Behavioral response inhibition in psychotic disorders: Diagnostic specificity, familiality and relation to generalized cognitive deficit

https://doi.org/10.1016/j.schres.2014.08.025Get rights and content

Abstract

Difficulty inhibiting context-inappropriate behavior is a common deficit in psychotic disorders. The diagnostic specificity of this impairment, its familiality, and its degree of independence from the generalized cognitive deficit associated with psychotic disorders remain to be clarified. Schizophrenia, schizoaffective and bipolar patients with history of psychosis (n = 523), their available first-degree biological relatives (n = 656), and healthy participants (n = 223) from the multi-site B-SNIP study completed a manual Stop Signal task. A nonlinear mixed model was used to fit logistic curves to success rates on Stop trials as a function of parametrically varied Stop Signal Delay. While schizophrenia patients had greater generalized cognitive deficit than bipolar patients, their deficits were similar on the Stop Signal task. Further, only bipolar patients showed impaired inhibitory control relative to healthy individuals after controlling for generalized cognitive deficit. Deficits accounted for by the generalized deficit were seen in relatives of schizophrenia and schizoaffective patients, but not in relatives of bipolar patients. In clinically stable patients with psychotic bipolar disorder, impaired inhibitory behavioral control was a specific cognitive impairment, distinct from the generalized neuropsychological impairment associated with psychotic disorders. Thus, in bipolar disorder with psychosis, a deficit in inhibitory control may contribute to risk for impulsive behavior. Because the deficit was not familial in bipolar families and showed a lack of independence from the generalized cognitive deficit in schizophrenia spectrum disorders, it appears to be a trait related to illness processes rather than one tracking familial risk factors.

Introduction

Stop Signal paradigms examine the interplay between response activation, triggered by internal plans or orienting toward salient stimuli, and inhibition processes, triggered by top-down control from goal-maintenance networks to stop prepotent responses. They are widely used to assess inhibitory behavioral control (Logan et al., 1984, Logan, 1994, Bissett and Logan, 2011). Participants respond as quickly as possible to Go cues; however, some Go cues are followed after a brief delay (Stop Signal Delay, SSD) by a Stop cue instructing subjects to inhibit their response. Difficulty inhibiting cued Go responses increases with longer delays, putatively because increasing SSD has the effect of delaying initiation of inhibitory processes relative to onset of response activation processes (Logan et al., 1984). Inhibitory control impairments are of clinical interest because of potential relations to substance abuse, impulsive behavior and suicide, particularly in bipolar disorder where disinhibited behavior is a defining characteristic.

Meta-analyses on inhibitory control deficits in schizophrenia (Sitskoorn et al., 2004) and bipolar disorder (Bora et al., 2009) and their first-degree relatives, mainly using the Stroop task (Stroop, 1935, Besnier et al., 2009, Kravariti et al., 2009, Levy and Weiss, 2010, Westerhausen et al., 2011), suggest that schizophrenia patients may show milder inhibitory deficits than bipolar patients. In contrast, in the antisaccade task of inhibitory control, greater deficits have been observed in schizophrenia than in bipolar disorder (Blackwood et al., 1996, Martin et al., 2007, Harris et al., 2009, Reilly et al., 2014). Relative to other tasks, the SST does not depend on semantic associations as in the Stroop paradigm, or require simultaneous response suppression and initiation demands as in the antisaccade task, so it is a potentially more direct approach for assessing inhibitory processes that has not yet been used in larger sample studies contrasting psychotic disorders.

Schizophrenia and bipolar patients, especially bipolar with psychosis, typically have generalized cognitive impairments as well as impaired inhibitory control (Bora et al., 2010, Harvey et al., 2010, Hill et al., 2013). Generalized neuropsychological deficits are typically greater in schizophrenia than bipolar disorder, with schizoaffective patients showing intermediate deficits (Woolard et al., 2010, Hill et al., 2013). It is unknown whether inhibitory deficits represent a specific cognitive deficit or one manifestation of generalized cognitive deficit across these disorders. Specific deficits can provide independent information for clinical evaluation, tracking treatment outcomes, and gene discovery. Moreover, there is interest in assessing inhibitory control deficits in relatives and whether they are familial endophenotypes (Ferrier et al., 2004, Allen et al., 2009, Giakoumaki et al., 2011, Christodoulou et al., 2012).

Stop Signal tasks can assess strategic adjustments made to enhance inhibitory control. Healthy individuals strategically delay reaction times to Go cues, allowing time for inhibitory processes if a Stop cue occurs (Verbruggen and Logan, 2008). Evidence supports reduced strategic latency adjustments in schizophrenia (Vink et al., 2006) but strategic slowing relative to a baseline control task has not been evaluated in psychotic patients (Verbruggen and Logan, 2008, Bissett and Logan, 2011).

We used a SST to evaluate behavioral response inhibition in a large sample of psychotic patients and their first-degree relatives. Familiality and degree of deficit not accounted for by general neuropsychological deficit were examined. We hypothesized that inhibitory control deficits would be distinct from generalized cognitive deficit and familial in psychotic bipolar patients.

