Work-related stressors among hospital physicians: a qualitative interview study in the Tokyo metropolitan area.

OBJECTIVES: We explored Japanese physicians' work-related stressors and identified those unique to this population, as well as clarified the influence of cultural and medical system diversity on these stressors to determine the content of future stress-reducing interventions for hospital physicians in Japan. DESIGN: We conducted a semistructured, face-to-face interview-based qualitative study between August and October 2017. The collected data were analysed using the grounded theory approach. SETTING: Hospitals around the Tokyo metropolitan area, Japan. PARTICIPANTS: Sixteen hospital physicians (mean age (SD)=33.9 (4.2) years; 11 men, 5 women). Seven worked in internal medicine and nine in surgery. RESULTS: We found unique stressors related to the Japanese medical system and culture, such as continuous all-day work after night shifts, and a hierarchical organisational system called Ikyoku. The results also indicated that Japanese physicians shared several stressors with Western physicians, such as sleep deprivation, high pressure and the limits of medicine. CONCLUSIONS: Our study clarifies some sources of work-related stressors among hospital physicians in Japan. While the key components of Western interventions might be useful in a Japanese context, the original evidence obtained from this study highlights the necessity of initiating interventions addressing the unique stressors of Japanese physicians. To reduce physicians' stress and enhance their well-being, psychological interventions for hospital physicians must be introduced in Japan.

Cyber bullying victimization and adolescent mental health: The differential moderating effects of intrapersonal and interpersonal emotional competence.

INTRODUCTION: Individuals who experience bullying victimization are at increased risk for future health and social problems. Despite this, studies show that not all bullying victims are in ill health, suggesting the importance of investigating protective factors that could counteract the adverse effects. The present study focused on investigating the moderating effects of emotional competence (EC) in the relationship between cyber-bullying victimization (CV) and mental health among adolescents. METHODS: Responses from 6403 adolescents aged 12 to 18 (1925 male, 4478 female, Mage = 16.35, SD = 1.46) with no missing data were used for analysis. The cross-sectional data analyzed in the present study was a part of a large longitudinal online survey conducted by the University of Tokyo in Japan. Participants were recruited among adolescent users of a social networking service widely used in Japan for communication. RESULTS: Results of regression analysis showed significant direct effects of CV on psychological distress/self-esteem, confirming the adverse effects of victimization. Results also suggested that high intrapersonal EC weakened the relationship between CV and psychological distress, whereas high interpersonal EC strengthened the relationship. There were no significant interactions between CV and EC in predicting self-esteem. CONCLUSIONS: Intrapersonal and interpersonal EC may play differential moderating roles in the relationship between CV and psychological distress, the former by buffering the effect and the latter by exacerbating it. Interventions targeting abilities to handle one's own emotions may help decrease distress among adolescents with CV experiences.

Altered expression of microRNA-223 in the plasma of patients with first-episode schizophrenia and its possible relation to neuronal migration-related genes.

Recent studies have shown that microRNAs (miRNAs) play a role as regulators of neurodevelopment by modulating gene expression. Altered miRNA expression has been reported in various psychiatric disorders, including schizophrenia. However, the changes in the miRNA expression profile that occur during the initial stage of schizophrenia have not been fully investigated. To explore the global alterations in miRNA expression profiles that may be associated with the onset of schizophrenia, we first profiled miRNA expression in plasma from 17 patients with first-episode schizophrenia and 17 healthy controls using microarray analysis. Among the miRNAs that showed robust changes, the elevated expression of has-miR-223-3p (miR-223) was validated via quantitative reverse transcription-polymerase chain reaction (qRT-PCR) using another independent sample set of 21 schizophrenia patients and 21 controls. To identify the putative targets of miR-223, we conducted a genome-wide gene expression analysis in neuronally differentiated SK-N-SH cells with stable miR-223 overexpression and an in silico analysis. We found that the mRNA expression levels of four genes related to the cytoskeleton or cell migration were significantly downregulated in miR-223-overexpressing cells, possibly due to interactions with miR-223. The in silico analysis suggested the presence of miR-223 target sites in these four genes. Lastly, a luciferase assay confirmed that miR-223 directly interacted with the 3' untranslated regions (UTRs) of all four genes. Our results reveal an increase in miR-223 in plasma during both the first episode and the later stage of schizophrenia, which may affect the expression of cell migration-related genes targeted by miR-223.

