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Parametric neurocognitive task design: a pilot study of sustained attention in adolescents with bipolar disorder
Journal of Affective Disorders 82S (2004) S79– S88 www.elsevier.com/locate/jad
Research report
Parametric neurocognitive task design: a pilot study of sustained attention in adolescents with bipolar disorder Melissa P. DelBello*, Caleb M. Adler, Jennifer Amicone, Neil P. Mills, Paula K. Shear, Juliet Warner, Stephen M. Strakowski Department of Psychiatry, University of Cincinnati College of Medicine, 231 Bethesda Ave., P.O. Box 670559, Cincinnati, OH 45267-0559, USA Received 8 September 2003; accepted 19 May 2004
Abstract Background: Disruption in attention is one of the core features of bipolar disorder (BP). Therefore, neurocognitive paradigms assessing brain function in response to tasks of increasing attentional difficulty may be useful to clarify the neurophysiology of bipolar disorder. The aim of this study was to obtain pilot performance data using a parametric task of sustained attention that might be useful as an experimental paradigm for future functional neuroimaging studies. We hypothesized that task performance would worsen as task difficulty increased in manic and euthymic bipolar and healthy subjects. Additionally, we hypothesized that the groups would exhibit a similar decline in task performance as level of task difficulty increased and that within each level of task difficulty there would be similar performance among groups. Methods: A novel parametric Continuous Performance Task-Identical Pairs (CPT-IP) version was administered to manic (N=10) and euthymic (N=10) adolescents with bipolar disorder and healthy controls (N=10). Results: There were no statistically significant group differences in task performance as measured by discriminability, percent correct, false positive hits, and reaction time. However, within each group, performance on all measures worsened with increased attentional difficulty ( pb0.0001). There were no statistically significant task difficulty by group interactions. Furthermore, medication exposure and comorbid attention-deficit hyperactivity disorder were not associated with most measures of task performance. However, BP subjects who were treated with medications had slower task performance compared with BP subjects who were unmedicated. Limitations: Larger studies examining the effects of specific medication classes on task performance are necessary. Conclusions: The results of this pilot study suggest that manic and euthymic BP patients do not exhibit attentional dysfunction as compared to healthy adolescents using a novel parametric version of the CPT-IP. Furthermore, our parametric CPT-IP version may be useful as a novel parametric neurocognitive paradigm for future functional neuroimaging studies of bipolar adolescents. D 2004 Elsevier B.V. All rights reserved. Keywords: Bipolar disorder; Adolescents; Sustained attention; Euthymia; Manic
* Corresponding author. Tel.: +1 513 558 5847; fax: +1 513 558 3399. E-mail address: [email protected] (M.P. DelBello). 0165-0327/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2004.05.014
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1. Introduction Bipolar disorder (BP) is a common, life-long illness that typically begins in adolescence or early adulthood and is associated with significant morbidity and mortality (Lish et al., 1994). However, there has been very little research on the neurobiology of pediatric BP. One technique that has been used to gather information about the neuropathophysiology of adult BP is functional magnetic resonance imaging (fMRI), which provides information about localized patterns of brain activation during specific tasks. The focus of this report is on the development of a paradigm to measure brain activation using fMRI in adolescents with BP during an attentional task. Disruptions in attentional and emotional modulation are two of the cardinal features of BP (Geller and Luby, 1997; Bearden et al., 2001; DelBello and Kowatch, 2003; Leibenluft et al., 2003). Therefore, investigations of the neural substrates responsible for these cognitive and affective functions represent a first step in clarifying the neruophysiological abnormalities that underlie this disorder. Specifically, studying differential patterns of regional brain activation in response to cognitive tasks related to attention and emotion in BP and healthy adolescents may clarify the neuropathophysiology of this illness. There is cumulating evidence to suggest that a neural network, the anterior limbic network, involving the prefrontal cortex, thalamus, amygdala, striatum, and the cerebellar vermis, regulates attentional and emotional functioning (Mayberg, 1997; Strakowski et al., 2000a,2002; Blumberg et al., 2002). Therefore, it is likely that dysfunction within the anterior limbic network underlies the neurophysiology of BP. Specifically, the amygdala and subcortical limbic regions, which are involved in processing emotional and inhibitory stimuli, have extensive interconnections with the subgenual and ventral anterior cingulate as well as the orbitofrontal and ventrolateral prefrontal cortex, which in turn have output projections to the thalamus and striatum. Dysfunction in these brain regions and their interconnections may result in the emotional dysregulation and impulsivity associated with bipolar disorder. Furthermore, there are reciprocal connections among these pathways and those involving the dorsal anterior cingulate, dorsolateral prefrontal cortex and other regions involved in the regulation of attention. Therefore, dysfunction within the regions involved in
modulation of emotion and impulsivity may also disrupt attentional regulation. Indeed, previous structural and functional neuroimaging studies and reports of brain lesions in secondary mania have implicated dysfunction in these brain regions in bipolar patients (Strakowski and Sax, 2000b; Strakowski et al., 2002). Furthermore, patients with bipolar disorder exhibit deficits in attention during periods of mania, depression and euthymia (Bearden et al., 2001). Thus, our imaging studies of patients with pediatric BP are designed with particular emphasis on using attentional paradigms to measure activation in these circuits. FMRI is a non-invasive technique that permits study of brain function without the risks of ionizing radiation, making it particularly useful for assessing brain function in children and adolescents. However, there are several challenges in designing neurocognitive activation paradigms for pediatric patients (Ernst and Rumsey, 2000; Pine, 2002; Leibenluft et al., 2003). First, an essential initial step to minimize activation differences resulting from decreased effort in task performance is to monitor subject performance. Second, it is important to select a task that is appropriately related to a given behavioral dimension for a particular disorder and for which performance does not differ between patients and healthy subjects, because poor task performance may be associated with increases in brain activation. Furthermore, excellent performance may be associated with decreases in activation until a certain level of task difficulty, at which no effort is made to complete the task (thus, no task related activation occurs) (Price and Friston, 1999; Casey et al., 2000). In other words, if patients perform substantially worse than healthy subjects on a particular task, it cannot be determined whether differences in brain activation are due to underlying brain abnormalities in patients, variability in task performance between groups, or patients simply not completing the task. However, if a task is too simple, inefficiencies in brain function may not become evident. Ideally, both patients and healthy volunteers should be able to perform a selected task, but task performance should be difficult enough to identify inefficiencies. One approach to this dilemma is to select a task for which group performance does not differ (i.e. a simplified version) (Casey et al., 2000). However, by selecting an isolated task, it remains uncertain whether brain regions involved are being sufficiently bstressedQ. A second approach is to
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select a task for which the load can be increased (Casey et al., 2000). Indeed, tasks that increase parametrically in difficulty have been used to evaluate brain activation associated with increasing working memory difficulty (N-back test) in patients with schizophrenia and BP and healthy subjects (Klingberg and Roland, 1997; Callicott et al., 1998; Adler et al., 2001b). Another advantage of using a parametric task is that if activation in a brain region varies with changes in task difficulty, a stronger argument can be made for that brain region being involved in task performance. Recently, several investigators have used parametric visual attention tasks to study neural activity as a function of attention load in healthy adults (Culham et al., 2001; Jovicich et al., 2001; Mazoyer et al., 2002). Results from these studies demonstrate that increases in attentional load are associated with parietal, dorsolateral prefrontal, inferior temporal, and cerebellar signal increases and precuneal, anterior cingulate, and medial superior frontal signal decreases, suggesting that these brain regions are directly involved in attention processes (Culham et al., 2001). Adler et al. (2001a) found that healthy adults exhibited greater activation in the left dorsolateral prefrontal cortex, bilateral posterior temporal cortex, bilateral putamen, and thalamus while performing a more demanding task of sustained visual attention (continuous performance task-identical pairs version, CPT-IP) as compared to performing a related, but less demanding task (continuous performance task-degraded stimuli version), even though task performance was similar during the two tasks. These results suggest that increases in processing demand are associated with increases in activation of specific attentional networks involving neuroanatomic structures implicated in the pathophysiology of bipolar disorder. However, to our knowledge, there have been no fMRI studies using parametric tasks of attention in healthy or bipolar youth. Sustained attention in adults with BP has been assessed using a variety of versions of the Continuous Performance Test (CPT) (Bearden et al., 2001). Some researchers have identified attentional deficits only during acute mood episodes (Kerry et al., 1983; Serper, 1993; Goldberg et al., 1993; Addington and Addington, 1997; Sax et al., 1998; Ferrier et al., 1999; Liu et al., 2002), while others suggest that these deficits are present, although to a lesser degree, during periods of clinical remission as well (Sax et al., 1995; Tham et al.,
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1997; Van Gorp et al., 1998; Ali et al., 2000; WilderWillis et al., 2001). Possible explanations for these conflicting results include differences in task difficulty and variability in the diagnostic and clinical characteristics of patient populations, (i.e. failure to account for medication status, affective state, and illness chronicity). To our knowledge, there have been two studies examining the neuropathophysiology that underlies attentional dysfunction in patients with BP. Sax et al. (1999) found significant correlations between performance on the CPT and prefrontal cortical and hippocampal volumes on MRI in patients with acute mania. In a second study, Ali et al. (2000) reported that deficits in performance on tasks of attention were associated with increased hippocampal volumes. There have been very few studies of cognitive functioning in bipolar youth (Castillo et al., 2000; Shear et al., 2002; McClure et al., 2003). Furthermore, to our knowledge, there is only one study evaluating attentional function in BP youth, which reported that BP children exhibited deficits in performance on a task of visual attention (Castillo et al., 2000). Given the paucity of neurocognitive data in BP youth, it is essential to obtain preliminary performance data for potential neurocognitive paradigms prior to studying these tasks with neuroimaging. With these considerations in mind, the goal of this study was to obtain pilot performance data for a novel parametric task of sustained attention in manic and euthymic adolescents with bipolar disorder. We used a novel, simplified parametric version of a well-studied task of sustained attention, the Continuous Performance Task-Identical Pairs version (Cornblatt et al., 1998). We hypothesized that task performance would worsen as task difficulty increased in manic and euthymic BP and healthy subjects. Additionally, we hypothesized that the groups would exhibit a similar decline in task performance as level of task difficulty increased. We also explored the effects of medications and other clinical variables on attentional functioning.
