- Email: [email protected]
hyperactivity disorder and comorbid oppositional defiant disorder
Clinical Neurophysiology 118 (2007) 356–362 www.elsevier.com/locate/clinph
EEG coherence in children with attention-deficit/hyperactivity disorder and comorbid oppositional defiant disorder Robert J. Barry a
a,*
, Adam R. Clarke a, Rory McCarthy b, Mark Selikowitz
b
Brain & Behaviour Research Institute and School of Psychology, University of Wollongong, Wollongong 2522, Australia b Sydney Developmental Clinic, Sydney, Australia Accepted 2 October 2006 Available online 30 November 2006
Abstract Objectives: This study is the first to investigate EEG coherence differences between two groups of children with attention-deficit/hyperactivity disorder combined type (AD/HD), with or without comorbid oppositional defiant disorder (ODD), and normal control subjects. Methods: Each group consisted of 20 males. All subjects were between the ages of 8 and 12 years, and groups were matched on age. EEG was recorded during an eyes-closed resting condition from 21 monopolar derivations. Wave-shape coherence was calculated for 8 intrahemispheric electrode pairs (4 in each hemisphere), and 8 interhemispheric electrode pairs, within each of the delta, theta, alpha, and beta bands. Results: Children with comorbid AD/HD and ODD had intrahemispheric coherences at shorter inter-electrode distances significantly reduced from those apparent in children with AD/HD without comorbid ODD. Such reduced coherences in the comorbid group appeared to wash out coherence elevations previously noted in AD/HD studies. Conclusions: The present results suggest that, rather than suffering an additional deficit, children with AD/HD and comorbid ODD show significantly less CNS impairment than AD/HD patients without comorbid ODD. Significance: These results have treatment implications, suggesting that behavioural training, perhaps using family-based cognitive behavioural therapy, could be useful for those children with AD/HD and comorbid ODD. This should focus on the ODD symptoms, in association with a medication regime focussed on the AD/HD symptoms. 2006 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. Keywords: AD/HD; Oppositional defiant disorder; Children; EEG; Coherence
1. Introduction EEG power studies have found fairly consistent group differences between children with and without AD/HD (see Barry et al., 2003 for a review). Major differences include increased theta activity (Satterfield et al., 1972; Janzen et al., 1995; Clarke et al., 1998, 2001a,b) which occurs primarily in the frontal regions (Mann et al., 1992; Chabot and Serfontein, 1996; Lazzaro et al., 1998), increased posterior delta (Matousek et al., 1984; Clarke et al., 1998, 2001b,c), and decreased alpha and beta activity (Dykman *
Corresponding author. Tel.:/fax: +61 2 4221 4421. E-mail address: [email protected] (R.J. Barry).
et al., 1982; Callaway et al., 1983), also most apparent in the posterior regions (Mann et al., 1992; Clarke et al., 1998, 2001b,c; Lazzaro et al., 1998). While such EEG studies have found consistent differences between children with and without AD/HD, this is often a highly comorbid disorder, being found in conjunction with anxiety and depressive disorders (Cohen et al., 1989; Velez et al., 1989), learning disabilities (Pliszka, 1998; Biederman et al., 1995), and conduct disorder (CD) or oppositional defiant disorder (ODD) (Jensen et al., 1997). The most common comorbid disorders in AD/HD are behavioural, with studies reporting that between 42% and 93% of children with AD/HD have CD or ODD (Anderson et al., 1987; Offord et al., 1989; Bird et al., 1993).
1388-2457/$32.00 2006 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.clinph.2006.10.002
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EEG studies of behaviourally-disordered children have used a number of different categories. These have included delinquency (Wiener et al., 1966; Swinton et al., 1977; Hsu et al., 1985) as well as children diagnosed as having a CD (Phillips et al., 1993). Most studies have failed to find significant EEG differences between their behaviourally-disordered groups and non-delinquent control subjects, but Baving et al. (2000) reported that the normal alpha asymmetry in the frontal regions was not present in boys with ODD. Few studies have compared EEG differences in AD/HD children with or without comorbid CD or ODD. Satterfield and Schell (1984) investigated EEGs of hyperactive adolescents, both with and without signs of delinquent behaviour. The EEGs of the delinquent hyperactive group were similar to the control group, and it was concluded that the disorder reflected an underlying environmental-social factor. Baving et al. (1999) examined patterns of frontal brain activation in AD/HD children with and without ODD, and found no differences associated with ODD. Clarke et al. (2002) investigated EEG power topographies in children with AD/HD with/without comorbid ODD, and matched controls. There were few differences between the AD/HD groups which were related to the ODD diagnosis. These results indicated that EEG correlates of AD/HD are not clouded by the presence of comorbid ODD, and suggested that the ODD comorbidity did not have a substantial neurological basis, compatible with the suggestion of Satterfield and Schell (1984). Both cognition and behaviour depend on the integration of activity in different brain regions (Luria, 1973), and hence examination of the coupling between regions should prove useful in understanding brain function in such clinical groups. EEG power estimates carry little information on regional coupling, but the coherence of the EEG activity between two sites, conceptualised as the correlation in the time domain between two signals in a given frequency band (Shaw, 1981), may provide useful insights into underlying cortical coupling. Barry et al. (2002) reported that AD/HD children had elevated intrahemispheric coherences at shorter interelectrode distances in the theta band and reduced lateral differences in the theta and alpha bands. At longer interelectrode distances, AD/HD children had lower intrahemispheric alpha coherences than controls. Frontally, AD/HD children had interhemispheric coherences elevated in the delta and theta bands, and reduced in the alpha band. An alpha coherence reduction in temporal regions, and a theta coherence enhancement in central/parietal/occipital regions, were also apparent. Coherence anomalies were generally greater in children with AD/HD of the combined type compared with the inattentive type. Collectively, these results are generally compatible with the few previous studies of coherences in AD/HD (e.g., Chabot and Serfontein, 1996; Chabot et al., 1996, 1999). The aim of this study was to investigate whether EEG coherence differences can be found between children with