Adolescent Victimization and Self-Injurious Thoughts and Behaviors: A Genetically Sensitive Cohort Study.

OBJECTIVE: Victimized adolescents have an increased risk of self-injurious thoughts and behaviors. However, poor understanding of causal and non-causal mechanisms underlying this observed risk limits the development of interventions to prevent premature death in adolescents. This study tested whether pre-existing family-wide and individual vulnerabilities account for victimized adolescents' increased risk of self-injurious thoughts and behaviors. METHOD: Participants were 2,232 British children followed from birth to 18 years of age as part of the Environmental Risk Longitudinal Twin Study. Adolescent victimization (maltreatment, neglect, sexual victimization, family violence, peer/sibling victimization, cyber victimization, and crime victimization) was assessed through interviews with participants and co-informant questionnaires at the 18-year assessment. Suicidal ideation, self-harm, and suicide attempt in adolescence were assessed through interviews with participants at 18 years. RESULTS: Victimized adolescents had an increased risk of suicidal ideation (odds ratio [OR] 2.40, 95% CI 2.11-2.74), self-harm (OR 2.38, 95% CI 2.10-2.69), and suicide attempt (OR 3.14, 95% CI 2.54-3.88). Co-twin control and propensity score matching analyses showed that these associations were largely accounted for by pre-existing familial and individual vulnerabilities, respectively. Over and above their prior vulnerabilities, victimized adolescents still showed a modest increase in risk for suicidal ideation (OR 1.45, 95%CI 1.10-1.91) and self-harm (OR 1.50, 95% CI 1.18-1.91) but not for suicide attempt (OR 1.28, 95% CI 0.83-1.98). CONCLUSION: Risk for self-injurious thoughts and behaviors in victimized adolescents is explained only in part by the experience of victimization. Pre-existing vulnerabilities account for a large proportion of the risk. Therefore, effective interventions to prevent premature death in victimized adolescents should not only target the experience of victimization but also address pre-existing vulnerabilities.

Severity-dependent and -independent brain regions of major depressive disorder: A long-term longitudinal near-infrared spectroscopy study.

BACKGROUND: Long-term longitudinal studies are necessary to establish neuroimaging indicators which contribute to the detection of severity changes over time in patients with major depressive disorder (MDD). METHODS: One hundred sixty-five patients with MDD underwent clinical assessments and near-infrared spectroscopy (NIRS) examination at the initial evaluation (T0). After 1.5 years, 45 patients who visited for the follow-up evaluation (T1.5) were included in the analysis. The authors conducted analyses using the 17-item Hamilton Rating Scale for Depression (HAMD) scores and mean oxy-hemoglobin concentration ([oxy-Hb]) changes during a cognitive task in NIRS at T0 (T0_HAMD, T0_[oxy-Hb]) and at T1.5 (T1.5_HAMD, T1.5_[oxy-Hb]), and their intra-individual longitudinal changes (ΔHAMD = T1.5_HAMD - T0_HAMD, Δ[oxy-Hb] = T1.5_[oxy-Hb] - T0_[oxy-Hb]). RESULTS: For severity-dependent regions, the Δ[oxy-Hb] in the right inferior frontal gyrus (IFG) was negatively correlated with the ΔHAMD. For severity-independent regions, the intra-class correlation coefficients between T0_ and T1.5_[oxy-Hb] were moderate in the bilateral middle frontal gyri (MFG). LIMITATIONS: The percentage of patients included in the follow-up examination was relatively small. CONCLUSIONS: Brain activation in the right IFG and the bilateral MFG as measured by NIRS may differentially indicate clinical severity and trait-related abnormalities in MDD.

Psychosocial Twin Cohort Studies in Japan: The Keio Twin Research Center (KoTReC).

The Keio Twin Research Center (KoTReC) was established in 2009 at Keio University to combine two longitudinal cohort projects - the Keio Twin Study (KTS) for adolescence and adulthood and the Tokyo Twin Cohort Project (ToTCoP) for infancy and childhood. KoTReC also conducted a two-time panel study of self-control and psychopathology in twin adolescence in 2012 and 2013 and three independent anonymous cross-sectional twin surveys (ToTcross) before 2012 - the ToTCross, the Junior and Senior High School Survey and the High School Survey. This article introduces the recent research designs of KoTReC and its publications.

Genetic influences on prefrontal activation during a verbal fluency task in children: A twin study using near-infrared spectroscopy.

