Decreased oral function in Japanese inpatients with schizophrenia.

AIM: Oral function in patients with schizophrenia has not been well-characterized. To address this, we performed a cross-sectional study of oral function in Japanese inpatients with schizophrenia. METHODS: We measured oral function, including occlusal force, tongue-lip motor function, tongue pressure, and masticatory function in 130 Japanese inpatients with schizophrenia. We then compared the frequency of clinical signs of oral hypofunction among 63 non-elderly and 67 elderly inpatients with schizophrenia, as well as data from 98 elderly control participants from a previous Japanese study. RESULTS: The frequency of reduced occlusal force was significantly higher in the elderly inpatients (76.2%) than in the non-elderly inpatients (43.9%) and elderly controls (43.9%). The frequency of decreased tongue-lip motor function in non-elderly inpatients (96.8%) and elderly inpatients (97.0%) was significantly higher than that in elderly controls (56.1%). The frequency of decreased tongue pressure in non-elderly inpatients (66.1%) and elderly inpatients (80.7%) was significantly higher than that in elderly controls (43.9%). Finally, the frequency of decreased masticatory function was highest in elderly inpatients (76.5%), followed by non-elderly inpatients (54.8%) and elderly controls (15.3%). CONCLUSION: Oral function was decreased in both non-elderly and elderly Japanese inpatients with schizophrenia compared with elderly controls.

Association between copy number variations in parkin (PRKN) and schizophrenia and autism spectrum disorder: A case-control study.

AIM: The present study aimed to examine the association between copy number variations (CNVs) in parkin (PRKN) and schizophrenia (SCZ) and autism spectrum disorder (ASD) in a large case-control sample. METHOD: Array comparative genomic hybridization was performed on 3111 cases with SCZ, 1236 cases with ASD, and 2713 controls. We systematically prioritized likely pathogenic CNVs (LP-CNVs) in PRKN and examined their association with SCZ and ASD. RESULTS: In total, 3014 SCZ cases (96.9%), 1205 ASD cases (97.5%), and 2671 controls (98.5%) passed quality control. We found that monoallelic carriers of LP-CNVs in PRKN were common (70/6890, 1.02%) and were not at higher risk of SCZ (p = 0.29) or ASD (p = 0.72). We observed that the distribution pattern of LP-CNVs in the Japanese population was consistent with those in other populations. We also identified a patient diagnosed with SCZ and early-onset Parkinson's disease carrying biallelic pathogenic CNVs in PRKN. The absence of Parkinson's symptoms in 10 other monoallelic carriers of the same pathogenic CNV further reflects the lack of effect of monoallelic pathogenic variants in PRKN in the absence of a second hit. CONCLUSION: The present findings suggest that monoallelic CNVs in PRKN do not confer a significant risk for SCZ or ASD. However, further studies to investigate the association between biallelic CNVs in PRKN and SCZ and ASD are warranted.

The three-factor structure of the Autism-Spectrum Quotient Japanese version in pregnant women.

Background: There is a rising interest in perinatal mental health studies, and proper psychometric tools to assess autistic traits among this population in Japan are vital. Objective: This study aimed to clarify the optimal factor structure of the AQ as part of a perinatal mental health research project. Methods: We used the Japanese version of the AQ (AQ-J) to measure autistic-like traits in pregnant women. Participants were 4,287 Japanese women who were pregnant or who had given birth within the last month. We performed exploratory factor analysis (EFA) using the first sample group (n = 2,154) to obtain factor structures for the final item selections. We performed confirmatory factor analysis (CFA) using the second sample group (n = 2,133) to obtain a model with good fit, then compared the model to all previously proposed models to determine the best-fitting model. Results: The EFA analysis identified a model consisting of 25 items distributed across three factors. Cronbach's alpha for the total 25-item AQ-J, 9-item "Social interaction" factor, 11-item "Non-verbal communication" factor, and 5-item "Restricted interest" factor was 0.829, 0.829, 0.755, and 0.576, respectively. McDonald's omega and its 95% confidence interval were 0.826 (0.821-0.836), 0.835 (0.821-0.837), 0.755 (0.744-0.766), and 0.603 (0.556-0.596), respectively. CFA confirmed that the three-factor structure had an acceptable fit (goodness of fit index: 0.900, comparative fit index: 0.860, root mean square error of approximation: 0.066). These findings indicated that the three-factor model was better than the 13 existing models. Conclusion: The findings are discussed in relation to the adequacy of the AQ-J for assessing autistic traits in perinatal women. We recommend the use of this 25-item, three-factor AQ-J model for this population owing to its superiority to all previous models.

