Antihistamine effects on prefrontal cortex activity during working memory process in preschool children: A near-infrared spectroscopy (NIRS) study

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Abstract

Histamine H1 receptor antagonists (antihistamines) are widely used for the treatment of allergic disorders in young children. This study examined the effects of antihistamine on prefrontal cortex activity in preschool children using near-infrared spectroscopy (NIRS), an emerging brain-imaging method suitable for psychological experiments, especially in young children. We examined the changes of oxygenated hemoglobin concentration in the prefrontal cortex while children performed a spatial working memory task, 3 h after taking a first-generation antihistamine (ketotifen), second-generation antihistamine (epinastine), or placebo. Fifteen healthy preschool children (mean age, 5.5 years) participated. Ketotifen significantly impaired behavioral performance and cortical activation at the lateral prefrontal cortex in the working memory task, compared with epinastine and placebo. There were no sedative effects on neural response or behavioral performance after epinastine administration. This paper demonstrates for the first time differential sedation effects of first- and second-generation antihistamines on brain hemodynamic response in young children. Also discussed is the utility of the NIRS technique in neuropsychopharmacological studies of children.

Introduction

Histamine H1 receptor antagonists (antihistamines) are widely used for the treatment of allergic disorders. It is well known that first-generation antihistamines such as chlorpheniramine and ketotifen have undesirable side effects including sedation (Yanai and Tashiro, 2007). In contrast, sedation is not a common side effect encountered with second-generation antihistamines such as fexofenadine and epinastine.

In adults there is considerable evidence showing differential sedation effects of the first- and second-generation antihistamines on behavioral performance (Shamsi and Hindmarch, 2000, Tashiro et al., 2005, Turner et al., 2006, Theunissen et al., 2006a, Theunissen et al., 2006c); H1 receptor occupancy rate (Tashiro et al., 2004, Tashiro et al., 2006, Mochizuki et al., 2004); and neural correlates with cognitive performance (Gevins et al., 2002, Mochizuki et al., 2002, Theunissen et al., 2006b, Tsujii et al., 2007). For example, Tsujii et al. (2007) demonstrated that ketotifen significantly impaired behavioral performance and frontal cortical activation during working memory tasks whereas epinastine did not influence behavioral and hemodynamic responses compared with placebo. However, it is not known whether these findings can be extrapolated to behavioral and neural performances in preschool children.

This study was conducted to examine the effects of antihistamines on behavioral performance and neural correlates in preschool children using near-infrared spectroscopy (NIRS), an emergent imaging technique for investigating cortical hemodynamic response (for a review, see Boas et al., 2004). Because oxygenated hemoglobin (oxy-Hb) and deoxygenated hemoglobin (deoxy-Hb) have different absorption spectra in the infrared range, changes in concentrations of oxy- and deoxy-Hb can be calculated by detecting infrared light at two different wavelengths on the skull (about 787 and 827 nm). Enhanced oxy-Hb and diminished deoxy-Hb are generally coupled with regional cortical activation.

NIRS is non-invasive, robust against body movements, and a validated technique suitable for psychological experiments, particularly in developmental studies. Indeed, recent NIRS studies have successfully measured children's cortical responses associated with cognitive performance (Minagawa-Kawai et al., 2008). For example, Tsujimoto et al. (2004) examined the cortical response of preschool children aged 5–6 years during spatial working memory performance and found that the oxy-Hb concentration is enhanced in the lateral prefrontal cortex, a brain region usually associated with working memory processes in adults (Allen et al., 2006, Jager et al., 2007, Smith and Jonides, 1998).

Recently, several papers have introduced the NIRS technique for the assessment of brain function under various conditions such as following acute stimulation with alcohol (Obata et al., 2005) and opioids (Hock et al., 1999) as well as psychopharmacological studies (Tsujii et al., 2007). For instance, Tsujii et al. (2007) examined the antihistamine effects of epinastine and ketotifen on the prefrontal hemodynamic response during working memory tasks in adult subjects, and demonstrated that ketotifen impairs changes of oxy-Hb concentration for working memory performance at the lateral prefrontal cortex. There was no sedative effect in the neural response after the administration of epinastine. Differential sedative effects of first- and second-generation antihistamines on prefrontal neural response were also found in a selective attention task. It is, however, still unclear whether this situation would also apply to preschool children.

In the present study we examined the effect of antihistamines on prefrontal activity in preschool children aged 5–6 years using NIRS. We recorded the oxy-Hb concentration change at the prefrontal region while children performed a spatial working memory task after the administration of epinastine, ketotifen, and placebo (Fig. 1). We employed a working memory task similar to that of Tsujimoto et al. (2004), a task known to activate the lateral prefrontal cortex in children. If first- and second-generation H1 antagonists produce differential sedative effects in preschool children, the likelihood of prefrontal activation associated with working memory processes should be lessened by the administration of ketotifen compared with epinastine and placebo.

Section snippets

Participants

Participants were right-handed Japanese preschool children with a history of Japanese cedar pollinosis. Fifteen participants (M/F, 7/8; mean age ± SD, 66.5 ± 6.2 [range, 54–80] months) were recruited. All participants had normal or corrected-to-normal vision and were in good health without a significant clinical history of physical and mental illness. They were excluded if they had a history of hypersensitivity to components of the study drugs or were receiving any concomitant medication likely to

Behavioral performance

Mean accuracy scores (d′) and RT in the working memory task for each treatment condition are summarized in Fig. 4. In the accuracy (d′), one-way ANOVA revealed a significant effect of treatment (F [2,26] = 4.67; P = 0.02). Paired comparison analysis showed that ketotifen reduced the d′ score compared with epinastine (t [26] = 3.03; P < 0.01). There were no significant differences between placebo and epinastine (t [26] = 1.15; P = 0.26) and between placebo and ketotifen (t [26] = 1.88; P = 0.07).

In addition,

Discussion

We examined treatment effects of first- and second-generation H1 receptor antagonists on working memory tasks in preschool children. Ketotifen detrimentally affected behavioral performance and cerebral NIRS response compared with epinastine and placebo. There was no sedative effect in behavioral and neural responses after epinastine administration. This is consistent with previous findings in adult subjects, involving behavioral studies (Shamsi and Hindmarch, 2000, Theunissen et al., 2006b,

Acknowledgments

Our thanks go to the 15 preschool children who participated in the study, as well as to their parents. We also thank Masahito Kobayashi, MD (Department of Neurosurgery, Keio University), Kenjiro Kosaki, MD (Department of Pediatrics, Keio University), and Shozo Kojima, PhD (Department of Psychology, Keio University), for valuable contributions toward the design and execution of this study. Funding for the study was provided by the Japanese Public Health Research Foundation (JPHRF). The study was

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