OBJECTIVE: The genetic and environmental influences on prefrontal function in childhood are underinvestigated due to the difficulty of measuring prefrontal function in young subjects, for which near-infrared spectroscopy (NIRS) is a suitable functional neuroimaging technique that facilitates the easy and noninvasive measurement of blood oxygenation in the superficial cerebral cortices. METHOD: Using a two-channel NIRS arrangement, we measured changes in bilateral prefrontal blood oxygenation during a category version of the verbal fluency task (VFT) in 27 monozygotic twin pairs and 12 same-sex dizygotic twin pairs ages 5-17 years. We also assessed the participant's full-scale intelligence quotient (FIQ) and retrieved parental socioeconomic status (SES). Classical structured equation modeling was used to estimate the heritability. RESULTS: The heritability of VFT-related brain activation was estimated to be 44% and 37% in the right and left prefrontal regions, respectively. We also identified a significant genetic contribution (74%) to FIQ, but did not to VFT task performance. Parental SES was not correlated with FIQ, task performance, or task-related prefrontal activation. CONCLUSIONS: This finding provides further evidence that variance in prefrontal function has a genetic component since childhood and highlights brain function, as measured by NIRS, as a promising candidate for endophenotyping neurodevelopmental disorders.

Increased sensitivity to sad faces in depressive symptomatology: A longitudinal study.

BACKGROUND: Negative bias to sad emotional stimuli has repeatedly been identified as a cognitive feature of major depressive disorder, particularly in facial expression recognition. However, it is unknown how negative bias applies to facial expression recognition in individuals with depressive symptoms. METHODS: A total of 58 university students' facial expression recognition and depression scores were measured using facial stimuli displaying the whole face, with 39 participants completing a 3-month follow-up assessment of depressive symptoms. We used an index that differentiates sensitivity to sadness from sensitivity to general facial expressions. Participants gave written informed consent after a complete description of the study. RESULTS: The group with higher depressive symptoms showed a higher sensitivity to sadness than those with lower depressive symptoms, indicating a relationship between negative bias in facial expression recognition and nonclinical depressive symptoms. From a longitudinal point of view, negative bias to sad expressions at one time point was found to predict the change in depression scores at the 3-month follow-up. LIMITATIONS: Since the participants included only college students, the generalizability of our results to other populations is limited. The three-month interval may not be sufficient to determine the prognosis of depression, suggesting the need for further replications. DISCUSSION: This study was the first to report the negative bias of facial expression recognition in individuals with nonclinical depressive symptoms. Given that negative bias predicts present and future depression, facial expression recognition has the potential to be used as a screening tool for early detection of depression.

Long term economic impact associated with childhood bullying victimisation.

Being bullied is associated with mental health problems in childhood, with increasing evidence of persisting negative impacts, and increased mental health service use, into adulthood. There are also impacts of bullying victimisation on employment, income and being in poverty, but little is known about the long-term economic impacts. We therefore aimed to estimate the most important economic consequences at age 50 of being bullied in childhood: to our knowledge this is the first study that does so. Using 1958 British birth cohort data collected in 1965, 1969, 1991, 2003 and 2008 (study samples size 7323-9242), we find substantial and durable individual and societal economic impacts four decades after the childhood bullying occurred. Both men and women who were bullied in childhood were less likely to be in employment and had accumulated less wealth in the form of home-ownership or savings than participants who were not bullied. Individual earnings from paid employment were lower for women who were bullied in childhood. Frequent bullying in childhood was also associated with higher societal employment-related costs for men and higher health service costs for women. Our findings underline the importance of preventing bullying in childhood and, as the consequences are so long-lasting and pervasive, supporting people still experiencing the negative consequences in the decades that follow.

Application of functional near infrared spectroscopy as supplementary examination for diagnosis of clinical stages of psychosis spectrum.