Usefulness of the autism spectrum quotient (AQ) in screening for autism spectrum disorder and social communication disorder.

BACKGROUND: In the Diagnostic and Statistical Manual and Mental Disorders, Fifth Edition (DSM-5), autism spectrum disorder (ASD) and social (pragmatic) communication disorder (SCD) were described as a new category of psychiatry nosography. SCD involves impairments in social communication and social interaction but not restricted, repetitive patterns of behavior, interests, or activities. The autism spectrum quotient (AQ) was developed to screen for autism tendencies in adults with normal intelligence. However, AQ cutoff scores for screening ASD and SCD in the DSM-5 have not been established. This study examined whether the Japanese version of the AQ (AQ-J) total scores could discriminate between an ASD group, an SCD group, and a neurotypical (NT) group. METHODS: Participants were 127 ASD patients, 52 SCD patients, and 49 NT individuals. Receiver operating characteristic (ROC) analyses were used to examine AQ-J total score cutoff values to distinguish between ASD and NT groups, SCD and NT groups, and ASD and SCD groups. RESULTS: In the ROC analysis for the ASD and NT groups, the area under the curve (AUC) was 0.96, and the optimum cutoff value was 23 points (sensitivity 92.9%, specificity 85.7%). The AUC for the SCD and NT groups was 0.89, and the optimum cutoff value was 22 points (sensitivity 84.6%, specificity 85.7%). The AUC for the ASD and SCD groups was 0.75; the optimum cutoff value was 32 points (sensitivity 67.7%, specificity 71.2%). CONCLUSION: Our findings suggest the usefulness of the AQ-J in screening for ASD and SCD.

Effects of MAP4K inhibition on neurite outgrowth.

Protein kinases are responsible for protein phosphorylation and are involved in important intracellular signal transduction pathways in various cells, including neurons; however, a considerable number of poorly characterized kinases may be involved in neuronal development. Here, we considered mitogen-activated protein kinase kinase kinase kinases (MAP4Ks), related to as candidate regulators of neurite outgrowth and synaptogenesis, by examining the effects of a selective MAP4K inhibitor PF06260933. PF06260933 treatments of the cultured neurons reduced neurite lengths, not the number of synapses, and phosphorylation of GAP43 and JNK, relative to the control. These results suggest that MAP4Ks are physiologically involved in normal neuronal development and that the resultant impaired neurite outgrowth by diminished MAP4Ks' activity, is related to psychiatric disorders.

High care and low overprotection from both paternal and maternal parents predict a secure attachment style with a partner among perinatal Japanese women.

This study aimed to determine how paternal and maternal parenting before adolescence affects adult attachment to a partner during the perinatal period, using three different models of attachment. We used the Parental Bonding Instrument (PBI) and the Relationship Questionnaire (RQ) to examine perceived parenting practices and adult attachment styles, respectively. The participants included 4586 Japanese women who were pregnant or who had given birth, up until one month after childbirth. We performed structural equation modeling analysis between PBI and RQ scores with three different category models, including the four-category model (secure, fearful, preoccupied, and dismissive attachment) as Model 1, the two-category model (model of the self and others) as Model 2, and the single-category model (total attachment style) as Model 3. Models 1 and 2 showed a good fit. Both path models showed a significant association between adult attachment style and perceived paternal and maternal parenting before adolescence, where high care and low overprotection from both paternal and maternal parents predicted adult attachment. Our findings indicate that attachment styles are best described using the four-category and two-category models, and suggest that both paternal and maternal overprotection and care influence adult attachment with a partner during the perinatal period.