2. Methods 2.1. Subjects Adolescents with a diagnosis of bipolar I disorder (BP), manic or mixed (N=10) or euthymic (N=10),
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were recruited from an ongoing outcome study of BP patients (Strakowski et al., 2000c). Patients were included in this study if they were 12–18 years old and met DSM-IV criteria for bipolar I disorder. Manic patients were included if they met DSM-IV criteria for a current mixed or manic episode and had a Young Mania Rating Scale (YMRS) (Young et al., 1978; Fristad et al., 1992) score of N20. Euthymic patients were included if they did not meet DSM-IV criteria for a current affective episode, had an YMRS score of b12, and had a Hamilton Depression Rating Scale Score (HDRS) of b8 for 4 weeks prior to and following study participation (Hamilton, 1960). Healthy subjects (N=10) between the ages of 12– 18 years old, matched for age, education, race and sex were recruited from the community. Healthy subjects were excluded for a history of psychiatric illness in themselves or any first-degree relative. All subjects were also excluded by: (1) a lifetime history of substance dependence or a history of a substance abuse within the prior three months; (2) a diagnosis of mental retardation (IQb70); (3) an unstable medical or neurological disorder; (4) a history of head trauma resulting in a loss of consciousness for greater than 10 min; or (5) a Tanner stage of b3. Diagnoses (in patients) or their absence (in controls) were confirmed using the Washington University in St. Louis Kiddie-Schedule for Affective Disorders and Schizophrenia (WASH-U KSADS) (Geller et al., 2001) by trained child and adolescent psychiatrists with established diagnostic reliability (diagnostic kappa=0.94, DelBello et al., 2001). Adolescent subjects and their parents or legal guardians were interviewed separately. Primary caregiver and adolescent responses were combined in order to ascertain diagnoses. All diagnoses were reviewed in a conference attended by the WASH-U KSADS interviewer and at least one other child and adolescent psychiatrist, and at which a consensus diagnosis was made. Demographic information was obtained by interviewing the adolescent and their parent or legal guardian. The Self-Rated Tanner Scale (Morris and Udry, 1980) was used to assess the stage of adolescent sexual development. Age at onset of bipolar disorder was defined as the age at which a DSM-IV affective episode initially occurred and was determined using the WASH-U K-SADS, information from medical records, personal recall and/or family
corroboration. Clinical interviews of the patient and their parent or legal guardians were used to determine current medications. YMRS and HDRS were administered on the day of attentional testing to assess severity of mania and depression, respectively. Overall level of functioning was assessed using The Children’s Global Assessment Scale (CGAS) scores (Shaffer et al., 1983). A child and adolescent psychiatrist or master’s level psychology graduate student, with previously established reliability for each rating scale, completed all ratings by interviewing the subject and their primary caregiver (ICCN0.9) on the day of study participation. Adolescent subjects provided written assent and their parents or legal guardians provided written informed consent after study procedures were fully explained. This study was approved by the University of Cincinnati and the Cincinnati Children’s Hospital Medical Center Institutional Review Boards. 2.2. Cognitive testing Verbal, Performance, and Full Scale IQ scores were assessed by having trained psychometricians administer the The Wechsler Abbreviated Scale of Intelligence (WASI) to each subject. A novel and computerized version of an Identical Pairs Continuous Performance Task (CPT-IP) was administered as a parametric task of sustained attention. During the CPT-IP, subjects viewed random single-digit numbers, which were presented every 750 ms. Subjects were instructed to respond by pressing a button with their dominant hand as quickly and as accurately as possible each time the same single digit appeared twice in succession. The random pixel substitution program incorporated into PsyScope was used to systematically degrade the stimuli by one (25%) and two (50%) levels (see Fig. 1), resulting in three levels of
Fig. 1. Example of the number b0Q, which has been systematically degraded (0%, 25%, and 50%) using the random pixel substitution program incorporated into PsyScope.
