Doing this will allow us to understand the changes in cellular excitability induced by TDCS.

The work proposed here is primarily of a basic scientific nature, addressing important questions about how the human brain controls and adapts movement. In the short to medium term the impact will be principally on researchers in the field of neuronal plasticity and adaption responses. Eventually, by furthering our understanding of these operations in the normal nervous system, we expect to impact on other areas of neurology and rehabilitation.

The plasticity we will study in the program of work presented here is focused onto the saccadic system, although the mechanisms by which such adaptive changes take place are likely to be applicable to other systems. Furthermore, the segregation of motor learning between neocortex and cerebellum and the interactions between these structures are likely to be relevant to, and probably common to, other types of motor learning. Thus, the research will be of a general relevance to those who have a more applied interest in adaptation in the brain, such as those refining rehabilitation strategies after brain injury.

For example, stroke to areas of the cortex involved in the control of eye movements can produce both motoric and cognitive symptoms, such as hemispherical neglect. Recent rehabilitation strategies for such visuo-attentional deficits have successfully utilised techniques that impose simple sensorimotor adaptation on the oculomotor system using prism glasses. Such recovery implicates adaptation in the oculomotor system as a method for redirecting visual attention in a meaningful way for recovery after stroke. Understanding the adaptive mechanisms and the areas of the brain that underlie these plastic changes will promote the clinical applications of sensorimotor adaptations such as prism adaptation and possibly saccadic adaptation in aiding recovery after brain damage.

The research will also impact on the field of transcranial direct current stimulation (TDCS). TDCS is a rapidly expanding technique of interest in the neurosciences, with many hoping such stimulation will aid rehabilitation following brain damage. However, the mechanisms by which TDCS influences the excitability of neural tissue. The results of our experiments on saccadic plasticity using TDCS will allow us to infer the effect of TDCS on the excitability of the cerebellum. We will confirm the effects of TDCS on the cerebellum by recording in the cerebellar output nuclei in the thalamus. Such recordings - a first - will allow us to definitively asses the effects of TDCS.

Our research will impact on our understanding of the basic mechanisms of brain plasticity. It will also impact on our understanding of the mechanisms by which TDCS induces excitatory and inhibitory changes in neural tissue. Combined our research will refine a framework within which we can ultimately explore the plastic and induced plastic changes (using transcranial stimulation) in the brain with the aim of impacting on current and future neuro-rehabilitative strategies.