Relationships among autistic traits, depression, anxiety, and maternal-infant bonding in postpartum women.

BACKGROUND: Although several studies have found significant relationships between autistic traits and depression/anxiety, the relationships between autistic traits and postpartum depression/anxiety remain unclear. Moreover, few studies have examined the relationships between autistic traits and mother-infant bonding while considering depression or anxiety. METHODS: This study used a cross-sectional data analysis design. Participants were 2692 women who completed the Autism-Spectrum Quotient (AQ), Hospital Anxiety and Depression Scale (HADS), and Mother-to-Infant Bonding Scale (MIBS) at 1 month postpartum. We performed path analysis that included parity, the five AQ subscales (social skills, attention switching, attention to detail, communication, and imagination), both HADS subscales (anxiety and depression), and the two MIBS subscales (lack of affection and anger and rejection). RESULTS: Our path analysis revealed that higher scores for social skills, attention switching, communication, and imagination were associated with higher scores for depression. Higher scores for social skills, attention switching, attention to detail, and communication were associated with higher scores for anxiety. Moreover, difficulties in social skills and imagination were associated with failure of maternal-infant bonding. However, more attention to detail was associated with better maternal-infant bonding. CONCLUSIONS: This study suggests that maternal autistic traits are related to anxiety and depression to a certain degree, but only slightly related to maternal-infant bonding at 1 month postpartum. To improve autistic women's quality of life and that of their newborns, perinatal mental health issues such as anxiety, depression, and maternal-fetal bonding difficulties should be appropriately addressed.

Deep exome sequencing identifies enrichment of deleterious mosaic variants in neurodevelopmental disorder genes and mitochondrial tRNA regions in bipolar disorder.

Bipolar disorder (BD) is a global medical issue, afflicting around 1% of the population with manic and depressive episodes. Despite various genetic studies, the genetic architecture and pathogenesis of BD have not been fully resolved. Besides germline variants, postzygotic mosaic variants are proposed as new candidate mechanisms contributing to BD. Here, we performed extensive deep exome sequencing (DES, ~300×) and validation experiments to investigate the roles of mosaic variants in BD with 235 BD cases (194 probands of trios and 41 single cases) and 39 controls. We found an enrichment of developmental disorder (DD) genes in the genes hit by deleterious mosaic variants in BD (P = 0.000552), including a ClinVar-registered pathogenic variant in ARID2. An enrichment of deleterious mosaic variants was also observed for autism spectrum disorder (ASD) genes (P = 0.000428). The proteins coded by the DD/ASD genes with non-synonymous mosaic variants in BD form more protein-protein interaction than expected, suggesting molecular mechanisms shared with DD/ASD but restricted to a subset of cells in BD. We also found significant enrichment of mitochondrial heteroplasmic variants, another class of mosaic variants, in mitochondrial tRNA genes in BD (P = 0.0102). Among them, recurrent m.3243 A > G variants known as causal for mitochondrial diseases were found in two unrelated BD probands with allele fractions of 5-12%, lower than in mitochondrial diseases. Despite the limitation of using peripheral tissues, our DES investigation supports the possible contribution of deleterious mosaic variants in the nuclear genome responsible for severer phenotypes, such as DD/ASD, to the risk of BD and further demonstrates that the same paradigm can be applied to the mitochondrial genome. These results, as well as the enrichment of heteroplasmic mitochondrial tRNA variants in BD, add a new piece to the understanding of the genetic architecture of BD and provide general insights into the pathological roles of mosaic variants in human diseases.