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attentional demand (0%, 25% and 50% degradation). The CPT-IP was presented in a periodic block-design paradigm in which 30-s intervals of the three attention conditions were randomly interleaved. Five 30-second intervals of stimuli from each of the three degradation levels (0%, 25% and 50% degradation) were randomly interleaved. There were five target responses for each 30-s. Therefore, for each of the three attention conditions (no degradation, 25% degradation, and 50% degradation), there were a total of 25 target responses (five correct responses/30-s intervalfive 30-s intervals of each degradation level) out of 200 (12.5%) stimuli. The CPT-IP was administered to all subjects using PsyScope running on a MacIntosh PowerBook laptop computer. All subjects completed the task in a small, quiet room without interruption. Subjects responded to targets using a button box. The responses were electronically recorded to permit calculation of response parameters of interest (i.e. discriminability, percent correct, false positive responses and reaction time). 2.3. Statistical analysis All statistical analyses were performed using the Statistical Analysis System (SAS Institute, Cary, NC, USA, 1998). Group comparisons in demographic and clinical variables were performed using analyses of variance for continuous variables and chi-square tests for dichotomous variables. Demographic variables were examined as potential covariates and none exhibited differences among groups (at pb0.2) except both manic and euthymic BP subjects had lower Full Scale and Performance IQ scores than healthy controls ( p=0.03 and p=0.01, respectively) (Table 1). Note that the group difference in IQ is due to the presence of slightly above average IQ scores in the healthy controls; scores in the patients groups are entirely within average clinical range. CPT-IP performance measures of interest included discriminability, percent correct, number of false positive hits, and reaction time. Percent correct was calculated as the number of correct responses divided by the total number of stimuli. Discriminability was calculated using the formula dV=Z (false positive
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Table 1 Demographic and clinical characteristics of manic (N=10) and euthymic (N=10) adolescents with bipolar disorder (BP) and healthy controls (HC) (N=10) Variable
BP euthymic (N=10)
BP manic (N=10)
HC (N=10)
Age, mean (S.D.) Sex, females, N (%) Race, Caucasian, N (%) Tanner stage, mean (S.D.) Young Mania Rating Scale, mean (S.D.)a Hamilton Depression Rating Scale, mean (S.D.)b Childhood Global Assessment Scale, mean (S.D.)c Attention-deficit hyperactivity disorder, N (%) Prior history of drug abuse, N (%) WASI, Full Scale IQ, mean (S.D.)d WASI, Verbal IQ, mean (S.D.) WASI, Performance IQ, mean (S.D.)e Age of onset of affective illness, mean (S.D.) Current medications Lithium Antiepileptics Atypical antipsychotics Psychostimulants Unmedicated
16 (1) 5 (50)
16 (2) 6 (60)
15 (2) 5 (50)
2 (20)
1 (10)
0 (0)
4.3 (0.6)
4.4 (0.7)
3.9 (0.8)
7 (5)
25 (6)
2 (1)
3 (2)
12 (12)
2 (1)
68 (18)
46 (15)
86 (8)
4 (40)
2 (20)
N/A
2 (20)
3 (30)
0 (0)
100 (11)
98 (15)
111 (7)
98 (13)
102 (14)
110 (7)
102 (9)
94 (15)
110 (9)
10.8 (4.2)
11.0 (3.9)
N/A
2 (20) 2 (20) 2 (20)
2 (20) 2 (20) 2 (20)
2 (20) 4 (40)
2 (20) 4 (40)
N/A
N/A
WASI=Wechsler Abbreviated Scale of Intelligence. a Significant difference: ANOVA: F(2, 27)=63.7, pb0.0001, healthy controlsbeuthymics and manics and euthymicsbmanics. b Significant difference: ANOVA: F(2, 27)=5.6, p=0.009, healthy controls and euthymicbmanics. c Significant difference: ANOVA: F(2, 27)=19.49, pb0.001, healthy controlsbeuthymics and manics and euthymicsbmanics. d Significant difference: ANOVA: F(2, 27)=3.8, p=0.03, healthy controlsNmanics. e Significant difference: ANOVA: F(2, 27)=4.90, p=0.01, healthy controlsNmanics.
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rate)Z (correct hit rate), where Z is the normal deviates (Coren and Ward, 1989). Discriminability has been used in signal detection theory as the ability to discriminate target from nontarget responses (Coren and Ward, 1989). Comparisons of group differences in performance within each level of degradation were performed using ANOVAs with group as the independent variable and performance measures as the dependent variables. Effect sizes for group differences were calculated for eachpperformance ffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi measure using the formula f ¼ ðk 1ÞF=N , where fN0.4 is characterized as a large effect size (Cohen, 1977). We then evaluated group by degradation interactions using analyses of covariance (ANCOVAs) with group and degradation level as the independent variables and discriminability, percent correct, false positive hits, and reaction time as the dependent variables. Spearman correlations were used to examine associations among CPT-IP performance measures within each level of task degradation and clinical variables, including IQ scores (for all subjects), CGAS scores (for all subjects), as well as YMRS and HDRS scores (for manic subjects). Additionally, ANCOVAs were performed evaluating group by level of degradation interactions and group differences in performance measures within each level of degradation, adjusting for Full Scale IQ scores and the presence of ADHD. We also assessed the effects of medications on CPT-IP performance. The effects of four classes of medications were examined: atypical antipsychotics, antiepileptic drugs (which included divalproex, N=3 and topiramate, N=1), lithium, and psychostimulants. None of the BP subjects were taking antidepressants or typical antipsychotics at the time of study participation. ANOVAs were used to examine differences in performance variables between BP subjects who were and were not taking each class of medications. A p value of b0.05 was used to determine significance for the Spearman correlations and Wilcoxon nonparametric tests. Other analyses were performed as necessary.
(Table 1). The number of unmedicated subjects, rates of exposure to each medication class, and rates of co-occurring attention-deficit hyperactivity disorder (ADHD) or substance use disorders were similar between the manic and euthmyic BP groups (Table 1).
Table 2 Continuous performance test performance in manic (N=10) and euthymic (N=10) adolescents with bipolar disorder and healthy controls (HC) (N=10) Variable 0% Degradation Discriminability, mean (S.D.)a Percent correct, mean (S.D.)b False positives, number of hits, mean (S.D.)c Reaction time, ms, mean (S.D.)d 25% Degradation Discriminability, mean (S.D.)a Percent correct, mean (S.D.)b False positives, number of hits, mean (S.D.)c Reaction time, ms, mean (S.D.)d 50% Degradation Discriminability, mean (S.D.)a Percent correct, mean (S.D.)b False positives, number of hits, mean (S.D.)c Reaction time, ms, mean (S.D.)d a
3. Results Healthy and BP manic and euthymic subjects were closely matched on demographic variables
BP euthymic (N=10)
BP manic (N=10)
HC (N=10)
5.1 (2.5)
5.0 (2.2)
5.9 (2.8)
85 (14)
90 (8)
94 (8)
2.4 (2.8)
1.3 (1.3)
1.4 (1.4)
516 (75)
483 (68)
480 (56)
4.4 (2.2)
5.1 (2.2)
6.3 (2.6)
85 (10)
90 (8)
92 (12)
1.9 (1.7)
1.9 (2.5)
0.6 (0.7)
559 (71)
496 (26)
532 (71)
3.0 (1.1)
3.1 (1.5)
3.8 (1.8)
72 (16)
69 (13)
80 (16)
3.8 (2.9)
3.4 (2.5)
2.7 (1.8)
579 (77)
576 (59)
574 (39)
F(2, 87)=8.5, p=0.0004, discriminability at 0% degradationN25% degradationN50% degradation. b F(2, 87)=17.1, pb0.0001, percent correct at 0% degradationN25% degradationN50% degradation. c F(2, 87)=6.8, p=0.002, false positive hits at 0% degradationb25% degradationb50% degradation. d F(2, 87)=13.5, pb0.0001.
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There was no statistically significant group difference in discriminability, percent correct, number of false positive hits, or reaction time within each level of task difficulty (see Table 2) (all pN0.1). Specifically, at 0% degradation the effect size for group differences among performance for each of the CPT-IP performance variables was f=0.3. At 25% degradation, the effect sizes ranged from f=0.2 for reaction time, discriminability, and false positive hits to f=0.3 for percent correct. At 50% degradation, the effect size was f=0.03 for reaction time and f=0.2 for each of other response variables. There were no statistically significant group by degradation level differences in performance measures [ F(8, 81)=0.7, p=0.6 for percent correct and reaction time, F(81, 8)=0.3, p=0.8 for false positive hits, and F(8, 81)=0.22, p=0.9 for discriminability]. However, within each group, discriminability, percent correct, false positive hits, and reaction time significantly worsened as level of degradation increased ( pb0.002, Table 2). The results of all analyses were unchanged by adjusting for Full Scale IQ scores and the presence of ADHD. For BP subjects, there were no statistically significant correlations among the CPT-IP performance variables and the YMRS or HDRS scores within each degradation level. However, for all subjects, higher CGAS scores were significantly correlated with fewer false positive hits and better discriminability at 25% and 50% task degradation (r=0.4, p=0.04 and r=0.4, p=0.05 at 25% degradation and r=0.4, p=0.03 and r=0.4 and p=0.03 at 50% degradation, respectively). Full Scale, Verbal, and Performance IQ scores were not statistically significantly associated with any of the task performance variables among all subjects. Eight of the twenty (40%) BP subjects were unmedicated at the time of study participation. There was no change in the results of the study after removing unmedicated patients or medicated BP subjects from analyses. However, at 50% degradation, medicated BP subjects performed the task slower than unmedicated BP subjects (572 vs. 499 ms, f=6.5, p=0.02). Furthermore, BP subjects who were treated with lithium, antiepileptic medications, or atypical antipsychotics had slower reaction times compared with unmedicated BP subjects ( pb0.05).
