Minyoung Jung

Oxytocin efficacy is modulated by dosage and oxytocin receptor genotype in young adults with high-functioning autism: a 24-week randomized clinical trial

Recent studies have suggested that long-term oxytocin administration can alleviate the symptoms of autism spectrum disorder (ASD); however, factors influencing its efficacy are still unclear. We conducted a single-center phase 2, pilot, randomized, double-blind, placebo-controlled, parallel-group, clinical trial in young adults with high-functioning ASD, to determine whether oxytocin dosage and genetic background of the oxytocin receptor affects oxytocin efficacy. This trial consisted of double-blind (12 weeks), open-label (12 weeks) and follow-up phases (8 weeks). To examine dose dependency, 60 participants were randomly assigned to high-dose (32 IU per day) or low-dose intranasal oxytocin (16 IU per day), or placebo groups during the double-blind phase. Next, we measured single-nucleotide polymorphisms (SNPs) in the oxytocin receptor gene (OXTR). In the intention-to-treat population, no outcomes were improved after oxytocin administration. However, in male participants, Clinical Global Impression-Improvement (CGI-I) scores in the high-dose group, but not the low-dose group, were significantly higher than in the placebo group. Furthermore, we examined whether oxytocin efficacy, reflected in the CGI-I scores, is influenced by estimated daily dosage and OXTR polymorphisms in male participants. We found that >21 IU per day oxytocin was more effective than ⩽21 IU per day, and that a SNP in OXTR (rs6791619) predicted CGI-I scores for ⩽21 IU per day oxytocin treatment. No severe adverse events occurred. These results suggest that efficacy of long-term oxytocin administration in young men with high-functioning ASD depends on the oxytocin dosage and genetic background of the oxytocin receptor, which contributes to the effectiveness of oxytocin treatment of ASD.

Sex Differences in the Default Mode Network with Regard to Autism Spectrum Traits: A Resting State fMRI Study

Autism spectrum traits exist on a continuum and are more common in males than in females, but the basis for this sex difference is unclear. To this end, the present study draws on the extreme male brain theory, investigating the relationship between sex difference and the default mode network (DMN), both known to be associated with autism spectrum traits. Resting-state functional magnetic resonance imaging (MRI) was carried out in 42 females (mean age ± standard deviation, 22.4 ± 4.2 years) and 43 males (mean age ± standard deviation, 23.8 ± 3.9 years) with typical development. Using a combination of different analyses (viz., independent component analysis (ICA), fractional amplitude of low-frequency fluctuation (fALFF), regional homogeneity (ReHo), and seed-based analyses), we examined sex differences in the DMN and the relationship to autism spectrum traits as measured by autism-spectrum quotient (AQ) scores. We found significant differences between female and male subjects in DMN brain regions, with seed-based analysis revealing a significant negative correlation between default-mode resting state functional connectivity of the anterior medial prefrontal cortex seed (aMPFC) and AQ scores in males. However, there were no relationships between DMN sex differences and autism spectrum traits in females. Our findings may provide important insight into the skewed balance of functional connectivity in males compared to females that could serve as a potential biomarker of the degree of autism spectrum traits in line with the extreme male brain theory.

Neural Basis of Psychological Growth following Adverse Experiences: A Resting-State Functional MRI Study

Over the past decade, research on the aftereffects of stressful or traumatic events has emphasized the negative outcomes from these experiences. However, the positive outcomes deriving from adversity are increasingly being examined, and such positive changes are described as posttraumatic growth (PTG). To investigate the relationship between basal whole-brain functional connectivity and PTG, we employed resting-state functional magnetic resonance imaging and analyzed the neural networks using independent component analysis in a sample of 33 healthy controls. Correlations were calculated between the network connectivity strength and the Posttraumatic Growth Inventory (PTGI) score. There were positive associations between the PTGI scores and brain activation in the rostral prefrontal cortex and superior parietal lobule (SPL) within the left central executive network (CEN) (respectively, r = 0.41, p < 0.001; r = 0.49, p < 0.001). Individuals with higher psychological growth following adverse experiences had stronger activation in prospective or working memory areas within the executive function network than did individuals with lower psychological growth (r = 0.40, p < 0.001). Moreover, we found that individuals with higher PTG demonstrated stronger connectivity between the SPL and supramarginal gyrus (SMG). The SMG is one of the brain regions associated with the ability to reason about the mental states of others, otherwise known as mentalizing. These findings suggest that individuals with higher psychological growth may have stronger functional connectivity between memory functions within the CEN and social functioning in the SMG, and that their better sociality may result from using more memory for mentalizing during their daily social interactions.