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AD/HD with comorbid ODD, and AD/HD without ODD, and to quantify the nature of these differences. Based on our previous coherence studies of AD/HD children, it was hypothesised that both AD/HD groups would have, in a range of frequency bands, elevated intrahemispheric coherences at shorter inter-electrode distances, and atypical frontal interhemispheric coherences, compared to control subjects. However, no coherence differences were anticipated between the two clinical groups. 2. Methods 2.1. Subjects Three groups of 20 boys participated in this study. All children were between the ages of 8 and 12 years, and right handed and footed. Subjects had a full-scale WISC-III IQ score of 85 or higher. This study used DSM-IV (APA 1994) criteria for the diagnosis of all clinical groups. The groups used were children diagnosed only with AD/HD of the combined type (AD/HD ), AD/HD (combined type) with comorbid oppositional defiant disorder (AD/ HD+), and a control group. Both clinical groups of children were drawn from new patients presenting at a Sydney-based paediatric practice for an assessment for AD/ HD. The AD/HD subjects had not been diagnosed as having AD/HD previously, had no history of medication use for the disorder, and were tested before being prescribed any medication. The control group consisted of children from local schools and community groups. The EEG power data for these groups were reported in Clarke et al. (2002). Inclusion in the AD/HD groups was based on a clinical assessment by a paediatrician and a psychologist; children were included only when both agreed on the diagnosis. Children were required to meet the full diagnostic criteria for AD/HD combined type (both groups) and oppositional defiant disorder (AD/HD+ group). Clinical interviews incorporated information from as many sources as were available. These included a history given by a parent or guardian, school reports for the past 12 months, reports from any other health professionals, and behavioural observations during the assessment. Children were excluded from the AD/HD groups if they had a history of a problematic prenatal, perinatal or neonatal period, a disorder of consciousness, a head injury resulting in cognitive deficits, a history of central nervous system diseases, convulsions or a history of convulsive disorders, a paroxysmal headache or tics, or an anxiety or depressive disorder. Inclusion in the control group was based on: an uneventful prenatal, perinatal and neonatal period; no disorders of consciousness, head injury resulting in cognitive deficits, history of central nervous system diseases, convulsions, history of convulsive disorders, paroxysmal headache, enuresis or encopresis after the fourth birthday, tics, stuttering, pavor nocturnes or excessive nailbiting, a diagnosable psychiatric condition, conduct disorders such
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as ODD, CD or delinquency, and no deviation with regard to mental and physical development. Assessment for inclusion as a control was based on a clinical interview with a parent or guardian similar to that of the AD/HD subjects, utilising the same sources of information. Children were excluded from all groups if spike wave activity was present in the EEG. Across all groups, subjects were matched in 1 year age bands. 2.2. Procedure All subjects were tested in a single session lasting approximately 2.5 h. Subjects were first assessed by a paediatrician, where a physical examination was performed and a clinical history taken, using a structured clinical interview. Handedness was assessed by ascertainment of the hand used to write with, catch and throw a ball, hold a bat, and foot used to kick a ball. Subjects then had a psychometric assessment consisting of a WISC-III, Neale Analysis of Reading and Wide Range Achievement TestR spelling. At the end of this assessment, subjects had an electrophysiological assessment consisting of evoked potentials and an EEG. The EEG was recorded at the end of this session in an eyes-closed resting condition, while subjects were seated on a reclining chair. Electrode placement was in accordance with the international 10–20 system, using an electrode cap. A single electro-oculogram (EOG) electrode referenced to Fpz was placed beside the right eye and a ground lead was placed on the left cheek. A linked ear reference was used with all EEG, and reference and ground leads were 9 mm tin disk electrodes. Impedance levels were set at less than 5 kX. The EEG was recorded and Fourier transformed by a Cadwell Spectrum 32, software version 4.22, using test type EEG, montage Q-EEG. The sensitivity was set at 150 lV per centimeter, low frequency filter 0.53 Hz, high frequency filter 70 and 50 Hz notch filter. The sampling rate of the EEG was 200 Hz and the Fourier transformation used 2.56 s epochs. Thirty epochs were selected from approximately 20 min of live trace and stored to floppy disk. Epoch rejection was based on both visual and computer selection. Computer reject levels were set using a template recorded at the beginning of the session which a trained technician initially appraised as being artefact free, and all subsequent epochs were visually compared to this. An epoch was rejected if the maximum amplitude from any electrode was greater than that of the template, and the technician considered this to have resulted from artefact. Epochs were always rejected if the EOG amplitude was greater than 50 lV. These data were further reduced to 24 epochs (1 min) by a second technician. The EEG was analyzed in four frequency bands: delta (1.5–3.5 Hz), theta (3.5–7.5 Hz), alpha (7.5–12.5 Hz), and beta (12.5–25 Hz). Coherence between an electrode pair for a particular band was defined as the cross-spectral power between the sites normalised by dividing by the square root of the product of the power at each
