Infantile spasms are generalized sezures specific to early infancy, and are believed to result from complex cortical-subcortical interactions during a critical period of development. We used positorn emission tomography (PET) to determine local cerebral metabolic rates for glucose (lCMRGlc) in 44 infants with spasms, in an attempt to define the neuroanatomical substrates that mediate these seizures. All infants were studied in the awake state during continuous electroencephalographic monitoring. The most consistent abnormality on PET, seen in 32 infants, was the symmetrical increase in lCMRGlc in the lenticular nuclei, compared to age-matched normal infants (p < 0.05). In 21 infants, even though the brain stem appeared to be visually more prominent compared to normal infants, statistically significant differences could not be demostrated. Relative hypermetabolism of the lenticular nuceli (1) occured irrespective of whether the spasms were cryptogenic or symptomatic, (2) was associated with focal cortical hypometabolism in 22 and focal cortical hypermetabolism in 5 of the 44 infants, and (3) was not characterized by any specific electroencephalographic abnormality during PET. These findings suggest that the lenticular nuclei may contribute to the pathophysiological state that predisposes to infantile spasms, and is consistent with the observation that spasms are clinically symmetrical even when focal cortical lesions are present. A scheme describing the neuronal circuitry likely to be involved in the generation of infantile spasms is proposed.