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Articles   |    
Preserved Working Memory and Altered Brain Activation in Persons at Risk for Psychosis
Siti N. Yaakub, B.Eng.(Hons.); Kavitha Dorairaj, B.A., B.Psych.(Hons.); Joann S. Poh, B.Psych.(Hons.); Christopher L. Asplund, Ph.D.; Ranga Krishnan, M.B.Ch.B.; Jimmy Lee, M.B.B.S, M.Med.; Richard S.E. Keefe, Ph.D.; R. Alison Adcock, M.D., Ph.D.; Stephen J. Wood, M.A., Ph.D.; Michael W.L. Chee, M.B.B.S.
Am J Psychiatry 2013;170:1297-1307. doi:10.1176/appi.ajp.2013.12081135
View Author and Article Information

Dr. Krishnan is a shareholder with Cenerx, Corcept, and Orexigen. Dr. Keefe has received investigator-initiated research funding from the Feinstein Institute for Medical Research, GlaxoSmithKline, Novartis, Psychogenics, the Research Foundation for Mental Hygiene, and the Singapore National Medical Research Council; he has received honoraria from and served as a consultant or advisory board member for Abbott, Amgen, Astellas, Asubio, BiolineRx, Biomarin, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, EnVivo, Helicon, Lundbeck, Merck, Mitsubishi, Novartis, Otsuka, Pfizer, Roche, Shire, Sunovion, Takeda, and Targacept; he receives royalties from the Brief Assessment of Cognition in Schizophrenia and the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery; and he is a shareholder in NeuroCog Trials. All other authors report no financial relationships with commercial interests.

Supported by the Singapore National Research Foundation under the National Medical Research Council Translational and Clinical Research Flagship Program (grant NMRC/TCR/003/2008) and the U.S. Department of Veterans Affairs and NIMH (to Dr. Keefe).

From the Neuroscience and Behavioral Disorders Program, Duke-National University of Singapore Graduate Medical School, Singapore; Research Division, Institute of Mental Health, Singapore; Department of Psychiatry and Behavioral Sciences and Center for Cognitive Neuroscience, Duke University, Durham, N.C.; School of Psychology, University of Birmingham, Edgbaston, United Kingdom; Melbourne Neuropsychiatry Center, Department of Psychiatry, University of Melbourne, Melbourne; and Melbourne Health, Melbourne.

Address correspondence to Dr. Chee (michael.chee@duke-nus.edu.sg).

Copyright © 2013 by the American Psychiatric Association

Received August 30, 2012; Revised November 27, 2012; Revised January 17, 2013; Accepted February 14, 2013.

Abstract

Objective  Patients with schizophrenia exhibit impairments in working memory that often appear in attenuated form in persons at high risk for the illness. The authors hypothesized that deviations in task-related brain activation and deactivation would occur in persons with an at-risk mental state performing a working memory task that entailed the maintenance and manipulation of letters.

Method  Participants at ultra high risk for developing psychosis (N=60), identified using the Comprehensive Assessment of At-Risk Mental States, and healthy comparison subjects (N=38) 14 to 29 years of age underwent functional MRI while performing a verbal working memory task. Group differences in brain activation were identified using analysis of covariance.

Results  The two groups did not show significant differences in speed or accuracy of performance, even after accounting for differences in education. Irrespective of task condition, at-risk participants exhibited significantly less activation than healthy comparison subjects in the left anterior insula. During letter manipulation, at-risk persons exhibited greater task-related deactivation within the default-mode network than comparison subjects. Region-of-interest analysis in the at-risk group revealed significantly greater right dorsolateral prefrontal cortex activation during manipulation of letters.

Conclusions  Despite comparable behavioral performance, at-risk participants performing a verbal working memory task exhibited altered brain activation compared with healthy subjects. These findings demonstrate an altered pattern of brain activation in at-risk persons that contains elements of reduced function as well as compensation.

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FIGURE 1. Examples of Stimuli Used in the Task and Presentation Timings Among Persons At-Risk for Psychosis and Healthy Comparison Subjectsa

a In the LTR condition, participants were presented with four target letters, maintained them in memory for 3 seconds, and then indicated whether any of the targets matched a probe letter. In the PLUS condition, participants were presented with two target letters, shifted each one forward alphabetically by one position, maintained the new targets in memory for 3 seconds, and then indicated whether either of the new targets matched the probe letter. The PLUS2 condition was identical to the PLUS condition except that participants had to shift each target letter forward by two positions. The control condition was designed to match the perceptual and motor elements of the actual task conditions. Four identical letters were presented, followed by a lowercase probe letter. The proportion of matched probes was 50% in all conditions.

FIGURE 2. Activation Maps of Significant Task-Related Activations Among Persons At Risk for Psychosis and Healthy Comparison Subjectsa

a The rows depict activation maps showing regions where MR signal change was significantly different from the control condition in the at-risk and healthy comparison groups for each of the three task conditions and the two manipulation contrasts. All maps were thresholded at p<0.0001 (Bonferroni corrected).

FIGURE 3. Whole-Brain Analysis of Covariance Maps of Regions With a Significant Main Effect of Groupa

a The images depict the left insula and posterior cingulate, and the bar graphs show the MR signal change across task condition and group in these regions.

FIGURE 4. Condition-By-Group Interaction and Relationship Between Brain Activation and Symptom Severitya

a The bar graph shows the MR signal change across task condition and group in the right dorsolateral prefrontal cortex region of interest. The scatterplot shows the correlation between the MR signal change associated with manipulation in the right dorsolateral prefrontal cortex and Positive and Negative Syndrome Scale (PANSS) total score in the at-risk group. There was a significant correlation between right dorsolateral prefrontal cortex activity and PANSS total score (r=0.40, df=58, p=0.001). The blue circles indicate at-risk participants who later converted to psychosis.

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TABLE 1.Demographic and Clinical Characteristics of Persons At-Risk for Psychosis and Healthy Comparison Subjectsa
Table Footer Note

a For continuous and discrete variables, t tests and chi-square tests, respectively, were used to assess group differences.

Table Footer Note

b Twenty-six at-risk participants were receiving selective serotonin reuptake inhibitors, six were receiving tricyclic or tetracyclic antidepressants, and three were receiving a combination of both types of antidepressants.

Table Footer Note

c One at-risk participant was previously treated with chlorpromazine at a low dosage but discontinued prior to entering the study.

Table Footer Note

d Of the six at-risk participants who were later diagnosed with psychosis, four met criteria for subgroup 2, and two met criteria for subgroup 1 based on the Comprehensive Assessment of At-Risk Mental States.

Table Footer Note

e Significant difference between groups.

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f Data were not available for one at-risk participant and 10 healthy comparison subjects.

Table Footer Note

g Data were not available for one at-risk participant.

Table Footer Note

h The total score is the sum of the severity and frequency scores for the components of unusual thought content, nonbizarre ideas, perceptual abnormalities, and disorganized speech.

+

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1.
This study hypothesized that persons at ultra high risk for psychosis would exhibit activation differences that reflect reduced efficiency of brain regions supporting working memory; which of the following regions are strongly implicated?
2.
The anterior insula is a part of the frontal lobe that
3.
The default-mode network may exhibit task-related deactivation, which is best described by which of the following?
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