site within that band, following John et al. (1987). Coherence estimates were derived for each band for eight intrahemispheric (F3–O1, F4–O2, Fp1–F3, Fp2–F4, T3–T5, T4–T6, C3–P3, C4–P4) and eight interhemispheric (Fp1– Fp2, F7–F8, F3–F4, C3–C4, T3–T4, T5–T6, P3–P4, O1– O2) electrode pairs. 2.3. Statistical analysis Prior to analysis, each coherence value was transformed using Fisher’s z-transform, and means obtained were inverse-transformed for reporting. The 16 sets of coherences were grouped for analysis into regions of interest – 2 for intrahemispheric coherences (involving either short/ medium or long inter-electrode distances), and 3 for interhemispheric coherences (involving different brain regions), following Barry et al. (2002). For each region of interest, an analysis of variance was used to examine the effects of group on coherences in each frequency band. Because volume conduction may artificially inflate EEG coherence more at short inter-electrode distances than at long distances, no comparisons involving inter-electrode distance as a variable were made. However, any such coherence inflation due to volume conduction would not be expected to affect group differences at either long or short inter-electrode distance. For the intrahemispheric coherences, the means within hemisphere were compared for each band for (i) the short/medium inter-electrode distances (left: Fp1–F3, T3– T5, C3–P3 and right: Fp2–F4, T4–T6, C4–P4) and (ii) long inter-electrode distances (left: F3–O1 and right: F4–O2). Within each of these two sets of analyses, laterality (left vs. right) was examined as a planned contrast on the electrode pairs listed. The interhemispheric coherences were separately examined within (iii) the frontal (Fp1–Fp2, F7–F8, F3–F4), (iv) temporal (T3–T4, T5–T6), and (v) central/parietal/occipital (C3–C4, P3–P4, O1–O2) regions. For these last 3 regional analyses, no within-region contrasts were examined. Within the group factor, planned contrasts compared the two AD/HD groups with controls, and the AD/HD+ group with the AD/HD group. As all these orthogonal contrasts are planned, and there are no more of them than the degrees of freedom for effect, no Bonferroni-type adjustment to a is required (Tabachnick and Fidell, 1989). All F values reported have (1, 57) degrees of freedom. 3. Results No significant differences were found between the three groups for age, reading accuracy, or comprehension. On the measure of spelling ability, the control group was significantly better than the two AD/HD groups (F = 13.33, p < .001) but there was no difference between the two clinical groups. Coherences for each group are shown in Fig. 1 as a function of frequency for the five electrode groupings
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analysed here. Generally, the comorbid group displayed lower coherences than the AD/HD group. 3.1. Intrahemispheric coherences With short-medium inter-electrode distances, across groups, there were higher coherences in the left hemisphere in the delta (F = 6.73, p < .05), theta (F = 4.66, p < .05), and beta (F = 4.74, p < .05) bands. These, and all other effects, are summarised in Table 1, which also indicates the laterality and AD/HD vs. control effects reported in Barry et al. (2002). Across hemispheres, Fig. 1A shows that the AD/HD+ group had lower coherences than the AD/HD group in the delta (F = 5.56, p < .05), theta (F = 7.33, p < .01), and beta (F = 5.47, p < .05) bands. With the long inter-electrode distances, there was a suggestion of higher coherences in the left hemisphere in the theta band (F = 3.66, p = .061), and this reached significance in the beta band (F = 4.75, p < .05). The AD/HD+ group demonstrated significantly lower coherences than AD/HD in the beta band (F = 4.24, p < .05); see Fig. 1B. 3.2. Interhemispheric coherences In the frontal regions (Fig. 1C), the AD/HD groups displayed greater coherences than controls in the delta band which approached significance (F = 3.57, p = .057), and this reached significance in theta (F = 8.16, p < .01). In temporal regions (Fig. 1D), the only group effect which approached significance was that theta coherences were somewhat lower in AD/HD children than in controls (F = 3.09, p = .084). In the central/parietal/occipital regions (see Fig. 1E), there were no significant group differences in coherences. 4. Discussion
Fig. 1. Coherences for each group as a function of frequency band (delta, theta, alpha, and beta) for the five coherence groupings analysed here: intrahemispheric coherences at short (A), and long (B) inter-electrode distances, and interhemispheric coherences in the frontal (C), temporal (D), and central/parietal/occipital regions (E).
Barry et al. (2002) reported that, at shorter inter-electrode distances, AD/HD children had elevated intrahemispheric coherences in the delta, theta and beta bands, which reached significance in theta. The present study, which compared the two AD/HD groups together against controls, indicated that none of those effects were apparent here. However, comparison of the clinical groups indicated that the AD/HD+ group had lower coherences than the AD/HD group in the same (delta, theta, and beta) bands. As shown in Fig. 1A, these reduced coherences in the comorbid group have washed out the elevations previously noted in AD/HD, and apparent here in AD/HD . The left hemisphere elevations noted here in the delta, theta, and beta bands are compatible with those reported in Barry et al. (2002). However, that study noted reduced lateralisation in coherences in the theta and alpha bands with AD/ HD, which were not apparent here. At longer inter-electrode distances, Barry et al. (2002) reported that AD/HD children had lower intrahemispheric alpha coherences than controls. This was not apparent
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Table 1 Summary of obtained effects Effect
Frequency band Delta
Theta
Alpha
Beta
Intrahemispheric coherences (i) Short-medium L vs. R AD/HD vs. Controls AD/HD+ vs. AD/HD L vs. R · AD/HD vs. Controls L vs. R · AD/HD+ vs. AD/HD–
L›* § §§ AD/HD+fl* – –
L›* § §§ AD/HD+fl** ## –
L§ – – ## –
L›* § §§ AD/HD+fl* – –
(ii) Long L vs. R AD/HD vs. Controls AD/HD+ vs. AD/HD– L vs. R · AD/HD vs. Controls L vs. R · AD/HD+ vs. AD/HD–
– – – – –
L›.061 – – – –
– ## – – –
L›* § – AD/HD+fl* – –
Interhemispheric coherences (iii) Frontal AD/HD vs. Controls AD/HD+ vs. AD/HD–
AD/HD›.057 §§ –
AD/HD›** §§ –
– –
## –
(iv) Temporal AD/HD vs. Controls AD/HD+ vs. AD/HD–
– –
AD/HDfl.084 –
## –
– –
(v) Central/parietal/occipital AD/HD vs. Controls AD/HD+ vs. AD/HD–
§§ –
§§ –
– –
– –
›, increased; fl, decreased; §, previously reported increased; §§, previously reported increased in AD/HD; #, previously reported decreased; ##, previously reported decreased in AD/HD; *p < .05, **p < .01, probability levels are shown for effects approaching significance.
