Applied Psychophysiology and Biofeedback, Vol. 31, No. 1, March 2006 ( C 2006) DOI: 10.1007/s10484-006-9001-y Functional Magnetic Resonance Imaging Investigation of the Effects of Neurofeedback Training on the Neural Bases of Selective Attention and Response Inhibition in Children with Attention-Deficit/Hyperactivity Disorder Mario Beauregard1,2,3,4,5 and Johanne Levesque1,4�� Published online: 22 March 2006 Two functional magnetic resonance imaging (fMRI) experiments were undertaken to mea- sure the effect of neurofeedback training (NFT), in AD/HD children, on the neural substrates of selective attention and response inhibition. Twenty unmedicated AD/HD children partic- ipated to these experiments. Fifteen children were randomly assigned to the Experimental (EXP) group whereas the other five children were randomly assigned to the Control (CON) group. Only subjects in the EXP group underwent NFT. EXP subjects were trained to en- hance the amplitude of the SMR (12���15 Hz) and beta 1 activity (15���18 Hz), and decrease the amplitude of theta activity (4���7 Hz). Subjects from both groups were scanned one week before the beginning of NFT (Time 1) and 1 week after the end of NFT (Time 2), while they performed a ���Counting Stroop��� task (Experiment 1) and a Go/No-Go task (Experiment 2). At Time 1, in both groups, the Counting Stroop task was associated with significant activation in the left superior parietal lobule. For the Go/No-Go task, no significant activity was detected in the EXP and CON groups. At Time 2, in both groups, the Counting Stroop task was associated with significant activation of the left superior parietal lobule. This time, however, there were significant loci of activation, in the EXP group, in the right ACC, left caudate nucleus, and left substantia nigra. No such activation loci were seen in CON subjects. For the Go/No-Go task, significant loci of activation were noted, in the EXP group, in the right ventrolateral prefrontal cortex, right ACcd, left thalamus, left caudate nucleus, and left substantia nigra. No significant activation of these brain regions was measured in CON subjects. These results suggest that NFT has the capacity to functionally normalize the brain systems mediating selective attention and response inhibition in AD/HD children. KEY WORDS: selective attention response inhibition AD/HD children neurofeedback functional magnetic resonance imaging prefrontal cortex anterior cingulate striatum. 1Centre de Recherche en Neuropsychologie et Cognition (CERNEC), Departement �� de Psychologie, Universit�� e de Montr�� eal. 2Departement �� de Radiologie, Universit�� e de Montr�� eal. 3Centre de recherche en sciences neurologiques (CRSN), Universit�� e de Montr�� eal. 4Centre de Recherche, Institut universitaire de geriatrie �� de Montr�� eal (CRIUGM). 5Address all correspondence to Mario Beauregard, Departement �� de Psychologie, Universit�� e de Montr�� eal, C.P. 6128, succursale Centre-Ville, Montr�� eal, Quebec, �� Canada H3C 3J7 e-mail: mario.beauregard@umontreal.ca. 3 1090-0586/06/0300-0003/1 C 2006 Springer Science+Business Media, Inc.

4 Beauregard and Levesque�� INTRODUCTION Attention Deficit Hyperactivity Disorder (AD/HD), a frequent developmental disorder of childhood, affects 3���7% of children and frequently continues into adulthood (Barkley, 1996). AD/HD in childhood negatively affects academic performance and leads to in- creased risk for antisocial disorders and drug abuse in adulthood (Mannuzza, Klein, Bessler, Malloy, & Hynes, 1997). This syndrome is mainly characterized by deficits in selective attention and response inhibition (Barkley, 1997). These symptoms reflect impairments in cognitive executive functions. These functions refer to the dynamic regulatory capacities for the initiation and maintenance of efficient attainment of goals (Lezak, 1990), as well as the inhibition of behavioral responses that are inappropriate in the current context (Shallice, 1988). This type of behavioral regulation is essential to successfully adapt one���s behavior to changing environmental demands. Cognitive executive functions are closely related with prefrontal and striatal brain systems (Godefroy, Lhullier, & Rousseaux, 1996 Leimkuhler & Mesulam, 1985 Smith & Jonides, 1999). In line with this, a number of structural magnetic resonance imaging (MRI) studies have found significant volumetric reduction of prefrontal cortical areas (Aylward et al., 1996 Castellanos et al., 1994, 1996, 2001, 2002 Durston et al., 2004 Filipek et al., 1997 Hill et al., 2003 Garavan, Ross, Murphy, Roche, & Stein, 1993 Kates et al., 2002 Mataro, Garcia-Sanchez, Junque, Estevez-Gonzalez, & Pujol, 1997 Mostofsky, Cooper, Kates, Denckla, & Kaufmann, 2002 Overmeyer et al., 2001 Sowell et al., 2003) and caudate nucleus (Castellanos et al., 1994, 1996, 2001, 2002 Filipek et al., 1997 Hynd et al., 1993 Mataro et al., 1997) in children and adolescents with AD/HD. Single photon emission computed tomography (SPECT) and positron emission to- mography (PET) studies carried out in