AIM: Research efforts aiming at neuroimaging-aided differential diagnosis for psychiatric disorders have been progressing rapidly. A previous multisite study has developed a supplementary diagnostic system using functional near-infrared spectroscopy (fNIRS) that can be easily applied to clinical settings. However, few neuroimaging biomarkers have been developed for the psychosis spectrum with various clinical stages. METHODS: We employed the fNIRS as a clinical examination device for 143 participants, comprising 47 ultra-high risk for psychosis (UHR) individuals, 30 patients with first-episode psychosis (FEP), 34 patients with chronic schizophrenia (ChSZ), and 33 healthy controls, who were independent of the previous study. A 12-month follow-up measurement was also carried out on 34 UHR individuals (72%), 21 patients with FEP (70%), and 33 controls. The fNIRS algorithm variables used for classification were the intensity and timing of prefrontal activation following the start of the cognitive task as used in the previous multisite study. RESULTS: The discrimination rate by timing of activation was modest but it became acceptable after adjusting confounding factors. Discrimination by intensity of activation was not improved by similar adjustment. A total of 63.8%, 86.7%, and 81.3% patients were classified as UHR, FEP, and ChSZ, respectively; and 85.1%, 86.7%, and 71.9% of patients in these groups, respectively, were classified as being on the psychosis spectrum. In the follow-up measurement, 88.2% of individuals with UHR and 95.0% of patients with FEP were successfully classified into the psychosis spectrum group. CONCLUSION: The fNIRS for supplementary clinical examination could be validly applied to differentiating people with the psychosis spectrum in various clinical stages. The fNIRS is a candidate biological marker for aiding diagnosis of psychosis spectrum in routine clinical settings.

Familial Influences on Mismatch Negativity and Its Association with Plasma Glutamate Level: A Magnetoencephalographic Study in Twins.

Mismatch negativity (MMN) or its magnetic counterpart (magnetic mismatch negativity; MMNm) is regarded as a promising biomarker for schizophrenia. Previous electroencephalographic studies of MMN have demonstrated a moderate-to-high heritability for MMN amplitudes. N-methyl-D-aspartate receptor-dependent glutamatergic neurotransmission is implicated in MMN generation. We hypothesized that the differences between identical twins in MMNm variables might be associated with differences in plasma levels of amino acids involved in glutamatergic neurotransmission. Thirty-three pairs of monozygotic (MZ) and 10 pairs of dizygotic (DZ) twins underwent MMNm recording. The MMNm in response to tone duration changes, tone frequency changes, and phonemic changes was recorded using 204-channel magnetoencephalography. Of these, 26 MZ and 7 DZ twin pairs underwent blood sampling for determination of plasma amino acid levels. MMNm peak strength showed relatively high correlations in both MZ and DZ twin pairs. The differences in MMNm latencies tended to correlate with the differences in plasma amino acid levels within MZ pairs, while no significant correlation was observed after the Bonferroni correction. We observed a familial trait in MMNm strength. The differences in MMN latency in MZ twins might be influenced by changes in glutamate levels and glutamate-glutamine cycling; however, the results need to be replicated.

Development of a neurofeedback protocol targeting the frontal pole using near-infrared spectroscopy.

AIM: Neurofeedback has been studied with the aim of controlling cerebral activity. Near-infrared spectroscopy is a non-invasive neuroimaging technique used for measuring hemoglobin concentration changes in cortical surface areas with high temporal resolution. Thus, near-infrared spectroscopy may be useful for neurofeedback, which requires real-time feedback of repeated brain activation measurements. However, no study has specifically targeted neurofeedback, using near-infrared spectroscopy, in the frontal pole cortex. METHODS: We developed an original near-infrared spectroscopy neurofeedback system targeting the frontal pole cortex. Over a single day of testing, each healthy participant (n = 24) received either correct or incorrect (Sham) feedback from near-infrared spectroscopy signals, based on a crossover design. RESULTS: Under correct feedback conditions, significant activation was observed in the frontal pole cortex (P = 0.000073). Additionally, self-evaluation of control and metacognitive beliefs were associated with near-infrared spectroscopy signals (P = 0.006). CONCLUSION: The neurofeedback system developed in this study might be useful for developing control of frontal pole cortex activation.

Detection of resting state functional connectivity using partial correlation analysis: A study using multi-distance and whole-head probe near-infrared spectroscopy.

