DEVELOPMENTAL MEDICINE & CHILD NEUROLOGY

ORIGINAL ARTICLE

Differentiating attention deficits in children with fetal alcohol spectrum disorder or attention-deficit–hyperactivity disorder LIBBE KOOISTRA

PHD

BONNIE J KAPLAN

1,2

PHD

| SUSAN CRAWFORD MSC 2 | BEN GIBBARD MD MSC 1 , 3 |

BARBARA RAMAGE

PHD

1

|

1,2

1 Department of Pediatrics, University of Calgary, Calgary, Alberta, Canada. 2 Behavioural Research Unit, Alberta Children's Hospital, Calgary, Alberta, Canada. 3 Developmental Clinic, Alberta Children's Hospital, Calgary, Alberta, Canada. Correspondence to Dr Libbe Kooistra at Department of Pediatrics, Behavioral Research Unit, Alberta Children's Hospital, 2888 Shaganappi Trail NW, Calgary, Alberta, Canada T3B 6A8. E-mail: [email protected]

PUBLICATION DATA

AIM The attention and inhibition problems found in children with attention-deficit–hyperactivity

Accepted for publication 19th March 2009. Published online 22nd June 2009.

disorder (ADHD) are also common in children with fetal alcohol spectrum disorders (FASDs). Attempts to distinguish ADHD from FASDs in terms of these deficits are rare and were pursued in this study. METHOD A total of 116 children (47 with ADHD, 31 males, 16 females; 30 with FASDs, 17 males, 13 females; and 39 comparison children, 20 males, 19 females) participated. The mean age was 9 years 4 months (SD 1y 8mo) in the ADHD groups, 8 years 10 months (SD 1y 2mo) in the FASD group, and 9 years 1 month (SD 1y 1mo) in the comparison group. Sustained attention was tested with a slow event rate continuous performance task (CPT). Inhibitory control was tested with both a slow and fast event rate Go ⁄ No-Go task. RESULTS On the CPT task, children with ADHD, combined type (ADHD-C), ADHD, primarily inattentive type (ADHD-PI), and FASDs showed greater declines in task performance as a function of time than comparison children, suggesting sustained attention problems in all clinical groups. Children’s Go ⁄ No-Go performance was event-rate dependent, with the ADHD-C group being affected in the slow condition and the ADHD-PI and FASD groups having problems with the fast condition. INTERPRETATION Children with ADHD-C are typically impaired in handling understimulation, while children with FASDs may have problems with overstimulation. The dissociation in responsivity to event rate between groups may have significant differential diagnostic value.

LIST OF ABBREVIATIONS

CPT Continuous Performance Task FASD Fetal alcohol spectrum disorder

The modern fetal alcohol spectrum disorders (FASDs) concept dates back to 1973, when it was first described as fetal alcohol syndrome (FAS).1 Since then, numerous papers have reported on the neurobehavioural symptoms associated with the disorders, including attention problems, restlessness, and impulsivity.2 Such problems are typically also seen in children with attention-deficit–hyperactivity disorder (ADHD). The fact that attention and impulsivity problems characterize both FASDs and ADHD has fuelled speculation regarding their overlap, but this possibility has rarely been tested by directly comparing both groups in the same design using neurocognitive tests of attention. Nanson and Hiscock3 compared children with FAS with children with ADHD and a comparison group on a series of attention tasks. While the children with FAS were slower than those in the other two groups, their impulsivity and attention problems were similar to those of the children with ADHD. In addition, Coles et al.4 directly compared the attention profiles of children with FAS and children with ADHD. Children with FAS had difficulties with encoding and shifting attention, while the children with ª The Authors. Journal compilation ª Mac Keith Press 2009

ADHD had problems with focusing and sustaining attention. Interestingly, children with ADHD were found to be impulsive, unlike the children with FAS. The clinical relevance of the attention and impulsivity problems in ADHD is undisputed. In the search for the etiology of these problems, however, the focus has shifted away from poor attention control. Instead, the leading theories emphasize inhibitory dysfunction5 and inadequate activation6 as the key deficits in ADHD. With regard to FASDs, there is extensive research on the attention component,7 but there is still ambiguity regarding the nature of the attention deficits, and whether those deficits differ from those found in ADHD.8 As such, the FASD field would benefit from theory-driven research aimed at delineating the inattention symptoms of FASDs in terms of cognitive processes and their brain regions. The current study investigated children with ADHD and children with FASDs in terms of sustained attention and inhibitory control. Sustained attention was tested with a slow event rate continuous performance task (CPT),9 which is DOI: 10.1111/j.1469-8749.2009.03352.x 205

widely used to probe alerting functions associated with right prefrontal brain regions10,11 and brainstem and thalamic structures.12 Slow event rate CPT studies have repeatedly shown greater performance declines as a function of time in children with ADHD than in participants without ADHD, indicating that ADHD is associated with activation and effort allocation problems.13,14 Inhibitory control was tested with a slow and fast event rate Go ⁄ No-Go task, which targets both alerting and executive functions supported by frontostriatal and limbic brain areas, and has differentiated ADHD groups from other clinical groups and controls.15,16 The consistent finding has been that Go ⁄ No-Go performance deteriorates under slow event rate conditions, supporting the view that a deficiency in effort ⁄ activation systems constitutes the key deficit in ADHD.17 Therefore, the present study sought to examine sustained attention and inhibitory control in children with ADHD or FASD from a differential diagnostic perspective. It was expected that children would be differentially affected by time on task as well as event rate manipulation.

