The three fundamental goals of my research are the following: 1) To understand the nature of the brain's own signals -- the "language" in which movement commands are expressed by neurons in the central nervous system. 2) To understand the mechanisms by which these signals are produced -- the nature of the connections among networks of neurons, and the transformations that occur in the signals as they propagate throughout these networks. 3) To develop applications of these basic principles that could be of therapeutic value to human patients. Much of this work is done in collaboration with students and faculty from the Biomedical Engineering Department and the Interdepartmental Neuroscience Program (NUIN).

In a practical sense, understanding how the brain encodes its movement commands comes down to the problem of deciphering the information contained in signals recorded from the brain. Neurons in motor areas of the cerebral cortex as well as in the brainstem, send their signals to the spinal cord, ultimately to control the activity of about 50 muscles of the arm and hand that are necessary for reaching, grasping and the manipulation of objects. Most of the experiments in my laboratory involve recordings made directly from the brains of animals during behavior. In these experiments, we are able to study the signals produced by individual neurons in the intricate circuits comprising real neural networks.

My research has shown that neurons in the motor cortex encode the activity of small groups of muscles that act synergistically to control movement. Different neurons control different groups of muscles, and together, the entire network produces coordinated movement. I have also studied two brainstem motor areas, the red nucleus, and the superior colliculus, which have similar organization, although each has a somewhat specialized function. Red nucleus controls predominantly groups of extensor muscles involved in hand function, while the certain parts of the colliculus control the shoulder muscles that help to direct reaching movements.

In the past, my lab has studied mainly the connections from these neurons to muscles. We are now beginning to look at the relations among neurons that give rise to their coordinated activity. This has become possible with the advent of chronically implanted arrays of electrodes that allow simultaneous recordings from 100 or more neurons. We are developing powerful computational tools to study the relations among these neurons, referred to as their "functional connectivity". While such tools can be developed (and are being studied) using simulated, artificial neural networks, comparison of such results with our data from actual neural networks is invaluable.

Our increased understanding of the signals in the brain, together with technological improvements in electronics and computers has given rise recently to a new field called "Brain Machine Interface". As the term implies, these are literally attempts to meld mind and machine. My laboratory is involved in several projects that use recordings from micro-electrodes implanted in the motor cortex as a source of control signals. Much work has been invested in the development of BMIs that are capable of controlling the position of a computer cursor or a robotic limb. However, because of my lab's interest in the control of muscles, we are instead working to develop a BMI that could restore control to the paralyzed muscles of a spinal cord injured patient. The approach is to record from the brain, predict the intended muscle activity, and bypass the injured spinal cord by directly activating the muscles through electrical stimulation. In addition to the potential of experiments like these to impact motor disorders in human patients, they also offer innovative new approaches to understanding the nature of the brain's command signals that control limb movement.

Holdefer RN, Miller LE (in press). "Dynamic Correspondence between Purkinje Neuronal Discharge and Forelimb Muscle Activation in the Macaque." Brain Research.

Fagg AH, Ojakangas G, Miller LE, Hatsopoulos NG (in press). "Kinetic trajectory decoding using motor cortical ensembles." IEEE Transactions on Neural Systems and Rehabilitation Engineering.

Fagg AH, Hatsopoulos NG, London BM, Reimer J, Solla SA, Wang D, Miller LE (2009). "Toward a Biomimetic, Bidirectional, Brain Machine Interface." 31st Annual International IEEE EMBS Conference, Minneapolis.

Pohlmeyer EA, Jordon LR, Kim P, and Miller LE. (2009). "A fully implanted drug delivery system for peripheral nerve blocks in behaving animals." Journal of neuroscience method. 182: 165-171.

Miller LE, Gibson A (2009). "The Red Nucleus." Squire L (ed) The New Encyclopedia of Neuroscience. Elsevier Ltd, Oxford. pp 55-62.

Pohlmeyer EA, Oby ER, Perreault EJ, Solla SA, Kilgore KL, Kirsch RF, Miller LE (2009). "Toward the Restoration of Hand Use to a Paralyzed Monkey: Brain-Controlled Functional Electrical Stimulation of Forearm Muscles." PLoS ONE 4: e5924.

Stevenson IH, Rebesco JM, Hatsopoulos NG, Haga Z, Miller LE, Kording KP (2009). "Bayesian inference of functional connectivity and network structure from spikes." IEEE Transactions on Neural Systems and Rehabilitation Engineering 17, 203-213.

Stevenson IH, Rebesco JM, Miller LE, Kording KP (2008). "Inferring functional connections between neurons." Curr Opin Neurobiol 18: 582-588.

Morrow MM, Pohlmeyer EA, Miller LE (2008). "Control of muscle synergies by cortical ensembles." Sternad D (ed) Progress in Motor Control - A Multidisciplinary Perspective. Springer, New York, pp 179-199.

London BM, Jordan LR, Jackson CR, Miller LE (2008). "Electrical stimulation of the proprioceptive cortex (area 3a) used to instruct a behaving monkey." IEEE Transactions on Neural Systems and Rehabilitation Engineering 16:32-36.

Pohlmeyer EA, Solla SA, Perreault EJ, Miller LE (2007). "Prediction of upper limb muscle activity from motor cortical discharge during reaching." Journal of Neural Engineering 4:369-379. PDF

Fagg AH, Hatsopoulos NG, de Lafuente V, Moxon KA, Nemati S, Rebesco JM, Romo R, Solla SA, Reimer J, Tkach D, Pohlmeyer EA, Miller LE (2007). "Biomimetic brain machine interfaces for the control of movement." JJ Neurosci 27: 11842-11846. PDF

Morrow, M.M., Jordan, L.R., and Miller, L.E. (2006). "A direct comparison of the task-dependent discharge of M1 in hand-space and muscle-space." J Neurophysiol. 97, 1786-1798. PDF

Holdefer, R.N., Houk, J.C., and Miller, L.E. (2005). "Movement-related discharge in the cerebellar nuclei persists after local injections of GABA(A) antagonists." J Neurophysiol 93, 35-43. PDF

Holdefer, R.N., and Miller, L.E. (2002). "Primary motor cortical neurons encode functional muscle synergies." Exp Brain Res 146, 233-243.

Stuphorn, V., Hoffmann, K.-P., and Miller, L.E. (1999). "Correlation of primate superior colliculus and reticular formation discharge with proximal limb muscle activity." Journal of Neurophysiology 81, 1978-1982.

Miller, L.E., and Houk, J.C. (1995). "Motor co-ordinates in primate red nucleus: preferential relation to muscle activation versus kinematic parameters." J. Physiol. 488, 533-548.

Miller, L.E., Theeuwen, M., and Gielen, C.C.A.M. (1992). "The control of arm pointing movements in three dimensions." Exp. Brain Res. 90, 415-426.