Multichannel near-infrared spectroscopy (NIRS) is a functional neuroimaging modality that enables easy-to-use and noninvasive measurement of changes in blood oxygenation levels. We developed a clinically-applicable method for estimating resting state functional connectivity (RSFC) with NIRS using a partial correlation analysis to reduce the influence of extraneural components. Using a multi-distance probe arrangement NIRS, we measured resting state brain activity for 8min in 17 healthy participants. Independent component analysis was used to extract shallow and deep signals from the original NIRS data. Pearson's correlation calculated from original signals was significantly higher than that calculated from deep signals, while partial correlation calculated from original signals was comparable to that calculated from deep (cerebral-tissue) signals alone. To further test the validity of our method, we also measured 8min of resting state brain activity using a whole-head NIRS arrangement consisting of 17 cortical regions in 80 healthy participants. Significant RSFC between neighboring, interhemispheric homologous, and some distant ipsilateral brain region pairs was revealed. Additionally, females exhibited higher RSFC between interhemispheric occipital region-pairs, in addition to higher connectivity between some ipsilateral pairs in the left hemisphere, when compared to males. The combined results of the two component experiments indicate that partial correlation analysis is effective in reducing the influence of extracerebral signals, and that NIRS is able to detect well-described resting state networks and sex-related differences in RSFC.

Association between impaired brain activity and volume at the sub-region of Broca's area in ultra-high risk and first-episode schizophrenia: A multi-modal neuroimaging study.

Recent studies have suggested that functional abnormalities in Broca's area, which is important in language production (speech and thoughts before speech), play an important role in the pathophysiology of schizophrenia. While multi-modal approaches have proved useful in revealing the specific pathophysiology of psychosis, the association of functional abnormalities with gray matter volume (GMV) here in subjects with an ultra-high risk (UHR) of schizophrenia, those with first-episode schizophrenia (FES), and healthy controls has yet to be clarified. Therefore, the relationship between cortical activity measured using functional near-infrared spectroscopy (fNIRS) during a verbal fluency task, and GMV in the Broca's area assessed using a manual tracing in magnetic resonance imaging (MRI), which considers individual structural variation, was examined for 57 subjects (23 UHR/18 FES/16 controls). The UHR and FES group showed significantly reduced brain activity compared to control group in the left pars triangularis (PT) (P=.036, .003, respectively). Furthermore in the FES group, the reduced brain activity significantly positively correlated with the volume in the left PT (B=0.29, P=.027), while significant negative association was evident for all subjects (B=-0.18, P=.010). This correlation remained significant after adjusting for antipsychotics dosage, and voxel-wise analysis could not detect any significant correlation between impaired cortical activity and volume. The significant relationship between neural activity and GMV in the left PT may reflect a specific pathophysiology related to the onset of schizophrenia.

Association between rostral prefrontal cortical activity and functional outcome in first-episode psychosis: a longitudinal functional near-infrared spectroscopy study.

BACKGROUND: Few biomarkers can be used easily and noninvasively to measure clinical condition and future outcome in patients with first-episode psychosis (FEP). To develop such biomarker using multichannel functional near-infrared spectroscopy (fNIRS), cortical function in the prefrontal cortex was longitudinally measured during a verbal fluency task. METHODS: Sixty-nine fNIRS measurements and 77 clinical assessments were obtained from 31 patients with FEP at baseline, 6-month, and 12-month follow-ups. Sixty measurements were obtained from 30 healthy controls matched for age, sex, and premorbid IQ. We initially tested signal changes for 12 months, and then investigated the relationship between fNIRS signals and clinical assessments. RESULTS: Signal changes from baseline to 12-month follow-up were not evident in any group. Patients with FEP had significant positive correlation coefficients between 6-month fNIRS signals and the 12-month Global Assessment of Functioning (GAF) score in the left middle frontal gyrus (FDR-corrected p=.0016-.0052, r=.65-.59). fNIRS signals at the 12-month follow-up were associated with 12-month GAF score in the bilateral superior and middle frontal gyri (FDR-corrected p=.00085-.018, r=.72-.55), and with the difference between baseline and 12-month GAF scores in the right superior frontal gyrus (FDR-corrected p=.000067-.00012, r=.80-.78). These associations were significant even after controlling for demographic variables. No association between baseline fNIRS signals and later GAF scores was found. DISCUSSION: fNIRS measurement can potentially be used as a biomarker to aid sequential assessment of neuro-clinical conditions through the early stage of psychosis.

Characterizing prefrontal cortical activity during inhibition task in methamphetamine-associated psychosis versus schizophrenia: a multi-channel near-infrared spectroscopy study.