METHOD Participants The study was approved by the Conjoint Health Research Ethics Board of the University of Calgary. Consent forms were signed by both parents and children. Participants (n=116) were all Caucasian children, aged 7 to 10 years (47 with ADHD, 30 with FASD, and 39 comparison children; Table I). The children with ADHD were recruited from two private schools and one clinic specializing in learning and attention problems in Calgary, Alberta, Canada. The school principals and clinic director sent letters inviting families with children suspected of having ADHD to participate. Interested parents contacted the researchers for further details. Children had to have been diagnosed with ADHD when aged between 5 and 7 years by a child psychiatrist or developmental pediatrician. A three-step procedure confirmed these diagnoses. First, the Summary ADHD Checklist18 was completed to give an indication regarding the presence or absence of ADHD. Next, the Conners’ Parent Rating Scale-Revised19 was administered to confirm symptomatology. Finally, the Diagnostic Interview for Children and Adolescents-IV20 was used to reconfirm the diagnosis and assign an ADHD subtype. In order to be

included children had to meet ADHD criteria on all three measures. Further exclusion criteria were the following: coexisting psychiatric disorders (e.g. oppositional defiant disorder, mood disorder), chronic medical conditions affecting cognitive function (e.g. seizures), and treatment with long-acting psychiatric medication (e.g. risperidone). Of the 47 children with ADHD, 31 were diagnosed as the combined type (ADHD-C), and 16 as having the predominantly inattentive type (ADHD-PI); and 43 were on stimulants. A 24-hour medication washout period was required before testing. All families whose 7- to 10-year-old children attended the FASD clinic at a pediatric hospital were invited to participate by letter from the clinic. Children had to have been identified by a pediatrician as having an FASD. Their classification was based on criteria formulated by the Fetal Alcohol Syndrome Diagnostic and Prevention Network Diagnostic Guide.21 This diagnostic framework provides a four-digit code representing the magnitude of expression (rated 1–4) of the four key FASD features: growth deficiency, FASD facial phenotype, brain dysfunction, and gestational alcohol exposure. Only children who fell in the categories G (sentinel physical findings ⁄ neurobehavioural disorder, alcohol exposed; n=5), H (neurobehavioural disorder, alcohol exposed; n=23), M (sentinel physical findings ⁄ neurobehavioural disorder, alcohol exposure unknown; n=1) and N (neurobehavioural disorder, alcohol exposure unknown; n=1) were included. Alcohol exposure was deemed to be etiologically significant for all children with alcohol ranks 3 and 4. The records of the two children with unknown alcohol exposure indicated strong evidence of alcohol exposure in utero. A similar three-step screening procedure as described for ADHD was used to verify co-occurring disorders in the children with FASDs. These additional disorders, while recorded, were not exclusion factors. The exclusion criteria for the children with FASDs were a chronic medical condition affecting cognitive function, central nervous system (CNS)-activating medication, and a history of recent child abuse. Twenty-nine of the 30 children with FASDs met criteria for ADHD, all ADHD-C. Twenty-seven of these children were on stimulant treatment and were not given medication for 24 hours preceding testing. The comparison children were recruited from two elementary schools through posters and parents’ councils. In the initial contact with parents, exclusion criteria were verified,

Table I: Characteristics of study and comparison groups

Variable

ADHD (n=47)

ADHD-C (n=31)

ADHD-PI (n=16)

FASD (n=30)

Comparison group (n=39)

Age y:mo mean (SD) Males ⁄ females SES, % Low Middle High Estimated FSIQ, mean (SD)

9:4 (1:8) 31 ⁄ 16

9:0 (1:11) 19 ⁄ 12

9:8 (0:11) 12 ⁄ 4

8:10 (1:2) 17 ⁄ 13

9:1 (1:1) 20 ⁄ 19

13.0 37.0 50.0 110.1 (12.8)

13.3 36.7 50.0 110.6 (12.9)

12.5 37.5 50.0 109.1 (13.1)

40.0 36.7 23.3 98.0 (15.5)

2.8 27.8 69.4 117.7 (10.0)

ADHD, attention-deficit–hyperactivity disorder; C, combined; PI, predominantly inattentive; FASD, fetal alcohol spectrum disorders; SES, socio-economic status; FSIQ, Full-scale IQ.

206 Developmental Medicine & Child Neurology 2010, 52: 205–211

including psychiatric concerns. Next, screening instruments were administered. Only children who scored in the nonclinical range on all screening steps were accepted in the comparison group. They were subject to the same exclusion criteria as their peers with ADHD or FASDs. No data on alcohol use during pregnancy in mothers of children from the comparison or ADHD groups were available because candidate families would have objected to questions on maternal alcohol use during pregnancy.

