Working memory and attention deficits in adolescent offspring of schizophrenia or bipolar patients: Comparing vulnerability markers

https://doi.org/10.1016/j.pnpbp.2011.04.009Get rights and content

Abstract

Background

Working memory deficits abound in schizophrenia and attention deficits have been documented in schizophrenia and bipolar disorder. Adolescent offspring of patients may inherit vulnerabilities in brain circuits that subserve these cognitive domains. Here we assess impairments in offspring of schizophrenia (SCZ-Offspring) or bipolar (BP-Offspring) patients compared to controls (HC) with no family history of mood or psychotic disorders to the second degree.

Methods

Three groups (n = 100 subjects; range: 10–20 yrs) of HC, SCZ-Offspring and BP-Offspring gave informed consent. Working memory was assessed using a delayed spatial memory paradigm with two levels of delay (2 s & 12 s); sustained attention processing was assessed using the Continuous Performance Task—Identical Pairs version.

Results

SCZ-Offspring (but not BP-Offspring) showed impairments in working memory (relative to HC) at the longer memory delay indicating a unique deficit. Both groups showed reduced sensitivity during attention but only BP-Offspring significantly differed from controls.

Conclusions

These results suggest unique (working memory/dorsal frontal cortex) and potentially overlapping (attention/fronto-striatal cortex) vulnerability pathways in adolescent offspring of patients with schizophrenia and bipolar disorder. Working memory and attention assessments in these offspring may assist in the clinical characterization of the adolescents vulnerable to SCZ or BP.

Highlights

► Memory and attention studied in offspring of schizophrenia or bipolar patients. ► Schizophrenia offspring impaired in memory; both groups in attention. ► Memory and attention are unique and overlapping vulnerability markers.

Introduction

The distinction between schizophrenia and bipolar disorder appears unclear from the perspective of neurobiology. For example, studies in molecular genetics suggest significant overlap in genetic vulnerability for each (Craddock and Owen, 2005) thereby implying a common etiological basis. If the genetic etiology is overlapping across phenotypes, it is plausible that neurodevelopment plays a critical role in the pathways toward each disorder. The idea that neurodevelopmental trends may distinguish between these disorders has been advanced (Murray et al., 2004), as has the general idea that complementary developmental trajectories contribute to distinct phenotypes post-adolescence (Keshavan et al., 2005a, Paus, 2005, Paus et al., 2008). In this view, complex interactions between programmed genetic development and environmental factors combine to alter or derail neurodevelopmental pathways during critical periods such as adolescence. This is now the modal view for all developmental hypotheses in schizophrenia (Lewis and Levitt, 2002), though its relevance for bipolar disorder is not yet established. These pathways may be realized through the disordered development of specific cortical systems in the brain, and therefore of cognitive domains that are closely tied to these cortical systems. Because both schizophrenia and bipolar disorder aggregate in families (Pavuluri et al., 2005), adolescent offspring of schizophrenia and bipolar patients are at increased risk for impaired cognition and psychopathology (Birmaher et al., 2009, Birmaher et al., 2010, Keshavan et al., 2005b) and are increasingly vulnerable to the disorders themselves. Estimates indicate that nearly 10%–15% of offspring of schizophrenia patients will be diagnosed with schizophrenia (Erlenmeyer-Kimling et al., 1997), and that 5%–15% of offspring of bipolar patients will develop a mood disorder in their lifetimes (Lapalme et al., 1997). Furthermore, increasing evidence suggests alterations in cortical systems in these subjects (Diwadkar et al., 2006), supporting the idea of neurodevelopmental derailment during adolescence. Therefore, understanding unique or non-specific patterns of cognitive impairment in these groups may prove informative.

