Increased intrasubject variability in response time in unaffected preschoolers at familial risk for bipolar disorder

doi:10.1016/j.psychres.2014.06.047

Psychiatry Research

Volume 219, Issue 3, 30 November 2014, Pages 687-689

https://doi.org/10.1016/j.psychres.2014.06.047 Get rights and content

Abstract

Increased intrasubject variability in response time (ISVRT) is evident in healthy preschoolers at familial risk for bipolar disorder, suggesting it may be an endophenotype.

Introduction

Attention deficits are a core, persistent feature of bipolar disorder (BD) (Torres et al., 2007) in children and adults (Fleck et al., 2005, Joseph et al., 2008). Intrasubject variability in response time (ISVRT) is a highly heritable (Kuntsi et al., 2006) measure of attention regulation. ISVRT measures variability in the duration of motor responses across trials, representing fluctuation in attention over time. Specifically, increased ISVRT is thought to result from intermittent attentional lapses that result in relatively long-RT trials. Thus, ISVRT serves as a direct, quantitative gauge of attention deficits. Increased ISVRT indicating attention dysregulation is present in BD regardless of mood state, medication, or comorbidity, and in unaffected, first-degree relatives (Bora et al., 2006, Brotman et al., 2009), supporting its potential role as a cognitively-based BD endophenotype (Gottesman and Gould, 2003).

ISVRT has been examined in both school-aged and adult first-degree relatives of children and adults with BD (Bora et al., 2009, Brotman et al., 2009). However, extending studies to younger populations is essential; BD is a developmental disorder (Kessler et al., 2005) with roots in early brain development (Post et al., 1996). Identification of risk factors appearing early in development would facilitate prevention. However, research in preschool-age populations entails specific challenges. Specifically, such research requires specialized expertise in the clinical assessment of preschoolers in addition to age-appropriate paradigms to probe the constructs of interest (e.g., attention regulation). Few studies of preschool-aged at-risk BD populations exist, and most have focused on temperament and psychopathology (Birmaher et al., 2010, Hirshfeld-Becker et al., 2006), rather than cognitive processes.

We compared unaffected preschoolers at familial-risk for BD to healthy children on a developmentally-appropriate attentional flanker task to determine whether increased ISVRT is present in at-risk children at that early developmental stage.

Section snippets

Methods

Forty-nine children (3.5–6.5 y) participated: 15 at-risk for BD (at-risk, AR; first-degree relative with BD: 3 siblings, 12 parents, mean age 4.6±0.6 y) and 34 not at-risk, healthy children (HC, 4.9±0.8 y; Table S1). Subjects were not related. Informed consent/assent was obtained. The Preschool Aged Psychiatric Assessment (PAPA; (Egger et al., 2006)) was used to ascertain psychiatric diagnoses (data unavailable: 1 AR, 6 HC).

Preschoolers completed a 120 trial flanker task (McDermott et al., 2007),

Results

Groups did not differ on age, IQ, or sex (P׳s>0.13). Based on the PAPA assessment, no subject in either group met criteria for a psychiatric disorder. Trend differences emerged in performance measures: hits (AR<HC, P=0.08), errors of omission (AR>HC, P=0.05).

ISVRT, as measured by CV-RT, was greater for AR than HC on all trials (P=0.02), incongruent trials (P=0.01), and, at trend level for congruent trials (P=0.08) (Fig. 1).

When covarying errors of omission, CV-RT for incongruent trials remained

Discussion

This study provides additional support that increased ISVRT may be an endophenotype for BD by documenting its presence in unaffected AR preschool-age relatives. Deficits at this early developmental stage suggest a close relationship between dysfunctional attention regulation and BD risk.

Increased ISVRT among AR subjects was observed across all trials, although more markedly during incongruent trials. The difference in ISVRT between AR and HC remained significant for incongruent trials after

Acknowledgment

This research was supported by the Intramural Research Program of the NIMH, NIH, and a NARSAD Young Investigator Grant (A.E.G.). We thank the staff of the Emotion and Development Branch at NIMH and subjects and families for their participation.

