Memory systems in schizophrenia: Modularity is preserved but deficits are generalized
Introduction
Memory impairment is a core feature of schizophrenia (Kahn and Keefe, 2013) related to functioning and prognosis (Green et al., 2004). Patients with schizophrenia and their first-degree relatives demonstrate impairment in working and episodic memory (Agnew-Blais and Seidman, 2012, Aleman et al., 1999, Forbes et al., 2009, Snitz et al., 2006, Trandafir et al., 2006) and both working memory (Glahn et al., 2003) and episodic memory are moderately heritable (Finkel and McGue, 1993, Owens et al., 2011). Thus, memory impairments may represent a biomarker of schizophrenia; however, questions about the generality of these deficits remain to be addressed.
First, despite group level memory impairment in schizophrenia, measures of memory performance are limited as individualized diagnostic classifiers (Glahn et al., 2007, Kern et al., 2011). It is unclear whether deficits across memory domains and modalities (e.g., working vs. episodic, verbal vs. visuospatial) reflect generalized impairment (Gold and Dickinson, 2013), a specific subgroup of patients exhibiting neurocognitive deficits in multiple domains (McDermid Vaz and Heinrichs, 2002), or different subsets of patients displaying deficits in different domains (Karlsgodt et al., 2011). Previous research in a large schizophrenia sample found that cognitive impairment was best explained by a single deficit factor (Keefe et al., 2006); however, this study did not include controls and so could not directly asses how patterns found in patients compare to typical cognitive structure. A model including executive functioning, memory and processing speed best discriminates schizophrenia from controls (Lam et al., 2014), which supports the theory that patients with schizophrenia are broadly cognitive impaired, but this study included relatively independent cognitive tasks and the structure within multiple memory-related tasks has not been measured. Additionally, more refined, cognitive neuroscience-based tasks might better identify discrete neurocognitive subsystems that are impaired in patient groups (Carter and Barch, 2007).
Second, it is unclear whether memory deficits associated with schizophrenia represent biomarkers of risk processes shared with other diagnostic syndromes, such as bipolar disorder (Kurtz and Gerraty, 2009) or attention-deficit–hyperactivity-disorder (ADHD) (Martinussen et al., 2005). While memory impairments in ADHD are likely more circumscribed (Castel et al., 2011), impairments in bipolar disorder may be closer to those found in schizophrenia, particularly among cases with psychotic symptoms (Glahn et al., 2006, Hill et al., 2013). Thus, it is important to assess the structure of cognitive dysfunction across diagnostic boundaries (Cuthbert and Insel, 2010).
This study sought to clarify the distribution and covariation of impairments across domains of memory in patients with schizophrenia and to determine to the extent to which these impairments are shared with bipolar disorder and ADHD. The psychiatric comparison groups allow us to examine memory impairment in schizophrenia in the context of individuals who are hypothesized to share genetic risk architecture with schizophrenia. A large reference sample of community volunteers (n = 1101) was collected to provide robust estimation of the normative distributions of performance on all measures, which included both established neuropsychological tasks and experimental tasks designed to isolate theoretically separable aspects of working and episodic memory functioning (Carter et al., 2008).
We hypothesized that among patients with schizophrenia, distributions on all measures of memory performance would be shifted downward compared with those of the reference population and that there would be consistency in terms of where particular patients scored in the distributions across domains and modalities. We further hypothesized that there would be a similar distributional shift and cross-distributional consistency among bipolar cases with psychotic features, but not among non-psychotic bipolar patients or subjects with ADHD.
Section snippets
Subjects
The study was approved by the Institutional Review Boards of UCLA and Yale University and participants provided written informed consent. Subjects were recruited via the UCLA Consortium for Neuropsychiatric Phenomics (www.phenomics.ucla.edu). 1101 healthy controls (CON) without history of psychosis or ADHD and no current mood or anxiety disorders were studied, as well as 58 schizophrenia (SCZ) patients, 49 bipolar (BP) patients, and 46 ADHD patients. Participants, aged 21–50, were recruited by
Sample characteristics
CON and SCZ/BP differed significantly on age and there was a significant difference in the proportion of males in SCZ compared with the other groups. Thus, age and gender were included as covariates in the group-contrast analyses. There were also significant group differences on ethnicity with CON and SCZ having higher percentages of Hispanic participants than BP and ADHD. As expected, patient groups differed on ratings of clinical variables, with more severe overall psychopathology, positive
Discussion
Despite moderate to large differences in group means across numerous verbal and spatial working and episodic memory tasks, memory performance is limited in its ability to separate SCZ from controls or to classify subjects with SCZ, bipolar disorder, and ADHD into separate groups. Performance distributions were unimodal, with only modest consistency in the membership of the lowest performing quintile of subjects across tasks. Further, variation in a general factor common to all tasks accounted
Contributors
RB, TC, NF, EL, and FS developed the study concept and study design. KK and EC contributed to the neurocognitive task design, programming, and scoring, and JV contributed to the recruitment and clinical assessment. KH and TC performed the data analysis and interpretation and drafted the paper and RB, EC, KK, EL, and FS provided critical revisions. All authors approved the final version of the paper for submission.
Role of Funding Agencies
None of the funding agencies had a role in collection, management, analysis or interpretation of the data or in preparation, review or approval of the manuscript.
Conflict of Interest
The authors report no conflicts of interest.
Acknowledgments
This work was supported by the Consortium for Neuropsychiatric Phenomics (NIH Roadmap for Medical Research grants UL1-DE019580 (Bilder, PI), RL1MH083269 (Cannon, PI) and PL1MH083271 (Bilder, PI)).
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