here, but the comorbid group had reduced coherences in the beta band. Lateralisation effects, weaker than at shorter inter-electrode distances, are generally compatible with those previously reported, and did not differ with comorbidity. Frontally, AD/HD children in the Barry et al. (2002) study had interhemispheric coherences elevated in the delta and theta bands, and reduced in the beta band. The frontal elevations noted here in the slow EEG bands are compatible with those data. An AD/HD alpha coherence reduction in temporal regions noted by Barry et al. (2002) was not apparent here, but some reduction in temporal coherences was suggested by data in the theta band. Previous suggestions of delta and theta coherence enhancements in central/parietal/occipital regions were not apparent here. None of the interhemispheric coherences varied significantly with comorbidity. Overall, it thus appears that the major finding of this study is that children with comorbid AD/HD and ODD have intrahemispheric coherences at shorter inter-electrode distances which are significantly reduced from those apparent in children with AD/HD without comorbid ODD. In a developmental study of AD/HD in boys, Barry et al. (2005b) related elevated short-distance coherences in boys to developmental delay, compatible with Thatcher’s twocompartment model of coherence (Thatcher et al., 1986). In that model, normal development is associated with an
increasing density of short fibres in specialised neuronal populations, which reduces coherences by increasing the complexity and competition of interactions within the cell population. This suggests that children with AD/HD and comorbid ODD have less developmental delay than is apparent in children with AD/HD without comorbid ODD. Most studies of children with a diagnosis of CD or ODD have failed to find any EEG differences between their clinical groups and normal children (Satterfield and Schell, 1984; Hsu et al., 1985; Phillips et al., 1993). With our previous EEG power study of the present groups of children, Clarke et al. (2002) found no significant main effects, and only two topographic differences, between AD/HD+ and AD/HD children. The AD/HD+ group was less deviant from controls in terms of absolute theta power in the right hemisphere, and in relative alpha at the posterior midline, than was the AD/HD group. Those minor comorbidity effects in absolute and relative power do not appear to be simply related to specific aspects of the present coherence results. They are, however, compatible with somewhat reduced deviance from controls in the comorbid group. From those EEG power studies, CD or ODD has been viewed as not having a significant electrophysiological component, suggesting that the disorders result from a social-environmental factor rather than abnormal CNS functioning (Satterfield and Schell, 1984). The significant
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differences in short-distance intrahemispheric coherences associated with comorbid ODD apparent in the present results are, at first glance, broadly compatible with such a perspective. Specifically, there is evidence of reduced developmental delay in the short-range intrahemispheric linkages functioning between neuronal clusters in the comorbid group. However, this finding allows stronger conclusions than those derived from our previous power study of these children. That is, whereas previous studies have supported the suggestion that there is no neurological deficit associated with the comorbidity, the present results argue that, at the CNS level, such children are significantly less impaired than AD/HD patients without comorbid ODD. However, this assumes that the electrophysiological correlates of impairment associated with the separate disorders add together in the comorbid group. Yordanova et al. (1997), in a study of AD/HD comorbid with tic disorder, utilised an additional control group of children with tic disorder without AD/HD. They were able to demonstrate that separate disorders may have electrophysiological differences from controls which partially cancel in the comorbid group without reduction in symptom severity. Banaschewski et al. (2003) used a similar 2 · 2 group design with AD/HD and ODD/CD in an ERP study, and also reported reduced impairment in the comorbid group, compatible with the non-additivity suggested by Yordanova et al. (1997). The present study, without an ODD-alone group, cannot address this interesting possibility. Another limitation of this study is the absence of symptom severity information. That is, although all patients met DSM-IV criteria for AD/HD of the combined type, we have no measure of the severity of these symptoms. Thus it is possible that some children presented to the clinic primarily because of the comorbid ODD, rather than their AD/HD. Such a selection bias could result in milder AD/ HD in the comorbid group compared to the pure AD/ HD group. Clarification of this issue will require further research including symptom severity indices. In a study comparing coherences in children with the two major subtypes of AD/HD (combined vs. inattentive), Barry et al. (2005a) related elevated coherence levels in children with AD/HD combined type to their higher levels of hyperactivity and impulsivity. We suggested that anomalously-increased connectivity between brain regions would result in shorter cortical processing times, allowing less opportunity for inhibitory processes to be evoked or to be executed effectively. From that perspective, while the AD/HD children without comorbid ODD appear to have a CNS basis for their impulsive/hyperactive symptom profile, the present results suggest that this is not so apparent in children with AD/HD and comorbid ODD. If this CNS impairment is reduced in those children with comorbid AD/HD and ODD, we must look for an additional cause contributing to their inappropriate behavioural profile. The most obvious of these is behavioural management problems at home and/or school.
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This finding of better cortical development, in AD/HD patients with comorbid ODD than those without, may have significant treatment implications. First, it would follow from the above that, apart from the ODD problems, the AD/HD impairment in these children may be less severe, indicative of a better prognosis. Second, the inclusion of behavioural training, perhaps using family-based cognitive behavioural therapy, could be useful for those children with AD/HD and comorbid ODD. This is compatible with previous suggestions of Swanson et al. (2001), which indicated modest benefits of additional behavioural training over medication alone in this comorbid group. Together these suggest that future research should explore how such interventions, focussed on the ODD symptoms, might interact with a medication regime focussed on the AD/HD symptoms, in order to optimise treatment outcomes for these children. References Anderson J, Williams S, McGee R, Silva P. DSM-III disorders in preadolescent children. Arch Gen Psychiatry 1987;44:69–76. Banaschewski T, Brandeis D, Heinrich H, Albrecht B, Brunner E, Rothenberger A. Association of ADHD and conduct disorder – brain electrical evidence for the existence of a distinct subtype. J Child Psychol Psychiatry 2003;44:356–76. Barry RJ, Clarke AR, Johnstone SJ. A review of electrophysiology in attention-deficit/hyperactivity disorder: I. Qualitative and quantitative electroencephalography. Clin Neurophysiol 2003;114:171–83. Barry RJ, Clarke AR, McCarthy R, Selikowitz M. EEG coherence in attention-deficit/hyperactivity disorder: a comparative study of two DSM-IV types. Clin Neurophysiol 2002;113:579–85. Barry RJ, Clarke AR, McCarthy R, Selikowitz M, Johnstone SJ. EEG coherence adjusted for inter-electrode distance in children with attention-deficit/hyperactivity disorder. Int J Pychophysiol 2005a;58:12–20. Barry RJ, Clarke AR, McCarthy R, Selikowitz M, Johnstone SJ, Hsu C-I, Bond D, Wallace MJ, Magee CA. Age and gender effects in EEG coherence: II. Boys with attention deficit/hyperactivity disorder. Clin Neurophysiol 2005b;116:977–84. Baving L, Laucht M, Schmidt MH. Atypical frontal brain activation in ADHD: preschool and elementary school boys and girls. J Am Acad Child Adolesc Psychiatry 1999;38:1363–71. Baving L, Laucht M, Schmidt MH. Oppositional children differ from healthy children in frontal brain activation. J Abnorm Child Psychol 2000;28:267–75. Biederman J, Newcorn J, Sprich S. Comorbidity of attention deficit hyperactivity disorder with conduct, depressive, anxiety, and other disorders. Amer J Psychiatry 1995;148:564–77. Bird H, Gould M, Staghezza B. Patterns of diagnostic comorbidity in a community sample of children aged 9 through 16 years. J Amer Acad Child Adolesc Psychiatry 1993;32:361–8. Callaway E, Halliday R, Naylor H. Hyperactive children’s event-related potentials fail to support underarousal and maturational-lag theories. Arch Gen Psychiatry 1983;40:1243–8. Chabot R, Merkin H, Wood L, Davenport T, Serfontein G. Sensitivity and specificity of QEEG in children with attention deficit or specific developmental learning disorders. Clin Electroencephalogr 1996;27:26–34. Chabot R, Orgill A, Crawford G, Harris M, Serfontein G. Behavioural and electrophysiological predictors of treatment response to stimulants in children with attention disorders. J Child Neurol 1999;14:343–51.