Methamphetamine abuse and dependence, frequently accompanied by schizophrenia-like psychotic symptoms [methamphetamine-associated psychosis (MAP)], is a serious public health problem worldwide. Few studies, however, have characterized brain dysfunction associated with MAP, nor investigated similarities and differences in brain dysfunction between MAP and schizophrenia. We compared prefrontal cortical activity associated with stop-signal inhibitory task in 21 patients with MAP, 14 patients with schizophrenia and 21 age- and gender-matched healthy controls using a 52-channel near-infrared spectroscopy (NIRS) system. Both the MAP and the schizophrenia groups showed significantly reduced activation in the bilateral ventrolateral prefrontal cortex compared with controls; however, only the MAP group showed reduced activation in the frontopolar prefrontal cortex. The MAP group demonstrated significant positive correlations between task performance and hemodynamic responses in the bilateral ventrolateral, polar and left dorsolateral regions of the prefrontal cortex. The MAP and schizophrenia groups demonstrated a significant difference in the relationship of impulsivity to hemodynamic changes in the bilateral premotor cortex. These findings characterize similarities and differences in prefrontal cortical dysfunction between psychosis associated with methamphetamine and schizophrenia. The reduced hemodynamic changes in the bilateral ventrolateral prefrontal cortex suggest a common underlying pathophysiology of MAP and schizophrenia, whereas those in the frontopolar prefrontal cortex point to an impaired state that is either inherent or caused specifically by methamphetamine use.

Concurrent fNIRS-fMRI measurement to validate a method for separating deep and shallow fNIRS signals by using multidistance optodes.

It has been reported that a functional near-infrared spectroscopy (fNIRS) signal can be contaminated by extracerebral contributions. Many algorithms using multidistance separations to address this issue have been proposed, but their spatial separation performance has rarely been validated with simultaneous measurements of fNIRS and functional magnetic resonance imaging (fMRI). We previously proposed a method for discriminating between deep and shallow contributions in fNIRS signals, referred to as the multidistance independent component analysis (MD-ICA) method. In this study, to validate the MD-ICA method from the spatial aspect, multidistance fNIRS, fMRI, and laser-Doppler-flowmetry signals were simultaneously obtained for 12 healthy adult males during three tasks. The fNIRS signal was separated into deep and shallow signals by using the MD-ICA method, and the correlation between the waveforms of the separated fNIRS signals and the gray matter blood oxygenation level-dependent signals was analyzed. A three-way analysis of variance ([Formula: see text]) indicated that the main effect of fNIRS signal depth on the correlation is significant [[Formula: see text], [Formula: see text]]. This result indicates that the MD-ICA method successfully separates fNIRS signals into spatially deep and shallow signals, and the accuracy and reliability of the fNIRS signal will be improved with the method.

Neuroimaging-Aided Prediction of the Effect of Methylphenidate in Children with Attention-Deficit Hyperactivity Disorder: A Randomized Controlled Trial.

Although methylphenidate hydrochloride (MPH) is a first-line treatment for children with attention-deficit hyperactivity disorder (ADHD), the non-response rate is 30%. Our aim was to develop a supplementary neuroimaging biomarker for predicting the clinical effect of continuous MPH administration by using near-infrared spectroscopy (NIRS). After baseline assessment, we performed a double-blind, placebo-controlled, crossover trial with a single dose of MPH, followed by a prospective 4-to-8-week open trial with continuous MPH administration, and an ancillary 1-year follow-up. Twenty-two drug-naïve and eight previously treated children with ADHD (NAÏVE and NON-NAÏVE) were compared with 20 healthy controls (HCs) who underwent multiple NIRS measurements without intervention. We tested whether NIRS signals at the baseline assessment or ΔNIRS (single dose of MPH minus baseline assessment) predict the Clinical Global Impressions-Severity (CGI-S) score after 4-to-8-week or 1-year MPH administration. The secondary outcomes were the effect of MPH on NIRS signals after single-dose, 4-to-8-week, and 1-year administration. ΔNIRS significantly predicted CGI-S after 4-to-8-week MPH administration. The leave-one-out classification algorithm had 81% accuracy using the NIRS signal. ΔNIRS also significantly predicted CGI-S scores after 1 year of MPH administration. For secondary analyses, NAÏVE exhibited significantly lower prefrontal activation than HCs at the baseline assessment, whereas NON-NAÏVE and HCs showed similar activation. A single dose of MPH significantly increased activation compared with the placebo in NAÏVE. After 4-to-8-week administration, and even after MPH washout following 1-year administration, NAÏVE demonstrated normalized prefrontal activation. Supplementary NIRS measurements may serve as an objective biomarker for clinical decisions and monitoring concerning continuous MPH treatment in children with ADHD.