Autistic empathy toward autistic others

Individuals with autism spectrum disorder (ASD) are thought to lack self-awareness and to experience difficulty empathizing with others. Although these deficits have been demonstrated in previous studies, most of the target stimuli were constructed for typically developing (TD) individuals. We employed judgment tasks capable of indexing self-relevant processing in individuals with and without ASD. Fourteen Japanese men and 1 Japanese women with high-functioning ASD (17–41 years of age) and 13 Japanese men and 2 TD Japanese women (22–40 years of age), all of whom were matched for age and full and verbal intelligence quotient scores with the ASD participants, were enrolled in this study. The results demonstrated that the ventromedial prefrontal cortex was significantly activated in individuals with ASD in response to autistic characters and in TD individuals in response to non-autistic characters. Although the frontal–posterior network between the ventromedial prefrontal cortex and superior temporal gyrus participated in the processing of non-autistic characters in TD individuals, an alternative network was involved when individuals with ASD processed autistic characters. This suggests an atypical form of empathy in individuals with ASD toward others with ASD.

Ventral striatum dysfunction in children and adolescents with reactive attachment disorder: functional MRI study

Background Child maltreatment is a major risk factor for psychopathology, including reactive attachment disorder (RAD). Aims To examine whether neural activity during reward processing was altered in children and adolescents with RAD. Method Sixteen children and adolescents with RAD and 20 typically developing (TD) individuals performed tasks with high and low monetary rewards while undergoing functional magnetic resonance imaging. Results Significantly reduced activity in the caudate and nucleus accumbens was observed during the high monetary reward condition in the RAD group compared with the TD group (P=0.015, family-wise error-corrected cluster level). Significant negative correlations between bilateral striatal activity and avoidant attachment were observed in the RAD and TD groups. Conclusions Striatal neural reward activity in the RAD group was markedly decreased. The present results suggest that dopaminergic dysfunction occurs in the striatum of children and adolescents with RAD, leading towards potential future risks for psychopathology. Declaration of interest None. Copyright and usage

Altered frontal pole development affects self-generated spatial working memory in ADHD.

BACKGROUND Spatial working memory (SWM) dysfunction is a feature of attention deficit hyperactivity disorder (ADHD). Previous studies suggested that behavioral performance in self-generated SWM improves through development in children with and without ADHD. Nevertheless, developmental changes in the neural underpinnings of self-generated SWM are unknown. METHOD Using near-infrared spectroscopy, hemodynamic activity in the prefrontal cortex (PFC) was measured in 30 children with ADHD (9.5 ± 1.6 years-old) and 35 TD children (9.0 ± 1.6 years-old) while they performed a self-generated SWM task. We then investigated correlations between age and behavioral performance, and between age and hemodynamic activity in the PFC for each group. RESULTS Both groups showed a negative correlation with age and number of errors [ADHD: r(28)=-0.37, p=0.040; TD: r(33)=-0.59, p<0.001], indicating that self-generated SWM improves through development. The TD group showed a positive correlation between age and oxygenated hemoglobin in the frontal pole [10ch: r(33)=0.41, p=0.013; 11ch; r(33)=0.44, p=0.008] and bilateral lateral PFC [4ch: r(33)=0.34, p=0.049; 13ch; r(33)=0.54, p=0.001], while no significant correlation was found in the ADHD group. Furthermore, regression slopes for the frontal pole significantly differed between the TD and ADHD groups [10ch: t(61)=2.35, p=0.021; 11ch: t(61)=2.05, p=0.044]. CONCLUSION Children with ADHD showed abnormalities in functional maturation of the frontal pole, which plays a role in manipulating and maintaining information associated with self-generated behavior.

Decreased structural connectivity and resting-state brain activity in the lateral occipital cortex is associated with social communication deficits in boys with autism spectrum disorder

ABSTRACT Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder characterized by atypical social communication and repetitive behaviors. In this study, we applied a multimodal approach to investigate brain structural connectivity, resting state activity, and surface area, as well as their associations with the core symptoms of ASD. Data from forty boys with ASD (mean age, 11.5 years; age range, 5.5–19.5) and forty boys with typical development (TD) (mean age, 12.3; age range, 5.8–19.7) were extracted from the Autism Brain Imaging Data Exchange II (ABIDE II) for data analysis. We found significantly decreased structural connectivity, resting state brain activity, and surface area at the occipital cortex in boys with ASD compared to boys with TD. In addition, we found that resting state brain activity and surface area in the lateral occipital cortex was negatively correlated with communication scores in boys with ASD. Our results suggest that decreased structural connectivity and resting‐state brain activity in the occipital cortex may impair the integration of verbal and non‐verbal communication cues in boys with ASD, thereby impacting their social development. HighlightsWe applied a multimodal approach to investigate the neuropathology of ASD.ASD showed decreased fALFF and surface area at the occipital cortex.ASD is associated with decreased FA and track length in left CCG and right UNC.Functional and structural changes were associated with ASD communication scores.

Differences in Brain Hemodynamics in Response to Achromatic and Chromatic Cards of the Rorschach

Abstract. In order to investigate the effects of color stimuli of the Rorschach inkblot method (RIM), the cerebral activity of 40 participants with no history of neurological or psychiatric illness was scanned while they engaged in the Rorschach task. A scanned image of the ten RIM inkblots was projected onto a screen in the MRI scanner. Cerebral activation in response to five achromatic color cards and five chromatic cards were compared. As a result, a significant increase in brain activity was observed in bilateral visual areas V2 and V3, parietooccipital junctions, pulvinars, right superior temporal gyrus, and left premotor cortex for achromatic color cards (p < .001). For the cards with chromatic color, significant increase in brain activity was observed in left visual area V4 and left orbitofrontal cortex (p < .001). Furthermore, a conjoint analysis revealed various regions were activated in responding to the RIM. The neuropsychological underpinnings of the response process, as described by Acklin and Wu-Holt (1996), were largely confirmed.