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4. Discussion Although prior investigators have used the CPT to evaluate attentional dysfunction in adults with BP (Kaskey et al., 1980; Sax et al., 1995; 1998; Fleck et al., 2001; Wilder-Willis et al., 2001; Harmer et al., 2002; Liu et al., 2002), to our knowledge, this is the first report to examine sustained attention using the CPT-IP in BP youth. The present version of the CPT-IP is a simplified, single digit version of the CPT-IP (Cornblatt et al., 1998) and, therefore, may be more developmentally appropriate for children and adolescents than the typical four digit CPT-IP, which has been widely used to measure sustained attention in adults with and without psychiatric illnesses. Additionally, in this study, we evaluated a parametric version of the simplified CPT-IP as a potential novel attentional paradigm for future functional neuroimaging studies of BP youth. The results of this study suggest that euthymic and manic BP adolescents and demographically matched healthy controls performed similarly on the CPT-IP within each level of task difficulty. However, within each group, there was a decline in task performance as attentional difficulty increased. Furthermore, all three groups exhibited a similar decline in task performance as the level of task difficulty increased. In contrast with prior studies of BP adults, our findings suggest that compared with healthy adolescents, both manic and euthymic BP adolescents have relatively intact performance on a simple task of sustained attention or as attentional difficulty increases. There are several possible explanations for the differences in results among studies. First, the sample size in our study was small, limiting our power to detect group differences. Second, prior investigations of sustained attention have typically involved BP patients who were further along in their illness course than in our study. Indeed, Denicoff et al. (1999) found that severe illness course as measured by greater duration and a larger number of affective episodes and hospitalizations was associated with poorer performance in tests of attention in BP adults. Additionally, prior studies assessing attentional deficits during mania have usually evaluated patients during hospitalization. Hospitalized BP patients exhibit greater deficits in sustained attention,
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than do manic outpatients (Liu et al., 2002). Finally, prior studies have employed a wide variety of CPT versions, including those that have included a greater working memory component than in our CTP-IP version (Kaskey et al., 1980). Prior studies have found mixed results regarding state effects on attentional functioning in BP patients. For example, Sax et al. (1998) reported that a group of BP patients performed worse than controls at the time of hospitalization for mania, however, not at 2month follow-up when patients had clinically improved. In contrast, others have reported attentional dysfunction in BP patients during periods of euthymia (Wilder-Willis et al., 2001; Harmer et al., 2002). We observed that euthymic and manic bipolar subjects performed similarly on the CPT-IP. However, all patients in our study were not hospitalized during the time of testing, which might explain their intact performance. Additionally, we did not evaluate the same subjects during periods of euthymic and mania, which may limit the interpretability of our findings. Although co-occurring ADHD was present in a small minority of the BP subjects (30%), we found little effect of co-occurring ADHD on attentional performance probably due to our small sample size or that 67% of the BP and ADHD patients were treated for their ADHD with stimulant medications. Consistent with prior studies, we found that slower task performance was associated with medication exposure (Kaskey et al., 1980). Although our sample size was relatively small, patients treated with either lithium, antiepileptic medications or atypical antipsychotics demonstrated slower reaction times. In contrast, in a study of BP adults, Wilder-Willis et al. found that slower reaction time in euthymic BP adults was not associated with medication exposure. However, there was only one unmedicated BP patient in that study. Nonetheless, future studies aimed at investigating the effects of specific medications on attentional performance are essential. Based on the results of our study, the parametric version of the CPT-IP has several properties that renders it useful as an experimental paradigm for future functional neuroimaging studies assessing differences in activation due to underlying brain dysfunction between BP and healthy adolescents. First, task performance between BP and healthy
subject groups was similar at each level of task difficulty, suggesting that any differences in regional brain activation would be secondary to underlying brain dysfunction rather than differences in task performance. Second, we observed a similar decline in task performance among groups as the level of attentional difficulty increased. Therefore, applying this task in future neruoimaging studies would help identify group differences in regional brain recruitment associated with increases in attentional load, which might help clarify the neural substrates associated with bipolar disorder. The findings of our study are limited by several factors that should be considered when interpreting our results. First, our sample size was relatively small and, therefore, we might have insufficient power to detect group differences. Effect size calculations suggest that there was a small to medium effect size for all of the group by task level of difficulty and group differences in CPT-IP performance. Second, group differences in IQ scores and other demographic variables not assessed may have affected the results of this study. Although IQ scores were not correlated with task performance, future studies using this and other tasks of sustained attention should attempt to minimize group differences in IQ scores. Third, the BP subjects in our study were recruited from an ongoing outcome study of BP patients following their first hospitalization for mania, and therefore, the patients in this study were relatively early in their illness course and their CPT-IP performance may not be representative of other BP patients. Fourth, task performance might differ when subjects perform this task during an MR scanning session as compared to while they are in a small, quiet room. Finally, there were very few patients treated with each class of medication, and there may be different effects on task performance of medications within a class. Therefore, additional investigations adequately examining the effects of specific medications on task performance are necessary. Despite these limitations, these pilot performance data suggest that our version of the CPTIP may be useful as a novel neurocognitive paradigm to study the neural activation associated with increasing attentional demand. Future functional neuroimaging studies using this parametric task of attention may be helpful to clarify the neurophysiology of bipolar disorder in youth.
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Acknowledgements NIMH grant MH63373 (Dr. DelBello) and MH58170 (Dr. Strakowski) and the Stanley Medical Research Institute.
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Leibenluft, E., Charney, D.S., Pine, D.S., 2003. Researching the pathophysiology of pediatric bipolar disorder. Biol. Psychiatry 53, 1009 – 1020. Lish, J.D., Dime-Meenan, S., Whybrow, P.C., Price, R.A., Hirschfeld, R.M., 1994. The National Depressive and Manicdepressive Association (DMDA) survey of bipolar members. J. Affect. Disord. 4, 281 – 294. Liu, S.K., Chiu, C.H., Chang, S.H., Hwang, T.J., Hwu, H.G., Chen, W.J., 2002. Deficits in sustained attention in schizophrenia and affective disorders: stable versus state-dependent markers. Am. J. Psychiatry 159, 975 – 982. Mayberg, H.S., 1997. Limbic–cortical dysregulation: a proposed model of depression. J. Neuropsychiatry Clin. Neurosci. 9, 451–458. Mazoyer, P., Wicker, B., Fonlupt, P., 2002. A neural network elicited be parametric manipulation of the attention load. NeuroReport 3, 2331 – 2334. McClure, E.B., Pope, K., Hoberman, A.J., Pine, D.S., Leibenluft, E., 2003. Facial expression recognition in adolescents with mood and anxiety disorders. Am. J. Psychiatry 160, 1172 – 1174. Morris, N.M., Udry, J.R., 1980. Validation of a self-administered instrument to assess stage of adolescent development. J. Youth Adolesc. Dev. 9, 271 – 280. Pine, D.S., 2002. Brain development and the onset of mood disorders. Semin. Clin. Neuropsychiatry 7, 223 – 233. Price, C.J., Friston, K.J., 1999. Scanning patients with tasks they can perform. Hum. Brain Mapp. 8, 102 – 108. Sax, K.W., Strakowski, S.M., McElroy, S.L., Keck Jr., P.E., West, S.A., 1995. Attention and formal thought disorder in mixed and pure mania. Biol. Psychiatry 37, 420 – 423. Sax, K.W., Strakowski, S.M., Keck Jr., P.E., McElroy, S.L., West, S.A., Stanton, S.P., 1998. Symptom correlates of attentional improvement following hospitalization for first episode of affective psychosis. Biol. Psychiatry 44, 784 – 786. Sax, K.W., Strakowski, S.M., Zimmerman, M.E., DelBello, M.P., Keck Jr., P.E., Hawkins, J.M., 1999. Frontosubcortical neuroanatomy and the continuous performance test in mania. Am. J. Psychiatry 156, 139 – 141.