Case report: Methylphenidate improved chronic pain in an adult patient with attention deficit hyperactivity disorder.

Introduction: Chronic pain remains a health problem that is difficult to treat adequately. Its unknown cause and complex comorbidity with other illnesses, including mental disorders, amplify the severity of symptoms, which consequently decreases the quality of life of patients long term. In our clinical practice, we coincidentally found evidence that methylphenidate (MPH) effectively managed chronic pain in an adult patient with attention deficit hyperactivity disorder (ADHD). The effectiveness of MPH in the treatment of ADHD is well-established; however, its utility in treating pain remains unclear. Case presentation: We present a rare case of a 43-year-old male patient with 15 years of chronic idiopathic pain symptoms that did not adequately respond to standard pain management, such as acetaminophen, non-opioid analgesics, and muscle relaxers. Pain also persisted after treatments with antidepressants and an epidural block. Furthermore, symptoms worsened following several sessions of modified electroconvulsive therapy. After a thorough assessment at our child and adolescent psychiatric outpatient clinic, we confirmed a diagnosis of adult ADHD with a predominantly inattentive type. Considering this newly established diagnosis, we prescribed osmotic-release oral system (OROS) methylphenidate. Within 1 month of treatment at a dose of 18 mg/day of OROS-MPH, the patient's chronic pain unexpectedly improved dramatically, and the patient no longer experienced pain symptoms. The dosage of OROS-MPH was titrated monthly, reaching 72 mg/day as a maintenance dose, and ADHD symptoms improved after 4 months of treatment. The patient was followed up regularly for 7 years during his OROS-MPH treatment. No adverse effects were reported, including stimulant addiction. He was stable overall and functioned well in his daily activities. His pain never recurred. Conclusion: This case report suggests that MPH may be potentially effective in treating chronic pain. Further studies are needed to confirm whether MPH improved chronic pain simultaneously with or separately from the improvement in ADHD. Moreover, elucidating the anatomical sites and molecular pharmacological mechanisms related to the action of MPH in pain modulation and perception is essential. Such sites include the descending dopaminergic pain pathway and higher cortical areas. Furthering our understanding may reinforce the justification for treating chronic pain using MPH.

Serum cortisol and insulin-like growth factor 1 levels in major depressive disorder and schizophrenia.

The pathophysiology underlying major depressive disorder (MDD) and schizophrenia is related to endocrine system functions and includes changes in the blood levels of cortisol and insulin-like growth factor 1 (IGF-1). However, these hormones have not been investigated simultaneously in patients with MDD and schizophrenia. We investigated the differences in serum cortisol and IGF-1 levels among patients with MDD and schizophrenia and controls. We included 129 patients with MDD, 71 patients with schizophrenia, and 71 healthy volunteers. Blood tests were performed between 6:00 am and 11:00 am after fasting. Serum cortisol levels were significantly higher in patients with schizophrenia than in patients with MDD and controls. Serum cortisol levels were significantly higher in patients with MDD than in controls. Serum IGF-1 levels were higher in both patient groups than in controls, whereas there was no significant difference between patients with MDD and schizophrenia. Both cortisol and IGF-1 levels were positively correlated with the Hamilton Rating Scale for Depression score in patients with MDD, whereas cortisol level was positively correlated and IGF-1 level was negatively correlated with the Brief Psychiatric Rating Scale score in patients with schizophrenia. The differences in the level of these hormones suggest pathophysiological differences between these disorders.

Factor structure of the parental bonding instrument for pregnant Japanese women.

