Effect of Atomoxetine Hydrochloride on Working Memory in Children with ADHD: A Functional Near-infrared Spectroscopy Study

Effect of Atomoxetine Hydrochloride on Working Memory in Children with ADHD: A Functional Near-infrared Spectroscopy Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Effect of Atomoxetine Hydrochloride on Working Memory in Children with ADHD: A Functional Near-infrared Spectroscopy Study Ziqi Liu, Xinru Wu, Mengjiao Tao, Yue Gu, Yike Zhu, Jing Sun, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7627616/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objective: This study aimed to investigate the effect of atomoxetine hydrochloride (ATX) on the activation of the prefrontal complex (PFC) in children with ADHD during a working memory task. Methods: We recruited 14 drug-naive children with ADHD. PFC functional blood oxygen was recorded by using fNIRS during the n-back task. Clinical symptoms were assessed by parents using the Swanson, Nolan, and Pelham-IV rating scale and Conners measuring scale (parent symptom questionnaire) at the same time. After 8 weeks of treatment with ATX, these children were re-evaluated by using fNIRS, SNAP-IV, and Conners scales. Statistical methods were used to compare the physiological and psychological test indicators in the pre- and post-ATX conditions. Simultaneously, oxygenated hemoglobin concentration variation and the scores of the two scales were used as indicators for correlation analysis between PFC activation and clinical symptoms. Results: Based on the performance data, children showed higher accuracy and lower omission error during the n-back task after ATX treatment. According to fNIRS data, the hemodynamic changes between pre-ATX and post-ATX conditions suggested that high-level activation in channel 36 was found in children under post-ATX conditions. The associated channels were located in frontopolar PFC, dorsolateral PFC, and orbitofrontal cortex. Enhanced trends were also found in channels 5 and 7. Regarding the rating scale scores, children under post-ATX conditions showed relatively lower inattention scores, hyperactivity scores, oppositional defiant score, and total scores on the SNAP-IV scale. Lower conduct problem score, learning problem score, hyperactivity-impulsivity score, and hyperactivity index of Conners measuring scale were observed in children who received treatment. These values were statistically and significantly different. A significantly negative correlation was observed between oxygenated hemoglobin concentration changes and the total score on the SNAP-IV scale. Conclusions: fNIRS is a helpful tool for identifying the effects of ATX on children with ADHD, and its combination with the SNAP-IV scale can provide an objective physiological index for evaluating the efficacy of ATX．ATX can improve the core symptoms and executive function of children with ADHD. Figures Figure 1 Figure 2 Figure 3 Introduction Attention-deficit/hyperactivity disorder (ADHD) is one of the most commonly diagnosed neurodevelopmental disorders in children. It is characterized by inattention and hyperactivity and has a prevalence rate of around 3%–5% [1] . The social function development of these children is affected, and the influence may persist into adolescence and adulthood. Previous studies have found that the core symptoms of ADHD are attributed to executive dysfunction, which are closely related to the function of the prefrontal cortex (PFC) [2] . Currently, executive dysfunction is usually assessed by neuropsychological testing. The evaluation of drug treatment effects is based on clinical observation and scale assessment. In recent years, the objective detection tool functional near-infrared spectroscopy (fNIRS) has been used to explore the effects of drug therapy on executive functions in children with ADHD [3] . fNIRS, a non-invasive optical imaging technique that measures cerebral hemodynamic changes associated with functional brain activity has become a promising tool for scientific research and clinical practice on ADHD, autism spectrum disorder, and epilepsy [4] . With its non-invasiveness, low noise, relative motion artifact tolerance, and high ecological validity, fNIRS is particularly suitable for investigating the executive functions of children with ADHD [5] . In our previous study, reduced activation was shown in the left dorsolateral PFC (DLPFC) in children with ADHD during working memory task by using fNIRS. The combination of drug and behavioral therapies is a common ADHD treatment. The non-stimulant drug atomoxetine (ATX) and the stimulant drug methylphenidate (MPH) are recommended as the first line treatment for ADHD patients. MPH can improve the core symptoms of ADHD effectively and rapidly. MPH’s common adverse reactions include headache, insomnia, and loss of appetite. Moreover, MPH poses the risk of addiction. ATX is a selective NA reuptake inhibitor that usually takes 4 to 5 weeks to show maximum effect [6] . Its adverse reactions are similar to MPH except for the risk of addiction. Based on previous research, the mechanism of drug therapy to improve the working memory function in children with ADHD is still unclear. Therefore, in this current study, the effect of the non-addictive drug ATX on the working memory function of children with ADHD was determined. To provide objective evidence for the improvement of ADHD children before and after intervention. Currently, fNIRS studies on the effects of drug therapy can be broadly divided into two categories, namely, acute and long-term neuropharmacological effects on the brain function of children with ADHD. In the acute efficacy test, according to the time of rapid onset of the drug, the investigator monitored the oxygenated hemoglobin signal changes of children with ADHD who were performing some cognitive tasks before and 1.5 h after drug therapy. Advantageously, children who are not sensitive to the drug can change the treatment plan in time, because assessment can be completed in a single-day hospital visit [7] . In the other type (long-term fNIRS), the investigator monitors the oxygenated hemoglobin signal changes of ADHD children before and more than a few weeks or even half a year after drug therapy to evaluate the brain function changes of the children after long-term treatment. This type of test may provide more objective evidence for the evaluation of drug efficacy than the other type [8] . In previous studies, the results of the acute efficacy tests were approximately consistent. The cognitive task recruited the right inferior and middle prefrontal gyri (IFG/MFG) after 1.5 h of ATX/MPH treatment in some studies, and this activation was absent in pre-medicated and placebo-administered children with ADHD [9] . However, the results of chronic efficacy tests varied widely. Some studies obtained similar results as those in the acute efficacy test, which showed increased activation in the right PFC after treatment. However, in several trials, the weakening activation of the left ventrolateral prefrontal lobe disappeared. Conversely, the decreased activation of PFC was found in children after medication in some studies. Moreover, some researchers detected increased brain activation in the PFC of children with ADHD during Working Memory (WM) task in simple mode, but decreased activation was found in hard mode [2] . The present study aimed to explore the long-term effects of ATX on brain function during working memory task by using fNIRS. We assumed that brain activity in the PFC will be altered after medication. Methods Subjects: The study was approved by the Ethics Committee of the Capital Center for Children’s Health, Capital Medical University. As all the participants were minors, written informed consents were collected from their guardians in accordance with the Declaration of Helsinki. Fourteen patients with ADHD (6–12 years old) were recruited from the Children’s Hospital Affiliated to Capital Institute of Pediatrics. All participants met the DSM-V diagnostic criteria for ADHD. Drug-naive individuals who were righthanded were included in the test group. IQ was evaluated using the Chinese version of the Wechsler Intelligence Scale for Children-Revised, and the IQ scores of the participants were ≥ 70. Furthermore, all patients have attended school and have the required knowledge to participate in the test. Exclusion criteria for all subjects included history of ADHD medication, developmental delay, head trauma or seizure, and diagnosis of a neurological disorder, genetic disorder, or any other physical disorder. Written consent was obtained from the subjects who were over 8 years old and from the parents of all participants. This study was approved by the Ethics Committee of Children’s Hospital Affiliated to Capital Institute of Pediatrics. Table A: Demographic and clinical profiles for subjects ID SEX AGE(years) 1 male 11 2 male 7 3 male 8 4 male 6 5 female 8 6 male 8 7 male 7 8 male 6 9 male 6 10 male 12 11 male 12 12 male 9 13 male 9 14 female 7 Mean ± SD 8.29 ± 2.09 Experimental design: We examined ADHD subjects twice to investigate the effect of ATX on the activation of the PFC in children with ADHD during the n-back task. Functional blood oxygen level was recorded by using fNIRS. Clinical symptoms were assessed by parent’s Swanson, Nolan, and Pelham-IV rating scale (SNAP-IV) and Conners measuring scale (parent symptom questionnaire, PSQ) at the same time. After the initial data collection, the subjects were administered an ATX dose of 0.5 mg/kg/d in the first week and then 1.2 mg/kg/d for 7 weeks. The children were re-evaluated by fNIRS, SNAP-IV, and Conners in the second visit after 8 weeks of medication. Experimental Task: The n-back task was generated by E-Prime2.0 and presented in a 17’’ desktop computer screen. The distance between the children’ eyes and the screen was ∼50 cm. The block-designed task consisted of block sets, and each set comprised the baseline acquisition and n-back task. The entire task lasted for 360 s. A 30 s baseline acquisition period preceded the n-back task segment. The n-back task incorporated alternating 0- and 1-back tasks. Each of the two tasks was conducted thrice. Every task block contained 15 trials, which consisted of single pseudo-random digits (0–9). Each digit was presented for 500 ms, followed by an interstimulus interval of 1500 ms. The alternating tasks were separated by 30 s resting segments. For the 0-back condition, the participants were instructed to press the button "√" whenever a digit that appeared on the computer screen in front of them was identical to the target digit. Otherwise, they were instructed to press the button “X.” For the 1-back condition, the participants were instructed to press the button “√” whenever the presented digit was identical to the preceding one. Otherwise, they were instructed to press the button “X”. The participants were instructed to press the “√” and “X” buttons using the index and middle fingers of the right hand, respectively. The environment was quiet, clean, and comfortable to ensure that the subjects remained relaxed during the test. Each participant performed a practice block before any measurement to ensure that the instructions were understood. Under the conditions, the subjects were instructed to respond to each trial as quickly as possible. The reaction time (RT), accuracy (ACC), commission error, and omission error for the trials were recorded. fNIRS Measurements: We used the continuous multichannel fNIRS system ETG-4000 (Hitachi Medical Corporation, Kashiwa, Japan) to measure relative concentration changes in oxygenated hemoglobin (HbO) and deoxygenated hemoglobin (Hb). This instrument worked with two different wavelengths of near-infrared light (695 and 830 nm), and the sampling frequency was 10 Hz. We used a set of 3 × 11 multichannel