Serper, M.R., 1993. Visual controlled information-procession resources and formal thought disorder in schizophrenia and mania. Schizophr. Res. 9, 59 – 66. Shaffer, D., Gould, M.S., Brasic, J., Ambrosini, P., Fisher, P., Bird, H., Aluwahlia, S., 1983. A children’s global assessment scale (CGAS). Arch. Gen. Psychiatry 40, 1228 – 1231. Shear, P.K., DelBello, M.P., Rosenberg, H.L., Strakowski, S.M., 2002. Parental reports of executive dysfunction in adolescents with bipolar disorder. Child Neuropsychol. 8, 285 – 295. Strakowski, S.M., DelBello, M.P., Adler, C.M., Cecil, K.M., Sax, K.W., 2000a. The neuropathology of bipolar disorder. Bipolar Disord. 2, 148 – 165. Strakowski, S.M., Sax, K.W., 2000b. Secondary mania: a model of the pathophysiology of bipolar disorder? In: Soares, J.C., Gershon, S. (Eds.), Basic Mechanisms and Therapeutic Implications of Bipolar Disorder. Marcel Dekker, New York, pp. 13 – 29. Strakowski, S.M., Williams, J.R., Fleck, D.E., DelBello, M.P., 2000c. Eight-month functional outcome following hospitalization for first episode mania. J. Psychiatr. Res. 34, 193 – 200. Strakowski, S.M., Adler, C.M., DelBello, M.P., 2002. Volumetric MRI studies of mood disorders: do they distinguish unipolar and bipolar disorder? Bipolar Disord. 4, 80 – 88. Tham, A., Engelbrekston, K., Mathe, A.A., Johnston, L., Olsson, E., Aberg-Wistedt, A., 1997. Impaired neuropsychological performance in euthymic patients with recurring mood disorders. J. Clin. Psychiatry 58, 26 – 28. Van Gorp, W.G., Altshuler, L., Theberge, D.C., Wilkins, J., Dixon, W., 1998. Cognitive impairment in euthymic bipolar patients with and without prior alcohol dependence. Arch. Gen. Psychiatry 49, 975 – 982. Wilder-Willis, K.E., Sax, K.W., Rosenberg, H.L., Fleck, D.E., Shear, P.K., Strakowski, S.M., 2001. Persistent attentional dysfunction in bipolar disorder. Bipolar Disord. 3, 58 – 62. Young, R.C., Biggs, J.T., Ziegler, V.E., Meyer, D.A., 1978. A rating scale for mania: reliability, validity, and sensitivity. Br. J. Psychiatry 33, 429 – 435.
Research report
Parametric neurocognitive task design: a pilot study of sustained attention in adolescents with bipolar disorder Melissa P. DelBello*, Caleb M. Adler, Jennifer Amicone, Neil P. Mills, Paula K. Shear, Juliet Warner, Stephen M. Strakowski Department of Psychiatry, University of Cincinnati College of Medicine, 231 Bethesda Ave., P.O. Box 670559, Cincinnati, OH 45267-0559, USA Received 8 September 2003; accepted 19 May 2004
Abstract Background: Disruption in attention is one of the core features of bipolar disorder (BP). Therefore, neurocognitive paradigms assessing brain function in response to tasks of increasing attentional difficulty may be useful to clarify the neurophysiology of bipolar disorder. The aim of this study was to obtain pilot performance data using a parametric task of sustained attention that might be useful as an experimental paradigm for future functional neuroimaging studies. We hypothesized that task performance would worsen as task difficulty increased in manic and euthymic bipolar and healthy subjects. Additionally, we hypothesized that the groups would exhibit a similar decline in task performance as level of task difficulty increased and that within each level of task difficulty there would be similar performance among groups. Methods: A novel parametric Continuous Performance Task-Identical Pairs (CPT-IP) version was administered to manic (N=10) and euthymic (N=10) adolescents with bipolar disorder and healthy controls (N=10). Results: There were no statistically significant group differences in task performance as measured by discriminability, percent correct, false positive hits, and reaction time. However, within each group, performance on all measures worsened with increased attentional difficulty ( pb0.0001). There were no statistically significant task difficulty by group interactions. Furthermore, medication exposure and comorbid attention-deficit hyperactivity disorder were not associated with most measures of task performance. However, BP subjects who were treated with medications had slower task performance compared with BP subjects who were unmedicated. Limitations: Larger studies examining the effects of specific medication classes on task performance are necessary. Conclusions: The results of this pilot study suggest that manic and euthymic BP patients do not exhibit attentional dysfunction as compared to healthy adolescents using a novel parametric version of the CPT-IP. Furthermore, our parametric CPT-IP version may be useful as a novel parametric neurocognitive paradigm for future functional neuroimaging studies of bipolar adolescents. D 2004 Elsevier B.V. All rights reserved. Keywords: Bipolar disorder; Adolescents; Sustained attention; Euthymia; Manic
* Corresponding author. Tel.: +1 513 558 5847; fax: +1 513 558 3399. E-mail address: [email protected] (M.P. DelBello). 0165-0327/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2004.05.014
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1. Introduction Bipolar disorder (BP) is a common, life-long illness that typically begins in adolescence or early adulthood and is associated with significant morbidity and mortality (Lish et al., 1994). However, there has been very little research on the neurobiology of pediatric BP. One technique that has been used to gather information about the neuropathophysiology of adult BP is functional magnetic resonance imaging (fMRI), which provides information about localized patterns of brain activation during specific tasks. The focus of this report is on the development of a paradigm to measure brain activation using fMRI in adolescents with BP during an attentional task. Disruptions in attentional and emotional modulation are two of the cardinal features of BP (Geller and Luby, 1997; Bearden et al., 2001; DelBello and Kowatch, 2003; Leibenluft et al., 2003). Therefore, investigations of the neural substrates responsible for these cognitive and affective functions represent a first step in clarifying the neruophysiological abnormalities that underlie this disorder. Specifically, studying differential patterns of regional brain activation in response to cognitive tasks related to attention and emotion in BP and healthy adolescents may clarify the neuropathophysiology of this illness. There is cumulating evidence to suggest that a neural network, the anterior limbic network, involving the prefrontal cortex, thalamus, amygdala, striatum, and the cerebellar vermis, regulates attentional and emotional functioning (Mayberg, 1997; Strakowski et al., 2000a,2002; Blumberg et al., 2002). Therefore, it is likely that dysfunction within the anterior limbic network underlies the neurophysiology of BP. Specifically, the amygdala and subcortical limbic regions, which are involved in processing emotional and inhibitory stimuli, have extensive interconnections with the subgenual and ventral anterior cingulate as well as the orbitofrontal and ventrolateral prefrontal cortex, which in turn have output projections to the thalamus and striatum. Dysfunction in these brain regions and their interconnections may result in the emotional dysregulation and impulsivity associated with bipolar disorder. Furthermore, there are reciprocal connections among these pathways and those involving the dorsal anterior cingulate, dorsolateral prefrontal cortex and other regions involved in the regulation of attention. Therefore, dysfunction within the regions involved in
modulation of emotion and impulsivity may also disrupt attentional regulation. Indeed, previous structural and functional neuroimaging studies and reports of brain lesions in secondary mania have implicated dysfunction in these brain regions in bipolar patients (Strakowski and Sax, 2000b; Strakowski et al., 2002). Furthermore, patients with bipolar disorder exhibit deficits in attention during periods of mania, depression and euthymia (Bearden et al., 2001). Thus, our imaging studies of patients with pediatric BP are designed with particular emphasis on using attentional paradigms to measure activation in these circuits. FMRI is a non-invasive technique that permits study of brain function without the risks of ionizing radiation, making it particularly useful for assessing brain function in children and adolescents. However, there are several challenges in designing neurocognitive activation paradigms for pediatric patients (Ernst and Rumsey, 2000; Pine, 2002; Leibenluft et al., 2003). First, an essential initial step to minimize activation differences resulting from decreased effort in task performance is to monitor subject performance. Second, it is important to select a task that is appropriately related to a given behavioral dimension for a particular disorder and for which performance does not differ between patients and healthy subjects, because poor task performance may be associated with increases in brain activation. Furthermore, excellent performance may be associated with decreases in activation until a certain level of task difficulty, at which no effort is made to complete the task (thus, no task related activation occurs) (Price and Friston, 1999; Casey et al., 2000). In other words, if patients perform substantially worse than healthy subjects on a particular task, it cannot be determined whether differences in brain activation are due to underlying brain abnormalities in patients, variability in task performance between groups, or patients simply not completing the task. However, if a task is too simple, inefficiencies in brain function may not become evident. Ideally, both patients and healthy volunteers should be able to perform a selected task, but task performance should be difficult enough to identify inefficiencies. One approach to this dilemma is to select a task for which group performance does not differ (i.e. a simplified version) (Casey et al., 2000). However, by selecting an isolated task, it remains uncertain whether brain regions involved are being sufficiently bstressedQ. A second approach is to
