Two Types of Grasp: Dissecting Cortical and Sub-cortical Contributions to Primate Hand Function

The primate hand is a highly versatile actuator, capable of flexible reconfiguration to achieve task goals. This is very different from the paw of lower mammals, which has a capability restricted to whole-hand grasp. There is some evidence that primates may have retained capacities for more primitive grasp, alongside the evolutionary development of dexterous hand function. This suggests that the hand can operate in two modes. In one, the fingers flex or extend together to grasp an object (the power grip). In the other mode, single fingers can be independently controlled, to produce arbitrary gestures or complex grasps exemplified by the precision (pinch) grip. We propose that these modes are underpinned by different control circuits within the brain and spinal cord. Whilst interesting to the basic science of the neural control of movement, this idea becomes especially important in patients who are recovering from damage such as after stroke or spinal cord injury. Then, key components of the precision grip network seem to be lost; recovery is limited to gross grasp. The hand becomes a paw.

In this proposal, we will determine which neural circuits contribute to the different types of hand use, using macaque monkeys which have very similar hand function to humans. We will first train monkeys to perform power grip, precision grip and an isolated index finger movement. Using fine microelectrodes, we will then record neural activity from the motor and pre-motor cortex, brainstem and spinal cord during performance of the different hand movements. By measuring the changes in cell activity as the tasks are carried out, we will be able to tell which areas contribute to each mode of hand operation. In some sessions, we will inject tiny quantities of a drug into an area to silence it; observing the types of hand deficits produced will confirm the role each area plays.

Commands to make any movement originate in the cerebral cortex, and must be transmitted to lower centres to allow them to be executed. In a second series of experiments using anaesthetised monkeys, we will place stimulating electrodes in the motor and pre-motor areas of the cortex, and measure cell responses in the brainstem and spinal cord following cortical stimulation. This will tell us how the cortex communicates its instructions to sub-cortical structures. In humans, it is possible to activate cortical outputs non-invasively using transcranial magnetic brain stimulation (TMS). If we change how the coil is held on the head, TMS seems to stimulate the brain differently, but we don't know what is activated in the various conditions. We will address this by also using TMS in the anaesthetised monkeys, to tell us if TMS can selectively access the circuits for power and precision grips depending on how the coil is oriented. Finally, we will test how cells in the various areas respond to stimulation of the sensory receptors in skin and muscle.

In studies in humans, we will apply the knowledge gained, using TMS in different orientations combined with sensory stimuli to probe specific components of the power and precision grip networks. After validating the methods in healthy human subjects, we will apply them to individuals who have recovered from spinal cord injury, thereby showing how the various circuits reconfigure to mediate recovery.

This work will reveal core information about the control of human hand function and its recovery after damage. This foundation is required to develop novel, principled approaches to grasp rehabilitation. As the hand is so central to activities of daily living, even small future improvements in function could have major impacts in alleviating disability and raising quality of life.

Unlike in lower mammals, the primate corticospinal tract connects monosynaptically to motoneurons. Such connections allow primates flexibly to choose from a range of grasp types. By contrast, non-primates only use a whole-hand 'power grip'. In primates the neural systems for power grip may also exist, providing parallel control circuits allowing different modes of hand function. This probably involves descending outputs from motor and pre-motor cortex which target sub-cortical relays including the brainstem reticular formation (origin of the reticulospinal tract), propriospinal interneurons located in spinal segments C3-C4, and segmental interneurons located in the cervical enlargement. We do not know how these centres contribute differently to power and precision grasps. This is important, as damage such as spinal cord injury or stroke frequently impairs corticospinal function. Recovery of hand function may then rely on the systems normally subserving power grip.

In this project, we will train monkeys to perform different grips, and then record cell spiking from primary motor cortex, ventral pre-motor cortex, supplementary motor area, the reticular formation, C3-C4 and C6-T1 spinal cord interneurons. Task-related firing will reveal how these areas contribute to different grasps. We will also focally inactivate each region by injecting inhibitory agonists, and assess the grip deficits produced. In anaesthetised monkeys, we will assess the cortical inputs to sub-cortical regions by testing the responses to cortical microstimulation via implanted electrodes, and transcranial magnetic brain stimulation with the stimulating coil held in different orientations. This information will allow us to design and interpret non-invasive methods to probe specific neural circuits in humans. After testing such approaches in healthy subjects, we will use them to quantify how different centres contribute to hand function in individuals after recovery from spinal cord injury.

A major beneficiary of this work will be academic researchers interested in the control of the hand. 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, brainstem and spinal cord will all find the results important in understanding the function of the region which is their primary interest.

Many movement disorders produce deficits in hand movement. These include the focal dystonias such as writer's cramp and musicians' dystonia which particularly involve the hand, but also disorders which involve movement more widely, such as Essential Tremor or Parkinson's Disease. Although such patients show widespread deficits, the importance of hand function in daily life means that difficulties in hand use may contribute disproportionately to disability. Improving our understanding of cortical and sub-cortical pathways for different grasps provides a framework in which clinicians can place their findings on patients, and begin to think rationally about new targeted therapy.

Once we know what afferent inputs are received by specific nodes in the grasp network, it may be possible to devise protocols which converge these inputs with precise timing to induce spike-timing dependent plasticity. We have recently explored this approach by pairing auditory clicks with electrical muscle shocks to potentiate or depress putative reticulospinal outputs (ref. [35] in Case for Support); we used a novel wearable electronic device developed in the Baker group, which allowed paired stimuli to be delivered continually for many hours whilst the subject went about normal daily life. This specific protocol is now at the clinical trial stage in stroke patients. Similar approaches could enable us to modify grasp circuits selectively to enhance rehabilitation after injury. Even restoring a primitive power grip to stroke or spinal cord injury patients could greatly improve their quality of life. We have everything needed to deploy such methods; we lack only the knowledge of how inputs are configured to different parts of the grasp circuit, which this project will provide. The Baker group in Newcastle is currently working on commercialisation of our wearable device technology for paired stimulation with a major company in Newcastle for two applications that are close to market. This existing relationship means that we have a clear and direct pathway to exploit any novel device-based plasticity protocols developed from the results of this project.

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.