Sub-cortical systems for stopping

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.

Instructions for movement are transmitted from the brain to the spinal cord over various descending tracts. In primates, there has been much past emphasis on the corticospinal tract, which is undoubtedly a major pathway. Recently, our group have shown that the reticulospinal tract also is important in primate motor control, even playing a role in precise movements of the hand. All of this work concerns generation of movement; however, in some circumstances it can also be important to inhibit a movement. Previous work has looked at the cortical processes behind stopping a movement, and assumed that these act to prevent corticospinal output from primary motor cortex. However, there is also evidence for a pathway to the reticular formation from basal ganglia which may allow sub-cortical inhibition of output. Very little data exist on this in primates; it is important to understand this system, as deficits in it may underlie a range of clinical problems such as spasticity, rigidity and dystonia.

In this project, we will use experiments in anaesthetised monkeys to characterise the different reticulospinal pathways capable of inhibiting spinal motoneurons, determining their input and output connections. We will then train monkeys to perform a reaction time task, in which they must respond to a 'go' cue, but prevent the movement whenever there is a 'stop' cue. We will characterise performance using the well-defined race model, allowing estimation of the stop signal reaction time. Neural recordings will be made from motor and pre-motor cortex, the reticular formation and spinal cord during task performance. Comparing the timing of neural activity with behaviour will show which centres could contribute to stopping. Finally, we will test the impact of stimulating these centres electrically or pharmacologically on behaviour, providing data on their causal contribution.

A major beneficiary of this work will be academic researchers interested in movement control, and the cognitive mechanisms contributing to response inhibition. The results will provide detailed physiological information on reticulospinal pathways for inhibition, as well as revealing how these are used in stopping a motor output. The project considers multiple areas of the central nervous system, and how they interact to generate a coordinated output. Scientists interested in the function of the motor and pre-motor cortex, basal ganglia, brainstem and spinal cord will all find the results important in understanding the function of the region which is their primary interest.

Clinicians who care for patients with movement disorders will also be interested in this work. As described in the Case for Support, there are multiple reticulospinal pathways for motor inhibition. The existing evidence is that these may contribute to the neurological signs of rigidity and spasticity. Diseases involving the basal ganglia such as Parkinson's, Huntington's, Tourette's and dystonia all may have dysfunction in the systems which we are studying here. Improving our understanding of these pathways provides a framework in which clinicians can place their findings on patients.

Once we understand these circuits, we can start to think about how we can intervene to change them and improve outcomes for patients. In our own group, we are currently exploring the potential of wearable electronic devices to deliver paired stimulation protocols to induce neural plasticity. We are conducting a clinical trial on one protocol aimed at strengthening reticulospinal output to extensor muscles, with the aim of improving hand function in stroke. This protocol arose directly out of the improved understanding of reticulospinal pathways and inputs to them which we gained from primate experiments. The results of the present project are also likely to inform the design of novel paradigms to improve symptoms. For example, we may be able to design paired stimulation protocols to reduce spasticity or rigidity once we understand how these circuits work. Other groups are also working on stimulus interventions to enhance rehabilitative outcomes, and the results are likely to be of interest to all in this field.

The post-doctoral research assistant employed on this project will be trained in a wide range of scientific skills, including behavioural training of the animals, surgical implant, electrophysiological recording, computational data analysis, presentation and report writing. This will stand them in good stead for their future scientific career, either within academia or in industry.