Working memory and sustained attention have been closely mapped to prefrontal and striatal circuitry (Cohen et al., 1997, Corbetta et al., 1998). Working memory in particular is heavily dependent on sustained activity in prefrontal circuitry that is necessary for the temporary maintenance of information (Braver et al., 1997, Fuster, 1989). Sustained attention or vigilance is tied to interactions between cortico-striatal circuitry (Buchel and Friston, 1997, Luna et al., 2001). In general, the development of frontal and striatal circuitry is particularly dynamic during adolescence (Booth et al., 2003, Rubia et al., 2006), marked by both increased coordination during attention and working memory in particular (Edin et al., 2007), and increased frontal engagement with age (Rubia et al., 2000). Developmental deviations in regional function in SCZ- and/or BP-Offspring may affect working memory and sustained attention.

Prefrontal dysfunction is a central correlate of schizophrenia pathophysiology (Lewis, 1997) and delayed working memory paradigms elegantly elucidate the bases of disordered prefrontal function in the diathesis (Goldman-Rakic, 1994). Electrophysiological studies in primates indicate that when memoranda must be maintained in memory over a delay, maintenance is sub-served by tonic activity of prefrontal neurons that persists over the duration of the memory interval (Goldman-Rakic, 1988). Furthermore, the duration of this activity scales with the duration of the memory interval indicating a direct parametric effect on the demands of the prefrontal cortex. SCZ-offspring are in fact characterized by disordered fronto-striatal function during working memory that scales with increased memory demand (Bakshi et al., 2011), and errors in memory in offspring are most apparent at increased memory delays (Diwadkar et al., 2001). Thus, parametric effects of working memory load are a useful metric for distinguishing between SCZ-Offspring and controls. By comparison, the relationship of working memory deficits to bipolar disorder is less well established. Early studies indicated that bipolar patients performing similarly to controls (Park and Holzman, 1992), though recent data present a more heterogeneous pattern. Working memory deficits in bipolar subjects may be mediated by the presence of psychosis (Glahn et al., 2006) or manic symptoms (Sweeney et al., 2000). fMRI studies suggest that working memory in bipolar disorder is characterized by aberrant increases in engagement of the frontal cortex (Adler et al., 2004, Chang et al., 2004, Monks et al., 2004), though the value of working memory as a vulnerability marker in the mood spectrum is not established. Also, the relationship of working memory to neurophysiological processes such as dopaminergic neurotransmission (Vijayraghavan et al., 2007) or reduced synchrony between GABA-ergic neurons (Lewis et al., 2005) is hypothesized as central in schizophrenia, though this translational angle appears absent in bipolar disorder. Thus, it is plausible that working memory deficits may reflect essential aspects of altered prefrontal circuitry in schizophrenia that may be inherited in, and unique to SCZ-Offspring.

Attentional processes are not dependent on sustained maintenance by prefrontal neurons but may depend on cortico-striatal structural and functional connectivity (Graham et al., 2009, Haber and Calzavara, 2009). Other studies indicate that neural activity in key striatal regions such as the caudate are central to attention, and translating attention into motor outputs (Hikosaka and Sakamoto, 1986), suggesting that the striatum and its constituents are more central in the brain's attention pathway. Sustained attention has in fact emerged as a common marker of deficit in both adult schizophrenia and bipolar populations (Cornblatt and Erlenmeyer-Kimling, 1989, Strakowski et al., 2004). Attention deficits appear to be stable and enduring, have been documented in adolescent offspring of schizophrenia patients (Michie et al., 2000), and may result from disordered fronto-striatal function (Diwadkar et al., 2011), suggesting that such deficits may be markers of genetic vulnerability for schizophrenia. Young bipolar offspring (age < 25) endorse attention deficits but objective measures of attention deficits have provided mixed results (Klimes-Dougan et al., 2006). Nevertheless, several reasons motivate the idea that attention deficits would reflect neurodevelopmental vulnerability in both groups. For example, striatal abnormalities are noted in the earliest phases of the illness in both schizophrenia (Lawrie et al., 2001) and bipolar disorder (Strakowski et al., 2005), and have been associated with deficits in attention.

