Increased event-related theta activity as a psychophysiological marker of comorbidity in children with tics and attention-deficit/hyperactivity disorders Juliana Yordanova, a, * Hartmut Heinrich, c,d Vasil Kolev, a and Aribert Rothenberger b a Institute of Physiology, Bulgarian Academy of Sciences, Acad. G. Bonchev str., bl. 23, 1113 Sofia, Bulgaria b Child and Adolescent Psychiatry, University of Go ¨ttingen, von Siebold-Strasse 5, D-37075 Go ¨ ttingen, Germany c Heckscher-Klinik, Deisenhofener Str. 28, 81539 Mu ¨ nchen, Germany d Child and Adolescent Psychiatry, University Clinics Erlangen, Schwabachanlage 6-10, 91054 Erlangen, Germany Received 11 August 2005; revised 15 March 2006; accepted 20 March 2006 Available online 26 May 2006 1053-8119/$ - see front matter D 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.neuroimage.2006.03.056 Abbreviations: ADHD, attention-deficit/hyperactivity disorder; CWT, continuous Wavelet transform; EEG, electroencephalogram; ERP, event- related potential; ETR, early theta response; LTR, late theta response; NT – A, non-target – attended; NT – NA, non-target – non-attended; RT, reaction time; T–A, target – attended; TF, time – frequency; TD, tic disorder; T – NA, target – non-attended; TR, theta response. * Corresponding author. Fax: +359 2 979 37 49. E-mail address: jyord@bio.bas.bg (J. Yordanova). Available online on ScienceDirect (www.sciencedirect.com). Objective: The question as to whether coexisting tic disorder (TD) and attention-deficit/hyperactivity disorder (ADHD) in children represent a combination of two independent pathologies, a separate nosologic entity manifested by both tics and hyperactivity or a phenotype subgroup of one of the two major clinical forms has received increasing attention. The aim of the present study was to classify the TD + ADHD comorbidity in the neurocognitive domain and to elucidate the neurophysiological background of TD + ADHD coexistence by analyz- ing event-related electroencephalographic (EEG) oscillations in the theta (3 – 7.5 Hz) frequency band. Methods: Event-related potentials were recorded at 10 electrodes in 53 children (9– 13 years old) from four groups (healthy controls, TD-only, ADHD-only, and combined TD+ADHD patients), while they per- formed an auditory selective attention task requiring a button press to a predefined target. Event-related theta oscillations were analyzed by means of time – frequency decomposition (wavelet analysis) in two latency ranges—early (0 – 200 ms) and late (200 – 450 ms). The effects of psychopathology factors (TD and ADHD) and task variables (attended channel and stimulus task relevance) on early (ETR) and late (LTR) theta responses were evaluated statistically. Theta response measures were further correlated with psychopathology scores and spontaneous theta EEG activity. Results: (1) The ETR was enhanced only in comorbid children and did not differ between the control, TD-only, and ADHD-only groups. (2) The LTR was larger in children with ADHD (ADHD-only and comorbid), but this effect was mediated by the spontaneous theta EEG activity. (3) The ETR was larger to attended stimuli at frontal– central electrodes contralateral to the side of attention, to the target stimulus type at frontal locations, and at the hemisphere contralateral to the side of the response. The functional reactivity and scalp distribution of ETRs were modulated by psychopathological factors. Conclusions: In the neurocognitive domain, the TD + ADHD comor- bidity can be identified as a unique nosologic entity. Both the spontaneous theta activity and late event-related theta oscillations appear as neurophysiological markers of the ADHD condition. In children, the early event-related theta oscillations may be associated with representations of relevant target features in working memory. Significance: (1) A new model is proposed according to which TD + ADHD comorbidity can be classified at different levels (from neurobiological to cognitive). (2) The functional significance of stimulus-synchronized theta oscillations in children is described for the first time. D 2006 Elsevier Inc. All rights reserved. Keywords: Attention-deficit/hyperactivity disorder; Tic disorder; Event- related theta oscillations; ERP; EEG; Memory and attention; Children Introduction Because of their prevalence and great social impact, hyper- motor symptoms in children have been increasingly focused on in recent child psychiatric research (Buitelaar and Rothenberger, 2004). Hypermotor behavior is identified in attention-deficit/ hyperactivity disorder (ADHD) and tic disorder (TD). The core clinical symptoms of ADHD are inattention, impulsivity, and general motor hyperactivity (e.g., Swanson et al., 1998). In contrast, though being a complex neuropsychiatric disturbance, TD is essentially characterized by multiple motor and/or phonic tics with fluctuating phenomenology (Rothenberger, 1991; Leck- man et al., 1997; Leckman, 2002). Extensive literature has www.elsevier.com/locate/ynimg NeuroImage 32 (2006) 940 – 955