This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Motor impairments represent the primary functional deficit observed following stroke. Over 80% of all stroke victims exhibit some form of movement disability with upper extremity impairments being the most common. Post stroke motor rehabilitation can often significantly improve motor function depending on the severity and location of the damage (Duncan et al., 2000). Although the specific neural mechanisms underlying motor recovery are unknown, recent neural imaging and cortical stimulation experiments have implicated functional compensation within residual neural tissue. Rehabilitation induced improvements in motor performance can alter both the pattern of cortical activity associated with movement (Cramer, 2002) and the locus of stimulation evoked movement representations within intact cortical tissue (Nudo et al., 1996; Kleim et al., 2003). Restoration of movement through motor rehabilitation may be supported by functional reorganization within intact motor areas. Understanding those factors contributing to the capacity for motor cortex reorganization will contribute to the development of putative therapeutic interventions for enhancing motor recovery after stroke.The development of skilled movement patterns has been shown to induce changes in cortical movement representations whereby there is an expansion of representations corresponding to the trained movements into neighboring cortical areas (Kleim et al., 1998; Nudo et al., 1996). Furthermore, the map changes appear to lag behind significant improvements in motor skill (Kleim et al., 2004). These results have lead to the hypothesis that the same neural mechanisms that support motor learning in the intact brain also support motor 'relearning' in the damaged brain (Kleim et al., 2003). Thus studying the relationship between differential motor experience and the neural organization of movement in the intact brain will provide insight into the neurophysiological correlates of motor recovery in the damaged brain. Such information has become particularly important as novel rehabilitation therapies are being implimented that restrict the use of the unimpaired limb in order to promote use of the impaired limb. Initial results suggest that such constraint induced movement therapy can significantly enhance motor ability in the impaired limb and induce changes in functional organization within motor areas of cerebral cortex (Schaechter et al., 2002). However, recent work has suggested that the contralesional hemisphere may also be involved in supporting motor recovery. Changes in the pattern of movement related brain activity in the intact hemisphere have been shown and are related to the degree of recovery (Zemke et al., 2003). Therefore, restricting the use of the unimpaired hand may have neurophysiological consequences in the contralesional hemisphere that can affect recovery of the impaired limb. Finally, recent work has demonstrated that there may be specific genetic profiles that predict the capacity for neural plasticity (Hariri et al., 2003; Egan et al., 2003). Polymorphisms in the BDNF gene have been shown to correlate with both memory capacity and synaptic plasticity. Thus these same mutations may predict capacity for motor learning, motor map plasticity and ultimately recovery from stroke. In addition, several mitochondrial genes have been implicated in metabolic processes during recovery after stroke. These same genes may also be involved in the cascade of cellular events that underly plasticity in the normal brain. The present study will examine the effects of differential motor experience on the topography of movement representations in healthy volunteers across time. Subjects will either be trained on a skilled digit movement (SDM) task, an unskilled digit movement (UDM) or receive no digit movement (NDM) training. The results will provide information regarding the impact of differential motor experience on motor performance and motor map organization. Furthermore, it will examine whether pretests of map plasticity in response to experience can predict capacity for plasticity and provide insight into the genetic factors contributing to brain plasticity, learning in the intact brain and relearning in the damaged brain.
SPECIFIC AIMSI n the proposed study, a pool of healthy volunteer subjects will be prescreened via phone interview and questionnaire. Blood samples will be drawn for genetic analysis from the arm contralateral to the dominant hand and used to detect the presence of various polymorphisms in the brain derived neurotrophic factor (BDNF) gene as well as the apoE gene and measures of mitochondrial genetics. Structural MRI will be performed in order to determine the stereotaxic location of the standard hand area, contralateral to the tested hand, on the posterior bank of the precentral gyrus. Prior to differential motor training, blood samples will be drawn and TMS will be used to establish a baseline map of the hand/forearm representation contralateral to the trained hand. Subjects will also be assessed using a battery of motor tasks to assess baseline motor performance. Transient ischemic nerve blockade will then be induced using a pressured tourniquet applied to the forearm for 35 mins. This procedure is entirely safe and has been shown to induce map reorganization and will be used to assess capacity for reorganization prior to motor training (Classen et al., 1998). The following day, subjects will be mapped using TMS and will be assigned to one of 3 motor training protocols: (1) a skilled digit movement task, (2) an unskilled digit movement task, or (3) no motor training. Subjects will all be asked to perform their respective motor training protocols for 30 mins each day at home. A second map will be taken after 30 mins of respective protocol performance on day 1. This procedure will be repeated on days 3,5,8,10 and 12. A final motor assessment will also be performed on the same battery of motor tasks used in pretraining on day 13. Single pulse TMS is a completely safe and non-invasive procedure. The methods to be employed at each TMS session are overall identical to those employed in the UCI IRB-approved study by the same PI (HS# 2004-3540 'Does mental practice of foot movement improve corticospinal conduction and motor status after spinal cord injury?).
SPECIFIC AIM OF THE PROPOSED STUDY is to test the hypothesis that differential motor experience will have direct impact on motor performance that will be reflected as changes in the topography of movement representations within primary motor cortex. Further, the capacity for experience-dependent plasticity will correlate with the baseline measure of map reorganization found in response to the tourniquet-sensory manipulation, as well as with each of the two tested genetic polymorphisms. Specifically, we propose that 1. Simple movement repetition (Unskilled Training) will not significantly influence motor performance or cause enduring changes in motor map topography. 2. Skilled training will induce initially transient changes in motor map topography that will co-occur with improvements in motor performance but will be followed by enduring changes in map topography. 3. Capacity for map reorganization observed during ischemic nerve blockade will correlate with skill learning capacity and map reorganization. 4. The presence of specific polymorphisms in the BDNF and apoE genes, as well as measures of mitochondrial genetics, will predict capacity for map plasticity and skill learning.References:Cramer S.C. et al (2002). Ann Neurol. 2002 Nov;52(5):607-616.Duncan, P.W, et al., (2000). Neuropharmacology, 39: 835-841.Egan et al., (2003). Cell, 112: 257-269.Harari et al., (2003) J. Neuroscience, 6690-6694.Kleim, J.A. et al., (2003). Neurological Res., 25, 789-793.Kleim, J.A. et al., (2004). J. Neurosci., 24, 628-633.Kleim J.A. et al., (1998). J Neurophysiol. 80:3321-3325.Nudo R.J. et al. (1996) Science, 272:1791-1794Schaechter J.D. et al., (2002). Neurorehabil Neural Repair.,16(4):326-38. Zemke A.C. et al., (2003). Stroke, 34(5):23-8.
Showing the most recent 10 out of 1825 publications