Here we investigated working memory and sustained attention deficits in age-matched HC, SCZ-Offspring and BP-Offspring using established measures of working memory (Diwadkar et al., 2001) and sustained attention (Salgado-Pineda et al., 2004). Based on the emerging literature, we expected that SCZ-Offspring (but not BP-Offspring) would show unique impairments in working memory reflected in greater error in a delayed match to sample spatial working memory task as a function of increased memory delay. By comparison, we expected offspring of both schizophrenia and bipolar patients to demonstrate non-specific impairments in sustained attention reflected in lower sensitivity to detect targets in a sustained attention task.

Section snippets

Subjects

One hundred subjects (10  Age  20 yrs) gave informed consent or assent to participate. All protocols were cleared by the Institutional Review Boards at the University of Pittsburgh and Wayne State University. Groups did not differ in age overall (F2,97 = .95, p > .35) or Full Scale IQ (F2,97 = .40, p > .65). Table 1 provides a characterization of subjects, with age, gender and Full Scale IQ scores. All subjects were free from medications at the time of assessments.

Clinical characterization

SCZ-Offspring and BP-Offspring were

Working memory

As seen in Fig. 1a, relative to control subjects, impairments in delayed working memory (12 s) appeared in SCZ-Offspring but not BP-Offspring, specifically at the long delay period. Consistent with this, a Group × Delay interaction was significant, F2,86 = 6.42, p < .003, MSe = 217.71 (effect size: partial η2 = .13) (Cohen, 1988). In addition, a main effect of group was observed, F2,86 = 4.39, p < .02, MSe = 348.03 (partial η2 = .09). Differences between groups at the longer delay were investigated using the

Discussion

This is one of the few studies directly comparing parametric working memory and attention performance in age- and gender-comparable adolescent offspring of schizophrenia and bipolar patients. The principle results were these: a) Working deficits were observed in SCZ-Offspring, specifically at the longer memory delay, reflecting the unique impact of memory demand on this sub-group. These results replicate previous demonstrations in SCZ-Offspring and suggest that impairments in working memory and

Conclusions

The expansion of biological psychiatry as a discipline has placed increased scrutiny of the Kraepelinian dichotomy, and of its value as a fundamental tenet of psychiatric classification. Current psychiatric classification schemes such as DSM IV that are an extension of the Kraepelinian dichotomy, categorically distinguish between schizophrenia and bipolar disorder, assuming these disorders to be distinct entities with clearly differentiable etiologies, symptoms and treatments. Emerging

Acknowledgments

This research was supported by NIH grants MH68680 (VAD), MH60952 (BB), MH45156 & MH45203 (MSK), NARSAD (VAD) and the Children's Research Center of Michigan (VAD). We thank Jean Miewald for data management, and Satish Iyengar and Mary Phillips for helpful discussions.

References (84)

  • S. Graham et al.

    Role of medial cortical, hippocampal and striatal interactions during cognitive set-shifting

    Neuroimage

    (2009)
  • S.N. Haber et al.

    The cortico-basal ganglia integrative network: the role of the thalamus

    Brain Res Bull

    (2009)
  • O. Hikosaka et al.

    Neural activities in the monkey basal ganglia related to attention, memory and anticipation

    Brain Dev

    (1986)
  • J. Kaufman et al.

    Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL): initial reliability and validity data

    J Am Acad Child Adolesc Psychiatry

    (1997)
  • M.S. Keshavan et al.

    Is schizophrenia due to excessive synaptic pruning in the prefrontal cortex?

    J Psychiatr Res

    (1994)
  • M.S. Keshavan et al.

    Premorbid indicators and risk for schizophrenia: a selective review and update

    Schizophr Res

    (2005)
  • B. Klimes-Dougan et al.

    Neuropsychological functioning in adolescent children of mothers with a history of bipolar or major depressive disorders

    Biol Psychiatry

    (2006)
  • S.M. Lawrie et al.

    Brain structure, genetic liability, and psychotic symptoms in subjects at high risk of developing schizophrenia

    Biol Psychiatry

    (2001)
  • D.A. Lewis

    Development of the prefrontal cortex during adolescence: insights into vulnerable neural circuits in schizophrenia

    Neuropsychopharmacology

    (1997)
  • B. Luna et al.

