When Working Memory isn’t Working: How and Why, and What it Means for Patients with Schizophrenia

Stephen I. Deutsch, MD, PhD
Anne Armistead Robinson Endowed Chair in Psychiatry; Professor and Chairman, Department of Psychiatry and Behavioral Sciences, Eastern Virginia Medical School; Attending Psychiatrist, Sentara Norfolk General Hospital, Norfolk, Va.

Disclosure: Dr. Deutsch has received grant support from the Commonwealth Health Research Board (State of Virginia).


Working memory is the ability to retain information on-line for short periods of time—seconds to minutes—in order to use this information to guide goal-directed behavior, eg, retention of a telephone number long enough to actually make the call. Working memory is commonly referred to as the “mental sketchpad” and is itself composed of component processes that are necessary for maintaining relevant information during encoding, inhibiting encoded information that is irrelevant to the desired goal from entering consciousness, and minimizing interference from distractors or irrelevant information at the time of retrieval when a goal-directed response is chosen, among other processes. Working memory is critical to learning, reasoning, verbal comprehension, and academic and vocational success, so it is perhaps unsurprising that a deficit in working memory—a cognitive deficit—would be likely to contribute to the poorer functional outcomes experienced by many schizophrenia patients.1


A recent study explored abnormalities of fMRI activation of specific brain regions in patients with schizophrenia while they performed a task that separated neural mechanisms for maintenance of information in working memory before a demand is imposed for inhibiting some of this information. This process normally inhibits information that becomes irrelevant in working memory, selecting the desired goal-directed response in spite of interference imposed by irrelevant, but familiar, information.1

Importantly, the working memory deficit in schizophrenia has generally been conceptualized as a failure of cognitive control over the inhibition of either irrelevant information contained in working memory or interference from irrelevant distractors when a goal-directed response is required. In this study, fMRI scanning was conducted while patients with schizophrenia and healthy controls were asked to retain four words in memory that they spent 4 seconds viewing; two of the words were presented in red and the other two in blue. After a delay of 6–8 seconds, subjects were cued for 2 seconds to retain only the words presented in one color. Thereafter, following an additional delay of 6–8 seconds, subjects were probed with a word and asked to respond affirmatively if the probe matched one of the colored words retained in working memory.1


With respect to the behavioral results, schizophrenia patients made significantly more errors, and responded significantly more slowly to all three probe types, compared with healthy controls. These data suggest that patients had difficulty inhibiting irrelevant information in working memory and were prone to interference by the familiarity of the lure probe at the time a goal-directed response was required.

With respect to differences in fMRI activation between schizophrenia patients and controls, patients maintained activation of the left posterior ventrolateral prefrontal cortex (VLPFC) after they were cued to inhibit irrelevant information (ie, one set of two same-colored words). Moreover, at the time of the goal-directed response (when retrieval of the correctly encoded word from working memory was required), patients showed significantly greater activation of the left mid-VLPFC for lure probes relative to control probes. There were also data showing that the initial failure to inhibit irrelevant information in working memory after being cued to do so may mediate and be primarily responsible for the deficit in behavioral performance.1

The data highlight the involvement of the mid- and posterior-VLPFC in eliminating interference from distractors when a response is required, and in proactively inhibiting irrelevant information in working memory when a future response will be required, respectively. Perhaps medications that inhibit activation of posterior-VLPFC after cuing may be associated with improved functional outcomes in patients with schizophrenia.



Eich TS, Nee DE, Insel C, Malapani C, Smith EE. Neural correlates of impaired cognitive control over working memory in schizophrenia. Biol Psychiatry. 2014;76:146-153.