Symptoms in individuals with adult-onset ADHD are masked during childhood

The continuity of neurodevelopmental disorders from childhood to adulthood has garnered much attention. However, three studies have recently examined the possibility that adult-onset attention-deficit hyperactivity disorder (ADHD) is a separate neurodevelopmental disorder from childhoodonset ADHD [1–3]. A cohort study [1] with 1037 participants found a 6% prevalence of childhood-onset ADHD and a 3% prevalence of adult-onset ADHD, with very little overlap. Moreover, other large-scale cohort studies [2, 3] have reported that a few patients met the diagnostic criteria for ADHD at both stages, suggesting that the causes of childhood-onset and adult-onset ADHD may differ and that the classification system for ADHD should be reconsidered. However, should the two forms of ADHD be regarded as separate disorders? After careful consideration of these studies [1–3], we decided to focus on the intelligence quotient (IQ) and ADHD symptom scores of these patients. All studies [1–3] reported lower IQs in patients with childhood-onset ADHD. In the longitudinal twin study [2], the average IQ of patients who met the ADHD diagnostic criteria in both periods was significantly lower (mean, 88.0) than: that of patients whose ADHD diagnosis was not maintained in adulthood (mean, 93.0), that of patients diagnosed with adult-onset ADHD (mean, 96.9), and that of the control group (mean, 101.4). Therefore, low intelligence could be a major factor in symptom expression in childhood-onset ADHD. This suggests that low intelligence, and thus low latent social adaptation ability, may cause the early manifestation of ADHD symptoms, leading to a high likelihood of an ADHD diagnosis. Patients diagnosed with adult-onset ADHD had above average IQ scores and executive functioning during childhood, even though they tended to have ADHD symptoms [1, 2]. Thus, their social adaptation abilities may have masked ADHD behavioral characteristics, complicating the diagnosis [2]. Similar to the studies discussed above, neuroimaging studies have also elucidated the characteristics of each group. Only children with ADHD showed shrinkage in regions of the brain cortex [4], possibly because the disorder affects brain maturation [5]. Among patients with symptoms persisting into adulthood, fractional anisotropy was lower than that in an unaffected control group [6]. These results suggest that structural abnormalities are present in patients whose symptoms persist into adulthood [4, 5], but not in patients whose symptoms do not [6]. We considered the relationship between the expression of ADHD symptoms and social adaptation ability (Fig. 1). Individuals with neurodevelopmental disorders show differences in individual ability and areas of skill. For example, consider that the mind is represented as a glass and social adaptation ability as the contained water. If a patient’s latent intelligence is high, the volume of water is large; however, if the patient has structural brain impairments or low intelligence, the volume may be low. Moreover, imagine that environmental factors can influence water levels. In individuals with typical development, even if the water level declines during periods of high demand of social interaction with peers or severe stress, their vulnerabilities may not be as exposed as those of individuals with neurodevelopmental disorders. In contrast, in individuals with neurodevelopmental disorders, when this water level drops, their vulnerabilities are easily exposed. During these times, they have difficulty adapting in their areas of weakness, and the symptoms of their neurodevelopmental disorder become apparent. Possibly, in cases of adult-onset ADHD, the patients had a good social environment during childhood, with strong family support, a stable school environment to * Hirotaka Kosaka hirotaka@u-fukui.ac.jp

Catechol-O-methyltransferase polymorphism is associated with the cortico-cerebellar functional connectivity of executive function in children with attention-deficit/hyperactivity disorder.

The cerebellum, although traditionally considered a motor structure, has been increasingly recognized to play a role in regulating executive function, the dysfunction of which is a factor in attention-deficit/hyperactivity disorder (ADHD). Additionally, catechol-O-methyltransferase (COMT) polymorphism has been reported to be associated with executive function. We examined whether the cortico-cerebellar executive function network is altered in children with ADHD and whether COMT polymorphism is associated with the altered network. Thirty-one children with ADHD and thirty age- and IQ-matched typically developing (TD) controls underwent resting-state functional MRI, and functional connectivity of executive function-related Crus I/II in the cerebellum was analysed. COMT Val158Met genotype data were also obtained from children with ADHD. Relative to TD controls, children with ADHD showed significantly lower functional connectivity of the right Crus I/II with the left dorsolateral prefrontal cortex. Additionally, the functional connectivity of children with ADHD was modulated by COMT polymorphism, with Met-carriers exhibiting significantly lower functional connectivity than the Val/Val genotype. These results suggest the existence of variations, such as ethnic differences, in COMT genetic effects on the cortico-cerebellar executive function network. These variations contribute to heterogeneity in ADHD. Further neuroimaging genetics study might lead to the development of fundamental therapies that target ADHD pathophysiology.