    Maturation of widely distributed brain function subserves cognitive development

    Neuroimage

    (2001)
  • R.M. Murray et al.

    A developmental model for similarities and dissimilarities between schizophrenia and bipolar disorder

    Schizophr Res

    (2004)
  • A.M. Passarotti et al.

    Emotion processing influences working memory circuits in pediatric bipolar disorder and attention-deficit/hyperactivity disorder

    J Am Acad Child Adolesc Psychiatry

    (2010)
  • T. Paus

    Mapping brain maturation and cognitive development during adolescence

    Trends Cogn Sci

    (2005)
  • M.N. Pavuluri et al.

    Pediatric bipolar disorder: a review of the past 10 years

    J Am Acad Child Adolesc Psychiatry

    (2005)
  • K. Rubia et al.

    Functional frontalisation with age: mapping neurodevelopmental trajectories with fMRI

    Neurosci Biobehav Rev

    (2000)
  • P. Salgado-Pineda et al.

    Decreased cerebral activation during CPT performance: structural and functional deficits in schizophrenic patients

    Neuroimage

    (2004)
  • F. Schneider et al.

    Neural correlates of working memory dysfunction in first-episode schizophrenia patients: an fMRI multi-center study

    Schizophr Res

    (2007)
  • M.K. Singh et al.

    Neuroanatomical characterization of child offspring of bipolar parents

    J Am Acad Child Adolesc Psychiatry

    (2008)
  • J.A. Sweeney et al.

    Neuropsychologic impairments in bipolar and unipolar mood disorders on the CANTAB neurocognitive battery

    Biol Psychiatry

    (2000)
  • J. Townsend et al.

    fMRI abnormalities in dorsolateral prefrontal cortex during a working memory task in manic, euthymic and depressed bipolar subjects

    Psychiatry Res

    (2010)
  • C.M. Adler et al.

    Changes in neuronal activation in patients with bipolar disorder during performance of a working memory task

    Bipolar Disord

    (2004)
  • N. Bakshi et al.

    Inefficiently increased anterior cingulate modulation of cortical systems during working memory in young offspring of schizophrenia patients

    J Psychiatr Res

    (2011)
  • C.E. Bearden et al.

    Evidence for disruption in prefrontal cortical functions in juvenile bipolar disorder

    Bipolar Disord

    (2007)
  • B. Birmaher et al.

    Psychiatric disorders in preschool offspring of parents with bipolar disorder: the Pittsburgh Bipolar Offspring Study (BIOS)

    Am J Psychiatry

    (2010)
  • B. Birmaher et al.

    Lifetime psychiatric disorders in school-aged offspring of parents with bipolar disorder: the Pittsburgh Bipolar Offspring study

    Arch Gen Psychiatry

    (2009)
  • P. Brambilla et al.

    Shared impairment in associative learning in schizophrenia and bipolar disorder

    Prog Neuropsychopharmacol Biol Psychiatry

    (2011)
  • C. Buchel et al.

    Modulation of connectivity in visual pathways by attention: cortical interactions evaluated with structural equation modelling and fMRI

    Cereb Cortex

    (1997)
  • F.X. Castellanos et al.

    Quantitative brain magnetic resonance imaging in attention-deficit hyperactivity disorder

    Arch Gen Psychiatry

    (1996)
  • M.V. Chafee et al.

    Inactivation of parietal and prefrontal cortex reveals interdependence of neural activity during memory-guided saccades

    J Neurophysiol

    (2000)
  • K. Chang et al.

    Anomalous prefrontal-subcortical activation in familial pediatric bipolar disorder: a functional magnetic resonance imaging investigation

    Arch Gen Psychiatry

    (2004)
  • J. Cohen

    Statistical power analysis for behavioral sciences

    (1988)
  • J.D. Cohen et al.

    Temporal dynamics of brain activation during a working memory task

    Nature

    (1997)
  • Cited by (0)

    View full text