The goals of this project are to understand how the brain uses spinal cord circuits to coordinate movement and how neurological disorders alter the functioning of spinal motor circuits. In FY2006, clinical studies focused on the long-term changes that occur in two disorders, each affecting distinct components of the volitional motor system. In primary lateral sclerosis, the corticospinal tract degenerates, but spinal motor neurons survive. In polio survivors, spinal motor neurons were lost during the initial infection, but corticospinal neurons survived. [unreadable] [unreadable] In FY05, we reported that surviving motor neurons in PLS exhibit non-linear changes in their firing patterns consistent with self-sustaining depolarizations, such as expression of channels that produce persistent inward currents. In FY06, we investigated changes in cortical areas outside the primary motor cortex in PLS. In this study, we assessed whether short-axon intracortical circuits generating pre-movement potentials were spared in PLS. We found that cortical potentials from pre-motor and motor areas were both diminished, indicating PLS causes a more widespread dysfunction of neurons than just the corticospinal cells of the primary motor area. However, pre-movement changes in oscillatory EEG activity were preserved, raising hope that these signals could be used in PLS to generate commands for prosthetic devices such as brain computer interfaces.[unreadable] [unreadable] Many of the polio survivors living today had polio during the epidemics of the 1940's and 50's, but recovered and remained neurologically stable for many decades. Some polio survivors develop a post-polio syndrome, with new weakness and fatigue. The etiology of PPS is uncertain, particularly in those patients without new muscle atrophy. We hypothesized that loss of spinal motor neurons during the original infection led to changes in the organization of cortical motor areas that normally project to those neurons. As a first step in exploring this hypothesis, in FY 06, we verified the integrity of the corticospinal projection by measuring central motor conduction times and cortical thresholds to all four limbs in 25 polio survivors. In a subset of patients, studies of intracortical physiology at rest and during sub-fatiguing and fatiguing exercise were carried out using transcranial magnetic stimulation. These studies will continue in FY07.