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EEG coherence in children with attention-deficit/hyperactivity disorder and comorbid oppositional defiant disorder Robert J. Barry a
a,*
, Adam R. Clarke a, Rory McCarthy b, Mark Selikowitz
b
Brain & Behaviour Research Institute and School of Psychology, University of Wollongong, Wollongong 2522, Australia b Sydney Developmental Clinic, Sydney, Australia Accepted 2 October 2006 Available online 30 November 2006
Abstract Objectives: This study is the first to investigate EEG coherence differences between two groups of children with attention-deficit/hyperactivity disorder combined type (AD/HD), with or without comorbid oppositional defiant disorder (ODD), and normal control subjects. Methods: Each group consisted of 20 males. All subjects were between the ages of 8 and 12 years, and groups were matched on age. EEG was recorded during an eyes-closed resting condition from 21 monopolar derivations. Wave-shape coherence was calculated for 8 intrahemispheric electrode pairs (4 in each hemisphere), and 8 interhemispheric electrode pairs, within each of the delta, theta, alpha, and beta bands. Results: Children with comorbid AD/HD and ODD had intrahemispheric coherences at shorter inter-electrode distances significantly reduced from those apparent in children with AD/HD without comorbid ODD. Such reduced coherences in the comorbid group appeared to wash out coherence elevations previously noted in AD/HD studies. Conclusions: The present results suggest that, rather than suffering an additional deficit, children with AD/HD and comorbid ODD show significantly less CNS impairment than AD/HD patients without comorbid ODD. Significance: These results have treatment implications, suggesting that behavioural training, perhaps using family-based cognitive behavioural therapy, could be useful for those children with AD/HD and comorbid ODD. This should focus on the ODD symptoms, in association with a medication regime focussed on the AD/HD symptoms. 2006 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. Keywords: AD/HD; Oppositional defiant disorder; Children; EEG; Coherence
1. Introduction EEG power studies have found fairly consistent group differences between children with and without AD/HD (see Barry et al., 2003 for a review). Major differences include increased theta activity (Satterfield et al., 1972; Janzen et al., 1995; Clarke et al., 1998, 2001a,b) which occurs primarily in the frontal regions (Mann et al., 1992; Chabot and Serfontein, 1996; Lazzaro et al., 1998), increased posterior delta (Matousek et al., 1984; Clarke et al., 1998, 2001b,c), and decreased alpha and beta activity (Dykman *
Corresponding author. Tel.:/fax: +61 2 4221 4421. E-mail address: [email protected] (R.J. Barry).
et al., 1982; Callaway et al., 1983), also most apparent in the posterior regions (Mann et al., 1992; Clarke et al., 1998, 2001b,c; Lazzaro et al., 1998). While such EEG studies have found consistent differences between children with and without AD/HD, this is often a highly comorbid disorder, being found in conjunction with anxiety and depressive disorders (Cohen et al., 1989; Velez et al., 1989), learning disabilities (Pliszka, 1998; Biederman et al., 1995), and conduct disorder (CD) or oppositional defiant disorder (ODD) (Jensen et al., 1997). The most common comorbid disorders in AD/HD are behavioural, with studies reporting that between 42% and 93% of children with AD/HD have CD or ODD (Anderson et al., 1987; Offord et al., 1989; Bird et al., 1993).
1388-2457/$32.00 2006 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.clinph.2006.10.002
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EEG studies of behaviourally-disordered children have used a number of different categories. These have included delinquency (Wiener et al., 1966; Swinton et al., 1977; Hsu et al., 1985) as well as children diagnosed as having a CD (Phillips et al., 1993). Most studies have failed to find significant EEG differences between their behaviourally-disordered groups and non-delinquent control subjects, but Baving et al. (2000) reported that the normal alpha asymmetry in the frontal regions was not present in boys with ODD. Few studies have compared EEG differences in AD/HD children with or without comorbid CD or ODD. Satterfield and Schell (1984) investigated EEGs of hyperactive adolescents, both with and without signs of delinquent behaviour. The EEGs of the delinquent hyperactive group were similar to the control group, and it was concluded that the disorder reflected an underlying environmental-social factor. Baving et al. (1999) examined patterns of frontal brain activation in AD/HD children with and without ODD, and found no differences associated with ODD. Clarke et al. (2002) investigated EEG power topographies in children with AD/HD with/without comorbid ODD, and matched controls. There were few differences between the AD/HD groups which were related to the ODD diagnosis. These results indicated that EEG correlates of AD/HD are not clouded by the presence of comorbid ODD, and suggested that the ODD comorbidity did not have a substantial neurological basis, compatible with the suggestion of Satterfield and Schell (1984). Both cognition and behaviour depend on the integration of activity in different brain regions (Luria, 1973), and hence examination of the coupling between regions should prove useful in understanding brain function in such clinical groups. EEG power estimates carry little information on regional coupling, but the coherence of the EEG activity between two sites, conceptualised as the correlation in the time domain between two signals in a given frequency band (Shaw, 1981), may provide useful insights into underlying cortical coupling. Barry et al. (2002) reported that AD/HD children had elevated intrahemispheric coherences at shorter interelectrode distances in the theta band and reduced lateral differences in the theta and alpha bands. At longer interelectrode distances, AD/HD children had lower intrahemispheric alpha coherences than controls. Frontally, AD/HD children had interhemispheric coherences elevated in the delta and theta bands, and reduced in the alpha band. An alpha coherence reduction in temporal regions, and a theta coherence enhancement in central/parietal/occipital regions, were also apparent. Coherence anomalies were generally greater in children with AD/HD of the combined type compared with the inattentive type. Collectively, these results are generally compatible with the few previous studies of coherences in AD/HD (e.g., Chabot and Serfontein, 1996; Chabot et al., 1996, 1999). The aim of this study was to investigate whether EEG coherence differences can be found between children with
