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