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select a task for which the load can be increased (Casey et al., 2000). Indeed, tasks that increase parametrically in difficulty have been used to evaluate brain activation associated with increasing working memory difficulty (N-back test) in patients with schizophrenia and BP and healthy subjects (Klingberg and Roland, 1997; Callicott et al., 1998; Adler et al., 2001b). Another advantage of using a parametric task is that if activation in a brain region varies with changes in task difficulty, a stronger argument can be made for that brain region being involved in task performance. Recently, several investigators have used parametric visual attention tasks to study neural activity as a function of attention load in healthy adults (Culham et al., 2001; Jovicich et al., 2001; Mazoyer et al., 2002). Results from these studies demonstrate that increases in attentional load are associated with parietal, dorsolateral prefrontal, inferior temporal, and cerebellar signal increases and precuneal, anterior cingulate, and medial superior frontal signal decreases, suggesting that these brain regions are directly involved in attention processes (Culham et al., 2001). Adler et al. (2001a) found that healthy adults exhibited greater activation in the left dorsolateral prefrontal cortex, bilateral posterior temporal cortex, bilateral putamen, and thalamus while performing a more demanding task of sustained visual attention (continuous performance task-identical pairs version, CPT-IP) as compared to performing a related, but less demanding task (continuous performance task-degraded stimuli version), even though task performance was similar during the two tasks. These results suggest that increases in processing demand are associated with increases in activation of specific attentional networks involving neuroanatomic structures implicated in the pathophysiology of bipolar disorder. However, to our knowledge, there have been no fMRI studies using parametric tasks of attention in healthy or bipolar youth. Sustained attention in adults with BP has been assessed using a variety of versions of the Continuous Performance Test (CPT) (Bearden et al., 2001). Some researchers have identified attentional deficits only during acute mood episodes (Kerry et al., 1983; Serper, 1993; Goldberg et al., 1993; Addington and Addington, 1997; Sax et al., 1998; Ferrier et al., 1999; Liu et al., 2002), while others suggest that these deficits are present, although to a lesser degree, during periods of clinical remission as well (Sax et al., 1995; Tham et al.,
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1997; Van Gorp et al., 1998; Ali et al., 2000; WilderWillis et al., 2001). Possible explanations for these conflicting results include differences in task difficulty and variability in the diagnostic and clinical characteristics of patient populations, (i.e. failure to account for medication status, affective state, and illness chronicity). To our knowledge, there have been two studies examining the neuropathophysiology that underlies attentional dysfunction in patients with BP. Sax et al. (1999) found significant correlations between performance on the CPT and prefrontal cortical and hippocampal volumes on MRI in patients with acute mania. In a second study, Ali et al. (2000) reported that deficits in performance on tasks of attention were associated with increased hippocampal volumes. There have been very few studies of cognitive functioning in bipolar youth (Castillo et al., 2000; Shear et al., 2002; McClure et al., 2003). Furthermore, to our knowledge, there is only one study evaluating attentional function in BP youth, which reported that BP children exhibited deficits in performance on a task of visual attention (Castillo et al., 2000). Given the paucity of neurocognitive data in BP youth, it is essential to obtain preliminary performance data for potential neurocognitive paradigms prior to studying these tasks with neuroimaging. With these considerations in mind, the goal of this study was to obtain pilot performance data for a novel parametric task of sustained attention in manic and euthymic adolescents with bipolar disorder. We used a novel, simplified parametric version of a well-studied task of sustained attention, the Continuous Performance Task-Identical Pairs version (Cornblatt et al., 1998). We hypothesized that task performance would worsen as task difficulty increased in manic and euthymic BP and healthy subjects. Additionally, we hypothesized that the groups would exhibit a similar decline in task performance as level of task difficulty increased. We also explored the effects of medications and other clinical variables on attentional functioning.
2. Methods 2.1. Subjects Adolescents with a diagnosis of bipolar I disorder (BP), manic or mixed (N=10) or euthymic (N=10),
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were recruited from an ongoing outcome study of BP patients (Strakowski et al., 2000c). Patients were included in this study if they were 12–18 years old and met DSM-IV criteria for bipolar I disorder. Manic patients were included if they met DSM-IV criteria for a current mixed or manic episode and had a Young Mania Rating Scale (YMRS) (Young et al., 1978; Fristad et al., 1992) score of N20. Euthymic patients were included if they did not meet DSM-IV criteria for a current affective episode, had an YMRS score of b12, and had a Hamilton Depression Rating Scale Score (HDRS) of b8 for 4 weeks prior to and following study participation (Hamilton, 1960). Healthy subjects (N=10) between the ages of 12– 18 years old, matched for age, education, race and sex were recruited from the community. Healthy subjects were excluded for a history of psychiatric illness in themselves or any first-degree relative. All subjects were also excluded by: (1) a lifetime history of substance dependence or a history of a substance abuse within the prior three months; (2) a diagnosis of mental retardation (IQb70); (3) an unstable medical or neurological disorder; (4) a history of head trauma resulting in a loss of consciousness for greater than 10 min; or (5) a Tanner stage of b3. Diagnoses (in patients) or their absence (in controls) were confirmed using the Washington University in St. Louis Kiddie-Schedule for Affective Disorders and Schizophrenia (WASH-U KSADS) (Geller et al., 2001) by trained child and adolescent psychiatrists with established diagnostic reliability (diagnostic kappa=0.94, DelBello et al., 2001). Adolescent subjects and their parents or legal guardians were interviewed separately. Primary caregiver and adolescent responses were combined in order to ascertain diagnoses. All diagnoses were reviewed in a conference attended by the WASH-U KSADS interviewer and at least one other child and adolescent psychiatrist, and at which a consensus diagnosis was made. Demographic information was obtained by interviewing the adolescent and their parent or legal guardian. The Self-Rated Tanner Scale (Morris and Udry, 1980) was used to assess the stage of adolescent sexual development. Age at onset of bipolar disorder was defined as the age at which a DSM-IV affective episode initially occurred and was determined using the WASH-U K-SADS, information from medical records, personal recall and/or family
corroboration. Clinical interviews of the patient and their parent or legal guardians were used to determine current medications. YMRS and HDRS were administered on the day of attentional testing to assess severity of mania and depression, respectively. Overall level of functioning was assessed using The Children’s Global Assessment Scale (CGAS) scores (Shaffer et al., 1983). A child and adolescent psychiatrist or master’s level psychology graduate student, with previously established reliability for each rating scale, completed all ratings by interviewing the subject and their primary caregiver (ICCN0.9) on the day of study participation. Adolescent subjects provided written assent and their parents or legal guardians provided written informed consent after study procedures were fully explained. This study was approved by the University of Cincinnati and the Cincinnati Children’s Hospital Medical Center Institutional Review Boards. 2.2. Cognitive testing Verbal, Performance, and Full Scale IQ scores were assessed by having trained psychometricians administer the The Wechsler Abbreviated Scale of Intelligence (WASI) to each subject. A novel and computerized version of an Identical Pairs Continuous Performance Task (CPT-IP) was administered as a parametric task of sustained attention. During the CPT-IP, subjects viewed random single-digit numbers, which were presented every 750 ms. Subjects were instructed to respond by pressing a button with their dominant hand as quickly and as accurately as possible each time the same single digit appeared twice in succession. The random pixel substitution program incorporated into PsyScope was used to systematically degrade the stimuli by one (25%) and two (50%) levels (see Fig. 1), resulting in three levels of
Fig. 1. Example of the number b0Q, which has been systematically degraded (0%, 25%, and 50%) using the random pixel substitution program incorporated into PsyScope.