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AD/HD with comorbid ODD, and AD/HD without ODD, and to quantify the nature of these differences. Based on our previous coherence studies of AD/HD children, it was hypothesised that both AD/HD groups would have, in a range of frequency bands, elevated intrahemispheric coherences at shorter inter-electrode distances, and atypical frontal interhemispheric coherences, compared to control subjects. However, no coherence differences were anticipated between the two clinical groups. 2. Methods 2.1. Subjects Three groups of 20 boys participated in this study. All children were between the ages of 8 and 12 years, and right handed and footed. Subjects had a full-scale WISC-III IQ score of 85 or higher. This study used DSM-IV (APA 1994) criteria for the diagnosis of all clinical groups. The groups used were children diagnosed only with AD/HD of the combined type (AD/HD ), AD/HD (combined type) with comorbid oppositional defiant disorder (AD/ HD+), and a control group. Both clinical groups of children were drawn from new patients presenting at a Sydney-based paediatric practice for an assessment for AD/ HD. The AD/HD subjects had not been diagnosed as having AD/HD previously, had no history of medication use for the disorder, and were tested before being prescribed any medication. The control group consisted of children from local schools and community groups. The EEG power data for these groups were reported in Clarke et al. (2002). Inclusion in the AD/HD groups was based on a clinical assessment by a paediatrician and a psychologist; children were included only when both agreed on the diagnosis. Children were required to meet the full diagnostic criteria for AD/HD combined type (both groups) and oppositional defiant disorder (AD/HD+ group). Clinical interviews incorporated information from as many sources as were available. These included a history given by a parent or guardian, school reports for the past 12 months, reports from any other health professionals, and behavioural observations during the assessment. Children were excluded from the AD/HD groups if they had a history of a problematic prenatal, perinatal or neonatal period, a disorder of consciousness, a head injury resulting in cognitive deficits, a history of central nervous system diseases, convulsions or a history of convulsive disorders, a paroxysmal headache or tics, or an anxiety or depressive disorder. Inclusion in the control group was based on: an uneventful prenatal, perinatal and neonatal period; no disorders of consciousness, head injury resulting in cognitive deficits, history of central nervous system diseases, convulsions, history of convulsive disorders, paroxysmal headache, enuresis or encopresis after the fourth birthday, tics, stuttering, pavor nocturnes or excessive nailbiting, a diagnosable psychiatric condition, conduct disorders such
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as ODD, CD or delinquency, and no deviation with regard to mental and physical development. Assessment for inclusion as a control was based on a clinical interview with a parent or guardian similar to that of the AD/HD subjects, utilising the same sources of information. Children were excluded from all groups if spike wave activity was present in the EEG. Across all groups, subjects were matched in 1 year age bands. 2.2. Procedure All subjects were tested in a single session lasting approximately 2.5 h. Subjects were first assessed by a paediatrician, where a physical examination was performed and a clinical history taken, using a structured clinical interview. Handedness was assessed by ascertainment of the hand used to write with, catch and throw a ball, hold a bat, and foot used to kick a ball. Subjects then had a psychometric assessment consisting of a WISC-III, Neale Analysis of Reading and Wide Range Achievement TestR spelling. At the end of this assessment, subjects had an electrophysiological assessment consisting of evoked potentials and an EEG. The EEG was recorded at the end of this session in an eyes-closed resting condition, while subjects were seated on a reclining chair. Electrode placement was in accordance with the international 10–20 system, using an electrode cap. A single electro-oculogram (EOG) electrode referenced to Fpz was placed beside the right eye and a ground lead was placed on the left cheek. A linked ear reference was used with all EEG, and reference and ground leads were 9 mm tin disk electrodes. Impedance levels were set at less than 5 kX. The EEG was recorded and Fourier transformed by a Cadwell Spectrum 32, software version 4.22, using test type EEG, montage Q-EEG. The sensitivity was set at 150 lV per centimeter, low frequency filter 0.53 Hz, high frequency filter 70 and 50 Hz notch filter. The sampling rate of the EEG was 200 Hz and the Fourier transformation used 2.56 s epochs. Thirty epochs were selected from approximately 20 min of live trace and stored to floppy disk. Epoch rejection was based on both visual and computer selection. Computer reject levels were set using a template recorded at the beginning of the session which a trained technician initially appraised as being artefact free, and all subsequent epochs were visually compared to this. An epoch was rejected if the maximum amplitude from any electrode was greater than that of the template, and the technician considered this to have resulted from artefact. Epochs were always rejected if the EOG amplitude was greater than 50 lV. These data were further reduced to 24 epochs (1 min) by a second technician. The EEG was analyzed in four frequency bands: delta (1.5–3.5 Hz), theta (3.5–7.5 Hz), alpha (7.5–12.5 Hz), and beta (12.5–25 Hz). Coherence between an electrode pair for a particular band was defined as the cross-spectral power between the sites normalised by dividing by the square root of the product of the power at each