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Behavioral and Neural Sustained Attention Deficits in Bipolar Disorder and Familial Risk of Bipolar Disorder
2017, Biological Psychiatry
Few neuroimaging studies compare individuals affected with bipolar disorder (BP), at high familial risk of BP, and at low risk to identify endophenotypes for BP. None have examined variability in attention, despite promising behavioral work in this area. We used functional magnetic resonance imaging (fMRI) methods uniquely powered to compare the neural correlates of attention variability in these three groups.
The present study examined 8- to 25-year-old individuals (n = 106) who completed an fMRI attention task: 24 with BP, 29 at risk based on a first-degree relative with BP, and 53 healthy, low-risk individuals. Group differences in intrasubject variability in reaction time were examined, and a sophisticated fMRI analytic approach was used to quantify precisely trialwise associations between reaction time and brain activity. The latter has not been examined previously in BP or risk of BP.
Relative to healthy individuals, those with BP or at risk for BP exhibited increased reaction time variability (F_2,102 = 4.26, p = .02, η_p² = .08). Importantly, we identified blunted relationships between trialwise variation in reaction time and brain activity in the inferior and middle frontal gyri, precuneus, cingulate cortex, caudate, and postcentral gyrus (all regions: p < .001, η_p² > .06) in both at-risk and BP individuals compared with healthy, low-risk individuals. This blunting partially mediated group differences in reaction time variability (β = .010, 95% confidence interval 0.002 to 0.020, Sobel Z = 2.08, p = .038).
Blunting in key frontal, cingulate, and striatal areas was evident in unaffected, at-risk individuals and in euthymic BP patients. Elucidating such novel neural endophenotypes can facilitate new approaches to BP prediction, diagnosis, and prevention.
A meta-analysis of neurocognition in youth with familial high risk for bipolar disorder
2017, European Psychiatry
Citation Excerpt :
We were not able to explore potential cognitive vulnerability factors in younger relatives of patients with BD as only a few studies have investigated such deficits in young offsprings of BD. One notable exception was Adleman et al. [44] who reported increased intrasubject variability in response time in preschoolers with FHR-BD. In addition to FHR-BD studies, several studies investigating premorbid phase of BD showed evidence for developmental cognitive impairment in BD.
Neuropsychological impairment, including deficits in social cognition is evident in subjects at genetic high-risk for psychosis. However, findings in youth at genetic risk to bipolar disorder (BP) have been suggested to be less supportive of premorbid deficits. We aimed to conduct a meta-analysis of cognitive deficits in youth with familiar risk for bipolar disorder (FHR-BD).
A novel meta-analysis of FHR-BD (mean age 10–25), including 18 studies (786 offsprings/siblings of patients with BD and 794 healthy controls), was conducted.
Both general cognition (d = 0.29, CI = 0.15–0.44) and social cognition (d = 0.23, CI = 0–0.45) were impaired in FHR-BD. In comparison to controls, FHR-BD had significant deficits in several cognitive domains, including visual memory (d = 0.35), verbal memory (d = 0.21), processing speed (d = 0.26) and sustained attention (d = 0.36). There was no significant difference between FHR-BD and controls in planning and working memory.
Cognitive deficits are evident in individuals who are at genetic high-risk for developing BD. Neurodevelopmental abnormalities are likely playing a role not only in schizophrenia but also in BD.
Decreased Cingulate Cortex activation during cognitive control processing in bipolar disorder
2017, Journal of Affective Disorders
Citation Excerpt :
Errors were subdivided into two types: omission errors, which occur when no response is given before the next stimulus appears, and errors of commission, which reflect incorrect responses. Finally, as several studies have shown that BPD patients exhibit increased intra-subject variability of response times (ISV-RT; Adleman et al., 2014; Bora et al., 2006; Brotman et al., 2009; Gallagher et al., 2015), we also examined within-subject patterns of performance. ISV-RT, defined as the average variability in the time an individual participant takes to respond to task stimuli, was calculated for each of the task conditions (control and interference).
Cognitive deficits are well-documented in patients with bipolar disorder (BPD) and may impact the efficacy of psychotherapy. Cognitive control, a form of executive functioning, is often used therapeutically to shift patients’ thoughts and behaviors from automatic, maladaptive responses to adaptive coping strategies. This study examined cognitive control processing in patients with BPD using the Multi-Source Interference Task (MSIT).