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attentional demand (0%, 25% and 50% degradation). The CPT-IP was presented in a periodic block-design paradigm in which 30-s intervals of the three attention conditions were randomly interleaved. Five 30-second intervals of stimuli from each of the three degradation levels (0%, 25% and 50% degradation) were randomly interleaved. There were five target responses for each 30-s. Therefore, for each of the three attention conditions (no degradation, 25% degradation, and 50% degradation), there were a total of 25 target responses (five correct responses/30-s intervalfive 30-s intervals of each degradation level) out of 200 (12.5%) stimuli. The CPT-IP was administered to all subjects using PsyScope running on a MacIntosh PowerBook laptop computer. All subjects completed the task in a small, quiet room without interruption. Subjects responded to targets using a button box. The responses were electronically recorded to permit calculation of response parameters of interest (i.e. discriminability, percent correct, false positive responses and reaction time). 2.3. Statistical analysis All statistical analyses were performed using the Statistical Analysis System (SAS Institute, Cary, NC, USA, 1998). Group comparisons in demographic and clinical variables were performed using analyses of variance for continuous variables and chi-square tests for dichotomous variables. Demographic variables were examined as potential covariates and none exhibited differences among groups (at pb0.2) except both manic and euthymic BP subjects had lower Full Scale and Performance IQ scores than healthy controls ( p=0.03 and p=0.01, respectively) (Table 1). Note that the group difference in IQ is due to the presence of slightly above average IQ scores in the healthy controls; scores in the patients groups are entirely within average clinical range. CPT-IP performance measures of interest included discriminability, percent correct, number of false positive hits, and reaction time. Percent correct was calculated as the number of correct responses divided by the total number of stimuli. Discriminability was calculated using the formula dV=Z (false positive
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Table 1 Demographic and clinical characteristics of manic (N=10) and euthymic (N=10) adolescents with bipolar disorder (BP) and healthy controls (HC) (N=10) Variable
BP euthymic (N=10)
BP manic (N=10)
HC (N=10)
Age, mean (S.D.) Sex, females, N (%) Race, Caucasian, N (%) Tanner stage, mean (S.D.) Young Mania Rating Scale, mean (S.D.)a Hamilton Depression Rating Scale, mean (S.D.)b Childhood Global Assessment Scale, mean (S.D.)c Attention-deficit hyperactivity disorder, N (%) Prior history of drug abuse, N (%) WASI, Full Scale IQ, mean (S.D.)d WASI, Verbal IQ, mean (S.D.) WASI, Performance IQ, mean (S.D.)e Age of onset of affective illness, mean (S.D.) Current medications Lithium Antiepileptics Atypical antipsychotics Psychostimulants Unmedicated
16 (1) 5 (50)
16 (2) 6 (60)
15 (2) 5 (50)
2 (20)
1 (10)
0 (0)
4.3 (0.6)
4.4 (0.7)
3.9 (0.8)
7 (5)
25 (6)
2 (1)
3 (2)
12 (12)
2 (1)
68 (18)
46 (15)
86 (8)
4 (40)
2 (20)
N/A
2 (20)
3 (30)
0 (0)
100 (11)
98 (15)
111 (7)
98 (13)
102 (14)
110 (7)
102 (9)
94 (15)
110 (9)
10.8 (4.2)
11.0 (3.9)
N/A
2 (20) 2 (20) 2 (20)
2 (20) 2 (20) 2 (20)
2 (20) 4 (40)
2 (20) 4 (40)
N/A
N/A
WASI=Wechsler Abbreviated Scale of Intelligence. a Significant difference: ANOVA: F(2, 27)=63.7, pb0.0001, healthy controlsbeuthymics and manics and euthymicsbmanics. b Significant difference: ANOVA: F(2, 27)=5.6, p=0.009, healthy controls and euthymicbmanics. c Significant difference: ANOVA: F(2, 27)=19.49, pb0.001, healthy controlsbeuthymics and manics and euthymicsbmanics. d Significant difference: ANOVA: F(2, 27)=3.8, p=0.03, healthy controlsNmanics. e Significant difference: ANOVA: F(2, 27)=4.90, p=0.01, healthy controlsNmanics.
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rate)Z (correct hit rate), where Z is the normal deviates (Coren and Ward, 1989). Discriminability has been used in signal detection theory as the ability to discriminate target from nontarget responses (Coren and Ward, 1989). Comparisons of group differences in performance within each level of degradation were performed using ANOVAs with group as the independent variable and performance measures as the dependent variables. Effect sizes for group differences were calculated for eachpperformance ffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi measure using the formula f ¼ ðk 1ÞF=N , where fN0.4 is characterized as a large effect size (Cohen, 1977). We then evaluated group by degradation interactions using analyses of covariance (ANCOVAs) with group and degradation level as the independent variables and discriminability, percent correct, false positive hits, and reaction time as the dependent variables. Spearman correlations were used to examine associations among CPT-IP performance measures within each level of task degradation and clinical variables, including IQ scores (for all subjects), CGAS scores (for all subjects), as well as YMRS and HDRS scores (for manic subjects). Additionally, ANCOVAs were performed evaluating group by level of degradation interactions and group differences in performance measures within each level of degradation, adjusting for Full Scale IQ scores and the presence of ADHD. We also assessed the effects of medications on CPT-IP performance. The effects of four classes of medications were examined: atypical antipsychotics, antiepileptic drugs (which included divalproex, N=3 and topiramate, N=1), lithium, and psychostimulants. None of the BP subjects were taking antidepressants or typical antipsychotics at the time of study participation. ANOVAs were used to examine differences in performance variables between BP subjects who were and were not taking each class of medications. A p value of b0.05 was used to determine significance for the Spearman correlations and Wilcoxon nonparametric tests. Other analyses were performed as necessary.
(Table 1). The number of unmedicated subjects, rates of exposure to each medication class, and rates of co-occurring attention-deficit hyperactivity disorder (ADHD) or substance use disorders were similar between the manic and euthmyic BP groups (Table 1).
Table 2 Continuous performance test performance in manic (N=10) and euthymic (N=10) adolescents with bipolar disorder and healthy controls (HC) (N=10) Variable 0% Degradation Discriminability, mean (S.D.)a Percent correct, mean (S.D.)b False positives, number of hits, mean (S.D.)c Reaction time, ms, mean (S.D.)d 25% Degradation Discriminability, mean (S.D.)a Percent correct, mean (S.D.)b False positives, number of hits, mean (S.D.)c Reaction time, ms, mean (S.D.)d 50% Degradation Discriminability, mean (S.D.)a Percent correct, mean (S.D.)b False positives, number of hits, mean (S.D.)c Reaction time, ms, mean (S.D.)d a
3. Results Healthy and BP manic and euthymic subjects were closely matched on demographic variables
BP euthymic (N=10)
BP manic (N=10)
HC (N=10)
5.1 (2.5)
5.0 (2.2)
5.9 (2.8)
85 (14)
90 (8)
94 (8)
2.4 (2.8)
1.3 (1.3)
1.4 (1.4)
516 (75)
483 (68)
480 (56)
4.4 (2.2)
5.1 (2.2)
6.3 (2.6)
85 (10)
90 (8)
92 (12)
1.9 (1.7)
1.9 (2.5)
0.6 (0.7)
559 (71)
496 (26)
532 (71)
3.0 (1.1)
3.1 (1.5)
3.8 (1.8)
72 (16)
69 (13)
80 (16)
3.8 (2.9)
3.4 (2.5)
2.7 (1.8)
579 (77)
576 (59)
574 (39)
F(2, 87)=8.5, p=0.0004, discriminability at 0% degradationN25% degradationN50% degradation. b F(2, 87)=17.1, pb0.0001, percent correct at 0% degradationN25% degradationN50% degradation. c F(2, 87)=6.8, p=0.002, false positive hits at 0% degradationb25% degradationb50% degradation. d F(2, 87)=13.5, pb0.0001.
