These findings suggest that PFC activation might be affected by MPH, depending on the degree of difficulty of the particular task. Although the MPH-induced change on behavior may or may not be obvious, NIRS measurements might be useful for assessing the psychological effects of MPH even when performance changes were not observed in the cognitive tasks.

Introduction

Attention-deficit hyperactivity disorder (ADHD) is a common developmental disorder that affects 3% to 7% of school–age children [1]. The current conceptual models of ADHD are centered on neuropsychological theories of impaired functioning of the frontal lobes, especially the prefrontal cortex (PFC). It has been suggested that the cognitive difficulties that are experienced by children with ADHD are accounted for by deficits in executive functions (EFs) [2]. “EFs” is an overarching term that refers to the mental control processes that enable physical, cognitive, and emotional self-control and that are necessary to maintain effective goal-directed behavior [3]. EFs generally include response inhibition, working memory (WM), cognitive flexibility, planning, and fluency. Among the various EFs, many studies have cited deficits in WM in children and adults with ADHD [4,5]. Kofler et al. suggested that WM is the core and causal cognitive process that is responsible for ADHD in “The Working Memory Model of ADHD” [6].

The term WM refers to a brain system that provides temporary storage and manipulation of the information that is necessary for such complex cognitive tasks as language comprehension, learning, and reasoning [7]. This definition has evolved from the concept of a unitary short-term memory system [7]. WM has been found to require the simultaneous storage and processing of information. It can be divided into the following 3 subcomponents: (i) the central executive, (ii) the visuospatial sketch pad, which manipulates visual images and (iii) the phonological loop [8]. A number of studies have suggested that WM impairments are central to ADHD [8,9]. However, there has been no robust evidence for which component is crucial for the impairment [10]. The most recent findings have indicated that there is growing evidence for impairments in visuospatial WM (VSWM) in patients with ADHD [8,11]. This evidence is consistent with neuropsychological and imaging studies that have mainly implicated right frontal-striatal circuitry impairments in patients with ADHD [12].

Stimulant medications, such as methylphenidate (MPH), are the most commonly prescribed and studied ADHD medications. MPH is highly effective in improving the core symptoms of ADHD [13]. For example, DeVito et al. found that MPH reduced risk-prone betting behavior on the Cambridge Gambling Task in children with ADHD [14]. In a recent review, Pietrzak et al. have found that MPH improved attention control, response inhibition, and sustained attention in approximately 70% of the studies examined [15]. As for WM, it has been reported that MPH also improves WM function by facilitating dopaminergic transmission [16]. Despite these positive effects of MPH on WM [17], there have been a limited number of studies investigating the efficacy of MPH on VSWM in children with ADHD [18]. The objective of the present study was to evaluate the effectiveness of MPH in detail on visuospatial working memory (as well as visuospatial short-term memory) and executive functions of children with ADHD. Therefore, it is very important that the efficacies of medication are assessed in detail from the viewpoint of VSWM because the impairments in VSWM is common to patients with ADHD [11].

The computerized Cambridge Neuropsychological Test Automated Battery (CANTAB®) is one of the most widely used methods to assess EF in pediatric clinical populations [19-22]. The CANTAB® has advantages over other measures of EF because it can be administrated on a computer, (which controls for variations across examiners), has more than 20 subtests for evaluating EF abilities, is nonverbal (requires touch-screen responses), and there is empirical support for the role of prefrontal and medial temporal brain regions in performance on the CANTAB® tasks [23]. It is a suitable battery for children with developmental disorders because of these advantages. The present study employs spatial working (and short-term) memory tasks as well as tasks to assess the executive functions in the CANTAB® in order to evaluate the effectiveness of MPH on those cognitive abilities of children with ADHD. Furthermore, because the CANTAB® includes several VSWM tasks, such as the spatial working memory (SWM) and spatial span (SSP) tasks, it is suitable for evaluating the effectiveness of MPH by implementing these tasks at two condition (MPH-off and MPH–on). For example, Rhodes et al. evaluated the acute neuropsychological effects of MPH in drug-naïve boys with ADHD by conducting many of the CANTAB® subtasks, including the SWM and SSP [24]. They found that MPH did not improve performance on any task. Additionally, there were no significant differences among the baseline, placebo, MPH 0.3 mg/kg, and MPH 0.6 mg/kg groups in scores on visuospatial tasks [24]. Few pharmacological studies have examined VSWM with CANTAB® tasks, and it has been difficult to detect improvements in CANTAB® scores. Additionally, due to the lack of neuroimaging methods in previous research, limited information relating to MPH effects on VSWM has been obtained. Therefore, we set out to examine not only changes in the CANTAB® scores, but also activation of PFC with a brain imaging tool in patients in MPH-on and MPH-off conditions.

Near-infrared spectroscopy (NIRS) is one of the most promising noninvasive functional neuroimaging tools that allows for comparative evaluations of cortical hemodynamic responses in children and individuals with psychiatric disorders. NIRS can measure the signals that reflect relative changes in oxyhemoglobin (oxy-Hb) and deoxyhemoglobin (deoxy-Hb), which are assumed to reflect regional cerebral blood volume. Although functional magnetic resonance imaging and positron emission tomography have many advantages, including high spatial resolution, they have serious limitations in evaluating a drug’s therapeutic effects in bedside settings, especially for children with certain developmental disorders. In contrast, NIRS has many advantages in that it is non-invasive, allows for examination in a natural sitting position, and can be easily attached and removed. In terms of measuring the effects of medications, NIRS is considered the ideal instrument for evaluating prefrontal activation. In fact, several NIRS studies have been performed in children with ADHD during several EF tasks, such as the Stroop Color-Word Task, the Reserve Stroop Task, and the Go/No-go task. Therefore, the pharmacological effects of MPH might be evaluated by changes that are detected in oxy-Hb with NIRS during the course of the performance on specific VSWM tasks of the CANTAB®.

A number of studies have used neurological test batteries, such as the CANTAB®, in children with ADHD, and some of these have suggested that response inhibition performance is improved with MPH compared to placebo. Solanto et al., have evaluated the effectiveness of MPH in 25 children with ADHD using neuropsychological batteries, such as the Continuous Performance Test and the Resistance to Cognitive Interference Test (Stroop Task). They found signifiant effects of MPH on performance on the Continuous Performance Test, but not on performance on the Stroop Task [13]. However, no studies have examined the effects of MPH in children with ADHD by simultaneously measuring the hemodynamic changes of oxy-Hb in prefrontal regions and performance on VSWM tasks. The combination of the CANTAB® tests to evaluate VSWM with NIRS to assess hemodynamic changes in the brain, would provide critical insight into the mechanisms of the effects of MPH. In short, combining the CANTAB® tasks and NIRS evaluations has the potential of elucidating a better understanding of the treatment of children with ADHD.

The present study was designed to investigate the acute effects of MPH on neuropsychological performance and hemodynamic changes in MPH-on and MPH-off conditions in children with ADHD who were performing VSWM tasks of the CANTAB®. Moreover, we examined the relationship between specific EFs, such as VSWM, and behavioral characteristics. To the best of our knowledge, this is the first pharmacological effects study of children with ADHD that has examined performance on CANTAB® tasks and simultaneously evaluated hemodynamic responses in the prefrontal area with NIRS.