Prolonged disuse of limbs?and corresponding brain systems?leads to detrimental plasticity that worsens clinical outcomes after stroke and brain injury. There is currently little understanding of the neurophysiology of disuse and, as a result, tools for assessment and therapy after neurological damage are severely limited. Prior work studying related models of plasticity in mice and nonhuman primates leads us to ask two questions about the neurophysiology of disuse: 1) Does disuse cause focal disinhibition of motor and control regions? 2) Can disuse account for reduced functional connectivity observed in stroke patients? To address these questions, we will use fiberglass casts to constrain use of the dominant upper extremity for two weeks in healthy participants. Casting causes a dramatic reduction in strength. Previous studies have shown that reduced strength following disuse likely involves a deficit of activating upper motor neurons in the primary motor cortex, rather than muscle atrophy or changes in the peripheral nervous system. To examine changes in the central nervous system, we will acquire 30 minutes of resting-state functional magnetic resonance imaging (fMRI) data every day for nearly two months before, during and after casting. Sensory deafferentation, a plasticity model showing some neurophysiological overlap with disuse, has been extensively studied in animal models. One key mechanism leading to plasticity in deafferentation is a focal disinhibition of the deafferented cortex. We hypothesize that similar disinhibition drives plasticity in disuse. Work in mice has shown that disinhibition of the barrel cortex causes increased fluctuations in resting-state activity, detectable with blood oxygen level-dependent (BOLD) measurements. Therefore, if disuse leads to disinhibition of motor and control structures, as we hypothesize, then we should be able to measure larger fluctuations in these structures in our resting-state fMRI data. Resting-state functional connectivity (RSFC) is a phenomenon in which functionally related regions show tight correlations in their resting-state activity. Studies of patients suffering strokes of the internal capsule, which contains motor axons of the corticospinal tract, found weakened RSFC between the left and right primary motor cortex. Further, the degree to which this functional connection was weakened predicted individual differences in motor impairment. We hypothesize that reduced RSFC in stroke patients may be driven by disuse of the impaired upper extremity. If this is correct, we should find similar changes in our model of disuse.
Prolonged disuse of limbs?and corresponding brain systems?leads to plasticity that worsens impairment after stroke and brain injury. To explore the neurophysiological processes contributing to plasticity in disuse, we will constrain the dominant upper extremity of healthy subjects for two weeks and acquire 30 minutes of resting-state functional connectivity MRI every day for approximately two months. We will use these data to ask if plasticity in disuse involves focal disinhibition of motor and control regions and to test if disuse can account for reduced functional connectivity observed in patients after stroke.