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There was no statistically significant group difference in discriminability, percent correct, number of false positive hits, or reaction time within each level of task difficulty (see Table 2) (all pN0.1). Specifically, at 0% degradation the effect size for group differences among performance for each of the CPT-IP performance variables was f=0.3. At 25% degradation, the effect sizes ranged from f=0.2 for reaction time, discriminability, and false positive hits to f=0.3 for percent correct. At 50% degradation, the effect size was f=0.03 for reaction time and f=0.2 for each of other response variables. There were no statistically significant group by degradation level differences in performance measures [ F(8, 81)=0.7, p=0.6 for percent correct and reaction time, F(81, 8)=0.3, p=0.8 for false positive hits, and F(8, 81)=0.22, p=0.9 for discriminability]. However, within each group, discriminability, percent correct, false positive hits, and reaction time significantly worsened as level of degradation increased ( pb0.002, Table 2). The results of all analyses were unchanged by adjusting for Full Scale IQ scores and the presence of ADHD. For BP subjects, there were no statistically significant correlations among the CPT-IP performance variables and the YMRS or HDRS scores within each degradation level. However, for all subjects, higher CGAS scores were significantly correlated with fewer false positive hits and better discriminability at 25% and 50% task degradation (r=0.4, p=0.04 and r=0.4, p=0.05 at 25% degradation and r=0.4, p=0.03 and r=0.4 and p=0.03 at 50% degradation, respectively). Full Scale, Verbal, and Performance IQ scores were not statistically significantly associated with any of the task performance variables among all subjects. Eight of the twenty (40%) BP subjects were unmedicated at the time of study participation. There was no change in the results of the study after removing unmedicated patients or medicated BP subjects from analyses. However, at 50% degradation, medicated BP subjects performed the task slower than unmedicated BP subjects (572 vs. 499 ms, f=6.5, p=0.02). Furthermore, BP subjects who were treated with lithium, antiepileptic medications, or atypical antipsychotics had slower reaction times compared with unmedicated BP subjects ( pb0.05).
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4. Discussion Although prior investigators have used the CPT to evaluate attentional dysfunction in adults with BP (Kaskey et al., 1980; Sax et al., 1995; 1998; Fleck et al., 2001; Wilder-Willis et al., 2001; Harmer et al., 2002; Liu et al., 2002), to our knowledge, this is the first report to examine sustained attention using the CPT-IP in BP youth. The present version of the CPT-IP is a simplified, single digit version of the CPT-IP (Cornblatt et al., 1998) and, therefore, may be more developmentally appropriate for children and adolescents than the typical four digit CPT-IP, which has been widely used to measure sustained attention in adults with and without psychiatric illnesses. Additionally, in this study, we evaluated a parametric version of the simplified CPT-IP as a potential novel attentional paradigm for future functional neuroimaging studies of BP youth. The results of this study suggest that euthymic and manic BP adolescents and demographically matched healthy controls performed similarly on the CPT-IP within each level of task difficulty. However, within each group, there was a decline in task performance as attentional difficulty increased. Furthermore, all three groups exhibited a similar decline in task performance as the level of task difficulty increased. In contrast with prior studies of BP adults, our findings suggest that compared with healthy adolescents, both manic and euthymic BP adolescents have relatively intact performance on a simple task of sustained attention or as attentional difficulty increases. There are several possible explanations for the differences in results among studies. First, the sample size in our study was small, limiting our power to detect group differences. Second, prior investigations of sustained attention have typically involved BP patients who were further along in their illness course than in our study. Indeed, Denicoff et al. (1999) found that severe illness course as measured by greater duration and a larger number of affective episodes and hospitalizations was associated with poorer performance in tests of attention in BP adults. Additionally, prior studies assessing attentional deficits during mania have usually evaluated patients during hospitalization. Hospitalized BP patients exhibit greater deficits in sustained attention,
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than do manic outpatients (Liu et al., 2002). Finally, prior studies have employed a wide variety of CPT versions, including those that have included a greater working memory component than in our CTP-IP version (Kaskey et al., 1980). Prior studies have found mixed results regarding state effects on attentional functioning in BP patients. For example, Sax et al. (1998) reported that a group of BP patients performed worse than controls at the time of hospitalization for mania, however, not at 2month follow-up when patients had clinically improved. In contrast, others have reported attentional dysfunction in BP patients during periods of euthymia (Wilder-Willis et al., 2001; Harmer et al., 2002). We observed that euthymic and manic bipolar subjects performed similarly on the CPT-IP. However, all patients in our study were not hospitalized during the time of testing, which might explain their intact performance. Additionally, we did not evaluate the same subjects during periods of euthymic and mania, which may limit the interpretability of our findings. Although co-occurring ADHD was present in a small minority of the BP subjects (30%), we found little effect of co-occurring ADHD on attentional performance probably due to our small sample size or that 67% of the BP and ADHD patients were treated for their ADHD with stimulant medications. Consistent with prior studies, we found that slower task performance was associated with medication exposure (Kaskey et al., 1980). Although our sample size was relatively small, patients treated with either lithium, antiepileptic medications or atypical antipsychotics demonstrated slower reaction times. In contrast, in a study of BP adults, Wilder-Willis et al. found that slower reaction time in euthymic BP adults was not associated with medication exposure. However, there was only one unmedicated BP patient in that study. Nonetheless, future studies aimed at investigating the effects of specific medications on attentional performance are essential. Based on the results of our study, the parametric version of the CPT-IP has several properties that renders it useful as an experimental paradigm for future functional neuroimaging studies assessing differences in activation due to underlying brain dysfunction between BP and healthy adolescents. First, task performance between BP and healthy
subject groups was similar at each level of task difficulty, suggesting that any differences in regional brain activation would be secondary to underlying brain dysfunction rather than differences in task performance. Second, we observed a similar decline in task performance among groups as the level of attentional difficulty increased. Therefore, applying this task in future neruoimaging studies would help identify group differences in regional brain recruitment associated with increases in attentional load, which might help clarify the neural substrates associated with bipolar disorder. The findings of our study are limited by several factors that should be considered when interpreting our results. First, our sample size was relatively small and, therefore, we might have insufficient power to detect group differences. Effect size calculations suggest that there was a small to medium effect size for all of the group by task level of difficulty and group differences in CPT-IP performance. Second, group differences in IQ scores and other demographic variables not assessed may have affected the results of this study. Although IQ scores were not correlated with task performance, future studies using this and other tasks of sustained attention should attempt to minimize group differences in IQ scores. Third, the BP subjects in our study were recruited from an ongoing outcome study of BP patients following their first hospitalization for mania, and therefore, the patients in this study were relatively early in their illness course and their CPT-IP performance may not be representative of other BP patients. Fourth, task performance might differ when subjects perform this task during an MR scanning session as compared to while they are in a small, quiet room. Finally, there were very few patients treated with each class of medication, and there may be different effects on task performance of medications within a class. Therefore, additional investigations adequately examining the effects of specific medications on task performance are necessary. Despite these limitations, these pilot performance data suggest that our version of the CPTIP may be useful as a novel neurocognitive paradigm to study the neural activation associated with increasing attentional demand. Future functional neuroimaging studies using this parametric task of attention may be helpful to clarify the neurophysiology of bipolar disorder in youth.
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Acknowledgements NIMH grant MH63373 (Dr. DelBello) and MH58170 (Dr. Strakowski) and the Stanley Medical Research Institute.
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