14 Mar 2011
15 March 2011. Efforts to explain faulty working memory in schizophrenia have focused on prefrontal cortical regions, but a new study fingers abnormal processing in sensory cortex instead. Daniel Javitt of the Nathan Kline Institute for Psychiatric Research in Orangeburg, New York, and colleagues measured event-related potentials in subjects with schizophrenia and in healthy subjects who were performing a task that taxes working memory. The results, published online in the Archives of General Psychiatry on March 7, tie working memory deficits in schizophrenia to reduced activation of the visual cortex, particularly in the low-resolution magnocellular pathway. Most importantly, the activation that best predicted task performance came from sensory rather than cognitive processing regions, adding to evidence that impaired working memory in schizophrenia reflects faulty stimulus encoding rather than just an inability to hold items in memory. These findings challenge the view that prefrontal dysfunction alone underlies working memory impairment in schizophrenia.
A recent meta-analysis found consistent support for large working memory deficits in schizophrenia (see Forbes et al., 2009). To assess these deficits, researchers often use the AX-type continuous performance test (AX-CPT), which tasks subjects with responding to letters that appear one at a time on a computer screen. To respond correctly, subjects must press a button only when the letter X follows the letter A and not after other sequences, collectively called BX or AY. Thus, they must correctly encode the first, or cue, letter, and keep it in memory until they see the second letter, called the probe.
During such tasks, subjects with schizophrenia show altered prefrontal activation compared to healthy subjects, according to functional magnetic resonance imaging studies (see meta-analysis by Minzenberg et al., 2009). In an interview with SRF, Javitt said that researchers have assumed that the working memory deficits in schizophrenia arise in dopamine-rich prefrontal cortex, despite evidence that sensory processing deficits also occur in schizophrenia (see SRF related news story). Furthermore, he noted, administering the N-methyl-D-aspartate receptor blocker ketamine to healthy subjects induces schizophrenia-like performance on the AX-CPT, as might be expected from glutamatergic and other whole-brain theories of schizophrenia (see SRF Current Hypothesis by Javitt).
Javitt said that individual imaging studies have not found decreased activity in visual cortex in schizophrenia, but he noted that they “have never really been optimized to look at the visual areas; they have been designed in such a way that they’re very sensitive to frontal cortex.” Consequently, he and his colleagues, including first author Elisa Dias, also of the Nathan Kline Institute, used event-related potentials, a measure more sensitive to visual processing, to explore whether sensory processing abnormalities can explain visual working memory deficits in schizophrenia. Specifically, they compared AX-CPT performance and corresponding brain activity in 30 patients with schizophrenia, all of whom were receiving treatment with antipsychotic drugs, and 17 healthy subjects.
In order to parse the cognitive processes involved, Dias and colleagues tested each subject with three different versions of the AX-CPT, which differed only in stimulus probabilities. For instance, the AX-70 version presented the AX sequence on 70 percent of trials, whereas in the AY-70, the most probable sequence consisted of an A followed by a letter other than X, and in the BX version, a non-A letter followed by X.
On all versions, patients were more likely than control subjects to fail to press the button when AX appeared. When they mistakenly pressed the button, they were more likely than controls to do so in response to BX than to AY sequences, reflecting a weakened ability to use cues to guide behavior. Yet patients were as capable as control subjects of adjusting their behavior to new stimulus probabilities. Behaviorally, their top-down processing seemed intact, yet their performance remained faulty.
Waves of data
To gauge neural activity in different parts of the processing pathway, Dias and colleagues recorded event-related sensory and cognitive potentials. Specifically, they recorded sensory potentials C1 at 60 to 120 milliseconds after the stimulus, P1 at 75 to 130 milliseconds, and N1 at 100 to 200 milliseconds. At later time points, they recorded cognitive potentials N2 at 220 to 350 milliseconds, and CNV, or contingent negative variation, at 1,200 to 1,250 milliseconds. Peak amplitude served as the outcome measure.
Patients with schizophrenia showed smaller activation of P1 and N1, but not C1, compared to healthy subjects. This shows that they may have deficits in early sensory processing, particularly in the magnocellular visual system, the more dorsal of the two pathways that carry sensory information to prefrontal areas. This system provides low-resolution information to guide action, whereas the parvocellular system supplies finer-honed information for identifying stimuli. The latter system, indexed by the C1, seems relatively intact in schizophrenia. Further tests of subjects’ ability to detect low-contrast stimuli at the spatial frequencies detected by the two systems further pointed to magnocellular processing deficits in schizophrenia.
Not surprisingly, patients with schizophrenia showed dampened activation at higher, cognitive levels of processing. Their N2 and CNV potentials—measures of activity in frontal regions—showed smaller peaks, evidence of impaired encoding of information about the cue.
Bottom-up versus top-down
Regression analyses found that the N1 potentials, which come from visual cortex, best predicted behavior. They correlated significantly with AX-70 performance (r = 0.37, P = .004), overshadowing N2’s marginal ties to performance.
Path analysis hinted that P1 sensory processing might be driving N2 cognitive potentials. This again put magnocellular deficits at the heart of schizophrenia-related impairments. This notion gained further support from significant correlations between task performance and subjects’ ability to detect the kinds of low-contrast stimuli processed by the magnocellular system.
Taken together, Dias and colleagues see their findings as further confirmation of the idea that working memory impairments in schizophrenia reflect failures of encoding rather than of memory retention. They do not dispute that top-down processing breaks down in schizophrenia; rather, they argue that bottom-up processing deficits deserve more attention than they have received. As Javitt said, these findings suggest “that not only are the frontal activation deficits in schizophrenia due to sensory deficits but, in fact, the behavioral deficits are really reflecting the sensory dysfunction more than the higher frontal dysfunction.”
Javitt thinks that such findings point to a need to rethink cognitive remediation in schizophrenia. Instead of directly targeting higher-level processes, such as attention and working memory, focusing on sensory processing might well produce effects that ripple through the brain. “That might not fix everything, but until you fix that, it will be hard for patients to learn and improve other aspects of performance,” he said.—Victoria L. Wilcox.
Dias EC, Butler PD, Hoptman MJ, Javitt DC. Early sensory contributions to contextual encoding deficits in schizophrenia. Arch Gen Psychiatry. 2011 Mar 7. Abstract