Working memory (WM) involves the temporary storage of items for use in current mental operations and the guidance of ongoing behavior (1
). Cognitive neuroscientists often view WM as involving an initial phase of encoding percepts; a middle phase of maintaining, updating, scanning and manipulating the WM contents; and a final phase of selecting and enacting responses. Preclinical research provides insights into WM neurobiology. Single-cell recordings in non-human primates indicate that some neurons in lateral prefrontal cortex (PFC) fire throughout the time period during which information is maintained in WM (2
). A somewhat distinct, but partially overlapping, population of PFC neurons fire in the response phase (4
Functional neuroimaging studies have generally supported the hypothesis that WM deficits in schizophrenia are related to PFC dysfunction. However, some investigators report that patients with schizophrenia (SZS) have deficient activation in PFC (5
), and others report no difference or even increased activation (8
). These conflicting findings may be related to the differential impact of increasing WM load on PFC activation in SZS and healthy comparison subjects (HCS) (9
The three phases of WM have distinct neurobiologies that may help to inform our understanding of cortical dysfunction in schizophrenia. Preclinical data suggest that the distinctive kinetics of N-methyl-D-aspartate (NMDA) glutamate receptor activation, facilitated by D1 receptor activity, allow prefrontal cortical networks to produce sustained, modulated activation necessary for WM maintenance (14
). In contrast, dopamine D2 receptors appear to destabilize PFC activity associated with WM maintenance (Seamans and Yang 2004) and may modulate activity associated with the response phase (18
). Deficits in NMDA and D1 receptor function may contribute to schizophrenia pathophysiology (15
). Anti-psychotic medication treatment which blocks the D2 receptor may further complicate the clinical picture. Thus, using WM phases to parse abnormalities in PFC activity associated with schizophrenia may shed light on the disorder’s neurobiology.
Based on the studies reviewed above, we hypothesized that SZS would display reduced PFC activation during the maintenance phase of WM. We further sought preliminary evidence that reduced persistence would be related to poor performance. In addition, we hypothesized that PFC activity during the response phase would be reduced in SZS.
In order to distinguish PFC activity associated with WM phases in humans using functional magnetic resonance imaging (fMRI), one must specially design WM paradigms and analytic techniques to compensate for the limited temporal resolution of the blood-oxygenated level-dependent (BOLD) signal. We selected an fMRI paradigm that was designed to resemble the ocular delayed response task, a paradigm often used in non-human primate WM studies, and has been shown to be sensitive to PFC maintenance activity in healthy human volunteers (25
). It includes a relatively long retention interval of 16s to separate initial responses, termed cue or encoding-related activity, from brain activity related to maintenance.
To analyze the results of our experiment we used an approach which we term “empirical timepoints” that involves calculating percent signal change from the BOLD timecourse data and requires fewer mathematical assumptions than traditional fMRI analysis. However, our hypotheses specified a decrease or decay of the BOLD signal over the course of the retention interval. This decay was best modeled by using a hemodynamic response function (hrf). Accordingly, on our major analyses we complemented the empirical timepoints approach with an analysis that deconvolved the hemodynamic response.