site within that band, following John et al. (1987). Coherence estimates were derived for each band for eight intrahemispheric (F3–O1, F4–O2, Fp1–F3, Fp2–F4, T3–T5, T4–T6, C3–P3, C4–P4) and eight interhemispheric (Fp1– Fp2, F7–F8, F3–F4, C3–C4, T3–T4, T5–T6, P3–P4, O1– O2) electrode pairs. 2.3. Statistical analysis Prior to analysis, each coherence value was transformed using Fisher’s z-transform, and means obtained were inverse-transformed for reporting. The 16 sets of coherences were grouped for analysis into regions of interest – 2 for intrahemispheric coherences (involving either short/ medium or long inter-electrode distances), and 3 for interhemispheric coherences (involving different brain regions), following Barry et al. (2002). For each region of interest, an analysis of variance was used to examine the effects of group on coherences in each frequency band. Because volume conduction may artificially inflate EEG coherence more at short inter-electrode distances than at long distances, no comparisons involving inter-electrode distance as a variable were made. However, any such coherence inflation due to volume conduction would not be expected to affect group differences at either long or short inter-electrode distance. For the intrahemispheric coherences, the means within hemisphere were compared for each band for (i) the short/medium inter-electrode distances (left: Fp1–F3, T3– T5, C3–P3 and right: Fp2–F4, T4–T6, C4–P4) and (ii) long inter-electrode distances (left: F3–O1 and right: F4–O2). Within each of these two sets of analyses, laterality (left vs. right) was examined as a planned contrast on the electrode pairs listed. The interhemispheric coherences were separately examined within (iii) the frontal (Fp1–Fp2, F7–F8, F3–F4), (iv) temporal (T3–T4, T5–T6), and (v) central/parietal/occipital (C3–C4, P3–P4, O1–O2) regions. For these last 3 regional analyses, no within-region contrasts were examined. Within the group factor, planned contrasts compared the two AD/HD groups with controls, and the AD/HD+ group with the AD/HD group. As all these orthogonal contrasts are planned, and there are no more of them than the degrees of freedom for effect, no Bonferroni-type adjustment to a is required (Tabachnick and Fidell, 1989). All F values reported have (1, 57) degrees of freedom. 3. Results No significant differences were found between the three groups for age, reading accuracy, or comprehension. On the measure of spelling ability, the control group was significantly better than the two AD/HD groups (F = 13.33, p < .001) but there was no difference between the two clinical groups. Coherences for each group are shown in Fig. 1 as a function of frequency for the five electrode groupings
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analysed here. Generally, the comorbid group displayed lower coherences than the AD/HD group. 3.1. Intrahemispheric coherences With short-medium inter-electrode distances, across groups, there were higher coherences in the left hemisphere in the delta (F = 6.73, p < .05), theta (F = 4.66, p < .05), and beta (F = 4.74, p < .05) bands. These, and all other effects, are summarised in Table 1, which also indicates the laterality and AD/HD vs. control effects reported in Barry et al. (2002). Across hemispheres, Fig. 1A shows that the AD/HD+ group had lower coherences than the AD/HD group in the delta (F = 5.56, p < .05), theta (F = 7.33, p < .01), and beta (F = 5.47, p < .05) bands. With the long inter-electrode distances, there was a suggestion of higher coherences in the left hemisphere in the theta band (F = 3.66, p = .061), and this reached significance in the beta band (F = 4.75, p < .05). The AD/HD+ group demonstrated significantly lower coherences than AD/HD in the beta band (F = 4.24, p < .05); see Fig. 1B. 3.2. Interhemispheric coherences In the frontal regions (Fig. 1C), the AD/HD groups displayed greater coherences than controls in the delta band which approached significance (F = 3.57, p = .057), and this reached significance in theta (F = 8.16, p < .01). In temporal regions (Fig. 1D), the only group effect which approached significance was that theta coherences were somewhat lower in AD/HD children than in controls (F = 3.09, p = .084). In the central/parietal/occipital regions (see Fig. 1E), there were no significant group differences in coherences. 4. Discussion
Fig. 1. Coherences for each group as a function of frequency band (delta, theta, alpha, and beta) for the five coherence groupings analysed here: intrahemispheric coherences at short (A), and long (B) inter-electrode distances, and interhemispheric coherences in the frontal (C), temporal (D), and central/parietal/occipital regions (E).
Barry et al. (2002) reported that, at shorter inter-electrode distances, AD/HD children had elevated intrahemispheric coherences in the delta, theta and beta bands, which reached significance in theta. The present study, which compared the two AD/HD groups together against controls, indicated that none of those effects were apparent here. However, comparison of the clinical groups indicated that the AD/HD+ group had lower coherences than the AD/HD group in the same (delta, theta, and beta) bands. As shown in Fig. 1A, these reduced coherences in the comorbid group have washed out the elevations previously noted in AD/HD, and apparent here in AD/HD . The left hemisphere elevations noted here in the delta, theta, and beta bands are compatible with those reported in Barry et al. (2002). However, that study noted reduced lateralisation in coherences in the theta and alpha bands with AD/ HD, which were not apparent here. At longer inter-electrode distances, Barry et al. (2002) reported that AD/HD children had lower intrahemispheric alpha coherences than controls. This was not apparent
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Table 1 Summary of obtained effects Effect
Frequency band Delta
Theta
Alpha
Beta
Intrahemispheric coherences (i) Short-medium L vs. R AD/HD vs. Controls AD/HD+ vs. AD/HD L vs. R · AD/HD vs. Controls L vs. R · AD/HD+ vs. AD/HD–
L›* § §§ AD/HD+fl* – –
L›* § §§ AD/HD+fl** ## –
L§ – – ## –
L›* § §§ AD/HD+fl* – –
(ii) Long L vs. R AD/HD vs. Controls AD/HD+ vs. AD/HD– L vs. R · AD/HD vs. Controls L vs. R · AD/HD+ vs. AD/HD–
– – – – –
L›.061 – – – –
– ## – – –
L›* § – AD/HD+fl* – –
Interhemispheric coherences (iii) Frontal AD/HD vs. Controls AD/HD+ vs. AD/HD–
AD/HD›.057 §§ –
AD/HD›** §§ –
– –
## –
(iv) Temporal AD/HD vs. Controls AD/HD+ vs. AD/HD–
– –
AD/HDfl.084 –
## –
– –
(v) Central/parietal/occipital AD/HD vs. Controls AD/HD+ vs. AD/HD–
§§ –
§§ –
– –
– –
›, increased; fl, decreased; §, previously reported increased; §§, previously reported increased in AD/HD; #, previously reported decreased; ##, previously reported decreased in AD/HD; *p < .05, **p < .01, probability levels are shown for effects approaching significance.