probe holder that consisted of 17 emitters and 16 detectors arranged alternately at an inter-probe distance of 3 cm. The midpoint of a pair of emitter and detector was defined as the channel (CH) location. These emitter and detector formed 52 measurement CHs. The probe holder was positioned on the head with regard to the relevant standard positions of the international 10–20 system for EEG electrode placement. The middle inferior optode was placed over Fpz, and the inferior row of optodes was oriented in the direction of T3 or T4. Analysis of fNIRS Data: The relative concentration changes in HbO and Hb were analyzed based on the modified Beer–Lambert Law. HbO is more sensitive to regional cerebral blood flow than Hb, and it has higher signal-to-noise ratio and retest reliability. Thus, we only focused on HbO data in the subsequent analysis. HBO was analyzed using the general linear model (GLM) to identify cortical regions significantly associated with stimuli given the task. The GLM model models the measured brain response as the sum of the predictable response due to the stimulus and the noise part. Statistical Analysis: The oxy-HB signals were analyzed statistically in a channel-wise manner. For the subjects, we generated the following contrasts. First, for the pre-medication contrast, we examined the difference between changes in oxy-HB peak and baseline using one sample t-test. Second, for the intra-medication contrast, we examined the difference between post- and pre-ATX medication contrasts in oxy-HB peak using a paired t-test with a statistical threshold of p < 0.05 to identify the CHs involved in the n-back task. Then, we performed statistical analysis on the behavioral therapeutic data for subjects during n-back task. To assess the medication effects on behavioral and therapeutic performances, we performed paired t-tests with a statistical threshold of p < 0.05 to compare the conditions after and before ATX treatment in terms of reaction time, accuracy, omission error, commission error, SNAP-IV, and Conners data. In addition, to determine whether a correlation existed between hemoglobin concentration and therapeutic data, we performed Kendall correlation analysis on hemoglobin concentration variation and the scores of SNAP-IV and Conners data. Results Behavioral Performance: Four indices were statistically analyzed in the behavior data during the n-back task. Table B summarizes the average accuracy, reaction time, commission errors, and omission errors for pre- and post- ATX conditions during the n-back task. The results of t-test showed significantly higher accuracy and lower omission error during the n-back task after ATX treatment. A downtrend was found in the reaction time and commission errors in the post-ATX condition. Table B and Fig. 1: Performance data associated with working memory during the n-back task. Performance pre-ATX (Mean ± SD) post-ATX (Mean ± SD) p -value ACC 8.564 ± 3.581 11.872 ± 1.068 0.001 RT 992.646 ± 219.144 948.286 ± 216.177 0.414 Omission Error 3.795 ± 3.041 1.436 ± 0.629 0.012 Commission Error 2.641 ± 2.030 1.692 ± 0.687 0.127 fNIRS: We screened for the fNIRS CHs that were involved in the n-back task. The hemodynamic changes between pre-ATX and post-ATX conditions suggested that high-level activations in CH 36 (mean = -0.006,0.096, SD = 0.089,0.105, p = 0.009) were found in subjects under post-ATX conditions. This CH was in right medial PFC containing part of frontopolar PFC (FPC), DLPFC, and orbitofrontal cortex (OFC). Enhanced trends were also found in CHs 5 and 7. Figure 3 is the waveform of the oxy-HB signals for CH 36. This finding indicated that the subjects under post-ATX conditions exhibited higher right FPC, DLPFC, and OFC activation during n-back task. Table C: Oxy-Hb concentration and p -value of 52 channels under pre- and post-ATX conditions Channel Pre-ATX (Mean ± SD) Post-ATX (Mean ± SD) p -value Channel Pre-ATX (Mean ± SD) Post-ATX (Mean ± SD) p -value 1 -0.027 ± 0.113 -0.016 ± 0.141 0.782 27 -0.014 ± 0.037 0.025 ± 0.076 0.200 2 0.016 ± 0.091 0.011 ± 0.155 0.919 28 0.005 ± 0.060 0.031 ± 0.080 0.316 3 0.074 ± 0.118 0.052 ± 0.131 0.515 29 0.013 ± 0.081 0.009 ± 0.130 0.924 4 0.038 ± 0.073 0.054 ± 0.083 0.595 30 0.011 ± 0.121 -0.029 ± 0.144 0.517 5 0.002 ± 0.084 0.053 ± 0.092 0.076 31 0.024 ± 0.086 -0.015 ± 0.143 0.494 6 -0.029 ± 0.091 -0.003 ± 0.057 0.427 32 0.019 ± 0.105 0.014 ± 0.141 0.940 7 -0.009 ± 0.072 0.063 ± 0.091 0.100 33 -0.002 ± 0.153 -0.037 ± 0.149 0.640 8 -0.017 ± 0.077 0.032 ± 0.091 0.145 34 0.025 ± 0.117 0.010 ± 0.130 0.815 9 -0.001 ± 0.103 0.036 ± 0.126 0.344 35 0.040 ± 0.110 0.054 ± 0.096 0.733 10 -0.017 ± 0.104 0.007 ± 0.146 0.621 36 -0.006 ± 0.089 0.096 ± 0.105 0.009 11 0.017 ± 0.182 -0.068 ± 0.106 0.165 37 0.028 ± 0.114 0.026 ± 0.124 0.961 12 -0.035 ± 0.114 0.012 ± 0.145 0.364 38 0.007 ± 0.136 0.065 ± 0.169 0.403 13 0.054 ± 0.146 0.051 ± 0.152 0.952 39 0.065 ± 0.113 0.049 ± 0.135 0.789 14 0.044 ± 0.067 0.033 ± 0.102 0.750 40 -0.021 ± 0.167 -0.071 ± 0.103 0.491 15 -0.004 ± 0.054 0.029 ± 0.062 0.184 41 -0.002 ± 0.135 -0.013 ± 0.160 0.884 16 -0.019 ± 0.069 0.026 ± 0.069 0.171 42 0.010 ± 0.144 0.043 ± 0.113 0.531 17 -0.028 ± 0.096 0.039 ± 0.099 0.192 43 0.046 ± 0.169 0.009 ± 0.147 0.538 18 -0.009 ± 0.071 0.020 ± 0.082 0.363 44 0.017 ± 0.196 0.009 ± 0.138 0.915 19 -0.040 ± 0.099 -0.004 ± 0.080 0.335 45 0.012 ± 0.112 0.025 ± 0.098 0.821 20 -0.009 ± 0.092 -0.006 ± 0.153 0.946 46 0.000 ± 0.127 -0.001 ± 0.122 0.988 21 -0.012 ± 0.106 0.001 ± 0.084 0.700 47 0.012 ± 0.124 0.042 ± 0.139 0.445 22 -0.036 ± 0.061 -0.034 ± 0.163 0.978 48 -0.019 ± 0.116 0.048 ± 0.141 0.228 23 0.015 ± 0.180 0.024 ± 0.222 0.913 49 0.020 ± 0.140 0.024 ± 0.166 0.952 24 0.059 ± 0.093 0.022 ± 0.108 0.342 50 -0.007 ± 0.103 0.019 ± 0.168 0.704 25 0.040 ± 0.058 0.041 ± 0.093 0.980 51 0.006 ± 0.152 -0.007 ± 0.163 0.883 26 -0.007 ± 0.062 0.023 ± 0.095 0.279 52 -0.017 ± 0.141 -0.010 ± 0.107 0.911 Table D: Activated channels with MNI coordinates and Brodmann area partition Channel Mean MNI coordinates Brodmann area X Y Z SD CH36 25.6 65.5 11.2 4.9 10 (67%), 11 (20%), 46 (13%) CH5 10.3 50.1 46.8 7.3 9 (80%), 8 (13%), 10 (7%) CH7 -29.1 38.3 46.4 5.2 8(7%)、9(80%)、46(13%) Rating-Scale Scores: Four indices were statistically analyzed in the SNAP-IV rating scale. Subjects under post-ATX conditions showed relatively low inattention scores, hyperactivity scores, oppositional defiant scores, and total scores in the paired t-test. These values were statistically and significantly different ( p < 0.05). The core symptoms of the subjects were alleviated after the treatment. In the Conners measuring scale, subjects under post-ATX conditions showed lower conduct problem scores, learning problem scores, hyperactivity-impulsivity scores, and hyperactivity index using paired t-test with a statistical threshold of p < 0.05 that those under pre-ATX conditions. No significant improvement was observed in the anxiety and mind body problem scores. In general, the behavior problems of subjects under post-ATX conditions were alleviated to some extent. Tables E and F summarize the results. Table E: the scores and p -values of SNAP-IV scale under pre- and post-ATX conditions SNAP-IV scale Pre-ATX Mean ± SD Post-ATX Mean ± SD t p -value hyperactivity scores 20.64 ± 4.37 14.36 ± 4.48 5.84 <0.001 inattention scores 16.71 ± 6.85 12.07 ± 5.98 3.67 0.003 oppositional defiant scores 12.00 ± 5.95 9.07 ± 5.73 2.58 0.023 total scores 49.35 ± 15.59 35.50 ± 13.51 5.42 <0.001 Table F: the scores and p -value of Conners scale under pre- and post-ATX conditions Conners measuring scale Pre-ATX Mean ± SD Post-ATX Mean ± SD t p -value Conduct problem scores 15.07 ± 8.00 10.29 ± 7.22 6.20 <0.001 Learning problem scores 8.71 ± 1.94 6.43 ± 1.99 3.66 0.003 Anxiety scores 2.86 ± 2.11 2.79 ± 1.93 0.19 0.856 Hyperactivity-impulsivity scores 7.07 ± 2.56 5.36 ± 2.82 4.16 0.001 Hyperactivity index 17.57 ± 6.43 12.43 ± 5.39 4.60 <0.001 Mind body problem scores 1.64 ± 1.95 1.50 ± 1.69 The data didn‘t conform to the normal distribution therefore we conducted a rank sum test on it. 0.672 To determine whether a correlation existed between hemoglobin concentration and therapeutic data, we performed Kendall correlation analysis on hemoglobin concentration variation and scores of the two abovementioned scales. A significantly negative correlation existed between oxygenated hemoglobin concentration changes and both the oppositional defiant and total scores of SNAP-IV scale(K=-0.580, p = 0.005). Thus, as the oxygenated hemoglobin of PFC increased, the oppositional defiant and total scores of the SNAP-IV scale decreased. Discussion This study aimed to investigate the effect of atomoxetine hydrochloride (ATX) on the activation of the PFC in children with ADHD during a working memory task. Compared with the children under pre-ATX conditions, children under post-ATX conditions exhibited increased brain activation in the right PFC, including FPC, DLPFC, and OFC during the n-back task blocks. A significantly negative correlation was found between oxygenated hemoglobin concentration and the scores of the SNAP-IV scale. fNIRS is a helpful tool for identifying the effects of ATX on children, and its combination with SNAP-IV scale can provide an objective physiological index for evaluating the efficacy of ATX in children with ADHD༎ Behavioral Performance for N-back Task: Behavioral performance can reflect specific cognitive capacity. This study used the n-back task as an assessment tool to measure children's working memory capacity on the behavioral level. This tool has been commonly used in many cognitive studies on ADHD. In our study, average accuracy and omission error significantly differed between pre- and post-ATX conditions, and downtrends were also found in reaction time and commission errors in the latter. A normalization effect was found on behavioral performance in the post-ATX condition. In previous studies on n-back test with ADHD, working memory deficits on the behavioral level have been generally confirmed [10, 11] . Some scholars found that post-MPH patients performed similar to healthy controls and significantly better than patients who did not receive medication in the n-back test on the behavioral level [12] . Thus, working memory capacity was improved on the behavioral level after the treatment, as we observed in our current study. fNIRS: Previous fNIRS studies on working memory reported frontal lobe activation. Thus, in our current study, we detected brain activation and analyzed the change in Oxy-Hb concentration of the PFC during n-back task blocks under pre- and post-ATX conditions. Based on the hemodynamic changes, high-level activations were found in CH 36 in medicated children, and enhanced trends were also found in CHs 5 and 7. CH 36 was located on the right PFC and consisted of BA10 (67%), BA 11 (20%), and BA46 (13%), which roughly corresponded with the frontopolar PFC (FPC), orbitofrontal cortex (OFC), and DLPFC, respectively [13] . In previous fNIRS studies, brain activation was detected in the right PFC of patients with ADHD after ATX treatment [8, 9] . Simultaneously, an EEG research suggested the greater participation of the right prefrontal areas in working memory similar to our findings. According to the study by Shin Jinhan et al., bilateral OFC and DLPFC will be activated in turn during WM tasks. The more obvious activation of right FPC in the present study and the above study may also be due to the higher proportion of right-handed children included. The FPC was the most obviously activated brain area in our study. According to a previous study, the FPC is the largest anterior region within the human PFC and plays a central role in high-order cognitive functions, including working memory, risk decision-making, rewards, and conflicts [57RP]. Anatomy studies indicated that human FPC consists