Twenty-nine patients diagnosed with BPD and 21 healthy control (HC) subjects completed the MSIT with concurrent functional magnetic resonance imaging (fMRI).
Patients with BPD generally performed worse on the MSIT relative to HC participants; the BPD group had significantly lower performance accuracy and made more omission errors. Further, fMRI analyses revealed differential patterns of activation between the groups during the MSIT. Region of interest (ROI) analyses revealed that relative to HC participants, patients with BPD activated significantly fewer voxels within the cingulate cortex (CC) and more voxels within prefrontal cortex (PFC), although the PFC findings did not survive more stringent significance thresholds.
Patients and HCs were not matched for age, sex, and premorbid verbal IQ, however, these variables were controlled for statistically. Medication usage in the BPD group may have possibly impacted the results. Given a priori hypotheses, ROI analyses were utilized.
Decreased CC activation and increased PFC activation may be associated with impaired cognitive control, demonstrated by BPD patients when completing the MSIT. Identifying the neural mechanisms which underlie key cognitive abnormalities in BPD may aid in clarifying the pathophysiology of this disorder and inform selection of potential targets for cognition remediation in BPD.
The search for neuroimaging and cognitive endophenotypes: A critical systematic review of studies involving unaffected first-degree relatives of individuals with bipolar disorder
2017, Neuroscience and Biobehavioral Reviews
Citation Excerpt :
Given the amount of evidence in some of the aforementioned fields, when more than 10 studies are cited, we refer to the respective table for an overview of the data. As seen from Table 1, 51 studies investigated ‘cold’ cognition (Adleman et al., 2014; Antila et al., 2007; Besnier et al., 2009; Bora et al., 2008; Brotman et al., 2014; Brotman et al., 2009; Brotman et al., 2008b; Chang and Lenzenweger, 2005; Christodoulou et al., 2012a,b; Civil Arslan et al., 2014; Costafreda et al., 2009; Daban et al., 2012; Deveci et al., 2013; Deveney et al., 2012; Dima et al., 2016; Doyle et al., 2009; Erk et al., 2014; Erol et al., 2014; Frangou, 2012; Frangou et al., 2005; Frantom et al., 2008; Hıdıroğlu et al., 2015; Juselius et al., 2009; Keri et al., 2001; Kim et al., 2015; Kim et al., 2012; Kosger et al., 2015; Kulkarni et al., 2010; Ladouceur et al., 2008; Li et al., 2015; Linke et al., 2013; Maziade et al., 2009; Nehra et al., 2014; Olsavsky et al., 2012; Patino et al., 2013; Pattanayak et al., 2012; Seidel et al., 2012; Sepede et al., 2012; Singh et al., 2014b; Sobczak et al., 2003; Sobczak et al., 2002; Szoke et al., 2006a,b; Teixeira et al., 2014; Thermenos et al., 2011; Trivedi et al., 2008; Tseng et al., 2015; Versace et al., 2010; Wessa et al., 2015; Zalla et al., 2004); these examined general intellectual functioning (k = 31; N = 844 URs, 1040 HCs), speed of processing (k = 14; N = 630 URs, 551 HCs), attention/vigilance (k = 13; N = 408 URs, 396 HCs), verbal learning and memory (k = 18; N = 654 URs, 635 HCs), visual learning and memory (k = 9; N = 341 URs, 389 HCs), reasoning and problem solving (k = 20; N = 718 URs, 734 HCs), working memory (k = 12; N = 390 URs, 412 HCs), verbal fluency (k = 12; N = 307 URs, 440 HCs), and executive function (k = 25; N = 888 URs, 981 HCs) (for an overview and study details see Table 1). All but one small study (Frantom et al., 2008) found no difference between URs and HCs on IQ measures, which indicates that general intelligence is not an illness-trait conferring genetic liability for BD.
The phenomenology and underlying pathophysiology of bipolar disorder (BD) are heterogeneous. The identification of putative endophenotypes for BD can aid in the investigation of unique patho-etiological pathways, which may lead to the development of personalised preventative and therapeutic approaches for this multi-faceted disorder. We included original studies involving unaffected first-degree relatives of BD patients (URs) and a healthy control (HC) comparison group with no first-degree family history of mental disorders, investigating: ‘cold’ and ‘hot’ cognition and functional and structural neuroimaging. Seventy-seven cross-sectional studies met the inclusion criteria. The present review revealed that URs in comparison with HCs showed: (i) widespread deficits in verbal memory, sustained attention, and executive function; (ii) abnormalities in the reactivity to and regulation of emotional information along with aberrant reward processing, and heightened attentional interference by emotional stimuli; and (iii) less consistency in the findings regarding structural and resting state neuroimaging, and electrophysiological measures.
