Dissecting the Biology of Prefrontal Cortical Dysfunction in Schizophrenia: Deficiency in Mnemonic Processing

Alterations in the normal recruitment of neuronal activity within prefrontal cortex (PFC) are directly related to changes in performance on cognitive tasks. Such alterations have particularly deleterious consequences for working memory, which has been considered to comprise the core cognitive deficit in schizophrenia and may prove to be the best predictor of outcome in patients. Neuroimaging studies promise to reveal important facets of altered prefrontal neuronal activity in multiple neuropsychiatric disorders in relation to different aspects of cognitive function. Elucidating the alterations in neuronal activity in relation to working memory processes dramatically enhances our capability to shed new insights into the biological mechanisms that are involved in prefrontal dysfunction. In their article in this issue, Driesen et al. ( ) squarely target the ability to maintain neuronal activity in particular regions of PFC as a core deficiency in prefrontal function in patients as compared with healthy control subjects performing a working memory task. This finding was made all the more significant by utilizing a task based on the knowledge gained from many years of research in the nonhuman primate. From the earliest studies in the monkey, it has been observed that many neurons in PFC fire during the delay period of delayed response tasks ( , ). As this delay activity appears to be selective for one memorandum or target location in the task and not another, it has been hypothesized to provide a cellular substrate for representation of a stimulus to be remembered, i.e., representational memory ( ). In this issue, Driesen et al. ( ) were able to examine the human parallel of this delay activity in the brains of patients with schizophrenia by employing a task in which the blood oxygen level-dependent (BOLD) response could be examined throughout and segregated into encoding, maintenance, and response phases of the working memory process. Capitalizing on a spatial delayed response task developed by Leung et al. ( ), they used a “cue” period wherein two or four spatial stimuli were presented followed by a long delay period of 16 seconds before presentation of the probe stimulus that required subjects to make a judgment as to whether it was a match or nonmatch to the locations of any of the cue stimuli. This paradigm allowed for a distinction between cue, delay, and response-related changes in the BOLD signal and identification of the impact of working memory load on these changes in patients as compared with control subjects. By these means, it became possible to resolve the hemodynamic response into an encoding peak, maintenance activity, and a response peak, much like the cue, delay, and response activity recorded in area 46 of nonhuman primates performing oculomotor delayed response tasks ( ). By elevating working memory load or increasing the length of the delay period in their study, Leung et al. ( ) pinpointed the role of middle frontal gyrus (MFG; Brodmann areas 46/9) in the maintenance component of working memory processing, at least within the spatial domain. This finding provided direct evidence for conservation of the role of dorsolateral PFC, particularly area 46, in the maintenance of a neural representation of spatial information across human and nonhuman primates.