Screening tools Summary ADHD checklist Parents completed the Summary ADHD Checklist18 an instrument based on the Diagnostic and Statistical Manual of Mental Disorders-Fourth edition (DSM-IV) consisting of a 25-item checklist rated on a fourpoint Likert scale. The checklist comprises the following five categories: (1) definitely not ADHD; (2) probably not ADHD; (3) unsure; (4) probably ADHD; and (5) definite ADHD. It has adequate reliability and validity.18 Conners' parent rating scale – revised (long version) The Conners’ Parent Rating Scale19 is a standardized DSMIV-based parent report checklist of a broad range of child and adolescent problems. Its 80 items, scored on a fourpoint scale, represent 14 diagnostic dimensions. A profile based on T-scores permits comparisons with normative age and sex groups. It is among the most prominent ADHD rating scales and has sound psychometric properties.22 Diagnostic Interview for Children and Adolescents-IV, parent version The Diagnostic Interview for Children and AdolescentsIV,20 a semi-structured computer-assisted diagnostic interview, was administered to parents. It branches to appropriate questions, depending on the respondents’ answers, and includes a DSM-IV-based diagnostic classification module. For this study, the program was configured for the assessment of ADHD, with an additional evaluation of concurrent mood, anxiety, and oppositional symptomatology. It is widely used, has good clinical validity, and moderate to high test– rest reliability.23 Experimental measures Continuous performance task Children were asked to fixate on a plus (+) sign in the centre of a computer screen, and to make button-press responses to target stimuli (but not to nontarget stimuli) with their dominant hand. After a variable inter-stimulus interval of 6000, 7000, or 8000ms, the + sign changed into a target (*) or a nontarget stimulus (0). For 25% of trials, a target was displayed, and for 75% of trials a nontarget was displayed. To examine performance decrement over time, the task performance was partitioned into three 9-minute time blocks of 249 trials. The dependent variables were mean response latency, standard deviation of response latency, percentage of errors, subdivided into percentage of omission errors (i.e. misses) and percentage

of commission errors (i.e. false alarms), calculated over each 9minute period.

Go ⁄ No-Go task Children were instructed to make a button-press response to frequent target stimuli (Go trials) with their dominant hand, and to withhold responses to infrequent nontarget stimuli (No-Go trials). Each trial began with a central face with a straight line for the mouth delineating the inter-stimulus interval, which changed to a ‘happy face’ ( ), indicating a Go, or a ‘frowning face’ ( ), indicating a No-Go trial. There were two conditions: fast, with inter-stimulus intervals varied between 1000, 1500, and 2000ms; and slow, with variable inter-stimulus intervals of 6000, 7000, or 8000ms. The total session consisted of one fast and one slow condition administered in a counterbalanced order by condition: one participant started with the fast condition, the next participant started with the slow condition. The fast condition consisted of 210 trials (75% Go, 25% No-Go); the slow condition consisted of 60 trials (75% Go, 25% No-Go). Conditions were matched on length: 7 minutes per condition. The dependent variables were response latency, standard deviation of response latency, percentage of errors, subdivided into percentage of omission errors, and percentage of commission errors, calculated for each event rate condition. Procedure Testing began with a short form of two subtests (i.e. block design, vocabulary) of the Wechsler Intelligence Scale for Children-III (WISC-III)24 to obtain an estimate of their fullscale intelligence quotient (FSIQ).25 Next, the attention tasks were administered in a counterbalanced order: one participant started with the Go ⁄ No-Go task, the next participant with the CPT task. A 5-minute training session preceded each task. Total test time was approximately 105 minutes, with 15-minute breaks between sessions. Socio-economic status (SES) was evaluated by categorizing parental employment using the Blishen index (low SES category 1–2, middle SES category 3–4, high SES category 5–6).26 Assessors were blind to the children’s diagnostic status and to results of other evaluations. Statistical analyses Group comparisons on demographics were made using analysis of variance (ANOVA) for continuous variables and v2 tests for categorical variables. Post-hoc group comparisons were made using the Scheffe´ test for continuous variables. According to Pedhazur,27 variables that were significantly different among groups were used as covariates for subsequent analyses only if they were significantly and at least moderately correlated (r‡0.30) with the variables in question. The CPT and Go ⁄ No-Go data were analysed using a series of separate repeated-measures ANOVAs followed by contrast analyses using pairwise comparisons. The betweenparticipants factor was group and the within-participants factor was time block for the CPT data; for the Go ⁄ NoGo data, group was the between-participants factor and event rate (fast vs slow) was the within-participants factor.

Attention Deficits in Fetal Alcohol Spectrum Disorder and ADHD Libbe Kooistra et al. 207

CPT data There was a significant group main effect for response latency (F(3,105)=5.97, p=0.001). Post-hoc group comparisons showed that, overall, the ADHD-C and the FASD groups were slower in terms of response latency than the comparison group (Fig. 1a). A significant group main effect for the standard deviation of response latency (F(3,105)=8.97, p