Section snippets

Participants

As part of the Bipolar and Schizophrenia Network on Intermediate Phenotypes (B-SNIP), participants were recruited at six sites: University of Chicago/University of Illinois-Chicago (Chicago, Illinois), Yale University/Institute of Living (Hartford, Connecticut), University of Texas Southwestern (Dallas, Texas), University of Maryland (Baltimore, Maryland), Wayne State University (Detroit, Michigan) and Beth Israel Deaconness Medical Center, Harvard University (Boston, Massachusetts). Primary

Results

An omnibus test on parameter b1 revealed significant differences among patient and HP groups F(4,1311) = 9.99, p < .0001 (Fig. 2). All patient groups performed significantly worse than HP (unadjusted p's < .002, FDR-adjusted p's < .01). Patient groups did not differ significantly from each other (unadjusted p's > .30). This contrasts with significant group differences in BACS performance, where SZ showed more deficit than SZA-BP, t(288) = 2.49, FDR-adjusted p = .03 and BPP, t(368) = 5.23, FDR-adjusted p = .006,

Discussion

This study yielded three main findings: 1) in contrast to robust and differential generalized cognitive deficit across psychotic disorders, patients groups were equally impaired in SST performance; 2) SST performance was primarily a manifestation of generalized cognitive deficit in schizophrenia spectrum disorders, while in BPP inhibitory behavioral control impairments appeared to represent a specific cognitive deficit; and 3) first-degree relatives of SZ and BPP did not demonstrate specific

Role of funding source

This research was funded in part by NIMH grants MH078113, MH077945, MH077852, MH077851, MH077862, MH072767, and MH083888. The NIMH had no further role in development of the paradigm or interpretation of experimental findings.

Contributors

LEE and MS contributed to data analysis and manuscript preparation. PAN contributed statistical design and analyses. JLR, SKH, RSEK, ESG, GDP, CAT, and MSK contributed to study design, data collection and interpretation. JAS contributed to study design, data collection, analysis and interpretation, and manuscript preparation. All authors have seen and approved the final manuscript.

Conflicts of interest

Author RSEK currently or in the past has received investigator-initiated research funding support from the Allon, AstraZeneca, Department of Veteran's Affair, Feinstein Institute for Medical Research, GlaxoSmithKline, National Institute of Mental Health, Novartis, Psychogenics, Research Foundation for Mental Hygiene, Inc., and the Singapore National Medical Research Council. He currently or in the past has received honoraria, served as a consultant, or advisory board member for Abbott, Abbvie,

Acknowledgments

This research was funded in part by NIMH grants MH078113, MH077945, MH077852, MH077851, MH077862, MH072767, and MH083888. We thank Dr. Gunvant Thaker for his input and collaboration on this project.

References (48)

  • C. Lancon et al.

    Stability of the five-factor structure of the Positive and Negative Syndrome Scale (PANSS)

    Schizophr. Res.

    (2000)
  • M.M. Sitskoorn et al.

    Cognitive deficits in relatives of patients with schizophrenia: a meta-analysis

    Schizophr. Res.

    (2004)
  • K.N. Thakkar et al.

    Response inhibition and response monitoring in a saccadic countermanding task in schizophrenia

    Biol. Psychiatry

    (2011)
  • F. Verbruggen et al.

    Response inhibition in the stop-signal paradigm

    Trends Cogn. Sci.

    (2008)
  • M. Vink et al.

    Striatal dysfunction in schizophrenia and unaffected relatives

    Biol. Psychiatry

    (2006)
  • R. Westerhausen et al.

    Impaired cognitive inhibition in schizophrenia: a meta-analysis of the Stroop interference effect

    Schizophr. Res.

    (2011)
  • A.A. Woolard et al.

    Intact associative learning in patients with schizophrenia: evidence from a Go/NoGo paradigm

    Schizophr. Res.

    (2010)
  • T. Zalla et al.

    Executive dysfunctions as potential markers of familial vulnerability to bipolar disorder and schizophrenia

    Psychiatry Res.

    (2004)
  • T.M. Becker et al.

    Prefrontal dysfunction in first-degree relatives of schizophrenia patients during a Stroop task

    Neuropsychopharmacology

    (2008)
  • Y. Benjamini et al.

    Controlling the false discovery rate: a practical and powerful approach to multiple testing

    J. R. Stat. Soc.

    (1995)
  • N. Besnier et al.

    Stroop and emotional Stroop interference in unaffected relatives of patients with schizophrenic and bipolar disorders: distinct markers of vulnerability?

    World J. Biol. Psychiatry

    (2009)
  • M. Birchwood et al.

    The Social Functioning Scale. The development and validation of a new scale of social adjustment for use in family intervention programmes with schizophrenic patients

    Br. J. Psychiatry

    (1990)
  • P.G. Bissett et al.

    Balancing cognitive demands: control adjustments in the stop-signal paradigm

    J. Exp. Psychol. Learn. Mem. Cogn.

    (2011)
  • D.H. Blackwood et al.

    Implications of comorbidity for genetic studies of bipolar disorder: P300 and eye tracking as biological markers for illness

    Br. J. Psychiatry Suppl.

    (1996)
  • Cited by (55)

    View all citing articles on Scopus
    View full text