The parental bonding instrument (PBI) is often used to examine the perceptions of children and adolescents regarding parenting practices. Previous studies have investigated the factor structure of the PBI. However, although it is important to examine the relationships between the perceived parenting practices and perinatal mental health, few studies have included perinatal women. We aimed to accurately clarify which PBI factor structure was useful in assessing perinatal women (n = 4633). Furthermore, we evaluated the measurement invariance between primipara and multipara groups, and between the paternal and maternal PBI forms. Our exploratory and confirmatory factor analyses revealed that a three-factor PBI structure was most plausible for perinatal women. Moreover, we found complete invariance (residual invariance) of the PBI ratings across primipara and multipara women for the paternal and maternal forms. In contrast, we found weak invariance (metric invariance) of the PBI ratings across the paternal and maternal forms. Our participants tended to rate fathers as less caring and less overprotective than mothers. This three-factor structure shows measurement invariance in perinatal women and can be used to accurately determine how the perceived parenting style before adolescence influences women's mental health in the perinatal period.

Association Between the Number of Remaining Teeth and Body Mass Index in Japanese Inpatients with Schizophrenia.

Purpose: There is little evidence regarding the effects of dental status on body mass index (BMI) in inpatients with schizophrenia. Thus, we performed a cross-sectional study to explore the associations between the number of remaining teeth and BMI in Japanese inpatients with schizophrenia. Patients and Methods: We performed multiple regression analysis to assess the effects of potential predictors (age, sex, number of remaining teeth, number of antipsychotics prescribed, chlorpromazine equivalent dose, and antipsychotic type) on BMI in 212 inpatients with schizophrenia. We then compared the number of remaining teeth between inpatients with schizophrenia and the Japanese general population (3283 individuals) from the Japan Dental Diseases Survey 2016, using an analysis of covariance with age and sex as covariates. Results: Multiple regression analysis showed that the number of remaining teeth and the number of antipsychotics prescribed were significantly correlated with BMI (standardized regression coefficient = 0.201 and 0.235, respectively). In the analysis of covariance, inpatients with schizophrenia had significantly fewer remaining teeth compared with the Japanese general population (mean 14.8 [standard deviation: 10.9] vs mean 23.0 [standard deviation: 8.1]). Conclusion: These results suggested that tooth loss and antipsychotic polypharmacy affect BMI in inpatients with schizophrenia, and that inpatients with schizophrenia lose more teeth compared with the general population.

The cyclin G-associated kinase (GAK) inhibitor SGC-GAK-1 inhibits neurite outgrowth and synapse formation.

Protein kinases are responsible for protein phosphorylation and are involved in important signal transduction pathways; however, a considerable number of poorly characterized kinases may be involved in neuronal development. Here, we considered cyclin G-associated kinase (GAK) as a candidate regulator of neurite outgrowth and synaptogenesis by examining the effects of the selective GAK inhibitor SGC-GAK-1. SGC-GAK-1 treatment of cultured neurons reduced neurite length and decreased synapse number and phosphorylation of neurofilament 200-kDa subunits relative to the control. In addition, the related kinase inhibitor erlotinib, which has distinct specificity and potency from SGC-GAK-1, had no effect on neurite growth, unlike SGC-GAK-1. These results suggest that GAK may be physiologically involved in normal neuronal development, and that decreased GAK function and the resultant impaired neurite outgrowth and synaptogenesis may be related to neurodevelopmental disorders.

Cross-Disorder Analysis of Genic and Regulatory Copy Number Variations in Bipolar Disorder, Schizophrenia, and Autism Spectrum Disorder.