of two cytoarchitectonically and functionally distinct areas, namely, lateral frontopolar area 1 (Fp1) and medial frontopolar area 2 (Fp2). Fp1 is involved in working memory, cognition, and perception, whereas Fp2 is involved in affective processing and social cognition [14] . The DLPFC also plays an important role in working memory. It is responsible for detecting, controlling, and organizing working memory content [15] . Our previous studies confirmed that the DLPFC shows a reduced activation in children with ADHD compared with the normal controls during the n-back task. Children with ADHD have defects in working memory and DLPFC [52CA]. In the current study, we found that DLPFC activation increased after ATX treatment, and the children’s working memory function improved. Thus, the normalization effect of ATX on the DLPFC activation and working memory was possibly confirmed. Imaging studies have shown that the FPC and DLPFC are adjacent to each other. A wide range of functional connections exists between them. They are both involved in the working memory process [16] , but the division of labor is functionally distinct [17] . A previous study confirmed that a brain network was activated in the working memory. The DLPFC plays a key role in the process, and FPC is recruited in complex multitask operations to achieve a higher-order control of goals [9, 18, 19] . In our study, the DLPFC and FPC were both activated during the task, which showed that children tried to achieve higher-order target control in the working memory test, and their working memory function significantly improved. The OFC is a region involved in emotion processing and decision making [20] , and it is critical to cognitive flexibility [21] . In a previous fMRI study, children with ADHD became normal-like only when a large-reward feedback was available in the n-back task. The OFC is associated with the functions of feedback and reward [22] and with obsessive-compulsive symptoms and various behavioral problems [23–25] . In our study, the scores of oppositional defiant and various behavioral problems decreased in the evaluation of the SNAP-IV and the Conners measuring scales, indicating that the OFC function improved after ATX treatment. Rating Scale: In the current study, by comparing the differences in scores between pre- and post- ATX conditions, we found that ATX could normalize the behavior of the children with ADHD. A significantly negative correlation was found between oxygenated hemoglobin concentration changes and total scores of the SNAP-IV scale. At the same time, the results showed that with increasing level of the oxygenated hemoglobin of PFC, the oppositional defiant and total scores of the SNAP-IV scale decreased, thereby suggesting that the fNIRS test results were consistent with the clinical results. The combination of fNIRS and SNAP-IV scale can provide an objective physiological index for the assessment of brain function in children with ADHD after ATX treatment. In a previous study, the researchers found a significantly negative correlation between oxygenated hemoglobin concentration and the scores of Conners scale; when children with ADHD performed the go–no go task, their PFC Oxy-Hb was negatively correlated with the scores of the Conners scale [26] . Perhaps due to the differences in psychological tasks and samples, our study only found a correlation between fNIRS and the SNAP-IV scale. The relationship between fNIRS and reasonable neuropsychological tests needs more experimental confirmation. Conclusion We monitored PFC activation through the fNIRS of children with ADHD before and after the administration of ATX. These children performed the n-back task. fNIRS was confirmed to be a helpful tool for identifying the effects of ATX on children, and its combination with SNAP-IV scale can provide an objective physiological index for evaluating the efficacy of ATX in children with ADHD. ATX can improve the core symptoms and executive function of children with ADHD. Abbreviations HbO: Oxygenated Hemoglobin Hb: Deoxygenated Hemoglobin GLM: General Linear Model RT: Reaction Time ACC: Accuracy MNI: Montreal Neurological Institute BA: Brodmann Area WM: Working Memory fMRI: functional Magnetic Resonance Imaging IFG: Inferior Frontal Gyrus MFG: Middle Frontal Gyrus EEG: Electroencephalographyeviations: Declarations Ethics approval and consent to participate The study was approved by the Ethics Committee of the Capital Center for Children’s Health, Capital Medical University. As all the participants were minors, written informed consents were collected from their guardians in accordance with the Declaration of Helsinki. Consent for publication All the authors have read and approved the final manuscript and consent to its publication. Availability of data and material The data supporting the findings of this study are available upon reasonable request from the corresponding author. Competing Interests All authors declare no conflicts of interest. Funding This work was supported by the National Natural Science Foundation of China (No. 82271579). Authors' contributions Ziqi Liu, Xinru Wu, Xiaoli Li and Jian Yang designed the study and developed the methodology. Xinru Wu, Yike Zhu, Jing Sun and Guannan Li collected the data. Ziqi Liu, Xinru Wu and Mengjiao Tao wrote the main manuscript text. Yue Gu performed the data analysis. Jian Yang, Xiaoli Li, Xin Wang and Jianzhao Zhang reviewed and edited the manuscript. Acknowledgements Not applicable. 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Efficacy of Methylphenidate Hydrochloride Sustained-release Tablets and Atomoxetine Hydrochloride on Symptoms and Executive Function in Children with Attention Deficit Hyperactivity Disorder [J]. Chinese Journal of Child Health Care, 2022, 30(12): 1291-6. HERNAUS D, CASALES SANTA M M, OFFERMANN J S, et al. Noradrenaline transporter blockade increases fronto-parietal functional connectivity relevant for working memory [J]. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, 2017, 27(4): 399-410. GRAF H, ABLER B, FREUDENMANN R, et al. Neural correlates of error monitoring modulated by atomoxetine in healthy volunteers [J]. Biol Psychiatry, 2011, 69(9): 890-7. KADUK K, HENRY T, GUITTON J, et al. Atomoxetine and reward size equally improve task engagement and perceptual decisions but differently affect movement execution [J]. Neuropharmacology, 2023, 241: 109736. OTA T, IIDA J, NAKANISHI Y, et al. Increased prefrontal hemodynamic change after atomoxetine administration in pediatric attention-deficit/hyperactivity disorder as measured by near-infrared spectroscopy [J]. Psychiatry and clinical neurosciences, 2015, 69(3): 161-70. INCE TASDELEN B, KARAKAYA E, OZTOP D B. Effects of Atomoxetine and Osmotic Release Oral System-Methylphenidate on Executive Functions in Patients with Combined Type Attention-Deficit/Hyperactivity Disorder [J]. J Child Adolesc Psychopharmacol, 2015, 25(6): 494-500. VAN STRALEN J P M. A Controlled Trial of Extended-Release Guanfacine and Psychostimulants on Executive Function and ADHD [J]. J Atten Disord, 2020, 24(2): 318-25. SCHULZ K P, CLERKIN S M, NEWCORN J H, et al. Guanfacine modulates the emotional biasing of amygdala-prefrontal connectivity for cognitive control [J]. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, 2014, 24(9): 1444-53. COULL J T, MIDDLETON H C, ROBBINS T W, et al. Contrasting effects of clonidine and diazepam on tests of working memory and planning [J]. Psychopharmacology, 1995, 120(3): 311-21. CHACKO A, BEDARD A V, MARKS D, et al. Sequenced neurocognitive and behavioral parent training for the treatment of ADHD in school-age children [J]. Child Neuropsychol, 2018, 24(4): 427-50. NG B, POLINE J B, THIRION B, et al. Bootstrapped Permutation Test for Multiresponse Inference on Brain Behavior Associations [J]. Information processing in medical imaging : proceedings of the conference, 2015, 24: 113-24. WESTWOOD S J, PARLATINI V, RUBIA K, et al. Computerized cognitive training in attention-deficit/hyperactivity disorder (ADHD): a meta-analysis of randomized controlled trials with blinded and objective outcomes [J]. Molecular psychiatry, 2023, 28(4): 1402-14. HINSHAW S P, HENKER B, WHALEN C K. Self-control in hyperactive boys in anger-inducing situations: effects of cognitive-behavioral training and of methylphenidate [J]. J Abnorm Child Psychol, 1984, 12(1): 55-77. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7627616","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":541421590,"identity":"364580d8-8a09-4bd8-bb12-8df4fedb92cf","order_by":0,"name":"Ziqi Liu","email":"","orcid":"","institution":"Capital Center for Children’s Health, Capital Medical University","correspondingAuthor":false,"prefix":"","firstName":"Ziqi","middleName":"","lastName":"Liu","suffix":""},{"id":541421592,"identity":"85df7489-f3a7-4d8f-a153-db5876820155","order_by":1,"name":"Xinru Wu","email":"","orcid":"","institution":"Capital Center for Children’s Health, 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1","display":"","copyAsset":false,"role":"figure","size":30980,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePerformance data associated with working memory during the n-back task.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7627616/v1/4dc7644ebf6c08a1fd183fd2.png"},{"id":95669212,"identity":"e45e8eca-a3f0-4d13-b188-365f3464bddd","added_by":"auto","created_at":"2025-11-11 17:09:41","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":170688,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe waveforms of oxy-HB in 52 channels under pre- and post-ATX conditions. The oxy-HB signals of pre-ATX is indicated in red. The oxy-HB signals of post-ATX is indicated in green.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7627616/v1/96f627f505e086b722664b61.png"},{"id":95799324,"identity":"ed33fe59-74c7-4616-be7a-0441f38dc25c","added_by":"auto","created_at":"2025-11-13 08:19:33","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":52827,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe waveforms of oxy-HB signals for CH 36. The oxy-HB signals of pre-ATX is indicated in red. The oxy-HB signals of post-ATX is indicated in green.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7627616/v1/93717b0c256d4a8033abc81f.png"},{"id":105432143,"identity":"d1201e2c-fe53-44b8-a739-60fd378754e9","added_by":"auto","created_at":"2026-03-26 02:41:16","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1733606,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7627616/v1/58e82ae2-15b3-4c72-80ef-66af22bf9329.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Effect of Atomoxetine Hydrochloride on Working Memory in Children with ADHD: A Functional Near-infrared Spectroscopy Study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAttention-deficit/hyperactivity disorder (ADHD) is one of the most commonly diagnosed neurodevelopmental disorders in children. It is characterized by inattention and hyperactivity and has a prevalence rate of around 3%\u0026ndash;5%\u003csup\u003e[1]\u003c/sup\u003e. The social function development of these children is affected, and the influence may persist into adolescence and adulthood. Previous studies have found that the core symptoms of ADHD are attributed to executive dysfunction, which are closely related to the function of the prefrontal cortex (PFC)\u003csup\u003e[2]\u003c/sup\u003e. Currently, executive dysfunction is usually assessed by neuropsychological testing. The evaluation of drug treatment effects is based on clinical observation and scale assessment. In recent years, the objective detection tool functional near-infrared spectroscopy (fNIRS) has been used to explore the effects of drug therapy on executive functions in children with ADHD\u003csup\u003e[3]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003efNIRS, a non-invasive optical imaging technique that measures cerebral hemodynamic changes associated with functional brain activity has become a promising tool for scientific research and clinical practice on ADHD, autism spectrum disorder, and epilepsy\u003csup\u003e[4]\u003c/sup\u003e. With its non-invasiveness, low noise, relative motion artifact tolerance, and high ecological validity, fNIRS is particularly suitable for investigating the executive functions of children with ADHD\u003csup\u003e[5]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eIn our previous study, reduced activation was shown in the left dorsolateral PFC (DLPFC) in children with ADHD during working memory task by using fNIRS.