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.

The lowest effective plasma concentration of atomoxetine in pediatric patients with attention deficit/hyperactivity disorder: A non-randomized prospective interventional study.

BACKGROUND: Atomoxetine (ATX) is used as a first-line, non-stimulant treatment for attention-deficit/hyperactivity disorder (ADHD), although no studies have systematically examined the relationship between plasma concentration and clinical efficacy. We conducted this non-randomized prospective interventional study to examine the relationship between plasma concentration of ATX and clinical efficacy. METHODS: Forty-three ADHD pediatric patients received ATX, and the steady-state through plasma concentration of the last daily dose that was maintained for at least 4 weeks were determined by high-performance liquid chromatography. RESULTS: The receiver operating characteristic curve suggested that when plasma concentration exceeded 64.60 ng/mL, scores on the ADHD-Rating Scale improved by 50% or more (P = .14). Although 6 of the 8 final responders were unresponsive at the initial dose (.72 ±â€Š.04 mg/kg [mean ±â€Šstandard deviation]), they responded after increasing the ATX dose to the final dose (1.52 ±â€Š.31 mg/kg). Excluding 7 outlier participants, the concentration was 83.3 ±â€Š32.3 ng/mL in 7 responders and was significantly higher than 29.5 ±â€Š23.9 ng/mL (P < .01) for the 29 non-responders. CONCLUSIONS: These results suggest that a minimum effective plasma concentration of ATX is required to achieve sufficient clinical efficacy. We hypothesized a mechanism that results in the realization of a clinical effect when the plasma concentration exceeds a certain threshold in the potential response group, whereas will not improve even if the plasma concentration is increased in the unqualified non-responder group.

Macaques Exhibit Implicit Gaze Bias Anticipating Others' False-Belief-Driven Actions via Medial Prefrontal Cortex.

The ability to infer others' mental states is essential to social interactions. This ability, critically evaluated by testing whether one attributes false beliefs (FBs) to others, has been considered to be uniquely hominid and to accompany the activation of a distributed brain network. We challenge the taxon specificity of this ability and identify the causal brain locus by introducing an anticipatory-looking FB paradigm combined with chemogenetic neuronal manipulation in macaque monkeys. We find spontaneous gaze bias of macaques implicitly anticipating others' FB-driven actions. Silencing of the medial prefrontal neuronal activity with inhibitory designer receptor exclusively activated by designer drugs (DREADDs) specifically eliminates the implicit gaze bias while leaving the animals' visually guided and memory-guided tracking abilities intact. Thus, neuronal activity in the medial prefrontal cortex could have a causal role in FB-attribution-like behaviors in the primate lineage, emphasizing the importance of probing the neuronal mechanisms underlying theory of mind with relevant macaque animal models.

Non-Linear Pharmacokinetics of Atomoxetine in Adult Japanese Patients With ADHD.

Objective: The objective was to reveal the relationship between dose and concentration of atomoxetine. Method: Fifty-five blood samples of 33 patients with ADHD were examined using high-performance liquid chromatography. Results: The plasma concentrations were 53.2 ± 67.0, 298.0 ± 390.5, and 639.3 ± 831.9 ng/mL at doses of 40 mg, 80 mg, and 120 mg, and the concentration/dose were 1.33 ± 1.67, 3.73 ± 4.88, and 5.33 ± 6.93 ng/mL/mg, respectively. Statistical analyses revealed a significant correlation between the concentration and the dose of atomoxetine (p = .004), and a trending toward significance in the difference in the concentration/dose in the three dosage groups (p = .064). The concentration/dose at 40 and 80 + 120 mg/day were 1.33 ± 1.67 and 4.22 ± 5.53 ng/mL/mg, the latter was significantly higher than the former (p = .006), which suggested non-linear pharmacokinetics. Conclusion: Clinicians should carefully titrate in high dose atomoxetine treatment.

Sex Differences in the Effect of Atomoxetine on the QT Interval in Adult Patients With Attention-Deficit Hyperactivity Disorder.

BACKGROUND: The effects of atomoxetine on QT in adults remain unclear. In this study, we examined whether the use of atomoxetine to treat attention-deficit hyperactivity disorder in adults is associated with QT prolongation. METHODS: Forty-one subjects with attention-deficit hyperactivity disorder were enrolled in this study. Participants were administered 40, 80, or 120 mg atomoxetine daily and were maintained on their respective dose for at least 2 weeks. We conducted electrocardiographic measurements and blood tests, measuring plasma atomoxetine concentrations after treatment. Electrocardiograms of 24 of the patients were also obtained before atomoxetine treatment. The QT interval was corrected using Bazett (QTcB) and Fridericia (QTcF) correction formulas. RESULTS: In these 24 patients, only the female patients had prolonged QTcB (P = 0.039) after atomoxetine treatment. There was no correlation between plasma atomoxetine concentrations and the corrected QT interval (QTc), or between atomoxetine dosage and the QTc. However, in female patients, there was a significant positive correlation between atomoxetine dosage and the QTcB (r = 0.631, P = 0.012), and there was a marginally significant positive correlation between atomoxetine dosage and the QTcF (r = 0.504, P = 0.055). In male patients, there was no correlation between atomoxetine dosage and the QTcB or QTcF intervals. There was no correlation between plasma atomoxetine concentrations and the QTc in either female or male patients. IMPLICATIONS: Clinicians should exhibit caution when prescribing atomoxetine, particularly for female patients.

Whole-exome sequencing in a family with a monozygotic twin pair concordant for autism spectrum disorder and a follow-up study.

Two truncating variations (WDR90 V1125fs and EFCAB5 L1210fs), identified by whole-exome sequencing in a family with a monozygotic twin pair concordant for autism spectrum disorder (ASD), were not detected in 257 ASD patients, 677 schizophrenia patients or 667 controls in a follow-up study. Thus, these variations were exclusively identified in the family, suggesting that rare truncating variations may have a role in the genetic etiology of ASD, at least in a subset of ASD patients.

Novel rare missense variations and risk of autism spectrum disorder: whole-exome sequencing in two families with affected siblings and a two-stage follow-up study in a Japanese population.

Rare inherited variations in multiplex families with autism spectrum disorder (ASD) are suggested to play a major role in the genetic etiology of ASD. To further investigate the role of rare inherited variations, we performed whole-exome sequencing (WES) in two families, each with three affected siblings. We also performed a two-stage follow-up case-control study in a Japanese population. WES of the six affected siblings identified six novel rare missense variations. Among these variations, CLN8 R24H was inherited in one family by three affected siblings from an affected father and thus co-segregated with ASD. In the first stage of the follow-up study, we genotyped the six novel rare missense variations identified by WES in 241 patients and 667 controls (the Niigata sample). Only CLN8 R24H had higher mutant allele frequencies in patients (1/482) compared with controls (1/1334). In the second stage, this variation was further genotyped, yet was not detected in a sample of 309 patients and 350 controls (the Nagoya sample). In the combined Niigata and Nagoya samples, there was no significant association (odds ratio = 1.8, 95% confidence interval = 0.1-29.6). These results suggest that CLN8 R24H plays a role in the genetic etiology of ASD, at least in a subset of ASD patients.