AD/HD children, adolescents, or adults have shown decreased metabolism in the striatum and diverse prefrontal regions during resting state (Amen & Carmichael, 1997 Kim, Lee, Shin, Cho, & Lee, 2002 Lou, Henriksen, Bruhn, Borner, & Nielsen, 1989 Sieg, Gaffney, Preston, & Hellings, 1995 Zametkin et al., 1990). Moreover, SPECT studies have demonstrated decreased perfusion in prefrontal areas involved in the control of attentional processes in AD/HD individuals (Amen & Carmichael, 1997 Kim et al., 2002), and a functional MRI (fMRI) study reported no activation of the anterior cingulate cortex (ACC) in adults with AD/HD while they per- formed a Counting Stroop task (Bush et al., 1999) (a variant of the Stroop task-Stroop, 1935). This task, which implicates selective attention and response inhibition, exploits the conflict between a well-learned behavior (i.e., reading) and a decision rule that re- quires this behavior to be inhibited. Converging evidence from PET and fMRI indicate that the dorsal division of the ACC (or ACcd, Brodmann area-BA-24b -c and 32 ) plays a key role in the various cognitive processes involved in the Stroop task (e.g., interfer- ence, allocation of attentional resources, response selection) (Bush et al., 1998 Bush, Luu, & Posner, 2000). The capacity to inhibit behaviors or responses that are inappropriate in the current context can be studied using Go/No-Go tasks, in which the participant is required to refrain from responding to designated items within a series of stimuli. Several studies (Castellanos et al., 2000 Hartung, Milich, Lynam, & Martin, 2002 Iaboni, Douglas, & Baker, 1995 Itami & Uno, 2002 Vaidya et al., 1998) have shown that AD/HD subjects

Functional Magnetic Resonance Imaging Investigation of the Effects 5 exhibit more errors on Go/No-Go tasks. Furthermore, the results of a number of fMRI studies during Go/No-Go tasks indicate that several prefrontal regions (ACC, dorsolateral prefrontal cortex, orbitofrontal cortex, ventrolateral prefrontal cortex) (Casey, Durston, & Fossella, 2001 Garavan, Ross, & Stein, 1999 Garavan et al., 2002 Kiehl, Liddle, & Hopfinger, 2000 Konishi, Nakajima, Uchida, Sekihara, & Miyashita, 1998 Liddle, Kiehl, & Smith, 2001 Menon, Adleman, White, Glover, & Reiss, 2001 Rubia, Smith, Brammer, & Taylor, 2003) and the striatum (Menon et al., 2001) are crucially involved in response inhibition. Underactivation of the striatum (Booth et al., 2005 Durston et al., 2003 Rubia et al., 1999 Teicher et al., 2000 Vaidya et al., 1998) and prefrontal regions (Booth et al., 2005 Rubia et al., 1999 Tamm, Menon, Ringel, & Reiss, 2004 Vaidya et al., 1998) has been observed in children and adolescent with AD/HD during Go/No-Go tasks. The results of several clinical studies carried out during the last thirty years sug- gest that neurofeedback may be efficacious in treating children with AD/HD (Fuchs, Birbaumer, Lutzenberger, Gruzelier, & Kaiser, 2003 Kropotov et al., 2005 Linden, Habib, & Radojevic, 1996 Lubar & Shouse, 1976 Lubar & Lubar, 1984 Lubar, Swartwood, Swartwood, & O���Donnell, 1995 Monastra, Monastra, & George, 2002 Rossiter & LaVaque, 1995 Rossiter, 2004 Shouse & Lubar, 1979 Tansey, 1984, 1985 Thompson & Thompson, 1998). In many of these studies, the operant enhancement of sensorimotor rhythm (SMR) (12���15 Hz) and/or beta 1 (15���20 Hz) EEG activity from the regions overlying the Rolandic area, was trained concomitantly with suppression of theta (4���7 Hz) activity. The basic assumption guiding this approach is that SMR enhancement reduces problems of hyperactivity, whereas increasing beta 1 activity and suppressing theta activity diminishes attention deficits (Lubar & Shouse, 1976). In keeping with this assump- tion, these studies demonstrated that neurofeedback training (NFT) can significantly reduce attention deficits and hyperactivity in children with AD/HD. In this context, the main objective of this work was to measure the effects of NFT, in AD/HD children, on the neural substrates of selective attention and response inhibition. FMRI experiments were conducted during a Counting Stroop task (Experiment 1) and a Go/No-Go task (Experiment 2). Behavioraly, we predicted that NFT would significantly improve performance on both tasks. Neurally, we predicted that NFT would significantly increase ACcd activity during the Counting Stroop task, and prefrontal as well as striatal activity during the Go/No-Go task. MATERIALS AND METHODS Subjects The study sample was composed of 20 AD/HD children. These AD/HD children were randomly assigned to either an Experimental (EXP) group or a control (CON) group. Fif- teen AD/HD children comprised the EXP group (4 girls and 11 boys, mean age: 10.2, SD: 1.3, range: 8���12) and five ADHD children comprised the CON group (5 boys, mean age: 10.2, SD: 0.8, range: 9���11). The EXP group received NFT whereas the CON group received no treatment (the CON group served specifically to measure the effect of passage of time). The parents of the subjects gave written informed consent and the study was approved