\u003c/p\u003e\u003cp\u003eThe combination of drug and behavioral therapies is a common ADHD treatment. The non-stimulant drug atomoxetine (ATX) and the stimulant drug methylphenidate (MPH) are recommended as the first line treatment for ADHD patients. MPH can improve the core symptoms of ADHD effectively and rapidly. MPH\u0026rsquo;s common adverse reactions include headache, insomnia, and loss of appetite. Moreover, MPH poses the risk of addiction. ATX is a selective NA reuptake inhibitor that usually takes 4 to 5 weeks to show maximum effect\u003csup\u003e[6]\u003c/sup\u003e. Its adverse reactions are similar to MPH except for the risk of addiction. Based on previous research, the mechanism of drug therapy to improve the working memory function in children with ADHD is still unclear. Therefore, in this current study, the effect of the non-addictive drug ATX on the working memory function of children with ADHD was determined. To provide objective evidence for the improvement of ADHD children before and after intervention.\u003c/p\u003e\u003cp\u003eCurrently, fNIRS studies on the effects of drug therapy can be broadly divided into two categories, namely, acute and long-term neuropharmacological effects on the brain function of children with ADHD. In the acute efficacy test, according to the time of rapid onset of the drug, the investigator monitored the oxygenated hemoglobin signal changes of children with ADHD who were performing some cognitive tasks before and 1.5 h after drug therapy. Advantageously, children who are not sensitive to the drug can change the treatment plan in time, because assessment can be completed in a single-day hospital visit\u003csup\u003e[7]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eIn the other type (long-term fNIRS), the investigator monitors the oxygenated hemoglobin signal changes of ADHD children before and more than a few weeks or even half a year after drug therapy to evaluate the brain function changes of the children after long-term treatment. This type of test may provide more objective evidence for the evaluation of drug efficacy than the other type\u003csup\u003e[8]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eIn previous studies, the results of the acute efficacy tests were approximately consistent. The cognitive task recruited the right inferior and middle prefrontal gyri (IFG/MFG) after 1.5 h of ATX/MPH treatment in some studies, and this activation was absent in pre-medicated and placebo-administered children with ADHD\u003csup\u003e[9]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eHowever, the results of chronic efficacy tests varied widely. Some studies obtained similar results as those in the acute efficacy test, which showed increased activation in the right PFC after treatment. However, in several trials, the weakening activation of the left ventrolateral prefrontal lobe disappeared. Conversely, the decreased activation of PFC was found in children after medication in some studies. Moreover, some researchers detected increased brain activation in the PFC of children with ADHD during Working Memory (WM) task in simple mode, but decreased activation was found in hard mode\u003csup\u003e[2]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eThe present study aimed to explore the long-term effects of ATX on brain function during working memory task by using fNIRS. We assumed that brain activity in the PFC will be altered after medication.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n \u003ch2\u003eSubjects:\u003c/h2\u003e\n \u003cp\u003eThe study was approved by the Ethics Committee of the Capital Center for Children\u0026rsquo;s Health, Capital Medical University. As all the participants were minors, written informed consents were collected from their guardians in accordance with the Declaration of Helsinki.\u003c/p\u003e\n \u003cp\u003eFourteen patients with ADHD (6\u0026ndash;12 years old) were recruited from the Children\u0026rsquo;s Hospital Affiliated to Capital Institute of Pediatrics. All participants met the DSM-V diagnostic criteria for ADHD. Drug-naive individuals who were righthanded were included in the test group.\u003c/p\u003e\n \u003cp\u003eIQ was evaluated using the Chinese version of the Wechsler Intelligence Scale for Children-Revised, and the IQ scores of the participants were \u0026ge;\u0026thinsp;70. Furthermore, all patients have attended school and have the required knowledge to participate in the test.\u003c/p\u003e\n \u003cp\u003eExclusion criteria for all subjects included history of ADHD medication, developmental delay, head trauma or seizure, and diagnosis of a neurological disorder, genetic disorder, or any other physical disorder.\u003c/p\u003e\n \u003cp\u003eWritten consent was obtained from the subjects who were over 8 years old and from the parents of all participants. This study was approved by the Ethics Committee of Children\u0026rsquo;s Hospital Affiliated to Capital Institute of Pediatrics.\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eTable A: Demographic and clinical profiles for subjects\u003c/strong\u003e\u003c/p\u003e\n \u003ctable id=\"Taba\" border=\"1\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eID\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSEX\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAGE(years)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003emale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003emale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003emale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003emale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003efemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003emale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003emale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003emale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003emale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003emale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003emale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003emale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003emale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003efemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8.29\u0026thinsp;\u0026plusmn;\u0026thinsp;2.09\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003ch3\u003eExperimental design:\u003c/h3\u003e\n\u003cp\u003eWe examined ADHD subjects twice to investigate the effect of ATX on the activation of the PFC in children with ADHD during the n-back task. Functional blood oxygen level was recorded by using fNIRS. Clinical symptoms were assessed by parent\u0026rsquo;s Swanson, Nolan, and Pelham-IV rating scale (SNAP-IV) and Conners measuring scale (parent symptom questionnaire, PSQ) at the same time. After the initial data collection, the subjects were administered an ATX dose of 0.5 mg/kg/d in the first week and then 1.2 mg/kg/d for 7 weeks. The children were re-evaluated by fNIRS, SNAP-IV, and Conners in the second visit after 8 weeks of medication.\u003c/p\u003e\n\u003ch3\u003eExperimental Task:\u003c/h3\u003e\n\u003cp\u003eThe n-back task was generated by E-Prime2.0 and presented in a 17\u0026rsquo;\u0026rsquo; desktop computer screen. The distance between the children\u0026rsquo; eyes and the screen was \u0026sim;50 cm. The block-designed task consisted of block sets, and each set comprised the baseline acquisition and n-back task. The entire task lasted for 360 s. A 30 s baseline acquisition period preceded the n-back task segment. The n-back task incorporated alternating 0- and 1-back tasks. Each of the two tasks was conducted thrice. Every task block contained 15 trials, which consisted of single pseudo-random digits (0\u0026ndash;9). Each digit was presented for 500 ms, followed by an interstimulus interval of 1500 ms. The alternating tasks were separated by 30 s resting segments.\u003c/p\u003e\u003cp\u003eFor the 0-back condition, the participants were instructed to press the button \"\u0026radic;\" whenever a digit that appeared on the computer screen in front of them was identical to the target digit. Otherwise, they were instructed to press the button \u0026ldquo;X.\u0026rdquo;\u003c/p\u003e\u003cp\u003eFor the 1-back condition, the participants were instructed to press the button \u0026ldquo;\u0026radic;\u0026rdquo; whenever the presented digit was identical to the preceding one. Otherwise, they were instructed to press the button \u0026ldquo;X\u0026rdquo;. The participants were instructed to press the \u0026ldquo;\u0026radic;\u0026rdquo; and \u0026ldquo;X\u0026rdquo; buttons using the index and middle fingers of the right hand, respectively.\u003c/p\u003e\u003cp\u003eThe environment was quiet, clean, and comfortable to ensure that the subjects remained relaxed during the test. Each participant performed a practice block before any measurement to ensure that the instructions were understood. Under the conditions, the subjects were instructed to respond to each trial as quickly as possible.\u003c/p\u003e\u003cp\u003eThe reaction time (RT), accuracy (ACC), commission error, and omission error for the trials were recorded.\u003c/p\u003e\n\u003ch3\u003efNIRS Measurements:\u003c/h3\u003e\n\u003cp\u003eWe used the continuous multichannel fNIRS system ETG-4000 (Hitachi Medical Corporation, Kashiwa, Japan) to measure relative concentration changes in oxygenated hemoglobin (HbO) and deoxygenated hemoglobin (Hb). This instrument worked with two different wavelengths of near-infrared light (695 and 830 nm), and the sampling frequency was 10 Hz. We used a set of 3 \u0026times; 11 multichannel probe holder that consisted of 17 emitters and 16 detectors arranged alternately at an inter-probe distance of 3 cm. The midpoint of a pair of emitter and detector was defined as the channel (CH) location. These emitter and detector formed 52 measurement CHs. The probe holder was positioned on the head with regard to the relevant standard positions of the international 10\u0026ndash;20 system for EEG electrode placement. The middle inferior optode was placed over Fpz, and the inferior row of optodes was oriented in the direction of T3 or T4.\u003c/p\u003e\n\u003ch3\u003eAnalysis of fNIRS Data:\u003c/h3\u003e\n\u003cp\u003eThe relative concentration changes in HbO and Hb were analyzed based on the modified Beer\u0026ndash;Lambert Law. HbO is more sensitive to regional cerebral blood flow than Hb, and it has higher signal-to-noise ratio and retest reliability. Thus, we only focused on HbO data in the subsequent analysis.\u003c/p\u003e\u003cp\u003eHBO was analyzed using the general linear model (GLM) to identify cortical regions significantly associated with stimuli given the task. The GLM model models the measured brain response as the sum of the predictable response due to the stimulus and the noise part.