Physiological and functional interactions between cortical and subcortical structures in skilled hand movements

Grasping and manipulating objects and using tools are all important skilled hand functions that we perform on a daily basis. Often we take these skills, such as writing and eating, for granted. This is of course until injury or disease prevents us from performing such activities. Deficits in hand function can have tremendous effects on the simplest of tasks. Rehabilitative interventions have proved useful for the improvement of hand function, but their benefits remain limited. Brain and spinal cord physiological mechanisms that underlie skilled grasping are complex and still are not well understood. Investigating these mechanisms and how they interact with one another will help us better understand the central nervous system in health and disease.

The first aim of this proposal is to investigate how particular areas of the brain involved in the grasping of objects, known as the premotor cortex, interact with circuits within the spinal cord. Research in monkeys has already shown that there are direct and indirect pathways from the brain to the spinal cord. Yet, whether these connections exist and are functional within the human is unknown. Therefore, using non-invasive magnetic and electrical stimulation techniques we will investigate how the premotor cortex interacts with two spinal cord circuits at rest and during skilled grasp (e.g. a precision grip - holding an object between the index finger and thumb). The first is a simple spinal reflex circuit and the second is a more complex system of spinal neurons that is thought to reshape signals from the brain on their way down to arm muscles, known as the propriospinal system. These experiments will characterise whether there are direct and/or indirect interactions between the premotor cortex and different spinal cord circuitry that innervate hand muscles.

Previous work investigating the propriospinal system's involvement in skilled grasping has yielded conflicting results. Yet, as this spinal circuit reshapes brain signals on their way to muscles it could play a particularly important role when unexpected internal or external changes occur during grasping. The propriospinal system has not been previously tested under these circumstances, therefore the second aim of this proposal is to examine the propriospinal system's contribution to unexpected changes during a grasping task. Again, we will apply non-invasive magnetic and electrical stimulation during two tasks. The first task will test how the propriospinal system is affected when an object of an unexpected weight is grasped. The second task will test how the propriospinal system is affected when the weight of an object is changed prior to grasping. These experiments will allow us to characterise when and during what unexpected circumstances the propriospinal system comes into play during skilled grasping.

This work has the potential to benefit research and clinical applications in motor disorders. Understanding the interactions between premotor areas and the spinal cord could provide alternative potential targets for stimulation protocols that are designed to increase activity in the brain or spinal cord, and ultimately improve hand motor function, after stroke or spinal cord injury. Non-human primate research has already shown the importance of the propriospinal system after spinal cord injury, so knowledge of how to facilitate this system could be important in rehabilitation strategies. Finally, the findings of this work could improve the design of software and robotic hands and prosthesis used for grasping for people with paralysed or absent limbs.

Skilled grasping involves complex neural mechanisms both within the brain and spinal cord. Descending motor commands and ascending afferent feedback must be integrated to perform successful skilled grasping. Cortico-cortical interactions and spinal cord circuits are vital for integrating and updating these signals. In the monkey, there are substantial connections from premotor areas to both upper and lower segments of the cervical spinal cord. The propriospinal system, located at segments C3-C4, is a circuit of spinal interneurons that receives inputs from the ventral premotor cortex (PMv). To date, it is unknown whether these anatomical projections exist in the human and whether they have functional benefits. In monkeys and humans, both the PMv and propriospinal system have roles to play in skilled grasping. However, the role of the propriospinal system in humans during dynamic grasping tasks is not well understood.

In this project, we will investigate the physiological interactions between PMv and the spinal cord using transcranial magnetic stimulation (TMS) and peripheral nerve stimulation (PNS). The interval between descending and peripheral volleys and stimulation intensity will be varied to characterise these interactions. Firstly, we will explore how reflexes in forearm and intrinsic finger muscles are modulated by descending volleys from the PMv. Secondly, we will study how PMv interacts with the propriospinal system. Combining PMv with low intensity paired motor cortex TMS and PNS will allow us to reveal if PMv has a causal influence on the propriospinal system. Finally, we will investigate how the propriospinal system is modulated during a dynamic grasping task. Here, we will manipulate the task demands after or prior to object contact to test whether the propriospinal system modulates corticospinal output. Importantly, this will allow us to show whether the propriospinal system updates motor commands "en route" to the motoneurons.

Our project has the potential to improve quality of life, health and well-being of people with motor disorders. Hand function is critical for daily life. Deficits in hand motor function have tremendous effects on activities which require skilled grasp such as manipulating small objects, eating, writing, etc. Motor disorders are extremely common, the prevalence of stroke and Parkinson's disease in Western countries is around 500 and 300 per 100,000, respectively. In the UK, there are 1.1 million people living with post-stroke motor deficits. The prevalence of other neurological motor disorders such as Essential tremor may be even greater. Indeed, in the States it is estimated that there are around 10 million people with Essential Tremor (International Essential Tremor Foundation). Another common cause of motor dysfunction is spinal cord injury (SCI). SCI affects approximately 12,000 people in the U.S. each year. More than 50% of these injuries involve cervical levels (www.nscisc.uab.edu 2010), resulting in large impairments in hand motor function (Snoek et al. 2004; Herrmann et al. 2010). In the UK and Ireland, around 1000 people sustain a SCI each year, primarily affecting young adults. Approximately, 50,000 people live with paralysis in the UK and Ireland, costing the NHS an estimated £1 billion per annum (Spinal Research UK).
Thus, basic research into understanding how the brain and spinal cord interact during skilled grasping could improve the treatment of motor disorders. Since that these disorders lesion the central nervous system at different levels, it is important to investigate the different pathways from the brain to the spinal cord and alternative spinal circuitry that could promote functional recovery. For instance, the primary motor cortex is an area of the brain that is commonly targeted for plasticity protocols in stroke, given the right parameters the premotor cortex could be an equally viable site to stimulate to increase corticospinal transmission and hand motor function. Similarly, the propriospinal system is located in the high cervical segments, with a better understanding of this system and its importance in grasping, plasticity protocols that specifically target the spinal cord (as pioneerd by Dr Bunday) could also target propriospinal neurons and effectively bypass some cervical lesions. In addition, it is known that in monkeys the propriospinal system is a likely mechanism by which skilled grasping is recovered. By investigating in the human what conditions facilitate the use of this system, this knowledge could be incorporated into rehabilitation strategies.
Another major area in which this research would be advantageous is in the brain machine interface (BMI) and the design of robotic limbs and hand prostheses. Currently, in BMIs brain activity is used to guide the robotic arm, however the signal processing module provides limited sensory feedback. Under predictable testing conditions these methods of coding work well. However, when grasping tasks are unpredictable an additional level of signal processing where ongoing signals can be updated and altered when the external environment suddenly changes could improve robotic grasp control hence its dexterity. Also, a system that relies on two direct parallel processors rather than one serial pathway, much like the brain relies on the premotor and primary cortex for grasping control, could be more efficient and contribute to more precise control of robotic digits. For example, recently Li et al. (2014) showed that the assistance of two control patterns enabled a BMI to achieve the motion control of a manipulator in the whole 3D workspace. Thus, understanding the parameters under which an additional pathway (i.e. premotor cortex to spinal cord) work would aid the programming of such systems.
References:
Herrmann KH et al. Spinal Cord 2010. Apr;49(4):534-43
Snoek GJ et al. Spinal Cord 2004;42: 526-532
Li T et al. J Neurosci Methods 2014;224: 26-38