OBJECTIVE To compare cortical function at rest and during limb movement in patients with progressive lower motor neuron degeneration (LMND) and amyotrophic lateral sclerosis (ALS). METHODS PET was used to measure regional cerebral blood flow (rCBF) in five patients with progressive LMND, six patients with classic ALS with a similar degree of motor impairment, and six age-matched control subjects; measurements were taken in the resting state and while subjects moved a joystick with their right hand. RESULTS rCBF at rest in the primary sensorimotor cortex (SMC) was significantly (p < 0.001) lower in ALS patients than in control subjects or LMND patients. rCBF at rest did not differ significantly between LMND patients and controls. During joystick movement, ALS patients showed significantly (p < 0.001) greater rCBF increases than controls or LMND patients in the hand/arm area of the SMC bilaterally, the face area of the contralateral SMC, the second somatic sensory (SII) cortex bilaterally, and the contralateral premotor and supplementary motor cortices. LMND patients showed significantly (p < 0.001) greater rCBF increases than controls and ALS patients only in the anterior insular cortex bilaterally. CONCLUSIONS The finding of reduced rCBF at rest, together with abnormal bilateral activation and altered somatotopy during movement, in the sensorimotor cortex of ALS but not LMND patients suggests that these abnormalities reflect loss of pyramidal neurons. Abnormal activation of perisylvian areas (insular and SII cortices) during limb movement in both LMND and ALS patients suggests that these may be accessory sensorimotor areas that are recruited nonspecifically in response to limb weakness.