\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eStatistical Analysis:\u003c/h2\u003e\u003cp\u003eThe oxy-HB signals were analyzed statistically in a channel-wise manner. For the subjects, we generated the following contrasts. First, for the pre-medication contrast, we examined the difference between changes in oxy-HB peak and baseline using one sample t-test. Second, for the intra-medication contrast, we examined the difference between post- and pre-ATX medication contrasts in oxy-HB peak using a paired t-test with a statistical threshold of \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 to identify the CHs involved in the n-back task. Then, we performed statistical analysis on the behavioral therapeutic data for subjects during n-back task. To assess the medication effects on behavioral and therapeutic performances, we performed paired t-tests with a statistical threshold of \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 to compare the conditions after and before ATX treatment in terms of reaction time, accuracy, omission error, commission error, SNAP-IV, and Conners data. In addition, to determine whether a correlation existed between hemoglobin concentration and therapeutic data, we performed Kendall correlation analysis on hemoglobin concentration variation and the scores of SNAP-IV and Conners data.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\n \u003ch2\u003eBehavioral Performance:\u003c/h2\u003e\n \u003cp\u003eFour indices were statistically analyzed in the behavior data during the n-back task. Table B summarizes the average accuracy, reaction time, commission errors, and omission errors for pre- and post- ATX conditions during the n-back task. The results of t-test showed significantly higher accuracy and lower omission error during the n-back task after ATX treatment. A downtrend was found in the reaction time and commission errors in the post-ATX condition.\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eTable B and Fig. 1: Performance data associated with working memory during the n-back task.\u003c/strong\u003e\u003c/p\u003e\n \u003ctable id=\"Tabb\" border=\"1\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePerformance\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003epre-ATX (Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003epost-ATX (Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eACC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8.564\u0026thinsp;\u0026plusmn;\u0026thinsp;3.581\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e11.872\u0026thinsp;\u0026plusmn;\u0026thinsp;1.068\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e992.646\u0026thinsp;\u0026plusmn;\u0026thinsp;219.144\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e948.286\u0026thinsp;\u0026plusmn;\u0026thinsp;216.177\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.414\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOmission Error\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.795\u0026thinsp;\u0026plusmn;\u0026thinsp;3.041\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.436\u0026thinsp;\u0026plusmn;\u0026thinsp;0.629\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.012\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCommission Error\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.641\u0026thinsp;\u0026plusmn;\u0026thinsp;2.030\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.692\u0026thinsp;\u0026plusmn;\u0026thinsp;0.687\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.127\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n \u003ch2\u003efNIRS:\u003c/h2\u003e\n \u003cp\u003eWe screened for the fNIRS CHs that were involved in the n-back task. The hemodynamic changes between pre-ATX and post-ATX conditions suggested that high-level activations in CH 36 (mean = -0.006,0.096, SD\u0026thinsp;=\u0026thinsp;0.089,0.105, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.009) were found in subjects under post-ATX conditions. This CH was in right medial PFC containing part of frontopolar PFC (FPC), DLPFC, and orbitofrontal cortex (OFC). Enhanced trends were also found in CHs 5 and 7. Figure \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e is the waveform of the oxy-HB signals for CH 36. This finding indicated that the subjects under post-ATX conditions exhibited higher right FPC, DLPFC, and OFC activation during n-back task.\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eTable C: Oxy-Hb concentration and\u003c/strong\u003e \u003cstrong\u003ep\u003c/strong\u003e\u003cstrong\u003e-value of 52 channels under pre- and post-ATX conditions\u003c/strong\u003e\u003c/p\u003e\n \u003ctable id=\"Tabc\" border=\"1\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eChannel\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePre-ATX\u003c/p\u003e\n \u003cp\u003e(Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePost-ATX\u003c/p\u003e\n \u003cp\u003e(Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eChannel\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePre-ATX\u003c/p\u003e\n \u003cp\u003e(Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePost-ATX\u003c/p\u003e\n \u003cp\u003e(Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.027\u0026thinsp;\u0026plusmn;\u0026thinsp;0.113\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.016\u0026thinsp;\u0026plusmn;\u0026thinsp;0.141\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.782\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.014\u0026thinsp;\u0026plusmn;\u0026thinsp;0.037\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.025\u0026thinsp;\u0026plusmn;\u0026thinsp;0.076\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.200\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.016\u0026thinsp;\u0026plusmn;\u0026thinsp;0.091\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.011\u0026thinsp;\u0026plusmn;\u0026thinsp;0.155\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.919\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.005\u0026thinsp;\u0026plusmn;\u0026thinsp;0.060\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.031\u0026thinsp;\u0026plusmn;\u0026thinsp;0.080\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.316\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.074\u0026thinsp;\u0026plusmn;\u0026thinsp;0.118\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.052\u0026thinsp;\u0026plusmn;\u0026thinsp;0.131\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.515\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.013\u0026thinsp;\u0026plusmn;\u0026thinsp;0.081\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.009\u0026thinsp;\u0026plusmn;\u0026thinsp;0.130\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.924\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.038\u0026thinsp;\u0026plusmn;\u0026thinsp;0.073\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.054\u0026thinsp;\u0026plusmn;\u0026thinsp;0.083\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.595\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.011\u0026thinsp;\u0026plusmn;\u0026thinsp;0.121\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.029\u0026thinsp;\u0026plusmn;\u0026thinsp;0.144\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.517\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.002\u0026thinsp;\u0026plusmn;\u0026thinsp;0.084\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.053\u0026thinsp;\u0026plusmn;\u0026thinsp;0.092\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.076\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.024\u0026thinsp;\u0026plusmn;\u0026thinsp;0.086\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.015\u0026thinsp;\u0026plusmn;\u0026thinsp;0.143\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.494\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.029\u0026thinsp;\u0026plusmn;\u0026thinsp;0.091\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.003\u0026thinsp;\u0026plusmn;\u0026thinsp;0.057\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.427\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.019\u0026thinsp;\u0026plusmn;\u0026thinsp;0.105\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.014\u0026thinsp;\u0026plusmn;\u0026thinsp;0.141\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.940\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.009\u0026thinsp;\u0026plusmn;\u0026thinsp;0.072\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.063\u0026thinsp;\u0026plusmn;\u0026thinsp;0.091\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.002\u0026thinsp;\u0026plusmn;\u0026thinsp;0.153\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.037\u0026thinsp;\u0026plusmn;\u0026thinsp;0.149\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.640\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.017\u0026thinsp;\u0026plusmn;\u0026thinsp;0.077\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.032\u0026thinsp;\u0026plusmn;\u0026thinsp;0.091\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.145\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.025\u0026thinsp;\u0026plusmn;\u0026thinsp;0.117\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.010\u0026thinsp;\u0026plusmn;\u0026thinsp;0.130\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.815\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.001\u0026thinsp;\u0026plusmn;\u0026thinsp;0.103\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.036\u0026thinsp;\u0026plusmn;\u0026thinsp;0.126\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.344\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.040\u0026thinsp;\u0026plusmn;\u0026thinsp;0.110\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.054\u0026thinsp;\u0026plusmn;\u0026thinsp;0.096\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.733\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.017\u0026thinsp;\u0026plusmn;\u0026thinsp;0.104\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.007\u0026thinsp;\u0026plusmn;\u0026thinsp;0.146\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.621\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.006\u0026thinsp;\u0026plusmn;\u0026thinsp;0.089\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.096\u0026thinsp;\u0026plusmn;\u0026thinsp;0.105\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.009\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.017\u0026thinsp;\u0026plusmn;\u0026thinsp;0.182\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.068\u0026thinsp;\u0026plusmn;\u0026thinsp;0.106\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.165\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.028\u0026thinsp;\u0026plusmn;\u0026thinsp;0.114\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.026\u0026thinsp;\u0026plusmn;\u0026thinsp;0.124\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.961\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.035\u0026thinsp;\u0026plusmn;\u0026thinsp;0.114\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.012\u0026thinsp;\u0026plusmn;\u0026thinsp;0.145\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.364\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.007\u0026thinsp;\u0026plusmn;\u0026thinsp;0.136\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.065\u0026thinsp;\u0026plusmn;\u0026thinsp;0.169\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.403\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.054\u0026thinsp;\u0026plusmn;\u0026thinsp;0.146\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.051\u0026thinsp;\u0026plusmn;\u0026thinsp;0.152\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.952\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.065\u0026thinsp;\u0026plusmn;\u0026thinsp;0.113\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.049\u0026thinsp;\u0026plusmn;\u0026thinsp;0.135\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.789\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.044\u0026thinsp;\u0026plusmn;\u0026thinsp;0.067\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.033\u0026thinsp;\u0026plusmn;\u0026thinsp;0.102\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.750\