BACKGROUND: We aimed to determine the similarities and differences in the roles of genic and regulatory copy number variations (CNVs) in bipolar disorder (BD), schizophrenia (SCZ), and autism spectrum disorder (ASD). METHODS: Based on high-resolution CNV data from 8708 Japanese samples, we performed to our knowledge the largest cross-disorder analysis of genic and regulatory CNVs in BD, SCZ, and ASD. RESULTS: In genic CNVs, we found an increased burden of smaller (<100 kb) exonic deletions in BD, which contrasted with the highest burden of larger (>500 kb) exonic CNVs in SCZ/ASD. Pathogenic CNVs linked to neurodevelopmental disorders were significantly associated with the risk for each disorder, but BD and SCZ/ASD differed in terms of the effect size (smaller in BD) and subtype distribution of CNVs linked to neurodevelopmental disorders. We identified 3 synaptic genes (DLG2, PCDH15, and ASTN2) as risk factors for BD. Whereas gene set analysis showed that BD-associated pathways were restricted to chromatin biology, SCZ and ASD involved more extensive and similar pathways. Nevertheless, a correlation analysis of gene set results indicated weak but significant pathway similarities between BD and SCZ or ASD (r = 0.25-0.31). In SCZ and ASD, but not BD, CNVs were significantly enriched in enhancers and promoters in brain tissue. CONCLUSIONS: BD and SCZ/ASD differ in terms of CNV burden, characteristics of CNVs linked to neurodevelopmental disorders, and regulatory CNVs. On the other hand, they have shared molecular mechanisms, including chromatin biology. The BD risk genes identified here could provide insight into the pathogenesis of BD.

Elevation of EGR1/zif268, a Neural Activity Marker, in the Auditory Cortex of Patients with Schizophrenia and its Animal Model.

The family of epidermal growth factor (EGF) including neuregulin-1 are implicated in the neuropathology of schizophrenia. We established a rat model of schizophrenia by exposing perinatal rats to EGF and reported that the auditory pathophysiological traits of this model such as prepulse inhibition, auditory steady-state response, and mismatch negativity are relevant to those of schizophrenia. We assessed the activation status of the auditory cortex in this model, as well as that in patients with schizophrenia, by monitoring the three neural activity-induced proteins: EGR1 (zif268), c-fos, and Arc. Among the activity markers, protein levels of EGR1 were significantly higher at the adult stage in EGF model rats than those in control rats. The group difference was observed despite an EGF model rat and a control rat being housed together, ruling out the contribution of rat vocalization effects. These changes in EGR1 levels were seen to be specific to the auditory cortex of this model. The increase in EGR1 levels were detectable at the juvenile stage and continued until old ages but displayed a peak immediately after puberty, whereas c-fos and Arc levels were nearly indistinguishable between groups at all ages with an exception of Arc decrease at the juvenile stage. A similar increase in EGR1 levels was observed in the postmortem superior temporal cortex of patients with schizophrenia. The commonality of the EGR1 increase indicates that the EGR1 elevation in the auditory cortex might be one of the molecular signatures of this animal model and schizophrenia associating with hallucination.

Polymorphisms in the hypoxia inducible factor binding site of the macrophage migration inhibitory factor gene promoter in schizophrenia.

BACKGROUND: Macrophage migration inhibitory factor (MIF) is a multifunctional cytokine that promotes neurogenesis and neuroprotection. MIF is predominantly expressed in astrocytes in the brain. The serum MIF level and microsatellites/single nucleotide polymorphisms (SNPs) in the MIF gene promoter region are known to be associated with schizophrenia (SCZ). Interestingly, previous studies reported that hypoxia, an environmental risk factor for SCZ, induced MIF expression through binding of the hypoxia inducible factor (HIF)-1 to the hypoxia response element (HRE) in the MIF promoter. METHODS: We investigated the involvement of MIF in SCZ while focusing on the HIF pathway. First, we conducted an association study of the SNP rs17004038 (C>A) in the HRE of the MIF promoter between 1758 patients with SCZ and 1507 controls. Next, we investigated the effect of hypoxia on MIF expression in primary cultured astrocytes derived from neonatal mice forebrain. RESULTS: SNP rs17004038 was significantly associated with SCZ (p = 0.0424, odds ratio = 1.445), indicating that this SNP in the HRE of the MIF promoter was a genetic risk factor for SCZ. Hypoxia induced MIF mRNA expression and MIF protein production and increased HIF-1 binding to the MIF promoter, while the activity of the MIF promoter was suppressed by mutations in the HRE and by deletion of the HRE in astrocytes. CONCLUSION: These results suggest that SNP rs17004038 in the HRE of the MIF promoter was significantly associated with SCZ and may be involved in the pathophysiology of SCZ via suppression of hypoxia and HIF pathway-induced MIF expression.

