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The cerebral cortex reorganizes in response to central or peripheral lesions. Although basal ganglia and cerebellum are key components of the network dedicated to movement control, their role in motor reorganization remains elusive. We therefore tested if slowly progressive neurodegenerative motor disease alters the subcortical functional anatomy of the basal ganglia-thalamo-cerebellar circuitry. Ten patients with amyotrophic lateral sclerosis (ALS) and ten healthy controls underwent functional magnetic resonance imaging (fMRI), while executing a simple finger flexion task. Cued by an acoustic trigger, they squeezed a handgrip force transducer with their right hand at 10% of their maximum voluntary contraction force. Movement frequency, amplitude, and force were controlled. Statistical parametric mapping of task-related BOLD-response revealed increased activation in ALS patients as compared to healthy controls. The main activation increases were found in the supplementary motor area, basal ganglia, brainstem, and cerebellum. These findings suggest that degeneration of cortical and spinal motor neurons in ALS leads to a recruitment of subcortical motor structures. These subcortical activation patterns strongly resemble functional activation in motor learning and might therefore represent adaptations of cortico-subcortical motor loops as a—albeit finally ineffective—mechanism to compensate for the ongoing loss of motor neurons in ALS. [ABSTRACT FROM AUTHOR]