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.021\u0026thinsp;\u0026plusmn;\u0026thinsp;0.167\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.071\u0026thinsp;\u0026plusmn;\u0026thinsp;0.103\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.491\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.004\u0026thinsp;\u0026plusmn;\u0026thinsp;0.054\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.029\u0026thinsp;\u0026plusmn;\u0026thinsp;0.062\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.184\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.002\u0026thinsp;\u0026plusmn;\u0026thinsp;0.135\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.013\u0026thinsp;\u0026plusmn;\u0026thinsp;0.160\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.884\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.019\u0026thinsp;\u0026plusmn;\u0026thinsp;0.069\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.026\u0026thinsp;\u0026plusmn;\u0026thinsp;0.069\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.171\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.010\u0026thinsp;\u0026plusmn;\u0026thinsp;0.144\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.043\u0026thinsp;\u0026plusmn;\u0026thinsp;0.113\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.531\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.028\u0026thinsp;\u0026plusmn;\u0026thinsp;0.096\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.039\u0026thinsp;\u0026plusmn;\u0026thinsp;0.099\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.192\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.046\u0026thinsp;\u0026plusmn;\u0026thinsp;0.169\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.009\u0026thinsp;\u0026plusmn;\u0026thinsp;0.147\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.538\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.009\u0026thinsp;\u0026plusmn;\u0026thinsp;0.071\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.020\u0026thinsp;\u0026plusmn;\u0026thinsp;0.082\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.363\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.017\u0026thinsp;\u0026plusmn;\u0026thinsp;0.196\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.009\u0026thinsp;\u0026plusmn;\u0026thinsp;0.138\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.915\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.040\u0026thinsp;\u0026plusmn;\u0026thinsp;0.099\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.004\u0026thinsp;\u0026plusmn;\u0026thinsp;0.080\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.335\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.012\u0026thinsp;\u0026plusmn;\u0026thinsp;0.112\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.025\u0026thinsp;\u0026plusmn;\u0026thinsp;0.098\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.821\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.009\u0026thinsp;\u0026plusmn;\u0026thinsp;0.092\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.006\u0026thinsp;\u0026plusmn;\u0026thinsp;0.153\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.946\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.000\u0026thinsp;\u0026plusmn;\u0026thinsp;0.127\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.001\u0026thinsp;\u0026plusmn;\u0026thinsp;0.122\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.988\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.012\u0026thinsp;\u0026plusmn;\u0026thinsp;0.106\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.001\u0026thinsp;\u0026plusmn;\u0026thinsp;0.084\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.700\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.012\u0026thinsp;\u0026plusmn;\u0026thinsp;0.124\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.042\u0026thinsp;\u0026plusmn;\u0026thinsp;0.139\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.445\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.036\u0026thinsp;\u0026plusmn;\u0026thinsp;0.061\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.034\u0026thinsp;\u0026plusmn;\u0026thinsp;0.163\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.978\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.019\u0026thinsp;\u0026plusmn;\u0026thinsp;0.116\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.048\u0026thinsp;\u0026plusmn;\u0026thinsp;0.141\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.228\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.015\u0026thinsp;\u0026plusmn;\u0026thinsp;0.180\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.024\u0026thinsp;\u0026plusmn;\u0026thinsp;0.222\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.913\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.020\u0026thinsp;\u0026plusmn;\u0026thinsp;0.140\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.024\u0026thinsp;\u0026plusmn;\u0026thinsp;0.166\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.952\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.059\u0026thinsp;\u0026plusmn;\u0026thinsp;0.093\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.022\u0026thinsp;\u0026plusmn;\u0026thinsp;0.108\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.342\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.007\u0026thinsp;\u0026plusmn;\u0026thinsp;0.103\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.019\u0026thinsp;\u0026plusmn;\u0026thinsp;0.168\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.704\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.040\u0026thinsp;\u0026plusmn;\u0026thinsp;0.058\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.041\u0026thinsp;\u0026plusmn;\u0026thinsp;0.093\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.980\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.006\u0026thinsp;\u0026plusmn;\u0026thinsp;0.152\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.007\u0026thinsp;\u0026plusmn;\u0026thinsp;0.163\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.883\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.007\u0026thinsp;\u0026plusmn;\u0026thinsp;0.062\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.023\u0026thinsp;\u0026plusmn;\u0026thinsp;0.095\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.279\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.017\u0026thinsp;\u0026plusmn;\u0026thinsp;0.141\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.010\u0026thinsp;\u0026plusmn;\u0026thinsp;0.107\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.911\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cdiv align=\"char\" class=\"colspec\"\u003e\u003cstrong\u003eTable D: Activated channels with MNI coordinates and Brodmann area partition\u003c/strong\u003e\u003c/div\u003e\n \u003ctable id=\"Tabd\" border=\"1\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eChannel\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"4\"\u003e\n \u003cp\u003eMean\u0026nbsp;MNI\u0026nbsp;coordinates\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eBrodmann\u0026nbsp;area\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eZ\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSD\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCH36\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e25.6\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e65.5\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e11.2\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e4.9\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e10 (67%), 11 (20%), 46 (13%)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eCH5\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e10.3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e50.1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e46.8\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e7.3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e9 (80%), 8 (13%), 10 (7%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eCH7\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e-29.1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e38.3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e46.4\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e5.2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e8(7%)、9(80%)、46(13%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n \u003ch2\u003eRating-Scale Scores:\u003c/h2\u003e\n \u003cp\u003eFour indices were statistically analyzed in the SNAP-IV rating scale. Subjects under post-ATX conditions showed relatively low inattention scores, hyperactivity scores, oppositional defiant scores, and total scores in the paired t-test. These values were statistically and significantly different (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05). The core symptoms of the subjects were alleviated after the treatment.\u003c/p\u003e\n \u003cp\u003eIn the Conners measuring scale, subjects under post-ATX conditions showed lower conduct problem scores, learning problem scores, hyperactivity-impulsivity scores, and hyperactivity index using paired t-test with a statistical threshold of \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 that those under pre-ATX conditions. No significant improvement was observed in the anxiety and mind body problem scores. In general, the behavior problems of subjects under post-ATX conditions were alleviated to some extent. Tables E and F summarize the results.\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003cdiv align=\"char\" class=\"colspec\"\u003e\u003cstrong\u003eTable E: the scores and\u003c/strong\u003e \u003cstrong\u003ep\u003c/strong\u003e\u003cstrong\u003e-values of SNAP-IV scale under pre- and post-ATX conditions\u003c/strong\u003e\u003c/div\u003e\n \u003cdiv align=\"char\" class=\"colspec\"\u003e\u003cbr\u003e\u003c/div\u003e\u003cbr\u003e\n \u003ctable id=\"Tabe\" border=\"1\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSNAP-IV\u003c/p\u003e\n \u003cp\u003escale\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePre-ATX\u003c/p\u003e\n \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePost-ATX\u003c/p\u003e\n \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003et\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ehyperactivity scores\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e20.64\u0026thinsp;\u0026plusmn;\u0026thinsp;4.37\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e14.36\u0026thinsp;\u0026plusmn;\u0026thinsp;4.48\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e5.84\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003einattention scores\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e16.71\u0026thinsp;\u0026plusmn;\u0026thinsp;6.85\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e12.07\u0026thinsp;\u0026plusmn;\u0026thinsp;5.98\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e3.67\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.003\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eoppositional defiant scores\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e12.00\u0026thinsp;\u0026plusmn;\u0026thinsp;5.95\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e9.07\u0026thinsp;\u0026plusmn;\u0026thinsp;5.73\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e2.58\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.023\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003etotal scores\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e49.35\u0026thinsp;\u0026plusmn;\u0026thinsp;15.59\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e35.50\u0026thinsp;\u0026plusmn;\u0026thinsp;13.51\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e5.42\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003cdiv align=\"char\" class=\"colspec\"\u003e\u003cbr\u003e\u003c/div\u003e\n \u003cdiv align=\"left\" class=\"colspec\"\u003e\u003cstrong\u003eTable F: the scores and\u003c/strong\u003e \u003cstrong\u003ep\u003c/strong\u003e\u003cstrong\u003e-value of Conners scale under pre- and post-ATX conditions\u003c/strong\u003e\u003c/div\u003e\n \u003cdiv align=\"char\" class=\"colspec\"\u003e\u003cbr\u003e\u003c/div\u003e\n \u003ctable id=\"Tabf\" border=\"1\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eConners measuring scale\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePre-ATX\u003c/p\u003e\n \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePost-ATX\u003c/p\u003e\n \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003et\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eConduct problem scores\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e15.07\u0026thinsp;\u0026plusmn;\u0026thinsp;8.00\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e10.29\u0026thinsp;\u0026plusmn;\u0026thinsp;7.22\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e6.20\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLearning problem scores\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e8.71\u0026thinsp;\u0026plusmn;\u0026thinsp;1.94\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e6.43\u0026thinsp;\u0026plusmn;\u0026thinsp;1.99\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e3.66\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.003\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAnxiety scores\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e2.86\u0026thinsp;\u0026plusmn;\u0026thinsp;2.11\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e2.79\u0026thinsp;\u0026plusmn;\u0026thinsp;1.93\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.19\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.856\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHyperactivity-impulsivity scores\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e7.07\u0026thinsp;\u0026plusmn;\u0026thinsp;2.56\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e5.36\u0026thinsp;\u0026plusmn;\u0026thinsp;2.82\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e4.16\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHyperactivity index\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e17.57\u0026thinsp;\u0026plusmn;\u0026thinsp;6.43\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e12.43\u0026thinsp;\u0026plusmn;\u0026thinsp;5.39\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e4.60\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMind body problem scores\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.64\u0026thinsp;\u0026plusmn;\u0026thinsp;1.95\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.50\u0026thinsp;\u0026plusmn;\u0026thinsp;1.69\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eThe data didn\u0026lsquo;t conform to the normal distribution therefore we conducted a rank sum test on it.\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.672\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003eTo determine whether a correlation existed between hemoglobin concentration and therapeutic data, we performed Kendall correlation analysis on hemoglobin concentration variation and scores of the two abovementioned scales. A significantly negative correlation existed between oxygenated hemoglobin concentration changes and both the oppositional defiant and total scores of SNAP-IV scale(K=-0.580, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.005). Thus, as the oxygenated hemoglobin of PFC increased, the oppositional defiant and total scores of the SNAP-IV scale decreased.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study aimed to investigate the effect of atomoxetine hydrochloride (ATX) on the activation of the PFC in children with ADHD during a working memory task. Compared with the children under pre-ATX conditions, children under post-ATX conditions exhibited increased brain activation in the right PFC, including FPC, DLPFC, and OFC during the n-back task blocks. A significantly negative correlation was found between oxygenated hemoglobin concentration and the scores of the SNAP-IV scale. fNIRS is a helpful tool for identifying the effects of ATX on children, and its combination with SNAP-IV scale can provide an objective physiological index for evaluating the efficacy of ATX in children with ADHD༎\u003c/p\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003eBehavioral Performance for N-back Task:\u003c/h2\u003e\u003cp\u003eBehavioral performance can reflect specific cognitive capacity. This study used the n-back task as an assessment tool to measure children's working memory capacity on the behavioral level. This tool has been commonly used in many cognitive studies on ADHD. In our study, average accuracy and omission error significantly differed between pre- and post-ATX conditions, and downtrends were also found in reaction time and commission errors in the latter. A normalization effect was found on behavioral performance in the post-ATX condition. In previous studies on n-back test with ADHD, working memory deficits on the behavioral level have been generally confirmed\u003csup\u003e[10, 11]\u003c/sup\u003e. Some scholars found that post-MPH patients performed similar to healthy controls and significantly better than patients who did not receive medication in the n-back test on the behavioral level\u003csup\u003e[12]\u003c/sup\u003e. Thus, working memory capacity was improved on the behavioral level after the treatment, as we observed in our current study.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003efNIRS:\u003c/h2\u003e\u003cp\u003ePrevious fNIRS studies on working memory reported frontal lobe activation. Thus, in our current study, we detected brain activation and analyzed the change in Oxy-Hb concentration of the PFC during n-back task blocks under pre- and post-ATX conditions. Based on the hemodynamic changes, high-level activations were found in CH 36 in medicated children, and enhanced trends were also found in CHs 5 and 7. CH 36 was located on the right PFC and consisted of BA10 (67%), BA 11 (20%), and BA46 (13%), which roughly corresponded with the frontopolar PFC (FPC), orbitofrontal cortex (OFC), and DLPFC, respectively\u003csup\u003e[13]\u003c/sup\u003e. In previous fNIRS studies, brain activation was detected in the right PFC of patients with ADHD after ATX treatment\u003csup\u003e[8, 9]\u003c/sup\u003e. Simultaneously, an EEG research suggested the greater participation of the right prefrontal areas in working memory similar to our findings. According to the study by Shin Jinhan et al., bilateral OFC and DLPFC will be activated in turn during WM tasks. The more obvious activation of right FPC in the present study and the above study may also be due to the higher proportion of right-handed children included.\u003c/p\u003e\u003cp\u003eThe FPC was the most obviously activated brain area in our study. According to a previous study, the FPC is the largest anterior region within the human PFC and plays a central role in high-order cognitive functions, including working memory, risk decision-making, rewards, and conflicts [57RP]. Anatomy studies indicated that human FPC consists of two cytoarchitectonically and functionally distinct areas, namely, lateral frontopolar area 1 (Fp1) and medial frontopolar area 2 (Fp2). Fp1 is involved in working memory, cognition, and perception, whereas Fp2 is involved in affective processing and social cognition\u003csup\u003e[14]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eThe DLPFC also plays an important role in working memory. It is responsible for detecting, controlling, and organizing working memory content\u003csup\u003e[15]\u003c/sup\u003e. Our previous studies confirmed that the DLPFC shows a reduced activation in children with ADHD compared with the normal controls during the n-back task. Children with ADHD have defects in working memory and DLPFC [52CA]. In the current study, we found that DLPFC activation increased after ATX treatment, and the children\u0026rsquo;s working memory function improved. Thus, the normalization effect of ATX on the DLPFC activation and working memory was possibly confirmed.\u003c/p\u003e\u003cp\u003eImaging studies have shown that the FPC and DLPFC are adjacent to each other. A wide range of functional connections exists between them. They are both involved in the working memory process\u003csup\u003e[16]\u003c/sup\u003e, but the division of labor is functionally distinct\u003csup\u003e[17]\u003c/sup\u003e. A previous study confirmed that a brain network was activated in the working memory. The DLPFC plays a key role in the process, and FPC is recruited in complex multitask operations to achieve a higher-order control of goals\u003csup\u003e[9, 18, 19]\u003c/sup\u003e. In our study, the DLPFC and FPC were both activated during the task, which showed that children tried to achieve higher-order target control in the working memory test, and their working memory function significantly improved.\u003c/p\u003e\u003cp\u003eThe OFC is a region involved in emotion processing and decision making\u003csup\u003e[20]\u003c/sup\u003e, and it is critical to cognitive flexibility\u003csup\u003e[21]\u003c/sup\u003e. In a previous fMRI study, children with ADHD became normal-like only when a large-reward feedback was available in the n-back task. The OFC is associated with the functions of feedback and reward\u003csup\u003e[22]\u003c/sup\u003e and with obsessive-compulsive symptoms and various behavioral problems\u003csup\u003e[23\u0026ndash;25]\u003c/sup\u003e. In our study, the scores of oppositional defiant and various behavioral problems decreased in the evaluation of the SNAP-IV and the Conners measuring scales, indicating that the OFC function improved after ATX treatment.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\u003ch2\u003eRating Scale:\u003c/h2\u003e\u003cp\u003eIn the current study, by comparing the differences in scores between pre- and post- ATX conditions, we found that ATX could normalize the behavior of the children with ADHD. A significantly negative correlation was found between oxygenated hemoglobin concentration changes and total scores of the SNAP-IV scale. At the same time, the results showed that with increasing level of the oxygenated hemoglobin of PFC, the oppositional defiant and total scores of the SNAP-IV scale decreased, thereby suggesting that the fNIRS test results were consistent with the clinical results. The combination of fNIRS and SNAP-IV scale can provide an objective physiological index for the assessment of brain function in children with ADHD after ATX treatment.\u003c/p\u003e\u003cp\u003eIn a previous study, the researchers found a significantly negative correlation between oxygenated hemoglobin concentration and the scores of Conners scale; when children with ADHD performed the go\u0026ndash;no go task, their PFC Oxy-Hb was negatively correlated with the scores of the Conners scale\u003csup\u003e[26]\u003c/sup\u003e. Perhaps due to the differences in psychological tasks and samples, our study only found a correlation between fNIRS and the SNAP-IV scale. The relationship between fNIRS and reasonable neuropsychological tests needs more experimental confirmation.\u003c/p\u003e\u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eWe monitored PFC activation through the fNIRS of children with ADHD before and after the administration of ATX. These children performed the n-back task. fNIRS was confirmed to be a helpful tool for identifying the effects of ATX on children, and its combination with SNAP-IV scale can provide an objective physiological index for evaluating the efficacy of ATX in children with ADHD. ATX can improve the core symptoms and executive function of children with ADHD.