Novel missense SETD1A variants in Japanese patients with schizophrenia: Resequencing and association analysis.

SETD1A has been identified as a substantial risk gene for schizophrenia. To further investigate the role of SETD1A in the genetic etiology of schizophrenia in the Japanese population, we performed resequencing and association analyses. First, we resequenced the SETD1A coding regions of 974 patients with schizophrenia. Then, we genotyped variants, prioritized via resequencing, in 2,027 patients with schizophrenia and 2,664 controls. Next, we examined the association between SETD1A and schizophrenia in 3,001 patients with schizophrenia and 2,664 controls. Finally, we performed a retrospective chart review of patients with prioritized SETD1A variants. We identified two novel missense variants (p.Ser575Pro and p.Glu857Gln) via resequencing. We did not detect these variants in 4,691 individuals via genotyping. These variants were not significantly associated with schizophrenia in the association analysis. Additionally, we found that a schizophrenia patient with the p.Glu857Gln variant had developmental delays. In conclusion, novel SETD1A missense variants were exclusively identified in Japanese patients with schizophrenia. However, our study does not provide evidence for the contribution of these variants to the genetic etiology of schizophrenia in the Japanese population.

Theory of mind tested by implicit false belief: a simple and full-fledged mental state attribution.

About 40 years have passed since 'theory of mind (ToM)' research started. The false-belief test is used as a litmus test for ToM ability. The implicit false-belief test has renewed views of ToM in several disciplines, including psychology, psychiatry, and neuroscience. Many important questions have been considered via the paradigm of implicit false belief. We recently addressed the phylogenetic and physiological aspects of ToM using a version of this paradigm combined with the chemogenetic technique on Old World monkeys. We sought to create animal models for autism that exhibit behavioral phenotypes similar to human symptoms. The simultaneous manipulation of neural circuits and assessments of changes in phenotypes can help identify the causal neural substrate of ToM.

Influence of Atomoxetine on Relationship Between ADHD Symptoms and Prefrontal Cortex Activity During Task Execution in Adult Patients.

Objective: We conducted this non-randomized prospective interventional study to clarify the relationship between improved attention-deficit hyperactivity disorder (ADHD) symptoms and regional brain activity. Methods: Thirty-one adult patients underwent near-infrared spectroscopy examinations during a go/no-go task, both before and 8 weeks after atomoxetine administration. Results: Clinical symptoms, neuropsychological results of the go/no-go task, and bilateral lateral prefrontal activity significantly changed. A positive correlation was observed between right dorsolateral prefrontal cortex activity and Conners' Adult ADHD Rating Scales scores. Before atomoxetine administration, no correlations between prefrontal cortex activity and clinical symptoms were observed in all cases. When participants were divided into atomoxetine-responder and non-responder groups, a positive correlation was observed between prefrontal cortex activity and clinical symptoms in the non-responder group before treatment but not in the responder group, suggesting that non-responders can activate the prefrontal cortex without atomoxetine. Conclusions: Individuals with increased ADHD symptoms appear to recruit the right dorsolateral prefrontal cortex more strongly to perform the same task than those with fewer symptoms. In clinical settings, individuals with severe symptoms are often observed to perform more difficultly when performing the tasks which individuals with mild symptoms can perform easily. The atomoxetine-responder group was unable to properly activate the right dorsolateral prefrontal cortex when necessary, and the oral administration of atomoxetine enabled these patients to activate this region. In brain imaging studies of heterogeneous syndromes such as ADHD, the analytical strategy used in this study, involving drug-responsivity grouping, may effectively increase the signal-to-noise ratio.