here, but the comorbid group had reduced coherences in the beta band. Lateralisation effects, weaker than at shorter inter-electrode distances, are generally compatible with those previously reported, and did not differ with comorbidity. Frontally, AD/HD children in the Barry et al. (2002) study had interhemispheric coherences elevated in the delta and theta bands, and reduced in the beta band. The frontal elevations noted here in the slow EEG bands are compatible with those data. An AD/HD alpha coherence reduction in temporal regions noted by Barry et al. (2002) was not apparent here, but some reduction in temporal coherences was suggested by data in the theta band. Previous suggestions of delta and theta coherence enhancements in central/parietal/occipital regions were not apparent here. None of the interhemispheric coherences varied significantly with comorbidity. Overall, it thus appears that the major finding of this study is that children with comorbid AD/HD and ODD have intrahemispheric coherences at shorter inter-electrode distances which are significantly reduced from those apparent in children with AD/HD without comorbid ODD. In a developmental study of AD/HD in boys, Barry et al. (2005b) related elevated short-distance coherences in boys to developmental delay, compatible with Thatcher’s twocompartment model of coherence (Thatcher et al., 1986). In that model, normal development is associated with an
increasing density of short fibres in specialised neuronal populations, which reduces coherences by increasing the complexity and competition of interactions within the cell population. This suggests that children with AD/HD and comorbid ODD have less developmental delay than is apparent in children with AD/HD without comorbid ODD. Most studies of children with a diagnosis of CD or ODD have failed to find any EEG differences between their clinical groups and normal children (Satterfield and Schell, 1984; Hsu et al., 1985; Phillips et al., 1993). With our previous EEG power study of the present groups of children, Clarke et al. (2002) found no significant main effects, and only two topographic differences, between AD/HD+ and AD/HD children. The AD/HD+ group was less deviant from controls in terms of absolute theta power in the right hemisphere, and in relative alpha at the posterior midline, than was the AD/HD group. Those minor comorbidity effects in absolute and relative power do not appear to be simply related to specific aspects of the present coherence results. They are, however, compatible with somewhat reduced deviance from controls in the comorbid group. From those EEG power studies, CD or ODD has been viewed as not having a significant electrophysiological component, suggesting that the disorders result from a social-environmental factor rather than abnormal CNS functioning (Satterfield and Schell, 1984). The significant
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differences in short-distance intrahemispheric coherences associated with comorbid ODD apparent in the present results are, at first glance, broadly compatible with such a perspective. Specifically, there is evidence of reduced developmental delay in the short-range intrahemispheric linkages functioning between neuronal clusters in the comorbid group. However, this finding allows stronger conclusions than those derived from our previous power study of these children. That is, whereas previous studies have supported the suggestion that there is no neurological deficit associated with the comorbidity, the present results argue that, at the CNS level, such children are significantly less impaired than AD/HD patients without comorbid ODD. However, this assumes that the electrophysiological correlates of impairment associated with the separate disorders add together in the comorbid group. Yordanova et al. (1997), in a study of AD/HD comorbid with tic disorder, utilised an additional control group of children with tic disorder without AD/HD. They were able to demonstrate that separate disorders may have electrophysiological differences from controls which partially cancel in the comorbid group without reduction in symptom severity. Banaschewski et al. (2003) used a similar 2 · 2 group design with AD/HD and ODD/CD in an ERP study, and also reported reduced impairment in the comorbid group, compatible with the non-additivity suggested by Yordanova et al. (1997). The present study, without an ODD-alone group, cannot address this interesting possibility. Another limitation of this study is the absence of symptom severity information. That is, although all patients met DSM-IV criteria for AD/HD of the combined type, we have no measure of the severity of these symptoms. Thus it is possible that some children presented to the clinic primarily because of the comorbid ODD, rather than their AD/HD. Such a selection bias could result in milder AD/ HD in the comorbid group compared to the pure AD/ HD group. Clarification of this issue will require further research including symptom severity indices. In a study comparing coherences in children with the two major subtypes of AD/HD (combined vs. inattentive), Barry et al. (2005a) related elevated coherence levels in children with AD/HD combined type to their higher levels of hyperactivity and impulsivity. We suggested that anomalously-increased connectivity between brain regions would result in shorter cortical processing times, allowing less opportunity for inhibitory processes to be evoked or to be executed effectively. From that perspective, while the AD/HD children without comorbid ODD appear to have a CNS basis for their impulsive/hyperactive symptom profile, the present results suggest that this is not so apparent in children with AD/HD and comorbid ODD. If this CNS impairment is reduced in those children with comorbid AD/HD and ODD, we must look for an additional cause contributing to their inappropriate behavioural profile. The most obvious of these is behavioural management problems at home and/or school.
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This finding of better cortical development, in AD/HD patients with comorbid ODD than those without, may have significant treatment implications. First, it would follow from the above that, apart from the ODD problems, the AD/HD impairment in these children may be less severe, indicative of a better prognosis. Second, the inclusion of behavioural training, perhaps using family-based cognitive behavioural therapy, could be useful for those children with AD/HD and comorbid ODD. This is compatible with previous suggestions of Swanson et al. (2001), which indicated modest benefits of additional behavioural training over medication alone in this comorbid group. Together these suggest that future research should explore how such interventions, focussed on the ODD symptoms, might interact with a medication regime focussed on the AD/HD symptoms, in order to optimise treatment outcomes for these children. References Anderson J, Williams S, McGee R, Silva P. DSM-III disorders in preadolescent children. Arch Gen Psychiatry 1987;44:69–76. Banaschewski T, Brandeis D, Heinrich H, Albrecht B, Brunner E, Rothenberger A. Association of ADHD and conduct disorder – brain electrical evidence for the existence of a distinct subtype. J Child Psychol Psychiatry 2003;44:356–76. Barry RJ, Clarke AR, Johnstone SJ. A review of electrophysiology in attention-deficit/hyperactivity disorder: I. Qualitative and quantitative electroencephalography. Clin Neurophysiol 2003;114:171–83. Barry RJ, Clarke AR, McCarthy R, Selikowitz M. EEG coherence in attention-deficit/hyperactivity disorder: a comparative study of two DSM-IV types. Clin Neurophysiol 2002;113:579–85. Barry RJ, Clarke AR, McCarthy R, Selikowitz M, Johnstone SJ. EEG coherence adjusted for inter-electrode distance in children with attention-deficit/hyperactivity disorder. Int J Pychophysiol 2005a;58:12–20. Barry RJ, Clarke AR, McCarthy R, Selikowitz M, Johnstone SJ, Hsu C-I, Bond D, Wallace MJ, Magee CA. Age and gender effects in EEG coherence: II. Boys with attention deficit/hyperactivity disorder. Clin Neurophysiol 2005b;116:977–84. Baving L, Laucht M, Schmidt MH. Atypical frontal brain activation in ADHD: preschool and elementary school boys and girls. J Am Acad Child Adolesc Psychiatry 1999;38:1363–71. Baving L, Laucht M, Schmidt MH. Oppositional children differ from healthy children in frontal brain activation. J Abnorm Child Psychol 2000;28:267–75. Biederman J, Newcorn J, Sprich S. Comorbidity of attention deficit hyperactivity disorder with conduct, depressive, anxiety, and other disorders. Amer J Psychiatry 1995;148:564–77. Bird H, Gould M, Staghezza B. Patterns of diagnostic comorbidity in a community sample of children aged 9 through 16 years. J Amer Acad Child Adolesc Psychiatry 1993;32:361–8. Callaway E, Halliday R, Naylor H. Hyperactive children’s event-related potentials fail to support underarousal and maturational-lag theories. Arch Gen Psychiatry 1983;40:1243–8. Chabot R, Merkin H, Wood L, Davenport T, Serfontein G. Sensitivity and specificity of QEEG in children with attention deficit or specific developmental learning disorders. Clin Electroencephalogr 1996;27:26–34. Chabot R, Orgill A, Crawford G, Harris M, Serfontein G. Behavioural and electrophysiological predictors of treatment response to stimulants in children with attention disorders. J Child Neurol 1999;14:343–51.
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