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e\u003cstrong\u003eHbO:\u0026nbsp;\u003c/strong\u003eOxygenated Hemoglobin\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHb:\u0026nbsp;\u003c/strong\u003eDeoxygenated Hemoglobin\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGLM:\u0026nbsp;\u003c/strong\u003eGeneral Linear Model\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRT:\u0026nbsp;\u003c/strong\u003eReaction Time\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eACC:\u0026nbsp;\u003c/strong\u003eAccuracy\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMNI:\u003c/strong\u003e Montreal Neurological Institute\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBA:\u003c/strong\u003e Brodmann Area\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWM:\u0026nbsp;\u003c/strong\u003eWorking Memory\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003efMRI:\u003c/strong\u003e functional Magnetic Resonance Imaging\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIFG:\u003c/strong\u003e Inferior Frontal Gyrus\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMFG:\u0026nbsp;\u003c/strong\u003eMiddle Frontal Gyrus\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEEG:\u003c/strong\u003e Electroencephalographyeviations:\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was approved by the Ethics Committee of the Capital Center for Children\u0026rsquo;s Health, Capital Medical University. As all the participants were minors, written informed consents were collected from their guardians in accordance with the Declaration of Helsinki.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll the authors have read and approved the final manuscript and consent to its publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data supporting the findings of this study are available upon reasonable request from the corresponding author.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors declare no conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the National Natural Science Foundation of China (No. 82271579).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eZiqi Liu, Xinru Wu, Xiaoli Li and Jian Yang designed the study and developed the methodology. Xinru Wu, Yike Zhu, Jing Sun and Guannan Li collected the data. Ziqi Liu, Xinru Wu and Mengjiao Tao wrote the main manuscript text. Yue Gu performed the data analysis. Jian Yang, Xiaoli Li, Xin Wang and Jianzhao Zhang reviewed and edited the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eRAJAPRAKASH M, LEPPERT M L. Attention-Deficit/Hyperactivity Disorder [J]. Pediatrics in review, 2022, 43(3): 135-47.\u003c/li\u003e\n\u003cli\u003eLI F, CUI Y, LI Y, et al. Prevalence of mental disorders in school children and adolescents in China: diagnostic data from detailed clinical assessments of 17,524 individuals [J]. J Child Psychol Psychiatry, 2022, 63(1): 34-46.\u003c/li\u003e\n\u003cli\u003eLU T, LI L, TANG Y, et al. ADHD and family life: A cross-sectional study of ADHD prevalence among pupils in China and factors associated with parental depression [J]. PLoS One, 2024, 19(3): e0281226.\u003c/li\u003e\n\u003cli\u003ePEISCH V, RUTTER T M, SARGENT C, et al. Longitudinal Stability of Neural Correlates of Pediatric Attention Deficit Hyperactivity Disorder: A Pilot Study of Event Related Potentials and Electroencephalography [J]. J Atten Disord, 2024, 28(4): 493-511.\u003c/li\u003e\n\u003cli\u003eCHEN Y, LIU P, YI S, et al. Investigating the shared genetic architecture between attention-deficit/hyperactivity disorder and risk taking behavior: A large-scale genomewide cross-trait analysis [J]. Journal of affective disorders, 2024, 356: 22-31.\u003c/li\u003e\n\u003cli\u003eISAAC V, LOPEZ V, ESCOBAR M J. Arousal dysregulation and executive dysfunction in attention deficit hyperactivity disorder (ADHD) [J]. Front Psychiatry, 2023, 14: 1336040.\u003c/li\u003e\n\u003cli\u003eDOEBEL S. Rethinking Executive Function and Its Development [J]. Perspectives on psychological science : a journal of the Association for Psychological Science, 2020, 15(4): 942-56.\u003c/li\u003e\n\u003cli\u003eMORIGUCHI Y, PHILLIPS S. Evaluating the Distinction between Cool and Hot Executive Function during Childhood [J]. Brain Sci, 2023, 13(2).\u003c/li\u003e\n\u003cli\u003eBARKLEY R A. Attention-deficit/hyperactivity disorder, self-regulation, and time: toward a more comprehensive theory [J]. Journal of developmental and behavioral pediatrics : JDBP, 1997, 18(4): 271-9.\u003c/li\u003e\n\u003cli\u003eLEE Y S, HAN D H, LEE J H, et al. The Effects of Methylphenidate on Neural Substrates Associated with Interference Suppression in Children with ADHD: A Preliminary Study Using Event Related fMRI [J]. Psychiatry investigation, 2010, 7(1): 49-54.\u003c/li\u003e\n\u003cli\u003eTANNOCK R, SCHACHAR R. Methylphenidate and cognitive perseveration in hyperactive children [J]. J Child Psychol Psychiatry, 1992, 33(7): 1217-28.\u003c/li\u003e\n\u003cli\u003eADLER L A, CLEMOW D B, WILLIAMS D W, et al. Atomoxetine effects on executive function as measured by the BRIEF--a in young adults with ADHD: a randomized, double-blind, placebo-controlled study [J]. PLoS One, 2014, 9(8): e104175.\u003c/li\u003e\n\u003cli\u003eWEI L, WU, DANDAN, et al. The effect of atomoxetine hydrochloride on executive function in children with attention deficit hyperactivity disorder [J]. Journal of Mental Health, 2012, 25(05): 330-2.\u003c/li\u003e\n\u003cli\u003eYAN L, ZHU W, SIYU D, et al. Efficacy of Methylphenidate Hydrochloride Sustained-release Tablets and Atomoxetine Hydrochloride on Symptoms and Executive Function in Children with Attention Deficit Hyperactivity Disorder [J]. Chinese Journal of Child Health Care, 2022, 30(12): 1291-6.\u003c/li\u003e\n\u003cli\u003eHERNAUS D, CASALES SANTA M M, OFFERMANN J S, et al. Noradrenaline transporter blockade increases fronto-parietal functional connectivity relevant for working memory [J]. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, 2017, 27(4): 399-410.\u003c/li\u003e\n\u003cli\u003eGRAF H, ABLER B, FREUDENMANN R, et al. Neural correlates of error monitoring modulated by atomoxetine in healthy volunteers [J]. Biol Psychiatry, 2011, 69(9): 890-7.\u003c/li\u003e\n\u003cli\u003eKADUK K, HENRY T, GUITTON J, et al. Atomoxetine and reward size equally improve task engagement and perceptual decisions but differently affect movement execution [J]. Neuropharmacology, 2023, 241: 109736.\u003c/li\u003e\n\u003cli\u003eOTA T, IIDA J, NAKANISHI Y, et al. Increased prefrontal hemodynamic change after atomoxetine administration in pediatric attention-deficit/hyperactivity disorder as measured by near-infrared spectroscopy [J]. Psychiatry and clinical neurosciences, 2015, 69(3): 161-70.\u003c/li\u003e\n\u003cli\u003eINCE TASDELEN B, KARAKAYA E, OZTOP D B. Effects of Atomoxetine and Osmotic Release Oral System-Methylphenidate on Executive Functions in Patients with Combined Type Attention-Deficit/Hyperactivity Disorder [J]. J Child Adolesc Psychopharmacol, 2015, 25(6): 494-500.\u003c/li\u003e\n\u003cli\u003eVAN STRALEN J P M. A Controlled Trial of Extended-Release Guanfacine and Psychostimulants on Executive Function and ADHD [J]. J Atten Disord, 2020, 24(2): 318-25.\u003c/li\u003e\n\u003cli\u003eSCHULZ K P, CLERKIN S M, NEWCORN J H, et al. Guanfacine modulates the emotional biasing of amygdala-prefrontal connectivity for cognitive control [J]. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, 2014, 24(9): 1444-53.\u003c/li\u003e\n\u003cli\u003eCOULL J T, MIDDLETON H C, ROBBINS T W, et al. Contrasting effects of clonidine and diazepam on tests of working memory and planning [J]. Psychopharmacology, 1995, 120(3): 311-21.\u003c/li\u003e\n\u003cli\u003eCHACKO A, BEDARD A V, MARKS D, et al. Sequenced neurocognitive and behavioral parent training for the treatment of ADHD in school-age children [J]. Child Neuropsychol, 2018, 24(4): 427-50.\u003c/li\u003e\n\u003cli\u003eNG B, POLINE J B, THIRION B, et al. Bootstrapped Permutation Test for Multiresponse Inference on Brain Behavior Associations [J]. Information processing in medical imaging : proceedings of the conference, 2015, 24: 113-24.\u003c/li\u003e\n\u003cli\u003eWESTWOOD S J, PARLATINI V, RUBIA K, et al. Computerized cognitive training in attention-deficit/hyperactivity disorder (ADHD): a meta-analysis of randomized controlled trials with blinded and objective outcomes [J]. Molecular psychiatry, 2023, 28(4): 1402-14.\u003c/li\u003e\n\u003cli\u003eHINSHAW S P, HENKER B, WHALEN C K. Self-control in hyperactive boys in anger-inducing situations: effects of cognitive-behavioral training and of methylphenidate [J]. J Abnorm Child Psychol, 1984, 12(1): 55-77.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7627616/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7627616/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjective: \u003c/strong\u003eThis study aimed to investigate the effect of atomoxetine hydrochloride (ATX) on the activation of the prefrontal complex (PFC) in children with ADHD during a working memory task.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eWe recruited 14 drug-naive children with ADHD. PFC functional blood oxygen was recorded by using fNIRS during the n-back task. Clinical symptoms were assessed by parents using the Swanson, Nolan, and Pelham-IV rating scale and Conners measuring scale (parent symptom questionnaire) at the same time. After 8 weeks of treatment with ATX, these children were re-evaluated by using fNIRS, SNAP-IV, and Conners scales. Statistical methods were used to compare the physiological and psychological test indicators in the pre- and post-ATX conditions. Simultaneously, oxygenated hemoglobin concentration variation and the scores of the two scales were used as indicators for correlation analysis between PFC activation and clinical symptoms.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e Based on the performance data, children showed higher accuracy and lower omission error during the n-back task after ATX treatment. According to fNIRS data, the hemodynamic changes between pre-ATX and post-ATX conditions suggested that high-level activation in channel 36 was found in children under post-ATX conditions. The associated channels were located in frontopolar PFC, dorsolateral PFC, and orbitofrontal cortex. Enhanced trends were also found in channels 5 and 7. Regarding the rating scale scores, children under post-ATX conditions showed relatively lower inattention scores, hyperactivity scores, oppositional defiant score, and total scores on the SNAP-IV scale. Lower conduct problem score, learning problem score, hyperactivity-impulsivity score, and hyperactivity index of Conners measuring scale were observed in children who received treatment. These values were statistically and significantly different. A significantly negative correlation was observed between oxygenated hemoglobin concentration changes and the total score on the SNAP-IV scale.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003efNIRS is a helpful tool for identifying the effects of ATX on children with ADHD, and its combination with the SNAP-IV scale can provide an objective physiological index for evaluating the efficacy of ATX．ATX can improve the core symptoms and executive function of children with ADHD.\u003c/p\u003e","manuscriptTitle":"Effect of Atomoxetine Hydrochloride on Working Memory in Children with ADHD: A Functional Near-infrared Spectroscopy Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-11 17:09:36","doi":"10.21203/rs.3.rs-7627616/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"3bde32da-a6d7-47bf-8cd4-3eeb171c6cad","owner":[],"postedDate":"November 11th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-03-26T02:40:37+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-11 17:09:36","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7627616","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7627616","identity":"rs-7627616","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}