Neurocognitive functioning in euthymic patients with bipolar disorder and unaffected relatives: A review of the literature
2016, Neuroscience and Biobehavioral Reviews
Neurocognitive deficits are present in bipolar disorder (BD) patients and their unaffected (nonbipolar) relatives, but it is not clear which domains are most often impaired and the extent of the impairment resulting from shared genetic factors. In this literature review, we address these issues and identify specific neurocognitive tasks most sensitive to cognitive deficits in patients and unaffected relatives.
We conducted a systematic review in Web of Science, PubMed/Medline and PsycINFO databases.
Fifty-one articles assessing cognitive functioning in BD patients (23 studies) and unaffected relatives (28 studies) were examined. Patients and, less so, relatives show impairments in attention, processing speed, verbal learning/memory, and verbal fluency.
Studies were more likely to find impairment in patients than relatives, suggesting that some neurocognitive deficits may be a result of the illness itself and/or its treatment. However, small sample sizes, differences among relatives studied (e.g., relatedness, diagnostic status, age), and differences in assessment instruments may contribute to inconsistencies in reported neurocognitive performance among relatives. Additional studies addressing these issues are needed.
Age-related differences in the neural correlates of trial-to-trial variations of reaction time
2016, Developmental Cognitive Neuroscience
Citation Excerpt :
The results of this and future studies of the phenomenon may be of particular use in understanding disorders associated with abnormal development of executive functions, such as ADHD (Shaw et al., 2007, 2012). On a related front, increased ISVRT has also been associated with many developmental neurological and psychiatric disorders (Bora et al., 2006; Leth-Steensen et al., 2000; Kaiser et al., 2008; Brotman et al., 2009; Castellanos et al., 2005; Epstein et al., 2011), and has even been observed in healthy people at increased familial risk for such disorders (i.e., first-degree relatives: Adleman et al., 2014; Brotman et al., 2009; Nigg et al., 2004; Bidwell et al., 2007). Therefore, understanding the brain mechanisms underlying ISVRT (i.e., RT-BOLD associations), is an important next step for the field.
Intra-subject variation in reaction time (ISVRT) is a developmentally-important phenomenon that decreases from childhood through young adulthood in parallel with the development of executive functions and networks. Prior work has shown a significant association between trial-by-trial variations in reaction time (RT) and trial-by-trial variations in brain activity as measured by the blood-oxygenated level-dependent (BOLD) response in functional magnetic resonance imaging (fMRI) studies. It remains unclear, however, whether such “RT-BOLD” relationships vary with age. Here, we determined whether such trial-by-trial relationships vary with age in a cross-sectional design. We observed an association between age and RT-BOLD relationships in 11 clusters located in visual/occipital regions, frontal and parietal association cortex, precentral/postcentral gyrus, and thalamus. Some of these relationships were negative, reflecting increased BOLD associated with decreased RT, manifesting around the time of stimulus presentation and positive several seconds later. Critically for present purposes, all RT-BOLD relationships increased with age. Thus, RT-BOLD relationships may reflect robust, measurable changes in the brain-behavior relationship across development.

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Brief reportIncreased intrasubject variability in response time in unaffected preschoolers at familial risk for bipolar disorder

Abstract

Introduction

Section snippets

Methods

Results

Discussion

Acknowledgment

Progress in Neuro-Psychopharmacology and Biological Psychiatry

Journal of Affective Disorders

Journal of the American Academy of Child and Adolescent Psychiatry

Journal of the American Academy of Child and Adolescent Psychiatry

Psychiatry Research

Developmental Cognitive Neuroscience

Biological Psychiatry

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

Evidence for higher reaction time variability for children with ADHD on a range of cognitive tasks including reward and event rate manipulations

Neuropsychology

Processing efficiency and sustained attention in bipolar disorder

Journal of the International Neuropsychological Society

Brief report
Increased intrasubject variability in response time in unaffected preschoolers at familial risk for bipolar disorder