Neuropsychology 1996, Vol. 10, No. 1,3-10 In the public domain PET Validation of a Novel Prefrontal Task: Delayed Response Alternation James M. Gold, Karen Faith Berman, Christopher Randolph, Terry E. Goldberg, and Daniel R. Weinberger National Institute of Mental Health Neuroscience Center at St. Elizabeths Deficits in working memory have been proposed to explain the performance failures of frontally lesioned primates on delayed alternation (DA) and delayed response (DR) tasks. The authors examined a computerized test of delayed response alternation (DRA), which combines elements of DR and DA in a sample of 18 normal volunteers who underwent oxygen-15 PET regional cerebral blood flow scans during the DRA and a sensorimotor control task. Significant activations were observed in a network of frontal, parietal, occipital, and temporal regions during initial task performance. A qualitatively similar but somewhat reduced set of activations was observed in a subset of participants who repeated the task after practice and instruction. These results are consistent with distributed models of working memory derived from studies of nonhuman primates and suggest that the frontal lobes contribute to human working memory function. There is general consensus within neuropsychology that the frontal lobes mediate a diverse and complex group of cognitive functions commonly subsumed under the term executive con- trol, including planning, judgment, reasoning, and self- monitoring (Stuss & Benson, 1986; Weinberger, 1993). Clini- cal testing instruments thought to measure executive functions are similarly complex and varied, such as the Wisconsin Card Sorting Test (WCST), Stroop Color Word Interference, Trail Making, and verbal fluency, and a more componential cogni- tive view of frontal lobe function have been lacking. However, several recent computational approaches have suggested that working memory may be a critical common denominator of several complex frontal tasks including the Wisconsin Card Sorting Test (Kimberg & Farah, 1993; Pennington, 1994). This perspective is consistent with a long history of research on nonhuman primates, which has suggested that the frontal cortex plays a critical role in the ability to hold perceptually absent information on line to guide action (Goldman-Rakic, 1987). This type of short-term or working memory appears to be an important common feature of the delayed response (DR) and delayed alternation (DA) paradigms that have proven to be sensitive to prefrontal lesions in nonhuman primates (Goldman- Rakic, 1987). In these paradigms, the animal must track either the location of a stimulus or of its own prior response choice in order to gain a food reward following the imposition of a delay period. Thus, there are no environmental cues available at the time the animal makes a response, necessitating the use of an James M. Gold, Karen Faith Berman, Christopher Randolph, Terry E. Goldberg, and Daniel R. Weinberger, Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health Neuroscience Center at St. Elizabeths. Christopher Randolph is now at the Departments of Psychiatry and Neurology, Northwestern University. Correspondence concerning this article should be addressed to James M. Gold, who is now at the Maryland Psychiatric Research Center, P.O. Box 21247, Baltimore, Maryland 21228. internal representation to guide action. This representation must be updated on every trial. In single cell recordings from the frontal cortex of behaving monkeys, increased firing of prefrontal neurons has been observed during the delay inter- vals of DR supporting the concept that these neurons are involved in the maintenance of information (Funahshi, Bruce, & Goldman-Rakic, 1989; Fuster, 1973). Goldman-Rakic and Friedman (1991) in summarizing a series of studies with 2-deoxyglucose (2DG) technique noted that the performance of delayed response tasks resulted in increased glucose utiliza- tion in the frontal cortex, hippocampus, thalamus, and parietal cortex, suggesting that a widely distributed network of intercon- nected anatomic regions participate in the performance of these tasks (see also Friedman & Goldman-Rakic, 1994). These paradigms have had limited use in human popula- tions, but the available data are encouraging. Patients with frontal lobe lesions have been found to perform poorly on DA and DR, and the extent of DR and DA impairment correlated with perseverative responses on the WCST (Freedman & Oscar-Berman, 1986). Impairments have also been observed most often on DA in patients with Parkinson's disease, KorsakofFs syndrome, and Alzheimer's disease (see Oscar- Berman, McNamara, & Freedman, 1991, for review). Of note, Verin et al. (1993) reported that patients with frontal lesions performed poorly on a classical delayed response test, but showed supernormal performance on a delayed alternation test, as these patients demonstrated an unusual alternation "bias." Although this result is somewhat at odds with the other studies in this area, their overall pattern of results on a series of alternation and reversal tasks suggest that the frontal cortex plays an important role in the sequential organization of behavior in response to changing environmental cues. Thus, their results can be seen as broadly compatible with a working memory framework. Initial applications of physiological imaging techniques have also suggested the involvement of the frontal cortex in elemen- tary working memory tasks. Jonides et al. (1993) recently reported that normal subjects studied with PET demonstrate