Sub-cortical systems for stopping

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We normally think of movement as an active process, requiring a positive decision to move. However, in some circumstances the brain must actively stop a movement from taking place - for example, when a pedestrian is about to step into the road but then sees an approaching car. The neural circuits for inhibiting movement have been less well studied, but deficits in these systems could underlie several important clinical disorders. Spasticity after stroke, rigidity in Parkinson's disease and dystonia are all examples of excess muscle contraction. In this project, we seek to understand an important set of pathways for inhibiting movement which pass from the base of the brain to the spinal cord - the 'reticulospinal tract'. Almost all existing data on these pathways comes from rat or cat, which have important differences from humans. We will study them in macaque monkeys, where the systems for controlling movement are very close to those in man, making data directly relevant to human patients.We will first study the organisation of these pathways in anaesthetised animals. We will use sophisticated electrode arrays with many sites to record the activity of a large number of cells in the reticular formation and spinal cord. We will assess how these cells are interconnected using mathematical analysis methods, and we will test how they respond to stimulation of sensory receptors from muscles, and to different parts of the cerebral cortex. This will show us what different reticulospinal routes exist in primates for movement inhibition. By determining what inputs these centres receive, we might in future be able to design ways of modulating them, for example by specific arrangements of sensory inputs. This could lead to improved therapies for movement disorders where there is a deficit in inhibition of movement.The next stage of the project is to measure how these systems are actually used to inhibit movement. We will train monkeys to perform a task requiring them to respond to a 'go' light by pressing a button. On some trials, another 'stop' light will also illuminate, indicating that they should not respond. By varying the delay between go and stop lights, we can manipulate how effectively the monkeys can prevent an inappropriate movement. Once the monkeys are trained, we will record from the activity of cells in motor areas of the cerebral cortex, brainstem and spinal cord. By comparing the timing of activity in these centres with the stop and go cues, we will be able to determine how they cooperate to stop a movement. Finally, we will manipulate neural activity either by delivering weak electrical stimuli, or injecting very small amounts of drugs directly into these centres. If a brain area is involved in movement inhibition, we predict that stimulating it will make it easier to stop a planned movement, but blocking activity with a drug will make stopping harder, so that movements are made even when the signal to stop is delivered in good time. This experiment will give us firm evidence of which neural centres causally contribute to motor inhibition.This basic research will provide a key framework in which to understand a wide range of movement disorders in human patients. Deficits in inhibiting movement or muscle contraction probably underlie many clinical signs, but it is not clear what different neural systems produce particular deficits. For example, spasticity after stroke is quite different from rigidity in Parkinson's disease; these are likely to arise from different sub-systems. Understanding how these work, and what goes wrong in disease, may allow us to suggest novel interventions to ameliorate symptoms.